MXPA97010172A - Derivatives of anti-ischemic hydroxylamine and pharmaceutical compositions - Google Patents
Derivatives of anti-ischemic hydroxylamine and pharmaceutical compositionsInfo
- Publication number
- MXPA97010172A MXPA97010172A MXPA/A/1997/010172A MX9710172A MXPA97010172A MX PA97010172 A MXPA97010172 A MX PA97010172A MX 9710172 A MX9710172 A MX 9710172A MX PA97010172 A MXPA97010172 A MX PA97010172A
- Authority
- MX
- Mexico
- Prior art keywords
- general formula
- compound
- formula
- alkyl
- defined above
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 7
- 230000002253 anti-ischaemic Effects 0.000 title abstract description 4
- AVXURJPOCDRRFD-UHFFFAOYSA-N hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 93
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 33
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 33
- 238000007792 addition Methods 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 239000011780 sodium chloride Substances 0.000 claims abstract description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 18
- 125000005843 halogen group Chemical group 0.000 claims abstract description 17
- 125000005842 heteroatoms Chemical group 0.000 claims abstract description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000002443 hydroxylamines Chemical class 0.000 claims abstract description 8
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000003884 phenylalkyl group Chemical group 0.000 claims abstract description 8
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims abstract description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 229910052717 sulfur Chemical group 0.000 claims abstract description 5
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 4
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 4
- 239000001301 oxygen Chemical group 0.000 claims abstract description 4
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical group O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims abstract description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000011593 sulfur Chemical group 0.000 claims abstract description 4
- -1 piperidino, piperazino Chemical group 0.000 claims description 19
- 125000002252 acyl group Chemical group 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 10
- 125000004423 acyloxy group Chemical group 0.000 claims description 6
- 101710016478 RNASEH2A Proteins 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 238000005755 formation reaction Methods 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 241000822135 Ula Species 0.000 claims 1
- 125000004663 dialkyl amino group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 abstract description 3
- 125000001589 carboacyl group Chemical group 0.000 abstract 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 68
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 56
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 52
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 239000000203 mixture Substances 0.000 description 27
- 238000005160 1H NMR spectroscopy Methods 0.000 description 25
- 229910052739 hydrogen Inorganic materials 0.000 description 25
- 238000003756 stirring Methods 0.000 description 25
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 22
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Inorganic materials [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 19
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- 238000004440 column chromatography Methods 0.000 description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 229910001868 water Inorganic materials 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 10
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 10
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 239000004202 carbamide Substances 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 238000001704 evaporation Methods 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 235000013877 carbamide Nutrition 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000009835 boiling Methods 0.000 description 5
- 125000004432 carbon atoms Chemical group C* 0.000 description 5
- ANJPRQPHZGHVQB-UHFFFAOYSA-N hexyl isocyanate Chemical compound CCCCCCN=C=O ANJPRQPHZGHVQB-UHFFFAOYSA-N 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000001187 sodium carbonate Substances 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 239000011976 maleic acid Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 description 3
- 230000000875 corresponding Effects 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- KQWGXHWJMSMDJJ-UHFFFAOYSA-N cyclohexyl isocyanate Chemical compound O=C=NC1CCCCC1 KQWGXHWJMSMDJJ-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 125000006362 methylene amino carbonyl group Chemical group [H]N(C([*:2])=O)C([H])([H])[*:1] 0.000 description 3
- YNAVUWVOSKDBBP-UHFFFAOYSA-N morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 3
- 229940113083 morpholine Drugs 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- HVYWMOMLDIMFJA-DPAQBDIFSA-N (3β)-Cholest-5-en-3-ol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- OQURWGJAWSLGQG-UHFFFAOYSA-N 1-isocyanatopropane Chemical compound CCCN=C=O OQURWGJAWSLGQG-UHFFFAOYSA-N 0.000 description 2
- GSLTVFIVJMCNBH-UHFFFAOYSA-N 2-isocyanatopropane Chemical compound CC(C)N=C=O GSLTVFIVJMCNBH-UHFFFAOYSA-N 0.000 description 2
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 2
- HSDAJNMJOMSNEV-UHFFFAOYSA-N Benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 2
- 210000004351 Coronary Vessels Anatomy 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 2
- VGEWEGHHYWGXGG-UHFFFAOYSA-N ethyl N-hydroxycarbamate Chemical compound CCOC(=O)NO VGEWEGHHYWGXGG-UHFFFAOYSA-N 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000002960 margaryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000002829 nitrogen Chemical class 0.000 description 2
- 125000004433 nitrogen atoms Chemical group N* 0.000 description 2
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 238000003825 pressing Methods 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 230000004083 survival Effects 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- ZNSIOEUWGZNHAQ-UHFFFAOYSA-N (3E)-N-diazoniopyridine-3-carboximidate Chemical compound [N-]=[N+]=NC(=O)C1=CC=CN=C1 ZNSIOEUWGZNHAQ-UHFFFAOYSA-N 0.000 description 1
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 1
- PITPTOAZHDTGBI-UHFFFAOYSA-N 1-(2-hydroxy-3-piperidin-1-ylpropoxy)-3-[3-(trifluoromethyl)phenyl]urea Chemical compound C1CCCCN1CC(O)CONC(=O)NC1=CC=CC(C(F)(F)F)=C1 PITPTOAZHDTGBI-UHFFFAOYSA-N 0.000 description 1
- KVEVZSKQVNJNQU-UHFFFAOYSA-N 1-(2-hydroxy-3-piperidin-1-ylpropoxy)-3-octylurea Chemical compound CCCCCCCCNC(=O)NOCC(O)CN1CCCCC1 KVEVZSKQVNJNQU-UHFFFAOYSA-N 0.000 description 1
- QNITVWLKRGEOEP-UHFFFAOYSA-N 1-(2-hydroxy-3-piperidin-1-ylpropoxy)-3-propan-2-ylurea Chemical compound CC(C)NC(=O)NOCC(O)CN1CCCCC1 QNITVWLKRGEOEP-UHFFFAOYSA-N 0.000 description 1
- XAVCWJUKSUDMRD-UHFFFAOYSA-N 1-(2-hydroxy-3-piperidin-1-ylpropoxy)-3-pyridin-3-ylurea Chemical compound C1CCCCN1CC(O)CONC(=O)NC1=CC=CN=C1 XAVCWJUKSUDMRD-UHFFFAOYSA-N 0.000 description 1
- JWYRPOYJRRHHIL-UHFFFAOYSA-N 1-(oxiran-2-ylmethyl)piperidine Chemical compound C1CCCCN1CC1CO1 JWYRPOYJRRHHIL-UHFFFAOYSA-N 0.000 description 1
- DHMLGEBWGDGODL-UHFFFAOYSA-N 1-aminooxy-3-piperidin-1-ylpropan-2-ol;1-(2-hydroxy-3-piperidin-1-ylpropoxy)-3-(4-methoxyphenyl)urea Chemical compound NOCC(O)CN1CCCCC1.C1=CC(OC)=CC=C1NC(=O)NOCC(O)CN1CCCCC1 DHMLGEBWGDGODL-UHFFFAOYSA-N 0.000 description 1
- HVUAHWLBZZDJBA-UHFFFAOYSA-N 1-cyclohexyl-3-(2-hydroxy-3-piperidin-1-ylpropoxy)urea Chemical compound C1CCCCN1CC(O)CONC(=O)NC1CCCCC1 HVUAHWLBZZDJBA-UHFFFAOYSA-N 0.000 description 1
- DOOWUNBVULOPKQ-UHFFFAOYSA-N 1-heptyl-3-(2-hydroxy-3-piperidin-1-ylpropoxy)urea Chemical compound CCCCCCCNC(=O)NOCC(O)CN1CCCCC1 DOOWUNBVULOPKQ-UHFFFAOYSA-N 0.000 description 1
- GFFGYTMCNVMFAJ-UHFFFAOYSA-N 1-isocyanato-3-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC(N=C=O)=C1 GFFGYTMCNVMFAJ-UHFFFAOYSA-N 0.000 description 1
- FMDGXCSMDZMDHZ-UHFFFAOYSA-N 1-isocyanato-4-methoxybenzene Chemical compound COC1=CC=C(N=C=O)C=C1 FMDGXCSMDZMDHZ-UHFFFAOYSA-N 0.000 description 1
- RFXBSYPBSRSQDU-UHFFFAOYSA-N 1-isocyanatoheptane Chemical compound CCCCCCCN=C=O RFXBSYPBSRSQDU-UHFFFAOYSA-N 0.000 description 1
- DYQFCTCUULUMTQ-UHFFFAOYSA-N 1-isocyanatooctane Chemical compound CCCCCCCCN=C=O DYQFCTCUULUMTQ-UHFFFAOYSA-N 0.000 description 1
- PBDXOXOTLLDQKT-UHFFFAOYSA-N 1-pentyl-3-(3-piperidin-1-ylpropoxy)urea Chemical compound CCCCCNC(=O)NOCCCN1CCCCC1 PBDXOXOTLLDQKT-UHFFFAOYSA-N 0.000 description 1
- DMJOXPLJMRFJPH-UHFFFAOYSA-N 1-tert-butyl-3-[3-(diethylamino)-2-hydroxypropoxy]urea Chemical compound CCN(CC)CC(O)CONC(=O)NC(C)(C)C DMJOXPLJMRFJPH-UHFFFAOYSA-N 0.000 description 1
- MGOLNIXAPIAKFM-UHFFFAOYSA-N 2-isocyanato-2-methylpropane Chemical compound CC(C)(C)N=C=O MGOLNIXAPIAKFM-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- FDPSIHMSJLZBPX-UHFFFAOYSA-N 3-(2-hydroxy-3-piperidin-1-ylpropoxy)-1,1-diphenylurea Chemical compound C1CCCCN1CC(O)CONC(=O)N(C=1C=CC=CC=1)C1=CC=CC=C1 FDPSIHMSJLZBPX-UHFFFAOYSA-N 0.000 description 1
- 210000002376 Aorta, Thoracic Anatomy 0.000 description 1
- 206010003119 Arrhythmia Diseases 0.000 description 1
- SESFRYSPDFLNCH-UHFFFAOYSA-N Benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 1
- 210000004369 Blood Anatomy 0.000 description 1
- 210000001772 Blood Platelets Anatomy 0.000 description 1
- NESWSFQFRNGNNR-UHFFFAOYSA-N C1(CCCCC1)NC(=O)NOCC(CN1CCCCC1)O.C1(CCCCC1)NC(=O)N(OCC(CN1CCCCC1)OC(C)=O)C(C)=O Chemical compound C1(CCCCC1)NC(=O)NOCC(CN1CCCCC1)O.C1(CCCCC1)NC(=O)N(OCC(CN1CCCCC1)OC(C)=O)C(C)=O NESWSFQFRNGNNR-UHFFFAOYSA-N 0.000 description 1
- 206010007521 Cardiac arrhythmias Diseases 0.000 description 1
- 229940107161 Cholesterol Drugs 0.000 description 1
- 208000003067 Myocardial Ischemia Diseases 0.000 description 1
- GRRYSIXDUIAUGY-UHFFFAOYSA-N N-methylcarbamoyl chloride Chemical compound CNC(Cl)=O GRRYSIXDUIAUGY-UHFFFAOYSA-N 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 101700011774 PEPD Proteins 0.000 description 1
- DGTNSSLYPYDJGL-UHFFFAOYSA-N Phenylisocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N Propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000010110 Spontaneous Platelet Aggregation Diseases 0.000 description 1
- 241000009298 Trigla lyra Species 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K Trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 210000003462 Veins Anatomy 0.000 description 1
- 208000003663 Ventricular Fibrillation Diseases 0.000 description 1
- 206010047302 Ventricular tachycardia Diseases 0.000 description 1
- DJDCODCBJIJRSQ-UHFFFAOYSA-N [1-(cyclohexylcarbamoylamino)oxy-3-piperidin-1-ylpropan-2-yl] acetate;hydrochloride Chemical compound Cl.C1CCCCN1CC(OC(=O)C)CONC(=O)NC1CCCCC1 DJDCODCBJIJRSQ-UHFFFAOYSA-N 0.000 description 1
- IQPQWNKOIGAROB-UHFFFAOYSA-N [N-]=C=O Chemical compound [N-]=C=O IQPQWNKOIGAROB-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000001204 arachidyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004429 atoms Chemical group 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000003467 diminishing Effects 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 1
- FFLYUXVZEPLMCL-UHFFFAOYSA-N ethylchloranuidyl formate Chemical compound CC[Cl-]OC=O FFLYUXVZEPLMCL-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000002349 favourable Effects 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 125000000755 henicosyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- DRAJWRKLRBNJRQ-UHFFFAOYSA-N hydroxycarbamic acid Chemical compound ONC(O)=O DRAJWRKLRBNJRQ-UHFFFAOYSA-N 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- YDNLNVZZTACNJX-UHFFFAOYSA-N isocyanatomethylbenzene Chemical compound O=C=NCC1=CC=CC=C1 YDNLNVZZTACNJX-UHFFFAOYSA-N 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical compound CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 description 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 125000001196 nonadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N oxygen atom Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004434 sulfur atoms Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 239000011778 trisodium citrate Substances 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 230000002883 vasorelaxant Effects 0.000 description 1
Abstract
The invention relates to novel hydroxylamine derivatives represented by the general formula (I), the pharmaceutically acceptable addition salts of the same and the pharmaceutical compositions containing them as an active ingredient. Another object of the invention is the preparation of the hydroxylamine derivatives and salts thereof. The compounds according to the invention have anti-ischemic effect. In the above formula, (I) X is O, -NH or a group of the formula -NR-, wherein R and Rï, independently of one another, are alkyl, cycloalkyl, phenylalkyl, a phenyl group optionally substituted with halo, haloalkyl, alkyl, alkoxy or nitro, or a hetero ring containing N; Rûes H or alkanoyl; Rýes H or hydroxy optionally acylated with alkanoyl; and Rües a group of the formula -N (R 4) R 5 wherein R 4 and R 5, independently one on the other, it can be H, alkyl or a group of the formula -C (O) -NH-R wherein R is as defined above, or R4 and R5, when taken together with the adjacent nitrogen attached thereto, from a Hereroanillo of 5 to 7 member which may contain an additional heteroatom selected from nitrogen, oxygen and sulfur and which is optionally substituted with phenylalkyl
Description
HYDROXYLAMINE DERIVATIVES ANTI-ISQUÉMICOS AND PHARMACEUTICAL COMPOSITIONS Technical Field The invention relates to novel hydroxylamine derivatives represented by the general formula (I), O // R-X-C \ N-0-CH2-CH-CH2-R3 (I) R1 R2
the pharmaceutically acceptable acid addition salts thereof as well as the pharmaceutical compositions containing them as an active ingredient. Another object of the invention is the preparation of hydroxylamine derivatives and salts thereof. The compounds according to the invention have anti-ischemic effect. Previous Technique In C.A. 67: 6886, 7321g and C.A. 113: 674 and 17169K have been described compounds of similar structure having effect of diminishing cholesterol level. Description of the Invention One objective of the present invention is the group of hydroxylamine derivatives represented by the general formula (I) and the pharmaceutically acceptable acid addition salts thereof. In the above formula X is O, -NH or a group of the formula -NR'-, wherein R and R ', independently of one another, are alkyl, cycloalkyl, phenylalkyl; a phenyl group optionally substituted with halo, haloalkyl, alkyl, alkoxy or nitro; or a hetero ring containing N, R1 is H or alkanoyl, R2 is H or hydroxy optionally acylated with alkanoyl, and R3 is a group of the formula -N (R4) RS wherein R4 and R5, independently of each other, can be H, alkyl or a group of the formula -C (0) -NH-R wherein R is as defined above, or R4 and R5, when taken together with the adjacent nitrogen attached thereto, form a hetero ring of 5 to 7 members which may contain an additional heteroatom selected from nitrogen, oxygen and sulfur and which is optionally substituted with an alkyl or phenylalkyl. Another object of the invention is a pharmaceutical composition containing at least one of the compounds of the general formula (I) or the pharmaceutically active acid addition salt thereof as the active ingredient. Still another object of the invention is a plurality of processes for preparing the compounds of the general formula (I) and the pharmaceutically acceptable acid addition salts thereof. Although these compounds can be prepared by any process known in the art by preparing compounds of similar structure, the most favorable methods for obtaining them include the following: a) To prepare compounds of the general formula (I) wherein Z is O, (i) ) a compound of the general formula (II) H2N-O-CH2-CH-CH2-R3 (II) k- Wherein R2 and R3 are as defined above, they were reacted with a compound of the general formula (III) OR
II R-O-C (lll) \ Y
Where R is as defined above and Y is halo or azido, or ii) a compound of the general formula (VI) O // ROC (VI) \ NH-OH It is reacted with a compound of the general formula (VII) ) Y-CH2-CH-CH2-R3 l 2 R2 (VII)
iii) a compound of the general formula (VI) is reacted with a compound of the general formula (VIII) CH2-CH-CH2-R3 (VIII)
iv) a compound of the general formula (VI) is reacted with a compound of the general formula (IX) CH2-CH-CH2-Y (IX) / O and subsequently with a compound of the formula R3H, wherein the formulas (VI), (VII), (VIII) and (IX) R, R2 and R3 are as defined above and Y is halo, b) to prepare compounds of the general formula (I) wherein X is -NH -, a compound of the general formula (II) in which R2 and R3 are as defined above, are reacted with a compound of the formula (IV) or (IVa) R_N = C = 0 (IV) O // R -NH-C (Iva) \ Y Where R is as defined above and Y is halo, or c) to prepare compounds of the general formula (I) wherein X is -NH- or NR'-, a compound of the general formula (X) O
II Z-0-CN-0-CH 2 -CH-CH 2 -R 3 (X) II R 1 R 2 wherein R 1, R 2 and R 3 are as defined above and Z is alkyl, aralkyl or optionally substituted aryl, is reacted with a composed of the general formula RNH2 or RR'NH, wherein R and R 'are as defined above, or d) to prepare compounds of the general formula (I) wherein
X is -NH-, R3 is -N (R4) R5, R4 is alkyl and R5 is -C (0) -NH-R, i) a compound of the formula (II) wherein R3 is -N (R4) R5, R4 is alkyl, R5 is H and R2 is as defined above, is reacted with an excess of a compound of the formula (IV) or (Iva) wherein R is as defined above and Y is halo, or ii) a compound of the general formula (I) wherein R 3 is -N (R 4) R 5, R 4 is alkyl, R 5 is H and R 2 is as defined above, is reacted with an excess of a compound of the formula ( IV) or (Iva) wherein R is as defined above and Y is halo, oe) to prepare compounds of the general formula (I) wherein X is -NR'-, a compound of the general formula (II) is it reacts with a compound of the general formula (V) R '0 \ II N - C (V) / \ RY where R, R'. R2 and R3 are as specified above and Y is halo, and if desired, a compound of the general formula (I) is transformed into its acid addition salt, or if desired, a compound of the general formula (I) where
R1 is H and R2 is hydroxy, it was transformed into a compound of the general formula (I) wherein R2 is acyloxy or R1 is acyl and R2 is acyloxy, optionally followed by the formation of salt. BEST MODE FOR CARRYING OUT THE INVENTION The preferred representatives of the different defined groups are as follows:
The alkyl groups and the alkyl portions of the alkanoyl groups mentioned in the specification may be straight or branched chain, lower or longer alkyl portions. The alkyl group, either alone or forming part of any of the above groups, can preferably contain from 1 to 12 carbon atoms. Preferably the number of carbon atoms is from 1 to 8. Examples of said group include, among others, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, pentyl, hexyl, heptyl, octyl and the isomers thereof. Alkyl groups with 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, pentyl, terpentyl and hexyl are preferred. Preferred longer alkyl groups contain from 9 to 21 carbon atoms such as iso-, n-nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl and heneicosyl and the like; more preferably C9-17 alkyl groups such as iso- or n-nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl and heptadecyl. The cycloalkyl group preferably contains from 3 to 6, more preferably from 5 to 7 carbon atoms. Said groups are e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like; more preferred are C3-7 cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The heteroaromatic ring containing N is preferably a 3- to 8-membered, preferably 5- or 6-membered, heteromonocyclic group which is unsaturated and contains 1 to 4 nitrogen atoms. Said groups are e.g., pyrrolyl, imidazolyl, pyrazolyl, pyridyl or the N-oxide thereof, pyridimyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, triazinyl or the like; or it may be a condensed cyclic hetero group containing from 1 to 5 nitrogen atoms, such as indolyl, isoindolyl, indosinyl, benzoimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, cinolyl, phthalisinyl, quinazolinyl, quinoxalinyl, purinyl, pteridinyl, quinolizinyl, naphthyridinyl and the like. The 5 to 7 membered unsaturated heterocyclic groups may also contain a nitrogen or an additional nitrogen, oxygen or sulfur atom or atoms. These groups are preferably aziridinyl, azetidinyl, oxaziridinyl, oxazolidinyl, thiazole, idinyl, pyrrolidinyl, imidazolidinyl, piolyl idylil, perhydrothiazolyl, perhydroisoxalolyl, piperidinyl, pyperazinyl, perihydropyrimidinyl, morpholinyl, thiomorpholinyl, perhydro-1H-azepinyl and the like. The alkanoyl group may contain both lower and higher chains and preferably it may be alkyl dicarbonyl preferably of C6-6, preferably C1-4, eg, acetyl, propanoyl or the like, or the acyl group of a higher fatty acid, preferably C? 2-? 8- R4 and R5 together with the adjacent nitrogen atom preferably form saturated heterocyclic groups, e.g., pyrrolidino, oxazolidino, thiazolidino, piperidino, morpholino, piperazino, thiomorpholino, azepino and the like.
According to process a), the carbamates of the general formula (I) wherein X is O are prepared by reacting the appropriate starting materials. The reaction according to process a), variant i) is preferably carried out in an inert organic solvent, at about 0 ° C, while the other variants are preferably carried out at elevated temperatures. According to process b) the ureas of the general formula (I) wherein X is -NH- is prepared by reacting the corresponding compounds of the formulas (II) and (IV) or (Iva) wherein R is as Defined before and Y is halo. The reaction is preferably carried out in an inert organic solvent at room temperature. According to process c), the compounds of the general formula (I) wherein X is -NH- or -NR- are prepared by reacting the compounds of the formula (X) and an amine of the formula RNH2 or RR ' NH The reaction is preferably carried out in an inert organic solvent at an elevated temperature. According to process d) the ureas of the general formula (I) wherein X is -NH- are prepared wherein R3 is -N (R4) R5 and R4 is alkyl and R5 is a group of the formula C (0) ) -NHR. In this reaction, a compound of the formula (II) wherein R4 is alkyl and R5 is H, is used as a starting material wherein 1 mole of the material is reacted with at least two moles of the compounds of the general formulas (IV) or (Iva). The reaction is preferably carried out in an organic solvent at room temperature. According to process d), the ureas of the general formula (I) wherein X is -NR'- are prepared by reacting the corresponding compounds of the formulas (II) and (IV) wherein R is as defined above . The reaction is preferably carried out in an inert organic solvent, at room temperature. If desired, a compound of the general formula (I) can be converted to the monoacylated (R = acyloxy) or diacylated derivative
(R1 = acyl, R2 = acyloxy). The acylation is preferably carried out with a corresponding derivative of aliphatic carboxylic acids of
C2-8 suitable acylation capable. The pharmaceutically acceptable salts of the compounds of the general formula (I) can be those formed with organic and inorganic salts. The compounds according to the invention have anti-ischemic effect. The reperfusion-induced arrhythmia (ventricular tachycardia, KT and ventricular fibrillation, KF) was tested in anesthetized rats. Myocardial ischemia was induced by pressing the coronary artery for 5 minutes followed by 10 minutes of reperfusion of the heart. The ECG was monitored permanently and the change in the mean period of KT and KF due to the effect of active materials was measured in the first 3 minutes of reperfusion. Survival was also monitored. The compounds were administered i.v. 5 minutes before pressing the coronary artery LAD at a dose of 1 mg / kg. The experimental results obtained by administering some representative compounds of the invention are listed below: Example No. 4 5 6 7 15 16 23 Control not treated
Survival% 67 67 100 86 60 83 80 0
The vasorelaxant effect of the compounds of the invention was tested in vitro in rabbit thoracic aorta isolated according to Am. J. Physiol. 257:, 1327-1333 (1989). The aggregation-inhibiting effect was demonstrated in blood samples from the vein obtained from human patients. To the samples, sodium citrate was added and 10 minutes later it was centrifuged at 1000 rpm. In the platelet-rich preparations thus obtained platelet aggregation was induced by the addition of ADP (control) while different concentrations of the test compounds were added to the preparations before ADP addition, the dose-effect curve was demonstrated and determined concentrations inhibited aggregation by 50% (ED50). The experimental results obtained by the addition of some representative compounds of the invention are listed below:
(1) Beppdyl [Eur J Pharm 166 (1989) 241-49] (2) Molsidornin (Takeda) The invention is illustrated more in detail by the following examples. However, the examples serve only to provide more information about the invention and not They limit in some way the scope of the protection to the same Example 1 N-phen? lN, - (2-h? drox? -3-p? per? d? no-propox?) - urea 0- (2-h drox? -3-p? per? d? no-prop? l) -h? drox? lam? na (1 74 g, 001 moles) were dissolved in 4 ml of chloroform and 09 ml (001 moles) of Phenyl isocyanate was added thereto while stirring. The reaction was monitored by chromatography. After the reaction was complete, the solution was evaporated and the oily residue was purified by column chromatography. The oil thus obtained was crystallized from diethyl ether Yield 06 g (20 g). %) Mp 101-103 ° C IR (KBr) 3288, 2935, 2678 1601, 1551, 1501, 1448 1333, 1250, 1094, 1038, 903, 866, 754, 694 cm "1 1 H-NMR (CDCU): 8.95 (1H, br, s, CONHO); 8.5-7.6 (1H, br, s,
NHCONHO); 7.55 (2x1H, t, J = 7.3 Hz), 7.27 (2x1H, t) and 7.05 (1H, t,
J = 7.3 Hz) (phenyl o-m-p); 4.05 (1H, m, CH-OH); 3.96-3.77 (1H, dd,
J = 11.1 y = 2.4 Hz; 1H, dd, J = 11.1 y = 7.6 Hz, OCH2); 2.7-2.2 (6H, m), 1.55 (4H, m) and 1.46 (2H, m) (piperidine). 13 C-NMR (CDCl 3): 158.5 (s, C = O); 138.2 (s), 128.8 (d), 119.3 (d) is 123.2 (d) (phenyl i-o-m-p); 79.4 (t, OCH2); 64.0 (d, CH-OH); 59.8 (t, CH-CH2-N); 54.5 (t), 25.8 (t) and 24.0 (t) (piperidine) Analysis: C15H23N3? 3 »0.5 H20: Calculated: C 59.0%, H 7.5%, N 14.0%; Found: C 59.6%, H 7.9%, N 13.9% Example 2: N- (2-hydroxy-3-piperidino-propoxy) -ethyl ester carbamate 0- (2-hydroxy-3-piperidino-propyl) -hydroxylamine was dissolved. (1.74 g, 0.01 mol) was dissolved in 40 ml of chloroform under stirring and 0.95 ml (0.01 mol) of ethyl chloroformate in 10 ml of chloroform were added thereto by dripping at 0 ° C. After 1 hour, the reaction mixture was washed with 40 ml of 10% sodium carbonate solution and the organic layer was dried over magnesium sulfate. After filtering and evaporating, the crude product thus obtained was purified by column chromatography. The oil thus obtained was crystallized from ether. Yield: 0.75 g (30%). Mp: 108-110 ° C. IR (KBr): 3225, 2943, 2654, 2542, 1739, 1458, 1379, .1331, 1256, 1171, 115, 1059, 974, 955, 862 cm "1.
1 H-NMR (CDCl 3) 106 (2x1H, br, NH + O), 450 (1H, m, CH-OH), 4 17 (2H, q, J = 7 1 Hz, CH 3 CH 2), 392-386 (1H, dd, J = 106 y = 48 Hz, 1H, dd, J = 106 y = 5 7 Hz, OCH2), 327-3 05 (1H, dd, J = 132 y = 1 7 Hz, 1H, dd, J = 132 y = 9 1 Hz, CH-CH¿-N), 320 (4H, m), 1 96 (4H, m) 1 65 (2H, m) (2H, m) (pipendine), 1 27 (3H, t, J = 7 1 Hz,
CH3) 13 C-NMR (CDCl 3) 1582 (s, C = O), 77 8 (t, OCH 2), 638 (d, CHOH), 61 9 (t) and 60 5 (t) (CH 3 CH 2 + CH-CH 2- N), 54 5 (t), 232 (t) and 22 1 (t) (p? Per? D? Na), 14 5 (, CH3) Analysis CnH22N2042H20 Calculated C 46 8%, H 7 9%, N 99 % Found C 474%, H 80%, N 98% The above compound was also prepared by two alternative processes I) 1 68g (003 moles) of potassium hydroxide were dissolved in 30 ml of ethanol and 1 05 g (001 moles) of N-hydroxyurethane were added thereto After stirring for half an hour, 1 62 g (001 mole) of 1-chloro-3-p? per? d? no-2-propanol 1n 10 ml of ethanol were added thereto drip and the mixture was boiled for 6 hours. The potassium chloride precipitate was filtered, the solution was evaporated and the crude product thus obtained was purified by column chromatography. Crystallizing the oil from the ether chromatography gave the title compound as a result. Yield 1 42 g (58%) II) 525 g (005 moles) of N-hydroxyurethane were dissolved in 50 ml pure and dry dimethyl formamide followed by the addition of 1.0 g (0.025 mole) of powdered sodium hydroxide and 4.7 ml (0.05 mole) of tertiary butanol. To the suspension thus obtained was added 7.8 g (0.055 mole) of N- (2,3-epoxypropyl) -piperidine [J.A. C.S. 80 :, 1257-9 (1958)] was added at 50 ° C while stirring. Stirring was continued for 4 hours at 80 ° C followed by evaporation in vacuo. The residue was absorbed in 50 ml of ethanolThe precipitate of sodium chloride was filtered and the crude product was purified by column chromatography. After crystallizing from ether, the title compound was obtained. Performance: 8.9g (72%). Example 3: N-isopropyl-N '- (2-hydroxy-3-piperidino-propoxy) urea 0- (2-hydroxy-3-piperidino-Propyl) -hydroxylamine (1.74 g, 0.01 mol) was dissolved in 25 ml of absolute chloroform and under stirring, 0.98 ml (0.01 mole) of iso-propyl isocyanate was added. The reaction was monitored by chromatography. At the end of the reaction, the solution was evaporated and the oily residue was purified by column chromatography. The oil thus obtained was crystallized with methanol-ether. Yield: 1.0 g (39%, Mp .: 78-79 ° C (methanol-ether) IR (KBr): 3242, 3055.2938, 2953, 2012, 1651, 1584, 1486, 1387, 1310, 1177, 1090, 1059, 1043, 949 cm "1. 1 H-NMR (DMSO-dfi): 8.98 (1H, s, CONH); 6.76 (1H, d, J = 7.9 Hz,
CHNHCO); 5.02 (1H, s, OH); 3.95-3.65 (3H, m, CHNH, CHOH, OCH2);
3. 55 (1H, dd, J = 10.5 y = 7.5 Hz, OCH2); 2.35 (4H, m, piperidine);
2. 27 (2H, d, J = 6.3 Hz, CH2N); 1.6-1.3 (6H, m, piperidine); 1.1 (6H, d, J = 6.6 Hz, (CH3) 2) 13 C-NMR (DMSO-d6): 159.2 (s, C = O); 79.1 (t, OCH2); 65.2 (d, CHOH); 61.3 (t, CHCH2N); 54.5 (t, piperidine); 40.5 (d, CH (CH3) 2); 25.4 (t), and 23.7 (t) (piperidine); 22.6 (q, CH3); 22.5 (q, CH3). Analysis: C? 2H25N3O3: Calculated: C 55.6%, H 9.7%, N 16.2%, Found: C 55.6%, H 9.3%, N 16.9%. Example 4: Nn-propyl-N '- (2-hydroxy-3-piperidino-propoxy) -urea 0- (2-hydroxy-3-piperidino-propyl) -hydroxylamine (1.74 g, 0.01 mol) was dissolved in 20 ml of chloroform and under stirring 0.95 ml (0.01 mole) of n-propyl isocyanate were added thereto. After 1 hour, an additional 0.3 ml (3.17 mmoles) of n-propyl isocyanate was added and the mixture was stirred for an additional 1 hour. The solution was evaporated and the oil thus obtained was purified by column chromatography. Yield: 1.3 g (50%). IR (KBr): 3319, 2934, 2878, 2802, 1666, 1551, 1456, 1393, 1308, 1155, 1092, 1040, 993, 889, 793 cm "1 H-NMR (DMSO-d 6): 8.98 (1H , s, NH), 6.95 (1H, t, J = 5.8 Hz CH2NHCO), 4.9 (1H, br, s, OH), 3.81 (1H, m, CHOH), 3.74 (1H, dd, J = 10.4 y = 3.2 Hz, OCH2), 3.56 (1H, dd, J = 10.4 y = 7.1 Hz, OCH2), 3.05 (2H,, J = 6.4) Hz, CjH2NH), 2.35 (4H, m, piperidine), 2.24 (2H, d, J = 6.4 Hz, CHCHÓN), 1.57-1.25 (6H, m, piperidine), 1.55-1.25 (2H, m, CH3CH_2), 0.84 (3H, t, J = 7.4 Hz, CH3). 13C-NMR ( DMSO-d6): 159.9 (s, CO), 79.1 (t, OCH2), 65.2 (d, CHOH), 61.4 (t, CH2N), 54.5 (t, piperidine), 40.3 (t, CH2NH), 25.3 (t, ); 23.7 (t), is 22.7 (t) (CH3CH2 + piperidine); 11.0 (q, CH3) 2.
The above compound was also prepared by the following alternative processes: N- (2-hydroxy-3-piperidino-propoxy) -ethyl carbamate (2.46 g, 0.01 mole) was dissolved in 30 ml of absolute tetrahydrofuran, 2.1 ml (0.015 mole) ) of triethylamine was added and subsequently 0.82 ml (0.59 g, 0.01 mole) of n-propylamine in 10 ml of absolute tetrahydrofuran were added dropwise while stirring. The mixture was boiled for 72 hours and then evaporated. The evaporation residue was purified by chromatography and the purified material was crystallized from petroleum ether to thereby obtain the title compound. Yield: 2.4 g (65%). Example 5: N-cyclohexyl-N '- (2-hydroxy-3-piperidino-propoxy) -urea
0- (2-hydroxy-3-piperidino-propyl) -hydroxylamine was dissolved
(1.74 g, 0.01 mole) in 40 ml of absolute chloroform and 1.29 g (0.01 mole) of cyclohexyl isocyanate with stirring. After 24 hours, the reaction mixture was evaporated and the residue was crystallized with methanol. Yield: 2.0 g (67%). Mp: 108-110 ° C (methanol).
GO. (KBr): 3319, 3287, 3188, 2930, 2853, 2797, 1637, 1574, 1452, 1354, 1331, 1300, 1101, 1098, 991 cm "1 H-NMR (CMSO-d6): 8.75 (1H, s, CONHO), 6.52 (1H, d, J = 7.7 Hz, CHNHCO), 4.71 (1H, s, CHOH), 3.80 (1H, m, CHOH), 3.76 (1H, dd, J = 10.4 y = 3.1 Hz , OCH2), 3.57 (1H, dd, J = 10.4 y = 7.2 Hz, OCH2), 3.45 (1H, m, CHNH), 2.37 (4H, t, J = 4.8 Hz) and 1.9-1.6 (4H, m) (piperidine), 1.6-1.3 (6H, m, piperidine), 1.3-1.1 (6H, m, cyclohexyl).
13 C-NMR (DMSO-d 6): 159.2 (s, CO); 79.1 (t, OCH2); 65.2 (d.CHOH); 61.3 (t, CHCH2N); 54.5 (t, piperidine); 47.4 (d, CHNH); 32.6 (t), 32.5 (t), 25.0 (t), 24.3 (t = and 23.7 (t) (cyclohexyl), 25.4 (t), 24.3 (t) and 23.7 (t) (pyperidine) Analysis: C12H23N3O30. 5 Calculated H2O: C 58.4%, H 8.5%, N 13.6%, Found: C 58.8%, H 9.3%, N 13.7% Example 6: Nn-hexyl-N '- (2-hydroxy-3-piperidino-propoxy ) -urea O- (2-hydroxy-3-piperidino-propyl) -hydroxylamine (1.85 g, 0.011 mol) was dissolved in 30 ml of chloroform and 1.17 ml (0.011 mol) of n-hexyl isocyanate were added with stirring. After 3 hours, the reaction mixture was evaporated and purified by column chromatography The oil thus obtained was slowly crystallized in the refrigerator and by rubbing the crystals in petroleum ether a white material was obtained Yield: 0.9 g (7%) Pf: 50-52 ° C IR (KBr): 3310, 2932, 2858, 2804, 1666, 1551, 1454, 1377,
1206, 1092, 1040, 995, 791, 725, 604 cm "1 H-NMR (DMSO-d 6): 8.97 (1 H, s, NH); 6.91 (1 H, t, J = 5.8 Hz, NH); (1H, s, OH), 3.82 (1H, m, CHOH), 3.72 (1H, dd, J = 10.4 y = 3.3 Hz, OCH2), 3.56 (1H, dd, J = 10.4 y = 7.1 Hz, OCH2) 3.05 (2H, q, CH2NH), 2.50 (4H, n, piperidine), 2.23 (2H, d, J = 6.4 Hz, CHCH2N), 1.55-1-3 (2H, m) and 1.27 (6H, m) ((CH2) 4, hexyl); 1.55-1.25 (6H, m, piperidine); 0.86 (3H, t, J = 6.4 Hz, CH3). 13C-NMR (DMSO-de): 159.8 (s, CO); 79., 0 (t, OCH2), 65.2 (d, CHOH), 61.4 (t, CHCH2N), 54.5 (t, piperidine), 38.5 (t, CH2NH), 30.08 (t), 29.5 (t) 25.7 (t ), and 21.8 (t) ((CH2) 4); 25.3 (t) and 23.7 (t) (piperidine); 13.7 (q, CH3).
Analysis C15H31N3O3 Calculated D 59 8%, H 104%, N 139%, Found C 60.0%, H 10 1% N 139% Example 7- N- (3-chlorophen? L) -N- (2-h? Drox? -3-p? Per? D? Nopropox?) - urea O- (2-h? Drox? -3-p? Pepd? No-prop? L) -h? Drox? Lam? Na was dissolved (2 g , 1148 mmoles) in 40 ml of chloroform and 14 ml (1148 mmoles) of 3-chlorophenisocyanate were added thereto and stirred for 4 hours at room temperature. The reaction mixture was evaporated and purified by column chromatography The chromatographically pure oil was crystallized from ether Yield 1 3 g (34%) PF 117-118ßC. IR (KBr) 3250, 2939, 2900, 1670, 1597, 1551, 1491, 1429, 1329, 1252, 1119, 972, 775, 718. 700 cpT '1 H-NMR (DMSO-de): 9.7 (1H, s, CONHO), 9 3 (1H, s, NH), 7 7
(1H, br, s), 7 44 (1H, d, J = 8 0 Hz), 7 30 (1H, t, J = 8 0 Hz), and 7 05 (1H, d, J = 8 0 Hz) , (phenyl); 5.35 (1H, s, OH), 4 0-3 8 (2H, m, CHOH, OCH2), 3.69 (1H, dd, J = 10.7 y = 7 9 Hz, OCH2), 327 (2H, d, J = 6 2 Hz, CHCH2N), 2.36 (4h, m) and 1.55-1.25 (t, H, m) (p? Per? D? Na) 13H-NMR (DMSO-d6): 157 1 (s, CO), 1404 (s), 132 9 (s), 130 1
(d), 121.9 (d), 117 9 (d) and 117 0 (d) (fep), 79 8 (t, OCH2), 65 3 (d, CHOH), 61 2 (t, CHCH2N), 54 5 (t), 25 4 (t) and 23 7 (t) (pipepdine) Analysis C? SH22CIN3O30 5 H20 Calculated- C 53.8%, H 6 9%, N 12 5%, Found C 53.9%, H 6 8%, N 12 3% Example 8 N-methyl-N '- (2-h? Drox? -3-p? Per? D? Non-propoxy) -urea O- (2-hydroxy-3-) was dissolved piperidino-propyl) -hydroxylamine (2.47 g, 0.0142 mol) in 40 ml of absolute chloroform and 0.84 ml (0.0142 mol) of methyl isocyanate were added thereto with stirring. The mixture was stirred for 2 hours at 25 ° C. Subsequently, the solution was evaporated and the residue was rubbed with ether. Performance: 2.5g (76%). Mp .: 98-101 ° C. GO. (K Br): 3356, 3217, 1943, 1658, 1556, 1414, 1377, 1292, 1132, 1092, 984, 908, 779, 741, 636 cm "1 H-NMR (DMSO-de): 9.0 (1H , s, CONHO), 6.91 (1H, q, J = 4.5 Hz, CH3NHCO), 4.82 (1H, br, s, OH), 3.8 (1H, m, CHOH), 3.7-3.5 (2H, dd, OCH2); 2.62 (3H, d, CH3N), 2.32 (m, 4H, piperidine), 2.25 (2H, d, CHCH2N), 1.6-1.3 (6H, m, piperidine), 13C-NMR (DMSO-d6): 160.4 ( s, CO), 78.9 (t, OCH2), 65.2 (d, CHOH), 61.5 (t, CH2N), 54.5 (t, piperidine), 25.54 (q, CH3N), 25.3 (t), and 23.7 (t) (piperidine) Analysis: C? 0H21N3O3: Calculated: C 51.9%, H 9.2%, N 18.2%; Found: C 51.7%, H 9.2%, N 18.6% The above compound was prepared according to the following alternative method : 0- (2-hydroxy-3-piperidino-propyl) -hydroxylamine (1.74 g, 0.01 mol) was dissolved in 50 ml of absolute chloroform and 0.94 g (0.01 mol) of N-methyl carbamoyl chloride in 10 ml of chloroform was added dropwise while stirring at 5 ° C. The mixture was stirred for 2 hours at room temperature followed by washing with 2x30 ml of 1N sodium hydroxide and 1x20 ml of water. The chloroform layer was dried over magnesium sulfate and after filtering the drying agent the solution was evaporated. The residue was triturated with ether, thereby obtaining the title compound. Performance: 1.9g (82%). Example 9: N-tert-butyl-N '- (2-hydroxy-3-piperidino-propoxy) -urea O- (2-hydroxy-3-piperidino-propyl) -hydroxylamine (2.53 g, 0.0145 moles) was dissolved in 40 ml of absolute chloroform and 1.66 ml of terbutyl isocyanate (0.0145 moles) were added thereto with stirring. The mixture was stirred for 2.5 hours. Subsequently, the solution was evaporated and the residue was triturated with petroleum ether and then purified by column chromatography. The oil thus obtained was crystallized with petroleum ether. Yield: 1.5 g (38%). Mp 71-73 ° C. JR. (KBr): 3314, 2945, 2916, 1651, 1555, 1460, 1393, 1384, 1335, 1254, 1111, 988, 903, 839, 781 cm'1. 1 H-NMR (DMSO-d 6): 8,788 (1H, s, CONHO); 6.6 (1H, s, CNHCO); 4.9 (1H, dd, s, OH); 3.8 (1H, m, CHOH); 3.55-3.45 (2H, dd, OCH2); 2.3 (m, 4H, piperidine); 2.25 (2H, d, CH2N); 1.5-1.3 (6H, m, piperidine). 13 C-NMR (DMSO-d 6): 159.2 (s, CO); 79.1 (t, OCH2; 65.0 (d,
CHOH); 61.2 (t, CH2N); 54.5 (t, piperidine); 49.2 (s, (CH3) 3C); 28.6 (q, (CH3) 3C); 25.3 (t) and 23.7 (t) (piperidine). Analysis: C? 3H27N303: Calculated: C 57.1%, H 9.9%, N 15.4%; Found: C 56.9%, H 9.9%, N 15.8%.
Example 10: N- (4-methoxyphenyl) -N '- (2-hydroxy-3-piperidino-propoxy) -urea O- (2-hydroxy-3-piperidino-propyl) -hydroxylamine (2.53 g, 0.0145 moles) was dissolved. ) in 40 ml of absolute chloroform and 1.9 ml (0.0145 mole) of 4-methoxyphenyl isocyanate were added thereto during stirring. After 3 hours, the solution was evaporated and the residue was purified by column chromatography. The oil thus obtained was crystallized from diethyl ether. Yield: 2.0 g (42%). Mp: 103-104 ° C. JR. (KBr): 3398, 3183, 3098, 2943, 2837, 1691, 1596, 1537,
1514, 1486, 1302, 1229, 982, 899, 831 cm "1 H-NMR (DMSO-de) '94 (1H, s, CONHO); 89 1H, s,
NHCONHO); 7.41 (2H, d) and 6.85 (2H, d) (phenyl), 5.25 (1H, br, s,
OH); 3.85 (1H, m, CHOH); 3.7 (3H, s, OCH3); 3.83-3.5 (2H, dd, OCH2); 2.33 (4H, m, piperidine); 2.29 (2H, d, CH2N); 1.46-1 35 (6H, m, piperidine). 13 H-NMR (DMSO-d 6): 1576 (s, CO); 154.7 (s), 131.7 (s), 120.5 (d) and 113.6 (d) (phenyl); 79.6 (t, OCH2); 65.3 (d, CHOH); 61 2 (t, CH2N); 54.9 (q, OCH3); 54.5 (t), 254 (t) and 23.8 (t) (piperidine). Analysis: Ci6H25N304: Calculated: C 594%, H 7.8%, N 13.0%; Found: C 59.1%, H 8.9%, N 138%. Example 11: N-benzyl-N -'- 2- (hydroxy-3-piperidino-propoxy) -urea 0- (2-hydroxy-3-piper? Dino-propyl) -hydrox was dissolved ? lamina (2.53 g, 0.0145 moles) in 40 ml of absolute chloroform and 1.8 ml
(0 0145 moles) of benzyl isocyanate were added thereto with stirring. The mixture was stirred for 2 hours, the solution was evaporated and the residue was crystallized from the ethanol-ether mixture. Yield: 2.1g (47%), Mw: 100-101 ° C. GO. (KBr): 3320, 3000, 2910, 1660, 1530, 1370, 1190, 1155, 1125, 1105, 1085, 976, 780, 695 cm'1. 1 H-NMR (DMSO-d 6): 9.20 ((1H, s, CONHO); 7.50 (1H, t,
CH2NHCO); 7.32-7.22 (5H, m, phenyl); 4.9 (1H, br, s, OH); 4.30 2H, d, J = 6.1 Hz, CH2NCO); 3.81 (1H, m, CHOH); 3.75 (1H, dd, OCH2);
3. 63 (1H, dd, OCH2); 2.34-2.2 (6H, m, CH2N); 1.44-1.33 (6H, m, piperidine) 13 C-NMR (DMSQ-dfi): 159.9 (s, CO); 140.0 (s); 127.9 (d), 126.6 (d), and 126-41 (d) (phylum); 79.2 (t, OCH2 (t, OCH2; 65.2 (s, CHOH); 61.5 (CHCH2N); 42.0 (t, PhCH2N); 25.3 (t) and 23.7 (t) (piperidine) Analysis: C? 6H25N303: Calculated: C 62.5%, H 8.2%, N 13.7%; Found: C 62.5%, H 8.0%, N 13.4% Example 12: N-isopropyl-N '- [2-hydroxy-3- (4-benzyl) hydrochloride piperazino) -propoxy] -urea 0- [2-Hydroxy-3- (4-benzyl-1-piperazino) -propyl] -hydroxylamine (2.65 g, 0.01 mol) was dissolved in 50 ml of absolute chloroform, 1 ml (0.01) moles) of isopropyl isocyanate were added thereto dropwise while stirring and stirring continued for an additional 3 hours After the reaction the oil obtained was evaporated and 3.5 g of oily material was obtained. The oil and 3.5 g of oily material were obtained The title compound was recovered from the oil by the addition of hydrochloric acid in ether Yield: 2.4 g By recrystallization of the dihydrochloride (1 g) in ethyl acetate, 0.85 g was obtained. of crystalline material White, Mp: 208-212 ° C (ethyl acetate, dec.). GO. (KBr): 3337, 3297, 3165, 2972, 2864, 1657, 1551, 1445, 1420, 1358, 951, 926, 746, 696 cm "1 H-NMR (DMSO-d 6): 13-12 (1H; br, s, NH +), 12-11 (1H, br, s, NH +), 9.15 (1H, br, s, CONHO), 7.7 (2H, m) and 75 (3H, phenyl or, m + p) 6.72 (1H, d, J = 8.0 Hz, CHNHCONH), 4.7-4.2 (3H, m, OCH2CH), 3.9-3.0 (12H, m, CHNH + CHCH2N + piperazine, NCH2-phenyl), 1.12 (6H, d , J = 6.4 Hz, 2xCH3). 13 C-NMR (DMSO-de): 158.9 (s, NHCO), 131.2 (d), 129.3 (d) and 128.6 (d) (phenyl); 77.2 (t, OCH2); 62.9 (d, CHOH), 40.6 (d, CHNH), 60-58, 50-46 (piperazine), 22.5 (q, CH3) Analysis: C18H32N4O3'0.5 H20: Calculated: C 50.0%, H 7.7%, N 12.9%; Found: C 50.2%, H 7.6%, N 13.2% Example 13: N-tert-butyl-N '- (2-hydroxy-3-diethylamino-propoxy) -urea 0- (2-Hydroxy-3-diethylaminopropyl) -hydroxylamine was dissolved in 40 ml of absolute chloroform and 3.08 ml (0.027 mole) of tert-butyl isocyanate were added thereto dropwise. The mixture was stirred at room temperature for 15 hours and evaporated. The product thus obtained was purified by column chromatography. The material thus obtained is in oily form which crystallizes when stored in the refrigerator. The crystals were filtered after trituration with petroleum ether. Yield: 1.44 g (20%). Mp .: 58-61 ° C. [R (KBr): 3325, 2965, 2934, 1670, 1549, 1460, 1393, 1236, 1092, 1067, 991, 783 crn "1. 1 H-NMR (DMSO-de): 8.63 (1H, br, s, CONHO); 6.35 (1H, br, s,
(CH3) 3CNHCO); 3.81 (1H, dd, J = 11.2 y = 2.9 Hz, OCH2); 3.60 (1H, dd,
J = 11.2 y = 8.1 Hz, OCH2); 3.8-3.7 (1H, m, CHOH, overlap);
2. 55 (4H, q J = 7.2 Hz, CH2CH3); 2.42 (2H, d, J = 6.3 Hz, CHCH2N); 1.32 (9H, s, (CH3) 3C); 0.97 (6H, t, J = 7.2 Hz, CH2CH3). 13 C-NMR (DMSO-dfi): 159.2 (s, NHCO); 79.0 (t, OCH2); 65.9 (d, CHOH); 55.5 (t, CH-CH2N); 49.2 (s, (CH3) 3C); 47.0 (t, 2xNCH2CH3); 28.6 (q (CH3) 3C); 11.5 (q, CH2CH3). Example 14: N '- (2-hydroxy-3-piperidinopropoxy) benzyl carbamate 0- (2-hydroxy-3-piperidino-propyl) -hydroxylamine (1.74 g, 0.01 mol) was dissolved in 40 ml of absolute chloroform and 1.41 ml (0.01 mol) of benzyl chloroformate in 10 ml of chloroform was added thereto by dripping at 0 ° C. The mixture was stirred at 20 ° C for 4 hours and another 1.41 ml (0.01 mole) portion of benzyl chloroformate was added and stirred for an additional 2 hours to the reaction mixture, 1.4 ml (0.01 mole) of triethylamine was added. and was stirred for 4 hours followed by evaporation and purifying the oily residue by column chromatography. Therefore, a light yellow oil was obtained. Yield: 1.62 g (53%).
1 H-NMR (DMSO-d 6); 10.4 (1H, br, s, NH); 7.35-7.3 (5H, m, phenyl); 5.1 (2H, PhCH20); 4.5 (1H, d, CHOH); 3.81-3.6 (3H, m, OCH2 + CHOH); 2.4-2.2 (6H, m) and 1.4-1.2 (6H, m) (piperidine). 13 H-NMR (DMSO-d 6): 156.7 (s, CO); 142.3 (s); 128.2 (d), 127.8 (d), 127.7 (d), 126.4 (d) and 126.2 (d) (phenyl); 79.2 (t, OCH2); 65.7 (t, PhCH20); 65.3 (d, CHOH); 61.5 (t, CH-CH2N); 54.5 (t), 25.3 (t), is 23.69 (t) (piperidine). The title compound was prepared by the following alternative method: 3.1 g (0.02 mole) of benzyl ester of N-hydroxy-carbamic acid and 2.24 g (0.04 mole) of sodium hydroxide were dissolved in the mixture of 10 ml of water and 3 ml of dimethyl sulfoxide, 3.1 ml (3.7 g, 0.04 mole) of epichlorohydrin were added to the solution while stirring at 0 ° C and the mixture was stirred for 8 hours at this temperature. 20 ml of water were added followed by extraction with 4x20 ml of ethyl acetate, the combined ethyl acetate layers were washed with 1x20 ml of water, dried over magnesium sulfate, filtered and the solution was evaporated. The oil thus obtained was dissolved in 40 ml of diethyl ether, 19.7 ml (17 g, 0.2 mole) of piperidine and 15 ml of 4N sodium hydroxide was added thereto. The mixture was boiled for 5 hours, the layers were separated, the ether layer was washed with 2x20 ml of saturated saline, dried over magnesium sulfate and evaporated. The oily residue was purified by column chromatography to obtain the title compound. Yield: 4.1 g (67%).
Example 15: N-cyclohexyl-N '- (2-hydroxy-3- [N- (cyclohexyl-carbamoyl) -N-terbutylamino] -propoxy) -urea 0- (2-hydroxy-3-terbutylaminopropyl) -hydroxylamine was dissolved (2.65 g, 0.01812 mol) in 50 ml of absolute chloroform and 4.6 ml (0.3624 mol) of cyclohexyl isocyanate were added thereto with stirring. The mixture was stirred for 2 hours at room temperature and evaporated. The residue was dissolved in ethyl acetate, treated with charcoal, followed by filtration and evaporation of the solution. The light yellow oil thus obtained was crystallized from the mixture of ethyl acetate and ether. Yield: 3.3 g (44%) Mp: 151-152 ° C. GO. (KBr): 3312, 2932, 2854, 1668, 155, 1450, 1292, 1354, 1252, 1220, 1130, 941, 891 cm "1.? -RMN (DMSO-de): 9.01 (1H, s, CONHO) 6.68 and 6.64 (1H, d, J = 8.7 Hz, 1H, d, J = 8.1 Hz, 2xCHNH), 6.25 (1H, d, J = 4.3 Hz, OH), 3.75 (1H, m, CHOH), 3.70 (1H, dd, J = 10.2 y = 3.5 Hz) and 3.55 (1H, dd, J = 10.2 y = 7.0 Hz) (OCH2CO), 3.40 (2x1H, m, ciciohexyl), 3.25 (1H, d, J = 16.0 Hz) and 3.00 (1H, dd, J = 16.0 Hz, J = 8.6 Hz) (CHCH_2N), 1.8-1.4 (2x4H, m, ciciohexyl), 1.29 (9H, s, CH3), 1.4-0.9 (2x6H, m , cyclohexyl). 13 C-NMR (DMSO-d 6): 159.3 (s) and 159.0 (s) (CO); 78.1 (t, OCH 2); 70.4 (d, CHOH); 54.9 (s, C (CH 3) 3) 48.1 (t, CHCH2N), 44.6 (d), and 44.5 (d) (cyclohexyl), additional signals: 33.0 (t), 32.7 (t), 32.6 (t), 28.4 (q, CH3), 25.2 (t), ); 25.0 (t); 24.3 (t); 24.1 (t) The title compound was prepared by the following alternative method:
N-cyclohexyl-N '- (2-hydroxy-3-N-terbutylamino-propoxy) -urea (2.88 g, 0.01 mole) was dissolved in 50 ml of absolute chloroform and 1.25 g (0.01 mole) of cyclohexyl isocyanate were added. with agitation. The mixture was stirred for 2 hours at room temperature and evaporated. The residue was dissolved in ethyl acetate, treated with charcoal, followed by filtration and the solution was evaporated. The residual oil thus obtained was crystallized from the mixture of ethyl acetate and ether to thereby obtain the title compound. Yield: 3.1 g (75%). Example 16: Nn-hexyl-N '- (3-piperidino-propoxy) -urea 0- (3-piperidino-propyl) -hydroxylamine (1.37 g, 8.66 moles) was dissolved in 25 ml of absolute chloroform and 0.92 g (8.66 moles) of n-hexyl isocyanate were added thereto with stirring. The reaction was followed by chromatography. After one day, another portion of n-hexyl isocyanate (0.46 ml, 4.33 mmol) was added and the mixture was stirred for 2 hours. The chloroform layer was washed with 20 ml of 10% sodium carbonate solution and 1x20 ml of water, dried over magnesium sulfate, filtered and the solution evaporated. Performance: 2.1g (85%). ! R (KBr): 3354, 2932, 2856, 2810, 2777, 1666, 1543, 1486,
1377, 1308, 1155, 1134, 1976 cm "1 H-NMR (CDCl 3): 8.12 (1 H, br, s, NH); 6.3 (1H, t, J = 5.6 Hz, CH 2 NHCO); 3.85 (2H, t , J = 5.9 Hz, OCH2), 3.27 (2H, dd, J = 7.1 y = 5.6 Hz, CH2NH), 2.3 (6H, M, piperidine), 1.85 (2H, m, OCH2CH2CH2), 1.7-1.2 (14H, m, piperidine + CH 3 (CH 2) 4), 0.92 (3H, t, J = 6.7 Hz. CH 3).
13 C-NMR (CDCU): 160.3 (s, CO); 76.5 (t, OCH2); 56.2 (t, OCH2CH2CH2N); 54.4 (t, piperidine); 39.5 (t, CH2NH); 31.4 (t), 30.2 (t), 26.4 (t,), 25.6 (t), 25.4 (t), 24.2 (t) and 22.4 (t), (? Iperidine + OCH2CH2CH2 + CH3 (CH2) 4); 13.8 (q, CH3). Example 17: N-cyclohexyl-N '- (2-acetoxy-3-piperidino-propoxy) urea hydrochloride N-cyclohexy I- N' - (2-h id roxi-3-pi pe ridi non-propoxy) was dissolved ) urea (0.67 g, 2238 moles) in 25 ml of absolute chloroform and 0.23 ml (2462 mmoles) of acetic anhydride were added thereto with stirring. The mixture was stirred overnight followed by evaporation. The hydrochloride salt was prepared from the oil obtained with hydrochloric acid in ether. Yield: 0.56 g (66%). Mp: 184-186 ° C. GO. (KBr): 3381, 3211, 2935, 1854, 1739, 2664, 2548, 1744, 1730, 1672, 1531, 1450, 1371, 1242, 1229 cm "1 H-NMR (DMSO-dfi): 10.7 (1H, br, s, NH +), 9.2 (1H, s, CONHO), 6.62 (1H, d, J = 8.2 Hz, CNHCO), 5.38 (1H, m, CHO-CO), 3.87 (2H, d, J = 4.7 Hz, OCH2), 3.4 (5H, m), 2.9 (2H,), 2.12 (3H, s, COCH3), 2.0-1.4 (10H, m), 1.45-0.95 (6H, m) .13C-NMR (DMSO -dfi): 169.7 (s, COCH3), 158.7 (s, CO), 74.3 (t,
OCH2); 65.9 (d, CHOCO); 55.8 (t), 52.9 (t), 52.1 (t), 47.8 (d, 2xcyclohexyl); 24.5 (t), 21.7 (t), 21.0 (q, CH3). Example 18: N-cyclohexyl-N'-acetyl-N '- (2-acetoxy-3-piperidino-propoxy) -urea N-cyclohexyl-N' - (2-hydroxy-3-piperidino-propoxy) - urea (1.2 g, 4.01 mmol) in 10 ml (0.106 mol) of acetic anhydride, 0.1 ml of pyridine were added and the mixture was allowed to stand overnight at room temperature. The mixture was then evaporated, dissolved in 30 ml of chloroform, followed by washing the chloroform layer with 10 ml of 10% sodium carbonate solution and 1x20 ml of water, dried over magnesium sulfate, filtered and it evaporated. Performance: 1.2g. IR (KBr): 3296, 2934, 2854, 2787, 1730, 1660, 1520, 1452, 1371, 1236, 1040, 891, 750, 621 cm "1 H-NMR (DMSO-d 6): 7.93 (1H, d , J = 7.8 Hz, NH), 5.13 (1H, m, CHO), 4.18 (1H, dd, J = 9.9 y = 2.9 Hz) and 4.08 (1H, dd, J = 9.9 y = 6.3
Hz) (NOCH2); 3.54 (1H, m, cyclohexyl, CH); 2.5-2.3 (6H, m, CH2N, piperidine); 2.27 (3H, s, NCOCH3); 2.02 (3H, s, OCOCH3); 1.9-1.1
(16H, m, cyclohexyl + piperidine). 13 C-NMR (DMSO-dfi): 171.8 (s, NCOCH 3); 169.5 (s, OCOCH3); 150.0 (s, NHCON); 75.0 (t, OCH2); 68.5 (d, CHOH); 57.7 (t,
CHCH2N); 54.2 (t, piperidine); 48.5 (d, CHNH); 31.9 (t, cyclohexyl); signals of the two rings: 25.3 (t); 24.8 (t); 23.6
(t) (cyclohexyl + piperidine); 22.9 (q) and 20.7 (q) (CH3COO and CH3CON).
Example 19: N- (3-nitrofenyl) -N '- (2-hydroxy-3-piperidino-prop oxy) -urea O- (2-hydroxy-3-piperidino-propyl) hydroxylamine (1.74 g, 0.01) was dissolved. moles) was dissolved in 25 ml of absolute chloroform and 1.64 g
(0.01 moles) 3-Nitrophenyl isocyanate in 10 ml of absolute chloroform were added thereto with stirring. After 1 hour of reaction, the mixture was evaporated and purified by column chromatography. The oil thus obtained was crystallized with diethyl ether. Yield: 1.84 g (54%). Mp: 137-139 ° C. R (KBr): 3281, 2943, 2828, 1672, 1607, 1560, 1529, 1486, 1437, 1254, 1283, 1115, 802, 739 cm "1 H-NMR (DMSO-de): 9.87 (1H, br , s) and 9.55 (1H, br, s) (2xNH),
8. 57 (1H, t, J = 2.1 Hz), 7.91 and 7.85 (2x1H, dd, J = 8.2 y = 2.1 Hz), 7.58 (1H, t, J? = J2 = 8.2 Hz) (phenyl); 5.16 (1H, br, s, OH); 3.95 (1H, m, CHOH); 3.88 (1H, dd, J = 10.5 y = 3.0 Hz) and 3.71 (1H, dd, J = 10.5 y = 7.4 Hz) (OCH2); 2.36 (4H, m, piperidine); 2.30 (2H, d, J = 6.3 Hz, CHCH2N); 1.46 (4H, m) and 1.36 (2H, m) (piperidine). 13 C-NMR (DMSO-d 6): 157.0 (s, CONH); 147.8, 140.2 129.7, 124.7, 116.7, and 112.6 (phenyl); 79.8 (t, OCH2); 65.4 (d, CHOH); 61.2 t, CHCH2N); 54.5 (t), 25.3 (t), and 23.7 (t) (piperidine). Example 20: Nn-hexyl-N '- (2-hydroxy-3-morpholinopropoxy) -urea maleate 0- (2-hydroxy-3-morpholino-propyl) -hydroxylamine (175 g, 0.01 mole) was dissolved in 25 g. ml of absolute chloroform and 1.06 ml (0.01 mole) of n-hexyl isocyanate were added thereto with stirring. The reaction was followed by chromatography. After 1 hour, an additional 0.5 ml portion (5 mmoles) of n-hexyl isocyanate was added and the mixture was stirred for 2 hours. The chloroform layer was washed with 20 ml of 10% sodium carbonate solution and 1x20 ml of water, dried over magnesium sulfate, filtered and evaporated. The oil thus obtained (2.57 g) was dissolved in 15 ml of ethyl acetate and isolated in the salt form by the addition of the equivalent amount (0.98 g) of maleic acid. Yield: 2.55 g (61%). Mp: 107-108 ° C (ethyl acetate). GO. (KBr): 3402, 2932, 2860, 1655, 1576, 1493, 1387, 1366, 1194, 1136, 1076, 993, 876, 866, 710, 559 cm "1 H-NMR (DMSO-d 6): 9.1 ( 1H, s, CONHO), 6.87 (1H, t, J = 5.7 Hz,
CH2NHCO); 6.1 (2H, s, maleic acid CH); 4.10 (1H, m, CHOH); 3.80 (2x2H, m, morpholine); 3.67 (2H, d, J = 5.4 Hz, OCH2); 3.2-2.9 (8H, m, CH (OH) CH2N + CH3 (CH2) 4CH2 + morpholine); 1.42 (2H, m,
C 3 { C 2) 3C j2); 1.25 (6H, br, CH3 (CH2) 3); 0.93 (3H, t, J = 6.5 Hz, CH3). 13 C-NMR (DMSO-dfi): 167.0 (s, maleic acid COOH); 159.7 (s, CONH); 135.1 (d, maleic acid CH); 77.5 (t, OCH2); 63.1 (t, morpholine); 62.6 (d, CHOH); additional signals: 58.6 (i) and 51.8 (t) (2xNCH2); 38.6 (t), 30.7 (t), 29.4 (t), 25.7 (t), 21.8 (t) and 13.6 (q) (hexyl). Example 21: N, N-diphenyl-N '- (2-hydroxy-3-piperidino-propoxy) -urea
0- (2-hydroxy-3-piperidino-propyl) -hydroxylamine was dissolved
(0.92 g, 5.28 mmol) in 20 ml of absolute chloroform and 1.1 ml (7.92 mmoles) of triethylamine were added thereto followed by the dropwise addition of 1.22 g (5.28 moles) of carbamoyl diphenyl chloride in 5 ml of tetrahydrofuran. . The mixture was stirred for 72 hours, the solid salt precipitate was filtered and the solution was evaporated. The evaporation residue was dissolved in chloroform, washed with 2x50 ml of 10% sodium carbonate solution and 2x50 ml of water, the organic phase was dried over magnesium sulphate, evaporated and purified by chromatography. The oil thus obtained was crystallized with petroleum ether. Yield: 1.2 g (61%), Mw .: 75-78 ° C. GO. (KBr): 3425, 3225, 2932, 2853, 2800, 1645, 1596, 1491, 1450, 1348, 1119, 957, 874, 764, 702 cm "1 H-NMR (DMSO-d 6): 9.50 (1H, br, s, CONHO), 7.35 (4H, m) and
7. 20 (6H, m) (phenyl, o, m + p); 4.7 (1H, br, s, OH); 3.9-3.5 (3H, m, OCH2CH); 2.4-2.1 (6H, m, piperidine, CHCH2N); 1.55-1.25 (6H,, piperidine). 13 C-NMR (DMSO-d 6): 157.5 (s, CO); 142.7 (s), 129.6; 127.6, and 126.5 (phenyl); 79.5 (t, OCH2); 66.0 (d, CHOH); 62.0 (t, CH-CH2-N); 55.1 (t), 25.0 (t) and 24.3 (t) (piper idi na). Example 22: N- (3-pyridyl) -N '- (2-hydroxy-3-piperidino-propoxy) -urea 4.2 g (0.0284 mol) of nicotinic azide were boiled for 8 hours in toluene under nitrogen and after addition 4.95 g (0.0284 mol) of 0- (2-hydroxy-3-piperidino-propyl) -hydroxylamine boiling was continued for one hour. The solvent was distilled and the residue was purified by column chromatography. The oil thus obtained was crystallized from the mixture of ether and petroleum ether. Yield 1.2 g (14%). Pf.:118-120°C. 1 H-NMR (DMSO-d 6): 9.78 and 9.32 (2x1H, br, s, NH); 8.67 (1H, d,
J = 2.4 Hz, pyridine-2-H); 8.21 (1H, dd, J = 4.7 y = 1.5 Hz, pyridine-6-H);
7. 97 (1H, dd, J = 8.3, 2.4 and 1.5 Hz, pyridine 4-h); 732 (1H, dd, J = 8.3 and
= 4.7 Hz, pyridine-5-H); 5.36 (1H, br, s, OH); 3.95 (1H, m, CH); 3.92 (1H, dd, J = 10.6 y = 3.0 Hz) and 3.70 (1H, dd, J = 10.6 y = 7.5 Hz) (OCH2);
2. 40 (4H, m, piperidine); 230 (2H, d, J = 6.4 Hz, CHCH2N); 1.55-1-25 (6H, m, piperidine). 13 C-NMR (DMSO-de): 157.3 (s, CO); 143.3 and 140.5 (2xd, pyridine-2-6-C); 135.5 (s, pyridine-3-C); 125.6 and 123.3 (2xd, pyridine-4-5-C); 79.8 (t, OCH2); 65.3 (d, CHOH); 61.2 (t, CHCH2); 54.5 (t), 25.3 (t) and 23.8 (t) (piperidine). Example 23: N-heptyl-N '- (2-hydroxy-3-piperidino-propoxy) -urea 0- (2-hydroxy-3-piperidino-propyl) -hydroxylamine (1.23 g, 7.08 mmol) was dissolved in 30 ml of absolute chloroform and 1.00 g (7.08 mmol) of heptyl isocyanate were added thereto while dripping while stirring. The mixture was stirred for 24 hours at room temperature and evaporated. The oily material thus obtained is crystallized while it is stored in the refrigerator. The crystals were triturated with petroleum ether and the white solid material was filtered. Performance: 1.8g (80.6%). Mp: 49-51 ° C. 1 H-NMR (CDCl 3: 7.62 (1H, br, s, CONHO); 6.74 (1H, t, J = 5.3 Hz, CH 2 -NHCO); 4.2-3.3 (1H, br, s, OH); 3.98 (1H, m, CHOH), 3.85 (1H, dd, J, = 11.1 Hz, J2 = 2.2 Hz, OCH2), 3.68 (1H, dd, ^ = 11.1 Hz, J2 = 7.4 Hz, OCH2), 3.25 (2H, m, CH3-NH), 2.7-2.2 (6H, m, piperidine-CH2 and piperidine-N-CH2), 1.7-1.2 (10H, m, (CH2) 5), 1.7-1.2 (6H, m, piperidine), 0.88 (3H, t, J = 6.6 Hz, CH3) .13C-NMR (CDCI3): 161.0 (s, CONH), 79.0 (t, OCH2), 64.0 (d, CHOH), 60.0 (t, CH (OH) CH2 ); 54.5 (t, piperidine-NCH2); 39.6 (t, CH2NH); 31.7 (t); 29.7 (t); 28.9 (t); 26.7 (y); 25.9 (t); 24.0 (t); 22.5 (t); t); (piperidine, - (CH2) S-); 14.0 (q, CH3) Example 24: N-octyl-N '- (2-hydroxy-3-piperidino-propoxy) urea 0- (2- hydroxy-3-piperidino-propyl) -hydroxylamine (1.74 g, 10.0 mmoles) in 30 ml of absolute chloroform and 1.55 g (10.0 mmoles) of octyl isocyanate were added thereto with stirring, the mixture was stirred for 24 hours at ambient temperature and evaporated, followed by purification by chromatography a in column. The material was crystallized by triturating with petroleum ether and the white solid product was filtered. Yield: 2.27 g (68.7%), Mw: 55-56 ° C. 1 H-NMR (CDC): 7.72 (1H, s, NH); 6.73 (1H, t, J = 5.3 Hz, NH); 4.4-3.6 (1H, s, OH); 3.97 (1H, m, CHOH); 3.88 (1H, dd, ^ = 11.1 Hz, J2 = 2.4 Hz, OCH2); 3.67 (1H, dd, ^ = 11.1 Hz, J2 = 7.5 Hz, OCH3); 3.23 (2H, m, CH2NH); 2.57 (2H, m, CHCH2N); 2.4-2.1 (4H, m, piperidine); 1.7-1.2 (6H, m, piperidine); 1.7-1.2 (12H, m, CH3 (CH2) 6CH2NH); 0.87 (3H, t, J = 6.8 Hz, CH3). 13 C-NMR (CDCl 3): 161.1 (s, CO); 79.0 (t, OCH2), 64.1 (d,
CHOH); 59.8 (t, CHCH2N); 54.5 (t, piperidine); 39.6 (t, CH2NH); 31.7 (t); 29.7 (t); 29.2 (t); 29.1 (t); 26.8 (t); 25.9 (t); 24.1 (t); 22.6 (t) (piperidine and CH3 (CH2) 6CH2NH; 14.0 (q, CH3). The following compounds were prepared substantially by the same method described in Example 24. Example 25: N-pentyl-N '- (2-hydroxy) -3-piperidino-propoxy) -urea Yield: 85.5%, Mp: 63-65 ° C. Example 26: N-pentyl-N '- (3-piperidino-propoxy) -urea (using 0- (3-piperidino -propyl) -hydroxylamine as starting material.) Yield: 70.8%.
1 H NMR (CDCl 3): 8.05 (1H, br, s, NH); 6.3 (1H, t, J = 5.6 Hz, CH2HCO); 3.85 (2H, t, J = OCH2); 3.25 (2H, dd, CH2NH); 2.3 (6H, m, piperidine); 1.85 (2H, m, OC2CH2CH2); 1.7-1.2 (12H, m, piperidine-CH3 (Cj ± -) 3); 0.9 (3H, t, CH3). 13 C-NMR (CDCl 3): 160.3 (s, CO), 75.0 (t, OCH 2); 56.2 (t, OCH2CH2CH2N); 54.4 (t, piperidine); 39.6 (t, CH2NH); 29.9 (t), 29.0 (t); 25.4 (t); 25.4 (t); 25.3 (t); 24.1 (t); 22.3 (t), (piperidine-OCH2CH2-CH3 (CH2) 3); 13.9 (q, CH3). Example 27: N- (3-trifluoromethyl-phenyl) -N '- (2-hydroxy-3-piperidino-propoxy) -urea. Yield: 60.9%. Mp: 108-110 ° C.
Claims (9)
- And pharmaceutically acceptable acid addition salts thereof wherein X is O, -NH or a group of the formula -NR'-, wherein R and R ', independently of each other, are alkyl, cycloalkyl, phenylalkyl; a phenyl group optionally substituted with halo, haloalkyl, alkyl, alkoxy or nitro; or a hetero ring containing N, R1 is H or alkanoyl, R2 is H or hydroxy optionally acylated with alkanoyl, and R3 is a group of the formula -N (R4) R5 wherein R4 and R5, independently of each other, can be H, alkyl or a group of the formula -C (0) -NH-R wherein R is as defined above, or R4 and R5, when taken together with the adjacent nitrogen attached thereto, form a hetero ring of 5 to 7 members which may contain an additional heteroatom selected from nitrogen, oxygen and sulfur and which is optionally substituted with an alkyl or phenylalkyl.
- 2. Compounds of the general formula (I) according to claim 1, wherein X is O and R, R ', R1, R2 and R3 are as defined in claim 1.
- 3. Compounds of the general formula (I) according to claim 1, wherein X is NH or NR 'and R, R ", R1, R2 and R3 are as defined in claim 1.
- 4. Compounds of the general formula (I) according to any of claims 1 to 3, wherein the group -N (R4) RS for R3 is optionally substituted by piperidino, piperazino or morpholino
- 5. Compounds of the general formula (I) according to any of claims 1 to 3, in where the group -N (R4) R5 for R3 is optionally dialkylamino
- 6. Compounds of the general formula (I) according to any of claims 1 to 3, wherein R3 is -N (R4) R5 and R4 is alkyl and R5 is -C (= 0) -NH-R.
- 7. Pharmaceutical composition comprising as active substance a compound of the general formula (I) as defined in any of claims 1 to 6 or the pharmaceutically active acid addition salts thereof.
- 8. Process for preparing the hydroxylamine derivatives represented by the general formula (I), O // R-X-C \ N-0-CH2-CH-CH2-R; (i) And pharmaceutically acceptable acid addition salts thereof wherein X is O, -NH or a group of the formula -NR'-, wherein R and R ', independently of each other, are alkyl, cycloalkyl, phenylalkyl; a phenyl group optionally substituted with halo, haloalkyl, alkyl, alkoxy or nitro; or a hetero ring containing N, R1 is H or alkanoyl, R2 is H or hydroxy optionally acylated with alkanoyl, and R3 is a group of the formula -N (R4) R5 wherein R4 and Rs, independently of each other, can be H, alkyl or a group of the formula -C (0) -NH-R wherein R is as defined above, or R4 and R5, when taken together with the adjacent nitrogen attached thereto, form a hetero ring of 5 to 7) which can contain an additional heteroatom selected from nitrogen, oxygen and sulfur and which is optionally substituted with an alkyl or phenylalkyl, a) To prepare compounds of the general formula (I) wherein Z is O, (i) a compound of the general formula (II) H2N-0-CH2-CH-CH2-R3 (II) | R2 Where R2 and R3 are as defined above, they were reacted with a compound of the general formula (III) O II R-O-C (lll) \ Y Where R is as defined above and Y is halo or azido, or iii) a compound of the general formula (VI) O // ROC (VI) NH-OH Reacted with a compound of the general formula (VII) Y-CH2-CH-CH2-R3 I R2 (VII) iii) a compound of the general formula (VI) is reacted with a compound of the general formula (VIII) CH2-CH-CH2-R3 (VIII) iv) a compound of the general formula (VI) is reacted with a compound of the general formula (IX) CH2-CH-CH2-Y (IX) / O and subsequently with a compound of the formula R3H, wherein the formulas (VI), (VII), (VIII) and (IX) R, R2 and R3 are as defined above and Y is halo, b) to prepare compounds of the general formula (I) wherein X is -NH-, a compound of the general formula (II) wherein R2 and R3 are as defined above, are reacted with a compound of the formula (IV) or (IVa) RN = C = 0 (IV) O // R-NH-C ( Iva) \ Y Where R is as defined above and Y is halo, or c) to prepare compounds of the general formula (I) wherein X is -NH- or NR'-, a compound of the general formula (X) OR II Z-0-CN-0-CH 2 -CH-CH 2 -R 3 (X) II R 1 R 2 wherein R 1, R 2 and R 3 are as defined above and Z is alkyl, aralkyl or optionally substituted aryl, is reacted with a composed of the general formula RNH2 or RR'NH, wherein R and R 'are as defined above, or d) to prepare compounds of the general formula (I) wherein X is -NH-, R3 is -N (R) RS, R 4 is alkyl and R 5 is -C (0) -NH-R, i) a compound of the formula (II) wherein R 3 is -N (R 4) R 5, R 4 is alkyl, R 5 is H and R 2 is as it was defined before, it is reacted with an excess of a compound of the formula (IV) or (Iva) wherein R is as defined above and Y is halo, or ii) a compound of the general formula (I) wherein R3 is -N (R4) R5, R4 is alkyl, R5 is H and R2 is as defined above, is reacted with an excess of a compound of the formula (IV) or (Iva) wherein R is as defined before and Y is halo, oe) to prepare compounds of the general formula (I) wherein X is -NR'-, a compound of the formula ula general (II) is reacted with a compound of the general formula (V) R '0 \ II N - C (V) / \ R Y where R, R'. R2 and R3 are as specified above and Y is halo, and if desired, a compound of the general formula (I) is transformed into its acid addition salt, or if desired, a compound of the general formula (I) wherein R1 is H and R2 is hydroxy, it was transformed into a compound of the general formula (I) wherein R2 is acyloxy or R1 is acyl and R2 is acyloxy, optionally followed by the formation of salt.
- 9. Use of the compounds of the general formula (I) and the pharmaceutically active acid addition salts thereof as defined in any of claims 1 to 6 in the preparation of pharmaceutical compositions.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU9501756A HU218480B (en) | 1995-06-15 | 1995-06-15 | Hydroxylamine derivatives, process for producing them and pharmaceutical compositions containing them |
| HUP9501756 | 1995-06-15 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| MX9710172A MX9710172A (en) | 1998-07-31 |
| MXPA97010172A true MXPA97010172A (en) | 1998-11-09 |
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