HRP20020177A2 - Sulfonyl carboxamide derivatives, method for their production and their use as medicaments - Google Patents
Sulfonyl carboxamide derivatives, method for their production and their use as medicaments Download PDFInfo
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- HRP20020177A2 HRP20020177A2 HR20020177A HRP20020177A HRP20020177A2 HR P20020177 A2 HRP20020177 A2 HR P20020177A2 HR 20020177 A HR20020177 A HR 20020177A HR P20020177 A HRP20020177 A HR P20020177A HR P20020177 A2 HRP20020177 A2 HR P20020177A2
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- Prior art keywords
- alkyl
- phenyl
- cycloalkyl
- substituent
- formula
- Prior art date
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- 239000003814 drug Substances 0.000 title claims description 10
- 238000004519 manufacturing process Methods 0.000 title claims description 8
- 238000000034 method Methods 0.000 title claims description 8
- SGCKSDJIMSBTFY-UHFFFAOYSA-N n-sulfonylformamide Chemical class O=CN=S(=O)=O SGCKSDJIMSBTFY-UHFFFAOYSA-N 0.000 title description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 175
- 150000001875 compounds Chemical class 0.000 claims description 64
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 43
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 32
- -1 2-tetrahydrofuranyl Chemical group 0.000 claims description 30
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 28
- 239000013543 active substance Substances 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 24
- 125000001424 substituent group Chemical group 0.000 claims description 23
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 20
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 18
- 229910052794 bromium Inorganic materials 0.000 claims description 18
- 229910052801 chlorine Inorganic materials 0.000 claims description 18
- 229910052731 fluorine Inorganic materials 0.000 claims description 18
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 13
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 12
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 12
- VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical compound C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 claims description 8
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 8
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 8
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 8
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 claims description 8
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 claims description 8
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 8
- 125000003386 piperidinyl group Chemical group 0.000 claims description 8
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 8
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 8
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 8
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 6
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 5
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 4
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims description 4
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 claims description 4
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 4
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 4
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 4
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical compound [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 claims description 4
- 125000004539 5-benzimidazolyl group Chemical group N1=CNC2=C1C=CC(=C2)* 0.000 claims description 4
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 claims description 4
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 4
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003524 antilipemic agent Substances 0.000 claims description 4
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 4
- 239000004305 biphenyl Substances 0.000 claims description 4
- 235000010290 biphenyl Nutrition 0.000 claims description 4
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims description 4
- 125000004531 indol-5-yl group Chemical group [H]N1C([H])=C([H])C2=C([H])C(*)=C([H])C([H])=C12 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 125000001305 1,2,4-triazol-3-yl group Chemical group [H]N1N=C([*])N=C1[H] 0.000 claims description 2
- 125000001414 1,2,4-triazol-5-yl group Chemical group [H]N1N=C([H])N=C1[*] 0.000 claims description 2
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000005322 morpholin-1-yl group Chemical group 0.000 claims description 2
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 claims description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 2
- 125000004526 pyridazin-2-yl group Chemical group N1N(C=CC=C1)* 0.000 claims description 2
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 claims description 2
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 238000002360 preparation method Methods 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
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- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol 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 6
- 239000000126 substance Substances 0.000 description 6
- 238000008214 LDL Cholesterol Methods 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
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- SOVZVOGWJIJMKL-UHFFFAOYSA-N 2,4-dichloro-5-[(3,5-dimethylpiperidin-1-yl)sulfamoyl]benzoic acid Chemical compound C1C(C)CC(C)CN1NS(=O)(=O)C1=CC(C(O)=O)=C(Cl)C=C1Cl SOVZVOGWJIJMKL-UHFFFAOYSA-N 0.000 description 3
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- 239000011777 magnesium Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical class OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 1
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- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical class S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
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- 238000013268 sustained release Methods 0.000 description 1
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Chemical class OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/26—Sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Izum se odnosi na derivate sulfonilkarboksamida kao i na njihove fiziološki podnošljive soli i njihove fiziološki funkcionalne derivate i njihovu upotrebu za proizvodnju lijekova za prevenciju i liječenje hiperlipidemije kao i arteriosklerotičnih bolesti.
U Chemical Abstracts-u 96, 142393m (1982) već su opisani sulfonilkarboksamidi.
U DE 2145686 su opisani derivati 2-klor-5-sulfamil-benzojeve kiseline kao sredstva za sniženje lipida.
Izum se temelji na zadatku da se proizvedu daljnji spojevi koji razvijaju terapeutski korisno hipolipidemijsko djelovanje. S tim u svezi, zadatak se je sastojao posebno u tome da se nađu spojevi čije hipolipidemijsko djelovanje je povišeno u usporedbi s derivatima 2-klor-5-sulfamil-benzojeve kiseline iz DE 2145686.
Izum se stoga odnosi na spojevi formule I,
[image]
u kojoj
X, R1, R2, R3 međusobno neovisno mogu predstavljati NR6R7, (CH2)-piridil, (CH3) n-fenil, gdje n = 0 - 6 i fenilni ostatak može biti do dvostruko supstituiran sa supstituentom iz skupine koju čine F, Cl, Br, CF3, NH2, CN, OCF3, O-(C1-C6)-alkil, S-(C1-C6)-alkil, (C1-C6)-alkil, (C3-C6)-cikloalkil, COO (C1-C6)-alkil, COO (C3-C6) cikloalkil, CONH2, CONH(C1-C6)-alkil, CON [ (C1-C6) alkil]2;
(C1-C8)-alkil, pirolidin, piperidin, piperazin, piperazin-2-on, morfolin, tetrahidropiridin, tetrahidro-kinolin, tetrahidroizokinolin, pri čemu prstenovi u svakom slučaju mogu biti supstituirani sa supstituentom iz skupine koju čine fenil, (C1-C6)-alkil-fenil, -OH, (C1-C8)-alkil, (C1-C6)-alkil-OH, O-fenil, S-fenil, (CO)-(C1-C6)-alkil, (CO)-fenil, pri čemu fenilni supstituent nije supstituiran ili je do dvostruko supstituiran sa supstituentom iz skupine koju čine F, Cl, Br, OH, CF3, CN, OCF3, O-(C1-C6)-alkil, S-(C1-C6)-alkil, SO-(C1-C6)-alkil, SO2-(C1-C6)-alkil, (C1-C6)-alkil, (C3-C6)-cikloalkil, COOH, COO (C1-C6) alkil, COO (C3-C6)-cikloalkil, CONH2, CONH (C1-C6) alkil, CON [(C1-C6) alkil] 2, CONH (C3-C6) cikloalkil, NH2, NH-CO-(C1-C6)-alkil, NH-CO-fenil;
R6 i R7 međusobno neovisno predstavljaju H, (C1-C6)-alkil, (C1-C6)-alkil-OH, (C1-C6)-alkil-NH2, (C1-C6)-alkil-O-(C1-C6)-alkil, O-(C1-C6)-alkil, (C3-C6)-cikloalkil, CO-(C1-C6)-alkil, (C1-C6)-alkil-NH-C(O)-(C1-C6)-alkil, (C1-C6)-alkil-NH-(C1-C6)-alkil, (C1-C6)-alkil-N-[(C1-C6)-alkil]2, (C1-C6)-alkil-di-fenil, (C1-C6)-alkil-O-fenil, CHO, CO-fenil,
(CH2)n-Ar, gdje n = 0 - 6 i
Ar može biti fenil, bifenil, 1- ili 2-naftil, 1- ili 2-tetrahidrofuranil, 2-, 3- ili 4-piridil, 2- ili 3-tienil, 2- ili 3-furil, 2-, 4- ili 5-tiazolil, 2-, 4- ili 5-oksazolil, 1-pirazolil, 3-, 4- ili 5-izoksazolil, (C3-C6)- cikloalkil, piperidinil, pirolidinil, oksopiridinil, 2- ili 3-pirolil, 2- ili 3-piridazinil, 2-, 4- ili 5-pirimidinil, 2-pirazinil, 2-(l,3,5-triazinil) , 2-, 3- ili 4-morfolinil, 2- ili 5-benzimidazolil, 2-benzotiazolil, 1,2,4-triazol-3-il, 1,2,4-triazol-5-il, tetrazol-5-il, indol-3-il, indol-5-il ili N-metil-imidazol-2-, 4- ili -5-il i
Ar može biti do dvostruko supstituiran sa supstituentom iz skupine koju čine F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-CH2-O, O-(C1-C6)-alkil, S-(C1-C6)-alkil, SO-(C1-C6)-alkil, SO2-(C1-C6-alkil, (C1-C6)-alkil, (C3-C6)-ciklo-alkil, COOH, COO (C1-C6) alkil, COO (C3-C6)-cikloalkil, CONH2, CONH(C1-C6) alkil, CON[(C1-C6) alkil]2, CONH(C3-C6) cikloalkil, NH2, NH-CO-(C1-C6)-alkil, NH-CO-fenil, pirolidin-1-il, morfolin-1-il, piperidin-1-il, piperazin-1-il, 4-metil-piperazin-1-il, (CH2) n-fenil, O-(CH)2-fenil, S-(CH2) n-fenil, SO2-(CH2)n-fenil, pri čemu n = 0-3; te njihove fiziološki podnošljive soli.
Prednost se daje onim spojevima formule I u kojima jedan ili više ostataka mogu imati slijedeće značenje:
R1, R2 međusobno neovisno predstavljaju NR6R7, pirolidin, piperidin, piperazin, tetrahidropiridin, pri čemu prstenovi u svakom slučaju mogu biti supstituirani sa supstituentom iz skupine koju čine fenil, (C1-C6)-alkil-fenil, (C1-C6)-alkil, (C1-C6)-alkil-OH, O-fenil, S-fenil, (CO)-(C1-C6)-alkil, (CO)-fenil, pri čemu fenilni supstituent nije supstituiran ili je supstituiran do dvostruko sa supstituentom iz skupine koju čine F, Cl, Br, CF3, CN, OCF3, O-(C1-C6)-alkil, S-(C1-C6)-alkil, (C1-C6)-alkil, (C3-C6)-cikloalkil, COOH, COO (C1-C6)-alkil, COO (C3-C6) cikloalkil, CONH2, CONH(C1-C6) alkil, CON[ (C1-C6) alkil]2, NH2, NH-CO-(C1-C6)-alkil, NH-CO-fenil;
R6, R7 međusobno neovisno mogu biti H, (C1-C6)-alkil, (C1-C6)-alkil-O-(C1-C6)-alkil, (C3-C6)-cikloalkil, CO-(C1-C6)-alkil, (C1-C6)-alkil-NH-C(O)-(C1-C6)-alkil, (C1-C6)-alkil-NH-(C1-C6)-alkil, (C1-C6)-alkil-N- [ (C1-C6)-alkil]2, (CH2)2-Ar, pri čemu n = 0 - 6 i
Ar može biti fenil, bifenil, 1 - ili 2-naftil, 2-, 3-ili 4-piridil, 2- ili 3-tienil, 2-, 4- ili 5-tiazolil, 2-, 4- ili 5-oksazolil, 3- ili 5-izoksazolil, (C3-C6)-ciklo-alkil, piperidinil, pirolidinil, 2-, 4- ili 5-pirimidinil, 2-, 3- ili 4-morfolinil, 2- ili 5-benzimidazolil, 2-benzotiazolil ili indol-3-il, indol-5-il i
Ar može biti do dvostruko supstituiran sa supstituentom iz skupine koju čine F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkil, S-(C1-C6)-alkil, SO-(C1-C6)-alkil, SO2-(C1-C6)-alkil, (C1-C6)-alkil, (C3-C6)-cikloalkil, COOH, COO (C1-C6) alkil, COO (C3-C6) cikloalkil, CONH2, CONH (C1-C6)-alkil, NH2, NH-CO-fenil, (CH2)2-fenil, O-(CH2) n-fenil, S-(CH2)n-fenil, pri čemu n = 0-3;
X, R3 međusobno neovisno predstavljaju NR8R9, pirolidin, piperidin, morfolin, (C1-Cβ)-alkil, (CH2)n-fenil, pri čemu n = 0 - 6 i fenilni ostatak može biti do dvostruko supstituiran sa supstituentom iz skupine koju čine F, Cl, Br, CF3, CN, OCF3, O-(C1-C6)-alkil, S-(C1-C6)-alkil, (C1-C6)-alkil, (C3-C6)-cikloalkil, COO (C1-C6)-alkil, COO (C3-C6)-cikloalkil, CONH2, CONH (C1-C6) alkil, CON[ (C1-C6) alkil] 2;
R8, R9 međusobno neovisno predstavljaju H, (C1-C6)-alkil, (C3-C6)-cikloalkil, CO-(C1-C6)-alkil, (C1-C6)-alkil-CO-(C1-C6)-alkil, SO2-benzil, SO2-benzil-OCH3, (CH2)n-Ar, pri čemu n = 0 - 6 i
Ar može biti fenil ili tienil i Ar može biti do dvostruko supstituiran sa supstituentom iz skupine koju čine F, Cl, Br, CF3, N02, CN, OCF2, 0-CH2-O, O-(C1-C6)-alkil, S-(C1-C6)-alkil, SO-(C1-C6)-alkil, S02-(C1-C6)-alkil, (C1-C6)-alkil, (C3-C6)-cikloalkil, NH-CO-fenil, (CH2)n-fenil, 0-(CH2)n-fenil, S-(CH2)n-fenil, SO2-(CH2)n-fenil, pri čemu n = 0-2; te njihove fiziološki podnošljive soli.
Posebnu prednost daje se spojevima formule I, u kojoj jedan ili više ostataka ima slijedeće značenje:
R1, R2 međusobno neovisno predstavljaju NR6R7, piperidin, piperazin, tetrahidropiridin, pri čemu prsten u svakom slučaju može biti supstituiran s fenilom, (C1-C6)-alkil-fenilom, (C1-C6)-alkilom, (CO)-(C1-C6)-alkilom;
R6, R7 međusobno neovisno predstavljaju H, (C1-C6)-alkil, (C1-C6)-alkil-NH-(C1-C6)-alkil, (C1-C6)-alkil-N-[-(C1-C6)-alkil]2,
(CH2)n-Ar, pri čemu n = 0 - 6 i
Ar može biti fenil, 2-, 3- ili 4-piridil, piperidinil, pirolidinil, 2-, 4- ili 5-pirimidinil, 2-, 3- ili 4-morfolinil i Ar može biti do dvostruko supstituiran sa supstituentom iz skupine koju čine s F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkil, (C1-C6)-alkil, COOH, NH2, (CH2)n-fenil, pri čemu n = 0-3;
X može biti NR8R9, piperazin, (C1-C6)-alkil, (CH2)n-fenil, pri čemu n = 0 - 6;
R3 je NR10R11, piperazin;
R8, R9 međusobno neovisno predstavljaju H, (C1-C6)-alkil, (C3-C6)-cikloalkil, CO-(C1-C6)-alkil, (C1-C6)-alkil-CO-(C1-C6)-alkil, SO2-benzil, SO2-benzil-OCH3, (CH2)n-Ar, pri čemu n = 0 - 6 i
Ar može biti fenil ili tienil;
R10, R11 međusobno neovisno predstavljaju H, (C1-C6)-alkil, (C3-C6)-cikloalkil, CO-(C1-C6)-alkil, (C1-C6)-alkil-CO-(C1-C6)-alkil, SO2-benzil, SO2-benzil-OCH3, (CH2)n-Ar, pri čemu n = 0 - 6 i
Ar može biti fenil ili tienil; kao i njihove fiziološki podnošljive soli.
Posve posebnu prednost daje se spojevima formule I u kojoj jedan ili više ostataka ima, odnosno imaju slijedeće značenje:
R1, R2 međusobno neovisno predstavljaju NR6R7, piperidin, piperazin, tetrahidropiridin, pri čemu prstenovi mogu biti u svakom slučaju supstituirani s fenilom, (C1-C6)-alkil-fenilom, (C1-C6)-alkilom, (CO)-(C1-C6)-alkilom;
R6, R7 međusobno neovisno predstavljaju H, (C1-Ce)-alkil, (C1-C6)-alkil-NH-(C1-C6)-alkil, (C1-C6)-alkil-N-[(C1-
C6)-alkil]2,
(CH2)n-Ar, pri čemu n = 0 - 6 i
Ar može biti fenil, 2-, 3- ili 4-piridil, piperidinil, pirolidinil, 2-, 4- ili 5-pirimidinil, 2-, 3- ili 4-morfolinil i
Ar može biti do dvostruko supstituiran sa supstituentom iz skupine koju čine F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkil, (C1-C6)-alkil, COOH, NH2, (CH2)n-fenil, pri čemu n = 0-3;
X može biti (C1-C6)-alkil, (CH2)n-fenil, pri čemu n = 0 - 6;
R3 je NR10R11, piperazin;
R10, R11 međusobno neovisno predstavljaju H, (C1-C6)-alkil, (C3-C6)-cikloalkil, CO-(C1-C6)-alkil, (C1-C6)-alkil-CO-(C1-C6)-alkil, SO2-benzil, SO2-benzil-OCH3, (CH2)n-Ar, pri čemu n = 0 - 6 i
Ar može biti fenil ili tienil; kao i njihove fiziološki podnošljive soli.
Izum se odnosi na spojeve formule I u obliku njihovih racemata, racemične smjese i čistih enantiomere, te na njihove diastereomere i njihove smjese. Alkilni, alkenilni i alkinilni ostaci u supstituentima X, R1, R2, R3, R6, R7, R8, R10 i R11 mogu imati ravan ili razgranati lanac.
Farmaceutski podnošljive soli su zbog svoje više topivosti u vodi u usporedbi s polaznim, odnosno bazičnim spojevima posebno prikladne za medicinsku upotrebu. Te soli moraju imati farmaceutski podnošljiv anion ili kation. Prikladne farmaceutski podnošljive kiselinske adicijske soli spojeva formule I su soli anorganskih kiselina, kao što su soli solne kiseline, bromovodične, fosforne, metafosforne, dušične, sulfonske i sumporne kiseline, te soli organskih kiselina kao npr. soli octene kiseline, benzolsulfonske, benzojeve, limunske, etansulfonske, fumarne, glukonske, glikolne, izetionske, mliječne, laktobionske, maleinske, jabučne, metansulfonske, jantarne, p-toluolsulfonske, vinske i trifluor octene kiseline. Prikladne farmaceutski podnošljive bazične soli su soli amonijaka, soli alkalijskih metala (kao natrijeve i kalijeve soli) soli zemno alkalijskih metala kao magnezijeve i kalcijeve soli) .
Soli s anionom koji nije farmaceutski podnošljiv također spadaju u okvir izuma kao korisni međuproizvodi za proizvodnju ili čišćenje farmaceutski podnošljive soli i/ili za upotrebu u ne-terapeutskoj, na primjer u vitro primjeni.
Prednost se daje solima metansulfonske kiseline, toluolsulfonske kiseline, maleinske kiseline i fosforne kiseline.
Posebnu prednost daje se metansulfonatima spojeva formule I.
Izum se odnosi, nadalje, na fiziološki funkcionalne derivate spojeva formule I. Pojam "fiziološki funkcionalan derivat", koji se ovdje rabi, označava svaki fiziološki podnošljiv derivat spoja prema izumu, npr. ester, koji dat sisavcu, npr. čovjeku, može (izravno ili posredno) dati takav spoj ili njegov aktivan metabolit.
Daljnji oblik ovog izum je upotreba predlijekova spojeva formule I. Takovi predlijekovi se mogu u vivo metabilizirati u spoj formule I. Sami predlijekovi mogu biti ili ne moraju biti učinkoviti.
Spojevi formule I mogu također postojati u različitim polimorfnim oblicima, npr. kao amorfni i kristalinični oblici. Svi polimorfni oblici spojeva formule I spadaju u opseg izuma i oni predstavljaju daljnji oblik izuma.
Nadalje, sve upute o "spoju (spojevima) formule I" odnose se na spoj (spojeve) formule (I) kako su prethodno opisani, kao i na njihove soli, solvate i fiziološki funkcionalne derivate.
Količina spoja formule (I), koja je potrebna za postizanje željenog biološkog učinka ovisi o nizu faktora, npr. o odabranom specifičnom spoju, predviđenoj upotrebi, načinu davanja i kliničkom stanju pacijenta. Općenito, dnevna doza je rasponu od 0,3 mg dg 100 mg (tipično od 3 mg i 50 mg) dnevno po kilogramu tjelesne težine, npr. 3 - 10 mg/kg/dnevno. Intravenska doza može biti npr. u rasponu od 0,3 mg do 1,0 mg/kg, koja se prikladno može dati kao infuzija od 10 ng do 100 ng po kilogramu i po minuti. Prikladne infuzijske otopine za tu svrhu mogu sadržavati npr. od 0,1 ng do 10 mg, tipično od 1 ng do 10 mg po mililitri. Pojedinačne doze mogu sadržavati npr. od 1 mg do 10 g aktivne tvari. Tako ampule za injekcije mogu sadržavati na primjer od 1 mg do 100 mg, a pojedinačne formulacije koje se mogu dati oralno, kao što su na primjer tablete ili kapsule mogu sadržavati na primjer od 1,0 do 1000 mg, tipično od 10 do 600 mg. U slučaju farmaceutski podnošljive soli, gore navedeni podaci se odnose na težinu soli spoja formule (I) . Za profilaksu ili terapiju gore navedenih stanja spojevi formule ,(I) mogu se upotrijebiti sami kao takovi, međutim oni su ponajprije prisutni zajedno s podnošljivim nosačem u obliku farmaceutske formulacije. Nosač mora naravno biti prihvatljiv u smislu da je on kompatibilan s drugim sastojcima formulacije i da ne šteti zdravlju pacijenta. Nosač može biti kruta tvar ili tekućina ili oboje i on se ponajprije formulira sa spojem kao pojedinačna doza, na primjer kao tablete koje mogu sadržavati od 0,05% do 95 mas. % aktivne tvari. Također mogu biti prisutne i daljnje farmaceutski aktivne tvari, uključiv i druge spojeve formule (I) . Farmaceutski pripravci prema izumu mogu se proizvesti nekim od poznatih farmaceutskih postupaka, koji se uglavnom sastoje u tome da se sastojci pomiješaju s farmakološki podnošljivim nosačima i/ili pomoćnim tvarima.
Farmaceutski pripravci prema izumu su takovi da su prikladni za oralno, rektalno, površinsko, peroralno (npr. suplingvalno) i parenteralno (npr. supkutano, intramuskularno, intradermalno ili intravensko) davanje, pri čemu najpovoljniji način davanja u svakom slučaju ovisi o vrsti i težini stanja koje liječi i o vrsti dotičnog upotrijebljenog spoja formule (I). Formulacije u obliku dražeja i formulacije za usporeno oslobađanje u obliku dražeja također spadaju u opseg izuma. Prednosne su formulacije postojane prema kiselinama i želučanom soku.
Prikladne prevlake koje su otporne prema želučanom soku uključuju celulozni acetat ftalat, polivinalacetat ftalat, hidroksipropil-metil celulozni ftalat i anionske polimere metakrilne kiseline i metil estera metakrilne kiseline.
Prikladni farmaceutski pripravci za oralno davanje mogu biti u odvojenim jedinicama, kao što su na primjer kapsule, kapsule od hostija, pastile ili tablete, koje u svakom slučaju sadrže određenu količinu spoja formule (I); kao prah ili granulat; kao otopina ili suspenzija u vodenoj ili ne-vodenoj tekućini; ili kao emulzija ulja u vodi ili vode u ulju. Ti pripravci mogu se proizvesti, kako je već spomenuto, bilo kojom prikladnom farmaceutskom metodom koja uključuje stupanj u kojem se aktivnu tvar dovede u dodir s nosačem (koji može sadržavati jedan ili više dodatnih sastojaka). Općenito, pripravci se proizvode ujednačenim i homogenim miješanjem aktivne tvari s tekućim i/ili fino podijeljenim nosačem, nakon čega se, prema potrebi, oblikuje proizvod. Tako se, na primjer, tablete mogu proizvesti tako da se prah ili granulat spoja ispreša ili oblikuje, prema potrebi, s jednim ili više dodatnih sastojaka. Isprešane tablete mogu se proizvesti tabletiranjem na prikladnom stroju za tabletiranje spoja u sipkom obliku, kao što je na primjer prah ili granulat, koji je prema potrebi pomiješan sa sastojcima, kliznim sredstvom, inertnim sredstvom za razrjeđivanje i/ili s jednim (ili više) površinski aktivnim sredstvom/sredstvima za dispergiranje. Oblikovane tablete mogu se proizvesti oblikovanjem praškastog spoja, navlaženog s inertnim tekućim sredstvom za razrjeđivanje u prikladnom stroju.
Farmaceutski pripravci koji su prikladni za peroralno (suplingvalno) davanje uključuju pastile koje sadrže spoj formule (I) s tvari za popravljanje okusa, obično saharozom i gumom arabikuom ili s nosačem i pastile koje sadrže spoj u inertnoj osnovi kao što je želatina i glicerin ili saharoza i guma arabika.
Prikladni farmaceutski pripravci za parenteralno davanje uključuju ponajprije sterilne vodene pripravke spoja formule (I), koji su prednosno izotonični s krvi predviđenog primaoca. Ti pripravci se daju ponajprije intravenski, iako se mogu dati također supkutano, intramuskularno ili intradermalno kao injekcija. Ti pripravci se mogu proizvesti ponajprije tako da se spoj pomiješa s vodom i dobivenu otopinu se sterilizira i učini izotoničnom s krvi. Pripravci prema izumu koji se mogu dati injekcijom sadrže općenito od 0,1 do 5 mas. % aktivnog spoja.
Prikladni farmaceutski pripravci za rektalno davanje su ponajprije pojedinačne doze u obliku čepića. Oni se mogu proizvesti tako da se spoj formule (I) pomiješa s jednim ili više prikladnih tvrdih nosača, na primjer s kakao maslacem i dobivenu smjesu se oblikuje u čepiće.
Prikladni farmaceutski pripravci za površinsku aplikaciju na kožu jesu ponajprije masti, kreme, losioni, paste, sprej, aerosol ili ulje. Kao nosači mogu se upotrijebiti vazelin, lanolin, polietilenglikol, alkohol i kombinacije dviju ili više tih tvari. Aktivna tvar je općenito prisutna koncentracijom od 0,1 do 15 mas. % pripravka, na primjer od 0,5 do 2%. Također je moguća i transdermalna aplikacija. Prikladni farmaceutski pripravci za transdermalnu primjenu mogu biti u obliku pojedinačnih flastera koji su prikladni za dugotrajan tijesan dodir s epidermom pacijenta. Takovi flasteri sadrže prikladno aktivnu tvar u vodenoj otopini koja je prema potrebi puferirana, otopljena i/ili dispergirana u ljepilu ili je dispergirana u polimeru. Odgovarajuća koncentracija aktivne tvari je pribl. 1% do 35%, ponajprije pribl. 3% do 15%. Kao posebna mogućnost, aktivna tvar se može osloboditi elektro-transportom ili ionoforezom, kao što je opisano, na primjer, u Pharmaceutical Research, 2(6): 318 (1986).
Slijedeći pripravci su dati zbog objašnjenja izuma i nije im namjera ograničenje izuma.
Primjer A
Meke želatinske kapsule koje sadrže 100 mg aktivne tvari po kapsuli:
po kapseli
aktivna tvar 100 mg
mjesa triglicerida fraktionirana iz kokosove masti 400 mg
sadržaj kapsule 500 mg
Primjer B
Emulzija koja sadrži 60 mg aktivne tvari u 5 ml:
za 100 ml emulzije
aktivna tvar 1/2 g
neutralno ulje q.s.
natrij karboksimetilceluloza 0, 6 g
polioksietilen stearat q.s.
glicerin, čisti 0,2 do 2,0 g
sredstvo za okus q.s.
voda (odsoljena ili destilirana) ad 100 ml
Primjer C
Rektalni oblik lijeka koji u čepiću sadrži 40 mg aktivne tvari
po čepiću
aktivna tvar 40 mg
osnovna naša za čepić ad 2 g
Primjer D
Tablete koje sadrže 40 mg aktivne tvari po tableti:
po tableti
laktoza 600 mg
kukuruzni škrob 300 mg
topivi škrob 20 mg
magnezijev stearat 40 mg
1000 mg
Primjer E
Dražeje koje sadrže 50 mg aktivne tvari po dražeji
po dražeji
aktivna tvar 50 mg
kukuruzni škrob 100 mg
laktoza 60 mg
sek. kalcijev fosfat 30 mg
topivi škrob 5 mg
magnezijev stearat 10 mg
koloidna silicijeva kiselina 5 mg
260 mg
Primjer F
Za proizvodnju sadržaja tvrdih želatinskih kapsula prikladne su slijedeće recepture:
a) aktivna tvar 100 mg
kukuruzni škrob 300 mg
400 mg
b) aktivna tvar 140 mg
mliječni šećer 180 mg
kukuruzni škrob 180 mg
500 mg
Primjer G
Kapljice se mogu proizvesti po slijedećem receptu (100 mg aktivne tvar u 1 ml = 20 kapljica) :
aktivna tvar 10 g
benzojeva kiselina metil ester 0,07 g
benzojeva kiselina etil ester 0,03 g
etanol, 96%-tni 5 ml
demineralizirana voda ad 100 ml
Predmet izuma je, nadalje, postupak za proizvodnju spojeva opće formule I, koji je naznačen time da se spoj opće formule I proizvede prema slijedećoj reakcijskoj shemi:
[image]
Slijedeći navedeni primjeri služe za objašnjenje izuma, a ne za njegovo ograničenje. Navedene temperature raspadanja nisu ispravljene i općenito ovise o brzini zagrijavanja.
Tablica 1: Primjeri
formula 1
[image]
[image] [image] [image] [image] [image] [image] [image] [image] [image]
Primjer 141
Metansulfonat iz primjera 54
2-[NH-etil-N-pirolidinil]-NH-pentil-5-metilsulfonil-4-(4-fenil-piperidin-1-il)benzamid
[image]
20,0 g slobodne baze iz primjera 54 otopi se u vrućem izopropanolu i pomiješa s 5,1 ml metansulfonske kiseline. Kad se otopina ohladi na sobnu temperaturu nastalu suspenziju se miješa još jedan sat pri temperaturi između 0°C i 5°C i zatim se proizvod dobije filtracijom. Sirov proizvod se prekristalizira iz 200 ml izopropanola i osuši u vakuumu pri 50°C. Dobije se 21,0 g soli s talištem pri 205°C do 208°C.
Primjer 142
Toluolsulfonat iz primjera 54
2-[NH-etil-N-pirolidinil]-NH-pentil-5-metifsulfonil-4-(4-fenil-piperidin-1-il)benzamid
[image]
Primjer 143
Maleinat iz primjera 54
2-[NH-etil-N-pirolidinil] -NH-pentpil-5-metilsulfonil-4-(4-fenil-piperidin-1-il)benzamid
[image]
Spojevi formule I odlikuju se povoljnim djelovanjem na izmjenu masnih tvari, i oni su posebno prikladni kao hipolipidemici. Ovi spojevi se mogu upotrijebiti sami ili u kombinaciji s drugim sredstvima za sniženje lipida. Takova daljnja sredstva za sniženje lipida su navedena npr. u Rote Liste, poglavlje 58. Ovi spojevi su prikladni za profilaksu kao i posebno za liječenje hiperlipidemije.
Arterioskleroza je složena bolest sistema za izmjenu tvari i krvotoka. Povišen LDL holesterin u plazmi je jedan od glavnih parametara rizika te bolesti. Kod ljudi LDL holesterin se pretežnim dijelom odstranjuje iz krvotoka preko LDL rezeptora u jetri. Smanjenje LDL holesterina u plazmi smanjuje i rizik arterioskleroze i time također ukupnu smrtnost. Spojevi prema izumu prikladni su time također za profifaksu i za liječenje arteriosklerotičnih oboljenja.
Učinkovitost spojeva ispitana je kako slijedi:
1) In-vitro određivanje indukcije LDL receptora ispitivanjem luciferaze
Indukcija LDL receptora određena je ispitivanjem luciferaze. U tu svrhu regulatorski fragment DNA (4kb) gena humanog LDL receptora, koji sadrži kompletno promotorsko područje, povezuje se na reporterski gen luciferaze iz krijesnica i stabilno se transficira u staničnu liniju Hep-G2. Stanice iz te linije se zasade u MEM (minimalni esencijalni medij, e. Minimum Esential Medium) na pločice s 96 jamica prevučene s kolagenom. Nakon 24 sata u kulturu se dodaju ispitne tvari, otopljene u DMSO, s krajnjim koncentracijama od 10 nM do 10 pM (DMSO krajnja koncentracija = 2%) . Tvari se inkubiraju 12-18 sati preko noći (u svakom slučaju 4 jamice/konc.), zatim se doda D-luciferin kao supstrat za luciferazu i mjeri se luminescenciju. Izmjerena luminiscencija, izražena kao postotak kontrole (kontrola = 100%), koja je bila inkubirana samo s DMSO, je mjera relativne indukcije LDL receptora (tablica 2).
Daljnji podaci o metodi opisani su u Current Protocols in Molecular Biology, F.M. Ausubel, R. Brent, R.E. Kingston, D.D. Moore, J.G. Seidman, J.A. Smit and Kevin Struhl, izd. J. Wiley and Sons Inc., U.S.A.
Tablica 2: Indukcija LDL receptora iz odabranih primjera u % u usporedbi s kontrolom
[image] [image]
2) In vivo određivanje smanjenja LDL-holesterina na hrčku Učinak induktora LDL receptora na smanjenje holesterina kod hiperlipidemičnih hrčaka
U ovom pokusu na životinjama istraženo je djelovanje induktira LDL receptora aplikacijom bolusa na hrčcima koji su jeli masnu hranu.
Kao pokusne životinje upotrijebljeni su mužjaci sirijskih hrčaka (Charles River) prosječne tjelesne težine od 100 - 120 g do početka prilagodbe. Životinje su podijeljene prema tjelesnoj težini u skupine (n = 6).
Davanjem hrane obogaćene s 15% maslaca i 3% holesterina izazvana je jaka hiperlipidemija. Liječenje je započeto 2 tjedna nakon takovog hranjenja. Ispitne tvari su aplicirane oralno pomoću sonde ždrijelo-želudac jednom dnevno tijekom vremenskog peR10da od 10 dana. Količina lipida u plazmi analizirana je nakon 10 dana.
Tablica 3 prikazuje relativne promjene količine lipida u usporedbi s kontrolnim životinjama koje su primale placebo u %.
Tablica 3.
[image]
Iz jasnog smanjenja ukupnog holesterina, LDL-holesterina i triglicerida može se vidjeti dobro djelovanje spojeva prema izumu u smislu sniženja lipida.
Proveden je usporedbeni pokus analizom gore opisane analize luciferaze s 2,4-diklor-5-(3,5-dimetil-piperidino-sulfamoil)-benzojevom kiselinom i sa spojem iz primjera 42.
[image]
Primjer 42
[image]
2,4-diklor-5-(3,5-dimetil-piperidino-sulfamoil)-benzojeva kiselina
Ispitivanje luciferaze:
Indukcija LDL receptora u % prema kontroli
[image]
Spojevi prema izumu formule I pokazuju ovdje jasno poboljšano djelovanje u usporedbi s 2,4-diklor-5-(3,5-dimetil-piperidino-sulfamoil)-benzojevom kiselinom.
Za bliže objašnjenje priprave u pojedinostima je opisan slijedeći primjer (br. 42).
Izvedbeni primjer:
2-[(2-dimetilamino-etil)-etil-amino]-N,N-dietil-5-fenil-metansulfonil-4-(4-fenil-piperidin-1-il)-benzamid (tablica 1, primjer 42)
1. Priprava 3-klorsulfonil-4-klor-6-fluor-benzojeve kiseline
20 g (0,115 mola) 4-klor-2-fluorbenzojeve kiseline stavi se pri 20°C uz miješanje i u obrocima u 100 ml klor-sulfonske kiseline. Reakcijsku smjesu se grije uz miješanje 5 sati pri 120°C. Za obradu, ohlađenu reakcijsku smjesu se prenese kap po kap uz snažno miješanje u 5 1 mješavine led/vode. Nastali talog se odsisa, ispere s vodom i zatim se suši 1 sat pri 50°C u vakuumskoj sušilici.
Dobije se 61,5 g 3-klorsulfonil-4-klor-6-fluor-benzojeve kiseline kao bezbojne kristale s talištem pri 135°C.
2. Priprava 5-karboksi-2-klor-4-fluor-benzosulfinska kiselina-bis-natrijeve soli
71 g (0,563 mola; 2,5 ekvivalenta) natrijevog sulfita otopi se u 200 ml vode i uz hlađenje ledom se pomiješa sa 61,5 g spoja iz propisa 1 (3-klorsulfonil-4-klor-6-fluor-benzojeva kiselina). Dodatkom vodene natrijeve lužine otopinu se namjesti na pH 9 i miješa se 6 sati pri 20°C. Zatim se s konc. solnom kiselinom zakiseli na pH 1, pri čemu se izluči nastala sulfinska kiselina. Kad se sulfinsku kiselinu odfiltrira, reakcijski proizvod se otopi u 600 ml vode i pH vrijednost otopine se namjesti na 10 dodatkom konz. vodene NaOH. Nakon filtracije preko aktivnog ugljena i odstranjivanja otapala u vakuumu uljasti ostatak se dovede do kristalizacije dodatkom 100 ml acetona.
Dobiveno je 59,2 bezbojnih kristala (93% od teorijskog), koji se izravno podvrgavaju slijedećoj reakciji.
3. Priprava 4-klor-2-fluor-5-fenilmetansulfonil-benzojeva kiselina-benzil estera
28,3 g (0,1 mola) spoja proizvedenog pod točkom 2 suspendira se u 250 ml N-metil-2-pirolidona i uzastopce se pomiješa sa 41 g (0,24 mola) benzil bromida i 4,6 g (0,3 mola) kalijevog karbonata. Reakcijsku smjesu se miješa 8 sati pri 60°C. Za obradu, kad se ohladi na sobnu temperaturu, reakcijsku smjesu se doda k 1,5 litre ledene vode, pri čemu se reakcijski proizvod izluči nakon 20 minuta u obliku bezbojne krute tvari koju se odfiltrira.
Dobije se 38,9 g (93% od teorijskog) 4-klor-2-fluor-5-fenilmetansulfonil-benzojeva kiselina-benzil estera; spoj se izravno, bez daljnjeg čišćenja, podvrgava slijedećem stupnju reakcije prema točki 4.
4. Priprava 4-klor-2-fluor-5-fenilmetansulfonil-benzojeve kiseline
1,26 g (1,2 ekvivalenta) NaOH pločica se otopi u 40 ml vode i pomiješa se s 11 g (26,3 mmola) 4-klor-2-fluor-5-fenilmetansulfonil-benzojeva kiselina-benzil estera, otopljenog u 40 ml tetrahidrofurana. Reakcijsku otopinu se pusti miješati 3 sata pri 20°C.
Zatim se, za obradu, prelije na 1 litru mješavine led/vode i dodatkom konc. solne kiseline namjesti se na pH 1,2. Reakcijski proizvod se izluči nakon nekog vremena u obliku bezbojnih kristala. Dobije se 8,4 g (97,7% od teor.) s talištem pri 180 do 184°C.
5. Priprava 4-klor-N,N-dietil-2-fluor-5-fenilmetansulfonil-benzamida
6,6 g (20 mmolova) karbonske kiseline iz primjera 4 suspendira se u 50 ml tionil klorida i uz miješanje grije se 1 sat pod refluksom. Zatim se ispari na rotacijskom isparivaču pod smanjenim tlakom, uljasti ostatak se otopi u 100 ml apsolutnog diklormetana i pri -10°C pomiješa se kap po kap s 3,1 g (2,1 ekvivalenta) dietilamina. Po završenom dodavanju, miješa se još 1 sat pri 20°C. Reakcijsku smjesu se zatim više puta uzastopce ispere s vodenom zasićenom otopinom bikarbonata i s vodom, osuši se pomoću natrijevog sulfata i otapalo se odstrani u vakuumu. Sirov proizvod koji se dobije na taj način očisti se kromatografijom na silika gelu (veličina zrna 40-63 μ, tvrtke Merck Darmstadt) s n-heptan/etil acetatom 1:1 kao mobilnom fazom (RF = 0,52).
Nakon odstranjivanja mobilne faze na rotacijskom isparivaču pod smanjenim tlakom dobije se 7,7 g 4-klor-N,N-dietnil-2-fluor-5-fenilmetansulfonil-benzamida (iskorištenje kvantitativno).
6. Priprava 4-klor-2-[(2-dimetilamino-etil)-etil-amino]-N,N-dietil-5-fenilmetansulfonil-benzamida
5,7 g (15 mmolova) 4-klor-N,N-dietil-2-fluor-5-fenil-metansulfoni)-benzamida otopi se u 50 ml etanola i nakon dodatka 2,6 g (22,5 mmola; 1,5 ekvivalenta) N,N-dimetil-etilendiamina grije se 18 sati pod refluksom. Zatim se otapalo odstrani pod smanjenim tlakom, ostatak se preuzme u 100 ml diklormetana i ispere se sa zasićenom vodenom otopinom bikarbonata, zatim se više puta ekstrahira u svakom slučaju sa po 30 ml vode. Organsku fazu se zatim osuši preko natrijevog sulfata i otapalo se odstrani na rotacijskom isparivaču u vakuumu.
Dobije se 7,3 g svjetlo žutog ulja koje se izravno pretvara u krajnji proizvod u slijedećoj reakciji (vidi propis 7).
7. Priprava 2-[(2-dimetilamino-etil)-etil-amino]-N,N-dietil-5-fenilmetansulfonil-4-(4-fenil-piperidin-1-il)-benzamida (primjer 42)
3,5 g (7,3 mmolova) 4-klor-2-[(2-dimetilamino-etil)-etil-amino]-N,N-dietil-5-fenilmetansulfonil-benzamida, iz opisa pod točkom 6, pomiješa se s 5,9 g 4-fenilpiperidina (5 ekvivalenata), proizvedenog hidriranjem komercijalno dostupnog 4-fenil-1,2,3,6-tetrahidro-piridina i miješa se 5 sati pri 150°C. Zatim se otopi u 150 ml diklormetana i izmućka sa zasićenom vodenom otopinom natrijevog bikarbonata, kao i s vodom. Nakon sušenja organske faze preko natrijevog sulfata, otapalo se odstrani na rotacijskom isparivaču pod smanjenim tlakom.
Za čišćenje, sirov proizvod se kroamtografira na silika gelu (veličina zrna 40-63 μ, tvrtke Merck Darmstadt) kao stacionarnom fazom upotrebom etil acetat/metanola s omjerom mješavine 2:1.
Dobije se 4,5 g 2-[(2-dimetilamino-etil)-etil-amino]-N,N-dietil-5-fenilmetansulfonil-4-(4-fenil-piperidin-1-il)-benzamida, svjetlo žuto ulje.
MS: C 35; H 48; N 4; O 3; S (604,9); maseni spektar 605,3 (M+H+).
Claims (12)
1. Spojevi formule I,
[image]
naznačeni time, da
X, R1, R2, R3 međusobno neovisno mogu predstavljati NR6R7, (CH2)-piridil, (CH3)n-fenil, gdje n = 0 - 6 i fenilni ostatak može biti do dvostruko supstituiran sa supstituentom iz skupine koju čine F, Cl, Br, CF3, NH2, CN, OCF3, O-(C1-C6)-alkil, S-(C1-C6)-alkil, (C1-C6)-alkil, (C3-C6)-cikloalkil, COO (C1-C6)-alkil, COO (C3-C6) cikloalkil, CONH2, CONH (C1-C6)-alkil, GON [ (C1-C6) alkil]2;
(C1-C8)-alkil, pirolidin, piperidin, piperazin, piperazin-2-on, morfolin, tetrahidropiridin, tetrahidro-kinolin, tetrahidroizokinolin, pri čemu prstenovi u svakom slučaju mogu biti supstituirani sa supstituentom iz skupine koju čine fenil, (C1-C6)-alkil-fenil, -OH, (C1-C8)-alkil, (C1-C6)-alkil-OH, O-fenil, S-fenil, (CO)-(C1-C6)-alkil, (CO)-fenil, pri čemu fenilni supstituent nije supstituiran ili je do dvostruko supstituiran sa supstituentom iz skupine koju čine F, Cl, Br, OH, CF3, CN, OCF3, O-(C1-C6)-alkil, S-(C1-C6)-alkil, SO-(C1-C6)-alkil, S02-(C1-C6)-alkil, (C1-C6)-alkil, (C3-C6)-cikloalkil, COOH, COO (C1-C6) alkil, COO (C3-C6)-cikloalkil, CONH2, CONH (C1-C6) alkil, CON[(C1-C6) alkil]2, CONH (C3-C6) cikloalkil, NH2, NH-CO-(C1-C6)-alkil, NH-CO-fenil;
R6 i R7 međusobno neovisno predstavljaju H, (C1-C6)-alkil, (C1-C6)-alkil-OH, (C1-C6)-alkil-NH2, (C1-C6)-alkil-O-(C1-C6)-alkil, O-(C1-C6)-alkil, (C3-C6)-cikloalkil, CO-(C1-C6)-alkil, (C1-C6)-alkil-NH-C(O)-(C1-C6)-alkil, (C1-C6)-alkil-NH-(C1-C6)-alkil, (C1-C6)-alkil-N-[(C1-C6)-alkil]2, (C1-C6)-alkil-di-fenil, (C1-C6)-alkil-O-fenil, CHO, CO-fenil,
(CH2)n-Ar, gdje n = 0 - 6 i
Ar može biti fenil, bifenil, 1- ili 2-naftil, 1- ili 2-tetrahidrofuranil, 2-, 3- ili 4-piridil, 2- ili 3-tienil, 2- ili 3-furil, 2-, 4- ili 5-tiazolil, 2-, 4- ili 5-oksazolil, 1-pirazolil, 3-, 4- ili 5-izoksazolil, (C3-C6)-cikloalkil, piperidinil, pirolidinil, oksopiridinil, 2- ili 3-pirolil, 2- ili 3-piridazinil, 2-, 4- ili 5-pirimidinil, 2-pirazinil, 2-(l,3,5-triazinil), 2-, 3- ili 4-morfolinil, 2- ili 5-benzimidazolil, 2-benzotiazolil, 1, 2,4-triazol-3-il, 1,2,4-triazol-5-il, tetrazol-5-il, indol-3-il, indol-5-il ili N-metil-imidazol-2-, 4- ili -5-il i
Ar može biti do dvostruko supstituiran sa supstituentom iz skupine koju čine F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-CH2-O, O-(C1-C6)-alkil, S-(C1-C6)-alkil, SO-(C1-C6)-alkil, SO2-(C1-C6-alkil, (C1-C6)-alkil, (C3-C6)-cikloalkil, COOH, COO (C1-C6) alkil, COO (C3-C6)-cikloalkil, CONH2, CONH (C1-C6) alkil, CON [ (C1-C6) alkil] 2, CONH (C3-C6) cikloalkil, NH2, NH-CO-(C1-C6)-alkil, NH-CO-fenil, pirolidin-1-il, morfolin-1-il, piperidin-1-il, piperazin-1-il, 4-meti1-piperazin-1-il, (CH2) n-fenil, O-(CH)2-fenil, S-(CH2)n-fenil, SO2-(CH2)n-fenil, pri čemu n = 0-3; te njihove fiziološki podnošljive soli.
2. Spojevi formule I, prema zahtjevu 1, naznačeni time, da R1, R2 međusobno neovisno predstavljaju NR6R7, pirolidin, piperidin, piperazin, tetrahidropiridin, pri čemu prstenovi u svakom slučaju mogu biti supstituirani sa supstituentom iz skupine koju čine fenil, (C1-C6)-alkil-fenil, (C1-C6)-alkil, (C1-C6)-alkil-OH, O-fenil, S-fenil, (CO)-(C1-C6)-alkil, (CO)-fenil, pri čemu fenilni supstituent nije supstituiran ili je supstituiran do dvostruko sa supstituentom iz skupine koju čine F, Cl, Br, CF3, CN, OCF3, O-(C1-C6)-alkil, S-(C1-C6)-alkil, (C1-C6)-alkil, (C3-C6)-cikloalkil, COOH, COO (C1-C6)-alkil, COO (C3-C6) cikloalkil, CONH2, CONH (C1-C6) alkil, CON[(C1-C6) alkil] 2, NH2, NH-CO-(C1-C6)-alkil, NH-CO-fenil;
R6, R7 međusobno neovisno mogu biti H, (C1-Ce)-alkil, (C1-C6)-alkil-O-(C1-C6)-alkil, (C3-C6)-cikloalkil, CO-(C1-C6)-alkil, (C1-C6)-alkil-NH-C(O)-(C1-C6)-alkil, (C1-C6)-alkil-NH-(C1-C6)-alkil, (C1-C6)-alkil-N-[(C1-C6)-alkil]2, (CH2)2-Ar, pri čemu n = 0 - 6 i Ar može biti fenil, bifenil, 1 - ili 2-naftil, 2-, 3-ili 4-piridil, 2- ili 3-tienil, 2-, 4- ili 5-tiazolil, 2-, 4- ili 5-oksazolil, 3- ili 5-izoksazolil, (C3-C6)-cikloalkil, piperidinil, pirolidinil, 2-, 4- ili 5-pirimidinil, 2-, 3- ili 4-morfolinil, 2- ili 5-benzimidazolil, 2-benzotiazolil ili indol-3-il, indol-5-il i
Ar može biti do dvostruko supstituiran sa supstituentom iz skupine koju čine F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkil, S-(C1-C6)-alkil, SO-(C1-C6)-alkil, SO2-(C1-C6)-alkil, (C1-C6)-alkil, (C3-C6)-cikloalkil, COOH, COO (C1-C6) alkil, COO (C3-C6) cikloalkil, CONH2, CONH (C1-C6)-alkil, NH2, NH-CO-fenil, (CH2) 2-fenil, O-(CH2)n-fenil, S-(CH2)n-fenil, pri čemu n = 0-3;
X, R3 međusobno neovisno predstavljaju NR8R9, pirolidin, piperidin, morfolin, (C1-C6)-alkil, (CH2) n-fenil, pri čemu n = 0 - 6 i fenilni ostatak može biti do dvostruko supstituiran sa supstituentom iz skupine koju čine F, Cl, Br, CF3, CN, OCF3, O-(C1-C6)-alkil, S-(C1-C6)-alkil, (C1-C6)-alkil, (C3-C6)-cikloalkil, COO (C1-C6)-alkil, COO (C3-C6)-cikloalkil, CONH2/ CONH (C1-C6) alkil, CON[(C1-C6) alkil]2;
R8, R9 međusobno neovisno predstavljaju H, (C1-C6)-alkil, (C3-C6)-cikloalkil, CO-(C1-C6)-alkil, (C1-C6)-alkil-CO-(C1-C6)-alkil, SO2-benzil, SO2-benzil-OCH3, (CH2) n-Ar, pri čemu n = 0 - 6 i Ar može biti fenil ili tienil i Ar može biti do dvostruko supstituiran sa supstituentom iz skupine koju čine F, Cl, Br, CF3, NO2, CN, OCF2, 0-CH2-O, O-(C1-C6)-alkil, S-(C1-C6)-alkil, SO-(C1-C6)-alkil, SO2-(C1-C6)-alkil, (C1-C6)-alkil, (C3-C6)-cikloalkil, NH-CO-fenil, (CH2)n-fenil, O-(CH2)n-fenil, S-(CH2)n-fenil, SO2-(CH2)n-fenil, pri čemu n = 0-2; te njihove fiziološki podnošljive soli.
3. Spojevi formule I, prema zahtjevu 1 ili 2, naznačeni time, da R1, R2 međusobno neovisno predstavljaju NR6R7, piperidin, piperazin, tetrahidropiridin, pri čemu prsten u svakom slučaju može biti supstituiran s fenilom, (C1-C6)-alkil-fenilom, (C1-C6)-alkilom, (CO)-(C1-C6)-alkilom;
R6, R7 međusobno neovisno predstavljaju H, (C1-C6)-alkil, (C1-C6)-alkil-NH-(C1-C6)-alkil, (C1-C6)-alkil-N-[(C1-C6)-alkil]2, (CH2)n-Ar, pri čemu n = 0 - 6 i
Ar može biti fenil, 2-, 3- ili 4-piridil, piperidinil, pirolidinil, 2-, 4- ili 5-pirimidinil, 2-, 3- ili 4-morfolinil i Ar može biti do dvostruko supstituiran sa supstituentom iz skupine koju čine s F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkil, (C1-C6)-alkil, COOH, NH2, (CH2) n-fenil, pri čemu n = 0-3;
X može biti NR8R9, piperazin, (C1-C6)-alkil, (CH2)n-fenil, pri čemu n = 0 - 6;
R3 je NR10R11, piperazin;
R8, R9 međusobno neovisno predstavljaju H, (C1-C6)-alkil, (C3-C6)-cikloalkil, CO-(C1-C6)-alkil, (C1-C6)-alkil-CO-(C1-C6)-alkil, SO2-benzil, SO2-benzil-OCH3, (CH2)n-Ar, pri čemu n = 0 - 6 i
Ar može biti fenil ili tienil;
R10, R11 međusobno neovisno predstavljaju H, (C1-C6)-alkil, (C3-C6)-cikloalkil, CO-(C1-C6)-alkil, (C1-C6)-alkil-CO-(C1-C6)-alkil, SO2-benzil, SO2-benzil-OCH3, (CH2) n-Ar, pri čemu n = 0 - 6 i
Ar može biti fenil ili tienil; kao i njihove fiziološki podnošljive soli.
4. Spojevi formule I, prema jednom ili više zahtjeva 1 do 3, naznačeni time, da R1, R2 međusobno neovisno predstavljaju NR6R7, piperidin, piperazin, tetrahidropiridin, pri čemu prstenovi mogu biti u svakom slučaju supstituirani s fenilom, (C1-C6)-alkil-fenilom, (C1-C6)-alkilom, (CO)-(C1-C6)-alkilom;
R6, R7 međusobno neovisno predstavljaju H, (C1-C6)-alkil, (C1-C6)-alkil-NH-(C1-C6)-alkil, (C1-C6)-alkil-N-[(C1-C6)-alkil]2, (CH2)n-Ar, pri čemu n = 0 - 6 i
Ar može biti fenil, 2-, 3- ili 4-piridil, piperidinil, pirolidinil, 2-, 4- ili 5-pirimidinil, 2-, 3- ili 4-morfolinil i
Ar može biti do dvostruko supstituiran sa supstituentom iz skupine koju čine F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkil, (C1-C6)-alkil, COOH, NH2, (CH2)n-fenil, pri čemu n = 0-3;
X može biti (C1-C6)-alkil, (CH2) n-fenil, pri čemu n = 0 - 6;
R3 je NR10R11, piperazin;
R10, R11 međusobno neovisno predstavljaju H, (C1-C6)-alkil, (C3-C6)-cikloalkil, CO-(C1-C6)-alkil, (C1-C6)-alkil-CO-(C1-C6)-alkil, SO2-benzil, SO2-benzil-OCH3, (CH2)n-Ar, pri čemu n = 0 - 6 i
Ar može biti fenil ili tienil; kao i njihove fiziološki podnošljive soli.
5. Lijek, naznačen time, da sadrži jedan ili više spojeva prema jednom ili više zahtjeva 1 do 4.
6. Lijek, naznačen time, da sadrži jedan ili više spojeva prema jednom ili više zahtjeva 1 do 4 i jedno ili više sredstava za sniženje lipida.
7. Spojevi prema jednom ili više zahtjeva 1 do 4, naznačeni time, da se upotrebljavaju kao lijek za liječenje hiperlipidemije.
8. Spojevi prema jednom ili više zahtjeva 1 do 4, naznačeni time, da se upotrebljavaju kao lijek za liječenje arteriokleroze.
9. Postupak za proizvodnju lijeka koji sadrži jedan ili više spojeva prema jednom ili više zahtjeva 1 do 4, naznačen time, da se aktivnu tvar pomiješa s farmaceutski prikladnim nosačem i tu smjesu se dovede u oblik prikladan za aplikaciju.
10. Upotreba spojeva prema jednom ili više zahtjeva 1 do 4, naznačena time, da se oni koriste za proizvodnju lijeka za liječenje hiperilipidemije.
11. Upotreba spojeva prema jednom ili više zahtjeva 1 do 4, naznačena time, da se oni koriste za proizvodnju lijeka za liječenje arterioskleroze.
12. Postupak za proizvodnju spojeva prema jednom ili više zahtjeva 1 do 4, naznačen time, da se po slijedećoj shemi formula
[image]
spoj formule II, u kojoj X i R3 imaju značenja navedena za formulu I, a Hal1 i Hal2 u svakom slučaju predstavljaju halogeni atom,
sa spojem R2-H, u kojem R2 ima značenje dato za formulu I, prevede u spoj formule III i on se sa spojem R1-H, u kojem R1 ima značenje dato za formulu I, prevede u spoj formule I
i on se prema potrebi s kiselinom prevede u farmakološki podnošljivu sol.
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| DE1999141540 DE19941540C2 (de) | 1999-09-01 | 1999-09-01 | Sulfonylcarboxamide zur Herstellung von Medikamenten zur Prophylaxe oder Behandlung von Hyperlipidämie |
| DE2000127611 DE10027611A1 (de) | 2000-06-06 | 2000-06-06 | Sulfonylcarboxamidderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
| PCT/EP2000/008027 WO2001016094A1 (de) | 1999-09-01 | 2000-08-17 | Sulfonylcarboxamidderivate, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
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| EP3896066A3 (de) * | 2015-08-07 | 2021-12-08 | Bayer CropScience Aktiengesellschaft | 2-(het)aryl-substituierte kondensierte heterocyclen-derivate als schädlingsbekämpfungsmittel |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4138399A (en) | 1970-09-14 | 1979-02-06 | Pfizer Inc. | Sulfamylbenzoic acid |
| GB1353357A (en) * | 1970-09-14 | 1974-05-15 | Pfizer | Substituted 5-sulphamylbenzoic acids |
| DE2517183A1 (de) * | 1975-04-18 | 1976-10-28 | Hoechst Ag | Basisch substituierte 5-sulfamoyl- anthranilsaeurederivate und verfahren zu ihrer herstellung |
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2000
- 2000-08-17 EP EP00953172A patent/EP1218341B1/de not_active Expired - Lifetime
- 2000-08-17 AT AT00953172T patent/ATE302754T1/de not_active IP Right Cessation
- 2000-08-17 BR BR0013727-8A patent/BR0013727A/pt not_active IP Right Cessation
- 2000-08-17 DE DE50011035T patent/DE50011035D1/de not_active Expired - Lifetime
- 2000-08-17 CZ CZ2002767A patent/CZ2002767A3/cs unknown
- 2000-08-17 ES ES00953172T patent/ES2246247T3/es not_active Expired - Lifetime
- 2000-08-17 SK SK268-2002A patent/SK2682002A3/sk unknown
- 2000-08-17 PL PL00353367A patent/PL353367A1/xx not_active Application Discontinuation
- 2000-08-17 CN CN00811269A patent/CN1372541A/zh active Pending
- 2000-08-17 MX MXPA02001696A patent/MXPA02001696A/es unknown
- 2000-08-17 EE EEP200200095A patent/EE200200095A/xx unknown
- 2000-08-17 PT PT00953172T patent/PT1218341E/pt unknown
- 2000-08-17 IL IL14814800A patent/IL148148A0/xx unknown
- 2000-08-17 JP JP2001519664A patent/JP4792186B2/ja not_active Expired - Fee Related
- 2000-08-17 KR KR1020027002650A patent/KR20020033778A/ko not_active Application Discontinuation
- 2000-08-17 RU RU2002107998/04A patent/RU2002107998A/ru not_active Application Discontinuation
- 2000-08-17 HU HU0202472A patent/HUP0202472A3/hu unknown
- 2000-08-17 CA CA002383781A patent/CA2383781A1/en not_active Abandoned
- 2000-08-17 DK DK00953172T patent/DK1218341T3/da active
- 2000-08-17 WO PCT/EP2000/008027 patent/WO2001016094A1/de active IP Right Grant
- 2000-08-17 AU AU65712/00A patent/AU774071B2/en not_active Ceased
- 2000-08-25 CO CO00063853A patent/CO5190698A1/es not_active Application Discontinuation
- 2000-08-29 MY MYPI20003962 patent/MY133732A/en unknown
- 2000-08-30 AR ARP000104517A patent/AR025444A1/es unknown
- 2000-09-01 US US09/654,841 patent/US6342512B1/en not_active Expired - Lifetime
-
2001
- 2001-09-27 US US09/963,380 patent/US6552048B2/en not_active Expired - Lifetime
-
2002
- 2002-02-19 NO NO20020811A patent/NO20020811L/no not_active Application Discontinuation
- 2002-02-27 HR HR20020177A patent/HRP20020177A2/hr not_active Application Discontinuation
-
2003
- 2003-02-18 HK HK03101152.9A patent/HK1048984A1/zh unknown
Also Published As
| Publication number | Publication date |
|---|---|
| RU2002107998A (ru) | 2003-11-10 |
| DE50011035D1 (de) | 2005-09-29 |
| CZ2002767A3 (cs) | 2002-06-12 |
| MY133732A (en) | 2007-11-30 |
| ATE302754T1 (de) | 2005-09-15 |
| MXPA02001696A (es) | 2002-08-06 |
| AR025444A1 (es) | 2002-11-27 |
| PT1218341E (pt) | 2005-11-30 |
| WO2001016094A1 (de) | 2001-03-08 |
| US6552048B2 (en) | 2003-04-22 |
| SK2682002A3 (en) | 2002-07-02 |
| AU774071B2 (en) | 2004-06-17 |
| US20020072520A1 (en) | 2002-06-13 |
| AU6571200A (en) | 2001-03-26 |
| CN1372541A (zh) | 2002-10-02 |
| HUP0202472A2 (hu) | 2002-12-28 |
| NO20020811L (no) | 2002-04-30 |
| JP4792186B2 (ja) | 2011-10-12 |
| IL148148A0 (en) | 2002-09-12 |
| NO20020811D0 (no) | 2002-02-19 |
| JP2003508380A (ja) | 2003-03-04 |
| KR20020033778A (ko) | 2002-05-07 |
| CO5190698A1 (es) | 2002-08-29 |
| HK1048984A1 (zh) | 2003-04-25 |
| EE200200095A (et) | 2003-04-15 |
| HUP0202472A3 (en) | 2005-03-29 |
| US6342512B1 (en) | 2002-01-29 |
| EP1218341A1 (de) | 2002-07-03 |
| CA2383781A1 (en) | 2001-03-08 |
| BR0013727A (pt) | 2002-05-07 |
| PL353367A1 (en) | 2003-11-17 |
| ES2246247T3 (es) | 2006-02-16 |
| EP1218341B1 (de) | 2005-08-24 |
| DK1218341T3 (da) | 2005-12-12 |
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