HRP960187A2 - USE OF 'alpha'1L ANTAGONISTS IN THE TREATMENT OF INCONTINENCE - Google Patents
USE OF 'alpha'1L ANTAGONISTS IN THE TREATMENT OF INCONTINENCE Download PDFInfo
- Publication number
- HRP960187A2 HRP960187A2 HR19514579.8A HRP960187A HRP960187A2 HR P960187 A2 HRP960187 A2 HR P960187A2 HR P960187 A HRP960187 A HR P960187A HR P960187 A2 HRP960187 A2 HR P960187A2
- Authority
- HR
- Croatia
- Prior art keywords
- hydrogen
- alkyl
- methyl
- imidazolidine
- halogen
- Prior art date
Links
- 206010021639 Incontinence Diseases 0.000 title 1
- 239000005557 antagonist Substances 0.000 title 1
- 239000001257 hydrogen Substances 0.000 claims description 85
- 229910052739 hydrogen Inorganic materials 0.000 claims description 85
- 150000002431 hydrogen Chemical class 0.000 claims description 71
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 69
- 150000001875 compounds Chemical class 0.000 claims description 32
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 31
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 29
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 29
- 229910052794 bromium Inorganic materials 0.000 claims description 29
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 28
- 239000000460 chlorine Substances 0.000 claims description 28
- 229910052801 chlorine Inorganic materials 0.000 claims description 28
- 229910052736 halogen Inorganic materials 0.000 claims description 27
- 150000002367 halogens Chemical class 0.000 claims description 27
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 24
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 16
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 15
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 15
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 15
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 13
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 12
- 239000011737 fluorine Substances 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 125000000204 (C2-C4) acyl group Chemical group 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 206010066218 Stress Urinary Incontinence Diseases 0.000 claims description 10
- 208000022170 stress incontinence Diseases 0.000 claims description 10
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 9
- -1 1,3-thiazolyl Chemical group 0.000 claims description 8
- YJWCIKMTOSENCW-UHFFFAOYSA-N 1-n-(4,5-dihydro-1h-imidazol-2-yl)-3-n,3-n,2-trimethylbenzene-1,3-diamine Chemical compound CN(C)C1=CC=CC(N=C2NCCN2)=C1C YJWCIKMTOSENCW-UHFFFAOYSA-N 0.000 claims description 8
- YATKIBKWDXFJQD-UHFFFAOYSA-N 4-bromo-3-n-(4,5-dihydro-1h-imidazol-2-yl)-1-n,1-n,2-trimethylbenzene-1,3-diamine Chemical compound CN(C)C1=CC=C(Br)C(N=C2NCCN2)=C1C YATKIBKWDXFJQD-UHFFFAOYSA-N 0.000 claims description 8
- 206010046543 Urinary incontinence Diseases 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- JCOPITWIWLFFPC-UHFFFAOYSA-N n-phenyl-4,5-dihydro-1h-imidazol-2-amine Chemical class N1CCN=C1NC1=CC=CC=C1 JCOPITWIWLFFPC-UHFFFAOYSA-N 0.000 claims description 7
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 6
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000011593 sulfur Substances 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 claims description 6
- TUJQUSVKLISURX-UHFFFAOYSA-N 3-n-(4,5-dihydro-1h-imidazol-2-yl)-2-methylbenzene-1,3-diamine Chemical compound CC1=C(N)C=CC=C1N=C1NCCN1 TUJQUSVKLISURX-UHFFFAOYSA-N 0.000 claims description 5
- ZBTNRNNXVHIZSX-UHFFFAOYSA-N 4-chloro-3-n-(4,5-dihydro-1h-imidazol-2-yl)-6-methylbenzene-1,3-diamine Chemical compound C1=C(N)C(C)=CC(Cl)=C1N=C1NCCN1 ZBTNRNNXVHIZSX-UHFFFAOYSA-N 0.000 claims description 5
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 claims description 5
- 239000000556 agonist Substances 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- DESQSCXTLOLOOG-UHFFFAOYSA-N n-[2-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-1h-imidazol-2-amine;nitric acid Chemical compound O[N+]([O-])=O.FC(F)(F)C1=CC=C(Cl)C(NC=2NCCN=2)=C1 DESQSCXTLOLOOG-UHFFFAOYSA-N 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 claims description 2
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000002636 imidazolinyl group Chemical group 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 2
- UCFFGYASXIPWPD-UHFFFAOYSA-N methyl hypochlorite Chemical compound COCl UCFFGYASXIPWPD-UHFFFAOYSA-N 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 claims description 2
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 2
- 125000004525 thiadiazinyl group Chemical group S1NN=C(C=C1)* 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- SACAEVOKRBNXPN-UHFFFAOYSA-N n-phenyl-4,5-dihydroimidazol-1-amine Chemical class C1=NCCN1NC1=CC=CC=C1 SACAEVOKRBNXPN-UHFFFAOYSA-N 0.000 claims 6
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims 2
- 125000001246 bromo group Chemical group Br* 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 239000013543 active substance Substances 0.000 description 11
- 238000002844 melting Methods 0.000 description 11
- 230000008018 melting Effects 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000036772 blood pressure Effects 0.000 description 5
- 239000008298 dragée Substances 0.000 description 5
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 5
- 229960001802 phenylephrine Drugs 0.000 description 5
- 210000000626 ureter Anatomy 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
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- 235000012222 talc Nutrition 0.000 description 3
- HFCFJYRLBAANKN-UHFFFAOYSA-N 2-methyl-3-nitroaniline Chemical compound CC1=C(N)C=CC=C1[N+]([O-])=O HFCFJYRLBAANKN-UHFFFAOYSA-N 0.000 description 2
- QYPPUFQYPQBDPR-UHFFFAOYSA-N 3-n,3-n,2-trimethylbenzene-1,3-diamine Chemical compound CN(C)C1=CC=CC(N)=C1C QYPPUFQYPQBDPR-UHFFFAOYSA-N 0.000 description 2
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 2
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- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- KPUSVKGMJNXHTC-UHFFFAOYSA-N n,n,2-trimethyl-3-nitroaniline Chemical compound CN(C)C1=CC=CC([N+]([O-])=O)=C1C KPUSVKGMJNXHTC-UHFFFAOYSA-N 0.000 description 2
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- 230000000144 pharmacologic effect Effects 0.000 description 2
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- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
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- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 206010041232 sneezing Diseases 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- CVWILQHZFWRYPB-UHFFFAOYSA-N tiamenidine Chemical compound CC1=CSC(Cl)=C1NC1=NCCN1 CVWILQHZFWRYPB-UHFFFAOYSA-N 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- XFYDIVBRZNQMJC-UHFFFAOYSA-N tizanidine Chemical compound ClC=1C=CC2=NSN=C2C=1NC1=NCCN1 XFYDIVBRZNQMJC-UHFFFAOYSA-N 0.000 description 1
- 229960000488 tizanidine Drugs 0.000 description 1
- KWBTZIFLQYYPTH-UHFFFAOYSA-N tolonidine Chemical compound ClC1=CC(C)=CC=C1NC1=NCCN1 KWBTZIFLQYYPTH-UHFFFAOYSA-N 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/44—Nitrogen atoms not forming part of a nitro radical
- C07D233/50—Nitrogen atoms not forming part of a nitro radical with carbocyclic radicals directly attached to said nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Description
Predloženi izum odnosi se na upotrebu α1L-agonista za proizvodnju lijekova za liječenje inkontinencije mokraće, naročito stresne inkontinencije.
Uzrok stresne inkontinencije kod žena najčešće je slabost donjeg dijela zdjelice, npr. nakon više teških poroda. Međutim, do nje može doći također i zbog unutarnjih poremećaja živčevlja donjeg dijela zdjelice, urođenog kratkog mokraćovoda ili rjeđe zbog operativnih ozljeda prstenastog mišića. Opadanje razine estrogena u postmenopauzi potiče stresnu inkontinenciju.
Kao stresna inkontinencija često se označava iznenadno ispuštanje mokraće uzrokovano inkompetencijom pražnjenja mjehura kod nenapadne motorike mjehura tijekom pojave interabdominalbog porasta tlaka zbog kašlja, pritiska, kihanja, teškog podizanja itd.
Na iznenađujući način pokazalo se je da α1L-podtip adrenergnih receptora signifikantno utječe na mehanizam kontinencije naprezanja mokraćovoda.
Izum se odnosi na upotrebu α1L-agonista adrenoreceptora za liječenje inkontinencije mokraće, naročito stresne inkontinencije, odnosno za proizvodnju lijekova za liječenje mokraćne inkontinencije, naročito stresne inkontinencije. Posebno je zanimljiva upotreba aminoimidazolina opće formule
[image]
te njihovih farmakološki podnošljivih kiselinskih adicijskih soli.
U općoj formuli I
Y predstavlja po potrebi supstituirani fenilni ili naftilni ostatak, ili
Y je peteročlani ili šesteročlani po potrebi maksimalno nezasićen i po potrebi supstituiran heterociklički prsten, koji kao heteroatome sadrži kisik, sumpor ili dušik,
X je -NH-, -CH2-, -OCH2-, -O-CHCH3-, -CH=N-NH-, -N=N-ili -NZ-, sa
Z je -CH2-CH=CH2 ili ciklopropilmetil.
Prednost imaju spojevi u kojima X je -NH- i/ili Y je po potrebi supstituirani tienil, furil, pirol, tetrahidro-pirolil, piridil, pirazinil, piranil, 1,3-tiazolil, imidazolil, imidazolinil, 1,2,4-triazolil, 1,2,3-triazolil, tetrazolil, izotiazolil, pirimidinil, tiazolil, tiadiazinil ili piperidinil, koji je na skupinu X vezan preko C-atoma. Prednost ima npr. upotreba tiamenidina.
Za tu upotrebu prednost imaju imidazolinoni opće formule Ib
[image]
odnosno imidazolidini opće formule II
[image]
u kojoj
R1, R2, R3, R4 i R5 su međusobno neovisno definirani kako slijedi:
vodik, C1-C6-alkil, ponajprije C1-C4-alkil, naročito metil, C3-C6-cikloalkil, ponajprije ciklopropil, C1-C6-alkoksi, ponajprije C1-C4-alkoksi, naročito metoksi, halogen, ponajprije klor ili brom, CF3, -OCF3 ili NR6R7 sa
R6 je vodik, C3-C6-cikloalkil, C1-C6-alkil, ponajprije C1-C4-alkil, naročito metil, ili C2-C4-acil, naročito acetil,
R7 je vodik, C3-C6-cikloalkil, ponajprije ciklopropil, C1-C6-alkil, ponajprije C1-C4-alkil, naročito metil, ili C2-C4-acil, naročito acetil; ili
R6 i R7 zajedno s dušikovim atomom tvore peteročlani ili šesteročlani zasićen ili nezasićen prsten, koji može sadržavati do dva daljnja heteroatoma iz skupine kisik, sumpor ili dušik, pri čemu svaki daljnji dušikov atom može biti supstituiran s C1-C4-alkilom, ponajprije s metilom; ili
R6 i R7 zajedno s dušikovim atomom tvore ftalimido; ili
R1 i R2 zajedno tvore dokondenzirani pirazol formule
[image]
R8 je C1-C3-alkil, ponajprije metil;
ili dokondenzirani tiadiazol formule
[image]
pri čemu su R3, R4 i R5 kao prethodno definirani, a ponajprije predstavljaju vodik, te njihove farmakološki prihvatljive kiselinske adicijske soli.
Formule I i I’ , odnosno Ib i II predstavljaju jednako vrijedne tautomerne strukture. Prikaz jedne od struktura (npr. Ib) uključuje uvijek i drugu strukturu (npr. II).
Prednost imaju nadalje imidazolini opće formule Ib
[image]
u kojoj
R1 je vodik, etil, metil, fluor, klor, brom ili CF3,
R2 je metil, fluor, klor, brom ili -NH6R7, gdje
R6 je vodik, C1-C4-alkil, ponajprije metil, C2-C4-acil, ponajprije acetil i
R7 je vodik, C1-C4-alkil, ponajprije metil, C2-C4-acil, ponajprije acetil i ili
R6 i R7 zajedno s dušikovim atomom tvore ftalimido;
R3 je vodik, fluor, klor, brom, C1-C4-alkil, ponajprije metil, NH2 ili ciklopropil;
R4 je vodik, C1-C4-alkil, ponajprije metil, fluor, klor, brom ili CF3;
R5 je vodik, C1-C4-alkil, ponajprije etil ili metil, fluor, klor, brom ili CF3; ili
R1 i R2 zajedno tvore dokondenzirani pirazol formule
[image]
u kojoj R je metil,
ili dokondenzirani tiadiazol formule
[image]
gdje R3, R4 i R5 su kao prethodno definirani, a ponajprije predstavljaju vodik; naročito oni u kojima
R1 je vodik ili metil;
R2 je metil, klor, CF3, NH2 ili N(CH3)2;
R3 je vodik, metil, klor ili brom;
R4 je vodik;
R5 je vodik, metil, metoksi, klor ili brom.
Naročito se ističe upotreba
2-(3-dimetilamino-2-metilfenilimino)imidazolidina,
2-(6-brom-3-dimetilamino-2-metilfenilimino)imidazolidina,
2-(5-amino-2-klor-4-metilfenilimino)imidazolidina,
2-(3-amino-2-metilfenilimino) imidazolidina, ili
2-(2-klor-5-trifluormetilfenilimino)imidazolidina.
Kao heterociklički primjeri za ostatak NR6 R7 navode se:
pirol, Δ2-pirolin, Δ3-pirolin, tetrahidropirol, pirolidin, pirolidinon, imidazol, imidazolin, 1,3-tiazol, piperidin, piperazin, 4-C1 do C4-alkilpiperazin, C1 do C4-alkilpiperazin, 2,5-diketopiperazin, ponajprije N-metil-piperazin, morfolin, tiomorfolin, ftalimido, sukcinimido.
Kao alkil, u smislu predložene definicije, podrazumijevaju se - također i kao sastojci drugih ostataka - razgranate ili nerazgranate alkilne skupine s 1 do 6 ugljikovih atoma, a navode se primjerice: metil, etil, n-propii, izo-propil, n-butil, izo-butil, sek.butil i terc.butil, n-pentil, izo-pentil, neo-pentil, heksil, izo-heksil.
Cikloheksil općenito predstavlja zasićen ciklički ugljikovodični ostatak s 3 do 6 ugljikovih atoma, koji po potrebi može biti supstituiran s jednim ili više halogenih atoma ili s jednom hidroksilnom skupinom, alkilnom skupinom, ponajprije s metilom, koji mogu biti jednaki ili različiti. Kao primjeri navode se ciklopropil, ciklobutil, ciklopentil, ciklopentenil, cikloheksil, cikloheksenil.
Jedan dio u općoj formuli Ib definiranog imidazolina je nov. Izum se stoga odnosi na nove supstituirane 2-fenil-imino-imidazolidine, njihovu upotrebu kao lijeka, te postupke za njihovu proizvodnju.
2- (fenilimino) -imidazolidini, njihova proizvodnja i njihova upotreba kao lijeka su poznati, npr. iz DE-OS 19 29 950 i 23 16 377, pri čemu su kod tamo opisanih spojeva u prvom planu svojstva sniženja krvnog tlaka.
Novi supstituirani 2-(fenilimino)-imidazolidini opće formule II
[image]
pokazuju iznenađujuća farmakološka svojstva i posebno su prikladni za liječenje inkontinencije mokraće.
Predmet izuma su time spojevi opće formule II
[image]
u kojoj
R1 je vodik, C1-C6-alkil, ponajprije C1-C4-alkil, naročito metil, C3-C6-cikloalkil, ponajprije ciklopropil, C1-C6-alkoksi, ponajprije C1-C4-alkoksi, naročito metoksi, halogen, ponajprije klor ili brom, CF3 ili -OCF3;
R2 je NR6R7 sa
R6 je vodik, C3-C6-cikloalkil, C1-C6-alkil, ponajprije C1-C4-alkil, naročito metil, C2-C4-acil, naročito acetil;
R7 je vodik, ciklopropil, C3-C6-cikloalkil, C1-C6-alkil, ponajprije C1-C4-alkil, naročito metil, ili C2-C4-acil, naročito acetil; ili
R6 i R7 zajedno s dušikovim atomom tvore peteročlani ili šesteročlani zasićen ili nezasićen prsten, koji može sadržavati do dva daljnja heteroatoma iz skupine kisik, sumpor ili dušik, pri čemu svaki daljnji dušikov atom može biti supstituiran s C1-C4-alkilom, ponajprije s metilom; ili R6 i R7 zajedno s dušikovim atomom tvore ftalimido;
R3 je vodik, halogen, C1-C6-alkil, ponajprije C1-C4-alkil, naročito metil, C1-C6-alkoksi, ponajprije C1-C4-alkoksi, naročito metoksi, CF3 ili -OCF3;
R4 je vodik, C1-C6-alkil, ponajprije C1-C4-alkil, naročito metil, vodik ili halogen;
R5 je vodik, C1-C6-alkil, ponajprije C1-C4-alkil, naročito metil, C1-C6-alkoksi, ponajprije C1-C4-alkoksi, naročito metoksi, halogen, CF3 ili -OCF3;
te njihove farmakološki podnošljive kiselinske adicijske soli, izuzev 2- (3-dietilaniino-2-metil) imidazolidina.
Prednost se daje spojevima opće formule II u kojima
R1 je vodik, C1-C4-alkil, ciklopropil, C1-C4-alkoksi, halogen, CF3 ili -OCF3;
R2 je NR6R7 sa
R6 je vodik, C3-C6-cikloalkil, C1-C4-alkil ili acetil,
R7 je vodik, ciklopropil, C1-C4-alkil ili acetil; ili
R6 i R7 zajedno s dušikovim atomom tvore ftalimido;
R3 je vodik, halogen, C1-C4-alkil, C1-C4-alkoksi, CF3 ili -OCF3;
R4 3e vodik, C1-C6-alkil, metil, halogen;
R5 je vodik, C1-C4-alkil, C1-C4-alkoksi, halogen, CF3 .ili -OCF3; naročito oni u kojima
R1 je vodik, C1-C3-alkil, n-butil, izo-butil, sek.-butil, ponajprije metil, ciklopropil, C1-C3-alkoksi, ponajprije metoksi, halogen, ponajprije klor ili brom, CF3;
R2 je NR6R7 sa
R6 je vodik, ciklopropil, C1-C4-alkil, ponajprije metil,
R7 je vodik, C1-C4-alkilr ponajprije metil, ili
R6 i R7 zajedno s dušikovim atomom tvore ftalimido;
R3 je vodik, C1-C3-alkil, n-butil, izo-butil, sek.-butil, ponajprije metil, ciklopropil, C1-C3-alkoksi, ponajprije metoksi, halogen, ponajprije klor ili brom, CF3;
R4 je vodik, C1-C3-alkil, n-butil, izo-butil, sek. -butil, ponajprije metil, ciklopropil, C1-C3-alkoksi, ponajprije metoksi, halogen, ponajprije klor ili brom;
R5 je vodik, C1-C3-alkil, n-butil, izo-butil, sek.-butil, ponajprije metil, ciklopropil, C1-C3-alkoksi, ponajprije metoksi, halogen, ponajprije klor ili brom, CF3; naročito oni u kojima
R1 je vodik ili metil,
R2 je NR6R7 sa
R6 i R7 međusobno neovisno su vodik, metil ili metoksi
ili
R6 i R7 zajedno s dušikovim atomom tvore ftalimido;
R3 je vodik, metil, fluor, klor ili brom;
R je vodik;
R5 je vodik, metil, klor ili brom;
te njihove farmakološki podnošljive kiselinske adicijske soli, naročito hidrobromidi ili hidrokloridi.
Naročito se ističu spojevi
2-(3-dimetilamino-2-metilfenilimino)imidazolidin,
2-(6-brom-3-dimetilamino-2-metilfenilimino) imidazolidin,
2-(5-amino-2-klor-4-metilfenilimino)imidazolidin i
2-(3-amino-2-metilfenilimino)imidazolidin.
Spojevi općih formula I i II mogu se proizvesti po poznatim postupcima analognim stanju tehnike. Izbor prednosnih postupaka prikazan je u slijedećoj shemi sinteze pomoću konkretnog primjera.
[image]
Postupci s prednošću objasnit će se pomoću pojedinačnih primjera proizvodnje spojeva prema izumu.
[image]
Metiliranje polaznog materijala, 2-metil-3-nitro-anilina može se provesti također analogno Leuckart-Walachovoj reakciji uz upotrebu HCOOH/CH2O ili upotrebom dimetilkarbonata umjesto dimetilsulfata.
Spoj 2 može se proizvesti bromiranjem spoja 1 pod uobičajenim reakcijskim uvjetima:
[image]
Slijedeća shema sinteze objašnjava proizvodnju spojeva 2, 3 i 4:
[image]
Daljnje varijante sinteze prikazane su u nastavku.
[image]
Analogno metodi koju je opisao N. R. Ayyangar (Synthesis 1984, 64) može se proizvesti spoj 5 i strukturno slični spojevi.
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Primjer 1
2-(3-dimetilamino-2-metilfenilimino)imidazolidin,
1. stupanj:
83,6 g 2-metil-3-nitroanilina/ 190 g K2CO3 i 260 ml vode zagrije se zajedno na 100°C. Tijekom 1 sata dokaplje se 27 ml dimetilsulfata, zatim se grije još jedan sat. Kad se ohladi na sobnu temperaturu gornji sloj se odvoji, a preostalu vodenu fazu ekstrahira se četiri puta s eterom.
Organski ekstrakti sjedine se s gornjim slojem, osuše s MgSO4 i zgusnu u vakuumu. Dobije se 73 g N,N-dimetil-2-metil-3-nitroanilina.
2. stupanj:
73 g N, N-dimetil-2-metil-3-nitroanilina otopi se u 800 ml metanola i pri 20°C i 5 bara vodika hidrira se uz upotrebu Ranev-nikla kao katalizatora. Dobije se 57 g 3-di-metilamino-2-metilanilina.
3. stupanj:
57 g 3-dimetilamino-2-metilanilina, 1,15 l acetona, 36, 6 g KSCN i 43, 8 ml benzoilklorida grije se zajedno 3 sata pod refluksom. Kad se ohladi na sobnu temperaturu reakcijsku smjesu istrese se na 2,4 kg razbijenog leda. Dobiveni talog grije se zajedno sa 85 g KOH, 85 ml vode i 255 ml etanola tijekom 2 sata pri 60°C. Nakon dodatka 850 ml vode etanol se odstrani destilacijom pod smanjenim tlakom. Nakon obrade dobivenog taloga dobije se 72 g N-(3-dimetilamino-2 -metilfenil)-tiouree.
4. stupanj:
72 g tiouree iz 3. stupnja preuzme se u 345 ml metanola i nakon dodatka 22,6 ml metiljodida grije se 2 sata pod refluksom. Dobivenu otopinu zgusne se pod smanjenim tlakom; dobije se 120 g hidrojodida N- (3-dimetilamino-2 -metil)fenil)-S-izotiouree .
5. stupanj:
120 g tiouree iz 4. stupnja grije se u 350 ml metanola s 34,4 ml 1,2-diaminoetana 17 sati pod refluksom. Reakcijsku smjesu zgusne se u vakuumu i ostatak se preuzme u vodu. S razrijeđenom solnom kiselinom namjesti se pH 7. Vodenu fazu ekstrahira se 3 puta s etilacetatom. Na kraju se vodenu fazu s 5N NaOH namjesti alkalnom i još 3 puta esktrahira s etilacetatorn, ti ekstrakti se sjedine, osuše s MgSO4 i zgusnu u vakuumu. Dobije se ulje, koje se kromatografira preko silika gela (protočno sredstvo toluol, dioksan, etanol, amonijak 10:80:3:1 = "super-T").
Dobije se 17,9 g 2-(3-dimetilamino-2-metilfenil-imino)-imidazolidina. Talište 116-118°C.
Primjer 2
2- (6-brom-3-dimetilamino-2-metilfenilimino) imidazolidin
6,55 g 2-(3-dimetilamino-2-metilfenilimino)-imidazolidina otopi se u 75 ml kloroforma i uz miješanje pri 0°C pomiješa se s 1,53 ml broma. Nakon 2 sata pri 0°C otopinu se zgusne pod smanjenim tlakom i tako dobiven ostatak pomiješa se s razrijeđenom solnom kiselinom. Vodenu otopinu ekstrahira se dva puta s eterom - na kraju se vodenu fazu namjesti alkalnom s razrijeđenim NaOH i još tri puta ekstrahira s eterom. Sjedinjeni organski ekstrakti zgusnu se pod smanjenim tlakom, a ostatak se obradi kromatografijom (silika gel, protočno sredstvo "super-T" (primjer 1)).
Dobije se 3,4 g 2- (6-brom-3-dimetilamino-2-metilfenil-imino)imidazolidina kao bijeli prah. Talište 157-158°C.
Analogno opisanim postupcima proizvedeni su slijedeći spojevi:
2-(4-brom-3-dimetilamino-2-metilfenilimino)-imidazolidin;
2-(4,6-dibrom-3-dimetilamino-2-metilfenilimino)-imidazolidin;
2-(6-klor-3-dimetilamino-2-metilfenilimino)-imidazolidin;
2-(3-acetilamino-6-klorfenilimino)-imidazolidin, talište 236-238°C;
2-(2-metil-3-ftalimidofenilimino)-imidazolidin, talište 189-190°C;
2-(6-klor-3-ftalimidofenilimino)-imidazolidin, talište 239-241°C;
2-(5-amino-2-klor-4-metilfenilimino) -imidazolidin, talište 155-157°C;
2-(3-amino-4-fluorfenilimino)-imidazolidin, (2HCl), talište 222°C;
2-(3-amino-4-metilfenilimino)-imidazolidin, (HCl), talište 204-206°C;
2-(3-amino-6-metilfenilimino)-imidazolidin, (HCl), talište 194-196°C;
2-(3-amino-6-klorfenilimino) -imidazolidin, (HCl), talište 197-198°C;
2-(3-amino-4,6-dibrom-2-metilfenilimino)-imidazolidin, talište 154-155°C;
2-(3-amino-2-metilfenilimino)-imidazolidin.
Pojedinačno se poimence navode slijedeći spojevi:
2-(2,4-dietilfenilimino)-imidazolidin;
2-(2-klor-6-metilfenilimino) -imidazolidin;
2-(2,6-diklor-fenilimino)-imidazolidin;
2-(2-klor-4-metilfenilimino)-imidazolidin;
2-(2,4-diklorfenilimino)-imidazolidin;
2-(2-klor-5-trifluormetilfenilimino)-imidazolidin;
2-(5-fluor-2-metilfenilimino)-imidazolidin;
2-(3-brom-2-metilfenilimino)-imidazolidin;
2-(2-klor-3-metilfenilimino)-imidazolidin;
2-(2-fluor-6-trifluormetilfenilimino)-imidazolidin;
2-(2-klor-4-ciklopropilfenilimino)-imidazolidin;
2-(4-amino-3,5-dibromfenilimino)-imidazolidin;
2-(3-fluor-4-metilfenilimino)-imidazolidin;
2-(6-brom-2-fluorfenilimino)-imidazolidin;
4-(2-imidazolin-2-il-amino)-2-metilindazol;
5-klor-4-imidazolin 2-il-amino) -benzotiazol (tizanidin);
2-[(2-klor-4-metil-3-tienil) amino]-2-imidazolin (tiamenidin);
2-(2,5-diklorfenilimino)-imidazolidin.
Spojevi prema izumu općih formula I i II mogu se na uobičajen način prevesti u svoje fiziološki podnošljive kiselinske adicijske soli. Za tvorbu soli prikladne kiseline su primjerice mineralne kiseline, kao solna kiselina, bromovodična kiselina, jodovodična kiselina, fluorovodična kiselina, sumporna kiselina, fosforna kiselina, dušična kiselina ili organske kiseline kao octena kiselina, propionska kiselina, maslačna kiselina, kapronska kiselina, kaprinska kiselina, valerijanska kiselina, oksalna kiselina, malonska kiselina, jantarna kiselina, maleinska kiselina, fumarna kiselina, mliječna kiselina, vinska kiselina, limunska kiselina, jabučna kiselina, benzojeva kiselina, p-hidroksibenzojeva kiselina, p-amino-benzojeva kiselina, ftalna kiselina, cimetna kiselina, salicilna kiselina, askorbinska kiselina, metansulfonska kiselina, etanfosfonska kiselina.
Kao kiselinske adicijske soli prednost imaju odgovarajući hidrobromidi i hidrokloridi.
Farmaceutski pripremci koji sadrže opisane spojeve, mogu se koristiti u obliku kapsula, čepića, otopina, sokova, emulzija ili disperznog praha. Odgovarajuće tablete mogu se dobiti primjerice miješanjem jedne ili više aktivnih tvari s poznatim pomoćnim tvarima, primjerice inertnim sredstvima za razrjeđenje kao što su kalcijev karbonat, kalcijev fosfat ili mliječni šećer, rasprsna sredstva kao kukuruzni škrob ili alginska kiselina, vezna sredstva kao škrob ili želatina, klizna sredstva kao magnezijev stearat ili talk, i/ili sredstva za postizanje efekta ulaganja, kao karboksipolimetilen, karboksimetil-celuloza, celulozna acetatftalat, ili polivinilacetat. Tablete se također mogu sastojati od više slojeva.
Dražeje se mogu proizvesti na odgovarajući način provlačenjem jezgri proizvedenih analogno tabletama s uobičajenim sredstvima koja se upotrebljavaju za prevlake dražeja, primjerice kolidon ili šelak, guma arabika, talk, titanov dioksid ili šećer.
Za postizanje efekta ulaganja, ili za sprečavanje inkompatibilnosti, jezgra se također može sastojati od više slojeva. Isti sastav mogu imati također i čahure dražeja za postizanje efekta ulaganja od više slojeva, pri čemu se mogu upotrijebiti pomoćne tvari spomenute gore kod tableta.
Sokovi aktivnih tvari prema izumu, odnosno kombinacije aktivnih tvari mogu dodatno sadržavati još sladilo kao saharin, ciklamat, glicerin ili šećer, te sredstva za poboljšanje okusa, npr. mirise kao valinin, ili ekstrakt naranče. Osim toga mogu sadržavati pomoćne tvari za suspendiranje ili zgušnjavanje, kao natrijevu karboksi-metilcelulozu, kvasilo, primjerice kondenzacijske proizvode masnih alkohola s etilenoksidom, ili konzervanse, kao p-hidroksibenzoat.
Injekcijske otopine proizvode se na uobičajen način, npr. uz dodatak konzervansa, kao p-hidroksibenzoata, ili stabilizatora, kao alkalnih soli etilendiamintetraoctene kiseline i pune se u injekcijske bočice ili ampule.
Kapsule koje sadrže aktivnu tvar, odnosno kombinaciju aktivnih tvari, mogu se proizvesti primjerice tako da se aktivnu tvar pomiješa s inertnim nosiocem, kao što su mliječni šećer ili sorbit, i puni se u želatinske kapsule.
Prikladni čepići mogu se proizvesti primjerice miješanjem s predviđenim nosiocem, kao neutralnim mastima ili polietilenglikolom, odnosno njihovim derivatima.
Za transdermalnu aplikaciju aktivne tvari prema izumu mogu se ugraditi u odgovarajuće prikladne nosioce (flastere), primjerice od poliakrilata. Mogu se umiješati i prikladni dodaci za povišenje oslobađanja.
Kao terapeutska učinkovita pojedinačna doza kod oralnih aplikacija predlaže se doza od l do 50 mg.
Primjer A
Tablete
2-(3-dimetilamino-2-metilfenilimino)-
imidazolidin HBr 10 mg,
mliječni šećer 65 mg
kukuruzni škrob 125 mg
sek. kalcijev fosfat 40 mg
topivi škrob 3 mg
magnezijev stearat 4 mg
koloidna silicijeva kiselina 4 mg
ukupno 252 mg
Priprava:
Aktivna tvar se pomiješa s dijelom pomoćnih tvari, intenzivno prognječi s vodenom otopinom topivog škroba i na uobičajen način granulira pomoću sita. Granulat se pomiješa s ostatkom pomoćnih tvari i preša u jezgre dražeja težine 250 mg, koje se zatim na uobičajen način pomoću šećera, talka ili gurne arabike prevlače u dražeje.
Primjer 2
Ampule
2- (3-dimetilaraino-2-metilfenilirnino) -
imidazolidin HBr 1,0 mg
natrijev klorid 18,0 mg
dest. voda do 2,0 ml
Priprava:
Aktivnu tvar i natrijev klorid otopi se u vodi i puni u staklene ampule u atmosferi dušika.
Primjer C
Kapljice
2-(3-dimetilamino-2-metilfenilimino)-
imidazolidin HBr 0,02 g
metilester p-hidroksibenzojeve kiseline 0,07 g
propilester p-hidroksibenzojeve kiseline 0,03 g
demineralizirana voda do 100 ml
Primjer D
Injekcijska otopina
2-(3-dimetilamino-2-metilfenilimino)-imidazolidin HBr 1,5 dijelova
natrijeva sol etilendiaminotetraoctene
kiseline 0,2 dijela
dest. voda do 100,0 dijelova
Priprava:
Aktivnu tvar i natrijevu sol etilendiaminotetraoctene kiseline otope se u dovoljno vode i nadopune s vodom na željeni volumen. Otopinu se odfiltrira od suspendiranih čestica i pod sterilnim i aseptičkim uvjetima puni u ampule. Svaka ampula sadrži 20 mg aktivne tvari.
Prednost opisanih spojeva temelji se na tome da oni u prvom redu djeluju na mokraćovod i pokazuju neznatno ili nikakvo djelovanje na kardiovaskularni sistem.
Selektivno farmakološko djelovanje spojeva prema izumu pokazano je na primjeru 2, 2-(6-brom-3-dimetilamino-2- metilfenilimino)-imidazolidinu i usporedbenom spoju, fenilefrinu - mjerenjem intralurninalnog tlaka u mokraćovodu i krvnog tlaka kod kunića.
Ženke japanskog bijelog kunića (težine 3,0 do 3,5 kg) anestezirane su s uretanom (1 g/kg tjelesne težine). Pomoću malog zareza u mokraćni mjehur uvedena je polietilenska kanila. Preko mjehura određene su promjene intraluminalnog tlaka u mokraćovodu, koji je sadržavao pribl. 1,5 rnl vode pri 37°C. Tlak u mokraćovodu prikazan je na poligrafu pomoću pretvornika tlačnog naprezanja.
Za mjerenje krvnog tlaka kanulirana je Arteria carotis u otvorenom području grla, a za pravilno održavanje disanja istovremeno je intubirana traheja. Promjene tlaka pokazane su na poligrafu pomoću pretvornika tlačnog naprezanja. Srčana frekvencija mjerena je tahometrom.
Fenilefrin i spoj iz primjera 2 dati su i.v. kroz polietilensku kanilu u venu Vena femoralis. Uspoređeno je doziranje od 30 µg/kg fenilferina sa 10 µg/kg spoja iz primjera 2.
Usporedba s fenilenfrinom pokazuje spoj prema izumu iz primjera 2 glede kontrakcije mokraćovoda djeluje jace za faktor 2,73, a za faktor 4,3 ima dulje trajanje djelovanja. U usporedbi s tim povišenje krvnog tlaka kod spoja prema izumu je više samo 1,39 puta prema usporedbenom spoju fenilenfrinu. Treba spomenuti da se povišenje krvnog tlaka u usporedbi s fenilenfrinom produljuje tek beznačajno (faktor 1,17). Ti pokusi potvrđuju da spojevi prema izumu djeluju selektivno na mokraćovod. Kao selektivni agonisti α1L-adrenoreceptora spojevi prema izumu prikladni su za liječenje inkontinencije mokraće, posebno za liječenje stresne inkontinencije.
Rezultati pokusa prikazani su u tablici I.
[image]
Podaci su naveni u postocima.
Primjer 2 = 2-(6-brom-3-dimetilamino-2-metilfenil-imino)-imidazolidin.
Claims (20)
1. Upotreba α1L -agonista, naznačena time, da se koristi za proizvodnju lijekova za liječenje inkontinencije mokraće, posebno stresne inkontinencije.
2. Upotreba prema zahtjevu 1, naznačena time, da α1L -agonisti imaju opću formulu I
[image]
u kojoj
Y predstavlja po potrebi supstituirani fenilni ili naftilni ostatak, ili
Y je peteročlani ili šesteročlani po potrebi maksimalno nezasićen i po potrebi supstituiran heterociklicki prstem , koji kao heteroatome sadrži kisik, sumpor ili dušik; i
X je -NH-, -CH2-, -OCH2-, -O-CHCH3-, -CH=N-NH-, -N=N-ili -NZ-, sa
Z je -CH2-CH=CH2 ili ciklopropilmetil,
te njihove farmakološki podnošljive kiselinske adicijske soli.
3. Upotreba prema zahtjevu 2, naznačena time, da u spoju formule I X je -NH-.
4. Upotreba prema zahtjevu 2 ili 3, naznačena time, da u spoju formule I Y je po potrebi supstituirani tienil, furil, pirol, tetrahidropirolil, piridil, pirazinil, piranil, 1,3-tiazolil, imidazolil, imidazolinil, 1,2,4-triazolil, 1, 2, 3-triazolil, tetrazolil, izotiazolil, pirimidinil, tiazolil, tiadiazinil ili piperidinil, koji je na skupinu X vezan preko C-atoma.
5. Upotreba prema jednom od zahtjeva 2 do 4, naznačena time, da spoj formule I je tiamenidin.
6. Upotreba fenilaminoimidazolina opće formule Ib
[image]
naznačena time, da R1, R2, R3, R4 i R5 su, međusobno neovisno, definirani kako slijedi:
vodik, C1-C6-alkil, C3-C6-cikloalkil, C1-C6-alkoksi, halogen, CF3, -OCF3 ili NR6R7 sa
R6 je vodik, C3-C6-cikloalkil, C1-C6-alkil, ili C2-C4-acil,
R7 je vodik, C3-C6-cikloalkil, C1-C6-alkil, ili C2-C4-acil; ili
R6 i R7 zajedno s dušikovim atomom tvore peteročlani ili šesteročlani zasićen ili nezasićen prsten, koji može sadržavati do dva daljnja heteroatoma iz skupine kisik, sumpor ili dušik, pri čemu svaki daljnji dušikov atom može biti supstituiran s C1-C4-alkilom,
ili R6 i R7 zajedno s dušikovim atomom tvore ftalimido;
ili
R1 i R2 zajedno tvore dokondenzirani pirazol formule
[image]
u kojoj
R8 je C1-C3-alkil, ili dokondenzirani tiadiazol formule
[image]
pri čemu su R3 , R4 i R5 kao prethodno definirani, te njihove farmakološki podnošljive kiselinske adicijske soli za proizvodnju lijekova za liječenje inkontinencije mokraće, naročito stresne inkontinencije.
7. Upotreba fenilaminoimidazolina opće formule Ib prema zahtjevu 6, naznačena time, da R1 , R2 , R3 , R4 i R5 su, međusobno neovisno, definirani kako slijedi:
vodik, C1-C4-alkil, naročito metil, ciklopropil, C1-C4-alkoksi, ponajprije metoksi, halogen, CF3, -OCF3 ili NR6R7 sa
R6 je vodik, C3-C6-cikloalkil, C1-C4-alkil, ponajprije metil, ili acetil,
R7 je vodik, ciklopropil, C1-C4-alkil, ponajprije metil, ili acetil; ili
R6 i R7 zajedno s dušikovim atomom tvore ftalimido; ili
ili
R1 i R2 zajedno tvore dokondenzirani pirazol formule
[image]
u kojoj
R8 je metil, ili dokondenzirani tiadiazol formule
[image]
pri čemu su R3 , R4 i R5 kao prethodno definirani, a ponajprije predstavljaju vodik.
8. Upotreba fenilaminoimidazolina opće formule Ib prema zahtjevu 6, naznačena time, da R1 , R2 , R3 , R4 i R5 su, međusobno neovisno, definirani kako slijedi:
vodik, etil, metil, ciklopropil, fluor, klor, brom, CF3 ili NR6R7 sa
R6 je vodik, metil ili acetil,
R7 je vodik, metil ili acetil; ili
R6 i R7 zajedno s dušikovim atomom tvore ftalimido; ili
R1 i R2 zajedno tvore dokondenzirani pirazol formule
[image]
u kojoj
R8 je metil, ili dokondenzirani tiadiazol formule
[image]
gdje R3, R4 i R5 su kao prethodno definirani, a ponajprije predstavljaju vodik.
9. Upotreba fenilaminoimidazolina opće formule Ib prema zahtjevu 6, naznačena time, da
R1 je vodik, etil, metil, fluor, klor, brora ili CF3,
R2 je metil, fluor, brom ili NR6R7, gdje
R6 je vodik, C1-C4-alkil, ponajprije metil, C2-C4-acil, ponajprije acetil i
R7 je vodik, C1-C4-alkil, ponajprije metil, C2-C4-acil, ponajprije acetil, ili
R6 i R7 zajedno s dušikovim atomom tvore ftalimido;
R3 je vodik, fluor, klor, brom, C1-C4-alkil, ponajprije metil, NH2 ili ciklopropil;
R4 je vodik, C1-C4-alkil, ponajprije metil, fluor, klor, brom ili CF3;
R5 je vodik, C1-C4-alkil, ponajprije etil ili metil, fluor, klor, brom ili CF3;
ili
R1 i R2 zajedno tvore dokondenzirani pirazol formule
[image]
u kojoj
R8 je metil, ili dokondenzirani tiadiazol formule
[image]
pri čemu su R3 , R4 i R5 kao prethodno definirani, a ponajprije su vodik.
10. Upotreba fenilaminoimidazolina opće formule Ib prema zahtjevu 6, naznačena time, da
R1 ne vodik ili metil,
R2 je metil, klor, CF3, NH2 ili N(CH3)2;
R3 je vodik, metil, klor ili brom;
R4 je vodik;
R5 je vodik, metil, metoksi, klor ili brom.
11. Upotreba fenilaminoimidazolina opće formule Ib prema zahtjevu 6, naznačena time, da je spoj
2-(3-dimetilamino-2-metilfenilimino)imidazolidin,
2-(6-brom-3-dimetilamino-2-metilfenilimino) imidazolidin,
2-(5-amino-2-klor-4-metilfenilimino)-imidazolidin,
2-(3-amino-2-metilfenilimino) -imidazolidin, ili
2- (2-klor-5-trifluormetilfenilimino)-imidazolidin.
12. Novi feniliminoimidazolidini opće formule II
[image]
naznačeni time , da
R1 je vodik, C1-C6-alkil, C3-C6-cikloalkil, C1-C6-alkoksi, halogen, CF3 ili -OCF3;
R2 je NR6R7 sa
R6 je vodik, C3-C6-cikloalkil, C1-C6-alkil, C2-C4-acil,
R7 je vodik, C3-C6-cikloalkil, C1-C6-alkil, C2-C4-acil,
ili
R6 i R7 zajedno s dušikovim atomom tvore peteročlani ili šesteročlani zasićen ili nezasićen prsten, koji može sadržavati do dva daljnja heteroatoma iz skupine kisik, sumpor ili dušik, pri čemu svaki daljnji dušikov atom može biti supstituiran s C1-C4-alkilom, ponajprije s metilom; ili R6 i R7 zajedno s dušikovim atomom tvore ftalimido;
R3 je vodik, halogen, C1-C6-alkil, C1-C6-alkoksi, CF3 ili -OCF3;
R4 je vodik, C1-C6-alkil, ili halogen;
R5 je vodik, C1-C6-alkil, C1-C6-alkoksi, halogen, CF3 ili -OCF3,
te njihove farmakološki podnošljive kiselinske adicijske soli, izuzev 2-(3-dietilamino-2-metil)imidazolidina.
13. Feniliminoimidazolidini prema zahtjevu 12, naznačeni time, da
R1 je vodik, C1-C4-alkil, ciklopropil, C1-C4-alkoksi, halogen, CF3 ili -OCF3;
R2 je NR6R7 sa
R6 je vodik, C3-C6-cikloalkil, C1-C4-alkil ili acetil,
R7 je vodik, ciklopropil, C1-C4-alkil ili acetil,
ili
R6 i R7 zajedno s dušikovim atomom tvore ftalimido;
R3 je vodik, halogen, C1-C4-alkil, C1-C4-alkoksi, CF3 ili -OCF3;
R4 je vodik, C1-C4-alkil, metil, halogen;
R5 je vodik, C1-C4-alkil, C1-C4-alkoksi, halogen, CF3 ili -OCF3.
14. Feniliminoimidazolidini prema zahtjevu 12, naznačeni time, da
R1 je vodik, C1-C3-alkil, n-butil, izo-butil, sek. -butil, ponajprije metil, ciklopropil, C1-C3-alkoksi, ponajprije metoksi, halogen, ponajprije klor ili brom, CF3;
R2 je NR6R7 sa
R6 je vodik, ciklopropil, C1-C4j-alkil, ponajprije metil,
R7 je vodik, C1-C4-alkil, ponajprije metil, ili
R6 i R7 zajedno s dušikovim atomom tvore ftalimido;
R3 je vodik, C1-C3-alkil, n-butil, izo-butil, sek. -butil, ponajprije metil, ciklopropil, C1-C3-alkoksi, ponajprije metoksi, halogen, ponajprije klor ili brom, CF3;
R4 je vodik, C1-C3-alkil, n-butil, izo-butil, sek. -butil, ponajprije metil, ciklopropil, C1-C3-alkoksi/ ponajprije metoksi, halogen, ponajprije klor ili brom;
R5 je vodik, C1-C3-alkil, n-butil, izo-butil, sek.-butil, ponajprije metil, ciklopropil, C1-C3-alkoksi, ponajprije metoksi, halogen, ponajprije klor ili brom, CF3.
15. Feniliminoimidazolidini prema zahtjevu 12, naznačeni time, da
R1 je vodik ili metil,
R2 je NR6R7 sa
R6 i R7 međusobno neovisno su vodik, metil ili metoksi ili
R6 i R7 zajedno s dušikovim atomom tvore ftalimido;
R3 je vodik, metil, fluor, klor ili brom;
R4 je vodik;
R5 je vodik, metil, klor ili brom.
16. Feniliminoimidazolidin prema zahtjevu 12, naznačen time, da je
2-(3-dimetilamino-2-rnetilfenilimino) imidazolidin,
2-(6-brom-3-dimetilamino-2-metilfenilimino)imidazolidin,
2-(5-amino-2-klor-4-metilfenilimino)-imidazolidin ili
2-(3-amino-2-metilfenilimino)-imidazolidin.
17. Farmaceutski pripravak, naznačeni time, da sadrži spoj opće formule II prema jednom od zahtjeva 12 do 16, te uobičajene pomoćne i/ili noseće tvari.
18. Postupak za proizvodnju farmaceutskih pripremaka prema zahtjevu 17, naznačen time, da se spojevi opće formule II miješaju s uobičajenim galenskim pomoćnim i/ili nosećim tvarima.
19. Upotreba spojeva opće formule II kako su definirani u jednom od zahtjeva 12 do 16, naznačena time, da se koristi za proizvodnju lijekova za liječenje inkontinencije mokraće, posebno stresne inkontinencije.
20. Analogni postupci za proizvodnju spojeva opće formule II
[image]
prema jednom od zahtjeva 12 do 16, naznačeni time, da se anilin opće formule
[image]
u kojoj R1 do R5 su kao prethodno definirani, kemijski pretvara s jednim od slijedećih spojeva
[image]
i spoj dobiven jednim od postupaka a-c prevodi se po potrebi u svoju farmakološki podnošljivu kiselinsku adicijsku sol.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19514579A DE19514579A1 (de) | 1995-04-20 | 1995-04-20 | Verwendung von alpha¶1¶¶L¶-Agonisten zur Behandlung der Harninkontinenz |
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| Publication Number | Publication Date |
|---|---|
| HRP960187A2 true HRP960187A2 (en) | 1997-12-31 |
Family
ID=7759982
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HR19514579.8A HRP960187A2 (en) | 1995-04-20 | 1996-04-19 | USE OF 'alpha'1L ANTAGONISTS IN THE TREATMENT OF INCONTINENCE |
Country Status (31)
| Country | Link |
|---|---|
| US (4) | US6268389B1 (hr) |
| EP (2) | EP0821585B1 (hr) |
| JP (2) | JP3379960B2 (hr) |
| KR (1) | KR19990007985A (hr) |
| CN (1) | CN1119148C (hr) |
| AR (1) | AR002043A1 (hr) |
| AU (1) | AU719710B2 (hr) |
| BG (1) | BG64116B1 (hr) |
| BR (1) | BR9608049A (hr) |
| CA (1) | CA2214338C (hr) |
| CZ (1) | CZ327197A3 (hr) |
| DE (2) | DE19514579A1 (hr) |
| EE (1) | EE04416B1 (hr) |
| ES (1) | ES2279521T3 (hr) |
| HR (1) | HRP960187A2 (hr) |
| HU (1) | HUP9801599A3 (hr) |
| IL (1) | IL117956A (hr) |
| MX (1) | MX9707570A (hr) |
| NO (1) | NO974821L (hr) |
| NZ (1) | NZ307509A (hr) |
| PE (1) | PE44297A1 (hr) |
| PL (1) | PL184881B1 (hr) |
| RU (2) | RU2230061C2 (hr) |
| SK (1) | SK138097A3 (hr) |
| TR (1) | TR199701212T1 (hr) |
| TW (1) | TW403739B (hr) |
| UA (1) | UA62913C2 (hr) |
| UY (1) | UY24206A1 (hr) |
| WO (1) | WO1996032939A1 (hr) |
| YU (1) | YU24496A (hr) |
| ZA (1) | ZA963131B (hr) |
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| GB2466622A (en) * | 2008-12-23 | 2010-06-30 | Trinity College Dublin | Alpha2-Adrenoceptor Ligands |
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-
1995
- 1995-04-20 DE DE19514579A patent/DE19514579A1/de not_active Withdrawn
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1996
- 1996-04-13 RU RU97119064/15A patent/RU2230061C2/ru not_active IP Right Cessation
- 1996-04-13 EE EE9700267A patent/EE04416B1/xx not_active IP Right Cessation
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- 1996-04-13 DE DE59611411T patent/DE59611411D1/de not_active Expired - Lifetime
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- 1996-04-13 WO PCT/EP1996/001568 patent/WO1996032939A1/de active IP Right Grant
- 1996-04-13 BR BR9608049A patent/BR9608049A/pt not_active Application Discontinuation
- 1996-04-13 NZ NZ307509A patent/NZ307509A/xx unknown
- 1996-04-13 EP EP96914912A patent/EP0821585B1/de not_active Expired - Lifetime
- 1996-04-13 AU AU56878/96A patent/AU719710B2/en not_active Ceased
- 1996-04-13 HU HU9801599A patent/HUP9801599A3/hu unknown
- 1996-04-13 CZ CZ973271A patent/CZ327197A3/cs unknown
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- 1996-04-13 EP EP02025309A patent/EP1285653A1/de not_active Withdrawn
- 1996-04-13 JP JP53145596A patent/JP3379960B2/ja not_active Expired - Fee Related
- 1996-04-13 UA UA97115588A patent/UA62913C2/uk unknown
- 1996-04-13 KR KR1019970707509A patent/KR19990007985A/ko active IP Right Grant
- 1996-04-14 UY UY24206A patent/UY24206A1/es not_active IP Right Cessation
- 1996-04-18 TW TW085104648A patent/TW403739B/zh not_active IP Right Cessation
- 1996-04-18 IL IL11795696A patent/IL117956A/en not_active IP Right Cessation
- 1996-04-19 HR HR19514579.8A patent/HRP960187A2/hr not_active Application Discontinuation
- 1996-04-19 YU YU24496A patent/YU24496A/sh unknown
- 1996-04-19 PE PE1996000273A patent/PE44297A1/es not_active Application Discontinuation
- 1996-04-19 ZA ZA963131A patent/ZA963131B/xx unknown
- 1996-04-22 AR ARP960102266A patent/AR002043A1/es unknown
-
1997
- 1997-10-15 BG BG101966A patent/BG64116B1/bg unknown
- 1997-10-17 NO NO974821A patent/NO974821L/no not_active Application Discontinuation
-
1999
- 1999-01-11 US US09/227,944 patent/US6268389B1/en not_active Expired - Lifetime
-
2000
- 2000-03-28 US US09/536,728 patent/US20020040150A1/en not_active Abandoned
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2002
- 2002-08-14 JP JP2002236562A patent/JP4141763B2/ja not_active Expired - Fee Related
- 2002-11-15 US US10/295,460 patent/US6858594B2/en not_active Expired - Lifetime
-
2003
- 2003-02-07 RU RU2003104267/15A patent/RU2003104267A/ru not_active Application Discontinuation
-
2004
- 2004-04-19 US US10/827,408 patent/US7019021B2/en not_active Expired - Fee Related
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