KR20020005671A - Pharmaceutical compounds - Google Patents
Pharmaceutical compounds Download PDFInfo
- Publication number
- KR20020005671A KR20020005671A KR1020017012971A KR20017012971A KR20020005671A KR 20020005671 A KR20020005671 A KR 20020005671A KR 1020017012971 A KR1020017012971 A KR 1020017012971A KR 20017012971 A KR20017012971 A KR 20017012971A KR 20020005671 A KR20020005671 A KR 20020005671A
- Authority
- KR
- South Korea
- Prior art keywords
- acid
- drugs
- test
- drug
- compounds
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 131
- 239000003814 drug Substances 0.000 claims abstract description 174
- 229940079593 drug Drugs 0.000 claims abstract description 171
- 239000002243 precursor Substances 0.000 claims abstract description 106
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 23
- 125000004429 atom Chemical group 0.000 claims abstract description 16
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 3
- -1 no obvious toxicity Chemical compound 0.000 claims description 244
- 238000012360 testing method Methods 0.000 claims description 116
- 239000000243 solution Substances 0.000 claims description 96
- 239000002253 acid Substances 0.000 claims description 88
- 238000011282 treatment Methods 0.000 claims description 47
- 150000003254 radicals Chemical class 0.000 claims description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- KCWZGJVSDFYRIX-YFKPBYRVSA-N N(gamma)-nitro-L-arginine methyl ester Chemical compound COC(=O)[C@@H](N)CCCN=C(N)N[N+]([O-])=O KCWZGJVSDFYRIX-YFKPBYRVSA-N 0.000 claims description 38
- 230000002496 gastric effect Effects 0.000 claims description 38
- 230000006378 damage Effects 0.000 claims description 35
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 claims description 31
- HDFGOPSGAURCEO-UHFFFAOYSA-N N-ethylmaleimide Chemical compound CCN1C(=O)C=CC1=O HDFGOPSGAURCEO-UHFFFAOYSA-N 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 29
- 241001465754 Metazoa Species 0.000 claims description 28
- 241000700159 Rattus Species 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- GHAZCVNUKKZTLG-UHFFFAOYSA-N N-ethyl-succinimide Natural products CCN1C(=O)CCC1=O GHAZCVNUKKZTLG-UHFFFAOYSA-N 0.000 claims description 26
- 229910052757 nitrogen Inorganic materials 0.000 claims description 25
- 238000004458 analytical method Methods 0.000 claims description 24
- 230000002829 reductive effect Effects 0.000 claims description 24
- 230000036542 oxidative stress Effects 0.000 claims description 23
- 239000000460 chlorine Substances 0.000 claims description 22
- 238000002835 absorbance Methods 0.000 claims description 21
- 230000005764 inhibitory process Effects 0.000 claims description 21
- 229910052801 chlorine Inorganic materials 0.000 claims description 19
- KSEBMYQBYZTDHS-HWKANZROSA-M (E)-Ferulic acid Natural products COC1=CC(\C=C\C([O-])=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-M 0.000 claims description 18
- 229960004308 acetylcysteine Drugs 0.000 claims description 18
- KSEBMYQBYZTDHS-HWKANZROSA-N ferulic acid Chemical compound COC1=CC(\C=C\C(O)=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-N 0.000 claims description 18
- 229940114124 ferulic acid Drugs 0.000 claims description 18
- 235000001785 ferulic acid Nutrition 0.000 claims description 18
- KSEBMYQBYZTDHS-UHFFFAOYSA-N ferulic acid Natural products COC1=CC(C=CC(O)=O)=CC=C1O KSEBMYQBYZTDHS-UHFFFAOYSA-N 0.000 claims description 18
- QURCVMIEKCOAJU-UHFFFAOYSA-N trans-isoferulic acid Natural products COC1=CC=C(C=CC(O)=O)C=C1O QURCVMIEKCOAJU-UHFFFAOYSA-N 0.000 claims description 18
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 claims description 17
- 230000036772 blood pressure Effects 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 16
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims description 16
- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 claims description 16
- 229960004963 mesalazine Drugs 0.000 claims description 16
- 229960000905 indomethacin Drugs 0.000 claims description 15
- 229920006395 saturated elastomer Polymers 0.000 claims description 15
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims description 14
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 14
- 235000018417 cysteine Nutrition 0.000 claims description 14
- 231100000419 toxicity Toxicity 0.000 claims description 14
- 230000001988 toxicity Effects 0.000 claims description 14
- 206010067125 Liver injury Diseases 0.000 claims description 12
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 12
- RRAFCDWBNXTKKO-UHFFFAOYSA-N eugenol Chemical compound COC1=CC(CC=C)=CC=C1O RRAFCDWBNXTKKO-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims description 11
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 claims description 11
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 11
- 231100000234 hepatic damage Toxicity 0.000 claims description 11
- 230000008818 liver damage Effects 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 229960002855 simvastatin Drugs 0.000 claims description 11
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 claims description 11
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 10
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 10
- 239000002876 beta blocker Substances 0.000 claims description 10
- 229940097320 beta blocking agent Drugs 0.000 claims description 10
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 10
- 229960005489 paracetamol Drugs 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 claims description 10
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 10
- 239000011734 sodium Substances 0.000 claims description 10
- 229910052708 sodium Inorganic materials 0.000 claims description 10
- 229940083542 sodium Drugs 0.000 claims description 10
- 150000003431 steroids Chemical class 0.000 claims description 10
- 229960001685 tacrine Drugs 0.000 claims description 10
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 9
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 claims description 9
- 229940124630 bronchodilator Drugs 0.000 claims description 9
- 239000000168 bronchodilator agent Substances 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 230000001713 cholinergic effect Effects 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 210000002889 endothelial cell Anatomy 0.000 claims description 9
- 229920000669 heparin Polymers 0.000 claims description 9
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 claims description 8
- 239000005541 ACE inhibitor Substances 0.000 claims description 8
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims description 8
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 claims description 8
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 8
- 229960000723 ampicillin Drugs 0.000 claims description 8
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 claims description 8
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims description 8
- 239000007900 aqueous suspension Substances 0.000 claims description 8
- 208000006673 asthma Diseases 0.000 claims description 8
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 claims description 8
- 229960004679 doxorubicin Drugs 0.000 claims description 8
- 239000003651 drinking water Substances 0.000 claims description 8
- 235000020188 drinking water Nutrition 0.000 claims description 8
- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical compound COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 claims description 8
- 150000002505 iron Chemical class 0.000 claims description 8
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 8
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 claims description 7
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 claims description 7
- 108010061435 Enalapril Proteins 0.000 claims description 7
- 238000010521 absorption reaction Methods 0.000 claims description 7
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 claims description 7
- 229960005174 ambroxol Drugs 0.000 claims description 7
- JBDGDEWWOUBZPM-XYPYZODXSA-N ambroxol Chemical compound NC1=C(Br)C=C(Br)C=C1CN[C@@H]1CC[C@@H](O)CC1 JBDGDEWWOUBZPM-XYPYZODXSA-N 0.000 claims description 7
- 239000003242 anti bacterial agent Substances 0.000 claims description 7
- 229940088710 antibiotic agent Drugs 0.000 claims description 7
- 239000002246 antineoplastic agent Substances 0.000 claims description 7
- 229940041181 antineoplastic drug Drugs 0.000 claims description 7
- 229940127217 antithrombotic drug Drugs 0.000 claims description 7
- 239000003443 antiviral agent Substances 0.000 claims description 7
- 230000006907 apoptotic process Effects 0.000 claims description 7
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 claims description 7
- 229960003009 clopidogrel Drugs 0.000 claims description 7
- 229960000873 enalapril Drugs 0.000 claims description 7
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 claims description 7
- 150000002148 esters Chemical class 0.000 claims description 7
- 239000003172 expectorant agent Substances 0.000 claims description 7
- 230000003419 expectorant effect Effects 0.000 claims description 7
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 claims description 7
- 229960001680 ibuprofen Drugs 0.000 claims description 7
- 238000001727 in vivo Methods 0.000 claims description 7
- OJLOPKGSLYJEMD-URPKTTJQSA-N methyl 7-[(1r,2r,3r)-3-hydroxy-2-[(1e)-4-hydroxy-4-methyloct-1-en-1-yl]-5-oxocyclopentyl]heptanoate Chemical compound CCCCC(C)(O)C\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC OJLOPKGSLYJEMD-URPKTTJQSA-N 0.000 claims description 7
- 229960005249 misoprostol Drugs 0.000 claims description 7
- 229940066491 mucolytics Drugs 0.000 claims description 7
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims description 7
- 229960002052 salbutamol Drugs 0.000 claims description 7
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 7
- 239000012085 test solution Substances 0.000 claims description 7
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 claims description 6
- ASJSAQIRZKANQN-CRCLSJGQSA-N 2-deoxy-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)CC=O ASJSAQIRZKANQN-CRCLSJGQSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 6
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 claims description 6
- NPBVQXIMTZKSBA-UHFFFAOYSA-N Chavibetol Natural products COC1=CC=C(CC=C)C=C1O NPBVQXIMTZKSBA-UHFFFAOYSA-N 0.000 claims description 6
- 239000005770 Eugenol Substances 0.000 claims description 6
- 241000699670 Mus sp. Species 0.000 claims description 6
- UVMRYBDEERADNV-UHFFFAOYSA-N Pseudoeugenol Natural products COC1=CC(C(C)=C)=CC=C1O UVMRYBDEERADNV-UHFFFAOYSA-N 0.000 claims description 6
- 229940125715 antihistaminic agent Drugs 0.000 claims description 6
- 239000000739 antihistaminic agent Substances 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 229960001803 cetirizine Drugs 0.000 claims description 6
- GHKISGDRQRSCII-UHFFFAOYSA-N chelidonine Natural products C1=C2C3N(C)CC4=C(OCO5)C5=CC=C4C3C(O)CC2=CC2=C1OCO2 GHKISGDRQRSCII-UHFFFAOYSA-N 0.000 claims description 6
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 claims description 6
- XYYVYLMBEZUESM-UHFFFAOYSA-N dihydrocodeine Natural products C1C(N(CCC234)C)C2C=CC(=O)C3OC2=C4C1=CC=C2OC XYYVYLMBEZUESM-UHFFFAOYSA-N 0.000 claims description 6
- 229960002819 diprophylline Drugs 0.000 claims description 6
- KSCFJBIXMNOVSH-UHFFFAOYSA-N dyphylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1N(CC(O)CO)C=N2 KSCFJBIXMNOVSH-UHFFFAOYSA-N 0.000 claims description 6
- 229960002217 eugenol Drugs 0.000 claims description 6
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 6
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 239000003112 inhibitor Substances 0.000 claims description 6
- AWJUIBRHMBBTKR-UHFFFAOYSA-N iso-quinoline Natural products C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 6
- 229960002009 naproxen Drugs 0.000 claims description 6
- 229960003966 nicotinamide Drugs 0.000 claims description 6
- 235000005152 nicotinamide Nutrition 0.000 claims description 6
- 239000011570 nicotinamide Substances 0.000 claims description 6
- 229960001180 norfloxacin Drugs 0.000 claims description 6
- 229960005205 prednisolone Drugs 0.000 claims description 6
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 claims description 6
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 claims description 6
- 229960004605 timolol Drugs 0.000 claims description 6
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 claims description 5
- 108010087806 Carnosine Proteins 0.000 claims description 5
- UCHDWCPVSPXUMX-TZIWLTJVSA-N Montelukast Chemical compound CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC(O)=O)CC1 UCHDWCPVSPXUMX-TZIWLTJVSA-N 0.000 claims description 5
- CQOVPNPJLQNMDC-UHFFFAOYSA-N N-beta-alanyl-L-histidine Natural products NCCC(=O)NC(C(O)=O)CC1=CN=CN1 CQOVPNPJLQNMDC-UHFFFAOYSA-N 0.000 claims description 5
- 229960004150 aciclovir Drugs 0.000 claims description 5
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 claims description 5
- 229940035676 analgesics Drugs 0.000 claims description 5
- 239000000730 antalgic agent Substances 0.000 claims description 5
- 230000003266 anti-allergic effect Effects 0.000 claims description 5
- 230000001088 anti-asthma Effects 0.000 claims description 5
- 230000001315 anti-hyperlipaemic effect Effects 0.000 claims description 5
- 239000000924 antiasthmatic agent Substances 0.000 claims description 5
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- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3839—Polyphosphonic acids
- C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
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- C07C327/00—Thiocarboxylic acids
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- C07C327/34—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups with amino groups bound to the same hydrocarbon radicals
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- C07—ORGANIC CHEMISTRY
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Abstract
일반식(Ⅰ): A-(B)의 화합물들 또는 그 염들로, 여기서Formula (I): compounds of A- (B) or salts thereof, wherein
A=R-T1-이고 R은 약물 라디칼이며 T1=(CO)t또는 (X)t´, 여기서 X= O, S, NR1C이고, R1C는 H 또는 1부터 5까지 탄소원자들을 갖는 알킬, 또는 자유원자가이며, t 및 t´는 t´=0일 때 t=1; t´=1일 때 t=0의 조건으로 정수들 및 0 또는 1이고, B=-TB-X2에서 t=0일 때 TB=(CO), t´=0일 때 TB=X, 상기 정의된 바와 같은 X; 1가 라디칼 X2는 A의 선구약물 및 B의 선구물질이 각각 본 명세서에 기술된 약리작용에 부합한다.A = RT 1 -, and R is the drug radical and T 1 = (CO) t or (X) t', and where X = O, S, NR 1C , R 1C is alkyl having carbon atoms from 1 to 5 or H , Or free atoms, t and t 'are t = 1 when t' = 0; t'= 1 day and t = 0 when the constant condition, and zero or one of the, when B = -T B -X 2 at t = 0 when T B = (CO), t' = 0 T B = X, X as defined above; The monovalent radical X 2 is the precursor of A and the precursor of B, respectively, corresponding to the pharmacological action described herein.
Description
본 발명은 산화성스트레스 및/또는 내피기능장애의 경우들에 사용되는 전신(全身)용 및 비전신용을 위한 새로운 약물, 및 그 조성물에 관한 것이다.The present invention relates to novel drugs for systemic and non-systemic use, and compositions thereof, for use in cases of oxidative stress and / or endothelial dysfunction.
산화성스트레스에 의한 경우란 세포 및 주변조직의 세포 모두에 손상을 초래하는 자유라디칼 또는 라디칼화합물의 발생을 의미한다(pathophysiology: the biological basis for disease in adults and children, McCance & Huether 1998. p48-54).Oxidative stress refers to the generation of free radicals or radicals that cause damage to both cells and cells of surrounding tissue (pathophysiology: the biological basis for disease in adults and children, McCance & Huether 1998. p48-54). .
내피기능장애에 의한 경우란 맥관내피세포에 관련되는 기능장애를 의미한다. 맥관내피손상은 차후에 설명되는 여러 기관(器官) 및 신체기관에 영향을 미치는 일련의 병리학적 과정을 초래할 수 있는 중요한 사건들 중의 하나로서 공지되어 있다(pathophysiology: the biological basis for disease in adults and children, McCance & Huether 1998 p1025).By endothelial dysfunction refers to a dysfunction associated with vasculature endothelial cells. Vascular endothelial injury is known as one of the important events that can lead to a series of pathological processes affecting several organs and body organs described later (pathophysiology: the biological basis for disease in adults and children, McCance & Huether 1998 p1025).
공지된 대로, 산화성스트레스 및/또는 내피기능장애는 차후에 기술된 대로 여러 가지 병리들에 관련된다. 산화성스트레스는 약효에 심각하게 영향을 미치는 매우 다양한 약물들의 독성에 의해 또한 초래될 수 있다.As is known, oxidative stress and / or endothelial dysfunction is involved in various pathologies as described later. Oxidative stress can also be caused by the toxicity of a wide variety of drugs that seriously affect drug efficacy.
상기 병리상의 사건들은 만성적이고, 쇠약 특성을 가지며, 노인들에게는 매우 전형적이다. 이미 기술한대로, 사용되는 약물들이 상기 병리상의 조건들에서는 현저하게 악화된 약효를 보여준다.These pathological events are chronic, debilitating, and very typical for older people. As already described, the drugs used show a markedly worse efficacy in these pathological conditions.
산화성스트레스 및/또는 내피기능장애에 의해 초래되거나, 노인들에게 나타나는 병리상태들의 예들은 이하이다:Examples of pathological conditions caused by oxidative stress and / or endothelial dysfunction or present in older people are:
- 심장혈관계: 심근 및 맥관허혈, 일반적으로 고혈압, 뇌일혈, 동맥경화 등Cardiovascular system: Myocardial and vascular ischemia, hypertension, cerebral hemorrhage, arteriosclerosis, etc.
- 결합조직: 류머티스성관절염 및 관련염증 등-Connective tissue: rheumatoid arthritis and related inflammation
- 허파계: 천식 및 관련염증 등-Lung system: asthma and related inflammation
- 위장계: 궤양성 및 비궤양성소화불량, 장염증 등-Gastrointestinal: Ulcerative and nonulcerative dyspepsia, enteritis
- 중추신경계: 치매 등Central nervous system: dementia, etc.
- 비뇨생식계: 발기부전, 실금-Urogenital system: erectile dysfunction, incontinence
- 피부계: 습진, 신경성피부염, 좌창-Skin system: eczema, neurodermatitis, acne
- 일반적인 전염병들(참조: schwarz-KB, Brady "Oxidative stress during viral infection: A review" Free radical Biol. Med. 21/5, 641-649 1996).Common infectious diseases (schwarz-KB, Brady "Oxidative stress during viral infection: A review" Free radical Biol. Med. 21/5, 641-649 1996).
또한 노화과정은 실제 병리조건으로서 고려될 수 있다(참조. pathophysiology: the biological basis for disease in adults and children, p 71-77).Aging processes can also be considered as actual pathological conditions (see pathophysiology: the biological basis for disease in adults and children, pp. 71-77).
공지된 약들을 산화성스트레스 및/또는 내피기능장애에 관련된 병리환자들에게 투입될 때, 낮은 활성 및/또는 높은 독성이 된다.When known drugs are introduced into pathological patients involved in oxidative stress and / or endothelial dysfunction, they become low activity and / or high toxicity.
이것은 예를 들어, 항염증약, 심혈관약, 호흡기관약들, 중추신경계약들, 골절계약들, 항생제, 비뇨생식기의 약, 내분비선의 약(endorcrin drugs) 등의 약물들에서 일어난다.This occurs, for example, in drugs such as anti-inflammatory drugs, cardiovascular drugs, respiratory tract drugs, central nervous contracts, fracture contracts, antibiotics, drugs of the genitourinary system, and endocrine drugs.
약물연구는 향상된 처치지수(효능/독성 비) 또는 위에서 언급된 병리조건들에서 낮은 유해/유익 비를 가지는 새로운 분자들을 발견하는 방향으로 가고 있고, 다수의 약들의 처치지수는 낮은 결과를 나타낸다. 실제 위에서 언급된 산화성스트레스 및/또는 내피기능장애의 조건들에서, 많은 약들에 의해 낮은 활동도 및/또는 높은 독성이 된다.Drug research is moving towards finding new molecules with improved treatment index (efficacy / toxicity ratio) or low hazard / benefit ratios under the above-mentioned pathologies, and treatment indexes for many drugs show low results. In fact, under the conditions of oxidative stress and / or endothelial dysfunction mentioned above, many drugs become low activity and / or high toxicity.
예를 들면, NSAID들과 같은 항염증약, 5-아미노살리시릭산 및 그 유도체 등과 같은 항대장염약은 이하의 결점들을 나타낸다. NSAID들은 특히 유기체가 산화성스트레스에 관련된 병의 조건들에 의해 허약하게 되거나 영향을 받게될 때 독성을 띠게된다. 상기 조건들은 예를 들어 이하의 조건들이다: 나이, 현존하는 궤양, 현존하는 위출혈, 특히 심장혈관, 신장, 혈액기질 등에 영향을 미치는 만성쇠약질환들이다("Misoprostol reduces serious gastrointestinal comlications in patients with rtheumatoid arthritis receiving non-steroidal anti-inflammatory drugs. A randomized, double blind, placebo-controlled trial." F.E. Silverstein et Al., Ann. Intern. Med. 123/4, 241-9, 1995; Martindale 31a ed. 1996, P 73, Current Medical Diagnosis and Treatment 1998, P 431 and 794).For example, anti-inflammatory drugs such as NSAIDs, anti-colitis drugs such as 5-aminosalicylic acid and derivatives thereof exhibit the following drawbacks. NSAIDs are particularly toxic when the organism is weakened or affected by conditions of the disease associated with oxidative stress. These conditions are, for example, the following conditions: chronic debilitating diseases affecting age, existing ulcers, existing gastric bleeding, especially cardiovascular, kidney, blood substrate, etc. ("Misoprostol reduces serious gastrointestinal comlications in patients with rtheumatoid arthritis receiving non-steroidal anti-inflammatory drugs.A randomized, double blind, placebo-controlled trial. "FE Silverstein et Al., Ann. Intern. Med. 123/4, 241-9, 1995; Martindale 31a ed. 1996, P 73 , Current Medical Diagnosis and Treatment 1998, P 431 and 794).
위에서 언급된 병리조건들의 환자에 대한 항염증약들의 투여는 현저한 독성현상을 방지하기 위해 처치에 사용되는 투여량보다 낮은 투여량만으로 행해질 수 있다. 따라서 항염증활성은 낮은 결과로 된다. 앙기나, 고혈압 및 심장 부정맥(arrhythmia)치료를 위해 사용되는 베타차단제들은 호흡기관들에 대한 부작용들(호흡곤란, 기관지수축)을 일으키고, 따라서 이들 약물들은 상기 기관들에 대한 병리상태(천식, 기관지염)에 있는 환자들에게 문제점을 초래할 수 있다. 따라서, 베타차단제들은 천식과 같은 호흡질환들을 더 악화시킬 수 있다. 따라서, 천식환자들에게는 호흡기능을 더 이상 해를 끼치지 않도록, 상기 약제들의 감소된 투여량이 사용되어야 한다. 그러므로 베타차단제의 효능은 매우 줄어드는 결과가 된다.Administration of anti-inflammatory drugs to patients with the above-mentioned pathologies can be done only at a lower dose than that used for the treatment to prevent significant toxicity. Thus, anti-inflammatory activity is low. Beta-blockers used to treat angina, hypertension and cardiac arrhythmia cause side effects on the respiratory organs (breath dysfunction, bronchial contraction), and therefore these drugs may cause pathologies for the organs (asthma, bronchitis). May cause problems for patients with). Thus, beta-blockers can worsen respiratory diseases such as asthma. Therefore, reduced dosages of the agents should be used so that asthma patients no longer harm respiratory function. Therefore, the efficacy of beta-blockers is greatly reduced.
혈전현상의 예방을 위해 사용되는 예를 들어, 디피리다몰(dipyridamole), 아스피린등의 혈전치료제(antithrombotics)은 동일한 결점들을 가진다. 산화성스트레스 및/또는 내피기능장애에 관련된 병에 걸린 환자들에서, 아스피린의 경우처럼 이런 악품들의 치료작용 또는 내성(tolerability)은 크게 줄게된다.For example, antithrombotics such as dipyridamole and aspirin used for the prevention of thrombosis have the same drawbacks. In patients with disease associated with oxidative stress and / or endothelial dysfunction, the therapeutic or tolerability of these components, as in the case of aspirin, is greatly reduced.
예를 들어 살부타몰(salbutamol)등의 기관지확장제는 천식 및 기관지염 치료에 사용되고, 콜린계에 활성인 콜린성요실금 등의 병에 사용된다. 이런 약물들의 투여는 심장처치 및 고혈압 모두의 환자들에게 문제점을 초래하는 심장혈관에 부작용을 발생시킬 수 있다. 심장처치 및 고혈압은 위에서 설명한 대로 산화성스트레스 및/또는 내피기능장애에 관련된 병이다. 또한, 이런 약물들은 위에서 설명한 것과 동일한 결점들을 나타낸다.For example, bronchodilators such as salbutamol are used to treat asthma and bronchitis, and are used in diseases such as cholinergic incontinence active in the cholinergic system. Administration of these drugs can cause side effects in the cardiovascular system that cause problems for patients with both cardiac and hypertension. Cardiac and hypertension are diseases related to oxidative stress and / or endothelial dysfunction as described above. In addition, these drugs exhibit the same drawbacks as described above.
호흡기관들의 염증상태의 처치에 사용되는 거담제 및 점액용해약들은 위에서 설명된 조건들에 의해 병에 걸린 환자들에게 결점으로 관측된다. 이런 약물들의 투여는 특히 노인들에게 가슴앓이 및 위자극과민을 일으킬 수 있다.The expectorant and mucolytic drugs used to treat the inflammatory state of the respiratory tracts are observed as defects in patients suffering from the conditions described above. Administration of these drugs can cause heartburn and irritability, especially in older people.
디포스포네이트(diphosphonates)(예를 들어 알렌드로네이트(alendronate), 등)와 같은 뼈흡수억제제들은 높은 위장관독성이 관측되는 약물들이다. 따라서, 이런 약들은 위에서 언급된 결점들과 동일한 결점들이 관측될 수 있다.Bone resorption inhibitors, such as diphosphonates (eg alendronate, etc.) are drugs in which high gastrointestinal toxicity is observed. Thus, these drugs can be observed the same defects as those mentioned above.
심장혈관 및 호흡계질환에 사용되는 예를 들어 실덴나필(sildenafil), 자프리나스트(zaprinast)와 같은 포스포디에스테라제억제제는 언급된 산화성스트레스 및/또는 내피기능장애의 병리조건들의 양호성 및/또는 효능에 동일한 문제점들에 의해 특징지어진다.Phosphodiesterase inhibitors such as, for example, sildenafil, zaprinast, which are used in cardiovascular and respiratory diseases, are preferred for the pathological conditions of oxidative stress and / or endothelial dysfunction mentioned. Characterized by the same problems with efficacy.
예를 들어, 세티리진(centirizine), 몬테루카스트(montelukast)의 항알레르기성약물은 특히 효능에 관련된 언급된 병리조건들에서 동일한 문제점들이 관측된다.For example, the antiallergic drugs of cetirizine, montelukast, and the like have been observed with the same problems, especially in the mentioned pathologies related to efficacy.
예를 들어, 에날아프릴, 캡토프릴 등의 ACE억제제 및 항안지오텐신약물들 예를 들어 로사탄 등의 수용체억제제들은 심장혈관처치에 사용된다. 이들 약물의 결점은 위에서 언급된 병리조건들의 호흡기관에 부작용(예를 들어, 기침)을 유도할 수 있다.For example, ACE inhibitors such as enalapril, captopril and anti-angiotensin drugs such as receptor inhibitors such as losartan are used for cardiovascular treatment. Drawbacks of these drugs can induce side effects (eg cough) in the respiratory tract of the above mentioned pathologies.
예를 들어, 설포닐우레아, 톨부타미드, 글리피리드, 글리클라자이드, 글리부라이드, 니코틴아미드 등의 인슐린-민감성 및 저혈당형 모두의 항당뇨약은 당뇨합병증들의 예방에는 효과가 없다. 이런 약물들의 투여는 예를 들어, 위병변과 같은 부작용을 일으킬 수 있다. 이런 현상들은 위에서 언급된 병리조건들에서 더욱 촉진된다.For example, antidiabetic drugs of both insulin-sensitive and hypoglycemic types, such as sulfonylureas, tolbutamide, glypiride, glyclazide, glyburide, nicotinamide, and the like, have no effect on the prevention of diabetic complications. Administration of such drugs can cause side effects such as, for example, gastric lesions. These phenomena are further facilitated by the pathologies mentioned above.
예를 들어, 암피실린, 클라리트로마이신 등의 항생제, 및 아시클로비르 등의 항바이러스약 등은 그들의 내용성으로 간주되는 문제점들을 나타내는데, 예를 들어 이런 약물들은 위장관과민성을 초래한다.For example, antibiotics such as ampicillin, clarithromycin, and antiviral drugs such as acyclovir present problems that are considered their content, for example, such drugs cause gastrointestinal sensitization.
예를 들어, 독소루비신, 다우노루비신, 시스프라티늄 등의 항종양약들은 위 및 내장간의 다른 장기들에게 높은 독성을 갖는다. 상기 독성은 위에서 언급된 산화성스트레스 및/또는 내피기능장애의 병리들에게 더욱 악화시킨다.For example, antitumor drugs such as doxorubicin, daunorubicin, cispratinium, and the like have high toxicity to other organs of the stomach and intestines. The toxicity is exacerbated by the above mentioned pathologies of oxidative stress and / or endothelial dysfunction.
예를 들어, 니코틴 및 콜리노미메틱스의 항치매약물들은 위에 언급된 병리들에 특히 낮은 내용성으로 특징지어진다.For example, anti-dementants of nicotine and cholinomimetics are characterized by a particularly low content in the pathologies mentioned above.
급성(천식 등) 또는 만성질환(장질환, 간질환, 호흡기질환, 여성생식기질환, 피부질환 등)의 처치에 사용되는 스테로이드구조를 가지는 약물들은 특히 위에서 언급된 산화성스트레스조건들에서 여러 기관들에 해를 주는 현저한 독성효과들로 특징지어진다. 하이드로코르티손, 코티손, 프레드니손, 프레드니솔론, 플루드로코티손, 데소시코티코스테론, 메틸프레드니솔론, 트리암시노론, 파라메타손, 베타메타손, 덱사메타손, 트리암시노론 아세토나이드, 플루오시노론 아세토나이드, 베클로메타손, 아세토시프레그넬론 등의 스테로이드약물들의 그룹(group)은 여러 기관들에 현저한 파마코-독성효과(farmaco-toxicological effects)를 가지며, 이런 이유로 해서 임상사용 및 중단 모두는 그 일부가 매우 치명적인 일련의 부작용들을 초래한다( 참조: Goodman & Gilman, "The pharmaceutical Basis of Therapeutics" 9판, 페이지 1459-1465, 1996).Drugs with a steroid structure used to treat acute (asthma, etc.) or chronic diseases (intestinal disease, liver disease, respiratory disease, female genital disease, skin disease, etc.) are particularly effective in various organs under the oxidative stress conditions mentioned above. Characterized by significant toxic effects that cause harm. Hydrocortisone, cortisone, prednisone, prednisolone, fludrocortisone, desoxycorticosterone, methylprednisolone, triamcinolone, paramethasone, betamethasone, dexamethasone, triamcinolone acetonide, fluorinolone acetonide, beclomethasone, Groups of steroid drugs, such as acetosipregnelone, have significant farmaco-toxic effects in various organs, which is why both clinical use and discontinuation are part of a series of very fatal side effects. (See Goodman & Gilman, "The pharmaceutical Basis of Therapeutics" 9th edition, pages 1459-1465, 1996).
상기 독성효과들은 뼈조직을 변질세포대사 및 높은 골다공증발생빈도로 유도하는 결과들, 고혈압증상을 발생시켜 심장혈관계에 영향을 주는 결과들, 위손상을 일으켜 위장관을 해치는 결과들로 언급될 수 있다(참조: Martindale "The extrapharmacopoeia", 30판, 페이지 712-723, 1993).The toxic effects may be referred to as the result of inducing bone tissue to metabolic metabolism and high osteoporosis incidence, to cause hypertension, affect the cardiovascular system, to cause gastrointestinal damage and to damage the gastrointestinal tract ( See Martindale "The extrapharmacopoeia", 30th edition, pages 712-723, 1993).
쓸개즙산에 속하는 스테로이드약물의 그룹은 간기능장애 및 담도산통의 처치에 사용되고 있다. 우르소데소시콜린산 또한 몇 가지 간기능장애(쓸개즙원인의 간경변 등)에 사용된다. 이들의 양호성은 위장관합병증(만성간손상, 궤양, 장염 등)의 존재를 더욱 악화된다. 또한, 쓸개즙산의 경우에 산화성스트레스는 현저하게 약의 효능에 영향을 미쳐, 케노데옥시콜린산 및 우르소데소시콜린산의 효능 및 내용성 모두가 현저하게 감소된다. 특히, 간에 대해 원치 않는 효과들이 증진되는 것이 관측된다. 스테로이드화합물들중에 에스트로겐이 디스리피다에미아스(dislipidaemias), 호르몬기능장애의 처치를 위해 언급될 수 있고, 여성장기종양처치도 언급될 수 있다. 또한 상기 스테로이드는 특히 간에서 위에서 언급된 부작용들을 나타낸다.Groups of steroid drugs belonging to the bile acids are used for the treatment of hepatic dysfunction and biliary colic. Ursodesuccinic acid is also used for some liver failures (such as cirrhosis of the gall bladder). Their goodness worsens the presence of gastrointestinal complications (chronic liver injury, ulcers, enteritis, etc.). In addition, in the case of bile acids, oxidative stress significantly affects the efficacy of the drug, so that both the efficacy and the tolerability of kenodeoxycholic acid and ursodesuccinic acid are significantly reduced. In particular, it is observed that unwanted effects are enhanced on the liver. Among the steroid compounds, estrogen may be mentioned for the treatment of dislipidaemias, hormonal dysfunction, and feminine organ tumor treatment may also be mentioned. The steroid also exhibits the side effects mentioned above, particularly in the liver.
위에서 언급된 종래기술에 따르면, 처치작용에서 부작용을 방지하는 것이 거의 불가능하게 보인다(위에서 언급된 Goodman의 "The pharmaceutical Basis of Therapeutics" 9판, 페이지 1474를 참조).According to the prior art mentioned above, it is almost impossible to prevent side effects from treatment (see Goodman's "The pharmaceutical Basis of Therapeutics" 9th edition, page 1474, mentioned above).
산화성스트레스 및/또는 내피기능장애의 질병상태의 환자에게 종래기술의 약물들의 결점들을 나타냄이 없이 약물들이 투여될 수 있도록, 개선된 처치효능, 즉 낮은 독성 및/또는 높은 효능 모두가 부여된 것을 보여주는 유용한 약물들에 대한 필요성이 있어왔다.Demonstrating that both patients with oxidative stress and / or endothelial dysfunction have been given improved treatment efficacy, ie low toxicity and / or high efficacy, so that drugs can be administered without exhibiting the drawbacks of prior art drugs. There has been a need for useful drugs.
산화성스트레스 및/또는 내피기능장애에 의한 환자들, 또는 일반적으로 노인들에게 약물들의 투여로 나타난 언급된 문제점들은 이후에 설명된 대로 새로운 클래스(class)의 약물들에 의해 해결된다는 것을 의외로 뜻밖에 알게된다.It is surprisingly surprising that the mentioned problems presented by the administration of drugs to patients with oxidative stress and / or endothelial dysfunction, or to the elderly in general, are solved by a new class of drugs as described later. .
본 발명의 목적은 이하 일반식Ⅰ,The object of the present invention is the following general formula I,
의 화합물들 또는 그 염들로,As compounds or salts thereof,
여기서:here:
R은 약물 라디칼이고R is a drug radical
T1=(CO)t또는 (X)t´, 여기서 X=O, S, NR1C이고, R1C는 H 또는 1부터 5까지 탄소원자들을 갖는 선형 혹은 분지형 알킬, 또는 자유원자가이며, t 및 t´는 t´=0일 때 t=1; t´=1일 때 t=0의 조건으로 정수들 및 0 또는 1이고, T 1 = (CO) t or (X) t', where X = O, S, and NR 1C, R 1C is a linear or branched alkyl, or a free valence or H having carbon atoms from 1 to 5, t And t ′ is t = 1 when t ′ = 0; integers and 0 or 1 under the condition t = 0 when t´ = 1,
t=0일 때 TB=(CO), t´=0일 때 TB=X, 상기 정의된 바와 같은 X;T B = (CO) when t = 0, T B = X when t ′ = 0, X as defined above;
1가 라디칼 X2는 B의 해당 선구물질이 시험5 및/또는 시험4에 부합하는 것과 같은 것이고; 화학식의 상기 선구물질, 여기서 TB자유원자가는 -OZ 또는 Z로 포화되고, Z=H 또는 R1a, R1aC1-C10=선형 또는 가능할 때 분지형 알킬, 바람직하게는 C1-C5,Monovalent radical X 2 is such that the corresponding precursor of B conforms to test 5 and / or test 4; Chemical formula Wherein said precursor of T B free atom is saturated with -OZ or Z, Z = H or R 1a , R 1a C 1 -C 10 = linear or possibly branched alkyl, preferably C 1 -C 5 ,
또는로 포화되고, 여기서 t, t´값들에 연관되어, TB=CO 또는 X 인지에 따라서, ZⅠ및 ZⅡ는 같거나 또는 서로 다르며 Z값들을 갖고;or Saturation of, where t, t 'is related to the values, depending on whether T B = CO or X, Z I and Z II are the same or different and have Z values;
단: 자유원자가가 t´=0일 때 O-Z(Z=H 또는 R1a임)로, 또는로 포화되고, t=0일 때 위에서 정의된 X-Z(x 및 z는 상기에서 정의한 대로임)로 포화되는 약물은 시험들 1 내지 3 중 적어도 하나와 부합되는 것과 같은 것이고;With OZ (where Z = H or R 1a ) when the free atom is t´ = 0, or Saturated with XZ (where x and z are as defined above) when t = 0 Is the same as matching at least one of the tests 1-3;
시험1은 대조군들(두 그룹들) 및 처치군들(두 그룹들)의 네 그룹들의 쥐들에게 수행되는 생체내시험로, 상기 대조군들 중의 한 그룹 및 상기 처치군들 중 한 그룹은 각각 N-에틸말레이미드(N-ethylmaleimide 이하 NEM) 25㎎/㎏ s.c.을 1회투여량으로 투여되고, 대조군들은 담체로 처치되고 처치군들은 담체+ 자유원자가가 상기와 같이 포화된 화학식의 약물로 처치되며, NEM을 받지 않은 쥐들에 의해 내성이 있는 최대치와 동일한 1회투여량 즉, 명백한 독성이 없는, 즉 증후학적으로 관찰할 수 있는 독성이 없는 약물을 동물에게 투여할 수 있는 가장 높은 분량으로 투여하는 시험이며: 약물은 시험1을 따르고, 즉 NEM+담체+약물로 처리된 쥐들그룹이 위장관 손상들을 보일 때, 또는 NEM+담체+약물로 처리된 그룹에서 담체로 처치된 그룹, 담체+약물로 처리된 그룹 또는 담체+NEM으로 처치된 그룹의 손상보다 큰 위장관 손상들이 관찰될 때, 약물은 일반식(Ⅰ) 및 (Ⅱ)의 화합물들을 조제하는 데 사용될 수 있고;Trial 1 is an in vivo test performed on four groups of rats of controls (two groups) and treatments (two groups), where one of the controls and one of the treatment groups are each N- 25 mg / kg sc of N-ethylmaleimide (NEM) was administered in a single dose, the control group was treated with a carrier and the treatment groups were carrier + free atoms saturated as described above. The highest dose that can be administered to an animal that is treated with the drug and that is equivalent to the maximum dose that is tolerated by rats that have not received NEM, that is, no obvious toxicity, that is, no symptoms that can be observed symptomatically. Tests administered in high doses: Drugs follow Test 1, ie when groups of rats treated with NEM + carrier + drug show gastrointestinal damage, or groups treated with carrier, carrier + in NEM + carrier + drug treated group. When gastrointestinal damages are observed that are greater than those of the drug treated group or the carrier + NEM treated drug, the drug can be used to formulate compounds of Formulas (I) and (II);
시험2(CIP)는 시험관내 실험으로, 배꼽정맥에서의 인간 내피세포가 표준조건들 하에 채취되고, 그 다음 하나는 배지에서 10-4M농도 약물의 최대치로 처리되고,다른 하나는 담체로 처리되는 두 그룹들(각 그룹은 5번 반복됨)로 나누어지고; 그 다음에 배지에 5mM농도를 갖는 큐멘하이드로퍼옥사이드(CIP)가 두 그룹들 각각에 첨가되는 시험이며; 약물은 시험2에 부합하고, 즉 약물은 CIP에 의해 유도된 세포자멸(세포손상)의 통계적으로 현저한 억제가 담체 및 CIP로 처치된 그룹에 대하여 p<0.01로 되지 않는 다면, 일반식(Ⅰ) 및 (Ⅱ)의 화합물들을 조제하는 데 사용될 수 있고;Test 2 (CIP) is an in vitro experiment in which human endothelial cells in the umbilical vein are collected under standard conditions, then one is treated with a maximum of 10 −4 M concentration of drug in the medium and the other with a carrier. Divided into two groups (each group repeated five times); Then a test in which cumene hydroperoxide (CIP) having a concentration of 5 mM in the medium is added to each of the two groups; The drug conforms to test 2, i.e., if the drug does not have a statistically significant inhibition of CIP-induced apoptosis (cytotoxicity) to p <0.01 for the carrier and the group treated with CIP, then the formula (I) And (II) can be used to prepare compounds;
시험3은(L-NAME) 대조군들(두 그룹) 및 처치군들(두 그룹)의 네 그룹들의 쥐들(각 그룹은 쥐 10마리로 구성됨)에게 4주동안 식수(drinking water)를 공급하여 수행되는 생체내시험로, 대조군들 및 처치군들 중 각각의 한 그룹에 400㎎/ℓ농도의 N-ω-니트로-L-아르기닌-메틸에스테르(N-ω-nitro-L-arginine-methyl ester 이하 L-NAME)를 첨가한 식수를 상기 4주 동안 공급하고, 대조군들은 담체가 4주동안 투여되며 처치군들은 담체+약물로 4주동안 처치되고, 담체 또는 약물+담체를 매일 한 번씩 투여하고, 약물은 L-NAME으로 선처치되지 않은 쥐들군에 의해 내성이 있는 최대 1회투여량, 즉, 명백한 독성이 없는, 즉 증후학적으로 관찰할 수 있는 독성이 없는 약물을 동물에게 투여할 수 있는 가장 높은 분량으로 투여하고; 상기 4주 후에 식수공급이 24시간동안 중단되며 그 후에 희생되고, 희생되기 1시간 전에 혈압을 측정하고, 쥐들의 희생 후에 플라즈마글루탐피루빈산트란스아미나제(GPT)를 측정하고, 위근육을 시험하는 시험이며; 약물은 시험3에 부합하고 즉, 담체만으로 처치된 그룹, 담체+약물로 처치된 그룹 또는 담체+L-NAME로 처치된 그룹 각각과 비교하여, L-NAME+담체+약물로 처리된 쥐들군에서 더 큰 간손상들(더 높은 값의 GPT로측정된) 및/또는 위 및/또는 심혈관손상들(더 높은 값의 혈압으로 측정된)이 발견될 때, 약물은 일반식(Ⅰ) 및 (Ⅱ)의 화합물들을 조제하는 데 사용될 수 있고;Trial 3 (L-NAME) was performed by feeding drinking water for four weeks to four groups of rats (each group consisting of 10 rats) of control groups (two groups) and treatment groups (two groups). In vivo testing, in which one of the control and treatment groups each contained 400 mg / L N-ω-nitro-L-arginine-methyl ester L-NAME) was added to the drinking water for 4 weeks, the control group was administered for 4 weeks, the treatment group was treated with carrier + drug for 4 weeks, the carrier or drug + carrier once daily, The drug can be administered to animals with up to a single dose that is tolerated by a group of mice not pretreated with L-NAME, i.e., no obvious toxicity, i.e. no toxicity that can be observed symptomatically. In high doses; After 4 weeks the drinking water supply was stopped for 24 hours and then sacrificed, blood pressure was measured 1 hour before sacrifice, plasma glutamate pyruvate transaminases (GPT) were measured after sacrifice of rats, and gastric muscle testing To test; The drug meets test 3, ie, in the group of rats treated with L-NAME + carrier + drug as compared to the group treated with carrier alone, the group treated with carrier + drug or the group treated with carrier + L-NAME, respectively. When large liver damages (measured by higher values of GPT) and / or gastric and / or cardiovascular damages (measured by higher blood pressures) are found, the drug is expressed in formulas (I) and (II). Can be used to prepare compounds of;
시험4는 DPPH(2, 2-dipheny1-1-picryl-hydrazyl-자유라디칼)의 메탄올용액에 10-4M농도로 B 또는 B1선구물질의 메탄올용액들의 일부들을 첨가함으로써 수행되는 분석적측정이며; 용액을 빛이 닿지 않는 실온에 30분동안 놓아둔 후, 시험용액 및 시험용액에서와 같은 양의 DPPH만을 함유하는 용액의 517㎚ 파장에서의 흡광도를 읽고; 그 후 DPPH에 의한 라디칼생성에 대한 선구물질에 의해 유도되는 억제율은 식Test 4 is an analytical measurement performed by adding a portion of methanol solutions of B or B 1 precursor to a methanol solution of DPPH (2, 2-dipheny1-1-picryl-hydrazyl-free radicals) at a concentration of 10 −4 M; The solution was left at room temperature without light for 30 minutes, and then the absorbance at 517 nm wavelength of the test solution and a solution containing only the same amount of DPPH as the test solution was read; The rate of inhibition induced by the precursors for radical production by DPPH is then
(1-AS/AC)×100(1-A S / A C ) × 100
에 의해 퍼센트로 계산되고,Calculated as a percentage by
여기서 AS및 AC는 각각 시험화합물+DPPH를 함유하는 용액 및 DPPH만을 함유하는 용액의 흡광도값이고;Wherein A S and A C are absorbance values of a solution containing only the test compound + DPPH and a solution containing only DPPH, respectively;
상기 정의된 %억제가 50% 이상이면 시험4는 B 선구물질들로 사용된 화합물들과 부합되고;If the% inhibition defined above is at least 50%, test 4 is consistent with the compounds used as B precursors;
시험5는 100mM 인산버퍼 및 1mM FeⅡ(NH4)2(SO4)2염과 물에서 2mM 디옥시리보오스용액을 혼합하여 형성된 용액에 B 선구물질들의 10-4M 메탄올용액들의 부분표본들(aliquots)을 첨가하여 수행되는 분석적 측정이고; 용액을 37℃의 일정온도에서 한시간동안 놓아둔 후, 2.8% 삼염화아세트산 및 0.5M 티오바르비투르산 수성현탁액의 부분표본들에 순서대로 첨가되고, 100℃에서 15분동안 가열되고 그 후 시험용액들의 흡광도가 532㎚에서 읽혀지고; FeⅡ에 의한 라디칼생성에 대항하여 B 선구물질들에 의해 유도되는 억제율은 식Test 5 aliquots 10 -4 M methanol solutions of B precursors into a solution formed by mixing a 100 mM phosphate buffer and a 1 mM Fe II (NH 4 ) 2 (SO 4 ) 2 salt with 2 mM deoxyribose solution in water. Is an analytical measurement carried out by addition); The solution was allowed to stand at a constant temperature of 37 ° C. for one hour, then added to the aliquots of 2.8% acetic acid trichloride and 0.5 M thiobarbituric acid aqueous suspension in order, heated at 100 ° C. for 15 minutes and then the test solution Absorbance is read at 532 nm; The rate of inhibition induced by B precursors against the generation of radicals by Fe II is given by
(1-AS/AC)×100(1-A S / A C ) × 100
을 통하여 퍼센트로 계산되고:Calculated as a percentage through:
여기서 AS및 AC는 각각 시험화합물 및 철염을 함유하는 용액 및 철염만을 함유하는 용액의 흡광도값이고; B 선구물질의 상기 정의된 바와 같은 %억제가 50%이상일 때 화합물들은 시험5에 부합한다.Where A S and A C are the absorbance values of the test compound and the solution containing the iron salt and the solution containing only the iron salt, respectively; Compounds meet test 5 when the% inhibition of the B precursor as defined above is greater than 50%.
바람직하게, 시험5에 부합하는 B 선구물질 화합물은,Preferably, the B precursor compound that meets test 5,
아미노산들: 아스팔틱산(PI), 히스티딘(PII), 5-히드록시트립토판(PIII), 4-티아조리딘카르복실산(PIV), 2-옥소-4-티아조리딘카르복실산(PV)Amino Acids: Asphatic Acid (PI), Histidine (PII), 5-hydroxytryptophan (PIII), 4-thiazolidinecarboxylic acid (PIV), 2-oxo-4-thiazoridinecarboxylic acid (PV )
모노 및 폴리알콜들 또는 티올들: 2-티오우라실(QI), 2-메르캅토에탄올(QII), 에스페리딘(QIII), 세칼시페롤(QIV), 1-α-OH비타민D2(QV), 플로칼시트리올(QVI), 22-옥사칼시트로올(QVII), 비타민A로 에스테르화된 비타민D3유도체(QVIII), 화학식(QIX)화합물, 1α,25-디히드록시비타민D2(QXI)로부터 유도된 24,28-메틸렌-1α-히드록시비타민D2(QX)화합물, 2-메르캅도이미다졸(QXII)Mono and polyalcohols or thiols: 2-thiouracil (QI), 2-mercaptoethanol (QII), esperidin (QIII), cecaliferol (QIV), 1-α-OHvitamin D2 (QV) From fluorocalcitriol (QVI), 22-oxalcicitrool (QVII), vitamin D3 derivatives (QVIII) esterified with vitamin A, from formula (QIX) compounds, 1α, 25-dihydroxyvitamin D2 (QXI) Derived 24,28-methylene-1α-hydroxyvitamin D2 (QX) Compound, 2-Mercapdoimidazole (QXII)
숙신산(RI)Succinic Acid (RI)
여기서 동일하거나 서로 다른 n°3은 0 또는 1과 같은 정수이고; 동일하거나 서로 다른 n3은 0 내지 3의 정수들이고; 동일하거나 서로 다른 W는 상기 정의된 바와 같은 X를 가지는 HX, COOH, R′, OR′중에 선택되고, 여기서 R′은 1부터 20까지 탄소원자들(바람직하게는 1부터 6까지 탄소원자들)을 갖는 선형 또는 가능할 때분지형알킬이고; R′와 같지만 H대신 할로겐원자, 바람직하게는 F를 적어도 하나 함유하는 Rf를 포함하는 Rf, ORf; 약물 반응기가 카르복실일 때 W라디칼들 중 적어도 하나는 XH이며; 또는 반응기가 XH일 때는 COOH이고;Wherein the same or different n ° 3 is an integer such as 0 or 1; The same or different n3 is an integer from 0 to 3; The same or different W is selected from HX, COOH, R ', OR' having X as defined above, where R 'is a carbon atom from 1 to 20 (preferably from 1 to 6 carbon atoms) Linear or possibly branched alkyl with; Rf, ORf, the same as R ', but including Rf containing at least one halogen atom, preferably F, instead of H; At least one of the W radicals is XH when the drug reactor is carboxyl; Or COOH when the reactor is XH;
n°3=0일 때 n3이 0과 다르다면 n3군의 자유원자가는 R′, OR′, Rf, ORf, H 중 하나로 포화되고, n°3=0 및 n3=0일 때 자유원자가는 H로 포화된다.If n3 is different from 0 when n ° 3 = 0, the free atoms of the n3 group are saturated with one of R ', OR', Rf, ORf, and H; when n ° 3 = 0 and n3 = 0, the free atoms are H Is saturated.
바람직하게 시험4에 부합하는 B 선구물질 화합물은 다음 화합물의 클래스에서 선택된다:Preferably, the B precursor compound that meets test 4 is selected from the class of compounds:
L-카르노신(화학식 CI), 안세린(CII), 세레노시스테인(CIII), 세레노메티오닌(CIV), 페니실아민(CV), N-아세틸-페니실아민(CVI), 시스테인(CVII), N-아세틸-시스테인(CVIII), 글루타티온(CIX) 또는 그 에스테르들 바람직하게는 에틸 또는 이소프로필 에스테르 중에 선택된 아미노산들:L-Carnosine (CI), Anserine (CII), Serenocysteine (CIII), Serenomethionine (CIV), Penicylamine (CV), N-acetyl-penicylamine (CVI), Cysteine (CVII ), N-acetyl-cysteine (CVIII), glutathione (CIX) or esters thereof, preferably amino acids selected from ethyl or isopropyl esters:
SH군이 존재하는 화합물들(CV), (CVI), (CVII) 및 (CVIII)에대해, s가 1 또는 2인 해당 화합물SN(O)s이 또한 SH 대신에 사용될 수 있고;For compounds (CV), (CVI), (CVII) and (CVIII) in which the SH group is present, the corresponding compound SN (O) s with s of 1 or 2 may also be used in place of SH;
히드록시산들: 갈산(화학식 DI), 페룰산(DII), 겐티스산(DIII), 시트르산(DIV), 카페산(DV), 히드로카페산(DVI), p-쿠마르산(DVII), 바닐산(DVIII), 클로로겐산(DIX), 키누렌산(DX), 시링산(DXI)에서 선택된다.Hydroxy acids: gallic acid (DI), ferulic acid (DII), gentisic acid (DIII), citric acid (DIV), caffeic acid (DV), hydrocaic acid (DVI), p-coumaric acid (DVII), bar It is selected from nitric acid (DVIII), chlorogenic acid (DIX), kynurene acid (DX), and silingic acid (DXI).
노르디히드로구아이아레트산(EI), 케르세틴(EII), 카테킨(EIII), 캠페롤(EIV), 설퍼에틴(EV), 아스코르빈산(EVI), 이소아스코르빈산(EVII), 히드로퀴논(EVIII), 고시폴(EIX), 환원산(EX), 메톡시히드로퀴논(EXI), 히드록시히드로퀴논(EXII), 프로필갈산염(EXIII), 자당(EXIV), 비타민E(EXV), 비타민A(EXVI), 8-퀴노롤(EXVII), 3-테르트-부틸-4-히드록시아니솔(EXVIII), 3-히드록시플라본(EXIX), 3,5-테트르-부틸-p-히드록시톨루엔(EXX), p-테트르-부틸-페놀(EXXI), 티모롤(EXXII), 크시보르놀(EXXIII), 3,5-디-테트르-부틸-4-히드록시벤질-티오글리코레이트(EXXIV), 4′-히드록시부틸아닐리드(EXXV), 과이어콜(EXXVI), 토콜(EXXVII), 이소유게놀(EXXVIII), 유게놀(EXXIV), 피페로닐알콜(EXXX), 알로푸리놀(EXXXI), 코니페릴알콜(EXXXII), 4-히드록시펜에틸알콜(EXXXIII), p-쿠마린알콜(EXXXIV), 쿠르쿠민(EXXXV)에서 선택된 방향성의 및 헤테로시클릭 모노- 및 폴리알콜들:Nordihydroguaiaretic acid (EI), quercetin (EII), catechin (EIII), camphorol (EIV), sulfur etin (EV), ascorbic acid (EVI), isoascorbic acid (EVII), hydroquinone (EVIII), Gosifol (EIX), reduced acid (EX), methoxyhydroquinone (EXI), hydroxyhydroquinone (EXII), propyl gallate (EXIII), sucrose (EXIV), vitamin E (EXV), vitamin A (EXVI), 8-quinolol (EXVII), 3-tert-butyl-4-hydroxyanisole (EXVIII), 3-hydroxyflavone (EXIX), 3,5-tet-butyl-p-hydride Oxytoluene (EXX), p-tetr-butyl-phenol (EXXI), timolol (EXXII), xylbornol (EXXIII), 3,5-di-tetyr-butyl-4-hydroxybenzyl-thioglyco Rate (EXXIV), 4′-hydroxybutylanilide (EXXV), Earcall (EXXVI), Tocol (EXXVII), Isoeugenol (EXXVIII), Eugenol (EXXIV), Piperonyl Alcohol (EXXX), Allo Aromatic and selected from furinol (EXXXI), coniferyl alcohol (EXXXII), 4-hydroxyphenethyl alcohol (EXXXIII), p-coumarin alcohol (EXXXIV), curcumin (EXXXV) Heterocyclic Mono- and Polyalcohols:
N,N′-디페닐-p-페닐렌디아민(MI), 에톡시퀸(MII), 티오닌(MIII), 히드록시우레아(MIV)에서 선택된 방향성의 및 헤테로시클릭 아민들:Aromatic and heterocyclic amines selected from N, N'-diphenyl-p-phenylenediamine (MI), ethoxyquine (MII), thionine (MIII), hydroxyurea (MIV):
3,3′-티오디프로피온산(NI), 푸마르산(NII), 디히드록시말레인산(NIII), 티옥트산(NIV), 에데트산(NV), 비리루빈(NVI), 3,4-메틸렌디옥시킨남산(NVII), 피레로닐산(NVIII)에서 선택되고, 적어도 하나의 자유산기를 포함하는 화합물들:3,3′-thiodipropionic acid (NI), fumaric acid (NII), dihydroxymaleic acid (NIII), thioctic acid (NIV), edetic acid (NV), bilirubin (NVI), 3,4-methylenedioxane Compounds selected from Namsan (NVII), Pyreronylic Acid (NVIII) and comprising at least one free acid group:
약물 및 B선구물질화합물은 종래기술의 공지된 방법들 및 예를 들어 참조로포함된 "The Merck Index, 12a Ed(1996)"에 기술된 방법에 따라 조제된다.Drugs and B precursor compounds are prepared according to known methods of the prior art and for example as described in "The Merck Index, 12a Ed (1996)", incorporated by reference.
레티노산(QⅧ)을 가진 비타민 D3유도체는 JP 93039261호(참조.C.A 119 117617)에 기술된 대로; 화학식(QⅨ)화합물은 EP 562497에 의해서; 24,28-메틸렌-1α-하이드록시비타민 D2(QX)는 EP 578494에 의해서; 디하이드록시비타민 D2(QⅩⅠ)의 유도화합물은 EP 549318에 의해서 조제된다.Vitamin D3 derivatives with retinoic acid (QVII) are described in JP 93039261 (see C.A 119 117617); Formula (QVII) compounds are described in EP 562497; 24,28-methylene-1α-hydroxyvitamin D2 (QX) is prepared according to EP 578494; Derivatives of dihydroxyvitamin D2 (QVII) are prepared according to EP 549318.
바람직한 B화합물들은 시험4를 만족하는 화합물들이다.Preferred B compounds are those that satisfy test 4.
화학식(Ⅰ)의 R라디칼의 약물선구물질을 확인하기 위해서 실행되는 시험들은 구체적으로 아래와 같다:The tests carried out to identify the drug precursor of the R radical of formula (I) are specifically:
시험 1(NEM): NEM(N-ethylmaleimide)의 투여에 수반하여 형성된 자유라디칼들에 의해 유도되는 산화성스트레스로부터 위장관손상의 평가(H.G. Utley, F. Bernheim, P. Hochstein "Effects of sulphydrill reagents on peroxidation in microsomes" Archiv. Biochem. Biophys. 118, 29-32 1967).Test 1 (NEM): Assessment of gastrointestinal damage from oxidative stress induced by free radicals formed following administration of N-ethylmaleimide (NEM) (HG Utley, F. Bernheim, P. Hochstein "Effects of sulphydrill reagents on peroxidation in microsomes "Archiv. Biochem. Biophys. 118, 29-32 1967).
동물들(쥐)은 아래의 그룹들로 나뉘어진다(한 그룹에 10마리의 동물들):The animals (rats) are divided into the following groups (10 animals in one group):
A)대조군들:A) Controls:
1°군: 처치: 담체만(약물이 입을 통해 투여될 때, 또는 피하, 복강, 정맥 또는 근육의 경로로 비경구적으로 생리용액이 투여될 때, 카르복시메틸셀롤로오스의 수용성 현탁액 1% w/v의 1회투여량: 5㎖/㎏),1 ° group: Treatment: Carrier only (when the drug is administered by mouth, or when the physiological solution is administered parenterally, subcutaneously, intraperitoneally, intravenously or intramuscularly), 1% w / aqueous suspension of carboxymethylcellulose single dose of v: 5 ml / kg),
2°군: 처치: 위에서 정의된 대로의 담체 + NEM,Group 2 °: Treatment: carrier as defined above + NEM,
B)약물로 처치된 그룹들:B) Groups treated with drugs:
군Ⅰ: 처치: 담체 + 약물,Group I: Treatment: Carrier + Drug,
군Ⅱ: 처치: 담체 + 약물 + NEM,Group II: treatment: carrier + drug + NEM,
투여경로는 약물들에 관해 공지된 경로들이고, 입 또는 피하, 복강, 정맥 또는 근육의 경로가 될 수 있다.Routes of administration are known routes for drugs and can be oral, subcutaneous, intraperitoneal, intravenous or intramuscular.
NEM투여량은 생리용액에서 25㎎/㎏이고(피하경로) 약물은 한시간 후 최대투여량 또는 NEM으로 전처치되지 않은 쥐들의 그룹에게 견딜 수 있는 가장 높은 투여량에 해당하는 1회투여량, 즉 독성의 증상으로 명백하게 인식될 수 있는 독성이 동물들에게는 없는 상기 그룹들에게 가장 높게 투여될 수 있는 투여량을 담체에 현탁액으로 투여된다. 동물들은 24시간 후에 희생되고 위장관의 점막층에 대한 손상의 평가가 진행된다.The NEM dose is 25 mg / kg in physiological solution (subcutaneous route) and the drug is the one dose corresponding to the maximum dose after one hour or the highest dose that can be tolerated in groups of mice not pretreated with NEM. The highest dose that can be clearly recognized as a symptom of toxicity is administered to the carriers in suspension in the above groups which are not present in animals. Animals are sacrificed after 24 hours and assessment of damage to the mucosal layers of the gastrointestinal tract proceeds.
약물은 시험1과 부합된다, 즉 NEM+담체+약물로 처치된 쥐들의 그룹에 위장관의 손상들이 관측되거나, 또는 상기 그룹에서 관측된 위장관의 손상들이 담체만으로 처치된 그룹, 또는 담체+약물로 처치된 그룹, 또는 담체+NEM으로 처치된 그룹에서 관측된 손상들보다 클 때, 일반식(Ⅰ) 및 (Ⅱ)의 화합물들을 조제하기 위해 사용될 수 있고, 특별한 시약들을 사용하여 분석된 약물의 처치효능은 현저하게 감소되지는 않는다.The drug is consistent with Test 1, ie damage to the gastrointestinal tract was observed in a group of rats treated with NEM + carrier + drug, or damage to the gastrointestinal tract observed in the group was treated with carrier alone, or treated with carrier + drug. When greater than the damages observed in the group, or in the group treated with carrier + NEM, it can be used to formulate compounds of formulas (I) and (II), and the treatment efficacy of the drug analyzed using special reagents It is not significantly reduced.
시험 2(CIP): 규멘 하이드로퍼옥사이드(CIP)에 의해 유도된 산화성스트레스에 대항하는 내피방어파라미터(parameter).Test 2 (CIP): Endothelial defense parameter against oxidative stress induced by silica men hydroperoxide (CIP).
인간의 배꼽혈관의 내피세포들은 일반정규처치에 의해서 조제된다. 신선한 배꼽혈관들을 0.1%의 콜라게나아제용액에 담겨지고 37℃에 5분 동안 배양된다.Endothelial cells of human umbilical vessels are prepared by normal regular treatment. Fresh navel vessels are soaked in 0.1% collagenase solution and incubated at 37 ° C. for 5 minutes.
그 후 혈관들은 예들에서 기술된 대로 다른 물질들이 더 첨가된 pH 7.4의 배지 M 199(GIBCO, Grand Island, NY)이 관류된다. 세포들은 원심분리에 의해 관류액으로부터 수집되고, 배양플라스크 T-75에서 배양되며 인간 피부로넥틴으로 전처리된다. 이후 세포들은 10ng/㎖의 소과의 시상하부성장요소가 더 첨가된 동일한 배지에서 배양된다. 초기세포배양의 세포들(즉, ex-vivo로부터 직접 얻음)이 융합성 세포들의 단일층(플라스크 당 8,000,000세포들)으로 형성될 때, 배양은 중단되고 층들은 세정되며 트립신으로 처리된다. 세포의 현탁액들은 24개의 웰들을 가지는 세포배양플레이트의 웰들로 운반되고, 이 웰들의 절반은 10-4M 농도의 약물을 함유하는 동일한 배양배지가 첨가되며, 37℃의 일정한 습기의 자동온도조절장치에서 채취된다. 상기 첫 번째 2차배양으로 생기는 세포들은 규멘 하이드로퍼옥사이드(CIP)와 함께 실험을 위해 사용된다. 세포들은 형태상의 시험 및 인자(factor)(Ⅷ)에 대한 특별한 면역반응에 의해 내피세포들로서 확인되며, 상기 배양은 근세포들 또는 섬유모세포들로부터의 오염이 관측되지 않는다.The vessels are then perfused with medium M 199 (GIBCO, Grand Island, NY), pH 7.4, to which other substances are added, as described in the examples. Cells are collected from the perfusate by centrifugation, incubated in a culture flask T-75 and pretreated with human dermalonectin. The cells are then cultured in the same medium with 10 ng / ml bovine hypothalamic growth factor added. When the cells of the initial cell culture (ie, obtained directly from ex-vivo) form a monolayer of fusion cells (8,000,000 cells per flask), the culture is stopped and the layers are washed and trypsinized. Suspensions of cells are transferred to wells of a cell culture plate with 24 wells, half of which are added with the same culture medium containing a drug at a concentration of 10 −4 M and a thermostatic constant temperature of 37 ° C. Is taken from. The cells resulting from the first secondary culture are used for experiments with silica with hydrosulfite (CIP). Cells are identified as endothelial cells by morphological testing and specific immune responses to factors, and the culture is not observed contamination from myocytes or fibroblasts.
시험을 시작하기 전에, 세포배양배지는 제거되고 세포층들은 조심스럽게 37℃의 생리용액에 의해 세정된다. 이후 배양플레이트의 웰들은 배양배지에 5mM농도의 CIP로 한 시간동안 배양된다. 세포손상(세포자멸)의 평가는 대조군(CIP만으로 처치)에 관한 DNA분쇄의 퍼센트변동측정, 및 405 내지 450㎚의 파장에서의 형광변동의 평가에 의해 실행된다.Before starting the test, the cell culture medium is removed and the cell layers are carefully washed with 37 ° C. physiological solution. The wells of the culture plate are then incubated for one hour at 5 mM CIP in the culture medium. The evaluation of cell damage (apoptosis) is carried out by measuring percent variability of DNA disruption relative to the control group (treated with CIP only) and fluorescence fluctuations at wavelengths of 405 to 450 nm.
약물이 시험에 부합된다, 즉 CIP만으로 처치된 그룹에 관해서 CIP로 유도된 세포자멸(세포손상)의 중요한 억제가 통계적으로 p < 0.01에서 얻어지지 않을 때,일반식(Ⅰ) 및 (Ⅱ)의 화합물들을 조제하기 위해 사용될 수 있다.The drug is matched to the test, i.e. when significant inhibition of CIP-induced apoptosis (cell damage) with respect to the group treated with CIP alone is not statistically obtained at p <0.01, the formulas (I) and (II) It can be used to prepare the compounds.
시험 3(L-NAME): L-NAME((NW-니트로-L-아르기닌-메틸에스테르)J. Clin. Investigation 90, 278-281, 1992)의 투여에 의해 유도되는 내피세포기능장애의 평가.Test 3 (L-NAME): Assessment of endothelial dysfunction induced by administration of L-NAME ((N W -nitro-L-arginine-methylester) J. Clin. Investigation 90, 278-281, 1992) .
내피세포기능장애는 위장관의 점막층에 대한 손상, L-NAME의 투여에 의해 유도되는 간손상 및 고혈압을 측정하여 평가된다.Endothelial dysfunction is assessed by measuring damage to the mucosal layer of the gastrointestinal tract, liver damage induced by administration of L-NAME, and hypertension.
동물들(쥐)은 아래의 그룹들로 나뉘어진다. L-NAME을 수용한 그룹은 4주 동안 음용수에 400mg/ℓ의 농도로 용해된 상기 화합물로 처치된다. 이하의 그룹들은 구성된다(한 그룹에 10마리의 동물들):Animals (rats) are divided into the following groups. The group receiving L-NAME was treated with the compound dissolved at 400 mg / L concentration in drinking water for 4 weeks. The following groups consist of (10 animals in one group):
A)대조군들:A) Controls:
1°군: 담체만(약물이 입을 통해 투여될 때, 비경구적으로 생리용액이 투여될 때, 카르복시메틸셀롤로오스의 수용성 현탁액 1% w/v의 1회투여량: 5㎖/㎏),1 ° group: carrier only (when the drug is administered by mouth, parenterally, when a physiological solution is administered, a single dose of 1% w / v of an aqueous suspension of carboxymethylcellulose: 5 ml / kg),
2°군: 담체 + L-NAME,2 ° group: carrier + L-NAME,
B)약물이 투여된 그룹들:B) Groups in which the drug was administered:
3°군: 담체 + 약물,Group 3 °: carrier + drug,
4°군: 담체 + 약물 + L-NAME,4 ° group: carrier + drug + L-NAME,
투여경로는 약물들에 관해 공지된 경로들이고, 입 또는 피하, 복강, 정맥 또는 근육의 경로가 될 수 있다. 약물은 L-NAME으로 전처치되지 않은 쥐들의 그룹에게는 견딜 수 있는 가장 높은 투여량으로 투여된다, 즉 동물들에서 독성의 증상으로 인식될 수 있는 명백한 독성이 없는 가장 높게 투여될 수 있는 투여량으로 투여된다. 약물은 4주에 하루씩 투여된다.Routes of administration are known routes for drugs and can be oral, subcutaneous, intraperitoneal, intravenous or intramuscular. The drug is administered at the highest dose that can be tolerated in a group of mice not pretreated with L-NAME, ie at the highest dose that can be seen without any apparent toxicity that can be recognized as a symptom of toxicity in animals. Administered. The drug is administered once every four weeks.
4주 처치의 말기에 물에 접근하는 것을 막고 24시간 후에 동물들은 희생된다.Animals are sacrificed 24 hours after access to water at the end of 4 weeks of treatment.
희생되기 1시간 전에 혈압을 측정하고, 혈압증가는 맥관내피세포에 대한 손상의 평가로서 취급된다. 위장관의 점막층에 대한 손상은 표1에서 설명된 대로 평가된다(실시예 F1을 참조). 간손상은 희생 후에 GPT(glutamic-pyruvic transaminase)증가의 평가에 의해 판단된다.Blood pressure is measured 1 hour before sacrifice, and blood pressure increase is treated as an assessment of damage to vasculature. Damage to the mucosal layer of the gastrointestinal tract is assessed as described in Table 1 (see Example F1). Liver damage is judged by evaluation of glutathione-pyruvic transaminase (GPT) increase after sacrifice.
약물은 시험3에 부합된다, 즉The drug meets test 3, ie
L-NAME+약물+담체로 처치된 쥐들의 그룹에서 담체만으로 처치된 그룹, 또는 담체+약물로 처치된 그룹, 또는 담체+L-NAME로 처치된 그룹의 손상과 비교해서 높은 간손상(GPT) 및/또는 높은 위손상 및/또는 높은 심장혈관(혈압)손상이 발견될 때, 일반식(Ⅰ) 및 (Ⅱ)의 화합물들을 조제하기 위해 사용될 수 있고, 특별한 시약들을 사용하여 분석된 약물의 처치효능은 현저하게 감소되지는 않는다.High liver damage (GPT) compared to damage in the group treated with carrier only, or the group treated with carrier + drug, or the group treated with carrier + L-NAME in the group of rats treated with L-NAME + Drug + Carrier and When high gastric and / or high cardiovascular (blood pressure) damage is found, it can be used to prepare compounds of general formulas (I) and (II), and the treatment efficacy of the analyzed drug using special reagents. Is not significantly reduced.
위에서 기술된 생체내의 시험들(1 및 3)에서 지적되는 상태에서, 약물이 효과적일 수 있는 일반투여량들은 더 이상 내용성이 없기 때문에 약물의 처치지수는 줄게된다.In the state indicated in the in vivo tests (1 and 3) described above, the treatment index of the drug is reduced because the general dosages for which the drug can be effective are no longer content.
시험4는 B의 선구물질이 DPPH(2,2-diphenyl-1-picryl-hydrazyl)로부터 라디칼들의 생성물을 억제하는지 여부를 확인할 수 있는 비색시험이다(M.S. Nenster et Al., Atheroscaler. Thromb. 15, 1338-1344, 1995). 시험된 물질들의 메탄올의 100mu M용액이 조제되고, 상기 용액들의 각각의 부분표본에 0.1M의 메탄올의 DPPH용액이 첨가된다. 실온에서 30분 동안 용액을 차광보관한 후에, 동일한 농도에서 대응하는 DPPH용액의 흡광도와 함께 동시에 517㎚의 파장에서 용액의 흡수율이 관측된다. 동일한 농도의 시험용액에서 DPPH용액의 흡광도에 관해서 감소하는 흡수율이 측정된다. DPPH에 의해 라디칼들의 형성을 억제할 때 시험된 화합물의 효능은 이하의 화학식:Test 4 is a colorimetric test to confirm whether the precursor of B inhibits the product of radicals from DPPH (2,2-diphenyl-1-picryl-hydrazyl) (MS Nenster et Al., Atheroscaler. Thromb. 15, 1338-1344, 1995). A 100 mu M solution of methanol of the materials tested was prepared and 0.1 M DPPH solution of methanol was added to each aliquot of the solutions. After shading the solution for 30 minutes at room temperature, the absorbance of the solution was observed at a wavelength of 517 nm simultaneously with the absorbance of the corresponding DPPH solution at the same concentration. The absorbance decreasing with respect to the absorbance of the DPPH solution in the same concentration of test solution is measured. The efficacy of the compounds tested when inhibiting the formation of radicals by DPPH is represented by the formula:
(1-AS/AC)×100(1-A S / A C ) × 100
으로 나타내고, 여기서 AS및 AC는 각각 DPPH와 함께 시험화합물을 포함하는 용액 및 DPPH만을 포함하는 용액의 흡수율들이다.Where A S and A C are the absorption rates of the solution including the test compound and the solution containing only DPPH, respectively, together with DPPH.
위의 관계식에 의해 퍼센트율로서 표현된 DPPH로부터의 라디칼생성물의 억제퍼센트율이 50%이상일 때, B의 화합물선구물질은 시험 4에 부합된다.When the percentage inhibition of radical product from DPPH expressed as percentage rate by the above relationship is greater than 50%, the compound precursor of B is in conformity with test 4.
시험 5는 시험된 생성물들의 10-4M 메탄올용액들의 0.1㎖부분표본이 2mM 데옥시리보스의 0.2㎖, pH7.4 100mM의 인산염버퍼의 0.4㎖ 및 2mM HCl에 1mM의 0.1㎖에 의해 형성된 용액을 포함하는 시험관들에 첨가되는 비색시험이다. 이후 시험관들은 37℃에서 한 시간동안 유지된다. 이후 각 시험관에 순서대로 물에 2.8%의 트리클로로아세트산용액의 0.5㎖ 및 디오바르비투리산의 0.1M 수용액의 0.5㎖가 첨가된다. 기준블랭크는 위에서 기술된 0.1㎖의 메탄올반응물수용액만을 포함하는 시험관에 첨가하여 형성된다. 시험관들은 밀폐되고100℃의 오일중탕에서 약 15분 동안 가열된다. 핑크착색은 라디칼산화감성이 되는 데옥시리보스의 양에 비례하여 색의 크기를 향상시킨다. 용액들은 실온에서 냉각되고 532㎚에서 이들의 흡수율들은 블랭크에 대해서 판독된다. FeⅡ에 의한 라디칼생성물에 대해서 B의 선구물질에 의해 유도되는 억제는 이하의 식Test 5 showed that a 0.1 ml aliquot of 10 -4 M methanolic solutions of the tested products was 0.2 ml of 2 mM deoxyribose, 0.4 ml of 100 mM pH phosphate buffer and 1 mM in 2 mM HCl. A colorimetric test is added to test tubes containing a solution formed by 0.1 ml of. The tubes are then kept at 37 ° C. for one hour. Thereafter, 0.5 ml of 2.8% trichloroacetic acid solution and 0.5 ml of 0.1 M aqueous solution of diobarbituric acid are added to each test tube in order. The reference blank was formed by addition to a test tube containing only 0.1 ml of methanol reactant solution described above. The test tubes are sealed and heated in an oil bath at 100 ° C. for about 15 minutes. Pink coloration improves the size of color in proportion to the amount of deoxyribose that becomes radically oxidative. The solutions are cooled at room temperature and their absorbances at 532 nm are read for the blank. Inhibition induced by the precursor of B for the radical product by Fe II is
(1-AS/AC)×100(1-A S / A C ) × 100
으로 판단되고, 여기서 AS및 AC는 각각 시험된 화합물+철염을 포함하는 용액 및 철염을 포함하는 용액의 흡수율들이며, 화합물은 위에서 B의 선구물질로부터 정의된 라디칼생성물의 %억제가 50%이상일 때 시험5를 부합한다.Where A S and A C are the absorption rates of the tested compound + solution containing iron salt and the solution containing iron salt, respectively, wherein the compound is at least 50% inhibition of the radical product defined from the precursor of B above. When test 5 is met.
산화성스트레스조건들 아래에서, 본 발명의 화학식(Ⅰ)의 생성물들은 선구물질의 약물에 비교해서 향상된 처치지수를 가진다.Under oxidative stress conditions, the products of formula (I) of the present invention have an improved treatment index compared to the precursor drug.
예시의 목적을 위해, 위에서 언급된 시험들은 이하의 화합물들을 참조한다. 표들을 보자.For purposes of illustration, the tests mentioned above refer to the following compounds. Let's look at the tables.
시험1: 선구물질약물: 인도메타신Test 1: precursor drug: indomethacin
쥐들에게 투여될 수 있는 최대투여량: 7.5mg/㎏ p.o. 높은 투여량으로 투여하여, 독성이 나타나고 죽기까지 장질환, 전율, 진정을 특징으로 한다(24시간이내).Maximum dose that can be administered to rats: 7.5 mg / kg p.o. Administration at high doses is characterized by intestinal disease, tremor and sedation until toxicity and death (within 24 hours).
위에서 언급된 투여량에서 NEM+인도메타신으로 처치된 쥐들의 그룹은 위점막손상을 보여준다.Groups of mice treated with NEM + indomethacin at the doses mentioned above show gastric mucosal damage.
NEM으로 처치된 그룹에서 인도메타신은 위점막손상들을 초래하기 때문에, 시험 1에 부합된다. 따라서 인도메타신은 본 발명의 화합물(Ⅰ) 및 (Ⅱ)를 조제하기 위한 약물로서 사용된다.Indomethacin in the group treated with NEM results in gastric mucosal damage and therefore meets test 1. Indomethacin is therefore used as a drug for preparing compounds (I) and (II) of the present invention.
시험 2: 선구물질약물: 인도메타신, 파라세타몰 및 메살아민Test 2: Prodrugs: Indomethacin, Paracetamol and Mesalamine
CIP에 의해 유도된 세포손상(세포자멸)억제가 조절들의 세포손상억제에 대해서 현저하게 다르지 않기 때문에, 인도메타신 및 파라세타몰은 시험2에 부합한다.Indomethacin and paracetamol meet Test 2 because the inhibition of apoptosis induced by CIP is not significantly different for the inhibition of apoptosis of the regulators.
따라서 위의 약물들은 본 발명의 화합물(Ⅰ) 및 (Ⅱ)를 조제하기 위한 약물들로서 사용될 수 있다.Therefore, the above drugs can be used as drugs for preparing the compounds (I) and (II) of the present invention.
반대로, 메살아민은 CIP에 의해 유도된 세포자멸을 억제하기 때문에 메살아민은 시험2와 만나지 않는다. 따라서 시험2에 따른 메살아민은 본 발명의 화합물(Ⅰ) 및 (Ⅱ)를 조제하기 위한 선구물질로서 사용될 수 없다. 하지만 시험1에 제출된 메살아민은 위점막층의 손상들을 초래한다는 것을 알게된다.In contrast, mesalamine does not meet test 2 because mesalamine inhibits apoptosis induced by CIP. Therefore, mesalamine according to test 2 cannot be used as a precursor for preparing compounds (I) and (II) of the present invention. However, the mesalamine submitted to test 1 is found to cause damage to the gastric mucosa.
따라서 메살아민 역시 본 발명의 화합물(Ⅰ) 및 (Ⅱ)를 조제하기 위한 선구물질로서 사용될 수 있다. 시험3(L-NAME)선구물질약물들: 파라세타몰, 심바스타틴, 오메프라조일Therefore, mesalamine can also be used as a precursor for preparing compounds (I) and (II) of the present invention. Test 3 (L-NAME) precursors: paracetamol, simvastatin, omeprazoil
파라세타몰 및 심바스타틴은 L-NAME+담체에 의해서 및 약물+담체에 의해서 유도된 손상들보다 큰 위손상 및 간손상을 초래하기 때문에 시험3에 부합된다.Paracetamol and simvastatin meet Test 3 because they cause greater gastric and hepatic damage than those induced by L-NAME + carrier and drug + carrier.
따라서 이들은 본 발명의 화합물(Ⅰ) 및 (Ⅱ)를 조제하기 위한 선구물질로서 사용될 수 있다.Therefore, they can be used as precursors for preparing compounds (I) and (II) of the present invention.
반대로 오메프라조일은 위손상 또는 간손상을 초래하지 않을 뿐 아니라, 혈압에 영향을 미치지 않는다는 것을 알게됐다. 시험3에 의해서 오메프라조일은 본발명의 화합물(Ⅰ) 및 (Ⅱ)를 조제하기 위한 선구물질로서 사용될 수 없다.Conversely, we found that omeprazoil does not cause stomach or liver damage, nor does it affect blood pressure. Omphrazoil cannot be used as a precursor to prepare compounds (I) and (II) of the present invention under test 3.
시험4(B의 화합물선구물질을 위한 시험)Test 4 (Test for Compound Precursor of B)
상기 시험에서 N-아세틸시스테인은 DPPH에 의해 유도되는 라디칼들의 생성물을 100%로 억제한다. 상기 퍼센트율은 50%의 제한보다 높기 때문에, 상기 약물은 B의 선구물질로서 본 발명에서 사용될 수 없다.N-acetylcysteine in this test inhibits the product of radicals induced by DPPH to 100%. Since the percentage rate is above the 50% limit, the drug cannot be used in the present invention as a precursor of B.
4-티아조일리딘-카르복실산은 DPPH(표V)에 의해 유도된 라디칼들의 생성은 전혀 억제하지는 않는다. 따라서 약물은 본 발명에 의해 요구되는 시험4에 부합되지 않고, 시험5에 부합한다면 B의 선구물질로서 사용될 수 있다.4-thiazoyridine-carboxylic acid does not inhibit the production of radicals induced by DPPH (Table V) at all. Thus, the drug does not meet the test 4 required by the present invention and can be used as a precursor of B if it meets the test 5.
시험5(B의 화합물선구물질을 위한 시험)Test 5 (Test for Compound Precursor of B)
이 시험에 관련되는 표 Ⅲ은 4-티아조일리딘카르복실산은 억제가 100%이기 때문에 시험5에 부합한다는 것을 보여준다. 따라서 화합물은 B의 선구물질로서 사용될 수 있다.Table III relating to this test shows that 4-thiazoyridinecarboxylic acid meets test 5 because the inhibition is 100%. Thus the compound can be used as a precursor of B.
바람직하게 본 발명의 화학식(Ⅰ)의 화합물들에서, B는 XZ 및의 하나 또는 그 이상 선택된 자유반응기들을 포함하고, 여기서 X, Z, ZⅠ및 ZⅡ는 상기 정의된 것과 같거나 또는 COOH, =NH이다.Preferably in the compounds of formula (I) of the invention, B is XZ and And one or more selected free reactors, wherein X, Z, Z I and Z II are as defined above or COOH, = NH.
B는 반응기으로 포화된 자유원자가를 갖는 화학식(III)B is of formula (III) having free atoms saturated with a reactor
의 화합물들과 반응하게 하여 B의 자유반응기와 반응할 수 있게 하고,React with the free compounds of B to react with
여기서 nⅨ는 0과 3 사이 정수, 바람직하게는 1이고;Wherein n 'is an integer between 0 and 3, preferably 1;
같거나 또는 서로 다른 RTⅨ, RTⅨ′는 H 또는 선형 또는 분지형 C1-C4알킬, 바람직하게는 RTⅨ, RTⅨ′는 H 이고;The same or different R TⅨ, TⅨ R 'is H or a linear or branched C 1 -C 4 alkyl, preferably R TⅨ, TⅨ R' is H;
Y3은 포화된, 불포화된 또는 방향성 헤테로고리로 적어도 하나의 질소원자를 함유하며, 상기 고리는 5 또는 6 원자들을 가진다. Y3고리은 선택적으로 예를 들어 CH2OH의 치환기들을 가질 수 있다.Y 3 is a saturated, unsaturated or aromatic heterocycle containing at least one nitrogen atom, the ring having 5 or 6 atoms. Y 3 ring may optionally have substituents of, for example, CH 2 OH.
화학식(III)의 Y3은 바람직하게Y 3 in formula (III) is preferably
에서 선택된다.Is selected.
Y3의 가장 바람직한 화합물은 Y12(피리딜)이다.The most preferred compound of Y 3 is Y12 (pyridyl).
화학식(I)화합물염들은 아세토니트릴, 테트라하이드로푸란과 같은 유기용제에서 대응하는 유기 또는 무기산의 동일분자량과의 반응에 의해 얻어질 수 있다.Compound salts of formula (I) may be obtained by reaction with the same molecular weight of the corresponding organic or inorganic acid in an organic solvent such as acetonitrile, tetrahydrofuran.
유기산들의 예들은 수산, 주석산, 말레인산, 숙신산, 시트르산.Examples of organic acids are hydroxyl, tartaric acid, maleic acid, succinic acid, citric acid.
무기산들의 예들은 질산, 염산, 황산, 인산.Examples of inorganic acids are nitric acid, hydrochloric acid, sulfuric acid, phosphoric acid.
본 발명에 따른 유도체들은 이하 예시된 이들 약물들의 몇 가지 그룹들에 대한 장점들을 얻을 수 있는 선구물질약물의 치료징후(therapeutic-indications)에 사용될 수 있다:Derivatives according to the present invention can be used in therapeutic-indications of prodrugs that can benefit from several groups of these drugs illustrated below:
- 항염증제NSAID들: 본 발명의 화합물들의 결과는 유기체조직이 허약해질지라도 매우 양호하고 효과적이며, 산화성스트레스의 조건들아래에서도 발견된다. 상기 약물들은 염증이 예를 들어, 암, 천식, 심근경색 등에 한정되지 않고 현저한 발병원으로 작용하는 이런 병리들에 역시 사용될 수 있다.Anti-Inflammatory NSAIDs: The results of the compounds of the present invention are very good and effective even if the tissues are weak, and are found even under conditions of oxidative stress. The drugs can also be used in these pathologies where inflammation acts as a significant pathogen and is not limited to cancer, asthma, myocardial infarction, and the like.
- α또는 β차단제형의 아드레날린차단제들: 화학식(Ⅰ)화합물들의 작용스펙트럼은 출발약물들의 작용스펙트럼보다 넓은 결과를 가지며, 혈관들의 수축을 지배하는 신경성베타아드레날린신호들의 억제는 근육조직상의 직접작용에 관여한다. 호흡기관에 영향을 끼치는 부작용들(호흡곤란, 기관지수축)은 감소한다.adrenergic blockers of the α or β blocker type: the spectrum of action of the compounds of formula (I) has a broader result than that of the starting drugs, and the inhibition of neuronal beta-adrenergic signals, which govern the contraction of blood vessels, has a direct effect on muscle tissue Get involved. Side effects that affect the respiratory tract (shortness of breath, bronchial contraction) are reduced.
- 항혈전약물들: 항혈소판작용은 강화되고 아스피린유도체들의 경우에 위의 내용성은 개선된다.Antithrombotic drugs: Antiplatelet action is enhanced and gastric contents are improved in the case of aspirin derivatives.
- 기관지확장제들 및 콜린계에 작용하는 약물들: 심혈관기관에 미치는 부작용들(빈박증, 고혈압)은 감소된다.-Bronchodilators and drugs that act on the cholinergic system: Side effects on the cardiovascular organs (retinopathy, hypertension) are reduced.
- 거담제 및 점액용해약들: 위장관의 양호성을 향상시킨다.Expectorants and mucolytic drugs: improve the goodness of the gastrointestinal tract.
- 디포스포네이트들: 위장관에 관여하는 독성이 현저히 감소했다.Diphosphonates: Significantly reduced toxicity associated with the gastrointestinal tract.
- 포스포디에스테라제(PDE)억제제들(기관지확장제들): 투여량은 동일해도 처치효능은 개선되고, 약물의 낮은 투여량으로 투여하고 부작용을 줄이기 위해서 본 발명의 화합물을 사용할 수 있다.Phosphodiesterase (PDE) inhibitors (bronchodilators): Compounds of the invention can be used to improve treatment efficacy even at the same dose, to administer at lower doses of the drug and to reduce side effects.
- 항백혈구약물: 좋은 효능.Anti-leukocyte drug: good efficacy.
- ACE억제제들: 좋은 처치효능 및 호흡기관에 미치는 낮은 부작용들(호흡곤란, 기침).ACE inhibitors: good treatment efficacy and low side effects on the respiratory tract (difficulty breathing, coughing).
- 항당뇨약물들(인슐린-민감성 및 저혈당), 항생제, 항바이러스약, 항종양약, 항결장염약, 치매처치용 약물들: 좋은 효능 및/또는 내용성.Antidiabetic drugs (insulin-sensitive and hypoglycemic), antibiotics, antiviral drugs, antitumor drugs, anticolonitis drugs, dementia drugs: good efficacy and / or content.
본 발명의 화합물들의 일반식에서 선구물질로서 사용될 수 있는 약물들은 위의 시험들(1,2,3)중의 적어도 하나와 부합되는 약물들이다. 사용될 수 있는 선구물질약물들의 예들은 이하와 같다:Drugs that can be used as precursors in the general formula of the compounds of the present invention are drugs that meet at least one of the above tests (1, 2, 3). Examples of precursor drugs that can be used are:
항염증제/진통제들에서, 이하는 예로서 언급될 수 있다:In anti-inflammatory / painkillers, the following may be mentioned by way of example:
항염증제들: 아세클로페낙, 아세메타신, 아세틸살리실산, 5-아미노아세틸살리실산, 알클로페낙, 아미노프로펜, 암페낙, 벤다작, 베르모프로펜, α-비사보롤, 브롬페낙, 브로모살리게닌, 부클록스산, 부티부펜, 카르프로펜, 신메타신, 클리다낙, 클로피락, 디클로페낙나트륨, 디플루니살, 디타조일, 엔펜암산, 에토도락, 에토펜암산염, 펠비낙, 펜부펜, 펜클로즈산, 펜도살, 페노프로펜, 펜티아작, 페프라디놀, 플루펜암산, 플루닉신, 플루녹사프로펜, 플루르비프로펜, 글루카메타신, 살리실산글리콜, 이부프로펜, 이부프록삼, 인도메타신, 인도프로펜, 이소페조락, 이소크세팍, 이소크시캠, 케토프로펜, 케토롤락, 롤녹시캠, 록소프로펜, 메클로펜암산, 메펜암산염, 멜록시캠, 메살아민, 메티아진산, 모페조일락, 나프록센, 니플룸산, 올사라진, 옥사세프롤, 옥사프로진, 옥시펜부타존, 파르살미드, 페리속살, 살리실산페닐아세틸, 피라조일락, 피록시캠, 피르프로펜, 피라노프로펜, 프로티진산, 살라세트아미드, 살리실아미드, O-아세트산, 살리술풀산, 살살산, 수린닥, 수프로펜, 숙시부존, 테녹시캠, 티아프로펜산, 티아르아미드, 티노리딘, 톨펜암산, 톨메틴, 트로페신, 크센부신, 크시모프로펜, 잘토프로펜, 조메피락, 토목시프롤;Anti-inflammatory agents: aceclofenac, acemethacin, acetylsalicylic acid, 5-aminoacetylsalicylic acid, alclofenac, aminopropene, amphenac, bendazac, vermopropene, α-bisabolol, bromfenac, bromosalgenin , Butoxoxane, butybufen, carpropene, synmethacin, clidanac, clopirac, diclofenac sodium, diflunisal, ditazoyl, enphenamic acid, etodorax, etofen ammonium, felbinac, fenbufen, pen Clomic Acid, Fendosal, Phenopropene, Pentiazac, Pepradinol, Flufenamic Acid, Flunicin, Fluoxaprofen, Flubiprofen, Glucametacin, Glycylic Acid Glycerate, Ibuprofen, Ibuprosam, India Methacin, indopropene, isofezolac, isoxepac, isoxycam, ketoprofen, ketorolac, rolloxycam, loxoprofen, meclofenamic acid, mefenamic acid salt, melooxycam, mesal Min, methiazine acid, mofezolac, naproxen, niflumum, olsarazine, oxaceprole, jade Prozin, Oxyfenbutazone, Parsalmid, Perisal Salicylic Acid, Phenylsalicylate, Pyrazoilac, Pyroxycam, Pirpropene, Pyranopropene, Proticinic Acid, Salacetamide, Salicylate, O- Acetic acid, salicylic acid, salicylic acid, surindoc, suprofen, succinic zone, tenoxycam, thiapropene acid, tiaramide, tinolidine, tolphenamic acid, tolmetin, tropecin, xenbucin, ximopro Pens, zaltoprofen, jomepilac, civil ciprolol;
진통제들: 아세트아미노펜, 아세트아미노사롤, 아미노클로르테녹사진, 2-아미노-4-피콜린 아세틸살리실산, 아세틸살리실살리실산, 아니레리딘, 베녹사프로펜, 벤질모르핀 , 아세테이트 5-브롬살리실산, 부세틴, 부프레노르핀, 부토르파놀, 카프사이신, 신코펜, 시라마돌, 크로메타신, 크로닉신, 코데인, 데소모르핀, 데조신, 디히드로코데인, 디히드로모르핀, 디메펩타놀, 디피로세틸, 엡타조신, 에탁사젠, 에틸모르핀, 유게놀, 플록타페닌, 포스포살, 글라페닌, 히드로코돈, 히드로모르폰, 히드록시페티딘, 이부페낙, p-락토페네타이드, 레보르파놀, 멥타지놀, 메타조신, 메토폰, 모르핀, 날부핀, 니코모르핀, 노르레보르파놀, 노르모르핀, 옥시코돈, 옥시모르폰, 펜타조신, 페나조신, 페노콜, 페노페리딘, 페닐부타존, 페닐살리실산, 페닐라미돌, 살리신, 살리실아미드, 티오르판, 트라마톨, 디아세린, 아크타리트;Analgesics: acetaminophen, acetaminosarol, aminochlortenoxazine, 2-amino-4-picolin acetylsalicylic acid, acetylsalicylicsalicylic acid, aniridine, benoxapropene, benzylmorphine, acetate 5-brosalicylic acid, Busetine, buprenorphine, buttorpanol, capsaicin, cinnafen, siramadol, chromatacin, croniccin, codeine, desormorphine, dezosin, dihydrocodeine, dihydromorphine, dimeptanol, dipy Rosetyl, Eptazosin, Etaxazen, Ethyl Morphine, Eugenol, Plutaphenin, Phosphosal, Glafenin, Hydrocodone, Hydromorphone, Hydroxyfetidine, Ibufenac, p-lactophenetide, Levorpanol, meptazinol, metazosin, methopone, morphine, nalbuphine, nicomorphine, norreborganol, normorphine, oxycodone, oxymorphone, pentazosin, phenazorcin, phenolcol, phenoferidine, phenylbuta John, Phenylsalicylic Acid, Phenylamidol, Salicycin, Salicylate Silamide, thiorphan, tramatol, diserine, acrotite;
호흡 및 비뇨생식기약물들(콜린성계에 작용하는 약물들 및 기관지확장제들, 거담제/점액용액성 약물, 항천식/항알레르기 항히스타민약물들)에 대해서, 이하로 언급될 수 있다:For respiratory and urogenital drugs (drugs that act on the cholinergic system and bronchodilators, expectorants / mucolytic drugs, anti-asthma / antiallergic antihistamines), the following may be mentioned:
콜린성계에 작용하는 약물들 및 기관지확장제들: 아세필린, 알부테롤, 밤부테롤, 바미필린, 베보니움메틸술프산, 비톨테롤, 카르부테롤, 클렌부테롤, 클로르프레날린, 디옥세테드린, 디필린, 에페드린, 에피네프린, 에프로지놀, 에타프레디닌, 에틸노르에피네프린, 에토필린, 페노테롤, 브롬화플루토프리움, 헥소프레날린, 브롬화이프라트로피움, 이소에타린, 이소프로테네롤, 마부테롤, 메타프로테네롤, 옥시부티닌, 부롬화옥시트로피움, 피르부테롤, 프로카테롤, 프로토킬롤, 프록시필린, 레프로테롤, 리미테롤, 살메테롤, 소테레놀, 테르부탈린, 1-테오브로민아세트산, 브롬화티오트로피움, 트레토퀴놀, 툴로부테롤, 자프리나스트, 시클로드린, NS-21, 2-히드록시-2,2-디페닐-N-(1,2,3,6-테트라히드로-피리딘-4-일메틸)아세트아미드;Drugs and bronchodilators acting on the cholinergic system: acefilin, albuterol, bambuterol, bamifilin, bebornium methylsulfonic acid, bitolterol, carbuterol, clenbuterol, chlorprenerin, dioxetine Drin, Diphylline, Ephedrine, Epinephrine, Eproginol, Etapredinin, Ethylnorpinephrine, Etophylline, Phenoterol, Plutoprimium, Hexoprelinin, Bromide Pratropium, Isoetarin, Isoprotenerol, Mabuterol, metaprothenerol, oxybutynin, oxytropinum bromide, pybuterol, procaterol, protochillol, proxiphylline, leproterol, limitrol, salmeterol, soterenol, terbutalin , 1-Theobromineacetic acid, thiotropium bromide, tretoquinol, tulobuterol, japrinast, cyclodrin, NS-21, 2-hydroxy-2,2-diphenyl-N- (1,2,3 , 6-tetrahydro-pyridin-4-ylmethyl) acetamide;
거담제/점액용액성 약물들: 암브로옥솔, 브롬헥신, 도미오돌, 에르도스테인, 구아이아콜, 구아이페네신, 이오딘산글리세롤, 레토스테인, 메스나, 소브레놀, 스테프로닌, 테르핀, 티오프로닌;Expectorants / mucolytic drugs: ambrooxol, brominehexine, domiodol, erdossteine, guaiacol, guapenesine, glycerol iodide, letosteine, mesna, sorbenol, stepronin, terpine , Thiopronin;
항천식/항알레르기 항히스타민약물들: 아크리바스틴, 알로클아미드, 암렉사녹스, 세티리진, 클로벤제팜, 크로모글리산, 클로몰린, 에피나스틴, 펙소페나딘, 포르모테롤, 히스타민, 히드록시진, 레보카바스틴, 로독스아미드, 바부테롤, 메트론s, 몬텔루카스트, 네도크로밀, 레피리나스트, 세라트로다스트, 수풀라타스트토실산, 테르펜아딘, 티아르아미드, 우루시올, 브롬헥신;Anti-asthmatic / antiallergic antihistamines: acribastine, allocamide, amlexoxox, cetirizine, clobenzepam, chromoglylic acid, clomoline, epinastine, fexofenadine, formoterol, histamine, hydroxyzin , Levocarbastine, rodoxamide, babuterol, metrons, montelukast, nedocromyl, repirinast, ceratodast, supulastastyl acid, terpenadine, tiaramide, urushiol, Brohexine;
ACE억제제들: 알라케플릴, 베나제프릴, 캡토프릴, 세르나프릴, 실라자프릴, 델라프릴, 에날라프릴, 에날라프릴라트, 포시노프릴, 이미다프릴, 리시노프릴, 노사르탄, 모벨티프릴, 나프토피딜, 페린도프릴, 퀴나프릴, 라미프릴, 스피라프릴, 테모카프릴, 트라돌라프릴, 우라피딜;ACE inhibitors: arachepril, benazepril, captopril, sernaphril, silazapril, delapril, enalapril, enalapril, posinopril, imidapril, risinopril, nosartan, mo Beltifril, naphthopidil, perindopril, quinapril, ramipril, spirapril, temocapryl, tradolapril, urapidil;
베타차단제들: 아세부토롤, 알프레노롤, 아모술라롤, 아로티노롤, 아테노롤, 베탁솔롤, 베반토롤, 부크모롤, 부페토롤, 부프라롤, 부니트로롤, 부프라노롤, 부토피롤, 카라조롤, 카프테오롤, 카르베디롤, 셀리프로롤, 세타모롤, 디레발롤, 에파노롤, 에스모롤, 인데노롤, 라베타롤, 메핀도롤, 메티프라노롤, 메토프로롤, 모프로롤, 나도롤, 나독소롤, 네비보롤, 니페나롤, 니프리다롤, 옥프레노롤, 펜부토롤, 핀도롤, 프라크토롤, 프로네타롤, 프로프라노롤, 소타롤, 술피나롤, 탈리노롤, 테트타토롤, 틸리소롤, 티모롤, 톨리프로롤, 크시베노롤;Beta-blockers: acebutorol, alprenolol, amosulolol, arotinolol, atenolol, betaxolol, bevantolol, bukmorol, bufetolol, bupralol, bunitrolol, bupranolol, bubutolol Topyrrole, Carrazorol, Capterool, Carvedilol, Celiprolol, Cetamolol, Direvalol, Epanolol, Esmolol, Indenolol, Labetalol, Mepindorol, Metipranolol, Metoprolol, Morphrolol, nadorol, nadoxoroll, nebivorol, nifenarol, nifridarol, oxprenolol, fenbutolol, pindorol, practorol, pronetrol, propranolol, sotarol, sul Pinarol, tallolinol, tetatorol, tilisorol, timolol, toliprolol, xibenolol;
항혈전성약물들 및 혈관확장제들: 아세트르판, 아세틸살리실산, 아르가트로반, 바메탄, 벤프로딜, 헤미숙신산, 베지오다론, 베타히스틴, 브로빈카민, 부펜요드, 시티콜린, 클로벤프롤, 클로피도그렐, 시클란델산, 달테파린, 디피리드아몰, 드로프렌닐아민, 에녹사파린, 펜딜린, 이펜프로딜, 일로프로스트, 인도부펜, 이스보그렐, 이소크수프린, 헤파린, 라미피반, 미도드린, 나드로파린, 니코티닐알콜, 닐리드린, 오자그렐, 페르헥실린, 페닐프로파놀아민, 프레닐아민, 파파베놀린, 레비파린염화나트륨, 리도그렐, 술로크티딜, 티노페드린, 틴자파린, 트리플루살, 크산티놀니아신산;Antithrombotic drugs and vasodilators: Acetpan, acetylsalicylic acid, argatroban, methane, benprodil, hemisuccinic acid, beziodarone, betahistin, brovincarmine, bufeniod, citcholine, chlorine Benprol, Clopidogrel, Cyclendelic Acid, Dalteparin, Dipyridamol, Droprenylamine, Enoxaparin, Pendylin, Ifenprodil, Iloprost, Indobufen, Isvogrerel, Isosuphrine, Heparin, Ramipivan , Mididorin, nadroparin, nicotinyl alcohol, niliderin, ozagrel, perhexylline, phenylpropanolamine, prenylamine, papavenoline, sodium levparin chloride, lidogrel, sulfoctidyl, tinophedrine , Tinzaparin, triflusal, xanthinolinic acid;
당뇨병처치제들: 아카르보스, 카르부트아미드, 글리보르누화글리부티아조일, 미글리톨, 레파글리니드, 트로글리타존, 1-부틸-3-메타닐-우에아, 톨레스타트, 니코틴아미드;Diabetic agents: acarbose, carbutamide, glyborgnuglybutiazoyl, miglitol, repaglinide, troglitazone, 1-butyl-3-methanyl-uea, tolesatt, nicotinamide;
항종양성약물들: 안시타빈, 안트라마이신, 아자시티딘, 아자세린, 6-아자우리딘, 비칼루트아미드, 카루비신, 카르지노필린, 클로르암부실, 클로로조토신, 시타라빈, 다우노루비신, 데포스프아미드, 데메콜신, 데노프테린, 6-디아조-옥소-L-노르레우신, 도세탁셀, 독시플루리딘, 독소루비신, 드롤록시펜, 에타트렉산, 에플로니틴, 에노시타빈, 에피루비신, 에피티오스타놀, 에타니다조일, 에토포시드, 펜레티니드, 플루다라빈, 플루오로우라실, 겜시타빈, 헥세스트롤, 이다루비신, 로니다민, 만노무스틴, 멜팔란, 메노가릴, 6-메르카프토푸린, 메토트렉산, 미토브로니톨, 미톨라크톨, 미토마이신, 미톡산트론, 모피다몰, 미코페놀산, 니노프테린, 노갈라마이신, 파클리탁셀, 펜토스타틴, 피라루비신, 피리트렉심, 플리카마이신, 포도필산, 포르머나트륨, 포르피로마이신, 프로파게르마늄, 푸로마이신, 라니무시틴, 레티노산, 로퀴니멕스, 스트레프토니그린, 스트레프토조신, 테니포시드, 테누아조산, 티아미프린, 티오구아닌, 토무덱스, 토포테칸, 트리메트렉스산, 투베르시딘, 우베니멕스, 빈블라스틴, 빈크리스틴, 빈데신, 비노렐빈, 조루비신;Antitumor drugs: Ancitabine, Anthramycin, Azacytidine, Azaserine, 6-Azauridine, Bicalutamide, Carrubicin, Carboxinophylline, Chlorambucil, Chlorozotocin, Cytarabine, Daunorubicin, Dephosphopamide, demecolsin, denophtherine, 6-diazo-oxo-L-norleucine, docetaxel, doxyfluidine, doxorubicin, droloxifene, etatrexane, eplonitine, enositabine, epi Rubicin, epithiostanol, etanidajoil, etoposide, penretinide, fludarabine, fluorouracil, gemcitabine, hexestrol, idarubicin, ronidamin, mannomustine, melphalan, meno Garyl, 6-mercaptopurine, methotrexane, mitobronitol, mitolactol, mitomycin, mitoxantrone, furdamol, mycophenolic acid, ninophtherine, nogalamycin, paclitaxel, pentostatin, pyrarubicin Sin, pyritrexim, plicamycin, grape phytic acid, sodium former, porphy Mycin, propagermanium, puromycin, lanimuscitin, retinoic acid, loquinimex, streptonigrin, streptozosin, teniposide, tenuazoic acid, thiamiprine, thioguanine, tomusdex, topotecan , Trimetrex acid, tubercidine, ubenimex, vinblastine, vincristine, vindesine, vinorelbine, zorubicin;
항궤양성약물들: ε-아세트아미드카프로산, 아르바프로스틸, 세트락스산, 시메티딘, 에카베트, 엔프로스틸, 에사프라조일, 이르소글라딘, 미소프로스톨, 오메프라조일, 오르노프로스틸, 판토프라조일, 플라우노톨, 리오프로스틸, 로사프로스톨, 로드락스산, 소팔콘, 트리모프로스틸;Anti-ulcer drugs: ε-acetamide caproic acid, arbaprostill, setaxic acid, cimetidine, ecabet, enprosteel, esaprazoil, irsogladine, misoprostol, omeprazoil, ornoprostill , Pantophrazoyl, flaunotol, lioprostil, rosaprostol, lordaxic acid, sofalcone, trimoprostill;
항고지혈성약물들: 아토르바스타틴, 실라스타틴, 테르모스타틴, 플르바스타틴, 로바스타틴, 메바스타틴, 니스타틴, 펜토스타틴, 펩스타틴, 나트륨프리바스타틴, 심바스타틴;Antihyperlipidemic drugs: atorvastatin, cilastatin, termostatin, flvastatin, lovastatin, mevastatin, nystatin, pentostatin, pepstatin, sodium prevastatin, simvastatin;
항생제들: 암디노실린, 아목시실린, 암피실린, 아팔실린, 아피시클린, 아스폭시실린, 아지드암페니콜, 아지도실린, 아즈로실린, 아즈트레오남, 벤조일파스, 벤질페니실린산, 비아페넴, 비코자마이신, 카프레오마이신, 카르베니실린, 카린다실린, 칼루모남, 세파크로르, 세파드록실, 세파만돌, 세파트리진, 세파제돈, 세파조일린, 세프부페라존, 세프클리딘, 세프디니르, 세프디토렌, 세페핌, 세페타메트, 세픽심, 페프메녹심, 세프메타조일, 세프미녹스, 세포디짐, 세포니시드, 세포페라존, 세포라니드, 세포탁심, 세포테탄, 세포티암, 세포크시틴, 세포조프란, 세프피미조일, 세프피르아미드, 세프피롬, 세프프로질, 세프록사딘, 세프술로딘, 세프타지딤, 세프테람, 세프테조일, 세프티부텐, 세프티오푸르, 세프티클래스심, 세프트리악손, 세푸록심, 세푸조남, 세파세트릴나트륨, 세팔렉신, 세팔로글리신, 세팔로리딘, 세팔로스포린C, 세팔로틴, 세파피린나트륨, 세프라딘, 클로르암페니콜, 클로르테트라시클린, 시녹사신, 클라불란산, 클로메토실린, 클로옥사실린, 시클라실린, 시클로세린, 데메클로시클린, 디클로옥사실린, 에피실린, 펜베실린, 플로목세프, 플로옥사실린, 헤타실린, 이미페넴, 네남피실린, 로라카프베프, 리메시클린, 마페니드, 메클로시클린, 메로페넴, 메타암피실린, 메타시클린, 메티실린나트륨, 메즐로실린, 미노시클린, 목살라크탐, 무피로신, 마이신, 네가마이신, 노보비오신, 옥사실린, 파니페넴, 염화칼륨페니실린G, 페니실린N, 페니실린O, 페니실린V, 염화칼륨페네티실린, 피파시클린, 피페라실린, 피르리마이신, 포르피로마이신, 프로피실린, 퀴나실린, 리티페넴, 롤리테트라실린, 산시클린, 세데카마이신, 스페크티노마이신, 술바크탐, 술베니실린, 테모실린, 테트라크실린, 타카르실린, 티게모남, 투베르시딘, 아지트로마이신, 클라리트로마이신, 디리트로마이신, 엔비오마이신, 에리트로마이신, 조사마이신, 미덱카마이신, 미오카마이신, 올레안도마이신, 리파부틴, 리파아미드, 리파마이신, 리파크시민, 로키타마이신, 스피라마이신, 트롤레안드로마이신, 비오마이신, 비르기니아마이신; 아미카신, 아프라마이신, 아르베카신, 디베카신, 디히드로스트렙토마이신, 포르티미신, 겐타미신, 마이크로노미신, 네오마이신, 네틸미신, 파로모마이신, 리보스타마이신, 시소미신, 스펙티노마이신, 스트렙토마이신, 토브라마이신, 트로스펙토마이신; 바캄피실린, 피복실세프카펜, 프록세틸세프포독심, 파니페넴, 피밤피실린, 피브세팔렉신, 술타미실린, 탈람피실린; 카르보마이신, 클린다마이신, 린코마이신, 미카마이신, 로사라미신, 시프로플록사신, 크리나플록사신, 디플록사신, 에녹사신, 엔로플로사신, 플레록사신, 플루메퀸, 글레파플록사신, 로메플록사신, 나디플록사신, 날리딕산, 노르플록사신, 오플록사신, 파주플록사신, 페플록사신, 피페미드산, 피로미드산, 루플록사신, 스파르플록사신, 토수플록사신, 트로바플록사신, 클로모시클린, 구아메시클린, 옥시테트라시클린, 니푸르피리놀, 니푸르프라진; p-아미노살리실산, p-아미노살리실산히드라지드, 클로파지민, 데옥시디히드로스트렙토마이신, 에탐부톨, 글리코니아지드, 이소니아지드, 오피니아지드, 페닐아미노살리실산, 리팜핀, 피파펜틴, 살리나지드, 4-4′-술피닐디아닐린, 아세디아술폰, 다프손, 숙시술폰, p-술파닐리벤질아민, 티아조일술폰, 아세틸술파메트옥시피라진, 마페니드, 4′-(메틸술파모일)술파닐아닐리드, 살라조술파디미딘, 술파벤즈아미드, 술파세트아미드, 술파클로르피리다진, 술파클리소이딘, 술파키틴, 술파디아진, 술파디크르아미드, 술파디메톡신, 술파독신, 술파에티돌, 술파구아니딘, 술파구아놀, 술팔렌, 술파메라진, 술파메테르, 술파메타진, 술파메티조일, 술파메토미딘, 술파메톡사조일, 술파메톡시피리다진, 술파메틸티아조일, 술파메트롤, 술파미도크리죠딘, 술파목솔, 술파닐아미드, 2-p-술파닐릴라닐리노에타놀, N4-술파닐릴술파닐아미드, 술파닐릴루레아, N-술파닐릴-3,4-크실아미드, 술파페린, 술파페나조일, 술파프로옥실린, 술파피라진, 술파피리딘, 술파소미조일, 술파시마진, 술파티아조일, 술파티오우레아, 술피소미딘, 술피소옥사조일, 4-술파닐아미도살리실산; 네가마이신, 카르모난, 클로옥시퀸, 니트로옥솔린, 아르기닌, 메트로니다조일;Antibiotics: Amdinocillin, Amoxicillin, Ampicillin, Apalcillin, Apicycline, Aspoxicillin, Azidamphenicol, Azidocillin, Azrocillin, Aztreonam, Benzoylpas, Benzylpenicillin, Viapenem, Bikozamycin, Capreomycin, Carbenicillin, Carindacillin, Kalumonam, Sephacror, Sephadroxil, Sephamandol, Sephatrizin, Sephazedon, Sephazolin, Sepbuferrazone, Cephclidine, Cef Dinir, ceftitorene, cefepime, cefetameth, seppicsim, pefmenoxime, ceftamezoyl, cefminox, cedidimide, cenisid, cefeperazone, celanide, cefotaxime, cetetan, ceftiam , Cytoxitine, cytozofran, cefepimizole, ceftyramide, ceftirom, ceftrozil, ceproxadine, ceftsulodine, ceftazidime, cefteram, ceftezoyl, ceftibuten, ceftiofur , Safety class, ceftriaxone, cepuroxime, cepuzo , Cephacetyl sodium, cephalexin, cephaloclycin, cephaloridine, cephalosporin C, cephalotin, cephapyrine sodium, cepradine, chloramphenicol, chlortetracycline, synoxacin, clavulanic acid , Clometocillin, Clooxacillin, Cyclacillin, Cycloserine, Demeclocycline, Diclooxacillin, Epicillin, Penvecillin, Flomoxef, Flooxacillin, Hetacillin, Imiphenem, Nenampicillin, Laura Capvef, Rimesiclin, Mafenide, Meclocycline, Meropenem, Metaampicillin, Metacycline, Sodium Methicillin, Mezlocillin, Minosicline, Moxalactam, Mupyrosine, Mycin, Nexamycin , Novobiocin, Oxacillin, Panichenem, Potassium Chloride Penicillin G, Penicillin N, Penicillin O, Penicillin V, Potassium Chloride Penicillin, Pipacycline, Piperacillin, Pyrimycin, Porphyromycin, Propicillin, Quinacillin , Riptpenem, lolitetracillin, shaanxi Clin, cedemycin, spectinomycin, sulfactam, sulfenicillin, temocillin, tetraxillin, tacarcillin, tigemonam, tubercidine, azithromycin, clarithromycin, dirithromycin, Enbiomycin, erythromycin, probemycin, middecamycin, myokamycin, oleandomycin, rifabutin, lipamide, rifamycin, lipamycin, locamycin, spiramycin, troleandromycin, biomycin, Virginiamycin; Amikacin, apramycin, arbecasin, dibecasin, dihydrostreptomycin, fortimycin, gentamicin, micronomycin, neomycin, netylmycin, paromomycin, ribostamycin, sisomicin, spec Tinomycin, streptomycin, tobramycin, tropectomycin; Bacampicillin, Cochsylcepchafen, Proxetylcepofoxime, Pannimem, Pibampicillin, Fibcephalexin, Sulamicillin, Talampicillin; Carbomycin, Clindamycin, Lincomycin, Micamycin, Rosaramimycin, Ciprofloxacin, Crinafloxacin, Difloxacin, Enoxacin, Enlofloscin, Floxacin, Flumequine, Glepafloxacin, Lomefloxacin , Nadifloxacin, nalidic acid, norfloxacin, oploxacin, pajufloxacin, pefloxacin, pipemide, pyromidic acid, lufloxacin, sparfloxacin, tosufloxacin, trobafloxacin , Chlomocycline, Guamecycline, Oxytetracycline, Nipurininol, Nipurrazine; p-aminosalicylic acid, p-aminosalicylic acid hydrazide, clofazimin, deoxydihydrostreptomycin, ethambutol, glyconiazide, isoniazid, opiniazide, phenylaminosalicylic acid, rifampin, pipefatin, salinazide, 4-4 ′ Sulfinyldianiline, acediasulfone, dapsone, succisulfone, p-sulfanilibenzylamine, thiazoylsulfone, acetylsulfamethoxypyrazine, maphenide, 4 '-(methylsulfamoyl) sulfanylanilide, sala Zosulfadimidine, Sulfabenzamide, Sulfacetamide, Sulfachlorpyridazine, Sulfaclisoidine, Sulfachitin, Sulfadiazine, Sulfadicuramide, Sulfadimethine, Sulfadoxin, Sulfathidol, Sulfaguanidine, Sulfagua Knol, Sulfalen, Sulfamerazine, Sulfameter, Sulfamethazine, Sulfametijoil, Sulfametomidine, Sulfametoxajo, Sulfamethoxypyridazine, Sulfamethylthiazole, Sulfametrol, Sulfamidorizo Dean, Sulfur , Sulfanyl amide, 2-p- sulfanyl GW carbonyl Reno ethanol, N 4 - sulfanyl rilsul isoquinoline amides, isoquinoline rilru Lea, N- sulfanyl-3,4 keusil vanillyl amide, sulfamic Perrin, Pape alcohol or one trillion days, Sulfaprooxylin, sulfapyrazine, sulfapyridine, sulfasomizoyl, sulfazimazin, sulfatiazoyl, sulfatiurea, sulfisomidine, sulfisoxazoyl, 4-sulfanamidosalicylic acid; Negamycin, Carmonan, Clooxyquine, Nitrooxolin, Arginine, Metronidazole;
항바이러스약물들: 아시클로비르, 아만타딘, 시도포비르, 시타라빈, 디다노신, 디데옥시아데노신, 에독수딘, 팜시클로비르, 플록수리딘, 간시클로비르, 이독수리딘, 인다나비르, 케톡살, 라미부딘, MADU, 펜실클로비르, 포도필로톡신, 리바비린, 리만타딘, 사퀴나비르, 소리부딘, 스타부딘, 트리플루리딘, 발라시클로비르, 비다라빈, 크세나조산, 잘시타빈, 지도부딘;Antiviral drugs: acyclovir, amantadine, sipofovir, cytarabine, didanosine, dideoxyadenosine, edoxsudine, famcyclovir, phloxuridine, gancyclovir, idoxuridine, indanavir, ke Toxal, lamivudine, MADU, pennylclovir, grapephylotoxin, ribavirin, rimantadine, saquinavir, sorivudine, stavudine, trifluridine, valacyclovir, vidarabine, xenazoic acid, zalcitabine, zidobudine;
골재흡수억제제들: 알렌드론산, 부테드론산, 에티드론산, 옥시드론산, 파미드론산, 리세드론산;Aggregate absorption inhibitors: alendronic acid, butedronic acid, etidronic acid, oxide acid, pamideronic acid, risedronic acid;
항치매약물들로 아미리딘, 라자베미드, 모페길린, 살벨루조일, 옥시라세탐, 이피다크린, 네브라세탐, 타크린, 벨나크린을 들 수 있다.Antidementants include amiridine, lazabemid, mopegiline, salvelozoil, oxyracetam, ipidacrine, nebracetam, tacrine, and belnakrine.
항염증제들: 아세틸살리실산, 5-아미노아세틸살리실산, 카르프로펜, 디클로페낙나트륨, 디플루니살, 에토도락, 플루펜암산, 플루닉신, 플루르비프로펜, 이부프로펜, 인도메타신, 인도프로펜, 케토프로펜, 케토롤락, 롤녹시캠, 록소프로펜, 메클로펜암산, 메펜암산, 멜록시캠, 메살아민, 나프록센, 니플룸산, 올사라진, 피록시캠, 살살산, 수린닥, 수프로펜, 테녹시캠, 티아프로펜산, 톨펜암산, 톨메틴, 조메피락, 토목시프롤;Anti-inflammatory agents: acetylsalicylic acid, 5-aminoacetylsalicylic acid, carpropene, diclofenac sodium, diflunisal, etodorak, flufenamic acid, flunicin, flurbiprofen, ibuprofen, indomethacin, indopropene, keto Propene, Ketorolac, Rolloxycam, Roxopropene, Meclofenamic Acid, Mefenamic Acid, Meloxycam, Mesalamine, Naproxen, Niplum Acid, Olsarazine, Pyrocamcam, Salsalic Acid, Surindak, Water Propene, tenoxycam, thiapropenic acid, tolfenamic acid, tolmetin, zomepilac, civil ciprolol;
진통제들: 아세트아미노펜, 아세틸살리실살리실산, 베녹사프로펜, 부프레노르핀, 부토르파놀, 카프사아신, 디아세린, 디히드로코데인, 에틸모르핀, 유게놀, 페닐부타존, 멥타지놀, 모르핀, 날부핀, 페나조신, 티오르판, 트라마톨, 아크타리트;Analgesics: acetaminophen, acetylsalicylicsalicylic acid, benoxapropene, buprenorphine, butorpanol, capsacin, diaserine, dihydrocodeine, ethylmorphine, eugenol, phenylbutazone, meptazinol, Morphine, nalbuphine, phenazosin, thiorphan, tramatol, acrotite;
콜린성계에 작용하는 약물들 및 기관지확장제들: 알부테롤, 카르부테롤, 클렌부테롤, 디필린, 에토필린, 페노테롤, 브롬화이프라트로피움, 메타프로테레놀, 옥시부티닌, 피르부테롤, 살메테롤, 테르부탈린, 브롬화티오트로피움, 자프리나스트, 시클로드린, NS-21, 2-히드록시-2,2-디페닐-N-(1,2,3,6-테트라히드로-피리딘-4-일메틸)아세트아미드;Drugs and bronchodilators acting on the cholinergic system: albuterol, carbuterol, clenbuterol, diphylline, etophylline, phenoterol, bromide pratropium, metaproterenol, oxybutynin, pybuterol, Salmeterol, terbutalin, thiopromium bromide, japriast, cyclodrin, NS-21, 2-hydroxy-2,2-diphenyl-N- (1,2,3,6-tetrahydro- Pyridin-4-ylmethyl) acetamide;
거담제/점액용액성 약물들: 암브록솔, 브롬헥신, 구아이아콜, 소브레놀;Expectorant / mucolytic drugs: ambroxol, brominehexine, guaiacol, sobreol;
항천식/항알레르기 항히스타민약물들: 세티리진, 히스타민, 레보카바스틴, 로독스아미드, 몬텔루카스트, 테르펜아딘, 브롬헥신;Anti-asthmatic / antiallergic antihistamines: cetirizine, histamine, levocarbastine, rodoxamide, montelukast, terpenadine, bromine hexine;
심혈관약물들(ACE억제제들, 베타차단제들, 항혈전성약물들 및 항종양성약물)에 대해서, 이하를 들수있다:For cardiovascular drugs (ACE inhibitors, beta blockers, antithrombotic drugs and antitumor drugs), the following may be mentioned:
ACE억제제들: 캡토프릴, 에날라프릴, 리시노프릴, 노사르탄, 라미프릴;ACE inhibitors: captopril, enalapril, ricinopril, nosartan, ramipril;
베타차단제들: 알프레노롤, 아테노롤, 부프라노롤, 라베타롤, 메티프라노롤,메토프로롤, 핀도롤, 프로프라노롤, 티모롤;Beta-blockers: alprenolol, atenolol, bupranolol, labetalol, metipranolol, metoprolol, pindorol, propranolol, timolol;
항혈전성약물들 및 혈관확장제들: 아세틸살리실산, 아세토프반, 아르가트로반, 클로피도그렐, 달테파린, 디피리드아몰, 에녹사파린, 헤파린, 일로프로스트, 미도드린, 오자그렐, 페닐프로파놀아민, 트리플루살;Antithrombotic drugs and vasodilators: acetylsalicylic acid, acetoban, argatroban, clopidogrel, dalteparin, dipyridalmol, enoxaparin, heparin, iloprost, midoderin, ozagrerel, phenylpropanolamine , Triflusal;
당뇨병처치제들: 톨레스타트, 니코틴아미드;Diabetic agents: torestat, nicotinamide;
항종양성약물들: 안트라마이신, 다우노루비신, 독소루비신, 에피루비신, 플루오로우라실, 메토트렉산, 빈블라스틴;Anti-tumor drugs: anthracycin, daunorubicin, doxorubicin, epirubicin, fluorouracil, methotrexane, vinblastine;
항궤양성약물들: 시메티딘, 오메프라조일, 판토프라조일;Anti-ulcer drugs: cimetidine, omeprazoil, pantophrazoil;
항고지혈성약물들: 로바스타틴, 프라바스타틴나트륨, 심바스타틴;Antihyperlipidemic drugs: lovastatin, pravastatin sodium, simvastatin;
항생제들: 아목시실린, 암피실린, 아즈트레오남, 비아페넴, 카르베니실린, 세파크로르, 세파드록실, 세파만돌, 세파트리진, 세포크시틴, 클라불란산, 디클로옥사실린, 이미페넴, 메클로시클린, 메타시클린, 목살라크탐,파니페넴, 술바크탐, 아지트로마이신, 에리트로마이신, 조사마이신, 미오카마이신, 리파부틴, 리파아미드, 리파마이신, 겐타미신, 파로모마이신, 시소미신, 바캄피실린, 카르보마이신, 클린다마이신, 시프로플록사신, 크리나플록사신, 디플록사신, 엔로플로사신, 로메플록사신, 나디플록사신, 노르플록사신, 피페미드산, 아피시클린, 클로모시클린, 옥시테트라시클린, 니푸르피리놀, 니푸르프라진, 이소니아지드, 리팜핀, 피파펜틴, 다프손, 티아조일술폰, 술파메톡사조일, 술파목솔, 메트로니다조일, 아르기닌;Antibiotics: Amoxicillin, Ampicillin, Aztreonam, Viapenem, Carbenicillin, Sephacror, Sephadroxil, Sephamandol, Sephatrizin, Selcytin, Clavulanic Acid, Diclooxacillin, Imipenem, Meclo Cyclin, metacycline, moksalactam, panipenem, sulbactam, azithromycin, erythromycin, probemycin, myokamycin, rifabutin, lipamide, rifamycin, gentamicin, paromomycin, sisomycin , Bacampicillin, Carbomycin, Clindamycin, Ciprofloxacin, Crinafloxacin, Difloxacin, Enlofloscin, Lomefloxacin, Nadifloxacin, Norfloxacin, Pipemedic acid, Apicycline, Chlomocycline , Oxytetracycline, nifurpynol, nipurrazine, isoniazid, rifampin, pipepafentin, dapson, thiazosulfone, sulfametoxazole, sulfamoxosol, metronidazole, arginine;
항바이러스약물들: 아시클로비르, 팜시클로비르, 간시클로비르, 펜실클로비르, 리바비린, 비다라빈, 지도부딘;Antiviral drugs: acyclovir, famcyclovir, gancyclovir, pencilclovir, ribavirin, vidarabine, zidovudine;
골재흡수억제제들: 알렌드론산, 에티드론산, 파미드론산;Aggregate absorption inhibitors: alendronic acid, etidronic acid, pamidronic acid;
항치매약물들: 옥시라세탐, 타크린, 벨나크린.Antidementants: Oxyracetam, tacrine, belnakrine.
위의 언급된 물질, R 선구물질은 종래기술에서 공지된 방법에 따라 조제된다. 여기에 참조로 포함된 "The Merck Index, 12a Ed.(1996)"을 예로서 참조한다. 사용할 때, 광학이성질체들을 포함하는 관련되는 이성질체들이 사용될 수 있다.The above mentioned materials, R precursors, are prepared according to methods known in the art. See, eg, "The Merck Index, 12a Ed. (1996)", incorporated herein by reference. In use, related isomers can be used, including optical isomers.
토모시프롤은 EP 12,866에서 기술된 방법에 따라서 얻어진다.Tomoxyprolol is obtained according to the method described in EP 12,866.
A=R-의 스테로이드화합물은 이하의 구조식을 가지며, 여기서 CH기들의 수소들 또는 일반식에서 언급된 CH2기들의 두 수소 치환에서The steroid compound of A = R- has the following structural formula, wherein the hydrogens of the CH groups or the two hydrogen substitutions of the CH 2 groups mentioned in the general formula
이하의 치환기들이 존재될 수 있다:The following substituents may be present:
1-2위치: 이중결합이 될 수도 있다;Position 1-2: may be a double bond;
2-3위치: 아래의 치환기가 될 수도 있다;Position 2-3: may be a substituent below;
2위치: Cl, Br이 될 수도 있다;2-position: may be Cl, Br;
3위치: CO,-O-CH2-CH2-Cl, OH;3-position: CO, -O-CH 2 -CH 2 -Cl, OH;
3-4위치: 이중결합이 될 수도 있다;3-4 position: may be a double bond;
4-5위치: 이중결합이 될 수도 있다;Position 4-5: may be a double bond;
5-6위치: 이중결합이 될 수도 있다;Position 5-6: may be a double bond;
5-10위치: 이중결합이 될 수도 있다;Position 5-10: may be a double bond;
6위치: Cl, F, CH3,-CHO이 될 수도 있다;6-position: may be Cl, F, CH 3 , -CHO;
7위치: Cl, OH이 될 수도 있다;7 position: may be Cl, OH;
9위치: Cl, F이 될 수도 있다;9 position: may be Cl, F;
11위치: OH, CO, Cl, CH3이 될 수도 있다;11-position: may be OH, CO, Cl, CH 3 ;
16위치: CH3, OH, =CH2이 될 수도 있다;16 position: CH 3 , OH, = CH 2 ;
17위치: OH, CH3, OCO(O)ua(CH2)vaCH3,또는17-position: OH, CH 3 , OCO (O) ua (CH 2 ) va CH 3 , or
이 될 수도 있다(ua는 0 또는 1의 정수이고, va는 0내지 4의 정수);May be (ua is an integer from 0 or 1 and va is an integer from 0 to 4);
16-17위치: 아래의 기들이 될 수도 있다:Position 16-17: May be the following:
서로 동일하거나 다른 R 및 R'은 수소 또는 1 내지 4탄소원자들의 선형 또는 분지형 알킬들, 바람직하게이 될 수 있다;R and R ', which are the same or different from each other, are hydrogen or linear or branched alkyls of 1 to 4 carbon atoms, preferably Can be;
R"는이고, 여기서 t=0일 때 t2=1이고 t=1일 때 t2=0인 조건으로, 그리고 A가 -OH기들을 포함하지 않을 때 t 및 t1, 또는 t2 및 t1은 동시에 0이 될 수 없는 것을 조건으로 하여, t, t1 및 t2는 0 또는 1로 서로 같거나 다른 정수들이다;R "is Where t2 = 1 when t = 0 and t2 = 0 when t = 1, and t and t1, or t2 and t1, when A does not contain -OH groups, cannot be zero at the same time Provided that t, t1 and t2 are 0 or 1 integers equal to or different from each other;
2가의 가교결합기(L)은으로부터 선택되고, 여기서 서로 동일하거나 다른 na, n'a, 및 n''a는 0 내지 6, 바람직하게는 1 내지 3의 정수들이며, 서로 동일하거나 다른 nb, n'b, n''b 및 n'''b는 0 또는 1인 정수들이며,서로 동일하거나 다른 R4, R5는 수소, 1 내지 5, 바람직하게는 1 내지 3탄소원자들의 선형 또는 분지형 알킬로부터 선택된다;The divalent crosslinking group (L) And na, n'a, and n''a, which are the same or different from each other, are integers from 0 to 6, preferably 1 to 3, and nb, n'b, n''b and the same or different from each other; n '''b is an integer equal to 0 or 1, wherein the same or different R 4 , R 5 is selected from hydrogen, linear or branched alkyl of 1 to 5, preferably 1 to 3 carbon atoms;
는 위에서 정의한 대로 X이거나,와 동일하며 여기서는 OH,, Cl,,, SH, 또는 Is X as defined above, Is the same as Is OH, , Cl, , , SH, or
으로 동일하고 바람직하게 R"=이다.Is the same and preferably R "= to be.
선구물질스테로이드들에서 위치3 및/또는 위치11에 수산기를 가지고/또는 R"의 말단위치에서 수산기 또는 카르복실기기능을 가지는 선구물질스테로이드들이 바람직하다.Precursor steroids having a hydroxyl group at position 3 and / or position 11 and / or having a hydroxyl or carboxyl function at the terminal position of R ″ in the precursor steroids are preferred.
언급될 수 있고 바람직한 A의 선구물질스테로이드들은 종래기술에서 공지된 처리과정에 따라 얻어질 수 있는, 이하에서 열거된 것들이다.Preferred precursor steroids of A that may be mentioned are those listed below, which can be obtained according to processes known in the art.
선구물질들 및 각 처리과정들로서, 여기서 참조로 포함된 1996년의 The Merck Index, ed 12에서 기술된 것들을 들 수 있다. 선구물질들(Merck 명칭에 따라서)은 이하이고, H2, H, R, R', R"는 이하 열거된 화합물들에서 언급된 의미를 가진다: 부데소나이드, 하이드로코티손, 알클로메타손, 알제스톤, 베클로메타손, 베타메타손, 클로로프레드니손, 클로베타조일, 클로베타손, 클로코토론, 클로프레드놀, 코티손, 코티코스테론, 디플라자코트, 데소나이드, 데소시메타손, 데사메타손, 디플로라손 디플루코토론, 디플루프레드네이트, 플루아자코트, 플루클로로나이드, 플루메타손, 플루니솔라이드, 플루오시노론 아세토나이드, 플루오시노나이드, 플루오코르틴 부틸, 플루오코토론, 플루오로메토론, 플루페로론 아세테이트, 플루프레드니덴 아세테이트, 플루프레드니솔론, 플루란드레놀리드, 포르모코탈, 할시노니드, 할로베타솔 프로피오네이트, 할로메타손, 할로프레돈 아세테이트, 하이드로코타메이트, 로테프레드놀 에타보네이트, 메드리손, 메프레드니손, 메틸프레드니소론, 모메타손 퓨로에이트, 파라메타손, 프레드니카르베이트, 프레드니소론, 프레드니소론 25-디에틸아미노아세테이트, 프레드니소론 인산나트륨, 프레드니손, 프레드니발, 프레드닐이덴, 리멕소론, 트리암시노론, 트리암시노론 아세토나이드, 21-아세토시프레그네노론, 코르티바조일, 암시노나이드, 플루티카손 프로피오네이트, 마지프레돈, 티소코르톨, 트리암시노론 헥사아세토나이드, 우르소데소시콜산, 체노데소시콜산, 미타트리에네디올, 모제스트롤, 에티닐에스트라디올, 에스트라디올, 메스트라놀.Precursors and individual treatments include those described in The Merck Index, ed 12, 1996, incorporated herein by reference. The precursors (according to the Merck name) are as follows and H 2 , H, R, R ', R "have the meanings mentioned in the compounds listed below: budesonide, hydrocortisone, alclomethasone, Alzestone, beclomethasone, betamethasone, chloroprednisone, clobetazoil, clobetason, clocotoron, clopredol, cortisone, corticosterone, diplazacoat, desonide, desocimethasone, desamethason , Diflorasone Diflucotorone, Difluprenate, Fluazacoat, Fluchloronide, Flumethasone, Flunisolide, Fluorinolone Acetonide, Fluorinide, Fluorocortin Butyl, Fluorocorone, Fluorine Rometorone, fluperonone acetate, fluprednide acetate, fluprednisolone, fluandrenolide, formocotal, hacinolone, halobetasol propionate, halomethasone, halopredone acetate, Hydrocotamate, loteprednol etabonate, meridone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate , Prednisolone sodium phosphate, prednisone, prednisolone, prednylidene, limexolone, triamcinolone, triamcinolone acetonide, 21-acetocypregnenolone, cortivazoil, amcinolone, fluticasone propio Nates, marzipredone, tiscorthol, triamcinolone hexaacetonide, ursodesoxycholic acid, chenodesisocholic acid, mitatrienediol, mozzestrol, ethynylestradiol, estradiol, mestranol.
화학식(Ⅰ)의 화합물은 이후에 언급된 대로 조제된다.Compounds of formula (I) are formulated as mentioned later.
약물들의 반응기(예를 들어, -COOH, -OH)가 예를 들어 에스테르, 아미드, 에테르의 공유결합에 포함된다면, 상기 기는 종래기술에 공지된 방법으로 복귀될 수 있다.If a reactor of drugs (eg -COOH, -OH) is involved in the covalent linkage of, for example, esters, amides, ethers, the group can be returned by methods known in the art.
화학식(Ⅰ)의 화합물을 얻기 위해 사용되는 반응들은 예를 들어 이 분야의 당업자에게 공지된 에스테르, 아미드, 티오에스테르의 결합들의 형성으로 유도되는 반응들이다.The reactions used to obtain the compounds of formula (I) are, for example, reactions which lead to the formation of bonds of esters, amides, thioesters known to those skilled in the art.
반응의 두 가지의 화합물에서 다른 기능기들(COOH 및/또는 HX 여기서 X는 위에서 정의된 것)이 존재한다면, 이들은 종래기술에 공지된 방법, 예를 들어 Th. W. Greene의 "Protective groups in organic synthesis", Harward University Press, 1980에 따른 반응 전에 보호되어야만 한다.If there are other functional groups (COOH and / or HX where X is defined above) in the two compounds of the reaction, they are known in the art, for example Th. Must be protected prior to reaction according to W. Greene, "Protective groups in organic synthesis", Harward University Press, 1980.
라디칼 B에서 XZ 및(X,Z, ZⅠ및 ZⅡ는 위에서 정의된 것)의 2차반응기, 또는 COOH, =NH기가 있을 때, 자유원자가가 B의 2차반응기와 결합되도록 반응기로 포화된 화학식(Ⅲ)에 해당하는 라디칼을 B에 결합하는 것이 가능하다. 또한 이런 경우에 반응기들은 종래기술에서 일반적으로 사용된 반응기들이다.XZ and in radical B (X, Z, Z I and Z II are those defined above), or when there is a COOH, = NH group, in the formula (III) saturated with the reactor so that the free atoms are combined with the B secondary reactor It is possible to bind the corresponding radicals to B. Also in this case the reactors are reactors generally used in the prior art.
얻어진 화합물은 약의 선구물질과 반응된다.The compound obtained is reacted with a precursor of the drug.
본 발명의 목적하는 화합물은 일반 부형제와 함께 종래기술의 공지된 방법에 따른 비경구적, 경구 및 국소사용을 위한 해당하는 약학조성물로 제제된다(참조: "Remington's Pharmaceutical Sciences 15a Ed").Compounds of interest of the present invention are formulated with corresponding excipients for parenteral, oral and topical use according to known methods of the prior art, together with general excipients ("Remington's Pharmaceutical Sciences 15a Ed").
이런 제제에서 유효성분 몰의 기준 양은 해당하는 선구물질약물에 사용되는 양에 비교해서 동일하거나 낮다.In such formulations the baseline amount of active ingredient is the same or lower than the amount used in the corresponding precursor drug.
하루에 투여될 수 있는 투여량은 선구물질약물의 투여량이거나, 경우에 따라 일일투여량은 본 분야의 간행물 예를 들어 "Physician's Desk reference"에서 알 수 있다.Dosages that can be administered per day are those of prodrugs or, in some cases, daily dosages can be found in publications in the art, such as "Physician's Desk reference."
이하의 예들은 본 발명을 예시하기 위한 목적을 가지며 본 발명의 한정으로간주되지는 않는다.The following examples are for the purpose of illustrating the invention and are not to be considered as limiting of the invention.
[실시예 1]Example 1
화학식Chemical formula
을 가지는 (S,S)-N-아세틸-S-(6-메톡시-α-메틸-2-나프탈렌 아세틸)시스테인의 합성.Synthesis of (S, S) -N-acetyl-S- (6-methoxy-α-methyl-2-naphthalene acetyl) cysteine having
선구물질은 나프록센(화학식(Ⅵ))이고, B의 선구물질은 화학식(CⅧ)의 N-아세틸시스테인이다.The precursor is naproxen (formula (VI)), and the precursor of B is N-acetylcysteine of formula (C ′).
a)(S,S)-N-아세틸-S-(6-메톡시-α-메틸-2-나프탈렌 아세틸)시스테인의 합성a) Synthesis of (S, S) -N-acetyl-S- (6-methoxy-α-methyl-2-naphthalene acetyl) cysteine
클로로포름(100㎖) 및 N,N-디메틸포름아미드(6㎖)의 6-메톡시-α-메틸-2-나프탈렌 아세트산(10g, 43.4㏖)의 용액에, 1,1'-카보닐디미다조일(7.04g, 43.4㏖)을 첨가한다. 15분 후에, 얻어진 용액은 (S)-N-아세틸시스테인(7.08g, 43.4㏖)으로 처리되고 실온에서 12시간동안 방치된다. 반응혼합물은 HCl(5%)로 세정되고, 그 후물로 나중에는 염류용액으로 세정한다. 유기상은 황산나트륨으로 무수화되고, 그 후에 감소된 압력에서 증발된다. 얻어진 찌꺼기는 에틸아세테이트으로 용리되는 실리카겔의 크로마토그래피에 의해 정제된다. 원하는 생성물의 11.66g은 122 내지 126℃의 융점을 가지는 백색고체의 형태로 얻어진다.To a solution of 6-methoxy-α-methyl-2-naphthalene acetic acid (10 g, 43.4 mol) of chloroform (100 mL) and N, N-dimethylformamide (6 mL), 1,1′-carbonyldiimidoyl (7.04 g, 43.4 mol) is added. After 15 minutes, the resulting solution was treated with (S) -N-acetylcysteine (7.08 g, 43.4 mol) and left at room temperature for 12 hours. The reaction mixture is washed with HCl (5%), and subsequently with a salt solution. The organic phase is anhydrous with sodium sulfate and then evaporated at reduced pressure. The resulting residue is purified by chromatography of silica gel eluted with ethyl acetate. 11.66 g of the desired product are obtained in the form of a white solid with a melting point of 122-126 ° C.
1H-NMR(CDCl3): 7.71-7.65(3H, m), 7.34(1H, dd), 7.16-7.09(2H, m), 6.36(1H, d), 4.67(1H, m), 4.00(1H, q), 3.90(3H, s) 3.32(2H, t), 1.84(3H, s), 1.59(3H, d). 1 H-NMR (CDCl 3 ): 7.71-7.65 (3H, m), 7.34 (1H, dd), 7.16-7.09 (2H, m), 6.36 (1H, d), 4.67 (1H, m), 4.00 ( 1H, q), 3.90 (3H, s) 3.32 (2H, t), 1.84 (3H, s), 1.59 (3H, d).
[실시예 2]Example 2
화학식Chemical formula
을 가지는 (S)-N-아세틸-S-{α-메틸{4-(2-메틸프로필)벤젠}아세틸}시스테인의 합성.Synthesis of (S) -N-acetyl-S- {α-methyl {4- (2-methylpropyl) benzene} acetyl} cysteine having
선구물질은 화학식(Ⅶ)의 이부프로펜이고, B의 선구물질은 화학식(CⅧ)의 N-아세틸시스테인이다.The precursor is ibuprofen of formula (VII) and the precursor of B is N-acetylcysteine of formula (CVII).
a)(S)-N-아세틸-S-{α-메틸{4-(2-메틸프로필)벤젠}아세틸}시스테인의 합성a) Synthesis of (S) -N-acetyl-S- {α-methyl {4- (2-methylpropyl) benzene} acetyl} cysteine
클로로포름(100㎖) 및 N,N-디메틸포름아미드(6㎖)의 α-메틸{4-(2-메틸프로필)벤젠}아세트산(10g, 48.48㏖)의 용액에, 1,1'-카보닐디미다조일(7.86g, 48.48㏖)을 첨가한다. 1시간 후에, 얻어진 용액은 (S)-N-아세틸시스테인(7.91g, 48.47㏖)으로 처리되고 실온에서 24시간동안 방치된다. 반응혼합물은 HCl(5%)로 세정되고, 그 후 물로 나중에는 염류용액으로 세정한다. 유기상은 황산나트륨으로 무수화되고, 그 후에 감소된 압력에서 증발된다. 얻어진 찌꺼기는 에틸아세테이트로 용리되는 실리카겔의 크로마토그래피에 의해 정제된다. 원하는 생성물의 13.3g은 오일의 형태로 얻어진다.1,1'-carbonyldi in a solution of α-methyl {4- (2-methylpropyl) benzene} acetic acid (10 g, 48.48 mol) of chloroform (100 mL) and N, N-dimethylformamide (6 mL) Midazole (7.86 g, 48.48 mol) is added. After 1 hour, the obtained solution was treated with (S) -N-acetylcysteine (7.91 g, 48.47 mol) and left at room temperature for 24 hours. The reaction mixture is washed with HCl (5%) and then with water and later with saline solution. The organic phase is anhydrous with sodium sulfate and then evaporated at reduced pressure. The resulting residue is purified by chromatography of silica gel eluted with ethyl acetate. 13.3 g of the desired product are obtained in the form of an oil.
1H-NMR(CDCl3): 10.17(1H, s) 7.13(2H, d) 6.54(1H, d), 4.76(1H, m), 3.93(1H, q), 3.42-3.30(2H, m), 2.49(2H, d), 1.85-1.83(4H, m), 1.55(3H, d), 0.93(6H, d). 1 H-NMR (CDCl 3 ): 10.17 (1H, s) 7.13 (2H, d) 6.54 (1H, d), 4.76 (1H, m), 3.93 (1H, q), 3.42-3.30 (2H, m) 2.49 (2H, d), 1.85-1.83 (4H, m), 1.55 (3H, d), 0.93 (6H, d).
[실시예 3]Example 3
화학식Chemical formula
을 가지는 (S)-N-아세틸-S-[1-(4-클로로벤조일)-5-메톡시-2-메틸-1H-인돌-3-아세틸]시스테인의 합성.Synthesis of (S) -N-acetyl-S- [1- (4-chlorobenzoyl) -5-methoxy-2-methyl-1H-indole-3-acetyl] cysteine having
선구물질은 화학식(Ⅷ)의 인도메타신이고, B의 선구물질은 화학식(CⅧ)의 N-아세틸시스테인이다.The precursor is indomethacin of formula (VII), and the precursor of B is N-acetylcysteine of formula (CVII).
a)(S)-N-아세틸-S-[1-(4-클로로벤조일)-5-메톡시-2-메틸-1H-인돌-3-아세틸]시스테인의 합성a) Synthesis of (S) -N-acetyl-S- [1- (4-chlorobenzoyl) -5-methoxy-2-methyl-1H-indole-3-acetyl] cysteine
클로로포름(100㎖) 및 N,N-디메틸포름아미드(2㎖)의 1-(4-클로로벤조일)-5-메톡시-2-메틸-1H-인돌-3-아세트산(10g, 28.00㏖)의 용액에, 1,1'-카보닐디미다조일(4.53g, 28.00㏖)을 첨가한다. 1시간 후에, 얻어진 용액은 (S)-N-아세틸시스테인(4.56g, 28.00㏖)으로 처리되고 실온에서 24시간동안 방치된다. 반응혼합물은 HCl(5%)로 세정되고, 그 후 물로 나중에는 염류용액으로 세정한다. 유기상은 황산나트륨으로 무수화되고, 그 후에 감소된 압력에서 증발된다. 얻어진 찌꺼기는 에틸아세테이트로 용리되는 실리카겔의 크로마토그래피에 의해 정제된다. 원하는 생성물의 7.79g은 129℃의 융점을 가지는 노란색 고체의 형태로 얻어진다.Of 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-1H-indole-3-acetic acid (10 g, 28.00 mol) of chloroform (100 mL) and N, N-dimethylformamide (2 mL) To the solution, 1,1'-carbonyldiimidoyl (4.53 g, 28.00 mol) is added. After 1 hour, the resulting solution was treated with (S) -N-acetylcysteine (4.56 g, 28.00 mol) and left at room temperature for 24 hours. The reaction mixture is washed with HCl (5%) and then with water and later with saline solution. The organic phase is anhydrous with sodium sulfate and then evaporated at reduced pressure. The resulting residue is purified by chromatography of silica gel eluted with ethyl acetate. 7.79 g of the desired product are obtained in the form of a yellow solid with a melting point of 129 ° C.
1H-NMR(CDCl3): 12.90(1H, s), 8.21(1H, d), 7.69-7.64(4H, m), 7.06(1H, d), 6.96(1H, d), 6.73(1H, dd), 4.33(1H, m), 4.02(2H, s), 3.77(3H, s), 3.33-2.96(2H, m), 2.22(3H, s), 1.78(3H, s). 1 H-NMR (CDCl 3 ): 12.90 (1H, s), 8.21 (1H, d), 7.69-7.64 (4H, m), 7.06 (1H, d), 6.96 (1H, d), 6.73 (1H, dd), 4.33 (1H, m), 4.02 (2H, s), 3.77 (3H, s), 3.33-2.96 (2H, m), 2.22 (3H, s), 1.78 (3H, s).
[실시예 4]Example 4
화학식Chemical formula
을 가지는 (S)-N-아세틸-[2-플로오르-α-메틸-(1,1'-비페닐)-4-아세틸]시스테인의 합성.Synthesis of (S) -N-acetyl- [2-fluoro-α-methyl- (1,1′-biphenyl) -4-acetyl] cysteine having
선구물질은 화학식(Ⅸ)의 플루르비프로펜이고, B의 선구물질은 화학식(CⅧ)의 N-아세틸시스테인이다.The precursor is flubiprofen of formula (VII), and the precursor of B is N-acetylcysteine of formula (CVII).
화합물은 예1에서 기술된 처리과정에 의해 합성된다. 화합물은 오일처럼 보이고 수율은 70%이다.The compound is synthesized by the treatment described in Example 1. The compound looks like an oil and the yield is 70%.
1H-NMR(CDCl3): 8.38(1H, d), 7.67-7.50(6H, m), 7.49-7.53(2H, m), 4.52-4.41(1H, m), 4.22(1H, q), 3.50-3.10(2H, m), 1.92(3H, s), 1.58(3H, d). 1 H-NMR (CDCl 3 ): 8.38 (1H, d), 7.67-7.50 (6H, m), 7.49-7.53 (2H, m), 4.52-4.41 (1H, m), 4.22 (1H, q), 3.50-3.10 (2H, m), 1.92 (3H, s), 1.58 (3H, d).
[실시예 5]Example 5
화학식Chemical formula
을 가지는 트란스-3-[4-{α-메틸{4-(2-메틸프로필)벤젠}아세틸옥시}-3-메톡시페닐]-2-프로페노산의 제조.Preparation of trans-3- [4- {α-methyl {4- (2-methylpropyl) benzene} acetyloxy} -3-methoxyphenyl] -2-propenoic acid having
선구물질은 화학식(Ⅶ)의 이부프로펜이고, B의 선구물질은 화학식(DⅡ)의 페룰산이다.The precursor is ibuprofen of formula (VII) and the precursor of B is ferulic acid of formula (DII).
a)트란스-3-[4-{α-메틸{4-(2-메틸프로필)벤젠}아세틸옥시}-3-메톡시페닐]-2-프로페노산의 합성a) Synthesis of trans-3- [4- {α-methyl {4- (2-methylpropyl) benzene} acetyloxy} -3-methoxyphenyl] -2-propenoic acid
클로로포름(100㎖) 및 N,N-디메틸포름아미드(5㎖)의 α-메틸{4-(2-메틸프로필)벤젠}아세트산(5.03g, 24.4㏖)의 용액에, 1,1'-카보닐디미다조일(4.25g, 24.8㏖)을 첨가한다. 1시간 후에, 얻어진 용액은 페룰산(4.90g, 25㏖)으로 처리되고, 에틸나트륨(89mg)이 첨가되며 그 후 실온에서 12시간동안 교반(stirring)하며 방치된다. 반응혼합물은 HCl(5%)로 세정되고, 그 후 물로 나중에는 염류용액으로 세정한다. 유기상은 황산나트륨으로 무수화되고, 그 후에 감소된 압력에서 증발된다.To a solution of α-methyl {4- (2-methylpropyl) benzene} acetic acid (5.03 g, 24.4 mol) of chloroform (100 mL) and N, N-dimethylformamide (5 mL), 1,1'-carbo Nyldimidazoyl (4.25 g, 24.8 mol) is added. After 1 hour, the resulting solution is treated with ferulic acid (4.90 g, 25 mol), ethyl sodium (89 mg) is added and then left to stir for 12 hours at room temperature. The reaction mixture is washed with HCl (5%) and then with water and later with saline solution. The organic phase is anhydrous with sodium sulfate and then evaporated at reduced pressure.
얻어진 찌꺼기는 에틸아세테이트/n-헥산7/3로 용리되는 실리카겔의 크로마토그래피에 의해 정제된다. 트란스-3-[4-{α-메틸{4-(2-메틸프로필)벤젠}아세틸}-3-메톡시페닐]-2-프로페노산의 5.1g은 131 내지 137℃의 융점을 가지는 백색고체로 얻어진다.The resulting residue is purified by chromatography on silica gel eluting with ethyl acetate / n-hexane 7/3. 5.1 g of trans-3- [4- {α-methyl {4- (2-methylpropyl) benzene} acetyl} -3-methoxyphenyl] -2-propenoic acid is white with a melting point of 131 to 137 ° C. Obtained as a solid.
1H-NMR(CDCl3): 7.72(1H, d), 7.32(2H, dd), 7.26(1H, m), 7.16-7.07(4H, m), 6.98(1H, d), 6.37(1H, d), 3.99(1H, q), 3.73(3H, s), 2.47(2H, d), 1.88(1H, m), 1.63(3H, d), 0.92(6H, d). 1 H-NMR (CDCl 3 ): 7.72 (1H, d), 7.32 (2H, dd), 7.26 (1H, m), 7.16-7.07 (4H, m), 6.98 (1H, d), 6.37 (1H, d), 3.99 (1H, q), 3.73 (3H, s), 2.47 (2H, d), 1.88 (1H, m), 1.63 (3H, d), 0.92 (6H, d).
[실시예 6]Example 6
화학식Chemical formula
을 가지는 트란스-3-[4-[2-플루오르-α-메틸-(1,1'-비페닐)-4-아세틸옥시]-3-메톡시페닐]-2-프로페노산의 합성.Synthesis of trans-3- [4- [2-fluoro-α-methyl- (1,1′-biphenyl) -4-acetyloxy] -3-methoxyphenyl] -2-propenoic acid having
선구물질은 화학식(Ⅸ)의 플루르비프로펜이고, B의 선구물질은 화학식(DⅡ)의 페룰산이다.The precursor is flurbiprofen of formula (VII) and the precursor of B is ferulic acid of formula (DII).
화합물은 예5에서 기술된 처리과정에 의해 합성된다. 전체공정수율은 60%이다. 화합물은 비정질고체처럼 보인다.The compound is synthesized by the treatment described in Example 5. Overall process yield is 60%. The compound looks like an amorphous solid.
1H-NMR(CDCl3): 7.75(1H, d), 7.52(2H, m), 7.46-7.26(4H, m) 7.26(3H, m),7.05(2H, m), 7.00(1H, d), 6.37(1H, d), 4.03(1H, q), 3.77(3H, s), 1.65(3H, d). 1 H-NMR (CDCl 3 ): 7.75 (1H, d), 7.52 (2H, m), 7.46-7.26 (4H, m) 7.26 (3H, m), 7.05 (2H, m), 7.00 (1H, d ), 6.37 (1H, d), 4.03 (1H, q), 3.77 (3H, s), 1.65 (3H, d).
[실시예 7]Example 7
화학식Chemical formula
을 가지는 N-아세틸-S-[(S)-α-(2-클로로페닐)-6,7-디하이드로디노[3,2-c]피리딘-5(4H)아세틸](S)-시스테인의 제조.Of N-acetyl-S-[(S) -α- (2-chlorophenyl) -6,7-dihydrodino [3,2-c] pyridine-5 (4H) acetyl] (S) -cysteine Produce.
선구물질은 화학식(ⅩⅠ)의 클로피도그렐이고, B의 선구물질은 화학식(CⅧ)의 N-아세트시스테인이다.The precursor is clopidogrel of formula (XI), and the precursor of B is N-acecysteine of formula (CVII).
화합물은 예1에서 기술된 처리과정에 따라 합성된다. 수율은 51%이다.The compound is synthesized according to the procedure described in Example 1. Yield 51%.
성분분석:Component Analysis:
계산된 C: 53.03% H: 4.67% N: 6.18% S: 14.16% Cl: 17.82%Calculated C: 53.03% H: 4.67% N: 6.18% S: 14.16% Cl: 17.82%
측정된 C: 53.00% H: 4.63% N: 6.15% S: 14.10% Cl: 17.87%Measured C: 53.00% H: 4.63% N: 6.15% S: 14.10% Cl: 17.87%
[실시예 8]Example 8
화학식Chemical formula
을 가지는 [3-메톡시-4-하이드록시페닐]-2-트란스-프로페놀-4-[(2-아미노-3,5-디브로모페닐)메틸아미노]시클로헥사놀에스테르의 제조Preparation of [3-methoxy-4-hydroxyphenyl] -2-trans-propphenol-4-[(2-amino-3,5-dibromophenyl) methylamino] cyclohexanol ester
선구물질은 화학식(ⅩⅡ)의 암브록솔이고, B의 선구물질은 화학식(DⅡ)을 가지는 페룰산에 의해 나타낸다.The precursor is an amproxol of formula (XII), and the precursor of B is represented by ferulic acid having formula (DII).
a)4-[(α-테르트-부토시카르보닐아미노-3,5-디브로모페닐)메틸아미노] 트란스 시클로헥사놀의 합성a) Synthesis of 4-[(α-tert-butoxycarbonylamino-3,5-dibromophenyl) methylamino] trans cyclohexanol
디옥산(35㎖) 및 물(50㎖)의 4-[(2-아미노-3,5-디브로모페닐)메틸아미노]시클로헥사놀(5g, 13.22㏖)의 혼합물에, 트리에틸아민(3.31㎖, 23.7㏖) 및 디테르트-부틸디카보네이트(3.46g, 15.86㏖)을 교반상태에서 첨가한다. 24시간 후에, 용액은 진공상태에서 농축되고, 중성pH(pH=7)로 될 때가지 1%의 HCl용액이 첨가되고 유기상은 에틸아세테이트에 의해 추출된다.To a mixture of dioxane (35 mL) and water (50 mL) 4-[(2-amino-3,5-dibromophenyl) methylamino] cyclohexanol (5 g, 13.22 mol), triethylamine ( 3.31 mL, 23.7 mol) and ditert-butyldicarbonate (3.46 g, 15.86 mol) are added under stirring. After 24 hours, the solution is concentrated in vacuo, 1% HCl solution is added until neutral pH (pH = 7) and the organic phase is extracted with ethyl acetate.
얻어진 용액은 페룰산(4.90g, 25㏖)으로 처리되고, 에틸나트륨(89mg)이 첨가되며 그 후 실온에서 12시간동안 교반(stirring)하며 방치된다. 유기상은 황산나트륨으로 무수화되고 진공상태에서 증발된다. 4-[(2-테르트-부토시카르보닐아미노-3,5-디브로모페닐)메틸아미노] 시클로헥사놀이 더 이상의 정제가 없이 얻어진다.The resulting solution was treated with ferulic acid (4.90 g, 25 mol), ethyl sodium (89 mg) was added and then left to stir for 12 hours at room temperature. The organic phase is anhydrous with sodium sulfate and evaporated in vacuo. 4-[(2-tert-butoxycarbonylamino-3,5-dibromophenyl) methylamino] cyclohexanol is obtained without further purification.
b)(3-메톡시-4-하이드로시페닐)-2-트란스-프로페놀-4-[(2-테르트-부토시카르보닐아미노-3,5-디브로모페닐)메틸아미노]시클로헥사놀 에스테르의 합성b) (3-methoxy-4-hydroxyphenyl) -2-trans-propphenol-4-[(2-tert-butoxycarbonylamino-3,5-dibromophenyl) methylamino] cyclo Synthesis of Hexanol Ester
0℃로 냉각된 테트라하이드로퓨란(40㎖)의 페룰산(4g, 20.5㏖)의 용액에, 1,1'-카보닐디미다조일(3.34g, 20.5㏖)을 첨가한다. 10분 후에, 용액은 4-[(2-테르-부토시카르보닐아미노-3,5-디브로모페닐)메틸아미노]시클로헥사놀(9.8g, 20.5㏖)으로 처리되고, 실온에서 4시간동안 반응하게 한다. 반응혼합물은 진공상태에서 농축되고, 메틸렌염화물로 처리되며 1%HCl용액으로 세정되고 이 후에 물로 세정된다. 유기상은 황산나트륨으로 무수화되고 이 후에 진공상태에서 증발된다. 남은 찌꺼기는 n-헥산/에틸아세테이트1/1로 용리되는 실리카겔의 크로마토그래피에 의해 정제된다. (3-메톡시-4-하이드로시페닐)-2-트란스 프로페놀 4-[(2-테르트-부토시카르보닐아미노-3,5-디브로모페닐)메틸아미노]시클로헥사놀 에스테르는 얻어진다.To a solution of ferulic acid (4 g, 20.5 mol) in tetrahydrofuran (40 ml) cooled to 0 ° C, 1,1'-carbonyldiimidazol (3.34 g, 20.5 mol) is added. After 10 minutes, the solution was treated with 4-[(2-ter-butoxycarbonylamino-3,5-dibromophenyl) methylamino] cyclohexanol (9.8 g, 20.5 mol) and 4 hours at room temperature. To react. The reaction mixture is concentrated in vacuo, treated with methylene chloride, washed with 1% HCl solution and then with water. The organic phase is anhydrous with sodium sulfate and then evaporated in vacuo. The remaining residue is purified by chromatography on silica gel eluting with n-hexane / ethyl acetate 1/1. (3-methoxy-4-hydrocyphenyl) -2-trans propphenol 4-[(2-tert-butoxycarbonylamino-3,5-dibromophenyl) methylamino] cyclohexanol ester Obtained.
c)[(3-메톡시-4-하이드로시)페닐]-2-트란스 프로페놀-4-[(2-아미노-3,5-디브로모-페닐)메틸아미노]시클로헥사놀 에스테르의 합성c) Synthesis of [(3-methoxy-4-hydrocy) phenyl] -2-trans propphenol-4-[(2-amino-3,5-dibromo-phenyl) methylamino] cyclohexanol ester
0℃로 냉각되고 교반상태로 유지된 에틸아세테이트(50㎖)의 (3-메톡시-4-하이드로시페닐)-2-트란스 프로페놀-4-[(2-테르-부토시카르보닐아미노-3,5-디브로모-페닐)메틸아미노]시클로헥사놀 에스테르(2g, 3.06㏖)의 용액에, 에틸아세테이트의 5N의 HCl용액이 첨가된다. 마지막으로 침전물은 여과된다. 얻어진 초기의 생성물은 에틸아세테이트로 처리되고, 5%의 중탄산나트륨요액이 첨가된다. 혼합물은 섞여지고 중탄산용액은 물로 대체된다. 혼합물은 다시 섞여지고, 유기상은 회수되고 황산나트륨으로 무수화되며 감소된 압력에서 증발된다. [3-메톡시-4-하이드로시페닐]-2-트란스프로페놀-4-[(2-아미노-3,5-디브로모-페닐)메틸아미노]시클로헥사놀 에스테르는 얻어진다. 수율은 41%이다.Ethyl acetate (50 mL) of (3-methoxy-4-hydroxyphenyl) -2-trans propphenol-4-[(2-tert-butoxycarbonylamino-) cooled to 0 ° C. and kept under stirring. To a solution of 3,5-dibromo-phenyl) methylamino] cyclohexanol ester (2 g, 3.06 mol), 5N HCl solution of ethyl acetate is added. Finally the precipitate is filtered off. The initial product obtained is treated with ethyl acetate and 5% sodium bicarbonate solution is added. The mixture is mixed and the bicarbonate solution is replaced with water. The mixture is mixed again, the organic phase is recovered, anhydrous with sodium sulfate and evaporated at reduced pressure. [3-methoxy-4-hydroxyphenyl] -2-transpropphenol-4-[(2-amino-3,5-dibromo-phenyl) methylamino] cyclohexanol ester is obtained. Yield 41%.
성분분석:Component Analysis:
계산된 C: 50.90% H: 4.62% N: 4.94% Br: 28.22%Calculated C: 50.90% H: 4.62% N: 4.94% Br: 28.22%
측정된 C: 50.81% H: 4.63% N: 4.89% Br: 28.18%Measured C: 50.81% H: 4.63% N: 4.89% Br: 28.18%
[실시예 9]Example 9
화학식Chemical formula
을 가지는 S-[[2-[4-(4-클로로페닐)페닐메틸)-1-피페라지닐]에톡시]아세틸]페니실라민의 제조Preparation of S-[[2- [4- (4-chlorophenyl) phenylmethyl) -1-piperazinyl] ethoxy] acetyl] penicillamine
선구물질은 화학식(ⅩⅣ)의 세티리진이고, B의 선구물질은 페니실라민(화학식 CⅤ)이다.The precursor is cetirizine of formula (XIV), and the precursor of B is penicillamine (CV).
a)S-[[2-[4-[(4-클로로페닐)페닐메틸]-1-피페라지닐]에톡시]아세틸]N-테르트-부토시카르보닐페니실라민의 합성a) Synthesis of S-[[2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetyl] N-tert-butoxycarbonylphenylsilamine
화합물은 N-아세틸 시스테인 대신 N-테르트-부토시카르보닐페니실라민을 사용하여, 예1에서 기술된 처리과정에 따라 조제된다.The compound is prepared according to the procedure described in Example 1, using N-tert-butoxycarbonylphenylsilamine instead of N-acetyl cysteine.
b)S-[[2-[4-(4-클로로페닐)페닐메틸)-1-피페라지닐]에톡시]아세틸]페니실라민의 합성b) Synthesis of S-[[2- [4- (4-chlorophenyl) phenylmethyl) -1-piperazinyl] ethoxy] acetyl] penicillamine
N-테르트-부토시카르보닐의 보호원자단을 제거하고 아민의 기능을 회수하기 위해서, 화합물은 예8의 단계 C)에 기술된 방법에 의해 이전물질로부터 얻어진다. 수율은 29%이다.In order to remove the protecting group of N-tert-butoxycarbonyl and restore the function of the amine, the compound is obtained from the previous material by the method described in step C) of Example 8. Yield 29%.
성분분석:Component Analysis:
계산된 C: 58.96% H: 6.59% N: 7.63% S: 5.83% Cl: 16.44%Calculated C: 58.96% H: 6.59% N: 7.63% S: 5.83% Cl: 16.44%
측정된 C: 58.89% H: 6.50% N: 7.58% S: 5.79% Cl: 16.40%Measured C: 58.89% H: 6.50% N: 7.58% S: 5.79% Cl: 16.40%
[실시예 10]Example 10
화학식Chemical formula
을 가지는 N-아세틸-S-[(S)-1-[N-[1-(에톡시카르보닐)-3-페닐프로필]-L-프로린]시스테인의 제조.Preparation of N-acetyl-S-[(S) -1- [N- [1- (ethoxycarbonyl) -3-phenylpropyl] -L-proline] cysteine having
선구물질은 화학식(ⅩⅤ)의 에날에이프릴이고 B의 선구물질은 N-아세틸시스테인(화학식(CⅧ))이다.The precursor is enamel April of formula (XV) and the precursor of B is N-acetylcysteine (CV).
화합물은 예1에서 기술된 방법에 따라 합성된다. 수율은 35%이다.The compound is synthesized according to the method described in Example 1. Yield 35%.
성분분석:Component Analysis:
계산된 C: 58.30% H: 6.96% N: 7.84% S: 5.98%Calculated C: 58.30% H: 6.96% N: 7.84% S: 5.98%
측정된 C: 58.25% H: 6.94% N: 7.88% S: 5.87%Measured C: 58.25% H: 6.94% N: 7.88% S: 5.87%
[실시예 11]Example 11
화학식Chemical formula
을 가지는 N-니코티놀-β-알라닐(L)-히스티딘의 제조Of N-nicotinol-β-alanyl (L) -histidine
선구물질은 화학식(ⅩⅩⅢ)의 니코틴아미드이고, B의 선구물질은 카르노신(화학식(CⅠ))이다.The precursor is nicotinamide of formula (XIII), and the precursor of B is carnosine (CII).
a)N-니코티놀-β-알라닐(L)-히스티딘의 합성a) Synthesis of N-nicotinol-β-alanyl (L) -histidine
0℃로 냉각된 테트라하이드로퓨란(40㎖)의 니코틴산(2.5g, 20.5㏖)의 용액에, 1,1'-카보닐디미다조일(3.34g, 20.5㏖)이 첨가된다. 10분 후에, 용액에 (L)-카르노신(4.6g. 20.5㏖)이 첨가되고, 실온에서 4시간동안 교반되며 방치된다. 반응혼합물은 진공상태에서 농축되고, 메틸렌염화물로 처리되며 1%의 HCl로 세정되고 이 후에 물로 세정된다. 유기상은 황산나트륨으로 무수화되고 이 후에 진공상태에서 증발된다. 남은 찌꺼기는 에틸아세테이트로 용리되는 실리카겔기둥으로 색층분석된다. N-니코티놀-β-알라닐(L)-히스티딘은 회수된다. 수율은 45%이다.To a solution of nicotinic acid (2.5 g, 20.5 mol) of tetrahydrofuran (40 mL) cooled to 0 ° C., 1,1′-carbonyldiimidazol (3.34 g, 20.5 mol) is added. After 10 minutes, (L) -carnosine (4.6 g. 20.5 mol) is added to the solution and left to stir for 4 hours at room temperature. The reaction mixture is concentrated in vacuo, treated with methylene chloride and washed with 1% HCl followed by water. The organic phase is anhydrous with sodium sulfate and then evaporated in vacuo. The remaining residue is chromatographed with a column of silica gel eluted with ethyl acetate. N-nicotinol-β-alanyl (L) -histidine is recovered. Yield 45%.
성분분석:Component Analysis:
계산된 C: 54.49% H: 4.88% N: 21.27%Calculated C: 54.49% H: 4.88% N: 21.27%
측정된 C: 54.30% H: 5.00% N: 21.30%Measured C: 54.30% H: 5.00% N: 21.30%
[실시예 12]Example 12
화학식Chemical formula
을 가지는 7-[2-하이드록시-3-[3-메톡시-5-하이드록시벤조일]트란스-2-프로페놀]데오필린의 제조.Preparation of 7- [2-hydroxy-3- [3-methoxy-5-hydroxybenzoyl] trans-2-propenol] deophylline having
선구물질은 화학식(ⅩⅩⅥ)의 디필린이고 B의 선구물질은 페룰산(화학식(DⅡ))이다.The precursor is depilin of formula (XVI) and the precursor of B is ferulic acid (DII).
약물은 예8에서 기술된 방법에 따라 합성된다. 수율은 28%이다.The drug is synthesized according to the method described in Example 8. Yield 28%.
성분분석:Component Analysis:
계산된 C: 57.66% H: 5.32% N: 10.13%Calculated C: 57.66% H: 5.32% N: 10.13%
측정된 C: 57.70% H: 5.37% N: 10.11%Measured C: 57.70% H: 5.37% N: 10.11%
[실시예 13]Example 13
화학식Chemical formula
을 가지는 N-아세틸-S-(2-아세틸벤조일)시스테인의 제조.Preparation of N-acetyl-S- (2-acetylbenzoyl) cysteine having
선구물질은 화학식(ⅩⅩⅦ)의 아세틸살리실산이고, B의 선구물질은 N-아세틸시스테인(화학식(CⅧ))이다.The precursor is acetylsalicylic acid of formula (VII), and the precursor of B is N-acetylcysteine (CVII).
화합물은 예1에서 기술된 처리과정에 따라 합성된다. 수율은 63%이다.The compound is synthesized according to the procedure described in Example 1. Yield 63%.
성분분석:Component Analysis:
계산된 C: 51.69% H: 4.65% N: 4.31% S: 9.86%Calculated C: 51.69% H: 4.65% N: 4.31% S: 9.86%
측정된 C: 51.64% H: 4.68% N: 4.33% S: 9.89%Measured C: 51.64% H: 4.68% N: 4.33% S: 9.89%
[실시예 14]Example 14
화학식Chemical formula
을 가지는 4-[3-[3-메톡시-5-하이드록시페닐]-2-프로페노록시]-2-메틸-N-2-피리디닐-2H-1,2-벤조디아진-3-카르복TM아미드-1,1-이산화물의 제조4- [3- [3-methoxy-5-hydroxyphenyl] -2-propenoxy] -2-methyl-N-2-pyridinyl-2H-1,2-benzodiazine-3 Preparation of -Carboxymidamide-1,1-Dioxide
선구물질은 화학식(ⅩⅩⅧ)의 피록시캄이고, B의 선구물질은 화학식(DⅡ)을 가지는 페룰산에 의해 나타낸다.The precursor is pyoxycamp of formula (i), and the precursor of B is represented by ferulic acid having formula (DII).
화합물은 예8에서 기술된 처리과정에 따라 합성된다. 수율은 25%이다.The compound is synthesized according to the procedure described in Example 8. Yield 25%.
성분분석:Component Analysis:
계산된 C: 59.14% H: 4.17% N: 8.31% S: 6.31%Calculated C: 59.14% H: 4.17% N: 8.31% S: 6.31%
측정된 C: 59.01% H: 4.09% N: 8.20% S: 6.21%Measured C: 59.01% H: 4.09% N: 8.20% S: 6.21%
[실시예 15]Example 15
화학식Chemical formula
의 S-[2-[(2,6-디클로로페닐)아미노)벤젠아세틸옥시]페니실라민의 제조Of S- [2-[(2,6-dichlorophenyl) amino) benzeneacetyloxy] penicillamine
선구물질은 화학식(ⅩⅩⅨ)의 디클록페낙이고, B의 선구물질은 페니실라민(화학식 CⅤ)이다.The precursor is diclofenac of formula (VII), and the precursor of B is penicillamine (CV).
화합물은 예9에서 기술된 처리과정에 의해 합성된다. 수율은 53%이다.The compound is synthesized by the treatment described in Example 9. Yield 53%.
성분분석:Component Analysis:
계산된 C: 49.88% H: 3.66% N: 7.30% S: 8.32% Cl: 18.40%Calculated C: 49.88% H: 3.66% N: 7.30% S: 8.32% Cl: 18.40%
측정된 C: 49.90% H: 3.64% N: 7.29% S: 8.25% Cl: 18.35%Measured C: 49.90% H: 3.64% N: 7.29% S: 8.25% Cl: 18.35%
[실시예 16]Example 16
화학식(Ⅸ)의 플루르비프로펜으로부터 시작하고, B의 선구물질은 화학식(PⅣ)의 (L)-4-티아조일리딘 카르복실산인Starting with flurbiprofen of formula (VIII), the precursor of B is (L) -4-thiazoyridine carboxylic acid of formula (PIV)
의 3-[2-플로오르-α-메틸-(1,1'-비페닐)-4-아세틸]티아조일리딘-4-카르복실산의 합성.Synthesis of 3- [2-Fluoro-α-methyl- (1,1′-biphenyl) -4-acetyl] thiazoyridine-4-carboxylic acid of
a)3-[2-플로오르-α-메틸-(1,1'-비페닐)-4-아세틸]티아조일리딘-4-카르복실산의 합성a) Synthesis of 3- [2-fluoro-α-methyl- (1,1'-biphenyl) -4-acetyl] thiazoyridine-4-carboxylic acid
0℃로 냉각된 톨루엔(100㎖) 및 N,N-디메틸포름아미드(10㎖)의 2-플로오르-α-메틸-(1,1'-비페닐)-4-아세트산(10g, 41㏖)의 용액에, 옥살일클로라이드(3.52㎖, 82㏖)는 첨가된다. 2시간 후에, 실온에서 용액은 감소된 압력에서 증발된다. 얻어진 찌꺼기는 아세톤(50㎖)으로 용해되고, 이 용액은 0℃로 냉각된 아세톤(50㎖)의 4-티아조일리딘카르복실산(5.44g, 41㏖) 및 트리에틸아민(14.9㎖, 106㏖)의 용액에 첨가된다. 2시간 후에 혼합물은 4N의 HCl로 산성화되고 진공상태에서 농축되며, 찌꺼기는 에틸아세테이트로 처리되며 유기상은 먼저 2N의 HCl로 세정되고 이후 물로 세정된다. 유기상은 황산나트륨으로 무수화되고 감소된 압력에서 증발된다. 에틸아세테이트/n-헥산에 의한 결정제에 의해, 원하는 생성물의 9.4㎖은 142 내지 147℃의 융점을 가지는 백색고체의 형태로 얻어진다.2-fluoro-α-methyl- (1,1'-biphenyl) -4-acetic acid (10 g, 41 mol) of toluene (100 mL) and N, N-dimethylformamide (10 mL) cooled to 0 ° C. To a solution of), oxalyl chloride (3.52 mL, 82 mol) is added. After 2 hours, the solution is evaporated at reduced pressure at room temperature. The resulting residue was dissolved in acetone (50 mL), and this solution was acetone (50 mL) of 4-thiazoyridinecarboxylic acid (5.44 g, 41 mol) and triethylamine (14.9 mL, 106) cooled to 0 ° C. Mol) solution. After 2 hours the mixture is acidified with 4N HCl and concentrated in vacuo, the residue is treated with ethyl acetate and the organic phase is first washed with 2N HCl and then with water. The organic phase is anhydrous with sodium sulfate and evaporated at reduced pressure. By crystallization with ethyl acetate / n-hexane, 9.4 ml of the desired product is obtained in the form of a white solid with a melting point of 142 to 147 ° C.
1H-NMR(CDCl3): 7.74-7.62(4H, m), 7.35(2H, t), 7.18-7.13(2H, m), 5.06(1H, m), 4.63(1H, d), 4.42(1H, d), 4.14(1H, q), 3.13(2H, m), 1.53(3H, d). 1 H-NMR (CDCl 3 ): 7.74-7.62 (4H, m), 7.35 (2H, t), 7.18-7.13 (2H, m), 5.06 (1H, m), 4.63 (1H, d), 4.42 ( 1H, d), 4.14 (1H, q), 3.13 (2H, m), 1.53 (3H, d).
[실시예 17]Example 17
화학식(Ⅵ)의 나프록센(naproxene)으로부터 시작하는Starting with naproxene of formula (VI)
의 3-(6-메톡시-α-메틸-2-나프탈렌아세틸)티아조일리딘-4-카르복실산의 합성.Synthesis of 3- (6-methoxy-α-methyl-2-naphthaleneacetyl) thiazoyridine-4-carboxylic acid of.
B의 선구물질은 (L)-4-티아조일리딘 카르복실산(화학식(PⅣ))이다.The precursor of B is (L) -4-thiazoyridine carboxylic acid (Formula IV).
a)3-(6-메톡시-α-메틸-2-나프탈렌아세틸)티아조일리딘-4-카르복실산의 합성a) Synthesis of 3- (6-methoxy-α-methyl-2-naphthaleneacetyl) thiazoyridine-4-carboxylic acid
0℃로 냉각된 톨루엔(30㎖) 및 N,N-디메틸포름아미드(0.3㎖)의 6-메톡시-α-메틸-2-나프탈렌아세트산(4.02g, 17.5㏖)의 용액에, 옥살일클로라이드(2.92㎖, 34.06㏖)는 첨가된다. 2시간 후에, 실온에서 용액은 감소된 압력에서 증발된다. 얻어진 찌꺼기는 아세톤(50㎖)으로 용해되고, 이 용액은 0℃로 냉각된 아세톤(50㎖)의 4-티아조일리딘카르복실산(2.33g, 17.5㏖) 및 트리에틸아민(6.34㎖, 45.5㏖)의 용액에 첨가된다. 2시간 후에 혼합물은 4N의 HCl로 산성화되고 진공상태에서 농축되며, 찌꺼기는 에틸아세테이트로 처리되며 유기상은 먼저 2N의 HCl로 세정되고 이후 물로 세정된다. 유기상은 황산나트륨으로 무수화되고 감소된 압력에서 증발된다. 원하는 생성물의 4.43g은 165 내지 168℃의 융점을 가지는 백색고체의 형태로 얻어진다.Oxalyl chloride in a solution of 6-methoxy-α-methyl-2-naphthaleneacetic acid (4.02 g, 17.5 mol) of toluene (30 mL) and N, N-dimethylformamide (0.3 mL) cooled to 0 ° C (2.92 mL, 34.06 mol) is added. After 2 hours, the solution is evaporated at reduced pressure at room temperature. The resulting residue was dissolved in acetone (50 mL), and this solution was acetone (50 mL) of 4-thiazoyridinecarboxylic acid (2.33 g, 17.5 mol) and triethylamine (6.34 mL, 45.5) cooled to 0 ° C. Mol) solution. After 2 hours the mixture is acidified with 4N HCl and concentrated in vacuo, the residue is treated with ethyl acetate and the organic phase is first washed with 2N HCl and then with water. The organic phase is anhydrous with sodium sulfate and evaporated at reduced pressure. 4.43 g of the desired product are obtained in the form of a white solid with a melting point of 165 to 168 ° C.
1H-NMR(CDCl3): 7.75-7.66(3H, m), 7.34(1H, d), 7.14-7.11(2H, m), 5.14(1H, m), 4.80-4.61(2H, m), 4.07(1H, q), 3.91(3H, s), 3.30-3.23(2H, m), 1.53(3H, d). 1 H-NMR (CDCl 3 ): 7.75-7.66 (3H, m), 7.34 (1H, d), 7.14-7.11 (2H, m), 5.14 (1H, m), 4.80-4.61 (2H, m), 4.07 (1H, q), 3.91 (3H, s), 3.30-3.23 (2H, m), 1.53 (3H, d).
[실시예 18]Example 18
화학식(Ⅵ)의 나프록센으로부터 시작하는Starting from naproxen of formula (VI)
의 3-(6-메톡시-α-메틸-2-나프탈렌아세틸)-(R)-2-옥소티아조일리딘-4-카르복실산의 합성.Synthesis of 3- (6-methoxy-α-methyl-2-naphthaleneacetyl)-(R) -2-oxothiazolidin-4-carboxylic acid of
B의 선구물질은 (L)-2-옥소-4-티아조일리딘 카르복실산(화학식(PⅤ))이다.The precursor of B is (L) -2-oxo-4-thiazoyridine carboxylic acid (formula (VV)).
a)3-(6-메톡시-α-메틸-2-나프탈렌아세틸)-(R)-2-옥소티아조일리딘-4-카르복실산의 합성a) Synthesis of 3- (6-methoxy-α-methyl-2-naphthaleneacetyl)-(R) -2-oxothiazolidin-4-carboxylic acid
0℃로 냉각된 톨루엔(100㎖) 및 N,N-디메틸포름아미드(10㎖)의 6-메톡시-α-메틸-2-나프탈렌아세트산(7.0g, 30.4㏖)의 용액에, 옥살일클로라이드(5.23㎖, 61㏖)는 첨가된다. 2시간 후에, 실온에서 용액은 감소된 압력에서 증발된다. 테트라하이드로퓨란(50㎖)에서 용해된 얻어진 찌꺼기의 용액에, -10℃로 냉각된 테트라하이드로퓨란(50㎖)에 2-옥소티아조일리딘-4-카르복실산(4.07g, 27.6㏖), 4-디메틸아미노피리딘(0.84g, 6.9㏖), 트리에틸아민(7.69㎖, 55.2㏖)으로 구성된 혼합물이 첨가된다. 실온에서 24시간동안 방치된다. 반응혼합물은 HCl(5%)로 세정되고, 그 후 물로 세정된다. 유기상은 황산나트륨으로 무수화되고 그 후에 감소된 압력에서 증발된다. 얻어진 찌꺼기는 메틸렌 클로라이드/메탄올 95/5로 용리되는 실리카겔의 크로마토그래피에 의해 정제된다. 원하는 생성물의 6.79g은 비정질고체의 형태로 얻어진다.Oxalyl chloride in a solution of 6-methoxy-α-methyl-2-naphthaleneacetic acid (7.0 g, 30.4 mol) of toluene (100 mL) and N, N-dimethylformamide (10 mL) cooled to 0 ° C (5.23 mL, 61 mol) is added. After 2 hours, the solution is evaporated at reduced pressure at room temperature. To a solution of the obtained residue dissolved in tetrahydrofuran (50 mL), 2-oxothiazolydine-4-carboxylic acid (4.07 g, 27.6 mol) in tetrahydrofuran (50 mL) cooled to -10 ° C, A mixture consisting of 4-dimethylaminopyridine (0.84 g, 6.9 mol) and triethylamine (7.69 ml, 55.2 mol) is added. It is left at room temperature for 24 hours. The reaction mixture is washed with HCl (5%) and then with water. The organic phase is anhydrous with sodium sulfate and then evaporated at reduced pressure. The resulting residue is purified by chromatography of silica gel eluting with methylene chloride / methanol 95/5. 6.79 g of the desired product are obtained in the form of an amorphous solid.
성분분석:Component Analysis:
계산된 C: 60.16% H: 4.76% N: 3.89% S: 8.92%Calculated C: 60.16% H: 4.76% N: 3.89% S: 8.92%
측정된 C: 60.22% H: 4.80% N: 3.83% S: 8.91%Measured C: 60.22% H: 4.80% N: 3.83% S: 8.91%
[실시예 19]Example 19
의 [2-[(2,6-디클로로페닐)아미노)벤젠아세틸옥시]-(L)-히스티딘의 제조Of [2-[(2,6-dichlorophenyl) amino) benzeneacetyloxy]-(L) -histidine
본 발명 화합물의 선구약물은 화학식(ⅩⅩⅨ)의 디클록페낙이고, B의 선구화합물은 화학식(PⅡ)의 (L)-히스티딘이다.The prodrug of the compound of the present invention is diclofenac of formula (VII), and the precursor of B is (L) -histidine of formula (PII).
a)[2-[(2,6-디클로로페닐)아미노)벤젠아세틸옥시]-(L)-히스티딘의 합성a) Synthesis of [2-[(2,6-dichlorophenyl) amino) benzeneacetyloxy]-(L) -histidine
0℃로 냉각된 테트라하이드로퓨란(50㎖)의 디클록페낙(3g, 10.13㏖)의 용액에, 1,1'-카보닐디미다조일(1.69g, 10.13㏖)이 교반상태중에 첨가된다. 10분 후에, 용액은 (L)-히스티딘(1.57g. 10.13㏖)으로 처리되고, 실온에서 4시간동안 교반되며 방치된다. 반응혼합물은 진공상태에서 농축되고, 메틸렌염화물로 처리되며 차례대로 1%의 HCl로 세정된 후 물로 세정된다. 유기상은 황산나트륨으로 무수화되고 진공상태에서 증발된다. 남은 찌꺼기는 에틸아세테이트로 용리되는 실리카겔기둥의 크로마토그래피에 의해 정제된다. [2-[(2,6-디클로로페닐)아미노)벤젠아세틸옥시]-(L)-히스티딘이 얻어진다. 수율은 61%이다.To a solution of diclofenac (3 g, 10.13 mol) of tetrahydrofuran (50 mL) cooled to 0 ° C., 1,1′-carbonyldiimidazol (1.69 g, 10.13 mol) is added while stirring. After 10 minutes, the solution is treated with (L) -histidine (1.57 g. 10.13 mol) and left to stir at room temperature for 4 hours. The reaction mixture is concentrated in vacuo, treated with methylene chloride, washed sequentially with 1% HCl and then with water. The organic phase is anhydrous with sodium sulfate and evaporated in vacuo. The remaining residue is purified by chromatography on a column of silica gel eluted with ethyl acetate. [2-[(2,6-dichlorophenyl) amino) benzeneacetyloxy]-(L) -histidine is obtained. Yield 61%.
성분분석:Component Analysis:
계산된 C: 55.45% H: 4.18% N: 12.92% Cl: 16.36%Calculated C: 55.45% H: 4.18% N: 12.92% Cl: 16.36%
측정된 C: 55.48% H: 4.23% N: 12.88% Cl: 16.25%Measured C: 55.48% H: 4.23% N: 12.88% Cl: 16.25%
약리작용 실험들Pharmacological experiments
실시예Example
급성중독Acute poisoning
급성중독은 실험될 조성물들 각각의 1회 분량 질량 20g를 캐뉼러로 카복시메틸셀룰로오즈 수성현탁액 2% w/v를 입으로 10마리의 쥐들 한 그룹에게 투여하여 측정되었다. 동물들은 14일 동안 관찰하였다. 1회투여량 100㎎/㎏의 투여 후에도 그룹내의 동물은 중독증상을 보이지 않았다.Acute poisoning was measured by administering a cannula of 20 grams of a mass of each of the compositions to be tested to a group of 10 rats by mouth with 2% w / v of carboxymethylcellulose aqueous suspension. Animals were observed for 14 days. After administration of a single dose of 100 mg / kg, the animals in the group showed no symptoms of intoxication.
[실시예 F1]Example F1
시험1 - 생체내에 N-에틸말레이마이드(N-ethylmaleimide 이하 NEM)가 있는 실험모델: 본 발명의 조성물들의 선구물질들로서 선별된 일부 약물들의 위내성(gastric tolerability)연구.Test 1-Experimental Model with N-ethylmaleimide (NEM) in vivo: A study of gastric tolerability of some drugs selected as precursors of the compositions of the present invention.
동물들(쥐들, 무게 200g)은 아래 그룹들(군당 10마리)로 구분된다.Animals (rats, 200g weight) are divided into the following groups (10 per group).
A) 대조군들:A) Controls:
1°군: 처리: 담체만(약물이 입으로 투여될 때, 또는 피하, 복강, 정맥 또는 근육의 경로로 비경구적으로 생리용액이 투여될 때, 카복시메틸셀룰로오즈 수성현탁액 1% w/v의 1회투여량: 5㎖/㎏)1 ° group: Treatment: Carrier only (when the drug is administered by mouth, or when the physiological solution is administered parenterally by subcutaneous, intraperitoneal, intravenous or intramuscular route, 1% of carboxymethylcellulose aqueous suspension 1% w / v Dosage: 5 ml / kg)
2°군: 처리: 담체 + NEM,2 ° group: Treatment: carrier + NEM,
B)각 약물이 투여된 그룹들:B) Groups in which each drug was administered:
군Ⅰ: 처리 : 담체 + 약물,Group I: Treatment: Carrier + Drug,
군Ⅱ: 처리 : 담체 + 약물 + NEM.Group II: Treatment: Carrier + Drug + NEM.
이 실험에서 함유된 약물들은 이하이다(표Ⅰ): 인도메타신, 암브록솔, 메사라민, 소딕알렌드로네이트, 타크린, 오메프라조일, 미소프로스톨.The drugs contained in this experiment are as follows (Table I): indomethacin, ambroxol, mesalamine, sodic allenronate, tacrine, omeprazoil, misoprostol.
인도메타신, 암브록솔 및 알렌드로네이트는 입으로, 메사라민은 내부결장(직장) 경로로, 그리고 타크린, 오메프라조일, 미소프로스톨은 피하경로로 투여된다.Indomethacin, ambroxol and alendronate are administered by mouth, mesalamine by the internal colon (rectal) route, and tacrine, omeprazoil, misoprostol by subcutaneous route.
상기 경로들로 NEM처리되지 않은 동물들에게 각 물질을 투여함으로써 결정된 최고허용 1회투여량이 표Ⅰ에 기록된다. 표에 기록된 것보다 높은 1회투여량에 의해 장병증, 설사, 우울증, 전율 및 진정이 동물들에게 나타났다.The maximum tolerated dose determined by administering each substance to animals not treated with NEMs by these routes is reported in Table I. Enteropathy, diarrhea, depression, tremor and sedation were seen in animals by a single dose higher than reported in the table.
이 실험모델에서 동물들은 처음에 1회투여량 25㎎/㎏의 생리용액을 피하주사로 NEM으로 처리된다. 약물은 1시간 후에 담체가 있는 현탁액으로 투여된다. 동물들은 24시간 후에 희생되고, 위장관 점막층의 손상 측정은 각 그룹내에, 시각시험로 위에 병변들이 있는 쥐들의 수를 세었다. 그후 상기 쥐들의 총수는 쥐들군의 총수로 나누고 100을 곱한다. 이와 같이 얻어진 퍼센트들은 표Ⅰ에 기록된다. 표는 NEM없이 상기 약물들로 처리된 쥐군에서 위병변이 검출될 수 없음을 보여준다.In this experimental model, animals were initially treated with NEM with a subcutaneous injection of a single dose of 25 mg / kg physiological solution. The drug is administered in a carrier suspension after 1 hour. Animals were sacrificed after 24 hours, and damage measurements of the gastrointestinal mucosa were counted in each group of mice with lesions on them by visual examination. The total number of rats is then divided by the total number of rat groups and multiplied by 100. The percentages thus obtained are reported in Table I. The table shows that gastric lesions could not be detected in the rat group treated with the drugs without NEM.
군Ⅱ의 모든 쥐들(NEM 처리됨)은 이하의 약물들을 투여한 후에 위병변을 보였다: 인도메타신, 암브록솔, 메사라민, 소딕알렌드로네이트, 타크린. 그러므로 상기 약물들은 본 발명의 조제물들 합성에 사용될 수 있다.All rats in group II (NEM treated) showed gastric lesions after administration of the following drugs: indomethacin, ambroxol, mesalamine, sodic allenronate, tacrine. Therefore, the drugs can be used to synthesize the preparations of the present invention.
대신 오메프라조일, 미소프로스톨은 시험1에서 제공된 결과들을 기초로 본 발명의 생성물들을 조제하는 데 사용될 수 없다.Instead omeprazoil, microprostol cannot be used to prepare the products of the present invention based on the results provided in test 1.
[실시예 F2]Example F2
시험2(실험관 내): 본 발명의 조성물들의 선구물질들로서 선별된 일부 약물들이 존재하는 상태에서 CIP에 의해 내피세포들에서 유도되는 세포자멸(DNA분쇄)의 억제.Test 2 (in vitro): Inhibition of apoptosis (DNA disruption) induced in endothelial cells by CIP in the presence of some drugs selected as precursors of the compositions of the present invention.
이하의 선구물질 약물들(표Ⅱ): 인도메타신, 파라세타몰, 클로피도그렐, 살부타몰, 암브록솔, 소딕알렌드로네이트, 디필린, 케티리진, 에나라프릴, 니코티나마이드, 암피킬린, 아키클로비르, 메사라민, 타크린, 심바스틴, 오메프라조일, 미소프로스톨로 처리되었다.Precursor Drugs (Table II): Indomethacin, Paracetamol, Clopidogrel, Salbutamol, Ambroxol, Sodic Allendronate, Diphylline, Kethyrizine, Enaapril, Nicotinamide, Ampicillin, Akiclovir , Mesalamine, tacrine, simvastin, omeprazoil, misoprostol.
인간 배꼽정맥의 내피세포들은 표준방법에 따라 준비된다. 새로운 배꼽정맥은 질량 0.1% 콜라겐분해효소용액으로 채워지고 5분동안 37℃에서 배양된다.Endothelial cells of the human umbilical vein are prepared according to standard methods. The new umbilical vein is filled with mass 0.1% collagenase solution and incubated at 37 ° C. for 5 minutes.
다음으로 정맥은 콜라겐분해효소 0.1%(질량/부피)을 가지는 M199(GIBCO, Grand Island, NY) pH 7.4의 배지에 살포되고, 10%의 소태아혈정(10mcg/㎖), 헤파린나트륨(50mcg/㎖), 티미딘(2.4mcg/㎖), 글루타민(230mcg/㎖), 페니실린(100UI/㎖), 스트렙토마이신(100mcg/㎖) 및 스트렙토마이신B(0.125mcg/㎖)가 첨가된다. 세포들은 관류액에서 800rpm의 원심분리법에 의해 채취되어 배양플라스크(T-75)에 수집되고, 인간의 파이부로넥틴으로 선처리된다. 그 다음 세포들은 동일한 배지에 수집되고, 소시상하부성장인자(100ng/㎖)가 첨가된다. 최초 세포배양의 세포들(배꼽정맥의 생체밖으로 제거된 세포들)이 융합성세포들(약 8,000,000세포/플라스크)의 단일층을 형성할 때, 수집은 멈춰지고 층들이 씻겨지고 트립신처리된다. 세포현탁액은 24개의 우물들을 가지며 그 중 절반에는 10-4M농도로 약물을 함유하는 동일 배지가 첨가되어 있는 배양판의 우물들에 옮겨지고, 온도 37℃에 일정습도(90%), CO2=5%에서 수집된다. 약물이 배지에 용해될 수 없을 때, 그것을 적은 양의 디메틸술폭사이드에 먼저 녹인다. 배지에 첨가될 수 있는 최대양의 디메틸술폭사이드는 0.5%이다. 이 제1계대배양으로부터 나온 세포들만이 큐멘하이드로페록사이드(CIP)로 시험되는 데 사용된다. 세포들은 형태학적 시험 및 인자 Ⅷ에 대한 특성 면역반응에 의해 내피세포와 동일하다; 이 배양들은 근세포 또는 섬유모세포로부터 오염이 보이지 않는다.The vein was then sprayed onto a medium of M199 (GIBCO, Grand Island, NY) pH 7.4 containing 0.1% collagen (mass / volume), 10% fetal bovine serum (10mcg / ml), heparin sodium (50mcg / Ml), thymidine (2.4mcg / ml), glutamine (230mcg / ml), penicillin (100UI / ml), streptomycin (100mcg / ml) and streptomycin B (0.125mcg / ml) are added. Cells are harvested from perfusate by centrifugation at 800 rpm, collected in a culture flask (T-75), and pretreated with human piburonectin. Cells are then collected in the same medium and bovine hypothalamic growth factor (100 ng / ml) is added. When cells of the original cell culture (cells removed ex vivo of the venous vein) form a monolayer of confluent cells (approximately 8,000,000 cells / flasks), the collection is stopped and the layers are washed and trypsinized. The cell suspension has 24 wells, half of which are transferred to wells of the culture plate to which the same medium containing the drug is added at a concentration of 10 -4 M, with constant humidity (90%), CO 2 at a temperature of 37 ° C. Collected at = 5%. When the drug cannot be dissolved in the medium, it is first dissolved in a small amount of dimethyl sulfoxide. The maximum amount of dimethyl sulfoxide that can be added to the medium is 0.5%. Only cells from this first subculture are used to be tested with cumene hydroperoxide (CIP). Cells are identical to endothelial cells by morphological testing and characteristic immune responses to factor VII; These cultures show no contamination from myocytes or fibroblasts.
시험을 시작하기 전에, 세포배지는 제거되고 세포층들은 조심스럽게 인산 0.1M에 의해 pH7.0으로 중화된 표준생리용액으로 씻겨진다. 그 다음으로 각 우물성분이 5mM농도 배지에서 CIP현탁액으로 1시간동안 배양된다. 세포손상(세포자멸)의 측정은 CIP만으로 처리된 대조군들에 대한 약물+CIP를 함유하는 배양들의 DNA분쇄 퍼센트변화를 결정함으로써 수행된다. 상기 DNA분쇄 %변화는 파장 405∼450㎚로 설정된 BX60 올림푸스마이크로스코프(Olympus Co.,Roma)에 의해 대조군들의 시각밀도에 대한 시험표본들의 형광변화를 측정함으로써 결정된다. 각 표본의 형광은 5번 반복으로 결정된다. 통계측정은 스튜던트t검정(p,0.01)으로 수행되었다.Before starting the test, the cell medium is removed and the cell layers are carefully washed with standard physiological solution neutralized to pH 7.0 with 0.1 M phosphate. Each well component is then incubated for 1 hour with CIP suspension in 5 mM concentration medium. Measurement of cell damage (apoptosis) is performed by determining the percent change in DNA disruption of cultures containing drug + CIP relative to CIP-only controls. The% change in DNA fragmentation is determined by measuring the fluorescence change of the test specimens with respect to the visual density of the controls by a BX60 Olympus Microscope (Olympus Co., Rome) set at a wavelength of 405-450 nm. Fluorescence of each sample is determined in 5 replicates. Statistical measurements were performed with the Student's t test (p, 0.01).
결과들은 표Ⅱ에 기입되고 인도메타신, 파라세타몰, 클로피도그렐, 살부타몰, 소딕알렌드로네이트, 디필린, 케티리진, 에나라프릴, 니코티나마이드, 암피킬린, 아키클로비르, 타크린, 오메프라조일은 확실하게 세포파멸이 억제되지는 않는다; 그러므로 이 약물들은 본 발명의 조제물들을 조제하는 데 사용될 수 있다.The results are listed in Table II and indomethacin, paracetamol, clopidogrel, salbutamol, sodickalendronate, diphylline, ketirizine, enarafril, nicotinamide, ampicillin, akiclovir, tacrine, omeprazoil Certainly cell destruction is not inhibited; Therefore these drugs can be used to prepare the formulations of the invention.
반대로, 암브록솔, 메사라민 및 심바스타틴은 세포파멸을 억제한다. 그러므로, 시험2의 결과들을 기초로 본 발명의 조제물들을 조제하는 데 사용될 수 없다.In contrast, ambroxol, mesalamine and simvastatin inhibit cell destruction. Therefore, it cannot be used to prepare the preparations of the present invention based on the results of test 2.
[실시예 F3]Example F3
시험3 - 생체내에 NW-니트로-L-아르기닌-메틸에스테르(NW-nitro-L-arginine-methyl ester 이하 L-NAME)가 있는 실험모델: 본 발명의 조성물들의 선구물질들로서 선별된 일부 약물들의 위내성(위장관의 손상발생), 간(GPT 1회투여량, 글루탐산피루빈트란스아미나제)내성 및 심혈관(혈압)내성.Test 3-nitro -L- arginine-methyl ester (N W -nitro-L-arginine -methyl ester following L-NAME) experimental model in vivo with N W: some drugs screened as precursors of the compositions of the present invention Gastrointestinal resistance (gastric duct injuries), liver (GPT single dose, glutamic acid pyruvintransaminase) resistance and cardiovascular (blood pressure) resistance of the children.
채용된 실험모델은 J.Clin. Investigation 90, 278-281, 1992에 따른다.The experimental model employed is J. Clin. Investigation 90, 278-281, 1992.
내피기능장애는 L-NAME투여에 의해 유도되는 손상을 위장관의 점막층, 간손상(GPT 증가) 및 고혈압과 같은 심혈관 또는 맥관내피 손상을 판정함으로써 측정된다.Endothelial dysfunction is measured by determining the damage induced by L-NAME administration by determining cardiovascular or vascular endothelial damage such as mucosal layers of the gastrointestinal tract, liver damage (increased GPT) and hypertension.
동물들(쥐들, 평균무게 200g)은 이하에서 설명된 그룹들로 나누어진다. L-NAME을 받는 그룹은 식수에 400㎎/ℓ농도로 용해된 상기 조성물로 4주동안 처치된다. 아래의 그룹들(군당 10마리)로 구성된다.Animals (rats, average weight 200 g) are divided into the groups described below. The group receiving L-NAME was treated for 4 weeks with the composition dissolved at 400 mg / l concentration in drinking water. It consists of the following groups (10 per group).
A) 대조군들:A) Controls:
1°군: 처리: 담체만(카복시메틸셀룰로오즈 수성현탁액 1% w/v, 1회투여량: 약물이 입으로 투여될 때 5㎖/㎏, 피경구경로에 의할 때 생리용액)1 ° group: Treatment: Carrier only (Carboxymethylcellulose aqueous suspension 1% w / v, single dose: 5 ml / kg when drug is administered by mouth, physiological solution by parenteral route)
2°군: 처리: 담체 + L-NAME,2 ° group: Treatment: carrier + L-NAME,
B)약물로 처치된 그룹들:B) Groups treated with drugs:
군Ⅰ: 처리 : 담체 + 약물,Group I: Treatment: Carrier + Drug,
군Ⅱ: 처리 : 담체 + 약물 + L-NAME.Group II: Treatment: Carrier + Drug + L-NAME.
시험에서 사용된 약물들은 파라케타몰, 독소루비신, 심바스타틴, 오메프라조일 및 미소프로스톨이다. 각 약물은 4주동안 하루에 한번씩 투여된다.The drugs used in the trials are paraketamamol, doxorubicin, simvastatin, omeprazoyl and misoprostol. Each drug is administered once a day for four weeks.
동물들에게 투여되는 약물의 최대허용 1회투여량은 미처치 동물들의 조사로 어림잡은 각각의 1회투여량에서 장병증, 설사, 우울증, 전전 및 진정이 동물들에게나타남을 측정함으로써 결정된다.The maximum tolerated single dose of drug administered to animals is determined by measuring the presence of enteropathy, diarrhea, depression, pre- and sedation in animals at each single dose estimated by investigation of untreated animals.
4주 후에 물에 접근하는 것이 금지되고 1시간 후에 동물들은 희생된다.Access to water is forbidden after four weeks and animals are sacrificed after one hour.
희생되기 한시간 전 혈압은 측정되었고 혈압증가는 맥관내피에 발생하고 있는 손상을 나타내는 것이다.One hour before sacrifice, blood pressure was measured, indicating an increase in blood pressure.
위점막의 손상은 시험1(ex. F1)에서 전술한 바와 같이 측정된다. 간손상은 글루탐산피루빈트란스아미나제(GPT 증가)에 의한 희생 후 측정에 의해 결정된다.Damage to the gastric mucosa is measured as described above in Test 1 (ex. F1). Liver damage is determined by post-sacrifice measurement with glutamic acid pyruvintransaminase (GPT increase).
약물은 시험3에 부합되고 그러므로 본 발명의 조성물을 조제하는 데 사용될 수 있다. 담체만으로 처치된 그룹 또는 담체 + 약물로 처치된 그룹과 비교하여 담체 + 약물 + L-NAME로 처치된 쥐들의 그룹에서 보다 높은 간손상(더 높은 GPT값들) 및/또는 더 높은 위손상 및/또는 더 높은 심혈관손상(더 높은 혈압)이 발견된다.The drug conforms to test 3 and can therefore be used to prepare the compositions of the invention. Higher liver damage (higher GPT values) and / or higher gastric damage and / or in the group treated with carrier + drug + L-NAME compared to the group treated with carrier alone or with a carrier plus drug Higher cardiovascular damage (higher blood pressure) is found.
시험결과는 표Ⅳ에 기록된다. %위병변은 시험1에서와 같이 결정되었다. %GPT 및 %혈압값들은 대조군들의 제1군의 동물들에서 발견된 해당하는 값을 가리킨다. 이 그룹의 혈압의 평균값은 105±8 ㎜Hg였다.The test results are recorded in Table IV. % Gastric lesions were determined as in trial 1. % GPT and% blood pressure values refer to the corresponding values found in animals of the first group of controls. The mean value of blood pressure in this group was 105 ± 8 mmHg.
얻어진 결과는 파라케타몰, 독소루비신, 심바스타틴은 간손상 및 위장병증을 일으킨다(GPT값들 및 위변병들은 L-NAME 없이 약물로 처치된 해당군들 및 L-NAME로 처치된 대조군들 모두와 비교하여 %가 더 높다).The results obtained indicate that paraketamamol, doxorubicin, and simvastatin cause liver damage and gastrointestinal disease (GPT values and gastric disease in% compared to both groups treated with drug without L-NAME and controls treated with L-NAME). Is higher).
그러므로, 이 약물들은 본 발명의 조제물들을 조제하는 데 사용될 수 있다.Therefore, these drugs can be used to prepare the formulations of the invention.
대신 오메프라조일 및 미소프로스톨는 이 시험을 기초로, 본 발명의 조제물들을 조제하는 데 사용되어서는 안된다.Instead omeprazoil and microprostol should not be used to prepare the inventive formulations based on this test.
[실시예 F4]Example F4
시험4 : B 선구물질들로서 사용되는 일부 물질의 DPPH로부터 라디칼생성의 억제.Test 4: Inhibition of radical formation from DPPH of some substances used as B precursors.
이 방법은 DPPH(2, 2-dipheny1-1-picryl-hydrazyl)이 화합물형성라디칼들(M.S. Nenseter et Al., Atheroscler. Thromb. 15. 1338-1344, 1995)로서 사용되는 색채계 시험에 의한다.This method is based on a colorimeter test in which DPPH (2, 2-dipheny1-1-picryl-hydrazyl) is used as compound forming radicals (MS Nenseter et Al., Atheroscler. Thromb. 15. 1338-1344, 1995). .
최종 농도 100μM의 피시험물질의 메탄올용액들은 처음에 준비된다. 이 용액들 각 0.1㎖이 DPPH 0.1M 메탄올용액의 1㎖ 부분표본에 첨가된 후 최종부피가 1.5㎖로 된다. 빛이 차단된 실온에 30분 동안 저장된 후, 파장 517㎚의 흡광도를 읽는다. 동일한 농도의 DPPH를 함유하는 용액의 흡광도에 대한 흡광도의 감소가 결정된다. 라디칼들의 생성 또는 항라디칼작용을 억제하는 시험화합물의 효능은 다음 식으로 표현되고:Methanol solutions of the test substance with a final concentration of 100 μM are prepared initially. 0.1 ml of each of these solutions is added to a 1 ml aliquot of DPPH 0.1 M methanol solution and the final volume is 1.5 ml. After 30 minutes of storage at room temperature where light is blocked, the absorbance at wavelength 517 nm is read. The decrease in absorbance relative to the absorbance of a solution containing the same concentration of DPPH is determined. The efficacy of a test compound to inhibit the production of radicals or antiradical activity is expressed by the formula:
(1-AS/AC)×100(1-A S / A C ) × 100
여기서 AS및 AC는 각각 시험화합물과 함께 +DPPH를 함유하는 용액의 흡광도값 및 DPPH만을 함유하는 용액의 흡광도값이다.Where A S and A C are the absorbance values of the solution containing + DPPH and the absorbance value of the solution containing only DPPH, respectively, together with the test compound.
본 발명에 따른 사용된 화합물은 라디칼생성이 억제가 상기와 같이 50% 이상이라면 시험4에 합치한다.The compounds used according to the invention conform to test 4 if the inhibition of radical production is at least 50% as described above.
표Ⅴ에서 이하의 물질들로 얻어진 결과들이 기록된다: N-아세틸시스테인, 시스테인, 페룰산, (L)-카르노신, 겐티스산, 4-티아조일리딘카르복실산 및 2-옥소-4-티아조일리딘카르복실산.In Table V, the results obtained with the following materials are reported: N-acetylcysteine, cysteine, ferulic acid, (L) -carnosine, gentisic acid, 4-thiazoyridinecarboxylic acid and 2-oxo-4- Thiazolidinecarboxylic acid.
표Ⅴ는 다음을 나타낸다:Table V shows the following:
N-아세틸시스테인, 시스테인, 페룰산, (L)-카르노신, 겐티스산이 DPPH에 의해 유도되는 라디칼들의 생성을 50% 이상 억제하기 때문에 시험4에 합치한다.N-acetylcysteine, cysteine, ferulic acid, (L) -carnosine, and gentisic acid comply with test 4 because they inhibit at least 50% of the generation of radicals induced by DPPH.
4-티아조일리딘카르복실산 및 2-옥소-4-티아조일리딘카르복실산은 DPPH로부터 라디칼생성을 억제하지 않기 때문에 효과가 없다. 그러므로 이들이 시험5에 합치한다면, 이들은 본 발명에 따른 화합물들의 합성에 화화물B의 선구물질로서 사용될 수 있다.4-thiazoyridinecarboxylic acid and 2-oxo-4-thiazoyridinecarboxylic acid are ineffective because they do not inhibit radical production from DPPH. Therefore, if they comply with test 5, they can be used as precursors of sulfide B in the synthesis of the compounds according to the invention.
[실시예 F5]Example F5
시험5: B선구물질들로서 사용되는 화합물들로부터의 FeⅡ로부터 라디칼생성의 억제.Test 5: Inhibition of radical formation from Fe II from compounds used as B precursors.
4-티아조일리딘카르복실산 및 2-옥소-4-티아조일리딘카르복실산의 10-4M 메탄올용액들의 0.1㎖ 부분표본들은 2mM HCl에 1mM FeⅡ(NH4)2(SO4)20.1㎖, 2mM 디옥시리보오스 0.2㎖ 및 100mM pH7.4 인산버퍼 0.4㎖ 혼합하여 형성된 수성용액을 함유하는 시험관들에 첨가된다. 그 다음 이 시험관들은 37℃의 온도에서 한시간동안 놓아둔다. 그 다음 각 실험관은 2.8% 삼염화아세트산 수용액 0.5㎖ 및 0.1M 티오바르비투르산 수용액 0.5㎖를 순서대로 첨가된다. 기준블랭크는 위의 메탄올 0.1㎖를 함유하는 시험화합물 메타올수용액의 0.1㎖의 부분표본을 대신하여 구성된다. 실험관들은 닫히고 100℃에서 15분동안 기름목욕으로 가열된다. 핑크착색은 라디칼산화적분해로 처리된 디옥시리보오스의 양에 비례하는 세기로 발전한다. 용액들은 실온에서 냉각되고 532㎚에서의 흡광도들은 블랭크에 대하여 읽혀진다.0.1 ml aliquots of 10 -4 M methanolic solutions of 4-thiazoyridinecarboxylic acid and 2-oxo-4-thiazoyridinecarboxylic acid were dissolved in 1 mM Fe II (NH 4 ) 2 (SO 4 ) 2 in 2 mM HCl. 0.1 ml, 0.2 ml of 2 mM deoxyribose and 0.4 ml of 100 mM pH7.4 phosphate buffer are added to the test tubes containing the aqueous solution formed by mixing. These tubes are then left to stand at 37 ° C for one hour. Each test tube is then added with 0.5 ml of 2.8% aqueous trichloroacetic acid solution and 0.5 ml of 0.1M thiobarbituric acid aqueous solution in that order. The reference blanks were made in lieu of 0.1 ml aliquots of the aqueous test compound metaol solution containing 0.1 ml methanol above. The tubes are closed and heated in an oil bath at 100 ° C. for 15 minutes. Pink pigmentation develops at an intensity proportional to the amount of deoxyribose treated by radical oxidative decomposition. The solutions are cooled at room temperature and the absorbances at 532 nm are read for blank.
B 또는 B1의 선구물질 또는 C-TC-Y-H(여기서 자유균형은 위에서 정한 바와 같이 채워진다)에 의해 FeⅡ로부터 라디칼생성에 대항하여 유도되는 억제는 아래의 식을 통하여 퍼센트로 결정되고:The inhibition induced against radical production from Fe II by the precursors of B or B1 or CT C -YH, where the free equilibrium is filled as defined above, is determined in percent through the formula:
(1-AS/AC)×100(1-A S / A C ) × 100
여기서 AS및 AC는 각각 시험화합물과 함께 +철염을 함유하는 용액의 흡광도값 및 철염만을 함유하는 용액의 흡광도값이다.Where A S and A C are the absorbance values of the solution containing the + iron salt together with the test compound and the absorbance values of the solution containing only the iron salt, respectively.
결과들은 첨부된 표에 기록되고, 이것은 두 산들이 철이온으로부터 라디칼생성을 억제하도록 작용한다는 것을 보여준다. 그러므로 이 화합물들은 본 발명의 화합물들을 얻기위하여 B선구물질들로서 사용될 수 있다.The results are reported in the attached table, which shows that both acids act to inhibit radical production from iron ions. Therefore these compounds can be used as B precursors to obtain the compounds of the present invention.
[실시예 F6]Example F6
L-NAME(NW-nitro-L-arginine-methyl ester)에 유도되는 내피트러블의 조건들에서 해당선구물질약물들에 대한 본 발명에 따른 화합물들의 위내성시험.Gastric resistance test of the compounds according to the present invention for the corresponding precursors in the conditions of phytogenic resistance induced by L-NAME (N W -nitro-L-arginine-methyl ester).
예 F3이 반복되고 이것은 본 발명에 따른 아래의 선구물질약물들 및 해당 유도체들의 위내성이 측정된다:Example F3 is repeated and this measures the gastro tolerance of the following precursor drugs and their derivatives according to the invention:
-Ex.15에 따른 디클로페낙(diclofenac) 및 해당 유도체,Diclofenac and its derivatives according to Ex. 15,
-Ex.14에 따른 피록시캠(piroxicam) 및 해당 유도체,Pyroxicam and its derivatives according to Ex.
-Ex.13에 따른 아스피린 및 해당 유도체.Aspirin and its derivatives according to Ex.
결과들은 첨부된 표Ⅳ에 기록되고, 이것은 동일한 1회투여량으로 본 발명의 합성물 및 해당 선구물질약물을 투여함으로써, 위병증 발생이 본 발명의 화합물들로 처치된 그룹들에서 현저하게 줄거나 나타나지 않았음을 보여준다.The results are recorded in the accompanying Table IV, which shows that by administering the same dose of the compound of the present invention and the corresponding precursor drug, the incidence of gastropathy is significantly reduced or not seen in the groups treated with the compounds of the present invention. Shows no.
[실시예 20]Example 20
화학식(ⅩⅩⅣ)의 프로프란노롤으로부터 시작하는Starting with propranolol of formula (XIV)
화학식(CCI)의 3(3-메톡시-4-히드록시-페닐)-2-트랜스 프로페노산1-[(1-메틸에틸)아미노]-3-(1-나프탈렌옥시)-2-프로필 에스테르 합성.3 (3-methoxy-4-hydroxy-phenyl) -2-trans propenoic acid 1-[(1-methylethyl) amino] -3- (1-naphthaleneoxy) -2-propyl of formula (CCI) Ester synthesis.
B선구물질은 페룰산(화학식 DII)이다.Precursor B is ferulic acid (DII).
화합물(CCI)은 예 8. 수율:30%의 과정에 따라 얻어졌다.Compound (CCI) was obtained following the procedure in Example 8. Yield: 30%.
성분분석Component Analysis
계산된 : C: 71.71 H: 6.71 N: 3.22Calculated: C: 71.71 H: 6.71 N: 3.22
측정된 : C: 71.79 H: 6.75 N: 3.17Measured: C: 71.79 H: 6.75 N: 3.17
[실시예 21]Example 21
화학식(XXXI)의 벤푸로딜헤미수키네이트로부터 시작하는Starting from benfulodilhemisukinate of formula (XXXI)
화학식(CCII)의 N-아세틸-S-[1-[5-(2,5-디히드로-5-옥소-3-푸라닐)-3-메틸-2-벤조푸라닐]에틸옥시-4-옥소-부타노일]-시스테인의 합성.N-acetyl-S- [1- [5- (2,5-dihydro-5-oxo-3-furanyl) -3-methyl-2-benzofuranyl] ethyloxy-4- of the formula (CCII) Synthesis of oxo-butanoyl] -cysteine.
B선구물질은 N-아세틸시스테인(화학식 CVIII)이다.The precursor B is N-acetylcysteine (CVIII).
화합물(CCII)은 예 1. 수율:13%의 과정에 따라 얻어졌다.Compound (CCII) was obtained following the procedure in Example 1. Yield: 13%.
성분분석Component Analysis
계산된 : C: 57.25 H: 5.00 N: 2.78 S: 6.37Calculated: C: 57.25 H: 5.00 N: 2.78 S: 6.37
측정된 : C: 57.30 H: 5.02 N: 2.72 S: 6.35Measured: C: 57.30 H: 5.02 N: 2.72 S: 6.35
[실시예 22]Example 22
화학식(DII)의 페룰산 및 화학식(XXII)의 4-히드록시오메프라조일로부터 시작하는Starting with ferulic acid of formula (DII) and 4-hydroxyomeprazoyl of formula (XXII)
화학식(CCIII)5-메톡시-2-[[[(3-메톡시-4-히드록시-페닐)-2-트랜스 프로페노일]-3,5-디메틸-2-피리디닐]메틸]술피닐]-1H-벤지미다조일의 합성.Formula (CCIII) 5-methoxy-2-[[[(3-methoxy-4-hydroxy-phenyl) -2-trans propenoyl] -3,5-dimethyl-2-pyridinyl] methyl] sul Synthesis of Finyl] -1H-benzimidazol.
화합물(CCIII)은 예 8. 수율:43%의 과정에 따라 얻어졌다.Compound (CCIII) was obtained following the procedure in Example 8. Yield: 43%.
성분분석Component Analysis
계산된 : C: 61.65 H: 4.78 N: 8.30 S: 6.33Calculated: C: 61.65 H: 4.78 N: 8.30 S: 6.33
측정된 : C: 61.71 H: 4.85 N: 8.25 S: 6.35Measured: C: 61.71 H: 4.85 N: 8.25 S: 6.35
[실시예 23]Example 23
화학식(XXI)의 심바스타틴 및 화학식(DII)의 페룰산으로부터 시작하는Starting with simvastatin of formula (XXI) and ferulic acid of formula (DII)
화학식(CCIV)의 [1S-[1α,3α,7β,8β,(2S*,4S*)]]-2,2-디메틸부타노산 1,2,3,7,8,8-헥사하이드로-3-,7-디메틸-8-[2-[테트라하이드로-4-[(3-메톡시-4-히드록시-페닐)-2-트랜스 프로페노이록시]-6-옥소-2H-피란-2--yl]에틸]-1-나프탈레닐 에스테르의 합성.[1S- [1α, 3α, 7β, 8β, (2S * , 4S * )]]-2,2-dimethylbutanoic acid 1,2,3,7,8,8-hexahydro-3 of formula (CCIV) -, 7-Dimethyl-8- [2- [tetrahydro-4-[(3-methoxy-4-hydroxy-phenyl) -2-trans propenohydroxy] -6-oxo-2H-pyran-2 Synthesis of --yl] ethyl] -1-naphthalenyl ester.
화합물(CCIII)은 예 8. 수율:21%의 과정에 따라 얻어졌다.Compound (CCIII) was obtained following the procedure in Example 8. Yield: 21%.
성분분석Component Analysis
계산된 : C: 70.68 H: 7.80Calculated: C: 70.68 H: 7.80
측정된 : C: 70.70 H: 7.82Measured: C: 70.70 H: 7.82
[실시예 24]Example 24
화학식(XVI)의 암피실린 및 화학식(CV)의 페니실라민으로부터 시작하는Starting with Ampicillin of Formula (XVI) and Penicillamine of Formula (CV)
화학식(CCV)의 S-[4-D-α-아미노벤질페니실아미노일]페니실아민의 합성.Synthesis of S- [4-D-α-aminobenzylphenylaminoyl] phenicylamine of the formula (CCV).
화합물(CCV)은 예 9. 수율:13%의 과정에 따라 합성되었다.Compound (CCV) was synthesized according to the procedure of Example 9. Yield: 13%.
성분분석Component Analysis
계산된 : C: 52.48 H: 5.87 N: 11.66 S: 13.34Calculated: C: 52.48 H: 5.87 N: 11.66 S: 13.34
측정된 : C: 52.51 H: 5.90 N: 11.61 S: 13.30Measured: C: 52.51 H: 5.90 N: 11.61 S: 13.30
[실시예 25]Example 25
화학식(XVII)의 아키클로비르 및 화학식(PII)의 히스티딘으로부터 시작하는Starting with aquiclovir of formula (XVII) and histidine of formula (PII)
화학식(CCVI)의 9-[[2-[(S)-α-아미노-1H-이미다조일-4-프로파노일-옥시]에톡시]-메틸]구아닌의 합성Synthesis of 9-[[2-[(S) -α-amino-1H-imidazoyl-4-propanoyl-oxy] ethoxy] -methyl] guanine of Formula (CCVI)
화합물(CCVI)은 예 19. 수율:17%의 과정에 따라 얻어졌다.Compound (CCVI) was obtained following the procedure in Example 19. Yield: 17%.
성분분석Component Analysis
계산된 : C: 50.14 H: 4.77 N: 27.29Calculated: C: 50.14 H: 4.77 N: 27.29
측정된 : C: 50.17 H: 4.75 N: 27.22Measured: C: 50.17 H: 4.75 N: 27.22
[실시예 26]Example 26
화학식(XXXVI)의 아렌드로론산 및 화학식(DII)의 페룰산으로부터 시작하는Starting from arendronic acid of formula (XXXVI) and ferulic acid of formula (DII)
화학식(CCVII)의 [4-아미노-[(3-메톡시-4-하이드록시-페닐)-2-트랜스-프로페노일]-1-히드록시부틸라이덴] 바이포스폰산의 합성Synthesis of [4-amino-[(3-methoxy-4-hydroxy-phenyl) -2-trans-propenyl] -1-hydroxybutylidene] biphosphonic acid of formula (CCVII)
화합물(CCVII)은 예 8. 수율:10%의 과정에 따라 얻어졌다.Compound (CCVII) was obtained following the procedure in Example 8. Yield: 10%.
성분분석Component Analysis
계산된 : C: 39.54 H: 4.98 N: 3.29 P: 14.57Calculated: C: 39.54 H: 4.98 N: 3.29 P: 14.57
측정된 : C: 39.57 H: 5.01 N: 3.24 P: 14.56Measured: C: 39.57 H: 5.01 N: 3.24 P: 14.56
[실시예 27]Example 27
화학식(XXXV)의 타크린 및 화학식(PII)의 히스티딘으로부터 시작하는Starting with tacrine of formula (XXXV) and histidine of formula (PII)
화학식(CCVIII)의 5-[[(S)-α-아미노-1H-이미다조일-4-프로파노일]아미노]-1,2,3,4-테트라히드로아크리딘의 합성Synthesis of 5-[[(S) -α-amino-1H-imidazoyl-4-propanoyl] amino] -1,2,3,4-tetrahydroacridine of Formula (CCVIII)
화합물(CCVIII)은 예 19. 수율:15%의 과정에 따라 얻어졌다.Compound (CCVIII) was obtained following the procedure in Example 19. Yield: 15%.
성분분석Component Analysis
계산된 : C: 68.04 H: 6.31 N: 20.88Calculated: C: 68.04 H: 6.31 N: 20.88
측정된 : C: 68.08 H: 6.37 N: 20.84Measured: C: 68.08 H: 6.37 N: 20.84
[실시예 28]Example 28
화학식(XXXII)의 독소루비신 및 화학식(DII)의 페룰산으로부터 시작하는Starting with doxorubicin of formula (XXXII) and ferulic acid of formula (DII)
화학식(CCIX)의 (8S-시스)-10-[(3-아미노,2,3,6-트리-데옥시-α-L-릭소-엑소피라노실)옥시]-7,8,9,10-테트라히드로,6,8,11-트리히드록시-8-[[[(3-메톡시-4-히드록시-페닐)-2-트랜스 프로페노일-옥시-]메틸-옥소]-1-메톡시-5,12-나프타켄네디온의 합성(8S-cis) -10-[(3-amino, 2,3,6-tri-deoxy-α-L-lyxo-exopyranosyl) oxy] -7,8,9,10 of formula (CCIX) -Tetrahydro, 6,8,11-trihydroxy-8-[[[(3-methoxy-4-hydroxy-phenyl) -2-trans propenoyl-oxy-] methyl-oxo] -1- Synthesis of Methoxy-5,12-naphthakenedione
화합물(CCIX)은 예 8. 수율:10%의 과정에 따라 얻어졌다.Compound (CCIX) was obtained following the procedure in Example 8. Yield: 10%.
성분분석Component Analysis
계산된 : C: 61.75 H: 5.18 N: 1.95Calculated: C: 61.75 H: 5.18 N: 1.95
측정된 : C: 61.81 H: 5.22 N: 1.90Measured: C: 61.81 H: 5.22 N: 1.90
[실시예 F7]Example F7
예 F1은 세 그룹들의 쥐들로 기록되었다(각 그룹은 10마리), 그들 중 모두가 NEM을 받고, 아래와 같이 입으로 투여된Example F1 was recorded in three groups of rats (10 in each group), all of whom received an NEM,
a. 대조군: 카복시메틸셀룰로오즈 수성현탁액 1% w/v로 형성된 매개체,a. Control: Mediator formed with 1% w / v of carboxymethylcellulose aqueous suspension,
b. 상기 매개체에 이부프로펜 100㎎/㎏(0.48 mmole/㎏)+ N-아세틸시스테인 79㎎/㎏(0.48 mmole/㎏)을 동시에 투여한 한 그룹(군 b-비교),b. One group (group b-comparison) in which ibuprofen 100 mg / kg (0.48 mmole / kg) + N-acetylcysteine 79 mg / kg (0.48 mmole / kg) was simultaneously administered to the mediator,
c. 상기 매개체에 인도메타신과 N-아세틸시스테인(ref. ex.2) 사이 에스테르 170㎎/㎏(0.48 mmole/㎏)를 투여한 한 그룹(군 c).c. One group (group c) to which the medium was administered 170 mg / kg (0.48 mmole / kg) of ester between indomethacin and N-acetylcysteine (ref. Ex. 2).
결과들은 표7에 기록되고 그룹 b(비교)에 투여된 혼합물은 위병변들을 줄이는 데 있어서 그룹 c에 투여된 본 발명의 화합물보다 효과가 적다.The results are reported in Table 7 and the mixture administered in group b (comparative) is less effective than the compounds of the invention administered in group c in reducing gastric lesions.
p.o.= 입으로; i.c.= 내부결장경로에 의해; s.c.= 피하경로에 의해.p.o. = blowjob; i.c. = by internal colon pathway; s.c. = by subcutaneous route.
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