CN1997370A - 用于预防或治疗肥胖和相关疾病的含有n-氨磺酰-n'-芳基哌嗪类的药物 - Google Patents
用于预防或治疗肥胖和相关疾病的含有n-氨磺酰-n'-芳基哌嗪类的药物 Download PDFInfo
- Publication number
- CN1997370A CN1997370A CNA2005800159695A CN200580015969A CN1997370A CN 1997370 A CN1997370 A CN 1997370A CN A2005800159695 A CNA2005800159695 A CN A2005800159695A CN 200580015969 A CN200580015969 A CN 200580015969A CN 1997370 A CN1997370 A CN 1997370A
- Authority
- CN
- China
- Prior art keywords
- group
- substituent group
- phenyl
- alkyl
- alkoxyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000011282 treatment Methods 0.000 title claims abstract description 24
- 208000008589 Obesity Diseases 0.000 title claims abstract description 19
- 235000020824 obesity Nutrition 0.000 title claims abstract description 19
- 239000003814 drug Substances 0.000 title claims description 24
- 238000011321 prophylaxis Methods 0.000 title abstract 2
- 150000003839 salts Chemical class 0.000 claims abstract description 56
- 239000002253 acid Substances 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims description 135
- -1 hydroxyl amino Chemical group 0.000 claims description 103
- 125000001424 substituent group Chemical group 0.000 claims description 97
- 229910052736 halogen Inorganic materials 0.000 claims description 54
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 54
- 150000002367 halogens Chemical class 0.000 claims description 53
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 51
- 239000000203 mixture Substances 0.000 claims description 50
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 45
- 239000003795 chemical substances by application Substances 0.000 claims description 38
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 30
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 28
- 230000003213 activating effect Effects 0.000 claims description 27
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 27
- 125000004432 carbon atom Chemical group C* 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 26
- 229910052799 carbon Inorganic materials 0.000 claims description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 23
- 239000008194 pharmaceutical composition Substances 0.000 claims description 23
- 208000011580 syndromic disease Diseases 0.000 claims description 23
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 22
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 22
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 21
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 239000000460 chlorine Substances 0.000 claims description 19
- 229910052801 chlorine Inorganic materials 0.000 claims description 19
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 201000010099 disease Diseases 0.000 claims description 17
- 241000124008 Mammalia Species 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 16
- 125000005493 quinolyl group Chemical group 0.000 claims description 16
- 102000004877 Insulin Human genes 0.000 claims description 15
- 108090001061 Insulin Proteins 0.000 claims description 15
- 230000004060 metabolic process Effects 0.000 claims description 15
- 125000001624 naphthyl group Chemical group 0.000 claims description 15
- 239000002775 capsule Substances 0.000 claims description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 14
- 229940125396 insulin Drugs 0.000 claims description 14
- 206010012601 diabetes mellitus Diseases 0.000 claims description 12
- 239000002552 dosage form Substances 0.000 claims description 12
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 12
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 claims description 11
- PGOWYQPWIHCLJF-UHFFFAOYSA-N 4-phenylpiperazine-1-sulfonamide Chemical compound C1CN(S(=O)(=O)N)CCN1C1=CC=CC=C1 PGOWYQPWIHCLJF-UHFFFAOYSA-N 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 239000001301 oxygen Substances 0.000 claims description 10
- 239000003826 tablet Substances 0.000 claims description 10
- 206010022489 Insulin Resistance Diseases 0.000 claims description 9
- 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 9
- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 claims description 9
- 229960002297 fenofibrate Drugs 0.000 claims description 9
- 229960004586 rosiglitazone Drugs 0.000 claims description 9
- 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 9
- 229960002855 simvastatin Drugs 0.000 claims description 9
- 229940124530 sulfonamide Drugs 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 8
- 229940002612 prodrug Drugs 0.000 claims description 8
- 239000000651 prodrug Substances 0.000 claims description 8
- 239000012453 solvate Substances 0.000 claims description 8
- 229940123208 Biguanide Drugs 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims description 7
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims description 7
- 231100000489 sensitizer Toxicity 0.000 claims description 7
- 150000003456 sulfonamides Chemical class 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- 239000012752 auxiliary agent Substances 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 238000005336 cracking Methods 0.000 claims description 6
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 6
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 6
- GKTQKQTXHNUFSP-UHFFFAOYSA-N thieno[3,4-c]pyrrole-4,6-dione Chemical compound S1C=C2C(=O)NC(=O)C2=C1 GKTQKQTXHNUFSP-UHFFFAOYSA-N 0.000 claims description 6
- 206010020772 Hypertension Diseases 0.000 claims description 5
- 229960003105 metformin Drugs 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- LEZCTXCXZDXCHF-UHFFFAOYSA-N 4-(2-chlorophenyl)piperazine-1-sulfonamide Chemical compound C1CN(S(=O)(=O)N)CCN1C1=CC=CC=C1Cl LEZCTXCXZDXCHF-UHFFFAOYSA-N 0.000 claims description 4
- WDDZIKQVLBYPLC-UHFFFAOYSA-N 4-(4-fluorophenyl)piperazine-1-sulfonamide Chemical compound C1CN(S(=O)(=O)N)CCN1C1=CC=C(F)C=C1 WDDZIKQVLBYPLC-UHFFFAOYSA-N 0.000 claims description 4
- KJMGGXBWXPNLDX-UHFFFAOYSA-N 4-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]piperazine-1-sulfonamide Chemical compound C1CN(S(=O)(=O)N)CCN1C1=NC=C(C(F)(F)F)C=C1Cl KJMGGXBWXPNLDX-UHFFFAOYSA-N 0.000 claims description 4
- NDJCYVRMNRZUMX-UHFFFAOYSA-N 4-[4-chloro-3-(trifluoromethyl)phenyl]piperazine-1-sulfonamide Chemical compound C1CN(S(=O)(=O)N)CCN1C1=CC=C(Cl)C(C(F)(F)F)=C1 NDJCYVRMNRZUMX-UHFFFAOYSA-N 0.000 claims description 4
- XZYYLFYBBUIPOJ-UHFFFAOYSA-N 4-pyridin-4-ylpiperazine-1-sulfonamide Chemical compound C1CN(S(=O)(=O)N)CCN1C1=CC=NC=C1 XZYYLFYBBUIPOJ-UHFFFAOYSA-N 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 150000007513 acids Chemical class 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 150000004283 biguanides Chemical class 0.000 claims description 4
- 208000029078 coronary artery disease Diseases 0.000 claims description 4
- 206010015037 epilepsy Diseases 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 239000011593 sulfur Substances 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 claims description 3
- 208000002705 Glucose Intolerance Diseases 0.000 claims description 3
- 206010018429 Glucose tolerance impaired Diseases 0.000 claims description 3
- 201000001431 Hyperuricemia Diseases 0.000 claims description 3
- 208000006575 hypertriglyceridemia Diseases 0.000 claims description 3
- ILPUOPPYSQEBNJ-UHFFFAOYSA-N 2-methyl-2-phenoxypropanoic acid Chemical compound OC(=O)C(C)(C)OC1=CC=CC=C1 ILPUOPPYSQEBNJ-UHFFFAOYSA-N 0.000 claims description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 2
- 108010023302 HDL Cholesterol Proteins 0.000 claims description 2
- WBOHXLDSPBIPTP-UHFFFAOYSA-N N,N-dimethyl-1,8-naphthyridin-4-amine Chemical compound CN(C1=CC=NC2=NC=CC=C12)C WBOHXLDSPBIPTP-UHFFFAOYSA-N 0.000 claims description 2
- 208000037849 arterial hypertension Diseases 0.000 claims description 2
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 2
- 208000035475 disorder Diseases 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 5
- 239000002131 composite material Substances 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 239000003112 inhibitor Substances 0.000 description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- 238000012360 testing method Methods 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 239000000556 agonist Substances 0.000 description 24
- 239000000243 solution Substances 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 239000008103 glucose Substances 0.000 description 17
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 16
- 239000005557 antagonist Substances 0.000 description 15
- 239000008280 blood Substances 0.000 description 14
- 210000004369 blood Anatomy 0.000 description 14
- 235000019197 fats Nutrition 0.000 description 14
- 241001465754 Metazoa Species 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- 102000016267 Leptin Human genes 0.000 description 12
- 108010092277 Leptin Proteins 0.000 description 12
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 12
- 235000013305 food Nutrition 0.000 description 12
- 229940039781 leptin Drugs 0.000 description 12
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 12
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 241000700159 Rattus Species 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 230000037396 body weight Effects 0.000 description 8
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 8
- 239000002956 ash Substances 0.000 description 7
- 230000008878 coupling Effects 0.000 description 7
- 238000010168 coupling process Methods 0.000 description 7
- 238000005859 coupling reaction Methods 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 208000037921 secondary disease Diseases 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 6
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 229960004756 ethanol Drugs 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 229960004844 lovastatin Drugs 0.000 description 6
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 6
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 229960005095 pioglitazone Drugs 0.000 description 6
- 229960002965 pravastatin Drugs 0.000 description 6
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 5
- JBMKAUGHUNFTOL-UHFFFAOYSA-N Aldoclor Chemical class C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC=NS2(=O)=O JBMKAUGHUNFTOL-UHFFFAOYSA-N 0.000 description 5
- 102000003846 Carbonic anhydrases Human genes 0.000 description 5
- 108090000209 Carbonic anhydrases Proteins 0.000 description 5
- 229940097420 Diuretic Drugs 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 239000002934 diuretic Substances 0.000 description 5
- 230000001882 diuretic effect Effects 0.000 description 5
- 230000003203 everyday effect Effects 0.000 description 5
- 238000005286 illumination Methods 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 4
- FXAAOALUHHXBSO-ILDUYXDCSA-N (3,3,5-trimethylcyclohexyl) (2s)-5-oxopyrrolidine-2-carboxylate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)[C@H]1NC(=O)CC1 FXAAOALUHHXBSO-ILDUYXDCSA-N 0.000 description 4
- FJLGEFLZQAZZCD-MCBHFWOFSA-N (3R,5S)-fluvastatin Chemical compound C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 FJLGEFLZQAZZCD-MCBHFWOFSA-N 0.000 description 4
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 4
- 208000004611 Abdominal Obesity Diseases 0.000 description 4
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 4
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 4
- 239000002083 C09CA01 - Losartan Substances 0.000 description 4
- 108010078791 Carrier Proteins Proteins 0.000 description 4
- 206010065941 Central obesity Diseases 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- KPSRODZRAIWAKH-JTQLQIEISA-N Ciprofibrate Natural products C1=CC(OC(C)(C)C(O)=O)=CC=C1[C@H]1C(Cl)(Cl)C1 KPSRODZRAIWAKH-JTQLQIEISA-N 0.000 description 4
- HEMJJKBWTPKOJG-UHFFFAOYSA-N Gemfibrozil Chemical compound CC1=CC=C(C)C(OCCCC(C)(C)C(O)=O)=C1 HEMJJKBWTPKOJG-UHFFFAOYSA-N 0.000 description 4
- LJIZUXQINHXGAO-ITWZMISCSA-N HR 780 Chemical compound C(\[C@H]1OC(=O)C[C@H](O)C1)=C/C=1C(C(C)C)=NC(C=2C=CC=CC=2)=CC=1C1=CC=C(F)C=C1 LJIZUXQINHXGAO-ITWZMISCSA-N 0.000 description 4
- RPTUSVTUFVMDQK-UHFFFAOYSA-N Hidralazin Chemical compound C1=CC=C2C(NN)=NN=CC2=C1 RPTUSVTUFVMDQK-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- AJLFOPYRIVGYMJ-UHFFFAOYSA-N SJ000287055 Natural products C12C(OC(=O)C(C)CC)CCC=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 AJLFOPYRIVGYMJ-UHFFFAOYSA-N 0.000 description 4
- 108020004101 alpha-2 Adrenergic Receptor Proteins 0.000 description 4
- 102000015006 alpha2-adrenergic receptor activity proteins Human genes 0.000 description 4
- 239000000010 aprotic solvent Substances 0.000 description 4
- 229960005370 atorvastatin Drugs 0.000 description 4
- 230000003796 beauty Effects 0.000 description 4
- 229960000516 bezafibrate Drugs 0.000 description 4
- IIBYAHWJQTYFKB-UHFFFAOYSA-N bezafibrate Chemical compound C1=CC(OC(C)(C)C(O)=O)=CC=C1CCNC(=O)C1=CC=C(Cl)C=C1 IIBYAHWJQTYFKB-UHFFFAOYSA-N 0.000 description 4
- 229960005110 cerivastatin Drugs 0.000 description 4
- SEERZIQQUAZTOL-ANMDKAQQSA-N cerivastatin Chemical compound COCC1=C(C(C)C)N=C(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 SEERZIQQUAZTOL-ANMDKAQQSA-N 0.000 description 4
- 235000012000 cholesterol Nutrition 0.000 description 4
- YZFWTZACSRHJQD-UHFFFAOYSA-N ciglitazone Chemical compound C=1C=C(CC2C(NC(=O)S2)=O)C=CC=1OCC1(C)CCCCC1 YZFWTZACSRHJQD-UHFFFAOYSA-N 0.000 description 4
- 229950009226 ciglitazone Drugs 0.000 description 4
- 229960002174 ciprofibrate Drugs 0.000 description 4
- KPSRODZRAIWAKH-UHFFFAOYSA-N ciprofibrate Chemical compound C1=CC(OC(C)(C)C(O)=O)=CC=C1C1C(Cl)(Cl)C1 KPSRODZRAIWAKH-UHFFFAOYSA-N 0.000 description 4
- 229960001214 clofibrate Drugs 0.000 description 4
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 4
- 229950002753 crilvastatin Drugs 0.000 description 4
- 229960004042 diazoxide Drugs 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 229960003765 fluvastatin Drugs 0.000 description 4
- 229960003627 gemfibrozil Drugs 0.000 description 4
- 229950000806 glenvastatin Drugs 0.000 description 4
- 230000000968 intestinal effect Effects 0.000 description 4
- 229960004773 losartan Drugs 0.000 description 4
- AJLFOPYRIVGYMJ-INTXDZFKSA-N mevastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=CCC[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 AJLFOPYRIVGYMJ-INTXDZFKSA-N 0.000 description 4
- 229950009116 mevastatin Drugs 0.000 description 4
- BOZILQFLQYBIIY-UHFFFAOYSA-N mevastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CCC=C21 BOZILQFLQYBIIY-UHFFFAOYSA-N 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- DHHVAGZRUROJKS-UHFFFAOYSA-N phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 description 4
- 229960002797 pitavastatin Drugs 0.000 description 4
- VGYFMXBACGZSIL-MCBHFWOFSA-N pitavastatin Chemical compound OC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 VGYFMXBACGZSIL-MCBHFWOFSA-N 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 description 4
- 229960000672 rosuvastatin Drugs 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 229960004425 sibutramine Drugs 0.000 description 4
- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 description 4
- 229960002256 spironolactone Drugs 0.000 description 4
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 4
- 235000000346 sugar Nutrition 0.000 description 4
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 description 4
- 229960001641 troglitazone Drugs 0.000 description 4
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 description 4
- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 description 4
- OLJAPHMBAMBVKL-UHFFFAOYSA-N 5-methyl-7-propyl-8-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]-3h-[1,2,4]triazolo[1,5-c]pyrimidin-2-one Chemical compound CCCC=1N=C(C)N2NC(=O)N=C2C=1CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 OLJAPHMBAMBVKL-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 108010005939 Ciliary Neurotrophic Factor Proteins 0.000 description 3
- 102100031614 Ciliary neurotrophic factor Human genes 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 3
- 208000035126 Facies Diseases 0.000 description 3
- 235000002918 Fraxinus excelsior Nutrition 0.000 description 3
- 102400000322 Glucagon-like peptide 1 Human genes 0.000 description 3
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 3
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 3
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 3
- 108010044467 Isoenzymes Proteins 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 229940086609 Lipase inhibitor Drugs 0.000 description 3
- 101800003845 Neuropeptide Y Proteins 0.000 description 3
- 102400000064 Neuropeptide Y Human genes 0.000 description 3
- 241001597008 Nomeidae Species 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 239000004743 Polypropylene Substances 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 229940123464 Thiazolidinedione Drugs 0.000 description 3
- ZUMPSVPHCDJCMD-UHFFFAOYSA-N abitesartan Chemical compound C1CCCC1(C(O)=O)CN(C(=O)CCCC)CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 ZUMPSVPHCDJCMD-UHFFFAOYSA-N 0.000 description 3
- 210000000577 adipose tissue Anatomy 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 230000001476 alcoholic effect Effects 0.000 description 3
- 230000036528 appetite Effects 0.000 description 3
- 235000019789 appetite Nutrition 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 235000008504 concentrate Nutrition 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- TYNBFJJKZPTRKS-UHFFFAOYSA-N dansyl amide Chemical compound C1=CC=C2C(N(C)C)=CC=CC2=C1S(N)(=O)=O TYNBFJJKZPTRKS-UHFFFAOYSA-N 0.000 description 3
- IDAWWPOAHPVPMY-UHFFFAOYSA-N elisartan Chemical compound CCCCC1=NC(Cl)=C(C(=O)OC(C)OC(=O)OCC)N1CC1=CC=C(C=2C(=CC=CC=2)C2=NNN=N2)C=C1 IDAWWPOAHPVPMY-UHFFFAOYSA-N 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 235000020828 fasting Nutrition 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 101150020161 flu-2 gene Proteins 0.000 description 3
- YONOBYIBNBCDSJ-UHFFFAOYSA-N forasartan Chemical compound N1=C(CCCC)N=C(CCCC)N1CC1=CC=C(C=2C(=CC=CC=2)C2=NNN=N2)N=C1 YONOBYIBNBCDSJ-UHFFFAOYSA-N 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 3
- 201000008980 hyperinsulinism Diseases 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 229940125425 inverse agonist Drugs 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 238000003305 oral gavage Methods 0.000 description 3
- 229920001993 poloxamer 188 Polymers 0.000 description 3
- 229940044519 poloxamer 188 Drugs 0.000 description 3
- 229920001155 polypropylene Polymers 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- DBGIVFWFUFKIQN-VIFPVBQESA-N (+)-Fenfluramine Chemical compound CCN[C@@H](C)CC1=CC=CC(C(F)(F)F)=C1 DBGIVFWFUFKIQN-VIFPVBQESA-N 0.000 description 2
- DBGIVFWFUFKIQN-UHFFFAOYSA-N (+-)-Fenfluramine Chemical compound CCNC(C)CC1=CC=CC(C(F)(F)F)=C1 DBGIVFWFUFKIQN-UHFFFAOYSA-N 0.000 description 2
- CEMAWMOMDPGJMB-UHFFFAOYSA-N (+-)-Oxprenolol Chemical compound CC(C)NCC(O)COC1=CC=CC=C1OCC=C CEMAWMOMDPGJMB-UHFFFAOYSA-N 0.000 description 2
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 description 2
- NXWGWUVGUSFQJC-GFCCVEGCSA-N (2r)-1-[(2-methyl-1h-indol-4-yl)oxy]-3-(propan-2-ylamino)propan-2-ol Chemical compound CC(C)NC[C@@H](O)COC1=CC=CC2=C1C=C(C)N2 NXWGWUVGUSFQJC-GFCCVEGCSA-N 0.000 description 2
- CRUVAUSVWLATAE-ZDUSSCGKSA-N (2s)-3-dibenzofuran-3-yl-2-(phosphonomethylamino)propanoic acid Chemical compound C1=CC=C2C3=CC=C(C[C@@H](C(=O)O)NCP(O)(O)=O)C=C3OC2=C1 CRUVAUSVWLATAE-ZDUSSCGKSA-N 0.000 description 2
- BIDNLKIUORFRQP-XYGFDPSESA-N (2s,4s)-4-cyclohexyl-1-[2-[[(1s)-2-methyl-1-propanoyloxypropoxy]-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([P@@](=O)(O[C@H](OC(=O)CC)C(C)C)CC(=O)N1[C@@H](C[C@H](C1)C1CCCCC1)C(O)=O)CCCC1=CC=CC=C1 BIDNLKIUORFRQP-XYGFDPSESA-N 0.000 description 2
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 2
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 description 2
- 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 description 2
- BOVGTQGAOIONJV-BETUJISGSA-N 1-[(3ar,6as)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-yl]-3-(4-methylphenyl)sulfonylurea Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1C[C@H]2CCC[C@H]2C1 BOVGTQGAOIONJV-BETUJISGSA-N 0.000 description 2
- LLJFMFZYVVLQKT-UHFFFAOYSA-N 1-cyclohexyl-3-[4-[2-(7-methoxy-4,4-dimethyl-1,3-dioxo-2-isoquinolinyl)ethyl]phenyl]sulfonylurea Chemical compound C=1C(OC)=CC=C(C(C2=O)(C)C)C=1C(=O)N2CCC(C=C1)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 LLJFMFZYVVLQKT-UHFFFAOYSA-N 0.000 description 2
- RPRNBLHRKYAXSM-UHFFFAOYSA-N 2-ethyl-4-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methoxy]-5,6,7,8-tetrahydroquinoline;hydrochloride Chemical compound Cl.C=12CCCCC2=NC(CC)=CC=1OCC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1 RPRNBLHRKYAXSM-UHFFFAOYSA-N 0.000 description 2
- SGUAFYQXFOLMHL-UHFFFAOYSA-N 2-hydroxy-5-{1-hydroxy-2-[(4-phenylbutan-2-yl)amino]ethyl}benzamide Chemical compound C=1C=C(O)C(C(N)=O)=CC=1C(O)CNC(C)CCC1=CC=CC=C1 SGUAFYQXFOLMHL-UHFFFAOYSA-N 0.000 description 2
- LBXHRAWDUMTPSE-AOOOYVTPSA-N 4-chloro-N-[(2S,6R)-2,6-dimethyl-1-piperidinyl]-3-sulfamoylbenzamide Chemical compound C[C@H]1CCC[C@@H](C)N1NC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 LBXHRAWDUMTPSE-AOOOYVTPSA-N 0.000 description 2
- UTKUVRNVYFTEHF-UHFFFAOYSA-N 4-nitro-3-(trifluoromethyl)aniline Chemical compound NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 UTKUVRNVYFTEHF-UHFFFAOYSA-N 0.000 description 2
- 102100024959 5-hydroxytryptamine receptor 2C Human genes 0.000 description 2
- 101710138093 5-hydroxytryptamine receptor 2C Proteins 0.000 description 2
- VGLGVJVUHYTIIU-UHFFFAOYSA-N 6-chloro-1,1-dioxo-3-[(prop-2-enylthio)methyl]-3,4-dihydro-2H-1$l^{6},2,4-benzothiadiazine-7-sulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC(CSCC=C)NS2(=O)=O VGLGVJVUHYTIIU-UHFFFAOYSA-N 0.000 description 2
- JDCJFONQCRLHND-UHFFFAOYSA-N 6-chloro-3-[(4-fluorophenyl)methyl]-1,1-dioxo-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazine-7-sulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2CC1=CC=C(F)C=C1 JDCJFONQCRLHND-UHFFFAOYSA-N 0.000 description 2
- 102100021641 Acetyl-CoA carboxylase 2 Human genes 0.000 description 2
- 102100022089 Acyl-[acyl-carrier-protein] hydrolase Human genes 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 244000141218 Alpinia officinarum Species 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- XPCFTKFZXHTYIP-PMACEKPBSA-N Benazepril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C2=CC=CC=C2CC1)=O)CC1=CC=CC=C1 XPCFTKFZXHTYIP-PMACEKPBSA-N 0.000 description 2
- BWSSMIJUDVUASQ-UHFFFAOYSA-N Benzylhydrochlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2CC1=CC=CC=C1 BWSSMIJUDVUASQ-UHFFFAOYSA-N 0.000 description 2
- 108010018763 Biotin carboxylase Proteins 0.000 description 2
- 239000002080 C09CA02 - Eprosartan Substances 0.000 description 2
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 2
- 239000002947 C09CA04 - Irbesartan Substances 0.000 description 2
- 239000002081 C09CA05 - Tasosartan Substances 0.000 description 2
- 239000002053 C09CA06 - Candesartan Substances 0.000 description 2
- 239000005537 C09CA07 - Telmisartan Substances 0.000 description 2
- JOATXPAWOHTVSZ-UHFFFAOYSA-N Celiprolol Chemical compound CCN(CC)C(=O)NC1=CC=C(OCC(O)CNC(C)(C)C)C(C(C)=O)=C1 JOATXPAWOHTVSZ-UHFFFAOYSA-N 0.000 description 2
- 206010008479 Chest Pain Diseases 0.000 description 2
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 2
- 229920001268 Cholestyramine Polymers 0.000 description 2
- NENBAISIHCWPKP-UHFFFAOYSA-N Clofenamide Chemical compound NS(=O)(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 NENBAISIHCWPKP-UHFFFAOYSA-N 0.000 description 2
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 2
- VPMWFZKOWULPGT-UHFFFAOYSA-N Clorexolone Chemical compound C1C=2C=C(Cl)C(S(=O)(=O)N)=CC=2C(=O)N1C1CCCCC1 VPMWFZKOWULPGT-UHFFFAOYSA-N 0.000 description 2
- 229920002911 Colestipol Polymers 0.000 description 2
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 2
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 2
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 2
- 206010063547 Diabetic macroangiopathy Diseases 0.000 description 2
- 206010012689 Diabetic retinopathy Diseases 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 2
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 2
- 108010039731 Fatty Acid Synthases Proteins 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- LYISDADPVOHJBJ-UHFFFAOYSA-N Galangin 3-methyl ether Natural products O1C2=CC(O)=CC(O)=C2C(=O)C(OC)=C1C1=CC=CC=C1 LYISDADPVOHJBJ-UHFFFAOYSA-N 0.000 description 2
- 101800002068 Galanin Proteins 0.000 description 2
- 102400001370 Galanin Human genes 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 101800001586 Ghrelin Proteins 0.000 description 2
- 102400000442 Ghrelin-28 Human genes 0.000 description 2
- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 description 2
- 201000005569 Gout Diseases 0.000 description 2
- 102000018997 Growth Hormone Human genes 0.000 description 2
- 108010051696 Growth Hormone Proteins 0.000 description 2
- WDZVGELJXXEGPV-YIXHJXPBSA-N Guanabenz Chemical compound NC(N)=N\N=C\C1=C(Cl)C=CC=C1Cl WDZVGELJXXEGPV-YIXHJXPBSA-N 0.000 description 2
- INJOMKTZOLKMBF-UHFFFAOYSA-N Guanfacine Chemical compound NC(=N)NC(=O)CC1=C(Cl)C=CC=C1Cl INJOMKTZOLKMBF-UHFFFAOYSA-N 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 108010041872 Islet Amyloid Polypeptide Proteins 0.000 description 2
- 102000004882 Lipase Human genes 0.000 description 2
- 108090001060 Lipase Proteins 0.000 description 2
- 239000004367 Lipase Substances 0.000 description 2
- SIKWOTFNWURSAY-UHFFFAOYSA-N Lipstatin Natural products CCCCCCC1C(CC(CC=CCC=CCCCCC)C(=O)OC(CC(C)C)NC=O)OC1=O SIKWOTFNWURSAY-UHFFFAOYSA-N 0.000 description 2
- 108010007859 Lisinopril Proteins 0.000 description 2
- ZPXSCAKFGYXMGA-UHFFFAOYSA-N Mazindol Chemical compound N12CCN=C2C2=CC=CC=C2C1(O)C1=CC=C(Cl)C=C1 ZPXSCAKFGYXMGA-UHFFFAOYSA-N 0.000 description 2
- SMNOERSLNYGGOU-UHFFFAOYSA-N Mefruside Chemical compound C=1C=C(Cl)C(S(N)(=O)=O)=CC=1S(=O)(=O)N(C)CC1(C)CCCO1 SMNOERSLNYGGOU-UHFFFAOYSA-N 0.000 description 2
- 108010007013 Melanocyte-Stimulating Hormones Proteins 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- CESYKOGBSMNBPD-UHFFFAOYSA-N Methyclothiazide Chemical compound ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)N(C)C(CCl)NC2=C1 CESYKOGBSMNBPD-UHFFFAOYSA-N 0.000 description 2
- IBAQFPQHRJAVAV-ULAWRXDQSA-N Miglitol Chemical compound OCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO IBAQFPQHRJAVAV-ULAWRXDQSA-N 0.000 description 2
- 239000005474 Milfasartan Substances 0.000 description 2
- 102000015494 Mitochondrial Uncoupling Proteins Human genes 0.000 description 2
- 108010050258 Mitochondrial Uncoupling Proteins Proteins 0.000 description 2
- UWWDHYUMIORJTA-HSQYWUDLSA-N Moexipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC(OC)=C(OC)C=C2C1)C(O)=O)CC1=CC=CC=C1 UWWDHYUMIORJTA-HSQYWUDLSA-N 0.000 description 2
- WPNJAUFVNXKLIM-UHFFFAOYSA-N Moxonidine Chemical compound COC1=NC(C)=NC(Cl)=C1NC1=NCCN1 WPNJAUFVNXKLIM-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 239000005480 Olmesartan Substances 0.000 description 2
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 2
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 2
- QZVCTJOXCFMACW-UHFFFAOYSA-N Phenoxybenzamine Chemical compound C=1C=CC=CC=1CN(CCCl)C(C)COC1=CC=CC=C1 QZVCTJOXCFMACW-UHFFFAOYSA-N 0.000 description 2
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 2
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 2
- UJEWTUDSLQGTOA-UHFFFAOYSA-N Piretanide Chemical compound C=1C=CC=CC=1OC=1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1N1CCCC1 UJEWTUDSLQGTOA-UHFFFAOYSA-N 0.000 description 2
- CYLWJCABXYDINA-UHFFFAOYSA-N Polythiazide Polymers ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)N(C)C(CSCC(F)(F)F)NC2=C1 CYLWJCABXYDINA-UHFFFAOYSA-N 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 2
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 2
- 239000005479 Ripisartan Substances 0.000 description 2
- 239000005478 Saprisartan Substances 0.000 description 2
- DUEWVPTZCSAMNB-UHFFFAOYSA-N Saprisartan Chemical compound NC(=O)C=1N(CC=2C=C3C(Br)=C(OC3=CC=2)C=2C(=CC=CC=2)NS(=O)(=O)C(F)(F)F)C(CC)=NC=1C1CC1 DUEWVPTZCSAMNB-UHFFFAOYSA-N 0.000 description 2
- 108010083387 Saralasin Proteins 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 241001655322 Streptomycetales Species 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 2
- KJADKKWYZYXHBB-XBWDGYHZSA-N Topiramic acid Chemical compound C1O[C@@]2(COS(N)(=O)=O)OC(C)(C)O[C@H]2[C@@H]2OC(C)(C)O[C@@H]21 KJADKKWYZYXHBB-XBWDGYHZSA-N 0.000 description 2
- NGBFQHCMQULJNZ-UHFFFAOYSA-N Torsemide Chemical compound CC(C)NC(=O)NS(=O)(=O)C1=CN=CC=C1NC1=CC=CC(C)=C1 NGBFQHCMQULJNZ-UHFFFAOYSA-N 0.000 description 2
- VXFJYXUZANRPDJ-WTNASJBWSA-N Trandopril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@H]2CCCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 VXFJYXUZANRPDJ-WTNASJBWSA-N 0.000 description 2
- FNYLWPVRPXGIIP-UHFFFAOYSA-N Triamterene Chemical compound NC1=NC2=NC(N)=NC(N)=C2N=C1C1=CC=CC=C1 FNYLWPVRPXGIIP-UHFFFAOYSA-N 0.000 description 2
- ICMGLRUYEQNHPF-UHFFFAOYSA-N Uraprene Chemical compound COC1=CC=CC=C1N1CCN(CCCNC=2N(C(=O)N(C)C(=O)C=2)C)CC1 ICMGLRUYEQNHPF-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 229950010933 abitesartan Drugs 0.000 description 2
- 229960002632 acarbose Drugs 0.000 description 2
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 description 2
- 229960002122 acebutolol Drugs 0.000 description 2
- GOEMGAFJFRBGGG-UHFFFAOYSA-N acebutolol Chemical compound CCCC(=O)NC1=CC=C(OCC(O)CNC(C)C)C(C(C)=O)=C1 GOEMGAFJFRBGGG-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000000048 adrenergic agonist Substances 0.000 description 2
- 239000004479 aerosol dispenser Substances 0.000 description 2
- 229960002213 alprenolol Drugs 0.000 description 2
- PAZJSJFMUHDSTF-UHFFFAOYSA-N alprenolol Chemical compound CC(C)NCC(O)COC1=CC=CC=C1CC=C PAZJSJFMUHDSTF-UHFFFAOYSA-N 0.000 description 2
- 229950007522 altizide Drugs 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 229960002576 amiloride Drugs 0.000 description 2
- XSDQTOBWRPYKKA-UHFFFAOYSA-N amiloride Chemical compound NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N XSDQTOBWRPYKKA-UHFFFAOYSA-N 0.000 description 2
- 229940025084 amphetamine Drugs 0.000 description 2
- 230000001773 anti-convulsant effect Effects 0.000 description 2
- 229940127003 anti-diabetic drug Drugs 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 239000003472 antidiabetic agent Substances 0.000 description 2
- 229960003965 antiepileptics Drugs 0.000 description 2
- 229960002274 atenolol Drugs 0.000 description 2
- MOTJMGVDPWRKOC-QPVYNBJUSA-N atrasentan Chemical compound C1([C@H]2[C@@H]([C@H](CN2CC(=O)N(CCCC)CCCC)C=2C=C3OCOC3=CC=2)C(O)=O)=CC=C(OC)C=C1 MOTJMGVDPWRKOC-QPVYNBJUSA-N 0.000 description 2
- 229950010993 atrasentan Drugs 0.000 description 2
- IIOPLILENRZKRV-UHFFFAOYSA-N azosemide Chemical compound C=1C=CSC=1CNC=1C=C(Cl)C(S(=O)(=O)N)=CC=1C1=NN=N[N]1 IIOPLILENRZKRV-UHFFFAOYSA-N 0.000 description 2
- 229960004988 azosemide Drugs 0.000 description 2
- PYVUMAGVCSQCBD-UHFFFAOYSA-N bemetizide Chemical compound N1C2=CC(Cl)=C(S(N)(=O)=O)C=C2S(=O)(=O)NC1C(C)C1=CC=CC=C1 PYVUMAGVCSQCBD-UHFFFAOYSA-N 0.000 description 2
- 229950004310 bemetizide Drugs 0.000 description 2
- 229960004530 benazepril Drugs 0.000 description 2
- 229960003515 bendroflumethiazide Drugs 0.000 description 2
- HDWIHXWEUNVBIY-UHFFFAOYSA-N bendroflumethiazidum Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2CC1=CC=CC=C1 HDWIHXWEUNVBIY-UHFFFAOYSA-N 0.000 description 2
- NDTSRXAMMQDVSW-UHFFFAOYSA-N benzthiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1N=C2CSCC1=CC=CC=C1 NDTSRXAMMQDVSW-UHFFFAOYSA-N 0.000 description 2
- 229960001541 benzthiazide Drugs 0.000 description 2
- 229950007003 benzylhydrochlorothiazide Drugs 0.000 description 2
- 229960004324 betaxolol Drugs 0.000 description 2
- CHDPSNLJFOQTRK-UHFFFAOYSA-N betaxolol hydrochloride Chemical compound [Cl-].C1=CC(OCC(O)C[NH2+]C(C)C)=CC=C1CCOCC1CC1 CHDPSNLJFOQTRK-UHFFFAOYSA-N 0.000 description 2
- 239000003613 bile acid Substances 0.000 description 2
- GJPICJJJRGTNOD-UHFFFAOYSA-N bosentan Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2N=CC=CN=2)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 GJPICJJJRGTNOD-UHFFFAOYSA-N 0.000 description 2
- 229960003065 bosentan Drugs 0.000 description 2
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 description 2
- 229960002802 bromocriptine Drugs 0.000 description 2
- MAEIEVLCKWDQJH-UHFFFAOYSA-N bumetanide Chemical compound CCCCNC1=CC(C(O)=O)=CC(S(N)(=O)=O)=C1OC1=CC=CC=C1 MAEIEVLCKWDQJH-UHFFFAOYSA-N 0.000 description 2
- 229960004064 bumetanide Drugs 0.000 description 2
- 229960000330 bupranolol Drugs 0.000 description 2
- HQIRNZOQPUAHHV-UHFFFAOYSA-N bupranolol Chemical compound CC1=CC=C(Cl)C(OCC(O)CNC(C)(C)C)=C1 HQIRNZOQPUAHHV-UHFFFAOYSA-N 0.000 description 2
- HGBFRHCDYZJRAO-UHFFFAOYSA-N butizide Chemical compound ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)NC(CC(C)C)NC2=C1 HGBFRHCDYZJRAO-UHFFFAOYSA-N 0.000 description 2
- 229950008955 butizide Drugs 0.000 description 2
- 229960000932 candesartan Drugs 0.000 description 2
- SGZAIDDFHDDFJU-UHFFFAOYSA-N candesartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SGZAIDDFHDDFJU-UHFFFAOYSA-N 0.000 description 2
- PBKZPPIHUVSDNM-WNHSNXHDSA-N canrenoic acid Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@](CC4)(O)CCC(O)=O)[C@@H]4[C@@H]3C=CC2=C1 PBKZPPIHUVSDNM-WNHSNXHDSA-N 0.000 description 2
- 229960000830 captopril Drugs 0.000 description 2
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 2
- BQXQGZPYHWWCEB-UHFFFAOYSA-N carazolol Chemical compound N1C2=CC=CC=C2C2=C1C=CC=C2OCC(O)CNC(C)C BQXQGZPYHWWCEB-UHFFFAOYSA-N 0.000 description 2
- 229960004634 carazolol Drugs 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 229960001222 carteolol Drugs 0.000 description 2
- LWAFSWPYPHEXKX-UHFFFAOYSA-N carteolol Chemical compound N1C(=O)CCC2=C1C=CC=C2OCC(O)CNC(C)(C)C LWAFSWPYPHEXKX-UHFFFAOYSA-N 0.000 description 2
- NPAKNKYSJIDKMW-UHFFFAOYSA-N carvedilol Chemical compound COC1=CC=CC=C1OCCNCC(O)COC1=CC=CC2=NC3=CC=C[CH]C3=C12 NPAKNKYSJIDKMW-UHFFFAOYSA-N 0.000 description 2
- 229960004195 carvedilol Drugs 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 229960002320 celiprolol Drugs 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 229960002155 chlorothiazide Drugs 0.000 description 2
- 201000001883 cholelithiasis Diseases 0.000 description 2
- 208000020832 chronic kidney disease Diseases 0.000 description 2
- 229960005025 cilazapril Drugs 0.000 description 2
- HHHKFGXWKKUNCY-FHWLQOOXSA-N cilazapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N2[C@@H](CCCN2CCC1)C(O)=O)=O)CC1=CC=CC=C1 HHHKFGXWKKUNCY-FHWLQOOXSA-N 0.000 description 2
- 229960002883 clofenamide Drugs 0.000 description 2
- 229960002896 clonidine Drugs 0.000 description 2
- 229960004070 clopamide Drugs 0.000 description 2
- 229960005315 clorexolone Drugs 0.000 description 2
- GMRWGQCZJGVHKL-UHFFFAOYSA-N colestipol Chemical compound ClCC1CO1.NCCNCCNCCNCCN GMRWGQCZJGVHKL-UHFFFAOYSA-N 0.000 description 2
- 229960002604 colestipol Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 229960003176 cyclothiazide Drugs 0.000 description 2
- BOCUKUHCLICSIY-QJWLJZLASA-N cyclothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2C1[C@H](C=C2)C[C@H]2C1 BOCUKUHCLICSIY-QJWLJZLASA-N 0.000 description 2
- FEJVSJIALLTFRP-LJQANCHMSA-N darusentan Chemical compound COC1=CC(OC)=NC(O[C@H](C(O)=O)C(OC)(C=2C=CC=CC=2)C=2C=CC=CC=2)=N1 FEJVSJIALLTFRP-LJQANCHMSA-N 0.000 description 2
- 229950008833 darusentan Drugs 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229960000632 dexamfetamine Drugs 0.000 description 2
- 229960004597 dexfenfluramine Drugs 0.000 description 2
- 208000033679 diabetic kidney disease Diseases 0.000 description 2
- 150000001991 dicarboxylic acids Chemical class 0.000 description 2
- 229960002877 dihydralazine Drugs 0.000 description 2
- VQKLRVZQQYVIJW-UHFFFAOYSA-N dihydralazine Chemical compound C1=CC=C2C(NN)=NN=C(NN)C2=C1 VQKLRVZQQYVIJW-UHFFFAOYSA-N 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- RUZYUOTYCVRMRZ-UHFFFAOYSA-N doxazosin Chemical compound C1OC2=CC=CC=C2OC1C(=O)N(CC1)CCN1C1=NC(N)=C(C=C(C(OC)=C2)OC)C2=N1 RUZYUOTYCVRMRZ-UHFFFAOYSA-N 0.000 description 2
- 229960001389 doxazosin Drugs 0.000 description 2
- 239000003651 drinking water Substances 0.000 description 2
- 235000020188 drinking water Nutrition 0.000 description 2
- 239000000890 drug combination Substances 0.000 description 2
- 229950000980 elisartan Drugs 0.000 description 2
- 229950006127 embusartan Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229960001208 eplerenone Drugs 0.000 description 2
- JUKPWJGBANNWMW-VWBFHTRKSA-N eplerenone Chemical compound C([C@@H]1[C@]2(C)C[C@H]3O[C@]33[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)C(=O)OC)C[C@@]21CCC(=O)O1 JUKPWJGBANNWMW-VWBFHTRKSA-N 0.000 description 2
- 229960004563 eprosartan Drugs 0.000 description 2
- OROAFUQRIXKEMV-LDADJPATSA-N eprosartan Chemical compound C=1C=C(C(O)=O)C=CC=1CN1C(CCCC)=NC=C1\C=C(C(O)=O)/CC1=CC=CS1 OROAFUQRIXKEMV-LDADJPATSA-N 0.000 description 2
- OUZWUKMCLIBBOG-UHFFFAOYSA-N ethoxzolamide Chemical compound CCOC1=CC=C2N=C(S(N)(=O)=O)SC2=C1 OUZWUKMCLIBBOG-UHFFFAOYSA-N 0.000 description 2
- 229950005098 ethoxzolamide Drugs 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 description 2
- 229960001582 fenfluramine Drugs 0.000 description 2
- 229960002637 fenquizone Drugs 0.000 description 2
- DBDTUXMDTSTPQZ-UHFFFAOYSA-N fenquizone Chemical compound N1C=2C=C(Cl)C(S(=O)(=O)N)=CC=2C(=O)NC1C1=CC=CC=C1 DBDTUXMDTSTPQZ-UHFFFAOYSA-N 0.000 description 2
- 230000037406 food intake Effects 0.000 description 2
- 229950003641 forasartan Drugs 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229960002490 fosinopril Drugs 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 2
- 229960003883 furosemide Drugs 0.000 description 2
- 208000020694 gallbladder disease Diseases 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- GNKDKYIHGQKHHM-RJKLHVOGSA-N ghrelin Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)CN)COC(=O)CCCCCCC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C1=CC=CC=C1 GNKDKYIHGQKHHM-RJKLHVOGSA-N 0.000 description 2
- 229960004580 glibenclamide Drugs 0.000 description 2
- 229960000346 gliclazide Drugs 0.000 description 2
- 229960004346 glimepiride Drugs 0.000 description 2
- WIGIZIANZCJQQY-RUCARUNLSA-N glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 description 2
- 229960001381 glipizide Drugs 0.000 description 2
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 description 2
- 229960003468 gliquidone Drugs 0.000 description 2
- 229960003236 glisoxepide Drugs 0.000 description 2
- ZKUDBRCEOBOWLF-UHFFFAOYSA-N glisoxepide Chemical compound O1C(C)=CC(C(=O)NCCC=2C=CC(=CC=2)S(=O)(=O)NC(=O)NN2CCCCCC2)=N1 ZKUDBRCEOBOWLF-UHFFFAOYSA-N 0.000 description 2
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 2
- 239000000122 growth hormone Substances 0.000 description 2
- 229960004553 guanabenz Drugs 0.000 description 2
- ACGDKVXYNVEAGU-UHFFFAOYSA-N guanethidine Chemical compound NC(N)=NCCN1CCCCCCC1 ACGDKVXYNVEAGU-UHFFFAOYSA-N 0.000 description 2
- 229960003602 guanethidine Drugs 0.000 description 2
- 229960002048 guanfacine Drugs 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 229960002474 hydralazine Drugs 0.000 description 2
- 229960002003 hydrochlorothiazide Drugs 0.000 description 2
- 229960003313 hydroflumethiazide Drugs 0.000 description 2
- DMDGGSIALPNSEE-UHFFFAOYSA-N hydroflumethiazide Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O DMDGGSIALPNSEE-UHFFFAOYSA-N 0.000 description 2
- 230000001631 hypertensive effect Effects 0.000 description 2
- 230000002218 hypoglycaemic effect Effects 0.000 description 2
- 229960001195 imidapril Drugs 0.000 description 2
- KLZWOWYOHUKJIG-BPUTZDHNSA-N imidapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1C(N(C)C[C@H]1C(O)=O)=O)CC1=CC=CC=C1 KLZWOWYOHUKJIG-BPUTZDHNSA-N 0.000 description 2
- 229960004569 indapamide Drugs 0.000 description 2
- NDDAHWYSQHTHNT-UHFFFAOYSA-N indapamide Chemical compound CC1CC2=CC=CC=C2N1NC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 NDDAHWYSQHTHNT-UHFFFAOYSA-N 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 229960002198 irbesartan Drugs 0.000 description 2
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 235000019421 lipase Nutrition 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- OQMAKWGYQLJJIA-CUOOPAIESA-N lipstatin Chemical compound CCCCCC[C@H]1[C@H](C[C@H](C\C=C/C\C=C/CCCCC)OC(=O)[C@H](CC(C)C)NC=O)OC1=O OQMAKWGYQLJJIA-CUOOPAIESA-N 0.000 description 2
- 229960002394 lisinopril Drugs 0.000 description 2
- RLAWWYSOJDYHDC-BZSNNMDCSA-N lisinopril Chemical compound C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 RLAWWYSOJDYHDC-BZSNNMDCSA-N 0.000 description 2
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 229960000299 mazindol Drugs 0.000 description 2
- 235000012054 meals Nutrition 0.000 description 2
- 229960004678 mefruside Drugs 0.000 description 2
- 210000002752 melanocyte Anatomy 0.000 description 2
- 229960003134 mepindolol Drugs 0.000 description 2
- 229960003739 methyclothiazide Drugs 0.000 description 2
- QVFVAKQHELFATN-UHFFFAOYSA-N methyl 2-[[4-butyl-2-methyl-6-oxo-5-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]pyrimidin-1-yl]methyl]thiophene-3-carboxylate Chemical compound O=C1C(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C2=NNN=N2)=C(CCCC)N=C(C)N1CC=1SC=CC=1C(=O)OC QVFVAKQHELFATN-UHFFFAOYSA-N 0.000 description 2
- LYVGOAYMIAQLHI-UHFFFAOYSA-N methyl 2-butyl-1-[[2-fluoro-4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]-6-oxopyridine-4-carboxylate Chemical compound CCCCC1=CC(C(=O)OC)=CC(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C2=NNN=N2)C=C1F LYVGOAYMIAQLHI-UHFFFAOYSA-N 0.000 description 2
- YLGXILFCIXHCMC-JHGZEJCSSA-N methyl cellulose Chemical compound COC1C(OC)C(OC)C(COC)O[C@H]1O[C@H]1C(OC)C(OC)C(OC)OC1COC YLGXILFCIXHCMC-JHGZEJCSSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 229960002704 metipranolol Drugs 0.000 description 2
- BLWNYSZZZWQCKO-UHFFFAOYSA-N metipranolol hydrochloride Chemical compound [Cl-].CC(C)[NH2+]CC(O)COC1=CC(C)=C(OC(C)=O)C(C)=C1C BLWNYSZZZWQCKO-UHFFFAOYSA-N 0.000 description 2
- 229960002817 metolazone Drugs 0.000 description 2
- AQCHWTWZEMGIFD-UHFFFAOYSA-N metolazone Chemical compound CC1NC2=CC(Cl)=C(S(N)(=O)=O)C=C2C(=O)N1C1=CC=CC=C1C AQCHWTWZEMGIFD-UHFFFAOYSA-N 0.000 description 2
- 229960002237 metoprolol Drugs 0.000 description 2
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 description 2
- 229960001110 miglitol Drugs 0.000 description 2
- 229950003561 milfasartan Drugs 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 229960005170 moexipril Drugs 0.000 description 2
- SLZIZIJTGAYEKK-CIJSCKBQSA-N molport-023-220-247 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CN)[C@@H](C)O)C1=CNC=N1 SLZIZIJTGAYEKK-CIJSCKBQSA-N 0.000 description 2
- 229960003938 moxonidine Drugs 0.000 description 2
- TUYWTLTWNJOZNY-UHFFFAOYSA-N n-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[2-(2h-tetrazol-5-yl)pyridin-4-yl]pyrimidin-4-yl]-5-propan-2-ylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C2=NNN=N2)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)C)C=N1 TUYWTLTWNJOZNY-UHFFFAOYSA-N 0.000 description 2
- 229960004255 nadolol Drugs 0.000 description 2
- VWPOSFSPZNDTMJ-UCWKZMIHSA-N nadolol Chemical compound C1[C@@H](O)[C@@H](O)CC2=C1C=CC=C2OCC(O)CNC(C)(C)C VWPOSFSPZNDTMJ-UCWKZMIHSA-N 0.000 description 2
- VTRAEEWXHOVJFV-UHFFFAOYSA-N olmesartan Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 VTRAEEWXHOVJFV-UHFFFAOYSA-N 0.000 description 2
- 229960005117 olmesartan Drugs 0.000 description 2
- LVRLSYPNFFBYCZ-VGWMRTNUSA-N omapatrilat Chemical compound C([C@H](S)C(=O)N[C@H]1CCS[C@H]2CCC[C@H](N2C1=O)C(=O)O)C1=CC=CC=C1 LVRLSYPNFFBYCZ-VGWMRTNUSA-N 0.000 description 2
- 229950000973 omapatrilat Drugs 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 description 2
- 229960001243 orlistat Drugs 0.000 description 2
- 201000008482 osteoarthritis Diseases 0.000 description 2
- 229960004570 oxprenolol Drugs 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 229950006493 paraflutizide Drugs 0.000 description 2
- 229960002035 penbutolol Drugs 0.000 description 2
- KQXKVJAGOJTNJS-HNNXBMFYSA-N penbutolol Chemical compound CC(C)(C)NC[C@H](O)COC1=CC=CC=C1C1CCCC1 KQXKVJAGOJTNJS-HNNXBMFYSA-N 0.000 description 2
- 229960002582 perindopril Drugs 0.000 description 2
- IPVQLZZIHOAWMC-QXKUPLGCSA-N perindopril Chemical compound C1CCC[C@H]2C[C@@H](C(O)=O)N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H]21 IPVQLZZIHOAWMC-QXKUPLGCSA-N 0.000 description 2
- 229960003418 phenoxybenzamine Drugs 0.000 description 2
- 229960003562 phentermine Drugs 0.000 description 2
- 229960002508 pindolol Drugs 0.000 description 2
- PHUTUTUABXHXLW-UHFFFAOYSA-N pindolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=NC=C[C]12 PHUTUTUABXHXLW-UHFFFAOYSA-N 0.000 description 2
- 229960001085 piretanide Drugs 0.000 description 2
- 229960005483 polythiazide Drugs 0.000 description 2
- 229920000046 polythiazide Polymers 0.000 description 2
- 229960000206 potassium canrenoate Drugs 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- KCTFTBCZZUBAKN-UHFFFAOYSA-N pratosartan Chemical compound CCCC1=NC=2CCCCC(=O)C=2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1 KCTFTBCZZUBAKN-UHFFFAOYSA-N 0.000 description 2
- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 2
- 229960001289 prazosin Drugs 0.000 description 2
- 238000011533 pre-incubation Methods 0.000 description 2
- 229960003912 probucol Drugs 0.000 description 2
- FYPMFJGVHOHGLL-UHFFFAOYSA-N probucol Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1SC(C)(C)SC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 FYPMFJGVHOHGLL-UHFFFAOYSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 229960003712 propranolol Drugs 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 2
- 229960001455 quinapril Drugs 0.000 description 2
- JSDRRTOADPPCHY-HSQYWUDLSA-N quinapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)CC1=CC=CC=C1 JSDRRTOADPPCHY-HSQYWUDLSA-N 0.000 description 2
- 229960000577 quinethazone Drugs 0.000 description 2
- AGMMTXLNIQSRCG-UHFFFAOYSA-N quinethazone Chemical compound NS(=O)(=O)C1=C(Cl)C=C2NC(CC)NC(=O)C2=C1 AGMMTXLNIQSRCG-UHFFFAOYSA-N 0.000 description 2
- 229960003401 ramipril Drugs 0.000 description 2
- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 description 2
- 230000009103 reabsorption Effects 0.000 description 2
- 239000000018 receptor agonist Substances 0.000 description 2
- 229940044601 receptor agonist Drugs 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- 229960002354 repaglinide Drugs 0.000 description 2
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 2
- 229960003147 reserpine Drugs 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- JZCPYUJPEARBJL-UHFFFAOYSA-N rimonabant Chemical compound CC=1C(C(=O)NN2CCCCC2)=NN(C=2C(=CC(Cl)=CC=2)Cl)C=1C1=CC=C(Cl)C=C1 JZCPYUJPEARBJL-UHFFFAOYSA-N 0.000 description 2
- 229960003015 rimonabant Drugs 0.000 description 2
- 229950004910 ripisartan Drugs 0.000 description 2
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 2
- 229950006241 saprisartan Drugs 0.000 description 2
- PFGWGEPQIUAZME-NXSMLHPHSA-N saralasin Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)CNC)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(O)=O)C1=CC=C(O)C=C1 PFGWGEPQIUAZME-NXSMLHPHSA-N 0.000 description 2
- 229960004785 saralasin Drugs 0.000 description 2
- 210000000582 semen Anatomy 0.000 description 2
- PHWXUGHIIBDVKD-UHFFFAOYSA-N sitaxentan Chemical compound CC1=NOC(NS(=O)(=O)C2=C(SC=C2)C(=O)CC=2C(=CC=3OCOC=3C=2)C)=C1Cl PHWXUGHIIBDVKD-UHFFFAOYSA-N 0.000 description 2
- 229960002578 sitaxentan Drugs 0.000 description 2
- 201000002859 sleep apnea Diseases 0.000 description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 2
- 229960002909 spirapril Drugs 0.000 description 2
- HRWCVUIFMSZDJS-SZMVWBNQSA-N spirapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2(C1)SCCS2)C(O)=O)CC1=CC=CC=C1 HRWCVUIFMSZDJS-SZMVWBNQSA-N 0.000 description 2
- 108700035424 spirapril Proteins 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 150000003460 sulfonic acids Chemical class 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000012622 synthetic inhibitor Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 229960000651 tasosartan Drugs 0.000 description 2
- ADXGNEYLLLSOAR-UHFFFAOYSA-N tasosartan Chemical compound C12=NC(C)=NC(C)=C2CCC(=O)N1CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 ADXGNEYLLLSOAR-UHFFFAOYSA-N 0.000 description 2
- GUTZRTRUIMWMJZ-UHFFFAOYSA-N teclothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC(C(Cl)(Cl)Cl)NS2(=O)=O GUTZRTRUIMWMJZ-UHFFFAOYSA-N 0.000 description 2
- 229950009303 teclothiazide Drugs 0.000 description 2
- 229960005187 telmisartan Drugs 0.000 description 2
- VCKUSRYTPJJLNI-UHFFFAOYSA-N terazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1CCCO1 VCKUSRYTPJJLNI-UHFFFAOYSA-N 0.000 description 2
- 229960001693 terazosin Drugs 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 229950000584 tezosentan Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 239000003451 thiazide diuretic agent Substances 0.000 description 2
- 150000001467 thiazolidinediones Chemical class 0.000 description 2
- 229960004605 timolol Drugs 0.000 description 2
- JIVZKJJQOZQXQB-UHFFFAOYSA-N tolazoline Chemical compound C=1C=CC=CC=1CC1=NCCN1 JIVZKJJQOZQXQB-UHFFFAOYSA-N 0.000 description 2
- 229960002312 tolazoline Drugs 0.000 description 2
- 229960005371 tolbutamide Drugs 0.000 description 2
- 229960004394 topiramate Drugs 0.000 description 2
- 229960005461 torasemide Drugs 0.000 description 2
- 229960002051 trandolapril Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- REZQBEBOWJAQKS-UHFFFAOYSA-N triacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO REZQBEBOWJAQKS-UHFFFAOYSA-N 0.000 description 2
- 229960001288 triamterene Drugs 0.000 description 2
- 229960004813 trichlormethiazide Drugs 0.000 description 2
- LMJSLTNSBFUCMU-UHFFFAOYSA-N trichlormethiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC(C(Cl)Cl)NS2(=O)=O LMJSLTNSBFUCMU-UHFFFAOYSA-N 0.000 description 2
- UHLOVGKIEARANS-QZHINBJYSA-N tripamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(=O)NN2C[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3C2)=C1 UHLOVGKIEARANS-QZHINBJYSA-N 0.000 description 2
- 229950004678 tripamide Drugs 0.000 description 2
- 229960001130 urapidil Drugs 0.000 description 2
- 229960004699 valsartan Drugs 0.000 description 2
- ACWBQPMHZXGDFX-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=NN1 ACWBQPMHZXGDFX-QFIPXVFZSA-N 0.000 description 2
- 238000009834 vaporization Methods 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 208000016261 weight loss Diseases 0.000 description 2
- 239000013585 weight reducing agent Substances 0.000 description 2
- 229960000537 xipamide Drugs 0.000 description 2
- MTZBBNMLMNBNJL-UHFFFAOYSA-N xipamide Chemical compound CC1=CC=CC(C)=C1NC(=O)C1=CC(S(N)(=O)=O)=C(Cl)C=C1O MTZBBNMLMNBNJL-UHFFFAOYSA-N 0.000 description 2
- FIKYECRHLXONOX-UHFFFAOYSA-N zolasartan Chemical compound CCCCC1=NC(Cl)=C(C(O)=O)N1CC1=CC=C(OC(=C2Br)C=3C(=CC=CC=3)C3=NNN=N3)C2=C1 FIKYECRHLXONOX-UHFFFAOYSA-N 0.000 description 2
- 229950004433 zolasartan Drugs 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- XHGNHWDDBNJZEJ-SYCWAMIZSA-N (1r,4r)-4-[4-(carboxymethyl)phenoxy]-2-[(2s)-2-[4-[(2-sulfobenzoyl)amino]imidazol-1-yl]octanoyl]cyclopentane-1-carboxylic acid Chemical compound O([C@@H]1CC([C@@H](C1)C(O)=O)C(=O)[C@H](CCCCCC)N1C=C(NC(=O)C=2C(=CC=CC=2)S(O)(=O)=O)N=C1)C1=CC=C(CC(O)=O)C=C1 XHGNHWDDBNJZEJ-SYCWAMIZSA-N 0.000 description 1
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 1
- WJXAVNPIJIPGMN-PNGYUKAISA-N (2s)-2-[[(2s)-1-[(2s)-2-[[(2s,3s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-5-(diaminomethylideneamino)-2-[[2-(methylamino)acetyl]amino]pentanoyl]amino]-3-methylbutanoyl]amino]-3-(4-methoxyphenyl)propanoyl]amino]-3-methylpentanoyl]amino]-3-(1h-imidazol-5-yl)propanoyl]py Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)CNC)C(C)C)C1=CC=C(OC)C=C1 WJXAVNPIJIPGMN-PNGYUKAISA-N 0.000 description 1
- HPOHWZYSJMJZSA-VXKWHMMOSA-N (2s)-2-[[1-[[(2s)-3-methyl-2-sulfanylbutanoyl]amino]cyclopentanecarbonyl]amino]-3-(4-phenylphenyl)propanoic acid Chemical compound N([C@@H](CC=1C=CC(=CC=1)C=1C=CC=CC=1)C(O)=O)C(=O)C1(NC(=O)[C@@H](S)C(C)C)CCCC1 HPOHWZYSJMJZSA-VXKWHMMOSA-N 0.000 description 1
- GGKXIITZBSPCQP-IZIWAXSGSA-N (2s,4s,5s)-5-[[(2s)-2-[[(2s)-2-benzyl-3-tert-butylsulfonylpropanoyl]amino]-3-(1h-imidazol-5-yl)propanoyl]amino]-n-butyl-6-cyclohexyl-4-hydroxy-2-propan-2-ylhexanamide Chemical compound C([C@@H]([C@@H](O)C[C@H](C(=O)NCCCC)C(C)C)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CC=1C=CC=CC=1)CS(=O)(=O)C(C)(C)C)C1CCCCC1 GGKXIITZBSPCQP-IZIWAXSGSA-N 0.000 description 1
- AXJQVVLKUYCICH-OAQYLSRUSA-N (4s)-5-(4-chlorophenyl)-n-(4-chlorophenyl)sulfonyl-n'-methyl-4-phenyl-3,4-dihydropyrazole-2-carboximidamide Chemical compound C=1C=C(Cl)C=CC=1C([C@H](C1)C=2C=CC=CC=2)=NN1C(=NC)NS(=O)(=O)C1=CC=C(Cl)C=C1 AXJQVVLKUYCICH-OAQYLSRUSA-N 0.000 description 1
- IZQCLVVNYNAYBS-UHFFFAOYSA-N (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-cyclopropyl-3-[4-[2-(2h-tetrazol-5-yl)phenyl]phenoxy]quinoline-4-carboxylate Chemical compound O1C(=O)OC(COC(=O)C=2C3=CC=CC=C3N=C(C=2OC=2C=CC(=CC=2)C=2C(=CC=CC=2)C2=NNN=N2)C2CC2)=C1C IZQCLVVNYNAYBS-UHFFFAOYSA-N 0.000 description 1
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 1
- KLVDUSUYBDMJKR-SANMLTNESA-N (6s)-1-[(4-amino-3-methylphenyl)methyl]-5-(2,2-diphenylacetyl)-6,7-dihydro-4h-imidazo[4,5-c]pyridine-6-carboxylic acid Chemical compound C1=C(N)C(C)=CC(CN2C=3C[C@H](N(CC=3N=C2)C(=O)C(C=2C=CC=CC=2)C=2C=CC=CC=2)C(O)=O)=C1 KLVDUSUYBDMJKR-SANMLTNESA-N 0.000 description 1
- UEMGWPRHOOEKTA-UHFFFAOYSA-N 1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1 UEMGWPRHOOEKTA-UHFFFAOYSA-N 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- PJHPFAFEJNBIDC-UHFFFAOYSA-N 1-(4-bromophenyl)piperazine Chemical compound C1=CC(Br)=CC=C1N1CCNCC1 PJHPFAFEJNBIDC-UHFFFAOYSA-N 0.000 description 1
- ZPFRAPVRYLGYEC-UHFFFAOYSA-N 1-(4-hydroxyphenyl)-3-(2,4,6-trimethoxyphenyl)propan-1-one Chemical compound COC1=CC(OC)=CC(OC)=C1CCC(=O)C1=CC=C(O)C=C1 ZPFRAPVRYLGYEC-UHFFFAOYSA-N 0.000 description 1
- NZFOMJUWHPFHLQ-UHFFFAOYSA-N 1-[4-(4-fluorophenyl)phenyl]piperazine Chemical compound C1=CC(F)=CC=C1C1=CC=C(N2CCNCC2)C=C1 NZFOMJUWHPFHLQ-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- VMJNTFXCTXAXTC-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-5-carbonitrile Chemical group C1=C(C#N)C=C2OC(F)(F)OC2=C1 VMJNTFXCTXAXTC-UHFFFAOYSA-N 0.000 description 1
- UKEZYWUWLICNPR-UHFFFAOYSA-N 2,6-dibutyl-5-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]-1h-pyrimidin-4-one Chemical compound N1C(CCCC)=NC(=O)C(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C2=NNN=N2)=C1CCCC UKEZYWUWLICNPR-UHFFFAOYSA-N 0.000 description 1
- JMBYBVLCYODBJQ-HFMPRLQTSA-N 2-(1-benzofuran-4-yl)-n-methyl-n-[(5r,7s,8s)-7-pyrrolidin-1-yl-1-oxaspiro[4.5]decan-8-yl]acetamide Chemical compound C([C@@H]([C@H](C1)N2CCCC2)N(C)C(=O)CC=2C=3C=COC=3C=CC=2)C[C@]21CCCO2 JMBYBVLCYODBJQ-HFMPRLQTSA-N 0.000 description 1
- XMQODGUTLZXUGZ-RPBOFIJWSA-N 2-[(3s)-3-[[1-[(2r)-2-ethoxycarbonyl-4-phenylbutyl]cyclopentanecarbonyl]amino]-2-oxo-4,5-dihydro-3h-1-benzazepin-1-yl]acetic acid Chemical compound C([C@@H](C(=O)OCC)CC1(CCCC1)C(=O)N[C@@H]1C(N(CC(O)=O)C2=CC=CC=C2CC1)=O)CC1=CC=CC=C1 XMQODGUTLZXUGZ-RPBOFIJWSA-N 0.000 description 1
- VWWMGPCUZVOLLK-UHFFFAOYSA-N 2-[4-[(2-cyclopropyl-7-methylimidazo[4,5-b]pyridin-3-yl)methyl]phenyl]benzoic acid Chemical compound C1CC1C1=NC=2C(C)=CC=NC=2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O VWWMGPCUZVOLLK-UHFFFAOYSA-N 0.000 description 1
- LQRYGEQNLPCYDT-FPYGCLRLSA-N 2-[4-[[2-[(e)-but-1-enyl]-4-chloro-5-(hydroxymethyl)imidazol-1-yl]methyl]phenyl]benzoic acid Chemical compound CC\C=C\C1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 LQRYGEQNLPCYDT-FPYGCLRLSA-N 0.000 description 1
- UUPNFNCKGJOLQE-UHFFFAOYSA-N 2-[4-[[2-butyl-4-chloro-5-(hydroxymethyl)imidazol-1-yl]methyl]phenyl]benzoic acid Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C(O)=O)C=C1 UUPNFNCKGJOLQE-UHFFFAOYSA-N 0.000 description 1
- OLQFKFSAJNUOPT-UHFFFAOYSA-N 2-[4-[[2-butyl-6-(cyclohexylcarbamoylamino)benzimidazol-1-yl]methyl]phenyl]benzoic acid Chemical compound C1=C2N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C(O)=O)C(CCCC)=NC2=CC=C1NC(=O)NC1CCCCC1 OLQFKFSAJNUOPT-UHFFFAOYSA-N 0.000 description 1
- ZHWGRXBJGUEATA-UHFFFAOYSA-N 2-[[4-[[2-butyl-6-[methylcarbamoyl(pentyl)amino]benzimidazol-1-yl]methyl]phenyl]carbamoyl]-3,6-dichlorobenzoic acid Chemical compound C12=CC(N(C(=O)NC)CCCCC)=CC=C2N=C(CCCC)N1CC(C=C1)=CC=C1NC(=O)C1=C(Cl)C=CC(Cl)=C1C(O)=O ZHWGRXBJGUEATA-UHFFFAOYSA-N 0.000 description 1
- ZGAFRHMPMVKTNA-UHFFFAOYSA-N 2-[[4-butyl-2-methyl-6-oxo-5-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]pyrimidin-1-yl]methyl]benzoic acid Chemical compound O=C1C(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2NN=NN=2)=C(CCCC)N=C(C)N1CC1=CC=CC=C1C(O)=O ZGAFRHMPMVKTNA-UHFFFAOYSA-N 0.000 description 1
- DLMNZGAILMQDHA-UHFFFAOYSA-N 2-[propyl-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]amino]pyridine-3-carboxylic acid Chemical compound N=1C=CC=C(C(O)=O)C=1N(CCC)CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 DLMNZGAILMQDHA-UHFFFAOYSA-N 0.000 description 1
- FLOKGHWIQFCIJW-UHFFFAOYSA-N 2-butyl-3-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]benzimidazole-4-carboxylic acid Chemical compound CCCCC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 FLOKGHWIQFCIJW-UHFFFAOYSA-N 0.000 description 1
- YILJWHUIUCRKEU-UHFFFAOYSA-N 2-butyl-3-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]imidazo[4,5-b]pyridine Chemical compound CCCCC1=NC2=CC=CN=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1 YILJWHUIUCRKEU-UHFFFAOYSA-N 0.000 description 1
- AIGVXGCHRIOQNR-UHFFFAOYSA-N 2-butyl-5-chloro-3-[[1-[2-(2h-tetrazol-5-yl)phenyl]indol-4-yl]methyl]imidazole-4-carboxylic acid Chemical compound CCCCC1=NC(Cl)=C(C(O)=O)N1CC1=CC=CC2=C1C=CN2C1=CC=CC=C1C1=NNN=N1 AIGVXGCHRIOQNR-UHFFFAOYSA-N 0.000 description 1
- DYYWUYUUDYPWON-UHFFFAOYSA-N 2-ethyl-5,7-dimethyl-3-[[9-(2h-tetrazol-5-ylmethyl)-9h-fluoren-2-yl]methyl]imidazo[4,5-b]pyridine Chemical compound CCC1=NC2=C(C)C=C(C)N=C2N1CC(C=1)=CC=C(C2=CC=CC=C22)C=1C2CC=1N=NNN=1 DYYWUYUUDYPWON-UHFFFAOYSA-N 0.000 description 1
- MGSBGAVGFLLRDU-UHFFFAOYSA-N 2-propyl-3-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]-5-[2-(2,2,2-trifluoroacetyl)pyrrol-1-yl]imidazole-4-carboxylic acid Chemical compound CCCC1=NC(N2C(=CC=C2)C(=O)C(F)(F)F)=C(C(O)=O)N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1 MGSBGAVGFLLRDU-UHFFFAOYSA-N 0.000 description 1
- QBFKQSDMKSSMRE-UHFFFAOYSA-N 3-methylbutyl n-[2-[4-[[5-[3-[butanoyl(pyridin-3-yl)amino]propanoyl]-4-ethyl-2-propylimidazol-1-yl]methyl]-3-fluorophenyl]phenyl]sulfonylcarbamate Chemical compound C=1C=CN=CC=1N(C(=O)CCC)CCC(=O)C1=C(CC)N=C(CCC)N1CC(C(=C1)F)=CC=C1C1=CC=CC=C1S(=O)(=O)NC(=O)OCCC(C)C QBFKQSDMKSSMRE-UHFFFAOYSA-N 0.000 description 1
- SWLAMJPTOQZTAE-UHFFFAOYSA-N 4-[2-[(5-chloro-2-methoxybenzoyl)amino]ethyl]benzoic acid Chemical class COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(C(O)=O)C=C1 SWLAMJPTOQZTAE-UHFFFAOYSA-N 0.000 description 1
- LUEFJAMKGZEOSL-UHFFFAOYSA-N 4-[4-(4-fluorophenyl)phenyl]piperazine-1-sulfonamide Chemical compound C1CN(S(=O)(=O)N)CCN1C1=CC=C(C=2C=CC(F)=CC=2)C=C1 LUEFJAMKGZEOSL-UHFFFAOYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 229940122200 5 Hydroxytryptamine uptake inhibitor Drugs 0.000 description 1
- RQGDXPDTZWGCQI-UHFFFAOYSA-N 5-(1,1,2,2,2-pentafluoroethyl)-2-propyl-3-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]imidazole-4-carboxylic acid Chemical compound CCCC1=NC(C(F)(F)C(F)(F)F)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C2=NNN=N2)C=C1 RQGDXPDTZWGCQI-UHFFFAOYSA-N 0.000 description 1
- LDILUHSYQQLZRC-UHFFFAOYSA-N 5-[[[4-[2-hydroxy-3-(propan-2-ylamino)propoxy]-1h-indole-2-carbonyl]amino]methyl]-2-propyl-3-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]imidazole-4-carboxylic acid Chemical compound CCCC1=NC(CNC(=O)C=2NC3=CC=CC(OCC(O)CNC(C)C)=C3C=2)=C(C(O)=O)N1CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 LDILUHSYQQLZRC-UHFFFAOYSA-N 0.000 description 1
- OFYWYKMCRWMPPQ-UHFFFAOYSA-N 5-ethyl-2-propyl-3-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]imidazole-4-carboxylic acid Chemical compound CCCC1=NC(CC)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C2=NNN=N2)C=C1 OFYWYKMCRWMPPQ-UHFFFAOYSA-N 0.000 description 1
- YROKAAIPBSCMJN-UHFFFAOYSA-N 5-hydroxy-2,4-dimethyl-8-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]pyrido[2,3-d]pyrimidin-7-one Chemical compound C12=NC(C)=NC(C)=C2C(O)=CC(=O)N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1 YROKAAIPBSCMJN-UHFFFAOYSA-N 0.000 description 1
- UIYUUEDFAMZISF-FTBISJDPSA-N 6-chloro-1,1-dioxo-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazine-7-sulfonamide;(2s)-3-methyl-2-[pentanoyl-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]amino]butanoic acid Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O.C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NNN=N1 UIYUUEDFAMZISF-FTBISJDPSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 229940118148 Aldose reductase inhibitor Drugs 0.000 description 1
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 102100022278 Arachidonate 5-lipoxygenase-activating protein Human genes 0.000 description 1
- 101710187011 Arachidonate 5-lipoxygenase-activating protein Proteins 0.000 description 1
- DTDADHMBRZKXSC-GKASHWOUSA-N Aricine Chemical compound C1=C(OC)C=C2C(CCN3C[C@H]4[C@H](C)OC=C([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 DTDADHMBRZKXSC-GKASHWOUSA-N 0.000 description 1
- 102100038495 Bile acid receptor Human genes 0.000 description 1
- 108010073466 Bombesin Receptors Proteins 0.000 description 1
- 108010076395 CGP 38560 Proteins 0.000 description 1
- RFVOIBFBFJXBMP-VGMFFHCQSA-N CN[C@H](C(=O)O)CC1=CC=C(O)C(O)=C1.CN[C@H](C(=O)O)CC1=CC=C(O)C(O)=C1 Chemical compound CN[C@H](C(=O)O)CC1=CC=C(O)C(O)=C1.CN[C@H](C(=O)O)CC1=CC=C(O)C(O)=C1 RFVOIBFBFJXBMP-VGMFFHCQSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 101710167917 Carbonic anhydrase 2 Proteins 0.000 description 1
- 102100024633 Carbonic anhydrase 2 Human genes 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 101710150887 Cholecystokinin A Proteins 0.000 description 1
- 229940122502 Cholesterol absorption inhibitor Drugs 0.000 description 1
- 241000931705 Cicada Species 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- 101000785223 Crocosmia x crocosmiiflora Myricetin 3-O-glucosyl 1,2-rhamnoside 6'-O-caffeoyltransferase AT1 Proteins 0.000 description 1
- 101000785259 Crocosmia x crocosmiiflora Myricetin 3-O-glucosyl 1,2-rhamnoside 6'-O-caffeoyltransferase AT2 Proteins 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- XUIIKFGFIJCVMT-GFCCVEGCSA-N D-thyroxine Chemical compound IC1=CC(C[C@@H](N)C(O)=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-GFCCVEGCSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000002249 Diabetes Complications Diseases 0.000 description 1
- 206010012655 Diabetic complications Diseases 0.000 description 1
- 206010054044 Diabetic microangiopathy Diseases 0.000 description 1
- UNBMQQNYLCPCHS-UHFFFAOYSA-N Ebelactone B Natural products CCC(C)C(O)C(C)C(=O)C(C)C=C(C)CC(C)C1OC(=O)C1CC UNBMQQNYLCPCHS-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 108010061435 Enalapril Proteins 0.000 description 1
- 229940118365 Endothelin receptor antagonist Drugs 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 102000018711 Facilitative Glucose Transport Proteins Human genes 0.000 description 1
- 102000000476 Fatty Acid Transport Proteins Human genes 0.000 description 1
- 108010055870 Fatty Acid Transport Proteins Proteins 0.000 description 1
- 229940122904 Glucagon receptor antagonist Drugs 0.000 description 1
- 102400000326 Glucagon-like peptide 2 Human genes 0.000 description 1
- 101800000221 Glucagon-like peptide 2 Proteins 0.000 description 1
- 229940123037 Glucocorticoid antagonist Drugs 0.000 description 1
- 108091052347 Glucose transporter family Proteins 0.000 description 1
- 102000004366 Glucosidases Human genes 0.000 description 1
- 108010056771 Glucosidases Proteins 0.000 description 1
- 102000007390 Glycogen Phosphorylase Human genes 0.000 description 1
- 108010046163 Glycogen Phosphorylase Proteins 0.000 description 1
- 108010010234 HDL Lipoproteins Proteins 0.000 description 1
- 241000506654 Haemulon album Species 0.000 description 1
- 102100030643 Hydroxycarboxylic acid receptor 2 Human genes 0.000 description 1
- 101710125793 Hydroxycarboxylic acid receptor 2 Proteins 0.000 description 1
- 108010000775 Hydroxymethylglutaryl-CoA synthase Proteins 0.000 description 1
- 102100028888 Hydroxymethylglutaryl-CoA synthase, cytoplasmic Human genes 0.000 description 1
- 102000011145 Hydroxysteroid Dehydrogenases Human genes 0.000 description 1
- 108010062875 Hydroxysteroid Dehydrogenases Proteins 0.000 description 1
- 102000003746 Insulin Receptor Human genes 0.000 description 1
- 108010001127 Insulin Receptor Proteins 0.000 description 1
- 102000036770 Islet Amyloid Polypeptide Human genes 0.000 description 1
- 102100027670 Islet amyloid polypeptide Human genes 0.000 description 1
- LINHZVMHXABQLB-ZDUSSCGKSA-N Isoboldine Chemical compound CN1CCC2=CC(OC)=C(O)C3=C2[C@@H]1CC1=C3C=C(OC)C(O)=C1 LINHZVMHXABQLB-ZDUSSCGKSA-N 0.000 description 1
- 108010078036 KRI 1177 Proteins 0.000 description 1
- 241000958270 Kitasatospora aburaviensis Species 0.000 description 1
- 238000007696 Kjeldahl method Methods 0.000 description 1
- 108010009384 L-Iditol 2-Dehydrogenase Proteins 0.000 description 1
- 102000000853 LDL receptors Human genes 0.000 description 1
- 108010001831 LDL receptors Proteins 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 101150051050 MC3R gene Proteins 0.000 description 1
- 101150110867 MC4R gene Proteins 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102400001132 Melanin-concentrating hormone Human genes 0.000 description 1
- 101800002739 Melanin-concentrating hormone Proteins 0.000 description 1
- 102000017351 Melanocortin 3 receptors Human genes 0.000 description 1
- 108050005365 Melanocortin 3 receptors Proteins 0.000 description 1
- 102000001796 Melanocortin 4 receptors Human genes 0.000 description 1
- 108050009019 Melanocortin 4 receptors Proteins 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 102000003979 Mineralocorticoid Receptors Human genes 0.000 description 1
- 108090000375 Mineralocorticoid Receptors Proteins 0.000 description 1
- ZFMITUMMTDLWHR-UHFFFAOYSA-N Minoxidil Chemical compound NC1=[N+]([O-])C(N)=CC(N2CCCCC2)=N1 ZFMITUMMTDLWHR-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102000002512 Orexin Human genes 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 102000004257 Potassium Channel Human genes 0.000 description 1
- 229940127315 Potassium Channel Openers Drugs 0.000 description 1
- 229940122767 Potassium sparing diuretic Drugs 0.000 description 1
- 239000005477 Pratosartan Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 108700028065 Sar(1)-Me-Tyr(4)- angiotensin II Proteins 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 102100026974 Sorbitol dehydrogenase Human genes 0.000 description 1
- 238000000944 Soxhlet extraction Methods 0.000 description 1
- 229940123185 Squalene epoxidase inhibitor Drugs 0.000 description 1
- 241000946767 Streptomyces toxytricini Species 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 241000282894 Sus scrofa domesticus Species 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 1
- 241000053227 Themus Species 0.000 description 1
- 244000299461 Theobroma cacao Species 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 102000008219 Uncoupling Protein 2 Human genes 0.000 description 1
- 108010021111 Uncoupling Protein 2 Proteins 0.000 description 1
- 102000008200 Uncoupling Protein 3 Human genes 0.000 description 1
- 108010021098 Uncoupling Protein 3 Proteins 0.000 description 1
- 108010059705 Urocortins Proteins 0.000 description 1
- 102000005630 Urocortins Human genes 0.000 description 1
- 101800001810 Urotensin-1 Proteins 0.000 description 1
- 229940116211 Vasopressin antagonist Drugs 0.000 description 1
- KNDHRUPPBXRELB-UHFFFAOYSA-M [4-[3-(4-ethylphenyl)butyl]phenyl]-trimethylazanium;chloride Chemical compound [Cl-].C1=CC(CC)=CC=C1C(C)CCC1=CC=C([N+](C)(C)C)C=C1 KNDHRUPPBXRELB-UHFFFAOYSA-M 0.000 description 1
- UUMKQZVEZSXWBY-HNNXBMFYSA-N [[(1s)-2-(4-phenylphenyl)-1-(2h-tetrazol-5-yl)ethyl]amino]methylphosphonic acid Chemical compound C([C@H](NCP(O)(=O)O)C1=NNN=N1)C(C=C1)=CC=C1C1=CC=CC=C1 UUMKQZVEZSXWBY-HNNXBMFYSA-N 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000009102 absorption Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 1
- 230000000895 acaricidal effect Effects 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000670 adrenergic alpha-2 receptor antagonist Substances 0.000 description 1
- 239000003288 aldose reductase inhibitor Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 1
- 239000001774 alpinia officinarum Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- PLOPBXQQPZYQFA-AXPWDRQUSA-N amlintide Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H]1NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CCCCN)CSSC1)[C@@H](C)O)C(C)C)C1=CC=CC=C1 PLOPBXQQPZYQFA-AXPWDRQUSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000002402 anti-lipaemic effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000002830 appetite depressant Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- UHDJCSZGZJGMDR-UHFFFAOYSA-N aricine Natural products COC(=O)C1=COC(C)C2(C)CN3CCc4c([nH]c5ccc(OC)cc45)C3(C)CC12C UHDJCSZGZJGMDR-UHFFFAOYSA-N 0.000 description 1
- 238000004380 ashing Methods 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- KGSXMPPBFPAXLY-UHFFFAOYSA-N azilsartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NOC(=O)N1 KGSXMPPBFPAXLY-UHFFFAOYSA-N 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 150000008107 benzenesulfonic acids Chemical class 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 229940124748 beta 2 agonist Drugs 0.000 description 1
- 102000015005 beta-adrenergic receptor activity proteins Human genes 0.000 description 1
- 108040006818 beta-adrenergic receptor activity proteins Proteins 0.000 description 1
- 150000005347 biaryls Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229960002781 bisoprolol Drugs 0.000 description 1
- VHYCDWMUTMEGQY-UHFFFAOYSA-N bisoprolol Chemical compound CC(C)NCC(O)COC1=CC=C(COCCOC(C)C)C=C1 VHYCDWMUTMEGQY-UHFFFAOYSA-N 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000003557 cannabinoid Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 150000001720 carbohydrates Chemical group 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 238000012754 cardiac puncture Methods 0.000 description 1
- MVCQKIKWYUURMU-UHFFFAOYSA-N cetilistat Chemical compound C1=C(C)C=C2C(=O)OC(OCCCCCCCCCCCCCCCC)=NC2=C1 MVCQKIKWYUURMU-UHFFFAOYSA-N 0.000 description 1
- 229950002397 cetilistat Drugs 0.000 description 1
- IHJCXVZDYSXXFT-UHFFFAOYSA-N chloraminophenamide Chemical compound NC1=CC(Cl)=C(S(N)(=O)=O)C=C1S(N)(=O)=O IHJCXVZDYSXXFT-UHFFFAOYSA-N 0.000 description 1
- 229960001523 chlortalidone Drugs 0.000 description 1
- JIVPVXMEBJLZRO-UHFFFAOYSA-N chlorthalidone Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C2(O)C3=CC=CC=C3C(=O)N2)=C1 JIVPVXMEBJLZRO-UHFFFAOYSA-N 0.000 description 1
- 235000019219 chocolate Nutrition 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229950007733 clazosentan Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229960001678 colestyramine Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940127113 compound 57 Drugs 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 229950010776 daglutril Drugs 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229960001767 dextrothyroxine Drugs 0.000 description 1
- 201000009101 diabetic angiopathy Diseases 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- 229960004890 diethylpropion Drugs 0.000 description 1
- XXEPPPIWZFICOJ-UHFFFAOYSA-N diethylpropion Chemical compound CCN(CC)C(C)C(=O)C1=CC=CC=C1 XXEPPPIWZFICOJ-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- CCYTUJPXAFHZHC-UHFFFAOYSA-L disodium;4-[[2-butyl-5-(carboxylatomethyl)-4-chloroimidazol-1-yl]methyl]benzoate Chemical compound [Na+].[Na+].CCCCC1=NC(Cl)=C(CC([O-])=O)N1CC1=CC=C(C([O-])=O)C=C1 CCYTUJPXAFHZHC-UHFFFAOYSA-L 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- UNBMQQNYLCPCHS-VYNDPHDASA-N ebelactone b Chemical compound CC[C@@H](C)[C@@H](O)[C@H](C)C(=O)[C@H](C)\C=C(/C)C[C@H](C)[C@@H]1OC(=O)[C@H]1CC UNBMQQNYLCPCHS-VYNDPHDASA-N 0.000 description 1
- 238000002565 electrocardiography Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229950010961 enadoline Drugs 0.000 description 1
- 229960000873 enalapril Drugs 0.000 description 1
- 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 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 239000002308 endothelin receptor antagonist Substances 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940095399 enema Drugs 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- JBEUFWOCGLXNCS-XSFVSMFZSA-N ethyl (2e)-2-[4-ethyl-4-methyl-6-oxo-1-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]piperidin-2-ylidene]acetate Chemical compound CCOC(=O)\C=C1/CC(C)(CC)CC(=O)N1CC1=CC=C(C=2C(=CC=CC=2)C2=NNN=N2)C=C1 JBEUFWOCGLXNCS-XSFVSMFZSA-N 0.000 description 1
- 238000000105 evaporative light scattering detection Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229960000815 ezetimibe Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000001506 fluorescence spectroscopy Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 235000013376 functional food Nutrition 0.000 description 1
- 208000001130 gallstones Diseases 0.000 description 1
- 239000003457 ganglion blocking agent Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229960001764 glibornuride Drugs 0.000 description 1
- RMTYNAPTNBJHQI-LLDVTBCESA-N glibornuride Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)N[C@H]1[C@H](C2(C)C)CC[C@@]2(C)[C@H]1O RMTYNAPTNBJHQI-LLDVTBCESA-N 0.000 description 1
- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 description 1
- TWSALRJGPBVBQU-PKQQPRCHSA-N glucagon-like peptide 2 Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O)[C@@H](C)CC)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=CC=C1 TWSALRJGPBVBQU-PKQQPRCHSA-N 0.000 description 1
- 239000003635 glucocorticoid antagonist Substances 0.000 description 1
- 230000004110 gluconeogenesis Effects 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 230000002430 glycogenolytic effect Effects 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- FVMMOSQBOWPRQW-UHFFFAOYSA-N heterophylline Natural products CC(=O)OC1C2(C)C(OC(=O)C=3C=CC=CC=3)CC(C(O3)(C)C)C(OC(=O)C=4C=NC=CC=4)C32C(C)CC1OC(=O)C1=CC=CN=C1 FVMMOSQBOWPRQW-UHFFFAOYSA-N 0.000 description 1
- 235000009200 high fat diet Nutrition 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 239000003395 histamine H3 receptor antagonist Substances 0.000 description 1
- 229940121372 histone deacetylase inhibitor Drugs 0.000 description 1
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 1
- 230000000055 hyoplipidemic effect Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 238000012528 insulin ELISA Methods 0.000 description 1
- 239000004026 insulin derivative Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 229960001632 labetalol Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940080435 lactose 250 mg Drugs 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 230000004132 lipogenesis Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000002171 loop diuretic Substances 0.000 description 1
- ZEUXAIYYDDCIRX-UHFFFAOYSA-N losartan carboxylic acid Chemical compound CCCCC1=NC(Cl)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C2=NNN=N2)C=C1 ZEUXAIYYDDCIRX-UHFFFAOYSA-N 0.000 description 1
- 208000020442 loss of weight Diseases 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 231100000682 maximum tolerated dose Toxicity 0.000 description 1
- 229950004994 meglitinide Drugs 0.000 description 1
- ORRDHOMWDPJSNL-UHFFFAOYSA-N melanin concentrating hormone Chemical compound N1C(=O)C(C(C)C)NC(=O)C(CCCNC(N)=N)NC(=O)CNC(=O)C(C(C)C)NC(=O)C(CCSC)NC(=O)C(NC(=O)C(CCCNC(N)=N)NC(=O)C(NC(=O)C(NC(=O)C(N)CC(O)=O)C(C)O)CCSC)CSSCC(C(=O)NC(CC=2C3=CC=CC=C3NC=2)C(=O)NC(CCC(O)=O)C(=O)NC(C(C)C)C(O)=O)NC(=O)C2CCCN2C(=O)C(CCCNC(N)=N)NC(=O)C1CC1=CC=C(O)C=C1 ORRDHOMWDPJSNL-UHFFFAOYSA-N 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- UQUFRFSCUYVXBM-UHFFFAOYSA-N methyl 2-hydroxy-3-[[3-(1h-imidazol-5-yl)-2-[[2-(naphthalen-1-ylmethyl)-4-oxo-4-(2-phenylethylamino)butanoyl]amino]propanoyl]amino]-5-methylhexanoate Chemical compound C=1C=CC=CC=1CCNC(=O)CC(CC=1C2=CC=CC=C2C=CC=1)C(=O)NC(C(=O)NC(CC(C)C)C(O)C(=O)OC)CC1=CN=CN1 UQUFRFSCUYVXBM-UHFFFAOYSA-N 0.000 description 1
- AWIVWBRKOUQKEI-UHFFFAOYSA-N methyl 3-[[4-[2-(butoxycarbonylsulfamoyl)phenyl]-2-chlorophenyl]methyl]-5-ethyl-2-propylimidazole-4-carboxylate Chemical compound CCCCOC(=O)NS(=O)(=O)C1=CC=CC=C1C(C=C1Cl)=CC=C1CN1C(C(=O)OC)=C(CC)N=C1CCC AWIVWBRKOUQKEI-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 230000003228 microsomal effect Effects 0.000 description 1
- 229960003632 minoxidil Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 1
- 230000000407 monoamine reuptake Effects 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- LJGUZUROJOJEMI-UHFFFAOYSA-N n-(3,4-dimethyl-1,2-oxazol-5-yl)-2-[4-(1,3-oxazol-2-yl)phenyl]benzenesulfonamide Chemical compound CC1=NOC(NS(=O)(=O)C=2C(=CC=CC=2)C=2C=CC(=CC=2)C=2OC=CN=2)=C1C LJGUZUROJOJEMI-UHFFFAOYSA-N 0.000 description 1
- LFWCJABOXHSRGC-UHFFFAOYSA-N n-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[2-(2h-tetrazol-5-yl)pyridin-4-yl]pyrimidin-4-yl]-5-methylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C2=NNN=N2)OCCO)=C1NS(=O)(=O)C1=CC=C(C)C=N1 LFWCJABOXHSRGC-UHFFFAOYSA-N 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 239000002767 noradrenalin uptake inhibitor Substances 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 229940127221 norepinephrine reuptake inhibitor Drugs 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229960001199 olmesartan medoxomil Drugs 0.000 description 1
- 239000003401 opiate antagonist Substances 0.000 description 1
- 238000007410 oral glucose tolerance test Methods 0.000 description 1
- 108060005714 orexin Proteins 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000000399 orthopedic effect Effects 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 235000011837 pasties Nutrition 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 229940023041 peptide vaccine Drugs 0.000 description 1
- 238000003359 percent control normalization Methods 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000003614 peroxisome proliferator Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000419 plant extract Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 108020001213 potassium channel Proteins 0.000 description 1
- 239000003286 potassium sparing diuretic agent Substances 0.000 description 1
- 229940097241 potassium-sparing diuretic Drugs 0.000 description 1
- ADJDSKWTIYUCDV-UHFFFAOYSA-M potassium;2-butyl-5-methylsulfanyl-3-[[4-[2-(propylcarbamoylsulfamoyl)phenyl]phenyl]methyl]imidazole-4-carboxylate Chemical compound [K+].CCCCC1=NC(SC)=C(C([O-])=O)N1CC1=CC=C(C=2C(=CC=CC=2)S(=O)(=O)NC(=O)NCCC)C=C1 ADJDSKWTIYUCDV-UHFFFAOYSA-M 0.000 description 1
- 229950005649 pratosartan Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 229940121649 protein inhibitor Drugs 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
- 230000001185 psoriatic effect Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- ZLQMRLSBXKQKMG-UHFFFAOYSA-N rauniticine Natural products COC(=O)C1=CC2CC3N(CCc4c3[nH]c5ccccc45)CC2C(C)O1 ZLQMRLSBXKQKMG-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 229940085605 saccharin sodium Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000000580 secretagogue effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- OSDQJFVHDVAJSD-UHFFFAOYSA-M sodium;2-[2-butyl-3-[[4-[(2-carboxybenzoyl)amino]phenyl]methyl]-5-chloroimidazol-4-yl]propanoate Chemical compound [Na+].CCCCC1=NC(Cl)=C(C(C)C([O-])=O)N1CC(C=C1)=CC=C1NC(=O)C1=CC=CC=C1C(O)=O OSDQJFVHDVAJSD-UHFFFAOYSA-M 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 229960002370 sotalol Drugs 0.000 description 1
- ZBMZVLHSJCTVON-UHFFFAOYSA-N sotalol Chemical compound CC(C)NCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 ZBMZVLHSJCTVON-UHFFFAOYSA-N 0.000 description 1
- VIDRYROWYFWGSY-UHFFFAOYSA-N sotalol hydrochloride Chemical compound Cl.CC(C)NCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 VIDRYROWYFWGSY-UHFFFAOYSA-N 0.000 description 1
- 229940031439 squalene Drugs 0.000 description 1
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000013179 statistical model Methods 0.000 description 1
- SIARJEKBADXQJG-LFZQUHGESA-N stearoyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)CCCCCCCCCCCCCCCCC)O[C@H]1N1C2=NC=NC(N)=C2N=C1 SIARJEKBADXQJG-LFZQUHGESA-N 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 150000003628 tricarboxylic acids Chemical class 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 239000000777 urocortin Substances 0.000 description 1
- PSHRXNWYHPYFQX-OXFOZPMTSA-N urotensin i Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(N)=O)CC1=CC=C(O)C=C1 PSHRXNWYHPYFQX-OXFOZPMTSA-N 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 229940120293 vaginal suppository Drugs 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 229940044977 vaginal tablet Drugs 0.000 description 1
- 239000000003 vaginal tablet Substances 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 239000003038 vasopressin antagonist Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- XBWMJMIOZSMYBR-UHFFFAOYSA-N ws-79089-b Chemical compound O=C1C2=CC=CC(O)=C2C(=O)C2=C1C(O)=C1C3=C(O)C(C(O)=O)=C(CC(C)O)C=C3CC(O)C1=C2OC XBWMJMIOZSMYBR-UHFFFAOYSA-N 0.000 description 1
- 238000011680 zucker rat Methods 0.000 description 1
- SFVVQRJOGUKCEG-OPQSFPLASA-N β-MSH Chemical compound C1C[C@@H](O)[C@H]2C(COC(=O)[C@@](O)([C@@H](C)O)C(C)C)=CCN21 SFVVQRJOGUKCEG-OPQSFPLASA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/26—Sulfur atoms
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Diabetes (AREA)
- Epidemiology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Pain & Pain Management (AREA)
- Urology & Nephrology (AREA)
- Child & Adolescent Psychology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Vascular Medicine (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Quinoline Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyridine Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明涉及已知和新的N-氨磺酰-N’-芳基哌嗪类化合物及其生理上相容的酸加成盐在预防或治疗肥胖和相关疾病中的应用。
Description
发明领域
本发明涉及已知和新的N-氨磺酰-N’-芳基哌嗪类化合物和其生理上相容的酸加成盐并涉及含有这些化合物的用于预防或治疗肥胖和相关疾病的药物组合物或药物。
背景技术
某些N-氨磺酰-N’-芳基哌嗪类化合物及其作为除草剂的应用描述在德国专利申请DE-OS1964441(同族专利:美国专利US3,709,677)中。类似的化合物及其作为杀虫剂和杀螨剂的应用还描述在文献WO95/09151中。
文件WO94/07867中公开了取代的4-嘧啶衍生物作为山梨醇脱氢酶抑制剂用于治疗或预防哺乳动物糖尿病并发症。
欧洲专利申请EP0470616A2中教导了用作醛糖还原酶抑制剂的筛选试剂的取代的4-嘧啶衍生物。
国际专利申请WO03/075929中提供了用于治疗例如癌症和银屑病的组蛋白脱乙酰酶抑制剂,它可以包括某些N-氨磺酰-N’-芳基哌嗪类。还公开了合成所述化合物的中间体。
美国专利US2,748,125中公开了具有抗惊厥活性的1-取代的4-氨磺酰哌嗪类。
J.M.McManus等(J Med Chem 8(1965)766-776)中教导了氨磺酰脲降血糖药。
从文件WO02/07821中得知了寻找适合于通过抑制碳酸酐酶来抑制脂肪生成从而治疗和/或预防哺乳动物和人肥胖的化合物的方法。
本发明的一个目的是提供用于治疗和/或预防肥胖及其伴发和/或继发性疾病或疾患的新药物,它们极为有效且可以按照简单方式获得。
目前令人意外地发现某些新的和已知的N-氨磺酰-N’-芳基哌嗪类或其生理上相容的酸加成盐适合于治疗和/或预防肥胖及其伴发和/或继发性疾病或疾患。
发明内容
根据本发明,通式I的N-氨磺酰-N’-芳基哌嗪或其生理上相容的酸加成盐可以用于治疗和/或预防肥胖及其伴发和/或继发性疾病或疾患:
其中:
Ar为单环或双环C6-10-芳基,
其环碳原子非必需地被氮、氧和/或硫置换1-3次;和/或
其C6-10-芳基环系非必需地含有3-5个双键;和/或
其C6-10-芳基环系非必需地被1、2或3个取代基取代,所述的取代基可以相同或不同且可以选自下列基团组成的组:卤素、羧基、羟基、羟基氨基甲酰基、三氟甲基、氰基、硝基、吡咯烷基、C1-4-烷基、C1-4-烷氧基、C0-4-烷氧基苯基、C1-4-烷硫基、C2-4烷酰基、C1-4-烷氧羰基、C1-4-烷基磺酰基;和与此C6-10-芳基环系的两个相邻碳原子连接且通过C1-2-亚烷基桥连的两个氧原子;或
其C6-10-芳基环系被一个或两个取代基取代,所述的取代基可以相同或不同且选自下列基团组成的组:卤素、羧基、羟基、羟基氨基甲酰基、三氟甲基、氰基、硝基、C1-4-烷基、C1-4-烷氧基、C1-4-烷硫基、C2-4-烷酰基、C1-4-烷氧羰基、C1-4-烷基磺酰基;与此C6-10-芳基环系的两个相邻碳原子连接且通过C1-2-亚烷基桥连的两个氧原子;或
其C6-10-芳基环系被下列基团取代:噻吩基、萘基、吡啶基;苯基或苄基,所述的苯基或苄基各自非必需地在苯基环上被1、2或3个取代基取代,所述的取代基可以相同或不同且可以选自卤素、三氟甲基、氰基、C1-6-烷基、C1-4-烷氧基或C1-4-烷基磺酰基。
更具体地说,在通式I的化合物中:
Ar为非必需地被1、2或3个取代基取代的苯基,所述的取代基可以相同或不同且可以选自下列基团组成的组:卤素、羧基、羟基、羟基氨基甲酰基、三氟甲基、氰基、硝基、C1-4-烷基、C1-4-烷氧基、C0-4-烷氧基苯基、C1-4-烷硫基、C2-4-烷酰基、C1-4-烷氧羰基、C1-4-烷基磺酰基和通过C1-2-亚烷基桥连的与相邻碳原子键接的两个氧原子;或
为被苯基或苄基取代的苯基,所述的苯基或苄基取代基各自非必需地在苯基环上被一个或两个取代基取代,所述的取代基可以相同或不同且可以选自卤素、三氟甲基、C1-4-烷基和C1-4-烷氧基;或
为:萘基;吡啶基;嘧啶基;吡嗪基;哒嗪基;三嗪基;喹啉基;异喹啉基;1,2,3,4-四氢异喹啉基;吲哚基;异二氢氮茚基(isoindolinyl);噻吩并[3,2-d]嘧啶基或吡唑并[1,5-a]嘧啶基,它们各自非必需地被一个或两个取代基取代,所述的取代基可以相同或不同且可以选自卤素、羟基氨基甲酰基、三氟甲基、氰基、硝基、吡咯烷基、C1-4-烷基、C1-4-烷氧基和C1-4-烷氧羰基组成的组。
如果通式I、Ia和/或Ib的化合物或本发明上下文中描述的其它化合物上的取代基为或含有C1-4烷基或C1-6烷基,那么它们可以各自为直链或支链的且优选甲基。如果通式I化合物上的取代基表示卤素,那么氟、氯、溴或碘是合适的。优选氟和氯。如果取代基含有C2-4-烷酰基,那么它可以为直链或支链的。优选乙酰基为C2-4烷酰基。
Ar优选表示:非必需地取代的苯基;吡啶基,特别是2-吡啶基或4-吡啶基;嘧啶基,特别是2-嘧啶基或5-嘧啶基;萘基或喹啉基。更优选苯基、吡啶基和嘧啶基。
如果Ar为非必需地取代的苯基,那么卤素、C1-4烷基、C1-4-烷氧基、三氟甲基、氰基、硝基和C1-4烷基磺酰基为优选的取代基。更优选卤素、C1-4烷基、C1-4-烷氧基和三氟甲基。未被取代的苯基是另外优选的。
如果Ar为非必需地取代的吡啶基、嘧啶基、萘基、喹啉基、异喹啉基、1,2,3,4-四氢异喹啉基、吲哚基或异二氢氮茚基,那么卤素、三氟甲基、氰基、C1-4烷基和C1-4-烷氧基是优选的取代基。
本发明可以使用且部分为新的、特别优选的化合物选自下列化合物组成的组:4-苯基-哌嗪-1-磺酰胺(=N-氨磺酰-N’-苯基哌嗪);4-(2-氯-苯基)-哌嗪-1-磺酰胺;4-(2-甲氧基-苯基)-哌嗪-1-磺酰胺;4-吡啶-4-基-哌嗪-1-磺酰胺;4-嘧啶-2-基-哌嗪-1-磺酰胺;4-(4-氟-苯基)-哌嗪-1-磺酰胺;4-(4-氯-3-三氟甲基-苯基)-哌嗪-1-磺酰胺和4-(3-氯-5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酰胺。
通式I化合物的生理上相容的酸加成盐为其与无机酸或与有机酸或与磺酸类形成的常规盐,所述的无机酸例如有硫酸、磷酸或氢卤酸,优选盐酸,所述的有机酸例如有低级脂族一羧酸、二羧酸或三羧酸,诸如马来酸、富马酸、乳酸、酒石酸、柠檬酸,所述的磺酸类例如有低级烷基磺酸类,诸如甲磺酸或三氟甲磺酸或在苯环上被卤素或低级烷基非必需地取代的苯磺酸类,诸如对-甲苯磺酸。优选通式I化合物的盐酸盐。
本发明在另一个方面中还涉及用作哺乳动物和人的药物的通式Ia的化合物及其生理上相容的酸加成盐和/或药物组合物,所述通式Ia化合物的结构式如下:
其中:
Ar1为非必需地被1、2或3个取代基取代的苯基,所述的取代基可以相同或不同且可以选自下列基团组成的组:卤素、羧基、羟基、羟基氨基甲酰基、三氟甲基、氰基、硝基、C1-4-烷基、C1-4-烷氧基、C0-4-烷氧基苯基、C1-4-烷硫基、C2-4-烷酰基、C1-4-烷氧羰基、C1-4-烷基磺酰基和通过C1-2-亚烷基桥连的与相邻碳原子连接的两个氧原子;或
为被苯基或苄基取代的苯基,所述的苯基或苄基取代基各自非必需地在苯基环上被一个或两个取代基取代,所述的取代基可以相同或不同且可以选自卤素、C1-4-烷基、C1-4-烷氧基和三氟甲基;或
为:萘基;吡啶基;2-嘧啶基;5-嘧啶基;吡嗪基;哒嗪基;三嗪基;喹啉基;异喹啉基;1,2,3,4-四氢异喹啉基;吲哚基;异二氢氮茚基;噻吩并[3,2-d]嘧啶基或吡唑并[1,5-a]嘧啶基,它们各自非必需地被一个或两个取代基取代,所述的取代基可以相同或不同且可以选自卤素、羟基氨基甲酰基、三氟甲基、氰基、硝基、吡咯烷基、C1-4-烷基、C1-4-烷氧基和C1-4-烷氧羰基组成的组;
所述的药物组合物包括药物有效量的通式Ia的化合物或其生理上相容的酸加成盐和常用的药物上可接受的助剂和/或载体。
本发明在另一个方面中涉及通式Ib的新N-氨磺酰-N’-芳基哌嗪类化合物及其生理上相容的酸加成盐:
其中:
Ar2为被下列基团取代一次的苯基:氟、3-氯、4-氯、溴、碘、羟基、C1-4-烷基、C2-4-烷氧基、C0-4-烷氧基苯基、C1-4-烷硫基、C2-4-烷酰基、C1-4-烷氧基羰基、羟基氨基甲酰基、羧基、三氟甲基、氰基、硝基、与相邻碳原子连接的通过C1-2-亚烷基桥连的两个氧原子和C1-4-烷基磺酰基;或
为被两个或三个取代基取代的苯基,所述的取代基可以相同或不同且可以选自卤素、羧基、羟基、羟基氨基甲酰基、三氟甲基、氰基、硝基、C1-4-烷基、C1-4-烷氧基、C1-4-烷硫基、C2-4-烷酰基、C1-4-烷氧基羰基、C1-4-烷基磺酰基和与相邻碳原子连接的通过C1-2-亚烷基桥连的两个氧原子组成的组;或
为被苯基或苄基取代一次的苯基,所述的苯基或苄基取代基非必需地在苯基环上被一个或两个取代基取代,所述的取代基可以相同或不同且可以选自卤素、三氟甲基、C1-4-烷基和C1-4-烷氧基;或
为:萘基;吡啶基;2-嘧啶基;5-嘧啶基;吡嗪基;哒嗪基;三嗪基;喹啉基;异喹啉基;吲哚基;异二氢氮茚基;噻吩并[3,2-d]嘧啶基或吡唑并[1,5-a]嘧啶基,它们各自非必需地被一个或两个取代基取代,所述的取代基可以相同或不同且可以选自卤素、羟基氨基甲酰基、三氟甲基、氰基、硝基、吡咯烷基、C1-4-烷基、C1-4-烷氧基和C1-4-烷氧基羰基组成的组;或
为被一个或两个取代基取代的1,2,3,4-四氢异喹啉基,所述的取代基可以相同或不同且可以选自卤素、羟基氨基甲酰基、三氟甲基、氰基、硝基、吡咯烷基、C1-4-烷基、C1-4-烷氧基和C1-4-烷氧基羰基组成的组。
属于本发明通式I范围内的某些N-氨磺酰-N’-芳基哌嗪类是已知的,例如来自专利申请DE-OS1964441(US3,709,677)、WO94/07867和/或WO95/09151;且可以按照这些说明书中所述的方法或类似方法生产它们。
一般来说,可以按照公知方式生产通式I的化合物(包括通式Ia和Ib的化合物),通过下列步骤进行:
a)使通式II的芳基哌嗪化合物与磺酰胺反应,
其中Ar具有上述含义;或
b)使通式II的芳基哌嗪与通式III的被叔丁氧羰基(=boc)保护的4-二甲氨基吡啶(=DMAP)试剂反应,
且随后在酸性条件下从获得的中间体化合物上裂解掉boc基团;或
c)使通式II的芳基哌嗪与通式IV的优选被boc基团保护的氨磺酰氯反应,
且随后在酸性条件下从获得的中间体产物上裂解去除boc基团,且如果需要,将所得的通式I的游离碱转化成其生理上相容的盐或将通式I化合物的盐转化成通式I的游离碱。
在方法变化形式a)中,该反应可以在在反应条件下为惰性的有机溶剂中、特别是在诸如甲苯或二甲苯这类非质子溶剂中或这类溶剂的混合物中进行。合适的反应温度为室温至溶剂或溶剂混合物的沸点、优选60℃-100℃。
在方法变化形式b)中,该反应可以在在反应条件下为惰性的有机溶剂中、特别是在诸如氯仿、二氯甲烷或二噁烷这类偶极非质子溶剂中或这类溶剂的混合物中进行。合适的反应温度为10℃-50℃、优选室温。随后可以按照公知方式在酸性介质、例如在盐酸的乙醇溶液中裂解掉boc保护基。
在方法变化形式c)中,该反应可以在在反应条件下为惰性的有机溶剂中、特别是在诸如氯仿或二氯甲烷这类偶极非质子溶剂中或这类溶剂的混合物中进行。合适的反应温度为10℃-50℃、优选室温。随后可以按照公知方式在酸性介质、例如在盐酸的乙醇溶液中裂解掉boc保护基。优选使用boc-保护的氨磺酰氯。然而,在本领域技术人员公知的适宜反应条件下,还可以使用在碱存在下的未被保护的氨磺酰氯。
通式II的化合物是一般公知的化合物或本领域技术人员可以根据公知方法并由已知原料常规制备这类化合物。例如,可以通过下列步骤制备通式II的化合物,其中Ar为非必需地取代的联芳基:使通式V的化合物与通式VI的化合物在有钯催化剂存在下反应,其中通式V化合物的结构式如下:
其中Ar3具有单环或双环C6-10-芳基的含义,其环碳原子非必需地地被氮、氧和/或硫置换1-3次,和/或其C6-10-芳基环系非必需地含有3-5个双键;且X为可裂解的离去基,如卤素,优选溴;
其中通式VI化合物的结构式如下:
其中Ar4具有如下含义:噻吩基、萘基、吡啶基;苯基或苄基,所述的苯基或苄基各自在苯基环上非必需地被1、2或3个取代基取代,所述的取代基可以相同或不同且可以选自卤素、三氟甲基、氰基、C1-6烷基、C1-4-烷氧基或C1-4烷基磺酰基。
该反应可以按照称作“Suzuki偶联反应”的方式在在反应条件下为惰性的有机溶剂中,特别是在偶极质子溶剂,诸如低级链烷醇,如甲醇或乙醇;或低级二价链烷醇的醚,如乙二醇二甲醚中;或在这类溶剂的混合物或这类溶剂与水的混合物中进行。合适的反应温度为100℃-200℃,优选120℃-180℃。可以便利地使用微波反应器进行该反应。该反应通常在有碱、如碱金属碳酸盐、优选碳酸钾存在下进行。合适的钯催化剂为钯-(II)的盐、如乙酸钯-(II)。
通式III和IV的化合物是一般公知的化合物且本领域技术人员可以常规地按照公知方法并由已知原料制备。通式V和VI的化合物是一般公知的化合物且本领域技术人员可以常规按照公知方法并由已知原料制备。
本发明在另一个方面中还涉及治疗或预防哺乳动物和人肥胖、代谢综合征和/或X综合征和/或心血管疾病的方法,包括对需要的受治疗者给予治疗有效量的通式I的化合物或其生理上相容的酸加成盐。
本发明中肥胖(Obesity)的含义包括导致体重增加的任何体脂增加,优选包括,但不限于肥胖的医学定义。本发明由此还涉及非医学的减体重、诸如美容性的减体重且包括一般性地改善身体外观。此外,术语肥胖的含义还包括药物诱发的肥胖和/或青少年肥胖。
可以各自用本发明化合物治疗的肥胖的伴发疾病(concomitantdiseases)或其继发性疾病(secondary diseases)特别包括代谢综合征和/或X综合征和心血管疾病。
本申请中所用的术语″代谢综合征(metabolic syndrome)″用以包括复杂的临床现象,除向心性肥胖(central obesity)外,还主要包括:高血压,特别是高动脉压(artefial hypertension);胰岛素抗性(insulinresistance),特别是II型糖尿病(diabetesmellitus typeII);葡萄糖耐受不良(glucose intolerance);异常脂蛋白血症(dyslipoproteinaemia),特别是作为与降低的HDL-胆固醇一起发生的伴随异常脂蛋白血症(dyslipoproteinaemia)的高甘油三酯血症(hypertriglyceridaemia);和可以导致痛风(gout)的高尿酸血症(hyperuricaemia)。根据从美国心脏协会(American HeartAssociation)得到的信息,代谢综合征与胰岛素抗性紧密相关。某些人因遗传而易患胰岛素抗性。诸如体脂过量和身体不活动这类后天因素可以在这些人中引起胰岛素抗性和代谢综合征。大部分具有胰岛素抗性的人患有向心性肥胖。在胰岛素抗性与代谢危害因素之间在分子水平上的生物机制尚未得到完全了解且看起来是复杂的。有发生代谢综合征危险的一组人为那些具有胰岛素作用缺陷且不能维持血液中合适的葡萄糖水平的糖尿病人。另一种是非糖尿病且胰岛素抗性但可以通过分泌大量胰岛素补偿的人,主要是患有高血压的人。这种疾病称作血胰岛素过多症(hyperinsulinemia)。第三组是患有血胰岛素过多症、但没有异常葡萄糖水平的不同于高血压的心脏病发作存活者。代谢综合征在如美国这类高度发达国家中已经逐步常见,其中据估计约20-25%的美国成年人患有这种疾病。没有充分认可的诊断代谢综合征的标准。
由国家胆固醇教育程序(NCEP)专家组在有关成年人高血胆固醇的检测、评价和治疗的第三次报告(Third Report of the NationalCholesterol Education Program(NCEP)Expert Panel on Detection,Evaluation,and Treatment of High Blood Cholesterol in Adults)中提出的标准(成年治疗组III)是最新和普遍使用的。根据ATP III标准,通过存在如下组分中的三个或多个鉴定代谢综合征:
●通过腰围测定的向心性肥胖(男性-超过40英寸;女性-超过35英寸)。
●禁食血液甘油三酯高于或等于150mg/dL。
●血液HDL胆固醇(男性-低于40mg/dl;女性-低于50mg/dl)。
●血压大于或等于130/85mmHg。
●禁食葡萄糖高于或等于110mg/dl。
术语“X综合征”与术语“代谢综合征”紧密相关且通常被认为命名了相同疾病或疾患。然而,根据从美国心脏协会(American HeartAssociation)得到的信息,术语“X综合征”还指存在提示缺血性心脏病的胸痛(chest pain)和心电图描记改变(electrocardiographicchanges)的心脏疾病,但其中没有冠心病的血管造影照片发现(angiographicfindings)。患有心脏X综合征的患者有时也具有脂质异常。
伴随肥胖的术语″心血管疾病″通常理解为冠心病(coronaryheart disease),它可以导致心力衰竭(heart failure)、脑血管病(cerebrovascular diseases)(例如可以伴随中风(strokes)的危险性增加)和外周闭塞性动脉病(peripheral occlusivearterial disease)。
通式I的化合物或其生理上相容的酸加成盐因其固有特性而还预计可用于治疗与肥胖无关的糖尿病疾病或病症(diabeticconditions or diseases)。这类糖尿病疾病或病症包括:例如II型糖尿病(diabetes mellitus type II)、糖尿病性神经病(diabeticneuropathy)、糖尿病性视网膜病(diabetic retinopathy)、糖尿病性肾病(diabetic nephropathy)、糖尿病性毛细血管病变(diabeticmicroangiopathy)或糖尿病性大血管病变(diabeticmacroangiopathy)。
肥胖的其它伴发和/或继发性疾病可以为:胆囊疾病(gall-bladder diseases),诸如胆结石(gallstones)形成;睡眠呼吸暂停综合征(sleep apnoea syndrome);矫形并发症(orthopaediccomplications),诸如骨关节炎(osteoarthritis)和心理社会障碍(psychosocial disorders)。
认为通式I的化合物还可用作预防或治疗哺乳动物和人癫痫的抗惊厥药。
本发明通式I的化合物为哺乳动物碳酸酐酶、特别是人碳酸酐酶同工酶亚型II和/或V(=hCA II和/或hCA V)的抑制剂。
药理学试验方法
药理学试验方法中所述的实施例序号指的是下述制备实施例。
1.人碳酸酐酶同工酶II(hCA II)的体外抑制
通过使用自动吸量器(CyBiWell_)用bidest水(aqua bidest)稀释在96孔微量培养板中的通式I的测试化合物。通过移液站(TecanGenesis_)将20μl等分部分从不同稀释平板中转至96孔黑试验平板。在第二步中,加入148μl磷酸钾缓冲液(20mM,pH7.4),且作为第三步,加入20μl酶溶液(1μM来自红细胞的人碳酸酐酶同工酶II(Sigma-Aldrich),溶于磷酸钾缓冲液),在室温下保温60分钟并在预保温期结束时(FLU-1)读取荧光信号(Tecan Ultra_荧光读出器;激发波长:280nm;发射波长:465nm)。预保温时间后,加入20μl丹磺酰胺水溶液(1mM溶于盐酸的丹磺酰胺(Sigma-Aldrich))并在37℃下每隔10分钟读取一次荧光信号,持续60分钟。为了进行计算,使用60分钟时间点(FLU-2)的荧光数据。试验混合物的总体积等于208μl。碳酸酐酶II的终浓度为10-7M/L、丹磺酰胺的终浓度为2.25×10-6且化合物的终浓度为10-8M/L-10-5M/L。作为化合物溶剂的DMSO终浓度为0.1mM。每个微量培养板中还含有不含化合物和酶的空白、不含化合物的对照品和依索唑胺(ethoxzolamide,终浓度5×10-8M/L)。所有数据均反映出单一测定值。将数据表示为通过下列公式计算后的抑制%:
抑制%=100((1-(FLU-2化合物-FLU-2空白-FLU-1化合物+FLU-1空白)/(FLU-2对照品-FLU-2空白-FLU-1对照品-FLU-1空白))
将各化合物的抑制%数据和相应的终浓度用于通过使用Prism 4软件计算IC50。通过应用非线性回归Prism算法(曲线-拟合)计算浓度作用数值:具有可变斜率和约束的S形剂量反应:最高值:100;且最低值:0。
在该试验模型中,下表1中列出的通式I的测试物质表现出下面给出的IC50值:
表1:测试物质在体外的hCA II抑制作用
实施例序号 | IC50[μM] |
2 | 5.1 |
3 | 7.8 |
4 | 3.7 |
7 | 1.8 |
8 | 1.7 |
9 | 7.3 |
10 | 4.0 |
11 | 0.5 |
12 | 1.2 |
13 | 0.9 |
14 | 0.2 |
15 | 0.4 |
16 | 0.3 |
17 | 1.9 |
18 | 1.6 |
19 | 0.08 |
20 | 0.3 |
21 | 0.2 |
2.在大鼠中进行的体内口服葡萄糖耐量试验
本研究在各自单个笼养的体重约为250-500g的雄性肥胖Zucker大鼠(n=10只/组)中进行。使大鼠保持在正常12/12小时光照/黑暗周期(光照在07.00开始)中并使它们随意进食(实验室固形食物)和饮水,但在实验过程中除外,此时使它们禁食过夜,此后进行葡萄糖攻击。
将通式I的测试物质悬浮于2%聚乙二醇(=PEG)1%羧甲基纤维素中并通过口服管饲法给予100mg/kg/天剂量;在08.30-09.30h时给予1/3剂量(1ml/kg,33mg/ml);在16.00-17.00h时给予剩余的2/3剂量(2ml/kg;33mg/ml)且在第2天早上给予最后的1/3剂量。对照组动物仅接受载体。在测试当天,在测试物质/载体的最终剂量后45分钟时立即采集血样(0分钟)(尾静脉),此后大鼠接受口服葡萄糖攻击(1.25g/kg;118mg/ml)。在葡萄糖攻击后30、60、90、120分钟时再采集血样。将每份样品的第二滴血置于葡萄糖测试条上,此后将其放入葡萄糖测量仪以测定血糖水平(Life Scan One Touch Ultra Blood_葡萄糖测量仪和Life Scan One Touch Ultra_测试条;Life Scan Inc.;Milpitas,CA 95035)。将每份样品剩余的血液离心并将血浆冷冻在-80℃下,此后分析胰岛素(1-2-3大鼠胰岛素ELISA试剂盒,Alpco Diagnostics)。
将获得的值绘图并确定测试化合物和载体的AUC(对葡萄糖和胰岛素而言),此后,估计对照AUC百分比(percent control AUC)、对照最大值百分比(percent control maximum value)和对照基线%(%control baseline)以便确定测试化合物对葡萄糖耐量的影响。
在上述试验模型中,测试物质表现出下列结果(表示为对照的百分数,%):
表2:测试物质对葡萄糖和胰岛素水平的影响
实施例序号 | 葡萄糖 | 胰岛素 | ||||
AUC | 最大作用 | 基线 | AUC | 最大作用 | 基线 | |
2 | 84 | 78 | 82 | 95 | 95 | 85 |
6 | 89 | 84 | 91 | 104 | 123 | 109 |
14 | 102 | 94 | 88 | 107 | 92 | 97 |
3.小鼠中的急性体内摄食试验
本研究在各自单独笼养的雄性C57B1/6小、鼠(n=8只/组)中进行。使小鼠保持在颠倒的12/12小时光照/黑暗周期(光照在22:00h开始)中并使它们随意进食(高热量食物)和饮水。每天测定食物的摄取和水的消耗量。将通式I的测试化合物悬浮于1%在水中的甲基纤维素和2%(v/v)伯洛沙姆188(Lutrol F68_)中并通过口服管饲法给予100mg/kg/天剂量。在7.00-9.00时给予一半剂量;在15.00-15.30时给予剩余的一半剂量。
在上述试验模型中,测试物质使动物24小时的摄食量比对照组下降至如下表3中所示的摄食百分比。
表3:测试物质对摄食的影响
实施例序号 | 摄食[对照%] |
2 | 68 |
7 | 78 |
12 | 53 |
15 | 79 |
21 | 76 |
4.对体内食物和水摄取和体重增加的长期影响
使雌性Wistar大鼠(体重在250-300g;Charles River,Margate,Kent)成对笼养在带有硬底板和锯屑垫的具有21±4℃温度和55±20%湿度的聚丙烯笼中。将动物维持在颠倒的光照-黑暗周期中(从10.00-18.00h停止照明8小时),在此期间,用红色光给室内照明。动物可以在所有时间自由获取粉状高脂肪膳食(VRF1+20%猪油)、磨碎的巧克力、磨碎的花生和自来水。三种不同的膳食包含在单独的带铝盖(Solmedia Laboratory Suppliers,Romford,Essex)的玻璃饲喂瓶中。每个盖上有切成的3-4cm的孔以便获取食物。使动物成对笼养12周。在开始基线读取前至少2周时,使动物单独各自寄居在带有金属丝格板的聚丙烯笼内以便记录每只大鼠的摄食情况。将带有笼垫的聚丙烯盘放在每只笼子的下方以检测任何食物溢出物。
在本研究开始时,给动物称重(使用电子top-pan天平,最精确至0.1g)并分成6个体重匹配的治疗组,各组中含有10只动物。在7天基线进入期(baseline run-in period)过程中对所有动物每天口服给予一次载体(1%Tylose MH50,0.1%伯洛沙姆188),此后如下表4中所述对大鼠给予载体或通式I的测试化合物,持续28天:
表4:用实施例2(=ex.2)的通式I化合物对大鼠的治疗方案
组 | 治疗1(0小时) | 治疗2(4小时) | n |
A | 口服载体 | 口服载体 | 10 |
B | ex.2,30mg/kg口服 | ex.2,30mg/kg口服 | 10 |
C | ex.2,50mg/mg口服 | ex.2,50mg/kg口服 | 10 |
将实施例2的测试物质悬浮于1% Tylose MH50,0.1%伯洛沙姆188中并通过口服管饲法给药(2ml/kg)。所有的给药均在8小时黑暗期开始时进行(跨越紧靠光照结束前后的时期)。在第一次治疗后4小时给予第二次治疗。每天在给予载体或测试物质时对大鼠、饲喂瓶和水瓶称重(最精确至0.1g)。在每次读取时,检验每只笼子下面的托盘上溢出的食物,使其返回至合适的瓶中,此后称重。不过,从饲喂瓶中溢出的食物是可以忽略不计的。通过以kJ/kg大鼠体重表示摄食结果,以说明不同类型食物的能量水平和体重改变。以g/kg表示饮水的结果。
在第29天本研究结束时处死动物(用CO2将任何流体丢失减小到最低限度)并通过心脏穿刺采集血样(5ml全血/动物)。通过离心分离血浆并储存在-75℃下至分析。在采血后,对动物尸体称重、冷冻并储存在-75℃下以用于身体组成分析。使用标准化学分析技术测定尸体的体脂、蛋白质、水和灰分水平。仅测定脂肪、蛋白质、水和灰分含量,因为其它成分(主要是碳水化合物)形成低于总身体组成的2%。
在液氮温度下研磨各尸体、混合并取两种有代表性的样品。通过将样品冻干至恒重测定尸体的水分。使用改进的Soxhlet提取方案(40-60℃下的石油醚)对冻干的样品测定尸体脂肪,其中应用FossSoxtec_HT2系统(Foss UK Ltd,Wheldrake,UK)及制造商推荐的方案。使用Foss 2012_消化块和Foss 2200_蒸馏设备(Foss UK Ltd)、应用micro-Kjeldahl法对冻干的样品测定尸体蛋白质。通过在高温下使用马弗灰化炉燃烧冻干的样品测定残余的尸体灰分。如果必要对化学分析参数进行重复测定(例如如果一式两份样品存在大于1%的差异)。
表5:实施例2的测试化合物对尸体水分、脂肪、蛋白质和灰分含量的影响:平均体重/大鼠
组 | 水(g) | 脂肪(g) | 蛋白质(g) | 灰分(g) | 尸体(g) |
载体 | 210.9±2.7 | 144.5±11.6 | 67.5±1.2 | 12.52±0.45 | 438.4±12.1 |
ex.2(30mg/kg) | 205.8±3.1 | 87.9±3.8** | 64.8±1.2 | 12.13±0.48 | 375.4±4.8** |
ex.2(50mg/kg) | 202.2±3.6 | 83.6±6.9** | 62.8±1.3 | 11.38±0.29* | 365.6±3.8** |
将结果表示为治疗组的平均值(所有的n=9-10且根据在基线下组之间体重的差异进行调整)与平均值的标准误差(=SEM;根据此统计模式的残数(residuals)计算)。通过ANCOVA(基线体重作为协变量(covariate))进行统计学比较,随后进行Williams′检验。
通过与载体比较**p<0.001、*°p<0.01、*p<0.05表示显著性差异。
表6:实施例2的测试化合物对尸体水分、脂肪、蛋白质和灰分含量的影响:最终平均体重百公比
组 | 水分(%) | 脂肪(%) | 蛋白质(%) | 灰分(%) | 总计(%) |
载体 | 48.8±1.0 | 31.9±1.4 | 15.7±0.4 | 2.91±0.12 | 99.3 |
ex.2(30mg/kg) | 55.2±0.8** | 22.8±1.0** | 17.4±0.3*° | 3.24±0.12 | 98.6 |
ex.2(50mg/kg) | 55.7±1.2** | 22.3±1.8** | 17.3±0.4*° | 3.14±0.1 | 98.4 |
如上所述表示结果和统计值。
表7:实施例2的测试化合物对膳食肥胖型雌性wistar大鼠中血浆参数的作用
组 | 葡萄糖(mM) | 胰岛素(ng/ml) | 瘦蛋白(leptin)(ng/ml) |
载体 | 8.2±0.7 | 2.33±0.53 | 144.6±22.7 |
ex.2(30mg/kg) | 8.6±0.5 | 1.53±0.33 | 68.8±9.4** |
ex.2(50mg/kg) | 7.9±0.5 | 1.40±0.41 | 58.8±11.6** |
如上所述表示结果和统计值。
本发明进一步提供了包括药理学上有效量的通式I化合物或其生理上相容的酸加成盐且优选进一步包括常用药物上可接受的助剂和/或载体的药物组合物或药物。
合适的药物上可接受的助剂和/或载体是本领域中众所周知的且包括药用级淀粉、甘露糖醇、乳糖、硬脂酸镁、糖精钠、滑石、纤维素、葡萄糖、蔗糖(或其它糖)、碳酸镁、明胶、油、醇、去污剂、乳化剂或水(优选无菌水)。该组合物可以为组合物的混合制剂或可以为同时、单独或依次使用(包括给药)的联合制剂。可以通过任意便利方法给予本发明用于上述适应征的化合物或其生理上相容的酸加成盐,例如通过口服(包括通过吸入)、非肠道、粘膜(例如口含、舌下、鼻部)、直肠或透皮给药且所述的组合物可以由此作适应性修饰。为了口服给药,可以将化合物配制成液体或固体,例如溶液、糖浆剂、混悬剂或乳剂、片剂、胶囊和锭剂。液体制剂一般由化合物或其生理上可接受的盐在合适的水或非水液体载体中的混悬液或溶液组成,所述的水或非水载体例如有水、乙醇、甘油、聚乙二醇或油。
该制剂还可以含有悬浮剂、防腐剂、增香剂或着色剂。可以使用常用于制备固体制剂的任意合适的药物载体制备片剂形式的组合物。这类载体的实例包括硬脂酸镁、淀粉、乳糖、蔗糖和微晶纤维素。可以使用常规的包囊方法制备胶囊形式的组合物。例如,可以使用标准载体制备含有活性组分的粉剂、颗粒或丸剂且然后将它们填入硬明胶胶囊;或者,可以使用任意合适的药物载体、例如含水的树胶、纤维素、硅酸盐或油制备分散体或混悬液,然后将它们装入软明胶胶囊。可以将口服给药用组合物设计成在其通过消化道时防止活性组分降解的形式,例如通过在片剂或胶囊上对制剂进行外层包衣来实现。典型的非肠道用组合物由化合物或其生理上相容的酸加成盐在无菌水或非水载体或非肠道可接受的油中的溶液或混悬液组成,所述的非肠道可接受的油例如有聚乙二醇、聚乙烯吡咯烷酮、卵磷脂、花生油或芝麻油。另一方面,可以冻干溶液且然后在临给药前用合适的溶剂重配。可以将鼻部或口服给药用组合物便利地配制成气雾剂、滴剂、凝剂和粉剂。
气雾剂制剂一般包括活性物质在生理上可接受的水或非水溶剂中的溶液或细混悬液且通常以单剂量或多剂量的无菌形式存在于密封容器内,所述容器可以采用筒或再填充形式与雾化装置一起使用。另一方面,密封容器可以为单位分配装置,诸如安装了计量阀的单剂量鼻吸入器或气雾剂分配器,所述的装置旨在一旦容器内含物耗尽则被废弃。如果剂型包括气雾剂分配器,那么它含有药物上可接受的抛射剂。气雾剂还可以采取泵-雾化器的形式。适合于口含或舌下给药的组合物包括片剂、锭剂和软锭剂,其中用诸如糖和阿拉伯胶、黄耆胶或明胶和甘油这类载体配制活性组分。直肠或阴道给药用组合物方便地为栓剂(含有常用的栓剂基质,诸如可可脂)、阴道栓、阴道片(vaginaltabs)、泡沫或灌肠剂形式。适合于透皮给药的组合物包括软膏、凝胶、贴剂和注射剂,包括粉针剂。组合物方便地采用单位剂型,诸如片剂、胶囊或安瓿。本发明的药物组合物用于预防和/或治疗肥胖、肥胖伴发和/或继发性疾病、其它医学性的体重减轻和非医学性的体重减轻和/或糖尿病疾病或病症。
本发明的化合物及其生理上相容的酸加成盐一般作为药物组合物给药,这些组合物因为存在本文公开的化合物而是本发明重要的和新的实施方案。在本发明的实施方案中,提供了药包或药盒,它们包括一个或多个填充了本发明药物组合物的一种或多种组分的容器。与这类容器放在一起的可以有各种书面材料,诸如使用说明书或控制药物产品制造、使用或销售的政府管理部门规定形式的介绍,该介绍反映出得到制造、使用或销售管理部门关于人或兽给药的批准。
本发明的另一个方面提供了制备如上所述的药物组合物的方法。可以通过本领域众所周知的标准技术进行制备且包括将本发明的化合物与药物上可接受的助剂和/或载体混合的步骤。组合物可以采用任意形式,包括片剂、液体、胶囊和粉末或食品形式,例如功能性食品。在后一种情况中,食品自身可以起药物上可接受的载体的作用。
优选对需要的患者给予所述化合物或组合物且用量足以预防和/或治疗疾患、障碍或疾病的症状。就本发明的所有方面、特别是医疗方面而言,化合物或组合物的给药具有最终由主治临床医师决定的且考虑到如下因素的剂量方案:诸如所用的化合物、动物类型、年龄、体重、症状的严重程度、给药方法、不良反应和/或其它禁忌症。可以通过标准设计临床试验并整体监测患者发展和恢复情况来决定具体确定的剂量范围。这类试验可以使用以低百分比的动物最大耐受剂量作为在人中的起始剂量并逐步增加剂量的设计。通常以如下每日剂量方案给予本发明生理上可接受的化合物(对成年患者而言),例如口服剂量1mg-2000mg、优选30mg-1000mg、例如10-250mg或静脉内、皮下或肌内剂量0.1mg-100mg、优选0.1mg-50mg、例如1-25mg以游离碱形式计算的通式I化合物或其生理上可接受的盐,每天将化合物给药1-4次。也可以对儿童或青少年给予本发明所用的化合物,同时在这些情况中的个体剂量方案特别需要由临床医师进行彻底调整且通常包括比成年人的给药量更低的剂量。
合适的情况是,将所述化合物连续给予一段治疗时间,例如至少1周,但通常为几周至几个月的较长期限。本发明还提供了用于维持指定体重或用于美容性减重的美容方法(非治疗性的),该方法包括给予本发明其它方面的化合物、优选与药物上可接受的载体或稀释剂一起给予。
优选将所述化合物或组合物对需要或迫切需要的受治疗者给药且用量足以维持指定的体重或美容性体重减轻。
在另一个方面中,可以将通式I的化合物和其生理上相容的酸加成盐有利地与一种或多种活性剂一起给药(作为联合药物组合物),所述的一种或多种活性剂选自:抗糖尿病药;减肥药或食欲调节剂;心血管活性剂,特别是抗高血压药;利尿药;改变脂质水平的活性剂,特别是降脂剂;和用于治疗和/或预防糖尿病导致的或与糖尿病相关的并发症的活性组分。
合适的抗糖尿病药包括:例如胰岛素;胰岛淀粉样多肽(amylin);诸如公开在例如WO98/08871中的那些GLP-1和GLP-2衍生物;和口服具有降血糖活性的活性组分。口服具有降血糖活性的活性组分优选包括:磺酰脲类,例如甲苯磺丁脲(tolbutamide)、格列本脲(glibenclamide)、格列美脲(glimepiride)、格列吡嗪(glipizide)、格列喹酮(gliquidone)、格列派特(glisoxepide)、格列波脲(glibomuride)或格列齐特(gliclazide);双胍类,例如二甲双胍(metformin);氯茴苯酸类,例如瑞格列奈(repaglinide);β3肾上腺素能激动剂;噁二唑烷二酮类;葡萄糖苷酶抑制剂,例如α-葡萄糖苷酶抑制剂,诸如米格列醇(miglitol)或阿卡波糖(acarbose);胰高血糖素受体拮抗剂、GLP-1激动剂、钾通道开放剂,如二氮嗪(diazoxide)或公开在WO97/26265或WO99/03861中的那些;CB-1(大麻素-1(cannabinoid-1)受体)拮抗剂/反激动剂;胰岛素敏化物,如噻唑烷二酮类,例如曲格列酮(troglitazone)、环格列酮(ciglitazone)、吡格列酮(pioglitazone)、罗西格列酮(rosiglitazone)或WO97/41097中公开的化合物,特别是5-[[4-[(3,4-二氢-3-甲基-4-氧代-2-喹唑啉基甲氧基]苯基]甲基]-2,4-噻唑烷二酮;胰岛素受体激酶激活物;参与刺激糖原异生和/或糖原分解的肝酶的抑制剂,例如糖原磷酸化酶抑制剂;和葡萄糖吸收和葡萄糖排泄调节剂。
合适减肥药或食欲调节剂包括以下中的一种或多种:5-HT(5-羟色胺)转运蛋白抑制剂、NE(去甲肾上腺素)转运蛋白抑制剂、CB-1(大麻素-1受体)拮抗剂/反激动剂、ghrelin抗体、ghrelin拮抗剂、H3(组胺H3)拮抗剂/反激动剂、MCHlR(黑素浓缩激素(melaninconcentrating hormone)1R)拮抗剂、MCH2R(黑素浓缩激素2R)激动剂/拮抗剂、NPY1(神经肽Y Y1)拮抗剂、NPY2(神经肽Y Y2)激动剂、NPY5(神经肽Y Y5)激动剂、瘦蛋白(leptin)、瘦蛋白(leptin)衍生物、阿片类拮抗剂、阿立新(orexin)拮抗剂、BRS 3(铃蟾肽受体亚型3)激动剂、CCK-A(缩胆囊素-A)激动剂、CNTF(睫状神经营养因子)、CNTF衍生物、GHS(生长激素促分泌素受体)激动剂、SHT2c(5-羟色胺受体2c)激动剂、Mc3r(黑皮质素3受体)激动剂、Mc4r(黑皮质素4受体)激动剂、单胺重摄取抑制剂、5-羟色胺重摄取抑制剂、GLP-1(胰高血糖素样肽1)激动剂、托吡酯(topiramate)、植物药化合物57、ACC2(乙酰辅酶A羧化酶-2)抑制剂、β3肾上腺素能激动剂、DGATl(二酰甘油酰基转移酶1)抑制剂、DGAT2(二酰甘油酰基转移酶2)抑制剂、FAS(脂肪酸合酶)抑制剂、PDE(磷酸二酯酶)抑制剂、甲状腺激素B激动剂、UCP-1(解偶联蛋白1)、2或3激活物、酰基-雌激素、糖皮质激素拮抗剂、11HSD-1(1型11-p羟基类固醇脱氢酶)抑制剂、SCD-1(十八酰辅酶A去饱和酶-1)抑制剂、二肽基肽酶IV(DP-IV)抑制剂、脂酶抑制剂、脂肪酸转运蛋白抑制剂、二羧酸转运蛋白抑制剂、葡萄糖转运蛋白抑制剂、磷酸转运蛋白抑制剂及其药物上可接受的盐和酯类。
合适的食欲调节剂(食欲抑制剂)包括西布曲明(sibutramine)或西布曲明(sibutramine)的单-和双去甲基化活性代谢物、芬氟拉明(fenfluramine)或右芬氟拉明(dexfenfluramine)、马吲哚(mazindol)、安非拉酮(diethylpropin)或芬特明(phentermine)、瘦蛋白(leptin)或修饰的瘦蛋白(leptin)、右苯丙胺(dexamphetamine)和苯丙胺(amphetamine)。
合适的脂酶抑制剂包括:奥利司他(orlistat)、panclicins、分离自微生物的脂酶抑制剂、诸如一制胰脂菌素(lipstatin)(分离自毒三素链霉菌(Streptomyces toxytricini))、抑脂酶免疫酮B(ebelactone B)(分离自阿布拉链霉菌(Streptomycesaburaviensis)、这些化合物的合成衍生物;2-氧基-4H-3,1-苯并噁嗪-4-酮衍生物,如Alizyme的ATL-962或结构相关的化合物;2-氨基-4H-3,1-苯并噁嗪-4-酮衍生物或已知具有脂酶抑制活性的植物提取物,例如高良姜(Alpinia officinarum)提取物或分离自这类提取物的化合物,如3-甲醚高良姜黄素(3-methylethergalangin)(分离自高良姜(A.officinarum));
合适的CB1-大麻素拮抗剂包括利莫那班(rimonabant)、SLV319、SR147778和CP-945598。
合适的心血管活性剂包括:血管紧张肽II受体拮抗剂,例如阿比沙坦(abitesartan)、苄基氯沙坦(benzyllosartan)、坎地沙坦(candesartan)、依利沙坦(elisartan)、恩布沙坦(embusartan)、enoltasosartan、依普罗沙坦(eprosartan)、fonsartan、福拉沙坦(forasartan)、甘氨酰氯沙坦(glycyllosartan)、厄贝沙坦(irbesartan)、isoteoline、氯沙坦(losartan)、米法沙坦(milfasartan)、奥美沙坦(olmesartan)、opomisartan、pratosartan、利匹沙坦(ripisartan)、沙普立沙坦(saprisartan)、沙拉新(saralasin)、sarmesin、他索沙坦(tasosartan)、替米沙坦(telmisartan)、缬沙坦(valsartan)、佐拉沙坦(zolasartan);Kissei KRH-94、Lusofarmaco LR-B/057、Lusofarmaco LR-B/081、Lusofarmaco LR B/087、Searle SC-52458、Sankyo CS-866、Takeda TAK-536、Uriach UR-7247、A-81282、A-81988、BIBR-363、BIBS39、BIBS-222、BMS-180560、BMS-184698、CGP-38560A、CGP-48369,、CGP-49870、CGP-63170、CI-996、CV-11194、DA-2079、DE-3489、DMP-811、DuP-167、DuP-532、GA-0056、E-4177、EMD-66397、EMD-73495、EXP-063、EXP-929、EXP-3174、EXP-6155、EXP-6803、EXP-7711、EXP-9270、FK-739、HN-65021、HR-720、ICI-D6888、ICI-D7155、ICI-D8731、KRI-1177、KT3-671、KW-3433、L-158809、L-158978、L-159282、L-159689、L-159874、L-161177、L-162154、L-162234、L-162441、L-163007、L-163017、LY-235656、LY-285434、LY-301875、LY-302289、LY-315995、ME-3221、PD-123177、PD-123319、PD-150304、RG-13647、RWJ-38970、RWJ-46458、S-8307、S-8308、SL-91.0102、U-96849、U-97018、UP-269-6、UP-275-22、WAY-126227、WK-1492.2K、WK-1360、X-6803、XH-148、XR-510、YM-358、YM-31472、ZD-6888、ZD-7155和ZD-8731或其任意生理上相容的盐、溶剂合物、前体药物或酯类;daglutril;非选择性α-肾上腺素受体拮抗剂,例如妥拉唑林(tolazoline)或酚苄明(phenoxybenzamine);选择性α-肾上腺素受体拮抗剂,例如多沙唑嗪(doxazosin)、哌唑嗪(prazosin)、特拉唑嗪(terazosin)或乌拉地尔(urapidil);β-肾上腺素受体拮抗剂,例如醋丁洛尔(acebutolol)、阿普洛尔(alprenolol)、阿替洛尔(atenolol)、倍他洛尔(betaxolol)、避索洛尔(bisoprolol)、布拉洛尔(bupranolol)、卡拉洛尔(carazolol)、卡替洛尔(carteolol)、塞利洛尔(celiprolol)、甲吲洛尔(mepindolol)、美替洛尔(metipranolol)、美托洛尔(metoprolol)、纳多洛尔(nadolol)、氧烯洛尔(oxprenolol)、喷布洛尔(penbutolol)、吲哚洛尔(pindolol)、普萘洛尔(propranolol)、施太可(sotalol)和噻吗洛尔(timolol);α-和β-肾上腺素受体混合拮抗剂,例如卡维地洛(carvedilol)或拉贝洛尔(labetolol);神经节阻断药,例如利舍平(reserpine)或胍乙啶(guanethidine);α2-肾上腺素受体激动剂(包括中枢作用α2-肾上腺素受体激动剂),例如可乐定(clonidine)、胍法辛(guanfacine)、胍那苄(guanabenz)、甲基多巴(methyldopa)和莫索尼定(moxonidine);肾素-抑制剂,例如alskiren;ACE-抑制剂,例如贝那普利(benazepril)、卡托普利(captopril)、西拉普利(cilazapril)、依那多林(enalapril)、福辛普利(fosinopril)、咪达普利(imidapril)、赖诺普利(lisinopril)、莫昔普利(moexipril)、喹那普利(quinapril)、培哚普利(perindopril)、雷米普利(ramipril)、螺普利(spirapril)或群多普利(trandolapril);混合或选择性内皮素受体拮抗剂,例如阿曲生坦(atrasentan)、波生坦(bosentan)、clazosentan、达卢生坦(darusentan)、西他生坦(sitaxsentan)、替唑生坦(tezosentan)、BMS-193884或J-104132;直接血管舒张药,例如二氮嗪(diazoxide)、双肼屈嗪(dihydralazine)、肼屈嗪(hydralazine)或咪诺地尔(minoxidil);混合ACE/NEP-抑制剂,例如奥马曲拉(omapatrilat);ECE-抑制剂,例如FR-901533;PD-069185;CGS-26303;CGS-34043;CGS-35066;CGS-30084;CGS-35066;SM-19712;Ro0677447;选择性NEP-抑制剂;加压素拮抗剂、醛固酮受体拮抗剂,例如依普利酮(eplerenone)或螺内酯(spironolactone);血管紧张肽疫苗;和硬骨鱼紧张肽II受体拮抗剂。
合适的利尿药包括:噻嗪类(thiazide)利尿药,例如阿尔噻嗪(althiazide)、贝美噻嗪(bemetizide)、苄氟噻嗪(bendroflumethiazide)、苄氢氯噻嗪(benzylhydrochlorothiazide)、苄噻嗪(benzthiazide)、布噻嗪(buthiazide)、氯噻嗪(chlorothiazide)、环噻嗪(cyclothiazide)、氢氯噻嗪(hydrochlorothiazide)、氢氟噻嗪(hydroflumethiazide)、甲氯噻嗪(methyclothiazide)、对氟噻嗪(paraflutizide)、泊利噻嗪(polythiazide)、四氯噻嗪(teclothiazide)、三氯噻嗪(trichlormethiazide);噻嗪类类似物利尿药,例如氯米非那胺(chloraminofenamide)、氯噻酮(chlortalldone)、氯非那胺(clofenamide)、氯帕胺(clopamide)、氯索隆(clorexolone)、芬喹唑(fenquizone)、吲达帕胺(indapamide)、美夫西特(mefruside)、美托拉宗(metolazone)、喹乙宗(quinethazone)、曲帕胺(tripamide)、希帕胺(xipamide);袢性利尿药,例如阿佐塞米(azosemide)、布美他尼(bumetanide)、呋塞米(furosemide)、吡咯他尼(piretanide)、托塞米(torsemide);留钾利尿药(potassiumsparing duretics),例如阿米洛利(amiloride)、坎利酸钾(potassium canrenoate)、螺内酯(spironolactone)、氨苯蝶啶(triamterene);或任意上述利尿药的任意生理上相容的互变体、盐、溶剂合物、前体药物或酯类。
改变脂质水平的合适的活性剂包括:改变脂质代谢的化合物,诸如抗高血脂活性组分和降血脂活性组分(antilipidemic activeingredients),如HMGCoA还原酶抑制剂,例如阿托伐他汀(atorvastatin)、berivastatin、西立伐他汀(cerivastatin)、克伐他汀(crilvastatin)、氟伐他汀(fluvastatin)、格仑伐地汀(glenvastatin)、洛伐他汀(lovastatin)、美伐他汀(mevastatin)、匹伐他汀(pitavastatin)、普伐他汀(pravastatin)、罗苏伐他汀(rosuvastatin)、辛伐他汀(simvastatin)或其任意生理上相容的盐、溶剂合物、前体药物或酯类;胆固醇转运/胆固醇摄取抑制剂;胆汁酸重吸收抑制剂或微粒体甘油三酯转运蛋白(MTP)抑制剂;减少食物摄取的化合物、PPAR(=过氧化物酶体增殖剂(proliferator)-活化的受体)和RXR激动剂和对β细胞的ATP-依赖性钾通道起作用的活性剂;fibricacids,例如苯扎贝特(bezafibrate)、环丙贝特(ciprofibrate)、氯贝丁酯(clofibrate)、非诺贝特(fenofibrate)或吉非贝齐(gemfibrozil);考来烯胺(cholestyramine)、考来替泊(colestipol)、普罗布考(probucol)、依泽替米贝(ezetimibe)和右甲状腺素(dextrothyroxine);HMGCoA合酶抑制剂、胆固醇吸收抑制剂、酰基辅酶A-胆固醇酰基转移酶(ACAT)抑制剂、胆固醇酯转运蛋白(CETP)抑制剂、角鲨烯合成酶抑制剂、抗氧化剂、PPARα拮抗剂、FXR受体调节剂、LXR受体激动剂、脂蛋白合成抑制剂、肾素血管紧张肽系统抑制剂、微粒体甘油三酯转运抑制剂、胆汁酸重吸收抑制剂、PEAR8激动剂、甘油三酯合成抑制剂、转录调节剂、角鲨烯环氧酶抑制剂、低密度脂蛋白受体诱导物、血小板聚集抑制剂、5-LO或FLAP抑制剂、PPAR8部分激动剂和烟酸或烟酸受体激动剂及其药物上可接受的盐和酯类。
可以适用于与本发明通式I化合物联用的其它活性剂可以选自CART激动剂、H3拮抗剂、TNF激动剂、CRF激动剂、CRF BP拮抗剂、尿皮质激素(urocortin)激动剂、β3-激动剂、MSH(促黑激素)激动剂、5-羟色胺重摄取抑制剂、混合的5-羟色胺-和去甲肾上腺素-重摄取抑制剂、5HT调节剂、MAO抑制剂、促生长激素神经肽(galanin)拮抗剂、生长激素、生长激素-释放化合物、TRH激动剂、解偶联蛋白2或3调节剂、瘦蛋白(leptin)激动剂、多巴胺激动剂(溴隐亭(bromocriptine)、doprexin)、RXR调节剂、hCNTF激动剂和TR-β-激动剂组成的组。
本发明优选的药物联用组合物包括至少一种通式I的化合物和至少一种双胍的组合、至少一种通式I的化合物与至少一种fibricacid的组合、至少一种通式I的化合物与至少一种HMGCoA还原酶抑制剂的组合和至少一种通式I的化合物与至少一种胰岛素敏化物的组合。
与一种或多种上述活性剂联用的优选通式I的化合物为4-苯基-哌嗪-1-磺酰胺、4-(2-氯-苯基)-哌嗪-1-磺酰胺、4-(2-甲氧基-苯基)-哌嗪-1-磺酰胺、4-吡啶-4-基-哌嗪-1-磺酰胺、4-嘧啶-2-基-哌嗪-1-磺酰胺、4-(4-氟-苯基)-哌嗪-1-磺酰胺、4-(4-氯-3-三氟甲基-苯基)-哌嗪-1-磺酰胺和/或4-(3-氯-5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酰胺。
二甲双胍(Metformine)为与至少一种通式I的化合物联用的优选双胍。
与至少一种通式I的化合物联用的优选fibric acids为苯扎贝特(bezafibrate)、环丙贝特(ciprofibrate)、氯贝丁酯(clofibrate)、非诺贝特(fenofibrate)和/或吉非贝齐(gemfibrozil)。最优选非诺贝特(fenofibrate)。
与至少一种通式I的化合物联用的优选HMGCoA还原酶抑制剂为阿托伐他汀(atorvastatin)、berivastatin、西立伐他汀(cerivastatin)、克伐他汀(crilvastatin)、氟伐他汀(fluvastatin)、格仑伐地汀(glenvastatin)、洛伐他汀(lovastatin)、美伐他汀(mevastatin)、匹伐他汀(pitavastatin)、普伐他汀(pravastatin)、罗苏伐他汀(rosuvastatin)和/或辛伐他汀(simvastatin)或其任意生理上相容的盐、溶剂合物、前体药物或酯类。最优选辛伐他汀(simvastatin)、洛伐他汀(lovastatin)和/或普伐他汀(pravastatin)。
与至少一种通式I的化合物联用的优选胰岛素敏化物为噻唑烷二酮类,特别是曲格列酮(troglitazone)、环格列酮(ciglitazone)、吡格列酮(pioglitazone)和/或罗西格列酮(rosiglitazone)。最优选罗西格列酮(rosiglitazone)和吡格列酮(pioglitazone)。
本发明更优选的组合为4-苯基-哌嗪-1-磺酰胺与二甲双胍(Metformine)的组合、4-苯基-哌嗪-1-磺酰胺与非诺贝特(fenofibrate)的组合、4-苯基-哌嗪-1-磺酰胺与辛伐他汀(simvastatin)的组合和4-苯基-哌嗪-1-磺酰胺与罗西格列酮(rosiglitazone)的组合。
在如上所述和本发明的药物联用组合物的一个实施方案中,可以获得和给予与不同活性剂例如在一种组合的单位剂型中、如在一种片剂或胶囊中,即在一种物理组合形式中的通式I的化合物。在这类组合的单位剂型中,例如,可以借助于在所述片剂中的不同层、例如通过使用本领域中公知的惰性中间层;或借助于在所述胶囊中的不同隔室使通式I的化合物与不同活性剂彼此隔离。还可以将相应的活性剂或其药物上可接受的盐以其水合物形式使用或包括用于结晶的其它溶剂。单位剂型可以为固定的组合。单位剂型、特别是通式I化合物与一种或多种不同活性剂的固定组合是该实施方案的优选方案。
在另一个实施方案中,可以获得并给予在两种或多种独立的单位剂型中、例如在两种或多种在物理形态上彼此分离的片剂或胶囊中的通式I化合物和不同活性剂。可以同时或逐步(分别)、例如依次按照任一种顺序给予两种或多种独立的单位剂型。因此,可以在同时或在一天的不同时间以任一种顺序给予通式I的化合物和不同活性剂,临床医师的处方通常决定最佳剂量方案。
下列实施例用于进一步解释本发明,但不限定其范围。
实施例1:
N-氨磺酰-N’-苯基哌嗪(=4-苯基-哌嗪-1-磺酰胺)
将25.0g苯基-哌嗪在77.0ml甲苯和17.8g磺酰胺中的混合物回流8小时。将该混合物在室温保持整个周末。将所得固体悬浮于200ml甲醇中并维持在90℃下60分钟。通过在减压下蒸发浓缩该混悬液(-140ml甲醇)、冷却并过滤、用乙醚洗涤且最终干燥。回收粗产物并使其从200ml甲醇中重结晶(上述步骤不经浓缩)。
实施例2:
N-氨磺酰-N’-苯基哌嗪盐酸盐
用盐酸乙醇溶液处理如上述实施例1中获得的结晶级分、蒸发并最终在65℃下溶于100ml甲醇。向该所得溶液中加入150ml异丙醇并在减压下除去甲醇。结晶过夜、过滤、用乙醚洗涤并在减压下干燥(油泵)而得到29.1g标题化合物,mp.=184℃。
表8:实施例2化合物的元素分析(MW 277.77):
计算值 | 测定值 | |
C% | 43.24 | 43.32 |
H% | 5.81 | 5.86 |
N% | 15.13 | 15.31 |
Cl-% | 12.76 | 12.77 |
实施例3:
4-(2-甲氧基-苯基)-哌嗪-1-磺酰胺盐酸盐
A)将12ml异氰酸氯磺酰酯滴加到13ml叔丁醇在100ml二氯甲烷中的冰冷溶液中。30分钟后,加入4-二甲基氨基吡啶(34.5g)。将所得混合物在室温下搅拌1小时并用二氯甲烷稀释至得到澄清溶液。用水将该溶液洗涤几次,分离有机层,用Na2SO4干燥、过滤并大量蒸发。使残余物从乙腈中重结晶而得到30.4g的BOC-保护的DMAP-试剂,mp.156℃。
B)将2-甲氧基-苯基-哌嗪(152mg)溶于10ml二氯甲烷。向该所得溶液中加入如上述获得的BOC-保护的DMAP-试剂(238mg)并将所得混合物在室温下保持过夜。然后蒸发该混合物并通过快速色谱法纯化残余物(固定相:硅胶;流动相:四氢呋喃+5%甲醇)而得到192mg的boc-保护的中间体。
C)将100ml无水乙醇在冰浴中冷却至0℃,此后滴加20ml的乙酰氯并将所得混合物搅拌20分钟。从由此制备的盐酸乙醇溶液中分离5ml,将如上述获得的boc-保护的化合物(192mg)溶于其中并在室温下搅拌3小时。然后将该混合物与乙醇一起蒸发几次,最终达到干燥,从而得到225mg标题化合物,mp.191℃。
实施例4:
4-吡啶-2-基-哌嗪-1-磺酰胺
A)将叔丁醇(6.5ml)溶于30ml二氯甲烷。将所得溶液滴加到异氰酸氯磺酰酯(6.0ml)在40ml二氯甲烷中的冰冷却的溶液中。30分钟的反应时间后,用二氯甲烷将所得混合物稀释至100ml而得到0.854摩尔储备溶液,将其不经进一步纯化用于下一步。
B)将新制备的叔丁基氨磺酰氯的储备溶液(1.67ml;在二氯甲烷中0.854摩尔,参见上述制备)加入到2-吡啶基-哌嗪(232mg)在4ml二氯甲烷中的溶液中并将所得混合物在室温下搅拌24小时。然后加入3ml HCl乙醇溶液(参见上文的实施例3C制备),此后将所得混合物在室温下保持过夜。在减压下蒸发溶剂后,分离粗固体。随后对该固体进行快速色谱(固定相:硅胶;流动相:四氢呋喃/甲醇/氨70∶30∶1v/v/v)并干燥产物级分而得到200mg标题化合物;液相色谱质谱(=LC-MS):M+H 243(99%ELSD)。
实施例5:
4-(4′-氟-联苯-4-基)-哌嗪-1-磺酰胺
A)将1-(4-溴苯基)-哌嗪(250mg)、4-氟苯硼酸(254mg)、碳酸钾(372mg,干燥并研磨的)和乙酸钯-(II)(23.3mg)溶于20ml乙二醇二甲醚/水/乙醇(7∶3∶2v/v/v)的混合物并将该体系倾入微波反应器(Emrys Optimizer_)。在150℃下的5分钟反应时间后,向目前的澄清溶液中加入甲基叔丁基醚,用水和盐水依次洗涤有机相并用Na2SO4干燥。在减压下大量蒸发有机相。生产另一等批量并将两批粗产物一起溶于二氯甲烷。用稀释的苏打溶液洗涤有机相、用Na2SO4干燥、在减压下大量蒸发溶剂并通过快速色谱法纯化残余物(固定相:硅胶;流动相:二氯甲烷/甲醇9∶1v/v)而得到0.6g的1-(4’-氟-联苯-4-基)-哌嗪。
1H-NMR(500MHz),δ[ppm]:7,62 d(1H),7,61 d(1H),7,22 t(2H),7,49 d(2H),6,98 d(2H),3,17 m(4H),3,09 m(4H)。
B)将如上述获得的1-(4’-氟-联苯-4-基)-哌嗪(0.6g)和磺酰胺(0.3g)溶于30ml二噁烷且然后在回流冷却下加热3小时。在冷却至室温后,在减压下大量除去溶剂。使所得固体从甲基叔丁基醚中结晶而得到0.4g标题化合物,m.p.243.5-245.2℃。
还可以按照上述实施例中所述的方法或按照与其类似的方法制备下面表9中所列的通式I的化合物:
表9:其它通式I化合物
实施例序号 | Ar | 盐 | m.p. |
6 | 4-吡啶基 | HCl | 243℃ |
7 | 2-嘧啶基 | ||
8 | 2,3-二甲基苯基 | HCl | 202℃ |
9 | 4-氟苯基 | HCl | 125℃ |
10 | 3-氯苯基 | ||
11 | 2-甲基-5-氯苯基 | HCl | 190℃ |
12 | 3-三氟甲基-4-氯苯基 | HC1 | 180℃ |
13 | 3-氰基-2-吡啶基 | HCl | 190℃ |
14 | 3-氯-5-三氟-2-吡啶基 | HCl | 159℃ |
15 | 4-乙酰基苯基 | HCl | 156℃ |
16 | 3,5-二氯-4-吡啶基 | HCl | 206℃ |
17 | 2-三氟甲基-4-喹啉基 | HCl | 191℃ |
18 | 4-三氟-2-嘧啶基 | HCl | 156℃ |
19 | 5-三氟-2-吡啶基 | HCl | 169℃ |
20 | 2-硝基-4-三氟苯基 | HCl | 134℃ |
21 | 2-氟-4-甲基磺酰基苯基 | HCl | 184℃ |
22 | 苯并[1,3]间二氧杂环戊烯-5-基甲基 | HCl | 233℃ |
23 | 1-萘基 | HCl | 193℃ |
24 | 4-乙氧基苯基 | ||
25 | 5,6-二甲基-噻吩并[2,3-D]-4-嘧啶基 | ||
26 | 2-甲基-巯基苯基 | ||
27 | 2-(叔丁基)-5-(三氟甲基)吡唑并[1,5-A]-7-嘧啶基 | ||
28 | 苄氧基苯基 | ||
29 | 5-氰基-6-甲基-2-烟酸乙酯 | ||
30 | 3,5-二氯苯基 | HCl | 185℃ |
31 | 3,4-二氯苯基 | HCl | 176℃ |
32 | 2,4-二氟苯基 | HCl | 165℃ |
33 | 4-三氟苯基 | HCl | 159℃ |
实施例I:
含有N-氨磺酰-N’-苯基哌嗪盐酸盐的胶囊:
生产每粒胶囊具有下列组成的胶囊:
N-氨磺酰-N’-苯基哌嗪盐酸盐 70mg
玉米淀粉 60mg
乳糖 250mg
乙酸乙酯(=EA) 适量
使用EA将活性物质、玉米淀粉和乳糖加工成均匀糊状混合物。研磨该糊状物并将所得颗粒放在合适的托盘上且在45℃下干燥以除去溶剂。使干燥的颗粒通过压碎机并在混合器中与下列其它助剂混合:
滑石 5mg
硬脂酸镁 5mg
玉米淀粉 10mg
且然后将其倾入400mg胶囊(=胶囊号0)。
Claims (39)
1.通式I的化合物及其生理上相容的酸加成盐在制备用于预防或治疗哺乳动物和人肥胖的药物中的用途,其中通式I化合物的结构式如下:
其中:
Ar为单环或双环C6-10-芳基,
其环碳原子非必需地被氮、氧和/或硫置换1-3次;和/或
其C6-10-芳基环系非必需地含有3-5个双键;和/或
其C6-10-芳基环系非必需地被1、2或3个取代基取代,所述的取代基可以相同或不同且可以选自下列基团组成的组:卤素、羧基、羟基、羟基氨基甲酰基、三氟甲基、氰基、硝基、吡咯烷基、C1-4-烷基、C1-4-烷氧基、C0-4-烷氧基苯基、C1-4-烷硫基、C2-4-烷酰基、C1-4-烷氧羰基、C1-4-烷基磺酰基;和与此C6-10-芳基环系的两个相邻碳原子键接且通过C1-2-亚烷基桥连的两个氧原子;或
其C6-10-芳基环系被一个或两个取代基取代,所述的取代基可以相同或不同且可以选自下列基团组成的组:卤素、羧基、羟基、羟基氨基甲酰基、三氟甲基、氰基、硝基、C1-4-烷基、C1-4-烷氧基、C1-4-烷硫基、C2-4-烷酰基、C1-4-烷氧羰基、C1-4-烷基磺酰基;与此C6-10-芳基环系的两个相邻碳原子键接且通过C1-2-亚烷基桥连的两个氧原子;或
其C6-10-芳基环系被下列基团取代:噻吩基、萘基、吡啶基;苯基或苄基,所述的苯基或苄基各自非必需地在苯基环上被1、2或3个取代基取代,所述的取代基可以相同或不同且可以选自卤素、三氟甲基、氰基、C1-6-烷基、C1-4-烷氧基或C1-4-烷基磺酰基。
2.权利要求1所述的通式I的化合物及其生理上相容的酸加成盐的用途,其中:
Ar为非必需地被1、2或3个取代基取代的苯基,所述的取代基可以相同或不同且可以选自下列基团组成的组:卤素、羧基、羟基、羟基氨基甲酰基、三氟甲基、氰基、硝基、C1-4-烷基、C1-4-烷氧基、C0-4-烷氧基苯基、C1-4-烷硫基、C2-4-烷酰基、C1-4-烷氧羰基、C1-4-烷基磺酰基和与相邻碳原子键接的、通过C1-2-亚烷基桥连的两个氧原子;或
为被苯基或苄基取代的苯基,所述的苯基或苄基取代基各自非必需地在苯基环上被一个或两个取代基取代,所述的取代基可以相同或不同且可以选自卤素、三氟甲基、C1-4-烷基和C1-4-烷氧基;或
为:萘基;吡啶基;嘧啶基;吡嗪基;哒嗪基;三嗪基;喹啉基;异喹啉基;1,2,3,4-四氢异喹啉基;吲哚基;异二氢氮茚基;噻吩并[3,2-d]嘧啶基或吡唑并[1,5-a]嘧啶基,它们各自非必需地被一个或两个取代基取代,所述的取代基可以相同或不同且可以选自卤素、羟基氨基甲酰基、三氟甲基、氰基、硝基、吡咯烷基、C1-4-烷基、C1-4-烷氧基和C1-4-烷氧羰基组成的组。
3.权利要求1或2所述的通式I的化合物及其生理上相容的酸加成盐的用途,其中:
Ar为非必需地被一个或两个取代基取代的苯基,所述的取代基可以相同或不同且可以选自下列基团组成的组:卤素、羟基、羟基氨基甲酰基、三氟甲基、氰基、硝基、C1-4-烷基、C1-4-烷氧基、C2-4-烷酰基、C1-4-烷氧羰基、C1-4-烷基磺酰基和与相邻碳原子键接的、通过C1-2-亚烷基桥连的两个氧原子;或
为:吡啶基;嘧啶基;萘基;喹啉基;异喹啉基;1,2,3,4-四氢异喹啉基;吲哚基或异二氢氮茚基,它们各自非必需地被一个或两个取代基取代,所述的取代基可以相同或不同且可以选自卤素、羟基氨基甲酰基、三氟甲基、氰基、硝基、C1-4-烷基、C1-4-烷氧基和C1-4-氧基羰基组成的组。
4.权利要求1-3之任一项所述的通式I的化合物及其生理上相容的酸加成盐的用途,其中:
Ar为被一个或两个取代基取代的苯基,所述的取代基可以相同或不同且可以选自下列基团组成的组:卤素、羟基、三氟甲基、氰基、硝基、C1-4-烷基、C1-4-烷氧基、C2-4-烷酰基、C1-4-烷基磺酰基和与相邻碳原子键接的、通过C1-2-亚烷基桥连的两个氧原子;或
为:吡啶基;嘧啶基或喹啉基;它们各自非必需地被一个或两个取代基取代,所述的取代基可以相同或不同且可以选自卤素、三氟甲基、氰基、硝基、C1-4-烷基和C1-4-烷氧基组成的组。
5.权利要求1所述的通式I的化合物及其生理上相容的酸加成盐在制备用于预防或治疗哺乳动物和人代谢综合征和/或X综合征的药物中的用途。
6.权利要求5所述的通式I的化合物的用途,其中所述的代谢综合征和/或X综合征包括选自下列的疾患或疾病:高血压,特别是高动脉压;胰岛素抗性,特别是II型糖尿病;葡萄糖耐受不良;异常脂蛋白血症,特别是与降低的HDL-胆固醇一起发生的伴随异常脂蛋白血症的高甘油三酯血症;和高尿酸血症。
7.权利要求1所述的通式I的化合物及其生理上相容的酸加成盐在制备用于预防或治疗哺乳动物和人心血管疾病的药物中的用途。
8.权利要求7所述的通式I的化合物的用途,其中所述的心血管疾病包括冠心病、脑血管疾病和外周闭塞性动脉病。
9.权利要求1所述的通式I的化合物及其生理上相容的酸加成盐在制备用于预防或治疗与肥胖无关的糖尿病病症或疾病的药物中的用途。
10.权利要求1所述的通式I的化合物及其生理上相容的酸加成盐在制备用于预防或治疗癫痫的药物中的用途。
11.用作哺乳动物和人的药物的通式Ia的化合物及其生理上相容的酸加成盐:
其中:
Ar1为非必需地被1、2或3个取代基取代的苯基,所述的取代基可以相同或不同且可以选自下列基团组成的组:卤素、羧基、羟基、羟基氨基甲酰基、三氟甲基、氰基、硝基、C1-4-烷基、C1-4-烷氧基、C0-4-烷氧基苯基、C1-4-烷硫基、C2-4-烷酰基、C1-4-烷氧羰基、C1-4-烷基磺酰基和与相邻碳原子键接的通过C1-2-亚烷基桥连的两个氧原子;或
为被苯基或苄基取代的苯基,所述的苯基或苄基取代基各自非必需地在苯基环上被一个或两个取代基取代,所述的取代基可以相同或不同且可以选自卤素、C1-4-烷基、C1-4-烷氧基和三氟甲基;或
为:萘基;吡啶基;2-嘧啶基;5-嘧啶基;吡嗪基;哒嗪基;三嗪基;喹啉基;异喹啉基;1,2,3,4-四氢异喹啉基;吲哚基;异二氢氮茚基;噻吩并[3,2-d]嘧啶基或吡唑并[1,5-a]嘧啶基,它们各自非必需地被一个或两个取代基取代,所述的取代基可以相同或不同且可以选自卤素、羟基氨基甲酰基、三氟甲基、氰基、硝基、吡咯烷基、C1-4-烷基、C1-4-烷氧基和C1-4-烷氧羰基组成的组。
12.权利要求11的用作哺乳动物和人的药物的通式Ia的化合物及其生理上相容的酸加成盐,其中:
Ar1为非必需地被一个或两个取代基取代的苯基,所述的取代基可以相同或不同且可以选自下列基团组成的组:卤素、羟基、羟基氨基甲酰基、三氟甲基、氰基、硝基、C1-4-烷基、C1-4-烷氧基、C2-4-烷酰基、C1-4-烷氧羰基、C1-4-烷基磺酰基和与相邻碳原子键接的通过C1-2-亚烷基桥连的两个氧原子;或
为:萘基;吡啶基;2-嘧啶基;5-嘧啶基;喹啉基;异喹啉基;1,2,3,4-四氢异喹啉基;吲哚基或异二氢氮茚基,它们各自非必需地被一个或两个取代基取代,所述的取代基可以相同或不同且可以选自卤素、羟基氨基甲酰基、三氟甲基、氰基、硝基、C1-4-烷基、C1-4-烷氧基和C1-4-烷氧羰基组成的组。
13.权利要求11或12的用作哺乳动物和人的药物的通式Ia的化合物及其生理上相容的酸加成盐,其中:
Ar1为非必需地被一个或两个取代基取代的苯基,所述的取代基可以相同或不同且可以选自卤素、羟基、三氟甲基、氰基、硝基、C1-4-烷基、C1-4-烷氧基、C2-4-烷酰基、C1-4-烷基磺酰基和与相邻碳原子键接的通过C1-2-亚烷基桥连的两个氧原子;或
为:吡啶基;2-嘧啶基;5-嘧啶基或喹啉基;它们各自非必需地被一个或两个取代基取代,所述的取代基可以相同或不同且可以选自卤素、三氟甲基、氰基、硝基、C1-4-烷基和C1-4-烷氧基组成的组。
14.权利要求11-13之任一项的用作哺乳动物和人的药物的通式Ia的化合物及其生理上相容的酸加成盐,其中:
Ar1为被一个或两个取代基取代的苯基,所述的取代基可以相同或不同且可以选自卤素、三氟甲基、C1-4-烷基、C1-4-烷氧基和C1-4-烷基磺酰基组成的组;或
为:吡啶基;2-嘧啶基;5-嘧啶基或喹啉基;它们各自非必需地被一个或两个取代基取代,所述的取代基可以相同或不同且可以选自卤素、三氟甲基、氰基、C1-4-烷基和C1-4-烷氧基组成的组。
15.权利要求11-14之任一项的用作哺乳动物和人的药物的通式Ia的化合物及其生理上相容的酸加成盐,其选自下列化合物组成的组:
4-苯基-哌嗪-1-磺酰胺;
4-(2-氯-苯基)-哌嗪-1-磺酰胺;和
4-(2-甲氧基-苯基)-哌嗪-1-磺酰胺。
16.药物组合物,包括药物有效量的权利要求11的通式Ia的化合物或其生理上相容的酸加成盐和常规的药物上可接受的助剂和/或载体。
17.通式Ib的化合物及其生理上相容的酸加成盐:
其中:
Ar2为被下列基团取代一次的苯基:氟、3-氯、4-氯、溴、碘、羟基、C1-4-烷基、C2-4-烷氧基、C0-4-烷氧基苯基、C1-4-烷硫基、C2-4-烷酰基、C1-4-氧基羰基、羟基氨基甲酰基、羧基、三氟甲基、氰基、硝基、与相邻碳原子键接的通过C1-2-亚烷基桥连的两个氧原子和C1-4-烷基磺酰基;或
为被两个或三个取代基取代的苯基,所述的取代基可以相同或不同且可以选自卤素、羧基、羟基、羟基氨基甲酰基、三氟甲基、氰基、硝基、C1-4-烷基、C1-4-烷氧基、C1-4-烷硫基、C2-4-烷酰基、C1-4-氧基羰基、C1-4-烷基磺酰基和与相邻碳原子键接的通过C1-2-亚烷基桥连的两个氧原子组成的组;或
为被苯基或苄基取代一次的苯基,所述的苯基或苄基取代基各自非必需地在苯基环上被一个或两个取代基取代,所述的取代基可以相同或不同且可以选自卤素、三氟甲基、C1-4-烷基和C1-4-烷氧基;或
为:萘基;吡啶基;2-嘧啶基;5-嘧啶基;吡嗪基;哒嗪基;三嗪基;喹啉基;异喹啉基;吲哚基;异二氢氮茚基;噻吩并[3,2-d]嘧啶基或吡唑并[1,5-a]嘧啶基,它们各自非必需地被一个或两个取代基取代,所述的取代基可以相同或不同且可以选自卤素、羟基氨基甲酰基、三氟甲基、氰基、硝基、吡咯烷基、C1-4-烷基、C1-4-烷氧基和C1-4-氧基羰基组成的组;或
为被一个或两个取代基取代的1,2,3,4-四氢异喹啉基,所述的取代基可以相同或不同且可以选自卤素、羟基氨基甲酰基、三氟甲基、氰基、硝基、吡咯烷基、C1-4-烷基、C1-4-烷氧基和C1-4-氧基羰基组成的组。
18.权利要求17的通式Ib的化合物及其生理上相容的酸加成盐,其中:
Ar2为被下列基团取代一次的苯基:氟、3-氯、4-氯、溴、碘、羟基、三氟甲基、氰基、硝基、C1-4-烷基、C2-4-烷氧基、C2-4-烷酰基、C1-4-烷基磺酰基和与相邻碳原子键接的通过C1-2-亚烷基桥连的两个氧原子;或
为被两个取代基取代的苯基,所述的取代基可以相同或不同且可以选自卤素、羟基、三氟甲基、氰基、硝基、C1-4-烷基、C1-4-烷氧基、C2-4-烷酰基、C1-4-烷基磺酰基和与相邻碳原子键接的通过C1-2-亚烷基桥连的两个氧原子组成的组;或
为:吡啶基;2-嘧啶基;5-嘧啶基;萘基;喹啉基;异喹啉基;吲哚基或异二氢氮茚基,它们各自非必需地被一个或两个取代基取代,所述的取代基可以相同或不同且可以选自卤素、三氟甲基、氰基、硝基、C1-4-烷基和C1-4-烷氧基组成的组;或
为被一个或两个取代基取代的1,2,3,4-四氢异喹啉基,所述的取代基可以相同或不同且可以选自卤素、三氟甲基、氰基、硝基、C1-4-烷基和C1-4-烷氧基组成的组。
19.权利要求17或18的通式Ib的化合物及其生理上相容的酸加成盐,其中:
Ar2为被下列基团取代一次的苯基:氟、3-氯、4-氯、溴、碘、羟基、三氟甲基、氰基、硝基、C1-4-烷基、C2-4-烷氧基、C2-4-烷酰基、C1-4-烷基磺酰基和与相邻碳原子键接的通过C1-2-亚烷基桥连的两个氧原子;或
为被两个取代基取代的苯基,所述的取代基可以相同或不同且可以选自卤素、羟基、三氟甲基、氰基、硝基、C1-4-烷基、C1-4-烷氧基、C2-4-烷酰基、C1-4-烷基磺酰基和与相邻碳原子键接的通过C1-2-亚烷基桥连的两个氧原子组成的组;或
为:吡啶基;2-嘧啶基;5-嘧啶基;喹啉基;它们各自非必需地被一个或两个取代基取代,所述的取代基可以相同或不同且可以选自卤素、三氟甲基、氰基、硝基、C1-4-烷基和C1-4-烷氧基组成的组。
20.权利要求17-19之任一项的通式Ib的化合物及其生理上相容的酸加成盐,其中:
Ar2为被下列基团取代一次的苯基:氟、3-氯、4-氯、溴、碘、三氟甲基、C1-4-烷基、C2-4-烷氧基和C1-4-烷基磺酰基;或
为被两个取代基取代的苯基,所述的取代基可以相同或不同且可以选自卤素、三氟甲基、C1-4-烷基、C1-4-烷氧基和C1-4-烷基磺酰基组成的组;或
为:吡啶基;2-嘧啶基;5-嘧啶基或喹啉基;它们各自非必需地被一个或两个取代基取代,所述的取代基可以相同或不同且可以选自卤素、三氟甲基、氰基、C1-4-烷基和C1-4-烷氧基组成的组。
21.权利要求17-20之任一项的通式Ib的化合物及其生理上相容的酸加成盐,选自下列化合物组成的组:
4-吡啶-4-基-哌嗪-1-磺酰胺;
4-嘧啶-2-基-哌嗪-1-磺酰胺;
4-(4-氟-苯基)-哌嗪-1-磺酰胺;
4-(4-氯-3-三氟甲基-苯基)-哌嗪-1-磺酰胺;和
4-(3-氯-5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酰胺。
22.治疗或预防哺乳动物和人的肥胖、代谢综合征和/或X综合征和/或心血管疾病和/或与肥胖无关的糖尿病病症或疾病和/或癫痫的方法,包括对需要的受治疗者给予治疗有效量的权利要求1的通式I的化合物或其生理上相容的酸加成盐。
23.通式I的化合物及其生理上相容的酸加成盐的生产方法,其中通式I化合物的结构式如下:
其中:
Ar为单环或双环C6-10-芳基,
其环碳原子非必需地被氮、氧和/或硫置换1-3次;和/或
其C6-10-芳基环系非必需地含有3-5个双键;和/或
其C6-10-芳基环系非必需地被1、2或3个取代基取代,所述的取代基可以相同或不同且可以选自下列基团组成的组:卤素、羧基、羟基、羟基氨基甲酰基、三氟甲基、氰基、硝基、吡咯烷基、C1-4-烷基、C1-4-烷氧基、C0-4-烷氧基苯基、C1-4-烷硫基、C2-4-烷酰基、C1-4-烷氧羰基、C1-4-烷基磺酰基;和与此C6-10-芳基环系的两个相邻碳原子键接并通过C1-2-亚烷基桥连的两个氧原子;或
其C6-10-芳基环系被一个或两个取代基取代,所述的取代基可以相同或不同且可以选自下列基团组成的组:卤素、羧基、羟基、羟基氨基甲酰基、三氟甲基、氰基、硝基、C1-4-烷基、C1-4-烷氧基、C1-4-烷硫基、C2-4-烷酰基、C1-4-烷氧羰基、C1-4-烷基磺酰基;与此C6-10-芳基环系的两个相邻碳原子键接并通过C1-2-亚烷基桥连的两个氧原子;或
其C6-10-芳基环系被下列基团取代:噻吩基、萘基、吡啶基;苯基或苄基,所述的苯基或苄基各自非必需地在苯基环上被1、2或3个取代基取代,所述的取代基可以相同或不同且可以选自卤素、三氟甲基、氰基、C1-6-烷基、C1-4-烷氧基或C1-4-烷基磺酰基:
该方法通过下列步骤进行:
a)使通式II的芳基哌嗪化合物与磺酰胺反应,
其中Ar具有上述含义;或
b)使通式II的芳基哌嗪与通式III的被叔丁氧羰基(=boc)保护的4-二甲氨基吡啶(=DMAP)试剂反应,
且随后在酸性条件下从获得的中间体化合物上裂解去除boc基团;或
c)使通式II的芳基哌嗪与通式IV的优选被boc基团保护的氨磺酰氯反应,
且随后在酸性条件下从获得的中间体产物上裂解去除boc基团,
且如果需要,将所得的通式I的游离碱转化成其生理上相容的盐或将通式I化合物的盐转化成通式I的游离碱。
24.药物组合物,包括药物有效量的下列各成分:
a)至少一种通式I的化合物作为第一活性剂;和
b)至少一种选自双胍类、fibric acids、HMGCoA还原酶抑制剂、和胰岛素敏化物的活性剂作为第二活性剂。
25.权利要求24的药物组合物,进一步包括常规的药物上可接受的助剂和/或载体。
26.权利要求24的药物组合物,适合于口服给药。
27.权利要求24的药物组合物,其中所述的活性剂以一种或多种剂型存在,所述的剂型选自片剂、包衣片、胶囊、糖浆剂、酏剂或混悬剂组成的组。
28.权利要求24的药物组合物,其中通式I的化合物选自:4-苯基-哌嗪-1-磺酰胺;4-(2-氯-苯基)-哌嗪-1-磺酰胺;4-(2-甲氧基-苯基)-哌嗪-1-磺酰胺;4-吡啶-4-基-哌嗪-1-磺酰胺;4-嘧啶-2-基-哌嗪-1-磺酰胺;4-(4-氟-苯基)-哌嗪-1-磺酰胺;4-(4-氯-3-三氟甲基-苯基)-哌嗪-1-磺酰胺和/或4-(3-氯-5-三氟甲基-吡啶-2-基)-哌嗪-1-磺酰胺。
29.权利要求28的药物组合物,其中通式I的化合物为4-苯基-哌嗪-1-磺酰胺。
30.权利要求24的药物组合物,其中所述的第二活性剂b)为双胍或其任何生理上相容的盐、溶剂合物、前体药物或酯。
31.权利要求30的药物组合物,其中所述的第二活性剂b)为二甲双胍。
32.权利要求24的药物组合物,其中所述的第二活性剂b)为fibric acid或其任何生理上相容的盐、溶剂合物、前体药物或酯。
33.权利要求32的药物组合物,其中所述的第二活性剂b)为非诺贝特。
34.权利要求24的药物组合物,其中所述的第二活性剂b)为HMGCoA还原酶抑制剂或其任何生理上相容的盐、溶剂合物、前体药物或酯。
35.权利要求34的药物组合物,其中所述的第二活性剂b)为辛伐他汀。
36.权利要求24的药物组合物,其中所述的第二活性剂b)为胰岛素敏化物或其任何生理上相容的盐、溶剂合物、前体药物或酯。
37.权利要求36的药物组合物,其中所述的第二活性剂b)为罗西格列酮。
38.治疗或预防哺乳动物和人的肥胖、代谢综合征和/或X综合征和/或心血管疾病和/或与肥胖无关的糖尿病病症或疾病和/或癫痫的方法,包括对需要的受治疗者给予有效量的作为第一活性剂的至少一种通式I的化合物与作为第二活性剂的至少一种活性剂的组合,其中所述的作为第二活性剂的至少一种活性剂选自双胍类、fibric acids、HMGCoA还原酶抑制剂和胰岛素敏化物组成的组。
39.药盒,包括在单一包装中的不同独立容器内的组合用药物剂型,包括:
i)在一个独立容器内的包括至少一种通式I的化合物的药物剂型;和
ii)在另一个独立容器内的包括至少一种活性剂的药物剂型,所述的至少一种活性剂选自双胍类、fibric acids、HMGCoA还原酶抑制剂和胰岛素敏化物组成的组。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US57223604P | 2004-05-19 | 2004-05-19 | |
EP04102210 | 2004-05-19 | ||
US60/572,236 | 2004-05-19 | ||
EP04102210.4 | 2004-05-19 | ||
PCT/EP2005/052281 WO2005110413A2 (en) | 2004-05-19 | 2005-05-18 | Medicaments containing n-sulfamoyl-n'-arylpiperazines for the prophylaxis or treatment of obesity and related conditions |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1997370A true CN1997370A (zh) | 2007-07-11 |
CN1997370B CN1997370B (zh) | 2011-06-01 |
Family
ID=34969508
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2005800159695A Expired - Fee Related CN1997370B (zh) | 2004-05-19 | 2005-05-18 | N-氨磺酰-n'-芳基哌嗪类化合物在制备用于预防或治疗肥胖和相关疾病的药物中的用途 |
Country Status (11)
Country | Link |
---|---|
EP (1) | EP1750712A2 (zh) |
JP (1) | JP2007538054A (zh) |
CN (1) | CN1997370B (zh) |
AU (1) | AU2005244450B2 (zh) |
BR (1) | BRPI0510137A (zh) |
CA (1) | CA2567166A1 (zh) |
IL (1) | IL178903A0 (zh) |
MX (1) | MXPA06013299A (zh) |
NO (1) | NO20065835L (zh) |
RU (1) | RU2395503C2 (zh) |
WO (1) | WO2005110413A2 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106559992A (zh) * | 2014-06-17 | 2017-04-05 | Ucb生物制药私人有限公司 | 作为激酶抑制剂的稠合的二环杂芳族衍生物 |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1866298A2 (en) | 2005-03-31 | 2007-12-19 | Takeda San Diego, Inc. | Hydroxysteroid dehydrogenase inhibitors |
ES2349160T3 (es) * | 2006-01-23 | 2010-12-28 | F. Hoffmann-La Roche Ag | Derivados de la ciclohexil sulfonamida con actividad frente a los receptores h3. |
WO2008089521A1 (en) | 2007-01-25 | 2008-07-31 | Verva Pharmaceuticals Ltd | Insulin sensitisers and methods of treatment |
EP2502921B1 (en) * | 2009-04-22 | 2015-05-20 | Axikin Pharmaceuticals, Inc. | Arylsulfonamide CCR3 antagonists |
RU2445963C2 (ru) * | 2010-07-09 | 2012-03-27 | Открытое акционерное общество "Химико-фармацевтический комбинат "АКРИХИН" (ОАО "АКРИХИН") | Фармацевтическая противодиабетическая композиция |
ME03564B (me) | 2013-03-13 | 2020-07-20 | Forma Therapeutics Inc | DERIVATI 2-HIDROKSI-1-{4-[(4-FENILFENIL)KARBONIL]PIPERAZIN-1-IL}ETAN-1-ONA l SRODNA JEDINJENJA KAO INHIBITORI SINTAZE MASNIH KISELINA (FASN) ZA LEČENJE KANCERA |
TWI767148B (zh) | 2018-10-10 | 2022-06-11 | 美商弗瑪治療公司 | 抑制脂肪酸合成酶(fasn) |
CN113382633A (zh) | 2018-10-29 | 2021-09-10 | 福马治疗股份有限公司 | (4-(2-氟-4-(1-甲基-1H-苯并[d]咪唑-5-基)苯甲酰基)哌嗪-1-基)(1-羟基环丙基)甲酮的固体形式 |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2748125A (en) | 1954-04-26 | 1956-05-29 | American Cyanamid Co | 1-substituted-4-sulfamylpiperazine and method of preparing the same |
FR2030116A1 (en) | 1969-01-02 | 1970-10-30 | Sandoz Sa | Herbicide compositions and prepn |
US3709677A (en) * | 1969-06-25 | 1973-01-09 | Sandoz Ag | N-substituted sulfamoyl compounds useful as herbicides |
DE4025387A1 (de) | 1990-08-10 | 1992-02-13 | Hoechst Ag | Substituierte pyrimidin-derivate, verfahren zu ihrer herstellung und ihre verwendung als reagenzien |
AU683620B2 (en) * | 1992-09-28 | 1997-11-20 | Pfizer Inc. | Substituted pyrimidines for control of diabetic complications |
JPH09504508A (ja) * | 1993-09-28 | 1997-05-06 | チバ−ガイギー アクチエンゲゼルシャフト | 殺虫剤及び殺ダニ剤としてのアクリル化スルホンアミド |
JP3563411B2 (ja) * | 1997-01-23 | 2004-09-08 | エフ・ホフマン−ラ ロシュ アーゲー | スルファミド−メタロプロテアーゼ阻害剤 |
DE10035227A1 (de) | 2000-07-20 | 2002-01-31 | Solvay Pharm Gmbh | Verfahren zum Auffinden von Verbindungen, welche zur Behandlung und/oder Prophylaxe von Fettleibigkeit geeignet sind |
EA007272B1 (ru) * | 2002-03-13 | 2006-08-25 | Янссен Фармацевтика Н. В. | Новые ингибиторы гистондеацетилазы |
EP1513516B1 (en) * | 2002-06-06 | 2008-12-03 | Boehringer Ingelheim Pharmaceuticals Inc. | SUBSTITUTED 3-AMINO-THIENO(2,3-b) PYRIDINE-2-CARBOXYLIC ACID AMIDE COMPOUNDS AND PROCESSES FOR PREPARING AND THEIR USES |
WO2005005382A2 (en) * | 2003-07-02 | 2005-01-20 | Cytokinetics, Inc. | Compounds, compositions and methods |
MX2007002240A (es) | 2004-08-28 | 2007-04-20 | Astrazeneca Ab | Derivados de pirimidinosulfonamida como moduladores del receptor quimiocina. |
-
2005
- 2005-05-18 BR BRPI0510137-9A patent/BRPI0510137A/pt not_active IP Right Cessation
- 2005-05-18 CN CN2005800159695A patent/CN1997370B/zh not_active Expired - Fee Related
- 2005-05-18 JP JP2007517257A patent/JP2007538054A/ja active Pending
- 2005-05-18 RU RU2006144812/04A patent/RU2395503C2/ru not_active IP Right Cessation
- 2005-05-18 AU AU2005244450A patent/AU2005244450B2/en not_active Ceased
- 2005-05-18 EP EP05749492A patent/EP1750712A2/en not_active Withdrawn
- 2005-05-18 CA CA002567166A patent/CA2567166A1/en not_active Abandoned
- 2005-05-18 MX MXPA06013299A patent/MXPA06013299A/es not_active Application Discontinuation
- 2005-05-18 WO PCT/EP2005/052281 patent/WO2005110413A2/en active Application Filing
-
2006
- 2006-10-26 IL IL178903A patent/IL178903A0/en unknown
- 2006-12-18 NO NO20065835A patent/NO20065835L/no not_active Application Discontinuation
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106559992A (zh) * | 2014-06-17 | 2017-04-05 | Ucb生物制药私人有限公司 | 作为激酶抑制剂的稠合的二环杂芳族衍生物 |
Also Published As
Publication number | Publication date |
---|---|
CN1997370B (zh) | 2011-06-01 |
RU2006144812A (ru) | 2008-06-27 |
MXPA06013299A (es) | 2007-02-02 |
BRPI0510137A (pt) | 2007-10-02 |
RU2395503C2 (ru) | 2010-07-27 |
JP2007538054A (ja) | 2007-12-27 |
AU2005244450B2 (en) | 2010-08-19 |
CA2567166A1 (en) | 2005-11-24 |
NO20065835L (no) | 2007-02-16 |
IL178903A0 (en) | 2007-03-08 |
WO2005110413A2 (en) | 2005-11-24 |
EP1750712A2 (en) | 2007-02-14 |
WO2005110413A3 (en) | 2006-07-13 |
AU2005244450A1 (en) | 2005-11-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1997370B (zh) | N-氨磺酰-n'-芳基哌嗪类化合物在制备用于预防或治疗肥胖和相关疾病的药物中的用途 | |
CN101326166A (zh) | 预防或治疗肥胖和相关病症的新的n-氨磺酰基-哌啶酰胺 | |
US8362063B2 (en) | Arylsulfonamide based matrix metalloprotease inhibitors | |
CN1972679B (zh) | 包括nep-抑制剂、内源性内皮缩血管肽产生系统抑制剂和at1受体拮抗剂的药物组合物 | |
US7772225B2 (en) | N-sulfamoyl-piperidineamides for the treatment or inhibition of obesity and related conditions | |
US7547708B2 (en) | N-sulfamoyl-N′-benzopyranpiperidine compounds and uses thereof | |
CN100453117C (zh) | 包含选择性ⅰ1咪唑啉受体激动剂和血管紧张素ⅱ受体阻断剂的药物组合物 | |
EP1951725B1 (en) | N-sulfamoyl-n -benzopyranpiperidines as inhbitors of carbonic anhydrases | |
US20050261292A1 (en) | Pharmaceutical composition containing N-sulfamoyl-N'-arylpiperazines for the treatment or inhibition of obesity and related conditions | |
WO2009153261A1 (en) | HYDROXYPHENYL-SUBSTITUTED PYRROLO[2,3d]PYRIMIDINE DERIVATIVES, PROCESSES AND INTERMEDIATE PRODUCTS FOR THEIR PREPARATION AND MEDICAMENTS CONTAINING THESE COMPOUNDS | |
US20100152285A1 (en) | Flavononol Renin Inhibitor Compounds and Methods of Use Thereof | |
KR20070022322A (ko) | N설파모일n′아릴피페라진을 함유한 비만 및 관련된상태의 예방 또는 치료용 의약 | |
WO2007051007A2 (en) | Combination of antihypertensives with cholesterol-lowering agent | |
CN101065135A (zh) | 涉及心力衰竭的组合物和方法 | |
WO2011134019A1 (en) | Novel biphenyl sartans |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1101274 Country of ref document: HK |
|
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20110601 Termination date: 20120518 |
|
REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1101274 Country of ref document: HK |