HRP950488A2 - Combination therapy for hypercholesterolemia - Google Patents
Combination therapy for hypercholesterolemia Download PDFInfo
- Publication number
- HRP950488A2 HRP950488A2 HR08/308,908A HRP950488A HRP950488A2 HR P950488 A2 HRP950488 A2 HR P950488A2 HR P950488 A HRP950488 A HR P950488A HR P950488 A2 HRP950488 A2 HR P950488A2
- Authority
- HR
- Croatia
- Prior art keywords
- compound
- inhibitor
- hmg
- alkyl
- coa reductase
- Prior art date
Links
- 208000035150 Hypercholesterolemia Diseases 0.000 title claims description 14
- 238000002648 combination therapy Methods 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims description 304
- -1 methylene, carbonyl Chemical group 0.000 claims description 138
- 238000000034 method Methods 0.000 claims description 95
- 239000002131 composite material Substances 0.000 claims description 74
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 62
- 239000003112 inhibitor Substances 0.000 claims description 51
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 43
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 42
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims description 42
- 239000001257 hydrogen Substances 0.000 claims description 39
- 229910052739 hydrogen Inorganic materials 0.000 claims description 39
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 30
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 30
- 125000003118 aryl group Chemical group 0.000 claims description 26
- 125000001153 fluoro group Chemical group F* 0.000 claims description 26
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 claims description 24
- 235000019000 fluorine Nutrition 0.000 claims description 24
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 23
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 23
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 23
- 229910052799 carbon Inorganic materials 0.000 claims description 22
- 229940122502 Cholesterol absorption inhibitor Drugs 0.000 claims description 21
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 19
- 241000124008 Mammalia Species 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 18
- 230000001906 cholesterol absorption Effects 0.000 claims description 17
- 150000002431 hydrogen Chemical class 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 102000003960 Ligases Human genes 0.000 claims description 16
- 108090000364 Ligases Proteins 0.000 claims description 16
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 16
- 125000004076 pyridyl group Chemical group 0.000 claims description 16
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 16
- 201000001320 Atherosclerosis Diseases 0.000 claims description 15
- CAHGCLMLTWQZNJ-RGEKOYMOSA-N lanosterol Chemical compound C([C@]12C)C[C@@H](O)C(C)(C)[C@H]1CCC1=C2CC[C@]2(C)[C@H]([C@H](CCC=C(C)C)C)CC[C@@]21C CAHGCLMLTWQZNJ-RGEKOYMOSA-N 0.000 claims description 15
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 claims description 14
- BQPPJGMMIYJVBR-UHFFFAOYSA-N (10S)-3c-Acetoxy-4.4.10r.13c.14t-pentamethyl-17c-((R)-1.5-dimethyl-hexen-(4)-yl)-(5tH)-Delta8-tetradecahydro-1H-cyclopenta[a]phenanthren Natural products CC12CCC(OC(C)=O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C BQPPJGMMIYJVBR-UHFFFAOYSA-N 0.000 claims description 13
- CHGIKSSZNBCNDW-UHFFFAOYSA-N (3beta,5alpha)-4,4-Dimethylcholesta-8,24-dien-3-ol Natural products CC12CCC(O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21 CHGIKSSZNBCNDW-UHFFFAOYSA-N 0.000 claims description 13
- XYTLYKGXLMKYMV-UHFFFAOYSA-N 14alpha-methylzymosterol Natural products CC12CCC(O)CC1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C XYTLYKGXLMKYMV-UHFFFAOYSA-N 0.000 claims description 13
- FPTJELQXIUUCEY-UHFFFAOYSA-N 3beta-Hydroxy-lanostan Natural products C1CC2C(C)(C)C(O)CCC2(C)C2C1C1(C)CCC(C(C)CCCC(C)C)C1(C)CC2 FPTJELQXIUUCEY-UHFFFAOYSA-N 0.000 claims description 13
- BKLIAINBCQPSOV-UHFFFAOYSA-N Gluanol Natural products CC(C)CC=CC(C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(O)C(C)(C)C4CC3 BKLIAINBCQPSOV-UHFFFAOYSA-N 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- LOPKHWOTGJIQLC-UHFFFAOYSA-N Lanosterol Natural products CC(CCC=C(C)C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(C)(O)C(C)(C)C4CC3 LOPKHWOTGJIQLC-UHFFFAOYSA-N 0.000 claims description 13
- CAHGCLMLTWQZNJ-UHFFFAOYSA-N Nerifoliol Natural products CC12CCC(O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C CAHGCLMLTWQZNJ-UHFFFAOYSA-N 0.000 claims description 13
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 13
- QBSJHOGDIUQWTH-UHFFFAOYSA-N dihydrolanosterol Natural products CC(C)CCCC(C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(C)(O)C(C)(C)C4CC3 QBSJHOGDIUQWTH-UHFFFAOYSA-N 0.000 claims description 13
- 239000003937 drug carrier Substances 0.000 claims description 13
- 229940058690 lanosterol Drugs 0.000 claims description 13
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 12
- 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 claims description 12
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 12
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 12
- 125000002541 furyl group Chemical group 0.000 claims description 12
- 150000004677 hydrates Chemical class 0.000 claims description 12
- 229960004844 lovastatin Drugs 0.000 claims description 12
- 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 claims description 12
- 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 claims description 12
- 125000000335 thiazolyl group Chemical group 0.000 claims description 12
- 125000004760 (C1-C4) alkylsulfonylamino group Chemical group 0.000 claims description 11
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 11
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 10
- 229940119502 Squalene cyclase inhibitor Drugs 0.000 claims description 10
- 229940123185 Squalene epoxidase inhibitor Drugs 0.000 claims description 10
- 125000003282 alkyl amino group Chemical group 0.000 claims description 10
- 125000002757 morpholinyl group Chemical group 0.000 claims description 10
- 125000003386 piperidinyl group Chemical group 0.000 claims description 10
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 10
- 239000004059 squalene synthase inhibitor Substances 0.000 claims description 10
- 125000001544 thienyl group Chemical group 0.000 claims description 10
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 9
- 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 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
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 9
- 229960002965 pravastatin Drugs 0.000 claims description 9
- 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 claims description 9
- 229960002855 simvastatin 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
- 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 claims description 8
- 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 claims description 8
- 229960005370 atorvastatin Drugs 0.000 claims description 8
- GPUADMRJQVPIAS-QCVDVZFFSA-M cerivastatin sodium Chemical compound [Na+].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 GPUADMRJQVPIAS-QCVDVZFFSA-M 0.000 claims description 8
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 8
- JXTPJDDICSTXJX-UHFFFAOYSA-N n-Triacontane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 229940032094 squalane Drugs 0.000 claims description 8
- 238000012546 transfer Methods 0.000 claims description 8
- 229940122680 Demethylase inhibitor Drugs 0.000 claims description 7
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- 125000001041 indolyl group Chemical group 0.000 claims description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 7
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 6
- 125000005862 (C1-C6)alkanoyl group Chemical group 0.000 claims description 6
- 125000004414 alkyl thio group Chemical group 0.000 claims description 6
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 125000002883 imidazolyl group Chemical group 0.000 claims description 6
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000002971 oxazolyl group Chemical group 0.000 claims description 6
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
- 125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 claims description 5
- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims description 4
- KGJWJWANAXKLRA-ISKFKSNPSA-N 2-[(3r,5r)-7-chloro-1-(2,2-dimethylpropyl)-5-naphthalen-1-yl-2-oxo-5h-4,1-benzothiazepin-3-yl]acetic acid Chemical compound S1[C@H](CC(O)=O)C(=O)N(CC(C)(C)C)C2=CC=C(Cl)C=C2[C@H]1C1=CC=CC2=CC=CC=C12 KGJWJWANAXKLRA-ISKFKSNPSA-N 0.000 claims description 4
- UWAPIZBSXPPGGH-ISKFKSNPSA-N 2-[(3r,5r)-7-chloro-1-(2,2-dimethylpropyl)-5-naphthalen-1-yl-2-oxo-5h-4,1-benzoxazepin-3-yl]acetic acid Chemical compound O1[C@H](CC(O)=O)C(=O)N(CC(C)(C)C)C2=CC=C(Cl)C=C2[C@H]1C1=CC=CC2=CC=CC=C12 UWAPIZBSXPPGGH-ISKFKSNPSA-N 0.000 claims description 4
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- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 claims description 4
- 125000001488 beta-D-galactosyl group Chemical group C1([C@H](O)[C@@H](O)[C@@H](O)[C@H](O1)CO)* 0.000 claims description 4
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 4
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- ANJHPXLVGHXNQU-PJMJKUDTSA-N (1R,2S,4S,5'R,6R,7S,8R,9S,12S,13S)-5',7,9,13-tetramethylspiro[5-oxapentacyclo[10.8.0.02,9.04,8.013,18]icosane-6,2'-oxane]-10-one Chemical compound O([C@@H]1[C@@H]([C@]2(C(=O)C[C@@H]3[C@@]4(C)CCCCC4CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 ANJHPXLVGHXNQU-PJMJKUDTSA-N 0.000 claims description 2
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- 229920000669 heparin Polymers 0.000 description 1
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- 125000005842 heteroatom Chemical group 0.000 description 1
- OHYHWAITIOIHFP-UHFFFAOYSA-L hexadecyl(trimethyl)azanium;sulfate Chemical compound [O-]S([O-])(=O)=O.CCCCCCCCCCCCCCCC[N+](C)(C)C.CCCCCCCCCCCCCCCC[N+](C)(C)C OHYHWAITIOIHFP-UHFFFAOYSA-L 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- LFKYBJLFJOOKAE-UHFFFAOYSA-N imidazol-2-ylidenemethanone Chemical compound O=C=C1N=CC=N1 LFKYBJLFJOOKAE-UHFFFAOYSA-N 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
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- 239000003999 initiator Substances 0.000 description 1
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- 238000006192 iodination reaction Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229960004125 ketoconazole Drugs 0.000 description 1
- 150000003951 lactams Chemical group 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- 210000001853 liver microsome Anatomy 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 238000011068 loading method Methods 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
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229950008446 melinamide Drugs 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- AJLFOPYRIVGYMJ-INTXDZFKSA-N mevastatin Chemical class 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 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 1
- 150000002921 oxetanes Chemical class 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000006213 oxygenation reaction Methods 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- IYDGMDWEHDFVQI-UHFFFAOYSA-N phosphoric acid;trioxotungsten Chemical compound O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.OP(O)(O)=O IYDGMDWEHDFVQI-UHFFFAOYSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 150000007949 saponins Chemical class 0.000 description 1
- 235000017709 saponins Nutrition 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol 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)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 description 1
- 229950005143 sitosterol Drugs 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- ILJOYZVVZZFIKA-UHFFFAOYSA-M sodium;1,1-dioxo-1,2-benzothiazol-3-olate;hydrate Chemical compound O.[Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 ILJOYZVVZZFIKA-UHFFFAOYSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical class 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 1
- 238000010186 staining Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000012622 synthetic inhibitor Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 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
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Substances [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- NJRXVEJTAYWCQJ-UHFFFAOYSA-N thiomalic acid Chemical compound OC(=O)CC(S)C(O)=O NJRXVEJTAYWCQJ-UHFFFAOYSA-N 0.000 description 1
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000020234 walnut Nutrition 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Urology & Nephrology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US30890894A | 1994-09-20 | 1994-09-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP950488A2 true HRP950488A2 (en) | 1997-08-31 |
Family
ID=23195885
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HR08/308,908A HRP950488A2 (en) | 1994-09-20 | 1995-09-20 | Combination therapy for hypercholesterolemia |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US5807834A (ja) |
| EP (1) | EP0782451A1 (ja) |
| JP (1) | JPH09511753A (ja) |
| AU (1) | AU2453295A (ja) |
| BR (1) | BR9504072A (ja) |
| CA (1) | CA2200436A1 (ja) |
| FI (1) | FI971151A (ja) |
| HR (1) | HRP950488A2 (ja) |
| IL (1) | IL115310A0 (ja) |
| MX (1) | MX9702175A (ja) |
| WO (1) | WO1996009827A2 (ja) |
| ZA (1) | ZA957879B (ja) |
Families Citing this family (33)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995018143A1 (en) * | 1993-12-28 | 1995-07-06 | Pfizer Inc. | Hypocholesterolemic agents |
| JPH10500702A (ja) * | 1994-12-23 | 1998-01-20 | ファイザー・インコーポレーテッド | スクアレンシンテターゼ阻害剤としてのナフチル−ベンゾキサゼピンまたは−ベンゾチアゼピン |
| WO1997048701A1 (en) * | 1996-06-20 | 1997-12-24 | Pfizer Inc. | 4,1-benzoxazepines or 4,1-benzothiazepines and their use as squalene synthetase inhibitors |
| US5965553A (en) * | 1996-06-20 | 1999-10-12 | Pfizer Inc. | Squalene synthetase inhibitors |
| KR20010012072A (ko) | 1997-04-21 | 2001-02-15 | 다케다 야쿠힌 고교 가부시키가이샤 | 4,1-벤족사제핀 및 이의 동족체, 및 소마토스타틴아고니스트로서의 이들의 용도 |
| US6180660B1 (en) * | 1997-08-26 | 2001-01-30 | Merck & Co., Inc. | Cholesterol-lowering therapy |
| US20030153541A1 (en) * | 1997-10-31 | 2003-08-14 | Robert Dudley | Novel anticholesterol compositions and method for using same |
| GB9923076D0 (en) * | 1999-09-29 | 1999-12-01 | Phytopharm Plc | Sapogenin derivatives and their use |
| NZ507355A (en) * | 1998-03-26 | 2004-02-27 | Phytopharm Plc | Membrane-bound receptors and their function; cognitive disfunction; treatments therefor; and compositions for use in such treatments |
| US6207664B1 (en) | 1998-11-25 | 2001-03-27 | Pfizer Inc. | Squalene synthetase inhibitor agents |
| GB9923078D0 (en) * | 1999-09-29 | 1999-12-01 | Phytopharm Plc | Sapogenin derivatives and their use |
| US6465011B2 (en) | 1999-05-29 | 2002-10-15 | Abbott Laboratories | Formulations comprising lipid-regulating agents |
| US6372251B2 (en) | 1999-06-11 | 2002-04-16 | Abbott Laboratories | Formulations comprising lipid-regulating agents |
| GB9923077D0 (en) * | 1999-09-29 | 1999-12-01 | Phytopharm Plc | Sapogenin derivatives and their use |
| GB0000228D0 (en) * | 2000-01-06 | 2000-03-01 | Phytopharm Plc | Fluoro substituted sapogenins and their use |
| US20030092745A1 (en) * | 2000-02-25 | 2003-05-15 | Pfizer Inc. | Combination therapy |
| GB0107822D0 (en) * | 2001-03-28 | 2001-05-23 | Phytopharm Plc | Sapogenin derivatives their synthesis and use methods based upon their use |
| CN102727501A (zh) * | 2002-03-27 | 2012-10-17 | 菲特法姆股份有限公司 | 皂角苷配基及其衍生物的用途 |
| US20050130948A1 (en) * | 2002-03-27 | 2005-06-16 | Daryl Rees | Therapeutic methods and uses of sapogenins and their derivatives |
| GB0215579D0 (en) | 2002-07-05 | 2002-08-14 | Astrazeneca Ab | Chemical compounds |
| AR040588A1 (es) * | 2002-07-26 | 2005-04-13 | Schering Corp | Formulacion farmaceutica que comprende un inhibidor de la absorcion del colesterol y un inhibidor de una hmg- co a reductasa |
| CA2503899C (en) * | 2002-10-28 | 2011-12-20 | Phytopharm Plc | Stereospecific reduction of sapogen-3-ones |
| US7235543B2 (en) | 2003-03-07 | 2007-06-26 | Schering Corporation | Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof |
| JP4589919B2 (ja) | 2003-03-07 | 2010-12-01 | シェーリング コーポレイション | 高コレステロール血症の処置のための、置換アゼチジノン化合物、これらの処方物および使用 |
| WO2005051298A2 (en) | 2003-11-19 | 2005-06-09 | Metabasis Therapeutics, Inc. | Novel phosphorus-containing thyromimetics |
| AU2004303742B2 (en) | 2003-12-23 | 2008-06-19 | Astrazeneca Ab | Diphenylazetidinone derivatives possessing cholesterol absorption inhibitory activity |
| JP4477474B2 (ja) * | 2004-11-15 | 2010-06-09 | 株式会社日立製作所 | 糞便懸濁ろ過用容器 |
| SA06270191B1 (ar) | 2005-06-22 | 2010-03-29 | استرازينيكا ايه بي | مشتقات من 2- أزيتيدينون جديدة باعتبارها مثبطات لامتصاص الكوليسترول لعلاج حالات فرط نسبة الدهون في الدم |
| AU2006304836A1 (en) | 2005-10-21 | 2007-04-26 | Novartis Ag | Combination of a renin-inhibitor and an anti-dyslipidemic agent and/or an antiobesity agent |
| AR060623A1 (es) | 2006-04-27 | 2008-07-02 | Astrazeneca Ab | Compuestos derivados de 2-azetidinona y un metodo de preparacion |
| US20100092479A1 (en) * | 2008-08-18 | 2010-04-15 | Combinatorx (Singapore) Pte. Ltd. | Compositions and methods for treatment of viral diseases |
| WO2010093601A1 (en) | 2009-02-10 | 2010-08-19 | Metabasis Therapeutics, Inc. | Novel sulfonic acid-containing thyromimetics, and methods for their use |
| US20130156720A1 (en) | 2010-08-27 | 2013-06-20 | Ironwood Pharmaceuticals, Inc. | Compositions and methods for treating or preventing metabolic syndrome and related diseases and disorders |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4602005A (en) * | 1982-05-17 | 1986-07-22 | Medical Research Foundation Of Oregon | Tigogenin cellobioside for treating hypercholesterolemia and atherosclerosis |
| US5063210A (en) * | 1989-04-20 | 1991-11-05 | Lange Iii Louis G | Use of sulfated polysaccharides to decrease cholesterol and fatty acid absorption |
| US5629295A (en) * | 1992-06-26 | 1997-05-13 | Pfizer Inc. | Steroidal glycosides for treating hypercholesterolemia |
| LT3300B (en) * | 1992-12-23 | 1995-06-26 | Schering Corp | Combination of a cholesterol biosynhtesis inhibitor and a beta- lactam cholesterol absorbtion inhibitor |
-
1995
- 1995-06-07 JP JP8511549A patent/JPH09511753A/ja active Pending
- 1995-06-07 CA CA002200436A patent/CA2200436A1/en not_active Abandoned
- 1995-06-07 WO PCT/IB1995/000447 patent/WO1996009827A2/en not_active Application Discontinuation
- 1995-06-07 AU AU24532/95A patent/AU2453295A/en not_active Abandoned
- 1995-06-07 US US08/793,802 patent/US5807834A/en not_active Expired - Fee Related
- 1995-06-07 MX MX9702175A patent/MX9702175A/es not_active Application Discontinuation
- 1995-06-07 EP EP95918721A patent/EP0782451A1/en not_active Withdrawn
- 1995-09-14 IL IL11531095A patent/IL115310A0/xx unknown
- 1995-09-19 BR BR9504072A patent/BR9504072A/pt not_active Application Discontinuation
- 1995-09-19 ZA ZA957879A patent/ZA957879B/xx unknown
- 1995-09-20 HR HR08/308,908A patent/HRP950488A2/hr not_active Application Discontinuation
-
1997
- 1997-03-19 FI FI971151A patent/FI971151A/fi not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| WO1996009827A3 (en) | 1996-05-23 |
| AU2453295A (en) | 1996-04-19 |
| CA2200436A1 (en) | 1996-04-04 |
| WO1996009827A2 (en) | 1996-04-04 |
| ZA957879B (en) | 1997-03-19 |
| BR9504072A (pt) | 1996-07-30 |
| US5807834A (en) | 1998-09-15 |
| MX9702175A (es) | 1997-06-28 |
| FI971151A0 (fi) | 1997-03-19 |
| FI971151A (fi) | 1997-03-19 |
| EP0782451A1 (en) | 1997-07-09 |
| IL115310A0 (en) | 1995-12-31 |
| JPH09511753A (ja) | 1997-11-25 |
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