BG63694B1 - Инхибитори на аполипопротеин-в синтеза - Google Patents

Инхибитори на аполипопротеин-в синтеза Download PDF

Info

Publication number: BG63694B1
Authority: BG; Bulgaria
Prior art keywords: alkyl; amino; formula; substituted; cis
Prior art date: 1994-10-27

Application number

BG101402A

Other languages

Bulgarian (bg)

English (en)

Other versions

BG101402A (en

Inventor

Jan Heeres

Leo Backx

Robert HENDRICKX

DER EYCKEN Luc VAN

CHAFFOY DE COURCELLES Didier DE

Original Assignee

Janssen Pharmaceutica N.V.

Priority date (The priority date 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 date listed.)

1994-10-27

Filing date

1997-04-10

Publication date

2002-09-30

1995-05-31 Priority claimed from US08/455,304 external-priority patent/US5521186A/en

1997-04-10 Application filed by Janssen Pharmaceutica N.V. filed Critical Janssen Pharmaceutica N.V.

1997-10-31 Publication of BG101402A publication Critical patent/BG101402A/xx

2002-09-30 Publication of BG63694B1 publication Critical patent/BG63694B1/bg

Links

230000015572 biosynthetic process Effects 0.000 title description 7
238000003786 synthesis reaction Methods 0.000 title description 4
239000003112 inhibitor Substances 0.000 title description 3
150000001875 compounds Chemical class 0.000 claims abstract description 74
239000001257 hydrogen Substances 0.000 claims abstract description 23
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 23
125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 12
125000003118 aryl group Chemical group 0.000 claims abstract description 11
239000003814 drug Substances 0.000 claims abstract description 11
238000000034 method Methods 0.000 claims abstract description 10
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
125000000623 heterocyclic group Chemical group 0.000 claims abstract description 7
125000004043 oxo group Chemical group O=* 0.000 claims abstract description 4
125000004356 hydroxy functional group Chemical group O* 0.000 claims abstract 10
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract 4
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract 2
125000000217 alkyl group Chemical group 0.000 claims description 53
-1 4-methyl-4H-1,2,4triazol-3-yl Chemical group 0.000 claims description 40
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 25
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Chemical group C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 19
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
125000001424 substituent group Chemical group 0.000 claims description 18
239000002253 acid Substances 0.000 claims description 17
125000003545 alkoxy group Chemical group 0.000 claims description 16
150000003839 salts Chemical class 0.000 claims description 16
125000004953 trihalomethyl group Chemical group 0.000 claims description 16
125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 14
229910052736 halogen Inorganic materials 0.000 claims description 12
150000002367 halogens Chemical class 0.000 claims description 12
208000031226 Hyperlipidaemia Diseases 0.000 claims description 11
238000002360 preparation method Methods 0.000 claims description 11
125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims description 10
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
239000002585 base Substances 0.000 claims description 8
229910052799 carbon Inorganic materials 0.000 claims description 8
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 8
238000006243 chemical reaction Methods 0.000 claims description 7
150000003852 triazoles Chemical group 0.000 claims description 7
FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 6
239000003937 drug carrier Substances 0.000 claims description 5
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
239000013543 active substance Substances 0.000 claims description 4
150000003536 tetrazoles Chemical group 0.000 claims description 4
ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical group C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 3
CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 3
125000004432 carbon atom Chemical group C* 0.000 claims description 3
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical group C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 3
125000004193 piperazinyl group Chemical group 0.000 claims description 3
229910052717 sulfur Inorganic materials 0.000 claims description 3
125000004434 sulfur atom Chemical group 0.000 claims description 3
VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical group C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 claims description 3
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
125000000524 functional group Chemical group 0.000 claims description 2
150000002460 imidazoles Chemical group 0.000 claims description 2
231100000252 nontoxic Toxicity 0.000 claims description 2
230000003000 nontoxic effect Effects 0.000 claims description 2
150000002916 oxazoles Chemical group 0.000 claims description 2
125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 2
150000003230 pyrimidines Chemical group 0.000 claims description 2
150000004867 thiadiazoles Chemical group 0.000 claims description 2
USWINTIHFQKJTR-UHFFFAOYSA-N 3-hydroxynaphthalene-2,7-disulfonic acid Chemical class C1=C(S(O)(=O)=O)C=C2C=C(S(O)(=O)=O)C(O)=CC2=C1 USWINTIHFQKJTR-UHFFFAOYSA-N 0.000 claims 1
125000001309 chloro group Chemical group Cl* 0.000 claims 1
230000008878 coupling Effects 0.000 claims 1
238000010168 coupling process Methods 0.000 claims 1
238000005859 coupling reaction Methods 0.000 claims 1
125000001153 fluoro group Chemical group F* 0.000 claims 1
239000012458 free base Substances 0.000 claims 1
230000009466 transformation Effects 0.000 claims 1
239000000203 mixture Substances 0.000 abstract description 39
239000003524 antilipemic agent Substances 0.000 abstract description 2
125000004209 (C1-C8) alkyl group Chemical group 0.000 abstract 2
125000001475 halogen functional group Chemical group 0.000 abstract 2
239000000460 chlorine Substances 0.000 description 80
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 43
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 40
239000000543 intermediate Substances 0.000 description 37
125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 37
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
239000000243 solution Substances 0.000 description 25
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
125000002887 hydroxy group Chemical group [H]O* 0.000 description 16
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
101710095342 Apolipoprotein B Proteins 0.000 description 14
102100040202 Apolipoprotein B-100 Human genes 0.000 description 14
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 12
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 11
239000002904 solvent Substances 0.000 description 11
108010007622 LDL Lipoproteins Proteins 0.000 description 10
102000007330 LDL Lipoproteins Human genes 0.000 description 10
239000003480 eluent Substances 0.000 description 9
150000003254 radicals Chemical class 0.000 description 9
239000003826 tablet Substances 0.000 description 9
JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 9
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
150000001204 N-oxides Chemical class 0.000 description 7
239000002552 dosage form Substances 0.000 description 7
230000002401 inhibitory effect Effects 0.000 description 7
CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 7
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 7
SYBYTAAJFKOIEJ-UHFFFAOYSA-N 3-Methylbutan-2-one Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 description 6
201000001320 Atherosclerosis Diseases 0.000 description 6
ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 6
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
108010062497 VLDL Lipoproteins Proteins 0.000 description 6
230000000694 effects Effects 0.000 description 6
238000009472 formulation Methods 0.000 description 6
150000002431 hydrogen Chemical class 0.000 description 6
230000005764 inhibitory process Effects 0.000 description 6
239000007788 liquid Substances 0.000 description 6
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
239000002775 capsule Substances 0.000 description 5
229910052801 chlorine Inorganic materials 0.000 description 5
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 5
229940079593 drug Drugs 0.000 description 5
235000011187 glycerol Nutrition 0.000 description 5
229910052757 nitrogen Inorganic materials 0.000 description 5
239000012044 organic layer Substances 0.000 description 5
238000010898 silica gel chromatography Methods 0.000 description 5
229910000029 sodium carbonate Inorganic materials 0.000 description 5
238000003756 stirring Methods 0.000 description 5
125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 4
YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
101150102415 Apob gene Proteins 0.000 description 4
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
208000035150 Hypercholesterolemia Diseases 0.000 description 4
LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 4
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
239000004480 active ingredient Substances 0.000 description 4
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
150000002148 esters Chemical class 0.000 description 4
LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 4
239000002244 precipitate Substances 0.000 description 4
239000000047 product Substances 0.000 description 4
HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 4
239000000725 suspension Substances 0.000 description 4
125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 3
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
102000018616 Apolipoproteins B Human genes 0.000 description 3
108010027006 Apolipoproteins B Proteins 0.000 description 3
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
229920002472 Starch Polymers 0.000 description 3
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
125000005997 bromomethyl group Chemical group 0.000 description 3
238000004440 column chromatography Methods 0.000 description 3
125000000753 cycloalkyl group Chemical group 0.000 description 3
239000011737 fluorine Substances 0.000 description 3
229910052731 fluorine Inorganic materials 0.000 description 3
238000010438 heat treatment Methods 0.000 description 3
150000002576 ketones Chemical class 0.000 description 3
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 3
125000004433 nitrogen atom Chemical group N* 0.000 description 3
229910000027 potassium carbonate Inorganic materials 0.000 description 3
239000000741 silica gel Substances 0.000 description 3
229910002027 silica gel Inorganic materials 0.000 description 3
235000019698 starch Nutrition 0.000 description 3
239000007858 starting material Substances 0.000 description 3
HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 2
IOCYQQQCJYMWDT-UHFFFAOYSA-N (3-ethyl-2-methoxyquinolin-6-yl)-(4-methoxycyclohexyl)methanone Chemical compound C=1C=C2N=C(OC)C(CC)=CC2=CC=1C(=O)C1CCC(OC)CC1 IOCYQQQCJYMWDT-UHFFFAOYSA-N 0.000 description 2
NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 description 2
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 2
ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 2
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 2
ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 2
238000007126 N-alkylation reaction Methods 0.000 description 2
ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
206010045261 Type IIa hyperlipidaemia Diseases 0.000 description 2
150000007513 acids Chemical class 0.000 description 2
239000000654 additive Substances 0.000 description 2
229910001854 alkali hydroxide Inorganic materials 0.000 description 2
229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
150000008041 alkali metal carbonates Chemical class 0.000 description 2
239000000010 aprotic solvent Substances 0.000 description 2
239000003613 bile acid Substances 0.000 description 2
230000037396 body weight Effects 0.000 description 2
238000009835 boiling Methods 0.000 description 2
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
229910052794 bromium Inorganic materials 0.000 description 2
239000000969 carrier Substances 0.000 description 2
239000003153 chemical reaction reagent Substances 0.000 description 2
235000012000 cholesterol Nutrition 0.000 description 2
239000006185 dispersion Substances 0.000 description 2
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
229940125753 fibrate Drugs 0.000 description 2
238000004128 high performance liquid chromatography Methods 0.000 description 2
XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
238000002347 injection Methods 0.000 description 2
239000007924 injection Substances 0.000 description 2
230000003993 interaction Effects 0.000 description 2
JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
239000008101 lactose Substances 0.000 description 2
AFVPRVLDAPXRCX-UHFFFAOYSA-N methyl naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)OC)=CC=C21 AFVPRVLDAPXRCX-UHFFFAOYSA-N 0.000 description 2
235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 2
239000002480 mineral oil Substances 0.000 description 2
235000010446 mineral oil Nutrition 0.000 description 2
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
JPYAHQUNMYHNDY-MHECFPHRSA-N n-[(1r,2s)-2-(3,4-dimethoxyphenyl)-7-methoxy-6-propan-2-yloxy-1,2,3,4-tetrahydronaphthalen-1-yl]-n-methylformamide Chemical compound C1=C(OC)C(OC)=CC=C1[C@H]1[C@@H](N(C)C=O)C2=CC(OC)=C(OC(C)C)C=C2CC1 JPYAHQUNMYHNDY-MHECFPHRSA-N 0.000 description 2
229960003512 nicotinic acid Drugs 0.000 description 2
235000001968 nicotinic acid Nutrition 0.000 description 2
239000011664 nicotinic acid Substances 0.000 description 2
150000002978 peroxides Chemical class 0.000 description 2
XCRBXWCUXJNEFX-UHFFFAOYSA-N peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 description 2
230000000144 pharmacologic effect Effects 0.000 description 2
239000006187 pill Substances 0.000 description 2
239000001267 polyvinylpyrrolidone Substances 0.000 description 2
229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
XXQBEVHPUKOQEO-UHFFFAOYSA-N potassium superoxide Chemical compound [K+].[K+].[O-][O-] XXQBEVHPUKOQEO-UHFFFAOYSA-N 0.000 description 2
239000000843 powder Substances 0.000 description 2
235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 2
QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
229960003415 propylparaben Drugs 0.000 description 2
239000011541 reaction mixture Substances 0.000 description 2
239000012312 sodium hydride Substances 0.000 description 2
229910000104 sodium hydride Inorganic materials 0.000 description 2
235000019333 sodium laurylsulphate Nutrition 0.000 description 2
239000007787 solid Substances 0.000 description 2
239000012453 solvate Substances 0.000 description 2
239000008107 starch Substances 0.000 description 2
230000001225 therapeutic effect Effects 0.000 description 2
239000008215 water for injection Substances 0.000 description 2
YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 1
YGTVRIJNXGNYDR-UHFFFAOYSA-N (4-methylphenyl)sulfonyloxy 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OOS(=O)(=O)C1=CC=C(C)C=C1 YGTVRIJNXGNYDR-UHFFFAOYSA-N 0.000 description 1
DEVSOMFAQLZNKR-RJRFIUFISA-N (z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-n'-pyrazin-2-ylprop-2-enehydrazide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C2=NN(\C=C/C(=O)NNC=3N=CC=NC=3)C=N2)=C1 DEVSOMFAQLZNKR-RJRFIUFISA-N 0.000 description 1
125000004277 1,3-dioxalan-2-yl group Chemical group [H]C1([H])OC([H])(*)OC1([H])[H] 0.000 description 1
150000000186 1,3-dioxalanes Chemical class 0.000 description 1
UGOUTHXWBJTASV-UHFFFAOYSA-N 1-(4-fluorophenyl)-2-[(2-methyl-1,2,4-triazol-3-yl)sulfanyl]ethanone Chemical compound CN1N=CN=C1SCC(=O)C1=CC=C(F)C=C1 UGOUTHXWBJTASV-UHFFFAOYSA-N 0.000 description 1
MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical class CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 1
FLAYZKKEOIAALB-UHFFFAOYSA-N 2-bromo-1-(4-chlorophenyl)ethanone Chemical compound ClC1=CC=C(C(=O)CBr)C=C1 FLAYZKKEOIAALB-UHFFFAOYSA-N 0.000 description 1
PGEMUXYWIMXUMT-UHFFFAOYSA-N 2-butan-2-yl-1h-1,2,4-triazol-3-one Chemical compound CCC(C)N1N=CNC1=O PGEMUXYWIMXUMT-UHFFFAOYSA-N 0.000 description 1
FFAQILVGBAELHN-UHFFFAOYSA-N 2-butan-2-yl-4-[4-[4-(4-hydroxyphenyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N(C(C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(O)=CC=2)C=C1 FFAQILVGBAELHN-UHFFFAOYSA-N 0.000 description 1
XIRBMNOJVJCHTR-UHFFFAOYSA-N 2-chloro-1-(2-fluorophenyl)ethanone Chemical compound FC1=CC=CC=C1C(=O)CCl XIRBMNOJVJCHTR-UHFFFAOYSA-N 0.000 description 1
PSCNKLHSBAUYBP-UHFFFAOYSA-N 2-methyl-1h-1,2,4-triazole-3-thione Chemical compound CN1N=CN=C1S PSCNKLHSBAUYBP-UHFFFAOYSA-N 0.000 description 1
MLRAJZNPKPVUDQ-UHFFFAOYSA-N 3-sulfanyl-1,2-dihydrotriazole Chemical compound SN1NNC=C1 MLRAJZNPKPVUDQ-UHFFFAOYSA-N 0.000 description 1
FQPZBLVAJJKCAM-UHFFFAOYSA-N 4-butan-2-yl-2-[4-[4-(4-hydroxyphenyl)piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N(C(C)CC)C=NN1C1=CC=C(N2CCN(CC2)C=2C=CC(O)=CC=2)C=C1 FQPZBLVAJJKCAM-UHFFFAOYSA-N 0.000 description 1
NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
102000009027 Albumins Human genes 0.000 description 1
108010088751 Albumins Proteins 0.000 description 1
208000007848 Alcoholism Diseases 0.000 description 1
239000005995 Aluminium silicate Substances 0.000 description 1
108010071619 Apolipoproteins Proteins 0.000 description 1
102000007592 Apolipoproteins Human genes 0.000 description 1
206010003211 Arteriosclerosis coronary artery Diseases 0.000 description 1
208000032841 Bulimia Diseases 0.000 description 1
206010006550 Bulimia nervosa Diseases 0.000 description 1
COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
ZJFYGIBBPDTLIG-UHFFFAOYSA-N C1(CCCC1)N1C=NNC1=O Chemical compound C1(CCCC1)N1C=NNC1=O ZJFYGIBBPDTLIG-UHFFFAOYSA-N 0.000 description 1
UHNRLQRZRNKOKU-UHFFFAOYSA-N CCN(CC1=NC2=C(N1)C1=CC=C(C=C1N=C2N)C1=NNC=C1)C(C)=O Chemical compound CCN(CC1=NC2=C(N1)C1=CC=C(C=C1N=C2N)C1=NNC=C1)C(C)=O UHNRLQRZRNKOKU-UHFFFAOYSA-N 0.000 description 1
BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
206010008635 Cholestasis Diseases 0.000 description 1
FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
239000001856 Ethyl cellulose Substances 0.000 description 1
206010059183 Familial hypertriglyceridaemia Diseases 0.000 description 1
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 1
208000000563 Hyperlipoproteinemia Type II Diseases 0.000 description 1
206010020850 Hyperthyroidism Diseases 0.000 description 1
208000026350 Inborn Genetic disease Diseases 0.000 description 1
108010028554 LDL Cholesterol Proteins 0.000 description 1
238000008214 LDL Cholesterol Methods 0.000 description 1
102100024640 Low-density lipoprotein receptor Human genes 0.000 description 1
241001465754 Metazoa Species 0.000 description 1
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
229920003091 Methocel™ Polymers 0.000 description 1
229920000168 Microcrystalline cellulose Polymers 0.000 description 1
FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
206010029164 Nephrotic syndrome Diseases 0.000 description 1
238000010934 O-alkylation reaction Methods 0.000 description 1
108090000854 Oxidoreductases Proteins 0.000 description 1
208000018262 Peripheral vascular disease Diseases 0.000 description 1
239000002202 Polyethylene glycol Substances 0.000 description 1
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
235000002357 Ribes grossularia Nutrition 0.000 description 1
244000171263 Ribes grossularia Species 0.000 description 1
240000007651 Rubus glaucus Species 0.000 description 1
235000011034 Rubus glaucus Nutrition 0.000 description 1
235000009122 Rubus idaeus Nutrition 0.000 description 1
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
MXZNUGFCDVAXLG-CHWSQXEVSA-N [(2S)-1-[(2R)-3-methyl-2-(pyridine-4-carbonylamino)butanoyl]pyrrolidin-2-yl]boronic acid Chemical compound CC(C)[C@@H](NC(=O)c1ccncc1)C(=O)N1CCC[C@@H]1B(O)O MXZNUGFCDVAXLG-CHWSQXEVSA-N 0.000 description 1
HHRFWSALGNYPHA-UHFFFAOYSA-N [N].C1CNCCN1 Chemical compound [N].C1CNCCN1 HHRFWSALGNYPHA-UHFFFAOYSA-N 0.000 description 1
238000010306 acid treatment Methods 0.000 description 1
208000037919 acquired disease Diseases 0.000 description 1
206010001584 alcohol abuse Diseases 0.000 description 1
208000025746 alcohol use disease Diseases 0.000 description 1
150000001298 alcohols Chemical class 0.000 description 1
229910052783 alkali metal Inorganic materials 0.000 description 1
150000008044 alkali metal hydroxides Chemical class 0.000 description 1
150000001340 alkali metals Chemical class 0.000 description 1
150000004974 alkaline earth metal peroxides Chemical class 0.000 description 1
125000003282 alkyl amino group Chemical group 0.000 description 1
230000029936 alkylation Effects 0.000 description 1
238000005804 alkylation reaction Methods 0.000 description 1
235000012211 aluminium silicate Nutrition 0.000 description 1
239000003098 androgen Substances 0.000 description 1
230000000843 anti-fungal effect Effects 0.000 description 1
125000004429 atom Chemical group 0.000 description 1
230000009286 beneficial effect Effects 0.000 description 1
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 1
239000011230 binding agent Substances 0.000 description 1
BFAKENXZKHGIGE-UHFFFAOYSA-N bis(2,3,5,6-tetrafluoro-4-iodophenyl)diazene Chemical compound FC1=C(C(=C(C(=C1F)I)F)F)N=NC1=C(C(=C(C(=C1F)F)I)F)F BFAKENXZKHGIGE-UHFFFAOYSA-N 0.000 description 1
150000001721 carbon Chemical group 0.000 description 1
230000001364 causal effect Effects 0.000 description 1
210000004027 cell Anatomy 0.000 description 1
238000005119 centrifugation Methods 0.000 description 1
230000002490 cerebral effect Effects 0.000 description 1
239000007810 chemical reaction solvent Substances 0.000 description 1
239000003795 chemical substances by application Substances 0.000 description 1
125000000068 chlorophenyl group Chemical group 0.000 description 1
230000007870 cholestasis Effects 0.000 description 1
231100000359 cholestasis Toxicity 0.000 description 1
238000004587 chromatography analysis Methods 0.000 description 1
208000020832 chronic kidney disease Diseases 0.000 description 1
208000022831 chronic renal failure syndrome Diseases 0.000 description 1
239000011248 coating agent Substances 0.000 description 1
238000000576 coating method Methods 0.000 description 1
239000008119 colloidal silica Substances 0.000 description 1
238000004040 coloring Methods 0.000 description 1
229940126208 compound 22 Drugs 0.000 description 1
238000001816 cooling Methods 0.000 description 1
208000029078 coronary artery disease Diseases 0.000 description 1
208000026758 coronary atherosclerosis Diseases 0.000 description 1
125000004122 cyclic group Chemical group 0.000 description 1
125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
230000003247 decreasing effect Effects 0.000 description 1
229940075894 denatured ethanol Drugs 0.000 description 1
206010012601 diabetes mellitus Diseases 0.000 description 1
108010037444 diisopropylglutathione ester Proteins 0.000 description 1
201000010099 disease Diseases 0.000 description 1
239000007884 disintegrant Substances 0.000 description 1
235000019325 ethyl cellulose Nutrition 0.000 description 1
229920001249 ethyl cellulose Polymers 0.000 description 1
238000002474 experimental method Methods 0.000 description 1
201000001386 familial hypercholesterolemia Diseases 0.000 description 1
239000007941 film coated tablet Substances 0.000 description 1
238000001914 filtration Methods 0.000 description 1
125000001207 fluorophenyl group Chemical group 0.000 description 1
230000002496 gastric effect Effects 0.000 description 1
239000007903 gelatin capsule Substances 0.000 description 1
208000016361 genetic disease Diseases 0.000 description 1
230000002068 genetic effect Effects 0.000 description 1
239000008103 glucose Substances 0.000 description 1
150000002334 glycols Chemical class 0.000 description 1
150000008282 halocarbons Chemical class 0.000 description 1
125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
150000004677 hydrates Chemical class 0.000 description 1
229930195733 hydrocarbon Natural products 0.000 description 1
150000002430 hydrocarbons Chemical class 0.000 description 1
239000008172 hydrogenated vegetable oil Substances 0.000 description 1
208000000522 hyperlipoproteinemia type IV Diseases 0.000 description 1
238000001114 immunoprecipitation Methods 0.000 description 1
239000012442 inert solvent Substances 0.000 description 1
239000004615 ingredient Substances 0.000 description 1
239000011630 iodine Substances 0.000 description 1
229910052740 iodine Inorganic materials 0.000 description 1
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
239000004310 lactic acid Substances 0.000 description 1
235000014655 lactic acid Nutrition 0.000 description 1
239000010410 layer Substances 0.000 description 1
238000004811 liquid chromatography Methods 0.000 description 1
210000005229 liver cell Anatomy 0.000 description 1
239000000314 lubricant Substances 0.000 description 1
235000019359 magnesium stearate Nutrition 0.000 description 1
238000004519 manufacturing process Methods 0.000 description 1
230000007246 mechanism Effects 0.000 description 1
125000005948 methanesulfonyloxy group Chemical group 0.000 description 1
229920000609 methyl cellulose Polymers 0.000 description 1
239000001923 methylcellulose Substances 0.000 description 1
235000010981 methylcellulose Nutrition 0.000 description 1
ZGEGCLOFRBLKSE-UHFFFAOYSA-N methylene hexane Natural products CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 1
235000019813 microcrystalline cellulose Nutrition 0.000 description 1
239000008108 microcrystalline cellulose Substances 0.000 description 1
229940016286 microcrystalline cellulose Drugs 0.000 description 1
150000007522 mineralic acids Chemical class 0.000 description 1
208000031225 myocardial ischemia Diseases 0.000 description 1
YGBMCLDVRUGXOV-UHFFFAOYSA-N n-[6-[6-chloro-5-[(4-fluorophenyl)sulfonylamino]pyridin-3-yl]-1,3-benzothiazol-2-yl]acetamide Chemical compound C1=C2SC(NC(=O)C)=NC2=CC=C1C(C=1)=CN=C(Cl)C=1NS(=O)(=O)C1=CC=C(F)C=C1 YGBMCLDVRUGXOV-UHFFFAOYSA-N 0.000 description 1
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
OPECTNGATDYLSS-UHFFFAOYSA-N naphthalene-2-sulfonyl chloride Chemical compound C1=CC=CC2=CC(S(=O)(=O)Cl)=CC=C21 OPECTNGATDYLSS-UHFFFAOYSA-N 0.000 description 1
239000012299 nitrogen atmosphere Substances 0.000 description 1
238000010899 nucleation Methods 0.000 description 1
125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
239000003921 oil Substances 0.000 description 1
235000019198 oils Nutrition 0.000 description 1
239000002674 ointment Substances 0.000 description 1
239000006186 oral dosage form Substances 0.000 description 1
150000007524 organic acids Chemical class 0.000 description 1
235000005985 organic acids Nutrition 0.000 description 1
150000001451 organic peroxides Chemical class 0.000 description 1
238000007254 oxidation reaction Methods 0.000 description 1
239000003961 penetration enhancing agent Substances 0.000 description 1
125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
150000004965 peroxy acids Chemical class 0.000 description 1
230000036470 plasma concentration Effects 0.000 description 1
229920001223 polyethylene glycol Polymers 0.000 description 1
239000011591 potassium Substances 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
230000002028 premature Effects 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
235000004252 protein component Nutrition 0.000 description 1
239000008213 purified water Substances 0.000 description 1
238000011002 quantification Methods 0.000 description 1
238000010992 reflux Methods 0.000 description 1
229920006395 saturated elastomer Polymers 0.000 description 1
229930195734 saturated hydrocarbon Natural products 0.000 description 1
230000028327 secretion Effects 0.000 description 1
238000010956 selective crystallization Methods 0.000 description 1
238000000926 separation method Methods 0.000 description 1
210000002966 serum Anatomy 0.000 description 1
229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
235000017557 sodium bicarbonate Nutrition 0.000 description 1
229910000033 sodium borohydride Inorganic materials 0.000 description 1
239000012279 sodium borohydride Substances 0.000 description 1
PFUVRDFDKPNGAV-UHFFFAOYSA-N sodium peroxide Chemical compound [Na+].[Na+].[O-][O-] PFUVRDFDKPNGAV-UHFFFAOYSA-N 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
SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical group [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 1
239000000600 sorbitol Substances 0.000 description 1
230000000707 stereoselective effect Effects 0.000 description 1
239000008223 sterile water Substances 0.000 description 1
238000007920 subcutaneous administration Methods 0.000 description 1
239000000126 substance Substances 0.000 description 1
235000000346 sugar Nutrition 0.000 description 1
150000008163 sugars Chemical class 0.000 description 1
239000000375 suspending agent Substances 0.000 description 1
208000011580 syndromic disease Diseases 0.000 description 1
239000006188 syrup Substances 0.000 description 1
235000020357 syrup Nutrition 0.000 description 1
230000009885 systemic effect Effects 0.000 description 1
150000003557 thiazoles Chemical class 0.000 description 1
230000002110 toxicologic effect Effects 0.000 description 1
231100000027 toxicology Toxicity 0.000 description 1
230000001131 transforming effect Effects 0.000 description 1
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
208000019553 vascular disease Diseases 0.000 description 1
239000000080 wetting agent Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- 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
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
General Health & Medical Sciences (AREA)
Veterinary Medicine (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Bioinformatics & Cheminformatics (AREA)
Pharmacology & Pharmacy (AREA)
Engineering & Computer Science (AREA)
Animal Behavior & Ethology (AREA)
Public Health (AREA)
Heart & Thoracic Surgery (AREA)
Cardiology (AREA)
Diabetes (AREA)
Hematology (AREA)
Obesity (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)
Steroid Compounds (AREA)
Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

BG101402A 1994-10-27 1997-04-10 Инхибитори на аполипопротеин-в синтеза BG63694B1 (bg)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
EP94203120		1994-10-27
US08/455,304 US5521186A (en)	1994-10-27	1995-05-31	Apolipoprotein-β synthesis inhibitors
PCT/EP1995/004111 WO1996013499A1 (fr)	1994-10-27	1995-10-19	Inhibiteurs de synthese d'apolipoproteines-b

Publications (2)

Publication Number	Publication Date
BG101402A BG101402A (en)	1997-10-31
BG63694B1 true BG63694B1 (bg)	2002-09-30

Family

ID=26136684

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
BG101402A BG63694B1 (bg)	1994-10-27	1997-04-10	Инхибитори на аполипопротеин-в синтеза

Country Status (30)

Country	Link
US (1)	US5929075A (fr)
EP (1)	EP0788496B1 (fr)
JP (1)	JP3025907B2 (fr)
KR (1)	KR100227231B1 (fr)
CN (1)	CN1068000C (fr)
AP (1)	AP779A (fr)
AT (1)	ATE198889T1 (fr)
AU (1)	AU697744C (fr)
BG (1)	BG63694B1 (fr)
BR (1)	BR9509436A (fr)
CA (1)	CA2203274C (fr)
CY (1)	CY2256B1 (fr)
CZ (1)	CZ286476B6 (fr)
DE (3)	DE122007000005I2 (fr)
DK (1)	DK0788496T3 (fr)
ES (1)	ES2155535T3 (fr)
FI (1)	FI119548B (fr)
GR (1)	GR3035519T3 (fr)
HR (1)	HRP950532B1 (fr)
HU (1)	HU219862B (fr)
IL (1)	IL115771A (fr)
LU (1)	LU91306I2 (fr)
NO (1)	NO311937B1 (fr)
NZ (1)	NZ295353A (fr)
OA (1)	OA10479A (fr)
PT (1)	PT788496E (fr)
RO (1)	RO118715B1 (fr)
SK (1)	SK281908B6 (fr)
TR (1)	TR199501295A2 (fr)
WO (1)	WO1996013499A1 (fr)

Families Citing this family (24)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
DE69804994D1 (de) *	1997-11-03	2002-05-23	Janssen Pharmaceutica Nv	Arzneimittel enthaltend lipidsenkende verbindungen
HUP0102052A3 (en) *	1998-04-27	2002-10-28	Janssen Pharmaceutica Nv	Pellets having a core coated with a lipid lowering agent and a polymer and process for their preparation
WO2000037463A1 (fr) *	1998-12-22	2000-06-29	Janssen Pharmaceutica N.V.	Composes s-oxide permettant d'abaisser le taux de lipides
DE19945982A1 (de)	1999-09-24	2001-03-29	Knoll Ag	Geschwindigkeitsbestimmte Partikel
US20050132022A1 (en) *	2003-12-12	2005-06-16	International Business Machines Corporation	Computer system with LAN-based I/O
JP4994043B2 (ja) *	2004-01-21	2012-08-08	エランコ・アニマル・ヘルス・アイルランド・リミテッド	ミトラタピデ経口用溶液
US7649002B2 (en)	2004-02-04	2010-01-19	Pfizer Inc	(3,5-dimethylpiperidin-1yl)(4-phenylpyrrolidin-3-yl)methanone derivatives as MCR4 agonists
US7262318B2 (en) *	2004-03-10	2007-08-28	Pfizer, Inc.	Substituted heteroaryl- and phenylsulfamoyl compounds
EP1737460A2 (fr) *	2004-04-09	2007-01-03	Janssen Pharmaceutica N.V.	Mode d'administration intermittent pour le traitement de l'obésité avec des inhibiteurs de mtp
US20050288340A1 (en) *	2004-06-29	2005-12-29	Pfizer Inc	Substituted heteroaryl- and phenylsulfamoyl compounds
PA8660701A1 (es)	2005-02-04	2006-09-22	Pfizer Prod Inc	Agonistas de pyy y sus usos
WO2006129193A2 (fr) *	2005-05-27	2006-12-07	Pfizer Products Inc.	Polytherapie pour le traitement de l'obesite ou le maintien du poids apres une perte ponderale
CA2617654A1 (fr) *	2005-08-04	2007-02-08	Pfizer Limited	Composes piperidinoyl-pyrrolidine et piperidinoyl-piperidine
US7741317B2 (en)	2005-10-21	2010-06-22	Bristol-Myers Squibb Company	LXR modulators
US7888376B2 (en)	2005-11-23	2011-02-15	Bristol-Myers Squibb Company	Heterocyclic CETP inhibitors
AU2007219236B2 (en) *	2006-02-23	2012-06-21	Pfizer Limited	Melanocortin type 4 receptor agonist piperidinoylpyrrolidines
US8383660B2 (en)	2006-03-10	2013-02-26	Pfizer Inc.	Dibenzyl amine compounds and derivatives
CN101583593A (zh)	2006-11-13	2009-11-18	辉瑞产品公司	二芳基、二吡啶基和芳基-吡啶基衍生物及其用途
ATE547394T1 (de)	2006-12-01	2012-03-15	Bristol Myers Squibb Co	N-((3-benzyl)-2,2-(bis-phenyl)-propan-1- aminderivate als cetp-hemmer für die behandlung von atherosklerose und herz-kreislauf- erkrankungen
MX2009012739A (es)	2007-05-25	2009-12-10	Janssen Pharmaceutica Nv	Sintesis mejorada del metansulfonato(ester) de (2s-cis)-2-(bromometil)-2-(4-clorofenil)-1,3-dioxolan-4-metanol.
JP5530438B2 (ja) *	2008-08-06	2014-06-25	ファイザー・リミテッド	Ｍｃ４作動薬としてのジアゼピンおよびジアゾカン化合物
AU2011254654B2 (en) *	2010-05-19	2016-01-07	Sandoz Ag	Process for the preparation of chiral triazolones
CR20200464A (es)	2018-03-08	2021-04-14	Incyte Corp	Compuestos diólicos de aminopirazina como inhibidores de pi3k-y
WO2020010003A1 (fr)	2018-07-02	2020-01-09	Incyte Corporation	DÉRIVÉS D'AMINOPYRAZINE UTILISÉS EN TANT QU'INHIBITEURS DE PI3K-γ

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US4218458A (en) *	1978-06-23	1980-08-19	Janssen Pharmaceutica, N.V.	Heterocyclic derivatives of (4-aryloxy-methyl-1,3-dioxolan-2-yl)methyl-1H-imidazoles and 1H-1,2,4-triazoles
US4313953A (en) *	1978-06-23	1982-02-02	Janssen Pharmaceutica, N.V.	Heterocyclic derivatives of (4-aryloxymethyl-1,3-dioxolan-2-yl)methyl-1H-imidazoles and 1H-1,2,4-triazoles
US4766125A (en) *	1981-06-23	1988-08-23	Janssen Pharmaceutica N.V.	N-aryl-piperazinealkanamides useful for protecting hearts from myocardial injury caused by ischaemia, anoxia or hypoxia
US4619931A (en) *	1983-02-28	1986-10-28	Janssen Pharmaceutica, N.V.	[[4-[4-(4-phenyl-1-piperazinyl)phenoxymethyl]-1,3-dioxolan-2-yl]methyl]-1H-imidazoles and 1H-1,2,4-triazoles
CA1292472C (fr) *	1985-12-03	1991-11-26	Alfonsus Guilielmus Knaeps	Derives des ({4-¬4-(4-phenyl-1-piperazinyl)-phenoxymethyl\|- 1,3-dioxolan-2-yl}methyl)-1h-imidazoles et 1h-1,2,4-triazoles
NZ223799A (en) *	1987-03-25	1989-12-21	Janssen Pharmaceutica Nv	Azolylmethyl-dioxolanylmethoxyphenyl-piperazinyl-phenyl-triazolones and antimicrobial compositions
CA1331757C (fr) *	1988-02-29	1994-08-30	Janssen Pharmaceutica Naamloze Vennootschap	5-lipoxygenase inhibant les 4-(4-phenyl-1-piperazinyl)phenols
AU6359594A (en) *	1993-03-04	1994-09-26	Cytoven International N.V.	Pharmaceutical tryptophan containing dipeptide compositions and methods of use thereof
US5521186A (en) *	1994-10-27	1996-05-28	Janssen Pharmaceutica N.V.	Apolipoprotein-β synthesis inhibitors

1995
- 1995-10-19 AU AU38680/95A patent/AU697744C/en not_active Ceased
- 1995-10-19 CA CA002203274A patent/CA2203274C/fr not_active Expired - Fee Related
- 1995-10-19 DE DE122007000005C patent/DE122007000005I2/de active Active
- 1995-10-19 DE DE1995619995 patent/DE122007000005I1/de active Pending
- 1995-10-19 JP JP8514288A patent/JP3025907B2/ja not_active Expired - Fee Related
- 1995-10-19 RO RO97-00812A patent/RO118715B1/ro unknown
- 1995-10-19 PT PT95937804T patent/PT788496E/pt unknown
- 1995-10-19 NZ NZ295353A patent/NZ295353A/en not_active IP Right Cessation
- 1995-10-19 AT AT95937804T patent/ATE198889T1/de active
- 1995-10-19 US US08/817,247 patent/US5929075A/en not_active Expired - Lifetime
- 1995-10-19 SK SK507-97A patent/SK281908B6/sk not_active IP Right Cessation
- 1995-10-19 DK DK95937804T patent/DK0788496T3/da active
- 1995-10-19 CZ CZ19971198A patent/CZ286476B6/cs not_active IP Right Cessation
- 1995-10-19 AP APAP/P/1997/000968A patent/AP779A/en active
- 1995-10-19 WO PCT/EP1995/004111 patent/WO1996013499A1/fr not_active Ceased
- 1995-10-19 BR BR9509436A patent/BR9509436A/pt not_active IP Right Cessation
- 1995-10-19 ES ES95937804T patent/ES2155535T3/es not_active Expired - Lifetime
- 1995-10-19 DE DE69519995T patent/DE69519995T2/de not_active Expired - Lifetime
- 1995-10-19 KR KR1019970702662A patent/KR100227231B1/ko not_active Expired - Fee Related
- 1995-10-19 EP EP95937804A patent/EP0788496B1/fr not_active Expired - Lifetime
- 1995-10-19 HU HU9701956A patent/HU219862B/hu not_active IP Right Cessation
- 1995-10-19 CN CN95195885A patent/CN1068000C/zh not_active Expired - Fee Related
- 1995-10-20 TR TR95/01295A patent/TR199501295A2/xx unknown
- 1995-10-26 IL IL11577195A patent/IL115771A/xx not_active IP Right Cessation
- 1995-10-27 HR HR950532A patent/HRP950532B1/xx not_active IP Right Cessation
1997
- 1997-04-10 BG BG101402A patent/BG63694B1/bg unknown
- 1997-04-24 NO NO19971895A patent/NO311937B1/no not_active IP Right Cessation
- 1997-04-25 FI FI971784A patent/FI119548B/fi not_active IP Right Cessation
- 1997-04-25 OA OA60997A patent/OA10479A/en unknown
2001
- 2001-03-05 GR GR20010400359T patent/GR3035519T3/el unknown
2002
- 2002-01-04 CY CY0200004A patent/CY2256B1/xx unknown
2007
- 2007-01-17 LU LU91306C patent/LU91306I2/fr unknown

Also Published As

Publication number	Publication date
SK281908B6 (sk)	2001-09-11
MX9703074A (es)	1997-07-31
IL115771A0 (en)	1996-01-19
OA10479A (en)	2002-04-09
DE122007000005I1 (de)	2007-04-26
CA2203274A1 (fr)	1996-05-09
NO311937B1 (no)	2002-02-18
AU3868095A (en)	1996-05-23
CN1161695A (zh)	1997-10-08
FI971784L (fi)	1997-04-25
US5929075A (en)	1999-07-27
TR199501295A2 (tr)	1996-06-21
CN1068000C (zh)	2001-07-04
HUT77360A (hu)	1998-03-30
HRP950532B1 (en)	2001-06-30
AU697744B2 (en)	1998-10-15
BR9509436A (pt)	1998-01-06
FI971784A0 (fi)	1997-04-25
AU697744C (en)	2002-08-22
ES2155535T3 (es)	2001-05-16
CA2203274C (fr)	2002-02-19
SK50797A3 (en)	1998-04-08
PT788496E (pt)	2001-07-31
NZ295353A (en)	1998-08-26
GR3035519T3 (en)	2001-06-29
NO971895L (no)	1997-04-24
NO971895D0 (no)	1997-04-24
JPH09511759A (ja)	1997-11-25
EP0788496A1 (fr)	1997-08-13
RO118715B1 (ro)	2003-09-30
KR100227231B1 (ko)	1999-11-01
AP9700968A0 (en)	1997-04-30
DE69519995D1 (en)	2001-03-01
FI119548B (fi)	2008-12-31
EP0788496B1 (fr)	2001-01-24
CZ286476B6 (en)	2000-04-12
AP779A (en)	1999-11-03
HU219862B (hu)	2001-08-28
CZ119897A3 (cs)	1998-03-18
HRP950532A2 (en)	1997-08-31
BG101402A (en)	1997-10-31
LU91306I2 (fr)	2007-03-19
CY2256B1 (en)	2003-07-04
ATE198889T1 (de)	2001-02-15
JP3025907B2 (ja)	2000-03-27
WO1996013499A1 (fr)	1996-05-09
DK0788496T3 (da)	2001-06-18
DE122007000005I2 (de)	2008-04-24
IL115771A (en)	2000-02-29
DE69519995T2 (de)	2001-08-23

Publication	Publication Date	Title
JP3025907B2 (ja)	2000-03-27	アポリポタンパク質−ｂ合成阻害剤
US5521186A (en)	1996-05-28	Apolipoprotein-β synthesis inhibitors
US6486187B1 (en)	2002-11-26	N-[4-(heteroarylmethyl)phenyl]-heteroarylamines
EP0871626B1 (fr)	2001-11-07	Triazolones utilises en tant qu'inhibiteurs de la synthese de l'apolipoproteine b
HK1012186B (en)	2002-02-22	Triazolones as apolipoprotein-b synthesis inhibitors
MXPA97003074A (en)	1997-12-01	Synthesis of apoliprotein synthesis