MXPA04005555A

MXPA04005555A - Procedimientos de tratamiento con agonistas selectivos del receptor ep4.

Procedimientos de tratamiento con agonistas selectivos del receptor ep4.

Info

Publication number: MXPA04005555A
Authority: MX; Mexico
Prior art keywords: compound; oxopyrrolidin; mmol; alkyl; propyl
Prior art date: 2002-03-18

Application number

MXPA04005555A

Other languages

English (en)

Spanish (es)

Inventor

Roscoe Knight Delvin Jr

Original Assignee

Pfizer Prod Inc

Priority date

2002-03-18

Filing date

2003-03-06

Publication date

2005-05-16

2003-03-06 Application filed by Pfizer Prod Inc filed Critical Pfizer Prod Inc

2005-05-16 Publication of MXPA04005555A publication Critical patent/MXPA04005555A/es

Links

238000000034 method Methods 0.000 title claims abstract description 266
101150109738 Ptger4 gene Proteins 0.000 title claims abstract description 79
229940044601 receptor agonist Drugs 0.000 title claims abstract description 46
239000000018 receptor agonist Substances 0.000 title claims abstract description 46
238000011282 treatment Methods 0.000 title claims description 38
229940002612 prodrug Drugs 0.000 claims abstract description 75
239000000651 prodrug Substances 0.000 claims abstract description 75
239000000203 mixture Substances 0.000 claims abstract description 59
150000003839 salts Chemical class 0.000 claims abstract description 56
206010020772 Hypertension Diseases 0.000 claims abstract description 21
150000001875 compounds Chemical class 0.000 claims description 411
-1 carbonylamino, hydroxysulfonyl Chemical group 0.000 claims description 247
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 149
239000002253 acid Substances 0.000 claims description 144
125000000217 alkyl group Chemical group 0.000 claims description 58
QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 claims description 49
229910052757 nitrogen Chemical group 0.000 claims description 44
159000000000 sodium salts Chemical class 0.000 claims description 35
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 21
125000003545 alkoxy group Chemical group 0.000 claims description 21
125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 14
229910052799 carbon Inorganic materials 0.000 claims description 14
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 13
239000000556 agonist Substances 0.000 claims description 13
125000001153 fluoro group Chemical group F* 0.000 claims description 13
229920006395 saturated elastomer Polymers 0.000 claims description 13
102000008866 Prostaglandin E receptors Human genes 0.000 claims description 12
108010088540 Prostaglandin E receptors Proteins 0.000 claims description 12
125000001589 carboacyl group Chemical group 0.000 claims description 12
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
125000004093 cyano group Chemical group *C#N 0.000 claims description 10
125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 10
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 7
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
125000000753 cycloalkyl group Chemical group 0.000 claims description 7
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 6
239000011593 sulfur Chemical group 0.000 claims description 6
229910052717 sulfur Inorganic materials 0.000 claims description 6
125000006598 aminocarbonylamino group Chemical group 0.000 claims description 5
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
125000001309 chloro group Chemical group Cl* 0.000 claims description 5
239000001301 oxygen Substances 0.000 claims description 5
229910052760 oxygen Inorganic materials 0.000 claims description 5
125000003342 alkenyl group Chemical group 0.000 claims description 4
125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 4
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
150000003573 thiols Chemical class 0.000 claims description 4
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 3
125000001091 aminosulfinyl group Chemical group [H]N([H])S(*)=O 0.000 claims description 3
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 3
125000005843 halogen group Chemical group 0.000 claims description 3
125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 3
125000001544 thienyl group Chemical group 0.000 claims description 3
125000005871 1,3-benzodioxolyl group Chemical group 0.000 claims description 2
125000001624 naphthyl group Chemical group 0.000 claims description 2
125000002619 bicyclic group Chemical group 0.000 claims 3
125000005842 heteroatom Chemical group 0.000 claims 3
125000001424 substituent group Chemical group 0.000 claims 3
125000004356 hydroxy functional group Chemical group O* 0.000 claims 2
125000004453 alkoxycarbonyl group Chemical group 0.000 claims 1
125000005111 carboxyalkoxy group Chemical group 0.000 claims 1
125000002950 monocyclic group Chemical group 0.000 claims 1
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
125000004043 oxo group Chemical group O=* 0.000 claims 1
206010019663 Hepatic failure Diseases 0.000 abstract description 16
208000010412 Glaucoma Diseases 0.000 abstract description 13
206010030043 Ocular hypertension Diseases 0.000 abstract description 11
208000007903 liver failure Diseases 0.000 abstract description 5
231100000835 liver failure Toxicity 0.000 abstract description 5
210000003017 ductus arteriosus Anatomy 0.000 abstract 1
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 468
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 404
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 219
235000019439 ethyl acetate Nutrition 0.000 description 199
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 144
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 129
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 123
239000000243 solution Substances 0.000 description 122
101150041968 CDC13 gene Proteins 0.000 description 119
238000004587 chromatography analysis Methods 0.000 description 110
239000002609 medium Substances 0.000 description 106
238000000746 purification Methods 0.000 description 103
238000005481 NMR spectroscopy Methods 0.000 description 100
MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid group Chemical group C(CCCCCC)(=O)O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 89
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 81
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 74
238000002360 preparation method Methods 0.000 description 71
239000011541 reaction mixture Substances 0.000 description 70
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 68
150000004702 methyl esters Chemical class 0.000 description 62
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 58
238000005160 1H NMR spectroscopy Methods 0.000 description 50
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 48
235000002639 sodium chloride Nutrition 0.000 description 48
239000002904 solvent Substances 0.000 description 46
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 41
210000004027 cell Anatomy 0.000 description 39
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 37
238000006243 chemical reaction Methods 0.000 description 35
HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 35
239000007810 chemical reaction solvent Substances 0.000 description 31
125000004494 ethyl ester group Chemical group 0.000 description 31
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 30
241000700159 Rattus Species 0.000 description 30
239000005711 Benzoic acid Substances 0.000 description 29
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 29
150000001450 anions Chemical class 0.000 description 29
239000007864 aqueous solution Substances 0.000 description 29
238000012360 testing method Methods 0.000 description 27
229910000104 sodium hydride Inorganic materials 0.000 description 25
125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 24
238000010992 reflux Methods 0.000 description 24
235000010233 benzoic acid Nutrition 0.000 description 23
230000002829 reductive effect Effects 0.000 description 23
150000002148 esters Chemical class 0.000 description 22
239000003921 oil Substances 0.000 description 22
235000019198 oils Nutrition 0.000 description 22
238000007920 subcutaneous administration Methods 0.000 description 22
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
TVQGDYNRXLTQAP-UHFFFAOYSA-N ethyl heptanoate Chemical compound CCCCCCC(=O)OCC TVQGDYNRXLTQAP-UHFFFAOYSA-N 0.000 description 20
239000012267 brine Substances 0.000 description 19
230000000694 effects Effects 0.000 description 19
210000002216 heart Anatomy 0.000 description 19
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
VMKAFJQFKBASMU-QGZVFWFLSA-N (r)-2-methyl-cbs-oxazaborolidine Chemical compound C([C@@H]12)CCN1B(C)OC2(C=1C=CC=CC=1)C1=CC=CC=C1 VMKAFJQFKBASMU-QGZVFWFLSA-N 0.000 description 18
125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 18
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
229960002986 dinoprostone Drugs 0.000 description 18
102000005962 receptors Human genes 0.000 description 18
108020003175 receptors Proteins 0.000 description 18
239000003981 vehicle Substances 0.000 description 18
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 17
238000001727 in vivo Methods 0.000 description 17
238000001990 intravenous administration Methods 0.000 description 17
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
102100024448 Prostaglandin E2 receptor EP2 subtype Human genes 0.000 description 16
150000001298 alcohols Chemical class 0.000 description 16
239000003153 chemical reaction reagent Substances 0.000 description 15
XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 15
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 15
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
230000004872 arterial blood pressure Effects 0.000 description 14
239000003054 catalyst Substances 0.000 description 14
239000003814 drug Substances 0.000 description 14
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 14
NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 14
RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 14
125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 13
102100024450 Prostaglandin E2 receptor EP4 subtype Human genes 0.000 description 13
239000002552 dosage form Substances 0.000 description 13
229940079593 drug Drugs 0.000 description 13
125000006239 protecting group Chemical group 0.000 description 13
239000003039 volatile agent Substances 0.000 description 13
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
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VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 12
230000035699 permeability Effects 0.000 description 12
NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 12
XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 12
WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 12
FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 12
239000007858 starting material Substances 0.000 description 12
238000003786 synthesis reaction Methods 0.000 description 12
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 11
241000282693 Cercopithecidae Species 0.000 description 11
208000000857 Hepatic Insufficiency Diseases 0.000 description 11
PGBFYLVIMDQYMS-UHFFFAOYSA-N Methyl thiophene-2-carboxylate Chemical compound COC(=O)C1=CC=CS1 PGBFYLVIMDQYMS-UHFFFAOYSA-N 0.000 description 11
ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 11
239000002775 capsule Substances 0.000 description 11
TYGXITCKYVKKFC-SNVBAGLBSA-N methyl 5-[3-[(2r)-2-formyl-5-oxopyrrolidin-1-yl]propyl]thiophene-2-carboxylate Chemical compound S1C(C(=O)OC)=CC=C1CCCN1C(=O)CC[C@@H]1C=O TYGXITCKYVKKFC-SNVBAGLBSA-N 0.000 description 11
230000003647 oxidation Effects 0.000 description 11
238000007254 oxidation reaction Methods 0.000 description 11
239000012279 sodium borohydride Substances 0.000 description 11
229910000033 sodium borohydride Inorganic materials 0.000 description 11
229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 10
239000002168 alkylating agent Substances 0.000 description 10
229940100198 alkylating agent Drugs 0.000 description 10
230000015572 biosynthetic process Effects 0.000 description 10
230000036772 blood pressure Effects 0.000 description 10
239000002131 composite material Substances 0.000 description 10
239000003085 diluting agent Substances 0.000 description 10
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 10
QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical group N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 9
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239000003638 chemical reducing agent Substances 0.000 description 9
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238000001802 infusion Methods 0.000 description 9
239000003112 inhibitor Substances 0.000 description 9
229910052763 palladium Inorganic materials 0.000 description 9
239000008194 pharmaceutical composition Substances 0.000 description 9
239000000546 pharmaceutical excipient Substances 0.000 description 9
238000012746 preparative thin layer chromatography Methods 0.000 description 9
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 description 8
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
239000002220 antihypertensive agent Substances 0.000 description 8
125000000524 functional group Chemical group 0.000 description 8
AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 8
239000012528 membrane Substances 0.000 description 8
OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 8
239000002243 precursor Substances 0.000 description 8
239000000126 substance Substances 0.000 description 8
VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 8
125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 7
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
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102100024447 Prostaglandin E2 receptor EP3 subtype Human genes 0.000 description 7
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
150000001350 alkyl halides Chemical class 0.000 description 7
229940030600 antihypertensive agent Drugs 0.000 description 7
238000003556 assay Methods 0.000 description 7
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239000002934 diuretic Substances 0.000 description 7
238000001914 filtration Methods 0.000 description 7
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125000004178 (C1-C4) alkyl group Chemical group 0.000 description 6
ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 6
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 6
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 6
208000001953 Hypotension Diseases 0.000 description 6
DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
150000001299 aldehydes Chemical class 0.000 description 6
150000001347 alkyl bromides Chemical class 0.000 description 6
150000001351 alkyl iodides Chemical class 0.000 description 6
150000008052 alkyl sulfonates Chemical class 0.000 description 6
239000000010 aprotic solvent Substances 0.000 description 6
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150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
230000008878 coupling Effects 0.000 description 6
238000010168 coupling process Methods 0.000 description 6
JGFBRKRYDCGYKD-UHFFFAOYSA-N dibutyl(oxo)tin Chemical compound CCCC[Sn](=O)CCCC JGFBRKRYDCGYKD-UHFFFAOYSA-N 0.000 description 6
UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
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