IL103436A - Substituted condensed bicyclic pyrimidinones their preparation and pharmaceutical compositions containing them - Google Patents

Substituted condensed bicyclic pyrimidinones their preparation and pharmaceutical compositions containing them

Info

Publication number: IL103436A
Authority: IL; Israel
Prior art keywords: compound; formula; methyl; carbon atoms; mixture
Prior art date: 1991-10-24

Application number

IL10343692A

Other languages

English (en)

Hebrew (he)

Other versions

IL103436A0 (en

Original Assignee

American Home Prod

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.)

1991-10-24

Filing date

1992-10-15

Publication date

1996-03-31

1991-10-24 Priority claimed from US07/782,025 external-priority patent/US5149699A/en

1992-04-07 Priority claimed from GB9207560A external-priority patent/GB2265899A/en

1992-06-25 Priority claimed from US07/901,485 external-priority patent/US5256654A/en

1992-10-15 Application filed by American Home Prod filed Critical American Home Prod

1993-03-15 Publication of IL103436A0 publication Critical patent/IL103436A0/xx

1996-03-31 Publication of IL103436A publication Critical patent/IL103436A/en

Links

238000002360 preparation method Methods 0.000 title description 4
VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical class OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 title description 3
239000000825 pharmaceutical preparation Substances 0.000 title 1
238000000034 method Methods 0.000 claims abstract description 16
206010020772 Hypertension Diseases 0.000 claims abstract description 7
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
206010019280 Heart failures Diseases 0.000 claims abstract description 4
206010007559 Cardiac failure congestive Diseases 0.000 claims abstract description 3
238000002399 angioplasty Methods 0.000 claims abstract description 3
238000004519 manufacturing process Methods 0.000 claims abstract 4
150000001875 compounds Chemical class 0.000 claims description 66
150000003839 salts Chemical class 0.000 claims description 34
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 31
-1 bicyclic compound Chemical class 0.000 claims description 26
239000004305 biphenyl Substances 0.000 claims description 21
125000004432 carbon atom Chemical group C* 0.000 claims description 19
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 11
125000000217 alkyl group Chemical group 0.000 claims description 11
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
150000001543 aryl boronic acids Chemical class 0.000 claims description 9
150000001412 amines Chemical class 0.000 claims description 7
150000001204 N-oxides Chemical class 0.000 claims description 6
239000002585 base Substances 0.000 claims description 6
229910052736 halogen Inorganic materials 0.000 claims description 6
150000002367 halogens Chemical class 0.000 claims description 6
125000006239 protecting group Chemical group 0.000 claims description 6
150000001540 azides Chemical class 0.000 claims description 5
239000003054 catalyst Substances 0.000 claims description 5
239000003795 chemical substances by application Substances 0.000 claims description 5
229910052763 palladium Inorganic materials 0.000 claims description 5
125000005010 perfluoroalkyl group Chemical group 0.000 claims description 5
230000002378 acidificating effect Effects 0.000 claims description 4
239000003153 chemical reaction reagent Substances 0.000 claims description 4
ZHXTWWCDMUWMDI-UHFFFAOYSA-N dihydroxyboron Chemical compound O[B]O ZHXTWWCDMUWMDI-UHFFFAOYSA-N 0.000 claims description 4
ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
150000007522 mineralic acids Chemical class 0.000 claims description 4
150000007524 organic acids Chemical class 0.000 claims description 4
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
125000003545 alkoxy group Chemical group 0.000 claims description 3
229910052739 hydrogen Inorganic materials 0.000 claims description 3
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 2
CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 2
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
239000003937 drug carrier Substances 0.000 claims description 2
239000001257 hydrogen Substances 0.000 claims description 2
NQLVQOSNDJXLKG-UHFFFAOYSA-N prosulfocarb Chemical compound CCCN(CCC)C(=O)SCC1=CC=CC=C1 NQLVQOSNDJXLKG-UHFFFAOYSA-N 0.000 claims description 2
DJPPOMGPZWRNGQ-UHFFFAOYSA-N 2,4-dimethyl-8-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]pyrido[2,3-d]pyrimidin-7-one Chemical compound C12=NC(C)=NC(C)=C2C=CC(=O)N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1 DJPPOMGPZWRNGQ-UHFFFAOYSA-N 0.000 claims 1
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
241000124008 Mammalia Species 0.000 claims 1
238000005903 acid hydrolysis reaction Methods 0.000 claims 1
238000010626 work up procedure Methods 0.000 claims 1
208000037803 restenosis Diseases 0.000 abstract description 2
239000000203 mixture Substances 0.000 description 86
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 56
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 54
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 45
239000000047 product Substances 0.000 description 42
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 40
238000005481 NMR spectroscopy Methods 0.000 description 36
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 34
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
239000007787 solid Substances 0.000 description 29
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 28
238000010992 reflux Methods 0.000 description 24
239000000284 extract Substances 0.000 description 22
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
239000000243 solution Substances 0.000 description 18
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
238000003818 flash chromatography Methods 0.000 description 15
235000019439 ethyl acetate Nutrition 0.000 description 14
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 14
229910052943 magnesium sulfate Inorganic materials 0.000 description 14
239000003921 oil Substances 0.000 description 14
235000019198 oils Nutrition 0.000 description 14
PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 12
JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 12
238000000746 purification Methods 0.000 description 12
239000012267 brine Substances 0.000 description 11
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
238000001665 trituration Methods 0.000 description 11
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 7
GCTFWCDSFPMHHS-UHFFFAOYSA-M Tributyltin chloride Chemical compound CCCC[Sn](Cl)(CCCC)CCCC GCTFWCDSFPMHHS-UHFFFAOYSA-M 0.000 description 7
230000004872 arterial blood pressure Effects 0.000 description 7
239000002244 precipitate Substances 0.000 description 7
239000011734 sodium Substances 0.000 description 7
239000000725 suspension Substances 0.000 description 7
150000003536 tetrazoles Chemical class 0.000 description 7
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 6
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
238000003556 assay Methods 0.000 description 6
239000012131 assay buffer Substances 0.000 description 6
239000012074 organic phase Substances 0.000 description 6
229940086542 triethylamine Drugs 0.000 description 6
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 6
239000012230 colorless oil Substances 0.000 description 5
239000006185 dispersion Substances 0.000 description 5
238000001914 filtration Methods 0.000 description 5
239000002480 mineral oil Substances 0.000 description 5
235000010446 mineral oil Nutrition 0.000 description 5
XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 5
150000003230 pyrimidines Chemical class 0.000 description 5
102000005962 receptors Human genes 0.000 description 5
108020003175 receptors Proteins 0.000 description 5
QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 5
239000002904 solvent Substances 0.000 description 5
239000007858 starting material Substances 0.000 description 5
238000005160 1H NMR spectroscopy Methods 0.000 description 4
125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 description 4
WDHAAJIGSXNPFO-UHFFFAOYSA-N 8h-pyrido[2,3-d]pyrimidin-7-one Chemical compound N1=CN=C2NC(=O)C=CC2=C1 WDHAAJIGSXNPFO-UHFFFAOYSA-N 0.000 description 4
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
239000000872 buffer Substances 0.000 description 4
WCQOBLXWLRDEQA-UHFFFAOYSA-N ethanimidamide;hydrochloride Chemical compound Cl.CC(N)=N WCQOBLXWLRDEQA-UHFFFAOYSA-N 0.000 description 4
150000002500 ions Chemical class 0.000 description 4
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
239000011541 reaction mixture Substances 0.000 description 4
229920006395 saturated elastomer Polymers 0.000 description 4
239000001632 sodium acetate Substances 0.000 description 4
235000017281 sodium acetate Nutrition 0.000 description 4
229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
238000003756 stirring Methods 0.000 description 4
239000008096 xylene Substances 0.000 description 4
150000003738 xylenes Chemical class 0.000 description 4
108010064733 Angiotensins Proteins 0.000 description 3
102000015427 Angiotensins Human genes 0.000 description 3
CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
229930006000 Sucrose Natural products 0.000 description 3
230000001476 alcoholic effect Effects 0.000 description 3
239000005557 antagonist Substances 0.000 description 3
239000008346 aqueous phase Substances 0.000 description 3
150000001499 aryl bromides Chemical class 0.000 description 3
238000006243 chemical reaction Methods 0.000 description 3
239000012043 crude product Substances 0.000 description 3
238000006073 displacement reaction Methods 0.000 description 3
230000000694 effects Effects 0.000 description 3
239000000706 filtrate Substances 0.000 description 3
239000006260 foam Substances 0.000 description 3
230000007062 hydrolysis Effects 0.000 description 3
238000006460 hydrolysis reaction Methods 0.000 description 3
238000001802 infusion Methods 0.000 description 3
150000007529 inorganic bases Chemical class 0.000 description 3
238000001953 recrystallisation Methods 0.000 description 3
239000005720 sucrose Substances 0.000 description 3
238000003786 synthesis reaction Methods 0.000 description 3
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
LFFIEVAMVPCZNA-UHFFFAOYSA-N 2-[4-(bromomethyl)phenyl]benzonitrile Chemical compound C1=CC(CBr)=CC=C1C1=CC=CC=C1C#N LFFIEVAMVPCZNA-UHFFFAOYSA-N 0.000 description 2
UNCQVRBWJWWJBF-UHFFFAOYSA-N 2-chloropyrimidine Chemical compound ClC1=NC=CC=N1 UNCQVRBWJWWJBF-UHFFFAOYSA-N 0.000 description 2
125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 2
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
102000005862 Angiotensin II Human genes 0.000 description 2
101800000734 Angiotensin-1 Proteins 0.000 description 2
102400000344 Angiotensin-1 Human genes 0.000 description 2
101800000733 Angiotensin-2 Proteins 0.000 description 2
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
208000003098 Ganglion Cysts Diseases 0.000 description 2
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
206010020571 Hyperaldosteronism Diseases 0.000 description 2
CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 2
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
241000700159 Rattus Species 0.000 description 2
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
208000005400 Synovial Cyst Diseases 0.000 description 2
239000007983 Tris buffer Substances 0.000 description 2
239000002253 acid Substances 0.000 description 2
229910021529 ammonia Inorganic materials 0.000 description 2
235000019270 ammonium chloride Nutrition 0.000 description 2
235000011114 ammonium hydroxide Nutrition 0.000 description 2
239000000538 analytical sample Substances 0.000 description 2
229950006323 angiotensin ii Drugs 0.000 description 2
230000003042 antagnostic effect Effects 0.000 description 2
229940124572 antihypotensive agent Drugs 0.000 description 2
125000003118 aryl group Chemical group 0.000 description 2
150000001503 aryl iodides Chemical class 0.000 description 2
150000001555 benzenes Chemical class 0.000 description 2
230000027455 binding Effects 0.000 description 2
230000015572 biosynthetic process Effects 0.000 description 2
238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
229940125797 compound 12 Drugs 0.000 description 2
239000012141 concentrate Substances 0.000 description 2
239000013078 crystal Substances 0.000 description 2
238000002425 crystallisation Methods 0.000 description 2
230000008025 crystallization Effects 0.000 description 2
FVALCTDLDKQADD-UHFFFAOYSA-N diethyl 2-(2,2,2-trifluoroacetyl)pentanedioate Chemical compound CCOC(=O)CCC(C(=O)C(F)(F)F)C(=O)OCC FVALCTDLDKQADD-UHFFFAOYSA-N 0.000 description 2
125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
238000010790 dilution Methods 0.000 description 2
239000012895 dilution Substances 0.000 description 2
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
238000004821 distillation Methods 0.000 description 2
GBRDREUTRFOKNX-UHFFFAOYSA-N ethyl 3-(4-chloro-2,6-dimethylpyrimidin-5-yl)propanoate Chemical compound CCOC(=O)CCC1=C(C)N=C(C)N=C1Cl GBRDREUTRFOKNX-UHFFFAOYSA-N 0.000 description 2
239000005457 ice water Substances 0.000 description 2
210000004731 jugular vein Anatomy 0.000 description 2
239000010410 layer Substances 0.000 description 2
IMYZQPCYWPFTAG-IQJOONFLSA-N mecamylamine Chemical compound C1C[C@@H]2C(C)(C)[C@@](NC)(C)[C@H]1C2 IMYZQPCYWPFTAG-IQJOONFLSA-N 0.000 description 2
229960002525 mecamylamine Drugs 0.000 description 2
239000012528 membrane Substances 0.000 description 2
MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 2
150000002825 nitriles Chemical group 0.000 description 2
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
235000005985 organic acids Nutrition 0.000 description 2
150000007530 organic bases Chemical class 0.000 description 2
238000010651 palladium-catalyzed cross coupling reaction Methods 0.000 description 2
HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
229910000027 potassium carbonate Inorganic materials 0.000 description 2
201000009395 primary hyperaldosteronism Diseases 0.000 description 2
238000000159 protein binding assay Methods 0.000 description 2
150000003217 pyrazoles Chemical class 0.000 description 2
125000001424 substituent group Chemical group 0.000 description 2
239000006228 supernatant Substances 0.000 description 2
238000002560 therapeutic procedure Methods 0.000 description 2
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 2
QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
239000005526 vasoconstrictor agent Substances 0.000 description 2
QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
MXYHHRIZRNXYAN-UHFFFAOYSA-N (3z,5z,7z)-1h-azocin-2-one Chemical group O=C\1N\C=C/C=C\C=C/1 MXYHHRIZRNXYAN-UHFFFAOYSA-N 0.000 description 1
XRNVSPDQTPVECU-UHFFFAOYSA-N (4-bromophenyl)methanamine Chemical compound NCC1=CC=C(Br)C=C1 XRNVSPDQTPVECU-UHFFFAOYSA-N 0.000 description 1
QPPDKOIDAYZUHN-UHFFFAOYSA-N (6-bromopyridin-3-yl)methanol Chemical compound OCC1=CC=C(Br)N=C1 QPPDKOIDAYZUHN-UHFFFAOYSA-N 0.000 description 1
AXFFJQDPDFDMGZ-UHFFFAOYSA-N (6-bromopyridin-3-yl)methoxy-tert-butyl-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OCC1=CC=C(Br)N=C1 AXFFJQDPDFDMGZ-UHFFFAOYSA-N 0.000 description 1
PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
QMNUDYFKZYBWQX-UHFFFAOYSA-N 1H-quinazolin-4-one Chemical class C1=CC=C2C(=O)N=CNC2=C1 QMNUDYFKZYBWQX-UHFFFAOYSA-N 0.000 description 1
DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical class O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 1
WOPFMBVSHKMGDD-UHFFFAOYSA-N 2-[5-(hydroxymethyl)pyridin-2-yl]benzonitrile Chemical compound N1=CC(CO)=CC=C1C1=CC=CC=C1C#N WOPFMBVSHKMGDD-UHFFFAOYSA-N 0.000 description 1
JDDAFHUEOVUDFJ-UHFFFAOYSA-N 2-iodobenzonitrile Chemical compound IC1=CC=CC=C1C#N JDDAFHUEOVUDFJ-UHFFFAOYSA-N 0.000 description 1
JDJBRMNTXORYEN-UHFFFAOYSA-N 6-bromopyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=C(Br)N=C1 JDJBRMNTXORYEN-UHFFFAOYSA-N 0.000 description 1
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UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
125000000714 pyrimidinyl group Chemical group 0.000 description 1
VIXWGKYSYIBATJ-UHFFFAOYSA-N pyrrol-2-one Chemical compound O=C1C=CC=N1 VIXWGKYSYIBATJ-UHFFFAOYSA-N 0.000 description 1
150000003233 pyrroles Chemical class 0.000 description 1
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229910052708 sodium Inorganic materials 0.000 description 1
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BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
230000001225 therapeutic effect Effects 0.000 description 1
210000003437 trachea Anatomy 0.000 description 1
150000003852 triazoles Chemical class 0.000 description 1
SYUVAXDZVWPKSI-UHFFFAOYSA-N tributyl(phenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=CC=C1 SYUVAXDZVWPKSI-UHFFFAOYSA-N 0.000 description 1
DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
238000007514 turning Methods 0.000 description 1
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239000011592 zinc chloride Substances 0.000 description 1
235000005074 zinc chloride Nutrition 0.000 description 1
JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- 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
- 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
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems

Landscapes

Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Cardiology (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Veterinary Medicine (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Heart & Thoracic Surgery (AREA)
Chemical Kinetics & Catalysis (AREA)
Pharmacology & Pharmacy (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Vascular Medicine (AREA)
Hospice & Palliative Care (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Plural Heterocyclic Compounds (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

IL10343692A 1991-10-24 1992-10-15 Substituted condensed bicyclic pyrimidinones their preparation and pharmaceutical compositions containing them IL103436A (en)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
US07/782,025 US5149699A (en)	1991-10-24	1991-10-24	Substituted pyridopyrimidines useful as antgiotensin II antagonists
GB9207560A GB2265899A (en)	1992-04-07	1992-04-07	Substituted pyrimidines
US07/901,485 US5256654A (en)	1991-10-24	1992-06-25	Substituted pyrrolopyrimidines, azepinopyrimidines and pyridopyrimidines useful as angiotensin II antagonists

Publications (2)

Publication Number	Publication Date
IL103436A0 IL103436A0 (en)	1993-03-15
IL103436A true IL103436A (en)	1996-03-31

Family

ID=27266132

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
IL10343692A IL103436A (en)	1991-10-24	1992-10-15	Substituted condensed bicyclic pyrimidinones their preparation and pharmaceutical compositions containing them

Country Status (21)

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EP (1)	EP0539086B1 (fi)
JP (1)	JP3240192B2 (fi)
KR (1)	KR100286624B1 (fi)
CN (2)	CN1039324C (fi)
AT (1)	ATE161537T1 (fi)
AU (1)	AU653635B2 (fi)
CA (1)	CA2080705C (fi)
DE (1)	DE69223734T2 (fi)
DK (1)	DK0539086T3 (fi)
ES (1)	ES2111617T3 (fi)
FI (1)	FI103971B1 (fi)
GR (1)	GR3025926T3 (fi)
HK (1)	HK1003031A1 (fi)
HU (2)	HU218786B (fi)
IL (1)	IL103436A (fi)
LV (1)	LV12047B (fi)
NO (1)	NO301275B1 (fi)
SG (1)	SG47626A1 (fi)
SK (1)	SK280292B6 (fi)
TW (1)	TW226375B (fi)
UA (1)	UA27748C2 (fi)

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SG47714A1 (en) *	1993-03-24	1998-04-17	American Home Prod	Substituted pyridopyrimidines as antihypertensives
EP0782996B1 (en) *	1994-09-20	1999-02-17	Wakunaga Seiyaku Kabushiki Kaisha	Process for producing n-biphenylmethylthiadiazoline derivative or salt thereof and intermediate for producing the same
IT1292437B1 (it) *	1997-06-30	1999-02-08	Zambon Spa	Processo di orto-metallazione utile per la sintesi di 1 - tetrazol- 5-il) benzeni 2-sostituiti
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AR033390A1 (es)	2000-08-22	2003-12-17	Novartis Ag	Una composicion farmaceutica que comprende un antagonista del receptor at1 y un potenciador de la secrecion de insulina, el uso de dicha composicion para la fabricacion de un medicamento y un kit de partes
US8168616B1 (en)	2000-11-17	2012-05-01	Novartis Ag	Combination comprising a renin inhibitor and an angiotensin receptor inhibitor for hypertension
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GB0327839D0 (en)	2003-12-01	2003-12-31	Novartis Ag	Organic compounds
GB0402262D0 (en)	2004-02-02	2004-03-10	Novartis Ag	Process for the manufacture of organic compounds
TW200605867A (en)	2004-03-17	2006-02-16	Novartis Ag	Use of organic compounds
ES2384637T3 (es)	2004-10-08	2012-07-10	Novartis Ag	Uso de inhibidores de la renina para la prevención o el tratamiento de disfunción diastólica o insuficiencia cardiaca diastólica
EP1749828A1 (en)	2005-08-04	2007-02-07	Farmaprojects S.L.	Process for preparing an angiotensin II receptor antagonist
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AU2010294214B2 (en)	2009-09-11	2015-05-07	Vivoryon Therapeutics N.V.	Heterocylcic derivatives as inhibitors of glutaminyl cyclase
ES2586231T3 (es)	2010-03-03	2016-10-13	Probiodrug Ag	Inhibidores de glutaminil ciclasa
MX2012010470A (es)	2010-03-10	2012-10-09	Probiodrug Ag	Inhibidores heterociclicos d ciclasa de glutaminilo (qc, ec .3 2. 5).
EP2560953B1 (en)	2010-04-21	2016-01-06	Probiodrug AG	Inhibitors of glutaminyl cyclase
US9616097B2 (en)	2010-09-15	2017-04-11	Synergy Pharmaceuticals, Inc.	Formulations of guanylate cyclase C agonists and methods of use
EP2686313B1 (en)	2011-03-16	2016-02-03	Probiodrug AG	Benzimidazole derivatives as inhibitors of glutaminyl cyclase
AP2014007766A0 (en)	2011-12-15	2014-07-31	Takeda Pharmaceuticals Usa Inc	Combination os azilsartan and chlorthlidone for treating hypertension black patients
EP2968439A2 (en)	2013-03-15	2016-01-20	Synergy Pharmaceuticals Inc.	Compositions useful for the treatment of gastrointestinal disorders
CA2905438A1 (en)	2013-03-15	2014-09-25	Synergy Pharmaceuticals Inc.	Agonists of guanylate cyclase and their uses
KR102272746B1 (ko)	2013-06-05	2021-07-08	보슈 헬스 아일랜드 리미티드	구아닐레이트 사이클라제 c의 초순수 작용제, 및 이의 제조 및 사용 방법
PL3461819T3 (pl)	2017-09-29	2020-11-30	Probiodrug Ag	Inhibitory cyklazy glutaminylowej

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EP0407342A3 (en) *	1989-07-06	1991-07-10	Ciba-Geigy Ag	Pyrimidine derivatives
US5100897A (en) *	1989-08-28	1992-03-31	Merck & Co., Inc.	Substituted pyrimidinones as angiotensin ii antagonists
EP0415886A3 (en) *	1989-08-30	1991-10-23	Ciba-Geigy Ag	Aza compounds
CA2075637A1 (en) *	1990-02-13	1991-08-14	William J. Greenlee	Angiotensin ii antagonists incorporating a substituted benzyl element
US5149699A (en) *	1991-10-24	1992-09-22	American Home Products Corporation	Substituted pyridopyrimidines useful as antgiotensin II antagonists

1992
- 1992-08-27 TW TW081106755A patent/TW226375B/zh active
- 1992-09-30 FI FI924397A patent/FI103971B1/fi not_active IP Right Cessation
- 1992-10-01 AU AU26079/92A patent/AU653635B2/en not_active Ceased
- 1992-10-06 HU HU9203161A patent/HU218786B/hu not_active IP Right Cessation
- 1992-10-14 AT AT92309333T patent/ATE161537T1/de not_active IP Right Cessation
- 1992-10-14 DK DK92309333.0T patent/DK0539086T3/da active
- 1992-10-14 DE DE69223734T patent/DE69223734T2/de not_active Expired - Fee Related
- 1992-10-14 SG SG1996003253A patent/SG47626A1/en unknown
- 1992-10-14 EP EP92309333A patent/EP0539086B1/en not_active Expired - Lifetime
- 1992-10-14 ES ES92309333T patent/ES2111617T3/es not_active Expired - Lifetime
- 1992-10-15 IL IL10343692A patent/IL103436A/en not_active IP Right Cessation
- 1992-10-16 CA CA002080705A patent/CA2080705C/en not_active Expired - Fee Related
- 1992-10-23 NO NO924121A patent/NO301275B1/no not_active IP Right Cessation
- 1992-10-23 CN CN92113781A patent/CN1039324C/zh not_active Expired - Fee Related
- 1992-10-23 JP JP28588592A patent/JP3240192B2/ja not_active Expired - Fee Related
- 1992-10-23 KR KR1019920019580A patent/KR100286624B1/ko not_active Expired - Fee Related
- 1992-10-26 SK SK3221-92A patent/SK280292B6/sk unknown
1993
- 1993-06-18 UA UA93003129A patent/UA27748C2/uk unknown
1995
- 1995-06-29 HU HU95P/P00549P patent/HU211915A9/hu unknown
1997
- 1997-05-13 CN CN97111592A patent/CN1175414A/zh active Pending
1998
- 1998-01-15 GR GR980400096T patent/GR3025926T3/el unknown
- 1998-03-09 LV LVP-98-45A patent/LV12047B/en unknown
- 1998-03-12 HK HK98102075A patent/HK1003031A1/xx not_active IP Right Cessation

Also Published As

Publication number	Publication date
FI103971B (fi)	1999-10-29
CA2080705C (en)	2002-12-03
NO301275B1 (no)	1997-10-06
JP3240192B2 (ja)	2001-12-17
TW226375B (fi)	1994-07-11
CN1072682A (zh)	1993-06-02
UA27748C2 (uk)	2000-10-16
ATE161537T1 (de)	1998-01-15
DK0539086T3 (da)	1998-02-02
JPH05222039A (ja)	1993-08-31
FI924397L (fi)	1993-04-25
EP0539086A2 (en)	1993-04-28
EP0539086A3 (en)	1993-06-16
SG47626A1 (en)	1998-04-17
AU2607992A (en)	1993-04-29
NO924121L (no)	1993-04-26
SK322192A3 (en)	1999-11-08
ES2111617T3 (es)	1998-03-16
HK1003031A1 (en)	1998-09-30
AU653635B2 (en)	1994-10-06
CN1175414A (zh)	1998-03-11
HU211915A9 (en)	1996-01-29
EP0539086B1 (en)	1997-12-29
LV12047B (en)	1998-08-20
FI924397A0 (fi)	1992-09-30
KR100286624B1 (ko)	2001-05-02
KR930007949A (ko)	1993-05-20
CN1039324C (zh)	1998-07-29
HUT62893A (en)	1993-06-28
LV12047A (lv)	1998-05-20
GR3025926T3 (en)	1998-04-30
FI103971B1 (fi)	1999-10-29
HU218786B (hu)	2000-12-28
IL103436A0 (en)	1993-03-15
DE69223734T2 (de)	1998-04-16
NO924121D0 (no)	1992-10-23
DE69223734D1 (de)	1998-02-05
SK280292B6 (sk)	1999-11-08
CA2080705A1 (en)	1993-04-25
HU9203161D0 (en)	1992-12-28

Publication	Publication Date	Title
EP0539086B1 (en)	1997-12-29	Condensed pyrimidine derivatives and their use as angiotensine II antagonists
US5149699A (en)	1992-09-22	Substituted pyridopyrimidines useful as antgiotensin II antagonists
JP3260415B2 (ja)	2002-02-25	アンギオテンシンｉｉ拮抗作用を有する複素環化合物
US5225414A (en)	1993-07-06	Substituted azoles, a process for their preparation, and their use
WO1993008170A1 (en)	1993-04-29	Substituted heterocycles as angiotensin ii antagonists
US5466692A (en)	1995-11-14	Substituted pyridopyrimidines and antihypertensives
WO1993008169A1 (en)	1993-04-29	Substituted aminopyrimidines as angiotensine ii antagonists
US5330989A (en)	1994-07-19	Heterocycles substituted with biphenyl-3-cyclobutene-1,2-dione derivatives
SK73293A3 (en)	1994-04-06	Benzimidazoles, process for their preparation and medicaments contained this compounds
US5283242A (en)	1994-02-01	Substituted benzimidazoles and quinazolines as antihypertensives
US5256654A (en)	1993-10-26	Substituted pyrrolopyrimidines, azepinopyrimidines and pyridopyrimidines useful as angiotensin II antagonists
EP0618207B1 (en)	1999-01-07	Substituted pyridopyrimidines as antihypertensives
GB2265899A (en)	1993-10-13	Substituted pyrimidines
US6096754A (en)	2000-08-01	N-3 substituted pyrimidin-4-ones with AII antagonistic activity
WO1993024501A1 (en)	1993-12-09	Phosphorus containing heterocyclic compounds as angiotensins antagonists
WO1993024487A1 (en)	1993-12-09	Nitrogen containing heterocyclic compounds as angiotensin-ii-antagonists

Legal Events

Date	Code	Title
1996-08-04	FF	Patent granted
1996-12-05	KB	Patent renewed
1999-03-12	KB	Patent renewed
2002-09-12	HCA	Change of name of proprietor(s) after amalgamation
2002-12-01	KB	Patent renewed
2007-07-06	MM9K	Patent not in force due to non-payment of renewal fees