PH26971A - 6-substituted purinyl piperazine derivatives useful as anti-arrhythmic agents - Google Patents

6-substituted purinyl piperazine derivatives useful as anti-arrhythmic agents Download PDF

Info

Publication number: PH26971A
Authority: PH; Philippines
Prior art keywords: lower alkyl; compound; ary; phenyl; halo
Prior art date: 1988-03-03

Application number

PH38279A

Other languages

English (en)

Inventor

Zoltan G Hajos

Ramesh M Kanojia

Jeffrey B Press

Original Assignee

Ortho Pharma Corp

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.)

1988-03-03

Filing date

1989-03-03

Publication date

1992-12-28

1989-03-03 Application filed by Ortho Pharma Corp filed Critical Ortho Pharma Corp

1992-12-28 Publication of PH26971A publication Critical patent/PH26971A/en

Links

-1 6-substituted purinyl piperazine Chemical class 0.000 title claims abstract description 18
229940066771 systemic antihistamines piperazine derivative Drugs 0.000 title abstract description 7
239000003416 antiarrhythmic agent Substances 0.000 title abstract description 5
150000001875 compounds Chemical class 0.000 claims abstract description 64
238000000034 method Methods 0.000 claims abstract description 33
125000000217 alkyl group Chemical group 0.000 claims description 39
229910052757 nitrogen Inorganic materials 0.000 claims description 35
239000000203 mixture Substances 0.000 claims description 33
KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 26
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
229910052739 hydrogen Inorganic materials 0.000 claims description 16
125000005843 halogen group Chemical group 0.000 claims description 15
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
125000001424 substituent group Chemical group 0.000 claims description 11
125000003545 alkoxy group Chemical group 0.000 claims description 10
125000001309 chloro group Chemical group Cl* 0.000 claims description 7
125000001153 fluoro group Chemical group F* 0.000 claims description 7
239000001257 hydrogen Substances 0.000 claims description 7
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
125000001246 bromo group Chemical group Br* 0.000 claims description 6
125000002346 iodo group Chemical group I* 0.000 claims description 6
229910052717 sulfur Inorganic materials 0.000 claims description 6
125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 6
125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 5
125000003342 alkenyl group Chemical group 0.000 claims description 4
125000000304 alkynyl group Chemical group 0.000 claims description 4
125000003118 aryl group Chemical group 0.000 claims description 4
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 4
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
125000001624 naphthyl group Chemical group 0.000 claims description 4
125000004076 pyridyl group Chemical group 0.000 claims description 4
125000001544 thienyl group Chemical group 0.000 claims description 4
230000000747 cardiac effect Effects 0.000 claims description 3
239000003937 drug carrier Substances 0.000 claims description 3
239000008194 pharmaceutical composition Substances 0.000 claims description 3
206010003119 arrhythmia Diseases 0.000 claims description 2
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 6
229910052736 halogen Inorganic materials 0.000 claims 3
150000002367 halogens Chemical class 0.000 claims 3
150000002431 hydrogen Chemical class 0.000 claims 3
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 3
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 2
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
208000019622 heart disease Diseases 0.000 claims 1
125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
239000000496 cardiotonic agent Substances 0.000 abstract description 2
230000015572 biosynthetic process Effects 0.000 abstract 1
238000003786 synthesis reaction Methods 0.000 abstract 1
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 111
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 108
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 52
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 50
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
239000007787 solid Substances 0.000 description 28
239000000243 solution Substances 0.000 description 26
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 24
239000000741 silica gel Substances 0.000 description 24
229910002027 silica gel Inorganic materials 0.000 description 24
239000000047 product Substances 0.000 description 20
239000012043 crude product Substances 0.000 description 16
239000003921 oil Substances 0.000 description 16
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
238000003818 flash chromatography Methods 0.000 description 15
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical class S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 14
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
239000002904 solvent Substances 0.000 description 12
BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 11
GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical class C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 10
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
239000000706 filtrate Substances 0.000 description 10
239000011541 reaction mixture Substances 0.000 description 10
HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 10
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
239000000725 suspension Substances 0.000 description 9
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
238000006243 chemical reaction Methods 0.000 description 8
238000001914 filtration Methods 0.000 description 8
229960001428 mercaptopurine Drugs 0.000 description 8
WEVYAHXRMPXWCK-UHFFFAOYSA-N methyl cyanide Natural products CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 8
239000011734 sodium Substances 0.000 description 8
239000002585 base Substances 0.000 description 7
239000006260 foam Substances 0.000 description 7
239000011521 glass Substances 0.000 description 7
229910000104 sodium hydride Inorganic materials 0.000 description 7
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
239000012044 organic layer Substances 0.000 description 6
229960005141 piperazine Drugs 0.000 description 6
238000003756 stirring Methods 0.000 description 6
QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
235000017557 sodium bicarbonate Nutrition 0.000 description 5
229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
TTXIFFYPVGWLSE-UHFFFAOYSA-N 1-[bis(4-fluorophenyl)methyl]piperazine Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)N1CCNCC1 TTXIFFYPVGWLSE-UHFFFAOYSA-N 0.000 description 4
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 4
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
150000001298 alcohols Chemical class 0.000 description 4
230000003177 cardiotonic effect Effects 0.000 description 4
229940079593 drug Drugs 0.000 description 4
239000003814 drug Substances 0.000 description 4
WFFQYWAAEWLHJC-UHFFFAOYSA-N mercaptopurine hydrate Chemical compound O.S=C1NC=NC2=C1NC=N2 WFFQYWAAEWLHJC-UHFFFAOYSA-N 0.000 description 4
229920006395 saturated elastomer Polymers 0.000 description 4
239000012312 sodium hydride Substances 0.000 description 4
229910052938 sodium sulfate Inorganic materials 0.000 description 4
235000011152 sodium sulphate Nutrition 0.000 description 4
239000011593 sulfur Substances 0.000 description 4
239000003826 tablet Substances 0.000 description 4
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
QSTASPNCKDPSAH-UHFFFAOYSA-N 6-chloro-9-(oxan-2-yl)purine Chemical compound C1=NC=2C(Cl)=NC=NC=2N1C1CCCCO1 QSTASPNCKDPSAH-UHFFFAOYSA-N 0.000 description 3
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
241001465754 Metazoa Species 0.000 description 3
239000002168 alkylating agent Substances 0.000 description 3
229940100198 alkylating agent Drugs 0.000 description 3
239000002775 capsule Substances 0.000 description 3
229910052799 carbon Inorganic materials 0.000 description 3
239000003153 chemical reaction reagent Substances 0.000 description 3
239000003795 chemical substances by application Substances 0.000 description 3
150000001805 chlorine compounds Chemical class 0.000 description 3
238000004587 chromatography analysis Methods 0.000 description 3
229910052500 inorganic mineral Inorganic materials 0.000 description 3
239000007788 liquid Substances 0.000 description 3
238000002844 melting Methods 0.000 description 3
230000008018 melting Effects 0.000 description 3
235000010755 mineral Nutrition 0.000 description 3
239000011707 mineral Substances 0.000 description 3
230000002107 myocardial effect Effects 0.000 description 3
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
125000002524 organometallic group Chemical group 0.000 description 3
NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
238000002360 preparation method Methods 0.000 description 3
238000001665 trituration Methods 0.000 description 3
AUGBBUFJMAJBGB-UHFFFAOYSA-N 1-[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]-3-chloropropan-2-ol Chemical compound C1CN(CC(CCl)O)CCN1CC1=CC=C(OCO2)C2=C1 AUGBBUFJMAJBGB-UHFFFAOYSA-N 0.000 description 2
PTLFMGDNZYQISN-UHFFFAOYSA-N 1-[bis(4-chlorophenyl)methyl]piperazine Chemical compound C1=CC(Cl)=CC=C1C(C=1C=CC(Cl)=CC=1)N1CCNCC1 PTLFMGDNZYQISN-UHFFFAOYSA-N 0.000 description 2
XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 2
KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
ZKBQDFAWXLTYKS-UHFFFAOYSA-N 6-Chloro-1H-purine Chemical compound ClC1=NC=NC2=C1NC=N2 ZKBQDFAWXLTYKS-UHFFFAOYSA-N 0.000 description 2
229950006316 6-mercaptopurine monohydrate Drugs 0.000 description 2
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
239000004593 Epoxy Substances 0.000 description 2
CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 description 2
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
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239000002253 acid Substances 0.000 description 2
239000004480 active ingredient Substances 0.000 description 2
150000001412 amines Chemical class 0.000 description 2
230000003288 anthiarrhythmic effect Effects 0.000 description 2
230000004872 arterial blood pressure Effects 0.000 description 2
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical class OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
238000009835 boiling Methods 0.000 description 2
150000001721 carbon Chemical group 0.000 description 2
239000002327 cardiovascular agent Substances 0.000 description 2
229940125692 cardiovascular agent Drugs 0.000 description 2
239000000969 carrier Substances 0.000 description 2
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150000008640 diphenylmethylpiperazines Chemical class 0.000 description 2
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230000000694 effects Effects 0.000 description 2
238000001704 evaporation Methods 0.000 description 2
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150000004678 hydrides Chemical class 0.000 description 2
230000000297 inotrophic effect Effects 0.000 description 2
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125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
239000002480 mineral oil Substances 0.000 description 2
235000010446 mineral oil Nutrition 0.000 description 2
KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
150000002924 oxiranes Chemical class 0.000 description 2
229910052760 oxygen Inorganic materials 0.000 description 2
239000002504 physiological saline solution Substances 0.000 description 2
150000004885 piperazines Chemical class 0.000 description 2
150000003053 piperidines Chemical class 0.000 description 2
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
239000000843 powder Substances 0.000 description 2
239000002244 precipitate Substances 0.000 description 2
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125000006239 protecting group Chemical group 0.000 description 2
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150000003212 purines Chemical class 0.000 description 2
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239000007858 starting material Substances 0.000 description 2
235000000346 sugar Nutrition 0.000 description 2
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IMCGHZIGRANKHV-AJNGGQMLSA-N tert-butyl (3s,5s)-2-oxo-5-[(2s,4s)-5-oxo-4-propan-2-yloxolan-2-yl]-3-propan-2-ylpyrrolidine-1-carboxylate Chemical compound O1C(=O)[C@H](C(C)C)C[C@H]1[C@H]1N(C(=O)OC(C)(C)C)C(=O)[C@H](C(C)C)C1 IMCGHZIGRANKHV-AJNGGQMLSA-N 0.000 description 2
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GEYTUMGLEUDGAQ-UHFFFAOYSA-N 1-(4-benzylpiperazin-1-yl)-3-chloropropan-2-ol Chemical compound C1CN(CC(CCl)O)CCN1CC1=CC=CC=C1 GEYTUMGLEUDGAQ-UHFFFAOYSA-N 0.000 description 1
UZKBSZSTDQSMDR-UHFFFAOYSA-N 1-[(4-chlorophenyl)-phenylmethyl]piperazine Chemical compound C1=CC(Cl)=CC=C1C(C=1C=CC=CC=1)N1CCNCC1 UZKBSZSTDQSMDR-UHFFFAOYSA-N 0.000 description 1
KKMSCNTZDCYNSC-UHFFFAOYSA-N 1-[(4-fluorophenyl)-phenylmethyl]piperazine Chemical compound C1=CC(F)=CC=C1C(C=1C=CC=CC=1)N1CCNCC1 KKMSCNTZDCYNSC-UHFFFAOYSA-N 0.000 description 1
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IQXXEPZFOOTTBA-UHFFFAOYSA-N 1-benzylpiperazine Chemical compound C=1C=CC=CC=1CN1CCNCC1 IQXXEPZFOOTTBA-UHFFFAOYSA-N 0.000 description 1
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AMYKHXZUUCXDOJ-UHFFFAOYSA-N 1-tritylpiperazine hydrate Chemical compound C1(=CC=CC=C1)C(N1CCNCC1)(C1=CC=CC=C1)C1=CC=CC=C1.O AMYKHXZUUCXDOJ-UHFFFAOYSA-N 0.000 description 1
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229920002472 Starch Polymers 0.000 description 1
239000004809 Teflon Substances 0.000 description 1
229920006362 Teflon® Polymers 0.000 description 1
NOQXXYIGRPAZJC-SECBINFHSA-N [(2r)-oxiran-2-yl]methyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OC[C@@H]1OC1 NOQXXYIGRPAZJC-SECBINFHSA-N 0.000 description 1
NOQXXYIGRPAZJC-VIFPVBQESA-N [(2s)-oxiran-2-yl]methyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OC[C@H]1OC1 NOQXXYIGRPAZJC-VIFPVBQESA-N 0.000 description 1
WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
239000012346 acetyl chloride Substances 0.000 description 1
150000008065 acid anhydrides Chemical class 0.000 description 1
230000001154 acute effect Effects 0.000 description 1
239000000443 aerosol Substances 0.000 description 1
229910000272 alkali metal oxide Inorganic materials 0.000 description 1
150000001340 alkali metals Chemical class 0.000 description 1
229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
150000001351 alkyl iodides Chemical class 0.000 description 1
VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
239000000908 ammonium hydroxide Substances 0.000 description 1
238000004458 analytical method Methods 0.000 description 1
150000008064 anhydrides Chemical class 0.000 description 1
150000001450 anions Chemical class 0.000 description 1
229940054051 antipsychotic indole derivative Drugs 0.000 description 1
239000007864 aqueous solution Substances 0.000 description 1
239000011230 binding agent Substances 0.000 description 1
239000002981 blocking agent Substances 0.000 description 1
238000004364 calculation method Methods 0.000 description 1
230000005792 cardiovascular activity Effects 0.000 description 1
NEHMKBQYUWJMIP-OUBTZVSYSA-N chloromethane Chemical class Cl[13CH3] NEHMKBQYUWJMIP-OUBTZVSYSA-N 0.000 description 1
239000003086 colorant Substances 0.000 description 1
239000012230 colorless oil Substances 0.000 description 1
238000013329 compounding Methods 0.000 description 1
238000001816 cooling Methods 0.000 description 1
150000003983 crown ethers Chemical class 0.000 description 1
239000013058 crude material Substances 0.000 description 1
238000002425 crystallisation Methods 0.000 description 1
230000008025 crystallization Effects 0.000 description 1
230000001186 cumulative effect Effects 0.000 description 1
239000003085 diluting agent Substances 0.000 description 1
NWVNXDKZIQLBNM-UHFFFAOYSA-N diphenylmethylpiperazine Chemical compound C1CNCCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 NWVNXDKZIQLBNM-UHFFFAOYSA-N 0.000 description 1
229960003638 dopamine Drugs 0.000 description 1
231100000673 dose–response relationship Toxicity 0.000 description 1
238000001035 drying Methods 0.000 description 1
GKIPXFAANLTWBM-UHFFFAOYSA-N epibromohydrin Chemical compound BrCC1CO1 GKIPXFAANLTWBM-UHFFFAOYSA-N 0.000 description 1
150000002148 esters Chemical class 0.000 description 1
150000002170 ethers Chemical class 0.000 description 1
GKWQBAIVNZBQNJ-UHFFFAOYSA-N ethyl 4-(3-chloro-2-hydroxypropoxy)piperazine-1-carboxylate Chemical compound CCOC(=O)N1CCN(OCC(O)CCl)CC1 GKWQBAIVNZBQNJ-UHFFFAOYSA-N 0.000 description 1
HQKSINSCHCDMLS-UHFFFAOYSA-N ethyl naphthalene-2-carboxylate Chemical compound C1=CC=CC2=CC(C(=O)OCC)=CC=C21 HQKSINSCHCDMLS-UHFFFAOYSA-N 0.000 description 1
LNOQURRKNJKKBU-UHFFFAOYSA-N ethyl piperazine-1-carboxylate Chemical compound CCOC(=O)N1CCNCC1 LNOQURRKNJKKBU-UHFFFAOYSA-N 0.000 description 1
238000011156 evaluation Methods 0.000 description 1
210000001105 femoral artery Anatomy 0.000 description 1
210000003191 femoral vein Anatomy 0.000 description 1
239000000796 flavoring agent Substances 0.000 description 1
235000013355 food flavoring agent Nutrition 0.000 description 1
150000002334 glycols Chemical class 0.000 description 1
239000003979 granulating agent Substances 0.000 description 1
230000002140 halogenating effect Effects 0.000 description 1
238000010438 heat treatment Methods 0.000 description 1
150000004677 hydrates Chemical class 0.000 description 1
238000007327 hydrogenolysis reaction Methods 0.000 description 1
230000007062 hydrolysis Effects 0.000 description 1
238000006460 hydrolysis reaction Methods 0.000 description 1
239000005457 ice water Substances 0.000 description 1
239000012442 inert solvent Substances 0.000 description 1
238000001802 infusion Methods 0.000 description 1
239000004615 ingredient Substances 0.000 description 1
239000007924 injection Substances 0.000 description 1
238000002347 injection Methods 0.000 description 1
238000001990 intravenous administration Methods 0.000 description 1
INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
230000001057 ionotropic effect Effects 0.000 description 1
238000012417 linear regression Methods 0.000 description 1
JDOZOOBCADNBIJ-UHFFFAOYSA-N lithium;2h-pyridin-2-ide Chemical compound [Li+].C1=CC=N[C-]=C1 JDOZOOBCADNBIJ-UHFFFAOYSA-N 0.000 description 1
SNHOZPMHMQQMNI-UHFFFAOYSA-N lithium;2h-thiophen-2-ide Chemical compound [Li+].C=1C=[C-]SC=1 SNHOZPMHMQQMNI-UHFFFAOYSA-N 0.000 description 1
239000000314 lubricant Substances 0.000 description 1
229910052751 metal Inorganic materials 0.000 description 1
239000002184 metal Substances 0.000 description 1
229910052987 metal hydride Inorganic materials 0.000 description 1
150000004681 metal hydrides Chemical class 0.000 description 1
229910000000 metal hydroxide Inorganic materials 0.000 description 1
150000004692 metal hydroxides Chemical class 0.000 description 1
150000004682 monohydrates Chemical class 0.000 description 1
210000003205 muscle Anatomy 0.000 description 1
CNHABSNTBAWVIX-UHFFFAOYSA-N naphthalen-2-yl(pyridin-2-yl)methanone Chemical compound C=1C=C2C=CC=CC2=CC=1C(=O)C1=CC=CC=N1 CNHABSNTBAWVIX-UHFFFAOYSA-N 0.000 description 1
BIVRXKDHCPNHTK-UHFFFAOYSA-N naphthalen-2-yl-pyridin-2-yl-thiophen-2-ylmethanol Chemical compound C=1C=C2C=CC=CC2=CC=1C(C=1N=CC=CC=1)(O)C1=CC=CS1 BIVRXKDHCPNHTK-UHFFFAOYSA-N 0.000 description 1
239000012299 nitrogen atmosphere Substances 0.000 description 1
125000004433 nitrogen atom Chemical group N* 0.000 description 1
239000006186 oral dosage form Substances 0.000 description 1
239000012074 organic phase Substances 0.000 description 1
NOQXXYIGRPAZJC-UHFFFAOYSA-N oxiran-2-ylmethyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCC1OC1 NOQXXYIGRPAZJC-UHFFFAOYSA-N 0.000 description 1
239000001301 oxygen Substances 0.000 description 1
AJYOOHCNOXWTKJ-UHFFFAOYSA-N p-Chlorobenzhydrol Chemical compound C=1C=C(Cl)C=CC=1C(O)C1=CC=CC=C1 AJYOOHCNOXWTKJ-UHFFFAOYSA-N 0.000 description 1
125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
239000008188 pellet Substances 0.000 description 1
229960001412 pentobarbital Drugs 0.000 description 1
WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
229940083251 peripheral vasodilators purine derivative Drugs 0.000 description 1
239000012071 phase Substances 0.000 description 1
125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
229960003641 piperazine hydrate Drugs 0.000 description 1
230000009090 positive inotropic effect Effects 0.000 description 1
229910000027 potassium carbonate Inorganic materials 0.000 description 1
230000002335 preservative effect Effects 0.000 description 1
230000002265 prevention Effects 0.000 description 1
230000002035 prolonged effect Effects 0.000 description 1
RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
238000011110 re-filtration Methods 0.000 description 1
239000000376 reactant Substances 0.000 description 1
238000010992 reflux Methods 0.000 description 1
230000004044 response Effects 0.000 description 1
230000004043 responsiveness Effects 0.000 description 1
210000005241 right ventricle Anatomy 0.000 description 1
239000002002 slurry Substances 0.000 description 1
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
238000010561 standard procedure Methods 0.000 description 1
235000019698 starch Nutrition 0.000 description 1
239000008223 sterile water Substances 0.000 description 1
230000000638 stimulation Effects 0.000 description 1
239000012258 stirred mixture Substances 0.000 description 1
239000000126 substance Substances 0.000 description 1
150000008163 sugars Chemical class 0.000 description 1
239000000375 suspending agent Substances 0.000 description 1
NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
238000012546 transfer Methods 0.000 description 1
238000001291 vacuum drying Methods 0.000 description 1
239000003981 vehicle Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring 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
- A61P9/06—Antiarrhythmics
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/28—Oxygen atom
- C07D473/30—Oxygen atom attached in position 6, e.g. hypoxanthine
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/36—Sulfur atom
- C07D473/38—Sulfur atom attached in position 6

Landscapes

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

PH38279A 1988-03-03 1989-03-03 6-substituted purinyl piperazine derivatives useful as anti-arrhythmic agents PH26971A (en)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
US07/163,487 US4876257A (en)	1988-03-03	1988-03-03	6-Substituted purinyl piperazine derivatives useful as cardiotonic and antiarrhythmic agents

Publications (1)

Publication Number	Publication Date
PH26971A true PH26971A (en)	1992-12-28

Family

ID=22590215

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
PH38279A PH26971A (en)	1988-03-03	1989-03-03	6-substituted purinyl piperazine derivatives useful as anti-arrhythmic agents

Country Status (20)

Country	Link
US (1)	US4876257A (de)
EP (1)	EP0331511B1 (de)
JP (1)	JPH0826019B2 (de)
KR (1)	KR940002822B1 (de)
CN (1)	CN1031056C (de)
AT (1)	ATE92067T1 (de)
AU (1)	AU614583B2 (de)
DE (1)	DE68907750T2 (de)
DK (1)	DK101589A (de)
ES (1)	ES2059724T3 (de)
FI (1)	FI92587C (de)
HU (1)	HU205760B (de)
IE (1)	IE63457B1 (de)
IL (1)	IL89458A (de)
MY (1)	MY104959A (de)
NO (1)	NO171500C (de)
NZ (1)	NZ228167A (de)
PH (1)	PH26971A (de)
PT (1)	PT89903B (de)
ZA (1)	ZA891623B (de)

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US5057517A (en) *	1987-07-20	1991-10-15	Merck & Co., Inc.	Piperazinyl derivatives of purines and isosteres thereof as hypoglycemic agents
US5164390A (en) *	1988-03-03	1992-11-17	Ortho Pharmaceutical Corporation	6-substituted purinyl piperazine derivatives
US5021574A (en) *	1988-03-03	1991-06-04	Ortho Pharmaceutical Corporation	6-substituted purinyl piperazine derivatives
US4885300A (en) *	1988-03-03	1989-12-05	Ortho Pharmaceutical Corporation	4-Substituted pyrazolo[3,4-D]pyrimidine derivatives
AU648070B2 (en) *	1990-04-23	1994-04-14	Ortho Pharmaceutical Corporation	Process for preparing optically active isomers of 6-substituted purinyl piperazine derivatives
NZ237766A (en)	1990-04-23	1993-03-26	Ortho Pharma Corp	Process for preparing optically active isomers of 6-substituted purinyl-piperazine or -piperidine derivatives; optically active intermediates
US5215987A (en) *	1990-04-23	1993-06-01	Ortho Pharmaceutical Corporation	Substituted benzhydryl 2-hydroxypropyl piperazine derivatives
US5252569A (en) *	1990-05-23	1993-10-12	Ortho Pharmaceutical Corporation	6-substituted purinyl piperazine derivatives
NZ238122A (en) *	1990-05-23	1994-01-26	Ortho Pharma Corp	6-substituted purinyl piperazine derivatives and pharmaceutical
DK0626968T3 (da) *	1992-02-13	2001-12-31	Merrell Pharma Inc	Thiacykliske piperidinylderivater
EP0603404B1 (de) *	1992-05-15	1999-03-17	Mitsui Chemicals, Inc.	Verfahren zur herstellung von glycidderivaten
ZA9610736B (en)	1995-12-22	1997-06-27	Warner Lambert Co	2-Substituted piperidine analogs and their use as subtypeselective nmda receptor antagonists
EP0930291B1 (de) *	1996-09-18	2002-08-14	Daiso Co., Ltd.	Verfahren zur herstellung von 3-amino-2-hydroxy-1-propylethern
DE69717653T2 (de) *	1996-09-18	2003-09-25	Daiso Co., Ltd.	Verfahren zur herstellung von glycidylethern
AU744986B2 (en) *	1997-07-12	2002-03-07	Cancer Research Technology Limited	Cyclin dependent kinase inhibiting purine derivatives
KR20030025153A (ko) *	2001-09-19	2003-03-28	이보섭	지방족 또는 방향족 관능기를 갖는 6-치환 아미노퓨린유도체 및 이를 함유한 화장료 조성물
CA2513529A1 (en) *	2003-01-17	2004-08-19	Cv Therapeutics Inc.	Substituted heterocyclic compounds useful in the treatment of cardiovascular diseases
KR102704242B1 (ko)	2017-06-20	2024-09-09	임브리아 파마슈티칼스, 인크.	심장 대사의 효율을 증가시키기 위한 조성물 및 방법
US12318382B2 (en)	2018-10-17	2025-06-03	Imbria Pharmaceuticals, Inc.	Methods of treating rheumatic diseases using trimetazidine-based compounds
WO2020243120A1 (en)	2019-05-31	2020-12-03	Imbria Pharmaceuticals, Inc.	Methods of treating fibrosis using compounds that promote glucose oxidation
US11530184B2 (en)	2020-06-30	2022-12-20	Imbria Pharmaceuticals, Inc.	Crystal forms of 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate
US11780811B2 (en)	2020-06-30	2023-10-10	Imbria Pharmaceuticals, Inc.	Methods of synthesizing 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate
US11883396B2 (en)	2021-05-03	2024-01-30	Imbria Pharmaceuticals, Inc.	Methods of treating kidney conditions using modified forms of trimetazidine

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US3238207A (en) *	1960-03-01	1966-03-01	Burroughs Wellcome Co	6-oxyorganopurines and method of preparing them
US3232937A (en) *	1962-08-02	1966-02-01	Burroughs Wellcome Co	6-benzylmercaptopurines
US3135754A (en) *	1962-08-09	1964-06-02	Burroughs Wellcome Co	Purine derivatives
GB1133989A (en) *	1964-12-08	1968-11-20	Chugai Pharmaceutical Co Ltd	Theophylline derivatives, their salts and process for preparing the same
DE1620576A1 (de) *	1966-11-25	1970-02-26	Troponwerke Dinklage & Co	Verfahren zur Herstellung von Theophyllin- und Theobrominverbindungen
ES377662A1 (es) *	1969-03-28	1973-01-01	Walter Bestian	Procedimiento para la preparacion de nuevos compuestos de derivados de dialcohil-xantina.
DE2334009A1 (de) *	1973-07-04	1975-01-23	Boehringer Mannheim Gmbh	Purin-derivate sowie verfahren zu ihrer herstellung
US4189579A (en) *	1977-05-20	1980-02-19	The Dow Chemical Company	Aminoalkylthiopurines
US4426383A (en) *	1980-09-04	1984-01-17	Eisai Co., Ltd.	Theophylline and theobromine derivatives
DE3200304A1 (de) *	1981-01-16	1982-08-26	Sandoz-Patent-GmbH, 7850 Lörrach	3-aminopropoxyaryl-derivate, ihre herstellung und sie enthaltende arzneimittel
DE3307395A1 (de) *	1982-03-02	1983-09-08	Eisai Co., Ltd., Tokyo	Arzneimittel zur behandlung von schmerzen, fieber, gewebe- und/oder knochen- und gelenkentzuendungen mit einem gehalt an theobromin- oder theophyllinderivaten als aktivem bestandteil
DK157135C (da) *	1982-04-07	1990-04-02	Pfizer	Analogifremgangsmaade til fremstilling af 1,2,4-triazol-forbindelser eller farmaceutisk acceptable syreadditionssalte deraf
DE3703633A1 (de) *	1986-02-14	1987-08-20	Sandoz Ag	Purin-derivate, ihre herstellung und sie enthaltende arzneimittel
US4710572A (en) *	1986-07-30	1987-12-01	American Home Products Corporation	Histamine H1 antagonists

1988
- 1988-03-03 US US07/163,487 patent/US4876257A/en not_active Expired - Fee Related
1989
- 1989-02-28 NZ NZ228167A patent/NZ228167A/xx unknown
- 1989-03-01 AU AU30882/89A patent/AU614583B2/en not_active Ceased
- 1989-03-02 DK DK101589A patent/DK101589A/da unknown
- 1989-03-02 IL IL89458A patent/IL89458A/xx not_active IP Right Cessation
- 1989-03-02 ZA ZA891623A patent/ZA891623B/xx unknown
- 1989-03-02 NO NO890893A patent/NO171500C/no unknown
- 1989-03-02 IE IE68489A patent/IE63457B1/en not_active IP Right Cessation
- 1989-03-02 FI FI891003A patent/FI92587C/fi not_active IP Right Cessation
- 1989-03-02 MY MYPI89000259A patent/MY104959A/en unknown
- 1989-03-03 KR KR1019890002603A patent/KR940002822B1/ko not_active Expired - Fee Related
- 1989-03-03 PH PH38279A patent/PH26971A/en unknown
- 1989-03-03 HU HU891033A patent/HU205760B/hu not_active IP Right Cessation
- 1989-03-03 CN CN89102516A patent/CN1031056C/zh not_active Expired - Fee Related
- 1989-03-03 JP JP1051804A patent/JPH0826019B2/ja not_active Expired - Lifetime
- 1989-03-03 PT PT89903A patent/PT89903B/pt not_active IP Right Cessation
- 1989-03-03 AT AT89302141T patent/ATE92067T1/de not_active IP Right Cessation
- 1989-03-03 EP EP89302141A patent/EP0331511B1/de not_active Expired - Lifetime
- 1989-03-03 ES ES89302141T patent/ES2059724T3/es not_active Expired - Lifetime
- 1989-03-03 DE DE89302141T patent/DE68907750T2/de not_active Expired - Fee Related

Also Published As

Publication number	Publication date
FI92587C (fi)	1994-12-12
IE63457B1 (en)	1995-04-19
JPH01279887A (ja)	1989-11-10
PT89903B (pt)	1994-05-31
IL89458A (en)	1993-07-08
EP0331511B1 (de)	1993-07-28
US4876257A (en)	1989-10-24
NO890893L (no)	1989-09-04
JPH0826019B2 (ja)	1996-03-13
DE68907750T2 (de)	1994-01-05
NZ228167A (en)	1991-08-27
NO890893D0 (no)	1989-03-02
NO171500C (no)	1993-03-24
CN1036765A (zh)	1989-11-01
DE68907750D1 (de)	1993-09-02
FI891003A0 (fi)	1989-03-02
NO171500B (no)	1992-12-14
ZA891623B (en)	1990-11-28
DK101589D0 (da)	1989-03-02
PT89903A (pt)	1989-11-10
DK101589A (da)	1989-09-04
ATE92067T1 (de)	1993-08-15
FI92587B (fi)	1994-08-31
KR890014538A (ko)	1989-10-24
EP0331511A1 (de)	1989-09-06
MY104959A (en)	1994-07-30
HUT49352A (en)	1989-09-28
HU205760B (en)	1992-06-29
ES2059724T3 (es)	1994-11-16
FI891003A7 (fi)	1989-09-04
AU614583B2 (en)	1991-09-05
IE890684L (en)	1989-09-03
IL89458A0 (en)	1989-09-10
CN1031056C (zh)	1996-02-21
KR940002822B1 (ko)	1994-04-04
AU3088289A (en)	1989-09-07