IL117927A - Antiarrhythmic and cardioprotective substituted indenoylguanidines, process for their preparation and pharmaceutical and diagnostic compositions containing them - Google Patents

Antiarrhythmic and cardioprotective substituted indenoylguanidines, process for their preparation and pharmaceutical and diagnostic compositions containing them

Info

Publication number: IL117927A
Authority: IL; Israel
Prior art keywords: alkyl; aryl; carbon atoms; substituted; formula
Prior art date: 1995-04-18

Application number

IL11792796A

Other languages

English (en)

Other versions

IL117927A0 (en

Original Assignee

Hoechst Ag

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.)

1995-04-18

Filing date

1996-04-16

Publication date

2001-12-23

1996-04-16 Application filed by Hoechst Ag filed Critical Hoechst Ag

1996-08-04 Publication of IL117927A0 publication Critical patent/IL117927A0/xx

2001-12-23 Publication of IL117927A publication Critical patent/IL117927A/en

Links

WBCXYMNAMCHKSU-UHFFFAOYSA-N n-(diaminomethylidene)-1h-indene-1-carboxamide Chemical class C1=CC=C2C(C(=O)NC(=N)N)C=CC2=C1 WBCXYMNAMCHKSU-UHFFFAOYSA-N 0.000 title claims abstract description 5
238000002360 preparation method Methods 0.000 title claims description 22
238000000034 method Methods 0.000 title claims description 18
239000000203 mixture Substances 0.000 title claims description 10
230000008569 process Effects 0.000 title claims description 6
230000003288 anthiarrhythmic effect Effects 0.000 title description 14
239000003416 antiarrhythmic agent Substances 0.000 title description 6
230000003293 cardioprotective effect Effects 0.000 title description 5
125000000217 alkyl group Chemical group 0.000 claims abstract description 82
125000004432 carbon atom Chemical group C* 0.000 claims abstract description 58
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 25
239000001257 hydrogen Substances 0.000 claims abstract description 22
125000001072 heteroaryl group Chemical group 0.000 claims abstract description 20
125000003118 aryl group Chemical group 0.000 claims abstract description 17
150000002431 hydrogen Chemical class 0.000 claims abstract description 15
125000003107 substituted aryl group Chemical group 0.000 claims abstract description 13
239000002253 acid Substances 0.000 claims abstract description 12
125000002877 alkyl aryl group Chemical group 0.000 claims abstract description 12
229910052740 iodine Inorganic materials 0.000 claims abstract description 11
125000003342 alkenyl group Chemical group 0.000 claims abstract description 10
125000000304 alkynyl group Chemical group 0.000 claims abstract description 10
125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 10
229910052794 bromium Inorganic materials 0.000 claims abstract description 10
229910052736 halogen Inorganic materials 0.000 claims abstract description 7
150000002367 halogens Chemical class 0.000 claims abstract description 7
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 6
229910052717 sulfur Inorganic materials 0.000 claims abstract description 6
229910052760 oxygen Inorganic materials 0.000 claims abstract description 5
229910052500 inorganic mineral Inorganic materials 0.000 claims abstract description 4
239000011707 mineral Substances 0.000 claims abstract description 4
231100000252 nontoxic Toxicity 0.000 claims abstract description 4
230000003000 nontoxic effect Effects 0.000 claims abstract description 4
125000002373 5 membered heterocyclic group Chemical group 0.000 claims abstract description 3
125000004070 6 membered heterocyclic group Chemical group 0.000 claims abstract description 3
125000003341 7 membered heterocyclic group Chemical group 0.000 claims abstract description 3
229910052731 fluorine Inorganic materials 0.000 claims abstract description 3
125000000896 monocarboxylic acid group Chemical group 0.000 claims abstract 6
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract 4
150000001875 compounds Chemical class 0.000 claims description 91
238000011282 treatment Methods 0.000 claims description 22
239000003814 drug Substances 0.000 claims description 18
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 10
206010061216 Infarction Diseases 0.000 claims description 9
201000010099 disease Diseases 0.000 claims description 9
230000007574 infarction Effects 0.000 claims description 9
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
150000003839 salts Chemical class 0.000 claims description 7
210000000056 organ Anatomy 0.000 claims description 6
238000011321 prophylaxis Methods 0.000 claims description 6
125000000547 substituted alkyl group Chemical group 0.000 claims description 6
CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 5
206010003119 arrhythmia Diseases 0.000 claims description 5
SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 5
125000004076 pyridyl group Chemical group 0.000 claims description 5
125000001424 substituent group Chemical group 0.000 claims description 5
125000002541 furyl group Chemical group 0.000 claims description 4
230000000302 ischemic effect Effects 0.000 claims description 4
239000008194 pharmaceutical composition Substances 0.000 claims description 4
206010002383 Angina Pectoris Diseases 0.000 claims description 3
206010020772 Hypertension Diseases 0.000 claims description 3
230000000747 cardiac effect Effects 0.000 claims description 3
230000004663 cell proliferation Effects 0.000 claims description 3
206010020718 hyperplasia Diseases 0.000 claims description 3
125000002883 imidazolyl group Chemical group 0.000 claims description 3
125000005956 isoquinolyl group Chemical group 0.000 claims description 3
230000002093 peripheral effect Effects 0.000 claims description 3
210000002307 prostate Anatomy 0.000 claims description 3
230000035939 shock Effects 0.000 claims description 3
125000001544 thienyl group Chemical group 0.000 claims description 3
125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 2
206010008190 Cerebrovascular accident Diseases 0.000 claims description 2
208000002249 Diabetes Complications Diseases 0.000 claims description 2
206010012655 Diabetic complications Diseases 0.000 claims description 2
206010019668 Hepatic fibrosis Diseases 0.000 claims description 2
206010028980 Neoplasm Diseases 0.000 claims description 2
208000006011 Stroke Diseases 0.000 claims description 2
230000000879 anti-atherosclerotic effect Effects 0.000 claims description 2
201000011510 cancer Diseases 0.000 claims description 2
230000003111 delayed effect Effects 0.000 claims description 2
230000003176 fibrotic effect Effects 0.000 claims description 2
230000002062 proliferating effect Effects 0.000 claims description 2
208000005069 pulmonary fibrosis Diseases 0.000 claims description 2
201000002793 renal fibrosis Diseases 0.000 claims description 2
238000003860 storage Methods 0.000 claims description 2
210000003169 central nervous system Anatomy 0.000 claims 1
238000003745 diagnosis Methods 0.000 claims 1
238000004519 manufacturing process Methods 0.000 claims 1
210000001428 peripheral nervous system Anatomy 0.000 claims 1
238000004321 preservation Methods 0.000 claims 1
125000005493 quinolyl group Chemical group 0.000 claims 1
-1 C2-C3-alkynyl Chemical group 0.000 abstract description 18
229910052801 chlorine Inorganic materials 0.000 abstract description 2
229910006069 SO3H Inorganic materials 0.000 abstract 2
125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 abstract 2
MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 abstract 1
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 17
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
230000015572 biosynthetic process Effects 0.000 description 14
238000003786 synthesis reaction Methods 0.000 description 14
239000002904 solvent Substances 0.000 description 11
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 10
239000000243 solution Substances 0.000 description 10
WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
XSDQTOBWRPYKKA-UHFFFAOYSA-N amiloride Chemical compound NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N XSDQTOBWRPYKKA-UHFFFAOYSA-N 0.000 description 8
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
241000700159 Rattus Species 0.000 description 7
229960002576 amiloride Drugs 0.000 description 7
238000006243 chemical reaction Methods 0.000 description 7
210000003743 erythrocyte Anatomy 0.000 description 7
239000011541 reaction mixture Substances 0.000 description 7
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
125000003545 alkoxy group Chemical group 0.000 description 6
125000000623 heterocyclic group Chemical group 0.000 description 6
239000011734 sodium Substances 0.000 description 6
238000012360 testing method Methods 0.000 description 6
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
125000002252 acyl group Chemical group 0.000 description 5
230000000694 effects Effects 0.000 description 5
229940098779 methanesulfonic acid Drugs 0.000 description 5
229910052708 sodium Inorganic materials 0.000 description 5
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 4
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 4
229910052757 nitrogen Inorganic materials 0.000 description 4
XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 4
230000010410 reperfusion Effects 0.000 description 4
238000003756 stirring Methods 0.000 description 4
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
208000003663 ventricular fibrillation Diseases 0.000 description 4
BINGGEWUXWUXMJ-UHFFFAOYSA-N 1h-indene-2-carboxylic acid Chemical class C1=CC=C2CC(C(=O)O)=CC2=C1 BINGGEWUXWUXMJ-UHFFFAOYSA-N 0.000 description 3
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
241000283973 Oryctolagus cuniculus Species 0.000 description 3
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
150000001338 aliphatic hydrocarbons Chemical class 0.000 description 3
230000006793 arrhythmia Effects 0.000 description 3
210000004369 blood Anatomy 0.000 description 3
239000008280 blood Substances 0.000 description 3
239000003995 emulsifying agent Substances 0.000 description 3
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
238000002474 experimental method Methods 0.000 description 3
125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
230000005764 inhibitory process Effects 0.000 description 3
208000028867 ischemia Diseases 0.000 description 3
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
230000003389 potentiating effect Effects 0.000 description 3
239000000047 product Substances 0.000 description 3
230000001681 protective effect Effects 0.000 description 3
230000000054 salidiuretic effect Effects 0.000 description 3
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
JEJQJCKVMQVOHZ-UHFFFAOYSA-N 5,6-dihydro-4h-1-benzothiophen-7-one Chemical compound O=C1CCCC2=C1SC=C2 JEJQJCKVMQVOHZ-UHFFFAOYSA-N 0.000 description 2
QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
LPMXVESGRSUGHW-UHFFFAOYSA-N Acolongiflorosid K Natural products OC1C(O)C(O)C(C)OC1OC1CC2(O)CCC3C4(O)CCC(C=5COC(=O)C=5)C4(C)CC(O)C3C2(CO)C(O)C1 LPMXVESGRSUGHW-UHFFFAOYSA-N 0.000 description 2
201000001320 Atherosclerosis Diseases 0.000 description 2
239000005711 Benzoic acid Substances 0.000 description 2
XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
208000007530 Essential hypertension Diseases 0.000 description 2
XDWQYMXQMNUWID-UHFFFAOYSA-N Ethyl 2-benzylacetoacetate Chemical compound CCOC(=O)C(C(C)=O)CC1=CC=CC=C1 XDWQYMXQMNUWID-UHFFFAOYSA-N 0.000 description 2
WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
206010020880 Hypertrophy Diseases 0.000 description 2
206010021143 Hypoxia Diseases 0.000 description 2
CPLXHLVBOLITMK-UHFFFAOYSA-N Magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 2
241001465754 Metazoa Species 0.000 description 2
102000050381 Na+/H+ exchanger Human genes 0.000 description 2
GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
239000005642 Oleic acid Substances 0.000 description 2
ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
LPMXVESGRSUGHW-GHYGWZAOSA-N Ouabain Natural products O([C@@H]1[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O1)[C@H]1C[C@@H](O)[C@@]2(CO)[C@@](O)(C1)CC[C@H]1[C@]3(O)[C@@](C)([C@H](C4=CC(=O)OC4)CC3)C[C@@H](O)[C@H]21 LPMXVESGRSUGHW-GHYGWZAOSA-N 0.000 description 2
KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
108091006672 Sodium–hydrogen antiporter Proteins 0.000 description 2
235000021355 Stearic acid Nutrition 0.000 description 2
244000166550 Strophanthus gratus Species 0.000 description 2
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
150000007513 acids Chemical class 0.000 description 2
230000003213 activating effect Effects 0.000 description 2
230000010933 acylation Effects 0.000 description 2
238000005917 acylation reaction Methods 0.000 description 2
229910000147 aluminium phosphate Inorganic materials 0.000 description 2
238000004458 analytical method Methods 0.000 description 2
150000001450 anions Chemical class 0.000 description 2
210000001367 artery Anatomy 0.000 description 2
SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
229940092714 benzenesulfonic acid Drugs 0.000 description 2
235000010233 benzoic acid Nutrition 0.000 description 2
AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical class BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
125000004369 butenyl group Chemical class C(=CCC)* 0.000 description 2
125000000484 butyl group Chemical class [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
125000000480 butynyl group Chemical class [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 2
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
239000000969 carrier Substances 0.000 description 2
210000004027 cell Anatomy 0.000 description 2
230000001413 cellular effect Effects 0.000 description 2
239000003795 chemical substances by application Substances 0.000 description 2
HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
238000004440 column chromatography Methods 0.000 description 2
238000001816 cooling Methods 0.000 description 2
210000004351 coronary vessel Anatomy 0.000 description 2
238000005859 coupling reaction Methods 0.000 description 2
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206010012601 diabetes mellitus Diseases 0.000 description 2
208000035475 disorder Diseases 0.000 description 2
239000002934 diuretic Substances 0.000 description 2
239000000839 emulsion Substances 0.000 description 2
XQKOXWIOMWAGIY-UHFFFAOYSA-N ethyl 1h-indene-2-carboxylate Chemical compound C1=CC=C2CC(C(=O)OCC)=CC2=C1 XQKOXWIOMWAGIY-UHFFFAOYSA-N 0.000 description 2
CRUSDTXUTKVYLW-UHFFFAOYSA-N ethyl 3-oxo-1,2-dihydroindene-2-carboxylate Chemical compound C1=CC=C2C(=O)C(C(=O)OCC)CC2=C1 CRUSDTXUTKVYLW-UHFFFAOYSA-N 0.000 description 2
229940093499 ethyl acetate Drugs 0.000 description 2
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RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
238000001704 evaporation Methods 0.000 description 2
239000000706 filtrate Substances 0.000 description 2
239000012458 free base Substances 0.000 description 2
239000008103 glucose Substances 0.000 description 2
150000007928 imidazolide derivatives Chemical class 0.000 description 2
239000012442 inert solvent Substances 0.000 description 2
238000001990 intravenous administration Methods 0.000 description 2
QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
239000004310 lactic acid Substances 0.000 description 2
235000014655 lactic acid Nutrition 0.000 description 2
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
208000010125 myocardial infarction Diseases 0.000 description 2
XRNKEFOSRDXRNI-UHFFFAOYSA-N n-(diaminomethylidene)-3-methyl-1h-indene-2-carboxamide;hydrochloride Chemical compound Cl.C1=CC=C2C(C)=C(C(=O)NC(N)=N)CC2=C1 XRNKEFOSRDXRNI-UHFFFAOYSA-N 0.000 description 2
AJDQRQQNNLZLPM-UHFFFAOYSA-N n-(diaminomethylidene)benzamide Chemical class NC(N)=NC(=O)C1=CC=CC=C1 AJDQRQQNNLZLPM-UHFFFAOYSA-N 0.000 description 2
230000007935 neutral effect Effects 0.000 description 2
239000011664 nicotinic acid Substances 0.000 description 2
229960003512 nicotinic acid Drugs 0.000 description 2
235000001968 nicotinic acid Nutrition 0.000 description 2
229910017604 nitric acid Inorganic materials 0.000 description 2
QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
235000021313 oleic acid Nutrition 0.000 description 2
LPMXVESGRSUGHW-HBYQJFLCSA-N ouabain Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1C[C@@]2(O)CC[C@H]3[C@@]4(O)CC[C@H](C=5COC(=O)C=5)[C@@]4(C)C[C@@H](O)[C@@H]3[C@@]2(CO)[C@H](O)C1 LPMXVESGRSUGHW-HBYQJFLCSA-N 0.000 description 2
229960003343 ouabain Drugs 0.000 description 2
235000006408 oxalic acid Nutrition 0.000 description 2
125000005981 pentynyl group Chemical class 0.000 description 2
239000000546 pharmaceutical excipient Substances 0.000 description 2
230000000144 pharmacologic effect Effects 0.000 description 2
239000002798 polar solvent Substances 0.000 description 2
239000000843 powder Substances 0.000 description 2
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238000005292 vacuum distillation Methods 0.000 description 1
125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
230000002792 vascular Effects 0.000 description 1
239000008158 vegetable oil Substances 0.000 description 1
235000013311 vegetables Nutrition 0.000 description 1
210000003462 vein Anatomy 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
- C07C279/22—Y being a hydrogen or a carbon atom, e.g. benzoylguanidines
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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
- A61P9/06—Antiarrhythmics
- 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
- A61P9/08—Vasodilators for multiple indications
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Landscapes

Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
General Health & Medical Sciences (AREA)
Veterinary Medicine (AREA)
Public Health (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Bioinformatics & Cheminformatics (AREA)
Pharmacology & Pharmacy (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
Engineering & Computer Science (AREA)
Cardiology (AREA)
Heart & Thoracic Surgery (AREA)
Diabetes (AREA)
Urology & Nephrology (AREA)
Obesity (AREA)
Hematology (AREA)
Endocrinology (AREA)
Surgery (AREA)
Emergency Medicine (AREA)
Vascular Medicine (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Optical Record Carriers And Manufacture Thereof (AREA)

IL11792796A 1995-04-18 1996-04-16 Antiarrhythmic and cardioprotective substituted indenoylguanidines, process for their preparation and pharmaceutical and diagnostic compositions containing them IL117927A (en)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
EP95105724		1995-04-18
US08/633,223 US5733934A (en)	1995-04-18	1996-04-16	Antiarrythmic and cardioprotective substituted indenoylguanidines

Publications (2)

Publication Number	Publication Date
IL117927A0 IL117927A0 (en)	1996-08-04
IL117927A true IL117927A (en)	2001-12-23

Family

ID=26138562

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
IL11792796A IL117927A (en)	1995-04-18	1996-04-16	Antiarrhythmic and cardioprotective substituted indenoylguanidines, process for their preparation and pharmaceutical and diagnostic compositions containing them

Country Status (23)

Country	Link
US (1)	US5733934A (de)
EP (1)	EP0738712B1 (de)
JP (1)	JPH08291131A (de)
CN (1)	CN1061648C (de)
AT (1)	ATE183498T1 (de)
AU (1)	AU706055B2 (de)
BR (1)	BR9601989A (de)
CA (1)	CA2174406A1 (de)
CZ (1)	CZ291538B6 (de)
DE (1)	DE69603771T2 (de)
DK (1)	DK0738712T3 (de)
ES (1)	ES2135811T3 (de)
GR (1)	GR3031540T3 (de)
HU (1)	HUP9600998A3 (de)
IL (1)	IL117927A (de)
NO (1)	NO305655B1 (de)
NZ (1)	NZ286380A (de)
PL (1)	PL182566B1 (de)
RU (1)	RU2182902C2 (de)
SI (1)	SI0738712T1 (de)
SK (1)	SK282011B6 (de)
TR (1)	TR199600316A1 (de)
ZA (1)	ZA963046B (de)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
EP0837055A1 (de) *	1996-07-30	1998-04-22	Hoechst Aktiengesellschaft	Substituierte Indanylidinacetylguanidine als Natrium-Protonen-Antiporter, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikamente oder Diagnostika und sie enthaltende Medikamente
JP2002502414A (ja) *	1997-06-02	2002-01-22	藤沢薬品工業株式会社	細胞中のＮａ▲上＋▼／Ｈ▲上＋▼交換の阻害剤としてのグアニジン誘導体
US6011059A (en) *	1997-12-24	2000-01-04	Bristol-Myers Squibb Company	Acyl guanidine sodium/proton exchange inhibitors and method
US6160134A (en) *	1997-12-24	2000-12-12	Bristol-Myers Squibb Co.	Process for preparing chiral cyclopropane carboxylic acids and acyl guanidines
TW462964B (en)	1998-05-26	2001-11-11	Sumitomo Pharma	Guanidine derivatives for the treatment and prevention of disorders caused by inhibiting hyperactivity of Na/H exchange transport system and process for producing the same
DE19859727A1 (de) *	1998-12-23	2000-06-29	Aventis Pharma Gmbh	Die Verwendung von Hemmern des Natrium-Wasserstoff-Austauschers zur Herstellung eines Medikaments zur Verhinderung von altersbedingten Organ-Dysfunktionen, altersbedingten Erkrankungen zur Lebensverlängerung
WO2000064445A1 (en)	1999-04-23	2000-11-02	Bristol-Myers Squibb Company	Bicyclic acyl guanidine sodium/proton exchange inhibitors and method
BRPI0411900B8 (pt) *	2003-06-26	2021-05-25	Biotron Ltd	compostos e composições farmacêuticas compreendendo os mesmos
US20070099968A1 (en) *	2004-06-26	2007-05-03	Biotron Limited	Antiviral compounds and methods

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US2734904A (en) *		1956-02-14		Xcxnhxc-nh
US3780027A (en) *	1970-04-29	1973-12-18	Merck & Co Inc	Anthranilic acid derivatives
US4544670A (en) *	1982-08-24	1985-10-01	William H. Rorer, Inc.	Method of treating coccidiosis with acyl guanidines
DE3929582A1 (de) *	1989-09-06	1991-03-07	Hoechst Ag	Benzoylguanidine, verfahren zu ihrer herstellung, ihre verwendung als medikament sowie sie enthaltendes medikament
DK0556673T3 (da) *	1992-02-15	1998-04-14	Hoechst Ag	o-Substituerede benzoylguanidiner til behandling og profylakse af hjerterytmeforstyrrelser og iskæmisk inducerede skader samt til inhiberering af celleproliferation
DE4326005A1 (de) *	1993-08-03	1995-02-09	Hoechst Ag	Benzokondensierte 5-Ringheterocyclen, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament, ihre Verwendung als Diagnostikum, sowie sie enthaltendes Medikament
EP0639573A1 (de) *	1993-08-03	1995-02-22	Hoechst Aktiengesellschaft	Benzokondensierte 5-Ringheterocyclen, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament, ihre Verwendung als Diagnostikum, sowie sie enthaltendes Medikament
DE4327244A1 (de) *	1993-08-13	1995-02-16	Hoechst Ag	Harnstoffsubstituierte Benzoylguandine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament

1996
- 1996-04-15 DK DK96105873T patent/DK0738712T3/da active
- 1996-04-15 EP EP96105873A patent/EP0738712B1/de not_active Expired - Lifetime
- 1996-04-15 ES ES96105873T patent/ES2135811T3/es not_active Expired - Lifetime
- 1996-04-15 SI SI9630097T patent/SI0738712T1/xx not_active IP Right Cessation
- 1996-04-15 AT AT96105873T patent/ATE183498T1/de not_active IP Right Cessation
- 1996-04-15 DE DE69603771T patent/DE69603771T2/de not_active Expired - Fee Related
- 1996-04-16 AU AU50676/96A patent/AU706055B2/en not_active Ceased
- 1996-04-16 CZ CZ19961096A patent/CZ291538B6/cs not_active IP Right Cessation
- 1996-04-16 CN CN96104990A patent/CN1061648C/zh not_active Expired - Fee Related
- 1996-04-16 NZ NZ286380A patent/NZ286380A/en unknown
- 1996-04-16 US US08/633,223 patent/US5733934A/en not_active Expired - Fee Related
- 1996-04-16 SK SK483-96A patent/SK282011B6/sk unknown
- 1996-04-16 IL IL11792796A patent/IL117927A/en not_active IP Right Cessation
- 1996-04-16 TR TR96/00316A patent/TR199600316A1/xx unknown
- 1996-04-17 PL PL96313809A patent/PL182566B1/pl unknown
- 1996-04-17 NO NO961521A patent/NO305655B1/no not_active IP Right Cessation
- 1996-04-17 ZA ZA963046A patent/ZA963046B/xx unknown
- 1996-04-17 RU RU96107258/04A patent/RU2182902C2/ru not_active IP Right Cessation
- 1996-04-17 HU HU9600998A patent/HUP9600998A3/hu unknown
- 1996-04-17 JP JP8094952A patent/JPH08291131A/ja active Pending
- 1996-04-17 CA CA002174406A patent/CA2174406A1/en not_active Abandoned
- 1996-04-18 BR BR9601989A patent/BR9601989A/pt active Search and Examination
1999
- 1999-10-15 GR GR990402627T patent/GR3031540T3/el unknown

Also Published As

Publication number	Publication date
GR3031540T3 (en)	2000-01-31
NZ286380A (en)	1997-09-22
EP0738712A1 (de)	1996-10-23
NO961521L (no)	1996-10-21
IL117927A0 (en)	1996-08-04
DE69603771T2 (de)	2000-09-07
CA2174406A1 (en)	1996-10-19
HU9600998D0 (en)	1996-06-28
CZ291538B6 (cs)	2003-03-12
CZ109696A3 (en)	1996-11-13
TR199600316A1 (tr)	1997-03-21
MX9601424A (es)	1997-07-31
SK282011B6 (sk)	2001-10-08
ATE183498T1 (de)	1999-09-15
SI0738712T1 (en)	1999-12-31
AU706055B2 (en)	1999-06-10
HUP9600998A3 (en)	1997-11-28
PL182566B1 (pl)	2002-01-31
HUP9600998A2 (en)	1997-01-28
AU5067696A (en)	1996-10-31
CN1061648C (zh)	2001-02-07
US5733934A (en)	1998-03-31
ES2135811T3 (es)	1999-11-01
DE69603771D1 (de)	1999-09-23
JPH08291131A (ja)	1996-11-05
CN1140164A (zh)	1997-01-15
NO305655B1 (no)	1999-07-05
ZA963046B (en)	1996-10-22
SK48396A3 (en)	1996-12-04
NO961521D0 (no)	1996-04-17
BR9601989A (pt)	1998-04-07
RU2182902C2 (ru)	2002-05-27
DK0738712T3 (da)	2000-03-06
EP0738712B1 (de)	1999-08-18

Legal Events

Date	Code	Title
2002-05-23	FF	Patent granted
2002-06-30	KB	Patent renewed
2006-12-27	MM9K	Patent not in force due to non-payment of renewal fees

Publication	Publication Date	Title
US5364868A (en)	1994-11-15	Amino-substituted benzoylguanidines, process for their preparation, their use as a medicament and medicament containing them
US5866610A (en)	1999-02-02	Substituted benzoylguanidines, process for their preparation, their use as a pharmaceutical as inhibitors of the cellular NA+/H+ exchange or as a diagnostic, and pharmaceutical containing them
US5693672A (en)	1997-12-02	3,4,5-substituted benzoylguanidines, process for their preparation, their use as a medicament or diagnostic and medicament containing them
IL109887A (en)	1998-02-22	Substituted benzoylguanidines, process for their preparation and pharmaceutical compositions containing them
US5516805A (en)	1996-05-14	3,5-substituted aminobenzoylguanidines, their use as a medicament or diagnostic and medicament containing them
IL114216A (en)	2001-01-11	Phenyl-substituted alkenylcarboguanidides carrying perfluoroalkyl groups, a process for their preparation and pharmaceutical compositions containing them
AU706055B2 (en)	1999-06-10	Antiarrhythmic and cardioprotective substituted indenoylguanidines
CA2211982C (en)	2007-09-18	Substituted indanylidineacetylguanidines, process for their preparation,their use as medicaments or diagnostic and medicaments containing them
US6156800A (en)	2000-12-05	4-fluoroalkyl-substituted benzoylguanidines, process for their preparation, their use as a medicament or diagnostic, and medicament containing them
MXPA97005737A (en)	1998-02-01	Substitute indianilidinacylukinides, procedure for its preparation, its use as medicines or diagnostic agents and medicines containing them
US5756535A (en)	1998-05-26	Substituted thiophenylalkenylcarboxylic acid guanidines, processes for their preparation, their use as a medicament or diagnositc, and a medicament containing them
CZ290027B6 (cs)	2002-05-15	Benzoylguanidin, jeho použití jako léčivo a léčivo tento benzoylguanidin obsahující
MXPA96001424A (en)	1997-12-01	Indenoilguanidines replaced antiarrhythmic and cardioprotect