DE4326005A1 - Benzo-fused 5-membered ring heterocycles, processes for their preparation, their use as a medicament, their use as a diagnostic, and medicament containing them - Google Patents
Benzo-fused 5-membered ring heterocycles, processes for their preparation, their use as a medicament, their use as a diagnostic, and medicament containing themInfo
- Publication number
- DE4326005A1 DE4326005A1 DE4326005A DE4326005A DE4326005A1 DE 4326005 A1 DE4326005 A1 DE 4326005A1 DE 4326005 A DE4326005 A DE 4326005A DE 4326005 A DE4326005 A DE 4326005A DE 4326005 A1 DE4326005 A1 DE 4326005A1
- Authority
- DE
- Germany
- Prior art keywords
- methyl
- substituents
- compound
- atom
- preparation
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
Links
- 239000003814 drug Substances 0.000 title claims description 19
- 238000002360 preparation method Methods 0.000 title claims description 17
- 238000000034 method Methods 0.000 title claims description 11
- 125000000623 heterocyclic group Chemical group 0.000 title claims description 6
- 230000008569 process Effects 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 45
- 125000001424 substituent group Chemical group 0.000 claims description 33
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 20
- 229910052760 oxygen Inorganic materials 0.000 claims description 20
- 239000001301 oxygen Substances 0.000 claims description 20
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 238000011282 treatment Methods 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- 125000004434 sulfur atom Chemical group 0.000 claims description 10
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 9
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 9
- 229960004198 guanidine Drugs 0.000 claims description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 6
- 210000000056 organ Anatomy 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000005493 quinolyl group Chemical group 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
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- 230000004663 cell proliferation Effects 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 4
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- IOERUDSXZKOKQI-UHFFFAOYSA-N 5-chloro-n-(n'-methylcarbamimidoyl)-1h-indole-2-carboxamide;hydrochloride Chemical compound Cl.ClC1=CC=C2NC(C(=O)N=C(N)NC)=CC2=C1 IOERUDSXZKOKQI-UHFFFAOYSA-N 0.000 claims description 3
- PPJSRJUPJJEHLL-UHFFFAOYSA-N 5-chloro-n-(n-chloro-n'-methylcarbamimidoyl)-1h-indole-2-carboxamide;hydrochloride Chemical compound Cl.ClC1=CC=C2NC(C(=O)N=C(NCl)NC)=CC2=C1 PPJSRJUPJJEHLL-UHFFFAOYSA-N 0.000 claims description 3
- SYMNTDYJQQFXAJ-UHFFFAOYSA-N 5-fluoro-n-(n'-methylcarbamimidoyl)-1h-indole-2-carboxamide;hydrochloride Chemical compound Cl.FC1=CC=C2NC(C(=O)N=C(N)NC)=CC2=C1 SYMNTDYJQQFXAJ-UHFFFAOYSA-N 0.000 claims description 3
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- 108091006672 Sodium–hydrogen antiporter Proteins 0.000 claims description 3
- MDAQTSRHKIGCSR-UHFFFAOYSA-N n-(n-chloro-n'-methylcarbamimidoyl)-1h-indole-2-carboxamide;hydrochloride Chemical compound Cl.C1=CC=C2NC(C(=O)NC(NCl)=NC)=CC2=C1 MDAQTSRHKIGCSR-UHFFFAOYSA-N 0.000 claims description 3
- 230000002093 peripheral effect Effects 0.000 claims description 3
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- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 2
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 206010002383 Angina Pectoris Diseases 0.000 claims description 2
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims description 2
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- 208000002249 Diabetes Complications Diseases 0.000 claims description 2
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- 102000050381 Na+/H+ exchanger Human genes 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 239000000654 additive Substances 0.000 claims description 2
- 230000000879 anti-atherosclerotic effect Effects 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
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- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- -1 alkyl radicals Chemical class 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
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- 238000000354 decomposition reaction Methods 0.000 description 9
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- 229960002576 amiloride Drugs 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
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- 238000006243 chemical reaction Methods 0.000 description 6
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- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
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- HCUARRIEZVDMPT-UHFFFAOYSA-N Indole-2-carboxylic acid Chemical class C1=CC=C2NC(C(=O)O)=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
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- 201000001320 Atherosclerosis Diseases 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 208000007530 Essential hypertension Diseases 0.000 description 2
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Classifications
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- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/26—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/28—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
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- C07D277/62—Benzothiazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
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- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
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- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D277/82—Nitrogen atoms
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- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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- C—CHEMISTRY; METALLURGY
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- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
Description
Die Erfindung betrifft benzokondensierte 5-Ringheterocyclen der Formel IThe invention relates to benzo-fused 5-ring heterocycles of the formula I.
worin bedeuten:
X N oder CR(6),
Y Sauerstoff, S oder NR(7),
einer der Substituenten R(1) bis R(6) eine -CO-N=C(NH₂)₂-Gruppe,
die jeweils anderen Substituenten R(1) bis R(6)
Wasserstoff, F, Cl, Br, I, (C₁-C₆)-Alkyl,
bis zu zwei der anderen Substituenten R(1) bis R(6)
CN, NO₂, N₃, (C₁-C₄)-Alkyloxy, CF3,
bis zu einem der anderen Substituenten
R(8)-CnH2n-Z-,
n Null bis 10,
wobei die Alkylenkette -CnH2n- geradkettig oder verzweigt ist und
wobei ein C-Atom durch ein Sauerstoff- oder S-Atom oder durch
ein N-Atom ersetzt sein kann,
R(8) Wasserstoff, (C₂-C₆)-Alkenyl, (C₃-C₁₀)-Cycloalkyl,
das unsubstituiert oder durch 1 bis 4 Methylgruppen
oder eine OH- Gruppe substituiert ist, oder eine
Ethylengruppe -CH=CH- enthalten kann, und worin
eine Methylengruppe durch ein Sauerstoff- oder S-
Atom oder durch ein N-Atom ersetzt sein kann,
Phenyl,
unsubstituiert oder substituiert durch 1 bis 3
Substituenten aus der Reihe
F, Cl, Br, I, CF₃, CH₃-S(O)s-,
s Null, 1 oder 2,
R(9)-Wy-,
R(9) H, Methyl, Ethyl,
W gleich Sauerstoff, NR(10),
R(10) H oder Methyl,
y Null oder 1,
CmF2m+1,
m 1 bis 3,
1- oder 2-Naphthyl, Pyridyl, Chinolyl oder Isochinolyl,
Z -CO-, -CH₂-, [CR(11)(OH)]q-
q 1, 2 oder 3,
R(11) H oder Methyl,
Sauerstoff, -NR(12)-,
R(12) H, Methyl,
-S(O)s-,
s Null, 1 oder 2,
-SO₂-NR(12)-,
R(12) H, (C₁-C₄)-Alkyl,
R(7) Wasserstoff, (C₁-C₁₀)-Alkyl, (C₂-C₁₀)-Alkenyl, R(8)-CnH2n-,
sowie deren pharmazeutisch verträgliche Salze.
in which mean:
XN or CR (6),
Y oxygen, S or NR (7),
one of the substituents R (1) to R (6) is a -CO-N = C (NH₂) ₂ group,
the other substituents R (1) to R (6)
Hydrogen, F, Cl, Br, I, (C₁-C₆) alkyl,
up to two of the other substituents R (1) to R (6)
CN, NO₂, N₃, (C₁-C₄) alkyloxy, CF 3,
up to one of the other substituents
R (8) -C n H 2n -Z-,
n zero to 10,
where the alkylene chain -C n H 2n - is straight-chain or branched and where a C atom can be replaced by an oxygen or S atom or by an N atom,
R (8) hydrogen, (C₂-C₆) alkenyl, (C₃-C₁₀) cycloalkyl,
which is unsubstituted or substituted by 1 to 4 methyl groups or an OH group, or can contain an ethylene group -CH = CH-, and in which a methylene group can be replaced by an oxygen or S atom or by an N atom,
Phenyl,
unsubstituted or substituted by 1 to 3 substituents from the series
F, Cl, Br, I, CF₃, CH₃-S (O) s -,
s zero, 1 or 2,
R (9) -W y -,
R (9) H, methyl, ethyl, W is oxygen, NR (10),
R (10) H or methyl, y zero or 1,
C m F 2m + 1 ,
m 1 to 3, 1- or 2-naphthyl, pyridyl, quinolyl or isoquinolyl,
Z -CO-, -CH₂-, [CR (11) (OH)] q -
q 1, 2 or 3, R (11) H or methyl,
Oxygen, -NR (12) -, R (12) H, methyl,
-S (O) s -, s zero, 1 or 2,
-SO₂-NR (12) -, R (12) H, (C₁-C₄) alkyl,
R (7) hydrogen, (C₁-C₁₀) alkyl, (C₂-C₁₀) alkenyl, R (8) -C n H 2n -,
and their pharmaceutically acceptable salts.
Enthalten die Substituenten R(1) bis R(7) ein oder mehrere Asymmetriezentren, so gehören sowohl S wie auch R konfigurierte Verbindungen zur Erfindung. Die Verbindungen können als optische Isomere, als Racemate oder als Gemische derselben vorliegen.If the substituents R (1) to R (7) contain one or more centers of asymmetry, so both S and R configured connections belong to the invention. The Compounds can be used as optical isomers, as racemates or as mixtures the same are present.
Die bezeichneten Alkylreste können sowohl geradkettig wie verzweigt vorliegen.The designated alkyl radicals can be either straight-chain or branched.
Bevorzugt sind Verbindungen der Formel I, worin bedeuten:
X CR(6) oder N,
Y NR(7),
und die Reste R(1) bis R(7) die angegebene Bedeutung besitzen.Compounds of the formula I are preferred in which:
X CR (6) or N, Y NR (7),
and the radicals R (1) to R (7) have the meaning given.
Besonders bevorzugt sind Verbindungen der Formel 1, worin bedeuten:
X CR(6) oder N,
Y NR(7),
und
einer der Substituenten R(1) bis R(6) eine -CO-N=C(NH₂)₂-Gruppe,
und die jeweils anderen Substituenten R(1) bis R(6)
Wasserstoff, F, Cl, Br, 1, (C₁-C₆)-Alkyl,
bis zu zwei der anderen Substituenten R(1) bis R(6)
CN, NO₂, N₃, CF₃, (C₁-C₄)-Alkyloxy,
bis zu einem der anderen Substituenten R(1) bis R(6)
R(8)-CnH2n-Z-,
n Null bis 6, wobei die Alkylenkette CnH2n- geradkettig oder
verzweigt sein kann und ein C-Atom durch ein Sauerstoff
oder S-Atom oder durch ein N-Atom ersetzt sein kann,
R(8) Wasserstoff, (C₃-C₆)-Alkenyl, (C₅-C₈)-Cycloalkyl,
das unsubstituiert ist oder durch 1-2 Methylgruppen
oder eine OH-Gruppe substituiert, und worin eine
Methylengruppe durch ein Sauerstoff- oder S-Atom
oder durch ein N-Atom ersetzt sein kann,
Phenyl,
das unsubstituiert ist oder 1 bis 3 Substituenten trägt
aus der Reihe
F, Cl, Br, I, CF₃, CH₃-S(O)s-
s Null, 1 oder 2,
R(9)-Wy-
R(9) H, Methyl, Ethyl,
W Sauerstoff, NR(10),
R(10) H oder Methyl,
y Null oder 1,
CmF2m+1,
m 1 bis 3,
Pyridyl, Chinolyl oder Isochinolyl
Z -CO-, -CH₂-, -[CR(11)(OH)]q-
q 1 bis 3,
R(11) H oder Methyl,
-O-, -NR(12)-,
R(12) H oder Methyl,
-S(O)s-,
s Null bis 2,
-SO₂-NR(12)-,
R(12) H oder (C₁-C₄)-Alkyl,
R(7) Wasserstoff, (C₁-C₆)-Alkyl, (C₂-C₄)-Alkenyl, R(8)-CnH2n-.Compounds of formula 1 are particularly preferred, in which:
X CR (6) or N, Y NR (7),
and
one of the substituents R (1) to R (6) is a -CO-N = C (NH₂) ₂ group, and the other substituents R (1) to R (6)
Hydrogen, F, Cl, Br, 1, (C₁-C₆) alkyl,
up to two of the other substituents R (1) to R (6)
CN, NO₂, N₃, CF₃, (C₁-C₄) alkyloxy,
up to one of the other substituents R (1) to R (6)
R (8) -C n H 2n -Z-,
n zero to 6, where the alkylene chain C n H 2n - can be straight-chain or branched and a C atom can be replaced by an oxygen or S atom or by an N atom,
R (8) is hydrogen, (C₃-C₆) alkenyl, (C₅-C₈) cycloalkyl which is unsubstituted or substituted by 1-2 methyl groups or an OH group, and wherein a methylene group by an oxygen or S atom or can be replaced by an N atom,
Phenyl that is unsubstituted or has 1 to 3 substituents out of line
F, Cl, Br, I, CF₃, CH₃-S (O) s -
s zero, 1 or 2,
R (9) -W y -
R (9) H, methyl, ethyl, W oxygen, NR (10), R (10) H or methyl, y zero or 1,
C m F 2m + 1 ,
m 1 to 3, pyridyl, quinolyl or isoquinolyl
Z -CO-, -CH₂-, - [CR (11) (OH)] q -
q 1 to 3, R (11) H or methyl,
-O-, -NR (12) -,
R (12) H or methyl,
-S (O) s -,
s zero to 2,
-SO₂-NR (12) -,
R (12) H or (C₁-C₄) alkyl,
R (7) hydrogen, (C₁-C₆) alkyl, (C₂-C₄) alkenyl, R (8) -C n H 2n -.
Insbesondere bevorzugt sind Verbindungen der Formel I, worin bedeuten:
X CR(6),
Y NR(7),
und
einer der Substituenten R(1) bis R(6) eine -CO-N=C(NH₂)₂-Gruppe,
und die jeweils anderen Substituenten R(1) bis R(6)
Wasserstoff, F, Cl, Br, (C₁-C₂)-Alkyl,
bis zu einem der Substituenten R(1) bis R(6)
R(8)-CnH2n-Z-,
n Null, 1 oder 2,
wobei die Alkylenkette -CnH2n geradkettig oder verzweigt ist und
wobei ein C-Atom durch ein Sauerstoff- oder S-Atom oder durch
ein N-Atom ersetzt sein kann,
R(8) Wasserstoff, (C₅-C₈)-Cycloalkyl,
das unsubstituiert ist oder substituiert durch 1-2
Methylgruppen oder eine OH-Gruppe,
Phenyl,
das unsubstituiert ist oder 1 bis 3 Substituenten trägt
aus der Reihe F, Cl, CF₃, CH₃-S(O)s-,
s Null oder 2,
R(9)-Wy-,
R(9) H, Methyl, Ethyl,
W Sauerstoff,
y Null oder 1,
CmF2m+1,
m 1, 2 oder 3,
Pyridyl, Chinolyl oder Isochinolyl,
Z -CO-, -CH₂-, [CR(11)(OH)]q-,
q 1 bis 3,
R(11) H oder Methyl, -S(O)s-
s Null bis 2,
-O-,
und
R(7) (C₁-C₆)-Alkyl, (C₃-C₆)-Alkenyl, R(8)-CnH2n-.Compounds of the formula I are particularly preferred, in which:
X CR (6), Y NR (7), and
one of the substituents R (1) to R (6) is a -CO-N = C (NH₂) ₂ group, and the other substituents R (1) to R (6)
Hydrogen, F, Cl, Br, (C₁-C₂) alkyl, up to one of the substituents R (1) to R (6)
R (8) -C n H 2n -Z-,
n is zero, 1 or 2, the alkylene chain -C n H 2n being straight-chain or branched and where a C atom can be replaced by an oxygen or S atom or by an N atom,
R (8) is hydrogen, (C₅-C₈) cycloalkyl which is unsubstituted or substituted by 1-2 methyl groups or an OH group,
Phenyl which is unsubstituted or carries 1 to 3 substituents from the series F, Cl, CF₃, CH₃-S (O) s -, s zero or 2,
R (9) -W y -,
R (9) H, methyl, ethyl, W oxygen,
y zero or 1, C m F 2m + 1 ,
m 1, 2 or 3,
Pyridyl, quinolyl or isoquinolyl,
Z -CO-, -CH₂-, [CR (11) (OH)] q -,
q 1 to 3, R (11) H or methyl, -S (O) s -
s zero to 2, -O-, and
R (7) (C₁-C₆) alkyl, (C₃-C₆) alkenyl, R (8) -C n H 2n -.
Ganz besonders bevorzugt sind die Verbindungen
5-Chlor-1-methyl-2-indolylcarbonyl-guanidin-hydrochlorid,
5-Chlor-1-ethyl-2-indolylcarbonyl-guanidin-hydrochlorid,
3-Chlor-1-methyl-2-indolylcarbonyl-guanidin-hydrochlorid,
3,5-Dichlor-1-methyl-2-indolylcarbonyl-guanidin-hydrochlorid,
5-Fluor-1-methyl-2-indolylcarbonyl-guanidin-hydrochlorid.The compounds are very particularly preferred
5-chloro-1-methyl-2-indolylcarbonyl-guanidine hydrochloride,
5-chloro-1-ethyl-2-indolylcarbonyl-guanidine hydrochloride,
3-chloro-1-methyl-2-indolylcarbonyl-guanidine hydrochloride,
3,5-dichloro-1-methyl-2-indolylcarbonyl-guanidine hydrochloride,
5-fluoro-1-methyl-2-indolylcarbonyl guanidine hydrochloride.
Die Verbindungen I sind substituierte Acylguanidine. Prominentester Vertreter der Acylguanidine ist das Pyrazinderivat Amilorid, das als kaliumsparendes Diuretikum in der Therapie Verwendung findet. Zahlreiche weitere Verbindungen vom Amilorid-Typ werden in der Literatur beschrieben, wie beispielsweise Dimethylamilorid oder Ethylisopropylamilorid.The compounds I are substituted acylguanidines. The most prominent representative of the acylguanidines is the pyrazine derivative amiloride, the used as a potassium-saving diuretic in therapy. Numerous further compounds of the amiloride type are described in the literature, such as dimethylamiloride or ethylisopropylamiloride.
Amilorid: R′, R′′ = H
Dimethylamilorid: R′, R′′ = CH₃
Ethylisopropylamilorid: R′ = C₂H₅, R′′ = CH(CH₃)₂Amiloride: R ′, R ′ ′ = H
Dimethylamilorid: R ′, R ′ ′ = CH₃
Ethyl isopropylamiloride: R ′ = C₂H₅, R ′ ′ = CH (CH₃) ₂
Darüber hinaus sind Untersuchungen bekannt geworden, die auf antiarrhythmische Eigenschaften von Amilorid hinweisen (Circulation 79; 1257 bis 1263 (1989)). Einer breiten Anwendung als Antiarrhythmikum steht jedoch entgegen, daß dieser Effekt nur schwach ausgeprägt ist und von einer blutdrucksenkenden und saluretischen Wirkung begleitet auftritt und diese Nebenwirkungen bei der Behandlung von Herz-Rhythmusstörungen unerwünscht sind.In addition, investigations have become known that are based on antiarrhythmic properties of amiloride indicate (Circulation 79; 1257 to 1263 (1989)). However, it is widely used as an antiarrhythmic contrary to the fact that this effect is only weak and of one hypotensive and saluretic effects accompanied occurs and this Side effects undesirable in the treatment of cardiac arrhythmias are.
Hinweise auf antiarrhythmische Eigenschaften des Amilorids wurden auch bei Experimenten an isolierten Tierherzen erhalten (Eur. Heart J. 9 (suppl. 1): 167 (1988) (book of abstracts)). So wurde beispielsweise an Rattenherzen gefunden, daß ein künstlich ausgelöstes Kammerflimmern durch Amilorid völlig unterdrückt werden konnte. Noch potenter als Amilorid war in diesem Modell das oben erwähnte Amiloridderivat Ethylisopropylamilorid.Evidence of antiarrhythmic properties of the amiloride was also given Experiments on isolated animal hearts were obtained (Eur. Heart J. 9 (suppl. 1): 167 (1988) (book of abstracts)). For example, on rat hearts found that an artificial ventricular fibrillation caused by amiloride completely could be suppressed. This model was even more potent than amiloride the above-mentioned amiloride derivative, ethylisopropylamiloride.
In der Europäischen Offenlegungsschrift 416 499 werden Benzoylguanidine mit antiarrhythmischen Eigenschaften beschrieben.In the European patent application 416 499 Benzoylguanidine with antiarrhythmic properties described.
In der US-Patentschrift 3,780,027 werden ebenfalls Acylguanidine beschrieben, die sich grundlegend von den hier beschriebenen erfindungsgemäßen Verbindungen I dadurch unterscheiden, daß es sich um trisubstituierte Benzoylguanidine handelt, die sich in ihrem Substitutionsmuster von im Handel befindlichen Diuretika, wie Bumetanid und Furosemid, ableiten und eine für die angestrebte salidiuretische Wirkung wichtige Aminogruppe in Position 2 bzw. 3 zur Carbonylguanidingruppe tragen. Entsprechend wird für diese Verbindungen eine starke salidiuretische Wirksamkeit berichtet.US Pat. No. 3,780,027 also describes acylguanidines, which are fundamentally different from the invention described here Compounds I differ in that they are trisubstituted Benzoylguanidines, which are in their substitution pattern from commercially existing diuretics, such as bumetanide and furosemide, and one for the desired salidiuretic effect important amino group in position 2 or 3 carry to the carbonylguanidine group. The same applies to these connections strong salidiuretic efficacy has been reported.
Es war daher überraschend, daß die erfindungsgemäßen Verbindungen keine unerwünschten und nachteiligen salidiuretischen, jedoch sehr gute antiarrhythmische Eigenschaften aufweisen, wie sie beispielsweise bei Sauerstoffmangelerscheinungen auftreten. Die Verbindungen sind infolge ihrer pharmakologischen Eigenschaften als antiarrhythmische Arzneimittel mit cardioprotektiver Komponente zur Infarktprophylaxe und der Infarktbehandlung sowie zur Behandlung der angina pectoris hervorragend geeignet, wobei sie auch präventiv die pathophysiologischen Vorgänge beim Entstehen ischämisch induzierter Schäden, insbesondere bei der Auslösung ischämisch induzierter Herzarrhythmien, inhibieren oder stark vermindern. Wegen ihrer schützenden Wirkungen gegen pathologische hypoxische und ischämische Situationen können die erfindungsgemäßen Verbindungen der Formel I infolge Inhibition des zellulären Na⁺/H⁺-Austauschmechanismus als Arzneimittel zur Behandlung aller akuten oder chronischen durch Ischämie ausgelösten Schäden oder dadurch primär oder sekundär induzierten Krankheiten verwendet werden. Dies betrifft ihre Verwendung als Arzneimittel für operative Eingriffe, z. B. bei Organ- Transplantationen, wobei die Verbindungen sowohl für den Schutz der Organe im Spender vor und während der Entnahme, zum Schutz entnommener Organe beispielsweise bei Behandlung mit oder deren Lagerung in physiologischen Badflüssigkeiten, wie auch bei der Überführung in den Empfängerorganismus verwendet werden können. Die Verbindungen sind ebenfalls wertvolle, protektiv wirkende Arzneimittel bei der Durchführung angioplastischer operativer Eingriffe beispielsweise am Herzen wie auch an peripheren Gefäßen. Entsprechend ihrer protektiven Wirkung gegen ischämisch induzierte Schäden sind die Verbindung auch als Arzneimittel zur Behandlung von Ischämien des Nervensystems, insbesondere des ZNS, geeignet, wobei sie z. B. zur Behandlung des Schlaganfalls oder des Hirnödems geeignet sind. Darüberhinaus eignen sich die erfindungsgemäßen Verbindungen der Formel I ebenfalls zur Behandlungen von Formen des Schocks, wie beispielweise des allergischen, cardiogenen, hypovolämischen und des bakteriellen Schocks.It was therefore surprising that the compounds according to the invention were none undesirable and disadvantageous salidiuretic, but very good have antiarrhythmic properties, such as in Oxygen deficiency symptoms occur. The connections are due to their pharmacological properties as antiarrhythmic drugs with cardioprotective component for heart attack prophylaxis and heart attack treatment as well as for the treatment of angina pectoris also preventively the pathophysiological processes during ischemic development induced damage, especially when triggered ischemically induced Cardiac arrhythmias, inhibit or greatly reduce. Because of their protective Effects against pathological hypoxic and ischemic situations the compounds of formula I according to the invention due to inhibition of cellular Na⁺ / H⁺ exchange mechanism as a drug to treat everyone acute or chronic damage caused by ischemia or thereby primary or secondary induced diseases can be used. this concerns their use as medicines for surgery, e.g. B. in organ Transplants, the connections both for the protection of the organs in the donor before and during removal, to protect removed organs for example when treated with or stored in physiological Bath liquids, as well as in the transfer into the recipient organism can be used. The compounds are also valuable, protective active drugs in performing angioplasty surgery for example on the heart as well as on peripheral vessels. According to her the compound is protective action against ischemically induced damage also as a medicine for the treatment of ischemia of the nervous system, especially of the CNS, suitable, they z. B. for the treatment of Stroke or cerebral edema. In addition, the Compounds of formula I according to the invention also for the treatment of Forms of shock, such as allergic, cardiogenic, hypovolemic and bacterial shock.
Darüberhinaus zeichnen sich die erfindungsgemäßen Verbindungen der Formel I durch starke inhibierende Wirkung auf die Proliferationen von Zellen, beispielsweise der Fibroblasten-Zellproliferation und der Proliferation der glatten Gefäßmuskelzellen, aus. Deshalb kommen die Verbindungen der Formel I als wertvolle Therapeutika für Krankheiten in Frage, bei denen die Zellproliferation eine primäre oder sekundäre Ursache darstellt, und können deshalb als Antiatherosklerotika, Mittel gegen diabetische Spätkomplikationen, Krebserkrankungen, fibrotische Erkrankungen wie Lungenfibrose, Leberfibrose oder Nierenfibrose, Organhypertrophien und -hyperplasien, insbesondere bei Prostatahyperplasie bzw. Prostatahypertrophie verwendet werden.In addition, the compounds of formula I according to the invention are distinguished due to strong inhibitory effect on cell proliferation, for example fibroblast cell proliferation and smooth proliferation Vascular muscle cells, from. Therefore, the compounds of formula I come as valuable therapeutics for diseases in question where cell proliferation is a primary or secondary cause, and can therefore be considered Antiatherosclerotics, remedies for late diabetic complications, Cancer, fibrotic diseases such as pulmonary fibrosis, liver fibrosis or kidney fibrosis, organ hypertrophy and hyperplasia, especially in Prostate hyperplasia or prostate hypertrophy can be used.
Die erfindungsgemäßen Verbindungen sind wirkungsvolle Inhibitoren des zellulären Natrium-Protonen-Antiporters (Na⁺/H⁺-Exchanger), der bei zahlreichen Erkrankungen (Essentielle Hypertonie, Atherosklerose, Diabetes usw.) auch in solchen Zellen erhöht ist, die Messungen leicht zugänglich sind, wie beispielsweise in Erythrocyten, Thrombocyten oder Leukozyten. Die erfindungsgemäßen Verbindungen eignen sich deshalb als hervorragende und einfache wissenschaftliche Werkzeuge, beispielsweise in ihrer Verwendung als Diagnostika zur Bestimmung und Unterscheidung bestimmter Formen der Hypertonie, aber auch der Atherosklerose, des Diabetes, proliferativer Erkrankungen usw . . Darüber hinaus sind die Verbindung der Formel I für die präventive Therapie zur Verhinderung der Genese des Bluthochdrucks, beispielweise der essentiellen Hypertonie, geeignet.The compounds of the invention are effective inhibitors of cellular sodium proton antiporter (Na⁺ / H⁺ exchanger), which at numerous diseases (essential hypertension, atherosclerosis, diabetes etc.) is also increased in cells that are easily accessible, such as in erythrocytes, thrombocytes or leukocytes. The Compounds according to the invention are therefore excellent and simple scientific tools, for example in their use as Diagnostics for the determination and differentiation of certain forms of Hypertension, but also atherosclerosis, diabetes, proliferative Diseases etc. . In addition, the compound of formula I for preventive therapy to prevent the genesis of high blood pressure, for example essential hypertension.
Die Erfindung betrifft weiterhin ein Verfahren zur Herstellung der Verbindungen I, dadurch gekennzeichnet, daß man Verbindungen der Formel IIThe invention further relates to a process for the preparation of the compounds I, characterized in that one Compounds of formula II
worin einer der Substituenten R(1)′ bis R(5)′ eine -CO-L-Gruppe bedeutet
und L für eine leicht nucleophil substituierbare leaving group steht, und
die jeweils anderen Substituenten R(1)′ bis R(5)′ die angegebene
Bedeutung besitzen,
mit Guanidin unter Bildung der in Formel I angegebenen Acylguanidingruppe,
-CO-N = C(NH₂)₂,
umsetzt.
Die aktivierten Säurederivate der Formel II, worin L eine Alkoxy-, vorzugsweise
eine Methoxygruppe, eine Phenoxygruppe, Phenylthio-, Methylthio-,
2-Pyridylthiogruppe, einen Stickstoffheterocyclus, vorzugsweise 1-Imidazolyl,
bedeutet, erhält man vorteilhaft in an sich bekannter Weise aus den
zugrundeliegenden Carbonsäurechloriden (Formel II, L = Cl), die man ihrerseits
wiederum in an sich bekannter Weise aus den zugrundeliegenden Carbonsäuren
(Formel II, L = OH) beispielsweise mit Thionylchlorid herstellen kann.
Neben den Carbonsäurechloriden der Formel II (L = Cl) lassen sich auch weitere
aktivierte Säurederivate der Formel II in an sich bekannter Weise direkt aus den
zugrundeliegenden heterocyclischen Carbonsäurederivaten (Formel II, L = OH)
herstellen, wie beispielsweise die Methylester der Formel II mit L = OCH₃ durch
Behandeln mit gasförmigem HCl in Methanol, die Imidazolide der Formel II durch
Behandeln mit Carbonyldiimidazol (L = 1-Imidazolyl, Staab, Angew. Chem. Int.
Ed. Engl. 1, 351 bis 367 (1962)), die gemischten Anhydride II mit Cl-COOC₂H₅
oder Tosylchlorid in Gegenwart von Triethylamin in einem inerten Lösungsmittel,
wie auch die Aktivierungen von Carbonsäuren mit Dicyclohexylcarbodiimid
(DCC). Eine Reihe geeigneter Methoden zur Herstellung von aktivierten
Carbonsäurederivaten der Formel II sind unter Angabe von Quellenliteratur in J.
March, Advanced Organic Chemistry, Third Edition (John Wiley & Sons, 1985),
S. 350 angegeben.wherein one of the substituents R (1) 'to R (5)' represents a -CO-L group and L represents an easily nucleophilically substitutable leaving group, and the other substituents R (1) 'to R (5)' have the meaning given,
with guanidine to form the acylguanidine group specified in formula I, -CO-N = C (NH₂) ₂.
The activated acid derivatives of the formula II, in which L is an alkoxy, preferably a methoxy, a phenoxy group, phenylthio, methylthio, 2-pyridylthio group, a nitrogen heterocycle, preferably 1-imidazolyl, are advantageously obtained in a manner known per se from the underlying carboxylic acid chlorides (formula II, L = Cl), which in turn can in turn be prepared in a manner known per se from the underlying carboxylic acids (formula II, L = OH), for example with thionyl chloride. In addition to the carboxylic acid chlorides of the formula II (L = Cl), other activated acid derivatives of the formula II can also be prepared in a manner known per se directly from the underlying heterocyclic carboxylic acid derivatives (formula II, L = OH), such as, for example, the methyl esters of the formula II with L. = OCH₃ by treatment with gaseous HCl in methanol, the imidazolides of the formula II by treatment with carbonyldiimidazole (L = 1-imidazolyl, Staab, Angew. Chem. Int. Ed. Engl. 1, 351 to 367 (1962)), the mixed Anhydrides II with Cl-COOC₂H₅ or tosyl chloride in the presence of triethylamine in an inert solvent, as well as the activations of carboxylic acids with dicyclohexylcarbodiimide (DCC). A number of suitable methods for the preparation of activated carboxylic acid derivatives of the formula II are given, citing source literature, in J. March, Advanced Organic Chemistry, Third Edition (John Wiley & Sons, 1985), p. 350.
Die Umsetzung eines aktivierten Carbonsäurederivates der Formel I mit Guanidin erfolgt in an sich bekannter Weise in einem protischen oder aprotischen polaren aber inerten organischen Lösungsmittel. Dabei haben sich bei der Umsetzung der Carbonsäuremethylester (II, L = OMe) mit Guanidin Methanol oder THF zwischen 20°C und Siedetemperatur als Lösungsmittel bewährt. Bei den meisten Umsetzungen von Verbindungen II mit Guanidin wurde vorteilhaft in aprotischen inerten Lösungsmitteln wie THF, Dimethoxyethan, Dioxan gearbeitet. Aber auch Wasser kann als Lösungsmittel bei der Umsetzung von II und Guanidin verwendet werden.The reaction of an activated carboxylic acid derivative of the formula I with guanidine takes place in a manner known per se in a protic or aprotic polar but inert organic solvents. Here, the implementation of Carboxylic acid methyl ester (II, L = OMe) with guanidine methanol or THF proven between 20 ° C and boiling temperature as a solvent. Both most reactions of compounds II with guanidine has been advantageous in aprotic inert solvents such as THF, dimethoxyethane, dioxane worked. But water can also be used as a solvent in the implementation of II and guanidine can be used.
Wenn L = Cl bedeutet, arbeitet man vorteilhaft unter Zusatz eines Säurefängers, z. B. in Form von überschüssigem Guanidin zur Abbindung der Halogenwasserstoffsäure.If L = Cl, it is advantageous to work with the addition of a Acid scavenger, e.g. B. in the form of excess guanidine to set the Hydrohalic acid.
Ein Teil der zugrundeliegenden heterocyclischen Carbonsäure-Derivate ist bekannt und in der Literatur beschrieben. Die unbekannten heterocyclischen Carbonsäuren II (L = OH) können nach literaturbekannten Methoden hergestellt werden.Part of the underlying heterocyclic carboxylic acid derivatives is known and described in the literature. The unknown heterocyclic Carboxylic acids II (L = OH) can be prepared by methods known from the literature become.
So erhält man beispielsweise die 2-Benzimidazolcarbonsäuren [Formel II mit R(1) = -COOH, X = N und Y = -NR(7)], welche zu bevorzugten erfindungsgemäßen Verbindungen führen, in an sich bekannter Weise durch Oxidation der entsprechenden 2-Hydroxymethyl-benzimidazole mit Kaliumpermanganat analog Bistrzycki und Przeworski (Ber. 45, 3483 [1912]).For example, 2-benzimidazole carboxylic acids [formula II with R (1) = -COOH, X = N and Y = -NR (7)], which are preferred according to the invention Compounds lead in a manner known per se by oxidation of the corresponding 2-hydroxymethyl-benzimidazole with potassium permanganate analog Bistrzycki and Przeworski (Ber. 45, 3483 [1912]).
Die zu bevorzugten Carbonylguanidinen der Formel I führenden Indol-2- carbonsäuren erhält man beispielsweise aus den 2-Nitrotoluolen nach J. R. Johnson et al. J. Am. Chem. Soc. 67, 423 (1945) [siehe auch Noland und Baude, Org. Synth. Coll. Vol. 5, 567 (1973), nach der Fischer-Indolsynthese aus Brenztraubensäure und Phenylhydrazon. Eine weitere Darstellungsmethode für Indol-2-carbonsäuren besteht in der Bromoform- oder Jodoform-Reaktion von 2- Acetylindolen, die nach Rajur et al., Synth. Commun. 22, 421-428 (1992) dargestellt werden können. Eine Darstellungsmethode aus 2-Ketoanilinen wird von Jones et al. (J. Org. Chem 37, 3622 [1972]) beschrieben.The indole-2- leading to preferred carbonylguanidines of the formula I carboxylic acids are obtained, for example, from the 2-nitrotoluenes according to J. R. Johnson et al. J. Am. Chem. Soc. 67, 423 (1945) [see also Noland and Baude, Org. Synth. Coll. Vol. 5, 567 (1973), according to the Fischer indole synthesis Pyruvic acid and phenylhydrazone. Another display method for Indole-2-carboxylic acids consist of the bromoform or iodoform reaction of 2- Acetylindoles, which according to Rajur et al., Synth. Commun. 22, 421-428 (1992) can be displayed. A representation method from 2-ketoanilines is by Jones et al. (J. Org. Chem 37, 3622 [1972]).
Ausgangsmaterialien zur Herstellung speziell substituierter Indol-2-carbonsäuren können auch Indol-2-carbonsäuren selbst bilden, an denen in literaturbekannter Weise leicht Substitutionsreaktionen durchgeführt werden. Besonders selektiv können dabei zahlreiche elektrophile Substitutionsreaktionen in 3-Position, aber auch in den restlichen Positionen durchgeführt werden. So verlaufen beispielsweise Halogenierungen mit einen Hal⁺-Überträger glatt und in vollständiger Umsetzung. Am Stickstoffatom in 1-Position können ebenfalls sehr leicht Alkylierungs- und Arylierungsreaktionen durchgeführt werden.Starting materials for the production of specially substituted indole-2-carboxylic acids can also form indole-2-carboxylic acids themselves, which are known in the literature Substitution reactions can be carried out easily. Particularly selective can do numerous electrophilic substitution reactions in the 3-position, however can also be carried out in the remaining positions. So run For example, halogenations with a Hal⁺ transmitter smooth and in full implementation. The nitrogen atom in the 1-position can also be very alkylation and arylation reactions can be easily carried out.
Benzoylguanidine I sind im allgemeinen schwache Basen und können Säure unter Bildung von Salzen binden. Als Säureadditionssalze kommen Salze aller pharmakologisch verträglichen Säuren in Frage, beispielsweise Halogenide, insbesondere Hydrochloride, Lactate, Sulfate, Citrate, Tartrate, Acetate, Phosphate, Sulfonsäuresalze wie Methylsulfonate, p-Toluolsulfonate usw.Benzoylguanidines I are generally weak bases and can acid bind to form salts. Salts of all come as acid addition salts pharmacologically acceptable acids, for example halides, in particular hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, Phosphates, sulfonic acid salts such as methyl sulfonates, p-toluenesulfonates, etc.
Arzneimittel, die eine Verbindung I enthalten, können dabei oral, parenteral, intravenös, rektal oder durch Inhalation appliziert werden, wobei die bevorzugte Applikation von dem jeweiligen Erscheinungsbild der Erkrankung abhängig ist. Die Verbindungen I können dabei allein oder zusammen mit galenischen Hilfsstoffen zur Anwendung kommen, und zwar sowohl in der Veterinär- als auch in der Humanmedizin.Drugs containing a compound I can be administered orally, parenterally, administered intravenously, rectally or by inhalation, the preferred one Application depends on the particular appearance of the disease. The compounds I can be used alone or together with galenic Excipients are used, both in the veterinary and also in human medicine.
Welche Hilfsstoffe für die gewünschte Arzneimittelformulierung geeignet sind, ist dem Fachmann auf Grund seines Fachwissens geläufig. Neben Lösemitteln, Gelbildnern, Suppositoriengrundlagen, Tablettenhilfsstoffen und anderen Wirkstoffträgern können beispielsweise Antioxidantien, Dispergiermittel, Emulgatoren, Entschäumer, Geschmackskorrigentien, Konservierungsmittel, Lösungsvermittler oder Farbstoffe verwendet werden.Which excipients are suitable for the desired pharmaceutical formulation is familiar to the expert on the basis of his specialist knowledge. In addition to solvents, Gelling agents, suppository bases, tablet excipients and others Active substance carriers can, for example, antioxidants, dispersants, Emulsifiers, defoamers, flavoring agents, preservatives, Solubilizers or dyes are used.
Für eine orale Anwendungsform werden die aktiven Verbindungen mit den dafür geeigneten Zusatzstoffen, wie Trägerstoffen, Stabilisatoren oder inerten Verdünnungsmittel vermischt und durch die üblichen Methoden in die geeigneten Darreichungsformen gebracht, wie Tabletten, Dragees, Steckkapseln, wäßrige, alkoholische oder ölige Lösungen. Als inerte Träger können z. B. Gummi arabicum, Magnesia, Magnesiumcarbonat, Kaliumphosphat, Milchzucker, Glucose oder Stärke, insbesondere Maisstärke, verwendet werden. Dabei kann die Zubereitung sowohl als Trocken- als auch als Feuchtgranulat erfolgen. Als ölige Trägerstoffe oder als Lösemittel kommen beispielsweise pflanzliche oder tierische Öle in Betracht, wie Sonnenblumenöl oder Lebertran.For an oral form of use, the active compounds with the for it suitable additives, such as carriers, stabilizers or inert Diluent mixed and by the usual methods in the brought suitable dosage forms, such as tablets, coated tablets, Push-fit capsules, aqueous, alcoholic or oily solutions. As an inert carrier can e.g. B. gum arabic, magnesia, magnesium carbonate, potassium phosphate, Milk sugar, glucose or starch, especially corn starch, can be used. The preparation can be used both as dry and as wet granules respectively. For example, come as oily carriers or as solvents vegetable or animal oils, such as sunflower oil or cod liver oil.
Zur subkutanen oder intravenösen Applikation werden die aktiven Verbindungen, gewünschtenfalls mit den dafür üblichen Substanzen wie Lösungsvermittler, Emulgatoren oder weiteren Hilfsstoffen in Lösung, Suspension oder Emulsion gebracht. Als Lösungsmittel kommen z. B. in Frage: Wasser, physiologische Kochsalzlösung oder Alkohole, z. B. Ethanol, Propanol, Glycerin, daneben auch Zuckerlösungen wie Glucose- oder Mannitlösungen, oder auch eine Mischung aus den verschiedenen genannten Lösungsmitteln.For subcutaneous or intravenous administration, the active compounds, if desired with the usual substances such as solubilizers, Emulsifiers or other auxiliaries in solution, suspension or emulsion brought. As solvents such. B. in question: water, physiological Saline or alcohols, e.g. As ethanol, propanol, glycerin, in addition Sugar solutions such as glucose or mannitol solutions, or a mixture from the various solvents mentioned.
Als pharmazeutische Formulierung für die Verabreichung in Form von Aerosolen oder Sprays sind geeignet z. B. Lösungen, Suspensionen oder Emulsionen des Wirkstoffes des Formel I in einem pharmazeutisch unbedenklichen Lösungsmittels, wie insbesondere Ethanol oder Wasser, oder einem Gemisch solcher Lösungsmittel. Die Formulierung kann nach Bedarf auch noch andere pharmazeutische Hilfsstoffe wie Tenside, Emulgatoren und Stabilisatoren sowie ein Treibgas enthalten. Eine solche Zubereitung enthält den Wirkstoff überlicherweise in einer Konzentration von etwa 0,1 bis 10, insbesondere von etwa 0,3 bis 3 Gew.-%.As a pharmaceutical formulation for administration in the form of aerosols or sprays are suitable e.g. B. solutions, suspensions or emulsions of Active ingredient of formula I in a pharmaceutically acceptable Solvent, such as especially ethanol or water, or a mixture such solvents. The wording can also be other, if necessary pharmaceutical excipients such as surfactants, emulsifiers and stabilizers as well contain a propellant. Such a preparation contains the active ingredient usually in a concentration of about 0.1 to 10, especially of about 0.3 to 3% by weight.
Die Dosierung des zu verabreichenden Wirkstoffs der Formel I und die Häufigkeit der Verabreichung hängen von der Wirkstärke und Wirkdauer der verwendeten Verbindungen ab; außerdem auch von Art und Stärke der zu behandelnden Krankheit sowie von Geschlecht, Alter, Gewicht und individueller Ansprechbarkeit des zu behandelnden Säugers.The dosage of the active ingredient of formula I to be administered and the frequency the administration depend on the strength and duration of action of the used Connections from; also on the type and strength of the treatment Illness as well as gender, age, weight and individual Responsiveness of the mammal to be treated.
Im Durchschnitt beträgt die tägliche Dosis einer Verbindung der Formel I bei einem etwa 75 kg schweren Patienten mindestens 0,001 mg, vorzugsweise 0,01 mg bis höchstens 10 mg, vorzugsweise höchstens 1 mg. Bei akuten Ausbrüchen der Krankheit, etwa unmittelbar nach Erleiden des Herzinfarkts, können auch noch höhere und vor allem häufigere Dosierungen notwendig sein, z. B. bis zu 4 Einzeldosen pro Tag. Insbesondere bei i. v. Anwendung, etwa bei einem Infarktpatienten auf der Intensivstation können bis zu 100 mg pro Tag notwendig werden. On average, the daily dose of a compound of formula I is an approximately 75 kg patient at least 0.001 mg, preferably 0.01 mg to at most 10 mg, preferably at most 1 mg. In acute Outbreaks of the disease, such as immediately after suffering a heart attack, even higher and above all more frequent doses may be necessary e.g. B. up to 4 single doses per day. Especially with i. v. Application, for example An infarct patient in the intensive care unit can take up to 100 mg a day become necessary.
0,01 M des Carbonsäurederivates der Formel II (L = OH) löst bzw. suspendiert man in 60 ml wasserfreiem Tetrahydrofuran (THF) und versetzt sodann mit 1,78 g (0,011 M) Carbonyldiimidazol. Nach dem Rühren für 2 Stunden bei Raumtemperatur werden 2,95 g (0,05 M) Guanidin in die Reaktionslösung eingetragen. Nach dem Rühren über Nacht destilliert man das THF unter vermindertem Druck (Rotationsverdampfer) ab, versetzt mit Wasser, stellt mit 2N HCl auf pH 6-7 und filtriert das entsprechende Acylguanidin (Formel I) ab.0.01 M of the carboxylic acid derivative of the formula II (L = OH) dissolves or suspends in 60 ml of anhydrous tetrahydrofuran (THF) and then mixed with 1.78 g (0.011 M) carbonyldiimidazole. After stirring for 2 hours 2.95 g (0.05 M) guanidine are added to the reaction solution at room temperature registered. After stirring overnight, the THF is distilled in reduced pressure (rotary evaporator), mixed with water, provides 2N HCl to pH 6-7 and filter the corresponding acylguanidine (formula I).
Die so erhaltenen heterocyclisch Acylguanidine können durch Behandeln mit wäßriger oder methanolischer Salzsäure oder anderen pharmakologisch verträglichen Säuren in die entsprechenden Salze übergeführt werden.The heterocyclic acylguanidines thus obtained can be treated with aqueous or methanolic hydrochloric acid or other pharmacologically compatible acids are converted into the corresponding salts.
1 Äquivalent eines entsprechenden Carbonsäureesters der Formel II sowie 5.0 Äquivalenten Guanidin werden in Isopropanol gelöst oder in THF suspendiert und bis zur vollständigen Umsetzung (TLC-Kontrolle) am Rückflußkühler gekocht (Reaktionszeit etwa 2-8 Stunden). Das Lösungsmittel wird unter vermindertem Druck (Rotationsverdampfer) abdestilliert, der Rückstand in Ethylacetat ausgenommen und 3 mal mit gesättigter Natriumhydrogencarbonat-Lösung gewaschen.1 equivalent of a corresponding carboxylic acid ester of the formula II and 5.0 Equivalents of guanidine are dissolved in isopropanol or suspended in THF and boiled on the reflux condenser until the reaction is complete (TLC control) (Response time about 2-8 hours). The solvent is reduced Pressure (rotary evaporator) distilled off, the residue in ethyl acetate excepted and 3 times with saturated sodium bicarbonate solution washed.
Trocknung der organischen Phase über Natriumsulfat, Abdestillieren des Lösungsmittels unter vermindertem Druck und Chromatographie des Rückstandes an Kieselgel unter Anwendung eines geeigneten Laufmittels. Überführung des erhaltenen entsprechenden heterocyclischen Acylguanidins der Formel I in das korrespondierende Hydrochlorid erfolgt analog Vorschrift I.Drying the organic phase over sodium sulfate, distilling off the Solvent under reduced pressure and chromatography of the Residue on silica gel using a suitable eluent. Conversion of the corresponding heterocyclic acylguanidine obtained of the formula I in the corresponding hydrochloride is carried out analogously to regulation I.
Entsprechend der allgemeinen Vorschriften I und II wurden die folgenden erfindungsgemäßen Verbindungen hergestellt:In accordance with general regulations I and II, the following were Compounds according to the invention prepared:
2-Benzifurylcarbonyl-guanidin-hydinchlorid, Fp. 279-283°C.2-benzifurylcarbonyl guanidine hydine chloride, Mp 279-283 ° C.
6-Chlor-2-benzofurylcarbonyl-guanidin-hydrochlorid, Fp. 272-274°C.6-chloro-2-benzofurylcarbonyl-guanidine hydrochloride, Mp 272-274 ° C.
7-Methoxy-2-benzofurylcarbonyl-guanidin-hydrochlorid, Fp. 266°C.7-methoxy-2-benzofurylcarbonyl-guanidine hydrochloride, Mp 266 ° C.
7-Brom-4-hydroxy-3-benzofurylcarbonyl-guanidin-hydrochlorid, Fp. 239°C.7-bromo-4-hydroxy-3-benzofurylcarbonyl-guanidine hydrochloride, Mp 239 ° C.
7-Hydroxy-2-benzofurylcarbonyl-guanidin-hydrochlorid, Fp. 243-244°C.7-hydroxy-2-benzofurylcarbonyl-guanidine hydrochloride, Mp 243-244 ° C.
5-Dimethylaminomethyl-2-benzofurylcarbonyl-guanidin-dihydrochlorid, Fp. < 250°C. 5-dimethylaminomethyl-2-benzofurylcarbonyl-guanidine dihydrochloride, Mp <250 ° C.
6-Dichlor-2-benzofurylcarbonyl-guanidin-hydrochlorid, Fp. < 250°C.6-dichloro-2-benzofurylcarbonyl-guanidine hydrochloride, Mp <250 ° C.
7-Amino-2-benzthiazolylcarbonyl-guanidin-dihydrochlorid, Fp. < 250°C.7-amino-2-benzothiazolylcarbonyl-guanidine dihydrochloride, Mp <250 ° C.
2-Amino-6-benzthiazolylcarbonyl-guanidin-dihydrochlorid, Fp. < 250°C.2-amino-6-benzothiazolylcarbonyl-guanidine dihydrochloride, Mp <250 ° C.
6-Chloro-3-methoxybenzol[b]thien-2-ylcarbonyl-guanidin-hydrochlorid,- Fp. 202°C.6-chloro-3-methoxybenzene [b] thien-2-ylcarbonyl-guanidine hydrochloride, Mp 202 ° C.
Benzothriazol-5-ylcarbonyl-guanidin-hydrochlorid, Fp. 270°C.Benzothriazol-5-ylcarbonyl-guanidine hydrochloride, Mp 270 ° C.
2-Benzthiazolylcarbonyl-guanidin-hydrochlorid, Fp. 273-275°C2-benzothiazolylcarbonyl guanidine hydrochloride, Mp 273-275 ° C
Benzo[b]thien-2-ylcarbonyl-guanidin-hydrochlorid, Fp. 296-298°C.Benzo [b] thien-2-ylcarbonyl guanidine hydrochloride, Mp 296-298 ° C.
2-Chlor-5-methylbenzo[b]thien-2-ylcarbonyl-guanidin-hydrochlorid, Fp. 221-222°C. 2-chloro-5-methylbenzo [b] thien-2-ylcarbonyl-guanidine hydrochloride, Mp 221-222 ° C.
5-Nitrobenzo[b]thien-2-ylcarbonyl-guanidin-hydrochlorid, Fp. 285°C.5-nitrobenzo [b] thien-2-ylcarbonyl guanidine hydrochloride, Mp 285 ° C.
5-Aminobenzo[b]thien-2-ylcarbonyl-guanidin-hydrochlorid, Fp. 250°C (Zersetzung).5-aminobenzo [b] thien-2-ylcarbonyl-guanidine hydrochloride, Mp 250 ° C (decomposed).
1H-Benzimidazol-5-yl-carbonyl-guanidin-hydrochlorid, Fp. 265°C1H-benzimidazol-5-yl-carbonyl-guanidine hydrochloride, Mp 265 ° C
1-(2-Chlorbenzyl)-1H-benzimidazol-5-yl-carbonyl-guanidin-hydrochlori-d, Fp. 265°C.1- (2-chlorobenzyl) -1H-benzimidazol-5-yl-carbonyl-guanidine hydrochloride, Mp 265 ° C.
1-(1-Hexyl)-1H-benzimidazol-5-yl-carbonyl-guanidin-hydrochlorid, Fp. 232-234°C.1- (1-hexyl) -1H-benzimidazol-5-yl-carbonyl-guanidine hydrochloride, Mp 232-234 ° C.
1-(2-Chlorbenzyl)-2-hydroxy-1H-benzimidazol-5-yl-carbonyl-guanidin- hydrochlorid, Fp. 283°C.1- (2-chlorobenzyl) -2-hydroxy-1H-benzimidazol-5-yl-carbonyl-guanidine- hydrochloride, Mp 283 ° C.
2-Methylthio-1H-benzimidazol-5-yl-carbonyl-guanidin-hydrochlorid, Fp. 211°C.2-methylthio-1H-benzimidazol-5-yl-carbonyl-guanidine hydrochloride, Mp 211 ° C.
1-(2-Chlorbenzyl)-2-methylthio-1H-benzimidazol-5-yl-carbonyl-guanidi-n- hydrochlorid, Fp. 220°C. 1- (2-chlorobenzyl) -2-methylthio-1H-benzimidazol-5-yl-carbonyl-guanidi-n- hydrochloride, mp. 220 ° C.
1-(1-Hexyl)-2-hydroxy-1H-benzimidazol-5-yl-carbonyl-guanidin-hydroch-lorid, Fp. 227-229°C.1- (1-hexyl) -2-hydroxy-1H-benzimidazol-5-yl-carbonyl-guanidine hydrochloride, Mp 227-229 ° C.
6-[N-Methyl-N-(2-phenylethyl)sulfamoyl]-1H-benzimidazol-4-yI-carbony-l-guanidin- hydrochlorid, Fp. 205°C.6- [N-methyl-N- (2-phenylethyl) sulfamoyl] -1H-benzimidazol-4-yI-carbony-l-guanidine- hydrochloride, mp. 205 ° C.
1-Methyl-2-methylthio-1H-benzimidazol-6-yl-carbonyl-guanidin-hydroch-lorid, Fp. 246°C.1-methyl-2-methylthio-1H-benzimidazol-6-yl-carbonyl-guanidine hydrochloride, Mp 246 ° C.
6-Sulfamoyl-1H-benzimidazol-4-yl-carbonyl-guanidin-hydrochlorid, Fp. 223°C.6-sulfamoyl-1H-benzimidazol-4-yl-carbonyl-guanidine hydrochloride, Mp 223 ° C.
2-(2-Phenylethyl)-6-N-pyrrolidinosulfonyl-1H-benzimidazol-4-yl-carbo-nyl guanidin-hydrochlorid, Fp. 192°C (Zersetzung).2- (2-phenylethyl) -6-N-pyrrolidinosulfonyl-1H-benzimidazol-4-yl-carbo-nyl guanidine hydrochloride, mp 192 ° C (decomposed).
6-Chlor-2-(2-phenylethyl)-1H-benzimidazol-4-yl-carbonyl-guanidin-hyd-rochlorid, Fp. 262-264°C.6-chloro-2- (2-phenylethyl) -1H-benzimidazol-4-yl-carbonyl-guanidine-hyd-rochloride, Mp 262-264 ° C.
6-N-Pyrrolidinosulfonyl-1H-benzimidazol-4-yl-carbonyl-guanidin-hydro-chlorid, Fp. 200-202°C (Zersetzung).6-N-pyrrolidinosulfonyl-1H-benzimidazol-4-yl-carbonyl-guanidine hydrochloride, Mp 200-202 ° C (decomposed).
6-Methylsulfonyl-2-(2-phenylethyl)-1H-benzimidazol-4-yl-carbonyl-gua-nidin hydrochlorid, Fp. 215°C. 6-methylsulfonyl-2- (2-phenylethyl) -1H-benzimidazol-4-yl-carbonyl-guanidine hydrochloride, mp. 215 ° C.
6-[N-Methyl-N-(2-phenylethyl)sulfamoyl]-2-(2-phenylethyl)-1H-benzimi-dazol-4-yl- carbonyl-guanidin-hydrochlorid, Fp. 130°C.6- [N-methyl-N- (2-phenylethyl) sulfamoyl] -2- (2-phenylethyl) -1H-benzimi-dazol-4-yl- carbonyl guanidine hydrochloride, mp 130 ° C.
2-Benzylthio-6-methylsulfonyl-1H-benzimidazol-4-yl-carbonyl-guanidin-- hydrochlorid, Fp. 215°C.2-benzylthio-6-methylsulfonyl-1H-benzimidazol-4-yl-carbonyl-guanidine-- hydrochloride, Mp 215 ° C.
5-Chlor-1-methyl-1H-benzimidazol-2-yl-carbonyl-guanidin-hydrochlorid-, Fp. 228°C.5-chloro-1-methyl-1H-benzimidazol-2-yl-carbonyl-guanidine hydrochloride, Mp 228 ° C.
5,6-Dichlor-1-methyl-1H-benzimidazol-2-yl-carbonyl-guanidin-hydrochl-orid, Fp. 274°C. (Zersetzung)5,6-dichloro-1-methyl-1H-benzimidazol-2-yl-carbonyl-guanidine hydrochloride, Mp 274 ° C. (Decomposition)
3-Indolylcarbonyl-guanidin-hydrochlorid, Fp. 270°C. (Zersetzung)3-indolylcarbonyl guanidine hydrochloride, Mp 270 ° C. (Decomposition)
5-Indolylcarbonyl-guanidin-hydrochlorid, Fp. 258°C. (Zersetzung)5-indolylcarbonyl guanidine hydrochloride, Mp 258 ° C. (Decomposition)
1-Benzyl-3-indolylcarbonyl-guanidin-hydrochlorid, Fp. 256°C. (Zersetzung)1-benzyl-3-indolylcarbonyl-guanidine hydrochloride, Mp 256 ° C. (Decomposition)
4-Indolylcarbonyl-guanidin-hydrochlorid, Fp. 270°C. (Zersetzung) 4-indolylcarbonyl guanidine hydrochloride, Mp 270 ° C. (Decomposition)
1-Methyl-3-indolylcarbonyl-guanidin-hydrochlorid, Fp. 250°C. (Zersetzung)1-methyl-3-indolylcarbonyl-guanidine hydrochloride, Mp 250 ° C. (Decomposition)
1-(2-N,N-Dimethylaminoethyl)-3-indolylcarbonyl-guanidin-dihydrochlor-id, Fp. 250°C. (Zersetzung)1- (2-N, N-dimethylaminoethyl) -3-indolylcarbonyl-guanidine-dihydrochloride-id, Mp 250 ° C. (Decomposition)
1-Methyl-2-indolylcarbonyl-guanidin-hydrochlorid, Fp. 280°C.1-methyl-2-indolylcarbonyl-guanidine hydrochloride, Mp 280 ° C.
2-Indolylcarbonyl-guanidin-hydrochlorid, Fp. 310-312°C.2-indolylcarbonyl guanidine hydrochloride, Mp 310-312 ° C.
5-Chlor-2-indolylcarbonyl-guanidin-hydrochlorid, Fp. 317-320°C.5-chloro-2-indolylcarbonyl-guanidine hydrochloride, Mp 317-320 ° C.
5-Methoxy-2-indolylcarbonyl-guanidin-hydrochlorid, Fp. 292°C.5-methoxy-2-indolylcarbonyl-guanidine hydrochloride, Mp 292 ° C.
5-Chlor-1-methyl-2-indolylcarbonyl-guanidin-hydrochlorid, Fp. 269°C.5-chloro-1-methyl-2-indolylcarbonyl-guanidine hydrochloride, Mp 269 ° C.
1-(3,4-Dichlorbenzyl)-2-indolylcarbonyl-guanidin-hydrochlorid, Fp. 195°C. 1- (3,4-dichlorobenzyl) -2-indolylcarbonyl-guanidine hydrochloride, Mp 195 ° C.
1-(2-N,N-Dimethylaminoethyl)-2-indolylcarbonyl-guanidin-dihydrochlor-id, Fp. 255°C. (Zersetzung)1- (2-N, N-dimethylaminoethyl) -2-indolylcarbonyl-guanidine-dihydrochloride-id, Mp 255 ° C. (Decomposition)
1-Benzyl-2-indolylcarbonyl-guanidin-hydrochlorid, Fp. 229°C.1-benzyl-2-indolylcarbonyl-guanidine hydrochloride, Mp 229 ° C.
1-Ethyl-2-indolylcarbonyl-guanidin-hydrochlorid, Fp. 200-201°C.1-ethyl-2-indolylcarbonyl-guanidine hydrochloride, Mp 200-201 ° C.
1-Benzyl-5-chlor-2-indolylcarbonyl-guanidin-hydrochlorid, Fp. 198°C.1-benzyl-5-chloro-2-indolylcarbonyl-guanidine hydrochloride, Mp 198 ° C.
5-Chlor-1-(2-N,N-dimethylaminoethyl)-2-indolylcarbonyl-guanidin -dihydrochlorid, Fp. 255°C. (Zersetzung)5-chloro-1- (2-N, N-dimethylaminoethyl) -2-indolylcarbonyl-guanidine dihydrochloride, Mp 255 ° C. (Decomposition)
5-Chlor-1-ethyl-2-indolylcarbonyl-guanidin-hydrochlorid, Fp. 255°C.5-chloro-1-ethyl-2-indolylcarbonyl-guanidine hydrochloride, Mp 255 ° C.
5-Chlor-1-propyl-2-indolylcarbonyl-guanidin-hydrochlorid, Fp. 255°C.5-chloro-1-propyl-2-indolylcarbonyl-guanidine hydrochloride, Mp 255 ° C.
5-Chlor-1-butyl-2-indolylcarbonyl-guanidin-hydrochlorid, Fp. 222°C. 5-chloro-1-butyl-2-indolylcarbonyl-guanidine hydrochloride, Mp 222 ° C.
5-Hydroxy-1-methyl-2-indolylcarbonyl-guanidin-hydrochlorid, Fp. 288°C.5-hydroxy-1-methyl-2-indolylcarbonyl-guanidine hydrochloride, Mp 288 ° C.
3,5-Dichlor-1-(2-N,N-dimethylaminoethyl)-2-indolylcarbonyl-guanidin dihydrochlorid, Fp. 246°C.3,5-dichloro-1- (2-N, N-dimethylaminoethyl) -2-indolylcarbonyl-guanidine dihydrochloride, Mp 246 ° C.
5-Methoxy-1-methyl-2-indolylcarbonyl-guanidin-hydrochlorid, Fp. 227°C.5-methoxy-1-methyl-2-indolylcarbonyl-guanidine hydrochloride, Mp 227 ° C.
3-Chlor-1-methyl-2-indolylcarbonyl-guanidin-hydrochlorid, Fp. 216°C.3-chloro-1-methyl-2-indolylcarbonyl-guanidine hydrochloride, Mp 216 ° C.
3-Chlor-2-indolylcarbonyl-guanidin-hydrochlorid, Fp. 222°C.3-chloro-2-indolylcarbonyl-guanidine hydrochloride, Mp 222 ° C.
3,5-Dichlor-1-(4-picolyl)-2-indolylcarbonyl-guanidin-dihydrochlorid,- Fp. 220°C.3,5-dichloro-1- (4-picolyl) -2-indolylcarbonyl-guanidine dihydrochloride, Mp 220 ° C.
5-Chlor-1-(4-picolyl)-2-indolylcarbonyl-guanidin-dihydrochlorid, Fp. 287°C.5-chloro-1- (4-picolyl) -2-indolylcarbonyl-guanidine dihydrochloride, Mp 287 ° C.
5-Chlor-1,3-dimethyl-2-indolylcarbonyl-guanidin-hydrochlorid, Fp. 258°C. 5-chloro-1,3-dimethyl-2-indolylcarbonyl-guanidine hydrochloride, Mp 258 ° C.
5,7-Dichlor-1,3-dimethyl-2-indolylcarbonyl-guanidin-hydrochlorid, Fp. 307°C.5,7-dichloro-1,3-dimethyl-2-indolylcarbonyl-guanidine hydrochloride, Mp 307 ° C.
4,6-Dichlor-1,3-dimethyl-2-indolylcarbonyl-guanidin-hydrochlorid, Fp. 296°C.4,6-dichloro-1,3-dimethyl-2-indolylcarbonyl-guanidine hydrochloride, Mp 296 ° C.
5-Chlor-1-methyl-3-phenyl-2-indolylcarbonyl-guanidin-hydrochlorid, Fp. 288°C.5-chloro-1-methyl-3-phenyl-2-indolylcarbonyl-guanidine hydrochloride, Mp 288 ° C.
3-Brom-1-methyl-2-indolylcarbonyl-guanidin-hydrochlorid, Fp. 208-210°C.3-bromo-1-methyl-2-indolylcarbonyl-guanidine hydrochloride, Mp 208-210 ° C.
5-Fluor-1-methyl-2-indolylcarbonyl-guanidin-hydrochlorid, Fp. 278°C.5-fluoro-1-methyl-2-indolylcarbonyl-guanidine hydrochloride, Mp 278 ° C.
3,5-Dichlor-2-indolylcarbonyl-guanidin-hydrochlorid, Fp. 208-210°C.3,5-dichloro-2-indolylcarbonyl-guanidine hydrochloride, Mp 208-210 ° C.
3,5-Dichlor-1-methyl-2-indolylcarbonyl-guanidin-hydrochlorid, Fp. 208-210°C.3,5-dichloro-1-methyl-2-indolylcarbonyl-guanidine hydrochloride, Mp 208-210 ° C.
4,5,6-Trichlor-1,3-dimethyl-2-indolylcarbonyl-guanidin-hydrochlorid,- Fp. 307°C.4,5,6-trichloro-1,3-dimethyl-2-indolylcarbonyl-guanidine hydrochloride, Mp 307 ° C.
Claims (18)
X N oder CR(6), Y Sauerstoff, S oder NR(7),
einer der Substituenten R(1) bis R(6) eine -CO-N=C(NH₂)₂-Gruppe, die jeweils anderen Substituenten R(1) bis R(6)
Wasserstoff, F, Cl, Br, I, (C₁-C₆)-Alkyl,
bis zu zwei der anderen Substituenten R(1) bis R(6)
CN, NO₂, N₃, (C₁-C₄)-Alkyloxy, CF3,
bis zu einem der anderen Substituenten
R(8)-CnH2n-Z-,
n Null bis 10, wobei die Alkylenkette CnH2n- geradkettig oder verzweigt ist und wobei ein C-Atom durch ein Sauerstoff- oder S-Atom oder durch ein N-Atom ersetzt sein kann,
R(8) Wasserstoff, (C₂-C₆)-Alkenyl, (C₃-C₁₀)-Cycloalkyl, das unsubstituiert oder durch 1 bis 4 Methylgruppen oder eine OH-Gruppe substituiert ist, oder eine Ethylengruppe -CH=CH- enthalten kann, und worin eine Methylengruppe durch ein Sauerstoff- oder S- Atom oder durch ein N-Atom ersetzt sein kann,
Phenyl, unsubstituiert oder substituiert durch 1 bis 3
Substituenten aus der Reihe F, Cl, Br, I, CF₃, CH₃-S(O)s-,
s Null, 1 oder 2,
R(9)-Wy-,
R(9) H, Methyl, Ethyl, W gleich Sauerstoff, NR(10), R(10) H oder Methyl, y Null oder 1,
CmF2m+1,
m 1 bis 3, 1- oder 2-Naphthyl, Pyridyl, Chinolyl oder Isochinolyl,
Z -CO-, -CH₂-, -[CR(11)(OH)]q-
q 1, 2 oder 3, R(11) H oder Methyl,
Sauerstoff, -NR(12)-,
R(12) H, Methyl,
-S(O)s-,
s Null, 1 oder 2,
-SO₂-NR(12)-,
R(12) H, (C₁-C₄)-Alkyl,
R(7) Wasserstoff, (C₁-C₁₀)-Alkyl, (C₂-C₁₀)-Alkenyl, R(8)-CnH2n-,
sowie deren pharmazeutisch verträgliche Salze.1. Benzocondensed 5-ring heterocycles of the formula I. in which mean:
XN or CR (6), Y oxygen, S or NR (7),
one of the substituents R (1) to R (6) is a -CO-N = C (NH₂) ₂ group, the other substituents R (1) to R (6)
Hydrogen, F, Cl, Br, I, (C₁-C₆) alkyl,
up to two of the other substituents R (1) to R (6)
CN, NO₂, N₃, (C₁-C₄) alkyloxy, CF 3,
up to one of the other substituents
R (8) -C n H 2n -Z-,
n from zero to 10, the alkylene chain C n H 2n being straight-chain or branched and where a C atom can be replaced by an oxygen or S atom or by an N atom,
R (8) is hydrogen, (C₂-C₆) alkenyl, (C₃-C₁₀) cycloalkyl which is unsubstituted or substituted by 1 to 4 methyl groups or an OH group, or can contain an ethylene group -CH = CH-, and in which a methylene group can be replaced by an oxygen or S atom or by an N atom,
Phenyl, unsubstituted or substituted by 1 to 3
Substituents from the series F, Cl, Br, I, CF₃, CH₃-S (O) s -,
s zero, 1 or 2,
R (9) -W y -,
R (9) H, methyl, ethyl, W is oxygen, NR (10), R (10) H or methyl, y zero or 1,
C m F 2m + 1 ,
m 1 to 3, 1- or 2-naphthyl, pyridyl, quinolyl or isoquinolyl,
Z -CO-, -CH₂-, - [CR (11) (OH)] q -
q 1, 2 or 3, R (11) H or methyl,
Oxygen, -NR (12) -,
R (12) H, methyl,
-S (O) s -,
s zero, 1 or 2,
-SO₂-NR (12) -,
R (12) H, (C₁-C₄) alkyl,
R (7) hydrogen, (C₁-C₁₀) alkyl, (C₂-C₁₀) alkenyl, R (8) -C n H 2n -,
and their pharmaceutically acceptable salts.
X CR(6) oder N, Y NR(7),
und die Reste R(1) bis R(7) wie in Anspruch 1 definiert sind. 2. Compound of formula I according to claim 1, characterized in that therein:
X CR (6) or N, Y NR (7),
and the radicals R (1) to R (7) are as defined in claim 1.
X CR(6) oder N, Y NR(7), und
einer der Substituenten R(1) bis R(6) eine -CO-N=C(NH₂)₂-Gruppe, und die jeweils anderen Substituenten R(1) bis R(6)
Wasserstoff, F, Cl, Br, I, (C₁-C₆)-Alkyl,
bis zu zwei der anderen Substituenten R(1) bis R(6)
CN, NO₂, N₃, CF₃, (C₁-C₄)-Alkyloxy,
bis zu einem der anderen Substituenten R(1) bis R(6)
R(8)-CnH2n-Z-,
n Null bis 6, wobei die Alkylenkette -CnH2n- geradkettig oder verzweigt sein kann und ein C-Atom durch ein Sauerstoff oder S-Atom oder durch ein N-Atom ersetzt sein kann,
R(8) Wasserstoff, (C₃-C₆)-Alkenyl, (C₅-C₈)-Cycloalkyl, das unsubstituiert ist oder durch 1-2 Methylgruppen oder eine OH-Gruppe substituiert, und worin eine Methylengruppe durch ein Sauerstoff- oder S-Atom oder durch ein N-Atom ersetzt sein kann,
Phenyl, das unsubstituiert ist oder 1 bis 3 Substituenten trägt aus der Reihe F, Cl, Br, I, CF₃, CH₃-S(O)s-
s Null, 1 oder 2,
R(9)-Wy-
R(9) H, Methyl, Ethyl, W Sauerstoff, NR(10), R(10) H oder Methyl, y Null oder 1,
CmF2m+1,
m 1 bis 3, Pyridyl, Chinolyl oder Isochinolyl
Z -CO-, -CH₂-, -[CR(11)(OH)]q-
q 1 bis 3, R(11) H oder Methyl,
-O-, -NR(12)-,
R(12) H oder Methyl,
S(O)s-,
s Null bis 2,
-SO₂-NR(12)-,
R(12) H oder (C₁-C₄)-Alkyl,
R(7) Wasserstoff, (C₁ -C₆)-Alkyl, (C₂-C₄)-Alkenyl, R(⁸)-CnH2n-.3. Compound of formula I according to claim 1, characterized in that therein:
X CR (6) or N, Y NR (7), and
one of the substituents R (1) to R (6) is a -CO-N = C (NH₂) ₂ group, and the other substituents R (1) to R (6)
Hydrogen, F, Cl, Br, I, (C₁-C₆) alkyl,
up to two of the other substituents R (1) to R (6)
CN, NO₂, N₃, CF₃, (C₁-C₄) alkyloxy,
up to one of the other substituents R (1) to R (6)
R (8) -C n H 2n -Z-,
n is zero to 6, where the alkylene chain -C n H 2n - can be straight-chain or branched and a C atom can be replaced by an oxygen or S atom or by an N atom,
R (8) is hydrogen, (C₃-C₆) alkenyl, (C₅-C₈) cycloalkyl which is unsubstituted or substituted by 1-2 methyl groups or an OH group, and wherein a methylene group by an oxygen or S atom or can be replaced by an N atom,
Phenyl which is unsubstituted or carries 1 to 3 substituents from the series F, Cl, Br, I, CF₃, CH₃-S (O) s -
s zero, 1 or 2,
R (9) -W y -
R (9) H, methyl, ethyl, W oxygen, NR (10), R (10) H or methyl, y zero or 1,
C m F 2m + 1 ,
m 1 to 3, pyridyl, quinolyl or isoquinolyl
Z -CO-, -CH₂-, - [CR (11) (OH)] q -
q 1 to 3, R (11) H or methyl,
-O-, -NR (12) -,
R (12) H or methyl,
S (O) s -,
s zero to 2,
-SO₂-NR (12) -,
R (12) H or (C₁-C₄) alkyl,
R (7) hydrogen, (C₁ -C₆) alkyl, (C₂-C₄) alkenyl, R (⁸) -C n H 2n -.
X CR(6), Y NR(7), und
einer der Substituenten R(1) bis R(6) eine -CO-N=C(NH₂)₂-Gruppe, und die jeweils anderen Substituenten R(1) bis R(6)
Wasserstoff, F, Cl, Br, (C₁-C₄)-Alkyl,
bis zu einem der Substituenten R(1) bis R(6)
R (8)-CnH2n-Z-,
n Null, 1 oder 2,
wobei die Alkylenkette CnH2n geradkettig oder verzweigt ist und wobei ein C-Atom durch ein Sauerstoff- oder S-Atom oder durch ein N-Atom ersetzt sein kann,
R(8) Wasserstoff, (C₅-C₈)-Cycloalkyl,
das unsubstituiert ist oder substituiert durch 1-2 Methylgruppen oder eine OH-Gruppe,
Phenyl, das unsubstituiert ist oder 1 bis 3 Substituenten trägt aus der Reihe F, Cl, CF₃, CH₃-S(O)s-,
s Null oder 2,
R(9)-Wy-
R(9) H, Methyl, Ethyl, W Sauerstoff, y Null oder 1,
CmF2m+1,
m 1, 2 oder 3, Pyridyl, Chinolyl oder Isochinolyl,
Z -CO-, -CH₂-, [CR(11)(OH)]q-
q 1 bis 3, R(11) H oder Methyl, -S(O)s-,
s Null bis 2, -O-, und
R(7) (C₁-C₆)-Alkyl, (C₃-C₆)-Alkenyl, R(8)-CnH2n-.4. Compound of formula I according to claim 1, characterized in that therein:
X CR (6), Y NR (7), and
one of the substituents R (1) to R (6) is a -CO-N = C (NH₂) ₂ group, and the other substituents R (1) to R (6)
Hydrogen, F, Cl, Br, (C₁-C₄) alkyl,
up to one of the substituents R (1) to R (6)
R (8) -CnH 2n -Z-,
n zero, 1 or 2,
where the alkylene chain C n H 2n is straight-chain or branched and where a C atom can be replaced by an oxygen or S atom or by an N atom,
R (8) hydrogen, (C₅-C₈) cycloalkyl,
which is unsubstituted or substituted by 1-2 methyl groups or an OH group,
Phenyl which is unsubstituted or carries 1 to 3 substituents from the series F, Cl, CF₃, CH₃-S (O) s -,
s zero or 2,
R (9) -W y -
R (9) H, methyl, ethyl, W oxygen, y zero or 1,
C m F 2m + 1 ,
m 1, 2 or 3, pyridyl, quinolyl or isoquinolyl,
Z -CO-, -CH₂-, [CR (11) (OH)] q -
q 1 to 3, R (11) H or methyl, -S (O) s -,
s zero to 2, -O-, and
R (7) (C₁-C₆) alkyl, (C₃-C₆) alkenyl, R (8) -C n H 2n -.
5-Chlor-1-methyl-2-indolylcarbonyl-guanidin-hydrochlorid,
5-Chlor-1-ethyl-2-indolylcarbonyl-guanidin-hydrochlorid,
3-Chlor-1-methyl-2-indolylcarbonyl-guanidin-hydrochlorid,
3,5-Dichlor-1-methyl-2-indolylcarbonyl-guanidin-hydrochlorid ,
5-Fluor-1-methyl-2-indolylcarbonyl-guanidin-hydrochlorid. 5. A compound of formula I according to claim 1, characterized in that it is selected from the group
5-chloro-1-methyl-2-indolylcarbonyl-guanidine hydrochloride,
5-chloro-1-ethyl-2-indolylcarbonyl-guanidine hydrochloride,
3-chloro-1-methyl-2-indolylcarbonyl-guanidine hydrochloride,
3,5-dichloro-1-methyl-2-indolylcarbonyl-guanidine hydrochloride,
5-fluoro-1-methyl-2-indolylcarbonyl guanidine hydrochloride.
eine Verbindung der Formel II worin einer der Substituenten R(1)′ bis R(5)′ eine -CO-L-Gruppe bedeutet und L für eine leicht nucleophil substituierbare leaving group steht, und die jeweils anderen Substituenten R(1)′ bis R(5)′ die angegebene Bedeutung besitzen,
mit Guanidin unter Bildung der in Formel I angegebenen Acylguanidingruppe, -CO-N = C(NH₂)₂, umsetzt.6. A process for the preparation of a compound of formula I according to claim 1, characterized in that
a compound of formula II wherein one of the substituents R (1) 'to R (5)' represents a -CO-L group and L represents an easily nucleophilically substitutable leaving group, and the other substituents R (1) 'to R (5)' have the meaning given,
with guanidine to form the acylguanidine group specified in formula I, -CO-N = C (NH₂) ₂.
Priority Applications (15)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4326005A DE4326005A1 (en) | 1993-08-03 | 1993-08-03 | Benzo-fused 5-membered ring heterocycles, processes for their preparation, their use as a medicament, their use as a diagnostic, and medicament containing them |
| EP94111765A EP0639573A1 (en) | 1993-08-03 | 1994-07-28 | Benzocondensed five membered heterocycles, process of their preparation, their use as drug, as diagnostic means and pharmaceuticals containing it |
| IL11050394A IL110503A (en) | 1993-08-03 | 1994-07-29 | Benzo-fused heterocyclic compounds having a 5-membered ring processes for their preparation and pharmaceutical compositions containing them |
| NZ264130A NZ264130A (en) | 1993-08-03 | 1994-07-29 | Guanidinocarbonyl-substituted benzoheterocyclic derivatives; pharmaceutical compositions and use as diagnostic agents |
| AU68844/94A AU682371B2 (en) | 1993-08-03 | 1994-08-01 | Benzo-fused heterocyclic compounds having a 5-membered ring,processes for their preparation, their use as medicaments, their use as diagnostic agents and medicaments containing them |
| FI943579A FI943579A7 (en) | 1993-08-03 | 1994-08-01 | Benzofused 5-ring heterocycles, a method for their preparation, their use as medicines, their use as diagnostic agents and medicines containing them |
| KR1019940019259A KR100343292B1 (en) | 1993-08-02 | 1994-08-02 | Molded Structures Composed of Thermoplastics, Their Manufacturing Methods, and Their Use |
| NO942864A NO301584B1 (en) | 1993-08-03 | 1994-08-02 | Benzo-condensed 5-ring heterocycles, their use in the manufacture of drugs and diagnostics, as well as drugs containing these |
| CA002129301A CA2129301A1 (en) | 1993-08-03 | 1994-08-02 | Benzo-fused heterocyclic compounds with a 5-membered ring, process for their preparation, their use as medicaments, their use as diagnostic agents, and medicaments containing them |
| CN94109516A CN1118347A (en) | 1993-08-03 | 1994-08-02 | Benzo five-membered heterocycles, their preparation and use as medicines and diagnostics |
| KR1019940019071A KR950005817A (en) | 1993-08-03 | 1994-08-02 | A benzo-fused heterocyclic compound having a 5-membered ring, its preparation method, its use as a medicine, its use as a diagnostic agent and medicaments containing it |
| ZA945734A ZA945734B (en) | 1993-08-03 | 1994-08-02 | Benzo-fused heterocyclic compounds having a 5-membered ring processes for their preparation their use as medicaments their use as diagnostic agents and medicaments containing them |
| JP6198940A JPH07145149A (en) | 1993-08-03 | 1994-08-02 | Benzo-fused heterocyclic compounds having a 5-membered ring and processes for their preparation |
| HU9402271A HU218790B (en) | 1993-08-03 | 1994-08-03 | Benzocondensed heterocyclic compounds, process for producing them and pharmaceutical compositions containing them |
| US08/872,180 US5852046A (en) | 1993-08-03 | 1997-06-10 | Benzo-fused heterocyclic compounds having a 5-membered ring processes for their preparation their use as medicaments their use as diagnostic agents and medicaments containing them |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4326005A DE4326005A1 (en) | 1993-08-03 | 1993-08-03 | Benzo-fused 5-membered ring heterocycles, processes for their preparation, their use as a medicament, their use as a diagnostic, and medicament containing them |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE4326005A1 true DE4326005A1 (en) | 1995-02-09 |
Family
ID=6494342
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE4326005A Withdrawn DE4326005A1 (en) | 1993-08-02 | 1993-08-03 | Benzo-fused 5-membered ring heterocycles, processes for their preparation, their use as a medicament, their use as a diagnostic, and medicament containing them |
Country Status (2)
| Country | Link |
|---|---|
| DE (1) | DE4326005A1 (en) |
| ZA (1) | ZA945734B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0738712A1 (en) * | 1995-04-18 | 1996-10-23 | Hoechst Aktiengesellschaft | Anti-arrhythmic and cardioprotective substituted indenoylguanidines |
| US7696240B2 (en) | 2005-12-15 | 2010-04-13 | Hoffmann-La Roche Inc. | Fused pyrrole derivatives |
| CN105130932A (en) * | 2015-07-14 | 2015-12-09 | 中国科学院微生物研究所 | Compounds and uses of compounds in preparation of PTP1B inhibitors and drugs for treatment and/or prevention of diabetes type II |
-
1993
- 1993-08-03 DE DE4326005A patent/DE4326005A1/en not_active Withdrawn
-
1994
- 1994-08-02 ZA ZA945734A patent/ZA945734B/en unknown
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0738712A1 (en) * | 1995-04-18 | 1996-10-23 | Hoechst Aktiengesellschaft | Anti-arrhythmic and cardioprotective substituted indenoylguanidines |
| US7696240B2 (en) | 2005-12-15 | 2010-04-13 | Hoffmann-La Roche Inc. | Fused pyrrole derivatives |
| CN105130932A (en) * | 2015-07-14 | 2015-12-09 | 中国科学院微生物研究所 | Compounds and uses of compounds in preparation of PTP1B inhibitors and drugs for treatment and/or prevention of diabetes type II |
| CN105130932B (en) * | 2015-07-14 | 2017-06-16 | 中国科学院微生物研究所 | Compound and its purposes in the medicine for preparing PTP1B inhibitor and treatment and/or prevention type II diabetes |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA945734B (en) | 1995-03-07 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 8130 | Withdrawal |