DE19543194A1 - New benzene-di:carboxylic acid di:guanidide derivs. - Google Patents
New benzene-di:carboxylic acid di:guanidide derivs.Info
- Publication number
- DE19543194A1 DE19543194A1 DE19543194A DE19543194A DE19543194A1 DE 19543194 A1 DE19543194 A1 DE 19543194A1 DE 19543194 A DE19543194 A DE 19543194A DE 19543194 A DE19543194 A DE 19543194A DE 19543194 A1 DE19543194 A1 DE 19543194A1
- Authority
- DE
- Germany
- Prior art keywords
- hydrogen
- independently
- alkyl
- methyl
- another
- 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- Withdrawn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
- 150000001732 carboxylic acid derivatives Chemical class 0.000 title description 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 38
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 5
- 239000001257 hydrogen Substances 0.000 claims description 58
- 229910052739 hydrogen Inorganic materials 0.000 claims description 58
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 53
- 150000001875 compounds Chemical class 0.000 claims description 48
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 48
- 125000004432 carbon atom Chemical group C* 0.000 claims description 36
- 125000001424 substituent group Chemical group 0.000 claims description 31
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 30
- 150000002431 hydrogen Chemical class 0.000 claims description 28
- 239000003814 drug Substances 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 18
- 238000011282 treatment Methods 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 13
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 12
- -1 methoxy, hydroxy, amino, methylamino Chemical group 0.000 claims description 12
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 12
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 9
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 8
- 125000001589 carboacyl group Chemical group 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 8
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 8
- 230000000302 ischemic effect Effects 0.000 claims description 7
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 6
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 6
- 210000000056 organ Anatomy 0.000 claims description 6
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
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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
- KKEYFWRCBNTPAC-UHFFFAOYSA-N benzene-dicarboxylic acid Natural products OC(=O)C1=CC=C(C(O)=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-N 0.000 abstract description 10
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- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- AJDQRQQNNLZLPM-UHFFFAOYSA-N n-(diaminomethylidene)benzamide Chemical compound NC(N)=NC(=O)C1=CC=CC=C1 AJDQRQQNNLZLPM-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- VWBWQOUWDOULQN-UHFFFAOYSA-N nmp n-methylpyrrolidone Chemical compound CN1CCCC1=O.CN1CCCC1=O VWBWQOUWDOULQN-UHFFFAOYSA-N 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000035778 pathophysiological process Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000009117 preventive therapy Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 201000004240 prostatic hypertrophy Diseases 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000002827 triflate group Chemical class FC(S(=O)(=O)O*)(F)F 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
- 238000005303 weighing Methods 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Die Erfindung betrifft Benzoldicarbonsäure-diguanidide der Formel IThe invention relates to benzenedicarboxylic acid diguanidides of the formula I.
worin bedeuten:
einer der Reste R(1), R(2), R(3), R(4) und R(5)in which mean:
one of the radicals R (1), R (2), R (3), R (4) and R (5)
-CO-N=C(NH₂)₂;-CO-N = C (NH₂) ₂;
und die jeweils anderen Reste R(1), R(2), R(3), R(4) und R(5)
R(1) und R(5)
unabhängig voneinander Wasserstoff, Alkyl mit 1, 2, 3 oder 4 C-Atomen,
F, Cl, -OR(32), -NR(33)R(34) oder -CF₃;
R(32), R(33) und R(34)
unabhängig voneinander Wasserstoff oder Alkyl mit 1, 2, 3 oder 4
C-Atomen;
R(2) und R(4)
unabhängig voneinander Wasserstoff, F, Cl, Br, I, OH, -CN, CF₃,
-CO-N=C(NH₂)₂, Alkyl mit 1, 2, 3, 4, 5, 6, 7 oder 8 C-Atomen, Alkenyl
mit 2, 3, 4, 5, 6, 7 oder 8 C-Atomen oder -(CH₂)mR(14);
m Null, 1 oder 2;
R(14) -(C₃-C₈)-Cycloalkyl oder Phenyl,
welches nicht substituiert oder substituiert ist mit 1-3
Substituenten ausgewählt aus der Gruppe bestehend aus F
und Cl, -CF₃, Methyl, Methoxy und -NR(15)R(16);
R(15) und R(16)
Wasserstoff oder -CH₃;
oder
R(2) und R(4)
unabhängig voneinander Pyrrol-1-yl, Pyrrol-2-yl oder Pyrrol-3-yl,
welches nicht substituiert oder substituiert ist mit 1-4
Substituenten ausgewählt aus der Gruppe bestehend aus F, Cl, Br,
I, -CN, (C₂-C₈)-Alkanoyl, (C₂-C₈)-Alkoxycarbonyl, Formyl, Carboxy,
-CF₃, Methyl und Methoxy;
oder
R(2) und R(4)
R(22)-SO₂-, R(23)R(24)N-CO-, R(28)-CO- oder R(29)R(30)N-SO₂;
R(22) und R(28)
unabhängig voneinander Methyl oder -CF₃;
R(23), R(24), R(29) und R(30)
unabhängig voneinander Wasserstoff oder Methyl;
oder
R(2) und R(4)
unabhängig voneinander -OR(35) oder -NR(35)R(36);
R(35) und R(36)
unabhängig voneinander Wasserstoff oder Alkyl mit 1, 2, 3, 4, 5
oder 6 C-Atomen;
oder
R(35) und R(36)
gemeinsam 4, 5, 6 oder 7 Methylengruppen, von denen eine CH₂-
Gruppe durch Sauerstoff, -S-, -NH-, -NCH₃ oder -N-Benzyl ersetzt
sein kann;
R(3) Wasserstoff, -SR(25), -OR(25), -NR(25)R(26) oder -CR(25)R(26)R(27);
R(25) Wasserstoff, Alkyl mit 1, 2, 3, 4, 5, 6, 7 oder 8 C-Atomen oder
Phenyl,
das unsubstituiert oder substituiert ist mit 1-3 Substituenten
ausgewählt aus der Gruppe bestehend aus F, Cl, -CF₃, CH₃,
Methoxy, Hydroxy, Amino, Methylamino und
Dimethylamino;
oder
R(25) -(C₁-C₉)-Heteroaryl,
das unsubstituiert oder substituiert ist mit 1-3
Substituenten ausgewählt aus der Gruppe bestehend aus F,
Cl, -CF₃, CH₃, Methoxy, Hydroxy, Amino, Methylamino und
Dimethylamino;
R(26) und R(27)
unabhängig voneinander wie R(25) definiert oder
Wasserstoff oder Alkyl mit 1, 2, 3, 4, 5, 6, 7 oder 8
C-Atomen;
sowie deren pharmazeutisch verträgliche Salze.and the other radicals R (1), R (2), R (3), R (4) and R (5)
R (1) and R (5) independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 C atoms, F, Cl, -OR (32), -NR (33) R (34) or -CF₃;
R (32), R (33) and R (34) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 C atoms;
R (2) and R (4) independently of one another are hydrogen, F, Cl, Br, I, OH, -CN, CF₃, -CO-N =C (NH₂) ₂, alkyl having 1, 2, 3, 4, 5 , 6, 7 or 8 C atoms, alkenyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms or - (CH₂) m R (14);
m is zero, 1 or 2;
R (14) - (C₃-C₈) -cycloalkyl or phenyl which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F and Cl, -CF₃, methyl, methoxy and -NR (15) R ( 16);
R (15) and R (16) are hydrogen or -CH₃; or
R (2) and R (4) independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl which is unsubstituted or substituted by 1-4 substituents selected from the group consisting of F, Cl, Br, I, -CN, (C₂-C₈) alkanoyl, (C₂-C₈) alkoxycarbonyl, formyl, carboxy, -CF₃, methyl and methoxy; or
R (2) and R (4) R (22) -SO₂-, R (23) R (24) N-CO-, R (28) -CO- or R (29) R (30) N-SO₂; R (22) and R (28) independently of one another are methyl or -CF₃;
R (23), R (24), R (29) and R (30) are independently hydrogen or methyl; or
R (2) and R (4) are independently -OR (35) or -NR (35) R (36);
R (35) and R (36) independently of one another are hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 C atoms; or
R (35) and R (36) together 4, 5, 6 or 7 methylene groups, of which one CH₂ group may be replaced by oxygen, -S-, -NH-, -NCH₃ or -N-benzyl;
R (3) is hydrogen, -SR (25), -OR (25), -NR (25) R (26) or -CR (25) R (26) R (27);
R (25) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, - CF₃, CH₃, methoxy, hydroxy, amino, methylamino and dimethylamino; or
R (25) - (C₁-C₉) -heteroaryl which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, -CF₃, CH₃, methoxy, hydroxy, amino, methylamino and dimethylamino;
R (26) and R (27) independently of one another are defined as R (25) or hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms;
and their pharmaceutically acceptable salts.
Bevorzugt sind Verbindungen der Formel I, in denen bedeuten:
einer der Reste R(1), R(2), R(3), R(4) und R(5)Preference is given to compounds of the formula I in which
one of the radicals R (1), R (2), R (3), R (4) and R (5)
-CO-N=C(NH₂)₂;-CO-N = C (NH₂) ₂;
und die jeweils anderen Reste R(1), R(2), R(3), R(4) und R(5)
R(1) und R(5)
unabhängig voneinander Wasserstoff, Alkyl mit 1, 2 oder 3 C-Atomen, F,
Cl, -OR(32), -NR(33)R(34) oder -CF₃;
R(32), R(33) und R(34)
unabhängig voneinander Wasserstoff oder Methyl;
R(2) und R(4)
unabhängig voneinander Wasserstoff, F, Cl, Br, I, OH, -CF₃,
-CO-N=C(NH₂)₂, Alkyl mit 1, 2, 3 oder 4 C-Atomen, Alkenyl mit 2, 3
oder 4 C-Atomen oder -(CH₂)mR(14);
m Null, 1 oder 2;
R(14) -(C₃-C₆)-Cycloalkyl oder Phenyl,
welches nicht substituiert oder substituiert ist mit 1-2
Substituenten ausgewählt aus der Gruppe bestehend aus F
und Cl, -CF₃, Methyl und Methoxy;
oder
R(2) und R(4)
unabhängig voneinander Pyrrol-1-yl, Pyrrol-2-yl oder Pyrrol-3-yl,
welches nicht substituiert oder substituiert ist mit 1-2
Substituenten ausgewählt aus der Gruppe bestehend aus F, Cl, Br,
I, -CN, (C₂-C₅)-Alkanoyl, (C₂-C₅)-Alkoxycarbonyl, Formyl, Carboxy,
-CF₃ und Methyl;
oder
R(2) und R(4)
unabhängig voneinander R(22)-SO₂-, R(28)-CO- oder R(29)R(30)N-SO₂;
R(22) und R(28)
unabhängig voneinander Methyl oder -CF₃;
R(29) und R(30)
unabhängig voneinander Wasserstoff oder Methyl;
oder
R(2) und R(4) unabhängig voneinander
-OR(35) oder -NR(35)R(36);
R(35) und R(36)
unabhängig voneinander Wasserstoff, Methyl oder Ethyl;
oder
R(35) und R(36)
gemeinsam 4-5 Methylengruppen, von denen eine CH₂-Gruppe
durch Sauerstoff, -S-, -NH- oder -NCH₃ ersetzt sein kann;
R(3) Wasserstoff, -SR(25), -OR(25), -NR(25)R(26) oder -CR(25)R(26)R(27);
R(25) Wasserstoff, Alkyl mit 1, 2, 3 oder 4 C-Atomen oder Phenyl,
das unsubstituiert oder substituiert ist mit 1-2
Substituenten ausgewählt aus der Gruppe bestehend aus F,
Cl, -CF₃, CH₃, Methoxy und Dimethylamino;
oder
R(25) -(C₁-C₉)-Heteroaryl,
das unsubstituiert oder substituiert ist mit 1-2
Substituenten ausgewählt aus der Gruppe bestehend aus F,
Cl, -CF₃, CH₃, Methoxy und Dimethylamino;
R(26) und R(27)
unabhängig voneinander Wasserstoff oder Alkyl mit 1, 2, 3
oder 4 C-Atomen;
sowie deren pharmazeutisch verträgliche Salze.and the other radicals R (1), R (2), R (3), R (4) and R (5)
R (1) and R (5) independently of one another are hydrogen, alkyl having 1, 2 or 3 C atoms, F, Cl, -OR (32), -NR (33) R (34) or -CF₃;
R (32), R (33) and R (34) are independently hydrogen or methyl;
R (2) and R (4) independently of one another are hydrogen, F, Cl, Br, I, OH, -CF₃, -CO-N =C (NH₂) ₂, alkyl having 1, 2, 3 or 4 C atoms, Alkenyl having 2, 3 or 4 carbon atoms or - (CH₂) m R (14);
m is zero, 1 or 2;
R (14) - (C₃-C₆) -cycloalkyl or phenyl which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F and Cl, -CF₃, methyl and methoxy; or
R (2) and R (4) independently of one another pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl, which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F, Cl, Br, I, -CN, (C₂-C₅) alkanoyl, (C₂-C₅) alkoxycarbonyl, formyl, carboxy, -CF₃ and methyl; or
R (2) and R (4) are independently R (22) -SO₂-, R (28) -CO- or R (29) R (30) N-SO₂;
R (22) and R (28) independently of one another are methyl or -CF₃;
R (29) and R (30) are independently hydrogen or methyl; or
R (2) and R (4) are independently -OR (35) or -NR (35) R (36);
R (35) and R (36) are independently hydrogen, methyl or ethyl; or
R (35) and R (36) together 4-5 methylene groups, of which one CH₂ group may be replaced by oxygen, -S-, -NH- or -NCH₃;
R (3) is hydrogen, -SR (25), -OR (25), -NR (25) R (26) or -CR (25) R (26) R (27); R (25) is hydrogen, alkyl having 1, 2, 3 or 4 C atoms or phenyl which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F, Cl, -CF₃, CH₃, methoxy and dimethylamino; or
R (25) - (C₁-C₉) -heteroaryl which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F, Cl, -CF₃, CH₃, methoxy and dimethylamino;
R (26) and R (27) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 C atoms;
and their pharmaceutically acceptable salts.
Besonders bevorzugt sind Verbindungen der Formel I, in denen bedeuten: einer der Reste R(1), R(2), R(3), R(4) und R(5)Particular preference is given to compounds of the formula I in which one of the radicals R (1), R (2), R (3), R (4) and R (5)
-CO-N=C(NH₂)₂;-CO-N = C (NH₂) ₂;
und die jeweils anderen Reste R(1), R(2), R(3), R(4) und R(5)
R(1) und R(5)
unabhängig voneinander Wasserstoff, Alkyl mit 1, 2 oder 3 C-Atomen, F,
Cl, -OR(32), -NR(33)R(34) oder -CF₃;
R(32), R(33) und R(34)
unabhängig voneinander Wasserstoff oder Methyl;
R(2) und R(4)
unabhängig voneinander Wasserstoff, F, Cl, OH, -CF₃, -CO-N=C(NH₂)₂,
Alkyl mit 1, 2, 3 oder 4 C-Atomen oder Pyrrol-1-yl,
welches nicht substituiert oder substituiert ist mit 1-2
Substituenten ausgewählt aus der Gruppe bestehend aus F, Cl, Br,
I, -CN, (C₂-C₅)-Alkanoyl, (C₂-C₅)-Alkoxycarbonyl, Formyl, Carboxy,
-CF₃ und Methyl;
oder
R(2) und R(4)
unabhängig voneinander R(22)-SO₂-;
R(22) Methyl oder -CF₃;
oder
R(2) und R(4)
unabhängig voneinander -OR(35) oder -NR(35)R(36);
R(35) und R(36)
unabhängig voneinander Wasserstoff, Methyl oder Ethyl;
R(3) Wasserstoff, -SR(25), -OR(25), -NR(25)R(26) oder -CR(25)R(26)R(27);
R(25) Wasserstoff, Alkyl mit 1, 2 oder 3 C-Atomen oder Phenyl,
das unsubstituiert oder substituiert ist mit einem
Substituenten aus der Gruppe F, Cl, CF₃ oder -CH₃;
oder
R(25) -(C₁-C₉)-Heteroaryl,
das unsubstituiert oder substituiert ist mit einem
Substituenten ausgewählt aus der Gruppe bestehend aus F,
Cl, CF₃ und CH₃;
R(26) und R(27)
unabhängig voneinander Wasserstoff oder Methyl;
sowie deren pharmazeutisch verträgliche Salze.and the other radicals R (1), R (2), R (3), R (4) and R (5)
R (1) and R (5) independently of one another are hydrogen, alkyl having 1, 2 or 3 C atoms, F, Cl, -OR (32), -NR (33) R (34) or -CF₃;
R (32), R (33) and R (34) are independently hydrogen or methyl;
R (2) and R (4) independently of one another are hydrogen, F, Cl, OH, -CF₃, -CO-N =C (NH₂) ₂, alkyl having 1, 2, 3 or 4 C atoms or pyrrole-1 yl which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F, Cl, Br, I, -CN, (C₂-C₅) alkanoyl, (C₂-C₅) alkoxycarbonyl, formyl, carboxy, -CF₃ and methyl; or
R (2) and R (4) independently of one another R (22) -SO₂-;
R (22) is methyl or -CF₃; or
R (2) and R (4) are independently -OR (35) or -NR (35) R (36); R (35) and R (36) are independently hydrogen, methyl or ethyl;
R (3) is hydrogen, -SR (25), -OR (25), -NR (25) R (26) or -CR (25) R (26) R (27); R (25) is hydrogen, alkyl having 1, 2 or 3 C atoms or phenyl which is unsubstituted or substituted by a substituent from the group F, Cl, CF₃ or -CH₃; or
R (25) - (C₁-C₉) heteroaryl which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, CF₃ and CH₃;
R (26) and R (27) are independently hydrogen or methyl;
and their pharmaceutically acceptable salts.
Ganz besonders bevorzugt sind Verbindungen der Formel I, in denen bedeuten: einer der Reste R(1), R(2), R(3), R(4) und R(5)Very particular preference is given to compounds of the formula I in which one of the radicals R (1), R (2), R (3), R (4) and R (5)
-CO-N=C(NH₂)₂;-CO-N = C (NH₂) ₂;
und die jeweils anderen Reste R(1), R(2), R(3), R(4) und R(5)
R(1) und R(5)
unabhängig voneinander Wasserstoff, Alkyl mit 1, 2 oder 3 C-Atomen, F,
Cl oder -CF₃;
R(2) und R(4)
Wasserstoff, OH, -CF₃, -CO-N=C(NH₂)₂, Alkyl mit 1, 2, 3 oder 4
C-Atomen oder Pyrrol-1-yl,
welches nicht substituiert oder substituiert ist mit 1-2
Substituenten ausgewählt aus der Gruppe bestehend aus F, Cl, Br,
I, -CN, (C₂-C₅)-Alkanoyl, (C₂-C₅)-Alkoxycarbonyl, Formyl, Carboxy,
-CF₃ und Methyl;
R(3) Wasserstoff, -OR(25) oder -CR(25)R(26)R(27);
R(25) Wasserstoff, Alkyl mit 1, 2 oder 3 C-Atomen oder Phenyl,
das unsubstituiert oder substituiert ist mit einem
Substituenten ausgewählt aus der Gruppe bestehend aus F,
Cl, -CF₃ und CH₃;
oder
R(25) -(C₁-C₉)-Heteroaryl,
das unsubstituiert oder substituiert ist mit einem
Substituenten ausgewählt aus der Gruppe bestehend aus F,
Cl, CF₃ und CH₃;
R(26) und R(27)
unabhängig voneinander Wasserstoff oder Methyl;
sowie deren pharmazeutisch verträgliche Salze.and the other radicals R (1), R (2), R (3), R (4) and R (5)
R (1) and R (5) independently of one another are hydrogen, alkyl having 1, 2 or 3 C atoms, F, Cl or -CF₃;
R (2) and R (4) are hydrogen, OH, -CF₃, -CO-N =C (NH₂) ₂, alkyl having 1, 2, 3 or 4 C atoms or pyrrol-1-yl,
which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, I, -CN, (C₂-C₅) alkanoyl, (C₂-C₅) alkoxycarbonyl, formyl, carboxy, -CF₃ and methyl;
R (3) is hydrogen, -OR (25) or -CR (25) R (26) R (27);
R (25) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or phenyl which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, -CF₃ and CH₃; or
R (25) - (C₁-C₉) heteroaryl which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, CF₃ and CH₃;
R (26) and R (27) are independently hydrogen or methyl;
and their pharmaceutically acceptable salts.
Die bezeichneten Alkylreste können sowohl geradkettig wie verzweigt vorliegen.The designated alkyl radicals can be both straight-chain and branched available.
Unter (C₁-C₉)-Heteroaryl werden Reste verstanden, die sich von Phenyl oder Naphthyl ableiten, in welchen eine oder mehrere CH-Gruppen durch N ersetzt sind und/oder in welchen mindestens zwei benachbarte CH-Gruppen (unter Bildung eines fünfgliedrigen aromatischen Rings) durch S, NH oder O ersetzt sind. Des weiteren können auch ein oder beide Atome der Kondensationsstelle bicyclischer Reste (wie im Indolizinyl) N-Atome sein.By (C₁-C₉) heteroaryl are meant radicals derived from phenyl or Derive naphthyl in which one or more CH groups are replaced by N. and / or in which at least two adjacent CH groups (under Formation of a five-membered aromatic ring) replaced by S, NH or O. are. Furthermore, one or both atoms of the condensation site bicyclic radicals (as in indolizinyl) N atoms.
Als Heteroaryl gelten insbesondere Furanyl, Thienyl, Pyrrolyl, Imidazolyl, Pyrazolyl, Triazolyl, Tetrazolyl, Oxazolyl, Isoxazolyl, Thiazolyl, Isothiazolyl, Pyridyl, Pyrazinyl, Pyrimidinyl, Pyridazinyl, Indolyl, Indazolyl, Chinolyl, Isochinolyl, Phthalazinyl, Chinoxalinyl, Chinazolinyl, Cinnolinyl.As heteroaryl furanyl, thienyl, pyrrolyl, imidazolyl, Pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, Pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, Isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl.
Ganz besonders bevorzugt sind die Heterocyclen Thienyl, Pyrrolyl, Imidazolyl, Pyrazolyl, Triazolyl, Tetrazolyl, Oxazolyl, Isoxazolyl, Thiazolyl, Isothiazolyl, Pyridyl, Pyrazinyl, Pyrimidinyl, Indolyl, Chinolyl und Isochinolyl.Very particular preference is given to the heterocycles thienyl, pyrrolyl, imidazolyl, Pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, Pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl and isoquinolyl.
Enthält einer der Substituenten R(1) bis R(5) ein oder mehrere Asymmetriezentren, so können diese unabhängig voneinander sowohl S als auch R konfiguriert sein. Die Verbindungen können als optische Isomere, als Diastereomere, als Racemate oder als Gemische derselben vorliegen.If one of the substituents R (1) to R (5) contains one or more Asymmetric centers, they can independently of each other both S and also be configured. The compounds can be used as optical isomers, as Diastereomers, as racemates or as mixtures thereof.
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 compounds of the formula II
worin R(1′) bis R(5′) die oben für R(1) bis R(5) angegebenen Bedeutungen
haben, von denen jedoch mindestens einer der Substituenten R(1′) bis R(5′) die
gezeichnete COL-Gruppe ist, und worin L für leicht nucleophil substituierbare
Fluchtgruppen steht,
mit Guanidin umsetzt.
in which R (1 ') to R (5') have the meanings given above for R (1) to R (5), of which, however, at least one of the substituents R (1 ') to R (5') has the subscribed COL Is group, and wherein L is slightly nucleophilically substitutable leaving groups,
with guanidine.
Die aktivierten Säurederivate der Formel II, worin L eine Alkoxy-, vorzugsweise eine Methoxygruppe oder Phenoxygruppe, eine Phenylthio-, Methylthio-, 2-Pyridylthiogruppe, oder 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 Benzoldicarbonsäurederivaten (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, 351-367 (1962)], die gemischten Anhydride II mit Cl-COOC₂H₅ oder Tosylchlorid in Gegenwart von Triethylamin in einem inerten Lösungsmittel, wie auch die Aktivierungen von Benzoldicarbonsäuren mit Dicyclohexylcarbodiimid (DCC) oder mit O-[(Cyano(ethoxycarbonyl)-methylen)amino]-1,1,3,3-tetra methyluronium-tetrafluoroborat] ("TOTU") [Proceedings of the 21. European Peptide Symposium, Peptides 1990, Editors E. Giralt and D. Andreu, Escom, Leiden, 1991]. Eine Reihe geeigneter Methoden zur Herstellung von aktivierten Carbonsäurederivaten der allgemeinen Formel II sind unter Angabe von Quellenliteratur in J. March, Advanced Organic Chemistry, Third Edition (John Wiley & Sons, 1985), S. 350 angegeben.The activated acid derivatives of the formula II, wherein L is an alkoxy, preferably a methoxy group or phenoxy group, a phenylthio, methylthio, 2-pyridylthio group, or a nitrogen heterocycle, preferably 1-imidazolyl, means, obtained in a conventional manner from the advantageous underlying carbonyl chlorides (formula II, L = Cl), which in turn again in a conventional manner from the underlying carboxylic acids (Formula II, L = OH), for example, with thionyl chloride can produce. In addition to the carboxylic acid chlorides of the formula II (L = Cl) can also be further activated acid derivatives of the formula II in a conventional manner directly from the underlying benzenedicarboxylic acid derivatives (formula II, L = OH) as, for example, the methyl ester of the formula II with L = OCH₃ by Treating with gaseous HCl in methanol, the imidazolides of the formula II Treatment with carbonyldiimidazole [L = 1-imidazolyl, Staab, Angew. Chem. Int. Ed. Engl. 1, 351-367 (1962)], the mixed anhydrides II with Cl-COOC₂H₅ or Tosyl chloride in the presence of triethylamine in an inert solvent, such as also the activations of benzenedicarboxylic acids with dicyclohexylcarbodiimide (DCC) or with O - [(cyano (ethoxycarbonyl) methylene) amino] -1,1,3,3-tetra methyluronium tetrafluoroborate] ("TOTU") [Proceedings of the 21st. European Peptide Symposium, Peptides 1990, Editors E. Giralt and D. Andreu, Escom, Leiden, 1991]. A set of suitable methods for the production of Activated carboxylic acid derivatives of general formula II are given from 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 Benzoldicarbonsäuremethylester (II, L = OMe) mit Guanidin Methanol, Isopropanol oder THF zwischen 20°C und Siedetemperatur dieser Lösungsmittel bewährt. Bei den meisten Umsetzungen von Verbindungen II mit salzfreien Guanidin wurde vorteilhaft in inerten Lösungsmitteln wie THF, Dimethoxyethan, Dioxan oder Isopropanol gearbeitet. Aber auch Wasser kann als Lösungsmittel dienen.The reaction of an activated carboxylic acid derivative of the formula I with guanidine takes place in a conventional manner in a protic or aprotic polar but inert organic solvents. In the process of implementation the benzene dicarboxylic acid methyl ester (II, L = OMe) with guanidine methanol, Isopropanol or THF between 20 ° C and boiling temperature of these solvents proven. For most reactions of compounds II with salt-free Guanidine has been advantageously used in inert solvents such as THF, dimethoxyethane, Dioxane or isopropanol worked. But even water can be used as a solvent serve.
Wenn L = Cl bedeutet, arbeitet man vorteilhaft unter Zusatz eines Säurefängers, z. B. in Form von überschüssigen Guanidin zur Abbindung der Halogenwasserstoffsäure.If L = Cl, one works advantageously with the addition of one Acid scavenger, z. B. in the form of excess guanidine for setting the Hydrohalic acid.
Die Einführung der im Phenylteil mit Schwefel-, Sauerstoff- oder Stickstoffnucleophilen substituierten Verbindungen gelingt durch literaturbekannte Methoden der nucleophilen Substitution an Derivaten der Benzoldicarbonsäure-dialkylester. Als Abgangsgruppe am Benzoldicarbonsäurederivat haben sich bei dieser Substitution Halogenide und Trifluormethansulfonate bewährt. Man arbeitet vorteilhaft in einem dipolar aprotischen Lösungsmittel, wie DMF oder TMU, bei einer Temperatur von 0°C bis zum Siedepunkt des Lösungsmittels, bevorzugt von 80°C bis zum Siedepunkt des Lösungsmittels. Als Säurefänger dient vorteilhaft ein Alkali- oder Erdalkalisalz mit einem Anion hoher Basizität und geringer Nucleophilie, zum Beispiel K₂CO₃ oder Cs₂CO₃.The introduction of the in phenyl part with sulfur, oxygen or Nitrogen nucleophiles substituted compounds succeed by literature methods of nucleophilic substitution on derivatives of Benzene dicarboxylic acid dialkyl. As a leaving group at the Benzoldicarboxylic acid derivative have in this substitution halides and Trifluoromethanesulfonates proven. It works advantageously in a dipolar aprotic solvents, such as DMF or TMU, at a temperature of 0 ° C up to the boiling point of the solvent, preferably from 80 ° C to Boiling point of the solvent. As an acid scavenger is advantageously an alkali or Alkaline earth salt with an anion of high basicity and low nucleophilicity, for Example K₂CO₃ or Cs₂CO₃.
Die Einführung der Alkyl- oder Arylsubstituenten gelingt durch literaturbekannte Methoden des Palladium-vermittelten cross-couplings von Arylhalogeniden mit beispielsweise Organozinkverbindungen, Organostannanen, Organoboronsäuren oder Organoboranen.The introduction of the alkyl or Arylsubstituenten succeeds by literature Methods of palladium-mediated cross-coupling of aryl halides with for example, organozinc compounds, organostannanes, organoboronic acids or organoboranes.
Benzoldicarbonsäure-diguanidide I sind im allgemeinen schwache Basen und können Säure unter Bildung von Salzen binden. Als Säureadditionssalze kommen Salze aller pharmakologisch verträglichen Säuren infrage, beispielsweise Halogenide, insbesondere Hydrochloride, Ascorbate, Lactate, Sulfate, Citrate, Tartrate, Acetate, Phosphate, Methylsulfonate, p-Toluolsulfonate. Benzoldicarboxylic acid diguanidides I are generally weak bases and can bind acid to form salts. As acid addition salts are salts of all pharmacologically acceptable acids in question, For example, halides, especially hydrochlorides, ascorbates, lactates, Sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates, p-toluenesulfonates.
In der US-Patentschrift 5 091 394 (HOE 89/F 288) und in der europäischen Offenlegungsschrift 0 556 674 (HOE 92/F 034) werden Benzoylguanidine, nicht jedoch Benzoldicarbonsäure-diguanidide beschrieben.U.S. Patent 5,091,394 (HOE 89 / F 288) and European Offenlegungsschrift 0 556 674 (HOE 92 / F 034) are Benzoylguanidine, not However, described bile dicarboxylic acid diguanidides.
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 Verbindungen 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.The compounds are due to their pharmacological properties as antiarrhythmic drugs with cardioprotective component Infarct prophylaxis and infarction treatment and for the treatment of angina Pectoris excellent, while they also preventively the pathophysiological processes are ischemic-induced on emergence Damage, especially in the induction of ischemic induced Cardiac arrhythmias, inhibit or greatly reduce. Because of their protective Effects against pathological hypoxic and ischemic situations can the compounds of the formula I according to the invention due to inhibition of cellular Na⁺ / H⁺ exchange mechanism as a drug to treat all acute or chronic ischemia-induced damage or primary or secondary induced diseases. this concerns their use as drugs for surgical procedures, eg. B. at Organ transplants, where the compounds for both the protection of the organs in the donor before and during the removal, for the protection of removed organs for example, during treatment with or storage in physiological Badflüssigkeiten, as well as in the transfer to the recipient organism can be used. The compounds are also valuable, protective acting drugs when performing angioplasty surgery for example at the heart as well as at peripheral vessels. According to her protective effects against ischemic induced damage are the Compounds also as medicaments for the treatment of ischemia of the Nervous system, in particular the CNS, suitable, wherein z. For treatment stroke or cerebral edema. In addition, are suitable the compounds of formula I according to the invention also for treatments 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, als. Deshalb kommen die Verbindungen der Formel I als wertvolle Therapeutika für Krankheiten infrage, 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. 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 Verbindungen der Formel I für die präventive Therapie zur Verhinderung der Genese des Bluthochdrucks, beispielweise der essentiellen Hypertonie, geeignet.In addition, the compounds of the formula I according to the invention are distinguished by strong inhibitory effect on the proliferation of cells, For example, fibroblast cell proliferation and proliferation of the smooth Vascular muscle cells, as. Therefore, the compounds of formula I come as valuable therapeutics for diseases in which cell proliferation is a primary or secondary cause, and therefore can be considered Antiatherosclerotics, remedies for diabetic late complications, Cancers, fibrotic diseases such as pulmonary fibrosis, liver fibrosis or kidney fibrosis, organ hypertrophy and hyperplasia, especially in Prostatic hyperplasia or prostatic hypertrophy. The compounds according to the invention are effective inhibitors of cellular sodium proton antiporter (Na⁺ / H⁺ exchanger) at numerous diseases (essential hypertension, atherosclerosis, diabetes etc.) is also increased in such cells, the measurements are easily accessible, such as in erythrocytes, platelets or leukocytes. The Compounds according to the invention are therefore suitable as outstanding 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 compounds of the formula I are for preventive therapy to prevent the genesis of hypertension, For example, the essential hypertension, suitable.
Gegenüber den meisten bekannten Verbindungen weisen die Verbindungen nach der Erfindung eine signifikant verbesserte Wasserlöslichkeit auf. Daher sind sie wesentlich besser für i.v.-Applikation geeignet.Compared with most known compounds, the compounds According to the invention, a significantly improved water solubility. Therefore they are much better suited for i.v. applications.
Die erfindungsgemäßen Verbindungen zeichnen sich gegenüber den bekannten gut wasserlöslichen Verbindungen durch ihre bessere Bioverfügbarkeit und Pharmakokinetik aus. The compounds according to the invention are distinguished from the known compounds good water-soluble compounds due to their better bioavailability and Pharmacokinetics off.
Außerdem zeigen sie ein überraschendes Wirkungsspektrum bezüglich der Subtypen des Na⁺/H⁺-Austauschs.In addition, they show a surprising spectrum of activity with respect to the Subtypes of Na⁺ / H⁺ exchange.
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 in der Veterinär- als auch in der Humanmedizin.Medicaments containing a compound I may be administered orally, parenterally, be administered intravenously, rectally or by inhalation, with the preferred Application is dependent on the particular appearance of the disease. The compounds I can be alone or together with galenic Excipients are used, both in the veterinary and in the 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 drug formulation, is familiar to the person skilled in the art on the basis of his specialist knowledge. In addition to solvents, Gelling agents, suppository bases, tablet excipients, and others Active substance carriers may, for example, be 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 application, the active compounds are those for suitable additives, such as carriers, stabilizers or inert Diluent mixed and by the usual methods in the suitable dosage forms such as tablets, dragees, Plug capsules, aqueous, alcoholic or oily solutions. As inert carrier can z. Gum arabic, magnesia, magnesium carbonate, potassium phosphate, Lactose, glucose or starch, in particular corn starch. The preparation may be both dry and wet granules respectively. As oily carriers or as solvents, for example 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 customary substances such as Solubilizers, emulsifiers or other excipients in solution, Brought suspension or emulsion. As a solvent come z. B. in question: Water, physiological saline or alcohols, e.g. For example, ethanol, propanol, Glycerin, as well as sugar solutions such as glucose or mannitol solutions, or a mixture of 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 der Formel I in einem pharmazeutisch unbedenklichen Lösungsmittel, 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 üblicherweise 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 for. As solutions, suspensions or emulsions of Active ingredient of the formula I in a pharmaceutically acceptable Solvent, such as in particular ethanol or water, or a mixture such solvents. The formulation may also have others as needed pharmaceutical excipients such as surfactants, emulsifiers and stabilizers as well contain a propellant gas. Such a preparation contains the active ingredient usually in a concentration of about 0.1 to 10, in particular of about 0.3 to 3 wt .-%.
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 the formula I to be administered and the Frequency of administration depend on the potency and duration of action of the used compounds; as well as the type and strength of the disease, 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/kg Körpergewicht, vorzugsweise mindestens 0,01 mg/kg Körpergewicht, bis höchstens 10 mg/kg Körpergewicht, vorzugsweise bis höchstens 1 mg/kg Körpergewicht. Bei akuten Ausbrüchen der Krankheit, etwa unmittelbar nach Erleiden eines 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 at at least 0.001 mg / kg body weight for a patient weighing approximately 75 kg, preferably at least 0.01 mg / kg body weight, up to a maximum of 10 mg / kg Body weight, preferably up to at most 1 mg / kg of body weight. In acute Outbreaks of the disease, such as immediately after suffering a heart attack, even higher and, above all, more frequent dosages may be necessary z. B. up to 4 single doses per day. Especially with i.v. Application, for example An infarct patient in the intensive care unit may take up to 100 mg per day become necessary.
Liste der Abkürzungen:List of abbreviations:
5 mmol des Benzoldicarbonsäure-dialkylesters der Formel II sowie 50 mmol Guanidin (freie Base) werben in 5 ml Isopropanol gelöst und bis zum vollständigen Umsatz (Dünnschichtkontrolle) unter Rückfluß gekocht (typische Reaktionszeit 2 bis 5 h). Anschließend wird mit 150 ml Wasser verdünnt und das Produkt abgesaugt. Gegebenenfalls wird an Kieselgel mit einem geeigneten Laufmittel, z. B. EE/MeOH 5 : 1 chromatographiert.5 mmol of the benzenedicarboxylic acid dialkyl ester of the formula II and 50 mmol Guanidine (free base) solubilized in 5 ml of isopropanol and dissolved until the complete conversion (thin layer control) refluxed (typical Reaction time 2 to 5 h). It is then diluted with 150 ml of water and the product is sucked off. Optionally, on silica gel with a suitable Eluent, z. B. EE / MeOH 5: 1 chromatographed.
2.9 g 5-t-Butyl-isophthalsäure-dimethylester werden nach der allgemeinen
Vorschrift zur Herstellung von Benzoldicarbonsäure-diguanididen (I) umgesetzt.
Man erhält 2.7 g weißer Kristalle, mp <270°C.
Rf (Aceton/Wasser 10 : 1) = 0.13 MS (ES) : 305 (M+H)⁺
2.9 g of dimethyl 5-t-butylisophthalate are reacted according to the general procedure for the preparation of benzenedicarboxylic acid diguanidides (I). This gives 2.7 g of white crystals, mp <270 ° C.
R f (acetone / water 10: 1) = 0.13 MS (ES): 305 (M + H) ⁺
1.0 g Isophthalsäure-dimethyester werden nach der allgemeinen Vorschrift zur
Herstellung von Benzoldicarbonsäure-diguanididen (1) umgesetzt. Man erhält 1.1
g weißer Kristalle, mp 251°C.
MS (ES) : 249 (M+H)⁺1.0 g isophthalic dimethyester be implemented according to the general procedure for the preparation of benzenedicarboxylic acid diguanidides (1). This gives 1.1 g of white crystals, mp 251 ° C.
MS (ES): 249 (M + H) ⁺
1.0 g Isophthalsäure-dimethyester werden nach der allgemeinen Vorschrift zur Herstellung von Benzoldicarbonsäure-diguanididen (1) umgesetzt. Man erhält 1.0 g weißer Kristalle, mp <270°C MS (ES) : 249 (M+H)⁺.1.0 g isophthalic dimethyester are according to the general rule for Preparation of benzenedicarboxylic acid diguanidides (1) implemented. You get 1.0 g of white crystals, mp <270 ° C MS (ES): 249 (M + H) ⁺.
Claims (18)
einer der Reste R(1), R(2), R(3), R(4) und R(5)-CO-N=C(NH₂)₂;und die jeweils anderen Reste R(1), R(2), R(3), R(4) und R(5)
R(1) und R(5) unabhängig voneinander Wasserstoff, Alkyl mit 1, 2, 3 oder 4 C-Atomen, F, Cl, -OR(32), -NR(33)R(34) oder -CF₃;
R(32), R(33) und R(34) unabhängig voneinander Wasserstoff oder Alkyl mit 1, 2, 3 oder 4 C-Atomen;
R(2) und R(4) unabhängig voneinander Wasserstoff, F, Cl, Br, I, OH, -CN, CF₃, -CO-N=C(NH₂)₂, Alkyl mit 1, 2, 3, 4, 5, 6, 7 oder 8 C-Atomen, Alkenyl mit 2, 3, 4, 5, 6, 7 oder 8 C-Atomen oder -(CH₂)mR(14);
m Null, 1 oder 2;
R(14) -(C₃-C₈)-Cycloalkyl oder Phenyl, welches nicht substituiert oder substituiert ist mit 1-3 Substituenten ausgewählt aus der Gruppe bestehend aus F und Cl, -CF₃, Methyl, Methoxy und -NR(15)R(16);
R(15) und R(16) Wasserstoff oder -CH₃; oder
R(2) und R(4) unabhängig voneinander Pyrrol-1-yl, Pyrrol-2-yl oder Pyrrol-3-yl, welches nicht substituiert oder substituiert ist mit 1-4 Substituenten ausgewählt aus der Gruppe bestehend aus F, Cl, Br, I, -CN, (C₂-C₈)-Alkanoyl, (C₂-C₈)-Alkoxycarbonyl, Formyl, Carboxy, -CF₃, Methyl und Methoxy; oder
R(2) und R(4) R(22)-SO₂-, R(23)R(24)N-CO-, R(28)-CO- oder R(29)R(30)N-SO₂;
R(22) und R(28) unabhängig voneinander Methyl oder -CF₃;
R(23), R(24), R(29) und R(30) unabhängig voneinander Wasserstoff oder Methyl; oder
R(2) und R(4) unabhängig voneinander -OR(35) oder -NR(35)R(36);
R(35) und R(36) unabhängig voneinander Wasserstoff oder Alkyl mit 1, 2, 3, 4, 5 oder 6 C-Atomen; oder
R(35) und R(36) gemeinsam 4, 5, 6 oder 7 Methylengruppen, von denen eine CH₂- Gruppe durch Sauerstoff, -S-, -N H-, -NCH₃ oder -N-Benzyl ersetzt sein kann;
R(3) Wasserstoff, -SR(25), -OR(25), -NR(25)R(26) oder -CR(25)R(26)R(27); R(25) Wasserstoff, Alkyl mit 1, 2, 3, 4, 5, 6, 7 oder 8 C-Atomen oder Phenyl, das unsubstituiert oder substituiert ist mit 1-3 Substituenten ausgewählt aus der Gruppe bestehend aus F, Cl, -CF₃, CH₃, Methoxy, Hydroxy, Amino, Methylamino und Dimethylamino; oder
R(25) -(C₁-C₉)-Heteroaryl, das unsubstituiert oder substituiert ist mit 1-3 Substituenten ausgewählt aus der Gruppe bestehend aus F, Cl, -CF₃, CH₃, Methoxy, Hydroxy, Amino, Methylamino und Dimethylamino;
R(26) und R(27) unabhängig voneinander wie R(25) definiert oder Wasserstoff oder Alkyl mit 1, 2, 3, 4, 5, 6, 7 oder 8 C-Atomen;
sowie deren pharmazeutisch verträgliche Salze.1. Benzoldicarboxylic acid diguanidides of the formula I in which mean:
one of the radicals R (1), R (2), R (3), R (4) and R (5) -CO-N = C (NH₂) ₂, and the respectively other radicals R (1), R ( 2), R (3), R (4) and R (5)
R (1) and R (5) independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 C atoms, F, Cl, -OR (32), -NR (33) R (34) or -CF₃;
R (32), R (33) and R (34) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 C atoms;
R (2) and R (4) independently of one another are hydrogen, F, Cl, Br, I, OH, -CN, CF₃, -CO-N =C (NH₂) ₂, alkyl having 1, 2, 3, 4, 5 , 6, 7 or 8 C atoms, alkenyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms or - (CH₂) m R (14);
m is zero, 1 or 2;
R (14) - (C₃-C₈) -cycloalkyl or phenyl which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F and Cl, -CF₃, methyl, methoxy and -NR (15) R ( 16);
R (15) and R (16) are hydrogen or -CH₃; or
R (2) and R (4) independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl which is unsubstituted or substituted by 1-4 substituents selected from the group consisting of F, Cl, Br, I, -CN, (C₂-C₈) alkanoyl, (C₂-C₈) alkoxycarbonyl, formyl, carboxy, -CF₃, methyl and methoxy; or
R (2) and R (4) R (22) -SO₂-, R (23) R (24) N-CO-, R (28) -CO- or R (29) R (30) N-SO₂;
R (22) and R (28) independently of one another are methyl or -CF₃;
R (23), R (24), R (29) and R (30) are independently hydrogen or methyl; or
R (2) and R (4) are independently -OR (35) or -NR (35) R (36);
R (35) and R (36) independently of one another are hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 C atoms; or
R (35) and R (36) together 4, 5, 6 or 7 methylene groups, of which a CH₂ group may be replaced by oxygen, -S-, -N H-, -NCH₃ or -N-benzyl;
R (3) is hydrogen, -SR (25), -OR (25), -NR (25) R (26) or -CR (25) R (26) R (27); R (25) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, - CF₃, CH₃, methoxy, hydroxy, amino, methylamino and dimethylamino; or
R (25) - (C₁-C₉) -heteroaryl which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, -CF₃, CH₃, methoxy, hydroxy, amino, methylamino and dimethylamino;
R (26) and R (27) independently of one another are defined as R (25) or hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms;
and their pharmaceutically acceptable salts.
einer der Reste R(1), R(2), R(3), R(4) und R(5) -CO-N=C(NH₂)₂;und die jeweils anderen Reste R(1), R(2), R(3), R(4) und R(5)
R(1) und R(5) unabhängig voneinander Wasserstoff, Alkyl mit 1, 2 oder 3 C-Atomen, F, Cl, -OR(32), -NR(33)R(34) oder -CF₃;
R(32), R(33) und R(34) unabhängig voneinander Wasserstoff oder Methyl;
R(2) und R(4) unabhängig voneinander Wasserstoff, F, Cl, Br, I, OH, -CF₃, -CO-N=C(NH₂)₂, Alkyl mit 1, 2, 3 oder 4 C-Atomen, Alkenyl mit 2, 3 oder 4 C-Atomen oder -(CH₂)mR(14);
m Null, 1 oder 2;
R(14) -(C₃-C₆)-Cycloalkyl oder Phenyl, welches nicht substituiert oder substituiert ist mit 1-2 Substituenten ausgewählt aus der Gruppe bestehend aus F und Cl, -CF₃, Methyl und Methoxy; oder
R(2) und R(4) unabhängig voneinander Pyrrol-1-yl, Pyrrol-2-yl oder Pyrrol-3-yl, welches nicht substituiert oder substituiert ist mit 1-2 Substituenten ausgewählt aus der Gruppe bestehend aus F, Cl, Br, I, -CN, (C₂-C₅)-Alkanoyl, (C₂-C₅)-Alkoxycarbonyl, Formyl, Carboxy, -CF₃ und Methyl; oder
R(2) und R(4) unabhängig voneinander R(22)-SO₂-, R(28)-CO- oder R(29)R(30)N-SO₂;
R(22) und R(28) unabhängig voneinander Methyl oder -CF₃;
R(29) und R(30) unabhängig voneinander Wasserstoff oder Methyl; oder
R(2) und R(4) unabhängig voneinander -OR(35) oder -NR(35)R(36);
R(35) und R(36) unabhängig voneinander Wasserstoff, Methyl oder Ethyl; oder
R(35) und R(36) gemeinsam 4-5 Methylengruppen, von denen eine CH₂-Gruppe durch Sauerstoff, -S-, -NH- oder -NCH₃ ersetzt sein kann;
R(3) Wasserstoff, -SR(25), -OR(25), -NR(25)R(26) oder -CR(25)R(26)R(27); R(25) Wasserstoff, Alkyl mit 1, 2, 3 oder 4 C-Atomen oder Phenyl, das unsubstituiert oder substituiert ist mit 1-2 Substituenten ausgewählt aus der Gruppe bestehend aus F, Cl, -CF₃, CH₃, Methoxy und Dimethylamino; oder
R(25) -(C₁-C₉)-Heteroaryl, das unsubstituiert oder substituiert ist mit 1-2 Substituenten ausgewählt aus der Gruppe bestehend aus F, Cl, -CF₃, CH₃, Methoxy und Dimethylamino;
R(26) und R(27) unabhängig voneinander Wasserstoff oder Alkyl mit 1, 2, 3 oder 4 C-Atomen.2. A compound of the formula I according to claim 1, in which
one of the radicals R (1), R (2), R (3), R (4) and R (5) -CO-N = C (NH₂) ₂, and the respectively other radicals R (1), R ( 2), R (3), R (4) and R (5)
R (1) and R (5) independently of one another are hydrogen, alkyl having 1, 2 or 3 C atoms, F, Cl, -OR (32), -NR (33) R (34) or -CF₃;
R (32), R (33) and R (34) are independently hydrogen or methyl;
R (2) and R (4) independently of one another are hydrogen, F, Cl, Br, I, OH, -CF₃, -CO-N =C (NH₂) ₂, alkyl having 1, 2, 3 or 4 C atoms, Alkenyl having 2, 3 or 4 carbon atoms or - (CH₂) m R (14);
m is zero, 1 or 2;
R (14) - (C₃-C₆) -cycloalkyl or phenyl which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F and Cl, -CF₃, methyl and methoxy; or
R (2) and R (4) independently of one another pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl, which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F, Cl, Br, I, -CN, (C₂-C₅) alkanoyl, (C₂-C₅) alkoxycarbonyl, formyl, carboxy, -CF₃ and methyl; or
R (2) and R (4) are independently R (22) -SO₂-, R (28) -CO- or R (29) R (30) N-SO₂;
R (22) and R (28) independently of one another are methyl or -CF₃;
R (29) and R (30) are independently hydrogen or methyl; or
R (2) and R (4) are independently -OR (35) or -NR (35) R (36);
R (35) and R (36) are independently hydrogen, methyl or ethyl; or
R (35) and R (36) together 4-5 methylene groups, of which one CH₂ group may be replaced by oxygen, -S-, -NH- or -NCH₃;
R (3) is hydrogen, -SR (25), -OR (25), -NR (25) R (26) or -CR (25) R (26) R (27); R (25) is hydrogen, alkyl having 1, 2, 3 or 4 C atoms or phenyl which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F, Cl, -CF₃, CH₃, methoxy and dimethylamino; or
R (25) - (C₁-C₉) -heteroaryl which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F, Cl, -CF₃, CH₃, methoxy and dimethylamino;
R (26) and R (27) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 C atoms.
einer der Reste R(1), R(2), R(3), R(4) und R(5) -CO-N=C(NH₂)₂;und die jeweils anderen Reste R(1), R(2), R(3), R(4) und R(5)
R(1) und R(5) unabhängig voneinander Wasserstoff, Alkyl mit 1, 2 oder 3 C-Atomen, F, Cl, -OR(32), -NR(33)R(34) oder -CF₃;
R(32), R(33) und R(34) unabhängig voneinander Wasserstoff oder Methyl;
R(2) und R(4) unabhängig voneinander Wasserstoff, F, Cl, OH, -CF₃, -CO-N=C(NH₂)₂, Alkyl mit 1, 2, 3 oder 4 C-Atomen oder Pyrrol-1-yl, welches nicht substituiert oder substituiert ist mit 1-2 Substituenten ausgewählt aus der Gruppe bestehend aus F, Cl, Br, I, -CN, (C₂-C₅)-Alkanoyl, (C₂-C₅)-Alkoxycarbonyl, Formyl, Carboxy, -CF₃ und Methyl; oder
R(2) und R(4) unabhängig voneinander R(22)-SO₂-;
R(22) unabhängig voneinander Methyl oder -CF₃; oder
R(2) und R(4) unabhängig voneinander -OR(35) oder -NR(35)R(36);
R(35) und R(36) unabhängig voneinander Wasserstoff, Methyl oder Ethyl;
R(3) Wasserstoff, -SR(25), -OR(25), -NR(25)R(26) oder -CR(25)R(26)R(27);
R(25) Wasserstoff-Alkyl mit 1, 2 oder 3 C-Atomen oder Phenyl, das unsubstituiert oder substituiert ist mit einem Substituenten aus der Gruppe F, Cl, CF₃ oder -CH₃; oder
R(25) -(C₁-C₉)-Heteroaryl, das unsubstituiert oder substituiert ist mit einem Substituenten ausgewählt aus der Gruppe bestehend aus F, Cl, CF₃ und CH₃;
R(26) und R(27) unabhängig voneinander Wasserstoff oder Methyl.3. A compound of the formula I according to claims 1 or 2, in which
one of the radicals R (1), R (2), R (3), R (4) and R (5) -CO-N = C (NH₂) ₂, and the respectively other radicals R (1), R ( 2), R (3), R (4) and R (5)
R (1) and R (5) independently of one another are hydrogen, alkyl having 1, 2 or 3 C atoms, F, Cl, -OR (32), -NR (33) R (34) or -CF₃;
R (32), R (33) and R (34) are independently hydrogen or methyl;
R (2) and R (4) independently of one another are hydrogen, F, Cl, OH, -CF₃, -CO-N =C (NH₂) ₂, alkyl having 1, 2, 3 or 4 C atoms or pyrrole-1 yl which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F, Cl, Br, I, -CN, (C₂-C₅) alkanoyl, (C₂-C₅) alkoxycarbonyl, formyl, carboxy, -CF₃ and methyl; or
R (2) and R (4) independently of one another R (22) -SO₂-;
R (22) independently of one another methyl or -CF₃; or
R (2) and R (4) are independently -OR (35) or -NR (35) R (36);
R (35) and R (36) are independently hydrogen, methyl or ethyl;
R (3) is hydrogen, -SR (25), -OR (25), -NR (25) R (26) or -CR (25) R (26) R (27);
R (25) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or phenyl which is unsubstituted or substituted by a substituent from the group F, Cl, CF₃ or -CH₃; or
R (25) - (C₁-C₉) heteroaryl which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, CF₃ and CH₃;
R (26) and R (27) independently of one another are hydrogen or methyl.
R(1) und R(5) unabhängig voneinander Wasserstoff, Alkyl mit 1, 2 oder 3 C-Atomen, F, Cl oder -CF₃;
R(2) und R(4) Wasserstoff, OH, -CF₃, -CO-N=C(NH₂)₂, Alkyl mit 1, 2, 3 oder 4 C-Atomen oder Pyrrol-1-yl, welches nicht substituiert oder substituiert ist mit 1-2 Substituenten ausgewählt aus der Gruppe bestehend aus F, Cl, Br, I, -CN, (C₂-C₅)-Alkanoyl, (C₂-C₅)-Alkoxycarbonyl, Formyl, Carboxy, -CF₃ und Methyl;
R(3) Wasserstoff, -OR(25) oder -CR(25)R(26)R(27);
R(25) Wasserstoff, Alkyl mit 1, 2 oder 3 C-Atomen oder Phenyl, das unsubstituiert oder substituiert ist mit einem Substituenten ausgewählt aus der Gruppe bestehend aus F, Cl, -CF₃ und CH₃; oder
R(25) -(C₁-C₉)-Heteroaryl, das unsubstituiert oder substituiert ist mit einem Substituenten ausgewählt aus der Gruppe bestehend aus F, Cl, CF₃ und CH₃;
R(26) und R(27) unabhängig voneinander Wasserstoff oder Methyl.4. A compound of formula I according to claims 1 to 3, in which: one of the radicals R (1), R (2), R (3), R (4) and R (5) -CO-N = C ( NH₂) ₂ and the respective other radicals R (1), R (2), R (3), R (4) and R (5)
R (1) and R (5) independently of one another are hydrogen, alkyl having 1, 2 or 3 C atoms, F, Cl or -CF₃;
R (2) and R (4) are hydrogen, OH, -CF₃, -CO-N = C (NH₂) ₂, alkyl having 1, 2, 3 or 4 C-atoms or pyrrol-1-yl, which is unsubstituted or is substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, I, -CN, (C₂-C₅) alkanoyl, (C₂-C₅) alkoxycarbonyl, formyl, carboxy, -CF₃ and methyl;
R (3) is hydrogen, -OR (25) or -CR (25) R (26) R (27);
R (25) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or phenyl which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, -CF₃ and CH₃; or
R (25) - (C₁-C₉) heteroaryl which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, CF₃ and CH₃;
R (26) and R (27) independently of one another are hydrogen or methyl.
mit Guanidin umsetzt. 5. A process for preparing a compound I according to claim 1, characterized in that a compound of formula II in which R (1 ') to R (5') have the meanings given in claim 1 for R (1) to R (5), of which at least one of the substituents R (1 ') to R (5') has the meanings given in Formula II is drawn COL group, and wherein L stands for easily nucleophilically substitutable leaving groups,
with guanidine.
Priority Applications (40)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19543194A DE19543194A1 (en) | 1995-11-20 | 1995-11-20 | New benzene-di:carboxylic acid di:guanidide derivs. |
| PL96316439A PL316439A1 (en) | 1995-11-20 | 1996-10-08 | Novel substituted derivatives of benzoyloguanidine, method of obtaining them, their application in production of pharmaceutic and diagnostic agents and pharmaceutic agent as such |
| PL96316438A PL316438A1 (en) | 1995-11-20 | 1996-10-08 | Novel substituted derivatives of benzoyloguanidine, method of obtaining them, their application in production of pharmaceutic and diagnostic agents and pharmaceutic agent as such |
| EP96117821A EP0774457A1 (en) | 1995-11-20 | 1996-11-07 | Substituted benzodicarboxylic acid diguanidines, process for their preparation, and their use as medicament or diagnostic agent |
| US08/747,004 US5731350A (en) | 1995-11-20 | 1996-11-07 | Substituted benzenedicarboxylic acid diguanides, process for their preparation, their use as a medicament or diagnostic, and medicament containing them |
| EP96117822A EP0774458A1 (en) | 1995-11-20 | 1996-11-07 | Substituted benzodicarboxylic acid diguanidines, process for their preparation, and their use as medicament or diagnostic agent |
| IL11963696A IL119636A0 (en) | 1995-11-20 | 1996-11-18 | Substituted benzenedicarboxylic acid diguanides process for their preparation their use as a medicament or diagnostic and medicaments containing them |
| SK1487-96A SK148796A3 (en) | 1995-11-20 | 1996-11-18 | Diguanides of subsituted benzenedicarboxylic acids, preparation method thereof, their use as a drug or diagnostic agent, as well as a drug containing them |
| NZ299772A NZ299772A (en) | 1995-11-20 | 1996-11-18 | Substituted benzene di-carboxylic acid di-guanides; medicaments |
| AU71804/96A AU703352B2 (en) | 1995-11-20 | 1996-11-18 | Substituted benzenedicarboxylic acid diguanides, process for their preparation, their use as a medicament or diagnostic, and medicament containing them |
| CZ963383A CZ338396A3 (en) | 1995-11-20 | 1996-11-18 | Diguanidines of substituted benzenedicarboxylic acids, process of their preparation, their use as a medicament or a diagnostic compound, as well as a medicament in which they are comprised |
| TR96/00916A TR199600916A2 (en) | 1995-11-20 | 1996-11-18 | Substituted benzol dicarbonic acid diguanidides, the method for their production, their use as a drug or diagnostics and the drug containing them. |
| TR96/00917A TR199600917A2 (en) | 1995-11-20 | 1996-11-18 | Substituted benzol dicarbonic acids, the method, drug or diagnostics for their manufacture and the medicament containing them |
| TW085114094A TW349945B (en) | 1995-11-20 | 1996-11-18 | Substituted benzenedicarboxylic acid diguanides, process for their preparation, their use as a medicament or diagnostic |
| TW085114093A TW353657B (en) | 1995-11-20 | 1996-11-18 | Substituted benzenedicarboxylic acid diguanides, process for their preparation, their use as a medicament or diagnostic, and medicament containing them |
| ARP960105231A AR004332A1 (en) | 1995-11-20 | 1996-11-18 | DIGUANIDINES OF SUBSTITUTED BENZENODICARBOXILIC ACIDS, PROCEDURE FOR THEIR PREPARATION, USE AS A MEDICINAL PRODUCT OR DIAGNOSTIC AGENT ASICOMO CONTAINING MEDICATION |
| ARP960105230A AR004331A1 (en) | 1995-11-20 | 1996-11-18 | DIGUANIDINES OF SUBSTITUTED BENZENODICARBOXILIC ACIDS, PROCEDURE FOR THEIR PREPARATION, USE AS A MEDICINAL PRODUCT OR DIAGNOSTIC AGENT ASICOMO CONTAINING MEDICINAL PRODUCT. |
| SK1488-96A SK148896A3 (en) | 1995-11-20 | 1996-11-18 | Diguanides of subsituted benzenedicarboxylic acids, preparation method thereof, their use as a drug or diagnostic agent, as well as a drug containing them |
| CZ963382A CZ338296A3 (en) | 1995-11-20 | 1996-11-18 | Diguanidines of substituted benzenedicarboxylic acids, process of their preparation, their use as a medicament or a diagnostic compound, as well as a medicament in which they are comprised |
| AU71803/96A AU7180396A (en) | 1995-11-20 | 1996-11-18 | Substituted benzenedicarboxylic acid diguanides, process for their preparation, their use as a medicament or diagnostic, and medicament containing them |
| IL11963796A IL119637A0 (en) | 1995-11-20 | 1996-11-18 | Substituted benzenedicarboxylic acid diguanides process for their preparation their use as a medicament or diagnostic and medicaments containing them |
| ZA969673A ZA969673B (en) | 1995-11-20 | 1996-11-19 | Substituted benzenedicarboxylic acid diguanides process for their preparation their use as a medicament or diagnostic and medicament containing them |
| HR19626327.1A HRP960548A2 (en) | 1995-11-20 | 1996-11-19 | Substituted benzodicarboxylic acid diguanidines, process for their preparation, and their use as medicament or diagnostic agent |
| HU9603195A HUP9603195A3 (en) | 1995-11-20 | 1996-11-19 | Substituted benzene dicarboxylic acid diguanidides, process for producing them, their use for preparing pharmaceutical compositions and diagnostics and pharmaceutical compositions containing them |
| CA002190692A CA2190692A1 (en) | 1995-11-20 | 1996-11-19 | Substituted benzenedicarboxylic acid diguanides, process for their preparation, their use as a medicament or diagnostic, and medicament containing them |
| BR9605617A BR9605617A (en) | 1995-11-20 | 1996-11-19 | Diguannidides of benzenodicarboxylic acid substituted process for its preparation its application as a medicine or diagnostic agent as well as medicine that contains them |
| NO964903A NO964903D0 (en) | 1995-11-20 | 1996-11-19 | Substituted benzenedicarboxylic acid diguanidide, process for their preparation, their use as a drug or diagnostic as well as drug containing them |
| NO964904A NO964904L (en) | 1995-11-20 | 1996-11-19 | Substituted benzenedicarboxylic acid diguanidides, processes for their preparation, their use as a drug or diagnostic, as well as drugs containing them |
| BR9605613A BR9605613A (en) | 1995-11-20 | 1996-11-19 | Diguanides of benzenodicarboxylic acid replaced processes for its preparation as a medicine or diagnosis as well as the medicine containing the same |
| JP8307831A JPH09169719A (en) | 1995-11-20 | 1996-11-19 | Substituted benzenedicarboxylic acid diguanide, its production, its use as medicine or diagnostic agent, and medicine containing it |
| HU9603201A HUP9603201A3 (en) | 1995-11-20 | 1996-11-19 | Substituted benzene dicarboxylic acid diguanidides, process for producing them, their use for preparing pharmaceutical compositions and diagnostics and pharmaceutical compositions containing the said compounds |
| MX9605675A MX9605675A (en) | 1995-11-20 | 1996-11-19 | Substituted benzenedicarboxylic acids diguanidines, process for their preparation, their use as medicament or diagnosis agent as well as medicament containing them. |
| JP8307830A JPH09169718A (en) | 1995-11-20 | 1996-11-19 | Substituted benzenedicarboxylic acid diguanide, its production, its use as medicine or diagnostic agent, and medicine containing it |
| NO964905A NO964905L (en) | 1995-11-20 | 1996-11-19 | Substituted benzenedicarboxylic acid diguanidides, process for their preparation, their use as drug or diagnostic, and drug containing the compound |
| ZA969674A ZA969674B (en) | 1995-11-20 | 1996-11-19 | Substituted benzenedicarboxylic acid diguanides process for their preparation their use as a medicament or diagnostic and medicament containing them |
| KR1019960055375A KR980002018A (en) | 1995-11-20 | 1996-11-19 | Substituted benzenedicarboxylic acid diguanides, methods for their preparation, their use as medicaments or diagnostic agents and medicaments containing them |
| MX9605674A MX9605674A (en) | 1995-11-20 | 1996-11-19 | Substituted benzenedicarboxylic acids diguanidides, process for their preparation, their use as medicament or diagnosis agent, as well as medicament containing them. |
| CA002190693A CA2190693A1 (en) | 1995-11-20 | 1996-11-19 | Substituted benzenedicarboxylic acid diguanides, process for their preparation, their use as a medicament or diagnostic, and medicament containing them |
| HR19624064.6A HRP960547A2 (en) | 1995-11-20 | 1996-11-19 | Substituted benzodicarboxylic acid diguanidines, process for their preparation, and their use as medicament or diagnostic agent, and medicaments containing them |
| KR1019960055717A KR980009237A (en) | 1995-11-20 | 1996-11-20 | Substituted benzenedicarboxylic acid diguanides, methods for their preparation, their use as medicaments or diagnostic agents and medicaments containing them |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19543194A DE19543194A1 (en) | 1995-11-20 | 1995-11-20 | New benzene-di:carboxylic acid di:guanidide derivs. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE19543194A1 true DE19543194A1 (en) | 1997-05-22 |
Family
ID=7777900
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19543194A Withdrawn DE19543194A1 (en) | 1995-11-20 | 1995-11-20 | New benzene-di:carboxylic acid di:guanidide derivs. |
Country Status (2)
| Country | Link |
|---|---|
| DE (1) | DE19543194A1 (en) |
| ZA (2) | ZA969674B (en) |
-
1995
- 1995-11-20 DE DE19543194A patent/DE19543194A1/en not_active Withdrawn
-
1996
- 1996-11-19 ZA ZA969674A patent/ZA969674B/en unknown
- 1996-11-19 ZA ZA969673A patent/ZA969673B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ZA969673B (en) | 1997-05-20 |
| ZA969674B (en) | 1997-05-20 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 8130 | Withdrawal |