AU703352B2 - Substituted benzenedicarboxylic acid diguanides, process for their preparation, their use as a medicament or diagnostic, and medicament containing them - Google Patents
Substituted benzenedicarboxylic acid diguanides, process for their preparation, their use as a medicament or diagnostic, and medicament containing them Download PDFInfo
- Publication number
- AU703352B2 AU703352B2 AU71804/96A AU7180496A AU703352B2 AU 703352 B2 AU703352 B2 AU 703352B2 AU 71804/96 A AU71804/96 A AU 71804/96A AU 7180496 A AU7180496 A AU 7180496A AU 703352 B2 AU703352 B2 AU 703352B2
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- treatment
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- methyl
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- 238000000034 method Methods 0.000 title claims description 19
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- LWXXXTJCPXKWJU-UHFFFAOYSA-N acetic acid;ethanol;heptane Chemical compound CCO.CC(O)=O.CCCCCCC LWXXXTJCPXKWJU-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 208000006752 brain edema Diseases 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000001269 cardiogenic effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000000451 chemical ionisation Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- OUAQANKYMKOXGY-UHFFFAOYSA-N dimethyl 4-chloro-5-phenylbenzene-1,3-dicarboxylate Chemical compound COC(=O)C1=CC(C(=O)OC)=C(Cl)C(C=2C=CC=CC=2)=C1 OUAQANKYMKOXGY-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229960000789 guanidine hydrochloride Drugs 0.000 description 1
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 1
- 238000005534 hematocrit Methods 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 230000002727 hyperosmolar Effects 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 150000007928 imidazolide derivatives Chemical class 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- 235000012245 magnesium oxide Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000002971 oxazolyl group Chemical group 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
- 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
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 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
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 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
- 230000002829 reductive effect Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 235000000891 standard diet Nutrition 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
- 239000005720 sucrose Substances 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
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 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
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002827 triflate group Chemical class FC(S(=O)(=O)O*)(F)F 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Emergency Medicine (AREA)
- Vascular Medicine (AREA)
- Obesity (AREA)
- Reproductive Health (AREA)
- Gastroenterology & Hepatology (AREA)
- Pulmonology (AREA)
- Epidemiology (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Hoechst Aktiengesellschaft HOE 95/F 269 K Dr. v. F.
Description Substituted benzenedicarboxylic acid diguanides, process for their preparation, their use as a medicament or diagnostic, and medicament containing them The invention relates to benzenedicarboxylic acid diguanides of the formula I R2 R3 R1 R4 N
NH
2 R5 O NH 2 in which: one of the radicals R(3) and R(4) is
-CO-N=C(NH
2 2 and the other radicals R(3) and R(4) in each case are: S 20 R(1) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, CI, Br, I, -OR(32), -NR(33)R(34) or CF 3 R(32), R(33) and R(34) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; R(2) and R(4) independently of one another are hydrogen, F, CI, Br, I, OH, -CN,
CF
3
-CO-N=C(NH
2 2 alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms or -(CH2)mR(14); m is zero, 1 or 2; R(14) is -(C 3
-C
8 )-cycloalkyl or phenyl, which is unsubstituted or substituted by 1 3 substituents selected from the group consisting of F and Cl, -CF 3 methyl, methoxy and -NR(15)R(16); and R(16) are hydrogen or -CH 3 or R(2) and R(4) independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3yl, each of which is unsubstituted or substituted by 1 4 substituents selected from the group consisting of F, CI, Br, I, -CN, (C2-C8)alkanoyl, (C 2
-C
8 )-alkoxycarbonyl, formyl, carboxyl, -CF 3 methyl, methoxy; or R(2) and R(4) independently of one another are R(22)-SO 2 R(23)R(24)N-CO-, R(28)-CO or R(29)R(30)N-SO 2 R(22) and R(28) independently of one another are methyl or -CF 3 R(23), R(24), R(29) and independently of one another are hydrogen or methyl; or R(2) and R(4) independently of one another are -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 carbon atoms; or R(35) and R(36) together are 4 7 methylene groups, of which a CH 2 group can be replaced by oxygen, -NCH 3 or -N-benzyl; R(3) is hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27); R(25) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
S
or phenyl, which is unsubstituted or substituted by 1 3 substituents selected from the group consisting of F, CI, CF 3 CH3, methoxy, hydroxyl, amino, methylamino and dimethylamino; or is -(Cl-C 9 )-heteroaryl, which is unsubstituted or substituted by 1 3 substituents selected from the group consisting of F, CI, CF 3
CH
3 methoxy, hydroxyl, amino, methylamino and dimethylamino; R(26) and R(27) independently of one another are defined as R(25) or are hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; is alkyl having 1, 2, 3 or 4 carbon atoms, F, CI, Br, I, X-(CH 2 )y -CF 3 or phenyl, which is unsubstituted or substituted by 1 3 substituents selected from the group consisting of F and CI, -CF 3 methyl, methoxy and -NR(6)R(7); R(6) and R(7) independently of one another are hydrogen or -CH 3 X is a bond or oxygen; y is zero, 1 or 2; and their pharmaceutically tolerable salts.
Preferred compounds of the formula I are those in which: one of the radicals R(3) and R(4) is
-CO-N=C(NH
2 2 and the other radicals R(3) and R(4) in each case are: R(1) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, CI, Br, -OR(32), -NR(33)R(34) or CF 3 0" R(32), R(33) and R(34) independently of one another are hydrogen or methyl; R(2) and R(4) independently of one another are hydrogen, F, CI, Br, I, OH, CF 3
-CO-N=(C(NH
2 2 alkyl having 1, 2, 3 or 4 carbon atoms, alkenyl having 2, 3 or 4 carbon atoms or -(CH 2 )mR(14); m is zero, 1 or 2; R(14) is -(C3-C 6 )-cycloalkyl or phenyl, which is unsubstituted or substituted by 1 2 substituents selected from the group consisting of F and CI, -CF 3 methyl and methoxy; or R(2) and R(4) independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3yl, which is unsubstituted or substituted by 1 2 substituents selected from the group consisting of F, CI, Br, I, -CN, alkanoyl, (C2-C 5 )-alkoxycarbonyl, formyl, carboxy, -CF 3 and methyl; or R(2) and R(4) independently of one another are R(22)-S0 2 R(28)-CO)- or R(29)R(30)N-S0 2 R(22) and R(28) independently of one another are methyl or -CF 3 R(29) and independently of one another are hydrogen or methyl; or R(2) and R(4) independently of one another are -OR(35) or -NR(35)R(36); R(35) and R(36) independently of one another are hydrogen, methyl or ethyl; or and R(36) together are 4 5 methylene groups, of which a CH 2 group can be replaced by oxygen, -NH- or -NCH 3 R(3) is hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27); R(25) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl, which is unsubstituted or substituted by 1 2 substituents selected from the group consisting of F, CI, CF 3 CH3, methoxy and dimethylamino; or R(25) -is -(C 1
-C
9 )-heteroaryl, which is unsubstituted or substituted by 1 2 substituents selected from the group consisting of F, CI, CF 3
CH
3 methoxy and dimethylamino; R(26) and R(27) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; is alkyl having 1, 2, 3 or 4 carbon atoms, F, CI, Br, CF 3 or phenyl, which is unsubstituted or substituted by 1 2 substituents selected from the group consisting of F and CI, -CF 3 methyl, methoxy and dimethylamino; and their pharmaceutically tolerable salts.
Particularly preferred compounds of the formula I are those in which: O one of the radicals R(3) and R(4) is -CO-N=C(NH2)2; and the other radicals R(3) and R(4) in each case are: R(1) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, CI, -OR(32), -NR(33)R(34) or CF 3 R(32), R(33) and R(34) independently of one another are hydrogen or methyl; R(2) and R(4) independently of one another are hydrogen, F, Cl, OH, CF 3 6
-CO-N=C(NH
2 2 alkyl having 1, 2, 3 or 4 carbon atoms or pyrrol-1yl, which is unsubstituted or substituted by 1 2 substituents selected from the group consisting of F, CI, Br, I, -CN, (C 2 (C2-C 5 )-alkoxycarbonyl, formyl, carboxyl, -CF 3 and methyl; or R(2) and R(4) independently of one another are R(22)-S0 2 R(22) is methyl or -CF3; or R(2) and R(4) independently of one another are -OR(35) or -NR(35)R(36); and R(36) independently of one another are hydrogen, methyl or ethyl; R(3) is hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27); 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, CI, CF 3 and CH 3 or R(25) is -(C 1 -Cg)heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, CF 3 and CH 3 R(26) and R(27) independently of one another are hydrogen or methyl; 25 R(5) is alkyl having 1, 2, 3 or 4 carbon atoms, F, CI, CF 3 or phenyl, which is unsubstituted or substituted by 1 2 substituents selected from the group consisting of F and CI, -CF 3 methyl and methoxy; and their pharmaceutically tolerable salts.
Very particularly preferred compounds of the formula I are those in which:
N
7 one of the radicals R(3) and R(4) is
-CO-N=C(NH
2 2 and the other radicals R(3) and R(4) in each case are: R(1) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, CI, CF 3 or methoxy; R(2) and R(4) independently of one another are hydrogen, OH, CF 3 -CO-N
C(NH
2 2 alkyl having 1, 2, 3 or 4 carbon atoms or pyrrol-1-yl, which is unsubstituted or substituted by 1 2 substituents selected from the group consisting of F, CI, Br, I, -CN, (C 2 (C2-C5)- alkoxycarbonyl, formyl, carboxyl, -CF 3 and methyl; R(3) is hydrogen, -OR(25) or -CR(25)R(26)R(27); 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, CI, CF 3 and
CH
3 or is -(Cl-C 9 )-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, CI, CF 3 and CH 3 R(26) and R(27) independently of one another are hydrogen or methyl; R(5) is alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, CF 3 or phenyl, which is unsubstituted or substituted by 1 2 substituents from the group consisting of F and CI, -CF 3 and methyl; and their pharmaceutically tolerable salts.
The designated alkyl radicals can be either straight-chain or branched.
.(C1-Cg)-Heteroaryl is understood as meaning radicals which are derived •from phenyl or naphthyl, in which one or more CH groups are replaced by 8 N and/or in which at least two adjacent CH groups (with formation of a fivemembered aromatic ring) are replaced by S, NH or O. In addition, one or both atoms of the condensation site of bicyclic radicals (as in indolizinyl) can also be N atoms.
Heteroaryl is, in particular, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl.
If one of the substituents R(1) to R(5) contains one or more centers of asymmetry, these can be present independently of one another in either the S or R configuration. The compounds can be present as optical isomers, as diastereomers, as racemates or as mixtures thereof.
The invention furthermore relates to a process for the preparation of the compounds I, which comprises reacting compounds of the formula II SR(2') 20 L T O0 L R(4') in which to have the meanings indicated above for R(1) to 25 but of which at least one of the substituents to is the COL group marked, and in which L is a leaving group which can be easily nucleophilically substituted, with guanidine.
The activated acid derivatives of the formula II, in which L is an alkoxy group, preferably a methoxy group or phenoxy group, a phenylthio, methylthio or 2-pyridylthio group, or a nitrogen heterocycle, preferably 1- 7 V 9 imidazolyl, are advantageously obtained in a manner known per se from the underlying carbonyl chlorides (formula II, L CI), which for their part can in turn be prepared in a manner known per se from the underlying carboxylic acids (formula II, L OH), for example using thionyl chloride. In addition to the carbonyl chlorides of the formula II (L CI) further activated acid derivatives of the formula II can be prepared in a manner known per se directly from the underlying benzenedicarboxylic acid derivatives (formula II, L OH), such as, for example, the methyl esters of the formula II where L OCH 3 by treating with gaseous HCI in methanol, the imidazolides of the formula II by treating with carbonyldiimidazole [L 1- Imidazolyl, Staab, Angew. Chem. Int. Ed. Engl. 1,351-367 (1962)], the mixed anhydrides II with CI-COOC 2
H
5 or tosyl chloride in the presence of triethylamine in an inert solvent, and also the activation of benzenedicarboxylic acids using dicyclohexylcarbodiimide (DCC) or using O-[(cyano)ethoxycarbonyl)methylene)amino]-1,1,3,3-tetramethyluronium tetrafluoroborate] ("TOTU") [Proceedings of the 21st European Peptide Symposium, Peptides 1990, Editors E. Giralt and D. Andreu, Escom, Leiden, 1991]. A number of suitable methods for the preparation of activated carboxylic acid derivatives of the formula II are indicated under details of source literature in J. March, Advanced Organic Chemistry, Third Edition (John Wiley Sons, 1985), p. 350.
The reaction of an activated carboxylic acid derivative of the formula I with guanidine is carried out in a manner known per se in a protic or aprotic polar but inert organic solvent. In the case of the reaction of the methyl benzenedicarboxylates (II, L OMe) with guanidine, methanol, isopropanol or THF between 20°C and the boiling points of these solvents have proven suitable here. Most reactions of compounds II with salt-free guanidine were advantageously carried out in inert solvents such as THF, dimethoxyethane, dioxane or isopropanol. However, water can also be used as a solvent.
If L CI, the reaction is advantageously carried out with addition of an acid scavenger, e.g. in the form of excess guanidine to bind the hydrohalic acid.
The introduction of the compounds substituted in the phenyl moiety by sulfur, oxygen or nitrogen nucleophiles is carried out by methods known from the literature for the nucleophilic substitution of derivatives of dialkyl benzenedicarboxylates. In this substitution, suitable leaving groups on the benzenedicarboxylic acid derivative have proven to be halides and trifluoromethanesulfonates. The reaction is advantageously carried out in a dipolar aprotic solvent, such as DMF or TMU, at a temperature from 0°C up to the boiling point of the solvent, preferably from 80°C up to the boiling point of the solvent. The acid scavenger used is advantageously an alkali metal or alkaline earth metal salt with an anion of high basicity and low nucleophilicity, for example K 2
CO
3 or CsCO 3 The alkyl or aryl substituents are introduced by methods known from the literature for the palladium-mediated cross-coupling of aryl halides with, for example, organozinc compounds, organostannanes, organoboronic acids or organoboranes.
In general, benzenedicarboxylic acid diguanides I are weak bases and can bind acid with formation of salts. Possible acid addition salts are salts of all pharmacologically tolerable acids, for example halides, in particular hydrochlorides, ascorbates, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates and p-toluenesulfonates.
The Offenlegungsschrift WO 94/26709 describes benzenedicarboxylic acid diguanides in which, however, none of the compounds have one of the substituents R(5) claimed here, which corresponds to the R(3) of this Offenlegungsschrift.
Surprisingly, it has been found that the introduction of certain substituents °ooee Surprisingly, it has been found that the introduction of certain substituents 11 R(1) and/or R(5) significantly increases the activity of the compounds and moreover positively affects their pharmacokinetics.
On account of their pharmacological properties, the compounds I are outstandingly suitable as antiarrhythmic pharmaceuticals having a cardioprotective component for infarct prophylaxis and infarct treatment and for the treatment of angina pectoris, where they also preventively inhibit or greatly decrease the pathophysiological processes in the formation of ischemically induced damage, in particular in the induction of ischemically induced cardiac arrythmias. Because of their protective actions against pathological hypoxic and ischemic situations, the compounds of the formula I according to the invention can be used, as a result of inhibition of the cellular Na+/H exchange mechanism, as pharmaceuticals for the treatment of all acute or chronic damage caused by ischemia or illnesses primarily or secondarily induced thereby. This relates to their use as medicaments for surgical interventions, e.g. in organ transplantation, where the compounds can be used both for the protection of the organs in the donor before and during removal, for the protection of removed organs, for example during treatment with or storage thereof in physiological bath fluids, and also during transfer to the recipient's body.
The compounds are also useful pharmaceuticals having a protective action when carrying out angioplastic surgical interventions, for example on the heart and also on peripheral vessels. In accordance with their protective action against ischemically induced damage, the compounds are also suitable as pharmaceuticals for the treatment of ischemias of the nervous system, in particular of the CNS, where they are suitable, for example, for the treatment of stroke or of cerebral edema. Moreover, the compounds of the formula I according to the invention are also suitable for the treatment
S
of forms of shock, such as, for example, of allergic, cardiogenic, hypovolemic and bacterial shock.
The compounds of the formula I according to the invention are moreover distinguished by potent inhibitory action on the proliferation of cells, for example fibroblast cell proliferation and the proliferation of vascular smooth muscle cells. The compounds of the formula I are therefore suitable as useful therapeutics for illnesses in which cell proliferation is a primary or secondary cause, and can therefore be used as antiatherosclerotics, agents against diabetic late complications, carcinomatous disorders, fibrotic disorders such as pulmonary fibrosis, fibrosis of the liver or fibrosis of the kidney, organ hypertrophies and hyperplasias, in particular in prostate hyperplasia or prostate hypertrophy.
The compounds according to the invention are effective inhibitors of the cellular sodium-proton antiporter (Na+/H exchanger), which is raised in numerous disorders (essential hypertension, atherosclerosis, diabetes etc.) even in those cells which are easily accessible to measurement, such as, for example, in erythrocytes, platelets or leucocytes. 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 of atherosclerosis, diabetes, proliferative disorders etc. The compounds of the formula I are moreover suitable for preventive therapy for the prevention of the genesis of high blood pressure, for example of essential hypertension.
oooo 9S Compared with most known compounds, the compounds according to the invention have a significantly improved water solubility. They are therefore significantly better suited to i.v. administration.
e Compared with the known readily water-soluble compounds, the compounds according to the invention are distinguished by their better 0 bioavailability and pharmacokinetics.
Pharmaceuticals which contain a compound I can be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred type of 13 administration being dependent on the particular clinical picture of the disorder. The compounds I can be used here on their own or together with pharmaceutical auxiliaries, for example in veterinary and also in human medicine.
On the basis of his expert knowledge, the person skilled in the art is familiar with which auxiliaries are suitable for the desired pharmaceutical formulation. Beside solvents, gelling agents, suppository bases, tablet auxiliaries and other active compound excipients, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers or colorants, for example, can be used.
For a form for oral administration, the active compounds are mixed with the additives suitable for this purpose, such as excipients, stabilizers or inert diluents and brought by the customary methods into the suitable administration forms, such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily solutions. Inert excipients which can be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch.
Preparation can in this case take place either as dry or as moist granules.
Suitable oily excipients or solvents are, for example, vegetable or animal oils, such as sunflower oil or fish liver oil.
For subcutaneous or intravenous administration, the active compounds are brought into solution, suspension or emulsion, if desired with the 25 substances customary for this purpose, such as solubilizers, emulsifiers or O other auxiliaries. Possible solvents are, for example: water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerol, additionally also sugar solutions such as glucose or mannitol solutions, or alternatively a mixture of the various solvents mentioned.
Pharmaceutical formulations suitable for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active compound of the formula I in a pharmaceutically acceptable solvent, such as, in particular, ethanol or water, or a mixture of such solvents. If required, the formulation can also contain still other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers, as well as a propellant. Such a preparation customarily contains the active compound in a concentration from approximately 0.1 to 10, in particular from approximately 0.3 to 3% by weight.
The dose of the active compound of the formula I to be administered and the frequency of administration depend on the potency and duration of action of the compounds used; additionally also on the measure and severity of the illness to be treated and on the sex, age, weight and individual responsiveness of the mammal to be treated.
On average, the daily dose of a compound of the formula I in the case of a patient weighing approximately 75 kg is at least 0.001 mg/kg of body weight, preferably at least 0.01 mg/kg of body weight, up to at most mg/kg of body weight, preferably to at most 1 mg/kg of body weight. In acute episodes of the illness, for example immediately after suffering a cardiac infarct, still higher and especially more frequent doses may also be necessary, e.g. up to 4 individual doses per day. In particular when administered for example in the case of an infarct patient in the intensive care unit, up to 100 mg per day may be necessary.
o*o* 25 List of abbreviations: SAIBN a,a-azo-bis-isobutyronitrile Bn benzyl Brine saturated aqueous NaCI solution 0 CH 2
CI
2 dichloromethane DCI desorption chemical ionization DIP diisopropyl ether DMA dimethylacetamide ooo**O
DME
DMF
EA
El eq
ES
Et
FAB
HEP
HOAc Me MeOH mp
MTB
NBS
NMP
RT
THF
TMU
Tol
CNS
dimethoxyethane N,N-dimethylformamide ethyl acetate (EtOAc) electron impact equivalent electrospray ionisation ethyl fast atom bombardment n-heptane acetic acid methyl methanol melting point methyl tertiary-butyl ether N-bromosuccinimide N-methylpyrrolidone room temperature tetrahydrofuran N,N,N',N'-tetramethylurea toluene central nervous system
S.
a a.
a a.
a Experimental section 25 General procedure for the preparation of benzenedicarboxylic acid diguanides from dialkyl benzenedicarboxylates (II, L O-alkyl) mmol of the dialkyl benzenedicarboxylate of the formula (II) and 50 mmol of guanidine (free base) are dissolved in 5 ml of isopropanol and boiled 30 under reflux (typical reaction time 5 minutes to 5 h) until reaction is complete (thin-layer checking). The mixture is then diluted with 150 ml of water and the product is filtered off with suction. If appropriate, it is chromatographed on silica gel using a suitable eluent, e.g. EA/MeOH 5 1.
16 Example 1: 4-Chloro-5-phenylisophthalic acid diguanide O N
NH
2 Cl
NH
2 N NH 2 \0
NH
2 a) 3-Bromo-2-chloro-5-methylbenzoic acid 25 g of 2-amino-3-bromo-5-methylbenzoic acid are diazotized in 500 ml of 6N aqueous HCI solution at 0°C using 8.3 g of NaNO 2 then the mixture is stirred at RT for 30 minutes and poured in portions onto a warm solution at of 22 g of CuCI in 200 ml of a saturated aqueous HCI solution. The mixture is stirred at 40-50 0 C for 20 minutes, and the precipitate is filtered off with suction, washed with water until it is neutral and dried at under reduced pressure. 23.3 g of pale yellow crystals are obtained, mp 170- 1720C.
Rf (EA/MeOH 5:1) 0.51 MS (DCI): 249 (M+H) b) 5-Bromo-4-chloroisophthalic acid 99 g of MgSO 4 x 7H 2 0 are dissolved in 600 ml of water, then 20 g of 3-bromo-2-chloro-5-methylbenzoic acid are added, the mixture is warmed to 90°C, then 63 g of KMnO 4 are added in portions at 90-1000C, and the mixture is stirred under reflux for 2 h. It is then allowed to cool to RT, 25 saturated aqueous Na 2
SO
3 solution is added dropwise until the violet color disappears, the mixture is adjusted to pH 12 with saturated aqueous Na 2
CO
3 solution and the MnO 2 is filtered off with suction. It is washed with saturated aqueous Na 2
SO
3 solution and with hot water, the filtrate is Sadjusted to pH 1 with aqueous HCI and the precipitate is filtered off with S 30 suction. 13.5 g of a colorless solid are obtained, mp 2750C.
Rf(DIP/2% HOAc) 0.18 MS (DCI): 279 (M+H) 9 9 9 17 c) Dimethyl 5-bromo-4-chloroisophthalate 13.5 g of 5-bromo-4-chloroisophthalic acid are dissolved in 200 ml of MeOH, 20 ml of SOC12 are added dropwise and the mixture is stirred under reflux for 5 h. The volatile constituents are then removed in vacuo and the residue is dried in a fine vacuum. 14 g of colourless crystals are obtained, mp 99'C MS (DCI): 307 (M+H) d) Dimethyl 3.1 g of dimethyl 5-bromo-4-chloroisophthalate, 1.2 g of benzeneboronic acid, 2.1 g of Na 2
CO
3 230 mg of Pd(OAc) 2 and 500 mg of triphenylphosphine are stirred under reflux for 6 h in 50 ml of toluene and ml of water. The mixture is allowed to cool to RT, and is diluted with 300 ml of toluene and washed 3 times with 100 ml of a saturated aqueous Na 2
CO
3 solution each time. The organic phase is dried over Na 2
SO
4 the solvent is removed in vacuo and the residue is then chromatographed on silica gel using EA/HEP 1:4. 1.5 g of a colorless oil are obtained.
Rf (EA/HEP 1:4) 0.22 MS (DCI): 305 (M+H) e) 4-Chloro-5-phenylisophthalic acid diguanide 2.6 g of potassium tert-butoxide are dissolved in 50 ml of anhydrous DMF and treated with 2.6 g of guanidine hydrochloride. The mixture is stirred at RT for 1.5 h, 700 mg of dimethyl 4-chloro-5-phenylisophthalate are added and it is stirred at 100°C for 2 h. The mixture is poured onto 1 I of water, and it is adjusted to pH 8 with aqueous NaHCO 3 solution and aqueous 25 HCI solution and then extracted 3 times with 200 ml of EA each time. The organic phase is dried over Na 2
SO
4 and the solvent is removed in vacuo.
The residue is suspended in 100 ml of water and filtered off with suction, then the precipitate is again suspended in 50 ml of EA and filtered off with suction. The product is dried in vacuo and 350 mg of colorless crystals are 30 obtained, mp 235°C (with decomposition).
Rf (acetone/water 10:1) 0.063 MS 359 (M+H) 1 18 Pharmacological data: Inhibition of the Na+/H exchanger of rabbit erythrocytes White New Zealand rabbits (Ivanovas) received a standard diet with 2% cholesterol for six weeks in order to activate Na+/H+ exchange and thus to be able to determine the Na influx into the erythrocytes via Na+/H+ exchange by flame photometry. The blood was taken from the ear arteries and rendered incoagulable by means of 25 IU of potassium heparin. A part of each sample was used for the duplicate determination of the hematocrit by centrifugation. Aliquots of 100 pl in each case were used to measure the Na starting content of the erythrocytes.
In order to determine the amiloride-sensitive sodium influx, 100 pi of each blood sample were incubated in each case in 5 ml of a hyperosmolar saltsucrose medium (mmol/l: 140 NaCI, 3 KCI, 150 sucrose, 0.1 ouabain, tris-hydroxymethylaminomethane) at pH 7.4 and 37 0 C. The erythrocytes were then washed three times with ice-cold MgCl2 ouabain solution (mmol/l: 112 MgCI2, 0.1 ouabain) and hemolyzed in 2.0 ml of distilled water. The intracellular sodium content was determined by flame photometry.
The net Na influx was calculated from the difference between sodium starting values and the sodium content of the erythrocytes after incubation.
The amiloride-inhibitable sodium influx resulted from the difference 25 between the sodium content of the erythrocytes after incubation with and o without amiloride 3 x 10- 4 mol/l. This procedure was also used in the case of the compounds according to the invention.
of the compounds according to the invention.
*t *l t* N; Results Inhibition of the Na+/H+ exchanger: Example '050 (mmol/i) 1 0.9 PateJAdakHmxxxxxxxxxxxxxxxiERxf&x29Sxxxxxxx Dr. v. F.
THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1. A benzenedicarboxylic acid diguanide of the formula I R2 R3 R1 R4 N r NH2 R4 2 O
NH
2 in which: one of the radicals R(3) and R(4) is
-CO-N=C(NH
2 2 and the other radicals R(3) and R(4) in each case are: R(1) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, CI, Br, I, -OR(32), -NR(33)R(34) or CF 3 R(32), R(33) and R(34) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; R(2) and R(4) independently of one another are hydrogen, F, CI, Br, I, OH, -CN, CF 3
-CO-N=C(NH
2 2 alkyl having 1, 2, 3, 20 4, 5, 6, 7 or 8 carbon atoms, alkenyl having 2, 3, 4, 6, 7 or 8 carbon atoms or -(CH 2 )mR(14); m is zero, 1 or 2; o I R(14) is -(C 3
-C
8 )-cycloalkyl or phenyl, which is unsubstituted or substituted by 1 3 i 25 substituents selected from the group consisting of F and CI, -CF 3 methyl, methoxy and -NR(15)R(16); and R(16) are hydrogen or -CH 3 or R(2) and R(4) independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl, each of which is unsubstituted or substituted by
Claims (22)
- 2. A compound of the formula I as claimed in claim 1 wherein one of the radicals R(3) and R(4) S.:is -CO-N=C(NH 2 2 and the other radicals R(3) and R(4) in each case are: 25 R(1) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, CI, Br, -OR(32), or -NR(33)R(34) or CF 3 R(32), R(33) and R(34) independently of one another are hydrogen or methyl R(2) and R(4) independently of one another are hydrogen, F, CI, Br, I, OH, CF 3 -CO-N=C(NH 2 2 alkyl having 1, 2, 3 or 4 carbon atoms, alkenyl having 2, 3 or 4 carbon atoms or -(CH 2 )mR(14); m is zero, 1 or 2; R(14) is -(C 3 -C 6 )-cycloalkyl or phenyl, which is unsubstituted or substituted by 1 2 substituents selected from the group consisting of F and CI, -CF 3 methyl and methoxy; or R(2)and R(4) independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl, each of which is unsubstituted or substituted by 1 2 substituents selected from the group consisting of F, CI, Br, I, -CN, (C 2 -C 5 )-alkanoyl, (C 2 -C 5 )-alkoxycarbonyl, formyl, carboxyl, -CF 3 and methyl; or R(2) and R(4) independently of one another are R(22)-SO2-, R(28)-CO- or R(29)R(30)N-SO 2 R(22) and R(28) independently of one another are methyl or -CF3; S 20 R(29), and independently of one another are hydrogen or methyl; or R(2) and R(4) independently of one another are -OR(35) or -NR(35)R(36); 25 R(35) and R(36) independently of one another are hydrogen, methyl or ethyl; or and R(36) together are 4 5 methylene groups, of which a CH 2 group can be replaced by oxygen, -NH- or -NCH 3 R(3) is hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27); is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl, which is unsubstituted or substituted by 1 2 substituents selected from the group consisting of F, CI, CF 3 CH 3 methoxy and dimethylamino; or -is -(C 1 -C 9 )-heteroaryl, which is unsubstituted or substituted by 1 2 substituents selected from the group consisting of F, CI, CF 3 CH 3 methoxy and dimethylamino; R(26) and R(27) independently of one another are hydrogen or alkyl having 1,2, 3 or 4 carbon atoms; is alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, CF 3 or phenyl, which is unsubstituted or substituted by 1 2 substituents selected from the group consisting of F and CI, -CF 3 methyl, methoxy and dimethylamino.
- 3. A compound of the formula I as claimed in claim 1 or 2, wherein: one of the radicals R(3) and R(4) is 20 -CO-N=C(NH 2 2 and the other radicals R(3) and R(4) in each case are: R(1) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, CI, -OR(32), -NR(33)R(34) or -CF 3 R(32), R(33) and R(34) 25 independently of one another are hydrogen or methyl; R(2) and R(4) independently of one another are hydrogen, F, CI, OH, CF 3 -CO-N=C(NH 2 2 alkyl having 1, 2, 3 or 4 carbon atoms or pyrrol-1 -yl, which is unsubstituted or substituted by 1 2 substituents selected from the group consisting of F, CI, Br, I, -CN, (C 2 -C 5 )-alkanoyl, C 2 -C 5 )-alkoxycarbonyl, formyl, carboxyl, -CF 3 and methyl; or R(2) and R(4) independently of one another are R(22)-S0 2 R(22) is methyl or -CF 3 or R(2) and R(4) independently of one another are -OR(35) or -NR(35)R(36); and R(36) independently of one another are hydrogen, methyl or ethyl; R(3) is hydrogen, -SR(25), -OR(25), -NR(25)R(26), -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, CI, CF 3 and CH 3 or R(3) is -(C 1 -C 9 )heteroaryl which is unsubstituted or substituted by a substituent selected from the group consisting of F, CI, CF 3 and CH3; R(26) and R(27) 20 independently of one another are hydrogen or methyl; is alkyl having 1, 2, 3 or 4 carbon atoms, F, CI, CF 3 or phenyl, which is unsubstituted or substituted by 1 2 o substituents selected from the group consisting of F and CI, -CF 3 methyl and methoxy.
- 4. A compound of the formula I as claimed in claim 1, 2 or 3, wherein one of the radicals R(3) and R(4) is -CO-N=C(NH 2 2 and the other radicals R(3) and R(4) in each case are: R(1) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, CI, CF 3 or methoxy; R(2) and R(4) independently of one another are hydrogen, OH, CF 3 -CO-N=C(NH2) 2 alkyl having 1,2,3 or 4 carbon atoms or pyrrol-1-yl, which is unsubstituted or substituted by 1 2 substituents selected from the group consisting of F CI, Br, I, -CN, (C2-C 5 )-alkanoyl, (C 2 -C 5 )-alkoxy- carbonyl, formyl, carboxyl, -CF 3 and methyl; R(3) is hydrogen -OR(25) or -CR(25)R(26)R(27); 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, CI, CF 3 and CH 3 or is -(CI-Cg)-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, CI, -CF 3 and CH R(26) and R(27) independently of one another are hydrogen or methyl; 20 R(5) is alkyl having 1, 2, 3 or 4 carbon atoms, F, CI, CF 3 or phenyl, which is unsubstituted or substitued by 1 2 substituents selected from the group consisting of F and CI, -CF 3 and methyl.
- 5. A process for the preparation of a compound I as claimed in claim 1, which comprises reacting a compound of the formula II R(2') R( L II O R(4') O in which to have the meanings indicated above for R(1) to of Swhich, however, at least one of the substituents to is the COL r -i .o/ group marked and in which L is a leaving group which can easily be nucleophilically substituted, with guanidine.
- 6. The use of a compound I as claimed in claim 1 for the production of a medicament for the treatment of arrhythmias.
- 7. A method for the treatment of arrhythmias, which includes administering to a person in need of such treatment an effective amount of a compound I as claimed in claim 1.
- 8. The use of a compound I as claimed in claim 1 for the production of a medicament for the treatment or prophylaxis of cardiac infarct.
- 9. The use of a compound I as claimed in claim 1 for the production of a medicament for the treatment or prophylaxis of angina pectoris.
- 10. The use of a compound I as claimed in claim 1 for the production of a medicament for the treatment or prophylaxis of ischemic conditions of the 20 heart.
- 11. The use of a compound I as claimed in claim 1 for the production of a medicament for the treatment or prophylaxis of ischemic conditions of the peripheral and central nervous system and of stroke.
- 12. The use of a compound I as claimed in claim 1 for the production of a medicament for the treatment or prophylaxis of ischemic conditions of peripheral organs and members.
- 13. The use of a compound I as claimed in claim 1 for the production of a medicament for the treatment of states of shock. k') ev, l
- 14. The use of a compound I as claimed in claim 1 for the production of a medicament for use in surgical operations and organ transplantation. The use of a compound I as claimed in claim 1 for the production of a medicament for the preservation and transport of transplants for surgical measures.
- 16. The use of a compound I as claimed in claim 1 for the production of a medicament for the treatment of illnesses in which cell proliferation is a primary or secondary cause, and thus their use as antiatherosclerotics, agents against diabetic late complications, carcinomatous disorders, fibrotic disorders such as pulmonary fibrosis, fibrosis of the liver or fibrosis of the kidney and prostate hyperplasia.
- 17. The use of a compouOd I as claimed in claim 1 for the production of a scientific tool for measuring the inhibition of the Na+/H+ exchanger.
- 18. The use of the scientific tool as claimed in claim 17 for the diagnosis of hypertension and proliferative disorders.
- 19. A pharmaceutical composition including an effective amount of a compound I as claimed in any one of claims 1 to 4, in combination with a pharmaceutically acceptable additive, adjuvant or carrier. A method for the treatment or prophylaxis of cardiac infarction which includes administering to a person in need of such treatment an effective S. a amount of a compound I as claimed in claim 1.
- 21. A method for the treatment or prophylaxis of angina pectoris which includes administering to a person in need of such treatment an effective amount of a compound I as claimed in claim 1. i
- 22. A method for the treatment or prophylaxis of ischemic conditions of the heart which includes administering to a person in need of such treatment an effective amount of a compound I as claimed in claim 1 additives.
- 23. A method for the treatment or prophylaxis of ischemic conditions of the peripheral and central nervous system and of stroke which includes administering to a person in need of such treatment an effective amount of a compound I as claimed in claim 1.
- 24. A method for the treatment or prophylaxis of ischemic conditions of peripheral organs and members which includes administering to a person in need of such treatment an effective amount of a compound I as claimed in claim 1. A method for the treatment of states of shock which includes administering to a person in need of such treatment an effective amount of a compound 1 as claimed in claim 1. o:o° 26. A method for the preservation of organ transplants for surgical measures which includes administering to a transplant organ in need of such treatment an effective amount of a compound I as claimed in claim 1.
- 27. A method for the treatment of illnesses in which cell proliferation is a primary or secondary cause including antiatherosclerosis, diabetic late complications, carcinomatous disorders, fibrotic disorders including pulmonary fibrosis, fibrosis of the liver or fibrosis of the kidney and prostate hyperplasia o which includes administering to a person in need of such treatment an effective amount of compound I as claimed in claim 1. DATED this 21st day of January 1999 HOECHST AKTIENGESELLSCHAFT WATERMARK PATENT TRADEMARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 SAUSTRALIA VAX DOC025 AU7180496.WPC: CJH/ALJ/RES Hoechst Aktiengesellschaft HOE 95/F 269 K Dr. v. F. Abstract Benzenedicarboxylic acid diguanides of the formula I R2 R3 R1 R4 NH2 O NH 2 in which R(1) to R(5) have the meanings given in the claims, are useful antiarrhythmic pharmaceuticals having a cardioprotective component, even for the prevention of ischemically induced damage, in particular in the induction of ischemically induced cardiac arrhythmias. As a result of inhibition of the cellular Na+/H exchange mechanism, they are used for the treatment of acute or chronic damage caused by ischemia. Moreover, they are distinguished by potent inhibitory action on the proliferation of cells. They are suitable for preventing the genesis of high blood pressure. 9* 9
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19543194 | 1995-11-20 | ||
| DE19543194A DE19543194A1 (en) | 1995-11-20 | 1995-11-20 | New benzene-di:carboxylic acid di:guanidide derivs. |
| DE19624064 | 1996-06-17 | ||
| DE1996124064 DE19624064A1 (en) | 1996-06-17 | 1996-06-17 | New benzene-di:carboxylic acid di:guanidide derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU7180496A AU7180496A (en) | 1997-05-29 |
| AU703352B2 true AU703352B2 (en) | 1999-03-25 |
Family
ID=26020502
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU71804/96A Ceased 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 |
Country Status (18)
| Country | Link |
|---|---|
| EP (1) | EP0774458A1 (en) |
| JP (1) | JPH09169719A (en) |
| KR (1) | KR980002018A (en) |
| AR (1) | AR004331A1 (en) |
| AU (1) | AU703352B2 (en) |
| BR (1) | BR9605617A (en) |
| CA (1) | CA2190693A1 (en) |
| CZ (1) | CZ338296A3 (en) |
| HR (1) | HRP960547A2 (en) |
| HU (1) | HUP9603201A3 (en) |
| IL (1) | IL119637A0 (en) |
| MX (1) | MX9605674A (en) |
| NO (2) | NO964905L (en) |
| NZ (1) | NZ299772A (en) |
| PL (1) | PL316438A1 (en) |
| SK (1) | SK148796A3 (en) |
| TR (1) | TR199600916A2 (en) |
| TW (1) | TW353657B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19819548A1 (en) | 1998-04-30 | 1999-11-04 | Merck Patent Gmbh | Biphenyl derivatives |
| DE10044732A1 (en) * | 2000-09-09 | 2002-03-21 | Mahle Ventiltrieb Gmbh | Roller tappet for an internal combustion engine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994026709A1 (en) * | 1993-05-17 | 1994-11-24 | Fujisawa Pharmaceutical Co., Ltd. | GUANIDINE DERIVATIVES AS INHIBITORS OF Na+/H+ EXCHANGE IN CELLS |
| US5373024A (en) * | 1992-02-15 | 1994-12-13 | Hoechst Aktiengesellschaft | 3,5-Substituted benzoylguanidines, process for their preparation, their use as a medicament of diagnostic and medicament containing them |
| WO1996004241A2 (en) * | 1994-08-05 | 1996-02-15 | Fujisawa Pharmaceutical Co., Ltd. | Benzoylguanidine derivatives as medicaments |
-
1996
- 1996-10-08 PL PL96316438A patent/PL316438A1/en unknown
- 1996-11-07 EP EP96117822A patent/EP0774458A1/en not_active Withdrawn
- 1996-11-18 SK SK1487-96A patent/SK148796A3/en unknown
- 1996-11-18 CZ CZ963382A patent/CZ338296A3/en unknown
- 1996-11-18 IL IL11963796A patent/IL119637A0/en unknown
- 1996-11-18 AU AU71804/96A patent/AU703352B2/en not_active Ceased
- 1996-11-18 TW TW085114093A patent/TW353657B/en active
- 1996-11-18 AR ARP960105230A patent/AR004331A1/en unknown
- 1996-11-18 TR TR96/00916A patent/TR199600916A2/en unknown
- 1996-11-18 NZ NZ299772A patent/NZ299772A/en unknown
- 1996-11-19 JP JP8307831A patent/JPH09169719A/en active Pending
- 1996-11-19 KR KR1019960055375A patent/KR980002018A/en not_active Withdrawn
- 1996-11-19 MX MX9605674A patent/MX9605674A/en unknown
- 1996-11-19 BR BR9605617A patent/BR9605617A/en unknown
- 1996-11-19 HR HR19624064.6A patent/HRP960547A2/en not_active Application Discontinuation
- 1996-11-19 NO NO964905A patent/NO964905L/en unknown
- 1996-11-19 NO NO964903A patent/NO964903D0/en unknown
- 1996-11-19 CA CA002190693A patent/CA2190693A1/en not_active Abandoned
- 1996-11-19 HU HU9603201A patent/HUP9603201A3/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5373024A (en) * | 1992-02-15 | 1994-12-13 | Hoechst Aktiengesellschaft | 3,5-Substituted benzoylguanidines, process for their preparation, their use as a medicament of diagnostic and medicament containing them |
| WO1994026709A1 (en) * | 1993-05-17 | 1994-11-24 | Fujisawa Pharmaceutical Co., Ltd. | GUANIDINE DERIVATIVES AS INHIBITORS OF Na+/H+ EXCHANGE IN CELLS |
| WO1996004241A2 (en) * | 1994-08-05 | 1996-02-15 | Fujisawa Pharmaceutical Co., Ltd. | Benzoylguanidine derivatives as medicaments |
Also Published As
| Publication number | Publication date |
|---|---|
| HU9603201D0 (en) | 1997-01-28 |
| MX9605674A (en) | 1997-05-31 |
| CA2190693A1 (en) | 1997-05-21 |
| TW353657B (en) | 1999-03-01 |
| AR004331A1 (en) | 1998-11-04 |
| SK148796A3 (en) | 1997-10-08 |
| TR199600916A2 (en) | 1997-06-21 |
| BR9605617A (en) | 1998-08-18 |
| NO964905L (en) | 1997-05-21 |
| JPH09169719A (en) | 1997-06-30 |
| NO964903D0 (en) | 1996-11-19 |
| NO964905D0 (en) | 1996-11-19 |
| CZ338296A3 (en) | 1998-05-13 |
| PL316438A1 (en) | 1997-05-26 |
| KR980002018A (en) | 1998-03-30 |
| HUP9603201A3 (en) | 1997-11-28 |
| IL119637A0 (en) | 1997-02-18 |
| NZ299772A (en) | 1998-12-23 |
| AU7180496A (en) | 1997-05-29 |
| EP0774458A1 (en) | 1997-05-21 |
| HRP960547A2 (en) | 1998-02-28 |
| HUP9603201A2 (en) | 1997-05-28 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |