US20010018449A1 - 1-(p-thienylbenzyl)imidazoles as agonists of angiotensin (1-7) receptors, processes for their preparation, their use, and pharmaceutical preparations comprising them - Google Patents
1-(p-thienylbenzyl)imidazoles as agonists of angiotensin (1-7) receptors, processes for their preparation, their use, and pharmaceutical preparations comprising them Download PDFInfo
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- US20010018449A1 US20010018449A1 US09/809,008 US80900801A US2001018449A1 US 20010018449 A1 US20010018449 A1 US 20010018449A1 US 80900801 A US80900801 A US 80900801A US 2001018449 A1 US2001018449 A1 US 2001018449A1
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- United States
- Prior art keywords
- phenyl
- compound
- formyl
- imidazole
- methyl
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 42
- 108010021281 angiotensin I (1-7) Proteins 0.000 title claims abstract description 30
- 230000008569 process Effects 0.000 title abstract description 29
- 239000000556 agonist Substances 0.000 title abstract description 6
- BKMHLMJNCPWYLO-UHFFFAOYSA-N 1-[(4-thiophen-2-ylphenyl)methyl]imidazole Chemical class C1=CN=CN1CC(C=C1)=CC=C1C1=CC=CS1 BKMHLMJNCPWYLO-UHFFFAOYSA-N 0.000 title abstract description 5
- 238000002360 preparation method Methods 0.000 title description 10
- 239000000825 pharmaceutical preparation Substances 0.000 title description 9
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims abstract description 42
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 claims abstract description 23
- 206010020772 Hypertension Diseases 0.000 claims abstract description 21
- 238000004519 manufacturing process Methods 0.000 claims abstract description 19
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- FCRIOPQKJNGNNX-UHFFFAOYSA-N formic acid;propan-2-one Chemical compound OC=O.CC(C)=O FCRIOPQKJNGNNX-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 238000002825 functional assay Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 150000005232 imidazopyridines Chemical class 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000003903 lactic acid esters Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229960002394 lisinopril Drugs 0.000 description 1
- CZRQXSDBMCMPNJ-ZUIPZQNBSA-N lisinopril dihydrate Chemical compound O.O.C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 CZRQXSDBMCMPNJ-ZUIPZQNBSA-N 0.000 description 1
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 1
- 229960004773 losartan Drugs 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 150000004701 malic acid derivatives Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- OFXSXYCSPVKZPF-UHFFFAOYSA-N methoxyperoxymethane Chemical class COOOC OFXSXYCSPVKZPF-UHFFFAOYSA-N 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004998 naphthylethyl group Chemical group C1(=CC=CC2=CC=CC=C12)CC* 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 229940127264 non-peptide agonist Drugs 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000002669 organ and tissue protective effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000813 peptide hormone Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000012495 positive regulation of renal sodium excretion Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000036316 preload Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- QQKDTTWZXHEGAQ-UHFFFAOYSA-N propyl carbonochloridate Chemical compound CCCOC(Cl)=O QQKDTTWZXHEGAQ-UHFFFAOYSA-N 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 210000001147 pulmonary artery Anatomy 0.000 description 1
- 238000003127 radioimmunoassay Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000009711 regulatory function Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 239000007974 sodium acetate buffer Substances 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- BUXTXUBQAKIQKS-UHFFFAOYSA-N sulfuryl diisocyanate Chemical class O=C=NS(=O)(=O)N=C=O BUXTXUBQAKIQKS-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 230000002227 vasoactive effect Effects 0.000 description 1
- 230000003639 vasoconstrictive effect Effects 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 230000002666 vasoprotective effect Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 238000011706 wistar kyoto rat Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000003738 xylenes Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- 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
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the invention relates to novel 1-(p-thienylbenzyl)imidazoles of formula (I),
- EP-A 512675 and WO 94/27597 describe thienylbenzyl-substituted imidazoles as angiotensin 11 receptor-antagonists and their use for the treatment of hypertension, cardiac insufficiency, migraine, Alzheimer's disease, and as antidepressants.
- thienylbenzyl-substituted imidazopyridines are disclosed in EP-A 513979 as antagonists of angiotensin 11 receptors and their use for the treatment of hypertension, cardiac insufficiency, migraine, and Alzheimer's disease, and in U.S. Pat. No.
- R(1) is (1) halogen
- aryloxy unsubstituted or substituted by a substituent selected from halogen, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-alkoxy, and trifluoromethyl;
- R(2) is (1) CHO
- R(3) is (1) (C 1 -C 4 )-alkyl
- R(4) is (1) hydrogen
- X is (1) oxygen; or
- Y is (1) oxygen; or
- R(5) is (1) hydrogen
- R(5) can only be hydrogen if Y has the meaning mentioned under (2);
- R(6) (1) (C 1 -C 5 )-alkyl
- R(1) may not be halogen when R(2) is COOH or CO—O-(C 1 -C 4 )-alkyl.
- alkyl means, if not stated otherwise, straight-chain or branched saturated hydrocarbon radicals. This also applies to substituents derived therefrom such as alkoxy or the radical S(O) m -alkyl.
- alkyl radicals are methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl.
- alkoxy are methoxy, ethoxy, n-propoxy, and isopropoxy.
- aryloxy are phenoxy or naphthoxy. Phenoxy is preferred.
- Alkenyl represents mono- or polyunsaturated hydrocarbon radicals in which the double bonds can be situated in any desired positions.
- alkenyl examples are vinyl, propenyl, and butenyl.
- Halogen represents fluorine, chlorine, bromine, or iodine, preferably chlorine or fluorine.
- Aryl represents phenyl or naphthyl, preferably phenyl.
- substituted aryl radicals the substituents can be situated in any desired position relative to one another.
- arylalkyl radicals are phenylmethyl (benzyl), phenylethyl, phenylpropyl, phenylbutyl, naphthylmethyl, naphthylethyl, naphthylpropyl, and naphthylbutyl.
- compounds of formula (I) contain one or more acidic or basic groups
- the invention also encompasses the corresponding physiologically tolerable salts, in particular the pharmaceutically utilizable salts.
- compounds of formula (I) which carry acidic groups, such as one or more COOH groups can be present, for example, as their alkali metal salts, preferably sodium or potassium salts, or as their alkaline earth metal salts, e.g., calcium or magnesium salts, or as ammonium salts, e.g., as salts with ammonia or organic amines or amino acids.
- Compounds of formula (I) which carry one or more basic, i.e., protonatable, groups, can also be used in the form of their physiologically tolerable acid addition salts with inorganic or organic acids, for example as hydrochlorides, phosphates, sulfates, methanesulfonates, acetates, lactates, maleates, fumarates, malates, or gluconates. If compounds of formula (I) simultaneously contain acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms outlined, internal salts, so-called betaines. Salts can be obtained from compounds of formula (I) by customary processes, for example by combination with an acid or base in a solvent or dispersant or otherwise from other salts by anion exchange.
- Physiologically tolerable salts of compounds of formula (I) are to be understood, for example, as also meaning organic and inorganic salts, such as are described in Remington's Pharmaceutical Sciences (17 th Edition (1985) 1418).
- preferred acidic groups are, inter alia, sodium, potassium, calcium, and ammonium salts
- preferred basic groups are, inter alia, salts of hydrochloric acid, sulfuric acid, phosphoric acid, or of carboxylic acids or sulfonic acids, such as, for example, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, and p-toluenesulfonic acid.
- the present invention furthermore comprises solvates of compounds of formula (I), for example hydrates or adducts with alcohols, and also derivatives of compounds of formula (I) such as, for example, esters, and prodrugs and active metabolites.
- Preferred compounds of formula (I) are those in which
- R(1) is (1) chlorine
- R(4) is (1) hydrogen
- R(5) is (1) hydrogen
- R(6) is (1) n-propyl or 2-isobutyl
- R(1) is halogen, preferably chlorine, (C 1 -C 4 )-alkoxy, preferably methoxy, ethoxy, or propyloxy, particularly preferably methoxy, or (C 1 -C 8 )-alkoxy, where 1 to 6 carbon atoms are replaced by the heteroatoms O, S, or NH, preferably O, preferably methoxyethoxy or methoxypropoxy;
- R(2) is CHO
- R(3) is aryl, preferably phenyl
- R(4) is halogen, preferably chlorine, or hydrogen
- R(5) is (C 1 -C 6 )-alkyl, preferably methyl, ethyl, propyl, or butyl;
- R(6) is (C 1 -C 5 )-alkyl, preferably ethyl, propyl, or butyl;
- X is oxygen
- Y is oxygen or —NH—
- radicals R(1), R(4), R(5), R(6), and Y have the abovementioned meaning, in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof.
- Preferred compounds of formula (I) are also those in which R(1) is (C 1 -C 4 )-alkoxy or (C 1 -C 8 )-alkoxy, where 1 to 6 carbon atoms are replaced by the heteroatoms O, S, or NH, preferably O, and the other radicals are as defined above, in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof.
- Particularly preferred compounds of formula (I) are also those in which R(2) is CHO, and the other radicals are as defined above, in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof.
- Preferred compounds of formula (I) are furthermore those in which X is O, and the other radicals are as defined above, in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof.
- the invention furthermore relates to processes for the preparation of compounds of formula (I), comprising the following reaction:
- R(3) has the abovementioned meaning and whose preparation is described, for example, in Chem. Pharm. Bull. 24 (1976) 960-969, and reacting with p-bromobenzyl bromides of formula (IV),
- R(3) and R(4) have the abovementioned meanings, where the alkylation can be carried out in the presence of an organic or inorganic base such as, for example, triethylamine, K 2 CO 3 , or Cs 2 CO 3 in an inert solvent such as, for example, DMF.
- organic or inorganic base such as, for example, triethylamine, K 2 CO 3 , or Cs 2 CO 3 in an inert solvent such as, for example, DMF.
- an organic or inorganic base such as, for example, triethylamine, K 2 CO 3 , or Cs 2 CO 3
- an inert solvent such as, for example, DMF.
- R(3), R(4), and R(6) are as defined above.
- This Suzuki-type cross-coupling reaction is preferably carried out using palladium(II) acetate and triphenylphosphine or tetrakistriphenylphosphinepalladium as catalysts in the presence of a base such as, for example, cesium or potassium carbonate, for example, in solvent mixtures of ethanol and toluene at temperatures up to the boiling point of the solvents; corresponding reactions are described, for example, in Synthetic Commun. 11 (1981) 513, J. Med. Chem. 38 (1995) 2357-2377, and Liebigs Ann. (1995) 1253-1257.
- R(3), R(4), and R(6) are as defined above, and R(1)′ represents the radicals mentioned under (2) to (8) for R(1).
- This substitution of the chlorine atom can be carried out in this case, for example, by treatment of compounds of formula (VIII) with alkoxides formed in situ by the action of bases such as NaOH or NaH on the alcohols generally used as solvents, such as, for example, methanol, ethanol, or ethylene glycol monomethyl ether, at temperatures of from 50° C. up to the boiling point of the alcohols.
- compounds of formula (IX) in which R(1)′ is (C 1 -C 4 )-alkoxy can be converted via an ether cleavage, by treatment preferably of the methoxy ethers of formula (IX) with concentrated acids such as HI and HBr, or with Lewis acids such as BF 3 , BCl 3 , BBr 3 , AlCl 3 , or their etherates, preferably with BBr 3 , in an inert solvent such as, for example, CH 2 Cl 2 , into the corresponding phenols, which can then be reacted by processes known per se with the suitably substituted halides such as, for example, 2-bromoethyl methyl ether or benzyl bromide in the presence of a base in an inert solvent at temperatures up to the boiling point of the solvent.
- concentrated acids such as HI and HBr
- Lewis acids such as BF 3 , BCl 3 , BBr 3 , AlCl 3 , or their etherates,
- the corresponding diphenyl ether compounds can be obtained from the reaction of the phenols of formula (IX) with boronic acids such as, for example, phenylboronic acid or 4-methoxyphenylboronic acid in the presence of copper catalysts such as, for example, Cu(OAc) 2 .
- boronic acids such as, for example, phenylboronic acid or 4-methoxyphenylboronic acid
- copper catalysts such as, for example, Cu(OAc) 2 .
- Appropriate reactions are described, for example, in Tetrahedron Lett. 39 (1998) 2937-2940.
- R(1), R(2), R(3), R(4), and R(6) are as defined above, and R(5) only has the meaning mentioned under (2) and (3).
- This reaction can be carried out in the presence of a base such as, for example, pyridine, and of an acylation accelerator, such as 4-pyrrolidinopyridine, at temperatures from room temperature (RT) to 150° C., but preferably at RT.
- a base such as, for example, pyridine
- an acylation accelerator such as 4-pyrrolidinopyridine
- R(5)-substituted isocyanates and isothiocyanates can be carried out in the presence of a base in an inert solvent at temperatures from RT to 150° C.
- Suitable bases are, for example, alkali metal or alkaline earth metal hydroxides, hydrides, amides, or alkoxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium hydride, potassium hydride, calcium hydride, sodium amide, potassium amide, sodium methoxide, sodium ethoxide, or potassium tert-butoxide.
- Suitable inert solvents are ethers such as THF, dioxane, ethylene glycol dimethyl ether, or diglyme, ketones such as acetone or butanone, nitriles such as acetonitrile, nitro compounds such as nitromethane, esters such as ethyl acetate, amides such as DMF or N-methylpyrrolidone, hexamethylphosphoramide, sulfoxides such as DMSO, and hydrocarbons such as benzene, toluene, or xylenes. Furthermore, mixtures of these solvents with one another are also suitable.
- ethers such as THF, dioxane, ethylene glycol dimethyl ether, or diglyme
- ketones such as acetone or butanone
- nitriles such as acetonitrile
- nitro compounds such as nitromethane
- esters such as ethyl acetate
- amides such as DMF
- Sulfonylureas of formula (Ib) may also be prepared by reaction of amines R(5)—NH 2 with sulfonyl isocyanate derivatives that result from sulfonamides of formula (IX), for example, by treatment with phosgene or a phosgene substitute such as triphosgene.
- sulfonylureas of formula (lb) can be prepared by reaction of sulfonamides of formula (IX) with 2,2,2-trichloroacetamide derivatives of a suitable amine R(5)—NH 2 in the presence of a base in an inert, high-boiling solvent such as, for example, DMSO or from the corresponding sulfonylurethane of formula (la) accessible by reaction with ethyl chloroformate by action of the corresponding amine R(5)—NH 2 in an inert, high-boiling solvent such as, for example, toluene, at temperatures up to the boiling point of the respective solvent, which is described, for example, in J. Med. Chem. 38 (1995) 2357-2377, and in Bioorg. Med. Chem. 5 (1997) 673-678.
- N-Unsubstituted sulfonylureas of formula (lb), in which R(5) is hydrogen, can be prepared by hydrolysis of sulfonamidonitriles resulting after reaction of sulfonamides of formula (IX) with cyanogen bromide in the presence of K 2 CO 3 in acetonitrile with sulfuric acid at temperatures of from ⁇ 10° C. to 0° C.
- R is hydrogen or a suitable protective group such as, for example, (C 1 -C 6 )-alkyl, preferably tert-butyl, and the radicals R(1), R(2), R(3), R(4), and R(6) are as defined above, in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof.
- a suitable protective group such as, for example, (C 1 -C 6 )-alkyl, preferably tert-butyl
- R(1), R(2), R(3), R(4), and R(6) are as defined above, in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof.
- compounds of formula (X) are valuable intermediates for the preparation of compounds of formula (I) according to the invention.
- compounds of formula (X) have a high affinity for the angiotensin (1-7) receptor and can be used as angiotensin (1-7) receptor agonists and thus as pharmaceuticals for the treatment and/or prophylaxis of illnesses which are primarily or secondarily caused or at least partly caused by a reduced production and/or release of the vasorelaxant, anti-thrombotic, and cardioprotective messengers cyclic 3′,5′-guanosine monophosphate (cGMP) and nitrogen monoxide (NO).
- cGMP 3′,5′-guanosine monophosphate
- NO nitrogen monoxide
- these compounds are used for the treatment and/or prophylaxis of high blood pressure, cardiac hypertrophy, cardiac insufficiency, coronary heart diseases such as angina pectoris, cardiac infarct, vascular restenosis after angioplasty, cardiomyopathies, an endothelial dysfunction or endothelial damage, e.g., as a result of arteriosclerotic processes or in diabetes mellitus, and also of arterial and venous thrombosis.
- coronary heart diseases such as angina pectoris, cardiac infarct, vascular restenosis after angioplasty, cardiomyopathies, an endothelial dysfunction or endothelial damage, e.g., as a result of arteriosclerotic processes or in diabetes mellitus, and also of arterial and venous thrombosis.
- the vascular endothelium is a metabolically active organ with a large number of regulatory functions, that is capable of the synthesis and release of vasoactive substances.
- a dysfunction of the endothelial layer lining the vessel is correlated with the pathogenesis of various cardiovascular disorders such as arteriosclerosis and hypertension ( Eur. J. Clin. Invest. 23 (1993) 670-685).
- An endothelial dysfunction is characterized by a reduced synthesis and/or release of the vasorelaxant, vasoprotective, antithrombotically, and antiproliferatively active messengers NO and cGMP, which play an important role in the prevention and regression of vascular remodeling and arterial hypertension. Substances that are able to stimulate the synthesis and release of these messengers are therefore valuable pharmaceuticals for the treatment of all diseases that are characterized by endothelial dysfunction.
- Hypertension 19 (Suppl. II) (1992)11-49-11-55, and Am. J. Cardiol. 82 (1998) 17S-19S, showed that angiotensin (1-7) stimulated the production and/or the release of NO/cGMP and the prostaglandins E 2 and I 2 , which is not blocked by pretreatment with AT 1 and AT 2 receptor antagonists.
- angiotensin (1-7) in sodium chloride-loaded, anesthetized normo-tensive Wistar rats also showed renal effects such as increased natriuresis and diuresis ( Am. J. Physiol. 270 (1996) F141-F147).
- Compounds of formula (I) described here are potent, nonpeptide agonists of the postulated angiotensin (1-7) receptors, which are preferably located in the vessels (including endothelium), in the kidney, in the CNS, and in the heart. They therefore mimic the biological action of the peptide hormone angiotensin (1-7) directed against angiotensin II, described above, which is to be attributed to the production and/or release of cGMP and NO from the endothelium, without in this case being subject to the rapid metabolic degradation of this hormone.
- angiotensin (1-7) receptor agonists of formula (I) described are valuable pharmaceuticals for the treatment and/or prophylaxis of illnesses which are primarily or secondarily caused, or at least partly caused, by a reduced production and/or release of the vasorelaxant, antithrombotic, and cardioprotective messengers cGMP and NO.
- These compounds can thus be employed, for example, in the treatment and/or prophylaxis of high blood pressure, cardiac hypertrophy, cardiac insufficiency, coronary heart diseases such as angina pectoris, cardiac infarct, vascular restenosis after angioplasty, cardiomyopathies, an endothelial dysfunction or endothelial damage, e.g., as a result of arteriosclerotic processes or in diabetes mellitus, and also of arterial and venous thrombosis.
- coronary heart diseases such as angina pectoris, cardiac infarct, vascular restenosis after angioplasty, cardiomyopathies, an endothelial dysfunction or endothelial damage, e.g., as a result of arteriosclerotic processes or in diabetes mellitus, and also of arterial and venous thrombosis.
- Compounds of formula (I) or their physiologically tolerable salts can thus be used in animals, preferably in mammals, and in particular in humans, as pharmaceuticals, either on their own, as mixtures with one another or together with other active compounds, in particular in the form of pharmaceutical preparations.
- the present invention therefore relates to the use of compounds of formula (I) and/or their physiologically tolerable salts for the production of a medicament for the therapy or prophylaxis of the abovementioned syndromes, and to pharmaceutical preparations which contain an efficacious dose of at least one compound of formula (I) and/or of a physiologically tolerable salt thereof as active constituent in addition to at least one customary, pharmaceutically innocuous vehicle and/or excipient.
- the pharmaceutical preparations can be intended for enteral or parenteral use, and normally contain 0.5 to 90% by weight of at least one compound of formula (I) and/or a physiologically tolerable salt thereof.
- the amount of active compound of formula (I) and/or a physiologically tolerable salt thereof in the pharmaceutical preparations is in general 0.2 to 500 mg, preferably 1 to 300 mg.
- compositions employed according to the invention which contain at least one compound of formula (I), and/or a physiologically tolerable salt thereof, can be administered enterally, for example orally or rectally, in the form of pills, tablets, film-coated tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, solutions such as aqueous, alcoholic, or oily solutions, juices, drops, syrups, emulsions, or suspensions. Administration can also be carried out parenterally, for example subcutaneously, intramuscularly, or intravenously in the form of injection solutions or infusion solutions. Further possible administration forms are, for example, percutaneous or topical administration, in the form of ointments, creams, pastes, lotions, gels, sprays, powders, foams, aerosols, or solutions, or use in the form of implants.
- the pharmaceutical preparations employed according to the invention can be prepared by the known standard processes for the production of pharmaceutical preparations.
- at least one compound of formula (I) and/or a physiologically tolerable salt thereof are brought together with at least one solid or liquid pharmaceutical vehicle and/or additive or excipient, and, if desired, in combination with at least one other pharmaceutical active compound having therapeutic or prophylactic action, for example cardiovascular-active pharmaceuticals such as, for example, calcium antagonists, ACE inhibitors, AT 1 receptor antagonists, NO donors, endothelin receptor antagonists, K + channel openers, phosphodiesterase inhibitors, diuretics, or ⁇ - and ⁇ -blockers, into a suitable administration form or dose form, which can then be used as a pharmaceutical in human medicine or veterinary medicine.
- cardiovascular-active pharmaceuticals such as, for example, calcium antagonists, ACE inhibitors, AT 1 receptor antagonists, NO donors, endothelin receptor antagonists, K + channel openers, phosphodiesterase inhibitors, diuretics, or ⁇ - and ⁇
- Possible vehicles are organic or inorganic substances which are suitable for enteral (for example oral) or parenteral (for example intravenous) administration or topical application and do not react with active compounds of formula (I), for example water, vegetable oils, alcohols such as ethanol, isopropanol, or benzyl alcohol, 1,2-propanediol, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, lanolin, petroleum jelly, acetonitrile, dimethylformamide, and dimethylacetamide.
- active compounds of formula (I) for example water, vegetable oils, alcohols such as ethanol, isopropanol, or benzyl alcohol, 1,2-propanediol, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, lanolin, petroleum jelly, acetonitrile, dimethylform
- pharmaceutical forms such as tablets, sugar-coated tablets, capsules, solutions, preferably oily or aqueous solutions, syrups, juices, or drops.
- suspensions or emulsions are used for oral and rectal administration.
- Mixtures of two or more vehicles can also be employed, for example, mixtures of two or more solvents, in particular also mixtures of at least one organic solvent with water.
- the pharmaceutical preparations can contain, for example, stabilizing and/or wetting agents, emulsifiers, salts, for example for affecting the osmotic pressure, lubricants, preservatives, colorants and flavorings, and/or aromatizers and buffer substances.
- compositions of formula (I) and/or their physiologically tolerable salts can also be lyophilized and the lyophilizates obtained can be used, for example, for the production of injection preparations. Liposomal preparations are also particularly suitable for topical application.
- the dose of at least one active compound of formula (I) to be administered and/or of a physiologically tolerable salt thereof in the case of use according to the invention depends on the individual case and is to be tailored to the individual conditions as customary for an optimal action. Thus it depends on the nature and severity of the illness to be treated, and on the sex, age, weight, and individual responsiveness of the human or animal to be treated, on the potency and duration of action of the compounds employed, on whether the therapy is acute or chronic or prophylaxis is carried out, or on whether further active compounds are administered in addition to compounds of formula (I).
- a dose range for the treatment of the abovementioned syndromes in humans of approximately 0.1 mg to approximately 100 mg per kg per day on administration to an adult weighing about 75 kg is adequate to achieve the desired action.
- a dose range of 1 to 20 mg per kg per day (in each case mg per kg of body weight) is preferred.
- the daily dose can be administered here as an individual dose or can be divided into a number, for example, 1, 2, 3, or 4, of individual doses. It can also be administered continuously. If appropriate, depending upon individual behavior, it may be necessary to deviate upwards or downwards from the daily dose indicated.
- Pharmaceutical preparations normally contain 0.2 to 500 mg, preferably 1 to 300 mg, of at least one active compound of formula (I) and/or a physiologically tolerable salt thereof.
- the invention also very generally comprises the use of preferably nonpeptide compounds which bring about a stimulation of angiotensin (1-7) receptors which are located, for example, in the vessels (including endothelium), in the kidney, in the CNS, and in the heart, as pharmaceuticals, preferably for oral administration, or for use as substances which stimulate the production and/or release of the vasorelaxant, antithrombotic, and cardioprotective messengers cGMP and NO, and as pharmaceuticals for the treatment and/or prophylaxis of illnesses which are primarily or secondarily caused or at least partly caused by a reduced production and/or release of the vasorelaxant, antithrombotic, and cardioprotective messengers cGMP and NO, in particular for the treatment and prophylaxis of high blood pressure, cardiac hypertrophy, cardiac insufficiency, coronary heart diseases such as angina pectoris, cardiac infarct, vascular restenosis after angioplasty, cardiomyopathies, an endothelial
- the title compound was prepared by reaction of the compound from Example 2a) with butyl chloroformate according to the process mentioned in Example 1d). In this case, starting from 106 mg (0.21 mmol) of the compound from Example 2a) after chromatographic purification on SiO 2 using EA/heptane (1:1) as eluent, 75 mg of the desired compound was obtained as an amorphous foam.
- the title compound was prepared by reaction of the compound from Example 2a) with propyl chloroformate according to the process mentioned in Example 1d). In this case, starting from 60 mg (0.12 mmol) of the compound from Example 2a) after chromatographic purification on SiO 2 using EA/heptane (1:1) as eluent, 61 mg of the title compound were obtained as an amorphous foam.
- the title compound was prepared by reaction of the compound from Example 2a) with ethyl chloroformate according to the process mentioned in Example 1d). In this case, starting from 60 mg (0.12 mmol) of the compound from Example 2a) after chromatographic purification on SiO 2 using EA/heptane (1:1) as eluent, 55 mg of the title compound were obtained as an amorphous foam.
- the title compound was prepared by reaction of the compound from Example 2a) with ethyl isocyanate according to the process mentioned in Example 6). In this case, starting from 60 mg (0.12 mmol) of the compound from Example 2a), 46 mg of the title compound were obtained.
- the title compound was prepared by reaction of the compound from Example 9a) with butyl chloroformate according to the process mentioned in Example 1d). In this case, starting from 70 mg (0.13 mmol) of the compound from Example 9a) after chromatographic purification on SiO 2 using EA/heptane (1:1) as eluent, 78 mg of the title compound was obtained as an amorphous foam.
- the title compound was prepared by reaction of 4-chloro-5-formyl-2-phenylimidazole with 4-bromo-2-chlorobenzyl bromide according to the process mentioned in Example la). In this case, starting from 2.0 g (9.68 mmol) of 4-chloro-5-formyl-2-phenylimidazole, 2.6 g of the title compound was obtained.
- the title compound was prepared by reaction of the compound from Example 10a) and 5-isobutyl-2-[(N-tert-butyl)sulfonamido]thiophene-3-boronic acid according to the process mentioned in Example 1b). In this case, starting from 2.0 g (4.88 mmol) of the compound from Example 10a), 1.2 g of the title compound were obtained in the form of a pale brown oil.
- Example 10b The title compound was prepared from the compound from Example 10b) according to the process mentioned in Example 1c). Starting from 1.2 g (1.99 mmol) of the compound from Example 10b), 606 mg of the title compound was obtained as an amorphous, yellow foam.
- the title compound was prepared from the compound from Example 10c) according to the process mentioned in Example 2a). In this case, starting from 400 mg (0.73 mmol) of the compound from Example 10c), 280 mg of the title compound was obtained in the form of a yellow, amorphous foam.
- Example 12a The title compound was prepared from the compound from Example 12a) according to the process mentioned in Example 1c). Starting from 1.9 g (3.56 mmol) of the compound from Example 12a), after chromatographic purification on SiO 2 using EA/heptane (1:2) as eluent, 1.1 9 of the title compound was obtained as a white solid.
- the title compound was prepared by reaction of the compound from Example 12b) with butyl chloroformate according to the process mentioned in Example 1d). In this case, starting from 100 mg (0.20 mmol) of the compound from Example 12b), after chromatographic purification on SiO 2 using EA/heptane (1:1) as eluent, 90 mg of the title compound were obtained.
- the title compound was prepared by reaction of the compound from Example 12b) according to the process mentioned in Example 2a). In this case, starting from 850 mg (1.70 mmol) of the compound from Example 12b), after chromatographic purification on SiO 2 using EA/heptane (1:2) as eluent, 460 mg of the title compound was obtained in the form of a white solid.
- the title compound was prepared by reaction of the compound from Example 13a) with butyl chloroformate according to the process mentioned in Example 1d). In this case, starting from 60 mg (0.12 mmol) of the compound from Example 13a), after chromatographic purification on SiO 2 using EA/heptane (1:1) as eluent, 52 mg of the title compound were obtained.
- the title compound was prepared by reaction of the compound from Example 13b) with dimethyl dicarbonate according to the process mentioned in Example 5). Starting from 75 mg (0.15 mmol) of the compound from Example 13b), after chromatography on SiO 2 using EA/heptane (2:1) as eluent, 66 mg of the title compound were obtained as an amorphous solid.
- the title compound was prepared by reaction of the compound from Example 13b) with N-methyl-2,2,2-trichloroacetamide according to the process mentioned in Example 8). Starting from 70 mg (0.14 mmol) of the compound from Example 13b), after chromatography on SiO 2 using EA/heptane (2:1) as eluent, 55 mg of the title compound were obtained as an amorphous solid.
- Test 1 Binding Assay
- test 1, a the cells were cultured in 75 cm 2 culture bottles (Becton Dickinson, Heidelberg) until achieving confluence. The cells were then taken up with ice-cold phosphate/NaCl/EDTA buffer (50 mmol/l NaHPO 4 , 0.15 mol/l NaCl, 5 mmol/l EDTA, pH 7.2), detached with a rubber scraper, and centrifuged (1500 ⁇ g, 5 min). The resulting cell pellet was frozen ( ⁇ 80° C.) for later membrane preparation.
- ice-cold phosphate/NaCl/EDTA buffer 50 mmol/l NaHPO 4 , 0.15 mol/l NaCl, 5 mmol/l EDTA, pH 7.2
- the thawed cell pellet was homogenized (glass/Teflon Potter, 1000 rpm, 10 strokes) in ice-cold phosphate/NaCl/EDTA buffer. Membrane isolation was carried out by subsequent centrifugation (30,000 ⁇ g, 20 min) of the cell homogenate.
- the cell pellet thus obtained was resuspended in modified HEPES buffer (10 nmol/l HEPES, 0.1 mol/l NaCl, 5 mmol/l MgCl 2 , pH 7.4) with addition of 0.2% bovine serum albumin and a protease inhibitor cocktail (COMPLETE®, Boehringer Mannheim). After subsequent protein determination (according to Lowry) of the membrane suspension, this was used immediately for the ligand binding test.
- the tests were carried out on 96-well opaque plates that are equipped with Durapore filters (0.65 ⁇ m pore size; Millipore, Eschborn). Before the beginning of the test, the filters were pretreated with 1% bovine serum albumin for 30 min in order to minimize the nonspecific binding of the radioactive ligand and of the cold substances to the filter material. The incubation was carried out in a total volume of 200 ⁇ l: 50 ⁇ l of 125 I-ANG (1-7), 20 ⁇ l of cold, nonradioactive ANG (1-7) or test substances of formula (I), 30 ⁇ l of buffer, and 100 ⁇ l of membranes (20 ⁇ g of protein). The binding reaction was started by addition of the radioactive ligand.
- the incubation of the samples was carried out with continuous shaking at RT for 45 min.
- the binding reaction was ended by means of vacuum filtration ( ⁇ 20 kPa vacuum; multiscreen filtration system, Millipore, Eschborn).
- the filters were washed in vacuo twice with 250 ⁇ l of ice-cold phosphate/NaCl/EDTA buffer (50 mmol/l of NaHPO 4 , 0.15 mol/l of NaCl, 5 mmol/l of EDTA, pH 7.2), and then dried.
- the radioactive content on the dried filters was determined by means of a gamma counter.
- Test 2 Functional Assay
- the endothelial cells were taken up in culture medium (Dulbecco's modified Eagle's Ham's F 12 Medium 1:1 with penicillin (10 U/l), streptomycin (10 ⁇ g/l), L-glutamine (1 mmol/l), glutathione, and L-(+)-ascorbic acid (in each case 5 mg/l) and heat-inactivated fetal calf serum (20%)), washed once (centrifugation at 170 ⁇ g, 10 min), and resuspended in culture medium.
- culture medium Dulbecco's modified Eagle's Ham's F 12 Medium 1:1 with penicillin (10 U/l), streptomycin (10 ⁇ g/l), L-glutamine (1 mmol/l), glutathione, and L-(+)-ascorbic acid (in each case 5 mg/l) and heat-inactivated fetal calf serum (20%)
- the cell suspension thus obtained was inoculated ( ⁇ 250 ⁇ g of protein or 3 ⁇ 10 ⁇ 5 cells per well) into 6-well plates (Nunc Intermed, Wiesbaden), made up with culture medium, and kept at 37° C. in an incubator which was humidified and aerated with 95% O 2 /5% CO 2 .
- the incubation medium was aspirated, and the remaining cells were immediately extracted into 1 N formic acid-acetone (v/v, 15:85) and scraped off.
- the suspension obtained was ultrasonicated (10 sec) and then centrifuged off (3000 ⁇ g, 10 min).
- the supernatant was lyophilized and taken up in sodium acetate buffer (0.05 mol/l; pH 6.2). The content (pmol) of intracellular cGMP was related to mg of cell protein.
- Test 3 Isolated, Working Rat Hearts
- a catheter having an electromagnetic measuring head placed in the pulmonary artery was used. After a 15-minute equilibration period, the heart is converted into the working mode, in which a preload of 15 mmHg and an afterload of 60 mmHg is set. The working load of the heart remains constant during the entire test time of 90 minutes.
- Flow and pressure signals for the analysis are recorded by means of a PLUGSYS measuring system (Hugo Sachs Elektronik). The analysis of the data is carried out at a collection frequency of 500 Hz, averaged every 2 seconds, using the software Aquire Plus VI.21f (PO-NE-MAH).
- Control hearts Coronary flow (ml/min) Time (min) 8.98 ⁇ 0.59 0 8.94 ⁇ 0.52 5 9.04 ⁇ 0.70 10 8.91 ⁇ 0.44 15
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Abstract
Description
-
- which are potent agonists of angiotensin (1-7) receptors and, because of the production and release of the vasorelaxant, antithrombotic, and cardio-protective messengers cyclic 3′,5′-guanosine monophosphate (cGMP) and nitrogen monoxide (NO) associated with the stimulation of these receptors on endothelial cells, are valuable pharmaceuticals for the treatment and prophylaxis of high blood pressure, cardiac hypertrophy, cardiac insufficiency, coronary heart diseases such as angina pectoris, cardiac infarct, vascular restenosis after angioplasty, cardiomyopathies, an endothelial dysfunction or endothelial damage, e.g., as a result of arteriosclerotic processes or in diabetes mellitus, and of arterial and venous thrombosis.
- EP-A 512675 and WO 94/27597 describe thienylbenzyl-substituted imidazoles as angiotensin 11 receptor-antagonists and their use for the treatment of hypertension, cardiac insufficiency, migraine, Alzheimer's disease, and as antidepressants. Moreover, thienylbenzyl-substituted imidazopyridines are disclosed in EP-A 513979 as antagonists of angiotensin 11 receptors and their use for the treatment of hypertension, cardiac insufficiency, migraine, and Alzheimer's disease, and in U.S. Pat. No. 5,444,067 as angiotensin 11 agonists and their use for the treatment of hypotension and of hypoaldosteronism. In addition, in EP-A 534706 thienylbenzyl-substituted quinazolinones and pyridopyrimidones and in EP-A 510812 thienylbenzyl-substituted triazoles are disclosed as antagonists of angiotensin II receptors.
- The 1-(p-thienylbenzyl)imidazoles of formula (I) described here and their use as agonists of angiotensin (1-7) receptors are in this case neither described, anticipated, nor suggested in the applications mentioned.
- Surprisingly, it has been found that 1-(p-thienylbenzyl)imidazoles of formula (I) have a marked action on angiotensin (1-7) receptors and mimic the biological action of the effector hormone angiotensin (1-7).
-
- in which:
- R(1) is (1) halogen;
- (2) hydroxyl;
- (3) (C1-C4)-alkoxy;
- (4) (C1-C8)-alkoxy, wherein 1 to 6 carbon atoms are replaced by the heteroatoms O, S, or NH, preferably by O;
- (5) (C1-C4)-alkoxy, substituted by a saturated cyclic ether such as tetrahydropyran or tetrahydrofuran;
- (6) O-(C1-C4)-alkenyl;
- (7) O-(C1-C4)-alkylaryl; or
- (8) aryloxy, unsubstituted or substituted by a substituent selected from halogen, (C1-C3)-alkyl, (C1-C3)-alkoxy, and trifluoromethyl;
- R(2) is (1) CHO;
- (2) COOH; or
- (3) CO—O-(C1-C4)-alkyl;
- R(3) is (1) (C1-C4)-alkyl; or
- (2) aryl;
- R(4) is (1) hydrogen;
- (2) halogen; or
- (3) (C1-C4)-alkyl;
- X is (1) oxygen; or
- (2) sulfur;
- Y is (1) oxygen; or
- (2) —NH—;
- R(5) is (1) hydrogen;
- (2) (C1-C6)-alkyl; or
- (3) (C1-C4)-alkylaryl;
- where R(5) can only be hydrogen if Y has the meaning mentioned under (2); and
- R(6) (1) (C1-C5)-alkyl;
- in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof;
- wherein R(1) may not be halogen when R(2) is COOH or CO—O-(C1-C4)-alkyl.
- The term alkyl means, if not stated otherwise, straight-chain or branched saturated hydrocarbon radicals. This also applies to substituents derived therefrom such as alkoxy or the radical S(O)m-alkyl. Examples of alkyl radicals are methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. Examples of alkoxy are methoxy, ethoxy, n-propoxy, and isopropoxy. Examples of aryloxy are phenoxy or naphthoxy. Phenoxy is preferred.
- Alkenyl represents mono- or polyunsaturated hydrocarbon radicals in which the double bonds can be situated in any desired positions. Examples of alkenyl are vinyl, propenyl, and butenyl.
- Halogen represents fluorine, chlorine, bromine, or iodine, preferably chlorine or fluorine.
- Aryl represents phenyl or naphthyl, preferably phenyl.
- In substituted aryl radicals, the substituents can be situated in any desired position relative to one another.
- Examples of arylalkyl radicals are phenylmethyl (benzyl), phenylethyl, phenylpropyl, phenylbutyl, naphthylmethyl, naphthylethyl, naphthylpropyl, and naphthylbutyl.
- If compounds of formula (I) contain one or more acidic or basic groups, the invention also encompasses the corresponding physiologically tolerable salts, in particular the pharmaceutically utilizable salts. Thus, compounds of formula (I) which carry acidic groups, such as one or more COOH groups, can be present, for example, as their alkali metal salts, preferably sodium or potassium salts, or as their alkaline earth metal salts, e.g., calcium or magnesium salts, or as ammonium salts, e.g., as salts with ammonia or organic amines or amino acids. Compounds of formula (I) which carry one or more basic, i.e., protonatable, groups, can also be used in the form of their physiologically tolerable acid addition salts with inorganic or organic acids, for example as hydrochlorides, phosphates, sulfates, methanesulfonates, acetates, lactates, maleates, fumarates, malates, or gluconates. If compounds of formula (I) simultaneously contain acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms outlined, internal salts, so-called betaines. Salts can be obtained from compounds of formula (I) by customary processes, for example by combination with an acid or base in a solvent or dispersant or otherwise from other salts by anion exchange.
- Physiologically tolerable salts of compounds of formula (I) are to be understood, for example, as also meaning organic and inorganic salts, such as are described inRemington's Pharmaceutical Sciences (17th Edition (1985) 1418). On account of the physical and chemical stability and the solubility, preferred acidic groups are, inter alia, sodium, potassium, calcium, and ammonium salts; preferred basic groups are, inter alia, salts of hydrochloric acid, sulfuric acid, phosphoric acid, or of carboxylic acids or sulfonic acids, such as, for example, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, and p-toluenesulfonic acid.
- The present invention furthermore comprises solvates of compounds of formula (I), for example hydrates or adducts with alcohols, and also derivatives of compounds of formula (I) such as, for example, esters, and prodrugs and active metabolites.
- Preferred compounds of formula (I) are those in which
- R(1) is (1) chlorine;
- (2) hydroxyl;
- (3) methoxy, ethoxy, or propyloxy;
- (4) methoxyethoxy or methoxypropoxy;
- (5) allyloxy; or
- (6) phenoxy;
- R(4) is (1) hydrogen; or
- (2) chlorine;
- R(5) is (1) hydrogen; or
- (2) (C1-C4)-alkyl;
- R(6) is (1) n-propyl or 2-isobutyl;
- and the other radicals are as defined above, in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof.
- Compounds of formula (I) are furthermore preferred in which
- R(1) is halogen, preferably chlorine, (C1-C4)-alkoxy, preferably methoxy, ethoxy, or propyloxy, particularly preferably methoxy, or (C1-C8)-alkoxy, where 1 to 6 carbon atoms are replaced by the heteroatoms O, S, or NH, preferably O, preferably methoxyethoxy or methoxypropoxy;
- R(2) is CHO;
- R(3) is aryl, preferably phenyl;
- R(4) is halogen, preferably chlorine, or hydrogen;
- R(5) is (C1-C6)-alkyl, preferably methyl, ethyl, propyl, or butyl;
- R(6) is (C1-C5)-alkyl, preferably ethyl, propyl, or butyl;
- X is oxygen;
- Y is oxygen or —NH—;
- in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof.
-
- in which the radicals R(1), R(4), R(5), R(6), and Y have the abovementioned meaning, in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof.
- Preferred compounds of formula (I) are also those in which R(1) is (C1-C4)-alkoxy or (C1-C8)-alkoxy, where 1 to 6 carbon atoms are replaced by the heteroatoms O, S, or NH, preferably O, and the other radicals are as defined above, in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof.
- Particularly preferred compounds of formula (I) are also those in which R(2) is CHO, and the other radicals are as defined above, in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof.
- Preferred compounds of formula (I) are furthermore those in which X is O, and the other radicals are as defined above, in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof.
- Particularly preferred compounds of formula (I) are:
- 4-chloro-5-formyl-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically tolerable salt thereof;
- 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]rmethyl]imidazole, or a physiologically tolerable salt thereof;
- 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-propyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically tolerable salt thereof;
- 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethoxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically tolerable salt thereof;
- 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(methoxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically tolerable salt thereof;
- 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butylaminocarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically tolerable salt thereof;
- 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically tolerable salt thereof;
- 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(methylaminocarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically tolerable salt thereof;
- 5-formyl-4-methoxyethoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically tolerable salt thereof;
- 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]-2-chlorophenyl]methyl]imidazole, or a physiologically tolerable salt thereof;
- 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]-2-chlorophenyl]methyl]imidazole, or a physiologically tolerable salt thereof;
- 4-chloro-5-formyl-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically tolerable salt thereof;
- 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically tolerable salt thereof;
- 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(methoxycarbonylsulfonamido)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically tolerable salt thereof;
- 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butylaminocarbonylsulfonamido)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically tolerable salt thereof;
- 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(methylaminocarbonylsulfonamido)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole, or a physiologically tolerable salt thereof;
- 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole sodium salt;
- 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole L-lysine salt; or
- 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole tris(hydroxymethyl)aminomethane salt.
- The invention furthermore relates to processes for the preparation of compounds of formula (I), comprising the following reaction:
-
-
-
- in which R(3) and R(4) have the abovementioned meanings, where the alkylation can be carried out in the presence of an organic or inorganic base such as, for example, triethylamine, K2CO3, or Cs2CO3 in an inert solvent such as, for example, DMF. Compounds of formula (IV) are commercially obtainable or can be prepared by methods known per se.
-
-
- in which R(3), R(4), and R(6) are as defined above. This Suzuki-type cross-coupling reaction is preferably carried out using palladium(II) acetate and triphenylphosphine or tetrakistriphenylphosphinepalladium as catalysts in the presence of a base such as, for example, cesium or potassium carbonate, for example, in solvent mixtures of ethanol and toluene at temperatures up to the boiling point of the solvents; corresponding reactions are described, for example, inSynthetic Commun. 11 (1981) 513, J. Med. Chem. 38 (1995) 2357-2377, and Liebigs Ann. (1995) 1253-1257.
-
- in which R(3), R(4), and R(6) are as defined above. This removal is preferably carried out by treatment of compounds of formula (VII) with organic acids such as, for example, concentrated trifluoroacetic acid in the presence of anisole.
-
- in which R(3), R(4), and R(6) are as defined above, and R(1)′ represents the radicals mentioned under (2) to (8) for R(1). This substitution of the chlorine atom can be carried out in this case, for example, by treatment of compounds of formula (VIII) with alkoxides formed in situ by the action of bases such as NaOH or NaH on the alcohols generally used as solvents, such as, for example, methanol, ethanol, or ethylene glycol monomethyl ether, at temperatures of from 50° C. up to the boiling point of the alcohols.
- Alternatively, compounds of formula (IX) in which R(1)′ is (C1-C4)-alkoxy can be converted via an ether cleavage, by treatment preferably of the methoxy ethers of formula (IX) with concentrated acids such as HI and HBr, or with Lewis acids such as BF3, BCl3, BBr3, AlCl3, or their etherates, preferably with BBr3, in an inert solvent such as, for example, CH2Cl2, into the corresponding phenols, which can then be reacted by processes known per se with the suitably substituted halides such as, for example, 2-bromoethyl methyl ether or benzyl bromide in the presence of a base in an inert solvent at temperatures up to the boiling point of the solvent.
- The corresponding diphenyl ether compounds can be obtained from the reaction of the phenols of formula (IX) with boronic acids such as, for example, phenylboronic acid or 4-methoxyphenylboronic acid in the presence of copper catalysts such as, for example, Cu(OAc)2. Appropriate reactions are described, for example, in Tetrahedron Lett. 39 (1998) 2937-2940.
-
- in which R(1), R(2), R(3), R(4), and R(6) are as defined above, and R(5) only has the meaning mentioned under (2) and (3). This reaction can be carried out in the presence of a base such as, for example, pyridine, and of an acylation accelerator, such as 4-pyrrolidinopyridine, at temperatures from room temperature (RT) to 150° C., but preferably at RT.
-
- in which R(1), R(2), R(3), R(4), R(6), and X are as defined above, and R(5) only has the meaning mentioned under (2) and (3). The reaction with R(5)-substituted isocyanates and isothiocyanates can be carried out in the presence of a base in an inert solvent at temperatures from RT to 150° C.
- Suitable bases are, for example, alkali metal or alkaline earth metal hydroxides, hydrides, amides, or alkoxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium hydride, potassium hydride, calcium hydride, sodium amide, potassium amide, sodium methoxide, sodium ethoxide, or potassium tert-butoxide. Suitable inert solvents are ethers such as THF, dioxane, ethylene glycol dimethyl ether, or diglyme, ketones such as acetone or butanone, nitriles such as acetonitrile, nitro compounds such as nitromethane, esters such as ethyl acetate, amides such as DMF or N-methylpyrrolidone, hexamethylphosphoramide, sulfoxides such as DMSO, and hydrocarbons such as benzene, toluene, or xylenes. Furthermore, mixtures of these solvents with one another are also suitable.
- Sulfonylureas of formula (Ib) may also be prepared by reaction of amines R(5)—NH2 with sulfonyl isocyanate derivatives that result from sulfonamides of formula (IX), for example, by treatment with phosgene or a phosgene substitute such as triphosgene.
- Alternatively, sulfonylureas of formula (lb) can be prepared by reaction of sulfonamides of formula (IX) with 2,2,2-trichloroacetamide derivatives of a suitable amine R(5)—NH2 in the presence of a base in an inert, high-boiling solvent such as, for example, DMSO or from the corresponding sulfonylurethane of formula (la) accessible by reaction with ethyl chloroformate by action of the corresponding amine R(5)—NH2 in an inert, high-boiling solvent such as, for example, toluene, at temperatures up to the boiling point of the respective solvent, which is described, for example, in J. Med. Chem. 38 (1995) 2357-2377, and in Bioorg. Med. Chem. 5 (1997) 673-678.
- N-Unsubstituted sulfonylureas of formula (lb), in which R(5) is hydrogen, can be prepared by hydrolysis of sulfonamidonitriles resulting after reaction of sulfonamides of formula (IX) with cyanogen bromide in the presence of K2CO3 in acetonitrile with sulfuric acid at temperatures of from −10° C. to 0° C.
-
- in which R is hydrogen or a suitable protective group such as, for example, (C1-C6)-alkyl, preferably tert-butyl, and the radicals R(1), R(2), R(3), R(4), and R(6) are as defined above, in any stereoisomeric form or mixture thereof in any ratio, or a physiologically tolerable salt thereof.
- Compounds of formula (X) are valuable intermediates for the preparation of compounds of formula (I) according to the invention. In addition, compounds of formula (X) have a high affinity for the angiotensin (1-7) receptor and can be used as angiotensin (1-7) receptor agonists and thus as pharmaceuticals for the treatment and/or prophylaxis of illnesses which are primarily or secondarily caused or at least partly caused by a reduced production and/or release of the vasorelaxant, anti-thrombotic, and cardioprotective messengers cyclic 3′,5′-guanosine monophosphate (cGMP) and nitrogen monoxide (NO). For example, these compounds are used for the treatment and/or prophylaxis of high blood pressure, cardiac hypertrophy, cardiac insufficiency, coronary heart diseases such as angina pectoris, cardiac infarct, vascular restenosis after angioplasty, cardiomyopathies, an endothelial dysfunction or endothelial damage, e.g., as a result of arteriosclerotic processes or in diabetes mellitus, and also of arterial and venous thrombosis.
- The vascular endothelium is a metabolically active organ with a large number of regulatory functions, that is capable of the synthesis and release of vasoactive substances. A dysfunction of the endothelial layer lining the vessel is correlated with the pathogenesis of various cardiovascular disorders such as arteriosclerosis and hypertension (Eur. J. Clin. Invest. 23 (1993) 670-685). An endothelial dysfunction is characterized by a reduced synthesis and/or release of the vasorelaxant, vasoprotective, antithrombotically, and antiproliferatively active messengers NO and cGMP, which play an important role in the prevention and regression of vascular remodeling and arterial hypertension. Substances that are able to stimulate the synthesis and release of these messengers are therefore valuable pharmaceuticals for the treatment of all diseases that are characterized by endothelial dysfunction.
- A large number of published experiments confirm that a degradation product of the renin-angiotensin system, the heptapeptide angiotensin (1-7), is a potent, endogenous effector hormone of the renin-angiotensin system (Hypertension 12 (Suppl. III) (1991) III-126-III-133), whose biological action is caused by the stimulation of specific receptors, which preferably bind angiotensin (1-7) (Peptides 14 (1993) 679-684; Hypertension 29 (part 2) (1997) 388-393). This action is in many cases directed against that of the vasoconstrictory hormone angiotensin II or opposes this in a counter regulatory manner (Hypertension 30 (part 2) (1997) 535-541; Regulatory Peptides 78 (1998) 13-18).
-
- An endothelium-dependent relaxation of intact coronary arteries of dogs and pigs was described inHypertension 27 (part 2) (1996) 523-528, and an endothelium-dependent relaxation of intact, KCl-precontracted rat aortas by angiotensin (1-7), which is not affected by AT1 receptor antagonists, was described in J. Cardiovasc. Pharmacol. 30 (1997) 676-682.
- The hypotensive action of angiotensin (1-7) in spontaneously hypertensive rats on continuous infusion by means of an osmotic minipump was shown inPeptides 14 (1993) 679-684, and in Am. J. Physiol. 269 (1995) H313-H319, angiotensin (1-7) in normotensive rats having no action on the blood pressure in the same dose. Complementary to these investigations, it was demonstrated in Hypertension 31 (1998) 699-705, that the infusion of an angiotensin (1-7) antibody increases the mean arterial blood pressure in conscious, spontaneously hypertensive rats which had been pretreated with lisinopril and losartan.
-
- The anti-proliferative action of angiotensin (1-7) on vascular smooth muscle cells was confirmed inHypertension 28 (1996) 104-108, and the inhibition of the proliferation of smooth muscle cells after vascular tissue damage was confirmed in Hypertension 33 (part II) (1999) 207-211.
- Moreover, angiotensin (1-7) in sodium chloride-loaded, anesthetized normo-tensive Wistar rats also showed renal effects such as increased natriuresis and diuresis (Am. J. Physiol. 270 (1996) F141-F147).
- Compounds of formula (I) described here are potent, nonpeptide agonists of the postulated angiotensin (1-7) receptors, which are preferably located in the vessels (including endothelium), in the kidney, in the CNS, and in the heart. They therefore mimic the biological action of the peptide hormone angiotensin (1-7) directed against angiotensin II, described above, which is to be attributed to the production and/or release of cGMP and NO from the endothelium, without in this case being subject to the rapid metabolic degradation of this hormone. Because of the stimulation of the production and/or release of these vasorelaxant, antithrombotic, and cardioprotective messengers, angiotensin (1-7) receptor agonists of formula (I) described are valuable pharmaceuticals for the treatment and/or prophylaxis of illnesses which are primarily or secondarily caused, or at least partly caused, by a reduced production and/or release of the vasorelaxant, antithrombotic, and cardioprotective messengers cGMP and NO. These compounds can thus be employed, for example, in the treatment and/or prophylaxis of high blood pressure, cardiac hypertrophy, cardiac insufficiency, coronary heart diseases such as angina pectoris, cardiac infarct, vascular restenosis after angioplasty, cardiomyopathies, an endothelial dysfunction or endothelial damage, e.g., as a result of arteriosclerotic processes or in diabetes mellitus, and also of arterial and venous thrombosis.
- The stimulation of endothelial angiotensin (1-7) receptors by agonists of formula (I) causes the release of vasodilatory and organ-protective autacoids. This mechanism differs here from that of ACE inhibition and AT1 receptor blockade by the avoidance either of lowered tissue angiotensin II (in the case of ACE inhibitors) or of effects which still cannot be estimated at present, which are associated with increased ANG II plasma values (in the case of AT1 receptor antagonists).
- Compounds of formula (I) or their physiologically tolerable salts can thus be used in animals, preferably in mammals, and in particular in humans, as pharmaceuticals, either on their own, as mixtures with one another or together with other active compounds, in particular in the form of pharmaceutical preparations. The present invention therefore relates to the use of compounds of formula (I) and/or their physiologically tolerable salts for the production of a medicament for the therapy or prophylaxis of the abovementioned syndromes, and to pharmaceutical preparations which contain an efficacious dose of at least one compound of formula (I) and/or of a physiologically tolerable salt thereof as active constituent in addition to at least one customary, pharmaceutically innocuous vehicle and/or excipient. The pharmaceutical preparations can be intended for enteral or parenteral use, and normally contain 0.5 to 90% by weight of at least one compound of formula (I) and/or a physiologically tolerable salt thereof. The amount of active compound of formula (I) and/or a physiologically tolerable salt thereof in the pharmaceutical preparations is in general 0.2 to 500 mg, preferably 1 to 300 mg.
- Pharmaceuticals employed according to the invention, which contain at least one compound of formula (I), and/or a physiologically tolerable salt thereof, can be administered enterally, for example orally or rectally, in the form of pills, tablets, film-coated tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, solutions such as aqueous, alcoholic, or oily solutions, juices, drops, syrups, emulsions, or suspensions. Administration can also be carried out parenterally, for example subcutaneously, intramuscularly, or intravenously in the form of injection solutions or infusion solutions. Further possible administration forms are, for example, percutaneous or topical administration, in the form of ointments, creams, pastes, lotions, gels, sprays, powders, foams, aerosols, or solutions, or use in the form of implants.
- The pharmaceutical preparations employed according to the invention can be prepared by the known standard processes for the production of pharmaceutical preparations. For this, at least one compound of formula (I) and/or a physiologically tolerable salt thereof are brought together with at least one solid or liquid pharmaceutical vehicle and/or additive or excipient, and, if desired, in combination with at least one other pharmaceutical active compound having therapeutic or prophylactic action, for example cardiovascular-active pharmaceuticals such as, for example, calcium antagonists, ACE inhibitors, AT1 receptor antagonists, NO donors, endothelin receptor antagonists, K+ channel openers, phosphodiesterase inhibitors, diuretics, or α- and β-blockers, into a suitable administration form or dose form, which can then be used as a pharmaceutical in human medicine or veterinary medicine.
- Possible vehicles are organic or inorganic substances which are suitable for enteral (for example oral) or parenteral (for example intravenous) administration or topical application and do not react with active compounds of formula (I), for example water, vegetable oils, alcohols such as ethanol, isopropanol, or benzyl alcohol, 1,2-propanediol, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, lanolin, petroleum jelly, acetonitrile, dimethylformamide, and dimethylacetamide. In particular, pharmaceutical forms such as tablets, sugar-coated tablets, capsules, solutions, preferably oily or aqueous solutions, syrups, juices, or drops. Furthermore, suspensions or emulsions are used for oral and rectal administration. Mixtures of two or more vehicles can also be employed, for example, mixtures of two or more solvents, in particular also mixtures of at least one organic solvent with water. As additives or excipients, the pharmaceutical preparations can contain, for example, stabilizing and/or wetting agents, emulsifiers, salts, for example for affecting the osmotic pressure, lubricants, preservatives, colorants and flavorings, and/or aromatizers and buffer substances. If desired, they can also contain at least one further active compound, for example at least one vitamin. Compounds of formula (I) and/or their physiologically tolerable salts can also be lyophilized and the lyophilizates obtained can be used, for example, for the production of injection preparations. Liposomal preparations are also particularly suitable for topical application.
- The dose of at least one active compound of formula (I) to be administered and/or of a physiologically tolerable salt thereof in the case of use according to the invention depends on the individual case and is to be tailored to the individual conditions as customary for an optimal action. Thus it depends on the nature and severity of the illness to be treated, and on the sex, age, weight, and individual responsiveness of the human or animal to be treated, on the potency and duration of action of the compounds employed, on whether the therapy is acute or chronic or prophylaxis is carried out, or on whether further active compounds are administered in addition to compounds of formula (I). In general, a dose range for the treatment of the abovementioned syndromes in humans of approximately 0.1 mg to approximately 100 mg per kg per day on administration to an adult weighing about 75 kg is adequate to achieve the desired action. A dose range of 1 to 20 mg per kg per day (in each case mg per kg of body weight) is preferred. The daily dose can be administered here as an individual dose or can be divided into a number, for example, 1, 2, 3, or 4, of individual doses. It can also be administered continuously. If appropriate, depending upon individual behavior, it may be necessary to deviate upwards or downwards from the daily dose indicated. Pharmaceutical preparations normally contain 0.2 to 500 mg, preferably 1 to 300 mg, of at least one active compound of formula (I) and/or a physiologically tolerable salt thereof.
- The invention also very generally comprises the use of preferably nonpeptide compounds which bring about a stimulation of angiotensin (1-7) receptors which are located, for example, in the vessels (including endothelium), in the kidney, in the CNS, and in the heart, as pharmaceuticals, preferably for oral administration, or for use as substances which stimulate the production and/or release of the vasorelaxant, antithrombotic, and cardioprotective messengers cGMP and NO, and as pharmaceuticals for the treatment and/or prophylaxis of illnesses which are primarily or secondarily caused or at least partly caused by a reduced production and/or release of the vasorelaxant, antithrombotic, and cardioprotective messengers cGMP and NO, in particular for the treatment and prophylaxis of high blood pressure, cardiac hypertrophy, cardiac insufficiency, coronary heart diseases such as angina pectoris, cardiac infarct, vascular restenosis after angioplasty, cardiomyopathies, an endothelial dysfunction or endothelial damage, e.g., as a result of arteriosclerotic processes or in diabetes mellitus, and also of arterial and venous thrombosis.
- List of abbreviations:
abs. absolute cGMP cyclic 3′,5′-guanosine monophosphate CH2Cl2 dichloromethane DCI desorption chemical ionization DMF N,N-dimethylformamide EA ethyl acetate ESI electron spray ionization FAB fast atom bombardment M.p. melting point satd saturated h hour(s) min minute(s) NO nitrogen monoxide RT room temperature THF tetrahydrofuran - The invention is illustrated by the examples below, without being restricted to these.
-
- a) 4-Chloro-1-[(4-bromophenyl)methyl]-5-formyl-2-phenylimidazole
- A solution of 8.0 g (32.0 mmol) of 4-chloro-5-formyl-2-phenylimidazole (prepared according toChem. Pharm. Bull. 24 (1976) 960-969) and 5.3 g (32.0 mmol) of K2CO3 in 200 ml of abs. DMF was stirred at RT for 20 min. A solution of 9.6 g (32.0 mmol) of 4-bromobenzyl bromide in 200 ml of abs. DMF was then added dropwise and the reaction solution was stirred at RT for 6 h. It was concentrated in vacuo, and the residue obtained was taken up in EA, washed with water, 10% strength KHSO4, 10% strength NaHCO3, and satd sodium chloride solution, and dried over Na2SO4. Chromatographic purification on SiO2 using EA/heptane (1:4) as eluent of the residue which remained after stripping off the EA yielded 11.5 g of the title compound in the form of a beige solid.
- M.p.: 92-95° C.
- Rf (SiO2, EA/heptane 1:4)=0.24
- MS (ESI): m/e=375/377 [M+H]+
- b) 4-Chloro-5-formyl-2-phenyl-1-[[4-[2-(N-tert-butylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole
- A solution of 7.2 g (22.6 mmol) of 5-isobutyl-2-[(N-tert-butyl)sulfonamido]-thiophene-3-boronic acid (disclosed in EP-A 512 675) in 125 ml of ethanol was added dropwise at RT to a solution of 8.5 g (22.6 mmol) of the compound from Example 1a) and 800 mg of tetrakistriphenylphosphinepalladium(0) in 100 ml of toluene. 26 ml of a 2 M Cs2CO3 solution were added and the resultant reaction solution was stirred at reflux for 5 h. It was concentrated to dryness and the residue that remained was taken up in EA/water (1:1). The organic phase was separated off, washed with water, dried over Na2SO4, and concentrated. Chromatographic purification of the residue on SiO2 using EA/heptane (1:4) as eluent afforded 6.7 g of the title compound as a white solid.
- M.p.: 104-105° C.
- Rf (SiO2, EA/heptane 1:2)=0.26
- MS (ESI): m/e=570 [M+H]+
- c) 4-Chloro-5-formyl-2-phenyl-1-[[4-[2-sulfonamido-5-isobutyl-3-thienyl]phenyl]-methyl]imidazole
- A solution of 3.3 g (5.96 mmol) of the compound from Example lb) and 3.5 ml (5.96 mmol) of anisole in 33 ml of trifluoroacetic acid was stirred at RT for 48 h. It was concentrated to dryness in vacuo and the residue was taken up in EA. The EA solution was washed with water, dried over Na2SO4, and concentrated. After chromatographic purification of the residue on SiO2 using EA/heptane (1:1) as eluent, 1.52 g of the desired compound was obtained, in the form of a slowly crystallizing solid.
- M.p.: 118-120° C.
- Rf (SiO2, EA/heptane 1:1)=0.32
- MS (ESI): m/e=515 [M+H]+
- d) 4-Chloro-5-formyl-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole
- A solution of 100 mg (0.19 mmol) of the compound from Example 1c) in 1.7 ml of abs. pyridine was treated successively with 3 mg (0.02 mmol) of 4-pyrrolidinopyridine and 252 μl (0.19 mmol) of butyl chloroformate in an argon atmosphere. The reaction solution was stirred at RT for 24 h. 0.7 ml of methanol were then added, the solution was concentrated to dryness, and the residue was taken up in EA. The EA solution was then washed with a 10% strength citric acid solution, water, and a satd sodium chloride solution, dried over Na2SO4, and concentrated. Chromatographic purification on SiO2 using EA/heptane (1:1) of the residue obtained after stripping off the solvent finally yielded 85 mg of the title compound in the form of an amorphous solid.
- Rf (SiO2, EA/heptane 1:1)=0.15
- MS (FAB): m/e=614 [M+H]+
-
- a) 5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-sulfonamido-5-isobutyl-3-thienyl]-phenyl]methyl]imidazole
- A solution of 850 mg (1.65 mmol) of the compound from Example Ic) in 25 ml of methanol was treated with 665 mg (16.53 mmol) of NaOH and stirred under reflux for 20 h. The reaction solution was concentrated, the residue was taken up in 60 ml EA/water (1:1), the pH of the solution was adjusted to 6 by addition of 1 N hydrochloric acid, and the organic phase was separated off. The aqueous phase was extracted twice with EA and the combined organic phases were dried over Na2SO4. Chromatographic purification on SiO2 using EA/heptane (1:1) as eluent of the residue obtained after stripping off the EA afforded 690 mg of the title compound in the form of a yellow, amorphous foam.
- Rf (SiO2, EA/heptane 1:1)=0.23
- MS (FAB): m/e=510 [M+H]+
- b) 5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole
- The title compound was prepared by reaction of the compound from Example 2a) with butyl chloroformate according to the process mentioned in Example 1d). In this case, starting from 106 mg (0.21 mmol) of the compound from Example 2a) after chromatographic purification on SiO2 using EA/heptane (1:1) as eluent, 75 mg of the desired compound was obtained as an amorphous foam.
- Rf (SiO2, EA/heptane 1:1)=0.18
- MS (ESI): m/e=610 [M+H]+
-
- The title compound was prepared by reaction of the compound from Example 2a) with propyl chloroformate according to the process mentioned in Example 1d). In this case, starting from 60 mg (0.12 mmol) of the compound from Example 2a) after chromatographic purification on SiO2 using EA/heptane (1:1) as eluent, 61 mg of the title compound were obtained as an amorphous foam.
- Rf (SiO2, EA/heptane 1:1)=0.13
- MS (ESI): m/e=596 [M+H]+
-
- The title compound was prepared by reaction of the compound from Example 2a) with ethyl chloroformate according to the process mentioned in Example 1d). In this case, starting from 60 mg (0.12 mmol) of the compound from Example 2a) after chromatographic purification on SiO2 using EA/heptane (1:1) as eluent, 55 mg of the title compound were obtained as an amorphous foam.
- Rf (SiO2, EA/heptane 1:1)=0.10
- MS (ESI): m/e=582 [M+H]+
-
- A solution of 80 mg (0.16 mmol) of the compound from Example 2a), 43.3 mg (0.32 mmol) of K2CO3, and 8.3 mg of dimethylaminopyridine in 6 ml of diethylene glycol dimethyl ether was treated with 16.8 11 (0.16 mmol) of dimethyl dicarbonate and then stirred under reflux for 1.5 h. The reaction solution was concentrated to dryness and the residue was taken up in a solution of EA and a 10% strength KH2PO4 solution (1:1). The organic phase was separated off, washed twice with a 10% strength KH2PO4 solution, dried over Na2SO4, and concentrated. Chromatographic purification of the residue on SiO2 using EA/heptane (2:1) as eluent, yielded 55 mg of the title compound in the form of an amorphous foam.
- Rf (SiO2, EA/heptane 4:1)=0.23
- MS (ESI): m/e=568 [M+H]+
-
- A solution of 60 mg (0.12 mmol) of the compound from Example 2a) in 2 ml of abs. DMF was treated successively with 48 mg (0.35 mmol) of K2CO3 and 13.2 μl (0.12 mmol) of n-butyl isocyanate and then stirred under reflux for 3 h. After cooling, 15 ml of a 10% strength KH2PO4 solution were added to the reaction solution and the solution obtained was extracted a number of times with EA. The combined organic phases were dried over Na2SO4 and concentrated. The residue obtained was treated with EA/diisopropyl ether and the precipitate deposited was filtered off with suction. Drying of the precipitate in vacuo afforded 55 mg of the title compound.
- M.p.: 131-133° C.
- Rf (SiO2, EA/heptane 4:1)=0.30
- MS (FAB): m/e=609 [M+H]+
-
- The title compound was prepared by reaction of the compound from Example 2a) with ethyl isocyanate according to the process mentioned in Example 6). In this case, starting from 60 mg (0.12 mmol) of the compound from Example 2a), 46 mg of the title compound were obtained.
- M.p.: 105-106° C.
- Rf (SiO2, EA/heptane 4:1)=0.30
- MS (ESI): m/e=581 [M+H]+
-
- A solution of 80 mg (0.16 mmol) of the compound from Example 2a) in 1.5 ml of DMSO was treated with 30.4 mg (0.17 mmol) of N-methyl-2,2,2-trichloroacetamide and-19.1 mg (0.47 mmol) of powdered NaOH and stirred at 80° C. for 1 h. The reaction solution was cooled, treated with ice, and the pH was adjusted to 4 by addition of 2 N hydrochloric acid. The precipitate that deposited in the course of this was filtered off with suction, washed with water, dried, and purified by chromatography on SiO2 using EA/heptane (2:1) as eluent. 62 mg of the title compound were obtained in the form of a white solid.
- M.p.: 102-103° C.
- Rf (SiO2, EA/heptane 4:1)=0.14
- MS (ESI): m/e=567 [M+H]+
-
- a) 5-Formyl-4-methoxyethoxy-2-phenyl-1-[[4-[2-sulfonamido-5-isobutyl-3-thienyl]phenyl]methyl]imidazole
- A solution of 200 mg (0.38 mmol) of the compound from Example 1 c) in 7.8 ml of ethylene glycol monomethyl ether was treated with 155 mg (3.89 mmol) of powdered NaOH in an argon atmosphere and then stirred at 80° C. for 5 h. It was concentrated to dryness and the residue obtained was taken up in a saturated NaHCO3 solution and EA. The EA phase was separated off and the aqueous solution was extracted several times with EA. The organic phases were combined, dried over Na2SO4, and concentrated. Chromatographic purification on SiO2 using EA/heptane (1:1) of the remaining residue yielded 140 mg of the title compound as a pale yellow-colored solid.
- M.p.: 91-92° C.
- Rf (SiO2, EA/heptane 1: 1)=0.12
- MS (FAB): m/e=554 [M+H]+
- b) 5-Formyl-4-methoxyethoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole
- The title compound was prepared by reaction of the compound from Example 9a) with butyl chloroformate according to the process mentioned in Example 1d). In this case, starting from 70 mg (0.13 mmol) of the compound from Example 9a) after chromatographic purification on SiO2 using EA/heptane (1:1) as eluent, 78 mg of the title compound was obtained as an amorphous foam.
- Rf (SiO2, EA/heptane 1:1)=0.07
- MS (ESI): m/e=654 [M+H]+
-
- a) 4-Chloro-1-[(4-bromo-2-chlorophenyl)methyl]-5-formyl-2-phenyl-imidazole
- The title compound was prepared by reaction of 4-chloro-5-formyl-2-phenylimidazole with 4-bromo-2-chlorobenzyl bromide according to the process mentioned in Example la). In this case, starting from 2.0 g (9.68 mmol) of 4-chloro-5-formyl-2-phenylimidazole, 2.6 g of the title compound was obtained.
- Rf (SiO2, EA/heptane 1:2)=0.56
- MS (DCI): m/e=409/411 [M+H]+
- b) 4-Chloro-5-formyl-2-phenyl-1-[[4-[2-(N-tert-butylsulfonamido)-5-isobutyl-3-thienyl]-2-chlorophenyl]methyl]imidazole
- The title compound was prepared by reaction of the compound from Example 10a) and 5-isobutyl-2-[(N-tert-butyl)sulfonamido]thiophene-3-boronic acid according to the process mentioned in Example 1b). In this case, starting from 2.0 g (4.88 mmol) of the compound from Example 10a), 1.2 g of the title compound were obtained in the form of a pale brown oil.
- Rf (SiO2, EA/heptane 1:2)=0.47
- MS (FAB): m/e=604 [M+H]+
- c) 4-Chloro-5-formyl-2-phenyl-1-[[4-[2-sulfonamido-5-isobutyl-3-thienyl]-2-chlorophenyl]methyl]imidazole
- The title compound was prepared from the compound from Example 10b) according to the process mentioned in Example 1c). Starting from 1.2 g (1.99 mmol) of the compound from Example 10b), 606 mg of the title compound was obtained as an amorphous, yellow foam.
- Rf (SiO2, EA/heptane 1:2)=0.32
- MS (FAB): m/e=548 [M+H]+
- d) 5-Formyl-2-methoxy-2-phenyl-1-[[4-[2-sulfonamido-5-isobutyl-3-thienyl]-2-chlorophenyl]methyl]imidazole
- The title compound was prepared from the compound from Example 10c) according to the process mentioned in Example 2a). In this case, starting from 400 mg (0.73 mmol) of the compound from Example 10c), 280 mg of the title compound was obtained in the form of a yellow, amorphous foam.
- M.p.: 60° C. (softening)
- Rf (SiO2, EA/heptane 1:2)=0.20
- MS (ESI): m/e=544 [M+H]+
- e) 5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]-2-chlorophenyl]methyl]imidazole
- The title compound was obtained from the reaction of the compound from Example 10d) with butyl chloroformate according to the process mentioned in Example 1d). Starting from 200 mg (0.37 mmol) of the compound from Example 10d), 167 mg of the desired compound were obtained in the form of a beige solid.
- M.p.: 58° C. (softening)
- Rf (SiO2, EA/heptane 1:1)=0.45
- MS (ESI): m/e=644 [M+H]+
-
- The title compound was obtained from the reaction of the compound from Example 10d) with ethyl isocyanate according to the process described in Example 7). In this case, starting from 74 mg (0.14 mmol) of the compound from Example 10d) after chromatographic purification on SiO2 using CH2Cl2/methanol (20:1) as eluent, 35 mg of the title compound was obtained in the form of a white solid.
- M.p.: 83° C. (softening)
- Rf(SiO2, EA/heptane 1:1)=0.30
- MS (ESI): m/e=614 [M+H]+
-
- a) 4-Chloro-5-formyl-2-phenyl-1-[[4-[2-(N-tert-butylsulfonamido)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole
- The title compound was prepared by the reaction of the compound from Example la) with 5-n-propyl-2-[(N-tert-butyl)sulfonamido]thiophene-3-boronic acid (disclosed in EP-A 512 675) according to the process mentioned in Example lb). In this case, starting from 4.8 g (13.1 mmol) of the compound from Example la) after chromatographic purification on SiO2 using EA/heptane (1:3) as eluent, 2.9 g of the title compound were obtained in the form of a white solid.
- M.p.: 140° C.
- Rf (SiO2, EA/heptane 1:2)=0.30
- MS (FAB): m/e=556 [M+H]+
- b) 4-Chloro-5-formyl-2-phenyl-1-[[4-[2-sulfonamido-5-n-propyl-3-thienyl]-phenyl]methyl]imidazole
- The title compound was prepared from the compound from Example 12a) according to the process mentioned in Example 1c). Starting from 1.9 g (3.56 mmol) of the compound from Example 12a), after chromatographic purification on SiO2 using EA/heptane (1:2) as eluent, 1.1 9 of the title compound was obtained as a white solid.
- M.p.: 93-95° C.
- Rf (SiO2, EA/heptane 1:2)=0.18
- MS (ESI): m/e=500 [M+H]+
- c) 4-Chloro-5-formyl-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole
- The title compound was prepared by reaction of the compound from Example 12b) with butyl chloroformate according to the process mentioned in Example 1d). In this case, starting from 100 mg (0.20 mmol) of the compound from Example 12b), after chromatographic purification on SiO2 using EA/heptane (1:1) as eluent, 90 mg of the title compound were obtained.
- Rf (SiO2, EA/heptane 1:1)=0.14
- MS (ESI): m/e=600 [M+H]+
-
- a) 5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-sulfonamido-5-n-propyl-3-thienyl]-phenyl]methyl]imidazole
- The title compound was prepared by reaction of the compound from Example 12b) according to the process mentioned in Example 2a). In this case, starting from 850 mg (1.70 mmol) of the compound from Example 12b), after chromatographic purification on SiO2 using EA/heptane (1:2) as eluent, 460 mg of the title compound was obtained in the form of a white solid.
- M.p.: 85-86° C.
- Rf (SiO2, EA/heptane 1:1)=0.22
- MS (ESI): m/e=496 [M+H]+
- b) 5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole
- The title compound was prepared by reaction of the compound from Example 13a) with butyl chloroformate according to the process mentioned in Example 1d). In this case, starting from 60 mg (0.12 mmol) of the compound from Example 13a), after chromatographic purification on SiO2 using EA/heptane (1:1) as eluent, 52 mg of the title compound were obtained.
- Rf (SiO2, EA/heptane 1:1)=0.18
- MS (ESI): m/e=596 [M+H]+
-
- The title compound was prepared by reaction of the compound from Example 13b) with dimethyl dicarbonate according to the process mentioned in Example 5). Starting from 75 mg (0.15 mmol) of the compound from Example 13b), after chromatography on SiO2 using EA/heptane (2:1) as eluent, 66 mg of the title compound were obtained as an amorphous solid.
- Rf (SiO2, EA/heptane 4:1)=0.18
- MS (ESI): m/e=554 [M+H]+
-
- The title compound was prepared by reaction of the compound from Example 13b) with n-butyl isocyanate according to the process mentioned in Example 6). Starting from 59 mg (0.12 mmol) of the compound from Example 13b), after chromatography on SiO2 using EA/heptane (1:1) as eluent, 54 mg of the title compound were obtained as an amorphous solid.
- Rf (SiO2, EA/heptane 4:1)=0.25
- MS (ESI): m/e=595 [M+H]+
-
- The title compound was prepared by reaction of the compound from Example 13b) with N-methyl-2,2,2-trichloroacetamide according to the process mentioned in Example 8). Starting from 70 mg (0.14 mmol) of the compound from Example 13b), after chromatography on SiO2 using EA/heptane (2:1) as eluent, 55 mg of the title compound were obtained as an amorphous solid.
- Rf (SiO2, EA/heptane 4:1)=0.15
- MS (ESI): m/e=553 [M+H]+
-
- 220 mg (0.38 mmol) of the compound from Example 7 were treated with 3.7 ml of a freshly prepared 0.1 molar sodium methoxide solution and the resulting solution was stirred at RT for 1 h. The reaction solution was concentrated to dryness and the residue obtained was dissolved in 4 ml of n-butyl acetate with slight warming. The precipitate crystallizing out after storage in a refrigerator for 3 days was filtered off with suction and washed with a little cold n-butyl acetate. Drying under high vacuum finally yielded 120 mg of the desired sodium salt.
- M.p.: 170° C.
- MS (ESI): m/e=603 [M+H]+
-
- A solution of 500 mg (0.86 mmol) of the compound from Example 7 and 125.8 mg (0.86 mmol) of L-lysine in 100 ml of ethanol and 25 ml of water was stirred at RT for 2 h. It was then concentrated to dryness, the residue was taken up in 30 ml of water, and the solution obtained was freeze-dried. 200 mg of the amorphous residue obtained were dissolved in 10 ml of hot toluene. After storage in a refrigerator for several days, the precipitate that crystallized out was filtered off and dried under high vacuum. 68 mg of the title compound was obtained as pale yellow-colored crystals.
- M.p.: 180° C.
- MS (ESI): m/e=727 [M+H]+
-
- A solution of 300 mg (0.516 mmol) of the compound from Example 7 and 62.6 mg (0.516 mmol) of tris(hydroxymethyl)aminomethane in 75 ml of ethanol and 15 ml of water was stirred at RT for 2 h. It was then concentrated to dryness, the residue was taken up in water, and the solution obtained was freeze-dried. The amorphous residue obtained was dissolved with heating in 30 ml n-butyl acetate. After storage in a refrigerator for several days, the precipitate that crystallized out was filtered off and dried under high vacuum. 120 mg of the title compound was obtained as pale yellow-colored crystals.
- M.p.: 144-145° C.
- MS (ESI): m/e=702 [M+H]+
- The affinity of compounds of formula (I) for angiotensin (1-7) binding sites, and their agonistic properties on endothelial cells, were demonstrated in the following assays (tests 1 and 2):
- Test 1: Binding Assay
- The affinity of compounds of formula (I) for angiotensin (1-7) receptors was measured by ligand displacement experiments on membrane preparations of primary bovine aorta endothelial cells, such as are also described, for example, in Hypertension 29 (part 2) (1997) 388-393.
- a) Membrane Preparation:
- Following obtainment of endothelial cells from bovine aortas (test 1, a), the cells were cultured in 75 cm2 culture bottles (Becton Dickinson, Heidelberg) until achieving confluence. The cells were then taken up with ice-cold phosphate/NaCl/EDTA buffer (50 mmol/l NaHPO4, 0.15 mol/l NaCl, 5 mmol/l EDTA, pH 7.2), detached with a rubber scraper, and centrifuged (1500×g, 5 min). The resulting cell pellet was frozen (−80° C.) for later membrane preparation. The thawed cell pellet was homogenized (glass/Teflon Potter, 1000 rpm, 10 strokes) in ice-cold phosphate/NaCl/EDTA buffer. Membrane isolation was carried out by subsequent centrifugation (30,000×g, 20 min) of the cell homogenate. The cell pellet thus obtained was resuspended in modified HEPES buffer (10 nmol/l HEPES, 0.1 mol/l NaCl, 5 mmol/l MgCl2, pH 7.4) with addition of 0.2% bovine serum albumin and a protease inhibitor cocktail (COMPLETE®, Boehringer Mannheim). After subsequent protein determination (according to Lowry) of the membrane suspension, this was used immediately for the ligand binding test.
- b) Binding Experiments:
- The tests were carried out on 96-well opaque plates that are equipped with Durapore filters (0.65 μm pore size; Millipore, Eschborn). Before the beginning of the test, the filters were pretreated with 1% bovine serum albumin for 30 min in order to minimize the nonspecific binding of the radioactive ligand and of the cold substances to the filter material. The incubation was carried out in a total volume of 200 μl: 50 μl of125I-ANG (1-7), 20 μl of cold, nonradioactive ANG (1-7) or test substances of formula (I), 30 μl of buffer, and 100 μl of membranes (20 μg of protein). The binding reaction was started by addition of the radioactive ligand. The incubation of the samples was carried out with continuous shaking at RT for 45 min. The binding reaction was ended by means of vacuum filtration (−20 kPa vacuum; multiscreen filtration system, Millipore, Eschborn). In order to completely remove the non-membrane-bound, free radioactivity, the filters were washed in vacuo twice with 250 μl of ice-cold phosphate/NaCl/EDTA buffer (50 mmol/l of NaHPO4, 0.15 mol/l of NaCl, 5 mmol/l of EDTA, pH 7.2), and then dried. The radioactive content on the dried filters was determined by means of a gamma counter.
- For the competition experiments (determination of “individual values” or IC50 values), a concentration of 7.5 to 10 nmol/l of 125I-ANG (1-7) (specific activity 1500-2100 mCi/mg) was employed, with and without increasing concentrations of the test substances of formula (I). The nonspecific binding was in each case measured in the presence of 10 μmol/l of nonradioactive ANG (1-7).
- c) Results:
Example IC50 (nM) 2a 20 2b 30 4 5 7 20 - The results confirm the high affinity of compounds of formula (I) for the angiotensin (1-7) receptor on endothelial cells.
- With respect to ANGII receptors of the AT1 and AT2 type, compounds of formula (I) in this case have no or only negligible (>10−6 M) affinity.
- Test 2: Functional Assay
- As a marker of the production and release of NO in endothelial cells, the stimulating action of compounds of formula (I) on the production of intracellular cGMP was measured on primary-cultured endothelial cells of bovine aortas, such as is described, for example, inJ. Pharmacol. Exp. Ther. 262 (1992) 729-733.
- a) Cell Cultures:
- After enzymatic digestion (Dispase II; Boehringer, Mannheim) of the endothelial cells from the bovine aorta, the endothelial cells were taken up in culture medium (Dulbecco's modified Eagle's Ham's F 12 Medium 1:1 with penicillin (10 U/l), streptomycin (10 μg/l), L-glutamine (1 mmol/l), glutathione, and L-(+)-ascorbic acid (in each case 5 mg/l) and heat-inactivated fetal calf serum (20%)), washed once (centrifugation at 170×g, 10 min), and resuspended in culture medium. The cell suspension thus obtained was inoculated (˜250 μg of protein or 3×10−5 cells per well) into 6-well plates (Nunc Intermed, Wiesbaden), made up with culture medium, and kept at 37° C. in an incubator which was humidified and aerated with 95% O2/5% CO2.
- b) cGMP Determinations:
- After reaching confluence (6-8 days after inoculation), the culture medium was removed and the cell monolayer was washed twice with warm HEPES/Tyrode's solution. The cells were then pre-incubated for 15 min at 37° C. in HEPES/Tyrode's solution which contains IBMX (3-isobutyl-1-methylxanthine, 10−4 mol/l, Serva, Heidelberg). The incubation was started by addition of SOD (superoxide dismutase from bovine erythrocytes, 3×10−7mol/l, Serva, Heidelberg) and the test substances of formula (I) in the given concentrations. After the appropriate incubation time, the incubation medium was aspirated, and the remaining cells were immediately extracted into 1 N formic acid-acetone (v/v, 15:85) and scraped off. The suspension obtained was ultrasonicated (10 sec) and then centrifuged off (3000×g, 10 min). For the determination of cGMP by means of radioimmunoassay (New England Nuclear, Boston, Mass.), the supernatant was lyophilized and taken up in sodium acetate buffer (0.05 mol/l; pH 6.2). The content (pmol) of intracellular cGMP was related to mg of cell protein.
- c) Results:
Example EC50 (nM) 2a 0.5 2b 0.3 4 0.1 7 0.5 - The results confirm the agonistic action of compounds of formula (I) on angiotensin (1-7) receptors.
- The action of the compound according to the invention on the production of cGMP as a marker of the NO synthesis and release is not affected here by preincubation with an angiotensin II receptor antagonist either of the AT1 subtype such as EXP3174, or of the AT2 subtype such as PD 123,319. In contrast to this, the described stimulating effect of the compound according to the invention on the cGMP is inhibited by preincubation with a selective antagonist of angiotensin (1-7) receptors, [D-Ala7]-angiotensin (1-7), which is described, for example, in Brain Res. Bull. 35 (1994) 293-298, which confirms the specificity of this functional effect.
- The action of compounds of formula (I) on the heart was demonstrated in the model of isolated, working rat hearts (test 3) which is described, for example, inJ. Cardiovasc. Pharrmacol. 8 (Suppl. 10) (1986) S91-S99.
- Test 3: Isolated, Working Rat Hearts
- a) Method:
- Isolated hearts of Wistar-Kyoto rats (280-300 g body weight) are perfused with a constant perfusion pressure of 60 mmHg according to the method of Langendorff using an oxygen-saturated (95% O2, 5% CO2), nonrecirculating, modified Krebs-Henseleit buffer solution (118 mmol/l of NaCl, 4.7 mmol/l of KCl, 2.5 mmol/l of CaCl2, 1.6 mmol/l of MgSO41 24.9 mmol/l of NaHCO3, 1.2 mmol/l of KH2PO4, 5.5 mmol/l of glucose, and 2.0 mmol/l of sodium pyruvate). For the measurement of the coronary flow, a catheter having an electromagnetic measuring head placed in the pulmonary artery was used. After a 15-minute equilibration period, the heart is converted into the working mode, in which a preload of 15 mmHg and an afterload of 60 mmHg is set. The working load of the heart remains constant during the entire test time of 90 minutes. Flow and pressure signals for the analysis are recorded by means of a PLUGSYS measuring system (Hugo Sachs Elektronik). The analysis of the data is carried out at a collection frequency of 500 Hz, averaged every 2 seconds, using the software Aquire Plus VI.21f (PO-NE-MAH).
- b) Results:
- On perfusion of the hearts (n=4) at a concentration of 10−6 mol/l of the compound from Example 2, the following values for the coronary flow were determined in comparison to control hearts (n=4):
- 1. Treated hearts:
Coronary flow (ml/min) Time (min) 8.92 ± 0.68 0 11.29 ± 0.90 5 12.17 ± 0.74 10 12.22 ± 0.10 15 - 2. Control hearts:
Coronary flow (ml/min) Time (min) 8.98 ± 0.59 0 8.94 ± 0.52 5 9.04 ± 0.70 10 8.91 ± 0.44 15 - The heart rate remained unchanged in both groups during the entire experiment.
- This significant increase in the coronary flow in isolated, working rat hearts confirms the cardioprotective action of compounds of formula (I).
- The action of compounds of formula (I) on collagen-induced platelet aggregation was investigated in human platelet-rich plasma, which is described, for example, in G. V. Born et al.,Nature (1962).
- Test 4:
- a) Method:
- Human platelet-rich plasma (PRP) from 6 blood donors was incubated with the test compound at 37° C. for 20 min, then activated with collagen, and the maximal aggregation of the platelets was quantified in % via light transmission.
- b) Result:
- On incubation of the platelet-rich plasma with 30 μM of the compound from Example 2, the following values were determined for platelet aggregation (n=6):
- Collagen (=maximal aggregation): 92±2.7% aggregation
- Collagen+30 μM of the compound from Example 2: 52±5.7% aggregation
- This significant inhibition of the platelet aggregation of human platelet-rich plasma confirms the antithrombotic action of compounds of formula (I).
- The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are to be considered in all respects as illustrative only and not restrictive. The scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope.
Claims (20)
Priority Applications (2)
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US09/809,008 US6429222B2 (en) | 1999-05-05 | 2001-03-16 | 1-(p-thienylbenzyl)imidazoles as agonists of angiotensin (1-7) receptors, processes for their preparation, their use, and pharmaceutical preparations comprising them |
US10/013,459 US20020077344A1 (en) | 1999-05-05 | 2001-12-13 | 1-(p-thienylbenzyl)imidazoles as agonists of angiotensin (1-7) receptors, processes for their preparation, their use, and pharmaceutical prepartions comprising them |
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DE1999120815 DE19920815A1 (en) | 1999-05-05 | 1999-05-05 | New sulfonamido substituted (thienyl-benzyl)-imidazole derivatives are angiotensin-(1-7) receptor agonists useful in treatment of cardiovascular and endothelial disorders |
DE19920815.8 | 1999-05-05 | ||
DE19920815 | 1999-05-05 | ||
DE19961686 | 1999-12-21 | ||
DE1999161686 DE19961686A1 (en) | 1999-12-21 | 1999-12-21 | New 1-(4-(2-sulfamoyl-3-thienyl)-imidazoles, are potent angiotensin (1-7) receptor agonists useful e.g. for treating hypertension, angina pectoris, cardiac infarction or thrombosis |
US09/564,544 US6235766B1 (en) | 1999-05-05 | 2000-05-04 | 1-(p-thienylbenzyl)imidazoles as agonists of angiotensin (1-7) receptors, processes for their preparation, their use, and pharmaceutical preparations comprising them |
US09/809,008 US6429222B2 (en) | 1999-05-05 | 2001-03-16 | 1-(p-thienylbenzyl)imidazoles as agonists of angiotensin (1-7) receptors, processes for their preparation, their use, and pharmaceutical preparations comprising them |
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US20020119504A1 (en) * | 1999-03-11 | 2002-08-29 | Millennium Pharmaceuticals, Inc. | Methods of identifying agents which bind GPR-9-6 |
US20030203834A1 (en) * | 2002-02-27 | 2003-10-30 | Tallant E. Ann | Angiotensin-(1-7) and angiotensin-(1-7) agonists for inhibition of cancer cell growth |
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FR2716882B1 (en) * | 1994-03-04 | 1996-04-05 | Roussel Uclaf | Use of imidazole derivatives for the treatment of conditions involving the AT1 and AT2 receptors of Angiotensin, some of these products, their preparation, pharmaceutical compositions. |
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2000
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- 2000-04-29 EP EP00929466A patent/EP1185527B1/en not_active Expired - Lifetime
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- 2000-04-29 TR TR2001/03171T patent/TR200103171T2/en unknown
- 2000-04-29 JP JP2000616200A patent/JP2002544130A/en active Pending
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- 2000-04-29 WO PCT/EP2000/003891 patent/WO2000068226A1/en not_active Application Discontinuation
- 2000-04-29 CA CA002373010A patent/CA2373010A1/en not_active Abandoned
- 2000-04-29 EE EEP200100572A patent/EE200100572A/en unknown
- 2000-04-29 DE DE50010835T patent/DE50010835D1/en not_active Expired - Lifetime
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- 2000-04-29 RU RU2001132724/04A patent/RU2247121C2/en not_active IP Right Cessation
- 2000-04-29 AU AU47536/00A patent/AU775244B2/en not_active Ceased
- 2000-04-29 NZ NZ515242A patent/NZ515242A/en unknown
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- 2000-04-29 CN CNB008067996A patent/CN1158279C/en not_active Expired - Fee Related
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- 2000-04-29 BR BR0010248-2A patent/BR0010248A/en not_active IP Right Cessation
- 2000-05-03 AR ARP000102117A patent/AR023837A1/en unknown
- 2000-05-04 US US09/564,544 patent/US6235766B1/en not_active Expired - Lifetime
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2001
- 2001-03-16 US US09/809,008 patent/US6429222B2/en not_active Expired - Lifetime
- 2001-10-30 NO NO20015309A patent/NO20015309L/en not_active Application Discontinuation
- 2001-11-05 HR HR20010814A patent/HRP20010814A2/en not_active Application Discontinuation
- 2001-12-13 US US10/013,459 patent/US20020077344A1/en not_active Abandoned
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Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
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US20020119504A1 (en) * | 1999-03-11 | 2002-08-29 | Millennium Pharmaceuticals, Inc. | Methods of identifying agents which bind GPR-9-6 |
US20030203834A1 (en) * | 2002-02-27 | 2003-10-30 | Tallant E. Ann | Angiotensin-(1-7) and angiotensin-(1-7) agonists for inhibition of cancer cell growth |
EP1485116A2 (en) * | 2002-02-27 | 2004-12-15 | Wake Forest University | Angiotensin-(1-7) and angiotensin-(1-7) agonists for inhibition of cancer cell growth |
EP1485116A4 (en) * | 2002-02-27 | 2006-06-07 | Univ Wake Forest | Angiotensin-(1-7) and angiotensin-(1-7) agonists for inhibition of cancer cell growth |
US7375073B2 (en) | 2002-02-27 | 2008-05-20 | Wake Forest University Health Sciences | Angiotensin-(1-7) and angiotensin-(1-7) agonists for inhibition of cancer cell growth |
WO2013192238A2 (en) * | 2012-06-18 | 2013-12-27 | Tarix Pharmaceuticals Ltd. | Compositions and methods for treatment of diabetes |
WO2013192238A3 (en) * | 2012-06-18 | 2014-04-03 | Tarix Pharmaceuticals Ltd. | Compositions and methods for treatment of diabetes |
US9511055B2 (en) | 2012-10-02 | 2016-12-06 | Tarix Pharmaceuticals Ltd. | Angiotensin in treating brain conditions |
US9333233B2 (en) | 2014-02-25 | 2016-05-10 | Tarix Pharmaceuticals Ltd. | Methods and compositions for the delayed treatment of stroke |
Also Published As
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HRP20010814A2 (en) | 2003-02-28 |
HUP0201311A3 (en) | 2003-03-28 |
AR023837A1 (en) | 2002-09-04 |
WO2000068226A1 (en) | 2000-11-16 |
EP1185527A1 (en) | 2002-03-13 |
HK1045519A1 (en) | 2002-11-29 |
KR20020012207A (en) | 2002-02-15 |
IL146198A0 (en) | 2002-07-25 |
ATE300535T1 (en) | 2005-08-15 |
US6235766B1 (en) | 2001-05-22 |
RU2247121C2 (en) | 2005-02-27 |
HK1045519B (en) | 2005-04-22 |
JP2002544130A (en) | 2002-12-24 |
TR200103171T2 (en) | 2002-06-21 |
US20020077344A1 (en) | 2002-06-20 |
AU775244B2 (en) | 2004-07-22 |
EE200100572A (en) | 2003-02-17 |
NO20015309D0 (en) | 2001-10-30 |
AU4753600A (en) | 2000-11-21 |
DE50010835D1 (en) | 2005-09-01 |
CN1349530A (en) | 2002-05-15 |
NZ515242A (en) | 2003-11-28 |
US6429222B2 (en) | 2002-08-06 |
BR0010248A (en) | 2002-02-13 |
HUP0201311A2 (en) | 2002-10-28 |
YU78601A (en) | 2005-07-19 |
PL351609A1 (en) | 2003-05-05 |
CN1158279C (en) | 2004-07-21 |
SK15942001A3 (en) | 2002-04-04 |
NO20015309L (en) | 2001-12-28 |
CZ20013907A3 (en) | 2002-02-13 |
EP1185527B1 (en) | 2005-07-27 |
CA2373010A1 (en) | 2000-11-16 |
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