AU2003250821B8 - Fluorinated cycloalkyl-derivatised benzoylguanidines and their use as a medicament - Google Patents
Fluorinated cycloalkyl-derivatised benzoylguanidines and their use as a medicament Download PDFInfo
- Publication number
- AU2003250821B8 AU2003250821B8 AU2003250821A AU2003250821A AU2003250821B8 AU 2003250821 B8 AU2003250821 B8 AU 2003250821B8 AU 2003250821 A AU2003250821 A AU 2003250821A AU 2003250821 A AU2003250821 A AU 2003250821A AU 2003250821 B8 AU2003250821 B8 AU 2003250821B8
- Authority
- AU
- Australia
- Prior art keywords
- treatment
- hydrogen
- disorders
- formula
- prophylaxis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- 239000003814 drug Substances 0.000 title claims description 60
- AJDQRQQNNLZLPM-UHFFFAOYSA-N n-(diaminomethylidene)benzamide Chemical class NC(N)=NC(=O)C1=CC=CC=C1 AJDQRQQNNLZLPM-UHFFFAOYSA-N 0.000 title claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 76
- 238000011282 treatment Methods 0.000 claims description 61
- 150000003839 salts Chemical class 0.000 claims description 51
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 49
- 239000001257 hydrogen Substances 0.000 claims description 46
- 229910052739 hydrogen Inorganic materials 0.000 claims description 46
- 208000035475 disorder Diseases 0.000 claims description 39
- 150000002431 hydrogen Chemical class 0.000 claims description 36
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 23
- 238000011321 prophylaxis Methods 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 125000004432 carbon atom Chemical group C* 0.000 claims description 20
- 239000004480 active ingredient Substances 0.000 claims description 19
- 210000000056 organ Anatomy 0.000 claims description 18
- 206010019280 Heart failures Diseases 0.000 claims description 14
- 230000003176 fibrotic effect Effects 0.000 claims description 13
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 13
- 230000000302 ischemic effect Effects 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 206010028980 Neoplasm Diseases 0.000 claims description 10
- 230000006378 damage Effects 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 10
- 201000001320 Atherosclerosis Diseases 0.000 claims description 9
- 206010048554 Endothelial dysfunction Diseases 0.000 claims description 9
- 230000001154 acute effect Effects 0.000 claims description 9
- 230000032683 aging Effects 0.000 claims description 9
- 206010012601 diabetes mellitus Diseases 0.000 claims description 9
- 230000008694 endothelial dysfunction Effects 0.000 claims description 9
- 210000001519 tissue Anatomy 0.000 claims description 9
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 8
- 210000003169 central nervous system Anatomy 0.000 claims description 8
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 8
- 201000011510 cancer Diseases 0.000 claims description 7
- 230000001472 cytotoxic effect Effects 0.000 claims description 7
- 210000002307 prostate Anatomy 0.000 claims description 7
- 230000009467 reduction Effects 0.000 claims description 7
- 230000010410 reperfusion Effects 0.000 claims description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 230000001451 cardiotoxic effect Effects 0.000 claims description 6
- 231100000433 cytotoxic Toxicity 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 239000011593 sulfur Substances 0.000 claims description 6
- 206010020772 Hypertension Diseases 0.000 claims description 5
- 208000007536 Thrombosis Diseases 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 230000002093 peripheral effect Effects 0.000 claims description 5
- 206010020880 Hypertrophy Diseases 0.000 claims description 4
- 206010022562 Intermittent claudication Diseases 0.000 claims description 4
- 206010027476 Metastases Diseases 0.000 claims description 4
- 239000000654 additive Substances 0.000 claims description 4
- 206010003119 arrhythmia Diseases 0.000 claims description 4
- 231100000457 cardiotoxic Toxicity 0.000 claims description 4
- 230000004663 cell proliferation Effects 0.000 claims description 4
- 230000006735 deficit Effects 0.000 claims description 4
- 206010020718 hyperplasia Diseases 0.000 claims description 4
- 208000021156 intermittent vascular claudication Diseases 0.000 claims description 4
- 210000004185 liver Anatomy 0.000 claims description 4
- 230000009401 metastasis Effects 0.000 claims description 4
- 208000010125 myocardial infarction Diseases 0.000 claims description 4
- 230000035939 shock Effects 0.000 claims description 4
- 208000003663 ventricular fibrillation Diseases 0.000 claims description 4
- 206010002383 Angina Pectoris Diseases 0.000 claims description 3
- 208000019901 Anxiety disease Diseases 0.000 claims description 3
- 208000003495 Coccidiosis Diseases 0.000 claims description 3
- 208000007530 Essential hypertension Diseases 0.000 claims description 3
- 206010020850 Hyperthyroidism Diseases 0.000 claims description 3
- 206010023076 Isosporiasis Diseases 0.000 claims description 3
- 208000028017 Psychotic disease Diseases 0.000 claims description 3
- 230000006793 arrhythmia Effects 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 201000004792 malaria Diseases 0.000 claims description 3
- 230000000144 pharmacologic effect Effects 0.000 claims description 3
- 244000144977 poultry Species 0.000 claims description 3
- 230000002829 reductive effect Effects 0.000 claims description 3
- 208000005057 thyrotoxicosis Diseases 0.000 claims description 3
- 238000002054 transplantation Methods 0.000 claims description 3
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 2
- JIWFLUAUHJQHCL-UHFFFAOYSA-N n-(diaminomethylidene)-4-[(3,3-difluorocyclobutyl)methylamino]-2-methyl-5-methylsulfonylbenzamide Chemical compound C1=C(C(=O)N=C(N)N)C(C)=CC(NCC2CC(F)(F)C2)=C1S(C)(=O)=O JIWFLUAUHJQHCL-UHFFFAOYSA-N 0.000 claims description 2
- XXBFGPARSXBJKD-UHFFFAOYSA-N n-(diaminomethylidene)-4-[(3,3-difluorocyclobutyl)methylamino]-5-ethylsulfonyl-2-methylbenzamide Chemical compound CCS(=O)(=O)C1=CC(C(=O)N=C(N)N)=C(C)C=C1NCC1CC(F)(F)C1 XXBFGPARSXBJKD-UHFFFAOYSA-N 0.000 claims description 2
- 210000000653 nervous system Anatomy 0.000 claims description 2
- 125000000565 sulfonamide group Chemical group 0.000 claims description 2
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 2
- 230000009692 acute damage Effects 0.000 claims 3
- 230000009693 chronic damage Effects 0.000 claims 3
- 206010010904 Convulsion Diseases 0.000 claims 2
- 208000020401 Depressive disease Diseases 0.000 claims 2
- 208000037976 chronic inflammation Diseases 0.000 claims 2
- 208000037893 chronic inflammatory disorder Diseases 0.000 claims 2
- 230000036461 convulsion Effects 0.000 claims 2
- 206010015037 epilepsy Diseases 0.000 claims 2
- 210000003734 kidney Anatomy 0.000 claims 2
- 230000037356 lipid metabolism Effects 0.000 claims 2
- 210000001428 peripheral nervous system Anatomy 0.000 claims 2
- 238000001356 surgical procedure Methods 0.000 claims 2
- 208000019622 heart disease Diseases 0.000 claims 1
- 210000001835 viscera Anatomy 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 description 38
- 102100022897 Sodium/hydrogen exchanger 10 Human genes 0.000 description 32
- 239000000243 solution Substances 0.000 description 25
- 230000002265 prevention Effects 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 15
- 230000000694 effects Effects 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- -1 isopropyl 1-methylethyl Chemical group 0.000 description 12
- 239000000126 substance Substances 0.000 description 9
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 8
- 102100030980 Sodium/hydrogen exchanger 1 Human genes 0.000 description 8
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 8
- 229960004198 guanidine Drugs 0.000 description 8
- 208000028867 ischemia Diseases 0.000 description 8
- 238000011084 recovery Methods 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 239000005557 antagonist Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 108091006647 SLC9A1 Proteins 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
- 206010061216 Infarction Diseases 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- 230000007574 infarction Effects 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- 108010007622 LDL Lipoproteins Proteins 0.000 description 4
- 102000007330 LDL Lipoproteins Human genes 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 108010062497 VLDL Lipoproteins Proteins 0.000 description 4
- NTECHUXHORNEGZ-UHFFFAOYSA-N acetyloxymethyl 3',6'-bis(acetyloxymethoxy)-2',7'-bis[3-(acetyloxymethoxy)-3-oxopropyl]-3-oxospiro[2-benzofuran-1,9'-xanthene]-5-carboxylate Chemical compound O1C(=O)C2=CC(C(=O)OCOC(C)=O)=CC=C2C21C1=CC(CCC(=O)OCOC(C)=O)=C(OCOC(C)=O)C=C1OC1=C2C=C(CCC(=O)OCOC(=O)C)C(OCOC(C)=O)=C1 NTECHUXHORNEGZ-UHFFFAOYSA-N 0.000 description 4
- 230000003178 anti-diabetic effect Effects 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 230000001419 dependent effect Effects 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 230000003834 intracellular effect Effects 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 230000001681 protective effect Effects 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000011534 wash buffer Substances 0.000 description 4
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- 208000035150 Hypercholesterolemia Diseases 0.000 description 3
- 208000031226 Hyperlipidaemia Diseases 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 238000001994 activation Methods 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 230000002349 favourable effect Effects 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 230000000055 hyoplipidemic effect Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000012160 loading buffer Substances 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 230000009257 reactivity Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 230000002792 vascular Effects 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- FAMVCMFMKPHCPH-UHFFFAOYSA-N (3,3-difluorocyclobutyl)oxymethylbenzene Chemical compound C1C(F)(F)CC1OCC1=CC=CC=C1 FAMVCMFMKPHCPH-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 2
- 239000001763 2-hydroxyethyl(trimethyl)azanium Substances 0.000 description 2
- RKATWUBDSJHPEV-UHFFFAOYSA-N 3,3-difluorocyclobutan-1-amine Chemical compound NC1CC(F)(F)C1 RKATWUBDSJHPEV-UHFFFAOYSA-N 0.000 description 2
- BFLCYDVYEGKWSQ-UHFFFAOYSA-N 3,3-difluorocyclobutan-1-ol Chemical compound OC1CC(F)(F)C1 BFLCYDVYEGKWSQ-UHFFFAOYSA-N 0.000 description 2
- PLRCVBKYFLWAAT-UHFFFAOYSA-N 3,3-difluorocyclobutane-1-carboxylic acid Chemical compound OC(=O)C1CC(F)(F)C1 PLRCVBKYFLWAAT-UHFFFAOYSA-N 0.000 description 2
- WQLHIJQFVUEOKA-UHFFFAOYSA-N 4-[(3,3-difluorocyclobutyl)amino]-2-methyl-5-methylsulfonylbenzoic acid Chemical compound C1=C(C(O)=O)C(C)=CC(NC2CC(F)(F)C2)=C1S(C)(=O)=O WQLHIJQFVUEOKA-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- 239000005541 ACE inhibitor Substances 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- 108090000209 Carbonic anhydrases Proteins 0.000 description 2
- 102000003846 Carbonic anhydrases Human genes 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 102000006786 Chloride-Bicarbonate Antiporters Human genes 0.000 description 2
- 108010086832 Chloride-Bicarbonate Antiporters Proteins 0.000 description 2
- 235000019743 Choline chloride Nutrition 0.000 description 2
- 208000003890 Coronary Vasospasm Diseases 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000001953 Hypotension Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 108090001030 Lipoproteins Proteins 0.000 description 2
- 102000004895 Lipoproteins Human genes 0.000 description 2
- CPLXHLVBOLITMK-UHFFFAOYSA-N Magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 2
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 2
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical class ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 2
- 102000004399 TNF receptor-associated factor 3 Human genes 0.000 description 2
- 108090000922 TNF receptor-associated factor 3 Proteins 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- BZKPWHYZMXOIDC-UHFFFAOYSA-N acetazolamide Chemical compound CC(=O)NC1=NN=C(S(N)(=O)=O)S1 BZKPWHYZMXOIDC-UHFFFAOYSA-N 0.000 description 2
- 229960000571 acetazolamide Drugs 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 229940127282 angiotensin receptor antagonist Drugs 0.000 description 2
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 2
- 229940124599 anti-inflammatory drug Drugs 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 239000003472 antidiabetic agent Substances 0.000 description 2
- 230000036523 atherogenesis Effects 0.000 description 2
- 230000000923 atherogenic effect Effects 0.000 description 2
- 230000003143 atherosclerotic effect Effects 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 150000001559 benzoic acids Chemical class 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 230000012292 cell migration Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- SGMZJAMFUVOLNK-UHFFFAOYSA-M choline chloride Chemical compound [Cl-].C[N+](C)(C)CCO SGMZJAMFUVOLNK-UHFFFAOYSA-M 0.000 description 2
- 229960003178 choline chloride Drugs 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 210000002808 connective tissue Anatomy 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 208000029078 coronary artery disease Diseases 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 2
- 239000002934 diuretic Substances 0.000 description 2
- 229940030606 diuretics Drugs 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229960004580 glibenclamide Drugs 0.000 description 2
- WIGIZIANZCJQQY-RUCARUNLSA-N glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 description 2
- 229960004346 glimepiride Drugs 0.000 description 2
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 2
- 108010093115 growth factor-activatable Na-H exchanger NHE-1 Proteins 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 2
- 208000021822 hypotensive Diseases 0.000 description 2
- 230000001077 hypotensive effect Effects 0.000 description 2
- JBFYUZGYRGXSFL-UHFFFAOYSA-N imidazolide Chemical compound C1=C[N-]C=N1 JBFYUZGYRGXSFL-UHFFFAOYSA-N 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 230000012105 intracellular pH reduction Effects 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- RNQJGJXGSYXOQI-UHFFFAOYSA-N methyl 4-(3,3-difluorocyclobutyl)oxy-2-methyl-5-methylsulfonylbenzoate Chemical compound C1=C(C)C(C(=O)OC)=CC(S(C)(=O)=O)=C1OC1CC(F)(F)C1 RNQJGJXGSYXOQI-UHFFFAOYSA-N 0.000 description 2
- VZWPEQIKRDSMFD-UHFFFAOYSA-N methyl 4-[(3,3-difluorocyclobutyl)amino]-2-methyl-5-methylsulfonylbenzoate Chemical compound C1=C(C)C(C(=O)OC)=CC(S(C)(=O)=O)=C1NC1CC(F)(F)C1 VZWPEQIKRDSMFD-UHFFFAOYSA-N 0.000 description 2
- QOGWKVLBWXCHPD-UHFFFAOYSA-N methyl 4-fluoro-2-methyl-5-methylsulfonylbenzoate Chemical compound COC(=O)C1=CC(S(C)(=O)=O)=C(F)C=C1C QOGWKVLBWXCHPD-UHFFFAOYSA-N 0.000 description 2
- PMBNYYUZOMOWDQ-UHFFFAOYSA-N n-(3,3-difluorocyclobutyl)methanesulfonamide Chemical compound CS(=O)(=O)NC1CC(F)(F)C1 PMBNYYUZOMOWDQ-UHFFFAOYSA-N 0.000 description 2
- JQODSDAABRDRKF-UHFFFAOYSA-N n-(diaminomethylidene)-4-(3,3-difluorocyclobutyl)oxy-2-methyl-5-methylsulfonylbenzamide Chemical compound C1=C(C(=O)NC(N)=N)C(C)=CC(OC2CC(F)(F)C2)=C1S(C)(=O)=O JQODSDAABRDRKF-UHFFFAOYSA-N 0.000 description 2
- ZVUZUKCWXZXQKJ-UHFFFAOYSA-N n-(diaminomethylidene)-4-[(3,3-difluorocyclobutyl)amino]-2-methyl-5-methylsulfonylbenzamide Chemical compound C1=C(C(=O)NC(N)=N)C(C)=CC(NC2CC(F)(F)C2)=C1S(C)(=O)=O ZVUZUKCWXZXQKJ-UHFFFAOYSA-N 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 229910001415 sodium ion Inorganic materials 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000011477 surgical intervention Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 230000002885 thrombogenetic effect Effects 0.000 description 2
- 239000005495 thyroid hormone Substances 0.000 description 2
- 229940036555 thyroid hormone Drugs 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 1
- BIDNLKIUORFRQP-XYGFDPSESA-N (2s,4s)-4-cyclohexyl-1-[2-[[(1s)-2-methyl-1-propanoyloxypropoxy]-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([P@@](=O)(O[C@H](OC(=O)CC)C(C)C)CC(=O)N1[C@@H](C[C@H](C1)C1CCCCC1)C(O)=O)CCCC1=CC=CC=C1 BIDNLKIUORFRQP-XYGFDPSESA-N 0.000 description 1
- ZQXCQTAELHSNAT-UHFFFAOYSA-N 1-chloro-3-nitro-5-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC(Cl)=CC(C(F)(F)F)=C1 ZQXCQTAELHSNAT-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- IFVCCPQNZIHQCC-UHFFFAOYSA-N 2-methoxy-2-methylpropane 1-methylpyrrolidin-2-one Chemical compound COC(C)(C)C.CN1CCCC1=O IFVCCPQNZIHQCC-UHFFFAOYSA-N 0.000 description 1
- GPPSQLLIFNWNSB-UHFFFAOYSA-N 3-phenylmethoxycyclobutan-1-one Chemical compound C1C(=O)CC1OCC1=CC=CC=C1 GPPSQLLIFNWNSB-UHFFFAOYSA-N 0.000 description 1
- SWLAMJPTOQZTAE-UHFFFAOYSA-N 4-[2-[(5-chloro-2-methoxybenzoyl)amino]ethyl]benzoic acid Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(C(O)=O)C=C1 SWLAMJPTOQZTAE-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 208000030090 Acute Disease Diseases 0.000 description 1
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 1
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010048962 Brain oedema Diseases 0.000 description 1
- 239000002083 C09CA01 - Losartan Substances 0.000 description 1
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 1
- 239000002947 C09CA04 - Irbesartan Substances 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 208000006029 Cardiomegaly Diseases 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 206010056370 Congestive cardiomyopathy Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 208000032781 Diabetic cardiomyopathy Diseases 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- 201000010046 Dilated cardiomyopathy Diseases 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 206010014476 Elevated cholesterol Diseases 0.000 description 1
- 108010061435 Enalapril Proteins 0.000 description 1
- 108050009340 Endothelin Proteins 0.000 description 1
- 102000002045 Endothelin Human genes 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 108010074860 Factor Xa Proteins 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 102000004366 Glucosidases Human genes 0.000 description 1
- 108010056771 Glucosidases Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 108010010234 HDL Lipoproteins Proteins 0.000 description 1
- 102000015779 HDL Lipoproteins Human genes 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 206010019668 Hepatic fibrosis Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000702479 Homo sapiens Sodium/hydrogen exchanger 1 Proteins 0.000 description 1
- 206010058558 Hypoperfusion Diseases 0.000 description 1
- 206010021137 Hypovolaemia Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 229940122355 Insulin sensitizer Drugs 0.000 description 1
- 102000016924 KATP Channels Human genes 0.000 description 1
- 108010053914 KATP Channels Proteins 0.000 description 1
- 239000007836 KH2PO4 Substances 0.000 description 1
- 238000000023 Kugelrohr distillation Methods 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 208000007177 Left Ventricular Hypertrophy Diseases 0.000 description 1
- 108010007859 Lisinopril Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- ZFMITUMMTDLWHR-UHFFFAOYSA-N Minoxidil Chemical compound NC1=[N+]([O-])C(N)=CC(N2CCCCC2)=N1 ZFMITUMMTDLWHR-UHFFFAOYSA-N 0.000 description 1
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- BCRJRWREWRYJOJ-UHFFFAOYSA-N N,N-dimethylformamide ethyl acetate 2-propan-2-yloxypropane Chemical compound CN(C)C=O.CCOC(C)=O.CC(C)OC(C)C BCRJRWREWRYJOJ-UHFFFAOYSA-N 0.000 description 1
- 101710172108 Na(+)/H(+) antiporter NhaC Proteins 0.000 description 1
- 108091006315 Na+/HCO3 − co-transport proteins Proteins 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229940126033 PPAR agonist Drugs 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- UJEWTUDSLQGTOA-UHFFFAOYSA-N Piretanide Chemical compound C=1C=CC=CC=1OC=1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1N1CCCC1 UJEWTUDSLQGTOA-UHFFFAOYSA-N 0.000 description 1
- CYLWJCABXYDINA-UHFFFAOYSA-N Polythiazide Polymers ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)N(C)C(CSCC(F)(F)F)NC2=C1 CYLWJCABXYDINA-UHFFFAOYSA-N 0.000 description 1
- 102000004257 Potassium Channel Human genes 0.000 description 1
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 102000003800 Selectins Human genes 0.000 description 1
- 108090000184 Selectins Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 102000006633 Sodium-Bicarbonate Symporters Human genes 0.000 description 1
- 102000052126 Sodium-Hydrogen Exchangers Human genes 0.000 description 1
- 108091006672 Sodium–hydrogen antiporter Proteins 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 108010023197 Streptokinase Proteins 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 235000019486 Sunflower oil Nutrition 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 102000003938 Thromboxane Receptors Human genes 0.000 description 1
- 108090000300 Thromboxane Receptors Proteins 0.000 description 1
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 1
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- NGBFQHCMQULJNZ-UHFFFAOYSA-N Torsemide Chemical compound CC(C)NC(=O)NS(=O)(=O)C1=CN=CC=C1NC1=CC=CC(C)=C1 NGBFQHCMQULJNZ-UHFFFAOYSA-N 0.000 description 1
- FNYLWPVRPXGIIP-UHFFFAOYSA-N Triamterene Chemical compound NC1=NC2=NC(N)=NC(N)=C2N=C1C1=CC=CC=C1 FNYLWPVRPXGIIP-UHFFFAOYSA-N 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- FPQVGDGSRVMNMR-JCTPKUEWSA-N [[(z)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-(dimethylamino)methylidene]-dimethylazanium;tetrafluoroborate Chemical compound F[B-](F)(F)F.CCOC(=O)C(\C#N)=N/OC(N(C)C)=[N+](C)C FPQVGDGSRVMNMR-JCTPKUEWSA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229960002478 aldosterone Drugs 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- XSDQTOBWRPYKKA-UHFFFAOYSA-N amiloride Chemical compound NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N XSDQTOBWRPYKKA-UHFFFAOYSA-N 0.000 description 1
- 229960002576 amiloride Drugs 0.000 description 1
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 description 1
- 229960000528 amlodipine Drugs 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 230000000879 anti-atherosclerotic effect Effects 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 239000003529 anticholesteremic agent Substances 0.000 description 1
- 229940127226 anticholesterol agent Drugs 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000002830 appetite depressant Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 208000006752 brain edema Diseases 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- MAEIEVLCKWDQJH-UHFFFAOYSA-N bumetanide Chemical compound CCCCNC1=CC(C(O)=O)=CC(S(N)(=O)=O)=C1OC1=CC=CC=C1 MAEIEVLCKWDQJH-UHFFFAOYSA-N 0.000 description 1
- 229960004064 bumetanide Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 1
- 230000001269 cardiogenic effect Effects 0.000 description 1
- 230000003293 cardioprotective effect Effects 0.000 description 1
- 231100000259 cardiotoxicity Toxicity 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000001364 causal effect Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 208000022831 chronic renal failure syndrome Diseases 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 230000002566 clonic effect Effects 0.000 description 1
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 1
- 229960003009 clopidogrel Drugs 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 229960004042 diazoxide Drugs 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 235000018823 dietary intake Nutrition 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 1
- 229960004166 diltiazem Drugs 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 1
- 229960000873 enalapril Drugs 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 description 1
- 230000001037 epileptic effect Effects 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 230000003480 fibrinolytic effect Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 238000012632 fluorescent imaging Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000005348 fluorocycloalkyl group Chemical group 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 229960002490 fosinopril Drugs 0.000 description 1
- 230000009760 functional impairment Effects 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 229960003883 furosemide Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- YRSVDSQRGBYVIY-GJZGRUSLSA-N gemopatrilat Chemical compound O=C1N(CC(O)=O)C(C)(C)CCC[C@@H]1NC(=O)[C@@H](S)CC1=CC=CC=C1 YRSVDSQRGBYVIY-GJZGRUSLSA-N 0.000 description 1
- 229950006480 gemopatrilat Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229960000789 guanidine hydrochloride Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000005003 heart tissue Anatomy 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 229960002003 hydrochlorothiazide Drugs 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 208000020346 hyperlipoproteinemia Diseases 0.000 description 1
- 239000005555 hypertensive agent Substances 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 150000007928 imidazolide derivatives Chemical class 0.000 description 1
- NDDAHWYSQHTHNT-UHFFFAOYSA-N indapamide Chemical compound CC1CC2=CC=CC=C2N1NC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 NDDAHWYSQHTHNT-UHFFFAOYSA-N 0.000 description 1
- 229960004569 indapamide Drugs 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229960002198 irbesartan Drugs 0.000 description 1
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229960002394 lisinopril Drugs 0.000 description 1
- RLAWWYSOJDYHDC-BZSNNMDCSA-N lisinopril Chemical compound C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 RLAWWYSOJDYHDC-BZSNNMDCSA-N 0.000 description 1
- 239000002171 loop diuretic Substances 0.000 description 1
- 229960004773 losartan Drugs 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
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
- 229960004844 lovastatin Drugs 0.000 description 1
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- 235000012245 magnesium oxide Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229950004994 meglitinide Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000006371 metabolic abnormality Effects 0.000 description 1
- 230000006680 metabolic alteration Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical class COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 229960002237 metoprolol Drugs 0.000 description 1
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 description 1
- 229960003632 minoxidil Drugs 0.000 description 1
- 108010007855 mitochondrial K(ATP) channel Proteins 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- LVRLSYPNFFBYCZ-VGWMRTNUSA-N omapatrilat Chemical compound C([C@H](S)C(=O)N[C@H]1CCS[C@H]2CCC[C@H](N2C1=O)C(=O)O)C1=CC=CC=C1 LVRLSYPNFFBYCZ-VGWMRTNUSA-N 0.000 description 1
- 229950000973 omapatrilat Drugs 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 231100000255 pathogenic effect Toxicity 0.000 description 1
- 230000035778 pathophysiological process Effects 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 239000002307 peroxisome proliferator activated receptor agonist Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 229960001085 piretanide Drugs 0.000 description 1
- 229960005483 polythiazide Drugs 0.000 description 1
- 229920000046 polythiazide Polymers 0.000 description 1
- 108020001213 potassium channel Proteins 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 230000009993 protective function Effects 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000003379 purinergic P1 receptor agonist Substances 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 description 1
- 229960003401 ramipril Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000031844 regulation of cellular pH Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 201000002793 renal fibrosis Diseases 0.000 description 1
- 239000002461 renin inhibitor Substances 0.000 description 1
- 229940086526 renin-inhibitors Drugs 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 229960002052 salbutamol Drugs 0.000 description 1
- 230000000894 saliuretic effect Effects 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
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229960005202 streptokinase Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 229960000187 tissue plasminogen activator Drugs 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 229960005461 torasemide Drugs 0.000 description 1
- 229960001288 triamterene Drugs 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 229960004699 valsartan Drugs 0.000 description 1
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 description 1
- 231100000216 vascular lesion Toxicity 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 108010047303 von Willebrand Factor Proteins 0.000 description 1
- 102100036537 von Willebrand factor Human genes 0.000 description 1
- 229960001134 von willebrand factor Drugs 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
- C07C317/48—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- 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
- A61P9/06—Antiarrhythmics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
- C07C317/46—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Cardiology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Diabetes (AREA)
- Neurology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Pain & Pain Management (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Obesity (AREA)
- Psychiatry (AREA)
- Rheumatology (AREA)
- Oncology (AREA)
- Vascular Medicine (AREA)
- Emergency Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
WO 03/106410 PCT/EP03/05738 FLUORINATED CYCLOALKYL-DERIVATIZED BENZOYLGUANIDINES AND THEIR USE AS A MEDICAMENT Fluorinated cycloalkyl-derivatized benzoylguanidines, process for their preparation, their use as a medicament, and medicament containing them.
The invention relates to compounds of the formula I
(H
2
H
2 R2 X R1 R3 N NH 2 R3 v\ R4 0
NH
2 in which the meanings are: X oxygen, sulfur or NR6; R6 hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or (CH2)k-CF3; k 0, 1, 2 or 3; m zero, 1, 2 or 3; n zero, 1, 2 or 3; p zero, 1, 2, or 3; q 1,2 or 3; r zero, 1, 2 or 3; where the total of m, n, p, q and r is at least 2; R1 hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, CI, -OR(7), -NR(8)R(9) or -CsF2s+l; R(8) and R(9) independently of one another hydrogen, alkyl having 1, 2 or 3 carbon atoms or (CH2)t-CF3; s 1,2, 3 or 4; t 0, 1, 2, 3 or 4; R2 hydrogen, F, CI, alkyl having 1, 2, 3 or 4 carbon atoms or CF 3 R3 hydrogen, F, CI, alkyl having 1, 2, 3 or 4 carbon atoms, CF 3 or 2 u zero, 1 or 2; alkyl having 1, 2, 3 or 4 carbon atoms or NR11R12; R11 and R12 independently of one another hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; R4 hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, CI, -OR(13), -NR(14)R(15) or -CvF2v+l; R(13), R(14) and independently of one another hydrogen, alkyl having 1, 2 or 3 carbon atoms or (CH2)w-CF 3 v 1, 2, 3 or 4; w 0, 1,2, 3, or 4; hydrogen or F; and the pharmacologically acceptable salts thereof.
Preference is given to compounds of the formula I in which the meanings are: X oxygen, sulfur or NR6; R6 hydrogen, methyl or CH 2
-CF
3 m zero, 1 or 2; n zero, 1 or 2; p zero, 1 or 2; q 1 or 2; r zero, 1 or 2; where the total of m, n, p, q and r is at least 2; R1 hydrogen, methyl, F, Cl, -NR(8)R(9) or -CF 3 R(8) and R(9) independently of one another hydrogen, methyl, CF 3 or CH 2
-CF
3 R2 hydrogen, F, CI, methyl or CF 3 R3 hydrogen, F, CI, alkyl having 1, 2, 3 or 4 carbon atoms, CF 3
SO
2
CH
3 or SO 2
NH
2 R4 hydrogen, methyl, F, CI, -OR(13), -NR(14)R(15) or -CF 3 R(13), R(14) and independently of one another hydrogen, methyl, CF 3 or CH 2
-CF
3 hydrogen or F; and the pharmacologically acceptable salts thereof.
Particular preference is given to compounds of the formula I in which the meanings are: X oxygen, sulfur or NR6; R6 hydrogen, methyl or CH 2
-CF
3 m zero or 1; n zero, 1 or 2; p zero or 1; q 1 or 2; r zero or 1; where the total of m, n, p, q and r is at least 2; R1 hydrogen, methyl, F, Cl, -NR(8)R(9) or -CF3; methyl, CF3 or CH2-CF3; R(8) and R(9) independently of one another hydrogen, methyl or CH 2
-CF
3 R2 hydrogen, F or Cl; R3 CF3, SO 2
CH
3 or SO2NH2; R4 hydrogen; R5 hydrogen or F; and the pharmacologically acceptable salts thereof.
Very particular preference is given to the following compounds of the formula I, selected from the group: N-[4-(3,3-difluorocyclobutoxy)-5-methanesulfonyl-2-methylbenzoyl]quanidine, N-[4-(3,3-difluorocyclobutylamino)-5-methanesulfonyl-2-methylbenzoyl]quanidine, N-{4-[(3,3-difluorocyclobutyl)methylamino]-5-methanesulfonyl-2-methylbenzoyl}guanidine and N-{4-[(3,3-difluorocyclobutyl)methylamino]-5-ethanesulfonyl-2-methylbenzoyl}guanidine and the pharmaceutically acceptable salts thereof.
The compounds of the formula I, for example the substituents R1 to R4, contain one or more syntheses of asymmetry and they may thus be, independently of one another, of the S or R configuration. The compounds may exist as optical isomers, as diasteriomers, as racemates or as mixtures thereof.
The present invention encompasses all tautomeric forms of the compounds of the formula I and II.
Alkyl radicals may be straight-chain or branched. This also applies if they have substituents or occur as substituents of other radicals, for example in fluoroalkyl radicals or alkoxy radicals. Examples of alkyl radicals are methyl, ethyl, n-propyl, isopropyl 1-methylethyl), n-butyl, isobutyl 2-methylpropyl), sec-butyl 1-methylproyl) and tert-butyl 1,1-dimethylethyl). Preferred alkyl radicals are methyl, ethyl, n-propyl and isopropyl. One or more, for example 1, 2, 3, 4 or 5, hydrogen atoms in alkyl radicals may be replaced by fluorine atoms. Examples of such fluoroalkyl radicals are trifluoromethyl, 2,2,2-trifluoroethyl and pentafluoroethyl. Substituted alkyl radicals may be substituted in any positions.
Preferred compounds of the formula I are those in which the total of m, n, o, p, q and r is from 2 to 6.
The invention additionally relates to a process for preparing a compound of the formula I, which comprises reacting a compound of the formula II
H
2
)P
2)q CF2 2F2)n
(H
2 )r
H
2 )m R2 (II) X R1 R3 L R4 O in which R(1) to R(5) and m to r have the stated meaning, and L is a leaving group which can easily undergo nucleophilic substitution, with guanidine.
The activated acid derivatives of the formula II in which L is an alkoxy, preferably a methoxy, group, a phenoxy group, phenylthio, methylthio, 2-pyridylthio group, a nitrogen heterocycle, preferably 1-imidazolyl, are advantageously obtained in a manner known to the skilled worker from the underlying carbonyl chlorides (formula II, L CI), which in turn can r themselves be prepared in a manner known to the skilled worker from the underlying carboxylic acids (formula II; L OH), for example using thionyl chloride.
Besides the carbonyl chlorides of the formula II (L CI) it is also possible to prepare other activated acid derivatives of the formula II in a manner known per se directly from the underlying benzoic acids (formula II; L OH), such as the methyl esters of the formula II with L OCH 3 by treatment with gaseous HCI in methanol, the imidazolides of the formula II by treatment with carbonyldiimidazole [L 1-imidazolyl, Staab, Angew. Chem. Int. Ed.
Engl. 1, 351 367 (1962)], the mixed anhydrides with CI-COOC 2
H
5 or tosyl chloride in the presence of triethylamine in an inert solvent, as activations of benzoic acids with dicyclohexylcarbodiimide (DCC) or with O-[(cyano(ethoxycarbonyl)methylene)amino]-1,1,3,3-tetramethyluronium tetrafluoroborate ('TOTU") [Proceedings of the 21. European Peptide Symposium, Peptides 1990, Editors E. Giralt and D. Andreu, Escom, Leiden, 1991] are possible. A number of suitable methods for preparing activated carboxylic acid derivatives of the formula II are indicated in J. March, Advanced Organic Chemistry, third edition (John Wiley Sons, 1985), page 350, indicating source literature.
Reaction of an activated carboxylic acid derivative of the formula II with guanidine takes place in a manner known to the skilled worker in a protic or aprotic polar but inert organic solvent. Those which have proved suitable for the reaction of the methyl benzoates (II; L OCH3 with guanidine are methanol, isopropanol or THF at temperatures from 200C to the boiling point of these solvents. Most reactions of compounds II with salt-free guanidine have advantageously been carried out in aprotic inert solvents such as THF, dimethoxyethane, dioxane or DMF. However, it is also possible to use water in the presence of a base such as, for example, NaOH as solvent in the reaction of II with guanidine.
If L is CI, it is advantageous to add an acid scavenger, for example in the form of excess guanidine, to bind the hydrohalic acid.
The carboxylic acid derivatives of the formula II can be prepared from compounds of the formula III. Some of the underlying benzoic acid derivatives of the formula III are known and described in the literature. The unknown compounds of the formula III can be prepared by methods known from the literature.
R2 L' J R1 L' RI(111)
(III)
R3) Et R4 0 The introduction of the fluorocycloalkyl nucleophiles into the 4 position takes place by nucleophilic aromatic substitution. Suitably protected benzoic acid derivatives of the formula III, such as, for example, the methyl or ethyl esters, are employed in this case. L' is a leaving group which can easily be replaced by nucleophilic aromatic substitution, such as F, Cl, Br, I or O-SO 2
CF
3 The benzoic acid derivatives of the formula II obtained are then reacted by one of the process variants described above to give compounds of the formula I of the invention.
Benzoylguanidines of the formula I are generally weak bases and are able to bind acid to form salts. Suitable acid addition salts are salts of all pharmacologically acceptable acids, for example halides, in particular hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates, p-toluenesulfonates.
The compounds of the formula I are substituted acylguanidines and inhibit the cellular sodium-proton antiporter (Na /H -exchanger, NHE).
The compounds of the invention, of the formula I, are distinguished by having unusually favorable ADME (absorption distribution metabolism excretion) properties compared with known benzoylguanidines, together with excellent activity in the inhibition of NA+/H+ exchange; these advantageous properties are dependent on the fluorinated cycloalkyl group.
In contrast to known acylguanidines, the compounds described herein show no unwanted and disadvantageous saluretic properties.
Because of the NHE-inhibitory properties, the compounds of the formula I and/or II and/or the pharmaceutically acceptable salts thereof are suitable for the prevention and treatment of diseases caused by activation or activated NHE, and of diseases caused secondarily by the NHE-related damage.
Since NHE inhibitors predominantly act via their effect on cellular pH regulation, they can generally be combined beneficially with other compounds which regulate the intracellular pH, with suitable combination partners being inhibitors of the carbonic anhydrase enzyme group, inhibitors of systems transporting bicarbonate ions, such as of the sodium bicarbonate cotransporter (NBC) or of the sodium-dependent chloridebicarbonate exchanger (NCBE), and NHE inhibitors with inhibitory effect on other NHE subtypes, because it is possible through them to enhance or modulate the pharmacologically relevant pH-regulating effects of the NHE inhibitors described herein.
The use of the compounds of the invention relates to the prevention and treatment of acute and chronic diseases in veterinary and human medicine.
Thus, the NHE inhibitors of the invention are suitable for the treatment of diseases caused by ischemia and by reperfusion.
The compounds described herein are suitable because of their pharmacological properties as antiarrhythmic medicaments.
Owing to their cardioprotective component, the NHE inhibitors of the formula I and/or II and/or the pharmaceutically acceptable salts thereof are outstandingly suitable for infarction prophylaxis and infarction treatment and for the treatment of angina pectoris, in which cases they also preventively inhibit or greatly reduce the pathophysiological processes associated with the development of ischemia-induced damage, in particular in the triggering of ischemia-induced cardiac arrhythmias. Because of their protective effects against pathological hypoxic and ischemic situations, the compounds of the formula I and/or II and/or the pharmaceutically acceptable salts thereof used according to the invention can, because of inhibition of the cellular Na+/H+ exchange mechanism, be used as medicaments for the treatment of all acute or chronic ischemia-induced damage or diseases induced primarily or secondarily thereby.
This also relates to their use as medicaments for surgical interventions.
Thus, the compounds can be used during organ transplantations, it being possible to use the compounds both to protect the organs in the donor before and during the removal, to protect removed organs for example during treatment with or storage thereof in physiological bath liquids, and during transference to the recipient organism.
The compounds of the invention are likewise valuable medicaments with a protective effect when performing angioplastic surgical interventions, for example on the heart as well as on peripheral organs and vessels.
It has emerged that the compounds of the invention are exceptionally effective medicaments for life-threatening arrhythmias. Ventricular fibrillation is terminated and the physiological sinus rhythm of the heart is restored.
Since NHE1 inhibitors of human tissue and organs, especially the heart, protect effectively not only against damage caused by ischemia and reperfusion but also against the cytotoxic effect of medicaments like those used in particular in cancer therapy and the therapy of autoimmune diseases, combined administration with compounds of the formula I and/or II and/or the pharmaceutically acceptable salts thereof is suitable for inhibiting the cytotoxic, especially cardiotoxic, side effects of said compounds. The reduction in the cytotoxic effects, especially the cardiotoxicity, resulting from comedication with NHE1 inhibitors makes it additionally possible to increase the dose of the cytotoxic therapeutic agents and/or to prolong the medication with such medicaments. The therapeutic benefits of such a cytotoxic therapy can be considerably increased by combination with NHE inhibitors.
In addition, the NHE1 inhibitors of the invention of the formula I and/or II and/or the pharmaceutically acceptable salts thereof can be used when there is heart-damaging overproduction of thyroid hormones, thyrotoxicosis, or on external supply of thyroid hormones. The compounds of the formula I and/or II and/or the pharmaceutically acceptable salts thereof are thus suitable for improving therapy with cardiotoxic medicaments.
In accordance with their protective effect against ischemia-induced damage, the compounds of the invention are also suitable as medicaments for the treatment of ischemias of the nervous system, especially of the central nervous system, being suitable for example for the treatment of stroke or of cerebral edema.
The compounds of the formula I and/or the pharmaceutically acceptable salts thereof are also suitable for the therapy and prophylaxis of diseases and disorders induced by overexcitability of the central nervous system, in particular for the treatment of epileptic disorders, centrally induced clonic and tonic spasms, states of psychological depression, anxiety disorders and psychoses. In these cases it is possible to use the NHE inhibitors described herein alone or in combination with other substances with antiepileptic activity or antipsychotic active ingredients, or carbonic anhydratase inhibitors, for example with acetazolamide, and with other inhibitors of NHE or of the sodium-dependent chloride-bicarbonate exchanger (NCBE).
The compounds used according to the invention of the formula I and/or the pharmaceutically acceptable salts thereof are additionally likewise suitable for the treatment of types of shock such as, for example, of allergic, cardiogenic, hypovolemic and bacterial shock.
The compounds of the formula I and/or the pharmaceutically acceptable salts thereof can likewise be used for the prevention and treatment of thrombotic disorders because they, as NHE inhibitors, are able to inhibit platelet aggregation themselves. They are additionally able to inhibit or prevent the excessive release, occurring after ischemia and reperfusion, of mediators of inflammation and coagulation, especially of von Willebrand factor and of thrombogenic selectin proteins. It is thus possible to reduce and eliminate the pathogenic effect of significant thrombogenic factors. The NHE inhibitors of the present invention can therefore be combined with other anticoagulant and/or thrombolytic active ingredients such as, for example, recombinant or natural tissue plasminogen activator, streptokinase, urokinase, acetylsalicylic acid, thrombin antagonists, factor Xa antagonists, medicinal substances with fibrinolytic activity, thromboxane receptor antagonists, phosphodiesterase inhibitors, factor Vila antagonists, clopidogrel, ticolopidine etc. Combined use of the present NHE inhibitors with NCBE inhibitors and/or with inhibitors of carbonic anhydrase such as, for example, with acetazolamide, is particularly beneficial.
The compounds of the formula I and/or the pharmaceutically acceptable salts thereof used according to the invention are additionally distinguished by a strong inhibitory effect on the proliferation of cells, for example fibroblast cellular proliferation and the proliferation of smooth vascular muscle cells. The compounds of the formula I and/or II and/or the pharmaceutically acceptable salts thereof are therefore suitable as valuable therapeutic agents for diseases in which cellular proliferation represents a primary or secondary cause, and can therefore be used as antiatherosclerotics, agents for chronic renal failure, cancers.
It was possible to show that cell migration is inhibited by the compounds of the invention. The compounds of the formula I and/or the pharmaceutically acceptable salts thereof are therefore suitable as valuable therapeutic agents for dieases in which cell migration represents a primary or secondary cause, such as, for example, cancers with a pronounced tendency to metastasis.
The compounds of the formula I and/or the pharmaceutically acceptable salts thereof are further distinguished by a retardation or prevention of fibrotic disorders. They are thus suitable as excellent agents for the treatment of cardiac fibroses, and of pulmonary fibrosis, hepatic fibrosis, renal fibrosis and other fibrotic disorders.
They can thus be used for the treatment of organ hypertrophies and hyperplasias, for example of the heart and the prostate. They are therefore suitable for the prevention and treatment of heart failure (congestive heart failure CHF) and for the treatment and prevention of prostate hyperplasia or prostate hypertrophy.
Since there is significant elevation in NHE in essential hypertensives, the compounds of the formula I and/or the pharmaceutically acceptable salts thereof are suitable for the prevention and treatment of high blood pressure and of cardiovascular disorders.
In these cases they can be used alone or with a suitable combination and formulation partner for high blood pressure treatment and of cardiovascular disorders. Thus, for example, one or more diuretics with a thiazide-like action, loop diuretics, aldosterone and pseudoaldosterone antagonists, such as hydrochlorothiazide, indapamide, polythiazide, furosemide, piretanide, torasemide, bumetanide, amiloride, triamterene, spironolactone or eplerone, can be combined. The NHE inhibitors of the present invention can further be used in combination with calcium channel blockers such as verapamil, diltiazem, amlodipine or nifedipine, and with ACE inhibitors such as, for example, ramipril, enalapril, lisinopril, fosinopril or captopril. Further beneficial combination partners are also beta-blockers such as metoprolol, albuterol etc., antagonists of the angiotensin receptor and its receptor subtypes such as losartan, irbesartan, valsartan, omapatrilat, gemopatrilat, endothelin antagonists, renin inhibitors, adenosine receptor agonists, inhibitors and activators of potassium channels such as glibenclamide, glimepiride, diazoxide, cromokalim, minoxidil and derivatives thereof, activators of the mitochondrial ATP-sensitive potassium channel (mitoK(ATP) channel), inhibitors of Kv1.5 etc.
It has emerged that NHE1 inhibitors of the formula I and/or the pharmaceutically acceptable salts thereof have a significant antiinflammatory effect and can thus be used as antiinflammatory drugs.
Inhibition of the release of mediators of inflammation is noteworthy in this connection. The compounds can thus be used alone or in combination with an antiinflammatory drug for the prevention or treatment of chronic and acute inflammatory disorders. Combination partners advantageously used are steroidal and non-steroidal antiinflammatory drugs. The compounds of the invention can also be used for the treatment of disorders caused by protozoa, of malaria and of coccidiosis in poultry.
It has additionally been found that compounds of the formula I and/or the pharmaceutically acceptable salts thereof show a beneficial effect on serum lipoproteins. It is generally acknowledged that blood fat levels which are too high, called hyperlipoproteinemias, represent an essential risk factor for the development of arteriosclerotic vascular lesions, especially coronary heart disease. The reduction of elevated serum lipoproteins therefore has exceptional importance for the prophylaxis and regression of atherosclerotic lesions. Besides the reduction in total serum cholesterol, it is particularly important to reduce the proportion of specific atherogenic lipid fractions of this total cholesterol, in particular of the low density lipoproteins (LDL) and of the very low density lipoproteins (VLDL), because these lipid fractions represent an atherogenic risk factor. By contrast, a protective function against coronary heart disease is ascribed to the high density lipoproteins. Accordingly, hypolipidemics should be able to reduce not only total cholesterol but, in particular, the VLDL and LDL serum cholesterol fractions. It has now been found that NHE1 inhibitors show 12 valuable therapeutically utilizable properties in relation to influencing the serum lipid levels. Thus, they significantly reduce the elevated serum concentrations of LDL and VLDL as are to be observed, for example, due to increased dietary intake of a cholesterol- and lipid-rich diet or in cases of pathological metabolic alterations, for example genetically related hyperlipidemias. They can therefore be used for the prophylaxis and regression of atherosclerotic lesions by eliminating a causal risk factor.
Included herein are not only the primary hyperlipidemias but also certain secondary hyperlipidemias occurring, for example, in association with diabetes. In addition, the compounds of the formula I and/or the pharmaceutically acceptable salts thereof lead to a marked reduction in the infarctions induced by metabolic abnormalities and, in particular, to a significant reduction in the induced infarct size and the severity thereof.
The compounds of the invention are therefore advantageously used for producing a medicament for the treatment of hypercholesterolemia; for producing a medicament for the prevention of atherogenesis; for producing a medicament for the prevention and treatment of atherosclerosis, for producing a medicament for the prevention and treatment of diseases induced by elevated cholesterol levels, for producing a medicament for the prevention and treatment of diseases induced by endothelial dysfunction, for producing a medicament for the prevention and treatment of atherosclerosis-induced hypertension, for producing a medicament for the prevention and treatment of atherosclerosis-induced thromboses, for producing a medicament for the prevention and treatment of hypercholesterolemia-induced and endothelial dysfunction-induced ischemic damage and post-ischemic reperfusion damage, for producing a medicament for the prevention and treatment of hypercholesterolemiainduced and endothelial dysfunction-induced cardiac hypertrophies and cardiomyopathies and of congestive heart failure (CHF), for producing a medicament for the prevention and treatment of hypercholesterolemiainduced and endothelial dysfunction-induced coronary vasospasms and myocardial infarctions, for producing a medicament for the treatment of said disorders in combinations with hypotensive substances, preferably with angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor antagonists. A combination of an NHE inhibitor of the formula I and/or the pharmaceutically acceptable salts thereof with an active ingredient lowering the blood fat levels, preferably with an HMG-CoA reductase inhibitor (for example lovastatin or pravastatin), the latter bringing about a hypolipidemic effect and thus increasing the hypolipidemic properties of the NHE inhibitor of the formula I and/or the pharmaceutically acceptable salts thereof proves to be a favorable combination with enhanced effect and reduced use of active ingredients.
Thus, compounds of the formula I and/or the pharmaceutically acceptable salts thereof lead to effective protection against endothelial damage of various origins. This protection of the vessels against the syndrome of endothelial dysfunction means that the compounds of the formula I and/or the pharmaceutically acceptable salts thereof are valuable medicaments for the prevention and treatment of coronary vasospasms, peripheral vascular diseases, in particular of intermittent claudication, atherogenesis and atherosclerosis, left ventricular hypertrophy and dilated cardiomyopathy and thrombotic disorders.
It has additionally been found that benzoylguanidine of the formula I and/or the pharmaceutically acceptable salts thereof are suitable in the treatment of non-insulin-dependent diabetes (NIDDM), in which case insulin resistance is repressed. It may in this connection be beneficial, to enhance antidiabetic activity and type of effect, for the compounds of the invention to be combined with a biguanide such as metformin, with an antidiabetic sulfonylurea such as glyburide, glimepiride, tolbutamide etc., with a glucosidase inhibitor, with a PPAR agonist such as rosiglitazone, pioglitazone etc., with an insulin product in a different administration form, with a DB4 inhibitor, with an insulin sensitizer or with meglitinide.
Besides the acute antidiabetic effects, the compounds of the formula I and/or the pharmaceutically acceptable salts thereof counteract the development of late complications of diabetes and can therefore be used as medicaments for the prevention and treatment of late damage from diabetes such as diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic cardiomyopathy and other disorders arising as a result of diabetes. In this connection they can be combined advantageously with the antidiabetic medicaments thus described under NIDDM treatment.
Combination with a favorable dosage form of insulin could be particularly important in this connection.
The NHE inhibitors of the invention, of the formula I, and/or the pharmaceutically acceptable salts thereof show, besides the protective effects against acute ischemic events and the subsequent reperfusion events which are equally acutely stressing, also direct therapeutically utilizable effects on disorders and impairments of the entire mammalian organism which are connected with manifestations of the chronically progressing aging process and which are independent of acute hypoperfusion states and occur under normal, nonischemic conditions.
These pathological age-related manifestations induced over the long time of aging, such as disease, illness and death, which can now be treated with NHE inhibitors, comprise disorders and impairments which are crucially caused by age-related changes in vital organs and their function, and become increasingly important in the aging organism.
Examples of disorders connected with an age-related functional impairment, with age-related signs of wear of organs, are inadequate responsiveness and reactivity of the blood vessels in relation to contraction and relaxation reactions. This age-related decline in vascular reactivity to constricting and relaxing stimuli, which are an essential process in the cardiovascular system and thus of life and health, can be significantly diminished or abolished by NHE inhibitors. An important function and a measure of the maintenance of vascular reactivity is the blocking or slowing of the age-related progression of endothelial dysfunction, which can be abolished highly significantly by NHE inhibitors. The compounds of the formula I and/or the pharmaceutically acceptable salts thereof are thus outstandingly suitable for the treatment and prevention of age-related progression of endothelial dysfunction, especially of intermittent claudication.
An example of another variable characterizing the aging process is the decrease in the contractility of the heart and the decrease in the adaptation of the heart to a required pumping performance of the heart. This reduced efficiency of the heart resulting from the aging process is in most cases associated with a dysfunction of the heart which is caused inter alia by deposition of connective tissue in the cardiac tissue. This deposition of connective tissue is characterized by an increase in the weight of the heart, by an enlargement of the heart and by restricted function of the heart. It was surprising that it was possible virtually completely to inhibit such an aging of the organ heart. The compounds of the formula I and/or the pharmaceutically acceptable salts thereof are thus outstandingly suitable for the treatment and prevention of heart failure, of congestive heart failure
(CHF).
Whereas preceding patents and patent applications have claimed the treatment of various types of cancers which have already occurred, it was now extremely surprising that not only the cancer which has already occurred can be cured by inhibition of proliferation, but that the age-related frequency of the development of cancer can be prevented and highly significantly delayed by NHE inhibitors. A particularly noteworthy finding is that disorders occurring in an age-related manner in all organs, and not just certain types of cancer, are suppressed or occur with a highly significant delay. The compounds of the formula I and/or the pharmaceutically acceptable salts thereof are thus outstandingly suitable for the treatment and, in particular, the prevention of age-related types of cancer.
There is now found to be not only a delay, shifted highly significantly in time and exceeding the statistical normal extent, in the occurrence of agerelated disorders of all investigated organs including the heart, vessels, liver etc., and a highly significant delay in age-related cancer. On the contrary, there is also, surprisingly, a prolongation of life to an extent which has not to date been achievable by any other group of medicaments or by any natural products. This unique effect of NHE inhibitors also makes it possible, besides use of the active ingredients alone on humans and animals, for these NHE inhibitors to be combined with other active principles, measures, substances and natural products used in gerontology and based on a different mechanism of action. Such classes of active ingredients used in gerontological therapy are: in particular vitamins and substances with antioxidant activity. Since there is a correlation between caloric loading or food intake and the aging process, combination with dietary measures is possible, for example with appetite suppressants.
Consideration may likewise be given to combination with hypotensive medicaments such as with ACE inhibitors, angiotensin receptor antagonists, diuretics, Ca 2 antagonists etc., or with metabolismnormalizing medicaments such as cholesterol-lowering agents.
The compounds of the formula I and/or the pharmaceutically acceptable salts thereof are thus outstandingly suitable for the prevention of agerelated tissue changes and for prolonging life while maintaining a high quality of life.
The compounds of the invention are effective inhibitors of the cellular sodium/proton antiporter (Na/H exchanger) which, in numerous disorders 16 (essential hypertension, artherosclerosis, diabetes etc.), is elevated also in cells which are easily amenable to measurements, such as, for example, in erythrocytes, platelets or leukocytes. The compounds used according to the invention are therefore suitable as excellent and simple scientific tools, for example in their use as diagnostic aids for the determination and differentiation of particular types of hypertension, but also of atherosclerosis, of diabetes and of late complications of diabetes, of proliferative disorders etc.
Additionally claimed is a medicine for human, veterinary or phytoprotective use comprising an effective amount of one or more compounds of the formula I and/or the pharmaceutically acceptable salts thereof, together with pharmaceutically acceptable carriers and additives, alone or in combination with other pharmacological active ingredients or medicaments.
Medicaments comprising a compound I can moreover for example be administered orally, parenterally, intravenously, rectally, percutaneously or by inhalation, with the preferred administration being dependent on the particular appearance of the disorder. The compounds I can moreover be used alone or together with pharmaceutical excipients, both in veterinary medicine and in human medicine. The medicaments generally contain active ingredients of the formula I and/or the pharmaceutically acceptable salts thereof in an amount of 0.01 mg to 1 g per dose unit.
Excipients suitable for the desired pharmaceutical formulation are familiar to the skilled worker on the basis of his expert knowledge. Besides solvents, gel formers, suppository bases, tablet excipients and other active ingredient carriers, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, masking flavors, preservatives, solubilizers or colors.
For a form for oral use, the active compounds are mixed with the additives suitable for this purpose, such as carriers, stabilizers or inert diluents, and converted by conventional methods into suitable dosage forms such as tablets, coated tablets, two-piece capsules, aqueous, alcoholic or oily solutions. Examples of inert carriers which can be used are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch. Preparation can moreover take place both as dry and as wet granules. Examples of suitable oily carriers or solvents are vegetable or animal oils such as sunflower oil or fish liver oil.
For subcutaneous or intravenous administration, the active compounds are converted into a solution, suspension or emulsion, if desired with the substances customary for this purpose, such as solubilizers, emulsifiers or other excipients. Examples of suitable solvents are: water, physiological saline or alcohols, for example ethanol, propanol, glycerol, as well as sugar solutions such as glucose or mannitol solutions, or else a mixture of the various solvents mentioned.
Suitable as pharmaceutical formulation for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active ingredient of the formula I in a pharmaceutically acceptable solvent such as, in particular, ethanol or water, or a mixture of such solvents.
The formulation may if required also comprise other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers, and a propellant gas. Such a preparation normally contains the active ingredient in a concentration of about 0.1 to 10, in particular of about 0.3 to 3% by weight.
The dosage of the active ingredient of the formula I to be administered and the frequency of administration depend on the potency and duration of action of the compounds used; also on the nature and severity of the disorder to be treated, and on the sex, age, weight and individual response of the mammal to be treated.
On average, the daily dose of a compound of the formula I for a patient weighing about 75 kg is at least 0.001 mg/kg, preferably 0.01 mg/kg, up to a maximum of 10 mg/kg, preferably 1 mg/kg, of bodyweight. For acute episodes of the disorder, for example immediately after suffering a myocardial infarction, it may be necessary for the dosages also to be higher. Especially on i.v. use, for example for an infarct patient in an intensive care unit, up to 700 mg per day may be necessary. The daily dose can be divided into several, for example up to 4, individual doses.
List of abbreviations:
ADME
CDI
DIP
DMF
EA
El eq.
ES
Et
HEP
KOtBu Me MeOH mp
NMP
MTB
RT
THEF
absorption-distribution-metabolism-excretion diimidazol-1 -yI-methanone diisopropyl ether N ,N-dimethylformamide ethyl acetate (EtOAc) electron impact equivalent electrospray ionization ethyl n-heptane potassium 2-methylpropan-2-olate methyl methanol melting point 1 -methyl pyrrolidin-2-one 2-methoxy-2-methyl propane room temperature tetrahydrofuran Example 1: N-[4-(3,3-Difluorocyclobutoxy)-5-methanesulfonyl-2methylbenzoyl]guanidine F F 0 H
H
N
N,
2500 0 Nl a) (3,3-Difluorocyclobutoxymethyl)benzene 20.0 g of 3-benzyloxycyclobutanone (Bull. Chem. Soc. Jpn. (1984), 57(6), 1637) were dissolved in 150 ml of CH 2 CI2, and a solution of 25.0 g of [bis(2-methoxyethyl)aminolsulfur trifluoride in 30 ml of CH2CI 2 was added dropwise at RT. After stirring at RT for 5 h, 12.0 g of diethylaminosulfur trifluoride were added. After stirring at RT for a further 20 h, the reaction 19 mixture was washed 3 times with 100 ml of water each time. It was dried over Na2SO 4 and the solvent was removed in vacuo. Chromatography on silica gel with EA/HEP 3:1 and subsequent kugelrohr distillation afforded 27.6 g of a colorless oil.
b) 3,3-Difluorocyclobutanol 22.4 g of (3,3-difluorocyclobutoxymethyl)benzene are dissolved in 100 ml of diethyl ether, and 1.4 g of 10% Pd/C are added. Hydrogenation was carried out at RT under 20 bar of H 2 for 5 h. The catalyst was washed with 10 ml of diethyl ether, and the solution was distilled. 14.0 g of the product (boiling point 80 0 C) were obtained as a mixture with diethyl ether and toluene. This mixture was reacted without further purification.
c) Methyl 4-(3,3-difluorocyclobutoxy)-5-methanesulfonyl-2-methylbenzoate 370 mg of methyl 4-fluoro-5-methanesulfonyl-2-methylbenzoate, 297 mg of 3,3-difluorocyclobutanol and 1.47 g of Cs 2
CO
3 were dissolved in 10 ml of anhydrous NMP and stirred at 60 0 C for 4 h. The reaction mixture was then diluted with 125 ml of a 50% concentrated aqueous NaHCO 3 solution and extracted 3 times with 100 ml of EA each time. It was dried over Na2SO4, and the solvent was removed in vacuo. Chromatography on silica gel with DIP resulted in 380 mg of a colorless oil.
Rf (DIP) 0.21 MS (DCI): 335 d) N-[4-(3,3-Difluorocyclobutoxy)-5-methanesulfonyl-2-methylbenzoyl]guanidine 566 mg of guanidinium chloride were dissolved in 5 ml of anhydrous DMF and added to a solution of 604 mg of KOtBu in 5 ml of anhydrous DMF.
This solution of guanidine in DMF prepared in this way was added to a solution of 360 mg of methyl 4-(3,3-difluorocyclobutoxy)-5methanesulfonyl-2-methylbenzoate in 5 ml of DMF and stirred at RT for 24 h. The reaction mixture was diluted with 125 ml of a 50% concentrated aqueous NaHCO 3 solution and extracted 3 times with 80 ml of EA each time. It was dried over Na 2
SO
4 and the solvent was removed in vacuo.
Chromatography on silica gel with EA/MeOH 5:1 afforded 175 mg of colorless crystals, mp 273 0 C (with decomposition).
Rf (EA/MeOH 5:1) 0.50 MS 362 Example 2 N-[4-(3,3-Difluorocyclobutylamino)-5-methanesulfonyl-2-methylbenzoyl]guanidine
FF
HN
0, O o 1 N NH 2
NH
2 a) 3,3-Difluorocyclobutylamine, hydrochloride 16.7 g of 3,3-difluorocyclobutanecarboxylic acid Org. Chem.. 1987, 52, 1872) were dissolved in 180 ml of CHCl 3 and 36 ml of H 2 SO4 were added. The mixture was heated to 50°C and, at this temperature, 16 g of NaN 3 were added in portions over the course of 45 minutes. The mixture was stirred at 50°C for 2 h and then cooled to room temperature and finally poured onto 250 g of ice. Extraction 3 times with 100 ml of diethyl ether each time recovered 0.7 g of unreacted 3,3-difluorocyclobutanecarboxylic acid. The aqueous phase was adjusted to pH 12-13 with aqueous NaOH solution and extracted 3 times with 100 ml of CH 2 C1 2 each time. The organic phase was washed with 100 ml of water, and then 130 ml of a 2N aqueous HCI solution were added and the volatile constituents were removed in vacuo. 15.3 g of a colorless solid were obtained, mp 315°C (decomposition).
b) N-(3,3-Difluorocyclobutyl)methanesulfonamide 0.60 g of 3,3-difluorocyclobutylamine, hydrochloride, were suspended in ml of CH 2 C1 2 and, at RT, 2.9 ml of triethylamine were added. This resulted in a clear solution. Then, at RT, 1.0 ml of methanesulfonyl chloride was slowly added dropwise, and the reaction mixture was left to stand at this temperature for 16 h. The volatile constituents were then removed in vacuo, and the residue was taken up and partitioned with 200 ml of EA and 100 ml of a saturated aqueous Na 2
CO
3 solution. The organic phase was subsequently washed twice with 20 ml of a saturated aqueous NaHSO 4 solution each time and twice with 30 ml of a saturated aqueous Na 2 C0 3 21 solution each time. MgSO 4 was used for drying, and the solvent was removed in vacuo. 700 mg of a colorless resin were obtained.
Rf 0.28 MS (DCI): 186 c) Methyl 4-(3,3-difluorocyclobutylamino)-5-methanesulfonyl- 2-methylbenzoate 0.70 g of N-(3,3-difluorocyclobutyl)methanesulfonamide, 0.93 g of methyl 4-fluoro-5-methanesulfonyl-2-methylbenzoate and 1.5 ml of N"-tert-butyl- N,N,N',N'-tetramethylguanidine were dissolved in 10 ml of NMP (anhydrous) and stirred at 150°C for 6 h. The reaction mixture was cooled to RT, diluted with 200 ml of EA and washed firstly 3 times with 20 ml of a saturated aqueous NaHSO 4 solution each time and then 3 times with 30 ml of a saturated aqueous Na 2
CO
3 solution each time. MgSO 4 was used for drying, and the solvent was removed in vacuo. Chromatography on silica gel with DIP afforded 220 mg of a colorless foam.
Rf (DIP) 0.31 MS 334 d) 4-(3,3-Difluorocyclobutylamino)-5-methanesulfonyl-2-methylbenzoic acid 210 mg of methyl 4-(3,3-difluorocyclobutylamino)-5-methanesulfonyl- 2-methylbenzoate were dissolved in 10 ml of dioxane, and 0.47 ml of a 2N aqueous NaOH solution was added. The mixture was stirred at RT for 18 h and then the solvents were removed in vacuo. The residue was taken up in ml of water, adjusted to pH 2 with aqueous HCI solution and extracted 3 times with 20 ml of EA each time. MgSO 4 was used for drying, and the solvent was removed in vacuo. 196 mg of an amorphous solid were obtained.
Rf (EA) 0.40 MS 318 e) N-[4-(3,3-Difluorocyclobutylamino)-5-methanesulfonyl-2-methylbenzoyl]guanidine mg of 4-(3,3-difluorocyclobutylamino)-5-methanesulfonyl- 2-methylbenzoic acid were dissolved in 1 ml of DMF (anhydrous) and, at RT, 26 mg of CDI were added, and the mixture was stirred at RT for 6 h to result in the intermediate imidazolide. Alongside, 72 mg of guanidine hydrochloride were stirred together with 70 mg of KOtBu in 1 ml of DMF (anhydrous) at RT for 30 minutes. This solution of the guanidine base was then added to the solution of the imidazolide, and the mixture was left to stand at RT for 18 h. It was then diluted with 50 ml of water and the pH was adjusted to pH 8 with dilute aqueous HCI solution. Three extractions were 22 carried out with 10 ml of EA each time and, after drying over MgSO 4 the solvent was removed in vacuo. 37 mg of an amorphous solid were obtained.
Rf (EA/MeOH 10:1)= 0.12 MS 360 The NHE-1 inhibition was determined as follows: FLIPR assay for determining NHE-1 inhibitors by measurement of the recovery in pHi in transfected cell lines which express human NHE-1 The assay is carried out in an FLIPR (fluorescent imaging plate reader) with black-walled 96-well microtiter plates with clear bases. The transfected cell lines expressing the various NHE subtypes (the parental cell line LAP-1 shows no endogenous NHE activity as a result of mutagenesis and subsequent selection) are seeded the preceding day at a density of 000 cells/well.
[The growth medium for the transfected cells (Iscove +10% fetal calf serum) additionally contains G418 as selection antibiotic in order to ensure the presence of the transfected sequences.] The actual assay starts with the removal of the growth medium and addition of 100 tl of loading buffer per well (5 pM BCECF-AM -6)-carboxyfluorescein, acetoxymethyl ester] in mM NH4CI, 115 mM choline chloride, 1 mM MgCI2, 1 mM CaCI2, 5 mM KCI, 20 mM HEPES, 5 mM glucose; pH 7.4 [adjusted with KOH]).
The cells are then incubated at 37°C for 20 minutes. This incubation leads to loading of the cells with the fluorescent dye whose fluorescence intensity depends on pHi, and with NH4CI which makes the cells slightly alkaline.
[The nonfluorescent dye precursor BCECF-AM is, as ester, membranepermeable. The actual dye BCECF which is not membrane-permeable is liberated inside cells by esterases.] After this incubation for 20 minutes, the loading buffer which contains
NH
4 CI and free BCECF-AM is removed by washing three times in a cell washer (Tecan Columbus) with in each case 400 pl of washing buffer (133.8 mM choline chloride, 4.7 mM KCI, 1.25 mM MgCI2, 1.25 mM CaCI2, 0.97 mM K2HPO4, 0.23 mM KH2PO4, 5 mM HEPES, 5 mM glucose; pH 7.4 [adjusted with KOH]). The residual volume remaining in the wells is pl (50-125 pl possible). This washing step removes the free BCECF-AM and results, as a consequence of the removal of the external NH4 ions, in intracellular acidification pHi 6.3 6.4).
Since the equilibrium of intracellular NH 4 with NH 3 and H is disturbed by the removal of the extracellular NH 4 and by the subsequent instantaneous passage of the NH 3 through the cell membrane, the washing process results in H remaining inside the cells, which is the cause of the intracellular acidification. This may eventually lead to cell death if it persists long enough.
It is important at this point that the washing buffer is sodium-free mM) because extracellular sodium ions would lead to an instantaneous recovery of the pHi through the activity of the cloned NHE isoforms.
It is likewise important for all the buffers used (loading buffer, washing buffer, recovery buffer) not to contain any HCO 3 ions, because the presence of bicarbonate would lead to activation of interfering bicarbonatedependent pHi regulatory systems present in the parental LAP-1 cell line.
The microtiter plates with the acidified cells are then (up to 20 minutes after the acidification) transferred to the FLIPR. In the FLIPR, the intracellular fluorescent dye is excited by light with a wavelength of 488 nm generated by an argon laser, and the measured parameters (laser power, illumination time and aperture of the CCD camera incorporated in the FLIPR) are chosen so that the average fluorescence signal per well is between 30 000 and 35 000 relative fluorescence units.
The actual measurement in the FLIPR starts with a photograph being taken by the CCD camera every two seconds under software control. After ten seconds, the recovery of the intracellular pH is initiated by adding 90 p/ of recovery buffer (133.8 mM NaCI, 4.7 mM KCI, 1.25 mM MgCI2, 1.25 mM CaCI2, 0.97 mM K2HPO 4 0.23 mM KH2PO 4 10 mM HEPES, 5 mM glucose; pH 7.4 [adjusted with NaOH]) by means of the 96-well pipettor incorporated in the FLIPR.
Positive control wells (100% NHE activity) are those to which pure recovery buffer is added, while negative controls NHE activity) receive washing buffer. Recovery buffer with twice the concentration of test substance is added to all the other wells. Measurement in the FLIPR terminates after measurements (two minutes).
The raw data are exported into the ActivityBase program. This program firstly calculates the NHE activities for each tested substance concentration 00 and, from these, the IC50 values for the substances. Since the progress of pHi ;Z recovery is not linear throughout the experiment, but falls at the end owing to decreasing NHE activity at higher pHi values, it is important to select for evaluation of the measurement the part in which the increase in fluorescence of the positive controls is linear.
00 Example NHE1 inhibition IC50 [nM] (Ni 1 5.9 Comprises/comprising and grammatical variations thereof when used in this specification are to be taken to specify the presence of stated features, integers, steps or components or groups thereof, but do not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.
Claims (16)
1. A fluorinated cycloalkyl-derivatized benzoylguanidine of the formula I 2)q F 2 )n H 2 )r H 2 )m R2 X R1 R3 NYNH 2 R4 O NH 2 in which the meanings are: X oxygen, sulfur or NR6; R6 hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or (CH2)k-CF3; k 0, 1, 2 or 3; m zero, 1, 2 or 3; n zero, 1, 2 or 3; p zero, 1, 2, or 3; q 1,2 or 3; r zero, 1, 2 or 3; where the total of m, n, p, q and r is at least 2; R1 hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, CI, -OR(7), -NR(8)R(9) or -CsF2s+l; R(8) and R(9) independently of one another hydrogen, alkyl having 1, 2 or 3 carbon atoms or (CH2)t-CF3; s 1,2, 3 or 4; t 0, 1, 2, 3 or 4; R2 hydrogen, F, CI, alkyl having 1, 2, 3 or 4 carbon atoms or CF3; R3 hydrogen, F, CI, alkyl having 1, 2, 3 or 4 carbon atoms, CF 3 or u zero, 1 or 2; alkyl having 1, 2, 3 or 4 carbon atoms or NR11 R12; R11 and R12 independently of one another hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; R4 hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, CI, -OR(13), -NR(14)R(15) or -CvF2v+l; R(13), R(14) and independently of one another hydrogen, alkyl having 1, 2 or 3 carbon atoms or (CH2)w-CF3; v 1,2, 3 or 4; w 0, 1,2, 3, or 4; hydrogen or F; and the pharmacologically acceptable salts thereof.
2. A compound of the formula I as claimed in claim 1, wherein the meanings are: X oxygen, sulfur or NR6; R6 hydrogen, methyl or CH 2 -CF 3 m zero, 1 or 2; n zero, 1 or 2; p zero, 1 or 2; q 1 or 2; r zero, 1 or 2; where the total of m, n, p, q and r is at least 2; R1 hydrogen, methyl, F, CI, -NR(8)R(9) or -CF 3 R(8) and R(9) independently of one another hydrogen, methyl, CF 3 or CH 2 -CF 3 R2 hydrogen, F, CI, methyl or CF 3 R3 hydrogen, F, CI, alkyl having 1, 2, 3 or 4 carbon atoms, CF3, SO 2 CH 3 or SO 2 NH 2 R4 hydrogen, methyl, F, CI, -OR(13), -NR(14)R(15) or -CF 3 R(13), R(14) and independently of one another hydrogen, methyl, CF 3 or CH 2 -CF 3 hydrogen or F; and the pharmacologically acceptable salts thereof.
3. A compound of the formula I as claimed in claim 1 or 2, wherein the meanings are: X oxygen, sulfur or NR6; R6 hydrogen, methyl or CH 2 -CF 3 m zero or 1; n zero, 1 or 2; p zero or 1; q 1 or 2; 00 O r zero or 1; Cl where the total of m, n, p, q and r is at least 2; S R1 hydrogen, methyl, F, CI, -NR(8)R(9) or -CF3; methyl, CF 3 or CH2-CF3; (N R(8) and R(9) independently of one another hydrogen, methyl or CH 2 -CF 3 00 0 R2 hydrogen, F or Cl; SR3 CF3, SO2CH 3 or SO2NH2; R4 hydrogen; R5 hydrogen or F; and the pharmacologically acceptable salts thereof.
4. A compound of the formula I as claimed in any one of claims 1, 2 and 3, selected from the group: N-[4-(3,3-difluorocyclobutoxy)-5-methanesulfonyl-2-methylbenzoyl]-quanidine, N-[4(3,3-difluorocyclobutylamino)-5-methanesulfonyl-2-methylbenzoyl]-quanidine, N-{4-[(3,3-difluorocyclobutyl)methylamino]-5-methanesulfonyl-2-methyl- benzoyl}guanidine and N-{4-[(3,3-difluorocyclobutyl)methylamino]-5-ethanesulfonyl-2-methyl- benzoyl}guanidine and the pharmaceutically acceptable salts thereof.
A compound of the formula I and/or the pharmaceutically acceptable salts thereof as claimed in any one of claims 1 to 4 for use as medicament.
6. The use of a compound of the formula I and/or the pharmaceutically acceptable salts thereof as claimed in any one of claims 1 to 4 for producing a medicament for the treatment or prophylaxis of acute or chronic damage, disorders or indirect sequelae of organs and tissues caused by ischemic events or by reperfusion events, for the treatment or prophylaxis of arrhythmias, of life- threatening ventricular fibrillation of the heart, of myocardial infarction, of angina 00 0 pectoris, for the treatment or prophylaxis of ischemic states of the heart, of c ischemic states of the peripheral and central nervous system or of stroke or of tischemic states of peripheral organs and tissues, for the treatment or prophylaxis ;Z of states of shock, or diseases in which cell proliferation represents a primary or c 5 secondary cause, of cancer, of metastasis, of prostate hypertrophy or of prostate hyperplasia, of atherosclerosis or of impairments of lipid metabolism, of high Sblood pressure, in particular of essential hypertension, of disorders of the central oo 0nervous system, especially of disorders resulting through CNS overexcitability, c such as epilepsy or centrally induced convulsions, of disorders of the central C 10 nervous system, especially of anxiety states, depressions or psychoses, for the c treatment or prophylaxis of non-insulin-dependent diabetes mellitus (NIDDM) or late damage from diabetes, of thromboses, or disorders resulting from endothelial dysfunction, of intermittent claudication, for the treatment or prophylaxis of fibrotic disorders of internal organs, fibrotic disorders of the liver, fibrotic disorders of the kidney, fibrotic disorders of vessels and fibrotic disorders of the heart, for the treatment or prophylaxis of heart failure or of congestive heart failure, acute or chronic inflammatory disorders, of disorders caused by protozoa, of malaria and of coccidiosis in poultry and for use in surgical operations and organ transplantations, for preserving and storing transplants for surgical procedures, for preventing age-related tissue change, for producing a medicament directed against aging or for prolonging life, for the treatment and reduction of the cardiotoxic effects in thyrotoxicosis or for producing a diagnostic aid.
7. The use of a compound of the formula I and/or the pharmaceutically acceptable salts thereof as claimed in any one of claims 1 to 4 in combination with other medicaments or active ingredients for producing a medicament for the treatment or prophylaxis of acute or chronic damage, disorders or indirect sequelae of organs and tissues caused by ischemic events or by reperfusion events, for the treatment or prophylaxis of arrhythmias, of life-threatening ventricular fibrillation of the heart, of myocardial infarction, of angina pectoris, for the treatment or prophylaxis of ischemic states of the heart, of ischemic states of the peripheral and central nervous system or of stroke or of ischemic states of peripheral organs and tissues, for the treatment or prophylaxis of states of shock, 28a 00 0 of diseases in which cell proliferation represents a primary or secondary cause, of cl cancer, of metastasis, of prostate hypertrophy or of prostate hyperplasia, of atherosclerosis or of impairments of lipid metabolism, of high blood pressure, in particular of essential hypertension, of disorders of the central nervous system, c 5 especially of disorders resulting through CNS overexcitability, such as epilepsy or centrally induced convulsions, of 00 disorders of the central nervous system, especially of anxiety states, depressions or psychoses, for the treatment or prophylaxis of non-insulin- dependent diabetes mellitus (NIDDM) or late damage from diabetes, of thromboses, or disorders resulting from endothelial dysfunction, of intermittent claudication, for the treatment or prophylaxis of fibrotic disorders of intemrnal organs, fibrotic disorders of the liver, fibrotic disorders of the kidney, fibrotic disorders of vessels and fibrotic disorders of the heart, for the treatment or prophylaxis of heart failure or of congestive heart failure, acute or chronic inflammatory disorders, of disorders caused by protozoa, of malaria and of coccidiosis in poultry and for use in surgical operations and organ transplantations, for preserving and storing transplants for surgical procedures, for preventing age-related tissue change, for producing a medicament directed against aging or for prolonging life, for the treatment and reduction of the cardiotoxic effects in thyrotoxicosis or for producing a diagnostic aid.
8. The use of a compound of the formula I and/or the pharmaceutically acceptable salts thereof as claimed in claim 7 in combination with cardiotoxic and cytotoxic medicaments or active ingredients for producing a medicament with reduced cardiotoxic and cytotoxic properties.
9. The use of a compound of the formula I and/or its pharmaceutically acceptable salts, alone or in combination with other medicaments or active ingredients, as claimed in claim 6 and/or 7 for producing a medicament for the treatment or prophylaxis of acute and chronic damage, disorders or indirect sequelae of organs and tissues caused by ischemic events or by reperfusion events.
The use of a compound of the formula I and/or the pharmaceutically acceptable salts thereof alone or in combination with other medicaments or active ingredients as claimed in claim 6 and/or 7 for producing a medicament for the treatment of life-threatening ventricular fibrillation of the heart.
11. The use of a compound of the formula I and/or the pharmaceutically acceptable salts thereof alone or in combination with other medicaments or active ingredients as claimed in claim 6 and/or 7 for producing a medicament for the treatment of or prophylaxis of metastasis. 00 O
12. The use of a compound of the formula I and/or its pharmaceutically c-I acceptable salts, alone or in combination with other medicaments or active ingredients, as claimed in claim 6 and/or 7 for producing a medicament for the treatment or prophylaxis of fibrotic heart diseases, of heart failure or of congestive c- 5 heart failure. c-
13. A medicine for human, veterinary and/or phytoprotective use comprising 00 oO 0an effective amount of at least one compound of the formula I and/or the V) c- pharmaceutically acceptable salts as claimed in any one of claims 1 to 4, together 0 10 with pharmaceutically acceptable carriers and additives.
14. A medicine for human, veterinary and/or phytoprotective use comprising an effective amount of at least one compound of the formula I and/or the pharmaceutically acceptable salts as claimed in any one of claims 1 to 4, together with pharmaceutically acceptable carriers and additives in combination with other pharmacological active ingredients or medicaments.
A compound substantially as hereinbefore described with reference to examples 1 and 2.
16. A method of treatment or prophylaxis of a condition described in any one of claims 6 to 12 by the administration of an effective amount of a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable derivative thereof to a subject in need. SANOFI-AVENTIS DEUTSCHLAND GMBH WATERMARK PATENT TRADE MARK ATTORNEYS P24900AU00
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10226462.7 | 2002-06-13 | ||
DE10226462A DE10226462A1 (en) | 2002-06-13 | 2002-06-13 | Fluorinated cycloalkyl-derivatized benzoylguanidines, process for their preparation, their use as medicament, and medicament containing them |
PCT/EP2003/005738 WO2003106410A1 (en) | 2002-06-13 | 2003-06-02 | Fluorinated cycloalkyl-derivatised benzoylguanidines and their use as a medicament |
Publications (3)
Publication Number | Publication Date |
---|---|
AU2003250821A1 AU2003250821A1 (en) | 2003-12-31 |
AU2003250821B2 AU2003250821B2 (en) | 2008-09-11 |
AU2003250821B8 true AU2003250821B8 (en) | 2008-10-02 |
Family
ID=29594510
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU2003250821A Ceased AU2003250821B8 (en) | 2002-06-13 | 2003-06-02 | Fluorinated cycloalkyl-derivatised benzoylguanidines and their use as a medicament |
Country Status (26)
Country | Link |
---|---|
EP (2) | EP2103598A1 (en) |
JP (1) | JP4383343B2 (en) |
KR (1) | KR20050010052A (en) |
CN (1) | CN1295213C (en) |
AR (1) | AR040201A1 (en) |
AT (1) | ATE442353T1 (en) |
AU (1) | AU2003250821B8 (en) |
BR (1) | BR0312134A (en) |
CA (1) | CA2489245A1 (en) |
DE (2) | DE10226462A1 (en) |
DK (1) | DK1515947T3 (en) |
ES (1) | ES2333216T3 (en) |
HK (1) | HK1076449A1 (en) |
HR (1) | HRP20041175A2 (en) |
MA (1) | MA27234A1 (en) |
MX (2) | MXPA04011361A (en) |
MY (1) | MY130810A (en) |
NO (1) | NO20050078L (en) |
PE (1) | PE20040559A1 (en) |
PL (1) | PL372054A1 (en) |
PT (1) | PT1515947E (en) |
RS (1) | RS105904A (en) |
RU (1) | RU2305093C2 (en) |
TW (1) | TWI291460B (en) |
WO (1) | WO2003106410A1 (en) |
ZA (1) | ZA200409418B (en) |
Families Citing this family (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10338554A1 (en) * | 2003-08-22 | 2005-03-31 | Aventis Pharma Deutschland Gmbh | Pentafluorosulfanylphenyl-substituted benzoylguanidines, process for their preparation, their use as a medicament or diagnostic agent, and medicament containing them |
DE102004043938A1 (en) * | 2004-09-11 | 2006-03-30 | Sanofi-Aventis Deutschland Gmbh | Pentafluorosulfanylphenyl-substituted benzoylguanidines, process for their preparation, their use as a medicament or diagnostic agent, and medicament containing them |
DE102004054847A1 (en) * | 2004-11-13 | 2006-05-24 | Sanofi-Aventis Deutschland Gmbh | Substituted benzoylguanidines, process for their preparation, their use as medicament or diagnostic agent, and medicament containing them |
BRPI0715160A2 (en) | 2006-08-08 | 2013-06-11 | Sanofi Aventis | arylamimoaryl-alkyl-substituted imidazolidine-2,4-diones, process for preparing them, drugs comprising these compounds, and their use |
EP2025674A1 (en) | 2007-08-15 | 2009-02-18 | sanofi-aventis | Substituted tetra hydro naphthalines, method for their manufacture and their use as drugs |
AU2009253961A1 (en) * | 2008-06-06 | 2009-12-10 | Ucb Pharma, S.A. | Compounds comprising a cyclobutoxy group |
UY31968A (en) | 2008-07-09 | 2010-01-29 | Sanofi Aventis | NEW HETEROCYCLIC DERIVATIVES, THEIR PROCESSES FOR THEIR PREPARATION, AND THEIR THERAPEUTIC USES |
WO2010068601A1 (en) | 2008-12-08 | 2010-06-17 | Sanofi-Aventis | A crystalline heteroaromatic fluoroglycoside hydrate, processes for making, methods of use and pharmaceutical compositions thereof |
US8785608B2 (en) | 2009-08-26 | 2014-07-22 | Sanofi | Crystalline heteroaromatic fluoroglycoside hydrates, pharmaceuticals comprising these compounds and their use |
WO2011107494A1 (en) | 2010-03-03 | 2011-09-09 | Sanofi | Novel aromatic glycoside derivatives, medicaments containing said compounds, and the use thereof |
EP2582709B1 (en) | 2010-06-18 | 2018-01-24 | Sanofi | Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases |
US8530413B2 (en) | 2010-06-21 | 2013-09-10 | Sanofi | Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments |
TW201215387A (en) | 2010-07-05 | 2012-04-16 | Sanofi Aventis | Spirocyclically substituted 1,3-propane dioxide derivatives, processes for preparation thereof and use thereof as a medicament |
TW201221505A (en) | 2010-07-05 | 2012-06-01 | Sanofi Sa | Aryloxyalkylene-substituted hydroxyphenylhexynoic acids, process for preparation thereof and use thereof as a medicament |
TW201215388A (en) | 2010-07-05 | 2012-04-16 | Sanofi Sa | (2-aryloxyacetylamino)phenylpropionic acid derivatives, processes for preparation thereof and use thereof as medicaments |
EP2683705B1 (en) | 2011-03-08 | 2015-04-22 | Sanofi | Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
EP2683698B1 (en) | 2011-03-08 | 2017-10-04 | Sanofi | Benzyl-oxathiazine derivates substituted with adamantane or noradamantane, medicaments containing said compounds and use thereof |
US8895547B2 (en) | 2011-03-08 | 2014-11-25 | Sanofi | Substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof |
WO2012120053A1 (en) | 2011-03-08 | 2012-09-13 | Sanofi | Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
WO2012120058A1 (en) | 2011-03-08 | 2012-09-13 | Sanofi | Oxathiazine derivatives which are substituted with benzyl or heteromethylene groups, method for producing them, their use as medicine and drug containing said derivatives and the use thereof |
US8809324B2 (en) | 2011-03-08 | 2014-08-19 | Sanofi | Substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof |
US8871758B2 (en) | 2011-03-08 | 2014-10-28 | Sanofi | Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof |
WO2012120052A1 (en) | 2011-03-08 | 2012-09-13 | Sanofi | Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof |
WO2012120055A1 (en) | 2011-03-08 | 2012-09-13 | Sanofi | Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
WO2013037390A1 (en) | 2011-09-12 | 2013-03-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
WO2013045413A1 (en) | 2011-09-27 | 2013-04-04 | Sanofi | 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
RU2518740C1 (en) * | 2013-03-22 | 2014-06-10 | Федеральное государственное автономное образовательное учреждение высшего профессионального образования "ЮЖНЫЙ ФЕДЕРАЛЬНЫЙ УНИВЕРСИТЕТ" | METHOD, INHIBITING Na+/H+-EXCHANGE, AND DIHYDROCHLORIDE OF 2-(3,4-METHYLENEDIOXYPHENYL)-9-MORPHOLINOETHYLIMIDAZO[1,2-a]BENZIMIDAZOLE |
RU2765117C2 (en) * | 2019-09-24 | 2022-01-25 | Федеральное государственное автономное образовательное учреждение высшего образования "Уральский федеральный университет имени первого Президента России Б.Н. Ельцина" | Use of sodium salt of diethyl ester of 4-oxo-1,4-dihydropyrazolo[5,1-c]-1,2,4-triazine-3,8-dicarboxylic acid, monohydrate as drug for treatment and prevention of late complications of diabetes mellitus |
CN113274380A (en) * | 2021-05-13 | 2021-08-20 | 武汉理工大学 | Application of S0859 in preparation of medicine for treating cerebral ischemia-reperfusion injury |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0602523A1 (en) * | 1992-12-15 | 1994-06-22 | Hoechst Aktiengesellschaft | Substituted benzoylguanidines, process for their preparation, their use as medicament or diagnostic agent, as well as a medicament containing them |
US6057322A (en) * | 1995-01-30 | 2000-05-02 | Hoechst Aktiengesellschaft | Basically-substituted benzoylguanidines, a process for preparing them, their use as a medicament or diagnostic agent, and a medicament containing them |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5665739A (en) * | 1992-12-15 | 1997-09-09 | Hoechst Aktiengesellschaft | Substituted benzoylguanidines, process and their preparation, their use as pharmaceutical or diagnostic, and pharmaceutical containing them |
DE4417004A1 (en) * | 1994-05-13 | 1995-11-16 | Hoechst Ag | Perfluoroalkyl-substituted benzoylguanidines, process for their preparation, their use as a medicament or diagnostic agent, and medicament containing them |
-
2002
- 2002-06-13 DE DE10226462A patent/DE10226462A1/en not_active Withdrawn
-
2003
- 2003-05-05 MX MXPA04011361A patent/MXPA04011361A/en unknown
- 2003-06-02 EP EP09005497A patent/EP2103598A1/en not_active Withdrawn
- 2003-06-02 BR BR0312134-8A patent/BR0312134A/en not_active IP Right Cessation
- 2003-06-02 EP EP03759904A patent/EP1515947B1/en not_active Expired - Lifetime
- 2003-06-02 MX MXPA04012231A patent/MXPA04012231A/en active IP Right Grant
- 2003-06-02 WO PCT/EP2003/005738 patent/WO2003106410A1/en active Application Filing
- 2003-06-02 RU RU2005100508/04A patent/RU2305093C2/en not_active IP Right Cessation
- 2003-06-02 PL PL03372054A patent/PL372054A1/en not_active Application Discontinuation
- 2003-06-02 DK DK03759904.0T patent/DK1515947T3/en active
- 2003-06-02 CN CNB038136139A patent/CN1295213C/en not_active Expired - Fee Related
- 2003-06-02 JP JP2004513243A patent/JP4383343B2/en not_active Expired - Lifetime
- 2003-06-02 AT AT03759904T patent/ATE442353T1/en not_active IP Right Cessation
- 2003-06-02 AU AU2003250821A patent/AU2003250821B8/en not_active Ceased
- 2003-06-02 RS YUP-1059/04A patent/RS105904A/en unknown
- 2003-06-02 CA CA002489245A patent/CA2489245A1/en not_active Abandoned
- 2003-06-02 KR KR10-2004-7020290A patent/KR20050010052A/en not_active Application Discontinuation
- 2003-06-02 PT PT03759904T patent/PT1515947E/en unknown
- 2003-06-02 DE DE50311897T patent/DE50311897D1/en not_active Expired - Lifetime
- 2003-06-02 ES ES03759904T patent/ES2333216T3/en not_active Expired - Lifetime
- 2003-06-11 TW TW092115780A patent/TWI291460B/en not_active IP Right Cessation
- 2003-06-11 AR ARP030102093A patent/AR040201A1/en unknown
- 2003-06-11 PE PE2003000580A patent/PE20040559A1/en not_active Application Discontinuation
- 2003-06-12 MY MYPI20032196A patent/MY130810A/en unknown
-
2004
- 2004-11-23 ZA ZA200409418A patent/ZA200409418B/en unknown
- 2004-12-08 MA MA27988A patent/MA27234A1/en unknown
- 2004-12-10 HR HR20041175A patent/HRP20041175A2/en not_active Application Discontinuation
-
2005
- 2005-01-06 NO NO20050078A patent/NO20050078L/en not_active Application Discontinuation
- 2005-09-23 HK HK05108396A patent/HK1076449A1/en not_active IP Right Cessation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0602523A1 (en) * | 1992-12-15 | 1994-06-22 | Hoechst Aktiengesellschaft | Substituted benzoylguanidines, process for their preparation, their use as medicament or diagnostic agent, as well as a medicament containing them |
US6057322A (en) * | 1995-01-30 | 2000-05-02 | Hoechst Aktiengesellschaft | Basically-substituted benzoylguanidines, a process for preparing them, their use as a medicament or diagnostic agent, and a medicament containing them |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2003250821B2 (en) | Fluorinated cycloalkyl-derivatised benzoylguanidines and their use as a medicament | |
US8008352B2 (en) | Pentafluorosulfanylbenzoylguanidines, processes for their preparation, their use as medicaments or diagnostic aids, and medicaments comprising them | |
US7772262B2 (en) | Substituted benzoylguanidines, method for production and use thereof as medicament or diagnostic and medicament comprising the same | |
AU2003242531B2 (en) | Pentafluorosulfanyl-benzoylguanidine, method for the production thereof and its utilization as medicament or diagnostic agent and medicament containing same | |
US7381841B2 (en) | Pentafluorosulfanylphenyl-substituted benzoylguanidines, processes for their preparation, their use as medicament or diagnostic aid, and medicament comprising them | |
AU2004268762B2 (en) | Pentafluorosulfanyl phenyl-substituted benzoylguanidines, method for their production, their use as medicaments or diagnostic agents and medicament containing said compounds | |
CA2551057C (en) | Pentafluorosulfanyl benzoylguanidines, method for their production, their use as medicaments or diagnostic agents and medicament containing the same | |
US6878748B2 (en) | Fluorinated cycloalkyl-derivatized benzoylguanidines, process for their preparation, their uses as medicament, and medicament containing them | |
US7446225B2 (en) | Pentafluorosulfanylphenyl-substituted benzoylguanidines, method for the production thereof, their use as a medicament or diagnostic agent, and a medicament containing these compounds | |
US7622611B2 (en) | Pentafluorosulfanylbenzoylguanidines, process for their preparation, use as a medicament or diagnostic aid, and medicament comprising same | |
NZ537168A (en) | Fluorinated cycloalkyl-derivatised benzoylguanidines to protect against the cytotoxic effects of medicaments such as those used in cancer therapy and the therapy of autoimmune diseases | |
NZ536579A (en) | Pentafluorosulfanyl-benzoylguanidine, method for the production thereof and its utilization as medicament or diagnostic agent and medicament containing same | |
MXPA06005136A (en) | Pentafluorosulfanyl benzoylguanidines, method for their production, their use as medicaments or diagnostic agents and medicament containing the same |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PC1 | Assignment before grant (sect. 113) |
Owner name: SANOFI-AVENTIS DEUTSCHLAND GMBH Free format text: FORMER APPLICANT(S): AVENTIS PHARMA DEUTSCHLAND GMBH |
|
TH | Corrigenda |
Free format text: IN VOL 22, NO 36, PAGE(S) 4329 UNDER THE HEADING APPLICATIONS ACCEPTED -NAME INDEX UNDER THE NAME SANOFI-AVENTIS DEUTSCHLAND GMBH, APPLICATION NO. 2003250821, UNDER INID (72), CORRECT THE INVENTOR TO KLEEMANN, HEINZ-WERNER |
|
FGA | Letters patent sealed or granted (standard patent) | ||
MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |