NO20024997L - 2-guanidino-4-arylkinazoliner som NHE-3-inhibitorer - Google Patents
2-guanidino-4-arylkinazoliner som NHE-3-inhibitorer Download PDFInfo
- Publication number
- NO20024997L NO20024997L NO20024997A NO20024997A NO20024997L NO 20024997 L NO20024997 L NO 20024997L NO 20024997 A NO20024997 A NO 20024997A NO 20024997 A NO20024997 A NO 20024997A NO 20024997 L NO20024997 L NO 20024997L
- Authority
- NO
- Norway
- Prior art keywords
- quinazolinylguanidine
- chloro
- methylphenyl
- formula
- phenyl
- Prior art date
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- 239000003112 inhibitor Substances 0.000 title claims description 20
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 208000028774 intestinal disease Diseases 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 229960003343 ouabain Drugs 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 230000036278 prepulse Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 210000000512 proximal kidney tubule Anatomy 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000020988 regulation of intracellular pH Effects 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 201000002859 sleep apnea Diseases 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid group Chemical class S(N)(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/84—Nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- 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
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
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- A61P3/06—Antihyperlipidemics
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- 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
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- 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
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- 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
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- 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
- A61P7/10—Antioedematous agents; Diuretics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- 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
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- A61P9/12—Antihypertensives
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- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Diabetes (AREA)
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- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Heart & Thoracic Surgery (AREA)
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- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pulmonology (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Oppfinnelsen vedrører forbindelser med formel I
hvor
Ar er usubstituert eller mono-R<3->substituert fenyl eller naftyl,
R<1>og R<2>er uavhengig av hverandre H, A, OA, Hal eller CF3,
R<3>er A, OA, Hal eller CF3,
A er alkyl med 1, 2, 3, 4, 5 eller 6 karbonatomer, og
Hal er F, Cl, Br eller I,
og deres fysiologisk akseptable salter og solvater, som NHE-3-inhibitorer.
Formel I dekker også de tautomeriske forbindelsene med formel I'
Andre inhibitorer for undertype 3 av natrium-/proton-bytteren er beskrevet for eksempel i EP 0 825 178.
Forbindelsene med formlene I og F er allerede blitt beskrevet i US patentskrift
nr. 3 131 187 som vedrører deres anvendelse for andre formål.
Kinazolinguanidinderivater er beskrevet av V.I. Shvedov et al. i Pharm. Chem. J.
(engelsk oversettelse) 1980, 14, 532-538 eller i Khim. Farm. Zh. 1980, 14, 38-43, og av S.C. Bell et al. i J. Med. Pharm. Chem. 1962, 5, 63-69.
Oppfinnelsen hadde det formål å finne nye forbindelser med verdifulle egenskaper, særlig de som kan anvendes til fremstillingen av medikamenter.
Overraskende er det blitt funnet at forbindelsene med formel I og deres salter tolereres godt og inhiberer undertype 3 av natrium-/proton-bytter. Forbindelsene med formel I kan anvendes som medikamentaktive bestanddeler innen human- og veterinærmedisin.
Det er kjent at Na<+->/H+<->bytteren utgjør en familie med minst 6 forskjellige isoformer (NHE-1 til NHE-6) som alle nå er blitt klonet. Mens undertype NHE-1 fordeles overalt i alle vev gjennom kroppen, uttrykkes de øvrige NHE-undertypene selektivt i bestemte organer, slik som i nyrene eller i hulromveggen og kontrahullromveggen i tynntarmen. Denne fordeling gjenspeiler de spesifikke funksjonene som de forskjellige isoformene tjener, nemlig på den ene side regulering av den intracellulære-pH-verdi og cellevolum ved hjelp av undertype-NHE-1, og på den andre siden Na<+->absorpsjon og -resorpsjon i tarmen og nyrene ved isoformene NHE-2 og NHE-3. Isoform NHE-4 er hovedsakelig blitt funnet i magen. Ekspresjon av NHE-5 er begrenset til hjerne- og nervevev. NHE-6 er isoformen som danner natrium-/proton-bytteren i mitokondriene.
Isoform NHE-3 uttrykkes særlig i spissmembranen til de proksimale nyrerør; en NHE-3-inhibitor utøver derfor blant annet en beskyttelsesvirkning på nyrene.
Den terapeutiske anvendelse av en selektiv inhibitor for NHE-3-isoformer er mangfoldig. NHE-3-inhibitorer hemmer eller reduserer vevsskade og cellenekrose etter patofysiologiske hypoksiske og iskemiske hendelser som resulterer i aktivering av NHE-akti vi teten, noe som er tilfellet under nyreiskemi eller under fjerning, transport og reperfusjon av nyre under en nyretransplantasjon.
Forbindelsene med formel I har en cytobeskyttende virkning ved at de forhindrer for mye absorpsjon av natrium og vann i cellene i organer som er underforsynt med oksygen.
Forbindelsene med formel I har en hypotensiv virkning og er egnet som
medikamentaktive bestanddeler til behandlingen av hypertoni. De er dessuten egnet som diuretika. Forbindelsene med formel I har alene eller i kombinasjon med NHE-inhibitorer av annen undertypespesifisitet, en anti-iskemisk virkning og kan anvendes i tilfellet med tromboser, aterosklerose, vaskulære spasmer, til beskyttelse av organer, for eksempel nyre og lever, før og under operasjoner, og i tilfellet med kronisk eller akutt nyresvikt. De kan dessuten anvendes til behandlingen av slag, cerebralt ødem, iskemier i nervesystemet, forskjellige former for sjokk, for eksempel allergisk, kardiologisk, hypovolemisk eller bakterielt sjokk, og til forbedring av respirasjonsstart, for eksempel ved de følgende tilstander: sentral søvnapné, krybbedød, postoperativ hypoksi og andre åndedrettsforstyrrelser. Gjennom kombinasjonen med en karboanhydraseinhibitor kan åndedrettsaktivitet forbedres ytterligere. Forbindelsene med formel I har en inhiberende effekt på proliferasjonen av celler, for eksempel fibroblastcelleproliferasjon og proliferasjonen av glattmuskelcellene, og kan derfor anvendes til behandling av sykdommer hvor celleproliferasjon er en primær eller sekundær årsak. Forbindelsene med formel I kan anvendes mot forsinkede komplikasjoner ved sukkersyke, kreftsykdommer, fibrotiske sykdommer, endotelisk dysfunksjon, organhypertrofi og -hyperplasi, særlig ved prostatahyperplasi eller prostatahypertrofi. De er dessuten egnet som diagnostiske midler til bestemmelsen og differensieringen av visse former for hypertoni, aterosklerose, sukkersyke og proliferative sykdommer. Ettersom forbindelsene med formel I også har en fordelaktig effekt på nivået av serumlipoproteiner kan de anvendes alene eller i kombinasjon med andre medikamenter, til behandling av et forøkt blodfettnivå.
Oppfinnelsen vedrører anvendelsen av forbindelser med formel I ifølge krav 1 og deres fysiologisk akseptable salter og/eller solvater til fremstilling av et medikament for behandling av trombose, iskemiske tilstander i hjertet, i det perifere og sentrale nervesystem, og av slag, iskemiske tilstander i perifere organer og ekstremiteter, og til behandlingen av sjokktilstander.
Oppfinnelsen vedrører dessuten anvendelsen av forbindelser med formel I ifølge krav 1 og deres fysiologisk akseptable salter og/eller solvater til fremstilling av et medikament for anvendelse ved kirurgiske operasjoner og organtransplantasjoner, til konservering og lagring av transplantater for kirurgiske formål.
Oppfinnelsen vedrører også anvendelsen av forbindelser med formel I ifølge krav 1 og deres fysiologisk akseptable salter og/eller solvater til fremstilling av et medikament for behandling av sykdommer hvor celleproliferasjon er en primær eller sekundær årsak, til behandling eller profylakse av forstyrrelser i fettmetabolisme eller forstyrret respirasj onsstyring.
Oppfinnelsen vedrører dessuten anvendelsen av forbindelser med formel I ifølge krav 1 og deres fysiologisk akseptable salter og/eller solvater til fremstilling av et medikament for behandling av nyreiskemi, iskemiske tarmsykdommer eller til profylakse av akutte eller kroniske nyresykdommer.
Fremgangsmåter for identifikasjon av stoffer som inhiberer natrium-/proton-bytter av undertype 3 er beskrevet for eksempel i US patentskrift nr. 5 871 919.
For alle radikaler i forbindelsene med formel I som opptrer mer enn én gang, slik som for eksempel A, er deres betydninger uavhengige av hverandre.
Uttrykket hydrater og solvater skal for eksempel bety hemi-, mono- eller dihydratene, og uttrykket solvater skal for eksempel bety alkoholaddisjonsforbindelser, slik som for eksempel med metanol eller etanol.
I formelen ovenfor er A alkyl, er rettkjedet eller forgrenet, og har 1, 2, 3, 4, 5 eller 6 karbonatomer. A er fortrinnsvis metyl, dessuten etyl, propyl, isopropyl, butyl, isobutyl, sek.-butyl eller tert.-butyl, dessuten også pentyl, 1-, 2- eller 3-metylbutyl, 1,1-, 1.2- eller 2,2-dimetylpropyl, 1-etylpropyl, heksyl, 1-, 2- eller 4-metylpentyl, 1,1-, 1,2-, 1.3- , 2,2-, 2,3- eller 3,3-dimetylbutyl, 1- eller 2-etylbutyl, 1-etyl-l-metylpropyl, l-etyl-2-metylpropyl eller 1,1,2- eller 1,2,2-trimetylpropyl.
OA er fortrinnsvis metoksy, etoksy, propoksy, isopropoksy eller butoksy.
Hal er fortrinnsvis F, Cl eller Br, men også I.
Ar er fortrinnsvis usubstituert fenyl eller naftyl, dessuten fortrinnsvis fenyl eller naftyl som er monosubstituert, for eksempel med A, fluor, klor, brom, jod, metoksy, etoksy, propoksy, butoksy eller CF3.
Oppfinnelsen vedrører følgelig særlig anvendelsen av forbindelsene med formel I hvor minst ett av de nevnte radikaler har én av de foretrukne betydninger angitt ovenfor. Noen foretrukne grupper av forbindelser kan uttrykkes ved hjelp av de følgende underformler Ia til II, som svarer til formel I og hvor radikalene som ikke er angitt nærmere, har betydningen angitt i formel I, men hvor
Oppfinnelsen vedrører også de nye forbindelsene valgt fra gruppen bestående av: 6-klor-4-(2-fluorfenyl)-2-kinazolinylguanidin,
6- brom-4-(2-fluorfenyl)-2-kinazolinylguanidin,
6,7-dimetoksy-4-fenyl-2-kinazolinylguanidin,
7- klor-4-(2-fluorfenyl)-2-kinazolinylguanidin,
6-klor-4-(4-metylfenyl)-2-kinazolinylguanidin,
8- metyl-4-fenyl-2-kinazolinylguanidin,
6-klor-4-(2-metylfenyl)-2-kinazolinylguanidin,
6-klor-4-(4-metylfenyl)-2-kinazolinylguanidin,
6-trifluormetyl-4-fenyl-2-kinazolinylguanidin,
6-klor-4-(3,4-dimetylfenyl)-2-kinazolinylguanidin,
6-klor-4-(3-fluor-4-metylfenyl)-2-kinazolinylguanidin, 6-klor-4-(3-klor-4-metylfenyl)-2-kinazolinylguanidin, 6-klor-4-(4-etylfenyl)-2-kinazolinylguanidin,
6-klor-4-(4-tirfluormetylfenyl)-2-kinazolinylguanidin, 6-klor-8-fluor-4-(4-metylfenyl)-2-kinazolinylguanidin, 6-klor-7-metyl-4-(4-metylfenyl)-2-kinazolinylguanidin, 6-klor-4-(2,4-dimetylfenyl)-2-kinazolinylguanidin,
6-klor-4-(3-bromfenyl)-2-kinazolinylguanidin,
6-klor-4-(4-bromfenyl)-2-kinazolinylguanidin,
6-klor-4-(4-isopropylfenyl)-2-kinazolinylguanidin,
6-klor-4-(2-bromfenyl)-2-kinazolinylguanidin,
6-klor-4-(3-fluor-4-trifluormetylfenyl)-2-kinazolinylguanidin, 6-klor-8-metyl-4-(4-metylfenyl)-2-kinazolinylguanidin, 6-klor-4-(4-fluorfenyl)-2-kinazolinylguanidin,
6-klor-4-(2-klorfenyl)-2-kinazolinylguanidin,
4-(3-metylfenyl)-2-kinazolinylguanidin,
6-klor-4-(3-fluorfenyl)-2-kinazolinylguanidin,
6-klor-8-klor-4-fenyl-2-kinazolinylguanidin,
6-klor-7-klor-4-fenyl-2-kinazolinylguanidin,
og deres fysiologisk akseptable salter og solvater.
Forbindelsene med formel I og også utgangsmaterialene for deres fremstilling fremstilles i tillegg ved hjelp av fremgangsmåter som er i og for seg kjent, som beskrevet i litteraturen (for eksempel i standardverkene, slik som Houben-Weyl, Methoden der Organischen Chemie, Georg-Thi enre-Veri ag, Stuttgart), for å være nøyaktig under reaksjonsbetingelser som er kjent og egnet for reaksjonene. Det kan her også gjøres bruk av varianter som er i og for seg kjent, men som ikke er nærmere nevnt her.
Utgangsmaterialene kan om ønsket også dannes in situ slik at de ikke isoleres fra reaksjonsblandingen, men i stedet omdannes umiddelbart videre til forbindelsene med formel I.
2-guanidino-4-arylkinazoliner med formel I fremstilles fortrinnsvis ved å omsette o-aminofenylketoner med formel II
hvor R<1>, R2 og Ar er som definert i krav 1, med 1-cyanguanidin.
Reaksjonen utføres i et inert oppløsningsmiddel.
Eksempler på egnede inerte oppløsningsmidler er slike hydrokarboner som heksan, petroleter, benzen, toluen eller xylen; slike klorerte hydrokarboner som trikloretylen, 1,2-dikloretan, tetraklormetan, kloroform eller diklormetan; slike alkoholer som metanol, etanol, isopropanol, n-propanol, n-butanol eller tert.-butanol; slike etere som dietyleter, diisopropyleter, tetrahydrofuran (THF) eller dioksan; slike glykoletere som etylenglykolmonometyl- eller -monoetyleter, etylenglykoldimetyleter (diglym); slike ketoner som aceton eller butanon; slike amider som acetamid, dimetylacetamid, N-metylpyrrolidon (NMP) eller dimetylformamid (DMF); slike nitriler som acetonitril; slike sulfoksider som dimetylsulfoksid (DMSO); karbondisulfid; slike karboksylsyrer som maursyre eller eddiksyre; slike nitroforbindelser som nitrometan eller nitrobenzen; slike estere som etylacetat; eller blandinger av de nevnte oppløsningsmidler.
DMF, vann eller en alkohol anvendes fortrinnsvis. Omsetningen utføres helt særlig foretrukket uten et oppløsningsmiddel, det vil si i smelte, ved temperaturer mellom 100 og 200 °C. Det er fordelaktig med tilstedeværelse av en sur katalysator, slik som AICI3, TiCl4, p-toluensulfonsyre, BF3, eddiksyre, svovelsyre, oksalsyre, POCl3eller fosforpentoksid. En foretrukket variant omfatter anvendelse av en av reaktantene allerede som et salt, for eksempel som hydrokloridet. En ytterligere verdifull fremgangsmåte for fremstilling av forbindelsene med formel I omfatter omsetning av en forbindelse med formel III
hvor
X er -SA, -SAr, -OA eller -OAr, og
Ar og A er for eksempel som definert i krav 1,
i stedet for 1-cyanguanidin,
med en forbindelse med formel II.
Endelig kan forbindelsene med formel I fremstilles ved omsetning av 2-klor-4-arylkinazoliner med formel IV
hvor Ar, R<1>og R2 er som definert i krav 1,
med guanidin.
En base med formel I kan omdannes til det ledsagende syreaddisjonssalt ved å anvende en syre, for eksempel ved omsetning av ekvivalente mengder av basen og syren i et slikt inert oppløsningsmiddel som etanol, etterfulgt av inndamping. Egnede syrer for denne reaksjonen er særlig de som gir fysiologisk akseptable salter. Det er således mulig å bruke uorganiske syrer, for eksempel svovelsyre, salpetersyre, hydrohalogensyrer slik som saltsyre eller hydrobromsyre, fosforsyrer, slik som ortofosforsyre, eller sulfaminsyrer, dessuten organiske syrer, særlig alifatiske, alisykliske, aralifatiske, aromatiske eller heterosykliske, én-basiske eller fler-basiske karboksyl-, sulfon- eller svovelsyrer, for eksempel maursyre, eddiksyre, propionsyre, pivalinsyre, dietyleddiksyre, malonsyre, ravsyre, pimelinsyre, fumarsyre, maleinsyre, melkesyre, vinsyre, eplesyre, sitronsyre, glukonsyre, askorbinsyre, nikotinsyre, isonikotinsyre, metan- eller etansulfonsyre, etandisulfonsyre, 2-hydroksyetansulfonsyre, benzensulfonsyre, p-toluensulfonsyre, naftalen-mono- og -disulfonsyrer, og laurylsvovelsyrer. Salter med fysiologisk uakseptable syrer, for eksempel pikrater, kan anvendes til isoleringen og/eller rensingen av forbindelsene med formel I.
Oppfinnelsen vedrører dessuten anvendelsen av forbindelsene med formel I som NHE-3-inhibitorer og/eller deres fysiologisk akseptable salter til fremstillingen av farmasøytiske preparater, særlig ved hjelp av ikke-kjemiske metoder. I dette tilfellet kan de omdannes til en egnet doseringsform sammen med minst én fast, flytende og/eller halvflytende eksipiens eller et hjepemiddel og om ønsket i kombinasjon med én eller flere aktive bestanddeler.
Oppfinnelsen vedrører dessuten farmasøytiske preparater som omfatter minst én NHE-3-inhibitor med formel I og/eller ett av dens fysiologisk akseptable salter og solvater.
Disse preparatene kan anvendes som medikamenter innen human- eller veterinærmedisin. Egnede eksipienser er organiske eller uorganiske stoffer som er egnet for enteral (for eksempel oral), parenteral eller topisk administrering, og som ikke reagerer med de nye forbindelsene, for eksempel vann, vegetabilseke oljer, benzylalkoholer, alkylenglykoler, polyetylenglykoler, glyseroltiracetat, gelatin, karbohydrater, slik som laktose eller stivelse, magnesiumstearater, talkum eller vaselin. Egnet for oral administrering er særlig tabletter, piller, belagte tabletter, kapsler, pulver, granulater, siruper, safter eller dråper, egnet for rektal administrering er suppositorier, egnet for parenteral administrering er oppløsninger, fortrinnsvis oljebaserte eller vann-oppløsninger, dessuten suspensjoner, emulsjoner eller implantater, og egnet for topisk applikasjon er salver, kremer eller pulver, eller transdermalt i plaster. De nye forbindelsene kan også lyofiliseres og de resulterende lyofilisater anvendes for eksempel til fremstillingen av injeksjonspreparater. De angitte preparater kan steriliseres og/eller omfatte hjelpemidler, slik som smøremidler, konserveringsmidler, stabiliseirngsmidler og/eller fuktemidler, emulgeringsmidler, salter for modifisering av det osmotiske trykk, bufferstoffer, fargestoffer og smaksstoffer, og/eller mange forskjellige ytterligere aktive bestanddeler, for eksempel ett eller flere vitaminer. Egnede farmasøytiske preparater for administrering i form av aerosoler eller sprayer er for eksempel oppløsninger, suspensjoner eller emulsjoner av den aktive bestanddel med formel I i et farmasøytisk akseptabelt oppløsningsmiddel.
Forbindelsene med formel I og deres fysiologisk akseptable salter og solvater kan anvendes til behandling og/eller profylakse av sykdommene eller sykdomstilstandene som er beskrevet ovenfor.
Generelt administreres stoffene ifølge oppfinnelsen fortrinnsvis i doser mellom ca. 0,1 og 500 mg, særlig mellom 1 og 10 mg, pr. doseringsenhet. Den daglige dose er fortrinnsvis mellom ca. 0,001 og 10 mg/kilo kroppsvekt. Den bestemte dose for hver pasient avhenger imidlertid av mange forskjellige faktorer, for eksempel av virkningsfullheten av den bestemte forbindelse som anvendes, av alderen, kroppsvekten, den generelle helsetilstand, kjønnet, av kosten, av tidspunktet og metoden for administrering, av utskillingshastigheten, medikamentkombinasjonen og alvorligheten av den bestemte sykdom som behandlingen gjelder for. Oral administrering er foretrukket.
Eksempler
Foretrukne NHE-3-inhibitorer er forbindelsene valgt fra gruppen bestående av: 4-fenyl-2-kinazolinylguanidin, smp. 247-250 °C (dekomponering); 4-fenyl-2-kinazolinylguanidin-hydroklorid, smp. 236-238 °C;
6-klor-4-fenyl-2-kinazolinylguanidin,
6-klor-4-fenyl-2-kinazolinylguanidin-hydroklorid, smp. 309-310 °C; 4-(4-bromfenyl)-2-kinazolinylguanidin-hydroklorid, smp. 185-189 °C; 4-(4-klorfenyl)-2-kinazolinylguanidin-hydroklorid, smp. 296-297 °C; 4-(4-metoksyfenyl)-2-kinazolinylguanidin-hydroklorid, smp. 275-277 °C; 4-(4-metylfenyl)-2-kinazolinylguanidin-hydroklorid, smp. 300-301 °C; 6- klor-4-(2-fluorfenyl)-2-kinazolinylguanidin-hydroklorid, smp. 275-276 °C; 7- metyl-4-fenyl-2-kinazolinylguanidin-hydroklorid, smp. 300-301 °C; 6-brom-4-(2-fluorfenyl)-2-kinazolinylguanidin-hydroklorid, smp. 294-295 °C;
7-klor-4-fenyl-2-kinazolinylguanidin-hydroklorid, smp. 288-290 °C; 7- metoksy-4-fenyl-2-kinazolinylguanidin-hydroklorid, smp. 280-282 °C; 5- metoksy-4-fenyl-2-kinazolinylguanidin-hydroklorid, smp. 272-273 °C; 6,7-dimetoksy-4-fenyl-2-kinazolinylguanidin-hydroklorid, smp. 220-222 °C; 6- metoksy-4-fenyl-2-kinazolinylguanidin-hydroklorid, smp. 278-279 °C; 8- klor-4-fenyl-2-kinazolinylguanidin-hydroklorid, smp. 309-310 °C; 5- klor-4-fenyl-2-kinazolinylguanidin-hydroklorid, smp. 300 °C;
7- klor-4-(2-fluorfenyl)-2-kinazolinylguanidin-hydroklorid, smp. 281-283 °C; 6- klor-4-(4-klorfenyl)-2-kinazolinylguanidin-hydroklorid, smp. 261-262 °C; 6-brom-4-fenyl-2-kinazolinylguanidin-hydroklorid, dekomp. 291-293 °C; 6-metyl-4-fenyl-2-kinazolinylguamdin-hydroklorid, smp. 295-296 °C; 6-fluor-4-fenyl-2-kinazolinylguanidin-hydroklorid, smp. 283-285 °C; 6-fluor-4-(4-metylfenyl)-2-kinazolinylguanidin-hydroklorid, smp. 193-195 °C; 6-klor-4-(4-metylfenyl)-2-kinazolinylguanidin-hydroklorid, smp. 312 °C; 8- metyl-4-fenyl-2-kinazolinylguanidin-hydroklorid, smp. 285-286 °C; 6-klor-4-(2-metylfenyl)-2-kinazolinylguanidin-hydroklorid, smp. 308 °C; 6-klor-4-(4-metylfenyl)-2-kinazolinylguanidin-hydroklorid, smp. 336 °C; 6-trifluormetyl-4-fenyl-2-kinazolinylguanidin-hydroklorid, smp. 300-302 °C; 6-klor-4(3,4-dimetylfenyl)-2-kinazolinylguanidin-hydroklorid, smp. 323-325 °C; 6-klor-4-(3-fluor-4-metylfenyl)-2-kinazolinylguanidin-hydroklorid, smp. 317-320 °C; 6-klor-4-(3-klor-4-metylfenyl)-2-kinazolinylguanidin-hydroklorid, smp. 336-338 °C; 6-klor-4-(4-etylfenyl)-2-kinazolinylguanidin-p-toluensulfonat, smp. 179-184 °C; 6-klor-4-(4-trifluormetylfenyl)-2-kinazolinylguanidin-dihydroklorid, smp. 329-332 °C; 6-klor-8-fluor-4-(4-metylfenyl)-2-kinazolinylguanidin-p-toluensulfonat, smp. 290-300°C; 6-klor-7-metyl-4-(4-metylfenyl)-2-kinazolinylguanidin-p-toluensulfonat, smp. 360°C; 6-klor-4-(2,4-dimetylfenyl)-2-kinazolinylguanidin-p-toluensulfonat; 6-klor-4-(3-bromfenyl)-2-kinazolinylguanidin-hydroklorid, smp. 319-323 °C; 6-klor-4-(4-bromfenyl)-2-kinazolinylguanidin-hydroklorid, smp. 330 °C; 6-klor-4-(4-isopropylfenyl)-2-kinazolinylguanidin-hydroklorid, smp. 326-329 °C; 6-klor-4-(2-bromfenyl)-2-kinazolinylguanidin-hydroklorid, smp. 316-318 °C; 6-klor-4-(3-fluor-4-trifluormetylfenyl)-2-ldnazolinylguanidin-hydroklorid, smp. 230-232 °C;
6-klor-8-metyl-4-(4-metylfenyl)-2-kinazolinylguanidin-hydroklorid, smp. 310 °C; 6-klor-4-(4-fluorfenyl)-2-kinazolinylguanidin-hydroklorid, smp. 346-348 °C; 6-klor-4-(2-klorfenyl)-2-kinazolinylguanidin-p-toluensulfonat, smp. 332-336 °C; 4-(3-metylfenyl)-2-kinazolinylguanidin-hydroklorid, smp. 160-163 °C; 6-klor-4-(3-fluorfenyl)-2-kinazolinylguanidin-hydroklorid, dekomponering fra 308 °C; 6-klor-8-klor-4-fenyl-2-kinazolinylguanidin-hydroklorid, smp. 163-166 °C; 6-klor-7-klor-4-fenyl-2-kinazolinylguanidin-p-toluensulfonat, smp. 269-271 °C.
Farmakologiske tester
Metoden som anvendes for karakteriseringen av forbindelsene med formel I som NHE-3-inhibitorer, er beskrevet nedenunder.
Forbindelsene med formel I blekarakterisertmed hensyn til deres selektivitet for NHE-1- til NHE-3-isoformene. De tre isoformene ble uttrykt i stabil form i musefibroblastcellelinjer. Inhibitorvirkningen til forbindelsene ble fastslått ved bestemmelse av det EIPA-sensitive opptak av<22>Na<+>i cellene etter intracellulær acidose.
Materialer og metoder
LAPI- cellelinjer som uttrykker de forskjellige NHE- isoformer
LAPI-cellelinjene som uttrykker NHE-1-, -2- og -3-isoformene (en musefibroblastcellelinje) ble erholdt fra Prof. J. Pouysségur (Nice, Frankrike). Transfeksjonen ble utført ved hjelp av metoden til Franchi et al. (1986). Cellene ble dyrket i Dulbeccos modifiserte eagle-medium (DMEM) med 10 % deaktivert føtalt kalveserum (FCS). For utvelgelse av de NHE-uttrykkende celler ble den såkalte "syredrepingsmetoden" til Sardet et al. (1989) brukt. Cellene ble først inkubert i 30 minutter i en NH4Cl-holdig bikarbonat- og natriumfri buffer. Det ekstracellulære NH4C1 ble så fjernet ved vasking med en bikarbonat-, NH4C1- og natriumfri buffer. Cellene ble deretter inkubert i en bikarbonatfri NaCl-holdig buffer. Bare de cellene som funksjonelt uttrykker NHE, var i stand til å overleve ved den intracellulære surgjøring som de ble underkastet.
Karakterisering av NHE- inhibitorer med hensyn til deres isoformselektivitet
Med de ovenfor nevnte musefibroblastcellelinjer som uttrykker NHE-1-, NHE-2-og NHE-3-isoformene, ble forbindelser testet med hensyn på selektivitet med hensyn til isoformene ved hjelp av fremgangsmåten beskrevet av Counillon et al. (1993) og Scholz et al. (1995). Cellene ble surgjort intracellulært ved hjelp av NH4Cl-prepuls-metoden og deretter ved inkubasjon i en bikarbonatfri Na -holdig buffer. På grunn av den intracellulære surgjøring ble NHE aktivert og natrium ble tatt opp i cellene. Effekten av testforbindelsen ble uttrykt som minimering av EIPA (etylisopropylamilorid)-sensitivt<22>Na<+->opptak.
Cellene som uttrykte NHE-1, NHE-2 og NHE-3, ble spredd ut ved en tetthet på 5-7,5 x 10<4>celler/brønn i 24-brønners mikrotiterplater og dyrket til sammenflytning i fra 24 til 48 timer. Mediet ble fjernet ved sug, og cellene ble inkubert i 60 minutter ved
37 °C i NH4Cl-buffer (50 mM NH4C1,70 mM cholinklorid, 15 mM MOPS, pH 7,0). Bufferen ble deretter fjernet og cellene ble hurtig tildekket to ganger med cholinklorid-vaskebufferen (120 mM cholinklorid, 15 mM PIPES/tris, 0,1 mM ouabain, ImM MgCl2, 2 mM CaCl2, pH 7,4); cellene ble inkubert i denne bufferen i 6 minutter. Etter utløpet av inkubasjonstiden ble inkubasjonsbufferen fjernet ved sug. For å fjerne ekstracellulær radioaktivitet ble cellene vasket hurtig fire ganger med iskaldt fosfatbufret saltoppløsning (PBS). Cellene ble så oppløseliggjort ved tilsetning av 0,3 ml 0,1N NaOH pr. brønn. De cellefragmentholdige oppløsninger ble overført til scintillasjonsrør. Hver brønn ble så vasket to ganger med 0,3 ml 0,1 N NaOH og vaskeoppløsningene ble likeledes innført i de tilsvarende scintillasjonsrør. Scintillasjonsblanding ble tilsatt til rørene inneholdende cellelysatet og radioaktiviteten tatt opp i cellene ble bestemt ved bestemmelse av P-strålingen.
Litteratur:
Counillon et al. (1993) Mol. Pharmacol. 44: 1041-1045
Franchi et al. (1986) Proe. Nati. Acad. Sei. USA 83: 9388-9392
Morgan and Canessa (1990) J. Membrane Biol. 118, 193-214
Sardet et al. (1989) Cell 56: 271-280
Scholz et al. (1995) Cardiovasc. Res. 29: 260-268
Eksemplene nedenunder vedrører farmasøytiske preparater.
Eksempel A: Injeksjonsglass
En oppløsning av 100 g av NHE-3-inhibitor med formel I og 5 g dinatriumhydrogenfosfat i 3 1 dobbeltdestillert vann reguleres til pH 6,5 ved å anvende 2N saltsyre, steril filtreres, overføres i injeksjonsglass og lyofiliseres under sterile betingelser og lukkes under sterile betingelser. Hvert injeksjonsglass inneholder 5 mg av den aktive bestanddel.
Eksempel B: Suppositorier
En blanding av 20 g av en NHE-3-inhibitor med formel I smeltes sammen med 100 g soyalecitin og 1400 g kakaosmør, helles over i støpeformer og får avkjøles. Hvert suppositorium innholder 20 mg av aktiv bestanddel.
Eksempel C: Oppløsning
En oppløsning fremstilles fra 1 g av en NHE-3-inhibitor med formel I, 9,38 g NaH2P04 2 H20, 28,48 g Na2HP04 12 H20 og 0,1 g benzalkoniumklorid i 940 ml dobbeltdestillert vann. pH-verdien reguleres til 6,8 og oppløsningen fylles opp til 1 1 og steriliseres ved bestråling. Denne oppløsningen kan brukes i form av øyedråper.
Eksempel D: Salve
500 mg av en NHE-3-inhibitor med formel I blandes med 99,5 g vaselin under aseptiske betingelser.
Eksempel E: Tabletter
En blanding av 1 kg av en NHE-3-inhibitor med formel 1,4 kg laktose, 1,2 kg potetstivelse, 0,2 kg talkum og 0,1 kg magnesiumstearat presses til tabletter på en vanlig måte slik at hver tablett inneholder 10 mg aktiv bestanddel.
Eksempel F: Belagte tabletter
Tabletter presses analogt med eksempel E og belegges deretter på vanlig måte med et belegg av sukrose, potetstivelse, talkum, tragant og fargestoff.
Eksempel G: Kapsler
2 kg av en NHE-3-inhibitor med formel I innføres i harde gelatinkapsler på vanlig måte slik at hver kapsel inneholder 20 mg av den aktive bestanddel.
Eksempel H: Ampuller
En oppløsning av 1 kg av en NHE-3-inhibitor med formel I i 60 liter dobbeltdestillert vann sterilfiltreres, overføres i ampuller, lyofiliseres under sterile betingelser og lukkes under sterile betingelser. Hver ampulle innholder 10 mg aktiv bestanddel.
Claims (7)
1. Forbindelser,
karakterisert ved at de har formel I
hvor
Ar er usubstituert eller mono-R <3-> substituert fenyl eller naftyl,
R1 og R <2> er uavhengig av hverandre H, A, OA, Hal eller CF3 ,
R<3> er A, OA, Hal eller CF3 ,
A er alkyl med 1, 2, 3,4, 5 eller 6 karbonatomer, og
Hal er F, Cl, Br eller I,
og deres fysiologisk akseptable salter og solvater, som NHE-3-inhibitorer.
2. Anvendelse av forbindelser med formel I ifølge krav 1 og deres fysiologisk akseptable salter og/eller solvater til fremstilling av et medikament for behandling av hypertoni, tromboser, iskemiske tilstander i hjertet, i det perifere og sentrale nervesystem, og av slag, iskemiske tilstander i perifere organer og ekstremiteter, og til behandling av sjokktilstander.
3. Anvendelse av forbindelser med formel I ifølge krav 1 og deres fysiologisk akseptable salter og/eller solvater til fremstilling av et medikament for anvendelse i kirurgiske operasjoner og organtransplantasjoner, og til konservering og lagring av transplantater for kirurgiske formål.
4. Anvendelse av forbindelser med formel I ifølge krav 1 og deres fysiologisk akseptable salter og/eller solvater til fremstilling av et medikament for behandling av sykdommer hvor celleproliferasjonen er en primær eller sekundær årsak, til behandling eller profylakse av forstyrrelser i fettmetabolisme eller forstyrret åndedrettsstyring.
5. Anvendelse av forbindelser med formel I ifølge krav 1 og deres fysiologisk akseptable salter og/eller solvater til fremstilling av et medikament for behandling av renal iskemi, iskemiske tannsykdommer eller til profylakse av akutte eller kroniske nyresykdommer.
6. Farmasøytisk preparat,
karakterisert ved et innhold av minst én NHE-3-inhibitor ifølge krav 1 og/eller ett av dens fysiologisk akseptable salter og/eller solvater.
7. Forbindelser,
karakterisert ved at de er valgt fra gruppen bestående av:
6-klor-4-(2-fluorfenyl)-2-kinazolinylguanidin,
6- brom-4-(2-fluorfenyl)-2-kinazolinylguanidin, 6,7-dimetoksy-4-fenyl-2-kinazolinylguanidin,
7- klor-4-(2-fluorfenyl)-2-kinazolinylguanidin, 6-klor-4-(4-metylfenyl)-2-kinazolinylguanidin,
8- metyl-4-fenyl-2-kinazolinylguanidin, 6-klor-4-(2-metylfenyl)-2-kinazolinylguanidin, 6-klor-4-(4-metylfenyl)-2-kinazolinylguanidin, 6-trifluormetyl-4-fenyl-2-kinazolinylguanidin, 6-klor-4-(3,4-dimetylfenyl)-2-kinazolinylguanidin, 6-klor-4-(3-fluor-4-metylfenyl)-2-kinazolinylguanidin, 6-klor-4-(3-klor-4-metylfenyl)-2-kinazolinylguanidin, 6-klor-4-(4-etylfenyl)-2-kinazolinylguanidin, 6-klor-4-(4-trifluormetylfenyl)-2-kinazolinylguanidin, 6-klor-8-fluor-4-(4-metylfenyl)-2-kinazolinylguanidin, 6-klor-7-metyl-4-(4-metylfenyl)-2-kinazolinylguanidin, 6-klor-4-(2,4-dimetylfenyl)-2-kinazolinylguanidin, 6-klor-4-(3-bromfenyl)-2-kinazolinylguanidin, 6-klor-4-(4-bromfenyl)-2-kinazolinylguanidin, 6-klor-4-(4-isopropylfenyl)-2-kinazolinylguanidin, 6-klor-4-(2-bromfenyl)-2-kinazolinylguanidin, 6-klor-4-(3-fluor-4-trifluormetylfenyl)-2-kinazolinyIguanidin, 6-klor-8-metyl-4-(4-metylfenyl)-2-kinazolinylguanidin, 6-klor-4-(4-fluorfenyl)-2-kinazolinylguanidin, 6-klor-4-(2-klorfenyl)-2-kinazolinylguanidin, 4-(3-metylfenyl)-2-kinazolinylguanidin, 6-klor-4-(3-fluorfenyl)-2-kinazolinylguanidin, 6-klor-8-klor-4-fenyl-2-kinazolinylguanidin, 6-klor-7-klor-4-fenyl-2-kinazolinylguanidin,
og deres fysiologisk akseptable salter og solvater.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10019062A DE10019062A1 (de) | 2000-04-18 | 2000-04-18 | 2-Guanidino-4-aryl-chinazoline als NHE-3 Inhibitoren |
| PCT/EP2001/003281 WO2001079186A1 (de) | 2000-04-18 | 2001-03-22 | 2-guanidino-4-aryl-chinazoline als nhe-3-inhibitoren |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NO20024997D0 NO20024997D0 (no) | 2002-10-17 |
| NO20024997L true NO20024997L (no) | 2002-10-17 |
Family
ID=7639090
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO20024997A NO20024997L (no) | 2000-04-18 | 2002-10-17 | 2-guanidino-4-arylkinazoliner som NHE-3-inhibitorer |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US20040224965A1 (no) |
| EP (1) | EP1274691A1 (no) |
| JP (1) | JP2004501082A (no) |
| KR (1) | KR20030011789A (no) |
| CN (1) | CN1422260A (no) |
| AR (1) | AR028914A1 (no) |
| AU (1) | AU2001293373A1 (no) |
| BR (1) | BR0109867A (no) |
| CA (1) | CA2406161A1 (no) |
| DE (1) | DE10019062A1 (no) |
| HU (1) | HUP0300909A3 (no) |
| MX (1) | MXPA02010264A (no) |
| NO (1) | NO20024997L (no) |
| PL (1) | PL356559A1 (no) |
| RU (1) | RU2002130246A (no) |
| SK (1) | SK13472002A3 (no) |
| WO (1) | WO2001079186A1 (no) |
| ZA (1) | ZA200209274B (no) |
Families Citing this family (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10043667A1 (de) * | 2000-09-05 | 2002-03-14 | Merck Patent Gmbh | 2-Guanidino-4-aryl-chinazoline |
| US6911453B2 (en) * | 2001-12-05 | 2005-06-28 | Aventis Pharma Deutschland Gmbh | Substituted 4-phenyltetrahydroisoquinolinium, process for their preparation, their use as a medicament, and medicament containing them |
| IL162316A0 (en) * | 2001-12-05 | 2005-11-20 | Aventis Pharma Gmbh | Substituted 4-phenyltetrahydroisoquinolines, method for the production thereof, the use thereof as medicaments, in addition t |
| DE10161767A1 (de) * | 2001-12-15 | 2003-06-26 | Merck Patent Gmbh | 2-Guanidino-4-heterocyclyl-chinazoline |
| DE10163239A1 (de) * | 2001-12-21 | 2003-07-10 | Aventis Pharma Gmbh | Substituierte Imidazolidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie enthaltendes Medikament |
| US20030187045A1 (en) | 2001-12-21 | 2003-10-02 | Uwe Heinelt | Substituted imidazolidines, process for their preparation, and their use as a medicament or diagnostic |
| DE10163914A1 (de) * | 2001-12-22 | 2003-07-03 | Aventis Pharma Gmbh | Substituierte 4-Phenyltetrahydroisochinolinium-Salze, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament, sowie sie enthaltendes Medikament |
| US6703405B2 (en) | 2001-12-22 | 2004-03-09 | Aventis Pharma Deutschland Gmbh | Substituted 4-phenyltetrahydroisoquinolinium salts, process for their preparation, their use as a medicament, and medicament containing them |
| DE10163992A1 (de) * | 2001-12-24 | 2003-07-03 | Merck Patent Gmbh | 4-Aryl-chinazoline |
| US7049333B2 (en) | 2002-06-04 | 2006-05-23 | Sanofi-Aventis Deutschland Gmbh | Substituted thiophenes: compositions, processes of making, and uses in disease treatment and diagnosis |
| US20050054705A1 (en) | 2003-02-04 | 2005-03-10 | Aventis Pharma Deutschland Gmbh | N-substituted (benzoimidazol-2-yl) phenylamines, process for their preparation, their use as medicament or diagnostic aid, and medicament comprising them |
| DE10304374A1 (de) | 2003-02-04 | 2004-08-05 | Aventis Pharma Deutschland Gmbh | Neue substituierte 2-Aminoimidazole, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
| DE10341240A1 (de) | 2003-09-08 | 2005-04-07 | Aventis Pharma Deutschland Gmbh | Substituierte Thienoimidazole, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
| DE102005001411A1 (de) | 2005-01-12 | 2006-07-27 | Sanofi-Aventis Deutschland Gmbh | Substituierte 4-Phenyltetrahydroisochinoline, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament, sowie sie enthaltendes Medikament |
| DE102005044817A1 (de) * | 2005-09-20 | 2007-03-22 | Sanofi-Aventis Deutschland Gmbh | Substituierte 4-Phenyltetrahydroisochinoline, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament, sowie sie enthaltendes Medikament |
| ATE479679T1 (de) | 2007-06-28 | 2010-09-15 | Sanofi Aventis Us Llc | Verfahren zur herstellung von n-(2-chlor-4-methyl-3-thienyl)-1h-benzimidazol- 2-amin hydrochlorid und zwischenprodukte dafür |
| EP2342178B1 (en) | 2008-09-02 | 2016-09-28 | Sanofi | Substituted aminoindanes and analogs thereof, and the pharmaceutical use thereof |
| WO2018129556A1 (en) | 2017-01-09 | 2018-07-12 | Ardelyx, Inc. | Compounds and methods for inhibiting nhe-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders |
| PL2384318T3 (pl) | 2008-12-31 | 2018-04-30 | Ardelyx, Inc. | Związki i sposoby inhibicji mediowanego przez NHE antyportu w leczeniu zaburzeń związanych z retencją płynów lub nadmiarem soli i chorób przewodu pokarmowego |
| US20120088737A2 (en) * | 2009-10-02 | 2012-04-12 | Ajinomoto Co., Inc | Novel acyl guanidine derivatives |
| US10376481B2 (en) | 2012-08-21 | 2019-08-13 | Ardelyx, Inc. | Compounds and methods for inhibiting NHE-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders |
| CN104902930A (zh) | 2012-08-21 | 2015-09-09 | 阿德利克斯公司 | 在治疗与液体潴留或盐分过载相关的疾病和胃肠道疾病中用于抑制nhe-介导的反向转运的化合物和方法 |
| WO2014169094A2 (en) | 2013-04-12 | 2014-10-16 | Ardelyx, Inc | Nhe3-binding compounds and methods for inhibiting phosphate transport |
| ME03311B (me) | 2014-07-25 | 2019-10-20 | Taisho Pharmaceutical Co Ltd | Fenil teтrahidroizokvinolinsko jedinjenje supsтituisano heteroarilom |
| MX2019008170A (es) | 2017-01-09 | 2020-02-07 | Ardelyx Inc | Compuestos útiles para tratar transtornos del tracto gastrointestinal. |
| AU2018206479B2 (en) | 2017-01-09 | 2022-07-14 | Ardelyx, Inc. | Inhibitors of NHE-mediated antiport |
| CA3071992A1 (en) | 2017-08-04 | 2019-03-28 | Ardelyx, Inc. | Glycyrrhetinic acid derivatives for treating hyperkalemia |
| EP3921327B1 (en) | 2019-02-07 | 2023-04-05 | Ardelyx, Inc. | Glycyrrhetinic acid derivatives for use in treating hyperkalemia |
| JP2022533251A (ja) | 2019-05-21 | 2022-07-21 | アルデリックス， インコーポレイテッド | 患者において血清リン酸塩を低下させるための組み合わせ |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3131187A (en) * | 1964-04-28 | Certain z-guantoino-x-aryl-quinazolines |
-
2000
- 2000-04-18 DE DE10019062A patent/DE10019062A1/de not_active Withdrawn
-
2001
- 2001-03-22 PL PL01356559A patent/PL356559A1/xx unknown
- 2001-03-22 US US10/257,636 patent/US20040224965A1/en not_active Abandoned
- 2001-03-22 MX MXPA02010264A patent/MXPA02010264A/es unknown
- 2001-03-22 WO PCT/EP2001/003281 patent/WO2001079186A1/de not_active Application Discontinuation
- 2001-03-22 CN CN01807951A patent/CN1422260A/zh active Pending
- 2001-03-22 AU AU2001293373A patent/AU2001293373A1/en not_active Abandoned
- 2001-03-22 KR KR1020027011796A patent/KR20030011789A/ko not_active Application Discontinuation
- 2001-03-22 CA CA002406161A patent/CA2406161A1/en not_active Abandoned
- 2001-03-22 RU RU2002130246/04A patent/RU2002130246A/ru not_active Application Discontinuation
- 2001-03-22 EP EP01969043A patent/EP1274691A1/de not_active Withdrawn
- 2001-03-22 HU HU0300909A patent/HUP0300909A3/hu unknown
- 2001-03-22 JP JP2001576787A patent/JP2004501082A/ja active Pending
- 2001-03-22 SK SK1347-2002A patent/SK13472002A3/sk unknown
- 2001-03-22 BR BR0109867-5A patent/BR0109867A/pt not_active IP Right Cessation
- 2001-04-18 AR ARP010101808A patent/AR028914A1/es not_active Application Discontinuation
-
2002
- 2002-10-17 NO NO20024997A patent/NO20024997L/no not_active Application Discontinuation
- 2002-11-14 ZA ZA200209274A patent/ZA200209274B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CA2406161A1 (en) | 2002-10-16 |
| CN1422260A (zh) | 2003-06-04 |
| JP2004501082A (ja) | 2004-01-15 |
| MXPA02010264A (es) | 2003-04-25 |
| BR0109867A (pt) | 2003-06-03 |
| NO20024997D0 (no) | 2002-10-17 |
| HUP0300909A2 (hu) | 2003-10-28 |
| ZA200209274B (en) | 2004-02-16 |
| RU2002130246A (ru) | 2004-03-27 |
| US20040224965A1 (en) | 2004-11-11 |
| PL356559A1 (en) | 2004-06-28 |
| DE10019062A1 (de) | 2001-10-25 |
| AU2001293373A1 (en) | 2001-10-30 |
| KR20030011789A (ko) | 2003-02-11 |
| SK13472002A3 (sk) | 2003-02-04 |
| EP1274691A1 (de) | 2003-01-15 |
| WO2001079186A1 (de) | 2001-10-25 |
| AR028914A1 (es) | 2003-05-28 |
| HUP0300909A3 (en) | 2004-01-28 |
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