NO313082B1 - Hemming av proliferasjon av glatte muskelceller og restenose - Google Patents
Hemming av proliferasjon av glatte muskelceller og restenose Download PDFInfo
- Publication number
- NO313082B1 NO313082B1 NO19943877A NO943877A NO313082B1 NO 313082 B1 NO313082 B1 NO 313082B1 NO 19943877 A NO19943877 A NO 19943877A NO 943877 A NO943877 A NO 943877A NO 313082 B1 NO313082 B1 NO 313082B1
- Authority
- NO
- Norway
- Prior art keywords
- smooth muscle
- compound
- restenosis
- cell proliferation
- muscle cell
- Prior art date
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- KVSASDOGYIBWTA-UHFFFAOYSA-N chloro benzoate Chemical compound ClOC(=O)C1=CC=CC=C1 KVSASDOGYIBWTA-UHFFFAOYSA-N 0.000 description 1
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- 239000000470 constituent Substances 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-M decanoate Chemical compound CCCCCCCCCC([O-])=O GHVNFZFCNZKVNT-UHFFFAOYSA-M 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
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- 238000009792 diffusion process Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
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- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- TVZISJTYELEYPI-UHFFFAOYSA-N hypodiphosphoric acid Chemical compound OP(O)(=O)P(O)(O)=O TVZISJTYELEYPI-UHFFFAOYSA-N 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000008069 intimal proliferation Effects 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
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- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
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- 230000007774 longterm Effects 0.000 description 1
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- 229940049920 malate Drugs 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
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- IZYBEMGNIUSSAX-UHFFFAOYSA-N methyl benzenecarboperoxoate Chemical compound COOC(=O)C1=CC=CC=C1 IZYBEMGNIUSSAX-UHFFFAOYSA-N 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- KVNYFPKFSJIPBJ-UHFFFAOYSA-N ortho-diethylbenzene Natural products CCC1=CC=CC=C1CC KVNYFPKFSJIPBJ-UHFFFAOYSA-N 0.000 description 1
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- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 238000003345 scintillation counting Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical class O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
Classifications
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- 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
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- 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
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
Proliferasjon av glatte muskelceller spiller en viktig rolle i sykdommer slik som atherosclerose og restenose. Vaskulær restenose etter transluminal perkutan koronar angioplasti (PTCA) er blitt vist å være en vevsrespsjon kjennetegnet ved en tidlig og en sen fase. Den tidlige fasen som skjer timer til dager etter PTCA, skyldes trombose med noen vasospasmer, mens den sene fasen synes å være dominert av eksessiv proliferasjon og migrering av glatte muskelceller. I denne sykdommen bidrar den økede cellebevegeligheten og koloniseringen av glatte muskelceller og makrofager, betydelig til patogenesen av sykdommen. Den eksessive proliferasjonen og migreringen av vaskulære, glatte muskelceller, kan være den primære mekanismen ved reokklusjon av koronære arterier etter PTCA, atherectomi, laser-angioplasti og arteriell bypass-podekirurgi. Se "Intimal Proliferation of Smooth Muscle Cells as an Explantation for Recurrent Coronary Artery Stenosis after Percutaneous Transluminal Coronary Angioplasty", Austin et al., Journal of the American College of Cardiology 8; 369-375 (aug. 1985).
Vaskulære restenoser forblir en hoved-langtidskomplikasjon etter kirurgisk intervensjon av blokkerte arterier ved perkutan transluminal koronar angioplasti (PTCA), atherekto-. mi, laser-angioplasti og arteriell bypass-graftkirurgi. I omkring 35$ av pasientene som gjennomgår PTCA, skjer reokklusjon innen tre til seks måneder etter prosedyren. De nåværende strategier for behandling av vaskulær restenose omfatter mekanisk intervensjon med anordninger slik som stenter eller farmakologiske terapier som inkluderer heparin, lavmolekylvekt-heparin, kumarin, aspirin, fiskeolje, kalsiumantagonist, steroider og prostacyklin. Disse strategi-ene har feilet i å dempe reokklusjonshastigheten, og har vært ineffektive som behandling og forhindring av vaskulær restenose. Se "Prevention of Restenosis after Percutaneous Transluminal Coronary Angioplasty: The Search for a "Magic Bullet", Hermans et al., American Heart Journal 122: 171-187 (juli 1991).
I patogenesen av restenose skjer eksessiv celleproliferasjon og migrasjon som et resultat av vekstfaktorer produsert av cellulære bestanddeler i blodet og den skadede arterie-preveggen som medierer proliferasjonen av glatte muskelceller i vaskulær restenose.
Midler som hemmer proliferasjon og/eller migrering av glatte muskeceller, er nyttige i behandlingen og forhindringen av restenose. Foreliggende oppfinnelse vedrører anvendelse av en forbindelse med formel (I) til fremstilling av et medikament som hemmer proliferasjonen av glatte muskeceller.
Foreliggende oppfinnelse vedrører også anvendelse av en forbindelse med formel (I) til fremstilling av et medikament for hemming av restenose.
Forbindelsen med formel (I) er definert som følger:
hvor
hvor r! og r<3> er hydrogen;
R2 er
farmasøytisk akseptable salter og solvater derav.
Foreliggende oppfinnelse angår det funn at en utvalgt gruppe av forbindelser, de med formel I, er nyttige for hemming av glattmuskelcelleproliferasjon og restenose. Uttrykket "hemme" er definert å omfatte dets generelt aksepterte betydning, som omfatter profylaktisk behandling til et menneskelig individ som er utsatt for glattmuskecelleproliferasjon eller restenose, og holde i sjakk og/eller behandle eksisterende glattmuskelcelleproliferasjon eller restenose. Som sådan omfatter foreliggende oppfinnelse både medisinskterapeutisk og/eller profylaktisk behandling etter behov.
Generelt blir forbindelsen formulert med vanlige eksipienter, fortynningsmidler eller bærere, og sammenpresset til tabletter eller formulert som eleksirer eller oppløsninger for formålstjenelig oral administrasjon, eller administrert ved intramuskulær eller intravenøs vei. Forbindelsene kan bli administrert transdermalt, og kan bli formulert som doseringsformer for vedvarende frigiving o.l.
Forbindelsene med formel I som anvendes ifølge foreliggende oppfinnelse, kan bli fremstilt ifølge etablerte prosedyrer, slik som de beskrevet i U.S.-patent nr. 4.133.814, 4.418.068 og 4.380.635, som alle er innlemmet heri som referanse. Generelt starter fremgangsmåten med et benzo[b]-tiofen med en 6-hydroksylgruppe og en 2-(4-hydroksyfenyl )-gruppe. Startforbindelsen blir beskyttet, alkylert og avbeskyttet å danne forbindelser med formelen I. Eksempler på fremstilling av slike forbindelser er vist i U.S. patentene beskrevet ovenfor.
Inkludert i oppfinnelsen er anvendelsen av de følgende forbindelsene:
Forbindelsene benyttet i fremgangsmåtene ifølge oppfinnelsen, danner farmasøytisk akseptabel syre og baseaddisjonssalter, med en stor variasjon av organiske og uorganiske syrer og baser, og omfatter de fysiologisk akseptable saltene som ofte blir benyttet i farmasøytisk kjemi. Slike salter er også deler av oppfinnelsen. Typiske uorganiske salter benyttet for å danne slike salter, omfatter saltsyre, hydrogenbromid,
j hydrogenjodid, salpetersyre, svovelsyre, fosforsyre, hypofosforsyre o.l. Salter avledet fra organiske syrer, slik som alifatiske mono- og dikarboksylsyrer, fenylsubstituerte alkanoinsyrer, hydroksyalkanoinsyrer og hydroksyalkandioin-syrer, aromatiske syrer, alifatiske og aromatiske sulfon-syrer kan også bli benyttet. Slike farmasøytisk akseptable salter omfatter således acetat, fenylacetat, trifluoracetat, akrylat, askorbat, benzoat, klorbenzoat, dinitrobenzoat, hydroksybenzoat, metoksybenzoat, metylbenzoat, o-acetoksy-benzoat, naftalen-2-benzoat, bromid, isobutyrat, fenyl-butyrat, p-hydroksybutyrat, butyn-1,4-dioat, heksyn-1,4-dioat, kaprat, kaprylat, klorid, cinnamat, sitrat, format, fumarat, glykollat, heptanoat, hippurat, laktat, malat, maleat, hydroksymaleat, malonat, mandelat, mesylat, nikoti-nat, isonikotinat, nitrat, oksalat, ftalat, teraftalat, fosfat, monohydrogenfosfat, dihydrogenfosfat, metafosfat, pyrofosfat, propiolat, propionat, fenylpropionat, salicylat, sebakat, suksinat, suberat, sulfat, bisulfat, pyrosulfat, sulfitt, bisulfitt, sulfonat, benzen-sulfonat, p-brom-fenylsulfonat, klorbenzensulfonat, etansulfonat, 2-hydroksy-
etansulfonat, metansulfonat, naftalen-l-sulfonat, naftalen-2-sulfonat, p-toluensulfonat, xylensulfonat, tartarat o.l. Et foretrukket salt er hydrokloridsaltet.
De farmasøytisk akseptable syreaddisjonssaltene blir typisk dannet ved å reagere en forbindelse med formel I med en likemolar eller overskuddsmengde av syre. Eeaktantene blir generelt blandet i et gjensidig oppløsningsmiddel slik som dietyleter eller benzen. Saltet ledes normalt ut fra oppløsning innen omkring én time til 10 dager, og kan bli isolert ved filtrering eller oppløsnlngsmidlet kan bli strippet av ved konvensjonelle midler.
Vanlig benyttede baser for dannelse av salter omfatter ammoniumhydroksyd og alkali- og jordalkalimetallhydroksyder, karbonater og bikarbonater, såvel som alifatiske og primære, sekundære og tertiære aminer, alifatiske diaminer og hydroksyalkylaminer. Baser som spesielt er nyttige i fremstillingen av addisjonssalter omfatter ammoniumhydroksyd, kaliumkarbonat, natriumbikarbonat, kaliumhydroksyd, metyl-amin, dietylamin, etyldiamin, cykloheksylamin og etanolamin.
De farmasøytisk akseptable saltene har vanligvis øket oppløselighetskarakteristikker sammenlignet med forbindelsen fra hvilken de er avledet, og er således ofte lettere anvendbare for formulering av væsker eller emulsjoner.
Farmasøytiske formuleringer kan bli fremstilt ved prosedyrer som er kjent i teknikken. For eksempel kan forbindelser bli formulert med vanlige eksipienter, fortynnere eller bærere og formet til tabletter, kapsler, suspensjoner, pulvere o.l. Eksempler på eksipienter, fortynnere og bærere som passer for slike formuleringer, omfatter de følgende: Fyllstoffer og utvidere slik som stivelse, sukkere, mannitol og kiesel-syrederivater; bindingsmidler slik som karboksymetylcellulose og andre cellulosederivater, alginater, gelatin og polyvinylpyrrolidon; fuktingsmidler slik som glyserol; disintegrer-ingsmidler slik som kalsiumkarbonat og natriumbikarbonat; midler for retardert oppløsning slik som paraffin; oppløs-ningsakseleratorer slik som kvaternære ammoniumforbindelser; overflateaktive midler slik som cetylalkohol, glyserolmono-stearat; adsorptive bærere slik som kaolin og bentonitt; og smøremidler slik som talk, kalsium og magnesiumstearat og faste polyetylenglykoler.
Forbindelsene kan også bli formulert som eliksirer og oppløsninger for konvensjonell oral administrasjon, eller som oppløsninger passende for parenteral administrasjon, for eksempel ved intramuskulær, subkutan eller intravenøs vei. I tillegg er forbindelsene vel tilpasset til formuleringer som doseringsformer med vedvarende frigiving o.l. Formuleringene kan være sammensatt slik at de frigir den aktive ingredien-sen muligens over en tidsperiode. Belegget, overtrekket og beskyttende matrikser kan eksempelvis bli fremstilt fra polymere stoffer eller vokser.
Den bestemte doseringen av en forbindelse med formel I, som behøves for å hemme glattmuskelcelleproliferasjon og restenose ifølge foreliggende oppfinnelse, vil avhenge av alvoret av tilstanden, administrasjonsvei og beslektede faktorer som vil bli bestemt av den ansvarlige lege. Generelt er aksepterte og effektive daglige doser fra omkring 0,1 til omkring 1000 mg/dag, og mer typisk fra omkring 50 til omkring 200 mg/dag. Slike doseringer vil bli administrert til et individ som trenger behandling fra én til tre ganger hver dag eller oftere, hvis nødvendig for effektivt å hemme glattmuskelcelleproliferasjone eller restinose.
Den lokale leveringen av hemmende mengder av aktiv forbindelse for behandlingen av restinose, kan bli gjort ved forskjellige teknikker som administrerer forbindelsen ved eller nær det proliferative setet. Eksempler på lokale leveringsteknikker er ikke ment å være begrensende, men å være illsutrative for de tilgjengelige teknikker. Eksempler omfatter lokal-leverende katatere, setespesifikke bærere, implanter, direkte injeksjon eller direkte applikasjoner.
Lokal levering ved et kateter, tillater administrasjonen av et farmasøytisk middel direkte til den proliferative lesjonen. Eksempler på lokal levering ved bruk av ballong-kateter, er beskrevet i EPO 383.492 A2 og U.S. patent 4.636.195 (Wolinsky, 13. januar 1978).
Lokal levering ved et implant, beskriver den kirurgiske plasseringen av en matriks som inneholder det farmasøytiske midlet i den proliferative lesjonen. Den implanterte matrisken frigir det farmasøytiske midlet ved diffusjon, kjemisk reaksjon eller oppløsningsmiddelaktivatorer. Lange, Science 249; 1527-1533 (september, 1990).
Et eksempel på lokal levering med et implant, er anvendelsen av et stent. Stentene er utformet for mekanisk å forhindre kollaps og reokklusjon av de koronare arteriene. Inlemming av et farmasøytisk middel i stentet, leverer medikamentet direkte til det proliferative setet. Lokal levering ved denne teknikk er beskrevet i Kohn, Pharmaceutical Technology (oktober, 1990).
Et annet eksempel er leverinssystemet hvor en polymer som inneholder det farmasøytiske midlet, blir injisert i lesjonen i væskeform. Polymeren herder så for å danne implantet in situ. Denne teknikken er beskrevet i PCT WO 80/03768 (Donn, 19. april 1990).
Et annet eksempel er leveringen av et farmasøytisk middel ved polymer endoluminal forsegling. Denne teknikken benytter et kateter for å tilføre et polymert implant til den indre overflaten av lumen. Det farmasøytiske midlet innlememt i det biodegraderbare polymerimplantet, blir derved frigitt ved det kirurgiske setet. Dette er beskrevet i PCT W0 90/01969 (Schindler, 23. august, 1989).
Det endelig eksempel på lokal levering ved et implant, er ved direkte injeksjon av vesikler eller mikropartikler i det proliferative setet. Disse mikropartiklene kan være sammensatt av stoffer slik som proteiner, lipider, karbohydrater eller syntetiske polymerer. Disse mikropartiklene har det farmasøytiske midlet innlemmet gjennom hele mikropartiklene eller over mikropartiklene som et belegg. Leveringssystemer som omfatter mikropartikler, er beskrevet i Lange, Science 249: 1527-1533 (september, 1990 ) og Mathiowitz, et al., J. App. Poly, Sei., 26:809 (1981).
Lokal levering ved setespesifikke bærere beskriver binding av det farmasøytiske midlet til en bærer som vil rette medikamentet til den proliferative lesjon. Eksempler på denne leveringsteknikken omfatter anvendelsen av bærere slik som en proteinligand eller et monoklonalt antistoff. Lange, Science 249; 1527-1533 (september).
Lokal levering ved direkte applikasjon omfatter anvendelsen av topikale applikasjoner. Et eksmepel på lokal levering ved direkte applikasjon, er påføring av det farmasøytiske midlet direkte på det arterielle bypass-graftet under den kirurgiske prosedyren.
Det er vanligvis foretrukket å administrere en forbindelse med formel I i form av et syreaddisjonssalt, som vanlig i administrasjonen av farmasøytika som bærer en basisk gruppe, slik som piperidinoringen. Det er også fordelaktig å administrere en slik forbindelse ved oral vei til et eldre menneske (f.eks. en post-menopausal kvinne). For slike formål er følgende orale doseringsformer tilgjengelige.
Formuleringer
I formuleringene nedenfor betyr "aktiv ingrediens" en forbindelse med formel I.
Formulering 1: Gelatinkapsler
Harde gelatinkapsler blir fremstilt ved anvendelse av det følgende:
Ingrediensene blir blandet, ledet gjennom en nr. 45 mesh U.S.-sikt og fylt i harde gelatinkapsler.
Eksempler på spesifikke kapselformuleringer av forbindelsen i formel 1 hvor R<2> er piperidino (raloxifen) som har blitt fremstilt, omfatter de vist under:
Formulering 2: Raloxifenkapsel
Formulering 3 Raloxifenkapsel Formulering 4: Raloxifenkapsel Formulering 5: Raloxifenkapsel
De spesifikke formuleringene ovenfor kan bli forandret i samsvar med de gitte fornuftige variasjoner.
En tablettformulering ble fremstilt ved anvendelse av ingrediensene under:
Formulering 6: Tabletter
Komponentene ble blandet og sammenpresset for å danne
tabletter.
Alternativt ble tabletter, hver inneholdende 0,1 - 1000 mg aktiv ingrediens, fremstilt som følger:
Formulering 7: Tabletter
Den aktive ingrediens, stivelse og cellulose ble ledet gjennom en nr. 45 mesh U.S.-sikt og blandet grundig. Oppløsningen av polyvinylpyrrolidon ble blandet med det resulterende pulver som så ble ledet gjennom en nr. 24 mesh U.S. sikt. De således produserte kornene ble tørket ved 50°-60°C og ledet gjennom en nr. 18 mesh U.S.-sikt. Natriumkar-boksymetylstivelsen, magnesiumstearatet og talket som på forhånd var ledet gjennom en nr. 60 U.S.-sikt, ble så tilsatt til kornene som etter blanding ble sammenpresset på en
tabletteringsmaskin for å gi tabletter.
Suspensjoner, hver inneholdende 0,1 - 1000 mg medikament pr. 5 ml dose, ble fremstilt som følger:
Formulerin<g> 8: Suspensjoner
Medikamentet ble ledet gjennom en nr. 45 mesh U.S.-sikt og blandet med natriumkarboksymetylcellulose og sirup for å danne en glatt pasta. Benzosyreoppløsningen, smaken og farven ble fortynnet med noe vann og tilsatt under omrøring. Tilstrekkelig vann ble så tilsatt for å produsere det ønskede volum.
TESTPROSEDYRE
Forbindelsene ifølge oppfinnelsen har kapasitet til å hemme vaskulær glattmuskelcelleproliferasjon. Dette kan bli demonstrert ved anvendelsen av kulturerte glattmuskelceller avledet fra kaninaorta, proliferasjon blir bestemt ved målingen av DNA-syntesen. Celler blir fremstilt ved eksplant-metoden som beskrevet i Ross, J. of Cell Bio. 50: 172 (1971), Celler blir utsådd i 96 brønners mikrotiterplater i fem dager. Kulturene ble sammenflytende og veksten stanset. Cellene ble så overført til Dulbecco's Modified Eagle's Medium (DMEM) inneholdende 0, 5- 2% blodplatefattig plasma, 1 mM L-glutamin, 100 U/ml penicillin, 100 >jg ml streptomycin, 1 pC/ml <3>H-tymidin, 20 ng/ml blodplateavledet vekstfaktor og varierende konsentrasjoner av forbindelsene. Stam-oppløsning av forbindelsene ble fremstilt i dimetylsulfoksyd og så fortynnet til passende konsentrasjoner (0,01 - 30 jiM) i analysemediet ovenfor. Celler blir så inkubert ved 37°C i 24 timer under 5$ C02/95# luft. Ved slutten av de 24 timene, ble cellene fiksert i metanol. ^H-tymidininnlemming i DNA ble så bestemt ved scintillasjonstelling som beskrevet i Bonin et al., Exp. Cell Res. 181; 475-482 (1989).
Hemming av glattmuskecelleproliferasjon med forbindelsene ifølge oppfinnelsen, er videre demonstrert ved bestemmelse av deres effekter på eksponentielt voksende celler. Glatte muskelceller fra kaninaorta ble utsådd i 12 brønners kulturplater i DMEM inneholdende 10% fetalt bovint serum, 2 mM L-glutamin, 100 TJ/ml penicillin og 100 ug/ml streptomycin. Etter 24 timer ble cellene festet, mediet ble erstatt sisafced DMEM inneholdende 10$ serum, 2 mM L-glutamin, 100 U/ml penicillin,' 100 jjg/ml streptomycin og angitt i konsentrasjoner av forbindelsene. Celler fikk vokse i fire dager. Celler ble behandlet med trypsin, og antallet celler i hver kultur ble bestemt ved telling ved bruk av en ZM-kulturteller.
Aktivitet i testene ovenfor indikerte at forbindelsene ifølge oppfinnelsen er potensielle i behandlingen av restenose.
Claims (5)
1.
Anvendelse av en forbindelse med formelen
hvor R1 og R<3> er hydrogen; R2 er
farmasøytisk akseptable salter og solvater derav, til fremstillingen av et medikament som er nyttig for hemming av glattmuskelcelleproliferasjon.
2.
Anvendelse ifølge krav 1, hvor nevnte forbindelse er hydrokloridsaltet derav.
3.
Anvendelse Ifølge krav 1, hvor nevnte forbindelse er
eller dets hydrokloridsalt.
4 .
Anvendelse av en forbindelse med formelen hvor R<*> og R3 er hydrogen; R2 er
farmasøytisk akseptable salter og solvater derav, i fremstillingen av et medikament som er nyttig for hemming av restenose.
5 .
Anvendelse ifølge krav 4, hvor nevnte forbindelse er hydrokloridsaltet derav.
Anvendelse ifølge krav 4, hvor nevnte forbindelse er eller dets hydrokloridsalt.
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US08/138,296 US5457113A (en) | 1993-10-15 | 1993-10-15 | Methods for inhibiting vascular smooth muscle cell proliferation and restinosis |
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Publication number | Priority date | Publication date | Assignee | Title |
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US4133814A (en) * | 1975-10-28 | 1979-01-09 | Eli Lilly And Company | 2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents |
US4230862A (en) * | 1975-10-28 | 1980-10-28 | Eli Lilly And Company | Antifertility compounds |
US4380635A (en) * | 1981-04-03 | 1983-04-19 | Eli Lilly And Company | Synthesis of acylated benzothiophenes |
US4418068A (en) * | 1981-04-03 | 1983-11-29 | Eli Lilly And Company | Antiestrogenic and antiandrugenic benzothiophenes |
US5075321A (en) * | 1987-03-24 | 1991-12-24 | University Of Pennsylvania | Methods of treating diseases characterized by interactions of IgG-containing immune complexes with macrophage Fc receptors using antiestrogenic benzothiophenes |
US5395842A (en) * | 1988-10-31 | 1995-03-07 | Endorecherche Inc. | Anti-estrogenic compounds and compositions |
DE4122484A1 (de) * | 1991-07-06 | 1993-01-07 | Teves Gmbh Alfred | Schaltungsanordnung zur erkennung von radsensordefekten |
JP3157882B2 (ja) * | 1991-11-15 | 2001-04-16 | 帝国臓器製薬株式会社 | 新規なベンゾチオフエン誘導体 |
-
1993
- 1993-10-15 US US08/138,296 patent/US5457113A/en not_active Expired - Fee Related
-
1994
- 1994-10-12 KR KR1019940026034A patent/KR950010888A/ko not_active Application Discontinuation
- 1994-10-13 CA CA002118095A patent/CA2118095A1/en not_active Abandoned
- 1994-10-13 PH PH49189A patent/PH31263A/en unknown
- 1994-10-13 NO NO19943877A patent/NO313082B1/no not_active IP Right Cessation
- 1994-10-13 NZ NZ264675A patent/NZ264675A/en unknown
- 1994-10-13 CZ CZ19942535A patent/CZ287419B6/cs not_active IP Right Cessation
- 1994-10-13 EP EP94307526A patent/EP0652003B1/en not_active Expired - Lifetime
- 1994-10-13 HU HU9402958A patent/HUT71234A/hu unknown
- 1994-10-13 RU RU94036774/14A patent/RU2154475C2/ru not_active IP Right Cessation
- 1994-10-13 JP JP6247752A patent/JPH07149641A/ja active Pending
- 1994-10-13 SG SG1996002689A patent/SG45280A1/en unknown
- 1994-10-13 ZA ZA948026A patent/ZA948026B/xx unknown
- 1994-10-13 TW TW083109470A patent/TW303298B/zh active
- 1994-10-13 CN CN94117122A patent/CN1053571C/zh not_active Expired - Fee Related
- 1994-10-13 AU AU75788/94A patent/AU670213B2/en not_active Ceased
- 1994-10-13 IL IL11128894A patent/IL111288A/xx not_active IP Right Cessation
- 1994-10-13 AT AT94307526T patent/ATE165510T1/de not_active IP Right Cessation
- 1994-10-13 ES ES94307526T patent/ES2115163T3/es not_active Expired - Lifetime
- 1994-10-13 DE DE69409913T patent/DE69409913T2/de not_active Expired - Fee Related
-
1995
- 1995-04-14 US US08/422,286 patent/US5462937A/en not_active Expired - Fee Related
- 1995-04-14 US US08/423,329 patent/US5492926A/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
CN1053571C (zh) | 2000-06-21 |
NO943877L (no) | 1995-04-18 |
TW303298B (no) | 1997-04-21 |
CZ287419B6 (en) | 2000-11-15 |
US5462937A (en) | 1995-10-31 |
NZ264675A (en) | 1997-07-27 |
SG45280A1 (en) | 1998-01-16 |
PH31263A (en) | 1998-06-18 |
ES2115163T3 (es) | 1998-06-16 |
US5457113A (en) | 1995-10-10 |
AU670213B2 (en) | 1996-07-04 |
CA2118095A1 (en) | 1995-04-16 |
NO943877D0 (no) | 1994-10-13 |
JPH07149641A (ja) | 1995-06-13 |
EP0652003B1 (en) | 1998-04-29 |
IL111288A (en) | 1999-05-09 |
CN1105359A (zh) | 1995-07-19 |
ATE165510T1 (de) | 1998-05-15 |
HU9402958D0 (en) | 1995-02-28 |
US5492926A (en) | 1996-02-20 |
DE69409913T2 (de) | 1998-09-24 |
KR950010888A (ko) | 1995-05-15 |
HUT71234A (en) | 1995-11-28 |
RU2154475C2 (ru) | 2000-08-20 |
CZ253594A3 (en) | 1995-05-17 |
DE69409913D1 (de) | 1998-06-04 |
ZA948026B (en) | 1996-04-15 |
AU7578894A (en) | 1995-05-04 |
EP0652003A1 (en) | 1995-05-10 |
IL111288A0 (en) | 1994-12-29 |
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