NO313403B1 - Anvendelse av 2-fenyl-3-aroylbenzotiofener til hemming av angiogenese og angiogene sykdommer - Google Patents
Anvendelse av 2-fenyl-3-aroylbenzotiofener til hemming av angiogenese og angiogene sykdommer Download PDFInfo
- Publication number
- NO313403B1 NO313403B1 NO19943875A NO943875A NO313403B1 NO 313403 B1 NO313403 B1 NO 313403B1 NO 19943875 A NO19943875 A NO 19943875A NO 943875 A NO943875 A NO 943875A NO 313403 B1 NO313403 B1 NO 313403B1
- Authority
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- Norway
- Prior art keywords
- compound
- angiogenesis
- angiogenic diseases
- formula
- phenyl
- Prior art date
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- 235000011180 diphosphates Nutrition 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229940126864 fibroblast growth factor Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 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
- 238000002513 implantation Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- TWBYWOBDOCUKOW-UHFFFAOYSA-M isonicotinate Chemical compound [O-]C(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-M 0.000 description 1
- 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
- 230000003902 lesion Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 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
- 230000007246 mechanism Effects 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- 230000009401 metastasis Effects 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
- 230000004089 microcirculation Effects 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
- 210000000056 organ Anatomy 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
- 239000012188 paraffin wax Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 210000003668 pericyte Anatomy 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 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
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000035755 proliferation 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
- 230000001185 psoriatic effect Effects 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229960001860 salicylate Drugs 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
- 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
- 238000003756 stirring Methods 0.000 description 1
- 229960005322 streptomycin Drugs 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
- 230000004083 survival effect Effects 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
- 230000001225 therapeutic effect Effects 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
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 230000000007 visual effect Effects 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
- A61K31/395—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
- A61K31/4523—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
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- Medicinal Chemistry (AREA)
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- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pyrane Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Pyrrole Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Foreliggende oppfinnelse vedrører anvendelse av 2-fenyl-3-aroylbenzotiofener til hemming av angiogenese og/eller angiogene sykdommer.
Angiogenese (eller neovaskularisering), utviklingen av blodårer, spiller en viktig rolle i embryonisk utvikling, i inflammatorisk respons, i utvikling av metastase (tumorindu-sert angiogenese eller TIA), i diabetisk retinopati, i dannelsen av arthritisk panus og i psoriasis. I tumor-angiogenese blir for eksempel kapillærskudd dannet, deres dannelse blir indusert ved en gruppe tumorceller. Disse skuddene utvikler seg så til mikrosirkulasjonsnettverk i tumormassen. Det er to hovedtyper tumor-angiogenese hva angår hendelsene som følger implanteringer av metastatiske kimer på overflaten og i organer.
Den første eller primære angionesen er den initielle vaskulariseringen av massen av multipliserende tumorceller, og er ansett som et essensielt krav for overlevelsen og den videre veksten av en metastatisk avsetning.
Den andre er en kontinuerlig eller sekundær angiogenese, og er fenomenet som opptrer i bølger ved periferien av en voksende tumormasse. Denne sekundære angiogenesen er essensiell for samlingen av nye mikrosirkulasjonsområder til tjeneste for den ekspanderende og infiltrerende tumor.
Det er tydelig at et kjemikalium som ville hemme angiogenesen, enten ved kompetitivt å hemme en angiogenesefaktor eller ved andre mekanismer, ville ha en negativ effekt på veksten av tumorer, på utviklingen av retinopati eller rheumatoid arthritis eller på utviklingen av den psoriatiske lesjon.
Foreliggende oppfinnelse omfatter anvendelse med formelen hvor R<1> og R<3> er hydrogen;
R<2> er valgt blant gruppen bestående av pyrrolldino og piperidino; eller et farmasøytisk akseptabelt salt eller solvat derav, til fremstilling av et medikament som er nyttig for hemming av angiogenese og/eller angiogene sykdommer, med det forhold at slike sykdommer ikke inkluderer behandling av bryst- eller prostatatumorer eller rheumatoid artritt.
Foreliggende oppfinnelse angår oppdagelsen av at en utvalgt gruppe av 2-fenyl-3-aroylbenzotiofener (benzotiofener), de med formel I, er nyttige for hemming av angiogenese og/eller angiogenetiske sykdommer.
Uttrykket "hemming" er definert å omfatte dets generelt aksepterte betydning, som omfatter profylaktisk behandling av et menneske som blir utsatt for å pådra seg angiogene og/eller angiogenetiske sykdommer, og å holde i sjakk og/eller behandle eksisterende angiogenese og/eller angiogenetiske sykdommer. Som sådan omfatter foreliggende oppfinnelse både medisinsk terapeutisk og/eller profylaktisk behandling etter behov.
Generelt blir forbindelsen formulert med vanlige eksipienter, fortynningsmidler eller bærere, og sammenpresset til
tabletter eller formulert til eliksirer eller oppløsninger passende for oral administrasjon, eller administrert ved intramuskulære eller intravenøse veier. Forbindelsene kan bli administrert transdermalt, og kan bli formulert som doseringsformer for vedvarende frigiving o.l.
Forbindelsene som anvendes ifølge foreliggende oppfinnelse kan fremstilles ifølge etablerte prosedyrer, slik som de beskrevet i "U.S. patent nr. 4.133.814, 4.418.068 og 4.380.6-35, som alle innlemmes som referanse. Generelt starter prosessen med et benzo[b]tiofen med en 6-hydroksylgruppe og en 2-(4-hydroksyfenyl)-gruppe. Startforbindelsen blir be-skyttet, alkylert og avbeskyttet, for å danne formel I-forbindelsene. Eksempler på preparater av slike forbindelser, er gitt i de ovenfor diskuterte U.S.-patenter.
Forbindelsene som anvendes ifølge oppfinnelsen, danner farmasøytisk akseptable 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, hydrogen-jodid, salpetersyre, svovelsyre, fosforsyre, hypofosforsyre o.l. Salter avledet fra organiske syrer, slik som alifatiske mono- og dikarboksylsyrer, fenylsubstituerte alkanoinsyrer, hydroksyalkanoinsyrer og hydroksyalkandioinsyrer, aromatiske syrer, alifatiske og aromatiske sulfonsyrer kan også benyttes. Slike farmasøytisk akseptable salter omfatter således acetat, fenylacetat, trifluoracetat, akrylat, askorbat, benzoat, klorbenzoat, dinitrobenzoat, hydroksyben-zoat, metoksybenzoat, metylbenzoat, o-acetoksybenzoat, naftalen-2-benzoat, bromid, isobutyrat, fenylbutyrat, e-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, nikotinat, 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-bromfenylsulfonat, klorbenzensulfonat, etansulfonat, 2-hydroksyetansulfonat, 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. Reaktantene blir generelt blandet i et felles oppløsningsmiddel slik som dietyleter eller benzen. Saltet utvinnes normalt fra oppløsning innen omkring én time til 10 dager, og kan isoleres ved filtrering eller oppløsningsmidlet kan strippes 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 oppløselighetskarakteristika sammenlignet med forbindelsen fra hvilken de er avledet, og er således ofte lettere anvendbare for formulering av væsker eller emulsjoner. Farmasøytiske formuleringer kan fremstilles ved prosedyrer som er kjent i teknikken. For eksempel kan forbindelser formuleres med vanlige eksipienter, fortynnere eller bærere og formes til tabletter, kapsler, suspensjoner, pulvere o.l. Eksempler på eksipienter, fortynnere og bærere som passer for slike formuleringer, omfatter de følgende: Fyllstoffer og ekstendere slik som stivelse, sukkere, mannitol og kiesel-syrederivater; bindemidler slik som karboksymetylcellulose og andre cellulosederivater, alginater, gelatin og polyvinylpyrrolidon; fuktemidler slik som glyserol; disintegrer-ingsmidler slik som kalsiumkarbonat og natriumbikarbonat; midler for retardert oppløsning slik som paraffin; oppløs-ningsakseleratorer slik som kvaternære ammoniumforbindelser; overflateaktive stoffer 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 formuleres som eliksirer og oppløsn-inger 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 fremstilles fra polymere stoffer eller voks.
Den bestemte doseringen av en forbindelse med formel I, som er nødvendig for å hemme endometriosis ifølge foreliggende oppfinnelse, vil avhenge av alvoret av tilstanden, admini-strasjonsveien og beslektede faktorer, som vil bli bestemt av ansvarshavende lege. Generelt vil aksepterte og effektive daglige doser være fra omkring 0,1 til omkring 1.000 mg/dag, og mer typisk fra omkring 50 til omkring 200 mg/dag. Slike doseringer vil administreres til et individ som trenger slik behandling, fra én gang til omrking tre ganger hver dag eller oftere, etter behov for effektivt å hemme endometriosis.
Det er vanligvis foretrukket å administrere en forbindelse med formel I i form av et syreaddisjonssalt, slik som er vanlig ved farmasøytika som bærer en basisk gruppe, slik som piperidinringen. Det vil også være fordelaktig å administrere en slik forbindelse ad oral vei til et voksent menneske. For slike formål er de 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 med formel I hvor R<2> er piperidino (raloxifen) som er fremstilt, omfatter de vist under:
Formulering 2: Raloxifenkapsel Formulering 3 Raloxifenkapsel
Formulering 4: Raloxifenkapsel Formulering 5: Raloxifenkapsel
De spesifikke formuleringene ovenfor kan forandres i samsvar med de gitte fornuftige variasjoner.
En tablettformulering ble fremstilt ved anvendelse av ingrediensene nedenfor:
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 talkum 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:
Formulering 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
Primære retinale kapillære endotelcellekulturer ble fremstilt hovedsakelig ifølge prosedyren beskrevet i Buzney et al., Retinal Vascular Endothelial Cell og Pericytes: Differential Growth Characteristics in vitro, Invest. Ophthalmol. Visual Sei. 24: 470-483 (1983) og separert fra kontaminerende celler som beskrevet i Voyta et al., Identification and Isolation of Endothelial Cells Based on their Increased uptake of Acetylated-low density Lipoprotein, J. Cell Biol. 99: 2034-2040 (1981).
Alternativt ble endotelceller fra bovint hjerte fremskaffet (American Type Cultur Collection; Rockville MD 20852) for anvendelse i analysen. Uansett kilden, ble endotelceller utsådd i 24 brønners vevskulturplater med celledensitet på 10.000 celler/brønn i Dulbecco's modifiserte Eagle Medium (GIBCO; Grand Island, N.Y.) tilsatt 10% bovint serum, 100 U/ml penicillin, 100 pg/ml streptomycin, 2 mM L-glutamin og 20 ng/ml fibroblast vekstfaktor. Etter inkubering over natten, ble forskjellige mengder av forbindelsene ifølge oppfinnelsen tilsatt til individuelle vekstbrønner. For sammenligning ble nativt PF-4 kjent for å hemme endotelceller og angiogenese, som tjente som en positiv kontroll testet over et område på 0,1 til 4 ug/ml. Endotelcellekulturene fikk så vokse i fire dager ved 37° C, 5% CO2 i fuktig vevskulturinkubator. Kulturene ble så høstet individuelt ved trypsinering og tellet i en Am-Coulter Counter (Coulter Electronics, Inc.; Opa Locka FL 33054).
Aktiviteten i testen ovenfor indikerer at forbindelsene ifølge oppfinnelsen er potensielle til behandling av angiogenese og/eller angiogenetiske sykdommer.
Nedenfor følger data for å demonstrere hemmingen av Human Umbilical Vein Endothelial Cell (HUVEC) proliferasjon ved en forbindelse med formel I der R<*> og R<3> er hydrogen og R<2> er pyrrolidino, som nedenfor er referet til som forbindelse A. Eksperimentet ble utført som beskrevet i testprosedyren over. Disse dataene indikerer at forbindelsene med formel I er nyttige ved hemming av angiogenese og/eller angiogene sykdommer.
Claims (4)
1.
Anvendelse av en forbindelse med formelen
hvor r! og R<3> er hydrogen;
R<2> er valgt blant gruppen bestående av pyrrolidino og piperidino; eller et farmasøytisk akseptabelt salt eller solvat derav, til fremstilling av et medikament som er nyttig for hemming av angiogenese og/eller angiogene sykdommer, med det forbehold at slike sykdommer ikke inkluderer behandling av bryst- eller prostatatumorer eller rheumatoid artritt.
2 .
Anvendelse ifølge krav 1, hvor nevnte forbindelse er saltsyresaltet derav.
3.
Anvendelse ifølge krav 1, hvor nevnte medikament er profylaktisk .
4 .
Anvendelse ifølge krav 1, hvor nevnte forbindelse er eller et salt derav.
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| US13770393A | 1993-10-15 | 1993-10-15 |
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| CN (1) | CN1058390C (no) |
| AT (1) | ATE205712T1 (no) |
| AU (1) | AU677701B2 (no) |
| CA (1) | CA2118097A1 (no) |
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| NO (1) | NO313403B1 (no) |
| NZ (1) | NZ264674A (no) |
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| PT (1) | PT652000E (no) |
| RU (1) | RU94036771A (no) |
| SI (1) | SI0652000T1 (no) |
| TW (1) | TW303367B (no) |
| UA (1) | UA32427C2 (no) |
| ZA (1) | ZA948027B (no) |
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| US5811447A (en) | 1993-01-28 | 1998-09-22 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| US6515009B1 (en) | 1991-09-27 | 2003-02-04 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| US6251920B1 (en) | 1993-05-13 | 2001-06-26 | Neorx Corporation | Prevention and treatment of cardiovascular pathologies |
| US6491938B2 (en) | 1993-05-13 | 2002-12-10 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| DE69435137D1 (de) | 1993-05-13 | 2008-10-16 | Poniard Pharmaceuticals Inc | Prävention und behandlung von pathologien, die mit einer abnormalen proliferationglatter muskelzellen verbunden sind |
| US6197789B1 (en) | 1995-06-07 | 2001-03-06 | Neorx Corporation | Prevention and treatment of cardiovascular pathologies with tamoxifen analogues |
| US5492927A (en) * | 1993-12-21 | 1996-02-20 | Eli Lilly And Company | Non-peptide tachykinin receptor antagonists to treat allergy |
| US5484808A (en) * | 1995-02-09 | 1996-01-16 | Eli Lilly And Company | Methods of inhibiting cell-cell adhesion |
| US5843974A (en) * | 1995-06-06 | 1998-12-01 | Eli Lilly And Company | Methods of inhibiting melanoma using Benzothiophenes as cytotoxic agents per se |
| US5532254A (en) * | 1995-06-07 | 1996-07-02 | Eli Lilly And Company | Modulation of calcium channels using benzothiophenes |
| US6265407B1 (en) | 1997-06-24 | 2001-07-24 | Janssen Pharmaceutica N.V. | Angiogenesis inhibiting thiadiazolyl pyridazine derivatives |
| US6537554B1 (en) | 1998-09-10 | 2003-03-25 | Curagen Corporation | Nucleotide sequences and amino acid sequences of secreted proteins involved in angiogenesis |
| ATE301129T1 (de) | 1999-05-04 | 2005-08-15 | Strakan Int Ltd | Androgen glykoside und die androgenische aktivität davon |
| KR100675252B1 (ko) | 2000-03-08 | 2007-02-08 | 한국생명공학연구원 | 신규 7,8-디히드로-잔테논-8-카르복실산 유도체 및 이를생산하는 신규 미생물 |
| US20030104573A1 (en) * | 2000-09-11 | 2003-06-05 | Shimkets Richard A. | Nucleotide sequences and amino acid sequences of secreted proteins involved in angiogenesis |
| US6632835B2 (en) | 2001-02-22 | 2003-10-14 | Nanodesign Inc. | Dibenzo[c]chromen-6-one derivatives as anti-cancer agents |
| ITMI20011495A1 (it) * | 2001-07-12 | 2003-01-12 | Pharmaproducts Uk Ltd | Sali di calcio ad attivita' citotossica |
| JP3887588B2 (ja) * | 2002-08-30 | 2007-02-28 | 株式会社リガク | Ｘ線回折による応力測定法 |
| ITMI20041279A1 (it) * | 2004-06-24 | 2004-09-24 | Pharmaproducts Uk Ltd | Uso di calcio trifluoroacetato per la preparazione di medicamenti ad effetto anti-angiogenetico |
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| US4133814A (en) * | 1975-10-28 | 1979-01-09 | Eli Lilly And Company | 2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents |
| 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 |
| 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 |
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1994
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- 1994-10-12 UA UA94105915A patent/UA32427C2/uk unknown
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- 1994-10-13 JP JP6247749A patent/JPH07149644A/ja active Pending
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- 1994-10-13 NO NO19943875A patent/NO313403B1/no not_active IP Right Cessation
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- 1994-10-13 TW TW083109472A patent/TW303367B/zh active
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- 1994-10-13 AU AU75791/94A patent/AU677701B2/en not_active Ceased
- 1994-10-13 CZ CZ19942532A patent/CZ287535B6/cs not_active IP Right Cessation
- 1994-10-13 ES ES94307523T patent/ES2161238T3/es not_active Expired - Lifetime
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- 1994-10-13 KR KR1019940026160A patent/KR950010889A/ko not_active Application Discontinuation
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Also Published As
| Publication number | Publication date |
|---|---|
| PH31260A (en) | 1998-06-18 |
| CN1105361A (zh) | 1995-07-19 |
| SI0652000T1 (en) | 2002-06-30 |
| RU94036771A (ru) | 1996-11-10 |
| CA2118097A1 (en) | 1995-04-16 |
| CZ287535B6 (en) | 2000-12-13 |
| EP0652000A1 (en) | 1995-05-10 |
| HU220607B1 (hu) | 2002-03-28 |
| US5610166A (en) | 1997-03-11 |
| JPH07149644A (ja) | 1995-06-13 |
| NO943875L (no) | 1995-04-18 |
| NZ264674A (en) | 1999-06-29 |
| DE69428325D1 (de) | 2001-10-25 |
| ES2161238T3 (es) | 2001-12-01 |
| PT652000E (pt) | 2002-01-30 |
| DK0652000T3 (da) | 2001-11-12 |
| ZA948027B (en) | 1996-04-15 |
| AU7579194A (en) | 1995-05-04 |
| DE69428325T2 (de) | 2002-06-20 |
| HUT71108A (en) | 1995-11-28 |
| HU9402955D0 (en) | 1995-02-28 |
| NO943875D0 (no) | 1994-10-13 |
| IL111289A0 (en) | 1994-12-29 |
| ATE205712T1 (de) | 2001-10-15 |
| CZ253294A3 (en) | 1995-05-17 |
| TW303367B (no) | 1997-04-21 |
| CN1058390C (zh) | 2000-11-15 |
| UA32427C2 (uk) | 2000-12-15 |
| EP0652000B1 (en) | 2001-09-19 |
| KR950010889A (ko) | 1995-05-15 |
| AU677701B2 (en) | 1997-05-01 |
| IL111289A (en) | 1999-09-22 |
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