NO144632B - ANALOGUE PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTICALLY ACTIVE DIANHYDROHEXITID ACYL DERIVATIVES - Google Patents
ANALOGUE PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTICALLY ACTIVE DIANHYDROHEXITID ACYL DERIVATIVES Download PDFInfo
- Publication number
- NO144632B NO144632B NO754374A NO754374A NO144632B NO 144632 B NO144632 B NO 144632B NO 754374 A NO754374 A NO 754374A NO 754374 A NO754374 A NO 754374A NO 144632 B NO144632 B NO 144632B
- Authority
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- Norway
- Prior art keywords
- dianhydro
- abs
- preparation
- dulcitol
- benzene
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title description 9
- 150000001875 compounds Chemical class 0.000 claims description 19
- -1 3-phenyl-propionyl Chemical group 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 206010028980 Neoplasm Diseases 0.000 description 16
- 239000003795 chemical substances by application Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 239000013078 crystal Substances 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 239000002253 acid Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- AAFJXZWCNVJTMK-GUCUJZIJSA-N (1s,2r)-1-[(2s)-oxiran-2-yl]-2-[(2r)-oxiran-2-yl]ethane-1,2-diol Chemical compound C([C@@H]1[C@H](O)[C@H](O)[C@H]2OC2)O1 AAFJXZWCNVJTMK-GUCUJZIJSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000013543 active substance Substances 0.000 description 5
- 230000010933 acylation Effects 0.000 description 5
- 238000005917 acylation reaction Methods 0.000 description 5
- 230000003217 anti-cancerogenic effect Effects 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 150000002924 oxiranes Chemical class 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000006188 syrup Substances 0.000 description 5
- 235000020357 syrup Nutrition 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- 231100000419 toxicity Toxicity 0.000 description 5
- AAFJXZWCNVJTMK-UHFFFAOYSA-N 1,2-bis(oxiran-2-yl)ethane-1,2-diol Chemical compound C1OC1C(O)C(O)C1CO1 AAFJXZWCNVJTMK-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 150000008065 acid anhydrides Chemical class 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 201000009030 Carcinoma Diseases 0.000 description 3
- 201000000274 Carcinosarcoma Diseases 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000001085 cytostatic effect Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- YBADLXQNJCMBKR-UHFFFAOYSA-M (4-nitrophenyl)acetate Chemical compound [O-]C(=O)CC1=CC=C([N+]([O-])=O)C=C1 YBADLXQNJCMBKR-UHFFFAOYSA-M 0.000 description 2
- 206010003445 Ascites Diseases 0.000 description 2
- 208000001382 Experimental Melanoma Diseases 0.000 description 2
- ODOISJJCWUVNDJ-WCTZXXKLSA-N [(2r,3r,4r,5r)-2,3,4,5-tetrahydroxy-6-methylsulfonyloxyhexyl] methanesulfonate Chemical compound CS(=O)(=O)OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)COS(C)(=O)=O ODOISJJCWUVNDJ-WCTZXXKLSA-N 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 238000006735 epoxidation reaction Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- FBPFZTCFMRRESA-GUCUJZIJSA-N galactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-GUCUJZIJSA-N 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 231100001274 therapeutic index Toxicity 0.000 description 2
- 230000002110 toxicologic effect Effects 0.000 description 2
- 231100000027 toxicology Toxicity 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000000844 transformation Methods 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- FXXACINHVKSMDR-UHFFFAOYSA-N acetyl bromide Chemical compound CC(Br)=O FXXACINHVKSMDR-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003005 anticarcinogenic agent Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 229950000758 dianhydrogalactitol Drugs 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- FBPFZTCFMRRESA-UHFFFAOYSA-N hexane-1,2,3,4,5,6-hexol Chemical compound OCC(O)C(O)C(O)C(O)CO FBPFZTCFMRRESA-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- QOHMWDJIBGVPIF-UHFFFAOYSA-N n',n'-diethylpropane-1,3-diamine Chemical compound CCN(CC)CCCN QOHMWDJIBGVPIF-UHFFFAOYSA-N 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- NRTLTGGGUQIRRT-UHFFFAOYSA-N triethylazanium;bromide Chemical compound [Br-].CC[NH+](CC)CC NRTLTGGGUQIRRT-UHFFFAOYSA-N 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/16—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by esterified hydroxyl radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/14—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by free hydroxyl radicals
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Epoxy Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Foreliggende oppfinnelse vedrører en analogifremgangsmåte ved fremstillling av nye terapeutisk aktive forbindelser med formel - The present invention relates to an analogue method for the preparation of new therapeutically active compounds with the formula -
I IN
hvori Q betyr en acetyl-, kloracetyl-, p-karbometoksy-propionyl-, 3-fenyl-propionyl- eller y- fenyl-butyryl-gruppe. wherein Q represents an acetyl, chloroacetyl, p-carbomethoxy-propionyl, 3-phenyl-propionyl or γ-phenyl-butyryl group.
Bianhydro-sukkeralkohol-derivatene av diepoksydtypen, som L-l,2-3,4-diepoksy-butan, 1,2-5,6-dianhydro-D-mannitol og 1,2-5,6-dianhydro-dulcitol er kjente midler med anticarcino- The bianhydro-sugar alcohol derivatives of the diepoxide type, such as L-1,2-3,4-diepoxy-butane, 1,2-5,6-dianhydro-D-mannitol and 1,2-5,6-dianhydro-dulcitol are known agents with anticarcino-
gen virkning (Jarman, M. Ross. W.X.j.: The formation of epox- gen action (Jarman, M. Ross. W.X.j.: The formation of epox-
ides from substituted hexitols. Carbonhydrate Research 9,139. ides from substituted hexitols. Carbohydrate Research 9,139.
1969, Jarman, M. Ross, W.CJ.: Formation of 1,2-5,6-dianhydro-D-mannitol from 1,6-dibroma- and 1,6-dimethanesulphonoxy-l,6-dideoxy-D-mannitol. Dhem.Ind. 42, 1789. 1967, Elson, A.L. , 1969, Jarman, M. Ross, W.CJ.: Formation of 1,2-5,6-dianhydro-D-mannitol from 1,6-dibromo- and 1,6-dimethanesulphonoxy-1,6-dideoxy-D- mannitol. Dhem.Ind. 42, 1789. 1967, Elson, A.L. ,
Jarman, M. Ross, W.C.J.: Toxicity, haematological effeets and antitumour activity of epoxides derived from disubstituted hexitols. Europ.J.Cancer 4, 617. 1968.) Jarman, M. Ross, W.C.J.: Toxicity, haematological effects and antitumour activity of epoxides derived from disubstituted hexitols. Europ.J.Cancer 4, 617. 1968.)
Blant disse forbindelsene besitter 1,2-5,6-dianhydro- Among these compounds, 1,2-5,6-dianhydro-
dulcitol de gunstigste farmakologiske egenskapene. dulcitol the most favorable pharmacological properties.
(Nemeth, L., Institåris, L., Somfai, S., Gal, F., Pålyi , I., (Nemeth, L., Institåris, L., Somfai, S., Gal, F., Pålyi, I.,
Sugér, J., Csuka, 0., Szentirmay, Z. , Kellner, B.:. Pharmaco- Sugér, J., Csuka, 0., Szentirmay, Z. , Kellner, B.:. Pharmaco-
logy and antitumoral effect of dulcitoldiepoxide. (1,2-5,6-dianhydro-galactitol, NSC-132313). Cancer Chemotherapy Rep. logy and antitumoral effect of dulcitol diepoxide. (1,2-5,6-dianhydro-galactitol, NSC-132313). Cancer Chemotherapy Rep.
1.56, 593. 1972, Institåris, L., Nemet, L., Somfai, S., Gål, 1.56, 593. 1972, Institåris, L., Nemet, L., Somfai, S., Gål,
F., Hercsel, I., Zaka, S., Kellner, B.: Investigation into F., Hercsel, I., Zaka, S., Kellner, B.: Investigation into
the Correlation of Cytostatic Activity with the in vitro Di- the Correlation of Cytostatic Activity with the in vitro Di-
epoxide Formation on.some. Terminally Substituted Hexitols. epoxide Formation on.some. Terminally Substituted Hexitols.
Neiplasma 17, 1, 15-24. 1970). Neiplasma 17, 1, 15-24. 1970).
De intramolekylære reaksjonene mellom de frie hydroksylgruppene The intramolecular reactions between the free hydroxyl groups
og epoksydringene forårsaker dog i pufret vandig losning også and the epoxy rings cause, however, in buffered aqueous solution as well
i fravær av biologiske medier omvandlinger av forbindelsene. in the absence of biological media transformations of the compounds.
Disse omvandlingene gir med henblikk på den cytostatiske virkningen ugunstige eller toksiske metabolitter. These transformations give unfavorable or toxic metabolites with regard to the cytostatic effect.
For å unngå nevnte folger tas tilsvarende beskyttelsesgrupper To avoid the aforementioned consequences, corresponding protective groups are taken
til hjelp som avspaltes under biologiske betingelser, hvorved diepoksyforbindelsene oppstår som aktive metabolitter. Des- for help that is broken down under biological conditions, whereby the diepoxy compounds arise as active metabolites. Dec-
suten modifiserer beskyttelsesgruppene av hydroksylgruppen los-elighetskarakteren av det ekstremt vannloselig heksitol-diepoksydet med henblikk på den cytostatiske virkningen for det meste gunstig. suten, the protecting groups of the hydroxyl group modify the solubility character of the extremely water-insoluble hexitol diepoxide with a view to the cytostatic effect mostly favorably.
Anvendelsen av slike forbindelser viser seg også fordelaktig The use of such compounds also proves advantageous
utfra andre farmakologiske overlegninger. De tidligere tumor-forsokene tyder på dette: som ble gjennomfort under anvendelse av enkelte medlemmer i denne forbindelsesrekken. Resultater viser f.eks. den betydelige senkningen av toksisiteten og virkningensendringene som utoves på tumorspekteret (forskjel- based on other pharmacological considerations. The previous tumor experiments indicate this: which were carried out using individual members of this compound series. Results show e.g. the significant lowering of the toxicity and the effect changes that are exerted on the tumor spectrum (difference
lige tumortyper). equal tumor types).
Undersokelse av den toksikologiske og anticar. cinoqene virkningen til 1, 2- 5„ 6- dianhvdro- 3, 4- diacyl- dulcitol Investigation of the toxicological and anticar. cinoqene the action of 1, 2- 5„ 6- dianhvdro- 3, 4- diacyl- dulcitol
Antitumorvirkningen til de fremstilte diepoksy-diacyl-dulcitol-derivatene uridersokes på transplanterte tumorer av ani-malsk opprinnelse. Hver av de fremstilte forbindélsene hindret avhengig av dosen veksten av de transplanterte tumorene. The anti-tumor effect of the produced diepoxy-diacyl-dulcitol derivatives was investigated on transplanted tumors of animal origin. Each of the prepared compounds inhibited the growth of the transplanted tumors in a dose-dependent manner.
Den toksikologiske og anticarcinogene virkningen av 4,6-diepoksy-diacyl-dulcitol ble sammenlignet den oppnådde virkningen til 1,2-5,6-dianhydro-dulcitol (utgangsdulcitol) i forskjellige forsokssystemer. The toxicological and anticarcinogenic effect of 4,6-diepoxy-diacyl-dulcitol was compared to the obtained effect of 1,2-5,6-dianhydro-dulcitol (starting dulcitol) in different test systems.
Betegnelse av forbindelsene Designation of the compounds
DAD = 1,2-5, 6-dianhydro-dulcitol DAD = 1,2-5, 6-dianhydrodulcitol
Diac-DAD = 1,2-5,6-dianhydro-3,4-di-(acetyl)-dulcitol DS - DAD = 1,2-5,6-dianhydro-3,4-di-(p-karbometoksy-propionyl)-dulcitol Diac-DAD = 1,2-5,6-dianhydro-3,4-di-(acetyl)-dulcitol DS - DAD = 1,2-5,6-dianhydro-3,4-di-(p-carbomethoxy- propionyl)-dulcitol
FB - DAD = 1,2-5,6-dianhydro-3 ,4-di (jf-f enyl-butyryl) -dulcitol FP - DAD = 1,2-5,6-dianhydro-3 ,4-di-((3-f enyl-propionyl )-dulcitol FB - DAD = 1,2-5,6-dianhydro-3,4-di(jf-phenyl-butyryl)-dulcitol FP - DAD = 1,2-5,6-dianhydro-3,4-di-( (3-phenyl-propionyl)-dulcitol
CA-DAD = 1,2-5,6-dianhydro-3,4-di-(kloracetyl)-dulcitol CA-DAD = 1,2-5,6-dianhydro-3,4-di-(chloroacetyl)-dulcitol
Akutt toksisitet Acute toxicity
Den akutte toksisiteten ble bestemt på normale Swiss-mus. Dødeligheten ble fastslått etter engangs dosering etter 21 dager. The acute toxicity was determined on normal Swiss mice. Mortality was determined after single dosing after 21 days.
Toksisiteten synker parallelt tilnærmet molekylvektens okning. Dodelighet oppnås så vel etter intraperitoneal som etter oral forgiftning på 5.-9. dag. Derav vises samtidig at alle midler (virkestoffer) også resorberes godt i mage-tarm-trakten. The toxicity decreases in parallel with the increase in molecular weight. Mortality is achieved both after intraperitoneal and after oral poisoning on the 5th-9th. day. This also shows that all agents (active substances) are also well absorbed in the gastrointestinal tract.
Kumulerende egenskaper ( toksisk kumulering) Cumulative properties (toxic cumulation)
Kumuleringsresten ble bestemt ifolge Druckreys metode. The cumulative residual was determined according to Druckrey's method.
t t
Virkning på transplantasjonstumorer Effect on transplant tumors
a) Ehrlich Ascites Carcinoma a) Ehrlich Ascites Carcinoma
Tumoren med 5 mill. tumorceller ble injisert i.p. i en mus. The tumor with 5 million tumor cells was injected i.p. in a mouse.
Behandlingen ble påbegynt 24 timer etter tumorinjiseringen og gjentatt daglig over 6 henholdsvis 8 dager. The treatment was started 24 hours after the tumor injection and repeated daily over 6 and 8 days respectively.
b) Walker 256 Carcinosarcoma Intramuscularis b) Walker 256 Carcinosarcoma Intramuscularis
Etter 24 timer fra injiseringen av 20 mill. tumorceller ble After 24 hours from the injection of 20 million tumor cells,
det gjennomfart en engangsbehandling. For bestemmelse av de terapeutiske indeksene ble det tatt den minste dosen som på den 10. dag forte til en bedommelse av en 90% overskridende tumorinhibering. it underwent a one-time treatment. For the determination of the therapeutic indices, the smallest dose was taken which, on the 10th day, resulted in a judgment of tumor inhibition exceeding 90%.
Alle undersokte midler er meget virksomme. Den terapeutiske indeksen for de nye midlene er gunstigere enn den for de usub-stituerte DAD, grensedosisen utgjor ved forbindelsene DAD, Diac-DAD og CA-DAD 8-10 mM, ved DS-, FB- og FP-DAD det dobbelte. All investigated means are very effective. The therapeutic index for the new agents is more favorable than that for the unsubstituted DAD, the limiting dose for the compounds DAD, Diac-DAD and CA-DAD is 8-10 mM, for DS-, FB- and FP-DAD it is twice that.
Den gjennom diacyl-diepoksydene fremkalte betydelig minskning av toksisiteten ledsages bare av en måtelig minskning av den anticarcinogene virkningen. The significant reduction in toxicity brought about by the diacyl diepoxides is accompanied by only a moderate reduction in the anticarcinogenic effect.
c) Virkning på Harding- Passey s. c. Melanoma c) Effect on Harding-Passey s. c. Melanoma
Den 1angsomtvoksende, mindre påvirkbare kjente tumoren ble The slow-growing, less susceptible tumor was known
fremkalt gjennom s.c. transplantasjon av et stykke tumorvev. Behandlingen ble begynt 24 timer etter transplantasjonen. induced through s.c. transplantation of a piece of tumor tissue. Treatment was started 24 hours after transplantation.
Målingene skjedde på den 21. dag av forsoket. The measurements took place on the 21st day of the experiment.
Virkningen av de foreslåtte forbindelsene på disse langsomt-voksende, mindre' ømfintlige tumorer overfor anticarcinogene midler, overgår vesentlig virkningen av de epoksyder som tjener som kontroll. The effect of the proposed compounds on these slow-growing, less sensitive tumors to anticarcinogenic agents significantly exceeds the effect of the epoxides that serve as controls.
d) Virkning på Guérin Carcinoma d) Effect on Guérin Carcinoma
Virkningen av Diac-DAD er avhengig av dosen. Virkningen av The effect of Diac-DAD is dose dependent. The effect of
de andre midlene ved samme dose er likeledes gunstig. the other remedies at the same dose are likewise beneficial.
Sammenfattende kan man fastslå at toksisiteten av de undersokte diepoksy-diacyl-dulcitol-forbindelsene i sammenligning med det opprinnelige epoksydet er sunket. Den anticarcinogene virkning av midlet kunne påvises på flere transplanterbare Tumor (Ehrlich ascites, Walker Carcinosarcoma, Harding-Passey Melanoma, Guérin Carcinoma), i enkelte tilfeller har disse sogar en bedre tumorinhibering enn det opprinnelige diepoksydet In summary, it can be stated that the toxicity of the examined diepoxy-diacyl-dulcitol compounds in comparison with the original epoxide has decreased. The anticarcinogenic effect of the agent could be demonstrated on several transplantable tumors (Ehrlich ascites, Walker Carcinosarcoma, Harding-Passey Melanoma, Guérin Carcinoma), in some cases these even have a better tumor inhibition than the original diepoxide
(Harding-Passey Melanoma). (Harding-Passey Melanoma).
Den beregnede terapeutiske indeks for Walker Carcinosarcoma er bedre hos alle nye midler enn den for DAD. Midlene resorberes godt i mage-tarm-trakten. The calculated therapeutic index for Walker Carcinosarcoma is better with all new agents than that for DAD. The agents are well absorbed in the gastrointestinal tract.
Med hensyn til rekkefølgen for innføring av acyloksygruppen og epoksydringen er to prinsipielle veier mulige: a) Påfølgende oppbygning av epoksydringen ut fra 3,4-diacyl-derivater With regard to the order of introduction of the acyloxy group and the epoxidation, two principal paths are possible: a) Subsequent construction of the epoxidation from 3,4-diacyl derivatives
b) Acylering av 1,2-5,6-dianhydro-heksitol. b) Acylation of 1,2-5,6-dianhydro-hexitol.
For fremstilling av de nye forbindelsene valgte man veien b), For the production of the new compounds, route b) was chosen.
fordi oksiranringdannelse etter acyleringen er forbundet med vanskeligheter. Ringslutningen skjer nemlig i alkalisk medium, hvori substituentene kan avspaltes. because oxirane ring formation after the acylation is associated with difficulties. The ring closure takes place in an alkaline medium, in which the substituents can be split off.
1,2-5,6-dianhydro-heksitol Forbindelse av formel I 1,2-5,6-Dianhydrohexitol Compound of formula I
Foreliggende oppfinnelse er altså karakterisert ved at man omsetter det tilsvarende 1,2-5,6-dianhydro-heksitol med et acyleringsmiddel som angir de innledningsvis definerte Q-grupper. The present invention is thus characterized by reacting the corresponding 1,2-5,6-dianhydrohexitol with an acylating agent which indicates the Q groups defined at the outset.
I nærmere detalj fremstilles de nye forbindelsene som føl-ger: 1 mol 1,2-5,6-dianhydroheksitol opploses i vannfritt, organisk løsningsmiddel, fordelaktig i benzen eller i en benzen-homolog ved et volum/vektdelsforhold på 40. Deretter tilsetter man losningen 2,0-3,01 mol av en organisk syrebindende base eller et uorganisk syrebindende middel. I enkelte tilfeller kan den syrebindende basen (f. eks. triétylamin eller pyridin) tilsettes i stort overskudd. Derved tjener dette overskuddet som løsningsmiddel. Losningen som inneholder det syrebindende midlet tilsetter man 2 mol acyleringsmiddel i form av en for-tynnet, ca. 0,5 m løsning, sådann at reaksjonstemperaturen i hvert.fall forblir under reaksjonsblandingens kokepunkt. En tilsetningstemperatur på 20-50°C er hensiktsmessig. Etter avslutningen av tilsetningen rores reaksjonsblandingen 10-180 min. ved denne temperaturen. I mange tilfeller er det nbd-vendig å rore 10-24 timer etterpå ved romtemperatur. In more detail, the new compounds are prepared as follows: 1 mol of 1,2-5,6-dianhydrohexitol is dissolved in an anhydrous, organic solvent, advantageously in benzene or in a benzene homolog at a volume/weight ratio of 40. Then one adds the solution 2.0-3.01 mol of an organic acid-binding base or an inorganic acid-binding agent. In some cases, the acid-binding base (e.g. triethylamine or pyridine) can be added in large excess. Thereby, this surplus serves as a solvent. To the solution containing the acid-binding agent, 2 mol of acylating agent are added in the form of a diluted, approx. 0.5 m solution, such that the reaction temperature in any case remains below the boiling point of the reaction mixture. An addition temperature of 20-50°C is appropriate. After the end of the addition, the reaction mixture is stirred for 10-180 min. at this temperature. In many cases, it is not necessary to stir 10-24 hours afterwards at room temperature.
Opparbeidingen av reaksjonsblandingen kan skje på to forskjellige måter, avhengig av om det som acyleringsmiddel anvendes syrehalogenid, henholdsvis syreanhydrid eller ester. The preparation of the reaction mixture can take place in two different ways, depending on whether an acid halide, acid anhydride or ester is used as the acylating agent.
a) Ved acyleringen med syrehalogenider filtreres de utfelte saltene etter reaksjonen henholdsvis etterroringen fra reaksjonsblandingen og vaskes med et vannfritt organisk løsnings-middel, fordelaktig med benzen. Den rene losningen inndampes ved en temperatur på 50°C til tbrrhet, resten blandes med metylalkohol eller andre løsningsmidler (fortrinnsvis med eter, etylacetat eller andre blandinger o.s.v.), og avkjøles så. Etter krystallisasjonen frafiltreres det erholdte produktet. Fra moderluten kan det utvinnes ved konsentrasjon eller utfel-ning med løsningsmiddel ytterligere krystallinsk produkt a) During the acylation with acid halides, the precipitated salts are filtered after the reaction or the afterstirring from the reaction mixture and washed with an anhydrous organic solvent, advantageously with benzene. The pure solution is evaporated at a temperature of 50°C to dryness, the residue is mixed with methyl alcohol or other solvents (preferably with ether, ethyl acetate or other mixtures, etc.), and then cooled. After crystallization, the product obtained is filtered off. Additional crystalline product can be recovered from the mother liquor by concentration or precipitation with a solvent
(II generasjon). Produktet utgjor nær 10-20% av det opprinne- (II generation). The product accounts for close to 10-20% of the originating
lige produktet (I generasjon). same product (I generation).
De erholdte produktene så vel I som II generasjon renses eventuelt ved omkrystallisasjon, eventuelt flere gangers omkrystallisasjon (hovedsakelig ved II generasjon). The obtained products, both I and II generation, are optionally purified by recrystallization, possibly several times of recrystallization (mainly in II generation).
b) Ved acyleringen med syreanhydrider eller estere inndampes reaksjonsblandingen etter reaksjonens avslutning til halvparten b) During the acylation with acid anhydrides or esters, the reaction mixture is evaporated to half after the end of the reaction
av dets opprinnelige volum og den inndampede reaksjonsblandingen helles under omrbring i 2-3 ganger volumet isvann. Den vandige fasen adskilles fra den organiske fasen. Såfremt, den vandige fase har en sur pHj vaskes den organiske fasen nbytral of its original volume and the evaporated reaction mixture is poured with stirring into 2-3 times the volume of ice water. The aqueous phase is separated from the organic phase. If the aqueous phase has an acidic pH, the organic phase is washed neutrally
helst ved utrystning med 5-10%'ig natriumhydrogenkarbonat-lbsning. Etter adskillelsen som folger den siste vaskingen inndampes den organiske fasen under redusert trykk og resten opp-arbeides videre ifblge forskriften i punkt a). (Blanding med løsningsmiddel, utkrystallisasjon og eventuelle omkrystallisa-sjoner). preferably by shaking with a 5-10% sodium bicarbonate solution. After the separation that follows the final washing, the organic phase is evaporated under reduced pressure and the residue is further worked up according to the regulations in point a). (Mixing with solvent, crystallization and possible recrystallizations).
Som utgangsstoffer anvendes 1,2-5,6-dianhydro-D-mannitol (smeltepunkt: 64-66°C, [oc]^ = +40° i vann, c = 1,25) hhv. 1,2-5,6-dianhydro-dulcitol (smeltepunkt: 98,5°C , [oc]D = +2° As starting materials, 1,2-5,6-dianhydro-D-mannitol is used (melting point: 64-66°C, [oc]^ = +40° in water, c = 1.25) or 1,2-5,6-dianhydro-dulcitol (melting point: 98.5°C , [oc]D = +2°
i vann, c = 1,25). Fremstillingen av disse forbindelsene er beskrevet i litteraturen. (Jarman, M. Ross, W.C.J.: The formation of epoxides from substituted hexitols. Carbohydrate Research 9, 139.1969, jarman, M. Ross, W.C.J.: Formation of 1,2-5,6-dianhydro-D-mannitol from 1,6-dibromo- and 1,6-dime-thanesulphonoxy-1,6-dideoxy-D-mannitol. Chem. Ind. 4_2, 1789. 1967). in water, c = 1.25). The preparation of these compounds is described in the literature. (Jarman, M. Ross, W.C.J.: The formation of epoxides from substituted hexitols. Carbohydrate Research 9, 139.1969, jarman, M. Ross, W.C.J.: Formation of 1,2-5,6-dianhydro-D-mannitol from 1,6 -dibromo- and 1,6-dime-thanesulphonoxy-1,6-dideoxy-D-mannitol. Chem. Ind. 4_2, 1789. 1967).
Som medium henholdsvis lbsningsmiddel finner de vannfrie organiske løsningsmidler anvendelse som ikke står i noen kjemisk vekselvirkning med reaksjonskomponentene, d.v.s. ikke reagerer med dem. Egnede løsningsmidler er de homologe av alifatisker-, cykloalkyl- og aromatiske hydrokarboner eller halogenerte hydrokarboner. Som medium er sogar de organiske syrebindende basene (f. eks. trietylamin, pyridin, o.s.v.) egnet, når de anvendes i tilsvarende overskudd. For vasking av det frafiltrerte saltet tar man hensiktsmessig den mengden vannfritt løsningsmiddel som svarer til den opprinnelige mengden anvendt løsningsmiddel for å unngå at det oppstår en losningsmiddel-blanding. Slike losningsmiddelblandinger vanskeliggjør nemlig opparbeidingen av reaksjonsblandingen. As a medium or solvent, the anhydrous organic solvents are used which are not in any chemical interaction with the reaction components, i.e. do not react with them. Suitable solvents are the homologues of aliphatic, cycloalkyl and aromatic hydrocarbons or halogenated hydrocarbons. As a medium, even the organic acid-binding bases (e.g. triethylamine, pyridine, etc.) are suitable, when they are used in a corresponding excess. For washing the filtered salt, the amount of anhydrous solvent is suitably taken which corresponds to the original amount of solvent used to avoid the formation of a solvent mixture. Such solvent mixtures make it difficult to work up the reaction mixture.
Som acyleringsmidler kommer syrehalogenider, syreanhydrider, blandede syreanhydrider eller ester, fortrinnsvis forbindelser med den generelle formel R-CO-X på tale, hvori R betyr en eventuelt substituert alkyl-, aryl-, aralkyl-, cykloalkyl-, alkyliden-cykloalkyl-, heterocyklisk eller alkyliden-heterocyklisk gruppe; X et halogenatbm eller en OR'-gruppe - hvori R' står for alkyl-, aryl-, acyl- eller aralkyl-gruppen. Acid halides, acid anhydrides, mixed acid anhydrides or esters, preferably compounds with the general formula R-CO-X, are mentioned as acylating agents, where R means an optionally substituted alkyl-, aryl-, aralkyl-, cycloalkyl-, alkylidene-cycloalkyl-, heterocyclic or alkylidene heterocyclic group; X a halogen atom or an OR' group - in which R' stands for the alkyl, aryl, acyl or aralkyl group.
Som syrebindende midler kan anvendes tertiære aminer, trialkyl-aminer, deres homologe, videre alkalikarbonater. Anvendelsen av trietylamin som loser 1,2-5,6-dianhydro-heksitider godt og hvorav de dannede salter lett kunne isoleres viste seg som fordelaktige. Tertiary amines, trialkyl amines, their homologues, further alkali carbonates can be used as acid binding agents. The use of triethylamine, which dissolves 1,2-5,6-dianhydrohexitides well and from which the formed salts could be easily isolated, proved advantageous.
Reaksjonsbetingelser: Acyleringen skjer i sin alminnelighet ved- en temperatur på 20-50°C. En unntagelse danner syrehalo-genidene som i oc-stilling er utstyrt med store romutfyllende grupper. Ved anvendelse av dem ved 50°C er en reaksjonstid på 1-3 timer nødvendig for å gjennomføre reaksjonen med godt utbytte. Den maksimale temperaturen kan nå kokepunktet for det anvendte losningsmidlet, henholdsvis reaksjonsblandingen. Temperaturen reguleres normalt ved tilsetningshastigheten Reaction conditions: The acylation generally takes place at a temperature of 20-50°C. An exception is the acid halides, which in the oc position are equipped with large space-filling groups. When using them at 50°C, a reaction time of 1-3 hours is necessary to carry out the reaction with good yield. The maximum temperature can reach the boiling point of the solvent used, or the reaction mixture. The temperature is normally regulated by the rate of addition
av acyleringsmidlet. En ytre kjøling er knapt nødvendig. of the acylating agent. An external cooling is hardly necessary.
Den benyttes bare når tilsetningen av acyleringsmidlet skjer It is only used when the addition of the acylating agent takes place
for raskt i begynnelsen. too fast in the beginning.
Det er særlig viktig at utgangsf.orbindelsene, løsningsmidler, syrebindende midler og reagensene (acyleringsmiddel) er full-stendig vannfrie. Denne tilstanden må ubetinget kontrolleres for anvendelsen og»om nodvendig, må forbindelsene underkastes videre vannfjerning og rensning. It is particularly important that the starting compounds, solvents, acid-binding agents and the reagents (acylating agent) are completely anhydrous. This condition must be checked before use and, if necessary, the compounds must be subjected to further water removal and cleaning.
Den farmakologiske anvendelsen av de anticarcinogene nye acy-lerte dianhydro-heks±ol-forbindelsene kan skje på forskjellige måter: Per os: den rene aktivsubstansen selv eller den rene aktivsubstansen med de for tablettering vanlige hjelpemidler (stivelse, laktose, talkum) blandet i form av tabletter. The pharmacological application of the anticarcinogenic new acylated dianhydro-hex±ol compounds can take place in different ways: Per os: the pure active substance itself or the pure active substance with the usual excipients for tableting (starch, lactose, talc) mixed in the form of tablets.
Intravenost: i vandig losning eller i losning i et fysiologisk inert organisk løsningsmiddel (forskjellige glykoler, o.s.v.) Intravenous: in aqueous solution or in solution in a physiologically inert organic solvent (various glycols, etc.)
Intramuskulært: i form av losning som ovenfor angitt eller Intramuscular: in the form of a solution as indicated above or
i form av suspensjon. in the form of suspension.
Intraperitonealt eller intracavitalis: også i form av losninger eller suspensjoner som ovenfor. Intraperitoneal or intracavitalis: also in the form of solutions or suspensions as above.
Lokalt: (in loco): i huden eller på operasjonsstedet anvendes aktivsubstansen selv eller blandet med vanlige antibakterielle-og sårmidler (su1fonamider, cortikoider, vitaminer, o.s.v.). Locally: (in loco): in the skin or at the site of the operation, the active substance is used by itself or mixed with common antibacterial and wound agents (sulphonamides, corticoids, vitamins, etc.).
Aktivsubstanskonsentrasjon i de forskjellige preparatene: Active substance concentration in the various preparations:
Fremstillingen av de anticarcinogene forbindelsene ifolge oppfinnelsen belyses gjennom de følgende eksempler. The production of the anticarcinogenic compounds according to the invention is illustrated through the following examples.
Eksempel 1 Example 1
Fremstilling av 1, 2- 5, 6- dianhydro- 3, 4- diacetyl- dulcitol Preparation of 1, 2- 5, 6- dianhydro- 3, 4- diacetyl- dulcitol
I en 100 ml trehalvskolbe med rorer, tilbakelopskjoler og dråpetrakt forelegges 1,46 g (10 minol) dianhydro-dulcitol og 60 ml abs. benzen og rores 10 min. ved romtemperatur. 1.46 g (10 minol) of dianhydrodulcitol and 60 ml of abs. benzene and stir for 10 min. at room temperature.
Til losningen settes 2,8 ml (20 mmol) abs. trietylamin (eller 2,45 gd.v.s. 20 m ol vannfritt kaliumkarbonat) og 2,45 g d.v.s. 1,4 7 ml (20 nmol) friskt destillert acetylbromid lost i 5 ml abs. benzen, rores 20 min. ved romtemperatur, så avsuges det utfelte trietylamin-hydrobromid på et glassfilter G3 og vaskes grundig med abs. benzen. De samlede filtratene inndampes i vakuum, den resterende sirup tilsettes 15 ml abs. eter og 5 ml abs. metylalkohol og avkjoles, hvorved straks en krystallinsk felling inntreffer. Blandingen blir latt stå natten over i kjoleskap, de utfelte krystallene avsuget og deretter omkrystallisert fra metylalkohol. Man får hvite nålaktige krystaller. Utbytte: 1,65 g ( 71 ,!/ <>) . Smeltepunkt: 91°C$Add 2.8 ml (20 mmol) of abs. triethylamine (or 2.45 gd.v.s. 20 m ol anhydrous potassium carbonate) and 2.45 g i.e. 1.4 7 ml (20 nmol) freshly distilled acetyl bromide dissolved in 5 ml abs. benzene, stir for 20 min. at room temperature, then the precipitated triethylamine hydrobromide is suctioned off on a glass filter G3 and washed thoroughly with abs. benzene. The combined filtrates are evaporated in vacuo, the remaining syrup is added to 15 ml abs. ether and 5 ml abs. methyl alcohol and cooled, whereby a crystalline precipitation immediately occurs. The mixture is left overnight in a refrigerator, the precipitated crystals are suctioned off and then recrystallized from methyl alcohol. White needle-like crystals are obtained. Yield: 1.65 g ( 71 ,!/ <>) . Melting point: 91°C$
Rf = 0,63 (benzen : metylalkohol = 90:15) - Rf = 0.63 (benzene : methyl alcohol = 90:15) -
Eksempel 2 Example 2
Fremstilling av 1, 2- 5, 6- dianhydro- 3, 4- diacetyl- dulcitol med eddiksvreanh<y>drid Preparation of 1,2-5,6-dianhydro-3,4-diacetyl-dulcitol with acetic acid
I en 100 ml trehalvskolbe med rorer, tilbakelopskjoler og dråpetrakt forelegges 1,46 g (10 mmol) dianhydro-dulcitol og 60 ml abs. benzen (eller vannfritt toluen) og rores 10 1.46 g (10 mmol) of dianhydrodulcitol and 60 ml of abs. benzene (or anhydrous toluene) and stirred 10
min. ved romtemperatur. Til losningen settes 2,8 ml (20 mmol) abs. trietylamin, 2,04 g d.v.s. 2,0 ml (20 mmol) friskt destillert eddiksyreanhydrid lost i 5 ml benzen over en time ved romtemperatur, så rores videre to timer ved 50°C. Losningen inndampes til torrhet, opptas så med 20 ml vann, rystes med 30 ml benzen, benzenet vaskes med en 10%'ig natriumhydrogen-karbonatolosning, torkes over magnesiumsulfat, filtreres og inndampes. Til den resterende sirup settes 15 ml abs. eter my. at room temperature. Add 2.8 ml (20 mmol) of abs. triethylamine, 2.04 g i.e. 2.0 ml (20 mmol) of freshly distilled acetic anhydride dissolved in 5 ml of benzene over one hour at room temperature, then stirred for a further two hours at 50°C. The solution is evaporated to dryness, then taken up with 20 ml of water, shaken with 30 ml of benzene, the benzene is washed with a 10% sodium hydrogen carbonate solution, dried over magnesium sulphate, filtered and evaporated. Add 15 ml abs to the remaining syrup. ether
og 5 ml abs. metanol, avkjoles, hvorved en momentan krystallinsk utfeining opptrer. Blandingen blir latt stå over natten i kjoleskap, så frafiltreres de utfelte krystallene og omkrystalliseres fra metylalkohol. Man erholder hvite nålaktige krystaller. Utbytte: 1,65 g (71,7%); Smeltepunkt: 91°C-, Rf = 0,63 (benzen : metylalkohol = 90:15). and 5 ml abs. methanol, is cooled, whereby a momentary crystalline phase occurs. The mixture is left overnight in a refrigerator, then the precipitated crystals are filtered off and recrystallized from methyl alcohol. White needle-like crystals are obtained. Yield: 1.65 g (71.7%); Melting point: 91°C-, Rf = 0.63 (benzene : methyl alcohol = 90:15).
Eksempel 3 Example 3
Fremstilling av 1. 2- 5, 6- dianhvdro- 3, 4- diacetyl- dulcitol med p- nitrofenylacetat Preparation of 1. 2- 5, 6- dianhydro- 3, 4- diacetyl- dulcitol with p- nitrophenyl acetate
I en 100 ml trehalvskolbe med rorer, tilbakelopskjoler og dråpetrakt forelegges 1,46 g (10 mmol) dianhydro-dulcitol og 60 ml abs. benzen (eller vannfritt dikloretan) og rores 10 min. ved romtemperatur. Losningen tilsettes 2,8 ml (20 mmol) abs. trietylamin og 3,62 g (20 mmol) p-nitro-fenylacetat, rores 6 timer ved 50°C og blir latt stå natten over ved romtemperatur. Losningen som inneholder det organiske losningsmidlet blir rystet med 20 ml vann og torket over magnesiumsulfat. 1.46 g (10 mmol) of dianhydrodulcitol and 60 ml of abs. benzene (or anhydrous dichloroethane) and stirred for 10 min. at room temperature. The solution is added to 2.8 ml (20 mmol) abs. triethylamine and 3.62 g (20 mmol) p-nitro-phenylacetate, is stirred for 6 hours at 50°C and is left to stand overnight at room temperature. The solution containing the organic solvent is shaken with 20 ml of water and dried over magnesium sulfate.
Den resterende sirup blir tilsatt 15 ml abs. eter og avkjolt. Blandingen får stå natten over i kjoleskap, så blir de utfelte krystaller suget av på et glassfilter G2. Utbytte: 2,5 g. Smeltepunkt: 72-78°c. Det således erholdte gule krystallinske produktet renses som folger: Krystallene loses i 20 ml benzen og behandles med dietylamino-propylamin. Etter en time tilsettes 10 ml vann og det hele fylles i en skylletrakt, den vandige fasen adskilles og opera-sjonen gjentas med 10 ml vann. Benzenlosningen torkes over magnesiumsulfat og inndampes. Den resterende sirup tilsettes 15 ml abs. eter og 5 ml abs. metanol og blir latt stå natten over i kjoleskap, så suges krystallene av. The remaining syrup is added to 15 ml abs. ether and cooled. The mixture is allowed to stand overnight in a refrigerator, then the precipitated crystals are sucked off on a glass filter G2. Yield: 2.5 g. Melting point: 72-78°c. The yellow crystalline product thus obtained is purified as follows: The crystals are dissolved in 20 ml of benzene and treated with diethylamino-propylamine. After one hour, 10 ml of water is added and the whole is filled into a rinsing funnel, the aqueous phase is separated and the operation is repeated with 10 ml of water. The benzene solution is dried over magnesium sulphate and evaporated. The remaining syrup is added to 15 ml abs. ether and 5 ml abs. methanol and is left overnight in a refrigerator, then the crystals are sucked off.
Utbytte: 1,58 g (69%); Smeltepunkt: 90°C. Yield: 1.58 g (69%); Melting point: 90°C.
Rf = 0,63 (benzen : metylalkohol = 90:18). Rf = 0.63 (benzene : methyl alcohol = 90:18).
Analyse Analysis
Når 1,2-5,6-dianhydro-D-mannitol tas som utgangsmaterial When 1,2-5,6-dianhydro-D-mannitol is taken as the starting material
oppnås etter ovenstående metode 1,65 g (70%) 1,2-5,6-dianhydro-3,4-diacetyl-D-mannitol. obtained by the above method 1.65 g (70%) 1,2-5,6-dianhydro-3,4-diacetyl-D-mannitol.
Eksempel 4 Example 4
Fremstilling av 1, 2- 5, 6- dianhvdro- 3. 4- di- kloracetyl- dulcitol Preparation of 1, 2- 5, 6- dianhdro- 3. 4- di- chloroacetyl- dulcitol
I en 200 ml trehalvskolbe med rorer, tilbakelopskjoler og dråpetrakt forelegges 5 g (34 mmol) dianhydro-dulcitol og 150 ml abs. benzen. Etter fire timers rbring tilsettes blandingen 10 ml (70 mmol) abs. trietylamin (eller 5,7 ml abs. pyridin) 5 g (34 mmol) of dianhydrodulcitol and 150 ml of abs. benzene. After stirring for four hours, 10 ml (70 mmol) of abs are added to the mixture. triethylamine (or 5.7 ml abs. pyridine)
og så innen ca. 5 min. ved romtemperatur tildryppes 8,94 g and then within approx. 5 min. at room temperature, 8.94 g are added dropwise
(6 ml; 68 mmol) friskt destillert kloracetyl-kloridlosning (6 mL; 68 mmol) freshly distilled chloroacetyl chloride solution
i 5 ml abs. benzen. Blandingen rores 30 min. ved romtemperatur, så avsuges trietylamin-hydrokloridet på et glassfilter G3 og filterkaken vaskes grundig med benzen. De samlede filtratene inndampes i vakuum. Den resterende sirupen tilsettes 15 ml abs. eter og 10 ml abs. metylalkohol, avkjoles, hvorved en momentant krystallutfelling inntreffer. Blandingen blir latt stå natten over i kjoleskap, så avsuges de utfelte krystallene og omkrystalliseres fra metylalkohol. Man erholder hvite nålaktige krystaller. in 5 ml abs. benzene. The mixture is stirred for 30 min. at room temperature, then the triethylamine hydrochloride is suctioned off on a glass filter G3 and the filter cake is thoroughly washed with benzene. The combined filtrates are evaporated in vacuo. The remaining syrup is added to 15 ml abs. ether and 10 ml abs. methyl alcohol, is cooled, whereby a momentary crystal precipitation occurs. The mixture is left overnight in a refrigerator, then the precipitated crystals are suctioned off and recrystallized from methyl alcohol. White needle-like crystals are obtained.
Utbytte: 4,4 g (43%); Smeltepunkt: 102°C. Yield: 4.4 g (43%); Melting point: 102°C.
Analyse: Analysis:
De videre eksemplene 5-8 er sammenfattet tabellarisk for å gi bedre oversikt. Sluttproduktene i de følgende eksemplene ble fremstilt som på den i de foregående eksemplene beskrevne måte. The further examples 5-8 are summarized in tabular form to provide a better overview. The end products in the following examples were prepared as in the manner described in the preceding examples.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU74MA00002630A HU172826B (en) | 1974-12-24 | 1974-12-24 | Process for preparing new acyl derivatives of 1,2-5,6-dianhydro-hexites with tumor inhibiting activity |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO754374L NO754374L (en) | 1976-06-25 |
| NO144632B true NO144632B (en) | 1981-06-29 |
| NO144632C NO144632C (en) | 1981-10-07 |
Family
ID=10998754
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO754374A NO144632C (en) | 1974-12-24 | 1975-12-23 | ANALOGUE PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTICALLY ACTIVE DIANHYDROHEXITID ACYL DERIVATIVES |
Country Status (17)
| Country | Link |
|---|---|
| JP (1) | JPS51125201A (en) |
| AT (1) | AT345303B (en) |
| BE (1) | BE837054A (en) |
| CH (1) | CH620208A5 (en) |
| CS (1) | CS220403B1 (en) |
| DD (1) | DD124803A1 (en) |
| DE (1) | DE2557033C2 (en) |
| DK (1) | DK156271C (en) |
| FI (1) | FI61187C (en) |
| FR (1) | FR2295743A1 (en) |
| GB (1) | GB1490649A (en) |
| HU (1) | HU172826B (en) |
| NL (1) | NL7514991A (en) |
| NO (1) | NO144632C (en) |
| PL (1) | PL101458B1 (en) |
| SU (1) | SU581860A3 (en) |
| YU (1) | YU40449B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU182227B (en) * | 1980-11-04 | 1983-12-28 | Chinoin Gyogyszer Es Vegyeszet | Process for preparing hexitols containing free carboxyl group |
| HU195754B (en) * | 1984-01-18 | 1988-07-28 | Chinoin Gyogyszer Es Vegyeszet | Process for producing 1,2-5,6-dianhydro-3,4-diacyl-dulcitol |
| JPH0228032A (en) * | 1988-07-14 | 1990-01-30 | Suzuki Motor Co Ltd | Automobile |
| JP2013537552A (en) * | 2010-08-18 | 2013-10-03 | デル マー ファーマスーティカルズ | Compositions and methods for improving the therapeutic efficacy of suboptimally administered compounds containing substituted hexitols such as dianhydrogalactitol and diacetyldianhydrogalactitol |
| US9901563B2 (en) | 2013-03-11 | 2018-02-27 | Delmar Pharmaceuticals, Inc. | Compositions to improve the therapeutic benefit of suboptimally administered chemical compounds including substituted hexitols such as dianhydrogalactitol and diacetyldianhydrogalactitol |
-
1974
- 1974-12-24 HU HU74MA00002630A patent/HU172826B/en not_active IP Right Cessation
-
1975
- 1975-12-18 DE DE2557033A patent/DE2557033C2/en not_active Expired
- 1975-12-19 AT AT966175A patent/AT345303B/en not_active IP Right Cessation
- 1975-12-22 FR FR7539338A patent/FR2295743A1/en active Granted
- 1975-12-23 CH CH1673675A patent/CH620208A5/en not_active IP Right Cessation
- 1975-12-23 DK DK589775A patent/DK156271C/en not_active IP Right Cessation
- 1975-12-23 NL NL7514991A patent/NL7514991A/en not_active Application Discontinuation
- 1975-12-23 GB GB52713/75A patent/GB1490649A/en not_active Expired
- 1975-12-23 YU YU3269/75A patent/YU40449B/en unknown
- 1975-12-23 PL PL1975185921A patent/PL101458B1/en unknown
- 1975-12-23 NO NO754374A patent/NO144632C/en unknown
- 1975-12-23 DD DD190504A patent/DD124803A1/xx not_active IP Right Cessation
- 1975-12-23 CS CS758837A patent/CS220403B1/en unknown
- 1975-12-23 FI FI753643A patent/FI61187C/en not_active IP Right Cessation
- 1975-12-24 JP JP50154665A patent/JPS51125201A/en active Granted
- 1975-12-24 BE BE163090A patent/BE837054A/en not_active IP Right Cessation
- 1975-12-24 SU SU7502302301A patent/SU581860A3/en active
Also Published As
| Publication number | Publication date |
|---|---|
| YU40449B (en) | 1986-02-28 |
| JPS51125201A (en) | 1976-11-01 |
| SU581860A3 (en) | 1977-11-25 |
| DK156271B (en) | 1989-07-24 |
| FI753643A (en) | 1976-06-25 |
| DE2557033A1 (en) | 1976-07-22 |
| NO754374L (en) | 1976-06-25 |
| BE837054A (en) | 1976-04-16 |
| FR2295743A1 (en) | 1976-07-23 |
| FI61187B (en) | 1982-02-26 |
| FR2295743B1 (en) | 1978-11-10 |
| YU326975A (en) | 1982-02-28 |
| PL101458B1 (en) | 1978-12-30 |
| DK589775A (en) | 1976-06-25 |
| JPS6129952B2 (en) | 1986-07-10 |
| DK156271C (en) | 1989-12-11 |
| DE2557033C2 (en) | 1983-12-22 |
| GB1490649A (en) | 1977-11-02 |
| NL7514991A (en) | 1976-06-28 |
| DD124803A1 (en) | 1977-03-16 |
| FI61187C (en) | 1982-06-10 |
| NO144632C (en) | 1981-10-07 |
| CS220403B1 (en) | 1983-04-29 |
| AT345303B (en) | 1978-09-11 |
| CH620208A5 (en) | 1980-11-14 |
| HU172826B (en) | 1978-12-28 |
| ATA966175A (en) | 1978-01-15 |
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