EP0000126B1 - Glucofuranosid-6-yl-Nitrosoharnstoffderivate, Verfahren zu ihrer Herstellung und sie enthaltende Arzneimittel - Google Patents
Glucofuranosid-6-yl-Nitrosoharnstoffderivate, Verfahren zu ihrer Herstellung und sie enthaltende Arzneimittel Download PDFInfo
- Publication number
- EP0000126B1 EP0000126B1 EP78100115A EP78100115A EP0000126B1 EP 0000126 B1 EP0000126 B1 EP 0000126B1 EP 78100115 A EP78100115 A EP 78100115A EP 78100115 A EP78100115 A EP 78100115A EP 0000126 B1 EP0000126 B1 EP 0000126B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- methyl
- substituted
- ethyl
- deoxy
- halogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 0 C*(*(C(C)(C(C*N)O*)OCO*)O*)O* Chemical compound C*(*(C(C)(C(C*N)O*)OCO*)O*)O* 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/12—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by acids having the group -X-C(=X)-X-, or halides thereof, in which each X means nitrogen, oxygen, sulfur, selenium or tellurium, e.g. carbonic acid, carbamic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the invention relates to new N 1 -glucofuranosid-6-yJ-N 2 nitrosoureas of the formula wherein R, and R 2 are hydrogen, optionally substituted alkyl by free or etherified hydroxy or halogen or optionally substituted by lower alkyl, free or etherified hydroxy, halogen or trifluoromethyl aralkyl or acyl, R, and R 2 together also represent alkylidene or cycloalkylidene, R 3 and R 5 optionally substituted by free or etherified hydroxy groups or halogen alkyl or optionally substituted by lower alkyl, free or etherified hydroxy, halogen or trifluoromethyl aralkyl or acyl, R 3 and R 5 together also mean alkylidene or cycloalkylidene, and R 6 optionally by free or etherified hydroxy groups or halogen-substituted alkyl means.
- radicals, radicals or compounds modified with the expression “lower” contain, unless stated otherwise, up to 7, primarily up to 4 carbon atoms.
- Alkyl is especially lower alkyl, e.g. B. isopropyl, straight-chain or branched, butyl, pentyl, hexyl or heptyl bound in any position and especially methyl, ethyl or n-propyl.
- Possible substituents of the optionally substituted alkyl group are primarily free or etherified hydroxy groups, e.g. B. lower alkoxy groups, or halogen atoms.
- the substituted alkyl radical such as lower alkyl radical, can carry one, two or more identical or different substituents, in particular free hydroxyl groups or halogen atoms.
- Aralkyl is, in particular, aryl-lower alkyl, the lower alkyl part above all corresponding to the above-mentioned lower alkyl, and being primarily methyl or ethyl.
- the aromatic part is in particular a monocyclic and bicyclic aryl radical, primarily phenyl, but also naphthyl. He can optionally, for. B. by lower alkyl groups, free or etherified hydroxy, for. B. lower alkoxy or lower alkylenedioxy, halogen atoms and / or trifluoromethyl be mono-, di- or poly-substituted. Particularly noteworthy are 2-phenylethyl, chlorobenzyl, methylbenzyl, hydroxybenzyl, methoxybenzyl or especially benzyl.
- the alkylidene radical is, in particular, a lower alkylidene radical, such as the 2-butylidene, 3-pentylidene and primarily isopropylidene radical.
- the cycloalkylidene radical preferably contains 5-7 ring carbon atoms and is primarily cyclopentylidene or cyclohexylidene.
- Acyl is in particular an acyl residue of an organic acid, in particular an organic carboxylic acid.
- Acyl is especially alkanoyl, especially with 2-18 carbon atoms, such as acetyl or propionyl, or also aroyl, such as naphthoyl-1, naphthoyl-2 and especially benzoyl or benzoyl substituted by halogen, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy or lower alkanoyloxy or naphthoyl.
- Acyl can also be an acyl residue of an organic sulfonic acid, e.g. B.
- an alkanesulfonic acid especially a lower alkanesulfonic acid, such as methanesulfonic acid or ethanesulfonic acid, or an arylsulfonic acid, especially an optionally lower alkyl-substituted phenylsulfonic acid, such as benzenesulfonic acid or p-toluenesulfonic acid, and the rest of a carbamic acid, such as unsubstituted carbamoyl, lower alkyl-carbamoyl or aryl- carbamoyl, such as methylcarbamoyl or phenylcarbamoyl.
- Lower alkyl as a substituent of the abovementioned radicals, is primarily methyl or ethyl, but also n-propyl, isopropyl or straight-chain or branched butyl.
- Lower alkoxy as a substituent of the abovementioned radicals, is in particular methoxy or ethoxy, furthermore n-propoxy, isopropoxy, n-butoxy or isobutoxy.
- Halogen is e.g. B. fluorine, chlorine or bromine.
- the new compounds can be in the form of mixtures of anomers or of pure a- or ⁇ -anomers.
- the new compounds have valuable pharmacological properties, in particular they have a very good effect in some different types of transplantable tumors and leukemias, as well as in part in virus-induced leukemia.
- doses of 25-500 mg / kg i.p. a strong inhibition of tumor growth in mice with z. B. Ehrlich ascites carcinoma or solid Harding-Passey melanoma, and in rats with z. B. Yoshida Ascites Sarcom.
- Analog doses prolong life compared to controls in mice with e.g. B. Leukemia L 1210 or Rauscher leukemia.
- the compounds according to the invention show a broad spectrum of activity not only against transplantable ascitic tumors (CrSa 180, Ehrlich carcinoma), but above all also against various solid, transplantable or chemically induced tumors.
- the invention relates in particular to compounds of the formula I in which R and R 2 are hydrogen, lower alkyl optionally substituted by hydroxyl, lower alkoxy or halogen, optionally substituted by hydroxy, lower alkoxy, halogen or trifluoromethyl, primarily in the para position, substituted benzyl, R, and R 2 also denotes lower alkylidene or cycloalkylidene with 5-6 carbon atoms, R 3 and R 5 optionally lower alkyl substituted by hydroxy, lower alkoxy or halogen, optionally substituted by hydroxy, lower alkoxy, halogen or trifluoromethyl, primarily in the p-position, substituted benzyl, or lower alkanoyl, e.g. B.
- acetyl or propionyl or optionally substituted by halogen, lower alkoxy, hydroxy or lower alkanoyloxy benzoyl, e.g. B. p-chlorobenzoyl, p-bromobenzoyl, p-methoxybenzoyl or o- or p-hydroxybenzoyl, but together also mean lower alkylidene or cycloalkylidene having 5-6 carbon atoms and R 6 is lower alkyl optionally substituted by halogen, hydroxy or lower alkoxy.
- R, lower alkyl and R 2 are hydrogen or R, and R 2 together are lower alkylidene
- R 3 and R 5 are lower alkyl or optionally substituted by halogen, hydroxy, lower alkoxy or alkyl, especially in the p-position
- Benzyl or R 6 optionally substituted with chlorine lower alkyl, e.g. B. represent methyl or chloroethyl.
- R 3 and R 5 are methyl
- R 6 is methyl or chloroethyl and R
- hydrogen, methyl, ethyl or propyl and R 2 is hydrogen or R
- R 2 together is the isopropylidene radical.
- the new compounds are obtained if a compound of the formula II nitrosated in a manner known per se.
- compound II is preferably reacted with nitrous acid, its salts or derivatives.
- a salt such as an alkali or alkaline earth metal, in particular the sodium salt of nitrous acid
- an acid such as a mineral acid, for.
- hydrochloric acid, sulfuric acid or nitric acid an organic acid such as carbonic acid, acetic acid or a sulfonic acid, e.g. B. a lower alkanesulfonic acid, such as methane or ethanesulfonic acid or a sulfonic acid group containing ion exchanger, for.
- B. Amberlite IR 120 the nitrous acid free. But you can also an anhydride of nitrous acid, especially a mixed anhydride with z.
- As the nitric acid or a hydrohalic acid use.
- reaction is preferably carried out at low temperature, e.g. B. -10 ° C to 30 ° C.
- the starting materials used in this process method are new. They can be obtained in a manner known per se from a corresponding glucofuranose which is unsubstituted in the 6-position, e.g. B. by converting to a reactive ester, e.g. B. with an alkanesulfonic acid, arylsulfonic acid or hydrohalic acid, then to an azide and reduction of the azide thus obtained to 6-deoxy-6-amino-glucofuranose, which then with a suitable NR 6 -carbamic acid derivative, such as a corresponding isocyanate for 6- Deoxy-6 - (- 3-R 6 -ureido) -glucofuranose is condensed. As mentioned above, these reactions are carried out in a manner known per se.
- Another method for the preparation of the new nitrosoureas consists in that a compound of formula III with a reactive derivative of an N-nitroso-NR s -carbamic acid (IV) implements.
- the reactive derivative can be, for example, an acid anhydride, preferably a mixed acid anhydride, such as an acid azide or an activated ester.
- Activated esters include, in particular, cyanomethyl esters, carboxymethyl esters, paranitrophenyl thioesters, paranitrophenyl esters, 2,4,5-trichlorophenyl esters, pentachlorophenyl esters, N-hydroxy-succinimide esters, N-hydroxy-phalimide esters, 8-hydroxyquinoline esters or N-hydroxypiperidine esters.
- This reaction is carried out in a manner known per se, preferably in a solvent such as water or a halogenated coal water serstoff, e.g. B. dichloro- or trichloroethane, an ether such as diethyl ether, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, or an optionally alkylated pyridine, such as pyridine, picoline, lutidine, or quinoline.
- a solvent such as water or a halogenated coal water serstoff, e.g. B. dichloro- or trichloroethane, an ether such as diethyl ether, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, or an optionally alkylated pyridine, such as pyridine, picoline, lutidine, or quinoline.
- the starting materials used are known or can be prepared in a manner known per se. So you can the amine of formula 111 from a corresponding, in the 6-position unsubstituted glucofuranose, for. B. by converting to a reactive ester, e.g. B. with an alkane or arylsulfonic acid or a hydrohalic acid, and then to an azide and reduction of the azide thus obtained to 6-deoxy-6-amino-glucofuranose.
- a reactive ester e.g. B. with an alkane or arylsulfonic acid or a hydrohalic acid
- the new compounds can be present as pure ⁇ or ⁇ anomers or as anomer mixtures.
- the latter can be separated into the two pure anomers in a known manner due to the physicochemical differences or constituents, e.g. By means of chromatographic separation, such as thin layer chromatography or any other suitable separation method.
- chromatographic separation such as thin layer chromatography or any other suitable separation method.
- the more effective of the two anomers is preferably isolated.
- the invention also relates to those embodiments of the process in which a starting material is formed under the reaction conditions or used in the form of a reactive derivative or salt.
- the starting materials used are preferably those which, according to the process, lead to the compounds described above as being particularly valuable.
- the present invention also relates to pharmaceutical preparations which contain compounds of the formula.
- the pharmaceutical preparations according to the invention are those for enteral, such as oral and rectal and parenteral administration to warm-blooded animals, which contain the pharmacological active ingredient alone or together with a pharmaceutically usable carrier material.
- the dosage of the active ingredient depends on the warm-blooded species, the age and the individual condition as well as on the mode of administration.
- the new pharmaceutical preparations contain from about 10% to about 95%, preferably from about 20% to about 90% of the active ingredient.
- Pharmaceutical preparations according to the invention can e.g. B. present in unit dosage forms such as coated tablets, tablets, capsules, suppositories or ampoules.
- the pharmaceutical preparations of the present invention are manufactured in a manner known per se, e.g. B. produced by means of conventional mixing, granulating, coating, solution or lyophilization processes.
- Suitable carriers are in particular fillers such as sugar, e.g. B. lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, e.g. As tricalcium phosphate or calcium hydrogen phosphate, further binders, such as starch paste using z. B.
- fillers such as sugar, e.g. B. lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, e.g. As tricalcium phosphate or calcium hydrogen phosphate, further binders, such as starch paste using z. B.
- ком ⁇ онентs such as the above-mentioned starches, furthermore carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar, Alginic acid or a salt thereof, such as sodium alginate, auxiliaries are primarily flow regulators and lubricants, e.g. B. silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol.
- flow regulators and lubricants e.g. B. silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol.
- Dragee kernels are provided with suitable, optionally gastric juice-resistant coatings, u. a. Concentrated sugar solutions, which optionally contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the production of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropylmethyl cellulose phthalate.
- the tablets or dragee coatings can contain dyes or pigments, e.g. B. for identification or labeling of different doses of active ingredient.
- the daily dose for a warm-blooded animal weighing approximately 70 kg is approximately 10-500 mg per day, preferably 50-300 mg per day .
- the residue is purified by column chromatography on silica gel with methylene chloride / ethyl acetate (85:15), the crystalline product is combined with the first crystals and recrystallized from ether / petroleum ether.
- the corresponding ⁇ -glucofuranoside shows the Rf value 0.11 in the same system.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biotechnology (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KE356085A KE3560A (en) | 1977-06-15 | 1985-09-12 | Glucofuranos-6-yl-nitroso prea derivatives,process for their preparation and pharmaceuticals containing them |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH735977 | 1977-06-15 | ||
CH7359/77 | 1977-06-15 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0000126A1 EP0000126A1 (de) | 1979-01-10 |
EP0000126B1 true EP0000126B1 (de) | 1982-12-01 |
Family
ID=4323894
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP78100115A Expired EP0000126B1 (de) | 1977-06-15 | 1978-06-07 | Glucofuranosid-6-yl-Nitrosoharnstoffderivate, Verfahren zu ihrer Herstellung und sie enthaltende Arzneimittel |
Country Status (27)
Country | Link |
---|---|
US (1) | US4273766A (no) |
EP (1) | EP0000126B1 (no) |
JP (1) | JPS545909A (no) |
AR (2) | AR221845A1 (no) |
AT (1) | AT358601B (no) |
AU (1) | AU517665B2 (no) |
CA (1) | CA1096859A (no) |
CS (1) | CS203193B2 (no) |
CY (1) | CY1263A (no) |
DD (1) | DD137360A5 (no) |
DE (1) | DE2862098D1 (no) |
DK (1) | DK267078A (no) |
ES (1) | ES470738A1 (no) |
FI (1) | FI65781C (no) |
GR (1) | GR73054B (no) |
HK (1) | HK2285A (no) |
HU (1) | HU179686B (no) |
IE (1) | IE47090B1 (no) |
IL (1) | IL54909A (no) |
MY (1) | MY8700029A (no) |
NO (1) | NO145843C (no) |
NZ (1) | NZ187571A (no) |
PL (2) | PL112747B1 (no) |
PT (1) | PT68164A (no) |
SG (1) | SG44284G (no) |
SU (2) | SU910118A3 (no) |
ZA (1) | ZA783430B (no) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2961524D1 (en) * | 1978-02-21 | 1982-02-04 | Ciba Geigy Ag | Glycofuranosyl-nitrosourea derivatives, process for their manufacture and their pharmaceutical preparations |
FR2487343A1 (fr) * | 1980-07-25 | 1982-01-29 | Anvar | Nouveaux nitroso-carbamates, procede pour leur preparation et application a la synthese selective de n-nitrosourees |
JPS57165398A (en) * | 1981-04-02 | 1982-10-12 | Tanabe Seiyaku Co Ltd | Nitrosourea derivative and its preparation |
JPS57200397A (en) * | 1981-06-03 | 1982-12-08 | Akira Kimura | Novel aldohexopyranose-, aldopentopyranose-, or and medicament composition comprising it aldopentofuranose- nitrosourea compound, its preparation |
US4902791A (en) * | 1983-08-30 | 1990-02-20 | Sanofi S.A. | Nitrosourea derivatives, process for their preparation and medicaments containing them |
US4613590A (en) * | 1985-08-19 | 1986-09-23 | Abbott Laboratories | Amino D-manno-2-octulopyranosidonate containing compounds, pharmaceutical compositions and method of use |
FR2614304A1 (fr) * | 1987-04-22 | 1988-10-28 | Sanofi Sa | Derives de nitrosourees, leur nouveau procede de preparation et leurs applications therapeutiques. |
CA2164827A1 (en) * | 1993-06-11 | 1994-12-22 | David S. Thomson | Immunomodulatory, anti-inflammatory, and anti-proliferative compounds: 5,6-dideoxy, 5-amino derivatives of idose and 6-deoxy, 6-amino derivatives of glucose |
DE602005026361D1 (de) * | 2004-12-17 | 2011-03-31 | Kao Corp | Make-up Zubereitung |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5230491B2 (no) * | 1974-07-05 | 1977-08-09 | ||
JPS5126819A (en) * | 1974-08-08 | 1976-03-05 | Tokyo Tanabe Co | Arukiru nn karubamiru n**22 kuroruechiru n** nitoroso dd gurukopiranoshidojudotaino seizoho |
JPS5126876A (en) * | 1974-08-08 | 1976-03-05 | Suami T | Shinkina nitorosonyosojudotaino seizohoho |
US3940383A (en) * | 1974-12-12 | 1976-02-24 | Stanford Research Institute | Streptozotocin analogs |
JPS5175072A (ja) * | 1974-12-18 | 1976-06-29 | Tokyo Tanabe Co | Ribofuranoozunonitorosokarubamirujudotaino seizoho |
-
1978
- 1978-06-05 FI FI781779A patent/FI65781C/fi not_active IP Right Cessation
- 1978-06-07 CY CY1263A patent/CY1263A/xx unknown
- 1978-06-07 DE DE7878100115T patent/DE2862098D1/de not_active Expired
- 1978-06-07 EP EP78100115A patent/EP0000126B1/de not_active Expired
- 1978-06-12 PT PT68164A patent/PT68164A/pt unknown
- 1978-06-13 CA CA305,315A patent/CA1096859A/en not_active Expired
- 1978-06-13 ES ES470738A patent/ES470738A1/es not_active Expired
- 1978-06-14 SU SU782626797A patent/SU910118A3/ru active
- 1978-06-14 AT AT433378A patent/AT358601B/de not_active IP Right Cessation
- 1978-06-14 IL IL54909A patent/IL54909A/xx unknown
- 1978-06-14 ZA ZA00783430A patent/ZA783430B/xx unknown
- 1978-06-14 GR GR56521A patent/GR73054B/el unknown
- 1978-06-14 NZ NZ187571A patent/NZ187571A/xx unknown
- 1978-06-14 AU AU37089/78A patent/AU517665B2/en not_active Expired
- 1978-06-14 CS CS783897A patent/CS203193B2/cs unknown
- 1978-06-14 DK DK267078A patent/DK267078A/da not_active Application Discontinuation
- 1978-06-14 IE IE1193/78A patent/IE47090B1/en unknown
- 1978-06-14 DD DD78206000A patent/DD137360A5/xx unknown
- 1978-06-14 PL PL1978207625A patent/PL112747B1/pl not_active IP Right Cessation
- 1978-06-14 PL PL1978217114A patent/PL113378B1/pl unknown
- 1978-06-14 NO NO782069A patent/NO145843C/no unknown
- 1978-06-14 HU HU78CI1835A patent/HU179686B/hu unknown
- 1978-06-15 JP JP7158978A patent/JPS545909A/ja active Pending
- 1978-06-18 AR AR272607A patent/AR221845A1/es active
-
1979
- 1979-03-12 SU SU792737152A patent/SU917699A3/ru active
- 1979-04-12 US US06/029,495 patent/US4273766A/en not_active Expired - Lifetime
- 1979-11-02 AR AR278757A patent/AR222844A1/es active
-
1984
- 1984-06-18 SG SG442/84A patent/SG44284G/en unknown
-
1985
- 1985-01-10 HK HK22/85A patent/HK2285A/xx unknown
-
1987
- 1987-12-30 MY MY29/87A patent/MY8700029A/xx unknown
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