WO1990009392A1 - New 4'-epi-4'-amino anthracyclines - Google Patents
New 4'-epi-4'-amino anthracyclines Download PDFInfo
- Publication number
- WO1990009392A1 WO1990009392A1 PCT/EP1990/000183 EP9000183W WO9009392A1 WO 1990009392 A1 WO1990009392 A1 WO 1990009392A1 EP 9000183 W EP9000183 W EP 9000183W WO 9009392 A1 WO9009392 A1 WO 9009392A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- amino
- deoxy
- glycoside
- group
- Prior art date
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- 229940045799 anthracyclines and related substance Drugs 0.000 title claims abstract description 25
- 229930182470 glycoside Natural products 0.000 claims abstract description 58
- 150000002338 glycosides Chemical class 0.000 claims abstract description 54
- 125000003277 amino group Chemical group 0.000 claims abstract description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 3
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 3
- 239000011737 fluorine Chemical group 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 39
- 150000001875 compounds Chemical class 0.000 claims description 37
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 35
- 238000002360 preparation method Methods 0.000 claims description 32
- 150000003839 salts Chemical class 0.000 claims description 27
- 239000002253 acid Substances 0.000 claims description 22
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- 125000006239 protecting group Chemical group 0.000 claims description 10
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- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- RBWSWDPRDBEWCR-RKJRWTFHSA-N sodium;(2r)-2-[(2r)-3,4-dihydroxy-5-oxo-2h-furan-2-yl]-2-hydroxyethanolate Chemical compound [Na+].[O-]C[C@@H](O)[C@H]1OC(=O)C(O)=C1O RBWSWDPRDBEWCR-RKJRWTFHSA-N 0.000 description 1
- CMXPERZAMAQXSF-UHFFFAOYSA-M sodium;1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate;1,8-dihydroxyanthracene-9,10-dione Chemical compound [Na+].O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=CC=C2O.CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC CMXPERZAMAQXSF-UHFFFAOYSA-M 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
-
- 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 present invention relates to a new class of anthracycline glycosides having antitumour activity, methods for their preparation, pharmaceutical compositions
- the invention also relates to the preparation of certain novel intermediates.
- the invention provides anthracycline glycosides having the general formulae 1 and 2 :
- R 1 is selected from the group consisting of
- R 2 and R 3 both represent hydroxy or one of R 2 and R 3 is hydrogen, nitro or amino and the other of R 2 and R 3 is hydroxy; and pharmaceutically acceptable salts thereof.
- Preferred salts are the hydrochloride salts.
- the anthracycline glycosides of the general formulae 1 and 2 include:
- the new anthracycline glycoside antibiotics of the invention i.e. those of formula 1 and 2, are condensation products of (a) aglycones of general formula 3 or 6:
- R 1 , R 2 and R 3 are as defined above with proviso that neither R 2 nor R 3 is an amino group and (b) a protected halosugar of the formula 4:
- X is a halogen, preferably chlorine.
- Method A is depicted in Scheme I and involves the use of the aglycone of formula 3
- Method B which is shown in Scheme II and involves the use of the aglycone of formula 16.
- the present invention provides a process for the preparation of an anthracycline glycoside of formula 1 or 2 as defined above with proviso that for a glycoside of formula 2 neither R 2 nor R 3 is an amino group, or a
- R 1 , R 2 and R 3 are as defined above except that neither R 2 nor R 3 is an amino group, with a 1-halo-2,3,4,6-tetradeoxy-4-(N-trifluoroacetamido)-L-erythro-hexopyranoside of formula 4:
- R 1 , R 2 and R 3 are as defined in step (i), so as to obtain a said anthracycline glycoside of formula 1 except that neither R 2 nor R 3 is an amino group;
- step (iii) if desired, converting the said glycoside of formula 1 obtained in step (ii) into a pharmaceutically acceptable acid addition salt thereof;
- step (iv) if desired, reducing a said glycoside of formula 1 wherein one of R 2 and R 3 is a nitro group obtained in step (ii) or a said salt thereof obtained in step (iii) so as to obtain a said glycoside of formula 1 wherein one of R 2 and R 3 is an amino group and, if desired, converting the said glycoside of formula 1 wherein one of R 2 and R 3 is an amino group into a pharmaceutically acceptable acid addition salt thereof;
- step (v) if desired, brominating the said glycoside of formula 1 obtained in step (ii) or pharmaceutically
- step (iii) and hydrolysing the 14-bromo derivative thus obtained to form a corresponding anthracycline glycoside of formula 2 as defined above;
- An aglycone of formula 3 is generally reacted at room temperature in step (i) with a compound of formula 4 in the presence of a molecular sieve and silver trifluoromethane-sulphonate to form one of the N-trifluoroacetyl glycosides 5a-f .
- Compounds of formula 1a-f are obtained by removing the amino protecting group by mild alkaline hydrolysis.
- step (ii) the compound of formula 5, dissolved in acetone, is submitted, at a temperature of 0°C and for one hour, to mild alkaline hydrolysis with 0.2 N aqueous sodium hydroxide to give a said glycoside of formula 1.
- step (iv) typically reduction is effected by treatment with Pd/C, for example 10% Pd/C.
- Pd/C for example 10% Pd/C.
- the nitro glycoside of formula 1 or salt thereof may therefore be refluxed in a mixture of methanol and cyclohexene in the presence of 10% Pd/C for ten minutes.
- the resulting amino glycoside of formula 1 can be isolated as its hydrochloride as above.
- glycoside of formula 2 as the hydrochloride is typically achieved by treating the glycoside with methanolic hydrogen chloride.
- N-protected glycoside 5a which, dissolved in acetone, is submitted at a temperature of 0oC and for one hour, to a mild alkaline hydrolysis with 0.2N aqueous sodium hydroxide to give the compound of formula 1a as a free base which, by treatment with anhydrous methanolic hydrogen chloride is isolated as its hydrochloride.
- the invention provides a process for the preparation of an anthracycline glycoside of formula 2 as defined above, with the proviso that neither R 2 nor R 3 is an amino group, or a pharmaceutically acceptable acid addition salt thereof, which process comprises:
- R 1 , R 2 and R 3 are as defined above except that neither R 2 nor R 3 is an amino group, with a 1-halo-2,3,4,6-tetradeoxy-4-(N-trifluoroacetamido)-L-erythro-hexopyranoside of formula 4 as defined above;
- R 1 , R 2 and R 3 are as defined above;
- R 1 , R 2 and R 3 are as defined above;
- step (i') the aglycone of formula 6 is reacted at room temperature with a 1-chloro-hexapyranoside of formula 4 in the presence of a molecular sieve and silver trifluoromethansulfonate.
- step (ii') the compound of formula 7 is treated at 0oC, for four hours and under a nitrogen atmosphere with potassium carbonate.
- step (iii') the compound of formula 8 is treated with triethyl orthoformate, for example in methylene chloride and in the presence of pyridinium p-toluensulfonate for one hour at room temperature.
- step (iv') the compound of formula 9 is subjected to mild alkaline aqueous hydrolysis to remove the N-trifluoroacetyl group and is treated with acetic acid to remove the orthoformate protecting group to obtain the said glycoside of formula 2 as a free base which, in step (v'), is treated with anhydrous methanolic hydrogen chloride to isolate the glycoside as its hydrochloride salt.
- This compound is dissolved in dry methylene chloride and reacted with 1-chloro-2,3,4,6-tetradeoxy-4-(N-trifluoro-acetamido)-L-erythro-hexopyranoside (4) as described above to give the protected 14-acetoxy-N-trifluoroacetyl glycoside 7d.
- compound 7d is first dissolved in methanol and treated with potassium carbonate for four hours at 0oC under nitrogen to give 8d, then is treated with triethyl orthoformate in methylene chloride and in the presence of pyridinium p-toluensulfonate for one hour at room temperature to give the 9,14-orthoformate derivative 9e.
- This is subjected to mild alkaline aqueous hydrolysis to remove the N-protecting group and finally treated with acetic acid to remove the orthoformate
- the present invention also provides a process for the preparation of an anthracycline glycoside of formula 2 above wherein R 1 is as defined above and one of R 2 and R 3 is hydroxy and the other of R 2 and R 3 is an amino group, or a pharmaceutically acceptable acid addition salt thereof, which process comprises:
- Scheme III shows the route to C-6 and C-11 amino anthracyclines of formula 2 starting from the corresponding C-6 and C-11 protected nitro glycosides.
- the 9,14-ortho-formate nitro derivatives 9e or 9f may be converted
- compounds 2g and 2h may be converted into their respective hydrochloride salts by treatment with anhydrous methanolic hydrogen chloride.
- the invention also provides pharmaceutical
- compositions comprising an anthracycline glycoside of formula 1 or 2 or a pharmaceutically acceptable acid
- composition may be formulated and administered in conventional manner.
- the compounds of the invention are useful in methods of treatment of the human or animal body by therapy. They are useful as antitumor agents.
- a therapeutically effective amount is administered to a patient.
- An amount sufficient to inhibit the growth of the tumour may be administered.
- the tumour may be a Colon adenocarcinoma or Gross leukemia tumour .
- IC50 concentration inhibiting by 50% colony growth
- the trifluoroacetyl protecting group was removed by dissolving compound 5a in acetone and treating with aqueous 0.2N sodium hydroxide at 0oC. After one hour the solution was adjusted to pH 8.1 and extracted repeatedly with methylene chloride. The combined organic extracts, after being dried and concentrated to a small volume were acidified to pH 3.5 with anhydrous methanolic hydrogen chloride. Upon addition of diethyl ether there was obtained 0.64 g (yield 54%) of the title compoun la as hydrochloride salt. m.p. 168-169oC (with dec).
- Compound 7d was dissolved with 200 ml of methanol, treated at 0°C with 2 ml of a 10% aqueous solution of potassium carbonate and left to stand for four hours at 0oC under nitrogen.
- the solution was neutralized with acetic acid, diluted with water and the product extracted with methylene chloride.
- Product 7e was dissolved with 1000 ml of methanol and, after cooling at 0oC, a 10% aqueous solution of sodium carbonate was added under stirring and nitrogen atmosphere. After three hours, the mixture was brought to pH 7 with acetic acid, diluted with water and the product was extracted with methylene chloride following standard procedure.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Pyridine Compounds (AREA)
- Indicating Measured Values (AREA)
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019910700835A KR920701227A (ko) | 1989-02-07 | 1990-02-02 | 4'-에피-4'-아미노 안트라사이클린 |
| SU905001277A RU2073681C1 (ru) | 1989-02-07 | 1990-02-02 | Антрациклиновый гликозид и способы его получения |
| FI913699A FI96605C (fi) | 1989-02-07 | 1991-08-02 | Menetelmä farmaseuttisesti käyttökelpoisten 4'-epi-4'-aminoantrasykliinien valmistamiseksi sekä menetelmässä käytettävät välituotteet |
| US08/001,229 US5412081A (en) | 1989-02-07 | 1993-01-06 | New 4'-epi-4'-amino anthracyclines |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8902709.8 | 1989-02-07 | ||
| GB898902709A GB8902709D0 (en) | 1989-02-07 | 1989-02-07 | New 4'-epi-4'-amino anthracyclines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1990009392A1 true WO1990009392A1 (en) | 1990-08-23 |
Family
ID=10651266
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1990/000183 WO1990009392A1 (en) | 1989-02-07 | 1990-02-02 | New 4'-epi-4'-amino anthracyclines |
Country Status (21)
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016071418A1 (en) | 2014-11-05 | 2016-05-12 | Nerviano Medical Sciences S.R.L. | Functionalized morpholinyl anthracycline derivatives |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1241927B (it) * | 1990-05-14 | 1994-02-01 | Menarini Farma Ind | 3'-deamino-4'-deossi-4'-amino-8-fluoroantra- cicline processi per la loro preparazione e composizioni farmaceutiche che le contengono |
| CN1089071C (zh) * | 1999-10-11 | 2002-08-14 | 葛水生 | 铁路列车卫星电视系统 |
| IT1317106B1 (it) * | 2000-11-16 | 2003-05-26 | Menarini Ricerche Spa | Processo per la sintesi di antracicline otticamente attive. |
| JP5105403B2 (ja) | 2006-12-06 | 2012-12-26 | 日本サーモスタット株式会社 | 感温インジケータ |
| RU2618523C2 (ru) * | 2012-11-05 | 2017-05-04 | Пфайзер Инк. | Аналоги сплицеостатина |
| DK2991993T3 (en) * | 2013-04-29 | 2018-07-30 | Nerviano Medical Sciences Srl | NEW MORPHOLINYLANTHRACYCLINE DERIVATIVES |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0051280A1 (en) * | 1980-11-01 | 1982-05-12 | FARMITALIA CARLO ERBA S.p.A. | Anthracycline glycosides, process for the preparation thereof, intermediate compounds and their preparation and pharmaceutical compositions |
| GB2091243A (en) * | 1981-01-21 | 1982-07-28 | Erba Farmitalia | Anthracycline glycosides |
| EP0328400A2 (en) * | 1988-02-10 | 1989-08-16 | FARMITALIA CARLO ERBA S.r.l. | 3'-Deamino-4'-deoxy-4'-amino anthracyclines |
-
1989
- 1989-02-07 GB GB898902709A patent/GB8902709D0/en active Pending
-
1990
- 1990-01-23 DE DE9090101309T patent/DE69000019D1/de not_active Expired - Lifetime
- 1990-01-23 DK DK90101309.4T patent/DK0381989T3/da active
- 1990-01-23 AT AT90101309T patent/ATE72445T1/de not_active IP Right Cessation
- 1990-01-23 ES ES199090101309T patent/ES2041050T3/es not_active Expired - Lifetime
- 1990-01-23 EP EP90101309A patent/EP0381989B1/en not_active Expired - Lifetime
- 1990-01-31 NZ NZ232305A patent/NZ232305A/xx unknown
- 1990-02-02 RU SU905001277A patent/RU2073681C1/ru active
- 1990-02-02 WO PCT/EP1990/000183 patent/WO1990009392A1/en active IP Right Grant
- 1990-02-02 AU AU49510/90A patent/AU628478B2/en not_active Ceased
- 1990-02-02 KR KR1019910700835A patent/KR920701227A/ko not_active Ceased
- 1990-02-02 IL IL9325890A patent/IL93258A/en not_active IP Right Cessation
- 1990-02-02 MY MYPI90000164A patent/MY105541A/en unknown
- 1990-02-02 HU HU901678A patent/HU206700B/hu not_active IP Right Cessation
- 1990-02-02 CA CA002046645A patent/CA2046645A1/en not_active Abandoned
- 1990-02-02 JP JP2502349A patent/JP3000562B2/ja not_active Expired - Fee Related
- 1990-02-05 ZA ZA90835A patent/ZA90835B/xx unknown
- 1990-02-05 IE IE40390A patent/IE62307B1/en not_active IP Right Cessation
- 1990-02-06 PT PT93071A patent/PT93071B/pt active IP Right Grant
-
1991
- 1991-08-02 FI FI913699A patent/FI96605C/fi active
-
1992
- 1992-02-21 GR GR920400293T patent/GR3003873T3/el unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0051280A1 (en) * | 1980-11-01 | 1982-05-12 | FARMITALIA CARLO ERBA S.p.A. | Anthracycline glycosides, process for the preparation thereof, intermediate compounds and their preparation and pharmaceutical compositions |
| GB2091243A (en) * | 1981-01-21 | 1982-07-28 | Erba Farmitalia | Anthracycline glycosides |
| EP0328400A2 (en) * | 1988-02-10 | 1989-08-16 | FARMITALIA CARLO ERBA S.r.l. | 3'-Deamino-4'-deoxy-4'-amino anthracyclines |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016071418A1 (en) | 2014-11-05 | 2016-05-12 | Nerviano Medical Sciences S.R.L. | Functionalized morpholinyl anthracycline derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| FI96605C (fi) | 1996-07-25 |
| ES2041050T3 (es) | 1993-11-01 |
| GR3003873T3 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) | 1993-03-16 |
| PT93071A (pt) | 1990-08-31 |
| FI96605B (fi) | 1996-04-15 |
| PT93071B (pt) | 1996-01-31 |
| JP3000562B2 (ja) | 2000-01-17 |
| IE62307B1 (en) | 1995-01-25 |
| FI913699A0 (fi) | 1991-08-02 |
| IE900403L (en) | 1990-08-07 |
| GB8902709D0 (en) | 1989-03-30 |
| JPH04503210A (ja) | 1992-06-11 |
| HUT58065A (en) | 1992-01-28 |
| EP0381989A1 (en) | 1990-08-16 |
| EP0381989B1 (en) | 1992-02-05 |
| DE69000019D1 (en) | 1992-03-19 |
| DK0381989T3 (da) | 1992-03-23 |
| NZ232305A (en) | 1991-11-26 |
| HU206700B (en) | 1992-12-28 |
| KR920701227A (ko) | 1992-08-11 |
| IL93258A0 (en) | 1990-11-29 |
| AU4951090A (en) | 1990-09-05 |
| HU901678D0 (en) | 1991-11-28 |
| IL93258A (en) | 1994-05-30 |
| ZA90835B (en) | 1990-11-28 |
| RU2073681C1 (ru) | 1997-02-20 |
| CA2046645A1 (en) | 1990-08-08 |
| ATE72445T1 (de) | 1992-02-15 |
| MY105541A (en) | 1994-10-31 |
| AU628478B2 (en) | 1992-09-17 |
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