GB2296495A - Morpholine and piperidine N-oxide based anthracycline derivatives as antitumour agents - Google Patents
Morpholine and piperidine N-oxide based anthracycline derivatives as antitumour agents Download PDFInfo
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- GB2296495A GB2296495A GB9426075A GB9426075A GB2296495A GB 2296495 A GB2296495 A GB 2296495A GB 9426075 A GB9426075 A GB 9426075A GB 9426075 A GB9426075 A GB 9426075A GB 2296495 A GB2296495 A GB 2296495A
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/048—Pyridine radicals
Description
1 ANTHRACYCLINE DERIVATIVES 2296495 The present invention relates to new
anthracycline analogues possessing antitumor activity, to a process for their preparation, and to pharmaceutical compositions containing them.
The present invention provides a compound which is an anthracycline analogue of formula A 52 4 R5 OH R3 nj0 R 7 '_,R6 N rl+l R X R 9 10 A wherein R, is a hydrogen atom or a hydroxy or methoxy group; R2 and R3 are both hydroxy groups or one of R2 and R3 is a hydroxy group and the other of R2 and R. is a hydrogen atom; R4 is a hydrogen atom or a hydroxy, methoxy, carboxy or carbomethoxy group; R.sis a group of formula COCH3, COCHOH, CH2CH3. CH(OH)CH3 or CH(OH)CH2OH; R, is an oxygen atom or a hydroxy group; R7 and R, are both hydrogen atoms or one of R7 and R, is a hydroxy group, a halogen atom or the group OSO,CH3 and the 2 other of R7 and R, is a hydrogen atom; X is an oxygen atom or -CH2_; R9 and RIO are both hydrogen atoms or one of R9 and Rio is a hydrogen atom and the other of R,, and RIO is a hydroxy group or the group O(C0),R,, in which R,, is a Cl-Cg alkyl, C3-C, cycloalkyl or phenyl C,_C6 alkyl group and n is 0 or 1, or one of R9 and R,,, is the group O(C0),Rll as defined above and the other of R9 and RIO is a methyl or hydroxymethyl group; or a pharmaceutically acceptable salt thereof.
In this specification, the hydrocarbon chain of the alkyl, alkoxy and acyloxy groups may be a straight or a branched chain.
Preferably, C,-C, alkyl is methyl, ethyl, n-propyl, iso-proyl, n-butyl, tbutyl, sec-butyl or n-pentyl.
Preferably, C3-C, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Preferably, phenyl C,-C,, alkyl is benzyl, phenylpropyl or phenylbutyl.
Preferably ions of pharmaceutically acceptable salt derivatives according to the invention are those derived from pharmaceutically acceptable acids, both inorganic acids such as hydrochloric acid and organic acids such as acetic, methanesulfonic or ethanesulfonic acid.
The present invention encompasses all the possible stereoisomers as well as their racemic or optically active mixtures. In such case (S) and (R) mean the configuration of a substituted carbon atom.
A preferred class of compounds according to the invention are the compounds of formula A, wherein R, is oxygen or hydroxy, more preferably hydroxy, X is oxygen or CH,, more preferably oxygen, and R, is hydrogen or nethoxy, R, and R3 are both hydroxy, R, is hydrogen, R, is a group of formula COCH3. COCH20H or COCH(OH)CH,0H, R, and R,,, are both hydrogen atoms or one of R, and R,,, is hydrogen and the other of R, and R,,, is. methoxy, preferably in the optically active configuration (S) or (R), R, is hydroxy and R, is hydrogen.
Example of specific preferred compounds of the invention are:
3 (Al):3'-deamino-3'[2(S)-methoxy-4-morpholinyll-doxorubicin N-oxide [Rj=0CH.1, R2=R3=0H, R4=H, RS=COCH20H, R6=0, Rg=H, R10=(S)OCH3. X=O, R7=0H, Rs=H] (A2):3'-deamino-3'[2(S)-methoxy-4-morpholinyl]-doxorubicin N-hydroxide chloride [Rj=0CH3, R2=R3=0H, R4=H, RS=COCH20H, R(,=OH, Rg=H, RI(=(S)OCH3. X=O, R7=0H, Rg=H] :3'-deamino-3'[2(R)-methoxy-4-morpholinyl]-doxorubicin N-oxide [R,=OCH3, R,=R3=0H, R.1=H, R.s=COCH,0H, R6=0, R,=H, RI,=(R)OCH3, X=O, R7=0H, R,=H] (A4): 3'-deamino-3'[2(R)-methoxy-4-morpholinyl]-doxorubicin N-hydroxide chloride [Rj=0CH3, R,=R3=0H, R4=H, R.i=COCHOH, R(,=OH, Rg=H, RI,=(R)OCH3. X=O, R7=0H, R,=H] (A5):4-demethoxy-3'-deamino-3'[2(S)-methoxy-4-morpholinyl] daunorubicin Noxide [RI=H, R2=R3=0H, R4=H, R.i=COCH3, R6=0, R,=H, R10=(S)OCH3f X=O, R7=0H, Rg=H] (A6):4-demethoxy-3'-deamino-3'[2(S)-methoxy-4-morpholinyl] daunorubicin N- hydroxide chloride [RI=H, R,=R3=0H, R.4=H, R.i=COCH.1, R6=0H, RI,=H, R1c, =(S)OCH3. X=O, R7=0H, R,=H] (A7):4-demethoxy-3'-deamino-3'[2(R)-methoxy-4-morpholinyl]daunorubicin Noxide [RI=H, R2=R3=0H, R4=H, R.5=COCHI, R6=0. R,=H, R,(,=(R)OCH3. X=O, R7=0H, R8=H] (A8):4-demethoxy-3'-deamino-3'[2(R)-methoxy-4-morpholinyl] daunorubicin N- hydroxide chloride [Rj=H, R,=R3=0H, R4=H, R.s=COCH3, R6=0H, R,=H, RI, =(R)OCH3. X=O, R7=0H, R,=H] (A9):3'-deamino-3'[4-morpholinyl]-doxorubicin N-oxide [R,=OCH3, R,=Rj=0H, R,=H, R5=COCH,0H, R,=O, R,=R,,=H, X=O, R7=0H, R,=H] (A10):3'-deamino-3'[4-morpholinyl]-doxorubicin N-hydroxide [R,=OCH, R, =R=OH, R4=H, Rs=COCHOH, R,=OH, R,=R,,=H, 4 X=O, R7=0H, R8=H] (All):13-dihydro-3'-deamino-3'[2-methoxy-4-morpholinyl] doxorubicin N-oxide [Rj=0CH.1, R2=R.3=0H, R4=H, R's=CH(OH)CH20H, R(,=O, Rg=H, Rg)=OCH3, X=O, R7=0H, RS=H] (A12):13-dihydro-3'-deamino-3'[2-methoxy-4-morpholinyl]- doxorubicin N-hydroxy chloride [Rj=0CH,3, R2=R3=0H, R4=H, R5=CH(OH)CH20H, P6=0H, P9=H, RI,=OCH3, X=O, R7=0H, R.=H] (A13):3'-deamino-3'[piperidine]-doxorubicin N-oxide [Rj=0CH3, R,,=R=OH, R.1=H, R5=COCH,0H, R,,=O, Rg=RI(,=H, X=CH, R7=0H, R,=H] (A14):3'-deamino3'[piperidine)-domorubicin N-hydroxy chloride [Rj=0CH3, R.)=Rj=0H, R4=H, R5=COCH,0H, R6=0H, Rg=RI()=H, X=CH,, R7OH, R,=H] Anthracyclines N-oxide of formula A (R.=0) may be prepared by a process which comprises:
i) reacting a compound of formula B 0 R R 2 4 R 5 OH i 1 Ii j - R U R - 1 3 0 0 R- N - 1 11 R -' 9 X 'RjO wherein R,, R_,, R,, R4, Rj, R7r R,, R,, R,, and X are as defined above with a peroxide compound.
Anthracyclines N-hydroxide of formula A (R.=OH) may be prepared by (ii) reacting the resultant N-oxide derivative of formula A with an organic or inorganic acid.
For example, a preferred process for the preparation of anthracycline Noxides of formula A comprises treating a compound of formula B as previously defined, in the form of a free base, in organic apolar solvent such as acetone, with a peroxide compound such as dinethyldioxirane at temperature from -400C to -100C, preferably at -300C, for from 5 to 30 minutes, then removing the solvent under reduced pressure and purifing the resultant N-oxide derivative, for example by flash chromatography on silica gel.
A preferred process for the preparation of anthracycline N-hydroxide of formula A comprises treating the anthracycline N-oxide, dissolved in an organic solvent such as methylene chloride, with an anhydrous acid, preferably anhydrous hydrogen chloride, at a temperature of from -100C to OOC, preferably -SOC.
Dimethyldioxirane may be prepared as described in J.Org.Chem., 1987, vol 52, 2800-2803. It should be noted that the use of dimethyldioxirane allows the formation of anthracycline N-oxide without formation of by- products. In addition, this reagent is easily removed from the reaction mixture under reduced pressure.
The starting anthracyclines, namely morpholino or morpholino ring substituted or piperidine derivatives, of formula B are well known from the literature, see Bioactive Molecules Vol.6, edited by J.W.Lown (Elsevier 1988). Preferred starting compounds are: (B1) 3'-deamino3'[2(S)-methoxy-4-morpholinyl)-doxorubicin [Rj=0CH3, R,=Rj=0H, R.;=H, R,5=COCH20H, R,=H, R1,=(S)0CH3. X=0.
R7=0H, Rs=H), (B2) 3'-deamino-3'[2(R)-methoxy-4-morpholinyl]-doxorubicin [Rj=0CHI, R,=R3=0H, R.1=H, R.s=COCH20H, R,=H, R1,=(R)0CH.3, X=O, R7=0H, R,=H] (B3) 4-demethoxy3'-deamino-3'[2(S)-methoxy-4-morpholinyl] daunorubicin 6 Rg=H, R,(,= (S) OCH3, X=O, R7=0H, [R,=H, R2=R3=0H, R4=H, R5=COCH30 R8=H] (B4) 4-demethoxy-3'-deamino3'[2(R)-methoxy-4-morpholinyl1 daunorubicin [RI=H, R2=R3=0H, R4=H, R5=COCH3i Rg=H, R10=(R)OCH3f X=O, R7=0H, R8=H] (B5) 3'-deamino-3'[4-morpholinyl]-doxorubicin [Rj=0CHI, R,=R3=0H, R.1=H, R5=COCHOH, 1?,,=Rl,=H, X=O, R7=0H, Rs=H] (B6) 13-dihydro-3'deamino-3'[2methoxy-4-morpholinylldoxorubicin (B7) 3'-deamino-3'[piperidine]-do>:orubicin [R,=OCH,, R,=R,=OH, R,=H, R=CCCHOH, R,=Rj,H, X=CH,, R7OH, R8=H] The new anthracycline derivatives of the present invention are water soluble, also in the form of an N- oxide. Surprisingly, while the N-oxide derivatives of formula A (R,=O) show cytotoxic activity on tumor cells similar to those of the starting anthracyclines of formula B, the corresponding N-hydroxide derivatives A (R,=OH) are from 10 to 100 fold more potent than the corresponding Noxide.
administratior The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier and, as an active principle, as anthracycline analogue of formula A or a pharmaceutically acceptable salt thereof.
Suitable routes of administration include parenteral.
For parenteral administration a liquid formulation nay be prepared using the active compound and a sterile diluent or carrier which nay either dissolve the active compound or provide a suspension for it. The parenteral. formulation may be prepared in the form of a sterile solid for reconstitution prior to administration with a suitable vehicle such as physiological saline, sterile water or other sterile vehicle.
The compounds of the invention are useful in methods of treatment of the humam and animal body by therapy. They are useful as anti-tumor agents in particular in the treatment of 7 leukaemia or colon adenocarcinoma. A therapeutically effective amount is administered to a patient having a tumor to ameliorate or improve the condition of the patient. An amount sufficient to inhibit the growth of the tumor may be administered. The dosage to be given can be ascertained using known dosage ranges for doxorubicin and daunorubicin modified by reference to the activity shown by the present compounds in in vitro and in vivo anti-tumor tests. Suitable dosages are generally in the range of 1 to 200 Mg/M2 body surface, preferably from 1 to 100 Ing/M2, depending on the nature and severity of the disease being treated and on the general condition of the patient.
The following Examples further illustrate -the present invention.
Example 1 3'-deamino-3'f2(S)-methoxy-4-morpholinyll-doxorubicin N-oxide (A1) 3'-deamino-3'[2(S)-methoxy-4-morpholinyl)-doxorubicin (111: 0.44g 0.6 mmole) is dissolved in anhydrous acetone (20 ml) at -300C and treated with a 0.1M solution of dimethyldioxirane in acetone (10 ml) for 30 minutes. Then the reaction mixture is concentrated under reduced pressure and the crude material is flash chromatographed on silica gel using a mixture of ffiethylene chloride and methanol (90:10 by volume) as an eluting system to give the title compound A1 (0.36 g).
TLC on Kieselgel plate F254 (Merck), eluting system methylene chloride, methanol, acetic acid, water (30:4:1:0.5 by volume) Rf: 0. 6.
Example 2 3'-deamino-3'r2(S)-methoxy-4-morpholinyll-doxorubicin Nhydroxide chloride (A2) Compound A1 (0.18g, 0.22 mmole), prepared as described in Example 1, is dissolved in anhydrous methylene chloride (5 ml) 8 at OOC and added with an equivalent amount of 0.1M methanolic solution of anhydrous hydrogen chloride. The title compound (A2, 0.22 g) is precipitated by adding a mixture of ethyl ether and petroleum ether (100 ml).
TLC on Kieselgel plate F254 (Merck), eluting system methylene chloride, methanol, acetic acid, water (30:4:1:0.5 by volume) Rf:O.6.
Example 3 3'-deamino-3'r2(R)-methoxy-4-morpholinyll-doxorubicin N-oxide (A3) Compound A3 is prepared from 3'-deamino-3 2 (R) -methoxy-4morpholinyl]- doxorubicin (B2) following the same procedure described in Example 1.
TLC on Kieselgel plate F254 (Merck), eluting system methylene chloride, methanol, acetic acid, water (30:4:1:0.5 by volume) Rf:O.63 Example 4 3'-deamino-3'f2(R)-rnethoxy-4-morpholinyll-doxorubicin N- hydroxide chloride (A4) Compound A4 is prepared from compound A3, prepared as described in Example 3, following the same procedure described in Example 2. TLC on Kieselgel plate F254 (Merck), eluting system methylene chloride, methanol, acetic acid, water (30:4:1:0.5 by volume) Rf:0.63 Example 5
4-demethoxy-3 ' -deamino-3 ' [ 2 (S) -methoxy-4-morpholinyl_l daunorubicin N-oxide (A5) CompoundAS is prepared from 4-demethoxy-3'-deamino-3' [2(S)methoxy-4- morpholinyl] (B3) following the same procedure described in Example 1. TLC on Kieselgel plate F254 (Merck), eluting system methylene chloride, methanol (20:1 by volume) Rf:O.28 9 Example 6
4-demethoxy-3'-deamino-3'r2(S)-nethoxy-4-morpholinylj daunorubicin Nhydroxide chloride (A6) Compound A6 is prepared from compound A5, prepared as described in Example 5, following the same procedure described in Example 2. TLC on Kieselgel plate F254 (Merck), eluting system methylene chloride, methanol (20:1 by volume) Rf:0.28 Example 7 3'-deamino-3'r4-morpholinyll-doxorubicin N-oxide Compound A9 is prepared from 3'-deamino-3'[4-morpholinyl]doxorubicin (B5) following the same procedure described in Example 1. TLC on Kieselgel plate F254 (Merck), eluting system methylene chloride, methanol, acetic acid, water (30:4:1:0.5 by volume) Rf:O.37 Example 8 3'-deamino-3' r4-morpholinyl I -doxorubicin N-hydroxide (A10) Compound A10 is prepared from compound A9, prepared as described in Example 7, following the same procedure described in Example 2. TLC on Kieselgel plate F254 (Merck), eluting system methylene chloride, methanol, acetic acid, water (30:4:1:0.5 by volume) Rf:0.37 Biological Activity 3'-deamino-3'[2(S)-methoxy-4-morpholinyl] doxorubicin N-oxide (Al) and 3'-deamino-3'[2(S)-methoxy-4-morpholinyl] doxorubicin N- hydroxide (A2) were tested in vitro on L1210, 48 h treatment, in comparison with 3'-deamino-3'[2(S)-methbxy-4morpholinyl] doxorubicin (111). The cytotoxic activity is'reported as IC50, the concentration inhibiting 50% of colony formation, calculated on concentration response curves. The N-hydroxy derivative of formula (A2) was found to be 20 fold more potent than the parent compound BI (Table 1) Table 1: in vitro cytotoxic activity (IC50) of 3'-deamino-3' (2 (S)methoxy-4-morpholinyl) doxorubicin N-oxide and 3'-deamino-3'[2(S)-methoxy4-morpholinyl] doxorubicin N-hydroxide (A2) on L1210 cells in comparison with 3'-dearino-3'[2(S)-methoxy-4morpholinyl)doxorubicin (Bi).
Compound A1 A2 B1 IC50 (ng/ml) 5.43 0.36 7.62 Colony assay: 48h treatment.
11
Claims (20)
1. A compound which is an anthracycline analogue of formula A R
2 4 R5 OH YR, 0 nR ^ 3 0 j R 7 /__,R6 N R9 X R10 A 1 wherein R, is a hydrogen atom or a hydroxy or nethoxy group; R2 and R3 are both hydroxy groups or one of R2 and R3 is a hydroxy group and the other of R, and R3 is a hydrogen atom; R4 is a hydrogen atom or a hydroxy, methoxy, carboxy or carbomethoxy group; R.5is a group of formula COCH3. COCH20H, CH2CH3. CH(OH)CH3 or CH(OH)CHOH; R6 is an oxygen atom or a hydroxy group; R7 and R, are both hydrogen atoms or one of R7 and Rg is a hydroxy group, a halogen atom or the group 0S02CH3 and the other of R7 and R, is a hydrogen atom; X is an oxygen atom or -CH2_; R, and R,, are both hydrogen atoms or one of R.9 and R,0 is a hydrogen atom and the other of R, and R,, is a hydroxy group or the group O(C0),,R,, in which R,, is a C,-C, alkyl, C.,-C,. cycloalkyl or phenyl C, _C6 alkyl group and n is 0 or 1, or one of R, and R,, is the group O(C0),, R,, as defined above and the other of R, and R,,, is a methyl or hydroxynethyl group; or a pharmaceutically acceptable salt thereof.
12 2. A compound according to claim 1 wherein R6 is a hydroxy group.
3. A compound according to claim 1 or 2 wherein X is an oxygen atom.
4. A compound according to any one of claims 1 to 3 wherein R, is hydrogen or methoxy, R2 and R3 are both hydroxy, R4 is hydrogen, R,, is a group of formula COCH3. COCH20H or COCH(OH)CH20H and R, and R,, are both hydrogen atoms.
5. A compound according to any one of claims 1 to 4 wherein R7 is a hydroxy group and R, is a hydrogen atom;
6. A compound according to claim 1 which is 3'-deamino-3'[2(S)-methoxy-4-morpholinyl]-doxorubicin N-oxide, 3'-deamino-3'[2(S)-methoxy-4-morpholinyl]-doxorubicin N- hydroxide chloride, 3'-deamino-3'[2(R)-methoxy-4-morpholinyl]-doxorubicin N-oxide, 3'-deamino-3'[2(R)-methoxy-4-morpholinyl]-doxorubicin N- hydroxide chloride, 4-demethoxy-3'-deamino-3'[2(S)-methoxy-4-morpholinyl]daunorubicin N-oxide, 4-demethoxy-3'-deamino-3'[2(S)-methoxy-4-morpholiny1 daunorubicin N-hydroxide chloride, 4-demethoxy-3'-deamino-3'[2(R)-methoxy-4-morpholinyl] daunorubicin N-oxide, 4-demethoxy-3'-deamino-3'[2(R)-methoxy-4-morpholinyl]-daunorubicin N-hydroxide chloride, 3'-deamino-3'[4-morpholinyll-doxorubicin N-oxide, 3'-deamino-3'[4-morpholinyl]-doxorubicin N-hydroxide, 13-dihydro-3'-deamino-3'[2-methoxy-4-morpholinyl]- doxorubicin N-oxide, 13-dihydro-3'-deamino-3'[2-methoxy-4-norpholinyl]- doxorubicin Nhydroxy chloride, 3'-deamino-3'[piperidine]-doxorubicin N-oxide or 3'-deamino-3'[piperidine]-doxorubicin N-hydroxychloride.
7. A compound according to any one of the preceding claims which is in the form of its hydrochloride salt.
8. A process for the preparation of a compound which is 13 an anthracycline analogue of formula A or a pharmaceutically acceptable salt thereof as defined in any one of the preceding claims, which process comprises (a) reacting with a peroxide compound a compound of formula B 2 4 OH R, 0 R3 -----7 R 0 7 / N,' ",C ", R9 X 10 B 0 wherein R,, R2, RI, R4, R.j, R7, R8, R,, R,,, and X are as def ined in claim 1, and, if desired (b) treating the resultant N-oxide with an organic or inorganic acid and, if desired, (c) converting the anthracycline analogue of formula A thus obtained into a pharmaceutically acceptable salt thereof.
9. A process according to claim 8 wherein step (a) is carried out in an organic apolar solvent and the peroxide compound is dimethyldioxirane.
10. A process according to claim 9 wherein the oganic apolar solvent is acetone.
11. A process according to any one of claims 8 to 10 14 wherein step (a) is conducted at a temperature of from -400 to -100C for from 5 to 30 minutes.
12. A process according to any one of claims 8 to 11 wherein step (b) is carried out in an organic solvent and the acid is anhydrous hydrogen chloride.
13. A process according to claim 12 wherein the organic solvent is methylene chloride.
14. A process according to claim 12 or 13 which is carried out at a temperature of from -100C to OOC.
15. A compound according to claim 1 specifically identified herein.
16. A process for preparing a compound as defined in claim 1 which process is substantially as described in any one of Examples 1 to 8.
17. A pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier and, as an active principle, an anthracycline analogue of formula A or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 7 or 15.
18. An anthracycline analogue of formula A or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 7 or 15 for use in a method of treatment of the human or animal body by therapy.
19. An anthracycline analogue of formula A or a pharmaceutically acceptable salt thereof as defined in-any one of claims 1 to 7 or 15 for use as an anti-tumor agent.
20. Use of an anthracycline analogue of formula A or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 7 or 15 in the manufacture of a medicament for the treatment of a tumor.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9426075A GB2296495B (en) | 1994-12-23 | 1994-12-23 | Anthracycline derivatives |
| IT95MI002614A IT1277073B1 (en) | 1994-12-23 | 1995-12-13 | ANTHRACYCLINIC DERIVATIVES |
| DE19547958.0A DE19547958B4 (en) | 1994-12-23 | 1995-12-21 | Anthracycline derivatives |
| JP33521695A JP4081148B2 (en) | 1994-12-23 | 1995-12-22 | Anthracycline derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9426075A GB2296495B (en) | 1994-12-23 | 1994-12-23 | Anthracycline derivatives |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB9426075D0 GB9426075D0 (en) | 1995-02-22 |
| GB2296495A true GB2296495A (en) | 1996-07-03 |
| GB2296495B GB2296495B (en) | 1998-04-15 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9426075A Expired - Lifetime GB2296495B (en) | 1994-12-23 | 1994-12-23 | Anthracycline derivatives |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JP4081148B2 (en) |
| DE (1) | DE19547958B4 (en) |
| GB (1) | GB2296495B (en) |
| IT (1) | IT1277073B1 (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2315067A (en) * | 1996-07-11 | 1998-01-21 | Pharmacia Spa | Morpholinyl bridged anthracycline derivatives |
| WO2004082579A2 (en) * | 2003-03-18 | 2004-09-30 | Pharmacia Italia S.P.A. | Nemorubicin as radiosensitizer in combination with radiation therapy against tumors |
| WO2009124468A1 (en) * | 2008-04-11 | 2009-10-15 | 天津和美生物技术有限公司 | Anthracycline antibiotic derivatives with high activity, preparation methods and uses thereof |
| RU2455307C1 (en) * | 2008-04-11 | 2012-07-10 | Тяньцзинь Химэй Байо-Тек Ко., Лтд | Tetracyclic antibiotic anthraquinone derivatives having high activity, synthesis method and use thereof |
| US8389697B2 (en) | 2008-07-15 | 2013-03-05 | Genentech, Inc. | Anthracycline derivative conjugates, process for their preparation and their use as antitumor compounds |
| US8470984B2 (en) | 2010-12-02 | 2013-06-25 | Nerviano Medical Sciences S.R.L. | Process for the preparation of morpholinyl anthracycline derivatives |
| US8742076B2 (en) | 2008-02-01 | 2014-06-03 | Genentech, Inc. | Nemorubicin metabolite and analog reagents, antibody-drug conjugates and methods |
| CN104125962A (en) * | 2012-03-06 | 2014-10-29 | 天津和美生物技术有限公司 | Tetracyclic anthraquinone derivatives |
| CN105164138A (en) * | 2013-04-29 | 2015-12-16 | 内尔维阿诺医学科学有限公司 | New morpholinyl anthracycline derivatives |
| WO2016071418A1 (en) | 2014-11-05 | 2016-05-12 | Nerviano Medical Sciences S.R.L. | Functionalized morpholinyl anthracycline derivatives |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2395660A1 (en) * | 1999-12-29 | 2001-07-12 | Immunogen, Inc. | Cytotoxic agents comprising modified doxorubicins and daunorubicins and their therapeutic use |
| AU2004222527A1 (en) * | 2003-03-18 | 2004-09-30 | Pharmacia Italia Spa | Combined therapy comprising nemorubicin and a cyclooxygenase-2-inhibitor |
| CN110776501B (en) * | 2019-08-22 | 2021-04-02 | 联宁（苏州）生物制药有限公司 | Preparation method of drug toxin PNU-159682 for antibody drug conjugate and intermediate thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4301277A (en) * | 1980-10-20 | 1981-11-17 | Sri International | 3-Deamino-3-(4-morpholinyl) derivatives of daunorubicin and doxorubicin |
| JPS57163393A (en) * | 1981-03-27 | 1982-10-07 | Microbial Chem Res Found | Novel anthracyclin derivative and its preparation |
| JPS59212499A (en) * | 1983-05-13 | 1984-12-01 | アドリヤ・ラボラトリ−ズ・インコ−ポレ−テツド | 4-demethoxy-3'-deamino-3'(4-morpholinyl) derivative |
| US4585859A (en) * | 1983-05-24 | 1986-04-29 | Sri International | Analogues of morpholinyl daunorubicin and morpholinyl doxorubicin |
-
1994
- 1994-12-23 GB GB9426075A patent/GB2296495B/en not_active Expired - Lifetime
-
1995
- 1995-12-13 IT IT95MI002614A patent/IT1277073B1/en active IP Right Grant
- 1995-12-21 DE DE19547958.0A patent/DE19547958B4/en not_active Expired - Lifetime
- 1995-12-22 JP JP33521695A patent/JP4081148B2/en not_active Expired - Lifetime
Cited By (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2315067B (en) * | 1996-07-11 | 2000-02-16 | Pharmacia Spa | Morpholinyl anthracycline derivatives |
| GB2315067A (en) * | 1996-07-11 | 1998-01-21 | Pharmacia Spa | Morpholinyl bridged anthracycline derivatives |
| WO2004082579A2 (en) * | 2003-03-18 | 2004-09-30 | Pharmacia Italia S.P.A. | Nemorubicin as radiosensitizer in combination with radiation therapy against tumors |
| WO2004082579A3 (en) * | 2003-03-18 | 2004-11-11 | Pharmacia Italia Spa | Nemorubicin as radiosensitizer in combination with radiation therapy against tumors |
| US8742076B2 (en) | 2008-02-01 | 2014-06-03 | Genentech, Inc. | Nemorubicin metabolite and analog reagents, antibody-drug conjugates and methods |
| US9492553B2 (en) | 2008-02-01 | 2016-11-15 | Genentech, Inc. | Nemorubicin metabolite and analog reagents, antibody-drug conjugates and methods |
| CN101555264B (en) * | 2008-04-11 | 2014-09-03 | 天津和美生物技术有限公司 | Derivative of highly active tetra cyclic anthroquinones antibiotics and preparation and application thereof |
| US9115165B2 (en) | 2008-04-11 | 2015-08-25 | Tianjin Hemay Bio-Tech Co., Ltd. | Tetracyclic anthraquinone antibiotic derivatives with high activity, process for preparing the same and use thereof |
| WO2009124468A1 (en) * | 2008-04-11 | 2009-10-15 | 天津和美生物技术有限公司 | Anthracycline antibiotic derivatives with high activity, preparation methods and uses thereof |
| RU2455307C1 (en) * | 2008-04-11 | 2012-07-10 | Тяньцзинь Химэй Байо-Тек Ко., Лтд | Tetracyclic antibiotic anthraquinone derivatives having high activity, synthesis method and use thereof |
| AU2009235897B2 (en) * | 2008-04-11 | 2012-04-12 | Tianjin Hemay Oncology Pharmaceutical Co., Ltd | Anthracycline antibiotic derivatives with high activity, preparation methods and uses thereof |
| US8900589B2 (en) | 2008-07-15 | 2014-12-02 | Genetech, Inc. | Anthracycline derivative conjugates, process for their preparation and their use as antitumor compounds |
| US8389697B2 (en) | 2008-07-15 | 2013-03-05 | Genentech, Inc. | Anthracycline derivative conjugates, process for their preparation and their use as antitumor compounds |
| US9695240B2 (en) | 2008-07-15 | 2017-07-04 | Genentech, Inc. | Anthracycline derivative conjugates, process for their preparation and their use as antitumor compounds |
| US8470984B2 (en) | 2010-12-02 | 2013-06-25 | Nerviano Medical Sciences S.R.L. | Process for the preparation of morpholinyl anthracycline derivatives |
| CN104125962A (en) * | 2012-03-06 | 2014-10-29 | 天津和美生物技术有限公司 | Tetracyclic anthraquinone derivatives |
| CN104125962B (en) * | 2012-03-06 | 2016-06-22 | 天津和美生物技术有限公司 | Fourth Ring anthraquinone derivative |
| CN105164138A (en) * | 2013-04-29 | 2015-12-16 | 内尔维阿诺医学科学有限公司 | New morpholinyl anthracycline derivatives |
| CN105164138B (en) * | 2013-04-29 | 2017-11-07 | 内尔维阿诺医学科学有限公司 | new morpholinyl anthracycline derivatives |
| US9828405B2 (en) | 2013-04-29 | 2017-11-28 | Nerviano Medical Sciences S.R.L. | Morpholinyl anthracycline derivatives |
| 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 |
|---|---|
| ITMI952614A1 (en) | 1997-06-13 |
| GB9426075D0 (en) | 1995-02-22 |
| JPH08231581A (en) | 1996-09-10 |
| JP4081148B2 (en) | 2008-04-23 |
| DE19547958B4 (en) | 2015-01-22 |
| DE19547958A1 (en) | 1996-06-27 |
| IT1277073B1 (en) | 1997-11-04 |
| GB2296495B (en) | 1998-04-15 |
| ITMI952614A0 (en) | 1995-12-13 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 730A | Proceeding under section 30 patents act 1977 | ||
| 732E | Amendments to the register in respect of changes of name or changes affecting rights (sect. 32/1977) | ||
| 732E | Amendments to the register in respect of changes of name or changes affecting rights (sect. 32/1977) | ||
| PE20 | Patent expired after termination of 20 years |
Expiry date: 20141222 |