Morpholinyl anthracycline derivatives

Patent metadata

Field	Value
Publication number	US-9828405-B2
Application number	US-201414787667-A
Country	US
Kind code	B2
Filing date	Apr 23, 2014
Priority date	Apr 29, 2013
Publication date	Nov 28, 2017
Grant date	Nov 28, 2017

Abstract

The present invention relates to new morpholinyl anthracycline derivatives which have cytotoxic activity and are useful in treating diseases such as cancer, cellular proliferation disorders and viral infections. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising them and methods of treating diseases utilizing such compounds or the pharmaceutical compositions containing them.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein:
R1 is halogen or NR4R5;
R2 is an optionally substituted group selected from straight or branched C 2 -C 6 alkyl, NR7R8-C 2 -C 6 alkyl, R6O—C 2 -C 6 alkyl and COR9;
R3 is hydrogen or a straight or branched C 1 -C 4 alkoxy;
R4 and R5 are independently hydrogen, a monosubstituted-benzyl, a disubstituted-benzyl, or an optionally substituted group selected from straight or branched C 1 -C 6 alkyl, NR7R8-C 1 -C 6 alkyl, R6O—C 1 -C 6 alkyl, R7R8N—C 1 -C 6 alkylcarbonyl, R6O—C 1 -C 6 alkylcarbonyl, R7R8N—C 1 -C 6 alkylaminocarbonyl, R6O—C 1 -C 6 alkylaminocarbonyl, R7R8N—C 1 -C 6 alkylsulphonyl, R6O—C 1 -C 6 alkylsulphonyl, R7R8N—C 1 -C 6 alkoxycarbonyl and R6O—C 1 -C 6 alkoxycarbonyl; or
R4 and R5, taken together with the N atom to which they are bound, form a heterocyclyl substituted with R4;
R6, R7 and R8 are independently hydrogen or an optionally substituted straight or branched C 1 -C 6 alkyl;
R9 is OR6, NR7R8 or an optionally substituted group selected from
straight or branched C 1 -C 4 alkyl, NR7R8-C 1 -C 4 alkyl and R6O—C 1 -C 4 alkyl,
or a pharmaceutically acceptable salt thereof.

2. A compound of formula (Ia) or (Ib), according to claim 1 ,

wherein R1 is fluorine or NR4R5, wherein one of R4 or R5 is hydrogen and the other is hydrogen or an optionally substituted group selected from straight or branched C 1 -C 6 alkyl, NR7R8-C 1 -C 6 alkyl, R6O—C 1 -C 6 alkyl, R7R8N—C 1 -C 6 alkylcarbonyl, R6O—C 1 -C 6 alkylcarbonyl, R7R8N—C 1 -C 6 alkylaminocarbonyl, R6O—C 1 -C 6 alkylaminocarbonyl, R7R8N—C 1 -C 6 alkoxycarbonyl and R6O—C 1 -C 6 alkoxycarbonyl.

3. The compound of formula (Ia), according to claim 2 ,
wherein R2 is COR9.

4. The compound of formula (Ia), according to claim 2 , which is selected from the group consisting of:
(8S,10S)-8-acetyl-1-fluoro-6,8,11-trihydroxy-10-{[(1S,3R,4aS,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-7,8,9,10-tetrahydrotetracene-5,12-dione,
(8S,10S)-1-fluoro-6,8,11-trihydroxy-8-(hydroxyacetyl)-10-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-7,8,9,10-tetrahydrotetracene-5,12-dione,
(8S,10S)-1-amino-6,8,11-trihydroxy-8-(hydroxyacetyl)-10-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-7,8,9,10-tetrahydrotetracene-5,12-dione,
(8S,10S)-8-acetyl-1-amino-6,8,11-trihydroxy-10-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-7,8,9,10-tetrahydrotetracene-5,12-dione,
(8S,10S)-8-acetyl-6,8,11-trihydroxy-1-[(2-hydroxyethyl)amino]-10-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-7,8,9,10-tetrahydrotetracene-5,12-dione,
(8S,10S)-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-[(2-hydroxyethyl)amino]-10-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-7,8,9,10-tetrahydrotetracene-5,12-dione,
(8S,10S)-8-acetyl-1-[(2-aminoethyl)amino]-6,8,11-trihydroxy-10-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-7,8,9,10-tetrahydrotetracene-5,12-dione, and
(8S,10S)-1-[(2-aminoethyl)amino]-6,8,11-trihydroxy-8-(hydroxyacetyl)-10-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-7,8,9,10-tetrahydrotetracene-5,12-dione.

5. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1 , and at least one pharmaceutically acceptable excipient, carrier or diluent.

6. A pharmaceutical composition according to claim 5 , further comprising one or more chemotherapeutic agents.

7. A product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1 , and one or more chemotherapeutic agents, as a combined preparation for simultaneous, separate or sequential use in anticancer therapy.

8. A method for treating cancer, which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I), as defined in claim 1 .

9. The method of claim 8 , wherein the mammal in need thereof is a human.

10. The method of claim 8 , wherein the cancer is selected from the group consisting of bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gall-bladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, skin carcinoma, squamous cell carcinoma, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, Burkitt's lymphoma, acute myelogenous leukemia, chronic myelogenous leukemia, myelodysplastic syndrome, promyelocytic leukemia, fibrosarcoma, rhabdomyosarcoma, astrocytoma, neuroblastoma, glioma, schwannoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, thyroid follicular cancer, Kaposi's sarcoma and mesothelioma.

11. A process for the preparation of a compound of formula (I) as defined in claim 1 , which comprises:
first, reacting
the compound of formula (VII)

wherein R3 and R10 are as defined in claim 1 and R9 is OR6 or NR7R8, wherein R6, R7 and R8 are as defined in claim 1 ,
or
the compound of formula (VIII)

wherein R3 and R10 are as defined in claim 1 ,
or
the compound of formula (III)

wherein R3 and R10 are as defined in claim 1 ,
or
the compound of formula (IX)

wherein R3 and R10 are as defined in claim 1 , and R12 is group selected from straight or branched C 1 -C 4 alkyl, NR7R8-C 1 -C 4 alkyl and R60-C 1 -C 4 alkyl,
or
the compound of formula (X)

wherein R3, R10 and R12 are as defined in claim 1 ,
or
the compound of formula (XI) or (XIa)

wherein R3, R6, R7, R8 and R10 are as defined in claim 1 ,
or
the compound of formula (XII) or (XIIa)

wherein R3, R6, R7, R8 and R10 are as defined in claim 1 ,
or
the compound of formula (V)

wherein R3 and R10 are as defined in claim 1 ,
or
the compound of

Assignees

• Nerviano Medical Sciences Srl

Inventors

• Beria Italo
• Caruso Michele
• Lupi Vittoria

Classifications

• A61P31/12

  Antivirals · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/04

  specific for metastasis · CPC title