WO1998002446A1

WO1998002446A1 - Morpholinyl anthracycline derivatives

Info

Publication number: WO1998002446A1
Application number: PCT/EP1997/003252
Authority: WO
Inventors: Michele Caruso; Pierpaolo Lovisolo; Cristina Geroni; Antonino Suarato
Original assignee: Pharmacia & Upjohn S.P.A.
Priority date: 1996-07-11
Filing date: 1997-06-20
Publication date: 1998-01-22
Also published as: GB2315067A; EP0889898A1; GB2315067B; DE69710573D1; DE69710573T2; JP4066389B2; GB9614621D0; JPH11513040A; EP0889898B1

Abstract

A morpholinyl derivative of formula (2) wherein: R1 is methoxy, hydroxy or hydrogen, R2 is hydrogen or hydroxy, R3 is a C1-C5 alkoxy group, and the chiral carbon atom configuration at the 2' and 3' positions are 2'(S), 3'(R), 3'(S), or a pharmaceutically acceptable salt thereof. The compounds are endowed with high antitumor activity.

Description

MORPHOLINYL ANTHRΛCYCLINE DERIVATIVES

The present invention relates to morpholmyl anthracyclme derivatives, to a process for their preparation and to pharmaceutical compositions containing them.

The morpholmyl anthracyclines are semisynthetic analogs of anthracycl es endowed with remarkable antitumor activity (see: Bioactive Molecules Vol. 6, Ed. J.W. Lown, Elviser 1988). Λt present, several morpholmyl anthracyclmes are under clinical evaluation. Among them, 3' -deammo-3' - [2" (S) -methoxy- ."-morpholmyl ] doxorubicin (_1) possesses high i n vi tro and i n vi vo activity on sensitive or multidrug resistant tumors including doxorubicm-resistant tumor cells (see: M. Grandi et al . , Cancer Treat. Rew., 1_7_, 133, 1990 and M. Ripamonti et al . , Br. J. Cancer, 6! , 703, 1992).

In US-A-4, 826, 964 (3989), E.D. Acton has described the preparation of bridged oxygen derivatives oi daunorubicin and doxorubicin. US-A-4 , 826, 964 also describes compounds of general formula A:

in which each of X and Z is an oxygen atom, Y is a methoxy group and R is the residue -COCH^OH. Compounds of formula A were prepared in small amounts by reductive alkylation of anthracyclmes with a dialdehyde of formula:

HOC- (CH ) .-0- (CH_?) _?-CH0 in the presence of reducing agents such as sodium or potassium cyanoborohydr de .

The present invention relates to new derivatives of morpholinyl anthracyclmes in which the morpholino ring is bridged with an oxygen atom to the position C-4' of the sugar residue. The present invention provides a morpholmyl anthracycl ne derivative of formula 2:

wherein: Ri is methoxy, hydroxy or hydrogen, R is hydrogen or hydroxy, R₃ is a

alkoxy group, and the chiral carbon atom configurations at the 2" anc 3" positions are 2"(S),3"(R) or 2" (R) , 3" (S) ; or a pharmaceutically acceptable salt thereof. R' may be methoxy, ethoxy, propoxy, butoxy or pentoxy, preferably methoxy. R¹ is preferably methoxy. R^ is preferably hydroxy. The invention also provides a process for the preparation of compounds of formula 2_, pharmaceutical compositions containing them and the use thereof in treating certain mammalian diseases.

Compounds of formula (2), 3' -deammo-3", 4 ' -anhydro- [ 2 "-alkoxy- 3"-hydroxy- "-morpholmyl] anthracycline derivatives, show highei cytotoxic efficacy compared to that of the parent morpholmyl anthracyclmes of formula

wherein Rj, R, , R. and the configuration at C-2" are as above defined.

The present invention also provides a process for preparing a compound of formula 2 or a pharmaceutically acceptable salt thereof, which comprises (a) reacting an N-oxide anthracycl me derivative of formula ( ) :

wherein Ri, R?, R3 and the configuration at C-2" are as above defined, with an iron (II) salt in presence of an iron-complexing agent, and

(b) if necessary converting the resultant compound of formula 2_ into a pharmaceutically acceptable salt thereof .

It should be stressed that the presence of iron- complexing agent is crucial for the formation of compound 2. The reaction proceeds with formation of single isomer and formation of the parent morpholinyl anthracycline of formula 3, which may be recovered. Preferably, the iron salt is iro (II) chloride tetrahydate. Preferably, the complexing agent is tartaric acid. Preferably, the reaction is performed in water. The reaction can be carried out at room temperature. Typically, the reaction ti e is 48 hours. The starting compounds of formula _ may be prepared as described in GB-A-2296495.

The new anthracycline derivatives of the present invention are endowed with antitumoral activity. The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier and, as an active principle, a morpholinyl anthracycline compound of formula 2_ or a pharmaceutically acceptable salt thereof. Suitable routes of administration include parenteral administration. For parenteral administration a liguid formulation may be prepared using the active compound and a sterile diluent or carrier which may 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 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 m vi tro and m vi vo anti-tumor tests. Suitable dosages are generally in the range of from 0.01 to 100 mg/m-' body surface, preferably from 0.1 to 10 mg/m^, 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: Preparation of 3^f -dean no-3"- ' -anhydro- \ 2 " (S) -methoxy-3" (R) -hydroxy-4 "-morpholinyl ] doxorubicin (2a)

3' deamιno-3' - [2" (S) -methoxy-4"-morpholιnyl ] -3' -N- ox ide-doxorub cm (1, 0.16g, 0.234mmol) is dissolved in a water solution (10ml) containing ιron(II) chloride tetrahydrate (O.llg) and tartaric acid (0.75g). The mixture is kept under stirring, in the dark at room temperature, for 48 hours. After that, methylene chloride (50ml) is added and the crude product is extracted in the organic phase from which the title compound 2a_ is separated after flash chromatography on silica gel (eluting system: methylene chloride/ethanol 24/1 v/v) . Yield 10 mg . TLC on kieselgel plate F_2b4

(Merck), eluting system methylene chloride/methanol (9/1 v/v), R,=0.62. FD-MS: E.H.C. 30mA; m/z 642 (93, [MH]+); m/z 641 (100, [M] + ). The structure of compound 2a. was assigned on the basis of ΕNMR studies.

'HΪMMR (400 MHz, CDCI δ:

1.38 (d, J=6.4Hz, 3H, CH_;,-5'); 1.72 (ddd, J=6.2, 6.2, 15.4Hz, 1H, H-2'β); 2.01 (ddd, J=5.5, 5.5, 15.4Hz, 1H, H-

2'α); 2.10 (dd, J=3.8, 14.9Hz, 1H, H-8az); 2.49 (ddd, J=1.7, 2.1, 14.9Hz, 1H, H-8eq) ; 2.73 ( , 1H, H-4"ax); 2.76 (π, III, H-2"eq) ; 3.00 (t, J=3.8Hz, 1H, CH_?-OH) ; 3.05 (d, J=19.2Hz, Hi, H-lOax); 3.25 (dd, J-1.7, 19.2Hz, 1H, H-lOeq); 3.37 (m, HI, H-3' ) ; 3.45 (s, 3H, OCH..-?"); 3.58 (m, 1H, H-5"eq) ; 3.91 (m, 1H, H-5"ax) ; 3.99 (dq, J=1.7_/ 6.4Hz, HI, H-5'); 4.08 (dd, J=1.7, 6.4Hz, 1H, H-4'); 4.08 (s, 3H, OCH₃-4) ; 4.45 (d, J-2-lHz, 1H, H-3"); 4.69 (d,

J=2.1Hz, 1H, H-2"); 4.75 (d, J-3.8Hz, 2H, CH_?OH) ; 4.87 (s, IK, 011-9); 5.31 (dd, J=?.l, 3.8Hz, 1H, H-7); 5.47 (dd, J-5.5, 6.2Hz, 1H, H-l'); 7.39 (d, J=7.7Hz, _H, H-3); 7.78 (dd, J=7.3, 7.7Hz, H-2); 8.02 (d, J=7.3Hz, III, H-l); 13.25 (s, 1H, OH-11); 13.99 (s, 1H, OH-6). Example 2: Biological Activity

3' -Deammo-3", 4' -anhydro- [ 2" (S) -methoxy-3" (R) - hydroxy-4"-morpholmyl ] doxorubicin 2_a was tested in vi tro on L1210 leukemia cells in comparison with 3' -deammo-3' - [2" (S) -methoxy-4"-morpholinyl] doxorubicin (1_) . The cytotoxic activity is reported as IC_₀, the concentration inhibiting 50% of colony growth, calculated on concentration response curves. Compound 2_a was found 2.5x10^ fold more potent than compound 1 (Table 1) .

Table 1 : In vi tro cytotoxic activity (IC₅₀) of 3' -deamino- 3", ' -anhydro- [2" (S ) -methoxy-3"-hydroxy-4"- morpholinyl] doxorubicin (2.) and 3' -deamino-3' - [2" (S ) - methoxy-4"-morpholmyl] doxorubicin (1) on L1210 leukemia cell s .

Growth inhibition test: 48h treatment

Compound IC₅₀

2a 0.000292 + 0.00008 1 7.38 + 1

Claims

A morpholinyl derivative of formula 2_

wherein: R, is methoxy, hydroxy or hydrogen, R, is hydrogen or hydroxy, R_ is a Ci-C*, alkoxy group, and the chiral carbon atom configurations at the 2" and 3" positions are 2"(S), 3" (R) or 2 " (R) , 3"(S); or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 wherein R_? is hydroxy.

3. A compound according to claim 1 or 2 wherein Rj_. s methoxy.

4. A compound according to any one of the preceding claims wherein R, is methoxy.

5. A compound according to any one of claims 1 to 4 which is 3' -deammo-3", 4' -anhydro- [2" (S) -methoxy-3" (R) - hydroxy-4"-morpholι nyl ] doxorubicin .

6. A process for the preparation of a compound as defined m claim 1, which comprises (a) reacting a N-oxide anthrayclme derivative of formula 4 :

wherein R , R₂, R and the configuration at C-2" are as defined in claim 1, with an iron (II) salt in presence of an iron complexing agent, and

(bj if necessary converting the resultant morpholmyl derivative of formula 2 into a pharmaceutically acceptable salt thereof.

1 . A process according to claim 6, wherein step

(a¹ is carried out in water, the iron salt is ιιon(II) c 011 do tot ra yαiatP and the complexing agent is >_.ι_πr cci .

8. A pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier and, as an active principle, a morpholmyl derivative of formula

(2), or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 5.

9. A morpholinyl derivative of formula 2, or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 5 for use in a method of treatment of the human or animal body by therapy. ¹⁰* A morphol yl derivative ol formula ?, or a pharmaceutically acceptable salt thereof, as defined m any one of claims 1 to 5 foi use as an anti-tumor agent.