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(21) Application Number:KElP/ 2009/ 000935   
       
(22) Filing Date: 27112/2007   
       
(30) Priority data: 0611492  28/12/2006  FR
       
(86)  PCT data    27112/2007 PCT/FR07/002171    wo 20081102075    28/08/2008

(73) Owner: SANOFI-AVENTIS of 174 Avenue de France, 75013 Paris, France

(72) Inventors: CASELLAS, Pierre of c/o Sanofi-A ventis, Departement Brevets, 174 avenue de France, F-75013 Paris, France and BOURRIE, Bernard of c/o Sanofi-Aventis, Departement Brevets 174 avenue de France F-75013 Paris, France

(74) Agent/address for correspondence: Kaplan & Stratton Advocates, P.O. Box 40111-00100, Nairobi   
               
(54)Title: NOVEL THERAPEUTIC USE FOR TREATING LEUKAEMIA

(57) Abstract: The invention relates to a novel therapeutic use for treating leukaemia, in particular myeloid leukaemia.
 
NOVEL THERAPEUTIC USE

FOR TREATING OF LEUKAEMIA

This invention relates to the treatment of leukaemias, in particular myeloid 5 leukaemias.

Leukaemia is a cancerous disease of the bone marrow and the blood. Four types of leukaemia can be distinguished: chronic myeloid leukaemia, acute myeloid leukaemia, chronic lymphoid leukaemia and acute lymphoid leukaemia.

Myeloid leukaemias of the acute type with a rapid progression are called

10    AML or acute myeloid leukaemia. Myeloid leukaemias of the chronic type with a gradual, less aggressive progression are called CML or chronic myeloid leukaemia. These are clonal diseases of the bone marrow characterized by a clonal expansion of myeloid cells which cannot differentiate normally and

accumulate in the bone marrow and the blood.

15 According to a study by the American Cancer Society, it is estimated that 11 ,930 new cases of AML and 4,500 new cases of CML will be diagnosed in 2006 in the United States. Over the period from 2002 to 2006, the 5 year survival rate is 20.4% for AML and 42.3% for CML (Cancer Facts and Figures 2006, American Cancer Society, www.leukemia-lymphoma.org/).

20 According to the French-American-British (FAB) classification of 1976, there are 8 subtypes of AML, referred to as MO to M7, depending on the type of cells from which the leukaemia develops (Bennett et al, 1976, "Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group". Br J Haemato/33 (4): 451-8).

25 About 95% of patients suffering from CML bear a gene translocation between chromosomes 9 and 22 of the leukaemic cells. This abnormality, known as Philadelphia chromosome (Ph 1), causes proliferation and uncontrolled multiplication of all the types of white cells and platelets.

30 Currently, several drugs are available for the treatment of leukaemias. However, there remains a need for new active therapeutic compounds for the improvement of the strategies for treatment of patients suffering from leukaemia or the development of a treatment alternative to the treatments already known (Pio et al, Mol Pharmacal, 2002, 62:304-312).

35

The product N-[2-(2, 1,3-benzothiadiazol-5-ylamino )-6-(2,6-dichlorophenyl) pyrido[2,3-d]pyrimidin-7-yi]-N'-(1,-dimethylethyl)-urea is described in the international application W02007/003765. Its formula is shown below:
 


By in vivo tests, it has been demonstrated that the compound N-[2-(2, 1,3-benzothiadiazol-5-ylamino )-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7 -yi]-N'-

15    (1, 1-dimethylethyl)-urea displays significant in vivo anti-tumour activity in animals bearing human leukaemias.

The object of the present invention is the utilization of the compound N-[2-(2, 1,3-benzothiad iazol-5-ylam ino )-6-(2,6-d ichlorophenyl )pyrido[2,3-d] pyrimid in-7-
yi]-N'-(1,-dimethylethyl)-urea or a hydrate, a salt or a solvate thereof, for the

20    preparation of a drug intended for the treatment of leukaemias. Leukaemia is understood to mean leukaemias such as chronic myeloid leukaemia, acute myeloid leukaemia, chronic lymphoid leukaemia, acute lymphoid leukaemia, and the various myeloproliferative syndromes.

25 In particular, the present invention relates to the utilization of the com pound N-[2-(2, 1,3-benzothiadiazol-5-ylamino )-6-(2,6-dichlorophenyl)pyrido-[2,3-d]pyrimidin-7-yi]-N'-(1,1-dimethylethyl)-urea,or a hydrate, a salt or a solvate thereof, for the preparation of a drug intended for the treatment of myeloid leukaemias. More particularly, the present invention relates to the utilization of the

30    compound N-[2-(2, 1 ,3-benzothiadiazol-5-ylamino)-6-(2,6-dichlorophenyl)pyrido-[2,3-d]pyrimidin-7-yi]-N'-(1,1-dimethylethyl)-urea,or a hydrate, a salt or a solvate thereof, for the preparation of a drug intended for the treatment of leukaemias of the AML type. More particularly, the present invention relates to the utilization of

the compound N-[2-(2, 1,3-benzothiadiazol-5-ylamino)-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7-yi]-N'-(1,-dimethylethyl)-urea, or a hydrate, a salt or a solvate thereof, for the preparation of a drug intended for the treatment of leukaemias of the CML type.

5    The object of the present invention relates to the utilizations cited above for the treatment of mammals, in particular of man.

In  the  present  invention,  the  compound  N-[2-(2, 1,3-benzothiadiazol-5-

ylamino)-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yi]-N'-(1, -dimethylethyl)-

10    urea can be administered to the animal tested by the oral route, the intravenous route, the intraperitoneal route or again by the intravenous route followed by an intraperitoneal route or again by the intravenous route followed by an oral route. In man, a conventional administration route is the intravenous route and/or the oral
route.

15 One object of the present invention is the utilization of the compound N-[2-(2, 1, 3-benzothiadiazol-5-ylamino )-6-(2, 6-dichlorophenyl)pyrido[2,3-d]pyrimid in-7-yi]-N'-(1,1-dimethylethyl)-urea, or a hydrate, a salt or a solvate thereof, for the preparation of a drug intended for the treatment of leukaemias of the AML type where the drug is intended to be used by administration by the intravenous route.

20 One object of the present invention is the utilization of the compound N-[2-(2, 1,3-benzothiadiazol-5-ylamino )-6-(2,6-dichlorophenyl)pyrido[2,3-d] pyrimid in-7-yi]-N'-(1,-dimethylethyl)-urea, or a hydrate, a salt or a solvate thereof, for the preparation of a drug intended for the treatment of leukaemias of the AML type where the drug is intended to be used by administration by the oral route.

25 One object of the present invention is the utilization of the compound N-[2-(2, 1 ,3-benzothiadiazol-5-ylamino )-6-(2, 6-dichlorophenyl)pyrido[2, 3-d]pyrimidi n-7-yi]-N'-(1,-dimethylethyl)-urea, or a hydrate, a salt or a solvate thereof, for the preparation of a drug intended for the treatment of leukaemias of the AML type where the drug is intended to be used by administration by the intravenous route
30    and oral route.

One object of the present invention is the utilization of the compound N-[2-(2, 1,3-benzothiadiazol-5-ylamino )-6-(2, 6-dichlorophenyl)pyrido[2, 3-d]pyrimidi n-7-yi]-N'-(1,-dimethylethyl)-urea, or a hydrate, a salt or a solvate thereof, for the
35    preparation of a drug intended for the treatment of leukaemias of the CML type where the drug is intended to be used by administration by the intravenous route.

One object of the present invention is the utilization of the compound N-[2-(2, 1, 3-benzothiadiazol-5-ylamino )-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidi n-7-

yi]-N'-(1,-dimethylethyl)-urea, or a hydrate, a salt or a solvate thereof, for the preparation of a drug intended for the treatment of leukaemias of the CML type where the drug is intended to be used by administration by the oral route.

One object of the present invention is the utilization of the compound N-[2-

5    (2, 1,3-benzothiadiazol-5-ylamino )-6-(2, 6-dichlorophenyl)pyrido[2,3-d] pyrimidin-7-yi]-N'-(1,-dimethylethyl)-urea, or a hydrate, a salt or a solvate thereof, for the preparation of a drug intended for the treatment of leukaemias of the CML type where the drug is intended to be used by administration by the intravenous route
and oral route.

10

In the present invention, the compound N-[2-(2, 1,3-benzothiadiazol-5-ylamino )-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7 -yi]-N'-1(, 1-dimethylethyl )-urea is typically formulated for administration in the form of a composition acceptable at the pharmaceutical level. These pharmaceutical compositions

15    contain an effective dose of the compound N-[2-(2, 1,3-benzothiadiazol-5-ylamino )-6-(2,6-dichlorophenyl)pyrido[2,3-d] pyrimidin-7 -yi]-N'-(1, 1-dimethylethyl)-urea or a pharmaceutically acceptable salt, a hydrate or solvate of the said compound, as well as at least one pharmaceutically acceptable excipient.

The said excipients are selected depending on the desired pharmaceutical

20    form and mode of administration, from the normal excipients which are known to the person skilled in the art.
In the pharmaceutical compositions of the present invention for oral or

intravenous administration, the compound N-[2-(2, 1 ,3-benzothiadiazol-5-ylamino)-

6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yi]-N'-(1,-dimethylethyl)-urea    or

25    possibly a salt, solvate or hydrate thereof can be administered to animals and to human beings in unit dosage form, mixed with conventional pharmaceutical excipients, for the prophylaxis or the treatment of the above disorders or diseases.

A PEG400 22% I Solutol 5% I G5 73% formulation is preferably used for the treatment by the intravenous route of mice bearing Kasumi1 tumours.

30 A Labrasol 21% I Solutol 5% I HCI 0.001 N 74% formulation is preferably used for the treatment by the oral route of mice bearing Kasumi1 or KG1 tumours.

A PEG400 22% I Solutol 5% I G5 73% formulation is preferably used for the treatment by the intraperitoneal route of mice bearing EOL-1 tumours.

A PEG400 22% I Solutol 5% I G5 73% formulation is preferably used for

35    the treatment, by the intravenous route followed by an intraperitoneal route, of

mice bearing C1V1 tumours.

A DMSO 5% I Tween SO 10% I H20 85% formulation is preferably used for the treatment, by the oral route, or by the intravenous route followed by an
 





5

intraperitoneal route, or again by the intravenous route followed by an oral route, of mice bearing KG 1a tumours.
A DMSO 5% I Tween80 10% I H20 85% formulation is preferably used for the treatment, by the intravenous route followed by an intraperitoneal route, of

5    mice bearing K562 or CML T1 tumours

A DMSO 5% I Tween80 10% I H20 85% formulation is preferably used for the treatment, by the intravenous route, of mice bearing KG1 tumours.

The appropriate unit dosage forms include forms by the oral route such as

10    tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions and intravenous administration forms.

There  may  be  special  cases  where  higher  or  lower  dosages  are

appropriate;  such  dosages  do  not  fall  outside  the  scope  of  the  invention.

15    According to the normal practice, the dosage appropriate for each patient is determined by the doctor depending on the mode of administration, and the weight and response of the said patient.

The therapy with the compound N-[2-(2, 1,3-benzothiadiazol-5-ylamino)-6-

20    (2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7 -yi]-N'-(1, -dimethylethyl)-urea according to the present invention can be utilized at the same time as other therapies. In particular, the compound N-[2-(2, 1,3-benzothiadiazol-5-ylamino)-6-(2,6-dichlorophenyl)pyrido[2, 3-d]pyrimidin-7 -yi]-N'-1(, 1-dimethylethyl)-urea according to the invention can be administered in combination with one (or more)

25    anti-cancer active principle(s), in particular antitumour compounds such as

alkylating agents such as the alkylsulphonates (busulfan), dacarbazine, procarbazine, cloretazine, the nitrogen mustards (chlormethine, melphalan, chlorambucil, cyclophosphamide, ifosfamide), the nitrosoureas such as carmustine, lomustine, semustine, streptozocine and altretamine;
30 antineoplastic alkaloids such as vincristine, vinblastine, vinorelbine and vindesine;

taxanes such as paclitaxel or taxotere;

antineoplastic antibiotics such as actinomycin and bleomycin; intercalating agents such as mitoxantrone;
35 antineoplastic antimetabolites: folate antagonists, methotrexate; inhibitors of purine synthesis; purine analogues such as mercaptopurine and 6-thioguanine; inhibitors of pyrimidine synthesis, aromatase inhibitors, capecitabine, pyrimidine
 




6

analogues such as fluorouracil, gemcitabine, cytarabine and cytosine arabinoside;

brequinar and nelarabine;

topoisomerase inhibitors such as irinotecan, exatecan, topotecan, teniposide,

camptothecin or etoposide;

5    anticancer hormone agonists and antagonists including tamoxifen;

kinase  inhibitors  such  as  imatinib,  nilotinib  and  dasatinib,  midaustorin,

sorafenib, lestaurtinib and tandutinib; growth factor inhibitors;

antiinflammatories such as pentosan polysulphate, corticosteroids, 10 prednisone and dexamethasone;

ceplene (histamine dihydrochloride);

anthracyclines such as daunorubicin, epirubicin, pirarubicin, idarubicin, zorubicin, aclarubicin, annamycin, doxorubicin, mitomycin and methramycin;

anticancer metal complexes, platinum complexes, cisplatin, carboplatin, 15 oxaliplatin and satraplatin;

alpha interferon, triphenylthiophosphoramide; antiangiogenic agents; thalidomide;

20    farnesyl transferase inhibitors such as tipifarnib; DNA methyl transferase inhibitors such as MG98;
immunotherapy adjuvants such as gemtuzumab ozogamicin and HuM 195; biotherapeutic agents such as CT388-IL3;

antisense agents such as GTI-2040;

25    vaccines.

More particularly, the compound N-[2-(2,1,3-benzothiadiazol-5-ylamino )-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yi]-N'-(1,1-dimethylethyl)-ureaaccording to the invention can be administered in combination with one or more compound(s) of the anthracycline family.
30    More particularly, the compound N-[2-(2,1,3-benzothiadiazol-5-ylamino )-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7 -yi]-N'-(1, -dimethylethyl)-urea according to the invention can be administered in combination with daunorubicin or in combination with cytosine arabinoside, or indeed in combination with daunorubicin and cytosine

arabinoside.

35 According to the present invention, the compound N-[2-(2, 1,3-be nzothiadiazol-5-ylamino )-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimid in-7-yi]-N'-(1, 1-dimethylethyl)-urea can also be administered in combination with one or more
 





7

other active principles useful in one of the pathologies mentioned above, for example an anti-emetic, analgesic, anti-inflammatory or anti-cachexia agent.

It is also possible to combine the compounds of the present invention with a radiation treatment.

5 These treatments can be administered simultaneously, separately, sequentially and/or spaced in time. The treatment will be adapted by the doctor depending on the patient to be treated.

In  the  present  invention,  the  product  N-[2-(2,1,3-benzothiadiazol-5-

10    ylamino )-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7 -yi]-N'-(1,1-dimethylethyl)-urea is administered according to a dosage scheme which enables the treatment of leukaemias. The dosage scheme varies depending on the administration route

and depending on the physical characteristics of the patient. The dosage schemes

suitable for this purpose include those which display therapeutic efficacy for the

15    treatment of disorders resulting from abnormal cellular proliferation. The product N-[2-(2,1,3-benzothiadiazol-5-ylamino )-6-(2,6-d ichlorophenyl)pyrido[2,3-d]-pyrimidin-7-yi]-N'-(1,1-dimethylethyl)-urea can be administered as often as is necessary to obtain the therapeutic effect sought.

20 The efficacy of the compound N-[2-(2,1,3-benzothiadiazol-5-ylamino )-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yi]-N'-(1,1-dimethylethyl)-ureaagainst leukaemias can be determined experimentally as in the following example which illustrates the invention.

25    EXAMPLE

Materials and methods

Scid CB-17 mice (supplied by Charles River, Lyon, France) are used. At the time of the randomization, the animals have an average weight of 20-22 g and are
aged from 6 to 9 weeks.

30    The animals are received at least one month before the experiment so as to allow perfect acclimatization. The health of the animals is examined the day before the implantation of the tumour and before the randomization so as to ensure that only animals in good health will be used for the experimental work. They are placed in
type Ill macrolon cages with filtering hoods (maximum 8 mice per cage) in a sterile

35    room where the air is continuously filtered to avoid all contamination. The sterility of the room is checked once a month. The cages are sterilized at 121oc before use and changed twice a week. The temperature of the room is maintained at 22°C and the relative humidity at 60+/-10%. The animals are placed in a natural
 




8

light cycle condition. The water is sterilized at 121 oc for 30 minutes. The water consumption is followed visually each day, and the bottles are changed twice a week. Food and water are given ad libitum. The litter is sterilized at 121 •c for 30 minutes and changed twice a week.

5    The day before the first administration of a compound, the animals bearing tumours are classified into several groups. Only animals bearing two tumours which are palpable or of determined weight are selected and distributed at random into the treated groups and control groups. Each group is made up of 5 to 10 mice. At the start of the study, each cage is labelled with a card indicating the day

10    of implantation of the tumour, the type of tumour, the compound tested and the mode of administration.
The implantation of the tumours is effected as follows: after removal of the tumour from the donor mouse, the tumour is cut up into fragments 2 to 3 mm in diameter, placed in a saline phosphate buffer, and implanted bilaterally with an adapted

15    trocar.

Determination of antitumour activity

The volume of the tumours and its conversion into weight is estimated

according  to the formula: weight:  (in mg) = (a  x  b2 )   I  2, where a and  b are

20    respectively the length and the width of the tumour (mm). The tumours are measured twice a week with callipers. In the following tables, P indicates the

weight of the tumours at the start of treatment.

Two parameters for estimation of antitumour activity are used: log10  of the

cells killed (Log cell kill) and TIC.

25    - Calculation of log10 of the cells killed = (T- C) I 3.32 x Td, where (T -C) is the delay in tumour growth and Td the volume (and weight) doubling time of the tumour (expressed in days). T is the median time in days for reaching a defined value (e.g.1 000 mg) in the treated group and C is the median time in days for
reaching this same value in the control group. A value of log10  of the cells killed

30    > 0.7 is indicative of antitumour activity of the molecule. A value of log 1o of the cells killed > 2.8 is indicative of a very high antitumour activity of the molecule (J Liang et al, Invest New Drugs 2005;23(3):213-24).

- Calculation of TIC: the treated groups and the control groups are evaluated

when the tumours of the control group reach approximately 1000 mg (median

35    value of the group). The median weight of the tumours of each treated group is then determined. The TIC value ((weight of the tumours of the treated groups I weight of the tumours of the control groups) x 100) in percent is an indication of the antitumour efficacy: a TIC value less than or equal to 42% is indicative of anti-
 





9

tumour activity according to the American National Cancer Institute (NCI). A T/C value less than 10% is representative of very high anti-tumour activity.

- The number of mice no longer displaying tumours a long time after the last administration (TFS = tumour-free survival), and considered as cured, can also

5    constitute a parameter of activity of the molecule.

- Evaluation of the toxicity of the compound tested: a weight loss greater than or equal to 20% or the appearance of any lethality in connection with the compound is considered as an excessively toxic treatment.

10    As examples, the results obtained with the compound N-[2-(2, 1,3-benzothiadiazol-5-ylamino )-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7 -yi]-N'-( 1, 1-dimethyl-ethyl)-urea are given in the following Tables 1 to 7.

TABLE 1

15    Activity of the compound N-{2-(2, 1,3-benzothiadiazol-5-ylamino)-6-(2,6-dichloropheny/)pyrido{2,3-d]pyrimidin-7-yi]-N'-(1, 1-dimethy/ethy/)-urea in mice

bearing KG1a tumours (AML)
    Formulation        p        Dose        Route    Administration    Total    TIC at    Log1o   
            mg    mglkglinjection        on days:    dose    22        cells   
                                    mglkg    days    killed   
                                                (TFSl   
    DMS05%    91-98    17            IVliP    5-13,15116, 18-    340    0%        >>6   
Tween80 10%                            20,22,24-                80% on   
    H2086%                            26,29,31                day   
                                                120)   
    DMS05%    147    40   •  2   (2    oral    15-44    2400    14.9%        3.0   
Tween80 10%            administrations                           
    H2086%            per    treatment                           
                day)                                   
                                                   
    DMS05%        1000    25 I    40 •    2 (2    IVIoral    22-30/31-44    225  I    not        >> 6   
    Tween80 10%            oral    administr-            1120    relevant       
                                               
    H20 85%            ations    per                           
                treatment dayj                           
                                           
                    ..                               
    IVIIP ts understood to mean admtmstratton by the Intravenous route followed by an tntrapentoneal   
route, here the transition is effected between day 15 and day 16. IVIoral is understood to mean

20    administration by the intravenous route followed by an oral route, here the transition is effected between day 30 and day 31. Treatment of tumours at the very advanced stage (1000 mg) by the IV route from days 22 to 30 at the dose of 25 mg/kg leads to a reduction in the tumour weight by 80%.

On day 31, the compound is administered by the oral route until day 44. At the end of this second treatment period, the tumours are no longer measurable (< 63 mg).

25    The cell line KG-1a (AML) is described by Koeffler et al., Blood 56: 265 (1980), and supplied by DSMZ ACC No. 421, Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH) MascheroderWeg 1b, 38124 Brunswick, Germany).

TABLE 2

30    Activity of the compound N-{2-(2, 1,3-benzothiadiazol-5-ylamino)-6-(2,6-dich/orophenyl)pyrido{2,3-d]pyrimidin-7-yi]-N'-(1, 1-dimethy/ethy/)-urea in mice
 

bearing KG1 tumours (AML)
 





10

Formulation    p        Dose    Route    Administration    Total    T/Cat    Log10   
        mg    mg/kg/injection        on days:    dose    28    cells   
                            mg/kg    days    killed   
                                    (TFS)   
DMS05%    127-    17        IV    19-28, 30,  32,    255    0%    >6   
Tween80 10%    130                34,36,38            (100%)   
H20 85%                                   
                                       
Labrasol21%    130-    40    X     2   (2    Oral    18-24, 26,  28,    1200    0%    4.3   
Solutol5%    132    administrations        30, 32, 34, 36,               
HCI 0.001N        per    treatment        38,40               
        day)                           
74%                                       
                                       
..
IV 1s understood to mean adm1n1stratlon by the Intravenous route.

The cell line KG-1 (AML) is described by Koeffler et al., Science 200: 1153-1154 (1978), and supplied by DSMZ ACC No. 14.

5    TABLE 3

Activity of    the compound N-[2-(2, 1,3-benzothiadiazol-5-y/amino)-6-(2,6-

dichlorophenyl)pyrido[2,3-d]pyrimidin-7-y/}-N'-(1, 1-dimethy/ethyl)-urea    in    mice

bearing Kasumi1 tumours (AML)
Formulation        p    Dose                Route    Administration    Total    T/Cat    Log1o   
        mg    mg/kg/injection            on days:    dose    28            cells   
                                    mg/kg    days    killed   
PEG400 22%    178    15    X    2    (2    IV    25-31 ;33;34.    255        20%            3   
Solutol5%            administrations            (One single                           
G5 73%            per treatment day)        administration on                           
                                day 30)                           
                                                           
Labrasol21%    178    40    X    2    (2    oral    25-31 ;33;34.    680        17.5%        2.4   
Solutol5%            administrations            (One single                           
HCI 0.001N 74%            per treatment day)        administration on                           
            ..                    day 30)                           
                                                           
IV 1s understood to mean adm1mstrat1on by the tntravenous route.                           
10    The cell line Kasumi-1 (AML) is described by Asou et al., Blood 77: 2031 (1991), and supplied by DSMZ ACC No. 220.

TABLE 4

Activity    of    the    compound    N-[2-(2, 1,3-benzothiadiazo/-5-y/amino)-6-(2,6-

15    dich/orophenyl)pyrido[2,3-d]pyrimidin-7-yi]-N'-(1, 1-dimethy/ethyl)-urea    in    mice
    bearing EOL-1 tumours (AML)                                   
    Formulation        p    Dose        Route    Administration    Total        TIC        Log10
            mg    mg/kg/injection        on days:    dose        at 14    cells
                                m!lik!l        days    killed
    PEG400 22%    133-    15X2    (2    IP    8-10; 12-17; 19    300        5.7%            3.1
    Solutol5%    146    administrations    per                               
                treatment day)                                   
    G5 73%            ..                                   
IP 1s understood to mean adm1mstratlon by the tntrapentoneal route.

The cell line EOL-1 (AML) is described by Saito et al., Blood 66: 1233-1240 (1985), and supplied by DSMZ ACC No. 386.

20

TABLE 5

Activity    of    the    compound    N-[2-(2, 1,3-benzothiadiazol-5-ylamino)-6-(2,6-

dich/orophenyl)pyrido[2,3-d]pyrimidin-7-yi]-N'-(1, 1-dimethy/ethyl)-urea    in    mice
 




11

                            mglkg    days    killed   
PEG400 22%    100    25        IVIIJ:'    17-23; 25-26 I    350    1.6%    1.7   
Solutol5%                    28-32               
G5 73%            ..                       
                                       
IVliP IS understood to mean adm1mstrabon by the mtravenous route followed by an mtrapentoneal route, here the transition is effected between day 26 and day 28.

The cell line CTV1 (AML) is described by Chen et al., Gann 75: 660-664 (1984), and supplied by DSMZ ACC No. 40.

5
 





12

    TABLE 6                                                                               
    Activity    of        the    compound        N-[2-(2, 1,3-benzothiadiazol-5-ylamino)-6-(2,6-   
    dichlorophenyl)pyrido[2, 3-d]pyrimidin-7-y/]-N'-( 1, 1-dimethy/ethyl)-urea    in    mice   
    bearing K562 tumours (CML)                                                       
5                                                                                       
        Formulation        p            Dose        Route        Administration        Total        T/Cat    Log,o   
                    mg        mg/kg/injection                        on days:        dose            28    cells   
                                                                mg/kg        days    killed   
                                                                                    (TFS)   
    DMS05%        63-80        25        IV/IP        4-11/12-25        550            0%    4,2   
    Tween80 10%                                                                        (43%   
    H20 85%                                                                            on day   
                            . .                                                    130).   
                                                                                   
    IV/IP IS understood to mean adm1n1strat1on by the Intravenous route followed by an mtrapentoneal   
    route, here the transition is effected between day 11 and day 12.                           
    The cell line K-562 (CML) is described by Lozzio et al., J Nat! Cancer lnst 50: 535 (1973) and by   
    Lozzio et al., Blood 45: 321 (1975), and supplied by DSMZ ACC No. 10.                           
10                                                                                       
    TABLE 7                                                                               
    Activity    of        the    compound    N-[2-(2, 1,3-benzothiadiazol-5-y/amino)-6-(2,6-   
    dich/orophenyl)pyrido[2,3-d]pyrimidin-7-y/]-N'-(1, 1-dimethy/ethyl)-urea    in    mice   
    bearinq CML T1 tumours (CML)                                                       
        Formulation        p            Dose            Route        Administration        Total            TIC    Log1o   
                    mg            mg/kg/injection            on days:        dose            at    cells   
                                                                    mg/kg            22    killed   
                                                                                days    (TFS)   
    DMS05%            palpable        20            IV/IP        3-7/10-14; 17-        300            1%    1.5   
    Tween80 10%    -30                                    21                            (50%   
    H20 85%                                                                            on day   
                                ..                                                    42)   
15    IV/IP 1s understood to mean adm1n1strallon by the mtravenous route followed by an mtrapentoneal   
route, here the transition is effected between day 7 and day 10.

The cell line CMLT1 (CML) is described by Kuriyama et al. in Blood, 74: 1989, 1381-1387, by Soda et al. in British Journal of Haematology, 59: 1985, 671-679 and by Drexler, in Leukemia Research, 18: 1994, 919-927 and supplied by DSMZ ACC No. 7.
 




13

CLAIMS


1.    Utilization of the compound N-[2-(2, 1,3-benzothiadiazol-5-ylamino )-6-(2,6-

dichlorophenyl)pyrido[2,3-d]pyrimidin-7 -yi]-N'-(1,-dimethylethyl)-urea    or    a

5    hydrate, a salt or a solvate thereof, for the preparation of a drug intended for the treatment of leukaemias.

2. Utilization of the compound N-[2-(2, 1,3-benzothiadiazol-5-ylamino )-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yi]-N'-(1,-dimethylethyl)-urea or a

hydrate, a salt or a solvate thereof, for the preparation of a drug intended for the

10    treatment of myeloid leukaemias.

3.    Utilization according to Claim 2, for the preparation of a drug intended for the treatment of leukaemias of the AML type.

4.    Utilization according to Claim 3, for the preparation of a drug intended for the treatment of leukaemias of the AML type where the drug is intended to be
15    used by administration by the intravenous route.

5.    Utilization according to Claim 3, for the preparation of a drug intended for the treatment of leukaemias of the AML type where the drug is intended to be used by administration by the oral route.

6.    Utilization according to Claim 3, for the preparation of a drug intended for

20    the treatment of leukaemias of the AML type where the drug is intended to be used by administration by the intravenous route and oral route.

7.    Utilization according to Claim 2, for the preparation of a drug intended for the treatment of leukaemias of the CML type.

8.    Utilization according to Claim 7, for the preparation of a drug intended for

25    the treatment of leukaemias of the CML type where the drug is intended to be used by administration by the intravenous route.

9.    Utilization according to Claim 7, for the preparation of a drug intended for the treatment of leukaemias of the CML type where the drug is intended to be used by administration by the oral route.

30    10. Utilization according to Claim 7, for the preparation of a drug intended for the treatment of leukaemias of the CML type where the drug is intended to be used by administration by the intravenous route and oral route.

11.    Utilization according to any one of Claims 1 to 10 characterized in that the
 

compound    N-[2-(2, 1,3-benzothiadiazol-5-ylamino)-6-(2,6-dichlorophenyl)pyrido-
 





14

[2,3-d]pyrimidin-7 -yi]-N'-(1, -dimethylethyl)-urea   can   be   administered    in

combination with one or more compound(s) of the anthracycline family.

12.    Utilization according to any one of Claims 1 to 10 characterized in that the

compound    N-[2-(2,1 ,3-benzothiad iazol-5-ylamino )-6-(2, 6-dichlorop henyl )pyrido-

5    [2,3-d]pyrimidin-7 -yi]-N'-1,1(-dimethylethyl)-urea can be administered in combination with daunorubicin or in combination with cytosine arabinoside, or indeed in combination with daunorubicin and cytosine arabinoside.

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