Compounds which can be used for the treatment of cancers

• US 8,519,188 B2
• Filed: 06/15/2009
• Issued: 08/27/2013
• Est. Priority Date: 06/13/2008
• Status: Active Grant

• Current Assignee: Marc-Henry Pitty
• Original Assignee: Marc-Henry Pitty
• Inventors: Carniato, Denis, Jaillardon, Karine, Busnel, Olivier, Gutmann, Mathieu, Briand, Jean-Francois, Deprez, Benoit, Thomas, Dominique, Bougeret, Ccile
• Primary Examiner(s): Kumar, Shailendra
• Application Number:
  US12/997,764
• Publication Number:
  US 20110104162A1
• Time in Patent Office: 1,534 Days
• Field of Search: 544/146, 544/165, 544/333, 544/379, 544/400, 546/163, 546/244, 546/337, 548/127, 548/253, 548/259, 548/315.1, 548/365.7, 548/568, 558/414, 564/155, 514/231.5, 514/252.12, 514/252.13, 514/256, 514/329, 514/357, 514/361, 514/438, 514/492, 514/616
• US Class Current: 564/153
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07C 237/22 having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated peptides C07K
• CPC Class Codes: C07C 237/24 having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
• CPC Class Codes: C07C 255/60 at least one of the singly-bound nitrogen atoms being acylated
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 323/63 the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
• CPC Class Codes: C07D 207/09 Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 211/66 having a hetero atom as the second substituent in position 4
• CPC Class Codes: C07D 213/56 Amides
• CPC Class Codes: C07D 215/38 Nitrogen atoms nitro radicals C07D215/18
• CPC Class Codes: C07D 231/56 Benzopyrazoles; Hydrogenated benzopyrazoles
• CPC Class Codes: C07D 233/64 with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 237/20 Nitrogen atoms nitro radicals C07D237/12
• CPC Class Codes: C07D 257/04 Five-membered rings
• CPC Class Codes: C07D 285/06 1,2,3-Thiadiazoles; Hydrogenated 1,2,3-thiadiazoles
• CPC Class Codes: C07D 295/092 with aromatic radicals attached to the chain
• CPC Class Codes: C07D 295/155 with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 307/14 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 307/52 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 317/58 Radicals substituted by nitrogen atoms nitro radicals C07D317/52
• CPC Class Codes: C07D 317/60 : Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 319/18 : Ethylenedioxybenzenes, not substituted on the hetero ring
• CPC Class Codes: C07D 333/24 : Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links

Abstract

The present invention relates to a compound of general formula (I): and also to the pharmaceutically acceptable salts thereof, to the isomers or isomer mixtures thereof in all proportions, in particular to an enantiomer mixture, and especially to a racemic mixture. The present invention also relates to the use of these compounds as a medicament, and in particular for the treatment of cancer, and also to the compositions containing them.

Claims

1. A pharmaceutical composition comprising at least one compound of formula (I):

2. The pharmaceutical composition according to claim 1, wherein the isomer mixture is an enantiomer mixture.

3. The pharmaceutical composition according to claim 2, wherein the enantiomer mixture is a racemic mixture.

4. The pharmaceutical composition according to claim 1, wherein R² represents a hydrogen atom, and R¹ represents a (C₃-C₁₀)cycloalkyl or aryl-(C₁-C₆)alkyl group,

said group being optionally substituted by one or more groups selected from a halogen atom, a (C₁-C₆)alkoxy, —

NH₂, —

COOH, —

CN, —

OH, —

NR⁷R⁸, —

O—

(C₁-C₆)alkyl-NR⁷R⁸, benzyloxy, aryloxy, —

C(O)O—

(C₁-C₆)alkyl, —

NH—

C(O)O—

(C₁-C₆)alkyl, —

C(O)NH₂, —

C(O)NR⁹R¹⁰, —

S—

(C₁-C₆)alkyl, —

S(O)—

(C₁-C₆)alkyl, —

SO₂—

(C₁-C₆)alkyl, —

SO₂NH₂, —

SO₂NR¹¹R¹², —

NR¹³SO₂R¹⁴ radical and a (C₁-C₆)alkyl group optionally substituted by one or more halogen atoms.

5. The pharmaceutical composition according to claim 4, wherein R¹ represents a cyclohexyl, cyclopentyl or benzyl group,

said group being optionally substituted by one or more groups selected from a halogen atom, a (C₁-C₆)alkoxy, —

NH₂, —

COOH, —

CN, —

OH, —

NR⁷R⁸, —

O—

(C₁-C₆)alkyl-NR⁷R⁸, benzyloxy, aryloxy, —

C(O)O—

(C₁-C₆)alkyl, —

NH—

C(O)O—

(C₁-C₆)alkyl, —

C(O)NH₂, —

C(O)NR⁹R¹⁰, —

S—

(C₁-C₆)alkyl, —

S(O)—

(C₁-C₆)alkyl, —

SO₂—

(C₁-C₆)alkyl, —

SO₂NH₂, —

SO₂NR¹¹R¹², —

NR¹³SO₂R¹⁴ radical and a (C₁-C₆)alkyl group optionally substituted by one or more halogen atoms.

6. The pharmaceutical composition according to claim 5, wherein R¹ represents a cyclohexyl, cyclopentyl or benzyl group,

said group being optionally substituted by one or more groups selected from a halogen atom and a (C₁-C₆)alkoxy, —

NH₂, —

COOH, benzyloxy, aryloxy, —

C(O)O((C₁-C₆)alkyl), —

NHC(O)O((C₁-C₆)alkyl) group.

7. The pharmaceutical composition according to claim 1, wherein —

NR1R2 represents the following piperazine ring;

8. The pharmaceutical composition according to claim 1, wherein R4 represents a (C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, phenyl, or thiophenyl group,

said group being optionally substituted by one or more groups selected from a halogen atom, a —

(CF₃)₂OH, —

CN, —

NH₂, —

OPO₃H₂, —

NR¹⁷R¹⁸, —

NO₂, —

COOH, —

OH, —

O(C₁-C₆)alkyl-OPO₃H₂, —

O—

(C₁-C₆)alkyl-O—

(C₁-C₆)alkyl, —

O(C₁-C₆)alkyl-NR¹⁹R²⁰, —

NR⁸¹(C₁-C₆)alkyl-NR⁸⁵R⁸⁶, benzyloxy, —

C(O)O—

(C₁-C₆)alkyl, —

NHC(O)O—

(C₁-C₆)alkyl, —

C(O)NH₂, —

C(O)NR²¹R²², —

S—

(C₁-C₆)alkyl, —

S(O)—

(C₁-C₆)alkyl, —

SO₂—

(C₁-C₆)alkyl, —

SO₂NH₂, —

SO₂NR²³R²⁴, —

NR²⁵SO₂R²⁶, 3 to 7-membered heterocycloalkyl, aryloxy radical, a (C₁-C₆)alkyl group optionally substituted by one or more halogen atoms and a (C₁-C₆)alkoxy optionally substituted by one or more fluorine atoms, and

the aryl and heteroaryl unit of said radical, when present, being optionally fused to a 5 or 6-membered heterocycle.

9. The pharmaceutical composition according to claim 1, wherein R³ represents a hydrogen atom and R⁴ represents an aryl or heteroaryl group

said group being optionally substituted by one or more groups selected from a halogen atom, a —

CF₃, —

B(OH)₂, —

CN, —

OH, —

NR¹⁷R¹⁸, —

NO₂, —

COOH, 3 to 7-membered heterocycloalkyl, (C₁-C₆)alkyl, —

S—

(C₁-C₆)alkyl, aryloxy, —

O(C₁-C₆)alkyl-NR¹⁹R²⁰ radical and a (C₁-C₆)alkoxy optionally substituted by one or more fluorine atoms, and

said group being optionally fused to a 5 or 6-membered heterocycle.

10. The pharmaceutical composition according to claim 9, wherein R4 represents a phenyl or thiophenyl group

said group being optionally substituted by one or more groups selected from a halogen atom, a —

CF₃, —

B(OH)₂, —

CN, —

OH, —

NR¹⁷R¹⁸, —

NO₂, —

COOH, 3 to 7-membered heterocycloalkyl, (C₁-C₆)alkyl, —

S—

(C₁-C₆)alkyl, aryloxy, —

O(C₁-C₆)alkyl-NR¹⁹R²⁰ radical and a (C₁-C₆)alkoxy optionally substituted by one or more fluorine atoms, and

said group being optionally fused to a 5 or 6-membered heterocycle.

11. The pharmaceutical composition according to claim 1, wherein R5 represents a (C₁-C₆)alkyl, heteroaryl, (C₃-C₁₀)cyclo alkyl-(C₁-C₆)alkyl, aryl-(C₁-C₆)alkyl or aryl group,

the aryl core of the aryl or aryl-(C₁-C₆)alkyl group being optionally fused to a 5 or 6-membered heterocycle, and being optionally substituted by one or more groups selected from a halogen atom, a —

CF₃, —

CN, —

NR²⁹R³⁰, —

NO₂, —

C(CF₃)₂OH, (C₁-C₆)alkoxy, aryloxy, (C₁-C₆)alkyl, (C₂-C₆)alkynyl, aryl and 5 or 6-membered heterocycloalkyl group.

12. The pharmaceutical composition according to claim 11, wherein the 5 or 6-membered heterocycle comprises two oxygen atoms.

13. The pharmaceutical composition according to claim 1, wherein the compound of formula (I) is selected from:

14. The pharmaceutical composition according to claim 1, further comprising at least one other active principle.

15. A pharmaceutical composition comprising:

(i) at least one compound of formula (I) as defined in claim 1, and

(ii) at least one other active principle,

as combination products for use simultaneously, separately or spread over time.

16. The pharmaceutical composition according to claim 14, wherein the at least one active principle is selected from cisplatin and the derivatives thereof;

vinca alkaloids;

purine analogues;

topoisomerase I inhibitors;

topoisomerase II inhibitors;

antitumoural nucleoside derivatives;

alkylating agents;

antitumoural anthracycline derivatives;

molecules targeting the IGF-I receptor;

tetracarcin derivatives;

corticosteroids;

antibodies;

selective oestrogen receptor antagonists or modulators;

aromatase inhibitors;

differentiating agents;

DNA methyltransferase inhibitors;

antifolates;

antibiotics;

antimetabolites;

apoptosis inducing agents and Bcl-2 inhibitor antiangiogenic agents;

agents binding to tubulin;

kinase inhibitors;

farnesyltransferase inhibitors;

histone deacetylase inhibitors;

inhibitors of the ubiquitin proteasome system; and

telomerase inhibitors.

17. The pharmaceutical composition according to claim 15, wherein the at least one active principle is selected from cisplatin and the derivatives thereof;

vinca alkaloids;

purine analogues;

topoisomerase I inhibitors;

topoisomerase II inhibitors;

antitumoural nucleoside derivatives;

alkylating agents;

antitumoural anthracycline derivatives;

molecules targeting the IGF-I receptor;

tetracarcin derivatives;

corticosteroids;

antibodies;

selective oestrogen receptor antagonists or modulators;

aromatase inhibitors;

differentiating agents;

DNA methyltransferase inhibitors;

antifolates;

antibiotics;

antimetabolites;

apoptosis inducing agents and Bcl-2 inhibitor antiangiogenic agents;

agents binding to tubulin;

kinase inhibitors;

farnesyltransferase inhibitors;

histone deacetylase inhibitors;

inhibitors of the ubiquitin proteasome system; and

telomerase inhibitors.

18. The pharmaceutical composition according to claim 16, wherein the cisplatin derivatives are selected from carboplatin and oxaliplatin;

the taxanes are selected from taxol, taxotere, paclitaxel and docetaxel;

the vinca alkaloids are selected from vinblastine, vincristine and vinorelbine;

the purine analogues are selected from mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine;

the topoisomerase I inhibitors are selected from compounds of camptothecin;

the topoisomerase II inhibitors are selected from epipodophyllotoxin, podophyllotoxin and the derivatives thereof;

thz antitumoural nucleoside derivatives are selected from 5-fluorouracil, leucovorin, gemcitabine and capecitabine;

the alkylating agents are selected from nitrogen mustards, nitrosoureas, alkyl sulphonates, ethyleneimines, methylmelamines, and tetrazines;

the antitumoural anthracycline derivatives are selected from daunorubicin, adriamycin, doxil, idarubicin and mitoxantrone;

the molecule targeting the IGF-I receptor is picropodophyllin;

the tetracarcin derivatives is tetrocarcin A;

the corticosteroid is prednisone;

the antibodies are selected from trastuzumab (anti-HER2 antibody), rituximab (anti-CD20 antibody), gemtuzamab, cetuximab, pertuzumab and bevacizumab;

the selective oestrogen receptor antagonists or modulators are selected from tamoxifen, fulvestrant, toremifene, droloxifene, faslodex and raloxifene;

the aromatase inhibitors are selected from exemestane, anastrozole, letrozole and vorozole;

the differentiating agents are selected from retinoids and retinoic acid metabolism blocking agents;

the DNA methyltransferase inhibitors are selected from azacytidine and decitabine;

the antifolate is disodium permetrexed;

the antibiotics are selected from antinomycin D, bleomycin, mitomycin C, actinomycin D, caminomycin, daunomycin and plicamycin;

the antimetabolites are selected from chlofarabine, aminopterin, cytosine arabinoside, floxuridine and methotrexate;

the apoptosis inducing agents and Bcl-2 inhibitor antiangiogenic agents are selected from YC 137, BH 312, ABT 737, gossypol, HA 14-1, TW 37 and decanoic acid;

the agents binding to tubulin are selected from combrestatin, colchicine derivatives and nocodazole;

the kinase inhibitors are selected from flavoperidol, imatinib mesylate, erlotinib and gefitinib;

the farnesyltransferase inhibitor is tipifarnib;

the histone deacetylase inhibitors are selected from sodium butyrate, suberoylanilide hydroxamic acid, depsipeptide, NVP-LAQ824, R306465, JNJ-26481585 and trichostatin A;

the inhibitors of the ubiquitin proteasome system are selected from MLN 0.41, bortezomib and yondelis; and

the telomerase inhibitor is telomestatin.

19. The pharmaceutical composition according to claim 17, wherein the cisplatin derivatives are selected from carboplatin and oxaliplatin;

the taxanes are selected from taxol, taxotere, paclitaxel and docetaxel;

the vinca alkaloids are selected from vinblastine, vincristine and vinorelbine;

the purine analogues are selected from mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine;

the topoisomerase I inhibitors are selected from compounds of camptothecin;

the topoisomerase II inhibitors are selected from epipodophyllotoxin, podophyllotoxin and the derivatives thereof;

thz antitumoural nucleoside derivatives are selected from 5-fluorouracil, leucovorin, gemcitabine and capecitabine;

the alkylating agents are selected from nitrogen mustards, nitrosoureas, alkyl sulphonates, ethyleneimines, methylmelamines, and tetrazines;

the antitumoural anthracycline derivatives are selected from daunorubicin, adriamycin, doxil, idarubicin and mitoxantrone;

the molecule targeting the IGF-I receptor is picropodophyllin;

the tetracarcin derivatives is tetrocarcin A;

the corticosteroid is prednisone;

the antibodies are selected from trastuzumab (anti-HER2 antibody), rituximab (anti-CD20 antibody), gemtuzamab, cetuximab, pertuzumab and bevacizumab;

the selective oestrogen receptor antagonists or modulators are selected from tamoxifen, fulvestrant, toremifene, droloxifene, faslodex and raloxifene;

the aromatase inhibitors are selected from exemestane, anastrozole, letrozole and vorozole;

the differentiating agents are selected from retinoids and retinoic acid metabolism blocking agents;

the DNA methyltransferase inhibitors are selected from azacytidine and decitabine;

the antifolate is disodium permetrexed;

the antibiotics are selected from antinomycin D, bleomycin, mitomycin C, actinomycin D, caminomycin, daunomycin and plicamycin;

the antimetabolites are selected from chlofarabine, aminopterin, cytosine arabinoside, floxuridine and methotrexate;

the apoptosis inducing agents and Bcl-2 inhibitor antiangiogenic agents are selected from YC 137, BH 312, ABT 737, gossypol, HA 14-1, TW 37 and decanoic acid;

the agents binding to tubulin are selected from combrestatin, colchicine derivatives and nocodazole;

the kinase inhibitors are selected from flavoperidol, imatinib mesylate, erlotinib and gefitinib;

the farnesyltransferase inhibitor is tipifarnib;

the histone deacetylase inhibitors are selected from sodium butyrate, suberoylanilide hydroxamic acid, depsipeptide, NVP-LAQ824, R306465, JNJ-26481585 and trichostatin A;

the inhibitors of the ubiquitin proteasome system are selected from MLN 0.41, bortezomib and yondelis; and

the telomerase inhibitor is telomestatin.

20. The pharmaceutical composition according to claim 19, wherein the compounds of camptothecin are selected from irinotecan and topotecan;

the podophyllotoxin derivatives are selected from etoposide and teniposide;

the nitrogen mustards are selected from cyclophosphamide, mechlorethamine, chlorambucil and melphalan;

the nitrosoureas are selected from carmustine, lomustine and streptozocin;

the alkyl sulphonate is busulphan;

the ethyleneimines and methylmelamines are selected from thiotepa and hexamethylmelamine;

the tetrazine is dacarbazine;

the retinoids are selected from retinoic acid and vitamin D; and

the retinoic acid metabolism blocking agent is accutane.

21. The pharmaceutical composition according to claim 19, wherein the compounds of camptothecin are selected from irinotecan and topotecan;

the podophyllotoxin derivatives are selected from etoposide and teniposide;

the nitrogen mustards are selected from cyclophosphamide, mechlorethamine, chlorambucil and melphalan;

the nitrosoureas are selected from carmustine, lomustine and streptozocin;

the alkyl sulphonate is busulphan;

the ethyleneimines and methylmelamines are selected from thiotepa and hexamethylmelamine;

the tetrazine is dacarbazine;

the retinoids are selected from retinoic acid and vitamin D; and

the retinoic acid metabolism blocking agent is accutane.

22. A method for treating a cancer comprising administering to a person in need thereof of an effective amount of a compound of formula (I) as defined in claim 1, wherein the cancer is selected from the group consisting of breast cancer, myeloma, and leukaemia.

23. The method according to claim 22, wherein the cancer is a cancer resistant to chemotherapy.

24. A compound of general formula (I):

25. The compound according to claim 24, selected from:

26. The method according to claim 23, wherein the cancer is resistant to adriamycin or doxorubicin.

27. A pharmaceutical composition comprising at least one compound of formula (I):

28. The pharmaceutical composition according to claim 27, wherein the compound of formula (I) is selected from: