Treatment of multiple myeloma by p38 MAP kinase and proteasome inhibition

• US 20060052390A1
• Filed: 08/19/2005
• Published: 03/09/2006
• Est. Priority Date: 12/24/2003
• Status: Abandoned Application

• Current Assignee: Scios, Inc. (Johnson & Johnson)
• Original Assignee: Scios, Inc. (Johnson & Johnson)
• Inventors: Schreiner, George F., Protter, Andrew A., Higgins, Linda S.
• Application Number:
  US11/208,055
• Publication Number:
  US 20060052390A1
• Time in Patent Office: Days
• US Class Current: 514/254.60
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Abstract

The present invention provides a method to treat multiple myeloma by the co-administration of one or more p38 MAP kinase inhibitors with one or more proteosome inhibitors.

Claims

1. A method to treat multiple myeloma in a subject, comprising:

co-administering to a subject in need of such treatment a therapeutically effective amount of a p38 inhibitor and a therapeutically effective amount of a proteasome inhibitor, whereby a symptom associated with multiple myeloma is ameliorated.

2. The method of claim 1, wherein the p38 inhibitor is of the formula:

and the pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, wherein

represents a single or double bond;

one Z² is CA or CR⁶A and the other is CR¹ or CR¹₂, wherein each R¹ is independently hydrogen is alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, NH-aroyl, halo, OR, NR₂, SR, SOR, SO₂R, OCOR, NRCOR, NRCONR₂, NRCOOR, OCONR₂, RCO, COOR, alkyl-OOCR, SO₃R, CONR₂, SO₂NR₂, NRSO₂NR₂, CN, CF₃, R₃Si, and NO₂, wherein each R is independently H, alkyl, alkenyl or aryl or the heteroforms thereof;

R⁶ is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, SOR, SO₂R, RCO, COOR, alkyl-COR, SO₃R, CONR₂, SO₂NR₂, CN, CF₃, or R₃Si wherein each R is independently H, alkyl, alkenyl or aryl or the heteroforms thereof;

A is —

W_i—

COX_jY wherein Y is COR² wherein R² is hydrogen, straight or branched chain alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl, each optionally substituted with halo, alkyl, SR, OR, NR₂, OCOR, NRCOR, NRCONR₂, NRSO₂R, NRSO₂NR₂, OCONR₂, CN, COOR, CONR₂, COR, or R₃Si wherein each R is independently H, alkyl, alkenyl or aryl or the heteroforms thereof;

or

wherein R² is OR, NR₂, NRCONR₂, OCONR₂, NRSO₂NR₂, heteroarylalkyl, COOR, NRNR₂, heteroaryl, heteroaryloxy, heteroaryl-NR, or NROR wherein each R is independently H, alkyl, alkenyl or aryl or the heteroforms thereof, and wherein two R attached to the same N atom may form a 3-8 member ring and wherein said ring may further be substituted by alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroalkyl, heteroarylalkyl, each optionally substituted with halo, SR, OR, NR₂, OCOR, NRCOR, NRCONR₂, NRSO₂R, NRSO₂NR₂, OCONR₂, or R₃Si wherein each R is independently H, alkyl, alkenyl or aryl or the heteroforms thereof wherein two R attached to the same atom may form a 3-8 member ring, optionally substituted as above defined, and

each of W and X is substituted or unsubstituted alkylene or alkenylene, each of 2-6 Å

, or

Y is tetrazole;

1,2,3-triazole;

1,2,4-triazole;

or imidazole;

each of i and j is independently 0 or 1;

Z³ is NR⁷ or O;

R⁷ is H or is optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, or heteroalkylaryl, or is SOR, SO₂R, RCO, COOR, alkyl-COR, SO₃R, CONR₂, SO₂NR₂, CN, CF₃, NR₂, OR, alkyl-SR, alkyl-SOR, alkyl-SO₂R, alkyl-OCOR, alkyl-COOR, alkyl-CN, alkyl-CONR₂, or R₃Si, wherein each R is independently H, alkyl, alkenyl or aryl or heteroforms thereof;

each R³ is independently halo, alkyl, heteroalkyl, OCOR, OR, NRCOR, SR, or NR₂, wherein R is H, alkyl or aryl or the heteroforms thereof;

n is 0-3;

L¹ is CO, SO₂ or alkylene (1-4C);

L² is alkylene (1-4C) or alkenylene (2-4C) optionally substituted with one or two moieties selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, NH-aroyl, halo, OR, NR₂, SR, SOR, SO₂R, OCOR, NRCOR, NRCONR₂, NRCOOR, OCONR₂, RCO, COOR, alkyl-OOCR, SO₃R, CONR₂, SO₂NR₂, NRSO₂NR₂, CN, CF₃, and R₃Si, wherein each R is independently H, alkyl, alkenyl or aryl or the heteroforms thereof, and wherein two substituents on L² can be joined to form a non-aromatic saturated or unsaturated ring that includes 0-3 heteroatoms which are O, S and/or N and which contains 3 to 8 members or said two substituents can be joined to form a carbonyl moiety or an oxime, oximeether, oximeester or ketal of said carbonyl moiety;

each R⁴ is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, NH-aroyl, halo, OR, NR₂, SR, SOR, SO₂R, OCOR, NRCOR, NRCONR₂, NRCOOR, OCONR₂, RCO, COOR, alkyl-OOCR, SO₃R, CONR₂, SO₂NR₂, NRSO₂NR₂, CN, CF₃, R₃Si, and NO₂, wherein each R is independently H, alkyl, alkenyl or aryl or the heteroforms thereof, and two of R⁴ on adjacent positions can be joined to form a fused, optionally substituted aromatic or nonaromatic, saturated or unsaturated ring which contains 3-8 members, or R⁴ is ═

O or an oxime, oximeether, oximeester or ketal thereof;

m is 0-4;

Z¹ is CR⁵ or N wherein R⁵ is hydrogen or OR, NR₂, SR or halo, wherein each R is independently H, alkyl, alkenyl or aryl or the heteroforms thereof;

each of 1 and k is an integer from 0-2 wherein the sum of 1 and k is 0-3;

Ar is an aryl group substituted with 0-5 noninterfering substituents selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, NH-aroyl, halo, OR, NR₂, SR, SOR, SO₂R, OCOR, NRCOR, NRCONR₂, NRCOOR, OCONR₂, RCO, COOR, alkyl-OOCR, SO₃R, CONR₂, SO₂NR₂, NRSO₂NR₂, CN, CF₃, R₃Si, and NO₂, wherein each R is independently H, alkyl, alkenyl or aryl or the heteroforms thereof, and wherein two of said optional substituents on adjacent positions can be joined to form a fused, optionally substituted aromatic or nonaromatic, saturated or unsaturated ring which contains 3-8 members.

3. The method of claim 1, wherein the proteasome inhibitor is selected from the group consisting of epoxomicin ((2R)-2-[Acetyl-(N-Methyl-L-Isoleucyl)-L-Isoleucyl-L-Threonyl-L-Leucyl]-2-Methyloxirane);

lactacystin(N-Acetyl-L-Cysteine, S-[2R,3S,4R]-3-Hydroxy-2-[(1S)-1-Hydroxy-2-Methylpropyl]-4-Methyl-5-Oxo-2-Pyrolidinecarbonyl]);

Z-Ile-Glu(OtBu)-Ala-Leu-H(Carbobenzoxy-L-Isoleucyl-Gamma-t-Butyl-L-Glutamyl-L-Alanyl-L-Leucinal;

Z-Leu-Leu-Leu-H [MG 132](Carbobenzoxy-L-Leucyl-L-Leucyl-L-Leucinal); and

Z-Leu-Leu-Nva-H [MG 115] (Carbobenzoxy-L-Leucyl-L-Leucyl-L-Norvalinal).

4. The method of claim 1, wherein the proteasome inhibitor is bortezombid (VELCADE), thalidomide or REVIMID.

5. The method of claim 1, wherein the symptom comprises a rate of MM cell growth which is reduced as compared to the MM cell growth rate of untreated MM cells.

6. The method of claim 1, wherein the symptom comprises production of a MM-related cytokine, which is reduced.

7. The method of claim 6, wherein the MM-related cytokine is selected from the group consisting of IL-6, VEGF, IL-11, and PGE-2.

8. The method of claim 1, wherein the p38 MAPK inhibitor and the proteasome inhibitor are administered simultaneously.

9. A method of inhibiting cytokine secretion from multiple myeloma cells, comprising:

providing a p38 MAP kinase inhibitor and a proteasome inhibitor a subject suffering from MM, wherein the secretion rate of a MM-related cytokine is reduced as compared to the secretion rate of a MM-related cytokine of untreated MM cells.

10. The method of claim 9, wherein the MM-related cytokine is selected from the group consisting of IL-6, VEGF, IL-11, and PGE-2.

11. The method of claim 9, wherein the p38 inhibitor is of the formula:

and the pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, wherein

represents a single or double bond;

one Z² is CA or CR⁸A and the other is CR¹, CR¹₂, NR⁶ or N wherein each R¹, R⁶ and R⁸ is independently hydrogen or noninterfering substituent;

A is —

W_i—

COX_jY wherein Y is COR² or an isostere thereof and R² is hydrogen or a noninterfering substituent, each of W and X is a spacer of 2-6 Å

, and each of i and j is independently 0 or 1;

Z³ is NR⁷ or O;

each R³ is independently a noninterfering substituent;

n is 0-3;

each of L¹ and L² is a linker;

each R⁴ is independently a noninterfering substituent;

m is 0-4;

Z¹ is CR⁵ or N wherein R⁵ is hydrogen or a noninterfering substituent;

each of 1 and k is an integer from 0-2 wherein the sum of 1 and k is 0-3;

Ar is an aryl group substituted with 0-5 noninterfering substituents, wherein two noninterfering substituents can form a fused ring.

12. The method of claim 9, wherein the proteasome inhibitor is selected from the group consisting of epoxomicin ((2R)-2-[Acetyl-(N-Methyl-L-Isoleucyl)-L-Isoleucyl-L-Threonyl-L-Leucyl]-2-Methyloxirane);

lactacystin(N-Acetyl-L-Cysteine, S-[2R,3S,4R]-3-Hydroxy-2-[(1S)-1-Hydroxy-2-Methylpropyl]-4-Methyl-5-Oxo-2-Pyrolidinecarbonyl]);

Z-Ile-Glu(OtBu)-Ala-Leu-H(Carbobenzoxy-L-Isoleucyl-Gamma-t-Butyl-L-Glutamyl-L-Alanyl-L-Leucinal;

Z-Leu-Leu-Leu-H [MG 132](Carbobenzoxy-L-Leucyl-L-Leucyl-L-Leucinal); and

Z-Leu-Leu-Nva-H [MG 115] (Carbobenzoxy-L-Leucyl-L-Leucyl-L-Norvalinal).

13. The method of claim 9, wherein the proteasome inhibitor is bortezombid (VELCADE), thalidomide or REVIMID.

14. The method of claim 9, wherein the p38 MAPK inhibitor and the proteasome inhibitor are administered simultaneously.

15. A method of overcoming drug resistance in MM tumor cells comprising:

identifying a drug resistant MM tumor cell; and

providing a p38 MAPK inhibitor and a chemotherapeutic agent effective in inhibiting MM cell growth, whereby a synergistic interaction of the p38 MAPK inhibitor and the chemotherapeutic agent overcome the drug resistance of the MM tumor cells.

16. The method of claim 15, wherein the p38 inhibitor is of the formula:

and the pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, wherein

represents a single or double bond;

one Z² is CA or CR⁸A and the other is CR¹, CR¹₂, NR⁶ or N wherein each R¹, R⁶ and R⁸ is independently hydrogen or noninterfering substituent;

A is —

W_i—

COX_jY wherein Y is COR² or an isostere thereof and R² is hydrogen or a noninterfering substituent, each of W and X is a spacer of 2-6 Å

, and each of i and j is independently 0 or 1;

Z³ is NR⁷or O;

each R³ is independently a noninterfering substituent;

n is 0-3;

each of L¹ and L² is a linker;

each R⁴ is independently a noninterfering substituent;

m is 0-4;

Z¹ is CR⁵ or N wherein R⁵ is hydrogen or a noninterfering substituent;

each of 1 and k is an integer from 0-2 wherein the sum of I and k is 0-3;

Ar is an aryl group substituted with 0-5 noninterfering substituents, wherein two noninterfering substituents can form a fused ring.

17. The method of claim 15, wherein the proteasome inhibitor is selected from the group consisting of epoxomicin((2R)-2-[Acetyl-(N-Methyl-L-Isoleucyl)-L-Isoleucyl-L-Threonyl-L-Leucyl]-2-Methyloxirane);

lactacystin(N-Acetyl-L-Cysteine, S-[2R,3S,4R]-3-Hydroxy-2-[(1S)-1-Hydroxy-2-Methylpropyl]-4-Methyl-5-Oxo-2-Pyrolidinecarbonyl]);

Z-Ile-Glu(OtBu)-Ala-Leu-H(Carbobenzoxy-L-Isoleucyl-Gamma-t-Butyl-L-Glutamyl-L-Alanyl-L-Leucinal;

Z-Leu-Leu-Leu-H [MG 132](Carbobenzoxy-L-Leucyl-L-Leucyl-L-Leucinal); and

Z-Leu-Leu-Nva-H [MG 115] (Carbobenzoxy-L-Leucyl-L-Leucyl-L-Norvalinal).

18. The method of claim 15, wherein the proteasome inhibitor is bortezombid (VELCADE), thalidomide or REVIMID.

19. The method of claim 15, wherein the p38 MAPK inhibitor and the proteasome inhibitor are administered simultaneously.

20. The method of claim 15, wherein the p38 MAPK inhibitor and the chemotherapeutic agent are provided to a subject containing one or more drug resistant MM tumor cells.