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Patent Application

App. No. 10/542,088

Pde4 inhibitors for the treatment of neoplasms of lymphoid cells

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Patent No.: US None
App. No.: 10/542,088

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Abstract

The invention relates to the use of certain PDE4 inhibitors alone or in combination with one or more differentiation inducing agents and/or an agent effective in raising intracellular concentrations of cAMP or a stable analogue of cAMP in the preparation of pharmaceutical compositions for the treatment of neoplasms of lymphoid cells.

Claims (62)

1 .- 38 . (canceled)

39 . A method of treating neoplasms of lymphoid cells in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound selected from the group consisting of

N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide [INN: PICLAMILAST], 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST], 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloro-1-oxy-pyrid-4-yl)-benzamide (Roflumilast-N-Oxide), 3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine [Research Code: V-11294A], N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide [Research Code: CI-1018), 3,7-dihydro-3-(4-chlorophenyl)-1-propyl-1H-purine-2,6-dione [INN: AROFYLLINE], N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide [Research Code: AWD-12-281], N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide [Research Code: AWD-12-343], Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]-2(1H)-pyrimidone [INN: ATIZORAM]; β-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide [Research Code: CDC-801], Methanesulfonic acid 2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN: LIRIMILAST], 3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinolin-5-ylcarbox-amido]pyridine-1-oxide [Research Code: SCH-351591], cis-4-cyano-4-[3-cyclopentyloxy-4-methoxyphenyl]cyclohexane-1-carboxylic acid [INN: Cilomilast],

a compound with the research code CDC-998, D-4396, IC-485, CC-1088 or KW4490,

and pharmaceutically acceptable salts thereof.

40 . A method for treating neoplasms of lymphoid cells in a mammal, comprising administering to said mammal therapeutically effective amounts of

(i) a compound selected from the group consisting of N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide [INN: PICLAMILAST], 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST], 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloro-1-oxy-pyrid-4-yl)-benzamide (Roflumilast-N-Oxide), 3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine [Research Code: V-11294A], N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzo-diazepin-3(R)-yl]pyridine-4-carboxamide [Research Code: CI-1018], 3,7-dihydro-3-(4-chlorophenyl)-1-propyl-1H-purine-2,6-dione [INN: AROFYLLINE], N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide [Research Code: AWD-12-281], N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide [Research Code: AWD-12-343], Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]-2(1H)-pyrimidone [INN: ATIZORAM]; β-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide [Research Code: CDC-801], Methanesulfonic acid 2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN: LIRIMILAST], 3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinolin-5-ylcarbox-amido]pyridine-1-oxide [Research Code: SCH-351591], cis-4-cyano-4-[3-cyclopentyloxy-4-methoxyphenyl]cyclohexane-1-carboxylic acid [INN: Cilomilast],

a compound with the research code CDC-998, D-4396, IC-485, CC-1088 or KW4490,

and pharmaceutically acceptable salts thereof,

and (ii) one or more differentiation inducing agents and/or an agent effective in raising intracellular concentrations of cAMP or a stable analogue thereof.

41 . A method for treating neoplasms of lymphoid cells in a mammal, comprising administering to said mammal therapeutically effective amounts of

a compound with the research code CDC-998, D-4396, IC-485, CC-1088 or KW4490,

and pharmaceutically acceptable salts thereof,

and (ii) one or more differentiation inducing agents.

42 . A method for treating neoplasms of lymphoid cells in a mammal, comprising administering to said mammal therapeutically effective amounts of

a compound with the research code CDC-998, D-4396, IC-485, CC-1088 or KW4490,

and pharmaceutically acceptable salts thereof,

and (ii) an agent effective in raising intracellular concentrations of cAMP or a stable analogue thereof.

43 . (canceled)

44 . The method according to claim 39 , wherein the compound of component (i) is selected from the group consisting of N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide [Research Code: AWD-12-281], cis-4-cyano-4-[3-cyclopentyloxy-4-methoxyphenyl]cyclohexane-1-carboxylic acid [INN: Cilomilast], 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST], 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloro-1-oxy-pyrid-4-yl)-benzamide (Roflumilast-N-Oxide) and pharmaceutically acceptable salts thereof.

45 . The method according to claim 39 , wherein the compound of component (i) is selected from the group consisting of 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST], 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloro-1-oxy-pyrid-4-yl)-benzamide (Roflumilast-N-Oxide) and pharmaceutically acceptable salts thereof.

46 . The method according to claim 39 , wherein the compound of component (i) is 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST] or a pharmaceutically acceptable salt thereof.

47 . The method according to claim 39 , wherein the compound of component (i) is 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloro-1-oxy-pyrid-4-yl)-benzamide (Roflumilast-N-Oxide) or a pharmaceutically acceptable salt thereof.

48 . The method according to claim 39 , wherein the compound of component (i) is N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide [Research Code: AWD-12-281] or a pharmaceutically acceptable salt thereof.

49 . The method according to claim 39 , wherein the compound of component (i) is cis-4-cyano-4-[3-cyclopentyloxy-4-methoxyphenyl]cyclohexane-1-carboxylic acid [INN: Cilomilast] or a pharmaceutically acceptable salt thereof.

50 .- 61 . (canceled)

62 . A treatment combination for neoplasms of lymphoid cells, comprising: therapeutically effective amounts of

a compound with the research code CDC-998, D-4396, IC-485, CC-1088 or KW4490

and pharmaceutically acceptable salts thereof,

and (ii) one or more differentiation inducing agents and/or an agent effective in raising intracellular concentrations of cAMP or a stable analogue of cAMP.

63 . A treatment combination for neoplasms of lymphoid cells, comprising: therapeutically effective amounts of

a compound with the research code CDC-998, D-4396, IC-485, CC-1088 or KW4490

and pharmaceutically acceptable salts thereof,

and (ii) one or more differentiation inducing agents.

64 . A treatment combination for neoplasms of lymphoid cells, comprising: therapeutically effective amounts of

a compound with the research code CDC-998, D-4396, IC-485, CC-1088 or KW4490

and pharmaceutically acceptable salts thereof,

and (ii) an agent effective in raising intracellular concentrations of cAMP or a stable analogue of cAMP.

65 . The treatment combination according to claim 62 , wherein the compound of component (i) is selected from the group consisting of

N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide [Research Code: AWD-12-281], cis-4-cyano-4-[3-cyclopentyloxy-4-methoxyphenyl]cyclohexane-1-carboxylic acid [INN: Cilomilast], 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST], 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloro-1-oxy-pyrid-4-yl)-benzamide (Roflumilast-N-Oxide) and pharmaceutically acceptable salts thereof.

66 . The treatment combination according to claim 62 , wherein the compound of component (i) is selected from the group consisting of 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide (INN: ROFLUMILAST], 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloro-1-oxy-pyrid-4-yl)-benzamide (Roflumilast-N-Oxide) and pharmaceutically acceptable salts thereof.

67 . The treatment combination according to claim 62 , wherein the compound of component (i) is 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST] or a pharmaceutically acceptable salt thereof.

68 . The treatment combination according to claim 62 , wherein the compound of component (i) is 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloro-1-oxy-pyrid-4-yl)-benzamide (Roflumilast-N-Oxide) or a pharmaceutically acceptable salt thereof.

69 . The treatment combination according to claim 62 , wherein the compound of component (i) is N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide [Research Code: AWD-12-281] or a pharmaceutically acceptable salt thereof.

70 . The treatment combination according to claim 62 , wherein the compound of component (i) is cis-4-cyano-4-[3-cyclopentyloxy-4-methoxyphenyl]cyclohexane-1-carboxylic acid [INN: Cilomilast] or a pharmaceutically acceptable salt thereof.

71 .- 74 . (canceled)

75 . The method according to claim 40 , wherein the differentiation inducing agent is selected from the group consisting of all trans retinoic acid, 13-cis-retinoic acid, CD437, rexinoids, histone deacetylase inhibitors, DNA methyltransferase inhibitors, hematopoietic growth factors, interferon α, interleukin 1, TRAIL, hexamethylene bisacetamide, cholecalciferol, arsenic trioxide, green tea catechin epigallocatechin-3-gallate, DNA topoisomerase II inhibitors, taraxinic acid, verticinone, PPAR-gamma agonists, antibodies versus CD19, CD20 or CD22, CD33-antibodies alone or as conjugate, alkylating cytostatika, purine analogs, cytosine-arabinosides, anticylines, vinca-alkaloids and glucocorticosteroids.

76 . The method according to claim 40 , wherein the differentiation inducing agent is a histone deacetylase inhibitor.

77 . The method according to claim 40 , wherein the differentiation inducing agent is all trans retinoic acid.

78 . The method according to claim 40 , wherein the agent effective in raising intracellular concentrations of cAMP is selected from the group consisting of prostaglandin E2, prostacyclin derivatives, dopamine, dobutamine, β2-adrenoreceptor agonists, adenosine A1 receptor agonists, adenosine A2 receptor agonists and forskolin.

79 . A treatment combination according to claim 62 , wherein the differentiation inducing agent is selected from the group consisting of all trans retinoic acid, 13-cis-retinoic acid, CD437, rexinoids, histone deacetylase inhibitors, DNA methyltransferase inhibitors, hematopoietic growth factors, interferon α, interleukin 1, TRAIL, hexamethylene bisacetamide, cholecalciferol, arsenic trioxide, green tea catechin epigallocatechin-3-gallate, DNA topoisomerase II inhibitors, taraxinic acid, verticinone, PPAR-gamma agonists, antibodies versus CD19, CD20 or CD22, CD33-antibodies alone or as conjugate, alkylating cytostatika, purine analogs, cytosine-arabinosides, anticylines, vinca-alkaloids and glucocorticosteroids.

80 . A treatment combination according to claim 62 , wherein the agent effective in raising intracellular concentrations of cAMP is selected from the group consisting of prostaglandin E2, prostacyclin derivatives, dopamine, dobutamine, β2-adrenoreceptor agonists, adenosine A1 receptor agonists, adenosine A2 receptor agonists and forskolin.

81 . A treatment combination according to claim 62 , wherein the differentiation inducing agent is a histone deacetylase inhibitor.

82 . A treatment combination according to claim 62 , wherein the differentiation inducing agent is all trans retinoic acid.

83 . (canceled)

84 . The method according to claim 39 , wherein the neoplasm of lymphoid cells is leukemia.

85 . The treatment combination according to claim 62 , wherein the neoplasm of lymphoid cells is leukemia.

Assignments (2)

CHANGE OF NAME Recorded Sep 4, 2007

From: ALTANA PHARMA AG

To: NYCOMED GMBH

Reel/Frame 019783/0625 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 14, 2005

From: BRAUNGER, JURGEN; SCHUDT, CHRISTIAN

To: ALTANA PHARMA AG

Reel/Frame 016882/0901 →