PHARMACEUTICAL COMBINATIONS

• US 20130178479A1
• Filed: 10/03/2011
• Published: 07/11/2013
• Est. Priority Date: 10/04/2010
• Status: Abandoned Application

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Chen, Yan, Huang, Xizhong, Murphy, Leon, Nyfeller, Beat
• Application Number:
  US13/876,021
• Publication Number:
  US 20130178479A1
• Time in Patent Office: Days
• US Class Current: 514/253.03
• 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 31/4188 condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
• CPC Class Codes: A61K 31/436 the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• 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
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention relates to a pharmaceutical combination which comprises (a) an mTOR catalytic inhibitor, such as a catalytic phosphatidylinositol-3-kinase (PI3K) and mTOR inhibitor compound which is an imidazoquinoline derivative and (b) at least one allosteric mTOR inhibitor compound, and optionally, at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use, in particular for the treatment of an mammalian target of rapamycin (mTOR) kinase dependent proliferative diseases; and the uses of such a combination in the treatment of mTOR kinase dependent proliferative diseases; a pharmaceutical composition comprising such a combination; the use of such a combination for the preparation of a medicament for the treatment of a proliferative disease; a commercial package or product comprising such a combination as a combined preparation for simultaneous, separate or sequential use; and to a method of treatment of a warm-blooded animal, especially a human.

Claims

1. A pharmaceutical combination comprising:

a) a compound of formula (I)

2. A pharmaceutical combination of claim 1 wherein the compound of formula (I) is 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile (Compound A) and its monotosylate salt.

3. A pharmaceutical combination of claim 1 wherein the compound of formula (I) is 8-(6-methoxy-pyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Compound B).

4. A pharmaceutical combination according to claim 1 wherein the allosteric mTOR inhibitor compound is selected from RAD rapamycin (sirolimus) and derivatives/analogs thereof such as everolimus (or RAD001);

CCI-779 and Deferolimus (AP-23573/MK-8669).

5. A pharmaceutical combination of claim 4, wherein the allosteric mTOR inhibitor compound is everolimus (RAD001) which is administered to a subject in need thereof in an amount between administered from about 0.001 nM to about 17.8 nM or from about 8.5×

10<sup>−

12</sup> Mole/kg to about 1.5×

10<sup>−

7</sup> Mole/kg, or from about 0.00056 mg/subject to about 10 mg/subject per daily dose.

6. A pharmaceutical combination of claim 1, wherein the proliferative disease is an mTOR kinase dependent proliferative disease.

7. A pharmaceutical combination of claim 1, wherein the proliferative disease is a benign or malignant tumor, carcinoma of the breast, brain, kidney, liver, adrenal gland, bladder, stomach, ovaries, colon, rectum, pancreas, lung (e.g., non small cell lung cancer), endometrial, non-Hodgkin'"'"'s B-cell lymphoma, vagina or thyroid, sarcoma, glioblastomas, multiple myeloma or or gastric gastrointestinal cancer, especially colon carcinoma or colorectal adenoma or a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, neuroendicrine, a neoplasia, a neoplasia of epithelial character, lymphomas, a mammary carcinoma or a leukemia.

13. A pharmaceutical composition comprising the pharmaceutical combination according to claim 1.

15. A pharmaceutical combination according to claim 13, wherein the allosteric mTOR inhibitor compound is everolimus (RAD001) which is administered to a subject in need thereof in an amount between administered from about 0.001 nM to about 17.8 nM or from about 8.5×

10<sup>−

12</sup> Mole/kg to about 1.5×

10<sup>−

7</sup> Mole/kg, or from about 0.00056 mg/subject to about 10 mg/subject per daily dose.

16. A method for improving efficacy of the treatment of a mammalian target of rapamycin (mTOR) kinase dependent proliferative disease comprising administering a combination comprising a compound of formula (I) according to claim 1 or a tautomer thereof, or a pharmaceutically acceptable salt, or a hydrate or solvate thereof, and at least one allosteric mTOR inhibitor compound to subject in need thereof, wherein the compound of formula (I) is administered to a subject in need thereof in an amount between about 1 nM to about 100 nM or about 9.5×

10<sup>−

8</sup> to about 9.5×

10<sup>−

6</sup> Mole/kg or about 3 to about 315 mg/subject per daily dose.

17. A method for treating or preventing a proliferative disease comprising administering to a subject in need thereof (a) a therapeutically effective amount of a compound of formula (I) according to claim 1 or a tautomer thereof, or a pharmaceutically acceptable salt, or a hydrate or solvate thereof, and (b) a therapeutically effective amount of at least one allosteric mTOR inhibitor compound and optionally at least one pharmaceutically acceptable carrier, wherein the compound of formula (I) is administered in an amount between about 1 nM to about 100 nM or about 9.5×

10<sup>−

8</sup> to about 9.5×

10<sup>−

6</sup> Mole/kg or about 3 to about 315 mg/subject per daily dose.

18. A method according to claim 17, wherein the compound of formula (I) is 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile (Compound A) or its monotosylate salt.

19. A method according to claim 17, wherein the mTOR inhibitor is selected from RAD rapamycin (sirolimus) and derivatives/analogs thereof such as everolimus (or RAD001);

CCI-779 and Deferolimus (AP-23573/MK-8669).

20. A method according to claim 17, wherein the allosteric mTOR inhibitor compound is everolimus (RAD001) which is administered to a subject in need thereof in an amount between administered from about 0.001 nM to about 17.8 nM or from about 8.5×

10<sup>−

12</sup> Mole/kg to about 1.5×

10<sup>−

7</sup> Mole/kg, or from about 0.00056 mg/subject to about 10 mg/subject per daily dose.

21. A method according to claim 17, wherein the proliferative disease is a benign or malignant tumor, carcinoma of the breast, brain, kidney, liver, adrenal gland, bladder, stomach, ovaries, colon, rectum, pancreas, lung (e.g., non small cell lung cancer), endometrial, non-Hodgkin'"'"'s B-cell lymphoma, vagina or thyroid, sarcoma, glioblastomas, multiple myeloma or gastric or gastrointestinal cancer, especially colon carcinoma or colorectal adenoma or a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, neuroendocrine, a neoplasia, a neoplasia of epithelial character, lymphomas, a mammary carcinoma or a leukemia.

8-12. -12. (canceled)

14. A pharmaceutical combination comprising 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile (Compound A) and an mTOR inhibitor selected from the group consisting of RAD rapamycin (sirolimus) and derivatives/analogs thereof such as everolimus (or RAD001);

CCI-779 and Deferolimus (AP-23573/MK-8669), wherein the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt, and optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate or sequential use for the treatment of benign or malignant tumor, carcinoma of the breast, brain, kidney, liver, adrenal gland, bladder, stomach, ovaries, colon, rectum, pancreas, lung (e.g., non small cell lung cancer), endometrial, non-Hodgkin'"'"'s B-cell lymphoma, vagina or thyroid, sarcoma, glioblastomas, multiple myeloma or gastric or gastrointestinal cancer, colon carcinoma or colorectal adenoma or a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, neuroendicrine, a neoplasia, a neoplasia of epithelial character, lymphomas, a mammary carcinoma or a leukemia, wherein Compound A is administered to a subject in need thereof in an amount between about 1 nM to about 100 nM or about 9.5×

10<sup>−

8</sup> to about 9.5×

10<sup>−

6</sup> Mole/kg or about 3 to about 315 mg/subject per daily dose.