Pharmaceutical Uses of Staurosporine Derivatives

• US 20070299049A1
• Filed: 06/17/2004
• Published: 12/27/2007
• Est. Priority Date: 06/18/2003
• Status: Active Grant

• Current Assignee: Novartis Pharmaceuticals Corporation (Novartis Ag)
• Original Assignee: Novartis Ag
• Inventors: Coutre, Steven
• Granted Patent: US 8,575,146 B2
• Time in Patent Office: Days
• US Class Current: 514/211.08
• CPC Class Codes: A61K 31/553 having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: A61P 27/14 Decongestants or antiallergics
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/10 Antioedematous agents; Diuretics
• CPC Class Codes: C07D 498/16 Peri-condensed systems

Abstract

This application relates to the use of staurosporines derivatives for the curative, palliative or prophylactic treatment of allergic rhinitis, allergic dermatitis, drug allergy or food allergy, angioedema, urticaria, sudden infant death syndrome, bronchopulmonary aspergillosis, multiple sclerosis, or mastocytosis; and to a method of treatment of warm-blooded animals in which a therapeutically effective dose of a compound of a Staurosporine Derivative is administered to a warm-blooded animal suffering from one of the diseases or conditions mentioned above.

Claims

1. Use of staurosporine derivatives of formula,

wherein R₁ , and R₂ are, independently of one another, unsubstituted or substituted alkyl, hydrogen, halogen, hydroxy, etherified or esterified hydroxy, amino, mono- or disubstituted amino, cyano, nitro, mercapto, substituted mercapto, carboxy, esterified carboxy, carbamoyl, N-mono- or N,N-di-substituted carbamoyl, sulfo, substituted sulfonyl, aminosulfonyl or N-mono- or N,N-di-substituted am inosulfonyl;

n and m are, independently of one another, a number from and including 0 to and including 4;

R₅ is hydrogen, an aliphatic, carbocyclic, or carbocyclic-aliphatic radical with up to 29 carbon atoms in each case, or a heterocyclic or heterocyclic-aliphatic radical with up to 20 carbon atoms in each case, and in each case up to 9 heteroatoms, or acyl with up to 30 carbon atoms;

X stands for 2 hydrogen atoms;

for 1 hydrogen atom and hydroxy;

for O;

or for hydrogen and lower alkoxy;

Q and Q′

are independently a pharmaceutically acceptable organic bone or hydrogen, halogen, hydroxy, etherified or esterified hydroxy, amino, mono- or disubstituted amino, cyano, nitro, mercapto, substituted mercapto, carboxy, esterified carboxy, carbamoyl, N-mono- or N,N-di-substituted carbamoyl, sulfa, substituted sulfonyl, aminosulfonyl or N-mono- or N,N-di-substituted aminosulfonyl;

or a salt thereof, if at least one salt-forming group is present, or hydrogenated derivative thereof, for the preparation of a pharmaceutical composition for the curative, palliative or prophylactic treatment of allergic rhinitis, allergic dermatitis, drug allergy or food allergy, angioedema, urticaria, sudden infant death syndrome, bronchopulmonary aspergillosis, multiple sclerosis, or mastocytosis.

4. Use according to claim 1 for the treatment of mastocytosis.

5. Use according to claim 4, wherein the disease or condition to be treated is resistant to treatment with imatinib.

6. A method for treating mammals suffering for the curative, palliative or prophylactic treatment of allergic rhinitis, allergic dermatitis, drug allergy or food allergy, angioedema, urticaria, sudden infant death syndrome, bronchopulmonary aspergillosis, multiple sclerosis, or mastocytosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of staurosporine derivatives as defined in claim 1.

7. A method according to claim 6 for treating mastoctosis with resistance to imatinib.

19. Use of a staurosporine derivative according to claim 1 in combination with imatinib, wherein each of the active ingredients, independent of each other, may be present in free form or in the form of a pharmaceutically acceptable salt, for the treatment of allergic rhinitis, allergic dermatitis, drug allergy or food allergy, angioedema, urticaria, sudden infant death syndrome, bronchopulmonary aspergillosis, multiple sclerosis, or mastocytosis.

2. The use of a staurosporin derivative selected from the compounds of formula,

wherein R₁ and R₂, are, independently of one another, unsubstituted or substituted alkyl, hydrogen, halogen, hydroxy, etherified or esterified hydroxy, amino, mono- or disubstituted amino, cyano, nitro, mercapto, substituted mercapto, carboxy, esterified carboxy, carbamoyl, N-mono- or N,N-di-substituted carbamoyl, sulfa, substituted sulfonyl, aminosulfonyl or N-mono- or N,N-di-substituted aminosulfonyl;

n and m are, independently of one another, a number from and including 0 to and including 4;

n′ and

m′

are, independently of one another, a number from and including 1 to and including 4;

R₃, R₄, R₈ and R₁₀ are, independently of one another, hydrogen, an aliphatic, carbocyclic, or carbocyclic-aliphatic radical with up to 29 carbon atoms in each case, a heterocyclic or heterocyclic-aliphatic radical with up to 20 carbon atoms in each case, and in each case up to 9 heteroatoms, an acyl with up to 30 carbon atoms, wherein R4 may also be absent;

or R₃ is acyl with up to 30 carbon atoms and R₄ not an acyl;

p is 0 if R₄ is absent, or is 1 if R₃ and R₄ are both present and in each case are one of the aforementioned radicals;

R₅ is hydrogen, an aliphatic, carbocyclic, or carbocyclic- aliphatic radical with up to 29 carbon atoms in each case, or a heterocyclic or heterocyclic-aliphatic radical with up to 20 carbon atoms in each case, and in each case up to 9 heteroatoms, or acyl with up to 30 carbon atoms;

R₇, R₆ and R₉ are acyl or -(lower alkyl)-acyl, unsubstituted or substituted alkyl, hydrogen, halogen, hydroxy, etherified or esterified hydroxy, amino, mono- or disubstituted amino, cyano, nitro, mercapto, substituted mercapto, carboxy,carbonyl, carbonyidioxy, esterified carboxy, carbamoyl, N-mono- or N,N-di-substituted carbamoyl, sulfa, substituted sulfonyl, aminosulfonyl or N-mono- or N,N-di-substituted aminosulfonyl;

X stands for 2 hydrogen atoms;

for 1 hydrogen atom and hydroxy;

for 0;

or for hydrogen and lower alkoxy;

Z stands for hydrogen or lower alkyl;

and either the two bonds characterised by wavy lines are absent in ring A and replaced by 4 hydrogen atoms, and the two wavy lines in ring B each, together with the respective parallel bond, signify a double bond;

or the two bonds characterised by wavy lines are absent in ring B and replaced by a total of 4 hydrogen atoms, and the two wavy lines in ring A each, together with the respective parallel bond, signify a double bond;

or both in ring A and in ring B all of the 4 wavy bonds are absent and are replaced by a total of 8 hydrogen atoms;

or a salt thereof, if at least one salt- forming group is present for the preparation of a pharmaceutical composition for the curative, palliative or prophylactic treatment of allergic rhinitis, allergic dermatitis, drug allergy or food allergy, angioedema, urticaria, sudden infant death syndrome, bronchopulmonary aspergillosis, multiple sclerosis, or mastocytosis.

3. The use of a staurosporin derivative of formula I,

wherein m and n are each 0;

R₃ and R₄ are independently of each other hydrogen, lower alkyl unsubstituted or mono- or disubstituted, especially monosubstituted, by radicals selected independently of one another from carboxy;

lower alkoxycarbonyl; and

cyano;

or

R₄ is hydrogen or —

CH₃, and

R₃ is acyl of the subformula R^o—

CO, wherein R^o is lower alkyl;

amino-lower alkyl, wherein the amino group is present in unprotected form or is protected by lower alkoxycarbonyl;

tetrahydropyranyloxy-lower alkyl;

phenyl;

imidazolyl-lower alkoxyphenyl;

carboxyphenyl;

lower alkoxycarbonylphenyl;

halogen-lower alkylphenyl;

imidazol-1-ylphenyl;

pyrrolidino lower alkylphenyl;

piperazino-lower alkylphenyl;

(4-lower alkylpiperazinomethylyphenyl;

morpholino-lower alkylphenyl;

piperazinocarbonylphenyl;

or (4-lower alkylpiperazino)phenyl;

or is acyl of the subformula R^o—

O—

CO—

, wherein R^o is lower alkyl;

or is acyl of the subformula R^oHN—

C(═

W)—

, wherein W is oxygen and R^o has the following meanings;

morpholino-lower alkyl, phenyl, lower alkoxyphenyl, carboxyphenyl, or lower alkoxycarbonylphenyl;

or R₃ is lower alkylphenylsulfonyl, typically 4-toluenesulfonyl;

R₅ is hydrogen or lower alkyl,

X stands for 2 hydrogen atoms or for O;

Z is methyl or hydrogen;

or a salt thereof, if at least one salt-forming group is present for the preparation of a pharmaceutical composition for the curative, palliative or prophylactic treatment of allergic rhinitis, allergic dermatitis, drug allergy or food allergy, angioedema, urticaria, sudden infant death syndrome, bronchopulmonary aspergillosis, multiple sclerosis, or mastocytosis.

8. Use of N-[(9S,10R,11R,13R)-2,3,10,11,12,13-hexahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy-1H,9H-diindolo[1,2,3-gh:

3′

,2′

,1′

-lm]pyrrolo[3,4j]I1,7]benzodiazonin-11-yl]-N-methylbenzamide of the formula (VII);

or a salt thereof, for the preparation of a pharmaceutical composition for the curative, palliative or prophylactic treatment of allergic rhinitis, allergic dermatitis, drug allergy or food allergy, angioedema, urticaria, sudden Infant death syndrome, bronchopulmonary aspergillosis, multiple sclerosis, or mastocytosis.

9. Use according to claim 8 for the treatment of mastocytosis or mastocytosis with resistance to omatinib.

11. A method for treating mammals, including man, suffering from allergic rhinitis, allergic dermatitis, drug allergy or food allergy, angioedema, urticaria, sudden infant death syndrome, bronchopulmonary aspergillosis, multiple sclerosis, or mastocytosis, comprising administering to a mammal in need of such treatment a therapeutically effective amount of N-[(9S,10R,11R,13R)-2,3,10,11,12,13-hexahydro-1 0-methoxy-9-methyl-1-oxo-9,13-epoxy-1H,9H-diindolo[1,2,3-gh:

3′

,2′

,1′

-lm]pyrrolo[3,4j][1,7]benzodiazonin-11-yl]-N-methylbenzamide of the formula (VII) as defined in claim 8.

12. A method according to claim 11 for treating of mastocytosis or mastocytosis with resistance to imatinib.

13. A method according to claims 8, wherein the therapeutically effective amount of the compound of formula VII is administered to a mammal subject 7 to 4 times a week or about 100% to about 50% of the days in the time period, for a period of from one to six weeks, followed by a period of one to three weeks, wherein the agent is not administered and this cycle being repeated for from 1 to several cycles.

14. Use or method according to claims 8, wherein the daily effective amount of the compound of formula VII, is 100 to 300 mg daily preferably 220 to 230 mg, most preferably 225 mg daily.

15. Use or method according to claim 8, wherein the compound of formula VII, is administered once, two or three times a day, for a total dose of 100 to 300 mg daily preferably of 220 to 230 mg, most preferably 225 mg daily.

16. Use or method according to claim 8, wherein the compound of formula VII, is administered three times a day, for a total dose of 220 to 230 mg, preferably 225 mg daily, and preferably a dose of 70 to 80 mg most preferably 75 mg per administration.

17. An article of manufacture comprising packaging material, and N-[(9S,10R,11R,13R)-2,3,10,11,12,13-hexahydro-10-methoxy-9-methyl-1 -oxo-9,13-epoxy-1H,9H-diindolo[1,2,3-gh:

3′

,2′

,1′

-lm]pyrrolo[3,4j][1,7]benzodiazonin-11-yl]-N-methylbenzamide of the formula (VII) as defined in claim 8 or a pharmaceutically acceptable salts thereof, contained within said packaging material, wherein said packaging material comprises label directions which indicate that said compound of formula (VII), or said pharmaceutically-acceptable salt, is to be administered to mammals suffering from allergic rhinitis, allergic dermatitis, drug allergy or food allergy, angioedema, urticaria, sudden infant death syndrome, bronchopulmonary aspergillosis, multiple sclerosis, or mastocytosis in an amount from 100 to 300 mg, preferably 220 to 230 mg, most preferably 225 mg following a specific dosage.

18. An article of manufacture according to claim 17 wherein the compound of formula VII is administered three times a day, for a total dose of 220 to 230 mg preferably 225 mg daily, and preferably a dose of 70 to 80 mg most preferably 75 mg per administration.

10. Pharmaceutical preparation for the curative, palliative or prophylactic treatment of allergic rhinitis, allergic dermatitis, drug allergy or food allergy, angioedema, urticaria, sudden infant death syndrome, bronchopulmonary aspergillosis, multiple sclerosis, or mastocytosis, comprising an N-[(9S,10R,11R,13R)-2,3,10,11,12,13-hexahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy-1H,9H-diindolo[1,2,3-gh:

3′

,2′

,1′

-lm]pyrrolo[3,4j][1,7]benzodiazonon-11-yl]-N-methylbenzamide of the formula (VII).