USE OF COMPOSITIONS TO ENHANCE INNATE IMMUNE RESPONSE

• US 20090088373A1
• Filed: 09/23/2008
• Published: 04/02/2009
• Est. Priority Date: 09/28/2007
• Status: Abandoned Application

• Current Assignee: Anton Stuetz, Richard L. Gallo, Thomas Hultsch
• Original Assignee: Anton Stuetz, Richard L. Gallo, Thomas Hultsch
• Inventors: Hultsch, Thomas, Stuetz, Anton, Gallo, Richard L.
• Application Number:
  US12/236,074
• Publication Number:
  US 20090088373A1
• Time in Patent Office: Days
• US Class Current: 514/1.100
• CPC Class Codes: A61K 31/215 of carboxylic acids
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/4353 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/593 9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
• CPC Class Codes: A61K 38/13 Cyclosporins
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention discloses methods of using of compounds for the enhancement of the innate immune system of a patient. In particular, the active compounds of the present invention include at least one calcineurin inhibitor, mTOR inhibitor or non-immunosuppresive derivative, or a derivative, isomer, or pharmaceutically acceptable salt thereof; and optionally, at least one calciferol or LMW inhibitor, or a derivative, isomer, or pharmaceutically acceptable salt thereof. Pharmaceutical formulations comprising same are also disclosed.

Claims

1. A method for the treatment of diseases in a patient in which enhancement of the innate immune response can treat the disease, which method comprises administering to the patient a therapeutically effective amount of a composition comprising:

(a) at least one calcineurin inhibitor, mTOR inhibitor or non-immunosuppressive derivative, or a derivative, isomer, or pharmaceutically acceptable salt thereof; and

(b) optionally, at least one calciferol or LMW inhibitor, or a derivative, isomer, or pharmaceutically acceptable salt thereof.

2. The method of claim 1 wherein the calcineurin inhibitor is selected from the group consisting of tacrolimus, pimecrolimus, ascomycin, cyclosporin A, tacrolimus, cypermethrin, deltamethrin, fenvalerate, vocyclosporin and the derivatives, isomers and pharmaceutically acceptable salts thereof.

3. The method of claim 1 wherein the mTOR inhibitor is selected from the group consisting of rapamycin, rapamycin derivatives, everolimus, 7-tert-Butyl-6-(4-chloro-phenyl)-2-thioxo-2,3-dihydro-1H-pyrido[2,3-d]pyrimidin-4-one, SAR943, 40-O-alkyl-rapamycin derivatives, 32-deoxo-rapamycin derivatives, 32-hydroxy-rapamycin derivatives, 32-deoxorapamycin, 16-O-substituted rapamycin derivatives, 16-pent-2-ynyloxy-32-deoxorapamycin, 16-pent-2-ynyloxy-32(S or R)-dihydro-rapamycin, 16-pent-2-ynyloxy-32(S or R)-dihydro-40-O-(2-hydroxyethyl)-rapamycin, rapamycin derivatives which are acylated at the oxygen group in position 40,40-[3-hydroxy-2-(hydroxy-methyl)-2-methylpropanoate]-rapamycin, rapamycin derivatives which are substituted in 40 position by heterocyclyl, 40-epi-(tetrazolyl)-rapamycin, rapalogs, 40-O-dimethylphosphinyl-rapamycin, AP23573, biolimus, 40-O-(2-ethoxy)ethyl-rapamycin, TAFA-93, AP23464, AP23675, AP23841, and the derivatives, isomers and pharmaceutically acceptable salts thereof.

4. The method of claim 1 wherein the immunosuppressive derivative is a compound of formula I to III

wherein the symbol represents a single bond or, when R_2a is absent, a double bond;

R₁ represents an optionally protected hydroxy group and R_1a represents hydrogen;

or R₁ and R_1a together represent oxo;

R₂ represents an optionally protected hydroxy group or together with R₄forms the —

OC(═

O)O—

group, and R_2a represents hydrogen or is absent;

whereby when the symbol is a single bond,

R₂ together with R_2a also represents oxo;

R₃ represents methyl, ethyl, n-propyl or allyl;

R₄ represents optionally protected hydroxy or together with R₂ forms the —

OC(═

O)O—

group, and R_4a represents hydrogen;

or R₄ together with R_4a represents oxo;

R₅ represents alkoxycarbonyloxy, halogen, optionally protected hydroxy, lower alkoxy, acyloxy or a group —

OC(═

X)N(R₁₀)R₁₁;

or R₅together with R_6a forms a group —

OC(═

X)N(R′

₁₀)—

attached with the nitrogen atom to the carbon atom carrying R_6a, whereby X represents oxygen or sulfur, R₁₀ and R₁₁ independently represent hydrogen or lower alkyl or together with the nitrogen atom form a five- or six-membered ring optionally containing a second heteroatom such as nitrogen or oxygen, and R′

₁₀ is hydrogen or lower alkyl;

or R₅ together with R_8a represents oxy, whereby R₈ represents hydroxy;

R₆ represents hydroxy, and R_6a represents hydrogen or together with R₅ forms a group —

OC(═

X)N(R′

₁₀)—

as defined above;

or R₆and R_6a together represent oxo;

R′

₅ represents optionally protected hydroxy, lower alkoxy or acyloxy and R′

₆represents hydroxy;

or R′

₅ and R′

₆ together form the —

OC(═

O)O—

group;

R″

₅ represents hydroxy or lower alkoxy and R″

.sub.6 represents hydroxy;

or R″

₅and R″

₆ together form the —

OC(═

O)O—

group;

R₇represents methoxy or hydroxy;

R₈ represents an optionally protected hydroxy group, acyloxy, imidazolylcarbonyloxy or alkoxycarbonyloxy and R_8a represents hydrogen;

or R₈ represents hydroxy and R_8a together with R₅ represents oxy;

or R₈ together with R_8a represents oxo; and

n represents 1 or 2;

and the derivatives, isomers and pharmaceutically acceptable salts thereof.

5. The method of claim 1 wherein the calciferol is selected from the group consisting of calciferol, calcipotriol, calcitriol, cholecalciferol, 22,23-dihydroergocalciferol, 25-hydroxycholecalciferol, 25-hydroxyergocalciferol, maxacalcitol, falecalcitol, falecalcitriol and tacalcitol, and the derivatives, isomers and pharmaceutically acceptable salts thereof.

6. The method of claim 1 wherein the LMW inhibitor is a compound of the formula

wherein either R₁ is phenyl, naphthyl, thienyl or pyridyl, or phenyl, naphthyl, thienyl or pyridyl monosubstituted by halogen, C₁-C₄ alkoxy, C₁-C₄ alkyl, di-C₁-C₄ alkylamino or cyano and

R₂ is hydrogen;

or

R₁ is hydrogen and

R₂ is pyridyl or 2-(5-chloro)pyridyl;

R₃ is hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, cyano, C₁-C₄ alkoxycarbonyl, C₁-C₄ alkylcarbonyl, amino or di-C₁-C₄ alkylamino; and

X is CH;

and the derivatives, isomers and pharmaceutically acceptable salts thereof.

7. The method of claim 1 wherein the disease is selected from the group consisting of acne, atopic dermatitis, wound infections, MRSA, viral skin infections, HSV, HPV, Poxvirus, onychomycosis, viral and bacterial infections of the oro-pharynx and respiratory tract, RSV, mycoplasm, infections of urinary tract, Chlamydia, viral and bacterial infections of the GI tract, psoriasis, contact dermatitis, eczematous dermatitises, seborrhoeic dermatitis, Lichen planus, Pemphigus, bullous Pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupus erythematous, Alopecia areata, cornefied epithelia, gingivitis, oro-pharyngitis, inflammatory bowel disease, Crohns disease, recurrent vaginitis (E. coli), urethritis)), and conjunctiva.

8. A pharmaceutical composition for enhancing an innate immune response in an patient comprising a therapeutically effective amount of:

(a) at least one calcineurin inhibitor, mTOR inhibitor or non-immunosuppressive derivative, or a derivative, isomer, or pharmaceutically acceptable salt thereof; and

(b) optionally, at least one calciferol or LMW inhibitor, or a derivative, isomer, or pharmaceutically acceptable salt thereof.

9. The composition of claim 8 wherein the calcineurin inhibitor is selected from the group consisting of tacrolimus, pimecrolimus, ascomycin, cyclosporin A, tacrolimus, cypermethrin, deltamethrin, fenvalerate, vocyclosporin and the derivatives, isomers and pharmaceutically acceptable salts thereof.

10. The composition of claim 8 wherein the mTOR inhibitor is selected from the group consisting of rapamycin, rapamycin derivatives, everolimus, 7-tert-Butyl-6-(4-chloro-phenyl)-2-thioxo-2,3-dihydro-1H-pyrido[2,3-d]pyrimidin-4-one, SAR943, 40-O-alkyl-rapamycin derivatives, 32-deoxo-rapamycin derivatives, 32-hydroxy-rapamycin derivatives, 32-deoxorapamycin, 16-O-substituted rapamycin derivatives, 16-pent-2-ynyloxy-32-deoxorapamycin, 16-pent-2-ynyloxy-32(S or R)-dihydro-rapamycin, 16-pent-2-ynyloxy-32(S or R)-dihydro-40-O-(2-hydroxyethyl)-rapamycin, rapamycin derivatives which are acylated at the oxygen group in position 40,40-[3-hydroxy-2-(hydroxy-methyl)-2-methylpropanoate]-rapamycin, rapamycin derivatives which are substituted in 40 position by heterocyclyl, 40-epi-(tetrazolyl)-rapamycin, rapalogs, 40-O-dimethylphosphinyl-rapamycin, AP23573, biolimus, 40-O-(2-ethoxy)ethyl-rapamycin, TAFA-93, AP23464, AP23675, AP23841, and the derivatives, isomers and pharmaceutically acceptable salts thereof.

11. The composition of claim 8 wherein the immunosuppressive derivative is a compound of formula I to III

wherein the symbol represents a single bond or, when R_2a is absent, a double bond;

R₁ represents an optionally protected hydroxy group and R_1a represents hydrogen;

or R₁ and R_1a together represent oxo;

R₂ represents an optionally protected hydroxy group or together with R₄ forms the —

OC(═

O)O—

group, and R_2a represents hydrogen or is absent;

whereby when the symbol is a single bond,

R₂ together with R_2a also represents oxo;

R₃ represents methyl, ethyl, n-propyl or allyl;

R₄ represents optionally protected hydroxy or together with R₂ forms the —

OC(═

O)O—

group, and R_4a represents hydrogen;

or R₄ together with R_4a represents oxo;

R₅ represents alkoxycarbonyloxy, halogen, optionally protected hydroxy, lower alkoxy, acyloxy or a group —

OC(═

X)N(R₁₀)R₁₁;

or R₅ together with R_6a forms a group —

OC(═

X)N(R′

₁₀)—

attached with the nitrogen atom to the carbon atom carrying R_6a, whereby X represents oxygen or sulfur, R₁₀ and R₁₁ independently represent hydrogen or lower alkyl or together with the nitrogen atom form a five- or six-membered ring optionally containing a second heteroatom such as nitrogen or oxygen, and R′

₁₀ is hydrogen or lower alkyl;

or R₅ together with R_8a represents oxy, whereby R₈ represents hydroxy;

R₆ represents hydroxy, and R_6a represents hydrogen or together with R₅ forms a group OC(═

X)N(R′

₁₀)—

as defined above;

or R₆ and R_6a together represent oxo;

R′

₅ represents optionally protected hydroxy, lower alkoxy or acyloxy and R′

₆represents hydroxy;

or R′

₅ and R′

₆ together form the —

OC(═

O)O—

group;

R″

₅ represents hydroxy or lower alkoxy and R″

.sub.6 represents hydroxy;

or R″

₅and R″

₆ together form the —

OC(═

O)O—

group;

R₇represents methoxy or hydroxy;

R₈ represents an optionally protected hydroxy group, acyloxy, imidazolylcarbonyloxy or alkoxycarbonyloxy and R_8a represents hydrogen;

or R₈ represents hydroxy and R_8a together with R₅ represents oxy;

or R₈ together with R_8a represents oxo; and

n represents 1 or 2;

and the derivatives, isomers and pharmaceutically acceptable salts thereof.

12. The composition of claim 8 wherein the calciferin is selected from the group consisting of calciferol, calcipotriol, calcitriol, cholecalciferol, 22,23-dihydroergocalciferol, 25-hydroxycholecalciferol, 25-hydroxyergocalciferol, maxacalcitol, falecalcitol, falecalcitriol and tacalcitol, and the derivatives, isomers and pharmaceutically acceptable salts thereof.

13. The composition of claim 8 wherein the LMW inhibitor is a compound of the formula

wherein either R₁ is phenyl, naphthyl, thienyl or pyridyl, or phenyl, naphthyl, thienyl or pyridyl monosubstituted by halogen, C₁-C₄ alkoxy, C₁-C₄ alkyl, di-C₁-C₄ alkylamino or cyano and

R₂ is hydrogen;

or

R₁ is hydrogen and

R₂ is pyridyl or 2-(5-chloro)pyridyl;

R₃ is hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, cyano, C₁-C₄ alkoxycarbonyl, C₁-C₄ alkylcarbonyl, amino or di-C₁-C₄ alkylamino; and

X is CH;

and the derivatives, isomers and pharmaceutically acceptable salts thereof.

14. A method for enhancing an innate immune response in an patient comprising administering to an patient a therapeutically effective amount of a composition comprising

(a) at least one calcineurin inhibitor, mTOR inhibitor or non-immunosuppressive derivative, or a derivative, isomer, or pharmaceutically acceptable salt thereof;

and

(b) optionally, at least one calciferol or LMW inhibitor, or a derivative, isomer, or pharmaceutically acceptable salt thereof.

15. The method of claim 14 wherein the calcineurin inhibitor is selected from the group consisting of tacrolimus, pimecrolimus, ascomycin, cyclosporin A, tacrolimus, cypermethrin, deltamethrin, fenvalerate, vocyclosporin and the derivatives, isomers and pharmaceutically acceptable salts thereof.

16. The method of claim 14 wherein the mTOR inhibitor is selected from the group consisting of rapamycin, rapamycin derivatives, everolimus, 7-tert-Butyl-6-(4-chloro-phenyl)-2-thioxo-2,3-dihydro-1H-pyrido[2,3-d]pyrimidin-4-one, SAR943, 40-O-alkyl-rapamycin derivatives, 32-deoxo-rapamycin derivatives, 32-hydroxy-rapamycin derivatives, 32-deoxorapamycin, 16-O-substituted rapamycin derivatives, 16-pent-2-ynyloxy-32-deoxorapamycin, 16-pent-2-ynyloxy-32(S or R)-dihydro-rapamycin, 16-pent-2-ynyloxy-32(S or R)-dihydro-40-O-(2-hydroxyethyl)-rapamycin, rapamycin derivatives which are acylated at the oxygen group in position 40,40-[3-hydroxy-2-(hydroxy-methyl)-2-methylpropanoate]-rapamycin, rapamycin derivatives which are substituted in 40 position by heterocyclyl, 40-epi-(tetrazolyl)-rapamycin, rapalogs, 40-O-dimethylphosphinyl-rapamycin, AP23573, biolimus, 40-O-(2-ethoxy)ethyl-rapamycin, TAFA-93, AP23464, AP23675, AP23841, and the derivatives, isomers and pharmaceutically acceptable salts thereof.

17. The method of claim 14 wherein the immunosuppressive derivative is a compound of formula I to III

wherein the symbol represents a single bond or, when R_2a is absent, a double bond;

R₁ represents an optionally protected hydroxy group and R_1a represents hydrogen;

or R₁ and R_1a together represent oxo;

R₂ represents an optionally protected hydroxy group or together with R₄forms the —

OC(═

O)O—

group, and R_2a represents hydrogen or is absent;

whereby when the symbol is a single bond,

R₂ together with R_2a also represents oxo;

R₃ represents methyl, ethyl, n-propyl or allyl;

R₄ represents optionally protected hydroxy or together with R₂ forms the —

OC(═

O)O—

group, and R_4a represents hydrogen;

or R₄ together with R_4a represents oxo;

R₅ represents alkoxycarbonyloxy, halogen, optionally protected hydroxy, lower alkoxy, acyloxy or a group —

OC(═

X)N(R₁₀)R₁₁;

or R₅ together with R_6a forms a group —

OC(═

X)N(R′

₁₀)—

attached with the nitrogen atom to the carbon atom carrying R_6a, whereby X represents oxygen or sulfur, R₁₀ and R₁₁ independently represent hydrogen or lower alkyl or together with the nitrogen atom form a five- or six-membered ring optionally containing a second heteroatom such as nitrogen or oxygen, and R′

₁₀ is hydrogen or lower alkyl;

or R₅ together with R_8a represents oxy, whereby R₈ represents hydroxy;

R₆ represents hydroxy, and R_6a represents hydrogen or together with R₅ forms a group —

OC(═

X)N(R′

₁₀)—

as defined above;

or R₆and R_6a together represent oxo;

R′

₅ represents optionally protected hydroxy, lower alkoxy or acyloxy and R′

₆represents hydroxy;

or R′

₅ and R′

₆ together form the —

OC(═

O)O—

group;

R″

₅ represents hydroxy or lower alkoxy and R″

.sub.6 represents hydroxy;

or R″

₅and R″

₆ together form the —

OC(═

O)O—

group;

R₇represents methoxy or hydroxy;

R₈ represents an optionally protected hydroxy group, acyloxy, imidazolylcarbonyloxy or alkoxycarbonyloxy and R_8a represents hydrogen;

or R₈ represents hydroxy and R_8a together with R₅ represents oxy;

or R₈ together with R_8a represents oxo; and

n represents 1 or 2;

and the derivatives, isomers and pharmaceutically acceptable salts thereof.

18. The method of claim 14 wherein the calciferol is selected from the group consisting of calciferol, calcipotriol, calcitriol, cholecalciferol, 22,23-dihydroergocalciferol, 25-hydroxycholecalciferol, 25-hydroxyergocalciferol, maxacalcitol, falecalcitol, falecalcitriol and tacalcitol, and the derivatives, isomers and pharmaceutically acceptable salts thereof.

19. The method of claim 14 wherein the LMW inhibitor is a compound of the formula

wherein either R₁ is phenyl, naphthyl, thienyl or pyridyl, or phenyl, naphthyl, thienyl or pyridyl monosubstituted by halogen, C₁-C₄ alkoxy, C₁-C₄ alkyl, di-C₁-C₄ alkylamino or cyano and

R₂ is hydrogen;

or

R₁ is hydrogen and

R₂ is pyridyl or 2-(5-chloro)pyridyl;

R₃ is hydrogen, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, cyano, C₁-C₄ alkoxycarbonyl, C₁-C₄ alkylcarbonyl, amino or di-C₁-C₄ alkylamino; and

X is CH;

and the derivatives, isomers and pharmaceutically acceptable salts thereof.

20. The method of claim 14 wherein the disease is selected from the group consisting of acne, atopic dermatitis, wound infections, MRSA, viral skin infections, HSV, HPV, Poxvirus, onychomycosis, viral and bacterial infections of the oro-pharynx and respiratory tract, RSV, mycoplasm, infections of urinary tract, Chlamydia, viral and bacterial infections of the GI tract, psoriasis, contact dermatitis, eczematous dermatitises, seborrhoeic dermatitis, Lichen planus, Pemphigus, bullous Pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupus erythematous, Alopecia areata, cornefied epithelia, gingivitis, oro-pharyngitis, inflammatory bowel disease, Crohns disease, recurrent vaginitis (E. coli), urethritis)), and conjunctiva.

21. (canceled)