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1. (WO2019002889) METHOD FOR TREATING AN AUTOIMMUNE NEUROLOGICAL DISEASE AND/OR NEURODEGENERATIVE DISEASE AND PHARMACEUTICAL FORMULATIONS FOR A LIQUID DOSAGE FORM AND A CONTROLLED RELEASE DOSAGE FORM
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What is claimed is:

1. A method for treating an autoimmune neurological disease and/or a neurodegenerative disease, comprising:

administering an effective amount of at least one compound having Formula (I), Formula (II) or Formula (III), or its geometric isomer, enantiomer, diastereomer or pharmaceutically acceptable salt to a subject in need thereof:

Formula (I);


Formula (II);


Formula (III),

wherein

is a single or double bond,

X is NCH3 or CH2,

Y is null, O or N,

Ri is H, OH, and

R2 is null, H, Ci-C8 alkyl, -(C=0)-alkyl, -(C=0)-aryl, -(C=0)-alkyl-aryl, - (C=0)-heteroaryl, cycloalkyl or heterocycloalkyl, which optionally substituted by one or more of -OH, -N02, -NH2, -NRsR t, carbonyl, alkoxyl, alkyl or -OCF3, wherein R3 and R4 independently are H, alkyl, -S02CH3, -(C=0)-CH3 or -(C=0)-NH2.

2. The method for treating an autoimmune neurological disease and/or a neurodegenerative disease as claimed in claim 1, wherein the at least one compound having Formula (I) comprises at least one compound having any one of Formula (IV) to Formula (XVI):


Formula (IV);


Formula (V);


Formula (VI);

Formula (VII);

Formula (VIII);


Formula (IX);


Formula (X);

Formula (XI);



Formula (XIII);


Formula (XIV);


Formula (XV);


Formula (XVI).

The method for treating an autoimmune neurological disease and/or a neurodegenerative disease as claimed in claim 1, wherein the at least one compound having Formula (II) comprises at least one compound having Formula (XVII):


Formula (XVII).

The method for treating an autoimmune neurological disease and/or a neurodegenerative disease as claimed in claim 1, wherein the at least one compound having Formula (III) comprises at least one compound having Formula (XVIII):


Formula (XVIII).

5. The method for treating an autoimmune neurological disease and/or a neurodegenerative disease as claimed in claim 1, wherein the at least one compound having Formula (I), Formula (II) or Formula (III), or its geometric isomer, enantiomer, diastereomer or pharmaceutically acceptable salt is the at least one compound having Formula (I).

6. The method for treating an autoimmune neurological disease and/or a neurodegenerative disease as claimed in claim 5, wherein the at least one compound having Formula (I) is at least one compound having Formula (IV), and is sobrerol:


Formula (IV).

7. The method for treating an autoimmune neurological disease and/or a neurodegenerative disease as claimed in claim 6, wherein the sobrerol comprises (+) trans- sobrerol, (-) trans-sobrerol, (+) cis- sobrerol, (-) cis -sobrerol or a combination thereof.

8. The method for treating an autoimmune neurological disease and/or a neurodegenerative disease as claimed in claim 7, wherein the sobrerol is (+) trans-sobrerol.

9. The method for treating an autoimmune neurological disease and/or a neurodegenerative disease as claimed in claim 7, wherein the sobrerol is (-) trans-sobrerol.

10. The method for treating an autoimmune neurological disease and/or a neurodegenerative disease as claimed in claim 7, wherein the sobrerol is a mixture of (+) trans-sobrerol and (-) trans-sobrerol.

11. The method for treating an autoimmune neurological disease and/or a

neurodegenerative disease as claimed in claim 1, wherein the autoimmune neurological disease comprises multiple sclerosis, Neuromyelitis optica, Lambert-Eaton myasthenic syndrome, autoimmune inner ear disease, narcolepsy, neuromyotonia, Guillain- Barre syndrome, myasthenia gravis, systemic lupus erythematosus, transverse myelitis or acute disseminated encephalomyelitis.

12. The method for treating an autoimmune neurological disease and/or a neurodegenerative disease as claimed in claim 1, wherein the neurodegenerative disease comprises Alzheimer's disease, Huntington' s disease, Parkinson's disease, Schizophrenia, depression, Amyotrophic lateral sclerosis, multi-infarct dementia, Motor neuron disease or neurofibromatosis.

13. A pharmaceutical formulation for a liquid dosage form of at least one compound having Formula (I), Formula (II) or Formula (III), comprising:

0.1-30 % by weight of at least one compound having Formula (I), Formula (II) or Formula (III), or its geometric isomer, enantiomer, diastereomer or pharmaceutically acceptable salt;

Formula (I);


Formula (II);

Formula (III),

wherein

is a single or double bond,

X is NCH3 or CH2,

Y is null, O or N,

Ri is H, OH, and

R2 is null, H, d-C8 alkyl, -(C=0)-alkyl, -(C=0)-aryl, -(C=0)-alkyl- aryl, -(C=0)-heteroaryl, cycloalkyl or heterocycloalkyl, which optionally substituted by one or more of -OH, -N02, - NH2, -NR3R4, carbonyl, alkoxyl, alkyl or -OCF3, wherein R3 and R4 independently are H, alkyl, -S02CH3, -(C=0)-CH3 or -(C=0)-NH2; and

0.1-15% by weight of a copolymer of poly(ethylene oxide) and poly(propylene oxide);

0.1-60% by weight of cyclodextrin or a derivative thereof; and

1-99% by weight of solvent.

14. The pharmaceutical formulation for a liquid dosage form of at least one compound having Formula (I), Formula (II) or Formula (III), as claimed in claim 13, wherein the at least one compound having Formula (I) comprises at least one compound having any one of Formula (IV) to Formula (XVI):


Formula (IV);
Formula (V);
Formula (VI);

Formula (VII);

Formula (VIII);
Formula (IX);
Formula (X);
Formula (XI); Formula (XII);


Formula (XIII);


Formula (XIV);

Formula (XV);


Formula (XVI).

15. The pharmaceutical formulation for a liquid dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in claim 13, wherein the at least one compound having Formula (II) comprises at least one compound having Formula (XVII):


Formula (XVII).

16. The pharmaceutical formulation for a liquid dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in claim 13, wherein the at least one compound having

Formula (III) comprises at least one compound having Formula (XVIII):


Formula (XVIII).

17. The pharmaceutical formulation for a liquid dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in claim 13, wherein the copolymer of poly(ethylene oxide) and poly(propylene oxide) comprises poly(ethylene oxide)x- poly(propylene oxide)y-poly(ethylene oxide)x (PEO-PPO-PEO), in which, x is an integer of 30-120 and y is an integer of 10-50.

18. The pharmaceutical formulation for a liquid dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in claim 13, wherein the derivative of cyclodextrin comprises 2-hydroxypropyl-beta cyclodextrin, 2-hydroxypropyl-Y-cyclodextrin, β-CD sulfobutyl ether sodium salt or randomly methylated β- cyclodextrin.

19. The pharmaceutical formulation for a liquid dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in claim 13, wherein the pharmaceutical formulation comprises:

0.1-30% by weight of the at least one compound having Formula (I), Formula (II) or Formula (III), or its geometric isomer, enantiomer, diastereomer or pharmaceutically acceptable salt;

0.1- 15% by weight of the copolymer of poly(ethylene oxide) and poly(propylene oxide), wherein the copolymer of poly(ethylene oxide) and poly(propylene oxide) is poly(ethylene oxide)x-poly(propylene oxide)y-poly(ethylene oxide )x (PEO-PPO-PEO), in which, x is an integer of 76 and y is an integer of 30; and

0.1-60% by weight of the cyclodextrin or derivative thereof, wherein the cyclodextrin or derivative thereof is 2-hydroxypropyl-beta cyclodextrin.

20. The pharmaceutical formulation for a liquid dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in claim 19, wherein the at least one compound having Formula (I), Formula (II) or Formula (III), or its geometric isomer, enantiomer, diastereomer or pharmaceutically acceptable salt is at least one compound having Formula (IV), and is sobrerol:


Formula (IV).

21. The pharmaceutical formulation for a liquid dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in claim 20, wherein the sobrerol comprises (+) trans- sobrerol, (-) trans-sobrerol, (+) cis-sobrerol, (-) cis-sobrerol or a combination thereof.

22. The pharmaceutical formulation for a liquid dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in claim 20, wherein the sobrerol is (+) trans-sobrerol.

23. The pharmaceutical formulation for a liquid dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in claim 20, wherein the sobrerol is (-) trans-sobrerol.

24. The pharmaceutical formulation for a liquid dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as

claimed in claim 20, wherein the sobrerol is a mixture of (+) trans- sobrerol and (-) trans-sobrerol.

25. A pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III), comprising:

a composition of a particle carrier;

a composition of a drug layer coated on the carrier, which comprises:

at least one compound having Formula (I), Formula (II) or Formula (III), or its geometric isomer, enantiomer, diastereomer or pharmaceutically acceptable salt;

Formula (I);

Formula (II);


Formula (III),

wherein

is a single or double bond,

X is NCH3 or CH2,

Y is null, O or N,

Ri is H, OH, and

R2 is null, H, Ci-C8 alkyl, -(C=0)-alkyl, -(C=0)-aryl, - (C=0)-alkyl-aryl, -(C=0)-heteroaryl, cycloalkyl or heterocycloalkyl, which optionally substituted by one or more of -OH, -N02, -NH2, -NR^, carbonyl, alkoxyl, alkyl or -OCF3, wherein R3 and R4

independently are H, alkyl, -S02CH3, -(C=0)-CH3 or -(C=0)-NH2; and

at least one binder; and

a composition of a controlled release layer coated on the drug layer, wherein in the pharmaceutical formulation for a controlled release dosage form, the composition of a particle carrier occupies 35-98% by weight, the composition of a drug layer occupies 1-64% by weight, and the composition of a controlled release layer occupies 0.5-50% by weight, and

wherein the at least one compound having Formula (I), Formula (II) or Formula (III), or its geometric isomer, enantiomer, diastereomer or pharmaceutically acceptable salt occupies 1-99% by weight of the composition of a drug layer.

26. The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in claim 25, wherein the composition of a particle carrier comprises microcrystalline cellulose, lactose, corn starch, mannitol, sodium carboxymethyl cellulose, common salt, or germanium dioxide.

27. The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in claim 25, wherein the at least one compound having Formula (I) comprises at least one compound having any one of Formula (IV) to Formula (XVI):


Formula (IV);

Formula (V);
Formula (VI);

Formula (VII);

Formula (VIII);
Formula (IX); Formula (X);
Formula (XI);


Formula (XII);

Formula (XIII);


Formula (XIV);


Formula (XV);


Formula (XVI).

28. The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in claim 25, wherein the at least one compound having Formula (II) comprises at least one compound having Formula (XVII):


Formula (XVII).

29. The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in claim 25, wherein the at least one compound having Formula (III) comprises at least one compound having Formula (XVIII):

Formula (XVIII).

30. The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in claim 25, wherein the at least one binder comprises hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl, polyvinyl alcohol or a combination thereof.

31. The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in claim 25, wherein the composition of a drug layer further comprises an anti-adherent and/or a plasticizer.

32. The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in claim 25, wherein the composition of a controlled release layer comprises at least one water-insoluble polymer or wax- like ingredient.

33. The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in claim 32, wherein the at least one water-insoluble polymer or wax-like ingredient comprises ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl acrylate-methyl methacrylate-trimethyl ammonium chloride ethyl methacrylate copolymer, methyl methacrylate-ethyl acrylate copolymer, polyvinylpyrrlidone, polyvinyl alcohol, hydrogenated castor oil, hydrogenated coconut oil, stearic acid, stearyl alcohol or a combination thereof.

34. The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in claim 32, wherein the composition of a controlled release layer further comprises an anti-adherent and/or a plasticizer.

35. The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in claim 27, wherein the at least one compound having Formula (I), Formula (II) or Formula (III), or its geometric isomer, enantiomer, diastereomer or pharmaceutically acceptable salt is at least one compound having Formula (IV), and is sobrerol:


Formula (IV).

36. The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in claim 35, wherein the sobrerol comprises (+) trans- sobrerol, (-) trans-sobrerol, (+) cis-sobrerol, (-) cis-sobrerol or a combination thereof.

37. The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in claim 35, wherein the sobrerol is (+) trans-sobrerol.

38. The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in claim 35, wherein the sobrerol is (-) trans-sobrerol.

39. The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in claim 35, wherein the sobrerol is a mixture of (+) trans- sobrerol and (-) trans-sobrerol.

40. The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in claim 35,

wherein

the composition of a particle carrier comprises microcrystalline cellulose, the composition of a drug layer comprises (-) trans-sobrerol, at least one binder comprising hydroxypropyl methyl cellulose, and an anti- adherent comprising talcum powder,

the composition of a controlled release layer comprises at least one water- insoluble polymer comprising ethyl cellulose and hydroxypropyl methyl cellulose, and an anti-adherent comprising talcum powder, and wherein in the pharmaceutical formulation for a controlled release dosage form, the composition of a particle carrier occupies 40-90% by weight, the composition of a drug layer occupies 15-50% by weight, and the composition of a controlled release layer occupies 1-15% by weight, and

wherein the (-) trans-sobrerol occupies 40-90% by weight of the composition of a drug layer.

41. The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in claim 35,

wherein

the composition of a particle carrier comprises microcrystalline cellulose, the composition of a drug layer comprises (-) trans-sobrerol and at least one binder comprising polyvinyl pyrrolidone,

the composition of a controlled release layer comprises at least one water- insoluble polymer comprising ethyl cellulose and hydroxypropyl methyl cellulose, and

wherein in the pharmaceutical formulation for a controlled release dosage form, the composition of a particle carrier occupies 35-95% by weight, the composition of a drug layer occupies 5-60% by weight, and the composition of a controlled release layer occupies 0.5-20% by weight, and

wherein the (-) trans-sobrerol occupies 40-90% by weight of the composition of a drug layer.

42. The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in claim 35,

wherein

the composition of a particle carrier comprises microcrystalline cellulose, the composition of a drug layer comprises a mixture of (+) trans-sobrerol and (-) trans-sobrerol and at least one binder comprising polyvinyl pyrrolidone,

the composition of a controlled release layer comprises at least one water- insoluble polymer comprising ethyl cellulose and hydroxypropyl methyl cellulose, and

wherein in the pharmaceutical formulation for a controlled release dosage form, the composition of a particle carrier occupies 35-95% by weight, the composition of a drug layer occupies 5-60% by weight, and the composition of a controlled release layer occupies 0.5-20% by weight, and

wherein the mixture of (+) trans-sobrerol and (-) trans-sobrerol occupies 40- 90% by weight of the composition of a drug layer.

43. The pharmaceutical formulation for a controlled release dosage form of at least one compound having Formula (I), Formula (II) or Formula (III) as claimed in claim 25, further comprising a composition of a coating layer coated on the controlled release layer,

wherein in the pharmaceutical formulation for a controlled release dosage form, the composition of a particle carrier occupies 35-98% by weight, the composition of a drug layer occupies 1-64% by weight, the composition of a controlled release layer occupies 1-50% by weight, and the composition of a coating layer occupies 1-35% by weight.