SUBSTRATE REDUCTION THERAPY

• US 20140080769A1
• Filed: 09/13/2013
• Published: 03/20/2014
• Est. Priority Date: 06/27/2007
• Status: Active Grant

• Current Assignee: United States Department Of Health And Human Services (Government of the United States of America)
• Original Assignee: The United States of America As Represented By The Secretary of Agriculture, Chancellor Masters & Scholars of The University of Cambridge (University of Cambridge)
• Inventors: Platt, Frances Mary, Lloyd-Evans, Emyr, Porter, Forbes Dennison
• Granted Patent: US 9,428,541 B2
• Time in Patent Office: Days
• US Class Current: 514/24
• 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 31/195 having an amino group
• CPC Class Codes: A61K 31/197 the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid carnitine A61K31/205
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/42 Oxazoles
• CPC Class Codes: A61K 31/431 containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/52 Purines, e.g. adenine
• CPC Class Codes: A61K 31/5375 1,4-Oxazines, e.g. morpholine
• CPC Class Codes: A61K 31/575 substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/661 Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
• CPC Class Codes: A61K 31/6615 Compounds having two or more esterified phosphorus acid groups, e.g. inositol triphosphate, phytic acid
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/685 one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 31/7008 Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
• CPC Class Codes: A61K 31/7012 Compounds having a free or esterified carboxyl group attached, directly or through a carbon chain, to a carbon atom of the saccharide radical, e.g. glucuronic acid, neuraminic acid gluconic acid A61K31/191; ascorbic acid A61K31/375
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 31/708 : having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
• CPC Class Codes: A61K 45/06 : Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 17/00 : Drugs for dermatological disorders
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 211/94 : Oxygen atom, e.g. piperidine N-oxide
• CPC Class Codes: C07D 473/16 : two nitrogen atoms
• CPC Class Codes: C07H 19/06 : Pyrimidine radicals
• CPC Class Codes: C07H 19/20 : with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07J 43/003 : not condensed
• CPC Class Codes: C07J 7/009 : by only one oxygen atom doubly bound

Abstract

The present invention provides a compound which is an inhibitor of sphingolipid biosynthesis for use in the treatment of a disease which has a secondary Niemann-Pick type C disease like cellular phenotype.

Claims

1. A method of treating a subject having a disease which has a secondary Niemann-Pick type C disease like cellular phenotype, provided that the disease is other than mucopolysaccharidosis and other than mucolipidosis IV, wherein the method comprises selecting the subject having the disease, and administering to the subject an effective amount of an inhibitor of sphingolipid biosynthesis.

7. The method of claim 1, wherein the inhibitor is an inhibitor of sphingolipid biosynthesis of one of the following formulae (I), (II), (III), (IV), (V), (IX) and (XII):

8. The method of claim 7 wherein the inhibitor of sphingolipid biosynthesis has the following formula (Ia):

9. The method of claim 8 wherein X is NR⁵;

n is 1;

Y is CHR⁶;

R¹¹ is H; and

R⁵ is selected from;

hydrogen;

unsubstituted or substituted C_1-20 alkyl which is optionally interrupted by 0; and

—

C_1-4 alkylene-O—

C_3-20 heterocyclyl, wherein said C_1-4 alkylene is unsubstituted and said C_3-20 heterocyclyl is a group of the following formula (m);

10. The method of claim 1 wherein the inhibitor of sphingolipid biosynthesis is selected from N-butyldeoxynojirimycin;

N-nonyldeoxynojirimycin;

N-butyldeoxygalactonojirimycin;

N-5-adamantane-1-yl-methoxypentyl-deoxynojirimycin;

alpha-homogalactonojirimycin;

nojirimycin;

deoxynojirimycin;

N7-oxadecyl-deoxynojirimycin;

deoxygalactonojirimycin;

N-butyl-deoxygalactonojirimycin;

N-nonyl-deoxygalactonojirimycin;

N-nonyl-6deoxygalactonojirimycin;

N7-oxanonyl-6deoxy-DGJ;

alpha-homoallonojirimycin;

beta-1-C-butyl-deoxygalactonojirimycin;

1,5-dideoxy-1,5-imino-D-glucitol, 1,5-(Butylimino)-1,5-dideoxy-D-glucitol;

1,5-(Methylimino)-1,5-dideoxy-D-glucitol;

1,5-(Hexylimino)-1,5-dideoxy-D-glucitol;

1,5-(Nonylylimino)-1,5-dideoxy-D-glucitol;

1,5-(2-Ethylbutylimino)-1,5-dideoxy-D-glucitol;

1,5-(2-Methylpentylimino)-1,5-dideoxy-D-glucitol;

1,5-(Benzyloxycarbonylimino)-1,5-dideoxy-D-glucitol, tetraacetate;

1,5-(Phenylacetylimino)-1,5-dideoxy-D-glucitol, tetraacetate;

1,5-(Benzoylimino)-1,5-dideoxy-D-glucitol, tetraacetate;

1,5-(Butylimino)-1,5-dideoxy-D-glucitol, tetraacetate;

1,5-(Ethyl malonylimino)-1,5-dideoxy-D-glucitol, tetraacetate;

1,5-(Hexylimino)-1,5-dideoxy-D-glucitol, tetraacetate;

1,5-(Nonylimino)-1,5-dideoxy-D-glucitol, tetraacetate;

1,5-(Benzyloxycarbonylimino)-1,5-dideoxy-D-glucitol, tetraisobutyrate;

1,5-(Butylimino)-1,5-dideoxy-D-glucitol, tetrabutyrate;

1,5-(Butylimino)-1,5-dideoxy-D-glucitol, tetrapropionate;

1,5-(Butylimino)-1,5-dideoxy-D-glucitol, tetrabenzoate;

1,5-Dideoxy-1,5-imino-D-glucitol, tetraisobutyrate;

1,5-(Hydrocinnamoylimino)-1,5-dideoxy-D-glucitol, tetraacetate;

1,5-(Methyl malonylimino)-1,5-dideoxy-D-glucitol, tetraacetate;

1,5-(Butylimino)-1,5-dideoxy-D-glucitol, tetraisobutyrate;

1,5-(Butylimino)-1,5-dideoxy-4R,6-O-(phenylmethylene)-D-glucitol, diacetate;

1,5-[(Phenoxymethyl)carbonylimino]-1,5-dideoxy-D-glucitol, tetraacetate;

1,5-[(Ethylbutyl)imino]-1,5-dideoxy-D-glucitol, tetraacetate;

1,5-(Butylimino)-1,5-dideoxy-D-glucitol, 2,3-diacetate;

1,5-(Hexylimino)-1,5-dideoxy-4R,6-O-(phenylmethylene)-D-glucitol, diacetate;

1,5-(Hexylimino)-1,5-dideoxy-D-glucitol, 2,3-diacetate;

1,5-[(2-Methylpentyl)imino]-1,5-dideoxy-D-glucitol, tetraacetate;

1,5-(Butylimino)-1,5-dideoxy-D-glucitol, 6-acetate;

1,5-[(3-Nicotinoyl)imino]-1,5-dideoxy-D-glucitol, tetraacetate;

1,5-(Cinnamoylimino)-1,5-dideoxy-D-glucitol, tetraacetate;

1,5-(Butylimino)-1,5-dideoxy-D-glucitol, 2,3-dibutyrate;

1,5-(Butylimino)-1,5-dideoxy-4R,6-O-(phenylmethylene)-D-glucitol, 2,3-dibutyrate;

1,5-(Phenylacetylimino)-1,5-dideoxy-D-glucitol, tetraisobutyrate;

1,5-[(4-Chlorophenyl)acetylimino]-1,5-dideoxy-D-glucitol, tetraacetate;

1,5[(4-Biphenyl)acetylimino]-1,5-dideoxy-D-glucitol, tetraacetate;

1,5-(Benzyloxycarbonylimino)-1,5-dideoxy-D-glucitol, tetrabutyrate;

1,5-Dideoxy-1,5-imino-D-glucitol, tetrabutyrate;

3,4,5-piperidinetriol, 1-propyl-2-(hydroxymethyl)-, (2S,3R,4R,5S);

3,4,5-piperidinetriol, 1-pentyl-2-(hydroxymethyl)-, (2S,3R,4R,5S);

3,4,5-piperidinetriol, 1-heptyl-2-(hydroxymethyl)-, (2S,3R,4R,5S);

3,4,5-piperidinetriol, 1-butyl-2-(hydroxymethyl)-, (2S,3S,4R,5S);

3,4,5-piperidinetriol, 1-nonyl-2-(hydroxymethyl)-, (2S,3R,4R,5S);

3,4,5-piperidinetriol, 1-(1-ethyl) propyl-2-(hydroxymethyl)-, (2S,3R,4R,5S);

3,4,5-piperidinetriol, 1-(3-methyl) butyl-2-(hydroxymethyl)-, (2S,3R,4R,5S);

3,4,5-piperidinetriol, 1-(2-phenyl) ethyl-2-(hydroxymethyl)-, (2S,3R,4R,5S);

3,4,5-piperidinetriol, 1-(3-phenyl) propyl-2-(hydroxymethyl)-, (2S,3R,4R,5S);

3,4,5-piperidinetriol, 1-(1-ethyl) hexyl-2-(hydroxymethyl)-, (2S,3R,4R,5S);

3,4,5-piperidinetriol, 1-(2-ethyl) butyl-2-(hydroxymethyl)-, (2S,3R,4R,5S);

3,4,5-piperidinetriol, 1-[(2R)-(2-methyl-2-phenyl)ethyl]-2-(hydroxymethyl)-, (2S,3R,4R,5S);

3,4,5-piperidinetriol, 1-[(2S)-(2-methyl-2-phenyl)ethyl]-2-(hydroxymethyl)-, (2S,3R,4R,5S), β

-L-homofuconojirimycin;

propyl 2-acetamido-2-deoxy-4-O-(β

-D-galactopyranosyl)-3-O-(2-(N-(β

-L-homofuconojirimycinyl))ethyl)-α

-D-glucopyranoside;

ido-N-(5-adamantane-1-yl-methoxy-pentyl)deoxynojirimycin;

N-(adamantane-1-yl-methoxypentyl)-L-ido-deoxynojirimycin;

N-(adamantane-1-yl-methoxypentyl)-D-galacto-deoxynojirimycin;

C1-beta-(adamantane-1-yl-methoxypentyl)-deoxynojirimycin;

N-methyl-C1-beta-(adamantane-1-yl-methoxypentyl)-deoxynojirimycin;

N-butyl-C1-beta-(adamantane-1-yl-methoxypentyl)-deoxynojirimycin;

2-O-(adamantane-1-yl-methoxypentyl)-deoxynojirimycin;

N-methyl-2-O-(adamantane-1-yl-methoxy-pentyl)-deoxynojirimycin;

N-butyl-2-O-(adamantane-1-yl-methoxy-pentyl)-deoxynojirimycin;

N-benzyloxycarbonyl-2-O-(adamantane-1-yl-methoxypentyl)-3,4,6-tri-O-benzyl-deoxy-nojirimycin; and

N-(5-adamantane-1-yl-methoxy-pentyl)deoxynojirimycin.

21. The method of claim 7 wherein the inhibitor of sphingolipid biosynthesis is of formula (IV) and wherein:

R^IVa and R^IVd are both H;

R^IVe is —

C(O)R^IVg;

R^IVg is unsubstituted C_1-20 alkyl;

R^IVb is —

CH═

CHR^IVf, wherein R^IVf is unsubstituted C_1-20 alkyl, or R^IVb is a group of the following formula (IVa);

25. The method of claim 1 wherein the inhibitor of sphingolipid biosynthesis is RNA.

28. The method of claim 1 wherein the disease which has a secondary Niemann-Pick type C disease like cellular phenotype is a disease which incurs the accumulation of a class II amphiphile.

29. The method of claim 28 wherein the class II amphiphile is a precursor or analogue of cholesterol.

30. The method of claim 1 wherein the disease which has a secondary Niemann-Pick type C disease-like cellular phenotype is selected from Smith-Lemli-Opitz Syndrome (SLOS), an inborn error of cholesterol synthesis, CHILD syndrome, XLD chondrodysplasia punctata type 2, Conradi-Hü

nnermann-Happle syndrome, HEM dysplasia, Tangier disease, Huntington'"'"'s disease, Cystic Fibrosis, Pelizaeus-Merzbacher disease, Mucolipidosis II (Icell), variant late infantile-Neuronal Ceroid Lipofuscinosis, a disorder which alters the activity of an enzyme involved in cholesterol synthesis or homeostasis, and autism.

31. The method of claim 1 further comprising coadministering the inhibitor of sphingolipid biosynthesis with cholesterol and/or an inhibitor of de novo cholesterol biosynthesis, wherein the disease is Smith-Lemli-Opitz Syndrome (SLOS).

33. The method of claim 1, wherein the inhibitor of sphingolipid biosynthesis is a compound of formula (I) and the disease is inborn error of cholesterol synthesis, Tangier disease, Pelizaeus-Merzbacher disease, Mucolipidosis II (cell), and variant late infantile-Neuronal Ceroid Lipofuscinosis.

34. The method of claim 33, wherein the inhibitor of sphingolipid biosynthesis is N-butyldeoxynojirimycin;

N-nonyldeoxynojirimycin;

N-butyldeoxygalactonojirimycin;

N-5adamantane-1-yl-methoxypentyl-deoxynojirimycin;

alpha-homogalactonojirimycin;

nojirimycin;

deoxynojirimycin;

N7-oxadecyl-deoxynojirimycin;

deoxygalactonojirimycin;

N-butyl-deoxygalactonojirimycin;

N-nonyl-6deoxy-DGJ;

alpha-homoallonojirimycin;

or beta-1C-butyl-deoxygalactonojirimycin.

35. The method of claim 34, wherein the disease is Tangier disease.

36. The method of claim 1, wherein the inhibitor of sphingolipid biosynthesis is a compound of formula (IV).

2-6. -6. (canceled)

11-20. -20. (canceled)

22-24. -24. (canceled)

26-27. -27. (canceled)

32. (canceled)