SUBSTRATE REDUCTION THERAPY

• US 20100204162A1
• Filed: 06/26/2008
• Published: 08/12/2010
• Est. Priority Date: 06/27/2007
• Status: Active Grant

• Current Assignee: United States Department Of Health And Human Services
• Original Assignee: United States Department Of Health And Human Services
• Inventors: Porter, Forbes Dennison, Lloyd-Evans, Emyr, Platt, Mary Frances
• Granted Patent: US 8,557,844 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 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, provided that the disease is other than mucopolysaccharidosis and other than mucolipidosis IV.

2. A compound as claimed in claim 1 which is an inhibitor of a glycosyltransferase or a sulfotransferase.

3. A compound as claimed in claim 2 wherein the glycosyltransferase is a glucosyltransferase, sialyltransferase, galactosyltransferase, ceramide galactosyltransferase, fucosyltransferase, or N-acetylhexosaminetransferase.

4. A compound as claimed in any one of claims 1 to 3 which is an inhibitor of glucosylceramide synthase.

5. A compound as claimed in claim 1 which is an inhibitor of ceramide biosynthesis.

6. A compound as claimed in claim 1 or claim 5 which is an inhibitor of serine palmitoyltransferase or an inhibitor of dihydroceramide synthase.

7. A compound as claimed in any one of the preceding claims which is an inhibitor of sphingolipid biosynthesis of one of the following formulae (I), (II), (III), (IV), (V), (IX) and (XII):

wherein;

X is O, S or NR⁵;

R⁵ is hydrogen, substituted or unsubstituted C_1-20 alkyl, substituted or unsubstituted C_1-20 alkylene-aryl, substituted or unsubstituted C_1-20 alkylene-C_3-20 heteroaryl, substituted or unsubstituted C_1-20 alkylene-C_3-25 cycloalkyl, substituted or unsubstituted C_1-20 alkylene-C_3-20 heterocyclyl, substituted or unsubstituted C_1-20 alkylene-O—

C_3-20 heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted C_3-20 heteroaryl, substituted or unsubstituted C_3-25 cycloalkyl or substituted or unsubstituted C_3-20 heterocyclyl, or R⁵ forms, together with R¹, R¹¹, R⁴ or R¹⁴, a substituted or unsubstituted C_1-6 alkylene group, wherein said C_1-20 alkyl and C_1-20 alkylene are optionally interrupted by N(R′

), O, S or arylene wherein R′

is H, C_1-6 alkyl or aryl;

n is 0 or 1;

Y is O, S or CR⁶R¹⁶;

R¹, R¹¹, R⁴ and R¹⁴, which may be the same or different, are independently selected from hydrogen, hydroxyl, carboxyl, amino, thiol, substituted or unsubstituted C_1-20 alkyl, substituted or unsubstituted C_1-20 alkoxy, substituted or unsubstituted aryloxy, acyl, ester, acyloxy, C_1-10 alkylamino, di(C_1-10)alkylamino, amido, acylamido, —

O—

C_3-25 cycloalkyl and —

O—

C_3-20 heterocyclyl, provided that one of R¹, R¹¹, R⁴ and R¹⁴ may form, together with R⁵, a substituted or unsubstituted C_1-6 alkylene group, wherein said C_1-20 alkyl is optionally interrupted by N(R′

), O, S or arylene;

R², R¹², R³, R¹³, R⁶ and R¹⁶, which may be the same or different, are independently selected from hydrogen, hydroxyl, carboxyl, amino, thiol, substituted or unsubstituted C_1-20 alkyl, substituted or unsubstituted C_1-20 alkoxy, substituted or unsubstituted aryloxy, acyl, ester, acyloxy, C_1-10 alkylamino, di(C_1-10)alkylamino, amido, acylamido —

O—

C_3-25 cycloalkyl and —

O—

C_3-20 heterocyclyl, wherein said C_1-20 alkyl is optionally interrupted by N(R′

), O, S or arylene;

R²¹ is selected from oxo, -L³⁰-R²³, -L³⁰-C(O)N(H)—

R²⁴ and a group of the following formula (VI);

L³⁰ is substituted or unsubstituted C_1-20 alkylene which is optionally interrupted by N(R′

), O, S or arylene;

R²³ is carboxyl, hydroxyl, ester, phosphonate ester, phosphate ester, phosphoric acid and phosphonic acid;

R²⁴ is C_1-20 alkyl which is unsubstituted or substituted with one or more groups selected from carboxyl, hydroxyl, ester, phosphonate ester, phosphate ester, phosphoric acid and phosphonic acid, wherein said C_1-20 alkyl is optionally interrupted by N(R′

), O, S or arylene;

R³⁰ is C_1-20 alkyl which is unsubstituted or substituted with one or more groups selected from carboxyl, hydroxyl, ester, amino, phosphonate ester, phosphate ester, phosphoric acid and phosphonic acid, wherein said C_1-20 alkyl is optionally interrupted by N(R′

), O, S or arylene; and

R²² is hydroxyl, oxo, acyloxy, phosphoric acid or —

OC(O)-alk-C(O)OH, wherein alk is substituted or unsubstituted C_1-20 alkylene which is optionally interrupted by N(R′

), O, S or arylene;

Base is selected from a group of any one of the following formulae (a), (b), (c), (d), (e), (f) and (g);

y is 0 or 1;

R³¹ is OH;

R³² is H or OH;

or, provided that y is 0, R³¹ and R³² together form —

O—

C(R³³)(R³⁴)—

O—

, wherein R³³ and R³⁴ are independently selected from H and methyl;

A is substituted or unsubstituted C_1-20 alkyl, substituted or unsubstituted C_1-20 alkylene-aryl, substituted or unsubstituted C_1-20 alkylene-C_3-20 heteroaryl, substituted or unsubstituted C_1-20 alkylene-C_3-25 cycloalkyl or substituted or unsubstituted C_1-20 alkylene-C_3-20 heterocyclyl, wherein said C_1-20 alkyl and C_1-20 alkylene are optionally interrupted by N(R′

), O, S or arylene, wherein R′

is H, C_1-6 alkyl or aryl, or A is a group of any one of the following formulae (g) to (k);

L⁷⁰, L⁷⁰¹ and L⁷⁰² are independently selected from —

O—

, —

C(R³⁵)(R³⁶)— and

—

NH—

, wherein R³⁵ and R³⁶ are independently selected from H, OH and CH₃;

R⁷⁰, R⁷¹ and R⁷⁰¹ are selected from OH, substituted or unsubstituted C_1-20 alkyl, substituted or unsubstituted C_1-20 alkoxy, substituted or unsubstituted C_1-10 alkylamino and -L⁷¹-(X²)_m-L⁷²-R⁷²;

wherein m is 0 or 1;

X² is O, S, —

C(R⁴⁵)(R⁴⁶)—

or —

O—

C(R⁴⁵)(R⁴⁶)—

, wherein R⁴⁵ and R⁴⁶ are independently selected from H, OH, phosphonic acid or a phosphonic acid salt;

L⁷¹ and L⁷² are independently selected from a single bond and substituted or unsubstituted C_1-20 alkylene, which C_1-20 alkylene is optionally interrupted by N(R′

), O, S or arylene, wherein R′

is H, C_1-6 alkyl or aryl; and

R⁷² is C_3-25 cycloalkyl or C_3-20 heterocyclyl;

L^J is substituted or unsubstituted C_1-20 alkylene;

R^J1, R^J2, R^J3, R^J4, R^J5, R^J6 and R^J7, which are the same or different, are independently selected from hydrogen, hydroxyl, carboxyl, amino, thiol, substituted or unsubstituted C_1-20 alkyl, substituted or unsubstituted C_1-20 alkoxy, substituted or unsubstituted aryloxy, acyl, ester, acyloxy, C_1-10 alkylamino, di(C_1-10)alkylamino, amido, acylamido, —

N(H)C(O)CH═

CH—

R^J8, —

O—

C_3-25 cycloalkyl and —

O—

C_3-20 heterocyclyl, wherein said C_1-20 alkyl is optionally interrupted by N(R′

), O, S or arylene, and wherein R^J8 is substituted or unsubstituted C_1-20 alkyl;

L^K1 and L^K2, which are the same or different, are independently selected from a single bond and substituted or unsubstituted C_1-20 alkylene;

X^K is N or C(R^K6), wherein R^K6 is H, COOH or ester;

Z^K is O or CH(R^K5);

p is 0 or 1;

R^K1, R^K2, R^K3, R^K4 and R^K5, which are the same or different, are independently selected from hydrogen, hydroxyl, carboxyl, amino, thiol, substituted or unsubstituted C_1-20 alkyl, substituted or unsubstituted C_1-20 alkoxy, substituted or unsubstituted aryloxy, acyl, ester, acyloxy, C_1-10 alkylamino, di(C_1-10)alkylamino, amido, acylamido, —

O—

C_3-25 cycloalkyl and —

O—

C_3-20 heterocyclyl, wherein said C_1-20 alkyl is optionally interrupted by N(R′

), O, S or arylene;

R^IVa and R^IVd, which are the same or different, are independently selected from H, substituted or unsubstituted C_1-6 alkyl or substituted or unsubstituted phenyl;

R^IVb is H, substituted or unsubstituted aryl, —

CH═

CHR^IVf, or substituted or unsubstituted C_1-20 alkyl, which C_1-20 alkyl is optionally interrupted by N(R′

), O, S or arylene wherein R′

is H, C_1-6 alkyl or aryl;

R^IVc is H, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted phenyl or —

C(O)R^IVg;

R^IVf is H or substituted or unsubstituted C_1-20 alkyl, which C_1-20 alkyl is optionally interrupted by N(R′

), O, S or arylene;

R^IVg is H or substituted or unsubstituted C_1-20 alkyl, which C_1-20 alkyl is optionally interrupted by N(R′

), O, S or arylene;

R^IVe is H, hydroxyl, carboxyl, amino, thiol, substituted or unsubstituted C_1-20 alkyl, substituted or unsubstituted C_1-20 alkoxy, substituted or unsubstituted aryloxy, acyl, ester, acyloxy, C_1-10 alkylamino, di(C_1-10)alkylamino, amido, acylamido, —

O—

C_3-25 cycloalkyl, —

O—

C_3-20 heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted C_3-20 heteroaryl, substituted or unsubstituted C_3-25 cycloalkyl or substituted or unsubstituted C_3-20 heterocyclyl, which C_1-20 alkyl is optionally interrupted by N(R′

), O, S or arylene;

L^IV is substituted or unsubstituted C_1-20 alkylene which C_1-20 alkylene is optionally interrupted by N(R′

), O, S or arylene;

R⁹¹ and R⁹², which are the same or different, are independently selected from H, substituted or unsubstituted C_1-20 alkyl, substituted or unsubstituted aryl and -L⁹¹-R⁹⁵, wherein L⁹¹ is substituted or unsubstituted C_1-20 alkylene, wherein said C_1-20 alkyl and said C_1-20 alkylene are optionally interrupted by N(R′

), O, S or arylene wherein R′

is H, C_1-6 alkyl or aryl, and wherein R⁹⁵ is substituted or unsubstituted aryl, amino, C_1-10 alkylamino or di(C_1-10)alkylamino;

R⁹³ is -L⁹²-R⁹⁶, wherein L⁹² is a single bond or substituted or unsubstituted C_1-20 alkylene, which C_1-20 alkylene is optionally interrupted by N(R′

), O, S or arylene, and wherein R⁹⁶ is amido or substituted or unsubstituted aryl;

R⁹⁴ is H or substituted or unsubstituted C_1-20 alkyl, which C_1-20 alkyl is optionally interrupted by N(R′

), O, S or arylene;

q is 0 or 1;

r is 0 or 1;

R^IXa is H, COON or an unsubstituted or substituted ester;

R^IXb is an unsubstituted or substituted C_1-6 alkyl;

R^IXc and R^IXd, which are the same or different, are each independently selected from H, unsubstituted or substituted C_1-6 alkyl and unsubstituted or substituted phenyl;

R^IXe and R^IXf, which are the same or different, are each independently selected from H, unsubstituted or substituted C_1-6 alkyl, unsubstituted or substituted phenyl and unsubstituted or substituted acyl;

either (a) one of R^IXg and R^IXh is H and the other is OR^IXr, wherein R^IXr is selected from H, unsubstituted or substituted C_1-6 alkyl, unsubstituted or substituted phenyl and unsubstituted or substituted acyl, or (b) R^IXg and R^IXh together form an oxo group;

R^IXi is H, unsubstituted or substituted C_1-6 alkyl, unsubstituted or substituted C_1-6 alkoxy and unsubstituted or substituted phenyl;

R^IXj is H, unsubstituted or substituted C_1-6 alkyl or a group of the following formula (X);

in which R^IXn and R^IXo, which are the same or different, are each independently selected from OH, unsubstituted or substituted C_1-6 alkoxy, unsubstituted or substituted phenoxy, amino, unsubstituted or substituted C_1-6 alkylamino and unsubstituted or substituted di(C_1-6)alkylamino;

R^IXk is H, unsubstituted or substituted C_1-6 alkyl or a group of the following formula (XI);

in which R^IXp and R^IXq, which are the same or different, are each independently selected from OH, unsubstituted or substituted C_1-6 alkoxy, unsubstituted or substituted phenoxy, amino, unsubstituted or substituted C_1-6 alkylamino and unsubstituted or substituted di(C_1-6)alkylamino;

R^IXm is selected from H and unsubstituted or substituted C_1-20 alkyl, which C_1-20 alkyl is optionally interrupted by N(R′

), O, S or phenylene, wherein R′

is H, C_1-6 alkyl or phenyl;

R^Xa is H, substituted or unsubstituted C_1-20 alkyl, substituted or unsubstituted C_1-20 alkylene-aryl, substituted or unsubstituted C_1-20 alkylene-C_3-20 heteroaryl, substituted or unsubstituted C_1-20 alkylene-C_3-25 cycloalkyl, substituted or unsubstituted C_1-20 alkylene-C_3-20 heterocyclyl, substituted or unsubstituted C_1-20 alkylene-O—

C_3-20 heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted C_3-20 heteroaryl, substituted or unsubstituted C_3-25 cycloalkyl or substituted or unsubstituted C_3-20 heterocyclyl wherein said C_1-20 alkyl and C_1-20 alkylene are optionally interrupted by N(R′

), O, S or arylene wherein R′

is H, C_1-6 alkyl or aryl; and

R^Xb and R^Xc, which are the same or different, are independently selected from H, unsubstituted or substituted C_1-10 alkyl and unsubstituted or substituted aryl;

or a pharmaceutically acceptable salt thereof.

8. A compound as claimed in claim 7 wherein the inhibitor of sphingolipid biosynthesis has the following formula (Ia):

wherein Y is O, S or CHR⁶; and

X, n, R¹, R², R³, R⁴ R⁵, R⁶ and R¹¹ are as defined in claim 7.

9. A compound as claimed in 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 O; 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);

in which each R^m is independently selected from C_1-6 alkyl, OH, acyloxy, SH, C_1-6 alkoxy, aryloxy, amino, C_1-10 alkylamino, di(C_1-10)alkylamino, amido and acylamido;

or R⁵ forms, together with R⁴, a substituted or unsubstituted C_1-6 alkylene group.

10. A compound as claimed in any one of the preceding claims which 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.

11. A compound as claimed in claim 8 wherein:

X is NR⁵;

Y is O or S;

n is either 0 or 1;

R¹¹ is H; and

R⁵ is selected from hydrogen and a group of the following formula (VIII);

in which;

R⁴⁰ and R⁴², which are the same or different, are independently selected from H, substituted or unsubstituted C_1-6 alkyl or substituted or unsubstituted phenyl;

R⁴¹ is H, substituted or unsubstituted aryl, —

CH═

CHR⁴⁴, or substituted or unsubstituted C_1-20 alkyl, which C_1-20 alkyl is optionally interrupted by N(R′

), O, S or arylene wherein R′

is H, C_1-6 alkyl or aryl;

R⁴³ is H, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted phenyl or —

C(O)R⁴⁷;

R⁴⁴ is H or substituted or unsubstituted C_1-20 alkyl, which C_1-20 alkyl is optionally interrupted by N(R′

), O, S or arylene;

R⁴⁷ is substituted or unsubstituted C_1-20 alkyl, which C_1-20 alkyl is optionally interrupted by N(R′

), O, S or arylene; and

L⁴⁰ is substituted or unsubstituted C_1-10 alkylene.

12. A compound as claimed in claim 8 or claim 11 which is selected from:

D,L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol;

D,L-threo-1-phenyl-2-hexadecanoylamino-3-morpholino-1-propanol;

D-threo-1-phenyl-2-palmitoilamino-3-pyrrolidino-1-propanol;

4′

-hydroxy-D-threo-1-phenyl-2-palmitoilamino-3-pyrrolidino-1-propanol;

3′

,4′

-ethylenedioxy-P4 and 2,5-dihydroxymethyl-3,4-dihydroxypyrrolidine.

13. A compound as claimed in claim 8 wherein:

X is O or S;

n is 1;

Y is CHR⁶;

R¹¹ is H;

R⁶ is H, hydroxyl, acyloxy, C_1-20 alkoxy, C_1-10 alkylamino or di(C_1-10)alkylamino;

R² and R³, which may be the same or different, are independently selected from H, hydroxyl, C_1-20 alkoxy, acyloxy or acylamido;

R⁴ is H, hydroxyl, acyloxy, thiol or C_1-20 alkyl, which C_1-20 alkyl is unsubstituted or substituted with one, two, three or four groups selected from hydroxyl, acyloxy and thiol; and

R¹ is C_1-20 alkoxy, aryloxy or —

O—

C_3-20 heterocyclyl.

14. A compound as claimed in claim 8 or claim 13 which is selected from:

15. A compound as claimed in claim 8 wherein:

X is O or S;

n is 1;

Y is CHR⁶;

R⁶ is H, hydroxyl, acyloxy or C_1-20 alkoxy;

R¹ and R¹¹ which may be the same or different, are independently selected from H, C_1-20 alkyl, hydroxyl, acyloxy, C_1-20 alkoxy, carboxyl, ester, —

O—

C_3-25 cycloalkyl, and a group of the following formula (VII);

wherein L⁶⁰ is substituted or unsubstituted C_1-20 alkylene;

x is 0 or 1;

y is 0 or 1;

A is CHR′

″ and

R is H, C_1-20 alkyl, C_3-20 heterocyclyl, C_3-25 cycloalkyl, aryl or C_1-20 alkoxy, wherein R′

″

is hydroxyl, C_1-6 alkoxy, aryloxy or acyl;

R² is H, C_1-20 alkyl, hydroxyl, acyloxy or —

O—

C_3-20 heterocyclyl;

R³ is H, hydroxyl, acyloxy, C_1-20 alkoxy or acylamido; and

R⁴ is H, carboxyl, ester or C_1-20 alkyl which is unsubstituted or substituted with one, two, three or four groups selected from hydroxyl and thiol.

16. A compound as claimed in claim 8 or claim 15 which is cytidin-5′

-yl sialylethylphosphonate, sialic acid or Soyasaponin I.

17. A compound as claimed in claim 7 wherein the inhibitor of sphingolipid biosynthesis is of formula (II), and wherein:

R²¹ is selected from oxo, -L³⁰-R²³, -L³⁰-C(O)N(H)—

R²⁴ and a group of the following formula (VI);

wherein

L³⁰ is substituted or unsubstituted C_1-6 alkylene,

R²³ is hydroxyl, carboxyl, ester or phosphate ester,

R²⁴ is C_1-6 alkyl which is unsubstituted or substituted with one or two carboxyl groups;

R³⁰ is C_1-6 alkyl which is unsubstituted or substituted with one or two groups selected from hydroxyl, carboxyl, amino and phosphonate ester; and

R²² is as defined in claim 7.

18. A compound as claimed in claim 7 or claim 17 which is selected from the compounds of formula (II) listed in Table 1.

19. A compound as claimed in claim 7 wherein the inhibitor of sphingolipid biosynthesis is of formula (III) and wherein:

Base is selected from (a), (b), (c), (d) and (e);

y is 0 and R³¹ and R³² are both —

OH;

A is either (g), (h) or (i);

L⁷⁰, L⁷⁰¹ and L⁷⁰² are selected from O, CH₂, CHOH, C(OH)(CH₃) and NH; and

R⁷⁰, R⁷¹ and R⁷⁰¹ are as defined in claim 7.

20. A compound as claimed in claim 7 or claim 19 which is selected from the compounds of formula (III) listed in Table 2.

21. A compound as claimed in claim 7 wherein the inhibitor of sphingolipid biosynthesis is of formula (IV) and wherein:

R^IVa and R^IVd are both H;

R^IVc 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);

in which R^IVh is H, C_1-6 alkyl or phenyl, or R^IVh forms, together with R^IVi, a bidentate group of the structure —

O-alk-O—

; and

R^IVi is H, C_1-6 alkyl or phenyl, or R^IVi forms, together with R^IVh, a bidentate group of the structure —

O-alk-O—

, wherein alk is substituted or unsubstituted C_1-6 alkylene; and

R^IVe is OH, substituted or unsubstituted aryl, substituted or unsubstituted C_3-20 heteroaryl, substituted or unsubstituted C_3-25 cycloalkyl or substituted or unsubstituted C_3-20 heterocyclyl.

22. A compound as claimed in claim 7 wherein the inhibitor of sphingolipid biosynthesis is of formula (V) and wherein

R⁹¹ is H, —

C_1-4 alkylene-amino, —

C_1-4 alkylene-C_1-10 alkylamino or —

C_1-4 alkylene-di(C_1-10)alkylamino;

R⁹² is —

C_1-4 alkylene-phenyl, wherein said phenyl is substituted or unsubstituted;

R⁹³ is -L⁹²-R⁹⁶, wherein L⁹² is unsubstituted C_1-10 alkylene and R⁹⁶ is amido or substituted or unsubstituted phenyl; and

R⁹⁴ is C_1-10 alkyl, which C_1-10 alkyl is unsubstituted or substituted with a hydroxyl group.

23. A compound as claimed in claim 7 or claim 22 which is selected from the compounds of formula (V) listed in Table 3.

24. A compound as claimed in any one of claims 1 and 5 to 7 which is Fumonisin, Myriocin or L-cycloserine.

25. A compound as claimed in claim 1 wherein the inhibitor of sphingolipid biosynthesis is RNA.

26. A compound as claimed in claim 1 wherein the inhibitor of sphingolipid biosynthesis is an inhibitor of ceramide degradation.

27. A compound as claimed in claim 1 or claim 26 wherein the inhibitor of sphingolipid biosynthesis is an inhibitor of acidceramidase.

28. A compound as claimed in any one of the preceding claims 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. A compound as claimed in claim 28 wherein the class II amphiphile is a precursor or analogue of cholesterol.

30. A compound as claimed in any one of the preceding claims 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. A compound as claimed in any one of the preceding claims which is for use in said treatment of said disease by coadministration with cholesterol and/or an inhibitor of de novo cholesterol biosynthesis, wherein the disease is Smith-Lemli-Opitz Syndrome (SLOS).

32. Use of a compound which is an inhibitor of sphingolipid biosynthesis in the manufacture of a medicament for the treatment of 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.