Substituted amino acids as neutral sphingomyelinase inhibitors

Details Substituted amino acids as neutral sphingomyelinase inhibitors Substituted amino acids as neutral sphingomyelinase inhibitors

2000-02-07

2001-10-23

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

C514S311000, C514S314000, C514S332000, C514S337000, C514S351000, C514S443000, C514S444000, C514S438000, C514S539000, C514S561000, C514S563000, C514S569000, C546S174000, C546S264000, C549S058000, C549S059000, C549S077000, C560S038000, C562S433000, C562S439000, C562S442000, C562S443000, C562S445000, C562S451000, C564S164000

Reexamination Certificate

active

06306911

ABSTRACT:

BACKGROUND OF THE INVENTION
Neutral sphingomyelinase is a magnesium sensitive enzyme that is a member of the sphingomyelinase family, that catalyzes the hydrolytic cleavage of sphingomyelin to ceramide and phosphocholine at neutral pH optima. Ceramide and phosphocholine have a role as lipid second messengers in multiple signal transduction pathways including pathways involved in cell proliferation, apoptosis, and differentiation. Neutral sphingomyelinase may be involved in a wide variety of human diseases and conditions, including insulin resistant diabetes, arthritis, inflammation, cancer, and atherosclerosis. A review of the properties of Neutral sphingomyelinase is found in Chatterjee, S., Chemistry and Physics of Lipids, 102 (1999) pp79-96.
This invention relates to a series of small molecules that bind to neutral sphingomyelinase and inhibit the enzyme's activity. The invention includes pharmaceutical compositions containing these compounds, their methods of production as well as intermediates used in their synthesis. The present invention also includes methods of treating a patient suffering from a disorder that is related to the activity of neutral sphingomyelinase.
SUMMARY OF THE INVENTION
The disclosed invention contemplates a series of small molecules that demonstrate inhibition of neutral sphingomyelinase, an enzyme that cleaves sphingomyelin to yield ceramide and phosphocholine. As such these compounds are potentially useful in the treatment of diseases associated with neutral sphingomyelinase. In addition, the invention contemplates methods of producing these compounds and intermediates used in their manufacture.
The invention includes compounds of the Formula I:
wherein:
R
1
is the side chain of a natural or unnatural-amino acids, where if said side chain contains a protectable group, that group may be protected with a member of the group consisting of succinyl, glutaryl, 3,3-dimethylglutaryl, C
1-5
alkyl, C
1-5
alkoxycarbonyl, acetyl, N-(9-fluorenylmethoxycarbonyl), trifluoroacetyl, omega-carboxyC
1-5
alkylcarbonyl, t-butoxycarbonyl, benzyl, benzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, phenylsulfonyl, ureido, t-butyl, cinnamoyl, trityl, 4-methyltrityl, 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl, tosyl, 4-methoxy-2,3,6-trimethylbenzenesulfonyl, phenylureido, and substituted phenylureido (where the phenyl substituents are phenoxy, halo, C
1-5
alkoxycarbonyl);
R
2
and R
3
may be taken together to form a six-membered aromatic ring which is fused to the depicted ring, or
are independently selected from the group consisting of hydrogen, C
1-5
alkyl, C
1-5
alkoxy, hydroxy, halo, trifluoromethyl, nitro, amino, phenyl, phenoxy, phenylC
1-5
alkyl, phenyl C
1-5
alkoxy,
substituted phenyl (where the substituents are selected from C
1-5
alkyl, C
1-5
alkoxy, hydroxy, halo, trifluoromethyl, nitro, nitrile, and amino),
substituted phenoxy (where the substituents are selected from C
1-5
alkyl, C
1-5
alkoxy, hydroxy, halo, trifluoromethyl, nitro, nitrile, and amino),
substituted phenylC
1-5
alkyl (where the substituents are selected from C
1-5
alkyl, C
1-5
alkoxy, hydroxy, halo, trifluoromethyl, nitro, nitrile, and amino),
substituted phenylC
1-5
alkoxy (where the substituents are selected from C
1-5
alkyl, C
1-5
alkoxy, hydroxy, halo, trifluoromethyl, nitro, nitrile, and amino), and
substituted amino (where the substituents are selected from one or more members of the group consisting of C
1-5
alkyl, halosubstitutedC
1-5
alkyl, C
1-5
alknyl, C
1-5
alkenyl, phenyl, phenylC
1-5
alkyl, C
1-5
alkylcarbonyl, halo substituted C
1-5
alkylcarbonyl, carboxyC
1-5
alkyl, C
1-5
alkoxyC
1-5
alkyl, cinnamoyl, naphthylcarbonyl, furylcarbonyl, pyridylcarbonyl, C
1-5
alkylsulfonyl, phenylcarbonyl, phenylC
1-5
alkylcarbonyl, phenylsulfonyl, phenylC
1-5
alkylsulfonyl substituted phenylcarbonyl, substituted phenylC
1-5
alkylcarbonyl, substituted phenylsulfonyl, substituted phenylC
1-5
alkylsulfonyl, substituted phenyl, and substituted phenylC
1-5
alkyl [where the aromatic phenyl, phenylC
1-5
alkyl, phenylcarbonyl, phenylC
1-5
alkylcarbonyl, phenylsulfonyl, and phenylC
1-5
alkylsulfonyl substitutents are independently selected from one to five members of the group consisting of C
1-5
alkyl, C
1-5
alkoxy, hydroxy, halogen, trifluoromethyl, nitro, nitrile, and amino]);
R
4
and R
5
may be taken together to form a six-membered aromatic ring which is fused to the depicted ring, or are independently selected from the group consisting of hydrogen, C
1-5
alkyl, C
1-5
alkoxy, hydroxy, halo, trifluoromethyl, nitro, amino, phenyl, phenoxy, phenylC
1-5
alkyl, phenyl C
1-5
alkoxy,
substituted phenyl (where the substituents are selected from C
1-5
alkyl, C
1-5
alkoxy, hydroxy, halo, trifluoromethyl, nitro, nitrile, and amino),
substituted phenoxy (where the substituents are selected from C
1-5
alkyl, C
1-5
alkoxy, hydroxy, halo, trifluoromethyl, nitro, nitrile, and amino),
substituted phenylC
1-5
alkyl (where the substituents are selected from C
1-5
alkyl, C
1-5
alkoxy, hydroxy, halo, trifluoromethyl, nitro, nitrile, and amino),
substituted phenylC
1-5
alkoxy (where the substituents are selected from C
1-5
alkyl, C
1-5
alkoxy, hydroxy, halo, trifluoromethyl, nitro, nitrile, and amino), and
substituted amino (where the substituents are selected from one or more members of the group consisting of C
1-5
alkyl, halosubstitutedC
1-5
alkyl, C
1-5
alknyl, C
1-5
alkenyl, phenyl, phenylC
1-5
alkyl, C
1-5
alkylcarbonyl, halo substituted C
1-5
alkylcarbonyl, carboxyC
1-5
alkyl, C
1-5
alkoxyC
1-5
alkyl, cinnamoyl, naphthylcarbonyl, furylcarbonyl, pyridylcarbonyl, C
1-5
alkylsulfonyl, phenylcarbonyl, phenylC
1-5
alkylcarbonyl, phenylsulfonyl, phenylC
1-5
alkylsulfonyl substituted phenylcarbonyl, substituted phenylC
1-5
alkylcarbonyl, substituted phenylsulfonyl, substituted phenylC
1-5
alkylsulfonyl, substituted phenyl, and substituted phenylC
1-5
alkyl [where the aromatic phenyl, phenylC
1-5
alkyl, phenylcarbonyl, phenylC
1-5
alkylcarbonyl, phenylsulfonyl, and phenylC
1-5
alkylsulfonyl substitutents are independently selected from one to five members of the group consisting of C
1-5
alkyl, C
1-5
alkoxy, hydroxy, halogen, trifluoromethyl, nitro, nitrile, and amino]);
W is selected from the group consisting of —CH═CH—, —S—, and —CH═N—;
Q is selected from the group consisting of —CH═CH—, —S—, and —CH═N—;
X is selected from the group consisting of carbonyl, C
1-5
alkyl, C
1-5
alkenyl, C
1-5
alkenylcarbonyl, C
2-5
alkynyl, C
2-5
alkynylcarbonyl and (CH
2
)
m
—C(O)— where m is 2-5;
Y is selected from the group consisting of carbonyl, C
1-5
alkyl, C
1-5
alkenyl, C
1-5
alkenylcarbonyl, C
2-5
alkynyl, C
2-5
alkynylcarbonyl and (CH
2
)
m
—C(O)— where m is 2-5;
Z is selected from the group consisting of hydroxy, C
1-5
alkoxy, phenoxy, phenylC
1-5
alkoxy, amino, C
1-5
alkylamino, diC
1-5
alkylamino, phenylamino, phenylC
1-5
alkylamino, piperidin-1-yl
substituted piperidin-1-yl (where the substituents are selected from the group consisting of C
1-5
alkyl, C
1-5
alkoxy, halo, aminocarbonyl, C
1-5
alkoxycarbonyl, and oxo;
substituted phenylC
1-5
alkylamino (where the aromatic substitutents are selected from the group consisting of C
1-5
alkyl, C
1-5
alkoxy, phenylC
1-5
alkenyloxy, hydroxy, halogen, trifluoromethyl, nitro, nitrile, and amino),
substituted phenoxy (where the aromatic substitutents are selected from the group consisting of C
1-5
alkyl, C
1-5
alkoxy, hydroxy, halogen, trifluoromethyl, nitro, nitrile, and amino),
substituted phenylC
1-5
alkoxy (where the aromatic substitutents are selected from the group consisting of C
1-5
alkyl, C
1-5
alkoxy, hydroxy, halogen, trifluoromethyl, nitro, nitrile, and amino),
—OCH
2
CH
2
(OCH
2
CH
2
)
s
OCH
2
CH
2
O—, —NHCH
2
CH
2
(OCH
2
CH
2
)
s
OCH
2
CH
2
NH—, —NH(CH
2
)
p
O(CH
2
)
q
O(CH
2
)
p
NH—, —NH(CH
2
)
q
NCH
3
(CH
2
)
s
NH—, —NH(CH
2
)
s
NH—, and (NH(CH
2
)
s
)
3
N,
where s, p, and q are independently selected from 1-7
and the salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
The terms used in describing the i

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