Drug – bio-affecting and body treating compositions – Enzyme or coenzyme containing – Hydrolases
Reexamination Certificate
2002-01-22
2004-02-24
Tate, Christopher R. (Department: 1651)
Drug, bio-affecting and body treating compositions
Enzyme or coenzyme containing
Hydrolases
C514S328000
Reexamination Certificate
active
06696059
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to combination drug therapy for the treatment of Gaucher's disease and other glycolipid storage diseases.
Gaucher's disease is a glycolytic storage disease caused by a genetic deficiency in activity of the catabolic enzyme beta-glucocerebrosidase. Beutler,
Proc. Natl. Acad. Sci. USA.
90, 5384-5390 (1993). Manifestations of this disease are impaired hematopoiesis, bone fractures, a thinning of the bone cortex and massive enlargement of the spleen and liver.
In recent years, several therapies have been proposed for the treatment of Gaucher's disease. An early therapeutic approach involved replacement of the deficient enzyme. See, for example, Dale and Beutler,
Proc. Natl. Acad. Sci. USA
73, 4672-4674 (1976); Beutler et al.,
Blood
78, 1183-1189 (1991); and Beutler,
Science
256, 794-799 (1992).
Leading commercial products for enzyme replacement are CEREDASE (glucocerebrosidase), which is derived from human placental tissues, and CEREZYME (recombinant human glucocerebrosidase), both of which are produced by Genzyme Corp. See, for example, U.S. Pat. Nos. 3,910,822; 5,236,838; and 5,549,892. See also U.S. Pat. Nos. 5,879,680 and 6,074,684 on cloned DNA for synthesizing human glucocerebrosidase.
Conjugates of the glucocerebrosidase enzyme with polyethylene glycol (PEG) have also been advanced by Enzon Inc. for treatment of Gaucher's disease. See, for example, U.S. Pat. Nos. 5,705,153 and 5,620,884.
Still another approach for treatment of the disease is gene therapy, which involves an ex vivo gene transfer protocol. See, for example, U.S. Pat. No. 5,911,983.
Another recent approach involves administration of the totally synthetic drugs, N-butyldeoxynojirimycin and N-butyldeoxygalactonojirimycin, as described, respectively, by Platt et al.,
J. Biol. Chem.
269, 8362-8365 (1994); Id. 269, 27108-27114 (1994). See also, U.S. Pat. Nos. 5,472,969; 5,786,368; 5,798,366; and 5,801,185.
N-butyldeoxynojirimycin (N-butyl-DNJ) and related N-alkyl derivatives of DNJ are known inhibitors of the N-linked oligosaccharide processing enzymes, &agr;-glucosidase I and II. Saunier et al.,
J. Biol. Chem.
257, 14155-14161 (1982); Elbein,
Ann. Rev. Biochem.
56, 497-534 (1987). As glucose analogs, they also have potential to inhibit glycosyltransferases. Newbrun et al.,
Arch. Oral Biol.
28, 516-536 (1983); Wang et al.,
Tetrahedron Lett.
34, 403-406 (1993). Their inhibitory activity against the glycosidases has led to the development of these compounds as antihyperglycemic agents and as antiviral agents. See, e.g., PCT Int'l. Appln. WO 87/030903 and U.S. Pat. Nos. 4,065,562; 4,182,767; 4,533,668; 4,639,436; 5,011,829; 5,030,638; and 5,264,356.
In particular, N-butyl-DNJ has been developed as an inhibitor of human immunodeficiency virus (HIV) as described by Fleet et al.,
FEBS Lett.
237, 128-132 (1988), and by Karpas et al.,
Proc. Nat'l. Acad. Sci. USA
85, 9229-9233 (1988), U.S. Pat. No. 4,849,430; and as an inhibitor of hepatitis B virus (HBV) as described by Block et al.,
Proc. Natl. Acad. Sci. USA
91, 2235-2239 (1994), PCT Int'l. Appln. WO 95/19172 and U.S. Pat. No. 6,037,351.
BRIEF DESCRIPTION OF THE INVENTION
In accordance with the present invention, a novel method and composition is provided for the treatment of a patient affected with Gaucher's disease or other such glycolipid storage diseases. The method of the invention comprises administering to said patient a therapeutically effective amount of both a N-alkyl derivative of 1,5-dideoxy-1,5-imino-D-glucitol having from about two to about 20 carbon atoms in the alkyl chain and a glucocerebrosidase enzyme. The N-alkyl substituent can be a short-chain alkyl group such as, e.g., ethyl, butyl or hexyl, or a long-chain alkyl group such as, e.g, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octadecyl and eicosyl.
A therapeutically effective amount is meant an amount effective in alleviating or inhibiting Gaucher's disease or other such glycolipid storage diseases in said patient. The glucocerebrosidase provides enzyme replacement for non-breakdown of glucocerebroside and the N-alkyl-DNJ jointly provides glycolipid inhibitory action. By use of the combination drug therapy of the invention, the medical benefits of both types of drugs should accrue to the patient with reduced amounts of either or both drugs than otherwise necessary to obtain equivalent or enhanced therapeutic results. That is, an additive or synergistic effect can reduce the frequency of the administration of the glucocerebrosidase enzyme and lower the dose of the long-chain N-alkyl-DNJ otherwise required for monotherapy of the disease.
The alkyl group in the short-chain N-alkyl-DNJ compounds preferably contains four to six carbon atoms (e.g., butyl or hexyl). A most preferred compound is N-butyl-1,5-dideoxy-1,5-imino-D-glucitol, also known as the N-butyl derivative of deoxynojirimycin (DNJ), which also is abbreviated herein as N-butyl-DNJ.
The alkyl group in the long-chain N-alkyl-DNJ compounds preferably contains nine to ten carbon atoms (i.e., nonyl and decyl). A most preferred compound is N-nonyl-1,5-dideoxy-1,5-imino-D-glucitol, also known as the N-nonyl derivative of deoxynojirimycin (DNJ), which also is abbreviated herein as N-nonyl-DNJ.
In the field of general organic chemistry, the long-chain alkyl groups are known to provide more hydrophobic properties to compounds than are the short-chain alkyl groups. That is, solubility with water decreases with increase in chain length and decrease in temperature. For example, at 46° C., caproic acid (short-chain hexyl group) dissolves 10% by weight of water, whereas stearic acid (long-chain octadecyl group) dissolves only 0.92% even at the higher temperature of 69° C.
Bailey's Industrial Oil and Fat Products,
ed. Daniel Swern, 3d ed. 1964, p. 126.
The long-chain N-alkyl derivatives of DNJ are known amino-sugar compounds. They were originally described as members of a group of short-chain and long-chain N-alkyl derivatives of DNJ having both glucosidase I inhibitory activity and antiviral activity, although no data on the long-chain N-alkyl derivatives was disclosed. See, e.g., DE 3,737,523, EP 315,017 and U.S. Pat. Nos. 4,260,622; 4,639,436; and 5,051,407.
In another early study, although N-alkylation of the base DNJ reduced the concentration required for 50% inhibition of glucosidase I, the inhibitory activity was reduced as the length of the N-alkyl chain was increased from N-methyl to N-decyl according to Schweden et al.,
Arch. Biochem. Biophys.
248, 335-340, at 338 (1986).
As far as the antiviral activity of the amino-sugar compounds against any particular virus is concerned, the activity of any specific analog cannot be predicted in advance. For example, in biologic tests for inhibitory activity against the human immunodeficiency virus (HIV), slight changes in the structure of the N-substituent were shown to have pronounced effects upon the antiviral profile as reported by Fleet et al.,
FEBS Lett.
237, 128-132 (1988). As disclosed in U.S. Pat. No. 4,849,430, the N-butyl derivative of DNJ was unexpectedly found to be more than two log orders more effective as an inhibitor of HIV than the N-methyl analog and three log orders more effective than the N-ethyl analog.
In another study of N-alkyl derivatives of DNJ for activity against glycolipid biosynthesis, the N-hexyl derivative of DNJ required a dose of 0.2 mg/ml, whereas the corresponding N-butyl analog required a dose of only 0.01-0.1. On the other hand, the N-methyl analog was inactive. Thus, it was believed that effective carbon chain length of the N-alkyl group for this activity ranged from 2 to 8 according to U.S. Pat. No. 5,472,969. No disclosure was made therein concerning the N-nonyl or other long-chain N-alkyl derivatives of DNJ.
N-nonyl-DNJ has been reported to be effective as an inhibitor of the Hepatitis B virus (HBV) based on inhibition of alpha-glucosidases in the cellular endoplasmic reticulum (ER) according to Block et al.,
Nature Me
Dwek Raymond A.
Jacob Gary S.
Flood Michele C.
G. D. Searle & Co.
Meyer Scott J.
Tate Christopher R.
LandOfFree
Combination drug therapy for glycolipid storage diseases does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Combination drug therapy for glycolipid storage diseases, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Combination drug therapy for glycolipid storage diseases will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3346687