U.S. patent application number 12/465069 was filed with the patent office on 2010-01-28 for gamma-hydroxybutyrate compositions containing carbohydrate, lipid or amino acid carriers.
This patent application is currently assigned to Orphan Medical, Inc.. Invention is credited to William Houghton, Mortimer Mamelak, Brian Miller, Dayton Reardan.
Application Number | 20100022643 12/465069 |
Document ID | / |
Family ID | 22882520 |
Filed Date | 2010-01-28 |
United States Patent
Application |
20100022643 |
Kind Code |
A2 |
Mamelak; Mortimer ; et
al. |
January 28, 2010 |
GAMMA-HYDROXYBUTYRATE COMPOSITIONS CONTAINING CARBOHYDRATE, LIPID
OR AMINO ACID CARRIERS
Abstract
The present invention provides compositions comprising at least
one GHB moiety bonded to at least one physiologically compatible
carrier molecule. The compositions can enhance the uptake of the
drug, deliver effective therapeutic doses in a time-delayed
fashion, or can target specific organs.
Inventors: |
Mamelak; Mortimer; (Toronto,
ON) ; Houghton; William; (St. Paul, MN) ;
Reardan; Dayton; (Shorewood, MN) ; Miller; Brian;
(Eden Prairie, MN) |
Correspondence
Address: |
SCHWEGMAN, LUNDBERG & WOESSNER, P.A.
P.O. BOX 2938
MINNEAPOLIS
MN
55402
UNITED STATES
612.373.6900
uspto@slwip.com
|
Assignee: |
Orphan Medical, Inc.
3180 Porter Drive
Palo Alto
CA
94304
|
Prior
Publication: |
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Document Identifier |
Publication Date |
|
US 20090215890 A1 |
August 27, 2009 |
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Family ID: |
22882520 |
Appl. No.: |
12/465069 |
Filed: |
May 13, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10/381,224 |
Aug 11, 2009 |
7572605 |
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PCTUS0129569 |
Nov 3, 2003 |
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12465069 |
May 13, 2009 |
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60/234,720 |
Sep 21, 2001 |
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Current U.S.
Class: |
514/546 ;
560/129 |
Current CPC
Class: |
A61P 25/04 20180101;
A61P 5/00 20180101; C07C 233/47 20130101; A61P 37/06 20180101; A61P
25/20 20180101; A61P 43/00 20180101; A61P 25/24 20180101; C07C
229/22 20130101; A61P 23/00 20180101; A61P 25/16 20180101; A61P
25/22 20180101; A61P 25/30 20180101; A61P 29/00 20180101; A61P
39/06 20180101; A61P 1/00 20180101; A61P 25/32 20180101; A61P 25/28
20180101; A61P 25/36 20180101; A61P 9/10 20180101; A61P 3/10
20180101; A61P 9/00 20180101; C07C 229/36 20130101; A61P 25/00
20180101; A61P 39/00 20180101; C07C 69/67 20130101; C07C 229/24
20130101; C07C 233/49 20130101; A61P 5/06 20180101; C07C 69/675
20130101; C07H 13/04 20130101; A61P 1/04 20180101 |
Class at
Publication: |
514/546 ;
560/129 |
International
Class: |
A61K 31/22 20060101
A61K031/22; C07C 69/003 20060101 C07C069/003; A61P 25/28 20060101
A61P025/28 |
Claims
1. A compound of the formula (II):
(R'O(CH.sub.2).sub.3CO.sub.2).sub.m(ROC(O)(CH.sub.2).sub.3OC(O)).sub.q--(-
X)--(Y).sub.n-(Z).sub.n--(CO.sub.2(CH.sub.2).sub.3CO.sub.2R).sub.p(O.sub.2-
C(CH.sub.2).sub.3OR').sub.k (II) wherein R' is H or a
hydroxyl-protecting group, R is H, (C.sub.1-C.sub.4)alkyl or
benzyl, X and Z are each residues of a hydroxy group-containing
amino acid or a bis(carboxy)amino acid, Y is a moiety covalently
linking X and Z, n is 0-1, m and k are 0 to the number of available
hydroxy groups on the amino acids X and Z; q and p are 0 to the
number of available CO.sub.2 groups on amino acids X and Z, with
the proviso that both m and q and both p and k are not zero, or a
pharmaceutically acceptable salt thereof.
2. A compound of the formula (III): ##STR7## wherein R.sup.1 is H
or a hydroxyl-protecting group, R is H, (C.sub.1-C.sub.4)alkyl or
benzyl, X is a residue of a hydroxy group-containing amino acids, Z
is the residue of a hydroxy group-containing amino acid or a
bis(carboxy) group-containing amino acid, Y is a moiety covalently
linking X and Z, n is 0-1, m is 1 to the number of available
hydroxy groups in amino acid X, p is 1 to the number of available
CO.sub.2 groups on the amino acid X or Z, or a pharmaceutically
acceptable salt thereof.
3. The compound of claim 1 wherein each of m, q, p and k is 1.
4. The compound of claim 1 wherein m and k are 0, and q and p are
1.
5. The compound of claim 1 wherein n=0, m=0 and k=0 and X is
glutamic acid, aspartic acid or tyrosine.
6. The compound of claim 2 wherein m=p=1, n is 0 and X is tyrosine,
threonine, or serine.
7. The compound of claim 2 wherein m=n=p=1 and Y is
C(O)CH.sub.2CH.sub.2C(O) or C(O)CH.dbd.CH(CO).
8. A compound of formula (IV): ##STR8## wherein L and L' are
individually H, (C.sub.1-C.sub.6)alkyl or a hydroxyl protecting
group or an organic moiety comprising at least one fatty alcohol,
fatty ester or analog thereof, wherein at least one of L and L' is
said moiety.
9. The compound of claim 8 wherein at least one of L' or L is
-(A)(Y)(Z).sub.n, wherein A is (C.sub.1-C.sub.6)alkyl, Y is H, OH
N(R.sup.1)(R.sup.2)(R.sup.3) or
[--O(PO.sub.3.sup.-)-AN(R.sup.1)(R.sup.2)(R.sup.3), wherein
R.sup.1, R.sup.2 and R.sup.3 are each (C.sub.1-C.sub.4)alkyl or
R.sup.1 and R.sup.2 together with N are a
(C.sub.5-C.sub.7)heterocyclic ring, optionally substituted with 1
or 2 N(R.sup.3), S, non-peroxide O or a combination thereof, n is
1-2 and Z is YR, wherein Y is O, S, NH, N(CH.sub.3), NHC(O) or
OC(O) and R is (C.sub.8-C.sub.22)alkyl, optionally substituted with
1-2 double bonds, or a pharmaceutically acceptable salt thereof,
with the proviso that when one of L or L' is
1,3-dihexadecanoylprop-2-yl, the other is not H.
10. The compound of claim 9 wherein L' is -(A)(Y)(Z).sub.n and L is
H, (C.sub.1-C.sub.6)alkyl or a hydroxyl protecting group.
11. The compound of claim 9 or 10 wherein Y is OC(O).
12. The compound of claim 8 wherein R is
(C.sub.10-C.sub.22)alkyl.
13. The compound of claim 9 or 10 wherein Y is
--O(PO.sub.3--)CH.sub.2CH.sub.2N(CH.sub.3).sub.3.sup.+.
14. The compound of claim 9 or 10 wherein (A)(Y)(Z).sub.n is
--CH[CH.sub.2Y][CH.sub.2Z].
15. A method for treating a mammal afflicted with a condition or
pathology amenable to treatment by gamma-hydroxy butyrate (GHB)
comprising administering to said mammal an effective amount of a
compound of formula (II):
(R'O(CH.sub.2).sub.3CO.sub.2).sub.m(ROC(O)(CH.sub.2).sub.3OC(O)).sub.q--(-
X)--(Y).sub.n-(Z).sub.n--(CO.sub.2(CH.sub.2).sub.3CO.sub.2R).sub.p(O.sub.2-
C(CH.sub.2).sub.3OR').sub.k (II) wherein R' is H or a
hydroxyl-protecting group, R is H, (C.sub.1-C.sub.4)alkyl or
benzyl, X and Z are each residues of a hydroxy group-containing
amino acid or a bis(carboxy)amino acid, Y is a moiety covalently
linking X and Z, n is 0-1, m and k are 0 to the number of available
hydroxy groups on the amino acids X and Z; q and p are 0 to the
number of available CO.sub.2 groups on amino acids X and Z, with
the proviso that both m and q and both p and k are not zero, or a
pharmaceutically acceptable salt thereof.
16. A method for treating a mammal afflicted with a condition or
pathology amenable to treatment by gamma-hydroxy butyrate (GHB)
comprising administering to said mammal an effective amount of a
compound of formula (III): ##STR9## wherein R.sup.1 is H or a
hydroxyl-protecting group, R is H, (C.sub.1-C.sub.4)alkyl or
benzyl, X is a residue of a hydroxy group-containing amino acids, Z
is the residue of a hydroxy group-containing amino acid or a
bis(carboxy) group-containing amino acid, Y is a moiety covalently
linking X and Z, n is 0-1, m is 1 to the number of available
hydroxy groups in amino acid X, p is 1 to the number of available
CO.sub.2 groups on the amino acid X or Z, or a pharmaceutically
acceptable salt thereof.
17. A method for treating a mammal afflicted with a condition or
pathology amenable to treatment by gamma-hydroxy butyrate (GHB)
comprising administering to said mammal an effective amount of a
compound of formula (IV): ##STR10## wherein L and L' are
individually H, (C.sub.1-C.sub.6)alkyl or a hydroxyl protecting
group or an organic moiety comprising at least one fatty alcohol,
fatty ester or analog thereof, wherein at least one of L and L' is
said moiety.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. application Ser.
No. 11/183,482, filed on Jul. 18, 2005, which is a divisional of
U.S. application Ser. No. 10/381,224, filed on Mar. 21, 2003, which
is a U.S. National Stage filing under 35 U.S.C. 371 from
International Application No. PCT/US01/29569, filed Sep. 21, 2001
and published in English as WO 02/24715 A2 on Mar. 28, 2002, which
claims priority from U.S. Provisional Application Ser. No.
60/234,720 filed on Sep. 22, 2000, the disclosures of which
applications and publication are incorporated by reference herein
in their entirety.
BACKGROUND OF THE INVENTION
[0002] Gamma-hydroxybutyric acid or "gamma-hydroxybutyrate" (GHB)
is an endogenous compound with hypnotic properties that is found in
many human body tissues. GHB is present, for example, in the
mammalian brain, the human nervous system and other tissues. The
extraordinary range of the pharmacological effects of GHB or its
salts has attracted scientific attention for more than three
decades. For example, GHB has been found to have tissue-protective
effects in animals and man in many different organs including
brain, liver, lung, heart, kidney, gut and pancreatic B cells. In
brain the highest GHB concentration is found in the hypothalamus
and basal ganglia and GHB is postulated to function as a
neurotransmitter (Snead and Morley, 1981). The neuropharmacologic
effects of GHB include increases in brain dopamine, depression of
glucose utilization but not oxygen consumption in the brain, and
hypothermia. GHB is converted to succinate and then metabolized via
the Krebs cycle. Clinical trials have shown that GHB increases
delta sleep and improves the continuity of sleep (Ladinsky et al.,
1983; Stock et al., 1973; Laborit, 1973; Lapierre et al., 1990;
Yamada et al., 1967; Grove-White and Kelman, 1971; Scharf,
1985).
[0003] In healthy human volunteers, low doses (about 30 mg/kg) of
GHB monosodium salt (sodium oxybate) promote a normal sequence of
NREM and REM sleep lasting about 2-3 hours. These low doses also
can induce REM and slow wave sleep and, in contrast to the
hypnotics in common use, without the development of tolerance to
these sleep-inducing effects in time. In addition, GHB increases
total sleep time and REM sleep, and it decreases REM latency
(Mamelak et al., 1973; Yamada et al., 1967; Bedard et al., 1989),
reduces sleep apnea (Series et al., 1992; Scrima et al., 1987), and
improves general anesthesia (Hasenbos and Gielen, 1985).
[0004] Studies by R. Broughton and M. Mamelak, Can. J. Neur. Sci.,
7, 23 (1980), L. Scrima et al., Sleep, 13, 479 (1990), and M. B.
Scharf et al., Am. Fam. Phys., 143 (July 1988) have evaluated the
effects of GHB in the treatment of narcolepsy. The results of these
studies confirm that GHB treatment substantially reduces the signs
and symptoms of narcolepsy (e.g., daytime sleepiness, cataplexy,
sleep paralysis and hypnagogic hallucinations).
[0005] GHB has several clinical applications other than the
treatment of sleep disorders. GHB has been reported to reduce
alcohol craving, the number of daily drinks consumed, and the
symptoms of alcohol withdrawal in patients (Gallimberti et al.,
1989; Gallimberti et al., 1992; Gessa et al., 1992). GHB has been
used to decrease the symptoms of opiate withdrawal, including both
heroin and methadone withdrawal (Gallimberti et al., 1994;
Gallimberti et al., 1993). It has analgesic effects that make it
suitable as a pain reliever (U.S. Pat. No. 4,393,236). Intravenous
administration of GHB has been reported to reduce intracranial
pressure in patients (Strong, A. 1984). Also administration of GHB
was reported to increase growth hormone levels in patients (Gerra
et al., 1994; Oyama et al., 1970). GHB is also an effective
therapeutic agent for the treatment of chronic fatigue syndrome and
fibromyalgia (Scharf, U.S. Pat. No. 5,990,162).
[0006] Unfortunately, the efficacy of GHB is limited by the high
doses required to produce a therapeutic effect and by its short
duration of action. Thus, a need exists for GHB compositions that
can enhance the uptake of the drug, deliver effective therapeutic
doses in a time-delayed fashion, and target specific organs.
SUMMARY OF THE INVENTION
[0007] The present invention provides a compound of formula (I):
##STR1## wherein Y is H or a hydroxyl-protecting group, X is the
residue of a carbohydrate and n has a value of 1 to the number of
available hydroxyl groups in said carbohydrate, or a
pharmaceutically acceptable salt thereof.
[0008] Preferably, X is a saccharide, and Y is H, a
(C.sub.4-C.sub.6)acetal, (C.sub.1-C.sub.5)acyl or
(C.sub.1-C.sub.5)alkyl.
[0009] Preferred carbohydrates are water-soluble or
water-dispersible. In yet another preferred embodiment of the
invention, X is the residue of a monosaccharide, the residue of a
disaccharide or the residue of a polysaccharide.
[0010] In such compounds, the monosaccharide, disaccharide or
polysaccharide can contain at least one CHOH--CHOH residue that is
protected as an acetal or ketal.
[0011] Examples of compounds of formula (I) include
1,2,3,4,6-pentakis(4-hydroxy-butyroyl)hexanose;
6-(4-hydroxy-butyroyl)hexanose and
1,2,3,4,6-pentakis(4-acetoxybutyroyl)hexanose.
[0012] In a further preferred embodiment of the compound of formula
(I), X is the residue of a chemically-modified cellulose. Useful
chemically-modified cellulose compositions include water-soluble or
water-dispersible celluloses such as hydroxypropyl-methylcellulose,
hydroxypropylcellulose or hydroxyethylcellulose.
[0013] Further provided by the present invention is a compound of
formula (II):
(R.sup.1O(CH.sub.2).sub.3CO.sub.2).sub.m(ROC(O)(CH.sub.2).sub.3C(O-
)).sub.q--(X)--(Y).sub.n-(Z).sub.n-(CO.sub.2(CH.sub.2).sub.3CO.sub.2R).sub-
.p(O.sub.2C(CH.sub.2).sub.3OR').sub.k (II) wherein R' is H or a
hydroxyl protecting group, R' is H, (C.sub.1-C.sub.4)alkyl or
benzyl, X and Z are each residues of a hydroxy group-containing
amino acid or a bis(carboxy)amino acid, Y is a moiety covalently
linking X and Z, n is 0-1, m and k are 0 to the number of available
OH groups is X and Z, q and p are 0 to the number of available
CO.sub.2 groups on X and Z, with the proviso that m and q are not
both zero and p and k are not both zero, or a pharmaceutically
acceptable salt thereof.
[0014] An embodiment of the compound of formula II is a compound of
formula (III): ##STR2## wherein R.sup.1 is H or a
hydroxyl-protecting group, R is H, (C.sub.1-C.sub.4) alkyl or
benzyl, X is a residue of a hydroxy group-containing amino acids, Z
is a residue of a hydroxy group-containing amino acid or a
bis(carboxy)amino acid, Y is a moiety covalently linking X and Z, n
is 0-1, m is 1 to the number of hydroxy groups on amino acid X, p
is 1 to the number of CO.sub.2H groups on the amino acid X or Z, or
a pharmaceutically acceptable salt thereof.
[0015] Preferably, m, p, q and k are individually 0-5, more
preferably 0-3, and most preferably 0-2.
[0016] In one preferred embodiment of the compound of formula
(III), m=p=1, n is O and X is glutamic acid, tyrosine, aspartic
acid, threonine, or a serine. In another preferred embodiment of
the compound of formula (III), m=p=1, n is 1, and Y is
C(O)CH.sub.2CH.sub.2C(O) or C(O)CH.dbd.CH(CO).
[0017] The present invention also provides a compound of formula
(IV): ##STR3## wherein L and L' are individually H,
(C.sub.1-C.sub.6)alkyl or a hydroxyl protecting group or an organic
moiety comprising at least one fatty alcohol, ester or analog
thereof. At least one of L and L' is said moiety (the FA moiety).
Preferably, the FA moiety is (A)(Y)(Z).sub.n, and wherein A is
(C.sub.2-C.sub.6)alkyl, Y is H, OH, N(R.sup.1)(R.sup.2)(R.sup.3) or
[--O(PO.sub.3.sup.-)-L-N(R.sup.1)(R.sup.2)(R.sup.3)] wherein
R.sup.1, R.sup.2 and R.sup.3 are each (C.sub.1-C.sub.4)alkyl or
R.sup.1 and R.sup.2 together with N are a
(C.sub.5-C.sub.7)heterocyclic ring, optionally substituted with 1
or 2 N(R.sup.3), S, non-peroxide O or a combination thereof; n is
1-2 and Z is YR, wherein Y is O, S, NH, N(CH.sub.3), NHC(O) or
OC(O) and R is (C.sub.8-C.sub.22)alkyl, optionally substituted with
1-2 double bonds.
[0018] Preferably, one of L or L' is (A)(Y)(Z).sub.n and the other
is H; n=1, YZ is (C.sub.10-C.sub.20)alkylC(O), R.sup.1, R.sup.2 and
R.sup.3 are methyl and/or A is propyl or ethyl. Preferably, when L'
is a 2-substituted lecithin moiety, i.e., the C.sup.2OC(O)R.sup.2
moiety of lecithin is replaced by C.sup.2C(O)(CH.sub.2).sub.3OL and
Y is hexadecanoyl; L is not H. Preferably n=1 and (A)(Y)(Z).sub.n
is --CH[CH.sub.2Y][CH.sub.2Z], e.g., is derived by replacement of
the 2'-acyloxyl moiety of lecithin with L-O(CH.sub.2).sub.3C(O)--.
When one of L or L' is 1,3-dihexdecanoylprop-2-yl, the other is not
H.
[0019] Generally, L and L' are derived from organic polyols, such
as glycerol, ethylene glycol, propylene glycol, 2,2'-hydroxyethyl
ether and the like. The organic moieties L and L' can also be
simple fatty acid esters of C.sup.4--OH or fatty alcohol esters of
CO.sub.2H.
[0020] The present invention also provides compounds of formula
(V): ##STR4## wherein L is defined above, n is 2-6, preferably 2-5,
most preferably 2-3, and L'' is (C.sub.2-C.sub.12) alkyl,
preferably (C.sub.3-C.sub.10)alkyl, most preferably
(C.sub.3-C.sub.6)alkyl, wherein the alkyl chain is optionally
interrupted by about 1-3-O-moieties, i.e., is the residue of an
alkylene polyol, preferably a 1,.omega.-alkylene diol such as
1,3-propane diol, or a polyoxyalkylene glycol. Examples of
compounds of formula (V) include
1,2,3-tris(4-hydroxy-butyroyoxyl)propane and
1,3-bis(4-acetoxybutyroyoxyl)propane.
[0021] The present invention also provides a pharmaceutical
composition comprising an effective amount of the compound of
formula (I), (II), (III) or (IV), or mixtures thereof in
combination with a pharmaceutically acceptable carrier. The
pharmaceutical composition of the present invention may be adapted
for parenteral, oral, topical or local administration.
[0022] The present invention also provides a therapeutic method
comprising administering to a mammal afflicted with a pathology or
condition ameliorated by GHB, an amount of a compound of formula I,
II, III, IV and/or V effective to treat said pathology or
condition.
[0023] As used herein, the term "effective amount" means that the
composition can deliver an amount of GHB to a target cell, tissue
or organ effective to accomplish a therapeutic objective, i.e., to
alter cellular metabolism or energetics or to ameliorate at least
one symptom of one of the pathologies discussed herein.
BRIEF DESCRIPTION OF THE FIGURES
[0024] The following drawings from part of the present
specification and are included to further demonstrate certain
aspects of the present invention. The invention may be better
understood by reference to one or more of these drawings in
combination with the detailed description of specific embodiments
presented herein.
[0025] FIG. 1A shows a compound comprising the GHB pentaester of a
fully charged hexopyranose.
[0026] FIG. 1B shows GHB triesters of partially charged
hexopyranoses.
[0027] FIG. 2 shows a GHB-sucrose ester.
[0028] FIG. 3 shows a GHB linked to representative amino acids.
[0029] FIG. 4 shows a GHB linked to amino acid conjugates.
DETAILED DESCRIPTION OF THE INVENTION
A. Definitions
[0030] The term "amino acid" comprises the residues of the natural
amino acids (e.g. Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Hyl,
Hyp, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val) in
D or L form, as well as unnatural amino acids (e.g. phosphoserine,
phosphothreonine, phosphotyrosine, hydroxyproline,
gamma-carboxyglutamate; hippuric acid, octahydroindole-2-carboxylic
acid, statine, 1,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid,
penicillamine, ornithine, citruline, .alpha.-methyl-alanine,
para-benzoylphenylalanine, phenylglycine, propargylglycine,
sarcosine, and tert-butylglycine). The term also comprises natural
and unnatural amino acids bearing a conventional amino protecting
group (e.g. acetyl or benzyloxycarbonyl), as well as natural and
unnatural amino acids protected at the carboxy terminus (e.g. as a
(C.sub.1-C.sub.6)alkyl, phenyl or benzyl ester or amide; or as an
.alpha.-methylbenzyl amide). Other suitable amino and carboxy
protecting groups are known to those skilled in the art (See for
example, T. W. Greene, Protecting Groups In Organic Synthesis;
Wiley: New York, 1981, and references cited therein). An amino acid
can be linked to the remainder of a compound of formula I through
the carboxy terminus, the amino terminus, or through any other
convenient point of attachment, such as, for example, through the
sulfur of cysteine.
[0031] The term "hydroxy amino acid" includes naturally occurring,
synthetic and semi-synthetic amino acids, such as serine,
threonine, tyrosine and hydroxyproline. Preferably the amino acids
are .alpha.-amino acids, most preferably with .omega.-hydroxyl
groups.
[0032] The term "carbohydrate" as used herein is defined to include
polyhydroxy aldehydes, or polyhydroxy ketones or substances that
yield such compounds on hydrolysis. The term "carbohydrate"
includes monosaccharides, oligosaccharides, disaccharides,
trisaccharides, tetrasaccharides, pentasaccharides,
hexasaccharides, polysaccharides, homopolysaccharides, and
heteropolysaccharides. The term includes any of the aldoses, as
well as glucose, dextrose, mannose, galactose arabinose, xylose,
ribose, fructose, sucrose, altrose, allose, idose, gulose, talose,
lyxose, threose, erythrose, apiose, and any of the same in acid
form. The term also includes deoxy sugars and deoxy-aldoses,
including rhamnose and fucose. The term further includes
glyceraldehyde, cellulose, starch, glycogen, and amylose. The term
also includes carbohydrate derivatives, such as acetals, ketals,
acyl esters and the like. Chemically modified polysaccharides such
as sucralfate and modified starches are also within the scope of
the term. Additional suitable carbohydrates of the present
invention may be found in Noller, C., Chemistry of Organic
Compounds, 2nd ed. (W. B. Saunders Co., 1957).
[0033] The term "saccharide" includes monosaccharides,
disaccharides, trisaccharides and polysaccharides. The term
includes glucose, sucrose, fructose and ribose, as well as deoxy
sugars such as deoxyribose and the like. Saccharide derivatives can
conveniently be prepared as described in International Patent
Applications Publication Numbers WO 96/34005 and 97/03995.
[0034] The term "oligopeptide" describes a sequence of 2 to 25
amino acids (e.g. as defined hereinabove) or peptidyl residues. The
sequence may be linear, branched or cyclic. For example, a cyclic
peptide can be prepared or may result from the formation of
disulfide bridges between two cysteine residues in a sequence. An
oligopeptide can be linked to the remainder of a compound of
formula I through the carboxy terminus, the amino terminus, or
through any other convenient point of attachment, such as, for
example, through the sulfur of a cysteine. Preferably a peptide
comprises 3 to 25, or 5 to 21 amino acids. Peptide derivatives can
be prepared as disclosed in U.S. Pat. Nos. 4,612,302; 4,853,371;
and 4,684,620.
[0035] The term "linking moiety" or "linker" as used herein refers
to an at least divalent organic molecule that can join two amino
acids or oligopeptidyl residues by reaction with functional groups
therein. Such moieties include alkane and alkene dicarboxylic acids
and diamines.
[0036] The term "alkyl" includes branched, straight-chain and
cyclic alkyl groups, including (cycloalkyl)alkyl.
[0037] A fatty alcohol is a (C.sub.8-C.sub.22)alkanol, preferably a
(C.sub.10-C.sub.20)alkanol, optionally comprising 1-3 double bonds;
a fatty acid is a (C.sub.8-C.sub.22)alkanoic acid (i.e.,
(C.sub.1-C.sub.11)C(O)OH), optionally comprising 1-3 double
bonds.
[0038] The term "hydroxyl protecting group" includes removable
hydroxy moiety protecting groups known to the art, such as acid- or
base-labile groups such as acetals (THP, (1-ethoxy)ethyl),
tris(alkyl)silyl groups (Me.sub.3, Si, (t-Bu(Me.sub.2)Si)),
(C.sub.2-C.sub.7)acyl groups (acetyl), as well as groups that can
be removed by hydrogenolysis, such as benzyl. See, also, part
(C)(a), hereinbelow, which references additional OH protecting
groups.
B. Applications
[0039] GHB has been shown to be effective in treating narcolepsy
and sleep disorders (Lee, 1977; Mamelak, 1977; Hoes, 1980; Scharf,
1985; Scrima, 1990; Gallimberti, 1992; Series, 1992; Lammers,
1993), reducing alcohol craving and alcohol withdrawal symptoms
(Gallimberti et al., 1989; Gallimberti et al., 1992; Gessa et al.,
1992), reducing opiate withdrawal symptoms (Gallimberti et al.,
1994; Gallimberti et al., 1993), reducing pain (U.S. Pat. No.
4,393,236), reducing intracranial pressure in patients (Strong, A.,
1984), and increasing growth hormone levels in patients (Gerra et
al., 1994; Oyama et al., 1970). The compounds and compositions of
the present invention can also be used in the treatment of any of
these disorders or conditions in patients.
[0040] GHB has been used with other analgesics, neuroleptics, or
with a subliminal barbiturate dose for use as an anesthesia. GHB
has been used in closed cranio-cerebral trauma and as soporifics
(U.S. Pat. No. 5,380,937). Therefore, the compounds of the present
invention can also be used in combination with analgesics,
neuroleptics or barbiturates for use as an anesthesia. The
inventors contemplate the use of the GHB compositions of the
present invention as a narcotic, hypnotic, or as a soporific.
[0041] The present invention provides compounds and pharmaceutical
compositions that can be used in the treatments of hypnosis;
narcolepsy (particularly cataplexy); drug abuse; anxiety;
cerebrovascular diseases; central nervous system disorders,
neurological disorders, including Parkinson's Disease and Alzheimer
Disease; Multiple Sclerosis; autism; depression; inflammatory
disorders, including those of the bowel, such as irritable bowel
disorder, regional illitis, and ulcerative collitis; autoimmune
inflammatory disorders; certain endocrine disturbances and
diabetes. The present compounds can also be administered for the
purpose of tissue protection, including protection following
hypoxia/anoxia such as in stroke, organ transplantation, organ
preservation, myocardial infarction or ischemia/reperfusion injury;
protection following radiation, progeria, or an increased level of
intracranial pressure, e.g., due to head trauma. The present
compounds can be used to treat other pathologies believed to be
caused or exacerbated by lipid peroxidation and/or free radicals,
such as pathologies associated with oxidative stress, including
normal aging.
C. Availability and Preparation of Compounds of the Present
Invention
[0042] GHB is available from the Aldrich Chemical Co., Milwaukee,
Wis., and can be employed to prepare the compounds within the scope
of formula (I) or (II). The GHB compositions of the present
invention can be prepared by and administered by any of the means
described herein, particularly those described in the section and
the examples, or by any means as would be known to those of skill
in the art.
[0043] A compound of the present invention can be employed as the
free acid or alcohol, or as a pharmaceutically acceptable salt or
ester thereof. Such salts can be formed from acids or amino groups
described herein, by methods available to one or ordinary skill in
the art. In cases where compounds are sufficiently basic or acidic
to form stable salts with nontoxic organic acids or metal salts,
administration of the compounds as salts may be appropriate.
Examples of pharmaceutically acceptable salts are organic acid
addition salts formed with acids which can form a physiological
acceptable anion, for example, tosylate, methanesulfonate, acetate,
citrate, malonate, tartarate, succinate, benzoate, ascorbate,
.alpha.-ketoglutarate, and .alpha.-glycerophosphate. Suitable
inorganic salts may also be formed, including hydrochloride,
sulfate, nitrate, bicarbonate, and carbonate salts.
Pharmaceutically acceptable salts may be obtained using standard
procedures well known in the art, for example by reacting a
sufficiently basic compound such as an amine with a suitable acid
affording a physiologically acceptable anion. Alkali metal (for
example, sodium, potassium or lithium) or alkaline earth metal (for
example calcium) salts of carboxylic acids can also be made. The
cations can also be readily exchanged with other metal or organic
cations, such as Ca.sup.+, K.sup.+, Li.sup.+, or (R).sub.4N.sup.+
wherein each R is H, phenyl, (C.sub.1-C.sub.6)alkyl or
hydroxy(C.sub.1-C.sub.6)alkyl, i.e., ammonium or hydroxyethyl amine
salts.
[0044] Hydroxy protecting groups such as esters, ethers, acetals
and ketals may be utilized in the present compounds. Useful hydroxy
protecting groups are descried in Greene, T. W.; Wutz, P. G. M.,
"Protecting Groups in Organic Synthesis", 2nd ed., John Wiley &
Sons, Inc (1991).
[0045] a) Preparation of Carbohydrate-GHB Compounds
[0046] GHB can be esterified with (C.sub.1-C.sub.4)alkanols or the
benzyl ester prepared. For ester preparation methods, see S. Ege,
Organic Chemistry, p. 454-455, 459, 466-467 (D.C. Heath and Co.,
1984). See also, Pouillart et al., Eur. J. Pharm. Sci., 7, 93-106
(1998). Then the OH group can be protected by formation of an
acetal or by alkanoylation or benzoylation with an alkanoyl or
benzoyl chloride or with anhydrides. Other useful acid- and
base-labile hydroxy-protecting groups are described in Greene, T.
W.; Wutz, P. G. M. "Protecting Groups In Organic Synthesis" second
edition, 1991, New York, John Wiley & Sons, Inc.
[0047] The ester can be removed and the acid can be activated if
necessary, i.e., by formation of an acid chloride or anhydride. For
preparation methods for 4-hydroxy-butanoic acid and its
derivatives, see, Marvel et al., J. Am. Chem. Soc., 51, 260 (1929);
Japanese patent 63174947, German Pat. Nos. 237310, 237308 and
237309.
[0048] The activated carboxyl group of GHB can be reacted with the
target hydroxyl groups in various sugars via ester bonds, as
described, for example, in P. Pouillart et al., Eur. J. Pharm.
Sci., 7, 93 (1998), P. R. Pouillart, Life Sciences, 63, 1739
(1998); P. Pouillart et al., J. Pharm. Sci., 81, 241 (1992), and
references cited therein. Most types of sugars, including triose
(or glycerol) tetroses, pentoses and hexoses can be used to make
the compounds of the present invention. In the latter two cases,
the open chain and ring (pyranoses and furanoses) forms may be used
as scaffolds. An example of hexopyranose is depicted in FIG. 1a,
where a maximum of 5 GHB molecules can be anchored to each sugar
monomer.
[0049] The therapeutic potential of these compounds is dependant on
the stability of the compounds in various environments. It is
contemplated that fully charged GHB compounds can be synthesized
from sucrose (containing a furanose and a pyranose ring), glucose
and one from any open chain hexose. These compounds may be
synthesized by a single step from free GHB or from its lactone.
[0050] In a fully charged molecule, i.e, (GHB).sub.5-Sugar, the
hydrocarbon chains may provide adequate protection from enzymes
present in the digestive tract. These compositions may be
susceptible to acid catalyzed hydrolysis, which depends on the
steric environments around each ester bond. For example, the 6-OH
ester bond will be readily hydrolyzed. These molecules may be
viewed as miniature micelles and can be transported into the
circulatory system via the fat absorption mechanism.
[0051] Linking GHB to partially charged sugars may provide for
better uptake and delivery of the drug. As seen in FIG. 1b, the
depicted compound has only 3-GHBs attached to the sugar. The choice
of hydroxyl groups for esterification can be based on the rates of
hydrolysis of the corresponding esters so that desired levels of
free GHB can be maintained within the cells of the target
organ.
[0052] Free hydroxyl groups can be used to anchor various groups.
Steric shielding of GHB-ester linkages enhances the stability of
the compounds in acidic medium. For example, one or more pairs of
adjacent OH group groups on the sugar ring can be protected as
acetals or as ketals, as taught by Pouillart et al., cited above,
using acetals. The ketone can be varied in bulk, in order to shield
the ester linkages to a greater or lesser extent. The attachment of
lipophilic groups, such as steroids or fatty acids, to GHB via
e.g., ketal or acetal linkages, can enhance the transfer across the
blood-brain barrier. The use of a ketosteriod or benzaldehyde to
form a ketal or acetal is shown in FIG. 1(b). A lipophilic
composition may also be useful for delivery of GHB via salves or
dermal patches. Free hydroxyl groups of the sugar may also be used
to attach a second complementary therapeutic agent to the GHB
composition.
[0053] b) Preparation of GHB Amino Acid Compounds
[0054] Amino acids (AA), serine, threonine, tyrosine, aspartic acid
and glutamic acid contain side chains containing OH groups and/or
second CO.sub.2H groups that can be coupled to GHB by ester
linkages, following N-protection (See FIG. 3). Each of these
compounds could be linked to two GHB molecules. Alternatively, the
carboxylic acid of GHB can be reacted with an acid-protected amino
acid to form the amide from the amine of the amino acid. Because
the ester linkages of these compounds have different steric
environments, the hydrolysis rates of these compounds in vivo will
vary. A significantly slow rate of hydrolysis will be seen with
serine and threonine, due to the ester linkages associated with
their side chains. For tyrosine, the ester linkage associated with
the phenoxy side chain can be very rapidly hydrolyzed. Single amino
acid compounds, i.e., AA-(GHB).sub.2 can only deliver 2 GHB
molecules, and due to the lack of steric shielding, these compounds
may have limited stability in the stomach pH. However, tailored
small peptides having 3 to 5 amino acids can significantly improve
the quantity of GHB delivered and have enhanced stability.
[0055] It is contemplated that the compounds of the present
invention may comprise two or more amino acids. Such compounds can
be constructed by using covalent linking moieties such as succinic
acid to couple the amino acids tyrosine and threonine, or using
maleic acid to couple aspartic and glutamic acids. Each of these
conjugates comprises 4 GHB per molecule, where each ester linkage
is in a significantly different steric shielding. (See FIG. 4). As
backbones of the compounds, the succinic and maleic acid linkers
have significantly different degrees of flexibility. Succinic acid
has full rotational freedom, whereas using maleic acid, GHB
molecules will be held in a cis orientation. Each compound, having
two amide and four ester linkages, can give rise to distinct
structural organizations with different stability and cellular
uptake.
[0056] c) Preparation of Compounds of Formulas (IV) and (V)
[0057] Analogs of naturally occurring phospholipids and lipids are
known to the art.
[0058] The compounds of formula III can be prepared as disclosed in
PCT WO 92/03462; U.S. Pat. No. 5,223,263; PCT/US91/04289; or
PCT/US94/05855. Lecithin or a sphingolipid can be partially
hydrolyzed to yield one or more free OH groups and GHB attached as
discussed above.
[0059] Compounds of formula (V) can be prepared by the reaction of
polyols (L''(OH).sub.n) with 4-halobutyroylchloride, which is then
hydrolyzed and the 4-hydroxyl group protected, or the 4-halo group
is displaced by L''O.sup.- or an equivalent thereof.
D. Administration
[0060] The invention provides a pharmaceutical formulation
comprising a compound of formula (I), (II), or (III), together with
one or more pharmaceutically acceptable carriers therefor and,
optionally, other therapeutic and/or prophylactic ingredients. The
cations and carrier(s) must be "acceptable" in the sense of being
compatible with the other ingredients of the formulation and not
deleterious to the recipient thereof, i.e., they do not produce an
adverse, allergic, or other untoward reaction when administered to
an animal, or a human, at appropriate levels.
[0061] Pharmaceutical formulations include those suitable for oral
or parenteral (including intramuscular, subcutaneous and
intravenous) administration. Forms suitable for parenteral
administration also include forms suitable for administration by
inhalation or insufflation or for nasal, or topical (including
buccal, rectal, vaginal, transdermal or sublingual) administration.
The formulations may, where appropriate, be conveniently presented
in discrete unit dosage forms, by bringing the active compound into
association with liquid carriers, solid matrices, semi-solid
carriers, finely divided solid carriers or combinations thereof,
and then, if necessary, shaping the product into the desired
delivery system.
[0062] a) Parenteral Administration and Dosage Forms
[0063] The active compounds of the invention may be formulated for
parenteral administration, e.g., formulated for injection via
intravenous, intraarterial, intramuscular, subcutaneous,
intralesional, intraperitoneal or other parenteral routes. The
preparation of an aqueous composition that contains a GHB agent as
an active component or ingredient will be known to those of skill
in the art in light of the present disclosure.
[0064] The pharmaceutical dosage forms suitable for injection or
infusion can include sterile aqueous solutions or dispersions or
sterile powders comprising the active ingredient which are adapted
for the extemporaneous preparation of sterile injectable or
infusible solutions or dispersions. The compounds of the invention
may be lyophilized for more ready formulation into a desired
vehicle where appropriate. For injection or infusion, the active
agent can optionally be encapsulated in liposomes. In all cases,
the ultimate dosage form should be sterile, fluid and stable under
the conditions of manufacture and storage.
[0065] The liquid carrier or vehicle can be a solvent or liquid
dispersion medium comprising, for example, water, ethanol,
glycerol, a polyol (for example, glycerol, propylene glycol, liquid
polyethylene glycols, and the like), vegetable oils, nontoxic
glyceryl esters, and suitable mixtures thereof. The proper fluidity
can be maintained, for example, by the formation of liposomes, by
the maintenance of the required particle size in the case of
dispersions, by the use of surfactants, or by the use of a
substance, such as lecithin (e.g., a coating). Solutions of the
active compounds as free acid or pharmacologically acceptable salts
can be prepared in water suitably mixed with hydroxypropylcellulose
and/or a pharmaceutically acceptable surfactant. The prevention of
the action of microorganisms can be brought about by various
antibacterial and antifungal agents, for example, parabens,
chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In
many cases, it will be preferable to include isotonic agents, for
example, sugars, buffers or sodium chloride. Prolonged absorption
of the injectable compositions can be brought about by the use in
the compositions of agents delaying absorption, for example,
aluminum monostearate and gelatin.
[0066] Sterile injectable solutions are prepared by incorporating
the active compounds in the required amount in the appropriate
solvent with various of the other ingredients as required, followed
by filtered sterilization. Generally, dispersions are prepared by
incorporating the various sterilized active ingredients into a
sterile vehicle which contains the basic dispersion medium and the
required other ingredients from those enumerated above. In the case
of sterile powders for the preparation of sterile injectable
solutions, the preferred methods of preparation are vacuum-drying
and freeze-drying techniques which yield a powder of the active
ingredient plus any additional desired ingredient from a previously
sterile-filtered, pyrogen-free solution thereof. The preparation of
more, or highly, concentrated solutions for direct injection is
contemplated, where the use of DMSO as solvent (although DMSO may
not now be a permitted human drug) is envisioned to result in
extremely rapid penetration, delivering high concentrations of the
active agents to a small area.
[0067] The compounds according to the invention may be presented in
unit dose form in ampules, pre-filled syringes, small volume
infusion containers, multi-dose containers with an added
preservative, or indwelling pumps or dispensers, or in devices
which allow for sustained release of the compounds.
[0068] The active GHB agent may be included within a therapeutic
composition to comprise about 0.1 to about 100 grams GHB per unit
dosage form, and multiple doses can also be administered. As an
example, one dosage could be dissolved in 1 ml of isotonic NaCl
solution and either added to 1000 ml of fluid or injected at the
proposed site of infusion (see, for example, "Remington's
Pharmaceutical Sciences" 15th Edition, pages 1035-1038 and
1570-1580). Some variation in dosage will necessarily occur
depending on the condition of the subject being treated. The person
responsible for administration will, in any event, determine the
appropriate dose for the individual subject.
[0069] b) Oral and Topical Administration and Dosage Forms
[0070] In addition to the compounds formulated for parenteral
administration, other pharmaceutically acceptable forms include,
e.g., tablets or other solids; liposomal formulations; time release
capsules; and any other form currently used, including creams or
lotions, which then may be admixed with an aqueous medium for oral
administration.
[0071] Pharmaceutical formulations suitable for oral administration
may be presented as discrete unit dosage forms such as hard or soft
gelatin capsules, cachets or tablets each containing a
predetermined amount of the active ingredient; as a powder or as
granules; as a solution, a suspension or as an emulsion; or in a
chewable base such as a synthetic resin or chicle for ingestion of
the active ingredient from a chewing gum. The active ingredient may
also be presented as a bolus, syrup, electuary or paste. Tablets
and capsules for oral administration may contain conventional
excipients such as binding agents, fillers, lubricants,
disintegrants, or wetting agents. The tablets may be coated
according to methods well known in the art, i.e., with enteric
coatings.
[0072] The tablets, troches, pills, capsules and the like may also
contain the following: a binder, natural as gum tragacanth, acacia,
cornstarch, or gelatin or synthetic as polyvinyl acetate;
excipients, such as dicalcium phosphate; a disintegrating agent,
such as corn starch, potato starch, alginic acid and the like; a
lubricant, such as magnesium stearate; and a sweetening agent, such
as sucrose, lactose, aspartame or saccharin may be added or a
natural or synthetic flavoring agent.
[0073] When the dosage unit form is a capsule for admixing with a
specific volume of an aqueous medium, it may contain, in addition
to materials of the above type, a liquid carrier, such as vegetable
oil or a polyethylene glycol. Various other materials may be
present as coatings or to otherwise modify the physical form of the
dosage unit. For instance, tablets, pills, or capsules may be
coated with gelatin, wax, shellac, sugar, natural or synthetic
polymers, or both. A syrup or elixir may contain the active
compounds, sucrose or fructose as a sweetening agent, a
preservative, a dye and/or a flavoring. Of course, any material
used in preparing any unit dosage form should be pharmaceutically
acceptable and substantially non-toxic in the amounts employed.
[0074] Such compositions and preparations should contain at least
0.1% of the active compound. The percentage of the compositions and
preparations may, of course, be varied and may conveniently be
between about 2 to about 75% of the weight of the unit, or
preferably between 25-60%. The amount of active compounds in such
therapeutically useful compositions is such that a suitable dosage
will be obtained.
[0075] The GHB-containing agent may be packaged separately from or
in combination with the excipients, salts, flavorings or any other
components described herein, to be admixed with an aqueous medium
in the case of oral or injectable formulations, or they may be
incorporated directly with the food (i.e., a beverage, candy bar or
cake) of the diet.
[0076] For topical administration, the present compounds may be
applied in pure form, i.e., when they are liquids. However, it will
generally be desirable to administer them to the skin as
compositions or formulations, in combination with a
dermatologically acceptable carrier, which may be a solid or a
liquid. Examples of useful dermatological compositions which can be
used to deliver the compounds of formula I, II, or III to the skin
are known to the art; for example, see Jacquet et al. (U.S. Pat.
No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S.
Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).
[0077] Useful solid carriers for dermatological compositions
include finely divided solids such as talc, clay, microcrystalline
cellulose, silica, alumina and the like. Useful liquid carriers
include water, alcohols or glycols or water-alcohol/glycol blends,
in which the present compounds can be dissolved or dispersed at
effective levels, optionally with the aid of non-toxic surfactants.
Adjuvants such as fragrances and additional antimicrobial agents
can be added to optimize the properties for a given use. The
resultant liquid compositions can be applied from absorbent pads,
used to impregnate bandages and other dressings, or sprayed onto
the affected area using pump-type or aerosol sprayers.
[0078] Ointments, pastes, gels, lotions, soaps and creams may, for
example, be formulated with an aqueous or oily base with the
addition of suitable thickening and/or gelling agents. Lotions may
be formulated with an aqueous or oily base and will in general also
contain one or more emulsifying agents, stabilizing agents,
dispersing agents, suspending agents, thickening agents, or
coloring agents. Thickeners such as synthetic polymers, fatty
acids, fatty acid salts and esters, fatty alcohols, modified
celluloses or modified mineral materials can be employed.
[0079] For systemic administration or as topical administration to
the epidermis, compound(s) of formula (I), formula (II), or formula
(III) may be formulated as the active ingredient of a transdermal
patch. Suitable transdermal delivery systems are disclosed, for
example, in A. Fisher et al. (U.S. Pat. No. 4,788,603), Chien et
al. (U.S. Pat. No. 5,145,682) or R. Bawa et al. (U.S. Pat. Nos.
4,931,279, 4,668,506 and 4,713,224). The active ingredient can also
be delivered via iontophoresis, e.g., as disclosed in U.S. Pat.
Nos. 4,140,122, 4,383,529, or 4,051,842.
[0080] Formulations suitable for topical administration in the
mouth include unit dosage forms such as lozenges comprising active
ingredient in a flavored base, usually sucrose and acadia or
tragacanth; pastilles comprising the active ingredient in an inert
base such as gelatin and glycerin or sucrose and acacia;
mucoadherent gels, and mouthwashes comprising the active ingredient
in a suitable liquid carrier.
[0081] When desired, the above-described formulations can be
adapted to provide sustained release of the active ingredient
employed, e.g., by combination with certain hydrophilic polymer
matrices, e.g., comprising natural gels, synthetic polymer gels or
mixtures thereof.
[0082] Pharmaceutical formulations suitable for rectal
administration wherein the carrier is a solid are most preferably
presented as unit dose suppositories. Suitable carriers include
cocoa butter and other materials commonly used in the art, and the
suppositories may be conveniently formed by admixture of the active
compound with the softened or melted carrier(s) followed by
chilling and shaping in molds.
[0083] Formulations suitable for vaginal administration may be
presented as pessaries, tampons, creams, gels, pastes, foams or
sprays containing, in addition to the active ingredient, such
carriers as are known in the art to be appropriate.
[0084] For administration by inhalation, the compounds according to
the invention are conveniently delivered form an insufflator,
nebulizer or a pressurized pack or other convenient means of
delivering an aerosol spray. Pressurized packs may comprise a
suitable propellant such as dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide
or other suitable gas. In the case of a pressurized aerosol, the
dosage unit may be determined by providing a valve to deliver a
metered amount.
[0085] Alternatively, for administration by inhalation or
insufflation, the compounds according to the invention may take the
form of a dry powder composition, for example, a powder mix of the
compound and a suitable powder base such as lactose or starch. The
powder composition may be presented in unit dosage form in, for
example, capsules or cartridges or, e.g., gelatin or blister packs
from which the powder may be administered with the aid of an
inhalator or insufflator.
[0086] For intra-nasal administration, the compounds of the
invention may be administered via a liquid spray, such as via a
plastic bottle atomizer. Typical of these are the Mistometer.RTM.
(Wintrop) and the Medihaler.RTM. (Riker). Nasal solutions are
usually aqueous solutions designed to be administered to the nasal
passages in drops or sprays. Nasal solutions are prepared so that
they are similar in many respects to nasal secretions, so that
normal ciliary action is maintained. Thus, the aqueous nasal
solutions usually are isotonic and lightly buffered to maintain a
pH of 5.5 to 6.5, though other pH ranges disclosed herein the
specific example, such as pH 3 to about pH 9, or pH 6 to about 7.5,
are contemplated. In addition, preservatives, similar to those used
in ophthalmic preparations, and appropriate drug stabilizers, if
required, may be included in the formulation. Various commercial
nasal preparations are known and include, for example, antibiotics
and antihistamines and are used for asthma prophylaxis.
[0087] c) Dosages
[0088] A good safety profile for GHB consumption, when used long
term for treatment of narcolepsy, has been reported. Patients have
been safely treated for many years with GHB without development of
tolerance (Scharf, 1985). Clinical laboratory tests carried out
periodically on many patients have not indicated organ or other
toxicities (Lammers, 1993; Scrima, 1990; Scharf, 1985; Mamelak,
1977; Mamelak; 1979; Gallimberti, 1989; Gallimberti, 1992; Gessa,
1992).
[0089] In the healthy volunteers study, the pharmacokinetics of
three rising GHB doses (12.5, 25, and 50 mg/kg) were investigated.
These findings indicate that both the oral absorption and
elimination processes of GHB were capacity-limited though the
degree of dose dependency was moderate (Palatini et al., 1993).
[0090] GHB has typically been administered in clinical trials as an
oral solution (Lee, 1977; Mamelak, 1977; Hoes, 1980; Scharf, 1985;
Scrima, 1990; Gallimberti, 1992; Series, 1992; Lammers, 1993). When
used as an oral solution, the dosages have ranged from 20-45
milligrams per kilogram body weight, twice daily. (Mamelak,
1977.)
[0091] It will be appreciated that the amount of the compound of
formula (I), (II), (III), (IV) or (V) required for use in treatment
will vary not only with the particular compound selected but also
with the route of administration, the severity of the condition
being treated and the age and condition of the patient and will be
ultimately at the discretion of the attendant physician or
clinician.
[0092] Useful dosages of the compounds of formula (I), (II), (III),
(IV) or (V) can be determined by comparing their in vitro activity,
and in vivo activity in animal models. Methods for the
extrapolation of effective dosages in mice, and other animals, to
humans are known to the art; for example, see U.S. Pat. No.
4,938,949.
[0093] Generally, the concentration of the compound(s) of formula
(I), (II), (III), (IV) or (V) in a liquid composition, such as a
lotion, will be from about 0.01-25 wt-%, preferably from about
0.5-10 wt-%. The concentration in a semi-solid or solid composition
such as a gel or a powder will be about 0.01-15 wt-%, preferably
about 0.5-2.5 wt-%.
[0094] In general, however, a suitable dose will be in the range of
from about 0.05 to 50 gm per day; or preferably from about 0.05 to
about 500 mg per kilogram body weight of the recipient per day,
preferably in the range of 0.1 to 200 mg/kg/day.
[0095] The compound is conveniently administered in unit dosage
form; for example, containing 0.1-20 g, conveniently 1-7.5 g, or
more conveniently, 2-5 g of active ingredient per unit dosage
form.
[0096] The total daily dose, i.e., of about 0.05-50 g, may be
administered for about 1-4 months, or longer, as needed.
[0097] Ideally, the active ingredient should be administered to
achieve peak plasma concentrations of the active compound of from
about 0.5 to about 75 .mu.M, preferably, about 1 to 50 .mu.M, most
preferably, about 2 to about 30 .mu.M. This may be achieved, for
example, by the intravenous injection of a 0.05 to 5% solution of
the active ingredient, optionally in saline, or orally administered
as a bolus containing about 1-100 mg of the active ingredient.
Desirable blood levels may be maintained by continuous infusion to
provide about 0.01-5.0 mg/kg/hr or by intermittent infusions
containing about 0.4-15 mg/kg of the active ingredient(s).
[0098] The desired dose may conveniently be presented in a single
dose or as divided doses administered at appropriate intervals, for
example, as two, three, four or more sub-doses per day. The
sub-dose itself may be further divided, e.g., into a number of
discrete loosely spaced administrations; such as multiple
inhalations from an insufflator or by application of a plurality of
drops into the eye.
Example 1
Preparation of 1,3-Bis(4-bromobutyroyl)propane (VII)
[0099] ##STR5##
[0100] A 500 ml round-bottomed flask was charged with 19.4 ml of
pyridine in 150 ml of dichloromethane (CH.sub.2Cl.sub.2), and
stirring initiated as the solution was cooled to 0.degree. C.
Propane-1,3-diol (8.0 g) was added, and stirring continued. A
mixture of 26.4 ml of 4-bromobutyroyl chloride in 75 ml
CH.sub.2Cl.sub.2 was added dropwise to the stirred
pyridine/CH.sub.2Cl.sub.2 and stirring continued for 5 hrs at
0.degree. C. The reaction mixture was washed with 300 ml H.sub.2O,
the organic layer was isolated and washed with 100 ml in HCl aq,
100 ml NaCl aq and dried over MgSO.sub.4 (anhydrous). The solvents
were removed in vacuo to yield the product (VII) as a translucent
low viscosity oil.
Example 2
Preparation of 1,3-Bis(4-acetoxybutyroyl)propane (VIII)
[0101] ##STR6##
[0102] A solution of 20.6 g potassium acetate and 3.49 g potassium
iodide in 306 ml acetic anhydride was stirred and the product (VII)
of Ex. 1 added. The reaction mixture was refluxed with stirring for
12-16 hrs, then cooled to 25.degree. C. and diluted with 100 ml
EtOAc. The reaction mixture was filtered, and the filtrate
concentrated in vacuo. Ethyl acetate (400 ml) was added and the
resultant solution was washed with 2.times.200 ml of 50% aq.
NaHCl.sub.3. The organic layer was isolated, dried (MgSO.sub.4
an.), filtered and concentrated in vacuo. Purification by flash
chromatography yielded product (VIII) in 66.3% yield as a viscous
light yellow oil (93% pure).
REFERENCES
[0103] Bedard et al., Clin. Neuropharmacol., 12(1) 29 (1989) [0104]
Broughton and Mamelak, Can. J. Neur. Sci., 7, 23 (1980) [0105]
Gallimberti et al., Lancet, 2(8666), 787 (1989) [0106] Gallimberti
et al., Alcohol Clin. Exp. Res., 16(4) 673 (1992) [0107]
Gallimberti et al., Neuropsychopharmacology, 9(1) 77 (1993) [0108]
Gallimberti et al., Eur. Arch. Psychiatry Clin. Neurosci., 244(3)
113 (1994) [0109] Gerra et al., Int. Clin. Psychopharmacol., 9(3)
211 (1994) [0110] Gessa et al., Clin. Neuropharmacol., 15 Suppl. 1
Pt. A 303A (1992) [0111] Grove-White and Kelman, Br. J. Anaesth,
43(2) 110 (1971) [0112] Hasenbos and Gielen, Anaesthesia, 40(10)
977 (1985) [0113] Hoes et al., Encephale, 6(1) 93 (1980) [0114]
Laborit, Laboratoire d' Eutonologie, Hopital Boucicaut Paris 15
France, 1973 [0115] Ladinsky et al., Naunyn Schmiedebergs Arch
Pharmacol., 322(1) 42 (1983) [0116] Lammers et al., Sleep, 16(3)
216 (1993) [0117] Lapierre et al., Sleep, 13(1) 24 (1990) [0118]
Lee, Biochem Med., 17(3) 284 (1977) [0119] Mamelak et al., Lancet,
2(7824) 328 (1973) [0120] Mamelak et al., Biol. Psychiatry, 12(2)
273 (1977) [0121] Mamelak et al., Biol. Psychiatry, 14(5) 821
(1979) [0122] Oyama et al., Br. J. Anaesth., 42(12) 1105 (1970)
[0123] Palatini et al., Eur. J. Clin. Pharmacol., 45(4) 353 (1993)
[0124] Scharf et al., J. Clin. Psychiatry, 46(6) 222 (1985) [0125]
Scharf et al., Am. Fam. Phys., 143 (1988) [0126] Scrima et al.,
Sleep, 13(6) 479 (1990) [0127] Series et al., Am. Rev. Respir.
Dis., 145(6) 1378 (1992) [0128] Scharf et al., J. Clin Psychiatry,
46(6) 222 (1985) [0129] Snead and Morley, Brain Res., 227(4) 579
(1981) [0130] Stock et al., Naunyn Schmiedebergs Arch Pharmacol.,
278(4) 347 (1973) [0131] Strong, Lancet, 1(8389) 1304 (1984) [0132]
Yamada et al., Electroencephalogr. Clin. Neurophysiol., 22(6) 558
(1967)
[0133] All publications, patents, and patent documents are
incorporated by reference herein, as though individually
incorporated by reference. The invention has been described with
reference to various specific and preferred embodiments and
techniques. However, it should be understood that many variations
and modifications may be made while remaining within the spirit and
scope of the invention.
* * * * *