U.S. patent application number 10/665448 was filed with the patent office on 2004-04-08 for methods of treating or preventing restless leg syndrome using sibutramine metabolites.
Invention is credited to Fang, Qun K., Jerussi, Thomas P., Senanayake, Chrisantha H..
Application Number | 20040067957 10/665448 |
Document ID | / |
Family ID | 25089293 |
Filed Date | 2004-04-08 |
United States Patent
Application |
20040067957 |
Kind Code |
A1 |
Jerussi, Thomas P. ; et
al. |
April 8, 2004 |
Methods of treating or preventing restless leg syndrome using
sibutramine metabolites
Abstract
Methods are disclosed for the treatment and prevention of
disorders and conditions such as, but are not limited to: eating
disorders; weight gain; obesity; irritable bowel syndrome;
obsessive-compulsive disorders; platelet adhesion; apnea; affective
disorders such as attention deficit disorders, depression, and
anxiety; male and female sexual function disorders; restless leg
syndrome; osteoarthritis; substance abuse including nicotine and
cocaine addiction; narcolepsy; pain such as neuropathic pain,
diabetic neuropathy, and chronic pain; migraines; cerebral function
disorders; chronic disorders such as premenstrual syndrome; and
incontinence. Pharmaceutical compositions and dosage forms are also
disclosed which comprise a racemic or optically pure sibutramine
metabolite and an optional additional pharmacologically active
compound.
Inventors: |
Jerussi, Thomas P.;
(Framingham, MA) ; Senanayake, Chrisantha H.;
(Shrewsbury, MA) ; Fang, Qun K.; (Wellesley,
MA) |
Correspondence
Address: |
JONES DAY
51 Louisiana Aveue, N.W
WASHINGTON
DC
20001-2113
US
|
Family ID: |
25089293 |
Appl. No.: |
10/665448 |
Filed: |
September 22, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10665448 |
Sep 22, 2003 |
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10278097 |
Oct 23, 2002 |
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10278097 |
Oct 23, 2002 |
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09770663 |
Jan 29, 2001 |
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6476078 |
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09770663 |
Jan 29, 2001 |
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09662135 |
Sep 14, 2000 |
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6339106 |
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09662135 |
Sep 14, 2000 |
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09372158 |
Aug 11, 1999 |
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6331571 |
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Current U.S.
Class: |
514/252.16 ;
514/262.1; 514/649 |
Current CPC
Class: |
A61K 31/52 20130101;
A61K 31/50 20130101; A61K 31/505 20130101; A61P 15/00 20180101;
A61K 31/52 20130101; A61P 25/00 20180101; A61K 31/495 20130101;
A61K 9/2059 20130101; A61K 45/06 20130101; A61K 31/40 20130101;
A61K 31/475 20130101; A61K 31/505 20130101; A61K 31/415 20130101;
A61K 31/137 20130101; A61K 31/40 20130101; A61K 31/50 20130101;
A61K 31/475 20130101; A61K 31/11 20130101; A61K 9/2054 20130101;
A61K 31/44 20130101; A61K 31/137 20130101; A61K 31/44 20130101;
A61K 31/495 20130101; A61K 31/135 20130101; A61K 31/135 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 31/415 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/252.16 ;
514/649; 514/262.1 |
International
Class: |
A61K 031/519; A61K
031/137 |
Claims
What is claimed is:
1. A method of treating or preventing sexual dysfunction which
comprises administering to a patient in need of such treatment or
prevention therapeutically or prophylactically effective amounts of
a sibutramine metabolite, or a pharmaceutically acceptable salt,
solvate, hydrate, clathrate, or prodrug thereof, and a
phosphodiesterase inhibitor.
2. The method of claim 1 wherein the sibutramine metabolite is
optically pure.
3. The method of claim 2 wherein the sibutramine metabolite is
(R)-desmethylsibutramine, (S)-desmethylsibutramine,
(R)-didesmethylsibutramine, or (S)-didesmethylsibutramine.
4. The method of claim 1 wherein the phosphodiesterase inhibitor is
a PDE5 or PDE6 inhibitor.
5. The method of claim 4 wherein the phosphodiesterase inhibitor is
sildenophil, desmethylsildenophil, vinopocetine, milrinone,
amrinone, pimobendan, cilostamide, enoximone, peroximone,
vesnarinone, rolipram, R020-1724, zaprinast, dipyridamole, or a
pharmaceutically acceptable salt, solvate, hydrate, clathrate,
prodrug, optically and pharmacologically active stereoisomer, or a
pharmacologically active metabolite thereof.
6. The method of claim 1 wherein the amount of sibutramine
metabolite administered is from about 0.1 mg to about 60
mg/day.
7. The method of claim 6 wherein the amount of sibutramine
metabolite administered is from about 2 mg to about 30 mg/day.
8. The method of claim 7 wherein the amount of sibutramine
metabolite administered is from about 5 mg to about 15 mg/day.
9. The method of claim 1 wherein the sibutramine metabolite and/or
the phosphodiesterase inhibitor is administered transdermally or
mucosally.
10. The method of claim 1 wherein the patient is male.
11. The method of claim 10 wherein the sexual dysfunction is
erectile dysfunction.
12. The method of claim 1 wherein the patient is female.
13. A method of treating or preventing a cerebral function disorder
which comprises administering to a patient in need of such
treatment or prevention therapeutically or prophylactically
effective amounts of a sibutramine metabolite, or a
pharmaceutically acceptable salt, solvate, hydrate, clathrate, or
prodrug thereof, and a phosphodiesterase inhibitor.
14. The method of claim 13 wherein the cerebral function disorder
is senile dementia, Alzheimer's type dementia, memory loss,
amnesia/amnestic syndrome, disturbance of consciousness, coma,
lowering of attention, speech disorders, Parkinson's disease,
Lennox syndrome, autism, epilepsy, hyperkinetic syndrome, or
schizophrenia.
15. The method of claim 13 wherein the sibutramine metabolite is
optically pure.
16. The method of claim 15 wherein the sibutramine metabolite is
(R)-desmethylsibutramine, (S)-desmethylsibutramine,
(R)-didesmethylsibutramine, or (S)-didesmethylsibutramine.
17. The method of claim 13 wherein the phosphodiesterase inhibitor
is a PDE5 or PDE6 inhibitor.
18. The method of claim 17 wherein the phosphodiesterase inhibitor
is sildenophil, desmethylsildenophil, vinopocetine, milrinone,
amrinone, pimobendan, cilostamide, enoximone, peroximone,
vesnarinone, rolipram, R020-1724, zaprinast, dipyridamole, or a
pharmaceutically acceptable salt, solvate, hydrate clathrate,
prodrug, optically and pharmacologically active stereoisomer, or a
pharmacologically active metabolite thereof.
19. The method of claim 13 wherein the amount of sibutramine
metabolite administered is from about 0.1 mg to about 60
mg/day.
20. The method of claim 19 wherein the amount of sibutramine
metabolite administered is from about 2 mg to about 30 mg/day.
21. The method of claim 20 wherein the amount of sibutramine
metabolite administered is from about 5 mg to about 15 mg/day.
22. A method of treating or preventing restless leg syndrome which
comprises administering to a patient in need of such treatment or
prevention a therapeutically or prophylactically effective amount
of a racemic or optically pure sibutramine metabolite, or a
pharmaceutically acceptable salt, solvate, clathrate, or prodrug
thereof.
23. The method of claim 22 wherein the sibutramine metabolite is
optically pure.
24. The method of claim 23 wherein the sibutramine metabolite is
(R)-desmethylsibutramine, (S)-desmethylsibutramine,
(R)-didesmethylsibutramine, or (S)-didesmethylsibutramine.
25. The method of claim 22 which further comprises the
administration of pergolide, carbidopa, levodopa, oxycodone,
carbamazepine, or gabapentin, or a pharmaceutically acceptable
salt, solvate, hydrate, clathrate, prodrug, optically and
pharmacologically active stereoisomer, or pharmacologically active
metabolite thereof.
26. A pharmaceutical composition comprising a sibutramine
metabolite, or a pharmaceutically acceptable salt, solvate,
hydrate, clathrate, or prodrug thereof, and a phosphodiesterase
inhibitor.
27. The pharmaceutical composition of claim 26 wherein the
sibutramine metabolite is optically pure.
28. The pharmaceutical composition of claim 27 wherein the
sibutramine metabolite is (R)-desmethylsibutramine,
(S)-desmethylsibutramine, (R)-didesmethylsibutramine, or
(S)-didesmethylsibutramine.
29. The pharmaceutical composition of claim 28 wherein the
phosphodiesterase inhibitor is sildenophil, desmethylsildenophil,
vinopocetine, milrinone, amrinone, pimobendan, cilostamide,
enoximone, peroximone, vesnarinone, rolipram, R020-1724, zaprinast,
dipyridamole, or a pharmaceutically acceptable salt, solvate,
hydrate, clathrate, prodrug, optically and pharmacologically active
stereoisomer, or a pharmacologically active metabolite thereof.
30. The pharmaceutical composition of claim 26 wherein the
sibutramine metabolite is in an amount of from about 0.1 mg to
about 60 mg.
31. The pharmaceutical composition of claim 30 wherein the
sibutramine metabolite is in an amount of from about 2 mg to about
30 mg.
32. The pharmaceutical composition of claim 31 wherein the
sibutramine metabolite is in an amount of from about 5 mg to about
15 mg.
33. The pharmaceutical composition of claim 26 wherein the
phosphodiesterase inhibitor is in an amount of from about 0.5 mg to
about 500 mg.
34. The pharmaceutical composition of claim 33 wherein the
phosphodiesterase inhibitor is in an amount of from about 1 mg to
about 350 mg.
35. The pharmaceutical composition of claim 34 wherein the
phosphodiesterase inhibitor is in an amount of from about 2 mg to
about 250 mg.
36. The pharmaceutical composition of claim 26 wherein the
pharmaceutical composition is adapted for oral, mucosal, rectal,
parenteral, transdermal, or subcutaneous administration.
37. The pharmaceutical composition of claim 36 wherein the
pharmaceutical composition is adapted for oral, mucosal, or
transdermal administration.
38. A lactose-free pharmaceutical composition which comprises a
sibutramine metabolite, or a pharmaceutically acceptable salt,
solvate, or clathrate thereof, a phosphodiesterase inhibitor, and a
pharmaceutically acceptable excipient.
39. The pharmaceutical composition of claim 38 wherein the
excipient is croscarmellose sodium, microcrystalline cellulose,
pre-gelatinized starch, or magnesium stearate.
40. The pharmaceutical composition of claim 39 wherein said
pharmaceutical composition is substantially free of mono- or
di-saccharides.
Description
[0001] This application is a continuation-in-part of U.S.
application Ser. No. 09/662,135, filed Sep. 14, 2000, which is a
continuation-in-part of U.S. application Ser. No. 09/372,158, filed
Aug. 11, 1999, both of which are incorporated herein by reference
in their entireties.
1. FIELD OF THE INVENTION
[0002] The invention relates to methods of using and compositions
comprising dopamine reuptake inhibitors such as racemic and
optically pure metabolites of sibutramine, optionally in
combination with other pharmacologically active compounds.
2. BACKGROUND OF THE INVENTION
[0003] Sibutramine, chemically named
[N-1-[1-(4-chlorophenyl)cyclobutyl]-3-
-methylbutyl]-N,N-dimethylamine, is a neuronal monoamine reuptake
inhibitor which was originally disclosed in U.S. Pat. Nos.
4,746,680 and 4,806,570. Sibutramine inhibits the reuptake of
norepinephrine and, to a lesser extent, serotonin and dopamine.
See, e.g., Buckett et al., Prog. Neuro-psychopharm. & Biol.
Psychiat., 12:575-584, 1988; King et al., J. Clin. Pharm.,
26:607-611 (1989).
[0004] Racemic sibutramine is sold as a hydrochloride monohydrate
under the tradename MERIDIA.RTM., and is indicated for the
treatment of obesity. Physician's Desk Reference.RTM. 1494-1498
(53.sup.rd ed., 1999). The treatment of obesity using racemic
sibutramine is disclosed, for example, in U.S. Pat. No.
5,436,272.
[0005] Sibutramine appears to have been extensively studied, and
reportedly could be used in the treatment of a variety of
disorders. For example, U.S. Pat. Nos. 4,552,828, 4,746,680,
4,806,570, and 4,929,629 disclose methods of treating depression
using racemic sibutramine, and U.S. Pat. Nos. 4,871,774 and
4,939,175 disclose methods of treating Parkinson's disease and
senile dementia, respectively, using racemic sibutramine. Other
uses of sibutramine are disclosed by PCT publications WO 95/20949,
WO 95/21615, WO 98/11884, and WO 98/13033. Further, the optically
pure entantiomers of sibutramine have been considered for
development. For example, PCT publications WO 94/00047 and 94/00114
disclose methods of treating depression and related disorders using
the R- and (S)-entantiomers of sibutramine, respectively.
[0006] Sibutramine is rapidly absorbed from the gastrointestinal
tract following oral administration and undergoes an extensive
first-pass metabolism that yields the primary metabolites,
desmethylsibutramine and didesmethylsibutramine, shown below. 1
[0007] It has been reported that desmethylsibutramine and
didesmethylsibutramine are more potent in vitro noradrenaline and
5-hydroxytryptamine (5HT; serotonin) reuptake inhibitors than
sibutramine. Stock, M. J., Int'l J. Obesity, 21(Supp. 1):S25-S29
(1997). It has further been reported, however, that sibutramine and
its metabolites have negligible affinities for a wide range of
neurotransmitter receptors, including serotonergic (5-HT.sub.1,
5-HT.sub.1, 5-HT.sub.1A, 5-HT.sub.2A, 5-HT.sub.2C, adrenergic,
dopaminergic, muscarinic, histaminergic, glutamate, and
benzodiazepine receptors. Id.
[0008] Sibutramine has a variety of adverse effects. See, e.g.,
Physician's Desk Reference.RTM. 1494-1498 (53.sup.rd ed., 1999).
Coupled with the reported benefits and therapeutic insufficiencies
of sibutramine, this fact has encouraged the discovery of compounds
and compositions that can be used in the treatment or prevention of
disorders such as, but not limited to, sexual (e.g., erectile)
dysfunction, affective disorders, weight gain or obesity, cerebral
function disorders, pain, obsessive compulsive disorder, substance
abuse, chronic disorders, anxiety, eating disorders, migraines, and
incontinence. In particular, compounds and compositions are desired
that can be used for the treatment and prevention of such disorders
and conditions while incurring fewer of the adverse effects
associated with sibutramine.
3. SUMMARY OF THE INVENTION
[0009] This invention encompasses methods of treating and
preventing disorders and conditions that are ameliorated by the
inhibition of neuronal monoamine uptake, which comprise
administering to a patient in need of such treatment or prevention
a therapeutically or prophylactically effective amount of a
neuronal monoamine reuptake inhibitor. Preferred neuronal monoamine
reuptake inhibitors are sibutramine metabolites. In specific
methods of the invention, the neuronal monoamine reuptake inhibitor
is optionally administered in combination with an additional
pharmacologically active compound.
[0010] Examples of disorders and conditions that are ameliorated by
the inhibition of neuronal monoamine uptake include, but are not
limited to: eating disorders; weight gain; obesity; irritable bowel
syndrome; obsessive-compulsive disorders; platelet adhesion; apnea;
affective disorders such as attention deficit disorders,
depression, and anxiety; male and female sexual function disorders;
restless leg syndrome; osteoarthritis; substance abuse including
nicotine and cocaine addiction; narcolepsy; pain such as
neuropathic pain, diabetic neuropathy, and chronic pain; migraines;
cerebral function disorders; chronic disorders such as premenstrual
syndrome; and incontinence.
[0011] This invention further encompasses pharmaceutical
compositions and dosage forms which can be used, for example, in
the methods disclosed herein. Preferred pharmaceutical compositions
of the invention comprise a therapeutically or prophylactically
effective amount of a sibutramine metabolite and optionally an
additional pharmacologically active compound.
[0012] 3.1. Definitions
[0013] As used herein, the term "prodrug" means a derivative of a
compound that can hydrolyze, oxidize, or otherwise react under
biological conditions (in vitro or in vivo) to provide the
compound. Examples of prodrugs include, but are not limited to,
derivatives of desmethylsibutramine and didesmethylsibutramine that
comprise biohydrolyzable moieties such as biohydrolyzable amides,
biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable
carbonates, biohydrolyzable ureides, and biohydrolyzable
phosphates. As used herein, prodrugs of didesmethylsibutramine do
not include desmethylsibutramine and sibutramine, and prodrugs of
desmethylsibutramine do not include sibutramine.
[0014] As used herein, the terms "biohydrolyzable carbamate,"
"biohydrolyzable carbamate," "biohydrolzyable ureide,"
"biohydrolyzable phosphate" mean a carbonate, ureide, or phosphate,
respectively, of a compound that either: 1) does not interfere with
the biological activity of the compound but can confer upon that
compound advantageous properties in vivo, such as uptake, duration
of action, or onset of action; or 2) is biologically inactive but
is converted in vivo to the biologically active compound.
[0015] Examples of biohydrolyzable carbamates include, but are not
limited to, lower alkylamines, substituted ethylenediamines,
aminoacids, hydroxyalkylamines, heterocyclic and heteroaromatic
amines, and polyether amines.
[0016] As used herein, the term "biohydrolyzable ester" means an
ester of a compound that either: 1) does not interfere with the
biological activity of the compound but can confer upon that
compound advantageous properties in vivo, such as uptake, duration
of action, or onset of action; or 2) is biologically inactive but
is converted in vivo to the biologically active compound. Examples
of biohydrolyzable esters include, but are not limited to, lower
alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters,
and choline esters.
[0017] As used herein, the term "biohydrolyzable amide" means an
amide of a compound that either: 1) does not interfere with the
biological activity of the compound but can confer upon that
compound advantageous properties in vivo, such as uptake, duration
of action, or onset of action; or 2) is biologically inactive but
is converted in vivo to the biologically active compound. Examples
of biohydrolyzable amides include, but are not limited to, lower
alkyl amides, .alpha.-amino acid amides, alkoxyacyl amides, and
alkylaminoalkylcarbonyl amides.
[0018] As used herein, the term "biohydrolyzable ureide" means a
ureide of a compound that either: 1) does not interfere with the
biological activity of the compound but can confer upon that
compound advantageous properties in vivo, such as uptake, duration
of action, or onset of action; or 2) is biologically inactive but
is converted in vivo to the biologically active compound.
[0019] As used herein, the term "biohydrolyzable phosphate" means a
phosphate of a compound that either: 1) does not interfere with the
biological activity of the compound but can confer upon that
compound advantageous properties in vivo, such as uptake, duration
of action, or onset of action; or 2) is biologically inactive but
is converted in vivo to the biologically active compound.
[0020] As used herein, the term "pharmaceutically acceptable salt"
refers to a salt prepared from a pharmaceutically acceptable
non-toxic inorganic or organic acid. Inorganic acids include, but
are not limited to, hydrochloric, hydrobromic, hydrojodic, nitric,
sulfuric, and phosphoric. Organic acids include, but are not
limited to, aliphatic, aromatic, carboxylic, and sulfonic organic
acids including, but not limited to, formic, acetic, propionic,
succinic, benzoic camphorsulfonic, citric, fumaric, gluconic,
isethionic, lactic, malic, mucic, tartaric, para-toluenesulfonic,
glycolic, glucuronic, maleic, furoic, glutamic, benzoic,
anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic),
methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic,
stearic, sulfanilic, alginic, and galacturonic acid.
[0021] As used herein, a composition that is "substantially free"
of a compound means that the composition contains less than about
20% by weight, more preferably less than about 10% by weight, even
more preferably less than about 5% by weight, and most preferably
less than about 3% by weight of the compound.
[0022] As used herein, the terms "optically pure,"
"enantiomerically pure," "pure enantiomer," and "optically pure
enantiomer" mean a composition that comprises one enantiomer of a
compound and is substantially free of the opposite enantiomer of
the compound. A typical optically pure compound comprises greater
than about 80% by weight of one enantiomer of the compound and less
than about 20% by weight of the opposite enantiomer of the
compound, more preferably greater than about 90% by weight of one
enantiomer of the compound and less than about 10% by weight of the
opposite enantiomer of the compound, even more preferably greater
than about 95% by weight of one enantiomer of the compound and less
than about 5% by weight of the opposite enantiomer of the compound,
and most preferably greater than about 97% by weight of one
enantiomer of the compound and less than about 3% by weight of the
opposite enantiomer of the compound. For example, optically pure
(R) sibutramine comprises at least about 80% by weight (t)
sibutramine and less than about 20% by weight (S) sibutramine.
[0023] As used herein, the term "neuronal monoamine reuptake
inhibitor" means a substance that inhibits the reuptake of neuronal
monoamines such as dopamine, serotonin, and norepinephrine as
determined using in vitro assays known to those skilled in the art.
Preferred neuronal monoamine reuptake inhibitors are dopamine
reuptake inhibitors, and sibutramine metabolites in particular.
More preferred neuronal monoamine reuptake inhibitors are optically
pure sibutramine metabolites.
[0024] As used herein, the term "dopamine reuptake inhibitor" means
a substance that inhibits the reuptake of dopamine as determined
using in vitro assays know to those skilled in the art. Preferred
dopamine reuptake inhibitors are sibutramine metabolites and
apomorphine.
[0025] As used herein, the term "sibutramine metabolite"
encompasses, but is not limited to, racemic and optically pure
desmethylsibutramine and didesmethylsibutramine, i.e.,
(R)-desmethylsibutramine, (S)-desmethylsibutramine,
(R/S)-desmethylsibutramine, (R)-didesmethylsibutramine,
(S)-didesmethylsibutramine, and (R/S)-didesmethylsibutramine.
Preferred sibutramine metabolites are optically pure.
[0026] It should further be noted that names used herein to
identify compounds of the invention may differ from those that are
concordant with International Union of Pure and Applied Chemistry
(IUPAC) naming conventions. If there is a discrepancy between a
structure depicted herein and a name given that structure, the
depicted structure is to be accorded more weight. In addition, if
the stereochemistry of a structure or a portion of a structure is
not indicated with, for example, bold or dashed lines, the
structure or portion of the structure is to be interpreted as
encompassing all stereoisomers of it.
4. DETAILED DESCRIPTION OF THE INVENTION
[0027] This invention relates, in part, to methods of treating and
preventing disorders and conditions in patients (e.g., mammals such
as humans, dogs, cats, and feedstock) that are ameliorated by the
inhibition of the reuptake of neuronal monoamines (e.g., dopamine,
serotonin, and norepinephrine). The invention further relates to
pharmaceutical compositions and dosage forms that can be used in
such methods.
[0028] Specific disorder and conditions that are ameliorated by the
inhibition of neuronal monoamine uptake include, but-are not
limited to: eating disorders such as weight gain and obesity;
platelet adhesion; apnea; obsessive-compulsive disorders; affective
disorders (e.g., ADHD), depression, or anxiety, male and female
sexual function disorders, such as erectile dysfunction; restless
leg syndrome; osteoarthritis; irritable bowel syndrome; substance
abuse including, nicotine addiction from cigarette smoking or
chewing tobacco, and cocaine addiction; migraines; chronic pain;
pain, such as neuropathic pain, such as diabetic neuropathy;
cerebral function disorders; chronic disorders; and
incontinence.
[0029] Methods of the invention comprise administering to a patient
in need of treatment or prevention a therapeutically or
prophylactically effective amount of neuronal monoamine reuptake
inhibitor. Preferred neuronal monoamine reuptake inhibitors are
dopamine reuptake inhibitors, such as sibutramine metabolites and
pharmaceutically acceptable salts, solvates, clathrates, and
prodrugs thereof. Preferred sibutramine metabolites are optically
pure. Specific preferred sibutramine metabolites are
(R)-desmethylsibutramine and (R)-didesmethylsibutramine. Another
preferred dopamine reuptake inhibitor is apomorphine.
[0030] A first embodiment of the invention encompasses a method of
treating or preventing a sexual function disorder in a patient in
need of such treatment or prevention, which comprises administering
to a patient in need of such treatment or prevention a
therapeutically or prophylactically effective amount of a dopamine
reuptake inhibitor, optionally in combination with a 5-HT.sub.3
antagonist. In one method of this embodiment, a sibutramine
metabolite is administered in combination with a 5-HT.sub.3
antagonist. In another method of this embodiment, apomorphine is
administered in combination with a 5-HT.sub.3 antagonist.
[0031] In a preferred method of this embodiment, a sibutramine
metabolite, or a pharmaceutically acceptable salt, solvate,
hydrate, clathrate, or prodrug thereof, is administered to a
patient orally, transdermally, or mucosally.
[0032] In another preferred method of this embodiment, the patient
in need of treatment or prevention is elderly or postmenstrual.
[0033] As used herein, the terms "sexual dysfunction" and "sexual
function disorder"encompass sexual dysfunction in men and women
caused by psychological and/or physiological factors. Examples of
sexual dysfunction include, but are not limited to, erectile
dysfunction, vaginal dryness, lack of sexual excitement, or
inability to obtain orgasm. The term "sexual dysfunction" further
encompasses psycho-sexual dysfunction Examples of psychosexual
dysfunction include, but are not limited to, inhibited sexual
desire, inhibited sexual excitement, inhibited female orgasm,
inhibited male orgasm, premature ejaculation, functional
dyspareunia, functional vaginisms, and atypical psychosexual
dysfunction.
[0034] Another embodiment of the invention encompasses a method of
treating or preventing an affective disorder which comprises
administering to a patient in need of such treatment or prevention
a therapeutically or prophylactically effective amount of a
sibutramine metabolite, or a pharmaceutically acceptable salt,
solvate, hydrate, clathrate, or prodrug thereof.
[0035] Affective disorders include, but are not limited to,
depression (e.g., melancholia), attention deficit disorder
(including attention deficit disorder with hyperactivity and
attention deficit/hyperactivity disorder), bipolar and manic
conditions, dysthymic disorder, and cyclothymic disorder. As used
herein, the terms "attention deficit disorder" (ADD), "attention
deficit disorder with hyperactivity" (ADDH), and "attention
deficit/hyperactivity disorder" (AD/HD), are used in accordance
with their accepted meanings in the art. See, e.g., Diagnostic and
Statistical Manual of Mental Disorders, Fourth Ed., American
Psychiatric Association, 1997 (DSM-IV.TM.) and Diagnostic and
Statistical Manual of Mental Disorders, 3.sup.d Ed., American
Psychiatric Association (1981) (DSM-III.TM.).
[0036] A preferred method of this embodiment is a method of
treating or preventing attention deficit disorder which comprises
administering to a patient in need of such treatment or prevention
a therapeutically or prophylactically effective amount of
sibutramine metabolite, or a pharmaceutically acceptable salt,
solvate, hydrate, clathrate, or prodrug thereof. In a particular
embodiment, the method can also be used to treat or prevent a
condition in children (e.g., ages 3-18).
[0037] Another preferred method of this embodiment is a method of
treating or preventing depression which comprises administering to
a patient in need of such treatment or prevention a therapeutically
or prophylactically effective amount of a sibutramine metabolite,
or a pharmaceutically acceptable salt, solvate, hydrate, clathrate,
or prodrug thereof.
[0038] As used herein, the term "treating or preventing depression"
means relief from or prevention of the symptoms of depression which
include, but are not limited to, changes in mood, feelings of
intense sadness, despair, mental slowing, loss of concentration,
pessimistic worry, agitation, and self-deprecation. Physical
changes can also be relieved or prevented by this method, and
include, but are not limited to, insomnia, anorexia, decreased
energy and libido, and abnormal hormonal circadian rhythms.
[0039] Another embodiment of the invention encompasses a method of
treating or preventing weight gain or obesity which comprises
administering to a patient in need of such treatment or prevention
a therapeutically or prophylactically effective amount of a
sibutramine metabolite, or a pharmaceutically acceptable salt,
solvate, hydrate, clathrate, or prodrug thereof, optionally in
combination with a lipase inhibitor.
[0040] As used herein, the term "treating or preventing weight gain
or obesity" means reduction of weight, relief from being
overweight, treating weight gain caused by the administration of
other drugs, relief from gaining weight, or relief from obesity,
and prevention from gaining weight, all of which are usually due to
unnecessary consumption of food. The invention also encompasses
methods of treating or preventing conditions incidental to obesity
including, but not limited to, hypertension, such as pulmonary
hypertension; cancers, such as breast, colon, gall bladder, and
endometrial; gall stones; cardiovascular disease, such as
dyslipidemia and carotid intimal medial thickening; hiatial hernia;
osteoarthritis; gout; thyroid disease, such as diabetes;
gastro-esophogeal reflux disease; menstrual dysfunction; and
infertility.
[0041] Another embodiment encompasses a method of treating or
preventing a disorder associated with the administration of a
lipase inhibitor for obesity or weight management, such as, for
example, orlistat (XENICAL.RTM.), which comprises administering to
a patient in need of such treatment or prevention a therapeutically
or prophylactically effective amount of a sibutramine metabolite,
or a pharmaceutically acceptable salt, solvate, hydrate, clathrate,
or prodrug thereof. As used herein, the term "treating or
preventing a disorder associated with the administration of a
lipase inhibitor" means alleviating or reducing adverse effects
associated with administration of a lipase inhibitor, which
include, but are not limited to, infectious diarrhea, oily fecal
spotting, flatus with discharge, fecal urgency, fatty/oily stool,
oily evacuation, increased defecation, anal leakage, and fecal
incontinence.
[0042] Another embodiment encompasses a method of treating or
preventing a cerebral function disorder which comprises
administering to a patient in need of such treatment or prevention
a therapeutically or prophylactically effective amount of a
sibutramine metabolite, or a pharmaceutically acceptable salt,
solvate, hydrate, or clathrate thereof.
[0043] Cerebral function disorders include, but are not limited to,
senile dementia, Alzheimer's type dementia, memory loss,
amnesia/amnestic syndrome, disturbance of consciousness, coma,
lowering of attention, speech disorders, Parkinson's disease,
Lennox syndrome, autism, epilepsy, hyperkinetic syndrome, and
schizophrenia Cerebral function disorders can be induced by factors
including, but not limited to, cerebrovascular diseases, such as
cerebral infarction, cerebral bleeding, cerebral arteriosclerosis,
cerebral venous thrombosis, and head injuries, and conditions
having symptoms selected from the group consisting of disturbances
of consciousness, senile dementia, coma, lowering of attention, and
speech disorders. As-used herein, the term "treating or preventing
a cerebral function disorder" means relief from or prevention of
one or more symptoms associated with cerebral function
disorders.
[0044] Another embodiment encompasses a method of treating or
preventing restless leg syndrome, which comprises administering to
a patient in need of such treatment or prevention a therapeutically
or prophylactically effective amount of a sibutramine metabolite,
or a pharmaceutically acceptable salt, solvate, hydrate, clathrate,
or prodrug thereof. In a preferred embodiment, the patient is at
least about 50, 60, or 70 years of age. In another preferred method
of this embodiment, the sibutramine metabolite is administered in
combination with at least one of pergolide, carbidopa, levodopa,
oxycodone, carbamazepine, gabapentin, or pharmaceutically
acceptable salts, solvates, hydrates, clathrates, prodrugs,
optically and pharmacologically active stereoisomers, or
pharmacologically active metabolites thereof.
[0045] As used herein, the term "restless leg syndrome" encompasses
a disorder that typically occurs during sleep or rest, or just
before sleep or rest, and which is characterized by uncomfortable
sensations in the legs. The disorder often occurs in patients older
than about 50 years of age. Examples of uncomfortable sensations in
the legs include, but are not limited to, pulling, drawing,
crawling, wormy, boring, tingling, pins and needles, prickly and
sometimes painful sensations that are usually accompanied by an
overwhelming urge to move the legs. As used herein, the term
"restless leg syndrome" also encompasses Ekbom Syndrome,
Wittmaack-Ecbom Syndrome, Hereditary Acromelalgia, and Anxieties
Tibialis.
[0046] Another embodiment encompasses a method of treating or
preventing pain which comprises administering to a patient in need
of such treatment or prevention a therapeutically or
prophylactically effective amount of a sibutramine metabolite, or a
pharmaceutically acceptable salt, solvate, hydrate, clathrate, or
prodrug thereof. In a particular embodiment, the pain is chronic
pain, such as neuropathic pain and diabetic neuropathy.
[0047] Still another embodiment of the invention encompasses a
method of treating or preventing obsessive-compulsive disorder
which comprises administering to a patient in need of such
treatment or prevention a therapeutically or prophylactically
effective amount of a sibutramine metabolite, or a pharmaceutically
acceptable salt, solvate, hydrate, clathrate, or prodrug
thereof.
[0048] As used herein, the terms "obsessive-compulsive disorder,"
"pre-menstrual syndrome, " "anxiety," and "eating disorder" are
used consistently with their accepted meanings in the art. See,
e.g., DSM-IV.TM. and DSM-III.TM.. The term "methods of treating or
preventing" when used in connection with these disorders means the
amelioration, prevention, or relief from symptoms and/or effects
associated with these disorders Another embodiment encompasses a
method of treating or preventing substance abuse which comprises
administering to a patient in need of such treatment or prevention
a therapeutically or prophylactically effective amount of a
sibutramine metabolite, or a pharmaceutically acceptable salt,
solvate, hydrate, clathrate, or prodrug thereof. In a particular
embodiment, the substance abuse is cocaine addiction or alcohol
addiction.
[0049] As used herein, the term "substance abuse" encompasses the
abuse of, and physical and/or psychological addiction to, drugs or
alcohol. The term "substance abuse" further encompasses its
accepted meaning in the art. See, e.g. DSM-IV.TM. and DSM-III.TM..
A preferred method encompassed by this embodiment is a method of
treating or preventing cocaine and/or heroin abuse.
[0050] Another embodiment encompasses a method of treating or
preventing nicotine addiction which comprises administering to a
patient in need of such treatment or prevention a therapeutically
or prophylactically effective amount of a sibutramine metabolite,
or a pharmaceutically acceptable salt, solvate, hydrate, clathrate,
or prodrug thereof. Nicotine addiction includes nicotine addiction
of all known forms, such as addiction to cigarettes, cigars and/or
pipes, and chewing tobacco.
[0051] Another embodiment encompasses a method of eliciting smoking
cessation which comprises administering to a patient who smokes
tobacco a therapeutically effective amount of a sibutramine
metabolite, or a pharmaceutically acceptable salt, solvate,
hydrate, clathrate, or prodrug thereof. In a preferred method
encompassed by this embodiment, the sibutramine metabolite, or
pharmaceutically acceptable salt, solvate, hydrate, clathrate, or
prodrug thereof is administered orally, mucosally, or
transdermally. In a more preferred method, the sibutramine
metabolite or pharmaceutically acceptable salt, solvate, hydrate,
or clathrate thereof is administered transdermally.
[0052] In another preferred method of this embodiment, the
sibutramine metabolite or pharmaceutically acceptable salt,
solvate, hydrate, clathrate, or prodrug thereof, is administered in
combination with a therapeutically or prophylactically effective
amount of nicotine. Preferably, the nicotine and/or sibutramine
metabolite or pharmaceutically acceptable salt, solvate, hydrate
clathrate, or prodrug thereof is administered orally, mucosally, or
transdermally. More preferably, the nicotine and/or sibutramine
metabolite or pharmaceutically acceptable salt, solvate, ester,
clathrate, or prodrug thereof is administered transdermally.
[0053] Another method encompassed by this embodiment is a method of
treating or preventing weight gain associated with smoking
cessation which comprises administering to a patient in need of
such treatment or prevention a therapeutically or prophylactically
effective amount of a sibutramine metabolite, or a pharmaceutically
acceptable salt, solvate, hydrate, clathrate, or prodrug
thereof.
[0054] Another embodiment encompasses a method of treating or
preventing weight gain associated with the administration of other
drugs that may induce weight gain, which comprises administering to
a patient in need of such treatment or prevention a therapeutically
or prophylactically effective amount of a sibutramine metabolite,
or a pharmaceutically acceptable salt, solvate, ester, clathrate,
or prodrug thereof.
[0055] Another embodiment encompasses a method of treating or
preventing a chronic disorder including, but not limited to,
narcolepsy, chronic fatigue syndrome, seasonal affective disorder,
fibromyalgia, and premenstrual syndrome (or premenstrual dysphoric
disorder), which comprises administering to a patient in need of
such treatment or prevention a therapeutically or prophylactically
effective amount of a sibutramine metabolite, or a pharmaceutically
acceptable salt, solvate, hydrate, clathrate, or prodrug thereof.
Preferred methods are methods of treating or preventing narcolepsy,
premenstrual syndrome, or chronic fatigue syndrome.
[0056] Another embodiment encompasses a method of treating or
preventing anxiety which comprises administering to a patient in
need of such treatment or prevention a therapeutically or
prophylactically effective amount of a sibutramine metabolite, or a
pharmaceutically acceptable salt, solvate, hydrate, clathrate, or
prodrug thereof.
[0057] Another embodiment encompasses a method of treating or
preventing an eating disorder including, but not limited to,
anorexia, bulimia, binging, and snacking, which comprises
administering to a patient in need of such treatment or prevention
a therapeutically or prophylactically effective amount of a
sibutramine metabolite, or a pharmaceutically acceptable salt,
solvate, hydrate, clathrate, or prodrug thereof.
[0058] Another embodiment encompasses a method of treating or
preventing migraines which comprises administering to a patient in
need of such treatment or prevention a therapeutically or
prophylactically effective amount of a sibutramine metabolite, or a
pharmaceutically acceptable salt, solvate, hydrate, clathrate, or
prodrug thereof.
[0059] Another embodiment encompasses a method of treating or
preventing incontinence with comprises administering to a patient
in need of such treatment or prevention a therapeutically or
prophylactically effective amount of a sibutramine metabolite, or a
pharmaceutically acceptable salt, solvate, ester, clathrate, or
prodrug thereof. In particular, the sibutramine metabolite can be
used to treat fecal incontinence, stress urinary incontinence
("SUI"), urinary exertional incontinence, urge incontinence, reflex
incontinence, passive incontinence, anal leakage, and overflow
incontinence.
[0060] As used herein, the term "treating or preventing
incontinence" means treatment, prevention of, or relief from the
symptoms of incontinence including involuntary voiding of feces or
urine, and dribbling or leakage or feces or urine, which may be due
to one or more causes including, but not limited to, pathology
altering sphincter control, loss of cognitive function,
overdistention of the bladder, hyper-reflexia and/or involuntary
urethral relaxation, weakness of the muscles associated with the
bladder or neurologic abnormalities.
[0061] A preferred method encompassed by this embodiment is a
method of treating or preventing stress urinary incontinence. In a
further preferred method encompassed by this embodiment, the
patient is an elder human of an age greater than about 50 or a
child of an age less than about 13.
[0062] In a specific embodiment of each of the methods of treatment
or prevention of the invention, a therapeutically or
prophylactically effective amount of a racemic or optically pure
sibutramine metabolite is administered to a patient in combination
with an additional pharmacologically active compound. Examples of
additional pharmacologically active compounds include, but are not
limited to, drugs that act on the central nervous system ("CNS"),
such as, but not limited to: 5-HT (e.g., 5-HT.sub.3 and
5-HT.sub.1A) agonists and antagonists; selective serotonin reuptake
inhibitors ("SSRIs"); hypnotics and sedatives; drugs useful in
treating psychiatric disorders including antipsychotic and
neuroleptic drugs, antianxiety drugs, antidepressants, and
mood-stabilizers; CNS stimulants such as amphetamines; dopamine
receptor agonists; antimonic agents; antipanic agents;
cardiovascular agents (e.g., beta blockers and angiotensin
converting enzyme inhibitors); phosphodiesterase inhibitors;
antivirals; antibiotics; antifingals; and antineoplastics. As
discussed in more detail herein, the particular additional
pharmacologically active compound used in a method will depend upon
the disease or condition being treated or prevented, as well as the
particular patient being treated.
[0063] The invention also encompasses pharmaceutical compositions
and single unit dosage forms that can be used, for example, in the
methods described herein. One embodiment of the invention
encompasses a pharmaceutical composition or dosage form that
comprises a sibutramine metabolite, preferably an optically pure
sibutramine metabolite. Particular pharmaceutical compositions and
single unit dosage forms of the invention comprise a sibutramine
metabolite and an additional pharmacologically active compound.
[0064] 4.1. Synthesis of Sibutramine Metabolites
[0065] Racemic sibutramine, desmethylsibutramine, and
didesmethylsibutramine can be prepared by methods known to those of
ordinary skill in the art. See, e.g. U.S. Pat. No. 4,806,570, which
is incorporated herein by reference; J. Med. Chem., 2540 (1993)
(tosylation and azide replacement); Butler, D., J. Org. Chem.,
36:1308 (1971) (cycloalkylation in DMSO); Tetrahedron Left., 155-58
(1980) (Grignard addition to nitrile in benzene); Tetrahedron
Lett., 857 (1997) (OH to azide); and Jeffery, J. E., et al., J.
Chem. Soc. Perkin. Trans 1, 2583 (1997). A preferred method of
preparing racemic sibutramine is provided below in Example 1.
[0066] Racemic sibutramine, desmethylsibutramine, and
didesmethylsibutramine can be prepared from each other, as can
optically pure forms of the compounds. Preferred methods of
preparing compounds from one another are provided below in Examples
2, 3, and 8. Optically pure enantiomers of sibutramine and its
metabolites can be prepared using techniques known in the art A
preferred technique is resolution by fractional crystallization of
diastereomeric salts formed with optically active resolving agents.
See, e.g., "Enantiomers, Racemates and Resolutions," by J. Jacques,
A. Collet, and S. H. Wilen, (Wiley-Interscience, New York, 1981);
S. H. Wilen, A. Collet, and J. Jacques, Tetrahedron, 2725 (1977);
E. L. Eliel Stereochemistry of Carbon Compounds (McGraw-Hill, NY,
1962); and S. H. Wilen Tables of Resolving Agents and Optical
Resolutions 268 (E. L. Eliel ed., Univ. of Notre Dame Press, Notre
Dame, Ind., 1972).
[0067] Because sibutramine, desmethylsibutramine, and
didesmethylsibutramine are basic amines, diastereomeric salts of
these compounds that are suitable for separation by fractional
crystallization are readily formed by addition of optically pure
chiral acid resolving agents. Suitable resolving agents include,
but are not limited to, optically pure tartaric, camphorsulfonic
acid, mandelic acid, and derivatives thereof. Optically pure
isomers of sibutramine, desmethylsibutramine, and
didesmethylsibutramine can be recovered either from the
crystallized diastereomer or from the mother liquor, depending on
the solubility properties of the particular acid resolving agent
employed and the particular acid enantiomer used. The identity and
optical purity of the particular sibutramine or sibutramine
metabolite isomer so recovered can be determined by polarimetry or
other analytical methods.
[0068] Racemic and optically pure sibutramine metabolites are
preferably synthesized directly by methods such as those disclosed
by Jeffery, J. E., et al., J. Chem. Soc. Perkin. Trans 1, 2583
(1996). A preferred method of directly synthesizing racemic
desmethylsibutramine comprises the reduction of
cyclobutanecatbonitrile (CCBC) to form an aldehyde intermediate
which is subsequently reacted with an amine such as, but not
limited to, methylamine. This method is applied below in Example
4.
[0069] Another preferred method of directly synthesizing racemic
desmethylsibutramine comprises the reaction of CCBC with a compound
of formula i-BuMX, wherein X is Br or I and M is selected from the
group consisting of Li, Mg, Zn, Cr, and Mn. Preferably, the
compound is of the formula i-BuMgBr. This reaction produces a
product which is subsequently reduced, converted to an intermediate
comprising an aldehyde bound to the nitrogen atom, which
intermediate is finally converted to desmethylsibutramine in a step
that comprises the addition of a lewis acid. Preferred lewis acids
are selected from the group consisting of BH.sub.3-THF,
BF.sub.3-THF, La(O-i-Pr).sub.3, Zr(O-i-Pr).sub.4,
Ti(O-i-Pr).sub.2Cl.sub.2, SnCl.sub.4, and MgBr.sub.2-OEt.sub.2. A
most preferred lewis acid is BH.sub.3-THF. This method is applied
below in Example 5.
[0070] The enantiomers of desmethylsibutramine can be resolved by
the formation of chiral salts as described above. Preferred chiral
acids used to form the chiral salts include, but are not limited
to, tartaric and mandelic acids. If tartaric acid is used,
preferred solvent systems include, but are not limited to,
ethanol/water and isopropyl alcohol/water. If mandelic acid is
used, a preferred solvent system is ethyl acetate/hexane. The
resolution of desmethylsibutramine is shown below in Examples 6 and
7.
[0071] A preferred method of directly synthesizing racemic
didesmethylsibutramine comprises the reaction of CCBC with a
compound of formula i-BuMX, wherein X is Br or I and M is selected
from the group consisting of Li, Mg, Zn; Cr, and Mn. Preferably,
the compound is of the formula i-BuMgBr. The product of this
reaction is then reduced under suitable reaction conditions.
Application of this method is shown below in Example 9.
[0072] The enantiomers of didesmethylsibutramine can be resolved by
the formation of chiral salts, as described above. Preferred chiral
acids used to form the chiral salts include, but are not limited
to, tartaric acid. Preferred solvent systems include, but are not
limited to, acetonitrile/water/methanol and acetonitrile/methanol.
The resolution of didesmethylsibutramine is shown below in Examples
11 and 12.
[0073] 4.2. Methods of Treatment and Prevention
[0074] In each of the methods of the invention, a therapeutically
or prophylactically effective amount of a sibutramine metabolite,
or a pharmaceutically acceptable salt, solvate, hydrate, clathrate,
or prodrug thereof, is administered to a patient. Preferred
sibutramine metabolites are optically pure.
[0075] In specific methods of the invention, the sibutramine
metabolite, or pharmaceutically acceptable salt, solvate, hydrate,
clathrate, or prodrug thereof, is administered to a patient in an
amount from about 0.1 mg to about 60 mg, preferably from about 2 mg
to about 30 mg, and more preferably from about 5 mg to about 15 mg.
Such amounts can be administered daily as needed for the treatment
of acute and chronic diseases and conditions.
[0076] Optionally, the sibutramine metabolite is adjunctively
administered (i.e., administered in combination) with one or more
additional pharmacologically active compounds. In other words, a
sibutramine metabolite and an additional pharmacologically active
compound can be administered to a patient as a combination,
concurrently but separately, or sequentially by any suitable route.
Suitable routes of administration include oral, mucosal (e.g.,
nasal, sublingual, buccal, rectal, and vaginal), parenteral (e.g.,
intravenous, intramuscular or subcutaneous), and transdermal
routes.
[0077] As physicians and those skilled in the art of pharmacology
will readily appreciate, the particular additional
pharmacologically active compounds that can be administered in
combination with a sibutramine metabolite will depend on the
particular disease or condition being treated or prevented, and may
also depend on the age and health of the patient to which the
compounds are to be administered.
[0078] Additional pharmacologically active compounds that can be
used in the methods and compositions of the invention include, but
are not limited to, drugs that act on the central nervous system
("CNS"), such as, but not limited to: 5-HT (e.g., 5-HT.sub.1 and
5-HT.sub.1A) agonists and antagonists; selective serotonim reuptake
inhibitors ("SSRIs"); hypnotics and sedatives; drugs useful in
treating psychiatric disorders including antipsychotic and
neuroleptic drugs, antianxiety drugs, antidepressants, and
mood-stablizers; CNS stimulants such as amphetamines; dopamine
receptor agonists; antimonic agents; antipanic agents;
cardiovascular agents (e.g., beta blockers and angiotensin
converting enzyme inhibitors); phosphodiesterase inhibitors;
antivirals; antibiotics; antifungals; and antineoplastics.
[0079] More specific drugs that act on the CNS include, but are not
limited to, SSRIs, benzodiazepine compounds, tricyclic
antidepressants, antipsychotic agents, anti-anxiolytic agents,
6-adrenergic antagonists, 5-HT.sub.1A receptor antagonists, and
5-HT.sub.3 receptor agonists. Even more specific drugs that act on
the CNS include, but are not limited to, lorazepam, tomoxetine,
olanzapine, respiradone, buspirone, hydroxyzine, and valium.
[0080] Examples of 5-HT.sub.3 antagonists that can be used in
compositions and methods of the invention include, but are not
limited to, granisetron (KYTRIL.RTM.), metoclopramide
(REGLAN.RTM.), ondansetron (ZOFRAN.RTM.), renzapride, zacopride,
tropisetron, and optically active stereoisomers, active
metabolites, and pharmaceutically acceptable salts, solvates,
hydrates, clathrates, prodrugs, optically and pharmacologically
active stereoisomers, and pharmacologically active metabolites
thereof. Preferred 5-HT.sub.3 antagonists are antiemetic
agents.
[0081] Selective serotonin reuptake inhibitors are compounds that
inhibit the central nervous system uptake of serotonin while having
reduced or limited affinity for other neurologically active
receptors. Examples of SSRIs include, but are not limited to,
citalopram (CELEXA.RTM.); fluoxetine (PROZAC.RTM.) fluvoxamine
(LUVOX.RTM.); paroxetine (PAXIL.RTM.); sertraline (ZOLOFT.RTM.);
venlafaxine (EFFEXOR.RTM.); and pharmaceutically acceptable salts,
solvates, hydrates, clathrates, prodrugs, optically and
pharmacologically active stereoisomers, and pharmacologically
active metabolites thereof.
[0082] Disorders that can be treated or prevented using a
sibutramine metabolite, or a pharmaceutically acceptable salt,
solvate, hydrate, clathrate, or prodrug thereof, in combination
with an SSRIs include, but are not limited to, depression,
affective disorders, anxiety, eating disorders, and cerebral
function disorders such as those described herein.
[0083] Benzodiazepine compounds that can be used in the methods and
compositions of the invention include, but are not limited to,
those described in Goodman & Gilman, The Pharmacological Basis
of Therapeutics, 362-373 (9.sup.th ed. McGraw-Hill, 1996). Examples
of specific benzodiazpines include, but are not limited to,
alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam,
clorazepate, demoxepam, diazepam, estazolam, flumazenil,
flurazepam, halazepam, lorazepam, midazolam, nitrazepam,
nordazepam, oxazepam, prazepam, quazepam, temazepam, triazolam,
pharmacologically active metabolites and stereoisomers thereof, and
pharmaceutically acceptable salts, solvates, hydrates, esters,
clathrates, and prodrugs thereof. The tradenames of some of these
compounds are provided below.
[0084] The clinician, physician, or psychiatrist will appreciate
which of the above compounds can be used in combination with a
sibutramine metabolite, or a pharmaceutically acceptable salt,
solvate, hydrate, clathrate, or prodrug thereof, for the treatment
or prevention of a given disorder, although preferred combinations
are disclosed herein.
[0085] Disorders that can be treated or prevented using a
sibutramine metabolite, or a pharmaceutically acceptable salt,
solvate, hydrate, clathrate, or prodrug thereof, in combination
with a benzodiazepine such as those listed above include, but are
not limited to, depression, affective disorders, anxiety, eating
disorders, and cerebral function disorders such as those described
herein.
[0086] The invention further encompasses methods of using and
pharmaceutical compositions comprising sibutramine metabolite, or a
pharmaceutically acceptable salt, solvate, hydrate, clathrate, or
prodrug thereof, in combination with an antipsychotic agent.
Antipsychotic agents are used primarily in the management of
patients with psychotic or other serious psychiatric illness marked
by agitation and impaired reasoning. These drugs have other
properties that possibly are useful clinically, including
antiemetic and antihistamine effects and the ability to potentiate
analgesics, sedatives, and general anesthetics. Specific
antipsychotic drugs are tricyclic antipsychotic drugs, of which
there are three subtypes: phenothiazines, thioxanthenes, and other
heterocyclic compounds, all of which can be used in the methods and
compositions of the invention. See, e.g., Goodman & Gilman, The
Pharmacological Basis of Therapeutics, 404 (9.sup.th ed.
McGraw-Hill, 1996).
[0087] Specific tricyclic antipsychotic compounds include, but are
not limited to, chlorpromazine, mesoridazine, thioridazine,
acetophenazine, fluphenazine, perphenazine, trifluoperazine,
chlorprothixene, thiothixene, clozapine, haloperidol, loxapine,
molindone, pimozide, risperidone, desipramine, and pharmaceutically
acceptable salts, solvates, hydrates, clathrates, prodrugs,
optically and pharmacologically active stereoisomers, and
pharmacologically active metabolites thereof. The tradenames of
some of these compounds are provided herein.
[0088] Disorders that can be treated or prevented using a
sibutramine metabolite, or a pharmaceutically acceptable salt,
solvate, hydrate, clathrate, or prodrug thereof, in combination
with an antipsychotic compound, and particularly a tricyclic
antipsychotic compound, include, but are not limited to, affective
disorders (e.g., depression), anxiety, eating disorders, and
cerebral function disorders (e.g., schizophrenia) such as those
described herein.
[0089] The invention further encompasses methods of using and
pharmaceutical compositions comprising a sibutramine metabolite, or
a pharmaceutically acceptable salt, solvate, hydrate, clathrate, or
prodrug thereof, in combination with a non-benzodiazepine or
non-tricyclic agents. Examples of such additional pharmacologically
active compounds include, but are limited to: olanzapine,
buspirone, hydroxyzine, tomoxetine, and pharmaceutically acceptable
salts, solvates, hydrates, clathrates, prodrugs, optically and
pharmacologically active stereoisomers, and pharmacologically
active metabolites thereof.
[0090] Chlorpromazine, which is chemically named
10-3-dimethylaminopropyl)- -2-chlorphenothiazine, is sold under the
tradename THORAZINE.RTM.. THORAZIN.RTM. is indicated, inter alia,
for the management of manifestations of psychotic disorders.
Physician's Desk Reference.RTM. 3101-3104 (53.sup.rd ed.,
1999).
[0091] The besylate salt of mesoridazine, which is chemically named
10-[2(1-methyl-2-piperidyl)ethyl]-2-methyl-sylfinyl)-phenothiazine,
is sold under the tradename SERENTIL.RTM.. SERENTIL.RTM. is
indicated in the treatment of schizophrenia, behavioral problems in
mental deficiency and chronic brain syndrome, alcoholism, and
psychoneurotic manifestations. Physician's Desk Reference.RTM.
764-766 (53.sup.rd ed., 1999).
[0092] Perphenazine, which is chemically named
4-[3-2-chlorophenothiazin-1- 0-yl)propyl-1-piperazineethanol, is
sold under the tradename TRILAFON.RTM.. TRILAFON.RTM. is indicated
for use in the management of the manifestations of psychotic
disorders and for the control of severe nausea and vomiting in
adults. Physician's Desk Reference.RTM. 2886-2888 (53.sup.rd ed.,
1999).
[0093] Trifluoperazine, which is chemically named
10-[3-(4-methyl-1-pipera-
zinyl)-propyl]-2-trifluoromethyl)-10-phenothiazine, is sold under
the tradename STELAZW.RTM.. STELAZWIE.RTM. is indicated for the
management of the manifestations of psychotic disorders and for the
short-term treatment of generalized non-psychotic anxiety.
Physician's Desk Reference.RTM. 3092-3094 (53.sup.rd ed.,
1999).
[0094] Thiothixene, which is chemically named
N,N-dimethyl-9-[3-(4-methyl--
1-piperazinyl)-propylidene]thioxanthene-2-sulfonamide, is sold
under the tradename NAVANE.RTM.. NAVANE.RTM. is indicated in the
management of manifestations of psychotic disorders. Physician's
Desk Reference.RTM. 2396-2399 (53.sup.rd ed., 1999).
[0095] Clozapine, which is chemically named
8-chloro-11-(4-methyl-1-pipera-
zinyl)5H-dibenzo[b,e][1,4]diazepine, is sold under the tradename
CLOZARIL.RTM.. CLOZARIL.RTM. is indicated for the management of
severely ill schizophrenic patients who fail to respond adequately
to standard antipsychotic drug treatment. Physician's Desk
Reference.RTM. 2004-2009 (53.sup.rd ed., 1999).
[0096] Haloperidol, which is chemically named
4-[4-(p-chlorophenyl)-4-hydr-
oxypiperidonol-4'-fluorobutyrophenone, is sold under the tradename
HALDOL.RTM.. HALDOL.RTM. is indicated for use in the management of
patients requiring prolonged parenteral antipsychotic therapy
(e.g., patients with chronic schizophrenia). Physician's Desk
Reference.RTM. 2190-2192 (53d ed., 1999).
[0097] Loxapine, which is chemically named
2-chloro-11-(4-methyl-1-piperaz- inyl)dibenz[b,f][1-4]oxaxepine, is
sold under the tradename LOXITANE.RTM.. LOXITANE.RTM. is indicated
for the management of the manifestations of psychotic disorders.
Physician's Desk Reference.RTM. 3224-3225 (53.sup.rd ed.,
1999).
[0098] Molindone, which is chemically named
3-ethyl-6,7-dihydro-2-methyl-5- -(morpholinomethyl)indol-4(5H)-one
hydrochloride, is sold under the tradename MOBAN.RTM.. MOBAN.RTM.
is indicated for the management of the manifestations of psychotic
disorders. Physician's Desk Reference.RTM. 978-979 (53.sup.rd ed.,
1999).
[0099] Pimozide, which is chemically named,
1-[1-[4,4-bis(4-fluorophenyl)b-
utyl]4-piperidinyl]-1,3-dihydro-2H-benzimidazole-2-one, is sold
under the tradename ORAP.RTM.. ORAP.RTM. is indicated for the
suppression of motor and phonic tics in patients with Tourette's
Disorder who have failed to respond satisfactorily to standard
treatment. Physician's Desk Reference.RTM. 1054-1056 (53.sup.rd
ed., 1999).
[0100] Risperidone, chemically named
3-[2-[4-(6-fluoro-1,2-benzisoxazol-3--
yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrim-
idin-4-one, is sold under the tradename RISPERDAL.RTM..
RISPERDAL.RTM. is indicated for the management of the
manifestations of psychotic disorders. Physician's Desk
Reference.RTM. 1432-1436 (53.sup.rd ed., 1999).
[0101] The hydrochloride salt of desipramine, which is chemically
named
5H-Dibenz[b,f]azepine-5-propanamine-10,11-dihydro-N-methyl-monohydrochlor-
ide, is sold under the tradename NORPRAMIN.RTM.. NORPRAMIN.RTM. is
indicated for the treatment of depression. Physician's Desk
References 1332-1334 (53.sup.rd ed., 1999).
[0102] Olanzapine, which is chemically named
2-methyl-4-(4-methyl-1-pipera-
zinyl)-10H-thieno[2,3-b][1,5]benzodiazepine, is sold under the
tradename ZYPREXA.RTM.. ZYPREXA.RTM. is indicated for the
management of the manifestations of psychotic disorders.
Physician's Desk Reference.RTM. 1641-1645 (53.sup.rd ed.,
1999).
[0103] The hydrochloride salt of buspirone, which is chemically
named
8-[4-[4-2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro-[4,5]decane-7,9-di-
one monohydrochloride, is sold under the tradename BUSPAR.RTM..
BUSPAR.RTM. is indicated for the management of anxiety disorders or
the short-term relief of the symptoms of anxiety. Physician's Desk
Reference.RTM. 823-825 (53.sup.rd ed., 1999).
[0104] The hydrochloride salt of hydroxyzine, which is chemically
named 1-(p-chlorobenzhydryl)-4[2-(2-hydroxyethoxy)-ethyl]
piperazine dihydrochloride, is sold under the tradename
ATARAX.RTM.. ATARAX.RTM. is indicated for symptomatic relief of
anxiety and tension associated with psychoneurosis and as an
adjunct in organic disease states in which anxiety is manifested.
Physician's Desk Reference.RTM. 2367-2368 (53.sup.rd ed.,
1999).
[0105] Disorders that can be treated or prevented using a racemic
or optically pure sibutramine metabolite, or a pharmaceutically
acceptable salt, solvate, or clathrate thereof, in combination with
an antipsychotic compound, and particularly a tricyclic
antipsychotic compound, include, but are not limited to, affective
disorders (e.g., depression), anxiety, eating disorders, and
cerebral function disorders (e.g., schizophrenia) such as those
described herein.
[0106] Disorders that can be treated or prevented using a racemic
or optically pure sibutramine metabolite, or a pharmaceutically
acceptable salt, solvate, or clathrate thereof, in combination with
a compound selected from the group consisting of lorazepam,
tomoxetine, olanzapine, respiradone, buspirone, hydroxyzine,
valium, pharmacologically active metabolites and stereoisomers
thereof, and pharmaceutically acceptable salts, solvates,
clathrates thereof include, but are not limited to, anxiety,
depression, hypertension, and attention deficit disorders.
[0107] The invention further encompasses methods of using and
pharmaceutical compositions comprising a racemic or optically pure
sibutramine metabolite, or a pharmaceutically acceptable salt,
solvate, or clathrate thereof, in combination with a 5-HT.sub.1A
receptor antagonist and/or a .beta.-adrenergic antagonists Examples
of 5-HT.sub.1A receptor antagonists and .beta.-adrenergic
antagonists that can be used in the methods and compositions of the
invention include, but are limited to: alprenolol; WAY 100135;
spiperone; pindolol; (S)-UH-301; penbutolol; propranolol;
tertatolol; a compound of the formula I as disclosed in U.S. Pat.
No. 5,552,429, which is incorporated herein by reference; and
pharmaceutically acceptable salts, solvates, hydrates, clathrates,
prodrugs, optically and pharmacologically active stereoisomers, and
pharmacologically active metabolites thereof.
[0108] Alprenolol, which is chemically named
1-(1-methylethyl)amino-3-[2-(- 2-propenyl)phenoxy]-2-propanol, is
described by U.S. Pat. No. 3,466,325, which is incorporated herein
by reference.
[0109] WAY 100135, which is chemically named
N-(t-butyl)-3-[4-(2-methoxphe-
nyl)-piperazin-1-yl]-2-phenylpropanamide, is described by U.S. Pat.
No. 4,988,814, which is incorporated herein by reference. See also,
Cliffe et al., J. Med. Chem., 36:1509-1510 (1993).
[0110] Spiperone, which is chemically named
8-[4-(4-fluorophenyl)-4-oxobut-
yl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one), is described by
U.S. Pat. Nos. 3,155,669 and 3,155,670, both of which are
incorporated herein by reference. See also, Middlmiss et al.,
Neurosci. and Biobehav. Rev., 16:75-82 (1992).
[0111] Pindolol, which is chemically named
4-(2-hydroxy-3-isopropylaminopr- opoxy)-indole, is described by
U.S. Pat. No. 3,471,515, which is incorporated herein by reference.
See also, Dreshfield et al., Neurochem. Res., 21(5):557-562
(1996).
[0112] (S)-UH-301, which is chemically named
(S)-5-fluoro-8-hydroxy-2-dipr- opylaminotetralin), is well known to
pharmacologists and pharmaceutical chemists. See, e.g. Hillyer et
al., J. Med. Chem., 33:1541-44 (1990) and Moreau et al., Brain Res.
Bull., 29:901-04 (1992).
[0113] Penbutolol, which is chemically named
(1-(t-butylamino)-2-hydroxy-3- -(2-cyclopentyl-phenoxy)propane), is
sold under the tradename LEVATOL.RTM.. LEVATOL.RTM. is indicated
the treatment of mild to moderate arterial hypertension. Physician
's Desk Reference.RTM. 2908-2910 (53rd ed., 1999).
[0114] The hydrochloride salt of propranolol, which is chemically
named 1-isopropylamino-3-(1-naphthalenyloxy)-2-propanol
hydrochloride, is sold under the tradename INDERAL.RTM..
INDERAL.RTM. is indicated in the management of hypertension.
Physician's Desk Reference.RTM. 3307-3309 (53.sup.rd ed.,
1999).
[0115] Tertatolol, chemically named
8-(3-t-butylamino-2-hydroxypropyloxy)-- thiochroman, is described
by U.S. Pat. No. 3,960,891, which is incorporated herein by
reference.
[0116] Disorders that can be treated or prevented using a racemic
or optically pure sibutramine metabolite, or a pharmaceutically
acceptable salt, solvate, or clathrate thereof, in combination with
a 5-HT.sub.1A receptor antagonist include, but are not limited to,
depression, obsessive-compulsive disorders, eating disorders,
hypertension, migraine, essential tremor, hypertrophic subaortic
stenosis and pheochromocytoma. A specific disorder that can be
treated or prevented is posttraumatic depression disorder.
[0117] Disorders that can be treated or prevented using a racemic
or optically pure sibutramine metabolite, or a pharmaceutically
acceptable salt, solvate, or clathrate thereof, in combination with
a .beta.-adrenergic antagonist include, but are not limited to,
post myocardial infarction depression.
[0118] The invention further encompasses methods of using and
pharmaceutical compositions comprising a racemic or optically pure
sibutramine metabolite, or a pharmaceutically acceptable salt,
solvate, or clathrate thereof, in combination with a
phosphodiesterase inhibitor. Examples of phosphodiesterase
inhibitors that can be used in compositions and methods of the
invention include, but are not limited to, those disclosed in U.S.
Pat. No. 5,250,534; U.S. Pat. No. 5,719,283; U.S. Pat. No.
6,127,363; WO 94/28902; WO 97/03675; WO 98/06722, all of which are
expressly incorporated herein by reference in their entirety.
Preferred phosphodiesterase inhibitors are PDE5 and PDE6
inhibitors. Particular phosphodiesterase inhibitors include, but
are not limited to, sildenophil (Viagra.RTM.),
desmethylsildenophil, vinopocetine, milrinone, amrinone,
pimobendan, cilostamide, enoximone, peroximone, vesnarinone,
rolipran, R020-1724, zaprinast, dipyridamole, and pharmaceutically
acceptable salts, solvates, hydrates, clathrates, prodrugs,
optically and pharmacologically active stereoisomers, and
pharmacologically active metabolites thereof.
[0119] Disorders and conditions that can be treated or prevented
using a sibutramine metabolite, or a pharmaceutically acceptable
salt solvate, hydrate, clathrate, or prodrug thereof, in
combination with a phosphodiesterase include, but are not limited
to, sexual dysfunction and cerebral function disorders. Others
disorders and conditions include, but are not limited to, pain,
migraines, osteoarthritis, and restless leg syndrome.
[0120] While all combinations of racemic and optically pure
sibutramine metabolites and pharmaceutically acceptable salts,
solvates, and clathrate thereof, and one or more of the
above-described pharmacologically active compounds can be useful
and valuable, certain combinations are particularly preferred.
Examples of preferred combinations include those wherein a racemic
or optically pure sibutramine metabolite, or a pharmaceutically
acceptable salt, solvate, clathrate, or prodrug thereof, is
combined with one of the following:
1 alprazolam; mesoridazine; tertatolol; brotizolam; thioridazine;
desipramine; chlordiazepoxide; acetophenazine; clonidine; clobazam;
fluphenazine; olanzapine; clonazepam; perphenazine;
methylphenidate; clorazepate; trifluoperazine; buspirone;
demoxepam; chlorprothixene; hydroxyzine; diazepam; thiothixene;
tomoxetine; estazolam; clozapine; sildenophil; flumazenil;
haloperidol; desmethylsildenophil; flurazepam; loxapine;
vinopocetine; halazepam; molindone; milrinone; lorazepam; pimozide;
amrinone; midazolam; risperidone; pimobendan; nitrazepam;
alprenolol; cilostamide; nordazepam; WAY 100135; enoximone;
oxazepam; spiperone; peroximone; prazepam; S(S)-pindolol;
vesnarinone; quazepam; R(R)-pindolol; rolipran; temazepam; racemic
pindolol; R020-1724; triazolam; (S)-UH-301; zaprinast; or
chlorpromazine; penbutolol; dipyridamole.
[0121] Suitable daily dosage ranges of additional pharmacologically
active compounds that can be adjunctively administered with
sibutramine metabolite can be readily determined by those skilled
in the art following dosages reported in the literature and
recommended in the Physcian's Desk Reference.RTM. (54.sup.th ed.,
2000).
[0122] For example, suitable daily dosage ranges of 5-HT.sub.3
antagonists can be readily determined by those skilled in the art
and will vary depending on factors such as those described herein
and the particular 5-HT.sub.3 antagonists used. In general, the
total daily dose of a 5-HT.sub.3 antagonist for the treatment or
prevention of a disorder described herein is from about 0.5 mg to
about 500 mg, preferably from about 1 mg to about 350 mg, and more
preferably from about 2 mg to about 250 mg per day.
[0123] Similarly, suitable daily dosage ranges of phosphodiesterase
inhibitors can be readily determined by those skilled in the art.
In general, the total daily dose of a phosphodiesterase inhibitor
will be from about 0.5 mg to about 500 mg, from about 1 mg to about
350 mg, or from about 2 mg to about 250 mg.
[0124] The therapeutic or prophylactic administration of an active
ingredient of the invention (e.g., sibutramine metabolites and
additional pharmacologically active compounds) is preferably
initiated at a lower dose and increased, if necessary, up to the
recommended daily dose as either a single dose or as divided doses,
depending on the global response of the patient. An example of a
lower dose of sibutramine metabolite is from about 0.1 mg to about
1 mg; an example of a lower dose of 5-HT.sub.3 antagonist is from
about 15 mg to about 60 mg. It is further recommended that patients
aged over 65 years should receive doses of sibutramine metabolite
in the range of from about 0.1 mg to about 10 mg per day depending
on global response. It may be necessary to use dosages outside
these ranges, which will be readily determinable by one of ordinary
skill in the pharmaceutical arts.
[0125] The dosage amounts and frequencies provided above are
encompassed by the terms "therapeutically effective,"
"prophylactically effective," and "therapeutically or
prophylactically effective" as used herein. When used in connection
with an amount of a racemic or optically pure sibutramine
metabolite, these terms further encompass an amount of racemic or
optically pure sibutramine metabolite that induces fewer or less
sever adverse effects than are associated with the administration
of racemic sibutramine. Adverse effects associated with racemic
sibutramine include, but are not limited to, significant increases
in supine and standing heart rate, including tachycardia, increased
blood pressure (hypertension), increased psychomotor activity, dry
mouth, dental caries, constipation, hypohidrosis, blurred or blurry
vision, tension, mydriasis, seizures, formation of gallstones,
renal/hepatic dysfunction, fevers, arthritis, agitation, leg
cramps, hypertonia, abnormal thinking, bronchitis, dyspnea,
pruritus, amblyopia, menstrual disorder, ecchymosis/bleeding
disorders, interstitial nephritis, and nervousness. See, e.g.,
Physician's Desk Reference.RTM. 1494-1498 (53.sup.rd ed., 1999).
However, the induction of fewer or less severe adverse-effects is
attributable to the administration of a sibutramine metabolite and
the efficacy of which may be less apparent or absent with the
administration of a combination therapy.
[0126] 4.3. Pharmaceutical Compositions
[0127] The invention encompasses pharmaceutical compositions and
single unit dosage forms comprising a sibutramine metabolite, or a
pharmaceutically acceptable salt, solvate, hydrate, clathrate, or
prodrug thereof. Preferred sibutramine metabolites are optically
pure. Certain pharmaceutical compositions and unit dosage forms
further comprise at least one additional pharmacologically active
compound.
[0128] The pharmaceutical compositions and dosage forms of this
invention are particularly useful in the methods herein, and may be
suitable for oral, mucosal (e.g., nasal, sublingual, buccal,
rectal, and vaginal), parenteral (e.g., intravenous, intramuscular
or subcutaneous), or transdermal administration.
[0129] Preferred pharmaceutical compositions and dosage forms
comprise a sibutramine metabolite, or a pharmaceutically acceptable
salt, solvate, hydrate, clathrate, or prodrug thereof in an amount
from about 0.1 mg to about 60 mg, preferably from about 2 mg to
about 30 mg, and more preferably from about 5 mg to about 15 mg.
Pharmaceutical compositions and dosage forms of the invention
typically also comprise one or more pharmaceutically acceptable
excipients or diluents.
[0130] Single unit dosage forms of the invention are suitable for
oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or
rectal), parenteral (e.g., subcutaneous, intravenous, bolus
injection, intramuscular, or intraarterial), or transdermal
administration to a patient. Examples of dosage forms include, but
are not limited to: tablets; caplets; capsules, such as soft
elastic gelatin capsules; cachets; troches; lozenges; dispersions;
suppositories; ointments; cataplasms (poultices); pastes; powders;
dressings; creams; plasters; solutions; patches; aerosols (e.g.,
nasal sprays or inhalers); gels; liquid dosage forms suitable for
oral or mucosal administration to a patient, including suspensions
(e.g. aqueous or non-aqueous liquid suspensions, oil-in-water
emulsions, or a water-in-oil liquid emulsions), solutions, and
elixirs; liquid dosage forms suitable for parenteral administration
to a patient; and sterile solids (e.g., crystalline or amorphous
solids) that can be reconstituted to provide liquid dosage forms
suitable for parenteral administration to a patient.
[0131] The composition, shape, and type of dosage forms of the
invention will typically vary depending on their use. For example,
a dosage form used in the acute treatment of disorder may contain
larger amounts of one or more of the active ingredients it
comprises than a dosage form used in the chronic treatment of the
same disorder. Similarly, a parenteral dosage form may contain
smaller amounts of one or more of the active ingredients it
comprises than an oral dosage form used to treat the same disease
or disorder. These and other ways in which specific dosage forms
encompassed by this invention will vary from one another will be
readily apparent to those skilled in the art. See, e.g.,
Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing,
Easton Pa. (1990).
[0132] Typical pharmaceutical compositions and dosage forms
comprise one or more excipients. Suitable excipients are well known
to those skilled in the art of pharmacy, and non-limiting examples
of suitable excipients are provided herein. Whether a particular
excipient is suitable for incorporation into a pharmaceutical
composition or dosage form depends on a variety of factors well
known in the art including, but not limited to, the way in which
the dosage form will be administered to a patient. For example,
oral dosage forms such as tablets may contain excipients not suited
for use in parenteral dosage forms. The suitability of a particular
excipient may also depend on the specific active ingredients in the
dosage form. For example, the decomposition of some active
ingredients, such as, desmethylsibutramine and
didesmethylsibutramine and its optically active enantiomers in
particular, can be accelerated by some excipients such as lactose,
or when exposed to water. Active ingredients that comprise primary
or secondary amines are particularly susceptible to such
accelerated decomposition. Consequently, this invention encompasses
pharmaceutical compositions and dosage forms that contain little,
if any, lactose or mono- or di-saccharides. As used herein, the
term "lactose-free" means that the amount of lactose present, if
any, is insufficient to substantially increase the degradation rate
of an active ingredient.
[0133] Lactose-free compositions of the invention can comprise
excipients that are well known in the art and are listed, for
example, in the U.S. Pharmocopia (USP) SP (XXI)/NF (XVI). In
general, lactose-free compositions comprise active ingredients, a
binder/filler, and a lubricant in pharmaceutically compatible and
pharmaceutically acceptable amounts. Preferred lactose-free forms
comprise active ingredients, microcrystalline cellulose,
pre-gelatinized starch, and magnesium stearate.
[0134] This invention further encompasses anhydrous pharmaceutical
compositions and dosage forms comprising active ingredients, since
water can facilitate the degradation of some compounds. For
example, the addition of water (e.g., 5%) is widely accepted in the
pharmaceutical arts as a means of simulating long-term storage in
order to determine characteristics such as shelf-life or the
stability of formulations over time. See, e.g., Jens T. Carstensen,
Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker,
NY, NY, 1995, pp. 379-80. In effect, water and heat accelerate the
decomposition of some compounds. Thus, the effect of water on a
formulation can be of great significance since moisture and/or
humidity are commonly encountered during manufacture, handling,
packaging, storage, shipment, and use of formulations.
[0135] Anhydrous pharmaceutical compositions and dosage forms of
the invention can be prepared using anhydrous or low moisture
containing ingredients and low moisture or low humidity conditions.
Pharmaceutical compositions and dosage forms that comprise lactose
and at least one active ingredient that comprises a primary or
secondary amine (e.g., desmethylsibutramine and
didesmethylsibutramine) are preferably anhydrous if substantial
contact with moisture and/or humidity during manufacturing,
packaging, and/or storage is expected.
[0136] An anhydrous pharmaceutical composition should be prepared
and stored such that its anhydrous nature is maintained.
Accordingly, anhydrous compositions are preferably packaged using
materials known to prevent exposure to water such that they can be
included in suitable formulary kits. Examples of suitable packaging
include, but are not limited to, hermetically sealed foils,
plastics, unit dose containers (e.g. vials), blister packs, and
strip packs.
[0137] The invention further encompasses pharmaceutical
compositions and dosage forms that comprise one or more compounds
that reduce the rate by which an active ingredient will decompose.
Such compounds, which are referred to herein as "stabilizers,"
include, but are not limited to, antioxidants such as ascorbic
acid, pH buffers, or salt buffers.
[0138] Like the amounts and types of excipients, the amounts and
specific types of active ingredients in a dosage form may differ
depending on factors such as, but not limited to, the route by
which it is to be administered to patients. However, typical dosage
forms of the invention comprise a racemic or optically pure
sibutramine metabolite, or a pharmaceutically acceptable salt,
solvate, clathrate, hydrate, or prodrug thereof in an amount of
from about 0.1 mg to about 60 mg, preferably in an amount of from
about 2 mg to about 30 mg, and more preferably in an amount of from
about 5 mg to about 15 mg.
[0139] 4.3.1. Oral Dosage Forms
[0140] Pharmaceutical compositions of the invention that are
suitable for oral administration can be presented as discrete
dosage forms, such as, but are not limited to, tablets (e.g.,
chewable tablets), caplets, capsules, and liquids (e.g., flavored
syrups). Such dosage forms contain predetermined amounts of active
ingredients, and may be prepared by methods of pharmacy well known
to those skilled in the art. See generally, Remington's
Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa.
(1990).
[0141] Typical oral dosage forms of the invention are prepared by
combining the active ingredient(s) in an intimate admixture with at
least one excipient according to conventional pharmaceutical
compounding techniques. Excipients can take a wide variety of forms
depending on the form of preparation desired for administration.
For example, excipients suitable for use in oral liquid or aerosol
dosage forms include, but are not limited to, water, glycols, oils,
alcohols, flavoring agents, preservatives, and coloring agents.
Examples of excipients suitable for use in solid oral dosage forms
(e.g., powders, tablets, capsules, and caplets) include, but are
not limited to, starches, sugars, micro-crystalline cellulose,
diluents, granulating agents, lubricants, binders, fillers, and
disintegrating agents.
[0142] Because of their ease of administration, tablets and
capsules represent the most advantageous oral dosage unit forms, in
which case solid excipients are employed. If desired, tablets can
be coated by standard aqueous or nonaqueous techniques. Such dosage
forms can be prepared by any of the methods of pharmacy. In
general, pharmaceutical compositions and dosage forms are prepared
by uniformly and intimately admixing the active ingredients with
liquid carriers, finely divided solid carriers, or both, and then
shaping the product into the desired presentation if necessary.
[0143] For example, a tablet can be prepared by compression or
molding. Compressed tablets can be prepared by compressing in a
suitable machine the active ingredients in a free-flowing form such
as powder or granules, optionally mixed with an excipient. Molded
tablets can be made by molding in a suitable machine a mixture of
the powdered compound moistened with an inert liquid diluent.
[0144] Binders suitable for use in pharmaceutical compositions and
dosage forms include, but are not limited to, corn starch, potato
starch, or other starches, gelatin, natural and synthetic gums such
as acacia, sodium alginate, alginic acid, other alginates, powdered
tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl
cellulose, cellulose acetate, carboxymethyl cellulose calcium,
sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl
cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose,
(e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and
mixtures thereof.
[0145] Suitable forms of microcrystalline cellulose include, but
are not limited to, the materials sold as AVICEL-PH-101,
AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (available from FMC
Corporation, American Viscose Division, Avicel Sales, Marcus Hook,
Pa.), and mixtures thereof. An specific binder is a mixture of
microcrystalline cellulose and sodium carboxymethyl cellulose sold
as AVICEL RC-581. Suitable anhydrous or low moisture excipients or
additives include AVICEL-PH-103.TM. and Starch 1500 LM.
[0146] Examples of fillers suitable for use in the pharmaceutical
compositions and dosage forms disclosed herein include, but are not
limited to, talc, calcium carbonate (e.g., granules or powder),
microcrystalline cellulose, powdered cellulose, dextrates, kaolin,
mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch,
and mixtures thereof. The binder or filler in pharmaceutical
compositions of the invention is typically present in from about 50
to about 99 weight percent of the pharmaceutical composition or
dosage form.
[0147] Disintegrants are used in the compositions of the invention
to provide tablets that disintegrate when exposed to an aqueous
environment. Tablets that contain too much disintegrant may
disintegrate in storage, while those that contain too little may
not disintegrate at a desired rate or under the desired conditions.
Thus, a sufficient amount of disintegrant that is neither too much
nor too little to detrimentally alter the release of the active
ingredients should be used to form solid oral dosage forms of the
invention. The amount of disintegrant used varies based upon the
type of formulation, and is readily discernible to those of
ordinary skill in the art. Typical pharmaceutical compositions
comprise from about 0.5 to about 15 weight percent of disintegrant,
preferably from about 1 to about 5 weight percent of
disintegrant.
[0148] Disintegrants that can be used in pharmaceutical
compositions and dosage forms of the invention include, but are not
limited to, agar-agar, alginic acid, calcium carbonate,
microcrystalline cellulose, croscarmellose sodium, crospovidone,
polacrilin potassium, sodium starch glycolate, potato or tapioca
starch, other starches, pre-gelatinized starch, other starches,
clays, other algins, other celluloses, gums, and mixtures
thereof.
[0149] Lubricants that can be used in pharmaceutical compositions
and dosage forms of the invention include, but are not limited to,
calcium stearate, magnesium stearate, mineral oil, light mineral
oil, glycerin, sorbitol, mannitol, polyethylene glycol, other
glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated
vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil,
sesame oil, olive oil, corn oil, and soybean oil), zinc stearate,
ethyl oleate, ethyl laureate, agar, and mixtures thereof.
Additional lubricants include, for example, a syloid silica gel
(AEROSIL 200, manufactured by W. R. Grace Co. of Baltimore, Md.), a
coagulated aerosol of synthetic silica (marketed by Degussa Co. of
Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold
by Cabot Co. of Boston, Mass.), and mixtures thereof. If used at
all, lubricants are typically used in an amount of less than about
1 weight percent of the pharmaceutical compositions or dosage forms
into which they are incorporated.
[0150] The magnitude of a prophylactic or therapeutic dose of an
active ingredient in the acute or chronic management of a disorder
or condition will vary with the severity of the disorder or
condition to be treated and the route of administration. The dose,
and perhaps the dose frequency, will also vary according to age,
body weight, response, and the past medical history of the patient.
Suitable dosing regimens can be readily selected by those skilled
in the art with due consideration of such factors.
[0151] 4.3.2. Delayed Release Dosage Forms
[0152] Active ingredients of the invention can be administered by
controlled release means or by delivery devices that are well known
to those of ordinary skill in the art. Examples include, but are
not limited to, those described in U.S. Pat. Nos.: 3,845,770;
3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533,
5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556,
and 5,733,566, each of which is incorporated herein by reference.
Such dosage forms can be used to provide slow or controlled-release
of one or more active ingredients using, for example,
hydropropylmethyl cellulose, other polymer matrices, gels,
permeable membranes, osmotic systems, multilayer coatings,
microparticles, liposomes, microspheres, or a combination thereof
to provide the desired release profile in varying proportions.
Suitable controlled-release formulations known to those of ordinary
skill in the art, including those described herein, can be readily
selected for use with the active ingredients of the invention. The
invention thus encompasses single unit dosage forms suitable for
oral administration such as, but not limited to, tablets, capsules,
gelcaps, and caplets that are adapted for controlled-release.
[0153] All controlled-release pharmaceutical products have a common
goal of improving drug therapy over that achieved by their
non-controlled counterparts. Ideally, the use of an optimally
designed controlled-release preparation in medical treatment is
characterized by a minimum of drug substance being employed to cure
or control the condition in a minimum amount of time. Advantages of
controlled-release formulations include extended activity of the
drug, reduced dosage frequency, and increased patient compliance.
In addition, controlled-release formulations can be used to affect
the time of onset of action or other characteristics, such as blood
levels of the drug, and can thus affect the occurrence of side
(e.g., adverse) effects.
[0154] Most controlled-release formulations are designed to
initially release an amount of drug (active ingredient) that
promptly produces the desired therapeutic effect, and gradually and
continually release other amounts of drug to maintain this level of
therapeutic or prophylactic effect over an extended period of time.
In order to maintain this constant level of drug in the body, the
drug must be released from the dosage form at a rate that will
replace the amount of drug being metabolized and excreted from the
body. Controlled-release of an active ingredient can be stimulated
by various conditions including, but not limited to, pH,
temperature, enzymes, water, or other physiological conditions or
compounds.
[0155] 4.3.3. Parenteral Dosage Forms
[0156] Parenteral dosage forms can be administered to patients by
various routes including, but not limited to, subcutaneous,
intravenous (including bolus injection), intramuscular, and
intraarterial. Because their administration typically bypasses
patients' natural defenses against contaminants, parenteral dosage
forms are preferably sterile or capable of being sterilized prior
to administration to a patient. Examples of parenteral dosage forms
include, but are not limited to, solutions ready for injection, dry
products ready to be dissolved or suspended in a pharmaceutically
acceptable vehicle for injection, suspensions ready for injection,
and emulsions.
[0157] Suitable vehicles that can be used to provide parenteral
dosage forms of the invention are well known to those skilled in
the art. Examples include, but are not limited to: Water for
Injection USP, aqueous vehicles such as, but not limited to, Sodium
Chloride Injection, Ringer's Injection, Dextrose Injection,
Dextrose and Sodium Chloride Injection, and Lactated Ringer's
Injection; water-miscible vehicles such as, but not limited to,
ethyl alcohol, polyethylene glycol, and polypropylene glycol; and
non-aqueous vehicles such as, but not limited to, corn oil,
cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl
myristate, and benzyl benzoate.
[0158] Compounds that increase the solubility of one or more of the
active ingredients disclosed herein can also be incorporated into
the parenteral dosage forms of the invention.
[0159] 4.3.4. Transdermal, topical, and Mucosal Dosage Forms
[0160] Transdermal, topical, and mucosal dosage forms of the
invention include, but are not limited to, ophthalmic solutions,
sprays, aerosols, creams, lotions, ointments, gels, solutions,
emulsions, suspensions, or other forms known to one of skill in the
art. See, e.g., Remington's Pharmaceutical Sciences, 16th and 18th
eds., Mack Publishing, Easton Pa. (1980 & 1990); and
Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea &
Febiger, Philadelphia (1985). Dosage forms suitable for treating
mucosal tissues within the oral cavity can be formulated as
mouthwashes or as oral gels. Further, transdermal dosage forms
include "reservoir type" or "matrix type" patches, which can be
applied to the skin and worn for a specific period of time to
permit the penetration of a desired amount of active
ingredients.
[0161] Suitable excipients (e.g., carriers and diluents) and other
materials that can be used to provide transdermal, topical, and
mucosal dosage forms encompassed by this invention are well known
to those skilled in the pharmaceutical arts, and depend on the
particular tissue to which a given pharmaceutical composition or
dosage form will be applied. With that fact in mind, typical
excipients include, but are not limited to, water, acetone,
ethanol, ethylene glycol, propylene glycol, butane-1,3-diol,
isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures
thereof to form lotions, tinctures, creams, emulsions, gels or
ointments, which are non-toxic and pharmaceutically acceptable.
Moisturizers or humectants can also be added to pharmaceutical
compositions and dosage forms if desired. Examples of such
additional ingredients are well known in the art. See, e.g.,
Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack
Publishing, Easton Pa. (1980 & 1990).
[0162] Depending on the specific tissue to be treated, additional
components may be used prior to, in conjunction with, or subsequent
to treatment with active ingredients of the invention. For example,
penetration enhancers can be used to assist in delivering the
active ingredients to the tissue. Suitable penetration enhancers
include, but are not limited to: acetone; various alcohols such as
ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as
dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide;
polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone;
Kollidon grades (Povidone, Polyvidone); urea; and various
water-soluble or insoluble sugar esters such as Tween 80
(polysorbate 80) and Span 60 (sorbitan monostearate).
[0163] The pH of a pharmaceutical composition or dosage form, or of
the tissue to which the pharmaceutical composition or dosage form
is applied, may also be adjusted to improve delivery of one or more
active ingredients. Similarly, the polarity of a solvent carrier,
its ionic strength, or tonicity can be adjusted to improve
delivery. Compounds such as stearates can also be added to
pharmaceutical compositions or dosage forms to advantageously alter
the hydrophilicity or lipophilicity of one or more active
ingredients so as to improve delivery. In this regard, stearates
can serve as a lipid vehicle for the formulation, as an emulsifying
agent or surfactant, and as a delivery-enhancing or
penetration-enhancing agent. Different salts, hydrates or solvates
of the active ingredients can be used to further adjust the
properties of the resulting composition.
[0164] 4.3.5. Kits
[0165] Typically, active ingredients of the invention are
preferably not administered to a patient at the same time or by the
same route of administration. This invention therefore encompasses
kits which, when used by the medical practitioner, can simplify the
administration of appropriate amounts of active ingredients to a
patient.
[0166] A typical kit of the invention comprises a unit dosage form
of a sibutramine metabolite, or a pharmaceutically acceptable
prodrug, salt, solvate, hydrate, or clathrate thereof, and a unit
dosage form of an additional pharmacologically active compound.
Examples of additional pharmacologically active compounds are
disclosed herein.
[0167] Kits of the invention can further comprise devices that are
used to administer the active ingredients. Examples of such devices
include, but are not limited to, syringes, drip bags, patches, and
inhalers.
[0168] Kits of the invention can further comprise pharmaceutically
acceptable vehicles that can be used to administer one or more
active ingredients. For example, if an active ingredient is
provided in a solid form that must be reconstituted for parenteral
administration, the kit can comprise a sealed container of a
suitable vehicle in which the active ingredient can be dissolved to
form a particulate-free sterile solution that is suitable for
parenteral administration. Examples of pharmaceutically acceptable
vehicles include, but are not limited to: Water for Injection USP;
aqueous vehicles such as, but not limited to, Sodium Chloride
Injection, Ringer's Injection, Dextrose Injection, Dextrose and
Sodium Chloride Injection, and Lactated Ringer's Injection;
water-miscible vehicles such as, but not limited to, ethyl alcohol,
polyethylene glycol, and polypropylene glycol; and non-aqueous
vehicles such as, but not limited to, corn oil, cottonseed oil,
peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and
benzyl benzoate.
[0169] The invention is further defined by reference to the
following examples. It will be apparent to those skilled in the art
that many modifications, both to materials and methods, can be
practiced without departing from the scope of this invention.
5. EXAMPLES
[0170] Examples 1-2 describe the preparation of racemic and
optically pure sibutramine.
[0171] Examples 3-8 describe the preparation of racemic and
optically pure forms of desmethylsibutramine (DMS). In each of
these examples, the enantiomeric purity of DMS was determined using
a Chirobiotic V analytical column (10 mm, 4.6 mm.times.25 mm) with
20 mm ammonium acetate/IPA (65:35) as the mobile phase. The UV
detector was set to a wavelength of 222 nm.
[0172] Examples 9-12 describe the preparation of racemic and
optically pure forms of didesmethylsibutramine (DDMS). In each of
these examples, the enantiomeric purity of DDMS was determined
using an ULTRON ES-OVM analytical column (150 mm.times.4.6 mm) with
0.01 M KH.sub.2PO.sub.4/MeOH (70:30) as the mobile phase. The UV
detector was set to a wavelength of 200 nm.
[0173] Examples 13-14 describe methods of determining binding
affinities of the compounds of the invention and binding affinities
measured using those methods.
[0174] Finally, Example 15 describes oral formulations comprising
compounds of the invention.
5.1. Example 1
Synthesis of Sibutramine
[0175] Synthesis of 1-(4-Chlorophenyl)cyclobutanecarbonitrile
[0176] To a suspension of NaH (17.6 g 60%, washed with hexane) in
dimethylsulfoxide (150 mL) at room temperature with mechanical
stirring was added over a one hour period a mixture of
chlobenzylnitrile (30.3 g) and 1,3-dibromopropaine (22.3 mL, 44.5
g). The reaction mixture was stirred for an additional 1 hour, and
isopropyl alcohol (10 mL) was added slowly to quench excess NaH.
Water (150 mL) was added. The reaction mixture was extracted with
t-butyl methyl ether (MTBE) (2.times.200 mL), and the combined
extracts were washed with water (3.times.200 mL), brine, and dried
over MgSO.sub.4. The solvent was removed in a rotoevaporator, and
the final product was purified by distillation to give the title
compound (22 g, 56%) as pale yellow oil, bp 110-120.degree. C./1.0
mm Hg. The product was characterized by .sup.1H NMR.
[0177] Synthesis of
1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine
[0178] A solution of isobutylmagnesium bromide (2M, 108 mL) in
diethyl ether (Aldrich) was concentrated to remove most of the
ether. The residue was dissolved in toluene (150 mL), followed by
addition of the nitrile made above (22 g). The reaction mixture was
heated to 105.degree. C. for 17 hours. The reaction mixture was
cooled to room temperature, and added to a slurry of NaBH.sub.4 in
isopropyl alcohol (450 mL). The reaction mixture was heated under
reflux for 6 hours, cooled to room temperature and concentrated.
The residue was diluted with water (350 mL), and extracted with
ethyl acetate (3.times.200 mL). The combined extracts were washed
with water (100 mL), and dried (MgSO.sub.4), and concentrated to
give 24.2 g crude product (83%).
[0179] Synthesis of Sibutramine Free Base
[0180] 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine (21.6 g)
was added to formic acid (27 mL) and aqueous formaldehyde (46 mL).
The reaction mixture was heated to 8595.degree. C. for 18 hours and
was cooled to room temperature. 30% NaOH was added until the
mixture was basic (pH>11). The solution was extracted with
chloroform (3.times.200 mL) and the extracts were combined and
washed with water and brine and concentrated to give 15 g
product.
[0181] Sibutramine HCl
[0182] Sibutramine free base (2.25 g) was dissolved in MTBE (20 mL)
and that solution was added to 20 mL 1M HCl in diethyl ether. The
reaction mixture was stirred for 30 minutes, and the solid was
collected by filtration to give 1.73 g after drying. The product
was characterized by .sup.1H NMR.
[0183] Resolution of Sibutramine
[0184] 12.3 g racemic sibutramine was dissolved in ethyl acetate
(85 mL), and a solution of 21.7 g L-dibenzyltartaric acid
("L-DBTA") in ethyl acetate (85 mL) was added thereto. The reaction
mixture was heated to reflux and cooled to room temperature. The
white precipitate was collected (ee of salt is ca 85%). The solid
was then suspended in 220 mL ethyl acetate and heated at reflux for
30 minutes. The solid was collected to give >95% ee. The salt
was further crystallized in isopropyl alcohol (450 mL) to give 11.3
g of salt with >99.3% ee. (S)-Sibutramine L-DBTA (yield 76%).
Free base was obtained by treatment of the salt with saturated
aqueous NaHCO.sub.3 and extracted with chloroform. The
(S)-sibutramine HCl salt was obtained with treatment of the free
base with HCl/Et.sub.2O as described above. Optical rotation of the
HCl salt was [.alpha.]=3.15 (c=0.9, H.sub.2O), .sup.1H NMR .sup.13C
(CD.sub.3OD), and M.sup.+=279. The resolution mother liquor was
treated with NaOH to give the partially enriched (R)-sibutramine
and was then treated with D-DBTA as described above to give
(R)-sibutramine-D-DBTA salt with >99.3% ee. The sibutramine
enantiomers were characterized by .sup.1H and .sup.13C NMR:
M.sup.+=279. The material was also characterized by HPLC and Chiral
HPLC.
5.2. Example 2
Sibutramine from its Metabolites
[0185] Racemic and optically pure sibutramine can also be prepared
by methylation of desmethylsibutramine or dimethylation of
didesmethylsibutramine under suitable reaction conditions. An
example of this method is shown in Scheme 1. 2
5.3. Example 3
Desmethylsibutramine from Sibutramine
[0186] (S)-Sibutramine (1.25 g) was dissolved in toluene (90 mL)
and diethylazodicarboxylate ("DEAD") was added (0.8 g, 10.1 eq).
The reaction mixture was heated at 50.degree. C. for 6 hours, and
0.8 g DEAD was added. The reaction was heated at 50.degree. C. for
another 6 hours, cooled to room temperature and the toluene was
removed under vacuum. The residue was suspend in 45 mL of ethanol
and 45 mL of saturated aqueous NH.sub.4Cl. The reaction mixture was
heated under reflux for 3 hours. The reaction mixture was cooled to
room temperature and concentrated to remove ethanol. Aqueous
NaHCO.sub.3 was added until the concentrate was basic. The basic
concentrate was extracted with dichloromethane, (3.times.50 mL).
The extracts were combined, dried with sodium sulfate, filtered and
concentrated to give a crude product. Flash column chromatography
(SiO.sub.2) (ethyl acetate/TEA 99:1) gave 0.43 g product. It was
characterized by .sup.1H and .sup.13C NMR, M.sup.+=266, and optical
rotation [.alpha.]=-10.6, c=3.3, (CHCl.sub.3.) The other enantiomer
and racemate were prepared similarly and the isomer was
characterized as the (S)-isomer.
[0187] Synthesis of Desmethylsibutramine Hydrochloride Isomers
[0188] To a solution of (S)-desmethylsibutramine (0.78 g) in ethyl
acetate (5 mL) at 0.degree. C. was added HCl/diethyl ether (1 M, 5
mL). The reaction mixture was stirred for 1 hour and the solid was
collected by filtration. The solid was then dried to give 0.68 g
white solid. The product was characterized by .sup.1H and 1.sup.3C
NMR (DMSO-d.sub.6), and a chemical purity of >99% was determined
by HPLC. [.alpha.]=-5.degree. (c=0.5, H.sub.2O). The racemate and
the other enantiomer were prepared and characterized in the same
way.
5.4. Example 4
(R/S)-Desmethylsibutramine
[0189] Another method of preparing racemic desmethylsibutramine
((R/S)-DMS) is shown in Scheme 2 and described in detail below:
3
[0190] Preparation of 1-(4-Chlorophenyl)-1-cyclobutyl
Carboxaldehyde
[0191] Following Scheme 2, diisobutylaluminum hydride (DIBAL-H) (87
mL, 1M in THF, 87.0 mmol) was added to a solution of
1-(4-chlorophenyl) cyclobutanecarbonitrile (CCBC; 10 g, 52.1 mmol)
maintained at -20.degree. C. The resulting mixture was stirred for
4-5 hours at 0.degree. C. and then poured into a 10% aqueous citric
acid solution and diluted with 200 mL MTBE. The mixture was stirred
at room temperature for 3-4 hours. The aqueous layer was washed
with MTBE (1.times.50 mL) and the combined organic layers were
dried over MgSO.sub.4 and concentrated to give 9 g (89%) of the
above-captioned aldehyde as an oil. .sup.1H NMR (CDCl.sub.3) d 9.52
(s, 1H), 7.35-7.06 (m, 4H), 2.77-2.68 (m, 2H), 2.43-2.32 9 m, 2H),
2.06-1.89 (m, 2H). .sup.13C NMR d 198.9, 139.4, 132.9, 128.9,
127.8, 57.1, 28.3, 15.8.
[0192] Preparation of 1-(4-chlorophenyl)-1-cyclobutyl
N-methylcarbamine
[0193] A mixture of 1-(4-chlorophenyl)-1-cyclobutyl carboxaldehyde
(3 g, 15.4 mmol) and methyl amine (12 mL, 40% aqueous w/w, 154
mmol) was stirred at room temperature for 18-40 hours. The reaction
mixture was extracted with MTBE (2.times.50 mL). The combined
organic layers were dried over K.sub.2CO.sub.3 and concentrated to
give 2.5 g (78%) of the above-captioned imine as an oil. .sup.1H
NMR (CDCl.sub.3) d 7.65 (m, 1H), 7.33-7.11 (m, 4H), 3.34 (s, 3H),
2.69-2.44 (m, 2H), 2.44-2.34 (m, 2H), 2.09-1.84 (m, 2H), .sup.13C
NMR d 168.0, 144.0, 131.8, 128.4, 127.4, 50.6, 30.6, 15.8.
[0194] Preparation of
1-(4-chlorophenyl)-N-methyl-2-(2-methylpropyl)-cyclo-
butanamethamine
[0195] To a solution of 1-(4-chlorophenyl)-1-cyclobutyl
N-methylcarbaimine (0.5 g, 2.4 mmol) cooled to 0.degree. C. was
added BF.sub.3.OEt.sub.2 (0.34 g, 2.4 mmol). The mixture was
stirred for 1 hour and then cooled to -78.degree. C. At this
temperature, isobutyl magnesium bromide (2.5 mL, 2M in ether, 5
mmol) was added to form a mixture which was stirred at -78.degree.
C. for 2 hours and then warmed to room temperature and stirred
overnight. The reaction was quenched with saturated NaHCO.sub.3
solution (10 mL) and diluted with MTBE (15 mL). The organic layer
was dried over MgSO.sub.4, concentrated, and purified by silicagel
chromatography (eluting with 1% NEt.sub.3 in ethyl acetate) to give
380 mg of the above captioned amine as an oil. .sup.1H NMR
(CDCl.sub.3) d 7.35-7.19 (m, 4H), 2.65-2.74 (m, 1H), 2.57 (s, 3H),
2.20-2.56 (m, 5H), 1.60-2.00 (m, 3H), 1.20-1.00 (m, 2H), 0.95-0.90
(m, 6H), 0.67-0.60 (m, 1H). .sup.13C NMR 144.7, 131.3, 129.1,
127.4, 65.5, 51.7, 41.4, 37.4, 33.7, 32.3, 25.4, 24.0, 22.0,
16.3.
5.5. Example 5
(R/S)-Desmethylsibutramine.HCl
[0196] A method of preparing the hydrochloride salt of racemic
desmethylsibutramine ((R/S)-DMS.HCl) is shown in Scheme 3: 4
[0197] Following Scheme 3, toluene (150 mL) and a solution of CCBC
(50.0 g, 261 mmol) in toluene (45 mL) were added to a solution of
isobutyl magnesium bromide in THF (392 mL, 1M in THF, 392 mmol).
The resulting mixture was distilled until the internal temperature
reached 105-110.degree. C. and as then refluxed at this temperature
for 2-4 hours. The reaction mixture was then cooled to 0.degree. C.
and quenched with methanol (295 mL). NaBH.sub.4 (11 g, 339 mmol)
was added portion-wise over 15 minutes to the reaction mixture at
0.degree. C. After stirring for 15 minutes, the reaction mixture
was transferred into a 2N aqueous HCl solution (365 mL). The
organic phase was distilled until the internal temperature reached
105.degree. C., and was then allowed to cool to room temperature.
Formic acid (24 g, 522 mmol) was then added to the reaction
mixture, which was then heated to reflux (92-96.degree. C.) for 6-8
hours after which time the reaction mixture was distilled until the
internal temperature reached 108.degree. C. The mixture was then
cooled to 10.degree. C. and BH.sub.3.THF (653 mL, 1.0 M, 653 mmol)
was added. The resulting mixture was heated to reflux (69.degree.
C.) for 15 hours. The mixture was then cooled to 5.degree. C.,
combined with methanol (105 mL), and refluxed again for 45 minutes.
The reaction mixture was distilled until the internal temperature
reached 116.degree. C., and then allowed to cool to 25.degree. C.
Hydrochloric acid in MTBE (373 g, 18 wt % of HCl, 1840 mmol) was
then added to the mixture to provide a white slurry which was
refluxed for 1 hour and then filtered to give 62.3 g (79.0%) of
(R/S)-DMS.HCl. NMR (CDCl.sub.3): .sup.1H (d), 0.85-1.1 (m, 6H),
1.24-1.5 (b, 2H), 1.65-2.14 (b, 4H), 2.2-2.5 (b, 4H), 2.5-2.7 (m,
2H), 3.4-3.6 (b, 1H), 7.3-7.5 (m, 4H), 9.0-9.5 (b, 2H). .sup.13C
(d): 15.5, 21.4, 23.5, 24.7, 31.4, 32.4, 33.2, 35.9, 49.1, 64.2,
128.5, 129.4, 133.0, 141.6.
5.6. Example 6
(R)-Desmethylsibutramine.HCl
[0198] A method of preparing the hydrochloride salt of
(R)-desmethylsibutramine ((R)-DMS.HCl) is shown in Scheme 4 and
described in detail below: 5
[0199] Formation of (R)-Mandelate Salt of (R)-DMS
[0200] (R/S)-Desmethylsibutramine HCl ((R/S)-DMS.HCl) (60 g) was
added to ethyl acetate (300 mL) and the resulting mixture was
cooled to 0.degree. C. Aqueous NaOH (1.5 N, 300 mL) was then added
to the reaction mixture, which was then stirred for 30 minutes. The
organic phase was separated, washed with water (150 mL), and
concentrated. (R)-Mandelic acid (30.3 g), ethyl acetate (510 mL
total), and heptane (204 mL) were then added to the concentrated
organic phase. The resulting mixture was then heated to reflux for
1 hour, after which time it was cooled to 20-23.degree. C.
Filtration of the resulting slurry yielded 36.4 g (43.8%) of
(R)-desmethylsibutramine-(R)-mandelate ((R)-DMS.(R)-MA; 95.5%
ee).
[0201] Enrichment of (R)-DMS.(R)-MA
[0202] A mixture of (R)-DMS.(R)-MA (30 g, 0.072 mol), ethyl acetate
(230 mL), and heptane (230 mL) was heated to reflux for 1 hour.
After cooling to 20-23.degree. C., the product was filtered and
dried to give 29.6 g (98%) of (R)-DMS.(R)-MA (99.9% ee).
[0203] Formation of HCl Salt of (R)-DMS
[0204] A mixture of (R)-DMS.(R)-MA (50 g, 0.12 mol), NaOH (100 ml,
3.0 N), and toluene (500 mL) was stirred for 30 minutes. The
organic phase was washed with water (200 mL), concentrated to about
300 mL, and cooled to room temperature. HCl/MTBE (100 mL, 14%, 0.34
mol) was then slowly added to the mixture to form (R)-DMS.HCl.
After stirring for 30 minutes, the slurry was filtered and the
resulting wet cake was washed two times with MTBE and dried to give
34.5 g (95.5%) of (R)-DMS.HCl (99.9% cc; 99.9% chemically pure by
NMR). NMR (CDCl.sub.3): .sup.1H (d), 0.85-1.1 (m, 6H), 1.24-1.5 (b,
2H), 1.65-2.14 (b, 4H), 2.2-2.5 (b, 4H), 2.5-2.7 (m, 2H), 3.4-3.6
(b, 1H), 7.3-7.5 (m, 4H), 9.0-9.5 (b, 2H). .sup.13C (d): 15.5,
21.4, 23.5, 24.7, 31.4, 32.4, 33.2, 35.9, 49.1, 64.2, 128.5, 129.4,
133.0, 141.6.
5.7. Example 7
(S)-Desmethylsibutramine-HCl
[0205] A method of preparing the hydrochloride salt of
(S)-desmethylsibutramine (S)-DMS.HCl) is shown in Scheme 5 and
described in detail below: 6
[0206] Formation of (S)-Mandelate Salt of (S)-DMS
[0207] Following Scheme 5, a mixture of (R/S)-DMS.HCl (5.0 g), NaOH
(1.5N, 20 mL) and ethyl acetate (50 mL) was stirred for 30 minutes.
The organic phase was washed with water (20 mL) and concentrated to
give desmethylsibutramine free base (4.2 g, 96%).
[0208] Desmethylsibutramine free base (1.1 g, 4.1 mmol) was
combined with (S)-mandelic acid (0.62 g, 4.1 mmol), ethyl acetate
(11 mL), and heptane (4.4 mL). The resulting mixture was heated to
reflux for 30 minutes and cooled to 20-23.degree. C. Filtration of
the resulting slurry gave 0.76 g of
(S)-desmethylsibutramine-(S)-mandelate salt ((S)-DMS.(S)-MA) (96%
ee).
[0209] Enrichment of (S)-DMS.(S)-MA
[0210] A mixture of (S)-Desmethylsibutramine.(S)-mandelate (0.76
g), ethyl acetate (5 mL), and heptane (5 mL) was heated to reflux
for 1 hour. After cooling to 20-23.degree. C., the product was
filtered and dried to give 0.72 g (95%) of(S)-DMS.(S)-MA (99.9%
cc).
[0211] Recovery of (S)-Mandelate Salt of (S)-DMS from Mother Liquor
of (S-DMS.(R)-MA
[0212] A solution of (S)-DMS.(R)-MA in ethyl acetate-heptane (67%
ee mother liquor) was charged with NaOH (3N, 400 mL) and the
reaction mixture was stirred for 30 minutes. The organic phase was
washed with water and concentrated. The resulting residue (130 g,
0.49 mol and 67% ee) was charged with (S)-mandelic acid (28.5 g,
0.49 mol), ethyl acetate (1400 mL), and heptane (580 mL). The
mixture was heated to reflux for 1 hour and then slowly cooled to
room temperature. The resulting slurry was filtered and dried to
give 147 g (86% based on (S)-isomer) of (S)-DMS.(S)-MA (99.9%
ee).
[0213] Formation of HCl Salt of (S)-DMS
[0214] (S)-Desmethylsibutramine-(S)-mandelate (20 g, 0.048 mol) was
added to a mixture of NaOH (60 ml, 3.0 N) and toluene (200 mL). The
mixture was stirred for 30 minutes and the organic phase was then
washed with water (100 mL), concentrated to about 100 mL, and
cooled to room temperature. Hydrochloric acid in MTBE (40 mL, 14%,
0.13 mol) was then added slowly to the mixture to form (S)-DMS.HCl.
After stirring for 30 minutes, the slurry was filtered and the
resulting wet cake was washed two times with MTBE and dried to give
14 g (96.7%) of (S)-DMS.(L)-MA (99.9% ee; 99.9% chemical purity).
NMR (CDCl.sub.3): .sup.1H (d), 0.84-1.1 (m, 6H), 1.25-1.5 (b, 2H),
1.65-2.15 (b, 4H), 2.2-2.5 (b, 4H), 2.5-2.7 (m, 2H), 3.4-3.6 (b,
1H), 7.3-7.5 (m, 4H), 9.0-9.5 (b, 2H). .sup.13C (d): 15.5, 21.4,
23.5, 24.7, 31.4, 32.4, 33.2, 35.9, 49.1, 64.2, 128.5, 129.4,
133.0, 141.6.
5.8. Example 8
Desmethylsibutramine from Didesmethylsibutramine
[0215] Racemic and optically pure didesmethylsibutramine can also
be prepared by methylation of didesmethylsibutramine under suitable
reaction conditions. An example of this method is shown in Scheme
6. 7
[0216] 5.9. Example 9
(R/S)-Didesmetrylsibutramine
[0217] A preferred method of preparing racemic
didesmethylsibutramine free base ((R/S)-DDMS) is shown in Scheme 7
and described in detail below. 8
[0218] Following Scheme 7, a 1 L three-necked round bottom flask
was charged with isobutyl magnesium bromide (200 mL, 2.0 M in
diethyl ether) and toluene (159 mL) and the resulting mixture was
distilled to remove most of the ether. After the mixture was cooled
to 20.degree. C., CCBC (50.0 g) in toluene (45 mL) was added, and
resulting mixture was refluxed for 2-4 hours. The reaction mixture
was then cooled to 0.degree. C. and methanol (300 mL) was added to
it, followed slowly by NaBH.sub.4 (11 g). The resulting mixture was
then stirred at about 0-10.degree. C. for 15 minutes. The reaction
mixture was then added slowly to an aqueous HCl solution (365 mL,
2N) kept at 0.degree. C., and the resulting mixture was warmed to
room temperature with continual stirring. After separation of the
organic phase, the aqueous phase was washed with toluene (200 mL).
The combined organic phases were washed with water (200 mL) and
concentrated to give (R/S)-DDMS (55 g, 85%). NMR (CDCl.sub.3):
.sup.1H (d), 0.6-0.8 (m, 1H), 0.8-1.0 (m, (6H), 1.1-1.3 (m, 1H),
1.6-2.6 (m, 7H), 3.0-3.3 (m, 1H), 7.0-7.6 (m, 4H). .sup.13C (d):
15.4, 21.5, 24.3, 24.7, 31.5, 31.9, 41.1, 50.73, 56.3, 127.7, 129,
131.6, 144.3.
5.10. Example 10
(R/S)-didesmethylsibutramine-(D)-tartrate
[0219] A preferred method of preparing the (D)-tartrate salt of
racemic didesmethylsibutramine ((R/S)-DDMS.(D)-TA) is shown below
in Scheme 8. It should be noted that the (L)-tartrate salt of
racemic didesmethylsibutramine ((R/S)-DDMS.(L)-TA) can be prepared
in an analogous manner. 9
[0220] Following Scheme 8, a mixture of racemic
didesmethylsibutramine (15.3 g) and toluene (160 mL) was heated to
70-80.degree. C. and (D)-tartaric acid (9.1 g) in water (20 mL) and
acetone (10 mL) was added slowly. The resulting mixture was
refluxed for 30 minutes, after which the water and acetone were
removed by distillation. The resulting mixture was cooled to room
temperature to provide a slurry which was then filtered. The
resulting wet cake was washed two times with MTBE (20 mL.times.2)
and dried to yield (R/S)-DDMS.(D)-TA (22.5 g, 98%). NMR (DMSO):
.sup.1H (d), 0.6-0.92 (m, 6H), 0.92-1.1 (m, 1H), 1.1-1.3 (m, 1H),
1.5-1.8 (m, 2H), 1.8-2.1 (m, 1H, 2.1-2.4 (m, 3H), 2.4-2.6 (m, 1H),
3.4-3.6 (m, 1H), 3.9-4.2 (s, 2H), 6.4-7.2 (b, 6H, OH, COOH, and
NH.sub.2), 7.3-7.6 (m, 4H). .sup.13C (d): 15.5, 2.1, 23.3, 3.7,
31.5, 31.8, 37.7, 39.7, 54.5, 72.1, 128, 129.7, 131.3, 149.2,
174.6.
5.11. Example 11
(R)-didemethylsibutramine-(D)-tartrate
[0221] Resolution from Didesmethylsibutramine Free Base
[0222] A method of isolating the (D)-tartrate salt of
(R)-didesmethylsibutramine ((R)-DDMS.(D)-TA) from racemic
didesmethylsibutramine free base is shown in Scheme 9A and
described in detail below: 10
[0223] Following Scheme 9A, a mixture of
(R/S)-didesmethylsibutramine (20.3 g), acetone/water/methanol (350
mL, 1:0.13:0.7, v:v:v), and (D)-tartaric acid (12.1 g) were added
to a 500 mL three-necked round bottom. The reaction mixture was
heated to reflux for 30 minutes and then cooled to 45.degree. C.
The reaction mixture was then seeded with (R)-DDMS.(D)-TA (10 mg;
99.6% ee) and stirred at 40-45.degree. C. for 30 minutes. The
mixture was then cooled to room temperature and stirred for 1 hour.
The resulting slurry was then filtered and the wet cake was washed
with cold acetone/water and dried to give 10.3 g (33%) of
(R)-DDMS.(D)-TA (90% ee).
[0224] Resolution from
(R/S)-Didesmethylsibutramine-(D)-tartrate
[0225] A method of isolating the (D)-tartrate salt of
(R)-didesmethylsibutramine ((R)-DDMS.(D)-TA) from the (D)-tartrate
salt of racemic didesmethylsibutramine is shown in Scheme 9B and
described in detail below. 11
[0226] Following Scheme 9B, a mixture of
(R/S)-didesmethylsibutramine.(D)-- TA (5.0 g) in acetone (50 mL),
water (6.7 mL), and methanol (3.3 mL) was refluxed for 30 minutes.
The mixture was then cooled to room temperature and the resulting
slurry was filtered to provide a wet cake which was then washed
with cold acetone and dried to give (R)-DDMS.(D)-TA (1.4 g, 28%;
92% ee).
[0227] Enrichment of (D)-Tartrate Salt of (R)-DDMS
[0228] A mixture of (R)-DDMS.(D)-TA (25 g, 92% ee) and
acetonitrile/water/ethanol (300 mL:65 mL:30 mL) was refluxed for 1
hour. The mixture was then cooled to room temperature to provide a
slurry which was filtered and dried to give (R)-DDMS.(D)-TA (18 g,
71.3%; 99.7% ee; and 99.91% chemical purity). NMR (DMSO-d.sub.6):
.sup.1H (d), 0.7-0.9 (m, 6H), 0.9-1.05 (t, 1H), 1.1-1.24 (b, 1H),
1.5-1.8 (b, 2H), 1.8-2.02 (b, 1H), 2.1-2.4 (3, 3H), 2.4-2.6 (b,
1H), 3.5 (m, 1H), 4.0 (s, 2H), 7.1-7.6 (m, 4H, with 6H from
NH.sub.2, OH and COOH). .sup.13C (d): 15.4, 21.5, 22.0, 22.2, 32.0,
32.2, 38.4, 49.0, 54.0, 72.8, 128.8, 130.0, 132.0, 143.0,
175.5.
5.12. Example 12
(S)-didesmethylsibutramine-(L)-tartrate
[0229] A method of isolating the (L)-tartrate salt of
(S)-didesmethylsibutramine ((S)-DDMS.(L)-TA) from racemic
didesmethylsibutramine free base is shown in Scheme 10 and
described in detail below: 12
[0230] Formation of (L)-Tartrate Salt of (S)-DDMS
[0231] (R/S) Didesmethylsibutramine (20.5 g),
acetone/water/methanol (350 mL, 1:0.13:0.7, v:v:v) and (L)-tartaric
acid (12.2 g) were added to a 500 mL three-necked round bottom
flask. The mixture was heated to reflux for 30 minutes and then
cooled to 45.degree. C. The reaction mixture was then seeded with
(S)-DDMS.(L)-TA (10 mg and 99.7% ee) and stirred at 40-45.degree.
C. for 30 minutes. The mixture was cooled to room temperature and
stirred for 1 hour. The resulting slurry was filtered to provide a
wet cake, which was washed with cold acetone/water and dried to
give 10.8 g (33.4%) of (S)-DDMS.(L)-TA (89.7% ee).
[0232] Preparation of (L)-Tartrate Salt of (S)-DDMS from Mother
Liquor of (R)-DDMS.(D)-TA
[0233] A solution of DDMS tartrate in acetone/water/methanol
(mother liquor of (R)-DDMS.(D)-TA) was concentrated to remove
acetone and methanol. The residue was treated with aqueous NaOH
(3N, 150 mL) and extracted with ethyl acetate. The organic phase
was washed with water (100 mL) and concentrated to give
didesmethylsibutramine free base (45 g, 0.18 mol and 36% ee of
(S)-isomer). The free amine was charged with (L)-tartaric acid
(53.6 g, 0.35 mol), acetone (600 mL), water (80 mL), and methanol
(40 mL). The mixture was heated to reflux for 1 hour and then
cooled to room temperature. The resulting slurry was filtered to
provide a wet cake, which was then washed with cold acetone/water
two times to give 26.7 g (56% based on (S)-didesmethylsibutramine)
of (S)-DDMS.(L)-TA (96% ee).
[0234] Enrichment of (S)-DDMS.(L)-TA
[0235] A mixture of (S)-DDMS.(L)-TA (26.7 g) in acetonitrile/water
(475 mL; 1:0.2, v:v) was refluxed for 1 hour and then cooled to
room temperature. The resulting slurry was filtered and dried to
give 17.4 g (65%) of (S)-DDMS.(L)-TA (99.9% ee; 99.94% chemical
purity). NMR (DMSO-d6): .sup.1H (d), 0.7-0.9 (m, 6H), 0.9-1.05 (m,
1H), 1.1-1.3 (b, 1H), 1.52-1.8 (b, 2H), 1.84-2.05 (b, 1H), 2.15-2.4
(b, 3H), 2.4-2.6 (b, 1H), 3.65-3.58 (m, 1H), 4.0 (s, 2H), 6.7-7.3
(b, 6H from NH.sub.2, OH and COOH) 7.1-7.6 (m, 4H). .sup.13C (d):
15.4, 21.5, 22.0, 22.2, 32.0, 32.2, 38.4, 49.0, 54.0, 72.8, 128.8,
130.0, 132.0, 143.0, 175.5.
5.13. Example 13
Determination of Potency an Specificity
[0236] A pharmacologic study is conducted to determine the relative
potency, comparative efficacy, binding affinity, and toxicity of
the racemic mixture of sibutramine, its enantiomers, the
metabolites of sibutramine, and their enantiomers. The profile of
relative specificity of monoamine reuptake inhibition is determined
from the compounds' inhibition of norepinephrine (NE) reuptake in
brain tissue with that of the inhibition of dopamine (DA) and
serotonin 5-HT) reuptake.
[0237] High-affinity uptake of the .sup.3H-radiomonoamines is
studied in synaptosomal preparations prepared from rat corpus
striatum (for inhibition of DA reuptake) and cerebral cortex (for
5HT and NE) using methods published by Kula et al., Life Sciences
34(26): 2567-2575, 1984, and Baldessarini et al., Life Sciences
39:1765-1777, 1986. Tissues are freshly dissected on ice and
weighed. Following homogenization by hand (14 strokes in 10-35 vols
of ice-cold isotonic 0.32M sucrose, containing nialamide, 34 .mu.M)
in a Teflon-on-glass homogenizer, the tissue is centrifuged for ten
minutes at 900.times.g; the supernatant "solution" that results
contains synaptosomes that are used without further treatment. Each
assay tube contains 50 mL of the cerebral homogenate,
radiolabelled-.sup.3H-monoamine, and the test compound (e.g., the
pure sibutramine enantiomers, the racemate, and appropriate
standards) in a freshly prepared physiologic buffer solution with a
final volume of 0.5 mL. Tissues are preincubated for 15 minutes at
37.degree. C. before the assay. Tubes are held on ice until the
start of incubation, which is initiated by adding .sup.3H-amine to
provide a final concentration of 0.1 .mu.M. Tubes are incubated at
37.degree. C for 10 minutes with .sup.3H-DA (26 Ci/mmol) and for 20
minutes with .sup.3H-5HT (about 20 Ci/mmol) and .sup.3H-NE (about
20 Ci/mmol). The specific activity of the radiomonoamine will vary
with available material and is not critical. The reaction is
terminated by immersion in ice and dilution with 3 mL of ice cold
isotonic saline solution containing 20 mM TRIS buffer (pH 7.0).
These solutions are filtered through cellulose ester microfilters,
followed by washing with two 3 mL volumes of the same buffer. The
filter is then counted for .sup.3H-radioactivity in 3.5 mL of
Polyfluor at about 50% efficiency for tritium. Blanks (either
incubated at 0.degree. C. or incubated with specific, known uptake
inhibitors of DA [GRB-12909, 10 .mu.M], 5HT-[zimelidine 10 .mu.M],
or of NE [desipramine 10 .mu.M]) are usually indistinguishable from
assays performed without tissue and average 2-3% of total CPM.
[0238] Comparison of the amounts of .sup.3H-radioactivity retained
on the filters provides an indication of the relative abilities of
the pure enantiomers and racemic mixture of sibutramine (and of
known DA, 5-HT, and NE reuptake inhibitors) to block the reuptake
of these monoamines in those tissues. This information is useful in
gauging the relative potency and efficacy of compounds of the
invention (e.g., dopamine reuptake inhibitors, such as a racemic or
optically pure sibutramine metabolite, and 5-HT.sub.3
antagonists).
[0239] The acute toxicities of the compounds of the invention are
determined in studies in which rats are administered progressively
higher doses (mg/kg) of the pure isomers or racemate. That lethal
dose which, when administered orally, causes death of 50% of the
test animals, is reported as the LD.sub.50. Comparison of LD.sub.50
values for the enantiomers and racemate provides a measure of the
relative toxicity of the compositions.
5.14. Example 14
Binding Affinities
[0240] The binding affinities of racemic and optically pure
sibutramine ((R/S)-, (R)-, and (S)-sibutramine),
desmethylsibutramine ((R/S)-, (R)-, and (S)-desMe), and
didesmethylsibutramine ((RIS)-, (R)-, and (S)-didesMe) were
determined at the nonselective muscarinic receptor and the
serotonin (5-HT) uptake site from rat cerebral cortex, the human
recombinant norepinephrine (NE) uptake site, and the
.beta..sub.3-receptor from rat adipose tissue. Compounds were
tested initially at 10 .mu.m in duplicate, and if 250% inhibition
of specific binding was observed, they were tested further at 10
different concentrations in duplicate in order to obtain full
competition curves. IC.sub.50 values (concentration required to
inhibit 50% specific binding) were then determined by nonlinear
regression analysis of the curves and tabulated below.
2 Binding IC.sub.50 Values (nM) Muscarinic NE 5-HT 5-HT Selectivity
Compound Receptor Uptake Uptake (NE/5-HT) (R/S)-Sibutramine 2,650
350 2,800 1,200 (R)-Sibutramine 4,010 110 2,100 650 (S)-Sibutramine
3,020 2,500 4,900 1,500 (R/S)-desMe 1,170 10 21 19 (R)-desMe -- 4
44 12 (S)-desMe 654 870 9,200 180 (R/S)-didesMe -- 16 63/14 39/26
(R)-didesMe -- 13 140 8.9 (S)-didesMe -- 6.2 4,300 12 Atropine 0.31
-- -- -- GBR 1909 -- -- -- 5.6/2.6 Imipramine -- -- 145/32 --
Protriptyline -- 3.6/0.9 -- -- Zimelidine -- -- 129 --
[0241] None of the compounds showed more than 15% inhibition of
binding at the .beta..sub.3-receptor, and affinity for the
muscarinic site was weak compared to atropine. Further, binding to
the NE and 5-HT uptake sites was orders of magnitude less than that
of the standards.
[0242] The above data, which was generated as described above in
Example 13, shows that (R)-desmethylsibutramine and
(R)-didesmethylsibutramine are potent inhibitors of NE uptake and
5-HT uptake, but have negligible activity at muscarinic
receptors.
5.15. Example 15
Oral Formulation
[0243] Hard gelatin capsule dosage forms that are lactose-free
comprising sibutramine metabolites can be prepared using the
following ingredients:
3 Component 5 mg capsule 10 mg capsule 20 mg capsule Racemic or
optically 5.0 10.0 20.0 pure sibutramine metabolite
Microcrystalline 90.0 90.0 90.0 Cellulose Pre-gelatinized 100.3
97.8 82.8 Starch Croscarmellose 7.0 7.0 7.0 Magnesium 0.2 0.2 0.2
Stearate
[0244] The racemic or optically pure sibutramine metabolite is
sieved and blended with the excipients listed. The mixture is
filled into suitably sized two-piece hard gelatin capsules using
suitable machinery and methods well known in the art. See, e.g.,
Remington's Pharmaceutical Sciences, 16th or 18th Editions, each
incorporated herein in its entirety by reference. Other doses can
be prepared by altering the fill weight and, if necessary, changing
the capsule size to suit. Any of the stable, non-lactose hard
gelatin capsule formulations above can be formed.
[0245] Compressed tablet dosage forms of sibutramine metabolites
can be prepared using the following ingredients:
4 Component 5 mg capsule 10 mg capsule 20 mg capsule Racemic or
optically 5.0 10.0 20.0 pure sibutramine metabolite
Microcrystalline 90.0 90.0 90.0 Cellulose Pre-gelatinized 100.3
97.8 82.8 Starch Croscarmellose 7.0 7.0 7.0 Magnesium 0.2 0.2 0.2
Stearate
[0246] The racemic or optically pure sibutramine metabolite is
sieved through a suitable sieve and blended with the non-lactose
excipients unit a uniform blend is formed. The dry blend is
screened and blended with the magnesium stearate. The resulting
powder blend is then compressed into tablets of desired shape and
size. Tablets of other strengths can be prepared by altering the
ratio of the active ingredient to the excipient(s) or modifying the
table weight.
[0247] The embodiments of the invention described above are
intended to be merely exemplary and those skilled in the art will
recognize, or be able to ascertain using no more than routine
experimentation, numerous equivalents to the specific procedures
described herein. All such equivalents are considered to be within
the scope of the invention and are encompassed by the following
claims.
* * * * *