U.S. patent application number 10/013142 was filed with the patent office on 2002-06-27 for use of hydroxyrisperidone for the manufacture of a medicament for the treatment and prevention of psychoses, emesis and symptoms of withdrawal from alcohol and nicotine.
This patent application is currently assigned to Sepracor Inc.. Invention is credited to Yelle, William E..
Application Number | 20020082245 10/013142 |
Document ID | / |
Family ID | 26792287 |
Filed Date | 2002-06-27 |
United States Patent
Application |
20020082245 |
Kind Code |
A1 |
Yelle, William E. |
June 27, 2002 |
Use of hydroxyrisperidone for the manufacture of a medicament for
the treatment and prevention of psychoses, emesis and symptoms of
withdrawal from alcohol and nicotine
Abstract
Methods and compositions utilizing compounds represented by
Formula III, 1 or a pharmaceutically acceptable salt thereof, for
the treatment and prevention of psychoses in humans are disclosed.
Compounds of the present invention exhibit fewer side effects than
risperidone, a lessened liability toward drug-drug interactions
than risperidone and a more predictable dosing regimen than
risperidone. Compounds of the invention are also useful for the
treatment and prevention of emesis and withdrawal syndromes.
Inventors: |
Yelle, William E.;
(Littleton, MA) |
Correspondence
Address: |
HESLIN ROTHENBERG FARLEY & MESITI PC
5 COLUMBIA CIRCLE
ALBANY
NY
12203
US
|
Assignee: |
Sepracor Inc.
Marlborough
MA
|
Family ID: |
26792287 |
Appl. No.: |
10/013142 |
Filed: |
December 10, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10013142 |
Dec 10, 2001 |
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09762968 |
Feb 15, 2001 |
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09762968 |
Feb 15, 2001 |
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PCT/US99/18631 |
Aug 17, 1999 |
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60113118 |
Dec 21, 1998 |
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60097004 |
Aug 18, 1998 |
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Current U.S.
Class: |
514/90 ;
514/259.41 |
Current CPC
Class: |
A61P 25/18 20180101;
A61K 31/505 20130101; A61P 25/32 20180101; A61P 1/08 20180101; A61K
31/51 20130101; A61K 31/675 20130101; A61P 25/34 20180101 |
Class at
Publication: |
514/90 ;
514/259.41 |
International
Class: |
A61K 031/675; A61K
031/519 |
Claims
What is claimed is:
1. A method of treating psychoses while avoiding the concomitant
liability of side effects associated with risperidone which
comprises administering to a human an amount of a compound
represented by Formula III, 5wherein R is chosen from --OH,
--P(O)(OH).sub.2 and --SO.sub.3H, or a pharmaceutically acceptable
salt thereof sufficient to treat psychoses but insufficient to
cause said side effects.
2. A method of providing a predictable dosing regimen in the
treatment of psychoses which comprises administering to a human a
therapeutically effective amount of a compound represented by
Formula III, 6wherein R is chosen from --OH, --P(O)(OH).sub.2 and
--SO.sub.3H, or a pharmaceutically acceptable salt thereof.
3. A method of reducing potential for drug-drug interactions in the
treatment of psychoses which comprises administering to a human a
therapeutically effective amount of a compound represented by
Formula III, 7wherein R is chosen from --OH, --P(O)(OH).sub.2 and
--SO.sub.3H, or a pharmaceutically acceptable salt thereof.
4. A method of suppressing emesis which comprises administering to
a human a therapeutically effective amount of a compound
represented by Formula III, 8wherein R is chosen from --OH,
--P(O)(OH).sub.2--SO.sub.3H, or a pharmaceutically acceptable salt
thereof.
5. A method of treating withdrawal from alcohol, nicotine or
narcotic drugs which comprises administering to a human a
therapeutically effective amount of a compound represented by
Formula III, 9wherein R is chosen from --OH, --P(O)(OH).sub.2 and
--SO.sub.3H, or a pharmaceutically acceptable salt thereof.
6. The method of any of claims 1-5 wherein R is --OH.
7. The method of claim 6 wherein the compound is administered
orally.
8. The method of claim 7 wherein the amount of the compound, or a
pharmaceutically acceptable salt thereof administered is from about
1 mg to about 20 mg per day.
9. The method of any of claims 1-5 wherein R is
--P(O)(OH).sub.2.
10. The method of claim 9 wherein the pharmaceutically acceptable
salt thereof is the N-methylglucamine salt.
11. The method of claim 10 wherein the compound is administered
intravenously.
12. A pharmaceutical composition for intravenous administration
comprising the N-methylglucamine salt of a compound represented by
Formula III', 10and a pharmaceutically acceptable carrier.
Description
FIELD OF THE INVENTION
[0001] This invention relates to compositions of matter containing
hydroxyrisperidone. The invention also relates to methods of
treating and preventing psychoses, emesis and symptoms of
withdrawal from alcohol and nicotine.
BACKGROUND OF THE INVENTION
[0002] Risperidone I is an orally active, potent antipsychotic
agent commercially available in the form of Rispendal.RTM. tablets
and oral solution from Janssen Pharmaceutica. 2
[0003] The C.sub.max of rispendone in humans is at about 3 to 9
hours after oral administration, and the serum half-life is about 2
to 22 hours; both of these parameters are highly variable,
depending on the subject's age, liver function, and CYP 2D6
phenotype, as will be discussed below. The major metabolite in
human serum is 9-hydroxyrisperidone II (hereinafter,
"hydroxyrisperidone"). 3
[0004] The hydroxylation of risperidone to its active metabolite,
hydroxyrisperidone, is catalyzed in vivo by the hepatic cytochrome
P450 enzyme, CYP2D6, an enzyme that is involved in the metabolism
of numerous other drugs, including tricyclic antidepressants and
selective serotonin reuptake inhibitors. CYP2D6-is polymorphically
expressed in the human population and the mutant allele constitutes
the recessive trait. Homozygous carriers of the mutation completely
lack CYP2D6 and are referred to as poor metabolizers (PM's);
persons homozygous for the "normal" allele are extensive
metabolizers (EM's); heterozygotes appear to be intermediate in
metabolic capacity.
[0005] It would be desirable to find a compound that has the
advantages of risperidone while providing a more predictable dosage
regimen in the patient population and decreasing the chances for
drug-drug interactions.
[0006] Risperidone is known to give rise to several side effects,
and in particular, to extrapyramidal effects such as tardive
dyskinesia. The most frequently observed adverse reactions include
orthostatic hypotension and dizziness, drowsiness, palpitations,
weight gain, erectile dysfunction, and a significant increase in
rashes and rhinitis.
[0007] The following adverse events have been reported in
risperidone-treated patients:
[0008] Psychiatric disorders--insomnia, agitation, anxiety,
somnolence, aggressive reaction, increased dream activity,
diminished desire, nervousness, depression, apathy, catatonic
reaction, euphoria, increased libido, amnesia, emotional lability,
nightmares, delirium, withdrawal syndrome, yawning.
[0009] Central and Peripheral Nervous system
disorders--extrapyramidal symptoms (including tremor, dystonia,
hypokinesia, hypertonia, hyperkinesia, oculogyric crisis, ataxia,
abnormal gait, involuntary muscle contractions, hyporeflexia,
akathisia, increased sleep duration, dysarthria, vertigo, stupor,
paraesthesia, confusion, aphasia, cholinergic syndrome,
hypoesthesia, tongue paralysis, leg cramps, torticollis, hypotonia,
coma, migraine, hyperreflexia and choreoathetosis.
[0010] Gastrointestinal system disorders--constipation, nausea,
dyspepsia, vomiting abdominal pain, increased salivation, anorexia,
toothache, reduced salivation, flatulence, diarrhea, increased
appetite, stomatitis, melena, dysphagia, hemorrhoids, gastritis,
fecal incontinence, eructation, gastroesophageal reflux,
gastroenteritis, esophagitis, tongue discoloration, cholelithiasis,
tongue edema, diverticulitis, gingivitis, discolored feces, GI
hemorrhage, hematemesis
[0011] Body as a whole/General disorders--back pain, chest pain,
fever, fatigue, edema, rigors, malaise, influenza-like symptoms,
pallor, enlarged abdomen, allergic reaction, ascites, sarcoidosis,
flushing
[0012] Respiratory system--rhinitis, coughing, sinusitis,
pharyngitis, dyspnea, hyperventilation, bronchospasm, pneumonia,
stridor, asthma, increased sputum, aspiration
[0013] Dermatological--rash, dry skin, seborrhea, increased
pigmentation, photosensitivity, increased sweating, acne, decreased
sweating, alopecia, hyperkeratosis, pruritus, skin exfoliation,
bullous eruption, skin ulceration, aggravated psoriasis,
furunculosis, verruca, dermatitis lichenoid, hypertrichosis,
genital pruritus, and urticaria.
[0014] Vision Disorders--abnormal accommodation, xerophthalmia,
diplopia, eye pain, blepharitis, photopsia, photophobia, and
abnormal lacrimation.
[0015] Metabolic and Nutritional Disorders--hyponatremia, weight
increase, creatine phosphokinase increase, thirst, weight decrease,
diabetes mellitus, decreased serum iron, cachexia, dehydration,
hypokalemia, hypoproteinemia, hyperphosphatemia,
hypertriglyceridemia, hyperuricermia, and hypoglycemia.
[0016] Urinary System Disorders--polyuria/polydipsia, urinary
incontinence, hematuria, dysuria, urinary retention, cystitis, and
renal insufficiency.
[0017] Musculo-Skeletal Disorders--arthralgia, myalgia, arthrosis,
synostosis, bursitis, arthritis, and skeletal pain.
[0018] Reproductive Disorders--(Female) menorrhagia, orgastic
dysfunction, dry vagina, nonpuerperal lactation, amenorrhea, female
breast pain, leukorrhea, vaginal hemorrhage, dysmenorrhea, femal
perineal pain, mastitis,and intermenstrual bleeding; (Male)
erectile dysfunction and ejaculation failure.
[0019] Liver and Biliary System Disorders--increased SGOT,
increased SGPT, hepatic failure, cholestatic hepatitis,
cholecystitis, cholelithiasis, hepatitis, and hepatocellular
damage.
[0020] Endocrine Disorders--gynecomastia, male breast pain, and
antidiuretic hormone disorder.
[0021] White Cell and Resistance Disorders--leukocytosis,
lymphadenopathy, leucopenia, and Pelger-Huet anomaly.
[0022] Red Blood Cell Disorders--anemia, hypochromic anemia, and
normocytic anemia.
[0023] Platelet, Bleeding and Clotting Disorders--epistaxis,
purpura, hemorrhage, superficial phlebitis, thrombophlebitis, and
thrombocytopenia.
[0024] Hearing and Vestibular Disorders--tinnitus, hyperacusis, and
decreased hearing.
[0025] Cardiovascular--tachycardia, orithostatic hypotension,
palpitation, hypertension, AV block, myocardial infarction,
ventricular tachycardia, angina pectoris, premature atrial
contractions, T wave inversions, ventricular extrasystoles, ST
depression, myocarditis, angioedema, atrial fibrillation, pulmonary
embolism and cardiopulmonary arrest.
[0026] Risperidone and hydroxyrisperidone have also been implicated
in a prolongation of QT interval, a condition associated with
torsades de pointes, a life-threatening arrhythmia.
[0027] Accordingly, an antipsychotic having the efficacy of
risperidone, but causing fewer side effects, would be
desirable.
SUMMARY OF THE INVENTION
[0028] Compounds used in the methods and compositions of the
present invention are represented by Formula III, 4
[0029] wherein R is chosen from --OH, --P(O)(OH).sub.2 and
--SO.sub.3H, or a pharmaceutically acceptable salt thereof The
compounds possess potent activity in the treatment of psychotic
disorders (e.g., schizophrenia) and other conditions, including
those that would benefit from an antidiarrheal, an inhibitor of
gastro-esophageal reflux and/or an antiemetic, especially in cancer
patients receiving chemotherapy and radiation. Compounds of Formula
III may also be used in combating autism, hypertension, vascular
disorders, obesity, and the withdrawal symptoms associated with
cessation of drinking and smoking. Compounds of Formula III provide
a more predictable dosage regimen in the patient population and
decrease the chances for drug-drug interactions by avoiding
oxidative metabolism for which the cytochrome P450 2D6 enzyme
system is required.
DETAILED DESCRIPTION OF THE INVENTION
[0030] The active compounds of the present compositions and methods
are represented by Formula III, above. Throughout this application,
various references are referred to, often, although not always,
within parentheses or square brackets. The disclosures of all of
these publications in their entireties are hereby incorporated by
reference as if written herein.
[0031] Compounds of Formula III possess a center of asymmetry at
the carbon to which R is attached (C-9), thereby giving rise to two
enantiomers. The present invention envisions the use of either pure
enantiomer or a mixture of the two enantiomers in any proportion.
Thus, the term "hydroxyrisperidone," for example, as used herein
means that a particular composition contains from 100% by weight of
(-)-hydroxyrisperidone to 100% by weight of (+)-hydroxyrisperidone,
and all intermediate mixtures. A preferred intermediate mixture is
the racemate. The registry number of racemic hydroxyrisperidone is
144598-754.
[0032] The term "adverse effects" includes, but is not limited to,
prolonged QT effect, extrapyramidal effects such as tardive
dyskinesia, orthostatic hypotension and dizziness, drowsiness,
palpitations, weight gain, erectile dysfunction, rashes and
rhinitis. The term is intended to encompass at least all of the
adverse effects reported in risperidone-treated patients as
previously described herein.
[0033] The literature describes a close resemblance in the
pharmacological profiles of risperidone and its 9-hydroxy
metabolite, and they have been shown to exhibit similar effects.
Megens and Awouters [Drug Development Research, 33:399-142 (1994)],
concluded that "[a]s metabolic conversion of risperidone to
9--OH-risperidone does apparently not result in any marked change
in activity profile, its major consequence seems to be a
prolongation of duration of action." van Beijsterveldt et al.
[Psychopharmacology, 114:53-62 (1994)] similarly concluded that the
pharmacological properties of the hydroxy metabolite are comparable
to the parent compound, "both in respect of the profile of
interactions with various neurotransmitters and its potency,
activity, and onset and duration of action."
[0034] It has now been discovered that compounds of Formula III are
superior agents for treating psychoses and other disorders in that
they provide effective treatment while exhibiting fewer or less
severe adverse effects than risperidone, less potential for
drug-drug interactions than risperidone, as well as a more
predictable dosing regimen than risperidone. Compounds of Formula
III also provide more predictable elimination and clearance in
elderly patients and patients with impaired renal function.
[0035] The present invention encompasses a method of treating
psychoses, which comprises administering to a human in need of such
therapy, an amount of a compound of Formula III, or a
pharmaceutically acceptable salt thereof, which is sufficient to
alleviate the symptoms of psychosis. The present invention further
encompasses a method of treating diarrhea, gastro-esophageal reflux
and emesis. The present invention yet further encompasses a method
of treating autism, hypertension, vascular disorders, obesity, and
the withdrawal symptoms associated with cessation of drinking and
smoking.
[0036] Preferably, the methods of the present invention are
practiced by administering a pharmaceutical composition in the form
of a tablet, capsule, or liquid comprising between about 1 and 20
mg of a compound of Formula III.
[0037] Utilizing compounds of Formula III provides enhanced dosage
predictability and an improved therapeutic index as compared to
risperidone. In particular, the compounds exhibit less variation in
the patient population between so-called extensive metabolizers and
poor metabolizers than does risperidone.
[0038] The magnitude of a prophylactic or therapeutic dose of a
compound of Formula III required for the acute or chronic
management of disease will vary with the severity of the condition
to be treated and the route of administration. The dose and perhaps
the dose frequency will also vary according to the age, body weight
and response of an individual patient. In general, the total daily
dose range for compounds of Formula III for the conditions
described herein is from about 1 mg to about 20 mg in single or,
preferably, divided doses. A preferred daily dose range is about 1
mg to about 10 mg in two divided doses. In managing a particular
patient, the therapy should be initiated at a lower dose, perhaps
at about 1 mg, and then increased up to about 10 mg or higher,
depending upon the patient's global response. It is further
recommended that children and patients over 65 years of age, as
well as those with impaired renal or hepatic function, initially
receive low doses, and that they be titrated based upon individual
response(s) and blood level(s). It may be necessary to use dosages
outside the indicated ranges in some cases, as will be apparent to
those skilled in the art. Further, it is noted that the clinician
or treating physician will know how and when to interrupt, adjust,
or terminate therapy in conjunction with individual patient
response. The terms "an amount sufficient to treat psychoses," "an
amount sufficient to alleviate the symptoms of emesis," "an amount
sufficient to treat diarrhea," and "an amount sufficient to treat
withdrawal," are encompassed by the above-described dosage amounts
and dose frequency schedule.
[0039] The relative activity, potency and specificity of compounds
of Formula III may be determined by a pharmacological study in
animals according to the method of Nyberg et al.
[Psychopharmacology, 119:345-348 (1995)]. The method provides an
estimate of relative activity, potency and, through a measure of
specificity, an estimate of therapeutic index. Although the
differential metabolism among patient populations can be determined
by a clinical study in humans, less expensive and time-consuming
substitutes are provided by the methods of Kerr et al. [Biochem.
Pharmacol., 47:1969-1979 (1994)] and Karam et al. [Drug Metab.
Dispos.,24:1081-1087 (1996)]. The potential for drug-drug
interactions may be assessed clinically according to the methods of
Leach et al. [Epilepsia, 37:1100-1106 (1996)], or in vitro
according to the methods of Kerr et al. [supra] and Turner and
Renton [Can. J. Physiol. Pharmacol. 67:582-586 (1989)].
[0040] Any suitable route of administration may be employed for
providing the patient with an effective dosage of a compound of
Formula III. Suitable routes of administration may include, for
example, oral, rectal, nasal, buccal, parenteral (such as,
intravenous, subcutaneous, intramuscular, intrasternal,
intrathecal, intrahepatic, intralesional, intracranial,
intra-articular, and intra-synovial), transdermal, and the like.
Due to their ease of administration, oral dosage forms, such as,
for example, tablets, troches, dispersions, suspensions, solutions,
capsules, soft gelatin capsules, and the like, may be
preferred.
[0041] Pharmaceutical compositions of the present invention
comprise a compound of Formula III, or a pharmaceutically
acceptable salt thereof, as the active ingredient, and may contain
a pharmaceutically acceptable carrier, as well as other therapeutic
ingredients. The terms "pharmaceutically acceptable salts," and "a
pharmaceutically acceptable salt thereof," refer to salts prepared
from pharmaceutically acceptable non-toxic acids or bases. Salts of
compounds of Formula III are more soluble than either risperidone
or hydroxyrisperidone and are therefore well-suited for parenteral,
and in particular, intravenous administration.
[0042] Since the hydroxy compound of Formula III is basic, salts
may be prepared from pharmaceutically acceptable non-toxic acids,
including both inorganic and organic acids. Suitable
pharmaceutically acceptable acid addition salts of Formula III
include, but are not limited to, acetic, benzenesulfonic
(besylate), benzoic, camphorsulfonic, citric, ethenesulfonic,
fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,
lactic, maleic, malic, mandelic, methanesulfonic (mesylate), mucic,
nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric,
tartaric, p-toluenesulfonic, and the like. The tartrate,
hydrochloride and pamoate salts are preferred salts of the hydroxy
compound.
[0043] The phosphate and sulfate compounds of Formula III are
acidic, and therefore allow for the preparation of salts of bases
as well as internal salts. Suitable pharmaceutically acceptable
base addition salts include, but are not limited to, metallic salts
made from aluminum, calcium, lithium, magnesium, potassium, sodium
and zinc, as well as organic salts made from chloroprocaine,
choline, N,N'-dibenzylethylenediamine, diethanolamine,
ethylenediamine, lysine, meglumine (N-methylglucamine) and
procaine. The N-methylglucamine salt of the phosphate compound is a
preferred compound for parenteral administration, and in
particular, for intravenous administration.
[0044] The compositions of the present invention may comprise, but
are in no way limited to, suspensions, solutions, elixirs and solid
dosage forms. Carriers, such as starches, sugars, and
microcrystalline cellulose, diluents, granulating agents,
lubricants, binders, disintegrating agents, and the like are
suitable in the case of oral solid preparations (such as, for
example, powders, capsules, soft gelatin capsules, tablets and the
like). In some cases, it may be advantageous to coat oral solid
dosage forms with an enteric or delayed-release coating, and such
may be accomplished by standard aqueous or nonaqueous techniques.
Oral dosage forms suitable for compounds of the present invention
are described in U.S. Pat. Nos. 5,158,952; 5,453,425; and
5,612,346. In addition to the common dosage forms set out above,
the compounds of the present invention may also be administered by
controlled release formulations, which are well known in the
art.
[0045] Pharmaceutical compositions of the present invention
suitable for oral administration may be presented in the form of
discrete units such as capsules, cachets, soft gelatin capsules,
and tablets, wherein each unit contains a predetermined amount of
the active ingredient, as a powder or as granules or as- a solution
or a suspension in an aqueous liquid, a non-aqueous liquid, an
oil-in-water emulsion, or a water-in-oil liquid emulsion. Such
compositions may be prepared by any of the methods of pharmacy, any
of which will typically include the step of bringing into
association the active ingredient with a carrier that constitutes
one or more necessary ingredients. In general, the compositions are
prepared by uniformly and intimately admixing the active ingredient
with liquid carriers or finely divided solid carriers or both, and
then, if necessary, shaping the product into the desired
presentation.
[0046] Tablets, for example, may be prepared by compression or
molding, optionally, with one or more accessory ingredients.
Compressed tablets may be prepared by compressing in a suitable
machine an amount of the active ingredient in a free-flowing form
such as powder or granules, optionally mixed with a binder,
lubricant, inert diluent, surface active agent or dispersing agent.
Molded tablets may be made by molding in a suitable machine, a
mixture of the powdered compound moistened with an inert liquid
diluent. Desirably, each tablet, or other presentation, contains
between about 1 to 10 mg, and more desirably, between about 1 to 5
mg of the active ingredient.
[0047] An enteric coating, such as the polyacrylate Eudragit L.RTM.
and Eudragit S.RTM. series, may be applied, preferably with an
aqueous dispersion of the coating polymer. Tablets of other
strengths may also be prepared by altering the ratio of active
ingredient to the excipients or to the final weight of the
tablet.
[0048] The invention is further defined by reference to the
following examples describing in detail the preparation of
compounds and compositions of the present invention. It will be
apparent to those skilled in the art that many modifications, both
to materials and methods, may be practiced without departing from
the spirit of the invention.
[0049] Preparation of Compounds of Formula III
[0050] Compounds represented by Formula III of the present
invention wherein R is --OH may be prepared as described in U.S.
Pat. No. 5,158,952. Example 3 of the reference teaches a method for
the preparation of (rac)-hydroxyrisperidone from
3-(2-chloroethyl)-6,7,8,9-te-
trahydro-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one and
6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole monohydrochloride
utilizing an art-known N-alkylation reaction.
[0051] Compounds represented by Formula III of the present
invention wherein R is --P(O)(OH).sub.2 may be prepared by various
methods. A first approach utilizes the same starting materials as
the above-described preparation of hydroxyrisperidone and is based
upon methods known in the art.
3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy4H-pyrido[1,2-a]pyrimi-
din-4-one is treated with diphenyl chlorophosphate and
N,N-dimethyl4-pyridinamine in dichloromethane according to the
protocol described in Example 13 of published PCT patent
application WO 95/19983. The diphenyl reaction product is then
submitted to a two-step hydrolysis as described in Example 15 of
that reference. The phosphate reaction product is then mixed with
6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole monohydrochloride in
accordance with the N-alkylation reaction described in Example 3 of
U.S. Pat. No. 5,158,952, whereby a compound of Formula III, wherein
R is --P(O)(OH).sub.2 is obtained.
[0052] In accordance with a second method, the phosphate compound
may be prepared from hydroxyrispendone by treating the hydroxy
compound with (1) iPr.sub.2NP(OCH.sub.2Ph), tetrazole; (2) t-BuOOH;
and (3) Pd/C, H.sub.2. In addition, the N-methylglucamine salt of
the phosphate compound may be obtained by including
N-methylglucamine in step (3).
[0053] Compounds of Formula III wherein R is --SO.sub.3H may be
prepared from hydroxyrisperidone according to the method of Laiv
and Goren [Carb. Res. 131 C, (1984)].
[0054] Preparation of Pharmaceutical Compositions Including a
Compound of Formula III
[0055] Preparation of 1 mg hydroxyrisperidone tablets:
1 hydroxyrisperidone 1.00 mg lactose 11.00 mg corn starch 2.85 mg
microcrystalline cellulose 1.00 mg hydrogenated vegetable oil 0.15
mg Total weight per tablet 16.00 mg
[0056] Hydroxyrisperidone, lactose and corn starch are mixed
together, water is added, and the mixture is kneaded, then dried in
vacuum at 40.degree. C. for 16 hours, ground in a mortar and passed
through a 16-mesh sieve to give granules. To this is added
microcrystalline cellulose and vegetable oil, and the ingredients
mixed thoroughly. The resultant mixture is made up into tablets,
each weighing 16 mg, on a rotary tableting machine. Tablets of
other strengths may be prepared by altering the ratio of active
ingredient to the excipients or to the final weight of the
tablet.
* * * * *