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.
Risperidone I is an orally active, potent antipsychotic agent, commercially available in the form of Risperidal(copyright) tablets and oral solution from Janssen Pharmaceutica. 
The Cmax of risperidone 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, xe2x80x9chydroxyrisperidonexe2x80x9d). 
The hydroxylation of risperidone to its active metabolite, hydroxyrisperidone, is catalyzed in vivo by the hepatic cytochrome P450 ene, 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 xe2x80x9cnormalxe2x80x9d allele are extensive metabolizers (EM""s); heterozygotes appear to be intermediate in metabolic capacity.
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.
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.
The following adverse events have been reported in risperidone-treated patients:
Psychiatric disordersxe2x80x94insomnia, 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.
Central and Peripheral Nervous system disordersxe2x80x94extrapyramidal 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.
Gastrointestinal system disordersxe2x80x94constipation, 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
Body as a whole/General disordersxe2x80x94back pain, chest pain, fever, fatigue, edema, rigors, malaise, influenza-like symptoms, pallor, enlarged abdomen, allergic reaction, ascites, sarcoidosis, flushing
Respiratory systemxe2x80x94rhinitis, coughing, sinusitis, pharyngitis, dyspnea, hyperventilation, bronchospasm, pneumonia, stridor, asthma, increased sputum, aspiration
Dermatologicalxe2x80x94rash, 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.
Vision Disordersxe2x80x94abnormal accommodation, xerophthalmia, diplopia, eye pain, blepharitis, photopsia, photophobia, and abnormal lacriniation.
Metabolic and Nutritional Disordersxe2x80x94hyponatremia, weight increase, creatine phosphokinase increase, thirst, weight decrease, diabetes mellitus, decreased serum iron, cachexia, dehydration, hypokalemia, hypoproteinemia, hyperphosphatemia, hypertriglyceridemia, hyperuricemia, and hypoglycemia.
Urinary System Disordersxe2x80x94polyuria/polydipsia, urinary incontinence, hematuria, dysuria, urinary retention, cystitis, and renal insufficiency.
Musculo-Skeletal Disordersxe2x80x94arthralgia, myalgia, arthrosis, synostosis, bursitis, arthritis, and skeletal pain.
Reproductive Disordersxe2x80x94(Female) menorrhagia, orgastic dysfiinction, dry vagina, nonpuerperal lactation, amenorrhea, female breast pain, leukorrhea, vaginal hemorrhage, mastitis, dysmenorrhea, femal perineal pain, and intermenstrual bleeding; (Male) erectile dysfinction and ejaculation failure.
Liver and Biliary System Disordersxe2x80x94increased SGOT, increased SGPT, hepatic failure, cholestatic hepatitis, cholecystitis, cholelithiasis, hepatitis, and hepatocellular damage.
Endocrine Disordersxe2x80x94gynecomastia, male breast pain, and antidiuretic hormone disorder.
White Cell and Resistance Disordersxe2x80x94leukocytosis, lymphadenopathy, leucopenia, and Pelger-Huet anomaly.
Red Blood Cell Disordersxe2x80x94anemia, hypochromic anemia, and normocytic anemia.
Platelet, Bleeding and Clotting Disordersxe2x80x94epistaxis, purpura, hemorrhage, superficial phlebitis, thrombophlebitis, and thrombocytopenia.
Hearing and Vestibular Disordersxe2x80x94tinnitus, hyperacusis, and decreased hearing.
Cardiovascularxe2x80x94tachycardia, orthostatic 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.
Risperidone and hydroxyrisperidone have also been implicated in a prolongation of QT interval, a condition associated with torsades de pointes, a life-threatening arrhythmia.
Accordingly, an antipsvchotic having the efficacy of risperidone, but causing fewer side effects, would be desirable.
Compounds used in the methods and compositions of the present invention are represented by Formula III, 
wherein R is chosen from xe2x80x94OH, xe2x80x94P(O)(OH)2 and xe2x80x94SO3H, 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 drining 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.
USPTO Backgrounds
USPTO Backgrounds