AU6172699A - Methods and compositions utilizing pure S()isomer fluoxetine - Google Patents

Description

V

AUSTRALIA

Patents Act COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged: too.

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i* Cl C C Complete Specification Lodged: Accepted: Published: Priority Related Art: Name of Applicant: Sepracor, Inc.

Actual Inventor(s): JAMES W YOUNG, TIMOTHY J BARBERICH Address for Service: PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Invention Title: METHODS AND COMPOSITIONS UTILIZING PURE S)ISOMER FLUOXETINE Our Ref POF Code: 602067 1443/70025 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): IP AUSTRALIA

RECEIVED

26 i0v 1999

MELBOURNE

6006q 1A METHODS AND COMPOSITIONS UTILIZING PURE ISOMER

FLUOXETINE

The present application is a divisional application from Australian Patent Application No. 18917/97 which is a divisional application from Australian Patent Application No. 13736/92, the entire disclosure of which is incorporated herein by reference.

1. BACKGROUND OF THE INVENTION This invention relates to a novel composition of matter which possesses potent antidepressant activity as a serotonin uptake inhibitor while avoiding the 15 usual detrimental factors, unwanted effects and adverse toxic or psychological effects associated with such agents. Also disclosed are methods of using said composition to treat depression while avoiding the usual detrimental factors, unwanted effects and side effects associated with such agents.

20 The invention further relates to a novel composition of matter containing optically pure fluoxetine which has activity as a weight loss agent while avoiding the usual detrimental factors, unwanted effects, and adverse toxic or psychological effects which are associated with the racemic mixture of fluoxetine. In addition, these compositions possess potent activity in the treatment of migraine headaches, pain, and obsessive-compulsive disorders, while avoiding the usual detrimental factors, unwanted effects and adverse toxic or psychological effects associated with the racemic mixture of fluoxetine. Also disclosed are methods of using these novel compositions of matter to treat migraine headaches, pain, obsessive-compulsive disorders and obesity or weight gain in a human by administering pure C:XwinwortlVAnnaWNBWODELETE\Speccation Specfication of 18917-97.cOc 11- i-_i-r-r 2 fluoxetine. These methods also avoid the usual detrimental factors, unwanted effects, and adverse toxic or psychological effects associated with administration of the racemic mixture of fluoxetine.

The active compound of this composition and method is an optical isomer of the compound fluoxetine which is described in U.S. Patent Nos. 4,018,895 aid 4,194,009 to Molloy, et al. Chemically, this isomer is (+)N-methyl-3-phenyl-3-[(a,a,a-trifluoro-p-tolyl)oxy]-propylamine, herein after referred to as fluoxetine.

Many organic compounds exist in optically active forms, they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes and or d and 1 are employed to designate the sign of rotation of plane-polarized light by the 20 compound, with or 1 meaning that the compound is levorotatory. A compound prefixed with or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric or racemic mixture.

Stereochemical purity is of importance in the field of pharmaceuticals, where 12 of the 20 most prescribed drugs exhibit chirality. A case in point is provided by the L-form of propranolol, which is known to be 100 times more potent than the Denantiomer.

Furthermore, optical purity is important since certain isomers may actually be deleterious 3 rather than simply inert. For example, the Denantiomer of thalidomide was a safe and effective sedative when prescribed for the control of morning sickness during pregnancy. However, its L-thalidomide counterpart was discovered to be a potent teratogen.

Fluoxetine (Prozac®), which is the subject of the present invention, is available only as a racemic mixture. That is, it is a mixture of optical isomers, called enantiomers.

The racemic mixture of fluoxetine, in addition to its use as an antidepressant, has a wide spectrum of actual and potential activities which include: Treatment of diabetes (EPA 88303930.7) Assisting in weight loss i.e., appetite suppression Patent No.

4,895,845) Treatment of alcohol abuse Patent No. 4,777,173) Analgesia control of pain (U.S.

Patent Nos. 4,698,342 and 4,594,358) Treatment of atherosclerosis (U.S.

Patent No. 4,444,778) Improvement of memory Patent No.

4,647,591) Treatment of anxiety Patent No.

4,590,213) Treatment of hypertension Patent No. 4,329,356) Treatment of Huntington's chorea and schizophrenia (Scrip's New Product Review No.7, "Fluoxetine", PJB Publications Ltd. 1986) Whereas the foregoing Molloy et al. patents, in addition to the above discussed European patent in addition to the above discussed European patent 4 application and U.S. patents, recognize that compounds such as fluoxetine have optically active forms, no example of an optically active form is given.

Furthermore, prior art studies with the enantiomers of fluoxetine have generally concluded that the fluoxetine enantiomers are equipotent and that there is no advantage in the use of the pure S-enantiomer.

See, Robertson et al., J. Med. Chem., 31: 1412-1417 (1988). However, it has now been discovered that there are indeed unforeseen advantages in the use of the pure S-enantiomer of fluoxetine.

Various researchers have presented a limited amount of pharmacological data on the enantiomers of fluoxetine. See, Fuller et al., Pharm. Biochem.

Behav., Vol. 24 pg. 281-284 (1986); Robertson et al., J. Med. Chem., Vol. 31 pg. 1412-1417 (1988); Wong et al. Drug Devel. Res. Vol. 6 pg. 397-403 (1985); Wong et al., Pharm. Biochem. Behav., Vol. 31 pg. 475-479 (1988). These references are limited by their failure to provide complete dose-response or pharmacokinetic analyses, resulting only in qualitative impressions on certain matters.

The primary use of fluoxetine is in the treatment of depression, which along with mania falls under the heading of affective disorders. Mania and depression are characterized by changes in mood as the primary symptom. Either of these two extremes of mood may be accompanied by psychosis with disordered thought and delusional perceptions. Psychosis may have, as a secondary symptom, a change in mood, and it is this overlap with depression that causes much confusion in diagnosis. Severe mood changes without psychosis frequently occur in depression and are often accompanied by anxiety. Depression is characterized by feelings of intense sadness or pessimistic worry, 5 agitation, self-deprecation, physical changes (including insomnia, anorexia, and loss of drive, enthusiasm, and libido), and mental slowing. Among the more common treatments for depression are the administration of a tricyclic antidepressant agent.

Fluoxetine is not in the class of drugs known as tricyclic antidepressants. Its antidepressant action is presumed to be based on its highly specific inhibition of serotonin uptake in serotonergic neurons and platelets in the brain. It is also chemically unrelated to tetracyclic or other available antidepressant agents.

Fluoxetine can also be used to assist in weight loss as disclosed in U.S. Patent No. 4,895,845 15 to Seed. The causes of excess body weight and/or obesity are complex; however, a common denominator in the overweight person's diet is a caloric intake which exceeds that person's body expenditures. One method of treating a person who is overweight and/or obese is to restrict that person's caloric intake, in combination with an exercise regimen. This method may be limited in its effectiveness since many overweight obese people have developed eating and activity patterns which are counterproductive to achieving weight reduction. Another method to treat overweight or obese patients is to administer appetite suppressant drugs in conjunction with a weight reduction program. The drawback to this method is that many appetite suppressant drugs produce unwanted or adverse effects which limit their usefulness such as long duration of action which results in severe appetite suppression.

It has also been suggested that fluoxetine could be used to treat migraine headaches which are a 3 paroxysmal disorder characterized by recurrent attacks 6 of said headaches, with or without associated visual and gastrointestinal disturbances. The cause is unknown, but evidence suggests a genetically transmitted functional disturbance of cranial circulation. Prodromal symptoms may be due to intracerebral vasoconstriction, and the head pain dilation of scalp arteries. Migraine may occur at age but usually beings between ages 10 and 30, mor often in women than in men. Migraine headaches ma preceded by a short period of depression, irritability, restlessness or anorexia, and in sow patients by scintillating scotomas, visual field defects, paresthesias, or (rarely) hemiparesis. T I: symptoms may disappear shortly before the headache 15 appears or may merge with it. Pain is either unilateral or generalized. Symptoms usually follc pattern in each patient, except that unilateral headaches may not always be on the same side. The patient may have attacks daily or only once in sev months.

Furthermore, it has also been suggested fluoxetine could be used to treat pain, in particu chronic pain. Pain is a complex subjective phenom comprised of a sensation indicating real or potent 25 tissue damage and the affective response this generates. Pain can be classified as either acute chronic pain. Acute pain is an essential biologic signal of the potential for or the extent of injury.

It is usually short-lived and is associated with hyperactivity of the sympathetic nervous system; e.g tachycardia, increased respiratory rate and blood pressure, diaphoresis, and pupillary dilation. The concurrent affect is anxiety. Treatment involves removal of the underlying etiology if possible and t' use of analgesic drugs. Chronic pain is defined as 7 pain persisting for greater than six months. Pain of this duration loses its adaptive biologic role.

Vegetative signs gradually develop; lassitude, sleep disturbance, decreased appetite, loss of taste for food, weight loss, diminished libido, and constipation. A depressed affect predominates. In many patients, organic disease may be insufficient to explain the degree of pain or may be altogether absent. In these patients, as well as in many with organic disease, the psychologic factors become the primary contributor to impairment. Therapy is often difficult and prognosis is guarded.

In addition, it has been postulated that fluoxetine is effective in the treatment of obsessivea. 15 compulsive disorders. This is a neurotic disorder characterized by the presence of recurrent ideas and fantasies (obsessions) and repetitive impulses or a actions (compulsions) that the patient recognizes as morbid and toward which he feels a strong inner 20 resistance. Anxiety is a central feature, but in contrast to the phobias (where the patient is anxious in the face of external dangers of which he perceives himself to be the passive victim), the anxiety arises in response to internally derived thoughts and urges that the patient fears he may actively carry out despite his wishes not to. Obsessive-compulsive patients comprise less than 5% of those with neurotic disorders, and about 0.05% of the population at large.

The neurosis affects men and women equally and tends to be found in individuals from upper socioeconomic levels and with higher intelligence.

Fluoxetine has been shown to have certain advantages over other antidepressant drugs.

Antagonism of muscarinic, histaminergic and a, has been hypothesized to be adrenergic receptors has been hypothesized to be -XSI-~~-i~42IT-V1~;^-1-I ^iiCI-lls-~i(~i~ 8 associated with various anticholinergic and cardiovascular effects of classical tricyclic antidepressant drugs. Fluoxetine binds to these and other membrane receptors from brain tissue much less potently than do these tricyclic antidepressants.

Thus, fluoxetine gives less anticholinergic side effects such as blurred vision, dry mouth, constipation and urinary retention. There is also less lowering of blood pressure, tachycardia and arrhythmias.

While fluoxetine has certain advantages, it also has disadvantages. Among these disadvantages are side effects which include unwanted effects and adverse toxic or psychological effects. The most 15 frequently reported side effects associated with racemic fluoxetine are headaches, nervousness, anxiety and insomnia. These are reported by 10% to 15% of patients treated with fluoxetine. These symptoms led to drug discontinuation in 5% of the patients treated with the drug. It is also known that in some patients, use of fluoxetine is associated with severe anxiety leading to intense violent suicidal thoughts and self mutilation. Teicher et al., Am. J.

Psychiatry, 147(2): 207-210 (1990). In other patients manic behavior follows treatment with fluoxetine.

Other side effects associated with fluoxetine include nausea, nervousness, tremor, fatigue, mouth dryness, dyspepsia, constipation, excessive sweating, upper respiratory infection, flu-like syndrome, diarrhea and drowsiness.

Another disadvantage of racemic fluoxetine is its long half-life and the concomitant delay in onset of action. The half-life of racemic fluoxetine is approximately 2 to 3 days. Steady state plasma i__jllxl_~_ 9 concentrations are achieved only after continuous dosing for weeks.

A further disadvantage of racemic fluoxetine is that it has a low response rate. Overall, 44% of the patients being treated with fluoxetine showed antidepressant effect. In patients who had not previously responded to other antidepressant therapy the response to fluoxetine was 43%. In addition, in patients with no previous treatment with antidepressants, or with a history of good response to previous treatment, response to fluoxetine was 56%.

(Scrip's New Product Review, "No. 7 Fluoxetine", pages 13-14, 1986).

Another disadvantage of racemic fluoxetine 15 is that in addition to its use as an antidepressant it has activities such as severe appetite suppression, drowsiness, analgesia and hypotension. These other activities may be unwanted effects when treating a patient suffering from depression or even when 20 treating obesity or weight gain, where only moderate appetite suppression of short duration is desired.

It is therefore desirable to find a compound with the advantages of fluoxetine which would not have the above described disadvantages.

2. SUMMARY OF THE INVENTION It has now been discovered that the isomer of fluoxetine does not have certain side effects, including causing nervousness, anxiety, insomnia, and adverse psychological effects; has a fast onset of action and an increased response rate.

It has also been discovered that with the use of the isomer of fluoxetine it is possible to avoid other activities of the racemic compound which would 10 be unwanted effects when treating a patient suffering from depression. Thus, the isomer of fluoxetine is useful for methods of treating depression and ir the compositions used thereof where these detrimental effects will be avoided.

It has also been discovered that with the use of the isomer of fluoxetine it is possible achieve weight reduction or weight loss through moderate appetite suppression while avoiding unwant effects, such as severe appetite suppression, and adverse toxic or psychological effects associated v. th administration of the racemic mixture of fluoxetine Also, the methods and compositions of the present invention utilizing optically pure fluoxetine 15 provide an increased response rate.

In addition, it has been discovered that t isomer of fluoxetine is useful in the treatmerof migraine headaches, the treatment of pain, in particular chronic pain, and in the treatment of obsessive-compulsive disorders. The unwanted effect and adverse toxic or psychological effects which are avoided or decreased by administering the iso.er of fluoxetine include but are not limited to headaches, nervousness, anxiety, nausea, diarrhea, anorexia, insomnia, severe appetite suppression, inner restlessness (akathisia) suicidal thoughts and self mutilation.

Novel compositions of matter containing optically pure fluoxetine which have appetite suppressant activity while avoiding the above described unwanted effects and adverse toxic or psychological effects associated with the racemic mixture of fluoxetine are also disclosed.

Further included within the present invention are novel compositions of matter containing i_ 11 optically pure fluoxetine which are useful in the treatment of migraine headaches, the treatment of pain, in particular chronic pain, and the treatment of obsessive-compulsive disorders. These novel compositions also avoid the above-described unwanted, adverse toxic or psychological effects associated with the racemic mixture of fluoxetine.

3. DETAILED DESCRIPTION OF THE INVENTION The present invention encompasses a method of eliciting an antidepressant effect while avoiding the concomitant liability of adverse toxic or psychological effects, delayed onset of action or low response rate associated with the racemic mixture 15 which comprises administering to a patient in need of antidepressant therapy an amount sufficient to alleviate human depression, but insufficient to cause said adverse toxic or psychological effects, delayed onset of action and low response rate, of 20 fluoxetine or a pharmaceutically acceptable salt thereof, substantially free of its stereoisomer.

The present invention also encompasses a method of treating obesity or weight gain in a human while avoiding unwanted effects, adverse toxic or psychological effects or low response rate associated with the racemic mixture of fluoxetine, comprising administering to a human in need of treatment of obesity or weight gain an amount of fluoxetine or a pharmaceutically acceptable salt thereof, substantially free of its stereoisomer, said amount being sufficient to alleviate said human's obesity or weight gain but insufficient to cause said unwanted effects and adverse toxic or psychological effects associated with administration of racemic fluoxetine.

12 In addition, the present invention encompasses a method of treating migraine headaches, pain or obsessive-compulsive disorders while avoiding concomitant liability of unwanted effects, adverse toxic or psychological effects or low response rate associated with the racemic mixture of fluoxetine, comprising administering to a patient in need of treatment of migraine headaches, treatment of pain treatment of obsessive-compulsive disorders, an amount of fluoxetine or a pharmaceutically acceptable salt thereof, substantially free of its stereoisomer, said amount being sufficient to treat the patient's migraine headache, pain or obsessive-compulsive disorders but insufficient to cause said unwanted effects, adverse toxic or psychological effects or low response rate associated with administration of racemic fluoxetine.

The present invention further encompasses a method of eliciting an antidepressant effect while avoiding unwanted effects, which comprises administering to a patient in need of antidepressant therapy an amount, sufficient to alleviate a human's depression, but insufficient to cause said unwanted effects, of fluoxetine or a pharmaceutically acceptable salt thereof, substantially free of its stereoisomer.

:The present invention also encompasses an antidepressant composition a i. for the treatment of a patient in need of antidepressant therapy which comprises an amount sufficient to alleviate the depression but insufficient to cause adverse toxic or psychological effects, delayed onset of action and low response rate of fluoxetine or a pharmaceutically acceptable salt thereof, substantially free of its stereoisomer.

C:XWIORD\KATEL\MARGARETDNOTE\P89l7A.O 13 Also embodied in the present invention is an antidepressant composition adapted for the treatment of a patient in need of antidepressant therapy which comprises an amount sufficient to alleviate the depression but insufficient to cause the unwanted effects of fluoxetine or a pharmaceutically acceptable salt thereof, substantially free of its stereoisomer.

Further, embodied in the present invention is a composition that is useful for treating obesity or weight gain in a human comprising an amount of o. fluoxetine or a pharmaceutically acceptable salt thereof, substantially free of its stereoisomer, said amount being sufficient to achieve weight loss or 15 prevent weight gain while avoiding unwanted effects, adverse toxic or psychological effects or low response rate associated with the racemic mixture of .fluoxetine.

In addition, the present invention 20 encompasses compositions that are adapted for treating migraine headaches, pain, or obsessive-compulsive disorders, comprising an amount of fluoxetine or a pharmaceutically acceptable salt thereof, substantially free of its stereoisomer, said amount being sufficient to alleviate the abovedescribed afflictions, but insufficient to cause unwanted effects, adverse toxic or psychological effects or low response rate of racemic fluoxetine.

Furthermore, pure fluoxetine is also more effective for the treatment of migraine headaches, the treatment of pain, in particular chronic pain, and to treat obsessive-compulsive disorders, since as previously discussed the racemic mixture of fluoxetine has a delayed onset of action, and has a low response rate whereas isomer of 14 fluoxetine does not cause unwanted effects or adverse toxic or psychological effects and it has a high response rate. Thus, it is more desirable to use th isomer of fluoxetine. With regard to migraine headaches in particular, the reductions of adverse toxic or psychological effects by the isomer fluoxetine allows for treatment of the symptoms or acute basis and also prophylactically, without the previously described adverse effects or complicati In addition, the present invention encompasses a method for treating a condition 0*n@ alleviated or improved by inhibition of serotonin

S""

t uptake in serotonergic neurons and platelets in a human while avoiding unwanted, adverse toxic or 15 psychological effects associated with the racemic mixture of fluoxetine which comprises administerin a human in need of such therapy an amount of fluoxetine or a pharmaceutically acceptable salt thereof, substantially free of its stereoisom: 20 said amount being sufficient to alleviate said condition but insufficient to cause said adverse effects. Conditions that may be alleviated or improved by inhibition of serotonin uptake in serotonergic neurons and platelets include but are limited to alcohol abuse, anxiety, memory disorders Huntington's chorea and schizophrenia.

Further encompassed in the present invention is a composition for the treatment of a condition alleviated or improved by inhibition of serotonin uptake in serotonergic neurons and platelets in a human which comprises an amount of fluoxetine or a pharmaceutically acceptable salt thereof, substantially free of its stereoisomer, said amount being sufficient to alleviate said condition but insufficient to cause unwanted, adverse toxic or 15 psychological effects associated with the administration of racemic fluoxetine.

The racemic mixture of fluoxetine a mixture of R and S stereoisomers) has antidepressant effect; however this racemic mixture causes adverse toxic or psychological effects, has a delayed onset of action, and has a low response rate. The isomer of fluoxetine does not cause these adverse toxic or psychological effects, has a rapid onset of action and has a high response rate. Thus, it is much more desirable to use the isomer of fluoxetine.

Furthermore, although there is some variability from one patient to another, it is generally observed that, by administering an effective 15 amount of only the isomer of fluoxetine it is possible to accomplished a more "targeted" therapy. A more "targeted" therapy means that by using the isomer of fluoxetine the compound's broad activity can be taken advantage of without also having unwanted 20 effects. This is important since it is not desirable for all patients to be administered a compound with such a complex and multifaceted spectrum of activity.

The term "unwanted effects" includes but is not limited to severe appetite suppression; (2) drowsiness or analgesia; and hypotension. Thus, by administering to a patient the isomer of fluoxetine, significant antidepressant activity is obtained without the above-identified unwanted effects which are associated with the racemic mixture of fluoxetine.

The term "adverse toxic or psychological effects" includes but is not limited to headaches, nervousness, anxiety, insomnia, nausea, diarrhea, drowsiness, mouth dryness, tremor, anorexia, dyspepsia, excessive sweating, upper respiratory 16 infection, flu-like syndrome, intense violent suicidal thoughts and manic behaviour.

The term "side effect" as used herein means effects which are undesirable or which act against the intended beneficial effect of the compositions. The term "side effect" encompasses adverse toxic or adverse psychological effects.

The terms "substantially free of the stereoisomer", "substantially optically pure fluoxetine" and "optically pure isomer of fluoxetine" as used herein mean that the composition contains a greater proportion of the isomer of fluoxetine in relation to the isomer fluoxetine. In a preferred embodiment the composition contains at least 90% by weight of fluoxetine and 10% by weight or less fluoxetine, these percentages being based on the total amount of fluoxetine present. In the most preferred embodiment the composition contains at least 99% by weight fluoxetine and 1% or less of fluoxetine. In another preferred embodiment, the composition contains 100% by weight of fluoxetine. Again, the above percentages are based on the total amount of fluoxetine present.

The term "eliciting an antidepressant effect" means relief from the symptoms associated with depression, which include but are not limited to feelings of intense sadness or pessimistic worry, agitation, self-deprecation, 20 physical changes C:%WINWORDU(ATEL\MARGAREDNOTES\P1 $017A.DOC 17 (including insomnia, anorexia, and loss of drive enthusiasm and libido) and mental slowing.

The term a "method of treating migraine headaches, pain or obsessivecompulsive disorders" as used herein means relief from the symptoms and/or effects associated with these disorders that are described above.

The term a "method of treating obesity or weight gain" as used herein means a method of non-severely suppressing the appetite of a human for a short time such that food consumption is reduced by the non-severe appetite suppression.

The term a "method for treating a condition alleviated or improved by inhibition of serotonin uptake in serotonergic neurons and platelets" as used herein means relief from the symptoms and/or effects associated with these disorders.

The synthesis of the isomer of fluoxetine can be performed by two methods which are as follows: Method 1 This method is disclosed in Gao, et al. J. Org. Chem. Vol. 53, No. 17, pp.

4 0 8 1 4 08 4 (1988). It involves the use of 1-phenyl-1,3-propanediols, which are 20 key intermediates. The 1-phenyl-1,3-propanediols are prepared from cinnamyl epoxy alcohols by Red-Al reduction. The chiral cinnamyl epoxy alcohols are made by asymmetric epoxidation of cinnamyl alcohols as disclosed in Gao, et al.

(+)-fluoxetine hydrochloride is prepared from (2R,3R)-epoxycinnamyl alcohol obtained by the asymmetric epoxidation disclosed in Gao et al. utilizing

(-)-DIPT.

C:NWINWORD\KATE\MARGARET)NOTESVI8 917A. 0C is The reaction scheme is as follows:

OH

0

OH

S *5

S

S*

S

S.

S. S S

(DIPT

Ti(O-iPr) 4

/TBHP

CH

2

CI

2 .200 C Red-Ate DME, 25- C MsCI Et 3 N/Ether 0

OH

NH

OHH

OH

OMS

OH

OH

N'I

OH

OMs 40% aq. MeNH 2 TH F, 65 0

C

NHMeaCF 3

OH

-NHMe 1) NaKIDMA 300N 2) p-chtoroben 20- 0

N

NHMe HCI Trifluordae 100-105 0

C

3) HCVether (S).(+)-Fluoxetine Hydrochloride- 19 (R)-(-)-fluoxetine hydrochloride is prepared from (2S,3S)-epoxycinnamfYl alcohol obtained by the asymmetric epoxidation disclosed in Gao et al.

utilizing

(+)-DIPT.

Method 2 This method is based on the asymmetric reduction of ketonie with a chiral borane reagent as disclosed in U.S. Patent No. 4,868,344 to H.C. Brown.

in The reaction scheme is as follows: 4 0 C1

OH

C1 (+)IPC2 BCI from -a-pinene (recrystallization) S CF3 Diethyl azodicarboxylate prh 3 p

OH

C1 C F 3 0 c C1 C F 3 C1

CF

3 Aq. MeNH 2 NHMe EIOH/aq. HO!. ether 20 The magnitude of a prophylactic or therapeutic dose of fluoxetine will, of course, vary with the nature and the severity of the condition to be treated and its route of administration. It will also vary according to the age, weight and response of the individual patient. In general, the daily dose range for use as an anti-depressant will lie within the range of from about 1 mg to about 100 mg per day, preferably about 20 mg to about 80 mg per day, and most preferably from about 40 mg to about mg per day, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases. The terms encompassed by the above-described amounts include: "an amount 15 sufficient to alleviate said human's depression but insufficient to cause said adverse toxic or psychological effects, delayed onset of action or low 4* 4 response rate", "said amount being sufficient to alleviate migraine headaches, pain or an obsessive- 20 compulsive disorder but insufficient to cause unwanted, adverse toxic or psychological effects", "said amount being sufficient to alleviate said human's obesity or weight gain but insufficient to cause said unwanted, adverse toxic or psychological effects", "said amount being sufficient to achieve weight loss but insufficient to cause said unwanted, adverse toxic or psychological effects", "said amount being sufficient to alleviate said condition but insufficient to cause said unwanted, adverse toxic or psychological effects" wherein said condition is alcohol abuse, anxiety, memory disorders, Huntington's chorea or schizophrenia.

Any suitable route of administration may be employed for providing the patient with an effective dosage of fluoxetine. For example, oral, rectal, 21 parenteral, transermal, subcutaneous, intramuscular, inhalation and the like may be employed. Dosage forms include tablets, trochees, dispersions, suspensions, solutions, capsules, patches and the like.

The pharmaceutical compositions of the present invention comprise fluoxetine as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids.

Since the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organi acids. Such acids include acetic, benzene-sulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, ptoluenesulfonic and the like. Particularly preferred and hydrobromic, hydrochloric, 9*° phosphoric and sulfuric acids.

The compositions include compositions suitable for oral, rectal, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated. The most preferred route .9 of administration in the present invention is oral. The compositions may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.

C:\WINWORD\(ATELWMARGARET\DNOTESP1 8917A.DOC 22 In the case where an oral composition is employed, a suitable dosage range for use is, from about 1 mg to about 100 mg of fluoxetine per day, preferably from about 20 mg to about 80 mg per day and most preferably from about 40 mg to about 80 mg per day.

In practical use, fluoxetine can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, favoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. The most preferred solid oral preparation is capsules. Because of their ease of administraton, tablets and capsules *represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.

In addition to the common dosage forms set out above, the compound of the present invention may also be administered by controlled release means C:\WINWORDUENNIFERWNBSODELETE\18917.DOC 23 and/or delivery devices such as those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719, the disclosures of which are hereby incorporated herein by reference. The use of a racemic mixture of fluoxetine in a sustained release formulation is disclosed and/or claimed in U.S.

Patent Nos. 4,797,286 and 4,847,092.

Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a nonaqueous 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 but all 9* methods include the step of bringing into association the active ingredient with the carrier which 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 presentaton. For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in S* a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, and/or surface active 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 contains from about 5 mg to about 100 mg of the active ingredient and each C:NWINWORDUENNIFERNBNODELETEIP18917.DOC 24 cachet or capsule contains from about 5 to about 100 mg of the active ingredient.

Most preferably the tablet, cachet or capsule contains 20 mg of active ingredient.

The invention is further defined by reference to the following examples describing in detail the preparation of the compound 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 wtihout departing from the purpose and interest of this invention.

All temperatures are in degrees Celsius.

S 10 4. EXAMPLES 4.1 EXAMPLE 1 Synthesis of and Fluoxetine Reduction of epoxycinnamvl alcohols with Red-A1; synthesis of fluoxetine Part 1 15 (R)-3-Phenyl-1, 3-dihydroxypropane 0

OH

9 OH (2) C:XWINWORDUENNIFER\MNNODELETE\P15917.DOC To a solution of (-)-(2S,3S)-epoxycinnamyl alcohol (1.5 g, 10.0 mmol) (synthesized by the method disclosed in Gao et al., J. Ora. Chem., Vol. 53, No.

17, pp. 4081-4084 (1988.), in dimethoxyethane (50 mL) was added a 3.4 molar solution of Red-A1??? in toluene (3.1 mL, 10.5 mmol) dropwise under nitrogen at 0 0 C. After stirring at room temperature for three hours, the solution was diluted with ether and quenched with 5 HCI solution. After stirring at room temperature for 30 min, the resulting white precipitate formed was filtered and boiled with ethyl acetate and filtered again. The combined organic solutions were dried with magnesium sulfate. Concentration gave (R)-3-phenyl-1,3-dihydroxypropane (2) 10 as a slightly yellow oil which was used without further purification (1.5 g, 1H NMR (CDCI3) 57.2-7.3 5 4.88-4.98 1 3.78-3.86(t,J=7.5 Hz, 3.3- 3.4 (br. s, 1 H) 2.85-2.95 (br. s, 1 1.84-2.08 2 the ratio of 1,3-diol to 1,2-diol was 20:1 by 1H NMR analysis of the derived diacetate.

(S)-3-Phenyl-1,3-dihydroxypropane was prepared according to the above 15 procedure starting with 300 mg of (-)-epoxycinnamyl alcohol to provide 300 mg of *(S)-3-phenyl-1,3-dihydroxypropane (1,3-diol:1,2-diol=21:1).

(S)-3-phenyl-1,3-dihydroxypropane (1,3-diol: 1,2-diol=21

S.

C:\WINWORDUENNIFER\MNB\NODELETE\Pl8917.DOC 26 Part 2 (S)-3-phenyl-3-hydroxypropyl-1 -methanesulfonate OH

OH

rOH OMs (4) To a solution of (S)-3-phenyl-1,3-dihydroxypropane (2.71 g, 17.8 mmol) and triethylamine (2.60 g, 25.6 mmol) in ether (90 mL) was added dropwise MsCI (1.45 mL, 18.7 mmol) under nitrogen at -10 0 C. After stirring at -10°C to 0°C for 3 h, the mixture was poured into ice water (30 mL) and washed with 20% H 2

SO

4 saturated aqueous NaHCO 3 brine, and dried over magnesium sulfate. The crude products were purified by chromatography eluting with 45% ethyl acetate in hexane to give the title compound as an oil (3.5 g, 'H NMR (CDCI 3 87.3- 7.4 5 4.85-4.91 J=7.7 Hz, 1 4.42-4.52 1 4.22-4.32 1 H), 3.0 3 2.3 1 2.1-2.2 J=7.7 Hz, 2 H).

(R)-3-Phenyl-3-hydroxypropyl-1-methanesulfonate was prepared from 3-phenyl-1,3-dihydroxypropane by the above procedure in 74% yeild.

These two compounds were either stored at 00C or used soon after preparation.

C:\WINWORDUENNiFERMNBNQOELETETP1 8917 DOC 27 Part 3 (S)-N-Methyl-3-phenyl-3-hyd roxypropylamine OH

OH

OMS M e (6) solution of (S)-3-phenyl-3-hydroxypropyl-1 -methanesulfonate (690 3.0 mmol) and methylamine (10 mL, 40% in water) in THF (10 ml-) was heated at 65'C for 3 h. After cooling, the solution was diluted with ether and washed with saturated aqueous sodium bicarbonate, brine, and dried with anhydrous potassium carbonate. Concentration to dryness provided the title compound (476 mg, 96 1H NMVR (ODC1 3 87.2-7.4 (in, 5 4.94 (dd, J=3.8, 7.2 Hz, 1 3.4-3.9 (br. s, 1 2.84-2.92 (in, 2 2.45 3 1.68-1.92 (in, 3

H).

Following a procedure identical to the above 1.15 g (R)-3-phenyl-3hyd roxypropyl-1 -methanesulfonate yielded 837 mg of (R)-N-inethyl-3-phenyl-3- .hydroxy-propylamine.

C:\WINWORD\UENNIFER\MINB\NODELETET18917.DOC 28 Part 4 (R)-Fluoxetine hydrochloride

CF

3 OH 0 NHMe NHMeHCI (8) To a solution of (R)-N-methyl-3-phenyl-3-hydroxy-propylamine (1.23 g, 7.45 mmol) in dimethyl acetaminde (7 mL) was added sodium hydride (215 mg, 8.95 mmol) with cooling. The mixture was heated at 900C for 1.5 h, and an orange solution resulted. To. this solution was then added 4chlorobenzotrifluoride (3.23 g, 2.40 mL, 17.9 mmol), and the mixture was heated at 100-1050C for 2.5 h. After cooling and dilution with toluene, the mixture was washed with water, and the aqueous layer was separated and extracted with toluene. The combined toluene solutions were then washed with saturated aqueous sodium bicarbonate, brine, and dried over magnesium sulfate.

Concentration provided (R)-fluoxetine as an orange oil (1.97 g, The oil was dissolved in ether and acidified with hydrogen chloride gas (pH 3-4) to give a acidic ethereal solution (no precipitate formed). The solution was concentrated at room temperature to give a yellow solid which was washed with ether to remove most of C:NWNWORADUENNIERWNBODELETEPI 8917DOC 29 the orange color. The slightly yellow solid was then recrystallized from acetonitrile at -20 0 C. The solid was collected and washed with ether to provide (R)-fluoxetine hydrochloride as a white powder (1.90 g, mp 140-142 0

C

(lit. mp 140-141.5 0 C; [c] 2 3 D-2.16'C (c 1.62, MeOH); (lit.[x2 3 D-1.97 0 [c 1.00, MeOH]); [ca] 2 3 D +7.080 (c 1.30, H 2 (lit. 23 D +10.320 [c 1.00, H 2 IR (Kbr, CDC1 3 2950, 2640, 2450, 1620, 1595, 1520, 1360, 1250, 1180, 1170, 1130, 1114, 1070, 840 cm-I; 1 H NMVR (CDCI 3 869.72 (br, s, 2 7.40-7.43 J=8.7 Hz, 2 H), 7.25-7.33 (in, 5 6.88-6.92 J=8.7 Hz, 2 5.45-5.50 (dd, J=4.6, 7.9 Hz, 1 3.12 (br, s, 2 2.55-2.62 (br, s, 3 2.42-2.52 (in, 2 Anal. Calcd, for 10 C 17

H-

18

CIF

3 N0: C, 59.05; H, 5.54; N, 4.05; F, 16.48; Cl, 10.25. Found: C, 58.84; H, 5.55; N, 3.94; F, 16.28; Cl, 10.50.

(S)-Fluoxetine hydrochloride was prepared by the above procedure from (S)-N-methyl-3-phenyl-3-hydroxyp ropylamine: mp 140-1420C (lit mp 135-1 37 0

C);

[a] 23 D -7.120 (c 1.53, H 2 lit [U] 23 D -10.850 [c 1.00, H 2 Anal. Calcd. for

C

17 H,,C1F 3 N0: C, 59.05; H, 5.54; N, 4.05. Found: C, 59.19; H, 5.42; N, 3.89.

C:\WINWORDUENNIFER\MNB\NODELETE\Pl 891 TDOC 4.2 EXAMPLE 2 ORAL FORMULATION Tablets: Formula Quantity per Tablet (mg.) A

B

Active Ingredient 10.00 20.00 Fluoxetine Hydrochloride) Lactose 62.75 52.75 Corn Starch 3.0 Water (per thousand Tablets) 30.0 ml 30.0 ml Corn Starch 18.75 18.75 Magnesium Stearate 0.5 125.00 125.00 The water evaporates during manufacture.

Blend the active ingredient fluoxetine hydrochloride with the lactose until uniform. Blend the smaller quantity of cornstarch with the water and add the resulting corn starch paste, then mix until a uniform wet mass is formed. Add the remaining corn starch to the resulting wet mass and mix until uniform granules are obtained. Screen the granules through a suitable milling machine, using a 1/4 inch stainless steel screen. Dry the milled granules in a suitable drying oven until the desired moisture content is obtained. Mill the dried granules through a suitable milling machine using 1/4 mesh stainless steel screen. Blend in the magnesium stearate and compress the resulting mixture into tablets of desired shape, thickness, hardness and disintegration.

C:AWINWOROUENNIFERWNBXNODELETEP18917.OC 31 4.3 EXAMPLE 3 ORAL FORMULATION Capsules: Quantity per Capsule Formula (mg.) A B Active ingredient 10.00 20.00 Lactose 65.75 55.75 Corn Starch 18.75 18.75 Magnesium Stearate 0.50 0.50 125.00 125.00 5 Blend the active ingredient, fluoxetine hydrochloride, lactose and corn starch until uniform; then blend the magnesium stearate into the resulting powder.

Encapsulate the mixture into suitable sized two-piece hard gelatin capsules.

o 59 CAW NWORUENNIFERNB\NODELETEP18917.DOC

Claims (31)

1. A pharmaceutical composition including an amount of fluoxetine or a pharmaceutically acceptable salt thereof, substantially free of its stereoisomer.

2. A pharmaceutical composition according to claim 1 further including a pharmaceutically acceptable carrier. 10

3. A pharmaceutical composition according to either claim 1 or claim 2 wherein the amount of fluoxetine or pharmaceutically acceptable salt thereof is at least 90% by weight of total fluoxetine.

4. A pharmaceutical composition according to any one of claims 1 to 3 15 wherein the amount of fluoxetine or pharmaceutically acceptable salt thereof is at least 99% by weight of total fluoxetine.

5. A pharmaceutical composition according to any one of claims 1 to 4 wherein the amount of fluoxetine or pharmaceutically acceptable salt thereof 20 is 100% by weight of total fluoxetine.

6. A pharmaceutical composition according to any one of claims 1 to which includes fluoxetine hydrochloride.

7. A pharmaceutical composition according to any one of claims 1 to 6 adapted for oral administration.

8. A pharmaceutical composition according to any one of claims 1 to 6 adapted for intravenous administration.

9. A pharmaceutical composition according to any one of claims 1 to 6 adapted for transdermal delivery.

C:\WINWORD\KATEL\KATE\MNBIODELET\PI917.DO -33- A method of eliciting an antidepressant effect while avoiding concomitant liability of adverse toxic or psychological effects, delayed onset of action or low response rate, which includes administering to a patient in need of antidepression therapy a pharmaceutical composition according to any one of claims 1 to 6 in an amount sufficient to alleviate human depression but insufficient to cause adverse toxic or psychological effects, delayed onset of action or low response rate associated with the administration of racemic fluoxetine.

11. A method of eliciting an antidepressant effect while avoiding 10 unwanted effects of racemic fluoxetine which includes administering to a patient in need of antidepressant therapy a pharmaceutical composition according to any one of claims 1 to 6 in an amount sufficient to alleviate human depression, but insufficient to cause unwanted effects of racemic fluoxetine. 15

12. A method of treating migraine headaches, pain or obsessive- compulsive disorders in a human while avoiding unwanted adverse toxic or "i psychological effects, including administering to a human in need of treatment o C *migraine headaches, pain or obsessive-compulsive disorders a pharmaceutical composition according to any one of claims 1 to 6 in an amount sufficient to 20 alleviate said human's migraine headaches, pain or obsessive-compulsive disorder but insufficient to cause said unwanted adverse toxic or psychological effects associated with racemic fluoxetine.

13. A method according to claim 11 wherein the unwanted effects include severe appetite suppression.

14. A method according to claim 11 or 13 wherein the unwanted effects include drowsiness.

15. A method according to claim 11, 13 or 14 wherein the unwanted side effects include analgesia. C:NW\NWORD\KATE\KATE\MNBNODELETEP18917.Dc -34-

16. A method according to claim 11, 13, 14 or 15 wherein the unwanted side effects include hypotension.

17. A method of treating obesity or weight gain in a human while avoiding unwanted adverse toxic or psychological effects, including administering to a human in need of treatment of obesity or weight gain a pharmaceutical composition according to any one of claims 1 to 6 in an amount sufficient to alleviate the obesity or weight gain but insufficient to cause unwanted adverse toxic or psychological effects associated with administration of racemic fluoxetine.

18. A method for treating a condition alleviated or improved by inhibition of serotonin uptake as serotonergic neurons and platelets in a human, while avoiding unwanted, adverse toxic or psychological effects associated with the racemic mixture of fluoxetine, including administering to a human in need of such 15 therapy a pharmaceutical composition according to any one of claims 1 to 6 in an amount to alleviate the condition but insufficient to cause unwanted, adverse toxic or psychological effects. SSSS*

19. A method according to claim 18 wherein the condition alleviated or 20 improved by inhibition of serotonin uptake in serotonic neurons and platelets is selected from the group consisting of alcohol abuse, anxiety, memory disorders, Huntington's disease and schizophrenia.

A method according to any one of claims 10 to 18 wherein the composition is administered by intravenous infusion.

21. A method according to any one of claims 10 to 18 wherein the composition is administered by transdermal delivery.

22. A method according to any one of claims 10 to 18 wherein the composition is administered orally as a tablet or capsule. C:WINWOROXATELUKATEWNBINODELETEIP18917.DOC

23. A method according to any one of claims 10 to 22 wherein the composition is administered from one to four times a day.

24. A method according to any one of claims 10 to 23 wherein the composition is administered twice a day. A method according to any one of claims 10 to 24 wherein the composition is administered once a day.

S.to 10

26. A pharmaceutical composition substantially as described herein with *5 reference to any one of the examples.

27. A method of treatment substantially as described herein with reference to any one of the examples.

28. The use of a pharmaceutical composition according to any one of claims 1 to 9 for the preparation of a medicament for the treatment of depression.

29. The use of a pharmaceutical composition according to any one of 20 claims 1 to 9 for the preparation of a medicament for the treatment of migraine headaches, pain of obsessive-compulsive disorders. Th use of a pharmaceutical composition according to any one of claims 1 to 9 for the preparation of a medicament for the treatment of obesity or weight gain.

C: WIORD\KATEL\ATEMNWODELETE\Pl agl7.DOC 36

31. The use of a pharmaceutical composition according to any one of claims 1 to 9 for the preparation of a med icament for the treatment of a condition alleviated or improved by inhibition of serotonin uptake in serotonergic neurons and platelets in a human. DATED: 5 July 1999 PHILLIPS ORMONDE FITZPATRICK Attorneys for: SEPRACOR, INC.D .4p% 0O 4* 0OSe 0* 0 0* S. S. S S *SOSS. 0 0S S C S S C. S e.g. C~ 0@ S S. S S. C 05 S. C:\WINWORDKATELKATNBV4DELETE\PI917.DOC