AU744990B2 - New treatment using phenethylamine derivatives - Google Patents

Description

AUSTRALIA

Patents Act COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority Related Art: Name of Applicant: American Home Products Corporation Actual Inventor(s): RICHARD LESLIE RUDOLPH, AhERT TI IOMA3 D,,,ERIVIA, ,-,RIC ANTI %1 IO." MVUil, •GERTRUDE VIRGINIA UPTON e*ee Address for Service: PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Invention Title: NEW TREATMENT USING PHENETHYLAMINE DERIVATIVES Our Ref" 623427 POF Code: 49377/1481 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): -1 0o^q 1A NEW TREATMENT USING PHENETHYLAMINE DERIVATIVES The present invention is a divisional application of Australian application 43783/00 the entire disclosure.of which is incorporated herein by reference.

The Prior Art A number of agents have been used to treat Generalized Anxiety Disorder (GAD). GAD may be a highly prevalent, chronic disorder that interferes with a patient's daily activities. The symptoms of this disease usually persist for at least six months. One disadvantage of the prior art is that existing agents may be useful for short-term therapy only. There is therefore a need for a drug that offers particular usefulness in respect of long-term efficacy for GAD. The art teaches GAD treatments using either benzodiazepine or tricyclic antidepressants, but these pose addiction concerns. Other antidepressants have been used but they do not yield comparable improvements in both 15 the somatic and psychic manifestations of GAD.

Hoehn-Saric et al., J. Clin. Psychiatry 49:8, August 1988, pp. 293-301 studied the utility and specificity of action against GAD of Alprazolam (a triazolobenzodiazepine) and Imipramine (a dibenzazepine). They noted that the substances provide significantly S 20 different relief. The benzodiazepine (Alprazolam) relieved predominantly somatic symptoms, as opposed to the predominantly psychic symptoms relieved by the dibenzazepine (Imipramine).

Rickels et al. (Arch. Gen. Psychiatry/Vol. 50, Nov. 1993, pp. 884-895) confirm 25 this distinction in psychic/somatic efficacy with their study of imipramine, trazodone (a substituted triazolopyridinone) and diazepam (a benzodiazepine) in treating GAD. The authors teach that Diazepam, like the benzodiazepine discussed by Hoehn-Saric et al., is predominantly successful in treating the somatic symptoms of GAD. Also similar to the findings of Hoehn-Saric et al., Rickels et al. found non-benzodiazepines imipramine and trazodone to be more efficacious in treating psychic symptoms of GAD. Rickels et al.

also found that relief was not immediate. Diazepam did not differ significantly from placebo until the second week of treatment. For imipramine and trazodone, significant improvement was not observed until the third week of treatment.

Thus there is a need for a drug that improves both the somatic and psychic symptoms of GAD. There is also a need for a drug that exhibits a rapid onset of action.

1B The above discussion of documents, acts, materials, devices, articles and the like is included in this specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these matters formed part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed in Australia before the priority date of each claim of this application.

W:\MarlolNODELETE'DJTSPECk53350-OO.doc AHP-92021-03 AU 27.07.00 -2- Background of the Invention The active ingredients of this invention include (1-[2-(dimethylamino)-1-(4methoxyphenyl) ethyl] cyclohexanol), or therapeutically acceptable salts thereof, which are known generally as venlafaxine and its analogues. Venlafaxine is disclosed in U. S.

Patent No. 4,535,186 (Husbands et al.) and has been previously reported to be useful as an antidepressant. U. S. Patent No. 4,535,186 and US Patent 5,043,466 teach the production of venlafaxine and its analogues and are incorporated herein as reference. For the purposes of this disclosure, and the claims that follow, the use of venlafaxine is understood to include the free base and pharmaceutically acceptable salt forms of venlafaxine, the racemate and its individual enantiomers, and venlafaxine analogs, both as racemates and as their individual enantiomers.

15 Venlafaxine has been shown to be a potent inhibitor of monoamine neurotransmitter uptake, a mechanism associated with clinical antidepressant activity.

:Due to its novel structure, venlafaxine has a mechanism of action unrelated to other available antidepressants, such as the tricyclic antidepressants desipramine, nostriptyline, protriptyline, imipramine, amitryptyline, trimipramine and doxepin.

It is believed that venlafaxine's mechanism of action is related to potent inhibition of the uptake of the monoamine neurotransmitters serotonin and norepinephrine. To a lesser degree, venlafaxine also inhibits dopamine reuptake, but it has no inhibitory activity on monoamine oxidase. O-desmethylvenlafaxine, venlafaxine's major 25 metabolite in humans, exhibits a similar pharmacologic profile. Venlafaxine's ability to inhibit norepinephrine and serotonin (5-HT) uptake has been predicted to have an efficacy which rivals or surpasses that of tricyclic antidepressants (Stuart A.

Montgomery, J. Clin. Psychiatry, 54:3, March 1993).

In contrast to classical tricyclic antidepressant drugs, venlafaxine has virtually no affinity for muscarinic, histaminergic or adrenergic receptors in vitro. Pharmacologic activity at these receptors is associated with the various anticholinergic, sedative and cardiovascular effects seen with the tricyclic antidepressant drugs.

SsuS!v-ss- AHP-92021-03 AU 27.07.00 -3- Description of the Invention In accordance with the present invention there is provided a method of treatment, prevention or control of generalized anxiety disorder in mammals, preferably humans, in need of such treatment, prevention or control.

Generalized Anxiety Disorder is a syndrome characterized by excessive or chronic anxiety or apprehension concerning two or more of life's circumstances. The disorder's signs and symptoms often include somatic complaints, such as tremor, dyspnea, palpitations, light-headedness and nausea.

The method of the present invention involves administering to a mammal in need .,thereof an effective amount of one or more compounds from a group of substituted phenethylamines. The compounds of this invention are the compounds having the 15 following structural formula:

:.R

N%

R2 R R7 in which A is a moiety of the formula

OR

4 *°eo

(CH

2 where the dotted line represents optional unsaturation; RI is hydrogen or alkyl of 1 to 6 carbon atoms;

R

2 is alkyl of 1 to 6 carbon atoms;

R

4 is hydrogen, alkyl of 1 to 6 carbon atoms, formyl, or alkanoyl of 2 to 7 carbon atoms;

R

5 and R 6 are independently hydrogen, hydroxyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 7 carbon atoms, cyano, nitro, alkylmercapto of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino in which each alkyl group is of 1 to 6 carbon AHP-92021-03 AU 27.07.00 -4atoms, alkanamido of 2 to 7 carbon atoms, halo, trifluoromethyl, or when taken together, methylene dioxy;

R

7 is hydrogen or alkyl of 1 to 6 carbon atoms; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof.

The preferred compounds are those of the formula:

.RI

N

'A

R7

R

5 R6 in which A is as defined supra; 10 RI is hydrogen or alkyl of 1 to 3 carbon atoms;

R

2 is alkyl of 1 to 3 carbon atoms;

R

5 is hydrogen, hydroxyl, alkoxy of 1 to 3 carbon atoms, chloro, bromo, trifluoromethyl or alkyl of 1 to 3 carbon atoms;

R

6 is alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, chloro, bromo, trifluoromethyl or alkanoyloxy of 2 to 3 carbon atoms;

R

7 is hydrogen or alkyl of 1 to 3 carbon atoms; or a pharmaceutically acceptable salt thereof.

The most preferred compounds are those in which R 5 and R 6 are in the meta or 20 para position and n is 2.

Of particular interest are the compounds 1-[(2-dimethylamino)-1-(4methoxyphenyl)ethyl]cyclohexanol and 1-[(2-dimethylamino)-1-(4hydoxyphenyl)ethyl]cyclohexanol and the enantiomers and pharmaceutically acceptable salts thereof.

The compounds in which R 4 is formyl or alkanoyl of 2 to 7 carbon atoms have been found to be not as potent as the corresponding free hydroxy bearing derivatives.

However, in long term therapy the acyloxy derivatives will act as pro drugs as the acyl group is removed in vivo either via acid hydrolysis in the stomach or enzymatically.

ABP-92021-03 AU 27.07.00 The pharmaceutically acceptable acid addition salts of the basic compounds of this invention are formed conventionally by reaction of the free base with an equivalent amount of any acid which forms a non-toxic salt. Illustrative acids are either inorganic or organic, including hydrochloric, hydrobromic, fumaric, maleic, succinic, sulfuric, phosphoric, tartaric, acetic, citric, oxalic and similar acids. For parenteral administration, the use of water soluble salts is preferred, although either the free base of the pharmaceutically acceptable salts are applicable for oral or parenteral administration of the antidepressant agents of this invention. The halo substituent representing R 5 or R 6 is intended to include the chloro, bromo, iodo or fluoro substituents.

Pharmaceutical compositions containing the compounds of this invention represent an additional aspect of this invention. The active ingredient can be compounded into any of the usual oral dosage forms including tablets, capsules and ~.liquid preparations such as elixirs and suspensions containing various coloring, 15 flavoring, stabilizing and flavor masking substances. For compounding oral dosage forms, the active ingredient can be mixed with various conventional tabletting materials such as starch, calcium carbonate, lactose, sucrose and dicalcium phosphate to aid the tabletting or capsulating process. Magnesium stearate, as an additive, provides a useful lubricant function when desired.

The active ingredients can be dissolved or suspended in a pharmaceutically ***acceptable sterile liquid carrier, such as sterile water, sterile organic solvent or a mixture of both. Preferably a liquid carrier is one suitable for parenteral injection. Where the active ingredient is sufficiently soluble it can be dissolved in normal saline as a carrier; if it is too insoluble for this it can often be dissolved in a suitable organic solvent, for instance aqueous propylene glycol or polyethylene glycol solutions. Aqueous propylene glycol containing from 10 to 75% of the glycol by weight is generally suitable. In other instances other compositions can be made by dispersing the finely-divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution, or in a suitable oil, for instance arachis oil. Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by intramuscular, intraperitoneal or subcutaneous injection.

Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules. In such form, the composition is sub-divided in unit doses containing appropniate quantities of the active ingredient; the unit dosage formns can be packaged compositions, for example, packeted powders or vials or ampoules. The unit dosage form can be a capsule, cachet or tablet itself, or it can be the appropriate number of any AHP-9 202 1-03 AU 27.07.00 -6of these in package form. The quantity of the active ingredient in a unit dose of composition may be varied or adjusted from 2 mg. or less to 50 mg. or more, according to the particular need and the activity of the active ingredient. The usual oral recommended dose of venlafaxine for humans may be between about 75 and about 200 mg/day and this dose may be administered in two or three divided doses, preferably with food if administered orally. A daily dose for humans of a compound of the invention would preferably be between about 50 mg and about 375 mg, but it will be understood by one skilled in the art that dosage under this invention will be determined by the particular circumstances surrounding each case.

One skilled in this art will also be aware that the routes of administering the compounds of this invention may vary significantly. In addition to other oral administrations, sustained release compositions may be favored. Other acceptable routes may include, but are not limited to, intravenous, intramuscular and intraperitoneal injections, subdermal implants, as well as buccal, sublingual, transdermal, topical, *rectal, vaginal and intranasal administrations. Bioerodible, non-bioerodible, :biodegradable and non -biodegradable systems of administration may also be used.

*It should also be understood that the present inventi on is I ntended to include all methods of, and reasons for, treating generalized anxiety disorder in mammals, preferably in humans. For the purposes of this invention, treating this disorder is to be understood as including all prophylactic, therapeutic, progression inhibiting, remedial, maintenance, curative or other treatments, regimens or administrations of or with venlafaxine that yield the desired effects in the mammal receiving venlafaxine.

The compounds of the invention such as venlafaxine exhibit usefulness against both the somatic symptoms and the psychic symptoms of GAD. Venlafaxine also has the advantages of a rapid onset of action and usefulness for both long term and short term treatment of GAD.

The following example is provided to demonstrate the use of venlafaxine in the treatment of generalized anxiety disorder. This example is merely illustrative and does not limit the scope of the present invention.

AHP-92021-03 AU 27.07.00 -7-

EXAMPLE

A multicenter, double-blind, randomized, placebo-controlled, flexible dose, single-section, parallel group study of the effects of venlafaxine hydrochloride extended release (ER) in the treatment of Generalized Anxiety Disorder was carried out with 238 human patients.

All potential patients for the study were excluded if they had received venlafaxine hydrochloride within the previous six months, had a history or presence of mental disorder due to a general medical condition, history or presence of any psychotic illness, or presence of a clinically significant psychiatric disorder other than GAD, including :::post-traumatic stress disorder, panic disorder or depression.

All patients in the study were outpatients, at least 18 years of age and legal age of consent, met DSM-IV criteria for Generalized Anxiety Disorder (GAD) and exhibited sufficient symptoms to require anxiolytic drug therapy, minimum prestudy and study day -1 total scores of 18 or more on the Hamilton Psychiatric Rating Scale for Anxiety (HAM-A) and scores E 2 on item I (anxious mood) and item 2 (tension), prestudy and study day -1 Covi Anxiety Scale total score higher than the Raskin Depression Scale total score and a Raskin Depression Scale total score of not more than 9.

S. 123 Patients were assigned to a group to receive placebo administration and 115 patients were assigned to a group to receive venlafaxine ER; All study medication consisted of identically appearing capsules which were administered whole, orally, once a day with food. Venlafaxine ER was supplied in 75 mg capsules. After a 7±3 day washout period, eligible patients were randomly assigned to receive either placebo or venlafaxine ER in a double-blind manner for up to six months.

From study day 1 through study day 7, all patients took one capsule in the AM mg/day venlafaxine ER, or placebo]. Beginning on study day 8, if clinically indicated to improve response, daily dose could be increased to two capsules in the AM [150 mg/day venlafaxine ER, or placebo]. Beginning on study day 15, if clinically indicated to improve response, daily dose could be increased to three capsules in the AM [225 mg/day venlafaxine ER, or placebo]. Dosage was not increased above 3 capsules each day. Dosage could be reduced at any time during the study in order to improve tolerance, but the minimum daily dose allowed after day 7 was one capsule in the AM mg venlafaxine ER, or placebo). Patients unable to tolerate this dose were AHP-92021-03 AU 27.07.00 -8discontinued from the study. On study completion or early termination, patients were tapered from their medication.

Efficacy of the treatment was assessed at Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, 24 and 28 weeks using the Hamilton Psychiatric Rating Scale for Anxiety (HAM-A), including psychic and somatic clusters. By way of example the results for the baseline and weeks I to 3, 12 and 16 are given below.

S~ C- N AHP-92021-03 AU 27.07.00 -9- Summary Statistics for HAM-A SOMATIC ANXIETY FACTOR Observed Cases Analysis Adjusted Mean Time Change P-Value On Therapy Number Raw From Overall Drug Group Patients Mean Baseline F Test Baseline Placebo 123 11.10 Venlafaxine ER 115 11.11 .'Week 1 Placebo 122 9.20 -1.82 .005 Venlafaxine ER 115 8.25 -2.82 20 Week 2 Placebo 109 7.97 -3.20 .018 Venlafaxine ER 110 7.05 -4.16 Week 3 Placebo 110 7.39 -3.80 .002 Venlafaxine ER 105 6.12 -5.12 Week 12 Placebo 70 5.87 -5.15 .030 Venlafaxine ER 85 4.74 -6.33 Week 16 Placebo 64 5.64 -5.66 <.001 Venlafaxine ER 76 4.09 -7.26 LT~~i~I rr; AHP-92021-03 AU 27.07.00 Summary Statistics for HAM-A PSYCHIC ANXIETY FACTOR Observed Cases Analysis Time On Drug Adjusted Mean Change Raw Mean Therapy Group Number Patients P-Value From Baseline Overall F Test Baseline Placebo Venlafaxine ER Week 1 20 Week 2 Week 3 Placebo Venlafaxine ER Placebo Venlafaxine ER Placebo Venlafaxine ER 123 115 122 115 109 110 110 105 70 85 13.78 13.84 11.80 11.10 10.95 9.13 10.22 8.10 8.21 4.88 8.69 4.74 -1.77 -2.58 -2.75 -4.67 -3.63 -5.82 -5.63 -9.01 -5.15 -9.02 .021 <.001 <.001 <.001 <.001 Week 12 Placebo Venlafaxine ER Week 16 Placebo Venlafaxine ER AHP-92021-03 AU 27.07.00 11 Summary Statistics for HAM-A TOTAL Observed Cases Analysis Adjusted Mean Time Change P-Value On Therapy Number Raw From Overall Drug Group Patients Mean Baseline F Test Baseline Placebo 123 24.88 Venlafaxine ER 115 24.96 Week 1 Placebo 122 21.00 -3.61 .003 Venlafaxine ER 115 19.36 -5.41 Week 2 Placebo 109 18.93 -5.95 <.001 Venlafaxine ER 110 16.17 -8.84 Week 3 Placebo 110 17.61 -7.43 <.001 Venlafaxine ER 105 14.23 -10.93 Week 12 Placebo 70 14.09 -10.81 <.001 Venlafaxine ER 85 9.62 -15.34 Week 16 Placebo 64 14.33 -10.77 <.001 Venlafaxine ER 76 8.83 -16.27 30 The tables above indicate the numbers of patients continuing at the identified points in the study and comparable patient improvements were demonstrated when the observation data were evaluated in a Last Observation Carried Forward (LOCF) format.

The results show the means of the psychic anxiety factors, somatic anxiety factors and HAM-A total scores for the individuals remaining in the study. Also provided is the "p-value" indicating the probability such an improvement over placebo administration would occur merely by chance. A probability of less than 5% (p-value less than 0.05) was considered statistically significant.

It will be seen from the above results that venlafaxine hydrochloride showed the ability to reduce comparably both the psychic and somatic symptoms of GAD. The results provided also show that venlafaxine administration exhibited a rapid onset of -12action. In particular it provided significant relief over placebo from both somatic and psychic symptoms during the first week of administration.

An analysis of five six-month clinical trials on patients with GAD showed that venlafaxine was highly effective in reducing specific symptoms of long-term GAD, such as excessive worry, tension, sleeping difficulty, and poor concentration.

Throughout the description and claims of this specification, the word "comprise" and variations of the word, such as "comprising" and "comprises", is not intended to exclude other additives, integers or process steps.

*•e *eee

Claims (2)

13- The clnims detining Lhe invention are as ol lows: 1. A method of treatment, prevention or control of generalized anxiety disorder in a mammal in need thereof of-such treatment, prevention or control, comprising administering to the mammal an effective amount of a compound having the formula: .R, N R2 A SR, R6 in which A is a moiety of the formula 9 .o o OR (CH 2 )n 10 wherein 9* the dotted line represents optional unsaturation; RI is hydrogen or alkyl of 1 to 6 carbon atoms; R 2 is alkyl of 1 to 6 carbon atoms; R 4 is hydrogen, alkyl of 1 to 6 carbon atoms, formyl, or alkanoyl of 2 to 7 carbon 15 atoms; R 5 and R 6 are, independently, hydrogen, hydroxyl, alkyl of I to 6 carbon atoms, alkoxy of I to 6 carbon atoms, alkanoyloxy of 2 to 7 carbon atoms, cyano, nitro, alkylmercapto of 1 to 6 carbon atoms, amino, alkylamino of I to 6 carbon atoms, dialkylamino in which each alkyl group is of 1 to 6 carbon atoms, alkanamido of 2 to 7 carbon atoms, halo, trifluoromethyl, or taken together, methylene dioxy; R 7 is hydrogen or alkyl of 1 to 6 carbon atoms; and n is0, 1,2, 3, or4; or a pharmaceutically acceptable salt thereof. 2 The method of Claim I wherein O RI is hydrogen or alkyl of I to 3 carbon atoms; R2 is alkyl of 1 to 3 carbon atoms; a. R 4 is hydrogen, alkyl of 1 to 6 carbon atoms, formyl, or alkanoyl of 2 to 7 carbon S_ toms 4 4* AHP-92021-03 AU

27.07.00 14- R 5 is hydrogen, hydroxyl, alkoxy of 1 to 3 carbon atoms, chloro, bromo, trifuoromethyl or alkyl of 1 to 3 carbon atoms; R 6 is alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, chloro, bromo, trifluoromethyl or alkanoyloxy of 2 to 3 carbon atoms and R 7 is hydrogen or alkyl of I to 3 carbon atoms. 3. The method of Claim 2 wherein R 5 and R 6 are in the meta or para positions and n is 2. 4. The method of Claim 2 wherein the compound is 1-[(2-dimethylamino)-1- (4-methoxyphenyl)ethyl]cyclohexanol or a pharmaceutically acceptable salt thereof. 5. The method of Claim 2 wherein the compound is 1-[2-(dimethylamino)-l- (4-hydroxyphenyl)ethyl]cyclohexanol or a pharmaceutically acceptable salt thereof. 6. The method of Claim 1 wherein the effective amount comprises a daily dose between 50 mg/day and about 375 mg/day. 7. The method of Claim 4 wherein the effective amount comprises a daily 20 dose between 75 mg/day and about 200 mg/day. 8. Use of a compound for the preparation of a medicament for the treatment, prevention or control of generalized anxiety disorder in a mammal in need of such treatment, prevention or control, wherein the compound is a compound having the formula: RI N R2 "A R 5 R7 5-- in which A is a moiety of the formula I- 4+ ThII .iYjijjiiigi;~i___ wherein the dotted line represents optional unsaturation; RI is hydrogen or alkyl of 1 to 6 carbon atoms; R 2 is alkyl of 1 to 6 carbon atoms; R 4 is hydrogen, alkyl of 1 to 6 carbon atoms, formyl, or alkanoyl of 2 to 7 carbon atoms; R 5 and R 6 are, independently, hydrogen, hydroxyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 7 carbon atoms, cyano, nitro, alkylmercapto of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino in which each alkyl group is of 1 to 6 carbon atoms, alkanamido of 2 to 7 carbon atoms, halo, trifluoromethyl, or taken together, methylene dioxy; R 7 is hydrogen or alkyl of 1 to 6 carbon atoms; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof. 9. The use of Claim 8, wherein RI is hydrogen or alkyl of 1 to 3 carbon atoms; R2 is alkyl of 1 to 3 carbon atoms; R4 is hydrogen, alkyl of 1 to 6 carbon atoms, formyl, or alkanoyl of 2 to 7 carbon atoms; is hydrogen, hydroxyl, alkoxy of 1 to 3 carbon atoms, chloro, bromo, trifuoromethyl S or alkyl of 1 to 3 carbon atoms; R6 is alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, chloro, bromo, trifluoromethyl or alkanoyloxy of 2 to 3 carbon atoms and R 7 is hydrogen or alkyl of 1 to 3 carbon atoms. The use of Claim 9 wherein R 5 and R6 are in the meta or para positions and n is 2. 11. The use of Claim 9 wherein the compound is 1-[(2-dimethylamino)-l-(4- methoxyphenyl)ethyl]cyclohexanol or a pharmaceutically acceptable salt thereof. 12. The use of Claim 9 wherein the compound is 1-[2-(dimethylamino)-l-(4- hydroxyphenyl)ethyl]cyclohexanol or a pharmaceutically acceptable salt thereof. 13. The use of Claim 8 wherein the compound is used in a daily dose between -T 07O mg/day and 375 mg/day. 16 14. The use of Claim 11I wherein the compound is used in a daily dose between 75 mg/day and 200 mg/day. DATED: 14 August, 2000 PHILLIPS ORMONDE FITZPATRICK Attorneys for: AMERICAN HOME PRODUCTS CORPORATION ,01