IE913256A1 - Pharmacologically active compounds and use - Google Patents

Abstract

Compounds of formula (I), wherein R<4> is hydrogen and either R<5> is hydrogen and R<6> is hydroxyl or R<5>, R<6> and the carbon to which they are attached together form a carbonyl group; or R<6> is hydrogen and R<4> and R<5> together form a bond; or R<4> is hydroxyl, R<5> is hydrogen and R<6> is hydrogen or hydroxyl inhibit monoamine oxidase-A and are useful in the treatment of disorders such as depression.

Description

PHARMACOLOGICALLY ACTIVE COMPOUNDS AND USE Monoamine oxidase (MAO) is the enzyme in brain principally responsible for intraneuronal oxidation of biogenic amine neurotransmitters to inactive forms. It is understood to occur as two independent forms, normally designated MAO-A and MAO-B (White and Glassman, J. Neurochem,. 29. 989-997, (1977) and Tipton et al. Monoamine Oxidase and its Selective Inhibitors, Beckmann and Riederer, Eds., Mod. Probl. Pharmacopsvchiat.. 19 15-30, Karger, Basel (1983)). MAO inhibition has been found to elevate neurotransmitter concentrations in the brain.

MAO inhibitors are used therapeutically in the treatment of a wide variety of conditions, especially depression, particularly when characterized by anxiety, obsessional neuroses, or appetite disorders. However, a number of such compounds, for example isocarboxazid, phenelzine and tranylcypromine, are nc selective, irreversible inhibitors of the enzyme and are characterised by an undesirable side effect associated with ingestion of food or drink containing a high level of tyramine, for example, certain cheeses. When a patient receiving such a drug ingests such a product, then his blood pressure may be raised, sometimes to a dangerous level. Such patients are therefore instructed to avoid foods and beverages of this nature.

Patent publication EP-A-0 150 891 discloses the thioxanthen-9-ones represented by the formula MJC/JH/29th August 1991 PB1262 wherein n is 0, 1 or 2, and physiologically acceptable salts thereof, and teaches them to be inhibitors of MAO-A and useful in the prophylaxis and treatment of mental disorders such as depression.

It has now been found that the compounds of formula (I), wherein 6 R is hydrogen and either R is hydrogen and R is hydroxyl and the carbon to which they are attached together form a 6 4 5 group; or R is hydrogen and R and R together form a bond; hydroxyl, is hydrogen and is hydrogen or hydroxyl, are useful in the treatment of disorders such as depression beings and are distinct from isocarboxazid and the like selective, reversible inhibitors of MAO-A. or r5,r6 carbonyl or R is in human in being The compounds are reversibly bound to MAO-A as shown by their removal by dialysis from their complexes with MAO-A.

No pharmacologically significant increase in response (elevation of blood pressure) has been observed in test mammals which have been given oral antidepressant doses of compounds of formula (I) prior to orally ingested tyramine.

In the compounds wherein is hydroxyl, the carbon to which the said group is attached forms a chiral centre and formula (I) should be understood to extend to and embrace both enantiomers of the said compounds together with mixtures, including the racemic mixtures, thereof.

MJC/JH/29th August 1991 PB1262 In particular, formula (I) thus includes the following: ( + )-1-(1-hydroxyethyl)phenoxathiin 10,10-dioxide ( + ) -1-(l-hydroxyethyl)phenoxathiin 10,10-dioxide (-)-1-(1-hydroxyethyl)phenoxathiin 10,10-dioxide 1-acetylphenoxathiin 10,10-dioxide 1-vinylphenoxathiin 10,10-dioxide 1- (2-hydroxyethyl)phenoxathiin 10,10-dioxide (±)-1-(1.2-dihydroxyethyl)phenoxathiin 10,10-dioxide (+) -1-(1,2-dihydroxyethyl)phenoxathiin 10,10-dioxide, and (-)-1-(1,2-dihydroxyethyl)phenoxathiin 10,10-dioxide.

Depression states in which the compounds are particularly useful are those defined in the Diagnostic and Statistical Manual of Mental Disorders. third edition, (DSM III), American Psychiatric Association, Washington, D.C. (1980), (DSM III, 296.2X to 296.6X and 301.13), including that characterized by anxiety or obsessional neuroses (DSM III, 300.40), or atypical depression (DSM III, 296.70 and 296.82), e.g., accompanied by a personality disorder.

Other therapeutic uses for the compounds include treatment of posttraumatic stress disorder (DSM III, 308.30 and 309.81), obsessive compulsive behavioral states (DSM III, 300.30), anxiety states (DSM III, 300.00, 300.01, 300.02, 300.21, 300.22, 300.23 and 300.29), e.g., which are accompanied in an acute phase by panic attacks with or without phobia (DSM III 300.21), phobia (DSM III 300.23 and 300.29), appetite disorders, e.g. , bulimia (DSM III, 307.51) and anorexia MJC/JH/29th August 1991 PB1262 (DSM III, 307.10), and borderline personality disorder (DSM III, 301.83). Still further therapeutic uses for the compounds include treatment of headaches, e.g., migraine, muscle contraction and mixed (i.e., combination of migraine and muscle contraction) headaches.

The compounds may be administered by, for example, the oral, rectal or parenteral route. In general, the compounds may be administered for the treatment of each of the disorders stated hereinabove, including depression, in the dosage range of about 0.1 mg to about 50 mg per kg of human bodyweight per day, preferably about 1 mg to about 40 mg per kg of human bodyweight per day and optimally about 10 mg per kg of human bodyweight per day, although the precise dosage will naturally depend upon a number of clinical factors, for example, the age of the recipient, the route of administration and the condition under treatment and its severity, and upon the identity of the compound employed: for administration by the oral route, a dosage regime of 0.3 to 30 mg per kg per day, preferably 2 to 20 mg per kg per day and optimally about 10 mg per kg per day, may be used. The desired daily dose is preferably given as two or three or more subdoses administered at appropriate intervals during the day. These subdoses may be presented in unit dosage form each containing, for example, from 100 to 500 mg, preferably 200 mg, of the compound.

While it is possible to administer the compounds as the raw chemicals, it is highly desirable to administer them in the form of a pharmaceutical formulation.

The present invention thus provides pharmaceutical formulations comprising a compound of formula (I) together with an acceptable carrier therefor. The carrier should be acceptable in the sense of being compatible with the other ingredients and not deleterious to the recipient thereof. The formulations may be adapted for oral, parenteral or rectal administration inter alia.

MJC/JH/29th August 1991 PBL262 The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the compound of formula (I) (the active ingredient) with the carrier which may comprise one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping or encapsulating the product.

Formulations 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; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a freeflowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, 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. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.

Formulations suitable for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter.

Formulations suitable for parenteral administration include aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and nonaqueous MJC/JH/29th August 1991 PB1262 sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit dose or multidose containers, for example sealed ampoules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example PEG 400:ethanol mixtures, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

Preferred unit dosage formulations are those containing a daily dose or unit daily subdose, as hereinabove recited, or an appropriate fraction thereof, of the active ingredient.

It should be understood that, in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include flavouring agents.

The compounds of formula (I) may be prepared by those methods known in the art for the synthesis of compounds of analogous structure and in this regard reference is made, by way of illustration only, to the following standard texts: i) Protective Groups in Organic Chemistry1' ed. J.F.W. McOmie, Plenum Press (1973), ISBN 0-306-30717-0; ii) Compendium of Organic Synthetic Methods ed. I.T.Harrison and S.Harrison, Uiley-Interscience, Vol.I (1971) ISBN 0-471-35550-X, Vol.II (1974) ISBN 0-471-35551-8 and Vol. Ill (ed. L.S.Hegedus and L.Wade) (1977) ISBN 0-471-36752-4; and iii) Rodd's Chemistry of Carbon Compounds second edition, Elsevier Publishing Company.

MJC/JH/2nd September, 1991 PB1262 All references identified hereinabove or in the following are hereby incorporated herein by reference thereto.

The individual enantiomers of those compounds having a chiral centre (vide supra) may in particular be prepared by, for example, i) isolation from the racemic mixture, either by use of a chiral chromatography column or by preparing and separating suitable diastereoisomeric addition products, or ii) stereospecific synthesis from appropriate precursors.

The preparative Examples herein provided are illustrative of such procedures .

The following Examples illustrate the present invention.

Example 1. (+)-1-(1-Hydroxyethyl)phenoxathiin 10,10-dioxide A. Phenoxathiin 10.10-dioxide To a slurry of phenoxathiin (81 g, Parish Chemical Co., Orem, Utah) in glacial acetic acid (250 mL) was added 30% hydrogen peroxide (250 mL). The mixture was heated with stirring at reflux for 2.5 hr and then allowed to cool overnight. It was heated at reflux for an additional 2 hr and cooled to room temperature. The white solid produced was collected by filtration and thoroughly washed with water (until acid-free and peroxide-negative), then dried in vacuo at 55°C to give phenoxathiin 10,10-dioxide (87 g), mp 145-146°C.

B. 1-Lithiophenoxathiin 10.10-dioxide A mixture of phenoxathiin 10,10-dioxide (50.5 g) in dry MJC/JH/2nd September, 1991 PB1262 tetrahydrofuran (500 mL) under nitrogen was cooled in an acetone/dry ice bath. To this slurry was added a 1.6 M solution of n-butyllithium in hexane (144 mL) at a rate which maintained the reaction temperature at -40’C, resulting after 30-45 min. in an orange solution of 1-lithiophenoxathiin 10,10-dioxide.

C. (+)-1-(l-Hydroxyethyl)phenoxathiin 10,10-dioxide To a batch of 1-lithiophenoxathiin 10,10-dioxide, prepared according to the procedure of step B. from 44 g of phenoxathiin ,10-dioxide chilled to < -50’C in a dry ice/ acetone bath, was slowly added chilled acetaldehyde (20.37 g). The reaction mixture was maintained at -50’C during the addition which took 45 min. It was then allowed to warm to room temperature, and the solvent was removed under reduced pressure. The yellow-orange residue was stirred overnight with 0.5 N hydrochloric acid (259 mL), filtered and washed with water (500 mL). It was then washed thoroughly with ethanol (1.5 L), filtered and dried to give (+) -1-(1-hydroxyethyl)phenoxathiin 10,10-dioxide (41 g).

A sample was recrystallized from ethyl acetate/hexanes to give an analytically pure sample of (+)-1-(1-hydroxyethyl)phenoxathiin ,10-dioxide as white crystals, mp 177-179’C.

Anal. Calcd.: C H^O^S: C, 60.83; H, 4.38; S, 11.60.

Found: C, 60.78; H, 4.40; S, 11.51. 1H-NMR (DMSO-d,) S 8.06 (dd, 1H, H9 or H2, J - 8.0, 1.5), 7.83 0 (ddd, 1H, H7, J - 7.7, 7.7, 1.7), 7.80 (dd, 1H, H3, J - 7.9, 7.9), 7.76 (dd, 1H, H2 or H9, J - 7.8, 1.2), 7.57 (br d, 1H, H6, J - 8.5), 7.75 (ddd, 1H, H8, J - 7.2, 7.2, 1.0), 7.46 (dd, 1H, H4, J - 8.0, 7.9), 5.74 (q, 1H, -CH(OH)CH3> J - 6.1), 5.66 (br, 1H, -OH), 1.45 (d, 3H, methyl, J = 6.0).

MJC/JH/2nd September, 1991 PB1262 Example 2. 1-Acetylphenoxathiin 10.10-dioxide A mixture of 29.83 g (0.14 mol) of pyridinium chlorochromate (Aldrich Chemical Co.), 25.2 g of 4A molecular sieves, 13.92 g (0.05 mol) of (±)1-(l-hydroxyethyl)phenoxathiin 10,10-dioxide and 580 mL of methylene chloride was stirred for 21 hours, and then filtered through a 4 cm deep layer of kieselguhr which removed color. The kieselguhr was washed with a total of 1 L of equal volumes of ethyl acetate and hexanes, and the reaction flask residue was washed with ethyl acetate, which was then passed through the same kieselguhr. Arbitrary cuts of the chromatography with the mixed solvents gave, after removal of solvents by vacuum concentration, fractions melting between 124.5°C and 142°C. These were combined by melting point into two batches and those separately recrystallized from ethyl acetate by addition of hexanes to the hot solutions to incipient turbidity. The higher-melting fractions gave 9.70g, mp 144.0°C. The lower-melting fractions gave an additional 1.16 g, mp 142.4°C. The fractions were combined and recrystallized from ethyl acetate by the addition of pentane to the hot solution to give 1-acetylphenoxathiin .10- dioxide, mp 142-144°C, showing one spot on TLC with 1:1 ethyl acetate :pentane (R^ - 0.8).

Anal. Calcd.: C^H^O^S: C, 61.30; H, 3.67; S, 11.69.

Found: C, 61.23; H, 3.70; S, 11.74.

LH-NMR (DMSO-d.) 5 u 7.61 (d, IH, H2, J - 7.5), 7.86 (dd, IH, H3, J - 8.4, 7.5), 7.71 (dd, IH, H4, J = 8.4, 0.9), 7.61 (d, IH, H6, J - 7.5),7.82 (ddd, IH, H7, J - 8.5, 7.3, 1.5), 7.50 (ddd, IH, H8, J - 8.0, 7.2, 1.1), 8.00 (dd, IH, H9, J = 7.9, 1.6), 2.63 (s, 3H, methyl).

Example 3. 1-Vinylphenoxathiin 10.10-dioxide A slurry of 1.06 g (0.00384 mol) of (+)-1-(l-hydroxyethyl)phenoxathiin .10- dioxide in 60 mL of methylene chloride and 0.730 mL of thionyl MJC/JH/29th August 1991 PB1262 chloride protected from atmospheric moisture was heated under reflux for 3.5 hr. After volatile materials had been removed (water aspirator, hot water bath), 10 mL of ethanol was added and similarly removed and the residue recrystallized from ethanol to give 290 mg of a white solid. An equal additional amount was obtained from the mother liquors by again distilling down and recrystallizing the residue from ethyl acetate/pentane. The combined solids were recrystallized from ethyl acetate/pentane to give 1-vinylphenoxathiin ,10-dioxide (0.310 g) , mp 143-145°C.

Anal. Calcd.: C1?HinOnS: C, 65.10; H, 3.90; S, 12.41. 1U 3 Found: C, 65.00; H, 3.97; S, 12.33. 1H-NMR (DMSO-d,) S o 7.72 (dd, IH, H2, J - 8.0, 1.6), 7.76 (dd, IH, H3, J - 8.0, 8.0), 7.50 (dd, IH, H4, J - 8.4,1,2), 7.56 (dd, IH, H6, J - 8.3, 1.2), 7.81 (ddd, IH, H7, J - 8.5, 7.2, 1.4), 7.52 (ddd, IH, H8, J = 8.6, 7.3, 1.5), 8.05 (dd, IH, H9, J - 8.1, 1.6), 7.55 (dd, IH, Hl', J - 17.2, 10.8), 6.02 (dd, IH, H2't, J - 17.3, 1.0), 5.61 (dd, IH, H2'c, J - 11.0, 1.0).

Example 4. (+) -1-(1,2-Dihydroxyethyl)phenoxathiin 10,10-dioxide A suspension of 10.1 g (0.0366 mol) of (±)-1-(l-hydroxyethyl)phenoxathiin 10,10-dioxide in 200 mL of methylene chloride and 20 mL of thionyl chloride was refluxed for 12 hours, and after the addition of a further 6 mL of thionyl chloride for another 6 hours. The reaction mixture was concentrated at water aspirator pressure in a hot water bath, and then two 88 mL portions of 97% formic acid were sequentially added and removed in vacuo. The residue was then treated with 100 mL of 97% formic acid and 4.5 mL of 30% aqueous hydrogen peroxide, and the mixture stirred at room temperature for 12 hours, treated with an additional 5 mL of 30% hydrogen peroxide, stirred for several hours and then heated on a steam bath to dissolve the solid. The cooled solution was treated MJC/JH/29th August 1991 PBL262 with 1 L of water and the acidic aqueous supernatant decanted from an oily residue. The latter was stirred with ethanol and an excess of IN aqueous sodium hydroxide solution for 1 hour and then extracted with methylene chloride. The methylene chloride solution was washed with water, then with IN hydrochloric acid, and then dried over magnesium sulfate. After distillation of solvent, the residue was chromatographed on silica gel with 1:1 ethyl acetate:hexanes, and the product-containing fractions were pooled. The solvent was removed in vacuo. and the residue was recrystallized from ethyl acetate by the addition of hexanes to yield (+)-1-(1,2 - dihydroxyethyl)phenoxathiin ,10-dioxide (2.52 g) as light yellow crystals, mp 114-116°C.

Anal. Calcd.: C^O S: C, 57.53; H, 4.14; N, 10.97.

Found: C, 57.61; H, 4.17; N, 10.89. 1H-NMR (DMSO-d,) S 8.04 (dd, ΙΗ, H9, J - 8.0, 1.5), 7.81 (ddd, ΙΗ, H8, o J - 8.6, 7.3, 1.6), 7.76 (dd, ΙΗ, H3, J - 8.0, 8.0), 7.69 (dd, ΙΗ, H2, J - 8.0, 1.4), 7.56 (dd, ΙΗ, H6, J - 8.3, 0.8), 7.52 (ddd, ΙΗ, H8, J 9.0, 7.2, 1.0), 7.46 (dd, ΙΗ, H4, J - 8.2, 1.2), 5.72 (d, 1H, -CH(OH)CH2(OH), J - 4.4), 5.61 (ddd, 1H, - CH(OH)CH2(OH), J - 7.2, 4.3, 2.6), 4.87 (t, 1H, -CH(0H)CH2(OH), J- 6.1), 3.71 (ddd, 2H, -CH(0H)CH2(0H), J - 11.2, 6.4, 2.9).

Example 5. 1 -(2-Hvdroxyethvl)phenoxathiin 10.10-dioxide A slurry of 10.2 g of (+)-1-(1,2-dihydroxyethyl)phenoxathiin ,10-dioxide in 100 mL each of ethanol and acetic acid and 5 mL of 70% perchloric acid was dehydroxylated using 0.52 g of Pearlman's catalyst (Aldrich Chemical Co.) in a Parr hydrogenator with hydrogen as taken up. The solution from which catalyst has been removed by filtration was evaporated to about 1/5 its previous volume and partitioned between methylene chloride and water, the organic layer washed with IN aqueous sodium hydroxide, dried over magnesium sulfate, and the solvent distilled off In vacuo. The residue was chromatographed on silica gel with ethyl acetate'.hexane (1:3) to give MJC/JH/29th August 1991 PB1262 first fractions yielding 0.240 g of 1-(2-hydroxyethyl)phenoxathiin ,10-dioxide as a white solid, mp 85-87°C.

Anal. Calcd.: C^H^O^S: C, 60.86; H, 4.38; S, 11.60.

Found: C, 60.79; H, 4.42; S, 11,57. 1H-NMR (DMSO-d,) S 7.36 (dd, 1H, H2, J - 7.5, 1.0), 7.69 (dd, 1H, H3, 0 J - 8.4, 7.5), 7.42 (dd, 1H, H4, J - 8.4, 1.0), 7.55 (dd, 1H, H6, J = 8.3, 0.8), 7.81 (ddd, 1H, H7, J - 8.7, 7.3, 1.7), 7.51 (ddd, 1H, H8, J - 8.1, 7.4, 1.0), 8.04 (dd, 1H, H9, J - 8.0, 1.4), 3.76 (t, 2H, Hl·', J - 6.7) , 3.30 (t, 2H, H2', J - 7.1).

Example 6. (+)-1-(l-Hydroxyethyl)phenoxathiin 10,10-dioxide The aqueous The organic To a stirred solution of 21 mL of S-alpine-borane (0.5 M in tetrahydrofuran (THF), Aldrich Chemical Co.) was added 1-acetylphenoxathiin 10,10-dioxide (1.06 gm) . The solution was kept under nitrogen. After 5 days the flask was dry and another 20 mL of S-alpine-borane then added. After another 20 days the THF had again evaporated. The residue was partitioned between 100 mL of ΙΝ-hydrochloric acid and 100 mL of methylene chloride. layer was extracted with methylene chloride (2 X 100 mL) portions were combined and concentrated. The material was purified by column chromatography on Silica Gel 60 (E. Merck, Darmstadt, Germany) eluting with methylene chloride and acetonitrile (step gradient of the acetonitrile, 0% to 5% in 1% increments, then to 10%). A clear oil was isolated which was further purified on a Waters Prep LC3000 using one Prep Pak Silica column (P/N 50040) , eluting with methylene chloride and acetonitrile (step gradient of the acetonitrile, 0% to 8%, changing 1% every 500 mL). Fractions containing the desired product were combined and concentrated to yield 0.41 gm of white solid, mp 113-115°C, with an appropriate proton NMR. [a]g0 - +13.8° (c. 1.50, chloroform) MJC/JH/29th August 1991 PB1262 Anal. Calcd.: C-.H^O.S: C.60.86; H.4.38; S.11.60. 12 4 Found: C, 60.98; H.4.42; S.11.53.

This material may also be made by reduction of 1-acetylphenoxathiin ,10-dioxide using the method of Corey, J .Amer.Chem.Soc.. 1987, 109. p.7925.

Example 7. (-)-1-(l-Hvdroxvethvl)phenoxathiin 10,10-dioxide A solution of 1-acetylphenoxathiin 10,10-dioxide (2.87 gm) and 42 mL of R-alpine-borane (0.5M in tetrahydrofuran (THF), Aldrich Chemical Co.) was stirred under nitrogen for 19 days; dry THF was added as needed to make up for evaporation losses. The reaction mixture was worked up by adding 2 mL of acetaldehyde and stirring for 15 minutes, then concentrating. The residue was mixed with 80 mL of diethyl ether and 0.5 mL of ethanolamine and allowed to sit overnight. Solvent was then evaporated and the residue purified by column chromatography (procedure similar to purification of the (+) enantiomer, q . v.). This yielded 0.18 gm of white solid, mp 114-116°C, with an appropriate proton NMR. [a]g0 - -10.4° (c. 1.50, chloroform) Anal. Calcd.: C-.H1o0.S: C.60.86; H,4.38; S.11.60 14 12 4 Found: C,60.91; H,4.36; S.11.53.

MJC/JH/29th August 1991 PB1262 Example 8. (-) -1 - (1,2-DihvdroxyethyDphenoxathiin 10,10-dioxide A. Chiral forms of 2.3-diphenyl-Μ,N'-bis(2,4.6- trimethvibenzy1) -1.4butanediamine Racemic 1,2 - diphenyl-1,2-diaminoethane was prepared by the method of Corey, J .Amer.Chem,Soc,. 1989, 111. p.5493 - supplement. The chiral material was obtained by mixing the diamine with 2 molar equivalents of (R)- (-)-mandelic acid (Aldrich Chemical Co.) in hot ethanol (5.6 mL per gm of diamine) and cooling in a dry ice/acetone bath, then warming to room temperature. The resulting salt was then recrystallized three times from ethanol (11 mL per gm of diamine) to yield a solid, mp 163-164°C. [q]J6 - -130.8° (c. 1.51, methanol) This salt was basified with 2.5 M sodium hydroxide to give the free (S,S) diamine (95.5% enantiomeric excess). [a]g2 - -102.1° (c. 1.07, methanol) The mother liquors from the (-)-mandelic acid salt were basified and treated with (S)- (+)-mandelic acid (Aldrich Chemical Co.) as above and the resulting salt basified to yield the free (R,R) diamine. (e]g2 - +100.2° (c. 1.07, methanol) A solution of the (R,R) diamine (2.50 gm), isochlorodurene (4.17 gm, Aldrich Chemical Co.), triethylamine (2.50 gm) and 50 mL acetonitrile was refluxed under nitrogen for one hour. The solvent was evaporated and the residue purified by column chromatography on Silica Gel 60 (E. Merck, Darmstadt, Germany), eluting with 5% ethyl acetate - 95% hexane. The resulting material was further purified on a Waters Prep LC3000 (one column), eluting with 5% ethyl acetate - 95% hexane, to yield 2.4 gm of (R,R)-(-) -2,3-diphenyl-Ν,N'-bis (2,4,6-trimethylbenzy1) MJC/JH/29th August 1991 PB1262 -1,4-butanediamine. Mass spectrum: M+1 - 477. [ct]g3 = -26.1° (c. 1.08, methanol) (+24.6° reported for the (S,S) form) B . (-)-1-(1,2 - DihvdroxyethyDphenoxathiin 10.10 - dioxide A solution of osmium tetroxide (1 gm, Aldrich Chemical Co.), (R,R)- (-)-2,3-diphenyl-N.N'-bis(2,4,6-trimethylbenzyl)-1,4-butanediamine (1.87 gm) and 250 mL of methylene chloride was cooled to -78°C (dry ice/acetone), stirring under nitrogen. To this was added 1-vinylphenoxathiin 10,10-dioxide (1.02 gm) in 50 mL methylene chloride, in a slow stream. After 2.25 hours the solution was allowed to warm to room temperature and then concentrated. The residue was refluxed for 2 hours with 200 mL of tetrahydrofuran (THF) and 200 mL of saturated sodium bisulphite solution. The aqueous layer was then basified with sodium bicarbonate and extracted with ethyl acetate (3X300 mL), the organic portions being combined with the THF layer and concentrated. The residue was purified by column chromatography on Silica Gel 60 (E. Merck, Darmstadt, Germany), eluting with ethyl acetate-hexane (1:1). The impure material (eluted wich the solvent front) was further purified on a Waters Prep LC3000 (one column, eluted with ethyl acetate-hexane, 1:1) to yield 0.89 gm of white solid, mp 135-137°C, with an appropriate proton NMR. [a]gO - -56.3° (c. 1.09, chloroform) Anal. Calcd.: C14H12O5S; C,57.52; H.4.15; S.10.97. Found: C.57.52; H.4.15; S.10.89.

MJC/JH/29ch August: 1991 PB1262 Example 9. Pharmaceutical Formulations In the following formulation examples, 'Active Ingredient' means a compound of formula (I).

A - 100 mg Compression Coated Tablet Ingredients Amount Per Tablet Core Active Ingredient 100 mg Cornstarch 25 mg Magnesium Stearate 2 mg Coating Coating Lactose Cornstarch Gelatin Magnesium Stearate 320 mg 50 mg 6 mg 4 mg The Active Ingredient and starch are granulated with water and dried. Magnesium stearate is added to the dried granules. Lactose and starch are granulated with a 10% w/v aqueous solution of gelatin and dried. Magnesium stearate is added to the dried granules. The granulated core is compressed with the granulated coating in a conventional compression molding machine.

B - 200 mg Capsule Ingredients Active Ingredient Lactose Talc Amount Per Capsule 200 mg 200 mg 40 mg MJC/JH/29th August 1991 PBL262 The Active Ingredient, lactose and talc are brought into intimate admixture with one another and 440 mg of the resultant mixture is introduced into a size 0 hard gelatin capsule.

C - 100 mg Capsule Amount Per Ingredients Capsule Active Ingredient 100 mg Lactose 100 mg Cornstarch 100 mg Magnesium Stearate 10 mg The ingredients are mixed together until homogeneous and 310 mg of the resulting mixture filled into each hard gelatin capsule.

D - 100 mg Capsule Amount Per Ingredients Capsule Active Ingredient 100 mg Gelucire 37/02 400 mg PEG 3350 50 mg The Gelucire 37/02 is melted by heating at 90°C. The PEG 3350 is added, and the mixture is stirred to give a uniform melt. While monitoring the temperature at 90°C, the Active Ingredient is added and the mixture stirred to give a homogeneous mixture. The mixture is added to size 0 hard gelatin capsules, cooled and capped. Gelucire 37/02 is a trademark of Gattefosse Corporation of Elmsford, NY for hydrogenated polyglycolized glycerides prepared from hydrogenated fatty acids, glycerol and MJC/JH/29ch August 1991 PB1262 PEG 300. PEG 300 is poly(ethylene glycol) of approximate molecular weight 300; PEG 3350 is poly(ethylene glycol) of approximate molecular weight 3350.

E - 100 mg Capsule Amount Per Ingredients Capsule Active Ingredient 100 mg Labrafil M 1944 CS 400 mg The Labrafil is heated to about 70’C, and the Active Ingredient is then added with stirring to give a homogeneous mixture. The mixture is added to size 0 hard gelatin capsules, cooled and capped. Labrafil M 1944 CS is a trademark of Gattefosse Corporation of Elmsford, NY for unsaturated polyglycolized glycerides prepared from apricot kernel oil and PEG 300.

F - 500 mg Tablet Amount Per Ingredients Tablet Active Ingredient 500 mg Cornstarch 100 mg Microcrystalline Cellulose 75 mg Magnesium Stearate 5 mg Granulated polyvinylpyrrolidone 10 mg (10% w/v in 50% w/v aqueous ethanol) The Active Ingredient, corn starch and microcrystalline cellulose are mixed together, and granulated with the alcoholic polyvinylpyrrolidone. The resulting granules are dried, and compressed to produce tablets, each tablet having a weight of approximately 690 mg.

MJC/JH/29th August 1991 PB1262 G - Suppository Ingredients Amount Per Suppository Active Ingredient Suppository Base 200 mg q.s. to 2 g dispersed into a The dispersion is The Active Ingredient in fine powder form is little of the molten Suppository Base at 50°C. incorporated into the bulk of the base at the same temperature, allowed to cool at 42’-45°C, poured into suitable 2 g suppository molds and allowed to set at 15°-20°C. Suitable suppository bases are Massa Esterinum C (Henkel International, Dusseldorf, Germany) and Witten H Suppository Compound.

H - Dispersible Tablet Ingredients Amount Per Tablet Active Ingredient 200 mg Corn Starch 40 mg Primojel (Trade name: sodium starch glycollate (125#m powder)) 50 mg Dicalcium Phosphate Dihydrate 50 mg Sodium Carboxymethyl Cellulose 2 mg Sodium Saccharin 5 mg Microcrystalline Cellulose 50 mg Magnesium Stearate 3 mg The Active Ingredient, half of the corn starch, the Primojel and dicalcium phosphate dihydrate are mixed together and then granulated with a solution of sodium carboxymethyl cellulose and sodium saccharin in a suitable volume of 50% ethyl alcohol. The MJC/JH/2nd September, 1991 PB1262 granules are dried, the remaining corn starch, the microcrystalline cellulose and the magnesium stearate are blended-in and the resulting mixture compressed into tablets.

Example 10. Biological Activity I. MONOAMINE OXIDASE INHIBITION A - In Vitro Inhibition MAO was assayed with [ H]serotonin (0.2 mM, 5 Ci/mole) and 14 [ C]y3-phenethylamine (10 μΜ, 3 Ci/mole) as substrates in a double-label assay (White and Glassman, J. Neurochem. 29:987-97 (1977)). Under these conditions, serotonin is selectively metabolised by MAO-A and /3-phenethylamine by MAO-B.

For studies of the kinetic mechanism of inhibition, the above method was used except that a single substrate, serotonin or tyramine, was varied over a 10-fold concentration range that included the K concentration. When tyramine was used as m substrate, the extract was pretreated with deprenyl (ΙμΜ) to inhibit all MAO-B activity. MAO-A activity was determined in the absence and presence of the compound under test at each substrate concentration in duplicate or triplicate assays.

Compounds of formula (I) produced a potent selective inhibition of MAO-A in mitochondrial extracts of rat brain, the IC^s (concentration producing 50% inhibition) being shown in the table. This inhibition was competitive vs. the substrates serotonin or tyramine.

B - In Vivo Inhibition To determine MAO inhibition in brains of rats pretreated with a MJC/JH/29th August 1991 PB1262 reversible inhibitor, it was necessary to use an assay procedure that minimized dilution of the compound. Thus, high concentrations of tissue homogenates were incubated for very short periods of time . For brain assays , initial tissue was 3-fold diluted into each assay. Substrate concentrations were not saturating, but were chosen relative to K values for m serotonin and $-phenethylamine in order to give an estimate of MAO-A and MAO-B, respectively.

Brains from pretreated male Sprague - Dawley rats (sacrificed hours after oral dosing with the test compound) were homogenized in a buffer consisting of 0.1 M potassium phosphate and 5% sucrose (pH 7.4) at a 1:1 tissue weight/buffer volume ratio, using a motorized Teflon/glass homogenizer. MAO-A and MAO-B were determined by incubating 100 μί. of tissue homogenate with 50 μί. of a double-label substrate mixture co give final 3 concentrations of [ H]serotonin, 0.4 mM (5 Ci/mole) and J%]/3-phenethylamine, 20 μΜ (3 Ci/mole). For blank assays, 100 μί. portions of homogenate were pre-incubated for 15 min. at 37’C with pargyline (4 mM) before substrate addition. Incubations with substrate present were at 37’C for 30 sec. Assay mixtures were then acidified and products extracted as in the above in vitro method (White and Glassman, loc.cit.).

The results are shown in the table, the EDg^ being the dose providing 80% inhibition. There was no significant inhibition of MAO-B.

MJC/JH/29th August 1991 PBL262 MAO - A Inhibition (rat brain) Compound In vitro ΙΟ^θ (μΜ) In vivo ED (mg/kg,p.o.) Ex.l Ex. 2 Ex. 3 Ex . 4 Ex . 5 0.4 2.0 0.04 1.2 0.02 70% @ 30* 20 20 55% @ 20* * % inhibition at indicated dose II. EFFECTS ON BLOOD PRESSURE RESPONSE TO ORAL TYRAMINE Compounds of formula (I) were tested for effects on the pressor response induced by orally administered tyramine in a conscious, unrestrained rat model. The method involves direct measurement of mean arterial blood pressure from a cannula implanted in a carotid artery and exteriorized through a small incision in the back of the neck. Peak changes in the pressor response following tyramine (p.o.) in animals pretreated with test compound (p.o.) were compared with changes seen in animals pretreated with either the known MAO inhibitor, phenelzine, (p.o.) or vehicle (water) alone.

To compare effects at equipotent doses that are relevant to antidepressant activity, either the test compound or phenelzine was given in a single oral dose that produced approximately 80% inhibition of brain MAO-A by the time of tyramine administration, 3 hours later. Under these conditions, liver MAO-A was inhibited by 90% or more by phenelzine .

MJC/JH/29th August 1991 PB1262 Rats pretreated with vehicle alone exhibited blood pressure elevations at relatively high doses of tyramine, i.e. above 27 mg/kg. Compounds of formula (I) did not cause a statistically significant increase in the pressor response to tyramine at threshold tyramine doses (15 mg/kg), while phenelzine (50 mg/kg., p.o.) caused a 57.5 (± 3.6) % increase in mean arterial blood pressure in response to the same dose of tyramine.

Claims (38)

1. What we claim is: 1. A pharmaceutical formulation comprising a compound of formula (I) wherein is hydrogen and either R^ is hydrogen and R^ is hydroxyl or R^,R^ and the carbon to which they are attached together form a carbonyl 6 4 5 4 group; or R is hydrogen and R and R together form a bond; or R is hydroxyl, R^ is hydrogen and R^ is hydrogen or hydroxyl, together with an acceptable carrier therefor.

2. A formulation according to claim 1 wherein the compound is (+)-1(l-hydroxyethyl)phenoxathiin 10,10-dioxide.

3. A formulation according to claim 1 wherein the compound is (+)-1(1-hydroxyethyl)phenoxathiin 10,10-dioxide.

4. A formulation according to claim 1 wherein the compound is (-)-1(l-hydroxyethyl)phenoxathiin 10,10-dioxide.

5. A formulation according to claim 1 wherein the compound is 1MJC/JH/3rd Septmber 1991 PB1262 -25acetylphenoxathiin 10,10-dioxide.

6. A formulation according to claim 1 wherein the compound is 1-vinylphenoxathiin 10,10-dioxide.

7. A formulation according to claim 1 wherein the compound is 1(2-hydroxyethyl)phenoxathiin 10,10-dioxide.

8. A formulation according to claim 1 wherein the compound is (+)-1(1,2-dihydroxyethyl)phenoxathiin 10,10-dioxide.

9. A formulation according to claim 1 wherein the compound is (-)-1(1,2-dihydroxyethyl)phenoxathiin 10,10-dioxide.

10. A formulation according to any of claims 1 to 9 in unit dosage form.

11. A formulation according to any of claims 1 to 10 adapted for oral administration.

12. A formulation according to claim 11 in the form of a capsule or tablet.

13. A formulation according to any of claims 1 to 10 adapted for parenteral administration. MJC/JH/3rd Septmber 1991 PB1262 -2614. A formulation according to any of claims 1 to 10 adapted for rectal administration.

14. 15. A method for the preparation of a formulation according to any of claims 1 to 14 comprising admixture of the ingredients thereof.

15. 16. Use of a compound as defined in any of claims 1 to 9 for the manufacture of a medicament for the medical treatment of a mammal.

16. 17. Use of a compound as defined in any of claims 1 to 9 for the manufacture of a medicament for inhibiting monoamine oxidase-A in the brain of a mammal.

17. 18. Use of a compound as defined in any of claims 1 to 9 according to either of claims 16 and 17 wherein the mammal is a human being.

18. 19. Use of a compound as defined in any of claims 1 to 9 for the manufacture of a medicament for the treatment of depression in a human being.

19. 20. A method for inhibiting monoamine oxidase-A in the brain of a mammal comprising the administration to the said mammal of an inhibition-effective amount of a compound as defined in any of claims 1 to 9.

20. 21. A method according to claim 20 wherein the mammal is a human being. MJC/JH/3rd Septmber 1991 PB1262 -2722. A method for the treatment of depression in a human being comprising the administration to the said human being of an antidepressant amount of a compound as defined in any of claims I to 9.

21. 23. A method according to any of claims 20 to 22 wherein the said compound is administered by the oral route.

22. 24. A method according to any of claims 20 to 23 wherein the said compound is administered together with an acceptable carrier therefor.

23. 25. A method according to claim 24 wherein the said compound is administered in the form of an orally ingestible capsule or tablet.

24. 26. A compound as defined in any of claims 1 to 9 for use in the medical treatment of a mammal.

25. 27. A compound as defined in any of claims 1 to 9 for use in inhibiting monoamine oxidase-A in the brain of a mammal.

26. 28. A compound as defined in any of claims 1 to 9 according to either of claims 26 and 27 wherein the mammal is a human being.

27. 29. A compound as defined in any of claims 1 to 9 for use in the treatment of depression in a human being.

28. 30. ( + ) -1-(1-Hydroxyethyl)phenoxathiin 10,10-dioxide. MJC/JH/3rd Septmber 1991 -28PB1262

29. 31. (-)-1-(1-Hydroxyethyl)phenoxathiin 10,10-dioxide.

30. 32. 1-Acetylphenoxathiin 10,10-dioxide.

31. 33. 1-Vinylphenoxathiin 10,10-dioxide.

32. 34. 1-(2-Hydroxyethyl)phenoxathiin 10,10-dioxide.

33. 35. (+)-1-(1,2-Dihydroxyethyl)phenoxathiin 10,10-dioxide.

34. 36. (-)-1-(1,2-Dihydroxyethyl)phenoxathiin 10,10-dioxide. MJC/JH/3rd Septmber 1991 -2937. A formulation substantially as hereinbefore described with reference to the Examples.

35. 38. A use substantially as hereinbefore described with reference to the Examples.

36. 39. A method of preparation substantially as hereinbefore described with reference to the Examples.

37. 40. A method of prophylaxis or treatment substantially as hereinbefore described with reference to the Examples.

38. 41. A compound substantially as hereinbefore described with reference to the Examples.