AU780197B2 - Method of treating psoriasis, arthritis and reducing the toxicity of cancer chemotherapy - 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: Pharmacia Upjohn Company Actual Inventor(s): Donald H Batts, Roger G Ulrich Address for Service: PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Invention Title: METHOD OF TREATING PSORIASIS, ARTHRITIS AND REDUCING THE TOXICITY OF CANCER CHEMOTHERAPY Our Ref: 658773 POF Code: 1459/285890 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): 2 METHOD OF TREATING PSORIASIS, ARTHRITIS AND REDUCING THE TOXICITY OF CANCER CHEMOTHERAPY BACKGROUND OF THE INVENTION This application is a divisional of Australian Patent Application 15823/99, the entire content of which is incorporated herein by reference.

1. Field of the Invention The present invention is the use of known oxazolidinones to treat arthritis.

2. Background Arthritis, inflammation of the joint tissues, has numerous causes including bacterial infection (septic arthritis), degeneration of articular surfaces 15 (osteoarthritis), immunologic reaction against joint tissues (rheumatoid arthritis), crystal induced arthritis (gouty arthritis, pseudogout) and other miscellaneous causes (Reiter's syndrome, etc). One common thread in all of these is inflammation in and around the joint. Present day therapeutics for arthritis are not curative unless the arthritis is infectious and the underlying pathogen is 20 eliminated by an antibiotic. For other types of arthritis medications can reduce pain or inflammation but do not cure the disease. The OXAZOLIDINONEs can be used to treat the inflammation and pain caused by arthritis, including those types of arthritis which are not caused by infection. This is important since all of the medications presently available to treat arthritis have severe side effects.

Steroidal medications (glucocorticoids like prednisone and cortisol) give stomach ulcers, cataracts, reduced resistance to infection, weight gain and thinning of skin. non-steroidal anti-inflammatory drugs (NSAIDS such as indomethacin or ibuprofen among others) can cause stomach ulcers, reduced kidney function and bone marrow effects. Chemotherapeutic agents (like methotrexate) can have severs adverse effects on bone marrow and liver function. The OXAZOLIDINONEs provide the opportunity for relief of symptoms of inflammation for patients intolerant of other types of arthritis medications.

W.\caskaVkipDeaes\15823-99-div 1 doc 3 The discussion of the background to the invention herein is included to explain the context of the invention. This is not to be taken as an admission that any of the material referred to was published, known or part of the common general knowledge in Australia as at the priority date of any of the claims.

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

SUMMARY OF INVENTION In one aspect the present invention provides use of (S)-N-[[3-[3-fluoro-4-(4and pharmaceutically acceptable salts thereof for the manufacture of a medicament for use in treating arthritis.

15 In a further aspect the present invention provides a method of treatment of arthritis comprising administration of a therapeutically effective amount of (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl]acetamide, or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION The oxazolidinones of the present invention are known, see EXAMPLES 1 thru 6 (OXAZOLIDINONEs) and pharmaceutically acceptable salts thereof.

Suitable pharmaceutical acceptable salts include the acid addition salts from 25 the both inorganic and organic acids including hydrochloric, hydrobromic, sulfuric, phosphoric, sulfonic acids, methanesulfonic, gluconic, galacturonic, citratic, oxylatic and acetic.

It is preferred that the person being treated for arthritis with OXAZOLIDINONEs does not have a gram positive bacterial infection at the time of being treated.

In treating arthritis, the OXAZOLIDINONEs can either be used individually or in combination with each other or in combination with non-OXAZOLIDINONEs.

In treating arthritis, the OXAZOLIDINONEs are administered orally, parenterally topically or rectally.

When administered orally, the OXAZOLIDINONEs can be administered in tablet, capsule or liquid (suspension, syrup or solution) dosage form. Regardless of the dosage form, an anti-arthritis effective amount of the OXAZOLIDINONEs is from about 50 mg to about 1,200 mg/day. It is preferred that the OXAZOLIDINONEs be given in two or more divided doses, more preferably in two divided doses.

ooo When administered parenterally, the OXAZOLIDINONEs should be administered IV. The IV infusion should be adjusted such that the flow rate delivers an anti-arthritis effective amount of from about 50 mg to about 1,200 mg/day. This can be done by a continuous infusion, or as divided doses given as short term infusions of 30-90 minutes, preferably twice a day.

When applied topically, the OXAZOLIDINONEs can be applied in many different pharmaceutical dosage forms all well known to those skilled in the art.

These include a solution, crteam, ointment, gel, lotion, suspension or emulsion.

Regardless of the pharmaceutical dosage form selected, the concentration of the OXAZOLIDINONEs should be from about 0.01% to about 10% (wt/wt).

Regardless of the pharmaceutical dosage form, the topical formulation should be applied one to four times daily.

When administered rectally, the OXAZOLIDINONEs should be administered as a suppository which delivers an anti-arthritis effective amount 15 of from about 50 mg to about 1,200 mg/day.

When administered systemically, whether orally, parenterally or rectally the OXAZOLIDINONEs should be administered either continuously or in cyclic courses of 7-28 days every 1 to 12 months. When administered topically, the OXAZOLIDINONEs should be applied either daily for 7 to 28 days every 1 12 20 months.

The exact dosage and frequency of administration depends on the particular OXAZOLIDINONE used, the severity of the condition being treated, the age, weight, general physical condition of the particular patient, other medication the individual may be taking as is well known to those skilled in the art and can be more accurately determined by measuring the blood level or concentration of the OXAZOLIDINONE in the patient's blood and/or the patient's response to the particular condition being treated.

DEFINITIONS AND CONVENTIONS The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the claims.

W.cskanki\speaes\15823-99-dr. 1 doc 6

DEFINITIONS

Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.

When the solubility of a solid in a solvent is used the ratio of the solid to the solvent is weight/volume (wt/v).

When the active ingredient of a pharmaceutical formulation is set forth, it is the ratio of the active ingredient of the entire pharmaceutical formulation and is expressed as weight/weight (wt/wt).

Alcohol refers to ethyl alcohol.

IV refers to parenteral administration by the intravenous route.

OXAZOLIDINONES refers to the compounds of EXAMPLES 1 thru 6.

Anti-cytotoxic refers to reducing and/or preventing normal cell death.

EXAMPLES

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following detailed examples describe how to prepare the various 20 compounds and/or perform the various processes of the invention and are to be construed as merely illustrative, and not limitations of the preceding disclosure S. in any way whatsoever. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques.

EXAMPLE 1 (S)-N-[[3-[3-Fluoro-4-[4-hydroxyacetyl)-1-piperazinyl]- (S)-N-[[3-[3-Fluoro-4-[4-(hydroxyacetyl)-1 oxazolidinyl]methyl]acetamide is known, see US Patent 5,652,238, EXAMPLE 1.

EXAMPLE 2 (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5oxazolidinyl]methyl]acetamide (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl]acetamide is known, see US Patent 5,688,792, EXAMPLE W \skalnkAspecies\1 582399-div 1 doc 7 EXAMPLE 3 [4(S)-cis]-(-)-N-[[3-[3-Fluoro-4-(tetrahydro-1-oxido-2Hthiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide.

A mixture of (S)-(-)-N-[[3-[3-fluoro-4-(3,6-dihydro-2H-thiopyran-4yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide S-oxide (International Publication No. WO 97/09328, 4.50 g) and platinum oxide (697 mg) in methanol (164 ml) is shaken on the Parr apparatus under a hydrogen atmosphere at psi for 18 hours. The catalyst is then removed by filtration through Celite, and the filtrate is concentrated under reduced pressure and the residue chromatographed on silica gel (230 400 mesh, 350 eluting with a gradient of methanol/methylene chloride (3/97 7/93). The appropriate fractions (those fractions with an Rf 0.44 by TLC; methanol/chloroform, 10/90) are pooled and concentrated to give the title compound, mp 203 204°.

EXAMPLE 4 N-((5S)-3-(3-Fluoro-4-(4-(2-fluoroethyl)-3-oxopiperazin-1- N-((5S)-3-(3-Fluoro-4-(4-(2-fluoroethyl)-3-oxopiperazin-1 -yl)phenyl)-2oxooxazolidin-5-ylmethyl)acetamide is known, see International Publication W097/27188 (Example 4).

1-t-Butoxyxcarbonyl-3-oxopiperazine (21.6 g) is dissolved in dry DMF (500 ml) and potassium t-butoxide (24.2 g) is added. The mixture is stirred at 20-25° for 30 minutes, then 1-(4-methylphenylsulfonyloxy)-2-fluoroethane (J.

S: Med. Chem., 23(9), 985-90 (1980), 25.9 g) is added and stirring continued at the same temperature for 24 hours. The solvent is removed and the residue partitioned between ethyl acetate and water. The organic phase is washed with water and concentrated. The residue is dissolved in isopropanol and diluted with iso-hexane forming a precipitate which is removed by filtration. The mixture is chromatographed (silica; eluting with a gradient increasing in polarity from 0 to 50% isopropanol in iso-hexane) to give 1-t-butoxycarbonyl-4-(2-fluoroethyl)- 3-oxopiperazine.

1-t-Butoxycarbonyl-4-(2-fluoroethyl)-3-oxopiperazine (6.65 g) is dissolved in dichloromethane (500 ml), cooled in an ice-bath and trifluoroacetic acid (150 ml) added. The mixture is stirred at the same temperature for 2 hours.

W:ciskankispecies\15823-99-dv 1.doc 8 The solvent is removed to give a crude product which is dissolved in the minimum volume of ethyl acetate. Slow addition of ether causes precipitation of 1-(2-fluoroethyl)-2-oxopiperazine as the mono trifluoroacetic acid salt.

1-(2-Fluoroethyl)-2-oxopiperazine trifluoroacetate (6.1 g) is dissolved in acetonitrile (100 ml). N,N-Diisopropylethylamine (13 ml) is added to the mixture, followed by 3,4-difluoronitrobenzene (3.39 g) and the mixture heated to reflux for 18 hours. The solvent is removed and the residue chromatographed (silica; eluting with a gradient increasing in polarity from 0 to 4% methanol in dichloromethane) to give 3-fluoro-4-(4-{2-fluoroethyl}-3-oxopiperazin-1yl)nitrobenzene.

3-Fluoro-4-(4-{2-fluoroethyl}-3-oxopiperazin-1-yl)nitrobenzene (4.35 g) is dissolved in a mixture of ethyl acetate (250 ml) and DMF (5 ml), and the solution flushed with argon. Palladium (10% on carbon, 200 mg) is added and the mixture hydrogenated under ambient pressure. After gas uptake had ceased, the mixture is filtered through celite and solvent removed. The residue is taken up in ethyl acetate, washed twice with water, dried over magnesium sulfate and the solvent is removed to give 5-amino-2-[4-(2-fluoroethyl)-3oxopiperazon-1-yl]fluorobenzene which is used without further purification.

5-Amino-2-(4-[2-fluoroethyl]-3-oxopiperazin-1-yl)fluorobenzene (2.6 g) is 20 dissolved in dry dichloromethane (50 ml) under argon. Pyridine (1.03 ml) is added, and the mixture cooled to -200. Benzyl chloroformate (1.6 ml) is added .and the mixture stirred for 10 minutes at -200, before allowing the temperature to rise to 20-250 over 1.5 hours. The solvents are removed and the residue is dissolved in dichloromethane and washed with sodium bicarbonate solution.

After drying over magnesium sulfate and removal of the solvent, the residue is chromatographed (silica, eluting with a gradient increasing in polarity from 0 to methanol in dichloromethane) to give 5-benzyloxycarbonylamino-2-(4-[2fluoroethyl]-3-oxopiperazin-1-yl)fluorobenzene.

A solution of lithium t-butoxide is prepared by addition of n-butyllithium (1.6 M in hexane, 2.9 ml) to a stirred solution of t-butanol (0.43 g) in anhydrous THF (10 ml) at -100 under argon. After cooling to -700, a solution of benzyloxycarbonylamino-2-(4-[2-fluoroethyl]-3-oxopiperazin-1-yl)fluorobenzene W.cakal\nk\secdes\1 5823-9giv.1 .doc 9 g) in dry THF (15 ml) is added. After 10 minutes, (R)-glycidylbutyrate (0.67 g) in dry THF (15 ml) is added to the resulting mixture, and stirring continued at -700 for 15 minutes, before allowing the temperature to rise to 20-250 over 16 hours. Methanol (10 ml) is added, followed by saturated sodium bicarbonate solution (20 ml) and water (10 ml). The organic phase is separated and extracted into ethyl acetate (3 x 25 ml), washed with saline and dried over magnesium sulfate. The solvent is removed and the residue purified by chromatography (silica; eluting with a gradient increasing in polarity from 0 to 3% methanol in dichloromethane) to give (5R)-3-(3-fluoro-4-[4-(2-fluoroethyl)-3oxopiperazin-1 -yl]phenyl)-5-hydroxymethyloxazolidin-2-one.

(5R)-3-(3-Fluoro-4-[4-(2-fluoroethyl)-3-oxopiperazin-1-yl]phenyl)-5hydroxymethyloxazolidin-2-one (0.8 g) is dissolved in pyridine (15 ml) and the mixture cooled to Triethylamine (0.38 ml) and methanesulfonyl chloride (0.19 ml) are added to the mixture, and stirring continued at 20-250 for 2 hours.

The solvent is removed and the residue dissolved in dichloromethane, washed with water, saline, dried overmagnesium sulfate and concentrated. The resulting residue is triturated with ether to give (5R)-3-(3-fluoro-4-[4-(2-fluoroethyl)-3oxopiperazin-1-yl]phenyl)-5-(methanesulfonyloxymethyl)oxazolidin-2-one (0.76 g) which is used without further purification.

20 (5R)-3-(3-Fluoro-4-[4-(2-fluoroethyl)-3-oxopiperazin-1-yl]-5- (methanesulfonyloxymethyl)oxazolidin-2-one (719 mg) is dissolved in dry DMF (15 ml) and sodium azide (647 mg) is added to the mixture. The mixture is i heated at 800 for 6 hrs and then concentrated to dryness. The resulting residue is dissolved in ethyl acetate, washed twice with water, and dried over magnesium sulfate. Removal of the solvent gives (5R)-5-azidomethyl-3-(3fluoro-4-(4-(2-fluoroethyl)-3-oxopiperazin-1-yl)phenyl)oxazolidin-2-one (413 mg) which is used without further purification.

(5R)-5-Azidomethyl-3-(3-fluoro-4-[4-(2-fluoroethyl)-3-oxopiperazin-1yl]phenyl)oxazolidin-2-one (360 mg) is dissolved in dry DMF (20 ml) and the mixture purged with argon. Palladium (10% on carbon, 72 mg) is added, followed by acetic anhydride (0.17 ml) and the mixture stirred at 20-250 under hydrogen confined in a balloon for 3 hr. The mixture is filtered through celite, concentrated to dryness and partitioned between ethyl acetate and water.

W:ciskal\nksspeciesX 15823-99-dv. .doc The organic extract is washed with saline, dried over magnesium sulfate and concentrated. The residue is chromatographed (silica gel; eluting with a gradient increasing in polarity from 0 to 2.5% methanol/dichloromethane). The appropriate fractions are pooled and concentrated to give the title compound.

EXAMPLE 5 (S)-N-[[3-[5-(30Pyridyl)thiopen-2-yl]-2-oxo-5oxazolidinyl]methyl]acetamide.

(S)-N-[[3-[5-(3-Pyridyl)thiopen-2-yl]-2-oxo-5-oxazolidinyl]methyl] acetamide is known, see US Patent 5,698,574 (Examples 124).

EXAMPLE 6 (S)-N-[[3-[5-(4-Pyridyl)pyrid-2-yl]-2-oxo-5-oxazolidinyl] methyl]acetamide hydrochloride (S)-N-[[3-[5-(4-Pyridyl)pyrid-2-yl]-2-oxo-5-oxazolidinyl]methyl]acetamide hydrochloride is prepared following the general procedure of US Patent 5,627,181 EXAMPLEs 36 and 52 and making non-critical variations but using a 4-pyridinyl adduct.

EXAMPLE A 47 Year Old White Male Psoriasis A 47 year old white male had a history of psoriasis since age 32. He had chronic psoriatic lesions of both elbows, groin, left leg, right leg, and lower back.

The lesions were treated in the past with coal tar and topical steroids but not UV light. He was allergic to the excipients in the steroidal topical preparations.

20 He was treated with 625 mg of (S)-N-[[3-[3-fluoro-4-(4morpholinyl)pphenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide IV twice daily for five days and then with 625 mg of the same pharmaceutical orally twice daily for nine days. Hence, the patient was givwen 625 mg of (S)-N-[[3-[3-fluoro-4-(4twice daily for fourteen days and noticed an immediate improvement in his psoriasis as soon as he started taking the medication. He had a complete clearing of the psoriasis from the time he took the medication until three months later when it gradually began to return. After six months it had returned to the pretreatment state.

During the time he took the oxazolidinone he did not use any other psoriasis treatment.

W.16skalnkspedes1 5823-99-div. 1 doc 11 EXAMPLE B 50 Year Old White Male Arthritis A 50 year old white male (Subject No 1912) who had a history of chronic obstructive pulmonary disease he was a smoker), hypertension, coronary artery disease and arthritis of the "legs, arms and shoulders" for which he took non steroidal antiinflammatory agents including aspirin, developed community acquired pneumonia with Streptococcus pneumoniae as evidenced by an abnormal chest X-ray. He is treated with 625 mg of (S)-N-[[3-[3-fluoro-4-(4twice daily intravenously for 3 days followed by 8 days of oral (S)-N-[[3-[3-fluoro-4-(4morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide at the same dose.

At long term follow up the patient stated that his arthritis was gone and he was taken no medications.

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Claims (14)

1. Use of (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5- oxazolidinyl]methyl]acetamide, and pharmaceutically acceptable salts thereof for the manufacture of a medicament for use in treating arthritis.

2. Use of an oxazolidinone according to claim 1 where the medicament is administered orally.

3. Use of an oxazolidinone according to claim 2 where the daily dose of the oxazolidinone is from about 50 to about 1,200 mg/day.

4. Use of an oxazolidinone according to claim 1 where the medicament is administered topically as a solution, cream, ointment, gel, lotion, suspension or 15 emulsion.

5. Use of an oxazolidinone according to claim 4 where the amount to be administered topically is from about 0.01% to about

6. Use of an oxazolidinone according to claim 1 where the medicament is S. administered IV.

7. Use of an oxazolidinone according to claim 6, where the amount to be administered IV is from about 50 to about 1,200 mg/day.

8. A method of treatment of arthritis comprising administration of a therapeutically effective amount of (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2- or a pharmaceutically acceptable salt thereof.

9. A method according to claim 8 where the oxazolidinone is administered orally.

A method according to claim 9 where the daily dose of oxazolidinone is from about 50 to about 1,200 mg/day. 14

11. A method according to claim 8 where the oxazolidinone is administered topically as a solution, cream, ointment, gel, lotion, suspension or emulsion.

12. A method according to claim 11 where the amount to be administered topically is from about 0.01% to about

13. A method according to claim 8 where the oxazolidinone is administered IV.

14. A method according to claim 13 where the amount to be administered IV is from about 50 to about 1,200 mg/day. A use according to claim 1, or a method according to claim 8, substantially as hereinbefore described with reference to Example B. DATED: 7 January, 2005 PHILLIPS ORMONDE FITZPATRICK Attorneys for: PHARMACIA UPJOHN COMPANY F& 4a;t4.