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WO1996011676A1 - Use of inhibitors of cyclooxygenase in the treatment of neurodegenerative diseases - Google Patents

Use of inhibitors of cyclooxygenase in the treatment of neurodegenerative diseases Download PDF

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Publication number
WO1996011676A1
WO1996011676A1 PCT/GB1995/002382 GB9502382W WO9611676A1 WO 1996011676 A1 WO1996011676 A1 WO 1996011676A1 GB 9502382 W GB9502382 W GB 9502382W WO 9611676 A1 WO9611676 A1 WO 9611676A1
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WO
WIPO (PCT)
Prior art keywords
cox
phenyl
treatment
agents
cyclooxygenase
Prior art date
Application number
PCT/GB1995/002382
Other languages
French (fr)
Inventor
Yves Ducharme
Jacques Yves Gauthier
Petpiboon Prasit
Yves Leblanc
Zhaoyin Wang
Serge Leger
Michel Therien
Raymond George Hill
Dalip Jaicaran Sastri Sirinathsinghji
Original Assignee
Merck Sharp & Dohme Limited
Merck Frosst Canada Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Sharp & Dohme Limited, Merck Frosst Canada Inc. filed Critical Merck Sharp & Dohme Limited
Priority to CA 2202173 priority Critical patent/CA2202173A1/en
Priority to AU36139/95A priority patent/AU715676B2/en
Priority to EP95933509A priority patent/EP0785778A1/en
Priority to JP8512770A priority patent/JPH10507445A/en
Publication of WO1996011676A1 publication Critical patent/WO1996011676A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a method of treating Alzheimers disease and to the use of compounds in the preparation of a medicament for the treatment of Alzheimers disease.
  • US Patent No. 5,192, 753 states inter alia that dementia in human beings may be treated with compounds selected from the non-steroidal anti-inflammatory group of cyclooxygenase inhibitors.
  • the non-steroid anti-inflammatory drugs (NSAIDs) referred to in US Patent No. 5,192,753 are all agents which possess significant ability to inhibit cyclooxygenase type 1 (COX-1).
  • NSAIDs non-steroid anti-inflammatory drugs
  • COX-1 cyclooxygenase type 1
  • COX Cyclooxygenase
  • the present invention provides a method of treating a neurodegenerative disease and in particular Alzheimers disease which comprises administering to a human in need thereof a therapeutically effective amount of a non-steroid COX-II inhibitor. From antoher aspect this invention provides the use of a COX-II inhibitor in the manufacture of a medicament for the treatment of a neurodegenerative disease and in particular Alzheimers disease.
  • treating includes treatment of existing disease and prophylactic treatment of those at risk of developing the disease.
  • COX-II inhibitor means a compound able to inhibit human COX-II enzyme without causing relatively significant inhibition of human COX-I enzyme.
  • compounds which bind at least 10 times as well to COX-I receptors as to COX-II receptors are chosen for use in the invention, more aptly 20 times as well, favourably 50 times as well most favourably at least 100 times as well, and preferably at least 1000 times as well
  • the COX-II inhibitors for use in this invention are most aptly those which are highly brain penetrant so that the maximum concentration of COX-II inhibitor after administration of the anti-neurodegenerative for example the anti-alzheimer effective dose of COX-II inhibitor is at least the binding IC50 value and preferably at least 10 times that value for example at least 100 times the binding IC50 value.
  • the COX-II inhibitor may be of any structural type other than a steroid. However, most aptly the COX-II inhibitor employed in this invention is not a carboxylic acid or a salt thereof. Most favourably it will possess a S0 2 CH 3 , NHS0 2 CH 3 , S0 2 NH 2 , S0 2 NHCH 3 or like substituent on an aromatic ring especially on a phenyl ring. * o -
  • this invention provides a method of treating a neurodegenerative disease and in particular Alzheimers disease which comprises administering to a patient therapeuticaUy effective amount of a compound generically disclosed (and preferably a compound specifically described) in US Patent No 4,375,479; 4,590,205; 4,820,827; 5,344,991; EP 0418845; WO 91/19708; WO 94/15932 or WO 94/13635.
  • the invention also provides the use of such compounds in the manufacture of a medicament for the treatment of neurodegenerative disease and in particular Alzheimers disease.
  • Favourably the COX-II inhibitor employed is one described in
  • WO/94 26751 (published November 24, 1994); WO 94/20480 (published September 15, 1994), US 5,436,265 (issued July 25, 1995), WO 95/00501 (published January 5, 1995); WO 95/18799 (published July 13, 1995) and GB 2283745 (published May 17, 1995) all of which are included herein by cross-reference (ie may be read together with this Specification).
  • COX-II inhibitor employed is one described in WO 95/00501, especially these wherein R 1 is a SO2CH3 group.
  • Preferred compounds for use in this invention are compounds named in WO 95/00501.
  • the medicaments for treating neurodegenerative disease may be formulated as described in the aforementioned referenced documents.
  • the medicament may be employed in the doses and regimens set out in the aforementioned referenced documents with respect to the treatment of diseases which benefit from the administration of a COX-II inhibitor. It is a great advantage of this invention that treatment may be carried out without causing gastric side effects of the type that can occur when COX I inhibitors are used for prolonged periods. Since neurodegenerative diseases such as Alzheimers disease are generally progressive treatment may need to take place for a number of years. Thus the provision of medicaments which are surprisingly effective without any significant tendency to cause gastric side effects at the therapeutic dose is of great use particularly to the elderly.
  • medicaments of this invention for the treatment of patients who are assymptomatic is also envisaged especially in those cases where genetic information suggests that the patient is likely to develop Alzheimers disease or other neurodegenerative disease especially those which may be termed dementia, for example senile demintia or pre-senile dementia.
  • the invention encompasses the use of a novel compound of Formula I useful in the treatment of a neurodegenerative disease such as Alzheimers Disease:
  • X-Y-Z- is selected from the group consisting of:
  • R 1 is selected from the group consisting of (a) S(0) 2 CH 3>
  • P(0)(CH 3 )OH, and (h) P(0)(CH 3 )NH 2 ⁇ R2 is selected from the group consisting of (a) Ci-6alkyl, (b) C 3) C4, C5, C ⁇ , and C7, cycloalkyl,
  • heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one hetero atom which is S, 0, or N, and optionally 1, 2, or 3 additionally N atoms; or the heteroaryl is a monocyclic ring of 6 atoms, said ring having one hetero atom which is N, and optionally 1, 2, 3, or 4 additional N atoms; said substituents are selected from the group consisting of
  • halo including fluoro, chloro, bromo and iodo
  • R3 is selected from the group consisting of (a) hydrogen,
  • R5, R5' ( R6 ( R7 anc ⁇ R8 are each independently selected from the group consisting of
  • Ci-ealkyl or R5 and R ⁇ or R 7 and R& together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms;
  • Q is C02H. C0 2 -C i-4alkyl, tetrazolyl-5-yl, C(R 7 )(R 8 )(OH), or C(R 7 )(R 8 )(0-C i-4alkyl);
  • R 4 and R 4 ' are other than CF 3 .
  • X-Y-Z- is selected from the group consisting of -C(0)-0-CR 5 (R 5 )- when side b is a double bond, and sides a and c are single bonds; and R 1 is selected from the group consisting of
  • R2 is selected from the group consisting of (a) C i-ealkyl,
  • R5, R5' and R ⁇ are each independently selected from the group consisting of
  • Ci- ⁇ alkyl, or R ⁇ and R ⁇ together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms.
  • alkyl is defined to include Hnear, branched, and cyclic structures, with Ci-6alkyl including including methyl, ethyl, propyl, 2-propyl, s- and t-butyl, butyl, pentyl, hexyl, 1, 1- dimethylethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • C i-6alkoxy is intended to include alkoxy groups of from 1 to 6 carbon atoms of a straight, branched, or cyclic configuration.
  • lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like.
  • Ci-6alkylthio is intended to include alkylthio groups of from 1 to 6 carbon atoms of a straight, branched or cyclic configuration.
  • lower alkylthio groups include methylthio, propylthio, isopropylthio, cycloheptylthio, etc.
  • the propylthio group signifies -SCH CH 2 CH .
  • Heteroaryl includes furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, 1,2,3-oxadiazole, 1,2,3- thiadiazole, 1,2,3-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,3,4- triazole, 1,2,5-oxadiazole, 1,2,5-thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,4,5-tetrazine, and the like.
  • Benzoheteroaryl includes the above heteroaryl rings to which it is possible to fuse a benzene ring.
  • Exemplifying the invention are: (a) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2- hydroxy-2-propyl)thiophene, (b) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene, (c) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2- propyl)thiophene,
  • Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
  • the present invention is meant to comprehend such possible diastereomers as well as their racemic and resolved, enantiomericaUy pure forms and pharmaceutically acceptable salts thereof.
  • the invention encompasses pharmaceutical compositions for inhibiting cyclooxygenase and for treating cyclooxygenase mediated diseases as disclosed herein comprising a pharmaceuticaUy acceptable carrier and a non-toxic therapeuticaUy effective amount of compound of formula I as described above.
  • the invention encompasses pharmaceutical compositions for inhibiting cyclooxygenase-2 and for treating cyclooxygenase-2 mediated diseases as disclosed herein comprising a pharmaceutically acceptable carrier and a non-toxic therapeuticaUy effective amount of compound of formula I as described above.
  • the invention encompasses a method of inhibiting cyclooxygenase and treating cyclooxygenase mediated diseases, advantageously treated by an active agent that selectively inhibits COX-2 in preference to COX- 1 as disclosed herein comprising: administration to a patient in need of such treatment of a non-toxic therapeuticaUy effective amount of a compound of Formula I as disclosed herein.
  • a preferred compound is said to selectively inhibit COX-2 in preference to COX- 1 if the ratio of the IC50 concentration for COX-1 inhibition to COX-2 inhibition is 100 or greater.
  • compositions used in the present invention comprise a compound of Formula I as an active ingredient or a pharmaceuticaUy acceptable salt, thereof, and may also contain a pharmaceuticaUy acceptable carrier and optionaUy other therapeutic ingredients.
  • pharmaceuticalaUy acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, Hthium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the Uke. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceuticaUy acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturaUy occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, chohne, N,N_-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorphoHne, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • references to the compounds of Formula I are meant to also include the pharmaceuticaUy acceptable salts.
  • compounds of formula I may be administered orally, topicaUy, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceuticaUy acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceuticaUy elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceuticaUy acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Patent 4,256,108; 4, 166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert sohd dUuent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water or an oU medium, for example peanut oil, liquid paraffin, or oUve oU.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethyl-ceUulose, methylceUulose, hydroxy-propylmethyceUulose, sodium alginate, polyvinyl-pyrroUdone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • dispersing or wetting agents may be a naturally-occ
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n- propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • preservatives for example ethyl, or n- propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n- propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n- propyl, p-hydroxybenzoate
  • flavoring agents such as sucrose, saccharin or aspartame.
  • sweetening agents such as sucrose, saccharin or aspartame.
  • OUy suspensions may be formulated by suspending the active ingredient in a vegetable oU, for example arachis oU, oUve oU, sesame ofl or coconut oU, or in mineral oU such as liquid paraffin.
  • the oUy suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions.
  • the oily phase may be a vegetable oU, for example olive oil or arachis oil, or a mineral oU, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterUe injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenteraUy-accep table diluent or solvent, for example as a solution in 1,3-butane diol.
  • oUs oleic acid
  • oleic acid find use in the preparation of injectables.
  • Compounds of formula I may also be administered in the form of a suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non- irritating excipient which is solid at ordinary temperatures but Uquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non- irritating excipient which is solid at ordinary temperatures but Uquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • topical use creams, ointments, jelfies, solutions or suspensions, etc., containing the compound of Formula I are employed.
  • topical apphcation shaU include mouth washes and gargles.
  • Dosage levels of the order of from about 0.01 mg to about 140 mg kg of body weight per day are useful in the treatment of the above- indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day.
  • inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per l ⁇ logram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form wiU vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Dosage unit forms wiU generaUy contain between from about 1 mg to about 500 mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

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Abstract

The invention describes a method of treating neurodegenerative disorders such as Alzheimer's Disease by using a COX-2 inhibitor.

Description

USE OF INHIBITORS OF CYCLOOXYGENESE IN THE TREATMENT OF NEURODEGENERATIVE DISEASES
The present invention relates to a method of treating Alzheimers disease and to the use of compounds in the preparation of a medicament for the treatment of Alzheimers disease.
US Patent No. 5,192, 753 states inter alia that dementia in human beings may be treated with compounds selected from the non-steroidal anti-inflammatory group of cyclooxygenase inhibitors. The non-steroid anti-inflammatory drugs (NSAIDs) referred to in US Patent No. 5,192,753 are all agents which possess significant ability to inhibit cyclooxygenase type 1 (COX-1). A number of publications have also occurred in the scientific literature which disclose that agents such as acetylacetic acid and indomethecin, which are generally viewed as potent inhibitors of COX-1, can be used in the treatment of Alzheimers disease; see for example:
McGeer et al, Lancet, 1990:335, 1037; Rogers et al, Neurology, 1993:43; 1609-1611; McGeer et al, Neurology, 1992:42, 447-449; and Breitner et al, Neurology, 1994, 227-232.
Cyclooxygenase (COX) exists in the human as cyclooxygenase type I (COX-I) and cyclooxygenase type II (COX-II). Hitherto there has been no suggestion that COX-II plays any role in Alzheimers disease. Indeed there has been no evidence which demonstrates that COX-II plays a part in any human central nervous system disorder. COX-II is inducilible by a number of agents such as mitogen, endotoxin, cytokines and the like but none of these agents which have been demonstrated as inducing COX-II have been shown to be causitive in Alzheimers disease. However, it has now been unexpectedly discovered that COX-II is found in neurones in the temporal lobes of humans suffering from Alzheimers disease. The present invention provides a method of treating a neurodegenerative disease and in particular Alzheimers disease which comprises administering to a human in need thereof a therapeutically effective amount of a non-steroid COX-II inhibitor. From antoher aspect this invention provides the use of a COX-II inhibitor in the manufacture of a medicament for the treatment of a neurodegenerative disease and in particular Alzheimers disease.
When used herein the term "treating" includes treatment of existing disease and prophylactic treatment of those at risk of developing the disease.
When used herein the term "COX-II" inhibitor means a compound able to inhibit human COX-II enzyme without causing relatively significant inhibition of human COX-I enzyme. Generally compounds which bind at least 10 times as well to COX-I receptors as to COX-II receptors (ie will have a IC50 COX-II receptor only one thenth the neumerical value of the COX-I receptor) are chosen for use in the invention, more aptly 20 times as well, favourably 50 times as well most favourably at least 100 times as well, and preferably at least 1000 times as well The COX-II inhibitors for use in this invention are most aptly those which are highly brain penetrant so that the maximum concentration of COX-II inhibitor after administration of the anti-neurodegenerative for example the anti-alzheimer effective dose of COX-II inhibitor is at least the binding IC50 value and preferably at least 10 times that value for example at least 100 times the binding IC50 value.
The COX-II inhibitor may be of any structural type other than a steroid. However, most aptly the COX-II inhibitor employed in this invention is not a carboxylic acid or a salt thereof. Most favourably it will possess a S02CH3, NHS02CH3, S02NH2, S02NHCH3 or like substituent on an aromatic ring especially on a phenyl ring. * o -
Our investigations and statements made in the more recent of the following patents indicate that Cox-II inhibitors may be found in US Patents Nos 4,375,479; 4,590,205; 4,820,827; 5,343,991; EP 0418845; WO 91/19708; WO 94/15932 and WO 94/13635. Each of the above documents is incorporated herein by cross reference.
Thus in one aspect this invention provides a method of treating a neurodegenerative disease and in particular Alzheimers disease which comprises administering to a patient therapeuticaUy effective amount of a compound generically disclosed (and preferably a compound specifically described) in US Patent No 4,375,479; 4,590,205; 4,820,827; 5,344,991; EP 0418845; WO 91/19708; WO 94/15932 or WO 94/13635.
The invention also provides the use of such compounds in the manufacture of a medicament for the treatment of neurodegenerative disease and in particular Alzheimers disease. Favourably the COX-II inhibitor employed is one described in
WO/94 26751 (published November 24, 1994); WO 94/20480 (published September 15, 1994), US 5,436,265 (issued July 25, 1995), WO 95/00501 (published January 5, 1995); WO 95/18799 (published July 13, 1995) and GB 2283745 (published May 17, 1995) all of which are included herein by cross-reference (ie may be read together with this Specification).
Most favourably the COX-II inhibitor employed is one described in WO 95/00501, especially these wherein R1 is a SO2CH3 group.
Preferred compounds for use in this invention are compounds named in WO 95/00501. The medicaments for treating neurodegenerative disease may be formulated as described in the aforementioned referenced documents. The medicament may be employed in the doses and regimens set out in the aforementioned referenced documents with respect to the treatment of diseases which benefit from the administration of a COX-II inhibitor. It is a great advantage of this invention that treatment may be carried out without causing gastric side effects of the type that can occur when COX I inhibitors are used for prolonged periods. Since neurodegenerative diseases such as Alzheimers disease are generally progressive treatment may need to take place for a number of years. Thus the provision of medicaments which are surprisingly effective without any significant tendency to cause gastric side effects at the therapeutic dose is of great use particularly to the elderly. The use of medicaments of this invention for the treatment of patients who are assymptomatic is also envisaged especially in those cases where genetic information suggests that the patient is likely to develop Alzheimers disease or other neurodegenerative disease especially those which may be termed dementia, for example senile demintia or pre-senile dementia.
The invention encompasses the use of a novel compound of Formula I useful in the treatment of a neurodegenerative disease such as Alzheimers Disease:
Figure imgf000006_0001
or pharmaceutically acceptable salts thereof wherein: X-Y-Z-is selected from the group consisting of:
(a) -CH2CH CH -,
(b) -C(0)CH2CH2.,
(c) -CH2CH2C(0)-,
(d) -CR5(R5')-0-C(0)-,
(e) -C(0)-0-CR5(R5').I
(f) -CH2-NR3-CH -,
(g) -CR (R5')-NR3-C(0)-, (h) -CR =CR4'-S-,
(i) -S-CR4=CR4'-, (j) -S-N=CH-, (k) -CH=N-S-, (1) -N=CR -0-, (m) -0-CR4=N- (n) -N=CR4-NH-;
(o) -N=CR -S-, and (p) -S-CR =N-; (q) -C(0)-NR3-CR5(R5')-;
(r) -R3N-CH=CH- provided RUs not -S(0) Me (s) -CH=CH-NR3- provided Rlis not -S(0)2Me
when side b is a double bond, and sides a an c are single bonds; and
X-Y-Z-is selected from the group consisting of: (a) =CH-0-CH=, and
(b) =CH-NR3-CH=,
(c) =N-S-CH=,
(d) =CH-S-N=,
(e) =N-0-CH=, (f) =CH-0-N=,
(g) =N-S-N=,
(h) =N-0-N= when sides a and c are double bonds and side b is a single bond; R1 is selected from the group consisting of (a) S(0)2CH3>
(b) S(0)2NH2,
(c) S(0)2NHC(0)CF3)
(d) S(0)(NH)CH3,
(e) S(0)(NH)NH2) (f) S(0)(NH)NHC(0)CF3l
(g) P(0)(CH3)OH, and (h) P(0)(CH3)NH2ι R2 is selected from the group consisting of (a) Ci-6alkyl, (b) C3) C4, C5, Cβ, and C7, cycloalkyl,
(c) mono-, di- or tri-substituted phenyl or naphthyl wherein the substituent is selected from the group consisting of (1) hydrogen,
(2) halo,
(3) C i-ealkoxy,
(4) C i-ealkylthio, (5) CN,
(6) CF3,
(7) Ci-ealkyl,
(8) N3,
(9) -C02H, (10) -C02-C i-4alkyl,
(11) -C(R5)(R6)-OH,
(12) -C(R5)(R6)-0-Ci-4alkyl, and
(13) -C i-6alkyl-C02-R5;
(d) mono-, di- or tri-substituted heteroaryl wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one hetero atom which is S, 0, or N, and optionally 1, 2, or 3 additionally N atoms; or the heteroaryl is a monocyclic ring of 6 atoms, said ring having one hetero atom which is N, and optionally 1, 2, 3, or 4 additional N atoms; said substituents are selected from the group consisting of
(1) hydrogen,
(2) halo, including fluoro, chloro, bromo and iodo,
(3) C i-ealkyl, (4) Ci-6alkoxy,
(5) Ci-6alkylthio,
(6) CN,
(7) CF3,
(8) N3, (9) -C(R5)(R6)-OH, and
(10) -C(R5)(R6)-0-C i-4alkyl;
(e) benzoheteroaryl which includes the benzo fused analogs of (d);
R3 is selected from the group consisting of (a) hydrogen,
(b) CF3,
(c) CN, (d) Ci-ealkyl,
(e) hydroxyCi-ealkyl, CO -C(0)-Ci-6alkyl,
(g) optionally substituted (1) -Ci-5 alkyl-Q,
(2)-Ci-3alkyl-0-Ci-3alkyl-Q, (3)-Cι.3alkyl-S-Ci-3alkyl-Q, (4)-Ci-5alkyl-0-Q, or (5)-Ci-5 lkyl-S-Q, wherein the substituent resides on the alkyl and the substituent is Ci- 3 alkyl; (h) -Q R4 and R4' are each independently selected from the group consisting of (a) hydrogen, (b) CF3,
(c) CN,
(d) Ci-ealkyl,
(e) -Q,
() -O-Q; (g) -S-Q, and
(h) optionally substituted (D-C1-5 alkyl-Q, (2) -O-C 1-5 alkyl-Q, (3) -S-C 1-5 alkyl-Q, (4)-Ci-3alkyl-0-Ci-3alkyl-Q,
(5) -Ci-3alkyl-S-Ci-3alkyl-Q, (6)-Ci-5alkyl-0-Q, (7)-Ci-5alkyl-S-Q, wherein the substituent resides on the alkyl and the substituent is Ci-3alkyl, and
R5, R5'( R6( R7 anc\ R8 are each independently selected from the group consisting of
(a) hydrogen,
(b) Ci-ealkyl, or R5 and R^ or R7 and R& together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms; Q is C02H. C02-C i-4alkyl, tetrazolyl-5-yl, C(R7)(R8)(OH), or C(R7)(R8)(0-C i-4alkyl);
provided that when X-Y-Z is -S-CR4= CR4', then R4 and R4' are other than CF3 .
One Class within this embodiment are the compounds of formula I
Figure imgf000010_0001
I or pharmacetically acceptable salts thereof wherein: X-Y-Z- is selected from the group consisting of -C(0)-0-CR5(R5 )- when side b is a double bond, and sides a and c are single bonds; and R1 is selected from the group consisting of
(a) S(0)2CH3,
(b) S(0)2NH2,
R2 is selected from the group consisting of (a) C i-ealkyl,
(b) C3, C4, C5, Cβ, and C7, cycloalkyl,
(c) heteroaryl (d) benzoheteroaryl (e) mono- or di-substituted phenyl wherein the substituent is selected from the group consisting of
(1) hydrogen,
(2) halo, (3) C i-6alkoxy, (4) Ci-6alkylthio, (5) CN, (6) CF3> (7) C i-6alkyl, (8) N3, (9) -C02H,
(10) -Cθ2-Ci-4alkyl,
(11) -C(R5)(R6)-OH,
(12) -C(R5)(R6)-0-Ci-4alkyl, and (13) -Ci-6alkyl-C02-R5;
R5, R5' and R^ are each independently selected from the group consisting of
(a) hydrogen,
(b) Ci-βalkyl, or Rδ and R^ together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms.
For purposes of this specification alkyl is defined to include Hnear, branched, and cyclic structures, with Ci-6alkyl including including methyl, ethyl, propyl, 2-propyl, s- and t-butyl, butyl, pentyl, hexyl, 1, 1- dimethylethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Similarly, C i-6alkoxy is intended to include alkoxy groups of from 1 to 6 carbon atoms of a straight, branched, or cyclic configuration. Examples of lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like. Likewise, Ci-6alkylthio is intended to include alkylthio groups of from 1 to 6 carbon atoms of a straight, branched or cyclic configuration. Examples of lower alkylthio groups include methylthio, propylthio, isopropylthio, cycloheptylthio, etc. By way of iUustration, the propylthio group signifies -SCH CH2CH . Heteroaryl includes furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, 1,2,3-oxadiazole, 1,2,3- thiadiazole, 1,2,3-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,3,4- triazole, 1,2,5-oxadiazole, 1,2,5-thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,4,5-tetrazine, and the like.
Benzoheteroaryl includes the above heteroaryl rings to which it is possible to fuse a benzene ring.
Exemplifying the invention are: (a) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2- hydroxy-2-propyl)thiophene, (b) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene, (c) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2- propyl)thiophene,
(d) 3-(4-(Aminosulfonyl)phenyl)-2-cyclohexylthiophene,
(e) 5-(4-Carboxyphenyl)-4-(4-
5 (methylsulfonyl)phenyl)thiophene-2-carboxylic acid,
(f) 4-(4-Fluorophenyl)-2-methyl-5-(4-
(methylsulfonyl)phenyl)thiazole,
(g) 2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2- 10 cyclopenten- 1-one
(h) 4-(4-(Methylsulfonyl)phenyl)-5-(4-fluorophenyl)- isothiazole,
(i) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)- furanone, 15 (j) 3-(4-Fluorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(5af/)- furanone,
(k) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)furan,
(l) 5,5-Dimethyl-3-(4-fluorophenyl)-4-(4- methylsulfonyl)phenyl)-2-(5H)-fnranone, 20 (m) 2-(4-(Aminosulfonyl)phenyl)-3-(4-fluorophenyl)thiophene, and
(n) 3-(4-(Trifluoroacetylaminosulfonyl)phenyl)-2-(4- fluorophenyl)thiophene,
(o) 3-(3-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)- 25 furanone,
(p) 5,5-Dimethyl-3-(3-fluorophenyl)-4-(4- methylsulfonyl)phenyl)-2-(5H)-furanone,
(q) 5,5-Dimethyl-3-(3-chlorophenyl)-4-(4- methylsulfonyl)phenyl)-2-(5H)-furanone, 30 (r) 3-(3,4-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-
(5H)-furanone,
(s) 3-(3,4-Dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-
(5H)-furanone,
(t) 5,5-Dimethyl-3-(3,4-difluorophenyl)-4-(4- 35 methylsulfonyl)phenyl)-2-(5-?-τ)-furanone,
(u) 5,5-Dimethyl-3-(3,4-dichlorophenyl)-4-(4- methylsulfonyl)phenyl)-2-(5H)-furanone, (v) 5,5-Dimethyl-3-(4-chlorophenyl)-4-(4- methylsulfonyl)phenyl)-2-(5H)-furanone, (w) 3-(2-Naphyhyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)- furanone, (x) 5,5-Dimethyl-3-(2-naphyhyl)-4-(4-
(methylsulfonyl)phenyl)-2-(5H)-furanone,
(y) 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone.
Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention is meant to comprehend such possible diastereomers as well as their racemic and resolved, enantiomericaUy pure forms and pharmaceutically acceptable salts thereof.
Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
In a second embodiment, the invention encompasses pharmaceutical compositions for inhibiting cyclooxygenase and for treating cyclooxygenase mediated diseases as disclosed herein comprising a pharmaceuticaUy acceptable carrier and a non-toxic therapeuticaUy effective amount of compound of formula I as described above.
Within this embodiment the invention encompasses pharmaceutical compositions for inhibiting cyclooxygenase-2 and for treating cyclooxygenase-2 mediated diseases as disclosed herein comprising a pharmaceutically acceptable carrier and a non-toxic therapeuticaUy effective amount of compound of formula I as described above.
In a third embodiment, the invention encompasses a method of inhibiting cyclooxygenase and treating cyclooxygenase mediated diseases, advantageously treated by an active agent that selectively inhibits COX-2 in preference to COX- 1 as disclosed herein comprising: administration to a patient in need of such treatment of a non-toxic therapeuticaUy effective amount of a compound of Formula I as disclosed herein. For purposes of this specification a preferred compound is said to selectively inhibit COX-2 in preference to COX- 1 if the ratio of the IC50 concentration for COX-1 inhibition to COX-2 inhibition is 100 or greater.
The pharmaceutical compositions used in the present invention comprise a compound of Formula I as an active ingredient or a pharmaceuticaUy acceptable salt, thereof, and may also contain a pharmaceuticaUy acceptable carrier and optionaUy other therapeutic ingredients. The term "pharmaceuticaUy acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, Hthium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the Uke. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceuticaUy acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturaUy occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, chohne, N,N_-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorphoHne, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
It wUl be understood that in the discussion of methods of treatment which foUows, references to the compounds of Formula I are meant to also include the pharmaceuticaUy acceptable salts.
For the treatment of any of these cyclooxygenase mediated diseases, compounds of formula I may be administered orally, topicaUy, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceuticaUy acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceuticaUy elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceuticaUy acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Patent 4,256,108; 4, 166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert sohd dUuent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water or an oU medium, for example peanut oil, liquid paraffin, or oUve oU. Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethyl-ceUulose, methylceUulose, hydroxy-propylmethyceUulose, sodium alginate, polyvinyl-pyrroUdone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n- propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
OUy suspensions may be formulated by suspending the active ingredient in a vegetable oU, for example arachis oU, oUve oU, sesame ofl or coconut oU, or in mineral oU such as liquid paraffin. The oUy suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions. The oily phase may be a vegetable oU, for example olive oil or arachis oil, or a mineral oU, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterUe injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenteraUy-accep table diluent or solvent, for example as a solution in 1,3-butane diol. .Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oUs are conventionaUy employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Compounds of formula I may also be administered in the form of a suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non- irritating excipient which is solid at ordinary temperatures but Uquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, jelfies, solutions or suspensions, etc., containing the compound of Formula I are employed. (For purposes of this appHcation, topical apphcation shaU include mouth washes and gargles.)
Dosage levels of the order of from about 0.01 mg to about 140 mg kg of body weight per day are useful in the treatment of the above- indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day. For example, inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per lάlogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form wiU vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms wiU generaUy contain between from about 1 mg to about 500 mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
It wiU be understood, however, that the specific dose level for any particular patient wiU depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
EXAMPLE
Using PCR analysis of mRNA extracted from the post-mortem hippocampus of 7 AD patients and 6 age-matched control patients (with no history of neurological or neuropsychiatric diseases, we found COX-II mRNA in 6 AD patients. Four of the control patients showed no COX-II mRNA. In situ hybridization histochemistry also showed COX-II mRNA in the hippocampus of 4 AD patients but not in 5 control patients. Western blot analysis of temporal lobe cortex showed COX-II protein in 3AD patients but not in 3 control patients.
These results show that COX-II is induced in the medial temporal lobe of AD patients, a brain region most severely affected during alzheimers disease process. The results indicate that the inflammatory condition associated with AD involve COX-II in its aetiology and show that treating AD patients with brain penetrant selective COX-II inhibitors wiU be effective.

Claims

1. The use of a non-steroid COX-II inhibitor in the manufacture of a medicament for the treatment of a neurodegenerative disease.
2. The use as claimed in Claim 1 wherein the neurodegenerative disease is Alzheimer's Disease.
3. The use as claimed in Claim 1 or 2 wherein the medicament is adapted for oral administration.
4. The use as claimed in any of Claims 1 to 3 wherein the medicament is in the form of a tablet.
5. The use as claimed in any of Claims 1 to 3 wherein the COX-II inhibitor wiU bind at least 20 times as weU to COX-II as to COX-I. The use as claimed in any of Claims 1 to 3 wherein the COX-II inhibitor wiU bind at least 100 times as weU to COX-II as to COX-I.
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