CA2202173A1 - Use of inhibitors of cyclooxygenase in the treatment of neurodegenerative diseases - Google Patents

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
TREAT~NT OF NEURODEGENERATIVE DISEASES

s The present invention relates to a method of treating ~l7.~imers 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-;nfl~mmatory group of cyclooxygenase inhibitors. The non-steroid anti-infl~mm~tory drugs (NSAIDs) referred to in US Patent No. 5,192,753 are all agents which possess signific~nt ability to inhibit cyclooxygenase type l (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; 1~09-1~11;
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 L91zheimers disease. Indeed 2s 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 sllffer-ng from Alzheimers disease.

The present invention provides a method of treating a neurodegenerative disease and in particular Alzheimers disease which comprises a~mini.~tering to a human in need thereof a therapeutically effective amount of a non-steroid COX-II inhibitor.
s 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 .signific~nt inhibition of human COX-I enzyme. Generally compounds which bind at least l0 times as well to COX-I receptors as to COX-II
receptors (ie will have a ICso 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 l000 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 atlmini~tration of the anti-neurodegenerative for example the anti-alzheimer effective do ;e of COX-II inhibitor is at least the binding ICso value and preferably at least 10 times that value for 2s example at least l00 times the binding ICso 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 thereo Most favourably it wili possess a S02CH3, NHS02CH3, S02NH2, S02NHCH3 or like substituent on an aromatic ring especially on a phenyl ring.

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 94/13~35. 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 a~mini~tering to a patient therapeutically effective amount of a compound generically disclosed (and preferably a compound specifically 0 described) in US Patent No 4,375,479; 4,590,205; 4,820,827; 5,344,991; EP
0418845; WO 91/19708; WO 94115932 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 descIibed in WO/94 26751 (published November 24, 1994); WO 94/20480 (published September 15, 1994), US 5,43~,2~5 (issued July 25, 1995), WO 95/00501 (published January 5, 1995); WO 9~/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 Rl is a SO7CH3 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 ~le.scrihed 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 a~1mini~tration 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 peliods. Since neurodegenerative diseases such as Alzheimers disease are generaliy progressive treatment may need to take place for a number of years. Thus the provision of medicaments which are surp~isingly effective without any nifir~nt tendency to cause gastlic side effects at the therapeutic dose is of great use particularly to the elderly. The use of merlicaments 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:

_y or pharmaceutically acceptable salts thereof wherein:
~-Y-Z-is selected from the group consisting of:
(a) -CH2CH~CH2-, (b) -C(O)CH2CH2-, (c) -CH2CH2C(O)-, (d) -CR5(R~ )-O-C(O)-, t (e) -C(o)-o-CR5(R5 )-, -CH2-NR3-CH2-, (g) -CR5(R5 )-NR3-C(o)-, (h) -CR4=CR4 -S-, (i)-S-CR4=CR4-, CA 02202l73 l997-04-08 (j) -S-N=C~I-, (k) -CH=N-S-, O-N=cR4-o-~
(m) -O-CR4=N-(n)-N=CR4-NH-;
(o)-N=CR4-S-, and (p) -S-CR4=N-;
(q)-C(O)-NR3 CR5(R6~)-;
(r) -R3N-CH=CH- provided R1is not -S(0)2Me o (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-Zis selected from the group consisting of:
(a) =CH-O-CH=, and (b) =CH-NR3-CH=, (c) =N-S-CH=, (d) =CH-S-N=, (e) =N-O-CH=, (f) =CH-O-N=, (g) =N-S-N=, (h) =N-O-N=, when sides a and c are double bonds and side b is a single bond;
Rl is selected from the group consisting of (a) S(0)2CH3, (b) S(0)2NH2, (c) S(0)2NHC(O)CF3, (d) S(O)(NH)CH3, (e) S(O)(NH)NH2, (~) S(O)(NH)NHC(O)CF3, (g) P(O)(CH3)0H, and (h) P(O)(CH3)NH2, R2 is selected from the group consisting of (a) C1 ~alkyl, (b) C3, C4, Cs, C~, 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) C1 Galkoxy, (4) C1 6alkylthio, (5) CN, (G) CF3, (7) C1 Galkyl, (8) N3, (9) -C02H, (10) -C02-C1 4alkyl, (1 1) -C(R5)(RG)-oH, (12) -C(R5)(RG)-O-Cl 4alkyl, and (13) -C1 6alkyl-CO2-R5;
(d) mono-, di- or tri-substituted heteroaryl wherein the 1S heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one hetero atom which is S, O, 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, includilig fluoro, chloro, bromo and iodo, (3) C1 Galkyl, 2~ (4) Cl Galkoxy, (5) Cl ~alkylthio, (G) CN, (7) CF3, (8) N3, (9) -C(R5)(R~)-oH, and (10) -C(R5)(RG)-o-C1 4alkyl;
(e) benzoheteroaryl which includes the benzo fused analogs of (d);
R3 is selected fiom the group consisting of 3~ (a) hydrogen, (b) CF3, (c) CN, (d) Cl ~alkyl, (e) hydroxyC1 ~alkyl, (f) -C(O)-Cl ~alkyl, (g) optionally substituted (1) -C 1 5 alkyl-Q, (2)-C1 3alkyl-O-C1 3alkyl-Q, (3) -C 1 3alkyl-S-C 3 3alkyl-Q, (4) -C1 5 alkyl-O-Q, or (5) -C1 5 alkyl-S-Q, o wherein the substituent resides on the alkyl and the substituent is C 1 3alkyl;
(h) -Q
R4 and R4 are each independently selected from the group consisting of (a) hydrogen, (b) CF3, (c) CN, (d) C1 Galkyl, (e) -Q, (f) -O-Q;
(g) -S-Q, and (h) optionallysubstituted (1) -Cl 5 alkyl-Q, (2) -O-C1 5 alkyl-Q, (3) -S-C1-5 alkyl-Q, 2s (4)-C1 3alkyl-O-C1 3alkyl-Q, (5)-C1 3alkyl-S-C1 3alkyl-Q, (~) -Cl 5 alkyl-O-Q, (7) -C1 5 alkyl-S-Q, wherein the substituent resides on the alkyl and the substituent is C 1 3alkyl, and R5, R~, RG, R7 and R8 are each independently selected from the group consisting of (a) hydrogen, (b) Cl ~alkyl, 3s or R5 and RG or R7 and R8 together with the carbon to which they are attached form a saturated monocyclic carbon ~ing of 3, 4, 5, G or 7 atoms;

Q is C02H, C02-Cl 4alkyl, tetrazolyl-6-yl, C(R7)(R8)(oH), or COE~7)(R8)(o-cl 4alkyV;

s 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

_y o or pharmacetically acceptable salts thereof wherein:
X-Y-Z- is selected from the gl`OUp consisting of -C(o)-o-CR5(R5 )- when side b is a double bond, and sides a and c are single bonds; and R1 is selected from the gl`OUp consisting of (a) S(0)2CH3, (b~ S(0)2NH2, R2 is selected fi~om the gl`OUp consisting of (a) Cl ~alkyl, (b) C3, C4, Cs, C6, and C7, cycloalkyl, (c) heteroaryl (d) benzoheteroaryl (e) mono- or di-substituted phenyl wherein the substituent is selected from the gl`OUp consisting of ( 1) hydrogen~
(2) halo, (3) C1 ~alko~y, (4) C 1-6alkYlthio, (5) CN, (G) CF3, (7) Cl ~alkyl, (8) N3, (9) -C02H, (10) -C02-C1 4alkyl, (1 1) -C(R5)(R~)-oH, (12) -C(R5)(R~)-O-Cl 4alkyl, and (13) -C1 ~alkyl-CO2-R5;
R5, R5 and RG are each independently selected from the group consisting of (a) hydrogen, (b) C1 ~alkyl, 0 or R5 and R~ together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 6, ~ or 7 atoms.

For purposes of this specification alkyl is defined to include linear, branched, and cyclic structures, with C 1 ~alkyl including including methyl, ethyl, propyl, 2-propyl, s- and t-butyl, butyl, pentyl, hexyl, 1,1-dimethylethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
~C;imil~rly, Cl ~alkoxy iS intended to include alkoxy groups offrom 1 to G
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, Cl ~alkylthio is intended to include alkylthio gl~OUpS of fiom 1 to ~ carbon atoms of a straight, branched or cyclic configuration. Examples of lower alkylthio groups include methylthio, propylthio, isopropylthio, cycloheptylthio, etc.
2s By way of illustration, the propylthio group signifies -SCH2CH2CH3.
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, pylidazine, pyrimidine, pyrazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,4,5-tetrazine, and the like.
Benzoheteroaryl includes the above heteroalyl 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-(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-o cyclopenten- 1-one ~h) 4-(4-~ethylsulfonyl)phenyl)-5-(4-fluorophenyl)-isothiazole, (i) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5~)-furanone, (~) 3-(4-Fluorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(5H)-furanone, (k) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)furan, (1) 5,5-Dimethyl-3-(4-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-2 -(5H)-furanone, (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-(SH)-furanone, (p) 5,5-Dimethyl-3-~3-fluorophenyl)-4-(4-methylsulfonyl)phenyl) -2 -(5H) -furanone, (Cl) S,5-Dimethyl-3-(3-chlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone, (r) 3-(3,4-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone, (s) 3-(3,4-Dichlorophenyl)-4-(4-(methylsulfollyl)phenyl)-2-(S~l)-furanone, (t) 5,5-Dimethyl-3-(3,4-difluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone, (u) 5,5-Dimethyl-3-(3,4-dichlorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone, W 09~11676 - ll- PCT/GB95/02382 (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 descIibed herein contain one or more o 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, enantiomerically pure forms and pharmaceutically acceptable salts thereof.
Some of the compounds described herein contain olefinic 15 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 20 a pharmaceutically acceptable carrier and a non-toxic therapeutically 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 25 comprising a pharmaceutically acceptable carriel and a non-toxic therapeutically 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 30 diseases, advantageously treated by an active agent that selectively inhibits COX-2 in preference to COX-l as disclosed herein comprising:
ar~mini.~tration to a patient in need of such treatment of a non-toxic therapeutically effective amount of a compound of Formula I as disclosed herein.
3~ 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 GOX- l inhibitioll to COX-2 inhibition is l00 or greater.
The pharmaceutical compositions used in the present invention comprise a compound of Formula I as an active ingredient or a 5 pharmaceutically acceptable salt, thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "ph~rm~ceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases 0 include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, 5 and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N_-dibenzylethylene~ mine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanol~mine, ethylene~ mine, N-ethylmorpholine, N-ethylpiperidine, 20 glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
It will be understood that in the discussion of methods of 25 treatment which follows, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
For the treatment of any of these cyclooxygenase mediated diseases, compounds of formula I may be a(1mini~teled orally, topically, parenterally, by inhalation spray or rectally in dosage Ullit formulations 30 containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parentelal as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
The pharmaceutical compositions containing the active 35 ingredient may be in a form suitable or 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, S cnloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, o sodium carbonate, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example, corn starch, or ~l~inic 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 desclibed in the U.S.
Patent 4,25~,108; 4,1G6,452; and 4,2~5,874 to form osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingledient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingledients is mixed with water 2s or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
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-cellulose, methylcellulose, hydroxy-propylmethycellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;
dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, o~; condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation J products of ethylene oxide with long chain aliphatic alcohols, for example 3s heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived fiom 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 susp~n.~ion~
may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more s ilavoring agents, and one or more sweetening agents, such as sucrose, s:~cr.ha~n or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily 10 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 20 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-watel emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for 2s 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 condensatioll products of the said partial esters with ethylene oxide, for example polyoxyethylene 30 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 35 and coloring agents. The pharmaceutical compositions may be in the form of a ste~ile injectable aqueous or oleagenous suspensioll. This suspension may be formulated according to the known art using those suitable W 096111676 - 15 - PCT/GB9~102382 dispersing or wetting agents and suspendillg agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvellt, for example as a solution in 1,3-butane diol. Among 5 the acceptable vehi-l~c and sol~ents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. Ill addition, fatty acids such as oleic acid lO find use in the preparation of injectables.
Compounds of formula I may also be administered in the form of a suppositories for rectal ad-nini~tration 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 liquid at 5 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, jellies, solutions or suspensions, etc., containing the compound of Formula I are employed.
(For purposes of this application, topical application shall include mouth washes and gargles.) Dosage levels of the order of fiom 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 ~ g per patient 25 per day. For example, infl~mmation may be effectively treated by the ac~mini.stration of fiom about 0.01 to 50 mg of the compound per kilogram 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 3n the carrier matelials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation illtended for the oral arlmini~tration of humans may contain fiom 0.5 mg to 5 g of active agent compounded with an appropIiate and convenient amount of carrier material which may vary 35 from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of W 096111676 - lG- PCT/GB95102382 an active ingredient, typically 25 mg, 50 mg, l00 mg, 200 mg, 300 mg, 400 mg, 500 mg, ~00 mg, 800 mg, or l000 mg.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of a~lmini.stration, route of a~mini.stration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

EXAMPLE
Using PCR analysis of mRNA extracted fiom the post-mortem hippocampus of 7 AD patients and ~ age-matched control patients (with no history of neurological or neuropsychiatric diseases, we found COX-II
mRNA in ~ 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 20 lobe of AD patients, a brain region most severely affected during alzheimers disease process. The results indicate that the infl~mmatory condition associated with AD involve COX-II in its aetiology and show that treating AD patients with brain penetrallt selective COX-II inhibitors will be effective.
2~

Claims (5)

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 will bind at least 20 times as well to COX-II as to COX-I.
The use as claimed in any of Claims 1 to 3 wherein the COX-II inhibitor will bind at least 100 times as well to COX-II as to COX-I.