Note: Descriptions are shown in the official language in which they were submitted.
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W 096/11676 1 PCT/GB95/02382
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.
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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.
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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
.
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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:
R2
_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-,
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(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
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(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,
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(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;
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W 096/11676 8 PCT/GB95/02382
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,
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W O 96/11676 9 PCT/GB95/02382
(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,
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(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,
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(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
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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.
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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
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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
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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
CA 02202173 1997-04-08
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~
