Note: Descriptions are shown in the official language in which they were submitted.
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USE OF A COX-2 INHIBITOR AND A NK-1 RECEPTOR
ANTAGONIST FOR TREATING INFLAM1VIATION
The present invention involves a drug combination comprising an
inhibitor of cyclooxygenase-2 in combination with a neurokinin-1 (NK-1)
receptor antagonist.
Inhibitors of cyclooxygenase-2 are a sub-class of the class of drugs
known as non-steroidal antiinflammatory drugs (NSAIDs). The NSAIDs
are active in reducing the prostaglandin-induced pain and swelling
associated with the inflammation process but are also active in affecting
other prostaglandin-regulated processes such as maintenance of the
gastric lining. Thus, use of high doses of most common NSAIDs can
produce severe side effects, including life threatenting ulcers, that limit
their therapeutic potential. An alternative to NSAIDs is the use of
corticosteroids, which have even more serious side effects, especially when
long term therapy is involved.
Previous NSAIDs have been found to prevent the production of
prostaglandin by inhibiting enzymes in the human arachidonic
acid/prostaglandin pathway including the enzyme cyclooxygenase (COX).
There are two isoforms of the COX enzyme, the first, COX-1, is
constitutiv~ely expressed and is involved with physiological functions and
the second, COX-2, is induced locally in inflamed tissue. While
conventional NSAIDs block both forms of the enzyme, the inducible COX-2
enzyme associated inflammation has provided a more focussed drug target
which should enable effective antiinflammatory analgesia with reduced
gastrointestinal side effects. Many compounds which have activity as
COX-2 inhibitors have been identified, and clinical trials are reported to
be in progress.
Neurokinin 1 (NK-1; substance P) receptor antagonists are being
developed for the treatment of a number of physiological disorders
associated with an excess or imbalance of tachykinins, and in particular
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-2-
substance P. Substance P has been implicated in the pathology of a
number of inflammatory conditions (see, for instance, International (PCT)
patent specification Nos. WO 95/16679, WO 95/18124 and WO 95/23798).
Improved therapies for treating and preventing inflammatory
disorders are currently being sought for the large number of individuals
who are at risk from these disorders. The present invention addresses this
problem by providing a combination therapy comprised of a COX-2
inhibitor with a NK-1 receptor antagonist. When administered as part of
a combination therapy, the COX-2 inhibitor together with the NK-1
receptor antagonist provide enhanced treatment options as compared with
administration of either the COX-2 inhibitor or the NK-1 receptor
antagonist alone.
The present invention provides a novel drug combination comprised
of a COX-2 inhibitor in combination with a NK-1 receptor antagonist,
which is useful for treating, preventing, reducing the progression, and/or
reducing the risk of developing inflammatory disorders.
The present invention accordingly provides the use of a COX-2
inhibitor in combination with a NK-1 receptor antagonist for the
manufacture of a medicament for the treatment or prevention of
inflammatory disorders.
The present invention also provides a method for the treatment or
prevention of inflammatory disorders, which method comprises
administration to a patient in need of such treatment an amount of a
COX-2 inhibitor and an amount of a NK-1 receptor antagonist, such that
together they give effective relief.
In a further aspect of the present invention, there is provided a
pharmaceutical composition for the treatment or prevention of
inflammatory disorders comprising a COX-2 inhibitor and a NK-1 receptor
antagonist, together with at least one pharmaceutically acceptable carrier
or excipient.
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It will be appreciated that the COX-2 inhibitor and the NK-1
receptor antagonist, may be present as a combined preparation for
simultaneous, separate or sequential use for the treatment or prevention
of inflammatory disorders. Such combined preparations may be, for
example, in the form of a twin pack.
In a further or alternative aspect of the present invention, there is
therefore provided a product comprising a COX-2 inhibitor and a NK-1
receptor antagonist as a combined preparation for simultaneous, separate
or sequential use in the treatment or prevention of inflammatory
disorders.
It will be appreciated that when using a combination of the present
invention, both the COX-2 inhibitor' and the NK-1 receptor antagonist will
be administered to a patient, within a reasonable period of time. The
compounds may be in the same pharmaceutically acceptable carrier and
therefore administered simultaneously. They may be in separate
pharmaceutical carriers such as conventional oral dosage forms which are
taken simultaneously. The term ''combination" also refers to the case
where the compounds are provided in separate dosage forms and are
administered sequentially. Therefore, by way of example, the COX-2
inhibitor may be administered as a tablet and then, within a reasonable
period of time, the NK-1 receptor antagonist may be administered either
as an oral dosage form such as a tablet or a fast-dissolving oral dosage
form. By a "fast dissolving oral formulation" is meant, an oral delivery
form which when placed on the tongue of a patient, dissolves within about
10 seconds.
By "reasonable period of time" is meant a time period that is not in
excess of about 1 hour. That is, for example, if the COX-2 inhibitor is
provided as a tablet, then within one hour, the NK-1 receptor antagonist
should be administered, either in the same type of dosage form, or another
dosage form which provides effective delivery of the medicament.
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It will be appreciated that the combination of the present invention
will be particularly useful in the treatment of a COX-2 mediated disease or
disorder. COX-2 mediated diseases and disorders includes inflammatory
diseases susceptible to treatment with a non-steroidal anti-inflammatory
agent. Such "inflammatory disorders" include rheumatoid arthritis,
degenerative joint diseases (osteoarthritis), bursitis, tendinitis, ankylosing
spondylitis, gout and synovitis.
The terms "inhibitor of cyclooxygenase-2", "cyclooxygenase-2
inhibitor" and "COX-2 inhibitor" as used herein embrace compounds which
selectively inhibit cyclooxygenase-2 over cyclooxygenase-1. Employing the
human whole blood COX-1 assay and the human whole blood COX-2 assay
described in C. Brideau et al, InfZamm. Res. 45: 68-74 (1996), herein
incorporated by reference, preferably, the compounds have a
cyclooxygenase-2 ICso of less than about 2 ~M in the human whole blood
COX-2 assay, yet have a cyclooxygenase-1 ICso of greater than about 5 ~tM
in the human whole blood COX-1 assay. Aiso preferably, the compounds
have a selectivity ratio of cyclooxygenase-2 inhibition over
cyclooxygenase-1 inhibition of at least 10, and more preferably of at least
40. The resulting selectivity may indicate an ability to reduce the
incidence of common NSAID-induced side effects.
As explained in J. Talley, Exp. Opin. Ther. Patents (1997), 7(1), pp.
55-62, three distinct structural classes of selective COX-2 inhibitor
compounds have been identified. One class is the methane sulfonanilide
class of inhibitors, of which NS-398, flosulide, nimesulide and L-745,337
are example members.
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NHS02CH3 NHS02CH3 NHS02CH3
O~ I ~ O I ~ I ~ X
F ~ F
N02 N02
O
NS-398 Nimesulide L-745,337, X = S
Flosufide, X = O
A second class is the tricyclic inhibitor class, which can be further
divided into the sub-classes of tricyclic inhibitors with a central
carbocyclic
ring (examples include SC-57666, 1, and 2); those with a central
monocyclic heterocyclic ring (examples include DuP fi97, SC-58125,
SC-58635, and 3, 4 and 5); and those with a central bicyclic heterocyclic
ring (examples include 6, 7, 8, 9 and 10). Compounds 3, 4 and 5 are
described in U.S. Patent No. 5,474,995.
CH3S0 "'-izSO; ~'-',SO;
SC-57666 1 2
CH3S0; CH3S02
I / N
CF3
Br
I
F /
DuP 697 SC-58125
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NH2S02 CH3S02
/ N'N CFs
O
i
HaC /
SC-58635 3
C
CFi3
O J
4 5
CH 3S0 2 CH 3S0 2
F
O
N%-/ S~ N
N~ N' J
N
6
NH 2S0 2
CH 3S0 2
~~N_N
-CF3
1
S
CH 30 ~ t
F 9
NH 2S0 2
~~N_N
\\-CF3
'J
CH 30~
10
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_7_
The third identified class can be referred to as those which are
structurally modified NSAIDS, and includes L-761,066 and structure 11 as
example members.
C02H
CH 30 ~ ~ ''''
N
Br ~ CH CI
L-761,066 O 11
In addition to the structural classes, sub-classes, specific COX-2
inhibitor compound examples, and reference journal and patent
publications described in the Talley publication which are all herein
incorporated by reference, examples of compounds which selectively
inhibit cyclooxygenase-2 have also been described in the following patent
publications, all of which are herein incorporated by reference: U.S.
Patent No.'s 5,344,991, 5,380,738, 5,393,790, 5,409,944, 5,434,178,
5,436,265, 5,466,823, 5,474,995, 5,510,368, 5,536,752, 5,550,142,
5,552,422, 5,604,253, 5,604,260, 5,639,780; and International Patent
Specification Nos. 94/13635, 94/15932, 94/20480, 94/26731, 94/27980,
95/00501, 95/15316, 96/03387, 96/03388, 96/06840; and International
Publication No.'s WO 94/20480, WO 96/21667, WO 96/31509, WO
96/36623, WO 97/14691, WO 97/16435.
Additional COX-2 inhibitor compounds which are included in the scope of
this invention include:
O,S O,S~
\i ,,
O
CI~, ,
O
O ~\
o J\
12 13
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WO 99/59635 PCTlGB99101632
_g_
O, / O,
/S~, S~,
O O
F
O ~~ O
14 F 15
~,S/ ~ S'/
O
.. ~ ~J
0
0
F
O ,,N
16 17 S
Q. /
S,
~O
J w
U
o ,
o'~ o
O ~ -o
18 O 19
S S,
~O
Na+ O
O
Cl O
20 21
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_g_
O, , O,
-- ~S O 0
O O
OH ~ OH
22 23
O, / O ~
S.
O SO
F
24 25
/ NH.,
S
W \\O
w
O
N
26
Some of the compounds above can also be identified by the following
chemical names:
3: 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone;
4: 3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone;
5: 5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-3-(3-fluorophenyl)-5H-furan-
2-one;
12: 5,5-dimethyl-4-(4-( methylsulfonyl )phenyl )-3-(2-propoxy)-5H-furan-2-
one;
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13: 5-chloro-3-(4-(methylsulfonyl)phenyl)-2-(2-methyl-5-pyridinyl)pyridine;
14: 2-(3,5-difluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-
one;
15: 5(S)-5-ethyl-5-methyl-4-(4-(methylsulfonyl)phenyl)-3-(2-propoxy)-5H-
furan-2-one;
16: 5-ethyl-5-methyl-4-(4-(methylsulfonyl)phenyl)-3-(3,4-difluorophenyl)-
5H-furan-2-one;
17: 3-((2-thiazolyl)methoxy)-4-(4-(methylsulfonyl)phenyl)-5,5-dimethyl-5H-
furan-2-one;
18: 3-propyloxy-4-(4-(methylsulfonyl )phenyl )-5,5-dimethyl-5H-furan-2-one;
19: 3-( 1-cyclopropylethoxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl)-5H-
furan-2-one;
20: sodium 2-(4-chlorophenyl)-3-(4-(methylsulfonyl)phenyl)-4-oxo-2-
pentenoate;
21:3-(cyclopropylmethoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-
furan-2-one;
22: 3-(cyclopropylmethoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-2,5-
dihydrofuran-2-ol;
23: 3-isopropoxy-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-2,5-
dihydrofuran-2-ol;
24: 5,5-dimethyl-3-(3-fluorophenyl)-2-hydroxy-4-(4-
(methylsulfonyl)phenyl)-2,5-dihydrofuran;
25: 5-chloro-3-(4-(methylsulfonyl)phenyl)-2-(3-pyridinyl)pyridine;
26: 4-(5-methyl-3-phenyl-4-isoxazolyl)benzenesulfonamide.
The following publications describe and/or provide methods for
making the compounds as indicated: compounds 12, 15, 17, 18, 19 and 21,
WO 97/14691; compounds 22, 23 and 24, WO 97/16435; compound 20, WO
96/36623; compound 14, U.S. Patent No. 5,536,?52; compound 16, U.S.
Patent No. 5,474,995. See Examples herein for compounds 13 and 25;
compound 26, U.S. Patent No. 5,633,272.
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Also incorporated herein by reference are those compounds
described in WO 96/41645 as having structural Formula I, shown below,
and the definition and preferred definitions and species described therein:
O 1
Rz~ // ~ R A
~ S ~ / A R3
O
Particularly preferred compounds of formula (I) include:
5-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-3-
(trifluoromethyl)pyrazole;
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-1-phenyl-3-
(trifluoromethyl)pyrazole;
4-(5-(4-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazol-1-
yl)benzenesulfonamide;
4-(3,5-bis(4-methylphenyl)-1H-pyrazol-1-yl)benzenesulfonamide;
4-(5-(4-chlorophenyl)-3-phenyl-1H-pyrazol-1-yl)benzenesulfonamide;
4-(3,5-bis(4-methoxyphenyl)-1H-pyrazol-1-yl)benzenesulfonamide;
4-(5-(4-chlorophenyl)-3-(4-methylphenyl)-1H-pyrazol-1-
yl)benzenesulfonamide;
4-(5-(4-chlorophenyl)-3-(4-nitrophenyl)-1H-pyrazol-1-
yl)benzenesulfonamide;
4-(5-(4-chlorophenyl)-3-(5-chloro-2-thienyl)-1H-pyrazol-1-
yl)benzenesulfonamide;
4-(4-chloro-3,5-diphenyl-1H-pyrazol-1-yl)benzenesulfonamide;
4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-I-
yl)benzenesulfonamide;
4-(5-phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide;
4-(5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
yl)benzenesulfonamide;
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4-(5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
yI)benzenesulfonamide;
4-(5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-
yl)benzenesulfonamide;
4-(5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
yl)benzenesulfonamide;
4-(4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
yl)benzenesulfonamide;
4-(3-(difluoromethyl)-5-(4-methylphenyl)-1H-pyrazol-1-
yl)benzenesulfonamide;
4-(3-(difluoromethyl)-5-phenyl-1H-pyrazol-1-yl)benzenesulfonamide;
4-(3-(difluoromethyl)-5-(4-methoxyphenyl)-1H-pyrazol-1-
yl)benzenesulfonamide;
4-(3-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-yl)benzenesulfonamide;
4-(3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-
yl)benzenesulfonamide;
4-( 5-( 3-fluoro-4-methoxyphenyl )-3-(trifl uoromethyl )-1H-pyrazol-1-
yl)benzenesulfonamide;
4-(4-chloro-5-phenyl-1H-pyrazol-1-yl)benzenesulfonamide;
4-(5-(4-chlorophenyl)-3-(hydroxyphenyl)-1H-pyrazol-1-
yl)benzenesulfonamide;
4-(5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
yl)benzenesulfonamide;
5-(4-fluorophenyl)-6-(4-(methylsulfonyl)phenyl)spiro(2.4]hept-5-ene;
4-(6-(4-fluorophenyl)spiro[2.4]hept-5-en-5-yl)benzenesulfonamide;
6-(4-fluorophenyl)-7-(4-(methylsulfonyl )phenyl)spiro [3.4] oct-fi-ene;
5-(3-chloro-4-methoxyphenyl)-6-(4-(methylsulfonyl)phenyl)spiro [2.4] hept-
5-ene;
4-(6-(3-chloro-4-methoxyphenyl )spiro [2.4] hept-5-en-5-
yl)benzenesulfonamide;
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5-(3,5-dichloro-4-methoxyphenyl )-6-(4-
(methylsulfonyl)phenyl)spiro [2.4] hept-5-ene;
5-(3-chloro-4-fluorophenyl )-6-(4-(methylsulfonyl )phenyl )spiro [2.4] hept-5-
ene;
4-(6-(3,4-dichlorophenyl)spiro[2.4]kept-5-en-5-yl)benzenesulfonamide;
2-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-(4-
methylsulfonylphenyl)thiazole;
2-(2-chlorophenyl)-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)thiazole;
5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-methylthiazole;
4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-trifluoromethylthiazole;
4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(2-thienyl)thiazole;
4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-benzylaminothiazole;
4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-( 1-propylamino)thiazole;
2-((3,5-dichlorophenoxy)methyl )-4-(4-fluorophenyl )-5-(4-
(methylsulfonyl)phenyl)thiazole;
5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethylthiazole;
1-methylsulfonyl-4-( 1,1-dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien-3-
yl)benzene;
4-(4-(4-fluorophenyl)-l,l-dimethylcyclopenta-2,4-dien-3-
yl)benzenesulfonamide;
5-(4-fluorophenyl )-6-(4-(methylsulfonyl)phenyl)spiro [2.4] hepta-4,6-dime;
4-(6-(4-fluorophenyl)spiro[2.4] hepta-4,6-dien-5-yl)benzenesulfonamide;
6-(4-fluorophenyl)-2-methoxy-5-(4-(methylsulfonyl)phenyl)-pyridine-3-
carbonitrile;
2-bromo-6-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)-pyridine-3-
carbonitrile;
6-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)-2-phenyl-pyridine-3-
carbonitrile;
4-(2-(4-methylpyridin-2-yl )-4-(trifluoromethyl )-1H-imidazol-1-
yl)benzenesulfonamide;
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4-(2-(5-methylpyridin-3-yl)-4-(trifl uoromethyl )-1H-imidazol-1-
yl)benzenesulfonamide;
4-(2-(2-methylpyridin-3-yl)-4-(trifluoromethyl )-1H-imidazol-1-
yl)benzenesulfonamide;
3-(1-(4-(methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-2-
yl)benzenesulfonamide;
2-(1-(4-(methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-2-
yl)pyridine;
2-methyl-4-( 1-(4-(methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-
2-yl)pyridine;
2-methyl-6-( 1-(4-(methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-
2-yl )pyridine;
4-(2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-
yl)benzenesulfonamide;
2-(3,4-difluorophenyl)-1-(4-(methylsuifonyl)phenyl)-4-(trifluoromethyl)-1H-
imidazole;
4-(2-(4-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-
yl)benzenesulfonamide;
2-(4-chlorophenyl )-1-(4-(methylsulfonyl)phenyl)-4-methyl-1H-imidazole;
2-(4-chlorophenyl)-1-(4-(methylsulfonyl)phenyl)-4-phenyl-1H-imidazole;
2-(4-chlorophenyl)-4-(4-fluorophenyl)-1-(4-(methylsulfonyl)phenyl)-1H-
imidazole;
2-(3-fluoro-4-methoxyphenyl)-1-(4-(methylsulfonyl)phenyl)-4-
(trifluoromethyl)-1H-imidazole;
1-{4-(methylsulfonyl)phenyl)-2-phenyl-4-trifluoromethyl-1H-imidazole;
2-(4-methylphenyl)-1-(4-(methylsulfonyl)phenyl)-4-trifluoromethyl-1H-
imidazole;
4-(2-(3-chloro-4-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-
yl)benzenesulfonamide;
2-(3-fluoro-5-methylphenyl)-1-(4-(methylsulfonyl)phenyl)-4-
(trifluoromethyl)-1H-imidazole;
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4-(2-(3-fluoro-5-methyiphenyl)-4-(trifluoromethyl)-1H-imidazol-1-
yl)benzenesulfonamide;
2-(3-methylphenyl)-1-(4-(methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-
imidazole;
4-(2-(3-methylphenyl)-4-(trifluoromethyi)-1H-imidazol-1-
yl)benzenesulfonamide;
1-(4-(methylsulfonyl)phenyl)-2-(3-chlorophenyl )-4-(trifluoromethyl )-1H-
imidazole;
4-(2-(3-chlorophenyl)-4-(trifluoromethyl)-1H-imidazol-1-
yl)benzenesulfonamide;
4-(2-phenyl-4-(trifluoromethyl)-1H-imidazol-1-yl)benzenesulfonamide;
4-(2-(4-methoxy-3-chlorophenyl)-4-(trifluoromethyl)-1H-imidazol-1-
yl)benzenesulfonamide;
1-allyl-4-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-5-(trifluoromethyl)-
1H-pyrazole;
4-( 1-ethyl-4-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol-3-
yl)benzenesulfonamide;
N-phenyl-(4-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-5-
(trifluoromethyl)-1H-pyrazol-1-yl)acetamide;
ethyl (4-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-5-(trifluoromethyl)-
1H-pyrazol-1-yl)acetate;
4-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-1-(2-phenylethyl)-1H-
pyrazole;
4-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-1-(2-phenylethyl)-5-
(trifluoromethyl)pyrazole;
1-ethyl-4-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-5-(trifluoromethyl)-
1H-pyrazole;
5-(4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(trifluoromethyl)-1H-
imidazole;
4-(4-(methylsulfonyl)phenyl)-5-(2-thiophenyl)-2-(trifluoromethyl)-1H-
imidazole;
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5-(4-fluorophenyl)-2-methoxy-4-(4-(methylsulfonyl)phenyl)-6-
(trifluoromethyl)pyridine;
2-ethoxy-5-(4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-6-
(trifluoromethyl)pyridine;
5-(4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-{2-propynyloxy)-6-
(trifluoromethyl)pyridine;
2-bromo-5-(4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-6-
(trifluoromethyl)pyridine;
4-(2-(3-chloro-4-methoxyphenyl)-4,5-difluorophenyl)benzenesulfonamide;
1-(4-fluorophenyl)-2-(4-(methylsulfonyl)phenyl)benzene;
5-difluoromethyl-4-(4-(methylsulfonyl)phenyl)-3-phenylisoxazole;
4-(3-ethyl-5-phenylisoxazol-4-yl)benzenesulfonamide;
4-(5-difluoromethyl-3-phenylisoxazol-4-yl)benzenesulfonamide;
4-(5-hydroxymethyl-3-phenylisoxazol-4-yl)benzenesulfonamide;
4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide;
1-(2-(4-fluorophenyl)cyclopenten-1-yl)-4-(methylsulfonyl)benzene;
1-{2-(4-fluoro-2-methylphenyl)cyclopenten-1-yl)-4-(methylsulfonyl)benzene;
1-(2-(4-chlorophenyl)cyclopenten-1-yl)-4-(methylsulfonyl)benzene;
1-(2-(2,4-dichlorophenyl)cyclopenten-1-yl)-4-(methylsulfonyl)benzene;
1-(2-(4-trifluoromethylphenyl)cyclopenten-1-yl)-4-(methylsulfonyl)benzene;
1-(2-(4-methylthiophenyl)cyclopenten-1-yl)-4-(methylsulfonyl)benzene;
1-(2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl)-4-
(methylsulfonyl)benzene;
4-(2-(4-fluorophenyl )-4,4-dimethylcyclopenten-1-yl )benzenesulfonamide;
1-(2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-yl)-4-
(methylsulfonyl)benzene;
4-(2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-yl)benzenesulfonamide;
4-(2-(4-fluorophenyl)cyclopenten-1-yl)benzenesulfonamide;
4-(2-(4-chlorophenyl)cyclopenten-1-yl)benzenesulfonamide;
1-(2-(4-methoxyphenyl)cyclopenten-1-yl)-4-(methylsulfonyl)benzene;
1-{2-(2,3-difluorophenyl )cyclopenten-1-yl )-4-(methylsulfonyl )benzene;
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4-(2-(3-fluoro-4-methoxyphenyl)cyclopenten-1-yl)benzenesulfonamide;
1-(2-(3-chloro-4-methoxyphenyl)cyclopenten-1-yl)-4-
(methylsulfonyl)benzene;
4-(2-(3-chloro-4-fluorophenyl)cyclopenten-1-yl)benzenesulfonamide;
4-(2-(2-methylpyridin-5-yl)cyclopenten-1-yl)benzenesulfonamide;
ethyl 2-(4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)oxazol-2-yl)-2-
benzyl-acetate;
2-(4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)oxazol-2-yl)acetic acid;
2-(tert-butyl)-4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)oxazole;
4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)-2-phenyloxazole;
4-(4-fluorophenyl)-2-methyl-5-(4-(methylsulfonyl)phenyl)oxazole; and
4-(5-(3-fluoro-4-methoxyphenyl)-2-trifluoromethyl-4-
oxazolyl)benzenesulfonamide;
or a pharmaceutically acceptable salt thereof.
NK-1 receptor antagonists of use in the present invention are
described in published European Patent Specification Nos. 0 360 390,
0 394 989, 0 429 366, 0 443 132, 0 482 539, 0 512 901, 0 512 902,
0 514 273, 0 514 275, 0 517 589, 0 520 555, 0 522 808, 0 528 495,
0 532 456, 0 533 280, 0 536 817, 0 545 478, 0 577 394, 0 590 152,
0 599 538, 0 610 793, 0 634 402, 0 686 629, 0 693 489, 0 694 535,
0 699 655, 0 699 674, 0 707 006, 0 708 101, 0 714 891, 0 723 959,
0 733 632 and 0 776 893; and in International Patent Specification Nos.
90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151,
92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 93/00330, 93/00331,
93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 93/09116, 93/10073,
93/14113, 93/18023, 93/19064, 93/21155, 9321181, 93/23380, 93/24465,
94/01402, 94/02461, 94/03429, 94/03445, 94/04494, 94/04496, 94/05625,
94/07843, 94/10165, 94/10167, 94/10168, 94/10170, 94/11368, 94/13639,
94/13663, 94/14767, 94/15903, 94/i9320, 94/19323, 94/20500, 94/26735,
94/26740, 94/29309, 95/02595, 95/04040, 95/04042, 95/06645, 95/07886,
95/07908, 95/08549, 95/11880, 95/14017, 95/15311, 95/16679, 95/17382,
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95/18124, 95/18129, 95/19344, 95/20575, 95/21819, 96/22525, 95/23798,
95/26338, 95/28418, 95/30674, 95/30687, 96/05193, 96/05203, 96/06094,
96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661, 96/29304,
96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553,
97/01554, 97/03066, 97/08144, 97/14671, 97/17362, 97/18206, 97/19084,
97/19942, 97/21702, 97/30055, 97/49710 and 98/01450; and in British
Patent Specification Nos. 2 266 529, 2 268 931, 2 269 170, 2 269 590, 2 271
774, 2 292 144, 2 293 168, 2 293 169, 2 302 689 and 2 309 458.
Particularly preferred NK-1 receptor antagonists are those
described in European Patent Specification No. 0 577 394, especially
compounds of formula (I):
X R'
(I)
R~~N Rs
R1
or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from the group consisting o~
(1) Ci-salkyl, substituted with one or more of the substituents
selected from:
(a) heterocycle, wherein the heterocycle is
selected from
the group consisting
of
{A) benzimidazolyl,
(B) imidazolyl,
(C) isoxazolyl,
(D) isothiazolyl,
(E) oxadiazolyl,
(F) pyrazinyl,
(G) pyrazolyl,
(H) pyridyl,
(I) pyrrolyl,
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(J) tetrazolyl,
(K) thiadiazolyl,
(L) triazolyl, and
(M) piperidinyl,
and wherein the
heterocycle is unsubstituted
or substituted with
one or
more substituent(s)
selected from:
(i) Ci-salkyl, unsubstituted or substituted
with halo, -CFs,
-OCHs, or phenyl,
~(ii) C1-salkoxy,
(iii) oxo,
(iv) thioxo,
(v) cyano,
(vi) -SCHa,
(vii) phenyl,
(viii) hydroxy,
(ix) trifluoromethyl,
(x) -(CH2)In-NR9R1, wherein m is 0, 1 or 2,
and R9 and Rlo
areindependently
selected from:
(I) hydrogen,
(II) C1-salkyl,
(III) hydroxyCl-salkyl, and
(IV) phenyl,
(xi) -NR9CORlo, wherein R9 and R1 are as defined
above,
and
(xii) -CONR9Rlo, wherein R9 and Rlo are as defined above,
Rz and R3 are independently selected from the group consisting o~
(1) hydrogen;
(2) Ci-salkyl
(3) Cz-salkenyl, and
(5) phenyl;
X is -O-;
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R4 is
Rs
R
/Y
Z Rs
R~ is phenyl, unsubstituted or substituted with halo;
Rs, R7 and Rg are independently selected from the group consisting of:
( 1 ) hydrogen,
(2) C1-salkyl,
(3) halo, and
(4) -CFs;
Y is -O-; and
Z is hydrogen or Ci-4alkyl;
and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of formula (I) are:
4-(3-(1,2,4-triazolo)methyl)-2(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(S)-
phenyl-morpholine;
4-(3-(1,2,4-triazolo)methyl)-2(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(R)-
phenyl-morpholine;
4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-2(S)-(3,5-
bis(trifluoromethyl)benzyloxy)-3(S)-phenyl-morpholine; and
2-(R)-( 1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-
4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine; or a pharmaceutically
acceptable salt thereof.
Further preferred NK-1 receptor antagonists are those described in
International (PCT) Patent Specification No. WO 95/18124, especially
compounds of formula (II) and pharmaceutically acceptable salts thereof:
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A~
O O i
A
N
I
RsiX w s
A
(II)
wherein:
A1 is fluorine or CF3;
A'-'' is fluorine or CFs;
A~3 is fluorine or hydrogen;
Rs is a 5-membered or 6-membered heterocyclic ring containing 2 or
3 nitrogen atoms optionally substituted by =O, =S or a Ci-4alkyl group,
and optionally substituted by a group of the formula ZNR7R8 where
Z is Ci-salkylene or Cs-scycloalkylene;
R7 is hydrogen, C1_4alkyl, Cs-7cycloalkyl or Cs-7cyc1oa1kylCi-4alkyl, or
C2_4alkyl substituted by C1-4alkoxy or hydroxyl;
R8 is hydrogen, Ci-4alkyl, Cs-7cycloalkyl or Cs-xycloalkylCi-4alkyl, or
CZ-4alkyl substituted by one or two substituents selected from Ci-4alkoxy,
hydroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or
two heteroatoms selected from N, O and S;
or R7, R8 and the nitrogen atom to which they are attached form a
heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by a
hydroxy group, and optionally containing a double bond, which ring may
optionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)a
or a second nitrogen atom which will be part of a NH or NR~ moiety where
R~ is Ci-4alkyl optionally substituted by hydroxy or C1_4alkoxy;
or R7, R$ and the nitrogen atom to which they are attached form a .
non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
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or Z, R7 and the nitrogen atom to which they are attached form a
heteroaliphatic ring of 4 to 7 ring atoms which may optionally contain an
oxygen ring atom;
X is an alkylene chain of 1 to 4 carbon atoms optionally substituted
by oxo; and
Y is a C1-alkyl group optionally substituted by a hydroxyl group;
with the proviso that if Y is C1-aalkyl, Rs is susbstituted at least by a
group of formula ZNR7R8 as defined above.
Particularly preferred compounds of formula (II) include:
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dirnethylamino)
methyl-1,2,3-triazol-4-yl)methyl-3-(S)-phenylmorpholine;
2-(R)-( 1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(dimethylamino)
methyl-1,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)morpholine;
2-( R)-( 1-( S )-(3, 5-bis(trifluoromethyl )phenyl )-2-hydroxyethoxy)-3-( S )-
( 4-
fluorophenyl)-4-(1,2,4-triazol-3-yl)methylmorpholine;
and pharmaceutically acceptable salts thereof.
Further preferred NK-1 receptor antagonists are those described in
European Patent Specification No. WO 95/23798, especially compounds of
formula (III):
Rs
R3 X Y \ R~
Z Rs (III)
z
R /N ~ Rl
(O)~ A
Ria Riz
or a pharmaceutically acceptable salt thereof, wherein:
Rz and R3 are independently selected from the group consisting of:
(1) hydrogen,
(2) C i-salkyl,
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(3) Ca-salkenyl, and
(4) phenyl;
Rs, R7 and R8 are independently selected from the group consisting of:
(1) hydrogen,
(2) C1-salkyl,
(3) fluoro,
(4) chloro,
(5) bromo,
(6) iodo, and
(7) -CFs;
Rll, R12 and
R13 are independently
selected
from the
group consisting
of:
( 1 ) fluoro,
(2) chloro,
(3) bromo, and
(4) iodo;
A is unsubstituted i-salkyl;
B is selected from the group consisting of:
N-N ,X X~ _H X~ _H
N p N O N S
X H
N-N X H X
N-N N-N N-N
S ~N~S ~N~O~X ~ ~S'X
X H N
X N-N N
N-N ~ ~ ,N
N N
N X X
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X N X
/ N ~~O / N
O N
H X H
H
/ N ,X / N X
N s ~ 0
t N N
X
pis0orl;
X is selected from:
(a) -PO(OH)O- ~ M+, wherein M+ is a pharmaceutically
acceptable monovalent counterion,
(b) -PO(O-)z ~ 2M+,
(c) -PO(O-)2 ~ D2+, wherein D2+ is a pharmaceutically acceptable
divalent counterion,
(d) -CH(R4)-PO(OH)O- ~ M+, wherein R4 is hydrogen or Cusalkyl,
(e) -CH(R4)-PO(O-)a ~ 2M+,
(f7 -CH(R4)-PO(O-)a ~ D2+,
(i) -CO-CHaCHa-COa' ~ M+,
(j) -CH(CHs)-O-CO-R~, wherein R5 is selected from the group
consisting of
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(i) ~O/~NH3' M.
H2, M.
(ii) ~O~/N~OH
,
(iii) ~O~C02-M+
C02~ M'
(iv)
O C02- M'
/COz_
(v) O ,
NH,~
C02 M+
(vi) -O COZ- M'
CO,, M+
C02~ M'
(vii) ~O ~ I ; and
Y is -O-;
Z is hydrogen or C 1-salkyl;
and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of formula (III) include:
(1) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-(5-oxo-
1H,4H-1,2,4-triazolo)methyl)morpholine N-oxide;
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(2) 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(3-(4-
(ethoxycarbonyloxy-1-ethyl)-5-oxo-1H-1,2,4-
triazolo)methyl)morpholine;
(3) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-
fluorophenyl)-4-(3-(4-monophosphoryl-5-oxo-1H-1,2,4-
triazolo)methyl)morpholine;
(4) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-
fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-1H-1,2,4-
triazolo)methyl)morpholine;
(5) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-
fluorophenyl)-4-(3-(2-monophosphoryl-5-oxo-1H-1,2,4-
triazolo)methyl)rnorpholine;
(6) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-
fluorophenyl)-4-(3-(5-oxyphosphoryl-1H-1,2,4-
triazolo)methyl)morpholine;
(7) 2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-
fluorophenyl)-4-(3-( 1-monophosphoryl-5-oxo-4H-1,2,4-
triazolo)methyl)morpholine;
and pharmaceutically acceptable salts thereof.
Further preferred NK-1 receptor antagonists are those described in
International Patent Specification No. WO 97/49710, especially
compounds of formula (IV):
R' Rz
(IV)
Ra
R4
wherein
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R~ represents hydrogen, hydroxy, C1_salkyl, Cz-salkenyl,
Cs-7cycloalkyl, Ca-7cycloalkylCl-4alkyl, C1-salkoxy, fluoroCl.salkoxy,
C1-salkoxyCi-4alkyl, C1-salkoxyCi-4alkoxy, fluoroCl-salkoxyCl.4alkyl,
Cz-salkenyloxy, Cs-7cycloalkoxy, Cs-7cyc1oa1kylCi-4alkoxy, phenoxy,
benzyloxy, cyano, halogen, NRaRu, SRa, SORa, S02Ra, OSOzRa, NRaCORI4,
CORa, COzRa or CONRaRb where Ra and Rb each independently represent
hydrogen, Cl~alkyl or fluoroCi-4alkyl;
Rz represents hydrogen, halogen, Ci-salkyl or Ci-salkoxy;
or R1 and Rz may be joined together such that there is formed a 5- or
6-membered saturated or unsaturated ring containing one or two atoms
selected from nitrogen, oxygen and sulphur, which ring is optionally
substituted by a group selected from Ci-4alkyl, CFs, =O or =S;
R~; represents hydrogen, halogen, C1-salkyl, fluoroCl-salkyl,
C1-salkoxy, fluoroCl-salkoxy, Cs-7cycloalkyl, Cs-7cycloalkylCi-4alkyl, cyano,
SRa, SOR~, SOaRa, NRaRb, NRaCORI4, CORa, COaRa, CONRaR~ or Ci-4alkyl
substituted by cyano, COaRa or CONRaR~ where R~ and R~ are as
previously defined;
R4 represents hydrogen, halogen, Ci-salkyl, C1-salkoxy, CF3, OCFs,
NOz, CN, SRa, SORa, SOzRa, COaRa, CONRaRb, Cz-salkenyl, Cz-salkynyl or
C1-alkyl substituted by C1-4alkoxy, where Ra and Rb are as previously
defined; and
the broken line represents an optional double bond;
and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of formula (IV) include:
(3R,5R,6S)-3-(2-methoxy-5-(trifluoromethoxy)phenyl)-6-phenyl-1-oxa-7-
aza-spiro[4.5]decane;
(3R,5R,6S)-3-(2-methoxy-5-(trifluoromethyl)phenyl)-6-phenyl-1-oxa-7-aza-
spiro[4.5]decane;
(3R,5R,6S)-7-benzyl-3-[2-methoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-1-
oxa-7-aza-spiro[4.5]decane;
(3R, 5R,6S)-3-(2-methoxy-5-trifluoromethoxyphenyl)-6-phenyl-1-oxa-7-aza-
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spiro [4.5] decane;
(3R,5R,6S)-3,6-bis(phenyl)-1-oxa-7-aza-spiro[4.5]decane;
(3R,5R,6S)-7-benzyl-3-(2-methoxy-5-trifluoromethoxyphenyl)-6-phenyl-1-
oxa-7-aza-spiro [4.5] decane;
(~)-(3R*,5R*,6S*)-3-(2-methoxyphenyl)-6-phenyl-1-oxa-7-
(phenylmethoxycarbonyl)aza-spiro[4.5]decane;
(3R, 5R,6S)-3-(2-methoxyphenyl )-6-phenyl-1-oxa-7-aza-spiro [4.5] decane;
(3S, 5R,6S)-3-(2-cyclopropoxy-5-(trifluoromethoxy)phenyl)-6-phenyl-1-oxa-
7-aza-spiro [4.5] decane;
{3R, 5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-
7-aza-spiro [4.5) decane;
(3S, 5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethyl)phenyl)-6-phenyl-1-oxa-7-
aza-spiro[4.5] decane;
and pharmaceutically acceptable salts thereof.
Another class of NK-1 receptor antagonists of use in the present
invention is that described in European Patent Specification No.
0 436 334, i.e. compounds of formula (V):
R'
R' Ri
R~
(\1)
Rs
a
Rs
Re-(~)
1 6
or a pharmaceutically acceptable salt thereof, wherein
Y is (CHz)n wherein n is an integer from 1 to 4, and wherein any one
of the carbon-carbon single bonds in said (CH2)~ may optionally be
replaced by a carbon-carbon double bond, and wherein any one of the
carbon atoms of said (CHa)~ may optionally be substituted with R4, and
wherein any one of the carbon atoms of said {CH2)~ may optionally be
substituted with R7;
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Z is (CH2)m wherein m is an integer from 0 to 6, and wherein any
one of the carbon-carbon single bonds of (CHa)m may optionally be replaced
by a carbon-carbon double bond or a carbon-carbon triple bond, and any
one of the carbon atoms of said (CH2)m may optionally be substituted with
Rs;
Rl is hydrogen or C1-salkyl optionally substituted with hydroxy,
C1-4alkoxy or fluoro;
R2 is a radical selected from hydrogen, C1-s straight or branched
alkyl, Cs-7cycloalkyl wherein one of the CHa groups in said cycloalkyl may
optionally be replaced by NH, oxygen or sulphur; aryl selected from phenyl
and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl,
thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and
quinolyl; phenyl-Ca-salkyl, benzhydryl and benzyl, wherein each of said
aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl -
Ca-salkyl and benzhydryl may optionally be substituted with one or more
substituents independently selected from halo, nitro, Ci-s alkyl, Ci-salkoxy,
trifluoromethyl, amino, C1-salkylamino, Ci-salkyl-O-CO, Ci-salkyl-O-CO-
C1-salkyl, Ci-salkyl-CO-O, Ci-salkyl-CO-C1-salkyl-O-, Ci-salkyl-CO,
C1-salkyl-CO-C1-salkyl-, di-Ci-salkylamino, -CONH-Ci-salkyl,
C1-salkyl-CO-NH-C1-salkyl, -NHCOH and -NHCO-C1-salkyl; and wherein
one of the phenyl moieties of said benzhydryl may optionally be replaced
by naphthyl, thienyl, furyl or pyridyl;
R5 is hydrogen, phenyl or C1-salkyl;
or R2 and R5 together with the carbon to which they are attached,
form a saturated ring having from 3 to 7 carbon atoms wherein one of the
CHz groups in said ring may optionally be replaced by oxygen, NH or
sulfur;
R3 is aryl selected from phenyl and naphthyl; heteroaryl selected
from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl,
isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7
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carbon atoms wherein one of the (CHz) groups in said cycloalkyI may
optionally be replaced by NH, oxygen or sulphur;
wherein each of said aryl and heteroaryl groups may optionally be
substituted with one or more substituents, and said Cs-7cycloalkyl may
optionally be substituted with one or two substituents, each of said
substituents being independently selected from halo, nitro, Ci-salkyl,
Ci-salkoxy, trifluoromethyl, amino, C1-salkylamino, -CO-NH- C1-salkyl,
C1-salkyl-CO-NH-C1-salkyl, -NHCOH and -NHCO-C1-salkyl;
R4 and R7 are each independently selected from hydroxy, halogen,
halo, amino, oxo, cyano, methylene, hydroxymethyl, halomethyl,
Ci-salkylamino, di-C1-salkylamino, Ci-salkoxy, Ci.salkyl-O-CO,
C~-salkyl-O-CO-C1-salkyl, Ci-salkyl-CO-O, Ci_salkyl-CO-Ci-salkyl-O-,
Ci-salkyl-CO-, C1-salkyl-CO-C~-salkyl, and the radicals set forth in the
definition of R2;
Rs is -NHCOR9, -NHCHzR9, S02Rs or one of the radicals set forth in
any of the definitions of Rz, R4 and R7;
Rs is oximino (=NOH) or one of the radicals set forth in any of the
definitions of R2, R4 and R~;
R9 is C1-salkyl, hydrogen, phenyl or phenylCi-salkyl;
with the proviso that (a) when m is 0, R$ is absent, (b) when R4, Rs, R~ or
R8 is as defined in R2, it cannot form together with the carbon to which it
is attached ,a ring with R5, and (c) when R4 and R7 are attached to the
same carbon atom, then either each of R4 and R7 is independently selected
from hydrogen, fluoro and C1-salkyl, or R4 and R7, together with the carbon
to which they are attached, for a Cs-s saturated carbocyclic ring that forms
a spiro compound with the nitrogen-containing ring to which they are
attached.
A particularly preferred compound of formula (V) is (2S,3S)-cis-3-(2-
methoxybenzylamino)-2-phenylpiperidine; or a pharmaceutically
acceptable salt thereof.
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Another class of NK-1 receptor antagonists of use in the present
invention is that described in International Patent Specification No. WO
93/21155, i.e. compounds of formula (VI):
0
-'s-CH-R1 (VI)
R
Rz
or a pharmaceutically acceptable salt thereof, wherein
radicals R are phenyl radicals optionally 2- or 3-substituted by a
halogen atom or a methyl radical;
Rl is optionally substituted phenyl, cyclohexadienyl, naphthyl,
indenyl or optionally substituted heterocycle;
R2 is H, halogen, OH, alkyl, aminoalkyl, alkylaminoalkyl,
dialkylaminoalkyl, alkyloxy, alkylthio, acyloxy, carboxy, optionally
substituted alkyloxycarbonyl, benzyloxycarbonyl, amino or acylamino;
R3 is optionally 2-substituted phenyl;
R4 is OH or fluorine when R5 is H;
or R4 and R~ are OH ;
or R4 and R5 together form a bond.
A particularly.preferred compound of formula (VI) is (3aS, 4S, 7aS)-
7,7-diphenyl-4-(2-methoxyphenyl)-2-[(2S)-(2-methoxyphenyl)propionyl]
perhydroisoindol-4-0l; or a pharmaceutically acceptable salt thereof.
Another class of NK-1 receptor antagonists of use in the present
invention is that described in European Patent Specification No.
0 591 040, i.e. compounds of formula (VII):
R Q
Ar-T-CO-N-CH2-C-CH2-CHZ-Am +, A (VII)
Ar'
wherein
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Ar represents an optionally substituted mono-, di- or tricyclic
aromatic or heteroaromatic group;
T represents a bond, a hydroxymethylene group, a
Ci-4alkoxymethylene group or a C1-salkylene group;
Ar' represents a phenyl group which is unsubstituted or substituted
by one or more substituents selected from halogen, preferably chlorine or
fluorine, trifluoromethyl, C1-4alkoxy, C1-4alkyl where the said substituents
may be the same or different; a thienyl group; a benzothienyl group; a
naphthyl group; or an indolyl group;
R represents hydrogen, Cmalkyl, c~-Ci-4alkoxyCl_4alkyl, or
co-C~~_4alkanoyloxyC2-4alkyl;
Q represents hydrogen;
or Q and R together form a 1,2-ethylene, 1,3-propylene or 1,4-
butylene group;
Am+ represents the radical
j
l
in which Xl, Xa and Xs, together with the nitrogen atom to which they are
attached, form an azabicyclic or azatricyclic ring system optionally
substituted by a phenyl or benzyl group; and
A- represents a pharmaceutically acceptable anion.
A particularly preferred compound of formula (VII) is (+) 1-[2-[3-
(3,4-dichlorophenyl)-1-[(3-isopropoxyphenyl)acetyl]-3-piperidinyl] ethyl]-4-
phenyl-1-azabicyclo(2,2,2]octane; or a pharmaceutically acceptable salt,
especially the chloride, thereof.
Another class of NK-1 receptor antagonists of use in the present
invention is that described in European Patent Specification No.
0 532 456, i.e. compounds of formula (VIII):
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Rs
R1-N~-X ~-X R° (VIII)
2 3
R -Xi
or a pharmaceutically acceptable salt thereof, wherein
R1 represents an optionally substituted aralkyl, aryloxyalkyl,
heteroaralkyl, aroyl, heteroaroyl, cycloalkylcarbonyl, aralkanoyl,
heteroarylalkanoyl, aralkoxycarbonyl or arylcarbamoyl group or the acyl
group of an a-amino acid optionally N-substituted by a lower alkanoyl or
carbamoyl-lower alkanoyl group;
Rz t:epresents cycloalkyl or an optionally substituted aryl or
heteroaryl group;
R3 represents hydrogen, alkyl, carbamoyl or an alkanoyl or alkenoyl
group optionally substituted by carboxy or esterified or amidated carboxy;
R4 represents an optionally substituted aryl group or an optionally
partially saturated heteroaryl group;
Xi represents methylene, ethylene, a bond, an optionally ketalised
carbonyl group or an optionally etherified hydroxymethylene group;
X2 represents alkylene, carbonyl or a bond; and
X3 represents carbonyl, oxo-lower alkyl, oxo(aza)-lower alkyl, or an
alkyl group optionally substituted by phenyl, hydroxymethyl, optionally
esterified or amidated carboxy, or (in other than the a-position) hydroxy.
A particularly preferred compound of formula (VIII) is (2R*, 4S*)-2-
benzyl-1-(3,5-dimethylbenzoyl)-N-(4-quinolinylmethyl)-4-piperidineamine;
or a pharmaceutically acceptable salt thereof.
Another class of NK-1 receptor antagonists of use in the present
invention is that described in European Patent Specification No.
0 443 132, i.e. compounds of formula (IX)
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i \
i
CHz
R3
R1-Y-A- N~CONH~HCON ~ (IX)
R°
or a pharmaceutically acceptable salt thereof, wherein
Rl is aryl, or a group of the formula:
\ ,x
z
X is CH or N; and
Z is O or N-R~, in which R~ is hydrogen or lower alkyl;
R2 is hydroxy or lower alkoxy;
R3 is hydrogen or optionally substituted lower alkyl;
R4 is optionally substituted ar(lower)alkyl;
A is carbonyl or sulfonyl; and
Y is a bond or lower alkenylene.
A particularly preferred compound of formula (IX) is the compound
of formula (IXa)
HO
O
N \ ~
~N
(IXa)
O CHI \
O
N
HiC/
or a pharmaceutically acceptable salt thereof.
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Another class of NK-1 receptor antagonists of use in the present
invention is that described in International Patent Specification No. WO
92/17449, i.e. compounds of the formula (X)
i
,,~~N ~ R
N J,,.~ Ra
H
(X)
or a pharmaceutically acceptable salt thereof, wherein
Rl is aryl selected from indanyl, phenyl and naphthyl; heteroaryl
selected from thienyl, furyl, pyridyl and quinolyl; and cycloalkyl having 3
to 7 carbon atoms, wherein one of said carbon atoms may optionally be
replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and
i0 heteroaryl groups may optionally be substituted with one or more
substituents, and said Cs-7cycloalkyl may optionally be substituted with
one or two substituents, said substituents being independently selected
from chloro, fluoro, bromo, iodo, nitro, Ci-loalkyl optionally substituted
with from one to three fluoro groups, Ci-ioalkoxy optionally substituted
with from one to three fluoro groups, amino, C1-loalkyl-S-, Ci-loalkyl-S(O)-,
Ci-loalkyl-S02-, phenyl, phenoxy, Ci-ioalkyl-SOzNH-,
C1-loalkyl-SOaNH-Ci-loakyl-, Ci-ioalkylamino-diCl_ioalkyl-, cyano, hydroxy,
cycloalkoxy having 3 to 7 carbon atoms, C1-salkylamino, C1-sdialkylamino,
HC(O)NH- and Ci-ioalkyl-C(O)NH-; and
R2 is thienyl, benzhydryl, naphthyl or phenyl optionally substituted
with from one to three substituents independently selected from chloro,
bromo, fluoro, iodo, cycloalkoxy having 3 to 7 carbon atoms, C1-loalkyl
optionally substituted with from one to three fluoro groups and C1-loalkoxy
optionally substituted with from one to three fluoro groups.
A particularly preferred compound of formula (X) is (2S,3S)-3-(2-
methoxy-5-trifluoromethoxybenzyl)-amino-2-phenylpiperidine; or a
pharmaceutically acceptable salt thereof.
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Another class of NK-1 receptor antagonists of use in the present
invention is that described in International Patent Specification No.
WO 95/08549, i.e. compounds of formula (XI)
R2
(CHZ)x
N I i
R
R1
H ~
a
R
R~ ~ (XI )
or a pharmaceutically acceptable salt thereof, wherein
RI is a C1-4aikoxy group;
Rz is
s
N
N
r
N-N '
R3 is a hydrogen or halogen atom;
R~ and R5 may each independently represent a hydrogen or halogen
atom, or a C1-4alkyl, C1-4alkoxy or trifluoromethyl group;
Rs is a hydrogen atom, a C1-alkyl, (CH2)mcyclopropyl,
-S(O)nCi-4alkyl, phenyl, NR7R8, CHaC(O)CFs or trifluoromethyl group;
R7 and R8 may each independently represent a hydrogen atom, or a
C1-4alkyl or acyl group;
x represents zero or 1;
n represents zero, 1 or 2; and
m represents zero or 1.
Particularly preferred compounds of formula (XI) are (2-methoxy-5-
tetrazol-1-yl-benzyl)-([2S,3S]-2-phenyl-piperidin-3-yl)-amine; and [2-
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methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-( [2S,3S] -2-phenyl-
piperidin-3-yl)-amine; or a pharmaceutically acceptable salt thereof.
Another class of tachykinin antagonists of use in the present
invention is that described in International Patent Specification No.
WO 95/14017, i.e. compounds of formula (XII)
R8 R4
R-(CH2)n C-CHZ N-(CHZ)o R3
I i2
NH R
(CO)~
((~HZ)n~
I (XII )
R1
or a pharmaceutically acceptable salt thereof, wherein
m is zero, 1, 2 or 3;
n is zero or 1;
o is zero, 1 or 2;
p is zero or 1;
R is phenyl, 2- or 3-indolyl, 2- or 3-indolinyl, benzothienyl,
benzofuranyl, or naphthyl;
which R groups may be substituted with one or two halo, C1-salkoxy,
trifluoromethyl, Cmalkyl, phenyl-C1-salkoxy, or C1-4alkanoyl groups;
R1 is trityl, phenyl, diphenylmethyl, phenoxy, phenylthio,
piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl,
benzothienyl, hexamethyleneiminyl, benzofuranyl, tetrahydropyridinyl,
quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl,
phenyl-(C1-4alkyl)-, phenyl-(C1-4alkoxy)-, quinolinyl-(C1-4alkyl)-,
isoquinolinyl-(C1-4alkyl)-, reduced quniolinyl-(C1-4alkyl)-, reduced
isoquinolinyl-(Ci-4alkyl)-, benzoyl-(C1-salkyl)-, Claalkyl, or -NH-CHa-R5;
any one of which Rl groups may be substituted with halo, C1-4alkyl,
Cmaikoxy, trifluoromethyl, amino, Ci-4alkylamino, di(C1-4alkyl)amino, or
C2-aalkanoylamino;
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or any one of which Rl groups may be substituted with phenyl,
piperazinyl, Ca-scycloalkyl, benzyl, C1-aalkyl, piperidinyl, pyridinyl,
pyrimidinyl, Ca-salkanoylamino, pyrrolidinyl, Ca-salkanoyl, or
C 1-4alkoxycarbonyl;
any one of which groups may be substituted with halo, C1-4alkyl,
Ci-4alkoxy, trifluoromethyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, or
C2-4alkanoylamino;
or Rl is amino, a leaving group, hydrogen, C1-4alkylamino, or
di(C1-4alkyl)amino;
R5 is pyridyl, anilino-(C1-salkyl)-, or anilinocarbonyl;
R2 is hydrogen, C1-aalkyl, Ci-4alkylsulfonyl, carboxy-(C1-salkyl)-,
C1-salkoxycarbonyl-(Ci-salkyl)-, or -CO-Rs;
Rs is hydrogen, Ci-4alkyl, Ci-shaloalkyl, phenyl, C1-aalkoxy,
Ci-shydroxyalkyl, amino, Ci-4alkylamino, di(Ci-4alkyl)amino, or -(CHZ)q-R7;
q is zero to 3;
R7 is carboxy, Ci-aalkoxycarbonyl, Ci-4alkylcarbonyloxy, amino,
Ci-4alkylamino, di(C~-4alkyl)amino, C1-salkoxycarbonylamino, or phenoxy,
phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl,
indolyl, benzothienyl, benzofuranyl, quinolinyl, phenyl-(Ci-4alkyl)-,
quinolinyl-(Ci-4alkyl)-, isoquinolinyl-(Ci-4alkyl)-, reduced quinolinyl-
(C1-4alkyl)-, reduced isoquinolinyl-(C1-4alkyl)-, benzoyl-C1-salkyl;
any one of which aryl or heterocyclic R7 groups may be substituted
with halo, trifluoromethyl, C1_4alkoxy, Ci-4alkyl, amino, C1-~alkylamino,
di(C1-4alkyl)amino, or Ca-~alkanoylamino;
or any one of which R7 groups may be substituted with phenyl,
piperazinyl, Cs-scycloalkyl, benzyl, piperidinyl, pyridinyl, pyrimidinyl,
pyrrolidinyl, Ca-salkanoyl, or C1-4alkoxycarbonyl;
any of which groups may be substituted with halo, trifluoromethyl,
amino, Ci-4alkoxy, Ci-4alkyl, C1-4alkylamino, di(Ci-4alkyl)amino, or
Cz-4alkanoylamino;
Rs is hydrogen or C1-salkyl;
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R3 is phenyl, phenyl-(Ci-salkyl)-, Cs-scycloalkyl, Cs-scycloalkenyl,
Ci-salkyl, naphthyl, Cz-salkenyl, or hydrogen;
any one or which groups except hydrogen may be substituted with
one or two halo, C1-salkoxy, C1-salkylthio, nitro, trifluoromethyl, or
C1-aalkyl groups; and
R4 is hydrogen or C1-salkyl;
with the proviso that if R1 is hydrogen or halo, R3 is phenyl,
phenyl-(Ci-salkyl)-, Cs-scycloalkyl, C5_8cycloalkenyl, or naphthyl.
A particularly preferred compound of formula (XII) is [N-(2-
methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-piperidin-1-
yl)piperidin-1-yl)acetylamino]propane; or a pharmaceutically acceptable
salt thereof.
The preferred compounds of formulae (I), (II) and (III) will have the
2- and 3-substituents on the morpholine ring in the cis arrangement, the
preferred stereochemistry being as shown in the following general
formula:
i
O ,~~~0
a
3 '~i ~
R W
Where the benzyloxy moiety is a-substituted, the preferred
stereochemistry of the a-carbon is either (R) when the substituent is an
alkyl (e.g. methyl) group or (S) when the substituent is a hydroxyalkyl
(e.g. hydroxymethyl) group.
The preferred compounds of formula (IV) will have the
stereochemistry of the 5- and 6-positions as shown below (5-(R), 6-(S)).
Where the optional double bond shown in formula (IV) is absent, the
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particularly preferred compounds will have the stereochemistry of the
3-position as shown below (3-(R)):
O' -
- \ /
' H
N, s .,~iC/ w
I
Unless otherwise defined herein, suitable alkyl groups include
straight-chained and branched alkyl groups containing from 1 to 6 carbon
atoms. Typical examples include methyl and ethyl groups, and straight-
chained or branched propyl and butyl groups. Particular alkyl groups are
methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl.
Unless otherwise defined herein, suitable alkenyl groups include
straight-chained and branched alkenyl groups containing from 2 to 6
carbon atoms. Typical examples include vinyl and allyl groups.
Unless otherwise defined herein, suitable alkynyl groups include
straight-chained and branched alkynyl groups containing from 2 to 6
carbon atoms. Typical examples include ethynyl and propargyl groups.
Unless otherwise defined herein, suitable cycloalkyl groups include
groups containing from 3 to 7 carbon atoms. Particular cycloalkyl groups
are cyclopropyl and cyclohexyl.
Unless otherwise defined herein, suitable aryl groups include
phenyl and naphthyl groups.
A particular aryl-C1-salkyl, e.g. phenyl-C1-salkyl, group is benzyl.
Unless otherwise defined herein, suitable heteroaryl groups include
pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl,
furyl, benzofuryl, thienyl, benzthienyl, imidazolyl, oxadiazolyl and
thiadiazolyl groups.
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The term "halogen" as used herein includes fluorine, chlorine,
bromine and iodine.
Suitable pharmaceutically acceptable salts of the NK-1 receptor
antagonists of use in the present invention include acid addition salts
which may, for example, be formed by mixing a solution of the compound
With a solution of a pharmaceutically acceptable non-toxic acid such as
hydrochloric acid, fumaric acid, malefic acid, succinic acid, acetic acid,
citric
acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid. Salts
of amine groups may also comprise the quaternary ammonium salts in
which the amino nitrogen atom carries an alkyl, alkenyl, alkynyl or
aralkyl group. Where the compound carries an acidic group, for example a
carboxylic acid group, the present invention also contemplates salts
thereof, preferably non-toxic pharmaceutically acceptable salts thereof,
such as the sodium, potassium and calcium salts thereof.
The compounds of use in this invention may have one or more chiral
centers and the present compounds may occur as racemates, racemic
mixtures and as individual diasteriomers or enantiomers with all such
isomeric forms and mixtures thereof being included within the scope of
this invention. Furthermore, some of the crystalline forms for compounds
of the present invention may exist as polymorphs and as such are intended
to be included in the present invention. In addition, some of the
compounds of the instant invention may form solvates with water or
common organic solvents. Such solvates and hydrates, as well as
anhydrous compositions, are encompassed within the scope of this
invention. Some of the compounds described herein may contain olefinic
double bonds, and unless specified otherwise, are meant to include both E
and Z geometric isomers.
The COX-2 inhibitors that may be used with this invention
encompass all pharmaceutically acceptable salt forms of the compounds.
Examples of such salt forms of COX-2 inhibitors include but are not
limited to salts derived from inorganic bases including aluminum,
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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, 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-dibenzylethylenediamine,
diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,
ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine,
glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,
methylglucamine, morpholine, piperazine, piperidine, polyamine resins,
procaine, purines, theobromine, triethylamine, trimethylamine,
tripropylamine, tromethamine, and the like.
The instant pharmaceutical combination comprising a COX-2
inhibitor in combination with a NK-1 receptor antagonist includes
administration of a single pharmaceutical dosage formulation which
contains both the COX-2 inhibitor and the NK-1 receptor antagonist, as
well as administration of each active agent in its own separate
pharmaceutical dosage formulation. Where separate dosage formulations
are used, the COX-2 inhibitor and the NK-1 receptor antagonist can be
administered at essentially the same time, i.e., concurrently, or at
separately staggered times, i.e, sequentially. The instant pharmaceutical
combination is understood to include all these regimens. Administration
in these various ways are suitable for the present invention as long as the
beneficial pharmaceutical effect of the COX-2 inhibitor and the NK-1
receptor antagonist are realized by the patient at substantially the same
time. Such beneficial effect is preferably achieved when the target blood
level concentrations of each active drug are maintained at substantially
the same time. It is preferred that the COX-2 inhibitor and the NK-1
receptor antagonist be co-administered concurrently on a once-a-day
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dosing schedule; however, varying dosing schedules, such as the COX-2
inhibitor once, twice or more times per day and the NK-1 receptor
antagonist once per day, is also encompassed herein. A single oral dosage
formulation comprised of both the COX-2 inhibitor and the NK-1 receptor
antagonist is preferred. A single dosage formulation will provide
convenience for the patient, which is an important consideration especially
for patients who already have an inflammatory disorder such as
rheumatoid arthritis and may be in need of multiple medications.
The term "therapeutically effective amount" is intended to mean
that amount of a drug or pharmaceutical agent that will elicit the
biological or medical response of a tissue, a system, animal or human that
is being sought by a researcher, veterinarian, medical doctor or other
clinician. The term "prophylactically effective amount" is intended to
mean that amount of a pharmaceutical drug that will prevent or reduce
the risk of occurrence of the biological or medical event that is sought to be
prevented in a tissue, a system, animal or human by a researcher,
veterinarian, medical doctor or other clinician. The dosage regimen
utilizing a COX-2 inhibitor in combination with a NK-1 receptor
antagonist is selected in accordance with a variety of factors including
type, species, age, weight, sex and medical condition of the patient; the
severity of the condition to be treated; the route of administration; the
renal and hepatic function of the patient; and the particular compound or
salt or ester thereof employed. Since two different active agents are being
used together in a combination therapy, the potency of each of the agents
and the interactive effects achieved by combining them together must also
be taken into account. A consideration of these factors is well within the
purview of the ordinarily skilled clinician for the purpose of determining
the therapeutically effective or prophylactically effective dosage amounts
needed to prevent, counter, or arrest the progress of the condition.
The term "patient" includes mammals, especially humans, who take
a COX-2 inhibitor in combination with a NK-1 receptor antagonist for any
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of the uses described herein. Administering of the drug combination to the
patient includes both self administration and administration to the
patient by another person.
The inhibitor of cyclooxygenase-2 may be administered at a dosage
level up to conventional dosage levels for NSAIDs. Suitable dosage levels
will depend upon the antiinflammatory effect of the chosen inhibitor of
cyclooxygenase-2, but typically suitable levels will be about 0.001 to 50
mg/kg per day, preferably 0.005 to 30mg/kg per day, and especially 0.05 to
l0mg/kg per day. The compound may be administered on a regimen of up
to 6 times per day, preferably 1 to 4 times per day, and especially once per
day.
A suitable dosage level for the NK-1 receptor antagonist is about
0.05 to 1500mg per day, preferably about 0.25 to 1500mg per day, and
especially about 0.25 to 500mg/kg per day. The compounds may be
administered on a regimen of up to 6 times per day, preferably 1 to 4 times
per day, especially 1 or 2 times daily.
The active agents employed in the instant combination therapy can
be administered in such oral forms as tablets, capsules (each of which
includes sustained release or timed release formulations), pills, powders,
granules, elixirs, tinctures, suspensions, syrups, and emulsions. The
instant invention includes the use of both oral rapid-release and time-
controlled release pharmaceutical formulations. A particular example of
an oral time-controlled release pharmaceutical formulation is described in
U.S Patent No. 5,366,738. Oral formulations are preferred. Such
pharmaceutical compositions are known to those of ordinary skill in the
pharmaceutical arts; for example, see Remington's Pharmaceutical
Sciences, Mack Publishing Co., Easton, PA.
In the methods of the present invention, the active agents are
typically administered in admixture with suitable pharmaceutical
diluents, excipients or carriers (collectively referred to herein as "carrier"
materials) suitably selected with respect to the intended form of
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administration, that is, oral tablets, capsules, elixirs, syrups and the like,
and consistent with conventional pharmaceutical practices.
For instance, for oral administration in the form of a tablet or
capsule, the active drug component can be combined with a non-toxic,
pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose,
glucose, modified sugars, modified starches, methyl cellulose and its
derivatives, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and
other reducing and non-reducing sugars, magnesium stearate, steric acid,
sodium stearyl fumarate, glyceryl behenate, calcium stearate and the like.
For oral administration in liquid form, the drug components can be
combined with non-toxic, pharmaceutically acceptable inert carrier such as
ethanol, glycerol, water and the like. Moreover, when desired or
necessary, suitable binders, lubricants, disintegrating agents and coloring
and flavoring agents can also be incorporated into the mixture.
Stabilizing agents such as antioxidants (BHA, BHT, propyl gallate,
sodium ascorbate, citric acid) can also be added to stabilize the dosage
forms. Other suitable components include gelatin, sweeteners, natural
and synthetic gums such as acacia, tragacanth or alginates,
carboxymethylcellulose, polyethylene glycol, waxes and the like.
The active drugs can also be administered in the form of liposome
delivery systems, such as small unilamellar vesicles, large unilamellar
vesicles and multilamellar vesicles. Liposomes can be formed from a
variety of phospholipids, such as cholesterol, stearylamine or
phosphatidylcholines.
Active drug may also be delivered by the use of monoclonal
antibodies as individual carriers to which the compound molecules are
coupled. Active drug may also be coupled with soluble polymers as
targetable drug carriers. Such polymers can include polyvinyl-
pyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol,
polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-polylysine
substituted with palmitoyl residues. Furthermore, active drug may be
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coupled to a class of biodegradable polymers useful in achieving controlled
release of a drug, for example, polylactic acid, polyglycolic acid, copolymers
of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy
butyric acid, polyorthoesters, polyacetals, polydihydropyrans,
polycyanoacrylates and cross linked or amphipathic block copolymers of
hydrogels.
Although the active agents of the present method may be
administered in divided doses, for example two or three times daily, a
single daily dose of each of the COX-2 inhibitor and the NK-1 receptor
antagonist is preferred, with a single daily dose of both agents in a single
pharmaceutical composition being most preferred.
The instant invention also encompasses a process for preparing a
pharmaceutical composition comprising combining the COX-2 inhibitor
and the NK-1 receptor antagonist with a pharmaceutically acceptable
carrier, as well as the pharmaceutical composition which is made by
combining the COX-2 inhibitor and the NK-1 receptor antagonist with a
pharmaceutically acceptable carrier.
A therapeutically effective amount of a COX-2 inhibitor and a NK-1
receptor antagonist can be used together for the preparation of a
medicament useful for preventing or reducing the risk of developing an
inflammatory disorder such as rheumatoid arthritis, halting or slowing
the progression of an inflammatory disorder such as rheumatoid arthritis,
once it has become clinically manifest, and preventing or reducing the risk
of a first or subsequent occurrence of an inflammatory disorder such as
rheumatoid arthritis. For example, the medicament may be comprised of
a COX-2 inhibitor in combination with about 1 mg to 300 mg of a NK-1
receptor antagonist, or more particularly about 3 mg to 100 mg of the
NK-1 receptor antagonist. More specific amounts of NK-1 receptor
antagonist which may be used in the medicament preparation include 1
mg, 3 mg, 5 mg, 10 mg, 20 mg, 30 mg, 50 mg, 100 mg and 300 mg, as well
as sub-milligram amounts of NK-1 receptor antagonists which have
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sufficient potency at such levels. As a further example, the medicament
may be comprised of a NK-1 receptor antagonist, for example, at the above
dosages, in combination with about 0.1 to 20 mg of a COX-2 inhibitor.
The instant invention also encompasses the use of a NK-1 receptor
antagonist for the manufacture of a medicament for the combined use with
a cyclooxygenase-2 inhibitor for preventing or reducing the risk of
developing an inflammatory disorder, for halting or slowing the
progression of an inflammatory disorder, or for preventing or reducing the
risk of occurrence or recurrence of an inflammatory disorder; and the use
of a cyclooxygenase-2 inhibitor for the preparation of a medicament for the
combined use with a NK-1 receptor antagonist for preventing or reducing
the risk of developing an inflammatory disorder, for halting or slowing the
progression of an inflammatory disorder, or for preventing or reducing the
risk of occurrence or recurrence of an inflammatory disorder.
The compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII),
(IX), (X), (XI) and (XII) may be prepared by the methods described in
EP-A-0 577 394 (or WO 95/16679), WO 95/18124, WO 95/23798,
WO 97/49710, EP-A-0 436 334, WO 93/21155, EP-A-0 591 040,
EP-A-0 532 456, EP-A-0 443 132, WO 92/17449, WO 95/08549 and
WO 95/14017, respectively.
Particularly preferred NK-1 receptor antagonists of the formulae (I),
(II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII) for use
in the
present invention are compounds which are potent NK-1 receptor
antagonists, i.e. compounds with an NK-1 receptor affinity (ICso) of less
than 100nM. Most preferred are compounds of formulae (I), (II), (III) and
(IV).
Even more preferred NK-1 receptor antagonists of use in the
present invention are compounds which are potent NK-1 receptor
antagonists with an NK-1 receptor affinity (ICso) of less than lOnM,
favourably less than 2nM and preferably less than lnM.
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Especially preferred NK-1 receptor antagonists of use in the present
invention are orally active, long acting, CNS-penetrant NK-1 receptor
antagonists, identified using a combination of the following assays:
ASSAY 1: NK-1 Receptor binding
NK-1 receptor binding assays are performed in intact Chinese
hamster ovary (CHO) cells expressing the human NK-1 receptor using a
modification of the assay conditions described by Cascieri et al, J.
Pharmacol. Exp. Tlaer., 1992, 42, 458. Typically, the receptor is expressed
at a level of 3x105 receptors per cell. Cells are grown in monolayer
culture, detached from the plate with enzyme-free dissociation solution
(Speciality Media Inc.), and washed prior to use in the assay. 125I_Tyr$-
substance P (O.lnM, 2000Ci/mmol; New England Nuclear) is incubated in
the presence or absence of test compounds (dissolved in 5~t1
dimethylsulphoxide, DMSO) with 5x104 CHO cells. Ligand binding is
performed in 0.25m1 of 50mM Tris-HCI, pH7.5, containing 5mM MnCl2,
150mM NaCI, 0.02% bovine serum albumin (Sigma), 50pg/ml chymostatin
(Peninsula), O.lnM phenylmethylsulphonyl fluoride, 2p.g/ml pepstatin,
211g/ml leupeptin and 2.8p.g/ml furoyl saccharine. The incubation proceeds
at room temperature until equilibrium is achieved (>40 minutes) and the
receptor-ligand complex is harvested by filtration over GF/C filters pre-
soaked in 0.1% polyethylenimine using a Tomtek 96-well harvester. Non-
specific binding is determined using excess substance P (lp,M) and
represents <10% of total binding.
ASSAY 2: Gerbil Foot-Tapping
CNS-penetrant NK-1 receptor antagonists for use in the present
invention can be identified by their ability to inhibit foot tapping in
gerbils
induced by central infusion of NK-1 receptor agonists such as GR73632,
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based on the method of Rupniak & Williams, Eur. J. Pharmacvl., 1994,
265, 179.
Male or female Mongolian gerbils (35-70g) are anaesthetised by
inhalation of an isoflurane/oxygen mixture to permit exposure of the
jugular vein in order to permit administration of test compounds or vehicle
in an injection volume of approximately 5m1/kg i.v. Alternatively, test
compounds may be administered orally or by subcutaneous or
intraperitoneal routes. A skin incision is then made in the midline of the
scalp to expose the skull. The selective NK-1 receptor agonist (e.g.
GR73632 (d Ala[L-Pro9,Me-Leul~)-substance P-(7-11)) is infused directly
into the cerebral ventricles (e.g. 3pmo1 in 5~1 i.c.v., depending on test
substance) by vertical insertion of a cuffed 27 gauge needle to a depth of
4.5mm below bregma. The scalp incision is closed and the animal allowed
to recover from anaesthesia in a clear perspex observation box
(approximately 25cm x 20cm x 20cm). The duration and/or intensity of
hind foot tapping is then recorded continuously for approximately 5
minutes.
ASSAY 3: Ferret Emesis
Individually housed male ferrets (1.0 -2.5 kg) are dosed orally by
gavage with test compound. Ten minutes later they are fed with
approximately 100g of tinned cat food. At 60 minutes following oral
dosing, cisplatin (lOmg/kg) is given i.v. via a jugular vein catheter
inserted under a brief period of halothane anaesthesia. The catheter is
then removed, the jugular vein ligated and the skin incision closed. The
ferrets recover rapidly from the anaesthetic and are mobile within 10-20
minutes. The animals are observed continuously during recovery from the
anaesthetic and for 4 hours following the cisplatin injection, after which
time the animals are killed humanely. The numbers of retches and vomits
occurring during the 4 hours after cisplatin administration are recorded by
trained observers.
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ASSAY 4: Footpad FCA Guinea Pig Model
Male Dunkin Hartly guinea pigs (1$Og-200g) are housed in groups
in a twelve hour dark/light cycle and given vitamin C supplemented food
and water ad libitum. Inflammation is induced by injection of 1001
Freunds Complete Adjuvant (FCA) into the right hind footpad. The FCA
is composed of l0mg/ml heat killed mycobacterium blended with sterile
paraffin. For the purposes of the study 6 animals are included in each
treatment group and are dosed with experimental compounds as provided
on a daily basis.
Inflammation is assessed as follows:
1. The diameter of the hind footpads is measured with vernier calipers
at a consistent mid plantar site.
2. Measurement of thermal hyperalgesia is determined by the
Hargreaves Method on unrestrained animals. The method
determines the withdrawal latency to an infra-red source (Ugo
Basile). Hyperalgesia is assessed 4 hours after dosing.
3. Mechanical hyperalgesia is assessed using the Ugo Basile analgesy-
meter according to the Randall-Selitto test. Force is applied onto the
foot pad at a designated site increasing at 4.8g per second.
Hyperalgesia is assessed 4 hours after dosing.
A suitable selection cascade for NK~ antagonists of use according to
the present invention is as follows:
(i) Determine affinity for human NKi receptor in radioligand
binding studies (Assay 1); select compounds with ICso <_ lOnM, preferably
ICso < 2nM, especially ICso < lnM.
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(ii) Determine ability of compounds to penetrate CNS by their
ability to inhibit foot tapping in gerbils induced by central injection of an
NKl agonist (Assay 2); select compounds that inhibit foot tapping with
ID5o < 3mg/kg i.v., and preferably ID~o < lmg/kg i.v. when administered
immediately prior to central NKl agonist challenge, or IDso <_ 30mg/kg p.o.,
and preferably IDso <_ lOmg/kg p.o. 1 hour prior to challenge.
(iii) Determine central duration of action of compounds in gerbil foot
tapping assay following intravenous administration 24 hours prior to
central NKl agonist challenge; select compounds showing <_ 25-fold loss of
potency compared with ID:;o determined in step (ii) above with the proviso
that ID5o _< lOmg/kg i.~~., and preferably <_ 5mg/kg i.v. after 24 hour
pre-treatment.
(iv) Determine oral bioavailability of compounds by
pharmacokinetic analysis, activity in gerbil foot tapping assay following
oral administration and/or by ability to inhibit cisplatin-induced emesis in
ferrets (Assay 3); select compounds with IDso <_ 3mg/kg p.o., and preferably
IDso <_ lmg/kg p.o.
Particularly preferred compounds of use in the present invention
are identified using steps (i) to (iv) followed by step (v):
(v) Determine activity of compounds in assays for inhibition of
pharmacologically evoked foot tapping in gerbils and/or inhibition of
adjuvant arthritis in guinea-pigs (Assay 4). Select compounds with ID5o <_
20mg/kg, and preferably IDso <_ lOmg/kg.
Yet further preferred compounds of use in the present
invention may be selected from those compounds which satisfy the NK-1
receptor binding criteria of step (i) which, in addition, have <_ 5-fold shift
in
affinity when incubated in the presence of human serum albumin (HSA) to
show non-specific protein binding.
One example of a NK-1 receptor antagonist of use in the present
invention is the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)-
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ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)-
morpholine, the preparation of which is described in International Patent
Specification No. WO 95/16679. In the aforementioned assays, this
compound has the following activity:
human NK-1 receptor binding: ICso=O.lnM
gerbil foot-tapping (5 mins.): IDso=0.36mg/kg i.v.
gerbil foot-tapping (24 hrs.): IDso=0.33mg/kg i.v.
ferret emesis: IDso~3mg/kg p.o.
Another example of a NK-1 receptor antagonist of use in the present
invention is the compound 2-(R)-(1-(R)-(3,5-
bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl-1,2,3-
triazol-4-yl)methyl-3-(S)-phenylmorpholine, the preparation of which is
described in International Patent Specification No. WO 95/18124. In the
aforementioned assays, this compound has the following activity:
human NK-1 receptor binding: ICso=0.25nM
gerbil foot-tapping (5 mins.): IDso=0.12mg/kg i.v.
gerbil foot-tapping (24 hrs.): IDso=0.17mg/kg i.v.
Especially preferred COX-2 inhibitors of use in the present
invention are identified using the following one or more of the following
selection criteria:
(i) Determine the affinity for human COX-2 in whole cell assay;
select compounds with IDso<_40nM, and preferably IDso<_20nM.
(ii) Determine oral bioavailability of compounds by
pharmacokinetic analysis or inhibition of carrageenan-induced paw
oedema in rats following oral administration. Select compounds with
EDso<_5mg/kg p.o., and preferably EDso<_2.5mg/kg p.o.
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(iii) Determine the ability of compounds to induce gastric
ulceration or increase in faecal 5~Cr excretion. Select compounds that have
no adverse gastrointestinal effects at __>100mg/kg p.o., when administered
up to two times a day.
(iv) Determine antinociceptive effects of compounds in
carrageenan-induced hyperalgesia in rats; select compounds with
EDso<_5mg/kg p.o., and preferably EDso52.5mg/kg p.o.
(v) Determine the affinity for COX-2 in human whole blood assay
which is used as an index for biochemical efficacy in the clinic and select
compounds with ICso<_1pM for inhibition of PGEz.
The following examples illustrate pharmaceutical compositions
according to the invention.
These formulations may be prepared with separate active
ingredients or with a combination of active ingredients in one composition.
In such combined preparations,
the ratio of the
COX-2 inhibitor and
the
NK-1 receptor antagonistll depend upon the choice of active
wi
ingredients.
EXAMPLE 1
Amount (mg) per tablet
NK-1 receptor antagonist50.0 100.0 300.0
Microcrystalline cellulose80.0 80.0 80.0
Modified food corn 80.0 80.0 80.0
starch
Lactose 189.5 139.5 139.5
Magnesium Stearate 0.5 0.5 0.5
The active ingredient, cellulose, lactose and a portion of the corn
starch are mixed and granulated with 10% corn starch paste. The
resulting granulation is sieved, dried and blended with the remainder of
the corn starch and the magnesium stearate. The resulting granulation is
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then compressed into tablets containing 50mg, 100mg and 300mg of the
NK-1 receptor antagonist per tablet.
EXAMPLE
2
Amount (m~per
tablet
NK-1 receptor antagonist50.0 100.0 300.0
COX-2 inhibitor 20.0 20.0 20.0
Microcrystalline cellulose80.0 80.0 80.0
Modified food corn 80.0 80.0 80.0
starch
Lactose 169.5 119.5 119.5
Magnesium Stearate 0.5 0.5 0.5
The active ingredients, cellulose, lactose and a portion of the corn
starch are mixed and granulated with 10°lo corn starch paste. The
resulting granulation is sieved, dried and blended with the remainder of
the corn starch and the magnesium stearate. The resulting granulation is
then compressed into tablets containing 20mg of the COX-2 inhibitor and
50mg, 100mg and 300mg of the NK-1 receptor antagonist per tablet.
EXAMPLE 3
Wet granulated tablet composition
Amount per tablet
(mg~
COX-2Inhibitor 25 12.5 10 5
Microcrystahine cellulose79.7 86 87.2 89.?
Lactose monohydrate 79.7 86 87.2 89.7
Hydroxypropyl cellulose 6 6 6 6
Croscarmellose sodium 8 8 8 8
Iron oxide 0.6 0.6 0.6 0.6
Magnesium stearate 1 1 1 1
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Tablet dose strengths of between 5 and 25 mg can be accomodated
by varying total tablet weight, and the ratio of the first three ingredients.
Generally it is preferable to maintain a 1:1 ratio for microcrystalline
cellulose:lactose monohydrate.
EXAMPLE 4
Directly compressed
tablet composition
Amount (mg) ner tablet
COX-2 inhibitor 25 12.5 10 5
Microcrystalline cellulose106.9 113.2 42.5 45
Lactose anhydrate 106.9 113.2 42.5 45
Crosmellose sodium '7.5 7.5 4 4
Magnesium stearate 3.? 3.7 1 1
Tablet dose strengths of between 5 and 25 mg can be accomodated
by varying total tablet weight, and the ratio of the first three ingredients.
Generally it is preferable to maintain a 1:1 ratio for microcrystalline
cellulose:lactose monohydrate.
EXAMPLE 5
Hard gelatin capsule composition
Amount (m~) per capsule
COX-2 Inhibitor 25
Microcrystalline cellulose 37
Lactose anhydrate 37
Magnesium stearate 1
Hard gelatin capsule 1 capsule
Capsule dose strengths of between 1 and 50 mg can be accomodated
by varying total fill weight, and the ratio of the first three ingredients.
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Generally it is preferable to maintain a 1:1 ratio for microcrystalline
cellulose : lactose monohydrate.
EXAMPLE 6
Oral solution
Amount per 5 ml dose
COX-2 Inhibitor 50 mg
Polyethylene oxide 400 to 5 ml
Solution dose strengths of between 1 and 50 mg/5ml can be
accomodated by varying the ratio of the two ingredients.
EXAMPLE 7
Oral suspension
Amount ner 5 ml dose
COX-2 Inhibitor 100 mg
Polyvinylpyrrolidone 150 mg
Polyoxyethylene sorbitan monolaurate 2.5 mg
Benzoic acid 10 mg
sorbitol solution (70%) to 5 ml
Suspension dose strengths of between 1 and 50 mg/5ml can be
accomodated by varying the ratio of the first two ingredients.
EXAMPLE 8
Intravenous infusion
Amount ner 200m1 dose
COX-2 inhibitor 1 mg
Polyethylene oxide 400 0.2 mg
Sodium chloride 1.8 mg
Purified water to 200m1
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While the invention has been described and illustrated with
reference to certain particular embodiments thereof, those skilled in the
art will appreciate that various changes, modifications and substitutions
can be made therein without departing from the spirit and scope of the
invention. For example, effective dosages other than the particular
dosages as set forth herein above may be applicable as a consequence of
variations in the responsiveness of the mammal being treated for any of
the indications for the active agents used in the instant invention as
indicated above. Likewise, the specific pharmacological responses
observed may vary according to and depending upon the particular active
compound selected or whether there are present pharmaceutical carriers,
as well as the type of formulation and mode of administration employed,
and such expected variations or differences in the results are contemplated
in accordance with the objects and practices of the present invention. It is
intended, therefore, that the invention be defined by the scope of the
claims which follow and that such claims be interpreted as broadly as is
reasonable.