Combination therapy for the treatment of migraine

Details Combination therapy for the treatment of migraine Combination therapy for the treatment of migraine

2000-06-26

2002-11-05

Jones, Dwayne C. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

Reexamination Certificate

active

06476042

ABSTRACT:

The present invention relates to a method of treating migraine in a mammal, including a human, by administering to the mammal a 5HT
1
receptor agonist and caffeine in combination with a cyclooxygenase-2 (COX-2) inhibitor. It also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier, a 5HT
1
receptor agonist and a COX-2 inhibitor. Examples of agonists of 5HT
1
receptors are agonists of one or more of the 5HT
1A
, 5HT
1B
, 5HT
1C
, 5HT
1D
, 5HT
1E
, and 5HT
1F
receptors.
The combined use of 5HT
1
agonists (e.g. eletriptan, rizatriptan, naratriptan, sumatriptan, zolmitriptan), caffeine and a COX-2 inhibitor for the acute treatment of migraine offers enhanced efficacy than currently used therapies.
Symptomatic treatment helps relieve the pain associated with migraine.
Abortive treatment targets the pathophysiology of migraine and decreases many of the symptoms of migraine, including pain, nausea, photophobia and phonophobia.
NSAIDS have been shown to help in the symptomatic treatment of migraine headache. Its combination with the abortive treatment of the 5HT
1
agonists is expected to provide an additional effect than the use of either treatment alone.
COX-2 inhibitors have evolved from the NSAIDS and are expected to have similar efficacy with additional safety and tolerability. By selectively inhibiting the COX-2 isoenzyme associated with inflammation and pain, COX-2 inhibitors would be expected to decrease migraine pain with less or no effect on the COX-1 isoenzyme. This isoenzyme maintains gastrointestinal and renal environments. The effect of the NSAIDS on the COX-1 isoenzyme is thought to be responsible for the large incidence of gastrointestinal and renal adverse experiences associated with NSAIDS treatment. Therefore, the use of the COX-2 inhibitors is advantageous with its additional safety and tolerability.
Caffeine has been found to be an analgesic adjuvant for numerous conditions including headache and pain (see Laska et al., JAMA, Vol. 252, 1711-1718 (1984), which is incorporated by reference in its entirety).
SUMMARY OF THE INVENTION
The present invention relates to pharmaceutical compositions for the treatment of migraine in a mammal, including a human, comprising a 5HT
1
receptor agonist or a pharmaceutically acceptable salt thereof, and caffeine with
(a) a compound of the formula:
 or the pharmaceutically acceptable salts thereof wherein
R
1
is hydrogen or C
1-4
alkyl; R
2
is C(═L′)R
3
or SO
2
R
4
; Y is a direct bond or C
1-4
alkylene; L and L′ are independently oxygen or sulfur;
Q is selected from the following:
(Q-a) C
1-6
alkyl,
(Q-b) halo-substituted C
1-4
alkyl,
(Q-c) C
3-7
cycloalkyl optionally substituted with one or two substituents independently selected from C
1-4
alkyl, halo-substituted C
1-4
alkyl, C
1-4
alkoxy, hydroxy and halo,
(Q-d) phenyl or naphthyl, the phenyl and naphthyl being optionally substituted with one, two or three substituents independently selected from halo, C
1-4
alkyl, halo-substituted C
1-4
alkyl, hydroxy, C
1-4
alkoxy, nitro, halo-substituted C
1-4
alkoxy, S(O)
m
R
5
, SO
2
NH
2
, SO
2
N(C
1-4
alkyl)
2
, amino, C
1-4
alkylamino, di-(C
1-4
alkyl)amino, NR
1
C(O)R
5
, CN, C
1-4
alkyl-OH and C
1-4
alkyl-OR
5
,
(Q-e) a 5-membered monocyclic aromatic group containing one heteroatom selected from O, S and N and optionally containing one, two or three nitrogen atom(s) in addition to said heteroatom, and said monocyclic armomatic group being optionally substituted with one, two or three substituents independently selected from halo, C
1-4
alkyl, halo-substituted C
1-4
alkyl, hydroxy, C
1-4
alkoxy, halo-substituted C
1-4
alkoxy, amino, C
1-4
alkylamino, di-(C
1-4
alkyl)amino, C
1-4
alkyl-OH and C
1-4
alkyl-OR
5
, and
(Q-f) a 6-membered monocyclic aromatic group containing one nitrogen atom and optionally containing one, two or three additional nitrogen atom(s), and said monocyclic armomatic group being optionally substituted with one, two or three substituents independently selected from halo, C
1-4
alkyl, halo-substituted C
1-4
alkyl, hydroxy, C
1-4
alkoxy, halo-substituted C
1-4
alkoxy, amino, C
1-4
alkylamino, di-(C
1-4
alkyl)amino, C
1-4
alkyl-OH and C
1-4
alkyl-OR
5
;
R
3
is —OR
6
, —NR
7
R
8
, N(OR
1
)R
7
or a group of formula:
Z is a direct bond, oxygen, sulfur or NR
5
;
R
4
is C
1-6
alkyl, halo-substituted C
1-4
alkyl, C
1-4
alkyl-OH, —NR
7
R
8
, phenyl or naphthyl, the phenyl and naphthyl being optionally substituted with one, two or three substituents independently selected from halo, C
1-4
alkyl, halo-substitutued C
1-4
alkyl, hydroxy, C
1-4
alkoxy and halo-substitutued C
1-4
alkoxy;
R
5
is C
1-4
alkyl or halo-substituted C
1-4
alkyl;
R
6
is C
1-4
alkyl, C
3-7
cycloalkyl, C
1-4
alkyl-C
3-7
cycloalkyl, halo-substitutued C
1-4
alkyl, C
1-4
alkyl-phenyl or phenyl, the phenyl moiety being optionally substituted with one, or two substituents independently selected from halo, C
1-4
alkyl, halo-substituted C
1-4
alkyl, hydroxy, C
1-4
alkoxy, C
1-4
alkylthio, amino, di-(C
1-4
alkyl)amino and nitro;
R
7
and R
8
are independently selected from the following:
(a) hydrogen,
(b) C
1-6
alkyl optionally substituted with a substituent independently selected from halo, hydroxy, C
1-4
alkoxy, amino, C
1-4
alkylamino and di-(C
1-4
alkyl)amino,
(c) C
3-7
cycloalkyl optionally substituted with a substituent independently selected from hydroxy, C
1-4
alkyl and C
1-4
alkoxy,
(d) C
1-4
alkyl-C
3-7
cycloalkyl optionally substituted with a substituent independently selected from hydroxy, C
1-4
alkyl and C
1-4
alkoxy, and
(f) C
1-4
alkyl-phenyl or phenyl, the phenyl moiety being optionally substituted with one or two substituents independently selected from halo, C
1-4
alkyl, halo-substitutued C
1-4
alkyl, hydroxy, C
1-4
alkoxy, C
1-4
alkylthio, nitro, amino, di-(C
1-4
alkyl)amino and CN;
X is independently selected from halo, C
1-4
alkyl, halo-substitutued C
1-4
alkyl, hydroxy, C
1-4
alkoxy, halo-substitutued C
1-4
alkoxy, C
1-4
alkylthio, nitro, amino, di-(C
1-4
alkyl)amino and CN;
m is 0, 1 or 2; n is 0, 1, 2 or 3; and r is 1, 2 or 3; or
(b) a compound of the formula:
 or its pharmaceutically acceptable salt thereof, wherein the variables of formula XX are defined as follows;
A is partially unsaturated or unsaturated five membered heterocyclic, or partially unsaturated or unsaturated five membered carbocyclic, wherein the 4-(sulfonyl)phenyl and the 4-substituted phenyl in the formula (I) are attached to ring atoms of Ring A adjacent to each other;
R
1
is aryl or heteroaryl, and the aryl or heteroaryl being optionally substituted by one to four substituents selected from halo, C
1-4
alkyl, halo-substituted C
1-4
alkyl, C
1-4
alkoxy, C
1-4
alkyl carbonyl, hydroxy, nitro, cyano and amino, with the proviso that when A is pyrazole, R
1
is heteroaryl;
R
2
is C
1-4
alkyl, halo-substituted C
1-4
alkyl, C
1-4
alkylamino, C
1-4
dialkylamino or amino;
R
3
, R
4
and R
5
are independently hydrogen, halo, C
1-4
alkyl, halo-substituted C
1-4
alkyl, C
2-5
alkenyl, C
2-5
alkynyl, C
1-4
alkoxy, hydroxy-C
1-4
alkyl, C
1-4
alkoxy C
1-4
alkyl, C
1-4
alkanoyl, cyano, nitro, cyano C
1-4
alkyl, carboxy, C
1-4
alkoxycarbonyl, aminocarbonyl, N—C
1-4
alkylaminocarbonyl, N,N-di-C
1-4
alkylaminocarbonyl, N-arylaminocarbonyl, N,N-diarylaminocarbonyl, N—C
1-4
alkyl-N-arylamiocarbonyl, aryl, aryloxy, aryloxy-C
1-4
alkyl, heteroaryl, heteroaryloxy, heteroaryloxy-C
1-4
alkyl, morpholino-carbonyl, C
1-4
alkoxyaminocarbonyl or C
1-4
alkyl-carbonylamino; or two of R
3
, R
4
and R
5
are taken together with atoms to which they are attached and form a 4-7 membered ring;
R
6
and R
7
are independently hydrogen, halo, C
1-4
alkyl, halo-substituted C
1-4
alkyl, C
1-4
alkoxy, C
1-4
alkylthio, C
1-4
alkylamino, N,N-di C
1-4
alkylamino, hydroxyl-C
1-4
alkyl, C
1-4
alkoxy-C
1-4
alkyl, C
1-4
alkyl-C
1-4
alkoxy, C
1-4
alkylamino-C
1-4
alkyl, hydroxy, amino-C
1-4
alkyl and N,N-di C
1-4
alkylamino-

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