Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-09-01
2001-07-03
Cook, Rebecca (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S626000, C514S323000, C514S383000, C514S415000
Reexamination Certificate
active
06255334
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 in combination with metoclopramide. It also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier, a 5HT
1
receptor agonist and metoclopromide. 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 metoclopramide and 5HT
1
agonists (e.g. eletriptan, rizatriptan, naratriptan, sumatriptan, but excluding zolmitriptan) for the acute treatment of migraine offers enhanced efficacy and less nausea than currenty used therapies.
In 1975, Volans showed that metoclopramide helped alleviate the gastric stasis that accompanies migraine attacks. (See Volans, G. N.,
British Journal of Pharmacology
, 1975 February; 2(1): 67-73; and Volans, G. N.,
Clinical Pharmacokinetics
, 1978 July; 3(4): 313-318.) He studied this effect and showed the blood levels of aspirin and acetaminophen (paracetamol), taken orally, were decreased in patients experiencing a migraine attack, and that these levels returned to normal in between migraine attacks. The use of metoclopramide with aspirin or acetaminophen increased the blood levels of these medications, making them more efficatious for the treatment of migraine.
It is believed that 5HT
1
agonists would exhibit substantially greater efficacy for the treatment of migraine when administered in combination with metoclopramide, in view of the increased blood levels of the oral 5HT
1
agonist and the antiemetic and antimigraine action of metaclopramide.
Metoclopramide is a benzamide derivative, and, although it is related to the neuroleptics, it has no significant antipsychotic or sedative properties. Metoclopramide is a dopamine and 5HT
3
receptor antagonist and also possesses some 5HT
4
agonist activity. The actions of metoclopramide include antagonism of emesis induced by apomorphine or ergotamine. It also induces hyperprolactinemia, a characteristic of dopaminergic blockade. Metoclopramide has relatively low affinity for the dopamine-2 (D2) receptor.
SUMMARY OF THE INVENTION
The present invention relates to pharmaceutical compositions for the treatment of migraine in a mammal, including a human, comprising metoclopramide; a 5HT
1
receptor agonist, or a pharmaceutically acceptable salt thereof, excluding zolmitriptan; and a pharmaceutically acceptable carrier.
This invention also relates to a method of treating migraine in a mammal, including a human, comprising administering to said mammal an amount of a pharmaceutical composition comprising metoclopramide; a 5HT
1
receptor agonist, or a pharmaceutically acceptable salt thereof, excluding zolmitriptan; and a pharmaceutically acceptable carrier; that is effective in treating migraine.
This invention also relates to a method of treating migraine in a mammal, including a human, comprising administering to said mammal metoclopramide; a 5HT
1
receptor agonist, or a pharmaceutically acceptable salt thereof, excluding zolmitriptan; in amounts that render the combination of such two active agents effective in the treatment or prevention of migraine.
Preferred embodiments of this invention relate to pharmaceutical compositions for the treatment of migraine and methods of treating migraine, as described above, wherein the 5HT
1
receptor agonist is selected from eletriptan, naratriptan, rizatriptan, sumatriptan almotriptan, avitriptan, frovatriptan, alniditan, LY 334370, LY 306258, BMS-180048 and BMS-181885. A most highly preferred embodiment is the pharmaceutical combination of eletriptan and metoclopramide wherein it is also expected that the pharmacokintetics of the eletriptan would be enhanced.
Other embodiments of this invention relate to pharmaceutical compositions for the treatment of migraine and methods of treating migraine, as described above, wherein the 5HT
1
receptor agonist is a compound of the formula
wherein R
3
, R
4
, and Z are selected, independently, from hydrogen, halo (e.g., chloro, fluoro, bromo or iodo), (C
1
-C
4
) alkyl optionally substituted with from one to three fluorine atoms, (C
1
-C
4
)alkoxy optionally substituted with from one to three fluorine atoms, and (C
1
-C
4
)alkoxy-(C
1
-C
4
)alkyl wherein each of the alkyl moieties may optionally be substituted with from one to three fluorine atoms;
W is —CH
2
—O—(C
1
-C
6
) alkyl wherein the alkyl moiety can be straight or branched;
or W is —CH
2
NR
1
R
2
wherein R
1
and R
2
are independently selected from hydrogen and straight or branched (C
1
-C
6
)alkyl;
or R
1
and R
2
, together with the nitrogen to which they are attached, form a saturated four membered monocyclic ring or a saturated or unsaturated nonaromatic five to seven membered monocyclic ring or a saturated or unsaturated nonaromatic seven to ten membered bicyclic ring which may optionally contain one or two heteroatoms in addition to the nitrogen of NR
1
R
2
, wherein said heteroatoms are independently selected from oxygen, nitrogen and sulfur, and wherein from one to three of the ring carbon atoms, or one of the ring nitrogen atoms, may optionally and independently be substituted with straight or branched (C
1
-C
4
) alkyl, straight or branched (C
1
-C6) alkoxy, straight or branched (C
1
-C
3
) alkyl-(C
3
-C
7
cycloalkyl, hydroxy, amino, cyano, halo, aryl-(straight or branched (C
1
-C
3
) alkyl) or heteroaryl-(straight or branched (C
1
-C
3
) alkyl), wherein said aryl is selected from phenyl and naphthyl and said heteroaryl is selected from oxazolyl, isoxazoyl, thiazolyl, isothiazolyl, furanyl, pyrazolyl, pyrrolyl, tetrazolyl, triazolyl, thienyl, imidazolyl, pyrazinyl, pyrazolyl, indolyl, isoindolyl, pyrazinyl, cinnolinyl, pyridinyl and pyrimidinyl;
with the proviso that in any ring formed by NR
1
R
2
: (a) there can be no more than one ring oxygen atom; (b) there can be no hydroxy, alkoxy, alkoxyalkyl, cyano, amino or alkylamino moiety bonded directly to any ring nitrogen atom; and (c) no ring carbon that is double bonded to another ring carbon and not part of an aromatic ring system can be bonded to a ring oxygen atom or ring nitrogen atom;
or a pharmaceutically acceptable salt thereof.
REFERENCES:
patent: 5698571 (1997-12-01), Audia et al.
patent: 2325161 (1998-11-01), None
patent: 98/02186 (1998-01-01), None
Kelly A M et al.: “Intravenous chlorpromazine versus intramuscular sumatriptan for acute migraine.”Journal of Accident and Emergency Medicine, (Jul. 1997) 14 (4) 209—11., XP000869766-page 210, col. 1, line 31-line 52.
Von Seggern R L et al.: “Cost consideration in headache treatment. Part 2: Acute migraine treatment.”Headache, (Sep. 1996) 36 (8) 493-502., XP000869685—p. 494, col. 1, line 26—line 48; page 498, column 1, line 7 line 13; page 501, column 1, line 1-line 12.
Schwarzberg M N: “Application of metoclopramide specificity in migraine attacks therapy.”Headache, (Jul.-Aug. 1994) 34 (7) 439-41., XP000869686—p. 440, col. 1, line 1-line 11; p. 440, column 2, line 49—p. 441, col. 1, line 3.
Seaber E J et al: “The novel anti-migraine compound zolmitriptan (Zomig 311C90) ha no clinically significant interactions with paracetamol or metoclopramide.”European Journal of Clinical Pharmacology, (1997) 53 (3-4) 229-34, XP000870485 abstract, p. 229, col 2, paragraph 2, table 1.
Rolan, P.: “Potential drug interations with the novel antimigraine compound zolmitriptan (Zomig, 311C90).”Cephalalgia, (Oct. 1997.) 17 Suppl 18 21—7. Ref. XP000870490, abstract p. 23, col. 2, paragraph 1.
Cook Rebecca
Ginsburg Paul H.
Nissenbaum Israel
Pfizer Inc
Richardson Peter C.
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