WO1998005337A1 - Utilisation de ligands de recepteurs gaba et nmda pour le traitement des cephalees de la migraine - Google Patents

Utilisation de ligands de recepteurs gaba et nmda pour le traitement des cephalees de la migraine Download PDF

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WO1998005337A1
WO1998005337A1 PCT/US1997/013430 US9713430W WO9805337A1 WO 1998005337 A1 WO1998005337 A1 WO 1998005337A1 US 9713430 W US9713430 W US 9713430W WO 9805337 A1 WO9805337 A1 WO 9805337A1
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hydroxy
pregnan
gaba
dihydroxy
methyl
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PCT/US1997/013430
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English (en)
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Nancy C. Lan
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Cocensys, Inc.
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Priority to AU39672/97A priority Critical patent/AU3967297A/en
Publication of WO1998005337A1 publication Critical patent/WO1998005337A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids

Definitions

  • This invention is in the field of medicinal chemistry.
  • the invention is related to the use of GABA A and/or NMDA receptor ligands for the treatment of migraine headache.
  • the invention is also related to pharmaceutical compositions comprising a GABA receptor ligand and an NMDA receptor ligand.
  • CSD cortical-spreading depression
  • WO96/15782 teaches endogenously occuring neuroactive steriods are preferred agents for acute and prophylatic treatment of migraine.
  • the invention is related to the discovery that it is possible to effectively treat or prevent migraine headache by administering a GABA A receptor agonist and/or an NMDA receptor antagonist.
  • the invention also relates to a composition of matter comprising a GABA A receptor agonist and an NMDA receptor antagonist.
  • the GABA A receptor agonist is 3 ⁇ -hydroxy-3 ⁇ -methyl-5 ⁇ -pregnan-20-one, 3 ⁇ - hydroxy-3 ⁇ -trifluoromethyl-5 ⁇ -19-nor-pregnan-20-one, 3 ⁇ ,21-dihydroxy-3 ⁇ - trifluoromethyl-19-nor-5 ⁇ -pregnan-20-one, 21-hemisuccinate, sodium salt or 2 ⁇ - ethynyl-3 ⁇ -hydroxy-5 ⁇ -pregnan-20-one
  • the NMDA receptor antagonist is 6,7-dichloro- 1 ,4-dihydro-5-nitroquinoxaline-2,3-dione or 7-chloro-4-hydroxy-3- (3-phenoxyphenyl)quinolin-2(lH)-one, or a pharmaceutically acceptable salt thereof.
  • kits comprising a carrier means having in close confinement therein two or more container means, wherein the first container means comprises a GABA A receptor agonist and the second container comprises an NMDA receptor antagonist.
  • the invention also relates to a method of treating or preventing migraine headache, comprising administering substantially simultaneously to an animal in need of such treatment a GABA A receptor agonist and/or an NMDA receptor antagonist.
  • GABA A receptor agonists are taught, for example, in U.S. Patent Nos. 5,120,723, 5,208,227, 5,232,917, 5,319,115, the contents of which are fully incorporated by reference herein. Certain GABA A receptor agonists are represented by the Formula /:
  • R is hydrogen, halogen, optionally substituted 1-alkynyl, lower alkoxy, alkyl, dialkylamino, or substituted alkyl;
  • R is a hydrogen, alkyl, alkenyl, optionally substituted aryl, optionally substituted aralkyl, alkynyl, optionally substituted aralkynyl, alkoxyalkyl, aminoalkyl, cyano, cyanoalkyl, thiocyanoalkyl, azidoalkyl, optionally substituted arylalkenyl, optionally substituted aralkylalkynyl, alkanoyloxyalkynyl, optionally substituted heteroaryloxyalkynyl, oxoalkynyl or a ketal thereof, cyanoalkynyl, optionally substituted heteroarylalkynyl, hydroxyalkynyl, alkoxyalkynyl, aminoalkynyl, acylaminoalkynyl, mercaptoalkynyl, hydroxyalkynyl dioic acid hemi-ester or a salt thereof, or alkyl
  • R 2 is hydrogen, hydroxy, alkoxy, alkanoyloxy, carbalkoxyl, a keto group or amino group
  • R 3 is an acetyl group, a ketal of an acetyl group; an alkoxyacetyl group, an alkylthioacetyl group, an alkylsulfinylacetyl group, an alkylsulfonylacetyl group, an aminoacetyl group, a trifluoroacetyl group; a hydroxyacetyl group; an alkoxyalkylacetyl group, e.g. a methoxymethylacetyl group or an ethoxymethyl-
  • acetyl group 2'-methylene acetyl group; a hydroxyalkyl group, e.g. a hydroxymethyl group, a 1 '-hydroxy ethyl group, a 1 '-hydroxypropyl group, or a 2'-hydroxy-2'-propyl group; a hydroxyacetyl dioic acid hemi-ester salt, e.g. a succinyloxyacetyl group; an alkanoyloxyacetyl group, e.g. an acetoxyacetyl group; or a sulfoxyacetyl group; an alkylacetyl group, e.g.
  • R 5 is hydrogen
  • R ⁇ is hydrogen, alkanoyl, aminocarbonyl, or alkoxycarbonyl
  • R 7 is hydrogen, halogen, hydroxy, alkoxy, alkanoyloxy, carbalkoxyl, a methylene group (together with R 3 ), or an alkoxymethylene group (together with R 3 );
  • R g is hydrogen or halogen
  • R is hydrogen, halogen, alkyl, alkoxy, arylalkoxy or amino
  • R 10 is hydrogen, halogen, alkyl, haloalkyl, hydroxy, alkoxy, alkanoyloxy, carbalkoxyl, cyano, thiocyano or mercapto; or a prodrug thereof.
  • Typical GABA A receptor ligands include those described in U.S. application 08/342,090 and WO96/I5782, the disclosures of which are fully incorporated by reference herein, as well as those listed in Table 1.
  • Theprefened compounds are neuroactive steroids with 2 ⁇ - or 3 ⁇ -substitution.
  • the endogenously occurring neuroactive steroids such as those described in
  • WO96/15782 do not contain 3 ⁇ -substitution. These steroids are metabolically unstable and thus result in low bioavailability and potential side effects derived from metabolic conversion back to the hormonal steroid.
  • the 3 ⁇ - substituted derivatives circumvent these problems and provide anti-migraine agents with less side effects and which are orally active.
  • the potency of modulating the GABA A receptor may be determined in an assay for inhibition of [ 35 SJTBPS binding to rat brain homogenates.
  • the procedures for performing this assay are fully discussed in (1) Gee, et al. , Eur. J. PhamacoL 136:419-423 (1987); and (2) Gee, K.W., et al. Molecular Pharmacology 50:218 (1986).
  • the results for a number of neuroactive steroids are shown in Table 1.
  • NMDA receptor antagonists are represented by the Formula //:
  • R is hydrogen, hydroxy, amino, -CH 2 CONHAr, -NHCONHAr, NHCOCH 2 Ar, -COCH 2 Ar, wherein Ar is an aryl group, or a radical having the Formula ///:
  • R 6 is hydrogen, lower alkyl of 1-6 carbon atoms or aryl
  • R 7 is hydrogen or lower alkyl of 1-6 carbon atoms
  • n is an integer from 0 to 5
  • R 8 is hydrogen, C,. 6 alkyl, or aralkyl
  • R', R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, hydroxy, acyloxy, aralkoxy, amino, alkanoylamino, halo, haloalkyl, nitro, alkyl, alkoxy, carboxy, alkanoyl, thioalkyl, alkoxyalkyl, aryloxyalkyl, arylalkyl, alkenyl, alkynyl, arylalkenyl, arylalkynyl, cyano, cyanomethyl, dicyanomethyl, cyanoamino, dicyanoamino, or azido; or where R 1 and R ⁇ R 2 and R 3 , or R 3 and R 4 form a fused 5- or 6-membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring.
  • Preferred 1 ,4-dihydroquinoxaline-2,3-diones include 7-chloro-6-methyl-5- nitroquinoxaline-2,3-dione; 6-chloro-7-methyl-5-nitroquinoxaline-2,3-dione; 7- fluoro-6-methyl-5-nitro-quinoxaline-2,3-dione; 7-fluoro-6-bromo-5- nitroquinoxaline-2,3-dione; 6,7-dimethyl-5-nitroquinoxaline-2,3-dione; 5,6,7- trifluoroquinoxaline-2 ,3 -dione ; 6,7-dichloro- 5 -nitroquinoxaline-2 ,3 -dione ; 6- chloro-7-fluoro-5-nitroquinoxaline-2,3-dione; 6-bromo-7-chloro-5- nitroquinoxaline-2,3-dione; 7-bromo-6-methyl-5-nitroquinoxaline
  • aza-l,4-dihydroquinoxaline-2,3-diones and the N-oxy derivatives thereof described in WO95/18616 are also preferred.
  • the most preferred compounds include 5-(N-oxy)azaquinoxalinedione, 7-chloro-5-(N-oxy)azaquinoxaline-2,3- dione, 7-methyl-5-(N-oxy)azaquinoxaline-2,3-dione; 7-bromo-5-(N- oxy)azaquinoxaline-2,3-dione; 7-nitro-5-(N-oxy)azaquinoxaline-2,3-dione; 7- trifluoromethyl-5-(N-oxy)azaquinoxaline-2,3-dione; 7-chloro-6-methyl-5-(N- oxy)azaquinoxaline-2,3-dione; 6,7-dichloro-5-(N-oxy)azaquinoxaline-2,3-dione; and 7-bromo-6-methyl-5
  • NMDA receptor antagonists include 2,5-dihydro-2,5-dioxo-lH- benzazepines and related compounds as disclosed in U.S. Patent Nos. 5,476,933, 5,254,683, and WO94/07500.
  • Preferred bezazepine type compounds include 6,8-dimethyl-3-hydroxy-l- benzazepine-2,5-dione; 7,8-dimethyl-3-hydroxy-l-benzazepine-2,5-dione; 8- chloro-3-hydroxy- 1 -benzazepine-2,5-dione; 6,7,8,9-tetrahydro-3-hydroxy- 1 - benzazepine-2,5-dione, 7,8-dimethyl-6,7,8,9-tetrahydro-3-hydroxy-l- benzazepine-2,5-dione; 6,7,8, 9-tetrahydro-3-hydroxy-l-benzazepine-2,5-dione; 7,8-dichloro-6,7,8,9-tetrahydro-3-hydroxy-l-benzazepine-2,5-dione;7,8-dichloro- 6-ethyl-6,7,8,9-tetrahydro-3-hydroxy-l
  • NMDA receptor antagonists include 5-aza-7-chloro-4- hydroxy-3-(3-phenoxy)phenylquinolin-2(lH)-one; 6,7-dichloro-3-cyano-4-oxo- quinoxalin-2( 1 H)-one; and 5,7-dichloro- 1 ,2,3,4-tetrahydroquinoline-2,3 ,4-trione- 3-acetyloxime.
  • Other NMDA receptor antagonists include the dioxotetrahydroquinoline derivatives disclosed in U.S. Patent no. 5,268,378.
  • Preferred compounds which exhibit potent in vivo activity following oral administration are the 3'-substituted 3-phenyl-4-hydroxy-2-quinolones described by Kulagowski et al., J. Med. Chem. 37: 1402-1405 (1994), including the orally active agent 7-chloro-4-hydroxy-3-(3- phenoxyphenyl)quinolin-2(lH)-one.
  • lower is referred to herein in connection with organic radicals or compounds defines such as one up to and including ten, preferably up to and including six, and advantageously one to four carbon atoms.
  • Such groups may be straight chain, branched chain, or cyclic.
  • Typical ., 4 aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl groups.
  • Typical carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Typical halo groups include fluorine, chlorine, bromine and iodine.
  • Typical C,. 10 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec. -butyl, tert. -butyl, 3-pentyl, hexyl and octyl groups. Also contemplated is a trimethylene group substituted on two adjoining positions on the benzene ring of the compounds of the invention.
  • Typical C ⁇ alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, and sec. -butenyl.
  • Typical C 2 . 4 alkynyl groups include ethynyl, propynyl, butynyl, and 2-butynyl groups.
  • Typical aralkyl groups include any of the above-mentioned C, . , 0 alkyl groups substituted by any of the above-mentioned C 6. ⁇ aryl groups.
  • Typical aralkenyl groups include any of the above-mentioned C ⁇ alkenyl groups substituted by any of the above-mentioned C 6.14 aryl groups.
  • Typical aralkynyl groups include any of the above-mentioned C 2J) alkynyl groups substituted by any of the above-mentioned C 6.I4 aryl groups.
  • Typical carbocycloalkyl groups include any of the above-mentioned C,. I0 alkyl groups substituted by any of the above-mentioned carbocyclic groups.
  • Typical haloalkyl groups include C, . , 0 alkyl groups substituted by one or more fluorine, chlorine, bromine or iodine atoms, e.g.' fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl and trichloromethyl groups.
  • Typical hydroxyalkyl groups include C, .10 alkyl groups substituted by hydroxy, e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups.
  • Typi cal alkoxy groups include oxygen substituted by one of the C , . , 0 alky 1 groups mentioned above.
  • Typical alkylthio groups include sulphur substituted by one of the C,. l0 alkyl groups mentioned above.
  • Typical alkanoylamino groups include any C, .6 alkanoyl substituted on nitrogen, e.g. acetamido, propionamido, butanoylamido, pentanoylamido, hexanoylamido as well as aryl-substituted C 2 . 6 substituted acyl groups.
  • Typical alkanoyloxy groups include any C,. 6 acyloxy groups, e.g. acetoxy, propionoyloxy, butanoyloxy, pentanoyloxy, hexanoyloxy and the like.
  • heterocyclic refers to carbon containing radicals having four, five, six, or seven membered rings and one, two or three O, N or S heteroatoms, e.g. , thiazolidine, tetrahydrofuran, 1 ,4-dioxane, pyrrolidine, piperidine, quinuclidine, dithiane, tetrahydropyran, e-caprolactone, e- caprolactam, ⁇ -thiocaprolactam, and mo ⁇ holine as well as pyranyl, piperidinyl, piperazinyl, imidazolindinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, isochromanyl, chromanyl, pyrazolidinyl, 1 ,3-benzodioxolyl, 1,4-benzodioxanyl and pyrazolinyl groups.
  • Typical heterocycloalkyl groups include any of the above-mentioned C 0 alkyl groups substituted by any of the above-mentioned heterocyclic groups.
  • heteroaryl refers to carbon containing 5-14 membered cyclic unsaturated radicals containing one, two, three or four O, N or S atoms and having 6, 10 or 14 ⁇ electrons delocalized in one or more rings, e.g., pyridine, oxazole, indole, purine, pyrimidine, imidazole, benzimidazole, indazole, 2H- 1,2,4-triazole, 1,2,3-triazole, 2H-l,2,3,4-tetrazole, lH-l,2,3,4-tetrazole, benzotriazole, l,2,3-triazolo[4,5-b]pyridine, thiazole, isoxazole, pyrazole, quinoline, cytosine, thymine, uracil, adenine, guanine, pyrazine, picolinic acid, picoline, furoic acid, furfural, furyl
  • heteroaryl group contains a nitrogen atom in a ring
  • nitrogen atom may be in the form of an N-oxide, e.g. a pyridyl N-oxide, pyrazinyl N-oxide, pyrimidinyl N-oxide and the like.
  • Typical heteroaralkyl groups include any of the above-mentioned C M0 alkyl groups substituted by any of the above-mentioned heteroaryl groups.
  • Typical heteroaralkenyl groups include any of the above-mentioned C 2.4 alkenyl groups substituted by any of the above-mentioned heteroaryl groups.
  • Typical heteroaralkynyl groups include any of the above-mentioned C 2.4 alkynyl groups substituted by any of the above-mentioned heteroaryl groups.
  • Typical amino groups include -N ⁇ 2 , -NHR 14 , and -NR l4 R 15 , wherein R 14 and R 15 are C,. 10 alkyl groups as defined above.
  • Typical carbonylamido groups are carbonyl groups substituted by -NH 2 , -NHR 14 , and -NR 14 R 15 groups as defined above.
  • dioic acids refers to C I 5 alkylene groups substituted with two carboxy groups, for example, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, and suberic acid. Hemi-ester salts of the dioic acids include the sodium, lithium, potassium, magnesium and calcium salts thereof.
  • ⁇ -acetyl-thiosulfate salt refers is intended to include the sodium, lithium, potassium, magnesium and calcium salts thereof.
  • esters or salts refers to esters or salts of the ligands derived from the combination of a compound of this invention and an organic or inorganic acid or base.
  • Ketals include diethers of lower alkanols, e.g. dimethyl and diethyl ketals, as well as cyclic ketals which include diethers of . 3 alkanediols, e.g. ethylene ketals and propylene ketals.
  • any one of the nitrogen atoms may be substituted independently by hydrogen, alkyl, or aryl groups.
  • the term “optionally substituted” or “substituted” refers to groups substituted by one to three, four or five substituents, independently selected from lower alkyl (acylic and cyclic), aryl (carboaryl and heteroaryl), alkenyl, alkynyl, alkoxy, halo, haloalkyl (including trihaloalkyl, e.g.
  • Optional substituents on the aryl, aralkyl, aryloxy, arylthioxy, aroyl, heterocyclic, heterocycloxy, heteroaryl, heteroaryloxy, cycloalkyl, and cycloalkoxy groups listed above include any one of the typical halo, haloalkyl, aryl, fused heterocyclic, fused carbocyclic, heterocyclic, heteroaryl, alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, amino, cyano, alkanoylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, and alkylthiol groups mentioned above.
  • Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate, and oxalate.
  • Organic basic salts may be prepared with an amine such as choline, TRIS, bis- tris-propane, N-methylglucamine or agrinine.
  • an amine such as choline, TRIS, bis- tris-propane, N-methylglucamine or agrinine.
  • the compounds employed in the present invention may exist as optical isomers and the invention includes both the racemic mixtures of such optical isomers as well as the individual enantiomers that may be separated according to methods that are well known to those of ordinary skill in the art.
  • prodrugs include ester or amide of formula I with R,-R 4 as hydroxyalkyl or aminoalkyl, by reacting such compounds with an anhydride such as succinic anhydride.
  • anhydride such as succinic anhydride.
  • the compounds of this invention may be prepared using methods well known to those skilled in the art and described in the patents and publication described herein.
  • the GABA A receptor agonists and NMDA receptor antagonists are administered either at the same time, e.g. when they are part of the same chemical or pharmaceutical composition, or when they are administered separately but where the duration of pharmacologic action of the two drugs overlap in the target animal.
  • compositions of the present invention are useful in treating headaches, in particular, migraine headaches.
  • the compositions will be therapeutically useful for migraine headache because of their expected low side effects, their ability to cross blood brain barrier and their systemic bioavailability.
  • compositions within the scope of this invention include all compositions wherein the compounds of the present invention are contained in an amount which is effective to achieve its intended purpose.
  • the GABA A receptor agonists and neuroactive steroids may be administered to humans by oral, intramuscular, i.v. or patch delivery.
  • the level of neuroactive steroids in the plasma delivered as parent compounds, pharmaceutical salts or prodrugs should achieve 1-100 ng/ml regardless the route of administration.
  • One can easily acheive this level by administration of the drug to a patient and assaying for the concentration of the drug in the blood by methods well known to those of ordinary skill in the art.
  • a dose of 1-100 ⁇ g/kg may be administered.
  • preferred compounds are water soluble steroids. Examples include 2 ⁇ -morpholinyl derivatives such as [(2 ⁇ ,3 ⁇ ,5 ⁇ )-3-hydroxy-2-(2,2- dimethylmo ⁇ holin-4-yl)pregnan-l 1,20-one (Anderson, A. et al, J. Med. Chem.
  • an emulsion composed of soya bean oil, acetyl triglycerides, egg yolk phosphatides, glycerol, water and steroids can be prepared (see, Powell, H., Anesthesia 47:287-290 (1992).
  • steroids with low bioavailability such as 3 ⁇ -hydroxy- 3 ⁇ -methyl-5 ⁇ -pregnan-20-one
  • a dose of lOO ⁇ g/kg to lOmg/kg should be administered.
  • steroids with relative high bioavailability such as 2 ⁇ -ethynyl-3 ⁇ -hydroxy-5 ⁇ -pregnane-20-one3 ⁇ -hydroxy-3 ⁇ -trifluoromethyl-5 ⁇ - 19-nor-pregnan-20-one or 3 ⁇ ,21-dihydroxy-3 ⁇ -trifluoromethy l-19-nor-5 ⁇ - pregnan-20-one, 21 -hemisuccinate, sodium salt
  • a lower dose of 20 ⁇ g/kg to 2 mg/kg may be administered.
  • the steroids When the steroids are delivered by oral administration, they may be prepared in solution complexed with 2-hydroxy- ⁇ - cyclodextrin or with ⁇ -cyclodextrin and suspended in ora Plus ® /ora Sweet ® to improve palatability.
  • the agents When the neuroactive steroids are used for prophylactic treatment of migraine, the agents are preferably taken after a meal to assure good adso ⁇ tion.
  • the dose is generally about one-half of the oral dose.
  • the NMDA receptor antagonists may be administered to humans by oral, intramuscular, or i.v. delivery. Because most of glycine site NMDA receptor antagonists do not penetrate the blood brain barrier, only a subset of NMDA receptor antagonists, such as 6,7-dichloro-l,4-dihydro-5-nitroquinoxaline-2,3- dione and dioxotetrahydroquinoline derivatives disclosed in U.S. Patent no. 5,268,378 are preferred for treating migraine headaches.
  • Preferred compounds are the 3 '-substituted 3-phenyl-4-hydroxy-2-quinolones described by
  • a dose of 0.1 to 10 mg/kg should be administered.
  • the dose is generally about half of the oral dose.
  • these agents may be given by i.v. or i.m. injection followed by oral treatment.
  • neuroactive steroids are given by i.v. or injection followed by oral administration of neuroactive steroids or NMDA receptor antagonists either alone or in combination.
  • these agents are preferably administered by oral route of administration either alone or in combination.
  • the oral dose may be about 10 ⁇ g/kg to 1 mg/kg for both agents. Because of the added or synergistic effects of these agents are expected in the treatment and prevention of migraine headache, lower doses are needed.
  • the dose of the two drugs can be modified by comparing the relative in vivo potencies of the drugs and the bioavailability using no more than routine experimentation.
  • the GABA A receptor agonist and NMDA receptor antagonist may be administered separately or as part of a unitary composition.
  • the two drugs may be supplied as part of a kit comprising a carrier means having in close confinement two container means such as bottles, tubes, vials and the like.
  • the first container means will contain the GABA A receptor agonist optionally mixed with a pharmaceutically acceptable carrier.
  • the second container means will contain the NMDA receptor antagonist, also optionally mixed with a pharmaceutically acceptable carrier.
  • the compounds of the invention may be administered as part of a pharmaceutical preparation containing suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the compounds into preparations which can be used pharmaceutically.
  • the preparations particularly those preparations which can be administered orally and which can be used for the preferred type of administration, such as tablets, dragees, and capsules, and also preparations which can be administered rectally, such as suppositories, as well as suitable solutions for administration by injection or orally, contain from about 0.01 to 99 percent, preferably from about 0.25 to 75 percent of active compound(s), together with the excipient.
  • the compounds are administered i.v. as part of a pharmaceutically acceptable aqueous solution that may also contain buffers or salts.
  • compositions of the invention may be administered to any animal which may experience the beneficial effects of the compounds of the invention.
  • animals are mammals, e.g., humans, although the invention is not intended to be so limited.
  • compositions of the present invention may be administered by any means that achieve their intended pu ⁇ ose.
  • administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, or buccal routes.
  • administration may be by the oral route.
  • the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
  • the pharmaceutical preparations of the present invention are manufactured in a manner which is itself known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes. Methods for preparing fine particles of therapeutically active substances are taught in U.S. Patent Nos. 5,510,118, 5,145,684, 4,540,602, 5,091 , 188, 4,851 ,421 , and 4,540,602. Fine particles are preferred for the steroidal
  • GABA A receptor agonists which are sparingly soluble in water.
  • Pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone.
  • fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose,
  • disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.
  • Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices.
  • concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropymethyl-cellulose phthalate, are used.
  • Dye stuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
  • Other pharmaceutical preparations which can be used orally include push- fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol.
  • the push-fit capsules can contain the active compounds in the form of granules which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin.
  • stabilizers may be added.
  • compositions which can be used rectally include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons.
  • gelatin rectal capsules which consist of a combination of the active compounds with a base.
  • Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.
  • Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water- soluble salts and alkaline solutions.
  • suspensions of the active compounds as appropriate oily injection suspensions may be administered.
  • Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400).
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension include, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran.
  • the suspension may also contain stabilizers.
  • NMDA receptor antagonists Since the steroidal GABA A receptor antagonist are highly lipophilic, they must be formulated in a lipophilic solvent for injection.
  • the NMDA receptor antagonists in general, can readily be formulated in aqueous or lipophilic formulations according to methods that are well known to those of ordinary skill in the art.

Abstract

Procédés de traitement ou de prévention des céphalées de la migraine, qui consistent à administrer à un animal un agoniste de récepteur GABA et un antagoniste de récepteur NMDA. Des compositions pharmaceutiques et des kits de traitement ou de prévention des céphalées de la migraine sont également décrits.
PCT/US1997/013430 1996-08-01 1997-07-31 Utilisation de ligands de recepteurs gaba et nmda pour le traitement des cephalees de la migraine WO1998005337A1 (fr)

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