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WO1998005337A1 - Use of gaba and nmda receptor ligands for the treatment of migraine headache - Google Patents

Use of gaba and nmda receptor ligands for the treatment of migraine headache Download PDF

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Publication number
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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Prior art keywords
hydroxy
pregnan
gaba
dihydroxy
methyl
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PCT/US1997/013430
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French (fr)
Inventor
Nancy C. Lan
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Cocensys, Inc.
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Publication date
Application filed by Cocensys, Inc. filed Critical Cocensys, Inc.
Priority to AU39672/97A priority Critical patent/AU3967297A/en
Publication of WO1998005337A1 publication Critical patent/WO1998005337A1/en

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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.

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Abstract

Methods of treating or preventing migraine headache are disclosed by administering to an animal a GABA receptor agonist and/or an NMDA receptor antagonist. Also disclosed are pharmaceutical compositions and kits for the treatment or prevention of migraine headache.

Description

Use of GABA and NMDA Receptor Ligands for the Treatment of Migraine Headache
Background of the Invention
Field of the Invention
This invention is in the field of medicinal chemistry. In particular, the invention is related to the use of GABAA 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.
Related Background Art
It has been proposed that during migraine attack, a sensory disturbance with unique changes of brain blood flow results in the development of characteristic migraine auras. Lauritzen, Science & Medicine 32-40 (July/August 1996). Since this unique phenomena has been replicated in animal experiments with cortical-spreading depression (CSD) (Leaό, A.A.P.J., Neurophysiol. 7: 359- 390 ( 1944)), CSD is considered an important phenomena in the pathophysiology of migraine with aura (Tepley et al. In: Biomagnetism, eds. S. Williamson, L. Kaufmann, pp. 327-330, Plenum Press, New York (1990)). The CSD is associated with the propagation (2-6 mm/s) of transient changes in electrical activity which relate to the failure of ion homeostasis in the brain, efflux of excitatory amino acids from the neurons and increased energy metabolism
(Lauritzen, M., Acta Neurol. Scand. 76 (Suppl. US): 4-40 (1987)).
It had been demonstrated the initiation of CSD in a variety of animals including human involved the release of glutamate (Curtis et al., Nature 191: 1010-1011 (1961); and Lauritzen et al, Brain Res. 475: 317-327 (1988)). Glutamate receptor antagonists (including MK-801 ) have been shown to be useful for blocking CSD. See EP 481,676 and EP 420,806. Chen and Levito, Headache 54:107-110 (1994), report that many women experience an improvement with regard to the frequency of migraine headache during pregnancy. The level of progesterone, and consequently its 3α-reduced metabolites (neuroactive steroids which are GABAA receptor antagonists), is elevated during pregnancy. H. Mickan and J. Zander, J. Steroid Biochem.
77:461-466 (1979).
It has also been proposed that plasma protein extravasation (PPS) is involved with the etiology of migraine headache. Moskowitz has reported that endogenously occuring neuroactive steroids block PPS. Moskowitz and Waeber, Neuroscientist 2(3): 191 -200 (1996); Limmroth et al, Br. J. Pharmacol. 117:99-
104 (1996); WO96/15782. WO96/15782 teaches endogenously occuring neuroactive steriods are preferred agents for acute and prophylatic treatment of migraine.
Summary of the Invention
The invention is related to the discovery that it is possible to effectively treat or prevent migraine headache by administering a GABAA receptor agonist and/or an NMDA receptor antagonist.
The invention also relates to a composition of matter comprising a GABAA receptor agonist and an NMDA receptor antagonist. Preferably, the GABAA receptor agonist is 3α-hydroxy-3β-methyl-5α-pregnan-20-one, 3α- hydroxy-3β-trifluoromethyl-5β-19-nor-pregnan-20-one, 3α,21-dihydroxy-3β- trifluoromethyl-19-nor-5β-pregnan-20-one, 21-hemisuccinate, sodium salt or 2β- ethynyl-3α-hydroxy-5α-pregnan-20-one, and 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.
The invention also relates to kits comprising a carrier means having in close confinement therein two or more container means, wherein the first container means comprises a GABAA 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 GABAA receptor agonist and/or an NMDA receptor antagonist.
Detailed Description of the Preferred Embodiments
Suitable GABAA 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 GABAA receptor agonists are represented by the Formula /:
Figure imgf000005_0001
"Mo
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 alky nyloxy alky nyl;
R2 is hydrogen, hydroxy, alkoxy, alkanoyloxy, carbalkoxyl, a keto group or amino group; R3 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-
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. a methylacetyl group; a haloacetyl group; an ethynyl group; an optionally substituted heteroarylacetyl group; an optionally substituted heteroaralkylacetyl group which is also optionally substituted on the alkylene with a hydroxy, alkoxy, alkanoyloxy or carbalkoxyl group; an optionally substituted heterocyclic-acetyl group; an acetyl thiosulfate salt; a cyano group; a alkylmethylene group (together with R7); or an alkoxymethylene group (together with R7); R4 is hydrogen or methyl,
R5 is hydrogen;
R^ is hydrogen, alkanoyl, aminocarbonyl, or alkoxycarbonyl;
R7 is hydrogen, halogen, hydroxy, alkoxy, alkanoyloxy, carbalkoxyl, a methylene group (together with R3), or an alkoxymethylene group (together with R3);
Rg is hydrogen or halogen;
R, is hydrogen, halogen, alkyl, alkoxy, arylalkoxy or amino; and
R10 is hydrogen, halogen, alkyl, haloalkyl, hydroxy, alkoxy, alkanoyloxy, carbalkoxyl, cyano, thiocyano or mercapto; or a prodrug thereof. Typical GABAA 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 2β- or 3β-substitution. The endogenously occurring neuroactive steroids such as those described in
WO96/15782 do not contain 3 β -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 3β- substituted derivatives circumvent these problems and provide anti-migraine agents with less side effects and which are orally active.
The potency of modulating the GABAA receptor may be determined in an assay for inhibition of [35SJTBPS 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.
Table 1
IC50 'MA
Name (nM) %
3β-(4'-Acetylphenyl)ethynyl-3α-hydroxy-5α-pregπan-20-one 4 90
3β-(4'-Acetylphenyl)ethynyl-3α,21-dihydroxy-5α-pregnan-20-one 4 92
3β-(4-Acetylphenyl)ethynyl-3α,21-dihydroxy-5α-pregnan-20-one 21 - 5 83 hemisuccinate sodium salt
3 β-(4'- Acetylphenyl)ethyny 1-3 α-hydroxy- 19-nor-5 β-pregnan-20-one 6 90
3β-(4'-Chlorophenyl)ethynyl-3α-hydroxy-5α-pregnan-20-one 6 38
3β-(4'-Carboxyphenyl)ethynyl-3α-hydroxy-5α-pregnan-20-one ethyl ester 7 79
3β-(4'-Carboxyphenyl)ethynyl-3α-hydroxy-5β-pregnan-20-one ethyl ester 8 97
3α-Hydroxy-3β-[4'-(l-oxopropyl)phenyl]ethynyl-5β-pregnan-20-oπe 9 95
3β-(4'-Hydroxybutyn- 1 '-yl)-3α-hydroxy-5β-pregnan-20-one 13 103
3 β-(4'- Acety lpheny l)ethyny 1-3 α-hydroxy-5 β-pregnan-20-one 14 97
3α-Hydroxy-2β-propoxy-21 -(pyrid-4-ylthio)-5α-pregnan-20-one 14 98
3β-(4'-Carboxyphenyl)ethynyl-3α-hydroxy-19-nor-5β-pregnan-20-one 15 94 ethyl ester
3 α-Hydroxy-3 β-(4-hydroxybutyny l)-21 -(pyrid-4-y lthio)-5 β-pregnan-20- 15 100 one
3α-Hydroxy-3β-(4'-methylphenyl)ethynyl-5α-pregnan-20-one 15 26
3β-(4-Acetylphenyl)ethynyl-3α,21 -dihydroxy-5β- 19-nor-pregnan-20-one 15 98
3β-(4'-Acetylphenyl)ethynyl-3α-hydroxy-17β-methoxy-19-nor-5β- 16 100 androstane
2β-propy loxy-3 α-hydroxy-5 α-pregnan-20-one 17 99
3α,21 -Dihydroxy-3β-[4'-( l-oxocyclopropylmethyl)phenyl]ethynyl-5β- 18 94 pregnan-20-one
3 β-(4'-Trifluoromethylphenyl)ethyny 1-3 α-hydroxy-5 α-pregnan-20-one 18 74
3α-Hydroxy-3β-(4'-methoxyphenyl)ethynyl-5α-pregnan-20-one 19 102
3α,20α-Dihydroxy-21 -methyl-2β-n-propoxy-5α-pregnane 19 34
3α,20α-Dihydroxy-21 -ethyl-5α-pregnane 20 13
3β-(4'-Acetoxybutyn-l'-yl)-3α-hydroxy-5β-pregnan-20-one 20 96
3β-(4-Acetylphenyl)ethynyl-l l α-dimethylamino-3α-hydroxy-5β-pregnan- 20 97 20-one ιc50 'MAX
Name (nM) %
3β-(4'-Acetylphenyl)ethynyl-3α-hydroxy-17β-methoxy-5β-androstane 20 104
2β-Ethynyl-3α-hydroxy-5α-pregnan-20-one 21 88
3α-Hydroxy-3β-(phenylethynyl)-5α-pregnan-20-one 21 35
2β-ethoxy-3α-hydroxy-5α-pregnan-20-one 22 96
3β-(4'-Hydroxybutyn- -yl)-3α-hydroxy-5β-19-nor-pregnan-20-one 22 102
3β-Cycloproρylethynyl-3α-hydroxy-5β-pregnan-20-one 22 94
3β-(4-Acetylphenyl)ethynyl-3α,21 -dihydroxy-5β-pregnan-20-one 22 99
3α-Hydroxy-3β-(indan-l -on-5-yl)ethynyl-5β-pregnan-20-one 22 102
3 α,21 -Dihydroxy-3 β-[4'-( 1 -oxopropyOpheny l]ethynyl-5β-pregnan-20-one 22 101
3α,21-Dihydroxy-3β-[4'-( l-oxopropyl)phenyl]ethynyl-5β-pregnan-20-one 22 104 21-hemisuccinate sodium salt
3 α-Hydroxy-3 β-methyl-5β- 19-nor-pregnan-20-one 23 94
3α-Hydroxy-21-(pyrid-4-ylthio)-5α-pregnan-20-one 23 98
2β-Ethyl-3α-hydroxy-5α-pregnan-20-one 23 99
3α-Hydroxy-2β-isopropoxy-5α-pregnan-20-one 24 94
3α-Hydroxy-3β-(3'-methyl-but-3'-en- 1 '-ynyl)-5β-pregnan-20-one 24 91
21-(4'-N,N-Dimethylaminophenoxy)-3α-hydroxy-2β-propoxy-5α- 28 88 pregnan-20-one
3α-hydroxy-5β-pregnan-20-one 25 64
3β-(chloroethynyl)-3α-hydroxy-5β-pregnan-20-one 26 87
3β-(4'-Hydroxybutyn- 1 '-yl)-3α-hydroxy- 17β-methoxy-5 β-androstane 26 105
3β-(4-Carboxaldehydephenyl)ethynyl-3α-hydroxy-5α-pregnan-20-one 26 41
3β-azidomethyl-3α-hydroxy-5α-pregnan-20-one 27 98
3α-Hydroxy-3β-(3'-methoxy- 1 '-propynyl)-5β-pregnan-20-one 27 105
3 α-Hydroxy- 17β-methoxy-3 β-(3'-methy l-but-3'-en- 1 '-yny l)-5 β-androstane 27 108
3β-(But-3'-en-r-ynyl)-3α-hydroxy-5β-pregnan-20-one 27 103
3β-(4'-Dimethylaminophenyl)ethynyl-3α-hydroxy-5β-pregnan-20-one 28 77
3β-[3-(2-propynyloxy)propyn-l -yl]-3α-hydroxy-5β-pregnan-20-one 28 105
3β-(4-Acetylphenyl)ethynyl-3α,21 -dihydroxy-5β- 19-nor-pregnan-20-one 28 89 21-hemisuccinate sodium salt IC5„ I MAX
Name (nM) %
3β-(4'-Acetylphenyl)ethynyl-3α-hydroxy-21-(pyrid-4-ylthio)-5β-pregnan- 29 94 20-one
3α-Hydroxy-2β-isopropoxy-17β-methoxy-5α-androstane 30 107
3 α-Hydroxy-3 β-( 1 -propyny l)-5 β-pregnan-20-one 31 93
3β-[4'-(carbmethoxy)methylphenyl]ethynyl-3α-Hydroxy-5β-pregnan-20- 32 92 one
3α,21-Dihydroxy-3β-(4'-methylphenyl)ethynyl-5α-pregnan-20-one 32 66
3α-hydroxy-3β-methyl-5β-pregnan-20-one 33 103
3α-Hydroxy-3β-(thien-2-yl)ethynyl-5β-pregnan-20-one 33 82
3α,20α-Dihydroxy-21-methyl-5α-pregnane 34 26
3β-(4-Carboxaldehydephenyl)ethynyl-3α-hydroxy-5β-pregnan-20-one 34 36
3 β-[4-[ 1 , 1 -( 1 ',2'-bismethoxycarbonyl)ethylenedioxy]ethyl]pheny lethyny 1]- 34 96 3α-hydroxy-5β-pregnan-20-one
3 β-ethyny 1-3 α-hydroxy-5 β-pregnan-20-one 35 105
3β-(4'-Hydroxybutyn- 1 '-yl)-3α-hydroxy-5α-pregnan-20-one 35 95
3α-Hydroxy-21-(3'-hydroxypropylthio)-2β-propoxy-5α-pregnan-20-one 35 101
3α-Hydroxy-21-(3'-hydroxypropylsulfonyl)-2β-propoxy-5α-pregnan-20- 36 99 one
3β-(4'-Acetylphenyl)ethynyl-21-chloro-3α-hydroxy-5α-pregnan-20-one 36 77
3α-hydroxy-5α-pregnan-20-oπe 37 96
3β-(4-Acetylphenyl)ethynyl-3α,21 -dihydroxy-5β-pregnan-20-one 21 - 37 96 hemisuccinate sodium salt
3α-Hydroxy-2β-(3'-methoxy-r-propynyl)-5α-pregnan-20-one 38 93
3α,21-Dihydroxy-3β-[4'-(l-oxocyclopropylmethyl)phenyl]ethynyl-5β- 38 101 pregnan-20-one 21 -hemisuccinate sodium salt
2α-Ethyl-3α-hydroxy-5α-pregnan-20-one 38 55
3β-Ethynyl-3α-hydroxy-19-nor-5β-pregnan-20-one 39 98
3α-hydroxy-3β-methoxymethyl-5β-pregnan-20-one 40 103
3α-Hydroxy-3β-methoxymethyl-21-(pyrid-4-ylthio)-5α-pregnan-20-one 40 97
3α-Hydroxy-3β-(5'-oxo-l-hexynyl)-5β-pregnan-20-one cyclic 5'-(l,2- 41 99 ethanediyl acetal)
3 β-etheny 1-3 α-hydroxy- 5 β-pregnan-20-one 42 102 >c50 'MAX
Name (nM) %
3β-(4'-biphenyl)ethynyl-3α-hydroxy-5β-pregnan-20-one 43 83
3β-Ethynyl-3α-hydroxy-21-(pyrid-4-ylthio)-5α-pregnan-20-one 43 103
3β-(l-Hexynyl)-3α-hydroxy-5β-pregnan-20-one 44 101
3β-(5'-Chloropentyn-l'-yl)-3α-hydroxy-5β-pregnan-20-one 44 98
3β-(5-Acetylthien-2-yl)ethynyl-3α-hydroxy-5β-pregnan-20-one 44 84
3α-Hydroxy-21 -(pyrid-4-yl)oxy-5β-pregnan-20-one 45 76
3 α-Hydroxy-3 β-(4'-nitropheny l)ethynyl-5 β-pregnan-20-one 46 103
3α-hydroxy-21-(2'H-l,2,3,4-tetrazol-2'-yl)-5β-pregnan-20-one 46 78
3β-(4'-Carboxyphen l)ethynyl-3α,21 -dihydroxy-5β-pregnan-20-one ethyl 46 99 ester
3 α-hydroxy-pregn-4-en-20-one 47 66
3α-Hydroxy-3β-(4'-methoxyphenyl)ethynyl-5β-pregnan-20-one 47 89
3β-(4'-Hydroxybutyn- 1 '-yl)-3α-hydroxy- 17β-methoxy-5α-androstane 47 104
3α-Hydroxy-21-(l '-benzimidazolyl)-5β-pregnan-20-one 49 63
3 β-Ethyny 1-3 α-hydroxy- 17β-methoxy-5 β-androstane 49 101
3α-Hydroxy-2β-phenylethynyl-5α-pregnan-20-one 49 93
21 -(4'-Fluorophenylsulfony l)-3α-Hydroxy-3β-methoxymethyl-5α- 49 99 pregnan-20-one
3α-hydroxy-3β-ethynyl-5α-pregnan-20-one 50 94
3α-Hydroxy-3β-(2'-propynyl)-5α-pregnan-20-one 50 43
3α-Hydroxy-2β-methyl-5α-pregnan-20-one 50 80
3β-Ethyl-3α-hydroxy-5β-pregnan-20-one 50 98
3α-Hydroxy-3β(E)-(2-phenylethenyl)-5α-pregnan-20-one 51 19
3β-(4'-benzophenyl)ethynyl-3α-hydroxy-5β-pregnan-20-one 51 99
2 β-m ethoxy-3 α-hydroxy-5α-pregnan-20-one 52 97
3β-(4'-Trifluoromethylphenyl)ethynyl-3α-hydroxy-5β-pregnan-20-one 52 87
3β-Ethynyl-3α-hydroxy- 17β-methoxy-5 β- 19-nor-androstane 52 109
3β-(4'-Hydroxybutyn-r-yl)-3α-hydroxy-21-(l'-imidazolyl)-5β-pregnan- 54 93 20-one
3 β-(4'-Chlorophenyl)ethyny 1-3 α-hydroxy-5β-pregnan-20-one 55 87
3α-Hydroxy-21 -[4'-(p-acetylphenyl)piperazino]-5β-pregnan-20-one 55 86 IC» ' AX
Name (nM) %
3β-(4'-Hydroxyburyn-l '-yl)-3α-hydroxy-21 -( 1 ,2,3-triazol-2-yl)-5β- 19-nor- 56 93 pregnan-20-one
3α-Hydroxy-21 -(2H- 1 ,2,3-triazol-2-yl)-5β-pregnan-20-one 56 79
3α-Hydroxy-2β-propoxy-21-sulfonylpropanesulfate-5α-pregnan-20-one 56 89 sodium salt
3β-(5'-Hydroxypentyn-l '-yl)-3α-hydroxy-5β-pregnan-20-one 58 100
3α-Hydroxy-21 -(pyrid-4-ylthio)-5β-pregnan-20-one 59 74
3α-Hydroxy-5β- 19-nor-pregnan-20-one 59 91
21 -(Benzimidazo-2-ylthio)-3α-hydroxy-5α-pregnan-20-one 60 76
3β-[4-( 1 , 1 -Dimethoxyethylpheny l)ethyny 1-3 α,21 -dihydroxy-5β-pregnan- 61 90 20-one
3α-Hydroxy-21 -[ 1 H-(4-methy l-5-carboxyl)imidazol- 1 -yI)-5β-pregnan-20- 62 100 one ethyl ester
3α-Hydroxy-17β-methoxy-5β-androstane 62 106
3β-(5-Acetylthien-2-yl)ethynyl-3α,21-dihydroxy-5β-pregnan-20-one 62 98
3β-( 1 -Octynyl)-3α-hydroxy-5β-pregnan-20-one 63 99
3β-(4'-Chlorophenyl)ethynyl-3α,21 -dihydroxy-5α-pregnan-20-one 63 75
3α-Hydroxy-3β-(phenylethynyl)-5β-pregnan-20-one 64 83
3α-Hydroxy- 17β-methoxy-3β-methoxymethyl-5α-androstane 64 100
3β-( 1 -Heptynyl)-3α-hydroxy-5β-pregnan-20-one 65 100
%o2 65 106
3α,21 -dihydroxy-3β-phenylethynyl-5α-pregnan-20-one 65 64
3α-hydroxy-3β-chloromethyl-5α-pregnan-20-one 66 33
3α-Hydroxy-3β-[3'-(2H- 1 ,2,3-triazol-2-yl)- l'-propynyl]-5β-pregnan-20- 66 98 one
3α-Hydroxy-3β-methoxymethyl-21-(4'-nitrophenylsulfonyl)-5α-pregnan- 66 98 20-one
3α-Hydroxy-3β-[(3',4'-methylenedioxyphenyl)ethynyl]-5β-pregnan-20- 66 91 one
3β-Chloroethynyl-3α,21-dihydroxy-5β-pregnan-20-one 66 100
3 α-Hydroxy-2 β-methy 1-5 β-pregnan-20-one 66 93
3α-hydroxy-17β-cyano-5α-androstane 67 93 IC5o •MAX
Name (nM) %
3α-Hydroxy-2β-propoxy-21-thiopropanesulfonate-5α-pregnan-20-one 67 101 sodium salt
3α,21-Dihydroxy-3β-(3'-methyl-but-3'-en-r-ynyl)-5β-pregnan-20-one 67 101 21 -hemisuccinate sodium salt
3 α-hydroxy-5 α-pregn- 1 -en-20-one 67 101
Bis (3α,21-dihydroxy-3β-ethynyl-5β-pregnan-20-one) 21 -hemisuccinate 68 56
3α-hydroxy-3β-methyl-5α-pregnan-20-one 69 92
3α-Hydroxy-21 -(9'H-purin-9'-yl)-5β-pregnan-20-one 69 59
3β-(l-Hexynyl)-3α-hydroxy-5α-pregnan-20-one 69 84
3 α-hydroxy-3 β-methoxymethyl-5α-pregnan-20-one 71 102
3α-Hydroxy-3β-[4'(R/S)-hydroxypentynyl]-5β-pregnan-20-one 71 103
3α-Hydroxy-21 -( 1 '-imidazolyl)-5α-pregnan-20-one 71 99
3α-Hydroxy-3β-(4'-trimethyIsilyloxybutyn-r-yl)-5β-19-nor-pregnan-20- 71 96 one
3α,21-Dihydroxy-3β-(3'-methyl-but-3'-en- -ynyl)-5β-pregnan-20-one 71 100
3β-(4-Acetylphenyl)ethyl-3α,21 -dihydroxy-5β-pregnan-20-one 72 96
3β-(4'-Cyanophenyl)ethynyl-3α-hydroxy-5β-pregnan-20-one 73 92
3α,21 -dihydroxy-5α-pregnan-20-one 21 -acetate 75 99
3α-Hydroxy-3β-(2'-propenyl)-5β-pregnan-20-one 75 98
3β-(3',3'-Dimethyl-r-butynyl)-3α-hydroxy-5β-pregnan-20-one 75 1 10
3 α,21 -dihydroxy-5 α-pregnan-20-one (5α-THDOC) 76 100
21 -chloro-3α-hydroxy-5α-pregnan-20-one 76 100
3α-Hydroxy-3β-trifluoromethyl-19-nor-5β-pregnan-20-one 76 101
3 α-Hydroxy-21 -( 1 '-i idazoly l)-5 β-pregnan-20-one 76 51
3α-Hydroxy-2β-(2'-propynyloxy)-5α-pregnan-20-one 76 94
3α-Hydroxy-3β-(4-methylsulfιnyI)phenylethynyl-5β-pregnan-20-one 76 109
3α-Hydroxy-21-(pyrid-3-yl)oxy-5β-pregnan-20-one 76 76
3α-hydroxy-3β-methyl-21-(quinolin-6-yloxy)-5α-pregnan-20-one 76 96
3 β-(But-3 '-en- 1 '-yny l)-3 α,21 -dihydroxy-5 β-pregnan-20-one 77 101
3 α-Hydroxy-3 β-methoxymethy 1-21 -(4'-nitrophenylsulfιnyl)-5α-pregnan- 77 100 20-one I MAX
Name (nM) %
3α-hydroxy-21 -methyl-5β-pregnan-20-one 78 87
3β-(4-Carbethoxyphenyl)ethynyl-3α,21-dihydroxy-5β-pregnan-20-one 78 100 21 -hemisuccinate sodium salt
3α,21 -Dihydroxy-3β-(4'-nitrophenyl)ethynyl-5β-pregnan-20-one 78 97
3β-Ethynyl-3α-hydroxy-5β-pregn-l l-en-20-one 79 97
3α-Hydroxy-3β-(pentafluorophenyl)ethynyl-5β-pregnan-20-one 79 69
3β-(4'-Hydroxybutyn-r-yl)-3α-hydroxy-5β-pregnan-20-one 4'- 79 105 hemisuccinate sodium salt
3β-(4'-Hydroxybutyn-l'-yl)-3α-hydroxy-21-(l,2,3-triazol-l -yl)-5β- 79 96 pregnan-20-one
2β-fluoro-3α-hydroxy-5α-pregnan-20-one 80 95
1 1 α-Dimethylamino-3β-ethynyl-3α-hydroxy-5β-pregnan-20-one 80 93
3β-Ethynyl-3α-Hydroxy-21-( l'-imidazolyl)-5β-pregnan-20-one 80 103
3β-(4'-Hydroxybutyl)-3α-hydroxy-5β-pregnan-20-one 80 98
3α-Hydroxy-3β-[3'-(lH-pyrazol- l-yl)-l '-propynyl]-5β-pregnan-20-one 81 98
3α-Hydroxy-21-(lH-3,5-dimethylpyrazolyl)-5β-pregnan-20-one 81 71
21 -[ 1 '-(4,5-Dichloro)imidazolyl]-3α-hydroxy-5β-pregnan-20-one 81 65
3α-Hydroxy-21-[4'-(2-pyrimidyl)piperazino]-5β-pregnan-20-one 82 85
3 α-hydroxy-5 β-pregn- 1 1 -en-20-one 83 88
3α-Hydroxy-3β-methyl-21-(2'H-l',2',3'-triazol-2'-yl)-5α-pregnan-20-one 85 99
3α,20α-Dihydroxy-2β-iso-propoxy-5α-pregnane 86 77
3β-[4'-(N,N-diethylcarboxamidophenyl)ethynyl-3α-hydroxy-5β-pregnan- 87 94 20-one
3α-Hydroxy-3β-(3'-methyl-but-3'-en-l '-ynyl)-5α-pregnan-20-one 88 95
3α-hydroxy-2β-trimethylsilylethynyl-5α-pregnan-20-one 88 90
2β-(4-Acetylphenyl)ethynyl-3α-hydroxy-5α-pregnan-20-one 88 74
3α-hydroxy-3β,21 -dimethyl-5α-pregnan-20-one 89 85
3α-Hydroxy-21-(imidazo-2-ylthio)-5α-pregnan-20-one 89 99
3α-Hydroxy-21 -(pyrid-2-ylthio)-5β-pregnan-20-one 90 66
3α-Hydroxy-3β-(4'-methylphenyl)ethynyl-5β-pregnan-20-one 90 86
3α-Hydroxy-3β-(6-oxo-l-heptynyl)-5β-pregnan-20-one 90 101 ICso 'MAX
Name (nM) %
3α-Hydroxy-3β-methyl-21-(4'-nitrophenoxy)-5α-pregnan-20-one 90 98
3 β-(4'-Hydroxybutyn- 1 '-y l)-3 α-hydroxy-21 -( 1 ,2,4-triazol- 1 -yl)-5β- 93 96 pregnan-20-one
3β-(4'-Hydroxybutyn- 1 '-yl)-3α-hydroxy-21 -(tetrazol- 1 -yl)-5β-pregnan-20- 93 101 one
3β-Ethynyl-3α-hydroxy-21-(3'-hydroxypropylthio)-5β-pregnan-20-one 93 97
3α,21-Dihydroxy-3β-(4'-methoxyphenyl)ethynyl-5β-pregnan-20-one 93 95
3β-(3'-Bromo-l-propynyl)-3α-hydroxy-5β-pregnan-20-one 94 88
3α-Hydroxy-21-(adenin-9-yl)-5β-preganan-20-one 94 45
3α-hydroxy-21 -methoxymethyl-5β-pregnan-20-one 96 66
3α-Hydroxy-21 -(pyrazol- 1 -yl)-5β-pregnan-20-one 96 63
3β-(5'-Acetoxypentyn-l'-yl)-3α-hydroxy-5β-pregnan-20-one 96 98
3α-Hydroxy-21 -( 1 '-imidazolyl)-3β-methyl-5α-pregnan-20-one 97 95
3α-Hydroxy- 17β-methoxy-3β-methyI-5α-androstane 97 97
3 α-hydroxy- 17β-methoxy-3 β-trifluoromethy l-5β- 19-nor-androstane 97 107
3 α-hydroxy-3 β-methy 1-21 -methoxymethyl-5 α-pregnan-20-one 98 102
3β-(4'-Hydroxybutyn- 1 '-yl)-3α-hydroxy-21 -( 1 '-imidazoly l)-5β~ 19-nor- 98 98 pregnan-20-one
3α,20α(S)-dihydroxy-5α-pregnane 100 42
3 α-Hydroxy-21 -( 1 '-pyrazolyl)-5α-pregnan-20-one 100 98
3β-(3'-Acetylphenyl)ethynyl-3α-hydroxy-5β-pregnan-20-one 100 39
3α-Hydroxy-2β-methylpregn-4-en-20-one 100 93
3α,21 -dihydroxy-5α-pregnan-20-one 21 -mesylate 101 97
3β-(2'-Hydroxyphenyl)ethynyI-3α-hydroxy-5β-pregnan-20-one 101 38
N-(3α-hydroxy-3β-methyl-5α-pregnan-20-ylidine)ethanolamine 101 93
3α-Hydroxy-2β-(2'-methoxyethoxy)-5α-pregnan-20-one 101 103
3 α-Hydroxy-3 β-methoxymethyl-21 -(4'-nitropheny lthio)-5α-pregnan-20- 102 99 one
3 α-Hydroxy-3 β-(3'-pheny 1- 1 '-propynyl)-5β-pregnan-20-one 103 95
3 α-Hydroxy-3 β-(3 '-pyridylethynyl)-5 β-pregnan-20-one 103 89
3α-hydroxy-3β-methyl-5α-19-nor-pregnan-20-one 105 79 ιc50 'MAX
Name (nM) %
3β-Ethynyl-3α-Hydroxy-21-(l '-pyrazolyl)-5β-pregnan-20-one 106 99
2β-fluoro-3α,20α-dihydroxy-5α-pregnane 107 48
Sodium S-[3α-hydroxy-3β-(4'-hydroxybutynyl)-5β-pregnan-20-on-21-yl] 107 97 thiosulfate
3α-Hydroxy-3β-(2'-pyridylethynyl)-5β-pregnan-20-one 108 98
3 β-(4'-Hydroxybutyn- 1 '-y l)-3 α-hydroxy- 17β-methoxy-5β-androstane 4'- 108 100 hemisuccinate sodium salt
3β-Benzyl-3α-hydroxy-5β-pregnan-20-one 109 103
3β-(2,4-Difluorophenyl)ethynyl-3α-hydroxy-5β-pregnan-20-one 109 102
21-(r-Benzimidazolyl)-3α-hydroxy-3β-methyl-5α-pregnan-20-one 109 95
3β-Ethynyl-3α-hydroxy-21 -(thiopropanesulfate)-5β-pregnan-20-one 1 13 104 sodium salt
3α,21-Dihydroxy-3β-(l -propynyl)-5β-pregnan-20-one 1 14 101
3α,21-Dihydroxy-3β-(4-nitrophenyl)ethynyl-5β-pregnan-20-one 21- 1 14 103 hemisuccinate sodium salt
3α-Hydroxy-21-(l'-pyrazolyl)-3β-methyl-5α-pregnan-20-one 1 15 98
2β-Ethynyl-3α-hydroxy-5α-pregnan-20-one 3α-hemisuccinate sodium salt 1 15 100
3-(4-n-Butylphenyl)- 1 -(4-n-butylbenzenesulfonyl)- 1 ,4,5,6,- 1 16 27 tetrahydropyridazine
3α-Hydroxy-21-[5H-pyrazolo-(3,4-d)pyrimid-4-one]-5β-pregnan-20-one 1 16 53
3β-(4'-Chlorophenyl)ethynyl-3α-hydroxy-21 -( 1 '-imidazolyl)-5α-pregnan- 1 16 73 20-one
3 α,21 -dihydroxy-5α-pregnan-20-one 21 -hemisuccinate 1 17 91
3β-ethenyl-3α-hydroxy-5α-pregnan-20-one 1 18 93
3α-Hydroxy-3β-(5'-oxo-l-hexynyl)-5β-pregnan-20-one 1 18 101
3 α-Hydroxy- 18-methy 1-3 β-trifluoromethyl- 19-nor-5 β-pregnan-20-one 1 18 104
3 α,21 -dihy droxy-5 β-pregnan-20-one 21 -acetate 1 19 49
21 -Bromo-3 α-hy droxy-5 β- 19-nor-pregnan-20-one 1 19 84
21-Chloro-3α-hydroxy-3β-methyl-5α-pregnan-20-one 121 81
3β-Ethynyl-3α-hydroxy-17β-methoxy-5α-androstane 122 106
3β-(4'-Hydroxybutyn- 1 '-yl)-3α-hydroxy-21 -( 1 ,2,3-triazol- 1 -yl)-5β- 19-nor- 124 95 pregnan-20-one IC50 'MAX
Name (nM) %
3β-(4'-Fluorophenyl)ethynyI-3α-hydroxy-5β-pregnan-20-one 124 94
3α-Hydroxy-3β-methyl-21-(r,2',4'-triazolyl)-5α-pregnan-20-one 125 105
3α-Hydroxy-2β-propoxy-21 -(pyrid-4-ylthio)-5α-pregnan-20-one N- 126 101 methyl iodide
3β-(5-Acetylthien-2-yl)ethynyl-3α,21 -dihydroxy-5β-pregnan-20-one 21 - 126 102 hemisuccinate sodium salt
3α-hydroxy-5α-pregn- 17(Z)-ene 127 66
3 α-hydroxy-3 β-methy 1-5 α-pregn-9-en-20-one 127 87
3β-Ethynyl-3α-hydroxy-2]-(r,2',4'-triazolyl)-5β-pregnan-20-one 127 98
21-(4'-Aminophenylthio)-3α-hydroxy-3β-methoxymethyl-5α-pregnan-20- 127 89 one
3α,21-Dihydroxy-3β-ethynyl-5α-pregnan-20-one 127 102
3β-(4-Acetylphenyl)ethyl-3α,21 -dihydroxy-5β-pregnan-20-one 21 - 129 98 hemisuccinate sodium salt
3 α-Hydroxy-21 -methoxycarbony 1-3 β-trifluoromethyl- 19-nor-5β-pregnan- 129 1 12 20-one
3α-Hydroxy-2β-propoxy-21 -(4'-N,N,N-trimethylaminophenoxy)-5α- 129 92 pregnan-20-one iodide salt
3β-(4'-Cyano- 1 '-butynyl)-3α-hydroxy-5β-pregnan-20-one 131 86
21 -(Benzimidazo-2-ylthio)-3α-hydroxy-3β-methyl-5α-pregnan-20-one 132 80
Sodium S-(3α-hydroxy-3β-methoxymethyl-5α-pregnan-20-on-21-yl) 132 103 thiosulfate
3β-Ethenyl-3α-hydroxy-17β-methoxy-5α-androstane 133 104
3α,21 -dihydroxy-3β-(3'-methoxy- 1 '-propynyl)-5β-pregnan-20-one 133 103
3 α,20α-Dihydroxy-2β-ethoxy-5 α-pregnane 134 81
3α-Hydroxy-2α-(2'-propenyl)-5α-pregnan-20-one 134 93
3α-Hydroxy-3β-(2'-phenylethyl)-5β-pregnan-20-one 135 98
3α,20α-Dihydroxy-2β-n-propoxy-5α-pregnane 135 94
3β-ethyl-3α-hydroxy-5β-pregnan-20-one 136 94
3α-Hydroxy-21-(l'-imidazolyl)-5α-pregnan-20-one hydrogen bromide 136 99
3 α-Hydroxy-3 β-methyl-21 -( 1 ',2',3'-triazol- 1 '-yl 5α-pregnan-20-one 136 99
Sodium S-(3α-hydroxy-5α-pregnan-20-on-21-yl) thiosulfate 136 100 ICso 'MAX
Name (nM) %
3 α-Hydroxy-3 β-(3'-hydroxypropyny l)-5 β-pregnan-20-one 137 87
3α-Hydroxy-3β-[3'(RS)-hydroxybutynyl]-5α-pregnan-20-one 140 99
3α-Hydroxy-21-(2'-hydroxyethylthio)-5β-pregnan-20-one 141 71
3β-Ethenyl-3α-hydroxy-21 -iodo-5α-pregnan-20-one 141 46
3β-[4'-(hydroxyacetyl)phenyl)ethynyl-3α-hydroxy-5β-pregnan-20-one 144 99
3α,21-Dihydroxy-3β-(4-methoxyphenyl)ethynyl-5β-pregnan-20-one 21 - 148 106 hemisuccinate sodium salt
3α-Hydroxy-3β-(4'-pyridylethynyl)-5β-pregnan-20-one 149 103
3α-Hydroxy-21 -methoxy-5α-pregnan-20-one 150 100
3β-[4-(l(R/S)-Hydroxyethyl)phenyl]ethynyl-3α,21 -dihydroxy-5β- 150 98 pregnan-20-one
Sodium S-(3α-hydroxy-3β-methyl-5α-pregnan-20-on-21 -yl) thiosulfate 151 101
3 α-Hydroxy-21 -( 1 \2',4'-triazol- 1 -y l)-5 β-pregnan-20-one 151 60
3α-Hydroxy-3β-[4'(R/S)-hydroxypentynyl]-5β-pregnan-20-one 4'(R/S)- 153 90 hemisuccinate sodium salt
3β-Chloroethynyl-3α,21 -dihydroxy-5β-pregnan-20-one 21 -hemisuccinate 153 104 sodium salt
3α-Hydroxy-3β-methyl-5β-19-nor-pregn-17(Z)-ene 154 99
3β-(5'-Cyanopentynyl)-3α-hydroxy-5β-pregnan-20-one 158 100
3β-(4-Acetyl-3-hydroxyphenyl)ethynyl-3α,21-dihydroxy-5β-pregnan-20- 159 97 one
3α-hydroxy-3β-propyl-5α-pregnan-20-one 162 42
3 β-[4-(Hydroxyacetyl)pheny l]ethyny 1-3 α,21 -dihydroxy-5 β-pregnan-20- 162 101 one
3α-Hydroxy-3β-methyl-17β-(2-propynyloxy)-5α-androstane 163 94
3β-Ethynyl-3α-hydroxy-21-methoxy-5β-pregnan-20-one 164 102
21-(4'-N,N-Dimethylaminophenoxy)-3α-hydroxy-3β-rnethyl-5α-pregnan- 167 91 20-one
5 α-pregnan-3 ,20-dione 168 15
3 α-Hydroxy-21 -( 1 'H-pyrazol- 1 '-y l)-5β- 19-nor-pregnan-20-one 169 80
3α-hydroxy-5β-pregn- 17(Z)-ene 170 63
3α-Hydroxy-21 -( 1 '-imidazoly l)-5β- 19-nor-pregnan-20-one 170 71 ICso 'MAX
Name (nM) %
3β-(4'-Acetoxyacetylphenyl)ethynyl-3α-hydroxy-5β-pregnan-20-one 171 91
3 α-Hydroxy-3β-(3 '-phenylpropyl)-5 β-pregnan-20-one 173 92
3 β-(4-Acetyl-2-hydroxyphenyl)ethynyl-3α,21 -dihydroxy-5β-pregnan-20- 174 94 one
3α,20-dihydroxy-20-methyl-5α-pregnane 176 40
20,20-ethylenedioxy-3α-hydroxy-5α-pregnan-20-one 176 86
21-(4'-Fluorophenylthio)-3α-hydroxy-3β-methoxymethyl-5α-pregnan-20- 176 97 one
3 α-Hydroxy-3 β-[4'(R/S)-hydroxypentynyl]-5 α-pregnan-20-one 178 101
3α,21-Dihydroxy-3β-ethynyl-5β-pregnan-20-one 21 hemisuccinate 179 82
3α,21-dihydroxy-5β-pregnan-20-one (5β-THDOC) 180 55
3α-Hydroxy-3β-meth l-21 -methylsulfonyl-5α-pregnan-20-one 180 96
21-Bromo-3α-hydroxy-3β-ethynyl-5α-pregnan-20-one 180 96
3β-Ethynyl-3α-hydroxy-21-(2'-hydroxyethylthio)-5β-pregnan-20-one 180 103
21-[9'H-(2,4-Diaminopurin-9'-yl)-3α-hydroxy-5β-pregnan-20-one 183 62
3α-Hydroxy-21-(imidazo-2-ylthio)-5β-pregnan-20-one 184 80
3α-Hydroxy-21 -(4-pyridylmethyl)-5β-pregnan-20-one 187 103
3β-(Bromomethyl)-3α-hydroxy-5α-pregnan-20-one 188 44
3α-Hydroxy-21 -(pyrid-4-ylthio)-5α-pregnan-20-one N-methyl iodide 188 100
Bis (3α,21-dihydroxy-3β-trifluoromethyl-5β-pregnan-20-one) 21 - 189 23 hemisuccinate
3β-Ethynyl-3α-hydroxy-21-(3'-hydroxypropylsulfonyl)-5β-pregnan-20- 194 107 one
3 α-hydroxy- 1 1 α-dimethylamino-5β-pregnan-20-one 198 70
3β-(4'-Chlorophenyl)ethynyl-3α,21-dihydroxy-5β-pregnan-20-one 198 97
3α,20α-dihydroxy-3β-methyl-5α-pregnane 199 50
3 α-Hydroxy-3 β-methyl-21 -methylthio-5α-pregnan-20-one 200 101
3α,20α-Dihydroxy-3β-ethynyl-5α-pregnane 202 56
3α-Hydroxy-3β-[3'(RS)-hydroxybutynyl]-5β-pregnan-20-one 202 102
3 α-Hydroxy-3 β-trifluoromethy 1-5 β-pregn- 1 1 -en-20-one 203 99
21 -[ 1 '-(4,5-Dicyano)imidazolyl]-3α-hydroxy-5β-pregnan-20-one 203 63 ICso 'MAX
Name (nM) %
3α,20β-dihydroxy-5β-pregnane 206 53
3α-hydroxy-17β-methoxy-3β-trifluoromethyl-5β-androstane 207 100
21-(4'-N,N-Dimethylaminophenylthio)-3α-hydroxy-3β-methoxymethyl- 208 74 5 α-pregnan-20-one
3α-Hydroxy-3β-methoxymethyl-21-(4'-pyrrolidιnophenyl)sulfonyl-5α- 208 101 pregnan-20-one
3β-(5'-Hydroxypentyn-l'-yl)-3α-hydroxy-5β-pregnan-20-one 5'- 209 101 hemisuccinate sodium salt
3α,21 -dihydroxy-3β-methyl-5α-pregnan-20-one 21-Hemisuccιnate, 21 1 104 sodium salt
3α-hydroxy-3β-fluoromethyl-5α-pregnan-20-one 213 78
3α-Hydroxy-3β-(2'-propynyl)-5β-pregnan-20-one 213 101
21-[ -(2'-Carboxaldehyde)imidazolyl]-3α-hydroxy-5β-pregnan-20-one 213 81
3α,21-Dihydroxy-3β-ethynyl-5β-pregnan-20-one 216 104
3α-hydroxy-2 l-methyl-5α-pregnan-l 7(Z)-ene 217 50
3α-hydroxy-3β-trifluoromethyl-5β-pregnan-20-one 218 97
3α-Hydroxy-21 -[ 1 'H-(4'-nitro)imidazol- 1 '-yl)]-5β-pregnan-20-one 218 71
3 α-hydroxy-5 α-pregn-9-en-20-one 222 90
3β-(6-Hydroxyhexyn-l-yl)-3α-hydroxy-5β-pregnan-20-one 222 103
3 α-Hydroxy-21 -[ 1 H-(2-methy l)imidazol- 1 -yl)-5 β-pregnan-20-one 222 95
3α,21 -dihydroxy-5β-pregnan-20-one 21 -hemisuccinate 224 71
3β-(3'-Acetoxypropyn- 1 '-yl)-3α-hydroxy-5β-pregnan-20-one 224 104
3 α-hydroxy-5 β-pregn-9-en-20-one 225 106
3α,21 -dihydroxy-3β-methyl-5α-pregnan-20-one 21-dibenzylphosphate 225 105
3 α,21 -Dihydroxy-3 β-ethyny 1- 19-nor-5β-pregnan-20-one 225 95
3 α,21 -Dihydroxy-3 β-[4'-( 1 -oxopropyl)phenyl]ethy I-5β-pregnan-20-one 225 96 21 -hemisuccinate sodium salt
3β-(Ethoxymethyl)-3α-hydroxy-5α-pregnan-20-one 227 102
3 α-hydroxy-21 -( 1 'H- 1 ,2,3 ,4-tetrazo 1- 1 '-y 1 )-5 β-pregnan-20-one 227 60
3 α-Hydroxy-3 β-(2'-propeny l)-5 α-pregnan-20-one 227 60
3α-Hydroxy-5β- 19-nor-pregn- 17(Z)ene 229 89 ICso 'MAX
Name (nM) %
3α,2 l-Dihydroxy-3β-trifluoromethyl- 19-nor-5β-pregnan-20-one 229 97
3 α-hydroxy-3 β-chloromethy 1-5 β-pregnan-20-one 231 103
1 l α-N,N-dimethylamino-3α-hydroxy-3β-trifluoromethyl-5β-pregnan-20- 235 96 one
3α-Hydroxy-21 -(pyrid-4-ylsulfinyl)-5β-pregnan-20-one 235 73
3α-hydroxy-3β-hydroxyethoxymethyl-5α-pregnan-20-one 237 94
3α-hydroxy-3β-(2'-methoxyphenyl)ethynyl-5β-pregnan-20-one 238 99
21 -Chloro-3α-hydroxy-2β-morpholino-5α-pregnan-20-one 239 97
3α,21-dihydroxy-3β-methyl-5α-pregnan-20-one 21 -Hemisuccinate 241 92
3α-Hydroxy-3β-methyl-5α-pregn-l l-en-20-one 242 76
3α,2β-Dihydroxy-5α-pregnan-20-one 2β-tosylate 248 93
3α-hydroxy-3β-ethyl-5α-pregnan-20-one 249 68
3α,21-dihydroxy-5α-pregnan-20-one 21 -hemisuccinate, sodium salt 251 92
3α,21-Dihydroxy-3β-ethynyl-5β-pregnan-20-one, 21 -acetate 251 101
3 α-hydroxy-21 -methoxy-3 β-trifluoromethy l-5β- 19-nor-pregnan-20-one 252 104
3α-hydroxy-3β-methyl-21-(quinolin-6-yloxy)-5α-pregnan-20-one N- 252 102 methyl iodide
3α-hydroxy-3β-trifluoromethyl-5α-pregnan-20-one 254 43
3α-Hydroxy-17β-ethynyl-5α-androstane 254 83
3α,2 l-dihydroxy-3β-methyl-5α-pregnan-20-one 21 -mesylate 255 100
3α-Hydroxy-21 -( -pyrazolyl)-3β-trifluoromethyl-5β-19-nor-pregnan-20- 257 1 10 one
3α,21-dihydroxy-3β-methyl-5α-pregnan-20-one 258 96
3α-Hydroxy-21-(4'-pyridyl)thio-5β-pregnan-20-one N-methyl iodide 263 53
3α,20-dihydroxy-3β,20-dimethyl-5α-pregnane 264 46
Sodium S-(3α-hydroxy-5β-pregnan-20-on-21-yl) thiosulfate 268 88
3β-(4'-Hydroxybutyn-l '-yl)-3α-hydroxy-5β-pregnan-l 1,20-dione 268 102
3β-(But-3-enyl)-3α-hydroxy-5α-pregnan-20-one 272 58
3β-[4'-(hydroxyacetyl)phenyl]ethynyI-3α-hydroxy-5β-pregnan-20-one 275 109 hemisuccinate sodium salt
3 α-Hydroxy-3 β-trifluoromethyl- 19-nor-5α-pregnan-20-one 278 42 ICso 'MAX
Name (nM) %
3β-[(3',4'-Dirnethoxyphenyl)ethynyl]-3α-hydroxy-5β-pregnan-20-one 283 106
3β-(Bromomethyl)-3α-hydroxy-5β-pregnan-20-one 283 1 1 1
3 β-Ethyny l-3α,21 -dihydroxy-5β- 19-nor-pregnan-20-one 21 - 283 101 hemisuccinate sodium salt
3α,2 l-dihydroxy-3β-methyl-5α-pregnan-20-one 21 -acetate 284 93
3 α,21 -Dihydroxy-3 β-etheny l-5α-pregnan-20-one 288 101
3α,20α-dihydroxy-5β-pregnane 292 85
3α,21-dihydroxy-5β-pregn-l l -en-20-one 292 86
3α-Hydroxy-21-(pyrid-3-yl)oxy-5β-pregnan-20-one N-oxide 292 62
3α-Hydroxy-3β-[3-(4(R/S)-hydroxy-2-pentynoxy)-l -propynyl]-5β- 295 98 pregnan-20-one
3β-(4'-Acetylphenyl)ethynyl-3α-hydroxy-5β-19-nor-androstane 295 81
3α-hydroxy-5α-pregnan-l 1 ,20-dione (Alphaxalone) 297 93
3α-Hydroxy-5β-pregn-20-ene-oxide 298 102
3α,21 -Dihydroxy-3β-(3-rnethoxy- 1 -propynl)-5β-pregnan-20-one 21 - 299 100 hemisuccinate sodium salt
21-Bromo-3α-hydroxy-5β-pregnan-20-one 302 88
Sodium S-(3 α-hydroxy-3 β-trifluoromethyl- 19-nor-5 β-pregnan-20-on-21 - 302 98 yl)thiosulfate
3 α,21 Dihydroxy-3β-( 1 -propyny l)-5β-pregnan-20-one 21 -hemisuccinate 303 105 sodium salt
3 α-Hydroxy-21 -( 1 H- 1 ,2,4-triazol- 1 -y I)-3 β-triΩuoromethy 1-5 β- 19-nor- 304 95 pregnan-20-one
3α-hydroxy-5α-androstan-17β-carboxylic acid, methyl ester 306 74
3 β-(6'- Acetoxyhexyn- 1 *-y l)-3 α-hydroxy-5 β-pregnan-20-one 306 99
3 α-Hydroxy-3 β-trifluoromethyl- 19-nor-5β-pregnan-20-one 21 - 306 1 10 carboxylate potassium salt
3α-Hydroxy-21-(l'-imidazolyl)-5β-pregnan-20-one hydrogen bromide 309 66
21-Bromo-3β-ethynyl-3α-hydroxy-5β-pregnan-20-one 315 106
3α,21-Dihydroxy-3β-(2'-propynyl)-5α-pregnan-20-one 316 82
17β-[3-(4-Acetylphenyl)-2-propynyloxy]-3α-hydroxy-3β-methyl-5α- 316 95 androstane 5337
-21-
ICso 'MAX
Name (nM) %
3α-Hydroxy-3β-{4'-[l(R/S)-hydroxyethyl]phenyl}ethynyl-17β-methoxy- 319 97 19-nor-5β-androstane
3α-hydroxy-5α-pregn-16-en-20-one 322 86
3β-Ethynyl-3α-hydroxy-21-thioethanesulfate-5β-pregnan-20-one 322 101 trimethylammonium salt
3α-Hydroxy-21-(7- and 9-hypoxanthine)-5α-pregnan-20-one 335 98
3β-(4'-Hydroxyacerylphenyl)ethynyl-3α-hydroxy-17β-methoxy-5β- 335 97 androstane
3α-hydroxy-17β-methoxy-3β-trifluoromethyl-5α-androstane 341 100
3β-Ethynyl-3α-hydroxy-21-thiopropanesulfonate-5β-pregnan-20-one 343 97 sodium salt
3α-hydroxy- 17(Z)-methoxymethylene-5α-androstane 346 101
3α,21 -Dihydroxy-3 β-trifluoromethy I-5β-pregnan-20-one 21 -propionate 347 104
3α-Hydroxy-3β-trifluoromethyI-5β-pregn-9(l l)-en-20-one 350 87
3α,21 -Dihydroxy-3β-trifluoromethyl-5β-pregnan-20-one 356 102
21 -Bromo-3 α-hydroxy-3 β-methoxymethyl-5α-pregnan-20-one 356 101
3β-(Buta-2,3-dienyl)-3α-hydroxy-5α-pregnan-20-one 358 57
3α,21 -dihydroxy-5β-pregn- 1 1 -en-20-one, 21 -acetate 360 78
3 β-Ethyny 1-3 α-hydroxy-5 β-pregnan- 11 ,20-dione 360 99
3β-Chloromethyl-3α-hydroxy-17β-methoxy-5α-androstane 361 98
3 α-Hydroxy-21 -( 1 '-i idazoly l)-3 β-trifluoromethy 1-5 β- 19-nor-pregnan- 366 105 20-one
3α-hydroxy-17(Z)-methoxymethylene-19-nor-5α-androstane 367 98
3α,21 -Dihydroxy-3β-trifluoromethyl-5β-pregnan-20-one, 21-acetate 370 88
3α-hydroxy-3β-benzyloxymethyl-5α-pregnan-20-one 371 57
3 a ,21 -Dihydroxy-3 β-etheny 1-5 α-pregnan-20-one 21 -hemisuccinate 377 89
3β-[4-[ 1 , 1 -(1 ',2'-carboxy)ethylenedioxy]ethyl]phenylethynyl]-3α- 379 107 hydroxy-5β-pregnan-20-one dipotassium salt
3α-Hydroxy-3β-methyl-21-morpholino-5α-pregnan-20-one 380 105
3α,21 -dihydroxy-5α-pregn-9-en-20-one 21 -acetate 381 38
3α-hydroxy-3β-phenyl-5β-pregnan-20-one 382 86
21 -Bromo-3 α-hydroxy-3 β-trifluoromethyl- 19-nor-5β-pregnan-20-one 386 95 ICso 'MAX
Name (nM) %
3α-Hydroxy-21-(4'-piperidone ethylene ketal)-5β-pregnan-20-one 387 83
3α-Hydroxy- 17β-methoxy-3β-(2'-propynyl)-5α-androstane 387 101
3α-Hydroxy-3 β-(4-hydroxy- 1 -butyny l)-21 -(1 '-uracil)-5β-pregnan-20-one 399 103
3α, 17α-dihydroxy-5α-pregnan-20-one 400 102
3β-(3'-Hydroxyphenyl)ethynyl-3α-hydroxy-5β-pregnan-20-one 407 99
3α-Hydroxy-21-moφholino-5β-pregnan-20-one hydrobromide salt 407 71
3α-Hydroxy-3β-methyl-21-(4'-trimethylaminophenoxy)-5α-pregnan-20- 407 101 one iodide salt
3[21-(3α-Hydroxy-5α-pregnan-20-one)ylthio]-propanoic acid 409 83
3α-Hydroxy-21-(l '-pyrazolyl)-3β-trifluoromethyl-5β-pregnan-20-one 410 98
21 -ethoxymethyl-3α-hydroxy-3β-methyl-21 -methylene-5α-pregnan-20- 421 97 one
3α-Hydroxy-2β-moφholino-5α-pregnan-20-one 421 100
3α-hydroxy-3β-trifluoromethyl-5β-pregnan-l l,20-dione 430 97
3α-Hydroxy-21-(7'H-purin-7'-yl)-5β-pregnan-20-one 430 71
3β-Acetoxyethoxymethyl-3α-hydroxy-5α-pregnan-20-one 434 99
3α-Hydroxy-21-(3'-methyl-l'-imidazoly -5β-pregnan-20-one iodide 441 50
3α-hydroxy-17β-hydroxymethyl-5α-androstane 455 69
3α,20β-dihydroxy-3β-methyl-5β-pregnane 455 105
3α-Hydroxy-2β-isopropoxy-5α-androstane 456 98
3 β-Ethyny 1-3 α-hydroxy-5β- 19-nor-pregn- 17(Z)-ene 460 98
3 β-(3'-Hydroxypropyn- 1 '-y l)-3α-hydroxy-21 -( 1 ,2,3-triazol-2-y l)-5β- 464 100 pregnan-20-one
3α-Hydroxy-21 -( 1 '-uracil)-5α-pregnan-20-one 464 90
3α-hydroxy- 19-nor-5α-pregn- 17(Z)-ene 465 97
3α-Hydroxy-3β-[3'-(pyrid-4-yloxy)- -propynyl]-5β-pregnan-20-one 465 94
3α-Hydroxy-21-(r-imidazolyl)-3β-trifluoromethyl-5β-pregnan-20-one 466 103
2β-Fluoro-3α,20β-dihydroxy-5α-pregnane 468 73
3β-Chloromethyl-3α-hydroxy-5α-pregnan-20-one 20-glycolic acid ketal 476 85
3α,21-Dihydroxy-3β-trifluoromethyl-5β-pregnan-20-one methyl 21- 480 86 succinate
Figure imgf000025_0001
ICso 'MAX
Name (nM) %
3α-Hydroxy-3β-[3'-( 1 H- 1 ,2,3-triazol- 1 -yl)- 1 '-propynyl]-5β-pregnan-20- 655 102 one
3α-hydroxy-3β-methyl-5α- 19-nor-pregn- 17(Z)-ene 662 93
3 α-Hydroxy-5 β-pregn- 16-en-20-one 663 98
3α-Hydroxy-3β-methyl-21 -methylsulfinyl-5α-pregnan-20-one 666 93
3α-Hydroxy-3β-propoxymethyl-5α-pregnan-20-one 682 92
3α-hydroxy-17-methylene-5α-androstane 687 70
3α,20β-Dihydroxy-3β-ethynyl-5β-pregnane 688 77
Dimethyl (3α-hydroxy-3β-methyl-5α-pregnan-20-onyl)phosphonate 698 102
3α,20-Dihydroxy-3β-ethynyl-20-methyl-5β-pregnane 703 97
3α,20α-Dihydroxy-3β-methoxymethyl-5α-pregnane 704 62
3α-hydroxy-3β-(2',2',2'-rrifluoroethoxymethyI)-5α-pregnan-20-one 706 109
3 β- Acety 1-3 α-hydroxy-5 β-pregnan-20-one 707 104
3α,21 -Dihydroxy-3β-trifluoromethyl-5β-pregnan-20-one, 21- 712 99 hemisuccinate, sodium salt
3α-hydroxy-5β-methylpregnan-20-one 714 86
3α-Hydroxy-21-sulfonic acid-5β-pregnan-20-one 21 -sodium salt 732 62
3 α-hydroxy- 17(Z)-methoxymethy lene-5 β-androstane 734 75
3α-Hydroxy-21-[2'(S)-carboxypyrrol-l -yl]-5β-pregnan-20-one methyl 736 97 ester
17α,20α-epoxy-3α-hydroxy-5α-pregnane 748 101
3 α-hydroxy-3 β-methoxymethy 1-5 α-pregn- 16-en-20-one 752 103
3α-hydroxy-3β-iodomethyl-5α-pregnan-20-one 764 49
3α,20β-Dihydroxy-3β-ethynyl-5α-pregnane 774 107
3β-Ethynyl-3α-hydroxy-21-(3'-hydroxypropylsulfιnyl)-5β-pregnan-20-one 782 107
3α-hydroxy-3β-[2-(phenylsulfinyl)ethyl]-5α-pregπan-20-one 796 79
3 α-Hydroxy-5β-androstane 815 83
1 ,7-Bis-(3α-hydroxy-5α-pregnan-20-on-2 l-yl)-hypoxanthine 816 68
3α-Hydroxy-3β-t2-(n-butylsulfιnyl)ethyl]-5α-pregnan-20-one 833 109
21-Bromo-3α-hydroxy-3β-trifluoromethyl-5β-pregnan-20-one 835 83 IC,o 'MAX
Name (nM) %
3 α-Hydroxy-3 β-[3'-( 1 H- 1 ,2,4-triazol- 1 -yl)- 1 '-propynyl]-5β-pregnan-20- 843 99 one
3α,20-Dihydroxy-3β-methyl-5α-pregn-20-ene 20-hemisuccinate sodium 887 102 salt
3α-hydroxy-3β-methyl-5α-pregn-16-en-20-one 899 101
3 α,21 -Dihydroxy-3 β-fluoromethy l-5α-pregnan-20-one 21 -hem isuccinate 907 86
3α,20-Dihydroxy-3β-ethynyl-20-methyl-5α-pregnane 910 89
3α-Hydroxy-3 β-methyl-21 ,21 ,21 -Trifluoromethyl-5α-pregnan-20-one 915 101
3α-lsobutyryloxy- 17β-methoxy-5 β-androstane 916 73
20,20-ethylenedioxy-3α-hydroxy-5β-pregnan-20-one 921 84
3 α-hydroxy-3 β-methyl-5 α-pregnane- 1 1 ,20-dione 958 100
3α,20β-Dihydroxy-5β-pregn-l 1-ene 979 101
Certain NMDA receptor antagonists are represented by the Formula //:
Figure imgf000027_0001
or a tautomer thereof; wherein
R is hydrogen, hydroxy, amino, -CH2CONHAr, -NHCONHAr, NHCOCH2Ar, -COCH2Ar, wherein Ar is an aryl group, or a radical having the Formula ///:
Figure imgf000027_0002
wherein R6 is hydrogen, lower alkyl of 1-6 carbon atoms or aryl; R7 is hydrogen or lower alkyl of 1-6 carbon atoms; n is an integer from 0 to 5; and R8 is hydrogen, C,.6 alkyl, or aralkyl;
R', R2, R3, and R4 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 R1 and R\ R2 and R3, or R3 and R4 form a fused 5- or 6-membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring.
Such l,4-dihydroquinoxaline-2,3-diones are disclosed in U.S. Patent No. 5,514,680. See also WO95/12417. Preferred l,4-dihydroquinoxaline-2,3-diones and related compounds are listed in Table 2. Also listed in Table 2 is the in vitro and in vivo potency of the compounds which was determined according to U.S. Patent No. 5,514,680.
Table 2
DCK IC50 Kb MES ED50
Name nM nM mg kg
7-Chloro-6-methy 1-5-nitro- 1 ,4-dihydroquinoxaline-2,3-dione 5 8 1
6-Chloro-7-methyl-5-nitro- 1 ,4-dihydroquinoxaline-2,3-dione 35 35 2
7-Fluoro-6-methyl-5-nitro-l,4-dihydroquinoxaline-2,3-dione 88 73 2
6-Bromo-7-fluoro-5-nitro- 1 ,4-dihydroquinoxaline-2,3-dione 43 3.5
6,7-Dimethy 1-5-nitro- 1 ,4-dihydroquinoxaline-2,3-dione 34 39 3.7
5,6,7-Trifluoro-l,4-dihydroquinoxaline-2,3-dione 1925 3670 4
6,7-Dichloro-5-nitro- 1 ,4-dihydroquinoxaline-2,3-dione 5 2.7 4.5
6-Chloro-7-fluoro-5-nitro- 1 ,4-dihydroxyquinoxaline-2,3-dione 70 4.5
6-Bromo-7-chloro-5-nitro- 1 ,4-dihydroquinoxaline-2,3-dione 7 5
7-Bromo-6-methy 1-5-nitro- 1 ,4-dihydroquinoxaline-2,3-dione 9 6 5
7-Chloro-5-nitro- 1 ,4-dihydroquinoxaline-2,3-dione 190 5
7-Chloro-5-cyano-6-methyl- 1 ,4-dihydroquinoxaline-2,3-dione 26 12 6
7-Bromo-6-chloro-5-nitro-l,4-dihydroquinoxaline-2,3-dione 8 7.5
7-Fluoro-6-methoxy-5-nitro- 1 ,4-dihydroquinoxaline-2,3-dione 1939 320 7.5
6-Azido-7-fluoro-5-nitro-l ,4-dihydroquinoxaline-2,3-dione 280 7.5
6-Chloro-7-ethyl-5-nitro- 1 ,4-dihydroxyquinoxaline-2,3-dione 30 20 7.5
5-Cyano-6,7-dichloro- 1 ,4-dihydroquinoxaline-2,3-dione 31 16 8
7-Chloro-6-methoxy-5-nitro- 1 ,4-dihydroquinoxaline-2,3-dione 142 8.5
5,7-Dichloro-l ,4-dihydroquinoxaline-2,3-dione 276 390 8.7
6,7-Dibromo-5-nitro- 1 ,4-dihydroquinoxaline-2,3-dione 22 5 10
5-Chloro-7-trifluoromethyl- 1 ,4-dihydroquinoxaline-2,3-dione 2242 370 10
7-Chloro-5-trifluoromethyl-l ,4-dihydroquinoxaline-2,3-dione 395 10
6-Chloro-5,7-difluoro- 1 ,4-dihydroquinoxaline-2,3-dione 578 1000 10
6-Bromo-7-ethyl-5-nitro- 1 ,4-dihydroquinoxaline-2,3-dione 70 27 10
7-Chloro-5-(N-oxy)aza- 1 ,4-dihydroquinoxaline-2,3-dione 812 600 1.3
7-Methy l-5-(N-oxy)aza- 1 ,4-dihydroquinoxaline-2,3-dione 1040 2400 1.3
7-Bromo-5-(N-oxy)aza- 1 ,4-dihydroquinoxaline-2,3-dione 1.3 DCK IC50 Kb MES ED50
Name nM nM mg/kg
5-Aza-7-chloro-4-hydroxy-3-(m-phenoxyphenyl)quinoline-2( 1 H 168 1 1 3 )-one
7-nitro-5-(N-oxy)aza- 1 ,4-dihydroquinoxaline-2,3-dione 149 320 4
6,7,8,9-Tetrahydro-6,7-dimethyl-3-hydroxy-l H-l-benzazepine- 222 120 5 2,5-dione
6,8-Dimethyl-3-hydroxy-lH-l-benzazepine-2,5-dione 293 800 5
3-Cyano-6,7-dichloro-2-oxo- 1 ,2-dihydroquinoxaline-4-oxide 135 5
5-(N-Oxy)aza-7-trifluoromethyl-l ,4-dihydroquinoxaline-2,3-dio 934 6700 6 ne
7-Chloro-6-methyl-5-(N-oxy)aza-l ,4-dihydroquinoxahne-2,3-di 140 7 one
7,8-Dimethyl-3-hydroxy-lH-l-benzazepine-2,5-dione 227 86 7.5
6,7,8,9-Tetrahydro-3-hydroxy-l H-l-benzazepine-2,5-dione 3184 740 7.5
6,7-Dichloro-8-(N-oxy)aza-l,4-dihydroquinoxaline-2,3-dione 140 7.5
8-Chloro-3-hydroxy-l H-l-benzazepine-2,5-dione 13 26 12.5
7-Bromo-6-methy l-5-(N-oxy)aza- 1 ,4-dihydroquιnoxaline-2,3-di 80 15 one
3-Acetyloxime-5,7-dichloroquinoline-2,3,4-trione 72 20
7,8-Dichloro-6,7,8,9-tetrahydro-3-hydroxy-lH- l-benzazepine-2 131 42 30 ,3-dιone
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-2,3-dione; 7- chloro-5-nitroquinoxaline-2,3-dione; 7-chloro-6-methyl-5-cyanoquinoxaline-2,3- dione; 7-bromo-6-chloro-5-nitroquinoxaline-2,3-dione; 7-fluoro-6-methoxy-5- nitroquinoxaline-2,3-dione; 6-azido-7-fluoro-5-nitroquinoxaline-2,3-dione; 6- chloro-7-ethyl-5-nitroquinoxaline-2,3-dione; 6,7-dichloro-5-cyanoquinoxaline- 2 , 3 - d i o n e ; 7-chloro-6-methoxy-5-nitroquinoxaline-2,3 -dione ; 5,7- dichloroquinoxaline-2,3-dione; 6,7-dibromo-5-nitroquinoxaline-2,3-dione; 5- chloro-7-trifluoromethylquinoxaline-2,3-dione; 7-chloro-5 - trifluoromethylquinoxaline-2,3-dione; 6-chloro-5,7-difluoroquinoxaline-2,3- dione; 5-chloro-7-trifluoromethylquinoxaline-2,3-dione; and 6-bromo-7-ethyl-5- nitroquinoxaline-2,3-dione.
Also preferred are aza-l,4-dihydroquinoxaline-2,3-diones and the N-oxy derivatives thereof described in WO95/18616. 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-(N-oxy)azaquinoxaline-2,3-dione. Other 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 -benzazepine-2,5-dione; and 7,8-dichloro- 6-methyl-6,7,8,9-tetrahydro-3-hydroxy-l-benzazepine-2,5-dione.
Other preferred 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.
With respect to the formulae above:
The term "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 C2.4 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 C6.Η aryl groups.
Typical aralkenyl groups include any of the above-mentioned C^ alkenyl groups substituted by any of the above-mentioned C6.14 aryl groups.
Typical aralkynyl groups include any of the above-mentioned C2J) alkynyl groups substituted by any of the above-mentioned C6.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 C2.6 substituted acyl groups.
Typical alkanoyloxy groups include any C,.6 acyloxy groups, e.g. acetoxy, propionoyloxy, butanoyloxy, pentanoyloxy, hexanoyloxy and the like.
The term "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, ω-thiocaprolactam, and moφholine 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.
The term "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 π 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 alcohol, carbazole, 9H-pyrido[3,4-b]indole, isoquinoline, pyrrole, thiophene, furan, 9(10H)-acridone, phenoxazine, phenothiazine, as well as benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, 2H-pyrrolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 4//-quinolizinyl, phthalzinyl, naphthyridinyl, quinozahnyl, cinnolinyl, pteridinyl, 5αH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acrindinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, furazanyl phenoxazinyl groups, 1 ,4- dihydroquinoxaline-2,3-dione, 7-aminoisocoumarin, pyrido[l ,2-a]pyrimidin-4- one, l,2-benzoisoxazol-3-yl, 4-nitrobenzofurazan, 2-oxindolyl and 2- oxobenzimidazolyl groups, each of which may be optionally substituted. Where the heteroaryl group contains a nitrogen atom in a ring, such 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 CM0 alkyl groups substituted by any of the above-mentioned heteroaryl groups.
Typical heteroaralkenyl groups include any of the above-mentioned C2.4 alkenyl groups substituted by any of the above-mentioned heteroaryl groups.
Typical heteroaralkynyl groups include any of the above-mentioned C2.4 alkynyl groups substituted by any of the above-mentioned heteroaryl groups.
Typical amino groups include -NΗ2, -NHR14, and -NRl4R15, wherein R14 and R15 are C,.10 alkyl groups as defined above.
Typical carbonylamido groups are carbonyl groups substituted by -NH2, -NHR14, and -NR14R15 groups as defined above. The term "dioic acids" refers to CI 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. The term "β-acetyl-thiosulfate salt" refers is intended to include the sodium, lithium, potassium, magnesium and calcium salts thereof.
The term "pharmaceutically acceptable 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.
When the group is an amidino or guinidino group, 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. trifluoromethyl), amino, mercapto, alkylthio, alkylsulfinyl, alkylsulfonyl, nitro, alkanoyl, alkanoyloxy, alkanoyloxyalkanoyl, alkoxycarboxy, carbalkoxy (-COOR, wherein R is lower alkyl), carboxamido (-CONRR', wherein R and R' are independently lower alkyl), formyl, carboxy 1, hydroxy, cyano, azido, keto and cyclic ketals thereof, alkanoylamido, heteroaryloxy, heterocarbocyclicoxy, and hemisuccinate ester salts. 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.
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.
Examples of prodrugs include ester or amide of formula I with R,-R4 as hydroxyalkyl or aminoalkyl, by reacting such compounds with an 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.
By "substantially simultaneously" is intended that the GABAA 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.
The 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.
Further, since certain of the GABAA receptor ligands and NMDA receptor antagonists behave synergistically in vivo, it is expected that much lower levels of the two drugs will be administered resulting in improved economy and efficacy. 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. In practice, the GABAA receptor agonists and neuroactive steroids may be administered to humans by oral, intramuscular, i.v. or patch delivery. Because the potencies of neuroactive steroids vary, and the bioavailability of these compounds by different routes of administration also vary, typically, 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.
For example, if the neuroactive steroid is delivered by i.v. injection, a dose of 1-100 μg/kg may be administered. When the neuroactive steroid is administered by i.v., preferred compounds are water soluble steroids. Examples include 2β-morpholinyl derivatives such as [(2β,3α,5α)-3-hydroxy-2-(2,2- dimethylmoφholin-4-yl)pregnan-l 1,20-one (Anderson, A. et al, J. Med. Chem. 40:1668-1681 (1997), 1 1 -N,N-dimethyl derivatives such as l l-α-N,N- dimethylamino-2β-ethoxy-3α-hydroxy-5α-pregnan-20-one, 21 -imidazolyl derivatives such as 3α-hydroxy-21-( -imidazolyl)-3β-methoxymethyl-5o.- pregnan-20-one and the ester derivative prodrugs such as 3α,21-dihydroxy-3β- trifluoromethyl-19nor-5β-pregnane, 21 -hemisuccinate, sodium salt. For water insoluble steroids, 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).
For oral delivery, steroids with low bioavailability, such as 3α-hydroxy- 3β-methyl-5α-pregnan-20-one, a dose of lOOμg/kg to lOmg/kg should be administered. However, for steroids with relative high bioavailability, such as 2β-ethynyl-3α-hydroxy-5α-pregnane-20-one3α-hydroxy-3β-trifluoromethyl-5β- 19-nor-pregnan-20-one or 3 α,21-dihydroxy-3 β-trifluoromethy l-19-nor-5β- pregnan-20-one, 21 -hemisuccinate, sodium salt, a lower dose of 20 μg/kg to 2 mg/kg may be administered. When the steroids are delivered by oral administration, they may be prepared in solution complexed with 2-hydroxy-β- cyclodextrin or with β-cyclodextrin and suspended in ora Plus®/ora Sweet® to improve palatability. When the neuroactive steroids are used for prophylactic treatment of migraine, the agents are preferably taken after a meal to assure good adsoφtion. For intramuscular injection, 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
Kulagowski et al, J. Med. Chem. 57:1402-1405 (1994), including 7-chloro-4- hydroxy-3-(3-phenoxyphenyl)quinolin-2(lH)-one. For oral route of administration, a dose of 0.1 to 10 mg/kg should be administered. For intramuscular injection, the dose is generally about half of the oral dose. For acute treatment of migraine headaches, these agents may be given by i.v. or i.m. injection followed by oral treatment. Preferably, 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. For prophylactic treatment of migraine headaches, these agents are preferably administered by oral route of administration either alone or in combination.
When neuroactive steroids and NMDA receptor antagonists are given in combination, lower doses of drugs should be administered than when they are given alone. For example, when the neuroactive steroid is 3α-hydroxy-3β- methyl-5α-pregnan-20-one and the NMDA receptor antagonist is 6,7-dichloro- l,4-dihydro-5-nitroquinoxaline-2,3-dione, the oral dose may be about 10 μg/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.
For other compounds listed in Tables 1 and 2, 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 GABAA receptor agonist and NMDA receptor antagonist may be administered separately or as part of a unitary composition. When administered separately, 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 GABAA 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. In addition to administering the compound as a raw chemical, 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. Preferably, 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. Preferably, for acute treatment of migraine headache, the compounds are administered i.v. as part of a pharmaceutically acceptable aqueous solution that may also contain buffers or salts.
The pharmaceutical compositions of the invention may be administered to any animal which may experience the beneficial effects of the compounds of the invention. Foremost among such animals are mammals, e.g., humans, although the invention is not intended to be so limited.
The pharmaceutical compositions of the present invention may be administered by any means that achieve their intended puφose. For example, administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, or buccal routes. Alternatively, or concurrently, 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
GABAA 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. If desired, 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. For this puφose, 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. In order to produce coatings resistant to gastric juices, solutions of 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. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin. In addition, stabilizers may be added. Pharmaceutical preparations 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. In addition, it is also possible to use 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. In addition, 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. Optionally, the suspension may also contain stabilizers. Since the steroidal GABAA 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.
Having now fully described this invention, it will be understood by those of ordinary skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations and other parameters without affecting the scope of the invention or any embodiment thereof. All patents and publications cited herein are fully incoφorated by reference herein in their entirety.

Claims

What Is Claimed Is;
1. A method of treating or preventing migraine headache, comprising administering to an animal in need of such treatment at least one of a GABAA receptor agonist and an NMDA receptor antagonist.
2. The method of claim 1 , wherein said GAB AA receptor agonist and
NMDA receptor antagonist are administered substantially simultaneously.
3. The method of claim 2, wherein said GABAA receptor agonist is a neuroactive steroid.
4. The method of claim 2, wherein said GABAA receptor agonist is 3α-hydroxy-3β-methyl-5α-pregnan-20-one, 3α-hydroxy-3β-trifluoromethyl-5β-
19-nor-pregnan-20-one or 3α,21 -dihydroxy-3β-trifluoro-methyl- 19-nor-5β- pregnan-20-one, 21 -hemisuccinate, sodium salt, and said NMDA receptor antagonist is 6,7-dichloro-l,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.
5. The method of claim 2, wherein said GAB AA receptor agonist and NMDA receptor antagonist are administered as part of a pharmaceutical composition which also comprises a pharmaceutically acceptable carrier.
6. The method of claim 2, wherein said GABAA receptor agonist and NMDA receptor antagonist are administered separately.
7. The method of claim 6, wherein said GAB AA receptor agonist and NMDA receptor antagonist are administered as part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
8. The method of claim 2, wherein said GABAA receptor agonist and NMDA receptor antagonist are administered together as part of a single composition.
9. The method of claim 8, wherein said GABAA receptor agonist and NMDA receptor antagonist are administered together as part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
10. The method of claim 1 , which comprises administering a GABAA receptor agonist and not an NMDA repector antagonist.
11. The method of claim 10, wherein said GAB AA receptor agonist is 3α-hydroxy-3β-methyl-5α-pregnan-20-one, 3α-hydroxy-3β-trifluoromethyl-5β-
19-nor-pregnan-20-one or 3α,21 -dihydroxy-3 β-trifluoromethyl- 19-nor-5 β- pregnan-20-one, 21 -hemisuccinate, sodium salt.
12. The method of claim 1 , which comprises administering an NMDA receptor antagonist and not a GABAA repector agonist.
13. The method of claim 12, wherein said NMDA receptor antagonist is 6,7-dichloro-l,4-dihydro-5-nitroquinoxaline-2,3-dione or 7-chloro-4-hydroxy- 3-(3-phenoxyphenyl)quinolin-2(lH)-one.
14. A composition of matter comprising a GABAA receptor agonist and an NMDA receptor antagonist.
15. The composition of claim 14, wherein said GABAA receptor agonist is a neuroactive steroid.
16. The composition of claim 14, wherein said GABAA receptor agonist is 3α-hydroxy-3β-methyl-5α-pregnan-20-one, 3α-hydroxy-3β- trifluoromethyl-5β-19-nor-pregnan-20-one or 3α,21-dihydroxy-3β- trifluoromethyl-19-nor-5β-pregnan-20-one, 21 -hemisuccinate, sodium salt, and said 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.
17. A pharmaceutical composition, comprising a GABAA receptor agonist and an NMDA receptor antagonist and a pharmaceutically acceptable carrier.
18. The composition of claim 17, wherein said GABAA receptor agonist is a neuroactive steroid.
19. The pharmaceutical composition of claim 18, wherein said GABAA receptor agonist is 3α-hydroxy-3β-methyl-5α-pregnan-20-one, 3α- hydroxy-3 β-trifluoromethy 1-5 β-19-nor-pregnan-20-one or 3α,21-dihydroxy-3β- trifluoro-methyl-19-nor-5β-pregnan-20-one, 21 -hemisuccinate, sodium salt, and said NMDA receptor antagonist is 6,7-dichloro-l,4-dihydro-5-nitroquinoxaline- 2,3-dione, or a pharmaceutically acceptable salt thereof.
20. A kit comprising a carrier means having in close confinement therein two or more container means, wherein the first container means comprises a GABAA receptor agonist and the second container comprises an NMDA receptor antagonist.
21. The kit of claim 20, wherein said GABAA receptor agonist is a neuroactive steroid.
22. The kit of claim 21, wherein said GABAΛ receptor agonist is 3α- hydroxy-3β-methyl-5α-pregnan-20-one, 3α-hydroxy-3β-trifluoromethyl-5β-19- nor-pregnan-20-one or 3 α,21 -dihydroxy-3 β-trifluoro-methyl- 19-nor-5 β-pregnan- 20-one, 21 -hemisuccinate, sodium salt, and said 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(l -r)-one, or a pharmaceutically acceptable salt thereof.
23. The kit of claim 21, wherein said GABAA receptor agonist and NMDA receptor antagonist are present as part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
PCT/US1997/013430 1996-08-01 1997-07-31 Use of gaba and nmda receptor ligands for the treatment of migraine headache WO1998005337A1 (en)

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