WO1994015920A1 - Benzanilide derivatives as 5-ht1d-antagonists - Google Patents

Benzanilide derivatives as 5-ht1d-antagonists Download PDF

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Publication number
WO1994015920A1
WO1994015920A1 PCT/EP1993/003708 EP9303708W WO9415920A1 WO 1994015920 A1 WO1994015920 A1 WO 1994015920A1 EP 9303708 W EP9303708 W EP 9303708W WO 9415920 A1 WO9415920 A1 WO 9415920A1
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Prior art keywords
compound
group
methyl
formula
alkyl
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PCT/EP1993/003708
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English (en)
French (fr)
Inventor
Malcolm Carter
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Glaxo Group Limited
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Priority claimed from GB929227125A external-priority patent/GB9227125D0/en
Priority claimed from GB929227116A external-priority patent/GB9227116D0/en
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to AU58155/94A priority Critical patent/AU5815594A/en
Publication of WO1994015920A1 publication Critical patent/WO1994015920A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D327/02—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms one oxygen atom and one sulfur atom
    • C07D327/04—Five-membered rings

Definitions

  • This invention relates to novel benzanilide derivatives, to processes for their preparation, and to pharmaceutical compositions containing them.
  • R 1 is inter alia the group
  • R 13 is inter alia a substituted triazolyl group
  • R 2 and R 3 each represents inter alia H, halogen C 1-4 alkyl or C 1-4 alkoxy; and r is zero, 1 or 2.
  • the compounds lack the characteristic piperazinyl substituent of the compounds of the present invention, and differ from the presently claimed compounds in their utility.
  • A is N or CH
  • Q is a single bond, C 1-3 alkylene, O or NR 16 ;
  • Q' Q" and Q"' is each inter alia a single bond
  • R 1 is an aromatic substituent
  • R 3 is inter alia
  • R 4 is inter alia a C 1 -12 alkyl group substituted by inter alia, an N- heterocyclic group bound to the alkyl via the cyclic nitrogen atom and capable of containing O, S or NR 16 as a further hetero ring member;
  • X-Y is inter alia -CONH-.
  • the compounds are said to have platelet activating factor antagonist activity. There is no suggestion of compounds wherein there are two phenyl rings between the heterocyclic group and the amide linkage
  • R 2 -CONH-R 3 wherein R 2 and R 3 each represents an optionally substituted aryl group. There is no suggestion of the particular substituted phenyl moieties of the compounds of the present invention.
  • R 1 represents a hydrogen atom, a halogen atom, C 1 -6 alkyl or C 1-6 alkoxy;
  • R 2a and R 2b which may be the same or different, each independently represents a hydrogen atom, a halogen atom, C 1-6 alkoxy, hydroxy or C 1-6 alkyl;
  • R 3 represents the group
  • R 4 and R 5 which may be the same or different, each independently represents a hydrogen atom, a halogen atom, hydroxy, C 1-6 alkoxy or C 1-6 alkyl;
  • Het represents a group selected from
  • R 6 represents a hydrogen atom, -NR 9 R 1 0 or C 1-6 alkyl optionally substituted by one or two substituents selected from C 1-6 alkoxy, hydroxy and -OCOR 1 1 ;
  • R 6a and R 6b which may be the same or different, each independently represent a hydrogen atom, a hydroxy group or C 1-6 alkyl optionally substituted by one or two substituents selected from C 1-6 alkoxy and hydroxy;
  • R 7 , R 8 and R 9 which may be the same or different, each independently represent a hydrogen atom or a C 1-6 alkyl group;
  • R 10 represents a hydrogen atom C 1-6 alkyl, COR 1 1 , benzoyl or -SO 2 R 1 1 ;
  • R 1 1 represents C 1-6 alkyl or phenyl
  • V and W which may be the same or different, each independently represent an oxygen or a sulphur atom
  • X represents an oxygen atom or the group NR 8 or S(O) k ;
  • Y represents an oxygen atom or the group NR 8 or SO 2 ;
  • Z represents a sulphur atom or the group NR 8 ;
  • k represents zero, 1 or 2;
  • the dotted line represents a double bond present in either of the positions indicated.
  • salts of the compounds of formula (I) will preferably be pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts of the compounds of formula (I) include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
  • acids examples include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicyclic, succinic, toluene-p-sulphonic, tartaric, acetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic and benzenesulphonic acids.
  • Other acids such as oxalic, while not in themselves pharmaceutically acceptable may be useful in the preparation of salts useful as intermediates in obtaining compounds of the invention and their pharmaceutically acceptable acid addition salts.
  • Salts derived from appropriate bases include alkali metal (e.g. sodium), alkaline earth metal (e.g. magnesium), ammonium and NR 4 + (where R is C 1-4 alkyl) salts.
  • alkali metal e.g. sodium
  • alkaline earth metal e.g. magnesium
  • ammonium e.g. sodium
  • NR 4 + where R is C 1-4 alkyl
  • the term 'C 1-6 alkyl' or ' C 1-6 alkoxy' as a group or part of a group means that the group is straight or branched and consists of 1 to 6 carbon atoms.
  • suitable alkyl groups include methyl, ethyl, n- propyl, i-propyl, n-butyl, s-butyl and t-butyl.
  • suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.
  • the term 'halogen' means fluorine, chlorine, bromine or iodine. It will be appreciated that R 6 , R 6a and R 6b may be attached to any available carbon atom in the group Het. R 6a and R 6b may be attached either to the same or different carbon atoms.
  • R 6a or R 6b is hydroxy
  • this may exist in the form of an oxo group where such keto tautomers are stable.
  • a preferred group of compounds of general formula (I) is that wherein the group Het, as defined above, on the phenyl ring B is attached at a position meta or para to the phenyl ring A in general formula (I).
  • a preferred group of compounds of general formula (I) is that wherein the group Het on the phenyl ring B is attached at the position para to the phenyl ring A in general formula (I).
  • a further preferred group of compounds of general formula (I) is that wherein the group Het on the phenyl ring B is attached at the position para to the phenyl ring A in general formula (I).
  • Another preferred group of compounds of general formula (I) is that wherein one of R 2a and R 2b on the phenyl ring B is attached at a position ortho to the phenyl ring A in general formula (I).
  • one of R 2a and R 2b represents H and the other of R 2a and R 2b represents H or C ⁇ alkyl, such as methyl.
  • R 1 represents a hydrogen atom or C 1-6 alkyl, especially methyl.
  • Another preferred group of compounds of general formula (I) is that wherein R 1 is attached at a position ortho to the phenyl ring B in general formula (I).
  • R 8 represents a hydrogen atom or C 1-6 alkyl, especially methyl, optionally substituted by C 1-6 alkoxy, especially methoxy. More preferably R 8 is a hydrogen atom or a methyl group.
  • a further sub group of compounds according to the invention is represented by compounds of formula (I) where Het represents a group
  • R 6a and R 6b each independently represent a hydrogen atom or C 1-6 alkyl, especially methyl, optionally substituted by C 1-6 alkoxy, especially methoxy. More preferably R 6a and R 6b each independently represent a hydrogen atom or a methyl group.
  • R 4 is attached at the para-position relative to the amide linkage.
  • Another preferred group of compounds of general formula (I) is that wherein R 4 is a halogen atom, especially a fluorine or chlorine atom, or a hydroxy or C 1-6 alkoxy, especially methoxy, group. More preferably R 4 represents methoxy.
  • R 5 is a hydrogen atom.
  • a yet further preferred group of compounds of general formula (I) is that wherein Het represents a group
  • R 7 is C 1-3 alkyl, especially methyl.
  • R 8 represents a hydrogen atom or C 1-3 alkyl, especially methyl.
  • Particularly preferred compounds of general formula (I) include:-
  • 5-Hydroxytryptamine is a neurotransmitter which is widely distributed within the central nervous system (CNS), platelets and the gastrointestinal tract. Changes in transmission in serotonergic pathways in the CNS are known to modify, for example, mood, psychomotor activity, appetite, memory and blood pressure. Release of 5-hydroxytryptamine from platelets can mediate vasospasm while changes in free 5-hydroxytryptamine levels in the gastrointestinal tract can modify secretion and motility.
  • a 5-HT 1 D antagonist is a non-naturally occurring (synthetic) compound that specifically and selectively antagonises 5-HT 1 D receptors, i.e. - blocks the specific actions of 5-hydroxytryptamine mediated by the 5-HT 1 D receptor.
  • Such compounds may be identified by a high level of affinity (pKi > 8) in the in vitro human cortex and guinea-pig striatum radioligand binding assays described by Hoyer et al. Neuroscience Letters, 1988, 85, p357-362.
  • compounds of the present invention have been shown to inhibit 5-hydroxytryptamine induced contraction of the dog isolated saphenous vein and to antagonise the 5-hydroxytryptamine induced inhibition of neurotransmission in central and peripheral neurones.
  • 5-HT 1 D antagonists and in particular the compounds of the present invention, may therefore be of use in the treatment of CNS disorders such as mood disorders, including depression, seasonal affective disorder and dysthymia; anxiety disorders, including generalised anxiety, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and post-traumatic stress disorder; memory disorders, including dementia, amnestic disorders and age-associated memory impairment; and disorders of eating behaviour, including anorexia nervosa and bulimia nervosa.
  • CNS disorders include Parkinson's disease, dementia in Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias, as well as other psychiatric disorders.
  • 5-HT 1 D antagonists may also be of use in the treatment of endocrine disorders such as hyperprolactinaemia, the treatment of vasospasm (particularly in the cerebral vasculature) and hypertension, as well as disorders in the gastrointestinal tract where changes in motility and secretion are involved. They may also be of use in the treatment of sexual dysfunction.
  • a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment of the aforementioned disorders.
  • a method of treating the aforementioned disorders which comprises administering an effective amount to a patient in need of such treatment of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof.
  • a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment of depression.
  • the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, different antidepressant agents such as tricyclic antidepressants (e.g. amitriptyline, dothiepin, doxepin, trimipramine, butriptyline, clomipramine, desipramine, imipramine, iprindole, lofepramine, nortriptyline or protriptyline), monoamine oxidase inhibitors (e.g. isocarboxazid, phenelzine or tranylcyclopramine) or 5-HT reuptake inhibitors (e.g.
  • tricyclic antidepressants e.g. amitriptyline, dothiepin, doxepin, trimipramine, butriptyline, clomipramine, desipramine, imipramine, iprindole, lofepramine, nortriptyline or protriptyline
  • fluvoxamine, sertraline, fluoxetine or paroxetine), and/or antiparkinsonian agents such as dopaminergic antiparkinsonian agents (e.g. levodopa, preferably in combination with a peripheral decarboxylase inhibitor e.g. benserazide or carbidopa, or a dopamine agonist e.g. bromocriptine, lysuride or pergolide).
  • dopaminergic antiparkinsonian agents e.g. levodopa, preferably in combination with a peripheral decarboxylase inhibitor e.g. benserazide or carbidopa, or a dopamine agonist e.g. bromocriptine, lysuride or pergolide.
  • dopaminergic antiparkinsonian agents e.g. levodopa, preferably in combination with a peripheral decarboxylase inhibitor e.g. benserazide or carbidopa, or a
  • a compound of general formula (I) or a physiologically acceptable salt or solvate thereof and an antiparkinsonian agent such as a dopaminergic antiparkinsonian agent, e.g. levodopa, and a peripheral decarboxylase inhibitor, e.g. benserazide or carbidopa, or a dopamine agonist e.g. bromocriptine, lysuride or pergolide in the presence of each other in the human or non-human animal body for use in the treatment of Parkinson's disease, dementia in parkinsonism, neuroleptic induced parkinsonism and tardive dyskinesias.
  • an antiparkinsonian agent such as a dopaminergic antiparkinsonian agent, e.g. levodopa, and a peripheral decarboxylase inhibitor, e.g. benserazide or carbidopa, or a dopamine agonist e.g. bromocriptine, lysuride or
  • a compound of general formula (I) or a physiologically acceptable salt or solvate thereof and one or more therapeutic agents it may be preferable to employ the active ingredients in the form of separate pharmaceutical formulations.
  • a combined formulation can be used, however, in such a combined formulation the active ingredients must of course be stable and mutually compatible in the particular formulation employed. It will be appreciated that administration of the active ingredients to a human or non-human patient may be simultaneous, separate or sequential. Where administration is not simultaneous, the delay in administering the second of the active ingredients should not be such as to lose the beneficial effect of the combination.
  • compositions comprising at least one compound of general formula (I) or a physiologically acceptable salt or solvate thereof.
  • Such compositions may be presented for use in a conventional manner in admixture with one or more physiologically acceptable carriers or excipients.
  • the carrier(s) must be “acceptable” in the sense of being compatible with “the other ingredients of the formulation and not deleterious to the recipient thereof.
  • compositions according to the invention may be formulated for oral, buccal, parenteral or rectal administration or in a form suitable for administration by inhalation or insufflation. Oral administration is preferred.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example, syrup, acacia, gelatin, orbital, tragacanth, mucilage of starch or polyvinylpyrrolidone; fillers, for example, lactose, sugar, microcrystaliine cellulose maize-starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methylcellulose, glucose/sugar syrup, gelatin, hydroxypropyl methylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non- aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives, for example, methyl or propyl p-hydroxybenzoates or sorbic acid.
  • the compositions may also be formulated as suppositories, e.
  • composition may take the form of tablets or lozenges formulated in conventional manner.
  • composition according to the invention may be formulated for parenteral administration by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dose form in ampoules, or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • compositions according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurised packs with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, or from a nebuliser.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas
  • the dosage unit
  • compositions according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit dosage form in, for example, capsules or cartridges of e.g. gelatin, or blister packs from which the powder may be administered with the aid of an inhaler or insufflator.
  • the pharmaceutical formulations according to the invention may also contain other active ingredients such as antimicrobial agents, or preservatives.
  • the compositions according to the invention may be prepared by mixing the various ingredients using conventional means.
  • a compound of general formula (I) required for use in treatment will vary not only with the particular compound selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will ultimately be at the discretion of the attendant physician or veterinarian.
  • a proposed dose of the compounds of the invention for administration in man is 0.5 to 1000mg, preferably I to 200mg of the active ingredient per unit dose which could be administered, for example, I to 4 times per day.
  • the compounds of the invention may be prepared by a number of processes as described in the following. In describing the processes which may be used for preparing the compounds of general formula (I) or intermediates useful in the preparation thereof, any of R 1 -R 1 1 , Het, V, W, X, Y Z, and k in the various formulae are as defined in general formula (I) unless otherwise stated.
  • R 7 , R 8 , R 9 and/or R 10 in intermediates used to prepare compounds of general formula (I) are hydrogen atoms.
  • Standard protection and deprotection procedures can be employed, for example formation of a phthalimide (in the case of a primary amine), benzyl, trityl, benzyloxycarbonyl or trichloroethoxycarbonyl derivatives. Subsequent removal of the protecting group is achieved by conventional procedures.
  • a phthalimide group may be removed by treatment with hydrazine or a primary amine, for example methylamine.
  • Benzyl or benzyloxycarbonyl groups may be removed by hydrogenolysis in the presence of a catalyst e.g. palladium, and trichloroethoxycarbonyl derivatives may be removed by treatment with zinc dust.
  • Trityl groups may be removed under acidic conditions using standard procedures.
  • carboxylic acid groups e.g. as esters
  • aldehyde or ketone groups e.g. as acyclic or cyclic acetals or ketals or as thioacetals or thioketals.
  • alkyl esters may be removed under conditions of acidic or basic hydrolysis
  • benzyl esters may be removed by hydrogenolysis in the presence of a catalyst e.g. palladium.
  • Acyclic or cyclic acetals or ketals may be removed under conditions of acidic hydrolysis and thioacetals and thioketals may be removed using a mercuric salt.
  • Hydroxyl groups may also need protection and these may be adequately protected under amenable conditions as their esters or trialkylsilyl, tetrahydropyran and benzyl ethers. Such derivatives may be deprotected by standard procedures.
  • the compounds of general formula (I) may be prepared by a carbonylation reaction involving an aniline (II)
  • Y represents a halogen atom e.g. bromine or iodine or the group -OSO 2 CF 3 .
  • the reaction takes place, for example, in the presence of carbon monoxide using a palladium salt as a catalyst.
  • the reaction is effected in the presence of a suitable base e.g. a tertiary amine such as triethylamine or tri-n-butylamine and may be conducted in a suitable solvent such as an amide e.g. dimethylformamide or a nitrile eg acetonitrile at a temperature within the range of -10°C to +120°C.
  • a suitable base e.g. a tertiary amine such as triethylamine or tri-n-butylamine
  • a suitable solvent such as an amide e.g. dimethylformamide or a nitrile eg acetonitrile at a temperature within the range of -10°C to +120°C.
  • Suitable palladium salts for the reaction include triarylphosphine palladium (II) salts such as bis(triphenylphosphine)palladium (II) chloride.
  • the compounds of general formula (I) may be prepared by treating a compound of formula (IV)
  • the reaction is conveniently effected in a polar solvent such as an alcohol (e.g. n- butanol) or a nitrile (e.g acetonitrile), optionally in the presence of a base, for example, an alkali metal carbonate such as sodium carbonate or potassium carbonate, or alternatively in a non-polar solvent (e.g. chlorobenzene) in the absence of a base.
  • a polar solvent such as an alcohol (e.g. n- butanol) or a nitrile (e.g acetonitrile)
  • a base for example, an alkali metal carbonate such as sodium carbonate or potassium carbonate
  • a non-polar solvent e.g. chlorobenzene
  • the compounds of general formula (I) may be prepared by reacting an aniline of formula (II) with an activated carboxylic acid derivative of formula (VI)
  • Suitable activated carboxylic acid derivatives represented in formula (VI) include acyl halides (e.g. acid chlorides) and acid anhydrides including mixed anhydrides. These activated derivatives may be formed from the corresponding acid of formula (VII)
  • acid chlorides may be prepared by reaction with phosphorus pentachloride, thionyl chloride or oxalyl chloride and acid anhydrides may be prepared by reaction with an appropriate acid anhydride (e.g. trifluoroacetic anhydride), an acid chloride (e.g. acetyl chloride), an alkyl or aralkyl haloformate (e.g. ethyl or benzyl chloroformate) or methanesulphonyl chloride.
  • an appropriate acid anhydride e.g. trifluoroacetic anhydride
  • an acid chloride e.g. acetyl chloride
  • an alkyl or aralkyl haloformate e.g. ethyl or benzyl chloroformate
  • methanesulphonyl chloride e.g. ethyl or benzyl chloroformate
  • Activated carboxylic acid derivatives of formula (VI) may also be prepared in situ by the reaction of the corresponding acids of formula (VII), with a coupling reagent such as carbonyldiimidazole, dicyclohexylcarbodiimide or diphenylphosphorylazide.
  • a coupling reagent such as carbonyldiimidazole, dicyclohexylcarbodiimide or diphenylphosphorylazide.
  • the conditions under which the activated carboxylic acid derivatives of formula (VI) are formed and subsequently reacted with the anilines of formula (II) will depend upon the nature of the activated derivative. However, in general the reaction between the compounds (II) and (VI) may be carried out in a non- aqueous medium such as, for example, dimethylformamide, tetrahydrofuran, acetonitrile or a halohydrocarbon such as dichloromethane at a temperature within the range -25°C to +150°C. The reaction may optionally be carried out in the presence of a base such as triethylamine or pyridine and the base may also be used as the solvent for reaction.
  • a base such as triethylamine or pyridine
  • the reaction may be carried out using the Schotten-Baumann technique in the presence of a suitable base, for example, aqueous sodium hydroxide, conveniently at a temperature between 0°C and 100°C, for example, room temperature.
  • a suitable base for example, aqueous sodium hydroxide
  • the compounds of general formula (I) may be prepared by treating a compound of formula (Vllla)
  • the compounds of general formula (I) may be prepared by treating a compound of formula (Vlllb)
  • Y represents a bromine or iodine atom or the group -OSO 2 CF 3 .
  • Both reactions may be effected in the presence of a transition metal catalyst such as (Ph 3 P) 4 Pd (where Ph represents phenyl) in a suitable solvent such as an ether (eg 1 ,2-dimethoxyethane or tetrahydrofuran) in the presence or absence of water, or an aromatic hydrocarbon (eg benzene).
  • a transition metal catalyst such as (Ph 3 P) 4 Pd (where Ph represents phenyl) in a suitable solvent such as an ether (eg 1 ,2-dimethoxyethane or tetrahydrofuran) in the presence or absence of water, or an aromatic hydrocarbon (eg benzene).
  • a base such as an alkali or alkaline earth metal carbonate (eg sodium carbonate) at a suitable temperature up to reflux.
  • Compounds of general formula (I) may also be prepared from other compounds of formula (I) by standard methods of interconversion.
  • R 2a or R2b represents a hydroxy or alkoxy group and/or when R 4 and/or R 5 represents hydroxy or alkoxy these groups may be interchanged by standard methods of O- alkylation or O-dealkylation.
  • a compound in which R 4 represents hydroxy may be prepared by treating a corresponding compound in which R 4 represents methoxy with a reagent system capable of removing the methyl group e.g. a mercaptide such as sodium ethylmercaptide in a solvent such as dimethylformamide, lithium iodide in collidine, boron tribromide in a halohydrocarbon solvent e.g. methylene chloride or molten pyridine hydrochloride.
  • a reagent system capable of removing the methyl group
  • a mercaptide such as sodium ethylmercaptide in a solvent such as dimethylformamide, lithium iodide in collidine, boron tribromide in a
  • reaction may be carried out at a temperature between 50°C and reflux, and optionally in a solvent such as an ether, e.g. tetrahydrofuran, or toluene.
  • a solvent such as an ether, e.g. tetrahydrofuran, or toluene.
  • the nitro group may be subsequently converted into an amine using standard methodology.
  • intermediates of formula (II) in which R 4 is adjacent to R 3 , and R 5 is a hydrogen atom may be prepared by nitration of a compound of formula (XII)
  • nitrating system such as sulphuric acid and potassium nitrate, or nitronium tetrafluoroborate
  • a solvent for example, acetonitrile followed by reduction of the nitro group using standard methodology.
  • the reduction may be effected by catalytic hydrogenation using a metal catalyst such as palladium or platinum or oxides thereof, preferably, in a solvent such as an alcohol e.g ethanol, or alternatively by using Raney nickel and hydrazine in a solvent such as an alcohol e.g. ethanol, or alternatively by using titanium trichloride in a suitable solvent such as aqueous acetone.
  • a metal catalyst such as palladium or platinum or oxides thereof, preferably, in a solvent such as an alcohol e.g ethanol, or alternatively by using Raney nickel and hydrazine in a solvent such as an alcohol e.g. ethanol, or alternatively by using titanium trichloride in a suitable solvent such as aqueous acetone.
  • a halogen substituent may be converted into a carboxyl group using standard methodology thus, for example, intermediates of formula (VII) may be prepared from an intermediate of formula (III) by lithiation using, for example, n-butyl lithium followed by quenching with carbon dioxide.
  • Salts of compounds of general formula (I) may also be converted to different salts of compounds of general formula (I) using conventional methods.
  • 1-(2-Methoxyphenyl)-4-methylpiperazine was acidified with 5N sulphuric acid and the excess water evaporated in vacuo. Concentrated sulphuric acid (95- 98%, 22ml) was added and the mixture stirred at room temperature until homogeneous. To the stirred, dark solution was added portionwise at room temperature potassium nitrate (3.07g) in ten portions at intervals of approximately 5min. The mixture was stirred at room temperature for 4h then poured onto ice ( ⁇ 500ml) and the mixture made slightly alkaline with anhydrous sodium carbonate. The basic mixture was extracted with ethyl acetate (4x150ml) and the combined extracts dried.
  • step (a) To a solution of the product of step (a) (5.07g) in ethanol (70ml) was added a paste of Raney Nickel in water (2g). To the warmed suspension was added, with constant agitation, hydrazine hydrate (5ml) dropwise during 20min with occasional warming. After the main effervescence had ceased, the suspension was heated for 15min and then filtered with the aid of ethanol under nitrogen. The residues were kept moist and washed with ethanol and the combined filtrate and washings were evaporated to dryness with the aid of ethanol. The dark residue was re- evaporated with ethanol (20ml), resuspended in ether (40ml) and the mixture filtered. The residue was washed with ether and dried to give a solid consisting of the title compound (2.365g)
  • n-Butyllithium (7.5ml of 1.6M solution in hexane) was added dropwise at -90 to - 100° to a stirred solution of Intermediate 4 (404mg) and triisopropylborate (2.77ml) in dry THF (20ml) over 45min under nitrogen, and stirring continued for 1.5h at -90 to -103° for 1.5h. After 3h at -78°, the cooling bath was removed and the mixture stirred at +23° for 11h. Water (4ml) was added, and, after 1 h, the mixture was evaporated.
  • active ingredient is used herein to represent a compound of formula (I).
  • the tablets may be coated with a thin polymer coat applied by film coating techniques well known to those skilled in art. Pigments may be incorporated in the film coat.
  • the contents of the cartridges may be administered using a powder inhaler.
  • Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted to that of maximum stability and/or to facilitate solution of the active ingredient using dilute acid or alkali or by the addition of suitable buffer salts.
  • Antioxidants and metal chelating salts may also be included.
  • the solution is prepared, clarified and filled into appropriate sized ampoules sealed by fusion of the glass.
  • the injection is sterilised by heating in an autoclave using one of the acceptable cycles.
  • the solution may be sterilised by filtration and filled into sterile ampoules under aseptic conditions.
  • the solution may be packed under an inert atmosphere of nitrogen.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/EP1993/003708 1992-12-30 1993-12-28 Benzanilide derivatives as 5-ht1d-antagonists WO1994015920A1 (en)

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GB929227125A GB9227125D0 (en) 1992-12-30 1992-12-30 Chemical compounds
GB929227116A GB9227116D0 (en) 1992-12-30 1992-12-30 Chemical compounds
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IL (1) IL108218A0 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
TW (1) TW240217B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
WO (1) WO1994015920A1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)

Cited By (32)

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WO1995015954A1 (en) * 1993-12-07 1995-06-15 Smithkline Beecham Plc Heterocyclic biphenylylamides useful as 5ht1d antagonists
WO1996031508A1 (en) * 1995-04-07 1996-10-10 Smithkline Beecham Plc Biphenylamide derivatives as 5ht1d antagonists
WO1997014689A1 (fr) * 1995-10-18 1997-04-24 Pierre Fabre Medicament Derives d'amines cycliques d'aryl-piperazines, leur preparation et les compositions pharmaceutiques les contenant
WO1997028141A1 (fr) * 1996-02-02 1997-08-07 Pierre Fabre Medicament Nouvelles piperazines aromatiques derivees de cycloazanes substitues, ainsi que leur procede de preparation, les compositions pharmaceutiques et leur utilisation comme medicaments
WO1997028139A1 (fr) * 1996-02-02 1997-08-07 Pierre Fabre Medicament Nouvelles naphtylpiperazines derivees de cycloazanes substitues, ainsi que leur procede de preparation, les compositions pharmaceutiques et leur utilisation comme medicaments
WO1998027058A3 (en) * 1996-12-19 1998-08-20 Smithkline Beecham Plc N-piperazin-1-ylphenyl-benzamide derivatives
JP2003518096A (ja) * 1999-12-22 2003-06-03 アー カールッスン リサーチ アーベー ドーパミン神経伝達の新規のモジュレーター
WO2003093248A1 (en) * 2002-04-30 2003-11-13 Smithkline Beecham Corporation Heteroaryl substituted biphenyl derivatives as p38 kinase inhibitors
US6743815B2 (en) 1998-08-07 2004-06-01 Chiron Corporation Estrogen receptor modulators
US7125898B2 (en) 2002-02-12 2006-10-24 Smithkline Beecham Corporation Nicotinamide derivatives useful as p38 inhibitors.
US7151118B2 (en) 2001-10-17 2006-12-19 Glaxo Group Limited Biphenylcarboxylic amide derivatives as p38-kinase inhibitors
US7166597B2 (en) 2000-08-22 2007-01-23 Glaxo Group Limited Fused pyrazole derivatives being protein kinase inhibitors
US7166623B2 (en) 2001-10-17 2007-01-23 Glaxo Group Limited 2′-Methyl-5′-(1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors
US7183297B2 (en) 2001-10-17 2007-02-27 Glaxo Group Limited Biphenyl-derivatives as p38-kinase inhibitors
US7208629B2 (en) 2001-10-17 2007-04-24 Glaxo Group Limited 5′-Carbamoyl-1,1-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors
US7271289B2 (en) 2003-04-09 2007-09-18 Smithkline Beecham Corporation Biphenylcarboxylic amide derivatives as p38 kinase inhibitors
US7384963B2 (en) 2001-10-17 2008-06-10 Glaxo Group Limited 2′-Methyl-5-(1,3,4-oxadiazol-2-yl)1, 1′-biphenyl-4-carboxaide derivatives and their use as p38 kinase
US7396843B2 (en) 2001-10-17 2008-07-08 Glaxo Group Limited 5′-carbamoyl-1,1′-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors
US7432289B2 (en) 2001-10-17 2008-10-07 Glaxo Group Limited 5-Acylamino-1,1′-biphenyl-4-carboxamide derivatives and their use as P38 kinase inhibitors
US7572790B2 (en) 2003-04-09 2009-08-11 Smithkline Beecham Corporation Biphenyl carboxylic amide p38 kinase inhibitors
US7626055B2 (en) 2003-04-09 2009-12-01 Smithkline Beecham Corporation Biphenyl-carboxamide derivatives and their use as p38 kinase inhibitors
US7642276B2 (en) 2002-07-31 2010-01-05 Smithkline Beecham Corporation Fused heteroaryl derivatives for use as P38 kinase inhibitors
US7737149B2 (en) 2006-12-21 2010-06-15 Astrazeneca Ab N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(3,5-dimethylpiperazin-1-yl)benzamide and salts thereof
US7838540B2 (en) 2003-08-11 2010-11-23 Glaxosmithkline Llc 3-aminocarbonyl, 6-phenyl substituted pyridine-1-oxides as p38 kinase inhibitors
JP2013542220A (ja) * 2010-10-30 2013-11-21 ルピン・リミテッド オキサゾール及びイソキサゾリンｃｒａｃ調節因子
US8957049B2 (en) 2008-04-09 2015-02-17 Infinity Pharmaceuticals, Inc. Inhibitors of fatty acid amide hydrolase
US9034849B2 (en) 2010-02-03 2015-05-19 Infinity Pharmaceuticals, Inc. Fatty acid amide hydrolase inhibitors
US9108989B2 (en) 2006-10-10 2015-08-18 Infinity Pharmaceuticals, Inc. Inhibitors of fatty acid amide hydrolase
US10420764B2 (en) 2012-12-21 2019-09-24 Astrazeneca Ab Pharmaceutical formulation of N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-YL]-4-[(3R,5S)-3 ,5-dimethylpiperazin-1-YL] benzamide
WO2020183011A1 (en) 2019-03-14 2020-09-17 Institut Curie Htr1d inhibitors and uses thereof in the treatment of cancer
WO2022074103A1 (en) * 2020-10-08 2022-04-14 Leukos Biotech, S.L. Potent and selctive compounds as serotonin 1b receptor modulators
US11498903B2 (en) 2017-08-17 2022-11-15 Bristol-Myers Squibb Company 2-(1,1′-biphenyl)-1H-benzodimidazole derivatives and related compounds as apelin and APJ agonists for treating cardiovascular diseases

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Cited By (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5801170A (en) * 1993-12-07 1998-09-01 Smithkline Beecham Plc Heterocyclic biphenylylamides useful as 5HT1D antagonists
WO1995015954A1 (en) * 1993-12-07 1995-06-15 Smithkline Beecham Plc Heterocyclic biphenylylamides useful as 5ht1d antagonists
WO1996031508A1 (en) * 1995-04-07 1996-10-10 Smithkline Beecham Plc Biphenylamide derivatives as 5ht1d antagonists
US5919932A (en) * 1995-04-07 1999-07-06 Smithkline Beecham P.L.C. Biphenylamide derivatives as 5HT1D antagonists
WO1997014689A1 (fr) * 1995-10-18 1997-04-24 Pierre Fabre Medicament Derives d'amines cycliques d'aryl-piperazines, leur preparation et les compositions pharmaceutiques les contenant
FR2740134A1 (fr) * 1995-10-18 1997-04-25 Pf Medicament Derives d'amines cycliques d'aryl-piperazines, leur preparation et les compositions pharmaceutiques les contenant
FR2744449A1 (fr) * 1996-02-02 1997-08-08 Pf Medicament Nouvelles piperazines aromatiques derivees de cycloazanes substitues, ainsi que leur procede de preparation, les compositions pharmaceutiques et leur utilisation comme medicaments
FR2744450A1 (fr) * 1996-02-02 1997-08-08 Pf Medicament Nouvelles naphtylpiperazines derivees de cycloazanes substitues, ainsi que leur procede de preparation, les compositions pharmaceutiques et leur utilisation comme medicaments
WO1997028139A1 (fr) * 1996-02-02 1997-08-07 Pierre Fabre Medicament Nouvelles naphtylpiperazines derivees de cycloazanes substitues, ainsi que leur procede de preparation, les compositions pharmaceutiques et leur utilisation comme medicaments
WO1997028141A1 (fr) * 1996-02-02 1997-08-07 Pierre Fabre Medicament Nouvelles piperazines aromatiques derivees de cycloazanes substitues, ainsi que leur procede de preparation, les compositions pharmaceutiques et leur utilisation comme medicaments
WO1998027058A3 (en) * 1996-12-19 1998-08-20 Smithkline Beecham Plc N-piperazin-1-ylphenyl-benzamide derivatives
US6743815B2 (en) 1998-08-07 2004-06-01 Chiron Corporation Estrogen receptor modulators
US6869969B2 (en) 1998-08-07 2005-03-22 Chiron Corporation Estrogen receptor modulators
JP2003518096A (ja) * 1999-12-22 2003-06-03 アー カールッスン リサーチ アーベー ドーパミン神経伝達の新規のモジュレーター
US7166597B2 (en) 2000-08-22 2007-01-23 Glaxo Group Limited Fused pyrazole derivatives being protein kinase inhibitors
US7183297B2 (en) 2001-10-17 2007-02-27 Glaxo Group Limited Biphenyl-derivatives as p38-kinase inhibitors
US7151118B2 (en) 2001-10-17 2006-12-19 Glaxo Group Limited Biphenylcarboxylic amide derivatives as p38-kinase inhibitors
US7166623B2 (en) 2001-10-17 2007-01-23 Glaxo Group Limited 2′-Methyl-5′-(1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors
US7208629B2 (en) 2001-10-17 2007-04-24 Glaxo Group Limited 5′-Carbamoyl-1,1-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors
US7309800B2 (en) 2001-10-17 2007-12-18 Glaxo Group Limited Biphenylcarboxylic amide derivatives as p38 kinase inhibitors
US7384963B2 (en) 2001-10-17 2008-06-10 Glaxo Group Limited 2′-Methyl-5-(1,3,4-oxadiazol-2-yl)1, 1′-biphenyl-4-carboxaide derivatives and their use as p38 kinase
US7396843B2 (en) 2001-10-17 2008-07-08 Glaxo Group Limited 5′-carbamoyl-1,1′-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors
US7432289B2 (en) 2001-10-17 2008-10-07 Glaxo Group Limited 5-Acylamino-1,1′-biphenyl-4-carboxamide derivatives and their use as P38 kinase inhibitors
US7125898B2 (en) 2002-02-12 2006-10-24 Smithkline Beecham Corporation Nicotinamide derivatives useful as p38 inhibitors.
US7514456B2 (en) 2002-02-12 2009-04-07 Smithkline Beecham Corporation Nicotinamide derivatives useful as p38 inhibitors
US7709506B2 (en) 2002-02-12 2010-05-04 Glaxosmithkline Llc Nicotinamide derivatives useful as p38 inhibitors
WO2003093248A1 (en) * 2002-04-30 2003-11-13 Smithkline Beecham Corporation Heteroaryl substituted biphenyl derivatives as p38 kinase inhibitors
US7642276B2 (en) 2002-07-31 2010-01-05 Smithkline Beecham Corporation Fused heteroaryl derivatives for use as P38 kinase inhibitors
US7626055B2 (en) 2003-04-09 2009-12-01 Smithkline Beecham Corporation Biphenyl-carboxamide derivatives and their use as p38 kinase inhibitors
US7271289B2 (en) 2003-04-09 2007-09-18 Smithkline Beecham Corporation Biphenylcarboxylic amide derivatives as p38 kinase inhibitors
US7572790B2 (en) 2003-04-09 2009-08-11 Smithkline Beecham Corporation Biphenyl carboxylic amide p38 kinase inhibitors
US7838540B2 (en) 2003-08-11 2010-11-23 Glaxosmithkline Llc 3-aminocarbonyl, 6-phenyl substituted pyridine-1-oxides as p38 kinase inhibitors
US9108989B2 (en) 2006-10-10 2015-08-18 Infinity Pharmaceuticals, Inc. Inhibitors of fatty acid amide hydrolase
US9688640B2 (en) 2006-12-21 2017-06-27 Astrazeneca Ab Methods of treating cancer with a pyrazole derivative
US7737149B2 (en) 2006-12-21 2010-06-15 Astrazeneca Ab N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(3,5-dimethylpiperazin-1-yl)benzamide and salts thereof
US8129391B2 (en) 2006-12-21 2012-03-06 Astrazeneca Ab N-[5-[2-(3,5-Dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-(3,4-dimethylpiperazin-1-yl)benzamide and salts thereof
US10301267B2 (en) 2006-12-21 2019-05-28 Astrazeneca Ab Compounds
US8604022B2 (en) 2006-12-21 2013-12-10 Astrazeneca Ab N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1h-pyrazol-3-yl]-4-(3,4-dimethylpiperazin-1-yl)benzamide and salts thereof
US8957049B2 (en) 2008-04-09 2015-02-17 Infinity Pharmaceuticals, Inc. Inhibitors of fatty acid amide hydrolase
US9034849B2 (en) 2010-02-03 2015-05-19 Infinity Pharmaceuticals, Inc. Fatty acid amide hydrolase inhibitors
US9951089B2 (en) 2010-02-03 2018-04-24 Infinity Pharmaceuticals, Inc. Methods of treating a fatty acid amide hydrolase-mediated condition
JP2013542220A (ja) * 2010-10-30 2013-11-21 ルピン・リミテッド オキサゾール及びイソキサゾリンｃｒａｃ調節因子
US10420764B2 (en) 2012-12-21 2019-09-24 Astrazeneca Ab Pharmaceutical formulation of N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-YL]-4-[(3R,5S)-3 ,5-dimethylpiperazin-1-YL] benzamide
US11498903B2 (en) 2017-08-17 2022-11-15 Bristol-Myers Squibb Company 2-(1,1′-biphenyl)-1H-benzodimidazole derivatives and related compounds as apelin and APJ agonists for treating cardiovascular diseases
WO2020183011A1 (en) 2019-03-14 2020-09-17 Institut Curie Htr1d inhibitors and uses thereof in the treatment of cancer
WO2022074103A1 (en) * 2020-10-08 2022-04-14 Leukos Biotech, S.L. Potent and selctive compounds as serotonin 1b receptor modulators
JP2023547346A (ja) * 2020-10-08 2023-11-10 レウコス バイオテク ソシエダッド リミターダ セロトニン１ｂ受容体モジュレーターとしての強力で選択的な新規化合物
EP4445901A3 (en) * 2020-10-08 2024-12-04 Leukos Biotech, S.L. New potent and selective compounds as serotonin 1b receptor modulators
JP7687636B2 (ja) 2020-10-08 2025-06-03 レウコス バイオテク ソシエダッド リミターダ セロトニン１ｂ受容体モジュレーターとしての強力で選択的な新規化合物

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CN1094037A (zh) 1994-10-26
AU5815594A (en) 1994-08-15

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