WO1991013885A1 - 1-azabicyclic compounds, processes and pharmaceutical compositons containing them - Google Patents
1-azabicyclic compounds, processes and pharmaceutical compositons containing them Download PDFInfo
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- WO1991013885A1 WO1991013885A1 PCT/GB1991/000367 GB9100367W WO9113885A1 WO 1991013885 A1 WO1991013885 A1 WO 1991013885A1 GB 9100367 W GB9100367 W GB 9100367W WO 9113885 A1 WO9113885 A1 WO 9113885A1
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- azabicyclo
- triazin
- heptane
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- 0 CCN(*)C[C@](C)* Chemical compound CCN(*)C[C@](C)* 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
Definitions
- This invention relates to compounds having pharmaceutical activity, to a process for their preparation and their use as pharmaceuticals.
- EP-0327155 discloses certain substituted pyrazines, pyrimidines and pyridazines useful in the treatment of senile dementia.
- a novel group of compounds has now been discovered which enhance acetylcholine function via an action at muscarinic receptors within the central nervous system and are therefore of potential use in the treatment and/or : - prophylaxis of dementia in mammals.
- R is selected from hydrogen, OR- ⁇ , SR- j _, NCR- ⁇ ) ⁇ NHCOR- j ⁇ , NHCOOCH3, NHCOOC 2 H 5 , NHOR j ⁇ , NHNH 2 , C 2 _ al enyl, C 2 _ 4 alkynyl, cyclopropyl or C- ] __ alkyl optionally substituted with OR ⁇ , N(R 1 ) 2 , SR- j ⁇ , C0 R 1 , CON(R 1 ) 2 or one, two or three halogen atoms, ' in which each R ⁇ is independently hydrogen or
- Certain compounds of formula (I) are capable of existing in a number of stereoisomeric forms including enantiomers.
- the invention extends to each of these stereoisomeric forms, and to mixtures thereof (including racemates) .
- the different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis.
- the compounds of formula (I) can form acid addition salts with acids, such as the conventional pharmaceutically acceptable acids, for example hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, andelic, tartaric, oxalic and methanesulphdnic.
- acids such as the conventional pharmaceutically acceptable acids, for example hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, andelic, tartaric, oxalic and methanesulphdnic.
- R- ] _ is hydrogen or methyl.
- Preferred values for R include hydrogen, C 1- alkyl, cyclopropyl, 0R- ] _, SR- ⁇ or N(R 1 ) 2 -
- R examples include hydrogen, methyl, ethyl, methoxy, methylthio, cyclopropyl, amino and dimethylamino.
- R is preferably methyl or ethyl.
- the invention also provides a process for the preparation of a compound of formula (I) , or a pharmaceutically acceptable salt thereof, which process comprises:
- A represents Z or a group convertible thereto and B represents -(CH 2 ) .L 1 where L ⁇ is a leaving group or A and L-L together represent -COO-; one of j, k and 1 is 1 and the other two independently represent an integer of 2 or 3, and R5 represents hydrogen or an N-protecting group; to give a compound of formula (Ila) :
- A represents an electron withdrawing group
- B represents hydrogen
- R5 represents -(CH 2 )_: L 2 where L 2 is a leaving group; one of k and 1 is 1 and the other and j independently represent an integer of 2 or 3; to give a compound of formula (lib) :
- K represents an electron withdrawing group or A' and the remaining variables are as previously defined; and thereafter, optionally or as necessary and in any appropriate order, removing any R5 N-protecting group, converting K to A' , converting A' to Z, optionally interconverting Z and/or forming a pharmaceutically acceptable salt; or
- R5 is hydrogen or an N-protecting group, and either C is one, D is another and E is the remainder of -(CH 2 ) r -, -(CH 2 ) S - and - (CH 2 ) t -CHA'-CH 2 - or groups convertible thereto.
- A' is Z or a group convertible thereto and L3 is a leaving group; or C is one and E is the other of -(C ⁇ )-.- and -(CH 2 ) S - or groups convertible thereto and D represents - (CH 2 ) t -CHA'-CH 2 - where A' and L3 together represent -COO-, and thereafter, optionally or as necessary and in any appropriate order, converting C, D and E to -(CH ) r ⁇ , -(CH 2 ) S ⁇ and - (CH 2 ) t -CHA'-CH 2 ⁇ , removing any R5 protecting group, converting A' to Z, optionally interconverting Z and/or forming a pharmaceutically acceptable salt; or
- F is one and G is the other of -(CH 2 ) r - and -(CH 2 ) S - or groups convertible thereto, and one of Y ⁇ and Y 4 is
- process variant (a) is a compound of formula (I) in which variable Y is hydrogen and that the product of process variant (b) or (c) is a compound of formula (I) in which variable X is hydrogen.
- examples of the leaving groups L ⁇ _ and L 2 include halo such as chloro or bromo, tosyloxy and mesyloxy.
- R5 when an N-protecting group examples include benzyl and substituted benzyl.
- a and A' examples include hydroxy, alkoxycarbonyl, benzyloxycarbonyl and cyano.
- the cyclisation reaction is a nucleophilic substitution which may be carried out under conventional conditions appropriate to the groups A and B.
- B is (CH 2 ) __;Br and A is C-j_ 4 alkoxycarbonyl
- the cyclisation is carried out in an inert solvent such as toluene or ether at elevated temperature.
- B is (CH 2 ) JOTOS or (CH 2 ) -sO-Mes
- it is preferably obtained by treatment of a (CH 2 ) -;OH group with a suitable reagent such as tosylchloride or mesyl chloride, in a base such as pyridine, whereupon the cyclisation may proceed at ambient temperature, or at elevated temperature in an inert solvent such as toluene.
- a and L- j _ together represent -COO- the cyclisation may be carried out in a lower alkanol such as ethanol in the presence of acid such as hydrogen bromide.
- A* " will be an alkoxycarbonyl group corresponding to the lower alkanol used for the cyclisation.
- R5 is an N-protecting group such as benzyl
- this may be removed by conventional hydrogenation, preferably catalytically over a suitable catalyst such as Pd/C.
- A' or K is benzyloxycarbonyl, deesterification and deprotection may be effected simultaneously by conventional hydrogenation.
- Examples of A when an electron withdrawing group include C- ] __ 4 alkoxycarbonyl and cyano.
- A is an electron withdrawing group such as C ⁇ _ 4 alkoxycarbonyl
- B is hydrogen and R5 is -(CH 2 ) ⁇ L 2 where L 2 is, for example, chloro
- the cyclisation may be effected by treatment of the compound of formula (II) with lithium diisopropylamide.
- examples of leaving groups L3 include halo such as chloro, hydroxy and tosyloxy.
- examples of A' include hydroxy, cyano and formyl.
- examples of L 4 include those given for L3.
- Examples of electron withdrawing groups K and W include C _ 4 alkoxycarbonyl and cyano.
- the cyclisation of compounds of formula (III) may be carried out by pyrolysis, by the method of D.O. Spry and H.S. Aaron, J. Org. Chem., 19_9, 34 » 3674, to yield a compound where A' is hydroxy.
- the cyclisation may be carried out under basic conditions where R5 is benzyl (F.I. Carrol, A.M. Ferguson, and J.B. Lewis, J. Org. Chem. 31. . 2957, 1966) .
- the cyclisation is a rearrangement reaction which can be carried out under acid conditions in a polar solvent, such as hydrogen bromide in ethanol, at ambient temperature, to yield a compound where A' is a carboxy ester group. It is preferred to protect the nitrogen atom with an R ⁇ N-protecting group such as benzyl, which may be subsequently removed by hydrogenation over a suitable catalyst such as Pd/C.
- the resulting ⁇ -keto ester is hydrolysed and decarboxylated under conventional conditions such as heating at reflux in dilute hydrochloric acid.
- the resulting ⁇ -keto nitrile is hydrolysed and decarboxylated under conventional conditions such as heating at reflux in dilute hydrochloric acid.
- the cyclisation may be carried out as described in EP-0094742 under basic conditions such as sodium hydride and potassium t-butoxide, in an inert polar solvent such as dimethylformamide.
- Conversions of the carbonyl group from process variants (b) and (c) and of groups A' and K, and interconversions of Z, may be carried out conventionally, see for example standard text books on heterocyclic chemistry such as 'Comprehensive Heterocyclic Chemistry', A.R. Katritzky and C.W. Rees, Pergamon, 1984.
- the carbonyl group may be reacted with tosylmethyl isocyanide to yield a compound where A' is cyano.
- the carbonyl group may be reduced to an A' hydroxy group with a suitable reducing agent such as sodium borohydride in ethanol at ambient temperature, or sodium in ethanol at elevated temperature, such as the boiling point of the solvent, under an inert atmosphere such as nitrogen, depending on the stereochemistry required.
- a suitable reducing agent such as sodium borohydride in ethanol at ambient temperature, or sodium in ethanol at elevated temperature, such as the boiling point of the solvent, under an inert atmosphere such as nitrogen, depending on the stereochemistry required.
- An A' hydroxy group may be converted to cyano by first converting it to a good leaving group such as mesyloxy or tosyloxy and then displacing it with cyanide ion.
- An A' hydroxy group may be oxidised to a carbonyl group by treatment with chromic acid or using dimethyl sulphoxide and dicyclohexylcarbodiimide.
- the A' or K group is first converted, as necessary, to a suitable starting group Z' for the chosen conversion reaction to give the required group Z.
- a Z' carboxy group may be obtained by conventional de-esterification of an A' alkoxycarbonyl group.
- a Z' chlorocarbonyl group may be obtained by treatment of a Z' carboxy group with thionyl chloride at elevated temperature.
- a Z' N-methoxy-N-methylcarboxamido group may be obtained by treatment of a Z' chlorocarbonyl group with N,0-dimethyl hydroxylamine hydrochloride in the presence of pyridine in a suitable solvent such as dichloromethane.
- a Z' aminocarbonyl group may be obtained by treatment of a Z' chlorocarbonyl group with ammonia.
- a Z' cyano group may be obtained by treatment of a Z' aminocarbonyl group with a dehydrating agent such as phosphorus pentoxide in toluene, or pyridine and trifluoroacetic anhydride.
- a dehydrating agent such as phosphorus pentoxide in toluene, or pyridine and trifluoroacetic anhydride.
- a Z' CH3CO- group may be obtained by treatment of a LiOOC group with methyl lithium, the LiOOC group being obtained by hydrolysis of an A' alkoxycarbonyl group with lithium hydroxide in water.
- a Z' CH3CO- group may be obtained by reaction of a Z'
- a Z' CH3CO- group may also be obtained by treatment of a cyano group with methyl lithium.
- a Z' bromomethylcarbonyl group may be obtained by treatment of a Z' COCH3 group either with bromine in a suitable solvent such as ethanol, the nitrogen of the azabicycle being protected as the hydrochloride or hydrobromide salt, or with lithium diisopropylamide and trimethylsilyl chloride at low temperature followed by N-bromosuccinimide in tetrahydrofuran at low temperature.
- a Z' -COC1 group may be converted to a -COCH 2 Br group by treatment with diazomethane in ether at low temperature followed by hydrogen bromide in acetic acid at ambient temperature.
- a Z' -COCHO group may be obtained by treatment of a Z' bromomethylcarbonyl group with dimethylsulphoxide followed by heating at elevated temperature.
- the ketosulphoxide can be reacted with a carboxylic acid anhydride, preferably trifluroacetic anhydride.
- the resulting keto aldehyde protected as the ⁇ -trifluoroacetoxy sulphide can be converted to the required triazine directly.
- the Pummerer rearrangement of sulphoxides using trifluoroacetic anhydride has been described by H. Sugihara, R. Tanikaga and A. Kaji, Synthesis, 881 (1978) .
- the Pummerer rearrangement can be carried out using an acid e.g. hydrochloric acid or trifluoroacetic acid.
- the resulting ⁇ -keto hemithioacetal can be deprotected to give the keto aldehyde intermediate using reported procedures e.g. mercury (II) chloride or copper (II) chloride.
- the ⁇ -ketosulphoxide intermediate may be prepared by treatment of a Z N-methoxy-N-methylcarboxamido group with the anion derived from either methylphenylsulphoxide or dimethylsulphoxide.
- the anion can be generated with a base such as lithium diisopropylamine or n-butyllithium.
- the ⁇ -ketosulphoxide may be prepared by reacting the approxiate sulphoxide with a carboxylic acid .
- ester (A alkoxycarbonyl) in the presence of a base such as potassium t-butoxide.
- the amidrazones are either known compounds or can be prepared via established routes. Formamidrazone can be generated in situ and used without isolation as described by H. Neunhoeffer and F. Weischedel Liebigs Ann. Chem. 1971 749 16.
- the reaction may be carried out in a suitable hydroxylic solvent such as methanol or water.
- the required triazine may be prepared directly by treating the ⁇ -trifluoroacetoxy sulphide with the appropriate amidrazone in the presence of a base such as sodium bicarbonate.
- a base such as sodium bicarbonate.
- the reagent is an aminoguanidine derivative such as the bicarbonate and the reaction is preferably carried out in aqueous medium at pH 4-7.
- the hydrolysis is carried out under alkaline conditions for example with potassium hydroxide.
- the 3-keto triazine can be alkylated. For example methylation can then be achieved using agents such as diazomet ane.
- Alkylation usually gives rise to a mixture of products from which the desired product of O-alkylation can be separated.
- an endo isomer may be obtained by epimerisation of a- corresponding exo isomer or vice versa.
- the epi erisation reaction being effected by standard procedures at any convenient stage in the process but preferably before the introduction of the group Y (J. Saunders e al.., J. Chem. Soc. Chem. Comm. 1988 p 1618) .
- the invention provides a process for the preparation of a compound of formula (I) , or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of formula (IVa) :
- r, s and t are as defined in formula (I)
- one of X and Y represents hydrogen and the other represents Z wherein Z is a group convertible to Z as defined in formula (I) , to convert Z to Z and thereafter optionally forming a pharmaceutically acceptable salt.
- the compound of formula (II) may be prepared by treating a compound of formula (V) :
- Rg is C ] __ 4 alkyl and the remaining variables are as previously defined, with lithium diisopropylamide, prepared in situ from diisopropylamine and n-butyllithium followed by reaction with a compound L ⁇ tC ⁇ J ⁇ L- ⁇ where L ⁇ is a leaving group, in an inert solvent such as ether at depressed to elevated temperature.
- L ⁇ and Lc are suitably bromo.
- the compound of formula (II) may be prepared by reacting the compound of formula (V) , treated with lithium diisopropylamide as before, with ethylene oxide in an inert solvent such as ether at depressed to elevated temperature.
- the compound of formula (II) where A and L- j _ together represent -COO, k is 2 and 1 is 1 may be prepared by a 1,3-dipolar cycloaddition reaction which involves reacting a compound of formula (VI) :
- A is an electron withdrawing group such as C- j __ 4 alkoxycarbonyl
- B is hydrogen
- R 5 is (CH 2 ) j L 2
- the compound of formula (II) may be prepared by reacting the compound of formula (V) where R ⁇ is hydrogen with a compound L5(CH 2 ).iL 2 where L5 is as previously defined, in a solvent such as acetone in the presence of a base such as potassium carbonate.
- the leaving group L5 is preferably bromo and L 2 is preferably chloro.
- Compounds of formulae (V) are known compounds or may be prepared by analogous methods to those for preparing known compounds.
- the compound of formula (V) where k is 2, 1 is 1 and R5 is benzyl may be prepared by the cyclisation of di-C-
- Intermediates of formula (IV) may be prepared from intermediates of formula (V) as described in, for example, Martell et al., J. Pharm. Sci., 1963, 52(4), 331, Sternbach et al., J.A.C.S., 1952, 74, 2215, Thill et al., J. Org. Chem., 1968, 33, 4376 and EP-0 0r_ 742.
- a compound of formula (VI) ' may be obtained by the reaction of ⁇ -butyrolactone with ethyl formate in the presence of base such as sodium hydride followed by reaction of the resulting formyl derivative (as the enol salt) with formaldehyde.
- a compound of formula (VII) may be obtained by the reaction of the primary amine R 7 NH 2 successively with chloromethyltrimethylsilane and formaldehyde followed by methanol and anhydrous potassium carbonate.
- compositions of formula (I) may be formed conventionally by reaction with the appropriate acid such as described above under formula (I) .
- the compounds of the present invention enhance acetylcholine function via an action at muscarinic receptors within the central nervous system and are therefore of potential use in the treatment and/or prophylaxis of dementia.
- the present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- compositions may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations such as oral or sterile parenteral solutions or suspensions.
- composition of the invention is in the form of a unit dose.
- Unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, for example syrup, acacia, "gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.
- binding agents for example syrup, acacia, "gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone
- fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine
- tabletting lubricants for example magnesium stearate
- disintegrants for
- the solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like.
- Oral liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
- Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (which may include edible oils) , for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
- suspending agents for example sorbitol, syrup, methyl cellulose
- fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle.
- the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
- adjuvants such as a local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle.
- the composition can be frozen after filling into ' the vial and the water removed under vacuum.
- Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration.
- the compound can be sterilized.by exposure to ethylene oxide before suspending in the sterile vehicle.' "
- a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the - compound.
- compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration.
- the invention also provides a method of treatment and/or prophylaxis of dementia in mammals including humans, which comprises administering to the sufferer an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
- suitable unit doses may be 0.05 to 100 mg. for example 0.2 to 50mg; and such unit doses may be administered more than once a day, for example two or three times a day, so that the total daily dosage is in the range of about 0.01 to 5 mg/kg; and such therapy may extend for a number of weeks or months.
- the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance.
- the invention further provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prophylaxis of dementia.
- the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment and/or prophylaxis of dementia.
- the title compounds (E15a) and (E15b) were prepared from cyclopropanecarboxamide hydrazone hydrochloride* using the method described in Example 13.
- the crude product, consisting of a 4:1 mixture of exo and endo isomers, was purified by chromatography on silica using a graded eluant of 5-15% methanol in chloroform to give the title exo isomer (E15a) as a pale yellow oil.
- the formamidrazone was generated from anhydrous hydrazine (0.06ml, 1.9mmol) and formamidine hydrochloride (0.15g, 1.9mmol) in methanol (4ml) following the procedure described by Neunhoeffer and Weischedel*. The mixture was allowed to warm to room temperature overnight, and then concentrated in vacuo to give a crude gum containing the exo and. endo isomers (El6a) and (E16b) in a ratio of 4:1. Purification as described in Example 11 afforded the major exo isomer (El6a) as an oil (40mg, 12%) .
- Cerebral cortex from Hooded Lister rats (Olac, UK) is homogenised in 2.5 vols ice-cold 50mM tris buffer pH 7.7 (at 25°C) . After centrifugation at 25,000 x g at 4°C for 15 min the pellet is resuspended in 2.5 vols buffer and the wash repeated 3 times more. The final resuspension is in 2.5 volumes and the homogenates are stored in 1ml aliquots at -20°C.
- Incubations (total volume 2ml) are prepared using the above buffer with the addition of 2mM magnesium chloride in the 3H-Oxotremorine-M (3.H-0X0-M) experiments.
- 3H-Quinuclidinyl Benzilate 1ml of stored membranes is diluted to 30ml and 0.1ml mixed with test compound and 0.27nM (c. 25,000 cpm) 3H-QNB (Amersham International " ).
- 3H-0X0-M 1ml of membranes is diluted to 6ml and 0.1ml mixed with test compound and 2nM (c. 250,000 cpm) 3H-0X0-M (New England Nuclear) .
- Non-specific binding of 3H-QNB is defined using l ⁇ M Atropine sulphate (2 ⁇ M Atropine) and of 3H-OXO-M using 10 ⁇ M Oxotremorine.
- Non-specific binding values typically are 5% and 25% of total binding, respectively.
- Incubations are carried out at 37°C for 30 min and the samples filtered using Whatman GF/B filters. (In the 3 ' H-OXO experiments the filters are presoaked for 30 min in 0.05% polyethylenimine in water) . Filters are washed with 3 x 4ml ice-cold buffer. Radioactivity is assessed using a Packard BPLD scintillation counter, 3ml Pico-Fluor 30 (Packard) as scintillant.
- This test provides an indication of the muscarinic binding activity of the test compound.
- the results are obtained as IC5 Q values (i.e. the concentration which inhibits binding of the ligand by 50%) for the displacement of the muscarinic agonist 3H-OXO-M and the muscarinic antagonist 3H-QNB.
- the ratio IC 50 (3H-QNB) /IC 50 (3H-OXO-M) gives an indication of the agonist character of the compound. Agonists typically exhibit a large ratio; antagonists typically exhibit a ratio near to unity.
Abstract
Description
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Priority Applications (3)
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EP91906519A EP0594605A1 (en) | 1990-03-14 | 1991-03-07 | 1-azabicyclic compounds, processes and pharmaceutical compositons containing them |
JP91506328A JPH05505804A (en) | 1990-03-14 | 1991-03-07 | new compound |
US07/927,678 US5324724A (en) | 1990-03-14 | 1991-03-07 | Compounds for the treatment of senile dementia |
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GB9005737.3 | 1990-03-14 | ||
GB909005737A GB9005737D0 (en) | 1990-03-14 | 1990-03-14 | Novel compounds |
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WO1991013885A1 true WO1991013885A1 (en) | 1991-09-19 |
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US (1) | US5324724A (en) |
EP (1) | EP0594605A1 (en) |
JP (1) | JPH05505804A (en) |
AU (1) | AU7546591A (en) |
GB (1) | GB9005737D0 (en) |
IE (1) | IE910824A1 (en) |
PT (1) | PT97013A (en) |
WO (1) | WO1991013885A1 (en) |
ZA (1) | ZA911804B (en) |
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US5750522A (en) * | 1995-07-13 | 1998-05-12 | American Home Products Corporation | Pyrrolo 1,2-d! 1,2,4!triazine derivatives |
AU2015251030B2 (en) * | 2014-04-24 | 2017-10-05 | Mitsubishi Tanabe Pharma Corporation | Novel disubstituted 1, 2, 4-triazine compound |
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WO2007025177A2 (en) | 2005-08-26 | 2007-03-01 | Braincells, Inc. | Neurogenesis by muscarinic receptor modulation |
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Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0327155A2 (en) * | 1988-01-30 | 1989-08-09 | Merck Sharp & Dohme Ltd. | Pyrazines, pyrimidines and pyridazines, useful in the treatment of senile dementia |
-
1990
- 1990-03-14 GB GB909005737A patent/GB9005737D0/en active Pending
-
1991
- 1991-03-07 WO PCT/GB1991/000367 patent/WO1991013885A1/en not_active Application Discontinuation
- 1991-03-07 AU AU75465/91A patent/AU7546591A/en not_active Abandoned
- 1991-03-07 US US07/927,678 patent/US5324724A/en not_active Expired - Fee Related
- 1991-03-07 JP JP91506328A patent/JPH05505804A/en active Pending
- 1991-03-07 EP EP91906519A patent/EP0594605A1/en not_active Ceased
- 1991-03-12 PT PT97013A patent/PT97013A/en not_active Application Discontinuation
- 1991-03-12 IE IE082491A patent/IE910824A1/en unknown
- 1991-03-12 ZA ZA911804A patent/ZA911804B/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0327155A2 (en) * | 1988-01-30 | 1989-08-09 | Merck Sharp & Dohme Ltd. | Pyrazines, pyrimidines and pyridazines, useful in the treatment of senile dementia |
Cited By (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993015080A1 (en) * | 1992-01-28 | 1993-08-05 | Smithkline Beecham Plc | Azabicyclo compounds as calcium channel antagonists |
US5750522A (en) * | 1995-07-13 | 1998-05-12 | American Home Products Corporation | Pyrrolo 1,2-d! 1,2,4!triazine derivatives |
US5733912A (en) * | 1997-02-19 | 1998-03-31 | Abbott Laboratories | 7A-heterocycle substituted hexahydro-1H-pyrrolizine compounds useful in controlling chemical synaptic transmission |
AU2015251030B2 (en) * | 2014-04-24 | 2017-10-05 | Mitsubishi Tanabe Pharma Corporation | Novel disubstituted 1, 2, 4-triazine compound |
EP3135668A4 (en) * | 2014-04-24 | 2018-03-21 | Mitsubishi Tanabe Pharma Corporation | Novel disubstituted 1, 2, 4-triazine compound |
US10029993B2 (en) | 2014-04-24 | 2018-07-24 | Mitsubishi Tanabe Pharma Corporation | Disubstituted 1, 2, 4-triazine compound |
US10329263B2 (en) | 2014-04-24 | 2019-06-25 | Mitsubishi Tanabe Pharma Corporation | Disubstituted 1, 2, 4-triazine compound |
US11162101B2 (en) | 2017-08-04 | 2021-11-02 | Skyhawk Therapeutics, Inc. | Methods and compositions for modulating splicing |
US11008572B2 (en) | 2017-08-04 | 2021-05-18 | Skyhawk Therapeutics, Inc. | Methods and compositions for modulating splicing |
US11021708B2 (en) | 2017-08-04 | 2021-06-01 | Skyhawk Therapeutics, Inc. | Methods and compositions for modulating splicing |
US11091475B2 (en) | 2017-08-04 | 2021-08-17 | Skyhawk Therapeutics, Inc. | Methods and compositions for modulating splicing |
US11326165B1 (en) | 2017-08-04 | 2022-05-10 | Skyhawk Therapeutics, Inc. | Methods and compositions for modulating splicing |
US11434489B1 (en) | 2017-08-04 | 2022-09-06 | Skyhawk Therapeutics, Inc. | Methods and compositions for modulating splicing |
US11603531B1 (en) | 2017-08-04 | 2023-03-14 | Skyhawk Therapeutics, Inc. | Methods and compositions for modulating splicing |
WO2020163382A1 (en) * | 2019-02-04 | 2020-08-13 | Skyhawk Therapeutics, Inc. | Methods and compositions for modulating splicing |
WO2020163248A1 (en) * | 2019-02-04 | 2020-08-13 | Skyhawk Therapeutics, Inc. | Methods and compositions for modulating splicing |
US11845744B2 (en) | 2019-02-05 | 2023-12-19 | Skyhawk Therapeutics, Inc. | Methods and compositions for modulating splicing |
US11964971B2 (en) | 2019-02-06 | 2024-04-23 | Skyhawk Therapeutics, Inc. | Methods and compositions for modulating splicing |
Also Published As
Publication number | Publication date |
---|---|
US5324724A (en) | 1994-06-28 |
GB9005737D0 (en) | 1990-05-09 |
PT97013A (en) | 1991-10-31 |
ZA911804B (en) | 1992-02-26 |
EP0594605A1 (en) | 1994-05-04 |
JPH05505804A (en) | 1993-08-26 |
IE910824A1 (en) | 1991-09-25 |
AU7546591A (en) | 1991-10-10 |
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