WO1993013104A1 - C.n.s. active tricyclic thienopyridine derivatives - Google Patents
C.n.s. active tricyclic thienopyridine derivatives Download PDFInfo
- Publication number
- WO1993013104A1 WO1993013104A1 PCT/GB1992/002298 GB9202298W WO9313104A1 WO 1993013104 A1 WO1993013104 A1 WO 1993013104A1 GB 9202298 W GB9202298 W GB 9202298W WO 9313104 A1 WO9313104 A1 WO 9313104A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- formula
- alkyl
- pharmaceutically acceptable
- acceptable salt
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/14—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
Thienopyridinecarboxylic acid esters of formula (I), processes for their preparation and their use as pharmaceuticals.
Description
C.N. S. active tricycl ic thienopyridine derivatives
This invention relates to compounds having pharmacological activity, to a process for their preparation, to compositions containing them and to their use in the treatment of mammals.
I. Lalezari, Journal of Heterocyclic Chemistry, 16, 603, (1979) describes the preparation of 4-aminothieno[2,3-b]pyridine-5-carboxylate derivatives of formula (A):
wherein Ra is hydrogen or ethyl; Rb and Rc are methyl, or Rb and Rc together are -(CH2)n- where n is 3, 4 or 5.
No pharmacological activity is attributed to compounds of formula (A).
EP 0 327 223 discloses certain 5,6,7,8-tetrahydrobenzo[b]thieno[2,3-b] pyridine-3-carboxylic acid derivatives having CNS activity, in particular anxiolytic and/or antidepressant activity.
A class of compounds has now been discovered, which compounds have been found to have CNS activity, in particular anxiolytic and/or
anti-depressant and/or anticonvulsant activity and/or activity useful in the treatment of sleep disorders.
Accordingly, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
A is C2-5 polymethylene optionally terminated or interrupted by oxygen, sulphur or NR4 wherein R4 is hydrogen, C1-6 alkyl optionally substituted by hydroxy, C1-7 alkanoyl, C1-6 alkylsulphonyl, C1-6 alkoxycarbonyl or C2-6 alkenyloxycarbonyl, and wherein any methylene group is optionally substituted by R5 where R5 is selected from C1-6 alkyl, C1-6
alkoxycarbonyl, C1-6 alkylthio, C2-7 alkanoyl, trifluoromethyl, cyano, carbamoyl and carboxy, and phenyl or phenyl C1-4 alkyl, in which any phenyl moiety in R5 is optionally substituted by a group selected from C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, C1-6 alkylthio, hydroxy, C2-7 alkanoyl, chloro, fluoro, trifluoromethyl, nitro, amino optionally substituted by one or two C1-6 alkyl groups or by C2-7 alkanoyl, cyano, carbamoyl and carboxy, with the proviso that A is not C4 polymethylene optionally substituted by R5;
R1 is hydrogen, C1-6 alkyl, phenyl or phenyl C1-4 alkyl wherein the phenyl moiety is optionally substituted by one or more C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, hydroxy, C2-7 alkanoyl, halo, trifluoromethyl, nitro, amino optionally substituted by one or two C1-6 alkyl groups or by C2-7 alkanoyl, cyano, carbamoyl or carboxy groups;
R2 and R3 are independently selected from hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl- C3-7 alkyl, C3-6 alkenyl, C1-7 alkanoyl, C1-6 alkylsulphonyl, di-( C1-6 alkyl)amino C1-6 alkyl, 3-oxobutyl, 3-hydroxy- butyl, phenyl, phenyl C1-6 alkyl, benzoyl, phenyl C2-7 alkanoyl and benzenesulphonyl any of which phenyl moieties are optionally substituted by one or two halogen, C1-6 alkyl, C1-6 alkoxy, CF3, amino or carboxy, or R2 and R3 together are C2-7 polymethylene optionally interrupted by oxygen or NR7 wherein R7 is hydrogen or C1-6 alkyl optionally
substituted by hydroxy; and
-CO2R6 is a pharmaceutically acceptable ester group; for pharmaceutical use.
By pharmaceutical use is meant the treatment or prophylaxis of disorders in mammals including humans. Compounds of formula (I) and their pharmaceutically acceptable salts have anxiolytic and/or anti-depressant and/or anticonvulsant activity and/or activity useful in the treatment of sleep disorders and are of particular use in the treatment or prophylaxis of CNS disorders, in particular anxiety, depression, sleep disorders or diseases treatable with anticonvulsant agents such as epilepsy. Thus the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of CNS disorders, in particular anxiety, depression, sleep disorders or diseases treatable with anticonvulsant agents such as epilepsy.
The invention further provides a method of treatment or prophylaxis of CNS disorders, in particular anxiety, depression, sleep disorders or diseases treatable with anticonvulsant agents such as epilepsy 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.
In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the
preparation of a medicament for the treatment or prophylaxis of CNS disorders, in particular anxiety, depression, sleep disorders or diseases treatable with anticonvulsant agents such as epilepsy.
The present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral or parenteral administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, or injectable or infusable solutions or suspensions. Orally administrable compositions are generally
preferred.
Tablets and capsules for oral ao!ministration may be in unit dose form, and may contain conventional exάpients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colourants.
For parenteral administration, fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, 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 sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
The dose of the compound used in the treatment of CNS disorders, such as
anxiety, depression, sleep disorders or diseases treatable with
anticonvulsant agents such as epilepsy will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, for anxiety more suitably 0.05 to 20.0 mg, for example 0.2 to 5 mg; and such unit doses may be administered more than once a day, for example two or three a day, so that, for anxiety, the total daily dosage is in the range of about 0.01 to 100 mg/kg; and such therapy may extend for a number of weeks or months.
Within the above indicated dosage range, no adverse toxicological effects are indicated with the compounds of the invention.
Alkyl moieties within the variables R1 to R5 and R7 are preferably C1-4 alkyl, such as methyl, ethyl and n- and iso-propvl.
It will be appreciated in selecting variables R2 and R3 that the nitrogen atom is not directly attached to unsaturated carbon. Values for A include -(CH2)3-, -(CH2)5-, -(CH2)n-O-(CH2)m-,
-(CH2)n-S-(CH2)m- and -(CH2)n-NR4-(CH2)m- wherein n and m are independently zero or an integer of 1 to 4 such that (n+m) is an integer of 2 to 4, R4 is hydrogen, C1-4 alkyl, C1-5 alkanoyl, C1-4 alkylsulphonyl, C1-4 alkoxycarbonyl or C2-4 alkenyloxycarbonyl and any methylene group is optionally substituted by R5 where R5 is C1-4 alkyl. Examples of R4 include hydrogen, methyl, formyl, acetyl, propionyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl and vinyloxycarbonyl. Preferably any methylene group within A is unsubstituted and R4 is formyl, acetyl or methoxycarbonyl.
Examples of A include -(CH2)3-, -(CH2)5-, -(CH2)2-O-CH2-,
-(CH2)2-S-CH2-, -(CH2)2-N(COCH3)-CH2-, -(CH2)2-NH-CH2-,
-(CH2)2-NCH3- CH2-, -(CH2)2-N(CO2CH3)-CH2-,
-(CH2)2-N(CO2C2H5)-CH2-, -(CH2)2-N(CHO)-CH2-,
-(CH2)2-N(COC2H5)-CH2-, -(CH2)2-N(SO2CH3)-CH2 and
-(CH2)2-N(CO2C(CH3)3)-CH2-, wherein the ethylene moiety is attached to carbon atom 'a '; and -(CH2)3-N(CO2C2H5)-, -(CH2)3-N(CO2CH3)- and -(CH2)3-N(CO2CH=CH2)- wherein the propylene moiety is attached to
carbon atom 'a'.
Preferably A is -(CH2)3-, -(CH2)2-N(COCH3)-CH2- or
-(CH2)2-N(CO2CH3)-CH2-.
Values for R1 include hydrogen, methyl, ethyl, n- and iso-propyl, phenyl and benzyl. Preferably, R1 is methyl.
Values for R2 and R3 include hydrogen, methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and tert-butyl, n-, sec, iso- and neo-pentyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentyl-C1-4 alkyl, cyclohexyl-C1-4 alkyl and cycloheptyl-C1-4 alkyl, where values for C1-4 alkyl include methylene and ethylene, but-2-enyl, but-3-enyl, 1-methylprop-2-enyl, formyl, acetyl, propionyl, methylsulphonyl, 3-dimethylaminobutyl, 3-oxobutyl,
3-hydroxybutyl, phenyl, benzyl, benzoyl, benzylcarbonyl and
benzenesulphonyl, or R2 and R3 together form -(CH 2)r-X-(CH2)s- wherein r and s are independently 1, 2 or 3 and X is a bond, O or NR7, for example C4 or C5 polymethylene, -(CH2)2-O-(CH2)2- or -(CH2)2-NR7-(CH2)2- where R7 is preferably methyl.
Preferably R2 is hydrogen and R3 is hydrogen or C1-6 alkyl, for example methyl. Most preferably R2 and R3 are hydrogen.
There is a preferred group of compounds within formula (I) of formula (II) or a pharmaceutically acceptable salt thereof:
Preferred values for A, R1 and R3 1 are as described for the corresponding variables in formula (I).
The invention further provides novel compounds within formula (I),
wherein the variable groups are as defined in formula (I) with the proviso that when A is -(CH2)3- or -(CH2)5-, R1 is methyl and R2 and R3 are hydrogen, R6 is other than ethyl. Such compounds are hereinafter referred to as compounds of formula (Ia).
The compounds of the formula (I) can form acid addition salts with acids, such as the conventional pharmaceutically acceptable acids, for example, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulphonic.
Suitable examples of pharmaceutical esters of the compounds of formula (I) include C1-6 alkyl esters wherein the alkyl moiety is optionally substituted by up to three halo atoms selected from chloro, fluoro and bromo, such as methyl, ethyl, n- and iso-propyl. n-, sec- and tert-butyl and 2,2,2-trifluoroethyl esters, C2-6 alkenyl esters such as vinyl, prop-1-enyl, prop-2-enyl, 1-methylvinyl, but-1-enyl, but-2-enyl, but-3-enyl, pent-4-enyl, 1-methylenepropyl and 1-methylprop-2-enyl, (in both their E and Z forms where stereoisomerism exists), C2-6 alkynyl esters such as prop-2-ynyl, but-2-ynyl, but-3-ynyl and pent 4-ynyl, C3-6 cycloalkyl esters such as cyclohexyl and C3-6 cycloalkyl-C1-4 alkyl esters such as
cyclopropylmethyl, cyclopropylethyl and cyclobutylmethyl. Preferably the pharmaceutically acceptable ester is the methyl, ethyl, propyl,
prop-2-enyl, prop-2-ynyl or but-2-ynyl ester, i.e. R6 is methyl, ethyl, propyl, prop-2-enyl, prop-2-ynyl or but-2-ynyl. Most preferably R6 is ethyl or prop-2-ynyl.
It will be appreciated that the compounds of formula (I) in which R2 or R3 is hydrogen may exist tautomerically in more than one form. The invention extends to each of these forms and to mixtures thereof.
Compounds of formula (I) may also form solvates such as hydrates, and the invention also extends to these forms. When referred to herein, it is understood that the term "compound of formula (I)" also includes solvates thereof. The present invention also extends to any single stereoisomers such as enantiomers or diastereomers, or mixtures thereof including racemates, of compounds of formula (I).
A process for the preparation of a compound of formula (I), or a
pharmaceutically acceptable salt thereof comprises the reaction of a compound of formula (III):
Suitable examples of the leaving group L include halogens, such as chloro and bromo. hydroxy, C1-6 acyloxy such as acetoxy or C1-6 alkoxy, such as methoxy or ethoxy, preferably methoxy. When L is hydroxy, it will be appreciated that the compound of formula (IV) exists in more than one tautomeric form.
Suitable examples of A' when other than A include C2-5 polymethylene optionally interrupted or terminated by NR4' wherein R4' is a nitrogen protecting group such as benzyloxycarbonyl. The reaction of compounds of formulae (III) and (IV) comprises a
condensation step followed by a cyclisation step, the acyclic enamine intermediate or imine tautomer thereof optionally being isolated before cyclisation. In a further aspect a compound of formula (I) or a pharmaceutically acceptable salt thereof may be prepared by cyclising the acyclic enamine intermediate or imine tautomer thereof obtainable by the condensation of compounds of formulae (III) and (IV) and thereafter carrying out the optional or necessary steps as previously defined.
The condensation step may be carried out under conditions conventional for condensation reactions, at elevated temperatures in an inert solvent such as toluene, benzene, ethanol, pyridine, dimethylformamide or dioxan, optionally in the presence of a catalyst such as para-toluene-sulphonic acid, with water separation.
The cyclisation of the enamine or imine tautomer thereof may also be carried out under conventional conditions, in the presence of a strong base such as an alkali metal alkoxide, for example sodium methoxide or sodium ethoxide in a suitable solvent such as methanol or ethanol, at elevated temperature, or in the presence of a Lewis acid such as ZnCl2, SnCl4 or CUOCOCH3 in a suitable solvent such as n-butyl acetate at elevated temperature. Lewis acid catalysed cyclisation using copper (I) acetate or tin (IV) chloride is preferred except when A contains oxygen or sulphur, when an alkali metal alkoxide is preferred.
Suitable examples of groups R6' include the groups hereinbefore described for -CO2R6, CORd where Rd is hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-4 alkyl or C3-7 cycloalkyl, CH=NOH, CO2H, CO2Q where Q is a protecting group such as benzyl wherein the benzyl moiety is optionally substituted in the phenyl ring by one or two of halogen, CF3, C1-6 alkoxy, C1-6 alkyl or nitro, cyano and -CONR8R9 where R8 and R9 are
independently selected from hydrogen, C1-6 alkyl and phenyl or phenyl
C1-4 alkyl optionally substituted as described above for optional substituents in the phenyl ring of a benzyl ester, or together form a C2-6 polymethylene chain optionally interrupted by oxygen or NR10 wherein R10 is hydrogen or C1-6 alkyl, e.g. morpholino or piperazino.
A protecting group Q may be removed by conventional hydrolysis or hydrogenolysis to yield the free acid which can then be esterified under conventional conditions by reaction with the appropriate alcohol R6OH, optionally with prior conversion of the acid to the acid chloride by reaction with a suitable chlorinating agent such as thionyl chloride, or with an alkylating agent R6X where X is a leaving group such as chloro, bromo or iodo, in the presence of a suitable base such as potassium hydroxide or carbonate in an inert solvent such as diimethylformamide. Alternatively, Q may be converted directly to R6 by transesterification under basic conditions. Interconversion of R6 may be effected similarly.
An intermediate amide may be hydrolysed to the free acid which can then be esterified as described above. An R6' cyano group may be converted under anhydrous conditions to an imino ester by reaction with the appropriate alcohol R6OH and then hydrolysed. to the group -CO2R6.
An R6' CH=NOH group may be converted to cyano by dehydration with a suitable dehydrating agent such as formic acid at elevated temperature, and the resulting cyano group converted to CO2R6 as just described.
Alternatively the CH=NOH group may be converted to formyl by hydrolysis, oxidised to the free acid using a suitable oxidising agent such as CrO3 and esterified as above.
R6' CORd α-methylene keto groups may be converted to CO2R6 via the acid by a haloform reaction and esterification.
Suitable examples of a leaving groups L1 and L2 when Y or M is COL1 or COL 2, include hydroxy and, more preferably, alkoxy such as C1-6 alkoxy, for example ethoxy or methoxy. The reaction of the compounds of formulae (III) and (IV) gives a resulting compound having an hydroxy group in the 4-position of the pyridine ring. The hydroxy group may be
converted to a leaving group such as those defined above for L, preferably halo such as chloro, by reaction with a halogenating agent such as phosphorus oxychloride or phosphorus oxybromide. The leaving group may be displaced by the compound HNR2'R3' under conventional conditions for nucleophilic aromatic displacements, at elevated
temperatures in an inert solvent such as toluene, methanol, ethanol, pyridine, dimethylformamide or dioxan. Alternatively, the reaction may be carried out in neat HNR2'R3' which functions as the solvent. An R2' or R3' protecting group such as p-methoxybenzyl may be removed conventionally.
Conversion of R2 and R3 hydrogen to other R2/R3 may be carried out in accordance with conventional procedures for the alkylation or acylation of a primary amine. Acylation may be carried out by reaction with the appropriate acyl halide. However, R2/R3 other than hydrogen or acyl groups are preferably introduced via the route in which Y or M is COL1 or COL2 in the compound of formula (III) or (IV), by displacement of the leaving group with the compound HNR2'R3' as discussed above.
An R4' nitrogen protecting group may be removed conventionally, for example benzyloxycarbonyl may be removed by catalytic hydrogenation, to give R4 hydrogen which may be alkylated or acylated as necessary to give R4 C1-6 alkyl optionally substituted by hydroxy, C2-7 alkanoyl or C1-6 alkoxycarbonyl.
Interconversions of R4 may be effected similarly. Thus, for example, R4 t-butoxycarbonyl may be removed by treatment with trifiuoroacetic acid to give R4 hydrogen. Where an R4 alkyl group is required, it is preferred to protect the nitrogen atom in the compound of formula (III) and effect conversion to R4 alkyl after cyclisation.
Examples of R11 N-protecting groups include trimethylsilyl and 2- (trimethylsilyl)ethoxymethyl, which may be removed conventionally, for example using tetra-n-butylammonium fluoride. Preferably R11 is hydrogen.
For the preparation of compounds of formula (I) in which R1 is hydrogen,
the compound of formula (IV) may be used in which L and M together represent a bond or L is hydroxy and M is hydrogen, and R1' is a C1-6 alkoxycarbonyl group. The reaction with the compound of formula (III) may then be followed by a decarboxylation step to give R1 hydrogen. Alternatively, a compound of formula (IV) may be used in which L is a leaving group and R1' is hydroxy. In the resulting compound, the R1' hydroxy may be converted to hydrogen by first replacing it by chloro by conventional chlorination with a chlorinating agent such as phosphorus oxychloride followed by reductive dehalogenation under conventional conditions, for example zinc in acetic acid.
An R1' group such as hydroxy or chloro may be converted to alkyl or phenyl C1-4 alkyl or phenyl, by a palladium mediated anion coupling reaction (V.N. Kalinin, Synthesis, 1992, 413).
Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or derivative.
It will be appreciated that the present invention also provides a process for the preparation of the novel compounds of formula (Ia) which process comprises the reaction of a compound of formula (III) with a compound of formula (TV) or the cyclisation of the acylic enamine intermediate or imine tautomer thereof obtainable by the condensation of compounds of formulae (III) and (IV), as described above.
A class of intermediates comprises compounds of formula (V) or a salt thereof:
wherein A' is as defined in formula (III), R1' is as defined in formula (IV), R6" is R6' as defined in formula (IV) and X is NH2, OH or chloro, provided that when X is NH2, A' is A and R1' is R1' R6" is other than -CO2R6, when X is NH2, A is -(CH2)3- or -(CH2)5- and R1' is methyl, R6"
is other than CO2H, and when A is -(CH2)3-, X is OH and R1' is
hydrogen, R6" is other than CO2H or CO2C2H5.
The compounds of formula (V) in which A is -(CH2)3- and -(CH2)5-, R6" is CO2H, X is NH2 and R1' is methyl have been described by I. Lalezari, J. Het. Chem., 16, 603, (1979).
German Patent DT 2447477 (Schering AG) discloses compounds of formula (V) in which A' is C2-5 alkylene optionally interrupted by O, S or N wherein any carbon or nitrogen atom is optionally substituted, X is hydroxy and R6" is carboxy, alkoxycarbonyl or acyloxyalkoxycarbonyl, for use as antimicrobial agents. The preparation of compounds of formula (V) in which Ais -(CH2)3-, R6" is CO2H and CO2C2H5, X is OH and R1' is hydrogen is described.
Novel compounds of formula (V) also form part of the invention.
Compounds of formulae (III) and (IV) are known or can be prepared by analogous processes to those used for preparing known compounds. In particular, compounds of formula (III) may be prepared using procedures similar to that in K. Gewald et al.; Chem. Ber. 1966, 94 by reacting
CH2(CN)2 and sulphur with the appropriate ketone of formula (VI):
appropriate acylating or alkylating reagent such as an alkyl chloroformate using the procedure of A.N. Brubaker and M. CoUey Jnr., J. Med. Chem. 1986 29 1528.
The following Examples illustrate the preparation of pharmacologically active compounds of the invention. Examples 3 to 23 illustrate the preparation of novel compounds of formula (Ia). The following
Descriptions illustrate the preparation of intermediates to the compounds
of the present invention.
Description 1
2-Amino-5,6-dihydro-4H-cyclopenta[4,5]th iophene-3-carbonitrile
(D1)
The title compound was prepared in 25% yield from cyclopentanone using a procedure similar to that of K. Gewald et al.; Chem. Ber. 1966, 94.
m.p. 1540.
Description 2 2-Am ino-5,6,7,8-tetrahydro-4H-cyclohepta[4,5]thiophene- 3-carbonitriIe (D2)
The title compound was prepared in 50% yield from cycloheptanone in a similar manner to that of Description 1.
NMR (CDCl3) δ: 1.30-2.00 (6H, br), 2.40-2.75 (4H, br), 4.50 (2H, s).
Description 3
2-Amino-4,5-dihydro-7H-thieno[2,3-c]pyran-3-carbonitrile (D3)
The title compound was prepared in 68% yield from
tetrahydro-4H-pyran-4-one in a manner similar to that of Description 1. NMR (d6 DMSO) δ: 2.52 (2H, m), 3.90 (2H, t, J=5Hz), 4.50 (2H, s), 7.20 (2H, s).
Description 4
2-Am ino-6-tert-butyloxycarbonyl-4,5,6,7-tetrahydrothieno[2,3-c] pyridine-3-carbonitrile (D4)
Treatment of a solution of 1-tert-butyloxycarbonyl 4-piperidone (27.93g; 0.14M), malononitrile (9.23g), sulphur (4.5g) in methanol (100ml) with diethylamine (27ml) as described in Description 1 gave the title compound
(23.3g; 60%).
NMR (CDCI3) δ: 1.49 (9H, s), 2.60 (2H, t), 3.66 (2H, t), 4.36 (2H, s), 4.37-4.90 (2H, br). Description 5
6-Acetyl-2-amino-4,5,6,7-tetrahydrothieno[2,3-clpyridine- 3-carbonitrile (D5) The title compound was prepared in 68% yield from 1-acetyl-4-piperidone using a method similar to that of Description 4. m.p. 220-225° (decomp). Found: C, 53.92, H, 5.13, N, 18.72%
C10H11N3OS requires: C, 54.28; H, 5.01; N, 18.99% The compounds of Descriptions 6 to 8 were prepared according to the following general procedure.
Diethylamine (1.86ml) was added dropwise to a stirred slurry of sulphur (0.6g), malononitrile (1.1g; 17mM) and the appropriate piperidone (17mM) in methanol (60ml). The mixture was stirred at 25° for 16h and then poured into water (500ml). The resultant precipitate was removed by filtration and dried in vacuo.
Description 6
2-A mino-3-cyano-4,5,6,7-tetrahydrothieno[2,3-3]pyridine-7- carboxylic acid, ethyl ester (D6)
56% yield.
NMR (CDCI3) δ: 1.33 (3H, t, J=8.5), 1.98 (2H, dt, J=5.7), 2.58 (2H, t, J=5.7), 3.77 (2H, t, J=5.7), 4.52 (2H, q, J=8.5).
Description 7 2-Amino-3-cyano-4,5,6,7-tetrahydrotbieno[2,3-b]pyridine-7- carboxylic acid, methyl ester (D7)
53% yield.
NMR (d6 DMSO) δ: 1.90 (2H, dt, J=5.7), 2.42 (2H, t, J=5.7), 3.68 (2H, t,
J=5.7), 3.70 (3H, s), 6.78 (2H, bs).
Description 8
2-Amino-3-cyano-4,5,6,7-tetrahydrothieno[2,3-b]pyridine-7- carboxylic acid, vinyl ester (D8)
57% yield.
NMR (d6 DMSO) δ: 1.94 (2H, dt, J=5.7), 2.44 (2H, t, J=5.7), 3.80 (2H, t, J=5.7), 4.65 (1H, dd, J=2.8, 8.5), 4.94 (1H, dd, J=2.8, 14.1), 6.90 (2H, bs), 7.15 (1H, dd, J=8.5, 14.1).
Description 9
N-3-(2-(3-Cyano-4,5-dihydro-7H-thieno[2,3-c]thiopyranyl)amino)-2- butenoic acid, methyl ester (D9)
2-Amino-4,5-dihydro-7H-tMeno[2,3-c]thiopyran-3-carbonitrile, prepared in a manner similar to that of D1, methyl 3-oxobutyrate and camphor sulphonic acid were heated under reflux in toluene using a procedure similar to that of Example 1. The crude product gave the title compound in 55% yield after chromatography on Kieselgel 60 using dichloromethane elution. m.p. 147-9° (from ethyl acetate).
Found: C, 52.86; H, 4.70; N, 9.56%
C13H14N2S2O2 requires: C, 53.04; H, 4.79; N, 9.52%
Example 1 4-Amino-6,7-dihydro-2-methyl-5H-cyclopenta[4,5] thieno
[2,3-b]pyridine-3-carboxylic acid, ethyl ester (E1)
A solution of D1 (6.85g; 41.8mM) and ethyl 3-ethoxycrotonate (7.93g;
50.2mM) in toluene (150ml) containing p-toluenesulphonic acid (20mg) was heated under reflux (Dean/Stark) for 2h. The mixture was
concentrated in vacuo, partitioned between ethyl acetate and water and the organic phase dried (Na2SO4) and evaporated to dryness. The residue in n-butyl acetate (100ml) and tin (IV) chloride (13.8g; 53mM), was heated
under reflux for 30 min and allowed to cool. The mixture was partitioned between 10% aqueous sodium hydroxide and ethyl acetate. The organic phase was dried (Na2SO4), evaporated to dryness and chromatography of the residue on Kieselgel 60 in dichloromethane gave the title compound (2g; 17%) on recrystallisation from ethanol. m.p. 129-131°.
Found: C, 61.00; H, 5.93; N, 10.17%
C14H16N2O2S requires: C, 60.85; H, 5.84; N, 10.14%
NMR (CDCl3) δ: 1.40 (3H, t), 2.42-2.55 (2H, m), 2.70 (3H, s), 2.92 (2H, t),
3.03 (2H, t), 4.30-4.42 (2H, q), 6.37 (2H, br, s).
Example 2
4-Amino-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[4,5]
thieno[2,3-b]pyridine-3-carboxylic acid, ethyl ester (E2)
The title compound was prepared from D2 in 20% yield using a method similar to that of Example 1. m.p. 141-143°
Found: C, 63.32; H, 6.80; N, 9.10%
C16H2ON2O2S requires: C, 63.13; H, 6.62; N, 9.20%.
Example 3
4-Amino-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno
[2,3-b]pyridine-3-carboxylic acid, 2-propynyl ester (E3)
The title compound E3 was prepared in 65% yield from the ethyl ester E2 by hydrolysis using aqueous ethanolic sodium hydroxide at reflux followed by alkylation with 2-propynyl bromide, using potassium carbonate as base, in dimethylformamide at room temperature. m.p. 159-160°C.
Found: C, 64.79; H, 5.77; N, 8.87%
C17H18N2O2S requires: C, 64.94; H, 5.77; N, 8.91%
Example 4 4-Amino-6,7-dihydro-2-methyl-5H-cyclopenta[4,51 thieno
[2,3-b]pyridine-3-carboxylic acid, 2-propynyl ester (E4)
E1 was converted into the title compound in 65% yield using a method
similar to that of Example 3. m.p. 163-164°
Found: C, 62.84; H, 4.99; N, 9.71%
C15H14N2O2S requires: C, 62.92; H, 4.93; N, 9.78% Example 5
5-Amino -3,4-dihydro-7-methyl-1H-pyrano[4',3,:4,5]
thieno[2,3-b]pyridine-6-carboxylic acid, ethyl ester (E5)
A solution of D3 (2g; 11.2mM) and ethyl 3-ethoxycrotonate (2.3g; 14.6mM) in toluene (50ml) containing p-toluenesulphonic acid (0.3g; 1.56mM) was heated under reflux for 3h. The reaction mixture was cooled and treated with a 1M solution of sodium ethoxide in ethanol (15ml). The mixture was heated under reflux, under nitrogen, for 1h, allowed to cool to room temperature, and then partitioned between ethyl acetate at water at pH 8.
The organic phase was dried (Na2SO4) and evaporated to dryness.
Chromatography of the residue on Kieselgel 60 in dichloromethane gave a white solid (1.1g) which, on recrystallisation from ethanol, gave the title compound E5 (0.69g; 21%). m.p. 133-134°
Found: C, 57.59; H, 5.64; N, 9.66%
C14H16N2O3S requires: C, 57.52; 5.52; N, 9.58% Example 6
4-Amino -7-tert-butyloxycarbonyl-2-methyl-5,6,7,8-tetrahydro- thieno[2,3-b:5,4-c']dipyridine-3-carboxylic acid, ethyl ester (E6) The aminonitrile D4 (10g; 35.4mM) and ethyl 3-ethoxycrotonate (8.51g; 53.9mM) were converted into the title compound (8.16g; 59%) using a method similar to that described in Example 1, except that copper (I) acetate (1.96g; 16mM) was used for the cyclisation step.
NMR (CDCl3) δ: 1.44 (3H, t, J=7.5), 1.50 (9H, s), 2.74 (3H, s), 3.08 (2H, t,
J=6), 3.78 (2H, t, J=6), 4.40 (2H, q, J=7.5), 4.64 (2H, s), 6.40-6.65
(2H, br, s).
Example 7
4-Amino-2-methyl-5,6,7,8-tetrahydrotbieno[2,3-b:5,4-c']
dipyridine-3-carboxylic acid, ethyl ester (E7)
A solution of E6 (2g; 5.11mM) in trifluoroacetic acid (50ml) was stirred at 25° for 1h and then evaporated in vacuo. The residue was partitioned between ammonia and ethyl acetate. The organic phase was washed with brine, dried (Na2Sθ4) and evaporated in vacuo. Recrystallisation from ethyl acetate-petroleum ether gave the title compound as off-white crystals (1.06g; 71%). m.p. 149°
Found: C, 57.77; H, 5.89; N, 14.40%
C14H17N3O2 requires: C, 57.71; H, 5.88; N, 14.42%.
NMR (CDCl3) δ: 1.42 (3H, t, J=7.5), 2.70 (3H, s), 3.00 (2H, br), 3.20 (2H, br), 4.02 (2H, s), 4.40 (2H, q, J=7.5), 6.52 (2H, s, br). Example 8
4-Amino-2,7-dimethyl-5,6,7,8-tetrahydrothieno[2,3-b:
5,4-c']dipyridine-3-carboxylic acid, ethyl ester (E8) A solution of E7 (2g; 6.8mM) in acetonitrile (3ml) and aqueous
formaldehyde (0.55ml; 6.8mM) at 0° was treated with sodium
cyanoborohydride (90mg; 1.4mM). The pH was adjusted to 5 with acetic acid and stirring continued for 2h. Work-up with ether was followed by chromatography on silica using dichloromethane. RecrystaUisation from ethyl acetate - petroleum ether gave the title compound (1g; 48%).
m.p. 125°.
Found: C, 58.84; H, 6.38; N, 13.69%
C15H19N3O2S requires C, 58.99; H, 6.27; N, 13.76%
Example 9
7-Acetyl-4-amino-2-methyl-5,6,7,8-tetrahydrothieno
[2,3-b:5,4-c']dipyridine-3-carboxylic acid, ethyl ester (E9)
A solution of E7 (1.5g; 5.1 mM) in dichloromethane (20ml) containing triethylamine (0.75ml) was stirred at -30° and acetic anhydride (0.5ml) added. Stirring was continued for 10min and the mixture was washed with water, dried (Na2SO4) and evaporated in vacuo. Recrystallisation of the residue from ethyl acetate gave the title compound (1.37g; 75%).
m.p. 178°
Found: C, 57.56; H, 5.71; N, 12.59%
C16H19N3O3S requires: C, 57.64; H, 5.74; N, 12.60%
A portion was converted into a tartrate salt and recrystallised from ethanol. m,p. 118-21°.
Found: C, 47.70; H, 5.28; N, 8.13%
C20H25N2O9S.H2O requires: C, 47.90; H, 5.43; N, 8.38%
Example 10
7-Acetyl-4-amino-2-phenyI-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c'] dipyridine-3-carboxylic acid, ethyl ester (E10)
The title compound was prepared in 32% overall yield from the amino nitrile D5 and ethyl 3-ethoxycinnamate using a method similar to that of Example 1. m.p. 184-6° (from ethyl acetate)
Found: C, 63.47; H, 5.41; N, 10.43%
C21H21N3O3S requires: C, 63.78; H, 5.35; N, 10.63%
Example 11
4-Amino-2-methyl-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c']
dipyridine-3-carboxylic acid, 2-propynyl ester (E11)
Treatment of E6 according to the method of Examples 3 and 7 gave the title compound in 26% overall yield. m.p. 159-60° (from ethanol)
Found: C, 59.40; H, 5.07; N, 14.08%
C15H15N3O2S requires: C, 59.78; H, 5.02; N, 13.94%
Example 12
4-Amino-2-methyl-5,6,7,8-tetrahydrotbieno[2,3-b:5,4-c,]dipyridine- 3,7-dicarboxylic acid, ethyl, methyl diester(E12)
Treatment of E7 (0.5g; 1.72mM) with methyl chloroformate (0.15ml;
1.89mM) according to the procedure of Example 9 gave the title compound (0.54g; 90%). m.p. 143-4°.
Found: C, 54.92; H, 5.46; N, 12.02%
C16H19N3O4S requires: C, 55.00; H, 5.48; N, 12.03% Example 13
4-Amino-2-methyl-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c']
dipyridine-3,7-dicarboxylic acid, diethyl ester (E12) Treatment of E7 with ethyl chloroformate according to the procedure of Example 9 gave the title compound in 44% yield. m.p. 128° (from ethyl acetate-petroleum ether).
Found: C, 56.09; H, 5.75; N, 11.42%
C17H21N3O4S requires: C, 56.18; H, 5.82; N, 11.56%
Example 14
4-Amino-7-formyl-2-methyl-5,6,7,8-tetrahydrotbieno[2,3- b:5,4-c']dipyridine-3-carboxylic acid, ethyl ester (E14)
Formic acetic anhydride was prepared using the procedure of L.I. Krimen, Org. Syn; Vol. 50, 1 and then reaction with E7 according to the method of Example 9 gave the title compound in 61% yield. m.p. 182-3° (from ethyl acetate).
Found: C, 56.39; H, 5.31; N, 12.96%
C15H17N3O3S requires: C, 56.41; H, 5.37; N, 13.16%
Example 15
4-Amino-2-methyl-7-propionyl-5,6,7,8-tetrahydrothieno[2,3-b:
5,4-c']dipyridine-3-carboxylic acid, ethyl ester (E15)
The title compound was prepared in 89% yield from E7 and propionyl chloride according to the method of Example 9. m.p. 171-2° (from ethyl acetate-petroleum ether).
Found: C, 58.90; H, 6.13; N, 11.95%
C17H21N3O3S requires: C, 58.77; H, 6.09; N, 12.09%
Example 16
4-Amino-2-methyl-5,6,7,8-tetrahydrothieno[2,3-b:5,4-b']
dipyridine-3,8-dicarboxylic acid, diethyl ester (E16)
A solution of D6 and ethyl 3-ethoxycrotonate in toluene was converted into the title compound, in 52% overall yield, using a method similar to that of Example 1. m.p. 185-70°.
Found: C, 56.10; H, 5.81; N, 11.47%
C17H21N3O4S requires: C, 56.18; H, 5.82; N, 11.56%
Example 17 4-Amino-2-methyl-5,6,7,8-tetrahydrothieno[2,3-b:5,4-b']
dipyridine-3,8-dicarboxylic acid, ethyl,methyl diester (E17)
A solution of ethyl 3-ethoxycrotonate and D7 in toluene was converted into the title compound, in 42% overall yield, using a method similar to that of Example 1. m.p. 195-7°.
Found: C, 55.13; H, 5.47; N, 11.97%
C16H19N3O4S requires: C, 55.00; H, 5.48; N, 12.03%
Example 18
4-Amino-2-methyl-5,6,7,8-tetrahydrothieno[2,3-b:5,4-b']
dipyridine-3,8-dicarboxylic acid, ethyl, vinyl diester (E18)
The title compound was prepared from D8 in 25% yield using the method of Example 1 m.p. 198-200°.
Found: C, 56.46; H, 5.31; N, 11.51%
C17H19N3O4S requires: C, 56.50; H, 5.30; N, 11.63%
Example 19
7-Acetyl-4-amino-2-methyl-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c'] dipyridine-3-carboxylic acid, 2-butynyl ester (E19).
The amino nitrile D4 and 2-butynyl-3-oxobutyrate were reacted, in 52% yield, according to the procedure of E1 using camphor sulphonic acid and copper (I) acetate to give 4-amino-7-tert-butyloxycarbonyl-2-methyl- 5,6,7,8-tetrahydrothieno[2,3-b:5,4-c']dipyridine-3-carboxylic acid, 2- butynyl ester (E19a). This was followed by deprotection using
trifluoroacetic acid as in Example 7 to give 4-amino-2-methyl-5,6,7,8- tetrahydrothieno[2,3-b:5,4-c']dipyridine-3-carboxylic acid, 2-butynyl ester (E19b). Acetylation of E 19b as in Example 9 gave the title compound in 60% overall yield. m.p. 200-1°
Found: C, 60.43; H, 5.32; N, 11.73%
C18H19N3O3S requires: C, 60.49; H, 5.36; N, 11.76%
Example 20 4-Amino-2-methyl-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c'] dipyridine- 3,7-dicarboxylic acid, 2-butynyl, methyl diester (E20)
Treatment of D4 according to the method of Example 19, using methyl chloroformate for the acylation step, gave the title compound in 20% overall yield. m.p. 202-4°
Found: C, 58.01, H, 5.23; N, 11.23%
C18H19N3O4S requires: C, 57.90; H, 5.13; N, 11.25%.
Example 21
5-Amino-3,4-dihydro-7-methyl-1H-tbiopyrano[4,,3,:4,5] thieno[2,3- blpyridine-6-carboxylic acid, ethyl ester (E21)
A solution of D9 in toluene was treated with sodium ethoxide according to the method of Example 5. Chromatography on Alumina using
dichloromethane elution followed by recrystallisation from ethyl acetate, gave the title compound in 69% overall yield, m.p. 167.5-169°
Found: C, 54.55; H, 5.22; N, 9.17%
C14H16N2S2O2 requires: C, 54.52; H, 5.23; N, 9.08%
Example 22 5-Amino -3,4-dihydro-7-methyl-1H-thiopyrano[4,,3,:4,5]thieno[2,3- blpyridine-6-carboxylic acid, methyl ester (E22)
The title compound was prepared in a similar manner to that of E21 using sodium methoxide to effect the cyclisation of D9. m.p. 220-2°
Found: C, 53.17; H, 4.81; N, 9.60%
C13H14N2S2O2 requires: C, 53.04; H, 4.79, N, 9.52%
Example 23 7-Methylsulfonyl-4-amino-2-phenyl-5,6,7,8-tetrahydrothieno[2,3- b:5,4-c'] dipyridine-3-carboxylic acid, ethyl ester (E23)
The title compound was prepared in 68% overall yield from the amine E7 and methanesulfonyl chloride using a method similar to that of Example 9. m.p. 185-6° (from ethyl acetate).
Found: C, 48.62; H, 5.11; N. 11.30%
C15 H19 N3 O4 S2 requires C, 48.76; H, 5.18; N, 11.37%
NMR (CDCI3) δ: 1.43 (3H, t, J = 10Hz), 2.72 (3H, s), 2.90 (3H, s), 3.21 (2H, m), 3.71 (2H, t, J=5Hz), 4.41 (2H, q, J=10,5Hz), 4.57 (2H, bs), 6.53 (2H, bs)
Examples 16-18
R4
E16 CO2C2H5
E17 CO2CH3
E18 CO2CH=CH2
Examples 21 and 22
R1
E21 CH3 C2H5 E22 CH3 CH3
Pharmacological Data
Geller-Seif ter Procedure
Potential anxiolytic properties are evaluated using the Geller-Seifter procedure based on that originally described by Geller and Seifter, (1960) Psychopharmacologia, 1, 482-492. This procedure has been shown to be selective for drugs with anxiolytic properties (Cook and Sepinwall, (1975) "Mechanism of Action of Benzodiazepines" ed. Costa, E. and Greengard, P., Raven Press, New York, pp. 1-28).
Rats are trained on a variable interval 30 sec schedule (VI30) to press a lever in order to obtain food reward. The 5 min sessions of the VI30 schedule alternate with 2-5 min of a schedule (FR5) in which every 5th lever press is followed by presentation of a food pellet paired with a 0.5 sec mild footshock. The total study lasts approximately 30 mins . Rats typically respond with high rates of lever pressing under the VI30 schedule and low response rates under the FR5 'conflict' session.
Anxiolytic drugs increase the suppressed response rates of rats in 'conflict' session.
Drugs are administered intraperitoneally or orally to groups of 3-8 rats 30 min before testing.
The results are expressed as the percentage increase in square root of the total number of lever presses in the FR5 'conflict' session. Square root transformation is necessary to normalise the data for statistical analysis using parametric methods (ANOVA).
Compounds E3, E4, E5, E9, E12, E14 and E17 showed an increase in responding in the 'conflict' session at a dose of 20 mg/kg p.o. Compounds E1, E2, E7, E8, E10, E11, E13, E15, E16 and E18-E23 showed no significant increase in responding at 20 mg/kg p.o. but would be expected to be active at higher dose or by other routes of administration.
[35S]-TBPS binding studies in vitro
[35s]-TBPS labels a site on or near the Cl- channel portion of the
GABAA/BDZ/CI- channel complex. Literature studies have shown that [35S]-TBPS binding is directly related to the permeability of the Cl- channel (e.g. Concas et al, 1988). Anxiolytic agents such as
benzodiazepines and barbiturates aUostericaUy inhibit the binding, whilst anxiogenic agents (e.g. benzodiazepine inverse agonists) potentiate the binding.
Modulation of [35s]-TBPS binding is measured by a method similar to that of Gee et al (1986), using well-washed rat cerebral cortex membranes. Specific binding using 2nM [35S]-TBPS (in the presence of either 1μM or 5μM GABA) represents 70-80% of total binding. Non-specific binding is defined by using 100μM picrotoxin. IC50 values are calculated from log concentration versus % inhibition curves.
Concas A. et al, (1988) J. Neurochem. 51(6), 1868-1876.
Gee K.W. et al, (1986) Mol. Pharmacol. 30, 218-225. Compounds E2-E5, E9, E10, E12, E13, E15, E16, E19-E21 and E23 showed an IC50 of less than 20μM and E6-E8, E11, E14 greater than 20μM . Solubility problems prevented the determination of reHable IC50 values for the remaining compounds. MES TEST
The maximal electroshock seizure (MES) test in rodents is one of the most widely used models of human grand mal epUepsy1. In this model, anticonvulsant agents elevate the threshold to electrically-induced seizures whilst proconvulsants lower the seizure threshold.
Method
Mice (male, Charles River, U. K. CD-1 strain, 25-30g) are randomly assigned to groups of 10-20 and dosed oraUy or intraperitoneally at a dose volume of 10ml/kg with various doses of compound (1-100 mg/kg) or vehicle. Mice are then subjected at 30 or 60 min post dose to a variable voltage electroshock (0.1 sec, 50 Hz, sine wave form) via a buccal and a
subcutaneous electrode. The mean voltage and standard error required to induce a tonic seizure in 50% (CV50) of the mice in the group is
determined by the 'up and down' method of Dixon and Mood (1948)2.
Statistical comparisons between vehicle- and drug-treated groups are made using the method of Litchfield and Wilcoxon (1949)3.
In control animals the CV50 is usually 40 - 50V. Hence the first animal in the control group is subjected to a voltage of 45V. If a tonic seizure does not ensue, the voltage is increased for a subsequent mouse. If a tonic convulsion does occur, then the voltage is decreased, and so on until all the animals in the group have been tested.
The percentage increase or decrease in CV50 for each group compared to the control is calculated.
Studies are carried out using a Heathkit shock generator with totally variable control of shock level from 0 to 200V and voltage steps of 5V are used. Drugs are suspended in 1% methyl cellulose.
Reference
1. Swinyard, E.A. (1972). Electrically-induced convulsions. In:
Experimental Models of Epilepsy ed. Purpura, D.P. et al., 433-458, Raven Press, New York.
2. Dixon, W.J. and Mood, A.M. (1948). J. Amer. Stat. Assn., 43, 109- 126.
3. Litchfield, J.T. and Wilcoxon, F. (1949). J. Pharmacol. Exp. Ther.
96, 99-113.
Results
Compound E12 was significantly active at 300 mg/kg p.o.
Claims
1. A compound of formula (I) or a pharmaceuticaUy acceptable salt
thereof:
wherein the variables are as defined in the description; for
pharmaceutical use.
2. A compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof with the proviso that, when A is -(CH2)3- or -
(CH2)5-, R1 is methyl and R2 and R3 are hydrogen, R6 is other than ethyl.
3. A compound according to claim 2 wherein A is selected from -(CH2)3-, -(CH2)5-, -(CH2)n-O-(CH2)m-, -(CH2)n-S-(CH2)m- and
-(CH2)n-NR4-(CH2)m- wherein n and m are independently zero or an integer of 1 to 4 such that (n+m) is an integer of 2 to 4, R4 is hydrogen, C1-4 alkyl, C1-5 alkanoyl, C1-4 alkylsulphonyl, C1-4 alkoxycarbonyl or C2-4 alkenyloxycarbonyl and any methylene group is optionally substituted by R5 where R5 is C1-4 alkyl.
4. A compound according to claim 2 or 3 wherein R1 is hydrogen, C1-3 alkyl, phenyl or benzyl.
5. A compound according to any of claims 2 to 4 where R2 and R3 are independently hydrogen or C1-6 alkyl.
6. A compound according to any of claims 2 to 6 where R6 is C1-6 alkyl optionally substituted by up to three halo atoms, C2-6 alkenyl, C2-6 alkynyl, C3-4 cycloalkyl or C3-4 cycloalkyl-C1-4 alkyl.
7. A compound selected from E3 to E23 as defined in the description or a pharmaceutically acceptable salt thereof.
8. A process for the preparation of a compound according to claim 2, which process comprises cyclising the acyclic enamine intermediate or imine tautomer thereof obtainable by the condensation of compounds of formulae (III) and (IV) as defined in the description and thereafter, optionally or as necessary, when Y or M is a group COL1 or COL2, converting the resulting hydroxy group to a leaving group and reacting the latter with a compound HNR2'R3' wherein R2' and R3' are R2 and R3 as defined in formula (I) or N-protecting groups, removing any R2' or R3' N-protecting group, removing any R11 N-protecting group, converting A' when other than A to A, converting R1' when other than R1 to R1, converting R6' when other than -CO2R6 to -CO2R6, interconverting A, R2, R3 and/or R6 and/or forming a pharmaceutically acceptable salt of the compound according to claim 2.
9. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
10. A compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of CNS disorders.
11. The use of a compound of formula (I) as defined in claim 1 or a
pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of CNS disorders.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB919127188A GB9127188D0 (en) | 1991-12-21 | 1991-12-21 | Novel compounds |
| GB9127188.2 | 1991-12-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1993013104A1 true WO1993013104A1 (en) | 1993-07-08 |
Family
ID=10706680
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB1992/002298 WO1993013104A1 (en) | 1991-12-21 | 1992-12-10 | C.n.s. active tricyclic thienopyridine derivatives |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU3091892A (en) |
| GB (1) | GB9127188D0 (en) |
| WO (1) | WO1993013104A1 (en) |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994025027A1 (en) * | 1993-05-05 | 1994-11-10 | Smithkline Beecham Plc | Btp receptor modulator of the gabaa/chloride channel complex for prolonging the duration of the gaba induced membrane current |
| US6023665A (en) * | 1994-10-14 | 2000-02-08 | Airport Technology In Scandinavia Ab | Aircraft identification and docking guidance systems |
| US6324489B1 (en) | 1999-10-29 | 2001-11-27 | Safegate International Ab | Aircraft identification and docking guidance systems |
| US6563432B1 (en) | 2001-01-12 | 2003-05-13 | Safegate International Ab | Aircraft docking system and method with automatic checking of apron and detection of fog or snow |
| WO2012021837A2 (en) * | 2010-08-12 | 2012-02-16 | Senomyx, Inc. | Method of improving stability of sweet enhancer and composition containing stabilized sweet enhancer |
| US8524722B2 (en) | 2007-09-14 | 2013-09-03 | Bayer Intellectual Property Gmbh | Substituted tricyclic compounds and methods of use thereof |
| US8609173B2 (en) | 2008-07-31 | 2013-12-17 | Senomyx Inc. | Compositions comprising sweetness enhancers and methods of making them |
| US9371317B2 (en) | 2013-02-19 | 2016-06-21 | Senomyx, Inc. | Sweet flavor modifier |
| US9382196B2 (en) | 2008-07-31 | 2016-07-05 | Senomyx, Inc. | Processes and intermediates for making sweet taste enhancers |
| US9420814B2 (en) | 2012-08-06 | 2016-08-23 | Senomyx, Inc. | Sweet flavor modifier |
| US9603848B2 (en) | 2007-06-08 | 2017-03-28 | Senomyx, Inc. | Modulation of chemosensory receptors and ligands associated therewith |
| US11945813B2 (en) | 2018-08-07 | 2024-04-02 | Firmenich Incorporated | 5-substituted 4-amino-1H-benzo[c][1,2,6]thiadiazine 2,2-dioxides and formulations and uses thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0327223A1 (en) * | 1988-01-22 | 1989-08-09 | Beecham Group Plc | Anxiolytic and antidepressant tetrahydrobenzothienopyridine derivatives |
| WO1991017165A1 (en) * | 1990-05-08 | 1991-11-14 | Beecham Group Plc | Tetrahydrobenzothienopyridines, processes for their preparation and their use as pharmaceuticals |
-
1991
- 1991-12-21 GB GB919127188A patent/GB9127188D0/en active Pending
-
1992
- 1992-12-10 WO PCT/GB1992/002298 patent/WO1993013104A1/en active Application Filing
- 1992-12-10 AU AU30918/92A patent/AU3091892A/en not_active Abandoned
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0327223A1 (en) * | 1988-01-22 | 1989-08-09 | Beecham Group Plc | Anxiolytic and antidepressant tetrahydrobenzothienopyridine derivatives |
| WO1991017165A1 (en) * | 1990-05-08 | 1991-11-14 | Beecham Group Plc | Tetrahydrobenzothienopyridines, processes for their preparation and their use as pharmaceuticals |
Non-Patent Citations (1)
| Title |
|---|
| JOURNAL OF HETEROCYCLIC CHEMISTRY. vol. 16, no. 3, 1979, PROVO US pages 603 - 604 I. LALETARI 'Synthesis of 4-aminothieno(2,3-b)pyridine-5-carboxylic acids (1)' cited in the application * |
Cited By (32)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994025027A1 (en) * | 1993-05-05 | 1994-11-10 | Smithkline Beecham Plc | Btp receptor modulator of the gabaa/chloride channel complex for prolonging the duration of the gaba induced membrane current |
| US6023665A (en) * | 1994-10-14 | 2000-02-08 | Airport Technology In Scandinavia Ab | Aircraft identification and docking guidance systems |
| US6807511B2 (en) | 1997-07-17 | 2004-10-19 | Safegate International Ab | Aircraft identification and docking guidance systems |
| US6324489B1 (en) | 1999-10-29 | 2001-11-27 | Safegate International Ab | Aircraft identification and docking guidance systems |
| EP2109063A2 (en) | 1999-10-29 | 2009-10-14 | Safegate International AB | Aircraft identification and docking guidance systems |
| EP2109064A2 (en) | 1999-10-29 | 2009-10-14 | Safegate International AB | Aircraft identification and docking guidance systems |
| EP2109062A2 (en) | 1999-10-29 | 2009-10-14 | Safegate International AB | Aircraft identification and docking guidance systems |
| EP2109065A2 (en) | 1999-10-29 | 2009-10-14 | Safegate International AB | Aircraft identification and docking guidance systems |
| US6563432B1 (en) | 2001-01-12 | 2003-05-13 | Safegate International Ab | Aircraft docking system and method with automatic checking of apron and detection of fog or snow |
| US9603848B2 (en) | 2007-06-08 | 2017-03-28 | Senomyx, Inc. | Modulation of chemosensory receptors and ligands associated therewith |
| US8524722B2 (en) | 2007-09-14 | 2013-09-03 | Bayer Intellectual Property Gmbh | Substituted tricyclic compounds and methods of use thereof |
| US9382196B2 (en) | 2008-07-31 | 2016-07-05 | Senomyx, Inc. | Processes and intermediates for making sweet taste enhancers |
| US10570105B2 (en) | 2008-07-31 | 2020-02-25 | Firmenich Incorporated | Processes and intermediates for making sweet taste enhancers |
| US8609173B2 (en) | 2008-07-31 | 2013-12-17 | Senomyx Inc. | Compositions comprising sweetness enhancers and methods of making them |
| US9732052B2 (en) | 2008-07-31 | 2017-08-15 | Senomyx, Inc. | Processes and intermediates for making sweet taste enhancers |
| US10087154B2 (en) | 2008-07-31 | 2018-10-02 | Senomyx, Inc. | Processes and intermediates for making sweet taste enhancers |
| US10308621B2 (en) | 2008-07-31 | 2019-06-04 | Senomyx, Inc. | Processes and intermediates for making sweet taste enhancers |
| US11129397B2 (en) | 2010-08-12 | 2021-09-28 | Firemenich Incorporated | Method of improving stability of sweet enhancer and composition containing stabilized sweet enhancer |
| CN106107406B (en) * | 2010-08-12 | 2020-06-09 | 弗门尼舍公司 | Methods of improving the stability of sweetness enhancers and compositions comprising stable sweetness enhancers |
| CN106107406A (en) * | 2010-08-12 | 2016-11-16 | 赛诺米克斯公司 | Improve the method for the stability of sweetness enhancers and comprise the compositions of stable sweetness enhancers |
| WO2012021837A2 (en) * | 2010-08-12 | 2012-02-16 | Senomyx, Inc. | Method of improving stability of sweet enhancer and composition containing stabilized sweet enhancer |
| CN103153096A (en) * | 2010-08-12 | 2013-06-12 | 赛诺米克斯公司 | Method of improving stability of sweet enhancer and composition containing stabilized sweet enhancer |
| WO2012021837A3 (en) * | 2010-08-12 | 2012-05-31 | Senomyx, Inc. | Method of improving stability of sweet enhancer and composition containing stabilized sweet enhancer |
| US9000054B2 (en) | 2010-08-12 | 2015-04-07 | Senomyx, Inc. | Method of improving stability of sweet enhancer and composition containing stabilized sweet enhancer |
| US10244779B2 (en) | 2010-08-12 | 2019-04-02 | Senomyx, Inc. | Method of improving stability of sweet enhancer and composition containing stabilized sweet enhancer |
| US9420814B2 (en) | 2012-08-06 | 2016-08-23 | Senomyx, Inc. | Sweet flavor modifier |
| US9745293B2 (en) | 2012-08-06 | 2017-08-29 | Senomyx, Inc. | Sweet flavor modifier |
| US9687015B2 (en) | 2012-08-06 | 2017-06-27 | Senomyx, Inc. | Sweet flavor modifier |
| US9695162B2 (en) | 2013-02-19 | 2017-07-04 | Senomyx, Inc. | Sweet flavor modifier |
| US9475803B2 (en) | 2013-02-19 | 2016-10-25 | Senomyx, Inc. | Sweet flavor modifier |
| US9371317B2 (en) | 2013-02-19 | 2016-06-21 | Senomyx, Inc. | Sweet flavor modifier |
| US11945813B2 (en) | 2018-08-07 | 2024-04-02 | Firmenich Incorporated | 5-substituted 4-amino-1H-benzo[c][1,2,6]thiadiazine 2,2-dioxides and formulations and uses thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| AU3091892A (en) | 1993-07-28 |
| GB9127188D0 (en) | 1992-02-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5817819A (en) | Condensed-ring thiophene derivatives, their production and use | |
| KR900007780B1 (en) | Process for preparing condensed pyrrolinone derivatives | |
| EP0582368B1 (en) | Thienobenzodiazepine derivatives for treatment of CNS disorders | |
| AU2004277311B2 (en) | Benzo (4, 5) thieno (2, 3-d) pyrimidin-4-ones and their use in therapy | |
| US7989464B2 (en) | mGluR1 antagonists as therapeutic agents | |
| US6159962A (en) | 3-substituted 3,4-dihydro-thieno[2,3-D]pyrimidine derivatives and production and use of the same | |
| CZ410791A3 (en) | Amides of thieno-triazolo-1,4-diazepino-2-carboxylic acid, process of their preparation and pharmaceutical preparation based thereon | |
| WO1993013104A1 (en) | C.n.s. active tricyclic thienopyridine derivatives | |
| WO2009093013A1 (en) | Fused thiophene derivatives as mek inhibitors | |
| US5093493A (en) | 4-amino-benzo[b]thieno[2,3-b]pyridines useful in the treatment of CNS disorders | |
| EP0472116B1 (en) | Thienopyridine Derivatives, their production and use | |
| US6355647B1 (en) | 3-substituted 3,4,5,7-tetrahedropyrrolo[3′,4′:4,5]thieno-[2,3-d]pyrimidine derivatives, their preparation and use | |
| AU641504B2 (en) | Tetrahydrobenzothienopyridines, processes for their preparation and their use as pharmaceuticals | |
| US5447937A (en) | CNS active tetrahydrobenzothienopyridines | |
| US6159981A (en) | 3-substituted pyrido [3',4':4,5] Thieno [2,3-d] pyrimidine derivatives, and production and use of the same | |
| WO2005123744A1 (en) | Thienopyridone carboxamides and their medical use | |
| WO1993009122A1 (en) | Cns active tetrahydrobenzothienopyridines | |
| EP0386778B1 (en) | Biphenyl derivatives | |
| US4474786A (en) | Tricyclic lactams and derivatives useful in increasing cardiac contractility | |
| WO1994018205A1 (en) | C.n.s. active tetrahydrobenzothienopyridines |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU CA JP KR NZ US |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE |
|
| DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
| 122 | Ep: pct application non-entry in european phase | ||
| NENP | Non-entry into the national phase |
Ref country code: CA |