PYRIDINE-3-CARBOXYLIC ACID ESTERS OR AMIDES USEFUL AS 5-HT3 ANTAGONISTS
This invention relates to novel compounds having pharmacological activity, to a process for their preparation and their use as pharmaceuticals.
EP-A-220011 (Beecham Group p.l.c.) describes the use of a benzamide derivative as a 5-HT3 receptor antagonist. GB 1555682 (Ciba-Geigy) describes a group of 2-methoxy-3-pyridylamides.
A group of novel compounds has now been discovered, which compounds are pyridinyl-amide and -ester derivatives, and possess 5-HT3 receptor antagonist activity.
Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof:
wherein
R 1 is C 1 -6 alkoxy, C3-8 cycloalkoxy or C3-8 cycloalkyl C1 -4 alkoxy;
R2 is hydrogen, halo, C 1 -6 alkyl, C 1 -6 alkoxy or amino optionally
substituted by one or two C 1 -6 alkyl groups;
R3 is hydrogen, halo or C 1 -6 alkyl;
L is O or NH; and
Z is a di-azacyclic or azabicyclic side chain;
having 5-HT3 receptor antagonist activity.
Suitable examples of alkyl moieties in R 1 to R3 include methyl, ethyl, n- and iso-propyl, n-, iso-, sec- and tert-butyl
Suitable examples of halo moieties include fluoro, chloro and bromo.
In particular, R1 is methoxy, R2 is NH2 and R3 is chloro.
Suitable examples of Z are described in the art relating to 5-HT3 receptor antagonists, ie. as follows: i) GB 2125398A (Sandoz Limited)
ii) GB 2152049A (Sandoz Limited)
iii) EP-A-215545 (Beecham Group p.l.c.)
iv) EP-A-214772 (Beecham Group p.l.c.)
v) EP-A-377967 (Beecham Group p.l.c.)
vi) WO 91/05174 (Beecham Group p.l.c.)
vii) EP-A-358903 (Dianippon) Particular side chains of interest are depicted thus:
Tropane
Granatane
Oxa/thia/aza-granatane
Quinuclidine
Isoquinuclidine
Isogranatane
Oxa/thia-isogranatane
Isotropane or
wherein
R is hydrogen or methyl; and X is oxygen, sulphur or nitrogen optionally substituted by C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl C1-4 alkyl, phenyl, naphthyl, phenyl C1-4 alkyl or naphthyl C1-4 alkyl wherein a phenyl or naphthyl moiety is optionally substituted by one or more of halo, C1-6 alkoxy or C1-6 alkyl.
Side chains Z of particular interest include tropane, granatane, oxagranatane and azagranatane, where R is methyl. Suitable values for N-substituents when X is N are as described in WO 91/05174, for example, iso-propyl or ethyl.
L is preferably NH.
Alternatively, COL in formula (I) may be replaced by a bioisostere therefor, for example, 1,2,4-oxadiazole and the other groups of structure h) described in EP-A-377967 (Beecham Group p.l.c).
The pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts with conventional acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric acids and pharmaceutically acceptable organic acids such as acetic, tartaric, maletc, citric, succinic, benzole, ascorbic, methanesulphonic, α-keto glutaric, α-glycerophosphoric, and gIucose-1-phosphoric acids.
Examples of pharmaceutically acceptable salts include quaternary derivatives of the compounds of formula (I) such as the compounds quatemised by compounds Rx-T wherein Rx is C 1 -6 alkyl, phenyl- C 1 -6 alkyl or C 5 -7 cycloalkyl, and T is a radical corresponding to an anion of an acid. Suitable examples of Rx include methyl, ethyl and n- and iso-propyl; and benzyl and phenethyl. Suitable examples of T include halide such as chloride, bromide and iodide.
Examples of pharmaceutically acceptable salts also include internal salts such as N-oxides. The compounds of the formula (I), their pharmaceutically acceptable salts, (including quaternary derivatives and N-oxides) may also form
pharmaceutically acceptable solvates, such as hydrates, which are included wherever a compound of formula (I) or a salt thereof is herein referred to. It will of course be realised that some of the compounds of the formula (I) have chiral or prochiral centres and thus are capable of existing in a number of stereoisomerfc forms including enantiomers. The invention extends to each of these stereoisomeric forms (including enantiomers), and to mixtures
thereof (including racemates). The different stereoisomeric forms may be separated one from the other by the usual methods.
The invention also 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 (II): .
with a compound of formula (III):
HLZ' (III) or a reactive derivative thereof, when L is O; wherein R 1', R2', R3' and/or Z' are R 1 , R2, R3 and/or Z respectively or groups or atoms convertible thereto; Q 1 is a leaving group; and the remaining variables are as hereinbefore defined; and thereafter optionally converting R1', R2', R3' and/or Z' to another group or atom R1 , R2, R3 or Z; and optionally forming a pharmaceutically acceptable salt of the resultant compound of formula (I).
Examples of leaving groups Q1 , displaceable by a nucleophile, include halogen such as chloro and bromo, hydroxy, C1 -4 alkoxy, such as CH3O and C2H5O-, PhO-, activated hydrocarbyloxy, such as Cl5C6O- or Cl3CO-; or COQ 1 , forms a mixed anhydride, so that Q 1 is carboxylic acyloxy; or an N-linked heterocycle, such as imidazoie. If a group Q 1 is a halide, or COQ1 forms a mixed anhydride, then the reaction is preferably carried out at non-extreme temperatures in an inert non-hydroxylic solvent, such as benzene, dichloromethane, toluene, diethyl ether, acetonitrile, tetrahydrofuran (THF) ordimethylformamide (DMF). It is also preferably carried out in the presence of an acid acceptor, such as an
organic base, in particular a tertiary amine, such as triethylamine,
trimethylamine, pyridine or picoline, some of which can also function as the solvent. Alternatively, the acid acceptor can be inorganic, such as calcium carbonate, sodium carbonate or potassium carbonate. Temperatures of 0°-100°C, in particular 10-80°C are suitable.
If a group Q 1 is C1 -4 alkoxy, phenoxy or activated hydrocarbyloxy then the reaction is preferably carried out in an inert polar solvent, such as toluene or dimethylformamide. It is also preferred that the group Q 1 is CI3CO- and that the reaction is carried out in toluene at reflux temperature.
If a group Q 1 is hydroxy, then the reaction is generally carried out in an inert non-hydroxyiic solvent, such as dichloromethane, THF or DMF optionally in the presence of a dehydrating agent such as a carbodiimide, for example dicyclohexylcarbodiimide. The reaction may be carried out at any
non-extreme temperature, such as -10 to 100°C, for example, 0 to 80°C. Generally, higher reaction temperatures are employed with less active compounds whereas lower temperatures are employed with the more active compounds.
[f a group Q 1 is carboxylic acyloxy, then the reaction is preferably carried in substantially the same manner as the reaction when Q 1 is halide. Suitable examples of acyloxy leaving groups include C1 -4 alkanoyloxy and C1 -4 alkoxycarbonyloxy, in which case the reaction is preferably carried out in an inert solvent, such as dichloromethane, at a non-extreme temperature for example ambient temperatures in the presence of an acid acceptor, such as triethylamine. C1 -4 alkoxycarbonyloxy leaving groups may be generated in situ by treatment of the correspondfng compound wherein Q 1 is hydroxy with a C1 -4 alkyl chloroformate.
If a group Q 1 is activated hydrocarbyloxy then the reaction is preferably carried out in an inert polar solvent, such as dimethylformamide. It is also preferred that the activated hydrocarbyloxy group is a pentachlorophenyl ester and that the reaction is carried out at ambient temperature.
When Y is O the compound of formula (III) may be in the form of a reactive derivative thereof, which is often a salt, such as the lithium, sodium or potassium salt.
An R2' or R3' group which is convertible R2 or R3 include a hydrogen substituent which is convertible to a halogen substituent by halogenation using conventional halogenating agents.
Z when other than Z may be wherein R is replaced by R' which is a hydrogenolysable protecting group which is benzyl optionally substituted by one or two groups selected from halo, C1 -4 alkoxy and C1 -4 alkyl. Such benzyl groups may, for example, be removed, when R1/R2 is not halogen, by conventional transition metal catalysed hydrogenolysis to give compounds of the formula (I) wherein R is hydrogen.
This invention also provides a further process for the preparation of a compound of the formula (I) wherein R is methyl or a pharmaceutically acceptable salt thereof, which comprises N-methylating a compound of formula (I) wherein R is hydrogen, and optionally forming a pharmaceutically acceptable salt of the resulting compound of the formula (I). In this further process of the invention 'N-methylation' may be achieved by reaction with a compound CH3Q2 wherein Q2 is a leaving group.
Suitable values for Q2 include groups displaced by nucleophiles such as Cl , Br, I, OSO2CH3 or OSO2C6H4PCH3, preferably Cl , Br or I.
The reaction may be carried out under conventional alkylation conditions for example in an inert solvent such as dimethylformamide in the presence of an acid acceptor such as potassium carbonate. Generally the reaction is carried out at non-extreme temperature such as at ambient or slightly above.
Alternatively, 'N-methylation' may be effected under conventional reductive alkylation conditions.
Interconverting R in the compound of the formula (III) before coupling with the compound of the formula (II) is also possible. Such interconversions are effected conveniently under the above conditions. It is desirable to protect any amine function with a group readily removable by acidolysis such as a C2-7 alkanoyl group, before R/Z intercon version.
It is often convenient in the preparation of such a compound of formula (III) to prepare the corresponding compound wherein the methyl group is replaced by alkoxycarbonyl. Such compounds may then be reduced using a strong reductant such as lithium aluminium hydride to the corresponding compound of formula (II).
The pyridine carboxylic acid derivative intermediates of formula (II) are known or may be prepared from substituted pyridines, for example as described in the Description hereinafter.
Compounds of the formula (III) are generally prepared from the
corresponding exocyclic keto derivative of the azabicyclic side chain, prepared by condensation methods, often using a substituted piperidine. They may be prepared by processes described in the aforementioned Patent Publications relating to values of the side chain Z.
It will be realised that in the compounds of the formula (I) having a tropane, granafane or oxa/thia/aza-granatane side chain, the -COL- linkage has an endo orientation with respect to the ring of the bicyclic moiety to which it is attached. A mixture of endo and exo isomers of the compound of the formula (I) may be synthesised non-stereospecificafly and the desired isomer separated conventionally therefrom e.g. by chromatography; or alternatively the endo isomer may if desired by synthesised from the corresponding endo form of the compound of the formula (II). Corresponding geometric isomeric pairs are possible for the isoquinuclidine, isogranatane, oxa/thia-isogranatane and isotropane side chains.
Pharmaceutically acceptable salts of the compounds of this invention may be formed conventionally.
The salts may be formed for example by reaction of the base compound of formula (l) with a pharmaceutically acceptable organic or inorganic acid.
The compounds of the present invention are 5-HT3 receptor antagonists and it is thus believed may generally be used In the treatment or prophylaxis of pain, emesis, CNS disorders and gastrointestinal disorders. Pain includes migraine, cluster headache, trigeminal neuralgia and visceral pain; emesis includes, in particular, that of preventing vomiting and nausea associated with
cancer therapy, post-operative emesis and nausea associated with migraine. Examples of cancer therapy include that using cytotoxic agents, such as platinum complexes including cisplatin, and also doxorubicin and
cyclophosphamide, particularly cisplatin; and also radiation treatment. CNS disorders include anxiety, psychosis including schizophrenia, cognitive disorders such as senile dementia and age associated memory impairment (AAMI), and drug dependence/withdrawal syndrome. Gastrointestinal disorders include irritable bowel syndrome and diarrohea. 5-HT3 receptor antagonists may also be of potential use in the treatment of obesity and/or arrhythmia.
Some of the compounds of formula (I), such as the compounds wherein Z is quinuclidine or an isogranatane, may also be 5-HT4 receptor agonists, of potential use in the treatment of disorders relating to impaired gastrointestinal motility, such as those described in EP-A-94742 (Beecham Group p.l.c).
The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Such compositions are prepared by admixture and are 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, injectable and infusable solutions or suspensions or suppositories. Orally administrable compositions are preferred, since they are more convenient for general use.
Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art, for example with an enteric coating. Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpolypyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate.
Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate. 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 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.
Oral liquid preparations are usually in the form of aqueous or oily
suspensions, solutions, emulsions, syrups, or elixirs or are 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, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and flavouring or colouring agents.
The oral compositions may be prepared by conventional methods of blending, filling ortablettiπg. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
For parenteral administration, fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local
anaesthetic, preservatives and buffering agents are also 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 sterilised by exposure of ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.
The invention further provides a method of treatment or prophylaxis of pain, emesis, CNS disorders and/or gastrointestinal disorders in mammals, such as humans, which comprises the administration of an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.
An amount effective to treat the disorders herein- before described depends on the relative efficacies of the compounds of the invention, the nature and severity of the disorder being treated and the weight of the mammal.
However, a unit dose for a 70kg adult will normally contain 0.05 to 1000mg for example 0.5 to 500mg, of the compound of the invention. Unit doses may be administered once or more than once a day, for example, 2, 3 or 4 times a day, more usually 1 to 3 times a day, that is in the range of approximately 0.0001 to 50mg/kg/day, more usually 0.0002 to 25 mg/kg/day.
No adverse toxicological effects are indicated within the aforementioned dosage ranges. The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance, in particular for use in the treatment of pain, emesis, CNS disorders and/or gastrointestinal disorders. The following Examples illustrate the preparation of compounds of formula (I); the following Description relates to the preparation of an intermediate of formula (II).
Description 6-Amino-5-chloro-2-methoxypyridine-3-carboxylic acid a) A solution of 12g of 2,6-difluoropyridine in 40 ml of iso-propanol was heated to 140°C with 20 ml of aqueous ammonia (d = 0.88) for 3 h in a sealed bomb. The cooled reaction was concentrated by rotary evaporation, the product extracted into ethyl acetate (100 ml) and the solution washed with aqueous Na2CO3 and dried (K2CO3). Evaporation afforded 2-amino-6- fiuoropyridine (7.1 g).
1H-NMR (CDCI3) δ: 4.59 (s, 2H) 6.20 (dd, 1H) 6.31 (dd, 1 H) 7.50 (q, 1H) b) A solution of 2-amino-6-fluoropyridine (4.2g) in CH2CI2 (100 ml) was treated with Et3N (8 ml) and pivaloyl chloride (5 ml) at 0°C to room
temperature overnight. The reaction mixture was washed with water (50 ml), 2N H2SO4 (50 ml), water (50 ml) and dried (Na2 SO4). Evaporation of the solvent afforded 6-fluoro-2-piva!oy!aminopyridine (6 g).
1H-NMR (CDCI3) δ: 1.33 (s, 9H) 6.65 (dd, 1H) 7.79 (q, 1H) 7.90 (brs, 1 H) 8.11 (dd, 1H) c) A solution of 6-fiuoro-2-pivaloylaminopyridine (2 g) in THF (30 ml) was cooled to -78°C and BuLi (15 mL of 1.6M in hexane) was added and the reaction stirred at 0°C for 2h. On re-cooling to -78°C, ethyl chloroformate (2 mL) was added and the reaction allowed to warm slowly to room temperature over 1h. Water (10 ml) was added and the products extracted into Et2O (3 × 50 ml) and dried (Na2SO4). Concentration afforded an oil which was triturated with petrol to give a solid, the isomeric 2-pivaloylamino-6- fluoropyridine-3-carboxylate (1 H NMR [CDCI3] δ: 1.36 (s, 9H), 1.43 (t, 3H), 4.41 (q, 2H), 6.64 (dd, 1 H), 8.45 (t, 1 H), 11.34 (brs, 1 H). The mother liquors were concentrated and purified by flash column chromatography (SiO2, Petrol to 5% Et2O/petrol to give ethyl 2-fluoro-6-pivaloylaminopyridine-3-carboxyfate (1.2 g).
1 H-NMR (CDCI3) δ: 1.33 (s, 9H) 1.41 (t, 3H) 4.40 (q, 2H) 8.07 (brs, 1 H) 8.20 (dd, 1 H) 8.40 (t, 1 H) d) A solution of methyl-6-pivaIoylamino-2-fluoropyridine-3-carboxylate (2.1 g) in MeOH (100 ml) was heated under reflux with KOBu-t (2.6 g) for 2h. The solvent was evaporated and aqueous NaHCO3 (50 mL) added. The solid product, methyl-6-amino-2-methoxypyridine-3-carboxylate was collected and dried (1.4 g).
1 H-NMR (CDCI3) δ: 3.82 (s, 3H) 3.96 (s, 3H) 4.78 (brs, 2H) 6.06 (d, 1 H) 8.01 (d, 1 H) e) A solution of methyl-6-amino-2-methoxypyridine-3-carboxylate (0.4 g) in acetic acid (10 ml) was treated with a solution of CI2 (0.19 g) in HOAc (4 ml) at room temperature for 3h. The AcOH was removed by rotary
evaporation and the residue treated with aqueous NaHCO3 (50 mL) and the product extracted into EtOAc (100 ml). Evaporation afforded methyl-6-amino- 5-chloro-2-methoxypyridine-3-carboxylate (0.32 g).
1 H-NMR (CDCI3) δ: 3.81 (s, 3H) 3.94 (s, 3H) 5.26 (brs, 2H) 8.05 (s, 1 H) f) A solution of methyl-6-amino-5-chloro-2-methoxypyridine-3- carboxylate (0.32 g) in MeOH (5 mL) was treated with 2.5N NaOH (0.6 mL) and H2O (5 mL) and the reaction stirred at room temperature until the reaction was complete by TLC. The MeOH was removed by rotary
evaporation and the residue carefully acidified with 5N HCI to give the title compound which was collected and dried (0.15 g).
1 H-NMR (d6-DMSO) δ: 3.82 (s, 3H) 7.08 (brs, 2H) 7.88 (s, 1 H) 12.10 (brs, 1 H)
Examples
Ex. No. R1 R2 R3 L Z mp°C
E1 OCH3 NH2 Cl NH NmG 194-5
E2 OCH3 NH2 Cl NH NmT 212-9
E3 OCH3 NH2 Cl NH NmipA -
Nm = N-methyl
G = granatane
T = tropane
ipA = 3-isopropylazagranatane
endo-6-Amino-5-chIoro-2-methoxy-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)pyridine-3-carboxamide (E1 )
A suspension of 6-amino-5-chloro-2-methoxypyridine-3-carboxylic acid (0.1 g and carbonyldiimidazole (0.08 g) in CH3CN (5 ml) was heated to 40°C for 1 h to give a solution. The reaction mixture was cooled to 0°C, a solution of endo-9-methyl-9-azabicyclo[3.3.1]nonan-3-amine (0.12 g) in CH3CN added and the reaction stood at room temperature overnight. The solvent was removed and the product partitioned between 2.5N NaOH (20 mL) and EtOAc (50 mL). The organic layer was separated, dried (K2CO3) and evaporated to give an oil which was purified by flash column chromatography (SiO2, CHCI3 containing increasing quantities of MeOH) to give the title compound which was converted to the monohydrochloride salt (0.08 g). mp 194-5°C. 1 H-NMR (CDCI3) (free base) δ: 0.95-1.10 (m, 2H) 1.20-1.32 (m, 2H) 1.45-1.55 (m, 1 H) 1.85-2.05 (m, 3H) 2.40-2.55 (m, 5H including 2.50, s 3H) 3.07 (brd, 2H) 3.99 (s, 3H) 4.43 (q, t, 1 H) 5.05 (brs, 2H) 7.49 (brd, 1 H)8.32 (s, 1 H)
The compounds of E2 and E3 were prepared analogously.
E3:- 1 H-NMR (DMSO) δ: 0.83(d, 6H), 2.37(s, 3H), 3.82(s, 3H), 7.64 (s, 1 H), 9.49 (d, 1 H).
MS M+ 381
5-HT3 RECEPTOR ANTAGONIST ACTIVITY a) in vivo Compounds are evaluated for antagonism of the von Bezold-Jarisch reflex evoked by 5-HT in the anaesthetised rat according to the following method:
Male rats 250-350g, are anaesthetised with urethane (1.25g/kg
intraperitoneally) and blood pressure and heart rate are recorded as described by Fozard J.R. et al., J. Cardiovasc. Pharmacol. 2, 229-245 (1980). A submaximal dose of 5-HT (usually 6μg/kg) is given repeatedly by the intravenous route and changes in heart rate quantified. The test compound is given Intravenously and the concentration required to reduce the
5-HT-evoked response to 50% of the control response (ED50) is then determined. b) in vitro binding
The method is as described by Nelson & Thomas, Biochem. Pharmacol. 38. 1693-1695 (1989). The compound E1 had a pKi of 10.4.