Anti-emetic azabicycloalkyl benzamides
This invention relates to substituted benzamides having useful pharmacological activity, to pharmaceutical compositions containing them and processes for their preparation.
EP 13138 discloses benzamides which are useful in the treatment of disorders related to impaired gastro-intestinal motility, emesis, and/or in the treatment of disorders of the central nervous system.
EP 55524 discloses benzamides which are described as having anti-emetic activity.
We have surprisingly found a hitherto not specifically disclosed group of compounds having anti-emetic activity.
Accordingly, the present invention provides compounds of the formula (I), and pharmaceutically acceptable salts thereof:
wherein:
R1 is C1-6 alkyl;
R2 is hydrogen or C1-7 acyl;
R3 and R4 are independently hydrogen or C1-6 alkyl or together form C2-5 polymethylene;
R5 is C4-7 alkyl, C3-8 cycloalkyl, C1-4 alkyl C3-8 cycloalkyl or benzyl optionally substituted by one or two substituents selected from C1-6 alkyl, C1-4 alkoxy, trifluoromethyl and halogen.
There is a group of compounds within formula (I) wherein R1 to R4 are as defined in formula (I) and R5 is benzyl optionally substituted by one or two substituents selected from C1-6 alkyl, C1-4 alkoxy trifluoromethyl and halogen.
Suitable examples of R1 include methyl, ethyl, n- and iso-propyl groups. Preferably R1 is methyl.
Suitable examples of R2 include hydrogen and C1-6 alkanoyl, such as formyl, acetyl, propionyl, n- and iso-butyryl groups. More suitably R2 is hydrogen or a formyl or acetyl group. Preferably R2 is hydrogen.
Suitable examples of R3 and R4 include hydrogen, methyl, ethyl, n- and iso-propyl groups. Preferably R3
is a methyl or ethyl group, in particular methyl. Preferably R4 is hydrogen.
Suitable examples of R5 include (CH2)u R16wherein u is 1 or 2 and R16 is a secondary or tertiary C3-6 alkyl group or a C3-8 cycloalkyl group for example, cyclopropylmethyl, cyclobutylmethyl, cylopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, eyelopentylethyl, cyc1ohexylethyl, tert-butylmethyl; iso-propylmethyl, iso-propylethyl and tert-butylethyl; and benzyl optionally substituted by methyl, ethyl, nand iso-propyl, n- sec- and tert- butyl; methoxy, ethoxy, n- and iso-propoxy; CF3, fluoro, chloro and bromo. Preferably R5 is unsubstituted benzyl.
The pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts with conventional acids such as hydrochloric, hydrobromic, phosphoric, sulphuric, citric, tartaric, lactic and acetic acid.
The pharmaceutically acceptable salts of the compounds of the formula (I) also include quaternary ammonium salts. Examples of such salts include such compounds quaternised by compounds such as R9-Y wherein R9 is C1-6 alkyl, phenyl-C1-6 alkyl or C5-7 cycloalkyl, and Y is an anion of an acid. Suitable examples of R9 include methyl, ethyl and n- and iso-propyl; and benzyl and phenethyl. Suitable examples of Y include the halides 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) can also form solvates such as hydrates.
In the compound of formula (I) it will be seen that the -CO-NH- linkage has β orientation with respect to the nortropane ring, that is:
A favoured group of compounds within formula (I) is of formula (II) and pharmaceutically acceptable salts
wherein:
R2 1 is hydrogen or a formyl or acetyl group;
R3 1 and R4 1 are independently hydrogen or methyl; and R5 is as defined in formula (I).
Suitable and preferred examples of R2 1, R3 1, R4 1 and R5 are as described for the corresponding variables in formula (I).
It will, of course, be realised that the compounds of the formula (I) have a prochiral centre, and thus other stereoisomeric forms outside formula (I) exist. The compounds of formula (I) may be separated from the other isomeric forms by the usual methods, or may be obtained by stereospecific synthesis.
The. invention also provides a process for the preparation of a compound of formula (I) which process comprises reacting a compound of the formula (III):
with a compound of formula (IV)
wherein:
Q is a leaving group;
R6 is amino, protected amino or nitro;
R7 is R5 as defined or a protecting group; and the remaining variables are as defined in formula (I); and thereafter if necessary converting a group R6 to NHR2,
R3 and/or R4 to other R3 and/or R4 and/or R7 to R5; and optionally forming a pharmaceutically acceptable salt of the resultant compound of formula (I).
Examples of N-protecting groups in R6 include C1-6 alkanoyl, for example acetyl, propionyl n- and isobutyryl and 2, 2-dimethylpropanoyl, benzoyl or benzene optionally substituted in the phenyl ring by one or two substituents selected from C1-4 alkyl, C1-4 alkoxy, trifluoromethyl, halogen or nitro; and C1-4 alkoxycarbonyl, for example tert-butoxycarbonyl.
Suitable examples of R7 protecting groups include those listed above for N-protecting groups in R6 which are hydrogenolysable.
The leaving group Q is a group readily displaceable by a nucleophile. Suitable examples of Q are hydroxy, halogen such as chloro and bromo and acyloxy such as C1-4 alkanoyloxy, C1-4 alkoxycarbonyloxy and activated hydrocarbyloxy such as pentachlorophenoxy.
If the leaving group is hydroxy, then the reaction is preferably carried out in an inert non-hydroxylic solvent, such as benzene, toluene or diethyl ether in the presence of a dehydrating catalyst, such as a carbodiimide, for example dicyclohexylcarbodiimide. The reaction may be carried out at a non-extreme temperature such as -10 to 100ºC, for example 0 to 80ºC.
If the leaving group is a Tialide, then the reaction is preferably carried out at a non-extreme temperature in an inert non-hydroxylic solvent, such as benzene, toluene or diethyl ether. 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.
If the leaving group is acyloxy, then the reaction is preferably carried in substantially the same manner as if the leaving group were hydroxy. Suitable examples of acyloxy leaving groups include C1-4 alkanoyloxy, mesyloxy, tosyloxy and triflate.
If the leaving group is C1-4 alkoxycarbonyloxy, then the reaction is preferably carried out in an inert solvent, such as methylenechloride, at a non-extreme temperature in the presence of an acid acceptor, such as triethylamine.
If the leaving group 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.
Conversion of R6 protected amino to amino may be effected conventionally.
When R6 is C1-6 alkanoyl-amino or optionally substituted benzoyl-amino as defined conversion to amino is conveniently effected by conventional base hydrolysis.
When R6 is C1-4 alkoxycarbonyl-amino or optionally substituted benzyl-amino as defined, conversion to
amino may be carried out conventionally, for example by hydrogenolysis. Suitable reactions are conventional transition - metal catalysed hydrogenation, using for example palladium - or platinum - charcoal, at atmospheric pressure or a light excess thereover. A dry, inert, polar solvent such as dry ethanol and ambient temperatures are apt.
R6 nitro groups may be converted to amino groups by conventional methods, such as reduction with metals in acid solution, for example with tin and hydrochloric acid.
Conversion of R3/R4 hydrogen to R3/R4 C1-6 alkyl may be carried out by conventional N-alkylation.
Conversion of R7 to R5 may be carried out by deprotection and subsequent reaction with R5L wherein L is a group or atom readily displaced by a nucleophile.
Suitable values for L include chloride, bromide, iodide, OSO2CH3 or OSO2-C6H5.p.CH3.
Favoured values for L include chloride, bromide and iodide.
De-protection may suitably be effected as described above for hydrogenolysable protected amino R6, under conventional conditions.
The reaction of the de-protected product with R5L 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 a non-extreme temperature such as at ambient or at a slightly elevated temperature.
In the preparation of the compounds of the invention it is preferred that R7 is R5 as in the desired compound of formula (I). It will be appreciated that where R5 is sensitive to reaction steps to intermediates it is preferred to use an inert group R7 during such steps, and to convert it to R5 subsequently as described above.
It will be appreciated that interconversions of R6 or R7 may take place in any desired or necessary order. The skilled man will appreciate that protection of an NHR2 amino group with a group such as trityl may be necessary when converting hydrogen to an R5 group.
It will be realised that in the compound of the formula (I) the -CO-NH- linkage has a β orientation with respect to the nortropane ring to which it is attached. A mixture of α and β isomers of the compound of the formula (I) may be synthesised nonstereospecifically and the desired isomer separated conventionally therefrom, e.g. by chromatography; or alternatively the β isomer may, if desired, be synthesised from the corresponding β form of the compound of the formula (IV).
Synthesis from the corresponding β isomer of the compound of the formula (IV) is in general preferred.
The β form of the compound of formula (IV) may, if desired, be prepared by known sterospecific processes, such as those leading to the β isomers of the compound of formula (IV), for example as described in EP 13138
The acid addition salts of compounds of the formula (I) may be prepared in entirely conventional manner by reacting a compound of the formula (I) in base form with the chosen acid.
The quaternary ammonium salts of the compounds of the formula (I) may be prepared in conventional manner for such salts, such as by reaction of the chosen compound of the formula (I) with a compound R9Y as defined. This reaction is suitaly carried out in an appropriate solvent such as acetone, methanol, ethanol, dimethylformamide, at ambient or raised temperature and pressure.
The nitrogen atom of the nortropane moiety may also form an N-oxide to give an internal N-oxide salt of the compound of the formula (I). The N-oxides may be prepared in conventional manner such as by reaction of the chosen compound of the formula (I) with an organic per-acid such as m-chloroperbenzoic acid. The reaction is suitably carried out at below ambient temperature in an organic solvent, preferably a chlorinated hydrocarbon solvent.
The intermediates of the formulae (III) and (IV) are either known compounds or can be prepared by analogous processes to known compounds. For example, intermediates of formula (III) may be prepared according to EP 47207 i.e. according to the following reaction sequence:
(III)
Intermediates of formula (IV) may be prepared as described in EP 13138.
It will be realised that compounds of formulae (V) and (VI ) :
(v)
(VI)
wherein:
R1, R3, R4, R6 and R7 are as hereinbefore defined, and R11 is hydrogen or a N-protecting group are useful novel intermediates, and as such form an aspect of the invention.
The compounds of the formula (I) are particularly useful in the treatment of emesis, because they combine a high level of anti-emetic activity with a good therapeutic ratio (based on CNS effects).
The invention, therefore, also provides a pharmaeutical composition comprising a compound of the formula (I), or a hydrate or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. Such compositions may be 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; the compositions may also favourably be in the form of suppositories, particularly when an oral formulation may not be advisable, such as in the treatment of cancer patients. Normally, orally administrable compositions are preferred.
Tablets and cpasules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, fillers, tabletting lubricants, disintegrants, and acceptable wetting agents and the like. 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 suspensions, solutions, emulsions, syrups, or elixirs, or may be presented in 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 flavouring or colouring agents.
For parenteral administration, fluid unit dosage forms are prepared utilizing the compound of the formula (I) 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 sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as
a local anaesthetic, preservatives and buffering agents can be dissolved in the vehicle. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
It will, of course, be realised that the precise dosage used in the treatment of any of the hereinbefore described disorders will depend on the actual compound of the formula (I) used, and also on other factors such as the seriousness of the disorder being treated.
The invention further provides a method of treatment of emesis and/or disorders related to impaired gastro-intestinal motility in animals including humans comprising the administration of an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof. The '' effective amount'' will depend in the usual way on a number of factors such as the nature and severity of the malady to be treated, the weight of the sufferer, and the actual compound used.
However, by way of illustration, unit doses will suitably contain 0. 01 to 100 mgs of the compounds of formula (I) more suitably from 0.01 to 50 mgs, for example 0.02 to 20 mgs.
Again by way of illustration, such unit doses will suitably be administered more than once a day, for
example 2, 3, 4, 5 or 6 times a day, in such a way that the total daily dose is suitably in the range 0.01 to 10 mg/kg per day.
Compounds of the formula (I) have the ability to potentiate the effect of conventional analgesics in migraine treatment when administered concurrently with the analgesic.
Thus the invention provides a pharmaceutical composition comprising a compound of the formula (I) and an analgesic.
The compound of the formula (I) and the analgesic, such as aspirin or paracetamol, will be present in the composition in amounts generally similar to their usual effective dose.
The composition can be a combination product, for example a tablet or capsule containing both a compound of the the formula (I) and an analgesic for oral administration, or a twin pack comprising the two active ingredients made up for separate administration.
The invention accordingly provides a method of treatment of migraine comprising the administration to the sufferer of a compound of the formula (I) and an analgesic.
The following Examples illustrate the preparation of the compounds of formula (I).
Example 3
4 -Amino-2-methoxy-3-methy aminosulphonyl-N-[33-(8-benzyl¬
8-azabicyclo(3,2,1)octyl)]benzamide
4-Amino-2-methoxy-5-methylaminosulphonyIbenzoic acid (2.34g, 0.01 mole) was dissolved in anhydrous dimethylformamide (20ml) containing triethylamine (1.01g, 1.4ml) and cooled to 0°C under a nitrogen atmosphere. Ethylchloroformate (1.09g, 0.96ml) was added dropwise maintaining the temperature at 0-5°. The solution was stirred at 0-5º for a further 20 minutes, then 8-benzyl-8-azabicyclo (3,2,1)octyl3-β-amine (2.16g) in anhydrous dimethylformamide (10ml) added slowly in one portion. The reaction mixture was left to reach ambiant temperatures over 24 hours.
The mixture was evaporated in vacuo and the residue treated with dilute ammonium hydroxide to precipitate a fine off-white solid. The solid was filtered, washed with ether and recrystallised from isopropranol to give the title compound. (2.5g; 55%) as colourless microcrystals mp 234°C.
C23H30N4O4S M+ Calculated 458.1988; Observed 458.1987
Required % N = 12.23; Found % N = 12.28, 12.24
The following examples were prepared in a similar manner from the appropriate benzoic acids.
Example 2
4-Amino-5-aminosulphonyl-2-methoxy-N-[3β -8-benzyl-8azabicyclo (3, 2, 1) octyl) ]benzamide
Colourless-hydrated-crystals (ex. isopropanol) mp 158-185°C
C22H28N4O4S M+ calculated 444-1831; observed 444.1829
Reσuired for monohydrate % N = 12.12, found % 12.30, 12.42
Example 3
4-Amino-5-dimethy]aminosulphonyl-2-methoxy-N-[3β-8-benzyl8-azabicyclo (3,2,1)octyl) ]benzamide
Colourless microcrystals (ex Ethylacetate-ether) mp 218-219°
C24H32N4O4S M+ Calculated 472.2142, observed 472.2120
Required % N = 11.86; Found % N = 12.05, 12.00
Example 4
In a similar manner, 4-amino-2-methoxy-5-methylaminosulphonyl-N-[38-{8-(2,2-dimethylpropyl)-8-azabicyclo(3.2.1) octyl}]benzamide was prepared from 4-amino-2-methoxy-5methylaminosulphonylbenzoic acid and 8-(2, 2-dimethylpropyl)8-azabicyclo(3.2.1)octyl-3β-amine.
Yield 74% m.p. 239 °C [isopropanol]
1H NMR (DMSO δ)
8.42 (s, 1H, Aromatic proton)
7.5 -7.3 (m, 1H, CONH)
6.85-6.50 (m, 1H, SO2NH)
6.4 (s, 1H, Aromatic proton)
6.0 (s, 2H, NH2)
4.5 -3.75 (m, 1H, NH
3.95 (s, 3H,
OCH
3.2 -2.9 (m, 2H, bridgehead protons)
2.55 (d, 3H SO2NHCH3)
2.0 (s, 2H, NCH2)
2.2 -1.4 (m, 8H, methylenes)
0.9 (s, 9H, C(CH3)3)
Pharmacological Data
Anti-emetic activity in the dog
Compounds were adminisitred sυbcutaneoυsly 30 minutes prior to administration of a standard dose of apomorphine HCl (0.1 mg/kg sυbcutaneously) and the vomiting response compared to that obtained when the same animals were dosed with apomorphine HCl and vehicle only. The compounds of Example 1 and 3 had an ED50 value of 0.01 mg/kg s.c. and the compounds of Examples 2 and 4 had an ED50 value of 0.1 mg/kg s.c.
Domamine Receptor Blocking Activity in the Central nervous System
Compounds were tested for inhibition of apomorhine induced climbing in the mouse. The test is based on that described by Protais, P., Constantin, J. and Schwartz J.C. (1976), Psychopharmacology, 50, 1.6.
Apomorphine 1 mg/kg s.c. induces mice to climb the wall of a wire cage (inverted food hopper - 11 x 7.5 x 18 cm high). Mice acclimatised in their home cages in groups of 5 are placed under the hoppers, immediately after the injection of apomorphine lmg/kg s.c. At 10.20 and 30 minutes after injection climbing behaviour is scored. The mice are observed for 30 seconds and scored according to the position they spend the majority of time in, score 0 - four paws on floor of cage; score 1 - four paws only on walls; score 2 - all paws on wall of cage. The scores at all 3 times and for each mouse are summed and mice drug treated orally compared to mice receiving apomorphine only. A saline only treated group is also included and any score 55% of maximum taken into account.
The compound of Example 2 was inactive at a dose of 10 mg/kg s.c. The compounds of Examples 1 and 3 were active at doses of 30 mg/kg s.c. and 10 mg/kg s.c. respectively.
Toxicity
No toxic effects were observed in the above tests,