EP0148233A1 - Anti-emetische azabicycloalkylbenzamide - Google Patents
Anti-emetische azabicycloalkylbenzamideInfo
- Publication number
- EP0148233A1 EP0148233A1 EP19840902596 EP84902596A EP0148233A1 EP 0148233 A1 EP0148233 A1 EP 0148233A1 EP 19840902596 EP19840902596 EP 19840902596 EP 84902596 A EP84902596 A EP 84902596A EP 0148233 A1 EP0148233 A1 EP 0148233A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- alkyl
- compound
- pharmaceutically acceptable
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
Definitions
- 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.
- R 1 is C 1-6 alkyl
- R 2 is hydrogen or C 1-7 acyl
- R 3 and R 4 are independently hydrogen or C 1-6 alkyl or together form C 2-5 polymethylene;
- R 5 is C 4-7 alkyl, C 3-8 cycloalkyl, C 1-4 alkyl C 3-8 cycloalkyl or benzyl optionally substituted by one or two substituents selected from C 1-6 alkyl, C 1-4 alkoxy, trifluoromethyl and halogen.
- R 1 to R 4 are as defined in formula (I) and R 5 is benzyl optionally substituted by one or two substituents selected from C 1-6 alkyl, C 1-4 alkoxy trifluoromethyl and halogen.
- R 1 examples include methyl, ethyl, n- and iso-propyl groups.
- R 1 is methyl.
- R 2 examples include hydrogen and C 1-6 alkanoyl, such as formyl, acetyl, propionyl, n- and iso-butyryl groups. More suitably R 2 is hydrogen or a formyl or acetyl group. Preferably R 2 is hydrogen.
- R 3 and R 4 include hydrogen, methyl, ethyl, n- and iso-propyl groups.
- R 3 is a methyl or ethyl group, in particular methyl.
- R 4 is hydrogen.
- R 5 examples include (CH 2 )u R 16 wherein u is 1 or 2 and R 16 is a secondary or tertiary C 3-6 alkyl group or a C 3-8 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; CF 3 , fluoro, chloro and bromo.
- u is
- 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 R 9 is C 1-6 alkyl, phenyl-C 1-6 alkyl or C 5-7 cycloalkyl, and Y is an anion of an acid.
- R 9 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.
- a favoured group of compounds within formula (I) is of formula (II) and pharmaceutically acceptable salts
- R 2 1 is hydrogen or a formyl or acetyl group
- R 3 1 and R 4 1 are independently hydrogen or methyl; and R 5 is as defined in formula (I).
- R 2 1 , R 3 1 , R 4 1 and R 5 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):
- Q is a leaving group
- R 6 is amino, protected amino or nitro
- R 7 is R 5 as defined or a protecting group; and the remaining variables are as defined in formula (I); and thereafter if necessary converting a group R 6 to NHR 2 , R 3 and/or R 4 to other R 3 and/or R 4 and/or R 7 to R 5 ; and optionally forming a pharmaceutically acceptable salt of the resultant compound of formula (I).
- N-protecting groups in R 6 include C 1-6 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 C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, halogen or nitro; and C 1-4 alkoxycarbonyl, for example tert-butoxycarbonyl.
- R 7 protecting groups include those listed above for N-protecting groups in R 6 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 C 1-4 alkanoyloxy, C 1-4 alkoxycarbonyloxy and activated hydrocarbyloxy such as pentachlorophenoxy.
- 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.
- 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.
- 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.
- the acid acceptor can be inorganic, such as calcium carbonate, sodium carbonate or potassium carbonate.
- the reaction is preferably carried in substantially the same manner as if the leaving group were hydroxy.
- Suitable examples of acyloxy leaving groups include C 1-4 alkanoyloxy, mesyloxy, tosyloxy and triflate.
- 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.
- an inert solvent such as methylenechloride
- 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.
- R 6 is C 1-6 alkanoyl-amino or optionally substituted benzoyl-amino as defined conversion to amino is conveniently effected by conventional base hydrolysis.
- R 6 is C 1-4 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.
- R 6 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.
- R 3 /R 4 hydrogen to R 3 /R 4 C 1-6 alkyl may be carried out by conventional N-alkylation.
- R 7 to R 5 may be carried out by deprotection and subsequent reaction with R 5 L wherein L is a group or atom readily displaced by a nucleophile.
- Suitable values for L include chloride, bromide, iodide, OSO 2 CH 3 or OSO 2 -C 6 H5.p.CH 3 .
- Favoured values for L include chloride, bromide and iodide.
- De-protection may suitably be effected as described above for hydrogenolysable protected amino R 6 , under conventional conditions.
- the reaction of the de-protected product with R 5 L 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.
- R 7 is R 5 as in the desired compound of formula (I). It will be appreciated that where R 5 is sensitive to reaction steps to intermediates it is preferred to use an inert group R 7 during such steps, and to convert it to R 5 subsequently as described above.
- R 6 or R 7 may take place in any desired or necessary order.
- protection of an NHR 2 amino group with a group such as trityl may be necessary when converting hydrogen to an R 5 group.
- the -CO-NH- linkage has a ⁇ orientation with respect to the nortropane ring to which it is attached.
- a mixture of ⁇ and ⁇ 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 ⁇ isomer may, if desired, be synthesised from the corresponding ⁇ form of the compound of the formula (IV).
- the ⁇ form of the compound of formula (IV) may, if desired, be prepared by known sterospecific processes, such as those leading to the ⁇ 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 R 9 Y 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.
- intermediates of the formulae (III) and (IV) are either known compounds or can be prepared by analogous processes to known compounds.
- intermediates of formula (III) may be prepared according to EP 47207 i.e. according to the following reaction sequence:
- R 1 , R 3 , R 4 , R 6 and R 7 are as hereinbefore defined, and R 11 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).
- compositions 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.
- 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.
- the compound can be dissolved for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
- 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.
- a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
- compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
- 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.
- 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.
- 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.
- the invention provides a pharmaceutical composition
- 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.
- 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.
- 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-3 ⁇ -amine.
- Compounds were adminisitred s ⁇ bcutaneo ⁇ sly 30 minutes prior to administration of a standard dose of apomorphine HCl (0.1 mg/kg s ⁇ bcutaneously) 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 ED 50 value of 0.01 mg/kg s.c. and the compounds of Examples 2 and 4 had an ED 50 value of 0.1 mg/kg s.c.
- 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.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB8317597 | 1983-06-29 | ||
GB838317597A GB8317597D0 (en) | 1983-06-29 | 1983-06-29 | Pharmaceutical compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0148233A1 true EP0148233A1 (de) | 1985-07-17 |
Family
ID=10544955
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP19840902596 Withdrawn EP0148233A1 (de) | 1983-06-29 | 1984-06-28 | Anti-emetische azabicycloalkylbenzamide |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP0148233A1 (de) |
GB (1) | GB8317597D0 (de) |
WO (1) | WO1985000170A1 (de) |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL59004A0 (en) * | 1978-12-30 | 1980-03-31 | Beecham Group Ltd | Substituted benzamides their preparation and pharmaceutical compositions containing them |
FR2489327B1 (fr) * | 1980-08-28 | 1984-05-18 | Ile De France | N (1 allyl 2 pyrrolidinyl methyl) 2 methoxy 4 amino 5 methylsulfa moyl benzamide, son procede de preparation et son application comme medicament |
ZA818221B (en) * | 1980-12-12 | 1982-10-27 | Beecham Group Plc | Pharmaceutical compounds |
EP0068700A1 (de) * | 1981-06-29 | 1983-01-05 | Beecham Group Plc | Azabicycloalkylbenzamide, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Zusammensetzungen |
DE3368061D1 (en) * | 1982-05-11 | 1987-01-15 | Beecham Group Plc | Azabicycloalkane derivatives, their preparation and medicaments containing them |
AU1508183A (en) * | 1982-06-04 | 1983-12-08 | Beecham Group Plc | Benzamide and anilide derivatives of 8-azabicyclo-(3.2.1)- -octane |
-
1983
- 1983-06-29 GB GB838317597A patent/GB8317597D0/en active Pending
-
1984
- 1984-06-28 EP EP19840902596 patent/EP0148233A1/de not_active Withdrawn
- 1984-06-28 WO PCT/GB1984/000230 patent/WO1985000170A1/en not_active Application Discontinuation
Non-Patent Citations (1)
Title |
---|
See references of WO8500170A1 * |
Also Published As
Publication number | Publication date |
---|---|
WO1985000170A1 (en) | 1985-01-17 |
GB8317597D0 (en) | 1983-08-03 |
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Legal Events
Date | Code | Title | Description |
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PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
AK | Designated contracting states |
Designated state(s): CH DE FR GB LI NL |
|
17P | Request for examination filed |
Effective date: 19850507 |
|
17Q | First examination report despatched |
Effective date: 19861209 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
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18D | Application deemed to be withdrawn |
Effective date: 19870422 |
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RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: WATTS, ERIC, ALFRED |