Medicaments for the treatment of emesis

Abstract: A method of treatment of emesis, anxiety and/or IBS in mammals, including humans, which method comprises ad­ ministering an effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof: Ar-CO-Y-Z (I) wherein Ar is a group of formula (a): wherein: R₁ and R₂ are independently selected from hydrogen, halogen, C₁₋₆ alkyl, C₁₋₄ alkoxy, hydroxy, amino optionally substituted by one or two C₁₋₄ alkyl groups, thiol, C₁₋₄ alkyl­ thio; X is CH₂, NR₃, -O- or -S- wherein R₃ is hydrogen, C₁₋₄ alkyl, C₃₋₅ alkenyl, phenyl or phenyl C₁₋₄ alkyl; or Ar is a group of formula (b): wherein R₄ to R₇ are independently hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy, amino optionally substituted by one or two C₁₋₄ alkyl, by C₁₋₄ alkanoylamino or pyrrolyl, one of R₄ to R₇ being other than hydrogen; Y is -O- or -NH-; and Z is a group of formula (c), (d) or (e): wherein n is 2, 3 or 4; R₈ is hydrogen, C₁₋₇ alkyl, C₃₋₅ alkenyl or phenyl C₁₋₄ alkyl optionally substituted by one of two halogen, C₁₋₄ alkoxy or C₁₋₄ alkyl; wherein: p is 1, 2 or 3; and R₉ is as defined above for R₈; and with the proviso that, when Ar is of formula (b) and Y is -NH-, Z is a group of formula (d) or (e); wherein R₁₀ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₆ alkenyl, phenyl or phenyl-C₁₋₃ alkyl; and one of the groups represented by R₁₁, R₁₂ and R₁₃ is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₂₋₆ alkenyl of phenyl-C₁₋₃ alkyl and each of the other groups, which may be the same or different, is hydrogen or C₁₋₆ alkyl.

Description: The present invention relates to treatment of emesis, such as cytotoxic agent or radiation induced nausea and vomiting in mammals including humans, and to the use of a compound in the preparation of a medicament for the treatment of such conditions. Floreczyk et al (Cancer Treat. Rep. Vol 66, 1982 p.187-189) describe the use of metoclopramide as an effective antiemetic agent in cisplatin induced vomiting in the ferret. GB 2125398A describes inter alia indolyl amides and esters having a azabicyclic side chain which are reported to be 5-HT receptor antagonists of potential use in the treatment of migraine. It has now been discovered that indole-[3α-(8-methyl-8-azabicyclo(3.2.1)octyl)]-3-carboxylate blocks the emetic response induced by cytotoxic agents such as cisplatin and also by radiation treatment. The compound is therefore of use in the treatment of nausea and vomiting associated with cancer therapy. Accordingly, the present invention provides the use of a compound of formula (A): or a pharmaceutically acceptable salt thereof; in the manufacture of a medicament for use in the treatment of emesis. The pharmaceutically acceptable salts of the compounds of the formula (A) include acid addition salts with conventional acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric acids and pharmaceutically acceptable organic acids such as acetic, tartaric, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, α-keto glutaric, α-glycerophosphoric, and glucose-1-phosphoric acids. The pharmaceutically acceptable salts of the compound of the formula (A)are usually acid addition salts with acids such as hydrochloric, hydrobromic, phosphoric, sulphuric, citric, tartaric, lactic and acetic acid. Preferably the acid addition salt is the hydrochloride salt. Examples of pharmaceutically acceptable salts include quaternary derivatives of the compounds of formula (A) including the compounds quaternised by compounds such as R-T wherein R is C₁₋₆ alkyl, phenyl-C₁₋₆ alkyl or C₅₋₇ cycloalkyl, and T is a radical corresponding to a anion of a acid. Suitable examples of R 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 of the compounds of formula (A) also include internal salts such as pharmaceutically acceptable N-oxides. The compound of the formula (A) and its pharmaceutically acceptable salts may also form pharmaceutically acceptable solvates, such as hydrates, which are included whenever a compound of formula (A) is herein referred to. The compound of the formula (A) may be prepared as described in the aforementioned U.K. patent application, or by analogous methods thereto. Examples of cytotoxic agents include those routinely used in cancer chemotherapy, such as cisplatin, doxorubicin, cyclophosphamide, particularly cisplatin. The administration of the compound of formula (A), or a pharmaceutically acceptable salt thereof may be by way of oral or parenteral administration. An amount effective to treat the disorders hereinbefore described depends on 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 0.5 to 100mg for example 1 to 500mg, of the compound of formula (A), or a pharmaceutically acceptable salt thereof. 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 0.001 to 50mg/kg/day, more usually 0.002 to 25mg/kg/day. No adverse toxicological effects are indicated at any of the aforementioned dosage ranges. It is preferred that the compound of formula (A) or a pharmaceutically acceptable salt thereof is administered in the form of a unit dose pharmaceutical composition in which is combined with a pharmaceutically acceptable carrier. Such compositions are prepared by admixture and are suitably 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 or tabletting. 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. The following Example illustrates the preparation of the compound of formula (A) and the following pharmacological data illustrate the invention. Example Indole-[3α-(8-methyl-8-azabicyclo(3.2.1)octyl)]-3-carboxylate Tropine (6.35g) in dry tetrahydrofuran (20ml) was cooled in a ice-bath and treated dropwise with butyl lithium (21.3ml of 1.6M solution in hexane). The mixture was stirred for 30 minutes at ice-bath temperature then it was evaporated in vacuo (<30 o C). The residue was treated with dry tetrahydrofuran (40ml) and cooled in an ice-bath. Indole-3-carboxylic acid chloride [prepared from 5g of acid] in dry tetrahydrofuran (20ml) was added dropwise and the resulting mixture was stirred at room temperature, under nitrogen, overnight. The mixture was diluted with dichloromethane and the organic phase was washed with saturated potassium carbonate and with brine, dried (Na₂SO₄) and evaporated to give a yellow solid (8.1g). This was chromatographed on silica gel (250g) using dichloromethane/methanol/ammonium hydroxide (90/10/0.25) then (90/10/0.5) as eluants to give a white solid (3.93g). A portion (2.93g) was recrystallised from ethyl acetate to give the title compound (1.57g) as white crystals. m.p. 199-202 o C C₁₇H₂₀N₂O₂ required: C, 71.81; H, 7.09; N, 9.85% found: C, 71.74; H, 7.16; N, 9.75% PHARMACOLOGICAL DATA Inhibition of Chemotherapy Induced Nausea and Vomiting Adult male ferrets (initial body weight 1.3-1.8kg) were individually housed, fed once daily (200g Chum Puppy Food plus 50g Lab Diet A) and were supplied with water ad libitum . Additionally, each animal was given ¼ pint of milk daily during an acclimatization period. To facilitate intravenous administration of drugs, a chronic indwelling catheter was surgically implanted into the jugular vein using a modification of the technique described by Florczyk and Schurig, 1981 (Pharmacol. Biochem. Behav., 14 , 255-257). Prior to surgery each animal was sedated with ketamine hydrochloride (40mg/animal intramuscularly) and anaesthetised with a halothane-N₂O-O₂ mixture. A four day recovery period was allowed before commencement of an experiment. For each group of animals, a preliminary study was carried out to establish an intravenous dose level of cytotoxic agent(s) which would give a consistent and reproducible emetic response. The appropriate dose of example was administered intravenously twice to each animal; 30 minutes before and 30-45 minutes after dosing with cytotoxic agent(s). Running controls received vehicle ad cytotoxic agent(s) only. A single emetic response commenced when an animal assumed a characteristic posture with retching and was concluded when either vomitus was expelled or was present in the mouth as evidenced by a chewing movement. The total number of emetic responses was determined during the four hour period following administration of cytotoxic agent(s) and the number of animals completely protected from emesis determined for each treatment. All solutions were prepared in water for injection. B.P. Cisplatin was prepared from vials of Neoplatin for injection (Mead Johnson; dose volume of 3ml/kg). Doxorubicin (Adriamycin ); Farmitalia Carlo Erba Ltd. Cyclophosphamide (Endoxana ); W.B. Pharmaceuticals Ltd. The results obtained are shown below: Treatment Dose mg/kg iv. Dose of Cisplatin No. of animals completely protected/No. of animals used Administered twice mg/kg iv. Vehicle 10 1/11 Compound 0.005 10 2/4 0.05 10 3/4 0.5 10 3/4

Claims: The use of a compound of formula (A): which is indole-[3α-(8-methyl-8-azabicyclo(3.2.1)octyl)]-3-carboxylate, or a pharmaceutically acceptable salt thereof; wherein the term 'pharmaceutically acceptable salt' also includes quaternary derivatives and N-oxides, in the manufacture of a medicament for use in the treatment of emesis. A use according to claim 1 wherein the medicament is for use in the treatment of cytotoxic agent or radiation induced nausea and vomiting. A use according to claim 2 wherein the cytotoxic agent comprises cisplatin. A use according to claim 2 wherein the cytotoxic agent comprises doxorubicin. A use according to claim 2 wherein the cytotoxic agent comprises cyclophosphamide. A use according to any one of claims 1 to 5 wherein the medicament is adapted for parenteral administration. A use according to any one of claims 1 to 5 wherein the medicament is adapted for intravenous administration. A use according to any one of claims 1 to 6, or claim 9, wherein the medicament is adapted for oral administration. The use of a compound of formula (A) as defined in claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of nausea and vomiting associated with cancer therapy. A use as defined in any one of claims 1 to 9 wherein the compound of formula (A) is in the form of a pharmaceutically acceptable salt which is an acid addition salt or a quaternary derivative.

Inventors: SANGER GARETH JOHN, WOOTTON GORDON, SANGER, GARETH JOHN, WOOTTON, GORDON
Applicants: BEECHAM GROUP PLC
Application year: 1986
Main classification: A61K31
IPC codes: A61K31, C07D403, A61P35, A61P1, A61P11, C07D453, C07D451, A61P25, C07D209