CA1310960C - Imidazole derivatives having 5-ht3 receptor antagonist activity - Google Patents
Imidazole derivatives having 5-ht3 receptor antagonist activityInfo
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- CA1310960C CA1310960C CA000593777A CA593777A CA1310960C CA 1310960 C CA1310960 C CA 1310960C CA 000593777 A CA000593777 A CA 000593777A CA 593777 A CA593777 A CA 593777A CA 1310960 C CA1310960 C CA 1310960C
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Abstract
Abstract Compounds of formula (I) and pharmaceutically acceptable salts thereof:
(I) wherein R1 and R2 are independently hydrogen or C1-6 alkyl;
Z is a group of sub-formula (a), (b), (c), (d) or (e):
(a) (b) (c) (d) wherein xa to xd are selected from hydrogen, halogen and hydroxy;
R3 is hydrogen and R4 is hydrogen or C1-6 alkyl, or R3 and R4 together are a bond;
R5 to R10 are independently selected from hydrogen or C1-6 alkyl; and R6 together with R4 may be C2-7 polymethylene when R3 is hydrogen, or R9 and R10 may together be C2-7 polymethylene;
having 5-HT3 receptor antagonist activity, processes for their preparation and their use as pharmaceuticals.
(I) wherein R1 and R2 are independently hydrogen or C1-6 alkyl;
Z is a group of sub-formula (a), (b), (c), (d) or (e):
(a) (b) (c) (d) wherein xa to xd are selected from hydrogen, halogen and hydroxy;
R3 is hydrogen and R4 is hydrogen or C1-6 alkyl, or R3 and R4 together are a bond;
R5 to R10 are independently selected from hydrogen or C1-6 alkyl; and R6 together with R4 may be C2-7 polymethylene when R3 is hydrogen, or R9 and R10 may together be C2-7 polymethylene;
having 5-HT3 receptor antagonist activity, processes for their preparation and their use as pharmaceuticals.
Description
13lo96o ~his invention relates to novel compounds having useful pharmacological properties, to pharmaceutical compositions 5 containing them, to a process and intermediates for their preparation, and to their use as pharmaceuticals.
EP-A-242973 (Glaxo Group Limited) discloses a class of indole derivatives which are 5-HT3 receptor antagonists.
EP-A-291172 (Glaxo Group Limited), published 17th November 1988, discloses a further group of 5-HT3 receptor antagonists wherein the indole moi~ty is replaced by another function, designated 'A' in formula (I) therein.
A class of novel, structurally dis~inct compounds has now been discovered which compounds have 5-HT3 receptor antagonist activity.
20 Accordingly, the present inventlon provides a compound of formula (I), or a pharmaceutically acc-ptaoie salt Lhe~eof:
ZC-(CH2)2 ~ R
N ~ NH
R2 (I) 30 wherein R1 and R2 are independently hydrogen or C1_6 alkyl;
Z is a group of su~-formula (a), (b), (c) or td):
Z~
R (a) X NH-~( OR7 (b) 2 s X ( c ) ~ (d) Rlo g 131096~
01 _ 3 _ 02 wherein 03 xa to Xd are selected from hydrogen, halogen and 04 hydroxy;
05 R3 is hydrogen and R4 is hydrogen or Cl_6 alkyl, or R3 06 and R4 together are a bond;
07 Rs to Rlo are independently selected from hydrogen or 08 C1_6 alkyl; and R6 together with R4 may be C2_7 09 polymethylene when R3 is hydrogen, or R g and Rln may together be C2_7 polymethylene.
12 Examples of moieties in alkyl or alkyl containing 13 groups in Rl, R2 and R4 to R10 include methyl, ethyl, 14 n- and iso-propyl, n-, iso-, sec- and tert-butyl, preferably methyl.
17 Suitable examples of R4 and R6 or Rg and R1o when 18 joined include C2, C3, C4, C5 or C6 polymethylene, 19 preferably C2, C3, C4 or C5 polymethylene.
21 xa to Xd are preferably selected from hydrogen, fluoro, 22 chloro and hydroxy, most preferably hydrogen.
24 Preferably the ZC0-~CH2)2- moiety is attached to the imidazole ring at the 4-position. Preferably R1 is 26 hydrogen or methyl, attached at the 5-position and R2 27 is hydrogen.
29 When Z is of sub~formula (a), R3 and R5 are preferably both hydrogen and one or both R4 and R6 (most 31 preferably both) are alkyl groups, such as methyl, or 32 are ~olned to form C2_7 polymethylene.
34 When Z is of sub-formula (b), R7 is preferably methyl.
36 When Z is of sub-formula (c)~ one of C0-(CH2)2- and R8 37 is attached at the 1-position and the other is attached 38 at tlle 3-position as depicted in sub-formula (C), and R8 is ~ preferably methyl or ethyl.
13~6Q
When Z is of su~-formula (d), one or both of Rg and R1o (most preferably both) are alkyl groups, such as methyl or are joined to form C2_7 polymethylene.
s 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, lactic, maleic, o citric, succinic, benzoic, ascorbic, methanesulphonic, a-keto glutaric, ~-glycerophosphoric, and glucose-1-phosphoric acids.
The pharmaceutically acceptable salts of the compounds of 5 the formula (I) 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 derivati~es of the compounds of formula (I) such as the compounds quaternised by compounds Ra-T wherein Ra is Cl_6 alkyl, phenyl-C1_6 alkyl or C5_7 cycloalkyl, and T is a 25 radical corresponding to an anion of an acid. Suitable examples of Ra include methyl, ethyl and n- and iso-propyl;
and benzyl and phenethyl. Suitable examples of T include halide such as chloride, bromide and iodide.
30 Examples of pharmaceutically acceptable salts of compounds of formula (I) also include internal salts such as pharmaceutically acceptable N-oxides.
The compounds of the formula (I), their pharmaceutically 35 acceptable salts, (including quaternary derivatives and 131~ 0 01 N-oxi~es) may also form pharmaceutically acceptable 02 solvates, such as hydrates, which are included wherever a 03 compound of formula (I) or a salt thereof is herein referred to.
06 It will of course be realised that some of the 07 compounds of the formula (I) have chiral or prochiral 08 centres and thus are capable of existing in a number of 09 stereoisomeric forms including enantiomers. The invention extends to each of these stereoisomeric forms 11 (including enantiomers), and to mixtures thereof 12 irlcludin~ racemates. The different stereoisomeric 13 forms may be separated one from another by the usual 14 methods.
16 It will be appreciated that the imidazole ring in 17 formula ~I) can exist as tautomers i.e. the hydrogen 18 atom can be on either of the imidazole nitrogen atoms.
19 The invention extends to both tautomers and mixtures thereof.
22 The invention provides process for the preparation of a 23 compound of formula (I) wherein Z is of formula (a) or 24 (b), or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of formula 26 (II):
28 ZlH (II) ~ 3 ~ 0 02 wherein zl is of sub-formula (a) or (b), with a 03 compound of formula ( III ):
08 ~C-(CH2)2 ~ R
09 ~IH
11 (III) 13 wherein Q is a leaving group and the remaining 14 variables are as deflned in formula (I); and thereafter lS optionally forming a pharmaceutically acceptable salt 16 thereof.
18 Examples of leaving groups Q, displaceable by a 19 nucleophile, include halogen such as chloro and bromo;
Cl_4 alkoxy, such as CH30 and C2H5O-; PhO-;
21 activated hydrocarbyloxy, such as C15C6O- or C13CO-;
22 succinimidyloxy; and imidazolyl. Preferably Q is 23 halogen, most preferably chloro.
If a group Q is a halide or imidazolyl, then the 26 reaction is preferably carried out at non-extreme 27 temperatures in an inert non-hydroxylic solvent, such 28 as benzene, dichloromethane, toluene, diethyl ether, 29 tetrahydrofuran ~THF) or dimethylformamide (DMF). It is also preferably carried out in the presence of an 31 acid acceptor, such as an organic base, in particular a 32 tertiary amine, such as triethylamine, trimethylamine, 33 pyridine or picoline, some of which can also function 34 as the solvent. Alternatively, the acid acceptor can be inorganic, such as calcium carbonate, sodium 36 carbonate or potassium carbonate. Temperatures of 37 0-100C, in particular 10-80C are suitable.
~2 ~
~S~IJ~O
01 ~ 7 ~
02 If a group Q is Cl_4 alkoxy, phenoxy, activated 03 hydrocarbyloxy or succinimidyloxy then the reaction is 04 preferably carried out in an inert solvent, such as 05 toluene or dimethylformamide. In this instance, it is 06 preferred that the group Q is C13CO- or succinimidyloxy 07 and that the reaction is carried out in toluene at 08 reflux temperature.
When the compound of formula (III) has an imidazolyl NH
11 moiety wherein Rl/R2 is hydrogen, adjacent to the point 12 of attachment of the QCO(CH2)- group, the compound of 13 formula (III) may be of formula (III)':
~1 18 ~ N ~
19 R2 (III)' 21 i.e. a cyclic anhydride.
23 The conditions for this reaction are similar to those 24 used when Q is C1_4 alkoxy.
26 The present invention also provides a process for the 27 preparation of a compound of formula (I) wherein Z is 28 of sub-formula (c) or (d) or a pharmaceutically 29 acceptable salt thereof, which process comprises reacting a compound of formula tIV):
32 Z2COCH3 (IV) 34 wherein z2 is of sub-formula (c) or (d) with a compound of formula (V):
1 310~0 01 -- 8 --.
05 HC ~ R
06 V~
P' 2 ( V ) 0`8 09 in the presence of a base (Claisen-Schmidt) reaction followed by reduction of the resulting compound of 11 formula ~VI):
13 o 145 Z CCH--CH ~ R
16 N ~NH
18 (VI ) wherein the variable groups are as deflned in formula 21 (I); and thereafter optionally forming a 22 pharmaceutically acceptable salt thereof.
.24 The Clalsen Schmidt reaction takes place in the presence of a base, preferably containing alkoxide or 26 hydroxide ion, for example sodium hydroxide in ethanol ;27 as solvent, at ambient temperature.
.29 The reduction is preferably carried out by catalytic hydrogenation using hydrogen-platinium although it may 31 also be carried out using reducing agents, such as 32 sodium borohydride in pyridine.
34 It will be appreciated that these reduction conditions Will probably also reduce the carbonyl group in formula 36 (VI) and therefore it will be necessary to oxidise the T~ .
D~3 1 3 ~
02 resulting alcohol using a appropiate oxidising agent, 03 such as sodium dichromate.
05 Alternatively, the reduction may be carried out using 06 sodium borohydride in methanol, which reduces only the 07 carbonyl group in formula (VI); the resulting a~
OB unsaturated alcohol is then heated under reflux in 09 ethanolic potassium hydroxide to produce the rearranged product of formula ~I).
12 The compounds of formula (II), ~III), (IV~ and (V) are 13 known or are prepared analogously to, or routinely 14 from, known compounds.
16 As regards zl and z2 in the compounds of formulae (II) and 17 (IV), reference is hereby made to the following:
19 ~a) ~P-A-297266 21 (b) E~-A-235878 23 ~C) EP-A-255297 and EP-A-289170.
26 (e) UK Patent 2125398 and EP-A-289170 .2~
.,~ g 31 (All European Patent References are in the name of 32 seecham Group p.l.c.).
34 Pharmaceutically acceptable salts of the compounds of this invention may be formed conventionally. The acid 36 addition salts may be formed for example by reaction of 37 the base compound of formula (I) with a ~, 1310~0 02 pharmaceutically acceptable organic or inorganic acid.
04 The compounds of the present invention are 5-HT3 05 receptor antagonists and it is thus believed may 06 generally be used in the treatment or prophylaxis of 07 emesis, migraine, cluster headaches, trigeminal 08 neuralgia and visceral pain. Compounds which are 5-HT3 09 antagonists may also be of potential use in the treatment of CNS disorders such as anxiety and 11 psychosis; drug withdrawal syndrome; arrhythmia;
12 obesity and gastrointestinal disorders such as 13 irritable bowel syndrome.
Antiemetic activity includes in particular that of 16 preventing cytotoxic agent or radiation induced nausea 17 and vomiting. Examples of cytotoxic agents include 18 cisplatin, doxorubicin and cyclophosphamide.
The invention also provides a pharmaceutical 21 composition comprising a compound of formula (I), or a 22 pharmaceutically acceptable salt thereof, and a 2 3 pharmaceutically acceptable carrier.
Such compositions are prepared by admixture and are 26 suitably adapted for oral or parenteral administration, 27 and as such may be in the form of tablets, capsules, 28 oral liquid preparations, powders, granules, lozenges, 29 reconstitutable powders, injectable and infusable solutions or suspensions or suppositories. Orally 31 administrable compositions are preferred, since they 32 are more convenient for general use.
34 Tablets and capsules for oral administration are usually presented in a unit dose, and contain 36 conventional excipients such as binding agents, 37 fillers, diluents, tabletting agents, lubricants, 38 disintegrants, colourants, flavourings, and wetting B-~
~31~0 . 0 1 ~
~02 agents. The tablets may be coated according to well 03 known methods in the art, for example with an enteric 04 coating.
06 Suitable fillers for use include cellulose, mannitol, 07 lactose and other similar agents. Suitable 08 disintegrants include starch, polyvinylpolypyrrolidone og and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, 11 magnesium stearate.
13 Suitable pharmaceutlcally acceptable wetting agents 14 include sodium lauryl sulphate. Oral liquid preparations may be in the form of, for example, 16 aqueous or oily suspensions, solutions, emulsions, 17 syrups, or elixirs, or may be presented as a dry lB product for reconstitution with water or other suitable 19 vehicle before use. Such liquid preparations may contain conventional additives such as suspending 21 agents, for example sorbitol, syrup, methyl cellulose, 22 gelatin, hydroxyethylcellulose, carboxymethylcellulose, 23 aluminium stearate gel or hydrogenated edible fats, 24 emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may 26 include edible oils)~ for example, almond oil, 27 fractionated coconut oil, oily esters such as esters of 28 glycerine, propylene glycol, or ethyl alcohol;
29 preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired 31 conventional flavouring or colouring agents.
33 Oral liquid preparations are usually in the form of 34 aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs or are presented as a dry product 36 for reconstitution with water or other suitable vehicle 37 before use. Such liquid preparations may contain ~2 ) ~10~3 02 conventional additives such as suspending agents, 03 emulsifying a~ents, non-aqueous vehicles (which may 04 include edible oils), preservatives, and flavouring or 05 colouring agents.
07 The oral compositions may be prepared by conventional 08 methods of blending, filling or tabletting. Repeated 09 blending operations may be used to distribute the active agent throughout those compositions employing 11 large quantities of fillers. Such operations are, of 12 course, conventional in the art.
14 For parenteral administratlon, fluid unit dose forms are prepared containing a compound of the present 16 invention and a sterile vehicle. The compound, 17 depending on the vehicle and the concentration, can be 18 either suspended or dissolved. Parenteral solutions 19 are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a 21 suitable vial or ampoule and sealing. Advantageously, 22 ad~uvants such as a local anaesthetic, preservatives 23 and buffering agents are also dissolved in the 24 vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water 26 removed under vacuum.
28 Parenteral suspensions are prepared in substantially 29 the same manner except that the compound is suspended in the vehicle instead of being dissolved and 31 sterilised by exposure of ethylene oxide before 32 suspending in the sterile vehicle. Advantageously, a 33 surfactant or wetting agent is included in the 34 composition to facilitate uniform distribution of the compound of the invention.
37 The invention further provides a method of treatment or !IB ' ~lQ~
02 prophylaxis of emesis, migraine, cluster headache, 03 trigeminal neuralgia, visceral pain, gastrointestinal 04 disorders and/or CNS disorders in mammals, such as 05 humans, which comprises the administration of an 06 effective amount of a compound of the formula (I) or a 07 pharmaceutically acceptable salt thereof.
09 An amount effective to treat the disorders herein-before described depends on the relative efficacies of 11 the compounds of the invention, the nature and severity 12 of the disorder being treated and the weight of the 13 mammal. However, a unit dose for a 70kg adult will 14 normally contain 0.05 to lOOOmg for example 0.1 to 500mg, of the compound of the invention. Unit doses 16 may be administered once or more than once a day, for 17 example, 2, 3 or 4 times a day, more usually 1 to 3 18 times a day, that is in the range of approximately 19 0.0001 to 50mg/kg/day, more usually 0.0002 to 25 mg/kg/day.
22 No adverse toxicological effects are indicated at any 23 of the aforementioned dosage ranges.
The invention also provides a compound of formula (I) 26 or a pharmaceutically acceptable salt thereof for use 27 as an active therapeutic substance, in particular for 28 use in the treatment of emesis, migraine, cluster 29 headache, trigeminal neuralgia, gastrointestinal disorders and/or CNS disorders.
32 The following Examples illustrate the invention.
~S
~,. ~1 1 3 ~
02 Example 1 04 N-(3,3-Dimethylindolin-l-vl)-3-(4-imidazol~l)Propion-05 amide monohvdrochloride (El 09 ~ N ~
~ N V NH
12 (El) 14 A suspension of 3-(4-imidazolyl)propionic acid monohydrochloride (2.og) (Chem. Ber. 66, 156 [1933]) in 16 thionyl chloride (10ml) and DMF (3 drops) was stirred 17 at room temperature for 3h. The excess thionyl 18 chloride was removed by rotary evaporation and the 19 residue re-evaporated with 2 x 50ml of dry toluene.
The residue was suspended in CH2C12 (1o0ml) and a 21 solution of 3,3-dimethyl indoline (1.7g) and 22 triethylamine (4ml) in CH2C12 (50ml) was added with 23 stirring and cooling. The reaction mixture was stirred 24 overnight, washed with saturated NaHCO3 and the lower organic layer dried ~Na2SO4). Concentration of the 26 organic extracts afforded the crude product which was 27 purified by column chromatography on silica, eluting 28 with CHC13 containing increasing quantities of 29 methanol. The title compound free base was converted to the hydrochloride salt by standard procedures.
31 m.p. 226-8C.
32 lH Nmr (D6-DMSO) 6:
33 9.11 (s, lH) 34 8.15 (d, lH) 7.58 (s, lH) 36 7.36 (d, lH) 37 7.27 (t, lH) ~s' 131~6~
02 7.13 (t, lH) 03 3.99 (s, 2H) 04 3.05 (br.s, 4H) 05 1.40 (s, 6H) 07 Following the procedures outlined in Example 1, the 08 following compounds were prepared.
Examples 2 to 5 12 N-(3.3-DimethYlindolin-1-vl)-3-~5-methYl-4-imidazolYl)-13 propionamide (E2) 7 ~ N NH
(E2) 22m.p. 151-3C
231H Nmr (CDC13) ~:
248.22 (d, lH) 257.42 (s, lH) 267.26-7.00 (m~ 4H) 273.71 ~s, 2H) 282.95 (t, 2Hj 292.71 (t, 2H) 302.20 ts, 3H) 311.31 (s, 6H) ~.~
-16~
02 N-(2-Methoxvphenyl)-3-(5-methyl-~-imidazolyl)propion-03 amlde [E3) og ¢~OCH
EP-A-242973 (Glaxo Group Limited) discloses a class of indole derivatives which are 5-HT3 receptor antagonists.
EP-A-291172 (Glaxo Group Limited), published 17th November 1988, discloses a further group of 5-HT3 receptor antagonists wherein the indole moi~ty is replaced by another function, designated 'A' in formula (I) therein.
A class of novel, structurally dis~inct compounds has now been discovered which compounds have 5-HT3 receptor antagonist activity.
20 Accordingly, the present inventlon provides a compound of formula (I), or a pharmaceutically acc-ptaoie salt Lhe~eof:
ZC-(CH2)2 ~ R
N ~ NH
R2 (I) 30 wherein R1 and R2 are independently hydrogen or C1_6 alkyl;
Z is a group of su~-formula (a), (b), (c) or td):
Z~
R (a) X NH-~( OR7 (b) 2 s X ( c ) ~ (d) Rlo g 131096~
01 _ 3 _ 02 wherein 03 xa to Xd are selected from hydrogen, halogen and 04 hydroxy;
05 R3 is hydrogen and R4 is hydrogen or Cl_6 alkyl, or R3 06 and R4 together are a bond;
07 Rs to Rlo are independently selected from hydrogen or 08 C1_6 alkyl; and R6 together with R4 may be C2_7 09 polymethylene when R3 is hydrogen, or R g and Rln may together be C2_7 polymethylene.
12 Examples of moieties in alkyl or alkyl containing 13 groups in Rl, R2 and R4 to R10 include methyl, ethyl, 14 n- and iso-propyl, n-, iso-, sec- and tert-butyl, preferably methyl.
17 Suitable examples of R4 and R6 or Rg and R1o when 18 joined include C2, C3, C4, C5 or C6 polymethylene, 19 preferably C2, C3, C4 or C5 polymethylene.
21 xa to Xd are preferably selected from hydrogen, fluoro, 22 chloro and hydroxy, most preferably hydrogen.
24 Preferably the ZC0-~CH2)2- moiety is attached to the imidazole ring at the 4-position. Preferably R1 is 26 hydrogen or methyl, attached at the 5-position and R2 27 is hydrogen.
29 When Z is of sub~formula (a), R3 and R5 are preferably both hydrogen and one or both R4 and R6 (most 31 preferably both) are alkyl groups, such as methyl, or 32 are ~olned to form C2_7 polymethylene.
34 When Z is of sub-formula (b), R7 is preferably methyl.
36 When Z is of sub-formula (c)~ one of C0-(CH2)2- and R8 37 is attached at the 1-position and the other is attached 38 at tlle 3-position as depicted in sub-formula (C), and R8 is ~ preferably methyl or ethyl.
13~6Q
When Z is of su~-formula (d), one or both of Rg and R1o (most preferably both) are alkyl groups, such as methyl or are joined to form C2_7 polymethylene.
s 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, lactic, maleic, o citric, succinic, benzoic, ascorbic, methanesulphonic, a-keto glutaric, ~-glycerophosphoric, and glucose-1-phosphoric acids.
The pharmaceutically acceptable salts of the compounds of 5 the formula (I) 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 derivati~es of the compounds of formula (I) such as the compounds quaternised by compounds Ra-T wherein Ra is Cl_6 alkyl, phenyl-C1_6 alkyl or C5_7 cycloalkyl, and T is a 25 radical corresponding to an anion of an acid. Suitable examples of Ra include methyl, ethyl and n- and iso-propyl;
and benzyl and phenethyl. Suitable examples of T include halide such as chloride, bromide and iodide.
30 Examples of pharmaceutically acceptable salts of compounds of formula (I) also include internal salts such as pharmaceutically acceptable N-oxides.
The compounds of the formula (I), their pharmaceutically 35 acceptable salts, (including quaternary derivatives and 131~ 0 01 N-oxi~es) may also form pharmaceutically acceptable 02 solvates, such as hydrates, which are included wherever a 03 compound of formula (I) or a salt thereof is herein referred to.
06 It will of course be realised that some of the 07 compounds of the formula (I) have chiral or prochiral 08 centres and thus are capable of existing in a number of 09 stereoisomeric forms including enantiomers. The invention extends to each of these stereoisomeric forms 11 (including enantiomers), and to mixtures thereof 12 irlcludin~ racemates. The different stereoisomeric 13 forms may be separated one from another by the usual 14 methods.
16 It will be appreciated that the imidazole ring in 17 formula ~I) can exist as tautomers i.e. the hydrogen 18 atom can be on either of the imidazole nitrogen atoms.
19 The invention extends to both tautomers and mixtures thereof.
22 The invention provides process for the preparation of a 23 compound of formula (I) wherein Z is of formula (a) or 24 (b), or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of formula 26 (II):
28 ZlH (II) ~ 3 ~ 0 02 wherein zl is of sub-formula (a) or (b), with a 03 compound of formula ( III ):
08 ~C-(CH2)2 ~ R
09 ~IH
11 (III) 13 wherein Q is a leaving group and the remaining 14 variables are as deflned in formula (I); and thereafter lS optionally forming a pharmaceutically acceptable salt 16 thereof.
18 Examples of leaving groups Q, displaceable by a 19 nucleophile, include halogen such as chloro and bromo;
Cl_4 alkoxy, such as CH30 and C2H5O-; PhO-;
21 activated hydrocarbyloxy, such as C15C6O- or C13CO-;
22 succinimidyloxy; and imidazolyl. Preferably Q is 23 halogen, most preferably chloro.
If a group Q is a halide or imidazolyl, then the 26 reaction is preferably carried out at non-extreme 27 temperatures in an inert non-hydroxylic solvent, such 28 as benzene, dichloromethane, toluene, diethyl ether, 29 tetrahydrofuran ~THF) or dimethylformamide (DMF). It is also preferably carried out in the presence of an 31 acid acceptor, such as an organic base, in particular a 32 tertiary amine, such as triethylamine, trimethylamine, 33 pyridine or picoline, some of which can also function 34 as the solvent. Alternatively, the acid acceptor can be inorganic, such as calcium carbonate, sodium 36 carbonate or potassium carbonate. Temperatures of 37 0-100C, in particular 10-80C are suitable.
~2 ~
~S~IJ~O
01 ~ 7 ~
02 If a group Q is Cl_4 alkoxy, phenoxy, activated 03 hydrocarbyloxy or succinimidyloxy then the reaction is 04 preferably carried out in an inert solvent, such as 05 toluene or dimethylformamide. In this instance, it is 06 preferred that the group Q is C13CO- or succinimidyloxy 07 and that the reaction is carried out in toluene at 08 reflux temperature.
When the compound of formula (III) has an imidazolyl NH
11 moiety wherein Rl/R2 is hydrogen, adjacent to the point 12 of attachment of the QCO(CH2)- group, the compound of 13 formula (III) may be of formula (III)':
~1 18 ~ N ~
19 R2 (III)' 21 i.e. a cyclic anhydride.
23 The conditions for this reaction are similar to those 24 used when Q is C1_4 alkoxy.
26 The present invention also provides a process for the 27 preparation of a compound of formula (I) wherein Z is 28 of sub-formula (c) or (d) or a pharmaceutically 29 acceptable salt thereof, which process comprises reacting a compound of formula tIV):
32 Z2COCH3 (IV) 34 wherein z2 is of sub-formula (c) or (d) with a compound of formula (V):
1 310~0 01 -- 8 --.
05 HC ~ R
06 V~
P' 2 ( V ) 0`8 09 in the presence of a base (Claisen-Schmidt) reaction followed by reduction of the resulting compound of 11 formula ~VI):
13 o 145 Z CCH--CH ~ R
16 N ~NH
18 (VI ) wherein the variable groups are as deflned in formula 21 (I); and thereafter optionally forming a 22 pharmaceutically acceptable salt thereof.
.24 The Clalsen Schmidt reaction takes place in the presence of a base, preferably containing alkoxide or 26 hydroxide ion, for example sodium hydroxide in ethanol ;27 as solvent, at ambient temperature.
.29 The reduction is preferably carried out by catalytic hydrogenation using hydrogen-platinium although it may 31 also be carried out using reducing agents, such as 32 sodium borohydride in pyridine.
34 It will be appreciated that these reduction conditions Will probably also reduce the carbonyl group in formula 36 (VI) and therefore it will be necessary to oxidise the T~ .
D~3 1 3 ~
02 resulting alcohol using a appropiate oxidising agent, 03 such as sodium dichromate.
05 Alternatively, the reduction may be carried out using 06 sodium borohydride in methanol, which reduces only the 07 carbonyl group in formula (VI); the resulting a~
OB unsaturated alcohol is then heated under reflux in 09 ethanolic potassium hydroxide to produce the rearranged product of formula ~I).
12 The compounds of formula (II), ~III), (IV~ and (V) are 13 known or are prepared analogously to, or routinely 14 from, known compounds.
16 As regards zl and z2 in the compounds of formulae (II) and 17 (IV), reference is hereby made to the following:
19 ~a) ~P-A-297266 21 (b) E~-A-235878 23 ~C) EP-A-255297 and EP-A-289170.
26 (e) UK Patent 2125398 and EP-A-289170 .2~
.,~ g 31 (All European Patent References are in the name of 32 seecham Group p.l.c.).
34 Pharmaceutically acceptable salts of the compounds of this invention may be formed conventionally. The acid 36 addition salts may be formed for example by reaction of 37 the base compound of formula (I) with a ~, 1310~0 02 pharmaceutically acceptable organic or inorganic acid.
04 The compounds of the present invention are 5-HT3 05 receptor antagonists and it is thus believed may 06 generally be used in the treatment or prophylaxis of 07 emesis, migraine, cluster headaches, trigeminal 08 neuralgia and visceral pain. Compounds which are 5-HT3 09 antagonists may also be of potential use in the treatment of CNS disorders such as anxiety and 11 psychosis; drug withdrawal syndrome; arrhythmia;
12 obesity and gastrointestinal disorders such as 13 irritable bowel syndrome.
Antiemetic activity includes in particular that of 16 preventing cytotoxic agent or radiation induced nausea 17 and vomiting. Examples of cytotoxic agents include 18 cisplatin, doxorubicin and cyclophosphamide.
The invention also provides a pharmaceutical 21 composition comprising a compound of formula (I), or a 22 pharmaceutically acceptable salt thereof, and a 2 3 pharmaceutically acceptable carrier.
Such compositions are prepared by admixture and are 26 suitably adapted for oral or parenteral administration, 27 and as such may be in the form of tablets, capsules, 28 oral liquid preparations, powders, granules, lozenges, 29 reconstitutable powders, injectable and infusable solutions or suspensions or suppositories. Orally 31 administrable compositions are preferred, since they 32 are more convenient for general use.
34 Tablets and capsules for oral administration are usually presented in a unit dose, and contain 36 conventional excipients such as binding agents, 37 fillers, diluents, tabletting agents, lubricants, 38 disintegrants, colourants, flavourings, and wetting B-~
~31~0 . 0 1 ~
~02 agents. The tablets may be coated according to well 03 known methods in the art, for example with an enteric 04 coating.
06 Suitable fillers for use include cellulose, mannitol, 07 lactose and other similar agents. Suitable 08 disintegrants include starch, polyvinylpolypyrrolidone og and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, 11 magnesium stearate.
13 Suitable pharmaceutlcally acceptable wetting agents 14 include sodium lauryl sulphate. Oral liquid preparations may be in the form of, for example, 16 aqueous or oily suspensions, solutions, emulsions, 17 syrups, or elixirs, or may be presented as a dry lB product for reconstitution with water or other suitable 19 vehicle before use. Such liquid preparations may contain conventional additives such as suspending 21 agents, for example sorbitol, syrup, methyl cellulose, 22 gelatin, hydroxyethylcellulose, carboxymethylcellulose, 23 aluminium stearate gel or hydrogenated edible fats, 24 emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may 26 include edible oils)~ for example, almond oil, 27 fractionated coconut oil, oily esters such as esters of 28 glycerine, propylene glycol, or ethyl alcohol;
29 preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired 31 conventional flavouring or colouring agents.
33 Oral liquid preparations are usually in the form of 34 aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs or are presented as a dry product 36 for reconstitution with water or other suitable vehicle 37 before use. Such liquid preparations may contain ~2 ) ~10~3 02 conventional additives such as suspending agents, 03 emulsifying a~ents, non-aqueous vehicles (which may 04 include edible oils), preservatives, and flavouring or 05 colouring agents.
07 The oral compositions may be prepared by conventional 08 methods of blending, filling or tabletting. Repeated 09 blending operations may be used to distribute the active agent throughout those compositions employing 11 large quantities of fillers. Such operations are, of 12 course, conventional in the art.
14 For parenteral administratlon, fluid unit dose forms are prepared containing a compound of the present 16 invention and a sterile vehicle. The compound, 17 depending on the vehicle and the concentration, can be 18 either suspended or dissolved. Parenteral solutions 19 are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a 21 suitable vial or ampoule and sealing. Advantageously, 22 ad~uvants such as a local anaesthetic, preservatives 23 and buffering agents are also dissolved in the 24 vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water 26 removed under vacuum.
28 Parenteral suspensions are prepared in substantially 29 the same manner except that the compound is suspended in the vehicle instead of being dissolved and 31 sterilised by exposure of ethylene oxide before 32 suspending in the sterile vehicle. Advantageously, a 33 surfactant or wetting agent is included in the 34 composition to facilitate uniform distribution of the compound of the invention.
37 The invention further provides a method of treatment or !IB ' ~lQ~
02 prophylaxis of emesis, migraine, cluster headache, 03 trigeminal neuralgia, visceral pain, gastrointestinal 04 disorders and/or CNS disorders in mammals, such as 05 humans, which comprises the administration of an 06 effective amount of a compound of the formula (I) or a 07 pharmaceutically acceptable salt thereof.
09 An amount effective to treat the disorders herein-before described depends on the relative efficacies of 11 the compounds of the invention, the nature and severity 12 of the disorder being treated and the weight of the 13 mammal. However, a unit dose for a 70kg adult will 14 normally contain 0.05 to lOOOmg for example 0.1 to 500mg, of the compound of the invention. Unit doses 16 may be administered once or more than once a day, for 17 example, 2, 3 or 4 times a day, more usually 1 to 3 18 times a day, that is in the range of approximately 19 0.0001 to 50mg/kg/day, more usually 0.0002 to 25 mg/kg/day.
22 No adverse toxicological effects are indicated at any 23 of the aforementioned dosage ranges.
The invention also provides a compound of formula (I) 26 or a pharmaceutically acceptable salt thereof for use 27 as an active therapeutic substance, in particular for 28 use in the treatment of emesis, migraine, cluster 29 headache, trigeminal neuralgia, gastrointestinal disorders and/or CNS disorders.
32 The following Examples illustrate the invention.
~S
~,. ~1 1 3 ~
02 Example 1 04 N-(3,3-Dimethylindolin-l-vl)-3-(4-imidazol~l)Propion-05 amide monohvdrochloride (El 09 ~ N ~
~ N V NH
12 (El) 14 A suspension of 3-(4-imidazolyl)propionic acid monohydrochloride (2.og) (Chem. Ber. 66, 156 [1933]) in 16 thionyl chloride (10ml) and DMF (3 drops) was stirred 17 at room temperature for 3h. The excess thionyl 18 chloride was removed by rotary evaporation and the 19 residue re-evaporated with 2 x 50ml of dry toluene.
The residue was suspended in CH2C12 (1o0ml) and a 21 solution of 3,3-dimethyl indoline (1.7g) and 22 triethylamine (4ml) in CH2C12 (50ml) was added with 23 stirring and cooling. The reaction mixture was stirred 24 overnight, washed with saturated NaHCO3 and the lower organic layer dried ~Na2SO4). Concentration of the 26 organic extracts afforded the crude product which was 27 purified by column chromatography on silica, eluting 28 with CHC13 containing increasing quantities of 29 methanol. The title compound free base was converted to the hydrochloride salt by standard procedures.
31 m.p. 226-8C.
32 lH Nmr (D6-DMSO) 6:
33 9.11 (s, lH) 34 8.15 (d, lH) 7.58 (s, lH) 36 7.36 (d, lH) 37 7.27 (t, lH) ~s' 131~6~
02 7.13 (t, lH) 03 3.99 (s, 2H) 04 3.05 (br.s, 4H) 05 1.40 (s, 6H) 07 Following the procedures outlined in Example 1, the 08 following compounds were prepared.
Examples 2 to 5 12 N-(3.3-DimethYlindolin-1-vl)-3-~5-methYl-4-imidazolYl)-13 propionamide (E2) 7 ~ N NH
(E2) 22m.p. 151-3C
231H Nmr (CDC13) ~:
248.22 (d, lH) 257.42 (s, lH) 267.26-7.00 (m~ 4H) 273.71 ~s, 2H) 282.95 (t, 2Hj 292.71 (t, 2H) 302.20 ts, 3H) 311.31 (s, 6H) ~.~
-16~
02 N-(2-Methoxvphenyl)-3-(5-methyl-~-imidazolyl)propion-03 amlde [E3) og ¢~OCH
3 ~E3) 12 m.p. 149-151C
13 lH_Nmr ~d6-DMS0) 6 14 8.65 ~brs, lH) 8.13 ~d, lH) 16 7.37 ~s, lH) 17 7.05-6.80 ~m, 3H) 18 3.82 ~s, 3H) 19 ~ 2.84 (t, 2H) 2.71 (t, 2H) 21 2.13 (s, 3H) 23 N-(2-Methoxy~henyl)-3-~4-imidazolyl)propionamide (E4 26 /NHcocH2cH2 27 ~ ~ ~
28 ~ OC~I3 N~"NH
(E4) 3~ m.p. 98-9C.
33 lH Nmr (CDC13) 6:
34 8.32 (d, lH) 7.90 (brs, lH) 36 7.52 ~s, lH) 37 7 .10-6 . 80 ~m, 4H) 3.84 (s, 3H) 3.01 (t, 2H) 2.78 (t, 2H) 131~60 ol -17-02 Pharmacoloqv 04 Antaqonism of the von Bezold-JarisCh reflex 06 The compounds were evaluated for antagonism of the von 07 sezold-Jarisch reflex evoked by 5-HT in the 08 anaesthetised rat according to the following method:
lo Male rats 250-350g, were anaesthetised with urethane 11 (1.25g/kg intraperitoneally) and blood pressure and 12 heart rate recorded as described by Fozard J.R. et al., 13 J. Cardiovasc. Pharmacol. 2, 229-245 (1980). A
14 submaximal dose of 5-HT (usually 6yg/kg) was given repeatedly by the intravenous route and changes in 16 heart rate quantified. Compounds were given 17 intravenously and the concentration required to reduce 18 the 5-HT-evoked response to 50% of the control response lS (EDso) was then determined.
21 The results are as shown in Table 1.
23 Table 1 ComPound ED~n ~q/k~ i.v.
27 E1 4.2 æ~
I
13 lH_Nmr ~d6-DMS0) 6 14 8.65 ~brs, lH) 8.13 ~d, lH) 16 7.37 ~s, lH) 17 7.05-6.80 ~m, 3H) 18 3.82 ~s, 3H) 19 ~ 2.84 (t, 2H) 2.71 (t, 2H) 21 2.13 (s, 3H) 23 N-(2-Methoxy~henyl)-3-~4-imidazolyl)propionamide (E4 26 /NHcocH2cH2 27 ~ ~ ~
28 ~ OC~I3 N~"NH
(E4) 3~ m.p. 98-9C.
33 lH Nmr (CDC13) 6:
34 8.32 (d, lH) 7.90 (brs, lH) 36 7.52 ~s, lH) 37 7 .10-6 . 80 ~m, 4H) 3.84 (s, 3H) 3.01 (t, 2H) 2.78 (t, 2H) 131~60 ol -17-02 Pharmacoloqv 04 Antaqonism of the von Bezold-JarisCh reflex 06 The compounds were evaluated for antagonism of the von 07 sezold-Jarisch reflex evoked by 5-HT in the 08 anaesthetised rat according to the following method:
lo Male rats 250-350g, were anaesthetised with urethane 11 (1.25g/kg intraperitoneally) and blood pressure and 12 heart rate recorded as described by Fozard J.R. et al., 13 J. Cardiovasc. Pharmacol. 2, 229-245 (1980). A
14 submaximal dose of 5-HT (usually 6yg/kg) was given repeatedly by the intravenous route and changes in 16 heart rate quantified. Compounds were given 17 intravenously and the concentration required to reduce 18 the 5-HT-evoked response to 50% of the control response lS (EDso) was then determined.
21 The results are as shown in Table 1.
23 Table 1 ComPound ED~n ~q/k~ i.v.
27 E1 4.2 æ~
I
Claims (20)
1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:
(I) wherein R1 and R2 are independently hydrogen or C1-6 alkyl;
Z is a group of sub-formula (a), (b), (c), (d) or (e):
(a) (b) (c) (d) wherein Xa to Xd are selected from hydrogen, halogen and hydroxy:
R3 is hydrogen and R4 is hydrogen or C1-6 alkyl, or R3 and R4 together are a bond;
R5 to R10 are independently selected from hydrogen or C1-6 alkyl; and R6 together with R4 may be C2-7 polymethylene when R3 is hydrogen, or R9 and R10 may together be C2-7 polymethylene.
(I) wherein R1 and R2 are independently hydrogen or C1-6 alkyl;
Z is a group of sub-formula (a), (b), (c), (d) or (e):
(a) (b) (c) (d) wherein Xa to Xd are selected from hydrogen, halogen and hydroxy:
R3 is hydrogen and R4 is hydrogen or C1-6 alkyl, or R3 and R4 together are a bond;
R5 to R10 are independently selected from hydrogen or C1-6 alkyl; and R6 together with R4 may be C2-7 polymethylene when R3 is hydrogen, or R9 and R10 may together be C2-7 polymethylene.
2. A compound of formula (I) according to claim 1, wherein Z is of sub-formula (a) and the remaining variables are as defined in claim 1.
3. A compound according to claim 2 wherein R3 and R5 are both hydrogen and one or both of R4 and R6 are C1-6 alkyl groups, or are joined to form C2-7 polymethylene.
4. A compound of formula (I) according to claim 1, wherein Z is of sub-formula (b) and the remaining variables are as defined in claim 1.
5. A compound according to claim 4 wherein R7 is methyl.
6. N-(3,3-Dimethylindolin-1-yl)-3-(4-imidazolyl)-propionamide, or a pharmaceutically acceptable salt thereof.
7. N-(3,3-Dimethylindolin-1-yl)-3-(5-methyl-4-imidazo lyl)propionamide, or a pharmaceutically acceptable salt thereof.
8. N-(2-methoxyphenyl)-3-(5-methyl-4-imidazolyl)-prop ionamide, or a pharmaceutically acceptable salt thereof.
9. N-(2-methoxyphenyl)-3-(4-imidazolyl)propionamide, or a pharmaceutically acceptable salt thereof.
10. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1, which process comprises either i) (when Z is of sub-formula (a) or (b)) reacting a compound of formula (II):
Z1H (II) with a compound of formula (III):
(III) wherein Q is a leaving group and the remaining variables are as defined in claim 1; or ii) (when z is of sub-formula (c) or (d)) reacting a compound of formula (IV):
Z2COCH3 (IV) wherein Z2 is of sub-formula (c) or (d), with a compound of formula (V):
(V) in the presence of a base (Claisen-Schmidt reaction) followed by reduction of the resulting compound of formula (VI):
(VI) wherein the variable groups are as defined in claim 1;
and thereafter optionally forming a pharmaceutically acceptable salt thereof.
Z1H (II) with a compound of formula (III):
(III) wherein Q is a leaving group and the remaining variables are as defined in claim 1; or ii) (when z is of sub-formula (c) or (d)) reacting a compound of formula (IV):
Z2COCH3 (IV) wherein Z2 is of sub-formula (c) or (d), with a compound of formula (V):
(V) in the presence of a base (Claisen-Schmidt reaction) followed by reduction of the resulting compound of formula (VI):
(VI) wherein the variable groups are as defined in claim 1;
and thereafter optionally forming a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprising a compound according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8 or 9, and a pharmaceutically acceptable carrier.
12. A compound according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8 or 9, for use as an active therapeutic substance.
13. A compound according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8 or 9, for use as a 5-HT3 receptor antagonist.
14. Use of a compound according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8 or 9, in the manufacture of a medicament for use as a 5-HT3 receptor antagonist.
15. Use of a compound according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8 or 9 in the manufacture of a medicament for use in the treatment of emesis, migraine, cluster headaches, trigeminal neuralgia and visceral pain.
16. A use according to claim 15, wherein the medicament is for use in the treatment of cytotoxic or radiation induced nausea and vomiting.
17. A use according to claim 14 wherein the medicament is for use in the treatment of CNS
disorders or gastrointestinal disorders.
disorders or gastrointestinal disorders.
18. Use of a compound according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8 or 9 in the treatment of emesis, migraine, cluster headaches, trigeminal neuralgia and visceral pain.
19. The use of claim 18 wherein the compound is used for the treatment of cytotoxic or radiation induced nausea and vomiting.
20. The use of a compound according to any one of claims 1, 2, 3, 4, 5, 6, 7 8 or 9 in the treatment of CNS disorders or gastrointestinal disorders.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000593777A CA1310960C (en) | 1987-10-02 | 1989-03-15 | Imidazole derivatives having 5-ht3 receptor antagonist activity |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB878723157A GB8723157D0 (en) | 1987-10-02 | 1987-10-02 | Compounds |
| CA000593777A CA1310960C (en) | 1987-10-02 | 1989-03-15 | Imidazole derivatives having 5-ht3 receptor antagonist activity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1310960C true CA1310960C (en) | 1992-12-01 |
Family
ID=25672526
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000593777A Expired - Fee Related CA1310960C (en) | 1987-10-02 | 1989-03-15 | Imidazole derivatives having 5-ht3 receptor antagonist activity |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1310960C (en) |
-
1989
- 1989-03-15 CA CA000593777A patent/CA1310960C/en not_active Expired - Fee Related
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