IE59336B1 - Capsaicin derivatives - Google Patents
Capsaicin derivativesInfo
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- IE59336B1 IE59336B1 IE415189A IE415189A IE59336B1 IE 59336 B1 IE59336 B1 IE 59336B1 IE 415189 A IE415189 A IE 415189A IE 415189 A IE415189 A IE 415189A IE 59336 B1 IE59336 B1 IE 59336B1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/04—Derivatives of thiourea
- C07C335/06—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms
- C07C335/10—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C335/12—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
Capsaicin derivatives of general formula I wherein R is O, S or NH, R1 to R7 may be a variety of substituents, and X is acyclic hydrocarbon, are useful as pharmaceuticals, in particular as analgesics and anti-inflammatory agents. Precursors of the above compounds are of the formulae X, VIII, V, II and III:-
Description
The present invention relates to novel compounds having pharmaceutical properties, to processes for their production, pharmaceutical compositions comprising them and their use as pharmaceuticals.
The present invention provides in one aspect compounds of formula I S Re R7 wherein: Rx is halogen, Ci_6alkoxy, R2 is hydrogen or has any one of the meanings given for Rx, R3 is hydrogen or Cx_4alkyl, R< and R5, independently, are hydrogen, halogen, Cx_5alkyl, substituted Cx_5alkyl, substituted or unsubstituted aryl, COOH, COORg or C0NR9R10 wherein Re is Ci_salkyl, and each ‘ 30 - 1 of R9 and Ri0 independently is hydrogen or Ci_5alkyl, R6 and R7, independently have the meanings given for R4 and Rs or, together vith the carbon atoms to vhich they are attached form a substituted or unsubstituted C3_7cydoalkyl group, R is 0, S or NH and X is -(CH2)„- or -(CHj)b-CH»CH-(CH2)r- vherein n is 1, 2 or 3 and each of m and r is independently zero or an integer of from 1 to 3, and physiologically hydrolysable and acceptable esters or amides and pharmaceutically acceptable salts thereof.
The compounds of formula I vherein X is -(CH2)B-CH-CH-(CH2)r- may exist in both cis or trans isomeric forms, i.e. as Z and E isomers. The present invention is to be understood as embracing both the individual cis and trans isomers as veil as mixtures thereof.
Substituted benzyloxy groups as Rx include benzyloxy substituted by halogen or phenyl. Substitutions may be, e.g. at the 2- and/or the 4-position of the benzyloxy group. Suitably the benzyloxy group is mono-substituted. Preferably the benzyloxy group is mono-substituted at the 4-position.
Alkyl groups as Rx through Ri0 as veil as the alkyl moiety of alkoxy groups as Rx or R2 may be branched or straight chain. Preferably such alkyl groups and moieties are straight chain.
By halogen is meant fluorine, chlorine, bromine or iodine.
Preferred aryl groups as R4 to R7 are phenyl or naphthyl. Such groups may be unsubstituted or substituted, e.g. mono-, di- or trisubstituted phenyl or naphthyl. Preferred substituents are selected from - 2 halogen, hydroxy, amino and carboxy. Especially preferred aryl groups as R< to R7 are phenyl or substituted phenyl.
A group of compounds of formula I comprises those compounds in which Ri is as defined above but excluding substituted benzyloxy and R, R2 to Rio and X are as defined above.
In the compounds of formula I, the following significances are preferred either Individually or in any combination or sub-combination: 1. Ri is halogen, alkyl, Ci_16alkoxy or substituted or unsubstituted benzyloxy, especially halogen, Ci_xialkoxy or substituted or unsubstituted benzyloxy. Vhen Rx is Ci_xealkoxy this is suitably n-octyloxy. When Rx is substituted benzyloxy, this is suitably halo- or pheny1-benzyloxy, especially 4-halo- or 4-phenyl-benzyloxy. Ri is preferably in the 4-position. 2. R2 is hydrogen, halogen or Ci_«alkyl, especially hydrogen or halogen. When Rj is other than hydrogen lt is preferably in the 2position. 3. R3 is hydrogen or aethyl, suitably methyl. 4. R« to R7, independently are hydrogen, methyl, ethyl, Cx_salkyl substituted by OH or NH2, phenyl or Ci_5alkyl-phenyl. More preferably at least one of R« to R« is hydrogen. Yet more preferably at least three of R< to R7, e.g. R<, R5 and R« are hydrogen. Most preferably all of R< to R7 are hydrogen.
. R is -0-. 6. X is -(CH2)„-, wherein n has the meanings given above. Preferably n is 1 or 2, especially 2. - 3 7. X is -(CH2)a-CH-CH-(CH2)r- in which one of m and r is zero and the other is 1. More preferably both m and r are zero. Most preferably such groups X are in Z isomeric form.
An especially preferred group of compounds of formula I are those wherein X has the meanings given under 6 above and especially such compounds wherein R2 and R2 are as defined under 1 and 2 above. A further preferred group of compounds of formula I are those wherein X has the meanings given under 6 above and each of R< to R7 is hydrogen, especially such compounds wherein Rx and R2 are as defined under 1 and 2 above.
By the term physiologically-hydrolysable and -acceptable esters or amides as used herein is meant esters (e.g. compounds of formula I wherein one or more of R« to R7 is -COOH and/or Rs is hydrogen) or amides which are hydrolysable under physiological conditions to produce acids or alcohols which are themselves non-toxic, i.e. have no significant undesirable side effects at desired dosage levels. Such esters include esters with mono- and di-carboxylic acids, e.g. esters of the compounds of formula I in which the 3-hydroxy group is acetylated and esters with lower, e.g. Cl-4 alkanols. Such amides include those derived from organic carboxylic acids e.g. acetic acid amides including amino acids e.g. glycine amides.
The present invention also provides a process for the production of the compounds, amides, esters and salts of the invention which process comprises: a) for the production of a compound of formula I reacting a compound of formula II s (XI) wherein R, Ri to R7 and X are as defined above, vith hydrazine b) for the production of a compound of formula I, removing at least one amino protecting group which is present in an amino protected compound of formula I, c) for the production of a physiologically-hydrolysable and -acceptable ester or amide of a compound of formula I, esterifying or amidatlng a compound of formula I, for example in which R3 is hydrogen, by reaction with an appropriate acylating or amidating agent, respectively, d) for the production of a compound of formula I wherein X is -(CH2)m-CH-CH-(CH2)r- in Z-isomeric form isomerising a compound of formula I wherein X is -(CH2)m-CH=CH-(CH2)r- in E-isomeric form and recovering a compound of formula I thus obtained in free or salt form.
Process step a) may be carried in analogy vith known methods, for example by reaction of the compound of formula II vith hydrazine hydrate in an inert solvent or diluent, e.g. alkane/alkanol, at ambient or elevated temperatures, e.g. at a temperature of from 0°C to reflux. Pro- 5 35 cess step b) may be carried out in accordance vith standard techniques for the removal of amino protecting groups as knovn in the art. Suitable amino protecting groups include p-toluene sulphonyl, benzyl, formyl and trifluoroacetyl.
Process step c) may also be performed employing conventional acylation or amidation methods e.g. by reaction vith an appropriate e.g. Ci_4 acyl halide or anhydride.
The trans isomers of compounds of formula I wherein X is -(CH2)B-CH»CH-(CH2)r- may be converted into the cis (Z) isomers in conventional manner, e.g. by irradiation. Individual cis and trans isomers may be obtained in accordance vith techniques knovn in the art, e.g. separation of cis/trans isomer mixtures, for example by chromatography.
Compounds of formula II used as starting materials in process step (a) may be produced by either of the following Reaction schemes, A or B - 6 REACTION SCHEME A S wherein R, Rj. to R7 and X are as defined above, Y is halogen, e.g. bromine and R' is 0 or S.
Compounds of formula VIII, in which R is 0, are described, along - 7 with processes for their production in, for example, published GB patent application 2,206,347A. Other compounds of formula VIII may be produced in similar or analogous fashion to the known compounds.
In Reaction Scheme B, on the following page, R, Rx to R7 and X are as defined above and Y is halogen, e.g. bromine. nh3*ci- RH di-t-butyldicarbonate (VII) REACTION SCHEME B Insofar as the production of the starting materials is not particularly described, the compounds may be prepared by analogy vith knovn methods.
The compounds of formula I as defined above may exist in free or salt form. Suitable pharmaceutically acceptable salts of compounds of formula I, e.g. vherein one or more of R< to R? is -COOH for use in accordance vith the present invention include for example the sodium, potassium and calcium salts as veil as quaternary ammonium, e.g. triethylammonium salts. Such salts also include pharmaceutically acceptable acid addition salts, e.g. salts vith inorganic or organic acids such as hydrochloric acid, acetic acid, fumaric acid, citric acid and benzoic acid.
The following Examples are illustrative of the process of the present invention.
The following abbreviations are used: DMF dimethylformamide TLC - thin layer chromatography EXAMPLE 1: N-[ 4—(2-Aainoethoxy)-3-Methoxy-Benzyl]-N'-[2-(4-Chlorophenyl)-Ethyl]Thiourea 2.0 g N-[4-(2-Phthalimidoethoxy)-3-methoxybenzyl]-N'-^-^-chlorophenyl) ethyl] thiourea (0.0038 mole) is suspended in 10 ml ethanol in a round bottomed flask and heated to 60° C until the solution becomes homogeneous. 0.10 ml 1-Hexene and 0.95 ml of a 64Z aqueous solution of hydrazine hydrate is added and the mixture heated for 90 minutes. After 15 minutes a white precipitate begins to form and a small amount of ethanol is added to keep the mixture mobile. The reaction is cooled, transferred to a separating funnel and 10 ml methyl-butyl ether, 5 ml water, 5 ml IN NaOH and 0.5 ml 50Z NaOH are added. The resulting mixture - 10 is shaken thoroughly and the organic layer extracted twice as above, then washed with brine. The organic layer is dried over Na2SO4, filtered and the solvent removed by evaporation. The residue is purified via flash column chromatography, eluting first with CH2C12 : MeOH (10:1) and then with MeOH. The product fractions are evaporated and dried in vacuo (30° C, 0.1 ram Hg) to give the title compound as a solid colourless glass.
The following compounds of formula Example R £1 £2 2 0 4-F H· 3 0 4-Cl 2-C I may be obtained analogously: R3 R4 to R7 X CH3 H (CH2)2 CHj H (CH2)2 and also the following compounds of formula I S (I) EXAMPLE 9 £11 benzyl 4-bromobenzyl N-octyl N-octyl 4-chlorobenzyl 4-phenylbenzyl n CHARACTERISING DATA 1. XH NMR data [400 MHz] Example 1: [D6DMSO] 52.8O(2H,t,J-7.2HZ), 2.99(2H,t,J-5.5HZ), 3.61(2H,S,broad), 3.75(3H,s), 4.00(2H,t,J-5.5Hz), 5.57(2H,s,broad), 6.79(lH,d,J«1.8Hz), 6.94(lH,d,J«8.1Hz), 6.96(lH,d,J-1.6Hz), 7.26(2H,d,J=8.2Hz), 7.34(2H,d,J-8.1Hz), 7.75(lH,s,broad), 7.99(lH,-s,broad) Example 2: [CDC13] 51.55(3H,s,broad), 2.84(2H,t,J-6.9Hz), 3.10(2H,t,J-5.3Hz), 3.74(2H,s, broad), 3.83(3B,s), 4.02(2H,t,J-5.3HZ), 4.41(2H,s,broad), 5.72(lH,s,broad), 6.18(lH,s,broad), 6.70-6.81(2H,m), 6.93-6.98(2H,m), 7.06-7.10(2H,m) Example 3: [CDC13] 51.52(3H,s,broad), 2.99(2H,t,H-7.0Hz), 3.11(2H,t,J-5.3Hz), 3.75(2H,s,broad), 3.84(3H,s), 4.03(2H,t,J«5.3Hz), 4.45(2H,s,broad), 5.82(lH,s,broad), 6.17(lH,s,broad), 6.79-6.84(4H,m), 7.10-7.17(3H,m), 7.35(2H,d,J-1.8HZ) Example 4: [CD30D] 52.80(2H,t,J=7.1Hz), 3.09(2H,t,J=5.1Hz), 3.68(2H,s,broad), 3.83(3H,s), 4.06(2H,t,Je5.1Hz), 4.60(2H,s,broad), 5.04(2H,s), 6.80- 7.13(5H,m), 7.29-7.43(4H,m) Example 5: [CD3OD] 52.78(2H,t,J-7.15Hz), .13(2H,t,J=5.1Hz), 3.68(2H,s,broad), 3.84(3H,s), 4.08(2H,t,J=5.1Hz), 4.60(2H,s,broad), 5.01(2H,s), 6.81- 7.12(7H,m), 7.43(4H,dd,J=8.3Hz,J=64.5Hz) Example 6: [CDjOD] 80.92(3H,m), 1.28-1.38(8H,m), 1.46(2H,m), 1.75(2H,m), 3.27(2H,t,J=5.OHz), 3.83(3H,s), 3.94(28,t,J-6.4Hz), 4.16(2H,t,J-S.OHz), 4.63(4H,s,broad), 6.82-7.90(5H,m), 7.19-7.21(2H,m) Example 7: [CDjOD] 80.90(3H,m), 1.28-1.35(8H,m), 1.46(2H,m), 1.74(2H,m), 79(2H,t,J«7.25Hz), 3.16(2H,t,J-5.15Hz), 3.68(2H,s,broad), 85(3H,s), 3.92(2H,t,J=6.45H2), 4.11(2H,t,J-5.15Hz), 63(2H,s, broad), 6.70-7.11(7H,m) Example 8: [CDjOD] 82.8(28,t,J-7.15Hz), 3.02(2H,t,J-5.25Hz), 3.68(28,s,broad), 3.83(3H,s), 4.03(2H,t,J-5.25Hz), 4.59(2H,s,broad), 5.03(2H,s), 6.80-6.97(58,m), 7.11(2H,d,J=8.45Hz), 7.38(4H,dd,J-8.5Hz,J-13.4Hz) Example 9: [dgDMSO] 82.74(2H,t,J-7.3HZ), 2.94(2H,t,J-5.65Hz), 3.56(2H,s,broad), 3.74<3H,s), 3.95(28,t,J-5.65Hz), 4.56(2H,s,broad), 5.12(2H,s), 6.78(lH,m), 6.80-6.97(4H,m), 7.15(2H,d,J-8.5Hz), 7.37(lH,m), 7.45-7.54(5H,m), 7.66-7.69(4H,m) The compound of Example 9 has a melting point of 90-92°C.
HPLC Retention time The retention times of the compounds of Examples 1 to 9 were measured on a C-18 Microbondapak* reverse phase column using the folloving gradient and conditions: - 13 35 Solution A: 0.1Z trifluoroacetic acid Solution B: acetonitrile TIME FLOW RATE ZA ZB (min) (ml/min) 0 2.25 90 10 2 2.25 90 10 6 2.25 45 55 22 2.25 40 60 29 2.25 0 100 31 2.25 90 10 The following results were obtained: EXAMPLE 9 RETENTION TIME (min) 9.404 9.415 9.740 9.752 10.297 10.827 11.317 10.080 10.482 Following the steps of Reaction Scheme B the compounds used as starting materials may be prepared as follows: a) t-Boc-vanillylamine 18.Og Vanillylamine hydrochloride (0.095 mole) and 10.6g triethylamine (0.11 mole) are dissolved in 250ml vater and placed in a IL round bottomed flask. 20.5g di-tert-butyldicarbonate (0.095 mole) in 200ml dioxan is added vith stirring, over a period of 15 minutes. The resulting mixture is stirred overnight at room temperature.
The dioxan is removed in vacuo and the aqueous residue extracted vith CHC13 (5x10ml). The combined extracts are dried over MgSO4, filtered and the solvent removed in vacuo to leave a brovn oil vhich is purified via flash column chromatography (cyclohexane : EtOAc / 5:2) to give a colourless oil vhich crystallises on standing, [t.l.c. cyclohexane : EtOAc / 1:1; r.f. = 0.5] b) t-Boc-(4-(2-bromoe thoxy)-3-methoxybenzylamine 21.Og t-Boc-vanillylamine (0.083 mole), 250ml 1,2.dibromoethane, 66ml 40Z KOH and 6.6ml 40Z tetrabutylammonium hydroxide are combined in a 500ml round bottomed flask and the resulting mixture is heated at 50°C for 3 hours vith rapid stirring.
The mixture is cooled, diluted vith 200ml CH2C12, washed vith vater (3x200ml) and the combined aqueous vashings extracted once vith 600ml CH2C12. The combined organic layers are washed vith brine, dried over MgS04, filtered and the solvent removed in vacuo to leave a white solid which is used without further purification, [t.l.c. cyclohexane : EtOAc / 1:1; r.f. = 0.6] 3Q c) t-Boc-(4-(2-phthalimidoethoxy)-3-methoxybenzylamine 23.Og t-Boc-(4-(2-bromoethoxy)-3-methoxybenzylamine (0.064 mole) and 11.8g potassium phthalimide (0.064 mole) are suspended in 500ml dry DMF in a round bottomed flask. The resulting suspension is heated at 50°C for 2 hours vith rapid stirring. After 30 mins of this heating/stirring, the mixture becomes homogeneous. The mixture is then cooled and the DMF removed under high vacuum. The resulting solid residue is purified via flash column chromatography (cyclohexane : EtOAc / 1:1) to give a white solid, [t.l.c. (cyclohexane : EtOAc / 1:1) rf 0.45. d) 4-(2-phthalimidoethoxy)3-methoxy benzylamine.TFA 26.5g t-Boc-(4-(2-phthalimidoethoxy)-3-methoxybenzylamine (0.062 mole) is dissolved in 200ml CH2CI2 in a 500ml round bottomed flask. 15ml trifluoroacetic acid is added dropwise with stirring. On completion of the addition, the mixture is stirred for a further 2 hours at room temperature (the reaction is shown to be completed by the loss of staring material (cyclohexane : EtOAc / 1:1)). The solvent is removed in vacuo, initially on the water pump and then high vacuum. The resulting colourless oil solidifies on standing and is used without further purification. e) N- [ 4-( 2-ph thal imidoe thoxy ) -3-me thoxy benzyl) -N- [2-( 4-chlorophenyl) ethyl]thiourea 2.0g 4-(2-phthalimidoethoxy)-3-methoxybenzylamine.TFA (0.005 mole) and 0.5g EtjN (0.005 mole) are suspended in 30 ml dry EtOAc under an atmosphere of dry nitrogen. 0.9g 2-(4-chlorophenyl)ethylisothiocyanate (0.0045 mole) in dry 10ml EtOAc is added dropwise and the mixture stirred at room temperature for 3 hours.
The EtOAc is removed in vacuo, the residue suspended in 50ml water and then extracted with 3x50ml CH2CI2· The combined organic layers are dried over MgSO<, filtered and the solvent removed in vacuo to leave a brown oil which is purified via column chromatography [tic (cyclohexane : EtOAc / 1:1) rf = 0.2]. Melting point = 59-61eC. - 16 The compounds and amides and esters of the invention have pharmacological, in particular analgesic and anti-inflammatory, activity and are therefore indicated to be useful as pharmaceuticals, e.g. for therapy.
In particular the compounds exhibit pharmacological activity as indicated in standard test models, for example as follows: 1. TAIL-FLICK TEST IN THE MOUSE The method is based on that of O'Amour et al. J. Pharmacol. Exp. Ther. 72, 74-79 (1941), but employing unstarved mice (o + o, 16-25 g). Animals are divided into control and test groups, control animals receiving a vehicle injection only. Each test animal is placed in an individual perspex cylinder to prevent movement with its tail protruding along a narrow groove. The tail of each animal is exposed to a beam of radiant heat at ca. 35 mm from the tail root, from a lamp of known output and temperature, place directly under the tail. Test substance is administered p.o. or s.c. 30 mins, post introduction into the cylinder. The time in seconds taken by the mouse to flick its tail out of the light beam is recorded 30 to 15 mins prior to administration of test substance. Animals whose reaction times differ by more than 25 X are discarded. Reaction time is re-determined 15 and 30 mins post administration. Extension of reaction time by > 75 Z over mean pre-treatment values in the same animal are taken as indicative of analgesic response. Three doses are employed per test substance and 10 animals per dose. EDso values (95 Z confidence limits) are estimated in accordance with the method of Litchfield and Vilcoxon and represent the dose prolonging treatment reaction time by > 75 Z in 50 Z of test animals. ' 30 Compounds and amides and esters of the invention are active in the above test model at dosages of the order of from about 1.0 to about 120.0 yra/kg, s.c. - 17 2. YEAST INDUCED INFLAMMATION TEST IN THE MOUSE yl, 20 X fresh yeast suspension is injected into the plantar region of one hind pav and saline is injected into the other. Degree of inflammation is estimated by the relative increase in pav veight (yeast injected v.s.saline) 2 hrs. post-injection. Test substance is administered s.c. at varying dosage at the same time as yeast/saline treatment. 5 animals are used/dose and testing at each dose is repeated 2-3 times, control and test values being compared statistically as above. EDS0 values are taken as the dosage required to effect 50 X inhibition of inflammation as compared vith control animals not receiving test substance, and are established from dose response curves plotting X inflammation vs. dose. Compounds and esters of the invention are active in the above test model at dosages of the order of from about 2.5 to 100 μΜ/kg, s.c.
The compounds, esters, amides and pharmaceutically acceptable salts of the invention are accordingly useful as pharmaceuticals, e.g. as analgesics for the treatment of pain of various genesis or aetiology, for example dental pain and headache, particularly vascular headache, such as migraine, cluster, and mixed vascular syndromes as veil as nonvascular, tension headache, and as anti-inflammatory agents for the treatment of inflammatory diseases or conditions, for example the treatment of arthritis and rheumatic diseases, Raynaud's disease, inflammatory bovel disorders, trigeminal or herpetic neuralgia, inflammatory eye disorders e.g. uveitis, psoriasis, cystitis as veil as other chronic inflammatory conditions.
Having regard to their analgesic/anti-inflammatory profile they are, in particular, useful for the treatment of inflammatory pain, for the treatment of hyperalgesia and, in particular, the treatment of severe chronic pain, e.g. for the treatment of deafferentation pain as an alternative to surgical procedures. - 18 According to a further embodiment, the compounds of formula I, their esters, amides and pharmaceutically acceptable salts are also useful for the prophylactic or curative treatment of epithelial tissue damages or dysfunction, e.g. spontaneous lesions, and for the control of disturbances of visceral motility at respiratory, genitourinary, gastrointestinal and vascular level, e.g. for treating wounds, burns, skin allergic reactions, pruritus and vitiligo, for the prophylactic or curative treatment of gastrointestinal disorders such as gastric ulceration, duodenal ulcers and diarrhoea, for the prophylactic or curative treatment of gastric lesions induced by necrotising agents, for example ethanol, for the treatment of vasomotor or allergic rhinitis and for the treatment of bronchial disorders or bladder disorders. The utility in treating as epithelial tissue damages or dysfunction may be shown in standard test models, for example as follows: ETHANOL-INDUCED GASTRIC LESIONS The tests are carried out employing male rats (200-250g) fasted overnight but with free access to vater. The test substance is administered s.c. or orally by a metal stomach tube. Absolute ethanol is given orally 30 min after the administration of the test substance and the animals are killed 1 hour later. The stomach is cut open along the greater curvature and pinned flat. Haemorrhagic erosions are quantified in two ways: area and length of the erosions.
On administration of a compound of formula I as test compound at a dosage of from ca. 0.1 to 20 mg/kg, substantial inhibition of the gastric lesions induced by ethanol is observed compared vith results for control groups receiving placebo in lieu of the test compound.
For the above uses the required dosage will of course vary depending on the mode of administration, the particular condition to be treated and the effect desired. An indicated daily dosage in the range of from - 19 about 2 to about 1,000 or 2,000 mg p.o., e.g. from about 75 to 750 or 1,500 mg p.o. for analgesic use, and of the order of from about 10 to about 2,000 mg p.o. e.g. from about 75 to 1,500 mg p.o., for antiinflammatory use, conveniently administered once, in divided dosages 2 to 4 times/day, or in sustained release or retard form. Dosage forms suitable for oral administration accordingly comprise from about 0.5 to about 500 or 1,000 mg, e.g. from about 20 to about 375 or 750 mg (analgesic use) or from about 2.5 to about 1,000 mg, e.g. from about 20 to about 750 mg, (anti-inflammatory use) active ingredient (i.e. compound, ester, amide or pharmaceutically acceptable salt of the invention) admixed vith an appropriate solid or liquid,- pharmaceutically acceptable, diluent or carrier therefor.
In accordance vith the foregoing the present invention also provides: A. A compound of formula I or physiologically-hydrolysable and -acceptable ester or amide thereof as hereinbefore defined, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical; B. A pharmaceutical composition comprising a compound of formula I or physiologically-hydrolysable and -acceptable ester or amide thereof as hereinbefore defined, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier therefor.
Suitable pharmaceutically acceptable salts of the compounds and esters of the invention include for example the sodium and potassium salts.
Claims (15)
1. A compound of formula I R 6 R 7 vherein R 3 is halogen, Ci_ 4 alkyl, phenyl, benzyl, substituted or unsubstituted benzyloxy, nitro, cyano, trifluoromethyl, formylamino or Ci_i 6 alkoxy, R 2 is hydrogen or has any one of the meanings given for R x , R 3 is hydrogen or Ci_ 4 alkyl, R 4 and R 5 , independently are hydrogen, halogen, Cj_ 5 alkyl, substituted Ci_ 5 alkyl, aryl, substituted or unsubstituted aryl, COOH, COORg or CONR9R10 vherein R 8 is Cx-salkyl, and each of R 9 and R 10 independently is hydrogen or Ci_5alkyl, R 6 and R 7 , independently have the meanings given for R 4 and R 5 or together vith the carbon atom to vhich they are attached form a substituted or unsubstituted C 3 _ 7 cycloalkyl radical, R is 0, S or NH and X is -(CH 2 ) n - or -(CH 2 ) B -CH=CH-(CH 2 ) r - vherein n is 1, 2 or 3 and each of m and r is independently zero or an integer of from 1 to 3, - 21 or physiologically hydrolysable and acceptable ester or amide thereof or pharmaceutically acceptable salt of such compound, ester or amide.
2. A compound, ester, amide or salt according to claim 1 in which: Ri is halogen, Ci_ 4 alkyl, Ci_i 6 alkoxy or substituted or unsubstituted benzyloxy, R 2 is hydrogen, halogen or Ci_ 4 alkyl, R 4 to R·? are each hydrogen, X is -(CH 2 ) n -, and R 3 , R and n have the meanings given in claim 1.
3. A compound, ester, amide or salt according to claim 2 in which: Ri is halogen, Ci_i 6 alkoxy or substituted or unsubstituted benzyloxy; R 2 is hydrogen or halogen, R 3 is hydrogen or methyl, R 4 to R 7 are each hydrogen, R is -0-; and X is -(CH 2 ) n - wherein n is 1 or 2.
4. A compound, ester, amide or salt according to any one of claims 1 to 3 in which any substituted benzyloxy group as Ri is halogen or phenyl substituted.
5. A compound, ester, amide or salt according to claim 4 in which any substituted benzyloxy group as Ri is mono-substituted at the 4-position.
6. A compound, ester, amide or salt according to any one of claims 1 to 3 in which R x is other than substituted benzyloxy. - 22
7. A compound according to claim 1 which is N-[4-(2-aminoethoxy)-3methoxybenzyl]-N'-(2-(4-chlorophenyl)ethyl]thiourea, or physiologically hydrolysable and acceptable ester or amide thereof or pharmaceutically acceptable salt of said compound, of such ester or of such amide.
8. A compound according to claim 1 selected from the group consisting of: a) N-(4-(2-aminoethoxy)-3-methoxybenzyl]-N'-(2-(4-fluorophenyl)ethyl]thiourea, b) N-[4-(2-aminoethoxy)-3-methoxybenzyl]-Ν'-[2-(2,4-dichlorophenyl)ethyl]thiourea, c) N-(4-(2-aminoethoxy)-3-methoxybenzyl]-Ν'-[2-(4-benzyloxyphenyl)ethyl]thiourea, d) N-(4-(2-aminoethoxy)-3-methoxybenzyl]-N'-[2-(4-(4-bromobenzyloxy)phenyl)ethyl]thiourea, e) N-[4-(2-aminoethoxy)-3-methoxybenzyl]-Ν'-(2-(4-(N-octyloxy)phenyl)ethyl]thiourea, f) N-[4-(2-aminoethoxy)-3-methoxybenzyl]-N'-(4-N-octyloxybenzyl]thiourea, g) N-(4-(2-aminoethoxy)-3-methoxybenzyl]-Ν'-[2-(4-(4-chlorobenzyloxy)phenyl)ethyl]urea; and h) N-[4-(2-aminoethoxy)-3-methoxybenzyl]-N'-[2-(4-(4-phenylbenzyloxy)phenyl)ethyl]thiourea; or physiologically hydrolysable and acceptable ester or amide thereof or pharmaceutically acceptable salt of such compound, ester or amide.
9. A process for the preparation of a compound of formula I as defined in claim 1 or an ester., amide or salt thereof, vhich comprises: - 23 fc a) reacting a compound of formula II (II) vherein R, R x to R 7 and X are as defined in claim 1, vith hydrazine; b) removing at least one amino protecting group vhich is present in an amino protected compound of formula I; c) for the production of a physiologically hydrolysable and acceptable ester or amide of a compound of formula I, esterifying or amidating a compound of formula I by reaction vith an appropriate acylating or amidating agent, respectively; d) for the production of a compound of formula I vherein X is -(CH 2 )„-CH=CH-(CH 2 ) r - in Z isomeric form, isomerising a compound of formula I vherein X is -(CH 2 )„-CH=CH-(CH 2 ) r - in E isomeric form; and recovering a compound of formula I thus obtained in free or salt form.
10. A pharmaceutical composition comprising a compound, ester, amide or salt as defined in claim 1 together vith a pharmaceutically acceptable diluent or carrier therefor. - 24
11. A compound, ester, amide or salt as defined in claim 1 for use as a pharmaceutical.
12. A compound of formula I as claimed in claim 1 substantially as described herein by way of example.
13. A process for the production of a compound of formula I as claimed in claim 9 substantially as described herein by way of example.
14. A compound of formula I whenever produced by a process as claimed in claim 9 or claim 13.
15. A pharmaceutical composition as claimed in claim 10 comprising a compound of formula I substantially as described herein by way of example.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB888830143A GB8830143D0 (en) | 1988-12-23 | 1988-12-23 | Improvements in or relating to organic compounds |
| GB898922440A GB8922440D0 (en) | 1989-10-05 | 1989-10-05 | Improvements in or relating to organic compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE894151L IE894151L (en) | 1990-06-23 |
| IE59336B1 true IE59336B1 (en) | 1994-02-09 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE415189A IE59336B1 (en) | 1988-12-23 | 1989-12-21 | Capsaicin derivatives |
Country Status (23)
| Country | Link |
|---|---|
| JP (1) | JPH0764803B2 (en) |
| AT (1) | AT397797B (en) |
| AU (1) | AU628902B2 (en) |
| BE (1) | BE1003848A3 (en) |
| CA (1) | CA2006115A1 (en) |
| CH (1) | CH678621A5 (en) |
| DE (1) | DE3942729A1 (en) |
| DK (1) | DK657089A (en) |
| ES (1) | ES2021182A6 (en) |
| FI (1) | FI896192A0 (en) |
| FR (1) | FR2640971B1 (en) |
| GB (1) | GB2226313B (en) |
| GR (1) | GR1000460B (en) |
| HU (1) | HU206082B (en) |
| IE (1) | IE59336B1 (en) |
| IL (1) | IL92830A (en) |
| IT (1) | IT1237479B (en) |
| LU (1) | LU87648A1 (en) |
| NL (1) | NL8903132A (en) |
| NZ (1) | NZ231965A (en) |
| PH (1) | PH27571A (en) |
| PT (1) | PT92674A (en) |
| SE (1) | SE8904306L (en) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2058492T3 (en) * | 1988-02-03 | 1994-11-01 | Hybritech Inc | IMPROVEMENTS IN OR RELATIVE TO MODIFIED HAPTENES USEFUL AS THERAPEUTIC AND IMAGE FORMATION AGENTS. |
| HU210683B (en) * | 1990-06-18 | 1995-06-28 | Sandoz Ag | Process for producing n-benzyl-n1-(phenyl-alkyl)-thiourea derivatives and pharmaceutical compositions containing the same |
| GB9519270D0 (en) * | 1995-09-21 | 1995-11-22 | Sandoz Pharma Uk | Organic compounds |
| GB9711962D0 (en) * | 1997-06-10 | 1997-08-06 | Reckitt & Colmann Prod Ltd | Therapeutically active compositions |
| DE10019670A1 (en) * | 2000-04-19 | 2001-10-31 | Diego Palermo | Medicament containing red pepper constituents useful as a dermatological agent, especially for treatment of damaged skin |
| MXPA03001535A (en) * | 2000-08-21 | 2004-12-13 | Pacific Corp | Novel thiourea derivatives and the pharmaceutical compositions containing the same. |
| MY138086A (en) | 2001-09-13 | 2009-04-30 | Smithkline Beecham Plc | Novel urea derivative as vanilloid receptor-1 antagonist |
| TW200403223A (en) | 2002-02-15 | 2004-03-01 | Glaxo Group Ltd | Novel compounds |
| GB0319150D0 (en) | 2003-08-14 | 2003-09-17 | Glaxo Group Ltd | Novel compounds |
| AT413646B (en) * | 2004-04-02 | 2006-04-15 | Hammer Johann Dr | USE OF CAPSAICIN AND / OR CAPSAICINOIDES |
| US7576099B2 (en) | 2005-02-28 | 2009-08-18 | Renovis, Inc. | Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same |
| WO2012045729A1 (en) | 2010-10-05 | 2012-04-12 | Glaxo Group Limited | Imidazo [1, 2 -a] pyridine and pyrazolo [1, 5 -a] pyridine derivatives as trpv1 antagonists |
| WO2012072512A1 (en) | 2010-11-29 | 2012-06-07 | Glaxo Group Limited | N-cyclobutyl-imidazopyridine or -pyrazolopyridine carboxamides as trpv1 antagonists |
| JP2014510768A (en) | 2011-04-11 | 2014-05-01 | グラクソ グループ リミテッド | N-cyclobutylimidazopyridine methylamine as a TRPV1 antagonist |
| CN111647537B (en) * | 2020-06-18 | 2022-04-26 | 浙江工业大学 | Salt-tolerant capsaicin degrading bacteria, application and kitchen waste treatment method |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU795462A3 (en) * | 1975-03-14 | 1981-01-07 | Эдьт Дьедьесерведьесети Дьяр (Фирма) | Method of preparing thiocarbamide derivatives |
| ES474449A1 (en) * | 1978-10-23 | 1979-05-01 | Invest Tecnica Aplicada | Anti-ulcer compositions |
| US4460602A (en) * | 1981-06-30 | 1984-07-17 | The Procter & Gamble Company | Urea derivatives |
| ES2061624T3 (en) * | 1987-03-09 | 1994-12-16 | Procter & Gamble | FENILIC COMPOUNDS REPLACED WITH AMINO-ETHYL IN BETA POSITION, AND ANTI-INFLAMMATORY OR ANALGESIC COMPOSITIONS THAT CONTAIN THEM. |
| GB8715357D0 (en) * | 1987-06-30 | 1987-08-05 | Sandoz Inst For Medical Resear | Organic compounds |
-
1989
- 1989-12-08 HU HU896479A patent/HU206082B/en not_active IP Right Cessation
- 1989-12-19 GB GB8928581A patent/GB2226313B/en not_active Expired - Lifetime
- 1989-12-20 CA CA002006115A patent/CA2006115A1/en not_active Abandoned
- 1989-12-20 FR FR8917031A patent/FR2640971B1/fr not_active Expired - Fee Related
- 1989-12-20 PH PH39737A patent/PH27571A/en unknown
- 1989-12-20 BE BE8901370A patent/BE1003848A3/en not_active IP Right Cessation
- 1989-12-21 AU AU47170/89A patent/AU628902B2/en not_active Ceased
- 1989-12-21 AT AT0290289A patent/AT397797B/en not_active IP Right Cessation
- 1989-12-21 IE IE415189A patent/IE59336B1/en not_active IP Right Cessation
- 1989-12-21 NZ NZ231965A patent/NZ231965A/en unknown
- 1989-12-21 DK DK657089A patent/DK657089A/en not_active Application Discontinuation
- 1989-12-21 ES ES8904323A patent/ES2021182A6/en not_active Expired - Lifetime
- 1989-12-21 SE SE8904306A patent/SE8904306L/en not_active Application Discontinuation
- 1989-12-21 FI FI896192A patent/FI896192A0/en not_active Application Discontinuation
- 1989-12-21 NL NL8903132A patent/NL8903132A/en not_active Application Discontinuation
- 1989-12-21 IL IL9283089A patent/IL92830A/en not_active IP Right Cessation
- 1989-12-21 IT IT04868289A patent/IT1237479B/en active IP Right Grant
- 1989-12-21 PT PT92674A patent/PT92674A/en not_active Application Discontinuation
- 1989-12-21 CH CH4601/89A patent/CH678621A5/de not_active IP Right Cessation
- 1989-12-22 DE DE3942729A patent/DE3942729A1/en not_active Withdrawn
- 1989-12-22 GR GR890100859A patent/GR1000460B/en unknown
- 1989-12-22 JP JP1334681A patent/JPH0764803B2/en not_active Expired - Lifetime
- 1989-12-22 LU LU87648A patent/LU87648A1/en unknown
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| MM4A | Patent lapsed |