Source: http://www.freepatentsonline.com/5298511.html
Timestamp: 2019-10-23 13:47:18
Document Index: 17402716

Matched Legal Cases: ['Application No. 0181568', 'Application No. 0344519', 'Application No. 0414076', 'Art. 9385', 'Art. 9303', 'Application No. 0385662']

Alkanoic acid derivatives - Imperial Chemical Industries PLC
Alkanoic acid derivatives
United States Patent 5298511
The invention concerns alkanoic acid derivatives of the formula I ##STR1## wherein Ar1 is optionally-substituted phenyl or naphthyl, or a 10-membered bicyclic heterocyclic moiety containing one or two nitrogen heteroatoms and optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur;
A1 is a direct link to X1 or is (1-3 C)alkylene;
n is 0, 1 or 2 and R1 is halogeno, (1-4 C)alkyl, (1-4 C)alkoxy or fluoro-(1-4 C)alkyl;
each of R2 and R3 is (1-4 C)alkyl, (2-4 C)alkenyl or (2-4 C)alkynyl; and
R4 is hydrogen or (1-4 C)alkyl;
Waterson, David (Bollington, GB2)
07/948594
Imperial Chemical Industries PLC (London, GB)
I.C.I. Pharma (Cedex, FR)
546/155, 546/174, 560/10, 560/56, 562/427, 562/466
A61K31/19; A61K31/215; A61P9/00; A61P9/10; A61P11/00; A61P29/00; A61P37/08; A61P43/00; C07B57/00; C07C67/31; C07C69/734; C07C317/44; C07C323/62; C07D215/14; C07D215/227; C07D215/22; (IPC1-7): C07D215/14; C07C69/76; C07C315/00; C07C321/00; C07D215/16
560/56, 560/10, 562/427, 562/466, 514/311
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5132328 Alcohol and ether derivatives 1992-07-21 Girodeau 514/716
5098930 Heterocyclic derivatives 1992-03-24 Edwards 514/459
4970215 Substituted 4-(quinolin-2-yl-methoxy)phenyl-acetic acid derivatives and anti-allergic use thereof 1990-11-13 Mohrs et al. 514/311
4960892 Naphthalenepropionic acid derivatives as anti-inflammatory/anti-allergic agents 1990-10-02 Kreft, III 546/152
4929626 α-substituted 4-(quinolin-2-yl-methoxy)phenylacetic acids and esters and lipoxygenase inhibition therewith 1990-05-29 Mohrs et al. 514/311
4772703 2-(phenoxymethyl)-quinazolines as antiallergic and antiinflammatory agents 1988-09-20 Musser 544/283
CA2023829A1 1991-02-25
EP0181568 1986-05-21 Anti-inflammatory/anti-allergic compounds.
EP0200101 1986-11-05 Aryl and heteroaryl ethers as agents for the treatment of hypersensitive aliments.
EP0344519 1989-12-06 Substituted 4-(quinolin-2-yl-methoxy)phenyl-acetic-acid derivatives.
EP0385679 1990-09-05 Heterocyclic cyclic ethers.
EP0414076 1991-02-27 Cyclic substituted (quinoline-2-yl-methoxy)phenylacetic acid derivatives.
Honda et al, "Synthesis of (.+-.)-Aphanorphine via an Aminylium Ion Intermediate", J. Chem. Soc. Perkin Trans. I, Mar. 1992, pp. 531-532.
1. An alkanoic acid derivative of the formula I
wherein Ar1 is phenyl or naphthyl, or a 10-membered bicyclic heterocyclic moiety containing one or two nitrogen heteroatoms and optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur, and Ar1 may optionally bear up to four substituents selected from halogeno, hydroxy, cyano, oxo, thioxo, (1-4 C)alkyl (1-4 C)alkoxy, fluoro-(1-4 C)alkyl, phenyl, benzoyl, phenyl-(1-4 C)alkyl and α,α-difluorobenzyl, and wherein said phenyl substituent or any of said substituents which contain a phenyl group may optionally bear a substituent selected from halogeno, (1-4 C)alkyl and (1-4 C)alkoxy;
n is 0, 1 or 2, and R1 is halogeno, (1-4 C)alkyl, (1-4 C)alkoxy or fluoro-(1-4 C)alkyl;
each of R2 and R3, which may be the same or different, is (1-4 C)alkyl, (2-4 C)alkenyl or (2-4 C)alkynyl; and
2. An alkanoic acid derivative of the formula I as claimed in claim 1 wherein Ar1, A1, X1, R1, n and R4 have any of the meanings defined in claim 1 and wherein each of R2 and R3, which may be the same or different, is (1-4 C)alkyl, (2-4 C)alkenyl, (2-4 C)alkynyl or fluoro-(1-4 C)alkyl;
3. An alkanoic acid derivative of the formula I as claimed in claim 1 wherein Ar1 is phenyl which may optionally bear a substituent selected from fluoro, chloro, methyl, tert-butyl, phenyl, benzoyl, benzyl and α,α-difluorobenzyl and wherein said phenyl, benzoyl, benzyl or α,α-difluorobenzyl substituent may optionally bear a fluoro or chloro substituent, or Ar1 is naphth-2-yl which may optionally bear a substituent selected from fluoro, chloro and methyl;
n is 0 or 1 and R1 is from fluoro, chloro or trifluoromethyl;
each of R2 and R3, which may be the same or different, is methyl, ethyl, propyl, allyl or 2-propynyl;
R4 is methyl, ethyl, propyl, butyl, or tert-butyl;
4. An alkanoic acid derivative of the formula I as claimed in claim 1 wherein Ar1 is 2-quinolyl, 6-quinolyl, 6-quinoxazinyl, 2-oxo-1,2-dihydroquinolin-3-yl, 2-oxo-1,2-dihydroquinolin-6-yl, 2-oxo-1,2-dihydroquinolin-7-yl, 3-oxo-2,3-dihydro-4 H-1,4-benzoxazin-7-yl or 3-oxo-2,3-dihydro-4 H-1,4-benzothiazin-7-yl, which may optionally bear one, two or three substituents selected from fluoro, chloro, methyl, ethyl and 2-fluoroethyl;
n is 0 or 1 and R1 is fluoro, chloro or trifluoromethyl;
each of R2 and R3, which may be the same or different, is methyl, ethyl propyl, allyl or 2-propynyl;
and R4 is methyl, ethyl, propyl, butyl or tert-butyl;
5. An alkanoic acid derivative of the formula I as claimed in claim 1 wherein Ar1 is 2-quinolyl, 6-quinolyl, 2-oxo-1,2-dihydroquinolin-3-yl or 2-oxo-1,2-dihydroquinolin-6-yl, which may optionally bear one substituent selected from fluoro, chloro, methyl and ethyl; A1 is a direct link to X1, or is methylene;
each of R2 and R3, which may be the same or different, is methyl, ethyl or allyl;
and R4 is methyl or ethyl;
6. An alkanoic acid derivative of the formula I as claimed in claim 1 wherein Ar1 is naphth-2-yl, 2-quinolyl or 1-methyl-2-oxo-1,2-dihydroquinolin-6-yl;
R2 is methyl, ethyl or allyl;
R3 is methyl or ethyl; and
7. The alkanoic acid derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in claim 1 selected from:
ethyl 2-ethyl-2-[3-(naphth-2-ylmethoxy)phenyl]butyrate,
methyl 2-methyl-2-[3-(naphth-2-ylmethoxy)phenyl]propionate,
ethyl 2-ethyl-2-[3-(2-quinolylmethoxy)phenyl]butyrate,
ethyl 2-ethyl-2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]butyra te,
ethyl 2-methyl-2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yl-methoxy)phenyl]buty rate and
ethyl 2-allyl-2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yl-methoxy)phenyl]butyr ate.
8. A pharmaceutical composition which comprises an alkanoic acid derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 7 in association with a pharmaceutically-acceptable diluent or carrier.
9. A method of treating a disease or medical condition mediated alone or in part by one or more leukotrienes which comprises administering to a warm-blooded animal requiring such treatment a 5-lipoxygenase-inhibitory amount of an alkanoic acid derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 7.
This invention concerns alkanoic acid derivatives and more particularly alkanoic acid derivatives which are inhibitors of the enzyme 5-lipoxygenase (hereinafter referred to as 5-LO). The invention also concerns processes for the manufacture of said alkanoic acid derivatives and pharmaceutical compositions containing them. Also included in the invention is the use of said alkanoic acid derivatives in the treatment of various inflammatory and/or allergic diseases in which the direct or indirect products of 5-LO catalysed oxidation of arachidonic acid are involved, and the production of new medicaments for such use.
As stated above the alkanoic acid derivatives described hereinafter are inhibitors of 5-LO, which enzyme is known to be involved in catalysing the oxidation of arachidonic acid to give rise via a cascade process to the physiologically active leukotrienes such as leukotriene B4 (LTB4) and the peptide-lipid leukotrienes such as leukotriene C4 (LTC4) and leukotriene D4 (LTD4) and various metabolites.
It is disclosed in European Patent Application No. 0181568 that 3-(2-quinolylmethoxy)phenylacetic acid and 2-[3-(2-quinolylmethoxy)phenyl]propionic acid and certain methyl or ethyl esters thereof possess anti-inflammatory properties.
It is further disclosed in European Patent Application No. 0344519 that certain 2-[4-(2-quinolylmethoxy)phenyl]acetic acid derivatives, wherein the 2-position of the acetic acid is mono-substituted with, for example, a cycloalkyl-alkyl group, are inhibitors of the enzyme lipoxygenase.
It is further disclosed in European Patent Application No. 0414076 that certain 2-[4-(2-quinolylmethoxy)phenyl]acetic acid derivatives, wherein the 2-position of the acetic acid is di-substituted with, for example, a but-1,4-diyl radical to form a cyclopentanecarboxylic acid derivative, are inhibitors of the enzyme lipoxygenase.
We have now discovered that certain novel phenylacetic acid derivatives wherein the 2-position of the acetic acid is di-substituted possess surprisingly potent 5-LO inhibitory activity. Thus, such compounds are of value as therapeutic agents in the treatment of, for example, allergic conditions, psoriasis, asthma, cardiovascular and cerebrovascular disorders, and/or inflammatory and arthritic conditions, mediated alone or in part by one or more leukotrienes.
According to the invention there is provided an alkanoic acid derivative of the formula I (set out hereinafter) wherein Ar1 is phenyl or naphthyl, or a 10-membered bicyclic heterocyclic moiety containing one or two nitrogen heteroatoms and optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur, and Ar1 may optionally bear up to four substituents selected from halogeno, hydroxy, cyano, oxo, thioxo, (1-4 C)alkyl (1-4 C)alkoxy, fluoro-(1-4 C)alkyl, phenyl, benzoyl, phenyl-(1-4 C)alkyl and α,α-difluorobenzyl, and wherein said phenyl substituent or any of said substituents which contain a phenyl group may optionally bear a substituent selected from halogeno, (1-4 C)alkyl and (1-4 C)alkoxy;
According to a further feature of the invention there is provided an alkanoic acid derivative of the formula I wherein Ar1, A1, X1, R1, n and R4 have any of the meanings defined hereinbefore and wherein each of R2 and R3, which may be the same or different, is (1-4 C)alkyl, (2-4 C)alkenyl, (2-4 C)alkynyl or fluoro-(1-4 C)alkyl; or a pharmaceutically-acceptable salt thereof.
It is further to be understood that, insofar as certain of the compounds of formula I defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic form which possesses the property of inhibiting 5-LO. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, inhibitory properties against 5-LO may be evaluated using the standard laboratory techniques referred to hereinafter.
A suitable value for Ar1 when it is naphthyl is, for example, 1-naphthyl or 2-naphthyl.
A suitable value for Ar1 when it is a 10-membered bicyclic heterocyclic moiety containing one or two nitrogen heteroatoms and optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur is, for example, a 10-membered benzo-fused heterocyclic moiety such as quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, 4 H-1,4-benzoxazinyl or 4 H-1,4-benzothiazinyl, or a hydrogenated derivative thereof such as 1,2-dihydroquinolyl, 1,2,3,4-tetrahydroquinolyl, 1,2-dihydroisoquinolyl, 2,3-dihydro-4 H-1,4-benzoxazinyl or 2,3-dihydro-4 H-1,4-benzothiazinyl. The heterocyclic moiety may be attached through any available position including from either of the two rings of the bicyclic heterocyclic moiety and including through an available nitrogen atom. The heterocyclic moiety may bear a suitable substituent such as, for example, a (1-4 C)alkyl, phenyl, benzoyl or phenyl-(1-4 C)alkyl substituent on an available nitrogen atom.
Suitable values for substituents which may be present on Ar1, or on the phenyl substituent on Ar1 or on any of the substituents on Ar1 which contain a phenyl group, or suitable values for R1 include, for example:
for halogeno: fluoro, chloro, bromo and iodo; for (1-4C)alkyl: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl; for (1-4C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for fluoro-(1-4C)alkyl: fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoro- ethyl, 2,2,2-trifluoroethyl and pentafluoroethyl; for phenyl-(1-4C)alkyl: benzyl, phenethyl, 3-phenyl- propyl and α-methylbenzyl.
A suitable value for A1 when it is (1-3 C)alkylene is, for example, methylene, ethylene or trimethylene.
A suitable value for R2, R3 or R4 when it is (1-4 C)alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl or tert-butyl; when it is (2-4 C)alkenyl is, for example, vinyl, allyl, prop-1-enyl, but-1-enyl, but-2-enyl, 2-methylprop-1-enyl or 2-methylprop-2-enyl; when it is (2-4 C)alkynyl is, for example, ethynyl, 1-propynyl or 2-propynyl; and when it is fluoro-(1-4 C)alkyl is, for example, fluoromethyl, 2-fluoroethyl or 2,2,2-trifluoroethyl.
Particular compounds of the invention are, for example, alkanoic acid derivatives of the formula I wherein:
(a) Ar1 is phenyl or naphthyl which may optionally bear one, two or three substituents selected from any of those substituents on Ar1 defined hereinbefore other than oxo and thioxo; and A1, X1, n, R1, R2, R3 and R4 have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention;
(b) Ar1 is phenyl or naphth-2-yl which may optionally bear one or two substituents selected from fluoro, chloro, methyl, ethyl, isopropyl, tert-butyl, methoxy, trifluoromethyl, phenyl, benzoyl, benzyl and α,α-difluorobenzyl, and wherein said phenyl, benzoyl, benzyl or α,α-difluorobenzyl substituents may optionally bear a substituent selected from fluoro, chloro, methyl and methoxy; and A1, X1, n, R1, R2, R3 and R4 have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention;
(c) Ar1 is a 10-membered benzo-fused heterocyclic moiety containing one or two nitrogen heteroatoms and optionally containing a further heteroatom selected from oxygen and sulphur, which heterocyclic moiety may optionally bear one or two oxo or thioxo substituents and up to two further substituents selected from any of those substituents on Ar1 defined hereinbefore other than oxo or thioxo; and A1, X1, n, R1, R2, R3 and R4 have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention;
(d) Ar1 is quinolyl, 1,2-dihydroquinolyl, isoquinolyl, 1,2-dihydroisoquinolyl, quinoxalinyl, 2,3-dihydro-4 H-1,4-benzoxazinyl or 2,3-dihydro-4 H-1,4-benzothiazinyl, which may optionally bear one or two oxo or thioxo substituents and up to two further substituents selected from any of those substituents on Ar1 defined hereinbefore other than oxo or thioxo; and A1, X1, n, R1, R2, R3 and R4 have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention;
(e) Ar1 is quinolyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydroquinolyl or 2,3-dihydro-4 H-1,4-benzoxazinyl which may optionally bear one oxo or thioxo substituent and up to two further substituents selected from any of those substituents on Ar1 defined hereinbefore other than oxo or thioxo; and A1, X1, n, R1, R2, R3 and R4 have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention;
(f) Ar1 is 2-quinolyl, 3-quinolyl, 6-quinolyl, 7-quinolyl, 3-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 2-quinoxalinyl, 6-quinoxalinyl, 4 H-1,4-benzoxazin-6-yl or 4 H-1,4-benzothiazin-6-yl, which may optionally bear one or two substituents selected from any of those substituents on Ar1 defined hereinbefore other than oxo or thioxo; and A1, X1, n, R1, R2, R3 and R4 have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention;
(g) Ar1 is 2-oxo-1,2-dihydroquinolinyl, 3-oxo-2,3-dihydro-4 H-1,4-benzoxazinyl or 3-oxo-2,3-dihydro-4 H-1,4-benzothiazinyl, or the corresponding thioxo derivatives thereof, which may optionally bear up to three substituents selected from any of those substituents on Ar1 defined hereinbefore other than oxo or thioxo; and A1, X1, n, R1, R2, R3 and R4 have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention;
(h) Ar1 is 2-oxo-1,2-dihydroquinolinyl, 2-thioxo-1,2-dihydro-quinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, 2-thioxo-1,2,3,4-tetrahydroquinolinyl or 3-oxo-2,3-dihydro-4 H-1,4-benzoxazinyl which may optionally bear up to three substituents selected from any of those substituents on Ar1 defined hereinbefore other than oxo or thioxo; and A1, X1, n, R1, R2, R3 and R4 have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention;
(i) Ar1 is 2-oxo-1,2-dihydroquinolin-3-yl, 2-oxo-1,2-dihydroquinolin-6-yl, 2-oxo-1,2-dihydroquinolin-7-yl, 3-oxo-2,3-dihydro-4 H-1,4-benzoxazin-7-yl or 3-oxo-2,3-dihydro-4H-1,4-benzothiazin-7-yl, which may optionally bear up to three substituents selected from any of those substituents on Ar1 defined hereinbefore other than oxo or thioxo; and A1, X1, n, R1, R2, R3 and R4 have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention;
(j) A1 is a direct link to X1, and X1 is oxy, thio, sulphinyl or sulphonyl; and Ar1, n, R1, R2, R3 and R4 have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention;
(k) A1 is methylene and X1 is oxy; and Ar1, n, R1, R2, R3 and R4 have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention;
(l) n is 0 or 1 and R1 is fluoro, chloro, methyl, methoxy or trifluoromethyl; and Ar1, A1, X1, R2, R3 and R4 have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention;
(m) each of R2 and R3, which may be the same or different, is methyl, ethyl, propyl, vinyl, allyl, ethynyl or 2-propynyl; and Ar1, A1, X1, n, R1 and R4 have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention;
(n) each of R2 and R3, which may be the same or different, is methyl, ethyl, propyl, vinyl, allyl, ethynyl, prop-2-ynyl, fluoromethyl or 2-fluoroethyl; and Ar1, A1, X1, n, R1 and R4 have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention; and
(o) R4 is hydrogen, methyl, ethyl, propyl, butyl or tert-butyl; and Ar1, A1, X1, n, R1, R2 and R3 have any of the meanings defined hereinbefore;
A preferred compound of the invention comprises an alkanoic acid derivative of the formula I wherein Ar1 is phenyl which may optionally bear a substituent selected from fluoro, chloro, methyl, tert-butyl, phenyl, benzoyl, benzyl and α,α-difluorobenzyl and wherein said phenyl, benzoyl, benzyl or α,α-difluorobenzyl substituent may optionally bear a fluoro or chloro substituent, or Ar1 is naphth-2-yl which may optionally bear a substituent selected from fluoro, chloro and methyl;
n is 0 or 1 and R1 is from fluoro, chloro or trifluoromethyl; each of R2 and R3, which may be the same or different, is methyl, ethyl, propyl, allyl or 2-propynyl;
A further preferred compound of the invention comprises an alkanoic acid derivative of the formula I wherein Ar1 is 2-quinolyl, 6-quinolyl, 6-quinoxazinyl, 2-oxo-1,2-dihydroquinolin-3-yl, 2-oxo-1,2-dihydroquinolin-6-yl, 2-oxo-1,2-dihydroquinolin-7-yl, 3-oxo-2,3-dihydro-4 H-1,4-benzoxazin-7-yl or 3-oxo-2,3-dihydro-4 H-1,4-benzothiazin-7-yl, which may optionally bear one, two or three substituents selected from fluoro, chloro, methyl, ethyl and 2-fluoroethyl;
A1 is a direct link to X or is methylene;
A further preferred compound of the invention comprises an alkanoic acid derivative of the formula I wherein Ar1 is phenyl which may optionally bear a substituent selected from fluoro, chloro, methyl, tert-butyl, phenyl, benzoyl, benzyl and α,α-difluorobenzyl and wherein said phenyl, benzoyl, benzyl or α,α-difluorobenzyl substituent may optionally bear a fluoro or chloro substituent, or Ar1 is naphth-2-yl which may optionally bear a substituent selected from fluoro, chloro and methyl;
A further preferred compound of the invention comprises an alkanoic acid derivative of the formula I wherein Ar1 is 2-quinolyl, 6-quinolyl, 2-oxo-1,2-dihydroquinolin-3-yl or 2-oxo-1,2-dihydroquinolin-6-yl, which may optionally bear one substituent selected from fluoro, chloro, methyl and ethyl; A1 is a direct link to X1, or is methylene;
A further preferred compound of the invention comprises an alkanoic acid derivative of the formula I wherein Ar1 is naphth-2-yl, 2-quinolyl or 1-methyl-2-oxo-1,2-dihydroquinolin-6-yl;
ethyl 2-methyl-2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yl-methoxy)phenyl]buty rate or
A compound of the invention comprising an alkanoic acid derivative of the formula I, or a pharmaceutically-acceptable salt thereof, may be prepared by any process known to be applicable to the preparation of structurally-related compounds. Such procedures are provided as a further feature of the invention and are illustrated by the following representative examples in which, unless otherwise stated, Ar1, A1, X1, n, R1, R2, R3 and R4 have any of the meanings defined hereinbefore.
(a) The coupling, preferably in the presence of a suitable base, of a compound of the formula II with a compound of the formula Ar1 -A1 -Z wherein Z is a displaceable group; provided that, when there is a hydroxy group in Ar1 any hydroxy group may be protected by a conventional protecting group or alternatively any such group need not be protected, whereafter any undesired protecting group in Ar1 is removed by conventional means.
A suitable base for the coupling reaction is, for example, an alkali or alkaline earth metal carbonate, (1-4 C)alkoxide, hydroxide or hydride, for example sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride; or an organometallic base such as (1-4 C)alkyl-lithium, for example n-butyl-lithium.
The coupling reaction is conveniently performed in a suitable inert solvent, for example N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulphoxide, acetone, 1,2-dimethoxyethane or tetrahydrofuran, and at a temperature in the range, for example, 10° to 150° C., conveniently at or near 100° C.
The reaction may conveniently be performed in the presence of a suitable catalyst, for example a metallic catalyst, for example palladium(O) or copper(I) such as tetrakis(triphenylphosphine)palladium, cuprous chloride or cuprous bromide.
A suitable protecting group for a hydroxy group is, for example, an acyl group, for example a (2-4 C)alkanoyl group (especially acetyl), an aroyl group (especially benzoyl) or an arylmethyl group (especially benzyl). The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-charcoal.
The starting materials of the formula Ar1 -A1 -Z and of the formula II may be obtained by standard procedures of organic chemistry. Starting materials of the formula II are obtainable by analogous procedures to those illustrated in the accompanying Examples or by modifications thereto which are within the ordinary skill of an organic chemist.
(b) The coupling, preferably in the presence of a suitable base as defined hereinbefore, of a compound of the formula Ar1 -A1 -X1 -H with a compound of the formula III wherein Z is a displaceable group as defined hereinbefore; provided that, when there is a hydroxy group in Ar1, any hydroxy group may be protected by a conventional protecting group as defined hereinbefore or alternatively any such group need not be protected, whereafter any undesired protecting group in Ar1 is removed by conventional means.
The coupling reaction is conveniently performed in a suitable inert solvent or diluent as defined hereinbefore, and at a temperature in the range, for example, 10° to 150° C., conveniently at or near 100° C.
Conveniently the reaction may be performed in the presence of a suitable catalyst as defined hereinbefore.
The preparation of starting materials of the formula Ar1 -A1 -X1 -H and of the formula III may be obtained by standard procedures of organic chemistry as illustrated in European Patent Application Nos. 0375404, 0385662, 0409413, 0420511, 0462813 and 0488602.
(c) The coupling of a compound of the formula Ar1 -A1 -X1 -Z wherein Z is a displaceable group as defined hereinbefore, or alternatively, when X1 is a thio group, Z may be a group of the formula Ar1 -A1 -X1 -, with an organometallic reagent of the formula IV wherein M is an alkali metal or an alkaline earth metal such as lithium or calcium or M represents the magnesium halide portion of a conventional Grignard reagent; provided that, when there is a hydroxy group in Ar1 any hydroxy group may be protected by a conventional protecting group as defined hereinbefore or alternatively any such group need not be protected, whereafter any undesired protecting group in Ar1 is removed by conventional means.
The coupling reaction is conveniently performed in a suitable inert solvent as defined hereinbefore and at a temperature in the range, for example, -80° to +50° C., conveniently in the range -80° C. to ambient temperature.
The preparation of starting materials of the formula Ar1 -A1 -X1 -Z and of the formula IV may be obtained by standard procedures of organic chemistry as illustrated in European Patent Application Nos. 0375404, 0385662, 0409413, 0420511, 0462813 and 0488602.
(d) For the production of those compounds of the formula I wherein X1 is a sulphinyl or sulphonyl group, the oxidation of a compound of the formula I wherein X1 is a thio group.
(e) For the production of those compounds of the formula I wherein Ar1 bears an alkyl substituent on an available nitrogen atom, the alkylation of a compound of the formula I wherein Ar1 bears a hydrogen atom on said available nitrogen atom.
A suitable alkylating agent is, for example, any agent known in the art for the alkylation of an available nitrogen atom, for example an alkyl halide, for example a (1-4 C)alkyl chloride, bromide or iodide, in the presence of a suitable base. A suitable base for the alkylation reaction is, for example, an alkali or alkaline earth metal carbonate, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride. The alkylation reaction is preferably performed in a suitable inert solvent or diluent, for example N,N-dimethylformamide, dimethylsulphoxide, acetone, 1,2-dimethoxyethane or tetrahydrofuran, and at a temperature in the range, for example, 10° to 150° C., conveniently at or near ambient temperature.
(f) For the production of those compounds of the formula I wherein Ar1 bears one or more thioxo substituents, the reaction of a compound of the formula I wherein Ar1 bears one or more oxo substituents with a thiation reagent such that each oxo substituent is converted into a thioxo substituent; provided that, when there is a hydroxy group in Ar1 any such group may be protected by a conventional protecting group as defined hereinbefore or alternatively any such group need not be protected, whereafter any undesired protecting group in Ar1 is removed by conventional means.
A suitable thiation reagent is, for example, any agent known in the art for the conversion of an oxo group to a thioxo group such as, for example, 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide (Lawesson's Reagent) or phosphorus pentasulphide. The thiation reaction is generally carried out with the required stoichiometric amount of thiation reagent in order to reduce the risk of damage to other functional groups. In general the reaction is carried out in a suitable solvent or diluent such as toluene, xylene or tetrahydrofuran and at a temperature, for example, at or near the reflux temperature of the solvent or diluent, that is in the range 65° to 150° C.
As stated previously, the novel compounds of the formula I are inhibitors of the enzyme 5-LO. The effects of this inhibition may be demonstrated using one or more of the standard procedures set out below:
b) An ex vivo assay system, which is a variation of test a) above, involving administration to a group of rats of a test compound (usually orally as the suspension produced when a solution of the test compound in dimethylsulphoxide is added to carboxymethylcellulose), blood collection, heparinisation, challenge with A23187 and radioimmunoassay of LTB4 and TxB2. This test provides an indication of the bioavailability of a test compound as an inhibitor of 5-LO or cyclooxygenase.
Although the pharmacological properties of the compounds of the formula I vary with structural changes as expected, in general compounds of the formula I possess 5-LO inhibitory effects at the following concentrations or doses in one or more of the above tests a)-c):
Test a): IC50 (LTB4) in the range, for example, 0.01-40 μM IC50 (TxB2) in the range, for example, 40-200 μM;
Test c): oral ED50 (LTB4) in the range, for example, 0.1-50 mg/kg.
Thus, by way of example, the compound ethyl 2-ethyl-2-[3-(naphth-2-ylmethoxy)phenyl]butyrate has an IC50 of 0.2 μM against LTB4 in test a). In general those compounds of the formula I which are particularly preferred have an IC50 of <1 μM against LTB4 in test a).
According to a further feature of the invention there is provided a pharmaceutical composition which comprises an alkanoic acid derivative of the formula I, or a pharmaceutically-acceptable salt thereof, in association with a pharmaceutically-acceptable diluent or carrier.
The amount of active ingredient (that is an alkanoic acid derivative of the formula I, or a pharmaceutically-acceptable salt thereof) that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
According to a further feature of the invention there is provided an alkanoic acid derivative of the formula I, or a pharmaceutically-acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy.
By virtue of their effects on leukotriene production, the compounds of the formula I have certain cytoprotective effects, for example they are useful in reducing or suppressing certain of the adverse gastrointestinal effects of the cyclooxygenase inhibitory non-steroidal anti-inflammatory agents (NSAIA), such as indomethacin, acetylsalicylic acid, ibuprofen, sulindac, tolmetin and piroxicam. Furthermore, co-administration of a 5-LO inhibitor of the formula I with a NSAIA can result in a reduction in the quantity of the latter agent needed to produce a therapeutic effect, thereby reducing the likelihood of adverse side-effects. According to a further feature of the invention there is provided a pharmaceutical composition which comprises an alkanoic acid derivative of the formula I, or a pharmaceutically-acceptable salt thereof as defined hereinbefore, in conjunction or admixture with a cyclooxygenase inhibitory non-steroidal anti-inflammatory agent (such as those mentioned above), and a pharmaceutically-acceptable diluent or carrier.
(ii) operations were carried out at ambient temperature, tha is in the range 18°-25° C. and under an atmosphere of an inert gas such as argon;
(iii) column chromatography (by the flash procedure) and medium pressure liquid chromatography (HPLC) were performed on Merck Kieselgel silica (Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silica obtained from E. Merck, Darmstadt, W. Germany;
(v) the end-products of the formula I have satisfactory microanalyses and their structures were confirmed by NMR and mass spectral techniques; unless otherwise stated, CDCl3 solutions of the end-products of the formula I were used for the determination of the NM spectral data, chemical shift values were measured on the delta scale and the following abbreviations are used; s, singlet; d, doublet; t, triplet; m, multiplet;
THF tetrahydrofuran; DHSO dimethylsulphoxide; DMF N,N-dimethylformamide; DMA N,N-dimethylacetamide.
A mixture of 2-bromomethylnaphthalene (0.088 g), ethyl 2-ethyl-2-(3-hydroxyphenyl)butyrate (0.1 g), potassium carbonate (0.11 g) and DMF (1.5 ml) was stirred at ambient temperature for 18 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 10:3 v/v mixture of hexane and ethyl acetate as eluent. There was thus obtained ethyl 2-ethyl-2-[3-(naphth-2-ylmethoxy)phenyl]butyrate (0.12 g, 80%) as an oil.
NMR Spectrum: 0.72 (t, 6 H), 1.14 (t, 3 H), 2.01 (m, 4 H), 4.08 (q, 2 H), 5.20 (s, 2 H), 6.88 (m, 3 H), 7.23 (m, 1 H), 7.48 (m, 3 H), 7.82 (m, 4 H).
The ethyl 2-ethyl-2-(3-hydroxyphenyl)butyrate used as a starting material was obtained as follows:
A mixture of 3-methoxyphenylacetic acid (10 g), concentrated sulphuric acid (0.56 ml) and ethanol (45 ml) was heated to reflux for 4 hours. The mixture was evaporated and the residue was partitioned between diethyl ether and water. The organic phase was washed with water and with a saturated sodium bicarbonate solution, dried (MgSO4) and evaporated. There was thus obtained ethyl 3-methoxyphenylacetate (9.4 g, 81%).
n-Butyl-lithium (1.6M in hexane, 3.75 ml) was added dropwise to a stirred solution of di-isopropylamine (0.84 ml) in THF (20 ml) which had been cooled to -78° C. The mixture was stirred at -78° C. for 30 minutes, allowed to warm to 0° C. and stirred for 10 minutes and recooled to -78° C. A solution of ethyl 3-methoxyphenylacetate (1.16 g) in THF (5 ml) was added and the mixture was stirred at -78° C. for 1 hour. Ethyl iodide (0.94 g) was added and the mixture was stirred for 18 hours at ambient temperature. The mixture was partitioned between diethyl ether and water. The organic phase was washed with dilute aqueous hydrochloric acid solution and with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 5:2 v/v mixture of hexane and ethyl acetate as eluent. There was thus obtained ethyl 2-(3-methoxyphenyl)butyrate (1.06 g, 80%) as an oil. NMR Spectrum: 0.88 (t, 3 H), 1.21 (t, 3 H), 1.78 (m, 1 H), 2.08 (m, 1 H), 3.4 (t, 1 H), 3.79 (s, 3 H), 4.10 (m, 2 H), 6.82 (m, 3 H), 7.20 (m, 1 H).
The product so obtained was alkylated with ethyl iodide using an analogous procedure to that described in the preceding paragraph. There was thus obtained ethyl 2-ethyl-2-(3-methoxyphenyl)butyrate (0.75 g, 67%) as an oil.
NMR Spectrum: 0.66 (t, 6 H), 1.10 (t, 3 H), 1.95 (m, 4 H), 3.72 (s, 3 H), 4.05 (q, 2 H), 6.72 (m, 3 H), 7.15 (m, 1 H).
A solution of a portion (0.53 g) of the product so obtained in methylene chloride (30 ml) was cooled to -78° C. and boron tribromide (1M in methylene chloride, 4.35 ml) was added. The mixture was stirred at -78° C. for 4 hours and at ambient temperature for 16 hours. Ethanol (1 ml) was added and the mixture was washed with a saturated aqueous sodium carbonate solution and with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 10:3 v/v mixture of hexane and ethyl acetate as eluent. There was thus obtained ethyl 2-ethyl-2-(3-hydroxyphenyl)butyrate (0.34 g, 69%) as an oil.
NMR Spectrum: 0.73 (t, 6 H), 1.18 (t, 3 H), 2.02 (m, 4 H), 4.12 (q, 2 H), 6.73 (m, 3 H), 7.18 (m, 1 H).
The procedure described in Example 1 was repeated except that methyl 2-(3-hydroxyphenyl)-2-methylpropionate was used in place of ethyl 2-ethyl-2-(3-hydroxyphenyl)butyrate. There was thus obtained methyl 2-methyl-2-[3-(naphth-2-ylmethoxy)phenyl]propionate in 76% yield, m.p. 64°-66° C.
The methyl 2-(3-hydroxyphenyl)-2-methylpropionate used as a starting material was obtained from 3-methoxyphenylacetic acid by analogous procedures to those described in the portion of Example 1 which is concerned with the preparation of starting materials except that methanol was used in place of ethanol in the esterification step, methyl iodide was used in place of ethyl iodide in the alkylation steps and methanol was used in place of ethanol when the boron tribromide step was quenched. There was thus obtained the required starting material in 30% yield as an oil.
NMR Spectrum: 1.55 (s, 6 H), 3.65 (s, 3 H), 5.30 (broad s, 1 H), 6.71 (m, 1 H), 6.84 (m, 2 H), 7.20 (m, 1 H).
The procedure described in Example 1 was repeated except that 2-chloromethylquinoline hydrochloride was used in place of 2-bromomethylnaphthalene and that a further equivalent of potassium carbonate was added to neutralise the hydrochloride salt. There was thus obtained ethyl 2-ethyl-2-[3-(2-quinolylmethoxy)phenyl]butyrate in 37% as a gum.
NMR Spectrum: 0.70 (t, 6 H), 1.15 (t, 3 H), 2.01 (m, 4 H), 4.08 (q, 2 H), 5.39 (s, 2 H), 6.83-6.92 (m, 2 H), 6.98 (m, 1 H), 7.22 (m, 1 H), 7.52-7.85 (m, 4 H), 8.07-8.24 (m, 2 H).
The procedure described in Example 1 was repeated except that 6-bromomethyl-1-methyl-1,2-dihydroquinolin-2-one (European Patent Application No. 0385662, Example 6, Note a.) was used in place of 2-bromomethylnaphthalene. There was thus obtained ethyl 2-ethyl-2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]butrya te in 56% yield as a gum.
NMR Spectrum 0.7 (t, 6 H), 1.15 (t, 3 H), 1.7-2.15 (m, 4 H), 3.75 (s, 3 H), 4.1 (q, 2 H), 5.1 (s, 2 H), 6.72 (d, 1 H), 6.8-6.95 (m, 3 H), 7.18-7.28 (m, 1 H), 7.35 (d, 1 H), 7.6-7.7 (m, 3 H).
Using an analogous procedure to that described in Example 1, 6-bromomethyl-1-methyl-1,2-dihydroquinolin-2-one was reacted with ethyl 2-(3-hydroxyphenyl)-2-methylbutyrate to give ethyl 2-methyl-2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]butyr ate in 44% yield as a gum.
NMR Spectrum: 0.82 (t, 3 H), 1.17 (t, 3 H), 1.50 (s, 3 H), 1.85-2.15 (m, 2 H), 3.75 (s, 3 H), 4.12 (q, 2 H), 5.12 (s, 2 H), 6.7-6.96 (m, 4 H), 7.22-7.42 (m, 2 H), 7.58-7.72 (m, 3 H).
The ethyl 2-(3-hydroxyphenyl)-2-methylbutyrate used as a starting material was obtained using the procedures described in the portion of Example 1 which is concerned with the preparation of starting materials except that methyl iodide was used in place of ethyl iodide in the second alkylation step. The intermediate so obtained, ethyl 2-(3-methoxyphenyl)-2-methylbutyrate, gave the following characteristic NMR signals: 0.84 (t, 3 H), 1.19 (t, 3 H), 1.5 (s, 3 H), 1.85-2.15 (m, 2 H), 3.8 (s, 3 H), 4.13 (q, 2 H), 6.72-6.92 (m, 3 H), 7.21 (m, 1 H).
Using an analogous procedure to that described in Example 1, 6-bromomethyl-1-methyl-1,2-dihydroquinolin-2-one was reacted with ethyl 2-allyl-2-(3-hydroxyphenyl)butyrate to give ethyl 2-allyl-2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]butyra te in 25% yield as a gum.
NNR Spectrum: 0.75 (t, 3 H), 1.16 (t, 3 H), 2.02 (m, 2 H), 2.75 (m, 2 H), 3.72 (s, 3 H), 4.10 (q, 2 H), 5.05 (m, 2 H), 5.10 (s, 2 H), 5.48 (m, 1 H), 6.72 (d, 1 H), 6.85 (m, 3 H), 7.22 (m, 1 H), 7.48 (d, 1 H), 7.65 (m, 3 H).
The ethyl 2-allyl-2-(3-hydroxyphenyl)butyrate used as a starting material was obtained using the procedures described in the portion of Example 1 which is concerned with the preparation of starting materials except that allyl bromide was used in place of ethyl iodide in the second alkylation step. The intermediate so obtained, ethyl 2-allyl-2-(3-methoxyphenyl)butyrate gave the following characteristic NMR signals: 0.76 (t, 3 H), 1.18 (t, 3 H), 2.05 (m, 2 H), 2.75 (m, 2 H), 3.80 (s, 3 H), 4.15 (q, 2 H), 5.15 (m, 2 H), 5.50 (m, 1 H), 6.80 (m, 3 H), 7.22 (m, 1 H). ##STR2##
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