GB2183637A

GB2183637A - Chemical compounds

Info

Publication number: GB2183637A
Application number: GB08624893A
Authority: GB
Inventors: Charles John Robert Hedgecock; David Alun Rowlands; Peter David Kennewell; Odile Le Martret
Original assignee: Roussel Laboratories Ltd
Current assignee: Roussel Laboratories Ltd
Priority date: 1985-10-18
Filing date: 1986-10-17
Publication date: 1987-06-10
Also published as: FR2588871A1; GB8525716D0; DE3635413A1; NL8602610A; IT1214729B; CH669599A5; IT8648565A0; JPS6299372A; FR2588871B1; GB2183637B; GB8624893D0

Abstract

Novel compounds of formula I <IMAGE> [wherein R1 and R2, which may be the same or different, each represents a hydrogen atom or a straight-chained or branched alkyl group containing from 1 to 4 carbon atoms; and A represents a phenyl group (optionally substituted by one or more halogen atoms or alkyl, trihalogenomethyl, alkoxy, cyclohexyl or heterocyclic (such as, for example, thienyl, furyl, tetrahydrofuranyl or pyridyl) groups)] and salts thereof, have application as medicaments for use as immuno modulators or for use in the treatment of inflammatory diseases or of asthma.

Description

SPECIFICATION Chemical compounds The present invention relates to thiophenacetic acid derivatives, to a process for their preparation, to pharmaceutical compositions containing them and to their application as medicaments.

According to one feature of the invention there are provided compounds of formula I

[wherein R, and R2, which may be the same or different, each represents a hydrogen atom or a straight-chained or branched alkyl group containing from 1 to 4 carbon atoms; and A represents a phenyl group (optionally substituted by one or more halogen atoms or alkyl, trihalogenomethyl, alkoxy, cyclohexyl or heterocyclic (such as, for example, thienyl, furyl, tetrahydrofuranyl or pyridyl) groups)] and salts thereof.

It will be appreciated that certain compounds of formula I may possess one or more asymmetric carbon atoms.

It is therefore to be understood that the present invention relates to all isomers of compounds of formula I and thus, where appropriate, includes compounds of formula I in optically active or racemic form.

The term "straight-chained or branched alkyl group containing from 1 to 4 carbon atoms" as used herein refers to a methyl or ethyl group, or to a straight-chained or branched propyl or butyl group.

The term "halogen atom" as used herein includes, for example, a fluorine, chlorine or bromine atom.

The term "trihalogenomethyl group" as used herein includes, for example, a trifluoromethyl group.

The term "alkoxy group" as used herein includes, for example, a methoxy or ethoxy group, or a straight-chained or branched propoxy or butoxy group.

It will be appreciated that, for pharmaceutical use, the salts referred to above will be physiologically acceptable salts, but other salts may find use, for example in the preparation of compounds of formula I and physiologically acceptable salts thereof. Suitable salts include, for example, alkali metal salts, e.g. sodium or potassium salts.

Preferred compounds according to the invention include those compounds of formula I wherein R1 represents an alkyl group; R2 represents a hydrogen atom or an alkyl group; and A represents a phenyl group.

Particularly preferred compounds according to the invention are: N-hydroxy- -methyl-5-benzoyl-2-thiophenacetamide; N-hydroxy-oc-methyl-5-benzoyl-2-thiophen-N-methyl- acetamide: and N-hydroxy-a-methyl-5-benzoyl-2-thiophen N-isopropyl-acetamide.

The compounds according to the invention may, for example, be prepared by the following process, which process constitutes a further feature of the present invention: Reaction of an acid of formula II

(wherein R1 and A are as hereinbefore defined) with a compound of formula III R2-NH-OH . HCI (III) (wherein R2 is as hereinbefore defined) in the presence of a condensing agent such as, for example, N,N'carbonyldiimidazole.

The reaction is preferably carried out in the presence of an organic solvent such as, for example, dichloromethane.

The compounds of formula II used as starting materials in the above process may, for example, be prepared following the process described in GB-1, 331, 505.

The compounds of formula I obtained from the process according to the invention may subsequently, if desired, be converted into salts thereof, particularly physiologically acceptable salts thereof, for example by conventional methods. Such salts may be prepared in situ in the reaction mixture without the necessity for intermediate isolation of the compounds of formula I themselves. Conversely the salts of the compounds of formula I obtained may, if desired, subsequently be converted into compounds of formula I or into further salts thereof.

The compounds according to the invention possess interesting pharmacological properties; in particular, they have been found, upon testing, to inhibit both the cyclo-oxygenase and the lipoxygenase arachidonic acid pathways. Moreover, they have been found to demonstrate anti-inflammatory activity both in vivo and in vitro, and to inhibit antigen-induced constriction of guinea pig lung in vitro. In view of their pharmacological effects, the compounds according to the invention are suitable for use as medicaments. The present invention therefore provides compounds of formula I and physiologically acceptable salts thereof for use as immunomodulators, and in the treatment of inflammatory diseases and asthma.

According to a still further feature of the present invention there are provided pharmaceutical compositions containing, as active ingredient, at least one compound of formula I as hereinbefore defined or a physiologically acceptable salt thereof in association with one or more inert pharmaceutical carriers and/or excipients.

For pharmaceutical administration the compounds of formula I or their physiologically acceptable salts may be incorporated into compositions currently used in human medicine for oral, rectal or parenteral administration, optionally in combination with other active ingredients. The pharmaceutical compositions may be in either solid or liquid form, using carriers and excipients conventionally employed in the pharmaceutical art. Preferred forms include, for example, plain tablets, coated tablets, capsules, granules, ampoules, suppositories and solutions, e.g.

for injection, prepared in traditional manner.

The active ingredient(s) may be used in conjunction with excipients customarily employed in pharmaceutical compositions such as, for example, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, animal or vegetable fats, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and/or preservatives.

Advantageously the compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient. The total daily dosage will vary depending on the compound used but will generally be within the range of from 1 to 300 mg, preferably from 50 to 200 mg, of active ingredient for administration to adult humans. This dosage may, however, also be varied according to the subjected treated, the route of administration and the complaint concerned.

According to a yet further feature of the present invention there is provided a method for the treatment of a patient suffering from, or susceptible to, inflammatory conditions, asthma or disorders of the immune system which comprises administering to the said patient an effective amount of a compound of formula I as herein before defined or a physiologically acceptable salt thereof.

The following non-limiting Examples serve to illustrate the present invention more fully: Example l:N-Hydroxy-e-methyl-5-benzoyl-2-thiophen-1\{-methylacetamide A solution of α-methyl-5-benzoyl-2-thiophenacetic acid (5 g) in dry CH2CI2 (50 ml) was treated with N,N'-carbonyldiimidazole (4.7 g) with vigorous stirring. After 10 minutes' stirring at room temperature N-methylhydroxylamine hydrochloride (3.2 g) was added. Stirring was continued for 48 hours at room temperature and the solvent was then evaporated. The residue was dissolved in 40% ethyl acetate/petroleum ether and chromatographed (SiO2) to give N-hydroxy--methyl-5-benzoyl-2-thiophen-N-methylacetamide (3.28 g, 59%), m.p. 94-6 C.

I.r.: UOH=3200, oc=o = 1625 cm1.

N.m.r. (DMSO): 10.18 (s, 1 H, OH), 7.81 (dd, 2H, aromatic), 7.50-7.75 (m, 4H, aromatic), 7.13 (d, 1 H, aromatic), 4.75 (q, 1 H, CH), 3.15 (s, 3H, MeN), 1.44 (d, 3H, Me-C).

Analysis (C15H14NO3S) Calc.: C 62.48, H 4.89, N 4.86, S 11.12% Found: C 62.29, H 5.23, N 4.95, S 10.74% Example 2: In a manner analogous to Example 1, but using hydrnxylamine hydrochloride as one of the reactants, N-hydroxy-a-methyl-5-henzoyl-2-thiophenacetamide was obtained.

Example 3: In a manner analogous to Example 1, but using N-isopropylhydroxylamine hydrochloride as one of the reactants, N-hydroxy- -methyl-5-benzoyl-2-thiophen-N-isopropl/lacetamide, m.p.114 C, was obtained.

I.r.: UoH=3100, vzc=o = 1630 cm1.

N.m.r. (DMSO): 9.61 (s, 1 H, OH), 7.80-7.85 (m, 2H, aromatic), 7.70-7.75 (m, 4H, aromatic), 7.10 (d, 1 H, aromatic), 4.50-4.75 (m, 2H, CH), 1.40 (d: J =7 Hz, 3H, CH3), 1.05-1.10 (2xd: J =7 Hz, 6H, isopropyl CHs).

Example 4: Tablets were prepared according to the following formulation: N- Hydroxy-z-methyl-5-benzoyl-2-thiophen- N -methylacetamide . . . .... .... 50 mg Excipient for one tablet up to ...................... ......................... ............... ............... 300 mg (details of the excipient: lactose, starch, talc, magnesium stearate).

Example 5: Tablets were prepared according to the following formulation: N-Hydroxy-α-methyl-5-benzoyl-2-thiophen- N-isopropylacetamide 50 mg Excipient for one tablet up to to................. .......... ............. ................ .......... ............. 300 mg (details of the excipient: lactose, starch, talc, magnesium stearate).

In the following Examples the expression "the compound of Example 1" refers to N-hydroxy-a-methyl-5- benzoyl-2-thiophen-N-methylacetamide.

Example 6: Modulation of arachidonic acid metabolism The compound of Example 1 was evaluated for its ability to inhibit both the cyclo-oxygenase and the lipoxygenase arachidonic acid pathways using two different experimental protocols. In the first of these, rat peritoneal polymorphs were pre-labelled with 3H-arachidonic acid and, after incubation with test compound, were exposed to the calcium ionophore A 23187. The quantity of label released into 5-lipoxygenase or other products was then calculated by t.l.c. The effect of the test compound is expressed in terms of IC50 values (micromolar) for inhibition of total release of label into the supernatant and into 5-lipoxygenase products.

In the second method, guinea-pig peritoneal polymorphs were pre-incubated with test compound before exposure to 3H-arachidonic acid together with the calcium ionophore. This method does not rely on the incorporation of arachidonic acid into the cellular phospholipids; the products of the incubation are separated by t.l.c. into the various arachidonic acid products produced. The effect of the test compound is expressed in terms of IC50 values (micromolar) for inhibition of formation of thromboxane B2 (TxB2), 1 2-hydroxyheptadecatrienoic acid (HHT) and 5-hydroxyeicosatetraenoic acid (5-HETE).

Results: Modulation of arachidonic acid (IC50) N-Hydrnxy-z-methyl-5-benzoyl- a-Methyl-5-benzoyl- 2-thiophen-N-methyl- 2-thiophen acetamide acetic acid Rat polymorph - total release > 1 > 100 - 5-lipox.

products 0.35 < 100 Guinea pig polymorph - TxB2 2.8 < 0.01 - HHT 2.5 < 0.01 - 5-HETE 0.2 > 1 Example 7: Modulation of arachidonic acid metabolism The compounds of formula I were tested as inhibitors of the synthesis of eicosanoids in guinea-pig peritoneal neutrophils, upon the addition of 14C-arachidonic acid and calcium ionophore A 23187, by a modification of the method published by Harvey, J. & Osborne, D.J. (J. Pharmacol. Methods, 1983, 9 [2], 147-55). The results are listed in Table I.

TABLE I

IC50 (micromolar) Guinea-pig polymorph R2 Thromboxane B2 5-HETE H 0.32 10 CH3 2.8 0.22 i-Pr 4.0 0.22 All the compounds showed potent inhibitory effects on the production of thromboxane B2, whilst the latter two compounds also potently inhibit the lipoxygenase enzyme.

Example 8: Anti-inflammatory activity The compound of Example 1 was evaluated in two in vivo tests, namely (i) carrageenan oedema, and (ii) inhibition of cellular accumulation in sponges, and in one in vitro test, namely the inhibition of PAF-induced rat poiymorph aggregation.

In the carrageenan oedema test, the test compound was administered orally 30 minutes before administration of carrageenan and the oedema was measured 3 hours after the administration of carrageenan.

In the sponge implantation model, the test compound was administered orally 30 minutes and 6 hours after implantation and the cells were harvested 24 hours after implantation. The results of these experiments are given in terms of the percentage inhibition of the response.

Anti-inflammatory activity (% inhibition) N - Hydroxy- -methyl- O!- Methyl-5- benzoyl- 5-benzoyl-2-thiophen- 2-thiophen N-methyl- acetic acid acetamide Carrageenan 20 mg/kg p.o. 50.5"" ED30=0.33 mg/kg p.o.

oedema 100 61.8"' Cellular 5 mg/kg p.o. x 2 - 18.5 accumulation 10 23.0"" 25 - 50.9"" 50 32.8"" Polymorph 1,uM 9.2 -13.9 aggregation 10 12.8 100 21.7 24.6 p < 0.005 Example 9: Anti-asthmatic activity The compound of Example 1 was also evaluated for its ability to inhibit antigen-induced constriction in vitro of guinea-pig lung. Lungs were taken from sensitised animals and perfused via the bronchi; oral dosing of compound 30 minutes before exposure to antigen enabled the extent of inhibition of antigen-induced lung dysfunction in sensitised guinea-pigs to be measured.

Anti-asthmatic activity (% inhibition) N- Hydroxy-z-methyl- 5-benzoyl-2-thiophen N-methyl-acetamide Perfused lung 1 -16.7 10 68.3" 100 100 Lung dysfunction 10 mg/kg p.o. -49.0 50 61.3"", 37.4" 100 - 6.7 "p < 0.05; "p < 0.005

Claims

1. Compounds of formula I

[wherein R1 and R2, which may be the same or different, each represents a hydrogen atom or a straight-chained or branched alkyl group containing from 1 to 4 carbon atoms; and A represents a phenyl group (optionally substituted by one or more halogen atoms or alkyl, trihalogenomethyl, alkoxy, cyclohexyl or heterocyclic (such as, for example, thienyl, furyl, tetrahydrofuranyl or pyridyl) groups)] and salts thereof.

2. Compounds as claimed in claim 1 wherein R1 represents an alkyl group; R2 represents a hydrogen atom or an alkyl group; and A represents a phenyl group.

3. N - Hydroxy-z-methyl -5- benzoyl-2-thiophenacetamide and salts thereof.

4. N- Hydroxy-z- methyl-5- benzoyl-2-thiophen- N-methylacetamide and salts thereof.

5. N-Hydroxy- -methyl-5-benzoyl-2-thiophen-N-isopropylacetamide and salts thereof.

6. Compounds as claimed in claim 1 as herein specifically disclosed in any one of the Examples.

7. A process for the preparation of compounds as claimed in claim 1 which comprises reacting an acid of formula II

(wherein R, and A are as defined in claim 1) with a compound of formula Ill R2-NH-OH . HCI (III) (wherein R2 is as defined in claim 1) in the presence of a condensing agent.

8. A process as claimed in claim 7 wherein the condensing agent is N,N'-carbonyldiimidazole.

9. A process as claimed in claim 7 or claim 8 wherein the reaction is effected in the presence of dichloromethane as solvent.

10. A process as claimed in any one of claims 7 to 9 wherein a compound of formula I initially obtained is subsequently converted into a salt thereof, or a salt of a compound of formula I initially obtained is subsequently converted into a compound of formula I or into a further salt thereof.

11. A process for the preparation of compounds as claimed in claim 1 substantially as herein described.

12. A process for the preparation of compounds as claimed in claim 1 substantially as herein described in any one of Examples 1 to 3.

13. Compounds as claimed in claim 1 when prepared by a process as claimed in any one of claims 7 to 12.

14. Compounds of formula I as defined in claim 1 and physiologically acceptable salts thereof for use in therapy.

15. Pharmaceutical compositions containing, as active ingredient, at least one compound of formula I as defined in claim I or a physiologically acceptable salt thereof in association with one or more pharmaceutical carriers or excipients.

16. Compositions as claimed in claim 15 in a form suitable for oral, rectal or parenteral administration.

17. Pharmaceutical compositions as claimed in claim 15 substantially as herein described.

18. Pharmaceutical compositions as claimed in claim 15 substantially as herein described in either of Examples 4 or 5.

19. The use of a compound as claimed in claim 1 in the preparation of a medicament for use as an immunomodulator or for use in the treatment of inflammatory diseases or of asthma.