CA1078400A - Anti-inflammatory compounds - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Compounds of the formula (I) are disclosed:

Description

34~
The present invention relates to thiophene derivatives, to their preparation and to compositions containing them.
Acidic anti-inflammatory agents such as suprofen tend to suffer from gastro-intestinal side effects.
Furthermore such compounds require somewhat long synthetic sequences for productionO Suprofen has the formula (O):

~ CO ~ CHC02H Co~

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and has been described in Arzneim. Forschung, 25 (11), 1975 and U.~. Patent No. 1,446,239. A group of non-acid anti-inflammatory agents has now been discovered which show a reduced propensity to cause slde effects such as gastro-; intestinal irritancy and which are prepared by a _ conveniently short synthetic sequence.
Accordingly the present invention provides the compounds of the formula (I):
O

; ~ ~ ~ 3 - C~3 (I~

;:

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:~(371~400 .~ wherein A is a -CHRCH2- or -CR=CH- group ~here R is a hydrogen atom or a methyl group and B is a CO, C~OH or ` C~OCORl group where Rl is a group such ~at HO.CORl is a pharmaceutically acceptable organic acid o~ up to 12 car~on atoms.
Suitably Rl is a hydrocarbon group such as an alkyl, alkenyl, aryl, aralkyl or like group optionally substituted by alkoxyl, carboxyl, carboxamide, hydroxyl, acyloxy, amino, or salted amino, acylamino, alkylamino,dialkylamino .. 10 or the like. More suitably Rl is such a gxoup which contains s up to 8 carbon atoms.
Preferred groups Rl include the phenyl group, alkyl ~- groups of 1-4 carbon atoms, alkyl groups of1-4 carbon . atoms substituted by a phenyl group, or one of these ~: 15 groups substituted by hydxoxyl, acetoxyl, methoxyl, acetamido, amino, saltèd`amino, Cl_4 alkylamino, di-Cl 4 alkylamino, .` carboxyl or the like groups.
Particularly suitable groups Rl include alkyl groups -of 1-4 carbon atoms such as the methyl, ethyl, and n-propyl ~ 20 groups. Other groups include the phenyl, benzyl, phenyl-ethyl, acetoxymethyl, methoxymethyl, hydroxymethyl, amino-methyl, 2-acetoxyphenyl, 4-~etnoxyphenyl, 3,4-dimethoxy-phenyl, 3,4,5-trimethoxyphenyl or the like groups.

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-` 10784~0 Aptly B is a CO, CHOH or CHOCOR group where R is an alkyl group of 1-4 carbon atoms.
Most suitably the phenyl moiety is 1-4 disubstituted ; as such compounds are particularly conveniently synthesised S as hereinafter described.
Thus particularly suitable compounds of the formula (I) include those of the formulae (II) and (III):
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` ~ CO ~ A - B - CH3 (II) .
`'i ~ CO ~ ~ - ~ - CH3 (III) .

wherein A and B are as defined in relation to formula (I)~
Favoured values for the group B in the compounds of the formulae (I), (II) and (III~ include the CO and CHOH groups.

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78~00 :' A particularly favoured value for the gxoup A in the compounds of the formulae (I~, (II~ and (III) includes ihe -CHCH3CH2- group, Thus further particularly suitable compounds of S this invention include those of the formula (IV) and (V):

CO ~ CHCH3 - CH2 - B - CH3 (IV) , .

CO ~ CHCH3 ~ CH2 - B - CH3 (V) , . ~

wherein B is as defined in relation to formula (I).
More suitably B the compounds of t~e formulae (IV) and (V) is a CO, CHOH or CHOCORl group.
Yet more favourably B in the compounds of the formulae (IV) and (V) is a CO or CHOH group.
Preferably B in the compounds of the formulae (IV) and (V) is a CO group.

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Of all the aforementioned compounds, the most generally preferred according to the invention, and to which the claims ars broadly directed, are those of formula ;~ ~ CN~CN2 - ~0 - CN3 wherein R is a hydrogen atom or methyl group.
Those compounds of this invention which contain a chiral centre may be in the form of R or S isomers or mixtures thereof such as the R,S-form about that centre.
Those compounds in which the group A is a CHCH3CH2 group more 10 suitably have the S- or R,S- conformation about the chiral centre as the ~-S- compounds are more potent anti-inflammatory agents than the corresponding R- compounds.
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The present invention also provides a pharmaceutical composition which comprises a compound of the formula (I) and a pharmaceutically acceptable carrier.
Normally the composition of this invention is adapted for oral administration.
The composition may be presented as any conventional dosage form such as tablets, capsules, sachets of reconstitutable powder or the like. Most suitably the composition is in the form of a unit dose containing 20 - 600 mg of a compound of the inventioni e.g. 50 to 400 mg.
Such compositions ~ay be administ~ed Dnce or more times per day so that the total daily dose for a 70 kg adult will be in the order of 40 - 1200 mg, for example 100 - 600 mg.
The compositions may be prepared in conventional manner by mixing, filling, tabletting and the like and the compositions may contain conventional excipients such as lubricants, disintegrants, binders, fillers, colouring agents, fiavours and the like. The compositions may be formulated in known manner as described for such known anti-inflammatory agents as indomethacin, naproxen, ketoprofen, phenylbutazone or the like.

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The present invention provides a process for the preparation of the compounds of the formula (I) which process com~rises:
J (a) the acylation of a compo~md of the formula (VI~:

B - C~3 (VI) wherein Bl is a gxoup within B as defined in relation to formula tI) but excluding the CHOH group with an acylating derivative of a thienylcarboxylic acid; and , thereafter if desired reducing the side chain carboxyl : group of a compound wherein Bl is a CO group:
(b) the acylation of thiophene with an acylating derivative of the acid of the formula (VII):

. ~ A - Bl - CH3 (VII) ~ . .
wherein B is as defined in relation to formula (VI~
and thereafter if desired reducing the side chain carboxyl ~ group of a compound wherein B i~ a CO group and thereafter ; 15 if desired acylating the xesulting hydroxyl group with ~ an acylating derivative of a lower alkyl carboxylic acid.

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` i~78400 Normally the aromatic acylation is brought about under conventional Friedel Craft acylating conditions~
~; for example by using an acid chloride in the presence of a Lewis acid such as aluminium chloride or antimony S chloride in an inert solvent such as carbon disulphide or methylene chloride.
Most suitably the reaction is performed upon a compound of the ~ormula (VI) or (VII) wherein Bl is a CO group.
Those compounds of the invention wherein B is a C~OH group may be prepared by reducing the corresponding compound wherein B is a CO group using sodium borohydride . in a solvent such as ethanol or by using lithium aluminium hydride in a solvent such as diethyl ether followed by -regenèration ofthe diaryl ketone using manganese dioxide in an inert solvent such as benzene.
Process (a) is generally used to provide the para-substituted compounds of the formulae (II) and (III).
. Process~ (b)_is genera~ly used to provide the 2-thiènyl --; 20 derivatives within formula tI). It will be appreciated that such short processes leading to compounds of the invention are very convenient.
The following Examples illustrate the invention:

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~71~400 Example 1 4-[4'-(2'-Thienoyl)-phenyl]-pentan-2-one To a stirred mlxture of aluminiumchloride (39 g) in carbon disulphide (150 ml) at 0C was added dropwise ; 5 over 1 hour a mixture of 4-phenyl-pentan-2-one (15 g) . and thienyl-2-carboxylic acid chloride (12.8 g). After ~ . the resulting dark solution had been left at room temperature ;~ overnight, the top layer wasdecanted off and the lower, more viscous layer was poured carefully onto cold water (about 500 ml). The crude product was extracted into chloroform (3 x 150 ml).~washed with dilute sodium bicarbonate solution (200 ml), dried (Na2SO4), concentrated by evaporation under reduced pressure and d~stilled (b.p. 190/0.08mm). The residual oil crystallised ~rom ethyl acetate/petrol to give pure 4-~4'-~2'-thienoyl)-phenyl]-pentan-2-one, m.p. 60 - 1C.

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~ y -1~37~400 Example 2 4-[4'-(2'-Thienoyl)-phenyl]-k~ltan-2-one The procedure of Example 1 was used except that benzyl acetone was used in place of the 4-phenylpentan-2-one.
S The initially produced somewhat crude product was crystallised from carbon tetrachloride/hexane to give pure;
4-E4r-~21-ThienoylJ-phenyII-hutan-2-one, m.p. 77 - 78C.

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~C~78400 Example 3 4-[4'-(3'-Thienoyl)-~henyl]-~utan-2-one `:

To a stirred mixture of 3-thienoyl chloride ~3.0 g) and benzyl acetone (3.0 g) at 0~ in methylene chloride (50 ml) was added dropwise over 30 minutes antimony pentachloride (3.3 ml). After the reaction mixture had been left at ` 0C for a further 30 minutes and then at room temperature for 3 hours, more antimony pentachloride (3.3 ml) was added dropwise and then the a~ber solution was Left for 1 hour at room tempera~ure be$ore-being poured onto cold. dilute `i aqueous hydrochloric acid (about 50 - 60 ml). The - aqueous layer was sepa~ated, washed with chloroform (2 x 100 ml) and then the combine~ organic layer was washed successivel~ with dilute aqueous sodium bicarbonate (about 100 ml~ and water (about 100 ml), dried (Na2S04) and concentrated by evaporation under reduced pressure. The crude oil (4.4 g) was chromatographed on silica using '' ether/40-50 petrol as eluant to afford a pale yellow ~, oil which slowly solidified on standing (1.1 g) to a pale amber coloured solid. This material was rechromatographed to yield a colourless solid (400 mg). Recrystallisation t of this solicl from ether/pentane gave analytically pure 4-~4'-(3'-thienoyl)-phenyl]-butan-2-one, m.p. 63 - 4C.

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Example 4 S-4-[4'-(2'-Thienoyl)-phenyl]-pentan-2-one To a stirred mixture of aluminium trichloride (24.45 g) in carbon disulphide (95 ml) at 0C was added dropwise over 1 hour a mixture of S-4-~henyl-pentan- -one (3.4 g) and thienyl-2-carboxylic acid chloride (8.02 g). After the resulting dark solution had been s~tirxed for 24 hours at room temperature, the top layer was decanted off and the lower viscous layer was poured carfully into ice cold dilute hydrochloric acid (about 300 ml). The crude product was extracted into chloroform (3 x 100 ml), washed with dilute sodium ~icarbonate solution (120 ml), dried (Na2SO4), concentrated by evaporation under reduced pres~ure~and distilled at l~6 178Q,~a,q8 mm to ~ield a dark oil (9 g). This was chromatographed on alumina using gradient elution with ether and hexane a- eluant.
The resultant analytically pure S-4-~4'-t2'-thienoyl)-phenyl]-pentan-2-one (5.9 g) had an optical rotation 18-5 = -76.53 (benzene) .. . . .

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S-4-phenyl-pentan-2-one was prepared from S-3-phenyl-butyric acid (~]D = -60.05 in benzene by the method of H. Rupe, Annelen 1901, 369, 311) via its acid chloride by the following method.
S Methyl lithium (100 ml o~ a 2M solution in ether:
0.2 mole) was added dropwise at 0C to cuprous iodide (19 g:
0.1 mole) in dry ether (60 ml) under nitrogen. The ` solution was then stirred for 10 minutes at 0C, cooled to -65 and S-3-phenyl-butyroyl chloride (from 4.93 g (0.03 mole) of S-3-phenyl-butyric ac~dand 10 ml of oxalyl chloride) in dry ether (60 ml) was added slo~ly. After .
15 minutes at -65, methanol (33 ml) was added dropwise and when the resulting mixture reached -30C dilute ~-- hydrochloric acid was used to neutralise the solution.
~ 15 After filtration through Kieselguhr, the ether layer was ;; .
separated and the aqueous layer further extracted with ;~ ether. The combined organic layer was then washed with . . .
; water, dilute aqueous sodium bicarbonate, dried (Na2S04), concentrated and distilled :to a~ford pure S-4-phenyl-pentan-2-one (4.1 g), b.p. 110 /11 mm: ~]D = ~74 5 (benzene).
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Example 5 R-4-[4'-(2'-Thienoyl)-phen~1]-pentan-2~-one This was prepared follow:ing the procedure of Example 4 except that R-4-phenyl-pentan--2-one was used as starting material. Pure R-4-~4'-(2'-thienoyl)-phenyl]-pentan-2-one, was o~tained, [a]l8 5 = +72.08 ~benzene).

,' ' R-4-phenyl-pentan-2-one was prepared from R-3-phenyl-butyric acid (t~]D3-3 = 57.12 in benzene by the method of A. Weidler and G. Bergson, Acta. Chem. Scand., 1964, 18, 1484) via its acid chloride as follows.
A mixture of~ethanol (1.7 ml) and carbon tetrachloride (0.34 ml) was added dropwise to dry magnesium (5.33 g).
, After the exothermic reaction had subsided, ether (35 ml) ; was added cautiously. Diethyl malonate (35.56 g), ether (35 ml)and ethanol (17.5 ml) were added at such a rate as to maintain reflux which was then continued overnight. To the resulting stirred solution was added dropwise R-3-phenyl-butyroyl chloride (from 28.29 g of R-3-phenyl-butyric acid and oxalyl chloride) in ether (100 ml) to maintain reflux which was then continued for a further hour after addition. After acidification .
. _ 1~8~10 .
with dilute hydrochloric acid the aqueous layer was extracted with ether and then the com~ined organic layer : washed with water and concentrated. Treatment of the resulting crude oil with dimethyl sulphoxide ~45 ml) and water (7 ml) at 140 for 5 hours gave, a~ter work-up in the usual manner, pure R-4-phenyl-pentan-2-one (24.7 g), b.p. 110/11 mm: []D' = +73,0 (benzene).

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~378400 Example 6 Composition Hard gelatin capsules may each ~e filled ~it~ a mixture of the compound of Example 1 (lOa mg~ and magnesiu~ stearate (5 mg~.
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Example 7 Pharmacology ; The compound of Example 1 showed good activity on the reduction of carrageenin induced oedema test at 10 mg/kg.
S At 10 mg/kg the compound of Example 1 did not cause severe irritation to the stomachs of the test animals.
When tested on the phenylquinone induced writhing test the compound of Example 1 had an ED50 of 4.2 mg/kg tc.f. 0.78 for suprofen~.
The compound of Example 4 produced a 47~ inhi~itlon of oedema in the carrageenin test at 125 mg/kg and 52 at 25 mg/kg. On this tPst the compound of Example 5 produced a 36~ inhibition at 125 mg/kg but only 14 at 25 mg/kg.

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Claims (15)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY OR
PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a compound of formula wherein R is a hydrogen atom or methyl group which comprises (a) acylating a compound of the formula wherein R is as defined, with an acylating derivative of a thienyl carboxylic acid; or (b) acylating thiophene with an acylating derivative of an acid of formula wherein R is as defined; and recovering the required compound.

2. A compound of the formula wherein R is hydrogen or methyl, when prepared by the process of claim 1(a) or 1(b) or an obvious chemical equivalent.

3. A process as claimed in claim 1(a) wherein the acylating derivative is a thienoyl choride in the presence of a Lewis acid.

4. A process as claimed in claim 3 wherein the acylating derivative is 2-thienoyl chloride in the presence of aluminum chloride.

5. A process as claimed in claim 3 wherein the acylating derivative is 3-thienoyl chloride in the presence of antimony pentachloride.

6. A process for the preparation of the compound 4-[4'-(2'-thienoyl)-phenyl]-pentan-2-one which comprises reacting 4-phenyl--pentan-2-one in an inert solvent with thienyl-2-carboxylic acid chloride in the presence of aluminum chloride and recovering the required compound.

7. 4-[4'-(2'-thienoyl)-phenyl]-pentan-2-one when prepared by the process of claim 6 or an obvious chemical equivalent.

8. A process for the preparation of the compound 4-[4'-(2'-thienoyl)-phenyl]-butan-2-one which comprises reacting benzyl acetone in an inert solvent with thienyl-2-carboxylic acid chloride in the presence of aluminum chloride and recovering the required compound.

9. 4-[4'-(2'-thienoyl)-phenyl]-butan-2-one when prepared by the process of claim 8 or an obvious chemical equivalent.

10. A process for the preparation of the compound 4-[4'-(3'-thienoyl)-phenyl]-butan-2-one which comprises reacting benzoyl acetone with 3-thienoyl chloride in an inert solvent in the presence of antimony pentachloride and recovering the required compound.

11. 4-[4'-(3'-thienoyl)-phenyl]-butan-2-one when prepared by the process of claim 10 or an obvious chemical equivalent.

12. A process for the preparation of the isomer S-4-[4'-(2'-thienoyl)-phenyl]-pentan-2-one which comprises reacting S-4--phenyl-pentan-2-one with thienyl-2-carboxylic acid chloride in an inert solvent in the presence of aluminum trichloride and recovering the required isomer.

13. S-4-[4'-(2'-thienoyl)-phenyl]-pentan-2-one when prepared by the process of claim 12 or an obvious chemical equivalent.

14. A process for the preparation of the isomer R-4-[4'-(2'-thienoyl)-phenyl]-pentan-2-one which comprises reacting R-4--phenyl-pentan-2-one with thienyl-2-carboxylic acid chloride in an inert solvent in the presence of aluminum trichloride and recovering the required isomer.

15. R-4-[4'-(2'-thienoyl)-phenyl]-pentan-2-one when prepared by the process of claim 14 or an obvious chemical equivalent.