IE45325B1 - Anti-inflammatory thiophene derivatives - Google Patents

Anti-inflammatory thiophene derivatives

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Publication number
IE45325B1
IE45325B1 IE1585/77A IE158577A IE45325B1 IE 45325 B1 IE45325 B1 IE 45325B1 IE 1585/77 A IE1585/77 A IE 1585/77A IE 158577 A IE158577 A IE 158577A IE 45325 B1 IE45325 B1 IE 45325B1
Authority
IE
Ireland
Prior art keywords
compound
group
formula
thienoyl
phenyl
Prior art date
Application number
IE1585/77A
Other versions
IE45325L (en
Original Assignee
Beecham Group Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beecham Group Ltd filed Critical Beecham Group Ltd
Publication of IE45325L publication Critical patent/IE45325L/en
Publication of IE45325B1 publication Critical patent/IE45325B1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Rheumatology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The compounds of the formula I are obtained by reacting a compound of the formula VI with an acylating derivative of a thienylcarboxylic acid or by reacting thiophene with an acylating derivative of an acid of the formula VII. The compounds which are obtained exhibit an antiinflammatory effect and, in contrast to the acidic antiinflammatory agents, exhibit less tendency to cause gastrointestinal irritations.

Description

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 production. Suprofen has the formula (0): and has been described in Arzneim. Forschung, 25 (11), 1975 and Patent Specification No. *. .3840,0, ’. A group of non-acid anti inflammatory agents has now. been discovered which show a reduced propensity to cause side effects such as gastrointestinal irritancy and which are prepared by a conveniently short synthetic sequence.
Accordingly the present invention provides the compounds of the formula (I): - 2 45325 I wherein A is a -CHRCH.,- cr -CR«CH- group where R is a hydrogen atom or a methyl group attached to the carbon-atom adjacent tv tne-benzene ring and B is a CO, CEOH or CHOCOR3 group where R3 is a group such that HO,COR''' is a pharmaceutically acceptable organic acid oS up to 12 carbon atoms'.
Suitably R3 is a hydrocarbon group such as an alkyl, alkenyl, aryl, or a-alkyl group optionally substituted by alkoxyl, carboxyl, carboxamide, hydroxyl, acyloxy, amino, or salted amino, acylamino, alky lamino, dialkylamino. jQ More suitably R3 is such a group which contains up to carbon atoms.
Preferred groups R3 include the phenyl group, alkyl groups of 1-4 carbon atoms, alkyl groups of 1-4 carbon atoms substituted by a phenyl group, or one of these groups substituted by hydrcyyl, acetoxyl, methoxyl, acetamido, amino, salted amino, C._, alkylamino, di-C1_Jj alkylamino, carboxyl.
Particularly suitable groups R1 include alkyl groups of 1-4 carbon atoms such as the methyl, ethyl, and n-propyl groups. Other groups include the phenyl, benzyl, phenylethyl, acetoxymethyl, mathoxymethyl, hydroxymethyl, aminomethyl, 2-acetoxyphenyi, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl groups. e 45323 II II Aptly E is a CO, CHOH or CHOCOS 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 5 as hereinafter described.
Thus particularly suitable compounds of the include those of the formulae (II) and (III); formula (I) (II) (XII) 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. <3335 A particularly favoured value for the group A in the compounds of the formulae (I), (II) εη-i (III) includes the -CHCH-CH.,- group.
J -feThus further particularly suitable compounds of 5 this invention include those of the formula (IV) and (V): wherein B is as defined in relation to formula (I).
More suitably fi in the compounds of the formulae (IV) and (V) is a Co, CHOH or CKCCOR1 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 s CO group. «53 25 Those compounds of this invention which contain a chiral centre may he 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 5 group more 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. - 6 «5325 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 5 for oral administration.
The composition may be presented as any conventional dosage form such as tablets, capsules, sachets of reconstitutable powder. Most suitably the composition is in the form of a unit dose containing - 600 mg of a compound of the invention, e,g. 50 to 400 mg Such compositions may be .administered once 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, fillin’, tabletting and the compositions may contain conventional excipients such as lubricants, disiiv.egrants, binders, fillers, colouring agents, . on flavour^. ' The compositions may be formulated in known manner as described for such known anti-inflammatory agents as indomethacin, naproxen, ketoprofen, and phenylbutazone ,. - 7 §2325 The present invention provides a process for the preparation of the compounds of the formula (I) which process comprises: (a) the acylation of a compound of the formula (VI): A - B - CH(VI) wherein B1 is a group within B as defined in relation to formula (I) 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 B1 is a CO groups (b) the acylation of thiophene with an acylating derivative of the acid of the formula (VII): wherein B1 is as defined In relation to formula (VI) and thereafter if desired reducing the side chain carboxyl group of a compound wherein B1 is a CO group and thereafter If desired acylating the resulting hydroxyl group with an acylating derivative of a lower alkyl carboxylic acid. 53 3 5 Normally the aromatic acylation is brought about under conventional Friadel Craft acylating conditions, for example by using an acid chloride in the presence of a Lewis acid such as aluminium chloride or antimony chloride in an inert solvent such as carbon disulphide or methylene chloride.
Most suitably the reaction is performed upon a compound of the formula (VI) or (VII) wherein 31 is a CO group.
Those compounds of the invention wherein B is a CHOH 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 . regeneration of the diary! kecone using manganese dioxide in an inert solvent such as benzene.
Process (a) is generally used to provide the parasubstituted compounds of the formulae (II) and (III). Process (b)_ is generally used to provide the. 2-thienyl derivatives within formula {"}. It will be appreciated that such short processes leading to compounds of the invention are vert· convenient.
The following Examples illustrate the invention: - 9 «5325 Example 1 4-[41-(21-Thienoyl)-phenyl]-pentan-2-one To a stirred, mixture of aluminium chloride (39 g) in carbon disulphide (150 ml) at 0°c was added dropwise 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 was decanted 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 (Na^SO^), concentrated by evaporation under reduced pressure and distilled (b.p. I90°/0.08mm). The residual oil crystallised from ethyl acetate/petrol to give pure 4-[4'-(-2,-thienoyl)phenyl]-pentan-2-one, m.p. 60 - l°c. 43323 Example 2 4-C4(2'-Thlenoylj-phenylj-butan-2-one The procedure of Example 1 was used except that benzyl acetone was used in place of the 4-phenylpentan-2-one.
The initially produced somewhat crude product was crystallised from carbon tatrachioride/hexane to give pure 4-E4r-C2'-Thienoyl)-phenyl]-hutan-2-one, m.p.77 - 78°C. - 11 > «5325 Example 3 4-(41-(31-Thienoyl)-phenyl]-butan-2-one To a stirred mixture of 3-thienoyl chloride (3.0 g) and benzyl acetone (3.0 g) at 0°c in methylene chloride (50 ml) was added dropwise over 30 minutes antimony pentachloride (3.3 ml). After the reaction mixture had been left at 0°C 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 amber solution was left for 1 hour at room temperature before being poured onto cold, dilute aqueous hydrochloric acid (about 50 - 60 ml). The aqueous layer was separated, washed with chloroform (2 x 100 ml) and then the combined organic layer was washed successively with dilute aqueous sodium bicarbonate (about 100 ml) and water (about 100 ml), dried (NajSO^) and concentrated by evaporation under reduced pressure. The crude oil (4.4 g) was chromatographed on silica using ether/40-60° 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 of this solid from ether/pentane gave analytically pure 4-[4'-(3'-thienoyl)-phenyl]-butan-2-one, m.p. 63 - 4°C.
Example 4 S-4-£41-(2'-Thlenoyl)-phenyl]-pentan-2-one To a stirred mixture of aluminium trichloride (24.45 g) in carbon disulphide (95 ml) at 0°C was added dropwise over 1 hour a mixture of 3-4-phenyl-pentan-2-one (9.4 g) and uhienyl-2-csrboxylic acid chloride (8.02 g). After the resulting dark solution had been stirred 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 3G0 ml). The crude product was extracted into chloroform (3 x 100 ml), washed with dilute sodium bicarbonate solution (120 ml), dried (Na2SO4), concentrated by evaporation under reduced pressure and distilled at 176-178°/Q,Q8 mm to yield a dark oil (9 g). This was chromatographed on alumina using gradient elution with ether and hexane as eluant.
The resultant analytically pure S-4-[4'-(2'-thienoyl)phenyl]-pentan-2-one (5.9 g) had an optical rotation " 76.53 (benzene).
I, 45325 S-4-phenyl-pentan-2-one was prepared from S-3-phenyl18 ~ butyric acid ([otJD = -60.05 in benzene by the method of H. Rupe, Annelen 1901, 369. 311) via its acid chloride by the following method.
Methyl lithium (100 ml of a 2M solution in ether: 0.2 mole) Was added dropwise at 0°C to cuprous iodide (19 g 0.1 mole) in dry ether (60 ml) under nitrogen. The solution was then stirred for 10 minutes at 0°C, cooled to -65° and S-3-phenyl-hutyroyl chloride (from 4.93 g (0.03 mole) of S-3-phenyl-butyric acid and 10 ml of oxalyl chloride) in dry ether (60 ml) was added slowly. After 15 minutes at -65°, methanol (33 ml) was added dropwise and when the resulting mixture reached -30°C dilute hydrochloric acid was used to neutralise the solution.
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 (NajSO^), concentrated and distilled -.to afford pure S-4-phenyl20 pentan-2-one (4.1 g), b.p. ll0°/ll mm: [ct]*8 = -74.5° (benzene). 4332a Example 5 R-4-[ 4' - (21-Thlenoyl)-phenyl3-pentan-2-one Thia was prepared following the procedure of Example 4 except that R-4-phenyl-pentan-2-one was used as starting material. Pure R-4"i4,-(2,-thienoyl5-phenyl]-pentan-2-one, T £ £ was obtained, fa]* ‘ ~ +72.08 (benzene).
R-4-phenyl-pentan-2-one was prepared from R-3-phenylfcutyric acid ([a]^’^ = 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 (G.34 ml) was added dropwise to dry magnesium (5.33 g). After the exothermic reaction had subsided, ether (35 ml) was added cautiously. Diethyl raalonate (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-2-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 ¢5325 with dilute hydrochloric acid the aqueous layer was extracted with ether and then the combined 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, after work-up in the usual manner, pure R-4-phenyl-peatan-2-one (24.7 g), b.p. 110°/ll mats [α]2θ·θ = +73.0 (benzene). «5328 Example 6 Composition Hard gelatin capsules may each be filled with a mixture of the compound of Example 1 (100 mg) and magnesium stearate (5 mg).
Example 7 Pharmacology The compound of Example 1 showed good activity on the reduction of carrageenin-induced oedema test at 10 mg/kg.
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-JLnduced writhing test the compound of Example 1 had an of 4.2 mg/kg (c.f. 0.78 for suprofen).
The compound of Example 4 produced a 47% inhibition of oedema in the carrageenin test at 125 mg/kg and 52% at 25 mg/kg. On this test the compound of Example 5 produced a 36% inhibition at 125 mg/kg but only 14% at 25 mg/kg.

Claims (5)

1.- 4333S
1. A compound of the formula (I); A - B - CH.
2. A compound as claimed in claim 1 wherein B is a 10 CO, CHOH or CHOCOR group where. R is an alkyl group of 1-4 carbon atoms. 3. '3 wherein A and B are as defined in claims 1 or 2. (III)
3. A compound as claimed in claims 1 or 2 of the formula (11) or (Ill); IS (III A - - B - CH·. '3 (I) wherein A ia a -CHRCHj- or -CR-CH- group where R is a 5 hydrogen atom or a methyl group -attached to the carbon atom acceptable organic acid of up to 12 carbon atoms.
4. A compound as claimed in any of claims 1 to 3 wherein B is a CO or CHOH group. 5. A compound as claimed in any of claims 1 to 4 wherein A is the -CHCHjCHj- group. 5 S. A compound as'claimed in claim 1 of the formula (IV1 or (V): COchch 3 - CH 2 - B - ch 3 (IV) wherein B is as defined in claim 2 4S325 7. A compound as claimed in claim 6 wherein 3 is a CO or CHOH group. 8. A compound as claimed in claim 6 wherein B is a CO group. 5 9. A compound as claimed in any of claims 1 to 8 which has a chiral centre which is in R-, S- or RS- form, 10. A compound as claimed in any of claims 6 to 8 wherein the chiral carbon atom a- to the phenyl ring is in the S- or SR- form. 10 11. 4-[4'-(2'-Thienoyl)-phenyl]-pentan-2-one. 12. 4 - [ 4' - (2'-Thienoyl)-phenyl]-butan-2-one. 13. 4-[4 1 -(3'-Thienoyl)-phenyl]-butan-2-one. 14. S-4-[4'-(2’-Thienoyl)-phenyl]-pentan-2-one. 15. R-4-[4'-(2 1 -Thienoyl)-phenyl]-pentan-2-one. «5325 16. A pharmaceutical composition which comprises a compound as claimed in any of claims 1 to 15 and a pharmaceutically acceptable carrier, 17. A composition as claimed in claim 16 in the form 5 of a unit dose adapted for oral administration and which contains 20 to 600 mg of a compound of any of claims 1 to 15. 18. A process for the preparation of a compound as claimed in claim 1 which process comprises: 10 (a) The acylation of a compound of the formula (VI): B 1 - CH, (VI) wherein B 3 is a group within B as defined in relation to formula (I) but excluding the CHOH group with an acylating derivative of a thienylcarboxylic acid; and thereafter if IS desired reducing the side chain carboxyl group of a compound wherein B 3 is a CO group: 22 «5325 t£>) the acylation of thiophene with an acylating derivative of the acid of the formula (VII}s ho 2 c A - B 1 - CH 3 (VIII wherein B 1 is as defined in relation to formula (VI) 5 and thereafter if desired reducing the side chain carboxyl group of a compound wherein B 1 is a CO group and thereafter if desired acylating the resulting hydroxyl group with an acylating derivative of a lower alkyl carboxylic acid. 10 19* A process as claimed in claim 18 wherein A is CKCCHjJCHj, 20. A process as claimed in claims 18 or 19 wherein B 1 is CO. 21. A process as claimed in any of claims 18 to 21 wherein the acylating derivative of thienylcarhoxylio acid is a 15 thienoyl chloride in the presence of a Lewis acid. 22. A process as claimed in claim 21 wherein the acylating derivative is 2-thienoyl chloride in the presence of aluminium chloride or 3-thienoyl chloride in the presence of antimony pentachloride.
5. 23. A process for the preparation of a compound as claimed in claim 1 said process substantially as described in any of Examples 1 to 5 herein.
IE1585/77A 1976-07-30 1977-07-29 Anti-inflammatory thiophene derivatives IE45325B1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB31852/76A GB1525434A (en) 1976-07-30 1976-07-30 Anti-inflammatory thiophene derivatives

Publications (2)

Publication Number Publication Date
IE45325L IE45325L (en) 1978-01-30
IE45325B1 true IE45325B1 (en) 1982-07-28

Family

ID=10329363

Family Applications (1)

Application Number Title Priority Date Filing Date
IE1585/77A IE45325B1 (en) 1976-07-30 1977-07-29 Anti-inflammatory thiophene derivatives

Country Status (16)

Country Link
JP (1) JPS5318558A (en)
AT (1) AT361466B (en)
AU (1) AU507121B2 (en)
BE (1) BE857128A (en)
CA (1) CA1078400A (en)
CH (1) CH636613A5 (en)
DE (1) DE2733683A1 (en)
DK (1) DK339877A (en)
ES (1) ES461037A1 (en)
FR (1) FR2359837A1 (en)
GB (1) GB1525434A (en)
IE (1) IE45325B1 (en)
IL (1) IL52503A (en)
NL (1) NL7708062A (en)
SE (1) SE7708591L (en)
ZA (1) ZA774222B (en)

Also Published As

Publication number Publication date
CA1078400A (en) 1980-05-27
FR2359837B1 (en) 1980-04-04
IL52503A0 (en) 1977-10-31
CH636613A5 (en) 1983-06-15
ZA774222B (en) 1978-06-28
BE857128A (en) 1978-01-25
ATA560477A (en) 1980-08-15
AT361466B (en) 1981-03-10
GB1525434A (en) 1978-09-20
FR2359837A1 (en) 1978-02-24
SE7708591L (en) 1978-01-31
IE45325L (en) 1978-01-30
DE2733683A1 (en) 1978-02-02
NL7708062A (en) 1978-02-01
AU507121B2 (en) 1980-02-07
IL52503A (en) 1981-06-29
AU2747177A (en) 1979-02-01
ES461037A1 (en) 1978-12-01
DK339877A (en) 1978-01-31
JPS5318558A (en) 1978-02-20

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