GB2189486A - Decenyl substituted N-hydroxy-N-methylbenzamides - Google Patents

Decenyl substituted N-hydroxy-N-methylbenzamides Download PDF

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GB2189486A
GB2189486A GB08709011A GB8709011A GB2189486A GB 2189486 A GB2189486 A GB 2189486A GB 08709011 A GB08709011 A GB 08709011A GB 8709011 A GB8709011 A GB 8709011A GB 2189486 A GB2189486 A GB 2189486A
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Charles John Robert Hedgecock
David Alun Rowlands
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Roussel Laboratories Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
    • C07C239/08—Hydroxylamino compounds or their ethers or esters
    • C07C239/14—Hydroxylamino compounds or their ethers or esters having nitrogen atoms of hydroxylamino groups further bound to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/10—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/64—Monocyclic acids with unsaturation outside the aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

GB 2 189 486 A 1
SPECIFICATION
Chemical compounds This invention relates to substituted benzamides, to processes fortheir preparation and to pharmaceutical 5 compositions containing them.
According to one feature of the present invention there are provided compounds of formula 1 0 11 OH 10 c 111 N R --a 1 LM3 (wherein R represents a dec-1 -(E)-enyl or dec-1 -(Z)-enyl group in them orp position) and salts thereof.
Itwill be appreciated that, for pharmaceutical use, the salts referred to above will be physiologically acceptable salts, but other salts mayfind use, for example in the preparation of compounds of formula land physiologically acceptable salts thereof. Suitable salts include, for example, alkali metal salts, e.g. sodium 20 salts.
Particularly preferred compounds according to the invention areas follows:
3-[dec-1 -(Z)-enyl I-N-hyd roxy-N-m ethyl benza m ide; 3-[dec-l-(Z)-enyll-N-hydroxy-N-methyibenzamide, sodium salt; 4-[dec-1 -(E)-enyll-N -hyd roxy-N -methyl benza m ide; 25 3-[dec-l-(E)-enyll-N-hydroxy-N-methyibenzamide, sodium salt; and 4-[dec-l-(Z)-enyll-N-hydroxy-N-methyibenzamide.
The compounds according to the invention may, for example, be prepared by the following process,which process constitutes a furtherfeature of the present invention:
Reaction of a compound of formula IIA 30 COCI -er 35 (wherein R is as hereinbefore defined) with a compound of formula 1113 / H 40 CH3 - N HX (1113) OH 45 (wherein X represents a halogen atom, preferabiya chlorineatom).
The reaction mayconveniently be carried out in the presence of a suitable solvent such asjorexample, tetra hyd rofu ra n:water, ata lowtemperature, e.g. O'C.
The compound of formula IIA mayconveniently be prepared bytreating a compound of formula 11 50 COOH 55 (wherein R isas hereinbefore defined) with a chlorinating agentsuch asjorexample, oxalyl chloride.
The reaction is conveniently carried out inthe presence of an organic solvent such asjorexample, benzene, in the presence of dimethylformamide, ata lowtemperature, e.g. O'C.
2 GB 2 189 486 A 2 The compounds of formula 11 maybe prepared by the following processes, which processes constitute still furtherfeatures of the present invention:
(A). Forthe preparation of compounds of formula 11 wherein R represents a dec-1 -(Z)-enyl group (i.e. compounds of formula H' COOH 5 R L 10 wherein Wrepresents a dec-1 -(Z)-enyl group):
Reaction of a compound of formula Vill 100All 15 R (Viii) 20 (wherein Wis as hereinbefore defined; and Alk represents a C1-6 alkyl group) with a base in the presence of water.
The reaction is conveniently carried out in the presence of an organic cosolvent.
The compound of formula VIII may conveniently be prepared by treating a compound of formula VI 25 0 CO0Atk H-C-Cr- (VI) (wherein Alk is as hereinbefore defined) with the compound of formula W CH3(CH2)8 P e Ph3. Br" (VII) 35 in the presence of a strong base.
The compound of formula VI may conveniently be prepared bytreating a compound of formula V COICIAlk (V) 40 Ha 12HIC --er (wherein Alk is as hereinbefore defined; and Hal represents a halogen atom, preferably a chlorine or bromine 45 atom) with a weak base in the presence of water.
The compound of formula V may conveniently be prepared by treating a compound of formula IV CO0Atk so 50 H3C-Cr (IV) (wherein Alk is as hereinbefore defined) with a halogenating agent such as, for example, chlorine, bromine, 55 N-bromoacetamide or N-bromosuccinimide, in the presence of a radical initiator and in the presence of light.
The compound of formula IV may conveniently be prepared by reacting a carboxylic acid of formula Ill COOH 60 H3C or a functional derivative thereof, with a C1-6 alkanol, or a derivative thereof. 65 3 GB 2 189 486 A 3 (B). Forthe preparation of compounds of formula II wherein R represents a dec-l-(E)-enyl group (i.e. compounds of formula 1V COOH R H wherein W' represents a dec-1 -(E)-enyl group): 10 Isomerisation of a compound of formula H' COOH R (:
(wherein Wis as hereinbefore defined) which may conveniently be carried out in the presence of iodine and light. 20 The reaction is conveniently carried out in the presence of a suitable organicsolvent such asJorexample, dichloromethane.
The compounds of formula 1 obtained from the process according to the invention may subsequently, if desired, be converted into saltsthereof, particularly physiologically acceptable salts thereof, for example by conventional methods. Such salts may be prepared in situ in the reaction mixture withoutthe necessityfor 25 intermediate isolation of the compounds of formula 1 themselves. Converselythe salts of the compounds of formula 1 obtained may, if desired, subsequently be converted into compounds of formula 1 or intofurther saltsthereof.
As mentioned earlier,the compounds according to the invention possess interesting pharmacological properties. In particular, they have been tested in respect of their activity as inhibitors of the synthesisof 30 eicosanoids by guinea pig peritoneal neutrophils following the addition of ["C]-arachidonic acid and calcium ionophore, using a modification of the method published by Harvey, J. and Osborne, D.J. in J. Pharmacol, Methods, 9 [2],147-155 (1983). The compounds according to the invention selectively inhibit 5-lipoxygenase product (5-HETE) synthesis. Less potent effects are shown against cyclooxygenase product (thromboxane B2) synthesis. These data are exhibited in the following Table: 35 1C50 (micromolar) Product of Example Thromboxane82 5-HETE 40 1 0.56 0.04 2 1.2 0.23 3 0.93 0.13 4 0.52 0.11 5 3.3 0.32 45 Such compounds arethus of use in the treatment of inflammatory diseases (including bronchial asthma, rheumatoid arthritis, psoriasis and collitis), immuno-regulatory diseases and cardiovascular diseases, and in othersyndromes in which leukotrienes (the products of the 5-lipoxygenase system) may be implicated. Thus, the present invention provides compounds of formula 1 and physiologically acceptable saltsthereof foruse 50 in therapy.
According to a yet furtherfeature of the present invention there are provided pharmaceutical compositions containing, as active ingredient, at least one compound of formula 1 as hereinbefore defined ora physiologically acceptable saitthereof in association with one or more pharmaceutical carriers andlor excipients. 55 For pharmaceutical administration the compounds of general formula 1 and their physiologically acceptable salts may be incorporated into conventional preparations in either solid or liquid form, optionally in combination with other active ingredients. The compositions may, for example, be presented in a form suitable for oral, rectal, parenteral ortopical administration.
Preferred forms include, for example, plain tablets, coated tablets, capsules, granules, ampoules, 60 suppositories and solutions, e.g. for injection.
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, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and/or preservatives. 65 4 GB 2 189 486 A 4 Advantageously the compositions maybe formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient. Suitable dosage units for administration to adults contain from 10 to 50Orng, preferablyfrom 50 to 250 mg, of active ingredient. The total daily dosage, which maybe varied according to the compound used, the subjecttreated and the complaint concerned, may, for example, be from 50 to 250 mg. 5 According to a still further feature of the present invention, there is provided a method for the treatment of a patient suffering from, or susceptibleto, inflammatory, immuno-regulatory, cardiovascular or related diseases which comprises administering to the said patient an effective amount of a compound of formula 1 as herein before defined or a physiol og icai ly acceptable salt thereof.
The following non-limiting Examples serve to illustrate the present invention more fully. 10 The abbreviations employed throughout the Examples are defined asfollows:
A1BN 2,2'-azobisisobutyronitrile; THF tetrahydrofuran; HMPA hexam ethyl phosphora m i de. 15 Example 1: 3-[Dec-1(Z)-enyll-N-hydroxy-N-methylbenzamide StepA: Methyl ester ofm-toluic acid (methyl m-toluate) 20 m-Toluicacid (100 g, 0.73 mol) in methanol (400 mi)wassaturated with dry HCI and heated under refluxfor 3 hrs. The solution was diluted with a large quantity of water. Theoil which separated outwas removed and the aqueoussolution extracted twice with ether. The combined organic extracts were washed withwater, saturated sodium bicarbonate solution and brine. After drying over M9SO4the solventwas removedin vacuoto leave 108 g of Vellowoil,which was used without further purification. 25 Step 8: Methyl3-formylbenzoate Methyl m-toluate (20 g, 0.13 mol) in CC14(200 m]) was stirred with Nbromosuccinimide (47.5 g,O.26 mol) and A1BN (1 g) underan atmosphere of dry N2. The reaction was irradiatedwith a 100watttungsten lamp close to the flask, whilst being heated undergentle reflux.After40 mins an exothermic reaction took placeto 30 give a pale orange solution. Heating under refluxfora further 1 hr gave a solution which was cooled in icelwater and then filtered. A' H-nmr spectrum of the crude product indicated the formation of the dibromide in approximately 80% yield, accompanied by about 10% of the monobromide.
NMR(CDC13):86.70(s,CHBr2);4.53(s,CH2Br).
The crude dibromide was suspended in water (400 mi) with powdered calcium carbonate (40 g) and heated 35 under refluxfor 3 hrs. The pure product could be isolated either by steam distillation or by ether extraction and chromatography. 16.5 g of methyl 3-formyibenzoate was recovered as a white crystalline solid, m.p.
56-580C (lit. 58OC) (77.5%yield) NMR (CIDC13): 8 10.09 (s, CHO); 8.55 (S), 8.33 (dd), 8.11 (dd), 7.66 (t), aromatic protons; 3.99 (s, CH30).
40 Step C: Methyl3-[dec-1-(Z)-enyll-benzoate (n-Nonyl)triphenylphosphonium bromide (11.4 g, 24.4 mmoi), in dry THF (200 mi) under an N2 atmosphere at -72'C, was treated dropwise with a 1.57 M solution of n-butyllithium in hexane (15.5 m], 24.4 mmol). The solution was stirred for 20 minutes before HMPA (20 mO was slowly added. After 5 minutes methyl 3-formylbenzoate (4 g, 24.4 mmol) in dry THF (50 ml) was added slowly. The reaction was leftto stir, slowly 45 warming to room temperature over 20 hrs. The solventwas removed in vacuo and petroleum ether (60-80'C, mi) was added with vigorous shaking. Water (80 m]) was added, the petrol layer separated and the aqueous layer extracted with further petroleum ether (2 x 50 mi). The combined organic extractswere washed with brine and concentrated to an oil. The productwas purified by flash chromatography in 60-80'C petroleum etherto give 5 g of colourless oil (75% yield). 50 NMR(CDC13):87.28-8.06(4H,m,Ar);6.43(1H,dd,J=11.5,1.5Hz);5.73(1H,dt,J=11.5, 1. 5Hz);3.93(s, CH30); 2.32 (m, CH2-C=Q 0.88 (t, CH3).
]R (film): 1725,767 cm-1.
C18H2602 requires C, 78.79%; H, 9.55%. 55 Found: C, 79.03%; H, 9.65%.
GB 2 189 486 A 5 Step D: 3-[Dec-1-(Z)-enyll-benzoic acid Methyl 3-[dec-l-(Z)-enyll-benzoate (2.2 g, 8 mmol) was dissolved in THFAeOWH20 Q:2:11) (50 mi) at room temperature and stirred with LiOH.H20 (2 g, 48 mmol) for 6 hrs. T.I.c. indicated complete hydrolysis. A drop of bromocresol purple solution was added and the reaction acidified with conc. FIC1 to give a permanentyellow colour. The organic solvents were removed in vacuo and the productwas extracted with ethyl acetate (3 X 50 5 mi). The organic extracts werewashed with brine and dried briefly over M9S04. The isolated yellow oil was purified by flash chromatography to give 1.91 g of a colourless oil which crystallised on standing (91.5% yield). The product, m.p.47-49'C, was recrystallised from petroleum ether (60-80'C)-dichloromethane.
NMR (CIDC13): 88.05 (s, H-2); 7.99 (dt, H-6,J=7,2 Hz); 7.50 (dt, H-4,J=7, 2 Hz); 7.46 (dd, H-5,J=7,7 Hz); 6.46 lo (dt, FIC=C-Ar,J=11 1.5,7 Hz); 5.79 (dt, -C=CHAr,J=11 1.5,7 Hz); 2.34 (ddt, CH2C= C, J=2,7,7 Hz); 0.86 (t, Me). 10 IR (KBr): 2660,2550 (br, COOH), 1685,1395 cm-1.
C17H2402 (260.78) requires C, 78.42%; H, 9.29%.
Found: C, 78.14%; H, 9.30%.
Step E: 3-[Dec- 1-(Z)-enyll-N-hydroxy-N-methylbenzamide 3-[Dec-1 -(Z)-enyi]-benzoic acid (4 g, 15.4 mmol) in dry benzene (40 mi) containing dimethylformamide (1.29 mi, 15.4 mmol), maintained at O'C in an ice/water bath, was treated dro. pwise with oxalyl chloride (2.68 m 1, 30.8 mmol). After 45 m ins petroleum ether (60-80'C, 100 mi) was added and the mixtu re was shaken 20 vigorously. The u pper layer was separated amd the remaining yel low oil was extracted with further petroleum ether (2 x 25 m]). The combined extracts were evaporated and the recovered oil was dissolved in THF: H20 (2:11,45 m 1). N-Methyl hydroxylami ne hydrochloride (1.55 g, 18. 5 mmol) was added to the solution at OOC. After stirring for 20 hrs, slowly warming to room temperature, the TH F was evaporated in vacuo. The crude product was taken up in ether and washed with bri ne. Pu rification by flash ch romatog raphy on 25 deactivated silica gel gave 400 mg ofthe N,O-clisubstituted hyd roxylamine derivative.
N M R (CDC13): 8 7.23-7.89 (811, m, 2 x Ar); 6.38 and 6.34 (2H, 2 X dt, J = 11.5,2.0 Hz, C=CHAr); 5.76 and 5.68 (2H, 2 x dt, J = 11.5,7.0 Hz, HC= C-Ar); 3.54 (s, N Me); 2.24 (4H, m, CF12-C=Q 0.86 (t, Me).
IR (film): 1760,1670,1596,1575 cm-1.
Further elution with 10-15% ethyl acetate - petroleu m ether (60-80'C) gave 3.32 g of the desiredproduct 30 (75% yield) as a colourless oil.
N M R (CIDC13): 8 8.83 (br, Offi; 7.43 (1 H, s, Ar); 7.39 (31A, s, Ar); 6. 40 (dd, J = 11.5,11.8 Hz, C=CHAr); 5.75 (dt, J = 11.5,7.5 Hz, HC= C-Ar); 3.43 (3H, s, MeN); 2.31 (ddt, J = 1.8,7.5,7.5 Hz, CH2C=C), 0.88 (t, Me).
[R (film): 3160 (br), 1610,1595,1575 cm-1.
35 C181H127NO2 (289.43) req u i res C, 74.70%; H, 9.40%; N, 4.84%.
Found: C, 74.47%; H, 9.37%; N, 4.73%.
Example 2:3-[Dec- 1-(Z)-enyll-N-hydroxy-N-methylbenzamide, sodium salt 40 A so] ution of 3-[dec-1 -(Z)-enyl I-N-hyd roxy-N -methyl benzamide (0.78 9, 2.68 mmol) in ethanol (20 ml) was treatedwithOA M sodium hydroxide solution (26.8 mi). Evaporation of solvent under reduced pressure and trituration ofthe residue with cold petroleum ether (40-60OC) gave the title compoundas a white crystalline solid (0.45 g, 54%), m.p. 129-131'C.
NMR (CDC13):86.95-7.22 (4H, m, aromatic); 6.12 (1 H, d,J=12.1 Hz,ArCH=C); 5.50(1H,dt,J=12.1,7.3Hz, 45 ArCH=CH);3.08(3H,s,NCH3);2.17(2H,m,-CH2C=C); 1.10-1.45(12H,m,aliphatic);0. 86(3H,t,CH3).
IR (KBr): 3700-2600 (br), 2920,1590,1200,1160,980 cm-1.
C18HA02Na + 1.75 mol H20 requires so 50 C, 63.04%; H, 8.67%; N, 4.09%.
Found: C, 62.92%; H, 8.50%; N, 3.89%.
Example 3:3-[Dec- 1-(E)-enyll-N-hydroxy-N-methylbenzamide, sodium salt 55 Step A: 3-[Dec- 1-(E)-enyllbenzoic acid A solution of3-[dec-1 -(Z)-enyll-benzoic acid (3.0 9) and iodine (2 crystals) in dichloromethane (100 mi), illuminated with a 1 OOW tungsten lamp, was stirred at room temperature for 18 hours. The solventwas evaporated and the crude product purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to 60 give the title acid (2.9 g, 97%) as a white crystalline solid.
NMR(CDC13):88.10(1H,t,J=2Hz,H-2);7.95(1H,dt,J=2,7Hz,H-6);7.60(1H,dt,J=2, 7Hz, H-4);7.40(1H, dd,J=7,7Hz,H-5);6.25-6.50(2H,m-CH=CH-);2.10-2.40(2H,m,-CH2C=C);1.05-1. 60(12H,m,aiiphatic);0.9 (3H,t,CH3).
6 GB 2 189 486 A 6 Step 8: 3-[Dec- 1-(E)-enyll-N-hydroxy-N-methylbenzamide Asolution of 3-[dec-l-(E)-enyll-benzoic acid (1 g,3.8 mmol) and dimethylformamicle (4drops) in dry benzene (40 mOwas cooledto O'C andtreated dropwisewith oxalyl chloride (0. 8 m], 9.2 mmol). The mixture wasstirredfor30 min, then water was added and the organic layerseparated. The aqueous layerwas extractedwith etherand the combined organicextracts evaporated.The oily residuewas dissolved in 5 THF:water(MA0 mi) and N-methyihydroxylamine hydrochloride (0.4g,4.8 mmol) added. Afterstirring at room temperature for 1 hour, water was added and the product extracted with ether. After drying over M9S04, the solvent was removed in vacuo and the residue purified by flash chromatography (silica gel, n-hexanelether) too give the title compound (0.74 9, 67%) as a colourless oil.
NIVIR (CDC13):87.25-7.55(4H, m, aromatic); 6.20-6.50 (2H, rn,-CH=CH-); 3. 40 (3H,s, NCH3); 2.15-2.30 (2H, 10 rn,-CH2C=C): 1.15-1.60 (12H, m, aiiphatic); 0.90 (3H, t, CH3).
Step C: 3-[Dec- 1-(E)-enyllN-hydroxy-N-methylbenzamide, sodium salt A solution of 34dec-l -(E)-enyll-N -hyd roxy-N -methyl benza mide (1.0 g, 3.5 mmol) in ethanol (20 m]) was treated with 1 M sodium hydroxide solution (3.5 mi). Evaporation of solvent in vacuo and trituration of the residue with cold n-hexane gave the title compound(l.0 g, 92%) as pale yellow crystals, m.p. 88-910C.
NIVIR (CD30D): 8 7.25-8.00 (4H, m, aromatic); 6.20-6.50 (2H, rn,-CH=CH-); 3.30 (3H, s, NCH3); 2.12-2.30 (2H, rn,-CH2C=Q 1.15-1.60 (12H, m, aliphatic); 0.90 (3H, s, CH3).
IR (KBr: 3700-2700 (br), 2920,1560,970 em-'.
20 Example 4: 4-[Dec- 1-(Z)-N-hydroxy-N-methylbenzamide Step A: 4-[Dec1-0-enyll-benzoic acid Asolution of (n-nonyl)tri phenyl phosphon i u m bromide (5.0 g, 10.7 mmol) in dryTHF (50 mi) under dry N2 was cooled to -720C and treated with a 1.6M solution of n-butyllithium in hexane (6.7 mi, 10.7 mmol). After 25 stirring for 30 min, HMPA (4.5 m]) was added dropwise, followed by a solution of methyl 4-formyibenzoate (1.6 g, 9.7 mmol) in dry THF (25 m]). The mixture was stirred for 3.5 hours, then warmed to room temperature, and the solventwas then removed in vacuo. Addition of an n-hexane: ether mixture (9: 1, 100 ml) gave a white precipitate which was removed byfiltration. Evaporation of the filtrate gave crude methyl 4-[dec-1 -(Z)-enyll-benzoate as an oil. 30 The oil was dissolved in TI-IF:rnethanol:water mixture (3:2:1,120 m]) and stirred with LiOH.H2P (10 g) at room temperature for 20 hours. The mixture was acidified with cone. HCl and then the organic solventswere removed in vacuo. The productwas extracted with ether (200 m]), and the organic extract was wpshed with brine, dried over M9S04 and finally evaporated to give a solid which on recrystallisation from n-hexane afforded the title compound(l.65 g, 62%) as a white crystalline solid, m. p. 67-69'C. 35 NIVIR (CDC13): 8 8.08 (2H, dd, J= 1.5,7 Hz, H-2 and H-6); 7.37 (2H, dd, J= 1.5,7 Hz, H-3 and H-5); 6.45 (1 H, broad d, J = 11.5 Hz, ArCH=Q 5.80 (1 H, dt, J=7,11.5 Hz, ArCH=CH-); 2.25- 2.45 (2H, m,-w-CH2C=C); 1.15-1.60 (1 2H, m, aliphatic); 0.88 (3H, t, CH3).
IR (KBr): 3400-2100 (br), 1670,1420,1290,870 em-'.
40 Step 8: 4-[Dec- 1-(Z)-enyll-N-hydroxy-N-methylbenzamide The title compound was prepared, using 4-[dec-1 -(Z)-enyll-benzoic acid (1.0 g, 3.8 mmol), by a method identical to that used forthe preparation of 3-[dec-1 -(E)-enyll-N- hydroxy-N-methyibenzamide. The crude productwas purified byflash chromatography (silica gel, n-hexane) to give the title compound(O.75 g, 68%) as a low-melting white crystalline solid. 45 NIVIR (MCIA: 8 8.00-9.50 (1 H, bs, Offi; 7.47-7.55 (2H, dd, J= 1.5,7 Hz, H-2 and H-6); 7.27-7.37 (2H, dd,J = 1.5, 7 Hz, H-3 and H-5); 6.42 (1 H, broad d, J = 11.5 Hz, ArCH=Q 5.80 (1 H, dt, J=7,11.5 Hz, ArCH=CH-); 3.45 (3H, s, NCH3); 2.20-2.40 (2H, rn,-CH2C=C); 1.15-1.55 (12H, m, aliphatic); 0.88 (3H, t, CH3).
IR (KBr): 3500-2450 (br), 2920,1600,1215 cm-1.
50 ClsH27NO2 requires C, 74.70%; H, 9.40%; N, 4.84%.
Found: C, 74.64%; H, 9.39%; N, 4.72%.
ExampleS:4-[Dec-l-(E)-enyll-N-hydroxy-Nmethylbenzamide 55 Step A: 4-[Dec1- (E)-enyll-benzoic acid The title compoundwas prepared by isomerisation of 4-[dec-1 -(Z)-enyll- benzoic acid, in a manner similar to that used for the preparation of 3-[dec-1 -(E)-enyll-benzoic acid, and was obtained as a white crystal 1 ine solid, m.p. 106-107'C, after purification byflash chromatography (silica gel, n-hexane/ether). 60 NIVIR (CDC13): 8 8.03 (2H, dd, J= 1.5,7 Hz, H-2 and H-6); 7.42 (2H, dd, J= 1.5,7 Hz, H-3 and H-5); 6.30-6.52 (2H, rn,-CH=CH-); 2.15-2.40 (2H, rn,-CH2C=Q 1.10-1.60 (12H, m, aliphatic); 0. 90 (3H, t, CH3).
IR (KBr): 3300-2300 (br), 1670,1420,1285 em-'.
7 GB 2 189 486 A 7 Step 84-[Dec-l-(E)-enyll-N-hydroxy-N-methylbenzamide The title compound was prepared using 4-[dec-l-(E)-enyll-benzoic acid (1. 0 g,3.9 mmol) bya method identical to that used forthe preparation of 3[dec-l-(E)-enyll-N-hydroxy-N-methyibenzamide. Thecrude produetwas purified byflash chromatography (silica gel, n-hexane/ether)to givethe title compound (0.74 g, 67%) as a white crystalline solid, m.p. 78-80'C. 5 NMR (CDC13):87.47 (2H, dd,J=1.5,7 Hz, H-2 and H-6); 7.38 (2H, dd,J=1.5,7 Hz, H-3 and H-5); 6.20-6.45(2H, rn,-CH=CHL); 3.41 (3H,s, NCH3); 2.12-2.30 (2H, m,-CH2C=C); 1.15-1.60 (12H, m, aliphatic); 0.88 (3H,t,CH3). IR (KBr): 3150 (br), 2920,1595,1210,965 em-'.
CisH27NO2 req u i res C, 74.70%; H, 9.40%; N, 4.84%. 10 Found: C, 74.36%; H, 9.26%; N, 4.79%.
Example 6
Tablets were prepared according to the formulation: 15 - compound of Example 1 20 mg - excipient q.s. for one tablet up to 200 mg (details of the excipient: lactose, starch, tale, magnesium stearate). 20 Example 7
Tabletswere prepared according to the formulation:
- compound of Example 4 20 mg 25 - excipient q.s. for onetablet up to 200 mg (details of the excipient: lactose, starch, talc, magnesium stearate).

Claims (27)

CLAIMS 30
1. Compounds of formula 1 0 91 OH 35 R C N 1 M3 40 (wherein R represents a dec-l-(E)-enyl ordec-l-(Z)-enyl groupinthemorp position) and salts thereof.
2. 3-[Dec-l-(Z)-enyll-hydroxy-N-methyibenzamide and its sodium salt.
3. 3-[Dec-l-(E)-enyll-hydroxy-N-methyibenzamide and itssodiumsalt.
4s
4. 4-[Dec-1 -0-enyl 1-hyd roxy-N -methyl benza m idea nd itssodiumsalt. 45
5. 4-[Dec-l-(E)-enyll-hydroxy-N-methyibenzamide and itssodiumsalt.
6. A process for the preparation of a compound offormula 1 as defined inclaim 1 whichcomprises reacting a compound of formula 11A so Oct (IIA) 50 R -er, 55 (wherein R is as defined in claim 1) with a compound of formula llB H CH3 - N HX (11 B)60 OH (wherein X represents a halogen atom).
i J GB 2 189 486 A
7. A process as claimed in claim 6 wherein a compound of formula HB in which X represents a chlorine atom is used.
8. A process as claimed in claim 6 or claim 7 wherein the compound of formula IIA is prepared bytreating a compound of formula 11 5 COOH 10 (wherein R is as defined in claim 1) with a chlorinating agent.
9. A process as claimed in claim 8 wherein the chlorinating agent is oxalyl chloride.
10. A process as claimed in claim 8 or claim 9 wherein a compound of formula 11 15 C OOH 20 in which R represents a dec-1-(Z)-enyl group, is prepared by reacting a compound of formula Vill C 00Atk 25 R' -Cf (VIII) 30 wherein Wrepresents a dec-1-(Z)-enyl group and Alk represents a C1-6 alkyl group, with abase in the presence of water.
11. A process as claimed in claim 10 wherein the compound of formula V111 is prepared by treating a compound of formula V1 0 COIDA1k 35 H C (VI) 40 wherein Alk is as defined in claim 10, with the compound of formula CH3(CH2)8POPh3. BrO (V11) 45 in the presence of a strong base.
12. A process as claimed in claim 8 or claim 9 wherein a compound of formula 11 so COOH 50 R-,C 1.
in which R represents a dec-1-(E)-enyl group is prepared by isomerisation of a compound of formula 11 in 55 which R represents a dec-1-(Z)-enyl group.
13. A process as claimed in claim 12 wherein the isomerisation is carried out in the presence of iodine and light.
14. A process as claimed in anyone of claims 6to 13 wherein a compound of formula] initially obtained is subsequently converted into a saitthereof and/or a salt of a compound of formul& is subsequently 60 converted into a compound of formula 1.
15. A process forthe preparation of compounds as claimed in claim 1 substantially as herein described.
16. A process forthe preparation of compounds as claimed in claim 1 substantially as herein described in anyone of Examples 1 to 5.
9 GB 2 189 486 A 9
17. Compounds of formula 1 as defined in claim land salts thereof whenever prepared by a process as claimed in anyone of claims 6to 16.
18. Compounds as claimed in anyone of claims 1 to 5 for use in therapy.
19. The use of a compound as claimed in anyone of claims 1 to 5forthe manufacture of a medicamentfor the treatment of inflammatory, immuno-regulatory, cardiovascular or related diseases. 5
20. Pharmaceutical compositions comprising, as active ingredient, at least one compound of formula 1 as defined in claim 1 or a physiologically acceptable salt thereof in association with a pharmaceutical carrier and/orexcipient.
21. Compositions as claimed in claim 20 wherein the active ingredient comprises a compound as defined in anyone of claims 2to 5. 10
22. Compositions as claimed in claim 20 or claim 21 in the form of dosage units.
23. Compositions as claimed in claim 22 wherein each dosage unit contains from 10 to 500 mg of active ingredient.
24. Compositions as claimed in claim 23 wherein each dosage unit contains from 50 to 250 mg of active ingredient. is
25. Pharmaceutical compositions as claimed in claim 20 substantially as herein described.
26. Pharmaceutical compositions substantially as herein described in Example 6 or Example 7.
27. Each and every novel method, process, compound and composition herein disclosed.
Printed for Her Majesty's Stationery Office by Croydon Printing Company (U K) Ltd,9187, D89916B5. Published by The Patent Office, 25 Southampton Buildings, London WC2A l AY, from which copies maybe obtained.
GB08709011A 1986-04-16 1987-04-15 Decenyl substituted N-hydroxy-N-methylbenzamides Withdrawn GB2189486A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2602767A1 (en) * 1986-08-12 1988-02-19 Roussel Uclaf NOVEL SUBSTITUTED BENZAMIDES AND THEIR SALTS, PROCESS FOR PREPARING THEM, THEIR APPLICATION AS MEDICAMENTS AND THE COMPOSITIONS COMPRISING THE SAME
WO1998055489A1 (en) * 1997-06-05 1998-12-10 Consortium für elektrochemische Industrie GmbH Multi-constituent system for modifying, degrading or bleaching lignin, materials containing lignin or similar substances, and method for using the same

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0161939A2 (en) * 1984-05-17 1985-11-21 E.R. Squibb & Sons, Inc. Arylhydroxamates

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0161939A2 (en) * 1984-05-17 1985-11-21 E.R. Squibb & Sons, Inc. Arylhydroxamates

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2602767A1 (en) * 1986-08-12 1988-02-19 Roussel Uclaf NOVEL SUBSTITUTED BENZAMIDES AND THEIR SALTS, PROCESS FOR PREPARING THEM, THEIR APPLICATION AS MEDICAMENTS AND THE COMPOSITIONS COMPRISING THE SAME
WO1998055489A1 (en) * 1997-06-05 1998-12-10 Consortium für elektrochemische Industrie GmbH Multi-constituent system for modifying, degrading or bleaching lignin, materials containing lignin or similar substances, and method for using the same

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FR2598409A1 (en) 1987-11-13
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GB8609282D0 (en) 1986-05-21
GB8709011D0 (en) 1987-05-20
JPS62281845A (en) 1987-12-07
IT1205817B (en) 1989-03-31
FR2598409B1 (en) 1990-05-04
CH672919A5 (en) 1990-01-15

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