GB2196629A - Chemical compounds hydroxamic acids as anti-leukotriene agents - Google Patents

Abstract

Compounds of formula I <IMAGE> [wherein R1 represents a group of formula <IMAGE> represents an unsaturated aliphatic hydrocarbylene group containing 3 to 19 carbon atoms); a group of formula R3-C IDENTICAL C- (in which R3 represents a hydrogen atom or a saturated or unsaturated aliphatic hydrocarbyl group containing 1 to 18 carbon atoms); or a group of formula R4-S- (in which R4 represents an aliphatic hydrocarbyl group containing 1 to 20 carbon atoms); R2 represents a C1-6 alkyl group, a C3-7 cycloalkyl group or a substituted or unsubstituted aryl group: and n is 0 or 1] and salts thereof possess interesting pharmacological properties. The compounds are anti-leukotriene agents and may be used in inflammatory, immuno-regulatory and cardio-vascular diseases.

Description

SPECIFICATION Chemical compounds This invention relates to substituted benzamides, to processes for their preparation and to pharmaceutical compositions containing them.

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

[wherein R1 represents a group of formula

(in which

represents an unsaturated aliphatic hydrocarbylene group containing 3 to 19 carbon atoms); a group of formula R-C=-C- (in which R3 represents a hydrogen atom or a saturated or unsaturated aliphatic hydrocarbyl group containing 1 to 18 carbon atoms); or a group of formula R4-S (in which R4 represents an aliphatic hydrocarbyl group containing 1 to 20 carbon atoms); R2 represents a C1-6 alkyl group, a C37 cycloalkyl group or a substituted or unsubstituted aryl group; and n is O or 1] and salts thereof.

Where R1 represents a group of formula

this may for example be a C4 20 polyalkenyl group. Where R1 represents a group of formula R3-C=C-, this may for example be a C2 20 alkynyl group or a C4 20 polyalkynyl group. Where R1 represents a group of formula R4-S-, this may for example be a C1-20 alkylthio group, a C2 20 alkenylthio group, a C2 20 alkynlthio group, a C4-20 polyalkenylthio group or a C4-20 polyalkynylthio group.

Alternatively, in R1 mixed unsaturated (i.e. both double and triple bonds) may be present.

The term "C4 20 polyaikenyl group" as used herein includes, for example, a 1,3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 1,3,5-hexatrienyl, 1 3-octadienyl, 1,4-octadienyl, 1,5-octadienyi, 1,6-octadienyl, 1 ,3,5-octatrienyl, 1,3,6-octatrienyl, 1,3,7-octatrienyl, 1,3,5,7-octatetraenyl, 1,3-undecadienyl, 1,4-undecadienyl, 1,5-undecadienyl, 1,7-undecadienyl, 1,1 0-undecadienyl, 1 ,3,5-undecatrienyl, 1 ,3,8-undecatrienyl, 1,3,5,7-undecatet raenyl, 1,3-hexadecadienyi, 1,7-hexadecadienyi, 1,3,5-heaxdecatrienyl, 1,4,7-heaxdecatrienyl, 1,3,5,8-hexadecatetraenyl, 1,3-eicosadienyl, 1,4-eicosadienyl, 1,3,8-eicosatrienyl or 1,3,16-eico satrienyl group.

The term ''C2-20 alkynyl group" as used herein includes, for example, an ethynyl group, or a straight-chained or branched 1-propynyl, 1-butynyl, 1-pentynyl, 1-hexynyl, 1-octynyl, 1-undecy- nyl, 1-tetradecynyl, 1-heptadecynyl or 1-eicosynyl group.

The term "C4 20 polyalkynyl group" as used herein includes, for example, a 1,3-butadiynyl, 1,3-pentadiynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 1,3,5-hexatriynyl, 1,3-octadiynyl, 1,5-octadiynyl, 1 ,3,5-octatriynyl, 1,3,7-octatriynyl, 1,3,5,7-octatetraynyl, 1,3-undecadiynyl, 1,5 undecadiynyl, 1 ,7-undecadiynyl, 1,3,5-undecatriynyl, 1,3,8-undecatriynyl, 1,3,5,7-undecatetraynyl, 1,3-hexadecadiynyl, 1 ,7-hexadecadiynyl, 1 ,4,7-hexadecatriynyl, 1,3,5,8-heaxdecatetraynyl, 1,3-eicosadiynyl, 1,4-eicosadiynyl, 1 ,3,8-eicosatriynyl or 1,3,16-eicosatriynyl group.

The term "C12o alkylthio group" as used herein includes, for example, a methylthio or ethyl thio group, or a straight-chained or branched propylthio, butylthio, pentylthio, hexylthio, octylthio, decylthio, undecylthio, tetradecylthio, heptadecylthio or eicosylthio group.

The term "C16 alkyl group" as used herein refers to a methyl or ethyl group, or a straightchained or branched propyl, butyl, pentyl or hexyl group.

The term "C37 cycloalkyl group" as used herein refers to a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group.

The term "a substituted or unsubstituted aryl group" as used herein includes, for example, an unsubstituted phenyl group or a phenyl group substituted by one or more halogen atoms, by a C16 alkyl group, or by a trifluoromethyl or nitro 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 salts.

Preferred compounds according to the invention include those compounds of formula I and salts thereof wherein R, represents a C4 20 dialkenyl group, a C6 20 trialkenyl group, a C2 20 alkynyl group, a C4 20 dialkynyl group, a C6 20 trialkynyl group or a C1 20 alkylthio group; R2 represents a C1 6 alkyl group, a C37 cycloalkyl group or a substituted or unsubstituted aryl group; and n is O or 1.

Mention may also be made of those compounds of formula I and salts thereof wherein Ri represents a C2 20 alkynyl group or a C1 20 alkylthio group; R2 represents a C15 alkyl group, a C37 cycloalkyl group or a substituted or unsubstituted aryl group; and n is O or 1.

Particularly preferred compounds according to the invention are as follows: N-hydroxyl-N-methyl-4-(octylthio)-benzamide; N-hydroxyl-N-methyl-3-(oct-l-ynyl)-benzamide; 3-(dec-l-ynyl)-N-hydroxy-N-methylbenzamide; 4-(dec-l-ynyl)-N-hydroxy-N-methylbenzamide; 3-(dec-l-ynyl)-N-hydroxy-N-methylcinnamamide; and salts thereof.

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 a compound of formula Ill

(wherein R1 and n are as hereinbefore defined and Hal represents a halogen atom, preferably a chlorine atom) with a compound of formula IV R2-NHOH. HX (IV) (wherein R2 is as hereinbefore defined and X represents a halogen atom, preferably a chlorine atom) and, if desired, subsequent salification of the compound of formula I thereby obtained.

The reaction may conveniently be carried out in the presence of a suitable solvent such as, for example, tetrahydrofuran/water, at a low temperature, e.g. 0 C.

The compound of formula Ill may conveniently be prepared by treating a compound of formula il

(wherein R, and n are as hereinbefore defined) with a halogenating agent, e.g. a chorinating agent such as, for example, oxalyl chloride, The reaction is conveniently carried out in the presence of an organic solvent such as, for example, benzene, in the presence of dimenylformamide, at a low temperature, e.g. 0 C.

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 Th 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, 5 10 15 20 25 30 35 40 45 50 55 60 65 subsequently be converted into compounds of formula I or into further salts thereof.

The compounds of formula II, when they are not already known, may be prepared by the following processes, which processes constitute still further features of the present invention: Process A: For the preparation of a compound of formula ll wherein R, represents a group of formula

(i.e. a compound of formula IIA

wherein

and n are as hereinbefore defined): Reaction of a compound of formula VII

(wherein

and n are hereinbefore defined and Alk represents a C16 alkyl group) with a base in the presence of water, followed by acidification of the resulting reaction mixture.

The reaction is conveniently carried out using lithium hydroxide monohydrate as the base, and in the presence of an organic cosolvent, e.g. tetrahydrofuran/methanol.

The compound of formula VII may conveniently be prepared by reacting a compound formula V

(wherein Alk is as hereinbefore defined) with a compound of formula VI

(wherein

is as hereinbefore defined; and YB represents a halide ion, preferably a bromide ion) in the presence of a strong base.

The reaction may, for example, be carried out using an alkyl lithium (e.g. n-butyllithium) as the base, in the presence of an organic solvent (such as, for example, tetrahydrofuran), conveniently in the presence of a co-solvent (such as, for example, hexamethylphosphoramide), at a low temperature, e.g. -78"C.

Under appropriate reaction conditions, the double bond in the 1-position of the R1 side-chain of the compound of formula IIA may become isomerised in situ so as ultimately to reside in the 2-position; such a process is desecribed in the Experimental section hereinbelow.

Process B: For the preparation of a compound of formula II wherein R1 represents a group of formula R3-C=C- (i.e. a compound of formula IIB

wherein R3 and n are as hereinbefore defined): Reaction of a compound of formula X

(wherein R3, n and Alk are as hereinbefore defined) with a base in the presence of water, followed by acidification of the resulting reaction mixture.

The reaction is conveniently carried out using lithium hydroxide monohydrate as the base, and in the presence of an organic cosolvent, e.g. tetrahydrofuran/methanol.

The compound of formula X may conveniently be prepared by reacting a compound of formula VIII

(wherein n and Alk are as hereinbefore defined; and Hal represents a halogen atom, preferably a bromine atom) with a compound of formula IX R3-C CH (IX) (wherein R3 is as hereinbefore defined) in the presence of a palladium (II) salt, a triarylphosphine and a copper (I) salt catalyst in an excess quantity of a tertiary amine/solvent mixture. A preferred system would, for example, be palladium (II) acetate, tiphenylphosphine and copper (I) iodide in the presence of 1:1 triethylamine:chloride.

Process C: For the preparation of a compound of formula II wherein Rl represents a group R4S-: Reaction of a compound of formula Xl

(wherein n is as hereinbefore defined) with a compound of formula Xll R4-Hal (ill) (wherein R4 is as hereinbefore defined and Hal represents a halogen atom, preferably a bromine atom) in the presence of a base, for example, triethylamine.

The reaction is conveniently carried out in the presence of a suitable organic solvent such as, for example, a lower alkanol (e.g. methanol).

Process D: For the preparation of a compound of formula II wherein R1 represents a group R4-S-: Reaction of a compound of formula VIII

(wherein n and Alk are as herein before defined and Hal represents a halogen atom, preferably a bromine atom) with a compound of formula XIII R4-SH (will) (wherein R4 is as hereinbefore defined), followed by deesterification of the compound thereby obtained, for example by means of acidification.

The reaction is conveniently carried out in the presence of a solvent such as, for example, hexamethylphosphoramide and of a strong base such as, for example, an alkali metal hydride (e.g. sodium hydride).

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 synthesis eicosanoids by guinea pig peritoneal neutrophils following the addition of ['4C]- 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-lipxygenase product (5-HETE) synthesis. Less potent effects are shown against cyclooxygenase product (thromboxane B,) synthesis.These data are exhibited in the following Table:

IC50 (micromolar) Product of Example Thromboxane B2 5-HETE 1 0.89 0.10 2 31.6 1.8 3 2.8 1.1 4 0.45 0.05 5 1.6 0.15 6 2.0 0.12 7 2.5 0.42 8 5.6 1.4 9 5.2 1.2 10 0.05 0.68 Such compounds are thus of use in the treatment of inflammatory diseass (including bronchial asthma, rheumatoid arthritis, psoriasis and collitis), immunoreglatory diseases and cardioyascular diseases, and in other syndromes in which leukotrienes (the products of the 5-lipoxygenase system) may be complicated.Thus, the present invention provides compounds of formula I and physiologically acceptable salts thereof for use in therapy.

According to a yet 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 pharmaceutical carriers and/or excipients.

For pharmaceutical administration the compounds of general formula I 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 the form suitable for oral, rectal, parenteral or topical administration.

Preferred forms include, for example, plain tablets, coated tablets, capsules, granules, ampoules, 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.

Advantageously the compositions may be 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 500 mg, preferably from 50 to 250 mg, of active ingredient. The total daily dosage, which may be varied according to the compound used, the subject treated and the complaint concerned, may, for example, be from 50 to 250 mg.

According to a still further feature of the present invention, there is provided a method for the treatment of a patient suffering from, or susceptible to, inflammatory, immuno-regulatory, cardiovascular or related diseases which comprises administering to the said patient an effective amount of a compound of formula I as hereinbefore defined or a physiologically acceptable salt thereof.

The following non-limiting Examples serve to illustrate the present invention more fully.

The abbreviations employed throughout the Examples are defined as follows: THF: tetrahydrofuran; HMPA: hexamethylphosphoramide.

Example 1: 3-(Dec-l-ynyl)-N-hydroxy-N-methylbenzamide Step A: 3-(Dec-l-ynyl)-benzoic acid A solution of methyl 3-bromobenzoate (10 g, 46.5 mmol) in a chloroform/dry triethylamine mixture (1:1; 100 ml) was deaerated under gentle vacuum and then kept under an atmosphere of dry nitrogen. Triphenylphosphine (300 mg, 1.1 mmol) and l-decyne (9.15 ml, 51 mmol) were then added, followed by palladium (II) acetate (90 mg, 0.4 mmol) and copper (I) iodide (50 mg, 0.26 mmol). The reaction mixture was heated at 80"C for 30 h.Solvent was then evaporated from the cooled mixture, and the residual dark brown oil was filtered through a bed of silica gel (15 g) in petroleum ether (60-800C) to give crude methyl 3-(dec-l-ynyl)-benzoate as a light yellow oil.

The crude oil was stirred vigorously with lithium hydroxide monohydrate (10 g) in a THF/methanol/water mixture (3:2:1; 200 ml) for 3 h and then the solvent was removed. The residue was partitioned between ethyl acetate and 1M HC1 and the organic layer separated. The aqueous layer was extracted with more ethyl acetate and the combined extracts were washed with saturated NaCI solution, dried over MgSO4 and finally evaporated to give a brown oil. Purification by flash chromatography [silica gel; 4:1 petroleum ether (60-80 C)/ethyl acetate] gave the desired acid (4.94 g, 41%) as a pale yellow oil which gave white crystals, m.p. 32-33"C, from n-hexane in the cold.

lH nmr (CDCl3): J 8.14 (1H, t: J=2 Hz, H-2); 8.01 (1H, dt: J=2 and 7 Hz, H-6); 7.64 (1H, dt: J=2 and 7 Hz, H-4); 7.41 (1H, t: J=7 Hz, H-5); 2.43 (2H, t: J=6 Hz, -CH2C=C); 1.20-1.75 (12H, m, aliphatic); 0.89 (3H, t, -CH3).

IR(KBr): 3300-2300(br), 2920, 2220, 1680, 1440, 1295 and 755 cm Step B: 3-(Dec-l-yn yl)-N-hydroxy-N-merh ylbenzamide A stirred solution of 3-(dec-l-ynyl)-benzoic acid (2.83 g, 11 mmol) and dimethylforamamide (0.80 g, 11 mmol) in dry benzene (25 ml) was cooled to 0 C and treated dropwise over 5 min with oxalyl chloride (1.9 ml, 22 mmol). The mixture was stirred at ice-bath temperature for 1 h and then the solution was decanted and the oily residue extracted with petroleum ether (60-80"C). The organic layers were combined, and the solution was evaporated to give the acid chloride as a yellow oil.

The crude acid chloride was dissolved in THF/water (2:1; 30 ml). The resulting solution was cooled to 0 C and treated with N-methylydroxylamine hydrochloride (1.85 g, 22 mmol). After stirring for 3 h, the THF was removed by evaporation under reduced pressure, and water was added to the residue. The product was extracted with ether, and the combined extracts were then washed with saturated NaCI solution, dried over MgSO4 and finally evaporated. Purification by flash chromatography (silica gel; 85:15 n-hexane/ethyl acetate) gave the desired hydroxamic acid (2.63 g, 83%) as a pale yellow oil.

1H nmr (CDCl3): a 7.29-7.56 (4H, m, aromatic); 3.41 (3H, s, -NCH3); 2.41 (2H, t: J=7 Hz, -CHC=-C); 1.25-1.75 (12H, m, aliphatic); 0.89 (3H, t, -CH3).

IR (film): 3170 (br), 2930, 2850, 2225, 1608, 1595, 1570 and 1205 cm-l.

Elemental Analysis Found: C, 75.03; H, 8.77; N, 4.76%.

C18H2sNO2 requires C, 75.22; H, 8.77; N, 4.87%.

Example 2: N-Cyclchexyl-3-(dec-I-yn yl)-N-hydroxybenzamide Prepared, using 3-(dec-l-ynyl)-benzoic acid (2.35 g, 9.1 mmol) and N-cyclohexylhydroxylamine hydrochloride (1.50 9, 10 mmol), by a method identical to that described in Example 1. The crude product was purified by flash chromatography (silica gel; n-hexane/ether), and crystallisation from n-hexane gave the title hydroxamine acid (0.6 9, 19%) as a white crystalline solid, m.p. 87-88"C.

'H nmr (CDCl3): a 7.25-7.55 (4H, m, aromatic); 5.75-7.25 (1H, bs, -N-OH); 3.70 (1H, bt, -NCH); 2.40 (2H, t: J=7.5 Hz, -CH2C=C); 1.00-2.05 (22H, m, cyclohexyl and aliphatic CH2); 0.89 (3H, t, -CH3).

IR (KRr): 3140 (br), 2930, 1595, 1565, 1160 and 745 cm-1.

Elemental Analysis Found: C, 77.49; H, 9.30; N, 3.91%.

C23H33NO2 requires C, 77.70; H, 9.36; N, 3.94%.

Example 3: 3-(Dec4-ynyl)-N-hydroxy-N-phenylbenzamide Prepared, using 3-(dec-l-ynyl)-benzoic acid (2.0 9, 7.75 mmol) and N-phenylhydroxylamine (0.84 9, 7.75 mmol), by a method identical to that described in Example 1. Purification by flash chromatography (silica gel; n-hexane/ether) and crystallisation from n-hexane afforded the title hydroxamic acid (2. 1 g, 78%) as a white crystalline solid, m.p. 46-48"C.

1H nmr (CDCl3): J 8.25-9.75 (1H, bs, -N-OH); 7.54 (1H, t: J=1.5 Hz, H-2); 7.10-7.45 (8H, m, aromatic); 2.35 (2H, t: J=8 Hz, -CH2C=C); 1.15-1.65 (12H, m, aliphatic); 0.89 (3H, t, -CH3).

IR (KBr): 3200 (br), 2920, 2220, 1615, 1595, 1365, 895 and 750 cm-l.

Elemental Analysis Found: C, 79.06; H, 7.87; N, 3.98%.

C23H27NO2 requires C, 79.05; H, 7.79; N, 4.01%.

Example 4: N-Hydroxy-N-methyl-3-foct-l-ynyl)-benzamide Step A: 3-(Oct-l-ynyl)-benzoic acid A mixture of methyl 3-bromobenzoate (7.53 9, 35 mmol), triphenylphoshine (0.28 g, 1.05 mmol), 1-octyne (4.29 g, 39 mmol), palladium (II) acetate (79 mg, 0.35 mmol) and copper (I) iodide (38 mg, 0.2 mmol), in a deaerated chloroform/dry triethylamine mixture (1:1; 100 ml), was stirred and heated at 80"C under an atmosphere of dry nitrogen for 24 h. Solvent was then evaporated from the cooled mixture, and the residual dark brown oil was purified by column chromatography (silica gel; 9:1 n-hexane/ethyl actate) to give the methyl ester of the title acid as a golden yellow liquid.

The ester was dissolved in THF/methanol/water mixture (3 :2:1; 200 ml), and lithium hydroxide monohydrate (10 9) was added to the solution. After stirring vigorously at room temperature for 4 h the solvent was evaporated from the mixture, and the residue was partitioned between ether and water. The aqueous layer was separated and acidified with conc. hydrochloric acid, and the product was extracted with ether. The extract was washed once with water, dried over MgSO4 and evaporated. Purification by column chromatography (silica gel; 95:5 CH2Cl2/CH30H) and crystallisation from cold petroleum ether (40-60"C) gave the desired acid (2.89 g, 36%) as a white crystalline solid, m.p. 52-54"C.

1H nmr (CDCl3): a 10.00-11.50 (1H, bs, -CO2H, exch. D20); 8.14 (1H, t: J=2 Hz, H-2); 8.01 (1H, dt: J=2 and 7 .Hz, H-6); 7.63 (1H, dt: J=2 and 7 Hz, H-4); 7.40 (1H, t: J=7 Hz, H-5); 2.42 (2H, t: J=7 Hz, -CH2C=-C); 1.20-1.75 (8H, m, aliphatic); 0.91 (3H, t, -CH3).

IR (KBr): 3300-2300 (br), 2920, 2220, 1690, 1450, 1295 and 755 cam~'.

Step B: N-Hydroxy-N-meth yl-3-(oct-l- yn yl)-benzamide Prepared, using 3-(oct-l-ynyl)-benzoic acid (2.76 9, 12 mmol) and N-methylhydroxylamine hydrochloride (2.00 9, 24 mmol), in a similar manner to that described in Example 1, Step B.

Purification by column chromatography (silica gel; 7:3 n-hexane/ethyl acetate) gave the desired hydroxamic acid (2.05 9, 66 ,6) as a colourless viscous oil.

1H nmr (CDCl3): a 8.00-9.50 (1H, bs, -N-OH, exch. D20); 7.30-7.70 (4H, m, aromatic); 3.38 (3H, s, -NCH3); 2.40 (2H, t: J=7 Hz, -CH2C=C); 1.21-1.52 (8H, m, aliphatic); 0.90 (3H, t, -CH3).

IR (film): 3500-3020 (br), 2930, 2220, 1610, 1590 and 1205 cm-'.

Elemental Analysis Found: C, 73.84; H, 8.17; N, 5.19%.

C16H2,NO2 requires C, 74.10; H, 8.16; N, 5.40%.

Example 5: 4-(Dec-l-yn yl)-N-h ydroxy-N-meth ylbenzamide Step A. 4-(Dec-l-ynyl)-benzoic acid Prepared, using methyl 4-bromobenzoate (1.0 9, 4.6 mmol) and l-decyne (0.7 g, 5.1 mmol), by a method identical to that described in Example 1, Step A, and obtained as a white crystalline solid (0.62 9, 52%), m.p. 109-1 100C.

1H nmr (CDCl3): a 8.02 (2H, d: J=7.5 Hz, aromatic); 7.47 (2H, d: J=7.5 Hz, aromatic); 2.43 (2H, t: J=6 Hz, -CH2C=-C); 1.15-1.72 (12H, m, aliphatic); 0.88 (3H, t, -CH3).

IR (KBr): 3300-2300 (br), 2220, 1680, 1600, 1420, 1280 and 765 cm-'.

Step B: 4- (Dec4-yn yl)-N-hydroxy-N-me th ylbenzamide Prepared, using 4-(dec-l-ynyl)-benzoic acid (1.0 9, 3.9 mmol) and N-methylhydroxylamine hydrochloride (0.5 9, 6.0 mmol), by an identical method to that described in Example 1, Step B.

The crude product was purified by flash chromatography (silica gel; n-hexane/ether), and crystallisation from cold n-hexane gave the desired hydroxamic acid (0.9 9, 81%) as a white crystalline solid, m.p. 62-63"C.

'H nmr (CDCl3): a 8.25-9.50 (1H, bs, -N-OH); 7.32-7.55 (4H, m, aromatic); 3.37 (3H, s, -NCHa); 2.42 (2H, t: J=7 Hz, -CH2C=C); 1.20-1.75 (12H, m, aliphatic); 0.89 (3H, t, -CH3).

IR (KBr): 3130 (br), 2920, 2220, 1595, 1580, 1215 and 845 cm-1.

Elemental Analysis Found: C, 75.33; H, 8.70; N, 4.84%.

C18H25NO2 requires C, 75.22; H, 8.77; N, 4.87%.

Example 6: 3-(Dec-l-ynylJ-N-hydroxy-N-methylcinnamamide Step A: 3-(Dec-l-ynylJ-cinnamic acid Prepared by the reaction of methyl 3-bromocinnamate (1 9, 4.15 mmol) with l-decyne (0.6 9; 4.35 mmol), using a method identical to that described in Example 1, Step A, and obtained as a white crystalline solid (0.6 g, 51%) from n-hexane, m.p. 105-107 C.

'H nmr (CDCI3): os 7.72 (1H, d: J=15 Hz, ArCH=C); 7.56 (1H, t: J=1 Hz, H-2); 7.25-7.50 (3H, m, aromatic); 6.42 (1H, d: J=15 Hz, -CHCO2H); 2.41 (2H, t: J=6 Hz, -CH2C3C); 1.15-1.72 (12H, m, aliphatic); 0.88 (3H, t, -CH3).

IR (KBr): 3300-2400 (br), 2920, 1680, 1630, 1430 and 1295 cm-1.

Step B: 3- (Dec-I- yn yl) -N-h ydroxy-N-methylcinnamamide Prepared, using 3-(dec-l-ynyl)-cinnamic acid (3.0 9, 10.5 mmol) and N-methylhydroxylamine hydrochloride (0.88 g, 10.5 mmol), in a similar manner to that described in Example 1, Step B.

Purification by flash chromatography (silica gel; n-hexane/ether) and crystallisation from n-hexane gave the desired hydroxamic acid (2.0 g, 61%) as a white crystalline solid, m.p. 89-910C.

lH nmr (DNSO-6): a 7.62 (1H, t: J=1 Hz, H-2); 7.47 (1H, d: J=15 Hz, ArCH=C); 7.32-7.42 (3H, m, aromatic); 7.23 (1H, d: J=15 Hz, C=CHCO-); 3.24 (3H, s, -NCHa); 2.43 (2H, t: J=6 Hz, -CH2CsC); 1.15-1.65 (12H, m, aliphatic); 0.89 (3H, t, -CH3).

IR (KBr): 3300-2400 (br), 3130, 2920, 2220, 1635, 1580, 1185 and 790 cam~1.

Example 7: 4-(Dec-1-ynyl)-N-hydroxy-N-methylcinnamamide Step A: 4-(Dec-l-ynyl)-cinnamic acid Prepared by the reaction of methyl 4-bromocinnamate (1 9, 4.15 mmol) with 1-decyne (0.6 9, 4.35 mmol), using a method identical to that described in Example 1, Step A, and obtained as a white crystalline solid (0.6 g, 51%) from n-hexane, m.p. 156-8"C.

'H nmr (CDCl3): a 7.67 (1H, d: J=15 Hz, ArCH=C); 7.33-7.55 (4H, m, aromatic); 6.40 (1H, d: J=15 Hz, -CH2C=C); 1.15-1.73 (12H, m, aliphatic); 0.88 (3H, t, -CH3).

Step B: 4-(Dec-l-ynyl)-N-hydroxy-N-methylcinnamamide Prepared, using 4-(dec-l-ynyl)-cinnamic acid (2.0 g, 7 mmol) and N-methylhydroxylamine hydrochloride (0.58 g, 7 mmol), in a similar manner to that described in Example 1, Step B.

Purification of the crude product by flash chromatography (silica gel; n-hexane/ether) and crystallisation from n-hexane gave the title hydroxamine acid (1.65 9, 75%) as a white crystalline solid, m.p. 107-109 C.

'H nmr (DMSO6): d 7.61 (2H, d: J=7.5 Hz, aromatic); 7.47 (1H, d: J=15 Hz, ArCH=C); 7.38 (2H, d: J=7.5 Hz, aromatic); 7.21 (1H, d: J=15 Hz, C=CHCO-); 3.22 (3H, s, -NCH3); 2.42 (2H, t: J=6Hz, -CH2C=-C); ; 1.15-1.65 (12H, m, aliphatic); 0.88 (3H, t, -CH3).

IR (KBr): 3300-2400 (br), 2920, 2220, 1635, 1570, 1185 and 830 cm-1.

Elemental Analysis Found: C, 76.56; H, 8.66; N, 4.45%.

C2oH27NO2 requires C, 76.64; H, 8.68; N, 4.47%.

Example 8: 3-[ 1(Z), 4(Z), 7(Z)-Hexadecatrienyq-N-hydroxy-N-methylbenzamide and 3-[2(E), 4(Z), 7(Z) Hexade ca trien yl]-N-hydroxy-N-me th ylbenzamide mixture Step A: Methyl 3-[1(Z),4(Z), 7(Z)-hexadecatrienyl]-benzoate and Methyl 3-[2(E),4(Z), 7(Z)-hexadeca- trienyl]-benzoate mixture A solution of [3(Z),6(Z)-pentadecadienyl]-triphenylphosphonium bromide (2.3 9; 4.2 mmol), in dry THF (50 ml) under an atmosphere of dry nitrogen, was cooled to -78"C and treated with nbutyllithium (2.67 ml, 1.57 M in n-hexane). After stirring from 20 min, HMPA (5 ml) was added dropwise, followed by a solution of methyl 3-formylbenzoate (0.69 g, 4.2 mmol) in dry THF (10 ml).The mixture was stirred for 40 min, then warmed to room temperature, and the solvent was removed under reduced pressure. Purification by fresh chromatography [silica gel; petroleum ether (60-800C)] gave a mixture of the 1(Z) and 2(E) isomers as a yellow oil (1.43 g). Separation by phlc (silica gel; n-hexane/1% ethyl acetate) and evaporation of solvent from the fractions containing the less-polar component gave methyl 3-[1 (Z), 4(Z), 7(Z)-hexadecatrienyl]-benzoate (0.53 9, 36%) as a yellow oil.

'H nmr (CDCl3): a 7.86-8.03 (2H, m, aromatic); 7.34-7.56 (2H, m, aromatic); 6.49 (1H, dt: J=11.5 and 1.9 Hz, C,-H); 5.74 (1H, dt: J=11.5 and 7.5 Hz, C2-H); 5.46 (2H, complex t, C5-H and C7-H); 5.36 (2H, m, C4-H and C8-H); 3.94 (3H, s, OCH3); 3.09 (2H, ddd: J=7.5, 5.5 and 1.9 Hz, 2xC3-H); 2.76 (2H, dd: J=6.0 and 4.8 Hz, 2xC6-H); 1.99 (2H, dt: J=6.5 and 6.0 Hz, 2xC9-H); 0.89 (3H, t, -CH3).

IR (thin film) 3010, 2920, 2850, 1724, 1435, 1275 and 765 cm-'.

Evaporation of fractions containing the more-polar component gave methyl 3-[2(E),4(Z),7(Z)- hexadecatrienyl]-benzoate (0.51 g, 34%) as a yellow oil.

'H nmr (CDCl3): J 7.89 and 7.59 (4H, m, aromatic); 6.44 (1H, qdd: J=15.0, 11.0 and 1.0 Hz, C3-H); 6.00 (1H, tt: J=11.0 and 1.0 Hz, C4-H); 5.81 (1H, dt: J=15.0 and 7.0 Hz, C2-H); 5.25-5.54 (3H, m, Q-H, C7-H, C8-H); 3.94 (3H, s, -OCH3); 3.51 (2H, broad d: J=7.0 Hz, 2xC,-H); 2.93 (2H, t: J=6.2 Hz, 2xC"-H); 1.95-2.15 (2H, m, 2xCg-H); 1.15-1.47 (12H, m, aliphatic); 0.89 (3H, t, -CH3).

Step B: 3-[ 1 (Z),4(Z), 7(Z)-Hexadecatrienyl]-benzoic acid and 3-[2(E),4(Z), 7(Z)-Hexadecatrienyl]-ben- zoic acid mixture A solution of the approximately 1:1 mixture of methyl 3-[1(Z),4(Z),7(Z)-hexadecatrienyl]-benzo- ate and methyl 3-[2(E),4(Z),7(Z)-Hexadecatrienyl]-benzoate obtained from Step A above (2.34 9, 6.6 mmol) in THF/methanol/water (3:2:1; 60 ml) was stirred with lithium hydroxide monohydrate (1.67 g) at room temperature for 5 h. The mixture was then acidified to pH 5.5 with 2M HCI and concentrated under reduced pressure, and the product was extracted with ether. The ethereal extract was washed once with saturated NaCI solution and dried over MgS04, and the solvent was evaporated.The crude product was purified by flash chromatography (deactivated silica gel: CH2CI2) to give a 3.2:1 2(E): 1(Z) isomeric mixture (1.02 g, 45%) of the title acids as an oil.

1H nmr (CDCl3): d 7.90-8.20 (2H, m, aromatic); 7.30-7.62 (2H, m, aromatic); 5.25-6.60 (6H, m, olefinic); 3.55 [1.52H, d: J=7.0 Hz, 2xC1-H (2(E) isomer)]; 3.09 [0.48H, m, 2xC3-H (1(Z) isomer)]; 2.94 [1.52H, t: J=6.2 Hz, 2xC6-H (2(E) isomer)]; 2.78 [0.48H, m, 2xC6-H (1(Z) isomer]; 1.87-2.30 (2H, m, 2xC9-H); 1.10-1.50 (12H, m, aliphatic); 0.89 (3H, t, -CH3).

IR (thin film): 2650, 2550, 1685, 945 and 745 cm-1.

Step C: 3-fl (Z), 4(Z), 7(Z)-Hexadecatrienyl]-N-hydroxy-N-methylbenzamide and 3-[2(E), 4(Z)-Hexade- catrienyl]-N-hydroxy-N-methylbenzamide mixture Prepared by the reaction of a mixture of 3-[1(Z),4(Z),7(Z)-hexadecatrienyl]-benzoic acid and 3 [2-(E),4(Z),7(Z)-hexadecatrienyl]-benzoic acid (1:3.2; 2.27 9, 6.68 mmol) with N-methylhydroxylamine hydrochloride (1.12 g, 13.36 mmol) in a manner similar to that described in Example 1.

The crude product was purified by flash chromomatography [silica gel; petroleum ether (60-80'C)] to give a 2.5:1 2(E):1(Z) isomeric mixture (1.24 9, 64%) of the title hydroxamic acids as a colourless oil.

1H nmr (CDCl3): a 8.60 (1H, broad s, -N-OH); 7.25-7.58 (4H, m, aromatic); 5.25-6.55 (6H, m, olefinic); 3.53 [1.44H, d: J=7.0 Hz, 2xC,-H (2(E) isomer)]; 3.44, 3.41 (3H, 2xs, -NCH3), 3.05 [0.56H, m, 2xC3-H (1(Z) isomer)]; 2.94 [1.44H, t: J=6.2 Hz, 2xC6-H (2(E) isomer)]; 2.78 2.78 [0.56H, m, 2xC6-H (1(Z) isomer)]; 1.87-2.50 (2H, m, 2xQ-H); 1.12-1.50 (12H, m, aliphatic); 0.89 (3H, t, -CH3).

IR (thin film): 3170, 2925, 2850, 1610, 1595, 1575, 908 and 735 cam~'.

Example 9: N-Hydroxy-N-me thyl-2-(undecylthio) -benzamide Step A: 2-(Undecylthio)-benzoic acid A mixture of thiosalicylic acid (20 g, 0.13 mol), triethylamine (55 ml) and 1-bromoudecane (34 g, 0.14 mol) in methanol (60 ml) was stirred at room temperature for 20 h. The solvent was removed under reduced pressure and the residual solid partitioned between ethyl acetate and dilute HCI. The organic layer was separated, washed with saturated NaCI solution and dried over MgS04, and the solvent was evaporated. Recrystallisation from methanol gave the title acid (36.5 9, 91%) as a white crystalline solid, m.p. 85-88"0.

1H nmr (CDCl3): os 8.13 (1H, dd: J=7.0 and 1.0 Hz, H-6); 7.10-7.58 (3H, m, aromatic); 2.94 (2H, t, -CH2S); 1.15-1.87 (18H, m, aliphatic); 0.89 (3H, t, -CH3).

IR (KBr): 2920, 2850, 2650, 2560, 1665, 1465 and 745 cm-'.

Step B: N-Hydroxy-N-methyl-2-(undecylthio)-benzamide Prepared, using 2-(undecylthio)-benzoic acid (5 9, 16.2 mmol) and N-methylhydroxylamine hydrochloride (2.72 9, 32.4 mmol), in a similar manner to that described in Example 1. Purification of the crude product by flash chromatography [silica gel; petroleum ether (60-800C)/ethyl acetate] gave the desired hydroxamic acid (4.81 g, 88%) as a pale orange oil which crystallised on standing, m.p. 45-48"C.

'H nmr (CDCI3): a 7.19-7.44 (4H, m, aromatic); 7.38 (1H, broad s, -N-OH, exch. D2O); 3.24 (3H, broad s, -NCH3); 2.94 (2H, t, -CH2S); 1.10-1.75 (18H, m, aliphatic); 0.88 (3H, s, -CH3).

IR (thin film): 3150, 3055, 2950, 1625, 1620, 1610, 1585, 1460, 1430, 935, 770 and 740 cm-'.

Elemental Analysis Found C, 67.77; H, 9.02; N, 4.13; S, 9.52%.

C19H31NO2S requires C, 67.61; H, 9.26; N, 4.15; S, 9.50%.

Example 10: N-Hydroxy-N-methyl-4-(octylthio)-benzamide Step A: 4-(Octylthio)-benzoic acid 1-Octanethiol (1.0 ml, 5.7 mmol) was added to a suspension of sodium hydride (80%, 0.2 9) in HMPA (10 ml), and the mixture was stirred for 40 min. Methyl 4-bromobenzoate (0.5 g, 2.3 mmol) was added, and stirring was continued for 1 h. Water was added, and the resulting solution was acidified (2N HCI) and extracted with ether. Purification of the residue obtained upon evaporation of the extract by flash chromatography (silica gel; dichoromethane/methyanol) gave the acid (0.52 9, 84%) as a colourless crystalline solid.

'H nmr (CDCl3): a 8.00 (2H, d: J=7.5 Hz, aromatic); 7.35 (2H, d: J=7.5 Hz, aromatic); 3.00 (2H, t: J=7 Hz, SCH2); 1.70 (2H, m, SCH2CH2); 1.25-1.55 (10H, m, 5xCH2); 0.88 (3H, t: J=7 Hz, CH3).

Step B: N-Hydroxy-N-methyl-4-(octylthio)-benzamide Prepared, using 4-(octylthio)-benzoic acid (3.5 g, 13.1 mmol) and N-methylhydroxylamine hydrochloride (3.0 g, 36 mmol), in a similar manner that described in Example 1, Step B. Purification by flash chormatography (silica gel; n-hexane/ether) gave the desired hydoxamic acid (2.7 9, 69%) as a colourless crystalline solid, m.p. 86-87"C.

1H nmr (DMSO-d6): J 9.7-10.2 (1H, broad s, OH); 7.58 and 7.30 (2x2H, 2xd; J=10 Hz, aromatic); 3.24 (3H, s, NCH3); 3.00 (2H, t: J=7 Hz, SCH2); 1.59 (2H, m, SCH2CH2); 1.10-1.50 (10H, m, 5xCH2); 0.85 (3H, t: J=7 Hz, CH3).

Elemental Analysis Found C, 65.13; H, 8.50; N, 4.71; S, 10.95% Cl6H25NO2S requires C, 65.05; H, 8.53; N, 4.74; S, 10.85%.

Example 11 Tablets were prepared according to the formulation: compound of Example 4 20 mg excipient q.s. for one tablet up to 200 mg (details of the excipient: lactose, starch, talc, magnesium stearate).

Example 12 Tablets were prepared according to the formulation: compound of Example 1 20 mg -excipient q.s. for one tablet up to 200 mg (details of the excipient: lactose, starch, talc, magnesium stearate).

Claims (32)

1. Compounds of formula I

[wherein R, represents a group of formula

(in which

represents an unsaturated aliphatic hydrocarbylene group containing 3 to 19 carbon atoms); a group of formula R3-C---C- (in which R3 represents a hydrogen atom or a saturated or unsaturated aliphatic hydrocarbyl group containing 1 to 18 carbon atoms); or a group of formula R4-S (in which R4 represents an aliphatic hydrocarbyl group containing 1 to 20 carbon atoms); R2 represents a C1 6 alkyl-group, a C37 cycloalkyl group or a substituted or unsubstituted aryl group; and n is O or 1] and salts thereof.

2. Compounds as claimed in claim 1 wherein R1 represents a C4 20 dialkenyl group, a C6-20 trialkenyl group, a C2 20 alkynyl group, a C4 20 dialkynyl group, a C6-20 trialkynyl group or a C, 20 alkythio group; R2 represents a C16 alkyl group, a C37 ccyloalkyl group or a substituted or unsubstituted aryl group; and n is O or 1.

3. Compounds as claimed in claim 2 wherein R1 represents a C2 20 alkynyl group or a C, 20 alkylthio group.

4. Compounds as claimed in claim 1 selected from: N-hydroxy-N-rnethyl-4-(octylthio)-benzamide; N-hydroxyl-N-methyl-3-(oct-l-ynyl)-benzamide; 3-(dec-l-ynyl)-N-hydroxy-N-methylbenzamide; 4-(dec-l-ynyl)-N-hydroxy-N-methylbenzamide, 3-(dec-l-ynyl)-N-hydroxy-N-methylcinnamamide; and salts thereof.

5. Physiologically acceptable salts of compounds of formula I as defined in claim 1.

6. Compounds as claimed in claim 1 as herein specifically disclosed in any one of Examples 1 to 10.

7. A process for the preparation of a compound as claimed in claim 1 which comprises reacting a compound of formula Ill

(wherein R, and n are as defined in claim 1 and Hal represents a halogen atom), with a compound of formula IV R2-NHOH. HX (IV) (wherein R2 is as defined in claim 1 and X represents a halogen atom).

8. A process as claimed in claim 7 wherein the reaction between the compound of formula Ill and the compound of formula IV is carried out in a mixture of tetrahydrodfuran and water as solvent.

9. A process as claimed in claim 7 or claim 8 wherein the compound of formula III is prepared by treating a compound of formula il

(wherein R1 and n are as defined in claim 1) with a halogenating agent.

10. A process as claimed in claim 9 wherein the halogenating agent used is oxalyl chloride.

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

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

13. A process for the preparation of compounds as claimed in claim 1 substantially as herein described in any one of Examples 1 to 10.

14. Compounds as claimed in claim 1 whenever prepared by a process as defined in any one of claims 7 to 10.

15. Compounds as claimed in any one of claims 1 to 4 for use in therapy.

16. The use of a compound as claimed in any one of claims 1 to 4 for the manufacture of a medicament for the treatment of inflammatory, immunoregulatory or cardiovascular diseases.

17. Pharmaceutical compositions, comprising as active ingredient, at least one compound of formula I as defined in claim 1 or a physiologically acceptable salt thereof in association with a pharmaceutical carrier and/or excipient.

18. Compositions as defined in claim 17 wherein the active ingredient comprises a compound as defined in any one of claims 2 to 4.

19. Compositions as claimed in claim 17 or claim 18 in the form of dosage units.

20. Compositions as claimed in claim 19 wherein each dosage unit contains from 10 to 500 mg of active ingredient.

21. Compositions as claimed in claim 20 wherein each dosage unit contains from 50 to 250 mg of active ingredient.

22. Pharmaceutical compostions as claimed in claim 17 substantially as herein described.

23. Pharmaceutical compositions substantially as herein described in Example 11 or 12.

24. Compounds of formula III as defined in claim 7.

25. Compounds of formula II as defined in claim 9 and salts thereof.

26. A process for the preparation of a compound of formula IIA

(wherein

and n are as defined in claim 1) which comprises reacting a compound of formula VII

(wherein

and n are as hereinbefore defined and Alk represents a C1 6 alkyl group) with a base in the presence of water, and if desired, subsequently converting the compound of formula IIA into a salt thereof.

27. A process as claimed in claim 26 wherein the compound of formula Vli is prepared by reacting a compound of formula V (wherein Alk is as defined in claim 26) with a compound of formula VI

(wherein

is as defined in claim 1; and Y represents a halide ion) in the presence of a strong base.

28. A process for the preparation of a compound of formula IIB

(wherein R3 and n are as defined in claim 1) which comprises reacting a compound of formula X

(wherein R3 and n are as defined above and Alk is as defined in claim 26) with a base in the presence of water, and if desired, subsequently converting the compound of formula IIB into a salt thereof.

29. A process as claimed in claim 28 wherein the compound of formula X is prepared by reacting a compound of formula VIII

(wherein n is as defined in claim 1 and Alk is as defined in claim 26; and Hal represents a halogen atom) with a compound of formula IX R3C-=CH (IX) (wherein R3 is as defined in claim 1) in the presence of a palladium (II) salt, a triarylphosphine and a copper (I) salt catalyst in an excess quantity of a tertiary amine/solvent mixture.

30. A process for the preparation of a compound of formula II

wherein R1 represents a group R4S- (in which R4 is as defined in claim 1), which comprises reacting a compound of formula XI

(wherein n is as defined in claim 1) with a compound of formula XII R4-Hal (Xll) (wherein R4 is as defined in claim 1 and Hal represents a halogen atom) in the presence of a base, and if desired, subsequently converting the compound of formula II into a salt thereof.

31. A process for the preparation of a compound of formula II wherein R1 represents a group R4-S-, (in which R4 is as defined in claim 1) which comprises reacting a compound of formula VIII

(wherein n is as defined in claim 1 and Alk is as defined in claim 26 and Hal represents a halogen atom) with a compound of formula XIII R4-SH (oil) (wherein R4 is as defined in claim 1), followed by deesterifying the compound thereby obtained, and if desired, subsequently converting the compound of formula II into a salt thereof.

32. Each and every novel compound, process, method and composition herein disclosed.