GB2279346A - Benzofuran intermediates - Google Patents

Abstract

Compounds of general formula (III> <IMAGE> wherein the symbols are as defined in the specification, and protected derivatives thereof are useful as intermediates in the preparation of pharmaceuticals.

Description

CHEMICAL INTERMEDIATES AND THE USE THEREOF This invention relates to novel compounds which are useful as intermediates in the preparation of pharmaceutical compounds, to processes for their preparation, and to their use in the preparation of pharmaceutical compounds.

European Patent Specification No. 05141 97A describes pharmaceutical compounds and intermediates thereto of the formula (I)

wherein R1 represents a hydrogen atom or a halogen atom or a group selected from C1 6alkyl, C2 6alkenyl, fluoroC1.6alkyl, C1.6alkoxy, -CHO, -CO2H or -COR2; R2 represents a group selected from Cl~,alkyl, C2.6alkenyl, C1-6alkoxy or the group -NR15R16; R3 represents a group selected from -NO2, -N H2, -CN, an optionally protected derivative of -CO2H, -NHSO2CF3, a protected derivative of -NH2 or an optionally protected derivative of a C-linked tetrazolyl group;; R4 and R5, which may be the same or different, each independently represent a hydrogen atom or a halogen atom or a C1 6alkyl group; R6 represents a hydrogen atom or a group selected from C1 6alkyl, C2 6alkenyl, C1 6alkylthio, C1 6alkoxy, C27cycloalkyl or C3-7cycloalkylC1-4 .4alkyl; R7a, R7b and R7C, which may be the same or different, each independently represent a hydrogen atom or a halogen atom or a group selected from cyano, nitro, C1 6alkyl, C2-6alkenyl, C3 7cycloalkyl, C37cycIoalkylC1 4alkyl, fluoroC1 6alkyl, -(CmH2m)R9, -(CH2)nCOR1 or-(CH2)pNR11COR12;; R9 represents a hydroxy or C1 6alkoxy group; R10 represents 8 hydrogen atom or a group selected from hydroxy, C1 6alkyl, C1 6alkoxy, phenyl, phenoxy, or the group -NR15R16; R11 represents a hydrogen atom or a C1.6alkyl group; R12 represents a hydrogen atom or a group selected from C1.6alkyl, C1.6alkoxy, phenyl, phenoxy, or the group -NR15R16; R15 and R16, which may be the same or different, each independently represent a hydrogen atom or a C1 4alkyl group or -NR15R16 forms a saturated heterocyclic ring which has 5 or 6 ring members and may optionally contain in the ring one oxygen atom; m represents an integer from 1 to 6; n represents zero or an integer from 1 to 4; and p represents an integer from 1 to 4; and salts or solvates thereof.

The compounds of EP-0514197A are described as being inhibitors of the action of the hormone angiotensin II. As such, they are particularly useful in the treatment or prophylaxis of, for instance, hypertension and congestive heart failure.

European Patent Specification No. 0514197A describes several methods for the preparation of the compounds of formula (I) as defined above. All of these methods rely, at some stage, upon the use of benzofuranyl intermediate of formula (II)

wherein R1, R3, R4 and R5 are as defined above and L is a leaving group, for example, a halogen atom such as chlorine, bromine or iodine, or a hydrocarbylsulphonyloxy group such as methanesulphonyloxy or ptoluenesulphonyloxy. Such intermediates were first described in European Patent Specification No. 0434249A.

According to the present invention, there is provided a novel class of benzofuranyl intermediates of general formula (III)

or a protected derivative thereof wherein R1 represents a hydrogen atom or a halogen atom or a group selected from C1 6alkyl, C2.6alkenyl, fluoroC1 6alkyl, C1 .6alkoxy, -CHO, -CO2H or -COR2; R2 represents a group selected from C1 6alkyl, C2.6alkenyl, C1 6alkoxy or the group NR15R16; R3 represents a group selected from -NO2, -N H2, -CN, an optionally protected derivative of -CO2H, -NHSO2CF3, a protected derivative of -NH2 or an optionally protected derivative of a C-linked tetrazolyl group;; R4 and R5, which may be the same or different, each independently represent a hydrogen atom or a halogen atom or a C1.6alkyl group; R6 represents a hydrogen atom or a group selected from C1.6alkyl, C2.6alkenyl, C1 .6alkylthio, C1 .6alkoxy, C3.7cycloalkyl or C3 7cycloalkylC1 4alkyl; R7a, R7b and R7C, which may be the same or different, each independently represent a hydrogen atom or a halogen atom or a group selected from cyano, nitro, C1 .6alkyl, C2.6alkenyl, C3-7cycloalkyl, C3-7cycloalkyl, C3.7cycloalkylC1 4alkyl, fluoroC1 .6alkyl, -(CmH2m)R9, -(CH2)nCOR10 or (CH2)pNR11COR12;; R9 represents an optionally protected hydroxy or C1 6alkoxy group; R10 represents a hydrogen atom or a group selected from hydroxy, C1 6alkyl, C1 6alkoxy, phenyl, phenoxy, or the group -NR15R16; R11 represents a hydrogen atom or a C1.6alkyl group; R12 represents a hydrogen atom or a group selected from C1.6alkyI, C1.6alkoxy, phenyl, phenoxy, or the group -NR15R16; R15 and R16, which may be the same or different, each independently represent a hydrogen atom or a C1.4alkyl group or -NR15R16 forms a saturated heterocyclic ring which has 5 or 6 ring members and may optionally contain in the ring one oxygen atom; m represents an integer from 1 to 6; n represents zero or an integer from 1 to 4; and p represents an integer from 1 to 4; and salts or solvates thereof.

A preferred class of compound of general formula (III) is that wherein R1 represents a hydrogen atom or a halogen atom or a group selected from C1 6alkyl, C1.6alkoxy or fluoroC1.6alkyl, and in particular a halogen atom or a -CF3 group, especially a bromine or chlorine atom.

Another preferred class of compound of general formula (III) is that wherein R4 and R5 each independently represent a hydrogen atom.

A further preferred class of compound of general formula (III) is that wherein R6 represents a C1.5alkyl or C3 5cycloalkyl group, in particular a C2.4alkyl group, especially an ethyl, or n-propyl group.

A yet further preferred class of compound of general formula (III) is that wherein R7a, R7b, and R7c each independently represent a hydrogen atom or a halogen atom or a group selected from C1 6alkyl, C3.7cycloalkyl, C3 7cycloalkylC1 4alkyl, -(CmH2m)R9 or -(CH2)nCOR1 . In particular R9 represents a hydroxy or C1.6alkoxy group or a protected hydroxy group, and preferably a hydroxy, methoxy, ethoxy, propoxy or butoxy group or a protected hydroxy group, and especially a hydroxy or methoxy group or a protected hydroxy group. R10, in particular, represents a hydrogen atom or a hydroxy, C1 6alkoxy or -NR15R16 group (especially wherein R15 and R16 each independently represent a hydrogen atom or a C1 4alkyl group), and preferably a hydrogen atom or a hydroxy, methoxy, ethoxy, propoxy or butoxy group, and especially a hydrogen atom or a hydroxy or methoxy group, and m is 1 or 2 and n is zero, 1 or 2.

In a particularly preferred class of compound of general formula (III), R7a, R7b and R7c each independently represent a hydrogen or chlorine atom or a group selected from methyl, ethyl, cyclopropyl, cyclopropylmethyl, -CH2OH, -C H2OC H3, -CHO, -CO2H, -CO2CH3, -CO2CH2CH3, -CON H2, -CONHCH3, -CH(CH3)OH or -C(C H3)20H.

Particularly preferred are those compounds of formula (III) wherein R7a represents a hydrogen atom or a C1.3alkyl group, and especially a methyl group.

Also preferred, are those compounds of formula (III) wherein R7b represents a hydrogen atom.

A further preferred class of compound of formula (III) is that wherein R7c represents the group -CH2OH or a group readily convertible thereto, for example, methyl, -CO2CH3, -CHO, -CO2H or a protected derivative of -CH2OH.

Another preferred class of compound of formula (III) is that wherein R7c represents -CH2OH or a protected derivative thereof, or a group selected from methyl, -CO2CH3, -CHO or -CO2H.

Especially preferred are those compounds of formula (III) wherein R7c represents the group -CH2OH or a protected derivative thereof.

Suitable hydroxyl protecting groups, their method of formation and suitable means of deprotection are described in Chapter 2 of "Protective Groups in Organic Synthesis" (2nd Edition) by T W Greene and P G M Wuts, John Wiley & Sons, Inc., New York (1991).

Thus, for example, a hydroxyl group may be protected as an ether, in particular as a tetrahydropyranyl (THP) ether, or as a silyl ether, in particular as a t- butyldimethylsilyl (TBDMS) ether, or as an ester, for example, an acetate ester. Cyclisation of the amide of formula (III) to form a compound of formula (I) may be effected at an elevated temperature, for example, between 1000 and 2000C, optionally in the presence of a strong acid such as polyphosphoric acid. Such use of a compound 6f formula (III) constitutes a further aspect of the present invention.

The compounds of formula (III) may be prepared, for example, by the reaction of a compound of formula (IV)

(wherein R1, R3, R4 and R5 are as defined in formula (III)) with a pyridine compound of formula (V)

(wherein R6, R7a, R7b and R7c are as defined in formula (III)), in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride. The reaction may be effected in the presence of a solvent, for example, a halogenated hydrocarbon such as dichloromethane, conveniently at room temperature.

Alternatively, the intermediates of formulae (IV) and (V) may be reacted under dehydrating conditions to give an intermediate imine of formula (Illa)

which may subsequently be reduced to give a compound of formula (III) using standard conditions, for example, hydrogenation in the presence of a metal catalyst such as palladium on charcoal.

The compounds of formula (III) may also be prepared by the reaction of a compound of formula (VI)

(wherein R1, R3, R4 and R5 are as defined in formula (III)) with a pyridine compound of formula (VII)

(wherein R6, R7a, R7b and R7C are as defined in formula (III) and L is as previously defined).

The reaction is conveniently effected at an elevated temperature, for example between 1500 and 2000C under which conditions the compound of formula (III) thus formed may cyclise to the corresponding compound of formula (I) in situ.

It will be appreciated that intermediates of formula (ill) may initially be reacted with an oxidizing agent such as meta-chloroperbenzoic acid (m-CPBA), thus forming the N-oxide of the compound of formula (VII). Following reaction with an intermediate of formula (VI) it may be necessary to remove the N-oxide using standard conditions.

Compounds of formula (IV) and formula (VI) are novel compounds and constitute further aspects of the present invention.

Intermediates of formula (IV) may be prepared, for example, from the corresponding compound of formula (Vlil)

(wherein L is as previously defined) by treatment with a base, such as sodium hydrogen carbonate. The reaction is conveniently effected in the presence of dimethylsulfoxide and optionally in the presence of a solvent such as xylene or an aromatic hydrocarbon, for example, toluene, at an elevated temperature, for example, between 1000 and 1 600C.

Intermediates of formula (Vl) may be prepared from a corresponding compound of formula (VIII) by reaction with a phthalimide derivative, for example, potassium phthalimide in a suitable solvent, for example, dimethylformamide. The desired amine of formula (VI) may be subsequently obtained by reaction with hydrazine hydrate in a suitable solvent, for example, an alcohol such as ethanol, at a temperature between room temperature and 1200C.

Alternatively, intermediates of formula (VI) may be prepared from a corresponding compound of formula (VIII) by reaction with an azide such as sodium azide, followed by reaction of the resultant azide intermediate using standard conditions such as hydrogenation in the presence of a metal catalyst, for example, palladium on charcoal.

Compounds of formula (VIII) are a sub-class of compound of formula (II), above.

The preparation of such compounds is discussed, for example, in European Patent Specification No. 0434249A.

Intermediates of formula (V) and (VII) may be prepared by conventional techniques from a compound of formula (IX) or (X), respectively,

using protection and deprotection where necessary. Thus the nitro group may be converted into an amino group under standard reducing conditions, for example, hydrogenation in the presence of a metal catalyst, such as palladium on charcoal, or using tin (Il) chloride in hydrochloric acid (see, for instance, J.Chem.Soc. Perkin Trans.l, 1980, 2400). The resultant amino group may then be converted into the desired amide by reaction with a suitable acyl halide or an hydrate under standard conditions of amide formation.

Suitable amine protecting groups, their method of formation and suitable means of deprotection are described in Chapter 7 of "Protective Groups in Organic Synthesis" (2nd Edition) by T W Greene and P G M Wuts, John Wiley & Sons, Inc.

New York (1991).

Thus for example, a particularly useful protecting group is a carbamate, for example, t-butyl carbamate (t-BOC). Such groups may be removed using, for example, trifluoroacetic acid optionally in a suitable solvent such as a halogenated hydrocarbon, for example, dichloromethane.

The following non-limiting examples serve to illustrate the present invention.

Temperatures are in OC. "dried" refers to drying use magnesium sulphate or sodium sulphate. Unless otherwise stated, thin layer chromatography (T.l.c.) was carried out on silica. Flash column chromatography (FCC) was carried out on silica gel (Merck 9385) unless otherwise stated. Nuclear magnetic resonance (n.m.r.) spectra were determined at 250MHz.

Intermediate 1 N-(2-Amino-4 .6-di methyi-3-pyridi nyl)propan amide trifluoroacetate salt (a) Bis(1.1 -dimethylethyl) (4.6-dimethyS3-nitro-2-pyridinyl)imidodicarbonate 4,6-Dimethyl-3-nitro-2-pyridineamine (10g) was dissolved in dichloromethane (500ml) and cooled to OOC under nitrogen. Di-tert-butyl dicarbonate (1 3.57g) was added in three portions followed by triethylamine (8.7ml). The reaction mixture was allowed to warm up to room temperature and stirred overnight. A further portion of di-tert-butyl carbonate (7.3g) and triethylamine (11.3ml) was added.

Stirring was continued for five days. The reaction mixture was washed with water (2x300ml), brine (200ml) and dried. Concentration invacuo gave a brown oil which was purified by FCC eluting with tert-butylmethyl ether:hexane (1:3) to give a yellow oil. Recrystallisation from ethyl acetate/hexane gave the title compound (8.99) as a white solid, m.p. 95"C.

(b) Bis (1.1 -Dimethylethyl) (3-amino-4.6-dimethyl-2-pyridinyl)imidodicarbonate A suspension of 5% palladium on charcoal catalyst in ethanol:ethyl acetate (3:1) (260ml) was prehydrogenated for 20min. A solution of the product of step (a) (8.99) in ethanol:ethyl acetate (3:1) (60ml) was added and the mixture stirred overnight under a hydrogen atmosphere. The catalyst was removed by filtration and the solution concentrated in vacuo to afford the title compound (8g) as a white solid, m.p. 149"C.

(c) Bis (1.1 -di methylethyl) [4.6-dimethyl-3-[(l -oxopropyl)ami no]-2-pyridi nyl] imidodicarbonate Triethylamine (2.95ml), propionyl chloride (1.82ml) and 4-N,N-dimethylaminopyridine (1 Omg) were added to a stirred solution of the product of step (b) (79) in dichloromethane (140ml) at 0 C. The reaction mixture was allowed to warm to room temperature and stirred overnight under nitrogen. A further portion of triethylamine (0.29ml) and propionyl chloride (0.18ml) was added and stirring continued for 4h. The reaction mixture was washed with brine (100my), dried and concentrated in vacuo to yield a pale yellow gum.Purification by FCC eluting with ethyl acetate:hexane (1:3) afforded the title compound (4.5g) as a white solid, m.p. 11 30C.

(d) N-(2-Amino-4.6-di methyl-3-pyridi nyl)propanamide trifluoroacetate salt Trifluoroacetic acid (7ml) was added to a mixture of the product of step (c)(4.5g) and phenol (100mg) at 0 C. The reaction was stirred at room temperature for 20min under nitrogen. The reaction mixture was concentrated invacuo and the resulting gum triturated with ether to yield the title compound (3.2g) as a white solid.

T.l.c. methanol:dichloromethane (1:10), Rf 0.25 Intermediate 2 3-Bromo-2-(2-nitrophenyl)-5-benzofurancarboxaldehyde A solution of 5-(bromomethyl)-2-(2-nitrophenyl)benzofuran (10g) in dimethylsulfoxide (20ml) was added to a suspension of sodium hydrogen carbonate (209) in dimethylsulfoxide (90ml) at 140"C. After 12min, the reaction mixture was cooled in ice and water (150ml) was added. The reaction mixture was extracted with ether (3x70ml). The combined organic extracts were washed with brine (100ml), dried and concentrated invacuo to give a yellow oil.

Purification by FCC eluting with ethyl acetate:hexane (1:3) afforded the title compound (4.129) as a yellow solid, m.p. 1290C.

Intermediate 3 N-(2-Chloro-4-methyl-3-pyridinyl)propanamide Propionic an hydrate (0.4ml) was added to a stirred solution of N-(2-chloro-4methyl-3-pyridinyl)amine (0.459) in toluene (40ml). The mixture was stirred at 100" for 3h before further propionic an hydrate (0.5ml) was added. After heating at 100" for a further 4h, a final portion of propionic an hydrate (0.6ml) was added and heating continued at 100" for 18h. After cooling, the solution was diluted with ethyl acetate (40ml) before being washed with water (50ml), 8% sodium bicarbonate (50ml), dried and concentrated in vacuo to afford an orange oil.Purification by FCC eluting with ether:hexane (1:1) increasing to ether and then to ether:ethyl acetate (1:1) afforded the title compound (0.219) as a white solid.

T.l.c. ethyl acetate:ether (1:1), Rf 0.3 Intermediate 4 3-Bromo-2-(2-nitrophenyl)-5-benzofuranmethanamine (a) 1-[[3-Bromo-2-(2-nitrophenyl)-5-benzofuranyl]methyl]-1 H-isoindole-1.3 (2H)-dione Potassium phthalimide (2.449) was added to a stirred solution of 5-(bromomethyl)2-(2-nitrophenyl)benzofuran (4.989) in dimethylformamide (100ml). The suspension was stirred rapidly for 24h and then allowed to stand over the weekend. The suspension was diluted with ethyl acetate (200ml) and water (150ml) and the resulting solid at the interphase was filtered off and dried in vacuo to give the title compound (4.49) as a yellow solid.

n.m.r. (DMSO) 6 4.97 (br s,2H), 7.49 (dd,1 H), 7.6 (br s,l H), 7.7 (d,1 H) ), 7.85-8.0 (m,7H), 8.23 (d,1 H) (b) 3-Bromo-2-(2-nitrophenyl)-5-benzofuranmethanamine A mixture of 85% hydrazine hydrate (2.0ml) and the product of step (a) (1.89) in ethanol (21 Oml) was heated at reflux for 3h. After cooling the suspension was concentrated in vacuo to afford a yellow solid which was partitioned between ether (100ml) and 2N sodium hydroxide (75ml). The aqueous phase was further extracted with ether (75ml) and the combined organic extracts were washed with water (70ml), dried and concentrated in vacuo to afford a yellow oil (1.49).

Purification by FCC eluting with dichloromethane:ethanol:ammonia (100:8:1) afforded the title compound (1.149) as a yellow oil.

T.l.c. dichloromethane:ethanol:ammonia (100:8:1), Rf 0.5 Example 1 N-(2-[[(3-Bromo-2-(2-nitrophenyl)-5-benzofuranyl]methylamino]-4.6-dimethyl-3- eXridinyl]propanamide To a stirred solution of Intermediate 1 (480mg) in dichloromethane (50ml) was added Intermediate 2 (858mg) followed by sodium triacetoxyborohydride (683mg) and glacial acetic acid (0.15ml). The mixture was stirred overnight under nitrogen.

8% Aqueous sodium hydrogen carbonate (30ml) was added and stirring continued for 1 Omin. The organic phase was separated. The aqueous layer was further extracted with dichloromethane (2x30ml). The combined organic extracts were washed with brine, dried and concentrated in vacuo to give a yellow oil.

Purification by FCC eluting with ethyl acetate:hexane (1:1) afforded the title compound (350mg) as a yellow solid.

T.l.c. methanol:dichloromethane (1:10), Rf 0.50 Mass spectrum = (MH+): 523.1 Example 2 3-[[3-Bromo-2-(2-nitrophenyl)-5-benzofuranylmethyl]-2-ethyl-5.7-dimethyl-3H- imidazof4.5-b]pyridine The product of Example 1 (350mg) was treated with polyphosphoric acid (200mg) and heated to 140"C for 9h then allowed to cool to room temperature. The black residue was treated with concentrated ammonia (3ml) to pH9 and the product extracted in dichloromethane (3x10ml). The combined organic extracts were combined and evaporated to give a dark brown gum. Purification by FCC eluting with ethyl acetate afforded the title compound (17mg) as a pale brown gum.

T.l.c. ethyl acetate, Rf 0.61 n.m.r.(CDCIs) 61.35 (t,3H), 2.6 (s,3H), 2.65 (s,3H), 2.85 (q,2H), 5.6 (s,2H), 6.9 (s,1 H), 7.15 (dd,1 H), 7.35 (dd,1 H), 7.4 (s,1 H), 7.65 (dt,1 H), 7.7 (dt,1 H), 7.85 (dd,1 H), 8.1 (dd,1 H) Example 3 3-[[3-Bromo-2-(2-nitrophenyl)-5-benzofuranylmethyl]-2-ethyl-7-methyl-3H- imidazo(4.5-bjpyndine A mixture of Intermediate 3 (0.29) and Intermediate 4 (0.329) was heated at 195 (oil bath temp) for 2h with stirring. After cooling the red gum was dissolved in dichloromethane (30ml) before being washed with water (20ml), dried and concentrated in vacuo to afford a yellow gum (0.429). Purification by FCC eluting with dichloromethane:ethanol:ammonia (200:8:1) afforded the title compound (0.15g) as a yellow foam.

T.l.c. dichloromethane:ethanol:ammonia (100:8:1), Rf 0.75 n.m.r.(CDCI) #1.38 (t,3H), 2.7 (s,3H), 2.88 (q,2H), 5.6 (s,2H), 7.05 (d,1H), 7.18 (dd,1 H), 7.35-7.4 (m,2H), 7.6-7.8 (m,2H),7.85 (dd,l H), 8.05 (dd,1 H), 8.22 (d,l H).

Claims (8)

Claims

1. Intermediates of general formula (III)

or a protected derivative thereof wherein R1 represents a hydrogen atom or a halogen atom or a group selected from C1 6alkyl, C26alkenyl, fluoroC1 6alkyl, C1 6alkoxy, -CHO, -CO2H or -COR2; R2 represents a group selected from C16alkyl, C26alkenyl, C1.6alkoxy or the group -NR15R16; R3 represents a group selected from -NO2, -NH2, -CN, an optionally protected derivative of -CO2H, -NHSO2CF3, a protected derivative of -NH2 or an optionally protected derivative of a C-linked tetrazolyl group;; R4 and R5, which may be the same or different, each independently represent a hydrogen atom or a halogen atom or a C1 6alkyl group; R6 represents a hydrogen atom or a group selected from C1 6alkyl, C26alkenyl, C1 6alkylthio, C1 6alkoxy, C37cycloalkyl or C3-7cycloalkylC1-4alkyl; R7a, R7b and R7C, which may be the same or different, each independently represent a hydrogen atom or a halogen atom or a group selected from cyano, nitro, C1 6alkyl, C26alkenyl, C3.7cycloalkyl, C3-7cycloalkylC1-4alkyl, fluoroC1.6alkyl, -(CmH2m)R9, -(CH2)nCOR10 or -(CH2)pNR11COR12;; R9 represents an optionally protected hydroxy or C1 6alkoxy group; R10 represents a hydrogen atom or a group selected from hydroxy, C1-6alkyl, C1.6alkoxy, phenyl, phenoxy, or the group -NR15R16; R11 represents a hydrogen atom or a C1 6alkyl group; R12 represents a hydrogen atom or a group selected from C1.6alkyl, C1 6alkoxy, phenyl, phenoxy, or the group -NR15R16; R15 and R16, which may be the same or different, each independently represent a hydrogen atom or a C14alkyl group or -NR15R16 forms a saturated heterocyclic ring which has 5 or 6 ring members and may optionally contain in the ring one oxygen atom; m represents an integer from 1 to 6; n represents zero or an integer from 1 to 4; and p represents an integer from 1 to 4; and salts or solvates thereof.

2. A compound of general formula (III) as claimed in claim 1 wherein R1 represents a hydrogen atom or a halogen atom or a group selected from C1 6alkyl, C1 6alkoxy or fluoroC1 6alkyl, and in particular a halogen atom or a -CF3 group, especially a bromine or chlorine atom.

3. A compound as claimed in claim 1 or claim 2 wherein R4 and R5 each independently represent a hydrogen atom.

4. A compound as claimed in any one claims 1 to 3 wherein R6 represents a C1 5alkyl or C3.5cycloalkyl group, in particular a C2,alkyl group, especially an ethyl, or n-propyl group.

5. A compound as claimed in any one of claims 1 to 4 wherein R7a, R7b, and R7e each independently represent a hydrogen atom or a halogen atom or a group selected from C1.6alkyl, C37cycloalkyl, C3-7cycloalkylC1-4alkyl, -(CmH2m)R9 or (CH2)nCOR' .

6. A compound as claimed in any one of claims 1 to 5 wherein R9 represents a hydroxy or C1 6alkoxy group or a protected hydroxy group.

7. A compound as claimed in any one of claims 1 to 6 wherein R10 represents a hydrogen atom or a hydroxy, C1 6alkoxy or -NR15R16 group (especially wherein R15 and R16 each independently represent a hydrogen atom or a C14alkyl group), and preferably a hydrogen atom or a hydroxy, methoxy, ethoxy, propoxy or butoxy group, and especially a hydrogen atom or a hydroxy or methoxy group, and m is 1 or 2 and n is zero, 1 or 2.

8. A process for preparing a compound of formula (III) which comprises: (A) reaction of a compound of formula (IV)

(wherein R1, R3, R4 and R5 are as defined in formula (III)) with a pyridine compound of formula (V)

(wherein R6, R7a, R7b and R7c are as defined in formula (III)), in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride or (B) reacting the intermediates of formulae (IV) and (V) under dehydrating conditions to give an intermediate imine of formula

which may subsequently be reduced to give a compound of formula (III) or (C) reaction of a compound of formula (VI)

(wherein R1, R3, R4 and R5 are as defined in formula (III)) with a pyridine compound of formula (ill)

(wherein R6, R7a, R7b and R7c are as defined in formula (III) and L is as previously defined).