GB2171095A

GB2171095A - Pharmaceutical compounds

Info

Publication number: GB2171095A
Application number: GB08529160A
Authority: GB
Inventors: Mark Andrew William Finch; John Richard Harris
Original assignee: Lilly Industries Ltd
Current assignee: Lilly Industries Ltd
Priority date: 1984-11-28
Filing date: 1985-11-27
Publication date: 1986-08-20
Also published as: ZA859077B; GB8430072D0; GB2171095B; EP0183532A3; AU5041285A; AU591643B2; EP0183532A2; JPS6248639A; US4801735A; GB8529160D0

Description

1 GB2171095A 1

SPECIFICATION

Pharmaceutical compounds This invention relates to novel compounds, pharmaceutical compositions containing them and 5 their use as pharmaceuticals.

The compounds of the invention have the formula R ox 2 X 1 01 R 2 (I) in which R' and R2 are each hydrogen, C,12 alkyl or C2-12 alkenyl, at least one of R' and R2 being 15 Cl-U alkyl or C2-12 alkenyl; X' and X2 are each hydrogen or a protecting group; and Y is (a) -(CH=CH)nZ in which n is 1, 2 or 3 and Z is -CHO, -CH2CH, -COR3, - (CH2LCOR 3 or -(CH2)PCH=CH(CH2),-COR 3 in which m is an integer of 1 to 12, p is an integer of 1 to 4, q is an integer of 1 to 10 and R 3 is (i) - OH or (ii) -NR 4 R5 where R 4 and R5 are each hydrogen, Cl-, alkyl or optionally substituted phenyl, or R 4 and R5 together with the nitrogen atom to which they are 20 attached form a morpholino, pyrrolidinyl or piperidino ring, (b) -CH=NFI6 in which R6 is (i) -OH, (") C 1 - 2 alkyl optionally substituted by -OH, -COOH or -NR 7 R" where R 7 and R" are each hydrogen or C,-4 alky], (iii) optionally substituted phenyl or (iv) -NR9RIO in which R9 is hydrogen and RIO is optionally substituted phenyl or Cl-, alkylCO-, or in which R9 and RIO together with the nitrogen atom to which they are attached form a morpholino, pyrrolidinyl or piperidino ring, (c) -CH,NHR 12 in which R" is C,.,, alkyl optionally substituted with hydroxy or carboxy or optionally substituted phenyl, or (d) -CHOR 12 o r 0 11 -CR 12 in which R 12 is hydrogen or ClA2 alky]; and lactones, salts and esters thereof; provided that when one of R' and R2 is hydrogen and the other is Cl-12 alkyl, Y is -(CH=CH).Z, n is 1 and Z is -COOH only salts are included.

Compounds of formula (1) when in unprotected form (X' and X 2 are both hydrogen) are inhibitors of leukotriene synthesis and are indicated for use in a variety of pharmacological conditions.

In the above formula (1) reference to an alkyl group includes, for example, methyl, ethyl, propyl, isopropy], tertiary butyl and groups contaning up to twelve carbon atoms, which may be straight or branched chain. When R' or R2 is alkyl it preferably contains from 3 to 7 carbon atoms.

Similarly an alkenyl group contains up to twelve carbon atoms and can be straight or branched. An alkenyl group is preferably of the formula: R 13 (CH = CHCHA- where R 13 is hydrogen or Cl-,, alkyl and r is 1 to 3, preferred examples being C,1-11,(CH=CHCH1 and allyi.

When X' and X 2 are protecting groups they can be any suitable group that protects the hydroxyl substituent during preparative reactions and such groups are well known in the art.

Examples include the tetrahydropyran or silyl protecting groups and an especially useful example 50 is the methyl methylether group formed, for example, by reacting a free hydroxyl with chlorome thyimethylether. Such groups can be readily displaced by acid to give compounds with the free hydroxyl when desired.

When one of the groups such as R 4, R5 or RIO is optionally substituted phenyl, it is preferably phenyl optionally substituted with hydroxyl, halo especially fluoro, chloro or bromo, C,-, alkyl especially methyl or ethyl, Cl-4 alkoxy especially methoxy or ethoxy, nitro and carboxy. When the phenyl ring is substituted there are generally 1 to 3 substituents and the most preferred are Cl-, alkyl, halo or hydroxy.

It is preferred that R' and R2 are Cl-12 alkyl or C2-12 alkenyl, and the most preferred compounds are those in which both R' and R2 areCl-12 alkyl or C2-12 alkeny]. Preferably an alkyl group 'S C2-11 60 alky]. The group Y is preferably of the formula -(CH=CH).Z. When Z is -CHO, -CH20H or -COR3 the preferred value of n is 2, and when Z is -(CH2L-COR3 or -(CH2)p CH=CH(C1-12), -COR3, n is preferably 1, and the values m and q are both preferably an integer of 1 to 4. Z is most preferably -COR3 and especially -COOH and esters de,- ived from the carboxy group.

The compounds of the invention include salts and these can be any of the well known base 65 2 GB2171095A 2 addition salts that form salts at a carboxyl group such as for example with those compounds in which Z is -COOH. Examples of such salts are those derived from ammonium hydroxide and alkali and alkaline earth metal hydroxides, carbonates and bicarbonates, as well as salts derived from aliphatic and aromatic amines and aliphatic diamines. Bases especially useful in the prepara tion of such salts include ammonium hydroxide, potassium carbonate, sodium bicarbonate, cal- 5 cium hydroxide, methylamine, diethylamine, ethylene diamine and cyclohexylamine. The potas sium and sodium salt forms are particularly preferred.

Also included in the invention are esters of the compounds of formula (1), principally those formed with compounds in which Z is -COOH. These can be any of the well known ester gro ups suitable for forming such derivatives. Preferred esters are those derived from and alcohol 10 or an aminoalcohol. In such instances Z has the value -COOR14 where R14 is C,-,, alkyl or -(CH,),NR15R'6 where R15 and R16 are each hydrogen or C, alkyl, especially methyl or ethyl, and s is 1, 2 or 3. The preferred esters are those derived from methanol and ethanol, that is, the methyl and ethyl esters of the compounds of formula (1).

Apart from pharmaceutically acceptable addition salts and esters, other salts and esters are 15 also included within the scope of the invention since they may serve as intermediates in the ' purification of compounds or in the preparation of other pharmaceutically acceptable derivatives, or they may be useful for identification, characterisation or purification of the free compound. A preferred group of compounds of formula (1) is of the following formula (CH-CE) n z R Cx2 2 X10 R in which R' and R 2 are each hydrogen, C,-12 alkyl or C2-,, alkenyl, at least one of R, and R 2 being Cl-,2 alkyl or C2-12 alkenyi, X' and X2 are each hydrogen or a protecting group, n is 1, 2 or 3, and Z is -COR 3 in which R3 is (i) -OH, (ii) -OR 14 where R14 'S Cl-12 alkyl or -(CH,),NR15R 16 where R15 and R16 are each hydrogen or C1-4 alkyl and s is 1, 2 or 3, or (iii) -NR 4 R5 where R 4 and R5 are each hydrogen, C, alkyl or phenyl optionally substituted by halogen or C,4 alky], or R 4 and R5 together with the nitrogen atom to which they are attached form a morpholino, pyrrolidinyl or piperidino ring, provided that when one of R' and R2 is hydrogen and the other is C,-12 alkyl, n is 1 and Z is -COR 3, R 3 is -OH or -NR 4 W; and salts thereof. Of these compounds a preferred group is one in which R' and R 2 are both C1A2 alkyl or C2-12 alkeny].

A further preferred group of compounds of formula (1) is of the following formula (CH-CH) n CORJ Rl 0E, 1 no R2 in which R' and R2 are each C3-, alkyl or R13(CH=CHCHI- where R13 is hydrogen or Cl, alkyl and 45 r is 1 to 3, and R3 is -OH, -OR 14 where R14 'S C,-4 alkyl or -(CH2)2NR'5R'6 where R15 and R16 are each hydrogen or C1- 4 alkyl, or -NWR5 where R4 and R5 are each hydrogen, C1-4 alkyl or phenyl optionally substituted by halogen or C1-4 alkyl; and salts thereof. Of these compounds those of the following formula are most preferred 3 2 R 1 CH 2 HO R in which R' and R' are both allyl or propyl, and R3 is -OH or -OR 14 where R 14 is C, alkyl; and salts thereof.

It will be appreciated that when Y is -(CH=CH).Z the compounds of formula (1) exist in 60 stereoisomeric (Z and E) forms about the C-C double bonds and such forms are included in the present invention, the E forms being preferred. Also it will be appreciated that compounds in which Z is -COOH and X2 is hydrogen can form internal lactones of the formula 3 GB2171095A 3 (CH-CE) n - c R -0 r2 11 R X 0 0 and such compounds are included within the scope of formula (1) above.

The invention also includes a process for preparing compounds of formula (1) which comprises 10 (a) heating a compound of formula Y C,112 1 R 10 (II) in which Y has the values given above and R' and R 2 areCl-12 alkenyl, to provide a compound 20 of formula (1) in which R' and R 2 areCl-12 alkenyl and X' and X2 are hydrogen, or (b) reacting a compound of the formula Rll OX 2 1 X 1 0 R 2 (M) (i) under Wittig or Knoevenagel conditions to provide a compound of formula (1) in which Y is 30 -(CH=CH,)Z, (ii) with hydroxylamine to provide a compound of formula (1) in which Y is -CH=NOH, (iii) with an amine of formula H2NHR6 in which R6 is Cl 12 alkyl optionally substituted by -OH, -COOH or -NR7R11 where R7 and R" are each hydrogen or Cl-, alkyl, optionally substituted phenyl, or -NR9R10 where R9 is hydrogen and R10 is optionally substituted phenyl or Cl-, alky1C0-, or in which R9 and W) together with the nitrogen atom to which they are attached form a morpholino, 35 pyrrolidinyl or piperidino ring, to provide a compound of formula (1) in which Y is -CH=NR6, or (iv) with a Grignard or alkyl lithium reagent of the formula R 12M in which M is Mg13r or lithium and R 12 is Cl-12 alky], to provide a compound of formula (1) in which Y is -CHOHR 12 optionally followed by oxidation; 40 optionally followed by reduction to provide a compound in which R' or R2 'S Cl-12 alkyl, or Y is 40 -(CHCH). CHO, - (CH=CH)nCH201-1 or -CH2NHR", or by conversion of one Z group to another, or by removal of a protecting group. The principal route for the preparation of the compounds is by the rearrangement of a compound of formula (11) above, preferably by heating the compound to a temperature of from 45 100'C to 250'C in an inert organic solvent such as for example nitrobenzene to effect the introduction of alkenyl substituent or substituents in the phenyl ring. The products of the rearrangement, namely, the compounds of formula (1) in which R' and R 2 are alkenyl can then optionally be reduced to give the corresponding compounds in which R' and R2 are alkyl. Compounds of formula (11) can be prepared by reacting a derivative of formula

HJ5 (IV) where R 'S Cl-4 alkyl, with a compound of formula RIX or R2X, R' and R 2 being alkenyl groups, and X a leaving group such as for example halogen, in the presence of a base, at a temperature of from 50'C to 7WC and in an inert organic solvent, followed by reduction to the aldehyde.

The aldehyde can then be converted to the appropriate value of side chain Y by one of the methods (b)(i), (ii), (iii) or (iv) defined above, namely, by reaction with Wittig or Knoevenagel reagent, with hydroxylamine, with amine of formula H2NIR6, or with Grignard or alkyl lithium reagent.

The above compound of formula (IV) can be reduced to the aldehyde by, for example, reaction with di-isobutyl aluminium hydride followed by a Collins oxidation, and the aldehyde reacted with 65 4 GB2171095A 4 Wittig or Knoevenagel reagent to form the appropriate ester. For example, reaction of a compound of formula CHO tOR2 (V1 R 10 with a Wittig reactant of formula PH.,P=CH-CO,Me, 0 Ph P-CH-CH-CR-CO Me or Ph P-CH C-N 0 gives, respectively, 3 2 3 2 \..-/ compounds of the formulae:

CH-CEICO 2 Me CH-KM-CH'C2CO2 Me 022 20 R 1 0 RJO t OR2 25 CS - CH 2 CON 0 OR 2 R 1 06 -30 Expressed more generally, the Wittig reagent employed is of the formula PH \Z/(CH=CH),- 3p ' -COR3, where n is 0, 1 or 2, Ph3PCH2(CH2),COR3 or Ph,PCHACH2)p CH=CH(C1-12),-COR3, in which R 3 'S -OC,-12 alkyl or -NR 4 R5 or P1- 13p\Y(CH=CH).CH0. The reaction is generally carried out at a 35 temperature of from O'C to 150'C in an inert organic solvent.

Alternatively, the unsaturated side chain can be introduced into the molecule by reaction of the appropriate aldehyde with CH,(C0Offi2 according to the reaction scheme:

R R 0 40 O+CE1 2 (Coon) 2 -CHCOOH 2 02.1 OR In order to obtain compounds in which n in formula (1) is 2 or 3, a carboxyl derivative may be 45 reduced to the corresponding aldehyde by conventional chemical reduction, and the condensation reaction repeated. The Knoevenagel reaction can be carried out in an organic solvent for example pyridine, at a temperature of from OOC to 1500C.

When it is desired to prepare the starting materials of formula (11) in which Y is -CH=NOH, the appropriate aldehyde of formula (V) is reacted with excess hydroxylamine at a temperature of, 50 for example, from O'C to 100'C in an inert solvent such as for example a mixture of water and ethanol.

When it is desired to prepare the starting materials of formula (11) in which Y is -CH=NR6, R6 being other than -OH, the appropriate amine is reacted with an aldehyde of formula (V) in an organic solvent such as for example toluene or benzene at reflux temperature and in the presence of an acid catalyst such as for example p-toluene sulphonic acid. A Dean and Stark apparatus can be used for this purpose, and the reaction leads to loss of water and formation of the required imine or hydrazone.

When it is desired to prepare the starting materials of formula (11) in which Y is -CHOHR 12 the aldehyde of formula (V) is reacted with a Grignard reagent or alkyl lithium in an organic solvent 60 such as for example tetrahydrofuran at a temperature of, for example, from -70'C to 20'C. The appropriate Grignard reagents and alkyl lithium derivavtives are well known in the art. If it is desired to prepare a compound in which Y is GB2171095A 5 0 11 -C-R12, the alcohol product of the above reaction can be oxidised using the Collins reaction.

It will be appreciated that the reactions described above can be carried out on a compound of formula R ' OX 2 X 1), R 2 (111) derived by rearrangement of the compound of formula (V) above and protection of the free hydroxyl groups if the subsequent reaction so requires.

Thus the Wittig and Knoevenagel reactions described above can be performed on the -rearranged- aldehyde, for example, a reaction:

CRO 1 1 0 R 2 X" t OX, - CH -COR R 1:z OX 2 1 1,5 2 X 0 R Wittig) followed by optional removal of protecting groups. Reactions with hydroxylamine, with amine of formula H2NR 6 and the Grignard and alkyl lithium reactions described above, process step (b) (ii), (iii) and (iv), can be utilised in this route for preparing the compounds of the invention. The reaction conditions are the same as those described above in relation to process step (a). 30 Compounds prepared by the above routes can be reduced to provide the derivatives in which R, or R 2 'S C2-,alkyl or is -(CH=CH).CHO, -(CH=CH).CH20H or -CH2NHR". The reduction process can be carried out by a chemical reaction method to prepare -(CH=CH).CHO or -(CH=CH)nCH20H, or by hydrogenating the double bond to prepare an alkyl group or -CH2NHR" by for example use of hydrogen and palladium on charcoal, or platinum on carbon, at a temperature of for example from O'C to WC such as from 2WC to 25'C.

It will be appreciated that compounds of formula (1) in which Z takes various values can often be readily interconverted by well known methods. For example when Z is carboxyl other derivatives, such as esters, amides and salts may be prepared by methods well known in the art. For instance derivatives can be prepared by reacting a compound of formula CH"C") nz 1 CX2 1 2 in which R' and R2 have the values given above, X' and X2 are protecting groups and Z is -COOH or -COCI, with an alcohol of the formula R 14 OH where R 14 'S C 1 12 alkyl or -(CH2),NR'5R'6 where s and R 15 and R16 are as defined above, or with an amine of formula HNR 4 R5 where R 4 and 50 R5 are as defined above.

An example of the preparation of a preferred group of compounds of the invention is illus trated in the following reaction scheme:

6 GB2171095A 6 E1O J5 CE 0,, ^, 1 reducticn CEO oxidatic 10 , [ r 0 Wittig o1 lli CCR n 0 COR 11: El0.

The compounds of the present invention are pharmacologically active, being inhibitors of leukotriene formation as shown by their action in the ionophore lipoxygenase test described by 25 Harvey and Osborne, Journal of Pharmacological Methods 9, 147-155 (1983). Elicited guinea pig peritoneal cells are preincubated with the test comound and challenged with a calcium ionophore in the presence of 14 C arachidonic acid. The radiolabelled metabolites are extracted and sepa rated by thin layer chromatography and the lipoxygenase products analysed by quantitative radiochromatogram scanning. In this test, the compounds of the invention described in the following Examples are active at concentrations of 30 micromolar or less. The compounds are also active in the "guinea-pig chopped lung test" described by Mongar and Schild in the Journal of Physiology (London) (3) 207 (1956), or by Brocklehurst, Journal of Physiology (London) 152, 414 (1960) at dosages of less than 30 micromolar.

The compounds are accordingly indicated for therapeutic use in the treatment of diseases in which leukotrienes ae implicated. These include immediate hypersensitivity diseases, allergic reactions of the pulmonary system in which leukotrienes are thought to be casual mediators of bronchospasm, for example, in allergic lung disorders such as extrinsic asthma and industrial asthmas such as Farmers lung and Pigeon Fanciers lung, and in other inflammatory disorders, for example, associated with acute or chronic infectious diseases such as allergic skin diseases, ectopic and atopic eczemas, psoriasis, contact hypersensitivity and angioneurotic oedema, bronchitis and cystic fibrosis and rheumatic fever. Furthermore, owing to their inhibition of leukotriene formation, the compounds have potential activity against a wide range of inflammatory diseases, and are also indicated for use in cancer treament.

The compounds may be administered by various routes, for example, by the oral or rectal route, by inhalation, topically or parenterally, for example by injection, being usually employed in the form of a pharmaceutical composition. Such compositions form part of the present invention and are prepared in a manner well known in the pharmaceutical art and normally comprise at least one active compound in association with a pharmaceutically acceptable diluent or carrier. In making the compositions of the present invention, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may, for example, be in the form of a capsule, sachet, paper or other container. Where the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Thus, the composition may be in the form of tablets, lozenges, sachets, cachets, elixirs, suspensions, aerosols as a solid or in a liquid medium, ointments containing for 55 example up to 10% by weight of the active compound, soft and hard gelatin capsules, supposi tories, injection solutions and suspensions and sterile packaged powders. For administration by inhalation, particular forms of presentation include aerosols, atomisers and vaporisers.

Some examples of suitable carriers are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, syrup, methyl cellulose, methyl and propylhydroxybenzoate, talc, magnesium stearate and mineral oil. The compositions of the invention may, as is well known in the art, be formulated so as to provide quick, sustained or delayed release of the active ingredient after adminstration to the patient.

Where the compositions are formulated in unit dosage form, it is preferred that each unit dosage form contains from 5 mg to 500 mg, more usually 25 to 200 mg, of the active 65 A 1 7 GB2171095A 7 ingredient. The term "unit dosage form" refers to physically discrete units suitable as unit dosages for human subjects and animals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier.

The active compounds are effective over a wide dosage range and for example dosages per day will n, ormally fall within the range of 0.5 to 300 mg/kg and in the treatment of adult humans, more usually in the range of from 5 to 100 mg/kg. However, it will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances including the condition to be treated, the choice of compound to be administered and the chosen route of administration and therefore the above dosage ranges 10 are not intended to limit the scope of the invention in any way.

The following Examples illustrate the invention. The structure of the compounds prepared was confirmed by I.R. and/or n.m.r and/or mass spectra and the purity of the product was checked in most cases by HPLC. The involatile products were examined by mass spectrometry using the fast atom bombardment (FAB) technique in the negative ion mode. Significant (M-H)ions (and 15 characteristic fragment ions) were observed.

EXAMPLE 1

Methyl-2,5-dihydroxybenzoate 2,5-Dihydrobenzoic acid (30g) was added to methanol (100 mi) which had been acidified with 20 hydrogen chloride gas. The solution was refluxed for 12 hours when the solvent was removed.

The resulting solid was taken up in diethyl ether (200 mi) and washed with water (2 X 100 mi).

The organic layer was dried over magnesium sulphate and the solvent removed under vacuum.

The resulting solid (30 9) (m.p. 83-84'C) was identified as the desired methyl ester.

EXAMPLE 2

Methyl-2,5-di-0-allylbenzoate To a solution of the methyl-2,5-dihydroxybenzoate (109) in acetone (120 mi) was added potassium carbonate (20.5 9) and allyl bromide (15.5 g). The mixture was refluxed for 3 hours when the solvent was removed under vacuum. The resulting solid was taken up in diethyl ether 30 (250 mi) and washed with water (2 X 150 mi). The organic layer was dried over magnesium sulphate and removed under vacuum to yield the desired 0-allylated product (13.5 g) as an oil.

EXAMPLE 3

2,5-Di-0-allylbenzyl alcohol To a stirred solution of the methyl ester (13.5 g) in dichloromethane (150 mi), at O'C and under an atmosphere of nitrogen was slowly added a solution of di- isobotyl-aluminium hydride (46 g, 20% in toluene). The reaction was quenched after 30 minutes by the slow, dropwise addition of water. After acidification with 2N HCl, the mixture was extracted with diethyl ether (2X 150 mi). The combined organic layers were dried over magnesium sulphate and the solvent 40 was removed under vacuum to yield the desired alcohol (10.5 g) as an oil.

EXAMPLE 4

2,5-Di-0-allylbenzaidehyde To a stirred solution of Collins reagent, made up from pyridine (44 g) and chromium trioxide 45 (28.6 9) in dry dichloromethane (500 m]) at O'C was slowly added a solution of the benzyl alcohol (10.5 9) in dry dichioromethane (30 mi). After 30 minutes the solvent was removed under vacuum and replaced with diethyl ether (250 mi). The resulting suspension was filtered through celite (RTM) and the residue was washed through with more diethyl ether. The com bined organic fractions were washed with 2N HCl (50 mi), then dried over magnesium sulphate. 50 Filtration and removal of solvent yielded the desired benzaldehyde (6.2 g) as a yellow oil.

Example 5

2,5-Dihydroxy-3,6-diallylbenzaldehyde The benzaidehyde (6.2 g) was heated, as a neat oil, at 18WC for 3 hours under an atmos- 55 phere of nitrogen. The resulting rearranged product was recrystallised from cyclohexane to yield the desired compound as yellow solid (4.1 9) (m.p. 102'C).

EXAMPLE 6

Ethyl-5-[2,5-dihydroxy-3,6-diallylphenyl]Pent-2E,4E-dieneoate To a stirred solution of the stabilised ylid (8g), preformed from the ethyl-5-bromo-crotanoate triphenyl phosphonium salt and sodium hydroxide, in toluene (1009) was added the benzal dehyde (4 g). After 1 hour the solvent was removed under vacuum and replaced with a small quantity of dichloromethane. This crude product was purified by column chromatography, silica gel with dichloromethane elution, to yield the desired ethyl ester (2.9 g) as an orange oil. 65 8 GB2171095A 8 The following compound was made by a similar method Methyi-3-(2,5dihydroxy-3,6-diallylphenyl-prop-2E-enoate EXAMPLE 7 Ethyl5-[2,5-di-0-methyimethyl ether-3,6-diallylphenyllpent-2E, 4E-dieneoate To a solution of the dihydroxy ester (1 g) in a two phase system of dichloromethane (20 m]) and aqueous sodium hydroxide (15%, 5 mi) containing a trace quantity of adogen 464 was added, dropwise, a solution of choloromethyimethyl ether (1.1 g). After 1 hour excess dichloromethane was added and the layers separated. The aqueous layer was extracted again with dichloromethane and the combined organic layers were dried over magnesium sulphate. Filtration 10 and removal of solvent yielded the di-0methyimethyl ether as an oil (0.9 9) after purification on a silica gel column with diethylether/hexane (1:1) elution.

EXAMPLE 8

5[2,5-di-0-methylmethyl ether-3,6-diallylphenyllpent-2,4-dieneoic acid To a solution of the ethyl ester (0.9 g) in dimethoxy ethane (5 mi) and water (5 mi) was added an excess of lithium hydroxide. After 24 hours the solvents were removed under vacuum and the resulting solid was taken up in water (25 mi), acidified with 2N HCI, and extracted with ethyl acetate (3X20 mi). The combined organic layers were dried over magnesium sulphate.

Filtration and removal of solvent yielded the desired acid (0.6 g).

EXAMPLE 9 1-[5-(2,5-di-0-methyimethyl ether-3,6-diallylphenyl)penta-2,4dienoyllpiperidine To a solution of the acid (0.6 9) in dicloromethane was added oxalyl chloride (1.2 equivalents) and a catalytic amount of dimethylformamide. After 30 minutes the solvent was removed under vacuum and replaced with fresh dichloromethane. This solution of the acid chloride was added slowly to a solution of piperidine (0.30 9) in dichloromethane (10 m]), at O'C and under an atmosphere of nitrogen. After 2 hours the reaction was quenched with water and the organic layer separated and dried over magnesium sulphate. Filtration and removal of solvent yielded the desired amide (0.32 9) as an oil.

EXAMPLE 10

1-[5-(2,5-dihydroxy-3,6-diallylphenyl)penta-2,4-dienoyll-piperidine The 2,5-di-0-methyimethyl ether derivative (0.3 g) was added to methanol which had been acidified with gaseous hydrogen chloride. The solution was stirred overnight when the solvent 35 was removed under vacuum. The resulting oil was taken up in the diethyl ether (20 mi) and washed with water (2X10 mi). The combined organic layers were dried and the solvent re moved to give the desired, 2,5-dihydroxy derivative as an oil (0.2 g).

EXAMPLE 11

1-Carboxyethenyl-3-[2,5-dihydroxy-3,6-diallylphenyllmorpholine To a solution of the stabilised ylid, preformed from the 3-chloro-ethenyl carboxy morpholine triphenyl phosphonium salt and sodium hydroxide in toluene was added 2,5- di-0-methyimethyl ether 3,6-diaiiyibenzaidehyde. The mixture was refluxed for 4 hours when the solvent was removed and the crude material purified by column chromatography, silica gel with diethyl ether 45 elution, to yield the desired amide after deprotection of the hydroxyl groups.

EXAMPLE 12

2,5-Dihydroxy-3,6-diallylphenyi-alkeny1 esters To a solution of the phosphonium bromide, Ph,P (CH,(CHIC0,Et Br, (1.1 equivalent) in dry 50 THF, at room temperature, and under an atmosphere of nitrogen was added K01Bu (1.2 equiva lents) Immediately a red coloured solution formed and was stirred a further 15 minutes when a solution of 2,5-di-0-methyimethylether-3,6-diallyI benzaldehyde (1 equivalent) in dry tetrahydrofu ran was added. The reaction mixture was stirred a further 4 hours then quenched with 2N HCl and extracted with diethylether. The resulting crude product was purified by column chromato- 55 graphy on silica gel using either dichloromethane or diethyl ethyl as eluting solvents.

The resulting olefins (E+Z isomers) were deprotected by stirring in a mixture of EtOH contain ing gaseous hydrogen chloride to give ethyl-(2,5-dihydroxy-3,6- diallylphenyi)hex-5-enoate.

The following compounds were prepared by a similar method:

Ethyl- 1 2-(2,5-dihydroxy-3,6-diallylphenyi)dodec- 'I l-enoate Methyl-9(2,5-dihydroxy-3,6-diallylphenyi)nona-5,8-dienoate Reduction with di-isobutyl aluminium hydride gave the following compound: 12-(2,5-Dihydroxy-3,6-diallylphenyi)dodec-1 1-en-l-ol.

Reduction by hydrogenation over 10% Pd/C gave: Ethyl 6-(2,5-dihydroxy-3,6-d ipropyl phenyl) hexanoate.

9 GB2171095A 9 EXAMPLE 13 2,5-Dihydroxy-3,6-diallylbenzaldehyde phenylhydrazine A mixture of 2,5-dially]-3,6-dihydroxy benzaldehyde (1.5 g), phenyl hydrazine (0.7 mi) and a catalytic amount of p-toluene suiphonic acid and toluene (150 mls) was refluxed under a Dean and Stark apparatus. The reaction was followed to completion using TLC. The toluene was removed under vacuum and the dark oil put down a silica-gel column with diethylether/hexane (1: 1) elution. The product was further purified by recrystallisation from CH2C12/petroleum ether 1 (40-60'C) to give a yellow solid, m.p. 79-81'C.

The following compounds were similarly prepared: 2,5-Dihydroxy-3,6diallyibenzaidehyde phenylhydrazone 79-8VC 2,5-Dihydroxy-3,6diaiiyibenzyiidene acety[hydrazide 193-194,C 2,5-Dihydroxy-3,6dialiyibenzaidehyde-4-nitrophenyihydrazone 218-220'C 1-(2,5-Dihydroxy-3,6dialiylbenzyiideneamino)morpholine 145-146'C 15 1-(2,5-Dihydroxy-3,6diaiiyibenzyiideneamino)piperidine N-(2,5-Dihydroxy-3,6diaiiyibenzyiidene)-2-hydroxy-5-chloroaniline 208-210'C 6-(2,5-Dihydroxy3,6-diaiiyibenzyiideneamino)hexanoic acid N-(2,5-Dihydroxy-3,6diaiiyibenzyiidene)dodecyla mine WC N-(2,5-Dihydroxy-3,6diaiiyibenzyiidene)N,N-dimethyi- 1,3-di-aminopropane EXA MPLE 14 2,5-Diallyl-3,6-dihydroxybenzaldoxime Hydroxylamine hydrochloride (2 g) was dissolved in 20 ml of water and added to 2,5-diallyl 3,6-dihydroxybenzaidehyde (2 g). Enough ethanol was added to completely solubilise the al dehyde. The mixture was heated on a steam bath for ten minutes until TLC showed the reaction 25 to be complete. The water and ethanol were evaporated and the solid recrystallised from ethanol/water, to give a beige solid, m.p. 241-243'C.

EXA MPLE 15 3,6-Diallyl-2,5-dihydroxyphenyl-alkyI ketones a) To the Grignard reagent, undecyl magnesium bromide, (1.1 equivalents) dry tetrahydrofuran (prepared from the halide and magnesium turnings) under nitrogen at room temperatue was added a solution of 2,5-di-0-ally] benzaldehyde (1 equivalent) in dry tetrahydrofuran. After stirring for 4 hours the reaction was quenched with 2N HCI and extracted with diethyl ether. The crude product was purified by column chromatography using silica gel, with dichloromethane as the 35 eluting solvent.

b) To a solution of the aldehyde 2,5-di-0-ally] benzaldehyde (1 equivalent) in dry THF at room temperature and under an atmosphere of nitrogen was added methyl lithium (1.1 equivalent).

After 2 hours the reaction was quenched with 2N HCI and extracted with diethylether. The crude product was purified as above.

c) To a stirred suspension of Collins reagent (6 equivalents) in dry dichloromethane at WC was slowly added the alcohol (1 equivalent). After 0.5 hours the solvent was removed under vacuum and replaced with diethyl ether. This suspension was then filtered through Celite and then washed with 2N HCI and dried overM9S04. Removal of the solvent left a crude material which was purified by column chromatography on silica gel with dichloromethane as the eluting solvent. 45 A neat solution of the 0-allyl ketone was heated at 180'-200'C, under an atmosphere of nitrogen, for 2 hours. The product was allowed to cool and purified by column chromatography on silica gel using dichloromethane as the eluting solvent.

The following compounds were prepared by this method:

2,5-Dihydroxy-3,6-diallylphenyl undecyl ketone, 2,5-Dihydroxy-3,6-diallyl acetophenone.

EXAMPLE 16 N-(2,5-Dihydroxy-3,6-dipropylbenzyl) alkyl(aryl)amines A solution of N-(2,5-dihydroxy-3,6-dialiyibenzylidene)-2-hydroxy-5chloroaniline in dry tetrahy drofuran was hydrogenated over 10% Pd/C at room temperature and atmospheric pressure.

After the required uptake of hydrogen had occurred the reaction mixture was filtered through Celite and the solvent removed under vacuum. The resulting amine, W(2,5- dihydroxy-3,6-dipro pylbenzyi)-2-hydroxy-5-chloroaniline, was recrystallised, m.p. 157-159'C.

The following compound was similarly prepared:

N-(2,5-dihydroxy-3,6-dipropyibenzyi)ethanolamine.

The following Examples illustrate the preparation of typical formulations containing an active ingredient according to the invention.

EXAMPLE 17

GB2171095A 10 Semi-Solid Matrix Capsule Each capsule contains Active ingredient 10 mg PEG 4000 250 mg The PEG 4000 is melted and mixed with the active ingredient. Whilst still molten the mixture is filled into capsule shells and allowed to cool.

EXAMPLE 18 Tablet Each tablet contains Active ingredient 10 mg 15 Calcium carbonate 300 mg - Magnesium stearate 10 mg Starch 30 mg Hydroxypropyimethylcellulose 10 mg Iron oxide 4 mg 20 The active ingredient is granulated with calcium cabonate and starch. The dried granulate is blended with lubricant and disintegrant and compressed into tablets of the required dosage strength. The tablet may then be coated.

EXAMPLE 19 Aerosol Active Ingredient 10 mg Ethanol 90 mg Propellant 11/12 900 mg The active ingredient is dissolved in ethanol and filled into a suitable pressurisable aerosol container. The container is filled with the propellant and sealed using conventional equipment. 35 The container may incorporate a metering valve.

Proportions: Propellant 11 30% Propellant 12 70% EXAMPLE 20 Hard Gelatin Capsule Each capsule contains Active ingredient 10 mg Starch 190 mg The active ingredient is mixed with starch and the mixture filled into hard gelatin capsules using conventional equipment.

Claims

CLAIMS 1. A compound of the formula

Y R ox 2 X 1 ol R 2 in which R' and R 2 are each hydrogen, C,, alkyl or C2-12 alkeny], at least one of R' and R 2 being 60 C,-, alkyl or C,-, alkeny]; X' and X2 are each hydrogen or a protecting group; and Y is (a) -(CH=CH).Z in which n is 1, 2 or 3 and Z is -CHO, -CH,OH, -COR3, -(C11jm-COR3 or -(CH2),CH=CH(CH2),,-COR 3 in which m is an integer of 1 to 12, p is an integer of 1 to 4, q is an integer of 1 to 10 and R 3 is (i) -OH or (ii) -NR 4R5 where R 4 and R5 are each hydrogen, C, alkyl or optionally substituted phenyl, or R4 and R5 together with the nitrogen atom to which 11 GB2171095A 11 they are attached form a morpholino, pyrrolidinyl or piperidino ring, (b) -CH=W in which R6 is (i) -OH, 00 Cl-12 alkyl optionally substituted by -OH, -COOH or -NR 7 W' where R 7 and W' are each hydrogen or Cl, alkyl, (iii) optionally substituted phenyl or (iv) -NR9RIO in which R9 is hydrogen and RIO is optionally substituted phenyl or Cl, alkyiCO-, or in which R9 and RIO together with the nitrogen atom to which they are attached form a morpholino, pyrrolidinyl or piperidino ring, (c) -CH2NHR" in which W' is Cl,, alkyl optionally substituted with hydroxy or carboxy or optionally substituted phenyl, or (d) -CH0HR12 or 0 11 -CR12 in which R12 is hydrogen or Cl-12 alkyl; and lactones, salts and esters thereof; provided that when one of R, and R2 is hydrogen and the other is Cl12 alkyl, Y is -(CH=CH)J, n is 1 and Z is -COOH only salts are included.
2. A compound according to claim 1 of the formula (CH-CE)nz 20 Rl( OX2 X 1 0 R 2 25 in which R' and R2 are each hydrogen, Cl 12 alkyl or C2 1, alkenyl, at least one of R' and R2 being Cl- 12 alkyl or C2-12 alkenyi, X' and X2 are each hydrogen or a protecting group, n is 1, 2 or 3, and Z is -COR3 in which R 3 is (i) -OH, (ii) -OR 14 where R 14 is Cl 12 alkyl or -(CH2),NR'5R'6 where R15 and R 16 are each hydrogen or Cl 4 alkyl and s is 1, 2 or 3, or (iii) -NWR5 where R 4 and R5 are each hydrogen, C1-4 alkyl or phenyl optionally substituted by halogen or C,-4 alkyl, or R 4 and 30 R5 together with the nitrogen atom to which they are attached form a morpholino, pyrrolidinyl or piperidino ring, provided that when one of R' and R2 is hydrogen and the other is Cl-12 alkyl, n is 1 and Z is -COR3, R 3 is -OH or -NR 4 R5; and salts thereof.
3. A compound according to claim 2 of the formula (CH.CH),CCR 3 tio RO 2 in which R' and R2 are each C3, alkyl or R13 (CH=CHCHI- where R13 is hydrogen or Cl, alkyl and r is 1 to 3, and R3 is -OH, -OR 14 is Cl-4 alkyl or -(CH2)2NR'5R 16 where R 15 and R 16 are each hydrogen or Cl-4 alkyl, or -NR 4 R' where R 4 and R5 are each hydrogen, C 1-4 alkyl or phenyl 45 optionally substituted by halogen or C, 4 alkyl; and salts thereof.
4. A compound according to claim 3 in which R' and R 2 are both allyl or propyl, and R3 is -OH or -OR 14 where R 14 'S C1-4 alkyl; and salts thereof.
5. A pharmaceutical formulation comprising a compound according to claim 1 in which X' X2 are both hydrogen, or a pharmaceutically-acceptable salt or ester thereof_in association with a 50 pharmaceutically-acceptable diluent therefor.
6. A process for preparing a compound according to claim 1 which comprises (a) heating a compound of formula Y OR2 1 R 1 (I1) in which Y has the values given above and R' and R2 are Cl-12 alkenyl, to provide a compound in 60 which R' and R2 areCl-12 alkenyl and X' and X2 are hydrogen, or (b) reacting a compound of the formula 12 GB2171095A 12 R ' ox 2 1 1 -R 2 X0 (111) (i) under Wittig or Knoevenagel conditions to provide a compound in which Y is -(CH=CH),Z, (ii) with hydroxylamine to provide a compound in which Y is -CH=NOH, (iii) with an amine of formula H2NR6 in which R6 is C,-12 alkyl optionally substituted by -01-1, 10 -COOH or -NRIR" where R 7 and Rs are each hydrogen or C, alkyl, optionally substituted phenyl, or -NR9R'0 where R9 is hydrogen and W0 is optionally substituted phenyl or C, alky1C0-, or in which R9 and W0 together with the nitrogen atom to which they are attached form a morpholino, pyrrolidinyl or piperidino ring, to provide a compound in which Y is -CH=NIRI, or (iv) with a Grignard or alkyl lithium reagent of the formula R 12M in which M is MgBr or lithium 15 and R 2 'S Cl-2 alkyl, to provide a compound in which Y is -CHOHR 12 optionally followed by oxidation; optionally followed by reduction to provide a compound in which R' or R2 'S Cl-12 alkyl, or Y is -(CH=CH), CHO, -(CH=CH),CH20H or -CH2NHR", or by conversion of one Z group to another, or by removal of a protecting group.
7. A compound according to claim 1 in which X' and X2 are both hydrogen, or a pharmaceutically-acceptable salt or ester thereof, for use as a pharmaceutical.
8. A compound according to claim 1 substantially as described with reference to any of Example 5 to 16.

Printed in the United Kingdom for Her Majesty's Stationery Office, Dd 8818935, 1986. 4235 Published at The Patent Office. 25 Southampton Buildings. London. WC2A 1 AY, from which copies may be obtained