GB2167745A

GB2167745A - 1,4-dihydropyridines

Info

Publication number: GB2167745A
Application number: GB08520487A
Authority: GB
Inventors: John Leheup Archibald; Terence James Ward; Albert Opalko
Original assignee: John Wyeth and Brother Ltd
Current assignee: John Wyeth and Brother Ltd
Priority date: 1984-08-17
Filing date: 1985-08-15
Publication date: 1986-06-04
Also published as: GB8520487D0; ZA855910B; US4694012A; GB2167745B; GB2163050B; DD236093A5; GB8421039D0; US4900750A; MX5840A; GB8520486D0; GB2163050A

Description

1 or salts thereof, wherein:

Ar is an optionally substituted aryl radical; SPECIFICATION

1,4-Dihydropyridines GB 2 167 745 A 1 This invention relates to heterocyclic compounds possessing pharmaceutical activity more particularly to 5 1,4-dihydropyridines, processes for preparing them and pharmaceutical compositions containing them.

In one aspect this invention provides compounds of formula Ar R 1 0 2 c C02 R2 1 1 B in A N I R (1) R represents hydrogen or an optionally substituted alkyl, aralkyl, or aryl group; R, and R2 are the same or different and are selected from hydrogen and saturated or unsaturated, cyclic or acyclic aliphatic hydrocarbon residues optionally substituted by one or more groups selected from halogen, OH, carboxy, CN, alkoxy, alkylthio, aryloxy, alkoxycarbonyl, amino, substituted amino, and 20 optionally substituted aryl; A and B independently represent a group of formula -XR3 wherein X is a group of formula -(CHR6)py(CHR7),,-- wherein Y represents -0-, -S-, - NR- or a direct bond; p and q each represent 0, 1 or 2 providing that p and q do not both represent 0 when Y is a direct bond; and R,, R7 and R8 are independently hydrogen or alkyl; and R3 is an optionally substituted nitrogen 25 ring heteroaryl radical optionally containing other ring heteroatoms selected from oxygen, nitrogen and sulphur; The term lower as used herein to qualify a group means the group contains 1 to 6 carbon atoms.

By the term aryl when used as a group or part of a group (e.g. aryloxy, arylaikyl) is meant any monov- alent carbocyclic or heterocyclic radical possessing aromatic character and includes such groups having 5 30 to 10 ring carbon atoms such as phenyl, naphthyl, pyridyl (e.g. 2-,3- or 4-pyridyl), thienyl (e.g. 2-thlenyl), furyl (e.g. 2-furyl), quinolyl (e.g. 2-, 3- or 4-quinolyi), isoquinolyl, (e.g. 2-,3- or 4-isoquinoiyl). Preferred heteroatoms are nitrogen, oxygen and sulphur. Examples of heterocyclic aromatic rings containing two heteroatoms are imidazolyl e.g. 1-imidazolyl, and thiazolyl, e.g. 5- thiazolyl.

The term alkyl when used to signify a group or part of a group such as aryfalkyl or alkyloxy means any 35 straight or branched saturated aliphatic hydrocarbon especially those having 1 to 6 carbon atoms, e.g. 1 4 carbon atoms, or cyclic saturated aliphatic hydrocarbons especially those of 5 to 7 carbon atoms. Ex amples are methyl, ethyl, n-propyl, isopropyl, n-butyl, n-hexyl and cyclohexyl.

By the term "optionally substituted" is meant optional substitution on carbon atoms by one or more substituents, e.g. substituents commonly used in pharmaceutical chemistry, e.g. halogen (e.g. Cl, Br, F), 40 alky], alkyloxy, haloalkyl (e.g. CF,) haloalkoxy (e.g. CF,CH,O-, CI-IF,O- ), NO,, NH,, CIM, alkylamino, dialkylam ino, carboxy, alkyloxycarbonyl, acy], acylamino.

Examples of the group R are groups as described above in connection with alkyl, aryl and arylalkyl and include hydrogen, methyl, ethyl, n-propyl, isopropyl and benzyl. Preferably R is hydrogen.

The groups R, and R2 can be independently hydrogen or saturated or unsaturated acyclic hydrogen 45 chains of 1 to 6 carbon atoms, e.g. lower alkyl or alkenyl optionally substituted by aryl of 5 to 10 carbon atoms, lower alkoxy, amino, diloweralkylamino, carboxyl or lower alkoxycarbonyl.

Examples of R, and/or R2 are methyl, ethyl, n-propyl, isopropyl, butyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxypropyl, aminoethyl, 2-aminoethyl, 3- aminopropyl, dimethylaminoe thyl, 2-carboxyethyl, ethoxycarbonyl methyl. When R' or R2 is alkyl substituted by optionally substituted 50 aryl (including heteroaryl) examples are pyridyimethyl or -ethyl (e.g. 3- pyridyl methyl) i mid azolyl methyl or -ethyl.

Preferred values for R, and/or R2 are methyl and ethyl.

Examples of R3 and are imidazolyl (e.g. 1 or 3-imidazolyl), pyridyl (e.g. 2 or 3-pyridyl), thiazoly] (e.g. 5 thiazolyl), pyrrolyl (e.g. 1-pyrrolyl) or bicyclic rings such as quinolyl (e.g. 2- or 4-quinolyl), isoquinolyl 55 (e.g. 1- or 4-isoquinolyl), imidazopyridyl (e.g. 5-imidazo [1,5-a]pyridyl). Preferred values are 1-imiclazolyl, 3-pyridyl and 5-imidazo[1,5-alpyridyl.

Examples of X are -NH-; -0-; -S-; -CH,; -CH(CH,,)-; -CH20_; -OCH,7-; (CH2)2)- -CH2CH(CH3) or groups of formula -CHi--Z-CH-, -CH2-Z-(C1-1j 7--, -(CH2)27--Z-CH27-- where Z is 0, S, NH or a direct bond.

Preferred examples of X are -CH20-, -CH,OCH,--, -CH20(CH2)2-, -CH-2 or CH2CH2--.

Examples of Ar are groups mentioned above for the definitions of aryl and included in the preferred values are 2- and/or 3- substituted phenyl groups, e.g. 2-and/or 3- nitrophenyl; 2,3-dichlorophenyl; 2-tri fluoromethylphenyl; pentafluorophenyl; naphthyl (e.g. l-naphthyi), pyridyl (e.g. 2-pyridyl), halopyridyl (e.g. 2- chloropyrid-3-yl), benzimidazolyl (e.g. 4- or 7-benzimidazolyl).

2 GB 2 167 745 A Particularly preferred compounds provided by this invention have formula]a:

2 R 12 R 11 R 1 0 c CO 2 2 2 het - XJ N X -het 10 1 R wherein R,R1 and R2 have the meanings given above het represents a pyridyl or imidazolyl group'X3 is -CHj---, -CH20CH,7-, -CH,O(CHJ27-, -CH2CH27, -(CH020CH- or -(CH,),O (CH2)27; R" and R12 are each 15 selected from hydrogen, nitro, halo or trifluoromethyl, or a salt thereof.

In formula la preferably R is hydrogen.

Examples of R, are H, Me or Et. Examples of R2 are Me and Et. When R11 is hydrogen examples of R12 are 2- or 3-nitro, 2-trifluoromethyl. Examples of R11 and R12 when substituents are 2,3-dihalo, (e.g. 2,3 dichloro), 3-halo-2-nitro and 2-halo-3-nitro. Preferably both het groups are the same e.g. 3-pyridyl or 1- 20 imidazolyl. Preferably both X3 groups are the same.

The compounds of formula I possess pharmaceutical activity in particular they inhibit thromboxane synthetase and inhibit blood platelet aggregation.

Since platelet aggregation is the initial step in thrombus formation it is considered that compounds which prevent aggregation or reduce platelet adhesiveness may inhibit the initiation of the atheroscler otic process. The effect of drugs on aggregation is measured in platelet- rich plasma containing a small amount of arachidonic acid which markedly increases aggregation in vitro and may be a physiological agent for doing so in vitro. The actual test procedure used is described below.

New Zealand white rabbits (2.5-3kg) are anaesthetised with an injection, via the marginal ear vein, of sodium pentobarbitone 30-40 mg/kg. The carotid artery is cannulated and blood (100-150 ml) is with- 30 drawn into 50 ml syringes containing 3.8% sodium citrate (Ratio blood: citrate = 9:1).

Blood is centrifuged at 200g (1500 r.p.m.) for 10 minutes at 5'C. and the platelet rich plasma (PRP) removed. The platelets are then kept at room temperature in a screw topped plastic centrifuge tube for the duration of the experiment.

A twin channel platelet aggregometer -(HU aggregometer, A.Browne Ltd, Leicester, UK) is used. 1.0 ml 35 aliquots of PRP are prewarmed for 5-10 minutes and stirred continuously at 1100 rpm. Aggregation is induced by addition of 250pm arachidonic acid, (8d volume) to the PRP samples. The aggregometer out put is set at maximum and the chart recorder sensitivity is altered to give a full scale deflection to this arachidonic acid response.

Control responses are recorded as the maximum deflection obtained after addition of 250LM arachi- 40 donic acid.

PRP samples are preincubated for 1 minute with the test compounds followed by arachidonic acid ad dition. The maximum deflection after the addition of arachidonic acid is then recorded. All drugs are screened initially at 10 -4M (final concentration), i.e. 10pl of a 1 X 10- 2M stock solution of the drug dis solved in distilled water is added to the PRP.

Dazoxiben, a thromboxane synthetase inhibitor (Randall, M.J. et al, Research 23 145-162, 1981) is used as a positive control and all test components are compared with Dazoxiben. The activity of the test com pound is expressed as the ratio IC,,, Dazoxiben/IC,,, Test where IC,, is the dose required to inhibit the A.A.

induced aggregation by 50%. The greater the ratio the more potent the compound relative to Dazoxiben.

3 GB 2 167 745 A 3 Compound Inhibition of blood platelet aggregation potency ratio (dazoxiben= 1) 1,4-Dihydro-2,6-di[(3-pyridyimethoxy)methyll-4-(3-nitrophenyi)- pyridine-3,5-dicarboxylic acid diethyl ester 0.5 1,4-Dihydro-2,6-di[(3-pyridyloxy)methyll-4-(3-nitrophenyl)pyridine- 3,5-dicarboxylic acid diethyl ester 0.9 1,4-Dihydro-2,6-di[2-(imidazol-l-yl)- ethyl] -4-(3-n itro phenyl) pyrid in e-3, 15 5-dicarboxylic acid diethylester 0.7 1,4-Dihydro-2,6-di[(3-pyridyimethoxy)- methyl 1-4-(2n itro p h enyl) pyrid i ne-3, 5-dicarboxylic acid diethyl ester 2.2 20 Compounds possessing thromboxane synthetase inhibitory activity are useful in the treatment or pre vention of diseases responsive to the inhibition of thromboxane synthetase especially cardiovascular dis orders such as thrombosis, atherosclerosis, cerebral ischaernic attacks; and angina pectoris; peripheral vascular diseases and migraine.

The compounds of formula I were tested for their ability to inhibit thromboxane production by the fol- 25 lowing standard test:

a) Generation of thromboxane Blood (approx. 75 ml) is obtained from an anaesthetised rabbit and centrifuged at 200g for 10 minutes to obtain platelet rich plasma (PRP). An aliquot of PRP is incubated for 10 minutes at 370C in the presence 30 of vehicle or drug. Platelet aggregation is induced by the addition of adenosine cliphosphate and adren alin. The tubes are incubated for 3 minutes, centrifuged at 10,000g for 3 minutes and a 50 ml aliquot of the supernatant taken for radio-immunoassay of thromboxane B, (TxB2).

b) Radio-immunoassay of TxB2 The total incubation volume is 150pi containing 50RI of 3H - TxB2 (0-005 VLCO, 50 ml of sample or au thentic TxB, ranging from 5 to 300 pg per tube as standards and 501il of rabbit anti-sera to TxB, (in a concentration which will bind 50% of H-TxB2). After incubation for 1 hour at room temperature the tubes are further incubated for 16-20 hours at 4C. 1 ml of dextrancoated charcoal is then added to the tubes which are further incubated on ice for 10 minutes. Following the incubation the samples are centrifuged 40 at 10,000g for 10 minutes and 500ml of the supernatant added to 5 ml of scintillation cocktail. Measure ment of the radioactivity in the supernatant quantifies the amount of [3H]-TxB, bound by the antibody.

The concentration of unlabelled TxB2 in the sample is then determined from a linear standard curve.

In the above mentioned test the compound 1,4-dihydro-2, 6-di[2-(imidazol1-yl)ethyll-4-(3-nitro- phenyl)pyridine -3,5-dicarboxylic acid cliethylester, had an IC,, value of 5.3[LM. An IC,,) value represents the concentration of drug which achieves 50% inhibition of TxB2' Some compounds of formula I have also been found to possess Phospholipase A, (PLA,) inhibitory activity and hence are also indicated for use as antiinflarnmatory and antiallergic agents. Of particular interest for this activity are compounds of formula I wherein Ar represents an aryl radical having a 2-nitro substituent. For example the compound of Example 2 produced a 72% inhibition of PLA2 activity at a concentration of 10ORM. PLA2 activity was assayed by a procedure based on Franson, R.C., Chapter 12.

Intracellular Metabolism of Ingested Phospholipids. Liposomes: from Physical structure to Therapeutic Applications. North-Holland Biomedical Press, 1981, pp 349-380 and involving measuring the hydrolysis of E.coli membrane phospholipids and the release of free [1-14C] oleic acid from the C-2 position of phos 55pholipids by human platelet PLA2.

Compounds of formula I have also shown anti hypertensive activity when tested on warm blooded ani mals and hence are indicated for the treatment of high blood pressure. This latter activity in combination with their blood platelet and thromboxane synthetase inhibitory properties makes these compounds po tentially very useful for the treatment of cardiovascular disorders, especially thrombosis.

Compounds of formula I were tested for anti-hypertensive activity by the following standard proce dure:

The blood pressures of male or female spontaneously hypertensive rats are measured in a 37'C con stant temperature housing by means of a tail cuff. Rats with systolic pressures below 155 mmHg are discarded. Groups of rats are dosed orally with the test substance in a suitable vehicle or with vehicle 6Ealone. Systolic pressures are recorded before dosing and at selected time points afterwards. Heart rates 65 4 GB 2 167 745 A 4 are derived from caudal artery pulses. Results are analysed statistically by means of 2 way analysis of variance (within group). In this procedure the compound of Example 2 at a dose level of 0.15 mmol/kg produced a 23% lowering of blood pressure, 2 hours after dosing. 5 This invention also provides processes for preparing the compounds of formula 1. A first general proc- 5 ess for preparing compounds of formula 1 as hereinbefore defined with the proviso that (a) when Y is -0-, -S- or -NRII- then p is 1 or 2 comprises reacting corresponding compounds of formula Ar R 1 0 2 c 10 11 B 0 R-NH, ill CO 2 R 2 20 IV 0 A wherein Ar, A, B, R, R, and R2 are as defined above.

In such a process, when B is a different group from A, in addition to the expected product having the formula Ar 2 B IN A R it is also possible to obtain 'bis' compounds having the formula r R102C C02R2 40 1 1 la 69 A 11A R 45 Accordingly compounds of formula 1 wherein B is A and proviso a) applies may be prepared by compounds of formula R 1 0 2 C ' Ar 50 Ila T 0 with compounds of formulae Ill and [V M 2 4 IV wherein Ar, R1, R2 and A are as defined above and T is an optionally substituted alkyl group.

The process is conveniently carried out by heating, e.g. at reflux, in an inert solvent preferably polar such as ethanol, toluene, dimethyfformamide, isopropanol, acetonitrile.

A second general process for preparing compounds of formula I as hereinbefore defined and subject to proviso a) as in the first process mentioned above, comprises reacting a corresponding compound of 65 formula 11 as shown above with a corresponding compound of formula 1.11 c 2 2 11 RHN A (V) GB 2 167 745 A 5 wherein A, B, Ar, R, R, and R2 are as defined above. This process may conveniently be carried out by 1() heating e.g. at reflux in an inert solvent (preferably polar) such as ethanol, acetonitrile, isopropranol, tol- 10 uene or dimethylformamide.

In yet a further process compounds of formula 1 wherein proviso (a) above applies may be prepared by reacting a compound of formula ArCHO with corresponding compounds of formula VI and V shown below R 1-02 c /C02?' 2 1 (V0 and (V) B 0 RNH A 20 wherein Ar, R, R, and R2 are as defined above. Such a process may be carried out by heating the reactants, e.g. at reflux, in an inert solvent (preferably polar) such as ethanol, acetonitrile, isopropanol, toluene or dimethylformamide.

A further process for preparing compounds of formula I as hereinbefore defined wherein B represents the same as the A group and proviso a) above applies comprises reacting compounds of formula ArCHO R NH2 (111), and C02 R2 (IV) A 0 in which formulae Ar, R, R2 and A are as defined immediately above. This process may be carried out by heating, e.g. at reflux in a suitable inert solvent, e.g. ethanol.

Compounds of formula I may be prepared by reacting corresponding compounds of formula 40 R 1 0 2C Ar CO 2 R2 B' 1 nw, (CHR 6)VZ1 (VIO 1 45 R and Z2(CHR7).R3 (Vill) 50 in which formulae Ar, R, W, R2, R3, R6 and R7 are as defined above. one of Z1 and Z2 is halogen or a sulphonyloxy group; the other of Z1 and Z2 is -YH or Y as appropriate (wherein Y is as defined above) and v and w are each 0, 1 or 2 providing that (i) when v and w = 0 then one of Z1 and Z2 is 0, S or NR8 and (ii) when v is 2 and Z2 is YH or Y then Z1 can also represent dialkylamino, e.g. -NMe, or a quaternary 55 ammonium group, e.g.-NMe3+1-; and B' is B as defined above or B' is Z' (CHR 6) v- wherein Z1, R6 and v are as defined above.

The reaction may be carried out in an inert solvent in the presence of base, e.g. K2C03 or a tertiary amine e.g. triethylamine. Anions of the requisite starting materials may be generated by the usual meth ods known in the art and reacted. Examples of sulphonyloxy are alkyl- or aralkyl- or aryl-sulphonyloxy, 60 e.g. tosyloxy or mesyloxy.

The starting materials of formula V11 wherein Z1 is halogen, sulphonyloxy as defined above may be prepared by known methods, e.g. from corresponding compounds of formula 6 GB 2 167 745 A Ar R 1 0 2C /C02R 2 6 B N (CHR) v OH 1 R OX) by methods known for the conversion of OH to halogen or sulphonyloxy. Compounds of formula VIII 10 wherein v=0 may be prepared by reacting a compound of formula X R 1 0 2 c (X) 6 1,11 1 B NRR wherein R, R' and B, are as hereinbefore defined with compounds of formulae A CO 2 R2 20 Ir (X0 CO 2 alkyl in which formula Ar and R2 are as defined above.

Compounds of formula IX wherein v is 1 or 2 may be prepared by reacting a compound of formula Ar 11 CO 2 R 30 1 (X11) 0 (CHR 6) v OH wherein v is 1 or 2 and Ar and R2 are as defined above with a compound of formula (X) as hereinbefore defined.

Compounds of formula VII wherein v is 2 and Z1 is -N(alkyl), or a quaternary ammonium group may be prepared by performing a Mannich reaction on a compound of formula 40 Ar R 10 2C C02R 2 1 1 B 1 CH3 (X111) 45 R using formaldehyde and secondary amine and if required reacting the product with an alkyl halide. Corn pounds of formula VII wherein Z1 is Ymay be prepared by known methods. For example, when Z1 is - 50 OH, -NHRI, or -SH anions may be formed in the presence of a strong base, e.g. an alkali metal hydride such as NaH or BuLL When Y is a direct bond carbanions may be prepared from the corresponding halo compound using for example, lithium diisopropylamine or BuLL In any of the aforementioned reactions reactive substituent groups may be protected if susceptible to the reaction conditions and deprotected afterwards.

Compounds of formula 1 wherein R is other than hydrogen may be prepared by alkylating a compound of formula 1 wherein R is H in the presence of a strong base, e.g. an alkali metal hydride, with a com pound of formula R halogen where R is as defined above other than hydrogen.

Compounds of formula 1 having ester functional groups, e.g. cyanoethyl- or t-butyl-ester, may be hy drolysed, selectively if appropriate, to give compounds of formula 1 having carboxyl groups. Alternatively 60 carboxyl groups can be esterified.

The compounds of formula 1 may possess one or more asymmetric centres and hence optical isomers and mixtures thereof are possible. All such isomers and mixtures thereof are included within the scope of this invention. Where any reaction process produces mixtures of such isomers standard resolution techniques may be applied to a separate a specific isomer.

7 GB 2 167 745 A 7 In any of the aforementioned reactions compounds of formula 1 may be isolated in free base form or as acid addition salts as desired. Examples of such salts include salts with pharmaceutical ly acceptable acids such as hydrochloric, hydrobromic, hydroiodic, sulphuric, phosphoric, nitric, acetic, citric, tartaric, fumaric, succinic, malonic, formic, maleic acid or organosulphonic acids such as methane sulphonic or p- tolyl sulphonic acids.

When acidic substituents are present it is also possible to form salts with bases e.g. alkali metal (such as sodium) or ammonium salts. Such salts of the compounds of formula 1 are included within the scope of this invention.

When basic substituents are present then quaternary ammonium salts may be formed by quaternizing with an alkylating agent such as alkyl-, aralkyl-halides.

Starting materials for the processes described herein are known compounds or can be prepared by analogous methods for known compounds.

This invention also provides pharmaceutical compositions comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof.

For the pharmaceutical compositions any suitable carrier known in the art can be used. In such a composition, the carrier may be a solid, liquid or mixture of a solid and a liquid. Solid form compositions include powders, tablets and capsules. A solid carrier can be one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, binders, or tablet disintegrating agents; it can also be encapsulating material. In powders the carrier is a finely divided solid which is in admix- ture with the finely divided active ingredient. In tablets the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5 to 99, preferably 10-80% of the active ingredient. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax and cocoa butter. The term "composition" is intended to include the formulation of an active ingredient with encapsulating material as carrier, to give a capsule in which the active ingredient (with or without other carriers) is surrounded by carriers, which is thus in association with it. Similarly cachets are included.

Sterile liquid form compositions include sterile solutions, suspensions, emulsions, syrups and elixirs.

The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both. The active ingredient can often be dissolved in a suitable organic solvent, for instance aqueous propylene glycol containing from 10 to 75% of the glycol by weight is generally suitable. Other compositions can be made by dispersing the finely-divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution, or in a suitable oil, for instance arachis oil.

Preferably the pharmaceutical composition is in unit dosage form, the composition is sub-divided in unit doses containing appropriate quantities of the active ingredient; the unit dosage form can be a packaged composition, the package containing specific quantities of compositions, for example packeted powders or vials or ampoules. The unit dosage form can be a capsule, cachet or tablet itself, or it can be the appropriate number of these in packaged form. The quantity of active ingredient in a unit dose of composition may be varied or adjusted from 10 to 500 mg or more, e.g. 25 mg to 250 mg, according to the particular need and the activity of the active ingredient. The invention also includes the compounds in the absence of carrier where the compounds are in unit dosage form. The following Examples illustrates the preparation of compounds of the invention:

Example 1

1,4-Dihydro-2,6-di[3-pyridylmethoxy)methyll-4-(3-nitrophenyl) pyridine-3, 5-dicarboxylic acid diethyl ester Ethyl 3-oxo-4-(3-pyridylmethoxy)butanoic acid (2.4g, 0.01 moll, m- nitrobenzaldehyde (0.8g, 0.053 moll and.880 ammonia (0.5 ml) in ethanol (50 ml) was refluxed for 30 hours. The solvent was removed under reduced pressure and the residue treated with 2N hydrochloric acid and diethyl ether. The aqueous ex- 50 tract was basified with ammonia, then extracted with chloroform. The extract was washed well with water, dried (MgSOJ and evaporated to give a solid. This was dissolved in acetone and acidified with ethanolic HCI to give crystals of the title compound (2.1g) mp 169-1710C.

Analysis:

C,H,,N,0,21-ICLI-120 requires C, 54.79; H, 5.34; N, 8.24% Found: C, 54.56; H, 5.48; N, 7.89%.

Example 2

1,4-Dihydro-2,6-dif(3-pyridylmethoxy) methyl]-4-(2-nitrophenyl)pyridine-3, 5-dicarboxylic acid diethyl ester 60 Ethyl 3-oxo-4-(3-pyridylmethoxy) butanoic acid (2.4g, 0.01 mol), 2- nitrobenzaldehyde (0.8g, 0.053 mol) and.880 ammonia (0.5 ml) in ethanol (50 ml) were refluxed for 48 hours. The solvent was removed un der reduced pressure and the residue treated with 2N hydrochloric acid and diethyl ether, then separated.

The aqueous phase was basified with 0.88 ammonia then extracted with chloroform (x3). The combined chloroform extracts were washed with water, dried (MgS04) and evaporated to give a residue which was 8 GB 2 167 745 A 8 dissolved in acetone and acidified with ethanolic HCL The dihydrochloride salt of the title compound crystallised and was collected by filtration and dried. m.p. 142-145'C.

Analysis:

C,11-1,,N,0,21-1C1 requires C, 56.28; H, 5.18; N, 8.47% Found: C, 56.25; H, 5.36; N, 8.25%.

Example 3

1,4-Dihydro-2,6-dif(3-pyridyloxyj-methyll-4-(3-nitrophonyl) pyridine-3,5dicarboxylic acid diethyl ester Ethyl 3-nitrobenzylideneacetoacetate (6.47g. 0.026mol), ethyl 3-oxo-4-(3- pyridyloxy)butanoate (5.8g, 10 0.026mol) and 0.88 ammonia (2.5ml) in ethanol were refluxed for 7 hours. The solvent was removed un der reduced pressure and the residue partitioned between 2N hydrochloric acid and diethyl ether. The aqueous acid was extracted with chloroform and this was washed with dilute ammonia solution, dried (MgSOJ and evaporated. The residue was purified by chromatography on silica with first chloroform then ethyl acetate as eluent to obtain the title compound. This was dissolved in ethanol and acidified 15 with ethanolic HCI to give the dihydrOGhloride salt of the title compound (0.95g) m.p. 206-208'C.

Analysis: C,,H,,,N,0,21-1C1 requires C, 54.98; H,437; N, 8.84% 20 Found: C, 54.92; H, 5.26; N,9.25%.

Example 4

1,4-Dihydro-2,6-di[2-imidazol- l-yl)ethyll-4-(3-nitrophenyl) pyridine-3,5dicarboxylic acid diethylester A mixture of 1,4-dihydro-2,6-di[3-(2-dimethylamino)-ethylj -4-(3- nitrophenyl)pyridine (2.52g, 5mmol) and imidazole (5.43g, 8Ommol) was refluxed vigorously in chlorobenzene (40mi) for 48 hours. More imidazole 25 (1.36g, 20 mmol) and chlorobenzene (10mi) were added and refluxing was continued for a further 24 hours. After cooling, the chlorobenzene phase was washed three times with water, dried NgSOJ and evaporated. The residue was treated with acetone (30mi) to give a solid product. This was suspended in boiling ethyl acetate (20mi) and excess ethanolic HCl was added. The mixture was stirred in the dark for 10 minutes while cooling slowly, then the solid collected, washed with ethyl acetate and dried to give the 30 title compound as the dihydrochloric, 314 hydrate salt, mp. 210-21 VC.

Analysis: C,,H,^0,2HCL314 H,0 requires: C, 52.22; H, 5.44; N, 13.53% 35 Found: C, 52.30; H, 5.37; N, 13.62.

Example 5

1,4-DI 6-di (3-pyridylethoxy)methyll hydro-2, [I -4-(3-nitrophenyl)pyridine-3,5-dicarboxylic acid diethyl ester A mixture of ethyl 3-nitrobenzylideneacetoacetate (3.0g), ethyl 3-oxo-4[2-(pyrid-3-yl)ethyloxylbutanoate (3.0g) and conc. ammonia (2 ml) in ethanol (50ml) was refluxed for 6 hours. The solvent was removed 40 under reduced pressure and the residue treated with ether and 2N hydrochloric acid, then separated. The aqueous acid phase was extracted with chloroform and the combined chloroform extracts washed with dilute ammonia solution, dried (NaSOJ and evaporated.

The residue was purified by chromatography on silica firstly using ethyl acetate as eluent.

The eluent was changed to ethyl acetate and ethanol (4:1 v,v) to give the title compound (0.85g). This 45 was dissolved in ethanol, acidified with ethanolic HCI to give on crystallisation the title compound as the dihydrochloride 3/4 hydrate, m.p. 132-134C.

Analysis:

C,,H,,,N40AHD.314 H20 requires: C, 56.37; H, 5.66; N, 7.97%.

Found: C, 56.11; H, 5.47; N, 8.04%.

Claims

1. A compound of formula (1) or a salt thereof; Ar R 1 0 2C C02 R 2 B A R 9 GB 2 167 745 A 9 wherein:

Ar is an optionally substituted aryl radical; R represents hydrogen or an optionally substituted alkyl, aralkyl, or aryl group; R, and R2 are the same or different and are selected from hydrogen and saturated or unsaturated, cyclic or acyclic aliphatic hydrocarbon residues optionally substituted by one or more groups selected 5 from halogen, OH, carboxy, CN, alkoxy, alkylthio, aryloxy, alkoxycarbonyl, amino, substituted amino, and optionally substituted aryl; A and B independently represent a group of formula -XR3 wherein X is a group of formula -(CHR6)PY(CHR7)'C__ wherein Y represents -0-, -S-, -NR- or a direct bond; p and q each represent 0,1 or 2 providing that p and q do not both represent zero when Y is a direct bond;and R6 R7 10 and R8 are independently hydrogen or alkyl; and R3 is an optionally substituted nitrogen ring heteroaryl radical optionally containing other ring heteroatoms selected from oxygen, nitrogen and sulphur.

2. A compound as claimed in Claim 1 in which R3 is selected from a monoor bicyclic nitrogen ring heteroaryl radical containing 5 to 10 ring atoms.

3. A compound as claimed in Claim 2 in which R3 is Selected from imidazolyl, pyridyl, thiazolyl, pyrro- 15 lyl, benzimidazolyl, quinolyl, isoquinolyl or imidazopyridyl.

4. A compound as claimed in any one of Claims 1 to 3 wherein X represents -NH-, -0-, -S-, -CH27-, -CH(CH,)-, -CH(CH,)CH2-, -CH2CH(CH3)_1-OCH2r--, -CH20_,-(CH2)2_0_, or a group of formula -CH2-Z-CH27, -(CH2)2Z-CH-, or -CH2- -Z(CH2)2- where Z is -0-, -S-, -NH- or a direct bond.

5. A compound as claimed in any one of claims 1 to 4 wherein Ar is optionally substituted phenyl, 20 pyridyl, quinolyl or benzimiclazolyl.

6. A compound as claimed in Claim 5 wherein Ar is 2- or 3-nitrophenyl, 2, 3-dichlorophenyl, 2-trifluo romethylphenyl, pentafluorophenyl, naphthyl, pyridyl or halopyridyl.

7. A compound as claimed in any one of Claims 1 to 6 wherein B is the same as A.

8. A compound as claimed in any one of Claims 1 to 7 wherein R is hydrogen, methyl, ethyl, n-proPYI, 25 isopropyl, benzyl, carbethoxymethyl or ca rb m ethoxym ethyl.

9. A compound as claimed in any one of Claims 1 to 8 wherein R, and/or R2 represent hydrogen or saturated or unsaturated acyclic hydrocarbon chains of 1 to 6 carbon atoms optionally substituted by aryl having 5 to 10 ring atoms, lower alkoxy, amino, diloweralkylamino, carboxy or loweralkoxycarbonyl.

10. A compound as claimed in any one of Claims 1 to 9 wherein R, and/or R2 is hydrogen, methyl, 30 ethyl, n-propyl, isopropyl, butyl, methoxymethyl, ethoxymethyl, methoxy, propyl, aminoethyl, 2-aminoe thyl, 3-aminopropyl, dimethylaminoethyl, 2-carboxyethyl, methoxycarbonylmethyl, ethoxycarbonylme thyl, pyridylmethyl, pyridylethyl, imidazolylmethyl or imidazolethyl.

11. 1,4-Di hyd ro-2,6-d i [(3-pyridiyl m eth oxy) m ethyl 1-4-(3-n itrop he nyl) pyridine-3,5-dicarboxylic acid die thyl ester or a pharmaceutically acceptable salt thereof.

12. 1,4-Di hyd ro-2,6-d i [(3-pyri dyl meth oxy) m ethyl 1-4-(2-n itrop h enyl pyridine-3,5-dicarboxylic acid diethyl ester or a pharmaceutically acceptable salt thereof.

13. 1,4-Di hyd ro-2,6-d i [ (3-pyri dyl oxy)-m ethyl I -4-(3nitrophenyl)pyridine-3,5-dicarboxylic acid diethyl es ter or a pharmaceutically acceptable salt thereof.

14. 1,4-Dihydro-2,6-di[2-(imidazol-1-yl)ethylI -4-(3-nitrophenyl)pyridine3,5-dicarboxylic acid diethyl es- 40 ter or a pharmaceutically acceptable salt thereof.

15. 1,4-Dihydro-2,6-di[(3-pyridylethoxy)methylI -4-(3nitrophenyl)pyridine-3,5-dicarboxylic acid diethyl ester or a pharmaceutically acceptable salt thereof.

16. A process for preparing a compound of formula I as claimed in Claim 1 or a salt thereof which comprises (i) reacting a compound of formula 11 or Ila R 1 0 2C Ar B 0 with compounds of formula RNH2 and R 1 0 2 c Ar T 0 (Ila) CO 2 R 2 55 1 IV 0 A 60 in which formulae A, B, Ar, R, R, and R2 are as defined in Claim 1 and T is an optionally substituted alkyl group providing that when Y is -0-, -S- or -NR- then p is 1 or 2, to give a compound of formula 1 or (ii) reacting a compound of formula 11 as defined in part (i) above with a compound of formula (V) GB 2 167 745 A Y."C02R 2 RNH A 5 wherein R, A, and R2 are as defined in Claim 1 providing that when Y is - 0-, -S- or -NR- then p is 1 or 2 to give a compound of formula 1 or (iii) reacting a compound of formula ArCHO with compounds of formula R107 ' 1 1, CH 2 R 2 -10 1 (V0 and (V) 1.1 f B 0 RNH A in which formulae Ar, R, W, R2, A and B are as defined in Claim 1 providing that when Y is -0-, -Sor -NRthen p is 1 or 2 to give a compound of formula 1, or (iv) reacting a compound of formula ArCHO with compounds of formula RNH2 and IV 2 20 (IV) 0 A 25 in which formula Ar, R, R2 and A are as defined in Claim 1 to give a compound of formula 1 wherein B is A and R, is the same as R2, or (v) reacting a compound of formula Ar 30 R 1 0 2 c C02 R 2 1 (V11) ]3n (CHR 6 v Z 1 R 35 with a compound of formula Z2(CHR7),,R3 (Vill) in which formulae Ar, R, W, R2, R3, R6 and R7 are as defined in Claim 1; sulphonyloxy, the other is -YH or -Y- as appropriate wherein Y is as defined in Claim 1 and v and w are each independently 0, 1 or 2 providing that a) when v and w are both zero then one of ZI and Z2 iS 0, S or NRI1, and b) when v is 2 and Z2 is YH or Y- then ZI can also represent dialkylamino or a quaternary ammonium 45 group; or (vi) alkylating in the presence of a strong base a compound of formula 1 as defined in Claim 1 wherein R is hydrogen with an alkylating agent of formula one of Z1 and Z2 is halogen or R- z3 where R is as defined in Claim 1 except hydrogen and Z3 is halogen or a sulphonyloxy group to give a corresponding compound of formula 1, or (vii) hydrolysing, selectively if desired, a compound of formula 1 as defined in Claim 1 having an ester group to give a compound of formula 1 having a carboxyl group, or (viii) esterfying a compound of formula 1 as defined in Claim 1 having a carboxy group to give a compound of formula 1 as defined in Claim 1 having an ester group, or (ix) reacting a compound of formula I as defined in Claim 1 having a carboxyl group with a base to form a salt thereof or acidifying a salt carboxylate of a compound of formula i to give the free acid, or (x) converting a compound of formula I as defined in Claim 1 to an acid addition salt thereof by 60 addition of acid or basifying an acid addition salt to give a compound of formula 1, or (xi) converting a compound of formula I as defined in Claim 1 having a basic substituent to a qua ternary ammonium salt thereof by reaction with an alkylating agent.

17. A process as claimed in Claim

18 for preparing a compound of formula I substantially as her einbefore described with reference to any one of Examples 1 to 5.

11 GB 2 167 745 A 11 18. A compound of formula I as claimed in Claim 1 whenever prepared by a process as claimed in Claim 16 or Claim 17.

19. A compound of formula I as claimed in any one of Claims 1 to 15 for use as a pharmaceutical.

20. A pharmaceutical composition comprising a compound of formula I as claimed in any one of 5 Claims 1 to 15 and a pharmaceutically acceptable carrier.

21. Use of a compound of formula I as claimed in any one of Claims 1 to 15 for the manufacture of a medicament for the treatment or prevention of cardiovascular disorders.

22. Use of a compound of formula I as claimed in any one of Claims 1 to 22 for the manufacture of a medicament for the treatment of prevention of thrombosis.

Printed in the UK for HMSO, D8818935, 4186, 7102. Published by The Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained.