IE940210L

IE940210L - Dihydropyridine derivatives, their preparation and their use

Info

Publication number: IE940210L
Application number: IE940210A
Authority: IE
Inventors: Hiroyuki Koike; Masafumi Yoshimoto; Hiroshi Nishino
Original assignee: Priorlucky Ltd; Kanegafuchi Chemical Ind
Priority date: 1986-10-09
Filing date: 1987-10-09
Publication date: 1988-04-09
Also published as: IE77041B1

Description

77041 1 DIHYDROPYRIDINE DERIVATIVES. THEIR PREPARATION AND THEIR USE The present invention relates to a series of new dihydropyridine derivatives, and provides a process for 5 preparing them as well as compositions for their pharmaceutical use.

Circulatory and coronary disorders are amongst the major causes of death in the industrialized world and, even where they do not result in death, some disablement 10 or a severe curtailment of lifestyle may result.

Notwithstanding this, the full etiology of such disorders has not been resolved, even though certain factors, notably genetic and dietary factors, have been implicated. There is, therefore, a substantial need for 15 medicines to treat this major problem. In attempting to treat circulatory and coronary disorders, attention has been focused on a variety of different pharmacodynamic activities, and the drugs used in such treatment have a variety of different structures, depending upon the 20 particular pharmacodynamic activity which it is desired to influence.

Of the many classes of drug proposed for use in such treatment, some compounds have a 4-(substituted phenyl)-1,4-dihydropyridine basic structure and included 25 within such general classes of drug are nifedipine (which is included amongst the compounds disclosed in British Patent Specification No. 1 173 862) and nicardipine (which is included amongst the compounds disclosed in British Patent Specification No. 30 1 455 502) . All of these compounds have in common a 4 - (nit rophenyl) - 2,6 - dimethyl -1,4- dihydropyridine -3,5-dicarboxylic acid ester structure. 77041 2 However, it is believed that the closest prior art to the compounds of the present invention is disclosed in Arzneim. - Forsh., 31, 1173 (1981) and in European Patent Publication No. 125 803. Both of these disclose compounds which are said to have cardiovascular activity, in much the same way as do the compounds of the present invention. However, the compounds of the former prior art differ from those of the present invention in the nature of the ester grouping at the l,4-dihydropyridine system. The latter prior art, although disclosing compounds some of which have an ester grouping resembling that of the present invention, differ in the overall structure of the compounds and notably in the nature of the groups at the 2- and 6-positions of the dihydropyridine ring.

Other related compounds are disclosed in European Patent Publication No. 207 674, available under Art 54(3) EPC only, but these differ from the compounds of the present invention in that the prior compounds contain a nitrooxy group in their molecular structure, which is not possesed by the compounds of the present invention.

Yet further related compounds are disclosed in Japanese Patent Publication 61-158962 (see Chem Abs 106 32851 Ja) , Gb Patent Specification 2014134, EP 63365, and EP 106276. All of these patent specifications dislcose 2,6-dimethyl-4-(substituted phenyl) -1,4 - dihydropyridine -3,5- dicarboxylic acid 3-aralkylheterocyclic 5-alkyl esters.

The compounds of the invention are those dihydropyridine derivatives of formula (I) : (I) in which: Ar represents a phenyl group having at least one substituent selected from nitro, C1 - C4 haloalkyl, 5 Ci ~ C4 haloalkoxy and cyano groups and halogen atoms; R represents a C1 - Clg alkyl group, a C3 - Cg cycloalkyl group, a - C4 alkyl group having a C3 - Cg cycloalkyl substituent, a Cj - C4 10 alkenyl group, a cinnamyl group or a C1 - Clg alkyl group having at least one substituent selected from hydroxy, - C4 alkoxy and alkylthio groups; R^" represents a hydrogen atom or a C1 - C3 alkyl 15 group (and may be a substituent on any of the carbon atoms of the nitrogen-containing heterocyclic group); O a O R and R are the same or different and each represents an unsubstituted phenyl group or a substituted phenyl group having at least one substituent 20 selected from alkyl, alkoxy and C1 - C4 haloalkyl groups and halogen atoms; R represents a methyl group; R represents an amino group and n is an integer from 1 to 3; 4 but excluding the compound in which Ar is a 3-nitrophenyl group, R is an isopropyl group, R1 is O K hydrogen, R and R are the same and are each an n * unsubstituted phenyl group, R is a methyl group, R 5 is an amino group and n is the integer 1; and pharmaceutically acceptable acid addition salts thereof.

The invention also provides a pharmaceutical composition for the treatment of cardiovascular 10 disorders, which composition comprises a dihydropyridine derivative in admixture with a pharmaceutically acceptable carrier or diluent, wherein said dihydropyridine derivative is at least one compound of formula (I) or a pharmaceutically acceptable salt 15 thereof.

The invention still further provides the use for the manufacture of a medicament, especially for the treatment of cardiovascular disorders, of a compound of formula (I) or a pharmaceutically acceptable salt 20 thereof.

The invention also provides processes for preparing the compounds of the invention, which are described in more detail hereafter.

The compounds of the present invention have been 25 found to have various valuable pharmacological activities such as calcivim antagonism, antihypertensive and vasodilator activity as well as low toxicity and are thus useful as medicines for the treatment of cardiovascular dysfunctions such as hypertension and 30 angina pectoris.

* In the compounds of the invention, Ar represents a phenyl group which has at least one, and preferably only one, nitro, - C4 haloalkyl, C1 - C4 haloalkoxy or cyano substituent, or at least one, and 5 preferably one or two, halogen substituents.

In particular, we prefer that Ar should represent a phenyl group having a single substituent selected from nitro groups, haloalkyl groups containing one or two carbon atoms (such as the trifluoromethyl or 10 2,2,2-trifluoroethyl groups), haloalkoxy groups containing one or two carbon atoms (such as the difluoromethoxy group, trifluoromethoxy group or 2,2-difluoroethoxy group) and cyano groups. Alternatively, we prefer that Ar should represent a 15 phenyl group containing one or two halogen atoms (such as the fluorine, chlorine, bromine or iodine atoms) as substituents. Preferred such groups represented by Ar are the o-nitrophenyl, m-nitrophenyl, p-nitrophenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, 20 o-cyanophenyl, m-cyanophenyl, o-trifluoromethylphenyl, m-trifluoromethylphenyl, o-difluoromethoxyphenyl, m-difluoromethoxyphenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl and 2,4-dichlorophenyl groups. Of these, we particularly 25 prefer the o-nitrophenyl, m-nitrophenyl, o-chlorophenyl, m-chlorophenyl and 2,3-dichlorophenyl groups.

R1 represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms. Examples of such groups include the methyl, ethyl, propyl and isopropyl 30 groups. The hydrogen atom and the methyl group are preferred, and the hydrogen atom is most preferred. 6 O a OV\ * R and R are the same or different and each represents a phenyl group which may be unsubstituted or have*at least one - C4 alkyl, C1 - C4 alkoxy, C. - C. haloalkyl or halogen substituent and the two Oa O groups represented by R and R may be the same or different, but they are preferably the same. Where the substituent is an alkyl group, this is preferably a C1 ~ C3 9rouP» such as a methyl, ethyl, propyl or isopropyl group. Where the substituent is an alkoxy 10 group, this is preferably a - C3 alkoxy group, such as a methoxy, ethoxy, propoxy or isopropoxy group. Where the substituent is a halogen atom, this is preferably a fluorine, chlorine, bromine or iodine atom. Where the substituent is a haloalkyl group, this 15 is preferably a C1 or C2 haloalkyl group, such as a trifluoromethyl or 2,2,2-trifluoroethyl group, especially a trifluoromethyl group.

Where R represents a straight or branched chain alkyl group containing from one to sixteen carbon atoms, 20 it preferably has from one to ten carbon atoms, and examples include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, octyl and decyl groups. Such groups may be unsubstituted or may have one or more, and preferably only one substituent, as defined 25 below.

The C1 - Clg alkyl groups represented by R may be unsubstituted or have at least one substituent selected from hydroxy groups, C1 - C4, preferably C1 " C3' alkoxy 9rouPs (such as the methoxy, ethoxy, 30 propoxy or isopropoxy groups) or C1 - C4, preferably C1 " C3' alkylthio 9rouPs (such as the methylthio, ethylthio, propylthio or isopropylthio groups).

Where R represents a cycloalkyl group containing from three to six carbon atoms, it may be, for example, a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group. Where R represents a C1 - C4 alkyl group having a C3 " cg cycloalkyl substituent, this is a cycloalkylalkyl group containing from four to eight carbon atoms, and examples include the cyclopropyl-methyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclopentylethyl and 2-cyclohexylethyl groups. Where R represents a C2 - C4 alkenyl group, it is preferably an alkenyl group containing three or four carbon atoms, for example an allyl or 2-butenyl group. 3 4 R is a methyl group and R represents an amino group; thus, the compounds of the present invention can be illustrated by formula (la): h3c n nh2 (la) h ROOC h2h (lb) H 8 4 A _ U in which Ar, n, R, R , R and R are as defined 2 cl 2^3 above; in these formulae, R and R are preferably the same groups.

Preferred classes of compounds of the present 5 invention are: (1) Those compounds of formula (I) in which: Ar represents a phenyl group having a single substituent selected from nitro, C1 - C2 haloalkyl, C1 - C2 haloalkoxy and cyano groups or having one or two halogen 10 substituents; R represents a C1 - C1Q alkyl group, a C3 - Cg cycloalkyl group, a C1 - C2 alkyl group having a C3 - Cg cycloalkyl substituent, a C3 - C4 alkenyl group, a cinnamyl group or a - C1Q alkyl group having at least one substituent selected from hydroxy, C1 - C3 alkoxy and - C3 alkylthio groups; R1 represents a hydrogen atom or a - C3 alkyl group; *5 a O V\ R and R are the same or different and each represents an unsubstituted phenyl group or a substituted phenyl group having at least one substituent selected from C1 - C3 alkyl, - C3 alkoxy and trifluoromethyl groups and halogen atoms; ■a A R represents a methyl group and R represents an amino group; and n is an integer from 1 to 3; 9 and pharmaceutically acceptable acid addition salts thereof. (2) Those compounds defined in (1) above in which R2a and R are the same.

More preferred classes of compounds of the present invention are: (3) Those compounds of formula (I) in which: Ar represents a phenyl group having a single substituent selected from nitro, trifluoromethyl, difluoromethoxy 10 and cyano groups or having one or two chloro substituents; R represents a alkyl group (especially one containing from one to six carbon atoms, such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or hexyl 15 group), an alkoxyalkyl group containing a total of from three to five carbon atoms (such as a 2-methoxyethyl, 2-ethoxyethyl or 2-propoxyethyl group), an alkylthioalkyl group containing a total of three or four carbon atoms (such as a 2-methylthioethyl, 3-methylthio-20 propyl or 2-ethylthioethyl group), a cycloalkyl group containing five or six carbon atoms (such as a cyclopentyl or cyclohexyl group), a cycloalkylalkyl group containing a total of from four to seven carbon atoms (such as a cyclopropylmethyl, cyclopentylmethyl or 25 cyclohexylmethyl group), an alkenyl group containing three or four carbon atoms (such as an allyl or 2-butenyl group), or a cinnamyl group; R1 represents a hydrogen atom or a methyl group; and 2sl R and R are the same and each represents a phenyl group or a phenyl group having a single substituent selected from chlorine atoms, fluorine atoms, trifluoromethyl groups, methyl groups and methoxy groups; and pharmaceutically acceptable acid addition salts thereof.

The most preferred classes of compounds of the present invention are: (4) Those compounds of formula (I) in which: Ar represents a 2-nitrophenyl group, a 3-nitrophenyl group, a 2-trifluoromethylphenyl group, a 3-trifluoromethylphenyl group, a 2-chlorophenyl group or a 2,3-dichlorophenyl group; R represents a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, 2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-methylthioethyl, 3-methylthiopropyl, 2-ethylthioethyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, allyl, 2-butenyl or a cinnamyl group; R1 represents a hydrogen atom or a methyl group; and R and R are the same and each represents a phenyl group or a p-fluorophenyl group; and pharmaceutically acceptable acid addition salts thereof.

The compounds of the invention can form acid addition salts. The nature of such salts is not critical to the present invention, except that, where the salts are to be used for therapeutic purposes, they 11 must be pharmaceutically acceptable, which, as is well understood in the art, means that the salts should not have reduced activity (or unacceptably reduced activity) and should not have increased toxicity (or unacceptably increased toxicity) as compared with the free compound. However, where the salt is to be employed for other purposes, for example as an intermediate in the preparation of other compounds, even this criterion does not apply. A wide variety of acids may be employed to form such salts and representative examples of such acids include: mineral acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, metaphosphoric acid, nitric acid or sulphuric acid; organic carboxylic acids, such as acetic acid, oxalic acid, tartaric acid, citric acid, benzoic acid, glycolic acid, gluconic acid, glucuronic acid, succinic acid, maleic acid or fumaric acid; and organic sulphonic acids, such as methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid or g-toluenesulphonic acid. Such acid addition salts may be prepared by conventional methods well known to those skilled in the art.

The compounds of formula (I) may contain several asymmetric carbon atoms, and thus can form a variety of optical isomers. The present invention includes both the individual isolated isomers and mixtures thereof.

Examples of specific compounds of the invention are given in the following formulae (1-1) to (1-7), in which the substituents are as defined in the corresponding one of Tables 1 to 7 [i.e. Table 1 relates to formula (I-l), Table 2 relates to formula (1-2) and so on]. The compounds of the invention are hereinafter, where appropriate, identified by the numbers appended to them in these Tables. In the Tables, the following abbreviations are used: 12 All allyl Bu butyl iBu isobutyl Bun 2-butenyl Cim cinnamyl Dc decyl DFM difluoromethyl Et ethyl Hp heptyl Hx hexyl cHx cyclohexyl Me methyl Oc octyl Ph phenyl Pn pentyl cPn cyclopentyl Pr propyl cPr cyclopropyl iPr isopropyl TFM . trifluoromethyl 13 14 rooc ,2 / ■ch h3C^N/> ,1 h —ch (1-3 ) V tPrOOC h ch \R2b ir-vi TABLE 1 Compound No.

Ar R R1 R2 1-1 o-N02Ph Me H Ph 1-2 o-N02Ph Et H Ph 1-3 o-N02Ph iPr H Ph 1-4 o-N02Ph Hx H Ph 1-5 o-N02Ph 2-MeOEt H Ph 1-6 o-N02Ph cHx H Ph 1-7 o-N02Ph Cim H Ph 1-8 m-N02Ph Me H Ph 1-9 m-N02Ph Et H Ph 1-10 m-N02Ph Pr H Ph 1-12 m-N02Ph Bu H Ph 1-13 m-N02Ph iBu H Ph 1-14 m-N02Ph Pn H Ph 1-15 m-N02Ph Hx H Ph 1-16 m-N02Ph Hp H Ph 1-17 m-N02Ph Oc H Ph 1-18 m-N02Ph Dc H Ph 1-19 IS-N02Ph 6-HOHx H Ph 1-20 m-N02Ph 2-MeOEt H Ph 1-21 m-N02Ph 2-EtOEt H Ph 1-22 iB-N02Ph 2-PrOEt H Ph 1-23 m-N02Ph 2-MeSEt H Ph 1-24 iQ-N02Ph 2-EtSEt H Ph 1-25 m-N02Ph 3 -MeSPr H Ph 1-26 rn-N02Ph cPn H Ph 1-27 m-N02Ph cHx H Ph 1-28 m-N02Ph cPrMe- H Ph 16 TABLE 1 (cont) Compound No.. Ar R Rl r2 1-29 m-N02Ph cPnMe- H Ph 1-30 m-N02Ph cHxMe- H Ph 1-31 m-N02Ph All H .

Ph 1-32 m-N02Ph Bun H Ph 1-33 m-N02Ph Cim H Ph 1-34 o-TFMPh Me H Ph 1-35 o-TFMPh iPr H Ph 1-36 o-TFMPh Hx H Ph 1-37 o-TFMPh 2-MeOEt H Ph 1-38 m-TFMPh Me H Ph 1-39 m-TFMPh iPr H Ph 1-40 m-TFMPh Hx H Ph 1-41 nj-TFMPh Cim H Ph 1-42 o-DFMOPh Me H Ph 1-43 o-DFMOPh Et H Ph 1-44 Q-DFMOPh iPr H Ph 1-45 o-CNPh Me H Ph 1-46 o-CNPh iPr H Ph 1-47 o-CNPh Hx H Ph 1-48 m-CNPh Me H Ph 1-49 m-CNPh iPr H Ph 1-50 m-CNPh Hx H Ph 1-51 m-CNPh 2-MeOEt H Ph 1-52 a-CtPh Me H Ph 1-53 2-C«Ph Et H Ph 1-54 o-C«Ph iPr H Ph 1-55 o-C«Ph Hx H Ph 1-56 Q-C£Ph Cim H Ph 1-57 2,3-diC«Ph Me H Ph 17 TABLE 1 (cont) Compound No.

Ar R R1 R2 1-58 2,3-diCsPh Et H Ph 1-59 2,3-diCsPh iPr H Ph 1-60 2,3-diCePh Hx H Ph 1-61 2,3-diCsPh 2-MeOEt H Ph 1-62 2,3-diC«Ph cHx H Ph 1-63 2,3-diC« Ph All H Ph 1-64 2, 3-diC«Ph Bun H Ph 1-65 2,3-diCePh Cim H Ph 1-66 m-N02Ph Me H E-FPh 1-67 m-N02Ph Et H E-FPh 1-68 m-N02Ph iPr H E-FPh 1-69 m-N02Ph Hx H E-FPh 1-70 m-N02Ph Me H E-C#Ph 1-71 m-N02Ph iPr H £-C«Ph 1-72 m-N02Ph cHx H E-CiPh 1-73 m-N02Ph Et H E-TFMPh 1-74 m-N02Ph iPr H B-TFMPh 1-75 m-N02Ph 2 - MeOEt H E-TFMPh 1-76 2,3-diCJPh iPr H E-FPh 1-77 m-N02Ph Me H ]D-MePh 1-78 m-N02Ph iPr H E-MeOPh 1-79 m-N02Ph Hx H p-MeOPh 1-80 m-N02Ph Me 3-Me Ph H 00 I H m-N02Ph Et 3-Me Ph 1-82 m-N02Ph iPr 3-Me Ph 1-83 m-N02Ph Hx 3-Me Ph 1-84 m-N02Ph Cim 3-Me Ph 1-85 m-N02Ph iPr 3-Me B-FPh 1-86 2,3-diC«Ph iPr 3-Me Ph 18 TABLE 1 (cont) Compound No.. Ar R R1 R2 1-87 2,3-diCJPh Hx 3-Me Ph 1-88 m-N02Ph iPr 2-Me Ph 1-89 m-N02Ph Hx 2-Me Ph 1-90 2,3-diCsPh Me 2-Me E"Fph 1-91 2,3-diCJPh iPr 2-Me Ph 19 TABLE 2 Compound No.

Ar R R1 R2 2-1 o-N02Ph Me H Ph 2-2 o-N02Ph Et H Ph 2-3 o-N02Ph iPr H Ph 2-4 o-N02Ph Hx H Ph 2-5 o-N02Ph cHx H Ph 2-6 m-N02Ph Me H Ph 2-7 m-N02Ph Et H Ph 2-8 m-N02Ph iPr H Ph 2-9 m-N02Ph Hx H Ph 2-10 m-N02Ph 6-HOHx H Ph 2-11 m-N02Ph 2 -MeOEt H Ph 2-12 m-N02Ph 2-MeSEt H Ph 2-13 ffi-N02Ph cPn H Ph 2-14 m-N02Ph cPrMe- H Ph 2-15 B»-N02Ph Bun H Ph 2-16 m-N02Ph Cim H Ph 2-17 2,3-diC«Ph Me H Ph 2-18 2,3-diC«Ph Et H Ph 2-19 2,3-diCePh iPr H Ph 2-20 2,3-diCePh Hx H Ph 2-21 2,3-diCePh 2 -MeOEt H Ph 2-22 2,3-diC«Ph All H Ph 2-23 2,3-diC«Ph Cim H Ph 2-24 m-TFMPh Me H Ph 2-25 m-TFMPh iPr H Ph 2-26 B-N02Ph Me H |>-FPh 2-27 m-N02Ph Et H E-FPh 2-28 gv-N02Ph iPr H E-FPh TABLE 2 (cont) Compound No.

Ar R R1 R2 2-29 m-N02Ph Hx H p-FPh 2-30 m-N02Ph 2-MeOEt H p-FPh 2-31 m-N02Ph Me H g-C«Ph 2-32 m-N02Ph 6-HOHx H p-C«Ph 2-33 m-N02Ph Et H g-MePh 2-34 m-N02Ph Bun H p-MePh 2-35 m-N02Ph iPr H p-TFMPh 2-36 m-N02Ph Cim H p-TFMPh 2-37 2,3-diCBPh Me H p-FPh 2-38 2,3-diC«Ph iPr H p-FPh 2-39 2,3-diCsPh Hx H p-FPh 2-40 S-N02Ph Me 3-Me - Ph 2-41 m-N02Ph iPr 3-Me Ph 2-42 m-N02Ph Hx 3-Me Ph 2-43 m-N02Ph iPr 3-Me p-FPh 2-44 2,3-diCJPh Me 3-Me Ph 2-45 2,3-diCJPh iPr 3-Me Ph 2-46 m-N02Ph iPr 4-Me Ph 2-47 m-N02Ph Hx 4-Me Ph 2-48 2,3-diC«Ph Me 4-Me Ph 2-49 2,3-diCsPh iPr 4-Me Ph 21 TABLE 3 Compound No. Ar R R1 R2 3-1 o-N02Ph Me H Ph 3-2 o-N02Ph Et H Ph 3-3 o-N02Ph iPr H Ph 3-4 Q-N02Ph Hx H Ph 3-5 o-N02Ph cPn H Ph 3-6 m-N02Ph Me H Ph ,3-7 m-N02Ph Et H Ph 3-8 rti-N02Ph iPr H Ph 3-9 ni-N02Ph Hx H Ph 3-10 m-N02Ph 6-HOHx H Ph 3-11 m-N02Ph 2-MeOEt H Ph 3-12 in-N02Ph 2 -MeSEt H Ph 3-13 m-N02Ph £Hx H Ph 3-14 in-N02Ph cPrMe- H Ph 3-15 m-N02Ph All H Ph 3-16 m-N02Ph Cim H Ph 3-17 2,3-diCiPh Me H Ph 3-18 2,3-diCtPh Et H Ph 3-19 2,3-diCtPh iPr H Ph 3-20 2,3-diCtPh Hx H Ph 3-21 2,3-diCtPh 2-MeOEt H Ph 3-22 2,3-diCtPh Bun H Ph 3-23 2,3-diC*Ph Cim H Ph 3-24 m-TFMPh Me H Ph 3-25 m-TFMPh iPr H Ph 3-26 m-CHF20Ph iPr H Ph 3-27 m-CHF2OPh Hx H Ph 3-28 Si-N02Ph Me H B-FPh 22 TABLE 3 (cont) Compound No.

Ar R R1 R2 3-29 m-N02Ph Et H E-FPh 3-30 m-N02Ph iPr H p-FPh 3-31 m-N02Ph Hx H E-FPh 3-32 m-N02Ph Me H E*C«Ph 3-33 m-N02Ph iPr H E-C8Ph 3-34 m-N02Ph iPr H E-MePh 3-35 m-N02Ph Hx H E-MePh 3-36 m-N02Ph Et H E-TFMPh 3-37 m-N02Ph iPr H E-TFMPh 3-38 2,3-diCsPh Me H E-FPh 3-39 2,3-die a Ph iPr H E-FPh 3-40 2,3-diC«Ph Hx H E-FPh 3-41 m-N02Ph Me 3-Me Ph 3-42 m-N02Ph Et 3-Me Ph 3-43 m-N02Ph iPr 3-Me Ph 3-44 m-N02Ph Hx 3-Me Ph 3-45 m-N02Ph Me 3-Me E-FPh 3-46 2,3-diCePh Me 3-Me Ph 3-47 2,3-diC«Ph iPr 3-Me Ph 3-48 ffi-N02Ph iPr 4-Me Ph 3-49 m-N02Ph Hx 4-Me Ph 23 TABLE 4 Compound No. n R2*3 7-1 1 4-FPh 7-2 1 4-C 8 Ph 7-3 2 4-FPh 7-4 2 4-C«Ph 7-5 3 4 -FPh 7-6 3 4 -C « Ph 24 Of the compounds listed above, the following are preferred, that is to say Compounds No. 1-9. 3-(l-Benzhydryl-3-azetidinyl) 5-ethyl 2-amino-6-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3, 5-5 dicarboxylate and salts thereof; 1-27. 3-(l-Benzhydryl-3-azetidinyl) 5-cyclohexyl 2-amino-6-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylate and salts thereof, especially its dihydrochloride; 1-59. 3-(l-Benzhydryl-3-azetidinyl) 5-isopropyl 2-amino-4- (2,3-dichlorophenyl) -6-methyl-l,4-dihydro-pyridine-3,5-dicarboxylate and salts thereof; 1-68. 3- [1- (4,4' -Difluorobenzhydryl) -3-azetidinyl] 5 - isopropyl 2 - amino - 6 - methyl - 4 - (3 - nitropheny 1) -1,4 -15 dihydropyridine-3,5-dicarboxylate and salts thereof; 1 - 82. 3 - (1-Benzhydryl - 3 -methyl - 3-azetidinyl) 5-isopropyl 2-amino-6-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylate and salts thereof; 2-8. 3-(l-Benzhydryl-3-pyrrolidinyl) 5-isopropyl 20 2-amino-6-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine- 3,5-dicarboxylate and salts thereof, especially its dihydrochloride; 2 - 9. 3 - (1 - Benzhydryl - 3 - pyrrol idinyl) 5 - hexyl 2-amino-6-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine -25 3,5-dicarboxylate and salts thereof, especially its dihydrochloride; 3-8. 3-(1-Benzhydryl-3-piperidyl) 5-isopropyl 2-amino-6 - methyl - 4 - (3 - nit ropheny 1) -1,4 - dihydropyridine -3,5- dicarboxylase and salts thereof, especially its 30 dihydrochloride; and Of these, Compounds No. 1-59 and 1-68 are most preferred.

The compounds of formula (I) in accordance with the present invention can be prepared, for example, by the following reaction, specifically, they can be prepared by reacting an a-benzylideneacetoacetic acid ester of formula (II): Ar I CH II c (II) ch3-C-C-COOR5 with an amidinoacetic acid ester of formula (III) : II 0 h2n-c-ch2-coor6 (III) II nh In the above formulae, Ar is as defined above, R represents a group of formula (IV): 6 2a (iv) (in which n, r1, r2a and r2b are as defined above) and the other of r5 and r6 represents a - Clg 26 alkyl group, a C3 - Cg cycloalkyl group, a C1 - C4 alkyl group having a C3 - Cg cycloalkyl substituent, a C2 - C4 alkenyl group, a cinnamyl group or a - Clg alkyl group having at least one substituent selected from hydroxy, - C4 alkoxy and - C4 alkylthio groups, i.e. any one of the groups defined above in respect of R.

More specifically, the reaction involved in the preparation of the compounds of the invention may be as illustrated below in order to prepare the compounds of formula (la): A r 0 (Ilia) (Ila) 27 28 l 2a In the above formulae, Ar, n, R, R , R and 2j^ R are as defined above.

In order to carry out this reaction, the compound of formula (II) or (Ila) is mixed with the compound of formula (III) or (Ilia), preferably in equimolar amounts, although a greater than equimolar amount of either of the reagents may be employed, if desired. However, this tends to be wasteful of reagents and so equimolar proportions are preferred. The reaction is preferably carried out in the presence of a solvent, more preferably an organic solvent, for example: an alcohol, such as ethanol, isopropanol or t-butanol; an ether, such as dioxane; a fatty acid amide, such as dimethylformamide; a sulphoxide, such as dimethyl sulphoxide; or a nitrile, such as acetonitrile; or in the presence of water; or a mixture of any two or more thereof. Alternatively, the reaction may be effected in the absence of a solvent.

The reaction will take place over a wide range of temperatures, and the precise temperature chosen is not critical to the present invention. However, we generally find it convenient to carry out the reaction at about room temperature or with heating, preferably at or about the reflux temperature of the reaction mixture, and normally at or about the reflux temperature of the solvent if a solvent is employed. Normally, we prefer to carry out the reaction under atmospheric pressure or under superatmospheric pressure. Most conveniently, the reaction is carried out in the presence of one or more of the above solvents under atmospheric pressure and at around the boiling point of the solvent employed.

The reaction time will vary depending upon many factors, notably the reaction temperature, and is not critical to the practice of the present invention. 29 However, at the temperatures suggested above, a period of from 30 minutes to five hours will usually suffice.

In this reaction, the compound of formula (III) or (Ilia) is preferably used in the form of an acid 5 addition salt, such as the hydrochloride, hydrobromide or acetate and, in that case, the reaction is preferably carried out in the presence of a base, preferably an equimolar amount of a base, and preferably an alkali metal (e.g. sodium or potassium) alkoxide, such as 10 sodium methoxide or sodium ethoxide.

After completion of the reaction, the desired compound of formula (I) or (la) may be recovered from the reaction mixture by conventional means, and, if necessary, it may be further purified by such 15 conventional purification techniques as recrystallization or the various chromatography techniques, notably column chromatography.

Of the starting materials employed in the reactions described above, the compound of formula (Ila) may be 20 prepared by the dehydrating condensation of an aldehyde of formula Ar-CHO with an acetoacetic acid ester of formula CH3COCH2COOR according to a known method [e.g., 6. Jones, " Knoevenagel Condensation", Org. Reactions, Volume 15, 204 (1967)]. The acetoacetic 25 ester employed in this reaction may be prepared from diketene and an alcohol of formula R-OH according to a known method [e.g., A. B. Boese, Jr., Industrial and Engineering Chemistry, 32, 16 (1940) ] . In the above formulae, Ar and R are as defined above.

The compound of formula (Ilia) can easily be prepared by reacting a cyanoacetic acid ester of formula (V) : / mc-chj-c—0 icty, i ; m—ch 2a \R2b (V) (in which n, R1, R2a and R2*3 are as defined above) with ammonia or with an ammonium salt according to a known method [S. A. Glickman and A. C. Cope, J. Amer. Chem. Soc., 67, 1017 (1945); S. M. McElvain and B. E. Tate, J. Amer. Chem. Soc., 73, 2760 (1951)].

The compound of formula conventional esterification an alcohol of formula (VI): (V) can be prepared by a between cyanoacetic acid and / ch \ r 2a (VI) 2b 1 O a o K (in which n, R , R and R are as defined above), e.g. a dehydration reaction catalyzed with an acid or in the presence of a carbodiimide, such as 1,3-dicyclohexylcarbodiimide.

The alcohol of formula (VI) can easily be prepared by reacting a cyclic amine of formula (VII) : ho / (ch2)n r1 nh (VII) (in which n and R are as defined above) with an optionally substituted benzhydryl halide of formula (VIII): R2a I X-CH (VIII) R2b O a O K (in which R and R are as defined above and X represents a halogen atom).

The alcohol of formula (VI) in which n is 1 can be prepared from epichlorohydrin and benzhydrylamine according to a known method [e.g. A. G. Anderson, Jr. and R. Lok., J. Org. Chem., 3>7, 3953(1972)].

Compounds of formula (VI) in which R1 represents a C1 - C^ alkyl group on the 3-position of the nitrogen-containing heterocyclic ring (i.e. on the same carbon atom as the hydroxy group), that is to say compounds of formula (VIc) , may also be prepared as illustrated by the following reaction scheme: 32 /R •CH V 2a step A1 (CH2)n (VIbl step A2 HO R1 / (CH2)n (Ylc) H— / CH \ ,2a 2b 1 Oa O V\ (in which n, R , R and R are as defined above) .

Step A1 of the above reaction scheme, in which the 5 hydroxy group is oxidized to a ketonic oxo group, may be carried out as described by A. Morimoto et al. [Chem. Pharm. Bull., 21, (1) , 228 - 231 (1973)] and D. Horton et al. [Carbohydr. Res., 7, 56 (1968)]. Step A2 of the reaction scheme involves the reaction of the compound of 10 formula (VIb) , prepared in Step Al, with a Grignard compound of formula R^gX' (in which R1 is as defined above and X' represents a halogen atom, preferably a chlorine, iodine or bromine atom), as described by S. S. Chatterjee gt al. [Synthesis, 1973. 15 153 - 154] . 33 Compounds of formulae (la) synthesized according to the reactions described above can form a number of stereoisomers, for example optical isomers, because of the presence in their molecules of a number of 5 asymmetric carbon atoms, e.g. at the 4-position of the dihydropyridine ring or in the alcohol moiety which forms the ester group. Geometric isomers (cis or trans) may also be formed in some cases as a result of the same alcohol moiety. The individual isolated isomers may, in 10 some cases, be prepared by stereospecific synthesis techniques or they may be isolated by methods known per se from mixtures of isomers. The present invention embraces both the individual isolated isomers and mixtures of isomers.

BIOLOGICAL ACTIVITY The dihydropyridine derivatives of the present invention exhibit significant calcium antagonism and antihypertensive activity as shown below. 1. Calcium Antagonism An isolated rat aorta was suspended in a calcium-free and high potassium Krebs-Henseleit solution maintained at a temperature of 37°C. The contractile response of the aorta to calcium chloride in -5 -2 concentrations ranging from 10 to 10 M was 25 recorded by means of an isometric transducer. The dose-response curve of the aorta was obtained before and after addition of a test compound at a concentration of 5nM. Addition of the test compound shifted the dose-response curve to the right, the magnitude of the 30 shift depending upon the potency of the Ca++-blocking activity* The test compounds showed a significant rightwards movement. 34 2. Antihypertensive activity The test animals were spontaneously hypertensive rats of the SHR strain, each aged about 15 weeks. The antihypertensive activities of the test compounds were 5 determined in these rats as follows.

Each animal was anaesthetized with sodium pentobarbital (50 mg/kg, intraperitoneally) and a polyethylene cannula was inserted into the abdominal aorta by the method of Weeks and Jones [J.R. Weeks and 10 J.A. Jones, Proc. Soc. Exptl. Biol. Med., 104. 646 - 648 (I960)]. The other end of the cannula left the animal's body at, and was fixed to, the neck. About l week after this surgery, when the animal had completely recovered from surgical stress, the free end of the aortic cannula 15 was connected to a sphygmomanometer to measure blood pressure and heart rate of the animal directly in the conscious, aparalytic and unrestrained state.

The blood pressure and heart rate were monitored, and, when these had stabilized, which was after about 1 20 hour, the stable values were recorded as control values. At this time, a test compound suspended in a 0.3% w/v aqueous carboxymethylcellulose solution was administered orally in the dose shown in the following Table 8. The blood pressure and heart rate were then 25 recorded every 15 minutes 'during the 24 hours after administration of the test compound.

The experiment was carried out with Compounds No. 1-59, 1-68, 2-8 and 3-8 (see foregoing Tables 1, 2 and 3) as well as with nifedipine and nicardipine, and the 30 results are recorded in the following Table 8.

TABLE 8 Cpd. No.

Ex. No.

Dose (mg/kg, po) 12 Hour Area T max (hours) T 0.5 max (hours) 1-59 7 1 -203 6.0 12.0 1-68 11 1 -218 7.0 11.8 2-8 14 l -172 6.0 11.2 3-8 16 1 -141 7.0 11.4 nifedipine nicardipine - 3 3 -237 -175 0.3 0.5 7.0 5.3 In the above Table, the results are reported as follows: T z the time in hours after administration of max the compound under test before the maximum change in blood pressure was recorded; T_ _ : the time in hours after administration 0.5 max of the compound under test which is required for the blood pressure to return to one half of its maximum value; 12 hour area: the integrated value of the area above the graph of blood pressure change against time after administration of the compound under test over a period of 12 hours after administration to show the potency of the blood pressure lowering action. 36 Although the maximum levels of hypotension produced by all of the compounds of the invention tested were found to be comparable with those produced by nifedipine and nicardipine, there was a considerable difference in the time of onset of activity and in the duration of activity between the compounds of the present invention and the prior art compounds used for comparison. In addition, nifedipine increased heart rate, which was most probably caused by a baroreceptor reflex due to the abrupt reduction in blood pressure. Similarly good results were achieved with the other compounds of the invention which we tested.

Accordingly, the compounds of the invention and pharmaceutically acceptable acid addition salts thereof can be used for the treatment of cardiovascular diseases, such as hypertension, angina pectoris miocardial infarction, arrhythmia, arteriosclerosis and cerebrovascular disorders, such as cerebral ischaemia.

The compounds may be administered in any suitable form, depending upon the nature and condition of the patient, the nature of the disorder and the desired route of administration. For example, the compounds may be administered orally in the form of tablets, capsules, granules, powders or syrups. Alternatively, the compounds may be administered non-orally by, for example, subcutaneous injection, intravenous injection or suppository. The compounds may, if desired, be mixed with carriers, excipients or other auxiliary substances commonly employed in the formulation of pharmaceutical preparations, for example diluents, binders, disintegrating agents, lubricants, flavours, solubilizers and suspending agents. The dose will vary, 37 depending upon the symptoms, age and body weight of the patient, as well as the nature and severity of the disease or disorder to be treated; however, a dose of from 3 to 300 mg per day will normally be appropriate 5 for an adult human patient, and this may be administered in a single dose or in divided doses.

The invention is further illustrated with reference to the following Examples. Preparation of certain of the starting materials employed in these Examples is 10 also illustrated in the subsequent Preparations.

REFERENCE EXAMPLE 1 3-(1-Benzhydryl-3-azetidinvl) 5-isopropvl 2-amino-6-methvl-4-(3-nitrophenvl)-1.4-dihydropyridine-3.5-dicarboxylate and its dihydrochloride Preparation of free base 0.27 g (0.005 mole) of sodium methoxide was added to a solution of 1.39 g (0.005 mole) of isopropyl 2-(3-nitrobenzylidene)acetoacetate and 1.62 g (0.005 mole) of the acetic acid salt of 1-benzhydryl-20 3-azetidinyl amidinoacetate (prepared as described in Preparation 2) dissolved in 80 ml of isopropanol, and the mixture was heated under reflux for 4 hours. At the end of this time, the mixture was cooled, insoluble materials were filtered off and the filtrate was 25 concentrated by evaporation under reduced pressure. The residue was dissolved in ethyl acetate and washed with water, after which it was dried over anhydrous sodium sulphate. The solvent was then removed by distillation under reduced pressure, and the residue was subjected to 30 column chromatography through silica gel, using a 3 : 1 by volume mixture of toluene and ethyl acetate as 38 eluent, to give 2.17 g (yield 74%) of the title compound (a free base) as pale yellow crystals, melting at 95 - 98°C.

Infrared Absorption Spectrum (KBr) cm'1: 3450, 3310 (NH) and 1675 (-C02*).

Mass Spectrum (CI) m/e : 583 (M+ + 1), 344 (M+ - benzhydrylazetidinyloxy) and 167 [+CH(phenyl)2].

Nuclear Magnetic Resonance Spectrum: (CDC13) 6 ppm: 1.08, 1.26 (6H, 2 x doublet, J=6Hz); 2.35 (3H, singlet); 2.63, 3.06, 3.50, 3.62 (4H, 4 x triplet, J=8Hz); 4.26 (1H, singlet); 4.87-5.04 (3H, multiplet); 6.04 (1H, broad singlet); 6.11 (2H, broad singlet); 7.1-8.17 (14H, multiplet).

The resulting free base was recrystallized from a mixture of benzene and hexane to afford pale yellow crystals, melting at 120 - 124°C.

The free base was also recrystallized from a mixture of 1,2-dimethoxyethane and hexane to afford pale yellow crystals melting at 162.5 - 164.5°C. The crystals contained an equimolar amount of 1,2-dimethoxyethane (determined by NMR spectrum). These crystals were dried above 100°C under reduced pressure, giving the desired compound as yellow crystals melting at 158 - 160°C.

Both kinds of crystals described above melting at 120 - 124°C and at 158 - 160°C were identified with the free base by NMR spectroscopy. 39 Elemental analysis: Calculated for C,,H,.N.O-: 33 34 4 6 C, 68.03%; Hf 5.88%; N, 9.62% Found : C, 68.36%; H, 5.94%; N, 9.20%. (free base) C, 68.49%; H, 5.71%; N, 9.62%. (after recrystallization from a mixture of benzene and hexane) C, 67.94%; H, 5.91%; N, 9.63 (after recrystallization from a mixture of 1,2-dimethoxyethane and hexane and drying at about 100°C under reduced pressure).

Preparation of dihydrochloride Hydrogen chloride was bubbled into a solution of 0.87 g of the free base in 20 ml of chloroform for 5 minutes. At the end of this time, the solvent was removed by evaporation under reduced pressure, giving 0.95 g of the title compound dihydrochloride as pale yellow crystals, melting at 118 - 120°C.

Infrared Absorption Spectrum: (KBr) v cm"1: max 3400, 3280 (NH) and 1685 (-C02-).

Mass Spectrum: m/e : 583 (M+ + 1) , 539 [M+ - CH(CH3)2], and 167 [+CH(phenyl)2] .

Elemental analysis: Calculated for C33H36N4OgCl2: C, 60.46%; H, 5.53%; N, Found: C, 60.59%; H, 5.81%; N, EXAMPLES 1 - 17 Following a procedure similar to that described in Reference Example l, the following compounds were obtained: 8.55%. 8.44%. 40 Example l 3-(1-Benzhydryl-3-azetidinyl) 5-methyl 2-amino-6-methyl- 4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, melting at 88 - 92°C.

Example 2 3-(l-Benzhydryl-3-azetidinyl) 5-hexyl 2-amino-6-methyl- 4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate dihydrochloride, melting at 106 - 108°C.

Example 3 3-(l-Benzhydryl-3-azetidinyl) 5-(2-methoxyethyl) 2-amino-6-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylate, melting at 83 - 85°C.

Ryampl e 4 3-(1-Benzhydryl-3-azetidinyl) 5-cinnamyl 2-amino-6-15 methyl - 4 - (3 - nitrophenyl) -1,4- dihydropyridine -3,5- dicarboxylate hydrate, melting at 114 - 117°C.

Example 5 3-(1-Benzhydryl-3-azetidinyl) 5-cyclohexyl 2-amino-6-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-20 dicarboxylate dihydrochloride, melting at 113 - 114.5°C.

Example 6 3-(1-Benzhydryl-3-azetidinyl) 5-isopropyl 2-amino-4-(2,3-dichlorophenyl) -6-methyl-1,4-dihydropyridine-3, 5-dicarboxylate, melting at 100 - 102°C. 41 Example 7 3-(1-Benzhydryl-3-azetidinyl) 5-isopropyl 2-amino-4-(2-chlorophenyl)-6-methyl-l,4-dihydropyridine-3,5-dicarboxylate, melting at 85 - 88°C.

Example 8 3-(1-Benzhydryl-3-azetidinyl) 5-ethyl 2-amino-6-methyl - 4 - (3 - nit ropheny 1) -1,4 - dihydropyridine -3,5-dicarboxylate hemihydrate, melting at 134 - 136°C.

Example 9 3-(1-Benzhydryl-3-azetidinyl) 5-cyclopropylmethyl 2-amino-6-methyl-4- (3-nitrophenyl) -l,4-dihydropyridine-3,5-dicarboxylate, melting at 156 - 160°C.

Rvamplp in 3- [1- (4,4' -Difluorobenzhydryl) - 3-azetidinyl] 5-isopropyl 15 2-amino-6-methyl-4- (3-nitrophenyl) -l, 4-dihydropyridine- 3,5-dicarboxylate, melting at 118 - 120°C.

Example 11 3-(1-Benzhydryl-3-azetidinyl) 5-isopropyl 2-amino-6-methyl-4- (3-trifluoromethylphenyl) -1,4 - dihydropyridine-20 3,5-dicarboxylate hydrate, melting at 96 - 98°C.

Example 12 3-(1-Benzhydryl-3-azetidinyl) 5-isopropyl 2-amino-4-(3 - cyanophenyl) - 6 - methyl -1,4- dihydropyridine -3,5-dicarboxylate hydrate, melting at 95 - 97°C. 42 Example 13 3-(1-Benzhydryl-3-pyrrolidinyl) 5-isopropyl 2-amino-6 -methyl-4-(3 -nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate dihydrochloride, melting at 166 - 169°C.

Example 14 3-(1-Benzhydryl-3-pyrrolidinyl) 5-hexyl 2-amino-6-methyl-4-(3-nitrophenyl)-l,4-dihydropyridine-3,5-dicarboxylate dihydrochloride hydrate, melting at 104 - 108°C.

Example 15 3-(1-Benzhydryl-3-piperidyl) 5-isopropyl 2-amino-6 -methyl-4-(3 -nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate dihydrochloride hydrate, melting at 174 - 177°C.

Example 16 3- (1-Benzhydryl-3-piperidyl) 5-hexyl 2-amino-6 -methyl-4-(3 -nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate dihydrochloride hydrate, melting at 151 - 155°C.

Example 17 3- (1-Benzhydryl-3-methyl-3-azetidinyl) 5-isopropyl 2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, melting at 116 - 118°C. 43 PREPARATION 1 l-Benzhvdrvl- 3-azetidinvl cyanoacetate 4.25 g (0.05 mole) of cyanoacetic acid and 11.95 g (0.05 mole) of 1-benzhydryl-3-hydroxyazetidine were dissolved in 400 ml of tetrahydrofuran. 12.38 g (0.06 mole) of l,3-dicyclohexylcarbodiimide were then added to the solution, whilst stirring, after which the mixture was stirred at 55°C for a further 11 hours. At the end of this time, the mixture was cooled, precipitated crystals were removed and the solvent was removed by distillation under reduced pressure. The residue was dissolved in ethyl acetate and the resulting solution was washed with water and then dried over anhydrous sodium sulphate.

The solution was then concentrated by evaporation under reduced pressure, and the residue was subjected to column chromatography through silica gel, using a 19 : l by volume mixture of toluene and ethyl acetate as eluent, to give 14.25 g (93%) of the title compound as a pale yellow oil.

Infrared Absorption Spectrum (capillary) vrnax cm'1: 2250 (CN) and 1745 (-C02-).

Mass Spectrum m/e: 306 (M+) and 167 [+CH(phenyl)23.

Nuclear Magnetic Resonance Spectrum: (CDC13) 6 ppm: 3.1 (2H, multiplet); 3.46 (2H, singlet); 3.6 (2H, multiplet); 4.37 (1H, singlet); .16 (1H, quartet, J=6 Hz); 7.1-7.5 (10H, multiplet). 44 PREPARATION 2 Acetic acid salt of 1-benzhydryl-3-azetidinyl amidinoacetate A solution of 7.0 g (0.0229 mole) of 1-benzhydryl-5 3-azetidinyl cyanoacetate (prepared as described in Preparation 1) and 1.26 g (0.0275 mole) of ethanol dissolved in 300 ml of chloroform was cooled with a mixture of salt and ice. Hydrogen chloride was then bubbled into the solution for 30 minutes, whilst 10 cooling, and the mixture was allowed to stand overnight, also whilst cooling. At the end of this time, the temperature of the mixture was allowed to rise to room temperature, and then the mixture was freed from the solvent by evaporation under reduced pressure. The 15 residue was dissolved in 300 ml of chloroform and ammonia was bubbled into the solution for 1 hour, whilst ice-cooling. The precipitated salt was removed by filtration,'and the solvent was distilled off under reduced pressure. The residue was dissolved in 50 ml of 20 acetonitrile, and 1.76 g (0.0229 mole) of ammonium acetate was then added to the solution. The mixture was stirred at 55°C for 1 hour. At the end of this time, unreacted ammonium acetate was removed from the still hot reaction mixture by filtration, and the solvent was 25 distilled off under reduced pressure. The residue was crystallized by adding diethyl ether, and the resulting crystals were collected by filtration and then dried under reduced pressure to afford 7.6 g (yield 87% based on the cyanoacetate) of the title compound as colourless 30 crystals, melting at 100 - 103°C.

Mass Spectrum m/e: 324 (M+ + 1) and 167 [+CH(phenyl)2]. 45 PREPARATION 3 1-(4.4'-Difluorobenzhvdryl)-3-hvdroxvazetidine 9.25 g (0.1 mole) of epichlorohydrin and 21.9 g (0.1 mole) of 4,4'-difluorobenzhydrylamine were 5 dissolved in 100 ml of methanol. The mixture was stirred at room temperature whilst shading it from the light for 3 days. At the end of this time, the mixture was heated under reflux whilst stirring for 3 days. The methanol was then distilled off under reduced pressure, 10 and the residue was dissolved in ethyl acetate. The resulting solution was washed, first with 100 ml of a 10% w/v aqueous solution of sodium hydroxide and then twice, each time with 100 ml of water. The organic layer was dried over anhydrous sodium sulphate, and the 15 solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, using a 3 : 2 by volume mixture of toluene and ethyl acetate as eluent, to give 6 g (yield 22 %) of the title compound as a pale yellow oil.

Infrared Absorption Spectrum (capillary) cm 1: 3360 (-OH).

Mass Spectrum (m/e): 275 (M+), 203 [+CH(e-fluorophenyl)21 • Nuclear Magnetic Resonance Spectrum (CDC«3) 6 ppm: 25 2.35 (1H, singlet); 2.86 (2H, multiplet); 3.46 (2H, multiplet); 4.30 (1H, singlet); 4.40 (1H, quintet, J = 5 Hz); 6.88-7.35 (8H, multiplet). 46 PREPARATION 4 1-Benzhydryl- 3-hydroxy- 3 -methvla zet idine (a) 7.17 g (0.03 mole) of 1-benzhydryl-3-hydroxy-azetidine were dissolved in a mixture of 35 ml of dimethyl sulphoxide and 20 ml of methylene chloride. 1 ml of pyridine, 0.5 ml of phosphoric acid and then 12.5 g (0.06 mole) of 1,3-dicyclohexylcarbodiimide were added, in turn, to the resulting solution. The reaction mixture was then stirred for 2 hours, after which water 10 was added to it. The reaction mixture was then extracted twice, each time with 200 ml of chloroform. The combined extracts were dried over anhydrous sodium sulphate, and the solvent was then distilled off under reduced pressure. The concentrate was subjected to 15 silica gel column chromatography, and 4.84 g (67%) of l-benzhydryl-3-oxoazetidine were obtained from the fractions eluted with a 9 : 1 by volume mixture of toluene and ethyl acetate.

Mass Spectrum (CI, m/e): 238 (M+ + 1), 167 20 [+CH(phenyl) 2 ] . (b) 7.26 g (0.03 mole) of 1-benzhydryl-3-oxoazetidine [obtained as described in step (a) above] were dissolved in 50 ml of diethyl ether. 60 ml of a 1M tetrahydrofuran solution of methylmagnesium bromide were then added to this solution, whilst ice-cooling. The reaction mixture was then stirred for 1 hour, after which 200 ml of water were added to it. The mixture was then extracted with 100 ml of diethyl ether. The organic extract was dried over anhydrous sodium 30 sulphate, and the solvent was removed by distillation 47 under reduced pressure. The concentrate was subjected to silica gel column chromatography, and 5.92 g (76 %) of the title compound were obtained from the fractions eluted with a 3 : 1 by volume mixture of toluene and ethyl acetate.

Mass Spectrum (CI, m/e): 254 (M+ + 1), 167 [+CH(phenyl)2].

Nuclear Magnetic Resonance Spectrum (CDCs^) 6 ppm: 1.5 (3H, singlet); 2.15 (1H, broad); 2.97 (2H, doublet, J = 8 Hz); 3.2 (2H, doublet, J = 8 Hz); 4.35 (1H, singlet); 7.15-7.45 (10H, multiplet).

PREPARATION 5 1 - Benzhydryl - 3 - hvdroxvpjperidine .05 g (0.05 mole) of 3-hydroxypiperidine and 13.82 g (0.1 mole) of potassium carbonate were suspended in 100 ml of dimethylformamide. 12.36 g (0.05 mole) of benzhydryl bromide were then added to the mixture, whilst stirring, and the mixture was stirred for 10 hours at room temperature. At the end of this time, the mixture was poured into 700 ml of water and extracted with ethyl acetate. The extracts were washed with water and dried over anhydrous sodium sulphate. The solvent was then distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and 10.53 g (yield 78%) of the title compound were obtained as a colourless material from the fractions eluted with a 9 : 1 by volume mixture of toluene and ethyl acetate. 48 Infrared Absorption Spectrum (capillary) vmax cm"1: 3340 (-OH).

Mass Spectrum (m/e): 267 (M+), 167 [+CH(phenyl)2].

Nuclear Magnetic Resonance Spectrum (CDCe^) 6 ppm: 5 1.4-2.5 (9H, multiplet); 3 .8 (1H, singlet); 4.3 (1H, singlet); 7.13-7.4 (10H, multiplet).

PREPARATION G 1 - Benzhydryl - 3 - hydroxypyrrol idine Following a procedure similar to that described in Preparation 5, except that 4.35 g (0.05 mole) of 3-hydroxypyrrolidine were used instead of the 3-hydroxypiperidine, 10.25 g (yield 81%) of the title 15 compound were obtained.

Infrared Absorption Spectrum (capillary) vmax cm 1: 3360 (-OH).

Mass Spectrum (m/e): 253 (M+) , 167 [+CH (phenyl) 21 .

Nuclear Magnetic Resonance Spectrum (CDC«3) 6 ppm: 20 1.64-2.82 (7H, multiplet); 4.20 (1H, singlet); 4.29 (1H, multiplet); 7.10-7.47 (10H, multiplet). 49 PREPARATIONS 7-10 The compounds described below were obtained in a similar manner to that described in Preparation 1.

Preparation 7 1- (4,4'-Difluorobenzhydryl)-3-azetidinyl cyanoacetate Mass Spectrum (EI, m/e): 342 (M+), 203 [+CH(p-fluorophenyl)2].

Preparation 8 l-Benzhydryl- 3 -methyl - 3 -azetidinyl cyanoacetate Mass Spectrum (CI, m/e) : 321 (M+ + 1) , 167 [+CH(phenyl)2].

Preparation 9 1-Benzhydryl-3-pyrrolidinyl cyanoacetate Mass Spectrum (EI, m/e) : 320 (M+) , 167 [+CH(phenyl)2].

Preparation 10 1 - Benzhydryl - 3 - piperidyl cyanoacetate Mass Spectrum (EI, m/e) : 334 (M+) , 167 (+CH(phenyl)2) 50 PREPARATIONS 11 - 14 The compounds described below were obtained in a similar manner to that described in Preparation 2.

Preparation 11 1-(4,4'-Difluorobenzhydryl)-3-azetidinyl amidinoacetate Mass Spectrum (CI, m/e): 360 (M+ + 1), 203 [+CH(e-fluorophenyl)2].

Preparation 12 1-Benzhydryl-3- methyl- 3 -azet idinyl amidinoacetate Mass Spectrum (CI, m/e): 338 (M+ + 1) , 167 [+CH(phenyl)2J.

Preparation 13 1-Benzhydryl-3-pyrrolidinyl amidinoacetate Mass Spectrum (CI, m/e): 338 (M+ + 1) , 167 [+CH(phenyl)2].

Preparation 14 1-Benzhydryl-3-piperidyl amidinoacetate Mass Spectrum (CI, m/e): 353 (M+ + 2), 167 [+CH(phenyl)21.

Attention is drawn to Irish Parent Application No. 2706/87. 51

Claims

1. Compounds of formula (I): rooc / ch \ r 2a ,2b (i) in which: Ar represents a phenyl group having at least one substituent selected from nitro, ^ - C4 haloalkyl, C1 - C4 haloalkoxy and cyano groups and halogen atoms; R represents a C^ - C^ alkyl group, a C3 - Cg cycloalkyl group, a C1 - C4 alkyl group having a C3 - Cg cycloalkyl substituent, a C2 - C4 alkenyl group, a cinnamyl group or a C1 - Clg alkyl group having at least one substituent selected from hydroxy, ^ - C4 alkoxy and Cx - C4 alkylthio groups; R1 represents a hydrogen atom or a C1 - C3 alkyl group; R2a and R2b are the same or different and each represents an unsubstituted phenyl group or a substituted phenyl group having at least one substituent selected from C1 - C4 alkyl, Cx - C4 alkoxy and 52 haloalkyl groups and halogen atoms; o d R represents a methyl group and R represents an amino group; and n is an integer from 1 to 3; but excluding the compound in which Ar is 3-nitrophenyl, R is an isopropyl group, R1 is hydrogen, R2a and 2j^ R are the same and are each an unsubstituted phenyl 3 4 group, R is a methyl group, R is an amino group and n is the integer 1; and pharmaceutically acceptable acid addition salts thereof.

2. Compounds according to Claim 1, in which: Ar represents a phenyl group having a single substituent selected from nitro, C1 - C2 haloalkyl, C1 - C2 15 haloalkoxy and cyano groups or having one or two halogen substituents; R represents a C1 - C1Q alkyl group, a C3 - Cg cycloalkyl group, a C1 - C2 alkyl group having a C3 - Cg cycloalkyl substituent, a C3 - C4 20 alkenyl group, a cinnamyl group or a C^ - C1Q alkyl group having at least one substituent selected from hydroxy, ^ - C3 alkoxy and C.^ - C3 alkylthio groups; R1 represents a hydrogen atom or a C1 - C3 alkyl 25 group; R2a and R2b are the same or different and each represents an unsubstituted phenyl group or a 53 substituted phenyl group having at least one substituent selected from C1 - C3 alkyl, C1 - C3 alkoxy and trifluoromethyl groups and halogen atoms; 3 4 R represents a methyl group; R represents an amino group; and n is an integer from 1 to 3.

3. Compounds according to Claim 1, in which: Ar represents a phenyl group having a single substituent selected from nitro, trifluoromethyl, difluoromethoxy and cyano groups or having one or two chloro substituents; R represents a C1 - Cg alkyl group, an alkoxyalkyl group containing from three to five carbon atoms, an alkylthioalkyl group containing three or four carbon atoms, a cycloalkyl group containing five or six carbon atoms, a cycloalkylalkyl group containing a total of from four to seven carbon atoms, an alkenyl group containing three or four carbon atoms or a cinnamyl group; R1 represents a hydrogen atom or a methyl group; and R and R are the same and each represents a phenyl group or a phenyl group having a single substituent selected from chlorine atoms, fluorine atoms, trifluoromethyl groups, methyl groups and methoxy groups. 54

4. Compounds according to Claim 1, in which: Ar represents a phenyl group having a single substituent selected from nitro, trifluoromethyl, difluoromethoxy and cyano groups or having one or two chloro substituents; R represents a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, 2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-methylthioethyl, 3-methylthiopropyl, 2-ethylthioethyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, allyl, 2-butenyl or cinnamyl group; R1 represents a hydrogen atom or a methyl group; and 2 —^ 2b R and R are the same and each represents a phenyl group or a phenyl group having a single substituent selected from chlorine atoms, fluorine atoms, trifluoromethyl groups, methyl groups and methoxy groups;

5. Compounds according to Claim 1, in which: Ar represents a 2-nitrophenyl group, a 3-nitrophenyl group, a 2-trifluoromethylphenyl group, a 3-trifluoromethylphenyl group, a 2-chlorophenyl group or a 2,3-dichlorophenyl group; R represents a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, 2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-methylthioethyl, 3-methylthiopropyl, 2 -ethylthioethyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, allyl, 2-butenyl or cinnamyl group; 55 R1 represents a hydrogen atom or a methyl group; and 2 a 2b R and R are the same and each represents a phenyl group or a p-fluorophenyl group.

6. Compounds according to Claim 1 or Claim 2, in which 2 a 2b 5 R and R are the same.

7. 3 -(1-Benzhydryl-3-azetidinyl) 5-ethyl 2-amino-6-methyl-4- (3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and pharmaceutically acceptable salts thereof. 10

8. 3-(1-Benzhydryl-3-azetidinyl) 5-cyclohexyl 2-amino- 6-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylate and pharmaceutically acceptcible salts thereof.

9. 3-(1-Benzhydryl-3-azetidinyl) 5-isopropyl 15 2 - amino - 4 - (2,3- dichlorophenyl) - 6 -methyl -1,4- dihydro - pyridine-3,5-dicarboxylate and pharmaceutically acceptcible salts thereof.

10. 3-[1-(4,4'-Difluorobenzhydryl)-3-azetidinyl] 5-isopropyl 2-amino-6-methyl-4-(3-nitrophenyl)- 20 1,4-dihydropyridine-3, 5-dicarboxylate and pharmaceutically acceptable salts thereof.

11. 3-(1-Benzhydryl-3-methyl-3-azetidinyl) 5-isopropyl 2-amino-6-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylate and pharmaceutically acceptable salts 25 thereof. 56

12. 3-(1-Benzhydryl-3-pyrrolidinyl) 5-isopropyl 2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and pharmaceutically acceptable salts thereof. 5

13. 3-(1-Benzhydryl-3-pyrrolidinyl) 5-hexyl 2-amino- 6 -methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5 -dicarboxylate and pharmaceutically acceptable salts thereof.

14. 3-(1-Benzhydryl-3-piperidyl) 5-isopropyl 2-amino-10 6-methyl-4- (3-nitrophenyl) -1, 4-dihydropyridine-3 , 5 - dicarboxylate and pharmaceutically acceptable salts thereof.

15. A pharmaceutical composition comprising an active compound in admixture with a pharmaceutically acceptable 15 carrier or diluent, in which said active compound is at least one compound according to any one of the preceding Claims.

16. A process for preparing a compound according to any one of Claims 1 to 14, which process comprises reacting 20 an a-benzylideneacetoacetic acid ester of formula (II) : Ar I CH II K (ID ch3-C-C-COOR5 II O 57 with an amidinoacetic acid ester of formula (III) : H2N-C-CH2-COOR6 (III) II NH [in the above formulae: Ar is as defined in Claim 1; and R6 represents a group of formula (IV): (in which n, R1, R2a and R2b are as defined in Claim 1) and the other of R^ and R^ represents a Cx - C16 alkyl group, a C3 - Cg cycloalkyl group, a C^^ - C4 alkyl group having a C3 - Cg cycloalkyl substituent, a C2 - C4 alkenyl group, a cinnamyl group or a C^^ - Clg alkyl group having at least one substituent selected from hydroxy, C1 - C4 alkoxy and C1 - C4 alkylthio groups)], and optionally salifying and/or desalifying the resulting product to give said compound of formula (I) or said pharmaceutically acceptable acid addition salt thereof.

17. The use for the manufacture of a medicament, especially for the treatment of cardiovascular disorders, of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of Claims 1 to 14. - 58 -

18. A process as claimed in Claim 16 substantially as described herein with reference to Examples 1 to 17 and Preparations 1 to 14.

19. A compound whenever prepared by a process as claimed in Claim 16 or 18.

20. Use as claimed in Claim 17 substantially as described herein with reference to Examples 1 to 17 and Preparations 1 to 14. TOMKINS & CO.