Pharmaceutically active 2-Thiomethyl-substituted-l,4- dihydropyridines.

The present invention relates to 2-thiomethy l-sub- sti tuted-1 ,4-di hydropyridines, to a method for their pre¬ paration and to pharmaceutical composition containing them. The compounds of the invention have the following formula I

wherein:

R represents acetyl, benzoyl, cyano, nitro groups, or groups of formula C0_R_ or C0NR,R_;

-. 5 O r

R is a phenyl ring unsubsti tuted or substituted with one or more C„-C, alkyl, C -C. alkoxy, halo-C -C, alkoxy, 1 6 1 6 1 -. halo-C -C alkyl, halogen, nitro, cyano, C -C alkoxy- i 6 1 6 carbonyl, C -C alkylthio, C -C a Iky Isu LphynyI; penta- 1 6 ' 1 6 fluorophenyl; o - or 3-naphtyI; a five- or six-membered h terocyclic ring; o-benzo/2,3-b/-1 ,4-di oxan-<X-y I; θς.-benzo furoxany I; R is a group of formula ^C0 ₂ ^R ' 0 is selected in the group consisting of: a) a thiol group free or esterified with a C -C fatty acid;

(+) (-) b) a thiouronium salt of formula -S-C(=NR )NR R Y wherein Y is a pharmaceutically acceptable anion and R„, R_, R„ _Λ , which a r e the same or different, are 8 9 10 hydrogen or C.-C. alkyl group;

1 4 c) a thioether residue -S(0) -R , wherein n is zero, 1 or n 4

2 and R. is selected from the group consisting of: 4 a*) a C -C,_ alkyl, a C -C alkenyl or a C -C, alkynyl 1 5 3 5 3 5 unsubst i tuted groups; b') a -C_ eye loaliphati c residue; c ¹ ) aryl group, optionally substituted by one or more substituents s.elected from the group consisting of halogen, hydroxy, nitro, cyano, acetyl,

C -C, alkyl, halo-C. -C, alkyl, amino, monoalkyl- 1 6 1 6 amino, di a Iky lamino, carboxy, C -C, alkoxycarbo¬ nyl, p- .imidazol-1-yI) , C -C -alkoxy, C -C -alkyl¬ thio, and-C -C acylamino _, groups; d') a saturated or unsaturated heterocyclic ring, unsubst i tuted or substituted by one or more sub¬ stituents selected from the group consisting of halogen, C -C, alkyl, C -C . alkoxy, halo-C -C, 1 6 1 6 1 6 alkyl, alkyl, monoa Iky lamino, ^" di a Iky lamino, cyano, carboxy, C.-C. alkoxycarbonyl, -C0NR,R_, aryloxy- 1 6 7 alkyl and aryl groups; e') a mono- or a poly-substi uted C -_-C alkyl chain, optionally interrupted by one or more oxygen or sulphur atoms wherein the substituents are select¬ ed from the group consisting of hydroxy, thio, cyano, halogen, amino, monoa Iky lami no, dialkylami- no, C -C. alkoxy, C -C. alkylthio, C.-C . acyloxy, 1 1 1

C.-C, acylthio, CO _^ H, C -C, alkoxycarbonyl, 1 1

CONR R , a C -C cyc loa I i phat i c residue, arylresi- 6 7 - 7 due or a saturated or unsaturated heterocyclic residue said residues having the above defined meani ngs; f') a C -C oxygenated alkyl chain of formula

-(CH.,) -A-(CH„) -B wherein A may be a cis- or 2 n 2 p trans-oxi rane ring and a masked or unmasked carbo¬ nyl moiety and B is hydrogen, C ~C, alkyl, cyano, carboxy, C -C . alkoxycarbonyl, C0NR,R_ groups, 1 4 6 7 amino, monoa Iky lami no, a ^c ~C eye loa li phat i c residue, an aryl or a saturated or unsaturated heterocyclic residues, said residues having the above defined meanings; g') a group of formula:

wherein P may be hydrogen, C -C alkyl and a group

1 o of formula -(CH_) - ; NP„P_ is a primary, secon- dary or tertiary amino group, an amidic or imidic residue wherein P . and P„, which are the same or

1 2 different, may be hydrogen, C -C, alkyl,

1 6

-(CH_) -W or C.-C, acyl group; P. and P_, taken 2 p 1 6 1 2 together with the nitrogen atom to which they are

/ \ linked, may form a cyclic amide or the -N X

\ / residue; P, taken together with P and the ni¬ trogen atom to which P is linked, may form a pyrrolidine or a piperidine ring; W is selected from the group consisting of hydrogen, me- thyl, saturated or unsaturated heterocyclic ring, a

C -C cycloalkyl ring, a phenyl . ring unsubsti tuted or substituted by one or more substituents selected from the group of halogen, nitro, p-imidazo1-1 -yI, hydroxy,

C ; P r bi s-(4-f luorophenyI)methane; P. and P_, which are the

4 5 same or different, may be hydrogen, C -C. alkyl or taken

1 4 together with the nitrogen atom to which they are Link-

/ \ ed, P, and P, form the radical -N X wherein X is as

^{4 5} \ / above defined;

R is hydrogen, a cation of ammonium or of an alkaline metal, a C -C, alkyl chain unsubstituted or subst tuted 1 6 by hydroxy, amino, monoaIkylamino, dia Ikylamino, or

C -C, alkoxy groups; C -C alkenyl; an optionally sub- 1 6 * 3 6 stituted aryl or C -C. aralkyl group;

1 4 each of R and R , which are the same or different, may be 6 7 hydrogen, C -C alkyl, benzyl or aryl; 1 6 n is an integer from 1 to 6; m is an integer from 1 to 3; p is zero or an integer from 1 to 6 and p. is zero or an integer from 1 to 3; with the proviso that when ff is a thioether substituent of formula -S(0) -R and R, is- a C -C alkyl group, n is n 4 4 1 5 different from zero.

Also the pharmaceutically acceptable salts as well as the optical antipodes, i.e. the enantiomers, the possi¬ ble geometric isomers, diastereoi somers and mixtures the¬ reof are included in the scope of the present invention.

The alkyl, alkenyl, alkoxy and alkanoyloxy groups are branched or straight chain groups.

A halo-C -C alkyl group is preferably trihalo- 1 6

C.-C alkyl, in particular trifluoromethyl. 1 6

A halo-C. -C, alkoxy group is preferably -0CH.F_.

A C -C alkyl group is preferably methyl, ethyl, 1 6 isopropyl or t-butyl. A C -C alkanoyl group is preferably acetyl, pro- pionyl, hexanoyl or heptanoyl.

An aryl group is preferably phenyl.

A C -C, alkenyl group is preferably allyl.

A C -C alkynyl group is preferably propargyl. A C -C cycloaliphatic radical is preferably cyclo- pentyl, cyclohexyl and cycloheptyl.

A monoalkyl amino group is preferably a methyl-, ethyl-, isopropyl- or benzyl-a ino group.

A dialkylamino group is preferably a linear group such as dimethyl-, diethyl-, benzyl-, methyl-amino group; or a cyclic group such as pyrro I idi ne-1 -y I; pi peridi ne-1 ^• * ^• yl, morpholin-1-y I, 4-methy l-pi perazi ne-1-y I, 4-phenyl-pi- perazine-1-yl,4-diphen lmethane-piperazine-1-yl, 4-bi s-(p- fluoropheny I) methane-pi perazi ne-1 -y I, 4-ethy l-pi perazi ne- 1-yl, 4-( ' -hydroxyethy I) pi peraz i ne-1 -y I .

A C -C alkoxycarbonyl, is preferably methoxy-, 1 4 ethoxy- and ter-butoxy-ca rbony I group.

C -C alkoxy is preferably methoxy and isopropo- 1 3 xy A C -C, alkylthio is preferably methylthio and 1 3 i sopropy 1th i o .

A masked carbonyl function is preferably an acetal of formula C (0-C._,a Iky I ) and more preferably a 1,3- dioxolane or 1,3-dioxane ring wherein one or both the oxygen atoms may be optionally substituted by sulphur

at oms .

When _p is a five- or six- membered heterocyclic ring, it is preferably pyridyl, furanyl or thienyl; when

R. i s an heterocyc li c ring, it may be either a heteromono- 4 cyclic ring or a heterobi eye li c ring containing at least one heteroatom selected from the group consisting of N, S, and 0.

Examples of preferred heteromonocyc li c residues are

Oc, A and ^-pyridyl; tet rahydrofury I; thienyl; c. - pyridy l-N-oxide; 3-hydroxy-o(.-pyri dyI; 2 and 4-pyrimidiny I; lH-1,2,4-triazol-3-yl; 1H-1 ,2,4-t ri azo l-4-y I; 2-thiazolyl;

1-methyl-tetrazol-5-yl; 2-methyl-1,3,4-thiadiazot-5-yl;

5-amino-1,3,4-thiadiazol-2-yl; 2-amino-1,2,4-t.riazol-5-yl;

2-hydantoinyI; 2-imidazolin I; 4-methy l-5-t ri f luorome- thy I-4H-1 ,2-,4-t ri azolin-3-yI; 1-methyl-imidazol-2-y I;

1-phenyl-lH-tetrazol-5-yl; 4,5-di phenyl-4-oxazolyn-2-y I;

5,5-disubstituted-hydantoin-2-yl; 4-phenoxymethyl-5-carbo- xy-imidazol-2-y I and esters thereof with C -C, lower

1 4 alcohols; 1,4,5,6-tetrahydro-pyrimidin-2-yl;4-substitu- ted-imidazol-2-y I; 5-carboxy-4-subst i tuted-i midazol-2-y I; pyri midin-2-y I and derivatives thereof with methyl, amino, oxo and/or carboxy groups in 4 and 6 positions of the pyri idine ring; pyri midi n-4-y I; pyri idi n-6-y I; 2,6-dia- mi no-pyπ ^' mi di n-4-y I; tet rahydropyran-2-yI; (3,4,5-tri ace- toxy-6-acetoxymethy I) et rahydropyran-2-y I; 5-carboethoxy- 4-oxo-pyrimidine-2-yl;6-propyl-4-hydroxy-pyri idin-2-yl and 6-propyl-4-amino-pyrimidin-2-yl.

Examples of preferred heterobi eye I i c residues are:

4-(3H) -qui nazoIin-4-one-2-yI; quinazo I i ny 1-2; 4-aminopyra- zo l .3,4-σ_7pyri midin-2-y I; 6-purinyl; 6,8-di hydroxy-2-puri -

nyl; benzoth i azo l-2-y I ; benzoxazo l-2-y I; benzi mi dazo l-2-y I and derivatives thereof substituted in the benzene ring with alkoxy and halo substituents; quinoli n-2- I ; 7-tri- fluoromethyl-quinolin-4-yl. The aryl and the heterocyclic radical of R, may be

4 linked to the sulfur atom by means of an alkyl chain, this alkyl chain being preferably a C -C. alkyl chain.

1 4

When R, is a mono-or a po ly - subst i tuted C -C._ 4 2 12 alkyl chain, optionally interrupted by one or more oxygen or sulphur atoms, this chain is preferably the residue of C -C alkyl thiols such as: 3-pheny l-propane-1 -th i o I, 3-cyclohexyl-propane-1-thiol, 3-cyclopentyl-propane-1- thio l, 2-propene-1 -thio I, 2-propyn-1 -th i o I, 2-mercapto-1 - ethanol, and ether or thioethers thereof such as 2-me- thoxy-ethane-1-thiol, 2-ethoxy-ethane-1-thiol, 2-propoxy- ethane-1 -thiol, 2-i sopropoxy-ethane-1 -thi o I, 2-pentoxy- ethane-1 -thi ol, 2-phenoxyethane-1-thiol, 3-phenoxy-propa- ne-1-thiol, 2-methy Lt io-ethane-1 -thio I, 2-ethy Ith io-etha- ne-1-thiol, etc.; 3-mercapto-1 , 2-propanedi o I and 1,2-ace- tals thereof; 2-fury l-methaneth i ol, 2- (2-fury I ) ethane-1 - thiol, 2-(2-thienyl)ethane-thiol, 2-(3-thienyl)ethane-1- thiol, 2-(4-methy l-5-thi azol) ethane-1 -thi ol, 2-(imidazol- 1-y I) ethane-1 -thio l,2-(J_-pyridy I ) ethane-1-th i ol, 3-( imida- zol-1-yl propane-1-th ol, 2-(y-pyridy I) ethane-1 -t io I, 2-(pyrrol-1-y I ) ethane-1 -thio I, 2-(2,5-di methy l-pyrro 1-1- y I) ethane-1 -thio I, 3-(2,5-dimethyl-pyrrol-1-yl propane-1- thiol; alky lamino-alky Ithiols such as 2-di methy lami no- ethane-1 -th i o I, 2-di ethy lami no-ethane-1 -th i o I , 2-butylami- no-ethane-1 -th io L, 2-(N-morphol ine) ethane-1 -thi ol, 2-(N- pyrro I idiny I) ethane-1 -thi ol, 2-(N-pi peri di ny I ) ethane-1 -

thiol, 2-(4*-N-substituted-pi perazi n-1-y I) ethane-1 -thiol; a inoa Iky Ithio Is such as cysteamine, homocysteamine, 4- aminobutane-1-thiol and derivatives thereof wherein the aminogroup is protected as BOC, acyla ide or cyclic i ide; 3-amino-, 3-monoa Iky lami no and 3-di a Iky laminoprόpane-1 - thiols; mercaptoacids i.e. th i oglyco li c _. thiolact i c and thiomalic acid and derivatives thereof such as esters, amides and nitriles; Cχ,-amino acids containing thiol groups such as cystein, homocystein and polypeptides obta- ined starting from these aminoacids as well as glutathion; R is preferably methyl, ethyl or isopropyl; R , R , R , R and R are preferably hydrogen.

When one of P and P_ is an acyl group, it is pre¬ ferably a C -C, acyl, chloroacety I, tri ch loroacety I, tri- 1" 4 f luoroacety I, tert-butoxycarbony I (BOC), optionally sub¬ stituted benzoyl with nitro or methoxy groups.

When NP.P- is a cyclic imide, it is preferably a cyclic imide obtained starting from succinic, glutaric, maleic, 2,3-di phenyIma lei c, phtalic, hexahydro or tetrahy- drophtalic acids.

When A is a masked carbonyl function it is prefera¬ bly 1 ,3-dioxolane and a dimethoxy or di ethoxyaceta I .

The non toxic salts that are pharmaceutically ac¬ ceptable include the hydroch lor des, hydrobromi des, hydro- iodides, ( lower) a Iky Isu Ifates, (lower)alkyl and aryl sul- fonates, phosphates, sulfates, maleates, fumarates, succi- nates, tartrates, citrates, and others commonly used in the art .

The salts obtained through the variation of the acid used in some cases have special advantage due to

increased stabi lity, increased solubility, decreased solu¬ bi lity, ease of crystallization, lack of objectionable taste, etc., but these are all subsidiary to the main physiological action of the free base, which is indepen- dent of the character of the acid used in the preparation of the sa It .

Specific examples of preferred compounds of the i nvent i on are

- 6-methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-2-methyl- sulphinylmethyl-1,4-dihydropyridine;

- 6-methyl-3,5-dicarboethoxy-4-(o-nitrophenyl -2-phenyl- thiomethy 1-1,4-di hydropyri dine;

- 6-methyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-2- (p-me- thoxypheny I )-thiomethyl/-1,4-di hydropyri dine; - 6-methy 1-3, 5-di carboethoxy-4- (m-ni t ropheny I ) -2-Z.(p-ace- tamidopheny I )-thiomethyL7-1,4-di hydropyri dine;

- 6-methy 1-3,5-di carboethoxy-4- (m-ni t ropheny I) -2-_T(p-ami - nophenyl)-thiomethyl7-1,4-dihydropyridine;

- 6-methyl-5-cyano-3-carboethoxy-4-(m-ni trophenyl)-6-Z.(p- chlorophenyl)-thiomethyl7-1,4-dihydropyridine;

- 6-methy 1-3,5-di carboethoxy-4- (m-ni t ropheny I) -2-£ ^" (1 -me¬ thy I i mi dazol-2-y I) -th omethyl_7-1,4-di hydropyri dine;

- 6-methy 1-3,5-di carboethoxy-4- (m-ni t ropheny I) -2«- (4-phe- noxymethyl-5 —carboethoxy-imidazol-2-yl -thiomethyl_7- 1 ,4-di hydropy ri di ne;

- 6-methy 1-3,5-carboethoxy-4- (m-ni t ropheny 1) -2- (2,3-di hy- droxypropylthio) -methy 1-1, -di hydropyri dine;

- 6-methy 1-3, 5-di carboethoxy-4- (m-ni trophen I) -2-(3-i so- propy lami no-2-hydroxypropylthio) -methy 1-1, -di hydropyri - dine;

- 6-methy1-3,5-di carboethoxy-4-(m-nitrophenyI)-2-(2-amino- 2-carboethoxy-ethylthio)-methy 1-1,4-dihydropyridine;

- 2-(p-fluorophenylthio) ethy1-3,5-di carboethoxy-4-(m-ni- t ropheny I)-6-methy1-1,4-dihydropyridine; - 6-methy1-3,5-di carboethoxy-4-(m-ni trophenyI)-2-(2-aceta- idoethylthio)-methy1-1, -dihydropyridine;

- 6-methy1-3,5-di carboethoxy-4-(m-ni trophenyI) -2-acetyI- thiomethyl-1,4-dihydropyridine;

- 6-methy1-3,5-dicarboethoxy-4-(m-n trophenyI) -2-mercapto- methy1-1 , -dihydrop ridine;

- S-Z~(6-methy1-3,5-di carboethoxy-4-(m-nitrophenyI) -1, -di- hydropyridin-2-yl)-methyl7-isothiouronium chloride;

- 6-methyl-3,5-dicarboethoxy-4-(m-nitrophenyI)- -/ ^" (p-metho xypheny I)-sulphinyl7-methy1-1,4-dihydropyr dine; - 6-methy1-3,5-di carboethoxy-4-(m-nitrophenyI)-2-/.(p-f luo- rophenyl)-sulphinylmethyl7-1, -di hydropyridine;

- 6-methy1-3,5-dicarboethoxy-4-(m-nitropheny1 -2-Z.(4-pheno xymethyl-5-carboethoxy-imidazol-2-yl)-sulphinyl_7-me hyl- 1 ,4-di hydropyridine; - 2-methyl-3-nitro-5-carboethoxy-4-(m-n trophenyI)-6-(bu- tylthio)-methyl-1,4-dihydropyridine;

- 2-methyl-3-nitro-5-carboethoxy-4-.m-nitrophenyl)-6-(2,3- dihydroxypropylthio)-methy1-1,4-dihydropyri dine;

- 6-methy1-3,5-di carboethoxsy-4-(m-nitrophenyI) -2-(2-amino- ethylsulphinyl)-methyl-1,4-dihydropyridine;

- 6-methyI-3,5-di carboethoxy-4-(m-nitropheny I)-2-(2-amino- 2-carboethoxyethylsulphonyI)-methy1-1, -d hydropyridine;

- 2-(2-aminoethylthio)methy1-3,5-di carboethoxy-4-(m-nitro- phenyl)-6-methyl-1,4-d.ihydropyridine; - 2-( -aminoethyIthiδ)methyl-3-carboethoxy-5-carbomethoxy-

4-(m-ni t rophen l)-6-meth 1-1 ,4-d hydrop ri di ne; aπu , - fumarate and maleate salts;

- 2-( -aminoethylthio)methy l-3-carboethoxy-5-carbomethoxy- 4-(m-chloro-pheny I) -6-methy 1-1,4-di hydropyri dine; - 2-(2-aminoethy lthio)methy l-3-carboethoxy-5-carboi sopro- poxy-4-(m-nitropheny I) -6-methy 1-1,4-di hydropyridine;

- 2-(2-ami noethylthio) ethy l-3-carboethoxy-5-carbomethoxy- 4-(m-trifluoromethylphenyl)-6-methyl-1,4-dihydropyridi- ne; - 2-(2-aminoethy Ithio) methy l-3-carboethoxy-5-carbomethoxy- 4-phenyl-6-methy1-1, -di hydropyridine;

- 2-(2-ami noethy Ith i o) methy l-3-carboethoxy-5-carboterbuto- xy-4-(m-nit ropheny I) -6-methy 1-1,4-di hydropyri dine;

- 2-(2-ami noethy Ithio)methyl-3-carboethoxy-5-methoxyethoxy_ carbonyl-4-(m-nit ropheny I) -6-methy 1-1,4-di hydropyri dine;

- 2-( 2-ami noethy Ithio) methy l-3-carboethoxy-5-Z ^" 2-(N-methy l- N-benzylamino)ethox _7carbonyl-4-(m-nitrophenyl)-6-me- thy 1-1,4-di hydropyridine;

- 2- ⁽ 3-aminopropy Ithio ⁾ methy l-3-carboethoxy-5-carbomethoxy- 4-(m-nit ropheny I) -6-methy 1-1 ,4-di hydropyri dine;

- 2- ⁽ 4-aminobuty Ithio) methy l-3-carboethoxy-5-carbomethoxy-4- ⁽ m-ni tropheny I ⁾ -6-methy 1-1,4-dihydropyridine;

- 2- ⁽ -aminopropy Ithio) methy l-3-carboethoxy-5-carbo ethoxy- 4- ⁽ m-nit ropheny I) -6-methy 1-1, -di hydropyri dine; - 2- ⁽ 2-N-methy laminoethy Ith o ⁾ methyl-3-carboethoxy-5-carbo- methoxy-4-(m-ni t ropheny I) -6-methy 1-1, -di hydropyri dine;

- 2- ⁽ 2-N-isopropy lami noethy Ithio ⁾ methy l-3-carboethoxy-5-car bomethoxy-4- ⁽ m-nit ropheny L ⁾ -6-methy1-1, -di hydropyri dine;

- 2- ⁽ 2-N-n-buty lami noethy Ithi o ⁾ methy 1-3, 5-di carboethoxy-4- ⁽ m-ni tropheny I) -6-methy 1-1, -di hydropyridinej

- 2-(2-N-n-buty laminoethyIthio)methy l-3-carboethoxy-5-car- bomethoxy-4- ⁽ m-nitrophen I)-6-methyl-1,4-dihydropyridine

- 2- ⁽ 2-N-benzy lami noethyIthio) ethy1-3,5-di carboethoxy-4- ⁽ m-ni ropheny I ⁾ -6-methy 1-1, -di ydropyridine;

5 - 2-/2-N- ⁽ -hydroxy-3-N-morpholinomethy l-5-methoxybenzyI)- aminoethylthio/methyl-3,5-dicarboethoxy-4-(m)nitrophenyl 6-methy1-1,4-di hydropyridine;

- 2- ⁽ -N,N-dimethy laminoethyIthio ⁾ methy 1-3,5-di carboethoxy 4- ⁽ m-nitrophenyI ⁾ -6-methy1-1,4-dihydropyridine; 0 - 2- ⁽ 2-aminoeth Isulphiny Dmethyl-3-carboethoxy-5-carbome- thoxy-4-(m-nitrophenyI)-6-methy1-1 ,4-dihydropyridine;

- 2-(3-pyridylmethyIthio)methy1-3,5-di carboethoxy- -(m- nitrophenyI)-6-methy1-1,4-dihydropyridine;

- 2-(5-amino-1 ,3,4-thi adiazol-2-yl)thiomethyl-3,5-dicarbo- ⁵ ethoxy —4-(m-nitrophenyI)-6-methy1-1 ,4-dihydropyridine;

- 2-(5-amino-1 ,2,4-tri azol-3-yUthiomethy1-3,5-di carboetho xy-4-(m-nitrophenyI)-6-methy1-1 ,4-dihydropyridine;

- 2-(carboethoxymethyIthio)methy 1-3,5-di carboethoxy-4-(m- nitrophenyI) -6-methy1-1, -dihydropyridine; ⁰ - 2-(2-cyanoethylthio)methy1-3,5-di carboethoxy—4-(m-ni- trophenyI)-6-methy1-1, -dihydropyridine;

- 2-(cyanomethyIthio)methy1-3,5-di carboethoxy- -(o-ch loro- phenyI)-6-methy1-1, -dihydropyridine;

- 2-(2-oxopropyIthio)methyl-3-carboethoxy-5-carbomethoxy- ^ 4-(m-n trophenyI)-6-methy1-1,4-dihydropyridine;

- 2-(2-phenyl-2-oxo-ethy Ithio)methyl-3,5-di c.arboethoxy-4- (m-nitropheny I)-6-methy1-1,4-dihydropyridine;

- 2-_.2-(4-imidazol-1-yl phenyl-2-oxoethylthio7methyl-3,5- dicarboethoxy-4-(m-trifluoromethylphenyI) -6-methy1-1,4- ^ di hydropyridine;

- 2-(2,2-di ethoxyethy Ithio) methy l-3-carboethoxy-5-carbome- thoxy-4-(m-trifluoromethylpheny I) -6-methy 1-1,4-dihydropy. ri dine;

- 2-(oxiran-2-ylmethylthio)methy 1-3,5-di carboethoxy-4-(m- nitrophenyI)-6-methy 1-1,4-di hydropyri dine;

- 2-(oxi ran-2-ylmethy Ithi o)methy 1-3,5-di carboethoxy-4-(m- ch loropheny I) -6-methy 1-1,4-dihydropy ri d ne;

- 2-/,(pyrrolidin-2-yl ⁾ methylthio_7methyl-3-carboethoxy-5- carbomethoxy-4-(m-nit ropheny I) -6-methy 1-1,4-di hydropyri - dine , enantiomers, diastereomers and .diastereomeric mi xtures thereof .

The compounds of the inventions are prepared by a process comprising: a) reacting a compound of formula II

wherein R R_, R, are as defined above and Hal is chlorine, bromine, iodine, with a thiol of formula III

R' ,SH (III) 4 wherein ι s hydrogen, C -C a Ikanoy I , 2 12

-C(=NR )NR R or R being R , R„, R„ and R _{Λ Λ} as defi - 8 9 10 ned above, so obtaining a compound of formula I wherein onium R _n , which may be optionally oxidized to give a compound of formu¬ la I wherein n is 1 or 2 and, if necessary, after remo¬ val of the known protect i ng groups, possibly present in

R,, converting a co pound of formula (I) into another 4 compound of formula (I), and/or, if desired, salifying a compound of formula (I) and/or, if desired, obtaining a free compound of formula (I) from a salt thereof and/or, if desired, separating a mixture of isomers into the single isomers; reacting a compound of formula Ia

wherein R are as defined above and 0 ' is a

'2' member selected from the group consisting of a thiol and of a masked thiol group such as thio-C -C alkano- ylester or a thiouronium salt -S-(C=NR )NR R ^ Y with a compound of formula IV

R -H (IV)

4 wherein R, is as defined above and M is a known leav- 4 ing group such as chlor ne, bromine, iodine, trifluoro- acetate, t ri f luoromethanesu Iphonate, an alkyl or an ary Isu Iphonate, to give a compound of formula I wherein

0 is -S(0) R, being R, as defined above and n is zero, n 4 4 which may be optionally oxidized to give a compound of formula I wherein n is 1 or 2 and, if necessary, after removal of the known protecting group, possibly pre¬ sent in R,, converting a compound of formula (I) into 4 another compound of formula (I) and/or, if desired, salifying a compound of formula (I) and/or, if desired, obtaining a free compound of formula (I) from a salt thereof and/or, if desired, separating a mixture of

isomers into the single isomers; c) reac ing a compound of general formula V

CH =CH-R", (V) _ 4 wherein R" is a member selected from the group consi- 4 sting of cyano, alkoxycarbonyl, -C0NR,R_, C0-(CH_) -B

6 7 2. p wherein R

6' 7' _ and p, are as defined above, with a compound of formula Ia to give a compound of formula lb

wherein R , R_, R , R",, are as above defined and n is zero, which may be,if desi red, oxi di zed to give a com¬ pound of formula lb wherein n is 1 or 2 and, if neces¬ sary, ^" converting a compound of formula lb in another compound of formula I and/or, if desired, separating a mixture of isomers into the single isomers; d) cyclizing a compound of formula VI

wherein R„ is as above defined, with an alkylidene com

1 - pound of formula VII

wherein R and n are as defined above and R' ι s a

2' substituted or an unsubstituted C -C alkyl chain, a

C -C alkenyl chain, an unsubstituted or substitued 3 6 aryl or C -C, aralkyl, to give a compound of formula Ic 1 4

wherein R„, R„, R',, R, and n are as defined above and, 1 5 4 if desired, after removal of the known protecting group possibly present in R,, converting a compound of formu-

4 la I in another compound of formula I and/or, if desir- ed, salifying a compound of formula I and/or, if desir¬ ed, obtaining a free compound of formula (I) from a salt thereof and/or, if desired, separating a mixture of isomers into the single isomers; e) reducing a compound of formula Id

wherein R„, R„, R__, m are as above defined and P* is

1 3

hydrogen or C -C_ alkyl, (CH_) -W, with a borohydride 1 8 a p and/or a cyanoborohydride of an alkaline metal or of a quaternary ammonium salt, in the presence of an ammo¬ nium salt of formula VIII H„ ®NP* „P- (VIII) 2 1 wherein each of P" and P'-,,, which are the same or different, may be hydrogen, C.-C, alkyl, (CH_) -W or,

• 6 2 p ₁ taken together with the nitrogen atom to which they are linked, form the residue -N X and p„ , W and X

\ / are as defined above, to give a compound of formula Ie

wherein R R ₃ P, P'_. P' -. and m are as above 1 2 defined, which may be transformed in another compound of formula I by oxidation of the sulphur atom or by salification or by optical resolution; reducing an ammonium salt of formula Ig

wherein R„ , R.,, R,, m, P* are as above defined and r 1 2 3 2 is an integer from 3 to 4 and Y ^* is a monovalent anion, by reaction with an alkaline or quaternary ammonium salt of a borohydride and/or a cyanoborohydride to give

a compound of formula Ih

H

(Ih) wherein R., R_, R_, m, r and P' are. as above defined, 1 2 3 2 ' which, if desired, may be optionally subjected to sepa- ration of the diastereoisomers; c leavaging an ox i rane ring of a compound of formula ⁽ Ii ⁾

wherein R . , R_ , R , B, n, n and p are as defined above, with a nucleophilic compound selected from the group consisting of water, C -C, lower alcohols, C -C, lower

1 3 1 3 alkylthiols, ammonia, a monoalkyl or a di a Iky lami ne, to give a compound of formula (ID

wherein R , R , R , B, n, n and p are as above defined and one of R__ and R„_, is hydroxy and the other may be 11 1

hydroxy, -NH_,, C -C, alkoxy, C -C, alkylthio, a 2 1 3 1 3 monoalkyl or a di a Iky lami ne .

Both the process of the invention comprising the reaction of a compound of formula II with a thiol of for- mula III to produce a compound of formula I and the pro¬ cess converting a thiol or a masked thiol of formula Ia in another compound of formula I, wherein 0 is-SR., by treat-

4 ment with a reagent of formula IV, represent an usual me¬ thod pursued in the art for introducing thiols and thio- ether groups in an organic substrate.

The process may be respectively performed by reac¬ tion with either stoichiometric amounts or a small excess of the reagents of formula III and of formula IV in a solvent, iscible or immiscible with water, in homogeneous or in heterogeneous phase or in phase-transfer conditions, in the presence of a base in equimolar amounts or in ex¬ cess.

Suitable solvents are C -C alcohols; amides such as forma ide, dimethylformamide, dimethylacetamide; cyclic or linears ethers such as di methoxyethane, dioxane, tetra- hydrofuran, di ethy I su Iphox i de, ketones and acetales such as acetone, butanone, methylale; esters such as ethylace- tate, ethy Iformi ate; halogenated hydrocarbons such as

CCl ., CH_Cl_, 1 , 2-di ch loroethane; aliphatic hydrocarbons 4 _ _ such as n-hexane, n-heptane; eye loa li phat i c hydrocarbons such as cyclohexane; aromatic hydrocarbons such as benze¬ ne, toluene, pyridine, as well as mixtures thereof.

The reaction may be carried out at temperatures ranging from about -30°C to about 100°C; preferably from about -15°C to about 60°C and more preferably from 0°C to

room temperature.

The reaction times range from few minutes to two days, but usually do not exceed two hours when it is car¬ ried out at room temperature. Preferred bases may be an inorganic base, e.g., an alkaline or an alkaline-earth hydroxide, carbonate, bicar¬ bonate, hydride, amide e.g. NaOH, CO,, Na CO , Li CO , KHCO , HeONa, EtONa, ter-buOK, (EtO) Mg, CaH , NaH, NaNH ; or an organic base such as alkylamine e.g. i sopropy lami ne, eye lohexy lamine, butylamine, t ri eth lami ne, or an aromatic base e.g. pyridine or an a Iky Isubst i tuted pyridine or cyclic amines e.g. N-methy l-pi peri dine and 1 ,4-di azabi cy- clo__2,2,2_7octane.

The reaction of a compound of formula VII with a compound of formula V is carried out with an excess of the

'compound of formula V e.g. at least 1.1 molar equivalents per mole of the compound of formula III preferably in presence of tet ramethy Iguanid ne as a catalyst, in inert solvents e.g. esters, halogenated hydrocarbons, linear or cyclic ethers or aromatic hydrocarbons, C -C, alcohols

1 5 preferably at room temperature.

The thioether bond of a compound I may be selecti¬ vely oxidized to give a sulphoxide or a sulphone, accord¬ ing to known methods. Selective oxidation of a sulphide to sulphoxide may be performed using one molar equivalent of an organic peracid such as perbenzoic, m-C l-perbenzoi c, monoperphta Ii c, peracetic, performic and peroxyt ri f luoro- acetic acid or using periodic acid or a salt thereof. Two molar equivalents or an excess of a peracid mentioned above are used for obtaining the corresponding sulphones

starting from a sulphide of formula I (n = 0), and on-e molar equivalent is necessary for the conversion of a compound of formula I (n = 0) into a compound of formula I (n = 2) . Suitable solvents are those which are inert to the oxidizing reagent; the reaction may be performed in the presence of an insoluble inorganic base such as Na CO , KHCO , NaHCO in order to remove the reduced ac i d from the reaction mixture; preferably the reaction is carried out at temperatures ranging from 0°C to room temperature and the reaction times range from few minutes to a few hours. The 1 ,4-di hydropyridine ring is not oxidized to pyridine ring under said reaction conditions.

The cyclization of a compound of formula VI with a compound of formula VII to give a compound Of formula Ic may be carried out by reaction with_ either stoichiometric amount or a small excess of the enamine VI in inert sol¬ vents such as benzene, toluene, tet rahydrofuran, CH Cl , CHCl,, 1 , -d ch loroethane, pyridine, acetic acid, C -C lower alcohols; or mixture thereof.

The reaction is preferably carried out at tempera¬ tures ranging from room temperature to the reflux tempera¬ ture of the reaction mixture; "the reaction is preferably carried out in a temperature range from 45° to 8o°C; as a consequence, the reaction times may vary from several days to few hours, but usually do not exceed four hours.

A reduction of t.he reaction time may be achieved by addition of catalytic amount of an inorganic or organic acid e.g. hydrochloric, p-to luensu Iphoni c or acetic acid, to the cooled reaction mixture after 2-3 hours heating.

Preferred compounds of the invention are compounds of formula (I) having a mono- or po lysubst i tuted thioether group. Particularly preferred substituents are hydroxy, amino, carbonyl, carboxyl, epoxy groups, which may be optionally protected with protective groups removable selectively and under mild reaction conditions.

Known protective groups are, for example, acetal- ethers, enolethers, silylethers for alcoholic and phenolic groups, amide and 3,5-dimethy Ipyrro I ^' for primary amines, acetals and ketals for carbonyl compounds, ter-butyl and alkoxymethylester for carboxyl c acids; all said protecti¬ ve groups may be removed easily by acid hydrolysis.

Cyclic imides may be used to protect primary amino groups and their removal may be easily carried out by treatment with hydrazines or other amines e.g. butylamine. Ana logously , i sothi ouronium saIts and aIkanoyIthio- _, esters may also be used to protect thiol groups; their removal is easily carried out by treatment with ammonia or lower alkyl amines. It should be understood that functio- nal groups such as amino, hydroxy, carbonyl, thiol, carbo¬ xyl optionally present in R 4. , R' 4,, R", groups in the com- pounds of formula III, IV, V and VII, may be present ei¬ ther in free or protected form: in the latter case, they may be deprotected in any convenient step of the synthetic process.

On the other hand, free amino, hydroxy, thiol, car¬ boxylic groups optionally present in the compounds of formula I, may be optionally converted into amides, Schiff bases, esters, silyl derivatives to make the puri- fication process of the final compounds easier.

On the other hand, using methods well-known in the art, reduction (for example with alkaline borohydride or cyanoborohydride or with their tet raa Ik lammoni um salts) of Schiff basesyields secondary amino groups, whi le reduc- tion of esters of °-*-ami noaci d yields 0(-aminoalcohols, intermediates for 5-di hydrooxazo l-2-ones . Simi larly, v ^' ici- naldiols, if present in R,, may be converted into epoxi- des, via monoa Iky I (ary D su Lphonates, the epoxide may be cleaved to produce for example CX-hydroxy-alkylamines, O-hydroxya Iky Ithiols, Ot-hydroxyether (or thioethers) .

Finally, reductive amination may be used to convert a carbonyl compound of formula Id into an amino compound of formula Ie. Particularly preferred reductive amination is that of a salt of a bifunctional ]f- (or o )-ami noketone of formula Ig into cyclic a ine of formula I -

The starting materials of formula III, IV, V, VI are known compounds, commercially avai lable and/or easi ly preparable with known methods.

The 2-ha lomethy 1-1 ,4-dihydropy ridines of formula II are described in the italian Pat. Appln. N° 21875 A/85 (6.8.1985) in the applicant's name.

The compounds of formula VII are prepared by reac¬ tion of an aldehyde of formula VIII ₂ CH0 (VIII) with a ^-ketoester of formula IX .-S-CH -CO-CH -C00R, (IX) J 2 2 5

(0) n

When the -ketoesters of formula IX are unknown com pounds, they may be prepared using known methods starting from the known acids of formula X

R - S - C H _ C 0 _ H ( X ⁾

4 2 2

( 0) n

An activated form of acid of formula X (e.g. chlori ^¬ de, imidazolide) may be reacted with Meldru acid or with the magnesium enolate of a malonic acid emiester. For mo¬ re detailed illustrations of general methods for -keto- ester synthesis see for ex. Y. Oikawa et al., J. Org. Chem. 43, 2087 (1978), D.G. Meli ^' llo et al., Tetrah. Lett. 21., 2783 (1980) and D.C. Brooks et al., Angew. Chem. Int. Ed., 1§, 72 (1979).

The compounds of the invention of formula I protect cellular membranes form oxidative injuries; a reduced malondiaIdehyde formation is observed after incubation of rat erithrocyte membranes (M. Aishita et al.. Arch. In- tern. Pharmacodyn. 261, 316, 1983) and of rat brain ho ogeneate (Stocks et al., Clin. Sci. Molec. Hed., 47, 215, 1974) with the compounds of the invention ^" .

Sudden death induced by bolus of arachidonic acid or of a mixture of ADP and collagene in mice and rabbits is prevented by previous oral and/or intraperi oneat treat¬ ment with the compounds of formula I.

The compounds of the invention were tested, accord¬ ing to the Godfraind's procedure (T. Godfraind et al., Arch. Intern. Pharmacol., 112, 235, 1968), to evaluate . their property of inhibiting the contraction induced by

+ CaCl in K -depolarized aorta strips, in_ comparison to nifedipine.

Many compounds of the invention showed ID ranging

-7 -10 -8 from 10 to 10 (nifedipine, ID, _Λ 2.7-10 ).

50 The anti ypertensive activity of the compounds of

the invention was also tested, at different times, after oral administration ^' to conscious s ontaneously hypertensi ^¬ ve rats (SH rats), measuring the decrease of the mean blood pressure (B.P.). Some compounds of the invention induce a 15% de¬ crease at least, of the basal values of the mean B.P. when administered at a dose level lower than 1/10 of the corre¬ sponding LD •

A 15% decrease of the mean B.P. is generally consi- dered to be a predictive indication for a significant' cardiovascular activity.

It is to be pointed out that a satisfactory corre¬ lation is not often observed between the calcium antagoni¬ st potency, as measured by "in vitro" test, and the an-ti- hypertensive, activity shown "in vivo" by some compounds of the present inventions.

Representative examples are reported in the follow¬ ing table:

Substance ID _CΛ (M) Decrease of the mean! aorta ⁵⁰ con_trac blood pressure in

6-methy1-3,5-di carbo¬ tility nh bi SH Rats ethoxy-4-(m-nitrophe- t i on mmHg doses Q____l_ ⁴ I__!_-.drog--ri _i di,n_! .mg/kg/os.

2-methyl-isothiouro- ium hydrochloride 2.2-10 45 3.1

2-(2 ^' ,3-dihydroxypropyl.

-8 thiomethyl 2.2.10 38 12.5

2-(acetylaminoethyD-

-9 th i omethy I 9.2-10 26 3.1

2-(2-hydroxyethyD- .

-8 thi omethy I 10 0-5 3.1

2-(2-cyanoethyD-

-8 thio ethy I 10 0-5 6.2

2-(2-ethoxycarbonyl- 2-ami no-ethy I ) -

-8 th i omethy I 10 30 3.1

2-(p-methoxyphenyD-

-8 th i omethyI 10 35 12

2-(p-methoxyphenyD- su Iphyny Imethy I 1θ ^"6 -10~ ⁷ 51 12

2-(p-fluorophenyD-

-6 thiomethyl 10 29 12.5

2-(p-fluorophenyD-

-8 su Iphyny Imethy I 10 40 12.5

2-(p-aminophenyD-

-8 thi omethy I 8.4*10 25 6.25 ^'

2-(5-amino-1,3,4- thiazol-2-yl)thio-

-6 methy I f 10 68* 12

2-(5-amino-1,3,4- thi adiazol-2-y D-

-6 -7 th i omethy I 10 -s- 10 67* 12

2- ⁽ 3- i sop ropy l am i no- 2-h yd ro x y-p ropy D -

-10 t h i omet hy I •8 10 5-12 3.1 -8

2-acetyIthiomethy I 2.5-10 20 6

(*) Long lasting activity,

The activity of the compounds of the invention on the gastrointestinal tract was also studied in order to assess a) cytoprotect i ve action against lesions induced by NSAI drugs; b) ability -to prevent the ulcers induced by the method of Togagi-Okabe (Japan J. Pharmacol. 1 _, 8, 9, 1968) .

2-(3,2-Dihydropropyl)thiomethyl-6-methyl-3,5-dicar- boethoxy-4- ⁽ m-ni t ropheny I) -1 ,4-di hydropyridi ne is a repre¬ sentative compound of the invention having an ED lower than 1 mg/kg by oral administration.

The compounds of the invention are moreover useful for the control of electrolyte fluxes through membranes of blood cellular components such as platelets, leucocytes, eritrocytes and for t-he regulati,on of their deformabi Ii ty and reactivity against -exαitatory stimuli. At the cellular level, they are also useful i-n the control of enzymatic processes involving both activation and inhibition of calcium-dependent enzymes. .

The compounds of the invention are consequently considered useful as vasodilators and hypotensive agents for the treatment of th romboembo I i c diseases, for treatment of myocardial, renal and cerebral ischemias. The compounds I are also particularly useful as cytoprotecti ve and anti- ulcer agents at gastric level. Dose order of 0.01 to 10 mg/kg/die and preferably ranging from 0.05 and 5 mg/kg/die can be given 1 to 2-3 times a day, the exact dose depending on the age, weight and condition of the patient and on the admi istration route. A dose for oral administration may comprise, for example, from 0.05 to 70 mg of active principle.

The amount for parenteral route may vary from 0.001 to 5 mg/kg/die, preferably from 0.01 to 2 mg/kg/die.

Some onosubsti tuted ami noa Iky Ith i omethy I compounds of the invention, such as 2-am noeth Ith i o-4- ⁽ m-ni - t ropheny D-3,5-di ethoxycarbonyl-6-methyL-1,4-dihydropyri¬ dine show peculiar properties such as a pronounced and- long lasting antihypertensive activity at very Low doses (for example 0.4 mg/kg/os) when tested in conscious SH rats- and in conscious DOCA-rats (i.e. rats made hyperten- sive by treatment with desoxycorti costerone acetate) by oral route.

Other typical monofuncti ona li zed compounds of the invention are for example: 2-L i2-ami noethy I)thi q7methyl-3-carboethoxy-5-carbomethoxy- 4-m-ni t ropheny L-6-methy L--1 ,4-di hydropyridine and the corre¬ sponding: - 4-o-ch loropheny I, 4-m-t ri f luoromethy L-pheny L, 4-m-ch loro-pheny L derivatives; 2-Z.(2-aminoethy I) th iq7me- thy l-3-carboethoxy-5-carboisopropoxy-4-m-nit ropheny I-6-me¬ thy 1-1 ,4-dihydrp.pi ridine hydroch Loride; 2-/C2-N-buty Lami - noethy D thi o7methy 1-3,5-di carboethoxy-4-m-nit ropheny L-6- methy 1-1 ,4-di hydropyri di ne and the corresponding N-methyl and N-isopropyl derivatives; 2-/_(2-aminopropy Dthio7me- thy L-3-carboethoxy-5-carbomethoxy-4-m-nitropheny I-6-me¬ thy 1-1 ,4-dihydropyridine and the 2-Z_(4-ami nobuty I ) thi q7me- thyl deri atives, and salts thereof.

The antihypertensive effect is strictly dose depen¬ dent in the investigated dosage range from 1.5 to 0.1 mg/kg/os. The maximum hypotensive effect, proportional to the administered dose, takes place 6-7 hours after the admin stration and the blood pressure is maintained at the

decreased Level for other 4-5 hours, at least.

The gradual onset of the antihypertensive effect is not coupled with reflex tachycardia, which is often obser¬ ved after treatment with other antihypertensive agents such as, for example, hydralazine and many di hydropyri di - nes, in the same experimental models.

On the contrary, no substantial modifications of the mean B.P. and heart rate are observed in normal con¬ scious rat after oral administration of these monofunctio- nalized ami noa lky Ith i omethy L-1 ,4-di hydropyri di nes at the same dose range Level (1.5-0.1 mg/kg) . It should be poin¬ ted out that the same compounds, investigated "in vitro", show modest to middle inhibitory properties against

+ CaCl -induced contraction of K -depolarized rat aorta

-6 -7 strips with calculated I ranging from 10 to 10 M.

Only after prolongation of the contact time of solutions of these compounds with the tissue preparations from the standard 2-5 minutes to 2-3 hours before the CaCl stimu¬ lated contractions, it is possible to calculate ID rang-

—8 -10 ing from 10 to 10 M.

The peculiar antihypertensive effect, its gradual onset, the long Lasting activity lead to suppose that the compounds of formula I and more precisely those of formula

Ih, Ie wherein R. is a carboxyester group, are more speci- fically useful in human and veterinary therapy for treat¬ ment of hypertensive diseases of different cause and seve¬ rity.

For the achievement of the desired effects in human and veterinary therapy, these compounds of formula Ie, Ih, of the invention, may be administered by oral route or by

parenteral route in a variety of dosage forms e.g. orally in the form of tablets . capsu les or liquids; rectally in the form of suppositories, subcutaneous Ly, i nt ra uscu Lar- Ly, or intravenously administration or by infusion in emergency situation.

The amounts of active ingredient may range from 1 μ g to 1 mg/kg/die preferably from 1 jug to 0.1 mg/kg/die by oral administration. The parenteral dosage may range from 0.1 μ to 0.5 mg/kg/die and preferably from 0.5 ug to 0.2 mg/kg/die. One dose for oral administration may contain, for example, from 50 μ g to 5 mg of active ingredient.

The compounds of the invention may be administered once a day, even if administrations more or less frequent may be sometimes convenient according to the age, weight and patient's condition and to the admin stration .route.

Suitable pharmaceutical- formulation may be prepared according to conventional techniques such as those descri¬ bed in Remington's Pharmaceutical Sciences Handbook", Hack Publishing Co., U.S.A. For the oral administration, the compound may be formulated in solid or liquid preparations such as capsu¬ les, pi lls, tablets, powders, solutions, suspensions or emulsions. The unit dosage form may be the hard or soft gelatine capsule containing for instance lubricants and inert excipients such as lactose, saccharose or starch. Alternatively, the compounds of the invention may be admi¬ nistered as tablets, on carriers such as lactose, saccha¬ rose or starch in combination with binders such as starch itself or gelatin, disintegrating agents such as potato starch, or alginic acid, and lubricants such as stearic

acid and magnesium stearate.

For parenteral administration the compounds of the invention may be administered in injectable forms, dissol¬ ved or suspended in pharmaceutically acceptable di luents, with a pharmaceutical carrier such as a sterile liquid such as water or an oi l, with or without the add.ition of other pharmaceutically acceptable excipients. Oi ls which may be used in sa d preparations are of mineral, vegetal, animal or synthetic kind. Generally, as a carrier for injectable solutions the following substances may be used: water, salts, aqueous solutions, dextrose or other sugars aqueous solutions, ethanol, glycols such as propy lenglycol and polyethy lenglyco Is .

For the rectal administrat on, the compounds may be formulated in forms of suppositories, mixed with conven¬ tional vehicles such as, for example, cocoa butter, wax, po lyvi ny Ipyrro I i done or po lyoxyethy leneg lyco Is, or deriva¬ tives thereof .

The administration route generally preferred is the oral route, whi le the preferred pharmaceutical formula¬ tions are capsu les .

The invention is illustrated by the following non limitative examples, wherein the abbreviations "DME", "Et 0", "AcOEt", "EtOH", "TEA", "AcOH", "THF", "MeOH" refer to 1 ,2-di methoxyethane, di ethy lethe r, ethy lacetate, ethanol, t ri ethy lami ne, tet rahydrofurane and methanol, respectively. EXAMPLE_1

A stirred ethanolic solution (200 ml) of an alkali- ne alkoxide, for example sodium ethoxide (20 g), is satur-

ated, at +10°C, with dry hydrogen sulfide, cooled to

-15°C, and added with a solution of 2-ch loromethy 1-3,5-di-. carboethoxy-4-(m-nitrophenyD-6-methy 1-1,4-dihydropyridine

(25 g) in DME (70 ml). After one hour, the reaction mixtu- re is warmed to 0°C, acidified with H_S0, (10% water solu-

_ 4 tion; 100 ml) and diluted with water (1400 ml). The preci¬ pitate is filtered off, dried in vacuum, and recrystalliz¬ ed from Et _? 0 to give 23 g of 2-mercaptomethy 1-3,5-di carbo¬ ethoxy-4-(m-nitrophenyI)-6-methy 1-1, -dihydropyridine, m.p. 145-147°C. EXAMPLE_2

A solution of 2-ch loromethy 1-3,5-di carboethoxy-4- (m-nitrophenyI) -6-methy1-1 ,4-dihydropyridine (1 g) and tetrabutylammonium hydrogen sulfide (0.7 g) in methylene chloride (10 ml) is stirred at -10°C for 20 minutes, neu¬ tralized with a drop of AcOH, evaporated under vacuum and the residue recrystall zed from ^E ^_0 to give 0.7 g of 2-mercaptomethy1-3,5-di carboethoxy-4-(m-nitrophenyD-6-met _ y1-1 ,4-dihydropyridine, m.p. 145-147°C. EXAMPLE_3

Potassium thioacetate (1.5 g) is added, at 10°C under N atmosphere, to a stirred solution of 2-chlorome- thy l-3-carboethoxy-5-cyano-4-(m-ni trophenyI)-6-methy1-1,4- dihydropyridine (5 g) in acetone (50 ml). After 20 mi-nutes the reaction mixture is evaporated to dryness ^* and the residue is partitioned between AcOEt (80 ml) and water (30 ml) .

The organic layer is washed with water (2 x 20 ml), dried on Na_S0, and the solvent is evaporated under va- _ 4 cuu . The residue is recrystallized from Et_0 to give .4.9

g of 2-(acety Ith i o ⁾ methy l-3-carboethoxy-5-cyano-4-(m-n - t ropheny I) -6-methy 1-1 ,4-dihydropyridine, m.p. 155-157°C.

A water solution of NH (28%, 5.3 ml) is added at 0°C under N atmosphere to a stirred solution of the above described compound (2 g) in DME (20 ml).

After 30 minutes the solution is diluted with ice water (100 ml) and extracted with Et 0 (3 x 30 ml) to give, after the usual work-up, 1.5 g of 2-mercaptomethy l- 3-carboethoxy-5-cyano-4-(m-nit ropheny I) -6-methy 1-1,4-di hy- dropyridine, oil.

NHR (CDCl ): <$ ⁽ TMS): 1.10-1.20 (3H, t ⁾ , 1.80-2.00 (1H, t); 2.20 (3H, s); 4.00-4.40 (4H, m); 5.10 (1H, s); 7.00- 8.20 (5H, m). EXAMPLE_4 A mixture of 2-ch loromethy 1-3, 5-di carboethoxy-4- (m-ni t ropheny I) -6-methy 1-1 ,4-di hydropyri di ne (6 g) and thiourea (1.2 g ⁾ in EtOH (60 ml) is refluxed for 3 hours; after cooling to room temperature,the crystalline precipi¬ tate is filtered off to give 4.8 g of S- ^" (6-methyl-3,5-di- carboethoxy-4- ⁽ m-ni t ropheny I ⁾ -1,4-d hydropyridin-2-y I) me¬ thy l_7 isothiouronium hydrochloride, m.p. 219-220°C.

The free isothiourea, as an oil, is prepared by treatment of a suspension of the isothiouronium salt (for example 1 g) in AcOEt (20 ml) with aqueous saturated NaHCO solution (2 x.10 ml). The organic phase is washed with water, dried on Na_S0, and evaporated to dryness.

2 4

By subsequent treatment of a solution of the free base in a suitable solvent (for example AcOEt) with a solution of equimolar amounts of an acid (for example fumaric and acetic acid) the ^" corresponding isothiouronium

salts: fumarate (m.p. 82-85°C) and acetate (m.p. 69-70°C ⁾ are obtained.

A solution of a isothiouronium salt (for example the hydroch lori de 4.7 g) and n-propy lami ne (0.7 g) in EtOH (50 ml) is heated to reflux for two hours, then cooled to room temperature, acidified with a few drops of AcOH and diluted with iced water (500 ml). The precipitate is fil¬ tered off, dried in vacuum and recrystallized from Et 0 to give 3.2 g of 2-mercaptomethy 1-3,5-di carboethoxy-4-(m-ni - t ropheny D-6-methy 1-1 ,4-di hydropyridine, m.p. 145-147°C. EXAMPLE_5

Using in the procedures described in the Examples 1-4 a suitable 2-ha lo ethy 1-1 ,4-di hydropyridi ne of formu¬ la II, th'e following 2-mercaptomethy l-6-methy 1-1 ,4-di hy- dropyridine are prepared:

- 3-carboethoxy-5-carbomethoxy-4-(m-ni tropheny I) ; m.p. 104-107°C;

- 3-carboethoxy-5-carbomethoxy-4-(m-ch loropheny I) ; m.p. 85-90°C; - 3,5-di carboethoxy-4-(m-t ri f luoromethy Ipheny I) ) ; m.p. 102-103°C;

- 3-carboethoxy-5-carboisopropoxy-4-(o-methylthiophenyl);

- 3,5-di carbomethoxy-4-(o-difluoromethoxypheny I);

- 3,5-di carbomethoxy-4-(_3-pyri dy D ; - 3,5-di carboethoxy-4-pheny I;

- 3,5-di carboethoxy-4- ⁽ p-fluoropheny I);

- 3,5-d carboethoxy-(2-furany I ) ;

- 3-carboethoxy-5-nitro-4-(m-nitrophenyl);

- 3-carboethoxy-5-cyano-4-(o-trif luoromethy Ipheny I ⁾ .

EXAMPLE_ 6

Using a suitable 2-halomethy1-1 ,4-di hydropyridine of formula II in the procedure of the Example 3, the fol¬ lowing 2-acety Ithi omethy 1-3,5-substituted-4-(substi tuted pheny I) -6-methy 1-1 ,4-di hydropyridi ne are prepared:

- 3,5-di carboethoxy-4-(m-ni tropheny I) ; m.p. 113—115°C;

- 3-carboethoxy-5-carbomethoxy-4- (m-ni t ropheny D ; m.p. 80- 82°C;

- 3,5-di carboethoxy-4-(m-trif luoromethy Ipheny I); - 3-carboethoxy-5-ni t ro-4-(m-ni tropheny D ;

- 3,5-dicarbomethoxy-(0--thienyl);

- 3-carboethoxy-5-carbomethoxy-4-(o-ch loropheny I) ; m.p. 141-145°C;

- 3,5-di carboethoxy-4-(o-ch Loropheny D ; m.p. 104-105°C. EXAMPLE_7

Using in the procedure of Example 4 a thiono-imide (-CS-NH-) compound selected from the group consisting of thiourea, 1 -methy L-2-th iourea, 1 ,3-di methy L-2-th iourea, 2-i mi dazol idineth ione and 3,4,5,6-tet rahydro-2-th io-pyri - midine and a suitable 2-ch loromethy 1-1 ,4-di hydropyri di ne the following compounds are prepared:

- S-Z.(6-methy 1-3,5-di carbomethoxy-4-(m-ch loropheny I) -1,4- dihydropyridin-2-yl)methyl7 isothiouronium hydrochloride;

- S-_ (6-methy l-3-carboethoxy-5-cyano-4-(o-trif luoromethyl- pheny I ) -1 ,4-di ydropyri di n-2-y I) methy 17 i soth i ouroni um fu- marate;

- S-/ ^~ (6-methy 1-3,5-di carboethoxy-4-pheny 1-1, -di hydropyri - din-2-yl)methyl7-1~-'-ethylisothiouronium hydrochloride;

- S-/K6-methy 1-3,5-di carboethoxy-4-(p-fluorophenyl) -1,4- dihydropyridin-2-yl)methyl_7-1,3-dimethylisothiouronium

hydrochloride;

- 2-__(1,4,5,6-tetrahydropyri id-2-yl)thio_7methyl-3,5-dicar boethoxy-6-methy1-4-(m-ni trophenyI)-6-meth.y1-1, -dihydro pyridine hydrochloride, m.p. 217-219°C; - 2- 7(4,5-dihydroimidazol-2-yI) thio/methy l-3-carbomethoxy- 5-carboethoxy-4-(m-trif luoromethyIpheny D-6-methy L—1 ,4- dihydropyridine hydrochloride; m.p. 190-192°C;

- 2-/(4,5-dihydroimidazo1-2-yI) thio./methy 1-3,5-di carboetho xy-4-(m-nit rophenyI)-6-methy 1-1,4-di hydropyridine hydro- chloride, m.p. 211-213°.

EXAMPLE_8

A mixture of 2-mercaptomethy1-3,5-di carboethoxy-4-

( -nitrophenyI) -6-mety1-1 ,4-di hydropyridine . (4.05 g), propionyl chloride (0.88 ml), and TEA (1.4 ml) in methyle- ne chloride (50 ml) is stirred- t room temperature, under

N atmosphere for two hours.

The reaction mixture is evaporated to dryness in vacuum, the residue partitioned between AcOEt (50 ml) and water (2 x 30 ml); the organic layer, dried on Na_S0, is

2 4 evaporated in vacuum. The residue is purified by SiO column chromatography (eluent: hexane/AcOEt 7/3) to give 3.6 g of 2-(propionyLthio)methy 1-3,5-d carboethoxy-4-(m- nitrophenyl)-6-methyl-1,4-dihydropyridine oi I. NMR (CDCl ) £ (TMS): 1.10-1.40 (9H, m); 2.20 (3H, s); 2.50 (2H, q); 3.80-4.20 (6H, m); 5.10 (1H, m); 6.90-8.10 (5H, m) . EXAMPLE_9

Using in the procedure of Example 8 an acylchloride selected in the group of propionyl chloride, hexanoyl chloride, heptanoyl and decanoyl chloride and a suitable

2-mercaptomethy l-6-methy 1-1 , -di hydropyri di ne, the follow¬ ing 6-methy 1-1 ,4-di hydropyridi ne are obtained:

- 2-(propiony Ith o) ethy 1-3,5-di carboethoxy-4-(o-ch loro¬ pheny D ; oil

5 - 2-(heptanoy lth i o) methy l-3-carboethoxy-5-carboi sopropoxy- 4- (m-ni t ropheny I) ; oil

- 2-(hexanoy Ith o) methy l-3-carboethoxy-5-carbomethoxy-4- (m-ch loropheny I ) ; oil

- 2-(decanoylthiomethyl)-3,5-dicarbomethoxy-4-(p-nitrophe- 10 nyl); oil.

EXAMPLE_10 >

A solution of 2-ch loromethy 1-3,5-di carboethoxy-4- (m-ni t ropheny I ⁾ -6-methy 1-1 ,4-di hydropyridi ne ⁽ 5.6 g ⁾ in EtOH/DME (5/1; 20 ml) is added dropwise at +10°C to a

15. stirred solution of sodium thiophenate (1.8 g ⁾ ,in ethanol (10 ml), under N atmosphere.. After two hours at room temperature the reaction mixture is evaporated under va¬ cuum and the residue is partitioned between Et_0 (100 ml) and water (50 ml). The organic phase is washed with a

20 satured solution of sodium bicarbonate (2 x 20 ml) and water (3 x 20 ml), dried (Na.SO,) and evaporated to dry-

2 4 ness. The residue is recrystallized from i sopropy lether to give 5.7 g of 2-(pheny lth io) methy 1-3,5-di carboethoxy-4- (m-ni tropheny I) -6-methy1-1 ,4-dihydropyridi ne, m.p. -92-

25 94°C.

EXAMPLE_11

Using in the procedure of Example 10 a substituted thiophenol and a suitable 2-ch loromethy 1-1 ,4-di hydropyri - dine the compounds listed in the following Table are pre-

30 pared.

TABL E

CO Et O-NO -C,H, H 135-136 2 6 5

CO Me m-N0 ₂ -C ₆ H ₅ H 125-126

CO Et m-Cl-C,H_ H oil 6 5

CO Et m-CF -C,H_ H oil J 6 j

CO Et O-Cl-C.H, H oi I 6 5

CN m-NO,-C,H_ H oil 2 6 5

NO m-NO -C,H_ H oil 2 6 5

CO Me ^-pyridyl H oi I

CO Me Λ-furany I H oi I

CO Et m-NO -C .H, o- -COOH 179-181 2 6 5

C0 ₂ E - m-NO -C^H, p- -OCH 164-166 2 6 J

C0 ₂ Et m-N0_-C,H_- 2 6 _> p- -F 103-105

CO Et m-NO_-C,H, 2 6 5 P- -Cl 124-126

C0 ₂ Et m-NO -C,H, p-NHCOCH 166-168 2 6 5

C0 ₂ Et m-NO_.-C .H, 2 6 5 p- -NH 104-106

CN m-NO_-C,H, p-NHCOCH 60-63 2 6 5 co ₂ εt y0-pyridyI p- -F oi I

CO Et m-NO_-C,H, o- -NH 104-106

EXAMPLE 12

A mixture of 2-mercaptomethy 1-3,5-di carboethoxy-4- (m-nitrophenyI)-6-methy1-1 ,4-di hydropyridihne (4.8 g), 2-bromoethy Ibenzene (2.3 g), tetrabutylammonium bromide (0.150 g), toluene (50 ml) and sodium hydroxide ⁽ 1N water

solution, 12 ml ⁾ is stirred at room temperature, under N a mosphere, for two hours.

The organic phase is separated, washed with a satu¬ red aqueous solution of NaH_P0, (2 x 20 ml) and water ⁽ 3 x

2 4 20 ml), dried on Na_S0, and evaporated to dryness in va-

2 4 cuum. The residue is purified by SiO column chromatogca- phy (150 g, hexane/AcOEt 80/20, as eluent), to give 4.4 g of 2-/.(2-phenylethyl) thi o_7 ethy 1-3,5-di carboethoxy-4-(m- ni t ropheny I) -6-methy 1-1 ,4-di hydropyri di ne, m.p. 73-75°C. EXAMPLE_13

Using the procedure of Example 12 the following compounds are prepared:

2- pheny Imethy I) thip7methy 1-3,5-di carboethoxy-4-(m-ni t ro¬ phenyD-6-methy1-1 , -di hydropyridine; m.p. 91-93°C; 2- (pheny Imethy I) thio_7methy 1-3,5-di carboethoxy-4-(o-ch lo¬ ropheny D-6-methy 1-1 ,4-di hydropyri di ne; oil; 2-Z.(phenylethyl)thio methyl-3-carboethoxy-5-carbomethoxy- 4-(o-methy lth iopheny I) -6-methy 1-1,4-di hydropyridine; oil. §XAMPLE_14

A solution of 2-ch loromethy 1-3,5-d carboethoxy-4-

(m-ni t ropheny D-6-methy 1-1 , -di hydropyri di ne (2.5 g) in

EtOH (25 ml) is added dropwise at -10°C to a solution of

2-mercaptopyr mi di ne (0.77 g) and sodium hydroxide (35% water solution, 0.84 ml) in EtOH (15 ml).

After two hours the solution is acidified with a few drops of AcOH and evaporated under reduced pressure; the residue is dissolved in AcOEt (50 ml), the organic phase is washed with water (4 x 10 ml), dried on Na_S0,

2 4 and evaporated to dryness. The residue is crystallized

from EtOH to give 2- 2-pyrimidyI) thiq7methy 1-3,5-di carbo- ethoxy-4-(m-ni tropheny I) -6-methy,l-1,4-di hydropyridine (2.7 g, m.p. 115-117°C> . EXAMPLE_15 Using in the procedure of Example 14 a suitable heterocyclic thiol of formula III, the compounds listed in the following Tables are prepared:

TABLE

TABLE (continued)

TABLE

m.p. (°C)

C0 ₂ Et o-Cl-C.H, oil 6 5

CO Me m-CF_.-C.H-. oil _> 6 5

CO Me _>-pyrid l oil υ.

CN m-NO -C H 163-165 2 6 5

N0„ 0-CF. oil

EXAMPLE_16

A solution of monoperphta I i c acid in AcOEt (0.37 M solution; 20 ml) is added at 0°C to a mixture of 2-(phe- ny Ithio) ethy1-3,5-di carboethoxy-4-(m-nitropheny I) -6-me- thyl-1,4-dihydropyridine (3.5 g) and NaHCO (3 g) in AcOEt

(20 ml). After 30 minutes the mixture is filtered and the eluate is washed with 1N solution of sodium thiosulfate (2 x 10 ml), with a saturated _so lut i on of NaHCO (2 x 20 ml) and then with water (3 x 10 ml). The organic layer is dried on Na_S0, and evaporated to dryness; the residue is 2 4 purified by chromatography on SiO (hexane/AcOEt 85/15, as eluent) to give 3.5 g of 2-(pheny Isu Ifi ny Dmethy l-3,5-di- carboethoxy-4-(m-ni tropheny I) -6-methy 1-1, -di ydropyridine, m.p. 160-162°C. EXAMPLE_17

Using the procedure of Example 16 the following compounds are prepared:

TABLE

,R _________

mNO. Cl 169-171

_ •-

mNO. 157-161

_>'-

oNO. oi I

<_ •-

oCl oi I

_>

TABLE (follows)

,x R __e____2

mNO. oi I

^N __)- ^S -

EXAMPLE_18

A solution of 1 -ch loro-2-pentanone" (1.6 g) in THF (15 ml) is added, at 0°C, under N atmosphere, to a solu¬ tion of the sodium salt of 2-mercaptomethy l-3-carboetho- xy-5-carbomethoxy-4-(m-nit ropheny I) -6-methy 1-1,4-d hydropy ridine (5.2 g), (prepared in situ from the corresponding thiol and NaH) in THF (30 ml).,

The reaction mixture is stirred at room temperature for two hours, then AcOEt is added (150 ml), the organic phase is washed wi th a saturated aqueous solution of NaH_P0.

2 4 (2 x 20 ml), dried on Na_S0, and evaporated to dryness. The

2 4 residue is recrystallized from ^Et -,° to give 4.25 g of 2-ZT ⁽ 2-oxopentyDthiα7π.ethyl-3-carboethoxy-5-carbomethoxy -4- m- ⁽ ni tropheny D-6-methy 1-1 , -di hydropy ri di ne, m.p. 128- 130°C.

EXAMPLE_19

Reacting a suitable 2-mercaptomethy1-1 ,4-dihydropy¬ ridine, prepared according to the procedures of the Example 1-4 with an activated halo compound selected from the group consisting of bromoacetone, ethy l-4-ch loroacetoace- tate, ethyl-3-bromopyruvate, phenacyl bromide, 1-bromo-3- phenyl-2-propanone, 1-bromo-5-acetylamino-2-pentanone, 1-bromo-6-acetylamino-2-hexanone, 1-bromo-2,2-diethoxy- ethane, 1-bromo-2,2-di methoxyethane, ethylch loroacetate, epi ch loridrine, ep bromidrine , N-(4-bromobutyI)phtalimide and p-(i idazo1-1-y I)-1-bromoacetophenone and carrying out the reaction as described in one of the Examples 12 and 18, the following compounds are prepared:

- 2-/~(2-oxopropyl)thio_7 ethyl-3-carboethoxy-5-carbometho- xy-4-(m-nitrophenyD-6-methy l-1 4-dihydropyridine; oil;

- 2-/ ^" (3-carboethoxy-2-oxopropyl)thio methyl-3-carboetho- xy-5-carbomethoxy-4-(m-nit rophenyI)-6-methy1-1,4-dihydro pyridine; oil;

- 2- ^* (2-pheny l-2-oxo-ethyI ⁾ thio Jmethyl-3-carboethoxy-5- carbomethoxy-4-(m-nitrophenyI)-6-methy1-1,4-dihydropyri- dine; m.p. 152-154°C;

- 2- ^* (3-pheny l-2-oxo-propy I )thio_7methyl-3-carboethoxy-5- carbomethoxy-4-( -ni trophenyD -6-methy 1-1,4-di hydropyri¬ dine; oil; - 2-/ ^" (3-phenyl-2-oxo-propyI)th iojmethy l-3-carboethoxy-5- carbomethoxy-4-(m-trifluoromethyIphenyI)-6-methy1-1,4- di hydrop r dine; oil;

- 2-/7(5-acetylamino-2-oxo-pentyl)thiq7.nethy'L-3-carboetho- xy-5-carbomethoxy-4-(m-ni tropheny I) --6-methy1-1,4-di hy- dropyridine; oil;

- 2-/~(6-acetylamino-2-oxo-hexyl)t iQ7methyl-3-carboethoxy- 5-carbomethoxy-4-(m-ni tropheny I) -6-methy 1-1, -di hydropy¬ ridine; oil;

- 2-£ ^" (2,2-diethoxyethyl)thio_7methyl-3-carboethoxy-5-carbo- methoxy-4-(m-nit ropheny I) -6-methy 1-1,4-di hydropyridine; amorphous solid;

- 2-/_( 2, -di methoxyethy I ) th i o7methy l-3-carboethoxy-5-car- bomethoxy-4-(m-trif luoromethy Ipheny I) -6-methy 1-1,4-di y¬ dropyridine; amorphous solid; - 2- .OX i ran-2-y I) methy lth i q7methy1-3,5-di carboethoxy-4- (m-ni tropheny I) -6-methy 1-1 , -di hydropyri dine, m.p. 107- 109°C;

- 2-/.(oxi ran-2-y I) methyIthi o_/methy l-3-carboethoxy-5-carbo- methoxy-4-(m-ni t rophenyD -6-methy1-1,4-di hydropyridine, m.p. 100-103°C;

- 2- .(ox iran-2-y I) methy Ithi o7methy l-3-carboethoxy-5-carbo- methoxy-4-(m-ch lorophenyI) -6-methy L-1,4-di hydropyridine, m.p. 80-84°C;

- 2-/ ^" 4-(N-phtalimido)butyLthi 7methyl-3-carboethoxy-5-car- bomethoxy-4-(m-ni tropheny I) -6-methy L-1,4-di hydropyri di¬ ne, m.p. 125-127°C;

- 2-(carboethoxymethy lth i o) methy L-3,5-di carboethoxy-4- (m- nitrophenyl)-1,4-dihydropyridine; oi I;

- 2-/.2-(4-imidazol-1-yl)phenyl-2-oxoethylthiq/met y 1-3,5- di carboethoxy-4-(m-trif luoromethy Ipheny I)-6-methy L-1, - di hydropyridine. EXAMPLE_20

A solution of 2-(pyrro L i din-1-y I) -1 -ch loroethane hydrochloride (2.8 g), 2-mercaptomethy 1-3,5-di carboetho- xy-4-(m-ni t ropheny I) -6-methy L-1 , -di hydropyridi ne (5.4 g)

and sodium ethoxide (2 g) in ethanol (70 ml) is heated to the reflux temperature for 6 hours, then it is neutralized with AcOH and evaporated under reduced pressure. The resi¬ due, after the usual work-up, is purified by column-chro- matography (Si 0 ; 210 g; eluent AcOH/MeOH 99/1) to give 2.8 g of 2- 2- ⁽ pyrrolidin-1-y I) ethy Ith i q/methy 1-3,5-di car¬ boethoxy-4- ⁽ m-nitrophenyD -6-methy L-1,4-di hydropyr dine, as an oil, that upon treatment with fumaric acid gi es the corresponding salt, m.p. 192-194°C. EXAMPLE_21

Using in the procedure of the Example 20, instead of 2-(pyrro I i di n-1 -y D -1 -ch loroethane a chloro compound selected from 2-(pi peri di n-1 -y I ) -1 -ch loroethane, 2-(mor- pholin-4-y D-1-ch Loroethane and 2-(4-methy Lpi perazi n-1 - yD-1-chloroethane the following 3-carboethoxy-5-carbome- thoxy-4-(m-ni tropheny I) -6-methy L-1, -di hydropyri dines are obtained:

- 2-_f2-(morpholi n-4-y I) ethy Ithio/methy L hydrochloride; m.p. 204-208°C; - 2- 2-(pi peridin-1 -y D eth Ithiq/methy I;

- 2-Z ^~ _-(4-methylpiperazin-1-yl)ethylthiq/ methyl. EXAMPLE_22

A THF solution (25 ml) of 2-_7 ^~ ( 2,2-di ethoxyethy I) - thio7π.ethyl-3-carboethoxy-5-carbomethoxy-4- (m-ni t ropheny I) - 6-methy L-1 , -di hydropyri d ne (5 g ⁾ , hydroquinone (0.5 g) and oxalic acid (1N water solution, 10 ml) is heated to the reflux temperature, under N atmosphere, for one hour, then the THF is evaporated in vacuum and the water layer is extracted with AcOEt (3 x 20 ml). The organic phases are washed with water (2 x 5 ml), a satured solution of

NaHCO, (2 x 5 ml) and water (3 5 mL), dried on Na.SO, 3 .2 4

and evaporated to dryness. The residue, after purification by column chromatography (SiO 120 g; eluent: hexane/iso- propyl ether 70/30), yields 3.8 g of pure 2-β- for ^' my Ime¬ thy Dthifl methyL-3-carboethoxy-5-carbomethoxy-4-(m-nitro- pheny I ) -6-methy L-1 ,4-di hydropyri di ne, oil.

NMR (CDCL ⁾ £ (TMS): 1.10-1.40 (3H, t); 2.40 (3H, s ⁾ ; 3.35 (2H, d); 3.70 (3H, s); 3.80-4.30 (4H, m); 5.10 (1H, s) ^' ; 7.20-8.20 (5H, m); 9.50 (1H, m) .

Using the same procedure described above the follo- wing compound is prepared: 2- ^" (formy Imethy I) th i qj ethy l- 3-carboethoxy-5-carbomethoxy-4-(m-tπ ^' f luoromethy Ipheny D- 6-methyl-1 ,4-dihydropyridine (oi D . EXAMPLE_23

A solution of 2-ch Loromethy l-3-ca rboethoxy-5-carbo- methoxy-4-(m-ni t ropheny D -6-methy L-1 , ^' 4-di hydropyri di ne (10 g) in EtOH/DME (5/1; 25 ml) is added dropwise under nitro¬ gen at -10°C to a solution of cysteamine hydrochloride (3.1 g) and sodium hydroxide (20% water solution, 8.6 ml) in EtOH (60 ml). After 30 minutes the reaction is warmed to room temperature, acidified (pH ^a ' 4.5) with AcOH and evaporated under vacuum. The residue is dissolved in water and washed with Et 0 (3 x 30 ml). The ethereal extracts are discarded and the water layer is made basic with a Na CO solution and extracted with AcOEt/Et 0 (1/1; 5 x' 50 ml). The organic layers are dried on Na_S0. and evaporated to

2 4 dryness to give 10.5 g of 2-_.(2-ami noethy I) thi gjmethy 1-3- carboethoxy-5-carbomethoxy-4-(m-nit ropheny L) -6-methy L-1,4- di hydropyridine C_ H_,N,0, S .

20 25 3 6

Said compound (10.5 g) is dissolved in AcOEt (180 ml) at 40°C and a solution of fumaric acid (2.8 g) in

methanol (30 ml), heated at 60°C.is added to give, after cooling, 12 g of the corresponding fumarate

C_. _Λ H__N,0,S.C H.0, m.p. 170-172°C. 20 25 3 6 4 4 4

EXAMPLE_24 Using in the procedure of Example 23 cysteamine hydrochloride and a 2-ch Lorometh 1-3,5-di carboxyesters-4- subst i tuted-6-methy L-1 ,4-d hydropyri di ne the compounds listed in the following tables are prepared.

TABLE

m.p. (°C) ⁽ Form characterized)

C0 ₂ t m-NO ^* 0 ₂ Et 95-97 (base)

CO Me m-NO CO Me 145-148 (hydrochloride)

C0 ₂ C ₃ H ₇ -i m-NO C0 ₂ Et 95-98 (hydrochloride)

CO_,Et o-Cl C0 ₂ Et 106-109 (base) V l rv)

CO Me o-CL 0 ₂ Et 124-125 (base)

CO Me m-CL C0 ₂ Et 148-152 (fumarate)

C0 ₂ Et o-CF C0 ₂ Et 85-88 (base)

CO Me m-CF ₃ C0 ₂ Et 112-115 (hydrochloride)

CO Me o-CF C0 ₂ Et 103-105 (base)

CO Me H C0 ₂ Et 99-100.5 (base)

CO Me p- 0 ₂ C0 ₂ Et 140-142 (fumarate)

COOEt 2,3-dichloro COOEt oil (base)

COOEt o-CHF 0- COOEt oil (base)

COOC H -i o-NO COOMe oil (base)

TABLE

m.p. (°C)

CO Me J_--pyridyl CO Me oil (base)

C0 ₂ Et -thienyl CO CH(CH ) oil (base)

CO CH(CH_) ₂ °--furanyl CO Me oil (base) l

EXAMPLE_25

Using in the procedure of Example 24 a 2-chlorome- thyl-3,5-di carboxyesters-4-(substi tuted p eny D -6-methy I- 1 ,4-di hydropyridine and a thiol selected from the group of N,N-dimethy Icysteamine, N-methy leysteami ne, N-buty Leystea- mine, 3-(N-phta Ii mi do) propy Lmercaptane, N-acety Icysteami- ne, 2-mercaptoethanol, 3-mercapto-1 ,2-propanedio L, L-cy- steine, L-cysteine ethyl ester, glutathione, D-cysteine methyl ester and glutathione diethyl esters the compounds Listed in the following Table are prepared.

TABLE

^R ι Z

"ϊ _4 m.p. (°C) ⁽ Form characterized)

CO Me m-NO C0 ₂ Et CH CH ₂ ⁽ CH ₃ ^)' ₂ 191-194 ⁽ hydrochloride)

CO Me m-NO C0 ₂ Et CH CH-NHCH 205-207 (fumarate)

CO Me m-NO C0 ₂ Et CH_CH_.NH-C.H -n 105-107 (base) 4 9

C0 ₂ Et m-NO C0 ₂ Et CH_CH_.NHC.H -n 129-131 (hydrochloride) 1 4 . CO Me m-NO CO Et CH CH ₂ NPhth ¹⁾ 140-142 v_π

1

CO Me m-NO C0 ₂ Et CH CH-NHCOCH 115-116 -

CO Et m-NO C0 ₂ Et CH CH NHCOCH 68-71 -

C0 ₂ Et o-CL C0 ₂ Et CH CH NHCHCO oil -

CO Me o-CF CO Me CH CH NHCOCH oil -

C0 ₂ Et m-NO C0 ₂ Et CH -CH(OH)CH OH 98-102 -

CO Me o-Cl C0 ₂ Et CH CH(OH ⁾ -CH OH oil -

- continued -

TABLE (continued)

m.p. (°C) (Form characterized)

C0 ₂ Et m-NO C0 ₂ Et CH CH OH 119-120 C0 ₂ Et m-NO C0 ₂ Et CH -CH(NH )C0 Et 130-135 (hydrochloride) CO Me m-NO C0 ₂ Et CH CH(NH )C0 Et amorphous solid (base) C0 ₂ Et m-NO C0 ₂ Et CH_CH(NH_)COOH 128-131 (base) CO Et m-NO C0 ₂ Et G_ ²⁾ oil

3) C0 ₂ Et m-NO C0 ₂ Et G-diethylester oil COOEt m-CF. COOEt CH CH(NH OOMe oil Wl CN

1): Phth : phtaloyl

2): G: glutathionyl = HO C-CH(NH ₂ )-CH ₂ CH ₂ C0NHCH-C0NHCH-,C0 H

-CH ₂

3): G-diethylester = EtO_C-CH(NHDCH-CH.-CONH-CH-CONHCH-CO_Et

2 2 2 2 I 2 2

-CH-

EXAMPLE_26

A solution of 2-ch loromethy l-3-carboethoxy-4-(m-ni - t ropheny D -5-ni t ro-6-methy 1-1 ,4-di hydropyri di ne (1.5 g ⁾ in

EtOH (15 ml) is added dropwise at 0°C under N atmosphere to a solution of cysteamine hydroc loride (0.9 g ⁾ and sodium hydroxide (0.32 g) in EtOH (45 ml). After two hours the solution is acidified (pH ^ 4) with AcOH, evaporated under reduced pressure and the residue is dissolved in water (50 ml) and extracted with Et 0 (2 x 20 ml). The ethereal extractions are discarded, the water layer is made basic with NaHCO and extracted with AcOEt (2 x 20 ml); the organic phase is washed with water ⁽ 3 x 10 ml ⁾ , dried (Na_S0,), added to a solution of fumaric acid (0.45 2 4 g) in MeOH (15 ml), and evaporated to dryness. The residue is crystallized from AcOEt to give 1.9 g of 2-/~(2-amino- ethyl)thio7methyl-3-carboethoxy-4-(m-nitrophenyl)-5-nitro-

6-methy 1-1,4-di hydropyridine fumarate

(C.-H-.N.O.S.C.H.O,), m.p. 182-185°C. 18 22 4 6 4 4 4

According to the above procedure, the following compounds are prepared:

- 2-__(2-(N-n-butylaminoethyl)thiq7 ethyl-3-carboethoxy-4- (m-nitrophenyl)-5-nitro-6-methyl-1,4-dihydropyridine fumarate; m.p. 198-200°C;

- 2-/. ^" (2-aminoethy I) thiq7methyl-3-carboethoxy-4-(m-trif luo- romethyLpheny I) -5-ni tro-6-methy L-1,4-di hydropyridine fumarate; m.p. 152-155°C;

- 2- C_ 2-ami noethy I) thi q7methyl-3-carboethoxy-4-(m-nit ro¬ pheny l)-5-cyano-6-methy 1-1,4-di hydropyridine fumarate; m.p. 181-183°C; - 2-/~(2-(N-n-buty Laminoethy I) thio7methy L-3-carboethoxy-4-

(m-ni tropheny I )-5-cyano-6-methy 1-1, -di ydropyri dine fumarate; m.p. 172-175°C; - 2- ft2-ami noethy I) thi oJ7methyl-3-carboethoxy-4-(m-ni tro¬ pheny D-5-acety 1-6-methy 1-1 ,4-di hydropyri dine, oi I; - 2-L (2-ami noethy I ) thio_7methy l-3-carboethoxy-4-(m-ni tro¬ pheny D-5-benzoy L-6-methy 1-1,4-di hydropyridine, oi I. EXAMPLE_27

A solution of 2-£ _ 2 3-di hydroxypropy I) thio_7methy L-

3,5-di carboethoxy-4-(m-ni t ropheny I) -6-methy L-1,4-di hydro- pyridine (5 g) and tosyl chloride (2 g) in pyridine (25 ml) is stirred at 0°C for two hours, then it is poured into iced water (250 mL) and extracted with Et 0 (100 ml).

The etherea I so lution is washed with aqueous 2N H_S0, (2 x

2 4

20 ml), and with water (2 x 30 ml), dried (Na_S0.) and

2 4 evaporated to dryness.

The residue (6 g) is dissolved at room temperature in THF (60 ml) and sodium hydroxide (4N water solution, 2.5 ml); after four hours the solution is neutralized with AcOH and evaporated in vacuum. After the usual work-up the residue is purified by column chromatography (SiO , 240 g, eluent: hexane/AcOEt 70/30) to give 3.2 g of 2-__ ^" (oxiran- 2-yl) methy Lth io_7methy l-3,5-dicarboethoxy-4-(m-nit ropheny D - 6-methy 1-1 ,4-dihydropyridine, m.p. 107-109°C. EXAMPLE_28 A solution of 2-/~(oxi ran-2-y D methy lth i olmethy l- 3,5-di carboethoxy-4-(m-nit ropheny I) -6-methy L-1,4-di hydro¬ pyridine (2.5 g) and i sopropy Lami ne (5.5 ml) in DME (20 ml) is heated to reflux for two hours, then it is evapora¬ ted to dryness and the residue purified by column chroma- tography (SiO 75 g; eluent: CHCL /MeOH 95/5) to give 2.3

g of pure 2-/ ⁽ 3-N-i sopropy lami no-2-hydroxyprop I) thi o/me- thyl-3, 5-di carboethoxy-4-( -nit ropheny D -6-methy I-1,4-di hy¬ dropyridine amorphous solid.

NMR (CDCL ) <_ (TMS): 0.8-1.30 (12H, m); 2.25 (3H, s); 2.45-3.00 (4H, ); 3.20-3.80 (4H, m); 3.80-4.30 (6H, m); 5.10 (1H, s); 6.90-8.30 (5H, m) . EXAMPLE_29

Using in the procedure described in Example 28 ammonia and 1 -_fbi s-(p-f Luoropheny L )_7methy L-pi perazi ne and a suitable 2-_f(ox i ran-2-y I) methy Ithi o7methy 1-1 ,4-di hydro¬ pyridine the following compounds are obtained: - 2- £(3-amino-2-hydroxypropy D thi o_7methy L-3-carboethoxy- 5-carbomethoxy-4-(m-nit ropheny I) -6-methy L-1, -di hydro¬ pyridine, oil; - 2-Z~3--(4-bi s-p-fluorophenylmethyl-piperaziή-1—yl ⁾ -2-hy- droxypropy Ithi o_7methy l-3-ca ^' rboethoxy-5-carbomethoxy-4- (m-nit ropheny D -6-methy 1-1,4-di hydropyri dine, oi I. EXAMPLE_30

A mixture of 2-_f(2-carboethoxy-2-aminoethyl)thiq7- methy l-3-carboethoxy-5-carbomethoxy-4-( -nit ropheny Iho¬ rnethy 1-1 ,4-di hydropyri di ne hydrochloride (3.7 g) and so¬ dium borohydride (1.3 g) in EtOH 95% (50 ml) is stirred under atmosphere for 18 hours, then it is acidified (pH - 4) with AcOH and evaporated in vacuum. The residue is dissolved in water (50 ml) and washed with Et 0 (3 x 20 ml). The organic phase is discarded, the aqueous phase is made basic with a few drops of NaOH (1N solution) and extracted with AcOEt (3 x 20 ml). The organic layers are then dri ed (Na_S0, ) , evaporated to dryness and the residue 2 4 purified by column chromatography (SiO , 120 g; eluent:

AcOEt/MeOH 80/20) to give 2.8 g of pure 2-Z ^" (3-hydroxy-2- amino-propy Ithio) thiq7methyl-3-carboethoxy-5-carbometho- xy-4-(m-ni trophenyI)-6-methy1-1 ,4-dihydropyridine as an oil. After salification, 2.8 g of the correspond ng fuma- rate, m.p. 68-71°C are obtained. EXAMPLE_31

A solution of 2-mercaptomethy 1-3,5-di carboethoxy- 4-(m-nitropheny I)-6-methy1-1 ,4-di hydropyr dine (5 g), aeryloni tri Le (0.66 g) and 1 ,1 ,3,3-tetramethy Iguanid ne (0.1 g) in EtOH (60 ml) is stirred at room temperature for 18 hours and then evaporated to dryness. After the usual work-up, the residue is recrystallized from Et_0 to give 5.2 g of 2- ~(2-cyanoethyI)thio7methy 1-3,5-di carboethoxy- 4-(m-nitrophenyI)-6-methy1-1 ,4-dihydropyridine m.p. 102- 104°C.

EXAMPLE_32

Using in the procedure of Example 31 an ^β f-^-unsat- ured-oxo compound selected from: c nnamaLdehyde, ethyl acrylate, acrylamide, 1-pheny L-1-oxo-2-propene, 1-(p-imi- dazo1-1-yI) pheny L-1 -oxo-2-propene, 2-cyc lohexen-1-one and 2-mereaptomethyl-3,5-di carboethoxy-4-(m-nitropheny D-6-me¬ thy 1-1 ,4-dihydropyridine, the following 3,5-di carboethoxy-4- (m-ni trophenyI)-6-methy 1-1 ,4-di hydropyridine are prepared:

- 2-Z~(3-oxo-1-phenylpropyl)thioJmethyl; - 2-_T(2-carboethoxyethy I) thiojmethy L;

- 2-_~(3-oxo-3-phenylpropyl)thioJmethyl;

- 2- T(3-oxo-3-(p-imidazolyl)phenylpropyl)thio_7 methyl;

- 2-_T(3-oxo-cyc lohexen-1 -y I) thi ojmethy I;

- 2- _T(2-carbamoylethyl)thio_7 methyl.

EXAMPLE_33

A mixture of 2-_7(2-oxopropy I ) thi ojmethy L-3-carbo- ethoxy-5-carbomethoxy-4-(m-ni tropheny I) -6-methy L-1,4-di hy¬ dropyridine (3 g), ammonium acetate (6 g) and sodium cyanoborohydride (0.43 g) in MeOH/ 1 ,2-di ch loroethane (3/1; 20 ml) is stirred under N atmosphere for 48 hours, then it is acidified with AcOH and evaporated in vacuum. After the usual work-up the residue, dissolved in AcOEt (25 ml), is added to a solution of fumaric acid (0.78 g) in MeOH (8 ml) at about 60°C, to give, after cooling, 3.2 g of 2- ^" (2-ami nopropy I) thi ojmethy L-3-carboethoxy-5-carbomethoxy- 4-(m-nitropheny I) -6-methy L-1,4-di hydropyridine fumarate, m.p. 127-130°C.

Using the above described procedure the following compounds are prepared:

- 2-/~(2-amino-2-phenylethyL)thioJ*methyl-3-carboethoxy-5- carbomethoxy-4-(m-nit ropheny D -6-methy 1-1,4-di hydropyri¬ dine fumarate, m.p. 182-184°C;

- 2- ^" (2-ami nopropy I) thi ojmethy L-3-carboethoxy-4-(m-nit ro- pheny I) -5-ni t ro-6-methy L-1 ,4-di hydropyri di ne fumarate, m.p. 148-152°C. __- _. ___ _. ___ _. E_34

A mixture, of 2-_f ⁽ 2-aminoethyl ⁾ thio methyl-3-carbo- ethoxy-5-carbomethoxy-4-(m-nit ropheny I) -6-methy 1-1,4-di hy- dropyridine (3.5 g), acetone (12 ml), AcOH (0.7 ml), so¬ dium cyanoborohydride (0.6 g) and molecular sieves 4 A in EtOH (30 ml) is stirred under N for 24 hours. After the usual work-up the residue is dissolved in AcOEt and satu¬ rated with gaseous HCl to precipitate 2.8 g of 2-Z~( 2-N- i sopropy lami noethyl) thi ojmethy L-3-carboethoxy-5-carbome-

thoxy-4-( -nitrophenyI) -6-methy L-1 ,4-d ydrop r d ne hy¬ drochloride, m.p. 184-186°C.

Using in the same procedure a salt (for example acetate or formate) of 2-Z ^" (5-amino-2-oxopentyl)thio me- thyl and of 2-/ ^" (6-amino-2-oxohexyI)thiojmethyl-3-carbo- ethoxy-5-carbomethoxy-4-(m-nit rophenyD -6-methy1-1,4-di hy¬ dropyridine, by ntramolecular reductive amination, the following 3-carboethoxy-5-carbomethoxy-4-(m-nitrophe¬ nyI)-6-methyL-1 ,4-dihydropyridines are respectively obtai- ned:

- 2-Z~(pyrrol idin-2-yDmethyLthiojmethy I, oil,

NMR (CDCl ); (TMS): 1.00-1.25 (3H, t); 1.50-2.00 (4H, m); 2.25 (3H, s); 2.40-3.00 (6H, m); 3.70 (3H, s); 3.80-4.10 (4H, m); 5.05 (1H, s); 7.20-8.10 (4H, m); 9.00-9.10 (1H, m);

- 2-_ ^" (piperidin-2-yl)methyLthiαJmethyl, oil,

NMR (CDCl ); (TMS): 1.00-1.20 (3H, t); 1.50-2.20 (6H, m); 2.25 (3H, s); 2.50-3.10 (6H, ); 3.80-4.20 (7H, ); 5.10 (1H, s); 7.20-8.20 (5H, ) . EXAMPLE_35

A solution of 2-/T(2-ami noethyD thiojmethy1-3,5-di - carboethoxy-4-(m-nit rophenyD-6-meth L-1,4-di hydropyridine (1.35 g) and 2-hydroxy-3-methoxy-5-morpho Li nomethy Lbenza l- dehyde (0.76 g) in EtOH (40 ml) is stirred at room tempe- rature for 30 minutes to give the correspond ng Schiff-ba- se. Sodium borohydride (0.12 g) is then added and after 30 minutes the mixture is neutralized with AcOH to give, after the usual work-up, 1.7 g of 2- 2.-CH-(2-hydroxy-3-me- thoxy-5-morpholino ethyDbenzylamino ethyIthio methy1-3,5- diearboethoxy-4-(m-nitrophenyI)-6-methyL-1 ,4-dihydropyri-

dine, which yields, upon treatment with fumaric acid, the corresponding salt (m.p. 168-170°C,

^C 34 ^H 44 ^N 4 ^S0 9- ^{: C H} 4° - ^H 2 ^{0 )} - EXAMPLE_36 According to the procedure described in the previo¬ us example the following compounds are prepared:

- 2-_ ^~ 2-Z~N-(2-hydroxy-5-methoxy-3-morpho I'inomethylbenzyD- ami nojethy Ithi ojmethy 1-3,5-di carboethoxy-4-(m-nit rophe¬ ny I) -6-methy L-1 ,4-di hydropyridi ne difumarate hydrate, m.p. 102-105°C;

- 2-/2- N-(4-hydroxy-3-methoxy-5-morpho I inomethy Lbenzy D - ami nojethy Ithi ojmethy 1-3,5-di carboethoxy- -(m-ni t rophe¬ ny D-6-methy 1-1 ,4-di hydropyridi ne difumarate hydrate, m.p. 175-178°C; - 2-ZT4-(N-benzy lamino) buty Lth i ojmethy 1-3,5-di carboethoxy- 4-(m-trif Luoromethy Ipheny D-6-methy 1-1,4-dihydropyridi¬ ne,

- 2-Z ^* 2-(p-N0 -benzy Lami no) ethy Ithiojmethy L-3,5-di carbome- thoxy-4-(o-ch loropheny L) -6-methy 1—1,4-di hydropyridine ma Leate . EXAMPLE_37

A water solution of hydrazine (40%, 1.6 ml) is dropped at 70°C in a solution of 2- 3-(N-phtalymido ⁾ pro- pylthioJmethyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophe- ny l)-6-methyl-1 ,4-d hydropyridine (3.3 g) in EtOH (35 ml). After an hour, it is cooled to room temperature, the ph- tha Lhydraz i de is filtered off and the eluate is evaporated to dryness, to give, after the usual work-up, 2.5 g of 2-Z(3-aminopropyl)th o_7methyl-3-carboethoxy-5-carbomethoxy 4-(m-ni t ropheny L ) -6-methy L-1 ,4-di hydropyri di ne. Using the

salification procedure described in Example 23, 2.6 g of the corresponding fumarate is obtained, m.p. 142-145°C.

According to the above described procedure, 2-/ ^" (4-ami- nobutyl)thiqJπ.ethyl-3-carboethoxy-5-carbomethoxy-4-(m-ni- tropheny I)-6-methy L-1 ,4-dihydropyridine fumarate, m.p.

109-111°C, is obtained.

EXAMPLE_38

A solution of m-ch loroperbenzoi c acid (1.3 g, 1 equiv. mol.) in 1 ,2-di ch loroethane (15 ml) is added at -10°C to a solution of 2-/7(2-ami noethy I) th i ojmethy l-3-car- boethoxy-5-carbomethoxy-4-(m-ni trophenyI ⁾ -6-methy L-1,4-di - hydropyridine hydroch l,ori de (3.5 g) in 1 ,2-di ch loroethane

(30 ml).

After 30 minutes the solution is filtered, washed with sodium thiosulfate (5% water solution, 3 x 5 mL), sodium bi carbonate (saturated water solution 3 x 10 ml ⁾ , water (3 x 10 mL), dried on Na_S0. and evaporated in va-

2 4 cuum to give 3.2 g of 2-/T(2-aminoethyl)suLfinylJmethyL-3- carboethoxy-5-icarbomethoxy-4-(m-ni tropheny D -6-methy L-1,4- dihydropyridine yielding, upon treatment with fumaric acid according to Example 23, the corresponding fumarate, m.p.

170-172°C.

EXAMPLE_39

Using the procedure described in Example 38, the following compounds are prepared:

- 2-(methy Isulfiny I) methy1-3,5-di carboethoxy-4-(m-ni t ro¬ phenyI) -6-methyL-1 ,4-dihydropyridine, m.p. 167-169°C;

- 2-(ethy Lsu Ifinyl) methy 1-3,5-di carboethoxy-4-(m-nit ro¬ pheny L ⁾ -6-methy 1-1 ,4-di hydropyri d.i ne, m.p. 128-130°C; - 2-_T(2-ami noethy I) su Lfi ny Ljmethy 1-3,5-di carboethoxy-4-

(m-nitrophenyl)-6-methyl-1, -di hydropyridine, m.p. 140-142°C. EXAMPLE_40

A solution of m-ch Loroperbenzo c acid (3.76 g, 2 equiv. mol.) in MeOH (30 ml) is added at 10°C to a solu¬ tion of 2-£ ⁽ .2-ami noethy L ) th i ojmethy l-3-carboethoxy-5-car- bomethoxy-4-(m-ni t ropheny D-6-met yl-1,4-d ydropyrid ne fumarate (5 g) in MeOH (100 ml); the reaction mixture is then warmed to +15°C and stirred for 30 minutes. The e- thanol is then evaporated under reduced pressure, the residue partitioned between di ch loromethane (80 ml) and water (30 ml). The organic phas.e is washed wit.h sodium thiosulfate (5% water solution, 2 x 10 mL), aqueous satu¬ rated NaHCO solution (3 x 20 ml), water (3 x 20 ml), dried on Na_S0,. and evaporated to dryness to give 3.8 g of 2 4

2-Z ^~ ( 2-ami noethy DsuLfony Umethy I-3-carboet oxy-5-carbome- thoxy-4-(m-nitrophenyl)-6-methyl-1 ,4-d.hydropyridine which is salified with fumaric acid to give 4.3 g of the corre¬ sponding fumarate, m.p. 147-149°C. EXAMPLE_41

A solution of tert-butyl-4-chloroacetoacetate (7 g) in EtOH (20 ml) is added at 0°C to a solution of the so¬ dium salt of 2-(N-phta Li mi do) ethy Lmercaptane (7.5 g) in EtOH under N . After one hour the solution is neutralized with AcOH and evaporated to give, after the usual work-up, 9.3 g or ter-butyl 4-Z2-(N-phtalimido)ethylJthioacetoacetate, m.p. 74-77°C.

A solution of this compound (8.8 g), m-nitrobenzal- dehyde (3.7 g), AcOH (0.6 ml) and piperidine (0.2 ml) in benzene (90 ml) is heated to reflux for 4 hours in a

Dean-Stark apparatus to give, after the usual work-up, 11.2 g of tert-butyl 2-(m-n t ropheny Imethy Len) -4-Z - ⁽ N-phta Li midoethy I ) th ioacetoacetate as an oil.

A solution of this compound (10 g) and methyl 3- aminocrotonate (2.4 g) in EtOH (150 ml) is heated to re¬ flux temperature for two hours then acidified ⁽ pH - 1 ⁾ with aqueous concentrated HCl (0.5 mL) cooled to room temperature and stirred for one hour before evaporation to dryness. The re sidue, after the usua I work-up, yi e Lds 7 g of 2-/2- ⁽ N-phta I i m_ do)ethylthio/methyl-3-carbotert-butoxy-5-carbornethoxy-4-m-n i trophenyl)-6-methy1-1 ,4-di ydropyri di ne, m.p. 65-70°C.

0.2 g are dissolved at 0°C in di ch loromethane (4 mL) and tri f Luoroacet i c acid (4 ml). After six hours the ixture is evaporated to dryness to give, after the usual work-up-, 0.08 g of the corresponding 3-carboxy acid deri¬ vative. EXAMPLE_42

A solution of 2-(2-ami noethy Ith io) methy 1-3,5-di car- boethoxy-4-(m-nit ropheny I) -6-methy 1-1,4-di hydropyridine (4.35 g) and acet i c anhydride (10 ml) in pyridine (25 mL) is stirred at room temperature for two hours ^* , then it is poured in iced water (250 mL) and extracted with AcOEt (3 x 30 ml) .

The organic phase is washed with H_S0, (2N, 2 x 10

2 4 ml), water (4 x 25 ml), dried on Na_S0 and evaporated in

2 4 vacuum. The residue is crystallized from Et 0 to give 4.6 g of 2-_~ ⁽ 2-N-acety Lami noethy I ) th i ojmethy 1-3,5-di carboetho- xy-4- ⁽ m-nit ropheny D -6-methy 1-1 ,4-di hydropy ridine, m.p. 68-71°C. Using the same procedure, 2-_T(2-acetoxyethyD-

thioJ ethyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1, 4-di hydropyridine (m.p. 84-86°C) is obtained starting from the corresponding 2- ^" (2-hydroxyethy D thi ojmethy L-dihydro¬ pyri di ne . |XAMPLE_43

S- (N-Tertbutoxycarbony D pro I i no L (4.0 g) is tran¬ sformed by reaction with tosy lch Lori de (4.5 g ⁾ in pyridine (20 ml), into S-(N-tert-butoxycarbony D proli no l-tosy late (6 g). A solution of this compound (6 g) in EtOH (60 ml) is reacted with potassium thioacetate (6 g) at the reflux tern perature for 40 minutes to give, after the usual work-up, 3.2 g of S-2-acetylthiomethyl-1-tert-butoxycarbonyl-pyrroLidine

A solution of this compound (3.2 g) is stirred at 0°C, under nitrogen, in EtOH (30 ml) and sodium hydroxide (1N, 14 ml); after 20 minutes a solution of 4-R, S-2-ch lo¬ romethyl-3-carboethoxy-5-carbomethoxy-4-(m-nitropheny I)-6- methyl-1,4-dihydropyridine (4.5 g) in EtOH/DME (1/1, 40 ml) is added dropwise. After one hour the mixture is neu¬ tralised with AcOH and evaporated to dryness to give, after the usual work-up and co lumn-c romatography purifi¬ cat on (SiO , 250 g, eluent: hexane/AcOEt 75/25) 4.3 g of 2' - ⁽ _, ⁾ -4 ⁽ R,S ⁾ -2-/ .1'-tert-butoxycarbonylpyrrolidin-2'-yl)me thy Ithi ojmethy l-3-carboethoxy-5-carbomethoxy-4-(m-nit ro¬ pheny I ⁾ -6-methy L-1 ,4-di hydropyri di ne (oil). NMR (CDCl ); 6 (TMS): 1.10-1.70 (12H, m); 1.70-2.10 (4H, m); 2.30 (3H, s); 3.20-4.30 (12H, m); 5.10 (1H, s); 7.10- 8.20 (5H, m).

The tert-butoxycarbonyL protective group is removed by treatment of a solution of the compound (3.6 g). in 1 ,2-di ch loroethane (20 ml) with t ri f Luoroacet i c acid (20

ml) at 0°C for two hours. The reaction mixture is evapora¬ ted in vacuum to dryness, the residue is dissolved in water (50 mL), and washed with Et 0 (3 x 20 ml ⁾ . The aque¬ ous phase is made basic with NaHCO and extracted with Et_0 (3 x 60 ml). The organic Layer is dried on Na_S0. and 2 2 4 evaporated to dryness to give 2.75 g of 2' ⁽ S ⁾ -4- ⁽ R,S) -2- ^" (pyrrolidin-2 ^l -yl)methylthioJ ethyl-3-carboethoxy-5-car- bomethoxy-4-(m-nit ropheny I) -6-methy 1-1,4-di hydropyridine as an oil. The fractional crystallization from AcOEt of the di astereoi someri c mixture gives one di astereoi somer, m.p. 154-155°C, €^-J = -88°C (C = 1%, CHCl ). Further recry- stal Li zations of the mother liquors from AcOEt/Et 0 (1/1) yields the other di astereoi somer, m.p. 114-116°C, £p<J = -14°C (C = 1%, CHCL ) .

Using in the procedure described above (_;) -(N-tert- butoxycarbonyI ⁾ prol i nol the following 3-carboethoxy-5-carbo- methoxy-4-(m-nit ropheny I)-6-methy 1-1,4-di hydropyridine derivatives are obtained: - 2' ⁽ _R ⁾ -4 ⁽ _?)-2-/(pyrroLidin-2'-yl)methyLthio/methyl; - 2' (R)-4(S) -2-/ (pyrrol idin- *-yI) ethylthio7methyl. EXAMPLE_44

A solution of methyl acetoacetate (7 g), 2-(N-ben- zy l-N-methy Lami no) et anoI (3 g) and 4-N,N-di methy lami nopy- ridine (2 g) in toluene is heated to reflux for 16 hours to give, after the usual work-up and purification on co¬ lumn chromatography (SiO , 2.0 g; eluent: methylene chlo¬ ride), 3 g of 2-(N-benzy l-N-methy Lami no) ethy I acetoaceta¬ te, m.p. 45-47°C. A solution of this compound (3 g) and ammonium

acetate (2 g) in EtOH (30 ml) is heated to the reflux temperature for one hour, then ethyl 2-(m-nitrophenyIme¬ thylen)-4-chLoro-3-oxo-butanoate (3.4 g) is added thereto. After 30 minutes, the reaction mixture is cooled to room temperature, acidified (pH ^y 1) with aqueous concentrated HCl (0.2 ml), stirred for one hour, neutralized with NaHCO and evaporated under reduced pressure, to _. give, after the usual work-up, 2.5 g of 2-ch loromethy L-3-carbo- ethoxy-5- 2-(N-benzy L-N-methy lamino)ethoxy carbony1-4-(m- nitrophenyl)-6-methy1-1 ,4-dihydropyridine, oil.

NMR (CDCL ); b (TMS): 1.00-1.25 (3H, t); 2.10-2.20 (6H, m); 2.50-2.80 (4H, ); 3.30-3.50 (2H, s); 3.80-4.40 (2H, Q); 4.60-5.10 (2H, dd); 5.20 (1H, s); 6.80-8.20 (10H, m) . An ethanol solution (10 ml) of this compound (1.9 g) is added to a solution of cysteamine hydrochloride (0.43 g) and sodium hydroxide (20% water solution, 0.6 ml) in ethanol (20 ml) according to the procedure of Example 23 to -give after the usual work-up, 1.5 g of 2-_T(2-amino¬ ethyDthiojmethyl-3-carboethoxy-5-Z~2-(N-benzyL-N-methyla- mino) ethoxy carbohy1-4-(m-ni trophenyI) -6-methy1-1 ,4-di hy¬ dropyridine, oil.

NMR (CDCL ); (TMS): 1.10-1.25 (3H, t); 2.10-2.20 (6H, m); 2.30-3.20 (10H, m); 3.30-3.50 (2H, s); 3.80-4.40 (4H, m); 5.10 (1H, s); 6.80-8.20 (10H, m) . EXAMPLE_45

A solution of 2- ^"( 2-aminoethyDthioJmethylr3,5-di- carboethoxy-4-(m-n trophenyD-6-methy 1-1,4-di hydropyridine (4.3 g) and acryloni tri Le (0.8 g) in EtOH (60 ml) is heat¬ ed to reflux for two hours, then it is cooled to room temperature and evaporated to dryness, to give, after the

usual work-up, 4.2 g of 2-/2-N- ⁽ 2-cyanoethy I) aminoethy l- th io_/methy 1-3,5-di carboethoxy-4- (m-ni t ropheny I) -6-methy L- 1,4-di hydropyridine, which upon treatment with fumaric acid according to the salification procedure described in Example 23, gives 4 g of the corresponding fumarate, m.p. 105-107°C.

Using in the above described procedure ethyl acry- late and acrylamide, the following 3,5-di carboethoxy-6-me- thyl-1,4-di hydropyri dine are obtained: - 2-/T2-N-(2-carboethoxyethy I) ami noethy lth i oJ-4-(o-ch Loro¬ pheny L ) ; - 2-_-2-N-(2-carbamoylethyl)aminoethylth _. i o_J-4- (.β-pyri dy I.) . EXAMPLE_46

A solution of 2- 2-aminoethylthiq7methyl-3,5-dicar- boethoxy-4-(m-ni tropheny I) -6-methy 1-1 ,4-di hydropyr di ne (1 g ⁾ , 2-ch loroacetamide (0.26 g) and t ri ethy lami ne (0.28 g) is refluxed for 24 hours, cooled ^' at room temperature, evaporated to dryness, to give,after the usual work-up,and purification by co lumn-ch romatography (SiO , 30 g; eluent: CHCl /MeOH 95/5), 0.5 g of 2-ZT2-N-(carbamoy ImethyI ) -amino¬ ethy Ithi qjmethy L-3,5-di carboethoxy-4- (m-ni t ropheny I) -6-me¬ thy L-1 ,4-di hydropyri di ne as an amorphous solid. NMR (CDCL ): 5 1.0-1.30 (6H, t); 2.30 (3H, s); 2.50-2.85 ⁽ 5H, m); 3.20 (2H,' s); 3.85-4.25 (6H, m); 5.10 (1H, s); 6.30 (1H, m); 7.00-8.2 (6H., m). EXAMPLE_47

A solution of 2-mercaptomethyL-3-carboethoxy-5-cya- no-4-(m-ni tropheny I) -6-methyL-1 ,4-di hydropyridine (3 g), 2-ch loroacetoni t ri-le (1 g) and 1 ,4-di azabi eye Lo/2,2,2/octa ne (0.8 g) in EtOH (30 ml) is heated at reflux temperature

for six hours. Then the reaction is cooled to room tempe¬ rature and after usual work-up and purification by column- chromatography (SiO 90 g; eluent Et_0/AcOEt 90/10) gives 1.8 g of 2-(cyanomethylthio)methyL-3-carboethoxy-5-cyano- 4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine. EXAMPLE_48

Using in the procedure of Example 47 a suitable 2- mercaptomethy1-1 ,4-di hydropyridine and an acti ated c loro- compound the following compounds are obtained: - 2-(2-cyanomethyI) -3-carboethoxy-5-ni tro-4-(m-ni trophe¬ nyD -6-methy1-1,4-di hydropyri dine; - 2-(2-ethoxycarbonylmethylthio)methyl-3-carboethoxy-5- cyano-4-(m-ch lorophenyD -6-methy 1-1,4-di hydropyri dine.