CA1320204C - Pharmaceutically useful dihydropyridinyldicarboxylate amides and esters - Google Patents

Abstract

Abstract of the Invention A series of 1,4-dihydropyridin-3,5-yl dicarboxylic acid amides and esters incorporating an arylpiperazinylalkyl moiety have been prepared possessing the general formula wherein R4 is cycloalkyl, aryl or hetaryl, generally with electron-withdrawing substituents; R2 and R6 are lower alkyl, alkanol, alkoxyalkyl, or alkylaminoalkyl; R5 is R2 or arylpiperazinylalkyl; X is 0 or NH; Y is lower alkylene, alkoxyalkylene, alkylaminoalkylene; and Z is phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, or pyrimidinyl.
Compounds of this series demonstrate activity as calcium and alpha-adrenergic blockers in in vitro testing and antihypertensive, anti-ischemic, and platelet function inhibiting actions in in vivo screens.

Description

~32~2~

~ 578A

P~ARMACEI~TICALLY USEFUI DIHYDROPYRIDINYLDICARBOXYLAl~
~MIDES AND ESTE~S

~ he pre~en~ lnventlo~ concerns the heeerocyclic carbon compounds o~ the 1,4-dihydropyrldine clas~ ~ith a 3- carboxylate or carboxamido group linked to an arylplperazlnylalkylene molety.
Th-~- compounts possess blo-affecting properties.

A substantial body of prior art has evolved over the last 13 2 ~ 2 0 decade involv$ng compounds of 4-aryl-1,4-dihydropyridine ser$es which have calclum antagonist properties and are useful in the treatment of cardiovascular diseases. These calcium blocking effects appear to medlate vasodilation making these compounds useful in treatlng angina and hypertension. These structures are typified by nifedipine (Formula l); ~

~ 2 H3C02C~ C2CH3 (1) chemlcall9 4-(2'-nitrophenyl)-2,6-dimethyl-3,5-dicarbomethoxy-1,4-dlhydropyridine. Nifedipine.and some related 4-aryl-1,4-dihydropyridines are the sub~ect of U.S. Patent 3,485,ô47 issued December 23, 1969.
Numerous subsequent patent have been granted covering 1,4-dihydro-pyrldines $n which other substituent groups have been incorporated at the varlous rlng positlons of the dihydropyridine moiety via a dlverslty of chemlcal bontlng groups.
Utll~zlng medlclnal chemlcal techniques, an ob~ect of the in~tant lnventlon was to design a therapeutic agent combinlng o,-atrenerglc blocklng properties with the calclum blocking action in a slngle molecular structure. The biological rationale for the combinatlon of actions suggests that such an agent woult provite potent ant efflcaclous treatment for vasospastic clrculatory disorders.
Art related to the series of compounds of the present lnventlon may be generallzet by the following structural formula (2):

R4 0 1 3 2 0 2 ~ 4 R5 ~ C-X-Y-N ~ -Z
l ll R6~ ~" N ~ R2 (2) wherein R2, R4, R5 and R6 could be any of a number of subseltuent groups which have been defined previously in the voluminous dihydro-pyridine literature; but with speclfic attention being given the definitlon for the substituent structure attached to the 3- position of the 1,4-dihydropyrldine ring. To our knowledge, no aryl- or hetaryl- piperazinylalkyl molety has been lncorporated heretofore in a 1,4-dihydropyrldlne ring compound via a carboxylate amide or ester functlonallty ln the 3- posltlon of the ring. The most relevant art to be disclosed ls, in our ~udgment, the divisional patents, U.S.
Patent 3,905,970 and U.S. Patent 3,974,275 issued to Bossert, et al., on Septembes 16, 1975, and August 10, 1976, respectively. The compounds dlscloset and claimed in these patents have~as the 3- substituent 81de chaln molety -X-Y-N ~ N-Z
~hown ln structure (2) above) the followlng (2a):
r\
-O-(Cl-C4alkylene)-N ~ ~ C~3 (2a) This same 3- substituent side chain (2a) was also disclosed in U.S. Patent 4,393,070 issued to Sato, et al., on July, 1983.

European Patent Applicatlon 88,903, published September 21, 1983 tiscloses 1,4-dihydropyrldine art wlth the ester group of the ~ 3202~4 3-carboxylate moiety having the following structure (2b):
Z
O-CH (CH2) (2b) wherein n is 0 to 5; Z ic aryl or hetaryl; and R is lower alkyl, S alkoxycarbonyl, or alkanoylamino. The point of novelty disclosed for these antihypertensive agents is based on Z, in that "...the introductlon of the aromatic ring or aromatic heterocyclic ring at alP~a-position of the cyclic amino alkyl ester moiety $n the side chaln causes increased aDd remarkably prolonged effectiveness."
Somewhat less related, European Patent Application 63,365, publlshed October 27, 1982 discloses 1,4-dihydropyridines with a 3-carboxylate ester group comprislng a plperidine ring (3):

-O- ( CH2) n~N-R5 (3) wherein n is O to 3, and R5 i8 arglalkyl or acyl, Attitlonally, there are 1,4-dlhydropyrldine compounts d~scloset whlch have an arylplperazine system attached by an alkyl or slkoxyalkyl chaln to the 2- posltlon of the dihytropyridine ring.
Aritoml, et al,, ln Chem. Pharm. Bull. 29 (11), 3163-71 (1980) tisclose compounds having the (4) group in rin8 position 2:

(CH2)n N~ II-R

(4) whereln n - 2 and R is alkyl, aryl, or arylalkyl. Speclfically 132~2 disclosed, as an example, is compound (4a).

~, N02 EtO2 ~C2Et Me ~ N ~ CH2C~

(4a) European Patent Appl~cation 60,674, published September 22, 1982 dlscloses ant$-ischemic and antlhypertensive agents of structure (5) R102C~ C02R

Me ~ N ~ CH 0-Y-N ~-R
a 2 (5) S wherein Y i8 an ethylene or propylene chain; and R5 is Cl 4 alkyl, aryl, srylalkyl, and the llke. These compou~ds are easlly distinguished structurally from the compounds of the instant inventlon bg virtue of ring po~ltion and the llnking functional group. ~hat is, compounds of the instant lnvention contain an ~-blocklng aryl- or hetaryl plperazine moiety llnked by an alkgl, alkoxyalkyl, or alkylaminoalkyl chain to a carboxylate or carboxamide functlon in rlng position 3.
All of the above mentioned compounds derive thelr therapeutlc usefulness, according to prevailing theorg of thelr biologlcal mechanlsm, due to thelr mnabe abllity to act as calclum channel blocke~s. In essence, the instant c ~ ~o~s2m~ay4 be distingulshed over compounds of the prior art both on the basis of molecular structure and also by biological action. The instant compounds possess both calcium channel and alpha-adrenergic blocking properties, therebY enhancing the usefulness of these compounds in treating hypertension and lschemic disorders. The instant compounds have also been found to possess useful actions in inhibiting certain functlons of blood platelets. There is nothing in the prior art which anticipate or suggests the compounds of the present invention.

The present invention includes the compounds of For~ula I

R502C ~ C-X-Y- ~ N-Z

and the aclt addltlon salts of theoe 8ubqtances. In the foregoing 6tructural formula the 5ymbols R , R , R5, R6, X, Y, and Z have the following meanlngs. R2 and R6 are independently selected from lower alkyl, hydroxyalkyl~ alkoxyalkyl, alkylaminoalkyl, or dialkylaminoalkyl and may be the same or different. Lower alkyl means Cl to C4;
alkoxyalkyl refers to a Cl to C4 alkylene chain and a Cl to C4 alkyl group connectet by an oxygen atom; similarly, alkylaminoalkyl and dialkylaminoalkyl refer to lower alkyl groups and a Cl to C4 alkylene chain connected by a 5econdary (-NH-) or tertlary ~ ~N-) amino group.
R ls cycloalkyl of 5 to 7 carbon atoms, bicvcloalkenyl of 7 to 9 1 3202~k carbon atoms, hetaryl, such as furanyl, indolyl, methylthiopyridyl>
thienyl, benzoxadiazolyl, benzothiadiazolyl, and the like; aryl meaning phenyl, naphthyl, or substituted phenyl, with the substituents comprising acetamino, lower alXyl, lower alXoxy, cyano, halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethylsulfonyl, and methylsulfonyl and the like. R5 is R2 or ~-Y-N ~ -Z. X is 0 or ~H;
Y is a lower (Cl~ ) alXyleDe chain, alkoxyalkylene, or alkylamino-alkylene chain; and Z is phenyl, pyridinyl, or pys~idinyl, either unsubst~tuted or substituted with one or more substituent groups selected from among lower alkyl, lo-~er alkoxy, cyano, halo, and trifluoromethyl.
Preferred compounds of the instant invention have the structure of Formula I wherein R and R are lower alkyl, R ls nitrophenyl, R5 ls lower alkyl or X-Y-N N-Z, X is 0 or NH, Y is a C2 to C5 alkylene chain, and ~ is substltuted phenyl. The most preferred compounds of the lnstant invention have the Formula I
~tructure wherei~ R and R are methyl, R is 2- or 3-nitropbenyl, R5 i8 methyl or X-Y-N ~ -Z, X ls 0, Y is a psopylene chain and Z is a 2-substltuted phenyl rlng, preferably o-methoxyphenyl.
The compounds of the present inventlon can exist as optical l~omers ant both the racemlc mlxtures of these lsomers as well as the lnd~vitual optlcal lsomers themselves are within the scope of the prcsent lnvention. The racemic mixtures can be separated lnto their lndlvldual lsomers through well known techniques such as the separation of the dlastereomeric salts formed with optically active acids, followed by conversion back to the optically active bases.
As lndicatet, the present invention also pertains to the pharmaceutlcally acceptable non-toxic salts of these baslc compounds.

132~2~
, such salts include those derlved from organlc and lnorganic acids such as, Y~thout limitation, hydrochloric acid, hydsobro~ic acid, phosphoric ac$d, sulfuric ac$d, ~ethanesulfon~c acid, -cetic ac~d, tartaric acid, lactic acid, succlnlc acid. sltric acit, ~aleic scid, S ~orbic acid, aconitic acld, salicylic acid, phthallc ~cid, embonic acid. enanthlc sc~d. and the like.
She compounds of the present invention may be produced by - the foll~ving processes which e~ploy variatio~s of the ~a~ezsch synthetic reaction applied to the appropriate start~ng ~aterials.
Specificall~. the present ~vention utilizes a dified ~ant2sch procc~s for prcparatlon of the co~pounds of Forwla ~
accoral~g to the reactlon che~-s following herel~below. The geDeral reactioD process and ma~y of the required inter~ediate compounds have b-en prc iowly de9cribed ln ~.S. Pate~t 4,614,213.
lS
CeDeral processes for preparation of:

R502C ~ C_X_~_151-Z
Il 11 R6--N ~ R2 tI) -r ~ - 8 -General Scheme:
1~2~2~

R4-c~o +

x) (1~
- ~IlI) O O
4 > ~C-X-R"

R' H2N R' (II) (IX) (I) In the foregoing general scheme, R and X are as defined in For~ula I. Rl may be either R or R of Formula I; R" may be e~ther R5 or Y-N N-Z. Preparation of the co~pounds of Formula I
accorting to the process of the general scheme generally comprises heatlng IX-type ant III-type intermetlate co~pounts together neat or in the presence of a wide variety of a reaction ~nert organic solvents.
Suitable solvents include but are not limited to benzene, toluene, tetrahydrofuran, dibutylether, butanol, hexanol, methanol, dimethoxy-ethane, ethyleneglycol, ethanol, propanol, etc. Suitable reaction 13202~
temperatures are from about 60 to 150C. No catalyst or condensation agent is usually required. The intermediate enamine esters or amides (IX) are generated by Hantzsch-type reaction conditions (NH4OAc/alcohol) fr~m II inter-mediates. ~he I~ intermediates (hereinafter defined) areusually not isolated but are allowed to react immediately with III compounds. The intermediate acylcinnamate com-pounds of structure III are prepared in general by utilizing known Knoevenagel condensation reaction condi-tions. In general, appropriately s~bstituted aldehydesand 1,3-dicarbonyl compounds were condensed to give III.
Thus the present invention provides a process for preparing a Formula XXI compound R O

X~

H R
XXI
15 and the pharmaceutically acceptable acid addition salts thereof wherein R2 ~nd R6 are independently ~elected from lower alkyl, hydroxyalkyl, alkoxyalkyl, alkylaminoalkyl, or dialkylaminoalkyl;
R4 is cycloalkyl of S to 7 carbons, bicyclo-alkenyl of 7-9 carbon atom5, hetaryl (compri~ing furanyl, indolyl, methylthiopvridyl, thienyl, benzoxadiazolyl, and benzothiadiazolyl~ aryl (com:

132~2~
prising phenyl, naphthyl, or substituted phenyl, havina sub~tituents which can be ~ epen~ently aoet~n~, lcwer a~l, lower a~y, cyano, halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethylsulfonyl, ~r methylsulfony~;
R5 is R2 or X-Y- ~ N-Z;
X is ~ or NH;
Y is a C2 to C5 alkylene chain, alkyleneoxv-alkylene, alkylenethioalkylene, or alkylene-amino21kylene chain; and Z is phenyl, pyridinvl, or pyrimidinyl, ~her.ein said phenyl, pyridinyl or pyrimidinyl can be either unsubstituted or substituted with one or more substituent group~ selected from among lower alkyl, lower alkoxy, cyano, halo, and trifluoromethyl;
which compri~es a process ~elected from the following group:
A) a piperazinyl alkanoylacetate compound of ~ormula IIc ~
C-OY~ JN-Z

R2(Me) IIc is treate~ with a 3-oxoalkanoate compound of Formula IIIb -lOa-132~20~

R O2C ~

R6~
IIIb under modified Hantzsch condensation conditions ~ammonium acetate/ethanol) to yield a compound of ~ormula XXI wherein X is oxygen;
B) 1) a haloalkyl alkanoylacetate of Formula IId, c~2 IId wherein V is a C2-C5 alkylene chain and W is halo~en, preferably chloride, i~ reacted with a 3-oxoelkanoate compound of Formula IIIb under modified Hantzsch condensation conditions ~ammonium acetate/ethanol) to give the intermediate product of Formula VIId;

R502CX~ C02Vh~

VIId -lOb-13~2~

2) the intermediate product VIId is reacted with the piperazine intermediate VIIId, V-~-Z
/
VII~d wherein ~ is hydrogen, hydroxyalkylene, sulfhydroalkylene, or aminoalkylamine, to give a product of Formula XXI wherein X is oxygen;
C) 1) a 1,3-dicarbonvl piperazine compound of Formula XI

O O
(Me)R2 N-H-Y-N~_JN-Z

XI

is reacted with an appropriate aldehyde of Formula X' R4-CHo X I

under Knovenagel conditions (piperidine and acetic acid in benzene) to qive the --lOc--13202~
intermediate carboxamido compound of Formula Illa R ., ~
~ CNH-Y-N~_~N-Z

(~R2 IIla 2) the intermediate compound IIIa is reacted with an enamine compound of Formula IVb 3~

IVb to yield a product of Formula XXI wherein X
is NH; and D) an enamine piperazine intermediate compound of Formula IVa is reacted, o C-X-y_~r~N_ z 1' ` ' H2N~R2 (R6) IVa if a Formula XXI compound having symmetry at the 3- and 5- pyridine ring positions is desired, with an appropriate aldehyde of ~ormula X' -lOd-13202~

R4-CHo under Hantzsch condensation conditi~ns, to give the XXI product.

Preferred variations of the general scheme are shown in the reaction schemes which follow.

-lOe-Sche~e 1 (X - 0) 132~0~
~' C2 Y Cl H0-Y-Cl 1) diketene~ ~ 2 (Vl~ O R (Me) (IIa) R4 (X~ ~ NH40Ac ($Ib) (IIIb) ~

R502 ~ C-0-Y-N N-Z < (VIII)2 ~ C-0-Y-Cl R N R2 (Me) R N R2 (Me) (VII) (I, X ~ 0) R50 C ~ C-0-Y-X-alk-~ ~ -Z (IX) R6 NH R2 (Me) (wherein alk - C2-C4-alkylene) ~, X ~ O) O

B. ~ C-OY- ~ -z /~-~ 1) tlketene , ~__J ~, ~R2 (Me) (Ilc) R502C ~J

R502C ~ C-0-Y-N~__/N-Z ~IIIb) (I, X ~ 0) Scheme 2 (X ~ NH) ~ 32~2~
R4 o ~ diketene ~ R CH0 ~ CNHY-N ~ -Z
H2N-Y-N N-Z ~ (Me)R ~ N-H-Y-N~_~N-Z (X) ~ ~ 2 P R ~Me) (IX) 2 ~ (Xl) R Cl (llIa) 3`
R6 `~H2 (IVb) ~

(I, X = NH) Scheme 3 (X ~ 0, R5 = YN N-Z) " ~
C-X-Y-N ~ -Z R -CH0 il (X) ~ (I, X ~ 0, R5 - YN ~ -Z ) H2N R2(R6) NH40Ac (IVa) In these foregoing schemes, R , R , R , R , X, Y, and Z are as defined in Formula I. 1 3 2 0 ~ ~ 4 According to Scheme 1, an intermediate 1,3-dic rbonyl compound II, generated by treatment of either a chloroalkanol (VI) or arylpiperazinylalkanol (V) with either ~eldrum's acid (cf: The ~erck Index, 10th Edition, ~635, page a28 (1983)) as ln Scheme 4, or with diketene is subjected tD ~odifi~d Nantzsch condensation condit1Ons (ammo~ium acetate/ethanol) f~llowed by TeaCtiOn with the ci~na3ate inter~ediate (lIla) to afford either a desired product of Formula (I), as in Scheme IB, or the chloroalkyl ester compound (YII) shown in Scheme lA. The intermediate compound (VII) may be reacted with either a s~mple arylpiperazine (YIII) or an arylpiperazinylalkyl alcohol or amine (IX) giving different embodiments of 3-carboxylate ester compounds of Formula (I), as shown in Scheme IA. The dihydro-pyridine products (I) obtained by the methods outlined ln Scheme 1àre isolaeed in moderate yields following chromatography.
Synthetic Scheme 2 illustrates the reaction sequence utllizet to obtain the 3-carboxamide subclass of Formula I products.
In Scheme 2, an aminoalkylpiperazine (IX, prepared from the corresponding arylpiperazine (VIII) and a chloroalkyl phthalimide via the well-known Cabriel 9ynthesis) ls treated with diketene or an approprlate alkanoylacetyl hallde to generate the lntermediate acetoacid amide (XI) which is converted to the cinnamic acid amide (IIIa) utilizing Knovenagel conditions (R CH0, piperitlne and acetic acit in benzene).
Appllcation of the general reaction to the intermediate compounds IIIa and IVb, as shown, ylelds the desired I product whereln X ~ NH.
Scheme 3 indlcates a route employed for the synthesis of symmetrlcal dihydropyrldines, l.e, the 3- and 5- carboxylate groups are identlcal. As sh~wn, lntermedlate compound IVa (prepared from 13 2 ~ 2 a 4 IIc under Hantzsch reaction conditlons) undergoes condensation with an approprlate R C~O to afford the desired I product.
Additional II and XI reaction intermediates utilized in preparation of the compounds comprlslng the instant invention can be prepared according to the following synthetic schemes or by modif~-cations thereof which would be obvious to practitioners skilled in the chemical art.
Scheme 4 (R2 and/or R is alkyl) A. O

R COCl ~ H-X-Y-N N-Z~ C-X-~-N ~ -Z
I pyritine X CH2C12 o"~R2 (Meldrum' 5 acid) IIa, X = O
XIa, X = NH

O ~ R6COCl R OH

x~J c 2 C~2 oJ~R6 IIb For more details of Scheme 4 cf: Y. Oikawa, et al., J. ~. Chem, 43, 2087 (1978).

Scheme 5 (R2 and/or R6 is alkyl-X-alkyl) 13 2 0 2 0 k Co2R5 X-alkyl ~ 0 { 502R5 Cl X-alkyl XV XIV tX e O or N alkyl) In Scheme 5, R could al~o be -Y-N ~ -Z. Additionally, lf the structural moiety represented by "alkyl" in XIV were a standard 0- or N-protecting group in organic synthesis, then its removal would generally glve rlse to lntermediates where R or R were alkanol or alkylamino as defined hereinabove. In general, XIV is prepared by treating a colt (0) solution of readily available intermediate XV
with llthium diisopropylamide followed by introtuct$on of an alkali metal salt of the X-alkyl reagent. Examples of this reagent would be ~odium methoxide, ~odlum ethoxide, 2-phenylethyl ethoxide, sodium phenoxide, lithlum methylamide, lithium d$methylamide, lithium methylphenyla~lde, and the llke. The reactlon medium is an inert organic liquid, preferably tetrahydrofuran or tetrahydrofuran-DMS0.
Isolation and purification of XIV is achieved by chromatography ou slllca gel.
The compounds o this invention have been found to possess several useful pharmacological propertles. The evaluation of these pharmacological properties was affected by means of both in vitro and in vlvo blologlcal screens. In vltro screening lncluded calcium act$vity in various smooth muscle systems sucQ as rat dorsal orta, portal vein, and trachea; and -binding affinities determined in rat heart and brain. In general, the preferred compounds of the instant lnvention possessed calcium entry blockade activity with potencies approximating the reference compound nifedipine. The a-binding activity was much greater for the instant compounds than for nifedipine with most members of the presen~ series being one or two orters of magnitude more potene.
Dose-shift studies, involving the response to phenylephrire ln gangllon-blocked, anesthetized rats, demonstrated that a-adreno-ceptor blockade uas the pharmacologlcal result of the a-binding. The methotology is described by Deitchman, et al., in J. Pharmacol.
Methods, 3, 311-321 (1980).
In vlvo testing included vasodilating results in the ganglion-blocked, angiotensin-II supported rat and antihypertensive screening in either the spontaneous hypertensive rat (SHR) or DOCA
salt rats. In general, vasodilating activity paralleled calcium blocking activity for members of the instant series. The antihyper-ten~ive screenlng data indlcated that good calcium and a-adrenergic blocking activity ln concert psoduced the most dramatic antlhyper-tensive effects. A most preferred compound, BMY 20064 ~ N02 OC

H3C02C ~lX C02'--N/~

was administered orally to both normotensive and spontaneously 1 ~ ~ Q 2 pertensive conscious rats. Doses of 1 and 10 mg/kg ellclted maximal mean arterial blood pressure reductions of 25 and 53 m~Hg, respectively, in the normotensive rat group and 34 and 100 m~Hg, respectively, in the spontaneously hypertens~ve rat group. These mean arterial blood pressure responses observed in both groups were rapid in onset (<10 minutes) and the significantly mean arterial blood pressure persisted for >4 hours after the higher dose of BMY 20064.
Additionally, BMY 20064 and nifedipine were studied in anesthetized beagle dogs to determine their comparatlve acute he~o-dynamic effects The two compounds exhibited similar potency and hemodynamic profiles in this particular hemodynamic model.
The specific tests employed in evaluation of the compounds of the instant inventlon were carried out according to the following procedures or with slight modification. Demonstration that the lnstant compounds possess specific blocking action on calcium ion channels resulted from in vitro testinl~ which consisted of suspending guinea pig ileal longitudinal smooth muscle strips in baths containing Tyrodes solutlon malntained at 37C aerated with 95% 2 ~ %5 C2~
The tlssues were equilibrated for 60 minutes prior to the start of 811 experiments. A 9ingle response to carbachol ls obtalned and used in all experiments as a control maximum. In between successive doses, the tissues are re-equilibrated and washed with Iyrodes solution every 15 minutes. To study the effect of the compounds, the tissues are exposed to the antagonist for 10 minutes prior to the addition of carbachol. For all experiments, only one antagonist in any one concentration is tested in any tissue. The results are 13 2 ~ k expressed as molar concentracions of antagonists which lnhiblt the muscle response by 50~. Since calcium antagonism generally inhibits excitation-contraction coupling ~n vascular smooth muscle, agents of this type usually evoke vasodilation. Testing of selectet compounts of the instant lnvention in the ganglion-blocked, angiotension II-supported rat model (Deitchman, et al., J. Pharmacol. Methods, 3, 311-321 (1980)) demonstrated vasodilation with its concomitant lowering of blood pressure.
Adtitionally, the selected compounds of the instant invention have been examined in vitro ant in vivo in laboratory tests developed to pretict a drug's potential to protect cardiac tissue from in~ury tue to ischemia. These tests utilize the knoun relationship betueen progressive depletion of high energy phosphate and the onset of lethal cell ln~ury in ischemic myocartium. Results of these screening lS tests demonstrate that the selected compounds possess potent anti-ischemia action.
Finally, compounds of the lnstant invention exhibit potent lnhlbltlon of various aspects of blood platelet function. These changes are not related to the compounds calclum block action. This ig e~ldenced by Table 1 whlch displays the comparative effects of BMY 20064 with two reference calclum entry blockers, nifedipine and verapamll.

Table 1 1 ~2a2~4 Comparative Effects of Calcium Entry Blockers on Various Aspec~s of Blood Platelet Function ln Platelet Rich Plasma (Rabbit) Activity (EC5 in mg/mL) Collagen Shape Pla~elet Clot Compound Aggre~ation Change Release Reaction Retsact~on Nifedipine 176 >128 >128 >128 Verapamil 151 128 84 >128 10 BMY 20064 11 12 12 0.1 As can be seen, there is little s~ilarity between the effects of BMY 20064 and the reference compounds on platelet function.
In summary of the foregoing discussion of biological activities, the instant compounds have cardiovascular properties particularly sulted to their use in hypertension and lschemia. Thus, another aspect of the lnstant invention concerns a process for ameliorating either hypertension or ischemia in a mammal in need of such treatment whlch comprises ~ystemic administration to such mammal of an effective dose of a Formula I compound or a pharamceutically acceptable acid add~tion salt thereof. On the basls of animal testing, an effective oral tose could be expected to from about 1 to 20 mg/kg and an effeceive parenteral dose could be expectet to be lower, in the range of about 0.05 to 1 mg/kg body weight.
For clinlcal applications, however, the dosage and dosage regimen must in each case be carefully adjusted, utilizing sound proessional ~udgment and considering the age, weight and condition of the recipient, the route of atministration and the nature and gravity of the illness. Generally the compounds of the instant lnvention wlll be adminlstered $n the same manner as for the reference drug nifedipine and the daily oral dose will comprise from about 5 to 132~2~
to about 50 mg, preferably lO to 20 mg administered from 1 to 3 times a day. In some instances, a sufficient therapeutic effect can be obtained at lower doses while in others, larger doses will be required.
The term systemic atministration as used herein refers to oral, rectal, and parenteral (i.e. ~ntra~uscular, intravenous, and subcutaneous) routes. Generally, it wilI be found that when a compound of the present invention is administered orally, which is the preferred route, a larger quantity of reactive agent is required to produce the same effect as a smaller quantity given parenterally.
In accordance with good clinical practice, it is preferred to administer the lnstant compounds at a concentration level that wlll produce effective antihypertensive and/or anti-ischemic effects without causing any har~ful or untoward side effects.
Therapeutically, the instant compounds are generally given 85 pharmaceutical compositions comprised of an effective antihyper-tensi~e and/or anti-ischemic amount cf a compound of Formula I or a pharmaceutlcally acceptable acit addltion salt thereof and a pharma-ceutically acceptable carrler. Pharmaceutical compositions for e~fectlng such treatment will contain a ma~or or minor amount, e.g.
from 95 to 0,5Z of at least one compount of the present invention ~n comblnation with the pharmaceutical carrier, the carrier comprlsing one or more solid, semi-solid, or liquid diluent, flller, ant formu-lation adjuvant which is non-toxic, inert and pharmaceutically acceptable. Such pharmaceutical compositions are preferably in tosage unlt forms; l.e., physlcally tiscrete units containing a pre-tetermlnet amount of the trug corresponding to a fractlon or multlple l32a~s~
of the dose which is calculated to produce the desired therapeutic response. The dosage units can contain l, 2, 3, 4, or more single doses, or, alternatively, one-half, one-ehird, or one-fourth of a single dose. A single dose preferably coneains an amount sufflcient to produce the desired therapeutic effect upon admlnistration at one application of one or more dosage units according to the pre-determined dosage regimen usually a whole, half, thlrd or quarter of the daily dosage administered once, twice, three, or four tlmes a day. Other therapeutic agents can also be present. Pharmaceutical compositions which provide from about l to 50 mg of the active ingredient per unit dose are preferred and are conventionally prepared as tablets, lozenges, capsules, powters, aueous or oily suspensions, syrups, elixirs, and aqueous solutions. Preferred oral compositions are in the form of tablets or capsules and may contain conventional excipients such as binting agents (e.g. syrup, acacia, gelatin, sorbitol, tragecanth, or polyvinylpyrrolidone), fillers (e.g. lactose, sugar, malze-starch, calcium phosphate, sor~itol, or glycine), lubricants (e.g. magnesium stearate, talc, polyethylene glycol or sillca), disintegrants (e.g. otarch) ant wettlng agents (e.g. sodium lauryl ~ulfate~. Solutions or suspenslons of a Formula I compound with conventlonal pharmaceutical vehlcles are employed for parenteral compo~ltions such as an aqueous solutlon ~or lntravenous injection or an oily suspension for intramuscular injection. Such compositions havlng the desired clarity, stability and adaptability for parenteral use are obtained by dissolving from 0.1% to 10% by weight of the actlve compound in water or a vehlcle consistlng of a polyhydric aliphstic alcohol such as glycerine, propyleneglycol, ant polyethelene glycols or mixtures thereof. The polyethyleneglycols consist of a mixture of non-volatile, usually liquid, polyethyleneglycols which 13 2 ~ 2 are soluble in both water and organic liquids and which have molecular weights from about 200 to lS00.

The compounds which constitute this invention and their methods of preparation will appear more fully from a consideration of the following examples which are given for the purpose of illustration only and are not to be construed as limiting the invention ln sphere or scope. All temperatures are understood to be in degrees ~ when not specified.
'The nuclear magnetic resonance (NMR) spectral characteristics refer to chemical shifts (~) expressed in parts per million (ppm) versus tetramethylsilane (TMS) as reference standard. The relative area reported for the various shifts in the proton ~MR spectral data corresponts to the number of hydrogen atoms of a particular functional type in the molecule. The nature of the shifts as to multiplicity is reported as broat singlet (bs), singlet (s), multiplet (m), doublet (d), toublet of doublets (td), or quarter (q). Abbreviations employed are DMSO-d6 (deuterodimethylsulfoxide), CDC13 (deuterochloroform), and ase otherwlse conventional. The infrared (IR) spectral descriptions lnclude only absorptlon wave number~ (cm 1) having functlonal group ldentlflcation ~alue. The IR determinations were employed using potassium bromlde (XBr) as dlluent. The elemental analyses are reported as percent by welght, SYnthesis of Intermediates ~ 3 2 A. Intermediates of Formula II

2-Chloroeth21 Acetoacetate A solution of 75 g (0.403 mole) of 5-(1-hydroxyethylidene)-2,2-dimethyl-1,3-dioxalane-4,6-dione (cf: Y. Oikawa, et al., J. ~
Chem., 43, 2087-2088 (1978)) and 200 mL of 2-chloroethanol was heated at 125C for 5 hr. After cooling the tark solution to room temperature, the excess 2-chlorethanol was removed in vacuo and the resulting 10 residue distllled to yield 49.4 g (74~) of product as clear liquid, b.p. 80-85C/0.4 mm).
E~AMPLE 2 3-Chloroprop~l Acetoacetate 3-Chloropropanol (47.3 g, 0.50 mole) and a catalytic amount of triethylamine at 65C were treatet dropwise with 42 g (0.50 le) of d$ketene. After the addition was complete, the reaction was stirred at 65C for an addltional hour. Distillation of the resitue furnished 72,9 g (82%) of product as a clear liquid, b.p. 78-85C at 150 mm.

Atdltional Formula II intermetiates can be prepared by modifications of the abo~e examples which would be understood by one skllled in the art of organic chemical synthesis.

B. Intermediates of Eormula III
~32~2~
EXA~PLE 3 Methyl 2-[~3-Nitrophenyl)methylene~-3-oxobutanoate A solution of 151 g (1.00 mole) of 3-nitrobenzaldehyde, 116 g (1.00 mole) of methyl acetoaceeate, 10 mL of glacial acetic acid, 4 mL of piperidine, and 400 mL of benzene was refluxet 2 hr during which time 21 mL of water was removed via a Dean-Star~ trap.
The dark yellow solution was cooled to ambient temperture and solidifi-cation occurred. Filtration followet by washing with ether afforded 10 180 g of product as a yellow solid. An additional 23 g product was obtained from the filtrate to yield a total of 203 g (82%) of product, m.p. 145-146C. (literature m.p., 158C; cf: Meyer, et al., Arzneim.-Forsch/Dru~ Research, 31, 407 (1981)).

Ethyl 2-[(3-Nitrophenyl)methylene]-3-oxobutanoate This compound was prepared ln molar scale according to the method described above in Example 3 and substituting ethyl aceto-acetate for the methyl ester. Recrystallization from ethanol yielded 182 g.(69%) of product as a yellow solid, m.p. 103-106C. (literature m.p., 110C.; cf: Ruhemann, J. Chem. Soc., 83, 717 (1903)).
Additional examples of lntermediates of Formula III which were prepared using the procedure glven above are listed in Table 2.

Table 2 13202~
Additional Formula III Intermediates R502C ~J

Me ~ 0 III -b.p. (C/
Ex. ~ _ R~ 0.1 mm) _ m.p. (C) 5 5 m-nitrophenyl i-propyl - -6 m-nitrophenyl butyl 7 m-nitrophenyl methoxyethyl - -8 m-nitrophenyl d~ethylamino-ethyl 9 p-nitrophenyl ethyl - 59.5-61.5 cyclohexyl ethyl 160-170 11 l-naphthyl ethyl 120-130 12 3-indolyl ethyl - 121-122.5 13 2-furanyl ethyl 118-120 14 2-thienyl ethyl 110-120 3-pyridyl ethyl 145-165 16 2-bicycloheptenyl ethyl 134-140 17 phenyl ethyl 97 18 m-cyanophenyl ethyl 130-160 20 19 o-chlorophenyl ethyl m-hydroxy-p- ethyl - _ nitrophenyl 21 o-fluorophenyl ethyl 130 22 m-chlorophenyl ethyl 120-123 23 m-erifluoromethyl ethyl 100-110 phenyl 13202~ b.p. (C/
~x ~ R5 0.1 mm) _ ~.p. (C) 24 p-hydroxy-m,nltro- ethyl - -phenyl 5 25 o-methoxyphenyl ethyl 26 m-methylphenyl ethyl 140 27 p-hydroxy-m, ethyl - 110-112 methoxy 28 p-acetomidophenyl ethyl - -10 29 m-methylsulfonyl ethyl mrtrifluoromethyl- ethyl sulfonylphenyl 31 o-chloro-m-nitro- ethyl phenyl 15 32 o-nitrophenyl methyl 33 ~rnitrophenyl methyl - 145-146 34 m-nitrophenyl n-propyl m-nitrophenyl 2-chloro- - 68-76 ethyl 20 36 m-nitrophenyl 3-chloropropyl 37 ' 2,3-dichloro- methyl phenyl 38 2,3-tichloro- methoxyethyl phenyl 25 39 4-benzoxadiazolyl ~ethyl 4-benzthiatiazolyl ethyl 41 3-(2-methylthio- methyl pyridinyl) C. Intermediates of Formula V 1 3 2 ~ 2 ~ 4 4-(2-Methoxyphenyl)-l-piperazinepropanol The synthesis for ehis and other V-type intermediates ls taken from Uu, et al., J. Med. Chem., 12, 876 (1969). A mixture of 1-(2-methoxyphenyl)piperazine (10.0 g, 52.1 ~mole), 3-chloropropanol (4.25 g, 45.0 mmole), micropulverized potassiu~ carbonate (6.21 g, 45 mmole), and 75 mL of acetonitrile was refluxed for 23 hr. After cooling to ambient temperature, 200 mL of water was added and the resulting mixture extracted with methylene chloride. The combined organic portions were washe~ with water and brine, and then dried over magnesium sulfate. Filtration and removal of volatiles in vacuo yielded 11.7 g of crude alcohol product. Recrystallization from acetonitrile afforded 9.4 g (72%) of product was white solid, m.p.
15 94-95C.

D. I~termediates of Formula VII

2-Chloroethyl Methyl 1,4-Dihydro-2,6-dimethyl-4-(3-ni.rophenyl)-3,5-pYridinedicarboxylate 20 Ammo~ium acetate (3.85 g, 50.0 ~mole) was added to a solution of acetoacetate prepared above in Example 1 (8.25 g, 50.0 mmole) and 50 mL of absolute ethanol, and the refluxed under nitrogen for 1 hr.
The cinnamate intermediate product prepared above in Example 3 (12.5 g, 50.0 mmole) was then added and the resulting yellow solution refluxed an additional 12 hr. After cooling to room temperature, the solvent was removed in vacuo and the residue recrystallized from ethanol tD yleld product as a yellow solid, m.p. 129-131C. (Literaturel 3 2 m.p., 130C; cf: Iwanami, ee al., Chem. Pharm. Bull., 27, 1426 (1979)).

3-Chloropropyl Methyl 1,4-Dihydro-2,6-d$methyl-_4-(3-nitrophenyl)-3t5-pYridinedicarboxYlate According to the method described aboYe in Example 43 but usin~ the intermediates prepared ln Examples 2 and 3, the sub~ect intermediate was prepared in a 99% yield on a 50 mmole scale to yield the product as a yellow solid, m.p. 125-130C.

Svnthesis of Products 2-~4-(2-Methoxyphenyl-l-piperazinyl)ethyl~
Methyl 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate Dihydrochloride HYdrate A solution of the VII intermediate prepared above in Example 43 (1.9ô g, 5.00 ~mole~, 1-(2-methoxyphenyl)piperazine (1.05 g, 5.5 mmole), triethylamine (0.61 g, 6.04 mmole), and 25 mL of tetrahydro-furan were refluxed for 36 hr under nitrogen. After remoYal of the volatlles in vacuo, the residue was dissolved in 2-propanol, 50 mL of lOZ aqueous HCl (V:V) added ant the solution heated on a steam bath for 15 min. After extraction with methylene chloride, the combined organic portions were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo to yield a brown oil.
The oil was crystallized from ethanol:ether to furnish 1.7 g (55%) of product as a light brown solid, m.p. 159-160C (dec.).
Anal. Calcd. for C29H34N4o7-2Hcl-o-7 H20: C, 54-76; H, 5-93;
N, 8.81. Found: C, 54.87; H, 6.21; N, 8.78.

NMR (DMSO-d6): 2.36 (3,s); 2.45 (3~s); 3.45 (lO,m); 3.62 ~3,s); 3.87 (3,s); 4.55 (2,m); 5.09 (l,s); 7.08 (4,m); 7.70 (2,m);
8.06 (2,m); 8.45 (2,bs); 9.60 (l,bs).
IR (RBr): 755, 1015, 1100, 1120, 1215, 1350, 1485, 1530, S 1650, 1700, 2450, 3360 cm 1.

~2-(4-Phenyl-l-piperazinyl)ethyl~ Methyl 1,4-Dihydro-2,6-dimethYl-4-(3-nitrophenyl)-3,5-pYridinedicarbox~late ~sing methodology similar to that described above ln Example 44, a solution of the dihydropyridine intermediate VII and phenylpiperazine were refluxet i~ acetonitrile using potassium carbonate as the acid acceptor. After hydrochloride formatlon and crystalllzation from acetonitrile-isopropyl ether, the product was obtained in 15% yield as a yellow solid, m.p. 201-204C.
Anal. Calcd. for C28~32~406 HCl: C, 60.37; H, 5.97; N, 10-06-Found: C, 60.48; ~, 6.11; N, 10.30.
NMR (DMSO-d6): 2.32 (3,sl; 2.40 (3,s); 3.21 (6,m); 3.44 (4,m); 3.60 (3,s); 4.48 (2,m); 5.04 (l,s); 6.92 (3,m); 7.28 (2,m);
7.64 (2,m); 8.01 (2,m); 9.40 (l,bs); 11.65 (l,bs).
IR (RBr): 695, 755, 1100, 1120, 1215, 1350, 1480, 1525, 1670, 1700, 2430, 3280 cm 1.

[3-~4-(2-Methoxyphenyl)-l-piperaz~nyl]propyl~
Methyl 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenvl)-3,5-pYridinedicarboxylate ~ydrate A solutlon of the dihydropyridine intermediate VII prepared above ln Example 44 (8.65 g, 20 mmole), 1-(2-methoxyphenyl)piperazine (4.1 g, 20 mmole), triethylamine (6 g), and a catalytic amount of potas~ium iodide ln 50 mL of acetonitrile was refluxed for 48 hr.

After removal of volatiles in vacuo, the residue was triturated ln acetonitrile to furnish 3.5 g (17%) of product as a yellow solid, m.p. 70-75C.
Anal. Cacld. for C30H36N407 5H2 S N, 9.77. Found: C, 62.50; H, 6.41; N, 9.43.
NMR (DMSO-d6): 1.72 (2,~); 2.30 (6,s); 2.40 (6,m); 2.92 (4,m); 3.56 (3,s); 3.77 (3,s); 4.02 (2,m); 5.02 (l,s); 6.87 ~4,~);
7.59 (2,m); 8.00 (2,m); 9.01 (l,bs).
IR (XBr): 750, 1100, 1120, 1215, 1240, 1350, 1500, 1530, 10 1685, 1700, 3400 cm l Methyl 1,4-Dihydro-5-~[[2-(4-(2-methoxyphenyl) l-piperazinyl)]ethyl]amino~carbonyl-2,6-dimethYl-4-(3-nitrophenyl)-3-pyridinecarboxylate Dlketene (1.85 g, 22.0 mmole) was slowly added dropwise to a 0C solution of 1-(2-amfnoethyl)-4-(2-methoxyphenyl)piperazine (4.7 g, 22 mmole; cf: Mull, et al., J. Med. Pharm. Chem., 5, 944 (1962) for preparation) in 20 mL of absolute ethanol. After the addltion was complete, the solution was allowed to warm to room temperature and was stirred 30 minutes. Concentration in vacuo gave 5.5 g of the crude acetoacidamide intermediate as a clear oil whlch wss used without further purification.
The Knovenagel condensation was achieved by refluxing the solutlon of 3-nitrobenzaldehyde (2.25 g, 15 ole), the acetoacidamide intermediate, 5 drops of glacial acetic acid, and 3 drops of piperidine in 25 ~ of benzene for several hours. After work up and flash chromatograophy (5% methanol:chloroform) 4.35 (44%) of product was obtained as a yellow oil.

A p~rtion of this yellow oll (3.5 g, 7.7 m~ole) methyl ~32a2 `~-aminocrotonate ~3.9 g, 7.8 ~ole) and 40 mL of 2-propanol was refluxed overnight (18 hr). Concentration in vacuo gave 3.5 g of a yellow gum. Flash chromatography ~2X methanol:chlorofor~; 3%
me~hanol:chloroform; and then 4Z methanol:chloroform) afforted 0.73 g (17Z) of product as a yellow foam, m.p. 83-88C.
Anal. Cacld. for C29H35N5O6-0.2-CHC13: C, 61.15; H, 6-19;
N, 12.21. Found: C, 61.08 ~, 6.18; N, 11.93.
NMR (CDC13): 2.30 (6,s~; 2.54 (6,m~; 3.01 t4,m); 3.32 (2,m); 3.63 (3,s); 3.85 (3,s); 4.96 (l,s); 6.16 (l,bs); 6.26 (l,bs);
6.92 (4,m); 7.38 (l,m); 7.68 (l,m); 8.05 (2,m).
IR (KBr): 750, 1110, 1240, 1350, 1500, 1530, 1625, 1660 cm EXAMP~ F 49 Methyl 1,4-Dihydro-5-[[[3-[4-(2-methoxyphenyl)-1-piperazlnyl]propyl]a~ino]carbonyl]-2,6-dimethYl-4-(3-nitrophenYl)-3-pyridinecarboxylate This compound was prepared in similar fashion to Example 48 but u~ing a stasting am~nop~opylpiperazine described ~n Wu, et al., J. Med. Chem., 12, 876 (1969). The desired product was isolated as a yellow Soam, m.p. 70-80C.
Anal. calcd. ~or C30H37N5o6~o~4cHcl3: C, 59.72 H, 6.17;
N, 11.45. Found: C, 59.54; H, 6.17; N, 11.38.
NMR (CDC13): 1.65 (2,m); 2.17 (3,s); 2.31 (3,s); 2.52 (6,m); 3.00 (4,m); 3.38 (2,m); 3.53 (3,s); 3.85 (3,s); 4.99 (l,s);
5.90 (l,bs); 6.89 (5,m); 7.52 (2,m); 8.03 (2,m.).
IR (RBr): 750, 1115, 1230, 1240, 1350, 1500, 1530, 1625, and 1680 cm 1 EXAMP~-E 50 ~ 3 2 0 2 `~ ~
bis-[3-~4-(2-Methoxvphenyl)-l-piperazinyl]propyl~
1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyr~dinedicarboxylate Dihydrochloride To a melt of the pipera~ine intermediate V, prepared above in Example 42 (5.00 g, 20.0 mmole~ in a 105C oil baeh was slowly added tiketene (1.68 g, 20.0 mmole). After the addition was complete, 50 mL of absolute ethanol, ammonium acetate (1.20 g, 16 mmole~, and 3-nitrobenzaldehyde (1.58 g, 10.4 mmole~ were added, and the resulting solution refluxed for 17 hr. After cooling to room tempera~ure, the ~eaction was concentrated in vacuo to yield 8.5 g of a dark yellow oil. The oil was taken up ln methylene chloride and washed wlth two portions of lOZ aqueous HCl (~:V) and the organic layer concentrated to yield a yellow solid. Recrystalli~ation from ethanol-ethyl ether 15 fùrnished 2.95 g (35Z) of product as a yellow solid, m.p. 155-175C
(dec.).
Anal Calcd- for C43H54N608-2HC1 0-5 H20 N, 9.72; H2O, 1.04. Found: C, 59.67; H, 6.90; ~ 9 54; H20, 1.04.
NMR (DMSO-d6): 2.18 (4,m); 2.38 (6,s); 3.18 (12,m); 3.44 (8,m); 3,79 (6,s); 4.08 (4,m); 5.00 (l,s); 6.93 (8,m); 7.70 (2,m);
8.02 (2,m); 9.46 (l,bs).
IR (KBr): 750, 1120, 1215, 1250, 1350, 1515, 1550, 1665, 1710, 2640, and 3400 cm 1.

EXAMPLE 51 13 2 0 2 ~ ~
4-[4-[(2-Methoxyphenyl)-l-piperazlnyl]-butyl] ~ethyl 1,4-Dihydro-2,6-dimeehyl-4-(3-nitrophenyl)-3,5-~yridined1carboxylate Dihydrochloride Diketene (4.6 g, 0,055 ~ole) was added tropwise to 4-(2-me~hoxyphenyl)-1-piperazinebutanol (13.2 g, 0.05 mole) (Brit.
803,403, Oct. 22, 1958) at 100~. The melt was heated for 20 min at 100. The melt was dissolved in 200 ~L ethanol and ammonium acetate (3.5 g, 0.05 ~ole) added. The solution was heated at reflux for 10 2 hr. Methyl m-nitro-2-acetylcinna~ate (8.4 g, 0.05 le) was added and refluxing was continued for 17 hr. The solution was concentrated in vacuo. The residue was purified by flash chromatography (2% MeOH
in CHC13 on silica gel). The product was converted to the hydrochloride with ethanolic HCl to give 1.55 g (4.7%) of product, m.p. 110~130.
Anal. Calcd. for C3lH38N407-2H M : C, 57-14; H, 6-19;
N, 8.60. Fount C, 57.35; H, 6.39; N, 8.51.

Additional examples of products of the instant invention are given in Table 3. These additional products are synthesized using the procedures described above in Examples 45-51.

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V~ o ~ ~1 Further Detailed Description of the Invention 13 2 ~ 2 ~ ~

Some additional compounds similar to those tef~ned herelnabove bg Formula I also have useful cardiovascular propertles. For instance, they possess calcium entry and alpha-adrenergic blockade as well as S antihypertensive activity. The significance of such findings has already been adequately discussed supra for the Formula I compounds.
The addltional c~mpounts are syntheslzed as illustrated in Examples 77 and 78 hereinbelow and are embodied in Formula I' along with the compounds of For~ula I.

R502C ~ C-X-Y-N N-Z

~' . .

F ds of Formula I' R2 R4 R5 R6, X and Z are as previously tefined for compounds of Formula I. The definition for Y, however, is expanded in Formula I' to lnclude alkylene chains of from 2 to 5 carbon atoms and alkylene chains containing a sulfur ato~
ln the chaln. The scope of the instant ~nvention is hereby expanted to inclute all compounds defined by Formula XXI (shown below) which lncorporates the compounds of I and I'. The present sub~ect matter now comprlses compounds of Formula BI

R502C ~ C-X-Y-N N-Z

or 8 pharmaceutically acceptable acld ad ~ ~o~ Qsa~ Q 4nd/or solvaee thereof whereln the symbols R2, R , R5, R6, X, Y and Z have the following meanings. R2 ant R6 are independently selected from lower alkyl, hydroxyalkyl, alkoxyalkyl, alkylaminoalkyl, or dialkylamino-alkyl and may be the same or tifferent. Lower alkyl means Cl-C4;
alkoxyalkyl refers to a Cl-C4 alkylene chain and a Cl-C4 alkyl group connected by an oxygen atom; similarly, aikylaminoalkyl and dialkyl-aminoalkyl refer to lower alkyl groups and a Cl 4 alkylene chain connected by a secondary (-N~-) or a tertiary (,N-) amino group.
R is cycloalkyl of 5 to 7 carbon atoms, blcycloalkenyl of 7 to 9 carbon atoms, hetaryl, such as furanyl, indolyl, methylthiopyridyl, thienyl, ber~oxadiazolyl, benzothiadiazolyl, and the llke; aryl meaning phenyl, naphthyl, or substituted phenyl, with a substieuerlt comprising acetamino, lower alkyl, lower alkoxy, cyano, haloge~, hydroxyl, nitro, trifluoromethyl, trifluoromethylsulfonyl, snd methylsulfonyl and the like. R5 ls R2 or X-Y-~ N-Z. X is 0 or N~. Y is an alkylene cha$n containing 2 to 5 carbon atoms, or an alkyleneoxyalkylene, alkylene-aminoalkylene, or alkylenethioalkylene chain. By alkyleneoxyalkylene is meant two C2 to C5 alkylene chains connected by an oxygen atom. Similarly, alkyleneaminoalkylene and alkylenethioalkylene denote C2 to C5 alkylene chains connected by NH and S, respectively. Z is phenyl, pyridyl, or pyrimidinyl, either unsubstituted or substituted with one or more ~ubstituent groups selected from among lower alkyl, lower alkoxy, cyano, halo, and trilfuoromethyl.
~he adtitional co~pounds embodied ln Formula I' can be prepared by adapting the syrthetic processes outlined as Schemes 1-3. Specifically, the compounds of Formuls I' are obtained by use of the methods for Formula I compounds previously set forth or by obvlous modification of these procedures. This is illustrated by the following examples.

EXAM2LE 77 1 3 2 0 2 ~ ~
[2-[[2-[4-t2-Methoxyphenyl)-l-plperazinyl]-ethyl]thio]ethyl] Methyl 1,h-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyrldine Dlcarboxylate Diketène (8.4 g, 100 m~ole) was added dropwise to 2,2-thio-dlethanol (12.2 g, 100 mmole) at 80 containing a catalytlc amount of triethylamine. The ixture was heated for 15 minutes at 80. The mixture was dissolved in 200 mL ethanol and a~monium acetate (7.7 g, 100 mmole) was added. The solut$on was then heated at reflux for an hour. Methyl 2-[~3-nitrophenyl)methylene]-3-oxobutanoate (Ex. 3, 24.9 g, lOO mmole) was added and refluxing continued for 18 hr. The solution was concentrated in vacuo and the resldue purified by flash chromatography (2Z MeOH in methyle~e chloride on silica gel) gave 5 g (21.8X) of a synthetlc lntermediate compound whose structure is a motif$cation of compound VII (Cl replaced by OH).
A solution of this intermed~ate alkylenethioalkanol compound (4.0 g, 9.2 mmole) ant thionyl chloride (1.1 g, 9.2 mmole) in 100 mL
chloroform was heated at reflux for about 1.25 hr. The solution was concentrated _ vacuo. The residue was dissolved in 300 mL acetonitrile and comblned wlth o-methoxyphenylpiperazine (3.5 g, 18 m~ole);
mlcropulverized potassium carbonate (2.5 g, 18 mmole); and a crystal of sodium lodlde. The mixture was heated at reflux for four days and concentrated in vacuo. The residue was purified by flash chromatography (0.5Z methanol and 1:4 ethyl acetate-methylene chloride on silica gel) to give 2.2 g (39.3%) of product, m.p. 52-63.
Anal- Calcd- for C31H38N47S C, 60-98; H~ 6.27; N~ 9-17-Found: C, 60.61; H, 6.24; N, 9.46.

FX~PLE 78 ~ 3202~
l5-[4-(2-Methoxyphenyl)-l-piperazinyl]pentyl]
Methyl 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxYlate Dichloromethane Solva~e Diketene (3.0 g, 36 mmole) was added slowly to a melt of 1-(5-hydroxypentyl)-4-(2-methoxyphenyl)piperazine (10.0 g, 36 mmole;
prepared according to Brit. Patent 803,403, October 22, 1958) at 85. After the addition uas complete, 100 mL abs. ethanol and ammonium acetate (2.8 g, 36 mmole) were added. After refluxing for 2 hr, methyl 10 2-[(3-nltrophenyl)methylene~-3-oxobutanoate (9.0 g, 36 mmol~; prepared ln Example 3) was added and reflux was continued for 17 hr. The solution ~as concentrated in ~acuo. The resldue was purified by flash chromato-graphy (1.5Z methanol and methylene chlorlde) to glve 5.2 g (23.7Z) of product, m.p. 52-62.
Anal- Calcd- for C32~40N47 -2CH2C12 N, 9.19. Found: C, 63.59; H, 6.73; N, 9.32.

Claims (8)

1. A compound of formula XXI' and the pharmaceutically acceptable acid addition salts thereof wherein R2 and R6 are independently selected from lower alkyl, hydroxylower-alkyl, lower-alkoxy-lower-alkyl, lower-alkylamino-lower-alkyl, or di-lower alkylamino-lower-alkyl;
R4 is cycloalkyl of 5-7 carbons, bicycloalkenyl of 7-9 carbon atoms, furanyl, indolyl, methylthiopyridyl, thienyl, benzoxadiazolyl, and benzothiadiazolyl; phenyl, naphthyl, or substituted phenyl, with a substituent selected from the group consisting of acetamino, lower alkyl, lower alkoxy, cyano, halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethylsulfonyl, and methylsulfonyl;
R5 is R2 or X is NH;
Y is a C2 to C5 alkylene chain, alkyleneoxyalkylene, alkylenethioalkylene, or alkyleneaminoalkylene chain wherein each alkylene moiety having 2-5 carbon atoms; and Z is phenyl, pyridinyl, or pyrimidinyl, either unsubstituted or substituted with a group selected from among lower alkyl, lower alkoxy, cyano, halo, and trifluoromethyl.

2. The compound of claim 1 wherein R2 and R6 are lower alkyl, R4 is nitrophenyl, R5 is lower alkyl or X is NH, Y is a C2-C4 alkylene chain or an alkyleneoxyalkylene chain wherein each alkylene moiety having 2-5 carbon atoms, and Z is phenyl substituted by lower alkyl, lower alkoxy, cyano, halo or trifluoromethyl.

3. The compound of claim 2 which is methyl 1 ,4-dihydro-5-[[[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]amino]carbonyl]-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate.

4. The compound of claim 2 which is methyl 1,4-dihyro-5-[[[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]amino]carbonyl]-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate.

5. A pharmaceutical composition for the treatment of cardiovascular disease consisting of angina, hypertension, or ischemia comprising from 5 to 50 mg of a compound claimed in any one of claims 1 to 4 in combination with a pharmaceutically acceptable, non-toxic inert carrier.

6. The use of a non-toxic effective vasodilating dose of a compound as claimed in any one of claims 1 to 4, for exerting a vasodilating effect in a mammalian host having a condition in which therapeutic benefit is derived from vasodilation.

7. The use of a non-toxic antihypertensive effective dose of a compound as claimed in any one of claims 1 to 4, for antihypertensive effect in a mammalian host having hypertension.

8. The use of a non-toxic antiischemia effective dose of a compound as