United States Patent [19]
`Campbell et al.
`
`[11] Patent Number:
`[45] Date of Patent:
`
`4,572,909
`Feb. 25, 1986
`
`[75]
`
`[54] 2-(SECONDARY AMINOALKOXYMETHYL)
`DIHYDROPYRIDINE DERIVATIVES AS
`ANTI-ISCHAEMIC AND
`ANTIHYPERTENSIVE AGENTS
`Inventors: Simon F. Campbell, Deal; Peter E.
`Cross, Canterbury; John K. Stubbs,
`Deal, all of England
`[73] Assignee: Pfizer Inc., New York, N.Y.
`[21] Appl. No.: 576,982
`Feb.3, 1984
`[22] Filed:
`
`Related U.S. Application Data
`[63] Continuation-in-part of Ser. No. 463,081, Feb. 2, 1983,
`abandoned.
`Foreign Application Priority Data
`[30]
`Mar. II, 1982 [GB] United Kingdom ................. 8207180
`[51]
`Int. Cl.4 .................. C07D 211/90; A61K 31!455
`[52] U.S. Cl ...................................... 514/356; 546/321
`[58] Field of Search ................ 544/333; 546/321, 283,
`546/274, 280, 257, 271, 167, 284, 270; 424/251,
`258, 266; 514/356
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`4,430,333 2/1984 Campbell et al. ................... 546/321
`FOREIGN PATENT DOCUMENTS
`318101 7/1981 European Pat. Off ............. 546/321
`OTHER PUBLICATIONS
`Schramm, M., "Novel Dihydropyridines with Positive
`Inotropic Action", Nature, vol. 303 (Jun. 9, 1983) pp.
`535-537.
`
`Bossert, F. et al, "4-Aryldihydropyridines", Angew.
`Chern. Int. Ed. Engl. 20, pp. 762-769 (1981).
`Primary Examiner-Henry R. Jiles
`Assistant Examiner-Dale A. Bjorkman
`Attorney, Agent, or Firm-Charles J. Knuth; Albert E.
`Frost; James M. McManus
`[57]
`ABSTRACT
`A dihydropyridine compound of the formula
`
`or a pharmaceutically acceptable acid addition salt
`thereof,
`wherein
`Y is -(CH2)z-, -(CH2)3-, -CHzCH(CH3)- or
`-CHzC(CH3)z-;
`R is aryl or heteroaryl;
`Rl and R2 are each independently C1-C4 alkyl or 2-
`methoxyethyl; and
`R3 is hydrogen, C1-C4 alkyl, 2-(C1-C4 alkoxy)ethyl,
`cyclopropylmethyl, benzyl, or
`-(CHz)mCOR4
`where m is 1, 2 or 3 and
`R4is hydroxy, C1-C4alkoxy or -NR5R6where R5 and
`R6 are each independently hydrogen or C1-C4 alkyl
`can be employed for treating or preventing a heart
`condition or hypertension.
`
`17 Claims, No Drawings
`
`DRL Ex. 1011, p. 001
`
`

`

`4,572,909
`
`1
`2-(SECONDARY AMINOALKOXYMETHYL)
`DIHYDROPYRIDINE DERIVATIVES AS
`ANTI-ISCHAEMIC AND ANTIHYPERTENSIVE
`AGENTS
`
`This is a continuation-in-part of U.S. patent applica-
`tion Ser. No. 463,081, filed Feb. 2, 1983, abandoned.
`BACKGROUND OF THE INVENTION
`This invention relates to certain dihydropyridines,
`specifically to certain 1,4-dihydropyridines having a
`substituted-amino containing group attached to the
`2-position, which have utility as anti-ischaemic and
`antihypertensive agents.
`The compounds of the invention reduce the move-
`ment of calcium into the cell and they are thus able to
`delay or prevent the cardiac contracture which is be-
`lieved to be caused by an accumulation of intracellular
`calcium under ischaemic conditions. Excessive calcium 20
`influx during ischaemia can have a number of additional
`adverse effects which would further. compromise the
`ischaemic myocardium. These include Jess efficient use
`of oxygen for A TP production, activation of mitochon-
`drial fatty acid oxidation and possibly, promotion of cell 25
`necrosis. Thus the compounds are useful in the treat-
`ment or prevention of a variety of cardiac conditions,
`such as angina pectoris, cardiac arrythmias, heart at-
`tacks and cardiac hypertrophy. The compounds also
`have vasodilator activity since they can inhibit calcium 30
`influx in cells of vascular tissue and they are thus also
`useful as antihypertensive agents and for the treatment
`of coronary vasospasm.
`SUMMARY OF THE INVENTION
`According to the invention, there are provided novel
`1,4-dihydropyridine derivatives of the formula:
`
`2
`mic mixtures or as separated d- and 1- optically-active
`isomeric forms.
`The pharmaceutically acceptable acid addition salts
`of the compounds of the formula (I) are those formed
`5 from acids which form non-toxic acid addition salts
`containing pharmaceutically acceptable anions, such as
`the hydrochloride, hydrobromide, sulphate, phosphate
`or acid phosphate, acetate, maleate, fumarate, lactate,
`10 tartrate, citrate and gluconate salts. The preferred salts
`are maleates.
`The term "aryl" as used in this specification, includes,
`for example, phenyl optionally substituted by one or
`two substituents selected from nitro, halo, C1-C4 alkyl,
`15 C1-C4 alkoxy, hydroxy, trifluoromethyl, and cyano. It
`also includes 1- and 2-naphthyl.
`The term "heteroaryl" as used in this specification
`includes, for example, benzofuranyl; benzothienyl; pyri-
`dyl optionally monosubstituted by methyl or cyano;
`quinolyl; benzoxazolyl; benzthiazolyl; fury!; pyrimi-
`dinyl; thiazolyl; 2,1,3-benzoxadiazol-4-yl; 2,1,3-benz-
`thiadiazol-4-yl; and thienyl optionally monosubstituted
`by halo or C1-C4 alkyl.
`"Halo" means fluoro, chloro, bromo or iodo.
`C3 and C4 alkyl and alkoxy groups can be straight or
`branched chain.
`R3 is preferably H, CH3, benzyl, 2-methoxyethyl,
`-CHzCOOCH3, -CHzCOOCzHs, -CHzCONHz,
`-CHzCONHCH3, or -CHzCOOH.
`R3 is most preferably H or CH3.
`R is preferably 2-chlorophenyl, 2-fluorophenyl, 2-
`methoxyphenyl, 3-chlorophenyl, 2-chloro-3-hydrox-
`35 yphenyl, 2-chloro-6-fluorophenyl, unsubstituted phenyl
`or 2,3-dichlorophenyl.
`Rl is preferably CH3.
`R2 is preferably CzHs.
`(I) 40 Y is preferably -(CHz)2- or -CHzCH(CH3)-.
`"m" is preferably 1.
`Most preferably, R is 2-chlorophenyl.
`Most preferably, Y is -(CHz)2.
`The most preferred compounds have the formula (I)
`45 wherein R is 2-chlorophenyl, Ri is CH3, R2is CzHs, R3
`is H or CH3, and Y is -(CHz)2-.
`The compounds of the formula (I) are primary or
`secondary amines and in one method they can be pre-
`pared by the removal of the amino-protecting group
`50 from the corresponding amino-protected dihydropyri-
`dines.
`This general method can be illustrated in more detail
`as follows:
`
`wherein
`Y is -(CHz)2-, -(CH2)3-, -CHzCH(CH3)- or
`-CHzC(CH3)2-;
`R is aryl or heteroaryl;
`Ri and R2 are each independently C1-C4 alkyl or 2-
`methoxyethyl; and
`R3 is hydrogen, C1-C4 alkyl, 2-(C1-C4 alkoxy)ethyl,
`-(CHz)mCOR4
`cyclopropylmethyl, benzyl, or
`where m is 1, 2 or 3 and R4 is hydroxy, C1-C4 alkoxy
`or -NR5R6where R5 and R6are each independently 55
`hydrogen or C1-C4 alkyl;
`and their pharmaceutically acceptable acid addition
`salts.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`The compounds of the formula (I) containing one or
`more asymmetric centres will exist as one or more pairs
`of enantiomers, and such pairs or individual isomers
`may be separable by physical methods, e.g. by fractional
`crystallisation of the free bases or suitable salts or chro-
`matography of the free bases. The invention includes
`the separated pairs as well as mixtures thereof, as race-
`
`,1 ,l
`
`> Compound (I).
`
`Removal of
`R
`H
`R1ooc.__;,:><ycooR2 protecting
`group
`CHz-O-Y-NR3
`I Q
`
`60
`
`CH3
`
`N
`H
`(II)
`
`(Q=an amino-protecting group and R, Ri, R2, R3and Y
`65 are as defined for formula [I]);
`
`OR
`
`DRL Ex. 1011, p. 002
`
`

`

`4,572,909
`
`3
`-continued
`
`Removal of
`
`CH3
`
`Compound (I)
`(R3 = H].
`
`4
`In a typical procedure, the ketoester (IV) and alde-
`hyde are heated under reflux in a suitable organic sol-
`protecting >
`R
`H
`gro::
`,t ~
`vent, e.g. a C1-C4 alkanol solvent such as ethanol, for
`R'ooc~cooR2 0
`~
`5 about 15 minutes, and then the aminocrotonate (III) is
`CH:rO-Y-N ~
`added. Alternatively the aminocrotonate (III), keto-
`N
`ester (IV) and aldehyde can be heated together in the
`H ~
`solvent. Preferably a small amount of a lower alkanoic
`I!
`10 acid such as acetic acid is added to neutralise the solu-
`0
`tion. The resulting solution can then be heated at
`60°-130° C., preferably under reflux, until the reaction
`is essentially complete, typically in 24 hours or less. The
`product of the formula (II) can then be isolated and
`purified by conventional procedures.
`The ketoesters (IV) are either known compounds or
`can be prepared by methods analogous to those of the
`prior art, such as the method illustrated in the Prepara-
`tions hereinafter, which are essentially the method of
`Troostwijk and Kellogg, J.C.S. Chern. Cornrn., 1977,
`page 932. Similarly the amino-crotonates (III) are either
`known compounds or can be prepared by conventional
`procedures. Also the aldehydes are either known or can
`be prepared by known methods.
`(b) The benzyl-containing intermediates (II) can also
`be prepared by the following process:
`f
`1
`00C)-:::::'CH +
`
`COOR2
`
`CH/
`II
`C
`'\.
`CH:rO-Y-NR3
`I
`CHzPH
`
`~Compound
`(II)
`
`15
`
`[R, Rl, R2 andY are as defined for formula (1)].
`One preferred amino-protecting group is benzyl. It is
`typically removed by hydrogenation, using e.g. Hz/Pd
`on charcoal under acidic conditions in a suitable organic
`solvent, e.g. methanol. The acidic conditions are prefer-
`ably obtained by using compound (II) in the form of an 20
`organic acid addition salt, e.g. as an oxalate or acetate
`salt.
`A typical procedure involving the removal of a ben-
`zyl group is as follows. Compound (II) as an oxalate salt 25
`in methanol is added to a suspension of 10% pre-
`hydrogenated palladium on charcoal in methanol, and
`the mixture is then stirred under hydrogen at 50 p.s.i.
`for up to about 18 hours, e.g. overnight, and at room 30
`temperature. If necessary, heating at up to about 60° C.
`can be provided. The product can then be isolated and
`purified by conventional procedures.
`When both Q and R3 are benzyl, hydrogenation 35
`under the above conditions normally only removes one
`···of the benzyl groups. Further hydrogenation of the
`resulting monobenzyl product under the above condi-
`. tions with fresh catalyst can then be used to remove the
`.remaining benzyl group.
`Many of the starting materials of the formula (II) in
`which Q is benzyl are described and claimed in our
`European patent application publication No. 0060674.
`Typical methods to the N-benzyl starting materials of 45
`the formula (II) are as follows:
`(a) The benzyl-protected intermediates (II) can be
`prepared by the Hantzsch synthesis, as follows:
`
`R
`
`CH3
`
`.:::::,0
`
`(V)
`
`/
`NH2
`(VI)
`
`40
`
`The crotonate (VI) is typically prepared in situ by
`reaction of the corresponding acetoacetate (IV):
`
`(IV)
`
`R 1ooc
`H
`'\./
`C
`II
`H3C.......--.....NH2
`
`+ RCHO +
`
`(III)
`
`COOR2
`
`/
`CH2
`
`I c
`~"
`CH2-0-Y-NR3
`0
`I
`CH2Ph
`
`(IV)
`
`H
`R
`R'OOCDCOOR'
`
`H3C
`
`N
`
`H
`
`CH2-0-Y-N-R3
`
`bHzPh
`
`50
`
`with ammonium acetate, e.g. by refluxing in a suitable
`organic solvent, e.g. a C1-C4 alkanol such as ethanol,
`for, say, up to an hour. The crotonate (VI) is then re-
`55 acted with compound (V), typically by heating in the
`solvent for up to about 5 hours at 60° C.-130° C., e.g.
`under reflux. The product (II) can then be isolated and
`purified by conventional procedures.
`The starting materials (V) are either known com-
`pounds or may be prepared by methods analogous to
`those of the prior art, see e.g. Can. J. Chern., 1967, 45,
`1001.
`The .compounds of the formula (I) in which R3 isH
`can be prepared from the corresponding phthalimido
`derivatives according to conventional procedures, e.g.:
`
`60
`
`65
`
`DRL Ex. 1011, p. 003
`
`

`

`5
`
`4,572,909
`
`6
`
`o
`~
`
`(a) a primary amine
`~ or (b) hydrazme hydrate
`
`· > ...._CH OYNH
`2
`2
`
`cH3
`
`protected starting materials necessary for this process
`can be prepared as follows:
`
`R
`H
`RtoocxJccooR2
`I
`I
`cH2-o-Y-N ~ or (c) an alkali metal hydroxide
`N
`H ~ followed by HCI or H2S04.
`I!
`0
`The prefered primary amine is methylamine. The
`preferred alkali metal hydroxide is potassium hydrox-
`ide.
`The reaction using methylamine is typically carried
`out in ethanol at room temperature, with heating if
`necessary. The reaction using hydrazine hydrate is typi- 15
`cally carried out in ethanol at the reflux temperature or
`below. The reaction using potassium hydroxide is typi-
`cally carried out at room temperature (although with
`heating if necessary) in tetrahydrofuran, following by
`the addition of the acid and heating at the reflux temper- 20
`ature or below. In all cases the product can be isolated
`conventionally.
`The phthalimido starting materials can again be ob-
`tained conventionally, e.g.:
`
`0
`
`~ ~
`
`~ NaH
`
`25
`
`(a)
`
`30
`
`II ex: N-Y-OH + ClCH,COCH,COOR'
`ex: N-Y-0-CH,COCH,COOR'.
`l /, ~
`
`or
`
`reduction>
`
`0
`II
`
`II
`0
`
`(b) 40
`
`0
`~
`
`Typically the reaction with 2,2,2-trichloroethyl chlo-
`roformate is carried by heating the reactants at up to
`reflux temperature in e.g. toluene. Many of the dialkyl-
`35 amino and N-alkyl-N-benzylamino starting materials
`needed to prepared these N-protected intermediates are
`described and claimed in our corresponding European
`patent application publication No. 0060674, and others
`can be prepared analogously.
`The compounds of the formula (I) where R3=H can
`COOR2
`also be obtained from the corresponding azido com-
`I
`pounds, the azido group being convertable to -NHz by
`CH2
`+ RCHO +
`I
`reduction, e.g. with triphenylphosphine, or zinc and
`hydrochloric acid, or Hz/Pd, under conventional con-
`0 CHzO-Y-N~ 45 ditions.
`I! 0
`
`55
`
`This is again the Hantzsch reaction.
`Compounds of the formula (I) in which R 3 is H can
`also be purified to very high levels by reacting them 60
`with phthalic anhydride to form the phthalimido deriv-
`atives which can then be converted back to the com-
`pounds in which R3 is H by the methods previously
`described.
`To prepare compounds in which R3 is C1-C4 alkyl, 65
`-COOCHzCCl3 can be used as the amino-protecting
`group. This can be removed in a conventional manner
`using zinc and either formic or acetic acid. The N-
`
`In a typical procedure using zinc dust, the reaction is
`carried out in methanol/aqueous hydrochloric acid.
`Heating is possible but is not generally necessary. Simi-
`larly hydrogenation can be carried out in e.g. methanol
`or ethanol in the presence of a catalyst such as
`Pd/CaC03 at room temperature.
`Again the azido starting materials can be prepared by
`the Hantzsch synthesis under conditions similar to those
`previously described:
`
`DRL Ex. 1011, p. 004
`
`

`

`7
`
`+ RCHO +
`
`H
`
`R
`
`R'OOCDCOOR'
`
`H3C
`
`N
`H
`
`CHz-0-Y-NJ
`
`The azide-containing acetoacetates can also be ob-
`tained by conventional procedures:
`
`4,572,909
`8
`test present in the saline solution. The concentration of
`compound required to reduce the response by 50% is
`recorded.
`The antihypertensive activity of the compounds is
`5 also evaluated after oral administration by measuring
`the fall in blood pressure in spontaneously hypertensive
`rats or renally hypertensive dogs.
`For administration to man in the curative or prophy-
`10 lactic treatment of cardiac conditions and hypertension,
`oral dosages of the compounds will be in the range of
`from 2-50 mg daily for an average adult patient (70 kg).
`Thus for a typical adult patient, individual tablets or
`capsules are likely to contain from 1 to 10 mg of active
`15 compound, in a suitable pharmaceutically acceptable
`vehicle or carrier. Dosages for intravenous administra-
`tion would be within the range 1 to 10 mg per single
`dose as required.
`In a further aspect the invention provides a pharma-
`20 ceutical composition comprising a compound of the
`formula (I), or a pharmaceutically acceptable acid addi-
`tion salt thereof, together with a pharmaceutically ac-
`ceptable diluent or carrier.
`The invention also provides a compound of the for-
`25 mula (I), or a pharmaceutically acceptable acid addition
`salt thereof, for use in treating ischaemic heart disease,
`especially angina, or hypertension, in a human being.
`The following Examples illustrate the invention: all
`temperatures are in ·c.:
`EXAMPLE 1
`Preparation of
`4-(2-chlorophenyl)-2-[2-(methylamino)ethoxymethyl]-
`3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1 ,4-
`dihydropyridine, oxalate salt
`
`Similarly the azido starting materials can also be pre-
`pared analogously to route (b) above for preparing the
`N-benzyl starting materials.
`Some of the compounds of the invention can be pre-
`pared from other compounds of the invention by con-
`ventional techniques, e.g.:
`
`30
`
`35
`
`Hal.(CHz)mCOO(CI-C4 alkyl),
`Base.
`(Hal = Cl or Br)
`
`Hydrolysis ;e.g. NaOH)
`
`\
`
`R5R6NH
`
`-......NH(CHz)mCOOH
`
`--NH(CHz)mCONR5R6.
`
`Cl
`
`N
`H
`
`40
`
`50
`
`Cl
`
`N
`H
`
`COOCHzCH3
`
`CHzOCHzCHzNHCH3
`
`The ability of the comoounds to inhibit the move-
`ment of calcium into the cell is shown by their effective- 55
`ness in reducing the response of isolated heart tissue to
`an increase in calcium ion concentration in vitro. The
`test is performed by mounting spirally cut strips of rat
`aorta with one end fixed and the other attached to a
`force transducer. The tissue is immersed in a bath of 60
`physiological saline solution containing potassium ions
`at a concentration of 45 millimolar and no calcium.
`Calcium chloride is added to the bath with a pipette to
`give a final calcium ion concentration of 2 millimolar.
`The change in tension caused by the resulting contrac- 65
`tion of the tissue is noted. The bath is drained and re-
`placed with fresh saline solution and, after 45 minutes,
`the test is repeated with the particular compound under
`
`A solution of 2-[2-(N-benzyl-N-methylamino)ethox-
`ymethyl]-4-[2-chlorophenyl]-3-ethoxycarbonyl-5-
`methoxycarbonyl-6-methyl-1 ,4-dihydropyridine, oxa-
`late salt (4.3 g) in methanol (220 ml) was added to a
`suspension of 10% (by weight) palladium on charcoal
`(0.4 g) pre-hydrogenated in methanol (50 ml). Stirring
`under hydrogen at 50 p.s.i. and room temperature over-
`night resulted in complete removal of the benzyl group.
`After removal of the catalyst by filtration, the methanol
`was removed by evaporation and the residue crystal-
`
`DRL Ex. 1011, p. 005
`
`

`

`4,572,909
`10
`9
`Iised from a little methanol to give the title compound
`ised in the form indicated, starting from the appropriate
`(2.4 g), m.p. 211•.
`N-substituted dihydropyridine oxalate and H2/Pd. It
`Analysis%: Calculated for C21H27ClN205.C2H204:
`should be noted that hydrogenation of the N,N-diben-
`C, 53.85; H, 5.70; N, 5.46; Found: C, 53.99; H, 5.76; N,
`zyl starting material in Example 8 produced the mono-
`5.60.
`S benzyl product which was in turn used as the starting
`The free base had a m.p. of 88•-90• (from ether).
`material in Example 9.
`EXAMPLES 2-10
`The following compounds were prepared similarly to
`the method described in Example 1 and were character-
`
`Example
`No.
`2
`
`R
`-Ph
`
`QF
`QOCH;
`Qa
`NOH
`YCJ
`
`4
`
`6
`
`7
`
`9
`
`10
`
`Form
`Characterised
`free base
`
`m.p.
`('C.)
`79-80
`
`oxalate
`
`205-7
`
`Analysis % (Thea·
`retical in brackets)
`C
`H
`N
`65.14
`7.33
`7.09
`(64.93
`7.26
`7.21)
`55.35
`5.84
`5.60
`(55.64
`5.84 5.64)
`
`free base
`
`103-5
`
`63.87
`(63.14
`
`7.60
`7.23
`
`6.56
`6.70)
`
`oxalate
`
`204-5
`
`54.14
`(53.85
`
`5.71
`5.70
`
`5.57
`5.46)
`
`oxalate
`
`203-4
`
`52.14
`(52.22
`
`5.68
`5.49
`
`5.29
`5.30)
`
`oxalate
`
`197-9
`
`52.03
`(52.03
`
`5.06
`5.41
`5.30 5.30)
`
`oxalate
`
`185
`
`59.18
`(59.13
`
`5.75
`5.65
`
`4.86
`4.76)
`
`-H
`
`maleate
`
`169
`
`54.83
`(54.91
`
`5.55
`5.57
`
`5.34
`5.34)
`
`oxalate
`
`105-7
`
`53.57
`(53.91
`
`6.10
`5.97
`
`4.91
`5.03)
`
`DRL Ex. 1011, p. 006
`
`

`

`11
`EXAMPLE 11
`
`4,572,909
`
`12
`EXAMPLE 12
`Preparation of
`2-[2-aminoethoxy)methyl)-4-(2-chlorophenyl)-3-ethox-
`ycarbonyl-5-methoxycarbonyl-6-methyl-1 ,4-dihy-
`dropyridine maleate
`
`Preparation of
`2-[ (2-aminoethoxy )methyl]-4-(2-chlorophenyl)-3-ethox-
`ycarbony 1-5-methoxycarbonyl-6-meth y 1-1 ,4-dihy-
`dropyridine maleate
`
`Zn/acid ::>
`
`5
`
`10
`
`15
`
`20
`
`25
`
`2-Azidoethanol (3 g) was converted to ethyl 4-(2-
`azidoethoxy)acetoacetate similarly to the method de- 35
`scribed in Preparation 3 hereinafter using ethyl 4-
`chloroacetoacetate, and the crude ketoester (not cha-
`racterised) was used in the Hantzsch reaction using the
`method described in Preparation 9, i.e. by reacting it 40
`with methyl 3-aminocrotonate and 2-chlorobenzalde-
`hyde. The crude Hantzsch product (not characterised)
`dissolved in methanol (250 ml) and 3N hydrochloric
`acid (200 ml) was stirred on a water bath at room tern- 45
`perature while zinc dust (15 g) was added portionwise
`over 10 minutes. After stirring a further 10 minutes the
`solution was decanted from excess zinc, the methanol
`evaporated and the aqueous acid residue washed with 50
`toluene (100 ml), basified with concentrated ammonia
`and extracted with methylene chloride (2 X 100 ml).
`The extracts were dried (NazC03), filtered and evapo-
`rated to dryness. The residue in toluene was chromato- 55
`graphed on a medium pressure column of silica (T.L.C.
`grade, Merck "Kieselgel" [Trade Mark] 60H, 7 g) elut-
`ing initially with toluene, changing gradually to methy-
`lene chloride and then to methylene chloride plus 3% 60
`methanol. Appropriate fractions were combined and
`converted to the maleate salt in ethyl acetate. Recrystal-
`lisation from acetone and ethyl acetate (1:1) gave the
`title compound (maleate salt) (190 mg, 1% yield from 65
`2-azido ethanol) as a white solid, m.p. 1690, identical by
`t.l.c. with the product obtained in Example 9.
`
`suspension of 2-(2-azidoethoxy)methyl-4-(2-
`A
`chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-
`methyl-1,4-dihydropyridine (103 g) in ethanol (2.5 1)
`was stirred for 16 hours at room temperature under an
`atmosphere of hydrogen in the presence of 5% palla-
`dium on calcium carbonate (40 g). The reaction mixture
`was filtered and evaporated and the residue treated with
`a solution of maleic acid (22 g) in ethanol (100 ml). The
`reaction mixture was stirred at room temperature for
`two hours and then the resulting solid collected,
`washed with ethanol, and dried to give the title com-
`pound (100 g), m.p. 169"-170.5".
`Analysis %: Found: C,54.82; H,5.62; N,5.46
`CzoHz5ClNz05.C4H404
`requires: C,54.91; H,5.57;
`N,5.34.
`
`EXAMPLES 13-15
`The following compounds were prepared similarly to
`Example 12 from the appropriate azide and Hz/Pd:
`
`Example
`No.
`13
`
`R
`
`Form
`characterised
`! fumarate
`! hydrate
`
`m.p.
`('C)
`171-
`173
`
`Analysis % (Theo-
`retical in brackets 2
`c
`N
`H
`51.7
`5.3
`5.5
`(51.8
`5.3
`5.5)
`
`14
`
`fumarate
`! hydrate
`
`158-
`168
`
`57.6
`(57.7
`
`6.2
`6.3
`
`5.8
`5.6)
`
`DRL Ex. 1011, p. 007
`
`

`

`13
`-continued
`
`4,572,909
`
`14
`
`5
`
`10
`
`Form
`characterised
`fumarate
`
`m.p.
`('C,)
`152
`
`Analysis% (Theo-
`retical in brackets)
`H N
`c
`56.95
`6.02
`5.93
`(56.68
`5.75
`5.5)
`
`Example
`No.
`15
`
`R
`
`II)F
`l
`
`- - - - - - - - - - - - - - - - - - - - - 15
`
`EXAMPLE 16
`Methyl
`N-(2-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-
`methoxycarbonyl-6-methyl-1 ,4-dihydropyrid-2-y l)me-
`thoxy }ethyl)aminoacetate
`
`Cl
`
`CJ
`
`COOC2Hs
`
`BrCH2COOCH3, >
`K2C03
`CH20CH2CH2NH2
`
`Cl
`
`Cl
`
`20
`
`25
`
`30
`
`35
`
`0 -..../'N/R3
`H
`
`Example
`No.
`17
`18
`
`m.p.
`('C.)
`-cH2C02CH2CH3 78-80
`-CH2C02CH3
`oil
`
`Analysis % or n.m.r.
`(Theoretical in brackets)
`C
`H
`N
`58.26
`6.30
`5.65
`(58.24
`6.31
`5.66)
`n.m.r. (CDCI3).T values:
`7.72 (IH, broads);
`6.96-7.51 (4H, m);
`5.43 (lH, s);
`4.78 (2H, s);
`4.10 (2H, q);
`3.78 (3H, s);
`3.63 (3H, s);
`3.3-3.7 (6H, m);
`2.38 (3H, s);
`1.20 (3H, t);
`
`EXAMPLE 19
`2-(2-{[ 4-(2-Chlorophenyl)-3-ethoxycarbonyl-5-methox-
`ycarbonyl-6-methy 1-1 ,4-dihydropyrid-2-yl]methoxy }e-
`thylamino )acetamide
`
`COOC2Hs
`
`40 CH300C
`
`Cl
`
`COOC2Hs
`
`CH20CH2CH2NHCH2COOCH3
`
`45
`
`CH20CH2CH2NHCH2COOC2Hs
`
`N
`H
`
`A solution of methyl bromoacetate (1.53 g) in aceto-
`nitrile (20 ml) was added dropwise over 30 minutes to a
`stirred, refluxing mixture of 2-[(2-aminoethoxy)methyl]-
`4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methox-
`ycarbonyl-6-methyl-1,4-dihydropyridine (5.01 g) and 50
`potassium carbonate (2.76 g) in acetonitrile (60 ml). The
`mixture was then heated under reflux for 3 hours, fil-
`tered, and evaporated. The residue was partitioned
`between ethyl acetate and water and the organic layer 55
`washed with water, dried (Na2S04), and evaporated.
`The residue was chromatographed on silica (t.l.c. grade
`Merck Kieselgel 60H, [Trade Mark] 40 g) eluting with
`dichloromethane plus 0-3% methanol. Appropriate
`fractions were combined and evaporated to give the 60
`title compound (2.10 g), m.p. 96°-98°.
`Analysis %: Found: C,53.25; H,5.49; N,5.48;
`C23H28CbN207 requires: C,53.60; H,5.48; N,5.44.
`EXAMPLES 17 AND 18
`The following compounds were prepared by the
`method described in Example 16 using appropriate
`starting materials.
`
`CJ
`
`COOC2Hs
`
`CH20CH2CH2NHCH2CONH2
`
`Ethyl N -(2-{[ 4-(2-chlorophenyl)-3-ethoxycarbonyl-
`5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-
`yl]methoxy }ethyl)aminoacetate (2.50 g) in a mixture of
`ethanol (40 ml) and 0.880 aqueous ammonia (30 ml) was
`stirred at room temperature for four days and then
`evaporated. The residue was partitioned between ethyl
`acetate and water and the organic layer washed with
`water, dried (MgS04), and evaporated. The residue was
`65 chromatographed on silica (t.l.c. grade Merck Kieselgel
`60H, [Trade Mark] 30 g) eluting with dichloromethane
`plus 0-5% methanol. Appropriate fractions were com-
`bined and evaporated. The residue was triturated with
`
`DRL Ex. 1011, p. 008
`
`

`

`4,572,909
`15
`16
`pound as a hemihydrate (0.56 g), m.p. 140°-150° (de-
`ethyl acetate and the resulting solid collected, washed
`comp.).
`with ethyl acetate, and dried to give the title compound
`Analysis %: Found: C,55.52; H,5.95; N,5.92;
`(1.23 g), m.p. 126°-129°.
`C22H27ClN207.!H20 requires: C, 55.52; H, 5.93; N,
`Analysis %: Found: C,56.78; H,6.06; N,8.68;
`5 5.89.
`C22H28ClN306 requires: C,56.71; H,6.06; N,9.02.
`EXAMPLE20
`The following compound was prepared by the
`method described in Example 19 using the same dihy-
`dropyridine and methylamine.
`
`EXAMPLE 22
`Preparation of
`2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethox-
`ycarbony 1-5-methoxycarbonyl-6-methyl-1 ,4-dihy-
`dropyridine maleate
`
`10
`
`Ethanolic methylamine, >
`
`or hydrazine hydrate,
`or KOH followed by HCI.
`
`Cl
`
`Cl
`
`COzCHzCH3
`
`/
`HC
`II
`CHzOCHzCHzNHz.HC
`
`COOH
`
`" COOH
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`Example
`No.
`20
`
`R3
`-CH2CONHCH3
`
`m.p.
`('C)
`123-
`124
`
`Analysis % or n.m.r.
`(Theoretical in brackets)
`c
`H
`N
`57.80
`6.55
`8.73
`(57.56
`8.76)
`6.30
`
`EXAMPLE 21
`N-(2-{[4-(2-Chlorophenyl)-3-ethoxycarbonyl-5-
`methoxycarbonyl-6-methy 1-1 ,4-dihydropyrid -2-y l]me-
`thoxy }ethyl)aminoacetic acid hemihydrate
`
`Cl
`
`ag. NaOH >
`
`CH3
`
`N
`H
`
`CHzOCHzCHzNHCHzCOOH
`
`Cl
`
`Method A (using ethanolic methylamine)
`4-(2-Chlorophenyl)-3-ethoxycarbonyl-5-methoxycar-
`bony 1-6-methyl-2-(2-phthalimidoethoxy )methy 1-1,4-
`dihydropyridine (80 g) was stirred in 33% ethanolic
`methylamine solution (1067 ml) at room temperature
`for three hours. The solvent was then evaporated and
`45 the residue was slurried in industrial methylated spirits
`(300 ml) then filtered. To the filtrate was added maleic
`acid (17.4 g) and after stirring a precipitate was pro-
`duced. This was collected by filtration and was washed
`with industrial methylated spirits. The solid was crystal-
`50 lized from industrial methylated spirits (430 ml) and
`dried at 55° to give the title compound (38.4 g) as a
`white solid confirmed spectroscopically to be identical
`with the products of Examples 9 and 12.
`Method B (using hydrazine hydrate)
`4-(2-Ch1orophenyl)-3-ethoxycarbonyl-5-methoxycar-
`bonyl-6-methyl-2-(2-phthalimidoethoxy )methyl-I ,4-
`dihydropyridine (383 g) was stirred in refluxing ethanol
`containing hydrazine hydrate (106.7 g). After two
`hours, the reaction mixture was cooled and filtered. The
`filtrate was evaporated and the residue was dissolved in
`methylene chloride (2000 ml) and the solution was
`washed with water (2000 ml). The organic solution was
`evaporated and the residual oil was dissolved in indus-
`trial methylated spirit (1120 ml). To this solution was
`added maleic acid (82.5 g) and the resulting precipitate
`was collected, washed with industrial methylated spirit
`and dried at 55° to give the title compound (304 g) as a
`
`N
`H
`
`CH20CH2CH2NHCHzCOOH 55
`
`A solution of methyl N-(2-{[4-(2-chlorophenyl)-3-
`ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihy-
`dropyrid-2-yl]methoxy }ethyl)aminoacetate (2.40 g) in 60
`dioxane (80 ml) was treated with 1M aqueous sodium
`hydroxide solution (10 ml) and the mixture stirred at
`room temperature for 2 hours and then evaporated. The
`residue was purified by ion exchange chromatography
`(Bio-Rad AG 50W-X8, [Trade Mark], 200-400 mesh, 65
`cation form, 40 g) eluting with dioxane initially fol-
`lowed by 2% pyridine in water. Appropriate fractions
`were combined and evaporated to give the title com-
`
`DRL Ex. 1011, p. 009
`
`

`

`A mixture of 2-[2-(N-benzyl-N-methylamino)ethox-
`ymethyl]-4-[2-chlorophenyl]-3-ethoxycarbonyl-5-
`methoxycarbonyl-6-methyl-I,4-dihydropyridine (4.8 g)
`and 2,2,2-trichloroethyl chloroformate (2. 7 g)_ was
`heated in toluene at reflux for 20 hours. After cooling to
`room temperature, the mixture was stirred with IN
`hydrochloric acid (50 ml) and extracted with ether. The
`extracts were evaporated to leave a crude oil (6.9 g)
`containing the corresponding 2-[2-(N-2,2,2-trichloroe-
`
`20
`
`18
`
`4,572,909
`17
`white solid, again confirmed spectroscopically to be the
`desired product.
`Method C (using KOH followed by HCI).
`4-(2-Chlorophenyl)-3-ethoxycarbonyl-5-methoxycar- 5
`bony 1-6-methyl-2-(2-phthalimidoethoxy )methy 1-I ,4-
`dihydropyridine (I5 g) was dissolved in a mixture of
`tetrahydrofuran (I 50 ml) and water (IOO ml) containing
`potassium hydroxide (3.I3 g). After stirring at room
`temperature for 1.5 hours 2N hydrochloric acid (IOO 10
`ml) was added and the resulting slurry was refluxed for
`2.5 hours. The solution was extracted twice with meth-
`ylene chloride (2X IOO ml) and the combined extrac~s
`were dried (MgS04) and evaporated to leave an ml
`which was dissolved in industrial methylated spirits (57 15
`ml). Maleic acid (3.24 g) was added and the resulting
`precipitate was collected, washed with i~dustrial meth-
`ylated spirits and dried at 55° to give the title compound
`(10.2 g) as an off-white solid, again confirmed spectro-
`scopically to be the desired product.
`EXAMPLES 22a-f
`The following compounds were prepared similarly to the procedure of Example 22 Method A from
`the corresponding phthalimido derivative but using aqueous (40%) methylamine instead of
`ethanolic methylamine:
`R
`
`R'OOCDCOOR'
`
`CH3
`
`N
`H
`
`CHzOCHzCHzNHz
`
`Example
`(a)
`
`(b)
`
`(c)
`
`(d)
`
`(e)
`
`(f)
`
`R
`2,3-dichlorophenyl
`2,3-dichlorophenyl *
`
`2-chloro-3-trifluoro-
`methylphenyl
`2,3-dichlorophenyl
`
`Rl
`
`CzHs
`
`CzHs
`
`CH3
`
`R2 m.p. ('C)
`131-2°
`CH3
`
`CzHs
`
`127-9°
`
`CzHs
`
`122°
`
`(CH3)zCH
`
`CzHs
`
`105-9°
`
`2,3-dichlorophenyl
`
`CH30CH2CH2-
`
`CzHs
`
`88-90°
`
`2-chloro-pyrid-3-yl-
`
`CH3
`
`CzHs
`
`129-131°
`
`Analysis%
`{Theoretical in brackets)
`c
`N
`H
`6.4
`5.5
`53.9
`(54.2
`5.5
`6.3)
`5.1
`52.8
`5.5
`(52.7
`5.6
`5.3)
`4.9
`5.75
`53.25
`(52.9
`5.9)
`5.1
`5.2
`51.8
`5.8
`(51.8
`6.0
`5.1)
`54.5
`5.8
`6.0
`(54.2
`5.75)
`5.8
`55.6
`10.6
`5.9
`(55.7
`10.25)
`5.9
`
`"' Isolated as the hemifumarate hemihydrate
`Isolated as the hemifumarate sesquihydrate
`
`EXAMPLE 23
`Preparation of
`4-(2-Chlorophenyl)-2-[2-(N -methylamino )ethoxyme-
`thyl]-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-
`I,4-dihydropyridine maleate
`
`C1
`
`N
`H
`
`(ii) Zn/HCOOH > 65
`
`(i) C13CCHzOzC.CI
`
`CH20CHzCHzN-CH3
`I
`CH2Ph
`
`thoxycarbonyl-N-methylamino)ethoxymethyl]deriva-
`tive.
`The said oil (3.0 g) was dissolved in dimethylformam-
`55 ide (10.5 ml) and formic acid (0.5 g) and at 5o zinc (0.7
`g) was added.
`The mixture was allowed to warm to room tempera-
`ture and kept for three days at this temperature. The
`reaction mixture was then decanted and poured into
`60 water (100 ml) and acidified to pHI with concentrated
`hydrochloric acid. The aqueous solution was washed
`with n-hexane (50 ml) then 0.88 ammonia solution was
`added to give a precipitate. This was collected and
`dried before dissolving in ethyl acetate. Maleic acid
`(0.34 g) was added followed by ether. After trituration,
`the solid was collected and dried to give a solid con-
`firmed by NMR and IR to be (apart from the salt form)
`identical to the product of Example 1.
`
`DRL Ex. 1011, p. 010
`
`

`

`19
`EXAMPLE 24
`Preparation of
`4-(2-chlorophenyl)-2-[2-(N -methylamino )ethoxyme-
`thyl]-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-
`1 ,4-dihydropyridine maleate
`
`4,572,909
`
`20
`EXAMPLE 25
`Preparation of
`2-(2-aminoprop-1-oxymethy 1)-4-(2-chlorophenyl)-3-
`5 ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1 ,4-dihy-
`dropyridine hemifumarate hemihydrate
`
`10
`
`+
`
`(I) CI3CCHzOzC.CI
`
`(2) Zn/HCOOH >
`
`15
`
`N
`H
`
`20
`
`25
`
`30
`
`45
`
`4-[2-chlorophenyl]-2-[2-(N,N-dimethylamino)ethox-
`ymethyl]-3-ethoxycarbonyl-5-methoxycarbonyl-6-
`methyl-1,4-dihydropyridine (147.6 g) and 2,2,2-tri- 35
`" chloroethylchloroformate (98. 7 g) were stirred together
`· in refluxing toluene for 20 ho