`
`[19]
`
`[11] Patent Number:
`
`4,572,909
`
`Campbell et 31.
`
`[45] Date of Patent:
`
`Feb. 25, 1986
`
`[54]
`
`2-(SECONDARY AMINOALKOXYMETHYL)
`DIHYDROPYRIDINE DERIVATIVES AS
`ANTI-ISCHAEMIC AND
`ANTIHYPERTENSIVE AGENTS
`
`[75]
`
`Inventors:
`
`Simon F. Campbell, Deal; Peter E.
`Cross, Canterbury; John K. Stubbs,
`Deal, all of England
`
`[73] Assignee:
`
`Pfizer Inc., New York, NY.
`
`[21] Appl. No.: 576,982
`[22] Filed:
`Feb. 3, 1984
`
`Related US. Application Data
`Continuation-impart of Ser. No. 463,081, Feb. 2, 1983,
`abandoned.
`
`[63]
`
`Foreign Application Priority Data
`[30]
`Mar. 11, 1982 [GB] United Kingdom ................. 8207180
`
`[51]
`Int. Cl.4 .................. C07D 211/90; A61K 31/455
`[52] US. Cl. ...................... 514/356; 546/321
`
`[58] Field of Searc
`................ 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
`
`................... 546/321
`2/1984 Campbe11 et a1.
`4,430,333
`FOREIGN PATENT DOCUMENTS
`
`318101
`
`7/1981 European Pat. Off.
`OTHER PUBLICATIONS
`
`546/321
`
`Schramm, M., “Novel Dihydropyridines with Positive
`lnotropic Action”, Nature, vol. 303 (Jun. 9, 1983) pp.
`535—537.
`
`Bossert, F. et a1, “4—Ary1dihydropyridines”, Angew.
`Chem. Int. Ed. Eng]. 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
`
`ABSTRACT
`[57]
`A dihydropyridine compound of the formula
`
`H
`
`R
`
`aloocfjcmxl
`N
`IH
`
`CH3
`
`CHz-O—Y—NHR3
`
`-—CH2CH(CH3)~— or
`
`or a pharmaceutically acceptable acid addition salt
`thereof,
`wherein
`Y is -——(CH2)2—, —(CH2)3—,
`—-CH2C(CH3)2—;
`R is aryl or heteroaryl;
`R1 and R2 are each independently C1-C4 alkyl or 2—
`methoxyethyl; and
`R3 is hydrogen, C1—C4 alkyl, 2-(C1—C4 alkoxy)ethy1,
`cyclopropylmethy],
`benzyl,
`or —-(CH2),,,COR4
`where m is 1, 2 or 3 and
`R4 is hydroxy, C1—C4 alkoxy or ——NR5R‘3 where 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
`
`SUN - |PR2020-01072, Ex. 1011, p. 1 of 17
`
`SUN - IPR2020-01072, Ex. 1011, p. 1 of 17
`
`
`
`1
`
`4,572,909
`
`2-(SECONDARY AMINOALKOXYMETHYL)
`DIHYDROPYRIDINE DERIVATIVES AS
`ANTI-ISCHAEMIC AND ANTIHYPERTENSIVE
`AGENTS
`
`This is a continuation-in-part of US. 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
`influx during ischaemia can have a number of additional
`adverse effects which would further compromise the
`ischaemic myocardium. These include less efficient use
`of oxygen for ATP production, activation of mitochon-
`drial fatty acid oxidation and possibly, promotion of cell
`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
`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
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`According to the invention, there are provided novel
`1,4-dihydropyridine derivatives of the formula:
`
`R'OOC
`
`H
`
`R
`
`coon2
`
`(I)
`
`40
`
`45
`
`50
`
`55
`
`CH3
`
`N
`H
`
`CHz—O—Y—NHR3
`
`-—CH2CH(CH3)—- or
`
`wherein
`Y is —(CH2)2—, —(CH2)3—,
`—CH2C(CH3)2—;
`R is aryl or heteroaryl;
`R1 and R2 are each independently C1—C4 alkyl or 2-
`methoxyethyl; and
`R3 is hydrogen, C1—C4 alkyl, 2-(C1—C4 a1koxy)ethyl,
`cyclopropylmethyl,
`benzyl,
`or ——(CHz)mCOR4
`where m is l, 2 or 3 and R4 is hydroxy, C1—C4 alkoxy
`or —NR5R6 where R5 and R6 are each independently
`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-
`
`2
`mic mixtures or as separated d- and l- optically-active
`isomeric forms.
`The pharmaceutically acceptable acid addition salts
`of the compounds of the formula (I) are those formed
`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,
`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,
`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,
`~CH2COOCH3, ~CH2COOCzH5, —CH2CONH2,
`—CH2CONHCH3, or --CH2COOH.
`R3 is most preferably H or CH3.
`2—
`R is preferably 2-chlorophenyl, 2-fluorophenyl,
`methoxyphenyl,
`3-chloropheny1, 2-chloro-3-hydrox-
`yphenyl, 2-chloro-6-fluorophenyl, unsubstituted phenyl
`or 2,3-dichlorophenyl.
`R1 is preferably CH3.
`R2 is preferably C2H5.
`Y is preferably —(CH2)2— or —CH2CH(CH3)—.
`“In” is preferably 1.
`Most preferably, R is 2-chlorophenyl.
`Most preferably, Y is —(CH2)2.
`The most preferred compounds have the formula (I)
`wherein R is 2-chlorophenyl, R1 is CH3, R2 is Csz, R3
`is H or CH3, and Y is ——(CH2)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
`from the corresponding amino-protected dihydropyri-
`dines.
`This general method can be illustrated in more detail
`as follows:
`
`R looc
`
`CH3
`
`H
`
`I
`
`R
`
`I
`
`H
`N
`(11)
`
`coon2
`
`Removal of
`protecting
`Jfla‘é Compound (I),
`cnz—o—Y—tlsipé
`Q
`
`(Q=an amino-protecting group and R, R1, R2, R3 and Y
`are as defined for formula [1]);
`
`65
`
`OR
`
`SUN - |PR2020-01072, Ex. 1011, p. 2 of 17
`
`SUN - IPR2020-01072, Ex. 1011, p. 2 of 17
`
`
`
`R'OOC
`
`CH3
`
`R
`
`l
`
`H
`
`I
`
`N
`H
`
`3
`-continued
`
`C00R2
`
`0
`\\
`
`CHz-O—Y—N
`
`//O
`
`Removal of
`protecting a
`group
`
`4,572,909
`
`5
`
`10
`
`4
`In a typical procedure, the ketoester (IV) and alde-
`hyde are heated under reflux in a suitable organic sol-
`vent, e. g. a Ci-C4 alkanol solvent such as ethanol, for
`about 15 minutes, and then the aminocrotonate (III) is
`added. Alternatively the aminocrotonate (III), keto-
`ester (IV) and aldehyde can be heated together in the
`solvent. Preferably a small amount of a lower alkanoic
`acid such as acetic acid is added to neutralise the solu-
`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. Chem. Comm, 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:
`
`coon2
`
`if
`R‘OOC éCH
`\
`\
`
`CH3
`
`(V)
`
`0
`
`+
`
`CH/
`II
`/c\
`NH;
`
`(VI)
`
`CHrO—Y—IIIR3
`CHZPH
`
`und
`
`C
`9 ompo
`(n)
`
`The crotonate (VI) is typically prepared in situ by
`reaction of the corresponding acetoacetate (IV):
`
`coon2
`
`(1V)
`
`/
`CH2
`Ic
`/ \
`
`o
`
`CH2—0—-Y—II~JR3CH2Ph
`
`Compound (I)
`[R3 = H].
`
`[R, R‘, R2 and Y are as defined for formula (I)].
`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- 20
`ably obtained by using compound (II) in the form of an
`organic acid addition salt, e.g. as an oxalate or acetate
`salt.
`
`15
`
`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 psi.
`for up to about 18 hours, e.g. overnight, and at room
`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
`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:
`
`30
`
`35
`
`40
`
`50
`
`Rlooc
`
`H
`
`\ /
`lcl:
`/\
`
`ch
`
`NH:
`
`(111)
`
`coon2
`
`/
`
`+ RCHO +
`
`(III-12
`C
`/ \
`
`o
`
`(IV)
`
`CHZ—o-Y—Ilsk3CH2Ph
`
`l
`
`H
`
`R
`
`Rlooc
`
`c00122
`
`H3C
`
`N
`H
`
`CHZ—o—Y—Ils—R3
`CH2Ph
`
`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-
`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. Chem, 1967, 45,
`1001.
`
`The compounds of the formula (I) in which R3 is H
`can be prepared from the corresponding phthalimido
`derivatives according to conventional procedures, e.g.:
`
`55
`
`.0
`
`65
`
`SUN - |PR2020-01072, Ex. 1011, p. 3 of 17
`
`SUN - IPR2020-01072, Ex. 1011, p. 3 of 17
`
`
`
`Rlooc
`
`CH3
`
`R
`
`|
`
`H
`
`I
`
`N
`H
`
`5
`
`coon2
`
`CH1—O-Y—N
`
`o
`“
`
`//o
`
`4,572,909
`
`' a
`1a! a primary amine
`or (b) hydrazine hydrate
`(c) an alkali metal hydroxide
`or
`followed by HG] or H1504.
`
`WCHZOYNHZ
`
`The prefered primary amine is methylamine. The
`preferred alkali metal hydroxide is potassium hydrox-
`ide.
`The reaction using methylamine is typically carried
`protected starting materials necessary for this process
`out in ethanol at room temperature, with heating if
`necessary. The reaction using hydrazine hydrate is typi- 15 can be Prepared as follows:
`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-
`ature or below. In all cases the product can be isolated
`conventionally.
`The phthalimido starting materials can again be ob—
`tained conventionally, e.g.:
`
`20
`
`25
`
`mCHz-O—Y—llq—(CVCA alkyl)
`COOCHzCC13
`
`or
`
`Cl.COOCH2CCl3
`
`CLCOOCHzCCl3
`CHz—O—Y—N(C1—C4 alkyl); ————————9
`
`(a)
`
`CHz-‘O—Y—Iii—(CFO; alkyl)
`benzyl
`
`30
`
`35
`
`40
`
`(*0
`
`45
`
`50
`
`55
`
`60
`
`65
`
`”CHz—O—Y—I'J—(Crci; alkyl)
`COOCH2CC13
`
`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-
`arnino 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
`also be obtained from the corresponding azido com-
`pounds, the azido group being convertable to ——-NH2 by
`reduction, e.g. with triphenylphosphine, or zinc and
`hydrochloric acid, or Hz/Pd, under conventional con-
`ditions.
`
`Rlooc
`
`CH3
`
`R
`
`l
`
`H
`
`l
`
`N
`H
`
`coon2
`
`CHz—O—Y—N3
`
`reduction 5
`
`H
`
`R
`
`Rlooc
`
`coon2
`
`CH3
`
`N
`H
`
`CHz-O—Y—NHz
`
`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/CaCO3 at room temperature.
`Again the azido starting materials can be prepared by
`the Hantzsch synthesis under conditions similar to those
`previously described:
`
`N—Y—OH + CICHZCOCHzCOORz
`
`\L NaH
`
`N——Y—O—CH2COCH2COOR2.
`
`0I
`
`I
`
`IIo
`
`0l
`
`l
`
`0
`
`Rlooc
`
`\
`
`CH
`II
`c
`/ \
`CH3
`
`NH2
`
`+ cho +
`
`coon2
`/
`CH2
`l
`c
`// \
`0
`
`CHrO-Y—N
`
`0
`\\
`
`//o
`
`R'OOC
`
`H
`
`|
`
`R
`
`l
`
`CH3
`
`N
`H
`
`COOR2 0
`\‘
`
`CH20YN
`
`//o
`
`This is again the Hantzsch reaction.
`Compounds of the formula (I) in which R3 is H can
`also be purified to very high levels by reacting them
`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,
`—-COOCH2CCI3 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-
`
`SUN - |PR2020-01072, Ex. 1011, p. 4 of 17
`
`SUN - IPR2020-01072, Ex. 1011, p. 4 of 17
`
`
`
`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
`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-
`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
`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-
`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-
`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)ethoxymethy]]-
`3-ethoxycarbon yl—5—methoxycarbonyl-6-methyl- l ,4-
`dihydropyridine, oxalate salt
`
`Cl
`
` CH300C
`
`COOCHQCH3
`
`CH3
`
`N
`H
`
`CH20CH2CH2119CH3
`CHzPh
`
`Hz/Pd
`___>
`
`Cl
`
`H
`
`CH3OOC
`
`COOCHzCH3
`
`CH3
`
`N
`H
`
`CH20CH2CH2NHCH3
`
`A solution of 2-[2-(N-benzyl-N-methylamino)ethox-
`ymethyl]~4-[2-chlorophenyl]-3-ethoxycarbonyl-5-
`oxa-
`methoxycarbonyl-6-methy1-l,4-dihydropyridine,
`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—
`
`7
`
`R‘OOC
`
`CH3
`
`\ /
`C
`c
`II
`/ \
`
`H
`
`NH2
`
`+ RCHO +
`
`/
`CH2
`c
`|
`/ \
`
`0
`
`coon2
`
`CHZ—O—Y—Ni
`
`H
`
`R
`
`R‘OOC
`
`coon2
`
`H3C
`
`N
`H
`
`CHz—O—Y—N3
`
`The azido-containing acetoacetates can also be ob—
`tained by conventional procedures:
`
`HO—Y—N3 + CLCH2COCH2c00R2 flH—>
`
`$00122
`?"2c
`1 \
`
`CHz—O—Y—N3.
`
`o
`
`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.:
`
`Rlooc H
`
`R coon2
`
`I
`
`N
`H
`
`CH3
`
`Rlooc
`
`|
`
`H
`
`Hal.(CH2)mCOO(C1—C4 alkyl),
`Base.
`(Hal = C] or Br)
`
`CH20YNH2
`R
`
`c00112
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`CH3
`
`N
`H
`
`CH20YNH(CH2),,,COO(C1—C4 alkyl) 45
`
`Hydrolysis l/(eig. NaOH) \ R5R6NH
`
`MNH(CH2),,,COOH -~NH(CH2),,,CONR5R9
`
`50
`
`The ability of the compounds 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-
`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
`
`65
`
`SUN - |PR2020-01072, Ex. 1011, p. 5 of 17
`
`SUN - IPR2020-01072, Ex. 1011, p. 5 of 17
`
`
`
`4,572,909
`
`9
`[ised from a little methanol to give the title compound
`(2.4 g), m.p. 211°.
`Analysis %: Calculated for C21H27CIN205C2H204:
`C, 53.85; H, 5.70; N, 5.46; Found: C, 53.99; H, 5.76; N,
`5.60.
`The free base had a m.p. of 88°—90° (from ether).
`EXAMPLES 2—10
`
`10
`ised in the form indicated, starting from the appropriate
`N—substituted dihydropyridine oxalate and Hz/Pd. It
`should be noted that hydrogenation of the N,N—diben—
`zyl starting material in Example 8 produced the mono-
`5 benzyl product which was in turn used as the starting
`material in Example 9.
`
`The following compounds were prepared similarly to
`the method described in Example 1 and were character-
`
`H
`R
`
`CH3OOC
`
`COOCH2CH3
`
`CH3
`
`N
`H
`
`CH20CH2CH2NHR3
`
`Analysis % (Theo-
`Example
`Form
`m.p.
`retical in brackets!
`
`No.
`R
`R3
`Characterised
`cc.)
`c
`H
`N
`2
`—Ph
`—CH3
`free base
`79-80
`65.14
`7.33
`7.09
`(64.93
`7.26
`7.21)
`
`—CH3
`
`oxalate
`
`205—7
`
`55.35
`(55.64
`
`5.84
`5.84
`
`5.60
`5.64)
`
`—CH3
`
`free base
`
`10375
`
`63.87
`(63.14
`
`7.60
`7.23
`
`6.56
`6,70)
`
`F
`
`OCH}
`
`Cl
`
`—CH3
`
`oxalate
`
`204—5
`
`54.14
`
`(53.85
`
`5.7l
`
`5.70
`
`5.57
`
`5.46)
`
`—CH;
`
`oxalate
`
`203-4
`
`5214
`(52.22
`
`5.68
`5.49
`
`5.29
`5.30)
`
`—CH3
`
`oxalate
`
`197—9
`
`52.03
`(52.03
`
`5.41
`5.30
`
`5.06
`5.30)
`
`—CH2Ph
`
`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)
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`Q
`
`OH
`
`CI
`
`,
`
`F
`
`C1
`
`C]
`
`CI
`
`10
`
`~CH2CH20CH3
`
`oxalate
`
`105-7
`
`53.57
`(53.91
`
`6.10
`5.97
`
`4.9]
`5.03)
`
`C1
`
`
`SUN - |PR2020-01072, Ex. 1011, p. 6 of 17
`
`SUN - IPR2020-01072, Ex. 1011, p. 6 of 17
`
`
`
`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
`
`Cl
`H
`
`l
`
`CH3OOC
`
`CH3
`
`COOCsz
`
`’
`
`N
`H
`
`CH20CH2CH2N3
`
`Zn/acid 5
`
`Cl
`
`H
`
`CH300C
`
`COOCH2CH3
`
`CH3
`
`N
`H
`
`CH20CH2CH2NH2.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Preparation of
`2-[2~amlnoethoxy)methyl]-4-(2-chlorophenyl)-3-ethox-
`ycarbonyl-S-methoxycarbonyl-6-methyl-1,4—dihy—
`dropyridine maleate
`
`Cl
`
`|
`
`N
`H
`
`H
`
`|
`
`CH300C
`
`CH3
`
`C00C2H5
`
`CH20CH2CH2N3
`
`,
`Hg/Pd
`-——>
`
`Cl
`
`H
`
`CH300C
`
`COOCH2CH3
`
`CH3
`
`N
`H
`
`CH20CH2CH2NH2.
`
`2-(2-azidoethoxy)methyl-4-(2-
`of
`A suspension
`chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-
`methyl-1,4-dihydropyridine (103 g) in ethanol (2.5 l)
`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), mp. 169°—170.5°,
`Analysis %: Found: C,54.82; H,5.62; N,5.46
`C20H25C1N205.C4H4O4
`requires: C,54.91; H,5.57;
`N,5.34.
`
`EXAMPLES 13— 1 5
`
`The following compounds were prepared similarly to
`Example 12 from the appropriate azide and Hz/Pd:
`
`H
`
`R
`
`CH3OOC
`
`COOC2H5
`
`CH3
`
`N
`1-1
`
`CH20CH2CH2NH2
`
`Analysis % (Theo-
`Example
`Form
`m.p.
`retical in brackets!
`
`No.
`R
`characterised
`(“C.)
`C
`H
`N
`13
`Cl
`éfumarate
`171—
`51.7
`5.3
`5.5
`éhydrate
`173
`(51.8
`5.3
`5.5)
`
`Cl
`
`14
`
`E?
`
`fumarate
`
`ihydrate
`
`158—
`
`57.6
`
`168
`
`(57.7
`
`6.2
`
`6.3
`
`5.8
`
`56)
`
`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, 1e. 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 tem»
`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
`toluene (100 ml), basified with concentrated ammonia
`and extracted with methylene chloride (2X100 ml).
`The extracts were dried (Na2CO3), filtered and evapo-
`rated to dryness. The residue in toluene was chromato-
`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%
`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
`2-azido ethanol) as a white solid, mp. 169°, identical by
`t.1.c. with the product obtained in Example 9.
`
`45
`
`50
`
`55
`
`60
`
`65
`
`SUN - |PR2020-01072, Ex. 1011, p. 7 of 17
`
`SUN - IPR2020-01072, Ex. 1011, p. 7 of 17
`
`
`
`13
`-continued
`
`H
`R
`
`CH3OOC
`
`COOCgHs
`
`I
`
`CH3
`
`|
`
`N
`H
`
`CH20CH2CH2NH2
`
`Analysis % (Theo-
`Example
`Form
`m.p.
`retical in brackets
`
`No.
`R
`characterised
`(°C.)
`C
`H
`N
`15
`fumarate
`152
`56.95
`6.02
`5.93
`(56.68
`5.75
`5.5)
`
`F
`
`
`EXAMPLE 16
`
`Methyl
`N-(2-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-
`methoxycarbonyl-é-methyl-1,4-dihydropyrid-2-yl]me-
`thoxy}ethyl)aminoacetate
`
`Cl
`
`Cl
`
`CH3OOC
`
`COOC2H5
`
`CH3
`
`I
`
`l
`
`N
`H
`
`CH20CH2CH2NH2
`
`K2CO3
`BrCH2COOCl-l3,
`
`E
`
`Cl
`
`Cl
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`4,572,909
`
`l4
`
`
`Cl
`
`CHJOQC
`
`C02CH2CH3
`
`CH3
`
`:2
`
`0
`
`R3
`
`\/\N/H
`
`18
`
`—CH2C02CH3
`
`oil
`
`Analysis % or n.m.r.
`Example
`(Theoretical in brackets
`m.p.
`No.
`
`R3
`('C-)
`C
`H
`N
`78-80
`5826
`6.30
`5.65
`17
`—CH2C02CH2CH3
`(58.24
`6.31
`5.66)
`n.m.r. (CDCI3).7- values:
`7.72 (1H, broad s);
`6.96-7.51 (4H, m);
`5.43 (1H, s);
`4.78 (2H, s);
`4.10 (2H, q);
`3.78 (3H, s);
`363 (31-1, 5);
`3.3—3.7 (6H, m);
`2.38 (3H, s);
`
`1.20 (3H, t);
`
`EXAMPLE l9
`
`2-(2-{[4-(2-Chlorophenyl)-3-ethoxycarbonyl-5—methox-
`ycarbonyl-G-methyl-1,4-dihydropyrid-Z-yl]methoxy}e-
`thylamino)acetamide
`
`CH300C
`
`COOC2H5
`
`CH3
`
`N
`H
`
`CH20CH2CH2NHCH2COOCH3
`
`CHJOOC
`
`4°
`
`|
`
`CH3
`
`|
`
`N
`H
`
`45
`
`c1
`
`coocsz
`
`CH20CH20H2NHCHZCOOCZH5
`
`NH3
`—9
`
`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-S-rnethox-
`ycarbonyl-é-methyl-l,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 (NaZSO4), 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
`title compound (2.10 g), m.p. 96°—98".
`Analysis %: Found: C,53.25; H,5.49; N,5.48;
`C23H23C12N207 requires: C,53.60; H,5.48; N,5.44.
`EXAMPLES 17 AND 18
`
`60
`
`65
`
`The following compounds were prepared by the
`method described in Example 16 using appropriate
`starting materials.
`
`c1
`
`CH300C
`
`cooczfls
`
`CH3
`
`N
`H
`
`CH20CH2CH2NHCH2CONH2
`
`Ethyl N-(Z-{[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 m1) 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 (MgSO4), and evaporated. The residue was
`chromatographed on silica (t.l.c. grade Merck Kieselgel
`60H, [Trade Mark] 30 g) eluting with dichlorornethane
`plus 0—5% methanol. Appropriate fractions were com-
`bined and evaporated. The residue was triturated with
`
`SUN - |PR2020-01072, Ex. 1011, p. 8 of 17
`
`SUN - IPR2020-01072, Ex. 1011, p. 8 of 17
`
`
`
`15
`ethyl acetate and the resulting solid collected, washed
`with ethyl acetate, and dried to give the title compound
`(1.23 g), m.p. 126°—129°.
`Analysis %: Found: C,56.78; H,6.06; N,8.68;
`C22H28C1N306 requires: C,56.71; H,6.06; N,9.02.
`EXAMPLE 20
`
`The following compound was prepared by the
`method described in Example 19 using the same dihy-
`dropyridine and methylamine.
`
`CH302C
`
`l
`
`|
`
`N
`H
`
`CH3
`
`Cl
`COOCzl—ls
`
`0
`
`\/\N
`H
`
`)3
`
`Example
`No.
`20
`
`R3
`—CH2CONHCH3
`
`Analysis % or n.m.r.
`(Theoretical in brackets
`c
`H
`N
`57.80
`6.55
`8.73
`(57.56
`6.30
`8.76)
`
`mp
`cc.)
`123—
`l24
`
`EXAMPLE 21
`
`N-(2—{[4—(2-Chlorophenyl)—3-ethoxycarbonyl-5-
`methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]me-
`thoxy}ethyl)aminoacetic acid hemihydrate
`
`Cl
`
`CH300C
`
`COOC2H5
`
`I
`
`CH3
`
`N
`H
`
`I
`
`as. NaOl-I 3
`CHgOCHgCHZNHCHzCOOH
`
`Cl
`
`CH300C
`
`COOC2H5
`
`CH3
`
`N
`H
`
`CH20CH2CH2NHCH2COOH
`
`A solution of methyl N—(2-{[4-(2—chlorophenyl)-3-
`ethoxycarbonyl-5~methoxyearbonyl-é-methyl-1,4—dihy-
`dropyrid-Z-yl]methoxy}ethyl)aminoacetate (2.40 g) in
`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 SOW-XS, [Trade Mark], 200—400 mesh,
`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-
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4,572,909
`
`16
`pound as a hemihydrate (0.56 g), m.p.
`comp.).
`Analysis %: Found: C,55.52; H,5.95; N,5.92;
`C22H27C1N207.§H20 requires: C, 55.52; H, 5.93; N,
`5.89.
`
`l40°—150° (de-
`
`EXAMPLE 22
`
`Preparation of
`2-[(2-aminoethoxy)methyl]-4—(2—chlorophenyl)—3-ethox-
`ycarbonyl—S-methoxycarbonyl-6-methyl-1,4-dihy-
`dropyridine maleate
`
`CH302C
`
`l
`
`CH3
`
`N
`
`CH302C
`
`CH3
`
`l
`
`l
`
`or hydrazine hydrate,
`Ethanolic methylamine, ;
`or KOH followed by HC].
`
`Cl
`
`COzOCHzCH3 0
`‘\
`
`CH20CH2CH2N
`
`//0
`
`Cl
`
`COzCHzCH}
`
`COOH
`
`I
`
`file
`CH20CH2CH2NH2HC
`
`COOH
`
`N
`H
`
`Method A (using ethanolic methylamine)
`4-(2-Chlorophenyl)-3-ethoxycarbonyl-S-methoxycar-
`bonyl-é-methyl-Z-(2-phthalimidoethoxy)methyl-1,4-
`dihydropyridine (80 g) was stirred in 33% ethanolic
`methylamine solution (1067 m1) at room temperature
`for three hours. The solvent was then evaporated and
`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-
`lized from industrial methylated spirits (430 m1) 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-Chlorophenyl)-3-ethoxycarbonyl-S-methoxycar-
`bonyl-6-methy1-2-(2-phthalimidoethoxy)methyl-1,4-
`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 m1) 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
`
`SUN - |PR2020-01072, Ex. 1011, p. 9 of 17
`
`SUN - IPR2020-01072, Ex. 1011, p. 9 of 17
`
`
`
`17
`white solid, again confirmed spectroscopically to be the
`desired product.
`
`4,572,909
`
`18
`-continued
`Cl
`
`Method C (using KOH followed by HCI).
`4.(2-Chlorophenyl)-3-ethoxycarbonyl-S-methoxycar-
`bonyl-6-methyl-2-(2ephthalimidoethoxy)methyl-1,4-
`dihydropyridine (15 g) was dissolved in a mixture of
`tetrahydrofuran (150 ml) and water (100 ml) containing
`potassium hydroxide (3.13 g). After stirring at room
`temperature for 1.5 hours 2N hydrochloric acid (100
`ml) was added and the resulting slurry was refluxed for
`2.5 hours. The solution was extracted twice with meth-
`A mixture of 2-[2-(N-benzyl-N-methylamino)ethox-
`ylene chloride (2X 100 ml) and the combined extracts
`ymethyl]-4-[2-chlorophenyl]-3—ethoxycarbonyl—5-
`were dried (MgSO4) and evaporated to leave an oil
`methoxycarbonyl-6-methyl-l,4-dihydropyridine (4.8 g)
`which was dissolved in industrial methylated spirits (57
`and 2,2,2—trichloroethy] chloroformate (2.7 g) was
`m1). Maleic acid (3.24 g) was added and the resulting
`heated in toluene at reflux for 20 hours. After cooling to
`precipitate was collected, washed with industrial meth-
`room temperature,
`the mixture was stirred with 1N
`ylated spirits and dried at 55° to give the title compound
`hydrochloric acid (50 ml) and extracted with ether. The
`(10.2 g) as an off-white solid, again confirmed spectro-
`extracts were evaporated to leave a crude oil (6.9 g)
`scopically to be the desired product.
`containing the corresponding 2-[2-(N-2,2,2-trichloroe-
`EXAMPLES 22a—f
`
`
`H
`
`CH302C
`
`C02CH2CH3
`
`CH3
`
`N
`H
`
`CH20CH2CH2NHCH3
`
`5
`
`10
`
`15
`
`20
`
`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 meth lamine:
`R
`
`Rlooc
`
`COOK?
`
`CH3
`
`N
`H
`
`CH20CH2CH2NH2
`
`Analysis %
`Theoretical in brackets
`
`Example
`R
`R1
`R2
`m.p. (“0.)
`c
`H
`N
`(a)
`2,3-dichlorophenyl
`C2H5
`CH3
`131—2”
`53.9
`5.5
`6.4
`(54.2
`5.5
`6.3)
`52.8
`5.5
`5.1
`(52.7
`5.6
`5.3)
`53.25
`4.9
`5.75
`(52.9
`5.1
`5.9)
`51.8
`5.8
`5.2
`(Sl.8
`6.0
`5.1)
`54.5
`5.8
`6.0
`(54.2
`5.8
`5.75)
`55.6
`5.9
`10.6
`129—131”
`C2H5
`CH3
`2-chloro-pyrid-3»ylv
`(f)
`
`(55.7 10.25) 5.9
`
`‘ Isolated as the hemifumarale hemiliydrale
`Isolated as the hemifumnmte sesquihydrate
`
`(b)
`
`(c)
`
`(d)
`
`(e)
`
`2,3-dichlorophenyl *
`
`2-chloro-3-trifluoro-
`methylphenyl
`2,3-diehlorophenyl
`
`CgHs
`
`CH3
`
`C2H5
`
`127—9“
`
`C2H5
`
`122°
`
`(CH3)2CH
`
`C2H5
`
`105—9“
`
`2,3-dichlorophenyl
`
`CH3OCH2CH2— C2H5
`
`88-90”
`
`EXAMPLE 23
`
`Preparation of
`4-(2-Chlorophenyl)-2-[2-(N-methylamino)ethoxyme-
`thyl]-3-ethoxycarbonyl-S-methoxycarbonyl-6-methy1-
`1,4-dihydropyridine maleate
`
`Cl
`
`H
`
`l
`
`N
`H
`
`CHJOZC
`
`CH3
`
`COzCHzCH;
`
`(i) Cl3CCH202C.Cl
`l W
`CH20CH2CH2N— CH3
`CHZPh
`
`55
`
`60
`
`65
`
`thoxycarbonyl-N-methylamino)ethoxymethyl]deriva-
`tive.
`The said oil (3.0 g) was dissolved in dimethylformam—
`ide (10.5 ml) and formic acid (0.5 g) and at 5" 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 mixtur