United States Patent
`Campbell et al,
`
`p15
`
`[11] Patent Number:
`
`[45] Date of Patent:
`
`4,572,909
`Feb. 25, 1986
`
`Bossert, F. et al, “4~Aryldihydropyridines”, Angew.
`Chem. 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
`
`ABSTRACT
`[57}
`A dihydropyridine compound of the formula
`
`[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, ail of England
`
`[73] Assignee:
`
`Pfizer Inc., New York, N.Y.
`
`[21] Appl. No.: 576,982
`[22] Filed:
`Feb. 3, 1984
`
`H_
`
`LR
`
`meeCooR?
`
`Related U.S. Application Data
`[63]|Continuation-in-part of Ser. No. 463,081, Feb, 2, 1983,
`CH;
`N
`CH;—O—-Y— NHR?
`abandoned.
`|H
`
`Foreign Application Priority Data
`[30]
`Mar. 11, 1982 [GB] United Kingdom...............4 8207180
`
`[51]
`Int. CL4 oe CO7D 211/90; A61K 31/455
`[52] OLS. Cle. ce
`eccsesstetseereeerecenenene 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
`
`2/1984 Campbell et al... 346/321
`4,430,333
`FOREIGN PATENT DOCUMENTS
`
`318101
`
`........... 546/321
`7/1981 European Pat. Off.
`OTHER PUBLICATIONS
`
`Schramm, M., “Novel Dihydropyridines with Positive
`Inotropic Action”, Nature, vol. 303 (Jun. 9, 1983) pp.
`535-537.
`
`or a pharmaceutically acceptable acid addition salt
`thereof,
`wherein
`Y is —(CH2)2.—, —(CH2)3—, —-CH2CH(CH3)— or
`—CH2C(CH3)2—;
`R is aryl or heteroaryl;
`R! and R2 are each independently Ci-C4 alkyl or 2-
`methoxyethyl; and
`R3 is hydrogen, C)-C4 alkyl, 2-(C)-C4 alkoxy)ethyl,
`cyclopropylmethy],
`benzyl,
`or —(CH2),,COR*
`where m is 1, 2 or 3 and
`R‘is hydroxy, C)-C4 alkoxy or —NR°R® where R5 and
`R¢ are each independently hydrogen or C;-Cy4 alkyl
`can be employed for treating or preventing a heart
`condition or hypertension.
`
`17 Claims, No Drawings
`
`SUN - IPR2020-01072, 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 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 compoundsof 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 ofintracellular
`calcium under ischaemic conditions. Excessive calcium
`influx during ischaemia can have a numberofadditional
`adverse effects which would further. compromise the
`ischaemic myocardium. These includeless efficient use
`of oxygen for ATP production,activation of mitochon-
`drial fatty acid oxidation and possibly, promotionofcell
`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.
`SUMMARYOF THE INVENTION
`
`Accordingto the invention, there are provided novel
`1,4-dihydropyridine derivatives of the formula:
`
`R!ooc
`
`coor?
`
`)
`
`CH3
`
`N
`H
`
`CH2—O—Y—NHR?
`
`25
`
`30
`
`40
`
`2
`mic mixtures or as separated d- and1- optically-active
`isomeric forms.
`The pharmaceutically acceptable acid addition salts
`of the compoundsof 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,
`10 tartrate, citrate and gluconate salts. The preferred salts
`are maleates.
`The term “ary]’’ as usedin this specification, mcludes,
`for example, phenyl optionally substituted by one or
`two substituents selected from nitro, halo, C);-Cq alkyl,
`15 C\-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-
`20 dyl optionally monosubstituted by methyl or cyano;
`quinolyl; benzoxazolyl; benzthiazolyl;
`furyl; pyrimi-
`dinyl;
`thiazolyl; 2,1,3-benzoxadiazol-4-yl; 2,1,3-benz-
`thiadiazol-4-yl; and thienyl optionally monosubstituted
`by halo or C)-Cy alkyl.
`“Halo” meansfluoro, chloro, bromooriodo.
`C3 and C4 alkyl and alkoxy groups can bestraight or
`branched chain.
`R3 is preferably H, CH3, benzyl, 2-methoxyethyl,
`—CH2COOCH;3, —CH2COOC:Hs, —CH2zCONHb2,
`—CH2CONHCH;, or —CH2COOH.
`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.
`R! is preferably CH3.
`R? is preferably CoHs.
`Y is preferably —(CH2)2— or —CH2CH(CH3)—.
`“m” is preferably 1.
`Most preferably, R is 2-chlorophenyl.
`Most preferably, Y is —(CH2)2.
`The most preferred compounds have the formula (I)
`45 Wherein R is 2-chlorophenyl, R!is CH3, R2 is CoHs, R3
`is H or CH, and Y is —(CH2)2—.
`The compounds of the formula (J) 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 beillustrated in more detail
`as follows:
`
`wherein
`Y is —(CHo)—, —(CH2)3—, —CH2CH(CH3)— or
`—CH2C(CH3)2—;
`R is aryl or heteroaryl;
`R! and R? are each independently C)-Cq alkyl or 2-
`methoxyethyl; and
`R3 is hydrogen, C)-C4 alkyl, 2-(C;-C4 alkoxy)ethyl,
`cyclopropylmethyl,
`benzyl,
`or
`-—(CH2)mCOR4
`where m is 1, 2 or 3 and R4 is hydroxy, C)-C, alkoxy
`or —NR5R° where R5 and R® are each independently
`Removal of
`hydrogen or C)-Cq alkyl;
`protecting
`and their pharmaceutically acceptable acid addition
`salts.
`—StU Compound (D.
`CH3
`DETAILED DESCRIPTION OF THE
`CH2—O-Y—NR?
`INVENTION
`Q
`
`55
`
`R'o00c
`
`coor?
`
`NH
`
`an
`
`The compoundsof the formula (I) containing one or
`more asymmetric centres will exist as one or morepairs
`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-
`
`(Q==an amino-protecting group and R, R!, R?, R3and Y
`65 are as defined for formula [I]);
`
`OR
`
`SUN - IPR2020-01072, Ex. 1011, p. 2 of 17
`
`SUN - IPR2020-01072, Ex. 1011, p. 2 of 17
`
`

`

`4,572,909
`
`-continued
`
`R'ooc
`
`CH3
`
`|
`
`|
`
`N
`H
`
`COOR?
`
`Oo
`\
`
`CHs-O—Y—N
`
`Removal of
`protecting >
`group
`
`u0
`
`Compound (D
`[R3 = H}.
`
`[R, R}, R2 and Y are as defined for formula (I)].
`One preferred amino-protecting groupis benzyl.It is
`typically removed by hydrogenation, using e.g. H2/Pd
`on charcoal underacidic conditionsin a suitable organic
`solvent, e.g. methanol. The acidic conditions are prefer-
`ably obtained by using compound(II) in the form of an
`organic acid addition salt, e.g. as an oxalate or acetate
`salt.
`
`25
`
`35
`
`A typical procedure involving the removalof a ben-
`zyl groupis as follows. Compound(II) as an oxalate salt
`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
`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 removethe
`remaining benzyl group.
`Manyofthe 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 (IDare as follows:
`(a) The benzyl-protected intermediates (II) can be
`prepared by the Hantzsch synthesis, as follows:
`
`50
`
`4
`In a typical procedure, the ketoester (IV) and alde-
`hyde are heated under reflux in a suitable organic sol-
`vent, e.g. a Cy-Cy4 alkanol solvent such as ethanol, for
`about 15 minutes, and then the aminocrotonate (IIDis
`added. Alternatively the aminocrotonate (III), keto-
`ester (IV) and aldehyde can be heated together in the
`solvent. Preferably a smali 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 underreflux, until the reaction
`is essentially complete, typically in 24 hoursorless. The
`product of the formula (ID can then be isolated and
`purified by conventional procedures.
`The ketoesters (IV) are either known compoundsor
`can beprepared by methods analogousto those ofthe
`prior art, such as the methodillustrated in the Prepara-
`tions hereinafter, which are essentially the method of
`Troostwijk and Kellogg, CS. Chem. Comm., 1977,
`page 932. Similarly the amino-crotonates(IIDare either
`known compoundsor can be prepared by conventional
`procedures. Also the aldehydes are either knownor can
`be prepared by known methods.
`(b) The benzyl-containing intermediates (II) can also
`be prepared by the following process:
`
`coor?
`
`t
`RI0OC, CH
`
`SS
`
`"O
`
`CH}
`(vy)
`
`cH’
`ll
`+ Dw
`NH)
`
`(v1)
`
`Compound
`
`(i)
`
`>
`
`“CHy-O—-Y—NR?
`CH2PH
`
`The crotonate (VJ) is typically prepared in situ by
`reaction of the corresponding acetoacetate (IV):
`
`CcOOR?
`
`av)
`
`tc
`¢™%
`CH2—O—Y-—-NR?3
`CH2Ph
`
`°
`
`R!00C
`
`H
`
`COOR?
`
`\ 7
`¢
`an
`
`H3C
`
`NH2
`
`+ RCHO +
`
`O°
`
`CH
`gr
`
`CH2—-O~-Y—NR?
`CH2Ph
`
`au)
`
`(iv)
`
`R!00C
`
`coor?
`
`H3C
`
`mz
`
`CH)—O—Y—N—R3
`CH2Ph
`
`with ammonium acetate, e.g. by refluxing in a suitable
`organic solvent, e.g. a C;-C,4 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 compoundsof the formula (I) in which R3 is H
`can be prepared from the corresponding phthalimido
`derivatives according to conventional procedures, e.g.:
`
`55
`
`60
`
`65
`
`SUN - IPR2020-01072, Ex. 1011, p. 3 of 17
`
`SUN - IPR2020-01072, Ex. 1011, p. 3 of 17
`
`

`

`R'00c
`
`|
`
`CH;
`
`R
`
`|
`
`mZ
`
`COOR?
`
`oO
`)
`
`CH;-O—Y—N
`
`4,572,909
`
`: >
`(a) a primary amine
`or (b) hydrazine hydrate
`(c) an alkali metal hydroxide
`or
`followed by HCI or H2S04.
`
`smaCH2OYNH2
`
`4o
`
`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 hydrateis typi-
`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 ofthe acid and heating at the reflux temper-
`ature or below.In all cases the product can beisolated
`conventionally.
`The phthalimido starting materials can again be ob-
`tained conventionally, e.g.:
`
`=o
`
`o°O=
`
`N—Y—OH + CICH2COCH2COOR?
`
`\ NaH
`
`N—Y—O—CHCOCH2COOR?.
`
`R'o00c
`
`\
`
`CH
`ll
`c
`/\
`CH; NH)
`
`+RCHO+
`
`COOR?
`/
`CH)
`|
`c
`aN
`O
`
`CHrO—Y—N
`
`°
`\
`
`(a)
`
`(6)
`
`4°
`
`as
`
`This is again the Hantzsch reaction.
`Compoundsof the formula (1) 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 R? is H by the methods previously
`described.
`To prepare compounds in which R3 is Cy-Cy alkyl,
`—COOCH?2CCl; 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-
`
`15
`
`protected starting materials necessary for this process
`can be prepared as follows:
`
`C1L.COOCH2CCl;
`CH;—O—Y——N(C-Cy alky)3 —————
`
`weenCH2- O-YmN=(C1-Ce alkyl)
`COOCH?2CCl3
`
`or
`
`25
`
`35
`
`50
`
`55
`
`60
`
`65
`
`CH2—-O—YN(C1-Cy alkyl)
`benzyl
`
`CLCOOCH3CC13
`
`awwCHOYNN(C1-Cy alkyl)
`COOCH?2CCI;
`
`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. Manyofthe dialky]-
`amino and N-alkyl-N-benzylamino starting materials
`needed to prepared these N-protected intermediatesare
`described and claimed in our corresponding European
`patent application publication No. 0060674, and others
`can be prepared analogously.
`The compoundsof the formula (1) 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 H2/Pd, under conventional con-
`ditions.
`
`R
`
`|
`
`R!o0c
`
`CH;
`
`|
`
`N
`H
`
`COOR?
`
`reduction >
`
`CH2—~-O--Y—N3
`
`R
`
`R'o00c
`
`COOR?
`
`CH3
`
`N
`H
`
`CH2—-O—Y-—-NH3
`
`In a typical procedure using zinc dust, the reactionis
`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 conditionssimilar to those
`previously described:
`
`SUN - IPR2020-01072, Ex. 1011, p. 4 of 17
`
`SUN - IPR2020-01072, Ex. 1011, p. 4 of 17
`
`

`

`4,572,909
`
`7
`
`R!00c
`
`H
`
`Cc
`Ui
`Cc
`YN
`
`CH3
`
`NH)
`
`COOR?
`
`7
`CH2
`I
`Cc
`
`+ RCHO +
`
`@
`Oo
`
`CH?—-O-Y—N3
`
`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 ofactive
`compound,
`in a suitable pharmaceutically acceptable
`vehicle or carrier. Dosages for intravenous administra-
`tion would be within the range 1 to 10 mg persingle
`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 ofthe for-
`mula (1), or a pharmaceutically acceptable acid addition
`salt thereof, for use in treating ischaemic heart disease,
`especially angina, or hypertension, i a human being.
`The following Examples illustrate the invention: all
`temperatures are in °C.:
`EXAMPLE1
`
`Preparation of
`4-(2-chloropheny])-2-[2-(methylamino)ethoxymethyl]-
`3-ethoxycarbonyl]-5-methoxycarbonyl-6-methy]-1,4-
`dihydropyridine, oxalate salt
`
`cl
`
` CH300C
`
`COOCH2CH3
`
`H2/Pd
`>
`
`CH3
`
`N
`H
`
`CH2O0CH2CH2NCH3
`CH2Ph
`
`cl
`
`15
`
`25
`
`30
`
`40
`
`R'90c
`
`COOR?
`
`CH2—O—Y—N3
`
`NH
`
`H3C
`
`The azido-containing acetoacetates can also be ob-
`tained by conventional procedures:
`
`HO—Y—N3 + Cl.CH,COCH;CooR? NaH
`
`goo?
`1"c
`oNoO
`CH2--O-- Y—N3.
`
`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 compoundsofthe invention can be pre-
`pared from other compounds of the invention by con-
`ventional techniques, e.g.:
`
`Riooc HR coor?
`
`|
`
`|
`
`CH3
`
`N
`H
`
`CH20YNH2
`
`Hal.(CH2),COO(C}-Cq alkyl),
`Base.
`(Hal = Cl or Br)
`
`R'00c
`
`CooR?
`
`CH3
`
`N
`H
`
`CH20OYNH(CH?),,COO(C1-Cg4 alkyl)
`
`Hydrolysis je NaOH) \e
`
`~~NH(CH2)COOH=~=*NH(CH2),CONRSR®.
`CH300C.
`COOCH2CH3
`
`The ability of the compoundsto inhibit the move-
`mentofcalcium into the cell is shownbytheir effective-
`ness in reducing the responseof 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
`
`CH3
`
`N
`H
`
`CH20CH2CH2NHCH3
`
`A. solution of 2-[2-(N-benzyl-N-methylamino)ethox-
`ymethyl]-4-[2-chlorophenyl]-3-ethoxycarbonyl-5-
`oxa-
`methoxycarbonyl-6-methyl-1,4-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 removalof the catalyst by filtration, the methanol
`was removed by evaporation and the residue crystal-
`
`SUN - IPR2020-01072, Ex. 1011, p. 5 of 17
`
`SUN - IPR2020-01072, Ex. 1011, p. 5 of 17
`
`

`

`9
`lised from a little methanol to give the title compound
`(2.4 g), mp. 211°.
`Analysis %: Calculated for C21H27CIN205.C2H204:
`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).
`EXAMPLES2-10
`
`4,572,909
`
`10
`ised in the form indicated,starting from the appropriate
`N-substituted dihydropyridine oxalate and H2/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.
`
`Thefollowing compounds werepreparedsimilarly to
`the method described in Example 1 and were character-
`
` R
`
`CH3;00C
`
`COOCH?2CH3
`
`CH20CH2CH2NHR?
`
`NH
`
`CH3
`
`Example
`No.
`2
`
`R
`—Ph
`
`3
`
`4
`
`. F
`: OCH3
`5 : al
`
`6
`
`OH
`
`cl
`
`R3
`—CH3
`
`—CH3
`
`Form
`Characterised
`free base
`
`m.p.
`CC.)
`79-80
`
`oxalate
`
`205-7
`
`Analysis % (Theo-
`retical in brackets)
`H
`N
`c
`7.09
`7.33
`65.14
`7.26
`7.21)
`(64.93
`5.60
`55.35
`(35.64
`5.64)
`
`5.84
`5.84
`
`—CH3
`
`free base
`
`103-5
`
`63.87
`(43.14
`
`7.60
`7.23
`
`6.56
`6.70)
`
`~CHs
`
`—CH3
`
`oxalate
`
`204-5
`
`54.14
`(53.85
`
`3.71
`5.70
`
`5.57
`5.46)
`
`oxalate
`
`203-4
`
`52.14
`(32.22
`
`5.68
`5.49
`
`5.29
`5.30)
`
`:
`
`—CH3
`
`oxalate
`
`197-9
`
`52,03
`(52.03
`
`5.41
`5.30
`
`5.06
`5.30)
`
`F ; cl
`. cl
`: cl
`: cl
`
`7
`
`8
`
`9
`
`10
`
`—CH2Ph
`
`oxalate
`
`185
`
`59.18
`(59.13
`
`5.75
`5.65
`
`4,86
`4.76)
`
`—H
`
`maleate
`
`169
`
`54,83
`(54.91
`
`3,55
`5.57
`
`5,34
`5.34)
`
`—CH2CH20CH3
`
`oxalate
`
`105-7
`
`53.57
`(53.91
`
`6.10
`3.97
`
`4.91
`5.03)
`
`SUN - IPR2020-01072, Ex. 1011, p. 6 of 17
`
`SUN - IPR2020-01072, Ex. 1011, p. 6 of 17
`
`

`

`11
`
`EXAMPLE11
`
`4,572,909
`
`12
`EXAMPLE12
`
`Preparation of
`2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethox-
`ycarbonyl-5-methoxycarbonyl-6-methy]-1,4-dihy-
`dropyridine maleate
`
`5
`
`Preparation of
`2-[2-aminoethoxy)methy]]-4-(2-chlorophenyl)-3-ethox-
`ycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihy-
`dropyridine maleate
`
`al
`
`cl
`H
`
`|
`
`|
`
`N
`H
`
`CH300C
`
`CH3
`
`COOC?Hs
`
`Zn/acid >
`
`CH20CH2CH2N3
`
`cl
`
`CH300C.
`
`COOCH2CH3
`
`CH3
`
`N
`H
`
`CH30CH2CH2NH?.
`
`2-Azidoethanol (3 g) was converted to ethyl 4-(2-
`azidoethoxy)acetoacetate similarly to the method de-
`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
`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) wasstirred 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 (2100 ml).
`The extracts were dried (Na2CO3),filtered and evapo-
`rated to dryness. The residue in toluene was chromato-
`graphed on a medium pressure columnofsilica (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 maleatesalt 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, m.p. 169°, identical by
`t.Lc. with the product obtained in Example 9.
`
`CH300C
`
`COOC2Hs
`
`|
`
`|
`
`N
`H
`
`CH3
`
`CH20CH2CH2N3
`
`cl
`
`.
`H2/Pd
`>
`
`CH300C
`
`COOCH?2CH3
`
`CH
`
`N
`H
`
`CH20CH2CH2NH).
`
`2-(2-azidoethoxy)methyl-4-(2-
`of
`A suspension
`chliorophenyl)-3-ethoxycarbony!-5-methoxycarbonyl-6-
`methyl-1,4-dihydropyridine (103 g) in ethanol (2.5 1)
`wasstirred 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
`wasfiltered and evaporated andthe 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
`9%: Found: C,54.82; H,5.62; N,5.46
`CyoH2sCIN205.C4H4O4
`requires: C,54.91; H,5.57;
`N,5.34.
`
`EXAMPLES13-15
`
`The following compounds were preparedsimilarly to
`Example 12 from the appropriate azide and H2/Pd:
`
`CH300C,
`
`COO0C2Hs5
`
`CH3
`
`N
`H
`
`CH20CH2CH2NH?2
`
`Example
`No.
`13
`
`R
`
`Form
`characterised
`Cl} fumarate
`+ hydrate
`
`Cl
`
`Analysis % (Theo-
`retical in brackets)
`m.p.
`CC
`H
`N
`(°C.)
`171-547
`5.3
`5.5
`173,
`(51.8
`5.3
`5.5)
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`350
`
`35
`
`60
`
`65
`
`14
`
`fumarate
`
`0 } hydrate
`
`158-
`
`168
`
`576
`
`(87.7
`
`62
`
`63
`
`5.8
`
`5.6)
`
`SUN - IPR2020-01072, Ex. 1011, p. 7 of 17
`
`SUN - IPR2020-01072, Ex. 1011, p. 7 of 17
`
`

`

`13
`-continued
`R
`
`CH300C
`
`COOC3Hs
`
`|
`
`CH;
`
`|
`
`N
`H
`
`CH20CH2CH2NH2
`
`4,572,909
`
`14
`
`
`5
`
`cl
`
`CH302C
`
`CO2CH2CH;
`
`Example
`No.
`15
`
`R
`
`Analysis % (Theo-
`retical in brackets
`C
`H
`N
`56.95
`602
`5.93
`(56.68
`5.75
`5.5)
`F
`
`
`Form
`characterised
`fumarate
`
`m.p.
`((C.)
`152
`
`CH3
`
`|
`
`|
`
`N
`H
`
`Oo
`
`;
`
`vk
`
`10
`
`15
`
`20
`
`25
`
`ON
`Analysis % or n.m.r.
`Example
`m.p.
`(Theoretical in brackets)
`No.
`R3
`CC)
`oc
`H
`N
`17
`—CH2CO7CH2CH3
`078-80
`58.26
`«6.30
`5.65
`(58.24
`631
`5.66)
`
`
`EXAMPLE16 oi)=on.m.r. (CDCI3).7 values:18 —CH2CO2CH3
`
`Methyl!
`7.72 (1H,broad s);
`N-(2-{[4-(2,3-dichloropheny])-3-ethoxycarbonyl-5-
`saacE oe m);
`methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]me-
`4.78 QH, 8);
`thoxy}ethyl)aminoacetate
`4.10 (2H, q);
`3.78 (3H,s);
`3.63 (3H,s);
`3.3-3.7 (6H, m);
`2.38 (3H,s);
`
`1.20 GH, 8);
`
`cl
`
`ci
`
`
`
`
`
`EXAMPLE19
`0
`COOCHs
`CH;00C
`| BrCH2COOCHSss,2-(2-{[4-(2-Chlorophenyl)-3-ethoxycarbony]-5-methox-|
`K2C03
`ycarbonyl-6-methy1-1,4-dihydropyrid-2-yl]methoxy}e-
`CHa
`N
`CH20CH2CH2NH2
`thylamino)acetamide
`cl
`
`35
`
`cl
`
`c)
`
`CH,00C
`
`COOC2Hs
`
`40 cH,00C
`
`COOC2Hs
`
`|
`
`|
`
`N
`H
`
`CH3
`
`CH20CH1CH2NHCH2COOCH3
`
`CH3
`
`45
`
`|
`
`|
`
`N
`H
`
`CH20CH2CH2NHCH2COOC2Hs5
`
`NH3
`=>
`
`50
`
`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)methy]]-
`4-(2,3-dichlorophenyl)-3-ethoxycarbony]-5-methox-
`ycearbonyl-6-methyl-1,4-dihydropyridine (5.01 g) and
`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 (Na2SO«), and evaporated.
`The residue was chromatographedonsilica (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
`9%: Found: C,53.25; H,5.49; N,5.48;
`C23H2gClgN207 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.
`
`65
`
`cl
`COOCaHS
`
`CH)OCH)CH)NHCHCONH;
`
`CH3O0C
`
`CH;
`
`|
`
`|
`
`N
`H
`
`Ethyl N-(2-{[4-(2-chlorophenyl)-3-ethoxycarbonyl-
`5-methoxycarbony!-6-methy]-1,4-dihydropyrid-2-
`yl]methoxy}ethyl)aminoacetate (2.50 g) in a mixture of
`ethanol (40 ml) and 0.880 aqueous ammonia (30 mi) was
`stirred at room temperature for four days and then
`evaporated. The residue waspartitioned between ethyl
`acetate and water and the organic layer washed with
`water, dried (MgSOq), and evaporated. The residue was
`chromatographedonsilica (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 wastriturated with
`
`SUN - IPR2020-01072, Ex. 1011, p. 8 of 17
`
`SUN - IPR2020-01072, Ex. 1011, p. 8 of 17
`
`

`

`4,572,909
`
`15
`ethyl acetate and the resulting solid collected, washed
`with ethyl acetate, and dried to give thetitle compound
`(1.23 g), m.p. 126°-129°,
`Analysis %: Found: C,56.78; H,6.06; N,8.68;
`C22H29CIN3O¢ 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.
`
`CH30%0C.
`
`cl
`COOC2Hs
`
`|
`
`|
`
`N
`H
`
`CH;
`
`-
`
`°
`
`SOON
`H
`
`5
`
`10
`
`15
`
`20
`
`16
`pound as a hemihydrate (0.56 g), m.p. 140°-150° (de-
`comp.).
`9%: Found: C,55.52; H,5.95; N,5.92;
`Analysis
`C22H27CIN207.4H2O requires: C, 55.52; H, 5.93; N,
`5.89.
`
`EXAMPLE22
`
`Preparation of
`2-[(2-aminoethoxy)methyl]-4-(2-chloropheny])-3-ethox-
`ycarbony]-5-methoxycarbonyl-6-methyl-1,4-dihy-
`dropyridine maleate
`
`Ethanolic methylamine, >
`or hydrazine hydrate,
`or KOHfoilowed by HCl.
`
`ca
`
`CH302C
`
`CO20CH2CH3
`
`Lo
`N
`
`CH3
`
`\
`
`CH,OCH;CH)N
`
`4°o
`
`cl
`
`CH302¢
`
`CO1CH2CH3
`
`COOH
`
`|
`
`CH3
`
`N
`H
`
`|
`
`Hc
`CH20CH2CH2NH2.HC
`
`COOH
`
`Method A (using ethanolic methylamine)
`4-(2-Chloropheny])-3-ethoxycarbonyl-5-methoxycar-
`bonyl-6-methyl-2-(2-phthalimidoethoxy)methyl-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
`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 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-Chlorophenyl)-3-ethoxycarbonyl-5-methoxycar-
`bonyl-6-methyl-2-(2-phthalimidoethoxy)methy]-1,4-
`dihydropyridine (383 g) wasstirred 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 wasdissolved 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
`wascollected, washed with industrial methylated spirit
`and dried at 55° to give the title compound (304 g) asa
`
`Example
`No.
`20
`
`R3
`= CH2CONHCH3
`
`Analysis % or nmr.
`(Theoretical in brackets
`c
`H
`N25
`57.80
`6.55
`8.73
`(57,56
`6.30
`8.76)
`
`m.p.
`(CC)
`123-
`124
`
`30
`
`35
`
`40
`
`45
`
`50
`
`65
`
`EXAMPLE21
`
`N-(2-{[4-(2-Chlorophenyl)-3-ethoxycarbonyl-5-
`methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl|me-
`thoxy}ethyl)aminoacetic acid hemihydrate
`
`cl
`
`CH300C.
`
`COOC1Hs
`
`|
`
`CH3
`
`N
`H
`
`|
`
`aq. NaQH >
`CH),0CH2CH2NHCH2COOH
`
`cl
`
`CH;00C
`
`COO0C2H5
`
`CH»O0CH2CH2NHCH2COOH
`
`NH
`
`CH3
`
`A solution of methy] N-(2-{[4-(2-chlorophenyl)-3-
`ethoxycarbonyl-5-methoxycarbony]-6-methyl-1,4-dihy-
`dropyrid-2-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 50W-X8, [Trade Mark], 200-400 mesh,
`cation form, 40 g) eluting with dioxaneinitially fol-
`lowed by 2% pyridine in water. Appropriate fractions
`were combined and evaporated to give the title com-
`
`SUN - IPR2020-01072, Ex. 1011, p. 9 of 17
`
`SUN - IPR2020-01072, Ex. 1011, p. 9 of 17
`
`

`

`17
`whitesolid, 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-5-methoxycar-
`bony]-6-methyl-2-(2-phthalimidoethoxy)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 andtheresulting slurry was refluxed for
`2.5 hours. The solution was extracted twice with meth-
`ylene chioride (2x 100 ml) and the combined extracts
`were dried (MgSOx4) and evaporated to leave an oil
`which was dissolved in industrial methylated spirits (57
`ml). Maleic acid (3.24 g) was added and the resulting
`precipitate was collected, washed with industrial 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.
`EXAMPLES22a-f
`
`5
`
`10
`
`~ 5
`
`20
`
`CH302C
`
`CO2CH2CH3
`
`CH3
`
`N
`H
`
`CH20CH2CH2NHCH3
`
`A mixture of 2-[2-(N-benzyl-N-methylamino)ethox-
`ymethyl]-4-[2-chloropheny]]-3-ethoxycarbonyl-5-
`methoxycarbony]-6-methyl-1,4-dihydropyridine (4.8 g)
`and 2,2,2-trichloroethy] chloroformate (2.7 g) was
`heated in tolueneat reflux for 20 hours. After cooling to
`room temperature,
`the mixture was stirred with 1N
`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-
`
`The following compounds were prepared similarly 10 the procedure of Example 22 Method A from
`the corresponding phthalimido derivative but using aqueous (40%) methylamine instead of
`ethanolic methylamine:
`R
`
`RI00C
`
`COOR2
`
`CH;
`
`N
`H
`
`CH20CH2CH2NH?2
`
`Analysis %
`
`{Theoreticalbrackets)in
`
`Cc
`H
`N
`Example
`R
`R!
`RR?
`mp. (C.)
`§3.9
`5.5
`64
`(a)
`2,3-dichlorophenyl
`CoHs5
`CH3
`131-2°
`(54.2
`5.5
`6.3)
`52.8
`5.5
`5.1
`(52.7
`3.6
`5.3)
`53.25
`4.9
`5.75
`(52.9
`5.1
`5.9)
`$1.8
`5.8
`5.2
`(51.8
`6.0
`5.1)
`54.5
`5.8
`6.0
`(54.2
`5.8
`5.75)
`55.6
`5.9
`10.6
`129-131°
`CoH5
`CH
`2-chioro-pyrid-3-yl-
`()
`
`(35.7 10.25) 5.9
`
`* Isolated as the hemifumarate hemihydrate
`Isolated as the hemifumarate sesquihydrate
`
`2,3-dichloropheny! *
`
`2-chioro-3-trifiuoro-
`methylpheny!
`2,3-dichloropheny!
`
`(b)
`
`(c)
`
`(d)
`
`(e)
`
`CoHs
`
`CH3
`
`CoHs
`
`127-9°
`
`C2Hs
`
`122°
`
`(CH3)2CH
`
`CoHs
`
`105-9°
`
`2,3-dichlorophenyl
`
`CH30CH2CH2— C2H5
`
`88-90°
`
`EXAMPLE 23
`
`Preparation of
`4-(2-Chlorophenyl)-2-[2-(N-methylamino)ethoxyme-
`thyl]-3-ethoxycarbony!-5-methoxycarbonyl]-6-methyl-
`1,4-dihydropyridine maleate
`
`cl
`
`H.
`
`|
`
`CH302C.
`
`CH3
`
`|
`
`N
`H
`
`CO2CH2CH3
`
`(i) Cl3CCH202C.Cl
`“Gizn7Coon
`CH20CH2CH2N--CH3
`CH2Ph
`
`55
`
`60
`
`65
`
`thoxycarbonyl-N-methylamino)ethoxymethyl]deriva-
`tive.
`The said oil (3.0 g) was dissolved in dimethyiformam-
`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 mixture was then decanted and poured into
`water (100 ml) and acidified to pH1 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 NMRandIRto be (apart from thesalt form)
`identic