.
`Unlted States Patent
`.
`Janssen et al.
`
`[19]
`
`_[54]
`[75]
`
`3-PIPERIDINYL-1,2-BENZISOXAZOLES
`Inventors: Cornelus G. M. Janssen, Vosselaar;
`Alfonsus G. Knaeps, Herentals; Ludo
`E. J. Kennis, Turnhout; Jan
`Vandenberk, Beerse, all of Belgium
`Janssen Pharmaceutics N.V., Beerse,
`Belgium
`
`[73] Assignee:
`
`[ ‘ ] Notice:
`
`The portion of the term of this patent
`513bse€1uent
`to OCI- 27’ 2009 has been
`d15cla1med.
`[21] Appl. No.: 932,142
`.
`F1led:
`
`[22]
`
`[60]
`
`[51]
`
`Aug. 19’ 1992
`.
`.
`Related U'S' Application Data
`Division of Ser. No. 422,847, Oct. 17, 1989, Pat. No.
`5,158,952, which is a continuation-in-part of Ser. No.
`267’857’ NOV' 7’ 1988’ abandoned.
`Int. Cl.5 .................. C07D 487/04; C07D 413/04;
`A61K 31/505
`
`|!||||||||il||Illlllllllllllllll||||lIlllllllllIlllllllllllllllllllllllllll
`U5005254556A
`[11] Patent Number:
`
`5,254,556
`
`at:
`
`[45] Date of Patent:
`
`Oct. 19, 1993
`
`[52] US. Cl. ..................................... 514/258; 544/282
`[58] Field of Search ......................... 544/282; 514/258
`[56]
`References Cited
`
`U'S' PATENT DOCUMENTS
`‘ ............. 544 282
`, 6
`4,
`
`______ 544/282
`5,121,223 gfigg; 3:12:35
`5,158,952 10/1992 Janssen ................................ 544/282
`
`Primary Examiner—Mark L. Berch
`Attorney, Agent, or Firm—Charles J. Metz
`
`ABSTRACT
`[57]
`The invention relates to C2.zoalkanoic acid esters of
`3-[2-[4-(6-iluoro-1,2-benzisoxazol-3-yl)—1-piperidiny1]e-
`thyl]-6,
`7,8,9-tetrahydro-9-hydroxy-2
`-methy1-4H-
`pyrido[1,2-a]pyrimidin-4-one, pharmaceutically accept-
`able acid addition salts thereof, and enantiomeric forms
`thereof, which are useful
`in the treatment of warm-
`blooded animals suffering from psychotic diseases.
`
`6 Claims, No Drawings
`
`Mylan V. Janssen (IPR2020-00440) EX. 1013 p. 001
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1013 p. 001
`
`

`

`1
`
`5,254,556
`
`2
`and/or R1 is halo, in particular fluoro and more in par-
`ticular 6-fluoro; and/or R2 is methyl.
`Among the above defined groups of compounds of
`formula (1) those compounds wherein R4 is C7.13alkyl,
`in particular heptyl, nonyl, undecyl or tridecyl are of
`particular interest.
`The most interesting compounds within the invention
`are selected from the group consisting of 3-[2-[4-(6-
`fluoro-1,2-benzisoxazol-3-yl)—1-piperidinyl]ethyl]-
`6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4fl-pyrido[l,2-
`a]pyrimidin-4-one,
`the pharmaceutically acceptable
`acid addition salt forms and the enantiomeric forms
`thereof.
`From formula (I) it is evident that the compounds of
`this invention have at least one asymmetric carbon atom
`in their structure, namely the carbon atom bearing the
`R3 substituent. The absolute configuration of this centre
`may be indicated by the stereochemical descriptors R
`and S, this R and S notation corresponding to the rules
`described in Pure Appl. Chem. 1976, 45, 11-30. Unless
`otherwise mentioned or indicated, the chemical desig-
`nation of compounds denotes the mixture of all possible
`stereochemically isomeric forms, said mixtures contain-
`ing all diastereomers and enantiomers of the basic mo-
`lecular structure. Sterochemically isomeric forms of the
`compounds of formula (I) are obviously intended to be
`embraced within the scope of the invention.
`The compounds of formula (I) can generally be pre-
`pared by N-alkylating a 3-piperidinyl-l,2-benzisoxazole
`of formula (II) with an alkylating reagent of formula
`(111) following art-known N-alkylation procedures.
`
`3-PIPERIDINYL-1,2-BENZISOXAZOLES
`
`This application is a division of our copending appli-
`cation Ser. No. 422,847, filed Oct. 17, 1989, now U.S.
`Pat. No. [5,158,952], which in turn was a continuation-
`in-part of application Ser. No. 267,857, filed Nov. 7,
`1988, now abandoned.
`
`BACKGROUND OF THE INVENTION
`
`In EP-A-0,196,l32 there are described a number of
`3-piperidinyl-l,2-benzisoxazoles having antipsychotic
`activity.
`The compounds of the present invention differ there-
`from by the speeific substitution on the (2-C1.4alkyl-
`6,7,8,9-tetrahydro-4-oxo-4B—pyrido[l,2-a]-pyrimidin—3-
`yl)a1kyl substituent at the 1 position of the piperidinyl
`moiety.
`DESCRIPTION OF THE INVENTION
`
`5
`
`10
`
`15
`
`20
`
`invention is concerned with novel 3-
`The present
`piperidinyl-1,2-benzisoxazoles having the formula
`
`
`
`(I)
`
`25
`
`3O
`
`the pharmaceutically acceptable acid addition salts
`thereof,
`and the stereochemically isomeric forms
`thereof, wherein
`Alk is Claalkanediyl;
`R1 is hydrogen, Claalkyl or halo;
`R2 is C1.4alkyl;
`R3 is hydroxy or R4—C(=O)O—; and
`R4 is C1.1galkyl.
`In the foregoing definitions Ciaalkanediyl defines
`bivalent straight and branch chained alkanediyl radicals
`having from 1 to 4 carbon atoms such as, for example,
`methylene,
`1,2-ethanediyl,
`1,3-propanediyl,
`1,4-
`butanediyl and the branched isomers thereof; CMalkyl
`defines straight and branch chained saturated hydrocar-
`bon radicals having from 1 to 4 carbon atoms such as,
`for example, methyl, ethyl, propyl, l-methylethyl, bu-
`tyl, l-methylpropyl, 2-methylpropyl and 1,1-dimethyl-
`ethyl; C1.19alkyl defines CMalkyl radicals as defined
`hereinabove and the higher homologs thereof having
`from 5 to 19 carbon atoms such as, for example, pentyl,
`hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl,
`tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl,
`octadecyl, nonadecyl and the like; halo is generic to
`fluoro, chloro, bromo and iodo. R3 as defined herein-
`above may be substituted on any of the 6,7,8 or 9 posi-
`tions
`of
`the
`6,7,8,9-tetrahydro-2—C1.4alkyl-4I-I_-
`pyrido[1,2-a]pyrimidin-4—one moiety.
`Particular compounds are those compounds of for-
`mula (I) wherein R3 is substituted on the 9 position of
`the
`6,7,8,9-tetrahydro-2-C1.4alkyl-4fl-pyridofl,2-
`a]pyrimidin-4-one moiety.
`More particular compounds within the invention are
`those particular compounds wherein Alk is ethanediyl;
`
`
`
`(11)
`
`N-alkylation reaction
`e0)
`
`50
`
`55
`
`65
`
`In formula (III) W represents an appropriate reactive
`leaving group such as, for example, halo, e.g. chloro,
`bromo or iodo; sulfonyloxy, e.g. methanesulfonyloxy,
`trifluoromethanesulfonyloxy, benzenesulfonyloxy,
`4-
`methylbenzenesulfonyloxy and the like leaving groups.
`Said N-alkylation reaction can conveniently be carried
`out by mixing the reactants, optionally in a reaction-
`inert solvent such as, for example, water, an aromatic
`solvent, e.g. benzene, methylbenzene, dimethylbenzene,
`chlorobenzene, methoxybenzene and the like; a C1-(,alk-
`anol, e.g. methanol, ethanol, l-butanol and the like; a
`ketone, e.g. 2-propanone, 4-methyl-2-pentanone and the
`like; an ester, e.g. ethyl acetate, 'y-butyrolactone and the
`like; an ether, e.g.
`l,1’-oxybisethane, tetrahydrofuran,
`1,4-dioxane and the like; a dipolar aprotic solvent, e.g.
`N,N-dimethylformamide, N,N-dimethylacetamide, di-
`methylsulfoxide, pyridine, l,3-dimethyl-3,4,5,6-tetrahy-
`dro-2(l§)—pyrimidinone,
`l,3-dimethyl—2-imidazolidi-
`
`Mylan V. Janssen (IPR2020-00440) EX. 1013 p. 002
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1013 p. 002
`
`

`

`4
`for example, alkali and earth alkaline metal carbonates,
`hydrogen carbonates, hydroxides, alkoxides or hy-
`drides, e.g. sodium carbonate, sodium hydrogen car-
`bonate, potassium carbonate, sodium hydroxide, sodium
`methoxide, sodium hydride or organic bases such as
`amines, e. g. N,N-diethylethanamine, 4-ethylmorpholine
`and the like bases. Suitable solvents are, for example,
`water; aromatic hydrocarbons, e.g. benzene, methyl-
`benzene, dimethylbenzene and the like; halogenated
`hydrocarbons, e.g. dichloromethane, trichloromethane,
`1,2-dichloroethane and the like;
`lower alkanols, e.g.
`methanol, ethanol, l-butanol and the like; ketones, e.g.
`2-propanone, 4-methyl-2-pentanone and the like; ethers,
`e.g. 1,4-dioxane, tetrahydrofuran and the like; dipolar
`aprotic solvents, e.g. N,N—dimethylformamide, N,N-
`dimethylacetamide, dimethylsulfoxide, l-methyl-Z-pyr-
`rolidinone and the like, or mixtures of such solvents.
`The compounds of formula (I) can also be obtained
`by cyclizing an activated oxime derivative of formula
`
`R3
`
`/
`
`N
`
`R2
`
`N
`
`II
`0
`
`_
`Alk N
`
`/
`
`N—O—L
`OH
`
`(V)
`
`'
`
`R1
`
`5,254,556
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`4O
`
`3
`l-methyl-Z-pyrrolidi-
`l,l,3,3-tetramethylurea,
`none,
`none, nitrobenzene, acetonitrile and the like; or a mix-
`ture of such solvents. The addition of an appropriate
`base such as, for example, an alkali metal or an earth
`alkaline metal carbonate, hydrogen carbonate, hydrox-
`ide, oxide, carboxylate, alkoxide, hydride or amide, e.g.
`sodium carbonate, sodium hydrogen carbonate, potas-
`sium carbonate, sodium hydroxide, calcium oxide, so-
`dium acetate, sodium methoxide, sodium hydride, so-
`dium amide and the like, or an organic base such as, for
`example, a tertiary amine, e.g. N,N-diethylethanamine,
`' N-(l-methylethyl)-2-propanamine, 4-ethylmorpholine,
`l,4-diazabicyclo[2.2.2]octane, pyridine and the like,
`may optionally be used to pick up the acid which is
`formed during the course of the reaction. In some in-
`stances the addition of an iodide salt, preferably an
`alkali metal iodide, or a crown ether, e.g. l,4,7,lO,l3,l6-
`hexaoxa-cyclooctadecane and the like, may be appro-
`priate. Stirring and somewhat elevated temperatures
`may enhance the rate of the reaction; more in particular
`the reaction may be conducted at the reflux temperature
`of the reaction mixture. Additionally, it may be advan-
`tageous to conduct said N-alkylation under an inert
`atmosphere such as, for example, oxygen-free argon or
`nitrogen gas.
`_
`Alternatively, said N-alkylation may be carried out
`by applying art-known conditions of phase transfer
`catalysis reactions. Said conditions comprise stirring the
`reactants, with an appropriate base and optionally
`under an inert atmosphere as defined hereinabove,
`in
`the presence of a suitable phase transfer catalyst such as,
`wherein L is an acid residue and more particularly is
`for example, a trialkylphenylmethylammonium,
`tet-
`formyl, (C1-6alkyl or aryl)-carbonyl, e.g. acetyl, propio-
`raalkylammonium,
`tetraalkylphosphonium,
`tetraaryl-
`nyl, benzoyl and the like; (C1.5alkyl or aryl)oxycarbo-
`phosphonium halide, hydroxide, hydrogen sulfate and
`nyl, e.g. methoxycarbonyl, ethoxycarbonyl, (1,1-dime-
`the like catalysts. Somewhat elevated temperatures may
`thyl)ethoxycarbonyl, phenyloxycarbonyl and the like;
`be appropriate to enhance the rate of the reaction.
`(C1-6alkyl or aryl)sulfonyl, e.g. methanesulfonyl, ben-
`In this and the following preparations, the reaction
`zenesulfonyl,
`4-methylbenzenesulfonyl,
`2-naph-
`products may be isolated from the medium and, if nec-'
`thalenesulfonyl and the like; N-acylaminocarbonyl, e.g.
`essary, further purified according to methodologies
`trichloromethylcarbonylaminocarbonyl and the like.
`generally known in the art such as, for example, extrac-
`Said cyclization reaction of the activated oxime deriva-
`tion, crystallization, trituration and chromatography.
`tive of formula (V) may conveniently be conducted by
`The compounds of formula (I) can also be obtained
`treatment with an appropriate base, preferably in a suit-
`by the cyclization of an oxime of formula (IV), wherein
`able reaction-inert solvent, at temperatures in the range
`Y is a reactive leaving group such as, for example, halo
`from 20° to 200° C., particularly from 50° to 150° C. and
`or nitro. Preferably Y is a halo group and more particu- 45 preferably at
`the reflux temperature of the reaction
`larly fluoro.
`mixture. In some instances however, it may be advanta-
`
`R3
`
`/
`
`N
`
`R2
`
`I
`
`Alk N
`
`N
`
`ll
`0
`
`NOl-I
`
`/
`
`Y
`
`"‘90)
`
`(IV)
`
`RI
`
`Said cyclization reaction of the oxime of formula (IV)
`may conveniently be conducted by treatment with an
`appropriate base, preferably in a suitable reaction-inert
`solvent at temperatures in the range of 20° to 200° C.,
`preferably at 50° to 150° C., and in particular at the
`reflux temperature of the reaction mixture. Or, if desir-
`able, said base may first be added, preferably at room
`temperature, whereupon the thus formed oxime salt is
`cyclized, preferably at an increased temperature and
`more preferably at the reflux temperature of the reac-
`tion mixture. Appropriate bases for said cyclization are,
`
`60
`
`65
`
`geous not to add a base to the reaction mixture and to
`remove the acid liberated during the reaction by destil-
`lation at normal pressure or, if desired, at reduced pres-
`sure. Alternatively, said cyclization may also be ef-
`fected by heating the oxime derivative (V) in vacuo
`without a solvent. Appropriate bases are for example,
`alkali and earth alkaline metal carbonates, hydrogen
`carbonates and organic amines, e.g. sodium carbonate,
`potassium carbonate, sodium hydrogen carbonate, N,N-
`
`Mylan v. Janssen (IPR2020-00440) EX. 1013 p. 003.
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1013 p. 003
`
`

`

`5,254,556
`
`5
`diethylethanamine, 4-ethylmorpholine, 1,4-diazabicy-
`clo[2.2.2]octane, pyridine and the like bases. Suitable
`solvents for said cyclization are, for example, aromatic
`hydrocarbons, e.g. benzene, methylbenzene, dimethyl-
`benzene and the like; ethers, e.g. 1,l'-oxybisethane,
`l,l’-oxybisbutane,
`tetrahydrofuran, 1,4-dioxane,
`l,l’-
`oxybis[2-methoxyethane],
`2,5,8,1 l-tetraoxadodecane
`and the like; dipolar aprotic solvents, e.g. N,N-dime-
`thylformamide, N,N-dimethylacetamide,
`l-methyI-Z-
`pyrrolidinone, .hexamethylphosphoric triamide, pyri-
`dine, acetic anhydride and the like; halogenated hydro-
`carbons, e.g.
`trichloromethane,
`tetrachloromethane,
`1,2-dichloroethane, chlorobenzene and the like sol-
`vents.
`
`The compounds of formula (I) wherein R3 is R4—(C-
`=O)—-O-——, said compounds being represented by for’
`mula (I-b), can be obtained by the O-acylation reaction
`of a compound of formula (I-a) wherein R3 is hydroxy,
`with a carboxylic acid of formula (VI) or a suitable
`reactive functional derivative thereof such as, for exam-
`ple, an acyl halide, symmetric or mixed anhydride, ester
`or amide, acyl azide and the like derivatives. Said func-
`tional derivatives may be prepared following art-known
`methods, for example, by reacting the carboxylic acid
`of formula (VI) with a halogenating reagent such as, for
`example,
`thionyl chloride, phosphorous trichloride,
`phosphoryl chloride, oxalyl chloride and the like, or by
`reacting said carboxylic acid (VI) with an acyl halide
`such as acetyl chloride and the like. Said derivatives
`may be generated in situ, or if desired, be isolated and
`further purified before reacting them with the com-
`pound of formula (I-a).
`
`6
`pyridinium iodide, phosphorus pentoxide, 1,1'-car-
`bonylbis[lH-imidazole], 1,1 ’-sulfonyl bis[ 1 H-imidazole]
`and the like reagents.
`Said O-acylation reactions can conveniently be car-
`ried out by stirring the reactants optionally in a suitable
`reaction-inert solvent such as, for example, a haloge-
`nated hydrocarbon, e.g. dichloromethane,
`trichloro-
`methane and the like; an aromatic hydrocarbon, e.g.
`benzene, methylbenzene and the like; an ether, e.g.
`l,I’-oxybisethane, tetrahydrofuran and the like; or a
`dipolar aprotic solvent, e.g. N,N-dimethylformamide,
`N,N-dimethylacetamide, or pyridine and the like. In
`some instances it may be appropriate to employ an ex—
`cess of one of the reagents as solvent. The water, acid,
`alcohol or amine which is liberated during the course of
`the reaction may be removed from the reaction mixture
`by art-known procedures such as, for example, azeo-
`tropical destillation, complexation, salt formation and
`the like methods. In some instances particularly the
`addition of a suitable base such as, for example, a ter-
`tiary amine, e.g. N,N-diethyl-ethanamine, 4-ethy1mor-
`pholine, pyridine or N,N-dimethyl-4-arninopyridine,
`may be appropriate. Further, in order to enhance the
`rate of the reaction, said acylation reaction may advan-
`tageously be conducted at a somewhat elevated temper-
`ature, and in particular instances at the reflux tempera-
`ture of the reaction mixture.
`The compounds of formula (I) can also be prepared
`following art-known cyclization procedures for prepar-
`ing pyrimidin-4-ones such as, for example, by reacting
`an amidine of formula (VII) with a B-dicarbonyl inter-
`mediate of formula (VIII), or by cyclizing a reagent of
`
`10
`
`15
`
`20
`
`25
`
`30
`
`no
`
`/
`
`N
`
`|
`
`ll
`0
`
`R4—(C=O)—OH (V12 5
`g-acylation reaction
`
`Alk—N
`
`
`
`(I-a)
`
`R4—coo
`
`/
`
`N
`
`R2
`
`\lN
`
`II
`o
`
`Alk—N
`
`
`
`(H!)
`
`formula (IX) with an enamine of formula (X). In formu-
`Alternatively, the compound of formula (La) and the
`carboxylic acid of formula (VI) may also be esterified in 65 lae (VIII), (IX) and (X) R5 represents an appropriate
`the presence of a suitable reagent capable of forming
`leaving group such as, for example, C1.6alkyloxy, hy—
`droxy, halo, amino, mono- or di-(C1-6alkyl)amino and
`esters such as, for example, a dehydrating reagent, e.g.
`the like.
`dicyclohexylcarbodiimide,
`2-chloro-1—methyl-
`
`Mylan v. Janssen (IPR2020-00440) EX. 1013 p. 004
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1013 p. 004
`
`

`

`5,254,556
`
`
`
`7
`
`R2
`
`0
`
`\
`
`+ 0\
`
`R5
`
`Alk —N
`
`NH;
`
`'N
`
`R3
`
`(VII)
`
`(VIII)
`
`(I)
`
`
`
`NH;
`
`R2
`
`+ 0\
`
`RS
`
`Alk—N
`
`R5
`
`IN
`
`R3
`
`(IX)
`
`(X)
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`(I-a)
`
`HO
`
`can be obtained by converting the racemic mixtures of
`the compounds of formula (I-a) with a suitable resolv-
`ing reagent such as, for example, a chiral acid, e.g. tar-
`taric, malic and mandelic acids, campher sulfonic acid,
`4,5-dihydro-lH-2-benzopyran-2-carboxylic acid and the
`like, or the reactive functional derivatives thereof, e.g.
`the acyl halides, to a mixture of diastereomeric salts or
`compounds, particularly esters; physically separating
`said mixtures of diastereomeric salts or compounds by,
`for example, selective crystallization or chromato-
`graphic techniques, e.g. liquid chromatography and the
`like methods; and finally converting said separated dias-
`tereomeric salts or compounds into the corresponding
`enantiomeric forms of the compounds of formula (I-a)
`by hydrolysis in an acidic or basic aqueous medium,
`optionally at an elevated temperature.
`Some of the intermediates and starting materials for
`use in the foregoing preparations are known com—
`pounds, while others are novel. The intermediates of
`formula (II) and methods of preparing them are known
`from EP-A-O,l96,132. The alkylating reagents of for—
`mula (III) are novel and can be prepared according to
`art-known methodologies of preparing similar com-
`pounds and will be described hereinafter in more detail.
`By condensing an optionally protected 2-aminopyri-
`dine derivative (XI) with an a-acyl lactone (XII) in the
`presence of an activating reagent in a suitable reaction-
`inert solvent, an intermediate of formula (XIII) can be
`obtained.
`
`Said cyclization reactions may generally be carried
`out by stirring the reactants, optionally in the presence
`of a suitable reaction-inert solvent such as, for example,
`an aliphatic, alicyclic or aromatic hydrocarbon, e.g.
`hexane, cyclohexane, benzene and the like; pyridine,
`N,N-dimethylformamide and the like dipolar aprotic
`solvents. In order to enhance the rate of the reaction it
`may be appropriate to increase the temperature, more
`particularly, it may be recommendable to carry out the
`reaction at the reflux temperature of the reaction mix-
`ture.
`
`The compounds of formula (I) have basic properties
`and, consequently, they may be converted to their ther-
`apeutically active non-toxic acid addition salt forms by
`treatment with appropriate acids, such as, for example,
`inorganic acids, such as hydrohalic acid, e.g. hydro-
`chloric, hydrobromic acid and the like, sulfuric acid,
`nitric acid, phosphoric acid and the like; or organic
`acids, such as, for example, acetic, propanoic, hydroxy-
`acetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedi-
`oic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-
`2-butenedioic,
`2-hydroxybutanedioic,
`2,3—dihydrox-
`ybutanedioic,
`2-hydroxy-l,2,3-propanetricarboxylic,
`methanesulfonic, ethanesulfonic, benzenesulfonic, 4-
`methylbenzenesulfonic,
`cyclohexanesulfamic,
`2-
`hydroxybenzoic, 4-amino-2-hydroxybenzoic and the
`like acids. Conversely the salt form can be converted
`into the free base form by treatment with alkali.
`The term acid addition salt as used hereinabove also
`comprises the solvates which the compounds of formula
`(I) are able to form and said solvates are meant to be
`included within the scope of the present
`invention.
`Examples of such solvates are e. g., the hydrates, alcoho-
`lates and the like.
`_
`Enantiomeric forms of the compounds of formula
`(I-a)
`
`Mylan V. Janssen (IPR2020-00440) EX. 1013 p. 005
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1013 p. 005
`
`

`

`9
`
`5,254,556
`
`10
`
`P—O
`
`\ NHz
`
`+
`
`’ N
`
`(XI)
`
`‘
`
`0
`II
`
`O
`.II
`
`R2—-—>
`
`0
`
`KAlk
`
`(X11)
`
`P—O
`
`/ z N
`
`N
`
`\
`
`R2
`
`Alk—W
`
`\/\l[
`II
`o
`(XIII)
`
`In the formulae (XI), (XIII) and hereinafter whenever it
`occurs, P represents hydrogen or a protective group
`which can be readily removed such as, for example, a
`hydrogenolyzable group, e.g. phenylmethyl and the
`like; a hydrolyzable group, e.g. methyl and the like.
`Appropriate activating reagents for said condensation
`reaction typically are halogenating reagents such as, for
`example, phosphoryl chloride, phosphoryl bromide,
`phosphorous trichloride, thionyl chloride and the like
`reagents.
`The subsequent catalytic hydrogenation of intermedi-
`ate (XIII) in a suitable reaction-inert solvent in the pres-
`ence of hydrogen, optionally at an elevated temperature
`and/or pressure, with a catalyst such as, for example,
`palladium-on-charcoal and the like, can yield a pro-
`tected intermediate (XIV) in case P is an alkyl group
`such as, for example, methyl;
`
`/
`
`N
`
`R2
`
`N
`
`H
`0
`
`Aik—W
`
`thane, 1,4-dioxane, tetrahydrofuran, 2-methoxyethanol
`and the like; halogenated hydrocarbons, e.g. trichloro-
`methane and the like; dipolar aprotic solvents, e. g. N,N-
`dimethylformamide and the like; esters, e.g. ethyl ace-
`tate, butyl acetate and the like; or a mixture of such
`solvents.
`
`The intermediate (XIV) wherein P represents an
`alkyl group may be deprotected to a reagent of formula
`(III-a) by heating the former with concentrated hydro-
`bromic or hydroiodic acid or by reaction with Lewis
`acids such as, for example, boron trihalides, e.g. boron
`trifluoride, boron trichloride and in particular boron
`tribromide; iodotrimethylsilane; or aluminum chloride
`and the like Lewis acids.
`
`The intermediate of formula (III-a) may be 0-
`acylated with a carboxylic acid of formula (VI) or a
`functional derivative thereof as defined hereinabove, to
`an alkylating reagent of formula (III-b) wherein R3 is
`R4—C(=O)——O— following the same procedures as
`described hereinabove for the O-acylation of the com-
`pounds of formula (I-a).
`
`I
`R4 c=o H
`(III-a) Q—acylation reaction
`
`R4—C00
`
`/
`
`N
`
`R2
`
`N
`
`\/\|[
`ll0
`(III-b)
`
`Alk—W
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`The intermediates of formula (IV) may be prepared
`by N-alkylating a reagent of formula (III) with an oxime
`derivative of formula (XV) following the same proce-
`dures as described hereinabove for the preparation of
`the compounds of formula (I) from the intermediates
`(II) and (III). The derivatives (XV) are known from
`EP-A-0, 196, 132.
`I
`
`/
`
`N
`
`R2
`
`-45
`
`(XIV)
`
`or, on the other hand, when P is hydrogen or a hy-
`drogenolyzable group such as, for example, phenyl-
`methyl, an alkylating reagent of formula (III-a) wherein
`R3 is hydroxy can be obtained directly.
`
`55
`
`(II-a)
`
`”N
`
`50
`
`R3
`
`N
`
`\l +
`
`AIk—W
`
`ll
`0
`(III)
`
`NOH
`
`/
`
`Y
`
`E-alkylation
`reaction
`
`a (I
`
`V
`
`)
`
`R1
`
`(XV)
`
`65
`
`Suitable solvents for said catalytic hydrogenation reac?
`tion comprise water; C14alkanols, e.g. methanol, etha»
`no_l, 2-propanol and the like; ethers, e.g. 1,1’-oxybise-
`
`The intermediates of formula (V) may be obtained by
`reacting an oxime of formula (XVI) with an activated
`acid derivative of formula L-Wl (XVII),
`
`Mylan V. Janssen (IPR2020-00440) EX. 1013 p. 006
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1013 p. 006
`
`

`

`R3
`
`11
`
`/
`
`N
`
`R2 .
`
`N \l
`
`ll
`O
`
`_
`Alk N
`
`(XVI)
`
`5,254,556
`
`12
`
`_ l
`L W (XVII) a (V),
`
`NOH
`
`/
`
`_
`
`OH
`
`R1
`
`wherein L is an acid residue as defined hereinabove and
`W1 represents a reactive leaving group such as, for
`example, halo, (aryl or C1.6alkyl)carbonyloxy, (aryl or
`C1-6alkyl)oxy and the like. As typical examples of the
`reagent of formula (XVII) there may be mentioned
`carboxylic acid anhydrides, e.g. acetic anhydride, ben-
`zoic anhydride and the like; carboxylic acid halides, e.g.
`acetyl chloride, benzoyl chloride and the like; carbono-
`chloridates, e.g. methyl, ethyl or phenyl carbonochlori-
`date and the like; di(C1.5alkyl)carbonates, e.g. dimethyl-
`carbonate, diethylcarbonate and the like. The reaction
`of the intermediates (XVI) with the activated acid de-
`rivatives (XVII) may be carried out following art-
`known esterification procedures, e.g. by stirring the
`reactants at a somewhat elevated temperature, prefera-
`bly in a reaction-inert solvent such as, for example, an
`aromatic hydrocarbon, e.g. benzene, methylbenzene
`and the like; a halogenated hydrocarbon, e.g. dichloro-
`methane, trichloromethane and the like; a ketone, e.g.
`2-propanone, 4-methyl-2-pentanone and the like; an
`ether, e.g. 1,l'-oxybisethane, 1,4-dioxane and the like, a
`dipolar aprotic solvent, e.g. N,N-dimethylformamide,
`pyridine and the like solvents. In some instances it may
`be appropriate to add a suitable base such as, for exam-
`ple,
`N,N-diethylethanamine,
`N-(l-methylethyl)-2-
`propanamine,
`4-ethylmorpholine, N,N-dimethyl-4-
`aminopyridine and the like bases to the reaction mix-
`ture.
`
`The intermediate of formula (XVI) in turn may be
`prepared by N-alkylating a reagent of formula (III) with
`an oxime derivative of formula (XVIII)
`
`R3
`
`N
`
`/
`
`N
`
`R2
`
`l
`
`+
`
`Alk—W
`
`ll
`0
`(III)
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`HN
`
`NOH
`
`/
`
`OH
`
`_
`E-alkylanon
`reaction
`
`XV
`
`I)
`
`5 (
`
`55
`
`R]
`
`(XVIII)
`
`following the same procedures as described herein-
`above for the preparation of the compounds of formula
`(I) from the intermediates (II) and (III).
`The compounds of formula (I) and some of the inter-
`mediates in the present invention contain at least one
`asymmetric carbon atom. Pure stereochemically iso-
`meric forms of said compounds and said intermediates
`
`65
`
`can be obtained by the application of art-known proce-
`dures. For example, diastereoisomers can be separated
`by physical methods such as selective crystallization or
`chromatographic techniques, e.g. counter current dis-
`tribution, liquid chromatography and the like methods.
`Enantiomers can be obtained from racemic mixtures by
`first converting said racemic mixtures with suitable
`resolving agents such as, for example, chiral acids, to
`mixtures of diastereomeric salts or compounds;
`then
`physically separating said mixtures of diastereomeric
`salts or compounds by, for example, selective crystalli-
`zation or chromatographic techniques, e.g. liquid chro-
`matography and the like methods; and finally convert-
`ing said separated diastereomeric salts or compounds
`into the corresponding enantiomers.
`Pure stereochemically isomeric forms of the com-
`pounds of formula (I) may also be obtained from the
`pure stereochemically forms of the appropriate interme-
`diates and starting materials, provided that the interven-
`ing reactions occur stereospecifically. The pure and
`mixed stereochemically isomeric forms of the com-
`pounds of formula (I) are intended to be embraced
`within the scope of the present invention.
`The compounds of formula (I), the pharmaceutically
`acceptable acid addition salts and stereochemically iso-
`meric forms thereof, are potent antagonists of neuro-
`transmitters and in particular of the mediators serotonin
`and dopamine. Antagonizing said mediators will sup-
`press or relieve a variety of symptoms associated with
`phenomena induced by the release,
`in particular the .
`excessive release, of these mediators. Therapeutic indi-
`cations for using the present compounds are mainly in
`the CNS area, the gastrointestinal and cardiovascular
`field and related domains. The compounds of formula
`(I) are particularly useful as antipsychotic agents. Sero-
`tonin antagonists are reportedly effective in combatting
`psychoses, aggressive behaviour, anxiety, depression
`and migraine. Dopamine receptor antagonists are
`known to have neuroleptic properties. Combined
`serotonin-dopamine antagonists are especially interest-
`ing as they appear to offer relief of both the positive and
`negative symptoms of schizophrenia. Further the pres-
`ent compounds also appear to be useful therapeutic
`agents for combatting autism. Therapeutic applications
`in the gastrointestinal field comprise their use as, for
`instance, anti-diarrhoeals,
`inhibitors of gastro-oeso-
`phageal reflux and particularly antiemetics, e.g. in can-
`cer patients receiving chemotherapy and radiation
`treatment. Further, serotonin is a potent broncho- and
`vasoconstrictor and thus the present antagonists may be
`used against hypertension and vascular disorders. In
`addition, serotonin antagonists have been associated
`with a number of other properties such as, the suppres-
`sion of appetite and promotion of weight loss, which
`may prove effective in combating obesity; and also the
`
`Mylan V. Janssen (IPR2020-00440) EX. 1013 p. 007
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1013 p. 007
`
`

`

`5,254,556
`
`13
`alleviation of withdrawal symptoms in addicts trying to
`discontinue drinking and smoking habits.
`The compounds of formula (I) show the additional
`advantage of being eliminated rather slowly from the
`body and thus of being long acting. This can be evi-
`denced, for example, by measuring the plasma levels
`after oral administration to dogs and by the long acting
`antiemetic effect exerted by the present compounds on
`dogs challenged with the dopamine agonist apomor-
`phine. Especially the compounds of formula (I) wherein
`R3 is a higher alkylcarbonyloxy radical have a long
`duration of action. Hence, the compounds of formula (I)
`only need to be administered at relatively large inter-
`vals, e.g. several days or weeks, the actual time of ad-
`ministration depending on the nature of the compound
`of formula (I) used and the condition of the subject to be
`treated. Consequently,
`the present compounds allow
`for a more efficient therapy: the slow elimination facili-
`tates maintaining a stable plasma concentration at a
`non-toxic, effective level and the reduction in the num-
`ber of administrations may be expected to result in bet-
`ter compliance of the subject to be treated with the
`prescribed medication.
`.
`In view of their useful pharmacological properties,
`the subject compounds may be formulated into various
`pharmaceutical forms for administration purposes. To
`prepare the pharmaceutical compositions of this inven-
`tion, an effective amount of the particular compound, in
`acid addition salt or base form, as the active ingredient
`is combined in intimate admixture with a pharmaceuti-
`cally acceptable carrier, which may take a wide variety
`of forms depending on the form of preparation desired
`for administration. These pharmaceutical compositions
`are desirably in unitary dosage form suitable, prefera-
`bly, for administration orally, rectally, percutaneously,
`or by parenteral injection. For example, in preparing
`the compositions in oral dosage form, any of the usual
`pharmaceutical media may be employed, such as, for
`example, water, glycols, oils, alcohols and the like in the
`case of oral
`liquid preparations such as suspensions,
`syrups, elixirs and solutions; or solid carriers such as
`starches, sugars, kaolin, lubricants, binders, disintegrat-
`ing agents and the like in the case of powders, pills, .
`capsules and tablets. Because of their ease in administra-
`tion, tablets and capsules represent the most advanta-
`geous oral dosage unit form, in which case solid phar-
`maceutical carriers are obviously employed. For paren-
`teral compositions,
`the carrier will usually comprise
`sterile water, at least in large part, though other ingredi-
`ents, for example, to aid solubility, may be included.
`Injectable solutions, for example, may be prepared in
`which the carrier comprises saline solution, glucose
`solution or a mixture of saline and glucose solution.
`Injectable solutions containing compounds of formula
`(I) wherein R3 is R4—C(=O)—-—-O— may be formulated
`in an oil for prolonged action. Appropriate oils for this
`purpose are, for example, peanut oil, sesame oil, cotton-
`seed oil, corn oil, soy bean oil, synthetic glycerol esters
`of long chain fatty acids and mixtures of these and other
`oils. Injectable suspensions may also be prepared in
`which case appropriate liquid carriers,
`suspending
`agents and the like may be employed. In the composi-
`tions suitable for percutaneous administration, the car-
`rier optionally comprises a penetration enhancing agent
`and/or a suitable wettable agent, optionally combined
`with suitable additives of any nature in minor propor-
`tions, which additives do not cause any significant dele-
`terious effects on the skin. Said additives may facilitate
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`4O
`
`45
`
`50
`
`55
`
`65
`
`14
`the administration to the skin and/or may be helpful for
`preparing the desired compositions. These composi-
`tions may be administered in various ways, e.g., as a
`transdermal patch, as a spo