`
`"3‘P'F'"—-———
`
`71-m-
`
`. fl//// /5/
`
`
`
`The present invention relates to imide deriva-
`
`tives, and their production and use. More particularly, it
`
`relates to novel
`
`imide compounds and their acid addition
`
`salts, and their production processes and their use as anti-
`
`psycotic agents (neuroleptic agents, anti—anxiety agents),
`
`especially for therapy of schizophrenia, senile insanity,
`
`manic—depressive psychosis, neurosis, etc.
`
`There are known some imide compounds having an
`
`antipsycotic activity, of which typical examples are as
`
`flfollows:
`'
`Structure
`
`Remarks
`
`Tiaspirone;
`
`/%>
`
`JP—A—61-251683,
`:_(CH2)4-Nbrim JP-A-53—110576
`
`0
`
`N-(CHz )4 Q<:>
`
`Buspirone;
`The Merck Index,
`
`1.1.: 229 {1989)
`
`O
`
`0
`
`O
`
`0
`
`-2(CH -NCN-<::\>
`
`Gepirone
`The Merck Index,
`
`“1;, 689 (1999)
`
`JP-B~01—28756
`
`N
`
`«cm-w >
`
`\_/
`
`[q-
`
`Page 1 of 92
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`SLAYBACK EXHIBIT 1048
`
`Page 1 of 92
`
`SLAYBACK EXHIBIT 1048
`
`
`
`i.
`
`- 2 -
`
`Structure
`
`Remarks
`
`0
`\1 CH
`
`N‘
`
`N
`
`'
`
`US-A-4,745,117
`
`JP-A-01~199967
`
`N\
`
`S
`
`N\
`
`0
`
`F .
`
`0
`
`o I
`
`o
`
`These conventional
`
`imide compounds are charac—
`
`teristic in that the imide portion and the piperazine or
`
`piperidine ring are bonded together with intervention of a
`
`straight alkylene chain.
`
`Conventional antipsychotic agents are generally.
`
`accompanied by a central or peripheral system side effect
`
`such as extrapyramidal motor disturbance (e.g. Parkinsonism)
`
`and depression of blood pressure (e.g. orthostatic hypo-
`
`tension) and produce a great problem on clinic (e.g. L.S.
`
`Goodman et al.:
`
`The Pharmacological Basis of Therapeutics,
`
`New York, p. 38? (1985); Gendai Iryo (Modern Medical
`
`Therapy), 23, p._22 (1990)).
`
`The problem underlying the present invention is to
`
`provide an excellent psychotic agent suppressed in the above
`
`side effect as generally observed on the conventional anti—
`psychotic agents. An extensive study has been made. As the
`
`result, it has been found that imide compounds wherein the
`
`imide portion and the piperazine or piperidine ring are
`
`Page 2 of 92
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`SLAYBACK EXHIBIT 1048
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`Page 2 of 92
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`SLAYBACK EXHIBIT 1048
`
`
`
`bonded with intervention of an alkylene chain comprising a
`
`non-aromatic hydrocarbon ring therein Show the desired
`
`pharmacological action. Any imide compound wherein the
`
`alkylene chain present between the imide portion and the
`
`piperazine or piperidine ring comprises a non-aromatic
`
`hydrocarbon ring has never been known.
`
`The present inven—
`
`tion is based on the above findings.
`
`Accordingly, an object of the present invention is
`
`to provide an imide compound of the formula:
`
`/’_\
`Z-D-N
`9-Ar
`
`(I)
`
`wherein
`
`Z is a group of the formula:
`
`0
`
`/
`
`..
`
`/
`
`R1
`
`R2
`
`(CH2) n
`
`R3
`
`R4
`
`in which E is a carbonyl group or a sulfonyl group, R1, R2,
`
`R3 and R4 are each a hydrogen atom or a lower alkyl group,
`
`or R1 and R2 or R1 and R3 may be combined together to make a
`
`non—aromatic hydrocarbon ring or R1 and R3 may be combined“
`
`together to make an aromatic ring, said nonmaromatic hydro~
`
`carbon ring being optionally bridged with a lower alkylene
`group or an oxygen atom therein and said aromatic hydro-
`
`carbon ring, said non—aromatic hydrocarbon ring and said
`
`lower alkylene group being each optionally substituted with
`
`«60*
`
`W “
`
`935
`
`F—H—‘h—
`
`Page 3 of 92
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`SLAYBACK EXHIBIT 1048
`
`Page 3 of 92
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`SLAYBACK EXHIBIT 1048
`
`
`
`at least one lower alkyl, and n is an integer of 0 or 1;
`
`D is a group of the formula:
`
`~(CH2)p-A-{CH2)q-
`
`in which A is a non—aromatic hydrocarbon ring Optionally
`
`bridged with a lower alkylene group or an oxygen atom, said
`non—aromatic hydrocarbon ring and said lower alkylene group
`
`being each optionally substituted with at least one lower
`
`alkyl, and p and q are each an integer of 0,
`
`1 or 2; and
`
`Ar is an aromatic group, a heterocyclic aromatic group,
`
`a benzoyl group, a phenoxy group or a phenylthio group and G
`
`is
`
`:N-,
`
`>CH- or
`"‘5.
`group and G is /C=, all of the above groups being each
`
`:COH— or Ar is a biphenylmethylidene
`
`optionally substituted with at least one of lower alkyl,
`
`lower alkoxy and halogen;
`
`and its acid addition salts.
`
`In the above significances,
`
`the term "lower" is
`
`intended to mean generally a group having not more than 8
`
`carbon atoms, particularly not more than 5 carbon atoms,
`
`unless otherwise specified.
`
`The term "lower alkyl" includes
`
`an alkyl group preferably having not more than 4 carbon
`
`atoms (e.g. methyl, ethyl, propyl, 2—propyl, butyl).
`
`The
`
`term "lower alkoxy" covers an alkoxy group preferably having
`
`not more than 4 carbon atoms (e.g. methory, ethoxy, propoxy,
`
`2—propoxy, butoxy).
`
`The term "lower alkylene“ covers an
`
`alkylene group preferably having not more than 3 carbon
`
`Page 4 of 92
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`SLAYBACK EXHIBIT 1048
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`SLAYBACK EXHIBIT 1048
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`
`
`
`
`atoms
`
`(e.g. methylene, ethylene,
`
`trimethylene).
`
`The term
`
`"halogen“ includes chlorine, bromine,
`
`iodine and fluorine.
`
`The non—aromatic hydrocarbon ring includes
`
`particularly the one having not more than 7 carbon atoms
`
`such as a cycloalkane ring having not more than 7 carbon
`
`atoms or a cycloalkene ring having not more than 7 carbon
`
`atoms. Examples of the cycloalkane ring include cyclo-
`
`propane, cyclobutane, cyclopentane, cyclohexane and
`
`cyclo-
`
`heptane. Examples of the cycloalkene ring are cyclopentene,
`
`cyclohexene, cycloheptene, etc.
`
`The non—aromatic hydrocarbon ring bridged with a
`
`lower alkylene group or an oxygen atom may be,
`
`for instance,
`
`the one having not more than 10 ring carbon atoms and
`
`includes specifically bicyclo[1.1.1]pentane, bicyclo—
`
`[2.1.1]hexane, bicyclo[2.1.l]hex-2—ene, bicyclo[2_2.1]—
`
`heptane, bicyclo[2.2.1]hept-2-ene, bicyclo[2.2.2]octane,
`
`bicyclo[2.2.2}oct—2-ene, bicyclo[4.1.1]octane, bicycle—
`
`[4.1.1}oct—2—ene, bicyclo[4.1.1]oct~3~ene, bicyclo[3.2.1]-
`
`octane, bicyclol3.2.1]oct—2—ene, bicyclof3.2.l]oct—3-ene,
`
`bicyclo[3.2.l]oct—6-ene, bicyclo[3.2.21nonane, bicycle-
`
`[3.2.2]non—2—ene, bicyclof3.2.2]non—3—ene, bicyclo[3.2.2]—
`
`non-6-ene, 2—oxabicyclo[1.1.llbutane, 2—oxabicyclo[2.l.l}-
`
`pentane, 2—oxabicyclo[2.1.1]pent—4—ene, 7-oxabicyclo[2.2.l]-
`hexane, 7—oxabicycloi2.2.llhexe2—ene, 7—oxabicyclo[4.l.l]—
`
`heptane, 7—oxabicyclo[4.1.llhept-Z—ene, 7—oxabicyclo[4.1.1]—
`
`hept-B—ene, 8—oxabicyclo[3.2.1]heptane, 8—oxabicyclo[3.2.l]—
`
`Page 5 of 92
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`SLAYBACK EXHIBIT 1048
`
`
`
`hept—Z—ene, 8-oxabicyolo[3.2.1]hept—3-ene, 8-oxabicyclo—
`
`[3.2.1]hept—6-ene, etc.
`
`The aromatic ring may be,
`
`for instance, any one
`
`having not more than 10 carbon atoms, of which specific
`
`examples are benzene and naphthalene.
`
`The non-aromatic hydrocarbon ring represented by
`
`the symbol A may be bonded to the alkylene chains present on
`
`its both sides, i.e. -{CH2)P- and -(CH2)q—, at the 1— and
`
`1-positions,
`the l- and 2-positions,
`the 1- and 4-positions or the like.
`
`the 1— and 3-positions,
`I
`
`The aromatic group represented by the symbol Ar
`
`may be monocyclic, bicyclic or the like and have usually not
`
`more than 10 carbon atoms, and its specific examples are
`
`phenyl, naphthyl, etc.
`
`The heterocyclic aromatic group
`
`represented by the symbol Ar may be also monocyclic, bi—
`
`cyclic or the like.
`
`The monocyclic heterocyclic aromatic
`
`group may be the one, for instance, having not more than 6
`
`carbon atoms and not more than 4 hetero atoms chosen from
`
`nitrogen, oxygen and sulfur, and its specific examples are
`
`pyridyl, pyrimidinyl, thiazolyl, oxazolyl,
`
`isoxazolyl,
`
`isothiazolyl, furyl,
`
`imidazolyl, etc.
`
`The bioyclic hetero—
`
`cyclic aromatic group may be the one,
`
`for instance, having
`
`not more than 10 carbon atoms and not more than 5 hetero
`
`atoms chosen from nitrogen, oxygen and sulfur, and its
`
`specific examples are a benzologous condensed ring group
`
`(e.g. benzisothiazolyl, benzisoxazolyl, benzofuryl,
`
`Page 6 of 92
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`SLAYBACK EXHIBIT 1048
`
`
`
`quinolyl,
`
`isoquinolyl,
`
`indolyl,
`
`indazolyl, benzimidazolyl,
`
`benzoxazolyl), naphthyridinyl, pteridinyl,
`
`thienofuryl,
`
`imidazothiophenyl,
`
`imidazofuryl, etc.
`
`The present invention covers the acid addition
`
`salt formed between the imide compound (I) and an organic or
`
`inorganic acid.
`
`Examples of the inorganic acid are hydro-
`
`chloric acid, hydrobromic acid, hydroiodic acid, sulfuric
`
`acid, etc., and examples of the organic acid are acetic
`
`acid, oxalic acid, citric acid, malic acid, tartaric acid,
`
`maleic acid,
`
`fumaric acid, etc.
`
`The imide compound (I) can have stereo and optical
`
`isomers, and this invention involves these isomers or their
`
`.mixtures as well.
`
`Among various groups represented by the symbol Ar,
`
`preferred are a bicyclic heterocyclic aromatic group, a
`
`naphthyl group, a bensoyl group, a phenoxy group, a phenyl—
`
`thio group, a biphenylmethylidene group, etc.,
`
`these groups
`
`being optionally substituted with at least one of lower
`
`alkyl,
`
`lower alkoxy and halogen. More preferred are a
`
`benzologous condensed ring group, a naphthyl group, a
`
`benzoyl group, a phenoxy group, a phenylthio group, etc.,
`
`these groups being optionally substituted with at least one
`
`of lower alkyl,
`
`lower alkoxy and halogen.
`
`The most
`
`preferred are benzisothiazolyl, benzisoxazolyl,
`
`indazolyl,
`
`indolyl, benzoyl, phenoxy, phenylthio, etc., which are
`
`optionally substituted with at least one of lower alkyl,
`
`Page 7 of 92
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`SLAYBACK EXHIBIT 1048
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`Page 7 of 92
`
`SLAYBACK EXHIBIT 1048
`
`
`
`- 00%
`4
`
`
`q§_—
`
`lower alkoxy and halogen.
`
`,Preferred examples of the group represented by the
`
`symbol 3 are those of the following formulas:
`
`(2'1)
`
`0
`
`N—
`8/
`
`L
`
`E
`
`R5
`
`wherein L is —CH2-CH2— or -CH=CH—, E is a lower alkylene
`
`group optionally subsituted with lower alkyl or an oxygen
`
`atom, R5 is a hydrogen atom or a lower alkyl group and B is
`
`a carbonyl group or a sulfonyl group,
`
`(2—2)
`
`'
`
`AD‘
`\
`
`,4
`
`R5
`
`fie
`
`0
`
`_
`
`B/
`
`deli..—
`
`-.
`wherein L, E, R
`
`5
`
`.
`and B are each as defined above,
`
`(2—3)
`
`/[o$7(
`
`\
`
`flfigfl,flee
`
`
`
`wherein R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 are
`
`each a hydrogen atom or a lower alkyl group, or two of those
`
`Page 8 of 92
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`SLAYBACK EXHIBIT 1048
`
`Page 8 of 92
`
`SLAYBACK EXHIBIT 1048
`
`
`
`
`
`.
`
`I
`
`'
`
`‘
`
`r
`I
`
`I
`
`.
`
`.
`
`.
`
`present at the neighbouring positions each other may be
`
`combined together to make a bond {i.e.
`
`forming a double bond
`
`between said two positions] and B is as defined above;
`
`r_,.___H
`
`(2—4)
`
`'
`
`. at
`/\\\
`
`R16
`
`0
`
`N-
`
`3/
`
`_
`
`R4
`
`=r§,,.___— wherein R16 and R17 are each a hydrogen atom or a lower
`
`alkyl group, or they may be taken together to make a
`
`saturated hydrocarbon ring, preferably a cycloalkane ring
`
`having not more than 7 carbon atoms (e.g. cyclopropaner
`
`cyclobutane, cyclopentane, cyclohexane, cycloheptane) and
`
`cr————~u—-
`
`R4 and B are each as defined above, and
`
`(3-5)
`
`fl:r*"‘*
`
`,_¢.——-—~
`
`TEVWL
`
`0
`
`B
`wherein B is as defined above.
`
`More preferred examples of the group represented
`
`by the symbol 2 are those of the following formulas:
`(Z-l')
`
`/__._.___.../
`
`Page 9 Of 92
`
`I
`
`SLAYBACK EXHIBIT 1048
`
`Page 9 of 92
`
`SLAYBACK EXHIBIT 1048
`
`
`
`J
`
`a
`
`|
`
`I
`
`.
`
`.
`
`wherein L'
`
`”#fl_fi_*_‘~‘ above,
`(Z-Z')
`
`{VIP
`
`m
`
`F (z—s')
`
`4(2):}
`
`¢=—-——————
`
`wherein L', E, R5 and B are each as defined above,
`
`wherein 116', 127', R8',_ R5“, 1210', Rll', R12”, R13... R14' and
`
`R1 1 are each a hydrogen atom or a lower alkyl and B is as
`
`defined above;
`
`(3-4')
`
`l/K/Q/f
`
`\
`
`R16
`
`R17
`
`R4
`
`0
`
`“—
`
`B/
`
`c#'*—“"”
`
`4
`wherein R , R
`
`16
`
`, R17 and B are each as defined above, and
`
`Page 10 of 92
`
`'I
`
`/
`
`SLAYBACK EXHIBIT 1048
`
`is —CH ~CH — and E, R5 and B are each as defined
`2
`
`
`
` 2
`
`Page 10 of 92
`
`SLAYBACK EXHIBIT 1048
`
`
`
`_ 11 c
`
`O
`
`K/
`
`N"
`
`(ff—HE (Z-S')
`4*
`
`wherein B is as defined above.
`
`The imide compounds
`
`(I) of the invention are
`
`obtainable by various procedures, of which typical examples
`
`are as shown below.
`
`Procedure (a):-
`
`The imide compound (I)
`
`is obtainable according to
`
`the following scheme:
`
`3
`
`-’/i)1227
`
`‘1
`11
`~c~ICH2)l~A~{CH2)m- —R
`
`18
`
`R
`
`19
`
`~———+
`
`(II)
`HOCHz-(CHZ)l-A—(QHzlm-CHZOH ————+
`
`(III)
`
`G-Ar
`EN
`L_/
`
`{V}
`XCH2~(CH2)l—A-(CH2}m—CH2x ——————————————+
`
`(IV)
`
`f_\
`
`_
`
`(CH 1
`
`-CH
`
`2>m+ GALX
`21
`N/
`\\1CH2)m-CH2
`k—J
`.-
`(VI)
`
`z-H
`
`(VII)
`
`-—————*——+
`
`Z-CH2—{CH2JI-A—(CH2)m-CH2-N
`
`G-Ar
`
`(I-a)
`
`J-
`
`Page 11 of92
`
`.
`
`/ 3 SLAYBACKEXHIBIT 1048
`
`Page 11 of 92
`
`SLAYBACK EXHIBIT 1048
`
`
`
`wherein A, G, Ar and Z are each as defined above and R
`
`and
`
`18
`
`R19 are each a hydroxy group or a lower alkoxy group, or
`
`they may be taken together to represent an oxygen atom, X is
`
`a leaving group such as halogen,
`
`lower alkylsulfonyloxy
`
`(e.g. methanesulfonyloxy), arylsulfonyloxy (e.g. p-toluene—
`
`sulfonyloxy, benzenesulfonyloxy) and l and m are each an
`
`integer of 0 or 1.
`
`Namely,
`
`the compound (II)
`
`is reduced to give the
`
`compound (III).
`
`The reduction may be carried out by treat-
`
`ment with a reducing agent
`
`(e.g. LiAlH4, NaBH4, Ca(BH4)2,
`
`LiAlH2(OCH2CH
`
`2
`
`OCH
`
`3’2)
`
`in an inert solvent at a temperature
`
`of 0°C to the reflux temperature of the reaction mixture to
`
`give the compound (III).
`
`The reducing agent is usually
`
`employed in an amount of about 1 to 10 mol to one mol of the
`
`compound (II). As the inert solvent,
`
`there may be used an
`
`ethereal solvent such as diethyl ether or tetrahydrofuran.
`
`The hydroxy groups in the compound (III) are then
`
`converted respectively into leaving groups to give the
`
`compound (IV). When the leaving group is a halogen atom
`
`(e.g. chlorine, bromine),
`
`the conversion may be carried out
`
`by reacting the compound (III) with thionyl halide (e.g.
`
`thionyl chloride,
`
`thionyl bromide), optionally in the
`
`presence of a base (e.g. pyridine). This reaction is
`
`preferably performed-in a solvent (e.g. pyridine,
`
`tetra—
`
`hydrofuran, dichloromethane) at a temperature of about 0 to
`
`30°C.
`
`The molar proportion of the compound (III) and
`
`Page 12 of 92
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`SLAYBACK EXHIBIT 1048
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`Page 12 of 92
`
`SLAYBACK EXHIBIT 1048
`
`
`
`I
`
`:
`
`.
`
`.
`
`thionyl halide may be usually about
`
`1
`
`:
`
`2 - 4.
`
`When the leaving group is sulfonyloxy,
`
`the
`
`conversion may be effected by reacting the compound (III)
`
`with a sulfonyl halide such as alkylsulfonyl halide {e.g.
`
`methanesulfonyl chloride) or arylsulfonyl halide (e.g.
`
`p-toluenesulfonyl chloride, benzenesulfonyl chloride),
`
`optionally in the presence of a base (e.g.
`
`triethylamine).
`
`This reaction is favorably perfomred in a solvent (e.g.
`
`pyridine,
`
`tetrahydrofuran, dichloromethane, chloroform) at a
`
`temperature of about 0 to 30°C.
`The molar proportion of the
`compound (III) and the sulfonyl halide is usually about 1
`:
`
`2 — 4.
`
`The compound (IV)
`
`is then reacted with the
`
`compound (v)
`
`to give the compound (VI).
`
`The reaction may be
`
`carried out in the presence of a base (e.g. potassium
`
`carbonate, sodium carbonate)
`
`in a solvent such as alcohol
`
`(e.g. methanol, ethanol, propanol, 2—propanol, butanol),
`
`acetonitrile or dimethylformamide at a temperature around
`
`the boiling point of the solvent.
`
`The base and the compound
`
`(V) may be used respectively in amounts of about 0.5 to 2
`
`mol and of about 1 to 1.5 mol to one mol of the compound
`
`(IV).
`
`The compound (V1)
`
`is then reacted with the
`
`compound (VII)
`
`to give the compound {I-a). This reaction is
`
`carried out optionally in the presence of a catalyst and a
`
`base {e.g. potassium carbonate, sodium carbonate, sodium
`
`Page 13 of 92
`
`[
`
`SLAYBACK EXHIBIT 1048
`
`Page 13 of 92
`
`SLAYBACK EXHIBIT 1048
`
`
`
`‘
`
`a
`
`n
`
`l
`
`‘
`
`I
`
`I
`
`.
`
`hydride, potassium hydride)
`
`in an aromatic solvent (e.g.
`
`toluene, xylene, chlorobenzene) at a temperature around the
`
`boiling point of the solvent. As the catalyst, a crown
`
`ether such as dibenzo—IB—crown-G—ether may be used, and its
`
`amount is normally from about 0.1 to 10 % by weight based on
`
`the compound (VI).
`
`The molar proportion of the compound
`
`(VI) and the compound (VII)
`
`to be used is usually about 1
`
`:
`
`1 w 1.5.
`
`Procedure (b):—
`
`The imide compound (I)
`
`is also produced according
`
`fl_____.___
`
`to the following scheme:
`
`AW
`‘\
`
`(IV)
`
`(V)
`
`(VII)
`..___;
`
`..
`2 CH2
`
`._
`
`_
`_ ._
`(CH2)1 A (CH2Jm CHZX
`
`(VIII)
`
`«For
`
`A
`,
`. v
`wherein X, Z, l and m are each as defined above.
`
`1.35 Ht”.
`M.Y.
`N-"K
`
`The compound (IV)
`
`is reacted with the compound
`
`(VII)
`
`in the presence of a base such as an inorganic base
`
`[e.g. potassium carbonate, sodium carbonate, sodium hydride,
`
`potassium hydride)
`
`to give the compound (VIII).
`
`The reac—
`
`tion is usually carried out in-a solvent (e.g. alcohol, di-
`
`methylformamide, acetonitrile); optionally in the coexist-
`
`ence of a reaction aid such as an alkali metal
`
`iodide (e.g.
`
`potassium iodide, sodium iodide), at a temperature around
`
`the boiling point of the solvent.
`
`The amounts of the base,
`
`Page 14 of 92
`
`[
`
`7’
`
`SLAYBACK EXHIBIT 1048
`
`Page 14 of 92
`
`SLAYBACK EXHIBIT 1048
`
`
`
`from about 1
`.
`about 0.1 to 1 mol to one mol of the compound (IV).
`
`from about 0.1 to 1 mol and from
`
`the reaction aid and the compound (VII) may be respectively
`#32
`J%.1.f?7i
`to £=mol,
`§
`t
`I
`M.Y.
`N T.
`M “
`
`The compound (VIII)
`
`is then reacted with the
`
`|
`
`compound (V)
`
`in the presence of a base {e.g. potassium
`
`carbonate, sodium carbonate, sodium hydride, potassium
`
`hydride)
`
`to give the compound (I—a).
`
`The reaction is
`
`normally carried out
`
`in a solvent (e.g. alcohol, dimethyl—
`
`formamide, acetonitrile), optionally in the coexistence of a
`
`reaction aid such as an alkali metal iodide (e.g. potassium
`
`iodide, sodium iodide), at a temperature around the boiling
`
`point of the solvent.
`The amounts of the base and the
`reaction aid may be respectively from about 1 to 2 mol and
`
`from about 0.1'to 1 mol to one mol of the compound (VIII).
`
`The molar proportion of the compound (VIII) and the comp0und
`(V) may be usually about 1
`:
`1 — 1.5.
`-
`
`Procedure to):-
`
`The imide compound (I)
`
`is further obtainable
`
`according to the following scheme:
`
`$557
`
`_ _
`_
`_
`_ _
`_
`H0~(CH2}p A (CH2)q OH ————+ H0 (CH2)p A [CHZJIq OR
`(IX)
`(X)
`
`20
`
`H2N—{CH21p—A-(CH2)q—OR
`
`{XI}
`
`Page 15 of 92
`
`20
`
`[
`
`
`
`
`
`SLAYBACK EXHIBIT 1048
`
`Page 15 of 92
`
`SLAYBACK EXHIBIT 1048
`
`
`
`-16—
`
`20
`
`Z—D—OR
`
`—————
`
`_
`Z-D—OH ————+
`
`(V)
`Z-D—X ——————+ {I}
`
`(XIII)
`
`(XIV)
`
`(xv)
`
`.fl
`
`wherein R1, R2, R3, R4, n, p, q, D, A, B, X and Z are each
`
`as defined above and R20 is a protective group for hydroxy
`
`(e.g. benzyl, halogen, methoxy or nitro-substituted benzyl,
`
`methoxymethyl, methoxyethoxymethyl,
`
`tetrahydrofuranyl).
`
`The compound (IX)
`
`is converted into the compound_
`
`(X) by application of a per se conventional protection
`
`procedure {9.9. T.W. Greene:
`
`"Protective Group in Organic
`
`Synthesis", John Willey & Sons, pages 10—39
`
`(1981))
`
`to the
`
`former. Examples of the protective group for hydroxy thus
`
`introduced are benzyl, substituted benzyl (e.g. halogen-,
`
`methoxy- or nitro—substituted benzyl), methoxymethyl,
`
`methoxyethoxymethyl,
`
`tetrahydrofuryl, etc.
`
`The compound (x)
`
`is then subjected to oxidation,
`
`oximation (i.e. oxime formation) and reduction in this order
`
`to give the compound (XI).
`
`The oxidation may be carried out
`
`by reacting the compound {x} with an oxidizing agent such as
`
`chromic acid or its salt (e.g. chromic anhydride, bichromic
`
`acid).
`
`The oximation may be carried out by reacting the
`
`oxidized product with hydroxylamine in an alcohol at a
`
`temperature of about 0 to 30°C. Hydroxylamine is normally
`
`used in an amount of about 1 to 2 mol to.one mol of the
`
`compound (X).
`
`The reduction may be carried out by reacting
`
`the oximated product with a reducing agent (e.g.
`
`lithium
`
`aluminum hydride)
`
`in an inert solvent (e.g. diethyl ether or
`
`Page 16 of 92
`
`1 % SLAYBACK EXHIBIT 1048
`
`Page 16 of 92
`
`SLAYBACK EXHIBIT 1048
`
`
`
`tetrahydrofuran) at a temperature around the boiling point
`
`of the solvent.
`The amount of the reducing agent is usually-
`from about 1 to i2211101 to one mol of the compound'(x) .
`if? 11””
`The compound (XI)
`thus obtained is reacted with PL:;
`the compound (XII)
`in a solvent {e.g. pyridine,
`toluene,
`:41“!
`
`xylene, chlorobenzene) at a temperature around the boiling
`
`point of the solvent to give the compound (XIII).
`
`The
`
`amount of the compound (XII)
`
`is ordinarily from about 1
`
`to 3
`
`mol to 1 mol of the compound (XI).
`
`The compound (XIII)
`
`is then subjected to elimina-
`
`tion of the protecting group by a per se conventional
`
`procedure (e.g. T.W. Greene:. "Protective group in organic
`
`synthesis", John Wiley & Sons, pages 10—39
`
`(1981))
`
`to give
`
`the compound (XIV).
`
`Conversion of the compound (XIV)
`
`into the compound
`
`(XV)
`
`is acc0mplished by introductin of a leaving group into
`
`the former. When the leaving group is halogen (e.g.
`
`chlorine, bromine),
`
`the compound (XIV) may be reacted with
`
`thionyl halide (e.g.
`
`thionyl chloride,
`
`thionyl bromide)
`
`in
`
`the presence of a base (e.g. pyridine)
`
`in a solvent (e.g.
`
`pyridine,
`
`tetrahydrofuran, dichloromethane) at a temperature
`
`of about 0 to 30°C.
`
`The amount of the thionyl halide is
`
`normally from about 2
`
`to 4 mol to 1 mole of the compound
`
`(XIV).
`
`-
`
`When the leaving group is sulfonyloxy,
`
`the
`
`compound (XIV)
`
`is reacted with a sulfonyl halide such as
`
`Page 17 of 92
`
`SLAYBACK EXHIBIT 1048
`
`Page 17 of 92
`
`SLAYBACK EXHIBIT 1048
`
`
`
`alkylsulfonyl halide (e.g. methanesulfonyl chloride) or
`
`arylsulfonyl halide (e.g. benzenesulfonyl chloride,
`
`p—
`
`toluenesulfonyl chloride) in the presence of a base (e.g.
`
`triethylamine). This reaction is usually carried out in a
`
`solvent (e.g. pyridine,
`
`tetrahydrofuran, dichloromethane,
`
`chloroform) at a temperature of about 0 to 30°C.
`
`The amount
`
`of the sulfonyl halide is normally from about 2 to 4 mol to
`
`one mol of the compound (XIV).
`
`The compound (XV)
`thus produced is reacted with
`the compound (V)
`in the presence of a base in the coexist—
`
`ence of a reaction aid to give the compound (I).
`
`The
`
`reaction is normally performed in a solvent
`
`(e.g. alcohol,
`
`dimethylformamide, acetonitrile) at a temperature around the
`
`boiling point of the solvent. As the base,
`
`there may be
`
`used an inorganic base (e.g. potassium carbonate, sodium
`
`carbonate, sodium hydride, potassium hydride). As the
`
`reaction aid, an alkali metal iodide (e.g. potassium iodide,
`
`sodium iodide)
`
`is usable.
`
`The amounts of the base,
`
`the
`
`reaction aid and the compound (V) are respectively from
`
`about 1 to 2 mol,
`
`from about 0.1 to 1 mol and from about 1
`
`to 1.5 mol to one mol of the compound (XV).
`
`Procedure (d):~
`
`The imide compound (I)
`
`is further obtainable
`
`according to the following scheme:
`
`Page 18 of 92
`
`__
`
`SLAYBACK EXHIBIT 1048
`
`Page 18 of 92
`
`SLAYBACK EXHIBIT 1048
`
`
`
`_ 19 _
`
`G-Ar
`
`x
`X\_._/
`
`(XI) ——-——-+ R
`
`{XVI}
`
`20
`
`G-Ar —)
`O—D—N
`LIJ
`
`/—\
`(XVII)
`
`b
`
`0%
`«(Db
`
`_
`
`r—\
`HO—D-N
`G—Ar
`\_/
`
`(VII)
`F‘\
`——-—-—> X-D-N
`G-Ar ——;
`\___/
`
`(I)
`
`(XVIII)
`
`{XIX}
`
`wherein R20, D, G, x and Ar are each as defined above.
`
`The compound (XI)
`
`is reacted with the compound
`
`(XVI)
`
`in the presence of a base in a solvent (e.g. alcohol,
`
`diglyme,
`
`toluene, chlorobenzene) at a temperature around the
`
`boiling point of the solvent to give the compound {XVII}.
`
`As the base,
`
`there may be used an inorganic base (e.g.
`
`potassium carbonate, sodium carbonate), and its amount is
`
`normally from about
`
`1
`
`to 2 mol to one mol of the compound
`
`(XI).
`
`The compound {XVI}
`
`is used ordinarily in an amount of
`
`about 1 to 1.5 mol to one mol of the compound (XI).
`
`The compound (XVII)
`
`is subjected to elimination of
`
`the protecting group by a per se conventional procedure
`
`(e.g. T.W. Greene:
`
`"Protective Group in Organic Synthesis",
`
`John Wiley & Sons, pages 10—39
`
`(1981])
`
`to give the compound
`
`(XVIII).
`
`Introduction of a leaving group into the compound
`
`(XVIII) affords the compound (XIX). When the leaving group
`
`is halogen (e.g. chlorine, bromine),
`
`the compound {XVIII} is
`
`Page 19of92 a ‘
`
`SLAYBACK EXHIBIT 1048
`
`Page 19 of 92
`
`SLAYBACK EXHIBIT 1048
`
`
`
`II
`
`.-
`
`,
`
`J
`
`'
`
`.
`
`_ 20 _
`
`reacted with thionyl halide (e-g.
`
`thionyl chloride,
`
`thionyl
`
`bromide), optionally in the presence of a base (e.g.
`
`pyridine).
`
`The reaction is normally carried out in a
`
`solvent (e.g. pyridine,
`
`tetrahydrofuran, dichlorcmethane) at
`
`a temperature of about 0 to 30°C.
`
`The amount of the thionyl
`
`halide may be from about 2 to 4 mol to 1 mol of the compound
`
`(XVIII).
`
`When the leaving group is sulfonyloxy,
`
`the
`
`compound (XVIII)
`
`is reacted with a sulfonyl halide such as
`
`an alkylsulfonyl halide (e.g. methanesulfonyl chloride) or
`
`an arylsulfonyl chloride (e.g. p-toluenesulfonyl chloride,
`
`benzenesulfonyl chloride), optionally in the presence of a
`
`base (e.g.
`
`triethylamine).
`
`The reaction is normally carried
`
`out in a solvent (e.g. pyridine,
`
`tetrahydrofuran, dichloro—
`
`methane, chloroform) at a temperature of about 0 to 30°C.
`
`The amount of the sulfonyl halide may be from about 2 to 4
`
`mol to one mol of the compound (XVIII).
`
`The compound (XIX)
`
`is reacted with the compound
`
`(VII)
`
`in the presence of a base (e.g. potassium carbonate,
`
`sodium carbonate, sodium hydride, potassium hydride)
`
`in a
`
`solvent (e.g. alcohol, acetonitrile, dimethylformamide) at a
`
`temperature around the boiling point of the solvent to give
`
`the compound (I).
`The amounts of the base and the compound
`(VII) may be respectively from about 0.5 to 2 mol and from
`
`about 1
`
`to 1.5 mol to 1 mol of the compound (XIX).
`
`The products in Procedures (a)
`
`to (d), i.e.
`
`the
`
`Page 20 of 92
`
`L, SLAYBACK EXHIBIT 1048
`
`Page 20 of 92
`
`SLAYBACK EXHIBIT 1048
`
`
`
`compounds {I} and (I—a), may be each purified by a per se
`
`conventional procedure such as recrystallization from a
`
`suitable solvent (e.g. alcohol, diethyl ether, ethyl
`acetate, hexane) or chromatography on a column of silica
`
`gel.
`
`It is also possible to convert the products into their
`
`acid addition salts and then purify by recrystallization
`
`from a proper solvent (e.g. acetone, diethyl ether,
`
`alcohol).
`
`Throughout Procedures (a)
`to (d),
`the introduction
`of a protective group is accomplished by a per se conven-
`I
`
`tional procedure. When,
`
`for instance,
`
`the protective group
`
`is benzyl, substituted benzyl (e.g. halogen-, methoxy- or
`
`nitro~substituted benzyl) or methoxymethyl,
`
`the starting
`
`compound into which the protective group is to be introduced
`
`may be reacted with a protective group-introducing reagent
`
`such as benzyl halide, substituted benzyl halide or methoxy-
`
`methyl halide in the presence of a basic substance such as
`
`an alkali metal hydride (e.g. sodium hydride, potassium
`
`hydride) or an organic base (e.g.
`
`triethylamine, dimethyl—
`
`aminopyridine)
`
`in an organic solvent (e.g.
`
`tetrahydrofuran,
`
`dimethylformamide) at a temperature of about ~10 to 30°C.
`
`The amount of the protective group-introducing reagent may
`
`be from about 1 to 2 mol to one mol of the starting
`
`compound.
`
`Elimination of the protective group may be also
`
`carried out by a per se conventional procedure. When,
`
`for
`
`Page 21 of 92
`
`fl
`
`SLAYBACK EXHIBIT 1048
`
`Page 21 of 92
`
`SLAYBACK EXHIBIT 1048
`
`
`
`instance,
`
`the protective group is benzyl or substituted
`
`benzyl,
`
`the elimination may be effected by hydrogenation
`
`using a noble metal catalyst (e.g. Pd-C, PtO, Pt—C) under a
`
`hydrogen pressure of l to 3 atm. When the protective group
`
`is benzyl, substituted benzyl or methoxymethyl,
`
`the elimi—
`
`nation may be accomplished by treatment with a strong acid
`
`(e.g. CF3
`
`COOH, HBr, HBr-CH CODE}.
`3
`
`Optical resolution of the compound (I) can be
`
`accomplished by dissolving in an inert solvent (e.g. aceto—
`
`nitrile, alcohol), adding an optically active acid thereto
`
`to form the optically active salt between the compound (I)
`
`and the acid, precipitating the formed salt, collecting the
`
`precipitated salt and treating the collected salt with a
`
`base to make the optically active compound (I)
`
`in a free
`
`form.
`
`As the optically active acid,
`
`there may be used,
`
`for instance, L—tartaric acid, D-tartaric acid, D—camphanic
`
`acid, L—mandelic acid, L-pyroglutamic acid, D—lD—CSA
`
`(D—lO—camphor—sulfonic acid), Duquinic acid, L—malic acid,
`
`dibenzoyl-L-tartaric acid, etc;, among which preferred are
`
`L—tartaric acid and D-tartaric acid.
`
`No particular limit~
`
`ation is present on the temperature at which the salt
`
`formation is to be carried out, and the salt formation may
`
`be effected within a wide range from room temperature to the
`
`refluxing temperature of the reaction system.
`
`For enhance—
`
`ment of the optical purity, however, it is favored that the
`
`Page 22 of 92
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`
`Page 22 of 92
`
`SLAYBACK EXHIBIT 1048
`
`
`
`reaction system is once heated to the refluxing temperature.
`
`Before collection of the precipitated salt by filtration,
`
`the mixture may be once cooled so as to increase the yield.
`
`The amount of the optically active acid as the resolving
`
`agent may be from 0.5 to 2.0 equivalents, preferably around
`
`one equivalent,
`
`to the substrate. When desired,
`
`the
`
`collected salt may be recrystallized from a proper solvent
`
`such as alcohol to give the optically active salt with a
`
`higher purity.
`
`The thus obtained salt may be treated with a
`
`base to release an optical isomer of the compound (I)
`
`in a
`
`free form.
`
`For the therapeutic use as an antipsyohotic agent,
`
`the imide compound (I) or its pharmaceutically acceptable
`
`salt may be used as such, but it is usually formulated into
`
`a pharmaceutical preparation such as tablets, capsules,
`
`syrups, suspensions, solutions, emulsions and suppositories
`
`by a per se conventional procedure. Depending upon the
`
`administration route such as parenteral or non—parenteral
`
`administration (e.g. oral administration,
`
`intravenous
`
`administration, rectal administration), an appropriate
`
`preparation form may be employed.
`
`In order to make said
`
`pharmaceutical preparation,
`
`the imide compound (I) or its
`
`pharmaceutically acceptable salt may be combined, if
`
`necessary, with any suitable additivets) such as carriers,
`
`diluents, fillers, binders and stabilizers.
`
`In case of an
`
`injectionable prepartion, pharmaceutically acceptable
`
`Page 23 of 92
`
`SLAYBACK EXHIBIT 1048
`
`Page 23 of 92
`
`SLAYBACK EXHIBIT 1048
`
`
`
`buffers, solubilizers,
`
`isotonizers, etc. may be incorporated
`
`therein.
`
`While the dosage of the imide compound (I) or its
`
`pharmaceutically acceptable salt varies greatly with the
`
`symptom, age and weight of the patient,
`
`the dosage form,
`
`the
`
`administration mode and the like, it may be generally given
`
`to an adult at a daily dose of from about 1
`
`to 1000 mg,
`
`preferably from about 5 to l00 mg,
`
`in case of oral admini—
`
`stration and at a daily dose of from about 0.1 to 100 mg,
`
`preferably from about 0.3 to 50 mg,
`
`in case of intraveous
`
`injection.
`
`Said dose may be applied in a single time or
`
`dividedly in two or more times.
`
`As stated above,
`
`the imide compound (I) and its
`
`pharmaceutically acceptable salts exert a significant
`
`antipsychotic activity. Yet,
`
`they are very weak in side
`
`effects as observed on the conventional neuroleptic drugs.
`
`The above facts are well evidenced by the pharma—
`
`cological test data as set forth below.
`
`(i) Dopamine D2 receptor binding assay (in vitro)
`
`It is known that there is a correlation between
`
`the antipsychotic activity and the dopamine D2 receptor
`
`binding activity. This assay is therefore to examine an
`
`affinity of the test compound to dopamine D2 receptor in
`
`membrane fractions of corpus striatum taken out from rat
`
`brain according to the method as described in T. Kuno et a1:
`
`J.Neurochem., El: 341 (1983].
`
`Page 24 of 92
`
`l
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`
`Page 24 of 92
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`
`
`
`Fresh corpus striatum taken out from rat brain
`
`is homogenized in a 30-fold volume of Tris—HCl buffer
`
`solution (pH, 7.4; 0.05 M) and centrifuged {31,360 x g)
`
`for
`
`10 minutes to give the membrane fractions, which are washed
`
`with the same volume of the buffer solution twice to give
`
`the membrane fractions for assay.
`
`The membrane fractions as above obtained [contain-
`
`ing 5 mg of protein) are incubated at 37°C for 30 minutes in
`
`a buffer solution comprising [3H] raclopride {0.45 nM),
`
`sodium chloride (120 mM),
`
`1 mM magnesium chloride,
`
`5 mM
`
`potassium chloride,
`
`2 mM calcium chloride, Tris—HCl
`
`(pH,
`
`7.4; 50 mM), 0.01 % ascorbic acid,
`
`1 mM pargyline and the
`
`test compound (10
`
`‘9 to 10"5
`
`M). Upon termination of the
`
`reaction,
`
`the membrane fractions are collected through a
`
`Whatman GF/B glass filter and number of [3H] raclopride
`
`bound to membranes is measured by the aid of a liquid
`
`scintillation counter. Number of
`
`[3H] raclopride binding
`
`specific to the 02 receptor in a designed concentration of
`
`the test compound is calculated according to the following
`
`equation and the IC
`
`50
`
`and Ki are determined on the basis of
`
`a hill plot according to the method as described in Life
`
`Sci., 32, 1781 - 1784 (1978). As
`
`the representative anti—
`
`pyhchotic drug, Haloperidol is used as control.
`
`Number of specific binding =
`
`(Number of non—specific
`(Total number of bindings} -
`bindingszse.g. number of bindings in co-existence
`of
`10
`M {+)Butaclamol)
`
`Page 25 Of 92
`
`$ SLAYBACK EXHIBIT 1048
`
`Page 25 of 92
`
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`
`
`
`./
`
`n
`
`.
`
`.
`
`_ 25 _
`
`(nM) = ICSO/(l + S/KD)
`concentration of [3H] raclgpride on assay
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