United States Patent [19]
`Saji et al.
`
`111111111111111111111111111111111111111111111111111111111111111111111111111
`US005532372A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,532,372
`Jul. 2, 1996
`
`[54]
`
`[75]
`
`IMIDE DERIVATIVES, AND THEIR
`PRODUCTION AND USE
`
`Inventors: Ikutaro Saji; Masayuki Muto;
`Norihiko Tanno; Mayumi Yoshigi, all
`of Osaka, Japan
`
`[73] Assignee: Sumitomo Pharmaceuticals Company,
`Ltd., Osaka, Japan
`
`[21] Appl. No.: 113,320
`
`[22] Filed:
`
`Aug. 30, 1993
`
`Related U.S. Application Data
`
`[63] Continuation of Ser. No. 726,172, Jul. 5, 1991, abandoned.
`
`[30]
`
`Foreign Application Priority Data
`
`Jul. 6, 1990
`
`[JP]
`
`Japan .................................... 2-180271
`
`Int. Cl.6
`....................... C07D 417/14; A61K 31/495
`[51]
`[52] U.S. Cl. .............................. 544/368; 546117; 546116;
`5461199; 546/200; 5461198; 546/201; 546/225;
`546/243; 544/230; 5441231; 514/255; 514/321
`[58] Field of Search ............................................... 544/368
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,411,901
`4,590,196
`4,656,173
`4,745,117
`4,812,461
`4,843,078
`4,937,249
`
`10/1983 Temple, Jr. et al. ............ ........ 544/368
`5/1986 Smith et al ............................. 544/368
`4/1987 Yevich et al ............................ 514/253
`5/1988 Ishizumi et al. ........................ 544/368
`3/1989 Antoku et al ........................... 546/198
`6/1989 Ishizumi et al ......................... 544/295
`6/1990 Antoku et al ........................... 546/187
`
`FOREIGN PATENT DOCUMENTS
`
`0009465
`0080104
`0109562
`0082402
`0196096
`0261688
`0314098
`3422411
`1570374
`
`4/1980
`6/1983
`6/1983
`4/1986
`10/1986
`3/1988
`5/1989
`1/1985
`7/1980
`
`European Pat. Off ................ 544/291
`European Pat. Off ................ 546/198
`European Pat. Off ................ 546/198
`European Pat. Off. . .............. 544/373
`European Pat. Off. ....... ........ 544/362
`European Pat. Off ................ 546/198
`European Pat. Off ................ 546/198
`Germany ................................. 546/16
`United Kingdom ................... 546/199
`
`OTHER PUBLICATIONS
`
`the Dopamamine
`Seeman "Dopamine Receptors and
`hypothesis of Schizophrenia" (Synapse) vol. 1, pp. 133-152
`(1987).
`Seeman "Brain Dopamine Receptors" (Pharrnaeological
`Reviews) vol. 32, No. 3, pp. 230-231 (1981).
`Ban "Psycopharacologlogly for the Agerl" pp. 42-73
`(Karger) (1980).
`
`Dunner et a!. "Psychopharmacology: The Third Generation
`of Progress" (Raven) (1987) pp. 1097-1083.
`Chemical Abstracts 78:58177q (1973).
`The Merck Index, 11, 229 (1989) No. 1493.
`The Merck Index, 11, 689 (1989) No. 4297.
`Chou "Drug Treatment of Acute Mania" (Drugs of Today)
`vol 28, No.2 pp.l19-130 (1992).
`Barnett "Pharmacological Evaluation of Antianxiety Agents
`in Laboratory Animals" (Antianxiety Agents) pp. 28-79
`(witey) (1986).
`Vogel et al. "A Simple and Reliable Conflict Procedere for
`testing Anti-Anxiety Agents" (Psychopharrnacologia) (Ber(cid:173)
`lin) vol 21, pp. 1-7 (1971).
`
`Primary Examiner-Robert T. Bond
`Attorney, Agent, or Finn-Birch, Stewart, Kolasch & Birch
`
`[57]
`
`ABSTRACT
`
`An imide compound of the formula:
`
`1 \
`Z-0-N
`G-Ar
`\._}
`
`wherein
`Z is a group of the formula:
`
`(I)
`
`in which the substituents are defined herein, and n is an
`integer of 0 to 1;
`D is a group of the formula:
`
`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 >COH- or Ar is a biphe(cid:173)
`nylmethylidene group and G is >C=, all of the above
`groups being each optionally substituted with at least
`one of lower alkyl, lower alkoxy and halogen; and its
`acid addition salts, useful as an antipsycotic agent.
`
`20 Claims, No Drawings
`
`Par Pharm., Inc.
`Exhibit 1060
`Page 001
`
`

`

`5,532,372
`
`1
`IMIDE DERIVATIVES, AND THEIR
`PRODUCTION AND USE
`
`This application is a continuation, of application Ser. No.
`071726,172 filed on Jul. 5, 1991, now abandoned.
`The present invention relates to imide derivatives, 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-depres(cid:173)
`sive psychosis, neurosis, etc.
`There are known some imide compounds having an
`anti-psycotic activity, of which typical examples are as
`follows:
`
`5
`
`2
`Conventional antipsychotic agents are generally accom(cid:173)
`panied by a central or peripheral system side effect such as
`extrapyramidal motor disturbance (e.g. Parkinsonism) and
`depression of blood pressure (e.g. orthostatic hypotension)
`and produce a great problem on clinic (e.g. L. S. Goodman
`et al.: The Pharmacological Basis of Therapeutics, New
`York, p. 387 (1985); Gendai Iryo (Modern Medical
`Therapy), 22, p. 22 (1990)).
`The problem underlying the present invention is to
`10 provide an excellent psychotic agent suppressed in the above
`side effect as generally observed on the conventional anti(cid:173)
`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
`bonded with intervention of an alkylene chain comprising a
`
`Structure
`
`0
`
`0
`
`0
`
`0
`
`f \ N)
`'
`N --1
`
`N -
`
`N-(CH2)4-N
`I
`\__)
`0
`
`Remarks
`
`Tiaspirone;
`JP-A-61-251683,
`JP-A-58-110576
`
`Buspirone;
`The Merck Index,
`II, 229 (1989)
`
`Gepirone
`The Merck Index,
`II, 689 (1989)
`
`JP-B-01-28756
`
`US-A-4,745,117
`
`1 \
`N-(CH2)4-N N~
`\__) N's ~
`
`~ N-(CH,),-N
`
`0
`
`JP-A-01-199967
`
`F
`
`These conventional imide compounds are characteristic
`in that the imide portion and the piperazine or piperidine ring 65
`are bonded together with intervention of a straight alkylene
`chain.
`
`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
`
`Par Pharm., Inc.
`Exhibit 1060
`Page 002
`
`

`

`5,532,372
`
`3
`hydrocarbon ring has never been known. The present inven(cid:173)
`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
`G-Ar
`\._}
`
`wherein
`Z is a group of the formula:
`
`4
`specifically bicyclo[l.l.l ]pentane, bicyclo[ -2.1.1 ]hexane,
`bicyclo[2.1.1 ]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,
`bicyclo[ -4.1.1 ]oct-2-ene,
`(I) 5 bicyclo[4.1.1]oct-3-ene,
`bicyclo[3.2.l]octane,
`bicyclo
`[3.2.1 ]oct-2-ene, bicyclo[3.2.1 ]oct-3-ene, bicyclo[3.2.1 ]oct-
`6-ene,
`bicyclo[3.2.2]nonane,
`bicyclo[3.2.2]non-2-ene,
`bicyclo[3.2.2]non-3-ene, bicyclo[3.2.2]-non-6-ene, 2-oxabi(cid:173)
`cyclo[l.l.l ]butane, 2-oxabicyclo[2.1.1 ]pentane, 2-oxabi-
`10 cycl o[2.1.1 ]pent -4-ene, 7 -oxabicycl o[2.2.1 ]hexane, 7 -ox(cid:173)
`abicyclo[2.2.1 ]hex-2-ene,
`7-oxabicyclo[ 4.1.1 ]heptane,
`7 -oxabicyclo[ 4.1.1]hept-2-ene, 7 -oxabicyclo[ 4.1.1 ]-hept-3-
`ene, 8-oxabicyclo[3.2.1 ]heptane, 8-oxabicyclo[3.2.1 ]-hept-
`15 2-ene, 8-oxabicyclo[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 I 0 carbon atoms, of which specific examples
`are benzene and naphthalene.
`The non-aromatic hydrocarbon ring represented by its
`both sides, i.e. -(CH2 )P- and -(CH2)q-, at the 1- and
`!-positions, the 1- and 2-positions, the 1- and 3-positions,
`the 1- and 4-positions or the like.
`The aromatic group represented by the symbol Ar may be
`25 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, bicyclic 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,
`fury!, imidazolyl, etc. The bicyclic heterocyclic 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, 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 hydrochloric 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 benzoyl group, a phenoxy group, a phe(cid:173)
`nylthio 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 oflower alkyl, lower alkoxy and
`halogen.
`
`, R2
`in which B is a carbonyl group or a sulfonyl group R 1
`, 20
`R3 and R4 are each a hydro~en atom or a lower alkyl group,
`or R 1 and R2 or R 1 and R may be combined to~ether to
`make a non-aromatic hydrocarbon ring orR 1 and R may be
`combined together to make an aromatic ring, said non(cid:173)
`aromatic hydrocarbon ring being optionally bridged with a
`lower alkylene group or an oxygen atom therein and said
`aromatic hydrocarbon ring, said non-aromatic hydrocarbon
`ring and said lower alkylene group being each optionally
`substituted with at least one lower alkyl, and n is an integer
`of 0 or I;
`D is a group of the formula:
`
`30
`
`35
`
`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 40
`G is >N-, >CH- or >COH- or Ar is a biphenylmeth(cid:173)
`ylidene group and G is >C=, all of the above groups being
`each 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 45
`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 50
`alkoxy" covers an alkoxy group preferably having not more
`than 4 carbon atoms (e.g. methoxy, ethoxy, propoxy, 2-pro(cid:173)
`poxy, butoxy). The term "lower alkylene" covers an alky(cid:173)
`lene group preferably having not more than 3 carbon atoms
`(e.g. methylene, ethylene, trimethylene). The term "halo- 55
`gen" 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. 60
`Examples of the cycloalkane ring include cyclopropane,
`cyclobutane, cyclopentane, cyclohexane and cycloheptane.
`Examples of the cycloalkene ring are cyclopentene, cyclo(cid:173)
`hexene, cycloheptene, etc.
`The non-aromatic hydrocarbon ring bridged with a lower 65
`alkylene group or an oxygen atom may be, for instance, the
`one having not more than 10 ring carbon atoms and includes
`
`Par Pharm., Inc.
`Exhibit 1060
`Page 003
`
`

`

`5,532,372
`
`5
`Preferred examples of the group represented by the sym(cid:173)
`bol Z are those of the following formulas:
`
`(Z-1)
`
`5
`
`10
`
`or -CH=CH-, E is a lower
`wherein Lis -CH2-CH2-
`alkylene group optionally substituted 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,
`
`6
`
`R~N-B
`
`wherein L', E, R5 and B are each as defined above,
`
`(Z-2')
`
`(Z-3')
`
`R'~N-
`
`B
`wherein L, E, R5 and B are each as defined above,
`
`(Z-2) 15
`
`20
`
`wherein R6 ·, RT, R8 ', R9 ', Rw, R 11 ·, R12·, R13·, R 14' and R 15~
`are each a hydrogen atom or a lower alkyl and B is a defined
`above;
`
`(Z-4')
`
`R9
`
`R8
`
`0
`
`(Z-3)
`
`25
`
`R12
`R13
`
`R~~~R6 I
`N-
`I
`R7 B
`R15
`R14
`, R 14 and R 15 are 30
`, R 12
`, R 13
`, R11
`, R 10
`, R9
`wherein R6
`, R7
`, R8
`each a hydrogen atom or a lower alkyl group, or two ofthose
`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;
`
`wherein R4
`
`, R 16
`
`, R 17 and B are each as defined above, and
`
`(Z-5')
`
`(Z-4)
`
`35
`
`wherein B is as defined above.
`The imide compounds (I) of the invention are obtainable
`by various procedures, of which typical examples are as
`40 shown below.
`Procedure (a):-
`The imide compound (I) is obtainable according to the
`following scheme:
`
`45
`
`0
`0
`II
`II
`R18 -C-(CHz)J-A-(CHz)m-C-R19 --7
`
`(Z-5)
`
`50
`
`(II)
`
`(III)
`
`wherein R16 and R 17 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. cyclopropane,
`cyclobutane, cyclopentane, cyclohexane, cycloheptane) and
`R4 and B are each as defined above, and
`
`0
`
`cGN-
`
`wherein B is as defined above.
`More preferred examples of the group represented by the
`symbol Z are those of the following formulas:
`
`55
`
`HN
`G-Ar
`\__)
`
`XCH, -(CH,)J -A -(CH,)m-CH,X __ __,_(V-')'----'::>
`
`0
`
`~N-
`
`Rs
`wherein L' is -CH2-CH2-
`defined above,
`
`(Z-1')
`
`60
`
`(]VI
`
`/(CHz)t-CHz'\ 1 \
`W
`A
`G-Ar.X-
`I
`'\
`(CHz)m-CHz
`
`\__)
`
`Z-H
`
`(VII) >
`
`5
`and E, R and B are each as
`
`65
`
`(VI)
`
`Par Pharm., Inc.
`Exhibit 1060
`Page 004
`
`

`

`5,532,372
`
`7
`-continued
`
`8
`Procedure (b):-
`
`G-Ar
`
`The imide compound (I) is also produced according to the
`following scheme:
`
`5
`
`(IV) (VII) >
`
`(VIII)
`
`IS
`
`wherein X, A, Z, I and m are each as defined above.
`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(cid:173)
`tion is usually carried out in a solvent (e.g. alcohol, dim(cid:173)
`ethylformarnide, 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 ofthe sol vent. The amounts of the base, the
`reaction aid and the compound (VII) may be respectively
`from about l to 2 mol, from about 0.1 to 1 mol and from
`about 0.1 to 1 mol to one mol of the compound (IV).
`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 (1-a). The reaction is normally carried
`out in a solvent (e.g. alcohol, dimethylformarnide, acetoni(cid:173)
`trile), 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
`35 1 mol to one mol of the compound (VIII). The molar
`proportion of the compound (VIII) and the compound (V)
`may be usually about 1:1-1.5.
`
`25
`
`wherein A, G, Ar and Z are each as defined above and R 18
`and R 19 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 alkylsulfony- 10
`loxy
`(e.g. methanesulfonyloxy), arylsulfonyloxy
`(e.g.
`p-toluene-sulfonyloxy, benzenesulfonyloxy) and 1 and m
`are each an integer of 0 or 1.
`Namely, the compound (II) is reduced to give the com-
`pound (III). The reduction may be carried out by treatment
`with a reducing agent (e.g. LiAIH4 , H 4 , NaBH4 , Ca(BH4h,
`LiAIH2(0CH2CH20CH3 ) 2 ) in an inert solvent at a tempera(cid:173)
`ture of 0° C. to the reflux temperature of the reaction mixture
`to give the compound (III). The reducing agent is usually 20
`employed in an amount of about I 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 com-
`pound (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 30
`base (e.g. pyridine). This reaction is preferably performed in
`a solvent (e.g. pyridine, tetrahydrofuran, dichloromethane)
`at a temperature of about 0° to 30° C. The molar proportion
`of the compound (III) and thionyl halide may be usually
`about l :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. methane(cid:173)
`sulfonyl chloride) or arylsulfonyl halide (e.g. p-toluene- 40
`sulfonyl chloride, benzenesulfonyl chloride), optionally in
`the presence of a base (e.g. triethylamine). This reaction is
`favorably performed in a solvent (e.g. pyridine, tetrahydro(cid:173)
`furan, dichloromethane, chloroform) at a temperature of
`about 0° to 30° C. The molar proportion of the compound 45
`(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. metha- 50
`nol, ethanol, propanol, 2-propanol, butanol), acetonitrile or
`dimethylformarnide 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 (VI) is then reacted with the compound
`(VII) to give the compound (I-a). This reaction is carried out
`optionally in tile presence of a catalyst and a base (e.g.
`potassium carbonate, sodium carbonate, sodium hydride, 60
`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-18-crown-6-ether may be used, and its amount is
`normally from about 0.1 to 10% by weight based on the 65
`compound (VI). The molar proportion of the compound (VI)
`and the compound (VII) to be used is usually about 1:1-1.5.
`
`Procedure (c):-
`
`The imide compound (I) is further obtainable according to
`the following scheme:
`
`HO-(CHz)p- A -(CH2)q-OH-----:;,.
`
`(IX)
`
`(X)
`
`(XI)
`
`Z-D-QR2D--Z-D-OH-----:;,.z-D-X~(I)
`
`(XIII)
`
`(XIV)
`
`(XV)
`
`, R4
`, R2
`wherein R 1
`, R3
`, 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
`
`Par Pharm., Inc.
`Exhibit 1060
`Page 005
`
`

`

`5,532,372
`
`10
`
`9
`(g.g. T. W. Greene: "Protective Group in Organic Synthe(cid:173)
`sis", John Willey & Sons, pages 10-39 (1981)) to the former.
`Examples of the protective group for hydroxy thus intro(cid:173)
`duced are benzyl, substituted benzyl (e.g. halogen-, meth(cid:173)
`oxy- or nitro-substituted benzyl), methoxymethyl, methoxy- 5
`ethoxymethyl, tetrahydrofuryl, etc.
`The compound (X) is then subjected to oxidation, oxi(cid:173)
`mation (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, bichro(cid:173)
`mic acid). The oximation may be carried out by reacting the
`oxidized product with hydroxylamine in an alcohol at a
`temperature of about oo to 30° C. Hydroxylamine is nor- 15
`mally 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 tetrahydrofuran) at a temperature around the boiling 20
`point of the solvent. The amount of the reducing agent is
`usually from about 1 to 10 mol to one mol of the compound
`(X).
`The compound (XI) thus obtained is reacted with the
`compound (XII) in a solvent (e.g. pyridine, toluene, xylene, 25
`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 elimination of 30
`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 35
`(XV) is accomplished by introduction 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. 40
`pyridine, tetrahydrofuran, dichloromethane) at a tempera(cid:173)
`ture of about oo 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 45
`(XIV) is reacted with a sulfonyl halide such as 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, tetrahydro- 50
`furan, dichloromethane, chloroform) at a temperature of
`about oo to 30° C. The amount of the sulfonyl halide is
`normal! y from about 2 to 4 mol to one mol of the compound
`(XIV).
`The compound (XV) thus produced is reacted with the 55
`compound (V) in the presence of a base in the coexistence
`of a reaction aid to give the compound (I). The reaction is
`normally performed in a solvent (e.g. alcohol, dimethylfor(cid:173)
`marnide, acetonitrile) at a temperature around the boiling
`point of the solvent. As the base, there may be used an 60
`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 65
`about 0.1 to I mol and from about 1 to 1.5 mol to one mol
`of the compound (XV).
`
`10
`Procedure (d):-
`
`The imide compound (I) is further obtainable according to
`the following scheme:
`
`1 \
`X
`G-Ar
`X
`\__}
`
`(X!) ---"-(X:....:V_,l)'----->3:>-
`
`1 \
`R20Q-D-N
`G-Ar--7
`\__}
`
`(XVII)
`
`1 \
`HO-D-N
`G-Ar--7
`\__}
`
`(XVIII)
`
`G-Ar (VII) >(I)
`X-D-N
`\__}
`
`(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 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, dichloromethane) at a tem(cid:173)
`perature 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 alkyl(cid:173)
`sulfonyl halide (e.g. methanesulfonyl chloride) or an aryl(cid:173)
`sulfonyl chloride (e.g. p-toluenesulfonyl chloride, benzene(cid:173)
`sulfonyl chloride), optionally in the presence of a base (e.g.
`triethylamine). The reaction is normally carried out in a
`solvent (e.g. pyridine, tetrahydrofuran, dichloromethane,
`chloroform) at a temperature of about oo 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 tempera-
`
`Par Pharm., Inc.
`Exhibit 1060
`Page 006
`
`

`

`5,532,372
`
`11
`ture 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 I to 1.5 mol to I mol of the compound (XIX).
`The products in Procedures (a) to (d), i.e. the compounds 5
`(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 chro(cid:173)
`matography on a column of silica gel. It is also possible to
`convert the products into their acid addition salts and then 10
`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 conventional
`procedure. When, for instance, the protective group is ben- 15
`zyl, substituted benzyl (e.g. halogen-, methoxy- or nitro(cid:173)
`substituted benzyl) or methoxymethyl, the starting com(cid:173)
`pound 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 meth- 20
`oxymethyl 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, dimethy(cid:173)
`laminopyridine) in an organic solvent (e.g. tetrahydrofuran,
`dimethylformamide) at a temperature of about -10° to 30° 25
`C. The amount of the protective group-introducing reagent
`may be from about I 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 instance, 30
`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 1 to 3 atm. When the protective group is benzyl,
`substituted benzyl or methoxymethyl, the elimination may 35
`be accomplished by treatment with a strong acid (e.g.
`CF3COOH, HBr, HBr-CH3COOH).
`Optical resolution of the compound (I) can be accom(cid:173)
`plished by dissolving in an inert solvent (e.g. acetonitrile,
`alcohol), adding an optically active acid thereto to form the 40
`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 45
`instance, L-tartaric acid, D-tartaric acid, D-camphanic acid,
`L-mandelic acid, L-pyroglutamic acid, D-10-CSA (D-10-
`camphor-sulfonic acid), D-quinic acid, L-malic acid, diben(cid:173)
`zoyl-L-tartaric acid, etc., among which preferred are L-tar(cid:173)
`taric acid and D-tartaric acid. No particular limitation is 50
`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 refiuxing tem(cid:173)
`perature of the reaction system. For enhancement of the
`optical purity, however, it is favored that the reaction system 55
`is once heated to the refiuxing temperature. Before collec(cid:173)
`tion 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 60
`substrate. When desired, the collected salt may be recrys(cid:173)
`tallized 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 antipsychotic agent, the
`imide compound (I) or its pharmaceutically acceptable salt
`
`65
`
`12
`may be used as such, but it is usually formulated into a
`pharmaceutical preparation such as tablets, capsules, syrups,
`suspension, solutions, emulsions and suppositories by a per
`se conventional procedure. Depending upon the administra(cid:173)
`tion route such as parenteral or non-parenteral administra(cid:173)
`tion (e.g. oral administration, intravenous administration,
`rectal administration), an appropriate preparation form may
`be employed. In order to make said pharmaceutical prepa(cid:173)
`ration, the imide compound (I) or its pharmaceutically
`acceptable salt may be combined, if necessary, with any
`suitable additive(s) such as carriers, diluents, filters, binders
`and stabilizers. In case of an injectionable preparation,
`pharmaceutically acceptable buffers, solubilizers, isotoniz(cid:173)
`ers, 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 100 mg, in case of oral admin(cid:173)
`istration 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 pharma(cid:173)
`ceutically acceptable salts exert a significant anti-psychotic
`activit