3766 Vol. 33 (1985)
`
`Chem‘ Pharm. Bull.
`[33( 9 )3766—-3774(1985):l
`Syntheses of (i)-2-[(Inden-7-yloxy)methyl]morpholine Hydrochloride
`(YM-08054, Indeloxazine Hydrochloride) and Its Derivatives
`with Potential Cerebral—Activating and
`Antidepressive Properties
`
`TADAO KOIIMA, KUNIHIRO NIIGATA,* TAKASHI FUJIKURA,
`SHIRO TACHIKAWA, YOSHIHISA NOZAKI, So1cH1 KAGAMI
`and K020 TAKAHASHI
`
`Central Research Laboratories, Yamanouc/ii Pharmaceutical Co., Ltd.,
`Azusawa 1—I—8, Itabas/zi-ku, Tokyo 174, Japan
`
`(Received December 17, 1984)
`
`The synthesis of ( i)-2-[(inden-7-yloxy)methyl]morpho1ine hydrochloride (7 - HC1, YM-08054,
`indeloxazine hydrochloride) and its optical resolution into levo- and dextro-isomers were investi-
`gated. A practical synthetic method for 7-HCl was established by employing preferential
`crystallization from an equilibrium mixture of 7-HCl and its tautomer, (i)-2-[(inden-4-yloxy)-
`methyl]morpholine hydrochloride (6-HCl), in the presence of a catalytic amount of base in MeOH.
`It was found that 7-HCl and its levo-rotatory isomer ((—)-7-HCl) showed not only strong
`antidepressive activities, but also potent cerebral-activating properties. The syntheses and phar-
`macological activities of related compounds are also discussed briefly.
`
`Keywords—~indene; antidepressant; cerebral activator; (j:)-2-[(inden-7-yloxy)methyl]mor-
`pholine; (i)-2-[(inden-4-y1oxy)methyl]morpholine; YM-08054; indeloxazine hydrochloride;
`iso-
`merization; optical resolution
`
`It is known that fl-adrenergic blocking agents such as 1-(1-naphthyloxy)-3-isopropyl~
`amino-2-propanol hydrochloride (propranolol, Fig. 1) have various activities on the central
`nervous system in addition to the main effects.” It is also known that a number of 2-aryl—
`oxymethylmorpholine derivatives (II), prepared by structural modification of aryloxypropa-
`nolamine derivatives (1), show increased antidepressive activitity as compared to I. For
`example, 2-(2-ethoxyphenoxymethyl)morpholine hydrochloride (viloxazine, Fig.
`1) has
`been shown to have a novel profile of neuropharmacological activity, possessing features in
`common with tricyclic antidepressants but without the [3-adrenergic blocking property?’
`Recently, Yamamoto et
`(11.3) of our
`laboratories found that
`(:)-2-[(inden-7—yloXy)-
`methyl]morpho'line hydrochloride (7 -HCI, YM-08054, indeloxazine hydrochloride) not only
`showed strong antidepressive properties, but also had an enhancing effect on learning be-
`havior, a protective effect on nitrogen—gas—induced amnesia and some other cerebral-
`activating properties in rats or mice. These kinds of pharmacological activities, particularly the
`cerebral-activating properties, are important in connection with the treatment of senile and
`
`/OH
`Ar—OCHg~CH
`CH2
`\
`
`TH
`R
`
`‘
`I
`pT0P1"an0101
`Ari Hlaphthyl
`R:
`iso-Pr
`
`/O\
`(W42
`Ar—OCl-l2—C‘3H
`CH2
`CH2
`\ /
`1)]
`R
`
`Fig.
`
`1
`
`H
`viloxazine
`Ar:
`2-ethoxyphenyl
`R;
`1-1
`
`MYLAN - EXHIBIT 1030
`NII—Electronic Library Service
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`




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`MYLAN - EXHIBIT 1030
`
`

`
`No. 9
`
`3767
`
`multi-infarct dementia. However, no report has been published on the cerebral-activating
`activities of 7-HCl type compounds.
`This report describes the synthesis of 7‘HCl and related compounds and the optical
`resolution of 7 - HCl, and also presents preliminary findings on the pharmacological activities.
`(i—)-2-[(Inden-7(or 4)-yloxy)methyl]morpho1ines (5a—j), were first prepared by modify-
`ing the method of Turner et al.2“’ (Chart 1). Treatment of propanolamine derivatives (2a—~j)
`
`9“
`OCH2CHCH2NHR
`
`1.‘
`9”
`OCH2CHCH2NCOCH2X
`
`
`
`XCH2COX
`
`2a—j
`a I H
`b 1 Me
`c 2 Et
`
`F
`
`-P
`
`di Pr
`Z’
`f : gs:
`E 5 tert-Bu
`h I P11
`i
`:CH2Ph
`j
`'. cyclohexyl
`
`3a—i
`
`MeONa
`
`0
`ocna: 1
`N
`I
`‘
`R
`
`_
`4a—J
`
`0
`
`O
`
`LiAlH4
`’?'——§ 0
`
`O
`
`ocuf J
`N
`I
`R
`
`5a~j
`
`/O\
`
`QCHEEOJ Ry
`(l:H2os03Na
`OCHECH-Cl-I2
`
`
`$9
`NCH2NH2 $ K2CO3T {'4 —————> 5b,c.i
`
`1 H
`
`5a
`
`12] es H3.)
`
`Chart 1
`
`with halogenoacetyl halide in the presence of an appropriate base afforded N-halogenoacetyl
`compounds (3a——j), which were cyclized with MeONa to produce the lactams (4a——j).
`Reduction of 4a—j with LiAlH4 in tetrahydrofuran (THF) gave the corresponding mor-
`pholine derivatives 5a~—j. However, this route was not very convenient and overall yields were
`generally low. An improved method for the synthesis of compounds 5a—j involves reaction
`with epoxide (1)2“’ (Chart 1). Treatment of 1 with excess 2-aminoethyl hydrogen sulfate and
`70% aqueous NaOH gave 5a in a good yield. Compound 5a was easily alkylated with
`appropriate alkyl halides to give N-substituted derivatives Sb, c, i in good yields. The physical
`properties of 4a—j are listed in Table I and those of 5a—~j are listed in Tables II and 111.
`All indenyl compounds thus prepared are tautomeric equilibrium mixtures of 4-indenyl
`and 7—indenyl isomers. For example, 5a was an equilibrium mixture of the 4-indenyl isomer
`(6) and 7-indenyl isomer (7) in a ratio of 1 :2. The ratio was determined by gas chromatog-
`raphy after converting the compounds to the corresponding N-trifluoroacetyl derivatives. The
`separation of 5a into 6 and 7 was achieved by fractional crystallization of its hydrochloride. In
`
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`




`
`

`
`Vol. 33 (1985)
`3768
`
`
`TABLE I.
`
`(1)-6-[(Inden-7 (or 4)-yloxy)methyl]morpholin-3-one Derivatives (4a—j)
`
`Compd.
`
`Yield
`_ (%)
`
`mp (°C)
`(Solvent)
`
`Formula
`
`4a
`
`4h
`
`4c
`
`4d
`
`4e
`
`41‘
`
`4g
`
`4h
`
`4i
`
`4j
`
`40.5
`
`79.0
`
`86.0
`
`88.2
`
`86.0
`
`78.5
`
`46.1
`
`84.6
`
`91.5
`
`82.6
`
`Oil“)
`
`Oil“)
`
`011“)
`
`Oil“)
`
`Oil“)
`
`Oil”
`
`Oil“)
`
`Oil“)
`
`Oil“)
`
`CMHUNO3
`
`CISHNNO3
`
`C16H19NO3
`
`CUHZINO3
`
`C17H2,NO3
`
`CLBHBNO3
`
`CIBHBNO3
`
`C20H,9NO3
`
`CZIHMNO3
`
`106-107
`
`CZOHZSNO3
`
`Analysis (%)
`Calcd (Found)
`
`C
`
`H
`
`N
`
`68.56
`(68.31
`69.48
`(69.19
`70.31
`(70.10
`71.06
`(70.94
`71.06
`(71.31
`71.73
`(71.46
`
`71.73
`(71.51
`74.75
`(74.99
`75.20
`(74.91
`73.37
`
`6.16
`6.00
`6.61
`6.36
`7.01
`6.84
`7.37
`7.10
`7.37
`7.51
`7.69
`7.43
`
`7.69
`7.46
`5.96
`6.07
`6.31
`6.45
`7.70
`
`5.71
`5.52)
`5.40
`5.35)
`5.12
`5.08)
`4.81
`4.57)
`4.81
`4.90)
`4.65
`4.59)
`
`4.65
`4.55)
`4.36
`4.13)
`4.18
`4.40)
`4.28
`
`NMR 6 (CDC13)
`'
`
`3.9-1.3 (1H, br 5, NH)
`
`2.4 (3H, s, CH3)
`
`1.2 (3H, t, J=7Hz, CH3)
`2.5 (2H, q, J=7Hz, CHZCH3)
`1.1 (3H, t, J=7Hz, CH3)
`1.5 (2H, m, Cl;I2CH3)
`1.2 (6H, d, J=7Hz, CH3 x 2)
`
`1.0 (9H, t, J=7Hz, CH3 x 3)
`1.0-1.8 (4H, m, CI;I2CI;I2CH3)
`2.4 (2H, t, CHZCHZCHZCH3)
`1.5 (9H, s, CH3)
`
`7.4 (5H, m, Ph-H)
`
`3.6 (2H, s, CH2Ph)
`7.4 (5H, m, Ph-H)
`0.8-2.0 (10H, m)
`
`4.00)
`
`4.6 (1H, m, N—CH-)
`
`(EtOH)
`
`(73.08
`
`7.51
`
`a) Oily compounds were purified by column chromatography on silica gel.
`
`TABLE II.
`
`(i)—2-[(Inden—7 (or 4)-yloxy)methyl]morpholine Derivatives (5a—j)
`
`Compd.
`
`H)
`
`'
`Y(1:i3]
`
`Salt
`
`0
`(lggliegg)
`
`Formula
`
`521
`
`Sb
`
`Sc
`
`511
`
`5e
`
`5f
`
`5g
`
`5h
`
`5i
`
`Sj
`
`42.0
`
`«
`
`HC1
`
`38.0
`
`91.3
`
`89.5
`
`87.9
`
`84.0
`
`60.4
`
`76.4
`
`89.0
`
`Oxalate
`
`Citrate
`
`Oxalate
`
`Citrate
`
`Oxalate
`
`Citrate
`
`HCl
`
`Oxalate
`
`73.06
`
`HC1
`
`a) Yield of free base.
`
`143-155
`(Acetone)
`146-147
`(EtOH—Et2O)
`84-86
`(EtOH—Et2O)
`2011-202
`(EtOH—EtZO)
`107-109
`(EtOH—Et2O)
`200
`(EtOH—Et2O)
`. 114-116
`(EtOH—Et2O)
`160-163
`(EtOH—Et2O)
`206-208
`(EtOH—Et2O)
`216-218
`(EtOH—Et2O)
`
`CMHHNO2-HC1
`
`C15H,9NO2 ~C2H2O4
`
`C,6H,,No, -C6H8O7
`
`CHHHNOZ -CZHZO4
`
`C17H23NO2 -C6H8O7
`
`C18H25NO2~C2H2O4
`
`C,8H25NO2--C6H8O7
`
`CMHZINOZ-HC1
`
`C21H23NO2 -CZHZO4
`
`C20H27NO2~HCl
`
`Analysis (‘X,)
`Cdlcd (Found)
`H
`N
`
`6.78
`6.70
`6.31
`6.29
`6.47
`6.55
`6.93
`6.90
`6.71
`6.66
`7.21
`6.93
`6.94
`6.91
`6.45
`6.36
`6.12
`6.07
`8.07
`8.00
`
`5.23
`4.99
`4.18
`4.21)
`3.10
`3.07)
`3.85
`3.64)
`3.01
`3.01)
`3.71
`3.68)
`2.92
`2.94)
`4.07
`4.03
`3.40
`3.40)
`4.00
`4.23
`
`C
`
`62.80
`(62.53
`60.89
`(60.90
`58.53
`(58.70
`62.80
`(62.99
`59.35
`(59.78
`63.65
`(63.90
`60.11
`(60.30
`69.86
`(70.01
`67.14
`(66.95
`68.65
`(68.58
`
`C1
`
`13.24
`12.91)
`
`10.31
`10.31)
`
`10.13
`10.49)
`
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`




`
`

`
`No. 9
`
`3769
`
`TABLE III. NMR Spectra Data for (i)-2-[(Inden—7 (or 4)-y1oxy)methy1]morpholine
`Derivatives (Sa-j)
`
`Compd.
`
`NMR (3 (CDCI3)
`
`5a
`
`51)
`
`5c
`
`Se
`
`5f
`
`5g
`
`5h
`
`5i
`
`5j
`
`1.9-3.1 (4H, m), 2.4 (1H, s, NH), 3.3-3.4 (2H, In), 3.6-4.3 (5H, II1),
`6.3-6.9 (2H, m), 7.0-7.3 (3H, In)
`1.9-3.1 (4H, In), 2.3 (3H, s, CH3), 3.3-3.4 (2H, In), 3.6-4.3 (5H, In),
`6.3-6.9 (2H, In), 7.0-7.3 (3H, III)
`1.1 (3H, t, J=7Hz, CHZCLI3), 1.9-3.1 (4H, In), 2.4 (2H, q, J=7Hz, CI;I2CH3),
`3.3-3.4 (2H, In), 3.6-4.3 (5H, In), 6.3-6.9 (2H, In), 7.0-7.3 (3H, m)
`0.9 (3H, t, J=7Hz, CHZCH3), 1.5 (2H, m, CHZCH3), 1.9-3.1 (4H, In),
`2.2 (2H, t, J=7Hz, CI;I2CH2CH3), 3.3-3.4 (2H, In), 3.6~—4.3 (5H, In),
`6.3-6.9 (2H, In), 7.0-7.3 (3H, In)
`1.5 (6H, d, J=7Hz, CH3 X 2), 1.9-3.1 (SH, In), 3.3-3.4 (2H, In),
`3.6-4.3 (SH, m), 6.3-6.9 (2H, In), 7.0-7.3 (3H, In)
`0.9 (3H, t, J=6Hz, CH3), 1.1-1.7 (4H, In, CI__I2CIj2CH3), 1.9-3.1 (4H, m),
`2.3 (2H, t, J=6Hz, NCI;I2CH2CH2-), 3.3-3.4 (2H, In), 3.6-4.3 (5H, In),
`6.3-6.9 (2H, In), 7.0-7.3 (3H, m)
`1.1 (9H, s, CH3 x 3), 1.9-3.1 (4H, In), 3.3-3.4 (2H, In), 3.6-4.3 (5H, In),
`6.3-6.9 (2H, In), 7.0-7.3 (3H, In)
`1.9-3.1 (4H, m), 3.3-3.4 (2H, In), 3.6-4.3 (SH, In), 6.3-6.9 (2H, In),
`6.3-7.4 (SH, m, Ph-H), 7.0-7.3 (3H, m)
`1.9-3.] (4H, In), 3.3-3.4 (2H, In), 3.6 (2H, s, CH2Ph), 3.6-4.3 (SH, In),
`6.3-6.9 (2H, In), 7.0-7.3 (3H, In), 7.4 (5H, s, Ph-H)
`
`1.0-2.0 (IOH, In, cyclohexyl-H), 1.9-3.1 (4H, In), 2.0-2.4 (1H, In, N-CH—),
`3.3-3.4 (2H, In), 3.6-4.3 (SH, In), 6.3-6.9 (2H, In), 7.0-7.3 (3H, In)
`
`OK
`
`OCH2
`0
`
`
`C@
`
`0
`2 5(Nj LiAl1-I4
`
`O1
`
`7
`
`6
`
`C (CeH5)3
`
`(C6H5)3
`
`o
`
`NC
`
`[ :[CHzX
`
`9 (position 4)
`11 (position 7)
`
`~
`
`0
`
`8
`
`3
`
`2
`
`H01
`
`5
`
`4 CHIE
`6
`
`7
`
`N
`
`,OCH§[0j
`1
`HC1/EIOH
`C1CsH5)3 2 N
`
`
`
`6
`
`5
`
`3
`
`4
`
`10 (position 4)
`12 (Position 7)
`
`7-HC1 (position 7)
`6-HCI (position 4)
`
`X :P'CH3Ce.H4SO3
`
`Chart 2
`
`order to confirm the strucures of 6-HCl and 7-HCI thus obtained, each of the authentic
`samples was also synthesized by the route illustrated in Chart 2.
`The starting material (8) (prepared from 2—hydroxymethylmorpholine“) was allowed to
`react with the potassium salt of 4-hydroxy—1-indanones" inpdimethylsulfoxide (DMSO) to
`furnish (: )-2-(1-oxoindan-4-y10xymethy1)-4-triphenylmethylmorpholine
`(9)
`in
`73.5"/,’,
`yield. Reduction of 9 with LiA1H4 in THF gave the hydroxyindanyl derivative (10) in a good
`
`
`
`NII—Electronic Library Service
`  
`




`
`

`
`3770
`
`Vol. 33 (1985)
`
`yield. Dehydration and deprotection of 10 with aqueous ethanolic HC1 under reflux gave the
`corresponding 7-indenyl derivative 7 ~ HC1, which was recrystallized from MeOH to yield pale
`yellow needles melting at
`l69—170°C in 73.4% yield. Similarly, the 4-indenyl derivative
`6-HC1 was synthesized from 8 and 7-hydroxy-1-indanonef" and recrystallized from iso-
`PrOH to yield pale yellow prisms melting at l75~—176 °C.
`In general, it is known that prototropic tautomerization in indene occurs under basic
`conditions to afford an equilibrium mixture.” A similar double bond isomerization between
`6-HC1 and 7~HCl in a methanol solution was observed in the presence of base and the
`equilibrium ratio of 6 to 7 was 1 :2, as described above. However, interestingly enough, it was
`found that 6- HC1 was predominantly isomerized to 7 -HC1 when a suspension of the
`crystalline equilibrium mixture of 6- HC1 and 7 - HC1 in a small Volume of MeOH was treated
`with a catalytic amount of base; the ratio of the crystals were changed to 0.3 : 9.7. It is likely
`that less soluble 7-HC1 crystallized out preferentially from a solution of the suspension
`system. Accordingly, the isolation of 7- HC1 could be easily performed in good yield simply by
`direct filtration of crystals from the reaction mixture. This method affords a simple and
`practical route for the manufacturing synthesis of 7- HC1.
`In order to investigate differences in biological activities between the two optical
`antipodes, 7 -HC1 was resolved into its optically active isomers, (—)-7- HC1 and (+)-7- HC1
`by using D-(+)- and L—(—)-dibenzoyl tartaric acid, respectively.
`The pharmacological activities of 7-HC1, its optical isomers and related derivatives are
`shown in Table IV. These compounds inhibited the uptake of norepinephrine (NE) and
`serotonin (5-HT) by rat brain synaptosomes, antagonized the reserpine-induced hypothermia
`in mice and potentiated the 5-hydroxytriptophan (5-HTP)-induced behavioral change in rats.
`The secondary amines (6~HCl and 7~ HC1) were found to be markedly more potent than the
`tertiary amine derivatives (5b~—j) and as active as the known tricyclic antidepressants,
`imipramine and amitriptyline. In particular,v7 - HC1 was the most potent in respect of both 5-
`HT uptake inhibition in vitro and 5-HTP potentiation in vivo. It is also very interesting that
`
`TABLE IV. Biochemical and Pharmaceutical Effects of (i)-2-[(II1d€Il-7 (or 4)-
`yloxy)methyl]morpholine Derivatives
`
`1Cso (HM)"’
`
`MED (mg/kg)
`
`Compd.
`‘
`
`5a - HC1
`6- HC1
`7 - HC1
`
`(+)-7~HCl
`(—)-7-HC1
`5b ~ oxalate
`5c - citrate
`5d - oxalate
`Se - citrate
`Sf-oxalate
`
`5g - citrate
`Sh - HC1
`5i- oxalate
`
`5j - HC1
`Imipramine
`Amitriptyline
`Viloxazine
`
`a) See Experimental.
`
`NE
`
`1 .8
`2.2
`3. 2
`
`11.0
`1.3
`42
`47
`44
`37
`25
`
`—
`W
`——
`
`——
`5.8
`2.9
`19
`
`5-HT
`
`Reserpine“)
`
`5-HTP“’
`
`1 .3
`1 .3
`0. 71
`
`0.83
`0.65
`5. l
`6.8
`6.8
`9.0
`8.8
`
`-
`~
`—
`
`—
`0.42
`0.70
`66
`
`»
`
`3
`3
`3
`
`——
`—
`30
`30
`30
`10
`30
`
`100
`100
`100
`
`—
`10
`3
`3
`
`25
`25
`20
`
`20
`20
`50
`50
`75
`50
`75
`
`——
`—
`—
`
`'-
`50
`25
`100
`
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`  
`




`
`

`
`
`
`No. 9 3771
`
`TABLE V. Cerebral-Activating Properties of 7-HCl (Indeloxazine Hydrochloride)
`
`.
`.
`.
`.
`Pharmacological activities
`
`.
`Species
`
`.
`.
`Dose (MED, mg/kg)
`Injection
`mute —“—-———Z-—
`7-HCl
`
`Enhancing effect on learning behavior
`Desynchronization of spontaneous EEG
`Protective effect ‘against nitrogen-gas-
`induced lethality
`Protective effect against nitrogen-gas—
`induced amnesia
`
`Facilitatory effect on recovery from
`experimental concussion
`
`Rat
`Rat
`Mice
`
`Rat
`
`Mice
`
`EEG, electroencephalogram in the cerebral cortex.
`
`i.p.
`z'.p.
`iv‘
`
`LP.
`
`ml
`
`3
`3
`3
`
`1
`
`3
`
`(—)—7- HCl showed an NE uptake inhibitory effect which was 10 times as potent as that of
`(+)-7 ~HCl, though in the 5-HT uptake inhibition, such enantioselectivity was not observed
`(Table IV). These serotonergic and noradrenergic activities have been reported to be
`responsible for mood elevation and increased activities in humans,“ respectively. Thus,
`7- HCl and (——)—7- HCl may have clinically useful activities as antidepressants. It is important
`to note that viloxazine, a compound structurally analogous to 6 - HCl or 7 - HCl, exhibited the
`least effect on 5-HT uptake and had no effect on 5-HTP responses (Table IV). The difference
`in the serotonergic actions of the two types of compounds may be related to the difference of
`chemical structures between 6- HCl or 7- HCl (indenyl) and viloxazine (2-ethoxyphenyl).
`Furthermore, Yamamoto et al.” of our laboratories recently found that 7 - HCl showed an
`enhancing effect on learning behavior, a protective effect on nitrogen—gas—induced amnesia
`and some other cerebral-activating properties in rats or mice (Table V). These cerebral-
`activating effects of 7 -HCl might be attributed, at least in part, to inhibitory effects on the
`uptake of the biogenic amines in the cerebral nervous system. Thus, 7-HCl appears to be
`promising as a cerebral activator as well as an antidepressant, and it is currently under clinical
`evaluation for efficacy and safety.
`
`Experimental
`
`Melting points were determined on a Yanagimoto micro melting point apparatus and are uncorrected. Nuclear
`magnetic resonance (NMR) spectra were recorded on a JNM-FX100 Fourier transform (FT)—NMR (‘H; 100 MHz)
`spectrometer using Me4Si as an internal standard. The following abbreviations are used: singlet (s), doublet (d), triplet
`(t), quartet (q), multiplet (in), broad singlet (br s), double doublet (dd) and double triplet (dt). Mass (MS) spectra
`were measured with a Hitachi M-80 mass spectrometer. Gas chromatography was done on a Hewlett Packard 5711A
`gas chromatograph (column, 3% OV-22 on Chromosorb W AW, glass, 1.8m X 1.8 mm id; temperature of column,
`190 °C; temperature of flame ionization detector, 250 °C; carrier gas, 43 ml/min of He). Specific optical rotations were
`measured on a Perkin-Elmer (model 241) polarimeter. Column chromatography was carried out on Wako gel C-200
`(Wako Pure Chemical Ind., Ltd.). Thin layer chromatography (TLC) was performed on Silica gel 60 F254 plates
`(Merck). Solutions were concentrated in rotary evaporators under reduced pressure.
`(i)-6-[(Inden-7(or 4)-yloxy)methyl]-4-isopropylmorpholin-3-one (4'e)———Bromoacetyl bromide (2.0 g, 0.01 mol)
`was added dropwise to a solution of l-(inden-7(or 4)-yloxy)-3-isopropylamino-2—propanol (2e) (2.5 g, 0.01 mol) and
`Et3N (1.2 g, 0.013 mol) in CHZCIZ (30 ml) with stirring at 0——5 “C, and the mixture was stirred at room temperature
`for 6h. The reaction mixture was washed with 5% HCl (10m1>< 2) and H20 (10 ml x 2), dried over MgSO4, and
`concentrated in vacuo. The residue (3.6 g) was dissolved in MeOH (30 ml), this solution was added to a solution of
`MeONa (0.7 g, 0.013 mol) in MeOH (20 ml), and the mixture was refluxed for 6h, then concentrated in vacuo. The
`residue was extracted with CHCI3 (50 ml), and the extract was washed with 10% HCl (10 ml x 2) and H20 (10 ml x 2),
`dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel
`(60 g) using CHCl3—EtOAc (5: 1, v/v) as an eluent to afford 4e (2.5 g, 86%) as an oil.
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`The following ‘compounds were similarly prepared. The physical data and total yields of (i)-6-[(inden-7(or 4)-
`yloxy)methyl]morpholin-3-one derivatives (4a-j) are shown in Table I.
`Citric Acid Salt of (i )-2-[(Inden-7(or 4)-yloxy)methyl]-4-isopropylmorpholine (Se v Citrate)-A solution of 4e
`(2.0 g, 0.007 mol) in THF (30 ml) was added dropwise with stirring to a cooled suspension of LiAlH4 (0.5 g, 0.013 mol)
`in TH F (30 ml) at 5-10 °C. The reaction mixture was stirred at 40-50 °C for 10h and then cooled. Excess reagent
`was decomposed with H20 and the resulting precipitates were filtered oil. The filtrate was dried over MgSO4 and
`concentrated in vacuo. The residue was purified by column chromatography on silica gel (30 g) using Cl-{Cl3—EtOAc
`(5: 1, v/v) as an eluent to afford Se-(1.5 g, 78.9%) as an oil.
`The oily product 5e (1.1 g, 0.004 mol) was treated with a solution of citric acid (1.0 g, 0.005 mol) in EIOH (l0ml)
`to give 5e-citrate (1.7 g, 89.9“/0).
`~
`The physical data and yields of ( i )-2-[(inden-7(or 4)-yloxy)methyl]morpholine derivatives (Sa-j) are shown in
`Tables 11 and III.
`'
`
`(1)-2'-[(Inden-7(or 4)-yloxy)methyl]morpholine Hydrochloride (5a~HCl)-A solution of 1-(inden-7(0r 4)-
`yloxy)-2,3-epoxypropane (1) (9.4 g, 0.05 mol) in MeOH (50 ml) was added dropwise to a solution of 70% aqueous
`NaOH (29 ml) and 2-aminoethyl hydrogen sulfate (35 g, 0.25 mol) with stirring at 50-55 °C. The mixture was stirred
`for l h and then 70% aqueous NaOH (50 ml) was added. The reaction mixture was stirred for 16 h at 50-55 “C, then
`diluted with H20 (300ml) followed by extraction with toluene (100 ml ><2). The extract was washed with H20
`(100 ml X2), and dried over MgSO4. After removal of the solvent, the oily residue was distilled under reduced
`pressure to afford 5a (617 g, 58%,) as a viscous oil, bp 146-156°C (0.5 mmHg).
`The oily product 521 (3.0 g, 0.013 mol) in acetone (30 ml) was treated with a solution 0f5% HC1 in iso-PrOH (15 ml)
`to give the salt (2.8 g, 82%), mp 143-155 “C (recrystallized from acetone). Anal. Calcd for CMHHNOZ -HC1: C, 62.80;
`H, 6.78; N, 5.23; C1, 13.24. Found: C, 62.63; H, 6.79; N, 5.05; Cl, 13.51. The NMR spectrum, melting point and Rf
`value on TLC were identical with those of 5a-HC1 obtained by the alternative route described above (listed in Tables
`11 and Ill).
`Isolation of (i)-2-[(Inden-4-yloxy)methyl]morpholine Hydrochloride (6- HC1) and (i)-2-[(Inden-7-yloxy)-
`methyl]morpholine Hydrochloride (7-HC1) from 5a-HC1-A solution of 5a (3.0 g, 0.0l3mol) in acetone (70 ml)
`was acidified with a solution of 10% HC1 in iso-PrOH and the resulting solution (equilibrium mixture of 6-HC1
`and 7-HC1 in a ratio of 1:2) was allowed to stand at 0-5 “C for 15 min. The precipitated crystals were col-
`lected by filtration and washed with acetone to provide 6'HCl (1.1 g, containing 15% of 7‘HCl). Repeated re-
`crystallization from iso-PrOH afforded isomer-free 6-HC1 (0.6 g, 17%), mp 175-176 5C. Anal. Calcd for
`C14H,7NO2-HC1: C, 62.80; H, 6.78; N, 5.23; C1, 13.24. Found: C, 62.87; H, 6.75; N, 5.35; Cl, 13.49. The mother
`liquor and washings were combined and evaporated to dryness in vacuo. The residual salt dissolved in acetone (30 ml)
`was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration and washed
`with acetone to provide 7 -HCl (1.7 g, containing 10‘’/,, 6-HC1). Repeated recrystallization from MeOH afforded
`isomer-free 7-HC1 (1.1 g, 31%), mp 169-170 “C. Anal. Calcd for CMHHNOZ-HC1: C, 62.80; H, 6.78; N, 5.23; Cl,
`13.24. Found: C, 62.82; H, 6.77; N, 5.20; Cl, 13.46. The structures of 6~HCl and 7-HC1 were confirmed by
`comparison of their NMR spectra, MS and melting points with those of authentic samples synthesized by an
`alternative route described later. The purities were checked by gas chromatography after triiluroacetylation (N-
`trifluoroacetyl-6, tk 17’57”; N-trifluoroacetyl—7, tx l5’24”).
`Isomerization of 5a-HCI into 7-HC1-A suspension of 5a-HC1 (10.0 g, 0.037 mol, equilibrium mixture of
`6- HC1 and 7-HC1 in a ratio of 1 :2) in acetone (30 ml) containing a catalytic amount of 5a (0.9 g, 0.0038 mol) as a
`base was stirred vigorously at room temperature for 24 h. The precipitated salts were collected by filtration and
`washed thoroughly with acetone. The resulting salts (9.8 g. containing 3% 6-HC1) were recrystallized from MeOH
`(35 ml) to provide isomer-free 7-HC1 (7.3 g, 73%), mp 169-170 °C. Free base 5a recovered from the filtrate was
`shown to be an equilibrium mixture of 6 and 7 in a ratio of l :2.
`( i)-4-triphenylmethyl-2-(p-toluenesu1fonyloxy-
`Preparation of Authentic 7 ~HCl
`(a) A solution of
`methyl)morpholine (8) (10 g, 0.019 mol) and the potassium salt of 4-hydroxy-l-indanone (3.6 g, 0.0l9mol) in di-
`methylformamide (DMF, 120 ml) were stirred at 100-105 °C for 17h. The reaction mixture was concentrated
`in vacuo. The residue was poured into ice water and the precipitated crystals were collected by filtration and washed
`with water
`to provide (i)-2-[(1-oxoindan-4-yloxy)methyl]-4-triphenylmethylmorpholine (9)
`(7.0 g, 73.5%),
`mp 213-215°C (recrystallized from EtOAc-hexane). MS m/z: 489 (M T). NMR (CHCl3) 6: 1.4-1.9 (2H, m),
`2.8-3.3 (2H, m), 2.5-3.0 (4H, 111), 3.8-4.1 (4H, m), 4.1-4.3 (1H, m), 6.9-7.6 (l8H, m). Anal. Calcd for
`C33H31NO_.,: C, 80.95; H, 6.38; N, 2.86. Found: C, 81.21; H, 6.57; N, 2.79.
`(b) A solution of 9 (10g, 0.02 mol) in THF (100 ml) was added dropwise to a suspension of LiAlH4 (1.17 g,
`0.03 mol) in THF (100 ml) at 5-10 °C and the reaction mixture was stirred at room temperature for 3 h and then
`cooled. Next, H20 (1.2 ml), 15% aqueous NaOH (1.2 ml) and H20 (3.6 ml) were successively added dropwise to the
`reaction mixture. The resulting precipitates were filtered off. The filtrate was concentrated to dryness under reduced
`pressure. The residue was triturated with EtOAc (3 ml)
`to give (1)-2-[(1-hydoxyindan-4—yloxy)rnethyl]-4-
`triphenylmethylmorpholine (10) (7.8 g, 77.7%), mp 222-224 °C (recrystallized from EtOAc). MS m/z: 491 (M").
`NMR (CDCI3) 6: 1.4-1.7 (1H, m), 1.6-1.8 (1H, brs), 1.7-2.0 (1H, m), 2.2-2.5 (1H, m), 2.5-3.0 (3H, m), 2.8-
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`3.3 (2H, m), 3.8-4.0 (4H, m), 4.1-4.3 (1H, m), 5.2 (1H, t, J=6 Hz), 6.6-7.6 (18H, m). Anal. Calcd for C33H33NO,:
`C, 80.62; H, 6.77; N, 2.85. Found: C, 80.84; H, 6.81; N, 2.59.
`(c) A mixture of 10 (2.0 g, 0.004 mol) and 0.5 N HC1 (140 ml) in EtOH (60 ml) was refluxed with stirring for 17h
`and then cooled. The reaction mixture was concentrated to half the initial volume under reduced pressure and washed
`with Et2O. The aqueous layer was saturated with NaCl and extracted with CHCI3 (50 ml x 3). The extract was dried
`over MgSO4 and concentrated under reduced pressure to give 7 - HC1 (0.8 g, 73.4%). Recrystallization of the salt from
`either MeOH or acetone was performed to give isomer-free 7-HC1, mp 169-170 “C (from MeOH) and mp 155-
`156 °C (from acetone); these products were polymorphs. MS m/z: 231 (M1). NMR (DMSO—d6) 6: 2.8-3.6 (4H, m),
`3.32 (2H, m), 3.6-4.3 (3H, m), 4.12 (2H, m), 6.56 (1H, dt, J= 2, 5 Hz), 6.86 (1H, dt, J=2, 5 Hz), 6.7-7.3 (3H, m),
`9.64 (2H, br s). Anal. Calcd for CMHUNOZ-HC1: C, 62.80; H, 6.78; N, 5.23;C1, 13.24. Found: C, 62.73; H, 6.52; N,
`5.09; C1, 13.49.
`Preparation of Authentic 6-HC1-—(a) ( i)-2-[(1-Oxoindan—7-yloxy)methyl]—4-triphenylmethylmorpholine (11)
`was prepared from 7-hydroxy—l-indanone in the same manner as described for 9. Recrystallization from EtOAc
`afforded 11 (87.8%), mp 170-171 °C. MS m/z: 489 (M"). NMR (CDC13) 6: 1.4-1.9 (2H, m), 2.8-3.3 (2H, m),
`2.5-3.2 (4H, m), 3.8-4.2 (4H, m), 4.2-4.4 (1H, m), 6.6-7.6 (18H, m). Anal. Calcd for C33H3,N03: C, 80.95; H,
`6.38; N, 2.86. Found: C, 81.09; H, 6.44; N, 2.71.
`(b) (i)-2-[(1-Hydroxyindan-7—yloxy)methyl]-4-triphenylmethylmorpholine (12) was prepared from 11 in the
`same manner as described for 10. Recrystallization from EtOAc afforded 12 (89.3%), mp 221-222 "C. MS m/z: 491
`(M *). NMR (CDCI3) 6: 1.6-1.8 (1H, m), 1.9-2.1 (1H, m), 2.2-2.4 (1H, m), 2.4-2.9 (3H, m), 2.9-3.1 (1H, br s),
`2.9-3.2 (2H, m), 3.8-4.1 (4H, m), 4.1-4.4 (1H, m), 5.36 (1H, dd, J=7, 7Hz), 6.5-6.6 (18H, m). Anal. Calcd for
`C33H33NO3: C, 80.62; H, 6.77; N, 2.85. Found: C, 80.73; H, 6.59; N, 2.64.
`(c) 6‘HCl was prepared from 12 in the same manner as described for 7-HC1. Recrystallization from lso-PrOH
`afforded 6-HC1 (81.8%), mp 175-176 °C. MS m/z: 231 (M"). NMR (DMSO-d,.,) 6: 2.8-3.6 (4H, m), 3.4 (2H, m),
`3.6-4.3 (3H, m), 4.10 (2H, m) 6.48 (1H, dt, J= 2, 5 Hz), 6.86 (1H, dt, J=2, 5 Hz), 6.7-7.2 (3H, m), 9.67 (2H, br s).
`Anal. Calcd for CMHHNOZ-HC1: C, 62.80; H, 6.78; N, 5.23; Cl, 13.24. Found: C, 62.64; H, 6.71; N, 5.14; C1, 13.40.
`(1)-2-Hydroxymethylmorpholine-{_-1;)-2-Hydroxymethyl-4-benzylmorpholinez" (10.0 g, 0.048 mol) was hy-
`drogenated over 10% Pd-C (500 mg) in MeOH (100 ml) at room temperature until H2 uptake ceased. The catalyst
`was filtered off and the filtrate was concentrated in vacuo. The residue was distilled to give 2-hydroxymethy1mor-
`pholine (8.1 g, 95%), as a colorless oil, bp 92-93 “C (1.1 mmHg). NMR (CDCl3) 5: 2.18 (2H, s), 2.5-3.0 (4H, m),
`3.2-4.0 (5H, m). Anal. Calcd for C51-IUNOZ: C, 51.26; H, 9.46; N, 11.96. Found: C, 51.08; H, 9.35; N, 12.06.
`(i )-2-Hydroxymethy1-4-triphenylmethylmorpho1ine—-A solution of triphenylchloromethane (4.3 g, 0.015 mol)
`in CI.-.[2Cl2 (20 ml) was added to a solution of (1)-2-hydroxymethylmorpholine (1.8 g, 0.015mol) and Et3N (1.6 g,
`0.016 mol) in CH2C12 (30 ml) with stirring at 0-5 °C. After being stirred at room temperature for 10h, the reaction
`mixture was diluted with H20. The organic layer was separated and washed with H20. The organic layer was dried
`over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography using CHCI3
`as an eluent to afford (i)-2-hydroxymethyl-4-triphenylmethylmorpholine (5.3 g, 96.4%) as an oil. NMR (CDCl3) 6 2
`1.2-1.9 (2H, m). 1.5 (1H, s), 2.9 (2H, d, J= 10 Hz), 3.5 (2H, m), 3.7-4.2 (3H, m), 7.0-7.6 (l5H, m). Anal. Calcd for
`C24H25N0z: C, 80.19; H, 7.01; N, 3.90. Found: C, 80.36; H, 6.89; N, 3.87.
`( : )-4-Triphenylmethyl-2—(p—toluenesulfonyloxyrnethyflmorpholine (8)-A solution ofp-toluenesulfonyl chloride
`(2.8 g, 0.015 mol) in CHZCIZ (50 ml) was added dropwise to a solution of (1: )-2-hydroxymethyl-4—triphenyl-
`methylmorpholine (5.2 g, 0.015mol) and pyridine (1.2 g, 0.015mol) in CHZCIZ (150 ml) with stirring at 0-5 “C.
`After being stirred for 15 h at room temperature, the reaction mixture was diluted with H20. The organic layer was
`separated and washed successively with H20, saturated NaHCO3 and brine, then dried over MgSO4. After re-
`moval of the solvent, the residue was recrystallized from ClCH2CHzCl to give 8 (5.2 g, 70%), mp 232-233 “C.
`NMR (CDC13) 6: 1.2-1.8 (2H, m), 2.4 (3H, s), 2.8 (2H, d, J= 10 Hz), 3.6-4.1 (5H, m), 7.0-7.5 (17H, m), 7.6 (2H,
`d, J==8Hz). Anal. Calcd for C31H3,NO4S: C, 72.49; H, 6.08; N, 2.73; S, 6.24. Found: C, 72.53; H, 5.97; N, 2.85; S,
`6.44.
`
`(+)-2-[(Inden-7-yloxy)methyl]morpho1ine Hydrochloride ((+)-7-HC1)-(a) A solution of LiOH H20 (42 g,
`1 mol) in abs. MeOH (800 ml) was added dropwise to a solution of L-( —)-dibenzoyltartaric acid monohydrate (452 g,
`1.2 mol) in abs. MeOH (1600 ml) at -10 to -20 °C with stirring. Then 7-HC1 (268 g, lmol) was added at room
`temperature and the whole was stirred at 2-5 °C for 60 h. The precipitated crystals were collected by filtration and
`repeated recrystallizations from abs. MeOH (g/10 ml volume) afforded the L-( —)-dibenzoyltartaric acid salt of
`(+)-2-[(inden-7-yloxy)methyl]morpho1ine (93.5 g, 15.6%), mp 181-182 °C. [ot]f,° -71.7 (c= 1, MeOH). MS m/z: 231
`(M"). NMR (CD3OD) 6: 2.8-3.5 (4H, m), 3.6-4.2 (5H, m), 5.9 (2H, s), 6.5 (1H, dt, J=2, 5 Hz), 6.8 (1H, dt, J=2,
`5 Hz), 6.7 (1H, q, J=2,
`8 Hz), 6.9-7.3 (2H, m), 7.3-7.7 (6H, m), 8.0-8.2 (4H,
`111). Anal. Calcd for
`CMH,7NO2-C,3H14O8-1/21-120: C, 64.21; H, 5.39; N, 2.34. Found: C, 64.44; H, 5.28; N, 2.32.
`(b) The L-(——)-dibenzoyltartaric acid salt of (+)-2-[(inden-7-yloxy)methyl]morpholine (60 g, 0.1 mol) was stirred
`with 0.1 N HC1 (1000 ml) and Et2O (500 ml) at 0-5 °C for 3 h. The aqueous layer was separated and washed with
`Et2O (500m1>< 5). After removal of the solvent, the residue was crystallized from iso-PrOH (70 ml). The crystals were
`collected by filtration and recrystallized from EtOH (50 ml) to give (+)—7~HCl (12 g, 44.9%), mp 112-113 "C. [or]?
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`+4.9 (c=5, MeOH). MS m/z: 231 (M+). NMR (CD3OD) 5: 3.0—3.6 (6H, In), 3.7—~4.3 (5H, m), 6.6 (1H, dt, J=6,
`2 Hz), 6.7~£.9 (2H, m), 7.0 (1H, dd, J= 7, 1 Hz), 7.2 (1H, t, J: 7 Hz). Anal. Calcd for CMHNNOZ ‘ HC1: C, 62.80; H,
`6.78; N, 5.23; C1, 13.24. Found: C, 62.67; H, 6.71; N, 5.27; C1, 13.24.
`(—)—2-[(Inden-7—yloxy)methyl]morpholine Hydrochloride (( —)-7»HCl)——(a) The D-(-1-)-dibenzoyltartaric acid
`salt of (~)-2-[-inden-7-y1oxy)methyl]morpholine was prepared from 7‘HCl
`(268 g,
`1 mol) and D-(+)-diben-
`zoyltartaric acid in the same manner as described for (+)-7 - HC1. Yield 65 g (109%), mp 181-182 °C.
`[oz]?
`+7l.6(c=1, MeOH). MS m/z: 231 (M +). NMR (CD30D) 6: 2.8~3.5 (4H, m), 3.64.2 (5H, m), 5.9 (2H, s), 6.5
`(1H, dt, J= 2, 5Hz), 6.8 (1H, dt, J=2, 5Hz),‘6.7 (1H, q, J=2, 8 Hz), 6.9-7.3 (2H, m), 7.3—7.7 (6H, m), 8.0—8.2
`(4H, m). Anal. Calcd for C,4H,,No,«C,,H,,o,-1/2H,o; C, 64.21; H, 5.39; N, 2.34. Found: C, 64.44; H, 5.28; N,
`2.32.
`
`(—)-2-[(inden-7—yloxy)-
`(—)—7‘ HC1 was prepared from the D-(+)-dibenzoyltartaric acid salt of
`(b)
`'
`methy1]morpholine (58 g, 0.1 mol) in the same manner as described for (+)-7~HC1. Recrystallization from iso-
`PrOH (70ml) afforded (—)-7<HCl (12.5 g, 466%), mp 142—142.5°C.
`[0430 ’—4.9 (c=5, MeOH). MS m/z: 231
`(M+). NMR (CD3OD) 6: 3.0——3.6 (6H, In), 3.7—4.3 (5H, m), 6.6 (1H, dt, J=6, 2 Hz), 6.7—6.9 (2H, m), 7.0 (1H, dd,
`J: 7, 1Hz), 7.2 (1H, t, J=7Hz). Ana]. Calcd for CMHNNOZ -HC1: C, 62.80; H, 6.78; N, 5.23; Cl, 13.24. Found: C,
`63.06; H, 6.83; N, 5.27; C1, 13.48.
`(i)-2-[(Inden—7(or 4)-yloxy)methyl]-4-methylmorpholine (Sb) from 5a———A mixture of 5a (5.0 g, 0.021 mol),
`Mel (3.0 g, 0.021 mol) and KZCO3 (3.0 g, 0.022 mol) was refluxed in EtOH_(100 ml) for 15 h. The solvent was removed
`under reduced pressure. The residue was extracted with CHCI3 (100 ml). The extract was washed with brine and dried
`over MgSO4. After removal of the solvent, the residue was purified by column chromatography on silica gel using
`CHCl3~EtOAc (5: 1, v/v) as an eluent to afford 5b (3.6 g, 67.9%) as an oil.
`The following compounds were similarly prepared.
`(1')-2-[(II1dCI1-7(OI 4)-y1oxy)methy1]-4-ethylmorpholine (5c): Oil. Yield 73.5%.
`(i)-2-[(Inden-7(or.4)-y1oxy)methy1]-4—benzylmorpholine (51): Oil. Yield 79.7 %. NMR spectra and Rf values on
`TLC of these compounds were identical with those of the product prepared by hydrogenation of 4 (4b, 4c and 4i).
`Inhibition of NE and 5-HT Uptake by the Rat Brain Synaptosome7a)_)The inhibition of uptake of
`[”'C]norepinephrine (NE) and [“‘C]hydroxytryptamine (5-HT) by the synaptosomes from rat whole brain was
`determined using 6 preparations for each concentration of the test compounds. The IC50s, the concentrations of the
`test compounds required to inhibit the uptake reaction by 50%, were obtained from the dose-response curves.
`Antagonism to the Effects of Reserpine"”——Reserpine, 10mg/kg z'.p., was given to mice 3 h before oral
`administration of a test compound (1, 3, 10, 30 or 100 mg/kg). The minimal effective dose (MED; m