Note: Descriptions are shown in the official language in which they were submitted.
~3C~
-- 1 --
SPECIFICATION
THERAPEUTIC AGENT FOR NEUROLOGICAL DISEASES
TEC~NOLOGICAL FIELD
This invention relates to a novel therapeutic
agent for neurological diseases in the peripheral nervous
system and the central nervous system of animals More
specifically, it relates to a novel therapeutic agent for
neurological diseases comprising a particular 2-pipera-
zinopyrimidine derivative or its pharmaceutically accept-
able salt.
~ACKGROUND TECENOLOGY
In the therapy of neurological diseases, namely
disorders in the central nervous system and the peripheral
nervous system, therapeutic agents for the central nervous
system have been vigorously studied and applied. In
contrast, very few therapeutic agents for diseases of the
peripheral nervous system, especially disorders of peri-
pheral nerves, have been put to practical use worldwide.
Japanese Laid-Open Patent Publication No.
34912/1977 discloses a pharmaceutical comprising a dis-
persion or solution of ganglioside in a medium, which is
effective for pathology at~ributed to neural stimulus
transmission disorders in the central nervous system and
the peripheral nervous syste~. Only ganglioside (a pro-
duct named Cronassial is sold in Italy), a natural carbo-
hydrate, disclosed in the above-cited laid-open publica-
tion~and mecobalamin, a kind of vitamin, have so far beenapplied clinically to diseases of the peripheral nervous
system, but no entirely satlsfactory effect has been
obtained.
Japanese Patent Publication No.~ 28548/lg84
discloses 2-isopropylaminopyrimidine ortho-phosphate
represented by the following formula
~3~ .Z
-- 2 --
~ NHCH ~ 3-H3Po4
and a therapeutic agent comprising this compound for
treatment of peripheral nerve diseases. As far as the
present inventors know, the above compound ~common name,
S isaxonine phosphate to be abbreviated hereinafter as
isaxonine) is the first synthetic compound which was used
in clinical research on peripheral nerve disorders (La
Nouvelle Presse Medicale, vol. 16, pages 1189-12B0, 1982).
It appears that this compound is not actually marketed
now. No synthetic compound has been known which is used
for treating peripheral nerve disorders.
Factors acting on the growth and regeneration of
nerves are kn~wn to exist in an animal. They are called a
nerve growth factor (NGF) or a neurotrophic factor~ These
factors are high-molecular proteins, and many problems
exis~ which have to be technically solved in applying them
to neurological diseases.
Japanese Laid-~pen Patent Publication No~
222424fl984 discloses that a gangliside mixture extracted
from the cow brain or a single component in ganglioside~
acts promotingly on the proliferatio~ of the primary
culture of nerve cells or neuroblasto~a cells, and the
formation and growth of the neurite, and that it has the
same effect as mecobalamin in an animal model of neuro-
logical disorder. ~urthermore, as stated above, ganglioside is actually used clinically for the treatment of
disorders in the peripheral nervous system and the central
nervous system (not psychopathy)
~anglioside, however, is a natural extract
originated from an ani~al of a different species, and the
antigenicity of itself or a foreign material contained in
it becoaes a problem. Another problea is that ~t is very
.
,
~L3~$~
difficult to specify and d~fine it as a uniform ~able
substance in drug preparation.
Japanese Laid-Open Patent Publication No~
144,765/1984 discloses a 2-(1-piperazinyl~pyrimidine
s havin~ the following formula (I)
~ ~ -N~_,N~X ~I)
p
wherein one of P and Q represents hydrogen or a
hydroxyl or lower alkyl group and the other
represents hydrogen, and X represent~ a c;roup of
the formula CO-Rl i~ which Rl is a lower alkyl
group, a group of the formula CO-CH-R2
NH-R3
in whïch R2 is hydrogen or a lower alkyl,
phenyl, p-hydroxyphenyl, benzyl, p-hydroxy-
benzyl, hydroxymethyl, l-hydroxyethyl or 3-
indolylmethyl group, R3 is hydrogen, a lower
alkylcarbonyl group, a benzoyl group, an acyl
group derived from an amino acid selected from
glycine, phenylglycine~ alanine, valine,
leucine, isoleucine, phenylalanine, tyrosine~
serine, threonine and tryptophan, or an acyl
group derived ~rom a dipeptide comprised of two
of the above amino acids, or R2 and R3 together
may form an ethylene group, a group of the
formula Alk-COOY in which Alk represents a liner
or branched alkylene group having 1 to 4 carbon
atoms and Y represents hydrogen or a lower alkyl
group, a gro~p of the formula ~lk-CH2OZ in which
Alk is as defined, and Z represents hydrogen or
a lower alkylt ~lower alkoxyl-lower alkyl, or
3~ lower alkylcarbonyl group, or a group of the
31 3~S~
formula Alk~CO-W in which Alk is as defined and
W represents a lower alkyl group or its pharma-
ceutically acceptable acid addition salts.
This patent document states that the compounds
of formula tI)- or acid addition salt5 thereof have
dopamine-type psychotherapeutic activity~
Japanese Laid-Open Patent Publication No.
144,766/1984 describes an acid addition salt of 2~
piperazinyl)pyrimidine with a dicarboxylic acid, and
states that this compound has good phrenotropic activity
having dopamine mechanism, particularly antipsychotic
activity, antimelanchoric activity and ataractic and
tranguilizing activity.
~apanese Laid-Open Patent Publication No~
155,316/1984 discloses a dr~g having dopamine-acting
phrenotropic activity comprising as an active ingredient
a 2-piperazinopyrimidine represented by the formula
N ~ _R2 tI~
: Rl
wherein Rl represents hydrogen or a hydroxyl
: ~ 20 group, and R represents hydrogen or an alkyl
~: group having l to 6 carbon atoms,
~ or a pharmacologically acceptable acid addition salt
; : thereof.
: ~ International Laid-Open WO85/00168 discloses
2~ piperazinyl)pyrimidine~2-naphthalenesulfonate re-
presented by the following~formula
:: :
and states that this compoand has dopamine phrenotropic
activity.
~3~
-- 5 --
However~ none of the above four cited patent
documents describe or suggest that 2-piperazinopyri~idines
are effective for reproducing neurocytes and can be
applied to peripheral nerve disorders, and central nerve
disorders which are not psychopathy.
It is an object of this invention therefore to
provide a novel therapeutic agent for neurological
diseases~
Another object o~ this invention provides a
novel therapeutic agent for neurological diseases ef-
fective for reproducing and repairing neurocytes.
Still another object of this invention is to
provide a novel therapeutic agent for neurological
diseases which can be applied to disorders of peripheral
nerves~
Yet another object of this invention is to
provide a novel therapeutic agent for neurological dis
orders which can be applied to central nerve disorders
that are regarded as being primarily due to the involve-
ment of derangement of the active and metabolic systems ofnerve transmitting substances.
Further sbjects of this invention along with its
advantages will become apparent from the following descrip-
tion.
According to this invention, the above objects
and advantages of this invention are achieved by a thera-
peutic agent for neuroIogical diseases~ comprising as an
active ingredient a pyrimidine represented by the follow-
ing formula ~I)
Rl-N~_,N - ~ ~ R~ ... (I)
R4
wherein
Rl represents a hydrogen atom, an acyl group
having 2 to 4 carbon atoms, an alkoxycarbonyl
~3(~S~
6 6756~-1058
group having 2 to 5 carbon atoms, an alkoxycarbonylmethyl
group havin~ 3 to 5 carbon atoms, benzyl, a 3,4-
dimethoxybenzoyl group or a 3,4-methylenedioxybenzyl group,
R~ represents a hydrogen atom, an amino group, a
monoalkylamino group having 1 to 4 carbon atoms, an alkoxy
group having 1 to 5 carbon atoms or an alkoxycarbonyl yroup
having 2 to 4 carbon atoms,
R3 represents a hydrogen atom, an al}coxycarbonyl group having
2 to 4 carbon a~oms, a dialkylaminocarbonyl group having 1 to
9 carbon atoms in each alkyl moiety, an alkoxy group having 1
to 5 carbon atoms, or a hydroxyethyl group,
R2 and R3, together with the carbon atoms to which they are
bonded, may form a 5- to 7-membered carbocyclic ring or a
heterocyclic ring having N, 0 or S as the hetero atom, and
wherein said carbocyclic or heterocyclic ring may be
: saturated or unsaturated, on or more of the carbon atoms ofthe ring may be substituted by =X wherein =X denotes =0 or
=N-R5 wherein R5 is hydroxyl, benzenesulfonyloxy or
toluenesulfonyloxy or one or more carbon atom~ of the ring
may be substituted by Cl-C4 alkyl or if the carbon atom is
linked to a double bond of the ring the carbon atom may be
substituted by formyl, Cl-C4 alkyl, C7-Cg aralkyl or metho~y
and if the hetero atom is nitrogen it may be substituted by
Cl-C10 alkyl, by an alkoxyalkyl group resulting from
substitution of an alkyl group having 2 to 4 carbon atoms,
with Cl-C4 alkoxy, by a Cl-C4 acyl, by a carbamoylmethyl, by
a C3-C4 alkenyl, by a C2-C~ hydroxyalkyl, by benzyl, by a
C3-C6 cycloalkyl, or R2 and R3 together represent
C
~31~S~2
6a 67566-1058
-S C~3 ~ and
R4 represents a hydrogen atom, an alkyl group havlnc~ 1 to 4
carbon atoms, or an al~ylthlo group having 1 to 4 carbon
atoms, with the provisos that Rl, R2, R3 and R4 are not
simultaneously hydrogen and that when R1 is acyl or
alkoxycarbonlymethyl, R and R3 are not simultaneously
hydrogen,
or a pharmaceutically acceptable salt thereof.
Other aspects of the invention include the use of such
therapeutic ayents to treat a neurological disease in a mammal and
a commercial package comprising such a therapeutic agent
containing an effective amount of the actlve ingredient along with
instructions for use to treat a neurologica1 disease in a mammal.
In formula (I), R repxesent~ a hydrogen atomr an acyl
group having 2 to 4 carbon atoms, an alkoxycarbonyl group having 2
to 5 carbon atoms, an alkoxycarbonylmethyl group having 3 to 5
carbon atoms, a benzyl group, or a 3,4-methylenedioxybenzyl group.
Examples of the acyl group having 2 to 4 carbon atoms
are acetyl, propionyl, butyroyl and ~sobutyroyl groups.
Examples of the alkoxycarbonyl group having 2 to 5
carbon atoms are methoxyaarbonyl and ethoxycarbonyl groups.
Examples of the alkoxycarbonylmethyl group having 3 to 5
carbon atoms are methoxycarbonylmethyl and ethoxycarbonylmethyl
groups.
In formula (I), R represents a hydrogen atom,
~5~2
-- 7
an amino group, a monoalkylamino group having 1 to 4
carbon atoms, an alkoxy group having 1 to 5 carbon atoms,
or an alkoxycarbonyl group having 2 to 4 carbon atoms.
Examples of the monoalkylamino group having 1 to
4 carbon atoms are methylamino, ethylamino, propylamino,
isopropylamino and sec-butylamino groups~
Examples of the alkoxy group havin~ 1 to S
carbon atoms are methoxy, ethoxy, propoxy, iso-propoxy~
butoxy, sec-butoxy, iso-butoxy and tert-butoxy groups.
Examples of the alkoxycarbonyl groups havin~ 2
to 4 carbon atoms may be the same as those given above for
In formula (I~, R3 represents a hydrogen atom,
an alkoxycarbonyl group hving 2 to 4 carbon atoms, a
dialkylaminocarbonyl group having 1 to 9 carbon atoms in
each alkyl moiety, an alkoxy group having 1 to 5 carbon
atomsp or a hydroxyethyl group.
Examples of the alkoxycarbonyl group having 2 to
4 carbon atoms ~ay be the same as those given hereinabove
with regard to Rl.
Examples of ~he dialkylaminocarbonyl groups
having 1 to 9 carbon atoms in each alkyl moiety are
- dimethylaminocarbonyl, diethylaminocarbonyl, diisopropyl-
aminocarbonyl and dibutylaminocarbonyl groups.
Examples of the alkoxy group having 1 to 5
carbon atoms may be the same as those given hereinabove in
regard to R .
In formula (I), R2 and R3 may form a 4- to
7-membered carbocyclic ring or a heterocyclic ring havi~g
N, O or S as the hetero atom together with the carbon
atoms to which they are bonded.
Examples o~ a group formed by R2 and R3 kogether
are shown below.
~a) ~CH2~
wherein ~1 is a number of 2, 3 or 4.
~3~5~
(b) ~CH2)R C-
2X
wherein X is -O or -N-RS in which R5 represents
a hydroxyl, benzylsul~onyloxy or toluenesulfonyloxy group,
and ~2 represents a nu~ber of 2, 3, or 4.
R6 E~ R8
~c) -N~CH2)Q C--~C ~
wherein R6 represents a hydrogen atom, an alkyl
group having 1 to 4 carbon atoms, or an alkoxy alkyl group
resulting from substitution of an alkyl group having 2 to
4 carbon atoms by an alkoxy group having 1 to 4 carbon
atoms, R7 and R8 are identical or different and each
represents a hydroge~ atom or an alkyl group having 1 to 4
carbon atoms, ~3 is 2 and ~ is 0~ or ~ is O and ~ is 1.
O R
. .
: Id) ~CH ~ -N-
S
wherein R9 represents a hydrogen atom or an
: alkyl group having 1 to 4 carbon atoms, and ~5 is a number
of 2 or 3.
10 o
(e~ ~CH ~ N------C--
wherein R10 represents a hydrogen ato~s, an
~ alkyl group having 1 to 10 carbon atoms, an acyl group
; having 1 to 4 carbon atoms, or a carbamoylmethyl group,
and ~6 is a number of 1 or 2
~: : :
ll p~12.o
n
~ If) -C=C~ N---C-
~s~
- 9 -
wherein Rll represents a hydrogen atom, a formyl
group~ an alkyl group having 1 to 4 carbon atoms, or an
aralkyl group having 7 to 9 carbon atoms, and R12 re-
presents a hydrogen atom, an alkyl group having 1 to 4
carbon atoms, an alkenyl group having 3 to 4 carbon atoms,
a hydroxyalkyl group having 2 to 4 carbon atoms, an alkoxy-
alkyl group resulting from substitution of an alkyl group
having 2 to 4 carbon atoms by an alkoxy group having 1 to
4 carbon atoms, a benzyl group, or a cycloalky} group
having 3 to 6 carbon atoms,
R13 R14 0
Il
(g) -N~CH ~ N---C
wherein R13 and R14 are identical or different,
and each represents a hydrogen atom or an alkyl group having 1
to 4 carbon atoms, and Q7 is a number of 0, 2 or 3,
(h) -E-G-
wherein E-G is -OCH2CH2-, OClCH3) , 2
-OCOC~2-, -C~2C(CH3~OCO-, -N~CH3~C~2CH2-, -CH=CH-CH=CH-~
: -CH=C~OCH33-C(OCH3)-CH-, or ~ c~3.
Examples of the alkyl group having 1 to 4 carbon
atoms ~or R6 in (c) above are methyl, ethyl, propyl,
isopropyl, butyl, sec-butyl, iso-butyl and tert-butyl~
Examples of the alkoxyalkyl group for R6
resulting from substitution of an alkyl group having 2 to
4 carbon atoms by an alkoxy group.having 1 to 4 carbon
atoms are methoxyethyl, ethoxyethyl, propoxyethyl,
butoxyetbyl, methoxypropyl and methoxybutyl~
Examples of the alkyl group having 1 to 4 carbon
atoms for R7 and R8 are the same as those given here
inabove with regard to R6.
~3~S~
Examples of the alkyl group havin~ 1 to 4 carbon
atoms for R9 in ~d) are the sa~e as those given above with
regard to R6.
Examples of the alkyl group having 1 to 10
S carbon atoms for R10 in (e) above are methyl, ethyl,
propyl, butyl, amyl, hexyl, heptyl, nonyl and decyl
groups.
Examples of the acyl group having 1 to 4 carbon
atoms for R10 are formyl, acetyl, propionyl and butyroyl
1~ groups.
Examples of the alkyl group having 1 to 4 carbon
: atoms for Rll in (f) are the same as those given above
with regard to R6.
Examples of the aralkyl group having 7 to 9
carbon atoms for Rll are benzyl, 4-methylbenzyl, 4-
methoxybenzyl, 4-nitrobenzyl, 2-phenylethyl and 3-phenyl-
ethyl groups.
: Examples of the alkyl group having 1 to 4 carbon
atoms for R12 are the same as those given above with
regard to R .
Examples of the alkenyl group having 3 to 4
carbon atoms ~or R12 are allyl, 4-methylallyl and 3-
methylallyl groups.
Examples of the hydroxyalkyl group having 2 to 4
carbon atoms for R12 are 2-hydroxyethyl, 3-hydroxypropyl,
4-hydroxybutyl, 2-hydroxypropyl and 2-hydroxybutyl groups.
: Examples of the alkoxyalkyl group resulting from
substitu~ion of an alkyl group having 2 to:4 carbon atoms
by an alkoxy group having 1 to:4 carbon atoms may be the
same:as those given hereinabove with regard to R6.
ExamplPs of the alkyl group having-l to 4 carbon
atoms for R13 and R14 in (9) above may be the ~ame as
those given above with regard to R6.
In formula (I), examples of the alkyl group
having 1 to 4 carbon atoms for R4 may be the same as those
given above with regard to R6.
~l3~ ;%
Examples of the alkylthio group having 1 to 4
carbon atoms for R4 are methylthio, ethylthio, propylthio,
butylthio, isopropylthio, and sec-butylthio groups.
Specific examples of the compounds of formula
tI) as the active ingredient of the t,herapeutic agent of
this invention for neurological diseases are exemplified
below in some groups divided according to the definitions
of R2 and R3 for the sake of convenience.
Compounds in which R2 and R3 are not bonded to
each other -
~3~ .Z
- 12 - 67566-1058
~100) C21150COC112-l~N~N~ c31l7
COOC H3
m.p. 7~-79C
10 2 ) IIN~ -r~!iC 2~15
CON ~n~C3H7 ~ 2
~10~1) Maleate of (102)
II ( i-C3117 )
(106) HN N-~Y~
~ CON tC2115 ) 2
(10B) Maleate o~ ~106)
;: (110) HN~r,~
CON (C2~l5~ 2
;~ ~ :(112) Maleate of ~llQ)
:
116) Maleate of ~114
~llB) HN Nf,N~/N~
N~ COO
(120) Maleate oE (118)
(122) H~ \N-G~3
C
~3~5~ %
(124) Maleate of (122)
(126) HN N ~ ~ O-(n-C4H9)
(128~ Maleate of (126
t130) ~ CH2-N~
~132) Maleate of (130)
, .
~O~C~3
(136~ Maleate of (134)
(138) ~ N-r ~ HCH3
~CH2) 20H
m.p. 195-197C
tl40) 2-Naphthalenesulfonate of (140)
m.p. 215-217C
~142j HN~_~N ~ OOC2~5
~ ~cooc2~s
(144) ~ydrochloride o ~142~
~3~5~ 67566-1058
Compounds of the following fo~mula ~ a
~ a
wherein Rl, R4 and Rl are as defined above, an~
~2 and ~3 are bonded to each other to form the
group ~CEI ~ .
1200~ HN N ~
m.p. 10.7-113C
~202) Hydrochloride of (200~ m.p. above 300C
4 ~ ~r~O
(206) Maleate of (204) m.p. 155-lG7C
(208) ~C~--N U~J3
m.p. 90-95C
Compounds of the following formula ~I)-b
: Rl_N N- ~ H2)~ b
R4 C
: wherein Rl~ R4, X and ~2~are as defined above,
and R2 and R3 ar~ bunded to each other to f~rm ~he
group ~CH ~ -.
1300)
n
~' .
67 566- lQ 58
- 15 -
(302~ Hydrochloride of ~300) m.p. 2B~-290C (decomp. )
3 r~c,
n
N~OH
~ r~o
N-OS02C6H5
~308~ HN N--~
N-OS02-~H3
Compounds of the following ~ormula ~ c
R6
1 Nr~
~;N ~ . . . ( I ) -c
C )~
R7 R8
wherein R , R4, R , R7, R8, e3 and Q4 are as
def ined above, and ~2 and R3 are bonded to each
7 U
R6 o R\ R
o~her to orm the group -N~CI~C~C~;~.
~.
C 2H S
(400) Il~_ ~N~
n
'
C~3
(4û2) HN~
N
O
~' .
~3~5~
- 16 -
C~ ~;
~ ~0
(406) Hydrochloride of (404~ m.p. above 300C
$408) Maleate of (4043 m~pO 179-182C
t410) Oleate of (404) m.p. 254-256C
~412) p-Toluenesulfonate of (404) m.p. 224-225C
t414) Citrate of (404~ m.p. 187-1~8C
(416) T~rtrate of t404) m.p. 230~232C ~decomp.)
~418) Phosphate of ~404) m.p. 286-289C (decomp.)
(420) 2-Naphthalenesulfonate of (404)
m.p. 282-283C ~decomp.)
(422) ~N N- ~ ~N ~ o ~
(424) Hydrochloride of (422) m.p.~above 300C
(CH2~2c~3
(426) HN N- ~
(4283 Hydrochloride of (426) m.p. 257-259C
(4303 Maleate of (426~ m.p. 158-160C
CH3
432) ~ CH2-~ N
~L3~
- 17 -
~434) 2-Naphthalenesulfonate of (432)
.p. 74-82~
. 3
(436) <~ ~ H2-N N ~
m.p. 122-124C
(4383 2-Naphthalenesulfonate of (436)
m.p. 234-239C (decomp.)
O CH3
(440) CH3C-N ~ ~ ~ \=O
m.p. 194-195C
r~ C~3
~442) C2H5C N~_~ ~ O
m.p. 170-171C
C~3
4) ~N ~ - ~
CH3 m~p. 167.2-169.2C
(446~Maleate of (4~4)m.p. 181-183C
(448) 8 ~ ~~' ~ \ 0
CH3 ~H3 m.p. 113-116 C
(450~ 2-Naphthale~esulfonate of ~448)
m.p. 211-212C
~3~ Z
-- 18 --
C 2~5
~452) HN~ Nr~\=o
(454~ Hydrochloride of (452) m.p. above 3û0C
, 3
( 456 ) ~CH2--N / ~
CH3 m.p. 142-146C
t458) ~C82N~ 71'3~< 0
CH3 C113 m.p. 7~-79C
, 2 ~ 3
( 460) ~CH2-~N-~
,
t 462 ) ~CH~-N N-~
: ~ CH3
C83
14 6 4 ) HN N-~
CH3
14~6~ Hydrochloride of ~464) m.p. above 300C
t 46 8 ~ Maleate of t 46 41 m . p . 1 81-183C ~deaomp .
~3~(15~
-- 19 --
Compounds of the following formula (I ~ -d
R~ H2~Q 5 ... ~I)-d
R4
wherein Rl, R4, R9 and Q 5 are as def ined above,
and R2 and R3 are bonded to each o~her to form
O R9
n ~
the g roup ~CH~-N- .
( 500 ~ NN~ r,~
(502) ~ydroc:hloride of (500)
(504) HN N~
CE~3
(50G ~ t~N~ r~)9
C2~s
~; Compoullds of the following formula ~ e
Rl--N~rh;~3~ \ 2 Q16 . . (I ) -e
: ~ R4 O
wherein Rl, R4, R10 and 4: are as defined above,
and R2 and R3 are bonded to each other to form
~3~
- 20 -
RlO o
n
the ~roup ~CH ~ N---C-O
(600~ HN N ~
~-~ ~ ~N-C~3
m.p. 182-183C
t602~ Hy~rochloride of (600) m.p. above 300C
~604) Maleate of (600~ m~p. 193-195C
(~06) Phosphate of (600) ~.p. above 300C
(608~ Naphthalenssulfonate of (600) m.p. 272-273C
(610) H ~ N ~ ~ \
/ ~3~N-n-C7H15
O
612) Hydrochloride of ~S10) m.p. 245-250C
(614~ HN
C2H5
~ ~ ~ O
: (616~ Hydrochloride of (614) ~ m.p. above 300C
: O
(620) Hydrochlorid~ of (618) m.p. above 300C
: :: : ~ :
~622~ H ~ N-rY ~
~:~ ~ N-~-C4Hg
O
:~
~ ~6243 Hydrochloride of (622) m.p. 250-255C (decomp.)
~3~ , 2
575S~-1058
- 21 -
(626) HN ~ -~ ~
~ N-iso-C3117
(628~ IIydrochloride of (626) m.p. 275-280C (decomp.l
~630) HN~_~N ~3~
i N iso-C3II7
(632~ HN N-~ ~
N C2H5
~634) ~IN N ~3~
o
~J r~3--
; O 4 9
:~ m.p. 110-115C
~63G) Maleate o ~636) m.p. 151-152C
(640) H~ N ~ ~ :
N tert-C4~9
O
m.p. L62-164C
(642) Maleate of ~640) m.p. 202-203C
5644) HN -r ~ /CH3
N~C ~
O n~3~7 m.p. I06-112C
S646) Maleate of (644) m.p. 134-136~C
~ '
5~2
67566-1058
- 22 -
(64~ HN N ~
N-COCII3
~650) 2-Naphthalenesulfonate of (6~
m.p. 260-263C ~decomp.)
~652) HN ~ -p ~ \
l~N-C H:2CONH2
m.p~ 239-241C (decomp.)
.
~654) 2-~aphthalenesulfonate o~ ~652)
m~p. 276-277C ~dccomp.)
(656~ ~ -CH2-N ~ ~r' ~
~ ~_~N-sec-C~H9
: m.p. 131-13~C
(65~) ~ CU2-N ~ ~
~N-C H-n -C 3 H7
CH3
m.p. 132-134C
: (660) ~ CH2-N N-~ ~
~J N~ te r t-C ~l H g
: m.p. 179-1~2C
: (662) ~ CH2-N N r~ ~
~`~/N-c~2cooc2l~5
m.p. 145-147C
~ 6 6 4 ) ~CH :Z ~ r~3~N-COC n 3
: Q
m.p. 176-17~ C
A~
~3(~5~
675G6-105
- 23 -
1666) ~ CH2~N N ~ `r'"
~ N Cl2CNI2
: m.p. 229-232C (decomp.)
r~ 3
~C~13
m.p. 152-154C
(670) 2-Naphthal~nesulfonate of ~668)
m.p. 180-lB4C
; Cl13
~672) HN~_~ r ~ =O
CH2COOC2H5
., ~
(674) 2-Naphthalenesulfonate of ~672)
: m.p. 70-77C
~676) HN N ~ ~ ~
~N-COOCH2CH3
O
~ m.p. 158-163C
`: : t673) 2~Naphthalenes:u1fonate of ~676)
m~p. 236-237C (decomp.)
C~
680) (~CH2~ ~H3
n
` ; : m.p. 129-132C
:
~' '
:`
:L3~
67566-1058
- 24
Cl13
~2) ~C~l2 N~ ~=O
C1~2COOC2~5
6 ~ ~ ) ~C ~ 2 ~ N~y -r~ `~\
~I~`N--COCII 2C113
o
m.p. 174-177C
Compounds of the ~ollowing formula (I)-f
Rll
Rl N ~ ~3~1 12 , . . ( I ) -~
N-R
I 4 n
R O
h r in Rl R4 Rll and R12 are as def ined above,
and R2 and R3 are bonded to each other to form
1~11 R12 o
Il
the g roup -C=CH-N--C- .
( 7 0 0 ) HN~ ~D
m.p. 252.~c
~70I) ilydrwhloride of ~700
~702) HN N-~r~
CH3 O
(704) ~
NE3
C2H5
~,
,f~, .
~3US~
67566-105
- 25 -
t706) II ~ N- ~ ~
N-CH3
Oil
(707) ~ydrcchloride of t706)
(708) EIN ~ - ~
2 5
n
m.p. 149-152C
~710~ Hydrochloride of (70a) m.p. 227-279C
(712) ~N ~ - ~ ~
~ N--iSo-c3H7
O
m.p. 161C
t713~ ~ydrochloride of ~712)
~714) HN ~ -~
~ N--n{:3H7
~ m.p. 143C
: ,
~715) Hydrochloride of:~714)
(716~ HN ~ - ~ ~
o
t718) HN ~ - ~
N -cH2~ 2ocE{3
: O
t720j HN~_~N- ~
~,N--cH2CH2OH:
0
.,
~ rJ
~3~
6 7 5 6 6 - 1 0 5 8
~ 2G -
t 7 2 2 ) ~!N~
N -C 113
CH3 0
(724) HN3-r~
~, N-C2115
C113 0
(72 6 ) HN~
~-~1~;,,N~C3~1
c~3 o
7 2 a ) EIN~ N
h~N CH~Cli Cl 2
CH3 0
Cl~l
( 7 3 ) ~HN~ 3
NH
1: n
O ~
:~ (73:2) HN~N-~
: N--CH3
: CH
(734) HN~-~
n N~C2HS
m.p. 170-172C
`
t736) HN~
NH
O
~3~ Z 67566-~058
-- 27 --
r~ N . 2 G 5
8) ~ N-r~ ~1~
~V~, N--C El 3
o
Cll C H
2 ~ 5
17 4 0 ) HN~ -~
h~ N -C 2 ~ 5
m . p . 231. 7C
CHO
t '7 4 2 ~ IIN N~
~I N--C 2 H 5
O
m.p. above 300c
(744) Hydrochloride oÇ t742) m.p. above 300C
t 7 4 6 ) HN N
N-CH
~: ~74~) Hydrochloride of t746)
Compounds o~ the followlng ~ormula (I ) -g
.
R13 ~ : I
Rl~N N_~3~N~(CII2~ 9
~ 4 --'~R14
: R 0
s
wherein R, R, R 3, R 4~ and,e7 ace as defined
above, and ~2 and R3 are bonded to each other to
Rl3 ~14 0
I I n
:: form 'che group -N~C~N--c-.
~3~
6 7 5 6 6 - 1 0 5 8
- 28 -
li
~800) HN NrY
N~~/ 3
n
(802) Hydrochloride of t800
Cz1~5
t 804 ) IIN3~
n ~ C H
C113
t806) HN Nr~3~N~
n N~ c~l
Compounds of the Eollowing formula ~r)-h:
R
wherein Rl, R4 and E-G are a~ defined above,
and R2 and R3 are bonded to each othe~ to form
the g roup E-G.
,_
( 9 0 0 ) H~ M~
m.p. 74-7~C
~902) Hydrochlorlde of ~900) m.p. 294C (decomp. )
~ ~s~
1~,.,.1 .
~3(~
67566-1058
~ 29 -
(904) HN~_~N ~ ~ ~ ~ C~13
CH3 m.p~ above 300C
~906) Hydrochloride o~ (904) m.p~ above 300C
~soa) I~ r~
m.p. 159-160C
(910) Maleate o~ ~9OB) ~.p. 183-185C
CH3
(912~ HN ~ -r ~
m.p. 63-65C
: ~914) 2-Naphthalenesulfonate of (912)
m.p. 160-162C
~916) HN N~ 3
.
(918) Hydrochloride of (916)
m.p. 274-276C ~decomp.)
~9~0) ~ Ci1~-N
: :
(922) p-Toluenesulfonate of ~920)
~ m.p. 214-218C (decomp.)
~3~
-- 30 --
( 924) ~C~2-N~-~/o
( 92 6 ) ~-CH2--N~
m.p. 121-123C
( 9 2 8 ) (~C H 2 ~ N/~-~C~
CH3 m.p. 1~1--123C
~930) ~CN2-N~I~>
m.p. 105-107C
( 9321 ~CH2--~ 3
O
(934~
CH3
(936l Malate of (934)
1938 ) H~31-~OC 3
(940~ Hydrochloride of ~938):~
~942) HN\JN~
'
13~ `Z
- 31 -
(944) CH3O
3 O ~ OCH3
m.p. 188~190C
The compound of formula (I) used as the active
ingredient in this invention can be produced by a method
known ~ se, particularly by the methods described in
Japanese Laid-Open Patent Publications Nos. 140568/1986,
87627fl986 and 1040568/1986 and by treating the inter-
mediates obtained by these methods in a method known per
se (for example, reductive elimination of the protective
group~. Examples lA to 48A below descri~e the production
of the compounds in detail.
The compound of formula (I) is usually used in
the form of a pharmaceutical composition, and administered
through various routes, for example, oral, su~cu~aneousr
intramuscular, intravenous, intrarhinal, skin permeation
~` 15 or intrarectal~
The present invention includes a pharmaceutical
; preparation comprising a pharmaceutically acceptable
carrier and the compound of general formula ~I) or its
pharmaceutically acceptable salt as an active ingredient.
The pharmaceutically acceptable salt includes acid ad-
dition salts or quaternary ammonium (or amine) salts.
Examples of the pharmaceutically acceptacle
salts of the compound ~I) include hydrochlorides, hydro-
bromides, sulfates, bisulfitesf phosphates, acidic
phosphates, acetates, maleates,~fumarates, succinates~
lac ates, tartrates, benzoates,~citrates, gluconatesr
glucanates, methanesulfonates, p-toluenesulfonates and
naphthalenesulfonates which are formed from acids capable
of forming pharmaaeutically acceptable anion-containing
nontoxic acid addition salts, hydrates thereof, and
quaternary ammonium ~or amine~ salts or hydrates thereof.
,
:, .
, . .
. ~ .
,,
. .
:~3~
The composition of this invention may be ~ormulated into
tablets, capsules, powders~ granulest troches, cachPt
wafer capsules, elixirs, emulsions, solutions, syrups,
suspensions~ aerosols, ointments, aseptic injectables,
molded cataplasmas, tapes, soft and hard gelatin capsules,
suppositories, and aseptic packed powclers. ~xamples of
the pharmaceutically acceptable carrier include lactose,
glucose, sucrose, sorbitol, mannitol, corn starch, cry-
stalline cellulose, gum arabic/ calcium phosphate,
alginates, calcium silicate, microcrystalline cellulose,
polyvinyl pyrrolidone, tragacanth gum, gelatin, syrup,
methyl cellulose, carboxymethyl cellulose, methylhydroxy-
benzoic acid esters, propylhydroxybenzoic acid esters,
talc, magnesium stearates, inert polymers, water and
lS mineral oils.
Both solid and liquid compositions may contain
the aforesaid fillers, binders, lubricants, wetting
agents, disintegrants, emulsifying agent~, suspending
agents, preservatives, sweetening agents and flavoring
agents. The composition of this inventio~ may be formu-
lated such ~hat after administration to a patient, the
active compound is released rapidly, continuously or
~ slowly.
: In the case of oral administration, the compound
f formula (I) is mixed with a carrier or diluent and
formed into tablets, capsules, etc. In the case of paren-
teral administration, the active ingredient is dissolved
in a 10% aqueous solution of glucose, isotonic salt water,
sterilized water or a like liquid, and enclosed in vials
~r ampoules for intravenous instillation or injection or
intramuscular injection. Advantageously, a dissolution
aid, a local anesthetic agent, a preservative and a buffer
may also be included into the me~iumO To increase
stability, it is possible to lyophilize the present
- composition after introduction into a vial or ampoule.
Another example of parenteral administration is the
~3~S~
33 -
administration of the pharmaceutical composition through
the skin as an ointment or a cataplasm. In this case, a
molded cataplasm or a tape is advantageous.
The composition of this invention contains 0~1
to 2000 mg, more generally O.S to 1000 mg, of the active
component for each unit dosage formO
The compound of formula ~I) is effective over a
wide dosage range. For example, the amount of the com-
pound administered for one day usually falls within the
range of 0.003 mg/kg to 100 mg/kg. The amount of the
compound to be actually administered is determined ~y a
physician depending, for example, upon the type of the
compound administered, and the age, body weight, reaction,
condition~ etc. of the patient and the administration
15 rOllte.
The above dosage range, therefore, does not
limit the scope of the invention. The suitable number of
administration~ is 1 to 6, usually 1 to 4, daily.
The compound of formula (I) by itself is an
effective therapeutic agent for disorders of the peri-
pheral nervous system and the central nervous system. If
required, it may be administered in combination with at
least one other equally effective drug. Examples of such
an additional drug are gangliosides~ mecobalamin and
isaxonine.
The formulation of the compounds of formula (I)
used in this invention and their biological activities
will now be illustrated in more detail by a series of
Examples B and C below. These examples, however, do not
limi the present invention. The following examples of a
composition use one of the compounds described in the
specification or another therapeutic compound within the
general formula (I) as an active ingredient.
~3~
- 34 -
E~AMPLES
Exam~ lA
2-~4-Benzylpiperaæino)-5,6-dihydro-6-oxofuro-
~2,3-d]pyrimidine (compound No. 920):-
(1) A mixture composed of 20 g (56.1 mmoles~ sfethyl 2-(4~benzylpiperazino)-4-hydroxypyrimidine-5-acetate
(prepared in acc~rdance with Referent:ial Exampl~ 70 of
Japanese Laid-Open Patent Publication No. 140568/1986),
7.5 g (114 moles) of 8S% KOH tablets and 320 ml of ethanol
was refluxed for 1 hour4 The reaction mixture was con-
centrated to a solid. Hydrochloric acid and saturated
aqueous sodium bicarbonate solution were added to adjust
the pH to 4, and the mixture was again concentrated. The
resulting crude crystals were recrystallized from water to
: 15 give 17 g (yield 92~) of 2-(4-benzylpiperazino)-4-hydroxy-
pyrimidine-5-acetic acid as a colorless solid.
H-NMR spectrum tCDC13-CD30D solution, ~ ppm):
2.62 t4H, m), 3.36 t2H, s), 3.65 t6H, m),
7.38 (SH, m), 7.60 ~lH, s).
20 (2) The compound obtained in ~1) above (3.28 g; 10
mmoles) was dissolved in 40 ml of chloroform, and 4.2 9
(20 mmoles) of trifluoroacetic anhydride was added to the
. : solution. The solution was stirred for 2 hours at room
: temperature. The reaction mixture was concentrated and
then extracted by adding saturated aqueous sodium bi-
carbonate solution and ethyl acetate. The organic layer
was dried and concentrated. The resulting violet solid
was slurried with ethyl:acetate to give the capt~oned
compound as colorless crystals tl~42 g; yield 46%~.
Melting point: 164.5-166.5 ~ (decomp.)
: Infrared absorption spectrum tC~C13 solution,
cm~1): 1821, 1631, 1559.
H-NNR spectrum (CDC13 solution, ~ ppm):
2052 (4HI m)~ 3.58 (2H~ s), 3.70 (2H, two
singletsj, 3.86 (4H, m), 7.36 t5H, m), 8.12
(lH, s).
~3~
- 35 -
Example 2A
2-~4-Benzylpiperazino)-5~6-dihydro 6-oxofuro-
[2,3-d3pyrimidine p-toluenesulfonate ~compound No. 922~:-
Ethyl acetate 130 ml~ was added to 0.16 g ~0.5
mmole~ of the compound (No. 920) obtai~ed in Example lA,and the mixture was heated to form a solution. A solution
of 0.086 g (0.5 mmole~ of p-toluenesulfonic acid in ethyl
acetate ~5 ml3 was added to the solution. The pre-
cipitated crystals were collected by filtration to give
0.23 g ~yield 96%) of the captioned compound as crystals.
Melting point: 214-218C ~clecompO)
Example 3A
2-(4-Benzylpiperazino)-5,6-dihydro-7-methyl-6-
oxo(7H)pyrrolot2,3-dlpyrimidine 2-naphthalenesulfonate
tCOmpound No. 434) _
1.29 g (4.0 mmoles) of 2-~4-benzylpiperazino)-
5,6 dihydro-7-methyl-6-oxo(7H)pyrrolo12,3-dlpyrimidine
~produced in accordance with Referential Example S~ of
Japanese Laid-Open Patent Publication ~o. 140568~1986~ was
dissolved in 200 ml of ethanolO A solu~ion of Oa83 9 (4~0
mmoles) of 2-naphthalenesulfonic acid in ethanol (20 ml)
was added to the solution, and the mixture was stirred at
room temperature for 1 hour. The reaction mixture was
concentrated to give 2~1 g of the captioned compound as a
2~ colorless solid.
Melting point: 74-82C
H-NMR spectrum ~DMSO-d6 solution, ~ ppm)
3.12 (3H, s~, 3.35 (8Hg m), 3.52 t2H, s),
4.32 ~2H, bs), 7.52 ~5H, m), 7.5-8.3 ~8H,
m).
; Exa~ple 4A
2-(4-Acetylpiperazino)-5,6-dihydro-7-methyl-6-
oxo(7~)pyrroloL2,3-d3pyrimidine (compound No. 440):-
Acetic anhydride (1.02 g; lOoO mmoles~ was added
dropwise to a solution composed of 1.44 g (~.18 mmoles) of
2-pipera~ino-5,6-dihydro-7-methyl-6-oxo(7~)pyrrolo[2,3-d}-
- 36 --
pyrimidine (produced in accordance with Referential
Example 55 of Japanese Laid-Open Patent Publication No.
140568/1986), 1.01 y of triethylamine and 20 ml of chloro-
form, and the mixture was stirred at room temperature for
15 minutes. The reaction mixture was concentrated. Ethyl
acetate was added to the resulting solid, and it was
reslurried at 50C. After cooling, the slurry was
filtered to give 1.02 g ~yield 60%) of the captioned
compound as crude crystals. Recrystallization from chloro-
form/ethyl acetate (1/10) gave a pure product.
Melting point: 194-195C
H~N~R spectrum ~C~C13 solution, S ppm):
2.16 (3H, s), 3.~0 ~3H, s), 3.43 (2H, two
: singletsj, 3.5-4.0 (8H, m), 7.92 ~lH, s).
lS Example SA
5,6-Dihydro-7-methyl-6-oxo-2-piperazino17H)-
pyrrolol2,3-dlpyrimidine phosphate (compound No. 418):-
A solution of 0.6 g of phosphoric acid in 10 ml
of ethanol was added to a solution of 1.4 9 (6.0 mmoles)
f 5~6-dihydro-7-methyl-6-oxo-2-piperazino(7H)pyrrolo-
12,3-d]pyrimiaine ~produced in accordance with ReferentiaI
Example 55 of Japanese Laid-Open Patent Publication No.
140568/1986~ in 40 ml of ethanol. The crystals that
: precipitated were collected by filtration to give ~.~ g (yield 76~) of the desired product.
Melting point: 286-289C (de~omp.)
H-NMR spectrum (DMSO-d6 solution, ~ ppm):
3.0 (4H, mi, 3.09 (3H, s~, 3.49 (2H, s~,
3.90 (4H, m), 7.99 ~lH, s)O
Similarly, the following compounds were pro-
duced.
~3~S~%
- 37 -
Com- Yield Melting l~NMR spectrum
pound (~) po~nt (DMSO-d6 solution, ~ ppm)
410 81 254-256 3.10 (7~, m~, 3.52 (2H, s~,
3.92 ~4~, m), ~.03 (lH, s).
412 80 244-225 2.30 ~3H~ s), 3.08 ~3H, 5~,
3.18 ~4H, m), 3.50 (2H, s),
3.95 (4H, m), 7.12 (2H, m),
7.52 (2~, m), 8.02 (lH, s).
414 9S 187-188 2.54 (4~, s), 3.10 (7H, m),
3.50 (2H, s)~ 3.92 (4H, m),
8.~2 ~1~, s)~
416 78 230-232 3.08 ~7H, ~, 3.48 t2H, s),
(decomp.) 3.88 t~H, m), 3.94 (2H, s),
7.99 (lH, s~.
Example 6A
.
2-(4-Benzylpiperazino)-6 ~l-methylp opyl)-5-
oxo-5,6-dihydro(7~)pyrrolo~3,4-dlpyrimidine tcompound No.
656):- ~
3O0 9 ~8 mmoles) of ethyl 2-~4-benæylpipera-
zino)-4-chloromethylpyrimidine-5-acetate tproduced in
accordance with Referential Example~41 of Japanese Laid-
Open Patent Publication No. 140568/lg86~ was dissolved in
;~ 10 30 ml of n-butanol, and S.9~g ~sa mmoles) of l-methyl-
propylamine was added. The ~ixture was stirred at 60C
for 3 hours and then at 130C for 4 hours. After the
reaction, the solvent was:evaporated, and the residue was
:~ :
dissolved in ethyl acetate and water. The aqueous layer
lS was separated, and the ethyl acetate layer was washed with
sa urated aqueous sodium bicarbonate solution, and dried
ove:r a~hydrous magnesium~ulfate. ~thyl acetate was
: :evaporated under reduced pressure, and the residue was
purified by silica gel column chromatography using e~hyl
~: ~
~ .
~3C~
~ 38
acetate to give 0.7 g ~yield 23%) of the desired product~
Melting point: 131-134C
H-N~R spectrum (CDC13 solution, ~ ppm)~
0.88 (3H, t, J=7 Hz), 1.24 S3H, d, J=7Bz~,
1.52 (2H, m), 2.52 ~4H, m), 3.58 ~2H, s),
3.96 (4H,m), 4012 (2H, ;), 4.30 (lH, m),
7.36 tSH, m), 8.68 ~lH, s).
Similarly, the following compounds were pro-
duced.
1 0 ~
Com- Yield Melting l~-NMR speotrum
pound ~) poOnt (CDC13 solution, ~ ppm)
: No. ( C)
65829 132-134 O.9-I.6 (lOH), 2.52 ~4~, m),
: 3.56 ~2H, 8), 3.94 (4H, m),
4.12 (2H, s3, 4.48 (1~, m),
7.34 (SH, m), 8.66 SlH, s).
66020 179-182 1.54 (9~, s), 2.54 t4~, m),
3.58 (2H, s~, 3~97 ~4H, m),
: : 4~24 ~2H, s~, 7.36 (5~, m),
8.86 ~lHr
::
`~ ~ 66219 145-147 ~ 1.30 (3H, t, J=7:Hz,), 2.53
: (4H, m~, 3.58 S~, s), 3.97
~ S4H, m3, 4.23 S2H,:q,:J=7 Hz~,
:~: 4.33 (2H, s), 4.36 S2H, s),
7.36 (SH, m), 8.70 (lH:, s).
: ~ :
_ .
:
: '
:~ Example 7A
:: 2-(4-Benzylpiperazino)-6-ace yl-S-oxo-5,6-
dihydro(7H)pyrrolot3,4-d]pyrimidine ~compound No. 664) -
: 0.3 g (25 mmoles) of 60% NaH was added to a
m1xture of 2.0 g ~6.5 mmoles;) of 2-(~4-benzylpipe:razino)-
~ : 5-oxo-5,6-dihydro(7H)pyrrolol3,4-d]pyrimidine (produced in
: ~ accordance with Referential Example 42 of Japanese Laid-
~: Open Patent Publication:No. 140568/1986) and 60 ml of
tetrahydrofuran, and the mlxtu~re ~as stirred at 20C for
~'
~ .
~L3~S~ 2
- 39 -
10 minutes. Then, 2 ml of acetyl bromide was added, and
the mixture was stirred for 1 hour. The re~ction mixture
was poured into a saturated aqueous sodium bicarbonate
solution and extracted with CH2C12, and the solvent was
evaporated. The residue was purified by silica gel column
chromatography tCH2C12:MeOH=95:5) to give 1.0 g (yield
44~) of the desired product.
Melting point~ 176-178C
lH-NMR spectrum (CDC13 solution, ~ ppm~:
2.54 ~4H, m), 2.65 (3H, s), 3.58 (2H, s),
4~02 (4H, m), 4.60 ~2H, s), 7.36 (5H, m),
8~74 (lH, s).
Example 8A
2-~4-Benzylpiperazino)-6-carbamoylmethyl-5 oxo-
5,6~dihydro~7H)pyrrolo~3,4-d]pyimidine (compound No.
666):-
3.6 9 (S9 mmoles3 of 28% aqueous ammonia and 4ml of ethanol were added to 1.0 g (2.5 mmoles) o~ 2-~4
benzylpiperazino)-6-ethoxycarbonylmethyl-S-oxo-5,6-
dihydro(7~)pyrrolot3,4-d~pyrimidine Scompound ~o~ 662 in
Example 6A), and the mixture was stirred overnight at room
temperature. The reaction mixture was concentrated, and
extracted with water and ~H~C12. The aqueous layer was
: separated, and ~he CH2C12 layer was dried over anhydrous
MyS04. CH2C12 was evaporated under reduced pressure, and
the residue was washed with ethyl~acetate to give OOS g
(yield 57%) of the desired compound.
Melting point: 229-232C (decomp.)
l~-NMR spectrum ~CDC13-DMS0-d6 solution, ~ ppm):
2.52 (4~, m), 3.58 ~2H, s), 3096 (4H, m),
: 4.22 ~2~, s~ t 4.39 (2~, s), 7.36 ~5H, m),
8.65 ~1~, s).
: Example 9A
6-Acetyl-2-piperazino-5-oxo-5,6-dihydro(7H)-
pyrrolot3,4-dlpyrimidine (compound No. 648~ :-
:~ A mixture composed of 008 g ~2~4 mmoles) of
~3~'S~
- .lo
Ç-acety1-2-(4-benzylpiperazino)-5-oxo-5,6-dihydro(7~-
pyrrolot3,4-dlpyrimidine ~compound No. 664 of Example 7A~,
0.2 9 of 10~ Pd-C, and 40 ml of e~hanol was stirred for 4
hours at 70C in a hydrogen atmosphere~ After the re-
action, Pd-C was separa~ed by fi1tration, and ethanol was
evaporated under reduced pressure to give 0.56 g (yield
90%~ of the desired product.
Melting point: 164-167C
1H-NMR spectrum ~CDC13 solution, ~ ppm~:
2.66 (3H, s), 2~96 (4H, m), 3.98 t4H, m),
4.62 (2H, s), 8.75 t1H, s~.
Similarly, the following compounds were pro-
duced.
Com- Yield Me1ting lH-NMR spectrum
pound ~%) po~nt ~CDC13 solution, ~ ppm)
No. ~ C)
__ _ _
636 92 lIO-115 0.90 (3Hr t, J=7 Hz), 1.24
~3H, d, J=7 Hz), 1.56 (2Ht m3,
2.94 ~4Hr m), 3.94 (4H, m),
4.14 (2H~ ~), 4.35 ~lH, m),
8.68 (lH, s).
644 99 10~-112 0.8-1.6 ~}OH, m), 2.94 ~4H, m),
3.92 ~4H, ~), 4.14 (2H, s),
4046:~1H, m), 8.68 ~1H, s).
640 99 162-164 1.54 t9H, s~, 2.92 ~4H, m),
3.90 ~4H, m), 4.28 ~2H, s),
8.62 ~1~, s).
652 87 239-241 2.94 (4H, m)~ 3.96 ~4H, m),
(decomp~) 4.22 ~2H, s), 4.43 ~2Hf s),
8~70 (lH, s).*
-
* CD~l3-CD30D 801ution.
~L3~ ;Z
- 41 -
6-Acetyl-2-piperazino-5-oxo 5,6-dihydro~7H)-
pyrrolo~3,4-d~pyrimidine naphthalene-2-sulfonate (compound
No. 650):-
A solution of 0.17 g of naphthalene-2-sulfonic
acid monohydrate in 10 ml of ethanol was added to a so~u-
tion of Oc20 g ~0.77 ~mole) of 6-acetyl-2-pip~razino-5-
oxo-5,6-dihydro(7H)pyrrolot3,4 d]pyrimidine (compound No.
648 of Example 9A) in 25 ml of 20g methylene chloride/
ethanol. The crystals that precipitated were collected by
filtration to give 0.24 g (yield 67~) of the desired
product.
Melting point: 260-263 C (decomp.)
lH-NMR spectrum (DMSO-d6 solution, ~ ppm):
2.68 (3H, s), 3.42 (4H, m), 4.26 (4H, m),
4.78 12H, s), 7.6 - 8.3 (7H), 9.03.(1H, s).
Similarly, the following compounds were pro-
duced.
.
Com-Yield Melting l~-NMR spectrum
pound~%) ~ v~nt ~DMSO-d6 solution, ~ ppm)
638 68 151-152 0.90 ~3H, t, J-7 Hz), 1~20
~3H, d, J=7 Hz), 1.58 (2H, m),
3.35 (4H, m), 4.08 (4H, m),
4.32 (2H, s), 6.06 (2H, s),
8.72 (lH, s).
646 68 134-136 0.8-1.6 (lOH), 3.24 (4H, m),
4.08 ~4~, m), 4.30 ~3H, m),
: 6~05 (2H, s), 8.70 (lH, s).
642 76 202-203 1.48 (9~ s), 3.22 ~4H, m),
4~07 (4H, m), 4.52 (2H, s),
6.05 (2H, s), 8.66 (1~, s).
654 72 276-277 3.30 (4H, m~, 4.1D ~6H, m),
(decomp.) 4.44 ~2H, s), 7.2-8.2 (7H~,
8.76 ~1~, s).
~3~IS1~ 2
- 42 -
Example llA
2-(4-Benzylpiperazino)-5,6-dihydro-5,7-dimethyl-
6-oxo(7H3pyrrolo[2,3-d~pyrimidine (compound No. 456):-
(1) A solution of 2.16 g (10 mmoles) of ethyl 2-
formyl-3-methylsuccinate [Zhur. Obshche i Khim., 30, 2250
(1960)3 was added to a mixture of 2.67 g ~10 mmoles) of
l-amidino-4-benzylpiperazine sulfate, 1.12 g ~10 mmoles)
of tert-C4HgOK and 12 ml of tert-C~OgOH. The mixture was
then refluxed for 6 hours. The reaction mixture was
cooled, and extracted by adding water and CHC13~ The
CHC13 layer was dried over anhydrous MgS04, and the sol-
vent was evaporated under reduced pressure. The residue
was purified by silica gel column chromatography (CH2Cl~:
C~30H=95:5) to give 0.68 g (yield 23%) of 2-(4-benzyl-
piperazino)-S-~l-ethoxycarbonylethyl~-4-hydroxypyrimidine.
Melting point: 145-148C
M-NMR spectrum ~CDC13 solution, ~ ppm):
1.17 (3H, t, J=7 Hz), 1.39 (3H~ d, J=7Hz),
2.56 (4H, m), 3.56 (3H, m), 3.74 (4H, m),
4.04 (2H, q, J=7Hz), 7.35 (5H, m), 7.68 (lH,
s) .
(23 A solution of 4.6 g ~12.4 mmoles) of the com-
pound obtained as in (1) above and 35 g of phosphorus
oxychloride was refluxed for 2 hours. The reaction
solution was poured into water, and extracted with ether.
; The ether layer was dried over anhydrous MgS04, and the
solvent was evaporated under reduced pressure to give 3.2
g Syield 67~ of 2-(4-benzylpiperazino)-S-(l-ethoxyc-
arbonylethyl)-4-chloropyrimidine as an oil.
lH-NMR spectrum ~CDC13 solution, ~ ppm):
1~24 t3M, t, J=7 Hz), 1.48 (3H, d, J=7 ~z~,
2.50 ~4H, m~, 3.56 (2H, s), 3.82 (S~, m),
4.16 (2H, q, J=7 Hz~, 7~34 (5H, m), 8.18
~lH, s~.
35 (3) A mix~ure of 3.2 9 (8.2 mmoles) of the compou~d
obtained in ~2) above, 1.3 g S16.5 mmoles) of a methanol
- 43 -
solution of 40% CH3NH2 and 7 ml of ethanol was put in a
pressure vessel, and heated at 120C for 6 hours. The
solvent was removed under reduced pressure. Water was
added, and the mixture was extracted with chloroform~ ~he
chloroform layer was dried over anhydrous MgSO4, and the
solvent was evaporated under reduced pressure. The re-
sidue was purified by silica gel column chromatography
(ethyl acetate) to give 2.1 9 (yield 75%) of the captioned
compound.
Melting point: 142-146C
H-NMR spectrum (CDC13 solution, ~ ppmj:
1.44 (3H, d, J-7 Hz), 2.52 ~4~, m), 3.19
(3H, s), 3.41 (lH, q, J=7 Hz), 3.57 (2H,
s), 3.87 (4H, m), 7.35 tSH, m~, 7.90 (lH,
s).
Example 12A
5,6-Dihydro-5,7-dimethyl-6-oxo-2-piperazino(7H)-
pyrrolot2,3-d~pyrimidine (compound No. 444):-
1.9 9 ~5.6 mmoles) of 2-(4-benzylpiperazino)-
20 5,6-dihydro-5,7-dimethyl-6-oxo-(7~pyrrolot2,3-d]pyrimidine
: (compound No. 456 of Example llA) and 0.2 9 of 10% Pd-C
were dissolved in 70 ml of ethanol, and the solution was
stirred for ~ hours at 70C in a hydrogen atmosphere.
: After the reaction, Pd-C was separated by filtration.
Ethanol was evaporated under reduced pressure to give 1.26
g (yield 90~) of the desired product.
Melting point: 167.2-169.2C
H-NMR spectrum (CDC13 solution, ~ ppm~:
1.44 ~3H, d, J=7 Hz)/ 2.94 (4H, m), 3.22
: 30 ~3H, s), 3.42 (lH, q, J=7 ~z), 3.82 ~4H,
m), 7.92 ~lH, s)~
Example 13A
5,6-Dihydro-5,7-dimethyl-6-oxo-2-pipera~ino-
(7~pyrrolo~2,3-d]pyrimidine maleate ~compound No. 446):-
A solution of 0.14 g (1.2 mmoles) of maleic acid
in 6 ml o~ ethanol was addea to a solution of ~.29 9 ~1.2
5~
- 44 -
mmoles) of 5,6-dihydro-5,7-dimethyl-6-oxo-2-piperazino-
~7H)pyrrolo[2,3-d}pyrimidine ~co~pound No. 444 of Example
12A~ in 20 ml of ethanol. The crystals that precipitated
were collected by filtration to give 0.26 g (yield 59%) of
the desired product.
Melting point: 181-183C
H-NM~ spectrum (DMSO-d6 solution, ~ ppm):
1.34 (3H~ d, J=7 Hz), 3.10 (3H, s), 3.20
(4H, m), 3.55 (lH, q, J-7 H~, 3.96 t4Ht
m), 6.05 12H, s~, 8.10 (lH, s).
Example 14A
2-(4-Benzylpiperazino)-5,6--dihydro-6-oxo-5,5,7-
trimethyl(7H)pyrrolol2,3-dlpyrimidine (compound ~o~ 458):-
4.0 g (12.4 ml~ of 2-~4-benzylpiperazino)-5,6-
: 15 dihydro 7-methyl-6-oxo(7H)pyrrolo~2,3-d]pyrimldine tpro-
duced in accordance with R~erential Example 54 of
Japanese Laid-Open Patent Publication No. 14~J68/1~86) was
dissolved in 200 ml of tetrahyrofuran, and 2.5 9 ~62.5
mmoles) of 60~ NaH was added at 20C, and the mixture was
;~ 20 stirred for 10 minutes. Thereafter, 4 ml o~ methyl iodide
~ was added and the mixture was stirred ~or 1 hour. The
: reaction solution was poured into water and extracted with
CH2C12. The solvent was evaporated, and ~he residue was
puri~ied by silica gel column chromatography to give 1.3 g
(yield 30%) of the desired product.
~;: Melting point o 76-79C
H-NMR spe~trum (CDC13 solution, ~ ppm):
1.36 (6H, s), 2.50 (4H, m), 3.1~ (3H, s),
3.54 (2H~:s), 3~86 (4H, m), 7.34 (5H, m),
:~ 30 7 ~ 8 8 ~ s ) ~
: In the same way as above, compound No. 682 was
syn~he$ized except that ethyl bromoacetate was used in-
: stead of methyl iodide; compound No. 684 was synthesized
: except that 2-t4-ben2ylpyrazino)-5-oxo-5,6-dihydro (7H) ~
pyrrolo[3,4-d3pyrimidine ~produced in accordance with
Referential Example 42 of Japanese Laid-Open Patent
~3~
- 45 -
Publication No~ 14056~/1986) and propionyl chloride were
used instead of 2-(4-benzylpiperazino)-5,6-dihydro-7-
methyl-6-oxo(7H)pyrrolo[2,3-d3pyrimidine and methyl
iodide; and compound No. 680 was synthesized except that
2-(4-benzylpiperazino)-5,6-dihydro-6-methyl-5-oxot7H)-
pyrrolol3,4-d]pyrimidine (produced in accordance with
Referential Example 44 of Japanese Laid-Open Patent
Publication No. 140568/1986) was used.
Com- Yield Melting lH-NMR spectrum
pound (%~ po~n~ (CDC13 solution, ~ ppm)
No. ( C)
682 26 Not 1.24 (3H, t, Ja7 Hz), 2.52
measured t48, m), 2.75 (lH, d, J=8 Hz),
2.98 tlH, d, J=4 Hz), 3.22
(3H, s), 3.58 ~2~, s), 3.72
tlH, dd, Ja4 and 8 Hz), 3.87
~4H, m), 4.16 t2H, q, J=7 Hz),
7.36 ~SH, m), 7.96 (lH, s).
684 44 174-177 1.24 ~3H, t, J=7 Hz), 2.54
~4H, m), 3.08 (2H, q, J=7 Hz),
3-59 (2H~ S) r 4~02 (4H~ m),
A.62 ~2H, s), 7.36 (SH, m),
8.74 ~lH, s).
-- _ .
680 25 129-132 1.46 ~3H, d, J=7 Hz), 2.52
(4~, m), 3O05 ~3H, s), 3.56
(2H, s), 3.56 (2H, s), 3.96
~4H, ml, 4.22 (lH, q, J=7 Hz),
~.34 ~SH, m), 8.66 (lH, s).
: 10 Example 15A
5,6-~ihydro-6-o~o-2-piperazino-5,5,7-trimethyl-
(7H)pyrrolo[2,3-d]pyrimidine (compound No. 448):-
A mixture composed of 1.1 g (3.1 mmoles) of
2-(4-benzylpiperazino)-5,6-dihydro-6-oxo-5,5,7-trimethyl-
~7H)pyrrolo12,3-d~pyrimidine tcompound No. 458 of Example
14A~, 0.1 9 of 10~ Pd-C, and 40 ml of ethanol was stirred
~3~
- 46 -
for 4 hours at 70C in a hydrogen atmosphere. After
cooling, Pd-C was separated by filtrationO Ethanol was
evaporated under reduced pressure to give 0.76 g (yield
94~) of the desired product
Melting point: 113-116C
lH-NMR (CDC13 solution, ~ ppm):
: 1.38 (6H, s), 2n94 (4HI m)~ 3.22 ~3H, s3,
3.83 ~4H, m), 7.90 (lH, s).
The following compounds were produced in the
: lQ same way as above except ~hat compounds Nos. 682, 684 and
680 produced in Example 14A were used respectively instead
of 2-~4-benzylpiperazino)-5,6-dihydro-6-oxo-5,5,7-tri-
methyl~7H)pyrrolot2,3 dJpyrimidine.
Com-Yield Melting lH-MMR spectrum
pound~%) po~nt (CDC13 solution, ~ ppm)
: No. ~ C)
__ _
~ 672 :98 Not 1025 (3H, t, J=7 Hz), 2A80
:~ measured (lH, d, J=8 Hz), 3.00 (lH,
d,:J=4:~z), 3.24 (3H, s3,
: 3.29 ~4H, m), 3.74 (lH, dd,
J=4.8 Hz~, 4.20 (6H, m), 7~99
H, s).
:
: 676 95 158-163 1.24 (3H, t, J=7 Hz), 2.96
t4H, m), 3.08 ~2H, q, J=7 Hz3,
: 3.98 t4H, m), 4.63 (2H, s),
8~75 tlH, s).
668 92 152-154 1.:48 (3H~ d, J=7 Hz), 2.96
; : (4H, m), 3008:(3H, s) f 3.94
~4H~ m), 4.23 (lH, q, J=7 Hz),
: 8.68 (lH, s).
_ __
:
-
Example 16A
: ~ : 5,6-Dihydro-6-oxo~--2-piperazino-5,5,7-trimethyl-
(7H)pyrrolot2,3-d~p~rimidine naphthalene-2-sulfonate
~compound No. 450):-
:
5~
- 47 -
A solution of 0.17 9 (Q.77 mmole) of naphthalene-
2-sulfonic acid monohydrate in 10 ml of ethanol w~s added
to a solution of 0~20 g (0.77 ~mole) of 5,6-dihydro-6-oxo-
2-piperazino 5,5,7-trimethyl~7H)pyrrolot2,3-d]pyrimidine
~compound No. 448 of ~xampl~ lSA) in 10 ml of ethanol, and
the mixture was stirred at eoom temperature for 1 hour.
The solvent was evaporated under reduced pressure, and the
residue was washed with ether to give 0.2 g (yield 81%) of
the desired product.
Melting point: 211-212C
H-NMR spectrum (CDC13 solution, ~ ppm):
1,36 ~6H, s), 3.15 t8H, s), 3.36 ~4H, m),
4.15 ~4H, m), 7.55 (2H, mj, 7.90 (5H, m),
8.44 (lH, s~.
lS The following compounds were produced in the
same way as above except that compounds Nos. 672, 676 and
668 produced in Example lSA were used respectively instead
of 5,6-dihydro~6-oxo-2-piperazino-5,5,7-trimethyl~7H~-
pyrrolo12~3-dlpyrimidine.
~0
Com-Yield Melting lH-NMR spectrum
pound(~t po~nt ~CDC13 solution, ~ ppm)
No. ( C~
674 8070-77 1.16 ~3H, t, J=7 Hz), 3.18
(3H, s), 3.28 ~6H, m), 4.08
17H, m), 7.5-8.2 (8H).
678 77236-237 1.12 ~3H, d, J=7 Hz~, 2.97
(deco~p.) ~2H, q, J=7 ~z), 3.32 ~4H, m),
: 4.13 ~4H, ml, 4.66 S2H, s),
7.5-8.2 (7H), 8.89 (lH, s).
.
670 87180-184 1~43 t3~, d, J-7 Hz), 3.06
(3H, s), 3.36 ~4H, m), 4.20
: lSH, m), 6.75-7.92 ~6H),
8~43 (1~, s), 8.66 ~lH, s).
* Measured in CDC13 solution.
~3~
- 48 -
Example 17A
5,~-Dihydro-7-methyl-2[4-(3,4-methylenedioxy-
phenylmethyl)piperazino]-6-oxo(7H)pyrrolo~2,3-d]pyrimidine
(compound No. 436):-
A solution consisting of 2.5 g ~16.4 mmoles) of
piperonyl alcohol, 2.3 g ~19.3 mmoles~ of SOC12 and 100 ml
of CH2C12 was stirred for 1 hour. Then, 3.8 g ~16~3
mmoles) of 5,6-dihydro-7-methyl-6-oxo(7H)pyrrolo[2,3-d]-
pyrimidine (produced in accordance with Referential
Example 55 of Japanese Laid-Open Patent Publication No.
140568/1986) and 2.5 9 of ~riethylamine were added, and
the mixture was stirred for 30 minutes and then refluxed
for 2 hours. The reaction solution was poured into water~
and extracted with CH2C12. The extract was dried over
anhydrous MgS04, and concentrated under reduced pressureO
The residue was purified by silica gel column chromato-
graphy to give 0.5 g Syield 3~) of the desired product.
Melting point: 122-124C
lH-NMR spectrum (CDC13 solution, ~ ppm):
2.47 (4H, m), 3.14 (3H, s~, 3025 ~2H, s),
3.43 (2H, s~, 3.82 (4H, m), 5.91 (2H, s~,
6.47 (2H, s), 6.87 (lH9 s), 7.86 (1~, s).
Example 18A
5,6-Dihydro-7-methyl-2t4-(3,4-methylenedioxy-
phenylmethyl)piperazino3-6-oxo(7H)pyrrolo[2,3-d]pyrimidine
naphthalene-2-sulfonate (compound No. 438):-
A solution consisting of 1.0 g ~2.7 mmoles~ of
5,6-dihydro-7-methyl-214-~3,4-methylenedioxyphenylmethyl)-
piperazlno]-6-oxo~7H)pyrrolo[2,3-d ]pyrimidine ~compound
No. 436 of Example 17A), 0.6 g ~2.7 mmoles) of naphthal-
ene-2-sulfonic acid monohydrate, 50 ml of CH~C12 and 50 ml
of ethanol was stirred at room temperature for 1 hour.
The solvent was evapvrated under reduced pressure, and the
residu~ was washed with ethanol to give 1.4 9 ~yield 90~)
of the desired product.
Melting pointO 234-239C (decomp.)
~L3~
- 49 -
H-NMR spectrum ~DMSO-d6-CDC13 solution~ ~ ppm):
3.12 t3H, s), 3.36 (8~, m)~ 3.48 (2H, s),
4.32 (2~, s), 6.05 (2H~ s), Ç.95 ~2H, m),
7~12 (lH~ s), 7.52 (2H, m), 7.90 ~5H, m),
8.25 ~lH, s).
Rxample l9A
2-(4-Ethoxycarbonylpiperazi}lo)-5,6-dihydro-7-
methyl-6-vxot7H)pyrrolot2,3-d~pyrimidine (compound No.
442):-
1~ Ethyl chloroformate ~2.0 g; 18.4 mmoles) was
added to a mixture composed of 2.0 g t6.2 mmoles) of
2-[4-benzylpiperazino)-5,6-dihydro-7-methyl-6-oxo(7H)-
pyrrolot2,3-d]pyrimidine (produced in accordance with
Referential Example 54 of Japanese Laid-Open Patent
Publication No. 140568/1986), 0.3 9 t6.8 mmoles) of 60
Na~ and 60 ml of te~rahydrofuran, and the mixture was
stirred for 2 hours. The reaction mixture was poured into
water and extracted with C~2C12. The organic layer was
dried over anhydrous MgSO4, and the solvent was evapo-
2~ rated. The residue was purified by silica yel column
chromatography to give 0.5 ~ (yield 26%)~ of the desired
product.
Melting point: 170-171C
H-NMR spectrum (CDC13 solution, ~ ppm):
1.30 (3~, t, J=7 Hz), 3.~3 (3H, s), 3.flS
(2~, s), 3.56 t4H, m), 3.84 (4H, m), 4.20
~2Hr g. J=7 Hz), 7O94 (lH, s).
Example 20A
2-t4-Benzylpiperazino~-5,6-dihydro-7-(2-
methoxyethyl)-6-oxo(7~)pyrrolo[2,3-d]pyrimidine tcompound
No. 460):-
Ethanol t200 ml) and 12.02 g (0.16 mole) of
methoxy~thylamine were added to 30.0 g t0.08 mole) of
; ethyl 2-t~-bPnzylpiperazino)-4-chloropyrimidine-5-acetate
tproduced in accordance with Referential Example 71 of
Japanese Laid-~pen Patent Pu~lication No. 140568/1986~,
~3~
-- so --
and the mixture was heated at 150C for 7 hours in an
autoolave. Ethanol was evaporated under reduced pressure,
and the residue was purified by silica gel column chrom-
atography to give 19.1 9 ~yield 65%) of the captioned
compound.
H-NMR spectrum (CDC13 solution, ~ ppm):
2.51 (4~, m~, 3.38 (3H, s~, 3.44 (2H, s),
3.57 t2H, s~, 3.82 ~8H, m), 7.36 ~5H, s),
7.92 (lil, s).
EXa-mple 21A
5,6-Dihydro-7-~2~methoxyethyl)-6-oxo-2 pipera-
zino(7H)pyrrolo[2,3-d]pyrimidine ~compound No. 426):-
13.0 g ~35.4 mmoles) of 2-(4-benzylpip~razino)-
5,6-dihydro-7-(2-methoxyethyl~-6-oxo~7H)pyrrolo[2,3-d]-
lS pyrimidine (compound No. 460 of Example 20A) was dissolvedin 180 ml of ethanol, and hydrogenated in the presence of
1.3 g of 10% Pd-C at ?0C under atmospheric pressure for
1.5 hours. The catalyst was separated by filtration, and
ethanol was evaporated under reduced pressure to give 9.82
g ~yield about 100~3 of the captioned compound.
~-NMR Spectum ~CDC13 solution, ~ ppm):
2.92 t4~, m), 3038 (3~, s), 3.44 (2H, s),
3.80 (8H, m), 7.92 (lH, s~.
Example 22A
S,6-Dihydro-7-(2-methoxyethyl)-6-oxo-2-pipera-
zino(7H~pyrrolot2,3-d]pyrimidine maleate (compound No.
430):
A solution of 1~3 g (11 mmoles) of maleic acid
in 30 ml of ethanol was addèd to a solution of 3.0 9
~11 mmoles) of 5,6-dihydro-7-(2-methoxyethyl)-6-oxo-2-
pipierazino(7H)pyrrolo12,3-d]pyrimidine (compound No. 426
of Example 21A) in 100 ml of e hanol. The mix~ure was
stirred for 1 hour~ The crystals that precipitated were
collected by fil~ration to give 3O3 g tyield 76~ of the
desired product~
Melting point: 158-160C
~3C~
- 51 -
H-NMR spectrum ~DMSO-d6 solution, ~ ppm)
3.2 - 3.8 (13H~, 3.95 (4H, m), 6.06 ~2H,
s~, 8.06 (lH, s).
Example 23A
2-~4-Benæylpiperazino)-5,7-dihydro-S-oxofuro-
13,4-dlpyrimidine (compound No. 924):-
~1) Ethanol (80 ml) and 2.6~ g (40.0 mmoles) of 85%
potassium hydroxide were added to 5.0 g ~13.3 mmoles) of
ethyl 2-~4-benzylpiperazino)-4-chloromethylpyrimidine-
S-carboxylate (produced in accordance with Referential
Example ~1 of Japanese Laid-Open Patent Publication No.
140568/1986), and the mixture was refluxed for 30 minutes.
Ethanol was evaporated under reduced pressure. The re-
sidue was dissolved in water, and adjusted to pH about 4
lS with concentrated hydrochloric acid. The crystals that
formed were collec~ed by filtration, and washed with
acetone to give 1.93 g lyield 44~ of 2-t4-benzylpipera-
zino)-4-hydroxymethylpyrimidine-5-carboxylic acid as
crystals~
Melting point: 252-253C (decomp.)
H-NMR spectrum (DMSO-d6 solution, ~ ppm):
3.16 t~H, m), 4.00 (6H, m), 4.80 ~2H, sj f
~: 7.54 t5Hr m), 8.79 ~lH, s).
12) Benzene (S0 ml), 0.15 9 (1.48 mmoles) of acetic
25 anhydride and 0.12 g (1.46 mmoles) of sodium acetate were
added to 0.40 9 (1.22 mmoles) of the carboxylic acid
obtained in ~1) above. The mixture was refluxed for 10.5
hours. A 10~ aqueous solution of sodium carbonate was
added, and the mixture was extracted with ethyl acetate.
The ethyl acetate layer was dried and concentrated. The
residue was purified b~ silica gel column chromatography
to give O.lS g lyield 40~) of the captio~ed compound.
; lH-~MR spectrum (CDC13 solution, ~ ppm):
2.54 ~4~, m~ 3.58 (2H~ s), 4.00 (4H, m),
5.04 (2~, s), 7.36 ~SH, s~, 8.75 (lH, s~.
~3~
- 52 ~
Exam~le 24A
S,7-Dihydro-S-oxo-2-piperazinofuro13,4-dl-
pyrimidine (compound No. 908~:-
A mixture composed of 1.5 9 ~4.8 mmoles) of
2-(4-benzylpiperazino~-5,7-dihydro-S-oxofurol3,4-d]-
pyrimidine (compound ~o. 924 of Example 23A), 0.2 g of 10
Pd-C and 60 ml of ethanol was stirred at 70C for 4 hours
in a hydroyen atmosphere. After the reaction, Pd-C was
: separated by filtration, and ethanol was evaporated under
reduced pressure to give 1.0 g (yield 94%) of the desired
product.
Melting point: 159-160C
H-NMR spectrum (CDC13 solution, ~ ppm):
2.05 (lH, s), 2.95 (4H, m), 3.97 (4H, m~,
155.03 ~2H, s), 8.74 (lH, s~.
Example 25A
5,7-Dihydro-S-oxo-2-piperazinofuro 13,4-d~-
pyrimidine maleate ~compound No. 91û) :-
A solution of 0.12 g ~1.0 mmole) of maleic acid
20 in lS ml of ethanol was added to a solution of 0.22 g(100 ~mole) of 5,7-dihydro-5-oxo-2-piperazinofurot3,4-dl-
pyrimidine (compound No. 908 of Example 24A) in 30 ml o~
et~anol. The mixture was stirred at room temperature for
1 hour. The crystals that precipitated were collected by
filtration to give 0.20 g (yield 60~) of the desired
product .
Melting point: 183-185C
H-~MR spectrum (DMSO-d6 solution, ~ ppm):
3.~8 ~4H, m), 4.12 ~4H, m), 5.25 (2H, s),
306.03 ~2H, s), 8.92 (lH, s).
- Example Z6A
2-(4-Benzylpiperazino)-6,7-dihydro~SH3cyclo-
pentapyrimidine ~compound No. 208):-
To a solution of 6.55 g (0.121 mole) of sodiummethoxide in S00 ml of ethanol was added 32~43 9 (0~121
molel of 1 amidino 4-benzylpiperazine sulfat~. A solu ion
~3q~
53 -
of 13.6 g (0.121 mole) of 2-hydroxymethylenecyclopentanone
[synthesized by the method of W. T. Caldwell et al., J.
Am. Chem. Soc., 63, 2188 (1941)] in 90 ml of e~hanol was
added dropwise to the resulting suspension over 1 hour.
After the addition, the mixture was refluxed for 8 hours.
Ethanol was evaporated, and the residue was purified by
silica gel column chromatography to give 2.18 g ~yield 6~)
of the captioned compound.
Mel~ing point: 90-95C
lH-NMR spectrum ~CDC13 solution, ~ ppm):
2.04 (2H, quintet, J=7 Hz), 2.52 (4H, m),
2.78 (2H, t, J=7 ~z), 2.81 (2H, t, J=7 Hz~,
3.56 (2H, s) t 3.83 t4H, m~, 7.35 (5H, s),
8.12 (lH, s~.
lS EXample 27A
6,7-Dihydro-2-piperazino(SH)cyclopentapyrimidine
~compound No. 200):-
2.0 g (6.79 mmoles) of 2-(4-benzylpiperazino)-
6,7-dihydro(SH~cyclopentapyrimidine ~compound No. 208 of
Example 26A) was dissolved in 40 ml of ethanol, and hy-
drogenated in the presence of 0.20 g of 10% Pd-C at 70aC
under atmospheric pressure. Four hours later, the cata-
lyst was separated by filtration. Ethanol was evaporated
to give 1.38 g (yield 99%) of the captioned compound as
CryStals.
Melting point: 107-113C
H-NMR spectrum (CDC13 solution, ~ ppm):
2.05 (2H, quintet, J-7Hz), 2.80 (2H, t, J=7
Hz), 2.83 (2~, t, J=7 Hz), 2.9b t4H, m),
3.81 (4H, m), 8.13 (lH, s).
Exam~le 28A
~ . .
6~7-Dihydro-2-piperazino(5~)cyclopentapyrimidine
hydrochloride ~compound No. 202~:-
0.47 9 ~2.30 mmoles) of 6,7-dihydro-2-piperazino-
3s (SH)cyclopentapyrimidine ~compound ~o. 200 of Example ~7A)was dissolved in S ml of ethanol, and 0022 g (2.57 mmoles~
~3~51aZ
-~ 54 -
of concentrated hydrochloric acid was added. The mixture
was stirred at room temperature for 10 minutes~ Acetone
~40 ml) was added, and the mixture was further stirred for
10 minutes. The crystals that precipitated were collected
by filtration to give Oa22 9 ~yield 40%) of the captioned
compound.
Melting point: higher than 300C
~-NMR spectrum (DMSO-d6 so]Lution, ~ ppm):
~.00 (2H, quintet, J=7 Hz), 2.78 (4H, t,
J-7 ~z~, 3.12 (4H, m), 3.96 t4~, m3, 8.24
(lH~ s), 9.33 ~2H, br).
Exam~e 29A
2 ~4-Benzylpiperazino)-5,6-dihydrofuro12,3-dl-
pyrimidine (compound No~ 926):-
(1) 10.0 g (73.5 mmoles) of 2-hydroxymethylene-
butyrolactone sodium salt tsynthesized by the ~ethod de-
scribed in J. O. Fissekis et al., J. Org., Chem. 29, 267
(1964)1 and 19.6 g (73.3 mmoles) of 1-amidino-4-benzyl-
piperazine sulfate were added to 360 ml of ethanol, and
the solution was refluxed for S hours. Ethanol was
evaporated, and the residue was mixed with water and
extracted with chloroform. The chloroform layer was
dried, concentrated, and puri~ied by silica gel column
chromatography ~o give 6.66 9 (yield 29%) of 2-(4-benzyl-
piperazino)-4-hydroxy-5-(2-hydroxyethyl)pyrimidine as
crystals.
Melting point: 166-170C
H-NMR spectrum (CDC13 solution,~ ppm):
2056 ~6H, m), 3.56 ~2~, s), 3.60 - 3.90
~6~ m) 9 7.35 t5~, s), 7~67 ~1~1, s~.
t~) Thionyl chloride ~40 ml~ was added at 0C to
2.0 q (6~36 mmoles~ of the compound obtained in ~1) above.
The mixture waæ stirred at 0C for 4 hours and a~ room
temperature for 12 hours. The excess of thionyl chloride
: 35 was evaporated under reduced pres~ure. Water was added ~o
dissolve the residue. The solution was made alkaline with
- 55 -
2N aqu~ous sodium hydroxide solution and then extracted
with chloroform. The chloroform layer was dried, concen-
trated~ and purified by silica gel column chromatography
to give 1.03 g (yield 55%~ of the captioned compound as
crystals.
Melting point: 121-123C
H-NMR spectrum tCDC13 solution, ~ ppm):
2.48 (4H, m), 3.Q9 (2H, t, J-7 Hz), 3.55
~2H, s), 3.~1 (4H, m), 4.60 ~2H, t, J=7
Hz), 7.34 (5H, s), 7.99 (lH, s~.
5,6-Dihydro-2-piperazinofuro[2,3-d]pyrimidine
(compound ~o. 900~:-
1.21 g t4.08 mmoles) of 2-t4~benzylpiperazino)-
5,6-dihydrofurot2,3-d]pyrimidine (compound No. 926 o~
Example 29A~ was dissolved in 40 ml of ethanol, and hy-
deogenated in the presence of 0~14 9 of 10% Pd-C at 70C
under atmospheric pressure. ~our hours later~ the cata-
lyst was separated by f iltration, and e~hanol was
evaporated to give 0.81 g (yield 96%) of the captioned
compound as crystals.
: Melting point: 74-78C
H-NMR spectrum tCDC13 solution, ~ ppm):
2.49 ~1~, s~, 2.92 (4H, m), 3.12 (2H, dt,
J=l, 7 Hz), 3.80 (4H, m), 4.62 (2H, t, J=7
Hz), 8.00 (lH, t, J=l Hz).
Example 31A
: : 5,6-Dihydro-2 piperazinofurol2,3-d]pyrimidine
hydrochloride (compound No. 902J:-
~ ~ 30 ~ 0.23 g ~1.12 mmoles) of 5,6-dihydro-2-pipera-
`~ zinofuro~2,3-d]pyrimidine ~compound ~o. 900 of Example
: 30A) was dissolved in lO:ml of ethanol, and 0.12 g ~1.18
: mmoles) o~ concentrated hydrochloric acid was added. The
mi~ture was stirred at room ~emperature for 1 hour. The
crystals that precipitated were collected by filtration,
and washed wi~h acetone to give 0.27 g (yield about 100%~
of the captioned compound.
~3l~53L~2
- 56 -
Melting point: 294C ~decompO3
H~NMR spectrum (DMSO-d6 solution,~ppm3:
3.16 (6H, m), 3.92 ~4~, m)~ ~.70 (3Ho t,
J=8 Hz), 8.10 tlH, s), 9,54 (2~r br).
Exampl_ 32A
2-(4-Benæylpiperazino~-4,6-climethylfuro[2,3-dl-
pyrimidine ~compound NoO 928~:-
To 14.45 g (54.1 mmoles) of 1-amidino-4-benzyl-
piperazine sulfate were added 15 ml of DMSO, 3.57 g tS4.1
mmoles) of 85~ potassium hydroxide and 10.0 g (64.9 mmoles)
of 3-carbomethoxy-5-hexyn-2-one lsynthesized by the method
described in K. E. Schulte et al., Arch. Pharm., 295, 627
(1962)1, and the mixture was heated at 140C for 4~5
hours. Water was added, and the mixture was extracted
15 with chloroform. The chloroform layer was washed with
water and saturated aqueous sodium ch}oride solution,
dried and concentrated. The residue was purified by
silica gel column chromatography to giYe 4.84 g Syield
28%) of the captioned compound as a yellou vil.
lH-NMR spectrum (CDC13 solution, ~ ppm)~
2.36 (3~, d, J=l ~z~ 9 2.47 ~3~, s3~ 2~51
(4~, m), 3O55 ~2H, s~ 3.87 (4H, m), 6.17
~lH, d, J=l Hz], 7.34 ~5H, 8).
~ 25 4,6-Dimethyl-2-piperazinofurot2,3-d]pyrimidine
: (compound No. 904):-
: 4.23 9 ~13.1 mmoles) of ~-(4-be~zylpiperazino)-
4,6-dimethylfurot2,3-dlpyrimidine ~compound No. 928 of
Example::32A) was dissolved in 50 ml of ethanol and hy-
~;~ 30 drogenated in the presence of 0.~0 g of 10% Pd~C at 70C
under atmospheric pressure. Five hours later, the cata-
lyst was separated by filtration, and washed with chloro-
form. The etha~ol layer and the chloro~vrm layer were
combined, concentrated, and recrystallized from et~anol to
35 give 1.94 g ~yield 64%) sf the captioned compound as
crystals.
~L3~5~
- 57 -
Melting point: higher than 300C
H-NMR spectrum ~CDC13-DMSO-d6 solution, ~ ppm):
2.40 t3~, d, J=l Hz), 2.50 (3H, s), 3.19
(4H, m), 4.12 (4~, m~, 6.35 ~lH, d, J=l
S ~z)~
Example 34A
4,6-Dimethyl-2-piperazinofuro[2,3-d]pyrimidine
hydrochloride (compound No. 906~:-
0.81 g ~3.49 mmoles) of 496-dimethyl-2-pipera-
zinofuro[2,3-d]pyrimidine (compound No. 904 of Example
33A) was dissolved in 200 ml of ethanol under heat, and
0~39 g 53.84 mmoles) of concentrated hydrochloric acid was
added. The mixture was stirred at room temperature for 30
minutes, and ethanol was evaporated under reduced pres-
sure. The residue was washed with acetone to give 0.88 g(yield ~4%) of the captioned compound as crystals.
Melting point: higher than 300C.
H-NMR spectrum.~DMSO-d6 solution, ~ ppmj:
2.36 (3Ht d, J-l Hz), 2.50 (3~, s), 3.1
~4H, m~, 3.98 (4~, m), 6.57 (lH, d, J=l
Hz), 9.60 (2~r br)~
~ Ex~ple 35A
: 2-t4-Benzylpiperazinoj-5,6-dihydro-7-methyl-
t7H)pyrrolot2,3-d~pyrimidine (compound No. 930):-
: ~5 ~1) Sodium borohydride (2.24 g) was added to 8.0 9
of 2-t4-benzylpiperazino)-5,6-dihydro-7-methyl-6-oxo-
t7~)pyrrolot2,3-d~pyrimidine Cproduced in accordance with
Referential Example 54 of Japanese Laid-Open Patent
Publication No. 140568/1986) and 400 ml of ethanol, and
; 30 the mixture was heated under reflux for 1.5 hours. The
reaction mixture was concentrated. The residue was mixed
with wa~er and extracted with ethyl acetate. The organic
: layer was dried:over anhydrous sodium sul~ate, and the
:~solvent was evaporated. The residue was purified by
silica gel column chromatoyraphy ~me~hanol:chloroform-
1:10), and recrystalli2ed from toluene to give 2.4 9
.
~3~ ;2
- 58 -
~yield 30~) of 2-(4 benzylpiperazino~-5-(2-hydroxyethylj-
4-methylaminopyrimidine as colorless crystals.
Melting point: 119-120C
lH-NMR spectrum ~CDC13 solution, ~ ppm)O
2.3-2.7 ~6~, m), 2.94 (3~, d, J=4.3 Hz),
3.55 (2H, s), 3.6-3.9 (6H, m~, 5.50 (lH,
br.d, J=4.3 Hz~, 7.2-7.5 tSH, m~, 7.61 (lH,
s) .
(21 The compound obtained in Sl) (8.0 g) and 80 ml
1~ o pyridine were cooled to -10 to 0C, and a~solution of
5.3 g of p-toluenesulfonyl chloride in 100 ml of pyridine
was added dropwise. After the addition, the mixture was
reacted at 0 to 5C for 6 hours. ~ solution of 205 g of
sodium hydrogen carbonate in 30 ml o~ water was gradually
added to the reaction mixture, and the mixture was further
stirred for lS minutes. The reaction mixture was mixed
with 200 ml of water, and extracted with 300 ml o~ ethyl
acetate. The ethyl acetate layer was washed with 200 ml
of water and dried over anhydrous sodium sulfate. Ethyl
acetate was evaporated. The residue was suspended in 100
ml of tetrahydrofuran, and 2.4 g of 60~ sodi~um hydride
washed with hexane was added as a`suspension in tetra-
hydrofuran. A~ter reacting;at room ~emperature for S
hours, lO ml of ice water was gradually added~ The
~ ~ 25 solvent was evaporated, ~and~200 ml of water and 300 ml
;~ of ethyl acetate were added to t~he residue. The aqueous
layer was sepa ated, and the ethyl acetate layer was
washed with 200 ml of water, and dried over anhydrous
sodium~sulfate. The ssl~vent was evaporated, and the
residue was~purified by silica gel chromatography
(acetone:hexane=l~ to give 1~.6 g~tyield 21%) of the
desired product as light brown crys ls.
Melting point: 105-107C
NMR spectrum~C~DC13 solution, ~ ppm~:
~ 35 2.48 (4H, m), 2.84 t2H, t, J=9 ~)9 3.50
-~ (2H, t, J=9 Hz), 3.55 ~2H, s), 3.78 ~4H,
), 7.34 (SH,~s~ 7.60 (lU~ s).
.
~3~
- 59 -
Ex~ e 36A
5,6-Dihydro-7-methyl-2-piperazino~7H)pyrrolo-
[2,3-d]pyrimidine (compound No. 91~
Ethanol (15 ml) was added to 1.4 g of 2-(4-
benzy1piperazino)-5,G-dihydro-7-methy].~7H)pyrroloI2,3-dl-
pyrimidine (compound No. 930 of Examp].e 35A3 and 0.14 g of
10~ Pd-C. The mixture was stirred at 60C for 8 hours in
a hydrogen atmosphere~ After coolingt the 10% Pd-C was
separated by filtration, and the solvent was evaporated to
give 0.94 g Iyield 95%) of ~he desirecl compound as color-
less crystals.
Melting point: 63-65 C
H-NMR spectrum tCDC13 solution, ~ ppm):
2.90 (2H, t, J=9 Hz~, 2.92 t4H, m), 3.48
(2H, t, J-9 Hz), 3.74 (4H, m), 7.62 ~lH,
s) .
Example 37A
5,6-Dihydro-7-me~hyl-2-piperazino(7H~pyrrolo-
t2,3-d]pyrimidine naphthalene-2-su1~onate ~compound No~
914) _
A solution of ~.26 g of 2-naphthalenesulfonic
acid monohydrate in 10 ml of ethanol was added to a
solu~ion of 0.25 g of 5,6-dihydro-7-me~hyl-2-piperazino-
~7H)pyrrolo[2,3-d~pyrimidine ~compound No. 912 of Example
36A). The solvent was evaporated to give 0.49 9 (yield
100%) of the desired product as solorles crystals.
Melting point: 160-162C
H NMR spectrum ~DMS0-d6 solution, ~ ppm):
2.88 ~3H, s~, 2.7-3.7 (8~, m~, 7.4-8.1 ~7H,
m~, 8.14 (lH~ s).
Example 38A
2-(4-Benzylpiperazino)-7,8-dihydro-7-methy1-
5-oxot5H)pyrano[4,3-d~pyrimidine ~compound No. 932):-
O.S g of 4,6-dioxo-2-methyloxane, 2.0 ml of
methyl orthoformate and 50 ml of acetic anhydride were
stirred at 130C for 3 hours. After ~he reaction, the
~L3~5~
- 6n -
solvent was evaporated by an evaporator to obtain a liquid
substance. 1.04 g of 1-amidino-4-benzylpiperazine sulfate
was added to 10 ml of 2% aqueous KOH solution. The mix-
ture was stirred at room temperature for 30 minutes, and
the above liquid substance was added to the r~sulting
solution. The mixture was stirred at room temperature for
1 hour. ~fter the reaction, methanol was evaporated, and
30 ml of water was added. The mixture was extracted with
50 ml of methylene chloride. The methylene chloride layer
was dried over anbydrous sodium sulfate, and the solvent
was evaporated. The residue was ~urified by silica gel
column chromatography tmethylene chloride:ethyl acetate=
2:1) to give 0.82 g ~yield 62%~ o~E the captioned compound
as a white solid.
lH-NMR spectrum tCDC13 solution, ~ ppm):
1.56 (3H, d, J=8.6 Hz), 2.56 (4H, m), 2.84
(2H, d, J=7.6 Hz), 3.60 (2H, ~), 4.00 ~4H,
m), 4.70 ~lH, m), 7.38 tSH, s), 8.86 ~
s) .
EXample 39~
7,8-Dihydro-7-methyl-5-oxo-2-piperazino~5H)-
pyranot4,3-dIpyrimidine (compound No. 916):-
0.15 g of 2-~4-benzylpiperazino)-7,8 dihydro-7-
methyl-5-oxo(SH)pyrano[4,3-d]pyrimidine ~compound No. 932
f Example 38A) was dissolved in 30 ml of ethanol, and 30
mg of 10~ Pd-C wa5 added under a nitrogen atmosphere. The
mixture was stirred at 50C for 2 hours in a nitrogen
atomosphere. After the reaction, Pd-C was sepaeated by
filtration~ The solution was concentrated to give 0.12 g
tyield 99%) of a solid.
EI-NMR spectrum (CDC13 solution, ~ ppm):
1.52 t3~, d, J=6.8 Hz3, 2.84 ~2H, d, J=7.6
~z), 2~94 (4H, m), 3.96 ~4H, m~, 4.64 (1~,
m) ~ 8.86 (lH, s~.
:~
~3~S~L~Z
Example 40~
7,8-Dihydro-7~methyl-S-oxo-2-piperazino(5H)-
pyrano~4,3-d~pyrimidine hydrochloride (compound No. 918):-
Five milliliters of a HCl-saturated ethanol
solution was added to 0.12 y of 7,8-dihydro 7-methyl-S-
oxo-2-piperazino~5H)pyranot4,3-d]pyrimidine tcompound No.
916 of Example 39A), and the mixture was sti~red at room
temperature for 10 minutes~ The reacl:ion mixture was
concentrated to give 0.13 g of the captioned compound as a
solid. Melting point: 274-276C ~decomp~)
Example 41A
2-(4-Ben~ylpiperazino)-5,6-dihydro-4,7-dimethyl-
6-oxo(7~)pyrroloC2,3 d]pyrimidine (compound No. 462):-
(1) Potassium hydroxide (3.1 g) was added to 200 ml
lS of ethanol, and the mixture was stirred for 30 minutes.
Then, 12.4 g of 1-amidino-4-benzylpiperazine sulfate was
added. The mixture was stirred at room temperature for
10 minutes. To the solution was added 12.~ g of diethyl
acetylsuccinate. The mixture was refluxed for 2 hours.
2~ Then, 200 ml of toluene was added, and the mixture was
refluxed ~or 3 hours. A~ter the reaction, ethanol was
evaporated, and the residue was poured into 50 ml o~ an
aqueous solution of hydrochloric acid. NaHC03 was added
to the solution to neutralize it. The precipitated solid
was washed with water and dried over P205 to give 2.55 9
(yield 15~) of 2-(4-benzylpiperazino)-5-ethoxycarbonyl-
methyl-4-hydroxy-6-methylpyrimidine as a white solid.
~H-NMR spectrum ~D~S0-d6 solution, S ppm):
1.36 ~3H, t, J=7.6 Hz), 2.25 (3H, s), 2.57
(4~, m), 3.55 ~2~, s), 3069 t2~, s), 3.77
(4H, m), 4.24 (4H, q, J=7.6 Hz), 7.51 (5~,
s) .
~2~ The compound ob~ained in ~1~ above (2~7 g) and
20 g of phosphorus oxychloride were refluxed for 3 hours.
Phosphorus oxychloride was evaporated under reduced pres-
sure, and 10 ml of toluene was added. The resul~ing solid
13~
- 62 -
was collected by filtration, and then stirred for about 1
hour together with 50 ml of methylene chloride and 50 ml
of saturated aqueous sodium bicarbonate solution. The
toluene layer and the methylene chloride layer were com-
bined, and dried over anhydrous sodium sulfate. Thesolution was concentrated to give 2.6L g lyield 92~) of
2-14-benzylpiperazino~-5-ethoxycarbonylmethyl-4-chloro-
6-methylpyrimidine as a light brown solid.
lH-NMR spectrum ~DMSO-d6 so:Lu~ion, S ppm):
1.26 (3H, t, J=7.6 Hz), 2.3S 13H, s), 2.48
(4H, m), 3.56 t2H, s), 3.65 (2H? s), 3.B2
(4H, m), 4.18 S2~, q, J=7.6 Hz), 7.34 t5H,
s) .
(3) 2.61 g of the compound obtained in (2) and a 40~
methylamine methanol solution containing 1.04 g of methyl-
amine were dissolved in ethanol, and the solution was
stirred at 120C for 18 hours in a nitrogen atmosphere in
a S0 ml autoclave. After cooling, the red crystals that
precipitated were collected by filtration to obtain ~
solid. The filtrate was concentrated to 3 ml to obtain
secondary crystals. The primary and secondary crystals
~ere combined to give 1.56 g lyield 62%) Qf the oaptioned
compound as red crystals.
1H-NMR spectrum (CDC13 solution, & ppm):
2.22 (3H, s), 2.50 (4H, m), 3.18 (3H, s),
3.34 (2H, s), 3.56 t2H, s) f 3.86 (4H, m),
7.35 (5~, s).
5,6-Dihydro-4,7-dimethyl-6-oxo-2-piperazino(7~)-
pyrrolol2,3-d]pyrimidine ~compound No. 464):-
1.56 g (4.6 mmoles) of 2-t4-benzylpiperazino)-
5,6-dihydro-4,7-dimethyl 6-oxo(7H)pyrrolo12,3-d]pyrimidine
(compound No. 462 of Example 41~ was dissolved in 60 ml
of ethanol, and 500 m~ of 10% Pd-C was added under a
nitrogen atmosphere. The mixture was s~irred at 70C or
2 hours in a nitrogen atmosphere. After ~he reaction,
~3~
- 63 -
Pd-C was separated by filtration, and the solution was
concentrated to give 1.04 9 ~yield 91%) of the captioned
- compound as a pale yellow solid.
lH-NMR spectrum (CDC13 solution? ~ ppm~:
2.24 ~3H, s), 2.92 (4EI, m), 3.20 (3H, s),
3.36 ~2H, s), 3.82 ~4~l, m)v
Ex~ple 43A
5,6-Dihydro-4,7-dimethyl-6-oxo-2-piperazino(7H)-
pyrrolo[2,3-d]pyrimidine hydrochloride ~compound No.
466):_
; 0.20 g of 5,6-dihydro-4,7-dimethyl-6-oxo-2-
piperazino(7H)pyrrolo[2,3-d]pyrimidine was dissolved in
20 ml of ethanol saturated with hydrochloric acidO The
mixture was stirred at room temperature for 10 minutes,
lS and concentrated to give 0.21 g of the captioned compound
having a melting point of more than 300C as a pale yellow
solid.
Example 44A
Methyl 2-(4-ethoxycarbonylmethylpiperazino)-4-
isopropylaminopyrimidine-5-carboxylate ~compound No.
100) :-
Ethyl bromoacetate ~0.5 g; 3.1 mmoles) was added
to 0.9 g (3.2 mmoles) of 2-piperazino-4-isopropylamino-
pyrimidine-5-carboxylate ~produced in accordance with
Referential Example 69 of Japanese Laid-Open Patent
Publication No. 140568/1986), 1~ ml of CHC13 and 0.54 9
~5.3 mmoles) of triethylamine, and the mixture was stirred
at room temperature for 6 hours Then, water was added,
and the mixture was extracted with CHC13~ The CHC13 layer
: ~ 3~ was dried over anhydrous MgSO4. CHC13 was evaporated
under reduced pressure. The residue was purified by
silica gel column chromatography (ethyl acetate) to give
1.0 g ~yield 88~) of the desired product.
.~ Melting point: 78-79C :
H-N~R spectrum (CDC13 solution, ~ ppm):
1.27 (6H, d, J=7 Hz~, 1.31 (3H, t, J=7 dz),
,
~3~S~
- 64 -
2~64 (4H, m), 3.27 (2H, s), 3.82 (3~, s),
3.96 (4H, m), 4.22 (2H, q, J=7 Hz~, 4.26
(lH, m), 7.94 ~lH, br. d, Ja7 Hz), 8.59
~lH, s).
Example 45A
2-Piperazino-S~(~-hydroxyethyl) 4-methylamino-
pyrimidine (compound No. 138):-
A mixture of 0.8 g ~2.54 mmoles) of 2-(4-benzyl-
piperazino)-5~(2-hydroxyethyl~-4-methylaminopyrimidine,
0.1 g of 10~ Pd-C and 10 ml of ethanol was stirred at 60C
for 7 hours in a hydrogen atmosphere. The reaction mix-
; ture was allowed to cool, and the catalyst was removed byfiltration. The filtrate was concentrated to give 0.56 g
~yield 96%) of the captioned compound as crystals.
Melting point: 195-197C
H-NMR spectrum tCDC13-DNS0-d6 sol~tionr ~ ppm):
2.50 (2H, t, J=7HzJ ! 2.92 (3~, s), 2098
~4H, m), 3.62 (2H, t, J=7 ~zl, 3~84 (4H,
m), 6.45 (lH, br), 7~58 ~lH, s).
EXample 46A
2-Piperazino-5-~2-hydroxyethyl)-4-methyl-
aminopyrimidine 2-naph~halenesulfonate (compound NoO
140):-
A solution of 0.18 g ~0.8 mmole) of 2
naphthalenesulfonic acid in 10 ml of ethanol was added toa solution of Ool9 g (0.8 mmole) of 2-pipera2ino-5-~2-
hydroxyethyl) 4-methylaminopyrimidine in 30 ml of ethanol.
The mixture was stirred~at room temperature for 30 minutes.
The reaction mixture was concentrated, and he precipi-
: 3n tated solid was slurried with a mixture of ether, tolueneand ethanol. The solid was collected by filtration, and
dried under reduced pres~ure to give 0.2 g (yield 54~) as
colorless crystals.
Melting point: 215 217C
- 65 -
6,7-Dimethoxy-2-t4-(3,4-dimethoxybenzoyl)-
piperazino]quinazoline tcompound No. 944):-
Two milliliters of isoamyl alcohol was added to
125 mg of 1-t3,4 dimethoxybenzoyl~piperazine ~synthesized
by the method described in Japanese Laid-Open Patent
Publication No. 150072/1981) and 112 mg of 2-chloro-6,7-
dimethoxyquinazoline, and the mixture w~s s~irred at lX0C
for 5.5 hours. The isoamyl alcohol was evaporated, and
the residue was purified by thin-layer chromatography
(ethyl acetate) to give 102 mg ~yield 47%) of the cap-
tioned compound as colorless crystals.
Melting point: 188-190C
lH-NMR spectrum ~CDC13 solutionf ~ ppm~
3.78 ~4H, br.s), 3.94 t3H, s), 3.97 t3H,
s), 3.99 (3H,s), 4.04 ~3H, s), 4.1 (4H,
br.s), 6.8-7.2 (5H, m), 8.85 (lH, s).
~ . .
In accordance with the methods described in
Japanese Laid-Open Patent Publication No. 140568/1986,
there were produced compounds encompassed within the above
formula (I), namely compounds Nos. t294), t206), ~300),
~302), (304), (306), (30/3), e400~, (402), ~04), (406),
t408), (420), (~22), (424), (4~8), ~432~, ~452), ~454),
(500), (502), ~504), ~50~), (600), (602~, (604), (606),
(608), (610), (612), t614), (616), ~618)~ (620), ~622),
(624), (626)/ (628), ~630), ~632), ~634), (700), (701),
~702), ~704), ~706), (707j, (7~8), t710), (712), ~714),
: (716), (718), (720), ~722), (724~, (726), (728)., (730),
(7323, (734) r (736), t738), (740), 1742), t744~, (746),
(748), (8~0), (802~, (804), (806), ~936~, (938), ~940),
and (942).
The physical property values of some of these
compounds in ~he 700 series are shown below.
Compound NoO 734
Melting point: 170-172C
13~
- 66 -
Infrared absorption spectrum (KBr tablet, cm 1):
1657, 161~3l 1578.
H-NMR spectrum (deuterochloroform, ~ ppm):
1.33 (3H, t, J=7.2), 1.66 (lH, s~, 2.17
(3H, d, J=1.3), 2.94 ~4H, m), 3O97 ~6Ht m),
7.10 (lH, q, J=1.3~, 9.24 ~lH, s).
Compound No. 714
Melting point: 143 C
Infrared absorption spectrum ~KBr tablet~ cm 1):
3325, 1660, 1622, 1576.
l~-NMR spectrum ~deuterodimethyl sulfoxide,
ppm):
: 0.88 (3H, t, J=8 Hz), 1.66 ~2H, m), 2.75
(4H, t, J=6 Hz), 2.8 tlH~ overlapping
2.75~, 3.76 - 3.91 (6H, m), 6.22 (lH, d,
J=8 Hz), 7.73 (lH, d, J=8 Hz), 9.08 ~lH,
s) .
Compound No. 712
Melting pointo 1~1C
Infrared absorption spectrum ~KBr tablet, cm 1):
3430, 1652, 1~18, 1584.~
H-NMR spec~rum ~deuterochloroform, ~ ppm):
1.31 (6~, d, J=8 Hz), 2.9~ t4H, br.s),
3.92 (4H, br.s), 5.05 ~lH, seq, J=8 Hz),
6.2 ~lH, br.s), 6.29 ~lEI, d, J=8 Hz), 7.83
(1~, d, J=8 Hz), 9.08 ~lH, s3.
` Compound No. 700
Melting point: 252.8C ~recrystallized from
ethanol)
~ Mass spectrum: 231 (~+)~
H-NMR spectrum ~D~SO-d~ solution, ~ ppm):
2.87 t4H, br.~s), 3.88 ~4H, br.s), 5O73
(lH, d, J=7 Hz), 6.98 ~lH, d, J=7 Hz), 9.02
~lH, s).
Compound No. 740
Melting point: 231.7C
Mass spectrum: 349 (molecular ion peak)
~' , '' .
~3~
- 67 -
Infrared ahsorption spectrum ~KBr tablet, cm 1):
3400, 292~, 1654, 1617, 157
lH NMR spectrum ~deuterodimethyl sulfoxide,
ppm):
1.24 S3H, t, J=7 Hz), 2.96 (4H, br.s),
3.80-4.12 (8H, m), 7.24 ~SH, s~, 7.80 (lH,
s3, 8.06 (lH, s).
Compound 708
Melting point: 149-152C
Infrared absorption spectrum (KBr CHC13~ cm 1):
1655, 1645, 1620, 157S.
H NMR spectrum ~deuterochloroformt ~ ppm):
1~34 (3H, t, J=7 Hz), 1.87 ~lH~ br.s),
2.94 (4H, t, J=6 Hz), 3.96 ~6H, m), 6.27
(lH, d, J=8 Hz), 7.29 ~lH, d, J=8 Hz~, 9.22
(lH, s).
Compound_706
Oily
H NMR spectrum (deuterochloroform, S ppm):
2~ 2~93 ~4H, m), 3.50 (3H, s), 3.94 (4H, m),
~ 4.40 (lH, br.s), 6025 (1~, d, J=8 H), 7.25
: (lH, d, J=8 Hz), 9.23 ~lH, s).
Compound No. 742 : ~ -
Melting point: higher tha~ 300~C
Infrared absorption spectru~ tnujol, cm ):
34~0, 1688, 1655.
: lH NMR spectrum (CDC13 solution, ~ ppm~:
~ :: 1.40 (3H, t, J=7.0 ~Z?, 2.95 (4H, m), 4.08
: ~6H, m), 8.19 (lH, s), 9.20:(lH, s), 10.55
~H~ 30 : (lH, s).:
: :Example lB
Tablets each~containing 10 mg of the active
component are prepared as follows:-
. ~
.
'
~L3~
- 68 -
Per tablet
Active component 10 mg
Corn starch 55 mg
Crystalline cellulose 35 mg
Polyvinyl pyrrolidone (as 10% 5 mg
aqueous solution~
Carboxymethyl cellulose calcium 10 mg
Magnesium stearate 4 mg
Talc _ _ _ I mg
Total 120 mg
The active component, corn starch and crystal-
line cellulose are passed through an 80-mesh sieve and
completely mixed. The resulting powder is mixed with the
polyvinyl pyrrolidone solution. The mixture is granulated
and passed through an 18-mesh sieve. The resulting
granules are dried at 50 to 60C, and again passed through
an 18-mesh sieve. Carboxymethyl cellulose calcium, magne-
sium stearate and talc, passed previously through an
80-mesh sieve, are added to the granules and mixed. The
mixture are formed into tablets each having a weight of
120 mg by a tableting machine.
Example 2B
Tablets each containing 200 mg of the active
component are prepared as follows:-
Per tablet
Active component 200 mg
Corn starch 50 mg
Crystalline cellulose 42 my
Soft silicic anhydride 7 mg
Ma~nesium stearate l mg
~ Total300 mg
;~ The above ingredients are passed through an
80-mesh sieve and completely mixed. The resulting powder
is compression-molded into tablets each having a weight of
300 mg.
~':
~ 3~ 5
- 69 -
Example 3B
Capsules each containing 100 mg of the active
component are prepared as follows:-
Per capsule
S Active component 100 mg
Co~n starch 40 mg
Lactose 5 mg
Magnesium stearate _ 5 mg
Total150 mg
1~ The above ingredients are mixed, passed through
an 80-mesh sieve, and completely mixed. The resulting
powder is filled in capsules each in an amvunt of 150 mg.
Example 4B
~ n injecting preparation containing 5 mg of the
active component in a vial is prepared as follows:-
Per vial
Active component 5 mg
Mannitol 50 mg
Prior to use, the above ingredients are dis-
solved in 1 ml of distilled water for injection.Example SB
An injecting preparation containing 50 mg of the
active component in an ampoule is prepared as follows:-
Per ampoule
; 25 Active component 50 mg
Sodium chloride 18 mg
Distilled water for injection suitable_ _ _ _ amount
Total~ 2~ml
: ~ 30 xample 6B
An adhesive patch containing 17.5 mg of the
active component is prepared as ollows:-
Ten parts of poly~ammonium acryla~e~ is dis-
solved in 60 parts of water. Separately, 2 parts of
glycerin diglycidyl ether is dissolved in 10 parts of
water while heating. Further, 10 parts of polyethylene
~3~
- 70 -
glycol (yrade 400), 10 parts of water and 1 part of the
active component are stirred to form a solution. While
the aqueous solution of poly(ammonium acrylate) is
stirred, the aqueous solution of glycerin diglycidyl ether
and the aqueous solution of the active component and
polyethylene glycol are added and mixed. The resulting
solution for hydrogel is coated on a pliable plastic film
50 that the amount of the active component is 0.5 mg per
cm . The surface is covered with r~leasing paper, and the
film is cut to pieces each having an area of 35 cm2 to
form an adhesive patch.
Example 7B
An adhesive patch containing 10 mg of the active
component is prepared as follows:-
An aqueous sol is prepared from 100 parts of
poly(sodium acrylate) r 100 parts of glycerin, 150 parts o~
water~ 0.2 part of triepoxypropyl isocyanurate, 100 parts
of ethanol, 25 parts of isopropyl myristate, 25 parts of
propylene glycol and 15 par~s of the active co~ponent.
The sol is then coated to a thickness of 100 micrometerson the non-woven fabric surface of a composite film com-
posed of a rayon non-woven fabric and a polyethy~ene ~ilm
to form an adhesive layer containing the drug. The amount
of the release aids ~isopropyl myristate and propylene
glycol) contained in this layer is about 20% by weight.
The adhesive layer is then crosslinked at 25C for 24
hours, and a releasing ilm-is bonded to the adhesive
layer surface, and the entire film is cut into pieces each
having an area of 35 cm2.
The biological activities in vitro of the com-
pounds of formula tIj on cells of the nervous system were
tested. The cells tested were human neuroblastoma cell
line GOTO [see Sekiguchi, M., Oota, T., Sakakibara, K.,
Inui, N. & Fujii, G., Japan. J. Exp. Med., 49, 67-83
(1~79)], and neuroblastoma cell line NB-l lsee Miyake,
S., Shimo, Y., Kitamura, T., Nojyo, Y., Nakamura, T.,
~3~
- 71 -
Imkashuku, S. and Abel T., The Autonomic Nervous System,
10, 115-120 (1973)], and mouse neuroblastoma cell line
neuro-2a (Dainippon Pharmaceutical Co., Ltd.) which have
been established as the cells of the nervous system. The
above neuve cells were grown in an incubator at 37C in
the presence of 5% caebon dioxide gas exponentially, and
then cultiva~ed for a ceetain period of ~ime together with
the compounds of formula ~I). The results demonstrated
that the compounds of formula (I~ have nerve cell growth
promoting activity and neurite formation and sprouting
promoting activity which are markedly higher with a signi-
ficance than a control, and are equal to, or higher than,
isaxonine as a control drug ~the compound described in
Japanese Patent Publication No. 28548~1984).
The biological activities of the compounds of
formaula ~I) in accordance with this invention on rat
PC-12 pheochromocytoma cell line were also tested. When
NGF is added to PC-12 cells, the neurites sprout. It was
shown that when the compound (I~ of this invention is
added at this time, the binding of NGF to the PC-12 cells
and the up-take of NGF into the cells increased.
When the ef~ect of the compounds (I) of this
invention on the binding of NGF to rabbit superior
cervical ganglion was examined, ~hey were found to promote
the NGF binding.
Rats whose sciatic nerves were crushed were
prepared as a model of peripheral nervous disorder, and
the effects of the compounds of this invention on it were
tested. I~ was made clear that the compounds tI) of the
present invention have an effect of promoting recovery of
the interdigi~ distance and the weight of the soleus
muscle to normal values.
Rats and mice models of central nervous dis-
orders were prepared, and the pharmacological effects
of the compounds (I) of this invention were tested.
Specifically, nigral dopamine cells o~ the rat brain were
~3~
- 7~ ~
chemically destroyed by injec~ing a very small amount of
6-hydroxydopamine to induce motor imbalance. Two weeks
later, dopamine cells of fetal brain were transplanted in
the caudate nucleus into the lesioned side of the rat
brain and an attempt was made to improve ~he motor
trouble. Specifically, beginning on the day of trans-
plantation, the compound (I) of the invention was intra-
peritoneally administered every day over 2 weeks, and the
activity of the compounds (I) of the invention on the
improvement of the motor imbalance and the growth of the
transplanted cells was examined. It was found that the
compounds SI) of the invention have a promoting effect on
the improvement of the motor trouble.
Rats and mice having a nerve trouble by mercury
poisoning were prepared and the activity of the compounds
~I) of the invention was tested. The compounds ~I) were
found to have a promoting ef~ect and a curative effect on
the improvement of the conditîon and recovery to a normal
condition.
Thus, it has been made clear that the compounds
(I) of this invention are useful as agents for improving
or curing various neurological diseases of mammals, such
as troubles in peripheral and central nerves.
Various types of neuropathy including, ~or
example, various peripheral nerve disorders accompanied by
motorgenic, seonsory or objective flex retardation, and
alcohol-induced or drug-induced, diabetic and metabolic,
or idiopathic peripheral nerve disorders, including
~ traumatic, inflammatory or immunological nerve root
;~ 30 lesions may be cited as such neurological diseases. More
specific examples include facial palsy, sciatic nerve
paralysis, spinal muscular atrophy, muscular dystrophy,
myasthenia gravis, multiple sclerosis, amyotrophic lateral
sclerosis, acute disseminated cerebromyelitis, Guillan-
Barre syndrome, postvaccinal encephalomyelitis, SMON
~3~
- 73
disease, dementia, Alzheimer syndrome, a condition after
cranial injury, cerebral ischemia, sequela of cerebral
infarction or cerebral hemorrhage, and rheumatism. These
ex~mples are not limitative.
By a toxicity test, the compounds of this
invention ~ere found to have only wealk toxicity, and be
useful as safe medicines.
Example lC
The effect of the compounds of this invention on
neuroblastoma cells was examined by the following method.
A culture medium [composed of 45% of RPMI 1640
medium, 45% modiied Bagle's medium (MEM~ and 10% of fetal
calf serum (FCS) and containing penicillin ~ sodium (100
units/ml) and streptomycin sulfate (100 microgram/ml)]
containing neurobalstoma cell line GOTO in the logarithmic
growth period was poured in an amount of 2 ml each into
polystyrene dishes S35 mm; made by Corning Co.) so that
the cell concentration was 2 to ~ x 104 cells per dish,
and the cells were cultured for 1 to 2 days in a carbon
2~ dioxide gas incubator containing S~ of carbon dioxide gas
in air at 37VC. Then, the culture fluid was remo~ed, and
: 2 ml of a fresh serum-free culture ~luid ~consisting of
50~ of ~PMI medium and 50~ of MEM medium and containing
penicillin G sodium and streptomycin sulfate in the same
amounts as above) was added~:At the same time, a pre-
sterilized PBS solution tphosphate buffered saline) of
each of the test compounds in various concentrations was
; added to each of the dishes. After culturing for 24
hours, the number of living cells was counted. Further-
more, the culture was photographed, and fro~ ~he photos,
the number and length of neurites per cell were measured.
The numer of living cells was counted for 3 to 6 dishes by
resistance to staining with~erythrosine dye. The number
; and length of the neurites were measured with regard to 6
3s photos (more than 200 cells per photo~
As a simple method of evaluation, the number of
~3~ ~-3~
- 74 -
cells having neurites with a length equal to, or larger
than, the long diameter of the cell was divided by the
total number of cells~ The results are shown in Tables 1
and 2.
In order to examine the effects of the test
compounds, the following method was also employed.
Mouse neuro 2a cells in the logarithmic growth
period in the Dulbecco's modified Eagle's medium (DMEM)
containing 10% FCS was seeded in a 48-well plate so that
the number of cells was 1,000 cells/well, and cultured for
one day in 0.25 ml of the culture fluid in each well. The
culture medium was then replaced by a medium containing
each of the test compounds and FCS, and the cells were
further cultured for 24 hours. Then, a 4~ aqueous
glutaraldehyde solution in the same amount as the medium
(0.25 ml) was added, and the culture fluid was left to
stand at room temperature for 2 hours to fix the cells.
After washing with water, a 0.05% aqueous solution of
methylene blue was added to stain the cells. Under a
microscope; the nu~ber of cells containing outgrown
neurites (cells having at least one neurite with a length
at least two times as large as;the long diameter of the
cell~ was counted visually~ and the proportion of these
cells in the entire cells was calculated. The well was
observed over 5 or more visual fields (at least 2~ of the
entire surface area of the well) continuous to the left
and right from a mark put at the center of the well, and
more than 200 cells was counted. One drug co~pound was
used in 6 different concentrations at most, and three runs
were conducted for each concentration. The results were
expressed as a mean ~S.D., and ~he results are shown in
Table 3.
~IL3~
- 75 -
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-- 76 --
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~ o I~ _ __ __ _._ __
~ _ ~ ~ ~ o oo ~ ~I ~ ~
,~ .,1 ~ o ~1 a~ ~ ~o D ~1 ~ O O
In ~ ~1 ~ ~ C`J ~ C~
a~ a o aJ d~ _l
~ ~: O ~ ~ cr~ a~ ,~ ~ ~1 c~ ,1 ~ a~
c~ ~ ~1 ~ ~r ~r~
.~ ~ ~ ~ ~ ~ ~ ~~ ~ ~ b,
~:: ~ ~ ~ _ ~ ~~ ~ ~ ~ ~ _.
O ~ _~ ~ ~ ~_I~U~ _to
c~ ~ a~ _~ r~ ~ ~ ~1~ 0 a~ a~
~t ~ ~ ~ ~~ ~I ~ ~-I
O ~ ~ _ ~ __ __ _~_ _~,
J S ~1~ ~ ~ O ~ ~t a~ a~ u~ ~D
_, a~ ~ ~~ ~ O ~ ~ ~r a~ oo _I o
~ 5~ ~ ~~i ~ ~ _~ _1 ~ ~ ~ ~
E~ :3 2J ,1 ~ ~ u~ ~ ~r
Z-~ ~ ~ ~C~ ~ ~ ~
__ _ _ . __ _ _
~ ~ ~î
a~ ~1 ~1 0 ~ O~ O ~1 0
~ n _l ~ ,~
_ _. _ . . _
~ ~0
O L~ ~ _~ _ ~ ~
: ~ 1: ~ ~ a: ~3 ~
o ~ ~n ~ ~ ~o co
V __ ___ _ _ . .
~_ ._~
:~
~:~
. ~
. Z N un~
'
'
~3~S~
- 80 -
4~ _._
o
1 0
a) o c:
O--~ o ,~ r~u~ o~co
dP . I
~, _ ~ cs~ a~ o ~ ~ ~ In a~
.~.
~: o
. . __ _ _. _
U~ .
. .
~ ~ ~_~ ~ O ~ ~D
o C~ C`~ Ln ~ ~ .
t~ _~ ~ .U~-- --
a~ o ~ ~ -
a)~ .~_ ~1--~ 00`'~
~,t: o CO _ ,~ ~ ~
.~ ~--a~ U~1 ~0--
L~ ~ Od'l--~ ~
~ al .a~ ,~~ ~ ~ o~ ~ In
U~ C~ ~ ~ ~,1_~ ~o
~, ~ o ~ ~ ,,~ .
.C ::1 ~ ,1 ~ ~ '
O ~ `~
.. -. ~o U~ `~
~s ~ ~ ~~ ,_~ ~ . .
a) a~ ~ ~u7 o~ . _; ~ t~
U~U~ ~ _
o ~oo~ .,,_ --
JJ ~_._ O_ ~ ~
u~ _I ~1 ~ co
.,~,~ . ~_~,~ ~
h ~1 __I~1 el~t--~1 ~I CO
O GJ elP _ ~ l
,C 0-- ~ ~ 00
~ U~O ~~ ~ ~1
U~ O ~ ~D~-I ~1 O ~1 a~
,
~ ~ _~:~ ~ ,~ ~ ~.
~ ~ ~ _ ~ ~
_,~ :3 0 ~ ~ O CO ~ O
q~ ~ ~o a~ .
O ~ ~ ~~ ~__ _,_
C`~ _ ~ _
Ll ~ ~ _ O --0 ~ U~ ~
~JJ ~ ~C~I ~1~ ~0
.Q ~ ~ C~ ~_I ~_
~; ~ ~ ~ CO~
E~:1 ~-rl ~ 'l ~~ ~
Z ~1 ~ ~1~1 _i a~ ~
. _ _ _
I ~~ ,~
C 0~1 ~ 0~1 0
a~ . O
t~ ~ ~ O ~i O O ~ O O
O ~J ~
C.) ~-1 ~~
. _ . _
_~ O
~S O S::
O s~ ., ~ _ ~
X ~ O
C ~ O ~
O O ~1 ._
. O
::~
C~
__ ~ _
~ o~ un~
_
~3~ ! 2
_ 81 --
Table 3: Activity on neuro-2a
.
Compound Number of cells having neurites with a
length at least twice as large as the
long diameter of cell/total number of
cells, % (compound concentration)
_ ___ _ _
(124) 4.6~0,5 (3.6 ~M), 3.3_1.2 ~36 ~M)
(132) 4.3~0.5 t27 ~M), 4.3~1~2 ~0.27,~M),
o 4.2+1.0 tO.027 ~M)
~; _
(128) 5.2~0.9 (28 ~M), 4.4+0.7 SO.02B~ M~,
304~0.6 (0.29 ~M)
Control 2.2+0.8
_ ___~ _
(108) 6.9+1.6 ~1 mM), 4.6~1.2 tO.3 mM)
(1~4) 10.6+4.6 tO.3 mM), 5.3+1.8 (1 mM)
.
(112) 3.5+S~.S (1 mM)
(120) 10.2+3.7 (0.1 mM)
(132) 11.2~1.3 (0.3 mM), 9.1~3.0 (1 mM)t
4.4+0.7 tO.l mM)
(136) 7.2~1.7 (0~1 mM~
(144) 19.4~3.2 (Q.3 mM~, 9.9~1.5 ~0.1 mM~
~652) 4.5+0.3 (1 ~M~
(442) g.l~O.8 tl mM), 7.1+~.6 (0.3 mM~,
5.7+0.5 (0.1 mM)
_ - _
Control 1.9~0.9
_
(604) 10.7+1.3 (1 mM), ~.6+0.g (0.3 mM)
z ~. . ~ - _ _
(408) 51.2+1.5 (0.1 mM), ~3.0~1.7 S0.05 mM),
_ __ _ 13.0+1.2 (0.03 m~), 7.9+1.8 (0.01 mM)
- to be continued -
~: :
~3~
- 82 -
Table 3 ~continued)
Compound Number of cells havlng neurites with a
length at least twice as large as the
lony diameter of cell/total number of
cells, % ~compound concentration~
_
t412) 44.2~1.4 tl mM), 16.6~2.6 (0.3 mM)
(~28) 30.1~2.4 tl mM), 17.3+0.8 (0.3 mM),
o 6.7~1.5 (0.03 mM)
~; ~
c Isaxinone 7.0+0.8 (1 mM), 6.8~1.2 (0.1 mM),
_ _ 4 7_0.4 tO.03 mM~ ~
Control 3.9+0.3
_ . __ _
(412) 47.8+0.4 tl mM), 27.9+2.9 (O.S mM),
15.8+2.3 tO.3 mM~
_ __ _ _ __ _
~408) 44.6+3.1 ~0.2 mM), 33.5+2.7 ~0.1 mM),
16.8+2.7 ~0.05 mM)
(406) 44.8~0.8 tO.5 mM), 29.9+2.6 (0.3 mMj,
16.2+3.7 (0.1 mM)
t428~ 29.1~2.4 (1 mM), 27.2~3.1 (0.5 mM),
13~7+2.1 (O.l`mM)
o (430) 13.4~0.4 ~1 mM), 11.7+1.8 (O.S mM),
Z 7.2+1.g ~0.1 mM)
:~ ~ _ _
t464) 13.1~1.1 (~ mM~, 10.1+1.9 (0.3 mM),
7.1+1.6 (0.1 mM)
. ~ _
(910 12.5+0.9 ~1 mM), 7.4+2.5 (0.1 mM)
Isaxinone 34.4~0.6 (10 mM), 13.6_2.3 ~3 mM),
5.7+1.2 (1 mM)
_ _ __
_ Control 3 ltO.2
(2063 6.7+0.7
z ~24) 27.1+2.1 (1 mM), 12.6+1.1 (0.5 mM)
~: _ _ _
_ (~08~ 23.5+2.5 (0.1 mM), 12.8+1.8 (0.05 mM)
; - to be continued -
iiL3~
- 83 -
Table 3 ~continued)
_
Compound Number of cells having neur}tes with a
length at least twice as large as the
long diameter of cell/total number of
cell~, % tcompound concentration)
_ __
(707) 36.1+3.7 (1 mM), 6.1*0.5 (O.Ol mM)
_
(701) 54.9~1.61 (mM), 16.2~1.2 (0.1 mM)
_ _
(406) 32.4+4.3 ~0.5 mM), 18.4+3.0 (0~3 mM),
7.S~1.8 (0~03 mM~
~n _ . _
. (~28) 15.6~1.0 (1 mM), 14.1~1.5 (0.5 m~),
æ 9.8~2.3 (0.3 mM)
_ _ _ _ _
(430~ 9.0~0~8 (1 m~3, 7.6+0.8 (0.3 mM~
__. _
(466) 13.1~1.4 (I mM), 5.4~0.3 (0.1 mM)
__.
Isaxinone 27.0+3.4 (10 mM), 6.8+2.2 ~1 mM)
_ _ . .
Control 4.5+0.3
,
(902) 6.9~0.8 (0.01 mM~, 6.7+0.9 tO.03 mM),
6.7~1~0 (1 mM)
_ _ __ _
: (202) S.6+~ 0.~ mMl
: _ _ _ _ _ _ _ _
~906) 7.4~1.0 ~OO1 mM), 7.0+0.6 (0.3 mM)
çn2) lO~O_O.9 (3 mM), 6.2~0.2 ~0.1 mM) .
z; _ __ _
~616~ 1006~1.5 ~0.3 mM)t 10.3+1.~ (1 mM)
~; _
(8023 7.5+2.2 ~0.1 mM)
_ __ _ _
(6203 20.7+2.5 (3 mM)~ 10.5+3.2 (1 mM),
7.~+~.3 (0.1 mM) ~ ~
_ _ _ _
; ~606) 11.9+2.1 ~3 mM), 6.9+1.~ ~.1 mM)
. _ ~ . _
~ - to be continued -
:
- 84 -
Table 3 (continued)
_ _ _
Compound Number of cells having neurites with a
length at least twice as large as the
long diameter of cell/total number of
cells, ~ (compound concent~ation)
. _ .
o Isaxinone 29.9+0.9 (10 mM3
z
Control 4.4+0.9
__
(408) 44.5~2~9 ~0~2 mM), 25.0~207 ~0.1 mM),
6.2~0- 9 (0.01 mM)
(406) 4~.2~3.4 (0.5 mM), 22.6+~ .3 mM),
10.3~ (0.1 mM) ~
(707) 21.4+1.7 ~1 mM), lO.S~1.5 (0.5 mM),
o 7.3_1.0 tO.3 mM) ~
_ ~
~701) 57.2^~1.2 ~1 mM), 42.5+1.8 ~0.5 mM),
6.8~0.8 ~0.03 mM)
_ ,
Isaxinone 24.9+1.0 ~10 mM)
_ _ _~ _
Control 2.5~0.7
_ _. _ _ _
t420j 47.5~0.6 (1 mM), 30.6+5.0 (0.5 mM),
16.5~2.1 ~0.3 mM) ~
_ _ _
(410) 36.7~6.1 (0.5 mM~, 22.4+2.9 ~0.3 mM),
15.5+0.3 (1 mM)
-- _
~412) 49.5+3.5 (O.S mM), 32.6+1.3 ~1 mM),
o _ 18.4~0.5 (0.3 mM)
Z ~414) 43.6+7.8 (1 mM), 33.~2.6 ~0.5 mM),
15.0+4.0 (0.3 mM) -
~; _ _ _
~416) 48.7+5.7 ~0.5 mM)I 40.4+9.2 ~0.3 mM),
__ 11.7_3.3 (0.1 mM) ~
~418~ 47.4+1.6 ~I mN), 29.6+3.3 ~0.5 mM),
16.6+1.1 (0.3 mM)
_. _ _
- to be continued -
,
~3q~
~,
Table 3 (continued)
. _ __ ~
Compound Number of cells having neurites with a
length at least twice as large as the
lon~ diameter of cell/tot~l number of
cells, % ~compound concentration~
_ _ _ . _
t502) 7.8~1.2 (1 mM), 5.5+2~0 (0.3 mM)
.
Isaxinone 28.2~1~6 (10 mM~
~::
Control 3.7_0.4 ~
(620) lg.~+O.5 (3 mM), 11.3+3.3 (1 mM),
_ 6.2_1.5 (0.3 mM) - _ _
(436) 15.6+7.3 (0.1 mM), 14.3+2.~ tO.03 mM),
12~5_6.2 ~0.3 mM)
__. _ _
~434) 6.0+1~2 (0.1 mM)
(440) 12.9+4.1 ~3 mM), 5.8+1.0 ~1 mM)
cn .. .. _ ~
z ~4421 13 8~1.2 (3 mM), 7.5+3 0 ~1 mM~
(140) 3,7+1.4 ~0.03 mM~
(~38) 6.5+0.2 ~0.1 mM)
~ _ - ~
(~42) 14.4 4.0 (0.3 mM), 9.5~1.2 (0.1 mM)
~446) 9.2+2~.~ (1 mM), 6.3+0.4 (0.5 mM)
_ _
Control 2~0+1.0
_ .
~ ~ - to be continued -
:~ :
:
~iL3~5~ 2
- 86 -
Table 3 (continued)
_ _ _
Compound Number of cell~ having neurites with a
length at least twice as large as the
long diameter of cell/total number of
cells, % ~compound concentration)
_
116 11.6~2.0 ~0.03 mM), 10.6~4.5 (0.1 mM~,
7.5+2.2 (0~01 mM)
_ _, _ _
120 6.5~1.7 (0.1 mM~, 2.G+0.6 tO.003 mM)
_
136 16.4~0.9 ~0.03 mM~, 12.6+1.4 ~0.1 mM),
: 5.8~1.6 ~0.01 mM~
: ~ 468 15.7+0.5 (1 mM3, 5.8~0.8 (0.3 m~
o _ ~
646 7.3~0.2 ~0.1 mM)
~ _
: ~ 914 4.9+0.9 ~0.1 mM), 4.6~0.8 S0.3 mM)
_ _ .
470 5.4+2.1 ~3 mM), 4.6~1.5 (1 mM),
. 3.2~0.7 (0.3 mM) ~
- . _ _ _ .
: : Isaxinone 30.0~1.1
:~ : Control 1.7+0.7 :
_ ~
940 17.0~1.2~0.3 mM), 1 L . 5~0 . 2 (0 . 1 mM )
- __
: ~ 674 6.7+1.3 ~0.1 mM), 4.5+1.9 ~0.3 mM),
4.2~0.8 ~0.03 mM~ ~
~ ~ z _ - ~ ~
678 16.1+1.6 ~1 mM)~, 9.1~2.2 (3 mM),
4.1-2~2 (0.1 mM) ~
_
:Control 2.5~0.6
~ : _ ~ _ _
:~ :
,
~; ~
~3~ J:;~
- 87 -
Example 2C
Gura~ive effect on rats with crushed sciatic
nerves:-
The curing effect of the compound (I) of the
invention was tested on rats having crushed sciatic nervesas a model of peripheral nervous disorder using ~1~ a
change in the action of the hind paw with the crushed
scia~ic nerves and (2) a change in the weight of the
muscle as an index of ~he course of degeneration and
regeneartion of peripheral nerves.
In the experiment, male Wistar rats (6 weeks
old), seven pee group, were used. The sciatic nerves were
crushed by a method similar to the method of Yamatsu et
al. ~see Kiyomi Yamatsu, Takenori Kaneko, Akifumi Kitahara
and Isao Ohkawa, Journal of Japanese Pharmacological
Society, 72, 259-268 (1976) and the method of Hasegawa et
al. (see Kazuo Hasegawa, Naoji Mikuni and Yutaka Sakai,
Journal of Japanese Pharmacological Society, 74, 721-734
(1978). Specifically, under anesthesia with pentobarbital
(40 mg/kg, i.p.~, the left side sciatic nerve was exposed
at the femur and that site of the exposed sciatic nerve
which was 5 mm to the center from the branched part
between the NO tibialis and the N. suralis was crushed
using a modified artery, klomme, having a width of 2 mm
and a gap of 0.1 mm. After the operation, the rats were
assigned to the test groups at random.
Compound No. 408~was selected as the compound
(I) of the invention and intraperitoneaIly administered to
the rats once a day from the day of operation to the 22nd
day. A group to which mecobalamin (made hy Gedeon Richter
Ltd.) was administered and a group to which 0.9% saline
was administered were used as controls. The ~ollowing
; items were measured with the lapse of time (on the 1st,
4th, 7th, 10th, 14th, 17th,-21st, and 23rd days after the
3s crushing of the sciatic nerves~.
~3~
- 88 -
(1) Chan~e in the action of the side of the
hind paw with the crushed sciatic nerve:-
The distance between digits was measured becausethis is a good index which functionally shows the de-
gellera~ion and regeneration of the nerve and its changecan be measured with the lapse of time.
By a method similar to ~he method of Hasegawa
tHasegawa~ K~, Experientia, 34~ 750-751 tl978)1, the
distance be~ween the first and fifth digits of the hind
paw was measured~
The ratio of the measured distance to the normal
distance was calculated and expressed in percentage ~%~.
The average calculated values and the standard errors (S~ :
E~) are shown in Table 4. To the values of the test
groups which are significantly different, by the t-test of
9tudent, from that of the control group to which physio-
logical saline was administered, superscript :is attached
where p<0.05 and superscript , where p<0~01.
: The distance between the digits was about half
(50~ of he normal distance immediately after the crush-
ing:of the sciatic nerve~ and tended to decline until the
tenth dayO No significant difference was seen among the
groups. Regeneration proceeded in the drug-administered
groups on the 14th and 17th:days, but they showed no
: ~ 25 significant dif~erence from the group to which saline was
administered. On the 21st day, there was an apparent
tendency ~o quicker recovery in the drug-administered
groups and the mecobbalamin-administered group, and these
groups also show significant differences from the group to
: 30 which saline was administered. Recovery continued also on
the 23rd day~
(2) Change in the weight of muscle
It is known that removal o~ a nerve or its
disorder causes atrophy of the muscle which is under its
control, and the atrophy is gradually cured by re-control
by the nerve. For this reason, a change in the weight of
,
~L3~
-- 8g --
the muscle, which is quantitative, was selected as an
index. Twenty-three days after the operation, the soleus
muscles of both sides of paws were extracted under
anesthesia with pentobarbital, and their weights were
measured. The ratio of the weight of the soleus muscle on
the crushed side to that of normal side was calculated and
expressed in percentage (%). The average values and the
standard errors ~S. E.) of the groups are shown in Table
4.
~ccording to experience with another experiment,
the weight of the muscle in the saline-administered group
began to decrease two days after the crushing of the
sciatic nerve and became about 90% of the normal Yalue
In 10 to 14 days, it reached about 40%, the lowest value,
and the atrophy of the muscle reached a maximum. There-
after~ the atrophy began to cure gradually.
In the present experiment, it is clear that in
the groups to which tbe compound of the invention was
administered, the recovery of the weight of the muscle was
2~ promoted dose-dependently with a significant difference
from the saline-adminsitered group on the 21st day.
~,3~
-- 90 --
~ -__ ~
o a) ~ ~ * t~ a~
c~ 3 ~a ~ o ~ r-
a~ a . O
,~
~1+1+1 +1 ~1 ~1
-- ~ c~ o ~ ~ a~ o ~1
o ~ ~ . . ~ . c:
~~ ~o~ ~ u~ a~
a E~
,~~ ~ ~
VP~ Ul
~ _ _ _ ~c
f:: ~c ~
0 ~r~D ~ ~ O
~:5, ^~ . . . . .
.~ ~ ~ ~ 1 +~ ~1 ~1 Q~
r ~ ~ ::
a~ q~ ~ ~ . . o
~: O O ~ ~1 0 ~ ~ ~ C~
u~ c I_ oo a~ I~ s~
:~ ~
U Ll
. ~ i~
UO ~ . ~ J~
aJ ~ :~ ~ ~ ~ ~q
,~ ra ~ u~ ~ ~o ~ ~1
~ ~ . . . . s:: o
~: o ~ ~ ~ 1 C~l .
.. ~ ~ u~ o a~ ,~ ~ o
3 a~ q~ ~ . . . ~ ~
~ J~ ~ ~ O ~ ~ 00 O~ I a.
J~ ~ C ~ ~ o 1~ a~
u ~ -I . _ c ~ o
~ .~ ~, u~
a~ a~ ~ ~ ~ o ~
u~ ~ ~ O ~ c
o o o o - a~
o ~; P~ ~
E~ 1 .~ ~ aJ
c~ , _
c, ..
.. ~o O
d' O : ~: u2 n a~
~r ~ ~ u~
~ ~5 ~ ~ o
::~ ~C _1 ~, V U~
~ _~:1
E~ ~ u~ Q. O ~
_ ~:
~3~ Lf~
91
Example 3C
Promoting effect on th~ improvement of motor
imbalance due to injury of the rat's brain cells by trans-
plantation of fetal cerebral cells:
Nigral dopaminergic nerve cells at the ~eft side
of the brain of 4-week old female Wist:ar rats tbody weight
100 g~ were lesioned by injecting a very small quantity
of 6 hydroxydopamine. The rats showed a tendency to
rotate spontaneously in a direction opposite to the
lesioned side for several days, but no apparent abnormal
action was observed after that. Upon administration of
methamphethamine (5 mg~kg, i~po~ to the rats having the
lesioned nigral dopaminergic nerve cells, they began
rotational movement toward the lesioned side.
After two weeks from the destruction by the
administration of the drug, portions of the truncus
corporis callosi containing dopamine cells (i. e., sub-
stantia nigra and the tagmentum at the abdomen side) were
cut from the brain of a fetal rat of 14 to 17 days of age,
cut finely, and treated with trypsin. Then, the extracted
tissues were incubated at 37C for 30 minu~es, and the
tissues were subjected to pipetting to form a suspensionO
Five microliters of the suspension wa~ transplanted each
into two sites of the caudate nucleus of the lesioned side
~10 microliters in total, about 105 cells).
Each of the compounds ~I~ in a dose oE 100 mg/kg
(i.p.) was administered every day over two weeks from the
day of transplantation. The rotational movements induced
by administration of methamphetamine were examined 2
weeks and 1 week before, and 2 weeks and 4 week~ after,
the transplantation and the administration of the drug.
The number of rotational movements within one minute was
counted at intervals of 10 minutes after the administra-
tion of methamphetamine, and the total number of rota-
tional movements counted six times was averaged to find amean number of the rotational movements.
The results are shown in Table 5.
~3~
-- 92 --
_ _ _
In ~D ~
~D In ~ CO~IC~l
. . . . o
C~
:3 +1 +1 +1 +1 ~~1 ~
C er ~ ~ ~ ~ ra
O ~ O 1`u~Ul
.,~ . . . . . ~ ~
~`i ~ o ~,~ ~ 0
~ ~ ~a o 3
0 . t:: Q~
W ~ ~ ~ o~ U~
,, o ~ ~ ~ r~ a~ O ~ O
u~ ~ . ~ O ~ ~ ~ a
1~,q c~ ~ ~
+l ~1 ~1 +1+1+1 qJ
~n s: ~ 0~ ~ ~ ~r ~ 3
a~ a) ~ oa~ ~ a
al ~ . . . . . . Q.
u~ ~~1
~~ ~ ~ ~ a
o a1 t) Q. --
o~4
o ~ a) u~ O Q, L~
t` ~ c~ ou~ ~ ~
Ll ._~ . . . . ~ O ~n
~ ~ s: Q~ U~
,c E~ o~: Y 0 3: +l +l +l +l +l ~1
J a) ,,., q) ~ ,~ ~ ~ a~
~11 0 l d' ~ ~`I ~1 0
~:: O 0 tl7 iC ~ ~ O aJO E~ ~ o t~ 1 o ~ '
O ::~ ~ ~ ~ ~ J~
~ ~ L~ ~ O ~ ~ X
:~ ~ 0 ~ ~ rl
E~
O O ~.,1 ~ ~O t` U~
,-1 ~ ~ ~:: co f~ ~ ~
. . . . . .- ..
~:: 0 ~ ~ ~ ~ ~ ~ 7 _1
~J Z O ~ ~ +l +l +l ~1 +1
o ~ a) c~ r~ ~ ~r
W SJ 't > l ~ ~ ~ O O
O Z; ~S . o ~
~ O O~ O ~ o ~ :
J
~- V _ : _
~: ~: ~
rl ~ .,1 rl
~:: ~ O
.. ~ ~ ~ :
In ~ O O ~O O ~ U~
~ ~ r ~ ::
o ca u~
1 V U~ tO
l:i : .
E~ _ _ . P~
: ~ N
O O
Z Z
:
3 ~
: ~ ~:
_ ___ _
~: ` : :
'
~3~ f,l~
- 93 -
The results given in Table 5 demonstrate that
the rats, tWQ and four weeks after administration of the
drug, showed less numbers of rotational movements than the
rats to which saline was administered, and the compounds
(I) have an effect of repairing and regernerating the
nerves and an effect of recovering motor functionO
Example 4C
The acute toxicity of the compounds of the
inven~ion was examined by the following method~
Male ddy-s~rain 5-week old mice and male Wistar-
strain 8 week old rats, five per group, were used as
experimental animals. Each of the compounds was dissolved
in saline and administered perorally~ and the toxicity of
the compound was assessed 24 hours after the administra-
tion. The results are shown in Tables 6 and 7.
~3~5~
- g4 -
Table 6: Acute to~icity ~I~50)
_ _ _
Animal Compound Nu~nber of dead anirllals~ Presumed
number of te~;t animals LD50
. __ _ _ (mg/kg p.o~, )
Dose
tmg/kg p.o. )
____ _ _
300S00 1.000
_ _
(710~ 0/5 3~5 5~5 3~0- 550
. _
(706~ 0~5 2~5 4/S ~50-1000
_ _ ._
(744) _ 0~5 3/5 ~50-100~
_ _
(701) 0/5 3/5 5/5 30~- 550
Mouse _ ~
(715) 0/5 0/5 4/5 550-1000
., ._ . __
(713) 0/5 0/5 2~5 ~1000
_ _ .. __
~ 1 4 4 ) 0 / 5 13 / 5 3 / 5 S 5 0 1 0 0 0
(120) 0/5 1/5 4/5 550-1000
.~ . . . _ _
~120 0/5 0/S 3/5 S59-~000
~lZ8) 0/5 3i5 4/5 300- 550
_ _ ,
Rat (710) 1/5 2~5 5/S 550-1000
_
. _ (706) 0/5 ~/5 3/S 550-1~00
ot carried out.
~3~
- 95 -
Table 7: Acute toxicity (LD50)
_ _
Animal Compound Number of dead animals~ Presumed
number of test animals ~D50
_ _ (mg~kg pOO.)
Dose
(mg~kg p . o . )
= . ~ ~
10~0 17~ 3~00
. _ _ _
620 0~5 _ _ >1000
602 0/5 0~5 3/5 1700-300
~ 606 0/5 _ _ >1000
_ .
608 0/S _ >1000
_ _ . _ _
616 0/5 ~/5 4~5 1700-3000
_ ._
42~ 0/5 _ _ ~1000
_ _
406 1/5 _ _ >1000
. ~ouse 502 0/S _ _ >1000
:: : . 428 0/5 ~ _ >1~00
~0~ 0/5 _ : _ >~0
: . 408 0/5 _ _ ~ >1000
438 0/5 _ _ ~1000
_ . .
.650 0~5 _ _ >1000
_ .
132 0/S _ _ >1000
_
: 6~8 0/5 _ _ >1000
_ _
~468 1/5 _ ~1000
. _ .
Rat 602 :0/S : _ >1700
616 _ 0/~ _ >1700
' _. _ _ _ _ _ .
-: :Not carried out~
:
~ .
~3~
- ~6 -
EFFECT5 OF T~ INVE~TION
The compounds of general formula ~I) provided by
this invention have a promoting effect on the prolifera-
tion of nerve cells and the formation and sprouting of
neurites and a nerve regenerating effect and a motor
function recovering effect in rats and mice having nerve
disorders, and can be used suitably for improving and
curing neurological diseases such as disorders of peri-
pheral nerves or central nerves. They are expected to be
used also suitably for the recovery, improving and curing
o~ neurologiaal diseases causèd by nervous tissues and
cells which have to do with perceptive and sensory func-
tions and an autonomic function.
It has been found that the compounds (I) of the
invention have biological activities equal to, or higher
than, those of isaxonine as a control a8 shown in Example
lC, Tables 1, 2 and 3. The toxicity of the compounds ~I)
of this invention are generally weak as shown in Example
~C, Tables 6 and 7~ Thus, the compounds ~I) of this
invention are generally considered to be highly active and
highly safe drugs with weak toxicity.
.:
,
.
