Note: Descriptions are shown in the official language in which they were submitted.
1 337603
~ITT-~ OF THE INV~NTION
DIBENZ [b,e] OXEPIN DERIVATIVE AS AN ANTIALLERGIC AND
ANTIINFLAMMATORY AGENT
This is a divisional application of copending
application S.N. 531,043 filed March 3, 1987.
~ACRGROUND OF THE INVENTION
Heretofore, it has been known that 11-
unsubstituted, ll-hydroxy or ll-oxodibenz [b,e] oxepin
derivative is used for antiinflammatory agents [J. Med.
Che., 21, 633 - 639 (1978)]
Further, it is known that dibenz [b,e] oxepin
derivative wherein substitutents R. and ~ at ll-position
have the following definitions, is employed in the
treatment and control of allergic conditions (USP
4,282,365).
R.: H, OH, lower alkoxy, lower alkylthio, lower
alkylsulfinyl, lower alkylsulfonyl, arylthio,
NH2, NHCHO or imidazolyl;
Rb : H or lower alkyl;
or R. and Rb taken together are = 0, z CH-RC wherein
Rc is H or aryl.
Furthermore, it is known that 11-(4-
methylpiperazino) diben~ [b,e] oxepin derivative has an
antiasthmatic activity (USP 4,396,550, USP 4,465,835, EP-
A-3856).
- 2 - I 337603
It is also known that dibenz [b,e]oxepin
derivative having the following formula:
S~ NRdR~
~Rf
wherein Rd and Re are lower alkyl and Rf is lower alkyl or
halogen, has an antiasthmatic activity (EP-A-85870).
Dibenz ~b,e] oxepin derivative having an anti-
allergic activity and having the following structural
formula:
0'(~
~ ~Ri
wherein R9 and Rh are alkyl, r is 2 or 3 and Rj is alkyl
or halogen is known (JP-A-227879/84).
Dibenz tb,e] oxepin derivative having an anti-
allergic activity and having the following structural
formula:
[~R}
1 337603
wherein R; is 4-alkylpiperazino, 3-quinuclidylamino or -
Xa~(CH2) ,-NR~R~ wherein Xais -NH-, -S- or -0-, s is 2 or
3 and R~ and R~ are alkyl, and ~ is CN, 5-tetrazolyl,
CONH2 or C02Rn wherein F~ i8 H, alkyl or 1- (ethoxycarbo-
nyloxy) ethyl is known (EP-A-130555).
Doxepin having an antidepressant activity and
having the following structural formula is known [Drugs,
13, 161 (1971)].
Dothiepin having an antidepressant activity and
having the following structural formula is known ~Arz.-
Forsch., 13 1039 (1963); ibid., 14 100 (1964)].
~,~CH~
[~1
As the compound having both an antiallergic
activity and an antiinflammatory activity, steroids are
known.
It is always desired that a novel compound
having an antiallergic activity or an antiinflammatory
activity be developed.
1 337603
8UMMARY OF TR~ INVENTION
The present invention relates to a dibenz [b,e]
oxepin derivative represented by the formula (I):
~ N(C~
~ C~OOOH
and pharmaceutically acceptable salts thereof, and to its
use for the treatment of allergic conditions and
inflammation.
The present invention further pertains to a
pharmaceutical composition containing an effective amount
of Compound (I) or a pharmaceutically acceptable salt
thereof as an active ingredient, and a carrier or an
excipient.
DETAILED DE8CRIPTION OF TRE l..v~...lON
The pharmaceutically acceptable salt of
Compound (I) includes pharmaceutically acceptable acid
addition salt, metal salt, ammonium salt, organic amine
addition salt, amino acid addition salt, etc.
The pharmaceutically acceptable acid addition
salt of Compound (I) includes inorganic acid salts such
` -
~ 5 ~ 1 337603
as hydrochloride, sulfate, phosphate, etc., and organic
acid salts such as acetate, maleate, fumarate, tartrate,
citrate, etc. The pharmaceutically acceptable metal salt
includes alkalimetal salts such as sodium salt, potassium
salt, etc., alkaline earch metal salts such as magnesium
salt, calcium salt, etc., and aluminium salt, zinc salt,
etc. The pharmaceutically acceptable organic amine
addition salt includes addition salt or morpholine and
piperidine and the pharmaceutically acceptable amino acid
addition salt includes addition salt of lysine, glysine,
phenylalanine, etc.
Compound (I) is prepared by using a compound
represented by the formula (II):
o
~CH2COOH
or a compound represented by the formula (III):
~ C~OOOH
m
Compound (II) is disclosed in J. Med. Chem.,
19, 941 (1976), ibid., 20, 1499 (1977) and JP-A-21679/83.
Compound (III) can be prepared according to the
method described in JP-A-21679/83 though it does not
occur in the publication.
- 6 - 1 337603
Process A
The carboxy group of Compound (II) is protected
according to the following reaction scheme.
H~ X OH ~ CH,CO~ ~ CH,
IV
~ CH,
Compound (II) is reacted with 1 to 5
equivalents of thionyl chloride and 1 to 5 equivalents of
2-amino-2-methyl-1-propanol on the basis of Compound (II)
in an inert solvent such as methylene chlooride, if
necessary in the presence of a base such as triethylamine
at a temperature of from 0C to room temperature for 1 -
24 hours to form Compound (IV). Compound (IV) can alsobe obtained by reacting Compound (II) with thionyl
chloride in advance and then with 2-amino-2-methyl-1-
propanol.
Compound (IV) is reacted with 1 - 5 equivalents
of thionyl chloride in an inert solvent such as methylene
chloride, toluene and benzene at a temperature of from
- _ 7 _ 1 337603
0C to room temperature for 1 - 24 hours to form Compound
(V) .
Compounds (I) and (Ia) can be prepared from
Compound (V) according to the following reaction scheme.
O H~Mg(CH~(CH~, HO (CH~N(CH~, o
,CH,~ ~ Vl ~ CH,~ ~
CH, ~ ~ ~ N-t-CH,
V V~
H (CH~CH~ H (CH~N(C~
-H,O ~ C~ O ~ ,C~COOH
O ~ CH, ~ O
h
S wherein Hal is halogen, and includes chlorine, bromine
and iodine.
Compound (V) is reacted with 1 - 5 equivalents
of Compound (VI) in an inert solvent such as
tetrahydrofuran and diethyl ether under atmosphere of an
inert gas such as nitrogen and argon to form Compound
(VII). The reaction is carried out at a temperature of
from 0C to room temperature and is usually completed in
1 - 24 hours.
- 8 - 1 337603
Compound (VII) is reacted with 1 - 5
equivalents of thionyl chloride or phosphoryl chloride in
an inert solvent such as methylene chloride in the
presence of a base such as pyridine to form Compound
(Ia). The reaction is carried out at a temperature of
from 0C to room temperature and is completed in 1 - 24
hours.
Compound (Ia) is incubated in an alcohol
containing water, such as aqueous methanol solution, in
the presence of an appropriate acidic catalyst such as p-
toluenesulfonic acid at a temperature of from room
temperature to the boiling point of the solvent to form
Compound (I). The reaction is completed in 1 - 24 hours.
Process B
The carboxy group of the compound represented
by formula (II) can be converted to a lower alkoxymethyl
group for a trityloxymethyl group according to the
following reaction scheme.
- 9 - 1 337603
C~COOH
L~UH,
OH
~ CH,C~OH
C~ ~ vm ~ H
OH o~
~C~,OC~ ~ CH,CH,O~
IX X
O~id~ ~.~
~CH2CI~OR,'
In the formulae, F~ is a lower alkyl group and
R9' is a trityl group or a lower alkyl group.
- lo 1 337 6 03
Compound (II) is reduced with 1 -5 equivalents
of lithium aluminium hydride in tetrahydrofuran at a
temperature of from 0C to room temperature for 1 - 24
hours to form Compound (VIII).
Compound (VIII) is reacted with 1 - 5
equivalents of trityl chloride in pyridine at a
temperature of from room temperature to 100C for 1 - 24
hours to form Compound (IX).
Compound (IX) is oxidized with 1 - 5
equivalents of an appropriate oxidizing agent such as
potassium permanganate and pyridinium chlorochromate in
an inert solvent such as methylene chloride and acetone
to form Compound (XI) wherein F9' is trityl. The
reaction is carried out at a temperature of from 0C to
the boiling point of the solvent and is completed in 1 -
24 hours.
Compound (VIII) is incubated in an alcohol of
R9OH in the presence of an appropriate acidic catalyst
such as sulfuric acid at a temperature of from room
temperature to the boiling point of the solvent to form
Compound (X). The reaction is usually completed in 1 -
24 hours.
Compound (X) is oxidized with 1 - 5 equivalents
of an appropriate oxidizing agent such as Jones reagent
in an inert solvent such as acetone to form Compound (XI)
wherein R9' is a lower alkyl. The reaction is carried
out at a temperature of from 0C to the boiling point of
the solvent and is usually completed in 1 - 24 hours.
- 11 - 1 33 7 6 03
The compound represented by the formulae (Ib)
and (Ic) and the compound of formula (I) can be
synthesized from Compound (XI) according to the following
reaction scheme.
~CHCHOR,'
H~CH~N(CH~
HO (CE~ N(CH,), H~
,C~O~ -H,O ~ CH,C~
X~ \ / Ib
H
H (C~,),N(CH,)2
[~CH2CH,OH
O~on
H (CH~)2N(CH~,
~CH,COOH
` - 12 - 1 33 76 03
In the formulae, ~', and Hal have the same
meanings as previously defined.
Compound (XI) is reacted with Compound (VI)
which is Grignard reagent according to the same manner as
in the reaction step from Compound (V) to Compound (VII)
in Process A to form Compound (XII).
Compound (XII) is subjected to reaction
according to the same manner as in the reaction step from
Compound (VII) to Compound (Ia) in Process A to form
Compound (Ib).
Compound (Ib) is incubated in a solvent
containing water such as aqueous dioxane in the presence
of an appropriate acidic catalyst such as p-
toluenesulfonic acid at a temperature of from room
temperature to the boiling point of the solvent to form
Compound (Ic). The reaction is usually completed in 1 -
24 hours.
Compound (Ic) can also be obtained in one step
by incubating Compound (XII) in a solvent containing
water such as aqueous dioxane in the presence of an
appropriate acidic catalyst such as sulfonic acid at a
temperature of from room temperature to the boiling point
of the solvent. The reaction is usually completed in 1 -
24 hour~.
If desired, Compound (Ic) is oxidized with 1 -
S equivalents of an appropriate oxidizing agent such as
Jones reagent in an inert solvent such as acetone to form
Compound (I). The reaction is carried out at a
- 13 - 1 33 76 03
temperature of from 0C to the boiling point of the
solvent and is usually completed in 1 - 24 hours.
Process C
H (CH~N(CH~
Il P~CH(CH~N(CH~ ~
~C~COOH xm ~ CH,COOH
I[ ~ I
Compound (II) is reacted with 1 - 5 equivalents
of Compound (XIII) in an inert solvent such as
tetrahydrofuran under atmosphere of an inert gas such as
nitrogen and argon at a temperature of from 0C to room
temperature for 1 - 24 hours to form Compound (I).
Compound (XIII) which is ylide, can be prepared
according to the method described in C.A. 63 16366a
(1965).
+ H~(CH~H~ ~ P~p(CH~,H~-H~ ~ P~P (CH~N(CH~-H~HH~) q
2)HH~
~V XV XVI
In the formulae, Hal has the same meaning as
previously defined and q is 1 or 2.
Compound (XIV) is reacted with an equivalent of
triphenylphosphine in toluene at reflux of the solvent
for 1 - 24 hours to form Compound (XV).
-
- 14 - 1 3 3 7 6 0 3
Compound (XV) is reacted with 1 - 5 equivalents
of HZ in ethanol at reflux of the solvent for 1 - 24
hours and excess HZ is distilled away under reduced
pressure. After the addition of 1 - 5 equivalents of
HHal on the basis of Compound (XV), the mixture is
incubated at a temperature of from 0C to the boiling
point of the solvent for 1 - 24 hours to form Compound
(XVI) which is Wittig reagent.
Compound (XVI) is treated with 1 - 2
equivalents of an appropriate base such as n-butyl
lithium in an inert solvent such as tetrahydrofuran under
atmosphere of an inert gas such as nitrogen and argon to
form ylide (XIII). The reaction is carried out at -78C
- room temperature and is usually completed in 1 - 24
hours.
The intermediates and the desired compounds in
each of the processes described above can be purified and
isolated by a purification method which is usually used
in the field of organic chemical synthesis, such as
filtration, extraction with organic solvent such as ethyl
acetate and methylene chloride, drying, concentration,
recrystallization, column chromatography, etc.
When Compound (I) is produced as a cis-trans
mixture, it is separated and purified by an appropriate
method which is usually used in the field of organic
chemical synthesis, such as column chromatography,
recrystallization, etc.
If desired, ciæ form can be converted to trans
form. For example, cis form is added to an acetic acid
-
` - 15 - 1 33 76 03
and the mixture is heated at reflux in the presence of an
appropriate catalyst such as p-toluenesulfonic acid for
1 - 24 hours to form trans form.
With regard to the denotation of cis form (or
cin form) and trans form (or anti form) of Compound (I),
Compound (I) wherein the substituent bound to the double
bond is on the same side as oxygen of oxepin, is cis form
(or cin form) and Compound (I) wherein the substituent is
on the opposite side is trans form (or anti form).
Further, if cis form or trans form is denoted
according to E - Z expression, cis form (or cin form) is
Z form and trans form (or anti form) is E form.
For example, the compound represented by the
following formula is cis form (or cin form or Z form)
H (CH~N(CH~
~,CH,COOH
The characteristic NMR signal of the proton H~
in the compound of formula I
Ha~(CH,)2N(C~)2
~CH,COOH
-
- 16 - 1 33 7 603
has been measured. The chemical shift of H, is 5.66 ppm
for the cis form, and 6.00 ppm for the trans form. These
chemical shifts were measured in DMSO-d6.
The retention time in HPLC for the cis and
trans derivatives of the compound of formula I is 9.93
minutes and 7.46 minutes respectively. The conditions
for the HPLC experiment were as follows:
Instrument: SHIMAZU LC-3A
Column : Yamamurakagaku YMC A-312
Elvent : 0.01M PIC B-8
in 61.3% MeOH
* PIC: Pic reagent (produced by Water Ass )
Pressure : 85-95 kg/cm2
Temperature: room temperature
The antiallergic activity and antiinflammatory
activity of Compound (I) are described below:
Test for antiallergic activity:
Antiallergic activity was investigated by a
homologous PCA (passive cutaneous anaphlaxis) of rats for
48 hours, where Wistar male rats having body weights of
180 to 220 g were used for sampling of antiserum and
Wistar male rats having body weights of 120 to 140 g were
used for the PCA test.
A) Preparation of anti EWA rat serum
Anti-egg white albumin (EWA) rat serum was
prepared according to Stotland and Share's method [Canad.
J. Physiol. Pharmacol. 52, 1114 (1974)]. That is, 1 mg
of EWA was mixed with 20 mg of aluminium hydroxide gel
and 0.5 ml of mixed vaccine of pertussis, diphtheria and
- 17 - 1 3 3 7 6 03
tetanus, and the mixture was subcutaneously administered
in four portions into rat's footpad. After 14 days,
blood was sampled from the carotid artery, and the serum
was separated from the sampled blood, and preserved under
freezing at -80C. The potency of the antiserum in the
homologous PCA for 48 hours was 1:32.
B) Homologous PCA test of rats for 48 hours
Groups each consisting of 3 rats were used, and
0.05 ml of anti-EWA rat serum diluted with a
physiological saline solution to 8 times as much was
incutaneously injected each at two positions of depilated
back to make the animals passively sensitised. After 47
hours, the compound of the present invention, or its
solution (physiological saline solution or CMC solution)
was orally administered. One hour thereafter, 0.5 ml/100
g of 1% Evan's blue physiological saline solution
containing 2 mg of the antigen EWA was administered into
the tail vein, and 30 minutes thereafter, the animals
were sacrificed by exsanguination. Then, the skins were
stripped and the amount of leaked pigment at the blue-
dyed parts was measured according to the Xatayama et al
method tMicrobiol. Immunol. 22, 89 (1978)]. That is, the
blue-dyed parts were cut out by scissors, and placed in
test tubes containing 1 ml of lN KOH and incubated at
37C for 24 hours. Then, 9 ml of a mixture of 0.6N
phosphoric acid and acetone (5:13) was added thereto, and
the mixture was shaked and centrifuged at 2,500 rpm for
10 minutes. Absorbancy of the supernatant at 620 ~m was
measured, and the amount of leaked pigment was
- 18 - 1 3 37 6 03
quantitatively determined by the calibration curve
prepared in advance. An average of measurements at the
two position was made a value for one zooid, and
inhibition rate for the individual zooid was calculated
by the following formula:
Inhibition rate (%) =
Average leaked amount Te~ke~ amount of
of solvent-admini- - test compound-
stered group administered group
x 100
Average leaked amount of
solvent-administered group
Cases where, the inhibition rate is So~ or
higher, were regarded as positive PCA inhibition
activity, and the minimum administered dosage, where a
positive case was observed in at least one of three
zooids was regarded as minimum effective dosage (MED).
The results are shown in Table 5.
Acute toxic test:
Groups each consisting of 3 dd, male mice
having body weights of 20 + 1 g were used, and the
compound of the present invention was administered orally
(po: 300 mg/kg) or intraperitoneally (ip: 100 mg/kg).
Mortality 7 days after the administration was observed to
obtain MLD (minimum lethal dosage). The results are
shown in Table 1.
- - 19 - 1 3 37 6 0 3
Table 1
Acute Antiallergic Activity
toxicity Number of positive zooids
Compound (MLD) in one group of 3 zooids M E D
mg/kg Dosage mg/kg mg/kg
po ip 100 10 1 O. 1 O. 01 O. 001
(trans) >300 ~100 2/3 2/3 3/3 3/3 0/3 0/3 0.1
(cisJ >300 ~100 3/3 3/3 3/3 3/3 1/3 0/3 0.01
Antiinflammatory activity test:
Antiinflammatory activity was examined
according to Rat carageenin paw edema [J. Pathol. 104,
15-29 (1971)], Groups each consisting of three Wistar
S male rats weighing 150 g were used. The test compound
was suspended in 0.3% aqueous CMC solution and the
suspension was given orally. Sixty minutes later, 0.1 ml
of 0.1% carageenin was subcutaneously injected in a hind
paw to form carageenin paw edema.
The volume of paw was measured before the
administration and 3 hours after the administration of
carageenin with plethysmometer.
The ratio of the volume 3 hours after the
administration to that before the administration of
1 337603
- 20 -
carageenin was calculated and each ratio is compared with
the ratio of control group (0.3% CMC was administered) to
give the edema inhibiting percentage.
PCA inhibiting activity is believed to be on
the basis of an activity inhibiting liberation of
chemical mediator such as histamine from fat skin cell.
Therefore, Compound (I) and pharmaceutically acceptable
salts thereof are believed to be useful for treating an
allergic disease such as bronchus asthma which is caused
by trachea contractile activity of chemical mediator such
as histamine.
On the other hand, carageenin paw edema
inhibiting activity is believed to be on the basis of
prostaglandin biosynthesis inhibiting activity. Thus,
Compound (I) and pharmaceutically acceptable salts
thereof are believed to be useful for treating an acute
inflammation and rheumatism which are ascribed to
excessive prostaglandin.
Compound (I) has both antiallergic and
antiinflammatory activities described above which is
useful for the treatment of allergic diseases accompanied
by inflammation.
In view of the pharmacological activity of
Compound (I), Compound (I) can be used in various
medicament forms for the administration purposes.
The present medicament composition can be
prepared by uniformly mixing an effective amount of a
free Compound (I) or a pharmaceutically acceptable salt
thereof as the active component with a pharmaceutically
- 21 - 1 337603
acceptable carrier or excipient. The carrier can take a
wide range of forms in accordance with a desirable
medicament form for the administration. These medicament
compositions are desirably in a unit dosage form suitable
for the oral administration or injection administration.
In the preparation of a composition in the oral dosage
form, any useful, pharmaceutically acceptable carrier can
be used. For example, an oral liquid preparation such as
a suspended medicament or syrup medicament can be
prepared using water; sugars such as sucrose, sorbitol,
fructose, etc.; glycols such as polyethylene glycol,
propylene glycol, etc.; oils such as sesame oil, olive
oil, soybean oil, etc.; antiseptics such as alkyl
parahydroxybenzoate, etc.; and flavors such as strawberry
flavor, peppermint, etc. Powder, pills, capsules and
tablets can be prepared using an excipient such as
lactose, glucose, sucrose, mannitol, etc.; a
disintegrator such as starch, sodium alginate, etc.; a
lubricant such as magnesium stearate, talc, etc.; a
bindersuch as polyvinyl alcohol, hydroxypropylcellulose,
gelatin, etc.; a surfactant such as fatty acid esters;
and a plasticizer such as glycerine, etc. Tablets and
capsules are the most useful, oral unit dosage forms
because of easy administration. To prepare tablets and
capsules, solid carriers for medicament are used.
Injection solution can be prepared using a carrier
consisting of a salt solution, a glucose solution or a
mixture of the salt solution and the glucose solution.
The effective dosage of Compound (I) is 1 to 20 mg/kg/day
1 337603
- 22 -
for a human being, and number of administration is 3 to
4 per day.
Examples and Reference Examples are given
below:
Reference example ~
(Raw material 1) Methyl ll-oxo-6,11-dihydrodibenz [b,e]
oxepin-2-carboxylate
In this example, 348.9 g of sodium salt of
methyl p-hydroxybenzoate, 402,4 g of phthalide and 200 g
of sodium chloride are mixed with one another and stirred
at 150C for 6 hours. After completion of the reaction,
the mixture is cooled until the temperature is brought
back to room temperature, 4 ~ of aqueous 10% acetic acid
solution is added thereto and the mixture is allowed to
stand at room temperature overnight. After stirring the
mixture at room temperature for 3 hours, deposited
crystals are separated by filtration, and 6 e of water is
added thereto. After stirring the mixture at room
temperature for 30 minutes, the deposited crystals are
separated by filtration. After the addition of 3 e of
toluene to the crystals, the mixture is stirred at room
temperature for one hour. The crystals are separated by
filtration and dried over heating under reduced pressure
to yield 393.9 g of 2-(4-methoxycarbonylphenoxy) methyl
benzoic acid.
-
- 23 - 1 3 3 7 603
IR (KBr disk):3400, 1700, 1610, 1260, 1235 cm~
The thus obtained 2-(4-methoxycarbonylphenoxy) methyl
benzoic acid (392.7 g) i8 suspended in 5.0 ~ of methylene
chloride and 266.0 g of trifluoroacetic anhydride is
added thereto. After stirring the mixture at room
temperature for one hour, 19.4 g of boron trifluoride-
ethylether complex is added thereto and the mixture is
stirred at room temperature for two hours. The reaction
solution is poured into ice water. After an organic
solvent layer is separated from the mixture, the organic
layer is washed with diluted aqueous sodium hydroxyde
solution and water, dried over anhydrous magnesium
sulfate and concentrated under reduced pressure to obtain
335.3 g of methyl 11-oxodibenz[b,e]oxepin-2-carboxylate
as a white crystal. Melting point and elemental analysis
are shown in Table 2.
IR(KBr disk): 1710, 1650, 1610, 1250, 1010 cm1
NMR (CDC13, ~, ppm): 3.84 (s, 3H), 5.14 (s, 2H),
6.87-8.93 (m, 7H)
- 24 - 1 3 3 7 6 03
Reference ex~mpl~ 2
(Raw material 2) 11-Oxo-6,11-dihydrodibenz[b,e~ oxepin -
2- acetic acid
Raw-materials 2 is produced by substituting p-
hydroxyphenyl acetic acid, for methyl p-hydroxybenzoate
in Reference example 1.
Melting point and elemental analysis thereof is
shown in Table 2.
Table 2
Raw Melting point Elemental analysis t%)
material (C)
1 128 -129 as C16H1204
C H
(Isopropyl Calculated 71.63 4.51
ether) Found 71.55 4.48
2 130 -132 as C16H1204
C H
(Ethyl Calculated 71.63 4.51
acetate) Found 71.86 4.55
-
` - 25 - l 33 7 6 03
R~ference Ex~mpl~ 3
(Reagent 1) (3-Dimethylaminopropyl) -triphenylphos-
phonium bromide hydrobromide
In this Example, 350.0 g of triphenylphosphine
and 270.0 g of dibromopropane are suspended in 700 ml of
toluene and the suspension is heated at reflux for 25
hours. After allowing the suspension to stand for
cooling, the formed product is separated by filtration
and washed with 2 e of toluene to obtain 550.0 g of (3-
bromopropyl)-triphenylphosphonium bromide hydrobromide
having m.p. 233-234C.
Then, 100.0 g of (3-bromopropyl) -triphenyl-
phosphonium bromide hydrobromide is suspended in 500 ml
of ethanol and 300 ml of 50 % aqueous dimethylamine
solution is added thereto. After heating the mixture at
reflux for 10 minutes, the mixture is allowed to stand
for cooling. The solvent is distilled away under
reduced pressure and the resultant crude product is
recrystallized from ethanol to obtain 64.0 g of the
desired product having the physicochemical properties as
identified in Table 3.
- 26 -
1 3376~13
Table 3
Reagent Melting point Elemental analysis (%)
(C)
287 - 289 as C23H28NPBr2
(Ethanol) C H N
C~ ted 54.24 5.54 2.75
Found 54.12 5.63 2.93
Example 1
1 1-(3-Dimethylaminopropylidene)-2-(2-triphenylmethyloxymethyl)
-6,11-dihydrodibenz[b,e] oxepin
(Compound 3)
Process A:
11-Hydroxy-2-(2-hydl o~ethyl)-6,11-dihydrodibenz [b,e] oxepin
In this process, 20 g of methyl 11-oxo-6,11-dihydrodibenz [b,e] oxepin-2-acet~te is
dissolved in 500 ml of tetrahydrofuran. To the solution is added 6.0 g of lithium ~lumini~
hydroxide and the mixture is stirred at room temperature for one hour. After decomposing an
excess of the reagent by the addition of water to the solution, the mLxture is filtered to remove
inorganic salts and the filtrate is concentrated to dryness under reduced pres~u-e to obtain 17.7 g
of the desired product as a white solid.
- 27 - 1 33 76 03
Nelting point: 132 - 136C
NMR (CDCl3 + DMS0-d6 + D20, ~, ppm): 2-59 (t,
2H, J=6.8Hz), 3.55(t, 2H, J=6.8Hz), 4.89
and 5.71(ABq, 2H, J=12.6Hz), 5.60(s, lH),
6.46-7.49(m, 7H)
Process B:
ll-Hydroxy-2-(2-triphenylmethyloxyethyl)-6, 11-
dihydrodibenztb,e] oxepin
In this process, 17.2 g of 11-hydroxy-2-(2-
hydroxyethyl)-6,11-dihydrodibenz[b,e] oxepin is dissolved
in 50 ml of pyridine. To the solution is added 30 g of
triphenylchloromethane and the mixture is stirred at 50C
15 for 5 hours. After adding water and stirring the mixture
for 2 hours, the solvent is distilled away under reduced
pressure. The mixture is extracted with 1000 ml of ethyl
acetate, washed with saturated aqueous sodium chloride
solution, and dried over anhydrous sodium sulfate. The
20 solvent is distilled away under reduced pressure and the
resultant residue is purified by column chromatography on
silica gel (eluent: hexane: ethyl acetate = 3:1) to
obtain 21.7 g of the desired product as a colorless
amorphous.
NMR (CDCl3 + D20, ~, ppm): 2.47-2.95(m, 2H), 2.96-
3.45(m, 2H), 4.87 and 5.71(ABq, 2H, J=13.2Hz),
5.43 (s, lH), 6.33-7.51(m, 22H)
- 28 - 1 33 7603
Process C:
ll-Oxo-2-(2-triphenylmethyloxyethyl)-6,11-
dihydrodibenz[b,e] oxepin
In this process, 10 g of 11-hydroxy-2-(2-tri-
phenylmethyloxyethyl)-6lll-dihydrodibenz[b~e] oxepin is
dissolved in a solution comprising 800 ml of acetone,
1000 ml of water, 20 ml of saturated aqueous magnesium
sulfate solution and 0.2 g of disodium phosphate. To the
solution is dropwise added 2.6 g of aqueous sodium
permanganate solution and the mixture is stirred at room
temperature for 4.5 hours. Then, 100 ml of methanol is
added thereto and the mixture is heated at reflux for 3
hours. After allowing the mixture to stand for cooling,
the mixture is filtered and the filtrate is extracted
with 1000 ml of ethyl acetate, washed with saturated
aqueous sodium chloride solution and dried over anhydrous
sodium sulfate. The solvent is distilled away under
reduced pressure and the resultant crude product is
recrystallized from isopropanol to obtain 8.0 g of the
desired product having melting point of 132 - 134C as a
white crystal.
Elemental analysis (%): as C3sH28O3
Calculated: C 84.65 H 5.68
Found: C 84.56 H 5.67
N~ (CDCl3, ~, ppm): 2.61-3.04(m, 2H), 3.05-3.46
(m, 2H), 5.01(s, 2H), 6.63-8.07(m, 22H)
- 29 - l 33 76 03
Process D:
11-(3-Dimethylaminopropyl)-ll-hydroxy-2-(2-
tripenylmethyloxyethyl)-6,11-dihydrodibenz[b,e] oxepin
To a solution of 3-dimethylaminopropyl
magnesium chloride obtained by reacting 0.2 g of
magnesium with 1.0 g of 3-dimethylaminopropyl chloride in
10 ml of tetrahydrofuran under a nitrogen atmosphere
using dibromoethane as a catalyst, is dropwise added a
solution obtained by dissolving 2.0 g of 11-oxo-2-(2-
triphenylmethyloxyethyl)-6,11-dihydrodibenz[b,e] oxepin
in 10 ml of tetrahydrofuran under ice cooling and the
mixture is stirred at room temperature for one day.
Aqueous ammonium chloride solution is added thereto and
the pH of the mixture is adjusted to 7.0 with aqueous 4N-
hydrochloric acid solution. The solvent is distilledaway under reduced pressure. The mixture is extracted
with 200 ml of methylene chloride and washed with
saturated aqueous sodium bicarbonate solution and
saturated aqueous sodium chloride solution in order.
After drying the extract over anhydrous sodium sulfate,
the solvent is distilled away under reduced pressure. The
resultant residue is purified by column chromatography on
silica gel (eluent: hexane: ethyl acetate: triethylamine
= 10 : 10 : 1) to obtain 1.2 g of the desired product as
a colorless amorphous.
NMR (CDCl3, ~, ppm): 0.85-1.83(m, 4H), 2.08(s, 6H),
2.67-3.44(m, 6H), 4.94 and 5.36(ABq, 2H, J=
15.8Hz), 6.63-8.13(m, 22H)
Mass spectrum (m/z): 583 (M~)
_ 30 _ 1 3 3 ~ 6 03
Process E:
11-(3-Dimethylaminopropylidene)-2-(2-triphenyl-
methyloxyethyl)-6,11-dihydrodibenz[b,e] oxepin
In this process, 1.2 g of 11-(3-dimethylamino-
S propyl)-ll-hydroxy-2-(2-triphenylmethyloxyethyl)-6,11-
dihydrodibenz~b,e] oxepin is dissolved in 50 ml of
pyridine. To the solution is dropwise added 0.8 g of
phosphorusoxychloride under a nitrogen atmosphere and
ice-cooling.
After stirring the mixture at room temperature
for one hour, the solvent is distilled away under reduced
pressure. The residue is extracted with 100 ml of
methylene chloride, and washed with saturated aqueous
sodium bicarbonate solution and saturated aqueous sodium
chloride solution in order. After drying the mixture
over anhydrous sodium sulfate, the solvent is distilled
away under reduced pressure. The resultant residue is
purified by column chromatography on silica gel (eluent:
hexane: ethylacetate: triethylamine = 10 : 10 : 1) to
obtain 0.82 g of the desired product as a colorless oily
matter.
NMR (CDCl3, ~, ppm): 2.16(s, 6H), 2.30-2.40(m, 4H),
2.79(t, 2H, J=6Hz), 3.24(t, 2H, J=6Hz), 5.97
(t, lH, J=7Hz), 6.60-7.40(m, 22H), (trans form)
Mass spectrum (m/z): 565 (M)
- 31 - 1 3 3 76 03
~xampl~ 2
11-(3-Dimethylaminopropylidene)-2-(2-hydroxy-
ethyl)-6,11-dihydrodibenztb,e] oxepin (Compound 2)
In this example, 0.92 g of 11-(3-dimethylamino-
propylidene)-2-(2-triphenylmethyloxyethyl)-6,11-dihydro-
dibenz[b,e] oxepin is dissolved in a mixed solvent of 20
ml of water and 20 ml of dioxane. To the solution is
added 60 mg of p-toluene sulfonic acid and the mixture is
heated at reflux for two hours. The solvent is distilled
away under reduced pressure and the residue is extracted
with 200 ml of ethylacetate, washed with saturated
aqueous sodium bicarbonate solution and saturated aqueous
sodium hydrochloride solution in order and dried over
anhydrous sodium sulfate. The solvent is distilled away
under reduced pressure. The resultant residue is
purified by column chromatography on silica gel (eluent:
ethylacetate: triethylamine = 10: 1) to obtain 0.4 g of
the desired product.
Cis form white solid,
Meltin~ point: 100 -102C (diethylether)
NMR (CDC13, ~, ppm): 2.32(s, 6H), 2.30-2.70(m, 4H),
2.76(t, 2H, J=6Hz), 3.78(t, 2H, J=6Hz), 5.66(t,
lH, J=7Hz), 6.30-7.40(m, 7H)
Mass spectrum: 323 (M )
- 32 -
1 337603
Trans form white solid,
Meltingpoint: 96 - 97C (diethylether)
NMR (CDC13, ~, PPM): 2.21(s, 6H), 2.30-2.70(m, 4H), 2.76(t, 2H, J=6Hz),
3.78(t, 2H, J=6Hz), 6.01(t, lH, J=7Hz), 6.68-7.40(m, 7H)
Mass spectrum (m/z): 323 (M+)
Example 3
11-(3-Dimethylaminopropylidene)-6,11-dihydrodibenz[b,e] oxepin-2-acetic acid
(Compound 1)
In this FY~mple, 2.2 g of 11-(3-dimethylaminopropylidene)-2-(2-l-yd~ yethyl)-6,
11-dihydrodibenz[b,e] oxepin is dissolved in 100 ml of acetone. The Jones reagent is added to the
solution until the reaction solution shows an orange color and the mixture is stirred at room
temperature for one hour. Sodium bicarbonate is added thereto and an inorganic subst~nce is
removed by filtration. The solvent of the filtrate is distilled away under reduced ple;,;,u.e to obtain
the desired product. The physiocochemical properties of the product coincide with those of the
product obtained in Example 6.
Example 4
Methyl 11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e] oxepin-2-
carboxylate (Compound 6)
In this Example, 45 g of (3-dimethylaminopropyl)-triphenylphosphonium bromide
hyd~oblolllide is suspended in 200 ml of tetrahydrofuran under a nitrogen atmosphere and 82 ml
of 1.6N-n-butyl lithium hexane
1 337603
- 33 -
solution is added thereto under ice-cooling. The mixture
is stirred under ice-cooling for one hour. To the
mixture is dropwise added under ice-cooling a solution
obtained by dissolving 10 g of methyl 11-oxo-6,11-
dihydrodibenz~b,e]oxepin-2-carboxylate in 200 ml of
tetrahydrofuran. After stirring the mixture at room
temperature for 2 hours, the mixture is extracted with
800 ml of ethyl acetate. After washing the extract with
saturated aqueous sodium chloride solution and drying the
extract over anhydrous magnesium sulfate, the solvent is
distilled away under reduced pressure. The residue is
purified by column chromatography on silica gel (eluent:
hexane:ethyl acetate:triethylamine = 10:10:1) to obtain
2.0 g of trans form and 5.6 g of cis form of the desired
product.
Cis form
NMR (CDCl3, ~, ppm): 2.23 (s, 6H), 2.17-2.81
(m, 4H), 5.28 (bs, 2H), 5.61 (t,lH), 6.80-8.10 (m, 7H).
trans form
NMR (CDC13, ~, ppm): 2.15 (s, 6H), 2.17-2.81
(m, 4H), 5.00-5.50 (broad, 2H), 6.06 (t, lH), 6.70-8.10
(m, 7H).
Example 5
Methyl ll-(3-dimethylaminopropylidene)-6,11-
dihydrodibenz[b,e] oxepin-2-acetate (Compound 4)
In this Example, 48 g of (3-dimethylamino-
propyl)-triphenylphosphonium bromide hydrobromide is
- 34 - 1 33 76 03
suspended in 200 ml of tetrahydrofuran under a nitrogen
atmosphere and 80 ml of 1.6N-n-butyl lithium hexane
solution is added thereto under ice-cooling. The mixture
is stirred under ice-cooling for one hour. A solution
obtained by dissolving 5.0 g of 11-oxo-6,11-
dihydrodibenz[b,e] oxepin-2-acetic acid in 120 ml of
tetrahydrofuran is dropwise added under ice-cooling.
After stirring the mixture at room temperature for two
hours, the solvent is distilled away under reduced
pressure. Then, 200 ml of water is added to the residue
and the mixture is washed with 200 ml of diethyl ether.
The pH of the mixture is adjusted to 1 with aqueous 4N-
hydrochloric acid solution and the mixture is washed with
diethyl ether.
Then, aqueous lON-sodium hydroxide solution is
added thereto to adjust the pH of the mixture to 7 and
the solvent is distilled away under reduced pressure.
The resultant residue is dissolved in 400 ml of methanol
and 5 g of p-toluene sulfonic acid is added thereto.
After heating the mixture at reflux for two hours, the
solvent is distilled away under reduced pressure. The
residue is extracted with 300 ml of ethyl acetate, washed
with saturated aqueous sodium bicarbonate solution and
saturated aqueous sodium chloride solution in order and
dried over anhydrous sodium sulfate.
The solvent is distilled away under reduced
pressure and the resultant residue is purified by column
1 337603
chromatography on silica gel (eluent: hexane : ethyl
acetate: triethylamine = 10 : 10 :1) to obtain 4.0 g of
the desired product as a colorless oily matter.
Cis form
NMR (CDCl3, ~, ppm): 2.06-2.67(m, 4H), 2.16(s, 6H),
3.46(s, 2H), 3.58(s, 3H), 5.08(bs, 2H), 5.69
(t, lH, J=7Hz), 6.53-7.30(m, 7H)
Trans form
NMR (CDCl3, ~, ppm): 2.06-2.67(m, 4H), 2.16(s, 6H),
3.46(s, 2H), 3.58(s, 3H), 5.08(bs, 2H), 6.06
(t, lH, J=7Hz), 6.53-7.30(m, 7H)
Example 6
11-(3-Dimethylaminopropylidene)-6,11-
dihydrodibenz[b,e] oxepin-2-carboxylic acid (Compound 5)
In this Example, 26.1 g of methyl 11-(3-
dimethylaminopropylidene)-6,11-dihydrodibenz[b,e] oxepin-
2-carboxylate is dissolved in a mixed solvent of 500 ml
of methanol and 30 ml of water and 6.2 g of sodium
hydroxide is added thereto. The mixture is heated at
reflux for two hours. After allowing the mixture to
stand for cooling, aqueous 4N-hydrochloric acid solution
is added thereto to adjust the pH to 7 and the mixture is
concentrated under reduced pressure. The concentrate is
purified by column chromatography on high porous polymer
(HP-20) eluent: water: methanol = 1 : 2) to obtain 25.0
g of the desired product.
- 36 - 1 3 3 7 6 03
Cis form white crystal
Melting point: 162 - 164C
NMR (DMSO-d6, ~, ppm): 2.28(s, 6H), 2.40-2.70(m, 4H),
5.20-5.40(broad, 2H), 5.72(t, lH, J=7.0Hz),
6.85-7.90(m, 7H)
IR (KBr disk, cm1): 3400, 1610, 1370, 1220, 1005
Elemental analysis (%): as C2oH21O3N l/3 H2O
C H N
Found: 73.00 6.67 4.14
Calculated: 72.93 6.63 4.25
Trans form white crystal
Melting point: 242 - 244C
NMR (DMSO-d6, ~, ppm): 2.25(s, 6H), 2.40-2.70(m, 4H),
5.20-5.40(broad, 2 H), 6.09(t, lH, J=7.0Hz),
6.78-7.90(m, 7H)
IR (KBr disk, cm1): 3400, 1610, 1380, 1222, 1010
Elemental analysis (%):
C H N
Found: 74.30 6.60 4.30
Calculated: 74.28 6.55 4.30
Exampl~ 7
11-(3-Dimethylaminopropylidene)-6,11-dihydro-
dibenztb,e] oxepin-2-acetic acid (Compound 1)
The product is obtained by hydrolysis as in the
same manner as in Example 6.
1 337603
Cis form white crystal
Melting point: 118 - 120C (Isopropanol)
NMR (DMSO-d6, ~, ppm): 2.16(s, 6H), 2.30-2.60(m, 4H),
4.04(s, 2H), 5.15(bs, 2H), 5.69(t, lH, J=7Hz),
6.73-7.40(m, 7H)
IR (KBr disk, cm 1): 3400, 1580, 1225, 1005
Mass spectrum (m/z): 337 (M~)
Elemental analysis (%): as C21H23O3N monohydrate
C H N
Found: 70.77 7.36 3.74
Calculated: 70.96 7.09 3.94
Trans form white crystal
Melting point: 158 - 160C (Acetonitrile)
NMR (DMSO-d6, ~, ppm): 2.05(s, 6H), 2.30-2.60(m, 4H),
4.04(s, 2H), 5.15(bs, 2H), 6.06(t, lH, J=7Hz),
6.73-7.40(m, 7H)
IR (neat, cm~1): 3380, 1575, 1220, 1005
Mass spectrum (m/z): 337 (M~)
Elemental analysis (%): as C21H23O3N monohydrate
C H N
Found: 71.06 6.66 3.92
Calculated: 70.96 7.09 3.94
