Note: Descriptions are shown in the official language in which they were submitted.
~ 600-6638
.,
,
~ 1064488
.;
~5-AMINO DERIVATIVES OF ?-PHENYL-1,4-DIAZEPINES
. }
This lnvention relates to 5-amino-7-phenyl-2,3-
dlhydro-lH-1,4-diazepine and its derivatives.
1~
The invention provides compounds of formula I,
, ~,
n- ~ 3
~ R5
~-.. i: NRlR2
;.,:1 ~ :
in which either Rl ls hydrogen, an alkyl qroup con- :
talnlng 1 to 6 carbon atoms, or
~ .
; an amino group,
: and R2 18 hydrogen or an alkyl group
~, ::
containing 1 to 6 carbon atoms,
provided that (1) Rl and R2 are not
both tertlary alkyl groups, and (2)
. when Rl is an amlno group,R2 is
hydrogen,
or Rl and R2 taken together are
.. ' ' , ' . ' ' ' .. ~ . . , . , '. ; ; , ' . . - ! , ' ' : . , . ' ,
--' ~064488
- 2 - 600-6638
,' ` ' .
/C~12-CH2 ~CH2-CH2 ~
\ CH -CH ~ CH2-CH /
/CH -CH
, ~ ~ CH2CH20~
: CH2 CH2 , ~ .
and R3, R4 and R5 are independently ;
hydrogen, an alkyl group con-
taining 1 to 4 carbon atoms, an
; alkoxy group containing 1 to 4
carbon atoms, fluorine, chlorine
or bromlne, or any two of R3,
R4 and R5 attached to adjacent
carbon atoms together are a
methylenedloxy group.
~-; 10 The compounds of formula I may exist in free base
and ln acid addltion salt form.
The lnvention also provldes processes for the prep-
aration of compounds of formula I, characterised by
(a) reactlng a compound of formula II,
4 II
.~, .; .
R' ::
lS in which R' is a primary or secondary alkyl group
contalning 1 to 4 carbon atoms, prefer-
~:r,` ' ably methyl or ethyl,
.:..~.
::- !
1064488
:' ~
. - 3 - 600-6638
-
and R3, R4 and R5 are as defined above,
: with an amine of formula III,
' ~:
NHRlR2 III
in which Rl and R2 are as defined above;
(b) producing a compound of formula Ia,
~ ~4 Ia
-~ ~ NHRi
.,
. 5 in which Ri is an alkyl group containing l to 6 car-
bon atoms, and
. R3, R4 and R5 are as deflned above,
by cyclislng a compound of formula IV,
, R
~-CH2~CH2-NH-C=CH_C ~ 3R4 IV
NHRi ~
in whlch Ri, R3, R4 and R5 are as defined above,
under strong acid conditions, ln an lnert organic iolvent
~ and under an lnert atmo~phere;
:, ~ (c) produclng a compound of formula Ib, :
~ ~ 4 Ib
': ::
. NH2 :
in which R3, R4 and R5 are as defined above, ~
. ~; :
3 `~
::
.. ~, `. .` ` :, . . , ... . . . . . ` . - .. ,; . . . ` . . .`. . -` .. - . . .... . . ` `
; ::
:1064488
- 4 - 600-6638
- .
by heating a compound of formula Ia, stated above, in
which Ri is a t-butyl group, in the presence of free
acid, or
; (d) producing a compound of formula Ic,
- ~1 s IC
'.;~ NHNH2
in which R3, R4 and R5 are as defined above, by
reacting a compound of formula Ia or Ib, stated above,
, . .
~, wlth hydrazine under an lnert atmosphere.
; ~ The reaction of process ta) may be carried out ln
the presence of an inert solvent, in which case from 1.05
to 10 moles of the compound III per mole of the compound
" ~ .
II are conveniently employed. Preferably, however, a
large molar excess of the amine of formula III, for
`- ~ example from 2 to 1000 moles per mole of the compound II,
is used as the solvent. When ammonia or a volatile
lS amlne having a boillng point lower than 60C is used, the
reaction is preferably carried out in a sealed reaction
vessel. A suitable reaction temperature is 20C to 115C,
preferably 60 to 115C. When the compound oP formula III
,,ir i ~
boils in the latter range, a convenient reaction temper-
ature is the reflux temperature of the mixture, and, in
,. ~ .
. . .
... ... ~ .. .. ,.. .. .. . . . ~ . . .. . . . . . . . .. .
... . , .. . ~ , -, . .. .. . . .. . . ~ . . . . ..
: ,~ : . . . . .
: . .- . ~ '~ .
-~ 1064488
. _~
- 5 - 600-6638
this case, the reaction is preferably effected under an
lnert, e.g. nltrogen, atmosphere. A suitable reaction
time ls from 5 minutes to 3 hours, preferably 10 minutes
to 2 hours.
. :;
..
In process b), suitable solvents include lower
alkanols, e.g. ethanol, n-propanol, isopropanol, n-butanol,
sec-butanol and isobutanol, preferably ethanol, n-propanol
~i or isopropanol, halogenated lower alkanes, e.g. 1,1,2-
`, trlchloroethane or 1,2-dichloroethane, cyclic ethers, e.g.
;. 10 ~-dioxane, acyclic ethers, preferably of 5 to 10 carbon
,.. .
atoms, and formlc acid amides, e.g. formamide and mono-
or di-lower alkyl derivatlves ethereof, e.g. N-ethylform-
amlde, N,N-dlmethyl- or di-ethylformamide or N-ethyl-N-
methylformamide. The preferred solvents are lower
,. ~ .
alkanols. Suitable aclds for use in process b) Lnclude
strong mlneral aclds, e.g. perchloric, hydrobromlc,
hydrochlorlc or sulphuric acid and strong organic acid~ `
. i ,
such as methanesulphonic, ethanesulphonlc, benzenesulphonic
~;~ or ~-toluenesulphonic acld. The acid may sultably be
20 employed as a concentrated aqueous solution, as a sol-
ution in an organic solvent, e.g. a lower alkanol, such ~ -
;~ as ethanol, n-propanol or isopropanol, or ln undlluted
form. For example, perchlorlc acid is suitably employed
.,
as a 70% aqueous solution, hydrochlorlc and hydrobromic
25 acids as saturated solutions of gaseous HCl or HBr in a
. . .
:, ~ ~;,
~ ,........ :
;':` .:
J` 1064488
. . ` -~
- 6 - 600-6638
-, .
lower alkanol, sulphuric acld as a concentrated solution,
- and sulphonlc aclds suitably as solids. Sufficlent acid
-~ii ls preferably employed to brlng the pH of the medium to
~ 0.1 to 6, preferably 1 to 4, in particular 2 to 3.
-~ 5 q'he lnert atmosphere ls sultably nitrogen gas.
r1J The reactlon ls sultably carried out at a temper-
ature of from 45-120C, preferably 55-100C. 1'he reac-
tion tlme ls suitably 30-180 minutes, preferably 60-120
mlnutes.
~': ' ''
i 10 In process (c), the compound of formula Ia in
;~ which R' ls a t-butyl group is conveniently heated above
~ its meltlng polnt ln the presence of free acld untll gas
,3 bubbles cease to be evolved. The use of acld addition
salt Porms, the anlons of whlch are llable to decompose
~ 15 at elevated temperatures, should be avolded. Preferably
`~ the compound Is ln the form of the methane-sulphonate acld
., ~ .
~ additlon salt. The acid addltlon salt form may be used
.,.. ,~ ,
as such or generated in situ from the free base form by
the addltlon of at least sllghtly more than one equlvalent,
....:
e.g. 1.01 to 5 equlvalents, of an acid.
~!~
Sultable reaction temperatures are from 150 to
~ 210C, and suitable reactlon tlmes are from 5 to 45 min-
.. 4~ utes. The reaction ls preferably run neat, although
high-boillng, inert organlc solvent may be employed, if
~'.",: .
.. ~ . . .
.~,..
.
- ~ '~ ~ r-- -: .
~ ~ ' "' ' ' " :
.
`"~ 1064488 ;
- 7 - 600-663
deslred. ~ -~
In process (d), the hydrazine used ls preferably
anhydrous and ls preferably us~d in excess, for example
a lO-1000 fold excess, as the reaction solvent. Suitable
reactlon temperatures are from 80C to the reflux temp-
erature of hydrazlne, the latter temperature being pref-
erred. The reactlon may, lf desired, also be carried out
.~ .
in the presence of an lnert organlc solvellt having a boil-
lng point above 80C, and, ln that event, l to 2 moles of
hydrazine per mole of compound Ia or Ib may suitably be
- used. Sultable reactlon tlmes are from 20-180 minutes,
preferably 30 to 60 minutes. The reactlon ls carried
out under an inert atmosphere, for example nitrogen.
~''~ ..
~ The r~sulting compounds of formula I may be isol-
1 15 ated and purlfied using conventlonal techniques. Where
.
requlred, free base forms of the compounds may be con-
verted lnto acid addltlon salt forms ln conventional
. i :
manner, and vice versa.
The compounds of formula II may be prepared by
, ~ -
reactlng a compound of formula V,
.:
.. .~::
~)~ V
N 5
~;. O
. ."
i ~ in whlch R3, R4 and R5 are as deflned above, -
~ ~ 7
`~ .
:`l
~ 1064488
- 8 - 600-6638
wlth a trialkyloxonlum tetrafluoroborate in an inert
organlc solvent. Preferred tetrafluoroborates are
trimethyloxonium and triethyloxonlum tetrafluoroborate.
Suitable lnert organic solvents include halogenated
lcwer alk~nes, preferably methylene dichloride. The
reaction may be carried out at a temperature of from 0
- to 30C, preferably at 20 to 25C, and suitably for a
period of from 25 to 120 mlnutes. Preferably the
reaction is carried out under an inert atmosphere, for
. .
example nitrogen. The compounds of for~ula II may be
isolated and purified by conventional techniques.
~, .
The compounds of formula IV may be prepared by
reacting a compound of formula VI,
Z~ ~ -RlA 3 VI
l where Ri, R3, R4 and R5 are as defined above,
; 15 and A~ is an anion which does not interfere
with the course of the reaction,
with ethylene diamine in an inert organic solvent.
Sultable anlons A~ include perchlorate, tetra-
~; fluorobrate, methylsulphate, ethylsulphate, bisulphate,
chlorlde, bromlde and iodide. Suitable lnert organic
solvents lnclude ha~ogenated alkanes, for example
. , '
_ _
:::; ` 8
, .
. ,~.. .... . . . . ..
. . . . . . ;; ~ . ~. .
: . .. . . -~ - .
... . . . .
, . . . - . .
-~ 1064488
- 9 - 600-6638
methylene dichloride; ethers, for example ~-dioxanei
- lower alkyl n~triles, for example acetonitrile and
substituted amides for example N,N-dimethylformamiae.
- Methylene dichloride is preferred. ~referably, the molar
ratio of e~hylene diamine to the compound of for~ula VI
ls at least 1.5:1, but, more preferably, a large molar
excess, for example from 2 to 10 moles of ethylene
diamine per mole of compound of formula VI, is used.
; The reaction is suitably carried out at a
,
temperature from -10 to 40C, preferably 10 to 35C,
and for a time from 20 to 120 minutes, preferably 30-90
minutes. Preferably the reaction 1s carrled out under
an inert atmosphere, for example nitrogen.
When required, the compounds of formula IV
; 15 may be isolated and purified by conventional techniques.
Alternatively, the compounds of formula IV may be used
directly, without isolation, in process (b).
The compounds of formulae V and VI are known or
may be prepared in conventional manner from available
; 20 materials.
The compounds of formula I possess pharmaco-
- logical activity. In partleular, they are indlcated
for use as antl-obesity and antl-dlabetic agents as
''' ' '
,
` ! '
. .
--- ~064488
-~ - 10 - 600-6638
.
indicated by (a) their abillty to inhibit intestinal
glucose transport in male Wlstar rats given orally
10-80 mg/kg body weight of the test compound after at
least 20 hours of fasting. One hour after receiving
the drug each animal is sacrificed and the upper small
intestine ls removed and washed with glucose-saline.
A 5 cm sectlon of the intestine is everted so that the
mucosal surface is on the outside. One end of the seg- -
ment is tied and the centre of the sac so formed is
filled with oxygen saturated Kreb's bicarbonate buffer.
, ; .
~he other end is then closed and the sac is incubated
in 10 ml of oxygen saturated bicarbonate buffer for
.jl . .
`60 mi~utes at 37C. Both the outside and inside sol-
ii'utions contaln lnltlally 0.3% of glucose. At the end
'~15 of the lncubatlon tlme, the glucose content of the outer i-
;(mucosal) and the inner (serosal) solution is determined,
,i
and compared wlth results for control animals; (b) their
hypoglycemlc effect in 6-8 week old male ICR mice havlng
a body weight of 30-35 g dosed orally with 75-200 mg/kg
body weight of the test compound after 16 hours of fast-
ing. A control group receivlng 0.5% carboxymethyl cell-
ulose vehicle is run concurrently. Two hours later the
`mice are anesthetized with sodium hexobarbital (85 mg/kg
i.p.) and blood is collected via cardiac puncture. ~he
blood is placed ln an Auto Analyzer cup contalning 0.025
'`" 10 ,
:,., '
. . ' . ' ' . ~' . ' '
' i'. ' . '
. .
~ -- ~ 1064488
~ 600-6638
ml of heparin preparatlon containing 1000 units/ml and
the samples are capped, shaken and kept in ice. The ~ -
glucose content of each sample is measured by the stand-
ard Auto Analyzer potasslum ferric cyanide method (N-2b). ~;
- 5 Results are compared with those obtained using a known
hypoglycemic standard; c) their anti-hyperglycemic
effect ln mice, tested according to procedure (b) with
the followi~g modification: llt2 hours after the mice
are dosed wlth the test compound or the carboxymethyl
cellulose vehicle, the mice recelve a glucose challenge
of 2 g/kg body weight p.o. tsee Laboratory Animal ~lgest
7 (4), 76 ~1972)] with the sodium hexobarbital anesthet-
isatlon (85 mg/kg l.p.) occurring 25 minutes later. The
blood i8 collected exactly 30 mlnutes after adminlstra-
tion of the glucose challenge. A known antl-hyperglycemlc `~
standard i8 lncluded each tlme the test is run for com-
parison.
An lndlcated sultably dally dosage ls from 75 to
2000 mg, preferably administered ln dlvlded dosages of
.. .. .
`~ 20 from about 20 to 1000 mg, 2 to-4 times a day, or in
~-; retard form.
. .
; . .
The compounds may be used in free base form or
in the form of pharmaceutically acceptable acld addltion
salts, whlch salt forms have the same order of activity
, . .
,, ~ . . . . ,. . : ,.
- 1064488
~ 12 - 600-6638 ;~ ~
- . :'
`
as the free base forms. Suitable acid addition salts
; include perchlorates, hydrochlorides, methanesulphonates
and tetrafluoroborates.
The compounds of formula I may be admixed with
s conventional pharmaceutlcally acceptable diluents or
carrlers and, optlonally, other excipients, and ad~ini-
:~;
stered ln such forms as tablets or capsules.
Preferred significances of the groups Rl-R5
are as follows:-
; ~ 10 Rl hydrogen; or alkyl, in particular t-butyl;
R2 hydrogen;
R3 hydrogen, ~-methyl, ~-methoxy, ~-ethyl or
~-ethoxy; ln particular hydrogen, ~-methyl
or ~-methoxy; ;
~; 15 R4 hydro~en or _-methyl;
R5 hydrogen.
A preferred group of compounds of formula I are
.~ .,; .
those ln whlch all the groups Rl to R5 have the preferred
slgnlficances lndicated above. A particularly preferred
compound of formula I ls 5-amino-7-phenyl-2,3-dihydro-
lH-1,4-diazepine, partlcularly ln the methanesulphonate
; salt form.
The compounds of formula I may also exist in
the form of their tautomeric equlvalents, such as those
of formula I', and, where R2 ls hydrogen, formula I'',
~.~: ~ 12
:~, . . .
".'' . ' ' '.' ' ' ' , ~, ~ .`' '' '' '' . ' ' ' '
' '.;'` ' ' , ~' ' ' ' `' ., , ' ' . ' . , . '
'" ' ~ ' ' ,' " ~ : ', . '
'' , : ,
1064488
- 13 - 600-6638
[~4 NH~R4
- I I I "
The possible tautomeric forms interconvert in
the presence of acid. While reference is made herein
solely to the form of formula I, or the corresponding
chemical name, lt is to be understood that the invention
is not lntended to be limlted to any particular tautom-
erlc form of the compounds.
~ The followlng Examples lllustrate the lnvention.
; '
.:
.", ~"''.
... .
:
, :.
: : '
~, . : ,.
' . ' :
,
~ .
. .,- ,
. ', .
13
.~ .
.
- . . : . . , . . , , :. . ... - .. .. ... .
1064488
.~
- 14 - 600-6638
EXAMPLE 1: [process (a)l
A. 5-Ethoxv-7-phenyl-2,3-dihYdro-lH-1,4-
diazepine
10.0 g (S3.0 mmol) of 7-phenyl-1,2,3,4-tetrahydro-
.. .. .
1,4-dlazepine-S-one was suspended ln 100 ml of dry methyl-
~ ene chlor~de under nitrogen and stirred. 10.1 g (53.0
.~ mmol) of triethyloxonium tetrafluoroborate was added to
- the stirred suspension over a 20 minute period to maintain
the reaction mixture at a temperature of 20-25C, the
reaction ~eing slightly exothermlc. After the addition
;,~, .
was completed, the reaction mixture was stirred for an
:'. . .
1~ additional 30 minutes at room temperature. The sclvent
was evaporated to obtain 16.6 g of olly crystals. The
..... .. .
sollds were triturated wlth ethyl acetate and recrystal- -
15 lised from chloroform to glve the headlng compound, in ~s~r
tetrafluoroborate salt form, m.p. 157.5-158.5C.
B. 5-Methylamlno-7-phenvl-2,3-dihydro-lH-
1,4-dlazepine (VII)
3.20 g of S-ethoxy-7-phenyl-2,3-dihydro-lH-1,4-
s'~ 20 diazepine tetrafluoroborate ana 15-20 ml of methylamine
~; were placed in a reactlon bomb and allowed to stand for
/2 hours. ~o complete the reaction, the reaction mix-
ture was heated at 40-50C for 11/4 hours. The excess
methylamine was allowed to evaporate, the resulting oil
.... , ~
`~ 14
.. ; ................................... . .
~, .
~;.~:`.
: ~ . ,- ~ ,
,, ~- . , ~. . .
i
`~ ~06448B
; ` - 15 - 600-6638
:
was dlssolved in chloroform, and the solution was filtered
and evaporated.
: Crystallisation from isopropanol/ether, followed
by solutlon in 5% methanol/chloroform, filtration through
S sillca gel and recrystalllsatlon from isopropanol/ether
gave the headlng product ln the form of its tetrafluoro-
borate salt, m.p. 121.5-123C.
. .. .
' ;; ~:
EXAMPLE 2: 5-n-Butylamlno-7-phenYl-2,3-dihydro-l~ 4
diazeplne (VIII) [process (a)]
2 g (6.07 mmol) of the product of Example lA)
and 10.0 ml of n-butylamlne were refluxed under nitrogen
for 5 mlnutes and the excess n-butylamlne evaporated off
: ~:
under reduced pressure. The resultlng oil was dlssolved
ln S0 ml of chloroform and the solutlon washed with 50 ml
of water and treated wlth 50 ml of cold 2N sodlum hydrox-
lde. The chloroform solution was then drled over
anhydrous magneslum sulphate and acidifled ln a solutlon
of 70% perchloric acid ln lsopropanol. The solvent was
~-~ evapo~ated off. Trituration w-lth water (1.8 g) ylelded
~ .
~ ~ 20 crystals of a by-product. The mother llquor was evapor-
,
ated to an oll and trlturation wlth ether and coolin~
yielded the heading compound, in perchlorate salt form,
~ m.p. 59 to 64C.
';, ~ : :
, "~ : .
~! ', , .
, ` :. "
:,''''1 ` ` "
~,',' ~ j .
"', . ' " :
~ '' ' ` ' :' ` ",' ' . .' '. ' ' ' :., . ' .,'~-`': . . . , ,' ' ` '
., . , ' . ' ' . ' ' ` `: ' . ' ' :' .: ` ... . : ' `~ ' ` . . .
- ~ 1064488
~ ~ - 16 - 600-6638
~- '' .
EXAMPLE 3: 5-Dimethylamlno-?-phenyl-2,3-dihydro-1}1-1,4-
-diazepine (IX) ~Process (a)]
The heading compound, in tetrafluoroborate salt
form, m.p. 126.5 to 128.5C, was obtained in ~anner
analogous to that of Example lB), using appropriate
startlng materials for 20 minutes at 100C in the reac-
tion bomb.
EXAMPLE 4: 5-Pyrrolidino-7-phenyl-2~3-dihydro~ 4
!~ . dlazeplne (X) tprocess (a)]
3.8 g of the Product of Example lA) were dissolved
in 10 ml of pyrrolldine and the solutlon heated to reflux
; for 10 mlnutes under nltrogen. The excess pyrrolidine
was then evaporated off and the resultlng oil was dissol- -~
ved in about 10 ml of lsopropanol. About 20 ml of dry
ether was added and the resultlng crystals recrystalllsed
; ~ from isopropanol to obtaln the heading compound ln tetra-
~ fluoroborate salt form, m.p. 139.5 - 140.5C.
,. , : :
.~.
EXAMPLE 5: 5-(N'-2-Hydroxyethylpleerazino)-7-phenyl-
~; 2,3-dlhydro-lH-1,4-dlazepine (XI) [Process (a)]
~. i
3.1 g of the product of Example lA) and 2.1 g
~ of freshly distilled N-(2-hydroxye~hyl)piperazine were
,~., ~ .. ...
.: . - . . . . - . .
, . . , .. . ~ . .: ,
.. . - ~
' ~ . ' ' ' , ' , ' , '' ~ , ~
1064488
- 17 - 600-6638
. ':
heated at 100C for 1 hour. After cooling, the product
was chromatographed on 100 ml of silica gel using gradient
- elution with methanol/chloroform mixtures. The fraction
; contalning the product was recrystallised from isopropanol
to yleld the heading compound in tetrafluoroborate salt
j~ form, m.p. 120 to 121.5C.
:. ' '` .:., :.
EXAMPLE 6: [proces~ (b)]
;~ A) ~-(2-Aminoethylamino)-P-(l,l-dimethylethyl-
amino)vinyl phenyl ketone
(1) 50.0 ml (750 mmol) of ethylene diamine was
~; dlssolved ln 700 ml of methylene chloride. 30.0 g
(100 mmol) of 2-t-butyl-5-phenyllsoxazolium perchlorate
[J. Org. Chem. 31, 2039 (1966)] was added to the solution
as a solld ln small portlons wlth stlrring over a period -
,
of 20 minutes.~ The temperature of the reaction mixture
was maintalned at 20 to 30C by cooling. Stirring
was contlnued for one hour after completion of the
: : .
~ addltion of the isoxazollum salt. The reaction mixture
.,, ~
was diluted by addltion of sufficlent methylene
chloride to brlng the volume to 1~1. The reaction mix-
; ture was then washed twice with 300 ml portlons of
water and dried over anhydrous magneslum sulphate. The
.. .
: .
:.; ' , ,:
':" ~, : '
. 1064488
- 18 - 600-6638
methylene chloride was evaporated under reduced pressure
to obtaln an oll. The oll was dissolved ln 300 ml of
anhydrous ether and filtered free of white solids. ~he
white sollds were washed wlth a small amount of anhydrous
; 5 ether and the washlngs were combined with the filtrate.
~; The comblned flltrate and washlngs were evaporated at
a reduced pressure to obtaln the heading comp~und as a
, .
colourless oil.
~ . . .
~,~,. .
:~".
(li) lOOg of 2-t-butyl-5-phenylisoxazolium perchlorate
were added, portlonwise, to a solution of l50 ml of
ethylenedlamlne ln 2 l of methylene chloride, stirred
~` vigorously, under nitrogen. The temperature was
maintaIned at 20 to 25C by varylng the rate of
addltion and by coollng. Stlrring was continued for l
. ~ ..
~i ~ 15 hour upon completlon of the addition and the reaction
,i i
mixture was extracted twlce wlth l l portlons of water,
and dried over anhydrous magneslum sulphate. The
methylene chloride was stripped off at reduced pressure
and the resulting oLl dlssolved ln l l of ether. The
::~
resulting solids were removed by filtration. The ether
~i
was evaporated off at reduced pressure to yield the
product as an oil.
. :, .
~....
': '
. ~ :
.. .. .
.:
: .
, :.. . , .. .. ~.. .. . . . . . - .
.. . . ~
, . . . ~ , . . :
: ~ . . .
.. ,
- 1064488
. .
, . .~ . .
The product can be converted into dihydrochloride
salt form, m.p. 175 (decomp.) by addition of gaseous
hydrogen chloride to a solution thereof.
B) S-t-Butylamino-7-phenyl-2~3-dihydro-lH-l~4
~ diazepine (XII)
: (i) 24.0 g. (92.0 mmol) of the product of (A) was dis- ;;
solved in 200 ml of absolute ethanol. The solution was
acidified to a pH of about 1 with 70~ perchloric acid, re-
- ~ fluxed under nitrogen for one hour and allowed to cool
.. . .
10 to room temperature. Addition of 500 ml of anhydrous ~ ~
:
ether gave the product in the form of white crystals.
Recrystallisation from ethanol/ether gave the heading
compound in the form of its perchlorate salt, m.p. 169-
171C. (decomp.).
(ii) The above procedure was repeated with the following
,~ . :.
;~ ~ modiications. The reaction mixture was acidified to a
pH of 1 to 2 and the refluxing was halted after 40 minutes.
The product was crystallised by adding 500 ml of anhydrous ~;
ether and cooling. The mother liquor was evaporated to
a volume of 200 ml at reduced pressure, allowed to reflux
under nitrogen for 1-1/2 hours and evaporated to a volume
of 50 ml at
. ...... : ,
".,i " ~ ~ ~ ; O,
~ , . .
: . :, ,
. ~ 30
r ~
, ,. ~ 1 9
~"`'.................................................................... . . .
. ~. ~. '
- , :
-- 1064488
~ ~ - 20 - 600-~638
. .
reduced pressure. 100 ml of w~ter was added to obtain
additlonal product ln the form of off-white crystals.
The two batches were combined and recrystallised from
absolute ethanol/ether to obtain the heading compound,
S in perchlorate sa~t form, m.p. 169-171C (decomp.).
~ ~ .
EXAMPLE 7: 5-t-Butylamino-7-phenyl-2,3-dihydro-l~ 4
(XII) [Process (b)]
2.5 g (9,S mmol)of the product of Example 6A) was
dissolved in 50 ml of absolute ethanol. 1.0 g (10.0 mmol)
of methanesulphonic acid was added, and the resulting
reactlon mlxture refluxed for 20 mlnutes. The mixture was
, .
allowed to cool and the ethanol was removed at reduced
pressure. The resulting oil was triturated with anhydrous
ether and the resultlng crystals recrystallised from
, .
isopropanol/ether to obtain the heading compound, ln
.: . .
'~ methanesulphonate salt form, m.p. 159-162C.
:.j , , .
10.0 g (29.5 mmol) of the above product was
dissolved ln 50 ml of water, the solutlon cooled on an
lce-bath and 50 ml of 2N sodium hydroxide added. The
..,: :
resulting mixture was extracte-d twice with 150 ml
~; ~
~b', ~ portions of chloroform, and the chloroform extracts
were combined and dried over anhydrous magnesium sulphate.
.~ .
.. . .. .
- . . . , . : : - . -
. : . . :
,., . - :
;' ' , . ~ ~ .
, .. ', .. .
- ` 1064488
Removal of the chloroform at reduced pressure yielded an
oil. Upon addition of 50 ml of anhydrous ether, most of
the oil dissolved leaving some off-white solids which were ~;~
~- removed by filtration. The filtrate was evaporated to a
minimum volume under reduced pressure and slow addition of
heptane and cooling yielded the product in free base form,
m.p. 102 - 103.5 C. A second crop, m.p. 93 - 97C.,
was also obtained.
EXAMPLE 8: S-t-Butylamino-7-(4~-methoxyphenyl)-2l3
dihydro-lH-1,4-diazepine (XIII) [Process (b)l
A) ~-(2-Aminoethylamino)-~-(l,l-dimethylethylamino)
vinyl-4'-methoxyphenyl kètone - ~ -
The heading compound is produced as an oil in
manner analogous to Example 6A) (ii) using 6.64 g (20.0
mmol) of 2-t-butyl-5-(4'-methoxyphenyl)isoxazolium per-
chlorate and 10 ml of ethylene diamine.
B) 5-t-Butylamino-7-(4'-methoxyphenyl)-2,3-dihydro-
- LH-1,4-diazepine
~ The oily product from A), above, was dissolved in ~ -
: ~ 20 100 ml of absolute ethanol, and the solution made slightly
.
~ acidic (pH about 5) by addition of a solution of hydrogen
f
chloride in absolute ethanol. The solution was refluxed
under nitrogen for 1-1/2 hours and the
, .
. ~ . . .
.~ . ,
~: ,.
., . ~ . .
.,.: :
, .. .. .
,; -.~ - :: .
... ~ .
.~
. ,: . :.
.- : .
..
:
- ~ - 21 -
'
1064488
`,, ~ .
- 22 - 600-6638
ethanol then removed at reduced pressure. The resulting
oil was dlssolved in 150 ml of water and neutralised with -
2N sodium hydroxlde. The free base was extracted with r
two 150 ml portions of chloroform and the con~,ined
- 5 extracts dried over anhydrous magnesium sulphate and; evaporated to an oll under reduced pressure. The productwas obtained from isopropanol by acidification with 70~
perchlorlc acid in isopropanol. Recrystallisation from
isopropanol yielded the heading compound, in perchlorate
salt form, m.p. 151-152.5C.
,.,
EXAMPLE 9: ~Process (b)]
In manner analogous to Example 6, and employing
approprlate start~ng materlals ln approxlmately equlv-
, alent amounts, the followlng compounds may be obtained:-
15 a) S-t-butylamlno-7-(4'-methoxyphenyl)-2,3-dihydro-lH-
1,4-diazeplne, perchlorate salt form, m.p. 151-152.5C
. .
XIIIl;
b) 5-methylamlno-7-phenyl-2,3-dlhydro-lH-1,4-dlazeplne,
perchlorate salt form (VII);
20 c) [using a solutlon of hydrogen chloride in ethanol
ln place of the perchlorlc acld]
.
5-t-butylamlno-7-(2'-chlorophenyl)-2,3-dlhydro-lH-
1,4-diazepine, hydrochloride salt form, m.p. 152-155C
tXIV)
.
.
, . .
. . ~ !
:, . ' ~ . , ' ' ,. ' ' :
." '', ' ' ` , ' " , ~
' . ' ~
- -- 1064488
- " - 23 - 600-6638
EX~MPLE.10: ~Process (b)]
In manner analogous to Example 7 and employing
approprlate ~arting materials ln approximately equiv-
alent amounts, the followlng compounds may be obtained:
a) 5-t-butylamino-7-(4-methylphenyl)-2,3-dihydro-lH-
1,4-dlazepine, methanesulphonate salt form, m.p.
174-177C (decomp.) (xV);
b) 5-t-butylamino-7-(3',4'-dimethylphenyl)-2,3-dihydro-
; lH-1,4-diazepine, me~hanesulphonate salt form,
m.p. 200-202C (decomp.) (XVI);
. ~ ,
c) S-ethylamino-7-phenyl-2,3-dlhydro-1~-1,4-diazeplne,
methanesulphonate salt form (XVII),
vla the corresponding compounds IV.
f~
EXAMPLE 11: ~Process (c)l
5-Amlno-7-phenyl-2,3-dlhydro-lH-114-
diazepine (XVIII)
2.0 g of 5-t-butylamino-7-phenyl-2,3-dihydro-lH-
,.............................................. . .
1,4-diazepine, methanesulphonate form, waq heated in
an oil bath at 160-165C for 15 minutes with one
drop of methanesulphonic acld. When the melt ceased to
~; bubble, the hot residue was dlssolved ln the minimum
quantity of isopropanol, and the headlng product was
precipltated by the addition of ether, as the ~ethane-
, .,
sulphonate salt form, m.p. 176-177.5C. The free base ~
. , .
form may be obtained in the manner describ~d in Example 7.
, . . .
, , .
:' '~ . .
, ~ . .
1064488 ~
.~ . .
- 24 - 600-6638
- EXAMPLE 12: [process (c)l
Followlng the procedure of Example 11, and
uslng approprlate starting materials in approximately
equivalent amounts, the following compounds may be
obtained:
; a) 5-amino-7-(4'-methylphenyl)-2,3-dihydro-1~l-1,4- ~ ~`
diazepine (methanesulphonate salt), m.p. 200-210C
(XIX);
b) S-am~no-7-(3',4'-dimRthylphenyl)-2,3-dihydro-lH-1,4-
diazepine (methanesulphonate salt), m.p. 180-181.5C
~; (XX).
.~ .
EXAMPLE 13: [process (d)]
S-Hydrazlnc-7-phenYl-2,3-dihydro-1~l-1,4-
diazeplne (XXI) `
5-t-autylamino-7-phenyl-2,3-dihydro-1~-1,4-diazepine
; '
methanesulphonate (5.0 g) was added to 25 ml of anhydrous
hydrazine and the mixture refluxed under nitrogen for
30 minutes. The excess hydrazine was evaporated under
reduced pressure. To the resulting oil, 50 ml of iso-
.,
propanol followed by 50 ml of anhydrous ether were added
-' to obtain crystals (m.p. 13g.5-141.5C) which were
-~ washed with 1:1 isopropanol/ether. The washing was
comblned with the mother li~uor and the mlxture evapor-
ated to an oll which was chromatographed on 125 ml of
-:
.. ,~, .
~.
.
: . . . . - i .
`
1064488
, :
" - 25 -- 600-6638
'
sillca gel uslng chloroform, 2% methanol in chloroform,
10~ methanol in chloroform and 50~ methanol ln chloro-
form as eluants. The 50% methanol/chloroform eluate
was evaporated at reduced pressure to obtaln an oil
which crystalllsed on trl~uratlon wlth dry ether to
gi~e the heading compound in free base form, m.p. 85-88C. Y~
The free base form was converted to the methane- -
... . .
sulphonate salt form by addltion of a solution of 0.5 g
of methanesulphonlc acld in 10 ml of isopropanol to
a solutlon of about 1.3 g of the crude free base in
~, ; 25 ml of lsopropanol with cooling. After a few minutes,
~ off-whlte crystals formed and 50 ml of anhydrous ether
;ii was added. The crystals were flltered, washed with
ether and recyratalllsed from absolute ethanol/ether
I 15 to give the product in the form of white crystals (1.4 g),
m.p. 190.5-191.5C.
:
EXAMPLE 14:
Spectroscoplc data for compounds of formula I
ln which R2 = H are tabul~ted below. All UV spectra were
~- 20 run ln methanol, IR and NMR spectra ln the medlum indlc-
: .
~ ated. All NMR spectra were taken at amblent temperature
,:: . ~ on a 60 MHz NMR spectrometer, chemlcal shifts being
"
; ~ measured in p.p.m. (~) relatlve to tetramethylsilane.
.'
, .
~. , .
- 1064488
- 26 - 600-6638
,~ .
~ Sere a single ~ value is given for anything other than
a singlet, it refers to its centre point. The nu~ber in
- brackets following the ~ value is the number of protons
:`:
in the peak; s = singlet, d =doublet, m = multiplet,
,, .
.~ x =exchangeable with D2O, b = broad.
,~;~ , ,.
.. Com- Salt ¦ I l UV ¦ NMR
~.pound Form ¦EX.I IR(cm 1) IAmax(mu)l ~ )
:: . . ,
-. . . (CD3.SO.CD3)
.. VII BF4 1 (nujol) 233 13,600 2.8 (3,d, s
. . 3380 after exchange)
: 159S 297 26, 3.45 (4,s~
. . 1545 . 4.7 ~l,s)
. . . 1310 7.0-8.0 (8, 3x)
. _ _:
. ~ -VIII C104 2 (KBr) 235 13,300 (CDC13)
3230 298 26,200 0.7-1.9 (7,m~
1590 3.0-3.8 (6,m)
~ 1535 5.15 (l,s~
;1 : 1110 . 5.45 (l,b,x)
i ~ . . 5.95 (2,x)
. 7.2-7'7 (5,~ ~ :
. . _ .
: XII C10-4 6 (nujol) 238 14,900 (CD3.SO.CD3)
: 3400 315 22,100 1.3 (9,s~
3340 . 3.5 (4,m)
1630 4.8 (l,s)
. . 1585 ... 7.4-8.2 (8,m, 3x~
~ . ~ '
r.
~: . il .
'`^`''' '' '
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- ~ :
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~, ~ ' ., .
~' ~ ' \ .
-` 1064488 ~;
.
- 27 - 600-6638 -
~:-
Com- Sa1t EX ~¦IR ( cm ) ~ ~ NMR
XII CH3SO3 7 (CD3 SO CD3
1.4 (9,s)
2.3 (3,s)
~ 3 6 (4,m)
5.0 (l,s)
_ 7.4-8.4 (8,m, 3x~
XIIfree 7 (nujol) (CD3.SO.CD3)
base 1620 23413,200 1.3 (9,s) :~
. 1580 31819,300 3.6 (4,m)
1315 4.65 (l,s)
1260 7.3 (7,m, 2x)
__ 1240
XIII C104 8, 9a (nu jol) (CD3.SO.CD3)
3400 2148,750 1.3 (9, s)
3350
1620 2589,650 3.5 (4,m) -
1575
1540 31823,200 3.8 (3,s)
~ 1515 `
; lSOS 4.9 (l,s)
_ _ 1080 6.9 - 8.3 (7, m,3~ -
XIV Cl9c (nu jol) (CD3.SO.CD3l
3200 2326,200 1.35 (9,s)
`i 1620 30617,000 3.6 (4,m)
1550 4.65 (l, s)
.i ;, ~ 1320 7.5 (4,m)
127 s 8.05 ( l ,m)
__ 1240 8.45 (2,m)
!
: !
~ - ;
~` 1064488
` - 28 - 600-6638
.ff.
W NMR
Cmund Salt EX. IR(cm ) ,~m.ax(m~) . ~ (~)
.
XVC~I3SO-3 lOa (CHC13) (CDC13) :~
3460 3320 243 15,300 1.~ (9,s)
3180 3020 318 23,400 2.3 (3, bs)
1620 1550 2.6 (3,s)
1490 1450 3~3-3.8 (4,m)
1380 1340 4.9 (l,bs)
1180 1055 7.0-8.4 (7,m, 3x~
_
XVI CH3SO-3 lOb (CHC13) (CDC13)
3430 3280 245 12,300 1.4 ~9,s)
3150 2990 319 21,400 2.25 (6, bs)
1625 1550 2.6 (3~s)
1490 1450 3.2-3.8 (4,m)
1405 1375 4.9 (l,bs)
1335 1235 7.0-7.5 (4,m, lx)
1175 1045 7.6-8.5 (2,n~ 2x)
.,:
XVIII CH3SO3- 11 (nujol) (CD3.SO.CD3)
3400 3310 237 15,100 2.3 (3,s~
3190 1650 313 18,600 3.2-3.8 (4,m)
~ I590 1580 4.85 (l,bs)
- ~ 1230 1180 7.2-7.85 (7,~, ~xj
1165 1110 8.2-8.8 (2,m, 2x)
XIX CH~SO~ I2a (nujol) (CD3.SO.CD3)
3 3300 3195 244 12,150 l2.36 (3,s)
1660 1635 314 16,900 2.43 (3~s)
1570 1535 3.50 (4,m)
1210 lI70 4.90 (l~s)
1050 7.40 (6,m, 2x1 -
8.50 (2,bd, 2x)
' ¦: _ ,.
l XXI free 13 _ _ _ (CDC13)
f: ~ bas~ 2.6-3.4 l4,m)
~;~ 4.8 (4,b~ 4x) ~
i~l 5.8 (l,s) '`
_ _ _ _ 7.0-7.8 (5,m)
" ' ~' .
: . - .
