Note: Descriptions are shown in the official language in which they were submitted.
OCT-24-1975
208~FTE-2
ED/vl
~C3163~Z ~ ~
This invention relates to novel substituted ureido~com~
pounds~ namely compounds containing the ureido- or
iso-ureido-function -N-C0-N- or -N-~-N- . More
: ~ i
specifically, this invention relates to therapeutically
active hydroxypolyhaloisopropyl-substituted ureido~
compounds selected ~rom the group of ureido-compounds
consisting of phenyl ureas and oxazolines
and quinazolines derivable from the said phenyl ureas.~ ~
The present ~nvention also relates to the preparation ~ ~ ;
Or the novel substituted ureido-compounds, to composi-
tions containing such compounds and to their use as ~;~
therapeutically active agents. ~ ~
We have found that certain ureido-compounds containlng ~;
as a substituent a hydroxypolyhaloisopropyl grouping ~;
exhibit use~ul therapeutic activity, more particularly -~
useful anti-hypertensive activity.
In one Or its aspects, the present invention provides
novel hydroxypolyhaloisopropyl-substituted ureido com-
pounds selected rrom ~he group consisting o~ phenyl -
ureas, oxazolines and quinazolines of the general
~ormula I
v . . ~ ..
~6 ~ ~
X~Z ''
X4 ~ X2
-2
.
~ov-6 - 1975
20~-FTE-~
~D/vl .
~Ll)63~ Z ~
and the pharmaceutically acceptable salts Or said oxa- :
zolines and qulnazolines, wherein
Z is a grouping containing the ureido-or-lso~ureido-
~unctions -N-CO-N- or -N-C N-,
R R
Z belng -N~CO-NHR2, -N-C_ ~ or,
~ogether with X2J the grouping -N-CO-N-CO-,
in which groupings
R is hydrogen, lower alkylJ alkoxy-lower alkyl or
dialkoxy-lower alkyl,
Rl is an ethylene grouping -CH2-CH2- or a methyl-
substituted ethylene ~rouping, and
R2 is hydrogen, methyl or -RlX where X is hydrogen
or halogenJ
~ X2 and X4 one is a hydroxypolyhaloisopropyl group-
ing designated Rf and o~ the formula Ia
-C-OH (Ia)J
CF2Y
in which Y independently represents hydrogen~ chlorine .
or rluoriné~ and the other of X2 and X4 is hydrogen,
lower alkyl, halogenJ lower alkoxy~ hydroxy lower alkyl
nitro, lower alkoxy carbonyl or aminocarbonyl~
X3 is hydrogen or lower alkyl, and
X5 and X6 independently represent hydrogenJ lower
alkyl J lower alkoxy or halogen, or together with the
carbon atoms
. . .
.. . . ..
. . : .
OCT-24-1975
208 3-FTE-4 :
106311Z ED/vl
to which they are attached represent a fused benzen-
oid ring, which ring may be substituted by lower
alkyl or halogen.
Unless otherwise specified,the term "lower alkyl" as
used herein means a straight or branched-chain alkyl
group containing one to four carbon atoms for example
methyl, ethyl~ isopropyl or t-butyl. Similarly, by
the term "lower alkoxy" is meant a group containing
- ~ .
one to four carbon atoms, for example methoxy, ethoxy,
isopropoxy or t-butoxy.
r , ;
"Alkoxy-lower alkyl" as used hereln means a grouping
wherein the al~yl moiety has two or three carbon atoms
and the alkoxy moiety one or two carbon atoms e.g. ~ ;~
,. . . ~
the groupings -CH2.CH2.0CH~ and -CH2.CH2ØCH2.CH~
The term "dial~oxy-lower alkyl" as used hereln means a
grouping whereln the alkyl moiety has two or three
carbon atoms and each alkoxy moiety one or two carbon
atoms, the term embracing groupings such as
~ O.CH 0-CH
-CH2.CH\ ~ as well as -CH2.CH~ ~ and
O~CH~ 0-CH2
~ ~-CH2-CH2
-CH2-CH~
~O-CH2-CH2 ~:
m e term "halogen" embraces ~luorine, chlorine, bromine
and iodine.
. . ~ .
In the grouping designated Rf, the moiet~-cy~ may e.g.
-4-
, ;:..
NOV-6-1975
20~-FTE-5
ED/vl
63~2
be -CH3 or the grouplng -CFY2 such as -CFC12, -CF2Cl
and CF~. Representative of Rr are the groupings:
IF3 ~FC12 1 3
-C-OH , -C-OH , -C-OH and9
l F2Cl l F2Cl CF2H
CF2Cl CF3
in particular, -C-OH or -C-OH.
IF2C1 CF
~;
The term "pharmaceutically acceptable salts" is employed
in its normal and well-known usage and includes pharma-
ceutically acceptable addition salts of both organic
and inorganic acids such as maleic, phthalic, succinic,
tartaric, citric, malic, cinnamic, sulphuric, hydro-
chloric, hydrobromic and phosphoric acids.
.
f X2 and ~4, preferably X4 is the grouping designated
ÇF2Cl ,'
Rf, while preferred values o~ Rf are -C-OH and
CF2Cl
-C\ ~ R is preferably hydrogen or methyl and R
preferably -CH2-CH2-. For R2 preferred groupings
are ethyl and -CH2.CH2.Cl~ When X4 is the grouping
designated Rf then X2 and X6 may ad~antageously be lower ~
alkyl. ~-
Illustrative of the preferred compounds of the present
inventionJ there may be mentioned:
N-(2-chloroethyl)-N'- r 4-(hexafluoro-2-hydroxy-2-propyl)
phenyl~ N'-methyl urea, N-e~hyl-N'-~4-thexafluoro-2--
hydroxy-2-propyl)phenyl]-N'-(2,2-dimethoxyethyl) urea and
2-~4-~hexafluoro-2-hydroxy-2-propyl)-N-methylanilino~ 2-
oxazoline. 5
';' ~
. .
,~. . ' ; ' '
OCT-24-1975 -
2083-FTE- 6
ED/vl
1~)631~
The compounds o~ the general ~ormula I may be prepared ~ ;
by methods known for the preparation Or previously :~
described compounds having similar structure.
. ~
:" . :~,
The following methods will now be described~
A: A ~irst general method comprises reacting an
aromatic amine Or the ~eneral formula II
X6 R
X ~ ~H :
X4 ~X2 ' ' ;~
X3 ~: `
with a reactive derivative of a carbamic acid o~ the
general ~ormula . :
R2NH.COOH
wherein R~ R2~ X2, X~ X4~ X5 and X6 are as de~ined for ~ .
~ormula I, and isolating in conventional manner the so~
obtained phenyl urea of the general formula I. Pre-
rerably the reactive derivative of the carbamic acid :
is an isocyanate of the formula R2NCO. It is also ~
envisaged, however, that other reactire derivatives such .
as a carbamic acid ester Or the formula R2NH.CO.OR~) where -
R4 is a hydrocarbon residue such as an alkyl or aryl
~: ~ group, or a substituted urea o~ the formula R2NH.CO.NH2
may be employed.
... . .
. .
As stated, however, the reactive derivative is prererably
an isocyanate of the ~ormula R2NCO~ The precise
. -
reaction conditions here are not considered to be cri- : ;
'; ' ~
-6-
:. :
OCT-24-1975
2083-~E~7
ED/vl
1~i3~L2
tical. Suitably, however, the reaction ls effected
in an inert medium such as a non-polar solvent among `~
which the ethers, speclfically diethyl ether, and aro-
matlc hydrocarbons may be mentloned~ The temperature
and reaction time employed are readily ascertainable
in any specific instance and may in general be from
ambient to reflux temperature and from one or more hours
up to about 1 day depending upon the nature o~ the ¦
- reactants. When the hydroxypolyhaloisopropyl grouping
designated Rr is in an ortho-position, that is X2 ~;
represents R~, it is pre~erred, however, to employ
ambient temperatures. As guldance, it may be mentioned
that in the preparation of N-(2-chloroethyl)-N'-r4-hexa-
rluoro-2-hydroxy-2-propyl)phenyl~ -N'-methyl urea,
reaction of 2-chloroethyl isocyanate with the 4-thexa- ;
fluoro-2-hydroxy-2-propyl)-N-methylaniline starting
material was conveniently effected in diethyl ether
by allowing the reaction mixture to stand overnight
at ambient temperature.
m e aromatic a~ine of the general formula II may be pre-
pared by suitable introduction of the required hydroxy-
polyhaloisopropyl grouping, such as by reaction of the
appropriate polyhaloketone or hydrate thereof with an
appropriately substituted aniline (see, for example,
E.E. Gilbert, J. Org. Chem.9 30, 1001, 1965). In `
general, it may be said that the hydroxypolyhaloisopropyl
grouping enters preferentlally in the para-posi~ion
-7~
.
. -...... .. : ~- .
. .
.
ocT-24-lg75
20~-FT~_8
63:1:12 ED/vl
although some ortho isomer may also be obtained.
0~ course lr the para-position is blocked, the hydroxy-
polyhaloisopropyl grouping must enter ln the ortho~
position .
'.
B: Another general method comprises reacting a
reactive derivative of an N-phenyl carbamic acid o~ the
general formula III
X5 ~ ~.COOH ; ;
X~ X2 ' : ~
X3
with an amine o~ the general formula R2NH2, whereln R,
R2'X2~ X3~ X4~ Xs and X6 are as de~ined for ~ormula I,
and then isolating in conventional manner the so-obtained
phenyl urea of the general formula I. ;
The react$ve derivative of the carbamic acid o~ the
general formula ma~ suitably be the corresponding carba-
mio acid ester -N-COOR4, where R4 is a hydrocarbon re-
sidue such as alkyl or ar~l, or the correspondlng carba-
moyl halide -~.COHal, where Hal is halogen, preferably
chlorine. When R is hydrogen then the reactive deri-
vative of the carbamic acid of the general formula may
be the corresponding isocyanate -N=C=O. It is also `
. ~ .
envisaged that the reactive derivative may be the corre-
R ; -
sponding carbamic acid amide -~-CONH2o ` ~
,`' ~ . ' '~'
'~ ~
.. ' . ' .. . , , , . . !
OCT-24-1975
2083-FTE- 9
ED/vl `~
In general, the reaction conditions are not consldered
to be critical and any suitable inert reaction medlum
or solvent may be employed and any appropriate reactlon
temperature.
m us for example an N-phenyl carbamoyl chloride may
typically be reacted with the required amine of the
~ormula R2NH2 employing ambient temperature and an
aromatic hydrocarbon as solvent. Similarly, an
N-phenyl carbamate may be reacted with ammon~a employin~
ambient temperature and an alcohol, su¢h as ethanol,
as solvent.
,;~
C: A further method comprises sub~ecting an N-phenyl
urea Or the general formula IV
X5~.CO.N~IRlQl ~ .
l ll (IV),
X4 ~ X
X ~ ,
to intramolecular condensation, wherein R, Rl, X2, X3,
X47 X5 and X6 are as de~ined for formula I and Ql
represents a reactive grouping such as a sulfonic acid `
ester grouping or a halogen a~om, preferably chlorine,
and isolating in conventional manner the so-obtained
oxazoline of the general formula I.
The condensation may typically be effected by heating the
N-phenyl urea to a temperature which suitably lies within
' ~.
.. ~ , . ,~ . . :
.
OCT-24-1975
2083-FTE-10
1063~12 ED/vl
the range of 50-100C and in an aqueous medium such as
an aqueous alcoholic medium containing more than about
10~ of water.
D; Yet another method comprises cyclising an
N-phenyl urea of the general formula V
X6 R
5 ~N.CO.NHR2 ~ :
- Jl ~ (v)
X4 ~ `COQ2
wherein Q2 is a reactive grouping capable o~ being ~;
eliminated as HQ2 under the reaction conditions employed `
and RJ R2, X3, X4, X5 and X6 are as defined for formula I
and then isolating in conventional manner the so-obtained
guin~zoline of the general formula I.
Typically, Q2 may be an alkoxy or aryloxy grouping and ;~
cyclisation may be effected in aqueous media in the ~j :
presence of a basic agent such as an alkali metal hydro~
xide. The cyclisation temperature is not considered - -
to be critical and typically ambient temperature may
be employed. Alternatlvely, an acid agent may be used.
.!;
E; A further method which is applicable to the pre-
paration of the compounds of the formula I bearing a
halo or nltro substituent ortho to the group Z, in
partioular for the preparation of the phenyl ureas of the
-10- '~
OCT-24-1975
208~-FTE-ll
~063112 ED/vl
general ~ormula I, comprises treating a corresponding
des-halo or des-nitro compound with an appropriate
halogenating or nitrating agent and isolating in con-
ventional manner the so-obta~ned compound of the general
~ormula I.
For the preparation of such phenyl ureas, the starting
material will typically be a compound of the general
formula Vl
X ~ ~ ll.CO.NHR2
X3 ~ ;
''.;
, R2, X~, X4, X5 and X6 are as defined for
~ormula I.
The halogenating agent is preferably a free halogen
e.g. bromine in an inert organic solvent such as lower~ ;
alkanoio acid e.g. acetic acicl. The nitrating agent
is prererably nitric acid, conveniently in a large
excess o~ sulfuric acid.
.~ '
F: Yet another method comprises N-alkylating a
compound of the general formula VII ~-
5 ~ (VII),
X ~ ~ X2
.~ , . ,, :
OCT-24-1975 ~ -~
208~-FTE- 12
~06311Z ED/vl ~ ~
X2, X3, X4, X5, X6 and Z are as defined for
formula I, with the exception that R in the grouplng
Z represents hydrogenJ whereby the required alkyl
or substituted alkyl group R is introduced onto the
nitrogen atom adjacent the benzenoid ring.
~ '''.' ~'.;
The N-alkylation may be effected in oonventional manner
such as ~or example by reacting the appropriate alk~
halide or alkyl sulfonate ester with the compound o~
the formula VII in the presence o~ a strong base and
in an organic solvent, pre~erably anhydrous. The strong
base may ror example be lithium hydroxide or sodamide ;`
and the solvent may for example be ethylene glycol,
diethyl or dimethyl ether.
G; A further method applicable to the preparation
, .,: , . ..
of R2 substituted quinazolines o~ the general formula I
comprises introduction of the required R2 group employing
conventional techniques. Thus a starting material ~,~
Or the general formula VIII
X~ C~O
X ~ C ~ (V~
wherein R, X~, Xl~ X5 and X6 are as defined for formula
I, ma~ be N-alkylated to introduce the required group R2
-12-
. ~
ocT-24-lg75
2083-FTE-13
ED/vl
~631 2
and the so-obtalned quinazoline of the general rormula I
isolated in conventional manner. In general, it may
be said that the alkylation conditions of process F
are applicable.
-13-
... . . .. , . ~ . .. . .=.. ..
,. . : .
OCT-24-1975
20&~-FTE-14
ED/vl ~`
~ ;3~L12
The preparation Or the compounds of the general ror
mula I will now be illustrated by way of the following
Examples in which Examples 1,3,7 and 13 illustrate the
preparation Or starting materials and the remaining
Examples to Example 16 illustrate the preparation of
the final compounds of the formula I.
Example 1
4-(1,3-dichloro-2-hydroxytetrafluoro-2-propyl)-N-methyl
aniline. ;~
To 21.4 g (0.2 mole) of N-methyl anillne in 50 ml or
toiuene add 2.0 g of p-toluenesulfonia acid. To this
mixSure add dropwise a mixture of 43.8 ~ (0.22 mole)
1,3-dichlorotetrafluoroacetone and 10 ml of toluene.
Followinæ reaction, allow the reaction mixture to cool, ~ ~
if desired concentrate partlally by evaporation, then ; ~-
wash the mixture with 50 ml o~ lN a~ueous sodium bi~
carbonate solution. Dry, and then remove the solvent
to obtain 54 g of a yellow solid as product. Recry- ;
stallize the product by dissolving in diethyl ether and ;
then adding hexane followed by evaporation of the `~
diethyl ether. ~ilter off the precipitate to obtain ` ~;~
....
42 g of 4-(1,3-dichloro-2-hydroxytetrafluoro-2-propyl)
-N-methyl aniline as a tan colored solid, m.p. ;
92-94 C. `~
,
,
-14- ~
-- . .-
OCT~24-1975
208~-FTE-15
ED/vl
~ 31~LZ
Example 2 ~
_
N-ethyl-N'-methyl-N'- ~4-(1,3-dichloro-2-h~droxyketra-
fluoro-2-propyl) ~henyl~ urea.
-- . :
Mix 7.1 g (20 m.mole) Or 4-(1,3-dichloro-2-hydroxytetra- ;
fluoro-2-propyl)-N-methylaniline obtained as described
in Example I and 2.8 g (40 m.mole) of ethyl isocyanate
in 70 ml of diethyl ether. A~ter 16 hoursJ evaporate -;
to obtain 8.6 g of a white solid. Recrystalliæe by ~
dissolving in methanol followed by adding water to ~'
lQ effect precipation and to give as produat 7.8 g of
N-ethyl-N'-methyl-N'- ~4-(1,3-dichloro-2-hydroxytetra-
fluoro-2-propyl)phenyl~urea as a white solid, m.p,
155-157C.
Example
Ethyl-5-(hexafluoro-2-hydroxy-2-propyl)anthranilate.
Mix 16.5 g (0.1 mole) of ethyl anthranilate with -
~8,6 g (0.20 ~ole) of hexafluoroacetone sesquihydrate
and reflux for 24 hours. Add 19.3 g (0,1 mole) of
hexa~luoroacetone sesquihydrate to the reaction mixture
and reflux for another 24 hours. Distil off the
excess hexafluoroacetone hydrate in vacuo. Wash the
residual solid with hexane to obtain 25 g of a pink
solid. Recrystallize by dissolving in ethanol and `
then adding water to effect precipitation to obtain
20 g of ethyl-5-(hexafluoro-2-hydroxy-2-propyl)anthra-
nilate as a pink solid, m.p. 115-117C.
-15-
: ~ . . , , , .;.................... . . . . . ~
: : - :: .
OCT-24-1975
20~3-FTE- 16
ED/vl
1~631~
xample 4 ;~
N-ethyl-N'- ~-(hexafluoro-2-h~droxy-2-propyl)-2
~ethoxycarbonyl)phenyl~ urea.
Mix 4.3 g (1~ m.mole) Or ethyl 5-(hexafluoro-2-hydroxy-
2-propyl)anthranilate, obtained as descrlbed in Example
3, with 1.8 g (26 m~mole) of ethyl isocyanate in 20 ml
of diethyl ether. Reflux for 5 days addinK each day a
further 1.8 g portion of ethyl isocyanate. Concen-~
trate the reaction mixture to obtain 5.5 g of a white
solid. Recrystallize by dissolving in diethyl ether,
adding hexane and then evaporating Or~ the diethyl ether
until precipitation is e~ected to obtain 4.5 g of N- ; ;
ethyl-N'- t4-(hexafluoro-2-hydroxy-2-propyl)-2-(etho- `~
xycarbonyl)phenylJ urea as a whlte solid, m.p,
144-146C.
',''-',`,
Example 5 ~ ~ ;
N hyl-N'- ~4-(hexafluoro-2-h~droxy-2-propyl)pheny~
urea. ;
Mix 20.7 g (80 m.mole) 4-(hexafluoro-2-hydroxy-2-
propyl)aniline (which may be obtained as described
by E.E. Gilbert, J. Org. Chem., ~0, 1001 (1965)) and
g of ethyl isocyanate in 100 ml of diethyl ether
and reflux for 16 hours. Conoentrate the reaction
mlxture to obtain 26 g of a white solid. Recrystal~
lize from a diethyl ether-hexane mixture as described
in Example 4 to obtain 24.5 g of N-ethyl-N'- ~4- - ;
(hexafluoro-2-hydroxy-2-propyl)phenyl~ urea, m.p. 178-179C.
-16- ;
`' ' . . ' " ' ' ' ' ' ~ . ~
,. . ., ', ' . , . '
OCT-24-1975
20~3-FTE- 17 "~
ED/vl
~;31~Z
Example 6
N-(2-chloroethyl)-N'- ~4-(hexafluoro-2-hydrox~-2-propyl)
phenyl~ -N'-methylurea. ~
Mix 4.1 g (15 m.mole)of 4-(hexafluQro-2-hydroxy-2-pro- ~ ;
pyl)-N-methylaniline (E.E. Gilbert, J. Org. Chem., 30
1001 ~1965)) and 1.9 g (18 m.mole) 2-chloroethyl iso-
cyanate ln 40 ml of diethyl ether~ Allow the mixture
. ,
to stand overni~ht, concentrate to obtain-6 g of a beige
solid. Recrystallize from a diethyl ether-hexane-mix~ ~
ture as described in Example 4 to obtain 5.5 g of N- -
(~-chloroethyl)-N'- ~4-~hexafluoro-2-hydroxy-2-propyl)
phenylJ -N'-methylurea as an off-white solid, m.p. 120-
121C~ ~
.' ~..~ -
:;..... :.'-,
Example 7
4-(hexafluoro-2-hydroxy-2-propyl)anilinoacetaldehyde
dimethyl acetal.
Mix 31.~ g (0.17 mole) of anilinoacetaldehydedimethyl-
acetal and 1.7 g of p-toluenesulfonic acid in 200 ml of
benzene. Bubble 32 g (0.2 mole) of hexafluoroacetone
into the reaction mixture under nitrogen and then reflux
for 20 minutes. Concentrate the reaction mixture and ~ `
: ::
partition between hexane and 200 ml of lN aqueous
~ sodium hydroxide. Stir the aqueous sodium hydroxide
I layer with 400 ml of diethyl ether and add 14.4 g of
acetio acid. Wash the diethyl ether layer with 250 ml ~ ;
of lN aqueous sodium bicarbonate solution. Dry and
treat the diethyl ether extract with decolorizing
', - .,;~.
-17-
: :.... . : . . . :
OCT-24 -1975
20~3~FTE-18
ED/vl
~63~12
charcoal. Concentrate to obtain 50 g Or brown solid.
Distil the brown solid at 0.1 mm Hg and collect ~1 g
of yellow oil between 140~144C which crystallizes upon
cooling. Recrystallize from a diethyl et;her-hexane
mixture as described in Example 4 to obtain 15 g of
4-(hexafluoro-2-hydroxy-2-propyl) an~lino--acetaldehyd~
dimethyl acetal as a tan solidJ m.p. 72-74C.
,, .~ , .. ...
: ~ ', ! ',, . ~
Example 8
., ~
N-ethyl-N'- L4-(hexafluoro-2-hydroxy-2-prop~Il)phenyl~
N'-(2,2-dimethoxyethyl)_urea. ~
Mix 20.0 g (56 m.mole) of 4-(hexafluoro-2-hydroxy-2- ~ ;
propyl)anilino aoetaldehyde dimethyl acetal (obtained
as described in Example 7) and 1.5 g (22 m.mole) ethyl
,,, ~ , ~ .
isocyanate in 200 ml of diethyl- ether. Allow the
15 reaction mixture to stand overnight and then concentrate
to obtain 25 g of a tan solid. Recrystallize from
a diethyl ether-hexane mixture as described in Example -
,
4 to obtain 16 g of the title compound as a white solid,
m.p. 138-140C.
"' ', ~
~ 20 Example 9
- ~:
N-ethyl-N'- [2-(hexafluoro-2-hydroxy-2-propyl)-1-naph-
thylJ urea.
Mix 6.1 ~ (20 m.mole) of 2-(hexafluoro-2-hydroxy-2-
propyl)-l-nàphthylamine (E.E. Gilbert, J. Org. Chem.,
~0, 1001 (1965)) and 2.8 g (40 m.mole) ethyl isocyanate
in 60 ml of diethyl ether. Concentrate after 1 hour
-18-
.
.
OCT-2l~-1975
20~ FTE_1 9
1 ~ ~3~ ~Z ED/vl
to obtain 7.5 g o~ a pink solid. Recrystallize
by dissolving the solid in methanol and then adding
water to effect precipitation to obtain 6.5 g of
N-ethyl-N'- ~2-(hexafluoro-2-hydroxy-2-propyl)-1-
naphthyl~ urea as a pink solid, m.p. 218-2200C.
,:
Example 10
~-ethyl-6-(hexafluoro-2-hydroxy-2-propyl)~uinaæoline-
2g4-dione
.
Mix 4 02 g (10 m.mole) Or N-ethyl-N'- ~4-(hexafluoro-
2 hydroxy-2 propyl) 2-(ethoxycarbonyl)phenylJ urea
(obtained as described in Example 4) with 21 ml (20
m.mole) of lN aqueous sodium hydroxide solution and
stir ror 1 minute. Acidify the reaction with lN
hydrochloric acid and extract with 100 ml of diethyl
ether. Dry and concentrate the extract to obtain ~.5 g
o~ a white solid. Recrystallize from a diethyl ether-
hexane mixture as described in Example 4 to obtain
2.5 g of white solid ~-ethyl-6-(hexafluoro-2-hydroxy-2-
propyl)quinazoline-2,4-dione) m.p. 268-270C.
:
Example 11
N-ethyl-N'- ,r2-bromo-4-(hexafluoro-2-hydroxy-2-propyl) ~ ;
phenyl~ urea.
Mix 4.9 g (15 m.mole) o~ N-ethyl-N'- ~4-(hexafluoro-2-
hydroxy-2-propyl)phenyl~ urea (obtained as described
in Example 5) and 1 ~ g (16.5 m.mole) of sodium acetate
with 2.4 g (15 m.mole) Or bromine in 70 ml of acetic
-19
. ~ ~
. , . -. ~ . ~ ~ .
-' . : . :; .:.
OCT-24-1975
2083-FTE-20
ED/vl i
~L~631~LZ . ~ ~
.,, ~
acid and stir for 20 hours. Pour the reaction mixture
into 700 ml Or iced water. Filter off the solld,
dissolve in dlethyl ether, dry and concentrate to obtain
5 g of foam. Treat the foam with methylene dichloride ;~
to form a solid. Recrystallize, by treating with ^~
methanol and chloro~orm and then evaporating to pre-
cipitate, to obtain 3.5 g of white solid N-ethyl-N'~
~2-bromo-4-(hexafluoro-2-hydroxy-2-propyl)pheny~ ure~
m.p. 125-127C.
Example 12
N-ethyl-N'- r4-~hexa~luoro-2-hydroxy-2-propyl)-2-nitro `
~henyl~ urea.
Dissolve 12.0 g (36 m.mole) of N-ethyl-N'- L4-(hexafluoro-
2-hydroxy-2-propyl)phenylJ urea (obtained as described~
in Example 5) in 72 ml of concen~rated sulfuri¢ acid
and cool to below 5C. Add dropwise a solution of -
~ .;.
2.8 ml of concentrated nitric acid in 24 ml of con-
¢entrated sul~uric acid and stir for 40 minutes. Pour ;
.
the reaction ~ixture into 800 ml o~ iced water and stir.
~ilter o~f the yellow solid and dissolYe in 400 ~
, of diethyl ether. Wash the diethyl ether solution ~;
twice with 450 ml portions of water. Dry and then
concentrate the diethyl ether extract to obtain 1~ g
o~ yellow solid. Recrystallize by dissolving the solid
in methan~ and then addlng water to effect precipitation
to obta~n 11 g of N-ethyl-N'- [(4-(hexafluoro-2-hydroxy- ;
2-propyl)-2-nitrophenyl~ urea as a yellow solid, m.p.
169-171C.
-20-
'.
ocT-24-lg75
2083-FTE- 21
~06311Z ED/vl ~ 1
Example~
Phenyl N- r4-(hexa~luoro-2-hydroxy-2-propyl)phenyl
`: ' ' .
carbamate.
Dissolve 10.3 g (40 m.mole) o~ 4-(hexafluoro-2-hydroxy-
2-propyl~ aniline in 50 ml Or methyl cyanide. Add
7.8 g (50 m.mole) of phenyl chloroformate followed
dropwise by ~.1 g of dry pyridine in 10 ml o~ methyl
c~Tanide. Pour the reaction m~xture into 400 ml of
water. Filter off the solid, dissolve in diethyl
ether, wash with 200 ml of water and then dry and
ooncentrate the ether extract to obtain 16 g Or w~lte
solld. Recrystallize f'rom a diethyl ether~hexane ~ -
mixture as described in Example 4 to obtaln 12.5 g
of phenyl N- ~4-(hexafluoro-2-hydroxy-2-propyl)phenyl)
carbamate as a white solid, m.p. 192-194C.
: ' .
Example 14 ~ ~
N- f4-~hexa~luoro-2-h~droxy-2-propyl)phen~1] urea. ~;
Mix 6.o g (16 m.mole) Or phenyl N- ~4-(hexa~luoro-2-
hydroxy-2-propyl)phenyll carbamate tobtained as
ammonia-
descrlbed in Example 1~) and 65 ml of/saturated ethanol.
A~ter 1/2 hour, pour the reaction mixture into 150 ml ~;
o~ water. Concentrate, cool to 0C and ~ilter o~f the
- white solid to obtaln 5.5 g o~ N- ~4-(hexa~luoro-2
hydroxy-2-propy~)phenyl~ urea, m.p. 181-18~C.
-21-
.
.
~ . .
:. , ~-,
OCT-24-1975 ^~
208~-FTE-22
ED/vl
i3~1Z
.
Example 15 ~;~
N-ethyl-N'-methyl-N'- C2~6-dimethyl-4-(hexafluoro-2-
hydroxy-2-propyl)pheny~ urea.
. . .
Heat at reflux for three hours 1~.5 g of N,2,6-tri- ~ ;
methylaniline (0.10 mole) and 40 g of hexafluoroacetone
sesquihydrate (0.21 mole). Allow to cool and then
: ~
pour into water. Collect the solid, dry and recry-
stallize from a diethyl ether-hexane mixture as des-
cribed in Example 4 to give 27.9 g of a white solid
m.p~ 14~-144C. Mix 6 ~ of the product, N~2,6^tri-
methyl-4-(hexafluoro-2-hydroxJ-2-propyl)anillne (20
m.mole) with 5.4 g of ethyl isocyanate (80 m.mole) in
di~thyl ether. After 16 hours, concentrate and
recrystallize the residual solid rrom a diethyl ether-
hexane mixture to give 6.2 g of a white solid, m.p.
i78-179C.
~. .
Example 16
?- E~-hexafluoro-2-hydroxy-2-propyl)-N-methylanilino~
-2-oxazoline.
Dissolve 10.0 g (26 m.mole) of N-(2-chloroethyl)-N~-
r4-~hexafluoro 2-hydroxy-2-propyl) pheny~ -N'-methyl-
urea in a mixture of 50 ml of methanol and 100 ml
of water. Heat for one hour on a steam bath. Concen-
trate, and partition between lN a~ueous sodium blcarbo-
nate solution and diethyl ether and then extract with
200 ml of lN hydrochloric acid. Add sodium bicarbonate
and then extract with 200 ml of diethyl ether. Dry
-22- ~
,
.
. ,
OCT-24-1975
208~-FTE23 ~-
11D631~Z ED/la
the ether extraot and concentrate to obtain 7.8 g of the
title compound as a white solid, m.p. 188-190C. The
salts may be prepared by standard techniques such as by
treatment of a solution of the free base i.n a suitable
or~anlc solvent, e.g. ether, with the desired acid, e.g. ;~
hydrochloric, and then filtering off the precip1tated
salt. The hydrochloride salt melts at 147-149C. -
:' ~
In analogous manner to that descr~bed in the foregoing
Examples, the following representative compounds of the
present invention may be prepared:
N-ethgl-N'[-2-(hexafluoro-2-hydroxy-2-propyl)phenyl]urea,~
N-ethyl-N'-~4-(hexafluoro-2-hydroxy-2-propyl)phenyll-N'-
methyl urea,
N-ethyl-N'-[4-(hexafluoro-2-hydroxy-2-propyl)-2-methyl-
phenyl~ urea, `~
N,N'-diekhyl-N'-[4-(hexafluoro-2-hydroxy-2-propyl)phenylJ
urea,
N-ethyl-N'-~4-(hexafluoro-2-hydroxy-2-propyl)phenylJ-N'- `
isopropyl urea,
N-ethyl-N'-~2-ethyl-4-(hexafluoro-2-hydroxy-2-propyl) ;~
phenyl~ urea,
: ~ :
N-ethyl-N~-[4-(hexa~luoro-2-hydroxy-2-propyl)phenylJ-N ' - -
propyl urea,
N-ethyl-N'-[4-(hexafluoro-2-hydroxy-2-propy~)-2-(methoxy-
carbonyl)phenyl J-N' -methyl urea,
-23-
. ........ : . .
20~2 FTE~
10631~Z
N-ethyl-N'-[4-(chloro-2-hydroxypentafluoro-2-propyl)phe~
nyl)-N'-methyl urea,
. :
N-ethyl-N'-~2-chloro-4-(hexafluoro-2-hydroxy-2-propyl) : :
phenyl] urea,
~: :
N-ethyl-N'-~4-(hexafluoro-2-hydroxy-2-propyl)-2-methyl- ~:
phenyl]-N'-methyl urea~
N-ethyl-N'-[2-(methoxycarbonyl)-4-(hexafluoro-2-hydroxy- ~:~
2-propyl)phenyl] urea,
N-ethyl-N'-~2-chloro-4-(hexarluoro-2-hydroxy-2-propyl)- ;
6-methyl phenyl~ urea,
N-ethyl-N'-~2J6-dimethyl-4-(hexa~luoro-2-hydroxy-2-pro-
pyl)phenyl]-N'-methyl urea,
N-~2-bromoethyl)-N'-[4-(hexafluoro-2-hydroxy-2-propyl)
phenyl 1-N ~ -methY1 urea,
N-ethyl-N'-~4-(hexafluoro-2-hydroxy-2-propyl)-2-(2-propo~
xycarbonyl)phenyl]-N'-methyl urea,
N-ethyl-N'-[4-(hexafluoro-2-hydroxy-2-propyl)-2-methyl-
6-~methoxycarbonyl)phenyl~ urea,
N-ethyl-N'-14-(hexafluoro-2-hydroxy-2-propyl)phenyl~-
N'-(2-methoxyethyl) urea,
: N~ethyl-N' ~2,3-dimethyl-6-(hexafluoro-2-hydroxy-2-propyl)
- phenyl~ urea,
, ~
N-[4-(1,~-dichloro-2-hydroxytetrafluoro-2-propyl)-2,6-
dimethyl phenyl]-N'-ethyl urea,
N-(2-chloroethyl)-N'-E4-(hexafluoro~2-hydroxy-2-propyl)
phenyl~ urea,
-24-
.
OCT-24-1975 `~ :
20~-FTE-25 ~
ED/la : - :
~6311Z ~;
:
N-ethyl-N'-[4-(hexafluorQ-2-hydroxy-2-propyl~-2-(hydroxy-
methyl)phenyl]-N'-methyl urea,
N-ethyl-N'-[2-(hexafluoro-2-hydroxy-2-propyl)-1-naphthy}J-
N'-methyl urea, ~:
N-ethyl-N'-[4-(2-hydroxypentafluoro-2-propyl)phenyl~-N'-
methyl urea J
N-ethyl-N'-[4-(hexafluoro-2-hydroxy-2-propyl)-2-amino-
carbonylphenyl~-N'-methyl urea
N-ethyl-N'-~4-(hexafluoro-2-hydroxy-2-propyl)-2-methyl~
6-t-butylphenyl] urea hydrate,
N-(2-chloroethyl)-N'-~2J6-dimethyl-4-(hexafluoro-2-hy- :~
droxy-2-propyl)phenyll-N'-methyl urea,
N-ethyl-N'-[4-(2-hydroxy-lJl,~-trichloro-1,3J~-trifluoro- ~''. ;
2-propyl)phenyl]-N'-methyl ureaJ
N-ethyl-N'-(2-ethoxyethyl)-N'-[4-(hexafluoro-2-hydroxy- ~ :
2-propyl)phenyl~ ureaJ
N-ethyl-N'-[4-(hexafluoro-2-hydroxy-2-propyl)phenyl~-N- ~.
(2,2-di-ethoxyethyl) urea,
NJN'-diethyl-N- E4- (hexa~luoro-2-hydroxy-2-propyl)2,6-
dimethylphenyl~ ureaJ
N-(2-chloropropyl)-N'-methyl-N'-~4-(hexafluoro-2-hydrox~-
2-propyl~phenyl] urea,
N-~5-bromo-2-(hexafluoro-2-hydroxy-2-propyl)-1-naphthyl~-
N'-n-propyl urea,
N-ethyl-N'-~2,6-dimethyl-4-(2-hydroxy-1,1,3-trichloro-
~ trifluoro-2-propyl)phenyl~ urea,
: -25- :
'.
;. ~ - . .: , ; .. , :
.. , .. ~ . - . ,. , .. . ; .
:: - . . . .. . . : - .
OCT-24-1975
2083~FTE-26
3L063~llZ ED/la
,.
N-ethyl-N'-~4-(Aexafluoro-2-hydroxy-2-propyl)-2~methyl- ~:
l-naphthylJ urea,
N-12-(hexafluoro-2-hydroxy-2-propyl)- l-naphthyll-N'-
methyl urea,
N-ethyl-N'-[4-(1,3-dichloro-2-hydroxytetrafluoro-2-propyl)-
2,6-diethyl phenyl~ urea, ~ ;
N-2-(chloroethyl)-N'-[2-(hexaf1uoro-2-hydroxy-2-propy~)- ;
l-naphthyl] urea,
N-ethyl-N'-[2,6-diethyl-4-~hexarluoro-2-hydroxy-2-propyl)
phenyl] urea, ~.
N-ethyl-N'-[4-(hexafluoro-2-hydroxy-2-propyl)phenyl~- :
N'-11,3-dioxolan-2-yl)methyl~ urea,
N-[7-methyl-2-(hexafluoro-2-hydroxy-2-propyl)-naphthyl~- .
N'-n-propyl urea,
2-~2-(hexafluoro-2-hydroxy-2-propyl)-1-naphthylamino~
2-oxazoline, ;:
2-~2-bromo-4-(hexafluoro-2-hydroxy-2-propyl)-anilino~-
2-oxazoline,
2-~4-(1,3-diohloro-2-hydroxy-tetrafluoro-2-propyl)-N-
propylanilino]-2-oxazoline,
2-l4-(hexafluoro-2-hydroxy-2-propyl)anllino~-2_oxa201ine,
~ 2-[N-2,6-trimethyl-4-(hexafluoro-2-hydroxy-2-propyl)ani-
lino~-2-oxazoline hydrochloride, .
2-~4-(hexafluoro-2-hydroxy-2-prop~l)-N-methyl anilino- .
5-methyl~2-oxazoline,
_26-
`;
.:: . , ,- . , , ,: - : .
..
. , . . . : . . .: . ; - .
.. ; . . .. :
NOV-6 - l 975 ' '
2083-FTE-27A
ED/vl
~C~63~
~,, `' `
or the co~pounds of the present invention, it may in
general be sald that the oxazolines form a prererred ::
area Or compounds on the basis of their favourable ;~
activity. Nevertheless, it has been noted that while ~:
the phenyl ureas may be somewhat less potent, in
certain instances such phenyl ureas give little or no
increase in heart rate.
Exemplary of further oxazolines which may be prepared
in the manner set ~orth in the Examples are~
Z-~4-(tetrafluoro~ dichloro-2-hydrox~-2-propyl)-N-
, : ,
methylanilino~-2-oxazollne hydrochloride, `.~
, . .
2-E4-(hexa~luoro-2-hydroxy-2-propyl)-2~chloro-N-methyl- ;~
anilino]-2-oxazoline hydrochloride,
: 2-~4-(hexafluoro-2-hydroxy-2-propyl)-N-n-propylanilino] ~`
-2-oxazollne bisulfate,
, ! . ,~ ,~,
2-[4-(1 J 1,1-trifluoro-2-hydroxy-2-propyl)-N-methylanilino]-
2-oxazoline bisul~ate,
, . . .
2-[2,6-dichloro-4-(hexafluoro-2-hydroxy-2-propyl)-N-
methylanilino]-2-oxaæoline bisulfate, ^
2-[2,6-dilsopropyl-4-(hexafluoro-2-hydroxy-2-propyl)-N- : .
. . :
methylanilino]-2-oxazoline bisulfate,
.- ~
2-~2,6-diethyl-4-(hexafluoro-2-hydroxy-2-propyl)-N- :~
methylanilino]-2-oxazoline bisulfate,
2-t2-chloro-4-(hexafluoro-2-hydroxy-2-propyl)-N,6-dl-
~ -27~
:
~ .
NOV-6-l97$
20~33-F'rE-27B
ED/vl - ~
~IL063~
~ :
methylanilino]-2 oxazollne bisulfate,
2-[4-(hexafluoro-2-hydroxy-2-propyl)-2-methoxy-N-
methylanilino]-2-oxazoline phosphate, methanol solvate,
2-[2-fluoro-4-(hexafluoro-2-hydroxy-2-propyl)-N-methyl~
anilino]-2-oxazoline bisulfate,
2-[4-(hexafluoro-2-hydroxy-2-propyl)-2,5-dimethyl-N-
methylanilino]-2-oxazoline bisulfate,
2-[4-(hexafluoro-2-hydroxy-2-propyl)-2,6-dimethoxy-N- :~
methylanilino]-2-oxazoline bisulfate,
2-~N-ethyl-4-(hexafluoro-2-hydroxy-2-propyl)anilino]-2-
oxazoline sulfate and
2-[4-(hexafluoro-2~hydroxy-2-propyl)-N,2-dimethylanili-
no]-2-oxazoline hydrochloride. ~;~
'; ':
, ~ . .
If in the formulation Examples hereafter described one
employs as active ingredient 2-~4-(hexafluoro-2-hydroxy-
2-propyl)-N-methylanilino]-2-oxazoline then it is
oonsidered that l mg per tablet or capsule represents
a suitable amount of ac~ive ingredlent. The ~ormula- ~
tion may be effected in essentially the same way as ~ :-
described in those Examples.
;,
.
-27 ~
- . . .
NOV~ -1975
208~-FTE-28
ED/vl
~31~Z :;
In the treatment of hypertension, a number of agents
are knownD Certain Or these, for example reserpine,
are ef~ective in lowering the blood pressure in some
patients but in other patients give rise to undesirable
and well known side errects. Other known agents
lack adequate potency or result in tolerance to the
drug developing. -~
,. ~
The compounds Or the present invention have been found
to exhibit useful anti-hypertensive activity. Further, ~ ;
representative compounds of the invention have been
found to be particularly active as antl-hypertens~ve
agents whlle avoiding or mitigating some of the dele-
terious side effects associated with known anti~hyper~
tensive agents. Based on laboratory tests and proce-
dures, lt is considered that the effective dosage~ the
ED50, b~ oral administration for a compound of the
present invention will typically lie within the range
of rrom 0.01 to 20 mg~kg of mammalian weight per day.
For the compound of Example 16 the expected dally human
dose would be about o.6 to 10 mg. For the purposes of
rurther illustration, it may be mentioned that for N- ~;
(2-chloroethyl)-N'-[4-hexafluoro-2-hydroxy~2-propyl)
phenyl~-N'-methyl urea the minimum effective dosage in
rats is 0.5 to 1.0 mg/kg. Regarding toxicity, the
aforementioned compound was nonlethal at a dose ra~e of -~
100 mg/kg.
The required daily dosage may be administered in single
-~ ~
-28- 1
NOV-6-1975
20~-FTE-29
ED/vl
~063~L~Z `
or divided doses. The exact dose to be administered
wlll, o~ course/ be dependent upon where the compound
in question lles within the above quoted dosage ranges
and upon the age and weight o~ the sub~ect mammal.
The compounds o~ the invention may be administered alone
or combined with other medlcinals such as ~- adrenergic
blocking agents, e.g~ propanolal hydrochloride. The
compounds are administered orally. In any event, a
suitable pharmaceutical carrier is employed, with the
carrier selected according to the physical properties
Or the compound ln the pharmaceutic composition. The
carrier should not reac~ ohemically wlth the compound
to be administered. The preparations containing the
active ingredients may typically be in the form o~
tablets~ capsules, syrups, elixirs or suspensions.
'~
. . :
"' ~
', ~
-29-
NOV-6-1975
20&3-~E-30
ED/vl
1C~63~
Represer-ll;ative rormulations ror the compounds of the
general formnla I ~Jill now be illustrated ~y way
of the followir~g Examples.
Example A
Tablet Formulations
Formulation I Milligrams per Tablet
Active ingredient: N-(2- -
chloroethyl)-N'- ~4-(hexa-
fluoro-2-hydroxy-2-propyl)
pheny~-N'-methyl urea ~................... 10
Lactose, direct compression grade .... 213
Microcrystalline cellulose ............... 30
Sodium Lauryl Sul~ate .................... 20
Corn starch .............................. 25
Magnesium stearate .......... ,............ 2.0
300.0
Formulation Il
Active lngredient: N-ethyl-N'-
4-(hexafluoro-2-hydroxy-2-pro-
pyl) phenyl~ -N'-(2,2-dimethoxy-
ethyl) urea ................. ...,.... 0.... 10
Lactose, direct compression grade....... 213
Microcrystalline Cellulose.............. 30 ~^
Sodium Iauryl Sul~ate................... 20 ~
Corn Starch ............................ 25 ! ~ -
Magnesium Stearate ..................... 2
300
:,
-30 `
.~,
.. . . . . . . . .
:: . . , . . . . . ~ .
NOV-6-1975
20~-FTE-31
~063112 ED~vl
Procedure for ~ormulations I and II.
"
Mix together-the stated active ingredient~ lactoseJ
microcrystalline cellulose, sodium lauryl sulfate and
corn starch. Pass through a No. 40 screen. Add the
magnesium stearate, mix and compress into desired shape
on a tablet machine.
Formulation III Milli~rams per Tablet
Active ingredient; N-
(2-chloroethyl)-N'- r4-
(hexafluoro-2-hydroxv-
2-propyl)pheny~-N-methyl
urea ... ,... ,,,,.. ,,,,....... ,... ,. 10
Lactose, U.S.P. ..........Ø......... 231
Dicalcium phosphate ................... 57
Sodium Lauryl Sulfate ................. 20
Polyvinylpyrrolidine .................. 10
Water 50 ml/1000 tablets
Corn Starch ............... ~.... ,,. 20
Magnesium Stearate .................... 2 `
~50
Formulation IV -
Active in~redient: N-ethyl-
-N'- ~4-thexafluoro-2-hy- -~
droxy-2-propyl)pheny~ -N'- ~
(2,2-dimethoxyethyl) urea ............. 10 ;
Lactose, U.S.P. ....................... 231 `~
Dicalcium Phosphate ................... 57
Sodium Lauryl Sulfate ........... ~. 20
Polyvinylpyrrolidone .................. 10
:~
-31-
..... ~ .. . :
., : . .
:. . . .. .
NOV-6-1975 ~ `
20~ 3-F~E-~2 ~ ' :~ `' ''`` ' ~ `
1063~1Z ED/vl ~ ~
.
Formulation IV (contd.) Milligrams per Tablet
, ~
Water 50 ml/iOOO tablets
~., .
Corn Starch ...........Ø............. 20
:, ~
Magnesium Stearate ................ 2
350 ~ ~
~. ,
-: , '
Procedure for rormulations III and IV.
Mix together the stated active ingredient,lactose,
dicalcium phosphate and sodium lauryl sulfate. Screen
, ,
the above mixture through a No. 60 screen and granulate
with an aqueous solution containing polyvinylpyrroli-
~.. ; ,
done. Add additional water, i~ necessary, to brlng the
powders to a pasty mass. Add corn starch and con~
i :
tinue mixing until uniform granules are formed. Pass - 1
through a No. 10 screen, tray and dry in an oven at ;~
40C for 12 to 14 hours. Reduce the dried granula~
1~ tion through a No. 16 screen. Add magnesium stea-
, .j .
rate, mix and compress into desired shape on a tablet `~
: .
maohine. ~
,
,
Example B
Capsule Formulations
~ .. . ,~
ormulation I Milligrams per Capsule
Active ingredient: N-
(2-chloroethyl)-N'- L4
(hexarluoro-2-hydroxy-2-
propyl)pheny~ -N'-methyl
urea ..... 0............................ 10 ^
Lactose, U.S.P. ...................... 213
.
-32- ~;
. ,: . .
:':; ., , ` ` :' :`. ' ` :, ' : , ' . I . . :
NOV-6-1~75
631 lZ 20~3-FTE-3
ED/vl
,
Formulation I (contd.) Milligrams per Capsule
Microcrystalline Cellulose ,,30
Sodium Lauryl Sulrate ..................... 20
Corn Starch .............~................. 25
Magnesium Stearate .................... ..... 2
300 ~ ;
!¦ ~
Formulation II
Active ingredient: N-ethyl-
N'- [4-(hexafluoro-2-hydroxy-
2-propyl)phenyl~ -N'-(2l2-di-
methoxyethyl) urea ..........~,....... ,,, 10
Lactose, U.S.P. .................... ..... 213
Miorocrystalline Cellulose ..,.......... , ~0
;.
Sodium Lauryl Sulfate ,............. ...... 20
Corn Starch .................,............ 25
Magnesium Stearate ..........,............. 2
~00
. ;
:
Procedure:
Mix together the stated active ingredient,lactose~ `
microcrystalline cellulose, sodium lauryl sulfate and
corn starch. Pass through a No. 80 screen. Add the ;-
magnesium stearate, mix and encapsulate into the proper
size two-pièce gelatin capsule.
:~ ,
' '~'
.
~,
,
