CA1063112A - Substituted ureido-compounds - Google Patents
Substituted ureido-compoundsInfo
- Publication number
- CA1063112A CA1063112A CA240,512A CA240512A CA1063112A CA 1063112 A CA1063112 A CA 1063112A CA 240512 A CA240512 A CA 240512A CA 1063112 A CA1063112 A CA 1063112A
- Authority
- CA
- Canada
- Prior art keywords
- general formula
- grouping
- phenyl
- hydroxy
- propyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
- C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
- C07D239/96—Two oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/28—Nitrogen atoms not forming part of a nitro radical
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
Described herein are novel hydroxylpolyhaloisopropyl-substituted ureido compounds exhibiting useful anti-hypertensive activity, processes for their preparation and pharmaceutical compositions containing these compounds. The ureido-compounds are selected from phenyl ureas, oxazolines and quinazolines represented by the formula:
and the pharmaceutically acceptable salts of the oxa-zolines and quinazolines, where Z represents , or, together with X2, the grouping in which R1 is ethylene or substituted ethylene and R and R2 represent other specified sub-stituents and wherein one of X2 and X4 is the hydroxy-polyhaloisopropyl grouping
Described herein are novel hydroxylpolyhaloisopropyl-substituted ureido compounds exhibiting useful anti-hypertensive activity, processes for their preparation and pharmaceutical compositions containing these compounds. The ureido-compounds are selected from phenyl ureas, oxazolines and quinazolines represented by the formula:
and the pharmaceutically acceptable salts of the oxa-zolines and quinazolines, where Z represents , or, together with X2, the grouping in which R1 is ethylene or substituted ethylene and R and R2 represent other specified sub-stituents and wherein one of X2 and X4 is the hydroxy-polyhaloisopropyl grouping
Description
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
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
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 . . .
.. . . ..
. . : .
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.
, ;:..
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.
~;
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 ';' ~
. .
,~. . ' ; ' ' 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
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- : ;
'; ' ~
:. :
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 ' : ~
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 ` ~
,`' ~ . ' '~' '~ ~
.. ' . ' .. . , , , . . !
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 ' ~.
.. ~ , . ,~ . . :
.
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
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- '~
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 . ~
ocT-24-lg75 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.
... . . .. , . ~ . .. . .=.. ..
,. . : .
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.
: ~ . . , , , .;.................... . . . . . ~
: : - :: .
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
~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
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 . . .
.. . . ..
. . : .
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.
, ;:..
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.
~;
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 ';' ~
. .
,~. . ' ; ' ' 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
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- : ;
'; ' ~
:. :
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 ' : ~
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 ` ~
,`' ~ . ' '~' '~ ~
.. ' . ' .. . , , , . . !
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 ' ~.
.. ~ , . ,~ . . :
.
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
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- '~
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 . ~
ocT-24-lg75 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.
... . . .. , . ~ . .. . .=.. ..
,. . : .
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.
: ~ . . , , , .;.................... . . . . . ~
: : - :: .
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- ;
`' ' . . ' " ' ' ' ' ' ~ . ~
,. . ., ', ' . , . ' 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
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- ;
`' ' . . ' " ' ' ' ' ' ~ . ~
,. . ., ', ' . , . ' 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 ', - .,;~.
: :.... . : . . . :
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 .
.
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 . ~ ~
. , . -. ~ . ~ ~ .
-' . : . :; .:.
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
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 ', - .,;~.
: :.... . : . . . :
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 .
.
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 . ~ ~
. , . -. ~ . ~ ~ .
-' . : . :; .:.
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.
'.
ocT-24-lg75 ~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.
.
.
~ . .
:. , ~-, 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- ~
, .
. , 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, . ........ : . .
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)- ;
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.
'.
ocT-24-lg75 ~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.
.
.
~ . .
:. , ~-, 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- ~
, .
. , 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, . ........ : . .
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, .
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- :
'.
;. ~ - . .: , ; .. , :
.. , .. ~ . - . ,. , .. . ; .
:: - . . . .. . . : - .
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 ' ' 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 -~ ~
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.
'~
. . :
"' ~
', ~
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 :, -30 `
.~, .. . . . . . . . .
:: . . , . . . . . ~ .
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 :~
..... ~ .. . :
., : . .
:. . . .. .
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.
:~ , ' '~' .
~, ,
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, .
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- :
'.
;. ~ - . .: , ; .. , :
.. , .. ~ . - . ,. , .. . ; .
:: - . . . .. . . : - .
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 ' ' 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 -~ ~
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.
'~
. . :
"' ~
', ~
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 :, -30 `
.~, .. . . . . . . . .
:: . . , . . . . . ~ .
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 :~
..... ~ .. . :
., : . .
:. . . .. .
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.
:~ , ' '~' .
~, ,
Claims (12)
1. A process for the preparation of a hydroxypolyhalo-isopropyl-substituted ureido-compound selected from the group consisting of phenyl ureas, oxazolines and quinazolines and of the general formula I
(I), and the pharmaceutically acceptable salts of said oxa-zolines and quinazolines, wherein Z is a grouping containing the ureido-or iso-ureido-functions or , Z being , or, together with X2, the grouping , in which groupings R is hydrogen, lower alkyl, alkoxy-lower alkyl or dialkoxy-lower alkyl, R1 is an ethylene grouping -CH2-CH2- or a methyl-substituted ethylene grouping, and R2 is hydrogen, methyl or -R1X where X is hydrogen or halogen, of X2 and X4 one is a hydroxypolyhaloisopropyl grouping designated Rf and of the formula Ia (Ia), in which Y independently represents hydrogen, chlorine or fluorine, and the other of X2 and X4 is hydrogen, lower alkyl, halogen, lower alkoxy, hydroxy lower alkyl, nitro, lower alkoxy carbonyl or aminocarbonyl, X3 is hydrogen or lower alkyl, and X5 and X6 independently represent hydrogen, lower alkyl, lower alkoxy or halogen, or together with the carbon atoms to which they are attached represent a fused benzenoid ring, which ring may be substituted by lower alkyl or halogen, which process comprises one of the following processes A to E:
A: reacting an amine of the general formula II
(II), with a reactive derivative of a carbamic acid of the general formula R2NH.COOH
in which formulae R, R2, X2, X3, X4, X5 and X6 are as defined for formula I;
B: reacting a reactive derivative of an N-phenyl carbamic acid of the general formula III
(III), with an amine of the general formula R2NH2, in which formulae R, R2, X2, X3, X4, X5 and X6 are as defined for formula I;
C: subjecting to intramolecular condensation an N-phenyl urea of the general formula IV
(IV), wherein R, R1, X2, X3, X4, X5 and X6 are as defined for formula I and Q1 is a reactive grouping capable of being eliminated as HQ1 under the reactive conditions employed;
D: cyclising an N-phenyl urea of the general formu-la V
(V), wherein R, R2, X3, X4, X5 and X6 are as defined for for-mula I and Q2 is a reactive grouping capable of being eliminated as HQ2 under the reaction conditions employed;
E: introducing a halo or nitro substituent into the benzenoid ring at a position ortho to the group Z by halo-genating or nitrating in conventional manner a correspon-ding des-halo or des-nitro compound of the general formula I;
said process selected from the processes A to E being followed if desired by the step of converting a so-obtained oxazoline or quinazoline of the general formula I into a pharmaceutically acceptable salt.
(I), and the pharmaceutically acceptable salts of said oxa-zolines and quinazolines, wherein Z is a grouping containing the ureido-or iso-ureido-functions or , Z being , or, together with X2, the grouping , in which groupings R is hydrogen, lower alkyl, alkoxy-lower alkyl or dialkoxy-lower alkyl, R1 is an ethylene grouping -CH2-CH2- or a methyl-substituted ethylene grouping, and R2 is hydrogen, methyl or -R1X where X is hydrogen or halogen, of X2 and X4 one is a hydroxypolyhaloisopropyl grouping designated Rf and of the formula Ia (Ia), in which Y independently represents hydrogen, chlorine or fluorine, and the other of X2 and X4 is hydrogen, lower alkyl, halogen, lower alkoxy, hydroxy lower alkyl, nitro, lower alkoxy carbonyl or aminocarbonyl, X3 is hydrogen or lower alkyl, and X5 and X6 independently represent hydrogen, lower alkyl, lower alkoxy or halogen, or together with the carbon atoms to which they are attached represent a fused benzenoid ring, which ring may be substituted by lower alkyl or halogen, which process comprises one of the following processes A to E:
A: reacting an amine of the general formula II
(II), with a reactive derivative of a carbamic acid of the general formula R2NH.COOH
in which formulae R, R2, X2, X3, X4, X5 and X6 are as defined for formula I;
B: reacting a reactive derivative of an N-phenyl carbamic acid of the general formula III
(III), with an amine of the general formula R2NH2, in which formulae R, R2, X2, X3, X4, X5 and X6 are as defined for formula I;
C: subjecting to intramolecular condensation an N-phenyl urea of the general formula IV
(IV), wherein R, R1, X2, X3, X4, X5 and X6 are as defined for formula I and Q1 is a reactive grouping capable of being eliminated as HQ1 under the reactive conditions employed;
D: cyclising an N-phenyl urea of the general formu-la V
(V), wherein R, R2, X3, X4, X5 and X6 are as defined for for-mula I and Q2 is a reactive grouping capable of being eliminated as HQ2 under the reaction conditions employed;
E: introducing a halo or nitro substituent into the benzenoid ring at a position ortho to the group Z by halo-genating or nitrating in conventional manner a correspon-ding des-halo or des-nitro compound of the general formula I;
said process selected from the processes A to E being followed if desired by the step of converting a so-obtained oxazoline or quinazoline of the general formula I into a pharmaceutically acceptable salt.
2. A process as claimed in claim 1 process A, wherein the amine of the general formula II is reacted with an isocyanate of the formula R2NCO in which R2 is a defined for formula I.
3. A process as claimed in claim 1 process B, wherein the reactive derivative of the N-phenyl carbamic and of the general formula III is a carbamoyl halide or carbamic acid ester.
4. A process as claimed in claim 1 process C, wherein in the starting material of the general formula IV Q1 is halogen.
5. A process for the preparation of a hydroxypolyhalo-isopropyl-substituted ureido-compound selected from the group consisting of phenyl ureas and oxazolines and of the general formula IA
(IA), and the pharmaceutically acceptable salts of said oxa-zolines, wherein Z is a grouping containing the ureido- or iso-ureido-functions or , Z being or in which groupings R is hydrogen or lower alkyl, R1 is an ethylene grouping -CH2-CH2- or a methyl-substituted ethylene grouping, and R2 is hydrogen, methyl or -R1X where X is hydrogen or halogen, Rf is a hydroxypolyhaloisopropyl grouping of the formula Ia (Ia) in which Y independently represents hydrogen, chlorine or fluorine, X2 represents hydrogen lower alkyl, halogen, lower alkoxy, hydroxy lower alkyl, nitro, lower alkoxy car-bonyl or aminocarbonyl, X3 is hydrogen or lower alkyl, and X5 and X6 independently represent hydrogen, lower alkyl or halogen, which process is selected from one of the following processes A to C:
A: reacting an amine of the general formula IIA
(IIA), with an isocyanate of the general formula.
in which formulae R, R2, X2, X3, X5 and X6 are as defined for formula IA;
B: reacting a reactive derivative of an N-phenyl carbamic acid of the general formula IIIA
(IIIA), with an amine of the general formula R2NH2, in which formulae R, R2, X2, X3, X5 and X6 are as defined for formula IA and Q is a halogen atom or an alkoxy or aryloxy grouping, C: subjecting to intramolecular condensation an N-phenyl urea of the general formula IVA
(IVA), wherein R, R1, X2, X3, X5 and X6 are as defined for formula IA and Q1 is a reactive grouping capable of being eliminated as HQ1 under the reactive conditions employed;
said process selected from processes A to C being followed if desired by the step of converting a so-obtained oxazoline into a pharmaceutically acceptable salt.
(IA), and the pharmaceutically acceptable salts of said oxa-zolines, wherein Z is a grouping containing the ureido- or iso-ureido-functions or , Z being or in which groupings R is hydrogen or lower alkyl, R1 is an ethylene grouping -CH2-CH2- or a methyl-substituted ethylene grouping, and R2 is hydrogen, methyl or -R1X where X is hydrogen or halogen, Rf is a hydroxypolyhaloisopropyl grouping of the formula Ia (Ia) in which Y independently represents hydrogen, chlorine or fluorine, X2 represents hydrogen lower alkyl, halogen, lower alkoxy, hydroxy lower alkyl, nitro, lower alkoxy car-bonyl or aminocarbonyl, X3 is hydrogen or lower alkyl, and X5 and X6 independently represent hydrogen, lower alkyl or halogen, which process is selected from one of the following processes A to C:
A: reacting an amine of the general formula IIA
(IIA), with an isocyanate of the general formula.
in which formulae R, R2, X2, X3, X5 and X6 are as defined for formula IA;
B: reacting a reactive derivative of an N-phenyl carbamic acid of the general formula IIIA
(IIIA), with an amine of the general formula R2NH2, in which formulae R, R2, X2, X3, X5 and X6 are as defined for formula IA and Q is a halogen atom or an alkoxy or aryloxy grouping, C: subjecting to intramolecular condensation an N-phenyl urea of the general formula IVA
(IVA), wherein R, R1, X2, X3, X5 and X6 are as defined for formula IA and Q1 is a reactive grouping capable of being eliminated as HQ1 under the reactive conditions employed;
said process selected from processes A to C being followed if desired by the step of converting a so-obtained oxazoline into a pharmaceutically acceptable salt.
6. A process for the preparation of a hydroxypolyhalo-isopropyl oxazoline of the general formula 1B
(1B), and the pharmaceutically acceptable salts thereof, which compri-ses subjecting to intramolecular condensation an N-phenyl urea of the general formula IVB
(IVB), wherein Q1 is a reactive grouping capable of being eliminated as HQ, under the reactive conditions employed, said process being followed if desired by conversion of the so-obtained compound into a pharmaceutically acceptable salt.
(1B), and the pharmaceutically acceptable salts thereof, which compri-ses subjecting to intramolecular condensation an N-phenyl urea of the general formula IVB
(IVB), wherein Q1 is a reactive grouping capable of being eliminated as HQ, under the reactive conditions employed, said process being followed if desired by conversion of the so-obtained compound into a pharmaceutically acceptable salt.
7. A process as claimed in claim 6, wherein in the start-ing material of the general formula IVB the grouping Q1 is halo.
8. A process as claimed in claim 6, wherein in the start-ing material of the general formula IVB the grouping Q1 is chloro
9. A ureido compound of the general formula I set forth in claim 1 and the specified pharmaceutically acceptable salts thereof, whenever prepared by a process as claimed in any one of claims 1 to 3 or by an obvious chemical equivalent thereof.
10. An oxazoline of the general formula I set forth in claim and the pharmaceutically acceptable salts thereof wherein in formula I
R, R1, X2, X3, X4, X5 and X are as defined in claim 1, whenever prepared by a process as claimed in claim 4, or by an obvious chemical equivalent thereof.
R, R1, X2, X3, X4, X5 and X are as defined in claim 1, whenever prepared by a process as claimed in claim 4, or by an obvious chemical equivalent thereof.
11. Phenyl ureas and oxazolines of the general formula IA
set forth in claim 5, and the specified pharmaceutically accept-able salts thereof, whenever obtained by a process as claimed in claim 5 or by an obvious chemical equivalent thereof.
set forth in claim 5, and the specified pharmaceutically accept-able salts thereof, whenever obtained by a process as claimed in claim 5 or by an obvious chemical equivalent thereof.
12. An oxazoline of the general formula 1B set forth in claim 6 and the pharmaceutically acceptable salts thereof, whenever obtained by a process as claimed in any one of claims 6 to 8 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US52860374A | 1974-12-02 | 1974-12-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1063112A true CA1063112A (en) | 1979-09-25 |
Family
ID=24106378
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA240,512A Expired CA1063112A (en) | 1974-12-02 | 1975-11-26 | Substituted ureido-compounds |
Country Status (26)
| Country | Link |
|---|---|
| JP (1) | JPS5182239A (en) |
| AR (2) | AR219478A1 (en) |
| AT (1) | AT357557B (en) |
| AU (1) | AU501512B2 (en) |
| BE (1) | BE835899A (en) |
| CA (1) | CA1063112A (en) |
| CH (1) | CH623044A5 (en) |
| CS (1) | CS188259B2 (en) |
| DD (1) | DD124730A5 (en) |
| DE (1) | DE2552933A1 (en) |
| DK (1) | DK535275A (en) |
| FI (1) | FI753332A (en) |
| FR (1) | FR2346000A1 (en) |
| GB (1) | GB1507340A (en) |
| HU (1) | HU175541B (en) |
| IE (1) | IE42759B1 (en) |
| IL (1) | IL48557A (en) |
| IT (1) | IT1051024B (en) |
| LU (1) | LU73888A1 (en) |
| NL (1) | NL7513804A (en) |
| NO (1) | NO146497C (en) |
| PH (1) | PH14474A (en) |
| PL (2) | PL102327B1 (en) |
| SE (2) | SE7513331L (en) |
| SU (2) | SU655311A3 (en) |
| ZA (1) | ZA757457B (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS52111541A (en) * | 1976-02-19 | 1977-09-19 | Scherico Ltd | Substituted ureido compound and medical composition containing it as active ingredient |
| US4107303A (en) | 1976-06-24 | 1978-08-15 | E. I. Du Pont De Nemours And Company | Antihypertensive hexafluorohydroxyisopropyl benzazepines and benzazocines |
| DE2839462A1 (en) * | 1978-09-11 | 1980-03-27 | Basf Ag | AROYL UREAS |
| US6316503B1 (en) | 1999-03-15 | 2001-11-13 | Tularik Inc. | LXR modulators |
| EP1476425A4 (en) | 2002-01-30 | 2010-05-05 | Amgen Inc | Heterocyclic arylsulfonamidobenzylic compounds |
| CA2474433A1 (en) | 2002-01-30 | 2003-08-07 | Tularik Inc. | Arylsulfonamidobenzylic compounds |
| US20030199578A1 (en) * | 2002-04-19 | 2003-10-23 | Turner Sean C. | Naphthalene amides as potassium channel openers |
| RU2712163C2 (en) * | 2014-10-24 | 2020-01-24 | Оно Фармасьютикал Ко., Лтд. | Activator of kcnq2-5 channels |
| JP6197971B1 (en) * | 2016-04-22 | 2017-09-20 | 小野薬品工業株式会社 | KCNQ2-5 channel-related disease prevention and / or treatment agent |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3453284A (en) * | 1966-01-19 | 1969-07-01 | Du Pont | Certain 2-(substituted-anilino)-2-oxazolines |
| DE1670751A1 (en) * | 1966-09-27 | 1970-12-23 | Bayer Ag | Process for the preparation of 2-phenylamino-2-oxazolines |
| FR1543534A (en) * | 1966-09-27 | 1968-10-25 | Bayer Ag | Manufacturing process of 2-phenylimino-oxazolidines |
| DE1670752A1 (en) * | 1966-09-27 | 1970-12-23 | Bayer Ag | Process for the preparation of 2-phenylamino-oxazolines |
| FR1543535A (en) * | 1966-09-27 | 1968-10-25 | Bayer Ag | Manufacturing process of 2-phenylamino-2-oxazolines |
-
1975
- 1975-11-21 CH CH1516475A patent/CH623044A5/en not_active IP Right Cessation
- 1975-11-25 BE BE162139A patent/BE835899A/en unknown
- 1975-11-26 FR FR7536178A patent/FR2346000A1/en active Granted
- 1975-11-26 GB GB48640/75A patent/GB1507340A/en not_active Expired
- 1975-11-26 IE IE2578/75A patent/IE42759B1/en unknown
- 1975-11-26 PH PH17810A patent/PH14474A/en unknown
- 1975-11-26 SE SE7513331A patent/SE7513331L/en not_active Application Discontinuation
- 1975-11-26 AR AR261362A patent/AR219478A1/en active
- 1975-11-26 AT AT898575A patent/AT357557B/en not_active IP Right Cessation
- 1975-11-26 ZA ZA757457A patent/ZA757457B/en unknown
- 1975-11-26 NO NO753984A patent/NO146497C/en unknown
- 1975-11-26 DE DE19752552933 patent/DE2552933A1/en not_active Withdrawn
- 1975-11-26 NL NL7513804A patent/NL7513804A/en not_active Application Discontinuation
- 1975-11-26 FI FI753332A patent/FI753332A/fi not_active Application Discontinuation
- 1975-11-26 AU AU86989/75A patent/AU501512B2/en not_active Ceased
- 1975-11-26 CA CA240,512A patent/CA1063112A/en not_active Expired
- 1975-11-27 IL IL48557A patent/IL48557A/en unknown
- 1975-11-27 DK DK535275A patent/DK535275A/en not_active Application Discontinuation
- 1975-11-27 LU LU73888A patent/LU73888A1/xx unknown
- 1975-11-27 JP JP50141811A patent/JPS5182239A/ja active Pending
- 1975-12-01 DD DD189793A patent/DD124730A5/xx unknown
- 1975-12-01 CS CS758133A patent/CS188259B2/en unknown
- 1975-12-01 HU HU75SCHE549A patent/HU175541B/en unknown
- 1975-12-01 PL PL1975193580A patent/PL102327B1/en unknown
- 1975-12-01 PL PL1975185156A patent/PL99122B1/en unknown
- 1975-12-01 SU SU752194050A patent/SU655311A3/en active
- 1975-12-02 IT IT29923/75A patent/IT1051024B/en active
-
1976
- 1976-10-20 AR AR265154A patent/AR218436A1/en active
- 1976-10-26 SU SU762414458A patent/SU685146A3/en active
-
1980
- 1980-06-11 SE SE8004364A patent/SE8004364L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| SU655311A3 (en) | 1979-03-30 |
| ZA757457B (en) | 1976-11-24 |
| DE2552933A1 (en) | 1976-06-10 |
| DK535275A (en) | 1976-06-03 |
| FR2346000A1 (en) | 1977-10-28 |
| AR218436A1 (en) | 1980-06-13 |
| LU73888A1 (en) | 1976-09-06 |
| AU501512B2 (en) | 1979-06-21 |
| JPS5182239A (en) | 1976-07-19 |
| IE42759L (en) | 1976-06-02 |
| CH623044A5 (en) | 1981-05-15 |
| IL48557A0 (en) | 1976-01-30 |
| AR219478A1 (en) | 1980-08-29 |
| BE835899A (en) | 1976-05-25 |
| FR2346000B1 (en) | 1978-11-17 |
| PH14474A (en) | 1981-08-07 |
| NO753984L (en) | 1976-06-03 |
| NO146497B (en) | 1982-07-05 |
| FI753332A (en) | 1976-06-03 |
| IE42759B1 (en) | 1980-10-08 |
| SE7513331L (en) | 1976-06-03 |
| CS188259B2 (en) | 1979-02-28 |
| PL99122B1 (en) | 1978-06-30 |
| SU685146A3 (en) | 1979-09-05 |
| IT1051024B (en) | 1981-04-21 |
| AT357557B (en) | 1980-07-25 |
| AU8698975A (en) | 1977-06-02 |
| SE8004364L (en) | 1980-06-11 |
| DD124730A5 (en) | 1977-03-09 |
| NO146497C (en) | 1982-10-13 |
| GB1507340A (en) | 1978-04-12 |
| IL48557A (en) | 1979-05-31 |
| ATA898575A (en) | 1979-12-15 |
| HU175541B (en) | 1980-08-28 |
| PL102327B1 (en) | 1979-03-31 |
| NL7513804A (en) | 1976-06-04 |
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