IE42759B1 - Hydroxypolyhaloisopropyl substituted ureido-compounds - Google Patents
Hydroxypolyhaloisopropyl substituted ureido-compoundsInfo
- Publication number
- IE42759B1 IE42759B1 IE2578/75A IE257875A IE42759B1 IE 42759 B1 IE42759 B1 IE 42759B1 IE 2578/75 A IE2578/75 A IE 2578/75A IE 257875 A IE257875 A IE 257875A IE 42759 B1 IE42759 B1 IE 42759B1
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- IE
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- Prior art keywords
- propyl
- compound
- formula
- hexafluoro
- ethyl
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- 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
The novel anilino-2-oxazolines of the general formula in which R, Rf, X2, X5 and X6 have the meaning given in Claim 1, are prepared by intramolecular condensation of compounds of the general formula in which Q1 is a reactive group. The novel compounds have antihypertensive action.
Description
This invention relates to novel substituted ureido-compounds, namely compounds containing the ureido- or ι ι ' iso-ureido-function -N-CO-N- or —N-g=N— . More specifically, this invention relates to therapeutically active hydroxypolyhaloisopropyl-substituted ureidocompounds selected from the group of ureido-compounds consisting of phenyl ureas and oxazolines and quinazolines derivable from the said phenyl ureas. The present invention also relates to the preparation of the novel substituted ureido-compounds, to compositions containing such compounds and to their use as therapeutically active agents.
We have found that certain ureido-compounds containing as a substituent a hydroxypolyhaloisopropyl grouping exhibit useful therapeutic activity, more particularly useful anti-hypertensive activity.
In one of its aspects, the present invention provides hydroxypolyhaloisopropyl-substituted ureido compounds selected from the group consisting of phenyl ureas, oxazolines and quinazolines of the general formula I
X.
X, '2
-242759 and the pharmaceutically acceptable salts of said oxazolines and quinazolines, wherein Z is a grouping containing the ureido-or iso-ureido-
functions -N-CO-N- or -N-C=N-, R J 1 0- R 5 Z being -N-CO-NHRg, -N-C=N. or, together with Xg, 0-/, the grouping -N-CO-N-CO- in which grouping the free valencies on the nitrogen
and carbon atoms are attached to the benzene ring respectively ortho and meta to X^ f lo in which groupings
R is hydrogen, lower alkyl, alkoxy-lower alkyl dialkoxy-lower alkyl, or alkylenedioxy-lower alkyl, is an ethylene grouping -CHg-CHg- or a methyl15 substituted ethylene grouping, and
Rg is hydrogen, methyl or -R-jX where X is hydrogen or halogen, of Xg and X^ one is a hydroxypolyhaloisopropyl grouping designated Rf and of the formula Ia
-C-OH (Ia), . \
CFgY in which Y independently represents hydrogen, chlorine or fluorine, and the other of Xg and X^ is hydrogen, lower alkyl, halogen, lower alkoxy, hydroxy lower alkyl, nitro, lower alkoxy carbonyl or aminocarbonyl, or when Xg together with Z represents the grouping - NR.CO.NRg.CO- , Xjj represents the grouping Rf,
X^ is hydrogen or lower alkyl, and
Xtj and X^ independently represent hydrogen, lower alkyl, lower alkoxy or halogen, or together with the carbon atoms
-342759 • -.c to which they are attached represent a fused benzenoid ring, which ring may be substituted by lower alkyl or halogen.
Unless otherwise specified,the terra lower alkyl” as 5 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.
Alkoxy-lower alkyl as used herein means a grouping wherein the alkyl moiety has two or three carbon atoms and the alkoxy moiety one or two carbon atoms e.g. the groupings -CHg.CHg.OCHj and -CHg.CHg.0.CHg.CH^·
The term dialkoxy-lower alkyl as used herein means a grouping wherein the alkyl moiety has two or three carbon atoms and each alkoxy moiety one or two carbon atoms, the term embracing groupings such as /°.CH^
O.CK,
Similarly, the term alkylenedioxy-lower alkyl means such grouping wherein the alkyl moiety has two or three carbon atoms and the alkylenedioxy moiety has two to four carbon a the term embracing such groupings as
The term 1 'halogen embraces fluorine, chlorine, bromine and iodine
In the grouping designated Rf, the moiety-CY^ may
- 4 e.g.
42753 be -CHj or the grouping -CFYg such as -CFClg, -CFgCl
and CF,. Representative Of Rf are the groupings: CF, 1 3 fTO12 -C-OH j » -C-OH J > -C-OH and, CFgCl CFgCl | CFgH CFgCl CF? in particular, -C-OH I or -C-OH. I CFgCl CFj
The term pharmaceutically acceptable salts is employed in its normal and well-known usage and includes pharmaceutically acceptable addition salts of both organic and inorganic acids such as maleic, phthalic, succinic, tartaric, citric, malic, cinnamic, sulphuric, hydro10 chloric, hydrobromic and phosphoric acids.
Of X_ and Xj,, preferably XA is the grouping designated 2 * * 9F2C1
Rf, while preferred values of R^ are -C-OH and CFgCl /CFj
-C-OH. R is preferably hydrogen or methyl and Rj CF? preferably -CHg-CHg-. For Rg preferred groupings are ethyl and -CHg.CHg.Cl. When X^ is the grouping designated Rf then Xg and Xg may advantageously be lower alkyl.
Illustrative of the preferred compounds of the present invention, there may be mentioned:
N-(2-chloroethyl)-N'-[4-(hexafluoro-2-hydroxy-2-propyl) phenyl]-N’-methyl urea, N-ethyl-N'-[4-(hexafluoro-2hydroxy-2-propyl)phenyl]-N’-(2,2-dimethoxyethyl) urea and 2-[4-(hexafluoro-2-hydroxy-2-propyl)-N-me thylaniliiio] -2oxazollne
-542758 ί
The compounds of the general formula I may be prepared by methods known foi· the preparation of previously described compounds having similar structure.
The following methods will now be described:
A: A first general method .comprises reacting an aromatic amine of the general formula 11
with a reactive derivative of a carbamic acid of the general formula
RgNH.COOH wherein R, Rg, Xg, X?, X^, X5 and Xg are as defined for formula I, and isolating in conventional manner the soobtained p'nenyl urea of the general formula I. Preferably the reactive derivative of the carbamic acid is an isocyanate of the formula RgNCO where Rg is other than hydrogen. Where Rg in the phenyl urea general formula I is hydrogen then an alkali metal cyanate may be used in the presence of an acid such as acetic acid. It is also envisaged however, that other reactive derivatives such as a carbamic ac:
ester of the formula RgNH.CO.ORj,, where R^ is a hydrocarbon residue such as an alkyl or aryl group, or a substituted urea of the formula RgNH.CO.NHg may be employed.
As stated, however, the reactive derivative is preferably an isocyanate of the formula RgNCO. The precise reaction conditions here are not considered to be cri- 6 42759 tical. Suitably, however, the reaction is effected in an inert medium such as a non-polar solvent among which the ethers, specifically diethyl ether, and aromatic hydrocarbons may be mentioned. 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 of the reactants. When the hydroxypolyhaloisopropyl grouping designated Rj„ is in an ortho position, that is Xg represents Rf, it is preferred, however, to employ ambient temperatures. As guidance, it may be mentioned that in the preparation of N-(2-chloroethyl)-N’-[4-hexafluoro-2-hydroxy-2-propyl)phenyl] -Ν'-methyl urea, reaction of 2-chloroethyl isocyanate with the 4-(hexafluoro-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.
The aromatic amine of the general formula II may be prepared by suitable introduction of the required hydroxypolyhaloisopropyl 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., $0, 1001, 1°65)· Ih general, it may be said that the hydroxypolyhaloisopropyl grouping enters preferentially in the pai'a-position
-742758 although some ortho isomer may also be obtained.
Of course If the para-position is blocked, the hydroxypolyhaloisopropyl grouping must enter in the orthoposition .
Bi Another general method comprises reacting a reactive derivative of an N-phenyl carbamic acid of the general formula III
(III), with an amine of the general formula RgNHg, wherein R, Rg,X2, X^, Xjj, X^ and Xg are as defined for formula I, and then isolating In conventional manner the so-obtained phenyl urea of the general formula I.
The reactive derivative of the carbamic acid of the general formula may suitably be the corresponding carbaR mic acid ester -N-COOR^ , where R^ is a hydrocarbon residue such as alkyl or aryl, or the corresponding carbamoyl halide -N.COHal, where Hal is halogen, preferably chlorine. When R is hydrogen then the reactive derivative of the carbamic acid of the general formula may be the corresponding isocyanate -N=C=0.
-842758
In general, the reaction conditions are not considered to be critical and any suitable inert reaction medium or solvent may be employed and any appropriate reaction temperature.
Thus for example an N-phenyl carbamoyl chloride may typically be reacted with the required amine of the formula RgNHg employing ambient temperature and an aromatic hydrocarbon as solvent. Similarly, an N-phenyl carbamate may be reacted with ammonia employing ambient temperature and an alcohol, such as ethanol, as solvent.
0» A further method comprises subjecting an N-phenyl urea of the general formula IV
to intramolecular condensation, wherein R, R^, Xg, X^,
X^, X^ and Xg are as defined for formula I and represents a reactive grouping capable of being eliminated as HQ^ under tbe reactive conditions employed such as a sulfo.nic acid ester grouping or a halogen atom, 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
-942759 the range of 50°-100°C and in an aqueous medium such as an aqueous alcoholic medium containing mone than 10% of water. Compounds in wh R
Z is -K-C = ti wherein R and R, are as defined above ii 1
O R·, aod particularly compounds in which R-. is ethylene, may be produced by · method. 1
D; Yet another method comprises cyclising an N-phenyl urea of the general formula V
(V), wherein Qg is a reactive grouping capable of being eliminated as HQg under the reaction conditions employed and R, Rg, X^, X^, X5 and Xg are as defined for formula I, and than Isolating in conventional manner the so-obtained quinazoline of the general formula I.
Typically, Qg maX be an alkoxy or aryloxy grouping, Rg may be methyl or.e and cyclisation may be effected in aqueous media in the presence of a basic agent such as an alkali metal hydro15 xide. The cyclisation temperature is not considered to be critical and typically ambient temperature may be employed. Alternatively, an acid agent may be used.
Ei A further method which is applicable to the preparation of the compounds of the formula I bearing a £q halo, substituent ortho to the group Z, or a nitro substituent ortho t<
groups x3 ana Z, in particular for the preparation of the phenyl ureas o·
-1042759 general formula I, comprises treating a corresponding des-halo or des-nitro compound with an appropriate halogenating or nitrating agent and isolating in conventional manner the so-obtained compound of the general formula I.
For the preparation of such phenyl ureas, the starting material will typically be a compound of the general formula VI
wherein R, Rg, Xj, X4, X^ and Xg are as defined for formula I.
The halogenating agent is preferably a free halogen e.g. bromine in an inert organic solvent such as
- acetic acid. The nitrating agent is preferably nitric acid, conveniently in a large excess of sulfuric acid.
Fi Yet another method comprises N-alkylating a compound of the general formula VII
(VII),
-1142759 wherein Xg, Xy X^, Xy Xg and Z are as defined for formula I, with the exception that R in the grouping Z represents hydrogen witn an alkylating agent RQ3 where Q3 is a reactive grouping capable of being eliminated under the reaction conditions emplo;
, and R is the required alkyl or substituted alkyl group R, whereby the required alkyl or substituted alkyl group R is introduced on1 the nitrogen atom adjacent the benzenoid ring. In this process, if R is alkylating agent RQ3 is other than methyl or RiH, R? (if present) is o than hydrogen. c
The N-alkylation may be effected in conventional manner such as for example by reacting the appropriate alkyl halide or alkyl sulfonate ester with the compound of the formula VII in the presence of a strong base and in an organic solvent, preferably anhydrous. The streng 15 base may for example be lithium hydroxide or sodamide » and the solvent may for example be ethylene glycol, 1 diethyl or dimethyl ether.
Gt A further method applicable to the preparation of Rg substituted quinazolines of the general formula I ϊθ comprises introduction of the required Rg group employing conventional techniques. Thus a starting material u of the general formula VIII
(VIII), wherein R, X3, X^, Xg and Xg are as defined for formula 1, may be N-aikylated to introduce the required group Rg,
-1242759 and the so-obtained quinazoline of the general formula I isolated in conventional manner. In general, it may be said that the alkylation conditions of process F are applicaole. Compounds in which I together with X9
R R 1 17 is the grouping -N-CO-N -CO- and R and Rg are other than hydrogen may be prepared by this process, however if R in the starting material is hydrogen, R and Rg in the product of formula I will be the same, i.e. methyl or ethyl.
The preparation of the compounds of the general formula I will now be illustrated by way of the following Examples in which Examples 1,5,7 and 13 illustrate the preparation of starting materials and the remaining
Examples to Example 16 illustrate the preparation of the final compounds of the formula I,
Example 1
4-(l,5-diehloro-£-hydroxytetrafluoro-2-propyl)-N-methyl anlline.
To 21.4 g (0.2 mole) of N-methyl aniline in 50 ml of toluene add 2.0 g of p-toluenesulfonic acid. ..To this mixture add dropwise a mixture of 43.8 g (0.22 mole) 1,5-dichlorotetrafluoroacetone and 10 ml of toluene. Following reaction, allow the reaction mixture to cool, if desired concentrate partially by evaporation, then wash the mixture with 50 ml of IN aqueous sodium bicarbonate solution. Dry, and then remove the solvent to obtain 54 g of a yellow solid as product. Recrystallize the product by dissolving in diethyl ether and then adding hexane followed by evaporation of the diethyl ether. Filter off the precipitate to obtain 42 g of 4-(1,3-dichlora-2-hydroxytetrafluoro-2-propyl) -N-methyl aniline as a tan colored solid, m.p.
92-94° C.
43759
Example 2
N-ethyl-N'-methyl-N'- /^-(1,3-dichloro-2-hydroxytetrafluoro-2-propyl) phenylj urea.
Mix 7·1 g (20 m.mole) of 4-(1,3-dichloro-2-hydroxytetrafluoro-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. After 16 hours, evaporate to obtain 8.6 g of a white solid. Recrystallize by dissolving in methanol followed by adding water to effect precipation and to give as product 7.8 g of N-ethyl-N'-methyl-N'- f4-(l,3-dlchloro-2-hydroxytetrafluoro-2-propyl)phenyl] urea as a white solid, m.p. 155-157°C.
Example 3
Ethyi-5-(hexafluoro-2-hydroxy-2-propyl)anthranilate.
Mix 16.5 g (0.1 mole) of ethyl anthranilate with j8.6 g (0.20 mole) of hexafluoroacetone sesquihydrate and reflux for 24 hours. Add 19·3 g (0.1 mole) of hexafluoroacetone 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)anthranilate as a pink solid, m.p. 115-117°C·
43759
Example 4
N-ethyl-Ν1- (4-(hexafluoro-2-hydroxy-2-propyl)-2(ethoxyoarbonyl)phenylj urea,
Mix 4.3 g (13 m.mole) of ethyl 5-(hexafluoro-2-hydroxy2-propyl)anthranilate, obtained as described in Example 3, with 1.8 g (26 m.mole) of ethyl isocyanate in 20 ml of diethyl ether. Reflux for 5 days adding each day a further 1.8 g portion of ethyl isocyanate. Coneen- ! trate the reaction mixture to obtain 5-5 g of a white solid. Recrystallize by dissolving in diethyl ether, adding hexane and then evaporating off the diethyl ether until precipitation is effected to obtain 4.5 g of Nethyl-N1- (4-(hexafluoro-2-hydroxy-2-propyl)-2-(ethoxycarbonyl)phenylj urea as a white solid, m.p.
144-146°C.
Example 5
N-ethyl-N1- [4-(hexaflu0ro-2-hydroXy-2-propyl)phenyl) urea.
Mix 20.7 g (80 m.mole) 4-(hexafluoro-2-hydroxy-2propyl)aniline (which may be obtained as described by E.E. Gilbert, J. Org. Chem., 30, 1001 (1965)) and 11.3g of ethyl isocyanate in 100 ml of diethyl ether and reflux for 16 hours. Concentrate the reaction mixture to obtain 26 g of a white solid. Recrystallize from a diethyl ether-hexane mixture as described in Example 4 to obtain 24.5 g of N-ethyl-N1- £4(hexafluoro-2-hydroxy-2-propyl)phenyl) urea, m.p. 178-179°C.
Example 6
N-(2-chloroethyl)-Ν1- r4-(hexafluoro-2-hydroxy-2-propyl) phenyl] -N1 -methylurea.
Mix 4.1 g (15 m.mole)of 4-(hexafluoro-2-hydroxy-2-propyl)-N-methylaniline (E.E. Gilbert, J. Org. Chem., 30, 1001 (1965)) and 1.9 g (18 m.mole) 2-chloroethyl isocyanate in 40 ml of diethyl ether. Allow the mixture to stand overnight, concentrate to obtain 6 g of a beige solid. Recrystallize from a diethyl ether-hexane mixture as described in Example 4 to obtain 5.5 g of N(2-chl oroethyl)-N'- (4-(hexafluoro-2-hydroxy-2-propyl) phenyl) -Ν'-methylurea as an off-white solid, m.p. 120121°C.
Example 7
4-(hexafluoro-2-hydroxy-2-propyl)anlllnoacetaldehyde dimethyl acetal.
Mix 31.3 g (0.17 mole) of anilinoacetaldehydedimethylacetal 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 IN aqueous sodium hydroxide. Stir the aqueous sodium hydroxide layer with 400 ml of diethyl ether and add 14,4 g of acetic acid. Wash the diethyl ether layer with 250 ml of IN aqueous sodium bicarbonate solution. Dry and treat the diethyl ether extract with decolorizing charcoal. Concentrate to obtain 50 g of brown solid. Distil the brown solid at 0.1 mm Hg and collect 31 £ of yellow oil between 14O-144°C which crystallizes upon cooling. Recrystallize from a diethyl ether-hexane mixture as described in Example 4 to obtain 15 g of 4-(hexafluoro-2-hydroxy-2-propyl) anilino-acetaldehyde dimethyl acetal as a tan solid, m.p. 72-74°C.
Example 8
N-ethyl-N1- £4-(hexafluoro-2-hydroxy-2-propyl)phenyl} N,-(2,2-dimethoxyethyl) urea.
Mix 20.0 g (56 m.mole) of 4-(hexafluoro-2-hydroxy-2propyl)anilino acetaldehyde 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 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-l4o°C.
Example 9
N-ethyl-N1- /2-(hexafluoro-2-hydroxy-2-propyl)-1-naphthyl j urea.
Mix 6.1 g (20 m.mole) of 2-(hexafluoro-2-hydroxy-2propyl)-l-naphthylamine (E.E. Gilbert, J. Org. Chem., 30, 1001 (1965)) and 2.8 g (40 m.mole) ethyl isocyanate in 60 ml of diethyl ether. Concentrate after 1 hour
1.8
43759 to obtain 7.5 g of 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-Ν'- |2-(hexafluoro-2-hydroxy-2-propyl)-lnaphthylj urea as a pink solid, m.p. 218-220OC.
Example 10
-ethyl-6-(hexafluoro-2-hydroxy-2-propyl)qulnazoline2,4-dione.
Mix 4.02 g (10 m.mole) of N-ethyl-Ν'- £4-(hexafluoro2-hydroxy-2-propyl)-2-( ethoxycarbonyl)phenylj urea (obtained as described in Example 4) with 21 ml (20 m.mole) of IN aqueous sodium hydroxide solution and stir for 1 minute. Acidify the reaction with IN hydrochloric acid and extract with 100 ml of diethyl ether. Dry and concentrate the extract to obtain 3.5 g of a white solid. Recrystallize from a diethyl etherhexane mixture as described in Example 4 to obtain 2,5 g of white solid 3-ethyl-6-(hexafluoro-2-hydroxy-2propyl)quinazoline-2,4-dione, m.p. 268-270°C.
Example 11
N-ethyl-N1- /2-bromo-4-(hexafluoro-2-hydroxy-2-propyl) phenylj urea.
Mix 4.9 g (15 m.mole) of N-ethyl-Ν’- Z4-(hexafluoro-2hydroxy-2-propyl)phenylj urea (obtained as described in Example 5) and 1.3 g (16.5 m.mole) of sodium acetate with 2.4 g (15 m.mole) of bromine in 70 ml of acetic acid and stir for 20 hours. Pour the reaction mixture into 700 ml of iced water. Filter off the solid, dissolve in diethyl 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 chloroform and then evaporating to precipitate, to obtain 3.5 g of white solid N-ethyl-N1[2-bromo-4- (hexaf luoro-2 -hydroxy-2-propyl) phenyl] urea! m.p. 125-127OC.
Example 12
N-ethyl-N1- /A-(hexafluoro-2-hydroxy-2-propyl)-2-nitro phenyl1 urea.
Dissolve 12.0 g (36 m.mole) of N-ethyl-N*- A-(hexafluoro 2-hydroxy-2-propyl)phenylJ urea (obtained as described in Example 5) in 72 ml of concentrated sulfuric acid and cool to below 5°C. Add dropwise a solution of 2.8 ml of concentrated nitric acid in 24 ml of concentrated sulfuric acid and stir for 40 minutes. Pour the reaction mixture into 800 ml of iced water and stir.
Filter off the yellow solid and dissolve in 400 ml 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 13 g of yellow solid. Recrystallize by dissolving the solid in methanol and then adding water to effect precipitation to obtain 11 g of N-ethyl-N1- Z”(4-(hexafluoro-2-hydroxy’ 2-propyl)-2-nitrophenylJ urea as a yellow solid, m.p. 169-171°C.
43759
Example 13
Phenyl N- ^4-(hexafluoro-2-hydroxy-2-propyl)phenyl?
carbamate.
Dissolve 10.3 g (40 m.mole) of 4-(hexafluoro-2-hydroxy5 2-propyl) aniline in 50 ml of methyl cyanide. Add
7·θ g (50 m.mole) of phenyl chloroformate followed dropwise by 3.1 g of dry pyridine in 10 ml of methyl cyanide. Pour the reaction mixture into 400 ml of water. Filter off the solid, dissolve in diethyl ether, wash with 200 ml of water and then dry and concentrate the ether extract to obtain 16 g of white solid. Recrystallize from a diethyl ether-hexane mixture as described in Example 4 to obtain 12.5 g of phenyl Ν- /4-(hexafluoro-2-hydroxy-2-propyl)phenyl) carbamate as a white solid, m.p. 192-194°c.
Example 14
N- f4-(hexafluoro-2-hydroxy-2-propyl)phenylJ urea.
Mix 6.0 g (16 m.mole) of phenyl N- Z4-(hexafluoro-2hydroxy-2-propyl)phenyl] carbamate (obtained as ammonia20 described in Example 13) and 65 ml of/saturated ethanol. After 1/2 hour, pour the reaction mixture into 150 ml of water. Concentrate, cool to 0°C and filter off the white solid to obtain 5.5 g of N- /4-(hexafluoro-2hydroxy-2-propyl)phenyl] urea, m.p. l8l-l83°0.
4275S
Example 1¾
N-ethyl-N'-methyl-N1- C2,6-dimethyl-4-(hexafIuoro-2hydroxy-2-propyl)phenyl] urea.
Heat at reflux for three hours 13.5 g of N,2,6-trimethylaniline (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 recrystallize from a diethyl ether-hexane mixture as described in Example 4 to give 27.9 g of a white solid, m.p. 143-144°C. Mix 6 g of the product, N,2,6-trimethyl-4-(hexafluoro-2-hydroxy-2-propyl)aniline (20 m.mole) with 5.4 g of ethyl isocyanate (80 m.mole) in diethyl ether. After 16 hours, concentrate and recrystallize the residual solid from a diethyl etherhexane mixture to give 6.2 g of a white solid, m.p. 178-179°C.
Example 16
2- ^:-(.t1exafluoro-2-hydroxy-2-propyl)-N-methylanilino3
-2-oxazollne.
Dissolve 10.0 g (26 m.mole) of N-(2-chloroethyl)-N'C4-(hexafluoro-2-hydroxy-2-propyl) phenyl] -Ν'-methyl(obtained in Example 6) urea/in a mixture of 50 ml of methanol and 100 ml of water. Heat for one hour on a steam bath. Concentrate, and partition between IN aqueous sodium bicarbonate solution and diethyl ether and then extract with 200 ml of IN hydrochloric acid. Add sodium bicarbonate and then extract with 200 ml of diethyl ether. Dry the ether extract and concentrate to obtain 7·θ g of the title compound as a white solid, m.p. 188-19O°C. The salts may be prepared by standard techniques such as by treatment of a solution of the free base in a suitable organic solvent, e.g. ether, with the desired acid, e.gi hydrochloric, and then filtering off the precipitated salt. The hydrochloride salt melts at 147-149°C.
I
In analogous manner to that described in the foregoing Examples, the following representative compounds of the present invention may be prepared:
N-efchyl-N'[-2-(hexafluoro-2-hydroxy-2-propyl)phenylJurea,
N-ethyl-N'-[4-(hexafluoro-2-hydroxy-2-propyl)phenylJ-Ν' methyl urea,
N-ethyl-N' - [4-(hexafluoro-2-hydroxy-2-propyl)-2-mefchylphenylj urea,
Ν,N'-diethyl-N'-[4-(hexafluoro-2-hydroxy-2-propyl)phenyl ] urea,
N-ethyl-N'-[4-(hexafluoro-2-hydroxy-2-propyl)phenyl]-Ν'Isopropyl urea,
N-ethyl-N*-[2-ethyl-4-(hexafluoro-2-hydroxy-2-propyl) phenylj urea,
N-ethyl-N'-[4-(hexafluoro-2-hydroxy-2-propyl)phenylJ-N* propyl urea,
N-ethyl-N'-(4-(hexafluoro-2-hydroxy-2-propyl)-2-(methoxycarbonyl) phenyl] -Ν' -methyl urea, «2739
N-ethyl-N'-[4-(chloro-2-hydroxypentafluoro-2-propyl)phenylJ-Ν'-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-methylphenyl] -Ν' -methyl urea,
N-ethyl-N'-[2-(methoxycarbonyl)-4-(hexafluoro-2-hydroxy2-propyl)phenyl] urea,
N-ethyl-N'-[2-chloro-4-(hexafluoro-2-hydroxy-2-propyl)6-methyl phenyl] urea,
N-ethyl-N'-(2,6-dimethyl-4-(hexafluoro-2-hydroxy-2-propyl)phenyl]-N*-methyl urea,
N-(2-bromoethyl)-N'-[4-(hexafluoro-2-hydroxy-2-propyl) phenyl]-Ν'-methyl urea,
N-ethyl-N'-[4-(hexafluoro-2~hydroxy-2-propyl)-2-(2-propoxycarbonyl)phenyl]-N'-methyl urea,
N-ethyl-N'-[4-(hexafluoro-2-hydroxy-2-propyl)-2-methyl6-(methoxycarbonyl)phenyl] urea,
N-ethyl-N'-[4-(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-(l,3-dichloro-2-hydroxytetrafluoro-2-propyl)-2,6~ dimethyl phenyl]-Ν'-ethyl urea,
N-(2-chloroethyl)-N'-[4-(hexafluoro-2-hydroxy-2-propyl) phenyl] urea,
N-ethyl-N'-[4-(hexafluoro-2-hydroxy-2-propyl)-2-(hydroxyme thyl) phenyl J -Ν' -me thyl urea,
N-ethyl-N' - [2-(hexafluoro-2-hydroxy-2-propyl)-1-naphthyl]Ν'-methyl urea,
N-ethyl-N1-[4-(2-hydroxypentafluoro-2-propyl)phenyl]-N'methyl urea,
N-ethyl-N'-[4-(hexafluoro-2-hydroxy-2-propyl)-2-aminocarbonylphenyl]-N1-methyl urea,
N-ethyl-N'-[4-(hexafluoro-2-hydroxy-2-propyl)-2-methyl10 6-t-butylphenyl] urea hydrate,
N-(2-chloroethyl)-N'-[2,6-dimethyl-4-(hexafluoro-2-hydroxy-2-propyl)phenyl]-N'-methyl urea,
N-ethyl-N'-[4-(2-hydroxy-l,l,3-trichloro-l,3,3-trlfluoro2-propyl)phenyl]-N*-methyl urea,
N-ethyl-N'-(2-ethoxyethyl)-N'-[4-(hexafluoro-2-hydroxy2-propyl)phenyl] urea,
N-ethyl-N'-[4-(hexafluoro-2-hydroxy-2-propyl)phenyl]-N(2,2-di-ethoxyethyl) urea,
Ν,Ν'-diethyl-N-[4-(hexafluoro-2-hydroxy-2-propyl)2,620 dimethylphenyl] urea,
N-ethyl-Ν'- [2,6-dimethyl-4-(2-hydroxy-l ,1,3-trichlorotrifluoro-2-propyl)phenyll urea,
N-ethyl-Ν'-[4-(hexafluoro-2-hydroxy-2-propyl)-2-methyll-naphthyl] urea,
N-[2-(hexafluoro-2-hydroxy-2-propyl) - l-naphthyl] -N' methyl urea,
N-ethyl-Ν'-[4-(l,3-dichloro-2-hydroxytetrafluoro-2-propyl)
2,6-diethyl phenyl] urea,
N-2-(chloroethyl)-N'-[2-(hexafluoro-2-hydroxy-2-propyl)1- naphthyl] urea,
N-ethyl-N'-[2,6-diethyl-4-(hexafluoro-2-hydroxy-2-propyl) 10 phenyl] urea,
N-ethyl-N' - [4-(hexafluoro-2-hydroxy-2-propyl)phenyl]N'-[l,3-dioxolan-2-yl)methyl] urea,
N-[7-methyl-2-(hexafluoro-2-hydroxy-2-propyl) -1 -naphthylG N’-n-propyl urea,
2- [2-(hexafluoro-2-hydroxy-2-propyl)-l-naphthylamino]2- oxazoline,
2-[2-bromo-4-(hexafluoro-2-hydroxy-2-propyl)-anilino]2-oxazoline,
2-[4-(l,3-diohloro-2-hydroxy-tetrafluoro-2-propyl)-N20 propylanilino]-2-oxazoline,
2-[4-(hexafluoro-2-hydroxy-2-propyl)anilino]-2-oxazoline,
2-[N-2,6-trimethyl-4-(hexafluoro-2-hydroxy-2-propyl)anilino]-2-oxazoline hydrochloride,
2-[4-(hexaf1uoro-2-hydroxy-2-propyl)-N-methyl anilino]~
-5-methyl-2-oxazQline,
2-[4-(chloro-2-hydroxypentafluoro-2-propyl)-N-methyl anilinoJ-2-oxazoline,
2-[2-(hexafluoro-2-hydroxy-2-propyl)-N-methyl anilino]2- oxazoline,
6-(l,3-dichloro-2-hydroxytetrafluoro-2-propyl)-3-ethyl quinazoline-2,4-dione,
3- ethyl-6-(hexafluoro-2-hydroxy-2-propylJqulnazoline2,4-dione,
3-ethyl-6-(hexafluoro-2-hydroxy-2-propyl)-1-methyl quina10 zoline-2,4-dione,
6- (ehloro-2-hydroxypentafluoro-2-propyl)-3-ethyl-l-methylquinazoline-2,4-dione,
-ethyl-6-(hexafluoro-2-hydroxy-2-propyl)quinazoline2,4-dione,
-bromoethyl-6-(hexafluoro-2-hydroxy-2-propyl)quinazoline2,4-dione,
7- methyl-6-(hexafluoro-2-hydroxy-2-propyl)quinazoline2,4-dione,
8- propyl-6-(hexafluoro-2-hydroxy-2-propyl)quinazoline20 2,4-dione, and N-ethyl-Ν'- L2,6-dimethyl-4-(hexafluoro-2hydroxy-2-propyl)phenylj -N‘-methyl-urea.
Of the compounds of the present invention, it may in general be said that the oxazolines form a preferred area of 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 forth in the Examples are:
2-[4-(tetrafluoro-l,3-diehloro-2-hydroxy-2-propyl)-Nmethylaniliho]-2-oxazoline hydrochloride,
2-[4-(hexaflUoro-2-hydroxy-2-propyl)-2-chloro-N-methylanilino]-2-oxazoline hydrochloride,
2-[4-(hexafluoro-2-hydroxy-2-propyl)- N -propylanilino]
-2-oxazoline bisulfate,
2-[4-(l,l,l-trifluoro-2-hydroxy-2-propyl)-N-methylanilino] 2-oxazoline bisulfate,
2-[2,6-dichloro-4-(hexafluoro-2-hydroxy-2-propyl)-Nmethylanilino]-2-oxazoline bisulfate,
2-[2,6-diisopropyl-4-(hexafluoro-2-hydroxy-2-propyl)-Nmethylanilino]-2-oxazoline bisulfate,
2-[2,6-diethyl-4-(hexafluoro-2-hydroxy-2-propyl)-Nmethylanilino]-2-oxazoline bisulfate,
2-[2-chloro-4-(hexafluoro-2-hydroxy-2-propyl)-N,6-di28
437S9 methylanilino]-2-oxazoline bisulfate,
2-[4-(hexafluoro-2-hydroxy-2-propyl)-2-methoxy-Nmethylanilino]-2-oxazoline phosphate, methanol solvate,
2-[2-fluoro-4-(hexafluoro-2-hydroxy-2-propyl)-N-methyl5 anilino]-2-oxazoline bisulfate,
2-[4-(hexafluoro-2-hydroxy-2-propyl)-2,5-dimethyl-Nmethylanilino]-2-oxazoline bisulfate, ;
2-[4-(hexafluoro-2-hydroxy-2-propyl)-2,6-dimethoxy-Nmethylanilino]-2-oxaz oline bi sulfate,
2-[N-ethyl-4-(hexafluoro-2-hydroxy-2-propyl)anilino]-2oxazoline sulfate and
2- [4-(hexafluoro-2-hydroxy-2-propyl)-N,2-dimethylanilino]-2-oxazoline hydrochloride.
If in the formulation Examples hereafter described one 15 employs as active ingredient 2-[4-(hexafluoro-2-hydroxy2-propyl)-N-methylanilino]-2-oxazoline then it Is considered that 1 mg per tablet or capsule represents a suitable amount of active ingredient. The formulation may be effected in essentially the same way as described in those Examples.
syau’sssassaaas
43759
In the treatment of hypertension, a number of agents are known. Certain of these, for example reserpine, are effective in lowering the blood pressure in some patients but in other patients give rise to undesirable and well known side effects. Other known agents lack adequate potency or result in tolerance to the drug developing.
The compounds of 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 anti-hypertensive agents while avoiding or mitigating some of the deleterious side effects associated with known anti-hypertensive agents. Based on laboratory tests and proce15 dures, It is considered that the effective dosage, the EDj-φ, by oral administration for a compound of the present invention will typically lie within the range of from 0.01 to 20 mg/kg of mammalian weight per day.
For the compound of Example 16 the expected daily human dose would be from 0.6 to 10 mg. For the purposes of further illustration, it may be mentioned that for N(2-chloroethyl) -Ν' -[4-hexafluoro-2.-hydroxy-2-propyl) phenyl]-Ν'-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 rate of 100 mg/kg.
The required daily dosage may be administered in single or divided doses. The exact dose to be administered will, of course, be dependent upon where the compound in question lies within the above quoted dosage ranges and upon the age and weight of the subject mammal.
The compounds of the invention may be administered alone or combined with other medicinals such as 6- 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 of the compound in the pharmaceutic composition. The carrier should not react chemically with the compound to be administered. The preparations containing the active ingredients may typically be in the form of tablets, capsules, syrups, elixirs or suspensions.
Thus the present invention also provides pharmaceutical compositions comprising a compound of formula (I) in association with a pharmaceutical carrier and process for producing such compositions which comprise admixing a compound of formula (I) with a suitable carrier.
Representative formulations for the compounds of the general formula I vzill now be illustrated by way of the following Examples.
Example A
Tablet Formulations
Formulation I Milligrams per Tablet
Active ingredient: N-(2- i chloroethyl)-Ν'- £4-(hexafluoro-2-hydroxy-2-propyl) pheny jj-N1 -methyl urea............... 10
Lactose, direct compression grade .... 213
Microcrystalline cellulose ........... 30
Sodium Lauryl Sulfate........ ......« 20
Corn-starch....... 25
W Magnesium stearate ................... 2.0
300.0
Formulation II
Active ingredient: N-ethyl-N1-f
4-(hexaflubro-2-hydroxy-2-propyl) phenylj -N'-(2,2-dimethoxy20 ethyl) urea........ 1°
Lactose, direct compression grade..... 213
Microcrystalline Cellulose....... 30
Sodium Lauryl Sulfate................. 20
Corn Starch ................. 25 25 Magnesium Stearate ................. 2
300
Procedure for formulations I and II.
Mix together·the stated active ingredient, lactose, 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 Milligrams per Tablet
Active ingredient; N(2-chloroethyl)-N'- L4(hexafluoro-2-hydroxy2-propyl)pheny^-N-methyl urea .......... 10
Lactose, U.S.P. ................... 231
Dicalcium phosphate ....... 57
Sodium Lauryl Sulfate ........... 20
Polyvinylpyrrolidine .............. 10
Water 50 ml/1000 tablets
Corn Starch............ 20
Magnesium Stearate ................ 2_
350
Formulation IV
Active ingredient: N-ethyl-N'- C4-(hexafluoro-2-hydroxy-2-propyl)phenyl] -N'(2,2-dimethoxyethyl) urea ......... 10
Lactose, U.S.P.................... 231
Dicalcium Phosphate ............... 57
Sodium Lauryl Sulfate ............. 20
Polyvinylpyrrolidone ......... 10
43759
Formulation IV (contd.)
Water 50 ml/1000 tablets Corn Starch ............
Magnesium Stearate .....
Milligrams per Tablet
... 20 ... _2_
350
Procedure for formulations 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 polyvinylpyrroli10 done. Add additional water, if necessary, to bring the powders to a pasty mass. Add corn starch and continue mixing until uniform granules are formed. Pass through a No. 10 screen, tray and dry in an oven at 40°C for 12 to 14 hours. Reduce the dried granula15 tion through a No. 16 screen. Add magnesium stearate, mix and compress into desired shape on a tablet machine.
Example B
Capsule Formulations
Formulation I
Milligrams per Capsule
Active ingredient: N= (2-chloroethyl)-Ν'- |_4(hexafluoro-2-hydroxy-2propylJphenylj -N'-methyl urea............................. 10
Lactose, U.S.P................... 213
43759
Formulation I (contd.) Milligrams per Capsule
Mlcroerystalline Cellulose ........... 3θ
Sodium Lauryl Sulfate ................ 20
Corn Starch .......................... 25
Magnesium Stearate ................... 2
300
Formulation II
Active ingredient: N-ethylΝ'- r4-(hexafluoro-2-hydroxy2-propyl)phenylj -N'-(2,2-dimethoxyethyl) urea ................... 10
Lactose, U.S.P.......................213
Microcrystalline Cellulose ........... 30
Sodium Lauryl Sulfate ................ 20
Corn Starch .......................... 25
Magnesium Stearate ....................2_
300
Procedure:
Mix together the stated active ingredient,lactose, microcrystalline cellulose, sodium lauryl sulfate and corn starch. Pass through a No. δθ screen. Add the magnesium stearate, mix and encapsulate into the proper size two-piece gelatin capsule.
Claims (1)
1. A hydroxypolyhaloisopropyl-substituted ureido-compound selected from the group consisting of phenyl ureas, oxazolines and quinazolines and of the general formula I v (I), ΙΟ and the pharmaceutically acceptable salts of said oxa 4 zolines and quinazolines, wherein Z is a grouping containing the ureido-or iso-ureidoi ι ι functions -N-CO-N- or -N-C=H-, l 0Z being -N-C0-NHR 2 , -N-C=N. or, R, in which groupini ι atoms ar to the benzene ring respectively ortho and meta to X together with Xg, the grouping -N-CO-N-COthe free valences on the nitrogen and carbon atoms are attacl 6 f in which groupings R is hydrogen, lower alkyl, alkoxy-lower alkyl } dialkoxy-lower alkyl, or alkylenedioxy-lower alkyl, R·^ is an ethylene grouping -CHg-CJIp- or a methylsubstituted ethylene grouping, and R 2 is hydrogen, methyl or -R^X where X is hydrogen or halogen, of X 2 and X^ one is a hydroxypolyhaloisopropyl grouping designated R f and of the formula Ia -3648758 / -C-OH (la), W in which Y independently represents hydrogen, chlorine or fluorine, and the other of Xg and X, f is hydrogen, lower alkyl, halogen, lower alkoxy, hydroxy lower alkyl, ' nitro, lower alkoxy carbonyl or aminocarbonyl, o r when Xg together with Z represents the grouping -NR.CO.NRg.CO-, X^ represents the grouping R f , X^ is hydrogen or lower alkyl, and lower alkoxy X^ and Xg independently represent hydrogen, lower alkyl,/ 10 or halogen, or together with the carbon atoms to which they are attached represent a fused benEe-noid ring, which ring may be euustttutod by lower alkyl or halogen. 1, wherein the 2. A compound as claimed in claim / CKY 2 grouping designated Rp is —C -OH ^CPgY where Y is as defined in claim 1. 1, wherein the 1, wherein the 3. A compound as claimed in claim grouping designated R. is -Cf-OH' ^ C? 3 4. grouping designated R f is -C-OH ^'CR-.Cl A compound as claimed in claim i: -3742759 5. A compound as claimed in any one of the preceding R claims, wherein Z represents -fi-CO-NHRg in which R and Rg are as defined in claim 1. 6. A compound as claimed in any one of claims 1 to 4, R wherein Z represents -N-C=N, in which Π and R. are as 0-0^ defined in claim 1. 7. A compound as claimed in any one of claims 1 to 4, wherein Z together with the grouping X„ represents J?2 -N-CO-N-CO- in which R and Rg are as defined in claim 1. 10 8. A compound as claimed in claim 5 or claim 7, wherein Rg is ethyl or -CHg.CHg-Cl. 9. A compound as claimed in claim 6 wherein R·^ is -CHg.CHg- . 10. A compound as claimed in any one of the precelo ding claims wherein R is hydrogen or methyl. 11. A compound as claimed in any one of the preceding claims wherein X^ is the grouping designated R f . 12. A compound as claimed in claim 5 or claim 6 , or any one of claims 8 to 11 -as dependent upon claim 5 or 20 claimg , wherein Xg and Xg are both lower alkyl. -38' 43789 13. · N-ethyl-N*- (4-(hexafluoro-2-hydroxy-2-propyl) phenyJ -N’-(2,2-dimethoxyethyl)urea. 14. N-(2-chloroethyl)-N*- [4-(hexafluoro-2-hydroxy2-propylJphenyfj -Ν'-methyl urea. s 15. N-ethyl-N* - ][4-(hexaFluoro-2-hydroxy-2-propyl) -2-hydroxymethyl-phenyl·] -N'-methyl urea. | 16. N-ethyl-N'- [ji-(hexafluoro-2-hydroxy-2-propyl) -2-methoxycarbonylphenylJ -Ν'-methyl urea. 17. N-ethyl-N'- [j!--(hexafluoro-2-hydroxy~2-propyl) 10 phenylj urea. l£. N-ethyl-N'-jj2-(hexafluoro-2-hydroxy-2-propyl) -1-naphthyl] urea. 19. N-ethyl-N 1 - [.4-(1,3-dichloro-2-hydroxy-tetra• fluoro-2-propyl)phenyl] -Ν'-methyl urea. 1» 20. N-ethyl-N'- [[2,6-diisopropyl-4-(hexafluoro-2hyclroxy-2-propyl)phenylJ urea. 21. N-ethvl-N'- [2,6-dimethyl-4-(hexafluoro-2-hydrOxy-2-propyl)phenyfj -Ν'-methyl-urea. 22. N- []2,6-diniethyl- 1 )-(l,3-dichloro-2-hydroxytetra3942759 fluoro-2-propyl)phcnylJ -N’-ethyl urea. 23. 3-ethyl-6-(hexafluoro-2-nydroxy-2-propyl)quina zoline-2,4-dione. 24.. 6-(ehloro-2-hydroxy-pentafluoro-2-propyl)-3“ 3 ethyl-1-methylquinaz oline-2,4-di one. 25. 2-Q 4-(hexafluoro-2-hydroxy-2-propyl)-N-methyl anilinoJ -2-oxazoline. 26. A process for the preparation of a ureidocompound of the general formula X set forth in claim 1, 10 which process comprises one of the following processes A to G: A: reacting an amine of the general formula II Xz (II). with a reactive derivative of a carbamie acid of the general formula RgNH.COOH in which formulae R, Rg, Xg, Xy X^, and Xg are as defined for formula I to form a compound of formula I in which Z is -NR-CO-NHRgj R: ; reacting a reactive derivative oF an N-phenyl -40 ^3758 earbamie acid of the general formula III (m), If with an amine of the general formula RgNHg, in which formulae R, Rg, Xg, Xy X^, X^ and Xg are as defined for formula I to form a compound of formula I in which Z is, R -n-co-nhr 2 > C: subjecting to intramolecular condensation an N-phcnyl urea of the general formula IV (IV), wherein R, R·^, Xg, X^, X^, X^ and Xg are as defined for formula I and is a reactive grouping capable of being eliminated as HQ-j. under the reactive conditions employed to form a compound of formula I in which Z is R -N-C=N I I > 0-R. D: 1 cyclising an N-phenyl urea of the general formula V (V), wherein R, Rg, Xy X^, X^ and Xg are as defined for formula I and Qg is a reactive grouping capable.of being -4142759 eliminated as HQg under the reaction conditions employed to form a compound of formula I in which Z together with X_ is the R R„ ά grouping -N-CO-N-CO-; E: introducing a halo substituent into the benzenoid ring .□ at a position ortho to the group Z or a nitro substituent into the benzenoid ring at a position ortho to the groups Z and X^ by halogenating or nitrating in conventional manner a des-*halo or des-nitro oompound corresponding to a compound of the general formula 1 in which Xg is halogen or nitro and/or Xg is halogen; in to form said compound of general formula I. P: N-alkylating a compound of the general formula VII x 6 wherein X^, X^ } Xjj, Xg, Xg, and Z are as defined for formula I except that R in the grouping Z is hydrogen with an alkylating agent R Qg where Qg is a reactive grouping capable of being eliminated under the reaction conditions employed and R is lower or alkylenedioxy lower alkyl alkyl, alkoxy 1-lower alkyl, dialkoxy-lower alkyl/, to form a compound of formula I in which R is other than hydrogen with the proviso that if the group R in the alkylating agent RQg is other than methyl or -R^H, Rg (if present) is other than hydrogen. G: introducing using conventional techniques the required R 2 substituent into the 3-position of a quinazoline of the genera formula VIII (VIII). -If?.42759 wlicrt’-i η H, Ii.,, X.,, X J( , X,. and Χ () an· an de Pined in formula 1 with the proviso that where R is hydrogen, Rg is methyl/, to form a compound of formula I in which Z together with X„ is R Rg ά the grouping -N-CO-N-CO- and R and Rg are other than hydrogen; 5 said process selected from the processes c to G being followed if desired by the step of converting a soobtained oxazoline or quinazoline of the general formula I into a pharmaceutically acceptable salt. I ι 2?. A process as claimed In claim 26 process A, Ιθ wherein the amine of the general formula II is reacted with an Isocyanate of the formula RgNCO wherein Rg Is methyl or R^ X, where R^ and X are as defined for formula I. 28. A process as claimed in claim 27, wherein Rg is ethyl or -CHg.CHgCl. 15. 29. A process as claimed in claim 26 process B, wherein the reactive derivative of the N-phenyl carbamic acid of the general ‘formula III Is a carbamoyl halide or carbamic acid ester. JO. A process as claimed in claim 26 process B or in ϋθ claim 29, wherein Rg in the amine of the general formula RgNHg is ethyl or -CHg.CHgCl. 31. A process as claimed in claim 26 process C, wherein in the starting material of the general formula 17, is halogen. -43. 42788 32. A process as claimed in claim 31, wherein is chlorine. 33. A process as claimed in claim 31 or claim 32, wherein R^ in the starting material of the general □ formula IV is ethylene. 34. A process as claimed in claim 26 process D, wherein in the starting material of the general formula V, Qg is an alkoxy or aryloxy grouping and cyclisation is effected in the presence of an aqueous alkali metal 10 hydroxide. 35· A process as claimed in claim 3^ j wherein in the starting material of the general formula V, Rg is methyl or ethyl. 36. A process as claimed in claim 26. process E, 1 o wherein a starting material of the general formula VI wherein R, Rg, Xy X^, X^ and Xg are as defined for formula I, is subjected to halogenation or nitration. 16. 20 37· A process as claimed in claim 26 process P, whereir N-alkylatlon is effected in conventional manner with a halide, of the general formula R Hal. wherein R is a substituent as defined for formula I. 38. A process as claimed in any one of claims 26 to 37, wherein in the specified starting material the z c?3 grouping designated R f is -C-OH. CP, 39. A process as claimed in any one of claims 26 to 37, wherein in the specified starting material the z cf 2 ci 10 grouping designated R_ is -C-OH x cf 2 ci 40. A process as claimed In any one of claims 26 to 39. wherein is the grouping designated R^. 41. A process as claimed in claim 26 nrocess ‘A to E and G, or in any one of claims ?7 to 56 and 38 to. 40, wherein R in the 15 starting material is methyl. 42. A process for the preparation of a compound as claimed in claim 1 substantially as hereinbefore described. 43. A substituted-ureido compound of the general formula I set forth in claim 1, whenever obtained by a process as claimed in any one of claims 26 to 42. 44. A pharmaceutical composition comprising as active -45ingredient a compound as claimed in any of claims 1 to 25 and 43 in association with a suitable pharmaceutical carr 45. A process for the preparation of a pharmaceutica composition which comprises admixing a compound as claime 5 in any one of claims 1 to 25 and 43 with a suitable pharmaceutical carrier. 46. A pharmaceutical composition, whenever prepared by a process as claimed in claim 45. 47. A pharmaceutical composition as claimed in claim 10 44 or 46 in shaped dosage form. 48. A pharmaceutical composition as claimed in claim and substantially as hereinbefore described.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US52860374A | 1974-12-02 | 1974-12-02 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE42759L IE42759L (en) | 1976-06-02 |
| IE42759B1 true IE42759B1 (en) | 1980-10-08 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE2578/75A IE42759B1 (en) | 1974-12-02 | 1975-11-26 | Hydroxypolyhaloisopropyl substituted ureido-compounds |
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| AR (2) | AR219478A1 (en) |
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| CS (1) | CS188259B2 (en) |
| DD (1) | DD124730A5 (en) |
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| DK (1) | DK535275A (en) |
| FI (1) | FI753332A (en) |
| FR (1) | FR2346000A1 (en) |
| GB (1) | GB1507340A (en) |
| HU (1) | HU175541B (en) |
| IE (1) | IE42759B1 (en) |
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| 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 |
| AU2003210811B2 (en) | 2002-01-30 | 2008-08-14 | Amgen Inc. | Arylsulfonamidobenzylic compounds |
| US20030199578A1 (en) * | 2002-04-19 | 2003-10-23 | Turner Sean C. | Naphthalene amides as potassium channel openers |
| JP6217866B2 (en) | 2014-10-24 | 2017-10-25 | 小野薬品工業株式会社 | KCNQ2-5 channel activator |
| 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 |
| DE1670752A1 (en) * | 1966-09-27 | 1970-12-23 | Bayer Ag | Process for the preparation of 2-phenylamino-oxazolines |
| FR1543534A (en) * | 1966-09-27 | 1968-10-25 | Bayer Ag | Manufacturing process of 2-phenylimino-oxazolidines |
| DE1670751A1 (en) * | 1966-09-27 | 1970-12-23 | Bayer Ag | Process for the preparation of 2-phenylamino-2-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 AT AT898575A patent/AT357557B/en not_active IP Right Cessation
- 1975-11-26 AR AR261362A patent/AR219478A1/en active
- 1975-11-26 CA CA240,512A patent/CA1063112A/en not_active Expired
- 1975-11-26 AU AU86989/75A patent/AU501512B2/en not_active Ceased
- 1975-11-26 FI FI753332A patent/FI753332A/fi not_active Application Discontinuation
- 1975-11-26 FR FR7536178A patent/FR2346000A1/en active Granted
- 1975-11-26 PH PH17810A patent/PH14474A/en unknown
- 1975-11-26 IE IE2578/75A patent/IE42759B1/en unknown
- 1975-11-26 GB GB48640/75A patent/GB1507340A/en not_active Expired
- 1975-11-26 SE SE7513331A patent/SE7513331L/en not_active Application Discontinuation
- 1975-11-26 NO NO753984A patent/NO146497C/en unknown
- 1975-11-26 ZA ZA757457A patent/ZA757457B/en unknown
- 1975-11-26 NL NL7513804A patent/NL7513804A/en not_active Application Discontinuation
- 1975-11-26 DE DE19752552933 patent/DE2552933A1/en not_active Withdrawn
- 1975-11-27 DK DK535275A patent/DK535275A/en not_active Application Discontinuation
- 1975-11-27 IL IL48557A patent/IL48557A/en unknown
- 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 HU HU75SCHE549A patent/HU175541B/en unknown
- 1975-12-01 PL PL1975185156A patent/PL99122B1/en unknown
- 1975-12-01 SU SU752194050A patent/SU655311A3/en active
- 1975-12-01 CS CS758133A patent/CS188259B2/en unknown
- 1975-12-01 PL PL1975193580A patent/PL102327B1/en unknown
- 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 |
|---|---|
| AR219478A1 (en) | 1980-08-29 |
| PL102327B1 (en) | 1979-03-31 |
| FR2346000A1 (en) | 1977-10-28 |
| DK535275A (en) | 1976-06-03 |
| DD124730A5 (en) | 1977-03-09 |
| HU175541B (en) | 1980-08-28 |
| SE8004364L (en) | 1980-06-11 |
| ZA757457B (en) | 1976-11-24 |
| PH14474A (en) | 1981-08-07 |
| IT1051024B (en) | 1981-04-21 |
| CA1063112A (en) | 1979-09-25 |
| CH623044A5 (en) | 1981-05-15 |
| SE7513331L (en) | 1976-06-03 |
| CS188259B2 (en) | 1979-02-28 |
| GB1507340A (en) | 1978-04-12 |
| FI753332A (en) | 1976-06-03 |
| BE835899A (en) | 1976-05-25 |
| AT357557B (en) | 1980-07-25 |
| NL7513804A (en) | 1976-06-04 |
| IL48557A0 (en) | 1976-01-30 |
| NO146497C (en) | 1982-10-13 |
| PL99122B1 (en) | 1978-06-30 |
| NO753984L (en) | 1976-06-03 |
| LU73888A1 (en) | 1976-09-06 |
| AU8698975A (en) | 1977-06-02 |
| DE2552933A1 (en) | 1976-06-10 |
| SU655311A3 (en) | 1979-03-30 |
| AU501512B2 (en) | 1979-06-21 |
| SU685146A3 (en) | 1979-09-05 |
| NO146497B (en) | 1982-07-05 |
| JPS5182239A (en) | 1976-07-19 |
| FR2346000B1 (en) | 1978-11-17 |
| AR218436A1 (en) | 1980-06-13 |
| IL48557A (en) | 1979-05-31 |
| IE42759L (en) | 1976-06-02 |
| ATA898575A (en) | 1979-12-15 |
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