IE44791B1 - Substituted anilino-2-oxazolines and thiazolines - Google Patents
Substituted anilino-2-oxazolines and thiazolinesInfo
- Publication number
- IE44791B1 IE44791B1 IE578/77A IE57877A IE44791B1 IE 44791 B1 IE44791 B1 IE 44791B1 IE 578/77 A IE578/77 A IE 578/77A IE 57877 A IE57877 A IE 57877A IE 44791 B1 IE44791 B1 IE 44791B1
- Authority
- IE
- Ireland
- Prior art keywords
- compound
- hydroxy
- propyl
- hexafluoro
- methylanilino
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D277/54—Nitrogen and either oxygen or sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- 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
-
- 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
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D263/48—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole 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
- C07D277/18—Nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
Substituted anilino-2-oxazolines and -thiazolines of the general formula in which R, R1, R2, R3, Y, X1, X2 and Z have the meaning stated in Claim 1, are prepared by cyclisation of compounds of the general formula in which Q is a reactive group. The compounds have antihypertensive effects.
Description
This invention relates to novel substituted anilino-2oxazolines and thiazolines, to processes for their preparation and to pharmaceutical compositions containing the same.
In accordance with the present invention there is provided substituted. anilino-2-oxazolines and thiazolines of the general formula I
and the pharmaceutically acceptable acid addition salts thereof, wherein
R is hydrogeh or a lower alkyl group having up to 6 carbon atoms,
R^, Rg and R^ independently represent hydrogen, bromine, chlorine, fluorine, nitro, lower alkyl, lower alkoxy or lower'-alka'noyloxy,
Y is hydrogert, chlorine or fluorine,
X^ is oxygeA or sulfur,
Xg is )>C=0 or ^kCHg, and
Z is hydrogen, chlorine, fluorine, hydroxy, lower alkoxy or lower alkanoyloxy,
44781 with the proviso that when Z is hydroxy and X^ is oxygen then Xg is ^bC=O.
The compounds of the general formula I have been found to exhibit useful therapeutic activity, more particularly useful anti-hypertensive activity.
Unless otherwise specified, the terms lower alkyl, lower alkoxy and lower alkanoyloxy as used herein mean such groups containing up to six carbon atoms. Exemplary of such groups are alkyl groups such as methyl, ethyl, n10 propyl, n-butyl, n-pentyl and n-hexyl and the corresponding branched chain isomers thereof, alkoxy groups such, as methoxy, ethoxy, isopropoxy and butoxy and alkanoyloxy groups such as acetoxy, propionyloxy arid butyryloxy and the corresponding branched chain isomers of the foregoing.
Exemplary of the pharmaceutically acceptable acid addition salts ai’e those formed with maleic, acetic, phthalic, succinic, laciic,. tartaric, citric, malic, cinnamic, methanesulfonic, hydrochloric, hydrobromic, sulfuric and phosphoric acids.
R is preferably a lower alkyl group containing up to 4 carbon atoms, most preferably a methyl group. R^ is preferably hydrogen and and Rg preferably hydrogen or lower alkyl.
ZCV . /Cf2y
The grouping -C—Z is preferably -C—OH with Y being X'cy3 X'CF2Y
- 3 Λα*®1 as defined for formula I and most preferably with Y being fluorine.
' A preferred compound of the general formula I where X^ is sulfur and Xg is CHg is 2-[4-(hexafluoro-2-hydroxy-25 propyl)-N-methylanilino]-2-thiazoline. Other thiazolines within the scope of this Invention include: 2-‘[4-(hexafluoro-2-hydroxy-2-propyl)-N-ethylanilino]-2thiazoline, / 2-[N,2,6-trimethyl-4-(hi5Xafluoro-2-hydroxy-2-propyl)
1° anilino]-2-thiazoline, and
2-[4rtetrafluoro-l,5-dichloro-2-hydroxy-2-propyl)-Nmethylanilino]-2-thiazoline.
Exemplary compounds of the general formula I where X^ is oxygen and Xg is >CHg are:
2-[4“(hexafluoro-2-methoxy-2-propyl)-N-methylanilinol-2~ oxazoline,
2-[4-(hexafluoro-2-acetoxy-2“propyl)-N-methylanilino]-2oxazoline and
2-[4-(2-chlorohexafluoro“2-propyl)“N-methylanilino[-220 oxazoline. ~
Preferred compounds of the general formula I where X2 is oxygen or sulfur and Xg is ^0=0 are 2-[A-(hexafluoro-2hydroxy-2-propyl)-N-methylanilino]-2-oxazolin-4-one and 2-[4-(hexafluoro-2-hydrOxy-2-propyl)-N-methylanilino]-2- 4 _ thiazolin-4-one. There may also he mentioned 2-[ /)-(hexafluoro-2-hydroxy-2-propyl)anilino]-2-oxazolin-4-one.
The compounds of the general formula I may be prepared by cyclising a compound of the general formula XII
wherein R, R^, Rg, R , X^, Xg, Y and Z are as defined for formula I and Q is a reactive grouping capable of being eliminated as HQ under the reaction conditions employed, said cyclisation being followed by isolation of the so-obtained 10 compound of the general formula I in free form or in the form of a pharmaceutically acceptable acid addition salt.
The group Q may typically be a labile leaving group such as halogen, preferably chlorine, or a sulfonic acid ester moiety such as tosyl or mesyl.
For the preparation of compounds of the general formula I wherein X^ is oxygen and Xg is ^C=0 or ^CH2, a substituted aniline starting material of the general formula II
R.
Nfi
R.
'2 (II), wherein R, R13 Rg, R^, Y and Z are as defined for formula I, may be reacted with.chloroacetyl- or 2-chloroethyl-isoeyanate to give, as intermediate, a compound of the general formula .5 III wherein X^ is oxygen, Xg is ^:0=0 or StCHg and Q is chlorine and R, R^, Rg, R^, Y and Z are as defined for formula III. Cyclisation of. the-intermediate III gives the required compound of the, general formula I. Cyclisation may be effected in any convenient manner. When Xg is ^C=0 then cyclisation is preferably effected using a base such as potassium tbutoxide in a suitable solvent such as tetrahydrofuran, diethoxyethane -or preferably dimethoxyethane. When Xg is ^rCHg then cyclisation is preferably effected by heating in an aqueous alcoholic medium preferably in the presence of a mineral acid.
The starting material of the general formula Ii where Z is hydroxy may be prepared by suitable introduction of the required hydroxjrpolyhaloisopropyl group, 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., 30, 1001, 1965). The hydroxy
- 6 44701 group in this starting material may then be converted into the other values of Z using known techniques.
The compounds of the general formula I wherein X^ is sulfur and Xg is ^C=0 may be prepared in an analogous manner to that described above using chloroacetyl isothiocyanate in place of chloroacetyl isocyanate. In this case, however, the intermediate corresponding to that of formula III cyclises spontaneously to the hydrochloride salt of the thiazolin4-one, pop the preparation of those compounds of the formula I wherein X-^ is sulfur and Xg is ^CHg,a starting material of the general formula II may be reacted with chloro- or bromo ethyl is^yanate, suitably by refluxing the materials in an inert solvent such as benzene, the so-obtained intermediate of the general formula III being spontaneously cyclised.
The pharmaceutically acceptable acid addition salts of the compounds of the general formula I may be prepared in conventional manner by treating a solution of the free base in a suitable organic solvent with the appropriate acid to precipitate the desired salt. Further purification may be effected by, for example, recrystallisation.
- 7 44791
The invention will now be exemplified by way of the following examples.
Example 1
2-(4-(Hexafluoro-2-hydroxy-2-propyl)-N-methylanilino]5 2-thiazoline
Mix 11.0 g £-(hexafluoro-2-hydroxy-2-propyl)-N-methylaniline (0.04 mole) and 9-7 g 2-ehloroethylisothiocyanate (0.08 mole) in 100'ml benzene. Heat the mixture, at reflux for 5 hours and then filter off the solid material. Dissolve this, in 300 ml water and basify with sodium carbonate.
Extract the solution with diethyl ether and then dry and concentrate the ether extract. Recrystallize the so-obtained residue from a hexane-diethyl ether mixture to give crystals,
m.p. l6O-3°C. The fumarate salt, prepared in methanol, has a*melting point of 175-7°C.
By use of the appropriately substituted aniline starting material in the foregoing Example, other thiazolines of the general formula I may be prepared,for example:
2-[4-(hexafluoro-2-hydroxy-2-propyl)-N-ethylanilino]-2r thiazoline,
2-[W,2,6-trimethyI-4-(hexafluoro-2-hydroxy-2-propyl)anilino]2-thiazoline and
2-[4-tetrafluoro-1,3-dichloro-2-hydroxy-2-propyl)-Nmethylanilinoj-2-thiazoline.
- 8 44791
Example 2
2—[4—(2-Chlorohexafluoro-2-propyl)-N-methylanilino]-2oxazoline
Combine 41.0 g (0.15 mole) of 4-(hexafluoro-2-hydroxy-25 propyl)-N-methylaniline (Gilbert, J. Org. Chem., 30, 1001 (1965)) and 19 g (0.18 mole) 2-chloroethyl isocyanate with 400 ml of EtgO. Allow the mixture to stand overnight and then concentrate to obtain a beige solid. Recrystallize from a diethyl ether-hexane mixture to obtain N-(2-chloro10 ethyl)-N'-[4-(hexafluoro-2-hydroxy-2-propyl)phenyl]-Π'methylurea as an off-white solid; m.p. 120-121°C.
Add 5.5 g of a 57 % solution of sodium hydride in mineral oil (0.I3 mole) to a solution of 22.7 g N-(2-chloroethyl)-Ν’[4-(hexafluoro-2-hydroxy-2-propyl)phenyl]-N'-methylurea (0.06 mole) in 100 ml of 1,2-dimethoxyethane. Stir one hour and then add slowly 15.1 g thionyl chloride (0,13 mole).
After one hour, pour the mixture into 800 ml water. Filter off the solid, dissolve in 200 ml methanol, and decant from the mineral oil. To the methanol add 16 g sodium borohydride (0.4 mole). Concentrate and dissolve the residue in ether.
Wash with water and concentrate to give a cream solid. Dissolve the so-obtained solid in 40 ml 2N sulfuric acid and 40 ml methanol. Reflux for 1 hour and then partially concentrate the mixture. Partition between ethyl acetate and aqueous sodium bicarbonate. Dry and concentrate the ethyl
- 9 4A·?91 acetate. Treat the so-obtained residual oil in ether with ethereal sulfuric acid and filter off the solid. Partition between ethyl, acetate and aqueous sodium bicarbonate. Dry the ethyl acetate, concentrate and distill, b.p. 123~31°C
. (0.1 mm). Treat the distillate in ether with ethereal sulfuric acid to give the bisulfate salt, m.p. l43~6°C.
Example 3
•. · ’l
2-[4-(Hexafluoro-2H-2-propyl)-N-methylanilino3-2-oxazoIine
To a solution of 1.6 g 2-[it-(2-chlorohexafluoro-2-propyl)10 N-methylanilino]-2-oxazoline bisulfate (0.003 mole), obtained as described in Example 2, in 40 ml ethanol add 0.1 g 5 55 palladium on charcoal. Shake 3 hours with hydrogen at 3 atm. pressure, filter and concentrate. Partition between ethyl acetate and aqueous sodium bicarbonate. Dry and concentrate the ethyl acetate. Treat the residual oil with 0.2 g orthophosphoric acid in methanol, dilute with ether and filter to give the phosphate salt of the title compound, m.p, 93-7°C·
Example 4
2-[4-(Hexafluoro-2-methoxy-2-propyl)-N-methylanilino]-220 oxazoline '
Add 8.3 g KgCO^ (0.06 mole) to a solution of 11.3 g N-(2-chloroethyl)-Nt-[4-(hexafluoro-2-hydroxy-2-propyl) - 10
447QI phenyl]-Ν'-methylurea (0.03 mole) and 17.0 g (0.12 mole) of methyl iodide in 120 ml acetonitrile. Stir 4 days, filter, and concentrate the filtrate. Dissolve the residue in ether and wash with water. Dry and concentrate the ether.
Reflux the residue 1 hour in 100 ml 5θ % methanol. Concentrate and partition between diethyl ether and IN hydrochloric acid. Neutralize the aqueous layer with sodium bicarbonate, extract with diethyl ether, dry and concentrate the ether. Dissolve the so-obtained oil in 10 ml methanol and treat with 2.0 g fumaric acid. Pour the solution into diethyl ether and filter to give the fumarate salt of the title compound, m.p. 89 - 91°C,
Example 5
2-[4-(2-Aeetoxyhexafluoro-2-propyl)-N-methylanilino]-215 oxazoline
Add 2.2 g of a 57 # solution of sodium hydride in mineral oil (0.05 mole) to a solution of 17-1 g 2-[4-(hexafluoro2-hydroxy-2-propyl)-N-methylanilino]-2-oxazoline in 150 ml
1,2-dimethoxyeth'ane. After 1 hour, add 3·9 g acetyl chloride (0,05 mole). After a further 1 hour, filter and then concentrate the filtrate. Dissolve the so-obtained residue in diethyl ether and IN hydrochloric acid. Neutralize the aqueous diethyl ether with sodium bicarbonate. Extract with diethyl ether and dry over magnesium sulfate. Treat
- 11 «θ1 the solution wjth ethereal hydrochloric acid. Collect the solid and recrystallize from methanol ether, to give the hydrochloride salt of the title compound, m.p. 1O2-4°C.
- . Example 6 .
2-[4-(ifg;afluofb-2-hydroxy-2-propyl)-N-methylaniiino3-2oxazolin.-4-one .'
To 12.0 g- N-methy1-4-(hexafluoro-2-hydroxy-2-propyl). aniline (0.044 mole) in 200 ml of benzene add 7·?- g of chloroacetyl isocyanate (0.06 mole) and stir for 1 hour,
Filter off the solid product and wash with benzene to obtain N'-methyl-N-chloroacetyl-N'~[4-)hexafluoro-2-hydroxy2-propyl)phenyl]urea, m.p. 158-160°C.
To N'-methyl-N-ehloroacetyl-N'-E4-¢lexafluoro-2-hydrσxy2-propyl)phenyl]urea (3.93 g, 0.01 mole) in dimethoxy15 ethane (100 ml), add potassium t-butoxide (2.24 g, 0.02 mole) and stir for 30 minutes. Concentrate, add water (100 ml) and acidify with concentrated HCl._Neutralise with sodium bicarbonate and then extract with diethyl ether.
. Dry the ethei* extract and then concentrate. Triturate 20 the so-obtained crude product with diethyl ether and then filter off the stolid_to give the title compound, m.p. 225227°C. ,
- 12 4479 1
Example 7
2-[4-(Hexafluoro-2-hydroxy-2-propyl)anilino3-2-oxazolin4-one
To N-chloroacetyl-N’-[4-(hexafluoro-2-hydroxy-2-propyl) 5 phenyljurea (9.7 g, 0.026 mole) in dimethoxyethane (500 ml) add potassium t-butoxide (5.7 g, 0.051 mole). Stir 16 hours, concentrate, add water, acidify with concentrated hydrochloric acid, neutralize with sodium bicarbonate and then extract with diethyl ether. Dry, concentrate, and recrystal10 lize the residue from diethyl ether, to obtain the product,
m.p. 272-274°C.
Example 8
2-[4-(Hexafluoro-2-hydroxy-2-propyl)-N-methylanilino]2-thiazolin-4-one
To £-(hexafluoro-2-hydroxy-2-propyI)-N-methylahiline (2.73 g, 0.01 mole) in dimethoxyethane (40 ml), add chloroacetyl isothiocyanate (1.50 g, 0.011 mole) and stir for 1 hour. Pour the reaction mixture into water and neutralize with sodium bicarbonate. Extract the mixture with diethyl ether, dry the extract and then concentrate. Recrystallize the residue from diethyl ether to obtain the title compound, m.p, 24O-242°C.
- 13 In analogous manner to that described in the foregoing Examples 6 and 7, the following respresentative oxazolin4-ones of the general formula I may be prepared:
2-[4-(1,3-dichloro-l,1,3,3-tetra f luoro-2-hydroxy-2-propyl)5 N-methylanilino]-2-oxazolih-4-one;
2-[2 ^-diisopropyl^-Chexafluoro^-hydroxy^-propyD-Nmefchylanilino ]-2-oxazolin-4-one;
2-[4-(1,1,1-trifluoro-2-hydroxy-2-propyl)-N-methylanilino]2-oxazolin-4-one;
2-[4-(chloropentafluoro-2-hydroxy-2~propyl)-N-methylanilino]2-oxazolin~4-one;
2-[2,6-dichloro-4-(hexafluoro-2-hydroxy-2-propyl)-N-methylanilino] -2-oxazolin-4-one;
2-[2,6-diethyl-4-(hexafluoro-2-hydroxy-2-propyl)-N-methyl15. anilino]-2--oxazolin-4-one;
2-[4-(heXafluoro-2-hydroxy-2-propyl)-2-methoxy-N-methylanilino]-2-oxazolin-4-one;
2-[2-fluoro-4-(hexafluoro-2-hydroxy~2-propyl)-N-methylanilino]-2-oxaz01in-4-one;
2-[4-(hexaflu.bro-2-hydroxy-2-propyl)-2,6-dimethoxy-Nmethylanilino]-k-oxazolin~4-one; and 2-[N-ethyl-4-(hexafluoro-2-hydroxy-2-propyl)anilino]-2oxazolin-4-one.
Similarly, by following the method described in Example 8 the corresponding thiazolin-4-ones of the general formula I
- 14 44791 may be prepared for example:
2-[4-(hexafluoro-2-hydroxy-2-propyl)-N-ethylanilino]-2thiazolin-4-one,
2-[N,2,6-trimethyl-4-(hexafluoro-2-hydroxy-2-propyl)anilino]5 2-thiazolin-4-one and
2-(4-(1,3-dichloro-l,1,3,3-tetrafluoro-2-hydroxy-2-propyl)N-methylanilino]-2-thiazolin-4-one.
In the treatment of hypertension, a number of agents are known. Certain of these, for example reserpine, are effec10 tive 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 t
while avoiding or mitigating some of tbe deleterious side effects associated with known anti-hypertensive agents.
Based on laboratory tests and procedures, it is considered that the effective dosage, the ED^q, by oral administration for a compound of the present invention will typically lie within the range of from 0.01 to 10.0 mg/kg of mammalian weight per day. .
-15 9*· i'
The minimum effective dose in rats was measured for a number of the compounds of the present invention and the following results obtained:
(The rats were spontaneously hypertensive rats (SHR) and 5 the method used was that of Bunag, Journal of Applied
Physiology, 34, pp 279 (1973).
Compound Minimum effective dose mg/kg
2-[4-(hexafluoro-2-hydroxy-2-propyl)~ M-methylanilino]-2-oxazolin-4-one 0.25
2-[4-(hexafluoro-2-hydroxy-2-propyl)- .·’ ;<
N-methylanilino]-2-thiazolin-4-one 0.25
2-[4-(hexafluoro-2-hydroxy-2-propyl)M-methylanilinol-2-thiazoline. 0.50
The above compounds were non-lethal at a dose rate-of 15 100 mg/kg.
The required daily dosage may be administered in single or divided doses. The exact dose to be administered will, . - - t - of course, be dependent upon where the compound in question .-.- 1 lies within the above quoted dosage range and upon the 20 :age and weight of the subject mammal.
The compounds of the general formula I are preferably administered, orally although administration by injection is
- 16 also possible. The compounds may be combined in conventional manner with any suitable pharmaceutical carrier to give a variety of formulations such as tablets, capsules, syrups, elixirs or suspensions.
Any acceptable pharmaceutical carrier may be employed in the foregoing formulations. A few of such carriers which may be mentioned are: sugars such as lactose and sucrose, starches, cellulose and derivatives such as sodium carboxymethyl cellulose, calcium phosphate, polyvinyl pyrroli10 done and vegetable oils.
In treating certain patients with the compounds of this invention it may be desirable to Include other pharmaceutically active ingredients in the same dosage unit. For example, in treating patients in whom salt and water re15 tention is a problem, effective amounts of conventional diuretics can be incorporated, such as the thiazide diuretics, e.g., hydrochlorothiazide or trichloromethiazide. Similarly, in treating patients in whom tachycardia might be a problem, an effective amount of a pharmaceutically acceptable β-blocking agent can be included, e.g., propranolol. The dosage unit may even contain a combination of a compound of formula I, e.g., 2-[4-(hexafluoro-2-hydroxy2-propyl)-N-methylanilino]-2-oxazolin-4-one, a diuretic, e.g., hydrochlorothiazide, and a (3-blocker, e.g., propranolol.
- 17 I
44.?« 4
Representative formulations for the compounds of the general formula I will now he illustrated by way of the following Examples:
Example A . Tablet Formulations
Formulation I
Ingredient
2-[4-(hexafluoro-2-hydroxy-2-propyl) N-methylanilino]-2-oxazolin-4-one Lactose, direct compression grade Microcrystalline cellulose Sodium Lauryl Sulfate
Corn starch
Magnesium stearate
Milligrams per Tablet
221 _2
300
Mix together the stated active ingredient, lactose, microcrystalline cellulose, sodium lauryl sulfate and corn starch. Pass through a No. 40: screen (U.S. Standard Sieve; sieve opening 0.42 mm). Add the magnesium stearate, mix and compress into desired shape on a table machine.
4479/
Formulation II
Ingredient Milligrams per Tablet
2-[4-(hexafluoro-2-hydroxy-2-propyl)N-methylanilino]-2-oxazolin-4-one 2
Lactose, U.S.P. 240
Dicalcium phosphate 56
Sodium lauryl sulfate 20
Polyvinyl pyrrolidone 10
Water 50 ml/1000 tablets
Corn starch 20
Magnesium stearate . _2
350
Mix together'the stated active ingredient, lactose, dicalcium phosphate'and'sodium lauryl sulfate. Screen the above mixture through a No. 60 screen (U.S. Standard Sieve; sieve opening 0.25>mm) and granulate with an aqueous solution containing >£he polyvinyl pyrrolidone. 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 (U.S. Standard Sieve; sieve opening 2.0 mm), tray and dry in an oven at 40°C for 12 to 14 hours’. Reduce the dried granulation through a No. 16 screen (U.S. Standard Sieve; sieve opening approx. 1.2 mm). Add the magnesium stearate, mix and compress into desired shape on a tablet machine.
- 19 I
447»1
Example Β
Capsule Formulation
Ingredient Milligrams per Capsule
2-(4-(hexafluoro-2-hydroxy-2-propyl)5 N-methylanilino]-2-oxazolin-4-one 2
Lactose, U.S.P. 220
Microcrystalline cellulose 30
Sodium lauryl sulfate 20
Corn starch 25
Magnesium stearate 2
300
Mix together the stated active Ingredient, lactose, microcrystalline cellulose, sodium lauryl sulfate and corn starch. Pass through a No. So screen (U.S. Standard Sieve; sieve opening 0.18 mm). Add the magnesium stearate, mix and encapsulate into the proper size two-piece gelatin capsule.
Claims (18)
1. CLAIMS and the pharmaceutically acceptable acid addition salts thereof, wherein R is hydrogen or a lower alkyl group having up to 6 carbon atoms, R^, Rg and R^ independently represent hydrogen, bromine, chlorine, fluorine, nitro, lower alkyl, lower alkoxy or lower alkanoyloxy, Y is hydrogen, chlorihe or fluorine, X 1 is oxygen or sulfur, Xg. is>C=O or >CHg, and Z is hydrogen, chlorine, fluorine, hydroxy, lower alkoxy or lower alkanoyloxy; with the proviso that when Z is hydroxy and X^ is oxygen then X 2 is > C=0. 21
2. A compound as claimed in claim 1, wherein R is a lower alkyl group having up to 4 carbon atoms.
3. A compound as claimed in claim 2, wherein R is methyl.
4.. A compound as claimed in any one of the preceding claims, wherein R^ is hydrogen. ι
5. A compound as claimed in any one of the preceding claims, wherein R^ and R 2 each represent a lower alkyl group.
6. A compound as claimed in any one of claims 1 to 4, wherein R^ and R 2 are each hydrogen. 'l
7. A compound as claimed in any one of the preceding claims, wherein 2 is hydroxy.
8. A compound as claimed in any one of the preceding claims, wherein 7 is fluorine.
9. A compound as claimed in any one of the preceding claims, wherein is oxygei or sulfur and X 2 represents ) C=0. · - 22 44791
10. A compound as claimed in any one of claims 1 to 8, wherein X^ is sulfur and X 2 represents CH 2 .
11. 2-(4- (Hexafluoro-2-hydroxy-2-propyl)-N-methylanilino ]-2-oxazolin-4-one.
12. 2-(4-(Hexafluoro-2-hydroxy-2-propyl)-N-methylanilino ]-2-thiazolin-4-one.
13. 2-(4-(Hexafluoro-2-hydroxy-2-propyl)-N-methylanilino ]-2-thiazoline.
14. Pharmaceutically acceptable acid addition salts of a compound as claimed in any one of claims 11 to 13.
15. jA process for the preparation of a compound of the general formula I set forth in claim 1, which process comprises cyclising a compound of the general formula III I - 23 - 0781 X-, Y and Z are as defined wherein R, R^, Rg, R^, X^, for formula I and Q is a reactive grouping capable of being eliminated as HQ under the reaction conditions employed.
16. A compound of the general formula I set forth in claim 1 whenever obtained by a process as claimed in claim 15.
17. A pharmaceutical composition comprising as active ingredient a compound as claimed in any one of claims 1 to 14 and 16 in association with a suitable pharmaceutical carrier.
18. A process for the preparation of a pharmaceutical composition which comprises bringing a compound as claimed in anyone of claims 1 to 14 and 16 into a form suitable for therapeutic administration.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/668,385 US4081547A (en) | 1974-12-02 | 1976-03-19 | Para-polyfluoroisopropyl-anilino-2-oxazoline compounds, pharmaceutical compositions and method of treating hypertension |
| US05/731,236 US4103018A (en) | 1976-10-12 | 1976-10-12 | 2-[4-(Polyhalo-2-hydroxy-2-propyl)anilino]-2-oxazolin-4-ones and thiazolin-4-ones corresponding thereto |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE44791L IE44791L (en) | 1977-09-19 |
| IE44791B1 true IE44791B1 (en) | 1982-04-07 |
Family
ID=27099887
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE578/77A IE44791B1 (en) | 1976-03-19 | 1977-03-16 | Substituted anilino-2-oxazolines and thiazolines |
Country Status (9)
| Country | Link |
|---|---|
| JP (1) | JPS52113960A (en) |
| AU (1) | AU506147B2 (en) |
| CH (1) | CH626356A5 (en) |
| DE (1) | DE2711330A1 (en) |
| FR (1) | FR2344548A1 (en) |
| GB (1) | GB1532351A (en) |
| IE (1) | IE44791B1 (en) |
| IL (1) | IL51669A (en) |
| NL (1) | NL7702846A (en) |
-
1977
- 1977-03-16 CH CH325377A patent/CH626356A5/en not_active IP Right Cessation
- 1977-03-16 JP JP2913177A patent/JPS52113960A/en active Pending
- 1977-03-16 IL IL51669A patent/IL51669A/en unknown
- 1977-03-16 DE DE19772711330 patent/DE2711330A1/en not_active Withdrawn
- 1977-03-16 IE IE578/77A patent/IE44791B1/en unknown
- 1977-03-16 NL NL7702846A patent/NL7702846A/en unknown
- 1977-03-16 FR FR7707851A patent/FR2344548A1/en active Granted
- 1977-03-16 GB GB11158/77A patent/GB1532351A/en not_active Expired
- 1977-03-17 AU AU23355/77A patent/AU506147B2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| IE44791L (en) | 1977-09-19 |
| AU2335577A (en) | 1978-09-21 |
| FR2344548B1 (en) | 1978-12-29 |
| AU506147B2 (en) | 1979-12-13 |
| IL51669A (en) | 1980-10-26 |
| DE2711330A1 (en) | 1977-09-22 |
| CH626356A5 (en) | 1981-11-13 |
| GB1532351A (en) | 1978-11-15 |
| JPS52113960A (en) | 1977-09-24 |
| IL51669A0 (en) | 1977-05-31 |
| NL7702846A (en) | 1977-09-21 |
| FR2344548A1 (en) | 1977-10-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US3995039A (en) | Pyrazolo [1,5-a] [1,3,5] triazines | |
| US4159335A (en) | Substituted anilino-2-thiazolines | |
| JPS63295589A (en) | Derivative of physiologically active substance k-252 | |
| EP0251453B1 (en) | Substituted amino-dihydrooxazoles, -thiazoles and -imidazoles, process for their preparation and pharmaceutical compositions containing them | |
| US4762832A (en) | Morpholine containing pyrrolidinones pharmaceutical compositions and use | |
| US4377576A (en) | 5-(Heterocyclic amino-propionyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-ones | |
| US3988464A (en) | Cyclopropylamines as pharmaceuticals | |
| US4378359A (en) | Theophyllinylmethyldioxolane derivatives, methods for their preparation and pharmaceutical compositions containing them | |
| JPH01294670A (en) | 2-(piperadinyl)-2-oxoethylene-substituted flavonoid derivative, its production and pharmaceutical composition containing said derivative | |
| US4058612A (en) | 6-(Polyhaloisopropyl)quinazoline-2,4-diones | |
| JPS5846089A (en) | Heterocyclic compound | |
| US4376121A (en) | Antiallerigically-active imidazothienopyrimidine derivatives | |
| US4150132A (en) | Oxadiazolopyrimidine derivatives | |
| US3931176A (en) | Hydroxyalkyl substituted-4,5-dihydropyridazin(2H)-3-ones | |
| US4103018A (en) | 2-[4-(Polyhalo-2-hydroxy-2-propyl)anilino]-2-oxazolin-4-ones and thiazolin-4-ones corresponding thereto | |
| US4177273A (en) | 6-(Substituted phenyl)-4,5-dihydro-pyridazin-3(2H)-ones | |
| IE44791B1 (en) | Substituted anilino-2-oxazolines and thiazolines | |
| US4102890A (en) | 2-Amino oxazolines and process for making the same | |
| US4530843A (en) | Isoindole amidoxime derivatives | |
| US3978044A (en) | Indazole derivatives, processes for making the same and pharmaceutical compositions | |
| US3790572A (en) | 2-hydroxyalkyl-4,5-dihydropyridazin-3(2h)-one derivatives | |
| US3997555A (en) | 4-Phenyl-1-hydroxyalkylpyrazoles | |
| US4228166A (en) | 2-Keto-4,5-dihydro-3 (2H)-pyridazinones, and their use in treating muscle tension | |
| US3635971A (en) | 3 (3 4-dihydro-3-oxo-2-quinoxalinyl) propionamides | |
| US4055644A (en) | Hydroxyalkyl substituted-4,5-dihydropyridazin(2H)-3-ones |