CA1128525A - 3-alkyl-5-(2-hydroxy-styryl)-isoxazoles and their preparation - Google Patents

3-alkyl-5-(2-hydroxy-styryl)-isoxazoles and their preparation

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CA1128525A
CA1128525A CA325,386A CA325386A CA1128525A CA 1128525 A CA1128525 A CA 1128525A CA 325386 A CA325386 A CA 325386A CA 1128525 A CA1128525 A CA 1128525A
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styryl
hydroxy
isoxazole
alkyl
methyl
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Peter C. Thieme
Hans Theobald
Albrecht Franke
Rolf Huber
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BASF SE
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07F9/653—Five-membered rings
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
    • C07C47/56—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing hydroxy groups
    • C07C47/565—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing hydroxy groups all hydroxy groups bound to the ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

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Abstract

O.Z. 0050/033158 ABSTRACT OF THE DISCLOSURE: 3-Alkyl-5-(2-hydroxy-styryl)-isoxazoles of the general formula (1) (1) where R is alkyl of 1 to 4 carbon atoms, and processes for their preparation. The novel compounds of the formula (1) are valuable intermediates for the synthesis of drugs;
in particular, alkylamino-hydroxypropyl-ethers of these intermediates can be used for the treatment of hypertonia, of coronary diseases of the heart and of cardiac arrhythmias.

Description

~L ~ ;~J ~3 5 2S o . z . o o 5 o, 03,158 3-Alkyl-5-(2-hydroxy-s-tyryl)-isoxazoles and their preparation The present invention relates to 3-alkyl-5-(2-hydroxy-styryl)-isoxazoles of the general formuIa (1) R
~o'~`i (1) ` ' C;i where R is alkyl of 1 to 4 carbon atoms, and to processes for their preparation.
The alkyl radicals, which may be straight-chain or branched, may be methyl, ethyl, n-propyl, iso~propyl~ n-butyl, sec.-butyl, iso-butyl or tert.-butyl.
Accordingly, examples o~ compounds according to the io invention are 3-methyl-5-(2-hydroxy-styryl)-isoxazole, 3-ethyl-5-(2-hydroxy-styry-)-isoxazole, 3-n-propyl-5-(2-hydroxy-st-~ryl)-isoxazole, 3-iso-propyl-5-(2-hydroxy-styryl)-isoxazole, 3-n-butyl-5-(2-hydroxy-styryl)-isoxazole, 3-sec.-butyl-5-(2-hydroxy-styryl)-isoxazole, 3-iso-butyl-5-(2-hydroxy-styryl)-isoxazole and 3-tert.-butyl-5-(hydroxy-styryl)-isoxazole,of which 3-methyl-5-(2-hydroxy-styryl)-isoxazole, 3-ethyl-5-(2-hydroxy-styryl)-isoxazole, 3-iso-propyl-5-(2~hydroxy-styryl~-isoxaæole and 3-tert.-butyl-5-(2-hydroxy-s~yryl)-isoxazole deserve particular mention.
The novel compounds of the formula (1) are valuaDle intermediates for the synthesis of dru~s.
The compounds of the formula (1) may be prepared by the following processes:

' :~28525
- 2 - O.Z. 0050/033158 1. By reaction of a phosphonic acid ester of the general formula (2) R
,oR2 (2) . 2 Op~z where R has the meanings given for formula (l) and R2 is lower alkyl of 1 to 3 carbon atoms, with a substituted salicylaldehyde of the general formula (3) ~ (3) where R3 is alkoxyal~yl of the formula (4) oR4 (4) ~where R4 and R5 are identical or di~ferent and each is lower alkyl of 1 to 3 carbon atoms, and R5 can also be hydro-gen) or R3 is tetrahydropyranyl, under the conventional con-ditions of the ~rittig-Horner reaction, to give a compound of the general formula (5) R

0''"~ (5) O~
followed by deta~mert ofthe protective group R3 under acid conditions .
The phosphonic acid esters of the general formula (2) are prepared ~y conventional methods from the -.:;

: - , .

corresponding 3-alkyl-5-chloromethyl-isoxazoles, ie. by reac-tion with trialkyl phosphites in the manner of an Arbusov reac-tion, as described in Houben-Weyl, Volume 12/1, pages 433 et seq. The 3-alkyl-5-chloromethyl-isoxazoles can be prepared by the process described in German Laid-Open Application DOS
2,549,962. 3-Methyl-isoxazole-5-methylene-phosphonate is de-scribed~in German Laid-Open Application DOS 1,939,~09, which also discloses its reaction with 2-(dimethylaminoethoxy)~ben-zaldehyde to give 5-~o-(2-dimethylamino)-ethoxy~-styryl-3~
methylisoxazole. The compounds of the formula ~1) claimed herein, and their preparation, are not described in or suggested by German Laid-Open Application DOS 1,939,809.
The protective group R3 is easily detachable under acid conditions but is stable in an alkaline medium; l-alko~y-alkyl groups, eg. l-methoxyethyl, are pre~erred. Salicyl-aldehydes o~ the general formula (3) are known or can be pre-pared in accordance with conventional methods by reacting a salicylaldehyde phenolate with a l-chloroalkyl alkyl ether, eg.
chloromethyl methyl ether or ~-chloroethyl methyl ether, or by reacting salicylaldehyde with an alkyl vinyl ether in the presence of an acid catalyst. The synthesis . . . ~

.~, ,, .

~, , , ,, ~ ~ .

l~Z85ZS
_ 4 _ O.Z. 0050/03~158 of such protected hydroxy-benzaldehydes has been disclosed, for example in the following publications:P Venturella and A. Bellino, Ann. Chimica 48 (1958), 706 - 722; R,L. Edwards and I Mir, J. Chem~ Soc. ~London], Sect C 1967, 411-13;
German Laid-Open Application DOS 2,209,128; A Arcoleo et al~, Ann. Chimica 47 (1957), 667-74.
The reaction of a compound of the ~eneral formula
(3) with a phosphonic acid ester of the general form~la (2) is advantageously carried out in a suitable solvent in the presence of a base, under conventional conditions, as des-cribed, for example, in Houben-Weyl, Volume 5/ld, pages 127 et seq. and in A, Maercker, Org. Reactions, Volume 14, pages 270 et seq, Suitable inert solvents are aromatic hydrocar-bons, eg. benzene, toluene and ~ylene, relatively high-boiling aliphatic or cycloaliphatic ethers, eg, ethylene gl~cbl dimethyl ether, tetrahydro~uran or dioxane, dirnethyl-formamide, dimethylsulfoxide and mixtures of the said sol~
vents. The reactions are advantageously carried GUt at room temperature or at elevated temperatures, viz, at from 30 to 80 C. Suitable bases are alkali metal hydrides~
amides and alcoholates, especially those of sodium and potassium, as well as but~l-lithium and phenyl-lithium.
The detachment of the protective group with libera-tion of the compounds according to the invention, of the formula (1), from the compounds of the formula (5) is carried out by conventional methods. As a rule, ~he com~
pound of the formula (5) is hydrolyzed without first being purified, The detachment of the protective group LS
carried out in an acid medium, using an inorganic acid. eg.

~8~
-5- O.Z. 0050~03~1~8 HCl or H2S04, or using an acidic ion exchanger resin in a suitable solvent, such as an alcohol, ether, ketone, hydrocarbon or the like~ especially methanol or ethanol, at room temperature or elevated temperatures.
Water/alcohol mixtures can also be used as the solvent, Preferred solvents are methanol/water and acetone/water mix-tures containing from l to lO~o Of acid~
2. By reaction o~ a phosphor~lidene of the formula (~) ~ C;
N ~ CH P \ C5 ~ (6) Co;i~

whers R has the meanings given for formula (l~, with salicyl-aldeh~yde or with a protected salicylaldehyde o~ the general formula (3), The reaction is carried out in accordance with conventional methods, as descr.ibed, for example, in Houben-Weyl, Volume 5/lb, pages38~ et seq. If a pro-tected salicylaldehyde is used, the protective group is detached again, as described under 1.
In the process according to the invention, the com-pounds of the general formula (l) are obtained as mixtures of cis- and trans-isomers, the latter as a rule predominat-ing. The cis- and trans-co~pounds can be readily separated from one another by cryst.allization or by column chromatography.
~ he compounds according to the invention, of the general formula (1), are valuable intermediates for the syn~hesis of pharmacologically active compounds. For - 6 O.Z~ oo50/o~i58 example, alkylation with an epihalohydrin or an a,~-dihalo-propan-2-ol, followed by reaction with an amine, gives a compound of ~he general formula (7) = ~ (7) o ~ NHR' Oi' ~rhere R is in particular isopropyl, tert.-butyl, cyclopropyl or 3-methyl but-l-yn-3-yl; these compounds can be used for the treatment of hypertonia, of coronary diseases of the heart and of cardiac arrhythmias.
The Examples ~hich follow illustrate the invention.
Preparation of the starting materials Exarnple I: o~ Methoxy-ethoxy)-benzaldehyde a) 610 g (5 molas) of salicylaldehyde are dissolved in 1,~ liters of xylene; 900 g (5 moles) of a 30% strength solutlon of NaOCH3 in methanol are added dropwise to this solutlon at 40 - 50C. The mixlure is then heated and the methanol is distilled off and is progressively replaced, in the reaction flask, by the same amount of xylene.
Heating is continued until the xylene begins to distil o~f (about 130C at the distillation bridge). The suspension of the Na salt of the salicylalde~
hyde is then cooled to 60C and reacted further as described under c).
b) A pinch of hydro~uinone is added to 200 ml of xylene, the mixture is cooled to from -20 to -30C and 290 g (5 mol~s) of vinyl methyl ether are condensed therein, 52~
- 7 - O.Z~ 0050/03~i58 183 g ~5 moles) of HCl gas are then introduced at -30C, and the solution is allowed to stand so as to come to room temperature. The resulting solution of l-chloroethyl methyl ether is reac-ted further as described under c), c) The solution of l chloroethyl methyl ether, prepared as described under b), is added dropwise to the solution, kept at 60C, of the Na salt o~ salicylaldehyde (see a);
the mixture is then stirred ~or about 1~ hours at 60C,if necessary the pH is brought to 8 - 9 with 30% strength NaOCH3 solution, and stirring is continued overnight at room temperature.
The sodium chloride which has precipitated is ~hen filtered off and washed with xylene, and the xylene is dis-tilled off on a rotary evaporator The residue which is left is distilled through a column under 2 mm Hg. 690 g of o-(a-methoxyethoxy)-benzaldehyde, of boiling point 94 -96C/2 mm Hg, are obtained.
Example II: (3-Methylisoxazol-5-yl)-methanephosphonic acid diethyl ester 445 g of 5-chloromethyl-3-methylisoxazole and 674 g of triethyl phosphite are slowly heated to 150aC and left at this temperature for 4 hours. After distillation, 546 g (69% of theory) of (3-methylisoxazol-5-yl)-methane-phosphonic acid diethyl ester of boiling point 118 - 121C/
0.3 mm Hg are obtained~
H-~R spectrum (CHC13, ~ith TMS as internal standard):
r = 3.85 ~d, J = 3 Hæ, lH), 4.17 (m, J = 8 Hz, 4H), 6.67 (d, J = 22 Hz, 2H), 7.72 (s, 3H), 8.67 ~t, J = 8 Hz, 6H) CgH16N04P (233.21) - ~28~;~5 - 8 - O.Z. 0050/0~31~8 calculated: C 46.~5% H 6.91% N 6.01% P 13.28%
found: C 45.9% H 7.~/~ N 6.o% P 13,0%
Example III: (3-Ethylisoxazol-5-yl)-methanephosphonic acid diethyl ester 15 g of 5-chloromethyl-3-ethyl-isoxazole and 18 g of triethyl phosphite are slo~ly heated to 150G and left at this temperature for 2-~ hours. After the mixture has cooled, it is distilled under reduced pressure. 18.2 g of (3-ethylisoxazol-5-yl) methanephosphonic acid diethyl ester of boiling point 120 -121C!0 2 mm Hg are obtained. Yield: 71.2%.
~_NMR spectrum (CDC13, with TMS as internal standard):
~r = 3 85 (d, J = 3 Hz, lH), 4.17 (m, J = Hz, 4H), 6 60 (d, H = 20 Hz, 2H), 7.35 (q, J = Hz, 2H), ~.50 - 8,93 (m, 9H) CloH18N4P (247-23) calculated: C 48.58% H 7,34% N 5,67% P 12.53%
found: C 48.4% H 7.1% N 5.7% P 12.3%
The following phosphonic acid esters were prepared by a similar method:
(3-isopropyl-isoxazol-5-yl)-methanephosphonic acid diethyl ester Boiling point: 117 - 122C/0.3 mm Hg. Yield 73%
(3-tert,-butyl-iso~azol-5-yl)-methanephosphonic acid diethyl ester Boiling point: 126 - 132C/0.3 mm Hg. Yield 88%
Preparation of^compounds according to the invention 3-Methyl-5-(2-hydroxy-styryl)-isoxazole ~28SZ~
- 9 - O.Z. 0050/0~31~8 - 8.8 g (0.2 mole) of a 55% strength sodium hydride suspension in paraffin oil are introduced into 100 ml o~
absolute dime-thylsulfoxide. 47 g (0,2 mole) of diethyl-(3-methyl-isoxazol-5-yl)-methylenephosphon2te are added dropwise at room temperature. Stirring is continued for 30 minutes, a~ter which 36 g (0.2 mole) of o~ methoxy-ethoxy)-benzaldehyde are added dropwise, l~hilst stirring9 and then the reaction mixture is stirred at room temperature for 24 hours. Therea~ter, it is poured onto 1 li-ter o~
ice water and extracted with three 80 ml portions o~
methylene chloride. The combined organic phases are dried with sodium sul~ate and concentrated on a rotary evaporator. The oily residue is dissolved in 80 ml of methanol and 10 ml of water, 2 ml o~ 5 N HCl are added and stirring is continued for 10 minutes. An excess of water is then slowly added to the mixture until a precipitate separates out. The precipitate is Liltered olf, washed with ~ater and recrystallized from ethanol. 19 g (47/0 of theory) of colorless crystals, melting point 236 - 238C.
C12Hl~N02 (201) calculated: C 71.6 H 5.5 N 7.0 found: C 71.8 H 5,5 N 6.8 3-Ethyl-5-(2-hydroxy-styryl)-isoxazole Using the method described in Example 1, 6 g ~0.02 mole) of dietnyl-(3-ethyl-isoxazol-5-yl)-methylene-phosphonate and 4.4 g (0.02 mole) of o~ methoxy-ethoxy)-benzaldehyde are reacted and tne product is recrystallized from isopropanol. 7 g (32% o~ theory) o~ colorless z~ ~

- 10 - O.Z. 0050/0~ 8 crystals. Melting point 175 - 176C.
C13Hl~N02 (215) Calculated: C 72.5 H 6.1 N 6.5 found: C 72.5 H 6.2 N 6.6 3-Iso~ropyl-5-(2-hydroxy-styryl)-isoxazole ~
Using the method described in Example 1, 32 g -(0.12 mole) of diethyl-(3-isopropyl-isoxazol-5-yl)-methylene-phosphonate and 22 g (0.12 mole) of o--(l-methoxy-ethoxy)-benzaldehyde are reacted and the product is recrystallized from toluene. 20 g (73% of theory) of colorless crystals.
Melting point 129 - 133C.
C16H15N02 (229) calculated: C 73.3 H 6.6 N 6.1 ~ound: C 73.7 H 6,7 N 5,8 3-tert.-~utyl-5-(2-hydroxy-styryl)-iOsoxazole Using the method described in Example 1, 35 g (0.13 mole) of diethyl-(3-tert.~butyl-isoxazol-5-yl)~
methylene-phosphonate and 23 g (0.13 mole) of o-(l-methoxy-ethoxy)-benzaldehyde are reacted and the product is recrystal-lized from toluene. 24.8 g ~78% of theory) of colorless crystals. Melting point 152 - 155C.
C15H17N02 (243) calculated: C 74.0 H 7Oo N 5.8 found: C 73.4 H 7,3 N 5.5 The following are examples of compounds of the formula (7) which may be used in the form of their addition salts with a physiologically acceptable acid: 3-methyl-5-~2-(2-hydroxy-35~i ~ O~Z. 0050/0~3158 3-isopropylamino-propoxy)-styryl]-isoxazole, 3-methyl-5-[2-(2-hydroxy-3-tert.-butylamino-propoxy)-styryl]-isoxazole, 3-ethyl-5-C2-(2-hydroxy-3-tert.-butylamino-propoxy)-styryl]-isoxazole, 3-ethyl-5-[2-(hydroxy-3-cyclopropylamino-propoxy)-sty~yl~-isoxazole and 3-methyl-5-[2-(2-hydro~y-3-(3-methyl-but-l-ynyl-3~mino-propoxy)-styryl]-isoxazole, These compounds can be characterized pharmacologi-cally as highly active ~-sympatholytic agents having an acute blood pressure-lowering or anti-hypertensive action.
This type of action is unusual inasmuch as conventional ~-sympatholytic agents, eg, propranolol, only have ~n anti-hypertensive action on administration for lengthy periods, Because of the effects men-tioned, the compounds are pharmacologically particularly suitable for the treatment of hypertonia, o~ coronary diseases of the heart and of cardlac arrhythmias.
The pharmacodynamic properties were examined by the following methods: -1, ~-S~mpatholytic action on isoproterenol-induced tachycardia of narcotized cats, The intravenous administration of 0.001 mg/kg of the ~-s~rmpathomimetic agent isoproterenol increases thepulse rate of mongrel cats (weight: 2 - 4 kg) urder hexobarbital narcosis (200 mg/kg administered intramuscularly) by an average of 61 beats (40%).
~ -Sympatholytic agents inhibit this increase in pulse rate specifically and as a function of the dose given.

~L~Lf~8525 - 12 - Q.Z. 0050/03~15 The substances tested are administered lO minutes before the isoproterenol, to groups of from 3 to 5 cats per dose.
The ED 50% is the dose ~/hich is found to inhibit the isoproterenol-indllced tachycardia by 50%.
2. Blood pressure-lowering action on r.arcotized rats.
To test the blood pressure-lowering action, the sub-stance isadministered intravenously to groupsof from 3 to 5 male Sprague-Dawley rats (weight 230 - 280 g) under urethane narcosis (1.78 g/kg administered intraperitoneally).
The blood pressure in the carotid artery is measured by means of a Statham transducer.
The ED 20k is the dose which is found to lower the mean carotid artery pressure by 20%.
3, Anti-hyper-tensive action on spontaneously hypertonic rats.
The substances are administered orall~ to groups of 8 male spontaneously hypertonic Okamoto rats (weight 280 -350 g), Before, and two hours after, the administration the systolic blood pressure is measured non-surgically on the rats~ tails by means of piezoelectric crystal sensors`.
The ED 20% is the dose which is found to lower the systolic pressure by 20%, taking into account the values found for untreated control animals.
4. Acute toxicity in rnice To determine the acute toxicity (LD 50~, the sub-stances are administered intraperi~oneally to groups of 10 female NMRI mice (weight l9 - 20 g). - The period of observation is 1 week.
The effective doses (see sections 1-3) werecalcula - 13 - 0.~. 0050/03~158 ted from the linear relationships between the logarlthms of the doses and of the action, with the aid o~ regression analysis~ The LD 50 (see section 4) was determined with:
:
ihe aid of Probit analysis. The reference substance was~ ~
the known ~-sympatholytic agent propranolol. ~ ~ -As may be seen from Table l, the ~-sympatholytic activity of the compounds 6, 7, 9 and 10 is from 6,1 to 20 times greater than that of the known ~-sympatholytic agent propranolol. The action of compound 8 is approximately equal to that of propranolol.
In addition to this effect, the substances according to the invention produce an acute lowering of the arterial blood pressure. After administration o~ 0.4 mg/kg of compound 7 to rats, a reduction inblood pressure averaging 20,~
is observed, In the same way, the cornpounds 6, 8, 9 and 10 lower the blood pressure in doses of from 0.65 to 1 mg/kg ~ED 20%). In-contrast, propranolol increases the blood pressure of rats up to doses of 2.15 mg/kg. It is only the sub-lethal dose of 4.64 mg/~g which lowers the pressure by an average of 36%. About twice this dose (10 mg/kg) kills 2 out of 6 animals. After administration of 10 mg/
kg of compound 7, 1 out of 6 animals dies. However, this dose is 25 t~mes higher than the blood pressure-lowering dose (0.4 mg/kg).
As has been shown for compound 7, the substan~es also have a blood pressure-lowering action after oral administration to spontaneously hypertonic rats. 14.5 mg/
kg lower the high blood pressure by an average of 20%.
Propranolol is ineffective in this test, up to a dose o~

2 ~ 5 ~ 5 - 14 _ O.Z. 0050/033158 lO0 mg/kg.
The lethal dose (LD 50 ~or intraperitoneal adminis-tration to mice) of cbrnpound 7 (123 mg/kg) is somewhat higher than that of propranolol (108 mg/kg), and that of compound lO is more than twice as high as that of propranolol.
Compounds 6, 8 and 9 are of the same t;oxicity, or somewhat more toxic, than propranolol. However, in view o~ the high activity (compo~nds 6 ~d 9) and of the overall novel type o~ action, this finding is of no significance.

. .
Compound ~-S~mpatholytic Blood Lethal No. action l) pressure- character 4) lowering action 2) ED 50% R.A, ED 20% LD 50 . ~ . . . .
6 0.007714.3 0,65 108 7 0.005520,0 0.40 123 8 0.12 0.9 0.83 95 9 0.018 6,1 0.93 84 0.017 6,5 l.00 247 Propranolol 0.11 l.0 3) 108 , l) Intravenous administra-tion to cats under hexobarbital narcosis.
ED 50% = dose, in mg/kg, which inhibits the isoproteren-ol-induced tachycardia by 50%, R.A. = relative activity. Propranolol = 1.00.
2) Intravenous administration to rats under urethane narcosis.
ED 20% = dose, in mg/kg, which lowers the blood pres-8 S Z~
- 15 - O.Z. 0050/033158 sure by 20%.
3) Up to 2,15 mg/kg the blood pressure is increased by 11%;
at 4,64 mg/kg it is lowered ~y 36%; at 10 mg/kg, 2 out of 6 animals died.
4) Intraperitoneal administration to mice. LD 50 in mg/
kg, Agents or formulations which in addition to conven-tional excipients or diluents contain a compound of the formula (7) as the active compound are prepared in the con-ventional manner, A suitable individual dose ~or man is from 1 to 100 mg, preferably from 3 to 50 mg.
Compound 1 3-~lethyl-5-~2-(2,3-epoxypropoxy)-styryl]-isoxazole:
6,44 g of 55~ strength sodium hydride in para~fin oil (0,15 mole) are irtroduced into 200 ml of absolute dimethylsulfoxide and 30 g (0,15 mole) of 3-methyl-5-(2-hydroxystyryl)-isoxazole, dissolved in 50 ml of dimethyl-sulfoxide, are added dropwise at room -temperature, ~hen the evolution of hydrogen has ceased, 20,2 g (0.15 moie) of epi-bromohydrin are added dropwise and the reaction mix-ture is stirred for 20 hours at room temperature, The mixture is then poured onto 1,5 liters of ice water and the solld precipitate is filtered o~f and recrystal-li~ed from isopropanol, 26,2 g (68% of theory~of color-less crystals, melting point 99 - 100C, C15H15N03 (257) calculated: C 70,0 H 5,9 N 5,4 found: C 70.0 H 5.9 N 5.5 - 16 - O.Z. oo50/033158 Compound 2 3-Ethyl-5-[2-(2,3-epoxypropoxy)-styryl]~isoxazole:
This compound is prepared by the method described for compound l, from 5.1 g of 55% strength sodium hydride (0,116 mole), 25 g (0.116 mole) of 3-ethyl-5-(2-hydroxy-styryl)-isoxazole and 15.9 g (0.116 mole) of epibromohydrin.
The reaction mixture is poured into sodium chloride solution and extracted by shaking with diethyl ether~ The ether solution is dried over anhydrous sodium sulfate, and con-centrated. 29.2 g (93% of theory) o- a colorless oil are obtained.
Compound 3 3-Isopropyl-5-~2-(2,3-epoxypropoxy)-styryl~-isoxazole:
This compound is prepared by the method described for co~pound 2, from 3.4 g of 55% strength sodium hydride (0.078 mole), l~, g (0,078 mole) of 3-isopropyl-5-(2-hydroxy-styryl)-isoxazole and 10.8 g (0.078 mole) of epibromohydrin.
21.5 g (97% of theory) of a colorless oil.
Compound 4 3-tert,-Butyl-5-[2-(2,3-epoxypropoxy)-styryl]-iso~azole:
This compound is prepared by the method described for compound 2, from 3.8 g of 55% strength sodium hydride (0.086 mole), 21 g (0.086 mol~) of 3-tert. butyl-5-(2-hydroxystyryl)~isoxazole and 11.8 g (0.086 mole) of epi-bromohydrin. 25.0 g (97% of theory) of a colorless oil.
Compound 5 l.0 g of 3-methyl-5-[2-(2,3-epoxypropoxy)-styryl~-isoxazole is dissolved in 20 ml of a 3 N solution of hydro-gen chloride in ether and-left to s-tand for 12 hours at oom ~5 ~ ~
- 17 - O.Z. 0050/033158 temperature. The resinous component formed is separated off and chromatographed on silica gel, using chloroform~
The product eluates are evaporated to dryness under reduced pressure and the crude product is then recrystallized from an acetone/cyclohexane mixture. 3-Methyl-5-[2-(2~
hydroxy-3-chloropropoxy)-styryl~-isoxazole whlch is pure according to NMR spectroscopy and has a melting point o~
67 - 68C is obtained. ~ -H-NMR spectrum (CDCl~, TMS as internal standard).
r = 2,30, 3.15 (m, 6H), 3092 (s, lH), 5.60 - 5,92 (m, 3H), 6.24 (d, J = 3.5 Hz, 2H), 6.77 (broad s, OH).
Compound 6 3-Methyl-5-~2-(2-hydroxy-3-isopropyl-aminopropoxy)-styryl~-isoxazole:
3.4 g (0.013 mole) of 3-methyl~5-~2-(2,3-epoxy-prop~xy)-styryl]-isoxazole and 2,3 g (0.039 mole) of iso-propylamine in 50 ml o~ isopropanol are refluxed for 8 hours.
When the reaction solution has cooled, it is filtered, and concentrated on a rotary evaporator 3,8 g o~ solid residue are obtained and are recrystallized from toluene, giving 2.4 g (58% of theory) of colorless crystals, melting point 106 - 108C.
C18H24N203 (316.4) calculated: C 68.3 H 7.6 N 8,9 found: C 68.4 H 7.6 N 9.0 Compound 7 3-Methyl-5-[2-(2-hydroxy-3-tert.-butylaminopropoxy)-styryl~-isoxazole:
This compound is obtained by the method described - I8 - O.Z. 0050/0~3158 for compound 6 from 5.0 g (0.019 mole) of 3-methyl-5-[2-(2?3-epox~propoxy)-styryl]-isoxazole and 1,56 g (Q.2 mole) of tert.-butylamine. 3.1 g (48% of theory) of colorless crystals, melting point 83 - 85C.
ClgH27N203- 5 H20 (339 calculated: C 67.3 H 8,0 N 8.3 found: C 57.2 H 7,9 N 8.1 30 g of crude 3-methyl-5-[2-(2-hydroxy-3-tert,-butylaminopropoxy)-styryl]-isoxazole are dissolved in a small amount of ethanol and a solution of hydrogen chloride in ether is added dropwise until the compound has precipita-ted completely. The precipitate of 3-methyl-5-[2-(2-hydroxy-3-ter~.-butylaminopropoxy)-styryl~-isoxazole 'n~dro-chloride is ~iltered o~f~ washed with dry ether, twice recrystallized from a 1 : 1 by volume methanol-ether mixture and dried.
'~ield: 33,8 g (79% of theory) of melting point 217C.
ClgH2703M2Cl (367) calculated: C 62.2 H 7~4 N 7.6 Cl 9.7 found: C 62.1 H 7,3 N 7.7 Cl 9,8 I~ the same ~ay, a solution of fumaric acid in ether gives the neutral ~umarate, melting point 188C.
ompound 8 3-Ethyl-5-[2-(2-hydroxy-3-cyclopropylaminopropoxy)-styryl]-isoxazole:
7 g (0.026 mole) of 3-ethyl-5-[2-(2,3-epoxypropoxy)-styryl]-isoxazoleand 2.3 g ofcyclopropylamine (0.04 mole) are reacted in 100 ml of isopropanol, by the method described for compound 6. 8,6 g of an oil are obtained 5 and this
5~5 - 19 - O.Z. 0050/033158 is freed from impurities on a 55 x 5 cm column of Silica gel 60 (Q.o63 - 0.20 mm) from ~erck. The eluant is a 9 : 1 mixture of methylene chloride and methanol. The purity of the fractions is tested by thin layer chromatography.
3.2 g of an oil are obtained; this is dissolved in 40 ml of isopropanol plus a small amount of ether and precipitated with 1.1 g of fumaric acid dissolved in hot isopropanol.
The crystals are ~iltered off and dried. 2.1 g (21% of theory), melting point 137 - 139C~
lo C22H26N205 (386.5) calculated: C 65.2 H 6,7 N 7.2 found: C 64,7 H 6,~ N 7.5 Compound 9 3-Ethyl-5-[2-(2-hydroxy-3-tert.-butylaminopropoxy)-styryl~-isoxazole:
7 g (0.026 mole) o~ 3-ethyl-5-[2-(2,3-epoxypropoxy)-styryl]-isoxazole and 3.0 g (0.04 mole) o~ tert,-butylamine are reacted by the method described for compound 6.
6,6 g (66% of theory), melting point 163 - 164C.

calculated: C 63,1 H 7,7 N 7.3 Cl 9.3 found: C 62.9 H 7,5 N 7.2 Cl 9,2 Compound 10 3-Methyl-5-~2-(2-hydroxy-3-(3-methyl-but-1-ynyl-3-amino)~
propo~y)-styryl]-isoxazole:
5 g (0,019 mole) of 3-methyl-5-~2 ~2,3-epoxypropo~r)-styryl]-isoxazole and 1.7 g (0.02 mole) of 3-methyl-3-amino-but-l-yne are reacted by the method described for compound 7 and the product is converted to the hydrochloride as des-5 ~
- 20 - O.Z. 0050/033158 cribed for compound 7. Yield: 3.5 g (49% of theory), melting point 191C.
20 25 2 3 (37 9) calculated: C 63.7H 6.7 N 7.4 C1 9,4 found: C 63.7 H 6.8 N 7~7 Cl 9.5

Claims (10)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
1. A process for the preparation of a 3-alkyl-5-(2-hydroxy-styryl)-isoxazole of the general formula (1) (1) where R is alkyl of 1 to 4 carbon atoms, wherein a phosphonic acid ester of the general formula (2) (2) where R has the meanings given for formula (1) and R2 is lower alkyl of 1 to 3 carbon atoms, is reacted with a subsituted salicylaldehyde of the general formula (3) (3) where R3 is alkoxyalkyl of the formula (4) (4) (where R4 and R5 are identical or different and each is lower alkyl of 1 to 3 carbon atoms, and R5 can also be hydrogen) or R3 is tetrahydropyranyl under the conditions of the Wittig-Horner reaction, after which the protective group R3 is detached under acid conditions.
2. A process as defined in claim 1 wherein R is methyl.
3. A process as defined in claim 1 wherein R is ethyl.
4. A process as defined in claim 1 wherein R is isopropyl.
5. A process as defined in claim 1 wherein R is tert-butyl.
6. A 3-alkyl-5-(2-hydroxy-styryl)-isoxazole of the general formula (1) (1) where R is alkyl of 1 to 4 carbon atoms, whenever produced by a process as defined in claim 1 or an obvious chemical equivalent thereof.
7. 3-methyl-5-(2-hydroxy-styryl)-isoxazole whenever produced by a process as defined in claim 2 or an obvious chemical equivalent thereof.
8. 3-ethyl-5-(2-hydroxy-styryl)-isoxazole whenever produced by a process as defined in claim 3 or an obvious chemical equivalent thereof.
9. 3-iso-propyl-5-(2-hydroxy-styryl)-isoxazole whenever produced by a process as defined in claim 4 or an obvious chemical equivalent thereof.
10. 3-tert.-butyl-5-(hydroxy-styryl)-sioxazole whenever produced by a process as defined in claim 5 or an obvious chemical equivalent thereof.
CA325,386A 1978-04-29 1979-04-11 3-alkyl-5-(2-hydroxy-styryl)-isoxazoles and their preparation Expired CA1128525A (en)

Applications Claiming Priority (2)

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DE19782818998 DE2818998A1 (en) 1978-04-29 1978-04-29 3-ALKYL-5- (2-HYDROXY-STYRYL) -ISOXAZOLES AND METHOD FOR THE PRODUCTION THEREOF
DEP2818998.2 1978-04-29

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AT (1) AT365582B (en)
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BE754405A (en) * 1969-08-05 1971-02-04 Thomae Gmbh Dr K NEW BETA-ARYL-2-AMINOALCOXYSTYRENES
DE2549962A1 (en) * 1975-11-07 1977-05-18 Basf Ag NEW ISOXAZOLES AND THE METHOD OF MANUFACTURING THEM

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DE2818998A1 (en) 1979-11-15
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SU814275A3 (en) 1981-03-15

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