DE2302027A1 - 3,4-DIHYDROCARBOSTYRIL DERIVATIVES AND THEIR SALTS, METHOD FOR THEIR MANUFACTURING AND THEIR USE IN MEDICINAL PRODUCTS - Google Patents

Description

OTSlHiA PHARMACEUTICAL CO., LTD., Tokyo, Japan

"3,4-Dihydrocarbostyril derivatives and their salts, method too Their manufacture and their use in medicinal products ".

Priority: April 13, 1972, Japan, No. "37 181 and 37

September 14, 1972, Japan, Kr. 92 ^ 557, 92 555 and

No. 92 560

December 2, 1972, Japan, No. 14 Dec. 1972, Japan, No. December 21, 1972, Jap3n, no.

The invention relates to 3,4-dihydrocarbostyril derivatives of all common formula I.

O -

(D

in which R is a water substance, an unbranched or twisted alkyl radical with 1 to 4 carbon atoms, an aralkyl radical or an alkynyl radical with 1 to 4 carbon atoms.

2
tet, R is a hydrogen atom or an AcyIrest of the general

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Formula COR ^ in which R ^ is an alkylres-L .ait 1 to 4 carbon atoms, a phenyl or 3i 4,5-trimethoxyphenyl group and R ¹ and R ", which can be the same or different, a hydrogen atom, an axkyl radical with T to 4 carbon atoms represent an aralkyl or cycloalkyl radical or R * and R ⁿ together with the nitrogen atom to which they are attached form a heterocyclic radical with 2 to 8 carbon atoms which can contain a further nitrogen atom or an oxygen atom in the ring , according to the proviso that the side chain is in the

12th
'5-position and R and Π hydrogen atoms mean that R ¹ and R ^{n are} not both V / water atoms or alkyls with 1 to 4 carbon atoms, and their salts with acids.

The new 3 _f 4-Dihydrocarbcstyril derivatives of the general formula I can be prepared according to the following reaction scheme:

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(VIII) I.

(IX)

- Y

E ¹

(VI)

OH OH XCH ₅ CH - CH

N / ^CVII)

OCH ₂ Z

(H)

(IV)

E «

E ¹

OH

τ? « OCEpCHCH ₂ N ^

OH

(III)

E ³ COCl (V)

(I) (B ² «H)

■ (R ² ^ COE ⁵ ) 3098 ^ 9/1193

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-M-

12 3 In the general formulas, R, R, R, R ¹ and R ″ have the meanings given above, X is a halogen atom, for example

a fluorine, chlorine, bromine or iodine atom, and Y and Z have the following meanings.
The new intermediates have the general formula II

OCH ₂ Z

(ID

in which R has the above meaning and Z is a remainder of

formula

- CH- CH ₂ - f -

\ /. or OH

represents in which Y represents a halogen atom.

The salts of the compounds of the general formula I can sJ ch of inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or organic acids such as oxalic acid, maleic acid, Fumaric acid, malic acid, tartaric acid, citric acid and ascorbic acid. The production of these salts takes place in known per se, e.g. by dissolving the free base and the corresponding acid in an organic solvent, such as acetone, and combining the solutions in s to chi one tri see Ilsngen conditions. Compared to the free base, the salts have a greater solubility in water and a higher stability compared with Tub and light.

As alkyl radicals, unbranched or branched alkyl radicals C. 1 to A carbon atoms, like the methyl, ethyl, n-Fropy! -

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Isopropyl, η-butyl, sec-butyl and tert-butyl groups are possible. The term "aralkyl radical" means an unsubstituted phenylalkyl radical with 1 to 4 carbon atoms in the alkyl radical, preferably the benzyl group. The term "alkene ^ .yl radical ¹¹ means unbranched or branched alkenyl radicals with 2 to 4 carbon atoms, preferably the allyl group. The expression" cycloalkyl radical "means a cycloalkyl radical with 4 to 6 carbon atoms, such as the cyclobutyl, cyclopentyl Examples of heterocyclic radicals of the general formula -ICR ¹ R "are the piperidino, piperazino and morpholino groups, which can be substituted by alkyl radicals having 1" to 4 carbon atoms.

The compounds of the general formula I in which R is a hydrogen atom means can be prepared by two different methods. The first method uses a 5-hydroxy-3,4-dihydrocarbostyril derivative of the general formula II with a secondary or tertiary amine of the general formula IV

in which R * and R ^{w have} the above meaning, implemented. This reaction can be carried out in the absence of a solvent. However, the reaction is preferably carried out in the presence of an inert organic solvent. Examples of suitable solvents are lower alkyl ethers such as diethyl ether, methyl ethyl ether, dipropyl ether, dioxane and tetrahydrofuran, hydrocarbons such as benzene, toluene and xylene, lower aliphatic alcohols such as methanol, ethanol, propanol, copropanol and butanol, water, dialkylformamides such as dimethyl

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formamide and diethylformamide. The solvents used are preferably methanol, ethanol, tetrahydrofuran, dioxane, benzene, toluene and dimethylformamide. Particularly preferred solvents are polar solvents such as methanol and ethanol. The amine is generally used in at least a stoichiometric amount. It is preferably used in a quantitative ratio of 6 to 8 mol 3e 1 mol of the 3,4-dihydrocarbostyril derivative of the general formula II. The reaction temperature is not particularly critical. The reaction proceeds smoothly at temperatures of "Raumterperatur to the boiling point of the solvent used. The preferred temperature range is between 40 and 6O ⁰ C, regardless of whether a Lösungsmittel'verwendet is. The reaction is preferably carried out at the boiling point of the solvent used, if as The reaction is generally carried out at atmospheric pressure, but it can also be carried out at pressures of 1 to 10 atm. The reaction time depends on the reaction temperature. The reaction is within 3 to 8 hours, generally within 4 to 5 hours. The reaction product can be isolated in a customary manner, for example by filtration or separating off the solvent from the reaction mixture by distillation. The purification can be carried out by customary methods, for example by recrystallization from a suitable solvent.

The second process for the preparation of the compounds of the al3 common Fornel I, in which R is a hydrogen atom, exists in the reduction of the corresponding (2-hydroxy-3-alkyl-

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iminoj-propoxycarbostyrile of the general formula I

CCH ₂ CHCH ₂ N ^

in which R ¹ , R ^f and R "have the above meaning. The reduction is carried out with hydrogen in the presence of a customary noble metal catalyst such as is used for the hydrogenation of organic compounds. Examples of these catalysts are Raney nickel, palladium black. Platinoid and platinum black. the hydrogenation is _r in an organic solvent at temperatures of from O to 15O ° C, preferably 50 at 70 ⁰ C, under normal pressure or under pressures of 1 to 200, preferably from 10 atm to 50 is performed. the slightly pressure depends on the When using palladium-on-carbon, the pressure is preferably in the range from 2 to 10 at, with nickel preferably between 50 and 150 at. Examples of suitable solvents are halogenated hydrocarbons and mixtures of halogenated hydrocarbons and lower aliphatic alcohols such as chloroform, carbon tetrachloride, dichloroethane and a mixture of methanol and chloro form or ethanol and carbon tetrachloride. Particularly preferred solvents are chloroform and carbon tetrachloride. For the hydrogenation, any organic solvent can be det USAGE, -Jas _E fcßenlil> fer ^{dt £ l} reaction te ilnchaftrn and the reaction product is inert. Examples of such solvents are

■ * T copy ^]

-AS-

-JS-

lower aliphatic alcohols such as methanol, ethanol, glacial acetic acid and ethyl acetate.

The 5- (2-hydroxy-3-alkylamino) propoxycarbostyriles of the general Formula III as well as the compounds form the more general. Formula I salts with acids. The reduction described above can also be carried out with the salts of the compounds of the general Formula III under the same conditions v; ic for the free base carried out. The compounds of general formula III are new and show the same physiological properties Properties such as the compounds of general formula I. They also form an object of the invention. These connections can easily be prepared according to the following reaction scheme:

XCHCH - CH-

"OCHCHCH ₂ JL OH

Cm)

OCH ₀ CH - CH ;,

X, R * and R ^M have the meanings given above. The starting compound (A) is in J. Org. Chem., 3d. 36 (23) Seitan 3 ^ 90 to 3 ^ 93 (1971).

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The compounds of the general formula I in which Π represents an acyl radical of the general formula COR ³ , in which R has the above meaning. can be prepared from the corresponding compounds of the general formula I, in which R represents a hydrogen atom, by acylation with an appropriate acylating agent. The acylation is preferably carried out with an acyl chloride of the general formula V.

R ^ -COCl ■ (V)

• performed, in which R ^{5 has} the above meaning. The acylation is carried out in the absence of a solvent, but it is preferably carried out in the presence of an inert organic solvent, such as a dial or xylene, a ketone such as acetone or ethyl ethyl ketone, or a dialkylformamide such as dimethylformamide or diethylformanide. Preferred solvents are acetone, toluene, xylene and benzene. The acylation generally proceeds smoothly without the use of an acid acceptor for the hydrogen chloride formed during the acylation. However, better results are obtained in the presence of an acid acceptor. Examples of suitable acid acceptors are alkali metal hydrides, such as Katriumhydrid and potassium hydride, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, and organic 3asen such as piperidine, piperazine, pyridine, and lower alkyl amines such as Diäthylaoin, Triäthylaiiin and methylamine. The acyl chloride of the angerwineo formula V is used in at least a stoichiometric amount. Generally it is used in an amount ratio of 5 to 5 moles each

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Hol des ^ -hydroxy-S-aminoJ-propoxy-J.A-dihydrocarbostyril- j Derivative used. The acylation temperature is not of particularly crucial. The acylation can be carried out at temperatures from room temperature "to the boiling point of the used Solvent are carried out. In general, will be very Obtained good results, the acylation in the presence of a verm suitable solvent and carried out at the boiling point of this solvent. The implementation is in general ended within 3 to 6 hours, preferably 4 to 5 hours.

As stated above, the invention also relates to new intermediates the general formula and III. The intermediates the general formula II can be implemented by of the corresponding 5-, 6-, 7- or 8-kydroxj'-3t ^ -dibydrocarbostyril derivative of the general formula VI

OH

in which R has the preceding meaning, with an epihalogen hydrin of the general formula VII

XCH ₂ CH - CH-

V ^(VIIJ

in which X has the above meaning, in the presence of a base produce. In general, 1 to 10 mol, preferably 1 to 3 mol of epihalohydrin per mol of the compound of the general Formula VI used. The compounds of the general formula VI

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are known and disclosed in Japanese Patent Publications No. 39 694/1971 and 38 783/1971. The production the 6-, 7- and 8-hydroxy compounds of the general formula VI is also in reports of the German former company, vol. 60 (Ί927), Pages 858 to 852 described.

For example, 5-hydroxy-3,4-dihydrocarbostyril derivatives of the general formula VT can be prepared from 3,4,5,6,7,8-kexahydrocarbor.tyril-5-one by bronzing and then heating the 8- or 6-3roa obtained -3,4,5,6,7 _f 8-hexahydrocarOostyril-5-oas can be prepared according to the following reaction scheme:

ι OE

Burnish

Br

■ OCX

Examples of suitable epihalohydrins are epibroahydrin, epichlorohydrin and epijcdhydrin. Examples of suitable bases are alkali metals, alkali hydroxides, alkali carbonates and organic bases. Preferred bases are sodium, potassium, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, piperidine, piperazine, pyridine and lower alkyl amines such as diethylamine, triethylamine and methylamine. The reaction of the compounds of the general formula VI and the compounds of the general formula VII can be carried out in the absence of a solvent. However, the reaction is preferably carried out in the presence of an inei Un L * sun§smillMs, 2.8. a lower aliphatic alcohol, water, a lower alkyl acetate or ketone. Preferred examples of lower aliphatic alcohols

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ORIGINAL INSPECTED

are methanol, ethanol, isopropanol, propanol and butanol. preferred examples of lower alkyl acetates are ethyl acetate, methyl acetate and propyl acetate. Preferred examples of ketones are acetone and I-ethylethyl ketone. Although any combination of solvent and base can be used, the solvent is preferably selected according to the ease used. Lower "aliphatic alcohols are preferably used together with alkali metals and water together with alkali metal hydroxides. When using organic bases, the reaction can be carried out in the absence of a solvent or in the presence of a lower aliphatic alcohol, lower alkyl acetate or ketone Alkali metals or alkali metal hydroxides as bases, the reaction temperature can be in the range from C ⁰ C, preferably from 50 ° C., to the boiling point of the solvent used. The reaction time is 4 to 6, preferably 4 to 5 hours reaction temperature in the range of 0 to 120 ° C, then preferably to 120 ⁰ C _1, and the reaction time is 4 to 6, preferably 5 to 6 hours. the reaction is usually carried out at Atinosphärendruck. in this reaction, precipitate as the reaction product both 5- or β - »7- or 8- (2,5-Hpoxy) -propoxy-3 _f 4-dihydrocarbostyri3-Deriv ate as well as 5- or 6-, 7- or 8- (2-hydroxy-3-halogen) -propoxy-3,4-dihydrocarbostyril derivatives of the general formula II, in which Y is the remainder

-CE-CH ₂ and -CH-CH ₂ Y

o in

means, uas Verigenverhriixjiis of the compounds of the general formula I and II depending on the type of liase used.

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-ZO-

Compounds of general formula I are predominant Amount formed when the implementation in counter \; kind strongly basic Compounds such as alkali metals and alkali metal hydroxides is performed. The compounds of the general formula II are formed in predominant amounts when the reaction is in counterv / art weakly basic compounds, such as organic bases, especially piperidine, carried out and the epihalohydrin in excess used v.'ird. These compounds can be separated from one another by conventional methods, e.g. by fractionating Crystallization, preferably by column chromatography on z. B. aktiveb aluminum oxide or Xieselgel.

The intermediates of the general formula II, in which 2 is the radical -CK-ClI ₂ -Y carstell L ₁ in which Y has the above meaning,

OH
can also by reacting a 5-hydroxy-3,4-dihydrocarbo-

styril derivative of the general formula VIII

όα

(viii;

in which R has the above meaning with a 3- ^r alogene-1,2-propanediol of the general formula IX

^ia ™ · '(ix,

in which Y has the above meaning. Preferably 1 to 5 mol, in particular 1 to 3 mol, of the compound of the general formula IX are reacted with 1 mol of the compound of the general formula VIII. This implementation is during

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-H-

3 to 6 hours, preferably 4 to 5 hours, at atmospheric pressure in the presence of a brominating agent such as pyridinium bromide, perbromide or bromine, in an inert solvent such as carbon tetrachloride, at temperatures from room temperature to the boiling point of the solvent used, preferably at or in near the boiling point of the solvent. Examples of suitable solvents are halogenated hydrocarbons and mixtures of halogenated carbon and lower aliphatic alcohols, such as chloroform, carbon tetrachloride, dichloroethane, a mixture of ethanol and chloroform or of ethanol and carbon tetrachloride. Particularly preferred solvents are chloroform and carbon tetrachloride. The compounds of the general formula VIII are known from Tetrahedron Letters, 1965, p. 2441. Preferably 1 to 3 KoI, in particular 1 to 1.5 hol bronzing agents per hol of the compound of the general formula VIII used.

It is known that certain carbostyril derivatives are valuable Medicines are. Typical compounds of this kind are in Japanese Patent Publication Nos. 1182/1967 and 38789/1971 and in Chemical Abstracts, 3d. 62, 1b 212e (1965). However, it is not known that compounds which have a 3-substituted arainopropoxy group in the 5-, 6-, 7- or 8-position of the carbostyril residue, excellent ß-receptor blockers are. Both the free bases and the salts of the compound of the invention show ß-sympatolytic activity and can therefore used to treat heart diseases such as arrhythmias, angina peetoris, coronary insufficiency and hypertension.

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H-

Accordingly, the invention also relates to the use of the combined, the general forms * I and III, Is medicinal substances. For the production of medicinal preparations, these compounds and their salts can be made up of eleven customary carriers and / or diluents and / or excipients and administered either orally or parenterally in the customary dosage form.
The examples illustrate the invention. "

example 1

1.53 g ^ Hydroxy ^ -dlhydrocarbostyril and 3.5 g epichlorohydrin are introduced into 30 al of a solution of 0.216 g Hatriuinaetall in methanol. The solution obtained is ^{stirred at 55 to 60 °} C. for 4 hours. After cooling, the crystallized sodium chloride is filtered off and vtrd eingedanpft the filtrate under reduced pressure for _Z dryness. The residue is digested with acetone. The crystals are filtered off and recrystallized from ethanol. Yield 0.8 g of colorless 5- (2,3-epoxy; -propo; y-3,4-dihydrocarbostyril VOA F. 172-173 ⁰ C The filtrate of the acetone solution is evaporated to dryness and the residue recrystallized from ethyl acetate to yield. 0.05 g of colorless 5- (2-hydroxy-3-chloro) propoxy-3,4-dihydrocarbostyril with a melting point of 157 to 158 ° C.

Example2

A solution of 0.6 g of sodium hydroxide in 40 ml of v / ater is treated with 2.5 g of 5-hydroxy-3,4-dihydrocarbostyril and 1.0 g of epibromohydrin and -erührt Λ hours at 60 to 65 ⁰ C. Make the cooling dilute Ax precipitated crystals filtered off υ-id recrystallized from ethanol. Yield 1.9 g of 5- (2,3-epoxy) -propoxy-3,4-ä <-

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hydrocarbostyril from m.p. 172 to 173 ° C

Example 3

4.7 g of epichlorohydrin and 5 drops of piperidine are added-Benzyl-5-hydroxy-3,4-dihydrocarbostyril 1 to 5.1 g, and the Genisch is stirred for 5 hours at 95 to 100 ⁰ C. The reaction mixture is then evaporated to dryness and the residue is dissolved in 60 ml of chloroform. The solution is washed first with 5% sodium hydroxide solution and then with '..' water and dried over sodium sulfate. The solution is then applied to a chromatography column filled with active aluminum oxide and the column is developed with chloroform. The first eluate, which contains 1-benzyl-5- (2,3-epoxy) -propoxy-3, ^ - dihydrocarbostyril, is evaporated to dryness and the residue is recrystallized from ethanol. 0.5 g of colorless product VGa F. 120 to 122 ° C. are obtained. The subsequent eluate, which contains 1-3enzyl-5- (2-hydroxy-3-chloro) propoxy-3,4-dihydrocarbostyril, is also evaporated to dryness and the residue is recrystallized from carbon tetrachloride. Yield 3.2 g of colorless product with a melting point of 105 to 107 ^° C.

Example h

3.8 g of epibromohydrin and 5 drops of piperidine make 3.0 g 1-Ethyl-5-hydroxy-3, ^ - dihydrocarbostyril tanning, and the genius is stirred at 95 to 10 ° C for 5 hours. Then the reaction mixture evaporated to dryness and the Piückctand in 10 · π1 Dissolved acetone. After adding 10 ml of ether and 20 ml of benzene is the solution on a ^ uut Kips! §el «^ filled Chroiüatocraphieiau I * given and the nags with a solution of acetone, Ether and benzene in volume ratio 1: 1: 2 develop L. ii.u

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The first eluate is evaporated to dryness and the residue is crystallized from n-Kexan u :: J:. Yield 0.3 g of colorless 1-ethyl-5- (2,3-epo;: yJ-propoxy-3 _t 4-dihydrocarbostyril from 50 to 52.5 ° C. The following eluate contains 1-iithyl-5- ( 2-hydroxy-3-broni) -propoxy ^ .- ^ - dihydrocarbostyril. It is evaporated to dryness and the residue is recrystallized from carbon tetrachloride. Yield 1.9 g of colorless product from 115 to 117.5 ° C.

Example5

4.2 g of epibromohydrin and 3 "drops of piperidine are added to 2.5 g of 1-allyl-5-hydroxi ^r -3, ^ - dihydrocarbostyril. After the reaction has ended, the key actions in Example 4 is worked out and chronographed. The first eluate contains'.-Allyl-5- (2,3-epoxy} -propoxy-3, ^ - dihyclrocarbostyril and is evaporated. After recrystallization from carbon tetrachloride, 0.4 g of colorless crystals with a melting point of 73.5 to 75, received 0 ⁰ C The following Zluat contains i-Allyi-5- (2-hydroxi'-3-brozi) -propo:. ^ '- 3,4-dihydrocarbostyril and is also evaporated by Uakristallisaticn of carbon tetrachloride, 1.7 g. colorless crystals with a melting point of 82 to 84 ° C. were obtained.

In the same way as in Example 4, the following compounds

manufactured:

1-Allyl-5- (2-hydrox>'-? - chloro) propoxy-3,4-dihydrocarbostyril _f

M.p. 65-67 ° C (CCl ₄ ); . .

1-Ethyl-5- (2-hydroxy-3-chloro) -propoxy-3, ^ - dihydrocarbostyril,

M.p. 65-67 ° C

-J-chlof) -propoxy- "i-iaethyl -J _t if-dlhydrocarbostyril, f

117-119 ° C

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5- (2-Hydroxy-3-bromoJ-prcpoxy-1-methyl-3,4-dih> irocarbostyril,

137-139 ° C (CCl ^);

5- (2,5-epoxy) -propoxy-1-isethyl-3,4-dihydrocarbostyril,

F. 76 - 78 ⁰ C (CCl ₄ /n-He-.an) and

5- (2-Hydroxy-3-broin) -propoxy-3,4-dihydroca-bostyril,

M.p. 133-135 ° C (diethyl ether).

Example 6

A solution of 8.3 g 3.4,? _F 6,7,8-hexahydrocarbostyril-5-one in 70 ml of Chlorofora is initially not 5.5 g of 3-chloro-1,2-preparation, diol and 8.9 g of N-3ronsuccini: nid The mixture is heated under reflux for 2 hours in the water bath, then left to cool and mixed with 50 ml of water. The precipitated crystals are filtered off and the chloroforal solution is separated off, washed with 5% sodium hydroxide solution and unc Water if removed and dried over sodium sulfate. Thereafter, the chlorofonal solution is evaporated under reduced pressure and the residue is digested with ether. The crystals are filtered off and recrystallized from ethyl acetate. Yield 2.8 g of colorless 5-C2-hydroxy-3-chlorine ) -propcxj'-J5,4-dihydrocarbostyril from mp to 158 ° C.

Example 7

A solution of 3.6 g Erom in 5C ml carbon tetrachloride becomes with ice cooling and stirring to a solution of 4.0 g 3 »4,5,6,7» 8-Kexahydrocarbostyril-5-one in 50 icl carbon tetrachloride. After standing for a minute, the precipitate formed is separated off by decanting. The carbon tetrachloride solution is evaporated at room temperature, and the crystals obtained are combined with the precipitate and washed with acetone.

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Wan receives the 3- or 6-bromo-3, ^, 5.6 _t 7,8-hexahydr3carbostyril-5-one in quantitative yield in the form of yellow crystals with a melting point of 126 to 127 ° C. The crystals are dissolved in 80 ml of carbon tetrachloride, and 3.0 g of 3-chloro-1,2-propanediol and 1.5 g of 2,4,6-tribromophenol are added to the solution. The mixture is refluxed for 2 hours and then worked up as in Example 6. Yield 2.1 g of colorless 5- (2-hydroxy-3-chloro) propoxy-3,4-dihydrocarbostyril with a melting point of 157 to 158 C.

Example 8

A solution of 40 g of 1-Kethyl-3,4 _f Se ^ rS-Eexahydrocarbostyril-S-one in 50 ml of chloroform is mixed with 6.6 g of 3-bromo-1,2-propanediol and 40 g of K-BrcESuccininide and 2 Heated under reflux for hours. After cooling, the mixture is first washed with 5 percent sodium hydroxide solution and saturated sodium chloride solution and then dried over sodium sulfate. The chloroform solution is evaporated under reduced pressure and the residue is digested with carbon tetrachloride. The crystals are filtered off and recrystallized from carbon tetrachloride. Yield 2.7 g of colorless 5- (2-hydroxy-3-bromo) propoxy-1-methyl-3,4-dihydrocarbostyril with a melting point of 155 to 157 ° C.

Example 9

A solution of 5.0 g of 1-benzyl-3,4,5,6,7,8-hexahydrocarbostyril-5-one in 60 ml of chloroform is mixed with 2.9 g of 3-chloro-i, 2-propanedici una 3, 5 g of Ιί-bromosuccinimide are added, the mixture is heated under reflux to an a ".. 'as scr bath for 2 hours and then worked up as in Example 8. After recrystallization from carbon tetrachloride, 3.7 g of colorless 1-benzyl-5- (2-hydroxy-3 -chlor) -propoxy-3,4-dihydroearbo.-tyril obtained from F. 105 bio ^ 07 ⁰ C.

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In the same way as in Example 8, the following compounds are grounded manufactured:

5- (2-Hydroxy-3-bronO -propo;: y-3, 4-dihydrocarbostyril,

F. ^133-1 35 ° C (diethyl ether);

5- (2-Hydroxy-3-chloro; -propoxy-1-methyl-3, ^ - dihydrocarbostyril,

F. 137-139 ⁰ C (CCl _4);

1-ethyl-5- (2-hydroxy-3-chloro-propoxy-5, ^/ t-aihydrocarboro-tyril,

117-119 ° C (CCl ₄ J;

1-ethyl-5- (2-hydroxy-3-bromoJ-propoxy-3, ^z * -dihydrocarbostyril,

F. 115 to 117.5 ⁰ C (CCl _4);

-5-C2-hydroxy-3-chloro) propoxy-3,4-dihydrocarbostyril,

M.p. 65-67 ° C (CCl ₄ ) and

1-allyl-5- C2-hydroxy-3-broni) propoxy-3,4-dihydrocarbostyril,

M.p. 82-84 ° C (CCl ₄ ).

Example 10

2.0 g of 5- (2,3-epoxy) -propoxy-3,4-dihydrocarbcstyril and 6.5 g of benzylamine v / earth are added to RO ml of ethanol, and the Gnadsch v. ^It is stirred for 4 hours. The reaction mixture is then evaporated under reduced pressure, the residue is dissolved in acetone and a solution of hydrogen chloride in ethanol is added. The crystals formed are filtered off and crystallized from methanol. Yield 1.7 g of colorless 5- (2-hydroxy-3-benzylanino) propoxy-3,4-dihydrocarbyl styril hydrochloride with a melting point of 210 to 212 ° C.

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OR / GffSJAL INSPECTED

Example 11

1.0 ζ 5- (2,3-epoxy; -propoxy-3,4-dihydric carbostyril and 1.5 g of di-n-propyl acine are added to 30 ml of ethanol, and the mixture is kept at 50 to 55 ° C. for 4 hours The reaction mixture is then evaporated under reduced pressure, the residue is dissolved in acetone and a solution of hydrogen chloride in ethanol is added. The crystals formed are filtered off and recrystallized from ethanol. Yield 0.7 g of colorless 5- (2-Hydro > -y-3-di-n-propylan ⁱ ino) -propoxy-3,4-dihydrocarbostyril hydrochloride with a melting point of 221 to 222 ° C.

Example 12

3.0 g of 5- (2,3-epoxy) -prcpoxy-3,4-dihydrocarbostyril and 6.0 g of cyclohexylanine are introduced into 40 ml of methanol, and the mixture obtained is stirred at 55 to 60 ° C. for 3 hours. After cooling, the crystals formed are filtered off, washed with acetone and recrystallized from methanol. Yield 3.5 g of colorless 5- (2-kydroxy-3-cyclohexylamino) -propxy-3,4-dihydrocarbostyril. The product is dissolved in 100 ml of ethanol, 2 g of fumaric acid are added and the mixture is stirred until crystallization. The crystals are filtered off and crystallized from ethanol. Yield 4.2 g of colorless 5- (2-hydroxy-3-cy <'chexylanino) propoxy-3,4-dihydrocarbostyril-fumarate of: F. 200-202 ⁰ C.

Example 13

2.0 g of 5-C2,3-epoxy; -propxy-3,4-dihydrocarbostyril and 5.0 g of diisobutyla; iiin are introduced into 30 ml of tetrahydrofuran and reacted and worked up according to Example 12. The free base is mixed with a solution of hydrogen chloride in ethanol

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Hydrochloride transferred. Wake recrystallization from acetone 1.4 g of 5- (2-hydroxy-3-diiscbutylamino) propoxy-3,4-dihydrocarbostyril hydrochloride obtained from mp 19O to 192 ° C.

Example 14

2.0 g of 5- (2-hydroxy-3-chloro; propoxy-3,4-dihydrocarbostyril and 5 g of tert-butylanine are introduced into 30 μl of dioxane, and the mixture obtained is refluxed and stirred for 3 hours. After the reaction has ended, the reaction mixture is evaporated under reduced pressure and the residue is mixed with a solution of hydrogen chloride in methanol and then mixed with acetone. The crystals formed are filtered off and recrystallized from a mixture of methanol and acetone. Yield 1.3 g of colorless 5- ( 2-Hydroxy-3-tert; -butylanino ) propoxy-3,4-dihydrocarbostyril hydrochloride with a melting point of 277 to 278 ° C. (decomp.).

Example 15

1.5 g of 5- (2-hydroxy-3-chlcr) -propo: -cy-3> 4- dihydro carbostyril and 2.5 g of isopropylamine are introduced into 25 si of methanol, and the resulting mixture is refluxed and stirred for 3 hours. After the reaction has ended, the reaction mixture is evaporated under reduced pressure. The residue is dissolved in acetone dissolved and treated with a solution of hydrogen chloride in isopropanol. The crystals formed are filtered off and ground recrystallized from a mixture of methanol and acetone. yield 1.1 g of colorless 5- (2-hydroxy-3-iscopylamino) propoxy-3,4-dihydrocarbostyril hydrochloride from 224 to 225 ° C.

3 0 9 3 4 9/1193 _f - ~ - * «

[COPY

- A.dihvdrocarboctyril

the chamois preserved below

^. .ο, .ee ^ aeter «- £« - ^ ^ _{0n 6elgst}

with a reading _{from ethanol to}

P «* - ™ **» ΤΛth

_CRITICALLY STALUSED. Yield .. «, ^ _DC ^ _{) e} . _tyrU . _BU «t of

, .tert .- ^ tyl ^ J '
F. 160 to 163

inO-prcpy-J. '-

«, 2 3

ac _ή -uoX e ^ se, and

₂ , isopropy ^^^ ^ ^ ^ ^

Geniscn preserved, _Rcaktlonsg e »isch under venninder

* "^ = K • ¹ « ^ ^t ^ _ee . _{R. Tofl mä Isopro} pan _Ol displaced., E formed

from the F. 154.5 W = 156.5 ° C

Example ¹⁸

* y-3. <.- dihydrocartostyril and

_{elnBetra £} en. and

the

309849/119 '

----- <.-.- · · ¹ Fcopy

dissolved and mixed with a solution of fumaric acid in methanol. The crystals formed are filtered off and recrystallized from ethanol. Yield 1.0 _ß colorless i-allyl-5- (Z-hydroxy ^ -tert.-butyla.inoJ-propoxy ^^ - dihydrocarbostyril-

fumarate of m.p. 209 Ms 210 ° C

B e i s ρ i e '1 19

Ο ₂ g i-benzyl-S ^ .S ^ ep ^ -propoxyO.Ad drocarbostyriJ and 4 '0 g of piperidine "ground in 30 ml Dimethylicrnamid added, the resulting mixture is _md 4 hour". W 60 Ws 65 ⁰ C ge ^. After the reaction has ended, the reaction mixture is worked up in Example 10. Yield 1.2 g of colorless 1-3enzyl- _5. (2-hydroxy-3-piperidino) -rr _O poxy-3,4-dihj-drccarbost _y ril-

hydrochloride, melting at 216.5 218.5 ⁰ C Ms

Example 20

i ₅ g LMethylStayy

styril and 3.0 g of Iscpropyla.in «earth in 20, 1 ethanol and the resulting mixture is i. Hours under R ** - _flu0 heated. Thereafter, the ReaKtionsgenisch is evaporated under verninder _th Pressure * and the residue »it a reading of hydrogen chloride in.". Ethan.l and added acetone. The crystals formed are filtered and recrystallized from a Hischung of "ethanol and acetone u ^ ristallisiert. Yield, , * β colorless

la, ino, pr _n p ^ -..-

«Ennobles des ₁ -Het _hyl 5 (
«Hydrocarbostyril-hydrochlorids vo. F. 157 to 159 C.

₂ ο _{β 1} . _Xtnvl -, - _(? - .. y _J rL ^e _y -3-ch _l or ₎ -prcp, _: ; «N- * .O« t.rt.-B «tyl» i »we, which is added to 20 .1 methanol

309843/1193 *

worn, and the resulting mixture is under 6 hours Heated to reflux. After that, the reaction gene is reduced Pressure evaporated and the residue with a solution of Hydrogen chloride ir. Methanol and acetone are added. The educated Crystals v.-earth filtered off and from ethanol

icrystallized. Yield 1.5 g colorless i-Ethyl-5- (2-hydroxy-3-tert-butylaminoI-propoxy-3,4-dihydrocarbostyril hydrochloride from F. 151 to 183 C.

B e i s. Ρ i e 1 22

2.5 g of '-5enzyl-5- (2,3-epoxyj-propoxy-3,4-dihydrccarbostyril and 2 g iscpropylanine are added to AO al ethanol, and the resulting mixture is stored for 4 hours at 60 to 65 ° C . gerühit Thereafter v; ith the Reaktionsgemxsch under prevented Pressure eingedanpft, the residue is dissolved in acetone and treated with a solution of hydrogen chloride in ethanol, the crystals formed are abfiitriert and uokristallisiert from ethanol yield ^1, 8 g of colorless 1-3enzyl-5... - (2-hydroxj ^r -3-isopropylamino) -propoxy-3,4-dihydrocarbostyril hydrochloride of m. 192

to 194

C.

Example 23

1.5 g of i-allyl-5- (2,3-epoxy; -propoxy-3,4-dihydric carbostyril -and 2.0 g of sec-butylarine are added to 30 nl of benzene, and the genic is unset and worked up in gen23 example 22. The free base is u-gev.-andelt in the Funarat with a solution of fumaric acid in methanol. After uncrystallization from ethanol 1.1 £ colorless 1-allyl-5- (2-hydroxy-3-sec.-butylaiJLno; -propoxy - ^. ^ - dihydrocarbostyril fumarate from m.p. 183 to 134.5 ° C obtain.

309849/1193

"" copy

Examples 24 to 5 ^!: -

In the same way as in the previous examples the following connections made.

309849/1193

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Table I.

- 27 -

. A.

ta ο to oo

to

Ex. R ¹ R ' R " Λ umkrlstal-
linlert. '
QUO properties 228-31 24 H H -CHCIIj (C ₂ Hc) HC1 Ethanol iristall-
shape 25th H H -CH ₂ CH (CHj) ₂ CHCOOH
CHCOOH Ethanol amorphous 203-5 26th H H - (CH ₂ ) JCHj HCl Ethanol
Methanol amorphous 251-5 27 H H .-O HCl Ethanol amorphous 208-10 28 H ¹ -CH (CHj) ₂ -CH (CHj) ₂ HCl Ioo-
propanol • iarbl.
Needles' color.
amorphous

ro co ο ro ο fo

Table I - F0rt.npt.7nnr

9302027

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Tobolle I - continued

- 29 -

LO O IO CO

56 -CHgCHj H - (CII ₂ ) jCH IiCl Ethanol color.
amorphous 126-8 57 · -CHgCHj H .-O- HCl Ethanol forbl.
MqdoIn 185-6 58
ι -CHgCHj H -CH ₂ - ^ ~ \ HCl Ethanol color.
amorphous 155-7 59 -CHgCHj -CHj . -CH ₂ - ^ HCl acetone color.
amorphous 216-7 W. ~ ^CH 2 "O -CHj -O HGl
* Ethanol color.
amorphous 128-31 41 - ^CH 2 -O H '-C (CHj) j HCl Mothanol color.
Dandruff 192-5 42 -CHgCH-CH ₂ H
j -CH (CHj) ₂ HOOCCII. '
HCCOOH Ethanol color.
amorphous 192-4

O NJ O Ni

T able I - continued

- 30 -

to ο ιο οο * · » IO

(O (O

43 H H -CH (CHj) ₂ CIlCCCiI
CiICOOH Ιπο-
propanol Carbl.
amorphous • 177-8 44 H H" -C (CHj) j OHCOOH
CiICCOU Ethanol color.
anorphic
I. 206-7 H H -C ₂ H ₅ CHGOCH
OHCOOIl Iso-
proponol color.
amorphous • 168-9 46 H H -CHCHj (C ₂ H ₅ ) CIICOOII
CIiCOOH iithnnol color.
Needles 142-4 47 H -CH ₂ CH (CHj) ₂ -CH ₂ CH (CHj) ₂ HCl 190-192 48 H · -CHj XX-C ₄ H ₉ CIICOOH
CHCOOH 121-123 49 -C ₂ H ₅
*. " ^CH 3 -CH ₂ - / ~ \

Uj ι

ro co ο ro ο ro

Table I - Continuation / τ

- 31 -

O τ?

to ο co

CD

to

<o

Ex. R ^{1 x} it ^M A. recrystalline
llsiert
the end properties F., ⁰ C. 50 H -O CHCOOH
CUCOOH Methanol Crystal-
shape 215-7 51 H _t - ^
-N 0 CHCOOH
CIICOOH Methanol color.
Needles 252-4 52 H -N N-CH,
^^ t 3 2-HCl Methanol color.
amorphous 256.5
(Dec.) 53 H CII,
-6 HCl Methanol color.
amorphous 125-5 54 -CH ₂ - / ~ \ / —S
-N. N-CH,
\ - / 3 2-HOl Ethanol color.
amorphous 247
(Decomposition *.) color.
amorphous

Cw I

ro co ο N) CD

Example 55

2.0 g of 6- (2,3-epoxy) -propoxy-3,4-dihydrocarbostyril and 4.5 g of tert-butylanine are added to 30 ml of methanol, and the mixture is stirred for 4 hours at 50 to 6O ⁰ C implemented. The reaction mixture is then evaporated under reduced pressure, the residue is dissolved in acetone and maleic acid is added. The crystals formed are filtered off and recrystallized from ethanol. Yield 1.5 g of colorless 6- (2-rydroxy-3-tert.-butylaminoj-propoxy ^^ - dihydrocarbostyril-malcat from P. 163 to 166 ⁰ C.

Example 56 2.5 g of 7- (2,3-epoxy) propoxy-3,4-dihydrocarbostyril and 5.0 g

"Isopropylamine are added in 60 nil of ethanol, and the mixture is reacted for 8 hours at 40 to 50 ⁰ C. Thereafter, the reaction mixture is evaporated under reduced pressure, dissolved in acetone and the .Rückstand treated with a solution of isopropanol in Chlcrv.'asserstoff . The crystals formed are filtered off and recrystallized from ethanol. yield 1.7 g colorless 7- (2-hydroxy-3-isopropylamino) -prcpoxy-3,4-dihydrocarbostyril hydrochloride, melting at 207 to 209 ⁰ C. The free base Melts at Λ kl up to 149 ° C (acetone).

Example 57

1.8 g of S- (2-Hydroxy-3-chloi ') - propoxy-3,4-dihydrocnrtoctyri3 ur.-j 3.5 g of isopropylamine are dissolved in 30 ml of isooropanol in pure, ether and 5 hours under reflux cooked. Then can KeaUtioru: reit i sch under reduced pressure e in. «*>J" inpf L, 6rr residue is dissolved in acetone and crosslinked with a Lusunc of üh-f-ruasserevon in isupropanol. The r ^ cbiitk Lcn Kri ^ i allo vcrJrr

309849/1193

copy '

and not crystallized from ethanol. Yield 0.7 g colorless

Hydrochloride from m.p. 230 to 232 ^C C. The free base melts at

157 to 159 ° C (acetone ;.

In the same way, the following connections are established:

fuaarat, F. 242 - 245 ⁰ C (acetone ;:
7- (2-Hydroxy-3-tert-butyianino; propoxy-5,4-dihydrocarbyl tyrilhydrochloride, mp 251-255 ° C (ethanol); the free base melts at -22 to 125 ° C (acetone; -,
3- (2-Hydroxy-3-tert-butylanino; -propoxT-3,4-dihydrocarbostyril hydrochloride, mp 236-23S ° C (ethanol;, the free base melts at 158-161 ° C (acetone ;.

Example 58

0.5 g of 5- (2-Hydro- <y-5-isopropyla = ir.oj-propoxycarbostyril verden dissolved in 100 ml of ethanol. The solution is added to 0.5 g Raney-iiickel placed in an autoclave and 5 hours at 40 bis 50 C and a '.'ass he fabric pressure of 50 at shaken. After finished The catalyst is filtered off and the filtrate is removed evaporated. Identify any uncrystallization of the residue Isopropanol v / earth 0.48 g of colorless 5- (2-kydroxy-3-isopropylanino; -propoxj'-3,4-dihydrocarbostyril from 144 to 145.5 ° C obtain.

Example 59

O ₁ 5 g 5-f2 - !: ydro?: Y-3-tert.-butylar: ir.o; -proOOx ^ / carbostvril-hvdrochlorid are dissolved in 5CC rcl ÄLhano), and the solution becomes zo sarcxen nit 0 , 5 g of Raney rubbers in an autoclave. The GE-

309849/1193

COPY

Mixture is hydrogenated in "i3 Example 58. 0.47 g of colorless 5- (2-Hydroxy-3-tert-butylarainoj-propoxy-3,4-dihydrocarbostyril hydrochloride of mp 27S ° C (dec .; ethanol) obtained.

Example 60 -

0.5 g of 5-C2-hydroxy-3-isopropylaiaizioJ-propoxycarbostyril are mixed with 0.01 g of Palladiuxasczr arz and 1C ml of glacial acetic acid. The mixture is shaken for 5 hours at room temperature under a VJasserstoiT pressure of 10 atm. When the reaction is complete, the catalyst is filtered off, the filtrate is evaporated, the residue is treated with water and the aqueous solution is made alkaline with ammonia. The precipitated crystals are filtered off and recrystallized from isopropanol. Yield 0.47 g of 5- (2-hydroxy-3-isopropylacino) -prcpoxy-3 »4 _r dihydrocarbostyril.

Example 61 2.0 g of 5-t2-hydroxoxy-3-tert-butylamino) propoxy-3,4-dihydrocarbostyril and 10 g of acetyl chloride are refluxed in 30 ml of acetone for 2 hours. After standing for 15 to 15 hours, the precipitated crystals are filtered off, washed with acetone and recrystallized from a mixture of methanol and acetone. Yield 1.7 g of pale yellow 5- (2-acetoxy-3-tert-butylamino) propoxy-S ^ -dihydrocarbostyril hydrochloride with a melting point of 231 ° C. (decomp. ) .

Example 6Γ

1 _f 8g of 5_ (2-hydroxy-3-tert-butylamino) propoxy-3,4-dihydrocarbostyril and 0.3 g of sodium hydride in 50 μl of toluene are refluxed for 1 hour. Then 1 g of benzoyl chloride dissolved in 30 ml of toluene is added. The mixture is 4 hours

309849/1193

COPY

. ,,. ~ „„ ^, - ^ ^J he reduced reflux and connect ^ un-ex

Pressure evaporated to dryness. The residue is dissolved in 150 ml of chloroform, the chloroform solution with 500 ml of water. and dried over sodium sulfate. The chloroform solution is then evaporated and the residue is dissolved in 50 μl of sulfuric oil. Hydrogen chloride gas is passed into the solution. The precipitated crystals are filtered off and recrystallized from ethanol. Yield 1.5 β of colorless ₅ - (2-benzoyloxy-3-tert-butylacdnoj-propo ^^^ - dihydrocarbostyril hydrochloride

from 207 to 209 ° C (dec.).

Example 63 1.5 g of 5- (2-Hytooxy-3-isoFro? Ylaa! Ir * o) -prc? Oxy-3, ^ - dihydrocarl> cstyril and 1 g acetylcfaloride in 50 = 1 acetone takes 2 hours, refluxed. Mach de = cooling the mixture to Evaporated dry and the residue dissolved in water. the Solution is made alkaline with aconia and extracted with ethyl acetate. The ethyl acetate extract is dried over sodium sulfate and evaporated. The residue is dissolved in acetone and a solution of oxalic acid in ether is added. The precipitated Crystals are filtered off. Yield 9.9 g of colorless 5- (2-acetoxy-3-isopropylaninoJ-propoxy-3, ^ - <iihydrocarbostyril-

hydrochloride, melting at 196-198 ⁰ C (dec.).

Example 64

According to Example 63, but using 1.5 g of 1-methyl-SU-hydroxy-S-icopropylanino-S. ^ - dihydrocarbostyril, the corresponding acel is obtained. After crystallization from a mixture of ethanol and isopropyl ether, 1.1 g of colorless 1-: 7et.hyl-5- (2-'Jcei.c: '. Y-3-i jop ^T ' oryln: rJ.rJo ; -propo7y-3, <i-

3098A9 / 11S3

Γ ^C0PY

dihydrocarbostyril hydrochloride was obtained melting at 194 to 196 ⁰ C (dec.).

Example 65

The acetoxy derivative is obtained according to Example 63, but using 2.0 g of 1-benzyl-5-C2-hydroxy-3-tert.-butylar, ino) -propo: cy-3, ^ -dihydrocarbostyril. ! lach uracrystallization of the crude product from a mixture of ethanol and acetone v / earth 1.4 g of 1-benzyl-5- (2-acetoxy-3-tert.-butylanino) propoxy-3, ^ - dihydrocarbostyril-inaleet from F. 19 * to 193 ^C C obtained.

Example 66

3.0 g of 5- (2-hydroxy-3-tert-butylaaino; -propoxy-3,4-dihydrocarbostyril and 0.1 g of sodium hydride in 60 ml of xylene are heated under reflux for 1 hour and then stirred in the Reaktionsgecisch within Λ hour, a solution of 2.8 g of _3: added dropwise in 40 nl xylene 4,5rlrimethoxyterizoylchlorid the obtained mixture is boiled for 4 hours under reflux and stirred, and thereafter eingedanrpft under reduced pressure .. the residue is dissolved in chloroform. Washed with water and extracted with hydrochloric acid for 3 seconds. The hydrochloric acid solution is separated off, made alkaline with sodium hydroxide solution and then extracted with chloroform. The chloroform extract is evaporated. The residue is dissolved in 60 ml of acetone and treated with maleic acid. The filled crystals are filtered off and Uncrystallized from methanol. Yield 2.1 g of fartlcces 5-t3-tfc = rt.-3utylanino-2- (3,4,5-trinethoxy} -benzoyloxv7-propoxy-'3i 4-dihydroc-: rbostyr i 1 taleate vox: f. 224 "oit 226 ^ C (Z * rs.;.

309843 / Π93

COPY

Example 67

According to Example 66, but using 3.0 β 5-C2-KydroxyO-isopropylarninoj-propoxy-J ^ -dihydrocarbostyril, 1.5 S colorless 5- / 3-isopropylamino-2- (3,4,5-trimethoxy) -benzoyloxyy-propoxy ^. ^ - dihydrocarbostyril maleate from F. 186

to 18S ⁰ C (decomposition in ethanol).

Example 68

A mixture of 2.0 g of 5- (2-I: hydroxy-3-tert.-butylamino) propoxy-3,4-dihydrocarbostyril and 7.7 g of butyryl chloride is 4 hours. refluxed and then evaporated to dryness under reduced pressure. V / ater is added to the residue, the mixture is made alkaline with annonia and extracted with ethyl acetate. The ethyl acetate extract is dried over sodium sulfate, evaporated and the residue is dissolved in acetone. A solution of oxalic acid in ether is added to the acetone solution. The precipitated crystals are filtered off and recrystallized from water. Yield 1.1 g of colorless 5- (2-butyryloxy-3-tert-butylamino) propoxy-3,4-dihydrocarbostyril oxalate, melting at 229.5 ⁰ C (dec.).

Example 69

2.5 g of 5- (2-hydroxy-3-tert-butylamino} -propc-xy-1-meth -'- l-3, ^ dihydrocarbostyril and 0.35 g of sodium hydride in 60 ml of benzene. Boiled under reflux for 1 hour and stirred. Then will a solution of 1.0 g of butyryl chloride in 20 ml of 3enzene was added to the reaction mixture. The genic will be another 4 hours boiled under reflux and stirred and then evaporated to dryness under reduced pressure. The residue is in Dissolved ethyl acetate, washed the ethyl acetate solution with water

309SA9 / 1193

COPY ^Λ

and dried over sodium sulfate and evaporated. The residue is dissolved in acetone and oxalic acid is added. The precipitated crystals are filtered off and ground. recrystallized from wet. Yield 1.4 g of 5- (2-butyryloxy-3-tert, -butylanino) of colorless -profoxy-1-methyl-3 | 4-dihydrocaroostyril oxalate of F. 207 ⁰ C (dec.).

The following connections are made in the same way:

5- (2-Benzoyloxy-3-isopropylani.no J-prcpoxy-S ^ -dihydrocarbo-

styril oxalate, m.p. 195-1S7 ° C (2ers .; Methanoi ;;

5- (2-Isobutyryl-3-tert-butylanino ) -propoxy ^, 4-dihydrocarbo-

styril hydrochloride, m.p. 244 - 245 ° C (2ers .; methanol);

5- / 3-tert. -Butylaaino-2- C 3, 4,5 trice thoxy) -benzoyl oxy / _{propoxy-1-methyl-3-f} 4-dihydrocarbostyril hydrcchlorid, F. 2'6 - 218 ⁰ C.

CZers .; Methanol),

i-Benzyl-i-Z ^ -isopropylanino ^ - (3,4,5-triae thoxy} -benzoyl oxy / -propoxy-S ^ -dihydrocarbostyril hydrochloride, 125 ° C (dec .;

Methanol);

1-Benzyl-5- / 3-ter1; .- butylamino-2- (3,4,5-trinethoxy) -benzoyl-

_OX y7-propoxy-3,4-dihydrocarbostyril hydrochloride, m.p. 192

- 194 ° C (dec .; acetone) and

1-allyl-5 - \ / 3-isopropylamino-2- (3,4,5-trimethoxy) -benzoyloxy / -propoxy-3,4-dihydrocarbostyril fumarate, Mp 185-187 ° C (dec .;

Methanol).

Example 70

In the same way as in Examples 61 to 69, the following proceed Connections made:

309849/1193

I COPY j

Tabel

- 39 -

O H H co CP H H

CH

H H H K H

R "

CH (CH ₃ J ₂ 3 ^ 2

CH (CH ^) ₂

CH (CH ₃ J ₂

OCH ₂ CHCH ₂ N ^

• A

R-

Recrystallized _crystal .

properties

the end

£ orm

CH,

C (CH ₃ J ₃

CH

3,4,5-tri.

methoxy

phenyl

HCl methanol

HCl isopropyl mol

HCl laopropanol

HCl Di Ii thy IU the r

HCl ethanol

COOH methanol
COOH

HCl methanol

color.
amorphous

F., ⁰ C.

23 ^ -236 (Dec. J.

210-212 (dec. J.

173-175 207-209

195-197 216-218

-AO-

Example 71

1 # 53 g of S-hydroxy-S ^ -dihydrocarbostyril and 3.5 U of epichlorohydrin are added to 30 ml of a solution of 0.216 g of atrium in methanol, and the solution obtained is 4 hours at 55 "to 6G ° C touched. After cooling, the sodium chloride crystallizes out filtered off and the filtrate under reduced pressure " evaporated. The residue is extracted with ethyl acetate. The ethyl acetate extract is evaporated and the residue is crystallized from a mixture of acetone and diethyl ether. Yield 1.0 g of colorless 5 - (?, 3-Hpoxy; -propox3 ^ -3,4-dihydrecarbostyril from 172 to 173 ° C. In the IR absorption spectrum characteristic absorption bands appear at 3020, 1665 and 1590 cm ~.

Example 72

A mixture of 1.63 g of 5-hydroxy-3, ^ - dihydrocarOostyril, 2.5 g Epibromohydrin and 2 drops of piperidine is given to 95 up to 4 hours 100 ° C heated and stirred. Then the Reaktior.sgeaisch evaporated to dryness under reduced pressure and the residue recrystallized from acetone. Yield 1.2 g of colorless 5- (2,3-epoxy) -propoxy-3,4-dihydrocarbostyril with a melting point of 172 bis 173 ° C.

Example 73

A solution of 0.6 g of sodium hydroxide in 40 ml of water is mixed with 2.5 g of 5-hydro: y-3,4-dihydrocarboGtyril and 2.5 upichlorohydrin and left on for 4 hours; C to 40 ° C awakened and moved. After cooling, the complete crystals are filtered off from acetone and are not crystallized. Yield 1.75 C colorless

3096 ^ .3 / 1 193

BAfi

B e i s ρ i e 1 74

1.5 g of isopropylamine in 50 ml of methanol are added to 1.0 g of 5- (2,3-

· - rrpfrpben. and the mixture epoxy; -propo: o / -3, '+ - dihydrocarbostyrii segecen, v: ith four hours box 45 to ₅ 0 ° C and then stirred for one; steamed. The residue is dissolved in acetone and mixed with a solution of maleic acid in acetone. The precipitated xri- "stals are filtered off and isolated from isopropanol. Yield 2.1 g of colorless 5- (2-hydroxy-3-isopropyl _P ropylamino} - _{P P} rc -0 ^ -3,4-dihydrocarbostyril maleate, melting at 218-220 ° C (ethanol J.

The haleate obtained is then treated with sodium hydroxide solution or potassium hydroxide solution. Of colorless ₅ - (2-hydroxy-3-ylamino Isopi-o- _P - _P ropoxy-3,4-ai ^ ydrocarbostyril T. from 145 to 145.5 ⁰ C.

Example 75

Example 74 is repeated except that hydrochloric acid is used instead of maleic acid. Colorless is obtained 5- (2-Hydroxy-3-isopropylanino; -propoxy-3, ^ - dihydrocarbostyril hydrochloride from 224 to 225 ° C.

Example 76

A mixture of 0.75 g of 5- (2,3-spoxy; -propoxy-3,4-dihydrocarbo-; styril, 1.0 g of tert-butylamine and 25 ml of ethanol is used for 4 hours: at 50 to 55 ° C The reaction mixture is then evaporated under reduced pressure and the residue is dissolved in acetone. 0.5 g of maleic acid is added to the acetone solution.

The crystals which have now precipitated out are filtered off and extracted from ethanol. Yield 1.15 g of colorless 5- (2-hydroxy-I-tert-butylamino ^ propoxy-I ^ -dihydrocarbostyril maleate of

309849/1193

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F. 206 to 207 ⁰ C.

Example 77

The testing of the compounds of the invention for blockade of the β-receptors against isopropylnoradrcnalin (Isopr ^ nalin * was carried out according to the method of CE Powell, IH Slater, J. Phanaac, Vol. 122 (1958), p. 480. In this method, the beta-receptor blocking "effect on blood pressure of anesthetized dog determined I-Ian first examines the Llutdrucksenkende and £ requenzsteigernde." - "MPACT of isoprenaline and then checks what percentage un blood pressure reduction and increase in frequency prevents v ^r ird, _ previously Venn a ß. Receptor blocker is given. For this experiment, customers with a body weight of 13 to 20 kg are anesthetized with 30 mg / kg body weight of pentobarbital I.'atriun, which is administered intravenously Compound administered to the anesthetized customer in a dose of 1C / kg body weight through the fesoral vein. Mach 5: 0.3 v / kg body weight isoprenaline is given to the dog for 1 minute through the fenoral vein. The results are shown in Table II.

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Table II

Tcs! Connect?

via Inonrrnr ι " ¹ in,; 4 Hernun? Blood pressure Pulse 1 8.9 9.3 2 35.7 12.8 3 35.3 12.7 4th 44.4 : 52.6 5 94.4 53.2 6th 46.8 25.6 7th 40.0 2C, 4 8th 27.6 10.8 9 75.4 35.1 10 23.7 5.5 11 * 6> 9 0 12th 100 82.8 13th 76.5 . 55.6 14th 13.3 10.0 15th 65.9 67.5 16 92.6 82.9 17th 100 100 18th 21.1 35.7 19th 15.8 18.4 20th 81.0 92.0 21 100 100

The test connections have the following forcsl:

3038 ^ 9/1

p copy ^r

H H H

-CHCH = CH ₂ -CH,

12th

H E E H E H H -COCH,

-C ₅ H ₇

-CH (CH ₅ ) 2 -C (CH ₅ ) ₅ -C (CHj) ₅ -CH (CH ₅ ) 2 -CH (CH ₅ ) 2

-C (CH,), H H H H E

OCH. Pumarat HCl ' XHCInIHC (CH-), OH ς
B. · ΙΛ ₀
E. L ₀
•
ττ

₂ ^ OB

ECl

3038A9 / 1 HCl

ECl Si rial eat ECl & Funärat

ECl Maleate ECl Fuiaarat

COOH COÖH

Haleat

No. 15

R ¹

-CHCH = CH ₂

HCl

Funarat HCl

0.CH ₂ CHCH ₂ RHB

OH

I.
H R. No. ethyl 16 I sopropy1 17th n-butyl 18th I; 50butyl 19th sec-butyl 20th tert-butyl 21

copy '

Claims (30)

Claims in which R is a hydrogen atom, a straight or branched one AlP-yl radical with 1 to 4 carbon atoms, an aralkyl radical or an alkenyl radical with 1 to 4 carbon atoms R represents a hydrogen atom or an acyl radical of the general formula COR ^, in which r 'is an alkyl radical having 1 to 4 carbon atoms, a phenyl or 3,4,5-trimethoxyphenyl group and R' and R "are the same or different can be a hydrogen atom, an alkyl group having 1 to 4 carbon atoms "represent an aralkyl or cycloalkyl group or ^R? and R" together the za.t. Nitrogen a system to which they are bonded form a heterocyclic radical with 2 to 8 carbon atoms, which can contain a further nitrogen atom or an oxygen atom in the ring, with the proviso that the side chain is in the 5-position and R ¹ and R hydrogen atoms mean that R ¹ and R "are not both hydrogen atoms or alkyl radicals having 1 to 4 carbon atoms, and their salts with acids. 2. ' 1-Kethyl-5- (2-hydroxy-3-tert-butylamino; -propoxy-3f4-dihydrocarbostyril. 309849/1193 j "COPY ^ -Af- 3. 1 -Methyl-5- (2-hydroxy-3-i ^! = Opropylaniino ) -propoxy-3,4-dihydrocarbostyril. A. 1-Ethyl-5- (2-hydroxy-3-tert-butylanino) -propoxy-3,4-dihydrocarbostyril. 5. 1-Ethyl-5- (2-hydroxy-3-isopropylann.no) -propoxy-314-dihydrocarbostyril. 6. 5- (2-Hydroxj - 3-cyclolie ^ / 13Ciino) -propo; cy-3, A-dihydrocarbostyril. 7. 5-25 ~ C3i ^ t 5-Trinethox ^ ^r ) -benzoyloxy-3-tert. - "butylaniirio / -propoxy-3,4-dihydrocartostyril. 8. 5- / 2- (3, A, 5-trinethoxy) -oenzoyloxy-5-isopropylamine q7-propoxy-3,4-dihydrocarbostyril. 9. 8- (2-Hydroxy-3-tert-butylamino ) propoxy-3,4-dihydrocarbostyril. 10. 8- (2-Kydroxy-3-isopropylaniino) -propxy-3 »4-dihydrocarbostyril. 11. 1-Allyl- (2-hydroxy-3-tert-txityla! 3ino) -propox5 '-3, ^z i-dihydrocarbostyril. 12. 1 -Allyl- (2-hydroxy-S-isopropylamino ) -propox>'-3,4-dihydrocarbostyril. 13-1y i: / cr jcsrbcs tyril. copy 23ÜZU27 14. 5- (2-Hydro: -: y-3-methylamino; -propox3 '- 3, ^Zi -dihydrocarbo5tyril, 15-5- (2-Hydroxy-3-ethylanino) -propoxy-3, '-dihydrocarbostyril. 16. 5-C2-IIydroxy-3-propylaniino) propoxy-3 ₅ ^z <-dihydrocarbostyril. 17. 5- C 2-hydroxy-3-butylaiuino ) propoxy-3,4-dihydrocarbostyril. 18. 5- (2-Hydroxy-3-tert-butylanino) -prop ~: -: y-3,4-dihvf'rocar ;; - styril. 19. Process? .Ur preparation of the 3, ^ - dihydrocarbostyril derivatives and their salts according to claim 1, characterized in that either (a) a 3, ^ - dihydrocarboctyril derivative of the general formula
II in which R ^{1 has} the meaning given in claim 1 and Z is a radical of the formula - CH CH ^, · or - CH - CH ₅ -Y \ _Λ / ² · ⁰ OH represents, in which Y is a Kalogenaton, nit one: Anin der general formula TV in which R ¹ and R "have the meaning given in claim 1
own, implement or ■. 309849/1193 COPY (b) a carbostyril derivative of the general formula III (III) in which R ₁ R ¹ and R "have the meaning given in claim ', or its salt is hydrogenated and in the presence of a nickel, palladium or platinum catalyst and in an organic solvent
Cc) optionally the compound obtained from the general Formula I, in which R means a './as^erstoffatoa, with a Acylating agent of the general formula V r ³ -coci (v; in which R- ^{3 has} the meaning given in claim 1, and converts the compound obtained according to (a), (b) or (cj) into a salt with an acid, if necessary. 20. The method according to claim 19 (aJ, characterized in that can carry out the reaction in the absence of a solvent. 21. The method according to claim 19 (a), characterized in that ' the reaction in Gegenv / kind of an inert solvent performs. 309843/1193 22. The method according to claim 21, characterized in that the amine is nit in at least a stoichiosetric amount 3,4-Dihydrocarbostyril at temperatures from Rauntenperatur to to the boiling point of the solvent used. 23. The method according to claim 19 (c), characterized in that that the acylation in the presence of an ether, an arenata see carbon or a ketone. 24. The method according to claim '9Cc) characterized in that the acylation is carried out in the presence of an acid acceptor. 25. 3,4-Dihydrocarbostyril derivatives of the general formula II (H) in which R ^{1 is} an hydrogen atom, an unbranched or branched alkyl radical having 1 to 4 carbon atoms, an aralkyl radical or an alkenyl radical having 1 to 4 carbon atoms and 2 is a radical of the formula - CH - CH ₅ - CH - CH ₀ Y - ■■. ^x 0 · ^or OH j - represents in which Y represents a halogen atom. ¹ 309849/1193 COPY 26. 5- (3-Clilor-2-hydroxy-propoxy-3f ^ -dihydrocarbostyril. 27. Process for the preparation of the 31 ^ -Oiiiydrocarbostyril-Derivate according to claim 25, characterized in that in? n the corresponding 5-, 6-, 7- or 8-hydroxy-3, ^ - dihydrocarbostyril of the general formula VI OH (VI) in the R ciie has the meaning given in claim 25, with an epihalohydrin of the general formula VII "XCH ₂ CH-CH O in which Z represents a Kalogenatoa, reacting a base at temperatures from 0 to 120 ⁰ C in the presence of. 28. The method according to claim 27, characterized in that the reaction is carried out in the presence of an alkali metal hydroxide, Performs alkali metal alcoholate or a basic amine. 29 · Process for the preparation of compounds of general formula OCH ₂ Z ' 209849/1193 COPY in which R ^{1 is} a hydrogen atom, an unbranched or branched alkyl radical having 1 to 4 carbon atoms, an _aralkyl radical or an alkenyl radical having 1 to 4 carbon atoms and Z is a group of the general formula - CH - CH ₂ Y OH represents, in which Y is a halogen atom _: characterized in that a compound ~ of the general formula VIII in which R ^{1 has} the above meaning with a 3-halo-1,2-propanediol of the general formula IX CH ₂ -CH-CH ₂ Y _(IX) OH OH represents in which T represents a halogen atom, in an inert Lösusgs _olt tel at temperatures from room temperature up to. The boiling point of the Losun _S smlttels used. 30. Vervenduns of the compounds _E e., 3 claim 1 in medicaments. ^r COPY '