DE2162721A1 - Substituted coumarins and processes for their preparation - Google Patents

Description

R = an alkyl radical with 1 to 4 carbon atoms, an alkenyl radical with 2 .to Φ carbon atoms, a urumbs bitter or with an AlkylreEst or Alkoxyreat with .1 to 4 carbon atoms or substituted with a halogen atom Arylreot or an AraLkyLrent with I to 3 C-atoms in the alkyl chain, the aryl nucleus being unsubstituted or with an alkyl radical or aikoxyre?: t with 1 to 4 carbon atoms or with halogen atoms is subordinated,

A = one; Amino group, a mono- or dialkylamino- ßruj.f.fj (in df: r die Λ l.ky I rentf> I to 6 carbon atoms each

209826/11 S6 BAD original

2 1 G 2 7 2 1

contain), a mono- or di- (hydroxyalkyl) amino group (in which the hydroxyalkyl radicals each have 1 to 4 G atoms contain), a pyrrolidine group, piperidine group, morpholine group or piperazine group, substituted in the 4-position by an alkyl radical with 1 to 4 carbon atoms, ß-hydroxyethyl, ß- (hydroxyethoxy) ethyl or

-CH ₂ CH ₂ OOC

where R _{2 is} an alkyl radical or alkoxy radical with 1 to 4 carbon atoms or a halogen atom and η has the value 0, 1, 2 or 3}

R. = a hydrogen atom, halogen atom or alkyl radical with 1 to 4 carbon atoms.

The invention also encompasses the non-toxic acid addition salts of these derivatives with organic and inorganic ones Acids and a process for making the compounds.

The compounds of formula (I) and their salts have beneficial effects on the cardiovascular system / Your ID ™ was determined by intravenous administration in the rat. In attempts to determine the effects of the new compounds on the vasculature in cats anesthetized with chloralose urethane, the change in carotid blood pressure after intravenous administration of a dose equal to 1/10 of the LDejq was measured. For comparison, 1-norepinephrine and phenylephrine were given in doses ». .. ._ the l / lO "-. ⁵ of the Relevant Ι.Γ> _{Γ) 0} corresponded, and DL-Isoprerialin used at a dose of 1 / 1O of LD ^ ₀ ^ The obtained He is fbnLsiie summarized in Table I below .

+) especially on disorders of the peripheral circulatory system Arteries and veins and the cerebral circulation.

209826/1156

BAD OFHQiNAL

Tabel I. average
lent change
of blood pressure Effect of the connections
the vessels; intravenous -21 Link * of the formula (I) on the print
Administration to the cat -20 1 Ll) ₅₀ mg / kg
(at the rat) -45 2 - 88 -16 3 51 -18 4th 36 -25 5 ■ 222 -45 VX) 211 -40 7th 315 -42 8th 274 -25 9 83 • -40 10 223 -20 11 309 -24 12th 34 • -30 13th 207 -20 14th 41 -27 15th 190 -10 16 323 +44 17th 34 +49 1-Uo ^ adrenaline 132 -15 Phenylephrine 1 DL-isoprenaline 10 135

* The numbers of the compounds correspond to the numbers given in Table II.

The compounds of formula (i) are according to the invention produced by reacting hydroxycoumarins of the formula 1

(II)

2 0 9 8 2 6/1 1 B6

in which R and IL have the meanings given above and M is a metal atom, particularly an alkali metal atom, preferably a sodium atom, with a halide the formula

A-CH ₂ -CHOH-CH ₂ -HaI (III)

in which A has the abovementioned meaning and Hal is a halogen atom, preferably a chlorine atom or bromine atom, generally in an organic solvent, preferably a lower ketone, for example acetone or methyl ethyl ketone, a lower nitrile, dimethylformamide or dimethyl sulfoxide, at one temperature in the range from 0 to 150 ⁰ C, preferably 40 to 50 ⁰ C,

The compounds of the formula (II) can also be treated with epichlorohydrin under the abovementioned conditions are implemented, whereupon the resulting 2,3-epoxypropoxycoumarin of the formula

CH ₀ -CH-CH ₀ O ^N 0 ^X

in which R and R _{1 have} the abovementioned meanings, under the abovementioned conditions with an amine of the formula

H-A (V)

in which A has the abovementioned meaning, is converted into the end product of the formula (I).

Instead of a salt of the hydroxycoumarin of the formula (II) the hydroxycoumarin can be used as such (formula II, M = hydrogen), with the reaction is carried out in the presence of an acid acceptor such as a tertiary base. '. ·. -

The salts of the compounds of formula (i) with orga-209826 / 1 1 B6

Niche or inorganic acids are made by reaction an equivalent amount of the base and the corresponding Acid in a non-aqueous solvent], preferably diethy] ether, dioxane or methyl ethyl ketone, hergeste]] t.

For the production of coated tablets and tablets containing the coumarin derivatives according to the invention a] s essential active ingredients can contain these derivatives with the usual solid tab] etti] gs, e.g. starch, lactose and ta] kum, be mixed. Any of the tab] etting agents and carriers commonly used in pharmaceutical practice can be used will.

HydroohJorides are used for the production of injection solutions the coumarin derivatives are particularly suitable, since most of them have good water solubility. Injection liquids, The water-insoluble products can of course be used in the usual way by using known products at the same time Suspending agents], emuigators and / or dissolving agents] can be produced.

209826/1 1 56

example 1

4-methyl-7- (5-diethylamino-2-hydroxypropoxy) coumarin (compound ITr. Ι in table I)

8.8 g (0.05 mol) of 4-methyl-7-hydroxycoumarin, which is suspended in 100 ml of anhydrous acetone, are digested with 2 g of powdered NaOH for about 1 hour. 1-chloro-3-diethylaminopropan ~ 2-ol, prepared from 9.2 g (0.1 mol) of epichlorohydrin, 7.3 g (0.1 mol) of diethylamine and 5 ml of isopropyl alcohol, is then slowly added dropwise without separation. The mixture is left to stand for 6 hours, cooled and filtered to separate off the sodium chloride. Dilution with 100 ml of acetone makes the solution slightly cloudy. After adding 2 g of activated charcoal, the mixture is filtered and then acidified with hydrogen chloride in diethyl ether. The precipitation can be completed by adding 100 ml of diethyl ether. The hydrochloride formed in this way is filtered off and recrystallized from anhydrous ethanol. Melting point 145 to 148 ^° C. The yield is 9 g.

Example 2

4,7-dimethyl-5- (3-di- (n-proyl) amino-2-hydroxypropoxy) -

coumarin

(Compound No. 16 in Table II)

9> 5 g (0 »05 mol) 4,7-dimethylhydroxycoumarin, which in 100 ml of anhydrous acetone is suspended, about 1 hour with 2 g of sodium hydroxide in 50 ml of anhydrous Acetone digests. After cooling down slightly, 1-chlorine

209826/1156

- 4Γ-

3-di- (n-propyl) aminopropan-2-ol (prepared by reacting 10.1 g (0.1 mol) n-propylamine with 9.2 g (0.1 mol) epihlorohydrin in the presence of 5 ml isopropanol without separation) was slowly added dropwise. The mixture is left to stand for 8 hours, then cooled and filtered to remove the sodium chloride. The mixture is then diluted with 100 ml of acetone and 2 g of activated charcoal are added. After filtration, the filtrate is treated with a saturated picric acid solution in absolute ethyl alcohol. The picrate formed is filtered off and recrystallized from absolute ethyl alcohol. This purification by precipitation of the picrate is necessary because attempts at direct precipitation of the hydrochloride have not led to good results. The picrate is converted into the free base by treatment with the ion exchange resin "Dowex 1 χ 4.10 ^w . The hydrochloride is then precipitated by treating the free base with an ethereal hydrochloric acid solution. The hydrochloride formed in this way is filtered off and recrystallized from absolute alcohol. Melting point 103 to 10 5 ^P C. Yield 6g.

Example 3

4-methyl-6- / 3- (4-2'-hydroxyethyl-1-piperazinyl) -2- hydroxypropoxy7coumarin (compound no.17 in Table II)

6.8 g (0.05 mol) of 4-methyl-6-hydroxycoumarin, which in 100 ml of anhydrous acetone is suspended, about 1 hour with 2 g of powdered sodium hydroxide in anhydrous acetone digested. After slight cooling, 1-chloro becomes ~ 3- (4-2'-hydroxyethyl-1-piperazinyl) propan-2-ol (prepared by reacting 13 g (0.1 mol) of 4- (2-hydroxyethyl) piperazine with 9.2 g (0.1 mol) of epichlorohydrin in the presence of 5 ml of isopropanol, without separation) slowly added dropwise. "The mixture is 8 hours left to stand, then cooled and used to separate the

209826/1 1 B6

Sodium chloride filtered. After dilution with 50 ml of anhydrous acetone, 2 g of activated charcoal are added. After filtration, the filtrate is evaporated on a rotary evaporator. The residue is dissolved in diethyl ether recorded. The ether phase-becomes with hydrogen chloride treated. The hydrochloride formed in this way is recrystallized from absolute ethanol. Melting point 151 to 153 ° C. The yield is 7 g.

Example 4

4-Phenyl-7- / 5-di- (n-propyl) amino-2-hydroxypropoxyy coumarin (Compound No. 11 in Table II)

11 g (0.05 mol) of 4-phenyl-7-hydroxycoumarin, which is suspended in 100 ml of anhydrous acetone, are digested for about 1 hour with 2 g of powdered sodium hydroxide in 50 ml of anhydrous acetone. After slight cooling, i-chloro-3-di ~ (n-propyl) aminopropan-2-ol (prepared by reacting 10.1 g (0.1 mol) of di (n-propyl) amine with 9.2 g (0.1 mol) epichlorohydrin in the presence of 5 ml of isopropanol, without separation) was slowly added dropwise. The mixture is allowed to stand for 10 hours, then cooled and filtered. The filtrate is treated with ethereal Salssäurelösung. The precipitated Hydrochloric is filtered off and recrystallized from absolute ethanol. Melting point recrystallized 153'bis 155 ⁰ C. The yield is 9 _g} 2 ".

The compounds of formula (i) which. on those in the Examples 1 to 4 are prepared in the manner described below in Table II.

209 826/1156

• link • 2 > * 4th E E *
' (Position) H ■ ■ H • H Table Ir Position of Melting point H A. Group A-CHp- of the hydra 3 ■ H H CHOH-CH ₂ O- chloride, ⁰ C 1 5 CH ₃ 7th 145-148 . 6th H ' H -IT (C ₂ H ₅ ) ₂ ro 7th CH ₃ H 7th 203-205 ο
co -N (nC ₃ H ₇ ) ₂ OO 8th CH ₃ 7th 162-164 ro
/ τ * 9 -H (nC ₄ H _g ) ₂ CH ₃ / CH, 7th 140-145 - » " ^Nn ^ CH ₉ CHpOH OT * ro CH ₃ > »CpH ₁ - 7th 137-139 • CH ₃ "" ¹¹ ^ OH ₂ CH ₂ OH '7 147-149 CH, -N (CH ₂ CH ₂ QH) ₂ 7th 213-215 3 OH, 7th 198-200 CH ₃ -O 7th 257-258 "TO" "W Π ti
V- / ³

Table II (continued)

Connection ER ₁ (position)

O CO CO

10 CH ₃ H 11 ^C 6 ^H 5 H 12 _s ^C 6 ^H 5 H 13th CH ₃ H Ή CH ₃ H 15th CH ₃ H 16 CH ₃ _ CH ₃ (7) 17th CH, ' CH (7)

Position of the melting point group A-CHp- of the hydro-CHOH-CH ₂ O-chloride, ⁰ C

-CHoCHoOH

-N H- <

CH ₂ CH ₂ OH

-Ή Ο

-CH ₂ CH ₂ OH

-CH ₂ CH ₂ OH

7th 7th 7th 6th 6th 6th 5 5

248-250 153-155 136-139 159-161 235-238 151-153 203-205 269-271

ISJ CD

Claims (22)

Patent claims R s = an alkyl radical with 1 to 4 carbon atoms, an alkenyl radical with 2 to 4 carbon atoms, an unsubstituted or with an alkyl radical or alkoxy radical with 1 to 4 carbon atoms or aryl radical substituted with a halogen atom or an aralkyl radical with 1 to 3 carbon atoms in the alkyl chain, the aryl nucleus being unsubstituted or having an alkyl radical or alkoxy radical having 1 to 4 carbon atoms or with halogen atoms is substituted, A = an amino group, a mono- or dialkylamine group (in which the alkyl radicals each have 1 to 6 carbon atoms contain), a mono- or di- (hydroxyalkyl) amino group (in which the hydroxyalkyl radicals each have 1 to 4 carbon atoms contain), a pyrrolidine group, piperidine group, morpholine group or piperazine group, substituted in the 4-position with an alkyl radical with 1 to 4 carbon atoms, ß-hydroxyethyl, ß- (hydroxyathoxy) ethyl or where R _{2 is} an alkyl radical or alkoxy radical having 1 to 4 carbon atoms or a halogen atom and η is 0, 1, 2 or 3; a hydrogen atom, halogen atom or alkyl radical with 1 to 4 carbon atoms, 209826/1156 and their non-toxic acid addition salts. 2) 4-Methy1-7- (3-diethylamino-2-hydroxypropoxy) coumarin and its non-toxic acid addition salts. 3) 4-methyl-7- / 5-di- (n-propyl) amino-2-hydroxypropoxy_7-coumarin and its non-toxic acid addition salts. 4) 4-Methyl-7- / 3-di- (n-butyl) amirio-2-hydroxypropoxyy ^r coumarin and its non-toxic acid addition salts. 5) 4-methyl-7-Z3- (li-methyl-N-2-hydroxyethylaniino) -2-hydroxy-propoxy / coumarin and its non-toxic acid addition salts. 6) 4-Methy1-7- / 3- (N-ethyl-N-2-hydroxyethylamino) -2-hydroxy-propoxy / coumarin and its non-toxic acid addition salts. 7) 4-methyl-7- / 3- (N, F-di-2-hydroxethylamino) -2-hydroxypropoxy ^ coumarin and its non-toxic acid addition salts. 8) 4-methyl-7- / 3-morpholine-2-hydroxy-propoxy7'cuInarin and its non-toxic acid addition salts. 9) 4-IvIethyl-7- / 3-piperidine-2-hydroxy-propoxyycaraarine and its non-toxic acid addition salts. 10) 4-methyl-7-Z3- (4-methyl-1-piperazinyl) -2-hydroxypropoxx / coumarin and its non-toxic acid addition salts. 11) 4-methyl-7- / 3- (4-2-hydroxyethyl-1-pipera.zinyl) -2-hydroxy-propoxy-7coumarin and.its non-toxic acid addition salts. 12) 4-Phenyl ~ 7- / 3-di- (n-propyl) amino-2-hydroxy-propox _€ Y7-cuniarin and its non-toxic acid addition salts. 209826/1 1 56 13) 4-Piienyl-7- / 3- (4-2 '-hydroxyethyl-i-piperazinyl) ^ - hydroxy-propoxyy-coumarin and its non-toxic acid addition salts. 14) 4-methyl-6- / 3-di- (n-proyl) amino-2-hydr oxy-pr άραχλο umar in and its non-toxic acid addition salts. 15) 4-Hethyl-6- ^ 3-niorpholin-2-hydroxy-propoxyy ^r coumarin and its non-toxic acid addition salts. 16) 4-methyl-6- ^ 3- (4-2'-bydroxyethyl-1-piperazinyl) -2-hydroxy-propoxy / coumarin and its non-toxic acid addition salts. . 17) 4,7-Dimettiyl-5- _i / "5-di- (n-propyl) amino-2-hydroxypropoxy / coumarin and its non-toxic acid addition salts. 18) 4,7-Dimethyl-5-Z3- (4-2 ^l -hydroxyethyl-1-piperazinyl) -2-hydroxy-propoxyy ^r coumarin and its non-toxic acid addition salts. 19) Process for the preparation of substituted coumarins according to claims 1 to 18, characterized in that one uses hydroxycoumarin salts of the formula in which R and R _{1 have} the meanings given in claim 1 and M is a hydrogen atom or a metal atom, with a halide of the formula A-CH ₂ -CHOH-CH ₂ Hal in which A has the meaning given in claim 1 and Hal is a halogen atom. 20) Method according to claim 19, characterized in that 209826/1156 that a halide of the formula A-CH ₂ -CHOH-CH ₂ Hal is used, in which M is a sodium atom and'Hai is a Is chlorine atom or bromine atom. 21) Method according to claim 19 or 20, characterized in that the reaction takes place in an organic Solvent carried out and as an organic solvent a lower ketone, a lower nitrile, Dimethylformamide or dimethyl sulfoxide is used. 22) Method according to claim 19 to 21, characterized in that the reaction is carried out at a temperature in the range from 0 to 150 ^° C. 209826/1 156