DE2239033A1 - DIHYDROBENZOPYRAN DERIVATIVES AND METHOD FOR MANUFACTURING THE SAME - Google Patents

Description

Dipl.-Ing. H. MITSCHERLICH Dipl.-Ing. K. GUNSCHMANN

Dr. rer. nat. W. KÖRBER Dipl.-Ing. J. SCHMiDT-EVERS PATENTANWÄLTE

8 MUNICH

Steinsdorfstrasse 10 ® (0811) * 29 66 84

8, -Augusc 19

65 - COURNON D ¹ AUVERGEE, France

E / Ne

Patent application ;

Juiliydrobenzopyranaefivate and process for the production;

the same

The invention relates to dihydrobenzopyran derivatives general formula I:,,

(D

in the R means *

1) a hydrogen atom,

2) a group of the general formula: - (CR ₂ R ^) ₁₁ -COOR., In which R ₂ and R ^ can be a hydrogen atom or a methyl radical and η is 1, 2 or 3;

in the R ^ means: -

1) a hydrogen atom: the acids so formed can with organic bases such as secondary amines or

309 8 08 / 138A

mineral. Bases (sodium hydroxide, potassium hydroxide), neutralized be,

2) a lower alkyl radical;

in the H ¹ means:

1) a hydrogen atom,

2) a hydroxyl group or a alkoxy group; in the R "means:

1) a hydrogen atom,

2) an alkyl radical;
where β ^Πί means:

1) an aryl radical which is optionally substituted, for example by a phenyl group of the general formula II:

(II)

in which R ^, H ₁ -, Rg> Bn and / or ß _{g can be} identical or different and can be a hydrogen atom, a halogen atom, a lower alkyl radical, a hydroxyl group, an alkoxy or nitro radical (nitro), with 2 substituents corresponding to a cycle Hg and Er ₇ can form a methylenedioxy group with illustration;

2) a pyridine nucleus, with the nucleus in the 2-, 3- or 4-position or its salts with organic or mineral acids such as maleic acid, iumaric acid, hydrochloric acid are bound;

3) an i'uranker, e.g. B. an optionally substituted thiophene nucleus;

Z means:

an oxygen atom or a group of the general formula III: = N-NH-CY

Il

in which represents:

X is an oxygen atom, sulfur atom or a group NH,

309808/1384

'- 5- 2233033

X is a substituted or unsubstituted radical of Formula IiH-Eq represents, in which Rq is a substituted or represents unsubstituted phenyl radical, where X and Y can combine to form a heterocyclic Connection, e.g. B. an imidazole nucleus with mineral acids such as HCl, hydriodic acid, nitric acid can. .

In this respect, the derivatives according to the invention are valuable pharmacological ones Substances considered to have remarkable cardiovascular properties, especially cardio-tonic, respiratory, Have antihypertensive properties. Some of them also have painlindeim.de and antibacterial properties.

The derivatives according to the invention are prepared by using substituted or unsubstituted phenyl alkyl ketones starts out, such as dihydro-2,4-acetone phenone, dihydroxy-2,4-propiophenone.

The production takes place according to two processes, wherein

1) R is a hydrogen atom :

The dihydroxy-2,4-phenylalkyl ketone (II) is allowed to react Aldehydes act:

a) if R '"is an optionally substituted phenyl nucleus, a benzene aldehyde, according to the following formula:

R ¹

CO-CH ₂ R "

■ + OHC

b) if K "" is A pyridine nucleus, the pyridine -2 or -3 or -4 aldehyde, according to one of the preceding reaction scheme,

c) if R " ^{1 is} a furan nucleus or a thiophene nucleus, the aldehydes correspond to these nuclei, according to an identical reaction scheme.

3098 08/1384

If Z is a grouping N-NH-C-Y, the invention

Il

Mass derivatives prepared by starting from the compounds obtained above and _{reacting with a compound of the formula NH 0} - NH - C - I.

C- Il

X
2) E is a grouping of the general formula (CR ₂ H ^) _n -COOR. is:

In a first stage, an intermediate, for example, is obtained according to the following scheme:

CO. CH ₂ R "^. 00-CH ₂ R"

+ C ₂ H ₅ COO - CH ₂ Br->

C ₂ H ₅ OCO-CH ₂ -O

If R "" = H, it can be hydroxy-1-acetyl - ^ - phenoxyethyl acetate when R "= CH, it can be hydroxy-3" propionyl-4-phenoxyethyl acetate be.

If one proceeds from these connections, one works further as it ^{is according to the different values of R 1 ″ and Z}
is specified in the first procedure.

The invention is illustrated below by means of various examples described in more detail without thereby limiting the scope of the invention.

example 1

/ Hydroxy-7- (pyridyl-4) - 2- chromium anonguanylhydrazone - ^ - dichlorohydrate (Compound no.5)

15 »2 g (0.1 mol) dihydroxy-2,4-acetophenone and 10.7 g (0.1 hol) Half of the pyridine-4-aldehyde is suspended in 200 ml of hydrochloric acid.

309808/138 4

suspended and heated under reflux for 6 hours. One gives 100 ml conc. HCl and refluxed for a further 12 hours, then let it cool down.

The residue is concentrated to dryness under vacuum absorbed with 100 ml of alcohol. After distilling off the Alcohol under vacuum gives 27 »2 g of hydrochloride Hydroxy-7- (pyridyl-4) -2-chromanone as a carmine powder.

14 g (0.055 mol) of the product are placed in 100 ml of absolute Ethyl alcohol in solution, gives 6.8 g (0.05 mol) aminoguanidine carbonate, then 5 ml (0.05 mol) of concentrated HCl and heated under reflux for 24 hours.

The alcohol is removed in vacuo and the residue is taken up in anhydrous ether.
Yield: 90 %. ....

Be i s ρ i e 1 2

/ J) imethoxy-3 ', 4'-hydroxy-7-fla-vanon- (phenyl-4-semicarbazone) -4 ^ -chlorohydrate (Connection No. 4 ?.

The production takes place in two stages; 1) Hydroxy-7-dimethoxy - 3 ', 4'-flavanones

A suspension of 15> 2 g (0.1 mol) of dihydroxy-2,4-acetophenone and 16.6 g is heated on the reflux condenser for 6 hours Half (0.1 mol) of dimethoxy-3,4-benzaldehyde in 150 ml of BDl. 100 ml of conc. HCl. and heated for another 12 hours. After cooling, the precipitate is filtered and up to washed to neutral pH with water. Yield: 97%

The intermediate product enables the preparation according to the invention to be produced Derivatives in a second stage:

3098 08/13 84

2) 15 »3 6 (0.055 mol) hydroxy-7-dimethoxy-3 ', 4 -'- f lav anon and 9 »^ 6 (°, O5 mol) phenyl-4-semicarbazide are 6 hours on Reflux in 100 ml of absolute ethanol in the presence of a few drops of conc. HGl heated. If the pressure is reduced, the Alcohol is distilled off and the residue is taken up in 100 ml of benzene. A gaseous stream of hydrochloric acid is passed through several Minutes through the suspension, filtered and washed with ether. Yield: 84%.

Following the procedure in Example 2, the following becomes

Derivative made:

Dihydroxy-4 ', 7-flavanone- (phenyl-4-semicarbazone) -4- (Compound No. 6).

In this case is produced in the first stage, the dihydroxy-4 ^1, 7-flavanone.

Example 3

(Methyl-4 -'-flavanonyl-7) -oxyacetic acid (compound no. 17)

The production takes place in two stages:

1) Hydroxy-3-acetyl-4-phenoxyethyl acetate.

22 g (0.16 mol) of potassium carbonate and 16 g (0.1 mol) of ethyl bromoacetate are added to a solution of 15.2 g (0.1 mol) of dihydroxy-2,4-acetophenone in 150 ml of acetone. The mixture is refluxed for 12 hours, the acetone is evaporated off under vacuum and the residue is abundantly washed with water. Yield: 90 %.

The hydroxy-3-propionyl-4-phenoxy- " ethyl acetate and from this intermediate the compound No. 18 in a second stage:

2) 23.8 g (0.1 mol) of hydroxy-3-acetyl-4-phenoxyethyl acetate and Half of 12 g of p-ethylbenzaldehyde are suspended in 200 ml of HGl and refluxed for 6 hours. Add 100 ml

309808/1384

conc. HCl and refluxed for a further 12 hours, filtered and washes copiously with water to neutral pH. Yield: 93%

Hydroxy-3-acetyl-4-phenoxyethyl acetate and hydroxy ~ 3-propionyl-4-phenoxyethyl acetate are intermediate products for the production of numerous other derivatives according to the invention of the following types:

Using the procedure of Example 3, make the following. links from:

a) (Methyl-3-fluoro-4'-flavanonyl-7) - oxyacetic acid (compound No. 7):

by reacting hydroxy ^ -propionyl - ^ - pheno ^ äthylacetat with PI ¹ Iuorbenzaldehyd.

b) (methyl-3-dichloro-2 ', 6 ^l -flavanonyl-7) -oxyacetic acid (compound no. 8)

using dichloro-256-benzaldehyde.

c) (methyl-3-chloro-4 ^l -flavanonyl-5 ') -oxyacetic acid (Compound No. 9).

using p-chlorobenzaldehyde.

d) (methyl-3-trihydroxy-2 ', 4', 6 ^l -flavanonyl-7) -oxyacetic acid (compound no. 10)

using Q? rihydroxy-2 _i 4,6-benzaldehyde. ■ e) (methyl-3-hydroxy-4'-flavanonyl-7) -oxyacetic acid (compound no. 11)

using p-hydroxybenzaldehyde.

f) (methyl-3-hydroxy-2 ^l -flavanonyl-7) -oxyacetic acid (compound "r. 12).

using o-hydroxybenzaldehyde.

g) (methyl-J-dimethoxy-J ', 4'-flavanonyl-7) -oxyacetic acid (compound No. 13)

using dimethoxy-3,4-benzaldehyde. h) (methyl-3-flavanonyl-7) -oxyacetic acid (compound no. 14) using benzaldehyde.

i) (Methyl-3-nitro-3'-flavanonyl-7) -oxyacetic acid (Compound No. 15)

3098 0.8 / 1384

using m-nitrobenzaldehyde.

J) (Dihydroxy-2 ', 4'-flavanonyl-7) -oxyacetic acid (Compound

No. 16)

by reacting ethylhydroxy-3-acetyl-4-phenoxyacetate with

Dihydroxy-2,4-benzaldehyde.

Example 4

Hydrochloride of / ^ pyridyl-3) -2-methyl-3-chromanone-Y1-'2 / -oxyacetic acid (Compound no.19)

by reacting ethylhydroxy-J-propionyl - ^ - phenoxyacetate with pyridine-3-aldehyde.

The following connections are made in the same way:

a) Chlorohydrate of / XPyridyl-4) -2-methyl-3-chloramon-I1-77 "-oxyacetic acid (Compound no.20)

using pyridine-4-aldehyde.

b) Chlorohydrate of / ^ pyridyl-4) ~ 2-chromanone ~ Y1-'2 / -oxyacetic acid (Compound No. 21).

using ethyl hydroxy - ^ - acetyl - ^ - phenoxyacetate.

Example 3
Ethyl (chloro-2'-flavanonyl-7) oxyacetate (compound no.25)

To a solution of 23.8 g (0.1 mol) of ethylhydroxy-3-acetyl-4 ~ 14 g of phenoxyacetate in 130 ml of absolute ethyl alcohol are added (0.1 mol) o-chlorobenzaldehyde and 30 ml of conc. Sulfuric acid.

The mixture is refluxed for 24 hours, the alcohol is evaporated off in vacuo and the residue is taken up in ethyl acetate. After this Neutralize the solution with an aqueous bicarbonate solution is decanted, the organic phase with demineralized Washed with water and dried over sodium sulfate.

The ethyl acetate is evaporated in vacuo. Yield: 84 %.

309808/1384

The following connections are made in the same way;

a) Ethyl (methyl-3-dimethoxy-3 ', 4'-flavanonyl-7) -oxyacetate (Connection Mr. 24) "

by converting ethyl hydroxy-3 ~ propionyl-4-phenoxyacetate) with dimethoxy-3,4-benzaldehyde.

b) ethyl (chloro-3'-flavanonyl-7) oxyacetate (compound 2Jr. 26) by reacting hydroxy-3-acetyl-4-ethylphenoxyacetate with Chloro-3-benzaldehyde.

c) ethyl (dichloro-2 ', 6'-flavanonyl-7) oxyacetate (compound .No. 27)

using dichloro-2,6-benzaldehyde.

d) ethyl- (nitro-3'-flavanonyl-7) -oxyacetate (compound Nrv23) using nitro-3-benzaldehyde.

e) ethyl- (trimethoxy-2 ', 4 ^l , 6 ^l -flavanonyl-7) - ^> oxyacetate (compound ITr. 29)

using trimethoxy-2 _t 4, S-benzaldehyde

f) Ethyl- (dichior-2 ', 4'-flavanonyl-7) oxyacetate (compound ITr. 30) '.

using dichloro-2,4-benzaldehyde.

g) ethyl- (trimethoxy-2 ', V _J 5'-fla ⁱ vanonyl-7) -oxyacetate (compound ITr. 31)

using trimethoxy-2,4,5-benzaldehyde. h) ethyl (hydroxy-4 ^l -flavanonyl-7) -oxyacetate (compound ITr .. 32) using p-hydroxybenzaldehyde.

i) Ethyl (trihydroxy-2 ', 4', 5 ^! ~ flavanGnyl-7) oxyacetate (compound no. 33) 'using trihydroxy-2,4,5-benzaldehyde. d) ethyl (dimethoxy-3's4'-flavanonyl-7) oxyacetate (compound no. 34)

using dimethoxy-3 ^ -benzaldehyde.

k) ethyl (methoxy-4'-flacanonyl-7) oxyacetate (compound no. 35) using p-methoxybenzaldehyde »

1) ethyl (methylenedioxy-3 ', 4'-flavanonyl-7) oxyacetate (compound No. 36) · using methylenedioxy-3> 4-benzaldehyde.

309808/1384

m) ethyl (fluoro-4'-flavanonyl-7) oxyacetate (compound no. 37) using p-iluobenzaldehyde.

η) ethyl- (ciilor-4'-flavanonyl-7) -oxyacetate (compound no. 38) using p-chlorobenzaldehyde.

o) ethyl- (dichloro-2 ', 4'-methyl-3-flavanonyl-7) oxyacetate (compound no. 39)

by. Implementation of ethyl (hydroxy-3-ρropionyl-4) -phenoxyacetate with dichloro-2,4-benzaldehyde.

p) ethyl (trimethoxy-2 ', 4', 6'-methyl-3-flavanonyl-7) oxyacetate (Compound no.40)

using trimethoxy ~ 2,4,6-benzaldehyde. q) ethyl (nitro-3'-methyl-3-flavanonyl-7) oxyacetate (compound No. 41)

using nitro-3-benzaldehyde.

r) ethyl (hydroxy-2'-methoxy-3 ¹ -methyl-3-flavanonyl-7) -oxyacetate (compound no. 42)

using hydroxy-2-methoxy-3-benzaldehyde. s) ethyl (dimethyl-4 ¹ , 3-flavanonyl-7) oxyacetate (compound no. 43)

using methyl-4-benzaldehyde. t) ethyl (methylenedioxy-3 ₎ 4'-methyl-3-flavanonyl-7) oxyacetate (compound no. 44)

using methylenedioxy-3,4-benzaldehyde. -u) Ethyl- (hydroxy-2'-dichloro-3 ', 5'-roethyl-3-flavanonyl-7) -oxyacetate (compound no. 45)
using (hydroxy-2-diochloro-3,5) -fcenzaldehyde.

Example 6

(Dichloro-2 ', 6' ~ ethoxycarbonylmethoxy-7-flavanonguanylhydrazone-4) chlorohydrate (Compound No. 47) ■

35.7 g (0.11 mol) of ethyl (dichloro-2 ¹ , 6 ^f -flavanonyl-7) oxyacetate and 13 »6 g (0.1 rlol) of iminoguanidine carbonate are suspended in 200 ml of absolute ethyl alcohol. 10 ml (0.1 mol) of conc. HCl and refluxed for 24 hours.

309808/1384

After evaporation of the alcohol, ether washed yield: 92 %.

The following connections are made in the same way:

a) (Nitro-3 '-ethoxycarbonylme] thoxy-7-flavanonguanylhydrazone-4) chlorohydrate (Compound No. 46)

using ethyl (nitro-3'-flavanonyl-7) oxyacetate.

b) (Clilor-4 '-ethoxycarbonylmethoxy ^ -flavanonguanylhydrazone ^) - chlorohydrate (Compound no.48)

using ethyl (chloro-4'-flavanonyl-7) oxyacetate.

c) (Trimethoxy-2 ', 4', 6 '-ethoxycarbonyltiiethoxy-7-fivanonguanylhydrazone-4) chlorohydrate (Compound No = 4-9) using ethyl (trimethoxy-2 ', 4', 6'-flavanonyl-7) oxyacetate. . .

E e i sp i e 1 7

Liiclilorhydrat der / ~ (Pyridyl-4) -2-flavanonguanylhydra2on-11-27-oxyacetic acid (Connection Mr. 22)

For the preparation, compound no. 21 is reacted according to Example 1 with aminoguanidine carbonate.

In the same way the nitrate of (chloro-4'-methyl-3-flavanonguanylliydrazone-4-ΪΙ-7) -oxyacetic acid received, (connection no. 2_ "y

nriter use of the nitrate of amino guanidine in nitric acid (and not HCl) and the compound no. 9

Example 8

^ Dimethoxy-3 ', 4'-hydroxy-7-flavanone- (N-imidazolinyl-2-hydrazone) -47-iodohydrate. (Connection Mr. 3)

The mixture is heated at reflux 30 g (, 1 part) of dimethoxy-3 ^t , 4'-hydroxy-7-flavanone and 22.8 g (, 1 mol) of the iodohydrate of hydrazine imidazoline for 20 hours in 200 ml of absolute

309 8 08/1384

ßAD GRlQfNAt

Alcohol.

After the alcohol has been removed under vacuum, you take it with you hot benzene and filtered the precipitate. Yield: 85%

Using the chlorohydrate of hydrazineimidazoline, the corresponding derivatives are obtained as chlorohydrates.

Example 9

Dihydroxy-7,4'-flavanonthiosemicarbazone - ^ - chlorohydrate. (Connection no.1)

25.6 g (0.1 mol) of dihydroxy-4- ', 7-flavanone are heated to reflux and 9.1 g (0.1 molI) thiosemicarbazide for 6 hours in 150 ml of absolute ethanol in the presence of a few drops conc. HCl.

The alcohol is removed under vacuum and taken with 100 ml of benzene and lets a stream of hydrochloric acid gas through the suspension. It is filtered and washed with ether. Yield: 87%.

In the same way i ¹ uryl-2-hydroxy-7-chromanonthiosemicarbazone-4-chlorohydrate (compound no. 2) is obtained by starting from l ¹ uryl-2-hydroxy-7-chromanone.

Example 10
Diethylamine (chloro-4'-flavanonyl-7) oxyacetate (Compound No. 18)

33.2 g (0.1 mol) of (chloro-4'-flavanonyl-7) -oxyacetic acid are suspended in 200 ml of absolute ethanol. 8 g (0.11 mol) of diethylamine are added and the mixture is refluxed until dissolved (approx 1/2 hour).

After filtering the solution obtained in <fer heat, the alcohol is removed under vacuum and taken up with anhydrous ether. Yield: 50%.

309808/1384

■ Η

VO

in he »

O LH

CM O

in

ο ο

CM

CM
. = 3

t - O

CTi

VO

ιη

VO

τΗ

ΟΛ

VO

ο

KN

LH

• Η
ΟΛ

Ln

OO

QO

Ln

ιη

νο

Ln

VO

VO

"1

co

CM CXJ

VO

VO KN CM

ON

ιη

σ- \

KN

OJ

CM
CVI

Ln

CM CM

to O

ON

■ Η

IA-

r νο

KN

■ Η

CM

"in

ON VO

O O KN Λ

KN

KN

CM

CM
CNJ O ~ *

S!

W 3

ο IU J

CM

V ^

H
O

CM

CM

ix!

-μ

• a

CM

KN VO

Table I (continued)

Produki
n °

CH "- COOH

R "

R "

V Λ-Ρ

Elemental analysis

F ⁰ C

101.5

Calculated

Found

62.10

H%

4.92

NiS

C%

65.09

M9 "

10

IL

- COOH

- COOH

CH ₀ - COOH

CH ₂ - COOH

CH.

Cl

Cl

97.5

54.20

4.03

CH-

Cl

95.1

59.30

4.69

OH

CH,

OH

93.9

57.15

4.26

OH

CH,

OH

149.3

62.40

5.22

54.87

59.48

57.15

4.67

■, 3-0

62.95

12 CH ₂ - COOH

CH,

143.1

62.40

5.22

OH

62.34

5.20

Table I (port setting)

co

CD

cb

OO

CO CQ

Produki

14th

15th

J. D

Ib

- COOH

- COOH

- COOH

- COOH

OIL - COOH

₀ - COOH

COOE

H .

R "

CH.

CH.

J / \

CH.

CiL

It t

NO

- \ - J- OH

OH

// Λ

Cl.

P ⁰ C

98.9

33 ·,

<30

<30

190

95

Elementaraaalys e

Calculated

61 ₅ 5O

65.5.0

.57.51

58.60

62.20

55.55

ÜÄ.

..67

4.56

4.63

5.16

5.96

4.94

3.73

3.4:

.3.82

Found

r.%

62.17

65.75

57.54

58.21

69.54

63.00

55, ö

YES.

5.60

5.21

4.46

4.55

5.48

5.72

5.06

3.47

3.06

3.78

CO CD OJ

Table I (port network g)

product

η ¹

R ^r

R "

R "'

P ⁰ C

_ Elementary analysis
Calculated

c%

E%

Found

C%

JtI ic

20th

- COOH

80

55.55

4.94

3.82

54.98

5.13

3.67

Cl

21

CH ₂ - COOH

<30 54.20

4.5!

3.96

54.39

4.56

3.86

CO CO CD CO

22nd

CH ₂ - COOH

N-NH-C, 2HCl

<30

44.10

Cl

5.01

!, 12

43.93

5.14

15.46

23

- COOH

N-NL-C,

ENT

> 300

47.16

4.58

14.47

47.07

4.59

14.47

24

H ₂ -COOC ₂ H

₂ H ₅

68, p

65.99

i, 04

OCH ^

66.09

5.8ö

25th

H _{0 0} H -COOC ⁰¹ ά

2

54

63.28

4.75

63.90

4, ö5

CD CD CO LO

Table I (continued)

ο co co

CD OO

00

a?

Product:
ri ⁰ R. Z R ' R " R "' P ⁰ C Element ar aii
Calculated CSS E% N% • alyse
Found E% m 26th CH ₂ -COOC ₂ H ₅ 0
i H H / - <" ^C1
"" VV <30 63.28 4.75 C% 4.62 27 CH - C00C.JL
C, 4-P Q H H ci- ^ ¹⁷ ^ <30 57.74 4.08 63.07 4.58 28 CH ₀ -COOC ₀ H _n
2 2 5 0 H H ^ NO ₂ . 62 61.45 5.22 3.75 57.10 5.45 3.60 29 CH ₂ -COOC H ₅ 0 H H OCH ,,
-y ^ VoCH
OCH ^ """^ «30 63.45 5.81 * 61.75 6.03 30th CH ₂ -COOC ₂ H 0 H H Cl
- © -01 30th 57.74 4.08 62.95 4.55 CH ₂ -COOC ₂ H ₅ 0 H H OCH ₃ .
DCH ₃ <30 63.45 5.81 57.90 5.61 62.90

TsJ NJ CO CO CD CO

Table I C Continuation)

product

R '

R "

R "

P ⁰ C

Elemental analysis

Calculated

E%

Found

c%

E%

M-OH

<3ü

66.66

5.30

6β, 4ο

5.34

33

CH ^ -COOCH

25th

OH

0 \ V OH

OH

<30

5Ö.1Ö

5.45

58.30

5.15

O CO CD O OO

34

CH, -

' ^y y och.

<50

65.30

5.74

64.78

5.6ö

35

OCH _n

<30

61.15

5.92

63.07

6.29

36

CH ₂ -COOC ₂ H ₅

50

64.67

4.89

64.74

4.90

37 H ₂ -COOC ₂ H ₅

<30

66.23

4.8ö

66, Sun

4.88

CJ CO CD CjJ LO

product

Table I (continued)

R '

R "'

P ⁰ C

Elementals

Calculated

E%

Found

C%

E%

3Ö

2

V ei

<30

63.20

4.75

4.46

• 39

CH ₀ -COOG _n H ₁ .

CH.

Cl

egg

<30

53.69

4.47

4.49

4ύ

CH ^ -COOC ₀ H ₁

CH,

OCH,

dch

<30

64.18

6 ₃ 09

64.40

41

CH,

<30

NO,

62,]

33

4.97

3,6.4

61.53

4.79

3.55

42

CH "-COOC_H

d i

^CH 3

f / Λ

QffOCH-

<30

65.28

65.13

43

CH ₂ -COOC ₂ H ₅

CH,

<-30

71.17-

■ 6.26

70.56

6.37

CO CD CO LO

product
ο 4η R. Z R ' R " R ™ P ⁰ C , Elemental analysis E% N ^ Found 0% 5.64 N ^ η 45 CH-COOC ₂ H 0 H CH ₃ <30 Calculated 5.24 65.07 4.21 ■ 46 ( CH ₂ -COOC ₂ H 0 H CH ₃ oh 'ei <30 c% 4.44 53.93 4.71 ω
Ct. 47 ( IH ₀ -COOC ₀ Hj-
2 do .NH
W-NH-C, HCl H H <30 65.62 4.78 15.10 51.08 4.82 15.18 19808/1 48 C JH ₀ -COOC ₀ H _n
2 2 5 .NH
N-NI.-C ^, HCl H H > 70 53.79 4.34 11.49 49.08 5.36 11.53 314 49 0 ; h "-cooc η N-NH-C, HCl H H <30 51.78 5.37 11.45 48.04 6.06 11.63 I ₂ -COOC ₂ H ₅ yNH
N-NH-C, HCl
Λ NH ₂ H H OCH.
Jj) -OCH ₃
ochT <30 49.25 ■ 5.94 10.62 52.61 10.50 43.20 52.66

Example 11

Measurement of the cardiovascular effect.

The action of the compounds according to the invention is determined on breathing and general metabolism as well as on the heart and blood pressure of a chloralized (chloralise) Dog.

EIg. 1 and 2 are diagrams showing the results of experiments ■ on the cardiovascular properties of Compounds No. β after injections with different concentrations.

At S ¹ Ig. 1 are from top to bottom the intratraeheal pressure (E), the recurrent thigh pressure (pression femorale recurrente) (PS ¹ ) ', the general blood pressure ₉ registered in the right femoral artery (PA) ₈ and the elasticity of the heart (force contractile deu coeur) '(S ¹ CCQ, a female dog of 10.5 K, anesthesia with chloralose, recorded. ”The dog's pulmonary and gastric nerve was intact. Artificial respiration was used.

Fig. 1 is divided as follows:

I: ¹ y. : Injection into the rose vein of 1 mg / kg compound

II:. : 20 minutes after I ".

/ j I

III: '2 ^: Injection into the rose vein with 1 mg / kg of the

Compound No. 5
* 50 minutes after T •, ·
IV: -zi injection into the rose vein with 5 mg / kg of the

Compound No. 5 · α

40 minutes after j ₂ °

V; : 20 minutes after ^ _x . .

_Λ ο "

VI: ■: 42 minutes after

At fflgc 2 the following are plotted from top to bottom: I ¹ GC, Pi-, PA

309808/1384

-22 and R of a sick dog of 15> 6 K, anesthesia with chloralose.

A bivagotomy, artificial breathing, and denervation are performed the main artery sinus (denervation of the carotid sinus) by.

Fig. 2 is divided as follows:

I \ _Λ : injection into the rose vein with 1 mg / kg of the

Compound No. 5

II Λ : 20 minutes after f ..

III L: injection into the artery with 1 mg / kg compound

No. 5

40 minutes after P _Λ .
,: Injection into the rose vein with 5 mg / kg of compound no. 5
20 minutes after

V: 20 minutes after

VI: 30 minutes after

VII: 40 minutes after /] V ,. VIII:: 70 minutes after vu.

The following effects were achieved:

a) stimulating the breathing: reinforcement of the breathing rhythm, oxygen consumption and carbon dioxide formation.

b) strengthening the heart: increasing the activity of the heart,

c) moderate decrease in blood pressure over a long period of time.

Among other things, the compound has a particularly low toxicity. DL 0 is higher at 1200 mg / kg per os in the mouse.

Example 12

Measurement of the antihypertensive effect.

nan determines the effect of the compounds on blood pressure

309808/1384

- 23 von. Hatten, anestbesie with ethyl methane. . ·

The connection, no. 20 causes at a dose of 20 mg / kg, injected intravenously, a remarkable decrease in pressure.

Example 13 »'''

Measurement of the analgesic effect.

The effect is determined with the test by Siegln and (Siegmund E; Cadmus R, "A method for evaluating both, non narcotic and narcotic analgesics". Proc. Soc. Exp. ELoI. 1957 »" b-j 2J? J 729-731) ·. · '

Injection of an irritant, phenylbenzoquinone in 0.02% strength Solution in the peritoneum of the mouse determines the 'stretching and turning movements (writhing syndrome), the frequency of which is determined by the preventive analgesic effect is reduced.

The compounds are injected orally 3P minutes before the irritant administered, lian represents the number of stretches between the 5th and 10th minute after the injection of the phenylbenzoquinone and calculates the percentage of animals that are favored. A mouse is considered to be favored if it has at least Do 5 stretches in 5 minutes.

Product Severe toxicity Dose administered % Protection Hr. PO mouse mg / kg

DL 50 mg / kg - -

23 '> 12OO. 300 · 70 ■ ·

27> 12OO. 300 .40

46 "^ 1200 200 5 °

These compounds have an analgesic effect at high doses Effect and against a weak toxicity.

303808/138 *

B e i s ρ i e 1 14

The effect on the vascular permeability of the hat whose back and loins were depilated is determined after Lefebvre method: "Lefebvre R. and coll., CR. Üoc. Biol, 1, (1962), 183-186.

Trypan blue becomes intraperitoneally at a concentration of 50 mg / kg injected.

After 3 hours, inject intradermally in everyone's back Animals 0.1 ml of a 0.5% solution of histamine chlorohydrate and determines the time in which the blue color appears in the area of the papule.

Compound No. 5 and the product of reference (anthocyanosides von Vaccinium Myrtillus) are administered at a dose of 15 mg / kg intraperitoneally for 24 hours and 90 minutes administered before the injection of the histamine.

The average time for the blue color to appear in the papule area is determined.

The results show that compound no. 5 delays the appearance of the blue color in 60% of the tests.

This effect is comparable to that obtained with the anthocyanosides under the same conditions.

Example 15 »

For the production of therapeutically usable compressed products advantageously the following composition is used:

3098U8 / 13 84

The compressed file consists of: ■

Compound No. 5. 0.100 g.

Diatomaceous earth 0.100 g

Sugar 0.40 g

(Talc 0.0 ^ 5 g

Starch 0.015 g

Magnesium stearate 0.005 g

2 to 3 compresses are administered per day. Example 16

Gelatin capsules:

0.250 g of compound no. 5 are used in one capsule « Administration 1 to 2 capsules per day.

■ B e i. s ρ i el 17

Injectable solution:

Compound No. 5 10 mg
, Water qsp 1 ml

The injections can be intramuscular or intravenous.

The invention is not limited to the examples given and in numerous embodiments within the scope of Claims possible.

Patent claims:

309808/1384

Claims (9)

- 26 patent claims in the E means: 1) a hydrogen atom 2) a grouping of the general formula: - (CE ^^ - COOE ^, in which R ₂ and E can be a hydrogen atom or a methyl group, and η is 1, 2 or 5; E. means: 1) a water atom: the acids formed in this way can be neutralized with organic bases such as secondary amines or mineral bases (NaOH etc.); 2) a lower alkyl radical; E ¹ means: 1) a hydrogen atom, 2) a hydroxyl group or an alkoxy group; E "means: 1) a hydrogen atom, 2) an alkyl radical; R "'means: 1) an aryl radical, which is optionally substituted z. B. by a phenyl group of the general formula II: 309808/1384 (H) in which R ^ ,, R ₁ -, R ^, R ₇ and / or Rg can be identical or different and represent a hydrogen atom, a halogen atom, a lower alkyl radical, a hydroxyl group, alkoxy group, nitro group; two substituents can form a cycle "for example Rg and Rr ₇ to form a methylenedioxy group, 2) ■ a pyridine nucleus, the nucleus in 2-, 3 "or 4-ötellu3qg is bound, and acidic salts with organic Columns like maleic acid,! Fumaric acid or mineral Acids, such as HCl, 3) a furan nucleus, an optionally substituted thiophene nucleus; Z means: an oxygen atom, a grouping of the formula III: = N-HH-GY, in which X is an oxygen atom, sulfur represents an atom or an amine group NH in which Ϊ is a substituted or unsubstituted one Amine radical is the l'Ormel HH-Rq, in which Rq a substituted or unsubstituted one l'lienyikem means; Z and Ic. can combine to form a Jleüorocyclus, z. B. an imidazole nucleus, which can fjoii) bound with mineralischen acids such as HGl, hydriodic acid, JJNO _{7 and the like.} JjGJ'LvoLf;mm; L · claim 1, characterized in that it au, '. I (.J fjendoij Vox ^ bijidurigeii besliehen: BAD 3098U8 /! 384 / Sydroxy-7- (pyridyl-4) ^ -cliromanonguanylhydrazone - ^ - di- chlorohydrate, / Bimethoxy-3 ¹ , 4 ¹ -hydroxy-7- (£ l & veno: a- (phenyl-4 ~ ßemicarba- Receipt) -4 / -chlorohydrate, Dihydroxy-4 ', 7-flavanone- (phenyl-4-eemicarbazone) -4, (methyl-4'-flavanoyl-7) -oxyacetic acid , (methyl-3-fluorine-4' -f lavanonyl-7) -o3cyeBig acid , (Methyl-3-dichlo2> -2 ', 6'-flavanonyl-7) -oryeeaetic acid, (meth.yl-3-c] ilor-4 ^l -f lavanonyl-7) -oxyesbigic acid ϊ (Methyl-3 - triliydroxy-2 ', 4' _l 6'-flvanonyl-7) -oxyacetic acid, (Methyl-3-liydroxy-4 ~ ^l flavanonyl-7) -oxyessigsaure -oxyeßsigsäure _t (methyl-3-hydroxy-2 · f lavanonyl-7), (Methyl-3-dimethoxy-3 ', 4'-flavauonjrl-7) -ojcyacetic acid _l (Methyl-3-flavanonyl-7) -oxyeesigßäure, (methyl-3-nitro-3'-flavanonyl-7) -oxyeBßigsäureι (dihydroxy-2 ', 4 ^l -flavanonyl-7) -oxyeBigB & ure, Hydrochloride der / tPyridyl-3) -2-methyl-3-chromanon-Y1-27 ~ oxyacetic acid, Hydrochloride of ^ pyridyl-4) -2-methyl-3-chromanon-I1-77- oxyacetic acid, Hydrochloride of ^ JPyridyl-4) -2-chromanon-Yi-2 / -oxyessig- eaure. ethyl- (chloro-2'-flavanonyl-7) -oxyacetate, Ethyl (methyl-3-dimethoxy-3 ', 4'-flavanonyl-7) oxyacetate, Ethyl (chloro-3'-flavanonyl-7) oxyacetate, ethyl (dichloro-2 ¹ , 6'-flavanonyl-7) oxyacetate ₁ Ethyl- (nitro-3'-flavaiioiiyl-7) -oxyacetate | , Ethyl- (trimethoxy-2 ¹ , 4 ', 6'-flavanonyl-7 / -oxyacetate, ethyl- (dichloro-2', 4'-flavanonyl-7) -oxyacetate, ethyl- (trimethoxy-2 ¹ _} 4 ^J - , 5'-fl & vanonyl-7) -oxyacetate, ethyl- (hyaroxy-4'-flavanonyl-7) -oxyacetate, ethyl- (trihydroxy-2 ', 4', 5'-flavaiionyl-7) -oxyacetate, ethyl- ( dimethoxy-3 ', 4'-flavanonyl-7) -oxyacetate, ethyl- (methoxy-4'-flavanonyl-7) -oxyacetate, ethyl- (methylenedioxy-3'i4'-flavanonyl-7) -oxyacetate, ethyl- ( fluoro-4'-flavanonyl-7) -oxyacetate, ethyl- (chloro-4 ¹ -flavanonyl-7) -oxyacetate, 3098Ü8 / 1384 Ethyl- (dichloro-2 ', 4'-methyl-3-flavanonyl-7) -oxyacetate, ethyl- (trimethoxy-2 ¹ , 4', 6'-methyl-3-flavanonyl-7) = oxyacetate, ethyl- ( nitro-3'-methy 1- ^ 3-f lavanonyl-7) -oxyacetate, ethyl- (hydroxy-2 · methoxy-3 ¹ -methyl- 3-flavanonyl-7) -oxyacetate, Ethyl (dimethyl-4 ¹ , 3-flavanonyl-7) oxyacetate, ethyl (methylenedioxy-3 '»4' -methyl-3-flavanonyl-7) oxyacetate, Ethyl- (hydroxy-2'-dichloro-3 ', 5'-methyl-3-flavanonyl-7) -oxyacetate, (Dichloro-2 ¹ , 6 ^l -ethoxycart>onylmethoxy-7-ila'vanonguanylhydrazone-4) chlorohydrate, (Mtro-3 '-ethoxycarborylylmethoxy-7-f lavanonguanylhydrazone- \ 4) -chiourhydrate, (Chloro-4'-ethoxycart) onylmethoxy-7-ilavanonguanylhydrazone-4) -chiorhydrate, (Trimethoxy-2 ¹ , 4 ', 6'-ethoxycar'bonylmethoxy - ^ - flavaiionguanylhydrazone-4) -chlorohydrate, Dichlorohydrate of _J / (pyridyl-4) -2-flavanonguanylhydrazone-Y1-77-oxyacetic acid, Mtrail of (ghlor-4'-methyl-3-flavanonguanylhydrazone-Ϊ1-7) -oxyacetic acid, ^ Tbimethoxy-3 ¹ _} 4 '-hydroxy- 7- flavanon- (N- imidazolinyl-2-hydrazone) -4 / - j οdhydrate, Dihydroxy-7>4'-flavanonthiosemicarbazon-4-chlorohydrate, I ¹ uryl - 2-hydroxy-7- chromium anonthio s emi c arb azon-4-chi orhydrate CChlor-4'-flavanonyl-7) -oxyacetate of diethylamine * 3 · Process for the preparation of the compounds of formula I. according to claim 1, wherein R is a hydrogen atom, thereby characterized in that one is dihydroxy-2,4-phenylalkyl ketone the formula: 309808/1384 R ' CO-CH ₂ E " directly with aldehydes of the structure corresponding to R ¹ ", as defined in claim 1, is reacted. 4. The method according to claim 3, characterized in that dihydroxy-2,4-phenylalkyl ketone (II) is reacted with a benzaldehyde to form a compound (I) in which R ¹ "is a phenyl nucleus which is optionally substituted. 5. Process according to Claim 3, characterized in that dihydroxy-2,4-phenylalkyl ketone (II) is reacted with pyridine-2 or -3 or -4-aldehyde to form a compound (I) in which R ¹ "is a pyridine nucleus is. 6. The method according to claim 3> characterized in that dihydroxy-2,4-phenylalkyl ketone (II) is reacted with a l'uran- or thiophenaldehyde to form a compound (I) in which R " ^{1 is} a gurankern or a thiophene nucleus. 7. Process for the preparation of compounds of the formula I. according to claim 1, wherein R is hydrogen and Z is a group of the formula = N-NH-C-Y, in which Σ and Y is the Il Corresponding to the definition in claim 1, characterized in that the reaction products between dihydroxy-2,4-phenylalkyl ketone (II) and the aldehydes as obtained according to claims 3 to 6 with a compound the general formula - NH ₀ -NH - C - Y t- Il X treated. 3098Ü8 / 1384 8. Process for the preparation of compounds of the formula I. according to claim 1, wherein E is a grouping represents, characterized in that dihydroxy-2,4 ^ · phenyl alkyl ketone (II) with a halogen compound of the lyp CpHc-COO-CHpBr converts under. Formation of the intermediate of the formula GH CpH ₅ -OCO-CH ₂ O and that the product obtained is treated by the process of claims 4 to 7 according to the values for R ^m and Z in general formula I of the compounds obtained. - - ■. 9. Medicinal cardio-tonic, respiratory and antihypertensive drugs Action, characterized in that it contains at least one active compound according to the claims 1 or 2 included. The patent attorney 98U8 / 1384