DE2142196C3 - 3- (N-acyl-indoly I) -acetic acid derivatives, process for their production and medicinal products - Google Patents

Description

Common Formula 1

(CH ₁ ),

CH ₂ - COOR ₂

(D

10

(It

CO

CH ₃

in which X is an oxygen atom or a methylene group, R ₁ —CO is a cinnamoyl, p-methyl, p-fluoro or p-chlorobenzoyl, I '-indancarbonyl-, S'-indanecarbonyl-, S'-indanecarbonyKCyclopropancarbonyKu-chlorophenylacetyl-, 2' -Furanacryloyl, 3 ', 4'-methylenedioxybenzoyl or nicotinoyl group and R ₂ denotes a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms and n has the value 1 or 2, and their pharmacologically acceptable salts.

2. Method of making the connections according to claim 1, characterized in that an N'-acylphenylhydrazine is used in a manner known per se of the general formula II

(11)

i5 .offaiom or a methylene group in which X is an oxygenatornod. _f _ ^

R ₁ -CO a CinnamoyU P,. ₅ '-lndancarhop-Chlorbenzoyk>-'"^J." -Chlorphenylacetyk nyl-, Cyclopropancarbo ^ _oxybenzoyl . _{O (kr}

T-furanacryloyi-, - ¹ > ** hydrogen atom or

Nicotinoyl group una £ 2 _Koh , _ensto ff _a tomen bepinen alkyl radical with I m * ^ _η ^ _{and their pharma} .

a

(St.

35

in which X, R ₁ —CO and ti have the meaning given in claim 1, with a levulinic acid derivative of the general formula III

CH ₃ -CO-CH ₂ -Ch ₂ -COOR ₂ (111)

in which R _{2 has} the meaning given in claim 1, condensed and, if appropriate, the compound obtained is converted into a salt by reaction with a base.

3. Medicinal preparations consisting of a compound according to claim 1 and pharmaceutical common carriers and auxiliary materials.

λ - R -CO and η have the above meaning "with a levulinic acid derivative" of the general

Formula IH

CH ₃ -CO-CH ₂ -CH ₂ -COOr ₂ (HD

in the R ₂

can the group

(CH ₂ ) ,,

It is known that some indolyl carboxylic acid derivatives have valuable anti-inflammatory properties. However, these connections have the disadvantage. 60 ücsuiiuui. «W _o

that they have a fairly high toxicity and are included in Formula 1 as a group

Occult bleeding often occurs in animal experiments at high doses

cause. It was therefore the object of the invention.

to create new S-indolylcarboxylic acid derivatives which "., ■

high anti-inflammatory activity. 65 ² '\

at the same time, however, a low toxicity and the X - ■

Distinguish the absence of side effects. This up-

i ': ihe is solved by the invention. a methylenedioxy ade trimethylcngruppe.

X -

IO

The N'-acylphynylhydrazine derivatives used according to the process of the general formula II are new compounds that are prepared by known processes can be.

The «» condensation of the N-acylphenylhydrazine

^U i- I 11 ^ U Ar.rr I Si.i.lmr:; .. r »J _n ,;, .., i

general rum · »- · ·· ■"·>«<-"'"-uui ^ unuuMii / jer all common formula III takes place in the presence or absence of condensation agents and organic solvents

Although the condensation proceeds smoothly even in the absence of solvents, it will in many cases preferably in the presence of solvents such as Omani acids, e.g. B. acetic acid, formic acid, Propionic acid, lactic acid or butyric acid, non-polar organic solvents such as cyclohexane, p-hexane, benzene or toluene, or polar organic Solvents such as dioxane or N, N-dimethylformamide, worked. If alcohols are used as the solvent, the corresponding one is obtained Esters of indole acetic acid.

The condensation is preferably carried out at temperatures of 50 to 200 ⁰ C, preferably 65 to 95 ° C. The reaction takes place rapidly and is generally over after a short time, usually after 1 or 2 hours. Preferably, in the presence of condensing agents such as inorganic acids, e.g. B. hydrochloric acid, sulfuric acid or phosphoric acid, metal halides ^ z. B. zinc or copper chloride, heavy metal powders, e.g. B. copper powder, Grignard reagents, e.g. B. boron fluorides, polyphosphoric acids or ion exchange resins worked. Hydrochloric acid and similar condensing agents are used in equimolar amounts or in excess, while z. B. copper powder is used in much smaller quantities.

After the reaction has ended, the Rcaktionseemisch is left stand at room temperature or in a refrigerator at around 5 ° C. This separates the compound of the general formula 1 is crystalline away.

If no crystals are obtained, the reaction mixture is concentrated under reduced pressure or mixed with water, acetic acid, water or petroleum ether. In this way it is always possible to get crystalline Products to receive. For recrystallization, ether, acetone, Acetone - water, ethanol, ethanol - water. benzene and acetic acid are used. The crystalline product is filtered off and washed with aqueous before drying Acetic acid, ethanol — water, water or petroleum ether. In general the connections are crystalline. However, sometimes the esters are obtained in an oily form.

The free acids of the general formula 1 can be converted into the corresponding with bases under mild conditions Salts are transferred. Special examples si.id the alkali and alkaline earth salts, z. B. with sodium, Potassium, magnesium, barium or calcium, aluminum salts, heavy metal salts, e.g. with zinc and Iron, or salts of organic amines, such as dimethylamine, Morpholine, choline, diethylaminoethanol, methylcyclohexylamine, histidine, arginine, lysine. Thiamine, Pyridoxamine or glucosamine.

The compounds of general formula I, in particular the free acids and salts, have excellent properties antipyretic, analgesic and anti-inflammatory properties. You can go to treatment of rheumatic and other inflammatory diseases as well as for prevention or suppression used by inflammatory processes. The compounds of the invention have one significantly greater activity than known compounds, like phenylbutazone. At the same time, they have a significantly lower toxicity than indomethacin. Even at high doses of 500 mg / kg when administered orally, they cause in rats and mice hardly any toxic symptoms and occult bleeding in the faeces. The experimentally produced carrageenin edema on the rat hind paw is strongly suppressed by the compounds of the invention. Here the compounds of the invention show an extremely high activity, as can be seen from the table can be deduced:

connection

dose

line kgl inhibition of

Canngcenin

LIX ₁₁ Ll) ₅ ,

(mg kgl p. o. (mg kgl p. o.

Indomethacin

Phenylbutazone

Benzydamine · HCI

1-Cinnamoyl ^ -melhyl-S ^ -mclhylenedioxy-3-indolyl-acetic acid

1- (p-Methylbenzoyl) -2-methyl-5,6-methylenedioxy-3-indolyl-acetic acid

10
20th

50
100
200

400 600

20th

50

KX)

200

20th

50

KX)

2 (X) 4.1.6
56.4
67.5

30.0
40.9
62.7

20.0

45.5

60.0
60.5
70.0
8-ί, ί

67.8
65.5
70.0
85.0

8 29? .6

230 720. 3.2

> 4oo 1050 <::. 6

IX> 30 (X)> 166.7

7> 2 (XX)> 285.7

connection

Hp-chlorobenzoyl ^ -methyl ^ o-cyclopenteno-3-indolyl-acetic acid

l- (p-Chlorobenzoyl) -2-methyl-5,6-ethylenedioxy-3-indolyl-acetic acid

1- (p-Chlorobenzoyl) -2-methyl-6,7-dihydrofuro [2,3-f] -3-indolylacetic acid

! - (p-Chlorobenzoyl ^ -methyl-S ^ cyclohexeno-3-indolyl-acetic acid

1- (p-Fluorobenzoyl) -2-methyl-5,6-methylenedioxy-3-indolyl-acetic acid

I - (1 '-indanecarbonyl) -2-methyl-5,6-cyclopenteno-3-indolylacetic acid

I-Cyclopropanecarbonyl ^ -methyl-S ^ cyclopenteno-3-indolylacetic acid

1- (u-Chlorophenylacetyl) -2-methyl-5,6-cyclopenteno-3 indolylacetic acid

1- (2'-Furanacryloyl) -2-methyl-5,6-cyclopenteno-3-indolylacetic acid

1- (3 ', 4'-methylenedioxybenzoyl) -2-methyl-5,6-methylenedioxy-3-indolyl acetic acid

1- (5'-Indaricarbonyl) -2-methyl-5,6-methylenedioxy-3-indolylacetic acid

1-Nicotinoyl ^ -methyl-S.o-methylenedioxy-3-indolylacetic acid

Isopropyl l- (p-methylbenzoyl) -2-methyl-5,6-ethylenedioxy-3-indolylacetate

21 42 196 γ 6th ED ₅ ,, LD ₅ ,, dose Inhibition of
Carrageenin
edema (mgkg) [>. ii. (mg kg I ρ. ο (mg / kg) (%) 7th > 2000 20th
50
100
200 67.5
70.5
75.2
80.6 7th 2000 20th
50
100
200 68.0
70.5
75.5
80.0 40 > 4000 20th
50
100 48.5
53.0
55.7 . 15th > 3000 20th
50
100
200 59.8
60.2
68.5
85.0 14th > 2000 20th
50
100
200 60.0
64.7
70.5
82.0 45 > 20 (K) 20th
50
100 45.0
55.3
60.5 19th 3000 20th
50
100 53.2
60S
75.0 13th 15 (K) 20th
50
100 60.0
66.5
78.3 15th 2000 20th
50
100 58.2
60.8
75.2 20th 3000 20th
50
100 50.0
55.0
70.2 23 > 2000 20th
50
100 48.0
54.3
62.0 18th 2000 20th
50
100 50.5
62.3
72.0 13th 1000 20-
50
100 60.0
68.2
75.0

285.7

142.9

> 44.4

157.9

133.3

150

> 86.9

The examples illustrate the invention. All wave numbers refer to the IR absorption.

example 1

a) A solution of 13 g of 3,4-methylenedioxyphenylhydrazine 4.1 g of acetaldehyde are added dropwise to 100 ml of diethyl ether at 0 to 5 ° C. for 20 minutes (8 ()%) added. The reaction mixture is then heated at 0 to 5 ° C. for a further 2 hours stirred, then the ethereal solution is separated off, dried over sodium sulfate and evaporated. At the Distilling the residue gives 11.5 g of acetaldehyde-3,4-methylenedioxyphenylhydrazone from Kp.

to 113 to 115 C / 0.07 Torr:, ■ "", "= 3300, 2850, 1620 and 920 cm "'.

b) A solution of 2 g of the phenylhydrazone from a) in 2 g of pyridine and 50 ml of diethyl ether is at 0 to 5 "C dropwise with 1.96 g of p-clilobenzoyl chloride offset. The reaction mixture is stirred for 2 hours at 0 to 5 ° C. and for 5 hours at room temperature and then poured into water. The crude product obtained gives 3 g on recrystallization from ethanol

Acetaldehyde-N ¹ - (p-chlorobenzoyl) -3,4-methylenedioxyphenylhydrazone with a melting point of 143 to 145 ° C; v _nulx = 1640, 1620 and 1580 cm- ¹ .

c) Hydrogen chloride gas is passed into a solution of 1.8 g of the N'-acylated phenylhydrazone from b) in 40 ml of ethanol for 3 hours at 0 to 3 ° ^{C. The ethanol is then removed at 20 to 25 °} C. under reduced pressure 300 ml of diethyl ether are added to the residue, 1.99 g of N'-fp-chlorobenzoylKM-methylenedioxyphenylhydrazine hydrochloride with a melting point of 189 to 190 ° C. (decomposition); N'-cinnamoyl-3,4-methylenedioxyphenylhydrazine hydrochloride,
F. 190 to 191'C.

v _max = 1670 and 1580 cm "

d) A mixture of 1.9 g of the phenylhydrazine hydrochloride from c) and 20 g of levulinic acid is ^{heated to 55 to 60 °} C. for 1 hour and to 80 to 90 ^° C. for 3 hours. After cooling to room temperature, the reaction mixture is poured into 200 ml of water. The precipitate is filtered off and washed with water. Recrystallization twice from acetone-water (5: 1) gives 1.19 g of 1 - (p - chlorobenzoyl) - 2 - methyl - 5,6 - methylenedioxy-3-indolylacetic acid with a melting point of 217 ° to 218 ° C .; r _max = 1700, 1680 and 1580 cm " ¹ .

e) A solution of 1.2 g of the 3-indolylacetic acid from d) in 50 ml of acetone is added dropwise at 0 to 2 ° C. with a solution of 0.132 g of sodium hydroxide in 10 ml of water. The reaction mixture is stirred for a further 2 hours at 15 to 20 ^° C. and then filtered. The filter residue, after washing three times with 10 ml of acetone, gives 1.2 g of the sodium salt of 1 - (p-chlorobenzoyl) -2-methyl-5,6-methylenedioxy-3-indolylacetic acid: r _max = 1680 and 1560 cm " ¹ .

According to example 1 b), the following compounds are produced:

35

Acetaldehyde-NMp-fluorobenzoyn-S ^ -melhylcndioxyphenylhydrazone.
'■ max = ¹⁶⁶ O, 1620 and 1600 cm " ¹ ,
Acetaldehyde-N ^ cinnamoyl-S ^ -methylenedioxyphenylhydrazone, 4 ° ■

F. 140 to 142 ° C,

Acetaldehyde-N ¹ - (3 ', 4'-methylenedioxybenzoyl) -3,4-methylenedioxyphynylhydrazone,
r _max = 1640, 1610 and 1600 cm " ¹ .
Acetaldehyde-N '- (5'-indanecarbonyl) -3,4-methylcenedioxyphenylhydrazone.
F. 151 to 153'C.

Acetaldehyde-N ¹ -nicotinoyl-S ^ -melhylenedioxyphenylhydrazone.

F. 138 to 139.5 ° C,

Acetaldehyde-N ¹ - (2 '-furanacryloyO-S ^ -melhylcndioxyphenylhydrazone,
F. 164 to 166 ° C,

Acetaldehyde-N ¹ - (I '-indancarbonyU-SAmethylenedioxyphenylhydrazone.

M.p. 168 to 171 ° C, and
Acetaldehyde-N ^ cyclopropanecarbonyl-3,4-methylenedioxyphenylhydrazone.
F. 171 to 17.VC.

According to example 1 c), the following compounds are established:

NMp-Fluorbcnzoylj-S ^ methylenedioxyphcnyl-

hydrazine hydrochloride,

v _max = 1600 and 1070 cm- ¹ . . .

N ¹ - (p-methylbenzoyl) -3,4-methylenedioxyphynylhydrazine hydrochloride.

. · = 1660 and 1600 cm " ¹ .

dioxyphenylhydrazine hydrochloride.

■ """= 1680 and 1690 cm" ¹ , NMS'-indancarbonyl-S ^ -methylenedioxyphenylhydrazine hydrochloride.

F. 203 to 204'C,
N ¹ -Nicotinoyl-3.4-methylcndioxyphenylhydrazine hydrochloride,

F. 213 to 214 ° C,
N ¹ - (2'-furanacryloyl) -3,4-methylcndioxyphcnylhydrazine hydrochloride,

F. 159.5 to 160.7 ° C,
N ¹ - (l'-indanecarbonyl) -3,4-methylenedioxyphenylhydrazine hydrochloride,

M.p. 185 to 188 ° C, and
N ^ Cyclopropanecarbonyl-S ^ -methylenedioxyphenylhydrazine hydrochloride.

F. 190 to 193 ° C.

According to example 1 d), the following compounds are established:

l-cinnamoyl-2-methyl-5,6-methylenedioxy-3-indolylacetic acid,

F. 190 to 191 C,
1- (p-Fluorobenzoyl) -2-methyl-5,6-methylenedioxy-3-indolylacetic acid.

F. 238 to 240 C,
l- (p-methylbenzoyl) -2-methyl-5,6-methylenedioxy-3-indolylacetic acid,

F. 204 to 206 ^r C.
1- (3 ', 4'-methylenedioxybenzoyl) -2-methyl-5,6-methylenedioxy-3-indolylessioic acid.

198 to 200 ° C.
1- (5'-indanecarbonyl) -2-methyl-5.6-methylcndioxy-3-indolylessic acid,

F. 190 to 192 C,
1-NicotinoyW-methyl-So-methylcndioxy-3-indolylessic acid.

F. 229 to 229.5 ¹ C.
1- (l'-indanecarbonyl) -2-methyl-5,6-methylcndioxy-3-indolylessia; acid.

F. 19C to 192 C.
l-CyclopropanecarbonyW-methyl-So-methylenedioxy-3-indolylacetic acid c.

F. 180 to 18.VC. and
Hl'-FuranacryloyH-i-methyl-S ^ -methylcndioxy-3-indolylessic acid.

F. 160 to 162 C. "

Example 2

a) A solution of 17 g of 3,4-ethylenedioxyphenylhydrazine in 100 ml of dietary ether is treated dropwise at 5 to 10 C for 30 minutes with 11 g of acetaldehyde (80%). The reaction mixture is stirred for hours at 5 to 10 ^° C., then the ethereal solution is separated off and dried over sodium sulfate. After evaporation of the ether and the distillation of the residue, 15.4 g of acetaldehyde-3,4-ethylenedioxyphenylhydrazone with a boiling point of up to 142 ^D C / 0.15 Torr are obtained; . · "" = 3400, 2800 to 3000, and 1590cm " ¹ .

b) A solution of 6.4 g of the phenyihydrazone from a) in 3.9 g of pyridine and 50 ml of diethyl ether is made at 0 to 5 C dropwise with 5.2 g of p-methylbenzoyl chloride offset. The rcaklionsucmix is 2 hours

609 608/175

at 0 to 5 C. then stirred for 5 hours at room temperature and then poured into water. After recrystallization from ethanol, the crude product gives 5.8 g of acetaldehyde - N '- (p - inclhylbenzoyl) -3,4 - ethylenedioxyphenylhydrazone with a melting point of 121 to 122.9 ° C .; r _mix = 1650 and 1620 cm " ¹ .

c) In a solution of 5.5 g of the N'-acylierlen Phcnylhydrazons from b) in 30 ml of ethanol is passed at 0 to 5 ° C for hours hydrogen chloride. The ethanol is then removed at room temperature under reduced pressure. After the addition of 200 ml of ether, the residue gives 5 g of N ¹ - (p-methylbenzoyl) -3,4-ethylenedioxyphenylhydrazine hydrochloride with a melting point of 166 to 168 C: r, "" = 1660 and 1600 cm " ¹ .

d) A mixture of 5 g of the phenylhydrazine hydrochloride from c) and 30 g of levulinic acid is ^{heated to 85 to 90 °} C. for 3 hours. After cooling to room temperature, the reaction mixture is poured into 200 ml of water. When twice recrystallizing the crude product from ethyl acetate to give the desired 1 - (p - methylbenzoyl) - 2 - methyl-5,6-ethylenedioxy-3-indolylacetic acid, melting at 170 to 17I ° C; 'r _m "= 1710, 1670, 1610 and 1590cm " ¹ .

According to example 2b) the following connections are established:

Acetaldehyde-N ^ ip-chlorbenzoyO-S ^ -äthylen-

dioxyphenylhydrazone,

F. 184 to 187 ° C,

Acetaldehyde-N'-cinnamoyl-S ^ -älhylenedioxy-

phenylhydrazone,

F. 135 to 137 ° C,

Acetaldehyde-N '- (p-fluorobenzoyl) -3,4-ethylcn-

dioxyphenylhydrazone.

F. 161 to 162 ° C,

Acetaldehyde-N '- (3', 4'-methylenedioxybenzoyl) -

3,4-ethylenedioxyphenylhydrazone,

F. 148.5 to 150 ⁰ C, and

Acetaldehyde-N ¹ - (5'-indanecarbonyl) -3,4-ethene-

dioxyphenylhydrazone,

F. 141 to 142.5 ⁰ C.

According to example 2c) the following connections are established:

N ¹ - (p-chlorobenzoyl) -3,4-ethylenedioxyphenyl-

hydrazine hydrochloride,

ι- = 1670 and 1590 cm " ¹ ,

N -CinnamoyW ^ -äthylenedioxyphenylhydrazine-

hydrochloride,

y _max = 1680 and 1620 cm " ¹ ,

N '- (p-fluorobenzoyl) -3,4-ethylenedioxyphenyl-

hydrazine hydrochloride.

F. 189 to 190 ° C.

N ¹ - (3'.4'-methylenedioxybenzoyl) -3,4-ethylene-

dioxyphenylhydrazine hydrochloride,

M.p. 167 to 168 ° C, and

N ¹ - (5'-indanecarbonyl) -3,4-ethylenedioxyphenyl-

fiydrazine hydrochloride,

F. 203 to 204.5 "C,

I- (3 ', 4'-methylenedioxybenzoyl) -2-methyl-5,6-ethylenedioxy-3-indolylessic acid,
>; _mx = 1730, 1640 and 1610 cm- ¹ , and
1 - (S'-indancarbonyl ^ -methyl-So-ethylenedioxy-

3-indolylacetic acid,
F. 202.5 to 203.5 C.

Example 3

a) A solution of 19.5 g of 2,3-dihydrobenzofuran 5-hydrazine in 100 ml of diethyl ether is ^{treated with 6.2 g of 80% acetaldehyde at 0 to 5 °} C. for 30 minutes. The reaction mixture is stirred for 2 hours at ( Stirred up to 5 ° C., then the ethereal solution is separated off and dried over sodium sulfate. After the evaporation of the ether, the residue is distilled to give 10.5 g of acetaldehyde-2,3-dihydrobenzofuran-5-hydrazone with a b.p. 126 to 128 ° C. (0.05 ° C.) Torr); v _max = 3300, 1600, 1640 and 1660 cm " ¹

b) A solution of 2 g of the hydrazone from a) in 2 § Pyndine and 50 ml of diethyl ether are heated to 0 to 5C mil a solution of 1.9 g of p-chlorobenzoyl chloride in 10 ml of diethyl ether are added. The reaction mixture is 3 hours at 0 to 5 C, then 5 hours at

Stirred at room temperature and then poured into water. The ether layer is separated, with washed three times 30 ml of water and dried over sodium sulfate. After the ether has evaporated you get the acetaldehyde-N'-ip-chlorobenzoyl) - ^ -

dinydrobenzofuran-5-hydrazone in the form of an oil: • ■ max = 1650, 1620 and 1590 cm " ¹ .

c) Hydrogen chloride is passed into a solution of 1.8 e of the N'-acylated hydrazone from b) at 0 to 5 ^{° C. for 1 hour.} Then another 3 hours

stirred at 0 to 5 ° C., then the ethanol is distilled off at 20 to 25 ° C. under reduced pressure. After treatment with 300 ml of ether, the cuckoo results in 1.7 g of N ^! - (p-Chlorobenzoyl) -2.3-dihyclrobenzo-iurane-5-hydrazine hydrochloride.

d) A mixture of 1.7 g of the hydrazine hydrochloride from c) and 30 g of levulinic acid is ^{heated to 85% for 3 hours}

poured into 200 ml of water before cooling to room temperature. The crystalline crude product is made twice

recrystallized from 95% ethanol. The desired 1- (p-Chlorbcnzoyl) -2-methyl-6.7-dihydroiuro- [2.3-f] -3-indolylacetic acid with a melting point of 216 to 218 ° C: '■ max = 1680, 1700 and 1930 cm " ^{1 is obtained} .

F. 181 to 182 ° C.

According to example 2d) the following connections are established:

Mp-ChlorbenzoyD ^ -mcthyl-S.ö-äthylcndioxy-

3-indolylacetic acid.

F. 162 to 163 ° C,

l-CinnamoyW-methyl-S.o-ethylcndioxy-

3-indoly! Cs:; igsäurc,

B c i s ρ i e 1 4

a) A solution of 26 g of 3,4-cyclopentenophenylhydrazine in 250 ml of diethyl ether at 0 to 5 C for 30 minutes with 8.2 g of acetaldehyde (80%) offset. The reaction mixture is still 2 hours

Stirred fei ½ to 5 C, then the ethereal solution separated off and dried over sodium sulfate. After the ether has evaporated, the residue is distilled. This gives 20 g of Acctaldehyd-3,4-CycIopentenonhcnylhydrazone from bp 113 to 15 ° C

K ₁ r ^Orr \ " ^m " * ^{= 3300} * ²⁹⁰⁰ * ^{! 6} «0" nd 1580cm " ¹ .

b) A solution of 10 g of the phenylhydrazone from a) in 6.8 g of _{gas and 8% of diethyl ether is used in}

9.56 g of cinnamoyl chloride are added to υ DiS 3 L. The *, ^R ^ ^kt ; ^o " ^s S ^cm 'sch is still 2 hours at .0 to 5 C .: Z η T" ^{bci Rau} "tcmperatur ecrührl and an-SpV J". ^aSScrcin 8 ^c 8 ° ^sscn · ^Bc when the crude product is recrystallized from ethanol, 10 g are obtained

Acctaldehyde-N ^I -cinnamoyl-3,4-cyclopcntcnophenyl-

hydrazone from m.p. 138 to 140 "C;r" _ax = 1660 and 1610cm- '.

c) In a solution of 10 g of the N'-acylicrtene phenylhydrazone from b) in 60 m! Ethanol is passed in for 3 hours at up to 5 ° C. Hydrogen chloride gas is passed in. After stirring for 5 hours at 0 to 5 ° C., the ethanol is distilled off at room temperature under reduced pressure. Treatment with ml of ether yields 10.1 g of N'-cinnamoyl-3, 4-cyclopentcnophenylhydrazin hydrochloride mp 150 ⁰ C (ZCRS.);>_<max = 1700-1660, 1620 and 1570 cm "^'1.

d) A mixture of 8 g of phenylhydrazine hydrochloride from c) and 50 g of levulinic acid is heated for 1 hour at 90 ° C and 2 hours at 95 to 100 ⁰ C. After cooling to room temperature, the reaction mixture is poured into 300 ml of water. The crystalline crude product is recrystallized twice from n-hexane-acetone (3: 1 (. This gives the desired 1-cinnamoyl ^ -methyl-S ^ -cyclopenteno ^ -indolyl acetic acid with a melting point of 144 to 146 ° C; > - _max 1710, 1670, and 1600 cm "" ¹ .

According to example 4b) the following compounds manufactured:

Acetaldehyde-N'-ip-chlorbenzoyl ^^ - cyclopentenophenylhydrazone,

F. 119 to 122 ° C,

Acetaldehyde-N ¹ - (p-fluorobenzoyl) -3,4-cyclopentenophenylhydrazone,

113 to 114 ° C,

Acetaldehyde-N'-ip-methylbenzoyO-S ^ cyclopentenophenylhydrazone,

F. 105 to 106 ⁰ C,

Acetaldehyde-N'-P '^' - methylenedioxybenzoyl) -3,4-cyclopentenophenylhydrazone,

F. 111 to 113 = C,

Acetaldehyde-N ^l - (5'-indancarbonyl) -3,4-cyclopentenophenylhydrazone,

F. 110 to 1I2 ° C,

Acetaldehyde-N'-i 1 '-indancarbonyl) -3,4-cycIopentenophenylhydrazone,

F. 115 to 117 ^C C,

Acetaldehyde-N'-cyclopropanecarbonyl-3,4-cyclopentenophenylhydrazone,

F. 111 to 113 ° C,

Acetaldehyde-N ¹ - (u-chlorophenylacctyf) -3,4-cyclopcntenophenylhydrazone,

M.p. 116 to 118 ° C, and

Acstaldehyd-K ^I - (2'-furanacryIoyI) -3,4-cyclopentenophenylhydrazone,

176.5 to 178 ° C.

According to example 4 c) the following compounds are produced:

N'-ip-chlorobenzoylH ^ yclopentenophenyl-

hydrazine hydrochloride,

F. 194 to 196 "C,

N '- (p-fluorobenzoyl) -3,4-cyclopentcnophenyl-

hydrazine hydrochloride,

F. 180 to 181 ° C,

N '- (p-methylbenzoyl) -3,4-cyclopcntenophenylhydrazine hydrochloride,

F. 176 to 177 "C.

F. 179 to 181 ° C,

N'-d'-lndancarbonylJ-S ^ -cyclopentenophenylhydrazine hydrochloride,

F. 211 to 212 ° C,

N'-Cydopropane carbonyl-S ^ -cyclopentenophenylhydrazine hydrochloride,

F. 158.5 to 159 ° C,

N'-yn-chlorophenylacetyO-S ^ -cyclopentenophenylhydrazine hydrochloride,

M.p. 137 to 139 ° C, and

N '- ^' - FuranacryloyO-S ^ cyclopentenophenylhydrazine hydiochloride,

F. 178 to 179 ° C.

According to example 4d) the following compounds manufactured:

l- (p-chlorobenzoyl) -2-methyl-5,6-cyclopenteno-3-indolylacetic acid,

F. 199 to 2O3 ° C,

1 - (p-FluorobenzoyO ^ -methyl-S ^ -cyclopente no-3-indolylacetic acid,

F. 208.5 to 209.5 ° C,

l- (p-methylbenzoyl) -2-methyl-5,6-cyclopenteno-3-indolylacetic acid,

F. 205 to 206 ⁰ C,

l- (3 ', 4'-methylenedioxybcnzoyl) -2-methyl-5,6-cyclopenteno-3-indolylacetic acid,

F. 198 to 20rC,

1 - (5'-indanecarbonyl) -2-methyl-5,6-cyclopentcno-3-indolyl acetic acid,

F. 210 to 211.5 ° C,

l- (l'-lndanecarbonyl) -2-methyl-5,6-cyclopenteno-3-indolylacetic acid,

F. 180.7 to 182.7 ° C,

l-CyclopropanecarbonyW-mclhyl-S.o-cyclopcnteno-3-indolyl acetic acid.

F. 178 to 18rC,

l - ((i-Chlorophenylacetyl) -2-methyl-5,6-cyclo ~ pcnteno-3-indolyl acetic acid,

F. 178 to 180 ° C, and

1- (2'-FuranacryIoyl) -2-methyl-5.6-cyclopenteno-3-indolylacetic acid,

v _max = 1710, 1670, 1600, 1000, 880 and.

700 cm- ¹ .

Example 5

yy
pentenophenylhydrazine hydrochloride, m.p. 184 to 186 ° C,

N '- (5'-lndanecarbonyl) -3,4-cyclopcntenophynylhydrazine hydrochloride.

a) A solution of 24 g of 3,4-cyclohexenophenylhydrazine in 200 ml of diethyl ether is treated dropwise at 0 to 5 ° C. for 40 minutes with 22 g of acetaldehyde (80%). The reaction mixture is stirred for a further 2 hours at 5 to 10 ° C., then the ethereal solution is separated off and dried over sodium sulfate. After the ether has been evaporated off, the residue is distilled. 30 g of acetaldehyde-3,4-cyclohexenophynylhydrazone of bp 131 are obtained to 133.5 ^U C / O, O9 Torr;, ·, "" = 3300, 2900 and cm " ¹ .

b) A solution of 9 g of the phenylhydrazone from a) in 6 g of pyridine and 50 ml of diethyl ether is treated with 8.7 g of p-chlorobenzoyl chloride at 0 to 5 ° C. The reaction mixture is stirred for 3 hours at 0 to 5 ° C. Then for hours at room temperature and then poured into water. When the crude product is recrystallized from ethanol, 10.9 g of acetaldehyde-N ¹ - (p-chlorobenzoyl) -3 are obtained, 4 - cyclohexenophenylhydrazone from mp 128 to 130C:. ", _UX = 1650. and 1580 cm" ¹ .

c) In a solution of 10 g of the N'-acylated Phcnylhydrazons from b) in 50 ml of ethanol is passed 3 hours at 0 to 3 ° C hydrogen chloride. The ethanol is then removed at 20 to 25 "C under reduced pressure. Treatment with 300 ml of ether gives the residue 5.3 g of N '- (p-chlorobinzoyl) -3,4-cyclohexenophenylhydrazine hydrochloride with a melting point of 180 to 181 ° C (dec.);! ■ "," = 1660 and 1570Cm " ¹ .

d) A mixture of 10.3 g of the phenylhydrazine hydrochloride from c) and 45 g of levulinic acid is heated to 85 to 92 ° C. for 3 hours. After cooling to room temperature, the reaction mixture is poured into 500 ml of water. The crystalline crude product is filtered off and washed three times with 20 ml of water. After recrystallization from ether-petroleum ether (3: 1), 9.5 g of the desired 1 - (p - chlorobenzoy 1) - 2 - methyl - 5,6 - cyclohexeno-3-indolylacetic acid with a melting point of 179 to 18TC are obtained; v _max = 1640 to 1680 and 1580 cm " ¹ .

Example 6

A mixture of 3 g of N ¹ -cinnamoyl-N ² -formyI-3,4-methylenedioxyphenylhydrazine and 30 ml of levulinic acid is heated to 70 to 75 ° C. for 3 hours in the presence of small amounts of hydrogen chloride gas. After cooling to room temperature, the reaction mixture is poured into 300 ml of water. The precipitate is filtered off and washed three times with water. After recrystallization from acetone / water (6: 1), the l-cinnamoyl-2-methyl-5,6-metklendioxy-3-indolylacetic acid with a melting point of 190 to 191 ί:) ■ „,„ = 1730, 1660 and 1620 cm " ¹ .

Example 7

A mixture of 2.5 gNMp-ChlorbenzoyO-N ^ formyl - 3,4 - cyclopcntenophcnylhydrazine and 25 g levulinic acid is ^{heated to 65 to 70 0} C for 3 hours in the presence of a small amount of sulfuric acid. After cooling to room temperature, the reaction mixture is poured into 300 ml of water. The crude product obtained is filtered off and washed three times with water. After recrystallization from acetone / water (5: 1), 1- (p-chlorobenzoyl) -2-methyl-5,6-cyclopenteno-3-indolyl acetic acid with a melting point of 198 to 201 is obtained
1580 cm

Example 9

A mixture of 3.5 g of N'-Ip-methylbenzoyl-N ² -acetyl-S ^ -cyclopcnlenophenylhydrazine and 20 g of lithium vulinic acid is mixed with a small amount of hydrochloric acid and heated to 60 to 65 ° C. for 3 hours and recrystallization of the crystalline product from acetone water (5: 1) gives the desired 1- (p-methylbenzoyl) -2-methyl-5,6-cyclopenteno-3-indolylessi2sicure vorr F. 205 to 206 ⁰ C: ■ · ""= 1720, 1690." 1670 and 1600 cm '.

Example 10

A solution of 3.5 g of N ¹ - (2'-furanacryloyl) -3.4 cyclopenylcnophenylhydrazine hydrochloride and 101 ethyl levulinate in 50 ml of ethanol is heated to 80 to 85 ° C. for 3 hours. After cooling to room temperature, the reaction mixture is ir

Poured 300 ml of water. The reaction product is extracted with three times 50 ml of ether, the extracts are washed after combining with water getrocknei over sodium sulfate and reduced under reduced tem pressure. The crude product is in ethyl

acetate dissolved and chromatographically purified using 150 g of silica gel and ethyl acetate as the eluent. This gives the 1- (2'-furan acryloy) - 2-methyl-5,6-cyclopenteno-3-indolyl acetic acid ethyl ester; r _max - 1710 and 1630 cm " ¹ .

Similarly, N'-cinnamoyl-3.4 cyclopentcnophenylhydrazine hydrochloride or NMp-methylbenzoylKVl-ethylenedioxyphynylhydra Zin hydrochloride and levulinic acid methyl ester or isopropyl ester of l-cinnamoyl-2-methyl-5 6-cyclo

penteno - 3 - indolyl acetic acid methyl ester (r _max 2950 1730, 1670, 1620, 1050, 760 cm " ¹ ) or Hp-methylbenzoyl) - 2 - methyl - 5,6 - ethylenedioxy - 3 - indolyl acetic acid isopropylier (r" _ax 1700 . 1660, 1370, 1270 1200, 1120, 1060 cm " ¹ ).

Example 11

A mixture of 8 g of the sodium salt before N ¹ - cinnamoyl - 3,4 - methylenedioxvphenvihvdrazine N ² -su1fit of the formula
45

C; y _max = 1700, 1680 and

Example 8

A solution of 3.5 g of N ¹ -cinnamoyl-N ² -acetyl-3,4-cyclopentenophenylhydrazine and 10 g of levulinic acid in 50 ml of acetic acid is heated to 60 to 65 ° C. for 3 hours in the presence of a small amount of sulfuric acid. The reaction mixture is heated After cooling to room temperature, it is poured into 300 ml of water, the precipitate obtained is filtered off and washed three times with water -S-indolylacetic acid with a melting point of 144 to 146 "C: v _max = 1710, 1670, 1630 and 1600 cm" ¹ .

N - NHSO ₃ Na
CO

CH = CH - QH ₅

and 45 ml of levulinic acid is in the presence of a small amount of sulfuric acid for 3 hours to 80 bi Heated to 85 ° C. After cooling to room temperature, the reaction mixture is poured into water This gives the l-CinnamoyI-2-methyl-5,6-me

thylcndioxy-3-indolylacetic acid, which, after being recrystallized twice from acetone / water (5: 1), melts at 190 to 192 ° C .; v _max = 1730, 1660 and 1620 cm ¹ .

Claims (1)

Claims: ι 3- (N-acyl-indolyl) -e- ^ acid derivatives of • ir J 1 κ meets 3- (N-acyl-indolyl) -acetic acid The Erfindungbetnfll i I «J
derivatives of allgemem _e nFor _m e ^