DE2519713A1 - ALPHA-CYANO-BETA-DIKETO COMPOUNDS, THE PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS - Google Patents

Description

DiPL-CHEM. DR. ELISABETH JUNG DIPL.-PHYS. DR. JORGEM SCHIRDEWAHN PATENTANWÄLTE DR.-1NG. GE RH A R D SCHMITT

S, ViONCHEN 4J,

CLEMENSSTRASSE 30 TELEFON 34 50 67 TELEGRAM ADDRESS: 1NVENT / MÜNCHEN TELEX 5-29 686

u.z .: J 614 C (J / vdB / k) Case A 838 / B 130

May 2nd 1975

BEECiIAM GROUP LIMITED,

Brentford, Middlesex, UK

<* - Cyano-ß-diketo compounds, Process for their preparation and medicinal products containing these compounds "

Priorities: May 4, 1974, Great Britain, No. 19721/74

and 7 November 1974, Great Britain, number 48115/74

The invention relates to new o ( -Cyano-ß-diketo compounds of the general formula I)

R.

(D

in which R ₁ , R ₂ , R ₃ and R ^ are identical or different and are hydrogen or halogen atoms or alkyl or alkoxy radicals,

509847/1205

where two of the radicals R,., Rp > R ^ and R ^ together with the neighboring ones Carbon atoms an optionally substituted one can form carbocyclic ring, and X is a bond or an oxygen atom, and their pharmacologically acceptable Salts.

These compounds are useful in inhibiting effects certain types of antigen-antibody reactions and in particular in the prophylaxis and treatment of diseases associated with allergic or immunological reactions, e.g. certain types of asthma and hay fever and also in the Treatment of rhinitis.

At. A literature search revealed that the following compounds are known:

1")

2-cyano-indan-1,3-dione ' and

2)

3-cyano-4-hydroxy-coumarin ^J.

1) = Zh. Org. Khim, 9 (1973), p. 1307

2) = Gazz. Chim. Ital. 98 (1968) p.1488

(Chem. Abs. 70, Sp. 96547).

Although the two compounds are described in the literature however, no biological efficacy has been recorded from them. There is also nothing in the literature Indication that such compounds may have some form of valuable biological activity, let alone that in some way an anti-allergic Effectiveness has been indicated.

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For this reason, the present invention also provides medicaments with an anti-allergic effect, those pharmacologically acceptable due to a content of at least one compound of the general formula I and / or their Salts are marked.

In these compounds of general formula I, the alkyl and alkoxy radicals conveniently have 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms. Examples of the radicals R> ,, Rp> R ^ ₅ and R * are hydrogen, fluorine, chlorine, bromine and iodine and the methyl, ethyl, n and isopropyl, n, sea and tert -Butyl, methoxy, ethoxy, n- and isopropoxy and the n, sea and tert-butoxy groups. In addition, the radicals R * and Rp, Rp and R- * or R ^ and R. together with the respective adjacent carbon atoms can form a phenyl, 1,2-cyclopentylene or a 1,2-cyclohexenylene ring which has one or may carry several of the aforementioned substituents.

The radicals R ^ and R are preferably hydrogen atoms and the radicals Rp and R ^, which can be the same or different, the methyl, ethyl, n-propyl, methoxy, ethoxy or the n-propoxy group.

Examples of suitable salts of the compounds of the general Formula I are alkali metal salts, especially the potassium and sodium salts, alkaline earth metal salts such as magnesium salts, Earth metal salts, such as aluminum salts, as well as salts with organic

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see bases such as amines or amino compounds.

Preferred substances of the present invention are the compounds listed below:

2-cyano-indan-1,3-dione, 2-cyano-5-methyl-indan-1,3-dione, 2-cyano-5,6-dimethyl-indan-1,3-dione, 2-cyano-4-methyl -indan-1,3-dione 2-cyano-4-methoxy-indan-1,3-dione 5,6-benzo-2-cyano-indan-1,3-dione 5-chloro-2-cyano-indan 1,3-dione 2-cyano-5,6-diethyl-indane-1,3-dione 3-cyano-4-hydroxycoumarin 3-cyano-6-ethyl-4-hydroxy-7-methyl-coumarin 3-cyano- 6,7-dimethyl-4-hydroxy-coumarin monohydrate 3-cyano-6,7-diethyl-4-hydroxy-coumarin 3-cyano-4-hydroxy-6-methyl-coumarin 3-cyano-4-hydroxy-7 -methyl-coumarin 3-cyano-7-ethyl-4-hydroxy-coumarin 3-cyano-7-ethoxy-4-hydroxy-coumarin-monohydrate 3-cyano-4-hydroxy-2-oxo-2H-naphtho / ~ 2 , 3-b / pyran 3-cyano-4-hydroxy-2-0X0-6,7, 8,9-tetrahydro-2H-naphtho- / ~ 2,3-b_7pyran

3-cyano-4-hydroxy-8-methyl-coumarin monohydrate 3-cyano-4-hydroxy-6-methoxy-coumarin 3-cyano-7> 8-dimethyl-3-hydroxy-coumarin monohydrate.

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The compounds of the general formula I can exist in a number of tautomeric forms. Obviously refer In the description, all references to the compound aa of the general formula I apply in the same way to their tautomers To shape. The predominant tautomeric forms for a particular compound of the general formula I depend on the nature of the Substituents X from. When X is a bond, the predominant tautomeric forms are:

(II)

(HA)

When X represents an oxygen atom, the predominant one is tautomeric Shape :

(III)

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The medicaments of the present invention are adapted for administration to humans and can be used as a microfine powder for insufflation, i.e. as a snuff, or in capsules made of hard gelatine. In such a case have the particles of the active compound suitably have a diameter below 50 / U, preferably below 10 / U. drug can be present with the aid of a sterile liquid carrier material for injection purposes »compounds of the general formula I who are active when administered orally can be made into syrups, tablets, capsules, or pills the like can be processed. The medicaments are preferably in the form of single doses or in a form in which the patient can self-administer a single dose. For example, if the drug is in the form of a tablet, Pill or capsule can be an appropriate dosage unit. Contains 1 to 500 mg of active substance »Possibly can use a small amount of a bronchodilator such as 1- (3,4-dihydroxyphenyl) -2-isopropyl-aminoethanol ("Isoprenaline"), in the agents of the present invention for both suppression a coughing stimulus as well as to provide immediate relief during an asthmatic attack will. The effective dose of a compound of general formula I depends on the particular compound used, however, it is usually in the range of 0.1 to 100 mg / kg / day.

The exact identity of the pharmacological carrier material is not important. Usual pharmacological practices can be used must be followed.

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As is customary, the remedies are usually written down or printed instructions for use in the medical treatment concerned, herein Trap as an anti-allergic agent for the prevention or treatment of e.g. asthma, hay fever or rhinitis.

The present invention also relates to a process for the preparation of the compounds according to the invention. Depending on the meaning of the substituent X in the general formula I, the following routes are followed. In the event that X denotes a bond, it is a matter of new compounds of the general formula II:

(ID

and their pharmacologically acceptable salts, where R *, Rp, R, and R. have the meanings given in the general formula I, but with the exception that R ^, R _? , R ^ and R / are not all hydrogen atoms at the same time. These compounds of the general formula II can now be prepared by

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a compound of the general formula V

CHCN

4 ·

(V)

in which R ^, Rp, R, and R / those in the general formula II Have given meanings, reacted with a base and then optionally the compound of the general in this way Formula II converted into a salt.

It has been found to be the most convenient for this implementation Bases are those of the general formula MOR in which M is an alkali metal or an alkaline earth metal ion and R is an organic residue of a straight-chain alcohol with 1 to 4 carbon atoms. Examples of such bases are Sodium methoxide and sodium ethoxide. However, others can Bases are used, including tertiary bases, such as. Pyridine and picoline, and trialkylamines such as triethylamine.

The choice of solvent for this reaction depends on the base used. For example, if the base is an alkoxide, as indicated above, the appropriate solvent is the appropriate alcohol. If the used Base is a tertiary base, then this can be used in the same way

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Base can also be the solvent for this reaction, or it can optionally be an inert solvent, such as a di-lower alkyl ether, Dioxane, tetrahydrofuran or dimethyl sulfoxide can be used.

The known compound 2-cyano-indan-1,3-dione (general formula II, in which R ₁ , Rp , R ^ and R are all hydrogen atoms) can also be prepared by this process, using a unsubstituted intermediate.

The compounds of the general formula V can be prepared by treating a suitably substituted phthalic anhydride with cyanoacetic acid in the presence of a base such as pyridine as an activator. It should be emphasized that when the anhydride in the phenyl ring is asymmetrically substituted, then this reaction isomeric cyanomethylene phthalides of the general Formula V delivers. However, these isomers only provide a compound of the general formula II when treated with a base.

The intermediates of the general formula V can also be prepared according to the following reaction scheme I (cf. H.Vi. Moore, Chem. Soc. Reviews 2 (1973), 41.5):

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SCHEMJl I

1 0

■ 4 0

(V)

H ₂ SO ₄

(i) 3r

(ii) NaOCOCH, ^R 3

NaN,

Another method of making the compounds of
general formula II, when X represents a bond, it consists in that one can obtain a compound of the general formula IX:

(IX)

in which R ^, R ^, R-, and R ^ have the meanings given in the general formula I and R ₅ and Rg are the same or different

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are separated and mean alkyl radicals, reacted with acetonitrile in the presence of a base and, if appropriate, then the obtained Compound of the general formula II converted into a salt.

Suitable bases for this reaction are strong bases such as alkali metal or alkaline earth metal salts, aliphatic alcohols, especially those having 1 to 4 carbon atoms such as sodium methoxide and sodium ethoxide _t.

If X is an oxygen atom, the new compounds have the general formula III:

(m)

and their pharmacologically acceptable salts, in which R., R-, R, and R- have the meanings given for general formula I, with the exception that R ^, R ~ »R- * and R ^ not at the same time all are hydrogen atoms. These compounds can now be prepared by using an appropriately substituted benzene derivative of the general Formula VI:

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(VI)

in which R R _nf r _un ci r, & ± _β have the meanings given in the general formula II and A is an activated carbonyl group, is reacted with a carbanion of the general formula R-CH-CN, in which R is a carboxylic acid ester radical and optionally then converting the compound of the general formula III obtained into a salt.

The carbanion R-CH-CN can by reacting a compound of

general formula NC-CHp-R with a base. Appropriate bases for this proton cleavage are sodium ethoxide and sodium hydride.

The radical A represents an activated carbonyl group, in particular of the general formula -CO-B, in which B is chlorine or Is bromine atom, or a residue of a mixed anhydride. The radical B is preferably a chlorine atom.

The nature of the carboxylic ester group R is not critical to successful implementation of the reaction, however it has been found that alkyl esters in which the alkyl radical Contains 1 to 4 carbon atoms, like the ethyl ester,

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- 13 are particularly suitable.

The reaction is preferably carried out in an inert anhydrous Solvent carried out. Appropriate solvents are Di-lower alkyl ethers, such as diethyl ether, dioxane, tetrahydrofuran and dimethyl sulfoxide.

The well-known compound 3-cyano - 4-hydroxy-coumarin of the general Formula III, in the Rw Rp > R ^ and R. are all hydrogen atoms can also be obtained by this method will. In this case, an unsubstituted compound of the general formula VI is used as the starting compound.

The examples illustrate the invention.

Example 1 a) 3-Cyanomethylene phthalide

A finely powdered mixture of 34 g (0.23 mol) of phthalic anhydride and 22 g (0.26 mol) of cyanoacetic acid is dissolved in 28 ml of anhydrous pyridine. The mixture is stirred at 60 to 70 ^° C. for 6 hours. After cooling overnight, the dark liquid is treated with 800 ml of water and adjusted to pH k to 5 with hydrochloric acid. The yellow solid obtained is filtered off, washed well with water and recrystallized from glacial acetic acid. Mp. 178-180 ⁰ C (mp. According to the literature 195 ° C).

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b) 2-cyanoindan-1, 3-d.ion

6.0 g (0.035 col) of 3-cyanomethylene phthalide are added to a solution of 0.8 g of sodium in 35 ml of methanol. The red solution is refluxed for 20 minutes. After cooling and acidification with a third of its volume with concentrated hydrochloric acid separated 204-207 ° C (decomposition) the indanedione than full yellow solid of mp. Is in the literature (201-202 ⁰ C).

Example 2 a) 3-Cyanomethylene-5- or -6-methyl-phthalide

37.2 grams (0.23 moles) of powdered 4-methyl-phthalic anhydride and 22 g (0.26 mol) of cyanoacetic acid are dissolved in 28 ml of anhydrous pyridine. The mixture is stirred at 60 to 70 ° C. for 6 hours .

After cooling and pouring into 800 ml of water, the mass is adjusted to pH 3 with concentrated hydrochloric acid. The ■ Oily phthalide is filtered off and recrystallized from glacial acetic acid. A yellow-brown solid with a melting point of 151 bis is obtained

152 ° C. for C ₁₁ H ₇ NO ₂ = - C. 3 H 7th N % analysis calculated: , 35 4th , 81 7th , 56 found: 71 , 19th , 08 , 49 71

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b) 2-cyano-5-methyl-indan-1,3-dione

The mixture of 5- and δ-methyl-cyanoethylene phthalide from stage a) (5.0 g; 0.027 mol) is added to a solution of 0.62 g of sodium in 27 ml of methanol. After heating the red solution under reflux for 20 minutes, the solution is cooled and treated with one third of its volume with concentrated hydrochloric acid. The precipitated yellow dione is filtered off and recrystallized from water. The hydrochloride melts at 176 to 178 ⁰ C.

Analysis for

calculated found:

59.73
60.50

5.01 4.20

6.33 % 6.39%

Example 3 a) 2-Bromo-6,7-dimethyl-naphtho-1,4-quinone

A solution of 20.0 g (0.107 mol) of 6,7-dimethyl-naphtho-1,4-quinone in 250 ml of glacial acetic acid is stirred and, in the process, is added dropwise with 5.6 ml (= 17.2 g; 0.107 mol) Bromine in 10 ml of acetic acid is added at 15 ° C. The mixture is stirred for a further 2 hours at this temperature. Then 20 g of anhydrous sodium acetate are added. The mixture is stirred first for 30 minutes at room temperature and then 90 minutes at 100 ⁰ C, then cooled and then poured into 2.5 1 v / ater. The yellow bromine compound is filtered off. After recrystallization from ethanol / chloroform, the compound melts at 156-159 ° C.

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analysis for C ₁₂ H ₉ BrO ₂ ^: 54 C. 3 H Br 14th calculated: 53 , 36 3 , 42 30, 23 found: , 47 , 39 30,

b) 2-Azido-6,7-dimethyl-naphtho-1,4-quinone

An aqueous solution of 4.4 g (0.068 mol) of sodium azide is made all at once to a refluxing suspension of 13.8 g (0.052 mol) of 2-bromo-6,7-dimethyl-naphtho-1,4-quinone given in 130 ml of ethanol. The red solution obtained is refluxed for a further 2 minutes. After cooling in the precipitated azide is separated off in an ice bath, washed well with water and recrystallized from ethanol. You get an orange-red solid with a melting point of 116 to 119 ° C (decomposition)

c) 3-cyanomethylene-5,6-dimethyl-phthalide

2.0 g of 2-azido-6,7-dimethyl-naphtho-1,4-quinone are added in 10 ing portions within 90 minutes to 30 ml of a concentrated sulfuric acid cooled to 0 to 5 ° C. and stirred vigorously. The red solution is stirred at 3 ° C. for a further 10 minutes until the evolution of nitrogen has ceased. The solution is then poured into 400 g of ice water, the phthalide separating out as a whitish solid. After recrystallization from ethanol in the presence of activated charcoal, the white solid melts at 165 to 181 ^° C. (mixture of the E and Z isomers).

analysis for ^c i; 72 C. 4th H 7th N 72 , 35 4th , 55 6th , 03 , 10 , 77 , 91 ? ^H 9 ^N0 2 ^: calculated: found:

5098 ^ 7/1205

d) 2-cyano-5,6-dimethyl-indan-1,3-dione

A solution of 2.0 g of 3-cyanomethylene-5,6-dimethyl-phthalide and 0.23 g of sodium in 10 ml of methanol is refluxed for 20 minutes, then cooled and acidified with 50 ml of 5N hydrochloric acid. After extracting the precipitated solid three times with 3000 ml of hot. Water and subsequent acidification of the extracts with 300 ml of concentrated hydrochloric acid gives the cyanoindan-dione as a yellow-orange solid with a melting point of 209 to 210 ^° C. (decomposition).

Analysis for C ₁₂ HqKO ₂ : CHN

calculated: 69.22 4.84 6.72% found: 69.61 5.14 6.71%.

Example 4 a) 3-Cyanomethylene-4- and -7-methyl-phthalide

Following the procedure described in Example 3, a ring closure reaction is carried out on 6.4 g of 2-azido-5-methyl-n £ phtho-1,4-quinone carried out using a mixture of 4- and 7-methyl-3-cyanomethylene phthalides obtained, which show an unclear melting point after recrystallization from ethanol.

Analysis for C ₁₁ H ^ NO ₂ : CHN

calculated: 71.35 3.81 7.56% found: 71.40 4.09 7.42%

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"b) 2-cyano-4-raethyl-indan-1,3-dione

2.1 g of the phthalide mixture obtained in step a) are mixed with a solution of 0.25 g of sodium in 11 ml of methanol for 20 minutes heated under reflux and worked up as described. A yellow solid is obtained which, after recrystallization from aqueous hydrochloric acid at 188 to 190 C melts with decomposition.

analysis for ( 71 C. 3 H 7th N 70 , 35 4th , 81 7th , 56 , 77 , 14 , 18 J ₁₁ H ₇ NO ₂ : calculated: found,:

B e i s, ρ i- e 1 5

2 ~ cyano-4-methoxy-indan-1,3-dione

A mixture of 18.1 g (0.0845 mol) of 3-methoxyphthalic acid dimethyl ester, 8.7 g (0.212 mol) of acetonitrile and 9.1 g (0.17 mol) of sodium metal dioxide are stirred ^{at 100 ° C. for 6 hours.} Then, after one hour, a further 10 ml of nitrile are added. After cooling and dilution with anhydrous ether, the precipitated yellow solid is filtered off, dissolved in as little water as possible and precipitated again using hydrochloric acid. A yellow-orange solid with a melting point of 186 ° to 189 ° C. (decomposition) is obtained.

Analysis for C ₁₁ H ₇ NO ^ H ₂ O:

calculated: found:

60.28 4.14 6.39 60.22 4.10 6.15

6 0 9847/1205

Example 6

2513713

According to the procedure given in Example 5, 24.4 g (0.1 mol) of naphthalene-2,3-dicarboxylic acid dimethyl ester in 5,6-Benzo-2-cyano-indan-1,3-d.ion transferred, which after recrystallization from aqueous hydrochloric acid at 264 to 265 C melts with decomposition.

Analysis for C ₁₄ H ₇ NO ₂ -H ₂ O:

calculated: found:

70.29 3.79 5.85
70.02 3.93 5.60

Example 7

Following the procedure in Example 5, 28.3 g (0.13 mol) of dimethyl 4-chlorophthalate at 13.0 g (0.345 mol) of acetonitrile in the presence of 13.75 g (0.25 mol) of sodium methoxide condensed. 5-chloro-2-cyano-indan-1,3-dione is obtained, that after recrystallization from benzene at 162 bis

170 ⁰ C melts with decomposition.

Analysis for C ₁₀ H ₄ ClNO ₂ : CH

calculated: 58.41 1.96 found: 58.49 1.98

Cl

6.81 17.25 % 6.79 16.79 %

Example 8

a) 6,7-diethyl-1-tetralone

3- (3 ', 4 ^! -Diethylbenzoyl) -propionic acid of melting point 93 ° C, the through

0 2 8 4 7/1205

Acylate is prepared by 1,2-diethylbenzene with succinic anhydride is added to 4- (3 ', 4 ^r -Diäthylphenyl) butanoic acid, bp. 143 catalytically reduced to 147 ⁰ C at 0.7 Torr. A mixture of this acid (59 g; 0.27 mol) and 450 g of 85 percent polyphosphoric acid are ^{heated to 80 °} C. for 30 minutes with stirring, then cooled and poured into 1 l of ice water. The oily product is extracted with ether, the ethereal solution with

-solution water and saturated sodium bicarbonate and again water

washed and then dried over magnesium sulfate.

After evaporation, an oil is obtained, which gives on distillation 48.30 g (= 89 percent of theory) tetralone, bp. 118 to 122 ⁰ C / 0.7 Torr.

Analysis for C ₁ ^ H ₁₈ O: CH

calculated: 83.12 8.97 % found: 82.95 9.21 %

If desired, 4- (3 ', 4'-Diäthy phenyl!) Butanoic acid (23.3 g; 0.106 mol) by 90-minute stirring at 100 ⁰ C with 115 ml · 80 percent sulfuric acid cyclize. After dilution, extraction with ether and distillation, 15.83 g (= 74 percent of theory) of the tetraion are obtained.

b) 6,7-diethyl-2-hydroxy-1,4-naphthoquinone

A 1m solution of potassium tert-butoxide in anhydrous tert-butanol (2 liters) is saturated with oxygen and with 48 g

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(0.24 mol) 6,7-diethyl-1-tetralone were added. The mixture will Stirred at room temperature, 2 equivalents of oxygen are absorbed are. Then the red solution is cooled and concentrated with Acidified hydrochloric acid. After most of the tert-butanol has been stripped off under reduced pressure, the Residue partitioned between water and chloroform. The organic phase is extracted with saturated sodium bicarbonate solution. After acidifying the bicarbonate extract, 34.60 g (= 63 percent of theory) of the naphthoquinone are obtained as orange-yellow solid. After recrystallization from aqueous ethanol in the presence of activated charcoal, yellow ones are obtained Crystals with a melting point of 105-109 ° C

analysis for C 70 C. 6th H % 70 , 28 6th , 32 % , 45 , 10 "14 14 3 * ^| / ^ί: - ^η 2 * '' calculated: found:

c.) 2-chloro-6,7-diethyl-1,4-naphthoquinone

A solution of 22 g (0.096 Mo-I) 6,7-diachyl-2-hydroxy-1,4-naphthoquinone in 250 ml thionyl chloride is refluxed for 12 hours. Then the solvent is removed under reduced pressure. The evaporation is repeated after adding anhydrous benzene. This gives an orange solid which after recrystallization from ethanol in the presence of activated carbon 18.04 g (= 76 percent of theory) predominates and has a melting point of 90-92 ⁰ C.

Analysis for C ₁₄ H ₁₃ ClO ₂ : CH Cl

calculated: 67.61 5.27 14.26 %

found: 67.21 5.39 14.21 tf

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d) 2-azido-6,7-diethyl-1,4-naphthoquinone

An aqueous solution of 6.15 g (0.095 mol) of sodium azide is added to a portion of a refluxing stirred solution of 18.0 g (0.073 Hol) of 2-chloro-6,7-diethyl-1,4-naphthoquinone in 180 ° ml of ethanol. The mixture is refluxed for an additional 2 minutes. The red solution is cooled. The orange-colored precipitate is then filtered off and washed with cold ethanol and then with water. After drying the product, 13.87 g (= 75 percent of theory) of the compound of melting point 73 to 76 ^° C. (decomposition) are obtained. After recrystallization from ethanol, orange-colored needles with a melting point of 74 to 76 ^° C. (decomposition) are obtained.

Analysis for Cw H ,. , N ^ Oρ:

calculated: 65 , 87 5 , 13 16 , 46 found: 65 , 64 5 , 27 16 , 66

e) 3-cyanomethylene-5,6-diethyl phthalide

6.0 g (0.024 mole) of 2-azido-6,7-diethyl-1,4-naphthoquinone be partly in the course of 2 hours at 0 to 5 ⁰ C cooled, stirred, concentrated sulfuric acid added. The red solution is stirred at this temperature until no further evolution of nitrogen is detected (approx. 15 min.). The products obtained by carrying out two such reactions are poured simultaneously into 1200 ml of ice water. The purple solid is filtered off and washed well with water. After recrystallization from ethanol in the presence

509847 / 12Q5

from. Activated charcoal you get 5.00 g (= 47 percent of theory) of a dirty-white solid with a melting point of 14? to 158 C. Another recrystallization yields a white sample from m.p. 159 to 168 ° C, the MMR spectrum is a mixture of Shows E and Z isomers.

Analysis for C. .H.3N

calculated: 73 , 99 5 , 77 6th , 16 found: 73 , 70 5 , 95 5 , 94

f) 2-cyano-5,6-diethyl-indan-1,3-dione

A mixture of 4.7 g (0.021 mol) of 3-cyanomethylene-5,6-diethylphthalide and methanolic sodium methoxide (from 0.48 g of sodium and 21 ml of methanol) is refluxed for 20 minutes and then chilled. The red solution is poured into 100 ml of 5N hydrochloric acid. The yellow precipitate is filtered off and reduced under reduced pressure Pressure dried over PpO, - / NaOH. 3.711 g are obtained (= 79 percent of theory) of the substance from melting point 172 to 173 ° C (decomposition).

Analysis for

calculated: found:

73.99
73.60

5.77
5.94

6.16 % 6.13 %

Example 9

3-cyano-4-hydroxycoumarin

13.45 g of 2-acetoxybenzoyl chloride in 100 ml of anhydrous ether

509847 / 120B

are slowly refluxed into a stirred suspension of an adduct of 7.82 g of sodium hydride given in a 60 percent suspension of mineral oil to 21.98 g of ethyl cyanoacetate in 300 ml of anhydrous ether. The refluxing is continued for 18 hours. Then the mixture is cooled and poured into 700 ml of water that Contains 20ml of a 10N sodium hydroxide solution. The alkaline phase is separated off, washed once with ether, with cold 12N hydrochloric acid acidified and filtered. Recrystallization from aqueous hydrochloric acid using activated charcoal is obtained 3-Cyano-4-hydroxycoumarin, melting point 267 to 269 ° C (decomposition).

Analysis for C ₁₀ H ₅ NO ₃ : CHN

calculated: 64.18 2.69 7.48 % found: 64.28 2.90 1.07%

Example 10

3-cyano-6-ethyl-4-hydroxy-7-methyl-coumarin a) 5-ethyl-4-methyl-salicylic acid

A mixture of 31.51 g of 4-ethyl-3-methyl-phenol and 91.25 g of anhydrous potassium carbonate is heated to 175 ° C. for 4 hours under a COp pressure of 91 kg / cm. The cooled reaction product is poured into 2 l of water. After acidification with hydrochloric acid, filtration and recrystallization of the solid from a mixture of ethanol and water 152.5, 5-ethyl-4-methylsalicylic acid, mp. To 154 ⁰ C.

509847/12 05

Analysis for C ₁₀ H ₁₂ O ₅ : CH

calculated: 66.65 6.71 %

found: 66.55 6.71 %

b) 2-acetoxy-5-eth3'-l-4-ffiethylbenzoic acid

A geraisch of 15.00 g of 5-ethyl-4-raethyl-salicylic acid, 80 ml of acetic anhydride and 80 ml of acetic acid is refluxed for 90 hours, poured into 1 liter of water and left to stand overnight. The solid formed is filtered off and recrystallized from benzene. To give 2-acetoxy-5-ethyl-4-methylbenzoic acid, mp. 132 to 134 ⁰ C.

analysis for C 64 C. 6th H % 64 , 85 6th , 35 % , 71 , 46 '12 ^H 14 ° 4 ^: calculated: found:

c) 2-Acetoxy-5-ethyl-4-methyl-benzoyl chloride

A mixture of 11.10 g of 2-acetoxy-5-ethyl-4-methylbenzoic acid and 20 ml of thionyl chloride in 100 ml of anhydrous benzene is refluxed for 6 hours, then cooled and reduced under reduced pressure The crude 2-acetoxy-5-ethyl-4-methylbenzoyl chloride is obtained as a liquid that as quickly as possible in the next stage of synthesis without further Cleaning is used.

d) 3-cyano-6-ethyl-4-hydroxy-7-methyl-coumarin

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11.5 g of 2-acetoxy-5-ethyl-4-methyl-benzoyl chloride in 75 ml of anhydrous. Ether slowly becomes a refluxing stirred suspension of an addition product of 5.00 g Sodium hydride in a 60 percent suspension in mineral oil in 14.97 g of ethyl cyanoacetate in 275 ml of anhydrous Ether given. The refluxing is continued for 18 hours. Then the mixture is cooled and poured into 500 ml of water, which contains 30 ml of 2.5 N sodium hydroxide solution. The alkaline phase is separated off, washed three times with ether, with 12-n Acidified hydrochloric acid and then filtered. After recrystallization from a mixture of ethanol and aqueous hydrochloric acid 3-cyano-6-ethyl-4-hydroxy-7-methyl-coumarin with a melting point of 224 ° to 226 ° C. is obtained.

Analysis for C .. JL, .NO,:

calculated: 68, 11 4th , 84 6, 11 found: 68, 22nd 5 , 01 5, 64

example

3-cyano-6,7-dimethyl-4-hydroxy-coumarin-monohydra.t

Else is as described in analog V / in Example 10 from 3,4-dimethylphenol 4,5-over dimethylsalicylic acid, mp. 204-105 ° C, 2-acetoxy-4,5-dimethyl-benzoic acid, mp. 128 to 130 ⁰ C and 2-acetoxy-4,5-dimethyl-benzoyl chloride produced the compound 3-cyano-6,7-dimethyl-4-hydroxy-coumarin monohydrate, which after recrystallization from a mixture of ethanol and aqueous hydrochloric acid at 262 to 264 ⁰ C melts.

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Analysis for C ₁₂ H ₉ NO ^ .1H ₂ O: CHN

calculated: 61.80 4.75 6.01 %

found: 62.09 4.83 5.62 %

Example 12 3-cyano-6,7-diethyl-4-hydroxy-coumarin

According to the procedure given in Example 10, 3,4-diethyphenol is converted about 4,5-diethyl-salicylic acid from mp. 126 to 128.5 ° C, 2-acetoxy-4,5-diethylbenzoic acid ve * "Γρ. 127 bis 129 ° C and 2-acetoxy-4,5-diethylbenzoyl chloride, 3-cyano-6,7-diethyl-4-hydroxy-coumarin produced, after recrystallization from a mixture of ethanol and dilute hydrochloric acid and then melts from a mixture of chloroform and petroleum ether at 198 to 200 ° C.

69 12th 5 , 39 5 , 76 68, 76 5 , 33 5 , 68

Analysis for C ^^ H ₁ , NO ^: CHN

calculated: found:

Example 13 3-Cyano-4-hydroxy-6-methyl-coumarin

According to the method given in Example 10, in an analogous manner from 4-methylphenol via 5-methyl-salicylic acid of melting point. 147 to 149 C, 2-acetoxy-5-methylbenzoic acid of melting point 142 to 144 ° C and 2-acetoxy-5-methyl-benzoyl chloride 3-cyano-4-

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produced hydroxy-6-methyl-coumarin, which melts ^{at 238 to 241 0} C after recrystallization from a mixture of ethanol and dilute hydrochloric acid.

analysis for calculated: 65 C. H . N 96 % found: 65 , 57 3.51 6, 98 % , 32 3.80 6,

example

3-cyano-4-hydroxv-7-methyl-coumarin

14th

After this. specified in Example 10 is salicylic acid 4-methyl-analogously from 2-acetoxy-4-methyl- "benzoic acid of mp. 132-133 ° C, and 2-acetoxy-4-methylbenzoyl chloride, bp. Ί20 to 122 ⁰ C. the 3-cyano-4-hydroxy-7-methyl-coumarin prepared at 1.5 Torr, melting after recrystallization from a mixture of ethanol and dilute hydrochloric acid at 261 to 264 ⁰ C.

Analysis for

calculated: found:

65.67 3.51 6.96 % 65.15 3.86 6.39 %

Example 15
3-cyano-7-ethyl-4-hydroxy-coumarin

According to the process described in Example 10, in an analogous manner, from 3-ethylphenol via 4-ethylsalicylic acid, melting point 122.5

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up to 125.5 ⁰ C, 2-acetoxy-4-ethyl-benzoic acid with a melting point of 84 to 87 ° C and 2-acetoxy-4-ethylbenzoyl chloride, the 3-cyano-7-ethyl-4-hydroxy-coumarin is produced, which is produced according to Recrystallize from a mixture of ethanol and dilute hydrochloric acid at 211 to 215 ° C melts.

Analysis for

calculated: found:

66.97
66.60

4.22 4.55

6.51 % 6.05 %

Example 16 3-cyano-7-ethyloxy-4-hydroxy-coumarin monohydrate

According to the procedure given in Example 10, in an analogous manner: from 4-ethyloxy-salicylic acid via 2-acetoxy-4-ethyloxybenzoic acid from melting point 122 to 124 ° C and 2-acetoxy ~ 4 ~ ethyloxybenzoyl chloride 3-cyano-7-ethyloxy-4-hydroxy-coumarin monohydrate produced, after recrystallization from a mixture of ethanol and dilute hydrochloric acid at 224 to 225 ° C melts.

Analysis for C ₁₂ H ₉ NO ₄ .H ₂ O:

calculated: 57 , 83 4th , 45 5 , 62 % found: 57 , 97 4th , 50 5 , 44 %

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Example 17 3-Cyano-4-hydroxy-2-oxo-2H-naphtho / ~ 2,3-b-7pyran

After the "described in Example 10 182-185 ⁰ C and in an analogous manner from 3-hydroxy-2-naphthoic acid 3-acetoxy-2-naphthoic acid, mp. 3-Acetoxy-2-naphtoylchlorid of mp. 88-89 ° C the 3-cyano-4-hydroxy-2-oxo-2H-naphtho- / ~ 2,3-b__7pyran produced, which after recrystallization from a mixture of ethanol and dilute hydrochloric acid at 297 to 299 ° C

melts. calculated: C. H Analysis for ( found: 70.89 2.97 70.50 3.17

5.90

5.60 %

Example 18

3-cyano-4-hydroxy-2-oxo-6,7,8,9-tetrahydro-2H-naphtho- £ ~ 2,3-b__7pyran

According to the process described in Example 10, in an analogous manner, from 5,6,7,8-tetrahydro-2-naphthol via 3-hydroxy-5,6,7,8-tetrahydro-2-naphthoic acid with a melting point of 180 ° to 182 ° C, 3-acetoxy-5,6,7,8-tetrahydro-2-naphthoic acid of melting point 149 to 150 ° C and 3-acetoxy-5,6,7,8-tetrahydro-2-naphthoyl chloride, the 3-cyano 4-hydroxy-2-oxo-6,7,8,9-tetrahydro-2H-naphtho - / "~ 2,3-b_7pyran prepared which melts after recrystallization from a mixture of ethanol and dilute hydrochloric acid at 265-267 ⁰ C. .

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Analysis for

calculated: found:

69.70
69.44

4.60 4.90

5.81 / ο 5.39

Example 19 3-Cyano-4-hydroxy-8-methyl-coumarin monohydrate

According to the process described in Example 10, in an analogous manner from 3-methyl-salicylic acid via 2-acetoxy-3-diethylbenzoic acid with a melting point of 115 bir. 1 ^ 7 ^O C and 2-acetoxy-3-methylbenzoyl chloride produced 3-cyano-4-hydroxy-8-methyl-coumarin monohydrate, which melts at 211 to 214 ° C after recrystallization from aqueous ethanol and dilute hydrochloric acid.

Analysis for

calculated: found:

C H

60.28 4.14 60.04 4.26

6.39% 5.91%

Example 20 3-Cyano-4-hydroxy-6-methoxy-coumarin

Following the procedure described in Example 10 156-158 ⁰ C and in an analogous manner from 5-methoxy-salicylic acid 2-acetoxy-5-methoxybenzoic acid, mp. 2-Acetoxy-5-methoxybenzoyl chloride, the 3 ~ cyano-4-hydroxy- 6-methoxy-coumarin produced according to. Recrystallization from water and dilute hydrochloric acid at 249 to 253 ° C melts with decomposition.

509S47 / 1205

Analysis for

calculated: found:

59.67

60.83 3.25 6.45 %

3.22 6.41 %

example

3-cyano-7,8-dimethyl-3-hydroxy-cunarin-raonohydrate

According to the method described in Example 10, in an analogous manner from 2,3-dimethylphenol via 3,4-dimethyl-salicylic acid vom ^ p. 192-193 ° C, 2-acetoxy-3,4-dimethyl-benzoic acid, mp. 142-144 ⁰ C and 2-acetoxy-3,4-dimethyl-bensoylchlorid the 3-cyano-7,8-dimethyl-3- Hydroxy-coumarin-monohydrate, which melts at 255 to 256 ⁰ C after recrystallization from ethanol and petroleum ether.

Ana lysis for ( 61 C. 4th H 6th N 62 , 79 4th , 76 6th , 01 , 04 , 80 , 04 ^ 2H ₉ NO ₃ .H ₂ O: calculated: found:

Biological results

The compounds prepared according to the above examples are examined biologically in the passive skin anaphylaxis test. The compounds are in the form of their sodium salts either in the case of soluble salts in a phosphate buffer solution pH 7.2 or, in the case of insoluble salts, in the form of a suspension in a one percent methyl cellulose solution.

509847/12

a) According to the method of I. Hota, "Immunology" 7 (1964), Page 631, heat-labile homocytotropc antibodies are produced in plates produced.

For this purpose, male V, ^r istar rats with a body weight of 250 to 300 g are given 0.5 ml of Bordatella portussis intraperitoneally.

A Q

Vaccine containing 4: 10 killed none per ml, and subcutctn 0.5 nl of an emulsion of 100 mg ovalbuniin in 2 ml L-sodium chloride solution and 3 ml of Freunds' incomplete adjuvant injected. On the 18th day, the rats are given blood by a cardiac puncture taken. The elut is collected and separated; the serum is stored at -20 C and only thawed before use.

b) The passive skin anaphylaxis test is used according to the procedure by A. Ovary and O.E. Beer, "Proc. Soc. Exp. Biol., Med." S1_ (1952), page 584, and J. Goose and A.M.J.N. Blair, "Immunology" _16 (1959), p. 769.

0.1 ml each of 6 samples of a double serum dilution series in 0.9 percent sodium chloride solution v / earth 250 to 350 g Injected intradermally into heavy Wistar rats at various points on the shaved back. 72 hours later the Animals i.v. 0.3 ml of a one percent ovalbumin solution des Dye "Pontamin sky blue" in isotonic, with phosphate on pH 7.2 buffered sodium chloride solution is injected. After 20 minutes the rats are sacrificed. It will be the diameter of the bruises measured at the antibody injection sites.

The serum dilution series is set up in such a way that the injection

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at the highest dilution no reaction and at the two or three lowest dilutions give maximum response he follows. In general, 6 samples of a two-fold serum dilution series from 1/4 to 1/128 are used.

The compounds according to the invention are tested for their ability the diameter of the bruises at the antibody injection sites to zoom out, which show no maximum response in the controls. A certain time before intravenous Ovalbumin injection is given to a group of 6 animals compound according to the invention administered by subcutaneous injection, in the neck as a solution of the compound in isotonic phosphate-buffered sodium chloride solution or as a suspension in one percent methyl cellulose. The diameter of the bruises that develop in the test group will be with the diameter of the spots of a control group of 6 animals compared which were treated in the same way, but with solutions without the compound according to the invention.

% Inhibition of passive skin

Anaphylaxis Tests = 100 * ( ¹ - §)

a = the mean sum of the diameters of the blue spots, which arise in the test group at the antibody injection sites, in which all control animals do not have a maximum Show reaction;

b = the mean sum of the diameters of the blue spots, those in the control group at the antibody injection sites

arise in which all animals show no maximum response

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The compound under investigation is preferably in a Buffer solution of pH 7 »2 dissolved, neutralized with sodium bicarbonate and then administered. In the case of compounds that form an insoluble sodium salt, the free cyano compound is 2,5n-IIstriumhydroxidlösung implemented, the salt filtered off and washed alkali-free with water. The dried salts are then used as a suspension in monopoly methyl cellulose administered.

The table below summarizes the results of the passive skin aryaphylaxis test.

Example 1 Example 2

CH,

Biological results

% Inhibition at

Dose time passive skin (mg / kg) (Hin.) Anaphylaxis test

25th 0 43 100 0 64 25th 30th 8th 100 30th 16 25th 0 45 100 :O 76 25th 30th 15th 100 30th 35

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r C. V-CN Il
O j s I. 0 V-CN ' Ii
0 > - 'CN dose
(mg / kg) Time
(There.) % Hemfeüh £ HDfeita °
passive skin
Anaphylaxis-Tec t • 88 5 O O V-CN χ. . H 70 Example 3 Ii
0 0 5 10
10 46
56 27 CH ^ Example 5 - 10 10 77 30th OCH ₃ Ii
0 20th 10 92 * 5 10 21 33
76
21 CH ^^ V ^
3
Example k 10 10 25th 15th CK-
ι- 20th 10 75 40 10 83 Example 6 5 10 28 10 10 16 20th 10 57 40 10 81 Example 7 25th 10 Xi 100 10 30th 100 30th 10
25th
10 10
10
^ o 25th 30th

ORIGINAL INSPECTED

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Dose (mg / kg)

Time

(Min.)

% Inhibition in the passive chewing anaphylaxis test

example 8th I. CH ₃ CH il
- 0 CH ₃ CH ₂ ^^^
example 9

example

CH ₅ CH ₂

\ -CN

Example 11

0.H ₂ O

Example 12

CH _x CH

5 10 20 AO

25 100

25 100

CH ₃ CH ₂

10 10 10 10

30th

30th

10 10 30th 30th

30th

30th

10 10 10 10

74 90 78 64

64 87 30 40

71 67 24

17th

51 72 16 11

64 72 68 93

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dose
(mg / kg)

Time (min.)

2513713

% Inhibition in the passive skin anaphylaxis test

Example 13

Example χ

CH

Ef

Example 16

0.H ₂ O

Example 17

OH

25th
100

30th

30th

30th

30th

30th

30th

10
10
10
10

60

60

14 40 21 22

45 74 14 18

34 64 27 17

59 71 86

73

9 15 23 18

9 84 7/1205

% Inhibition leg

Dose time passive skin (mg / kg) (Min.) Anarthylaxic-IEC "!:

Example 13 Example ig

3H3

Example 20

. OK

CEUQ ^. ^ L

CH

Example 2I QH

CH.

1 10 2 10 k 10 8th 10 25th 0 100 0 25th 30th 100 30th 25th 0 100 0 25th 30th 100 30th 2.5 10 5 10 10 10 20th 10

5098 A7 / 1205

Claims (16)

Claims 1. / ci-cyano-ß-diketo compounds of the general formula (I) (I) O in which FL, Rp, FU and R. are identical or different - and are hydrogen or halogen atoms or alkyl or alkoxy radicals, two of the radicals R ^, R ₂ J Rz and R- together with the adjacent carbon atoms an optionally substituted carbocyclic Can form a ring and X is a bond or an oxygen atom, and their pharmacologically acceptable salts. 2. Compounds according to claim 1 with the proviso that R .., Rp » R-, and R- do not all mean hydrogen atoms at the same time. 3. Compounds according to claims 1 and 2 _S characterized in that Rp and R ^ are hydrogen atoms u.id R ₂ and Rz are identical or different and are methyl, ethyl, n-propyl, methoxy, ethoxy or mean n-propoxy groups. 4. The connections
2-cyano-indan-1,3-dione 509847/1205 ■ 2-cyano-5 - "" ethyl-indan-1,3-dione 2-cyano-5 »6-dimethyl-indan-1,3-dione 2-cyano-4-ynethyl-indan-1,3-dicn 2-cyano-4-methoxy-indan-1,3-dione 5,6-benzo-2-cyano-indan-1,3-dione 5-chloro-2-cyano-indan-1,3-dione 2-Cyano-5> 6 ~ diethyl-indan-1,3 ~ dione 3-cyano-4-hydroxycoumarin 3-cyano-6-ethyl-4-hydroxy-7-ynethylcoumarin 3-cyano-6,7-dimethyl-4-hydroxy-coumarin monohydrate 3-cyano-6,7-diethyl-4-hydroxy-coumarin 3-cyano-4-hydroxy-6-ynethyl-coumarin 3-cyano-4-hydroxy-7-diethyl-coumarin 3-cyano-7-ethyl-4-hydroxy-coumarin 3-cyano-7-ethoxy-4-hydroxy-coumarin monohydrate 3-cyano-4-hydroxy-2-oxo-2H-naphtho / ~ "2,3-b7pyran 3-cyano-4-hydroxy-2-oxo-6,7,8,9-tetrahydro-2H-naphtho / 2,3-b-7pyran 3-cyano-4-hydroxy-8-methyl-coumarin monohydrate 3-cyano-4-hydroxy-6-methoxy-coumarin 3-cyano-7 »8-dimethyl-3-hydroxy-coumarin-nionohydrate, and their pharmacologically acceptable salts. 5. Compounds according to at least one of claims 1 to in the form of their sodium or potassium salts. 509847/1205 6. Process for the preparation of the compounds according to Claims 1 to 5, characterized in that one a) in the event that X. signifies a bond, 1) a compound of the general formula (V) R ₁ CHCN (V) in which R ₁ , Rp, R ^ and R / have the meanings given in claim 1, with a base or .. 2) a compound of the general formula (IX) ' CO ₂ R ₅ CO ₂ R ₆ (IX) in which R ₁ , Rp, R ^ and R. have the meanings given in claim 1 and Rj- and Rg are identical or different and denote alkyl radicals, reacts with acetonitrile in the presence of a base and 3) after steps (1) or (2), the compound formed into a compound of the general formula (I) or 5098.47 / 1205 their salts transferred or b) in the event that X is an oxygen atom, d) a compound of the general formula (VI) in which R ^, Rp, R ^ and R. the meanings given in claim 1 and A is an activated carbonyl group, with a carbanion of the general formula R - CH - CN, in which R denotes a carboxylic acid ester radical, and, if appropriate, then the compound obtained converted into a salt. 7. The method according to claim 6, characterized in that one in steps (1) or (2) is an alkali metal or Alkaline earth metal salt of an aliphatic alcohol is used as a base. 8. The method according to claim 6, characterized in that a compound of the general formula (VI) is used, in which A denotes the group -CO-B in which B is a chlorine or bromine atom or the remainder of a mixed anhydride 5Q98A7 / 1205 means. 9. The method according to claim 8, characterized in that a compound of the general formula (VI) 'is used, in which in the grouping -CO-B the radical B is a chlorine atom. 10. Compounds of the general formula V CKCM (V) in which R ,,, R ₂ , R- * and R, which have the meaning given in claim 1, as intermediate compounds. 11. Medicines with an anti-allergic effect, characterized by a content of at least one compound of the general formula (I) and / or pharmacologically thereof compatible salts. 12. Medicament according to claim 11 in the form of a microfine powder for insufflation. 13. Medicament according to claim 11, characterized by an additional content of a compound with bronchodilator V / irkun.r. 5 ο ο ο, ·. - / -, ο r ι-, 14. Medicament according to claim 13, characterized by a additional content of 1- (3j4-dihydroxyphenyl) -2-isopropyl-aminoethanol. 15. Medicament according to at least one of claims 11 to 14, characterized by an additional content of a sterile liquid carrier material for injection purposes. 16. Medicament according to at least one of claims 11 to 14, characterized by a content of a solid carrier material. 509847/1205