DE2448450A1 - TETRAZOLE-5-YL-CUMARIN DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS - Google Patents

Description

"Tetrazol-S-yl-coumarin derivatives, process for their preparation and these compounds entlTälTeffde Arzneimittel""..---.•"" ^r

Priority: October 11th

Great Britain - number 47 484/73

The invention relates to new TetrazoT-5-yl-coumarin derivatives which advantageous for the inhibition of certain antigen-antibody reactions t are and therefore for prophylaxis and treatment - γόη Diseases caused by allergic or immunological reactions, such as asthma or hay fever, as well as for the ' Treatment of rhinitis are appropriate. The invention also relates to processes for the preparation of these compounds and these Medicines containing compounds. . -.-. ■ '"■

The invention relates to tetrazol-5-yl-coumarin derivatives general formula I or their pharmacologically acceptable salts -. - .. · ..

509817/1158

ORIGINAL INSPECTED

(D

in which R is an alkyl or aryl radical and R ^ .R, FU and R ₁ , are identical or different and are hydrogen or halogen atoms or alkyl, alkoxy, aryl, aralkyl, acyloxy or heterocyclic radicals or carboxyl groups , the salts of which mean 'or esters, where in each case two of the _: R ₁ , R ₂ , R "and R ₁ radicals can form a substituted or unsubstituted carbocyclic or heterocyclic ring, with the proviso, ;; w: ehn R-, Rp, R ^ and Rh are all hydrogen atoms, in which case R is not a methyl group.

The aforementioned definition of the compounds thus includes the Compound 4-methyl-j5- (tetrazol-5-yl) -coumarin from as this compound is already known from the literature (cf. J.Chem.Soc. Perkin Trans. I (1972), 779). In this publication the authors stated that this compound was not antiallergic Effectiveness. Surprisingly, it has been found that this connection nevertheless has an essential anti-allergic effect possesses, so that there was an encouragement to believe that the compounds of general formula I are also effective Are antiallergic drugs.

In the compounds of the general formula I, R is ^ or aryl radicals. Examples of suitable alkyl or aryl groups are

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ORIGINAL INSPECTED

:. -3- 2Λ48Α50

the methyl, ethyl, η and isopropyl, η, sec- or tert-butyl, Cyclohexyl, cyclopentyl, cycloheptyl and the phenyl group. Lower alkyl radicals are preferred, especially the methyl • group. ·

Examples of the radicals R ₁ , R ₂ , R-, and R ₁ ^ in the compounds of the present invention are hydrogen, fluorine, chlorine, bromine and iodine atoms, methyl, ethyl, n- and isopropyl, n -, sec. and tert. butyl, cyclohexyl, methoxy, ethoxy, n- and iso-propoxy, n-, sec- and tert-butoxy, phenyl, benzyl, pyridyl -, tetrazolyl, carboxyl and acetoxy groups, as well as alkoxycarbonyl, acyloxyrnethoxycarbonyl and 'ok-acyloxyethoxycarbonyl radicals. In addition, two adjacent radicals R. and Rp, Rg and R ^ or R ^ and Rj. Together can form the radical of a 1,2-phenylene or a 1,2-cyclohexylene ring.

Preferred subgroups of the compounds of the general formula I. are those where:

a) Rj ^ is a halogen atom,

b) Rp is a lower alkyl radical, in particular the methyl group means,

c) Rp und.R-z represent lower alkyl radicals, in particular methyl groups put and -

d) R- represents a lower alkoxy radical.

Including examples of specific compounds according to the invention their pharmacologically acceptable salts are: 6-bromo-4-methyl-3- (tetrazol-5-yl) -coumarin 6-chloro-4-methyl -> - (tetrazol-5-yl) -coumarin,

509817/1158

6-bromo-4-ethyl-3- (tetrazol-5-yl) -coumarin, 8-chloro-4-methyl-3- (tetrazol-5-yl) -coumarin, 4-ethyl 1-3- (tetrazol-5-yl) -coumarin j 4-methyl-8-nitro-3- (tetrazol-5-yl) -coumarin, 6-methoxy-4-methyl-3- (tetrazol-5-yl) -coumarin, 6,7-dichloro-4-methy1-3- (tetrazol-5-yl) -coumarin, 4,6,8-trimethyl-3- (tetrazol-5-yl) -coumarin, 4-n-propyl-3- (tetrazol-5-yl) -coumarin, 4,6-dimethyl-3- (tetrazol-5-yl) -coumarin, 4,7-dimethyl-3- (tetrazol-5-yl) -coumarin, 7, 8-Benzo-4-methyl-3- (tetrazol-5-yl) -coumarin, 4-phenyl-3- (tetrazol-5-yl-) -coumarin, 6,7-diethyl-4-methyl-3- (tetrazol-5-yl) -coumarin, 4,6,7-trimethyl-3- (tetrazol-5-yl) -coumarin, 8-bromo-4-methy1-3- (tetrazol-5-yl) -coumarin and 7-methoxy-4-methyl-3- (tetrazol-5-yl) -coumarin.

Suitable pharmacologically acceptable salts of the compounds of the general formula I are non-toxic metal salts, such as the sodium, potassium, aluminum or calcium salts.

The compounds of the invention can be prepared by mixing a suitable 3-cyano-coumarin with ammonium azide implements. Preferably the reaction is carried out in an inert organic solvent such as dimethylformamide at one temperature above room temperature. Preferably the ammonium azide is formed in situ, e.g., by the reaction of sodium azide with ammonium chloride.

5Ö9817 / 1158

Another object of the invention are medicaments that by a content of a tetrazol-5-yl-coumarin derivative of general formula I and at least one pharmacologically acceptable carrier material and / or diluent are.

The medicaments according to the invention can be used as finely divided powders for insufflation, e.g. as snuff, or in Capsules made of hard gelatin or together with a sterile liquid carrier material for injections. Some of the Compounds of general formula I are effective when-taken orally, and in these cases the drugs may be in the form of tablets, capsules, pills or syrups. The medicaments according to the invention are preferably in single doses before or in a form from which the patient can take a single dose.

If necessary, the medicaments according to the invention can be used in small amounts Amounts of a compound that acts as a bronchodilator, such as isoprenaline, DL-I- (3j ^ -dihydroxyphenyl) -2-isopropylaminoethanol, added to suppress the urge to cough during insufflation and provide immediate relief during an asthmatic attack To provide.

The effective dose of the compounds of the general formula I depends on the corresponding compound; in general, however Administered amounts from 0.1 to 100 mg / kg / day.

The exact identity of the pharmacological carrier material is

509817/1158

not significant. Standard pharmacological practices can be used must be followed.

According to a further embodiment of the present invention, the medicament can be 4-methyl-3- (tetrazol-5-yl) -coumarin or its pharmacologically acceptable salt together with at least one solid pharmacologically acceptable carrier material and / or diluent contain. Examples of suitable carrier materials are gelatin capsules, lactose and mannitol.

The examples illustrate the invention. Example 1 relates to the preparation of the known compound 4-methyl-3- (tetrazol-5-yl) -coumarin in view of its biological activity being confirmed below. Examples 2 through 12 illustrate the preparation of some compounds according to the invention.

example 1

A solution of 7 * 9 ^ g (0 * 043 mol) 3-cyano-4-methyl-coumarin in 45 ml of dimethylformamide are added to a mixture of 2.92 g (0.044 Mol) sodium azide and 2.36 g (0.044 mol) ammonium chloride. The mixture is heated on the steam bath with stirring for 24 hours. After removing the solvent under reduced pressure 100 ml of water are added. The solid is filtered off. After acidifying the piltrate and other aqueous extracts the compound 4-methyl-3- (tetrazol ~ 5-yl) -coumarin is obtained with a melting point of 213 ° to 214 ° C. after recrystallization from ethanol.

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% I. 89 ίο % 55 57, 58 3.53 24, 41 57, 3.51 24,

■ 7 - 2Λ48Λ50

Analysis for C ₁₁ HgN ₂ ^ O ₂ : CHN

ber .:
found:

Example 2

Following the procedure of Example 1, the compound 6-bromo-4-methyl-3- (tetrazol-5-yl) is obtained from 6-bromo-3-cyano-4-methyl-coumarin (melting point 187 to 192 ^{° C.)} ) -coumarin of m.p. 238 to 239 ° C after recrystallization from ethanol.

Analysis for C. H ₇ BrN ₂ , 0 _p ·: CHN

calc .: 43.27 2.50 18.38 found: 43.02 2.30 18.24

Example 3

Following the procedure of Example 1, 6-chloro-3-cyano-4-methyl-coumarin is obtained from 6-chloro-3-cyano-4-methyl-coumarin the compound 6-chloro-4-methyl-3- (tetrazol-5-yl) -coumarin of melting point 219 ° to 223 ° C. after recrystallization from ethanol.

Analysis for C ₁₁ H ₇ ClNhOp: CH

■ I J. I "£ - of of

calc .: 50.04 2.84 21.63

found: 50.30 2.69 21.33

Example4

Following the procedure of Example 1, 3-cyano-4,6,7-trimethylcoumarin is obtained (Mp. 193 ° C) the compound 3- (tetrazol-5-yl) -

5.09817 / 1158

4,6,7-trimethyl-coumarin at pp. 226 to 228 ° C after recrystallization from ethanol.

Analysis for

about gef

60.75
60.93

N %

4.85 21.87 4.72 21.86

Example 5

To a solution of 16.4 g (0.083 mol) of 3-cyano-4,6-dimethylcoumarin in 88 ml of dimethylformamide, 5.69 g of sodium azide and 4.60 g of ammonium chloride were added. After stirring for 29 hours at 100 ° C the solvent is evaporated from the cooled reaction mixture under reduced pressure. The solid residue is with Water extracted. After acidification of the extracts, white crystals of are obtained after recrystallization from ethanol 4,6 ~ Dimethyl-3- (tetrazol-5-yl) -coumarin of bp 206 to 209 ° C.

Analysis for ^c ₁₂ ^H 10 ^N 4 ° 2- ^:

ber .: 59, 50 4, 16 23, 13th found : 59, 25th 4, 46 22 86

Example 6

Following the procedure of Example 5, 22.71 g (0.14 Möl) 3-Cyano-4,7-dimethyl-coumarin in 4,7-dimethyl-3- (tetrazol-5-yl) -curnarin with a melting point of 211 ° -214 ° C. after recrystallization from ethanol convicted.

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-5- 2A48A50

analysis for C ₁ ,
Lt 59 C.
% 4th H 23 N 59 , 50 4th , 16 23 , 13 , 72 , 15 , 15 , H ₁₀ N ₄ O ₂ : ber .: found :

Example'7

Following the procedure of Example 1, 8-chloro-3-cyano-4-methyl-coumarin is obtained from 8-chloro-3-cyano-4-methyl-coumarin the compound 8-chloro-4-methyl-3 ~ (tetra zol-5-yl) -coumarin of pp. 2JO to 232 ° C after recrystallization from ethanol.

analysis for C ₁₁ H ₇ ClN ₄ O ₂ : 50 C.
% 2 H
% N
% - 33 Cl
% 50 about ,: 50 , 30 3 , 69 21 55 13, 22nd found : , 23 , 05 21 13,

Example8

Following the procedure of Example 1, 20 g (0.107 mol) 7,8-Benzo-j5-eyano-4-methy! -Coumarin after recrystallization Ethanol white crystals on 7,8-Benzo-4-methyl-3- (tetrazol-5-yl) -coumarin from pp. 249 to 251 ° C.

analysis for C ₁ , 64 C.
% 3 H
% N
% 13th 63 , 74 3 , 62 20, 66 , 35 , 71 19 3H ₁₀ Nj ₊ O ₂ : ber .: found :

Example9

Following the procedure of Example 1, I-cyano-4-ethylcoumarin is obtained the compound 4-ethyl-3- (tetrazol-5-yl) -coumarin of Pp.

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-ίο- 2Λ48450

210 to 212 ° C after recrystallization from ethanol.

Analysis for C ₁₀ H _1n NhO ₀ : CHN

^{12 10 4 2} %%%

ber .: "59.50 k, 16 2 ^, 12

found: 59.55 4.29 25.25

Example 10

Following the procedure of Example 1, 41, 67 S (0.196 Mol) 5-cyano-4-n-propyl-coumarin the compound 4-n-propyl-5 ~ (Tetrazol-5-yl) -coumarin of bp 178 to 18l ° C after recrystallization from ethanol.

analysis for C ₁ , C.
fo 4, H N 60.95 4, 72 21.86 61.05 95 22.48 5H ₁₂ N ₄ O ₂ : ber .: found ':

Example Il

Following the procedure of Example 1, from 12 g (Ο, θ49 Mol) 5-cyano-4-phenyl-coumarin the compound 4-phenyl-5- (tetrazol-5-yl) -coumarin from m.p. 250 to 252 ° C (decomposition) after Umkri crystallize from ethanol.

analysis for C _{1 (} 66 C.
% 5 Ή
% 19 N
% 66 , 20 5 , 47 19 50 , 06 , 74 55 3H ₁₀ N ₄ O ₂ : ber .: found :

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2A48450

Example 12

(A) A mixture of 29 g (0.151 mol) of 4,5-diethyl-2-hydroxyaeetophenol and 24 ml of ethyl cyanoacetate becomes a
Added a solution of 0.70 g of sodium in 200 ml of ethanol. The mixture is left to stand at room temperature for 1 hour. After refluxing for every hour, the mixture is cooled and the
white crystalline precipitate filtered off. After recrystallization from ethanol, 3-cyano-6,7-diethyl-4-methyl-coumarin with a mp of 169.degree. C. is obtained.

analysis for C ₁ 5H ₁₅ NO ₂ : 74 C.
% 6th H
% 5, N
% ber .: 74 , 67 6th , 27 5, 80 found : , 53 , 37 81

(b) Following the procedure of Example 5, 17 g are obtained
(0.07 mol) 3-cyano-6,7-diethyl-4-methyl-coumarin the compound
6,7-Diethyl-4-methyl-3- (tetrazol-5-yl) -coumarin of m.p. 202 to
204 ° C after recrystallization from ethanol.

analysis for C ₁ , C. ι 34 5 H 19th N 63, 28 5 , 67 19th , 71 63, , 97 , 56 -H ₁₆ N ₄ O ₂ : ber .: found:

Biological results

All of the compounds prepared according to the preceding examples are examined biologically in the passive skin anaphylaxis test. .

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a) According to the method of I. Mota, "Immunology" 7 (1964), Page 681, heat-labile homocytotropic antibodies are produced in rats produced.

For this purpose, male Wistar rats with a body weight of 250 to 300 g are given 0.5 ml of Bordatella pertussis intraperitoneally

10

Vaccine containing 4 × 10 killed germs per ml and subcutaneously injected 0.5 ml of an emulsion of 100 mg ovalbumin in 2 ml sodium chloride solution and 3 ml incomplete Freunds' adjuvant. On the 18th day the blood is drawn from the rats by hypotension. The blood is collected and separated; Serum is stored at -20 ⁰ C and thawed just prior to use.

b) ■ The passive skin anaphylaxis test is performed according to the procedure by A. Ovary and O.E. Beer, "Proc. Soc. Exp. Biol. Med." 81. (1952), p. 584, and J. Goose and A.M.J.N. Blair, "Immunology" , 16 (1969), p. 769.

Each 0.1 ml of 6 samples of a double serum dilution series in 0.9 percent sodium chloride solution is 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. After 20 minutes the rats are sacrificed. It will be the diameter of the bruises measured at the antibody injection sites.

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The serum dilution series is set up so that at the injection site at the highest dilution there is no reaction, at the lowest dilution there is a maximum reaction. 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
to reduce the diameter of the bruises at the antibody injection sites, which was not a maximum in the controls
Reaction, show, investigated. The compound according to the invention is administered to a group of 6 animals a certain time before the intravenous ovalbumin injection.

The diameter of the bruises that develop in the test group becomes the diameter of the spots
a control group of 6 animals compared to the same
Were treated manner, but with solutions without the compound according to the invention.

% Inhibition of passive skin

Anaphylaxis test = 100 (1 - |)

a = the mean sum of the diameters of the blue spots,

those in the test group at the antibody injection sites
arise 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 to the antibody "injection"

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Z448450

places arise in which all animals show no maximum reaction.

The compound to be examined is preferably in a buffer solution of pH 7.2. dissolved, neutralized with sodium bicarbonate and then administered. .

The table below shows the results of the passive skin anaphylaxis test.

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example 1

% Inhibition of passive

Dose time _from skin img / kg) (min) anaphylaxis

test

25 100

25 100

0 0

60 60

Example 2

25 100

25 100

60

60

example 3 Me
XT - 25th
100
25th 0
0
60 - Ο * χ r ^ 0 ^ 0 N 100 60 21
27
28 35 N
ι

Example 4

N-

25th 0 22nd 100 'O 34 25th 30th 47 100 30th 70

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-Λ6 -

Example 6

" N
ti dose Time % Inhibition 35 / ^N (mg / kg) (rain at the pass- . 70 ^; venous skin
t) anaphylaxis 32 25th O test 19th 100 0 N- " 25th 60 H 100 60

25th 0 31 100 0 67 25th 30th 1 + 2 100 30th

Example 7 Example 8

25th 0 62 100 0 71 25th 30th 19th '100 30th 26th

25th
100

25th 100

60

60

16. 21

20 30

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Example 9

Dose (mg / kg)

25 100

25 100

# Inhibition during the passi-time yen skin (min) anaphylaxis test

0
0

30th
30th

33 11 19 70

Example 10

25th

100

25 100

0
0

30th
30th

-11 - 1 -12

Example 11

25 100

25th

100

30th 30th

-12 - 2 -10

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Example 12 dose
(mg / kg)

25th
100

25th

100

Time

% Inhibition of passive skin

vn skin (mm) anaphylaxis test

10
10
60
60

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Claims (1)

2.A4845Q Claims . ¹ IjL tetrazol ~ 5-yl-coumarin derivatives of the general formula I or their pharmacologically acceptable salts (D in which R is an alkyl or aryl radical and R ₁ , R ₂ , R- and R ^ are identical or different and are hydrogen or halogen atoms or alkyl, alkoxy, aryl, aralkyl, acyloxy or heterocyclic radicals or carboxyl groups, their salts or esters, where two of the radicals R-, Rp, R-, and R ^ can also form a substituted or unsubstituted carbocyclic or heterocyclic ring, with the proviso that R-, R ₃ , R- , and R ₁ . are all hydrogen atoms, so that R is not a methyl group. '2. Compounds according to Claim 1, characterized in that R is a lower alkyl radical. 3. Compounds according to claim 2, characterized in that · R is the methyl group. 4. Compounds according to claims 1 to 3 * characterized in that that R ^ is a halogen atom. 509817/1158 5. Compounds according to claims 1 to 3, characterized in that that Rp is a lower alkyl radical. 6. Compounds according to claims 1 to 3, characterized in that FU and FU are lower alkyl radicals. 7. Compounds according to claims 1 to 3, characterized in that that FU is a lower alkoxy radical. 8. The connections 6-bromo-4-ir _; ethyl-3- (tetrazol-5-yl) -coumarin, 6-chloro-4-methyl-3- (tetrazol-5-yl) -coumarin, 6 ~ bromo-4-ethij-l-3- (te trazol-5-yl) - © urnaritt, 8 ~ chloro-4-methyl ~ 3 ~ (tetrazol-5-yl) -coumarin, 4 ~ ethyl- 3- (tetrazol-5-yl) -coumarin, 4-I-ie thy l-8-nitro-3- (te trazol-5-yl) -coumarin, 6-methoxy-4-methyl ~ 3- (tetrazole- 5-yl) -coumarin, 6,7-DiChIOr- ¹ J -me thy 1-3- (tetrazol-5-yl) - coumarin, 4,6,8-trimethyl ~ 3- (tetra2ol-5 ~ yl) ~ coumarin, 4 ~ n ~ propyl ~ 3- (tetrazol-5-yl) -coumarin, 4,6-dimethyl-3- (tetrazol-5-yl) ~ curnarin, 4,7-dimethy1-3- (totrazol- 5-yl) -coumarin, 7,8-benzo-4-methy1-3- (tetrazol ~ 5-yl) -coumarin, 4-phenyl ~ 3- (tetrazol-5-yl) -coumarin, 6,7-diethyl -4-methyl-3- (tetrazol-5-yl) -coumarin, 4,6,7-trimethyl-3- (tetrazol-5-yl) -coumarin, 8-bromo-4-methyl-3- (tetrazole- 5-yl) coumarin and 7-methoxy-4-methyl-3- (tetrazol-5-yl) coumarin. 509817/1158 2A48450 9. Process for the preparation of the tetrazol-5-yl-coumarin derivatives according to claim 1, characterized in that there is a connection the general formula CN in which R, TL, Rp, R ^ and R ^ have the meanings given in claim 1 own, reacts with ammonium azide. 10. The method according to claim 9, characterized in that the ammonium azide is formed in situ. 11. Medicament, characterized by a content of a compound according to claim 1 and at least one pharmacologically compatible carrier material, and / or diluent. 12. Medicinal products, characterized by a content of 4-methyl-3- (tetrazol-5-yl) coumarin or their pharmacological properties compatible salts and at least one pharmacologically compatible carrier material and / or diluent. 5098 17/1158