DE2837236A1 - INDOLOPYRONS AND THEIR USE - Google Patents

Description

where mean:
^l 2

and R-, which can be the same or different, individually Hydrogen or halogen atoms, hydroxy groups, short-chain alkyl or alkoxy groups with 1 to 6 carbon atom (s), trifluoromethyl radicals, nitro radicals, or together a methylenedioxy radical;

R-. a hydrogen atom, a short-chain alkyl radical with 1 to 6 carbon atom (s), an aryl, ζ.B. Phenyl radical or a substituted aryl radical and

R _{4 is} a carboxamido, cyano or tetrazolyl radical, as well as their pharmaceutically acceptable inorganic or organic salts.

The indolopyrones according to the invention are obtained if they are adhered to following reaction stages:

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In the first stage, an ester of a substituted indolopyrone of the formula II in the presence of a solvent, for example water, a low molecular weight alcohol or an aqueous-alcoholic solution, is converted with ammonia to an indolopyronamide according to the invention, in which R ₁ , R- and R ₃ have the meaning given and R _{4 is} a carboxamido radical, implemented.

COOR ₅₅

II

The indolopyrone esters of the formula II, in which R-, R ₂ and R _{3 have} the meaning given and R _{g stands} for a short-chain alkyl radical having 1 to 6 carbon atom (s), are obtained in a manner corresponding to that in US Pat 028 383 and the US patent application with serial no. 764 110 is described.

In detail, the indolopyrone esters of the formula II are obtained by reacting a methyl ketone of the general formula:

OH

with a short-chain alkyl ester of oxalic acid, ζ.B. "Diethyloxalate in the presence of a strong base, e.g. sodium amide, potassium tert-butoxide, sodium hydride or preferably Sodium ethoxia. The implementation is usually in one

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Solvents such as ethanol, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide and the like.

The invention also relates to medicaments with antiallergic and antiasthmatic activity which, if appropriate, together with a pharmaceutically acceptable carrier, an effective amount of at least one indolopyron of formula I contains.

The pharmaceutically acceptable salts of the (free) indolopyrones of the general formula (I) are obtained in accordance with customary methods known processes with equivalent amounts of inorganic or organic solutions. Examples of pharmaceutical acceptable salts are the metal salts obtained with sodium or potassium hydroxide.

The indolopyrones of the general formula I and their pharmaceuticals Acceptable inorganic and organic salts are topically in the form of ointments, creams or aerosols applied or optionally mixed with a liquid or solid pharmaceutical diluent or carrier administered enterally or parenterally. The preferred injection medium is water with customary pharmaceutical additives for injection solutions, e.g. stabilizers, solubilizing agents and buffers, e.g. ethanol, complexing agents, such as ethylenediaminetetraacetic acid, tartrate and citrate buffers and high molecular weight polymers such as polyethylene oxide, used for viscosity control. Examples of suitable carriers are starch, lactose, mannitol, methyl cellulose, Talc, highly dispersed silicic acids, high molecular weight fatty acids such as stearic acid, and high molecular weight Polymers such as polyethylene glycol. Oral forms of administration can of course contain flavors, sweeteners, Contain preservatives, suspending agents, thickeners and emulsifiers.

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The indolopyrones according to the invention arrive more effectively in the form Dpsis units or unit doses for use. Under an effective unit dose or unit dose is one given sufficient to bring about the desired antiasthmatic or antiallergic effect in vivo Understand amount of active ingredient.

According to the invention, mammals and humans inhibit or alleviate allergic and asthmatic conditions by giving the mammals or humans an effective antiallergic or antiasthmatic amount of at least one indolopyrone of the general formula I or one pharmaceutically acceptable salt thereof administered.

The dosage of the indolopyrones of the formula I or their pharmaceutically acceptable salts depends of course on the type and severity of the asthmatic or allergic condition to be controlled and the route of administration. When tested according to Herzig "Immunopharmacology" Editors M.E. Rosenthale and H.C. Mansmann, publisher John Wiley and Sons, New York 1975, it has been shown that the indolopyrones according to the invention and their pharmaceutical acceptable salts are able to inhibit allergic conditions or passive skin anaphylaxis in mammals, when given to the mammals in question per kg of body weight in an amount of 0.1 to 10.0 mg orally, parenterally or administered intravenously.

The following examples are intended to illustrate the invention in more detail.

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example 1

4,5-Dihydro-5-methyl-4-oxopyrano ^ 3, 2 ~ bJ indole-2-carboxamide the formula:

A suspension of 11.0 g (40.7 itiMole) of ethyl 4,5-dihydro-5-methyl-4-oxopyrano £ 3,2-bJindol-2-carboxylate in 500 ml of ethanol is poured into ice while passing in gaseous ammonia Stirred until the reaction mixture has assumed ^{a temperature of 20 °} C. (after about 10 min). The ice bath is then removed and stirring is continued at room temperature for a total of 24 hours. The pale yellow solids formed in this way are filtered off and washed with a little cold ethanol. When recrystallizing from 50% aqueous dimethylformamide, light yellow needles with a melting point of more than 295 ^° C. are obtained.

Example 2

4,5-Dihydro-5-ethyl-4-oxopyranol / j3, 2-b] indole-2-carboxamide the formula:

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-F-

According to Example 1, from ethyl 4,5-dihydro-5-ethylr4-oxopyrano [3,2-b7indole-2-carboxylate 4,5-dihydro-5-ethyl-4-oxopyranol [] 3 _/ 2-bJindol- 2-carboxamide. After repeated recrystallization of the reaction product obtained

obtained from aqueous dimethylformamide / tan-colored needles

mp 224-226 ° C.
Example 3

4,5-Dihydro-4-oxo-5-phenylpyrano £ 3,2-b-iindole-2-carboxamide the formula:

In accordance with Example 1, ethyl 4,5-dihydro-4-oxo-5-phenylpyrano [3,2-b] indole-2-carboxylate is obtained 4,5-dihydro-4-oxo-5-phenylpyrano £ 3,2-b] indole-2-carboxamide. After repeated recrystallization of the reaction product from acetone or aqueous dimethylformamide, white needles are obtained having a mp of 263-265 ° C.

Example 4

4,5-Dihydro-5-methyl-4-oxopyranol £ 3,2-b3indole-2-carbonitrile the formula:

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.9.

A mixture of 10.5 g (43.3 mmoles) 4,5-dihydro-5-methyl-4-oxopyrano £ 3,2-b] indole-2-carboxamide, 12.6 g (66.2 mmoles) p -Toluenesulfonyl chloride and 10.3 g (10.5 ml, 130 mmol) of pyridine in 55 ml of dimethylformamide is heated for 4 hours on a steam bath under a nitrogen atmosphere. After cooling, the cold mixture is poured into 500 g of ice water. The mixture is stirred for 20 minutes after which the pink solids are filtered off and washed with cold water. After two recrystallization from ethanol, light pink needles with a melting point of 190 192 ^° C. are obtained.

Example 5

4,5-dihydro-5-ethyl-4-oxopyranof3,2-b-iindole-2-carbonitrile the formula:

C ₂ ed

In a manner similar to that in Example 4, 4,5-dihydro-5-ethyl-4-oxopyrano £ 3, 2-hl indole-2-carboxamide 4,5-dihydro-5-ethyl-4-oxopyranoC3,2- bJ indole-2-carbonitrile. After repeated recrystallization from ethanol, yellow needles with a melting point of 183.5 ° -185 ° C. are obtained.

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./10-

Example 6

4,5-dihydro-4-oxo-5-phenylpyranoC3,2-b-iindole-2-carbonitrile the formula:

According to Example 4, 4,5-dihydro-4-oxo-5-phenyIpyrano C 3,2-b] indole-2-carboxamide is obtained 4,5-dihydro-4-oxo-5-phenylpyranoC3 ^ -bjindole ^ -carbonitrile . When recrystallizing from ethanol or acetonitrile, pink needles with a melting point of 191.5 to 193 ^° C. are obtained.

Example 7

5-methyl-2 (1H-tetrazol-5-yl) pyrano £ 3,2-bI indol-4 (5H) -one the formula:

A mixture of 4.0 g (17.9 mmoles) of 4,5-dihydro-5-methyl-4-oxopyranoC3,2-b-iindole-2-carbonitrile and 4.0 g (61.6 mmol)

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Sodium azide in 500 ml of tetrahydrofuran is mixed with 5.3 g (39.8 mmol) of anhydrous aluminum chloride in portions within 20 to 30 minutes under a nitrogen atmosphere. After stirring for 21 hours at reflux temperature, the reaction mixture is cooled and a further 2.0 g (30.8 mmol) of NaN ₃ and 4.8 g (36.3 mmol) of AlCl _{3 are} added in the manner described. Thereafter, stirring is continued for a total of 61 h at reflux temperature. After cooling in ice, the reaction mixture is carefully poured into 2.0 l of ice water. On acidification with 4N-HCI (it escapes HN ₃₎ at a temperature of at most 5 ⁰ C is obtained tan solids. These are filtered off, digested on a steam bath for 30 minutes with 200 ml of water and then filtered warm. The crude product is stirred in 150 ml of acetone for 20 minutes and the solids are filtered off again. Recrystallization from aqueous dimethylformamide gives yellow plates with a melting point of 270 ^° C. (with decomposition).

Example 8

5-phenyl-2 (1H-tetrazol-5-yl) pyranoC3,2-b] indol-4 (5 ^ -one the formula:

N-

In a manner similar to that in Example 7, axis 4,5-dihydro-4-oxo-5-phenylpyrano / j3,2-b is obtained. Jindol-2-carbonitrile 5-phenyl-2 (iH-tetrazol-5-yl) pyranoL "3,2-b] indol-4 (5H) -

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on, being heated to reflux temperature for 87 h and the Acetone treatment is omitted prior to recrystallization. After recrystallizing twice from aqueous

man
Dimethylformamide receives / tan needles with an mp of

245 ⁰ C (with decomposition).

As already stated, the indolopyrones according to the invention can expediently and usually in oral Administration form, e.g. as tablets or capsules. The manufacture of such oral dosage forms is made by combining an effective amount of each indolopyron with any oral pharmaceutically acceptable inert diluents such as lactose, starch, dicalcium phosphate, calcium sulfate, Kaolin, mannitol and powdered sugar. If necessary, suitable binders, lubricants, disintegration-promoting agents and dyes are added. Suitable binders are starch, gelatine, sugar, such as cane sugar, molasses and lactose, natural and synthetic gum such as acacia gum, sodium alginate, Irish moss extract, Carboxymethyl cellulose, methyl cellulose and polyvinylpyrrolidone, polyethylene glycol, ethyl cellulose and waxes. Typical lubricants in these administration forms include boric acid, sodium benzoate, sodium acetate, Sodium chloride, leucine and polyethylene glycol. Suitable agents that promote disintegration include starch, methyl cellulose, Agar-agar, bentonite, cellulose and wood products, alginic acids, guar gum, citrus pulp, carboxymethyl cellulose and sodium lauryl sulfate. Optionally, commonly pharmaceutically acceptable dyes, such as standard FD & C dyes, may also be used.

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Claims (11)

Claims 1.Ihdolopyrone of the formula: 25 AUG. 1S78 where mean: R ₁ and R ₂ , which can be identical or different, individually hydrogen or halogen atoms, hydroxy radicals, short-chain alkyl or alkoxy radicals with 1 to 6 carbon atom (s), trifluoromethyl radicals, nitro radicals or together a methylenedioxy radical; Ro is a hydrogen atom, a short-chain alkyl radical with 1 to 6 carbon atom (s), or an optionally substituted aryl radical and R. a carboxamido, cyano or tetrazolyl radical, as well as their pharmaceutically acceptable organic and inorganic salts. 2. indolopyrones according to claim 1, characterized in that they correspond to the formula given, in which: 9098U / 08S1 R ₁ and R _{2 are} hydrogen atoms; R,. a hydrogen atom, a short-chain alkyl radical with 1 to 6 carbon atom (s) or a phenyl radical and R _{4 is} a carboxamido, cyano or tetrazolyl radical, as well as their pharmaceutically acceptable organic or inorganic salts. 3. 4,5-dihydro-5-methyl-4-oxopyranoC3,2-b-iindole-2-carboxamide. 4. 4,5-Dihydro-5-ethyl-4-oxopyranol [3,2-b] indole-2-carboxamide. 5. 4,5-Dihydro-4-oxo-5-phenylpyrano D, 2-b] indole-2-carboxamide. 6. 4,5-Dihydro-5-methyl-4-oxopyranol C3,2-b] indole-2-carbonitrile. 7. 4,5-Dihydro-5-ethyl-4-oxopyranoC3,2-bJ indole-2-carbonitrile. 8. 4,5-Dihydro-4-oxo-5-phenylpyrano [3, 2-bI indole-2-carbonitrile. 9. 5-methyl-2 (iH-tetrazol-5-yl) pyranof3,2-b] indol-4 (5H) -one. 10. 5-Phenyl-2 (1H-tetrazol-5-yl) pyrano β, 2-b] indol-4 (5H) -one. 11. Use of indolopyrones according to one or more of the preceding claims for combating allergic or asthmatic conditions in mammals and humans. 9098U / 06I1