EP0127634A1 - Pyrrolocoumarin derivatives, their manufacture and utilisation - Google Patents

Abstract

New pyrrolocoumarin derivatives of general formula (I) where .... represents a single or double bond, R4 and R8 each represent a hydrogen or an alkyl having between 1 and 4 carbon atoms, R6 represents a hydrogen or a hydroxyl, and R5 and R9 each represent a hydrogen, a hydroxyl, an alkyl having between 1 and 4 carbon atoms or an alkoxy having between 1 and 4 carbon atoms, provided that R6 can only be a hydroxyl when .... represents a single bond and that R5 and R9 do not represent a hydroxyl when R6 is a hydroxyl; these derivatives are useful as active ingredients in pharmaceutical products, as colorants and as intermediates. A preferred class of formula (Ia) in which R4 and R8 each represent a hydrogen or an alkyl having between 1 and 4 carbon atoms, and R5 and R9 each represent a hydrogen, a hydroxyl, an alkyl comprising between 1 and 4 carbon atoms or an alkoxy having between 1 and 4 carbon atoms, can be used in pharmaceutical compositions for the photochemotherapy of psoriasis. The compounds of formula (I) can be prepared by a cyclization reaction in accordance with Pechmann, preferably followed by a dehydrogenation or dehydration reaction in order to form compounds of formula (Ia).

Description

Pyrrolocoumarin derivatives, their manufacture and utilization.

This invention relates to novel pyrrolocoumarin derivatives which are useful in the pharmaceutical and dyestuff industries, as well as to methods of preparing such derivatives and to pharmaceutical compositions containing the same.

The novel pyrrolocoumarin derivatives of the present invention may be represented by the following general formula I:

wherein .... represents a single or double bond,

R ⁴ and R ⁸ each are hydrogen or C _1-4 alkyl,

R ⁶ is hydrogen or hydroxyl, and

R ⁵ and R ⁹ each are hydrogen, hydroxyl, C _1-4 alkyl or C _1-4 alkoxy, with the proviso that R ⁶ can only be hydroxyl when represents a single bond, and that R ⁵ and R ⁹ are different from hydroxyl when R ⁶ is hydroxyl.

A preferred group of compounds among the pyrrolocoumarin derivatives of formula I is represented by the following general formula Ia:

wherein R ⁴ and R ⁸ each are hydrogen or C _1-4 alkyl, and R ⁵ and R ⁹ each are hydrogen, hydroxyl, C ₁ _ ₄ alkyl or C _1-4 alkoxy. In the above formula I and Ia, the C _1-4 alkyl group may be straight or branched and may be methyl, ethyl, propyl, isopropyl, butyl, sec.butyl, isobutyl or tert. butyl, with reference for methyl and ethyl. Likewise, the C _1-4 alkoxy group may be straight or branched and may be methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec.butoxy, isobutoxy or tert.butoxy, with special preference for methoxy and ethoxy groups.

The pyrrolocoumarin derivatives of formula Ia have pharmacological activities and may be used e.g. in the photochemotherapy of psoriasis. Derivatives outside the scope of formula Ia but covered by formula I will have coloring properties and may be used e.g. as fluorescent colors in laser devices. Further, some of the derivatives of formula I may be useful as intermediates in the synthesis of pharmacologically or otherwise useful derivatives of the same general formula I.

With regard to pharmacological activities, it should be noted that certain furocoumarin derivatives have been disclosed in literature as useful agents in the photochemotherapy of psoriasis (J. Investigative Dermatology, 77, 39-44 (1981) and Br.J. Dermatology, 101, 379-389 (1978) .The derivatives of the present invention differ from these known compounds in terms of chemical structure. The pyrrolocoumarin derivatives of the present invention may be prepared along various routes. Preferably, howevsr, their preparation involves a cyclization reaction wherein a compound of formula II

is Condensed with malic acid or with a compound of the formula

R ⁴ -CO-CH ₂ -COOH III to form a dihydropyrrolocoumarin derivative of formula Ib: In these formulas (II, III, Ib) R is C _1-4 alkyl, R ⁴ and R ⁸ each are hydrogen or C _1-4 alkyl, R ⁶ is hydrogen or hydroxyl, and R ⁵ and R ⁹ each are hydrogen, hydroxyl, C _1-4 alkyl or C _1-4 alkoxy, with the proviso that R ⁵ and R ⁹ are different from hydroxyl if R ⁶ is hydroxyl.

The above cyclization reaction is of the type known as a "Pechmann reaction" and may be effected in accordance with generally known principles (compare "Organic Reactions", Volume VII, pages 1 and following, London 1953).

The resulting compound of formula Ib has a single bond between its positions 6 and 7. In case it is desired to have a double bond there, the synthesis may be continued by subjecting the compound of formula Ib to dehydrogenation (if R ⁶ is hydrogen) or dehydration (if R ⁶ is hydroxyl).

Both reactions can be effected in a way known per se

(compare A.I. Vogel, A textbook of Practical Organic

Chemistry, 3rd Edition, London 1956, pages 239, 828 and following, 947 and 1024) and will need no.further explanation here. The result is a pyrrolocoumarin derivative of formula Ia, wherein R ⁴ , R ⁵ , R ⁸ and R ⁹ have the above-mentioned meanings.

The route of synthesis chosen may sometimes be completed by converting the resulting derivatives of formula Ib or Ia to other derivatives of the same general formula.

Thus, eg a compound of formula Ib or Ia may be subjected to alkylation at its 8-position when R ⁸ is hydrogen. In the same way, compounds of formula Ib or Ia may be subjected to alkylation at their 5-position and / or 9-position if R ⁵ and / or R ⁹ are hydroxyl groups. Reaction conditions for such alkylation reactions will be known to those skilled in the art and may be derived from handbooks, compare Houben-Weyl,

Methods of Organic Chemistry, Stuttgart 1965, Volume VI / 3, Part 3, pages 54 and following, and further WJ Houlihan, Indoles, Part one, New York 1972, page 128 and following.

The invention further relates to pharmaceutical compositions comprising an effective amount of a compound of formula Ia together with a pharmaceutical carrier or diluent. Such compositions may have the form of dosage units and can be used for topical, intraperitoneal or any other type of application.

In the abovicted route of synthesis, the starting compounds of formula II may be prepared from easily accessible starting materials in a way known to those skilled in the art. Some of the various conceivable routes have been shown in the next part of the description.

The preparation of some preferred compounds of the present invention is illustrated by the following examples which are not meant to restrict the invention.

Example 1

Synthesis of 4,8-dimethyl-1H-pyrrolo- [3,2-g] -chromen-2-one

(Formula Ia, wherein R ⁴ = R ⁸ = methyl, R ⁵ = R ⁹ = H). a) Acetic anhydride (86 g), ice acetic acid (84 g) and powdered zinc (0.4 g) are added to m-anisidine (106 g).

The mixture is refluxed for 30 minutes, then poured into ice water (500 g) and agitated for 30 minutes. The resulting precipitate is collected by filtration, washed with cold water and dried in vacuo, thus giving N-acetyl-m-anisidine (mp 81 ° C) in 94% yield. b) N-acetyl-m-anisidine (33.0 g) is added to a suspension of sodium hydride (10 g) in boiling p-xylene (400 ml) and agitated under reflux for one hour. After adding dimethyl sulphate (28.0 g), the mixture is agitated under reflux for another hour. The reaction mixture is concentrated in vacuo and extracted with ethyl acetate. The extract is concentrated and n-hexanes is added, thus giving N-acetyl-N-methyl-m-anisidine (mp 64 ° C) in 65% yield. c) N.acetyl-N-methyl-m-anisidine (23 g) is heated under reflux in 50% sulfuric acid (150 ml) for 6 hours. After cooling, the mixture is neutralized with 20% aqueous sodium hydroxide and extracted with diethyl ether. The extract is concentrated and the resulting crude product is destilled in vacuo, thus giving N-methyl-m-anisidine (bp 131 ° C / 17 Torr) in 60% yield. d) Chloroacetyl Chloride (145 g) is added to N-methyl-m-anisidine (176 g) in dry benzene (420 ml) and refluxed therein for 1/2 hour. After cooling, water (500 ml) is added to the reaction mixture. The organic phase is separated, dried upon anhydrous magnesium sulphate and concentrated, thus giving N-chloroacetyl-N-methyl-m-anisidine (sm.p. 102 ° C) in 75% yield. e) N-chloroacetyl-N-methyl-m-anisidine (65 g) is ground in a mortar with anhydrous aluminum chloride (80 g) and heated to initiate a vigorous reaction. After cooling, ice water (400 ml) is added to the reaction mixture. The resulting product is collected by filtration and crystallized from ethanol, thus giving 6-hydroxy-N-methyl-2,3-dihydroindole- 2-one (mp 209 ° C) in 73% yield. f) 6-hydroxy-N-methyl-2,3-dihydroindole-2-one (32 g) are dissolved into anhydrous tetrahydrofurane (1400 ml) and a suspension of lithium aluminum hydride (39 g) in anhydrous tetrahydrofurane (150 ml) is added goal. The reaction mixture is refluxed under agitation for 6 hours and ice water (1700 ml) is added after after cooling. The mixture is neutralized with 6N hydrochloric acid and extracted 8 times with ethyl acetate (300 ml). The organic phase is dried upon sodium sulphate and extracted 5 times with 1N hydrochloric acid (150 ml each). The aqueous phase is evaporated to dryness (residueA).

The organic phase is also evaporated to dryness (residueB) and ice acetic acid (130 ml) and sodium borohydride (5 g) are added as. The mixture is agitated for two hours, chilled with ice and diluted with water (400 ml). Then, the mixture is neutralized with aqueous potassium hydroxide and potassium hydrogen carbonate, and extracted with ethyl acetate. The organic phase is re-extracted with 1N hydrochloric acid and the re-extract is evaporated to dryness after adding residue A starting, thus giving 6-hydroxy-N-methyl-2,3-dihydroindole hydrochloride in 56% yield. g) Ethanol (120 ml), acetoacetic ethyl ester (28.6 g), triethylamine (12.1 g) and anhydrous zinc chloride (44.5 g) are added to 6-hydroxy-N-methyl-2,3-dihydroindole hydrochloride (20.3 g) and the mixture is refluxed for 16 hours. After cooling, the resulting product is collected by filtration (residueA). The filtrate is evaporated to dryness, dissolved into ethanol (100 ml) and chloroform (900 ml) and washed with water until free of chloride ions. The organic phase is dried upon sodium sulphate and evaporated to dryness (residueB). Both residues are combined, subjected to column chromatography on silica gel (with methylene chloride as elution agent) and recrystallized from ethyl acetate.

The result is 4,8-dimethyl-6,7-dihydro-1H-pyrrolo- [3,2-g] -chromene-2-one in 79% yield. Mp 221.5 - 222.5 ° C. h) Mesitylene (50 ml) and 10% palladium-carbon catalyst (0.1 g) are added to 4,8-dimethyl-6,7-dihydro-1H-pyrrolo- [3,2-g] -chromen-2-one (1 g) and the mixture is refluxed for 12 hours. The catalyst is filtrated off and washed with methanol. The organic phases are combined and concentrated in vacuo. Then, the product is purified by chromatography on a silica gel column, thus giving 4,8-dimethyl-1H-pyrrolo- [3,2-g] -chromen-2-one (750 mg) of mp 209.5 - 210 ° C .

Example 2

Synthesis of 8-ethyl-4-methyl-1H-pyrrolo- [3,2-g] -chromen-2-one (formula Ia, wherein R ⁴ = methyl, R ⁸ = ethyl, R ⁵ = R ⁹ = H) . a) N-acetyl-m-anisidine (33.5 g) is dissolved into anhydrous tetrahydrofurane (200 ml). The resulting solution is added dropwise to a refluxed Suspension of lithium aluminum hydride (12 g) in anhydrous tetrahydrofurane (200 ml). After refluxing for 6 hours, the reaction mixture is cooled with ice, treated with water (12 ml) and a solution of 15% sodium hydroxide (12 ml) and water (36 ml) and agitated for 20 minutes.

The resulting precipitate is collected by filtration and washed with diethyl ether and chloroform. The organic phases are combined and concentrated in vacuo. The residu is dissolved into 10% aqueous hydrochloric acid (250 ml), extracted with ethyl acetate (a small amount) and precipitated with potassium hydrogen carbonate.

The second precipitate is extracted with diethyl ether and the organic phase is dried upon sodium sulfate and concentrated in vacuo. The residu is destilled in vacuo

(0.1 mmHg), thus giving N-ethyl-m-anisidine (bp 80 ° C / 0.1 mmHg) in 73% yield. b) N-ethyl-m-anisidine is reacted with chloroacetyl chloride under the conditions of example 1d, thus giving N-ethyl-N-chloroacetyl-m-anisidine in 66% yield. c) N-ethyl-N-chloroacetyl-m-anisidine is converted to 1-ethyl-6-hydroxy-2,3-dihydroindole-2-one under the conditions of example 1e in 70% yield. d) 1-ethyl-6-hydroxy-2,3-dihydroindole-2-one (20 g) are dissolved into anhydrous tetrahydrofurane (400 ml). The solution is added dropwise to a refluxed suspension of lithium aluminum hydride (22 g) in anhydrous tetrahydrofurane (100 ml) and the mixture is refluxed for another 6 hours.

The reaction mixture is cooled with ice and, after an addition of ice under nitrogen gas, is poured into water (1 1). The mixture is neutralized with 6N hydrochloric acid and extracted 5 times with ethyl acetate (200 ml). The organic phase is extracted 3 times with 1N hydrochloric acid (50 ml) and the aqueous phase is washed with water and concentrated in vacuo (residueA). The ethyl acetate phace is also concentrated and its residueis dissolved into acetic acid (50 ml). Then, sodium borohydride (3.8 g) is added in portions to the agitated solution. The mixture is agitated for another two hours, cooled in ice and poured into water (300 ml). The resulting mixture is neutralized with potassium hydrogen carbonate and worked up in the same way as above (residueB). Residues A and B are combined and dissolved into methanol (150 ml). After treating with activated carbon, the solution is concentrated and its residueis dried upoO P ₂ O ₅ and KOH, thus giving 1-ethyl-6-hydroxy-2,3-dihydroindole hydrochloride in 74% yield. e) A mixture of 1-ethyl-6-hydroxy-2,3-dihydroindole hydrochloride (16.1 g), triethylamine (8.5 g), ethyl acetate (20.8 g) and zinc chloride (32.6 g) in anhydrous ethanol (80 ml ) is refluxed for 5 hours.

After cooling, ethanol (200 ml) and dichloromethane (1 1) are added to the reaction mixture and the organic phase is washed with water until free from chloride ions. The organic phase is evaporated to dryness. The resulting crude product is subjected to chromatography on a silica gel column with dichloromethane and is recrystallized from ethyl acetate and from ethanol-petroleum ether, thus giving 8-ethyl-4-methyl-6,7-dihydro-1H-pyrrolo-

[3.2 g] -chromene-2-one (mp 101-102 ° C) in 78% yield. f) 8-ethyl-4-methyl-6,7-dihydro-1H-pyrrolo- [3,2-g] - chromen-2-one are dissolved in mesitylene (100 ml) and, after addition of 10% palladium on carbon (0.6 g), the solution is refluxed for 6 hours. Then, the catalyst is filtrated off and washed with ethanol and the combined filtrates are evaporated to dryness. The resulting crude product is purified by chromatography on silica gel (with toluene-ethyl acetate 80:20 as elution agent) and recrystallized from ethyl acetate, thus giving 8-ethyl-4-methyl-1H-pyrrolo- [3,2-g ] -chromen-2-one (mp 114.5 - 115 ° C) in 64% yield.

Example 3 Synthesis of 4-methyl-1H-pyrrolo- [3,2-g] -chromene-2-one (formula 1a, wherein R ⁴ = methyl, R ⁵ = R ⁸ = R ⁹ = H). a) Concentrated sulfuric acid (500 ml) is cooled to 5 ° C and 2,3-dihydroindole (90 g) is added after in 20 minutes while keeping the temperature at 5-10 ° C. Then, the mixture is cooled to 0 ° C and a mixture of anhydrous nitric acid (35 ml) in anhydrous sulfuric acid (300 ml) is added dropwise and under agitation, while keeping the reaction temperature at 3-5 ° C. After agitation for one hour, the mixture is poured into ice water (4 x 1500 ml) and allowed to stand overnight.Then, the mixture is filtrated and neutralized with sodium hydroxide and potassium hydrogen carbonate. The resulting product is collected by filtration, washed with water and dried on phosphorus pentoxide, thus giving 6-nitro-2,3-dihydroindole (mp 67-69 ° C) in 88% yield. b) 6-nitro-2,3-dihydroindoles (115 g) are dissolved into diethyl ether (2000 ml) and pyridine (56 ml) and a solution of benzoyl chloride (98.5 g) in diethyl ether (100 ml) are added. The mixture is agitated for another hour. Then, the precipitate is collected by filtration, washed with diethyl ether (a small amount) and combined with 2N hydrochloric acid (350 ml) and dichloromethane (1600 ml). The organic phase is washed with sodium chloride solution and water and thereupon dried and evaporated to dryness. The residue is taken up into diethyl ether and filtrated, thus giving 1-benzoyl-6-nitro-2,3-dihydroindole (mp 166-168 ° C) in 90% yield. c) 1-benzoyl-6-nitro-2,3-dihydroindole (21.5 g) is dissolved into a heated mixture of tetrahydrofurane

(300 ml) and ice acetic acid (300 ml). After cooling, 10% palladium on carbon (1 g) is added to the -ixture and hydrogenation is carried out for one hour at a pressure of 2.8 kg / cm ² . The catalyst is filtrated off and washed with tetrahydrofurane. The combined filtrates are concentrated in vacuo and their residueis taken up into 1N hydrochloric acid (100 ml) and extracted 3 times with dichloromethane (50 ml each). The aqueous phase is neutralized with potassium hydrogen carbonate. The precipitate is collected by filtration, washed with water and dried above phosphorus pentoxide, thus giving 6-amino-1-benzoyl-2,3-dihydroindole (mp 183 ° C) in 93% yield. d) A solution of 6 amino-1-benzoyl-2,3-dihydroindoles (83.3 g) in 1N hydrochloric acid (1050 ml) is cooled to -5 ° C. Then, a one molar sodium nitrite solution is added after, while keeping the temperature at -5 to -2 ° C. The reaction mixture is kept for another 45 minutes in the ice bath, allowed to stand for 15 minutes at room temperature and heated at 70-75 ° C for two hours. Then, the mixture is cooled by an ice bath and the resulting product is collected by filtration, washed with cold water and dried upon phosphorus pentoxide.

The resulting crude product is refluxed in chloroform (300 ml). After cooling, the product is collected by filtration and washed again with chloroform until the latter is colored only weakly yellow. The result is 1-benzoyl-6-hydroxy-2,3-dihydroindole (m.p. 229 ° C) in 71% yield. e) 1-benzoyl-6-hydroxy-2,3-dihydroindole (20 g) is refluxed for one hour in 65% sulfuric acid (110 ml).

After cooling, the precipitate is collected by filtration and washed with water. The aqueous solutions are neutralized with sodium carbonate and potassium hydrogen carbonate and thereupon 4 times extracted with a mixture of ethyl acetate and n-butanol (3: 1). The organic phase is dried with sodium sulphate and re-extracted 3 times with 2N hydrochloric acid (100 ml each) and one time with water (50 ml). The aqueous phase is washed with diethyl ether (a small amount) and concentrated in vacuo, thus giving 6-hydroxy-2,3-dihydroindole hydrochloride in 66% yield. f) 6-hydroxy-2,3-dihydroindole hydrochloride (5.6 g), triethylamine (3.5 g), ethyl acetoacetate (6.5 g) and zinc chloride (13.6 g) in anhydrous ethanol (30 ml) are refluxed for 48 hours under nitrogen gas. Then, the mixture is concentrated and the residue is taken up in ethyl acetate and washed with water until free from chloride ions. The organic phase is dried upon sodium sulphate and concentrated. The residueis subjected to chromatography on a silica gel column with dichloromethane-acetone (96: 4). The product is recrystallized from ethyl acetate, thus giving 4-methyl-6,7-dihydro-1H-pyrrolo- [3,2-g] -chromen-2-one (mp 213-214 ° C) in 40% yield. g) 4-methyl-6,7-dihydro-1H-pyrrolo- [3,2-g] -chromene-2-one (3 g) is dissolved in butyl acetate (300 ml) and refluxed for 4 hours after addition of 10% palladium / carbon (700 mg). Then, the catalyst is filtrated off and washed with hot butyl acetate.

The organic phase is concentrated and the residue is subjected to chromatography on a silica gel column with dichloromethane. The product is recrystallized from ethyl acetate-ethanol (1: 1), thus giving 4-methyl-1H-pyrrolo- [3,2-g] -chromen-2-one (mp 241-242.5 ° C) in 50% yield .

Claims

Pyrrolocoumarin derivatives of the general formula I:

wherein ...... represents a single or double bond,

R ⁴ and R ⁸ each are hydrogen or C _1-4 alkyl,

R ⁶ is hydrogen or hydroxyl, and

R ⁵ and R ⁹ each are hydrogen, hydroxyl, C _1-4 alkyl or C _1-4 alkoxy, with the proviso that R ⁶ can only be hydroxyl when ....... represents a single bond, and that R ⁵ and R ⁹ are different from hydroxyl when R ⁶ is hydroxyl.

2. Pyrrolocoumarin derivatives as claimed in claim 1, represented by the general formule Ia:

wherein R ⁴ and R ⁸ each are hydrogen or C _1-4 alkyl, and R ⁵ and R ⁹ each are hydrogen, hydroxyl, C _1-4 alkyl or C _1-4 alkoxy.

3. 4-methyl-1H-pyrrolo [3,2-g] -chromene-2-one.

4. 4,8-dimethyl-1H-pyrrolo [3,2-g] -chromene-2-one.

5. 8-ethyl-4-methyl-1H-pyrrolo [3,2-g] -chromen-2-one.

6. A method of preparing pyrrolocoumarin derivatives of the general formula I:

wherein represents a single or double bond, R ⁴ and R ⁸ each are hydrogen or C _1-4 alkyl,

R ⁶ is hydrogen or hydroxyl, and R ⁶ and R ⁹ each are hydrogen, hydroxyl, C _1-4 alkyl or C _1-4 alkoxy, with the proviso that R ⁶ can only be a hydroxyl group when ...... represents a Single bond, and that R ⁵ and R ⁹ different from hydroxyl when R ⁶ is hydroxyl, comprising the Steps of: a) providing a compound of formula II:

wherein R ⁵ and R ⁹ each are hydrogen, hydroxyl, C _1-4 alkyl or C _1-4 alkoxy,

R ⁶ is hydrogen or hydroxyl, R ⁸ is hydrogen or C _1-4 alkyl, with the proviso that R ⁵ and R ⁹ are different from hydroxyl when R ⁶ is hydroxyl; b) condensing the compound of formula II with malic acid or with a beta-keto ester of formula III:

R ⁴ -CO-CH ₂ -COOR (III)

wherein R is C _1-4 alkyl, and R ⁴ is hydrogen or C _1-4 alkyl, to form a compound of formula Ib:

wherein R ⁴ , R ⁵ , R ⁶ , R ⁸ and R ⁹ have the same meaning as in formula II with the proviso that R ⁵ and R ⁹ are different from hydroxyl when R ⁶ is hydroxyl; c) optionally dehydrogenating the compound of formula Ib (if R ⁶ is hydrogen) or optionally dehydrating the compound of formula Ib (if R ⁶ is hydroxyl) to form a compound of formula Ia: wherein R ⁴ and R ⁸ each are hydrogen or C _1-4 alkyl, and R ⁵ and R ⁹ each are hydrogen, hydroxyl, C _1-4 alkyl or

C ₁ _ ₄ alkoxy; d) optionally subjecting the resulting compound of formula Ib or Ia to alkylation at its 8-position when R ⁸ is hydrogen; and e) optionally subjecting the resulting compound of formula Ib or Ia to alkylation at its 5-position (if R ⁵ is hydroxyl) and / or its 9-position (if R ⁹ is hydroxyl)

7. A pharmaceutical composition, comprising an effective amount of a pyrrolocoumarin derivative of formula Ia:

wherein R ⁴ and R ⁸ each are hydrogen or C _1-4 alkyl, and R ⁵ and R ⁹ each are hydrogen, hydroxyl, C _1-4 alkyl, or C _1-4 alkoxy.