HK1123280B - N-substituted indole-3-glyoxylamides having anti-asthmatic, antiallergic and immunosuppressant/immuno-modulating action - Google Patents

Description

N-substituted indole-3-glyoxylamides having antiasthmatic, antiallergic and immunosuppressive/immunomodulating action

The application is a divisional application of Chinese patent application with the application date of 1997, 8/16, application number of 97197128.5, and the invention name of 'N-substituted indole-3-glyoxylamide compound with anti-asthma, anti-allergy and immunosuppressive/immunoregulatory effects'.

Indole-3-glyoxylamides have a variety of uses and can be used as pharmaceutically active compounds and as synthesis starting materials in pharmaceutical chemistry.

Patent application NL 6502481 describes compounds with anti-inflammatory and antipyretic action and analgesic activity.

British patent GB 1028812 proposes indolyl-3-glyoxylic acid derivatives and their amides having analgesic, anticonvulsant and β -adrenergic activity.

3-indolyl glyoxylamides are described by G.Domschke et al (Comm (Ber.)194, 2353(1961)) without describing the pharmacological profile of the compounds.

Indolyl-3-glyoxylic acid derivatives having inhibitory activity against phosphoglycerate dehydrogenase and lactate dehydrogenase are reported by E.Walton et al in the journal of medicinal chemistry (J.Med.chem.)11, 1252 (1968).

European patent Specification EP 0675110A1 describes 1H-indole-3-glyoxylamides which are sPLA2 inhibitors and are useful for the treatment of septic shock, pancreatitis, allergic rhinitis and rheumatoid arthritis.

The invention aims to provide a novel series of indolyl-3-glyoxylic acid compounds having anti-asthmatic and immunoregulatory effects.

Methods for preparing these compounds, as well as pharmaceutical methods for converting the novel compounds into medicaments and dosage forms thereof are also described.

The invention relates to a compound of general formula (I),

formula I

Wherein the group R, R₁、R₂、R₃、R₄Z has the following meanings

R is hydrogen, (C)₁-C₆) -alkyl, wherein the alkyl may be mono-or polysubstituted by phenyl, which phenyl may itself be substituted by halogen, (C)₁-C₆) Alkyl radicals, (C)₃-C₇) Cycloalkyl, carboxy, with (C)₁-C₆) -alkanol esterified carboxy, trifluoromethyl, hydroxy, methoxy, ethoxy, oxy and benzyl mono-or polysubstituted in the phenyl part of the benzyl group by (C)₁-C₆) Alkyl, halogen or trifluoroMethyl mono-or poly-substituted;

R₁can be a quilt (C)₁-C₆) Alkyl radicals, (C)₁-C₆) -alkoxy, hydroxy, benzyloxy, nitro, amino, (C)₁-C₆) -alkylamino, (C)₁-C₆) -alkoxycarbonylamino, carboxy or with (C)₁-C₆) -an alkanol-esterified carboxyl mono-or poly-substituted benzene ring, or a pyridine structure of formula II,

formula II

Wherein the pyridine structure may be attached to ring carbon atoms 2, 3 or 4 and may be substituted by a substituent R₅And R₆And (4) substitution. R₅And R₆May be the same or different and may be (C)₁-C₆) Alkyl radicals, (C)₃-C₇) -cycloalkyl, (C)₁-C₆) -alkoxy, nitro, amino, hydroxy, halogen, trifluoromethyl, ethoxycarbonylamino and carboxyalkoxy in which the alkyl moiety contains 14 carbon atoms;

R₁it may also be a 2-or 4-pyrimidinylheterocycle or pyridylmethyl, where CH₂May be in the 2-, 3-or 4-position, wherein the 2-pyrimidinyl radical may also be mono-or polysubstituted by methyl, and may furthermore be substituted by (C)₁-C₆) Alkyl, halogen, nitro, amino and (C)₁-C₆) -alkylamino-substituted 2-, 3-and 4-quinolyl structures or 2-, 3-and 4-quinolylmethyl in which the pyridyl methyl and quinolylmethyl ring carbon atoms may be replaced by (C)₁-C₆) Alkyl radicals, (C)₁-C₆) -alkoxy, nitro, amino and (C)₁-C₆) -alkoxycarbonylamino substitution;

R₁in the case where R is hydrogen or benzyl, it may also be natural orAcyl groups of synthetic amino acids, such as α -glycyl, α -sarcosyl, α 0-alanyl, α 1-leucyl, α 2-isoleucyl, α 3-seryl, α -phenylalanyl, α -histidyl, α -prolyl, α -arginyl, α -lysyl, α -asparaginyl (α -asparagyl) and α -glutamyl, wherein the amino group of each amino acid may be in an unprotected or protected form, and the amino functional group protecting group may be a benzyl ester group (Z group), a tert-butoxycarbonyl group (BOC group) or an acetyl group. When R is₁When it is asparaginyl or glutamyl, the second unbound carboxyl group is either free or is linked to C₁-C₆The form of an ester of an alkanol, for example a methyl, ethyl or tert-butyl ester. R₁It may also be allylaminocarbonyl-2-methylpropan-1-yl. If R is₁Is aminoalkylene, R and R₁Together with the nitrogen atom to which they are attached, may also form a piperazine or homopiperazine (homopiperazine) ring of the formula III, where

Formula III

R₇Is alkyl, can be (C)₁-C₆) Alkyl radicals, (C)₁-C₆) Alkoxy, halogen, nitro, amino, (C)₁-C₆) -alkylamino, benzhydryl and di-p-fluorobenzhydryl (Bis-p-fluorobenzylbenzyl) mono-or polysubstituted phenyl rings.

R₂Can be hydrogen or (C)₁-C₆) -alkyl, wherein the alkyl may be mono-or polysubstituted by halogen and phenyl, which phenyl in turn may be substituted by halogen, (C)₁-C₆) Alkyl radicals, (C)₃-C₇) Cycloalkyl, carboxy, with (C)₁-C₆) -an alkanol esterified carboxy, trifluoromethyl, hydroxy, methoxy, ethoxy or benzyloxy group, mono-or polysubstituted. As R₂Is (C)₁-C₆) The alkyl radical may alsoSubstituted by 2-quinolyl and 2-, 3-and 4-pyridyl which in turn may be substituted by halogen, (C)₁-C₄) -alkyl or (C)₁-C₄) -alkoxy is mono-or polysubstituted. R₂It may also be aroyl, where the aryl moiety on which the group is based is a phenyl ring, which may be substituted by halogen, (C)₁-C₆) Alkyl radicals, (C)₃-C₇) Cycloalkyl, carboxy, with (C)₁-C₆) -an alkanol esterified carboxy, trifluoromethyl, hydroxy, methoxy, ethoxy or benzyloxy group, mono-or polysubstituted.

R₃And R₄May be the same or different and may be hydrogen, hydroxy, (C)₁-C₆) Alkyl radicals, (C)₃-C₇) -cycloalkyl, (C)₁-C₆) Alkanoyl, (C)₁-C₆) -alkoxy, halogen and benzyloxy. R₃And R₄Can also be nitro, amino, (C)₁-C₄) -mono-or dialkyl-substituted amino, (C)₁-C₃) -alkoxycarbonylamino or (C)₁-C₃) -alkoxycarbonylamino- (C)₁-C₃) -an alkyl group.

Z is O or S.

It is to be understood that the group R, R₁、R₂、R₃、R₄、R₅、R₆And R₇The alkyl, alkanol, alkoxy or alkylamino in (1) refers to both "straight chain" and "branched chain" alkyl groups, where "straight chain" may be, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl, and "branched chain alkyl" refers, for example, to isopropyl or tert-butyl. "cycloalkyl" is understood to mean, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

The term "halogen" denotes fluorine, chlorine, bromine or iodine. The term "alkoxy" denotes, for example, methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy or pentoxy.

The compounds of the invention may also be in the form of acid addition salts, for example salts of inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid; salts of organic acids such as acetic, lactic, malonic, maleic, fumaric, gluconic, glucuronic, citric, embonic, methanesulfonic, trifluoroacetic and succinic acids.

The compounds of formula I and their salts are biologically active. The compounds of formula I can be administered in free form or in the form of a salt with a physiologically tolerable acid.

Administration can be oral, parenteral, intravenous, transdermal or inhalation.

The invention also relates to pharmaceutical preparations which comprise at least one compound of the formula I or a salt thereof with a physiologically tolerable inorganic or organic acid, if appropriate together with pharmaceutically acceptable excipients and/or diluents or auxiliaries.

Suitable administration forms include, for example, tablets, coated tablets, capsules, solutions or ampoules, suppositories, patches, powders for inhalation, suspensions, creams and ointments.

The compounds of the invention have good anti-asthmatic, anti-allergic and immunosuppressive/immunomodulatory effects on diseases such as transplantation, psoriasis, rheumatoid arthritis and chronic polyarthritis in the following pharmacological models:

inhibition of "late stage" eosinophilia in guinea pig BAL 24 hours after allergen challenge

Male guinea pigs (200-250g, Dunkin Hartley Shoe) were injected subcutaneously with ovalbumin (10. mu.g ovalbumin +1mg Al (OH)₃) Sensitization and enhancement after 2 weeks. After 1 week of ovalbumin boost, animals were challenged by imbibing ovalbumin (0.5% strength solution) for 20-30 seconds. After 24 hours, the animals were sacrificed by urethane overdose, exsanguinated and bronchoalveolar lavage (BAL) was performed with 2X 5ml of 0.9% physiological saline solution.

The lavage fluid was collected and centrifuged at 400g for 10 minutes, and the sediment was suspended in 1ml of 0.9% physiological saline solution. Eosinophils were counted by microscopy in a Neubauer chamber after staining with Becton Dickinson test kit 5877. The test kit contains phloxine B as a selective stain for eosinophils. Eosinophils in the BAL of each animal were counted and expressed as eosinophils (million/animal). The mean and standard deviation of each group were measured. The percentage inhibition of eosinophils in the test substance-treated group was calculated according to the following formula:

(a-B) - (B-C)/(a-C) x 100 ═ inhibition

Where a eosinophils correspond to the untreated challenge group, B eosinophils correspond to the treated group, and C eosinophils correspond to the non-challenged control group.

Animals were challenged with histamine H2 hours before challenge with allergen₁Antagonists (Nitrogen)Statin; 0.01mg/kg, oral) to avoid death. Test substances or vehicles were administered 4 hours after allergen challenge. The percent inhibition of eosinophilia in BAL was calculated using a group of 6-10 animals.

Table: inhibition of "late stage" eosinophilia in guinea pigs 24 hours after allergen challenge

Substance(s)	Dosage [ mg/kg]	Administration of drugs	n	% inhibition
					Cyclosporin A	51030	Intraperitoneal +4 hours oral +4 hours	171110	50.047.068.8
Compound of example 1	51030	Intraperitoneal +4 hours oral +4 hours	10109	27.855.456.1

Assays for peptidyl-prolyl isomerase (PPIase) Activity and inhibition

The PPIase activity of the cyclophilin was determined enzymatically as described by Fischer et al (1984). After the substrate is isomerized by peptidyl proline isomerase, it is contacted with chymotrypsin which cleaves the chromophore p-nitroaniline. To determine the inhibitory effect of the test substances on PPIase activity, recombinant human Cyp B was used. The interaction of Cyp B with potential inhibitors was accomplished as follows:

a concentration of purified Cyp B was incubated with 1. mu.M substrate for 15 minutes. The reaction of PPIase was initiated by adding substrate solution to the reaction mixture containing HEPES buffer, chymotrypsin and test-or control samples. Under these conditions, first order kinetics are obtained, with a constant K_{Observation of}＝K₀+K_enzIn which K is₀Is a spontaneous isomerization of K_enzIs the rate of isomerization of PPIase activity. The reaction was carried out at a constant reaction temperature of 10 ℃ using a Beckman DU70 spectrophotometerAn extinction value corresponding to the amount of cleaved chromophore is determined.

The residual activity observed in the presence of each substance was compared with that of cyclophilin treated with solvent only. Results are expressed as% residual activity. Cyclosporin a (csa) was used as a reference compound. The inhibitory effect on PPIase was also examined by SDS-PAGE.

Colorimetric assay for non-radioactive quantification of cell proliferation and viability (based on MTT assay)

Cell proliferation and activation by growth factors and cytokines such as IL-2 and IL-4 are quantified using MTT quantification and anti-proliferative or toxic effects are quantified.

The assay is based on yellow tetrazolesSalt MTT is cleaved by metabolically active cells to purple-red formazanAnd (4) crystallizing.

Cells were cultured in 96-well tissue culture plates, and the cultured cells were incubated with a yellow MTT solution for about 4 hours. After heat preservation, purple-red nails are formedAnd (4) crystallizing the salt. The salt crystals are insoluble in aqueous solution, but can be dissolved by adding a solubilizer and incubating the plate overnight.

Dissolving the nailThe products were quantified spectrophotometrically using an ELISA reader. An increase in the number of viable cells can result in an increase in the total metabolic activity in the sample. Increased metabolic activity and formation of purplish red nailsThe amount of crystallization is directly related, AThe amount of crystals was measured by absorbance.

Substance(s)	Inhibition of PPIase Activity [% ]]	CD 3-mediated inhibition of IL-2 production [% ]]			Inhibition of lymphocyte proliferation [% ]]
								Concentration [ mu.M ]]		0.1	1	10	0.1	1	10
The compound of example 1, cyclosporin A	80-10080-100	3456	7282	9594	188	397	6111

Methods of preparing the compounds of the present invention are described in schemes 1 and 2 below, as well as in general methods. All compounds can be prepared according to the methods described or analogously.

Compounds of formula I can be prepared according to the following scheme 1, scheme 1 giving the synthesis of the compound of example 1:

reaction scheme 1

General procedure for the preparation of Compounds of formula I according to scheme 1

The first step is as follows:

indole derivatives, which may be unsubstituted or mono-or polysubstituted at C-2 or phenyl, are dissolved in a protic, dipolar aprotic organic solvent or a nonpolar organic solvent such as isopropanol, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methyl-pyrrolidone, dioxane, toluene or dichloromethane and added dropwise to a suspension of a molar or excess amount of a base such as sodium hydride, powdered potassium hydroxide, potassium tert-butoxide, dimethylaminopyridine or sodium amide in a suitable solvent, the base suspension being prepared in a three-necked flask under a nitrogen atmosphere. The desired alkyl, aralkyl or heteroaralkyl halide is then added, if desired, with a catalyst such as copper, and the mixture is then reacted for a period of time, for example 30 minutes to 12 hours, the reaction temperature being maintained in the range from 0 ℃ to 120 ℃, preferably between 30 ℃ and 80 ℃, in particular between 50 ℃ and 65 ℃. After the reaction is completed, the reaction mixture is added to water, the solution is extracted with, for example, diethyl ether, dichloromethane, chloroform, methyl t-butyl ether or tetrahydrofuran, and the resulting organic phase is dried over anhydrous sodium sulfate. The organic phase is concentrated in vacuo and the remaining residue is crystallized by trituration or the oily residue is purified by recrystallization, distillation or flash or column chromatography on silica gel or alumina. The eluent used is, for example, a mixture of dichloromethane and diethyl ether (8: 2 by volume) or a mixture of dichloromethane and ethanol (9: 1 by volume).

Second step of

The N-substituted indole obtained in the first step above is dissolved under a nitrogen atmosphere in an aprotic or apolar organic solvent such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane, toluene, xylene, dichloromethane or chloroform and then added to a solution prepared under a nitrogen atmosphere of an excess of oxalyl chloride of only a molar amount up to 60% in an aprotic or apolar solvent such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane, toluene, xylene, dichloromethane or chloroform, the temperature being maintained at from-5 ℃ to 20 ℃. The reaction mixture is then heated for 30 minutes to 5 hours at a temperature of between 10 ℃ and 130 ℃, preferably between 20 ℃ and 80 ℃, particularly preferably between 30 ℃ and 50 ℃, and the solvent is then evaporated. The residue of the "indolyl-3-glyoxyl chloride" thus prepared is dissolved in an aprotic solvent such as tetrahydrofuran, dioxane, diethyl ether, toluene or a dipolar aprotic solvent such as dimethylformamide, dimethylacetamide or dimethylsulfoxide, cooled to a temperature of from 10 ℃ to-15 ℃, preferably from-5 ℃ to 0 ℃, and then mixed with a solution of a primary or secondary amine in a diluent in the presence of an acid scavenger.

The diluent that can be used is the above solvent for dissolving the indole-3-glyoxyl chloride. The acid scavengers used are triethylamine, pyridine, dimethylaminopyridine, basic ion exchangers, sodium carbonate, potassium carbonate, powdered potassium hydroxide and excess primary or secondary amines used in the reaction. The reaction is carried out at a temperature of from 0 ℃ to 120 ℃, preferably from 20 ℃ to 80 ℃, particularly preferably from 40 ℃ to 60 ℃. After 1-3 hours of reaction and 24 hours at room temperature, the acid scavenger hydrochloride is filtered off, the filtrate is concentrated in vacuo, and the residue is recrystallized from an organic solvent or purified by column chromatography on silica gel or alumina. The eluent used is, for example, a mixture (95: 5 by volume) of dichloromethane and ethanol.

Examples

According to the general procedures of steps 1 and 2, which scheme 1 is based on, compounds having the following respective chemical names are synthesized. In Table 1 below, the substituents R and formula I₁-R₄And Z the structures of these compounds and their melting points can be seen.

Example 1

N- (pyridin-4-yl) - [1- (4-fluorobenzyl) indol-3-yl]Glyoxylamides

Step 1

1- (4-fluorobenzyl) indoles

A solution of 11.72g (0.1mol) indole in 50ml dimethylsulfoxide was added to a mixture of 2.64g sodium hydride (0.11mol, mineral oil dispersion) and 100ml dimethylsulfoxide. The mixture was heated at 60 ℃ for 1.5 hours, then cooled and 15.9g (0.11mol) of 4-fluorobenzyl chloride was added dropwise. The solution was warmed to 60 ℃, left overnight and then poured into 400ml of water with stirring. The mixture is extracted several times with a total of 150ml of dichloromethane, the organic phase is dried over anhydrous sodium sulfate, filtered and the filtrate is concentrated in vacuo. The residue was distilled under high vacuum: 21.0g (96% of theoretical yield) b.p (0.5 mm): 140 deg.C

Step 2

N- (pyridin-4-yl) - [1- (4-fluorobenzyl) indol-3-yl]Glyoxylamides

A solution of 4.75g (21.1mmol) of 1- (4-fluorobenzyl) indole in 25ml of diethyl ether is added dropwise to a solution of 2.25ml of oxalyl chloride in 25ml of diethyl ether at 0 ℃ under nitrogen. The mixture was refluxed for 2 hours, and then the solvent was distilled off. 50ml of tetrahydrofuran are then added to the residue, the solution is cooled to-5 ℃ and a solution of 4.66g (49.5mmol) of 4-aminopyridine in 200ml of THF is added dropwise. The mixture was refluxed for 3 hours and then left overnight at room temperature. The 4-aminopyridine hydrochloride was removed by suction filtration, the precipitate was washed with THF, the filtrate was concentrated in vacuo and the residue was recrystallized from ethyl acetate.

Yield of the product: 7.09g (90% of theory)

Melting Point：225-226℃

Elemental analysis:

calcd for C70.77H 4.32N 11.25

Found C71.09H 4.36N 11.26

Example 2N- (pyridin-4-yl) - (1-methylindol-3-yl) glyoxylamide

Example 3N- (pyridin-3-yl) - [1- (4-fluorobenzyl) -indol-3-yl ] glyoxylamide

Example 4N- (pyridin-3-yl) - (1-Benzylindol-3-yl) glyoxamide

Example 5N- (pyridin-3-yl) - [1- (2-chlorobenzyl) -indol-3-yl ] glyoxylamide

Example 6N- (4-fluorophenyl) - [1- (4-fluorobenzyl) -indol-3-yl ] glyoxylamide

Example 7N- (4-Nitrophenyl) - [1- (4-fluorobenzyl) -indol-3-yl ] glyoxylamide

Example 8N- (2-Chloropyridin-3-yl) - [1- (4-fluorobenzyl) -indol-3-yl ] glyoxylamide

Example 9N- (pyridin-4-yl) - (1-Benzylindol-3-yl) glyoxamide

Example 10N- (pyridin-4-yl) - [1- (3-pyridylmethyl) -indol-3-yl ] glyoxylamide

Example 11N- (4-fluorophenyl) - [1- (2-pyridylmethyl) -indol-3-yl ] glyoxylamide

Example 12N- (4-fluorophenyl) - [1- (3-pyridylmethyl) -indol-3-yl ] glyoxylamide

Example 13N- (pyridin-4-yl) - [1- (4-chlorobenzyl) -indol-3-yl ] glyoxylamide

Example 14N- (pyridin-4-yl) - [1- (2-chlorobenzyl) -indol-3-yl ] glyoxylamide

Example 15N- (pyridin-2-yl) - [1- (4-fluorobenzyl) -indol-3-yl ] glyoxylamide

Example 16N- (pyridin-4-yl) - [1- (2-pyridylmethyl) -indol-3-yl ] glyoxylamide

Example 17 (4-Phenylpiperazin-1-yl) - [1- (4-fluorobenzyl) -indol-3-yl ] glyoxylamide

Example 18N- (pyridin-2-yl) - (1-Benzylindol-3-yl) glyoxamide

Example 19N- (pyridin-4-yl) - [1- (4-fluorobenzyl) -6-ethoxycarbonylaminoindol-3-yl ] glyoxylamide

Example 20N- (pyridin-4-yl) - [1- (4-fluorobenzyl) -5-ethoxycarbonylaminoindol-3-yl ] glyoxylamide

Example 21N- (pyridin-4-yl) - [1- (4-fluorobenzyl) -6-cyclopentyloxycarbonylaminoindol-3-yl ] glyoxylamide

Example 224- (pyridin-4-yl) -piperazin-1-yl) - [1- (4-fluorobenzyl) -indol-3-yl ] glyoxylamide

Example 23N- (3, 4, 5-trimethoxybenzyl) -N- (allylaminocarbonyl-2-methylpropan-1-yl) - [1- (4-fluorobenzyl) -indol-3-yl ] glyoxylamide

Example 24N- (pyridin-4-yl) - [1- (4-fluorobenzyl) -5-methoxyindol-3-yl ] glyoxylamide

Example 25N- (pyridin-4-yl) - [1- (4-fluorobenzyl) -5-hydroxyindol-3-yl ] glyoxylamide

Example 26N- (pyridin-4-yl) - [1- (4-fluorobenzyl) -5-ethoxycarbonylaminomethylindol-3-yl ] glyoxylamide

Formula 1

Table 1: new indolylacetalamides according to scheme 1

Table 1: new indolylacetalamides according to scheme 1

Table 1: new indolylacetalamides according to scheme 1

Table 1: new indolylacetalamides according to scheme 1

Starting materials for the compounds of the general formula I listed in Table 1, prepared according to scheme 1

All of the precursors used in the final synthesis steps of examples 1-22 and 24-26 are commercially available.

Furthermore, compounds of general formula I can also be prepared according to scheme 2, which scheme 2 gives the synthesis of the compound of example 27:

synthesis scheme 2

General procedure for the preparation of Compounds of formula 1 according to scheme 2

Step 1:

the indole derivative, which may be unsubstituted or substituted on C-2 or phenyl, is dissolved in a solvent, for example the solvent used to dissolve oxalyl chloride, and this solution is added dropwise at between-5 ℃ and +5 ℃ to a solution prepared under nitrogen atmosphere of only a molar to 60% excess of oxalyl chloride in an aprotic solvent or in a non-polar solvent such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane or dichloromethane. Then, the reaction solution is heated at 10 ℃ to 120 ℃ for 1 to 5 hours, preferably at 20 ℃ to 80 ℃, more preferably at 30 ℃ to 60 ℃, and then, the solvent is distilled off. The residual (indol-3-yl) glyoxyl chloride is dissolved or suspended in an aprotic solvent such as tetrahydrofuran, dioxane, diethyl ether, toluene or a dipolar aprotic solvent such as dimethylformamide, dimethylacetamide or dimethylsulfoxide, cooled to a temperature of from-10 ℃ to +10 ℃, preferably from-5 ℃ to 0 ℃, and then mixed with a solution of the primary or secondary amine in a diluent in the presence of an acid scavenger. Diluents which may be employed are the solvents used to dissolve the "indolyl-3-glyoxyl chloride". The acid scavengers used are triethylamine, pyridine, dimethylaminopyridine, basic ion exchangers, sodium carbonate, potassium carbonate, powdered potassium hydroxide and excess primary or secondary amines used in the reaction. The reaction is carried out at 0 ℃ to 120 ℃, preferably 20 ℃ to 80 ℃, more preferably 40 ℃ to 60 ℃. The reaction is carried out for 1 to 4 hours and is left at room temperature for 24 hours, then the reaction solution is filtered, the precipitate is digested with water, and the solid is filtered out by suction and dried in vacuum. The desired compound is purified by recrystallization from an organic solvent or by column chromatography on silica gel or alumina. The eluent used is, for example, a mixture (10: 1, volume ratio) of dichloromethane and ethanol.

Step 2:

the "indol-3-yl glyoxylamide" obtained in step 1 above is dissolved in a protic, dipolar aprotic or apolar organic solvent such as isopropanol, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dioxane, toluene or dichloromethane and added dropwise to a suspension of only a molar amount or an excess of a base such as sodium hydride, powdered potassium hydroxide, potassium tert-butoxide, dimethylaminopyridine or sodium amide in a suitable solvent, the base suspension being obtained in a three-necked flask under a nitrogen atmosphere. The desired alkyl, aralkyl or heteroaralkyl halide is then added in undiluted form or as a solution in a diluent, for example also for dissolving the "indol-3-yl glyoxylamide", if desired with addition of a catalyst, for example copper, and the mixture is then reacted for a period of time, for example from 30 minutes to 12 hours, the reaction temperature being kept in the range from 0 ℃ to 120 ℃, preferably between 30 ℃ and 80 ℃, in particular between 50 ℃ and 70 ℃. After the reaction is completed, the reaction mixture is added to water, the solution is extracted with, for example, diethyl ether, dichloromethane, chloroform, methyl t-butyl ether, tetrahydrofuran or n-butanol and the resulting organic phase is dried over anhydrous sodium sulfate.

The organic phase is concentrated in vacuo and the residue left to crystallize by trituration or the oily residue is purified by distillation or silica gel or alumina column chromatography or flash chromatography. The eluent used is, for example, a mixture of dichloromethane and diethyl ether (8: 2 by volume) or a mixture of dichloromethane and ethanol (9: 1 by volume).

Examples

The compounds, which have been prepared according to the synthetic procedure of scheme 1 and are listed in table 1, are synthesized according to the general procedures of steps 1 and 2, which scheme 2 is based on. The corresponding precursors of these compounds are listed in table 2.

Example 27

N- (pyridin-4-yl) - [1- (4-fluorobenzyl) indol-3-yl]Glyoxylamides

(Final Material, same as in example 1)

Step 1:

n- (pyridin-4-yl) - (indol-3-yl) glyoxylamides

A solution of 10g (85.3mmol) of indole in 100ml of diethyl ether is added dropwise at 0 ℃ to a solution of 9ml of oxalyl chloride in 100ml of dry diethyl ether. The mixture was kept under reflux for 3 hours. Then, a suspension of 12g (127.9mmol) of 4-aminopyridine in 500ml of tetrahydrofuran was added dropwise at-5 ℃ and the reaction mixture was heated under reflux with stirring for 3 hours and then left at room temperature overnight. The precipitate was filtered off, treated with water and the dried compound was purified on a silica gel column (silica gel 60, Merck AG, Darmstadt) eluting with dichloromethane/ethanol (10: 1, volume ratio).

Yield of: 9.8g (43.3% of theory)

Melting Point：＞250℃

Step 2

N- (pyridin-4-yl) - [1- (4-fluorobenzyl) indol-3-yl]Glyoxylamides

The N- (pyridin-4-yl) - (indol-3-yl) glyoxylamide obtained in step 1 is reacted with 4-fluorobenzyl chloride according to the "benzylation method" (page 9) and the resulting compound is isolated.

Yield of: of theoretical yield41％

Melting Point：224-225℃

Elemental analysis:

calcd for C70.77H 4.32N 11.25

Found C70.98H 4.40N 11.49

Example 28N- (4-Nitrophenyl) - [1- (4-fluorobenzyl) indol-3-yl ] glyoxylamide (final substance, same as in example 7)

Example 29N- (4-fluorophenyl) - [1- (4-fluorobenzyl) indol-3-yl ] glyoxylamide (final substance, same as in example 6)

Example 30N- (pyridin-3-yl) - [1- (4-fluorobenzyl) indol-3-yl ] glyoxylamide (final substance, same as in example 3)

The following precursors (step 1 of scheme 2, Table 2) were prepared according to scheme 2.

Example 31N- (pyridin-4-yl) - (indol-3-yl) glyoxylamide

Example 32N- (4-Nitrophenyl) - (indol-3-yl) glyoxylamide

Example 33N- (4-fluorophenyl) - (indol-3-yl) glyoxylamide

Example 34N- (pyridin-3-yl) - (indol-3-yl) glyoxylamide

Formula 1

Table 2: new indolylacetalamides according to scheme 2

Claims (8)

1. N-substituted indole-3-glyoxylamides of the formula I or acid addition salts thereof,

wherein

R is selected from hydrogen; (C)₁-C₆) -alkyl, wherein alkyl is optionally substituted by a phenyl ring, said phenyl ring being optionally substituted by halogen, (C)₁-C₆) Alkyl radicals, (C)₃-C₇) Cycloalkyl, carboxy, with (C)₁-C₆) -alkanol-esterified carboxy, trifluoromethyl, hydroxy, methoxy, ethoxy, benzyloxy or benzyl, optionally substituted in the phenyl part thereof by (C)₁-C₆) -alkyl, halogen or trifluoromethyl substitution;

R₁selected from phenyl, said phenyl being optionally substituted by (C)₁-C₆) Alkyl radicals, (C)₁-C₆) -alkoxy, hydroxy, benzyloxy, nitro, amino, (C)₁-C₆) -alkylamino, (C)₁-C₆) -alkoxycarbonylamino, carboxy or with (C)₁-C₆) -alkanol-esterified carboxy substitution; a pyridine structure of formula II, wherein the pyridine structure is attached at the 2, 3 or 4-position and is optionally substituted by R₅And R₆Substitution;

pyridylmethyl attached at the 2-, 3-or 4-position; a 2-or 4-pyrimidinylheterocycle wherein the 2-pyrimidinylring is optionally substituted with methyl; 2-, 3-and 4-quinolyl, wherein the quinolyl is selectively substituted by (C)₁-C₆) Alkyl, halogen, nitro, amino or (C)₁-C₆) -alkylamino substitution; 2-, 3-or 4-quinolylmethyl in which a ring carbon atom of the pyridylmethyl or quinolylmethyl group is selectively replaced by (C)₁-C₆) Alkyl radicals, (C)₁-C₆) -alkoxy, nitro, amino or (C)₁-C₆) -alkoxycarbonylamino substitution; and allylaminocarbonyl-2-methylpropan-1-yl;

in case R is hydrogen, benzyloxycarbonyl, tert-butoxycarbonyl, acetyl or benzyl₁Or acyl radicals of natural or synthetic amino acids, where the amino group of the respective amino acid may be in protected or unprotected form, and in the case of asparaginyl or glutamyl, the unbound carboxyl group may be the free carboxyl group or the carboxyl group with C₁-C₆-in the form of an ester formed by an alkanol;

if R is₁Is aminoalkylene, R and R₁Taken together with the nitrogen atom to which they are attached may form a piperazine or homopiperazine ring of formula III;

R₂is (C)₁-C₆) -an alkyl group optionally substituted with halogen; substituted by phenyl, optionally substituted by halogen, (C)₁-C₆) Alkyl radicals, (C)₃-C₇) Cycloalkyl, carboxy, with (C)₁-C₆) -an alkanol-esterified carboxy, trifluoromethyl, hydroxy, methoxy, ethoxy or benzyloxy substitution; substituted by 2-quinolyl which is optionally substituted by halogen, (C)₁-C₄) -alkyl or (C)₁-C₄) -alkoxy substitution; substituted by 2-, 3-or 4-pyridyl optionally substituted by halogen, (C)₁-C₄) -alkyl or (C)₁-C₄) -alkoxy substitution; or R₂Is benzoyl in which the phenyl ring is optionally substituted by halogen, (C)₁-C₆) Alkyl radicals, (C)₃-C₇) Cycloalkyl, carboxy, with (C)₁-C₆) -an alkanol-esterified carboxy, trifluoromethyl, hydroxy, methoxy, ethoxy or benzyloxy substitution;

R₃and R₄Independently selected from hydrogen, (C)₁-C₆) Alkyl radicals, (C)₃-C₇) -cycloalkyl, (C)₁-C₆) Alkanoyl, (C)₁-C₆) -alkoxy, halogen, benzyloxy, nitro, amino, (C)₁-C₄) -mono-or dialkyl-substituted amino, (C)₁-C₃) -alkoxycarbonylamino and (C)₁-C₃) -alkoxycarbonylamino- (C)₁-C₃) -an alkyl group;

R₅and R₆Independently selected from (C)₁-C₆) Alkyl radicals, (C)₃-C₇) -cycloalkyl, (C)₁-C₆) -alkoxy radicalAlkyl, nitro, amino, hydroxy, halogen, trifluoromethyl, ethoxycarbonylamino and carboxyalkoxy in which the alkyl moiety contains 1 to 4 carbon atoms; and

R₇selected from alkyl, phenyl, said phenyl being optionally substituted by (C)₁-C₆) Alkyl radicals, (C)₁-C₆) Alkoxy, halogen, nitro, amino, (C)₁-C₆) -alkylamino, benzhydryl and di-p-fluorobenzhydryl substitution.

2. An N-substituted indole-3-glyoxylamide according to claim 1, wherein

R is hydrogen;

R₁is a pyridine structure of formula II; and

R₂is (C)₁-C₆) -alkyl, wherein alkyl is substituted by phenyl, said phenyl being optionally substituted by halogen, (C)₁-C₆) Alkyl radicals, (C)₃-C₇) Cycloalkyl, carboxy, with (C)₁-C₆) -alkanol-esterified carboxy, trifluoromethyl, hydroxy, methoxy, ethoxy or benzyloxy substitution.

3. An N-substituted indole-3-glyoxylamide according to claim 1, wherein

R is hydrogen;

R₁is 4-pyridyl or 4-fluorophenyl;

R₂is benzyl, 4-chlorobenzyl, 4-fluorobenzyl, 3-pyridylmethyl, 4-bromobenzyl; and

R₃and R₄Is hydrogen.

An N-substituted indole-3-glyoxylamide, wherein the N-substituted indole-3-glyoxylamide is N- (pyridin-4-yl) - [1- (4-chlorobenzyl) -indol-3-yl ] glyoxylamide, or an acid addition salt thereof.

5. Use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament having antiasthmatic, antiallergic and immunosuppressive/immunomodulatory effects for transplantation, psoriasis, rheumatoid diseases and chronic polyarthritis.

6. Medicaments containing at least one compound according to any one of claims 1 to 4 and customary excipients and/or diluents or adjuvants.

7. A medicament according to claim 6 in a form selected from the group consisting of tablets, coated tablets, capsules, solutions or ampoules, suppositories, patches, powders administrable by inhalation, suspensions, creams and ointments.

8. Process for the production of medicaments, characterized in that compounds of the formula I according to any of claims 1 to 4 are processed together with customary pharmaceutical excipients and/or diluents or other auxiliaries into pharmaceutical preparations.