NO780473L - PROCEDURE FOR THE PREPARATION OF INDOLYLGLYCOCACIC ACID DERIVATIVES - Google Patents

Description

The invention relates to new indolylglyoxylic acid derivatives

particularly 3-Hydroxy-indolyl-2-glyoxylic acid derivatives of the general formula

where Y means optionally etherified or acylated hydroxy, R

means Hydrogen optionally substituted Lower alkyl or Cycflroalkyl and - OR^ means optionally etherified Hydroxy in which

either R^ means lower alkyl, Lower alkyloxy, Cycloalkyl, Hyd-

roxy, Phenoxy, Halogen or Nitro, R^means Lower alkyl, Loweralcoxy or Hydroxy R^and R^means independently of each-

other Hydrogen or Lower alkyl in at least one of the residues R^, R^, R^ and R^ means in the 5- and/or 6-position bonded

Lower alkyl or R^ and R,, together to two adjacent carbon atoms linked Alkylene with 3 to 5 chain carbon atoms

and R^ and R^ mean Hydrogen and their salts as precursors

way of their preparation, further pharmaceutical prepa--

rates containing the compounds of the formula I or salts thereof, and the use of the new compounds.

In the context of the present description, the

where "lower" designated organic residues and compounds especially up to and including 7»preferably up to and including h Carbonato-

more •

Lower alkyl then for example Meifihyl, Aethyl,n-Pro-

pyl, Isopropyl, n-Butyl or n-Pentyl.

Etherated Hydroxy is, for example, optionally substituted Lower Alkoxy -OR.

o

Substituents of substituted Lower alkyl Rrrespectively Rq are Hydroxy or Lower alkyl, one or more substituents may be present.

Lower alkyl means, for example, Methoxy, Aethoxy, n-Propyloxy', Isopropyloxy, n-Butyloxy, Isobutyloxy, tert. - Butyloxy, n-Pentyloxy or n-Hexyloxy.

Hydroxy- or Lower-Alkoxy-lower alkyl is especially 2-/or 3-Hydroxy-lower-alkyl, for example 2-Hydroxy-ethyl, 3-Hydroxy-propyl or 2,3-Dihydroxy-propyl, or 2- or 3-Lower-Alkoxy-lower-alkyl, for example 2-Methoxyathyl , 2-Ethoxyethyl or 3-Methoxypropyl.

Cycloalkyl preferably contains 5 to 8, primarily 5-7 ring atoms and is, for example, Cyclopentyl or Cycloheptyl or, above all, Cyclohexyl.

IN

Phenoxy is preferably unsubstituted Phenoxy, but can also be substituted with Lower alkyl <:> such as Methyl, Lower Alkoxy such as Methoxy, Halogen such as Chlorine and/or Nitro.

Halogen is in particular Halogen with an atomic number up to and including 35, i.e. Fluorine, Chlorine or Bromine.

Acylated Hydroxy is, for example, derived from an organic carboxylic acid, Acyloxy. As a carboxylic acid, preferably substituted aliphatic or aromatic carboxylic acids such as optionally phenyl-substituted alkane or alkene carboxylic acids, preferably one of the aforementioned Lower alkyl - or derivatives thereof Lower alkanes containing lower alkenyl residues - respective lower alkene carboxylic acids are as well aromatic carboxylic acids, for example benzoic acid or pyridine carboxylic acids.

In the mentioned acids, aromatic residues can optionally be substituted with Laverealkyl, Laveralkoxy, Halogen and/or Nitro. Acylated Hydroxy is thus preferably straight or branched Laverealkanoyloxy, for example Acetoxy, Propionoloxy, i 'Butyryloxy, Isobutyryloxy, Valeroyloxy or Pivaloyloxy, or optionally as indicated substituted<*>Phenylacetyloxy - alphaphenylpropionyloxy-, Benzyoloxy-, Nicotinoyloxy-, Isonicotinoyloxy - or Picolyloxy ester.

When R and R^ together form Alkylene with 3 to 5 carbon atoms is particularly rectilinear Alkylene, such as 1,3-Propylene or 1,4-Butylene or, in other cases, 1,5-Pentylene.

Salts of compounds mSdrtfioimel I are primarily pharmaceutically usable salts, the salts in particular being acid addition salts with suitable inorganic or organic acids, for example with phosphoric - or sulfuric acid, chlorine - or hydrobromic acid, acetic, 'glycol, maleic fumar - , malic, tartaric, citric, benzo, salicylic, embonic, nicotinic, methanesulfonic, 22-Hydroxyethanesulfonic, 4-Meth^lbenzenesulfonic, or 2-Naphthalenesulfonic acid, further also as intermediate products usable acid addition salts, for example with Picric, Picrolonic, Flavian, Reinecke or Perchloric acid. Furthermore, compounds of formula I in which RR stands for Hydrogen can also form internal salts or salts with bases. Salts with bases are, for example, alkali metal - or alkaline earth metal - for example sodium, potassium, magnesium - or calcium salts, further ammonium salts with ammonia or amines such as lower^^<y->'-or hydroxyl lower alkylamines for example trimethylamine, triethylamine or Di(2-hydroxyethyl)amine.

With the compound of formula I where Y means Hydroxy, it can also be present by means of formula

referred to the tautomer (desmotrope) 3-Ketoform.

The new compounds show valuable pharmacological properties. In particular, they have anti-allergic effects which, for example, can be detected in rats in doses from approx. 0.3 to approx.

10 mg. per kg. by intravenous and iædos from approx. il to approx. 100

mg. per kg. by oral administration in a passive cutaneous Anaphylaxdld test (PCA reaction), which is carried out analogously to the method described by Goose and Blair immunology volume 16 page 7^9 (1969) in that the passive cutaneous Anaphylaxis is produced after that of Ovary progressive allergy volume 5 page k59 (1958) mentioned procedure. The compound according to the invention can therefore be used as inhibitors of allergic reactions, for example in the treatment and prophylaxis of allergic diseases such as

asthma both extrinsic and intrinsic asthma or others

allergic diseases such as hay fever, conjunctivitis, urticaria and eczema.

The invention primarily relates to a compound of formula I in which Y has the meaning R and Rq independently of each other mean Hydrogen, Lower alkyl with up to h Carbon atoms Hydroxyllower alkyl with up to and including k Carbon atoms, Hydroxylayeralkyl with up to and including h Carbon atoms, in which Hydroxy is bound in the 2dg-/or 3-position or Lower alkyl lower alkyl with up to and including 7 carbon atoms in which the lower alkyl group is bound in the 2- or 3- position and in which either R^means lower alkyl with up to and including h carbon atoms ©^.-G^-Cycloalkyl, Hydroxy, Lower alkyl with up to and including h Carbon atoms, Halogen with atomic number up to and including 35 or Nitro and R^, R^ and R^ independently of each other mean Hydrogen or Lower alkyl with up to and including h Carbon atoms at least one of the residues is, R£, R^ and R^ mean in the 5j_ and/or 6-position bonded lower alkyl with up to k carbon atoms or R^ and R^ together form in the 5,6 - position bonded straight alkylene with 3 to 5 carbon atoms and R^ and R ^means Hydrogen "§amt salts of the above compounds in particular corresponding to pharmaceutically usable salts.

The invention relates in particular to connection with

formula

in which Y means Hydroxy, C^-C^- Alkoxy such as Methoxy or Eth-oxy or C^- C^- Alkanoyloxy, such as Acetoxy, R^ and R^ independently mean Hydrogen or Lower alkyl with even h Carbon atoms for example Methyl or Aethyl, Hydroxyl lower alkyl with up to and including h Carbon atoms in which Hydroxy is bound in the 2-/or 3- position, for example 2-Hydroxyethyl or 2,3-Di-hydroxy-propyl, or Lower alkoxy lower alkyl with up to and including 4 Carbon atoms in which the Lavereal/-oxy group is bound to the 2- or 3-position, for example 2-Methoxyathyl, and in which either one of the residues Rr. and Rg means Lower alkyl with up to and including h Carbon atoms for example Methyl, one of the remaining residues Rg, R^, and Rg means 7

Hydrogen, Lower alkyl with up to and including 4 carbon atoms for example Methyl, Halogen with atomic number up to and including 35 for example Chlorine, Lower alkyl with up to and including 4 carbon atoms for example Methoxy, Hydroxy or Nitro and the third of the residues Rg, R^ and Rg means Hydrogen or Lower alkyl with up to 4 carbon atoms, for example Methyl or Rg means Hydrogen and R^ and Rg together form Alkylene with 3 or 4 chain carbon atoms, for example 1,3-Propylene as well as salts and above-mentioned compounds in particular equivalent to pharmaceutically usable salts.

The invention primarily relates to a compound of formula I in which Y means Hydroxy R^ and R,, means Hydrogen or Lower alkyl with up to and including 4 carbon atoms, for example Merphjyl or Aethyl or in another series Hydroxyl-?e realkyl with up to and including 4 carbon atoms in which Hydroxy is bound in the 2- and/or 3-position, for example 2-Hydroxyethyl or 2,3-Dihydroxy-propyl, or Lower alkyl lower alkyl with up to 4 carbons in which the Lower alkyl group is bound in the 2- or 3- position for example Methoxy-ethyl and in which Rg, R^, and Rg mean Hydrogen or Methyl or R^ and Rg together mean 1,3-Propylene or 1,4 Bmtyien^ j in that at least one of the residues R^ and Rg is different from Hydrogen in particular in which Y means Hydroxy Rq means Hydrogen or Lower alkyl with up to 14 Carbon atoms such as Methyl or Aethyl 4 Carbon atoms such as Met howl, and the other possibly means Hydrogen or R,-, and

Rg together form 3- to 3-linked lower alkylene such as 1,3-propylene as salts of the above-mentioned compounds, particularly corresponding pharmaceutically usable salts.

The compound of formula I is prepared in a manner known per se as a compound of the general formula

wherein R, R , R , R„ , R , and R, have the indicated meaning

+ 4 pv

means an Onium group and X~means the anionic residue of an acid or a salt from which is hydrolyzed and if desired a formed compound of formula I is transferred into another compound of formula I and/or if desired a free compound formed is transferred into a salt or a other salt in the free compound or in another salt.

In a starting material with formula II, which is usually formed in situ, an onium group is understood as a positively charged group whose free valence starts from the positively charged heteroatom, especially nitrogen and sulfur atom.

Preferred as residue X^p is an Ammonium<g>ru<pp>e in which Nitrogen atoms can optionally be mono - di- or tri-substituted with mono, or bivalent substituents. Such substituents are especially those/of an aliphatic character which optionally substituted mono - or divalent aliphatic as well as cyclo-aldiphatic, cycloaliphatic aliphatic or araliphatic Hydrocarbon residues primarily Lower alkyl or Lower alkylene in which Carbon atoms can be replaced by Heteroatoms such as Oxygen - or optionally for example with Lower alkyl, such as Methyl substituted Nitrogen atoms for example Methyl, Aethyl, 3-Oxa-n-butyl, 1,4-Butylene, 1,5-Pentylene, 3-Oxa-1,5-pentylene or 3-Methyl-3-aza -1,5-pentylene, further Cycloalkyl, for example Cyclohexyl, or Phenyllaverealkyl,

for example Benzyl. Preferred Ammonium group

with formula

in which Ra and R^ mean Hydrogen or preferably Lower alkyl, for example Methyl or Aljfch^l or together form Lower alkylene where a Carbon atom can be replaced by an Oxygen atom or an optionally substituted, for example Lower alkylated Nitrogen atom, for example 1,5-Pentylene, 3- 0xa-1,5-pentylene or 3-Methyl-3-aza-1,5-pentylene. As an additional substituent of the Nitrogen atom in an Ammonium group, for example, an Amidino group in the above-mentioned partial formula Ila can therefore R& ^ for example "also mean

Amidino and R, Hydrogen.

Further Onium groups are Sulfonium groups, which are, for example, substituted by mono- or divalent substituent central aliphatic character, as those mentioned above especially with Loweralkyl or Loweralkylene in which the Carbon atoms can be replaced with Heteroatoms such as Oxygen or optionally, for example with Loweralkyl such as Methyl, substituted tuated Nitrogen atoms, for example Methyl, Ethyl, 1,4-Butylene or 1,5-Pentylene, /and preferably contains a 5-oxido group.' Such groups are primarily those with

in which R and R^ mean Lower alkyl, for example Methyl, or together form the Lower alkylene, for example 1,4-Butylene or 1,5-PSntylene and n means 0 or preferably 1.

Anions X^-* of acids are primarily those of strong acids such as inorganic acids\lfor example a Halogen - such as Chlorine - further Bromic acid or also sulfuric acid or of strong organic Carboxyl - or Sulphonic acids. The anion X^1 therefore primarily means a halogen, especially the chlorine ion.

Hydrolysis is preferably carried out in an acidic medium, especially when treated with dilute acid as a mineral - for example hydrohalic acid, such as hydrochloric acid or hydrobromic acid and sulfuric acid. Thereby, one can work in the presence of an organic, preferably water-miscible solution - or diluent if necessary during cooling or heating (for example in a temperature range from approx. 0°C to approx. 100°C), in a closed vessel and/or in an inert gas mo.sphere.

Starting material with formula II can, for example, be obtained in the substituted Anilin^itoea formula

in which R' is different from Hydrogen and means a group R or Acyl, such as Laverealkanoyl or optionally substituted Benzyol, for example Formyl, Acetyl or Benzpyl, or acid addition salt thereof is reacted with 2,3-Di-X-maleic anhydride in which the residue X means equally or differently reactive, esterified Hydroxy groups, for example with 2,3 - Dihalogen, especially 2,3-Dichloro-maleic anhydride, in the presence of a Lewis acid, for example Aluminum Chloride1 and a thus formed compound of formula in which X has the above meaning , and in the first place Halogen means especially Chlorine if necessary with treatable with a base such as an Alkali metal-, for example Sodium hydroxide is ring-closed to a compound with the formula

possibly during cleavage of Acyl R.'

In the above-mentioned Aniline compound of formula III, the residues R^, R^, R^, and R^ have the above-mentioned meanings, with the exception that R^ does not mean Nitro. A Lower Alkoxy group R^ and/or R^ can, under the reaction conditions, undergo a Friedel-Crafts reaction to be converted into Hydroxy, and if desired, vvéd Alkylation again reverts to a Lower Alkoxy group.

In an intermediate product/formula V obtainable according to the above-mentioned method, the free carboxyl group can, for example, by treating the acid with formula V be esterified with an optionally substituted Lower alkanol in the presence of an acid or a condensing agent or to form a Hydroxyllower ealkylester, with Epoxylower alkane, or by reacting an alkali metal salt of the acid with an optionally substituted Lower alkyl halide or the lower alkyl sulphate or by treating the corresponding acid chloride with an optionally substituted Lower alkanol, for example in the presence of a basic agent. Thereby, in an esterification reagent, the substituents can be present in a functionally modified form and then released in the esterified intermediate. Thus, for example, 2,3-Epoxy-propyl chloride can be used as the esterification reagent and in the formed ester the 2,3-Epoxy-propyl grouping can then be hydrolysed to the desired 2,3-Dihydro-roxy-propy1 group . ■

Furthermore, a Nitro group can, for example, by treatment with nitric acid, if necessary,! presence of sulfuric acid is introduced into the<g>arbocyclicaromatic part of the Indole ring. Furthermore, a Hydroxy group can, for example, by treatment with a Lower alkyl sulfate in the presence of a base, for example of Potassium carbonate, be converted into a Lower Alkoxy group.

In an intermediate product with formula V, the group X can for

in a manner known per se, the conversion of the onium group X®, of the starting material is ial e with formula II, since the formation of the starting material usually takes place in situ. Thus, one can treat a compound of formula V with Ammonia or an Amine, for example a compound of formula R a - NH - R, (Vi), and then form the desired Ammonium group if necessary, with treatment with an acid possibly also in acidic medium of the Hydrolysis reaction according to the invention. Analogously, an intermediate with formula V can be treated with a Sulfoxide or a Sulfide,

and thus arrive at the desired starting material of formula II, in which ether is a sulfonium group.

A compound obtained according to the invention with formula I can be converted in a manner known per se into another compound with formula I.

The compound with ^formula I can further be prepared in that a compound with formula in which one of the residues X and X^ means an optionally functional modified carboxy group and the other means Hydrogen or a salt thereof, is condensed intramolecularly and, if desired, a formed compound with formula I is transferred in another connection with t?ormel. I and/or if desired a formed salt is transferred in the free compound or in another salt and/or a formed compound of formula I in which R means Hydroxy is transferred in a salt.

Functionally modified carboxy groups are, for example, functionally modified containing cyano or oxo groups

Carboxy groups above all esterified Carboxy groups such as Lower ealkoxycarbonyl, for example Methoxy- or Aethoxycarbonyl. Salts of compounds of formula IX are especially alkali metal, such as sodium or potassium salts, of compounds of formula VI, in which X 2 , X and/or -COORQ are carboxy.

The intramolecular condensation takes place in the usual way, for example thermally, for example at approx. 60 to 300°C, and/or by treatment with a base, for example with an Al-potassium metal hydroxide, -alcoholate, -amide or -carboxylate such as Sodium or Potassium hydroxide, Natriniunethanplat or -methanolate, Sodium amide or Lithium diisopropylamide or Sodium acetate, if necessary in an inert solvent for example in benzene, toluene, a xylene, dimethylformamide or acetic anhydride.

In a preferred embodiment of the method, for example, a compound of formula VI is treated in which R means Hydrogen, X^esterified Carboxy and X^Hydrogen with an Alkali metal avereal alkanolate, preferably with Sodium methoxide or ethanolate, in Benzol or Toluene, preferably working at about. 60 to 130°C for example at 80 - 100°C.

In a modification of this method, one can also proceed from the corresponding Nitrile, i.e. a compound of formula VI in which X, respectively, is Cyano. Thereby, the corresponding compound with formula is primarily obtained as an isolable intermediate whose exocyclic NH group is hydrolysed under the conditions for processing to Oxo.

The starting materials formula VI can, as far as they are not already known, be prepared according to methods known per se.

For example, compounds of formula VI in which X? means Hydrogen and X^means possibly esterified .Carboxy, a compound of formula is prepared there

or an Alkali metal, for example Sodium salt thereof, is condensed in the usual way with a Halogenoxaloacetic acid ester, for example with Bromooxaloacetic acid ethyl ester, and if necessary, an esterified Carboxy group X^ is hydrolysed to Carboxy. Compound of formula VI in which X represents optionally functionally modified Carboxy. and X^ means Hydrogen, can for example be obtained as a compound with.formula

or an Alkali metal, for example sodium salt thereof, is reacted in the usual way with a Halogenpyruvic acid ester, for example with 'Bromopyruvic acid ester.

Compound of formula I can further be prepared in-it in a compound of formula

in which means one in the group of formula -CO-COOR^transfer-

bar residue is transferred X^in the group of formula -CO-COORq and, if desired, a formed compound of formula I is transferred

in another compound of formula I and/or if desired, a formed salt is transferred in the free compound or another salt and/or a formed compound of formula I in which X stands for Hydroxy to a salt.

To groups with the formula -CO-COOR^transferable residues are particularly hydrolytic, these transferable residues especially in the Oxalo group hydrolyzable residues for example low groups with the formula -CO-COORq differently functionally modified Oxal residues. Such residues are, for example, those with the formula - C( =X^) -COORQ-C(=0)-X6 and in another row - 6( =X^)- X^, in which Xg means a functionally modified oxo group and X^ means a from optionally esterified Carboxy group -COORq differently functionally modified Carboxy group. Functionally modified Oxo groups are especially Thioxo and preferably substituted Imino groups, for example Hydroxy or Phenylimino. Functionally modified Caboxy groups Xg are especially Trihalogenmethyl groups, for example Trichlormethyl. \

The hydrolysis of the aforementioned groups into Oxalogroups takes place, for example, in the presence of acidic or otherwise basic hydrolysis agents if the necessary presence of additional aids, for example starting from compounds of formula IX, in which X^ means a group -C(=X^) -COORQ and X ^means Thixo of Oxidizing agents, for example Hypohalogenites such as Sodium hypochlorid, or Per compounds such as Hydrogen peroxide. Acid hydrolysis agents are preferably mineral acids such as hydrochloric or sulfuric acid. Basic hydrolysis agents are preferably alkali metal hydroxides, for example sodium hydroxide, or ammonium bases, for example ammonium hydroxide.

In a preferred embodiment of the above-mentioned methods, one hydrolyzes, for example, a compound of formula IX, in which X means a group of formula -C(=NOH)-COOH or -C(=N-Ar)-C00 H3N- Ar', where Ar means an optionally, for example, lower alkyl, lower alkyl, halogen and/or nitro substituted phenyl radical, in the presence of hydrochloric acid in an aqueous solvent, such as aqueous acetic acid.

The starting substances of formula IX in which X^means a group of formula -C(=S)-COORq can for example be prepared as a compound of formula

is condensed in the usual way with Rhodanin and the condensation product is hydrolysed with diluted alkalis, <for example with 10$> in caustic soda. From a thus formed compound of formula IX in which X^means -C(=S)-COOH, the preferred starting substances can then be obtained by ordinary reaction with Hydroxylamine or a compound of formula H^N-Ar, in which X means a group of formula -C(=NOH)-COOH respectively -C(=NAr)-C00"H^N+ -Ar. The compound ^ with formula X is in turn available by reacting compounds with the formulas

Treatment of condensation products first with potassium cyanide and then with ammonium sulphide and ring closure with sulfuric acid.

Compounds obtainable according to the invention can

in

1 are converted into each other.

Thus, in a compound of formula I in which 'Y means Hydroxy, this can be done in the usual way, for example

methylate with Dimethylsulphate, or acylate by ordinary reaction with an acylating agent such as an acid anhydride or acid halide, for example -chloride, or Keten to Acyloxy. Analogously, one can convert the compounds of formula I in which -OR means Hydroxy, for this per se known etherification procedures in an etherified Hydroxy group preferably into an optionally substituted Lower Alkoxy group.

Carboxy can also be esterified, for example, by treatment with a Dazola lower alkane or an alcohol such as an optionally substituted lower alkanol in the presence of an acid such as a mineral acid, for example hydrochloric acid or sulfuric acid, or a suitable condensation agent such as a dehydrating agent, for example Dicyclohexylcarbodiimide, or for the formation of a Hydroxyllower ealkyl es t is, with e\ t Epoxylower alkane, for example Aethylene oxide, in a Carboxy group with i orme 1 -C(=0)-ORQ(Ib). Furthermore, one can react a compound of formula I in which a free carboxyl group of formula Ib is present in salt form, for example in alkali metal - such as sodium salt form 1 with a reactive ester of an alcohol

as optionally substituted Lower alkanol, for example with a strong acid such as a corresponding Lower alkyl halide, for example - chloride, - bromide or - iodide, or ' Dilavere alkyl sulfate, or a compound of formula I in which a free carboxyl group of formula Ib is an anhydride form, preferably as Halogencarbonyl, for example Chlorcarbonyl group which can for example be obtained by treating a compound of formula I in which -ORq means Hydroxy, with a Halo generating agent for example Thd/onyl chloride, with an optionally substituted metal avereal alkanolate, which corresponds to Alkali metal-, for example Sodium or Potassium alcoholate, or with an alcohol, such as an optionally substituted Lower alkanol, if necessary in the presence of a base, and thus arrive at a compound of formula I in which -ORq means an angiitifc ethereal Hydroxy group. Thereby, a hydrogenation reagent can have the substituent present in a functionally modified form, and then be released in a compound of formula I in which -ORq means substituted Lower Alkoxy, in which the substituent is present in a functionally modified form. Thus, as the esterification reagent, for example, 2,3-Epoxy-propyl chloride can be used and in it

formed ester subsequently hydrolyze the 2,3-Epoxy-propyl grouping to the desired 2,3-Dihydroxy-propyl grouping.

In a compound of formula I in which -ORq denotes an etherified hydroxy group, this can be transesterified, for example by treatment with an alcohol such as a possibly substituted lower alkanol in the presence of a suitable transesterification catalyst, such as an optionally substituted alkali metal, for example sodium or Potassium lavereal akanolate compound, is converted into another etherified Hydroxy group.

In a compound of formula I, one can transfer an esterified carboxyl group of formula -C(=0)-ORq (lb), in which Rq means 'esterified hydroxy group in the usual way to a free carboxyl group of formula Ib, in which RQ means hydrogen, for for example by hydrolysis usually in an alkaline medium, for example by treatment with water in the presence of an alkali metal or alkaline earth metal hydroxide, for example sodium hydroxide. Analogously, Acyloxy Y $il Hydroxy can also be hydrolyzed.

Furthermore, in a compound of formula I, a phenolic Hydroxy group R^ and/or R^ can be transferred in a manner known per se to a Lower Alkoxy group, for example by treating the Phenol compound or the corresponding Phenolate as an Alkali metal, for example Sodium - or Potassium phenolate, with a reactive<r>esl; from a Lower alkanol, such as a Lower alkyl halide or Dilave alkyl sulfate, when using the free Phenol compound, one works in the presence of a basic agent such as an Alkali metal, for example Sodium or Potassium carbonate.

Formed free compounds can be transferred in a manner known per se in salt, in acid addition salts, among others. a. by reacting, for example, a solution of the free compound in a suitable solvent or solvent mixture with an acid, such as one of the above-mentioned acids or with a solution thereof, or with a suitable anion exchanger, and in salts with bases i.a. a. by treatment with a base or with a suitable salt of a carboxylic acid usually in the presence of a solvent or diluent.

Formed salts can be converted in a manner known per se into the free compounds, acid addition salts, for example by treatment with a base, for example a Alkali metal hydroxide, a metal carbonate or hydrogen carbonate or ammonia, and with a suitable anion exchanger,

and salts with bases, for example by treatment with an acidic reagent, such as a mineral acid.

Formed salts can in and of themselves be transferred into other salts, acid addition salts, for example by treatment with an anion exchanger or by treatment of a salt of an inorganic acid with a suitable metal salt such as a sodium, barium or silver salt of an acid in a suitable solvent in which a formed inorganic salt is insoluble and thus separates from the reaction mixture.

The compound, including its salts, can also be obtained in the form of its hydrates or contains the solvent used for crystallization."'

due to the close relationship between the new for-

in

bonds in free form and in the form of their salts are in the preceding and following with free compounds or their salts and also possibly and understand the corresponding salts respectively free compounds.

The invention also relates to the embodiments of the method where one starts from one or another process step as an intermediate formed compound and carries out the missing process steps, or in which a starting substance f is formed under the reaction conditions, or is used in the form of a derivative thereof possibly of a salt.

In the method according to the invention, such starting materials are preferably used which lead to the initially particularly valuable compounds mentioned.

The invention likewise relates to pharmaceutical preparations containing compounds of formula I or pharmaceutically usable salts thereof. The pharmaceutical preparations are those for enteral, such as oral or rectal, as well as parenteral administration to warm-blooded animals, which contain the pharmacologically active substance alone or together with a pharmaceutically usable carrier material. The dosage of the active substance depends on the type of warm blood, never on the individual condition and the method of application.

The new pharmaceutical preparations contain, for example, from approx. 10$ to approx. 95$, preferably from approx. 20 fo

to approx. 90$ of the active substance. Pharmaceutical preparations-

are, for example, suitable for inhalation or insufflation as aerosol or spray form, or in dosage unit forms such as dragees, tablets, capsules, suppositories, further ampoules.

The pharmaceutical preparations according to the invention are prepared in a manner known per se, for example by conventional mixing-granulation-coating-dissolution or lyophilization methods. Thus, pharmaceutical preparations for oral use can be obtained by combining the active substance with solid carriers, optionally granulating a formed mixture, and processing the mixture or granulate if desired or necessary after adding suitable excipients for tablets or dragé cores.

Suitable carriers are especially fillers such as sugar, for example Lactose, Sucrose, Mannitol or Sorbitol, Cellulose preparations and/or Calcium phosphates, for example Tricalcium phosphate or Calcium hydrogensulphate, further binders such as starch pastes for example corn, wheat, rice or potato starch pastes, gelatins, tragacanth, methyl- cellulose and/or polyvinylpyrrolidone and/or if desired," blasting agents such as the above-mentioned starches, further Carboxymethyl starch, cross-linked Polyvinylpyrrolidone, Agar, Alginic acid or a salt thereof, such as Sodium Alginate. Aids are primarily weaning, regulating and lubricating agents, for example, silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate and/or polyethylene glycol. Dragon cores are equipped with suitable, possibly stomach-juice-resistant covers, using, among other things, concentrated sugar solutions that may contain gum arabic, talc, polyvinyl porrolidone, polyethylene glycol and/or is Titanium Dioxide,. varnish solutions in suitable organic solvents or solvent mixtures or for the production of gastric juice-resistant coatings, solutions of suitable cellulose preparations such as Acetylcellulose phthalate or Hydroxy-propylmethylcellulose phthalate. Dyes or pigments can be added to the tablet or dragéoAter features, for example for identification or for characterizing different effective drug doses.

Further orally usable pharmaceutical preparations are capsules made of gelatin, as well as soft, closed capsules made of gelatin of a plasticizer such as glycerol or sorbitol. The suppositories may contain the active substance in the form of a granulate, for example in a mixture with fillers such as lactose, binders such as starches and/or lubricants such as talc or magnesium tearate, and possibly stabilizers.

In soft capsules, the active substance is preferably dissolved or dissolved in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, where stabilizers may be added.

As rectally applicable pharmaceutical preparations, for example, suppositories which consist of a combination of the active substance with a suppository base material come into consideration. Natural or synthetic Triglycerides, Parafin hydrocarbons, Polyethylene glycols or higher alkanols are suitable as Suppository base material, for example. Furthermore, gelatin rectal capsules can also be used which contain a combination of the active substance with a base material) as a base material, for example, liquid Triglycerides, Polyethylene Glycols or Paraffin Hydrocarbons can be used.

For parenteral administration, aqueous solutions of an active substance in water-soluble form, for example a water-soluble salt, and suspensions of the active substance, such as corresponding oily injection suspensions, using suitable lipophilic solvents or carriers, are suitable for parenteral administration. fatty oils, for example Sesame oil, or synthetic fatty acid esters, for example Aethyloleate or Triglycerides, or aqueous injection suspensions containing viscosity-increasing substances, for example Sodium carboxymethylcellulose, Sorbit and/or Dextran and optionally also stabilizers.

Inhalation or insufflation preparations for treatment of the respiratory tract by nasal or buccal administration of, for example, insufflation capsules, which make it possible to insufflate the active substance in the form of a powder with the breath or aerosols or sprays, which can distribute the pharmacologically active substance in the form of a powder or in the form of in drops of a solution or suspension. Preparations with powder properties contain, in addition to the active substance, usually adjuvants, insufflation capsules, for example solid carriers such as Lactose and Aerosol, respectively spray preparations, for example a liquid propellant with a boiling point below room temperature, as well as, if desired, additional carriers such as liquid or solid non-ionic or anionic surfactants and/or solid diluents. Preparations in which the pharmacologically active substance is present in solution contain, in addition to this, a suitable propellant, further, if necessary, an additional solvent and/or a stabilizer. In addition to the propellant gas, compressed air can also be used, as this can be produced by means of a suitable compression draft and relaxation device as required.

Pharmaceutical preparations for topical and local use are, for example, for the treatment of skin lotions and creams, which contain a liquid or semi-solid oil in water or water in oil emulsion, and ointments (as such preferably contain a preservative), for the treatment of the eyes, eye drops, which contains the active compound

in water deiigy or j esolution and eye ointments which< are preferably produced in sterile form, for treatment of the nose powder,

aerosols and sprays (similar to those mentioned above for the treatment of the respiratory tract), as well as coarse powders that are administered by rapid inhalation through the nostrils, and nasal drops containing the active compound in a permanent oil solution, or for local treatment of the mouth lozenges containing the active compound in a usually of sugar and gum arabic or tragacanth formed mass which may have added flavourings, such as lozenges containing the active substance in a single mass, for example of gelatin and glycerol or sugar and gum arabic.

The invention likewise relates to the use of the new compounds of formula I and salts thereof as pharmacologically active compounds, especially as antiallergic drugs, preferably in the form of pharmaceutical preparations. The daily dose, as a warm-blooded animal of approx. 70 kg. administered from approx. 200 mg. to approx. 1200 mg.

The invention will be explained in more detail with the help of some examples.

Example 1

a) Dissolve 10.6 g of 2-Carboxychloromethylene-1,5,6-trimethyl-indoxyl in 150 ml of ethanol. At 50°C, add in drops

then 6.8g piperidine in 30 ml. Ethanol and hplder dissolve?, the ning one hour at 50<G>C. Ice water is diluted to 600 ml. adds 45. ml. concentrated hydrochloric acid, filters off the crude product and cleans it in the manner mentioned under point c. After pm-crystallization from methanol • 3-Hydroxy-1,5»6-trimethyl-indolyl-2-gly©:xylic acid melts at 195-197°C.

The same product can also be obtained according to method variant b or c below. b) 7.8 g of 2-Carboxychloromethylene-1,5,6-trimethylindoxyl in 50 ml. glacial acetic acid is mixed slowly with 5.4 g Guanidine carbonate. The solution is then stirred for 24 hours at 60°C, diluted with ice water and the separated crude product is purified in the manner mentioned under point c. c) A mixture of 5.0 g of 2-Carboxychloromethylene 1,5, 6-trimethyl-indoxyl in 26 ml..Dimethylsulf oxide and 4 ml. water is stirred for one hour at 70°C, mixed with 100 ml of water and stirred for 30 min. at 65°C. The separated crystals are cooled and filtered off. The crystals are washed with 50 ml. cold water and dissolve them in a mixture of 300 ml. water and 20 ml. 30$ in soda ash. The solution is filtered through a schicht "Hyflo". The filtrate is made Congolese with concentrated hydrochloric acid, the separated crystals are filtered off and washed with 100 ml. water and dissolve them in 30 ml. 2-n. Baking soda. The usual alkaline solution is filtered through a layer of "Hyflo".

The filtrate is acidified with 2-normal hydrochloric acid and the darker crystals of melting point 194-196 °C are filtered off. After the recrystallization from Methanol, 3-Hydroxy-1,5,6-trimethyl-indolyl-2-glycolic acid melts at 195-497°C.

Starting material can be prepared as follows;

In a flask equipped with an HCl diverter, have 60 ml. 1,2-Dichloroethane and 40 g of powdered anhydrous AlCl^ (0.3 Mol) and cooled with an external ice/Methanol bath to 0°C. 13.5 S (0.1 Mol) N-Methyl-3,4-dimethyl-aniline (freshly distilled) is then added dropwise at 00-3°C over the course of 20 minutes and the resulting suspension is stirred at this temperature for 30 minutes. Now add in small portions 16.7 S (0.1 Mol) Dichloromaleic anhydride (95 µg) and stir the reaction mixture for 20 hours at 20-25°C. The bdanried dark-green solution is then poured into approx. 500 g ice, stir for 30 min. and decants the common phase. Add 10 ml to the oily residue. acetic acid ethyl ester, on which violet crystals form. After filtration and drying, 2"Carboxychloromethylene-1,5,6-trimethyl-indoxyl is obtained in the form of violet crystals with a melting point above 220°C, which can be converted further without further purification.

Example 2

20.0 g of 2-Carboxychloromethylene-5,6-dimethyl-indoxyl is reacted in 280 ml of ethanol with 13.6 g of piperidine during 3 hours at 50°C with stirring and then diluted with ice and water to 750 ml. After addition of 50 ml. concentrated hydrochloric acid is filtered off, the product is dissolved in 800 ml. water while adding 50 ml. 30$ Sodium lye and the solution is clarified by filtration. The filtrate is made Congolese with hydrochloric acid, with secreted 5,6 Dimethyl-3-hydroxyrindolyl-2-glyoxylic acid is filtered off and washed with water and dried. After recrystallization from glacial acetic acid, it shows a melting point of 238°C during cleavage.

The same product can also be prepared in the following way: 5.0 g of 2-Carboxychloromethylene-5,6-dimethyl-indoxyl in 42 ml. Dimethyl sulfoxide and 8 ml. water is kept under stirring for 16 hours at 75°C, then mixed with 150 ml. water and filtered. The product is dissolved in 300 ml. water while adding 20 ml. 30% caustic soda, clarified by filtration and the filtrate made congo acid by adding hydrochloric acid. The secreted crude product is purified as described under point a.

Starting material can be produced as follows:

In a flask equipped with an HCl diverter ass. 200 ml. 1,2-Dichloroethane and 350 g of powdered anhydrous AlCl^

(2.625 Mol) and cooled with a further ice bath to 0°C. Then add 0-10°C over approx. 30 min. while stirring 100 g. (0.6 l Mol) 3,4-Dimethylacetanilide in 200 ml.

Ethylene chloride and then within 10 min. 102 g (0.61 Mol) solid Dichloromaleic anhydride ($95)• After 30 min. stirring at 20-25°C, the reaction mixture is stirred for a further 22 hours at 40°C. The reaction mixture is then introduced into a mixture of water and ice (Final volume approx. 3-4 litres). The water is then decanted, and the brown-yellow, tough residue is stirred with 1000 ml. acetic acid ethyl ester and suction. The suction material is dried at 50 o C in a vacuum drying cabinet. You get 165.5 g of a yellow product. This is mixed with 600 ml. 10 µg of aqueous NaOH and cooled with ice so that the reaction temperature does not exceed 32°C. After 5 1/2 hours of stirring at 20-25°C, the reaction mixture is heated to 40°C within one hour. After repeated cooling to 20-25°C, the formed red suspension is suctioned off. The resulting red crystals are dried after careful washing with water at 40°C in a vacuum. The mother liquor is adjusted with concentrated HC1 to pH 1, and the red precipitate formed is suctioned off. After thorough washing with water, the absorbent material is dried and combined with the main quantity. 2-Carboxychlormethylene-5,6-Dime-thyl-indoxyl is obtained, which can be converted directly.

Analogously, when starting from N,3-Dimethylacetanilide over 2-Carboxychloromethylene-1,6-dimethyl-indoxyl, 1,6-Dimethyl-3-'hydroxy-indolyl-2-glyoxylic acid and a melting point above 150°C will be obtained.

Example 3

A solution of 7.0 g of 5,6-Dimethyl-2-(-methoxycarbonyl-piperidino-methylene)-indoxyl in 80 ml. 10% sulfuric acid is stirred for 30 minutes at 60°C and cooled. The separated crystals are filtered off and washed with 20 ml. water and dried below 0.01 torr at 40° C. After recrystallization from Methanol, the 5»6-Dimethyl-3-hydroxy-indolyl-2-glyoxyl acid methyl ester melts at 188-192°C.

The starting material can be prepared as follows:

251.5 g (1.0 mol) of 2-Carboxychloromethylene-5,6-dimethylindoxyl are suspended in 300 ml. water is adjusted with concentrated caustic soda and Pjj7. Then, over 60 hours, 378 g (3.0 Mol) of dimethylsulphate are added at 20-25°C, with the PH value controlled by a P^-stat being maintained by dripping

of 10$ soda solution of 6.8-7.2. After 20 hours of stirring

at P„ 6.8-7.2. After 20 hours of stirring at B„ 6.8-7.2

ten ten

the suspension is filtered off and washed well with water and dried at 60 C/100 t orr. Thereby 5 > 6-Dimethyl-2,-methoxy-carbonchloromethylene-indoxyl appears in red crystals which melt at 208-210°C. Recrystallization from glacial acetic acid raises the melting point to 215-218°C.

To a suspension of 98.0 g of 5»6-Dimethyl-2-methoxy-carbonchloromethylene-indoxyl in 1500 ml. Ethanol is dripped while stirring at room temperature 79-7ml. Pipi-ridin. One stirs for 30 min. at room temperature, then 18 hours at 60°C and evaporated under reduced pressure to dryness. The residue is mixed with 200 ml. water and 1000 ml. acetic acid ethyl ester, shake well, separate the organic phase and wash it again with 100 ml. water. It is then dried and, with magnesium sulphate, evaporated under reduced pressure to dryness. The crystalline residue is chromatographed on 2000 g of silica gel. Those with each time 1000 ml. Ether eluted fractions 17-23 contain the pure 5'6-Dimethyl-2-methoxycarbonyl-(C-piperidino-methylene)-indoxyl. These fractions are purified and expelled with 100 ml. ether. The crystallized product melts at <7>0-1 7 3°C •

Example h

Analogous to example 3, when starting from 2-Carboxychloromethylene-5,6-trimethylene-indoxyl over 2-Methoxycarbonylchloromethylene-5,6-trimethylene-indoxyl of melting point above 220°C and 2 (ca—Methoxycarbonyl-cL- piperidino-methylene)-5,6-trimethylene-indoxyl of melting point l66-168°C get 3-Hydroxy-5,6-trimethylene-indolylr2-glyoxylic acid methyl ester and melting point 200-202°C.

Example 5

A solution of 12 g (0.114 Mol) of 2-Methoxycarbonylchloromethylene-1,5»6-trimethyl-indoxyl in 100 ml. Ethanol of its cob and within 30 min. a solution of 19.2 g (0.228 mol) piperidine in 50 ml is added dropwise. Ethanol at 20-25°C. The dark red solution is then stirred for 10-20 minutes at 20-25°C. It is then added drop by drop under ice cooling during 30 min. 200 ml. 10 µg of aqueous sulfuric acid and let it stir for 1 hour at 20-25°C. The dark brown suspension is suctioned off, washed with water and dried at 60°C and 100 torr. 25.7 g of blackish crystals of 3-Hydroxy-1,5»6-trimethyl-indolyl-2-glyoxylic acid methyl ester are obtained, which also contain few impurities. Recrystallization from acetic acid ethyl ester with the addition of activated charcoal gives yellow-green crystals of melting point 169-171°C.

Starting materials can be obtained analogously to example 3 when starting from 2-Carboxychlormethylene-1,5»6-trimethyl-indoxyl (for the preparation see example i). It melts recrystallized from ethyl acetate at 134-136°C.

Example 6

Analogous to example 5, when starting from 1-Aethyl-2-carboxychloromethylene-5,6-dimethyl-indoxyl of melting point 1 30°C during cleavage, which can be obtained analogously to the method mentioned in examples 1 and 2 for the production of the 2-Carboxychloromethylene-indoxyl used there into 1-Aethyl-5,6-dimethyl-2-methoxycarbonylchloromethylene-indoxyl

and melting point 110-111°C (from acetic ester) get 1-Aethyl-5,6-dimethyl-3-hydroxy-indolyl-2-glyoxylic acid methyl ester and melting point 142-143°C (from Cyclohexane).

Example 7

Analogous to example 5, when starting from 2-Carboxychlormethylene-1,5,6-trimethyl-indoxyl-over 2-Aethoxy-carbonylchloromethylene-1,5,6-trimyl-indoxyl of melting point 9 3_94°C you can get 3- Hydroxy-1,5,6-trimethyl-indolyl-2-glyoxylic acid ethyl ester of melting point 126-127°C (from Cyclohexane).

Example 8

A solution of 3.0 g of 3-Hydroxy-1,5,6-trimethyl-indoxyl-2-glyoxylic acid methyl ester in 200 ml. Methanol is mixed with 2 3 ml. of one normal and the other in sodium hydroxide solution and stirred for 20 hours at room temperature. The suspension is then evaporated to dryness under reduced pressure at kO°C. The residue is dissolved in 300 ml. water. The aqueous solution is acidified with 30 ml. 2-Normal hydrochloric acid and the secreted dark red suspension are extracted with 700 ml. acetic acid ethyl ester. The organic phase is then shaken with 100 ml. 0, 5-nortnal Sodium bicarbonate solution as Sodium salt of 3-Hydroxy-1,5»6-trimethyl-indolyl-2-glyox-yl acid separates as orange crystals. The product is filtered off and dried below 0.01 torr at 60°C. It contains one mole of crystal water and melts at 235°C during cleavage. After recrystallization Tra Methanol "it melts at Zjk-235°C

Analogously, starting from 1.5 g of 5,6-Dimethyl-3-hydroxy-indolyl-2-glyoxylic acid methyl ester, you can get Sodium salt of 5»6-Dimethyl-3-hydroxy-indolyl-2-glyoxylic acid and melting point 265 °C during decomposition as well as when proceeding from 1,6-Dimethyl-3-hydroxy-indolyl-2-glyoxylic acid its sodium salt, melting point above 250°C.

Example 9

Solution of 1.0 g of sodium salt of 3-Hydroxy-1,5,6-trimethyl-indolyl-2-glyoxylic acid in 10 ml. absolute Dimethylformamide is mixed with stirring at room temperature with 0.5 g Dimethylsulphate. The solution is stirred for 2 hours at room temperature, mixed again with 0.5 g of dimethylsulphate and stirred for 15 hours at room temperature. The solution is then diluted with 100 ml. of water, filter off the precipitated crystals and dissolve them in 100 ml. acetic acid ethyl ester. The solution is extracted with 20 ml. water, then 2 times with 10 ml each time. Sodium bicarbonate solution and again with 20 ml. water, dried over magnesium sulphate and evaporated to dryness under reduced pressure. Reside is crystallized from acetic acid ethyl ester. 3-Hydroxy-1,5,6-trimethyl-indolyl-2-glyoxylic acid methyl ester melts at 169-1717<*>0.

In an analogous way, when starting from 0.8 g of sodium salt of 5»6-Dimethyl-3-hydroxy-indolyl-2glyoxylic acid, you can get 5»6-Dimethyl-3-hydroxy-indolyl-2-glyoxylic acid methyl ester and melting point 188-192°C (from Methanol).

Example 10

Analogously to examples 1-9, the following can also be prepared: 5-Aethyl-3-hydroxy-1-methyl-indolyl-2-glyoxylic acid and its Methylest is,

1.5- Dimethyl-3-hydroxy-indolyl-2-glyoxylic acid and its Methyl Ester,

6-Aethyl-3-hydroxy-1-methyl-indolyl-2-glyoxylic acid and its Methyl Ester,

1.6- Dimethyl-3-hydroxy-indolyl-2-glyoxylic acid methyl ester,

1,6-Dimethyl-3-pivaloyloxy-indolyl-2-glyoxylic acid

and its Methyl Ester,

^-Hydroxy-^-oxo-1,5,6-trimethyl-indolyl-2-glyoxyl-acid butyl ester,

5,6-Dimethyl-3-hydroxy-indolyl-2-glyoxylic acid butyl ester,

3-Hydroxy-5,6-trimethylene-indolyl-2-glyoxylic acid,

3-Hydroxy-1-methyl-5,6-trimethylene-indolyl-2-glyoxylic acid methyl ester and

3-Acetoxy-1,5» 6-trimethyl-indolyl-2-glyoxylic acid.

Example 11

2 g (0.0066 mol) of 3-Hydroxy-1,5,6-trimethyl-indolyl-2-glyoxylic acid methyl ester are stirred in 35 ml. of acetic anhydride with 0.2 g of anhydrous sodium acetate for one hour at 100 6C. After cooling, the sodium acetate is separated and the brown solution is evaporated. Recrystallization from cyclohexane gives blue-yellow crystals of 3-Acetoxy-1,5,6-trimethyl-indolyl-2-glyoxylic acid methyl ester of melting point 153-154°C.

Example 12

5 g of 3-Hydroxy-1,5,6-trimethyl-indolyl-2-glyoxyl acid methyl ester are mixed in 10 ml. Ethylene glycol under nitrogen with 2.8 g of anhydrous sodium carbonate and stirred for 1 hour at 40°C. The reaction mixture is cooled to room temperature and mixed with 100 ml. acetic acid methyl ester. Then add 50 ml. 10% sulfuric acid, whereupon the 3-Hydroxy-1,5»6-trimethyl-indolyl-2-glyoxylic acid (2-hydroxyethyl)-ester precipitates out. This is filtered off and recrystallized from toluene. Mon

get yellow-orange needles of melting point 154-156°C.

By substituting ethylene glycol in the corresponding amount of the alcohol in question, you can.

— i

further prepare 3-Hydroxy-1,5,6-trimethyl-indolyl-2-glyoxylic acid-neopentyl ester, melting point 115-117°G» 3-Hydroxy-1,5>6-trimethyl-indolyl-2-glyoxylic acid-n -octyl ester, melting point 65-67°C and 3-Hydroxy-1,5,6-trimethyl-indolyl-2-glyox-sylic acid-isopropyl ester, melting point 154-156°C.

Example 13

A suspension of 15.75 g of 3-Hydroxy-1,5»6-trimethyl-indolyl-2-glyoxylic acid in 1500 ml. Acetone is mixed dropwise with stirring with a solution of 9.51 g Triethanolamine in 70 ml. Acetone. The orange solution is evaporated below 11 Torr to a volume of approx. 50 ml. The separated crystals are filtered off, washed with a little Acetone and dissolved in 80 ml. hot ethanol. When the solution cools, the triethanolamine salt of 3-Hydroxy-1,5»6-trimethyl-indolyl-2-glyoxylic acid crystallizes. The crystals are filtered off, melting point 132-134°C.

Example 14

Analogous to example 3, 1.2 g of 2-(<£X-Methoxycarbonate-ct-piperidinomethylene)-5,6-trimethylene-indoxyl will yield 3-Hydroxy-5,6-trimethylene-indolyl-2-glyoxylic acid methyl -ester, melting point 198-202°C (from ethyl acetate). Output material can be produced as follows: Analog ; for example 2, for example, from 10.5 g of 6-Acetamido-indane and 10.2 g of Dichloromaleic anhydride, 2-Carbdxychlormethylene-5,6-trimethylene-indoxyl, melting point 200°C (Decomposition after recrystallization from glacial acetic acid).

Analogous to example 3, 6.0 g of 2-carboxychloromethylene-5,6-trimethylene will yield 2-Methoxycarbonylchloromethylene-5,6-trimethylene-indoxyl, melting point 183-184°C (from ethyl acetate).

A suspension of 5.5 g of 2-Methoxycarbonylchloromethylene-5,6-trimethylene-indoxyl in 28 ml. Methanol is stirred after adding 3.74 g of piperidine while introducing nitrogen during 18 hours at 60°C. A dark red solution is then mixed with ice and water. The separated oil is extracted with 50 ml. Ethyl acetate. The ethyl acetate extract is washed with 10 ml. water, drying over magnesium sulfate and evaporating it below 11 Torr to dryness. The residue, an oil, is chromatographed on 180 g of silica gel. Fractions 1-3,

of one with every 200 ml. Ether, contains contains starting material. Fractions 4-7i, eluted with ether, contain the pure 2-(cx-Methoxycarbonyl-CC-piperidino-methylene)-5,6-tri-methylene-indoxyl, melting point 160-162°C (from ether).

Example 15

1 g of 1,5»6-Trimethyl-3-hydroxy-indolyl-2-glyoxyl-_ acid methyl ester is suspended in 30 ml. 10% sodium carbonate solution and stir with k ml. Dimethylsulfate for 2k hours at room temperature. The precipitated 1,5»6-trimethyl-3-methoxy-indolyl-2-glyoxylic acid methyl ester is filtered off and recrystallized from Cyclohexane. It melts at 141-143°C.

Example 16

Tablets, containing 0.1 g of active substance, for example 3-Hydroxy-1,5" 6-trimethyl-indolyl-2-glyoxylic acid methyl ester, are prepared as follows:

The active substance is mixed with part of the wheat starch with the lactose and the colloidal silicic acid and the mixture is passed through a sieve. A further part of the wheat starch is pasted with five times the amount of water in a water bath and the above-mentioned powder mixture is crushed with this terk paste until a weak plastic mass is formed. The plastic mass is pressed through a sieve of approx. 3mm mesh size, dries and the dry granules are run through a sieve again. The remaining wheat starch, talcum powder and magnesium stearate are then mixed in and the resulting mixture is pressed into tablets of 0.25 g.

Example 17

A suitable for inhalation, approx. 2% aqueous solution of etbi free form of sodium salts water-soluble active substance according to the invention can for example be prepared in the following composition:

Manufacturing:

The active substance is dissolved while adding the aquimolecular amount of 2 normal sodium hydroxide solution in freshly distilled water. The stabilizer and preservative are then added. After complete dissolution of all components, it is filled up! prepared solution to 100 ml., is filled into bottles and these are closed gas-tight.

Example 18

For insufflation suitable approx. 25 mg of an active substance according to the invention containing capsules can, for example, be prepared according to the following composition:

Manufacturing:

The active substance and Lactose mix well. The resulting powder is then sieved and filled in portions of 50 mg each time into 1000 gelatin capsules.

Example 19

. Analogous way as in examples 13-15, it can be done corresponding pharmaceutical preparations containing another of the compounds mentioned in examples 1-12 with the general formula il.

Pat entkrav

Process for the preparation of new 3-Hydroxy-indolyl-2-glyoxylic acid derivatives of the general formula I

in which Y means optionally etherified or acylated Hydroxy, R means Hydrogen optionally substituted Lower alkyl or Cycloalkyl and -ORq means optionally etherified Hydroxy, and in which either R^ means Lower alkyl, Lower alkyl, Cycloalkyl, Hydroxy, Phenoxy, Halogen or Nitro, R^ means Lower alkyl, Lower alkyl or Hydroxy and R^ and R^ independently mean Hydrogen or Lower alkyl, where at least one of the residues R. j R^, R^ and R^ means 5- and/or 6-position bonded Lower alkyl, or R^ and R^ means together two adjacent carbon atoms bonded Alkylene, with 3 to 5 chain carbon atoms and R^ and R^ means Hydrogen daint their salts are ca r a c t - erized in that a compound with the general formula

in which R,RQ, R^, R^, R^and R^have the indicated meaning, X<*>means an Onium group and X ? means the anion residue of an acid, or a salt thereof is hydrolysed, or

a preposition with a formula

in which one of the residues X,-, and X^ means an optionally functionally modified Carboxy group and the other means Hydrogen or a salt thereof is condensed intramolecularly or

in a connection with formula

in which X^ means a residue transferable to the Oxalo group, X^ is transferred to the Oxalo group in and, if desired, a formed compound of formula I is transferred into another compound of formula I and/or if desired, a formed free compound is transferred in a salt or a formed salt in the free compound or in another salt. 2©Procedure according to kæcav: 1. characterized in that the free valence of the Onium group X<®> in a starting material according to formula II proceeds from the positively charged Heteroatom. 3. Method according to claim 1 or 2, characterized in that an Onium group XV is an Ammonium group. 4. Method according to claim 1 or 2 characterized in that an Onium group X<®> is a Sulfonium group e. 5. Method according to claim 1-4 characterized in that the Hydrolysis is carried out in an acidic medium. ' -' 6. Method according to claim 1, characterized in that it starts from a compound of formula VI, in which R means Hydrogen, X^ means esterified Carboxy

and X^means Hydrogen.

7. Process according to claim 1, characterized in that a compound of formula IX is hydrolyzed, in which X^ means a group of formula -C(=X^)-COORQ, -C(=0)-X6 or -C(=X ) -X6' and X^ mean a functionally modified Oxo group and X^ means a functionally modified Carboxy group from the group -COORQdiffers. 8. Method according to claim 7, characterized in that the starting point is a compound of formula IX, in which X^means a group of formula -C(=S)-COOH or -C(=NAr)-COO H^N-Ar and Ar means an optionally substituted Ph:enyl. 9. Method according to claim 7 or 8, characterized in that the Hydrolysis is carried out in an acidic medium. 10. Method according to one of the claims 1 - 9, characterized in that one starts from one or other method step as an intermediate formed compound and carries out the missing method steps. 11. Method according to claims 1-10 characterized by forming a starting substance under the reaction condition or using it/in the form of a derivative. 12. Method according to one of claims 1-11, characterized in that a compound with the general formula I according to claim 1 is prepared, in which R and R^ independently of each other mean Hydrogen, Lower alkyl with up to k Carbon atoms, Hydroxyllower alkyl with up to and including h Carbon atoms, in which Hydroxy is bonded in the 2- and/or 3-position, or Lower alkyl lower alkyl with up to and including 7 carbon atoms, in which the lower alkyl group is bonded in the 2- or 3-position, and in which either R^means lower alkyl with up to and including 4 carbon atoms, C^- C^-Cycloalkyl, Hydroxy, Lower Alkoxy with up to and including h Carbon atoms, Halogen and atomic number up to and including 35 or Nitro, and R2, R^ and R^ independently of each other mean Hydrogen or Lower Alkyl with up to and including h Carbon atoms, at least one of the residues R^, R^, R^ and R^ means 5- and/or 6-position bonded Lower alkyl with up to h Carbon atoms or R^ and R^ form together in the 5-6-position bonded rectilinear Alkylene with 3 to 5 Carbon atoms , and R^and R^mean \

Hydrogen as well as salts of the above-mentioned compounds, particularly equivalent to pharmaceutically usable salts.

13-Procedure according to one of claims 1 - 11, characterized in that a compound with formula is prepared

in which Y means Hydroxy or C^-C^-Alkanoyloxy, R. and R^ independently mean Hydrogen or Lower alkyl with to and f with h Carbon atoms, for example Methyl or Aethyl, Hydroxy-lower alkyl with tiib and with h Carbon atoms, in which Hydroxy is bound in the 2- and/or 3-position, for example 2-Hydroxyethyl

or 2,3-Di-hydroxy-propyl, or Lower alkoxy-lower alkyl with up to and including h Carbon atoms, in which the Lower alkoxy group is bound in the 2- or 3-position, for example 2-MeMioxyethyl, and in which either one of the radicals R~ and RQ means Lower alkyl with to

and with h Carbon atoms, for example Methyl, one of the remaining residues Rg, R^ and Rg means Hydrogen Lower alkyl with up to and including h Carbon atoms for example Methyl, Halogen with atomic number up to and including 35 for example Chlor, Lower Alkoxy with up to and with h Carbon atoms, for example Methoxy , Hydroxy or Nitro, and the third of the residue Rg, R^, and Rg means Hydrogen or Lower alkyl with even k carbon atoms, for example Methyl, or Rg g means Hydrogen and R^ and Rg together Alky-in with 3 or k chain carbon atoms, for example 1,3-Propylene, as well as salts of the above-mentioned compound, especially corresponding pharmaceutically usable salts.

14. Method according to claims 1-11, characterized in that a compound of the general formula Ia according to claim 13 is prepared, in which Y means Hydroxy, R

and R^means in the first row each Hydrogen or Lower alkyl with up to and including h Carbon atoms, for example Methyl or , Aethyl, or in the second row"Hydroxylower alkyl with up to and

with. k Carbon atoms in which Hydroxy is bound in the 2- and/or 3-position, for example 2-Hydroxyethyl or 2,3-Dihydroxy-propyl, or Lower alkoxy lower alkyl with tifl> and with k Carbon atoms in which the Lower alkoxy group is bound in the 2- or 3-position , for example Methoxy ethyl, and in which Rg, R,-, and Rg mean Hydrogen or Methyl or R^, and Rg together mean 1,3-Propylene or 1,4,Butylene, with at least one of the residues R~ and Rg being different from Hydrogen, as well as salts of the above-mentioned compound, in particular corresponding pharmaceutically usable salts.

15. Process according to one of claims 1-11, characterized in that a compound with the general formula Ia according to claim 13 is prepared, in which Y means Hydroxy, R means Hydrogen or Lower alkyl with up to k Carbon atoms such as Methyl or Aethyl, R means Lower alkyl

with up to k Carbon atoms such as Methyl or Aethyl, Rg means Hydrogen and at least one of the residues R,,, and Rg means Lower alkyl with up to k Carbon atoms such as Methyl, and the other optionally means Hydrogen or R^ and Rg together means 3- to 4- linked Lower alkylene, such as 1,3-Propylene and pharmaceutically usable salts thereof.

16. Process according to one of the claims 1 - Ilkar-acterized in that 3-Hydroxy-1,5" 6-trimethyl-indolyl-2-glyoxylic acid methyl ester is produced. 17. Method according to one of claims 1-11, characterized in that 1-Aethyl-5,6-dimethyl-3-hydroxy-indolyl-2-glyoxylic acid methyl ester is produced. 18. Method according to one of claims 1-11, characterized in that 3-Hydroxy-1,5" 6-trimethyl-indolyl-2-glyoxylic acid methyl ester is produced. 19" Method according to one of the claims 1-11, characterized in that 5" 6-Dimethyl-3-hydroxy-indolyl-2-glyoxylic acid methyl ester is produced. 20. Method according to one of claims 1-11, characterized in that 3-Hydroxy-5,6-trimethylene-indolyl-2-glyoxylic acid methyl ester is produced. 21. Method according to one of claims 1-11, characterized in that 3-Hydroxy-1,5»6-trimethyl-indolyl-2-glyoxylic acid or its sodium salt is produced. 22. Method according to one of claims 1 - 11, characterized in that 5'6-Dimethyl-3-hydroxy-indolyl-2-glyoxylic acid or its sodium salt is produced. 23. Method according to one of claims 1 - 11, characterized in that 1,6-Dimethyl-3-hydroxy-indolyl-2-glyoxylic acid or its sodium salt is produced. 2h. Method according to one of claims 1 - 11, characterized in that 3-Hydroxy-5,6-trimethylene-indolyl-2-glyoxylic acid or its sodium salt is produced. 25. Method according to one of claims 1 - 11, characterized in that 3-Hydroxy-1,5»6-trimeth<y>l-indole<y>l-2-<g>l<y>ox<y> is produced ls<y>re/(<2>-h<y>drox<y>aeth<y>l) - est is<.>26. Method according to one of claims 1 - 11, characterized in that 3-Hydroxy-1,5" 6-trimethyl-indolyl-2-glyoxylic acid neopentyl ester is produced. 27. Method according to one of claims 1 - 11, characterized in that 3-Hydroxy-1,5,6-trimethyl-indolyl-2-glyoxylic acid-n-octyl ester is produced. 28. Method according to one of claims 1 - 11, characterized in that 3-Hydroxy-1,5'' 6-trimethyl-indolyl-2-glyoxylic acid isopropyl ester is produced.