AU493473B2 - 3-amino-indazolecarboxylic acid derivatives, process for their preparation and their use as medicaments - Google Patents

Description

87170/75 The present invention relates to new 3-amino-indazole-

carboxylic acid derivatives, a process for their preparation

and their use as compounds which act on the central nervous

system, and especially as analgesics.

It has already been disclosed that 3-amino-indazoles

have an action on the central nervous system and can be used

as analgesics and antipyretics (compare German Auslegeschrift

(German Published Specification) 1,280,878). In this

published specification,

which is chemically the nearest compound of the same type of

action, is particularly singled out as a compound having

especially advantageous therapeutic properties.

3-Amino-indazoles find their main use in dyestuff

chemistry and are known, inter alia, as starting materials

for the preparation of dyestuffs (compare German Auslege-

schrift (German Published Specification) 1,149,839).

According to the present invention we provide 3-amino-

indazolecarboxylic acid derivatives of the isomeric formulae

1 SR .R1 R2 R R2 R

N N CO-Y

(I a) (I b)

in which

Y represents alkoxy, alkylamino or dialkylamino, R represents hydrogen or methyl, R represents hydrogen, methyl or formyl and 2 R represents 1, 2 or 3-substituents independently.

selected from hydrogen, alkyl, alkoxy, nitro, amino,

49 3,473

8 717 0 alkoxycarbonylamino, alkylamino, dialkylamino, acylamino, alkoxycarbonyl, and halogen, trifluoromethyl, cyano and their salts. the compounds of The compounds of the invention

the formulae la) and Ib) and their salts have powerful especially actions on the central nervous system, and and antiphlogistic possess very good analgesic, antipyretic compounds of the invention properties. Consequently, of those acceptable which are salts, those which are pharmaceutically

are prepared. derivatives of the The 3-amino-indazolecarboxylic acid a formulae (I a) and (I b) may be obtained by reacting

3-amino-indazole of the tautomeric formulae. NH _NH 2 2K 2

R

2 2 in which R has the abovementioned meaning

with a carbonic acid derivative of the formula

Y CO (III)

R4 3 NR5 in which Y represents the radical OR or the radical

wherein 5 R3 R 4 and R each denote lower alkyl, OR3 the X represents halogen, or, if Y represents 3 radical O-COOR or of the formula X and Y conjointly denote an imide group =NR wherein R denotes lower alkyl, agent and, in the presence of an inert organic solubilising 49 3,473 if appropriate, in the presence of an acid-binding agent, +250oC and there- usually at a temperature between -20 and step the amino after, if appropriate, in a further reaction acid or group in the 3-position is formylated with formic of formic acid. methylated with formaldehyde in the presence the corresponding The resulting compounds may be converted to with a salts by conventional techniques, e.g. by reaction base in an inert solvent. acid Surprisingly, the new 3-amino-indazolecarboxylic toleration derivatives according to the invention show better as well and a substantially greater analgesic and antipyretic the amino- as antiphlogistic (anti-oedematous) action than than indazoles known from the start of the art, especially which is chemically the The nearest active compound of the same type of action. an en- compounds according to the invention thus represent richment of pharmacy. The reaction scheme which follows shows, by way of can example, the reactions of the individual reactants which be used according to the invention: a) H 2 0NH 2 CH

N

COOCH3

4 493,4 73

87170/75

CF3 ja _r N +lCO )C2 o :NH +C1-COOC 2H 5 I H )OOC 2S

C) +C 1-CO-K H3N CH- H __-CH 3 (-Hcl C H

~N82

CO-N,-H 3

d) NCN2 NC NH2 OCN-c 4 H

H CO-NH-C H9

Reaction course of an optional subsequent bis- methylation of the NH2 -group:

CF 3 3 N ,C 3 CH3 2CH 20, +2HCOOH

COOc(CH 3) (-2002, -2H 20) COOCbo cHcr)3

The formation of the two isomeric forms (Ia) and (Ib) of the compounds according to the invention can be influenced by the choice of the reaction temperature. At lower temperatures, the isomeric form with the substituenta in the 2-position, is formed preferentially, whilst at higher temperatures compounds of the isomeric form (Ia),

493,473

87170/7i5 with the substituents in the 1-position, are formed preferentially, lb-isomers can also be rearranged to the Ia-isomers by subsequent heating (see the equation for reaction a) and In the formula Rpreferably represents 1 or 2 substituents independently selected from hydrogen, nitro,

amino, cyano, trifluoromethyl, halogen, alkyl, alkoxy, alkylamino, dialkylamino, alkoxycarbonyl, alkoxycarbonyl- amino and acylamino, halogen being, in particular, chlorine or bromine, and the alkyl, alkoxy and acyl radicals mentioned containing 1 to 4 carbon atoms, especially 1 or 2 carbon atoms. Compounds of the formula(II) in which R2represents hydrogen, nitro, amino, halogen, trifluoromethyl, cyano, and alkoxycarbonylamino are particularly important. The 3-amino-indazoles of the tautomeric, formula (IJ .to be used as starting materials are known or can be prepared according to known processes (comparEF J. Amer. chem. Soc. (1943), 1804, J. chem. Soc. (London) 19,2363, Liebigs Amn. Chem. 716 (1968), 47). The following may be mentioned as individual examples: 3-amino-indazole, 3-amino-4-methyl-indazole, propyl-indazo'le, 3-amno-6-n-butyl-indazole, 3-amino-4 ,7-bis-

methyl-indazole, 3-amiLno-5 ,6-bis-ethyl-indazole, ethyl-6-isopropyl-indazole, 3-amino-6-methoxy-indazole, 3- 3-amino-5 ,6-bis-methoxy-indazole, 3- amino-4-methyl-7-n-propoxy-indazolet 3-amino-5,7-dinitro-indazole, 3,5-diainino-indazole, 3,5,7-tris- amino-indazole, 3, 5-diamino-7-nitro-indazole, amino-indazole, 3-amino-5-t-butylamino-indazole, dimethylamino-indazole, 3-amino-5-formylamino-indazole, 3- 493A473

8 717 0/75 7bis-formylamino-ildazole, 3-amino-5-acetylamIifl0-

indazole, 3-amino-5-pivaloylamliflo-ifldazole, 3-amino-4-chloro-

indazole, 3-ajino-5-chloro-ifldazole, 3-arino-6chlr-indazole, 3-amino-6-fluoro-ilda7zole, 3-amino-

4, 7-dichioro-indazole 3aio4mty-6clr-naoe

3-p-mino-4-ethyl-5-bromo-ifldazole, 3-a-ino-4-ethoxy-6-chloro-

indazole, 3-amino-4-trifluorometliyl-ifldazole, fluoromethyl-indazole, 3-arino-6-trifl1oromethylinfdazole,

3-aynino-7-trifluoromethyl-ildazole, 6-ethyl-indazole, 3-mn--ehx--rfurmty-naoe 3-mn--rfiirmty--ir-naoe 2,

trifluoromethyl-indazole, 3-amino-5-triflxoromethyl-7-fl-butyl- am-ino-indazole, 3-amino-5-trifluoromethyl-7i-prpioflylamino- indazole, 3-axino-5-cyano-indazole, 3-arino-5-cyano-7-fitr0-

indazole, 3-mn--yn--omlmn-naoe ethoxycarbonyl-indazole, 3-formylamino-indazole, 3-methylamino-indaZOle, 3-dimethyl- ainino-indazole, 3-formylamino-5-ethyl-indazole, 3-dimethyl- amino-6-ethoxy-indazole, 3-dimethylaxnino-5, 6-bis-methoxy- indazole, 3- formyl-5-nitro-indazole, indazole, 3-dimethylamino-6-chloro-ildazole and 3-formylamino-

The carbonic acid derivatives of the formula (III) to be. used as starting materials are known or can be prepared by the known method. The following may be listed individually: a) Pyrocarbonic acid esters: pyrocarbonic acid methyl eater, pyrocarbonic acid ethyl ester, pyrocarbonic acid propyl ester, p~rocarbonic isopropyl ester and pyrocarbonic acid butyl ester (compare Liebigs Ann. Chem. 624, pages 30-36, (1959)). b) Chiorocarbonic acid esters: chlorocarbonic acid methyl ester, chlorocarbonic acid ethyl ester, chiorocarbonic acid propyl ester, chiorocarbonic acid isopropyl ester and chloro- 493.473

87170/75 carbonic.acid butyl ester (compare Beilsteins Handbuch der

Organischen Chemie (Beilstein's Handbook of Organic Chemistry),

edition IV, 3rd supplement, volume 3, pages 23-26).

c) Carbamic acid halides: dimethylcarbamic acid chloride,

dimethylcarbamic acid bromide, diethylcarbamic acid chloride,

methyl-ethyl-carbamic acid chloride, methyl-ethylcarbamic acid

bromide, dipropylcarbamic acid bromide, diisopropylcarbamic

acid chloride and dibutylcarbamic acid bromide (compare Beil-

steins Handbuch der Organischen Chemie (Beilstein's Handbook

of Organic Chemistry), edition IV, 3rd supplement, volume 4,

pages 144, 222 and 301).

d) Carbonic acid imides (isocyanates); methyl isocyanate,

ethyl isocyanate, propyl isocyanate, isopropyl isocyanate,

n-butyl isocyanate and tert.-butyl isocyanate (compare

Beilsteins Handbuch der Organischen Chemie (Beilstein's Hand-

book of Organic Chemistry), edition IV, 3rd supplement,

volume 4, pages 156, 227, 263, 279, 303, 321 and 325).

In the formula (III) 3 Y preferably represents the OR radical,

wherein

R 3 represents alkyl with 1 to 4 C atoms, especially 1 to 2 C atoms, or 4

Y preferably represents the radical N

wherein

R4 and R5 preferably denote alkyl with 1 to 4 C atoms

and

X preferably represents halogen, especially chlorine

or, if Y represents OR 3 the radical O-COOR 3 wherein

R has the abovementioned meaning, or

X Y conjointly preferably represent the imide group

8- 493,473

8 7 170/ of the formula =NR wherein R6 denotes alkyl with 1-4 C atoms, especially .with 1 to 2 C atoms.

In the formulae I, II and III preferred alkyl groups are straight-chain or branched alkyl groups with 1 to 4, especially with 1 to 2, C atoms. Methyl, ethyl, n- and i-propyl and i- and t-butyl may be mentioned as examples. Preferred alkoxy groups are straight-chain or branched alkoxy groups with 1 to 4, especially 1 to 2, C atoms. Methoxy, ethoxy, n- and i-propoxy and i- and t-butoxy may

be mentioned as examples. Preferred alkylamino and dialkylamino groups are straight-chain or branched alkylamino or dialkylamino with 1 to 4, especially 1 to 2, C atoms in the alkyl groups. Methylamino, dimethylamino, ethylamino, diethylamino, methyl- ethylamino, n- and i-propylamino, n- and i-dipropylamino, i- and t-butylamino, i- and t-dibutylamino and propyl- butylamino may be mentioned as examples. Preferred acylamino groups are straight-chain or branched acylamino with 1 to 6, especially 1 to 4, C atoms in the acyl radical. Formylamino, acetylamino, propionyl- amino, n- and i-butyrylamino, valeroylamino, isovaleroylamino and pivaloylamino may be mentioned as examples. Preferred halogen atoms are fluorine, chlorine, bromine and iodine, especially chlorine or bromine. Preferred alkoxycarbonyl groups are straight-chain or branched alkoxycarbonyl with 1 to 4, especially 1 to 2, C atoms in the alkoxy radical. Methoxycarbonyl, ethoxy- carbonyl, n- and i-propoxycarbonyl and i- and t-butoxy- carbonyl may be mentioned as examples. -9 493.473

8 7 17 0/75 Preferred alkoxycarbonylamino groups are straight-chain or branched alkoxycarbonylamino with 1 to especially

1 to 2, C atoms in the alkoxy radical. zxamples which may

be mentioned are methoxycarbonylami. ethoxycarbonylamino,

n- and i-propoxycarbonylamino and i- and t-butoxycarbonyl-

amino.

Diluents which can be used are all organic solvents

which are inert towards the particular reactants.

These preferentially include aliphatic alcohols such as

methanol, ethanol, isopropanol or butanol, hydrocarbons such

as benzine, toluene and xylene, halogenohydrocarbons such as

chloroform, carbon tetrachloride, chlorobenzene and dichloro-

benzenes, carboxylic acid esters such as ethyl acetate,

nitriles such as acetonitrile and propionitrile, ketones such

as acetone and methyl isobutyl ketone, ethers such as tetra-

hydrofurane or dioxane, carboxylic acid amide such as dimethyl-

formamide or dimethylacetamide, heterocyclic bases such as

pyridine, picolines, lutidines, collidines, quinoline or

isoquinoline, and also commercially available technical mixtures of these solvents. In the reaction with pyro-

carboxylic acid esters it is also possible to use an excess of

these pyrocarboxylic acid esters, which at the same time act

as solvents.

In carrying out the process according to the invention,

suitably 100 to 1 000 ml of the diluent are employed per mol

of the 3-amino-indazole of the formula(II).

The reaction can be carried out under normal pressure

but also under elevated pressure. In general, it is carried

out under normal pressure.

In the course of the reaction according to the invention,

the starting materials as a rule dissolve entirely or

493,473

8 7 17 0/75 partially whilst the end products crystallise out. The

separating-out of the end products can be accelerated by

cooling and/or by adding precipitants such as lower aliphatic

ethprs, for example diethyl ether and dibutyl ether, or lower

aliphatic hydrocarbons, for example petroleum ether, light

benzine, ligroin or halogenohydrocarbona :for example carbon tetrachloride.

The reaction temperatures can be varied within a sub-

stantial range. In general, temperatures between -20 and +250 0C, preferably between -10 and 10000°C, especially between 0

and 500 are used.

The thermal rearrangement of the I b compounds, which

are substituted in the 2-position, to the I a compounds, which

are substituted in the 1-position, can be effected by heating

the I b compounds, in the absence of solvents, to temperatures

above their melting point, or by heating them in the presence

of solvents. Suitable solvents for the rearrangement are

all inert higher-boiling organic solvents, especially etherx

such as diethylene glycol dimethyl ether, diethylene glycol.

diethyl ether and diethylene glycol dibutyl ether, carboxylic

acid amides,such as dimethylformamide and dimethylacetamide,

aromatic hydrocarbons or aromatic hydrocarbon derivatives,

such as xylene, tetralin, chlorobenzene, dichlorobenzenes,

nitrobenzene or anisole. Heterocyclic bases such as pyridine,

picolines, lutidines, collidines, quinoline and isoquinoline

are particularly suitable as well as mixtures of these bases

with other organic solvents.

The reaction temperatures for this rearrangement can be

varied within a substantial range. In general, the reaction

is carried out at temperatures between 20 and 250 0 C,

preferably between 50 and 20000°C, especially between 100 and

1700C. 11 493,4 73

87 170/175 The formylation or methylation of the NH2 group in heating the 3-position in the.formula I is carried out by formic with formic acid or a mixture of formaldehyde and acid at temperatures around 1000C. All customary acid-binders can be used as the acid- as binding agents. These include inorganic bases such or alkali metal hydroxides, for example calcium hydroxide earth barium hydroxide, alkali metal carbonates or alkaline metal carbonates such as sodium carbonate, potassium carbonate, amides such calcium carbonate or sodium bicarb-nate, as well as as soda:nide and organic bases such as tertiary amines, for quinol- example triethylamine, N,N-dimethylaniline, pyridines, ines and isoquinolines. The use of pyridines, lutidines and

collidines or quinoline as acid-binding agents is particularly may also be appropriate, since these bases at the same time used as especially suitable diluents. The following may be mentioned individually as new active compounds: 3 -amino-indazole-l-carboxylic acid methyl 3-amino- ester, 3-aino-indazole-2-carboxylic acid ethyl ester, 2 indazole-l-carboxylic acid n-butylamide, 3-amino-indazole- carboxylic acid dimetaylamide, 3-dimethylamino-indazole-l- carboxylic acid ethyl ester, 3-formylamino-indazole-l-carboxy- lic acid n-butyl ester, 3-amino-5-methyl-indazole-1-carboxylic acid diethylamide, 3-amnino-5,6-bis-methoxy-indazole-l- carboxylic acid ethyl ester, 3-amino-5,6-bis-methoxy-indazole- 2-carboxylic acid ethyl ester, 1-carboxylic acid i-propylamide, indazole-l-carboxylic acid ethyl ester, 3-amino-5,7-bis- etboxycarbonylamino-indazole-l-carboxylic acid ethyl ester, 3-amino-4-chloro-indazole-2-carboxylic acid methyl ester, 3- amino-5-chloro-indazole-1-carboxylic acid n-propylamide, 3- acid dimethylamide, 3- -12- 493.473

8 7170/715 acid ri-vropyl

ester, 3-formylamino-indazole-l-carboxylic acid ethylamlide, 3-,amino-6-chloro-indazole-l-carboxylic acid methyl ester,

3-amino-6-chloroindazole-l-carboxylic acid ethyl ester, 3- amino-6-d~l1ooindazole-2-carboxylic acid ethyl ester, 3-amino- 6 6-chloro-indazole-l-carboxylic acid n-butyl ester, 3-amino- chloro-indazale-l-carboxylic acid dimethylanide, 3-amiflo-6- 6 chloro-indazole-2-carboxylic acid dimethylainide, 3-amino- chloro-indazole-l-crboxylic acid n-butylamide, 3-dimethyl- amjno-6-chloro-indazole-l-carboxylic acid ethyl ester, 3- formylamino-6-chloro-ifdazole-lcarboxylic acid di-n-propyl- amide, 3-amino-4 7dichloro-indazole-l-carboxylic acid ethyl ester, 3-mn--rm-naoelcroyi acid dimethyl-

amide, 3-mn--looidaoelcroyi acid t-butyl

ester, 3-mn--rfurmty-naoelcroyi acid

xethyl ester, 3.aio4tilooehy-naoe2croyi acid dimethyl-amide, 3-mn--rflooety-naoelcr boyylic acid. methyl ester, 2-carboxylic acid methyl ester, indazole-l-carboxylic acid ethyl ester, rethyl-indazole-2-carboxylic acid ethyl ester, f3.uorontylindazole-l-carboxylic -acid i-butyl ester, 3-amino-

trifluoro-methyl-indazole-l-carboxylic acid dimethylamide, acid n-butyl-

amide, acid-ethyl ester, 1-cai-boxylic acid di-n-butylamide,

methyl-indazole-l-carboxylic acid n-propylamide, trifluoromethyl-7-ethoxyCarbofylamifl-ifdazolel-carboxliO acid ethyl ester, 3-anino-5-cvano-indazole-2-carboxylic acid

methyl ester and 3- 493,473

87 170n5 carboxylic acid n-butylamide. action on the The new active compounds show a strong show an analgesic central nervous system, and in particular action and an action, an antiphlogistic (anti-oedematous) antipyretic action. a pharmaceutical The present invention therefore provides a compound of the corposition containing as active ingredient or liquefied gaseous invention in admixture with a solid diluent other than a diluent, or in admixture with a liquid 200 (preferably less solvent of a molecular weight less than surface active agent. than 350) except in the presence of a compo- The invention further provides a pharmaceutical a compound of the in- sition containing as active ingredient isotonic aqueous solution. vention in the form of a sterile or in dosage unit The invention also provides a medicament either alone or form comprising a compound of the invention in admixture with a diluent. in the form The invention also provides a medicament dragees, cap- of tablets (including lozenges and granules), comprising a com- sules, pills, ampou-es or suppositories alone or in admixture with the pound of the invention either diluent. means "Medicament" as used in this Specification suitable for medical physically discrete coherent portions .administration. "Medicament in dosage unit form" as used in coherent portions this Specification means physically discrete containing a daily suitable for medical administration each or sub-multiple (down dose or a multiple (up to four times) compound of the inven-. to a fortieth) of a daily dose of the a daily dose or, for tion. Whether the medicament contains of a daily dose will example, a half, a third, or a quarter -14- 493.473

8 7 17 0 pend on whether the medicament is to be administered once

for example, twice, three times or four times a day re-

ectively. The pharmaceutical compositions according to the in-

ntion may, for example, take the form of ointments, gels, stes, creams, sprays (including aerosols), lotions, sus-

nsions, solutions and emulsions of the active Ingredient in

ueous or non-aqueous diluents, syrups, granules or powders.

The diluents to be used in pharmaceutical compositions

granulates) adapted to be formed into tablets, dragees,

psules and pills include the following:

fillers and extenders, e.g. starch, sugars, mannitol, and

licic acid; binding agents, e.g. carboxymethyl cellulose

d other cellulose derivatives, alginates, gelatine and poly-

nyl pyrrolidone; moisturizing agents, e.g. glycerol; disintegrating agents, e.g. agar-agar, calcium carbonate

Ld sodium bicarbonate; agents for retarding dissolution

g. paraffin; resorption accelerators, e.g. quaternary

monium compounds; surface active agents, e.g. cetyl

cohol, glycerol monostearate; adsorptive carriers, e.g.

olin and bentonite; lubricants, e.g. talc, calcium and

gnesium stearate and solid polyethylene glycols.

The tablets, dragees, capsules and pills formed from

Le pharmaceutical compositions of the invention can have the

Lstomary coatings, envelopes and protective matrices, which

y contain opacifiers. They can be so constituted that they

lease the active ingredient only or preferably in a particu-

ir part of the intestinal tract, possibly over a period of

.me. The coatings, envelopes and protective matrices may

made, for example, of polymeric substances or waxes.

The ingredient can also be made up in microencapsulated

15 493,473

8 7170/75 form together with one or several of the above-mentioned di- luents. The diluents to be used in pharmaceutical compositions adapted to be formed into suppositori- can, for example, be

the usual water-soluble or water-insoluble diluents, such as polyethylene glycols and fats cocoa oil and high esters

C1 4 -alcohol with C1 6 -fatty acid]) or mixtures of these diluents. The pharmaceutical compositions which are ointments, pastes, creams and gels can, for example, contain the usual diluents, e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene gly- co.s, ailicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances. The pharmaceutical compositions which are powders and sprays can, for example, contain the usual diluents, e.g.. lactose, talc, silicic acid, aluminium hydroxide, calcium silicate, and polyamide powder or mixtures of these sub- stances. Aerosol sprays can, for example, contain the usual propellants, e.g. chlorofluorohydrocarbons. The pharmaceutical compositions which are solutions and emulsions can, for example, contain the customary diluents (with, of course, the above-mentioned exclusion of solvents having a molecular weight below 200 except in the presence of a surface-active agent), such as solvents, dissolving agents and emulsifiers; specific examples of such diluents are water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils [for example ground nut oil], glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitol or -16- 493.4 73 mixtures thereof.

For parenteral administration, the solutions and emul-

sions should be sterile, and, if appropriate, blood-isotonic.

The pharmaceutical compositions which are suspensions

can contain the usual diluents, such as liquid diluents, e.g.

water, ethyl alcohol, propylene glycol, surface-active agents ethoxylated isostearyl alcohols, polyoxyethylene sorbite

and sorbitane eaters), microcrystalline cellulose, aluminium

metahydroxide, bentonite, agar-agar and tragacanth or mixtures

thereof.

All the pharmaceutical compositions according to the

invention can also contain colouring agents and preservatives

as well as perfumes and flavouring additions peppermint

oil and eucalyptus oil) and sweetening agents saccharin).

The pharmaceutical compositions according to the in-

vention preferably contain about 0.1 to 99.5, more Preferably

from about 0.5 to 90% of the active ingredient by weight of the total composition.

In addition to a compound of the invention, the pharma-

ceutical compositions and medicaments according to the invention

can also contain other pharmaceutically active compounds. They

may also contain a plurality of compounds of the invention.

Any diluent in the medicaments of the present invention

may be any of those mentioned above in relation to the pharma-

ceutical compositions of the present invention. Such medica-

ments may include solvents of molecular weight less than 200

as sole diluent. The discrete coherent portions constituting the medica- ment according to the invention (whether in dosage unit form or not) may be, for example, any of the following: tablets, (including lozenges and granules), pills, dragees, capsules, 17- 493.473

8 71 70/75 suppositories and ampoules. Some of these forms may be made

up for delayed release of the active ingredient. Some, such

as capsules, include a protective envelope which renders the

portions of the medicament physically discrete and coherent.

The preferred daily dose for administration of the

medicaments of the invention is 0.5 mg to 5 g of active ingredient.

The production of the above-mentioned pharmaceutical

compositions and medicaments is carried out by any method

known in the art, for example, by mixing the active ingredi-

ent(s) with the diluent(s) to form a pharmaceutical compo-

sition a granulate) and then forming the composition

into the medicament tablets).

This invention further provides a method of combating

(including prevention, relief and cure of) the above-mentioned diseases in human and non-human animals, which comprises ad-

ministering to the animals a compound of the invention alone

or in admixture with a diluent or in the form of a medicament according to the invention. It is envisaged that these active compounds will be administered perorally, parenterally (for example intra- muscularly, intraperitoneally or intravenously), rectally

or locally, preferably orally or parenterally. Preferred

pharmaceutical compositions and medicaments are therefore those adapted for oral or parenteral administration. In the case of oral use, tablets can of course also contain, in addition to the excipients mentioned, additives such as sodium citrate, calcium carbonate and calcium phos- phate, together with various further substances such as starch, preferably potato starch, gelatine and the like. Purthermore, lubricants such as magnesium stearate, sodium

-18- 493,473

8717 0/75 for tablet-making. lauryl-sulphate and talc can be co-used and/or elixirs which are In the case of aqueous suspensions compounds can be mixed intended for oral use, the active in with various flavour-improving agents or dyestuffs addition to the abovementioned auxiliaries. of In the case of parenteral application, solutions suitable liquid the active compounds can be employed, using advan- excipiente. A fact which has proved particularly is that the tageous for the case of parenteral -application readily water- compounds according to the invention can form the compounds soluble salts. These salts are obtained when are according to the invention, in a suitable solvent, inorganic or combined with the equimolar amount of a non-toxic sodium organic base. As examples there may be mentioned: ethanolamine, hydroxide solution, potassium hydroxide solution, diethanolamine, triethanolamine, amino-tris-hydroxymethyl- methane, glucosamine and N-methyl-glucosamlne. oral Such salts can also be of increased importance for in application of the compounds according to the invention, that they accelerate or delay the resorption, as desired. In addition to the salts already mentioned above, examples salts, which may be mentioned are magnesium salts, calcium aluminium salts and iron salts. In general it has proved advantageous, in the case of parenteral administration, to administer amounts of about of body 0.01 to 50 mg/kg, preferably about 0.1 to 10 mg/kg weight daily to achieve effective results, whilst in the case of oral administration the dosage is about 0.1 to 500 daily. mg/kg, preferably 0.5 to 100 mg/kg of body weight

Nevertheless it can at times be necessary to deviate

from the amounts mentioned and in particular to do so as a

19 493,473 or of the nature function of the body weight of the test animal because of the species .of of the administration route, but also towards the medicament, or animal and its individual behaviour latter, and the time or the nature of the formulation of the Thus, it may in some interval at which it is administered. the abovementioned cases suffice to manage with less than the upper limit mentioned minimum amount whilst in other oases are administered it can must be exceeded. Where major amounts individual be advisable to divide these into several the day. administrations over the course of compounds These statements apply to the use of the medicine and in according to the invention both in veterinary human medicine. the tail flick The analgesic action was determined by pheylquinone writhing test on the tails of rats and by the flick the tail of male rats test on rats. In the tail In this test, is irradiated with a focussed heat ray. time of untreated animals react, after an average irradiation away the tail. 5.1+0.8 seconds (reaction time) by drawing compounds, this Under the influence of analgesically active which, reaction time becomes longer. Active compounds the animals of at after administration give a reaction time of active. least 20 seconds are considered to be analgesically is the dose which animals are employed per dose. The ED50 th6 animals on average lengthens the reaction time of 50% of Wolff, H.G., employed to at least 20 seconds (literature: Measurement of J.D. Hardy and H. Goodell: Studies on pain. on the the effect of Morphine, Codeine and other opiates to the. pain threshold and an analysis of their relation (1940)). pain experience. J. Clin. Invest., 12, 659-680 the In the phenylquinone writhing test, 100 pg of 20- 493.473 bstanoe, dissolved in 0.5 ml of 5% strength alcohol, are in- cted intraperitoneally into rats.A few minutes after admini- ration,the animals show the charac- .ristic writhing reaction, ich consists of the animals showing extreme backward extension the hind paws, flexing the back and lifting the tail. At e same time, wave-like contractions frequently pass over the iominal muscles. The inhibition of this writhing syndrome assessed to be an analgesic effect. The substance to be restigated is administered 30 minutes (in the case of bcutaneous administration) or 60 minutes (In the case of al administration) before the injection of phenylquinone. inimals are employed per substance and per dose. The is the dose at which the number of writhing reactions in animals employed is on average reduced to half that of control group (literature: Siegmung, R. Cadmus and Lu: A method for Evaluation both non-Narcotic and *cotic Analgesics. Proc. Soo. exp. Biol. Med. 95, 729-731

The antiphlogistic and anti-oedematous action of the ipounds according to the invention was determined by the Libition of the carrageenin oedema on the paw of rats. In .s test, a reference measurement on the normal paws of rate carried out an hour before and f an hour after oral linistration of the compound to be tested, using an anti- ogmeter. One hour after administration of the substance, oedema is started by injecting a carrageenin solution

o the planta pedis of one hind paw. 2+ hours and 3 hours er the carrageenin injection, the effect on the oedematously ected paw is measured. The relative paw volume is expressed a percentage of the reference measurement 100). The

21 493,473

87170n.

EDo is the dose at which, in 50% of the animals employed per dose, the difference between the relative paw volume of the treated animals and the relative pz volume of the 10 control groups is 100. The antipyretic action is determined on rate to which a beer yeast suspension has been administered subcutaneously. The body temperature is measured rectally before, and 16 hours after, administration of the beer yeast. The substance to be tested is administered orally to groups of 5 rats, of which 0 the body temperature has been raised by at least 1 C. Thereafter, the temperature drop is tested rectally. A 0 drop in the body temperature by at least 1 C is assessed as an antipyretic effect. The ED5 0 is the dose at which, in of the animals employed, the raised body temperature is lowered by 10 C by administration of the active substance according to the invention. The table which follows shows the individual actions of the compounds according to the invention. 3-Amino-trifluoro- methyl-indazole, which is chemically the nearest compound known from the state of the art, was employed for comparison.

22 493,473

23 49 3.4 73 wo 0

424

e44 ;ft .0

04

4Od

4-~

00 0

0s 0 U-

0 0

0

-443 E-4 0

24 493,473

8 7 13or n a 4- 0 u-0

(D01 Hi 00 #4 IRCo Hf

0 O

0 c$4 4) 0 Id~ as

0

4) 0 0 0 4) 0 1~ 0 cmc H 144 4) 0 4 4 t H. H,,

C043-

ti~qo I

HH co~ Ho 0

4) i 0

0 A1

Nm

C? C) 0 I0- I~-8 0) 0 C) ii'

25 5 -493,4 73 g'7 17 0 /715

26 6 -493.47 3

87170/7 Preparation examples Example 1 NH2

01 "6l a,-00002

0.3 mol of 3-amino-6-chloro-indasole in 250 ml of pyrocarbonic acid diethyl eater are heated, uhilet atirring, to 50C for about 5 hours, until the evolution of 002 has ceased. After cooling, 250 .l of diethyl ether are ad4pd and 90% of theory of 3-amino-6-chloro-indazole-2-carboxyli.c acid ethyl eater are isolated, by filtration, in the form of yellow crystals. Melting point: 163-165o0. Example 2 The reaction product of Example 1 is also obtained, in yield, on reacting 0.1 mol of 3-amino-6-chloro-indasole End 0.15 mol of pyrocarbonic acid diethyl eater in 50 ml of ethanol in 2 hours at 500 C. Example 3 The reaction product of Example 1 is also obtained, in 654% yield, on reacting 0.2 mol of 3-amino-6-chloro-indazole, 0.22 mol of chlorocarbonio acid ethyl eater and 0.22 maol of sodium bicarbonate in 150 ml acetone in 3 hours at 20-300C. Example 4

N OC H5 Cco 2

Analogously to Example 1, 0.01 mol of 3-amino-indazole and 0.01 mol of pyrocarbonic acid diethyl eater in 20 ml of dimethylformamide give 3-amino-indazole-2-carboxylic acid ethyl eater (melting point: 182-183 0 oC 78% of theory) in 0 minutes at 5-10 C 27 493,473

87170m Example 01

NH2 6 N-00000

Analogously to Example 1, 0.2 mol of 3-ezino-4-cbloro- indazole in 100 ml of pyrocarbonic acid diethyl eater gives 3-aaino-4-chloro-indaole-2-arboxylic acid ethyl eater (melt- ing point: 109-111 0C; 63% of theory) in 3 hours at 2030OO. Example 6

.Cl.01 -COOCE4J

Analogously to Example 1, 0.1 mol of 3-amino-6-chloro- indazole in 50 ml of pyrocarbonic 'acid dimethyl ester gives 3-amino-6-chloro-idazole-2-carboxylic acid methyl ester (melt- ing point: 198-20000; 90% of theory) in 30 minutes at 30500. Exam~le 7

al Ja ~lw- COOC4H Analogously to Example 1, 0.05 mol of 3-anino-6-chloro- indazole and 0.075 aol of pyrocarbonic acid di.'n-butyl eater give 3-amino-6-chloro-indazole-2-carboIylic acid n-butyi ester (melting point: 169-170 0 C; 81% of theory) in 5 hours at 5000. Example 8

NR2

N -COOC 2E

Analogously to Example 1, 0.06 mol of 3-amino-4- triluoromethyJ-indazole in 50 ml of pyrocarbonic acid diethyl ester gives 3-amino-4-trifluoromethyl-indazole-2-carboxylic -28- 493,473

87170/75

acid ethyl eater (melting point: 100-1OOC; 85% of theory) in 10 minutes at 2000. Example 2

P3C /I-COCI

Analogously to Example 1, 0.1 mol of trifluoromethyl-indazole in 50 m1 of pyrocarbonic acid dimethyl eater gives 3-amino-5-trifluoromethyl-indazol.-2-carboxylio acid methyl eater (melting point: 164-1650C; 64% of theory) in 2 hours at 500C. Examvle

-COOCi2H .IN

Analogously to Bxample 1, 0.1 mol of trifluoromethyl-indazole and 0.125 mol of pyrocarbonio acid diethyl ester in 100 ml of ethanol give methyl-indazole-2-carbcylic acid ethyl ester (molting point: 182-184OC; 82% of theory) in 1 hour at 80 0 C. Bxamnle 1

F3C cJ ~Tu2 I-COOCH 3

Analogouly to Example 1, 0.05 mol of trifluoromethyl-indazole and 0.055 mol of pyrocarbonic acid di-isopropyl eater give 3-amino-5-trifluoromethyl-indazole-2- carboxylic acid isopropyl ester (melting point: 184-1860 C; 82% of theory) in 5 minutes at 20.;30C.

29 493,473

97170/75 Examule 12

P3C NE2 N-N-COOC 4 E.

Analogously to Example 1, 0.05 mol of trifluoromethyl-indazole end 0.055 mi of pyrocarbonic acid di-n-butyl ester give 3-amino-5-trifluoromethyl-indazole-2- carboxylic acid n-butyl ester (melting point: 147-1490C; 0 73% of theory) in 5 minutes at 20-30 a. Examyle 13

N 2 N002H C

Analogously to Example 1, 0.04 mol of 3-amino-6- trifluoromethyl-indazole and 50 ml of pyrocarbonic aoid diethyl ester in 25 ml of ethanol give 3-amino-6-trifluoromethyl- indazole-2-carboxylic acid ethyl ester (melting point: 153- 155 0 77% of theory) in 1 hour at 20 0 C. Example 14

Analogously to Example 1, 0.05 mol of 3-amino-6- trifluoromethyl-indazole and 0.055 aol of pyrocarbonic acid di-n-butyl ester give 3-amino-6-trifluoromethyl-indazole-2- carboxylie acid n-butyl eater (melting point: 139-1400C; 93% of theory) in 1 hour at 500 0 Example

S -C00C2 CP3 /V 493.473

87170/75 Analogously to Example 1, 0.05 mol of 3-amino-7- trifluoromethyl-idazole and 0.055 mol of pyrocarbonic acid diethyl ester give 3 -amino-7-trifluoromethy1-indazole-2- carboxylic acid ethyl ester (melting point: 1 7 4 -1 7 5 0C; 93% 0 of theory) in 5 minutes at 20-25 C. Example 16

02 >H2

Analogously to Example 1, 0.2 mol of indatole and 0.22 mol of pyrocarbonic acid diethyl ester in 2 100 ml of dimethylforamide give 3-amino-5-nitro-indazole- 0 carboxylic acid ethyl ester (melting point: 226-227 C; 76% 0 of theory) in 8 hours at l0-20 C. Example 17 Cl S NH2 NCOOC 2H

C1

Analogously to Example 1, 0.15 mol of 3-amino-4,7- dichioro-indazole in 100 ml of pyrocarbonic acid diethyl eater gives 3-amino-4 ,7-dichloro-indazole-2-carboxylic acid ethyl ester (melting point: 143-145 0C 69% of theory) in 5 hours at 500 C. Example 18

H2 P 3 C00C 2 E

NO 2

Analogously to Example 1, 0.1 mol of trifluoromethyl-7-nitro-indazle and 150 ml of pyrocarbonie -31 493,473

8717/75 acid diethyl eater in 100 ml of ethanol give trifluoromethyl-7-nitro-indazole-2-carboxylic acid ethyl eater minutes (melting point: l86-187OC; 74% of theory) in 30 at 800. Example 19 CF3,._ M2

N'C00C 2H

'H2

Analogously to Example 1, 0.1 mol of 3,7-diamino-5- trifluoromethyl-IFdazole in 70 ml of pyrocarbonic acid diethyl ester gives 3,7-di iio--5-trifluoromethyl-indazole-2-carboxlio theory) acid ethyl ester (melting point: 193-940C; 90% of in 1 hour at 20-300C. Example C 00 A

NH-C0C 2H

Analogously to Example 1, 0.1 mol of 3,7-diamino-5- diethyl trifluoromethyl-indazole in 70 ml of pyrocarbonic acid ester gives -amlno-5-trifluoromethyl -7-ethoycarb indazole-2-carboIylic acid ethyl ester (melting point: 229- 0 230 C; 89% of theory) in 20 minutes at 70 C. Examle 21

0.1 mol of 3-amino-6-chloro-indazole in 100 ml of hours to pyrocarbonic acid diethyl ester is heated for 5 diethyl 100C, whilst stirring. After cooling, 100 ml of -32- 493,473

8 7 170 ether are added and 3-amino-6-chloro-indazole-l-carboxylio acid ethyl ester is isolated, by filtration, in the form of colourless crystals (melting point: 190-19200; 60% of theory). Example 22 The reaction product of Example 21 is also obtained, in yield, on reacting 0.2 mol of 3-amino-6-chloro-indazole and 0.5 mol of pyrocarbonic acid diethyl ester in 500 ml of ethanol in 10 hours at Example 23 The reaction product of Example 21 is also obtained, in yield, on reacting 0.2 mol of 3-amino-6-chloro-indazole and 0.22 mol of chlorocarbonic acid ethyl eater in 150 ml of pyridine in 1 hour at 20-300 C. Example 24 The reaction product of Example 21 is also obtained, in yield, on reacting 0.2 mol of 3-amino-6-chloro-indazole 2-carboxylic acid ethyl ester in 80 ml of 2,4,6-trimethyl- pyridine in 15 minutes at 170 0 C. Example The reaction product of Example 21 is also obtained, in yield, on reacting 0.1 mol of 3-amino-6-chloro-indazole and 0.12 mol of pyrocarbonic acid diethyl eater in 50 ml of quinoline in 1 hour at 20-300 C and subsequently 30 minutes at 16000. Example 26

c00ooc 2H Analogously to Example 24, 0.07 mol of 3-amino- indazole-2-carboxylic acid ethyl ester in 50 ml of nitrobenzene -33- 493.473

87170/75 gives 3-amino-indazole-l-carboxyli acid ethyl eater (melting point: 163-1650 CI 83% of theory) in 10 minutes at 2100C. Example 27

&Y'2

0 00CH

Analogously to Example 23, 0.05 mol of 3-anino-4- chioro-indazole and 0.055 mol of chiorocarbonc acid methyl eater in 50 ml of pyridine give 3-amino-4-chloro-indazole-l- carboxylic acid methyl ester (melting point: 190-191C; 0 58% of theory) in 1 hour at 20-30 C. ExaMple_28 Cl

booc 2

Analogously to Example 23, 0.1 ml of 3-amino-4- chioro-indazole and 0.105 mol of chlorocarbonic acid ethyl ester in 80 ml of pyridine give 3-amino-4-cbloro-iFdazole-l- 0 carboxylic acid ethyl ester (melting point: 167-169 C; 62% 0 of theory) in 1 hour at 50 C. Example 29 NH2

CO OCR,

Analogously to Example 24, 0.05 mol of 3-amino-6- chloro-indazole-2-carboxylic acid methyl ester in 50 ml of 2-methyl-pyridine gives 3-amino-6-chloro-ndazole-l-carboxylic

-34- 493,473

87170/75 acid methyl eater (melting point: 210-211 0C; 55% of theory) in 15 minutes at 1250C. Example

NE2

COOC4 H9

Analogously to Example 24,0.04 mol of 3-amino-6- chloro-indazole-2-carboxylic acid n-butyl eater in 25 m. of pyridine gives 3-amino-6-chloro-indazole-l-carboxylic acid n-butyl ester (melting point: 139-140 0 C; 61% of theory) in 0 minutes at 100 C* Example 31 P3 SH2

N -N

Analogously to Example 21, 0.06 mol of 3-amino-4- trifiuoromethyl-ndazole in 50 ml of pyrocarbonic acid diethyl ester gives 3-amino-4-trifuorome+thyl-indazole--carboxylio acid ethyl ester (melting point: 185-1860 C; 68% of theory) in 2 hours at 75 C.0

Example 32

P3C NE2

COOCH,

Analogously to Example 24, 0.065 mol of trifuoromethyl-indazole-2-carboxylic acid methyl ester in ml of 4-methyl-pyridine gives

493.473

87170'n5

indazole-l-carboxylio acid methyl eater (melting point: 177- 1780 C; 55% of theory) in 5 minutes at 140 0 C. Example 33

Cooc2 H

Analogously to Example 24, 0.175 mol of trifluoromethyl-indazole-2-carboxylic acid ethyl eater in ml of 2,4,6-trimethyl-pyridine gives methyl-indazole-l-carboxyli acid ethyl ester (melting point: 181-1830C; 87% of theory) in 30 minutes at 1700C. Example 34 The reaction product of Example 33 may also be obtained in 86% yield by reacting a mixture of 1.6 mol of 3-amino- 5-trifluoromethyl-indazole-2-carboxylic acid ethyl eater, 370 ml of xylene and 20 ml of pyridine for ten minutes at 135-140C. Example

COO-CH

Analogously to Example 24, 0.04 mol of trifluoromethyl-indazole-2-carboxylic acid isopropyl eater in ml of nitrobenzene gives 1-carboxylic acid isopropyl eater (melting point: 162-1630 C; 57% of theory) in 15 minutes at 2100 C.

36 493,473

87170M5 Example 36

P3CN NH2

COOC H9

Analogously to Example 24,0.02 mel of trifluoromethyl-indazole-2-carboxlic acid n-butyl ester in ml of l, 2 -dichlorobenzene gives

indazole-l-carboxylic acid n-butyl eater (melting point: 125-127C; 80% of theory) in 15 minutes at 1750 C. Example 37

COOC

Analogously to Example 22, 0.04 mol of 3-amino-6- 'rifluromethylindazole and 50 m! of pyrocarbonic acid tiethyl ester in 25 ml of ethanol give 3-amino-6-trfiflro-

rethyl-indazole-l-carboxyl c acid ethyl ester (melting ooint: 168-1690 C; 64% of theory) in 2 hours at 8000.

3 I COOC 4N9

Analogously to Example 24, 0.03 mol of 3-aknmno-- rifl-oromethyl-indazole-2-carboxylic acid n-butyl ester in ml of nitrobenzene gives 3-a-in-6-trifluoromethyl-ndazole- -carboxylic acid n-butyl eater (melting point: 3-134OC; S% of theory) in 10 minutes at 200 0C.

37 493473

8717 0

Example 39

02N

000 2 H

Analogously to Example 24, 0.05 mol of nitro-indazole-2-carboxylic acid ethyl ester in 50 ml of nitrobenzene gives 3-amino-5-nitro-indazole-l-carbozylic acid ethyl eater (melting point: 236-237oC; 93% of theory) in minutes at 2100 C.

Example

C2 00C-HN

C000C2 H

Analogously to Example 21, catalytic hydrogenation of 0.15 mol of 3-amino-5-nitro-indazole with Raney nickel in tetrahydrofurane at 75 0 C, followed by reaction of the solu- tion, which has been freed from the catalyst, with 0.6 mol of pyrocarbonic acid diethyl ester, in 2 hours at 500 C, gives 3-

38 493,473

87170/75 acid ethyl 0 ester (melting point: 173-174 C; 42% of theory). Example 41

NC

COOCH5 2

Analogously to Example 24, 0.07 mol of cyano-indazole and 0.08 mol of pyrocarbonic acid diethyl ester in 50 ml of 3-methyl-pyridine give 3-amino-5-cyano-indazole-1- carboxylic acid ethyl eater (melting point: 252 0 C; 57% of 0 0 theory) in 15 minutes at 20 C followed by 10 minutes at 100 C. Examnlic 42

P3 C'M2

NH2 O002H

Analogously to Example 24, 0.1 mol of 3,7-diamlno-5- trifluoromethyl-inde-zole-2-arbxoylic acid ethyl ester in 30 ra of nitrobenzene gives l-carboxylic acid ethyl ester (melting point: 217-218 0 C; of theory) in 1 hour at 210 0G Examle 43 PC N IN

H5 C200C-NHI COOC 2H

Analogously to Example 24, 0.025 mol trifluoromethyl7'-ethoxycarbonylamino-indazole-2-carboxyli acid ethyl eater in 30 ml of dimethylformamide gives 3-amino- -39- 49a473

87170/75

5-trifluoromAthyl-7-ethoxycarbonylaioindazole-caboxylio acid ethyl ester (melting point: 236-237OC; 65% of theory) 0 in 1 hour rt 155 C. Example 44 NH ,,CH3 C1 3-C CH3 CE3

0.15 mol of dimethylcarbamic acid chloride is added dropwise, whilst stirring, to 0.1 mel of 3-amino-6-chloro- indazole in 50 ml of pyridine, in the course of which the temperature rises to 45 C. After 1+ hours, 250 ml of water are allowed to run in and the reaction product is isolated by filtration. After dissolving the product in chloroform, filtering off a by-product of melting point 237-238SC and evaporating the solution, 3-amino-6-chloro- indazole-2-carboxylic acid dimethylamide (melting point: 178-1800C; 58% of-theory) is obtained. Examle

_N2

Cl CO-N CH3

0.06 mel of 3-amino-6-chloro-indazole-2-carboxylic acid 0 dimethylamide in 25 ml of nitrobenzene is heated to 210 C for 15 minutes under N2 Evaporation in vacuo and recrystal- lisation of the residue from ethanol gives 3-amino-6-chloro- indazole-l-carboxylic acid-dimnethylamide (melting point: 170-172 0 C; 68% of theory).

40 493,473

87170-/75 Example 46

0FM2 CF3 rj

C 0 -NE-C H9

0.0275 nol of n-butyl isocyanate is added dropvise to 0.025 mol of 3-amino-6-trifluoromethyl-indazole in 25 ml of chloroform, in the course of which the temperature rises to 0 C. The mixture is stirred for 3 hours at 20 0C and finally for 15 minutes at 600 C, and after evaporation 3-amino- 6-trifluoromethyl-indazole-2..carboxylic acid n-butylamide (melting point: 81-83 C) is obtained; this is rearranged, 0 by brief heating to 200 0C in nitrobenzene, to 3-amino-6- trifluoromethy-indazole-l-carboxylic acid n-butylamide (melt- ing point l40-142OC; 86% of theory). Example 47

NH

60-NH-CH3

Analogously to Example 46, 0.1 mol of 3-amino-6-chloro- indazole and 0.1 mol of met-hyl isocyanate in 100 ml of pyridine give 3-amino- 6-ch-oro-:ndazole-.-carboxylic acid methylamide (melting point: 148-150C; 50% of theory) in 30 minutes at 1015 C. Example 48 PC NH2

N

CO-N~-C2H5

41 493,473 of Analogously to Example 46, 0.05 mol of ethyl isocysnate in trifluoromethyl-ndazole and 0.05 mol 100 ml of pyridine give joint: 131-1320 C 47% carboxylic acid ethylamide (melting 0 of theory) in 1 hour at 10-15 C. Example 49 C

CH3

COOC2H

0.05 mol of 3-amino-4-chloro.-indazole-l-carboxlio strength formaldehyde acid ethyl eater and 0.125 mol of 40% heated to 10000 for solution in 50 ml of formic acid are and distillation of hours. After evaporation in vacuo the residue, 3-dimethylamino-4-chlro-indazole-l-carboxlio 160O0C melting points acid ethyl eater (boiling pointO. 4 60-620 C; 70% of theory) is obtained. Bmazsmle

~0"3 ,CEl

COOC 2 E

of 3-amino-6-chloro- Analogously to Example 49, 0.1 mol and 0.25 mol of indazole-l-carboxylic acid ethyl ester 150 ml of formic acid give strength formaldehyde solution in acid ethyl 3-dimethylamino-6-ch1oro-indaole-l-carboxylic 0 of theory) in 5 hours eater (melting point: 98-100 C; 69% at 1000C. Examle 51 42 493,473 c NIK CH 3

0 "CH3

0.04 mol of 3 -dimethylamino-6-chloro-indazole and

0.04 mol of sodium amide in 50 ml of toluene are heated to the boil for 1 hour. 0.04 mol of dimethlcarbami acid chloride

is added dropwise at 6000 and this temperature is maintained

for 7 hours, whilst stirring. After cooling, the solution

is filtered and evaporated in vacuo. Distillation of the

residue gives 3 -dimethylamino-6-lloro-indazole-l-carboxrlic

acid dimethylamide (boiling point 0 35 17000, melting point:

65-66C; 75% of theory). Example 52 -CH3 "'CE Cl NN1

C000 4E9

Analogously to Example 21, 0.01 mel of 3-dimethylamino- 6-chloro-indazole and 0.0125 mel of. pyrocarbonic acid di-n- butyl ester give 3 -dimethylamino-6-chloro-indazole-l- 0 carboxylic acid n-butyl ester (melting point: 80-81C; 71%

of theory) In 5 hours at 2000. Example 53 P30 N N

COOC 2 E3

43 493,473

8.7170/75

mol of 3-dimethYl- Analogously to Example 21, 0.025 and 0.0275 mol of pyrocarbonio amino-5-trifluoromethy3indazole acid diethyl eater give 0 acid ethyl ester (boiling point 0 1 310 0, indazole-l-carboxylic 0 theory) in 1+ hours at 70-80 C. melting point: 84-86OO; 93% of Example 54 CP 3 NH-4HO

I CR

0.2 mol of 3 acid chloride in 20 ilof and 0.05 mol of dimetylcarbamic to 500 C. After cooling, pyridine are heated for 4 hours run in and the reaction product 150 ml of water are allowed to by filtration. which has crystallised out is isolated Recrystallisation from ethanol gives acid dimethylarlide (melting fluoromethyl-indazole-l-carboxylic 0 point: 198-200 C; 57% of theory). Example

P3C NH-CHO PN C

COOc2 H

mol of 3-formylamino- Analogously to Rzample 54, 0.05 and 0.1 mol of chloroCarbonic acid give ethyl eater in 100 ml of pyridine acid ethyl eater (melting fluoromethyl-indazole-l-carboylic in 3 hours at 3000. point: l85-187 0; 65% of theory)

44 493,473

87170/75 Example 56

The reaction product of Example 55 is also obtained, in 78% yield, on reacting 0.1 mol of indazole-l-carboxylic acid ethyl ester and 50 ml of formic acid in 5 hours at 1OO0 C. Example 57

NH-CHO N'

COOC 2 H

Analogously to Example 56, 0.085 mol of 3-amino-6-chloro- indazole-l-carboxylic acid ethyl uster and 100 ml of formic acid produce 3-formylamino-6-chlcro-indazole-l-carboxylic acid ethyl ester in 3.5 hours at 10000 (melting point 227-2300 (decomposition), yield: 71% of theory). Example 58 CH 3 NC )6 Nh2 NC H3C COOC 2R

0.86 mol of 3-amino-4,6-dimethyl-5-cyano-ndazole are stirred together with 0.13 mol of pyrocarbonic acid diethyl ester and 75 ml ethanol. The mixture is allowed to stand for two hours at room temperature and, after the addition of diethyl ether 3-amino-4, 6-dimethyl-5-cyano-indazole-2-carboxylic acid ethyl ester is isolated (melting point: 235-237 0, 90% of theory). After refluxing for 20 minutes in 250 ml of 1,2- dichloro-benzene, 3-amino-4,6-dimethyl-5-cyano-indazole-l- carbonic acid ethyl ester is obtained (melting point 240-241 0 C; of theory).

45 493.473

The structure of the reaction products was confirmed by elementary analysis and in part also by mass-spectrometric molecular weight determination. In the case of isomeric

compounds, the consistency and position of the substituente was above all confirmed by physico-chemical methods of 1 investigation, especially H and F19- nuclear resonance, IR.

spectroscopy and UV-spectroscopy. Examples of the preparation of starting materials not hitherto described in the literature: 3-Amino-4-trifluoromethyl-indazole (melting point:

129-1300 C) from 2,6-dimethylbenzonitrile by chlorination to give 2-chiloro-6-trichloromethyl-benzonitrile (melting point: 121-1220C) and subsequent fluorination to give 2-chloro-6- 0 trifluoromethyl-benzonitrile (melting point: 45-47 and

reaction with hydrazine hydrate in dioxane at 1500C in an autoclave. 3-Amino-7-trifluoromethyl-indazole (melting point: 101-102oC) from 2,3-dimethyl-benzonitrile by chlorination to give 2-chloro-3-trichloromethyl-benzonitrile (melting point:

106-107oC) and fluorination to give 2-chloro-3-trifluoromethyl- 0 and reaction with benzonitrile (melting point: 37-39 0 hydrazine hydrate in diozane at 150 C in an autoclave.

Soc. 3-Amino-5-trifluoromethyl-7-nitro-indazole (melting point: 227-228 0C) from 2-methoxy-3-nitro-5-trifluoromethyl- benzonitrile and hydrazine hydrate, analogously to J. chem.

[London) ]IM, 2363 3,7-Diamino-5-trifluoromethyl-indazole (melting point: 198-199 0C0) from 3-ajno-5-trifluoromethyl-7-nitro-indazole by catalytic hydrogenation with Raney nickel in dimethylformamide at 50 0 C. (melting point: 224-225 0 C) -46- 493,473 from 4-chloro-isophthalic acid dinitrile and hydrazine hydrate analogously to J. chem. Soc. LLondon] 1252, 2363.

3-Dimethylamino-6-chloro-iXdazole (melting point:

ll-1320C) from 3-dimethylamino-6-chloro-indazole-l-carboxlic acid ethyl ester and 10% strength sodium hydroxide solution 0 in methanol at pH 10 and 20 C. (melting

point: 193-1960 C) from indazole-l-carboxylic acid ethyl ester and 10% strength sodium 0 hydroxide solution in methanol at pH 10 and 20 C. 3-Amino-4,6-imethyl-5-yano-indazole (melting point: l 260-262 0 C) from 2-amjno-4,6-dimethyl-5-cyao-benzonitri e

by diazotization and subsequent reduction with sulphrous acid.

47 493,473

Claims (1)

1. 87170/75 The claims defining the invention are as follows:

   1. A 3-Amino-indazolecarboxylic acid derivative of the

   formula 1 R

   R or v R2N R or 2 CO-Y

   CO-Y

   (I a) (I b)

   in which

   Y represents alkoxy, alkylamino or dialkylamino,

   R represents hydrogen or methyl,

   R1 represents hydrogen, methyl or formyl and 2 substituents independently R represents 1, 2 or

   selected from hydrogen, alkyl, alkoxy, nitro, amino,

   alkylamino, dialkylamino, acylamino, alkoxycarbonylamino,

   halogen, trifluoromethyl, cyano and alkoxycarbonyl,

   or a salt thereof.

   2. A compound according to claim 1 wherein Y is an alkoxy

   group containing from 1 to 4 carbon atoms or an alkyl- or

   dialkyl amino group in which the or each alkyl group contains 2 from 1 to 4 carbon atoms and R represents 1, 2, or 3 sub-

   stituents independently selected from hydrogen, alkyl groups

   of from 1 to 4 carbon atoms, alkoxy groups of from 1 to 4

   carbon atoms, nitro, amino, alkyl- and dialkyl amino groups

   in which the or each alkyl group contains from 1 to 4 carbon

   atoms, acylamino groups containing from 1 to 6 carbon atoms

   in their acyl parts, alkocycarbonylamino groups containing

   from 1 to 4 carbon atoms in their alkoxy part, chlorine,

   bromine, trifluoromethyl, cyano and alkoxycarbonyl groups

   containing from 1 to 4 carbon atoms in their alkoxy parts.

   48 49 3,473

   2 3. A compound according to claim 1 or claim 2 wherein R

   represents one or two substituents independently selected

   from hydrogen, nitro, amino, halogen, trifluoromethyl and

   alkoxycarbonylamino.

   4. A compound of the formula

   C0 C2

   or a salt thereof.

   A compound of the formula

   01 2 C 00CH 3

   or a salt thereof. 6. A compound of the formula

   C01 COOC 2 H 5

   or a salt thereof. 7. A compound of the formula

   2

   COOCr asalt thereof.

   or a salt thereof.

   49 493,473

   8. A compound of the formula

   l- NH2

   Cl I N

   CO-N(CH 3 2

   or a salt thereof. 9. A compound of the formula

   2 SNH

   1 N/A-co-CHN CH 2

   or a salt thereof. A compound of the formula

   01- (CH)2

   Cl

   C 0002H

   or a salt thereof. 11. A compound of the formula

   F C N H-CHO

   CO-N(CH 3 2

   or a salt thereof.

   12. A compound of the formula

   kNrN

   COOCH3

   or a salt thereof. 50 493.4 7.

   8 7 170

   13. A compound of the formula

   F 3C 'M2!

   Coo00C 2H

   or a salt thereof. 14. A compound of the formula NH

   PC 2 booc2H

   or a salt thereof. A compound of the formula

   F3 C ~2 H

   bo-vH-c2 H or a salt thereof.

   16. A process for preparing a compound according to any one of claims 1 to 16comprising reacting a 3-amino-indazole of the tautomeric formula

   NH2 R2 R2 H

   (b) (II)

   51- 493,473

   8 71 70 175

   a carbonic acid in which R is as defined in claim 1 with 2

   derivative of the formula Y -CO -X(I)

   in which R4 3 Y represents the radical OR or the radical N 5 lower alkyl, wherein R 3 R4 and R each denote 3 the X represents halogen, or, if Y represents OR 3 wherein R3 has the meaning indicated radical O-COOR under Y, or

   X and Y conjointly denote an imide group of the 6 6 formula =NR wherein R denotes lower alkyl agents and in the presence of inert organic -olubilising in the presence of an acid-binding agent and

   thereafter, in a further reaction step the formic acid amino group in the 3-position is formylated with of formic -acid. or methylated with formaldehyde in the presence '6 is A process according to claimAI wherein the reaction 0 effected /6. at a temperature of from -20 to +250 C. 4- A process for the production of a compound according in any to Claim 1 substantially as hereinbefore described of Examples I to 33 and 35 to 56. by Compounds according to claim 1 whenever prepared process according to any one of claims 1 to 41.i a2.0 active 2P. A pharmaceutical composition containing as an claims 1 toxi6 ingredient a compound according to any one of

   493,473

   87170/75

   inf the form of a sterile or isotonic aqueous solution. and e

   A composition according to claimA containing n3. active ingredient. from 0.5 to 95% by weight of the said

   2.2

   A medicament in the form of tablets, pills, dragees, a compound capsules, ampoules, or suppositories comprising Iq either alone according to any one of claims 1 to4 16 andA,10,

   or in admixture with a diluent. 23 or fever in 96. A method of combating pain, inflammation to human and non-human animals whicj comprises administering one of claims the animals an active compound according to any a diluent 1 -to 16 and 20 either alone or in admixture with 2Z or in the form of a medicament according to claim.A. l. 23 active 2-7. A method according to claim a6 in which the

   compound is administered in an amount of 0.01 to 50 mg per day. per kg body weight

   a8. A method according to claim 26 or claim FT in which

   the active compound is administered orally.

   2.9. A compound according to claim 1 as described in Example 57

   or 58. 2-7 1 3. A process for preparing a compound according to claim

   substantially as hereinbefore described in Example 34, 57 or

   58.

   34. A compound according to claim I prepared by a method

   according to claim 34, 57 or 58. N. A composition according toA one of claims to wherein the active ingredient is a compound according

   claim 29 or 31.

   53 493,473

   I

   87170n5

   0C. 22 weentesi 33. A medicament according to claim4 wherein the said 26 .rl compound is a compound according to claimq wherein I. A method according to any one of claimsA 26 to claim is a compound according the active compound

   this 1st day of December, 1975. DATED

   BAYER AKTIENGESELLSCHAFT, By their Patent Attorneys,

   ARTHUR S. CAVE CO.

   54 493,473