NO774285L - ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE INDANDATIVE DERIVATIVES - Google Patents

ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE INDANDATIVE DERIVATIVES

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Publication number
NO774285L
NO774285L NO774285A NO774285A NO774285L NO 774285 L NO774285 L NO 774285L NO 774285 A NO774285 A NO 774285A NO 774285 A NO774285 A NO 774285A NO 774285 L NO774285 L NO 774285L
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protons
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Michel Bayssat
Francis Sautel
Jean-Claude Depin
Annie Betbeder-Matibet
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Lipha
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C307/02—Monoamides of sulfuric acids or esters thereof, e.g. sulfamic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/28—Halogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/46—Doubly bound oxygen atoms, or two oxygen atoms singly bound to the same carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Diabetes (AREA)
  • Rheumatology (AREA)
  • Hematology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Furan Compounds (AREA)

Description

Analogifremgangsmåte ved fremstilling av terapeutiskAnalogy procedure in the preparation of therapeutic

aktive indanderivater.active indane derivatives.

Foreliggende oppfinnelse vedrører en analogifremgangsmåte ved fremstilling av forbindelser med anti-inflammatorisk, analgetisk og mot aggregering av blodplater virkende aktivt middel som danner syrer og derivater av forbindelse med den generelle formel (I) The present invention relates to an analogous method for the production of compounds with an anti-inflammatory, analgesic and anti-platelet aggregation active agent which forms acids and derivatives of compounds with the general formula (I)

hvor R er en fenylgruppe substituert med minst en substituent valgt fra halogener og gruppene acetamido, dialkylamino, alkylsulfonyl, dialkylaminosulfpnyl og sulfamido, where R is a phenyl group substituted with at least one substituent selected from halogens and the groups acetamido, dialkylamino, alkylsulfonyl, dialkylaminosulfpnyl and sulfamido,

en tienylgruppe substituert med minst en substituent valgt blant halogenene og en lavere alkylgruppe, eller en furylgruppe substituert med en lavere alkylgruppe. a thienyl group substituted with at least one substituent selected from the halogens and a lower alkyl group, or a furyl group substituted with a lower alkyl group.

Når R er en fenylgruppe er den fortrinnsvis substituert med minst en substituent valgt fra klor og gruppene acetamido, dimetylamino, metylsulfonyl, dimetylsulfonyl og sulfamido. When R is a phenyl group, it is preferably substituted with at least one substituent selected from chlorine and the groups acetamido, dimethylamino, methylsulfonyl, dimethylsulfonyl and sulfamido.

Når R er en substituert tienylgruppe er den substituert med minst en substituent valgt fra klor og en metylgruppe. Når R er en furylgruppe er den substituert med en metylgruppe. When R is a substituted thienyl group, it is substituted with at least one substituent selected from chlorine and a methyl group. When R is a furyl group, it is substituted with a methyl group.

De nye syrene er særlig 5-(para-dimetylamino-benzoyl)-indan-karboksylsyre, 5-(para-metylsulfonyl-benzoyl)-indan-i 2-karboksylsyre, 3-(para-sulfamido-benzoyl)-indan-2-karboksyl syre, 5-(para-dimetyl-aminosulfonyl-benzoyl)-indan-2-karboksylsyre, 5-(4'-acetamido-3<1->klor-benzoyl)-indan-2-karboksylsyre, 5-(3'-metyl-2'-tenoyl)-indan-2-karboksylsyre, 5-(4<1>,5<1->diklor-2'-tenoyl)-indan-2-karboksylsyre, 5-(5'-metyl-2'-furoyl)-indan-2-karboksylsyre. The new acids are in particular 5-(para-dimethylamino-benzoyl)-indane-carboxylic acid, 5-(para-methylsulfonyl-benzoyl)-indane-i 2-carboxylic acid, 3-(para-sulfamido-benzoyl)-indane-2- carboxylic acid, 5-(para-dimethyl-aminosulfonyl-benzoyl)-indan-2-carboxylic acid, 5-(4'-acetamido-3<1->chloro-benzoyl)-indan-2-carboxylic acid, 5-(3' -methyl-2'-thenoyl)-indan-2-carboxylic acid, 5-(4<1>,5<1->dichloro-2'-thenoyl)-indan-2-carboxylic acid, 5-(5'-methyl- 2'-furoyl)-indane-2-carboxylic acid.

Foreliggende oppfinnelse vedrører også fremstilling av amino-estere som lavere dialkyl-amio-lavere alkylestere. Disse aminoesteré er derivater av karboksylsyrene med den generelle formel (I) der R er en tienyl- eller furylgruppe. Amino-esterne er særlig N,N-dietylamino-2<1->etylester av 5-(2'-tenoyl)-indan-2-karboksylsyre og N,N-dietylamino-2'-etylester av 5-(2'-furoyl)-indan-2-karboksylsyre. The present invention also relates to the production of amino esters such as lower dialkyl-amio-lower alkyl esters. These amino esters are derivatives of the carboxylic acids of the general formula (I) where R is a thienyl or furyl group. The amino esters are in particular N,N-diethylamino-2<1->ethyl ester of 5-(2'-thenoyl)-indan-2-carboxylic acid and N,N-diethylamino-2'-ethyl ester of 5-(2'- furoyl)-indane-2-carboxylic acid.

Foreliggende oppfinnelse vedrører også fremstilling av amider som lavere alkylamino-lavere alkylamidderivater av karboksylsyrene med den generelle formel (I) der R er en fenylgruppe som eventuelt er substituert med to halogener eller en tienylgruppe- Karboksamidene er særlig dietylaminoetylkarboks-amider som 5-benzoyl-N-[2 ' - (N ' ,N 1-dietylamino)-etyl]-indan-2-karboksamid, 5-(21-tenoyl)-N-[2'-(N1,N'-dietylamino)-etyl] - indan-2-karboksamid og 5-(2',5'-diklor-benzoyl)-N-[21 -(N, N-di.etylamino) -etyl] -indan-2-karboksamid. The present invention also relates to the production of amides as lower alkylamino-lower alkylamide derivatives of the carboxylic acids with the general formula (I) where R is a phenyl group optionally substituted with two halogens or a thienyl group - The carboxamides are in particular diethylaminoethylcarboxamides such as 5-benzoyl-N -[2 ' - (N ' ,N 1-diethylamino)-ethyl]-indan-2-carboxamide, 5-(21-thenoyl)-N-[2'-(N1,N'-diethylamino)-ethyl] - indane-2-carboxamide and 5-(2',5'-dichloro-benzoyl)-N-[21-(N,N-diethylamino)-ethyl]-indane-2-carboxamide.

Man kan fremstille de nye derivatene ifølge oppfinnelsen ved alkalisk hydrolyse av en ester med formel (II) der R' fortrinnsvis er en lavere alkylgruppe: The new derivatives according to the invention can be prepared by alkaline hydrolysis of an ester of formula (II) where R' is preferably a lower alkyl group:

Den foregående forbindelsen bringes til reaksjon under samme betingelser som Friedel-Crafts-reaksjonen med et aroylhalogen The preceding compound is reacted under the same conditions as the Friedel-Crafts reaction with an aroyl halide

I med formel (III): i hvor R har samme betydning som ovenfor angitt og X betegner et halogen. I with formula (III): i where R has the same meaning as stated above and X denotes a halogen.

Reaksjonen kan eksempelvis utføres med eller uten løsning-middel, men fortrinnsvis med et egnet løsningsmiddel som metylenklorid, karbondisulfid etc. ved temperaturer fra 0°C til løsningsmiddelets kokepunkt, fortrinnsvis ved løsningsmiddelets tilbakeløpstempuratur. Blant anvendelige Lewis-syrer foretrekkes aluminiumklorid. De anvendte for-skjellige reagensene kan foreligge i støkiometriske mengder eller i overskudd hvorunder overskudd foretrekkes med hensyn til aroylhalogenet og aluminiumkloridet og overskuddet kan være opp til 400%. The reaction can, for example, be carried out with or without solvent, but preferably with a suitable solvent such as methylene chloride, carbon disulphide etc. at temperatures from 0°C to the solvent's boiling point, preferably at the solvent's reflux temperature. Among applicable Lewis acids, aluminum chloride is preferred. The various reagents used may be present in stoichiometric amounts or in excess, wherein excess is preferred with respect to the aroyl halide and the aluminum chloride and the excess may be up to 400%.

Med hensyn til forbindelsene hvor R er en fenylgruppe substituert med en sulfamidogruppe eller dimetylsulfamidogruppe går man ut fra en ester med formelen (IV): With regard to the compounds where R is a phenyl group substituted with a sulphamido group or dimethyl sulphamido group, the starting point is an ester with the formula (IV):

i in

hvor R' er en lavere alkylgruppe og R er en fenylgruppe substituert med en aminogruppe. where R' is a lower alkyl group and R is a phenyl group substituted with an amino group.

Forbindelsen (IV) hvor R og R<1>har ovenfor angitte betydning diazoteres på i og for seg kjent måte hvoretter det erholdte aryldiazoniumsaltet behandles med en løsning av svoveldioksyd i eddiksyre i nærvær av et kobbersalt, fortrinnsvis kobberklorid, på en slik måte at man erholder en forbindelse med formel (IV): The compound (IV) where R and R<1> have the meaning given above is diazotized in a manner known per se, after which the obtained aryldiazonium salt is treated with a solution of sulfur dioxide in acetic acid in the presence of a copper salt, preferably copper chloride, in such a way that obtains a compound of formula (IV):

hvor R' er som ovenfor angitt og R er en fenylgruppe som er egnet substituert med en klorsulfonylgruppe. where R' is as indicated above and R is a phenyl group which is suitably substituted with a chlorosulfonyl group.

Foregående forbindelse behandles med ammoniakkgass eller en ammoniakløsning i vann eller.i en lavere alkanol hvilket gir forbindelsene med formel (IV) hvor R er en fenylgruppe som er substituert med en sulfamidogruppe. Om man erstatter ammoniakken med dimetylamin erholder man en forbindelse med formel (IV), hvor R er en fenylgruppe substituert med en dimetylsulfamidogruppe. The preceding compound is treated with ammonia gas or an ammonia solution in water or in a lower alkanol which gives the compounds of formula (IV) where R is a phenyl group which is substituted with a sulfamido group. If one replaces the ammonia with dimethylamine, a compound of formula (IV) is obtained, where R is a phenyl group substituted with a dimethylsulfamido group.

Med hensyn til forbindelsene hvor R er en fenylgruppe substituert med en dimetylaminogruppe, behandler man en forbindelse med formel (IV), hvor R' er en lavere alkylgruppe og R ér en fenylgruppe substituert med en aminogruppe med formaldehyd for å danne dens monomerer, ren eller i vandig løsning i nærvær av hydrogen og en hydrogeneringskatalysator, fortrinnsvis palladium-på-karbon ved en passende temperatur. With regard to the compounds where R is a phenyl group substituted by a dimethylamino group, one treats a compound of formula (IV), where R' is a lower alkyl group and R is a phenyl group substituted by an amino group with formaldehyde to form its monomers, pure or in aqueous solution in the presence of hydrogen and a hydrogenation catalyst, preferably palladium-on-carbon at a suitable temperature.

Således får man forbindelsene med formel (IV) hvor R er en fenylgruppe substituert med en dimetylaminogruppe og R<1>er som tidligere angitt. Thus, the compounds of formula (IV) are obtained where R is a phenyl group substituted with a dimethylamino group and R<1> is as previously indicated.

Endlig når R er en gruppe substituert med minst et halogen får man disse forbindelser ved behandling av en forbindelse med formel (IV) hvor R er en monosubstituert fenyl-, tienyl-eller furylgruppe og R' er som tidligere angitt, med en løsning av halogen i eddiksyre, hvorved denne løsningen enten er mettet eller ikke og -reaksjonen skjer ved temperaturer fra omgivelsestemperaturen.til dens tilbakeløpstem- Finally, when R is a group substituted by at least one halogen, these compounds are obtained by treating a compound of formula (IV) where R is a monosubstituted phenyl, thienyl or furyl group and R' is, as previously indicated, with a solution of halogen in acetic acid, whereby this solution is either saturated or not and the reaction takes place at temperatures from ambient temperature to its reflux temperature

I peratur.In perature.

I IN

Foreliggende forbindelses farmakologiske virkninger, dvs. i antiinflammatorisk og analgetisk virkning samt virkning mot aggregering av blodplater er vist på.dyr. The present compound's pharmacological effects, i.e. in anti-inflammatory and analgesic effects as well as effects against aggregation of blood platelets, have been shown in animals.

A. Produktene er generelt lite toksiske; LDj-q ble bestemt på rotte. A. The products are generally not toxic; LDj-q was determined in rats.

B. Den analgetisk aktiviteten ble bestemt på rotte ifølge metoden til Koster et al (Fed. Proe. 1959, 18, 412). Man fån produktets aktive dose 50 ad den pr. oralt administrete dose minsker med 50% kontraksjonssmerter som fremkalles ved intraperitoneal injeksjon av en løsning av eddiksyre. C. Den anti-inflammatoriske aktiviteten vises ved karra-geninødemforsøket ifølge Winter et al (Proe. Exp. Biol. Med. 111, 544-47). Man undersøker beskyttelsen som oppstår ved behandling da produktene ble administrert pr. oralt til rotte sammenliknet med et ødem som ble fremkalt ved injeksjon under fothulen av en suspensjon av karragen. Den aktive dosen AD3Qer den som inhiberer 3 0% av ødemet. D. Den beskyttende virkningen med hensyn til tidlig utviklet inflammasjon ble bestemt av albino marsvin ifølge metoden til Winder et al. (Arch. Inv. Pharmacodyn. 1958, B. The analgesic activity was determined in the rat according to the method of Koster et al (Fed. Proe. 1959, 18, 412). You get the product's active dose of 50 ad den per orally administered dose reduces by 50% the contraction pain induced by intraperitoneal injection of a solution of acetic acid. C. The anti-inflammatory activity is shown by the carrageenan edema test according to Winter et al (Proe. Exp. Biol. Med. 111, 544-47). The protection arising from treatment when the products were administered per orally to the rat compared with an edema induced by subcutaneous injection of a suspension of carrageenan. The active dose AD3Q is the one that inhibits 30% of the oedema. D. The protective effect with respect to early developed inflammation was determined in albino guinea pigs according to the method of Winder et al. (Arch. Inv. Pharmacodyn. 1958,

116, 261). Man undersøkte AD^q for den pr. oralt til dyret administrerte produktet som med 50% reduserte den rødflam-ming som oppstod ved at marsvinets ved hårfjerning blottede ble eksponert for ultrafiolett bestråling. 116, 261). One examined AD^q for it per administered the product orally to the animal, which reduced by 50% the red flaming that occurred when the guinea pig's skin was exposed to ultraviolet radiation during hair removal.

E. Virkning mot aggregering av blodplater ble bestemtE. Effect against platelet aggregation was determined

"in vitro" ved aggregering fremkalt med kollagen ifølge Borns metode. "in vitro" by aggregation induced with collagen according to Born's method.

Resultatene er sammenstilt i nedenstående tabell. De aktive dosene er uttrykt i mg pr. kg med unntakelse for aggregering av blodplater der de minste aktive konsentrasjoner er angitt i Y pr. ml. The results are compiled in the table below. The active doses are expressed in mg per kg with the exception of aggregation of blood platelets where the minimum active concentrations are indicated in Y per ml.

I IN

De terapeutiske komposisjonene inneholder som aktiv bestand-del minst en forbindelse ifølge oppfinnelsen og et farma-søytisk bæremiddel eller et fortynningsmiddel i fast eller væskeform for dannelse av tabletter, injiserbare løsninger, suppositorer og liknende. The therapeutic compositions contain as active ingredient at least one compound according to the invention and a pharmaceutical carrier or diluent in solid or liquid form for the formation of tablets, injectable solutions, suppositories and the like.

EKSEMPEL PÅ TILBEREDNINGEXAMPLE OF PREPARATION

De terapeutiske komposisjonene inneholder som aktiv bestand-del et indanderivat ifølge oppfinnelsen i en slik anti-inflammatorisk, analgetisk og mot blodplåteaggregering virkende dose som omfatter fra 50 til 500 mg pr. enhets-dose. Posologin skal reguleres for å gi terapeutisk op-timale effekt. The therapeutic compositions contain as active ingredient an indane derivative according to the invention in such an anti-inflammatory, analgesic and anti-platelet aggregation acting dose that comprises from 50 to 500 mg per unit dose. The dosage must be regulated to provide optimal therapeutic effect.

Nedenfor gis eksempler på fremstilling av forbindelseneExamples of the preparation of the compounds are given below

som illustrerer med ikke begrenser oppfinnelsen. which illustrate by not limiting the invention.

EKSEMPEL 1 I EXAMPLE 1 I

5- ( 3'- metyl- 2'- tenoyl)- indan- 2- karboksylsyre5-( 3'- methyl- 2'- thenoyl)- indan- 2- carboxylic acid

a) Metylester av 5-( 3'- metyl- 2'- tenoyl)- indan- 2- karboksylsyre a) Methyl ester of 5-(3'-methyl-2'-thenoyl)-indan-2-carboxylic acid

I en 250 ml reaktor som var utstyrt med rører, kjøler og et kalsiumkloridrør, en bromampulle og et termometer ble 18,5 g (0,13 9 mol) aluminiumklorid og 14,1 g (0,08 mol) metyl-indan-2-karboksylat tilsatt dråpevis f ra bronampulle.n. Ved slutten av tilsetningen nådde temperaturen 35°C. Man varmet lett for å homogenisere. Når temperaturen nærmet seg 20°C ble 12,8 g (0,08 mol) av kloridet av 3-metyl-2-tiofen-kar boksylsyre tilsatt dråpevis. Man oppvarmet siden opp til 70 - 80°C. Derpå ble denne temperaturen holdt i 30 minutter, hvoretter den fikk synke til 40°C. Deretter ble metylenklorid tilsatt og siden ble den erholdte løsning helt i isvann som inneholdt saltsyre. Den organiske fasen ble dekantert, vasket med natriumhydroksyd og deretter med vann. Så ble den organiske fasen tørket over natriumsul- In a 250 ml reactor equipped with a stirrer, condenser and a calcium chloride tube, a bromine ampoule and a thermometer, 18.5 g (0.139 mol) aluminum chloride and 14.1 g (0.08 mol) methyl-indan-2 -carboxylate added drop by drop from brona ampule.n. At the end of the addition, the temperature reached 35°C. It was gently heated to homogenize. When the temperature approached 20°C, 12.8 g (0.08 mol) of the chloride of 3-methyl-2-thiophene-carboxylic acid was added dropwise. The side was heated to 70 - 80°C. This temperature was then held for 30 minutes, after which it was allowed to drop to 40°C. Methylene chloride was then added and then the resulting solution was completely dissolved in ice water containing hydrochloric acid. The organic phase was decanted, washed with sodium hydroxide and then with water. Then the organic phase was dried over sodium sul-

fat og filtrert, hvoretter filtratet ble konsentrert og resten destillert. Således fikk man en tykk oljeaktig fraksjon. barrel and filtered, after which the filtrate was concentrated and the residue distilled. Thus a thick oily fraction was obtained.

kP 7 Torr: 180 - 200°CkP 7 Dry: 180 - 200°C

IR-spektrum: V CO : 1 740 V CO = 1 64 0. cmIR spectrum: V CO : 1 740 V CO = 1 64 0. cm

NMR-spektrum:NMR spectrum:

- flere topper av 5 aromatiske protoner ble sentrert ved- several peaks of 5 aromatic protons were centered at

7,4 ppm7.4 ppm

I - topp av 3 protoner OCH^ ved 3,4 ppm I - peak of 3 protons OCH^ at 3.4 ppm

- topp av 3 protoner CH^ved 2,4 ppm - peak of 3 protons CH^ at 2.4 ppm

I b) Omdannelse til 5-( 3'- metyl- 2'- teonyl)- indan- 2- karboksylsyre I b) Conversion to 5-(3'-methyl-2'-theonyl)-indan-2-carboxylic acid

I en 250 ml reaktor utstyrt med rører og kjøler innførtesInto a 250 ml reactor equipped with stirrer and cooler was introduced

i rekkefølge 6,7 g (0,0223 mol) av den under punkt a) erholdte ester i løsning i 30 ml metanol, 2,8 g (0,05 mol) pottaske i løsning i 30 ml metanol. Så oppvarmet man ved tilbakeløp i 1 time. Deretter ble konsentrert til tørrhet, gjennoppløst i vann og vasket med eter i alkalisk miljø. Vannfasen ble surgjort under kjøling med saltsyre og en felling oppstod. Fellingen ble lufttørket, vakset med vann og tørket. Ved omkrystallisasjonen fra etylacetat fikk man et fast stoff som smeltet ved 136 - 138°C (kapil-larrør) . in order 6.7 g (0.0223 mol) of the ester obtained under point a) in solution in 30 ml of methanol, 2.8 g (0.05 mol) of pot ash in solution in 30 ml of methanol. It was then heated at reflux for 1 hour. It was then concentrated to dryness, redissolved in water and washed with ether in an alkaline environment. The water phase was acidified under cooling with hydrochloric acid and a precipitate formed. The precipitate was air-dried, waxed with water and dried. The recrystallization from ethyl acetate gave a solid which melted at 136 - 138°C (capillary tube).

IR-spektrum: V CO : 1 700 cm"<1>VCO : 1 635 cm"<1>NMR-spektrum: IR spectrum: V CO : 1700 cm"<1>VCO : 1635 cm"<1>NMR spectrum:

- flere topper av 5 aromtiske protoner sentrert ved 7,32 ppm- several peaks of 5 aromatic protons centered at 7.32 ppm

- topp av 5 protoner indan ved 3,4 ppm- peak of 5 protons in at 3.4 ppm

- topp av 3 protoner ved 2,4 7 ppm- peak of 3 protons at 2.4 7 ppm

- topp av 1 proton OH ved 10,7 ppm- peak of 1 proton OH at 10.7 ppm

Surhetsgrad: funnet: 195, beregnet: 1,9 0Acidity: found: 195, calculated: 1.9 0

ElementæranalyseElementary analysis

EKSEMPEL 2 5-( 5'- metyl- 2'- furoyl)- indan- 2- karboksylsyre EXAMPLE 2 5-(5'-methyl-2'-furoyl)-indan-2-carboxylic acid

' a) Metylester av 5-( 5'- metyl- 2'- furoyl)- indan- 2- karboksylsyre<C>17<H>16°4 a) Methyl ester of 5-(5'-methyl-2'-furoyl)-indan-2-carboxylic acid<C>17<H>16°4

I en 250 ml reaktor utstyrt med rører, kjøler forsynt med kalsiumkloridrører, en bromampulle og et termometer ble tilsatt 11,4 g (0,086 mol) aluminiumklorid i en suspensjon i 30 ml metylenklorid samt 5,5 g (0,0382 mol) av 5-metyl-furan-2-karboksylsyreklorid i en løsning i 30 ml metylenklorid. Deretter ble omrørt langsomt ved en temperatur på 20°C og deretter dråepvis tilsatt en løsning av 5,6 g (0,0318 mol) metyl-indan-2-karboksylati 50 ml etylenklorid. Reaksjonsblandingen ble deretter rørt 2 timer ved romtemperatur hvoretter den ble oppvarmet 3 timer ved tilbake-løp. Så fikk blandingen stå natten over, hvorpå den bie helt i et beger med surgjort isvann. Så fulgte ekstrak- In a 250 ml reactor equipped with stirrers, a cooler equipped with calcium chloride stirrers, a bromine ampoule and a thermometer were added 11.4 g (0.086 mol) of aluminum chloride in a suspension in 30 ml of methylene chloride as well as 5.5 g (0.0382 mol) of 5 -methyl-furan-2-carboxylic acid chloride in a solution in 30 ml of methylene chloride. It was then stirred slowly at a temperature of 20°C and then a solution of 5.6 g (0.0318 mol) methyl-indan-2-carboxylate 50 ml of ethylene chloride was added dropwise. The reaction mixture was then stirred for 2 hours at room temperature after which it was heated for 3 hours at reflux. Then the mixture was allowed to stand overnight, after which it was poured completely into a beaker of acidified ice water. Then followed extract-

sjon med metylenklorid, vask av ekstraktet med natriumhydroksyd, med vann, tørking over natriumsulfat, filtra- tion with methylene chloride, washing the extract with sodium hydroxide, with water, drying over sodium sulfate, filtration

sjon, konsentrering av filtratet og destillering av resten. Således fikk man en fraksjon kp, , ^ : 195 - 205°C tion, concentration of the filtrate and distillation of the residue. Thus a fraction kp, , ^ : 195 - 205°C was obtained

_, 1 torr _^_, 1 torr _^

IR-spektrum: V CO : 1 740 cm V CO : 1-645 cmIR spectrum: V CO : 1,740 cm V CO : 1-645 cm

NMR-spektrum:NMR spectrum:

- flere topper av 4 aromatiske protoner ved 7,3 3 ppm- several peaks of 4 aromatic protons at 7.3 3 ppm

- 1 aromatisk proton ved 6,2 ppm- 1 aromatic proton at 6.2 ppm

- topp av 5-protoner indan ved 3,3 ppm- peak of 5-protons indan at 3.3 ppm

topp av 3 protoner OCH^ved 3,7 ppmpeak of 3 protons OCH^ at 3.7 ppm

- topp av 3 protoner CH^ ved 2,47 ppm- peak of 3 protons CH^ at 2.47 ppm

b) Omdannelse til 5-( 5'- metyl- 2'- furoyl)- indan- 2- karboksylsyre b) Conversion to 5-(5'-methyl-2'-furoyl)-indan-2-carboxylic acid

I en 50 ml reaktor ble innført i rekkefølge 2,7 g (0,0095In a 50 ml reactor, 2.7 g (0.0095

mol) av den under punkt a) erholdte ester i løsning i 16,5mol) of the ester obtained under point a) in solution in 16.5

ml metanol og 1,16 g (0,0208 mol) pottaske i løsning i 16,5 ml vann. Reaksjonsblandingen fikk stå ved omgivelsestemperatur i 48 timer. Deretter ble den konsentrert til tørrhet, tatt opp i vann, vakset med eter i alkalisk miljø hvoretter vannfasen ble surgjort. Den surgjorte vannfasen ble ekstrahert med eter, tørket på natriumsulfat, filtrert og filtratet konsentrert. Resten som erholdes etter omkrystallisasjon fra en blanding av etylacetat-heksan smeltet ml of methanol and 1.16 g (0.0208 mol) of pot ash in solution in 16.5 ml of water. The reaction mixture was allowed to stand at ambient temperature for 48 hours. It was then concentrated to dryness, taken up in water, waxed with ether in an alkaline environment, after which the aqueous phase was acidified. The acidified aqueous phase was extracted with ether, dried over sodium sulfate, filtered and the filtrate concentrated. The residue obtained after recrystallization from a mixture of ethyl acetate-hexane melted

med 128-130°C (kapillarrør).with 128-130°C (capillary tube).

IR-spektrum: V CO : 1 700 cm"1 V CO : 1 635 cm"1 NMR-spektrum: IR spectrum: V CO : 1,700 cm"1 V CO : 1,635 cm"1 NMR spectrum:

- 1 proton OH ved 10,6 ppm- 1 proton OH at 10.6 ppm

- flere topper av 4 aromatiske protoner sentrert ved 7,5 ppm - several peaks of 4 aromatic protons centered at 7.5 ppm

- 1 aromatisk proton ved 6,8 ppm- 1 aromatic proton at 6.8 ppm

- 5 protoner indan ved 3,3 6 ppm- 5 protons in at 3.3 6 ppm

- 3 protoner CH^ ved 2,47 ppm- 3 protons CH^ at 2.47 ppm

EKSEMPEL 3 EXAMPLE 3

5-( 4'- dimetylamino- benzoyl)- indan- 2- karboksylsyre 5-(4'-Dimethylamino-benzoyl)-indan-2-carboxylic acid

a) Metylesteren av 5-( 4'- dimetylamino- benzoyl)- indan- karboksylsyre a) The methyl ester of 5-(4'-dimethylamino-benzoyl)-indane-carboxylic acid

Forbindelsen fremstilles på følgende måte: The compound is produced in the following way:

a) I en 250 ml autoklav ble innført 5 g (0,017 mol) av metylesteren av 5-(4'-amino-benzoyl)-indan-2-karboksylsyre, 100 a) Into a 250 ml autoclave were introduced 5 g (0.017 mol) of the methyl ester of 5-(4'-amino-benzoyl)-indan-2-carboxylic acid, 100

ml etanol,-2 6 ml formaldehyd i 3 6% i vann i nærvær av 2 g Pd/C i 5%. Reaksjonsblandingen ble oppvarmet ved ca. 4 0°C under røring hvorunder autoklaven ble fylt med hydrogengass. Etter absorpsjon av den teoretiske mengden ble blandingen filtrert for å fjerne katalysatoren. Etanolen ble konsentrert under vakuum, blandet med vann og ekstrahert med eter. Deretter ble tørket over natriumsulfat, filtrert og filtratet konsentrert. Den erholdte rest etter omkrystal-\ lisasjon fra en blanding av etylacetat-diisopropylester ml of ethanol, -2 6 ml of formaldehyde in 3 6% in water in the presence of 2 g of Pd/C in 5%. The reaction mixture was heated at approx. 4 0°C with stirring during which the autoclave was filled with hydrogen gas. After absorption of the theoretical amount, the mixture was filtered to remove the catalyst. The ethanol was concentrated under vacuum, mixed with water and extracted with ether. It was then dried over sodium sulphate, filtered and the filtrate concentrated. The residue obtained after recrystallization from a mixture of ethyl acetate-diisopropyl ester

1 smeltet, ved 87 - 89°C (kapillarør).1 melted, at 87 - 89°C (capillary tube).

IR-spektrum: V CO : 1 740 cm"1 v> CO : 1 640 cm"1 IR spectrum: V CO : 1,740 cm"1 v> CO : 1,640 cm"1

forskyvning av Nl^-båndetshift of the Nl^ band

NMR-spektrum:NMR spectrum:

- doblet 2 aromatiske protoner: 7,85'ppm- doubled 2 aromatic protons: 7.85'ppm

- mulgiplett 1 aromatisk proton: 7,25 ppm- mold stain 1 aromatic proton: 7.25 ppm

- multiplett 2 aromatiske protoner: 7,55 ppm- multiplet 2 aromatic protons: 7.55 ppm

- doblet 2 aromatiske protoner: 6,7 ppm- doubled 2 aromatic protons: 6.7 ppm

- topp 3 protoner CH^: 3,8 ppm- top 3 protons CH^: 3.8 ppm

- flere topper 5 protoner indan: 3,3 5 ppm- more peaks 5 protons in: 3.3 5 ppm

- topp 6 protoner CH^: 3,1 ppm- top 6 protons CH^: 3.1 ppm

E lementæranalyse E lementary analysis

b) I en 125 ml autoklav ble innført 9,6 g (0,068 mol) metyl-jodid, 4,9 g (0,034 mol + 5%) K2C03, 30 ml dimetylformamid b) 9.6 g (0.068 mol) methyl iodide, 4.9 g (0.034 mol + 5%) K2CO3, 30 ml dimethylformamide were introduced into a 125 ml autoclave

og 5 g (0,017 mol) av metylesteren av 5-(4'-amino-benzoyl)-indan-2-karboksylsyre. Blandingen fikk stå under røring i 24 timer. Dimetylformamidet ble avdampet under vakuum hvoretter blandingen ble blandet med vann og ekstrahert med eter. Ekstraktet ble tørket over sulfat og filtrert hvoretter filtratet ble konsentrert. Den erholdte reste ble omkrystallisert fra en blanding av etylacetat-diisopropylester. På denne måten fikk man et produkt hvis fysikalske karakteristikka og spektra var identiske med dem for den i punkt a) erholdte produkt. and 5 g (0.017 mol) of the methyl ester of 5-(4'-amino-benzoyl)-indan-2-carboxylic acid. The mixture was allowed to stand under stirring for 24 hours. The dimethylformamide was evaporated under vacuum after which the mixture was mixed with water and extracted with ether. The extract was dried over sulfate and filtered, after which the filtrate was concentrated. The residue obtained was recrystallized from a mixture of ethyl acetate-diisopropyl ester. In this way, a product was obtained whose physical characteristics and spectra were identical to those of the product obtained in point a).

b) Omdannelse til 5-( 4'- dimetylamino- benzoyl)- indan- 2- karboksylsyre b) Conversion to 5-(4'-dimethylamino-benzoyl)-indan-2-carboxylic acid

I likhet med eksempel 1 b) og ut fra 5,6 g (0,017 mol) av metylesteren av 5-(4<1->dimetylamino-benzoyl)-indan-karboksylsyre og 1,95 g (0,0348 mol) pottaske i 60 ml metanol bie den ovenfor angitte karboksylsyre fremstilt. Etter omkrystallisasjon fra etylacetat fikk man et fast stoff som smeltet ved \ 164 - 165°C (kapillarrør). Similar to example 1 b) and starting from 5.6 g (0.017 mol) of the methyl ester of 5-(4<1->dimethylamino-benzoyl)-indan-carboxylic acid and 1.95 g (0.0348 mol) pot ash in 60 ml of methanol with the above-mentioned carboxylic acid prepared. After recrystallization from ethyl acetate, a solid was obtained which melted at 164 - 165°C (capillary tube).

I IR-spektrum: v CO : 1 730 cm V CO : 1 620 cm NMR-spektrum: - flere topper av 7 aromatiske protoner sentrerte ved 7,23 ppm I IR spectrum: v CO : 1730 cm V CO : 1620 cm NMR spectrum: - several peaks of 7 aromatic protons centered at 7.23 ppm

- topp av 5 protoner indan ved 3,3 ppm- peak of 5 protons in at 3.3 ppm

- topp av 6 protoner CH^ved 3,1 ppm- peak of 6 protons CH^ at 3.1 ppm

ElementæranalyseElementary analysis

EKSEMPEL 4. EXAMPLE 4.

5-( para- metylsulf onyl- benzoyl)- indan- 2- karboksylsyre 5-(para-methylsulfonyl-benzoyl)-indan-2-carboxylic acid

a) I likhet med eksempel 1 a) ble metylesteren av 5-(para-metylsulf onyl-benzoyl ) -indan-karboksylsyre fremstilt ut fra 14,5 g (0,107 mol) aluminiumklorid og 11 g (0,0475 mol) parametylsulfonylbenzosyreklorid. Dette ble tilsatt 60 ml metylenklorid samt 7 g (0,03 97 mol) metylester av indan-2-karboksylsyre i 30 ml metylenklorid. Etter konsentrering og opptak av resten i heksan fikk man et fast stoff som ble anvendt som sådant. b) I likhet med eksempel 1 b) ble syren fremstilt ut fra 3 g (0,0084 mol) av den under punkt a) erholdte ester og 1,1 g (0,02 mol) pottaske i 50 ml metanol. Ved omkrystallisasjon fra etanol fikk man et fast stoff som smeltet ved 187 - 190°C (karillarrør). 1 -1 ■ a) Similar to example 1 a), the methyl ester of 5-(para-methylsulfonyl-benzoyl)-indan-carboxylic acid was prepared from 14.5 g (0.107 mol) aluminum chloride and 11 g (0.0475 mol) paramethylsulfonylbenzoic acid chloride. To this was added 60 ml of methylene chloride and 7 g (0.03 97 mol) methyl ester of indane-2-carboxylic acid in 30 ml of methylene chloride. After concentration and absorption of the residue in hexane, a solid was obtained which was used as such. b) Similar to example 1 b), the acid was prepared from 3 g (0.0084 mol) of the ester obtained under point a) and 1.1 g (0.02 mol) pot ash in 50 ml methanol. Recrystallization from ethanol gave a solid which melted at 187 - 190°C (Carillar tube). 1 -1 ■

IR-spektrum: vCO : 1 710 cm V CO : 1 670IR spectrum: vCO : 1710 cm V CO : 1670

NMR-spektrum:NMR spectrum:

- flere topper av 7 aromatiske protoner sentrert ved 7,8 ppm topp av 5 protoner indan ved 3,3 3 ppm - several peaks of 7 aromatic protons centered at 7.8 ppm peak of 5 protons indan at 3.3 3 ppm

- topp av 3 protoner CH3ved 3,17 ppm- peak of 3 protons CH3 at 3.17 ppm

Surhetsgrad: Funnet: 155 beregnet: 163 Acidity: Found: 155 calculated: 163

ElementæranalyseElementary analysis

EKSEMPEL 5 5-( parasulfamido- benzoyl)- indan- 2- karboksylsvre EXAMPLE 5 5-(parasulfamido-benzoyl)-indan-2-carboxylic acid

a) Metylester av 5-( para- klorsulfonyl- benzoyl)- indan- 2-karboksylsyre a) Methyl ester of 5-(para-chlorosulfonyl-benzoyl)-indan-2-carboxylic acid

C18H15C105S C18H15C105S

I en 250 ml reaktor med rør ing-/"•termometer og bromampulle' ble 14,7 g (0,05 mol) metylester av 5-(4<1->amino-benzoyl)-indan-2-karboksylsyre innført. Ved en temperatur mellom 0 og 10°C ble tilsatt 40 ml hydrogenklorid på 24% og deretter mellom 0 og 5°C en løsning av 3,8 g natriumnitrit i 10 ml vann. Det derved dannede diazoniumsalt sattes så ved 15°C til en rørt blanding av 80 ml eddiksyre mettet med svoveldioksyd og 2,8 g kopperklorid oppløst i 5 ml vann.Blandingen fikk i nå omgivelsestemperatur og ble så varmet til 4 0°C for å avslutte reaksjonen og fikk så stå natten over. Følgende dag ble blandingen satt i isvann og fellingen som dannet ble lufttørket. Det erholdte produktet ble fastslått gjennom NMR-spektrum og'IR-spektrum. 14.7 g (0.05 mol) methyl ester of 5-(4<1->amino-benzoyl)-indan-2-carboxylic acid was introduced into a 250 ml reactor with a tube ing-/"•thermometer and bromine ampoule'. a temperature between 0 and 10° C was added 40 ml hydrogen chloride of 24% and then between 0 and 5° C a solution of 3.8 g sodium nitrite in 10 ml water. The diazonium salt thus formed was then added at 15° C to a stirred mixture of 80 ml of acetic acid saturated with sulfur dioxide and 2.8 g of copper chloride dissolved in 5 ml of water. The mixture was brought to ambient temperature and then heated to 40°C to terminate the reaction and then allowed to stand overnight. The following day the mixture was set in ice water and the precipitate formed was air-dried.The product obtained was determined by NMR spectrum and IR spectrum.

b) Omdannelse til metylester av 5-( para- sulfamido- benzoyl)-indan- 2- karboksylsyre b) Conversion to methyl ester of 5-(para-sulfamido-benzoyl)-indan-2-carboxylic acid

I en 500 ml reaktor med røring, kjøling og bromampuller In a 500 ml reactor with stirring, cooling and bromine ampoules

ble innført 15,6 g (0,041 mol) av det under punkt a) erholdte derivat samt 150 ml kloroform. Derpå ble under god omrøring 100 ml ammoniakk tilsatt. Blandi Jigen ble rørt 1,5 time ved omgivelsestemperatur. Deretter ble vann og kloroform tilsatt. Kloroformfasen ble dekantert, tørket over natriumsulfat, filtrert og konsentrert. Ved krystallisasjon av resten f ra en blanding av etylacet at - diisopropylester f ikk man et fast stoff som smeltet ved 147-149°C. 15.6 g (0.041 mol) of the derivative obtained under point a) and 150 ml of chloroform were introduced. Then, with good stirring, 100 ml of ammonia was added. The mixture was stirred for 1.5 hours at ambient temperature. Water and chloroform were then added. The chloroform phase was decanted, dried over sodium sulfate, filtered and concentrated. Crystallization of the residue from a mixture of ethyl acetate and diisopropyl ester gave a solid which melted at 147-149°C.

IR-spektrum: V NH : 3 400 - 3 320 cm"<1>, v<>>CO : 1 745 cm"<1>IR spectrum: V NH : 3,400 - 3,320 cm"<1>, v<>>CO : 1,745 cm"<1>

yCO : 1 660 cm"<1>yCO : 1,660 cm"<1>

NMR-spektrum:NMR spectrum:

- flere topper av 7 aromatiske protoner ved 7,66 ppm- several peaks of 7 aromatic protons at 7.66 ppm

- topp av 2 protoner Nf^ ved 6,1 p<p>m- peak of 2 protons Nf^ at 6.1 p<p>m

- topp av 3 protoner OCH^ved 3,7 ppm- peak of 3 protons OCH^ at 3.7 ppm

- topp av 5 protoner indan ved 3,3 ppm- peak of 5 protons in at 3.3 ppm

c) Omdannelse til syre:c) Conversion to acid:

Man arbeider i likhet med eksempel lb) men gikk ut fra 11 g One works in the same way as example lb) but started from 11 g

(0,0306 mol) av den under punkt b) erholdte ester i løsning(0.0306 mol) of the ester obtained under point b) in solution

i 100 ml etanol samt 3,4 g (0,06. mol) pottaske i en løsning i 100 ml vann. Slik fikk man etter omkrystallisasjon av J in 100 ml ethanol as well as 3.4 g (0.06 mol) pot ash in a solution in 100 ml water. This is how it was obtained after recrystallization by J

jdet erholdte produktet fra en blanding av eddiksyre-vann et fast stoff som smeltet ved 157 - 158°C (kapillarrør). jdet obtained the product from a mixture of acetic acid-water a solid which melted at 157 - 158°C (capillary tube).

IR-spektrum: V NH : 3 320 cm"1 V CO : 1 72 0 cm"<1>IR spectrum: V NH : 3,320 cm"1 V CO : 1,720 cm"<1>

V CO : 1 650 cm"<1>V CO : 1,650 cm"<1>

NMR-spektrum:NMR spectrum:

- flere topper av 7 aromatiske protoner ved 7,6 ppm- several peaks of 7 aromatic protons at 7.6 ppm

- topp av 2 protoner NH2ved 6,6 ppm- peak of 2 protons NH2 at 6.6 ppm

- 1 proton OH ved 10,5 ppm- 1 proton OH at 10.5 ppm

- 5 protoner indan ved 3,4 ppm- 5 protons in at 3.4 ppm

ElementæranalyseElementary analysis

EKSEMPEL 6 5-( para- metylamino- sulfonyl- benzoyl)- indan- 2- karboksylsyre a) Metylester av 5-( para- dimetylamino- sulfonyl- benzoyl)- indan-2- karboksylsyre EXAMPLE 6 5-(para-methylamino-sulfonyl-benzoyl)-indan-2-carboxylic acid a) Methyl ester of 5-(para-dimethylamino-sulfonyl-benzoyl)-indan-2-carboxylic acid

Forbindelsen ble fremstilt i likhet med eksempel 5 b) men ut fra 28 g (0,074 mol) av metylesteren av 5-(para-klorsulf-nyl-benzoyl)-indan-2-karboksylsyre i 90 ml kloroform, 34 ml (0,148 mol) av en løsning av dimetylamin på 40% i vann. The compound was prepared similarly to example 5 b) but from 28 g (0.074 mol) of the methyl ester of 5-(para-chlorosulf-nyl-benzoyl)-indan-2-carboxylic acid in 90 ml of chloroform, 34 ml (0.148 mol) of a 40% solution of dimethylamine in water.

i in

' b) Omdannelse til syren' b) Conversion to the acid

I likhet med eksempel 5 c), men ut fra 21 g (0,0545 mol) av den under punkt a) erholdte rå ester i 200 ml vann og 6,15 g (0,11 mol) pottaske i 200 ml etanol. Etter omkrystallisasjon fra en blanding av etylacetat - heksan fikk man et fast stoff som smeltet ved 144 - 145°C (kapillarrør). Similar to example 5 c), but from 21 g (0.0545 mol) of the crude ester obtained under point a) in 200 ml of water and 6.15 g (0.11 mol) of pot ash in 200 ml of ethanol. After recrystallization from a mixture of ethyl acetate - hexane, a solid was obtained which melted at 144 - 145°C (capillary tube).

IR-spektrum: V CO : 1 700 cm"<1>V CO : 1 660.cm"<1>NMR-spektrum: IR spectrum: V CO : 1,700 cm"<1>V CO : 1,660.cm"<1>NMR spectrum:

- topp av 4 aromatiske protoner 7,97 ppm- peak of 4 aromatic protons 7.97 ppm

- flere topper av 3 aromatisek protoner ved 7,53 ppm- several peaks of 3 aromatic protons at 7.53 ppm

- topp av 5 protoner indan ved 3,3 ppm- peak of 5 protons in at 3.3 ppm

- toppp av 6 protoner CH^ ved 2,8 ppm Elementæranalyse - peak of 6 protons CH^ at 2.8 ppm Elemental analysis

EKSEMPEL 7 EXAMPLE 7

Etylester av 5-( 4'- acetamido- 3'- klor- benzoyl)- indan- 2- karboksylsyre Ethyl ester of 5-(4'-acetamido-3'-chloro-benzoyl)-indan-2-carboxylic acid

I en 250 ml reaktor med røring, kjøling, bromampulle og termometer ble 8,8 g (0,025 mol) av etylesteren av 5-(para-acetamido-benzoyl)-indan-2-karboksylsyre og 30 ml eddiksyre innført. Into a 250 ml reactor with stirring, cooling, bromine ampoule and thermometer, 8.8 g (0.025 mol) of the ethyl ester of 5-(para-acetamido-benzoyl)-indan-2-carboxylic acid and 30 ml of acetic acid were introduced.

Ved en temperatur nær 10°C tilsattes dertil 40 ml eddiksyre mettet med klor dråpevis. Den opprinnelige suspensjonen forsvant etterhvert. Blandingen fikk stå en time ved omgivel- ji sestemperatur hvoretter eddiksyren ble fordampet i vakuum. Således fikk man en olje som ved omkrystallisasjon fra en blanding av etylacetat-heksan ga et fast stoff som smeltet ved 126 - 127°C (kapillarrør). At a temperature close to 10°C, 40 ml of acetic acid saturated with chlorine was added dropwise. The original suspension eventually disappeared. The mixture was allowed to stand for one hour at ambient temperature, after which the acetic acid was evaporated in a vacuum. Thus, an oil was obtained which, on recrystallization from a mixture of ethyl acetate-hexane, gave a solid which melted at 126 - 127°C (capillary tube).

IR-spektrum: V NH:3 350 cm"<1>, \PC0 : 1 740 cm"<1>IR spectrum: V NH:3 350 cm"<1>, \PC0 : 1 740 cm"<1>

V CO : 1 690 cm"<1>, V CO : 1 650 cm"<1>NMR-spektrum: V CO : 1690 cm"<1>, V CO : 1650 cm"<1>NMR spectrum:

- 1 aromatisk proton ved 8,6 ppm- 1 aromatic proton at 8.6 ppm

- flere topper av 6 atomatiske protoner sentrert ved 7,5 ppm - several peaks of 6 atomic protons centered at 7.5 ppm

- kvartett 2 protoner CH2ved 4,2 ppm- quartet 2 protons CH2 at 4.2 ppm

- 5 protoner indan ved 3,33 ppm- 5 protons in at 3.33 ppm

- topp av 3 protoner CH^ved 2,2 3 ppm- peak of 3 protons CH^ at 2.2 3 ppm

- topp av 3 protoner CH^ ved 1,2 ppm Elementæranalyse EKSEMPEL 8 5-( 4', 5'- diklor- 2'- tenoyl)- indan- 2- karboksylsyre I en 250 ml reaktor som var utstyrt med rører, kjøler, bromampulle og et rør som tillot gassavgang fra rekasjonsblandin-gens midte ble 5,2 g (0,017 mol) av 5-(5<1->klor-2'-tenoyl)-indan-2-karboksy lsyre innført / Dette ble brakt til en tem- ■ peratur på 15°C hvoretter 28 ml eddiksyre mettet med klor ml ble tilsatt. Deretter ble reaksjonsblandingen oppvarmet i et vannbad til 7 5°C hvilket ga kloravgang fra midten av reaksjonsblandingen. Etter nedkjøling ble et fast stoff isolert ved lufttørking. Det siste ble omkrystallisert fra etylacetat og dets smeltepunkt faststlås til 190 - 192°C - peak of 3 protons CH^ at 1.2 ppm. bromine ampoule and a tube which allowed gas to escape from the center of the reaction mixture, 5.2 g (0.017 mol) of 5-(5<1->chloro-2'-thenoyl)-indan-2-carboxylic acid was introduced / This was brought to a tem- ■ temperature of 15°C after which 28 ml of acetic acid saturated with chlorine ml were added. The reaction mixture was then heated in a water bath to 75°C, which produced chlorine discharge from the center of the reaction mixture. After cooling, a solid was isolated by air drying. The latter was recrystallized from ethyl acetate and its melting point was determined to be 190 - 192°C

(kapillarrør).(capillary tube).

IR-spektrum: v> CO : 1 720 cm"1 VCO : 1 650 cm"1 NMR-spektrum: - flere topper av 3 protoner indan pluss 1 proton tiofen sentrert ved 7,5 ppm IR spectrum: v> CO : 1,720 cm"1 VCO : 1,650 cm"1 NMR spectrum: - several peaks of 3 protons indane plus 1 proton thiophene centered at 7.5 ppm

- topp av 5 protoner indan ved 3,33 ppm- peak of 5 protons indan at 3.33 ppm

Elementær analyse, - Elementary analysis, -

EKSEMPEL 9 2'-( N, N- dietylamino)- etylester av 5 —( 2'- tenoyl)- indan- 2-karboksylsyre EXAMPLE 9 2'-(N,N-diethylamino)-ethyl ester of 5-(2'-thenoyl)-indan-2-carboxylic acid

a) i en 500 ml reaktor utstyrt med røring, kjøling og en bromampulle ble i rekkefølge innført 27,1 g (0,1 mol). 5-(2<1->tenoyl)-indan-2-karboksylsyre, 200 ml isopropanol, 16,6 g (0,1 mol + 2 0%) kaliumkarbonat, 17,2 g (0,1 mol) av hydrokloridet av klor-etyldietylamin og 150 ml isopropanol. Blandingen ble oppvarmet 15 timer ved tilbakeløp. Deretter ble a) in a 500 ml reactor equipped with stirring, cooling and a bromine ampoule, 27.1 g (0.1 mol) were successively introduced. 5-(2<1->thenoyl)-indan-2-carboxylic acid, 200 ml isopropanol, 16.6 g (0.1 mol + 2 0%) potassium carbonate, 17.2 g (0.1 mol) of the hydrochloride of chloroethyldiethylamine and 150 ml of isopropanol. The mixture was heated at reflux for 15 hours. Then became

i den konsentrert til tørrhet, blandet med vann og fortynnet in it concentrated to dryness, mixed with water and diluted

saltsyre og vasket med eter i surt miljø, Vannfasen ble gjort alkalisk og ekstrahert med eter. Eterskiktet ble tørket over natriumsulfat og filtrert hvoretter filtratet ble konsentrert. Resten ble destillert og en fraksjon kp^ torr: 230 -240 oppsamlet. hydrochloric acid and washed with ether in an acidic environment, The water phase was made alkaline and extracted with ether. The ether layer was dried over sodium sulfate and filtered, after which the filtrate was concentrated. The residue was distilled and a fraction kp^ torr: 230 -240 collected.

IR-spektrum: VCO : 1 740 cm<-1>v>CO : 1 650 cm"<1>NMR-spektrum: IR spectrum: VCO : 1,740 cm<-1>v>CO : 1,650 cm"<1>NMR spectrum:

- flere topper av 6 aromatiske protoner ved 7,47 ppm- several peaks of 6 aromatic protons at 7.47 ppm

- triplett av 2 protoner CH2 ved 4,2 ppm- triplet of 2 protons CH2 at 4.2 ppm

- topp av 5 protoner indan ved.. 3,3 3 ppm- peak of 5 protons inside at.. 3.3 3 ppm

- flere topper av 6-protoner CH2ved 2,7 ppm- several peaks of 6-protons CH2 at 2.7 ppm

- triplett av 6 protoner CH^ ved 1,07 ppm- triplet of 6 protons CH^ at 1.07 ppm

b) Omdannelse til hydroklorid:b) Conversion to hydrochloride:

C01H„,C1N00S M = 407,94 C01H2,C1N00S M = 407.94

2.1A. b j2.1A. b j

Ved kjent teknikk erholdes etter omkrystallisasjon fra etanol et fast stoff som smelter ved 157 - 158°C.(kapillarrør). With known techniques, a solid is obtained after recrystallization from ethanol which melts at 157 - 158°C (capillary tube).

Surhetsgrad: Funnet: 132 Beregnet: 137 IR-spektrum: VCO : 1 745 cm"<1>V CO : 1 630 cm Elementæranalyse Acidity: Found: 132 Calculated: 137 IR spectrum: VCO : 1,745 cm"<1>V CO : 1,630 cm Elemental analysis

EKSEMPEL 10 2'-( N, N- dietylamino) etylester av 5-( 2'- furoyl)- indan- 2- kar-boksylat EXAMPLE 10 2'-(N,N-diethylamino)ethyl ester of 5-(2'-furoyl)-indan-2-carboxylate

Forbindelsen ble fremstilt i likhet med eksempel 9, men ut fra 21,4 g (0,0835 mol) 5-(2'-furoyl)-indan-2-karboksylsyre, 14,2 g (0,0835 mol + 20%) kaliumkarbonat og 14,4 g (0,0835 mol) av hydrokloridet av klorétyldietylamin. Ved destilla-sjon fikk man en fraksjon kp^5o 4 torr<:><2>0°~2^^°c The compound was prepared similarly to Example 9, but from 21.4 g (0.0835 mol) of 5-(2'-furoyl)-indan-2-carboxylic acid, 14.2 g (0.0835 mol + 20%) potassium carbonate and 14.4 g (0.0835 mole) of the hydrochloride of chloroethyldiethylamine. By distillation, a fraction kp^5o 4 torr<:><2>0°~2^^°c was obtained

IR-spektrum: V CO : 1 740 cm v> CO : 1 650 cm"1IR spectrum: V CO : 1,740 cm v> CO : 1,650 cm"1

MNR-spektrum:MNR spectrum:

- flere topper av 3 aromatiske protoner ved 7,83 ppm- several peaks of 3 aromatic protons at 7.83 ppm

- flere topper av 2 aromatiske protoner ved 7,3 ppm- several peaks of 2 aromatic protons at 7.3 ppm

- 1 aromtisk proton ved 6,53 ppm- 1 aromatic proton at 6.53 ppm

- flere topp av 2 protoner CH2ved 4,1 ppm- several peaks of 2 protons CH2 at 4.1 ppm

- topp av 5 protoner indan ved 3,3 3 ppm- peak of 5 protons in at 3.3 3 ppm

- flere topper av 6 protoner CH2ved 2,7 ppm- several peaks of 6 protons CH2 at 2.7 ppm

- flere topper av 6 protoner CH, ved 1,07 ppm- several peaks of 6 protons CH, at 1.07 ppm

Overføring til hydrokloridConversion to hydrochloride

C21H25C1N04C21H25C1N04

Etter omkrystallisasjon fra en blanding fra etylacetet - etanol fikk man et fast stoff som smeltet ved 165 - 166,5°C (kapillar-rør) . After recrystallization from a mixture from ethyl acetate - ethanol, a solid was obtained which melted at 165 - 166.5°C (capillary tube).

Surhetsgrad: Funnet: 14 2 Beregnet: 14 3 Acidity: Found: 14 2 Calculated: 14 3

Elementæranalyse ( hydroklorid)Elemental analysis (hydrochloride)

EKSEMPEL 11 EXAMPLE 11

5- benzoyl- N-[ 2'-( N', N'- dietylamino) etyl]- indan- 2- karboksamid5- benzoyl- N-[ 2'-( N', N'- diethylamino) ethyl]- indan- 2- carboxamide

I I I I

I en 250 ml reaktor utstyrt med rører, kjøler, en bromampulle og et termometer ble 25,5 g (0,2 mol + 10%) 2-(N',N<1->dietylamino)etylamin i 50 ml dioksan innført. En temperatur mellom 10° og 20°C beholdes under tilsetning av en løsning av 30,2 g (0,1 mol) 5-benzoyl-indan-2-karboksylsyreklorid i 50 ml dioksan. Blandingen fikk deretter gjeninnta romtemperatur, hvoretter den ble rørt en time ved denne temperaturen. Dioksan ble avdampet under vakuum, resten satt i isvann og ekstrahert med eter i alkalisk miljø. Eterekstraktet ble tørket over sulfat, filtrert og filtratet konsentrert. Into a 250 ml reactor equipped with a stirrer, cooler, a bromine ampoule and a thermometer, 25.5 g (0.2 mol + 10%) of 2-(N',N<1->diethylamino)ethylamine in 50 ml of dioxane were introduced. A temperature between 10° and 20°C is maintained during the addition of a solution of 30.2 g (0.1 mol) of 5-benzoyl-indan-2-carboxylic acid chloride in 50 ml of dioxane. The mixture was then allowed to return to room temperature, after which it was stirred for one hour at this temperature. Dioxane was evaporated under vacuum, the residue put in ice water and extracted with ether in an alkaline environment. The ether extract was dried over sulfate, filtered and the filtrate concentrated.

Således fikk man en olje hvorav et oksalat ble fremstilt.Thus an oil was obtained from which an oxalate was produced.

Etter omkrystallisasjon fra en blanding av aceton-alkoholAfter recrystallization from an acetone-alcohol mixture

fikk man et smeltepunkt på 153-154°C (kapillarrør). a melting point of 153-154°C was obtained (capillary tube).

Surhetsgrad: Funnet: 226 Beregnet: 246Acidity: Found: 226 Calculated: 246

IR-spektrum: V CO : 1 660 cm"<1>IR spectrum: V CO : 1,660 cm"<1>

Elementæranalys<e>^<H>25<H>30<N>2°6^Elemental analysis<e>^<H>25<H>30<N>2°6^

EKSEMPEL 12 5-( 21- tenoyl)- N-[ 2'-( N', N'- dietylamino) etyl]- indan- 2-karboksamid EXAMPLE 12 5-(21-thenoyl)-N-[2'-(N',N'-diethylamino)ethyl]-indan-2-carboxamide

Forbindelsene ble fremstilt i likhet med eksempel 11, men ut fra 9,4 g (0,03 mol) 5-(2<1->tenoyl)-indan-2-karboksylsyreklorid, 7,7 g (0,066 mol) 2-(N'-N'-dietylamino)etylamin og 120 ml dioksan. Ved overføring til oksalatet fikk man etter omkrystallisasjon fra aceton et fast stoff som smeltet ved 110,5 - 112°C (kapillarrør). The compounds were prepared similarly to Example 11, but from 9.4 g (0.03 mol) 5-(2<1->thenoyl)-indan-2-carboxylic acid chloride, 7.7 g (0.066 mol) 2-( N'-N'-diethylamino)ethylamine and 120 ml of dioxane. When transferred to the oxalate, after recrystallization from acetone, a solid was obtained which melted at 110.5 - 112°C (capillary tube).

Surhetsgrad: Funnet: 247 Beregnet: 243Acidity: Found: 247 Calculated: 243

IR-spektrum: V CO : 1 630 cm"<1>IR spectrum: V CO : 1,630 cm"<1>

NMR-spektrum:NMR spectrum:

- flere topper av 6 aromatiske protoner ved 7,4 ppm- several peaks of 6 aromatic protons at 7.4 ppm

- flere topper av 5-protoner indan +8 protoner CH2ved 3,3 3 ppm - triplett av 6 protoner CH3ved 1,27 ppm - several peaks of 5 protons within +8 protons CH2 at 3.3 3 ppm - triplet of 6 protons CH3 at 1.27 ppm

Elementæranalys<e>^23H28N2^6^^Elemental analysis<e>^23H28N2^6^^

EKSEMPEL 13 5-( 2', 5'- diklorbenzoyl)- N-( 2'-( N', N'- dietylamino) etyl]- indan-2- karboks amid i EXAMPLE 13 5-(2',5'-dichlorobenzoyl)-N-(2'-(N',N'-diethylamino)ethyl]-indan-2-carboxamide in

Forbindelsene ble fremstilt i likhet med eksempel 11, men ut The compounds were prepared similarly to Example 11, but out

fra 17,6 g (0,048 mol) av 5-(2',5'-diklor-benzoyl)-indan-2 karboksylsyreklorid, 13,9 g (0,12 mol) 2-(N',N'-dietylamino) etylamin og 80 ml dioksan. Ved omdannelse til oksalatet og etter omkrystallisasjon fra aceton fikk man et fast stoff som smeltet ved 103 - 104°C (kapillarrør). from 17.6 g (0.048 mol) of 5-(2',5'-dichloro-benzoyl)-indan-2 carboxylic acid chloride, 13.9 g (0.12 mol) of 2-(N',N'-diethylamino) ethylamine and 80 ml of dioxane. On conversion to the oxalate and after recrystallization from acetone, a solid was obtained which melted at 103 - 104°C (capillary tube).

Surhetsgrad: Funnet: 206 Beregnet: 216Acidity: Found: 206 Calculated: 216

IR-spektrum: V CO : 1 670 cm"1IR spectrum: V CO : 1,670 cm"1

NMR-spektrum:NMR spectrum:

- flere topper av 6 aromatisek protoner sentrert ved 7,4 6 ppm- several peaks of 6 aromatic protons centered at 7.4 6 ppm

- flere topper av 5 protoner indan + 8 protoner CH2ved 3,43 ppm - several peaks of 5 protons indan + 8 protons CH2 at 3.43 ppm

-. triplett av 6 protoner CH2ved 1,33 ppm-. triplet of 6 protons CH2 at 1.33 ppm

- 1 proton NH ved 8,3 ppm- 1 proton NH at 8.3 ppm

Elementæranalyse (C2^H2gCl2N20g)Elemental analysis (C2^H2gCl2N20g)

Claims (7)

1. Analogifremgangsmåte ved fremstilling av forbindelsen med antiinflammatorisk, analgetisk og mot aggregering av blodplater virkende aktivitet med formel1. Analogous method for the preparation of the compound with anti-inflammatory, analgesic and anti-platelet aggregation activity with formula R-CO COOH hvor R er en fenylgruppe substituert med minst en substituent valgt blant halogenene og gruppene acetamido, dialkylamino, alkylsulfonyl, dialkylaminosulfonyl og sulfamido, en tionyl-gruppe substituert med minst en substituent valgt blant halogenene og en lavere alkylgruppe, eller en furylgruppe substituert med en lavere alkylgruppe, som kan være fri syre eller salt eller estere derav, karakterisert ved at en forbindelse med formel R-COf ^^xl COOR' hvor R har samme betydning som ovenfor og R' betegner en lavere alkylgruppe hvilken forbindelsen erholdes ved reaksjon av en halogenforbindelse med formel R - COX hvor R har samme betydning som ovenfor og X betegner et halogen ifølge Friedel-Craft-reaksjonen, hydrolyseres alkalisk. R-CO COOH where R is a phenyl group substituted with at least one substituent selected from the halogens and the groups acetamido, dialkylamino, alkylsulfonyl, dialkylaminosulfonyl and sulfamido, a thionyl group substituted with at least one substituent selected from the halogens and a lower alkyl group, or a furyl group substituted with a lower alkyl group, which can be a free acid or salt or esters thereof, characterized in that a compound of formula R-COf ^^xl COOR' where R has the same meaning as above and R' denotes a lower alkyl group which the compound is obtained by reaction of a halogen compound of formula R - COX where R has the same meaning as above and X denotes a halogen according to the Friedel-Craft reaction, is hydrolyzed alkaline. 2. Analogifremgangsmåte ifølge krav 1, karakterisert ved at en forbindelsen med formel R-CO ^^^^^^^^^^COOR' hvor R har samme betydning som ovenfor og R <1> betegner en lavere i2. Analogy method according to claim 1, characterized in that a compound of formula R-CO ^^^^^^^^^^COOR' where R has the same meaning as above and R <1> denotes a lower in alkylgruppe, hvilken forbindelse erholdes ved reaksjon mellom en forbindelsen med formelalkyl group, which compound is obtained by reaction between a compound of formula hvor R <1> har samme betydning som ovenfor og en aroylhalogen-forbindelse med formel R - COX, hvor R har samme betydning som ovenfor og X betegner et halogen ifølge Friedel-Craft-reaksjon, hydrolyseres alkalisk. where R <1> has the same meaning as above and an aroylhalogen compound of formula R - COX, where R has the same meaning as above and X denotes a halogen according to the Friedel-Craft reaction, is hydrolyzed alkaline. 3. Analogifremgangsmåte ved fremstilling av en forbindelse ifølge krav 1 hvor R er en fenylgruppe substituert med en sulfamidogruppe eller en dimetylsulfamidogruppe, k a r a k- tertisert ved at en forbindelse med formel 3. Analogous method for the preparation of a compound according to claim 1 where R is a phenyl group substituted with a sulfamido group or a dimethylsulfamido group, k a r a k- tertiated in that a compound of formula hvor R er en fenylgruppe substituert med en aminogruppe og R' er samme som ovenfor angitt diazoteres hvoretter det erholdte aryldiazoniumsaltet settes til en løsning av svoveldioksyd i eddiksyre i nærvær av et kobbersalt og den erholdte forbindelsen hvor substituenten R i formelen betegner en klorsulfonylfenylgruppe behandles med ammoniakk eller dimetylamin.where R is a phenyl group substituted with an amino group and R' is the same as stated above diazotized after which the obtained aryldiazonium salt is added to a solution of sulfur dioxide in acetic acid in the presence of a copper salt and the compound obtained where the substituent R in the formula denotes a chlorosulfonylphenyl group is treated with ammonia or dimethylamine. 4. Analogifremgangsmåte ved fremstilling av en forbindelse ifølge krav 1 hvor R er en dimetylaminofenyl-gruppe, karakterisert ved at formaldehyd omsettes i nærvær av hydrogen og en hydrogeneringskatalysator med en forbindelse med formel I 4. Analogous method for the preparation of a compound according to claim 1 where R is a dimethylaminophenyl group, characterized in that formaldehyde is reacted in the presence of hydrogen and a hydrogenation catalyst with a compound of formula IN hvor R er en fenylgruppe substituert med en aminogruppe og R' er som ovenfor angitt. where R is a phenyl group substituted with an amino group and R' is as indicated above. 5. Analogifremgangsmåte ved fremstilling av en forbindelse ifølge krav 1 hvor R er en gruppe substituert med minst et halogen, karakterisert ved at en for- bindelse med formel 5. Analogous method for the preparation of a compound according to claim 1 where R is a group substituted by at least one halogen, characterized in that a bond with formula hvor R er en monosubstituert fenylgruppe, tienylgruppe eller furylgruppe og <Rl> er som ovenfor angitte, behandles med et halogen i eddiksyreløsning. where R is a monosubstituted phenyl group, thienyl group or furyl group and <Rl> is as indicated above, is treated with a halogen in acetic acid solution. 6. Analogifremgangsmåte ved fremstilling av indankarboksyl-syrederivatens aminosyreestere som har antiinflammatorisk, analgetisk og mot aggregering av blodplater virkende aktivitet og som representeres av lavere dialkylamino-lavere alkylestere, karakterisert ved at ved tilbakeløpstem-peraturen kondenserer man et indansyrederivat hvor R i formelen er en tienylgruppe eller furylgruppe med et halogen-alkyldialkylamin i alkoholholdig løsningsmiddel. 6. Analogous method for the production of the indane carboxylic acid derivative's amino acid esters which have anti-inflammatory, analgesic and anti-platelet aggregation activity and which are represented by lower dialkylamino-lower alkyl esters, characterized in that at the reflux temperature one condenses an indane acid derivative where R in the formula is a thienyl group or furyl group with a haloalkyldialkylamine in alcoholic solvent. 7. Analogifremgangsmåte ved fremstilling av indankarboksyl-syrederivatenes karboksamider som har antiinflammatorj.sk, analgetisk og mot aggregering av blodplater virkende aktivitet og som representeres av de lavere-alkylamino-lavere alkyl- i amidene, karakterisert ved at ved en temperatur mellom +10 og +20°c kondenseres et indansyreklorid-derivat hvor R i formelen er en fenylgruppe som eventuelt er substituert med to halogener eller en tienylgruppe sammen med et dialkylaminoalkylamin.7. Analogous method for the production of the carboxamides of the indane carboxylic acid derivatives which have anti-inflammatory, analgesic and anti-platelet aggregation activity and which are represented by the lower-alkylamino-lower alkyl-i amides, characterized in that at a temperature between +10 and + At 20°c, an indanic acid chloride derivative is condensed where R in the formula is a phenyl group optionally substituted with two halogens or a thienyl group together with a dialkylaminoalkylamine.
NO774285A 1976-12-14 1977-12-13 ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE INDANDATIVE DERIVATIVES NO774285L (en)

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