DE1946638A1 - Heterocyclic compounds - Google Patents

Description

Folder 22059- Dr _o P / Hr
Case PH »21352

DESCRIPTIVE aur patent application by

IMPERIAL CHEMICAL IKDÜSTBIES LIMITED, London S ₀ W ₀ i / ßroßbr «

concerning

"Heterocyclic compounds"

Priority » Great Britain September 13, 1968 - Έτ, 43628/68

The present invention relates to new heterocyclic ones Compounds and in particular to new oxadiazole and tiaiadiazole derivatives, which is an anti-inflammatory, analytical and have antipyretic effectiveness »

According to the invention, new heterocyclic compounds are the formula

OR ¹ H ² R ³

proposed wherein Y -inen phenyl "Monohalogenphectyl ·» or Dihalogenphenylreet beseiclmet "wcb * i the halogen substituents are selected from fluoro * ·, Chloi" -and- & firom, tom & B _y and either

003836/2201

8AO ORlGtNAU

1946633

4 2

R is a methyl radical, R is hydrogen or a methyl, Go-6 "" Alkoxycarbonyl, bensylozycarbonyl or phenoxy carbonyl radical and

"5
R a carboxy? G «g-alkoxycarbonyl, bensyloxycarbonyl or

2 denote phenoxycarbonyl radical and, if R is a C "g" -alkoxy- *

is carbonyl, benäyloxycarbonyl or phenoxycarbonyl radical, R- ^

1 2

denotes the same radical, or R and R are both hydrogen and R " ^{5 is} a Garboxymethyl (-CH ₀ CO ₀ H) - ₉ C""" Alkosycarbony! methyl-,

^ ^d - '"' denote»,

Bensyloxyoarbonylmethyl or phenoxycarbonylmethyl radical and A an oxygen or sulfur atom, as well as non-toxic pharmaceutically acceptable salts of these compounds, with the exception of ß-CS-phenyl- ¹ , 2,4-xadiazol-5-yl) -propionic acid and the 1 ethyl ester thereof.

Those Ferbindungen according to the Brfitidusg, wherein Y is a Monohalogeuphenyl- or Dihalogensphenylrest 1st, are special preferred because they are generally more effective than their counterparts unsubstituted phenyl derivatives.

2 3
Is a suitable remainder for R and R when they are C _? -.- Alkoxy- »carboxyl radical is, for example, a methoxycarbanyl or ethoxycarbanyl radical. A suitable radical for R when this is a 0 »" -alkoxycarbonylmethyl is, for example, a methoxycarbonylffiethyl or ethoxycarbonylmethylrea.

In the case where R is a carboxy or carboxymethyl radical. designated, Bind suitable mates with alkali metals or alkaline earth metals or aluminum or ammonium salts or salts with non-toxic pharmaceutically acceptable organic bases such as triethanolamine.

Preferred compounds of the invention are diethyl-of- (3 ~ pchlorophenyl »! "2,4 ~ thiaaiaaol-5-yl) -O (» methylmalonate, methyl-of-

0098 3 6/2201 JAMiOfSO QAB BAD OFUGlNAL

(3-.p-chlorophenyl ~ 1, 2,4-oxadiazol-5-yl) ~ propioxiate, methyl-0G- (5-polyphenyl-1,2,4-oxadia2ol-3-yl) -isobutyrate and ß- ( 3 ~ p-chlorophenyl-1,2,4-oxadiazol ~ 5-yl) propionic acid ₀

According to another feature of the invention, a method for the preparation of compounds of the formula

1 2
wherein A, Ύ, R and R have the meanings given above and R be3eichnet a C ^ C alkyl, or phenyl Benssyl-, vorgee <äilagen ₉ which consists in that a Alkalimetallderivät a compound of formula

• 2

"JbT R ^

2 A
where A, Y, R and R have the meanings given above, is reacted with methyl chloride, bromine or «Tod, _o

It should be noted * that the above procedure ssur Introduction of a methyl ref3te (the Η atom on the Of carbon atom of the starting material is replaced by a methyl stress £ 5t) or from two methyl radicals (i.e., in the starting "

2
material is R a hydrogen atom and this Wasoerstoffatoa and the remaining hydrogen atom on the oC -carbonatora are replaced by methyl radicals) _o The reaction can take place in an organic diluent or solvent, for example dioxane

009836/2201

8AD ORlQiNAL

or dimethyl sulfoxide can be carried out and it can be carried out by An the use of heat can be accelerated or terminated, for example by being carried out at reflux temperature «

According to another. Feature of the invention is a method for the preparation of compounds of the formula

8 E ¹

C-CO "R ^{4 2}

14th
proposed, in which A ₉ Y, R and R have the above

meanings and R denotes hydrogen or a methyl radical ₉ . which consists in that a compound of the formula

1 5
where A _r . Y, R and R have the meanings given above ^ with sodium or potassium or a hydride, amide or C ₁ ', alkoxide of the same and a carbonate of the formula COo (OR) _{o is} reacted.

4th
where R has the meaning given above «,

The latter process is preferably carried out using an excess of the carbonate as the reactant, for example with an excess of ύο®. 5 Ms 20 hol of the carbonate. Furthermore kaim an organic Msimgsaiittelf, feel "spi ^ lOTCiee xylene" gewitogshteafalls zngQgQn was "- The can duTüh'Anw & pAwots of farm © 'accelerated oüqt

009838/2201

for example by being carried out at reflux temperature,

Another feature of the invention is a method for Preparation of compounds of the formula

R ¹

1 5
where A, Y, R and R have the abovementioned meaning

1 5
have or where -CE R- is the group -CH ₂ CH ₂ -, as well as the

non-toxic pharmaceutically acceptable salts thereof are proposed, which consists in being a compound of the formula

is hydrolyzed »in which A, J, R and R ^ have the meanings given above and R is cyano, carbamoyl, C ^ g

acarbonyl, phenoxyoarbonyl or bengyloxycarbonyl radical

Al »suitable hydrolyzing agents are, for example, one etarlte inorganic base, for example an alkali metal hydroxide, or an inorganic acid, for example sulfuric acid, called »The hydrolysis is carried out in the presence of water, in which case an organic solvent is also present • ei »can. The implementation can be accelerated through the use of heat or terminated, for example, by performing it at the return flow temperature

V 009836/2201

.... 6AO ORIGINAL

1946633

According to a further feature of the invention, a method for the preparation of compounds of the formula

wherein Y has the meaning given above, as well as non-toxic pharmaceutically applicable salts of the same, which consists in that water consists of a compound of the formula

is removed, where Y has the meaning given above «,

The removal of the water can be done by the process of azeotropic Distillation can be carried out, for example, by azeotropic distillation in conjunction with xylene.

According to another feature of the invention, a method for the preparation of compounds of the formula

Y-ET -3_ CR ¹ R ⁵ R ⁷

suggested, wherein A and Y have the meanings given above

1 5

have and either R is a methyl radical, R 'is hydrogen or

7th
a methyl radical and R a Q ₀ * · -Alkoxyoarbonyl-, BeKSyloxyoarbonyl «or PlienoaEycarboiiylrQst or R and R ^ hydrogen

.009838 / 2201

- * 8AD ORIGINAL

1946633

Μ »/ IB»

and R is a C, "-Alkoxy carbonylmethyl- ·, Benzyloxycarbonylmethyl- or phenoxycarbonylmethyl radical ", and that consists in that the corresponding carboxylic acid or a salt thereof is esterified

The esterification can be carried out by a generally known process, for example by reacting the corresponding carboxylic acid with the corresponding C ^ - alkanol or benzyl alcohol in the presence of an inorganic acid, such as hydrochloric or sulfuric acid, or by reacting a salt of the corresponding carboxylic acid, for example an alkali metal salt with a C ₁ . c-alkyl chloride, bromide or iodide or benzyl chloride, bromide or iodide. The corresponding phenyl esters can be obtained by reacting an alkyl ester in which the alkyl radical contains up to 5 carbon atoms with phenol in the presence of an ester exchange catalyst, such as, for example, dibutyltin dilaurate. The effect of heat, for example at up to 150 ⁰ C, can be obtained »

According to a further feature of the invention there is provided a method for the preparation of compounds of the formula

CHR ¹ .

suggested, wherein A and Y have the meanings given above

1 1

and either R is a methylreat or -OHR - € ie the group -CHpCH- is _e which would require & t that a compound of the formula

009836/22 0T

SAD ORlGtNAL

CR

¹ (CO ₂ E ⁴ ),

where A, Y and R have the meanings given above and ent « neither R is a Methylreet or -CR = the group -CHg.CHs, with a strong inorganic base in the presence of water tmd if the effect of heat is implemented »

The strong inorganic base can, for example, be an alkali metal hydroxide and the reaction is preferably carried out under reflux.

It should be noted that the heterocyclic compounds used as starting materials in the above processes all can be produced by generally known processes «

According to a further feature of the invention, pharmaceutical substance compositions are proposed which have a heterocyclic Compound of formula

-CR ¹ R ² R ³

Ά '

wherein Y denotes a phenyl, or Monohalogenphenyl- Dihalogenphenylrest, wherein the halogen substituents are selected from fluorine, chlorine and bromine atoms, and either

1 2

R is a methyl radical, R is hydrogen or a methyl, C " _ß -alkoxycarbonyl-, benzyloxycarbonyl or phenoxycarbonyl radical and R" is a carboxy, G ₂ _g-alkoxycarbonyl, bonsyloxycarbonyl or phenoxycarbonyl radical and, if R ^ is a Co ^ G

009836/2201 SAD ORIGINAL

"5 carbonyl, benzyloxyearbonyl or phenoxycarbonyl radical let, Er

1 2 denotes the same residue »or R and E. both hydrogen and Br denote a carboxymethyl, O »" -alkoxycaxbonylmothyl ", bengyloxycarbonylmethyl or phenoxyoarbonylmethyl radical and A denotes an oxygen or sulfur atom, or a non-toxic pharmaceutically acceptable salt thereof and an inert, non-toxic, pharmaceutically acceptable carrier or diluent contain.

The pharmaceutical compositions of matter. can, for example, in the form of bosing units; such as tablets, pills, capsules or suppositories or in the form of non-sterile, aqueous or non-aqueous solutions, or suspensions, sterile in soluble aqueous or non-aqueous solutions or suspensions, creams, lotions or ointments, bladder ingredient compositions can usually The pharmaceutical compositions can, if desired, additionally contain a known agent which is anti-inflammatory and / or analgesic, for example aspirin, paracetamol, codeine, chlorocinin, phenylbutazone, oxyphenbutaaon, indusiethacin , Mefenamic acid, Flufenamic acid, Ibufenao, or an anti-inflammatory steroid such as Prednlsolotto hylbromid and / or an antacid, such as Aluminiumhydroiyd, or haratfeÜ "·" - όΛΜ means, such as probenecid, contain _o Those 3toff3UßBÄmensetzung6n which determines for topleche application »ind, in addition, if desired, a vaeodilatoiilsahee means beiepielsweiae Tolazolin, or

009Ö36 / 2I01

^ t-; ⁵ O 8AD ORIGINAL

Means »such as adrenaline, a local anesthetic, "for example amethocaine or an anti-irritant, for example Capsikum contain and / or at least one agent selected from the class of the following compounds: antibactericidal agents, including Sulfonamides and antibiotics, which is an antibactericidal Have an effect, for example neomycin, antifungal agents, for example hydroxyquinoline, antihistaminisclie agents., for example promethasin and redness SEdttel, for example Methyl nicotinato.

The invention is explained in more detail in the following examples:

example 1

Ethyl-5-p-chlorophenyl-i, 2,4-oxadiazol-5-ylacetate (10 g) was added to a stirred suspension of sodium hydride (1 g) in troubal dioxane (15OCu ¹ So). » After 5 minutes, methyl iodide (6g) was added to the thick slurry and the mixture was stirred and refluxed for 30 minutes. The mixture was cooled and an additional 1 g of jiatrium hydride was then added and after an additional 10 minutes 30 B of methyl iodide. The resulting mixture was refluxed for 1 1/2 hours, cooled, and filtered. The FII appeared was evaporated in vacuo, diluted with petroleum ether (boiling point 60 to 80 ⁰ C, 300 com), and the extract was evaporated in vacuo to give crystals, soft at (60 to 80 ⁰ C boiling point) naöh recrystallization from petroleum ether -50 ⁰ C the methyl ~ ce (3-p-chlorophenyl-1,2,4-oxadiaj2ol <~ 5-yl) ~ isobutyrate with a melting point το «. 53 to 54 ⁰ C to result.

The methyl 3-p-chlorophenyl-1,2,4-oxadlazol-5-ylacetate used as the starting material was made by the following procedure;

009030/2201

^; - '^ ^! · ^ I /. - 8ADOHiGlNAL-. -. /

p-Ohlorbenzamidoxim (ΐβ g) and Dimethylmalosat · (62 g) were rückfluSbehandelt in 200 cc of xylene and the steam in a 12 ^ fractionation guided * which was filled with Dixonringen WXD ₀ Ifethanol »Water Zvlol were slowly distilled off until only pure xylene 2o * ücMuieb ₉ which, after 5 hours DER case was "the rest Liehe xylene was evaporated from the mixture in vacuo and daa resulting oil was fractionally distilled in" vacuo to give methyl ~ 3 ~ r ~ chlorophenyl-1 ₉ 2 _f 4 ~ oxadia2ol-5 ~ yl acetate with a boiling point tq ". 151" to 156 0/1 mm acid result ".

Example .. ^
5 g

s a suspension Ύοη 0.33 ß Katriuiohydrid in 60 cc of dry-Jceneir Dirnethylsulfoxyd added under .Rühren "H & eh 1 hour were 9 3 _r ^ S methyl iodide sugesetzt vnö. the rülir treatment. Banned for 2 days. The mixture was poured into 250 g clay mixture ein® 3IS and 250 cc of water "and three times with 200 cc of ether extrohJ.ei-t _n D3e combined extracts was determined using Wassertr n.ew sodium sulfate getrcoknet. Vrnu. Ohromatogi by-aphie. ir. · orlner Aluii; iniumoxydkoloni? .e (230 χ 25 now) cleaned with 400 ecm Jithex «The solvent -urde from the cleaning liquid sigkoli abjg.eieffipftj lain an oil!? u result ₉ riach the Uiakrietalliaiereai from petroleum ether ( Boiling point 60 to 80 ⁰ G) at -70 ⁰ O]) i ätbyl ~ o? - (3 "-p-chlorophenyl ~ 1 ₁ 2 _? 4""t

a "ücliißelapunlct" of 37 to 39 C sau result

Ali3 Auegsoigsinatfcrial used malonate (Schc.elzp'xnkt 129 to 131 ° C) wxrAe. in a manner analogous to the well-known 3- ~ £ heny! connection hex gfiüt r rushes.

009836/2201

BATH OR161HM.

Example 5

16 g 3 ~ p-oleophenyl-5-a1; hyl-1 _? 2 _{s of} 4-oxadiasol were refluxed for 3 hours with 20 g of sodium hydride in 1.60 ecm of dimethyl carbonate. The mixture was poured in small portions into 1200 g of ice. and then extracted three times with 200 ocm ether each time. The organic extract was washed with water then dried with anhydrous sulfuric acid and "The solvent was evaporated in vacuo, au give a Ql _f the Metliyl-0 ^ of ^ - (3-p - chlorophenyl ~ 1 j, 2i, 4" O2: adiazol * -5 ~ yl) ~ propionate au result (R "-" value O ₉ 6, thin-layer chromatography in silica * treatment liquid Benaol) ο

Example 4

The methyl ester obtained according to Example 3 was stirred for 2 hours with 200 ecm 2 η sodium hydraiside and treated on the Rüokflusskühllei * The mixture was then cooled and washed three times with ^ e 100 ecm ether. The aqueous solution was acidified with 2 η hydrochloric acid and three times extracted with 200 cc of ether * the ether extract was washed with water, dried with anhydrous sulfuric acid and the solvent ™ was evaporated in vacuo "the solid residue was au: 3 petroleum ether (boiling point 100 MS 120 ⁰ C) umlcrista3J.isiert _r; to cf- (3-p-chloro ~ phenyl-1,2s4-oxadla2; ol ~ 5-yl) -propion3äui'e with a melting point of 95 to 96 ° G au ,, ■

The heterocyclic starting material (melting point 25 till 42 ⁰ G) in an analogous manner as the known 3 '"Phe: ayl-5-niethylTerbin & ung prepared

Example 5

In the same way as described in Example 2, under

009836/2201

CUuä BAD ORlGINAU

Use of Dijaethyl ^ ~ (3 ~ p-chlorophenyl ~ 1, 2 ₉ 4 ~ thiadiasol-5 »» yX) -malonate the dimethyl-0f ~ (3-p = ohlorphe2iyl-1, '2 »4-thiadiasol-5- yl) -of-methylmalonate obtained _o The product was obtained from the H-methylated material by fractional crystallization from PetrolSther (boiling point 60 to 80 ⁰ ) "at -60 ⁰ G and it had a melting point of 64

Example 6

In a manner similar to that described in Example 1, when using methyl-Cr (5-p-chlorophenyl-1,2 _> 4-oxadiazol ~ 3-yl) -. acetate as starting material, crude methyl - (> (5-p-chlorophenyl-1,2,4-o3: adiazol-3-yl) isobutyrate obtained mm diameter and 300 mm long) was diluted with benzene in 20 cc fractions purified ₀ the fractions YO Ms 26 e, the oily product (If tfcielten ₀ m ₀ R, spectrum T ^ I »8 m to 2.7, 4H | aromatic ring, ^ 6.2S ß> 3H _f OH ₃ O-, <# 8.3 s,. 6E, ^

The one as an exit aiaateria! The ethyl ester used was as follows manufactured

118 g of Oi-Oarbamoylacetamidoxim were dissolved in a mixture of 4 liters of water, 120 ecm 2 η sodium hydroxide and 120 cem p-chlorobenzoylochloride and the mixture was stirred vigorously for 1 hour. «. Chlorobenzoylacetamidoxime was filtered off, washed twice with 250 ecm 2 of sodium hydroxide each time and then twice with 250 oa water each and dried at 10O ⁰ C
better a melting point of 163 to

The product obtained in an amount of 83 g became i »3 liters of xylene

Dried Waeeer washed and dried at 10O ⁰ C. The receiving product

009136/2201

■, w ;; rW üf-Ä. BATH

1946633

Refluxed for 4 hours, the mil; was fitted with a Bean and Stark attachment to separate the water ”. At the. Cooling separated out crude 5-p-chlorophenyl-t, 2,4 ~ oxadiazol-3 ~ yl-acetamide and was filtered off »The crude material was purified by recrystallization from aqueous dioxane and then had a melting point of 209-211 G ₀ 33g this amides were stirred in 1.2 l of dry methanol and dry hydrogen chloride gas was passed through for 20 minutes, the temperature rising ^{to ^ 36 ° C.} After 4 hours, the resulting solution was poured out onto 3 kg of bis and the precipitated solid was filtered off and crystallized from methanol to give methyl- <X- (5 ~ p-chlorophenyl-1,2,4-oxadiazal-3-yl) - to give acetate with a melting point of 103 to 104 ⁰ C «

Example 7

A mixture of 8.5 g of p-chlorobenzamidoxime and 5 g of succinic anhydride in TOO ecm xylene was treated for 5 hours in the reflux condenser, which was provided with a Dean and Staate attachment to separate water from the reaction mixture. The Reaktionsmiachung was then cooled to room temperature and filtered W, and in this way a solid residue which SS (3-p-chlorophenyl-t, 2,4 ~ oxadiazol-5-yl) propionic acid having a melting point 144-146 ⁰ C received.

Similarly, when p-bromobenzaridoxime was used instead of p-chlorobenzamidoxime, β- (3-p-bromophenyl-1,2,4-oxadiaaol-5-yl) propionic acid with a melting point of 157 to 160 ° C. and at using 2,4-Dichlorbenaamidoxim instead of p-Chlorbenzamidoxim was the _.beta.-J ^ - (2,4-Dichlorphönyl) -1,2,4-oxadiaztol-5-yl / propionic acid having a melting point of 135-136 ⁰ C. obtain.

009836/2201

8AD OBiOiNAL

- 15 -

Example 8

2.5 g of β- (3-p-chlorophenyl-1? 2,4-oxadia2ol-5-yl) propionic acid was dissolved in 50 ecm of methanol, and dry hydrogen chloride gas was bubbled through the solution for 15 minutes. The reaction mixture was kept at room temperature for 3 hours and then filtered to obtain a solid residue. Methyl ~ ß- (3-pchlorphenyl-1,2,4-oxadiazQl-5-yl) propionate with a, oil point of 90 "to 91 ⁰ C after recrystallization from methanol give

Example 9

0,4β g S-chloroethyl-Sp-chlorphemyl-i, 2,4-oxadiazole in 1 cc of dry dimethyl sulfoxide were added to a solution of O _s 35 CX-Sodiodiäthylmalonat g in 5 cc of dry dimethylsulfoxide eye sets, 'The mixture was stirred for 1 hour at Stirred at room temperature, diluted with 10 ecm 6 η sodium hydroxide solution, stirred again for 1 hour and then washed three times with 20 ecm ether each time. The aqueous layer was acidified to a pH value of 1 ~ 4 η hydrochloric acid, heated for 15 minutes to 70 ⁰ G and then cooled to 0 ° C The resulting precipitate of crude .beta. (3 ~ p ~ 0hlorphenyl-1,2,4 Oxadiafc-l- »5-yl) propionic acid was filtered off and purified by extraction with 5 ecm 2 η ammonium hydroxide, whereupon the extract was acidified with 2 η hydrochloric acid to a pH value of 1 at ^{0 0} O. The melting point of the purified acid was 145 to 146 ⁰ C ₀

The sodium salt of this acid was obtained as follows:

2.24 g of β- (3-p-chlorophenyl-1,2,4-oxadiaaol-5-yl) propionic acid were dissolved in 100 ecm of ether and an aqueous solution of 1 ecm 10 η sodium hydroxide was added to the solution under pipes. The resultant precipitate was filtered off and n & t

009836/2201

6AO ORIGINAL

Ether well washed xm the latriujEsala su result _t that one Sehmelspimkt over 300 ⁰ C possessed

The corresponding caleiumsal was made as follows:

2 _f 5 g of the above Uatritims & lzes were dissolved in 50 cc of water and the solution mirde a solution of 10 g Caleiuinchloriddihydrat in 100 cc of water was added. The precipitated Galciumsalz was abf 11 _s trated washed with water and dried in Yafcium about Phosphorpemtoxyd. In this way Ca3.ei "ü3H-ß_ (3-p-chlorophenyl" -1.2 "4-oxadia2Ol-5-3 ^r l) -propionate tetralydxate with a Schmelaprai & t of 200 to 23O ⁰ C (slow water loss) obtain.

ExampleJO

A mixture of 150 g of 3) ethyl »0 ^ - (3-p - chlorophen3'-l ~ 1 _f 2 _f 4-thia ™ dia! 3ol" -5-yl) -c4 »met} iylaalo2? .At - and 300 g corn starch vnirde with a sufficient amount of HO Joiger (weight / Voltuaen) starch paste

Granules were passed through a 20 Maschensiob and whether gotroclcnet "at eiaer Toffiperatur% On ^ c G," The dried granules were mixed with 4 g ^{Magnesiuiratearai;?.} Mixed overall "and su icomprimiert tablets which V} 0-750 ng da" active ingredients contained. The older table-vtaa are suitable for oral administration for therapeutic purposes

Instead of the Dx & iüiyl ~ 0f- (3 ~ p-clilorpheny 1-1 _s 2,4-tli3.adiaa ol-5 "* y 1) Οζ-inethylmaloaatswui'de with the same weight i3" (3 ~ p- "Glorpkenyl -1, 2 _s 4-osadiaRel-5-yl) - p?. Opionic acid geai-baitt'sr and in this way tablets were obtained in an ataJLieher manner which are suitable for oral administration in the therapeutic area ",

009836/2 201 SAD ORIGINAL

Claims (1)

Claims ι 1o j & Lne heterocyclic compound of the formula wherein Y is a PhenyX-, HonohaXogenphenyX- or DihaiogenphenyX-rest bezeiohnet, wcbei the HaXogensubstituenten are auegewählt from fluorine, chlorine and bromine atoms "and wherein either E a MethyXrest» R ² is hydrogen or a methyl, C ₂ _ ₆ -AXkoxycarbonyX * ", BeausyXcocyearbonyX- or PhenoxycarbonyXrest and R a carboxy-, Q ₀ ^ -AXkoxycarbonyX-, BensyXoxycarbonyX- or fe "* o ο Phenoxyq «rboöyXre» t denote, and if R is a C _2ee g ~ AXkoxy- oarbonyi-, Benzyloxycartonyl- or Phenosycarbonylreetjiet, R ³ den 12 '3 the same radical denotes »or R and R are both hydrogen and R a CarboxymethyX-, C ~ "-AXkoxycarbonylinethyX- ,. Benayloxy 2 "'' oeaeichnen» carbonyXmethyX- or PhenoxycarbonyXmethyXrest'mw A denotes a Sauer- et off- or sulfur atom, or non-toxic pharmaceutically usable substances dereelbei, but exclusively ß - (^ PlienyX-t, 2 _t 4 * <«adia« oX «-5-yX ) -propioneers and <! "# Ethyl ester of these 2 · Connection according to claim t, characterized in that Y is a PhenyX-, fXuorpbenyX-, GfcXorphenyl-, BroaphenyX- or 1 2 Mohlorphenylreet and either R a Methylreat, R hydrogen or a # n methyl, Möthoxyoarbonyl-, Ithoxycarbonyl-, Beaizyl oxy carbonyl or Phenoxy oarbonyXröst and Br a carboxy, Kethoxycarbonyl-, Äthoxycarbonyl-, Bonzyloiycarbonyl- or Phenomycmrboylreet, and if be a methoxycarbonyl-, ithoiycarbonyl-, Benayloxycarbonyl- or Phenoxyoarbonylreatiet, 009836/2201 _{W (WWL} 13 - ^ 12 R ^ denotes the same radical, odor R and R both hydrogen and R a carboxymethyl, methostycarbonylniethyl, ethoxycarbonylmethyl, benzyloxycarbonylmethyl or phenoxycarbonylmethyl radical and Jk denotes an oxygen or sulfur atom or a non-toxic pharmaceutically acceptable salt of this compound, however, with the exception of τοη ß ~ (3 ~ phenyl-1,2 _s 4-oxadiaaol-5 ~ yl) ~ .propionic acid and its ethyl ester » 3o connection according to claim 1 or 2, characterized in that ™ that Y denotes a monohalophenyl or dihalophenyl radical. 4o A salt of the compounds according to any one of claims 1 to 3? characterized in that this is an alkali metal salt, alkaline earth metal salts Aluminum sala or ammonium sai or a salt with a non-toxic pharmaceutically acceptable organic base. 5.Dietnyl-O (- (3-p-chlorophenyl-1 ^^ - thiadiaaol-S-ylJ-Oi-methylmalonate, 6o Wethyl-OC- (3-p-chlorophenyl-1,2,4-oxadiazol-5-yl) propionate 7o methyl-oi- (5 ~ p-chlorophenyl-1,2,4-oxadia25ol ~ 3-yl) isobutyrato 8 _O .beta. (3-p-chlorophenyl-1 ,, 2 _s 4-oacadiazol-5-yl) propionic acid ~ ₀ 9 “Process for the preparation of compounds of the formula R ¹ I ₂ 009836/2 2 01 8AO ORIGINAL 1 7
in which A, Y, R and E "have the meanings given in claim 1 and R denotes a C.sub.1 -C -alkyl, benzyl or hienyl radical, characterized in that an alkali metal derivative of a compound of the formula H -ST wherein A, Y, R and R have the meanings given above, with methyl chloride, bromide or -; iodide is reacted _o 1Oo process for the preparation of compounds of the formula NR ¹ I Il » R ⁵ wherein A, Y and R have the meanings given in claim 1, 4. " R has the meaning given in spoke 9 and R is hydrogen or a methyl red denoted by the fact that a pre-binding of the formula ir ι 5
wherein A, Y, B and R have the above meanings angsgebenen _f with sodium potassium odor odox · _r a Hydrad amide or C ^ ^ -Alkoacyd 0098 36/220 StHO * 3A & BATH ORIGINAL the same and a carbonate of the formula GOe (OR) «, in which R ^{4 has} the meaning given _{above o} Process for the preparation of compounds of the formula where A _? Y and R have the meanings given in claim 1 and c R has the meaning given in claim tO or wherein -CR R- means; · the group -CH ₂ CH ₂ - / and non-toxic pharmaceutically acceptable salts thereof, characterized in that a compound of the formula . R ¹ - C-R ° I ₅ 15 ■ h in which A, Y, R and R- ^ have the meanings given above and R denotes a cyano, carbamoyl, G ₀ , .- alkoxycarbonyl, phenoxyoarbonyl or benzyloxycarbonyl radical, is hydrolyzed _e 12o Process for the preparation of compounds of the formula wherein Y has the meaning given in claim 1, as well as of poisonous phannazeutisoh applicable to salts thereof, thereby g © ~ 009.83 6/22 0 1. BAD OBiQlNAt denotes g that av.s a compound of the formula YC-HH ₂
1.0 ο GO, wherein Y has the meaning given above, removes water 13o Process 2 for the preparation of compounds of the formula CR ¹ R ⁵ R ⁷ wherein A "and Y have the meanings given in claim 1 1 «5 and either R is a methyl radical _f R is hydrogen or a Methyl radical and R a G ₀ r -alkoxycarbonyl-, benzyloxycarbonyl- d "~ o ₁ c 7 or Phenoxycarbonyi.rest, or R ¹ and Br hydrogen and R is a C ~ ^ -Alkoxyearbonylmethyl-, Benzyloxycarbony! methyl- odor Phenoxycarbonylmethylrest denote gekennaeichnocj ₅ characterized in that the corresponding carboxylic acid or a salt thereof esterified Process for the preparation of compounds of the formula N, viorin A and Ύ have the meanings given in claim 1 1 1 and either R denotes a methyl radical or -CHR ~ is the group -CHgCHg-, in that a compound of the formula 009836/2201 BADOBTOlNAL _ 22 -. -YY Ij wherein A and Y have the meanings given above, R has the meaning given in claim 9 and either R is a methyl radical or -CR = the group -CH ₂ O CH = is ^ with a strong inorganic base in the presence of water and under the action of heat is implemented o 15e A pharmaceutical composition of matter comprising a heterocyclic compound of the formula wherein Y is a phenyl, monohalophenyl or dihalophenyl radical where the halogen substituents are selected are made up of fluorine, chlorine and bromine atoms, and either R is one »2
Methyl radical, R is hydrogen or a methyl, C ₂ _ £ -alkoxycarbonyl, benzyloxycarbonyl or phenoxy carbonyl radical and R is a carboxy, C ", - alkoxycarbonyl, benzyloxycarbonyl or α — ο 2 Phenoxycarbohyl radical, and when R denotes a C ₂ g-alkoxycarbonyl, benzyloxycarbonyl or phenoxycarbonyl radical, R '' is the same radical ₉ or R and R are both hydrogen and R ^ a carboxymethyl, C ^^ - alkoxyoarbonylmethyl, banzyloxycarbonylmethyl or Denote phenoxycarbonylmethylrost, and A is an oxygen or sulfur atom, or non-toxic pharmaceutically acceptable salts thereof and an inert, non-toxic pharmaceutically acceptable diluent or carrier. 009836/2201
ORIGINAL 16ο A composition of matter according to claim 15 in the form of tablets, pills, capsules, suppositories, non-sterile aqueous or non-aqueous solutions or suspensions, sterile injectable aqueous or non-aqueous solutions or suspensions, creams, lotions or exercises ₀ 17. St off composition according to claim 15 or 16, characterized characterized in that it also contains a known agent that has anti-inflammatory and / or analgesic activity 18. Substance composition according to claim 17 for oral administration, characterized in that it contains an anticholinergic agent and / or an antacid or diuretic agent 19ö substance composition according to claim 17 for topical administration, characterized in that this is a vasodilator or vasoconstricting agent, a local anesthetic or an anti-irritant and / or at least one agent is selected contains from the following classes of substances: iacterieide, Fungicides, Antihletastiniea and skin reddeningrai-ttal MTWTANWXL TE eiWN ».H.FINCItt DIPL-ΙΝβ. H.! EAR DIH - INQ!. «TAKER 009836/2201