DE1493426A1 - 4'-tert-Aminoalkoxy-biphenyls substituted in the 4-position - Google Patents

Description

DR. I. M. MAAS

DR. W. G. PFEIFFER 193-26

PATENIANWSLTB ι ** ^ s / -τ «- ν

MÖNCHEN 23 P 14 93 426.0 ÜNGERERSIE. 25 - TEL »C236

Documents (Art 7 § 1 Ate. 2 No. 1 Clause 3 of the amendment oea .

American Cyanamid Company Wayne, New Jersey, V, St _e A,

S88S8SSBSSSSSS8SSSSSSSSSSSS

^ * - tert - Aminoalkoxy-blphenyls substituted in the ^ -position

The invention relates to substituted in ^ -position V-terto-aminoalkoxy-biphenyls and their preparation · The Compounds according to the invention are new and can be represented by the following general formula

? i? 2
- OCCN

U.

are reproduced «In this formula: Z denotes a halogen atom, a nitro, lower alkanoyl, carboxy« lower carbalkoxy, trifluoromethyl, sulfonamide, methyl

sulfonyl or 1-hydroxy-1-methyl-2-propynyl group; R ₁ , R ₂ * R3 and R ^ j hydrogen atoms or methyl or ethyl groups which, together with alkylene groups to which they are bonded, contain up to 6 carbon atoms; R- and Rg

_o lower alkyl groups or together with the nitrogen atom,

to which they are bound, a pyrrolodin, piperidino, morpholino, thiomorpholino or a 1-plperazino group substituted in the 3-position by a lower alkyl radical.

New documents (Art. 7, Paragraph 1, Paragraph 2, No. 1, Clause 3 of the Ä-Jc-unasges. V. 4. 9.1W7.

BATHROOM ORIGINAL

The lower alkyl and lower alkanoyl groups which come into consideration in the context of the invention and eolohe Alt 1 to 4 carbon atoms, z «B * methyl, xthyl, n-propyl, Ieopropyi or a butyl or, acetyl propionyl or n-butyryl« Suitable lower carbalkoxy groups unite with I bis 6 carbon atoms, ζ, Bo Carboaethoxy or Cavbäthoxy * Suitable halogens are, for example, chlorine, bromine or iodine.

Atherosclerosis-iat a form of arteriosolerosis in which Cholesterol and lipoid substances are deposited in the form of plates on the intimate area of large and medium-sized arteries- with the arterloscleroae did a degenerative change in the Arterial walls are connected by processes that are not yet clearly known. However, there is a statistical relationship between hyperchdesteremia and the occurrence of

Disruptions. For some time it became ale

viewed favorably, high cholestarin and lipoid levels in the People as a possible preventive measure against

Athero-oleroea has been attempted to lower the oily sterol level in the blood by the oral administration of certain substances commonly referred to as hypocholesterolemic agents. Typical of such substances are lecithin, cotton-wool oil and male oil.

909817/0748

BATH ORIGINAL "'

Xe has now been found that the erbältlichen according to erfindungsgeaäßen method new, substituted in 4-3teilung 4 "-tert .. ~ aminoalkoxy biphenyls ale aueüben hypocholeeteränlsche a stronger effect of the agents used bieher" Ee not let known manner in which the inventively. available novel compounds lowering dee Choleeterlnepiegels in ülutserum cause "

It was also found that "* -trinuor" described in Example 12, ethyl-V- (2-pyrrole-dinosthoxy) -biphenyl and its acid addition and quaternary compounds are effective anti-inflammatory agents and can be used for the treatment of malignant prostheses in humans . The dose of island or daily dose to be administered below is about up to 500 ng of effective sub et anhexogen on the oily seed of the person treated below.

The organic bases obtainable according to the invention form non-toxic acid additions and quaternary acid additions with a large number of organic and inorganic, as-forming reagents. Acid addition salts are obtained in this way, which form by mixing the free organic base with an acid in a neutral solvent, for example the following acids; Sulfuric acid ₉ phosphoric acid, hydrochloric acid, bromine-phenolic acid. Sulfamic acids

90981 7/0748 BAD ORIGINAL ^

Lemon, milk, apple, amber, wine, Bseig, Bensoe, Know gluoon and ascorbic acid «quaternary» ammonium salts by tJmsetung the free baaen with sahlrelohen organieohen Esters τοπ sulfuric acid, hydrohalic acids and aromatic sulfonic acids «earth. The sur manufacture quaternary ammonium salts used organic reagents are preferably lower alkyl halides, Jedooh are auoh other organic reagents for the preparation of quaternary Ammonium salts suitable. Examples of this are bensyl chloride, Phenäthylohlorid, Vanhthylsiethylohlorid, Dimethylsulfat, Methylhensol sulfonate, ethyl toluene sulfonate, allyl chloride, Methallyl bromide and orotyl troid. The free bases are Their non-toxic acid addition and quaternary acid addition salts are equiral.

The compounds obtainable according to the invention are substances the duroh recrystallization from common organic solvents, see B. Xther, acetone or bensol, cleaned «earth can. They are lsi general in fasser insolioh, jedooh Relatively soluble in organic solvents, see B. lower alkanols, prayers · Xthem. Ketones «bensol, toluene or chloroform. The acid addition and quaternary amino acids are the organic bases obtainable from the invention Generally crystalline tea substances, Tsrhaltnlsmä01g Löilioh in water, methanol and Xthanol, but Ysrhabenaäeig

909817 / 07A8 BATH ORIGINAL

unlöelioh In nonpolar organlaohen solvents, β 'Β · Xther, Bensol or toluene "Am Torteil the erfindungagemäß erhältllohen connections iat their effectiveness when given orally" You can _y belapielaweiae with an inert diluent or old one aeeimilierbaren genuJfähigen carrier, in hard or soft Selatlnekapeelna or ala tablets can be administered orally. Ausgedrucktt for the total weight of the daily Dosierungaeinheit Bwieohen is usually about 0 ₉ 1 to 1.0 go

The new compounds can be easily implemented by implementing the Sodium or potassium salts one substituted in 4_division 4 'Hydroxydiphenyls are prepared with an appropriately substituted tertiary aminoalkyl halide, as described in the following action topic is given 1st;

909817 / 07A8

U93.426

in which B is sodium, potassium or hydrogen, I is halogen or hydroxyl and Z, R ₁ , R ₂ t R ^ * R ^ t ß «and R ^ which have already defined meaning. This is Umse'tsung Yorsugeweiee, iB τοη in a "lower alkanol, dioxane, tetrahydrofuran or toluene at temperatures up to UO ⁰ O on in a period ▼ in a" solvent about 80 about 1 bie 48 hours or Aehr performed Venn * \ X is a Hydroxyl group and B is a hydrogen atom, the conversion is preferably carried out in the presence of an "entepreotoend substituted tert" -aminoalkanol _{9, for} example 1, N '^ dioyolohexyloarbodiiaid.

Are used for therapeutic application, erfindungegeaäS erhältliohen active compounds with carriers and can rermieoht beiepieleweiee in form τοη tablets, Täfelohen, capsules, elixirs, suspensions, syrups, wafers or Kauguaal used "Solohe Zueamaeneetsungen and preparations should contain at least 0.1 $ of the active compound. The prosentual proportion in the masses and preparations can of course be changed and is usually about 5 to 75 H or more of the weight of the dosage unit. Preferred masses or preparations become

909817/0748

• ο produced, AaB · 1η · Doeierungeelnhelt about 10 bia Contains 200 mg of active compound.

The tablets, tablets, pills or caplets can contain the following ingredients: a binding agent, beieplelewelee tragacanth, loacie, corn starch or gelatine, an agent that promotes disintegration, e.g. You can use a sweetener, b »B. 8aooharoee or Saaoharln ». Or an Oeeohnaoketoff, beitf • pielewelee Ffeffernins» WintergrUnOl or Kireoharoaa au- • etsen. A syrup or an elixir can contain the active compounds in the form of their non-toxic 8 acid additions, such as "Saooharoae all sweeteners, methyl" or propyl paraben, all concentrating agents, a color and a Geaohmaok pot, for example a cherry or orange flavor. ,.

The following examples explain the invention * without ale

to restrict

EXAMPLE 1

Sine suspension of 0.4 g sodium hydride (50 »9 ^ -ig» suspended in mineral oil), 2.1 g 4 ~ brom ~ 4 '~ hydroxybiphenyl and

909817/0748 BATH ORIGINAL

U93426

50 ml of dry toluene was refluxed for up to 2 hours. The sodium derivative of 4 ~ brom ~ 4 '~ -hydroxybiphenyl was added 1, 4 g of Ν, Η-diethyl-2-chloroethylamine and the reaction was kept under reflux for a further 90 hours * After cooling, the suspension was filtered, the clear filtrate was concentrated to a solid residue and the crude product was dissolved in 200 ml of ether. The ethereal extract was decolorized with activated charcoal, dried over anhydrous sodium sulfate and treated with dry hydrogen chloride ^ου .

Example 2

Following the procedure of Example 1, 1.72 g of 4-hydroxy-4'-nitrobiphenylp, 0.4 g of sodium hydride and 1.4 g of N, N-diethyl-2-chloroethylamine in 200 ml of dry toluene and 75 ml of n-amyl alcohol were added erhitst hours under reflux * the crude product was recrystallized twice from a Xther / petroleum ether LÖeung umkrietallialert and afforded the desired 4 ~ (2-diethyl-aminoethoxy) 4'-nitrobiphenyl _f Sohmelspunktt 49 ** 5O ⁰ C ₄

909817/0748

BATHROOM ΟΝΟΙΝΑΙΐΑ »Γ?: Γ {> - '

Example 3

! times the procedure and working up described in Example 1 were added 5 »0 g of the potassium derivative of 4 Hydroxy = ^4} -nitrobiphenyl and 3.3 g of N, N-diisopropyl ~ 2 ~ ohloräthyleein in 200 ml of dry toluene and 75 Bl η-amyl alcohol Heated under reflux for about 1 hour. After recrystallizing twice from Xther / petroleum ether, the crude product yielded the 4 ~ (2 diieopropylaralnoethoxy) -4 'nitrobiphenyl, melting point? 50 51 ⁰ cn

Example 4

A mixture of 6.8 g of 4 bromine ~ 4 '~ hydroxybiphenylp 4.2 g 2-Dimethylamino-2-methyl-1 "propanol and 6.8 g of NpH'-Dioyolohexylcarbod LiHLid were 8 * ■ 20 in a closed tube After cooling, the semi-solid residue was dissolved in Xther, separated from the uniösliehen Ν * Ν 'dicyclohexylurea by filtration and removed from the ethereal Piltrat a tubular mixture of isomers by concentration won. The crude isomers thus obtained were separated by partition chromatography and their structure was determined kernmagnet! see resonance cleared up. Kit this way of working

909817 / 07A8 BAD ORIGfNAi,> ^ Γ

U93426

- ίο -

4 ~ bromine ~ 4 ^l - £ (2-dlmethylamino 2,2 ~ dimethyl) ethoxy / biphenyl and 4 bromine 4 'L (2-dimethylamino ~ 1, 1-dimethyl) -Xthoxy / biphenyl could be isolated from the same reaction mixture.

Example 5

Following the procedure described in Example 4 , 5.4 g of 4-chloro 4 '~ hydroxybiphenyl, 4.2 g, 2 ~ diaethylaaino-2 methyl 1-propanol and 6.8 g of H _S N ⁵ dicyclohexyl-oarbodiimide were obtained

in a sealed tube 48 hours at 100 ⁰ C erhitst "The gewUnsohen isomers, 4 ~ Chlo2 ^ 4 ⁱ ~ [(2 ~ dieathylajnino ~ l, l ~ dimethyl) -äthoxyj biphenyl and 4-chloro-4 ⁷ - f (2- dimethylaaino -2,2-dimethyl) ethoxybiphenyl, were isolated with the help of a column filled with dlatomaceous earth (Celite) and a solution medium system of ethylene glycol monomethyl ether / n-heptane,

Example 6

A suspension of 10.2 g of the potassium salt of 4 ~ hydroxy-4 · - nltrobiphenyl, 5.4 g of N, K-dimethyl-1-methyl-2-chloroethylamine in 100 Ä ethanol and 100 al water was under for 15 hours RüokfluB heated, ethanol and water were removed under reduced pressure on the steam bath, leaving a semisolid

909817/0748
BATH ORIGINAL

U93426 --ff-

Residue · 01 · organic substances were extracted twice with 100 ml of dry ether each time and the ethereal extract, after being decolorized with activated charcoal, dried over anhydrous sodium sulphate and concentrated to a low-melting yellow solid residue. The Verteilungsohromatophie (diatomaceous earth} Vethoxyäthanol and n-heptane) afforded 4- £ (2 ~ Dlmethylamino-2-methyl) -4 -äthoxyj ^v -nitrobiphenyl (Sohmelspunkt 62-64 ⁰ O) and 4- £ (2-dimethylamino -methyl 1 ) ~ ethoxyj 4 * -nitrobiphenyl In approximately equal amounts _o

Example 7

Following the procedure of Example 6, 10.2 g of the potassium were obtained SalBSS of 4-hydroxy-4'mtrobiphenyl, 5.4 g of H, H »dirnethyl- 1,1-dimethy1-2-chloroethylamine in 100 ml of ethanol and 100 ml

Water obtained under reflux for 15 hours * In the case of the above

The work-up described was an Ieomer "Ctemleoh 4- [(2-dimethylamino-2,2-dimethyl-ethoxy] -4 '-nitrobiphenyl and 4- f (2'-dimethylamino-1,1-dimethyl) ~ ethoxyj-4 · -nitrobl phenyl (SohmelBpunkt 74 -? 5 ° C) isolated.

Example 8

According to the example! The procedure described were 6.0 g of 4 "acetyl-4 ^f ~ hydroxybiphenyl, 1.2 g of sodium hydride (54 # 7 effective content) and 3 * 8 g of N, H-diethyl-2-chloroethylamine

909817/0748

heated under reflux in 60 ml of toluene and 30 ml of η-amyl alcohol for 16 hours. The crude product obtained in this way was recrystallized from an ether / petroleum ether solution and gave the desired 4-acetyl-4M2-diethylaminoethoxy) -biphenyl (melting point 113-1U ⁰ C),

Example 9

4- (2-Diethylaminoethoxy) * biphenyl-Bagne8ium-broinid (prepared from 7.6 g of 4-bromine-4M2 -diethylSyninoethoxy) -biphenyl and 0.5 g of magnesium in 20 ml of xther and 10 al of tetrahydrofuran) was solidified to 200 g Poured carbon dioxide. The semi-solid product thus obtained was hydrolyzed with cold dilute hydrochloric acid. The aqueous layer was made alkaline, extracted twice with 100 ml of Xther each time, decolorized with activated charcoal and then adjusted to a pH of 6-7 by adding dilute hydrochloric acid in portions. A crystalline substance separated out on standing. This was filtered off, dissolved 'in anhydrous methanol and acidified with anhydrous hydrogen chloride, the desired Monohydroohlörid of j 4-Garboxy ~ 4 ^l -. (2-diäthylaainoäthoxy) ~ biphenyl)' separated out in the form of colorless grains from Schmelspunktt 261 -. 262 ⁰ C (softening at 26O ⁰ C) ₉

909817/0748

~ 13 - ■
Example 10

4-acetyl-4 '~ (2 <diäthylaminoäthoxy) biphenyl (4T9 g) was added a solution yon Lithiumaoetylid JBU In flüaeigem ammonia at -70 ⁰ C (the Lithiumaoetylid was prepared from 0.3 g of lithium «50 ml of liquid ammonia and excess dry Acetylene produced) and the suspension shaken for 18 hours at room temperature in a sole autoclave. The reaction mixture was then removed from the autoclave and the excess ammonia was evaporated in a stream of dry nitrogen. About 3.0 g of ammonium chloride were added to the residue, and the crude product was extracted twice, each 200 ml of ether. The ether extracts were combined and washed twice with 100 ml of dilute sulfuric acid each time "The acidic washings were combined" decolorized with activated charcoal and made alkaline with dilute sodium hydroxide "The crude solid, which separated from the alkaline solution, was collected and recrystallized from ether / Pstrol ether held the desired 4 (1-hydroxy, methyl-2-propynyl) -4'- {2- dläthylamlnoäthöxy) -biphenyls, melting point 116 - 118 °° -

909817/0748

Example 11

According to the procedure described in Example 1 and on. In the process, 18.97 g of the potassium derivatives τοη 4- "Hydroay-tf ^l ~ nltrobiphenyl and 2.8 g N (3ChIcrättiy ^ pyrrolidin) in 200-1 toluene and 200 ml η amyl alcohol were refluxed for about 68 hours. The crude reaction mixture yielded dae ge "wish nitro 4 4 ⁴ -. (2-pyrrolidino% * äiyl -blphenyl consisting Xther / petroleum ether melting point was twice umkrietalliaiert 71 ~ 72 ⁰ C,

Example 12

The mixture of 89.9 g of p-iodobesotrifluoride, 152.5 g of p-iodine anisole and 322.7 g of copper powder was heated with stirring for about 5 days _f 0 1 η heptane extracted for 2 days «On cooling to room temperature, 4» 4 ^: Dimethoxybiphenyl separated out as a white crystalline mass. The mother liquor was concentrated and the crude 4-methoxy-4'-trifluoromethylbiphanyl was obtained. After four recrystallization from petroleum ether (30-60 ° C.), the desired product was isolated in the pure state. 21.7 g substance (26 i> yield) of melting point 125-126 ⁰ C.

909817/0748

22 g of 4-methoxy-4'-trifluoromethylbJphenyi were dissolved in 850 ml of glacial acetic acid and 175 ml of 48 # hydrobromic acid and refluxed under nitrogen for about 24 hours. The solution was concentrated to a crude solid which was washed with water and then dried in air "The crude product was recrystallized from ether / petroleum ether (30 - 6O ⁰ C) recrystallized u» d afforded 11 _# 8 g 4-hydroxy ~ 4 ⁱ ~ trifluor- methylbiphenyl, m.p. 147 ~ 148 ⁰ O

4 ~ hydroxy-4 ^J -trifluormethylbipheny.l (%, 5 g) was dissolved in 100 ml of dry dimethylformamide and 2.7 g of sodium hydrld * (54 * 2 £ effective content in mineral oil disperglert) behandelt- the sodium derivative was N - (2-chloroethyl) pyrrolidine (S ₀ O g) sixsetKt and the suspension heated under reflux for 18 hours. "Then the suspension was cooled and filtered and the clear mother liquor was concentrated to a brown, solid residue." The crude product was recrystallized from acetone5. wobbles and the first fraction with a melting point of 105 110 ⁰ _Λ C from methanol / grabber recrystallized ■> * 8 to give 9 g (49 #) of the desired 4 (2 _r PyrroHdinoäthoxy) -4 tri fluorine thy lbi phenyl- melting point 108 - 110 ⁰ C,

909817/0748
BAD ORiQiNAt

U93426

κ- 16 * -

example _ι 13th

To a solution of sodium sulphide (10.0 g) in 200 ml of water, ^ Aoetami-do-4 ^f -chloroulfonylbiphenyl (6 ^ 2 g) was added and the mixture was stirred at room temperature for 20 hours Sodium hydroxide solution was added partially in order to keep the solution alkaline during the reduction. The aqueous suspension was diluted to 1.0 liter, filtered and acidified with concentrated sulfuric acid. A white solid P precipitated out, which was filtered off and combined with a second fraction obtained by concentrating the filtrate (total yield 5.5 g)

4-Acetamido-4'-biphenylsulfinic acid (5.5 g) was suspended in 100 ml of water and potassium carbonate was added until a clear solution was obtained (pH-8 9). Methy ^ odide (4.3 g) in 300 ml Ethanol was added and the reaction was carried out for 64 hours with stirring and reflux. After cooling, the precipitate was filtered off and the mother liquor was concentrated, a second fraction of material being obtained. The combined crude product was triturated twice with 3-100 ml of water before it was recrystallized from methanol (3 * 1 g) (Soften at 264 ⁰ C).

909817/0748

■ U-Mu.: · SAD OBIGtNAL

«17 -

A suspension of 4-aoetanido-4-methylsulfonylbiphenyl (1.9 g) in 100 μl of 20% hydrochloric acid was refluxed for 20 hours, filtered hot and then made alkaline with sodium hydroxide plate and then made alkaline hot Methanrtl uncrietallleiert and delivered 1.42 g of the desired 4 Amino - ^ '- aethylBulfonylbiphenyl (melting point 205 205 ⁰ O) "

The diazotization of 4 amino 4 ⁵ methyleulfonyi-biphenyl '

takes place by adding 2.3 g of the amine iu Uli ice tea and 14 ml of 40% sulfur oleic acid. Cooling the suspension at -5 ° C and adding a solution of 1.6 g Hatrlumnltrlt, about O A ₉ ml of water in a tent of 20 minutes. After the addition was complete, ^{urea was added at 0} ° C. in order to destroy excess nitrous acid. Until diazonium solution was slowly added to 5 «5 ml of boiling 40 % sulfuric acid». It different calibration from a rubber-like mass, (Ue solid on cooling wurde- -Dae crude product was filtered added to 'n-Ha * Ifiumhydroxydlösung and acidified.

1.7 g of the desired ?, hydroxy ^ "methyl-sulfonylbi yl (melting point 189-19O" C) were obtained.

4 Kj.'ci r ο ^ y 4 ¹ '- niwthy.l au .!. Fonr / lbiphenyl (1.7 g) became \ n about 90 η ·. ; .o <5kenem Dimethyü ^ rmaniid dissolved and with 0 _v 2 g sodium-

909817/0748 BAD ORiQINAi.

U93426

hydride (54 * 7 fi effective content, dispersed in mineral oil). After the fermentation had ceased, the suspension was heated to reflux until the sodium vapor had dissolved. The alkylation was carried out by adding 1.2 g of K- (2 chloroethyl) pyrrolidine in 10 mJ dry toluene to the cooled suspension and then heating the reaction mixture for a further 68 dogs. Kaoh cooling was decolorized the dark brown solution with charcoal, filtered and the clear Pil joined to a £ eaten residue concentrated, This was taken up in about 300 ia1 Bcitaol, - Tiber anhydrous sodium carbonate, dried, filtered and dae clear Pll joined with eineru UbcreuhuB before ,. Treated hydrogen chloride. The gummi ar ti ^ e .. gelba Hydrüßhit »vid \ Yui * de dissolved in water (100 ml) and made strongly alkaline with / tritiiumhydvoxyd. The alkali eche j'.otüung me de ^ / once extracted with 75 ml of benzene each time. 'The vi'roi.i »it, /r.trakte tön delivered after the track / ies and ^v-i. Iero: ii i _v 0 g dec QwUnschten 4- (2-Pyrroll · -

P dinoethoxy) 4 Toalhy.LanlfönylbipUenyl-. Sohmeiszpunkt: »53 - ■ i54 ° C (sintering at 150 ⁰ O)

Example H

4 ~ hydroxy -4 ^: -eül.fonamldob5 phenyl (8.0 g) was dissolved in 200 ml of toluene and 150 ml of n-al ^ yl alcohol _{with 0 tf} 8 g _

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BAD OR (QiNAL

Vatrlunhydrld (54.7 # active content, dispersed in mineral oil) treated, the sodium derivative obtained was refluxed for about hours with 4.0 g of BM2 -chloroethyl) pyrrolidine. N _e cooling, the Reaktionsniechung was filtered and "u a semisolid RUoketand eingeengt- Dae crude Heaktloneprodukt _y was dissolved in benzene, decolorized with charcoal and dried over anhydrous sodium carbonate. Trooken hydrogen chloride was passed through the clear benzene solution * the insoluble substances were collected and dissolved in 100 μl of water. The acidic solution was treated with excess sodium hydroxide and provided the desired

4 'Bulfonamidobiphenyl)?

90981 7/0748 BAD OR (GfNAL

Claims (1)

Claims StBI «ft88t * ltSS» * SSSSStaitltt 1 · Compounds of the formula in which Z is a halogen atom, a nitro, lower alkanoyl, carboxy, lower carbalkoxy, trifluorraethyl, sulfonamido, methyleulfonyl or i-hydroxy-1-methyl-2-propynyl group; R ₁ , R ₂ , R * and R ₁ , water off atoms or methyl or ethyl groups which together ^{contain 2} I carbon atoms; Re and R ^ are lower alkyl radicals or together with the nitrogen atom to which they are bonded a pyrrolidino, piperidino, norphollno, thiomorpholine or a 1-plperasino radical substituted in the 4 position by a lower alkyl group, and their nontoxic acid additlons and quaternary ammonium salts. 2 · Compound of Formula Documents (Μ. Τ § I Paragraph I Nt. L Salt 3 of the Lake Change, v. 4 9.1W7 909817/0748 3 * Process for the preparation of compounds of the formula in which Z is a halogen atom, a nitro »lower alkanoyl _V carboxy · - ·« lower Cai & CLkoxy -> trifluoromethyl, sulfonamido, methyiaulphonyl or hydroxy-1 methyl-2 propynyl groupj R ₁ PR «* K *« nd R * hydrogen atoms or methyl or ethyl groups _v di <* zimaumuh contain up to 4 carbon atoms; R _h and K ^ lower AJ.kylreate odex · jjuaaiLmeiti with the sticküioffatoiB ,. are bonded to the al 'a pyrrolidino, P.Lperidi.no--, Morpholirio- "thiomorpholino or in position A Uuvcit a lower alkyl group substituted Plperazinoreat i b ^ _v DOUTEN characterized in" that ü ^ n "of VeiLindung 909817/0748 BAOOFUQINAt. U93426 in which B is an alkali metal or hydrogen and Z has the meaning given above with a compound dsr formula, iio-o-o. kC in which X is a neck atom or a hydroxyl group , us3 is 11; ν TIg ₉ υ *, Η.,? Rc and R ^ the meaning given above i) ul; en "heated in an isieri solvent to a temperature of 80 - MO ⁰ O ^ 909817/0748 BADOftlGINAL