DE1543764A1 - Phenoxy-substituted alkanoic acids and processes for their preparation - Google Patents

Description

Phenoxy-substituted alkane acids and processes su their production

The invention relates to a novel group of 4-phenoxysubatituierten Alkaneäuren and their nichttoxisohe, pharmakologiach acceptable Säureadditionesalae, Eater- and amide Derlvate having a valuable denCholeateringehalt dee blood lowering activity and are therefore useful in the treatment of Arteribskleroee.

Clinical studies have shown that cholesterol apparently lt an essential role in the formation arterioelElerotieoher spots _e pi _#, Indea it accelerates the deposition of lipids in the blood in the artery wall · Be

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let a goal of the invention «a new class of chemical To show compounds which have an effect on the concentration of cholesterol and other mpoids in the blood serum and thus improve the condition which is usually associated with the deposition of too much blood.

The 4-phenoxy-substituted alkanoic acids according to the invention are products of the formula below

^ -0-0-0H ₂ -CHR-OOOH

where «R is hydrogen or low molecular weight alkyl»

1 2 for example methyl and so on, R and H same or different low molecular weight alkyl radicals, sB methyl «ethyl, propyl and so on» X hydrogen «halogen * eg chlorine» bromine »fluorine and so on» low molecular weight alkyl »eg methyl» A * 'contains tbyl and so on "halogenated lower alkyl, sB trihaloethyl, such as trifluoromethyl and so Welter, cycloalkyl, for example, monocyclic cycloalkyl which S to 6 nuclear carbon atoms such as Oyclopentyl» cyclohexyl, and so on, lower alkoxy, sB methoxy »ethoxy and so on , low molecular weight

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Alkylthio, lB Mtthylthio, jfcthyltöio and βϋ mtter, 8 · Β. Phenyl, Sol / 1 «IyIy 1 and au further _r Arrilfcyl» t »B, Btnsylf Phenathyl and so on» Aryloxy: .Phenoxy ao veiter · Aralkoxy, see Bensylosy and so on. it sä su « aejnengenouen can add 2 caste X to neighboring lohies. » Atoffatonen dee Bensolringes be united under Bllduug a »Hydro» carlbylenkette (dae lieisef elms eweiwerti L crganiaohen fieeta, which & ueöchli «& f: '.: ■ - ana Kohl ^ afeicCf UK * VMsaratoff iueaa» ®ngeeet «t ISt) ₁ welöiie 3 fei β lohlenatoffstoae iwiecban your Ter3c & ttpftt» p: points #st » billtt beiapialawelse 1 _$ 3 ~ But &äif> n7len (H && heilst ·

-CH-ÜH-OH-OE-) and se .irvlter ukä η a f & s. _; ;: s S & kl sit the vert I to 3.

The invention also relates to the acidic acid present 4-phenoxyeubated alkane acids; these Salie are made by reacting the named acids with a Baee divided, wlobe possesses an iiohttoxieches, phamakologiaoh acceptable cation. In general, any baee which forms an acid addition with a carboxylic acid and whose pharmacological properties do not cause harmful physiological effects when absorbed by the body ayatem, all in the trees of the earth.

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found lying down. Accordingly, the useful bases include, for example, the alkali and alkaline earth hydroxides, carbonates and so on »ammonia, primary, secondary and tertiary amines, such as monoalkylanines,» dialkyl amines, trialkyl amines, nitrogen- containing heterooyolic amines, eg piperidine and so on. The Säureadditionsealze thus produced are the funktionelien equivalents of the corresponding 4-phenoxysubstituiert ^ alkanoic acid products and it is veretäwdlich skilled in the art that, in the mass, in which the inventive acids are therapeutically useful, the Verechiedenartigkeit limited the encompassed by the invention, S & ureadditlonsealze only by the condition iat that the bases which are used in the formation of the salts * are both non-toxic and physiologically acceptable «

The invention further relates to the ester and amide derivatives of the present products, which are prepared by conventional methods known to the person skilled in the art. For example, the ester derivatives can be prepared by reacting a 4 phenoxysubatituiarten alkanoic acid according to the invention with an alcohol, for example a low molecular weight alkenol, a di-lower molar alkylaminoalkanol,

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such as Dinethylaainoäthanol, or with a heterocyclically substituted low molecular weight alkenol, such as 3-hydroxymethylpyridine and. eo further "or nan can convert the 4-phenoxy-substituted alkaline acid into its acid halide in conventional ways and the acid halide thus formed can be a bit of a low molecular weight alkane!" M-lower mol.-alkylaainoalkanol, 3-hydroxymethylpiperidine and so on are reacted in order to obtain the corresponding 4-phenoxyalkanoic acid ester Esters of the 4-phenoxy-substituted alkanoic acid reagent used. The amide derivatives of the present 4-phenoxy-substituted alkanoic acid can be prepared by treating the acid halide of these ( acids with ammonia or a suitable monoalkylamine, dialkylarain or dialkylaminoalkylamine, e.g. Methylhydrain, 1,1-dimethylhydrin, guanidine and so on to obtain the corresponding amide. Another method for the preparation of the amide derivatives mentioned is to convert an ester of a 4-phenoxy-substituted one

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Alkanoic acid, which is prepared as described above, in its corresponding Aaid by treating this ester ait Amoniak or "it a suitable Monoelkylamin, Dialkylaaln, Dialkylaainoalkylaain, Hydrasin · I-Methylhydra * in, 1,1-Dimethylhydrawin, Guanidine and so on, ^ to obtain the corresponding amide compound see below. These

and other equivalent processes for the preparation of the ester and ald derivatives of the underlying products are generally known and in which these derivatives are both non-toxic and for the body system are physiologically acceptable, the esters and amides are the functional equivalents of the corresponding 4-phenoxy « substituted alkanoic acids.

The 4-phenoxy-substituted alkanoic acids are one of the subgroups according to the invention general formula

OH ₄ -CBo-OOCH

12th

where E and R are identical or different low molecular weight alkyl radicals, s.B. Methyl and so on and X halogen, e.g. chlorine and so on is «Einechlos ·

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This preferred embodiment also includes the non-toxic, pharmaceutically acceptable acid addition salts, ester and amide derivatives of the above-mentioned 4-ptenoxy- substituted AlkanaMure-JProuts, 'at opielm ·,! " , like dit Hatrlatö-, £ -. ■ .-. Ü- ■ ■■; *; - or calcium salts, the low molecular weight Alif.j! ■ ·, } "> ■ .. ~ i · ■ ' ^: ." ■■ ^!;> ■ o1 * <- alkylaminoalkyl "and 3-PyridylB> etfayl - JI -, ^.i: ■ .. ·: ίο corresponding amide derivatives of whether ^;> ■ ■"..? .. · ■■ -) t :. _ä for example, their Aiaido · "Honoalkv; ■ ■ .. -:..... '■■■ - ■ [C ^ -" Dialkylaminoalkylamido-, HydraElct ·· _s i> - '■ ' . ■ '.yi% ■ -' ·: derivatives, such as the amide derivatives '. vft' ■■■■.. ■:. ■■. ■■ "■■ methylamine, ethylamine, and eo ws l. ethylamine and so on, Blm.et ^; : yl {>. <: ■ ■ ■■ ■. ... ',;■■,>. ■. ■, ': ;;; ^ aiainoäthylamin and ac welter, H; ,, d. ). ■. ■■■■ 'Iv ..' -κ. ·· ^; '''-"·;,:..-.:':" ■ 1,1 ~ J) imethylhydrazine, guanidine -n! ., ;; .. v: i; - ::. ... ί: [ ., ■■:% are,

according to the invention & seen ProU. >
from the corresponding Es * ^ j λ β <· ί} ^ _{: il} ··> · ated 2-alkenoic acids (IY); «ΰα ■: '■. · η; ϊ'.;. η called fcii 2-alkenoic acid ( If) trit; ? e ^ rjfm Ke ^ ■ '■;■'? ■ which enables iat ₉ Vinylengryope (dae t.'s group -CHeCR-) to the corresponding Atbyltr, -I he / Γ-u;

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(that means: OH ₂ -CHR-) and anaohlieeeende hydrolysis of the resulting 4-phenoxy-substituted alkane acid ester derivatives (V) sum the desired acid product (I). Any of a variety of reducing agents can be used to convert said 4-phenoxy-2-alkenoic acid ester (IV) to the corresponding 4-phenoxyalkane acid ester derivative (V), but catalytic hydrogenation has for example hydrogenation in the presence of a suitable metallic one Catalyst «such as ruthenium on carbon catalyst, has proven to be a particularly advantageous process with which the reduction can be achieved. The following series of formulas explains the implementation

R ¹ ^ -0., C-CHsCR-COOR ³

* 2 R ¹

-O-C-CHg-CHR-COOR '

CH ₉ -CHR-COOH

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in which the radicals B, H ¹ , R ² , X and η have the meaning given above and B ^{5 is} an alkyl radical, 8 «B. is a low molecular weight alkyl radical, such as ethyl and eo is bit

ι The hydrolysis stage of the above series is carried out in conventional,

Carried out in a manner »for example by handling the

esterified intermediate (T) alt an aqueous solution: ■ a Ββββ, β.B. an aqueous solution of sodium hydroxide or sodium carbonate and solubilizing treatment 'dta ^:

carboxylate salsea formed in this way with an acid like SaIs

acid.

The inventive products are generally as obtained crystalline solids, and can »if desired, by recrystallization from any suitable solution

cleaning agents »for example a hydrocarbon solvent such as cyolohexane, and so on. i

The outcomes of the above-mentioned Heratellunge process * materials used 4-phenoxy-2-alkenoic acid ester (Iv) are sweckmässlgerweise from their corresponding in the core substituted 2-phenoxyalkanal precursors produced by

treating them with an Alkoxyoarbonylalkyliden-triarylphοsphoran or with an ürialkylphosphonoalkanoat.

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Suitable reagents which can be used in the process include, for example, the low molecular weight alkoxycarbonylalkylidene triphenylphoephoranes and so on and the tri-lower aol-alkylphosphonoacetate (and 2-propionates and so on) and their homologous derivatives. The reaction can be carried out in any solvent in which the reactants can reasonably be expected are soluble and which is usefully inert with respect to the starting materials used; However glycol dimethyl ether and benzene have proven to be special Suitable reaction media have been found to be suitable and if the preferred solvents are desired for the present process. Palis, a catalyst can be used to reduce the Facilitate implementation. For example, when the starting material used is an alkoxycarbonylalkylidene-triarylphosphorane, benzoic acid is found to be particular effective catalytic reagent, while when using a trialkylphosphonoalkanoate, sodium hydride, are preferably used in solution in the reaction solvent, for example ßlykoldimethyläther. The following series of formulas explains the process.

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-O-C-CHO

II

(H ³ O) ₉ P-CHH-COOR

ir

15Λ3764

C) I-CR-OOOR ³

lpe

wherein the reagents R, R »R, JB, X and r; the ob.v. £ ii; feg? Benc meaning have υηά R mononuclear aryl, ζ B-. }. ^{J is} hcnyi and so on .

The PboL-pho used as starting materials in the aforementioned reaction with the Phe / iory: ¹ channel reagents

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and phosphonoalkanoates are either known compounds or can be prepared by methods known to those skilled in the art. For example, treating a suitable alkyl 2-haloalkanoate such as ethyl 2-bromoacetate gives JS. ethyl - ^ - bromopropionate, methyl 2-bromopropionate and so on with an appropriate trialkylphoepb.it the corresponding trialkylphosphonoalkanoate. They reaction is preferably carried out at elevated temperatures for extended periods of time, for example at temperatures in the range of 130 to 19O ⁰ C for up to 4 hours. The alkoxycarbonylalkylidene-triarylphosphorane derivatives are also obtained from suitable alkyl-2-haloalkanoates, but by treating them with a mononuclear iriarylphosphine and subsequent reaction of the phosphonium salt thus formed with an aqueous solution of a base, for example with a dilute solution of sodium hydroxide. This implementation is also promoted by the use of moderate heating. The following series of formulas explains the preparation of the phosphorane and phosphonoalkanoate starting materials. _

X ¹ ^ CHR-COOR ³ (H ³ O) ^ g> (R ³ O) ₂ P-CHR-COOE ³

Base ι

J *

(R ⁴ ), Ps = CR-C 0OR ⁵

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wherein Ä, H ⁵ , R * and X ^{1 have} the meaning given above.

The above-mentioned Heratellenverfahren described 2-phenoxys-substituted alkanals (II) are made from their corresponding 2-fhenoxy-alkanaic acids (III) hergesteilt by treating these acids as a mixture of lithium "aluminum" hydride in anhydrous ethyl ether and subsequent oxidation of the 2-phenoxyalkanol thus formed Compound (Fl below) Sun Desired Aldehyde · A mixture of dioyolohexylcarbodiimide and anhydrous dimethyl sulfoxide is the most suitable oxidizing reagent, with which the alkanol intermediate (71) can be converted from the desired alkanal (II), but the person skilled in the art is familiar with the fact that there are a large number of others Oxidizing agents can also be used in an analogous manner with similar results The following series of formulas explains this manufacturing process:

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E ¹

-0-d

~ OOCB

"2 B ¹

^R I

III. ^ ^^

II

12th
in which R, R ₉ X and η have the meaning given above • 1-t.

Let it not be clear what stains the Cboleetertntyntheee in the formation of arterioeclerotic, eudes, but ugly suspicions underneath »they do Assumption that cholesterol is a tiny bitch in the world Patbogeneee of arterlosclerosis plays, ds ee alongside others

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Lipoids and fibrin represent the substance »which is accumulates in the arterial intima and sub intima, causing damage and clogging of the arteries.

Since cholesterol is present to a certain extent in every normal form of nutrition, and 3s * s . When the origin of the biological substance is synthesized, the development of a chemotherapeutic agent was considered desirable, which brings about a significant lowering of the cholesterol level in the blood serum. When searching Naeh dersrtigen chemotherapeutic agents were erfindunge "measured products tested and -zeigten doing a surprisingly good, the blood cholesterol lowering effect and may be used alone or in Koinbinat: * üb j-χϊ-" n the chemotherapeutic agents in a Einzeldcüi s-Anr cation form and in admixture with a pharmaceutical carrier

The following examples explain the invention further without limiting aie,

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example 1

4- (4-chlorophenoxy) -4 ~ methylpentanoic acid

Stage A: Ethy1-4- (4-chlorophenoxy) -4-methyl-2- pentenoate

Suspending 415 g (0.1 mol) of sodium hydride (50 # in Mineral oil) in 50 ml of glycol dimethyl ether and add 22.4 g (0.1 mol) dropwise with stirring for one hour Add triethylphosphonoacetate in 225 ml of glycol dimethyl ether; to the The mixture gives 19.9 g (0.1 mol) of 2 * (4-chlorophenoxy) ~ 2 ~ methylpropionaldehyde in 50 ml of glycoid methyl ether added and then stirred for 3 hours and 16 hours ditched. The supernatant glycol dimethyl ether solution the precipitate is decanted off, diluted with water and the glycol dimethyl ether is evaporated. The watery one The residue is weakly acidified by adding hydrochloric acid and then extracted with ether. The ether extract is washed very quickly with cold 5 # sodium hydroxide and with water. The ether layer becomes dried over sodium sulfate and evaporated the back remaining 21.7 g of ethyl 4- (4 chlorophenoxy) -4-methyl 2 pentenoate will be used for the next without further purification Level used.

Level B "ethyl ~ 4 ~ (4 ^j Cblorphenoxy) -4 ~ methylpentanoate Dissolve the Äthy!" 4- (4-chlorophenoxy / -4-methyl ~ 2 -pentenoat

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from stage A (21.7 g) in TOO ml of ethanol and set 5 g 10 £ igea fiuthenium-on-charcoal, see below; the mixture is then in a hydrogen atmosphere at an initial pressure of 2.87 kg / cm shaken until the calculated hydrogen amount is absorbed (time required about 2 to 3 hours). ,

Ban one separates off the catalyst, the ethanol evaporates,

takes the back and in ether, washes with 5 J & Lgem

Sodium hydroxide and with waaaer and dries over magnesium

sulfate. The ether is evaporated and 17.45 g is obtained almost colorless ethyl 4- (4-chlorophenoxy) -4-methylpentanoate.

Step Ct 4- (4-chlorophenoxy) -4 "methylpentanoic acid

4.15 g (0.074 mol) of potassium hydroxide are dissolved in the minimum amount of water and 10 g of the ethyl acetate 4- (4-chlorophenoxy) -4-methylpentanoate prepared according to stage B, dissolved in 100 ml of ethanol, see below, is added to the solution - -schliesaend the mixture for 3 hours on reflux conditions, evaporates the ethanol and dissolves the Rüokstand in water. After extracting with ether, the solution is acidified with concentrated hydrochloric acid and the resulting semi-solid precipitate dissolved in ether. You wash them Ether solution with water, dries over magnesium sulphate and receives 6.72 g of one after evaporation of the ether

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white solids, which is umkrietallisiert from cyclohexane to give 5.53 g of 4 ~ (4-chlorophenoxy} -4-eethylpentansäure, mp. yield 77-78 ⁰ C. Analysis C ₁₂ H ^ ι 5OIO-

calcd. O 59.39 H 6.23 Cl 14.61 found. 0 59.60 H 6.51 Cl 14.59.

Bti replacement of the appropriate 2-phenoxyalkanal and trialkylphosphonoacetate instead of 2- (4-chlorophenoxy) -2-ethyl- propionaldehyde and Xriäthylphosphonoaeetat ges & as With » Game 1, Step A and where "essentially" follows the process of Steps A, B and C of this example all 4-phenoxy-substituted alkanoic acids according to the invention getting produced. The following series of fozmeles is explained the reaction of steps A, B and C of Example 1 and are susamen bit table I the 2-phenoxyalkanal and For alkylphosphonoacetate reactants of this process and the corresponding 4-phenoxy-substituted alkanoic acid products (I) prepared in this way:

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X »X ² fi ¹

χ *.

-0-C-CHO + (C ₂ H ₅ O) ₂ P-CHR-OOOR J ²

3 NaH

l / Λ.

^ O-C-CH «CR-CqOR-

Ru / C

- QC-CH ₂ -CHR-C OGH ³

K0H / H ₉ 0

O ₂ H ₅ OH

HCl

R ¹

-0-C-CH ₂ -CHR-COOH I «

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E. S ⁵ f a b < t-1 1 Λ1 « H X ³ H H X ⁴ H '; u | a - -C ^ ₃ -SOHj H E ' At- '
game -OHj E- ' H -OHj H -CH,
7th 2 H -CH ₃ - ^ H ₃ - CH «· *" • i'-f ,,; ^ - ·
". '« F. \ Tti ^.; ·'' H H -OBj 3 -OH ₃ -O ₂ H ₅ H H Cl Oil E. 4th -CHj -G ₂ H ₅ - ^ H ₃ -OH, H H 5 H -CE ₇ - ^ B ₃ - ⁰ A H H 6th -OHj -CHj ^ Hj -GH ₃ Cl H H 7th -Ctij -OgH ₅ B. Oil H 8th H -CHj ** A -0, H ₇ H H Cl 9 H -OHj H -CSj Cl 10 -OHj -CH ₃ * 9Hj -OH, H H egg 11 -OHj ^ ₂ H ₅ -C ₂ H ₅ H Cl 12th H -CH ₃ -C ₃ H ₇ B. H -CVCH ₂ -, 13th -OH ₃ .CHj -βΗ « -Often -CH-OH-CH-GH- H H H -CHj -CH ₃ -O ₂ H ₅ 15th H -OHj ^ ₃ .C ₄ H ₉ H 16 -OH ₃ -OHj -O ₄ H ₉ -CHj ^. . 17th rCHj -CHj -6Hy -9a, -CHj- 18th H -OHj 90Hj -O ₂ H ₅ Cl 19th ^ H ₃ -O ₂ H ₅ 20th -OIL

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The products according to the invention can be used in thoi ^ fl Doeen applied in conventional carriers, wise by means of oral application in the form of a doublet as well as by intravenous injection, wides / hiE frann die Can of the product can be varied over a wide range, e.g. * in the form of notched tablets * which are 25, 50, 100 » Contain 150, 250 and 500 mg of the active ingredient » for symptomatic adaptation of the dose to the patient to be treated «These dosages are abundantly inadequate. below the toxic or lethal dose of the products.

A suitable single-dose application form of the invention i: ciulve can be prepared by mixing of 50 mg of a 4-PüeiiüxyalkaiAäur # or © ines suitable Acid addition salssee, Beter- or Aaid ^ .Oerivatii Kit 1f> 0 rag lactose and placing the 200 mg mixture in a gelatin capsule No. 3. In a corresponding manner, by using of more active ingredient and less lactose other Doaie * Forms in gelatine capsules Mr. 5 can be accommodated and} should ea be required, more than 200 mg stock « To mix parts together, larger capsules can be used »One can press tablets, pills or other Prepare unit doses as required «around the

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products according to the invention by conventional methods ingestion and they can, if desired, "ala slexiere or injectable solutions according to the pharmacist known methods are prepared.

Ee is also within the scope of the invention 2 or more ^ to combine according to the invention compounds in a single dose application or one or more of these compounds with other known, the Choleaterin levels dea blood lowering compounds or to be prepared with other desired therapeutic and / or nutritional agents in an island dose application form.

The following example serves to explain the production of a representative Bosierungsform

Example 21

Dry-filled capsules containing 500 mg of active ingredient per capsule _;

.Ie capsule ι

4- (4-Chlorophenoxy) -4-. ΒthyIpentanoic acid 500 mg Lactose 144 mg

Magnesium stearate 6 mg Capsule size No. 00 650 mg

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BtKMBtmI ^ t gates! ·: - / '^;;i'v. ■: ■■. "^ C w ti τ ^, 'b

oo iv ??

S & tepreohende dry-filled L & setsen dee Virketoffe d © e -ΐ-Ιίρ · «:! the other new © rfindungsfenaäea fertilize can be prepared.

Aue of the above special terms, the invented 4-phenoxyalkanes & ures (I) represent a full range of products not previously produced . Taonaann of ee is veratftndlicii that the above examples are illustrative only and the variation and Modifisitnmg widely Auraase sugttnglioh eisd, absuweiohen without worn Sahaen the invention ·

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Claims (1)

Merck & Co., Inc. 925 '! (M 69 625) claims 1. Compound of the alicine formula R ¹ ■ n # - " ¹ Sy-OC-CH ₀ -CHR-COOH and their pharmacologically compatible salts, in which mean R hydrogen or low molecular weight alkyl « P. R and R "£." oak or various low molecular weight Al kyl residues, X is hydrogen, halogen, lower molar alkyl, halo lower molar alkyl, cycloalkyl, lower molar alkoxy, lower molar alkylthiOs aryi, aralkyl, aryloxy, aralkoxy, with 2 X radicals on adjacent carbon atoms of the benzene ring forming a hydrocarbylene chain can be combined which contain 3 to k carbon atoms between their points of attachment, η eir «ca: .se number from 1 to 3. ν ;; y) - ': - !, ethyl peniansHure. - 24 - 909881/1648 8AD ORJGJNAL 925 * Process for the production of connections geaXes Anaprüohen 1 and 2, thereby separated “lehnet, am * “ en “la“ connection 4er tlltßmmimm Wmnml V ^ HRi 4MM »IM φ #» φ ^ W ^ 4m WHHB ι λ ³ AUcyl let, ait eiMM eo fefcllileten% .; »• reeirt. - 25 - BAD ORIG'NAL • 80 9881 / 1Si 8