DE2260138A1 - BISPHENOL ALCANDER DERIVATIVES IN METABOLISM - Google Patents

Description

FARBWERKE H0ECH3T AG vorrnalc. "'Eister Luciu'5 & Brüning reference number: hoe 72 / l · ¹

Date: November 30, 1972 'Dr. D / stl Metabolically effective bisphenol alkane derivatives

The invention relates to metabolic active agents, the derivatives from üisphenoialkanen of the general l'Orraels I and II

R ₁ R,

/ ¹ V-

■ ^0H

R ₂ R ₂

^R * OH V \ / ^R 6 - { 1 V / / I. ^R 6 J ^R 8

II

where mean:

R "is a hydrogen atom or an alkyl group with 1 to Carbon atoms

R ■ is an alkyl radical with 1 to 9 carbon atoms

R "is a hydrogen atom or an alkyl radical with 1 to 'C atoms

a hydrogen atom, an alkyl radical with 1 to 18 carbon atoms.

409824/1060

BADORlGfNAL '

^ ":: cE 72 / F 376

a pnenyl radical which can be derived from -ya ^ oxyi, L ^ logen, Vrif luor: aethy 1 or alkyl may be substituted, or the group

₂ -p

"• ■ '-Χι

OH

-C (CH)

R _rJ R, hydrogen or ¹ alkyl radical with 1 to 12 carbon atoms. RW as rs ers to ff or an alkyl radical with 1 to: 1B carbon atoms

Iv- an alkyl group with 2 to 18 carbon atoms, if IL. or R, - means hydrogen, can Rr, also V'assorstoff or set up a methyl group

contained as an active ingredient.

in the definitions above and below, the term alkyl radical always understood to be one with a straight or branched chain.

A number of compounds which correspond to the formula I and II are described in the literature (beisp.ielsv? Eiae in Liebigs Annalen aer Chemie 363 (1908), 3. 2 ^ 6, 2'55; [Jiederl and McCoy: J. Amor. Chem. Soc. Vol. 63, p. 1731 (19M); Journal Chera. 3oc. (1939), pp. 1 ^ 22).

It is produced by acidic or alkaline condensation of mono- or dialkyphenols with aliphatic or aromatic Aldehydes bzvi. Dialkyl or alley 1-ar.y! Ketones. Depending on the position and the meaning of R and R "and especially of R ^ depends on it whether alkaline or acidic condensation is preferred.

The acidic catalysts are, for example, mineral acids, ie Hydrochloric acid, sulfuric acid, phosphoric acid, hydrofluoric acid; organic acids, such as glacial acetic acid, and Friedel-Crafts catalysts or ion exchangers in question. The alkaline condensation is preferably carried out with matron or potassium hydroxide solution.

409824/1060 '. BAD original

" ⁵ ποκ 7Γ. / Ρ 376

In some cases it is from ßtex'i.s ^ bxn Grünjon rweckrnäMg, tongue-I ^f? T the base body by the condensation of phenol with the aldehyde or ketone to produce, and then in a further step, the alkylation with the olefin ζ.ΰ. Carry out isobutylene and di-isobutylon or alkyl chloride in the presence of catalysts,

The field of application of the bisphenol compounds is very wide, For example, they serve as external connections for production of epoxy resins or polycarbonates, they are also used to stabilize plastics as such, mineral oils, rubber etc., used. As a result of their fungicidal and bactericidal properties v / ground them for cosmetics, for lacquer resins and paints used.

It is also known from US Patents 3 ^ V-) 772 and J 529 066 that certain βisphenol compounds lower the "cholesterol level. However, this effect has not yet been described for compounds of the formulas I and II.

It has now been found that bisphenol alkane derivatives of the formulas I and II act on the metabolism and can therefore be used as medicinal products, "The hypolipldainioche and found antihyperglygienic effectiveness and the associated Use was surprising and not evident from the prior art.

The invention therefore relates to 'metabolically active agents characterized by a content of Disphenolalkanaerivaten Formulas I and II and processes for their preparation.

.The compounds of the formulas I and II v / ground by known methods τ 'id in an additional Verfahrenssehritt into a pharmaceutically suitable application form transferred.

Of the active ingredients represented by the formulas I and II, preference is given to those in which PL and R ^ denote alicyclic radicals with 1 to k carbon atoms, and these may be the same or different. R-, preferably represents a hydrogen atom "or an alkyl radical of 1 to 4 * carbon atoms and R _; an AlRyl group with 1 to % carbon atoms"

40982471060 - ■■ -. '.

BATH ORIGINAL

376 or a phenyl red which, given ^ mT ^ Hs, is substituted by halogen

is. Rr- and \\ _r mean in particular hydrogen or alkyl radicals 5 u

with up to 12 carbon atoms and R hydrogen or alkyl with 1 to ^ carbon atoms, while for Rr alkyl radicals with up to 7 carbon atoms are preferred.

The compounds of formulas I and II have valuable therapeutic properties Properties. So they lower serum lipids and can therefore for the therapy of primary hyperlipidemia and certain secondary hyperlipid arias, which occur e.g. in diabetes can be used, with the beneficial effect on the diabetic metabolic disorder in particular Obese also in a certain antinyperglycaemic Activity of these compounds expresses.

Since an increased blood fat content is the most important risk factor for the development of coronary heart diseases and completely generally elevated serum lipids levels as significant risk factors for the development of arterial-oclerotic phenomena also represent other localizations, not only in the area of the coronary vessels, therefore comes from the lowering of increased serum lipids for the prophylaxis and therapy of arteriosclerosis, especially in the area of the coronary arteries, an extraordinary one Importance to. Since the substances described in more detail above can lower normal and elevated serum lipids in animals, they are used in the treatment and prophylaxis of human and animal arteriosclerotic diseases, especially in the Area of the coronary vessels, but also other vascular areas, of use.

The hypolipidemic activity of the compounds of formulas I and II could, among others; shown on the following Tic models comparative compounds of those disclosed in U.S. Patents 3,599,772 and 3,529,066 a hypocholesterolemic effect has been described.

1 · Male had a normal serum lipid content. The fourths given in Table 1 represent the changes in

40982A / 1060 B ^AD o ^RlGINAL

HCE 72 / F 376

Serum concentrations of certain lipid classes after a eight-day treatment in various daily dosages listed there.

The application was carried out orally with the stomach tube. In the As a rule, blood was drawn before and after the treatment and the concentration of cholesterol in the serum according to the method of Lauber and Richterlich, and those of triglycerides according to the Method determined by Eggstein and Kreutz. In the examples given in Table 1 below, these are due to changes in serum lipids that have occurred after treatment with the substances defined as follows:

a) the percentage changes in the post-value of the treated group, based on the pre-value of the treated group, the pre-value being set at 100 % and

b) the change in the post-value of the treated group in relation to the post-value of an accompanying untreated control group (placebo group), the placebo group being set at 100 % . The value in front of a dash represents the percentage change compared to the starting point

. value j the value after a dash the percentage

Change in the preparation group in relation to the placebo group, represent.

2. Dietetic-drug hypercholesteirinemia of the male rat

All animals are fed a diet enriched with 2% cholesterol, 2 % sodium cholate, 0.3 % methylthiouracil, 20 % coconut fat and kk% cane sugar. The serum lipid concentration of the animals treated with the compounds listed is compared with an untreated control group under the same diet, in which the serum cholesterol concentration increases to about ten times, the serum triglycerides to three times and the phospholipids in the serum to four times the value within a week. The Lipidphosphbr was according to the method of

409824/1060

"HOE 72 / F 3 7 <">

Boehringer Mannheim definitely. With the start of the diet, the listed compounds are used once a day for 8 days long administered to a collective of 10 rats with the pharynx. The percentage reduction in serum lipid concentration compared to the control group (diet alone without preparation) is shown in Table 2.

3. The carbohydrate- induced hype caused by the administration of pructose rtrigly ce ri därni e in male rats is reduced by a three-day oral pretreatment with the substances listed compared to a placebo group (Table 3).

409824/1060

Tabel

KOE 72 / F

Serum lipid decrease in normolipene rats

% Change after

8 oral applications on the d "'rat with mg / kg / day

100

30th

oo connection

Serum cholesterol

Serum trigly ceride

Serum cholesterol

Serum triglycerides

Serum Chole Serum Triglysterol. 'ceride

Example 1 Example 2 Example 3 Example 4 Example 6 Example 7 ' Example 8 Example 9 Example Example Example

■ 3 ^ / - 22 ■ 42 / -27 • 27 / -2S ■ 13 / / -15

■ 58 / -64 ■ 36 / -11 ■ 28 / -2Ο ■ 39 / -27

/ -16 • 48 / -34 ■ 36 / -17 • 37 / -17 • 8 / -15

-33 / ^ 32 -26 / -2O ■ 14 / ■ 25 / -34

■ 35 / -31 ■ 11 / -10

-31 / -22

• 16 / -21

• 16 / -10

■ 44 / -47

■ 18 / -24

■ 31 /

• 10 /

■ 19 / / -19 ■ 22 / -13

• 9 / -22

/ -29 / -23

• 9 / -16 • 34 / -37 / -36

■ 32 / -13 • 2 / -12

• 11 / -

• 10 / -16

/ -13

■ 11 / -22 ■ 9Z-25 ■ 11 / -15

- 8th/-

/ -17

18 /

continuation

Tabel

hoe 72 / F 376

100

10

Comparison Serum- Serum- Serum- Serun Sorun Serum- links Cholesterol Trigly Cholesterol Trigly Cholesterol Trigly sterol ride sterol r.idc sterol ride

(4-tert-butyl-6-.methy phenol), 2,2'-methylidene-bis 2, 2 '. RÄthyliden-bis (M-tert, butyl-6-inethylphenol) ,, 2.2 ■' - Methylide-n-Ms- (ü-octyl-6- ~ ^:

-methylphenol) 2,2 '* -Methy Ii den-bis (4-methy1-6-tert. butylpheTiol)

12-Tns thy1- 6 -1 e rt.

2.2 »-MethyIi den-b i s (4,6-di-tert-butylphenol)

-I8 / -I6 + 16 / + 2U

-19 / - 5 -15 / +

-16 / -

-I8 / -27

-IB / - 7

- 8 / - 9

Tabel

hoe 72 / F

Ariti'hyper'Iip'idamische effect on o * rats, in which, starting with the 1st application of the preparation
dietetic - drug induced hyperlipidemia
Effect after "'8 applications

: 'v ¹ :'. ■; · i "'■■ .. * ■

■ ⁱ " % change compared to placebo group of

link

'mg / kg / day

Serum cholesterol Serum triglycerides Phospholipids in serum

Example 1. -. 100 example 2, _ .100 Example 3. - 100 Example Λ - 100 Example 8 100 Example 9. .100

70 81 88 79

64

-29 -60 -75 -56 -43 -44

Ki) CD CD

continuation

Table 2

hoe 72 / F 376

Comparison connection

mg / kg / day serum cholesterol serum triglycerides phospholipids in serum

2,2'-methylidene-bis (J * -octyl-6-me thy! phenol) + 36

+ 6

2,2 ^f -Methyliden-bis - (^ - ethyl-6-tert. Butylphencl)

100 -11

+ 59

-8th

¹ ^, 4'-cyclohexyl! danbi5-i2-me_thyl- £ - .. .. tert.butylphenoi) ■ '■■■■

100 -18

+ 89

Tabel

hoe 72 / F 376

% Change after fructose exposure and 3 oral applications to the 6 rat with mg / kg / day

link

Serum Choles' animal

100

Serum-

Trigly

30th Serum-* Serum- , Ch ole- Trigly st ari η ce ride

10 Serum- Serum- ChoIe- Trisly sterol ceride

example 1
Example 2
Example 3
Example \
Example 6
Example 8
Example 9 '"
Example 10 '

-25

-24 -46 -3Ö -28 -40

-47 ..- Γ28 ... ¹

-67

-16

-82 -29 -22 -28 -38

-33

-58

Ki) CfD

30th HOE Serum- 10 Serun ChοIe- Serum- Serum- Trigly sterol Trig Iy Cholesterol ceride ceride sterol

-23

-15

- 3

-11

IsJ CD

Comparison connection

Port setting tab 100 Serum- Serum- Cholesterol Trigly sterol ceride

2.2 »-AthyIi den-b i s (1-tert-butyl-6-methy! Phenol)

2, 2'-methylidene-bis (^ -octyl-ö-methylphenol)

2,2'-KethyIiden-bis (i-ethyl-6-tert. buty! phenol)

2,2 ^1- methylidene bis <4-methyl-6-tert. buty! phenol)

2.2 »-Methy Üden-bis

buty! phenol)

- 13 - HCK ηΐ / 'ν

The beneficial effect of the compounds of formulas I and II on diabetic metabolism, especially obese and overweight people is not only based on the normalization of the disturbed fat metabolism, i.e. on the aritihyperlipidemic effect, but also on an effect on the carbohydrates tafi'v / echscl.

The blood sugar lowering effect was determined as follows: the blood sugar level is tinned with the autoanalyzer became. The hypocholesterol drugs described in the aforementioned US patents were also used as comparison compounds.

1. In normal α "rats after δ oral applications and 2k hours of hunger before blood sampling (Table ¹ \)

2. After oral fructose exposure <? Rats that were 3 days with the Test substance were pretreated: 2 ^ hours after the last Application, the blood sugar content of the treated group of animals was compared with that of a placebo group (Table ^).

3. On alloxandiabetic patients, temporarily with Insulin-substituted male rats with food ad. libitum, once a day for eight consecutive days received an oral application of 100 mg / kg / day of the test substance (Table 5)

Due to the beneficial effect on fat and carbohydrate metabolism the compounds of the formulas I and II are particularly suitable as hypolipidemics and antidiabetic agents.

409824/1060

\ ß

U.

C)

r-

ω ·, ^ rf £ Λ -j α> to 45 fc.T rf 4- '■ · r-H Λ O) K ω XJ " E: φ \\ Γ) CO O Q) rf C. '6 φ CO C. O ■ Η 'ί ¹ rf • Η φ γ-Η Ό P. C, ο., t: 3 : rf rf f '< E-; Φ Ci ίπ ι-I hO rf • ^. O C. ω FJ IS! KN 4-i ^ J .Γ! ! -] O cn rf C. CJ cö • Η '-! θ ITi γ: C. O QJ • Η 'd 4- ClJ U ■ r-i O (H > ρ] 4Y Cl «Ι rf 'ο C. ■ α W. r-l 4_> rf ^ s ω O Ό 33 co C. rf bO C.

J *.

O)

ο ω

• Η

£ 3

bO O

O ΚΛ

O O vH

• j

¹ C *

• Η

.Q U 0.)

oo

O τΗ

LT \ VO

cr \ I

co

CA I

rH

Γ— f \ J OJ
IA
1 rH
I. I. ! I. r-i I. CM
IA
t C \ J
I. I. I. CO ^ O I. I.

LT \

rl rH rH rH rH rH r-l

Φ (U (!) O) O) Φ O Oi ■ rH •H • Η • Η • Η •• J ■ Η • Η P. P- P, Jl, P, Pj Pl P. 03 to to O CO to Kl •H •H • Η • Η • Η • Η • Η • Η CP OJ Φ O θ: Ί) ω ω ra ω OQ ! -Q , • λ ΙΏ

40982Λ / 1060

Port setting

Tabel

HOE 7.2 / F 3 76

% Change in blood sugar after % change in blood sugar after 8 oral applications with
mg / kg / day

Fructose load after 3 oral applications on the 'rat mg / kg / day

Comparison connection

10

100

30th

10

2,2'-methylidene-bis (4-tert. butyl-6-methylphenol)

2,2'-ethylidene-bis (4-tert. butyl-6-methylphenol) + 36 / + 8

σ> 2.2 »-Methylidene-bis (4-methy 1- ° 6-tert-butylphenol) Λ-20 / + 10

~ H

2,2'-methylidene-bis (4-octy 1-6-niethylphenol) + 2

2,2 * -Methylidene-bis (4-ethyl-6-tert-butylphenol)

2 _> 2 ^f -methylidene-bis (4-methyl-6-tert-butylphenol) + 16

- 8th

MOE 72 / F 3 7δ

Tabel

Antidiabetic effect in * rats in which alloxandxabetes was produced. Effect after 8 applications

% Change from baseline compared to placebo group of

CD CO OO

Compound mg / kg / day

Serum cholesterol serum triglycerides blood sugar

Example 3

100

-11 / -55

/ -61

-12 / -38

ISJ CD CD

- 17 - HOi-. -f.'J} <

The compounds of formulas I and II can be used either alone or mixed with pharmacologically acceptable carriers . Oral use is preferred. For this purpose, the active compounds are mixed with substances known per se and brought into suitable dosage forms by methods known per se, such as tablets, hard capsules, aqueous or oily suspensions or aqueous or oily solutions. Magnesium carbonate, lactose or corn starch with the addition of other substances such as magnesium stearate can be used as inert carriers. The preparation can take place either as dry or moist granules. Possible oily excipients or solvents are especially vegetable and animal oils come _t such as sunflower oil or cod liver oil. The daily dose is expediently about 10 to 200 mg / kg of active substance.

A particular application of the new compounds is in the combination with other active ingredients. In addition to other suitable substances, these include above all:

Antidiabetic drugs such as glycodiazine, tolbutamide, glibenciamide

or ;

Krei s running mid th in vieltes sense, especially Coronardilata-

gates such as chromonary or prenylamine and substances that lower blood pressure such as reserpine, ex-methyl-dopa or clonidines, other lipid-lowering agents or geriatric drugs,

Psychoph armaka such as chlordiazepoxide, diazepam or meprobamate and

Vitamins.

BATH ORIGINAL

409824/1060

Heisniel 1 - 1 8 -,. _0K? . _{2 / T 3? 6}

'J, ^ i * -Liuty Ii den-bio (2,5-dii :: ethy lphenol)

122 g 2,5-dimethylphenol (1iol), 36 g n-butyraldehyde (0.5 mol) are dissolved in 150 nil heptane and add 20 ml of conc. hydrochloric acid added.

The batch is heated to 60 ° C. and stirred at this temperature for 10 hours. After cooling, the product precipitates in crystalline form, but brown in color. By Uir.ki-istallisation from toluene with addition of 10% bleaching earth (Z.3. ^W 'Tonsil Optimum FP Südchenie Company, Munich), lied to crude product which H, 4' -Butylicien-bin (2,5 · dimethylphenol) as a white, crystalline compound with a melting point of 190 ^° C.

Analysis: ^C ₂ O ^H 26 ° 2

calculated C 80.5 % Vi 8.7 %

found C 80.1 ϊ Η 8.9 jS

Example 2

^, 4 '-Isopropy liden-bis (2-tert .buty! .Phenol)

In the ^ -necked flask v; ground 600 g o-tert. Buty lphenol (^ mol), 58 g of acetone (1 mol) and 0.1 ml of Λthy Inercaptan and saturated with stirring at 10 C with dry hydrogen chloride. After a condensation time of about 12 hours at 10 ° C., the temperature is allowed to rise to 20 to 25 ° C. and condensation is continued for about 2 hours. The excess o-tert-butylphenol is then distilled off.

The resulting crude product is recrystallized from toluene. Melting point: 113 ° C

Analysis: C ₀ -JI ₇₂ O

BATH ORIGINAL

409824/1060

no '·: 72 / V 376

calculated
found

Ice pie 1 \

C 81.1 % C 80.6 %

H 9.5 % ■ H 9, ^] \%

* i, 4'-butylidene-bis (3-metliy 1-6-tert .butylphenol)

328 g of 3-> lethy 1-6-tert-butylphenol (2 mol) are dissolved in 200 ml of methanol dissolved and gas at room temperature while cooling with hydrogen chloride saturated. 72 g of n-butyraldehyde are now added dropwise. To When the aldehyde has been completely added, the reaction mixture is brought to reflux temperature and held at reflux for 2 hours,

After cooling, the mixture is aufgenoir.ir.en in ether and initially with Sodium bicarbonate solution, then washed neutral with water. To Separating the ethereal phase, this is dried with sodium sulfate, then the ether is drawn off. The crude residue becomes off Heptane crystal lsi site.

Melting point: 212 ° C.

Analysis: , C 26 ^H. 38 ° 2 calculated: C. 81 , 5 % found: ' ^C 81 % Example 4

H 9 ₃ 9 % H 9.8 %

l, 'l, 3 ~ trio (2-methy 1 - ^ - hydroxy-5-tert-buty! phenyl) -butane

g 3-Methy 1-6-tert ".butylphenol (3 mol), 300 g methanol and 100 g conc. Hydrochloric acid are introduced and at 50 C in about 90 min. 70 g of crotonaldehyde (1 mol) were added dropwise. After the addition has ended, the mixture is refluxed for 2 hours. After cooling, the precipitated one becomes Sucked off precipitate and washed neutral with water / water. The raw product is recrystallized from toluene.

40 9 824/1060

no :: 7:; / F 376

Tendon point I86 C

Analysis: C -, ^ Η ^^ Ο,

calculated: C 81.6 % II 9.9 %

found: C 81.7 % H 9.9 %

, 4 '-Me thy Ii de η- b is (2,6-di-tert. Buty! Phenol)

206 β 2,6-di-tert.buty! Phenol (1 ^T! Ol) and 56 g of potassium hydroxide are introduced into 400 ml of ethanol and to Absolutein g at 25 to 30 C 82 a ^l \ 0 / iigen Formalinlöoung (1,1 Mol) slowly added dropwise. The mixture is then stirred for a few more hours. The product is precipitated by adding water. The precipitate is washed with ¹ Was.1 he addition of a neutral Netzriittels GeV / ash. The crude product is recrystallized from alcohol. The melting point

lies by 153 ⁰ C. C. i
C. 82 , 2 % H 10.4 Analysis: C. 82 , 0 % H 10.1 calculated: found: Example 6

4.4 ^t -benzylidene-bis (2,6-di-tert-butylphenol)

206 g of 2,6-di-tert-butyphenol (1 mol) and 56 g of caustic potash in Submitted 400 ml of ethanol and 106 g of benzaldehyde (1 mol) slowly added dropwise at room temperature. After the addition is complete, Stirred for about 12 hours. The deposited precipitate is filtered off and unicrystallized.

Melting point 162-163 ° C

BATH ORIGINAL

Analysis: C ₇₅ H ^ O

409 824/1060

l'üli 72 / Ρ 1Γ / 6

calculated: found:

C 83.55 % C 83.42 %

H x 9.66 2 ■ H 9.40 JS

Example 7 '"

4 _S 4'-butylidene-bis (2-methy! Phenol)

108 g of o-cresol (1 mol) and 36 g of n ~ butyraldehyde (0.5: 4οι) are dissolved in 150 ml of heptane and 12 g of conc. Hydrochloric acid added. The reaction mixture is heated to 40 to 50 C; and with this one Stirred temperature for 5 hours.

After cooling, it is washed with sodium bicarbonate solution, then with V / ater washed neutral. After distilling off the solvent the resinous residue is unicrystallized from aqueous ethanol A resinous substance is obtained.

Analysis:

calculated: found:

Example 8

^C 18 ^H 22 ° 2

C 80.0 %. C 79.7 %

H 8.15 % K 8.1 %

4.4 ^t ~ benzylidene bis (2,6-dimethyl-phen oil)

134 g dime thy! Phenol (i. Mol) and 56-g of potassium hydroxide are introduced into 350 ml of ethanol and lüö g of benzaldehyde (1 mole) at 20 ⁰ C is slowly added dropwise. ·

Then stir. 10 hours after.

The deposited precipitate is filtered off and extracted from chloroform recrystallized.

Melting point: 163 ^° C. '

ORIGINAL

- 22 Analysis: C ^ H ^ Og 110.72A ₃ -C

calculated: C 83.2 % II 7.2 %

found C 83.0 % II 7.1 %

Example 9

^, 4'-methylidene-bis (2-methy1-6-tert-butylphenol)

6.6 g of potassium hydroxide are dissolved in 400 ml of isopropanol and 1 ^ 3 g of 2-methyl 1-6-tert-butylphenol (1 mol) are added under a nitrogen atmosphere. The mixture is warmed to about 30 ° C. and 50 g are slowly added dropwise
30% formaldehyde solution too. After the addition, the
Temperature increased to 60 C and stirred at this temperature for 2 ... hours. After cooling, the product is precipitated with water and taken up in ether, the ethereal phase is washed several times with water and dried with sodium sulfate. The ether is stripped off and the residue is recrystallized from hexane.

Melting point: 100 ° c 81 32 O ₂ Analysis: C ₂₃ H 80 > o % H 9.4 % calculated: C. > 9 % H 9.3 % found: C. s ( Example 10 2, 6-dimethyl-phenol) ^ • -Butylidene-bi

122 g of 2,6-dimethylphenol (1 mol), 36 g of n-butyraldehyde (0.5 mol) are dissolved in 200 ml of hexane and 20 ml of conc. Hydrochloric acid added. The batch is ^{stirred at 50 °} C. for 10 hours. The solvent is distilled off with a water pump, the crude, crystalline precipitate is washed with water, dried and recrystallized from hexane. >

HOE .72 / K 376

Melting point: 107 ° C

Analysis: ^C 2O ^1I 2d ° 2

calculated: C 80.5 % H 8.7 %

found: C 80.5 £ H 8.8 %

3eisp_iel_ll ■ ".

4, -'J '- (l-r-lethy ld odecy Ii den j-bis (2' -tert .buty! Phenol)

300 g of o-tert-buty! Phenol (2 mol), 99 g of methyl dodecy! Ketone (0 and 0.5 g of thyroid! mercaptan are presented and at room temperature saturated with dry hydrogen chloride. The! Condensation time bet3 "takes approx. 48 hours. The excess o-tert-buty! phenol and the unreacted starting products are distilled off under vacuum. A viscous oil remains behind.

Analysis: C ₃₁₁ H ₅₁₁ O ₂

calculated ·: C 82.5 % · H 10.9 %

Found:, C 81.6 % H 10.4 %

Example 12. .

4,4'-propylidene-bis (2-tert.buty1-5-methy! Phenol). .

82 g of 3 "methyl-6-tert. Butylphenol 'and 1'9 ^: g of propionaldehyde dissolved in 300 ml of heptane and saturated with hydrogen chloride gas . Washed neutral with water: ...-..-

Melting point: 190 G -. '■ . · .. "· _ ■ -

Analysis: C _otr ß., _R O " -..-- ..

^eij ^ ^d BAD ORIGINAL ■

calculated: C 8l, 5 % H 9.8 %

found: C 81.2 % H 9.7 %

A0 9824 / 106Q -.

_t > \ '-lieptyliucn-bis (2-t.crt.l-.utyl " ^l .5-mothvlOMonül).

. 328 β 3 - "] etnyl-6;.. -Tert.hutylphGno1 (2 Ιοί), 37 C n-heptanal (0.5Mo and 30 ml of concentrated hydrochloric acid v / ground at about 6O ⁰ C is condensed 8 hours. The oily substance is washed neutral in ether-cenon-in-ion and with 20% of sodium bicorbonate solution.

Melting point: 160 ° C

Analysis: ^C 29 ^H ^^ ° 2 '

calculated: C 82.2 % H 10, Ί %

found: C 82.3 % H 10.2 %

For example Ik

2.2 ^! -IsopropyIiden-bis ( k -isonony! Phenol)

220 g of isononylphenol (1 mol) is pre-precipitated, heated to 65 ° C. and 1 ^ g of acetone is added in portions over a period of about 5 hours. ^ Then condensation takes place at 6.0 to 65 C for approx. * »8 hours. Xylene is now added and the water formed by the condensation is distilled off. Xylene and nonylphenol are drawn off at 165 ° C. and 0.2 Torr .-. ■ -..-.-, ·. A slightly yellow, highly viscous oil remains as the residue. ,

Analysis: C ₇ ^ H "0

calculated: C 82.5 % H 10.8 %

found: C 81.9 % H 10.2 %

. . , ·. _; , BAD ORJGIN ^ 409824/1060

"- 25 -

At spie ?! 15 HOii 7 2 / F

2,2'-methylidene-bi3 (4-tert.any! Phenol)

16 ^ g of tert-amylphenol (1 mol), 15 g of p-formaldehyde (0.5 mol) and 20 ml of conc. Hydrochloric acid is dissolved in ² JOO ml of heptane and stirred at 20 ° C. for ^{2 2 J hours.} The deposited precipitate is filtered off, the adhering hydrochloric acid is removed with V / water and recrystallized again from heptane.

Melting point: 1 ^L \ 9 ⁰ C (white crystals) Analysis: C ₂₃ H ₃₂ O ₃ . .

calculated: C 81.3 % H 9.4 %

found: C 8l, 0 % H 9.3 %

example ± 6

500 ml of the ground compound from Example 3 are 200 ng Milk sugar piv. and 20 mg ascorbic acid in a hard gelatin capsule filled.

In an analogous manner, capsules are obtained which contain, as active ingredient, compounds which are described in Examples 1, 2 and k to 15.

Example 17

Tablets are made from the following components:

Ground compound from Example 9 250 mg

Corn starch l ^J 10 mg

Milk sugar piv. '45' mg

Talc '30' mg ""

Amylopectin 30 mg

Magnesium stearate 5 mg

Be in an analogous way. Tablets with active ingredients according to Example 1 to 8 and 10 to 15 were obtained.

" _An " 09824/106 "

BAD ORiQ / _NAL

Claims (3)

Claims Π0Γ>:> · "' 1. Metabolic agents, characterized by a content of bisphenol alkane derivatives of the general formulas I and II I ¹ ^ ³ T ¹ HO // V-c (· '\ OH R ₂ R ₅ OH / T ~ \ - c / ^N > Ii where mean: R is a hydrogen atom or an alkyl radical with 1 to 12 Carbon atoms R_ is an alkyl radical with 1 to 9 carbon atoms R, a hydrogen atom or an alkyl radical ranges from I to 18 j Carbon atoms a hydrogen atom, an alkyl radical with 1 to 18 carbon atoms, a phenylreFt, which is represented by hydroxyl, halogen, trifluoromethyl Or alkyl can be substituted, or the group -CH ₁₅ -CH-CH, ^{C (CH} 3 ⁾ 3 409824/1060 HCiC 73 / ί '3 7k ■ ■■■ · -. R,., R, -Wassers toff "or Alky Ires te Fit 1 to 12 C-Atonen 5 ο - . _ - -. .-.; .- ■ :. R _{7 is} hydrogen or an alkyl Ires t with 1 to 18 carbon atoms Rn is an alkyl group with 2 to 1-8 carbon atoms, "if R- or ' R _r denotes hydrogen, Ii, can. also hydrogen or ■ 6 ³ ο - ■■; ..- ■ to represent a Methyü group ^: ' as an active ingredient. . 2. Process "for the production of substances effective / insecticidal preparations, characterized in that bisphenol alkanes of the claim produces lower level formulas according to processes known per se and in a further process step into a suitable dosage form possibly with the addition of pbarT.azeutiy.ch usual Auxiliary and carrier materials transferred. 3. Use of bisphenolalkane derivatives of the formulas given in claim as hypolipidemics and anticiiabe'tikaJ BATH 09 8 247 TD 6 0 '"■■