DE2036421C - - Google Patents

Description

R ₁

CO-R ₂

in which R: and R- have the meaning given above, in the presence of a base or with a carboxylic acid derivative of the general formula IV

in which R ₁ and R _; Met'nv! Groups or R _{1 is} a methyl group and "R _{; is} an ethyl group. Λ is a hydroxyl or Athovv group and Li is a cyclopentene, cyclohexenyl, 2-benzothiazoiyl pharmakoiog: -ch compatible salts

2. Medicines to lower de-. Bliucho! E> 'erinspiegeU. characterized by a content of active ingredients according to claim I and usual carrier -doff

X-C-CO-A R-

The invention relates to new Pli-jno \\ carbo; i> aure derivatives and medicaments containing them for the treatment of high bluichole termspieeel or ! .ipid levels.

Aiherosclerosis is a disease of adults, For which there has not yet been a satisfactory therapy. The cause of aherosclerosis has not yet been found known. The disease shows up histopathologically in the deposition of cholesterol or lipids; m Blood. A number of experimental and clinical findings have been reported to suggest that the reduction of high biulcholesterol levels! is especially important in preventing atherosclerosis.

The object of the invention was to develop new phenoxycarboxylic acid derivatives to create that are effective in lowering blood cholesterol and are practically non-toxic are. This object is achieved by the invention.

The invention thus relates to phenoxycarboxylic acid derivatives of the general formula 1

R,

; - o-C -CO-A

in which R ₁ and R, methyl groups or R _{1 is} a _{methyl unit, R 2 is} an ethyl group. A is a hydroxyl or ethoxy group and B is a hydroxy group. Cyclohexenyl-. 2-E5enzothiazolyl or 2-benzoxazolyl group. and pharmacologically compatible salts.

The phenoxycarboxylic acid derivatives of the general formula I and their pharmacologically acceptable ones Salts can be prepared in a manner known per se by using a phenol of the general Formula Π

O - OH in the R ₁ . R- and A have the above meanings and X is a flalogen atom or a hydroxyl group. converts, and also the product obtained is either esterified or saponified and, if necessary:

: o the free acid obtained by reaction with a; Base with pharmacologically acceptable canon:;. the salt transforms.

In the reaction of the phenol of the general formula II with chloroform and a carbony 1 connec-

When the general formula III is used in the presence of a base, at least 1 mole of chloroform is capped in a mixture containing 1 mole of the phenol and at least one; 1 NK> 1 of the carbony! Compound of the ai ^; common forms! III contains. The implementation will ■ ::

-, o Presence of at least 3 moles of the base durchgc leads. Examples of bases that can be used are sodium hydroxide and potassium hydroxide. The reaction v.u .. at temperatures from 20 to 150 C and more true: 30 minutes to 40 hours. The l.'m-e: ■

The tongue can be inert in the presence or absence Diluent or in the presence of excess chloroform and / or excess Carbony linkage of the general Fc mcl III can be carried out. Examples of ine;. ·

Λο Diluents are dioxane. Benzene and Toiuc According to another embodiment, <;.! · ..- phenoxycarboxylic acid derivatives of the general formula 1 by reaction of the phenol of al '· common formula I with the carboxylic acid Deriv ··!

4s of the general formula IV can be prepared. Who.r, the radical X in the carboronic acid derivative of the general Formula IV denotes a halogen atom, ζ. Β a chlorine. Bromine or iodine atom, becomes as follows worked: The phenol of general form

so mcl II is made in an inert solvent such as benzene. Toluene or an alcohol, suspended or dissolved and then with a base such as an alkali metal hydroxide. Alkali metal alcoholates an alkali metal. Alkali metal hydride, an alkali metal arho-

ss nat or an organic tertiary amine. how Pyridm. Or a trialkylamine. treated. Subsequently the carboxylic acid derivative of the general formula IV is added dropwise into the mixture. The implementation vs ird at temperatures from 10 to 150 C and during

performed for 30 minutes to 10 hours. Subsequently the reaction product is worked up in the usual way and the crude product is purified.

If the radical X in the compounds of the general formula IV is a hydroxyl group.

<>> is the condensation reaction in the presence of a acidic catalyst, such as sulfuric acid or p-toluene | [) sulfonyl chloride. accomplished.

The free phenoxycarboxylic acids of the general

Formula 1. in which A is a hydroxyl group, köt.nen in the usual way by implementation with a " Base with a pharmacologically acceptable cation can be converted into the corresponding salt. Examples aqueous solutions of Alkali metal hydroxides! "!. Alkali metal carbonates !!. -Valkali metal bicarbonates or ammonia. You can also use free acid with an alkali metal alcohol in an organic solvent, preferably in a lower alk ^ vil. like methanol or ethanol or with an alkali metal hydroxide, carbonate or hydrogen carbonate in an organic solvent. '. Sometimes in acetone or methanol, and if necessary ■■ mseizen in the presence of a small amount of water. The alkali metal salts obtained can by implementation, e.g. B. with calcium chloride, in the »■■, •.! Speaking alkaline earth metal salts are transformed

Most of the &: salts obtained from the above-described V. :: ise are water-soluble. ! The what-ER ¹ -Raise salts may be prepared by washing a wäüngen ■■ solution of the salts with an organic Losiings-: a water-soluble polar solvent 'el and then adding the aqueous Lösuiiii seven · ^..:, i...

■; 'p.en werdeii. in which the salts are insoluble. You can also use the aqueous solution, for. B. evaporate in a spray dryer. That way you can iic salts can be obtained in powder form.

as long as the salts: are only sparingly soluble in water.

'r.or.nen them by filtration, subsequent- washing IiJ ₁ cleaning with an organic solvent.

λ ie ether or benzene, obtained pasture. Unless

T.ib-jlle i

I'hcmv

the purification of the free phenoxycarboxylic acids of the general formula I by recrystallization or similar processes are difficult, the acid is first esterified and then the ester chroma

strictly cleaned. The purified ester obtained we, then stranded to form free acid.

Phenols of the general formula I used here according to the process can be prepared according to known rivets, e.g. B. by condensation of a Cvdoalkyldiene with phenol in the presence of an acidic catalyst such as sulfuric acid or phosphoric acid, or according to the in the journal .1. At the. Chem. Soc. Vol. 48 (1926) p. 783. or Vol. 75 Π ') 53ι p. 5967. described method.

The examples illustrate the invention.

example 1

A mixture of 5 gp-C-CyclopentenvU-phenol and 7.7 g sodium hydroxide are added to acetone.

- ■; ■ Then 10g of chloroform are added to the mixture added dropwise to 35 C with stirring. The reaction mixture is refluxed for 13 'hours. The solvents are then distilled off. while water is added to the mixture at the same time

ι? will. The mixture is made with dilute hydrochloric acid acidified. 2.4 g of p- (2-cyclopentene \ liphenoxyisobutyric acid fall here from 69 to 72 C.

Examples 2 to 8

According to Example 1, those listed in Table 1 are Connections made.

product

phenol
K'.fö μι

pi: -C> Llohcv: n \ l -
phenol

ι? gl

■ i P -.-- CV.-Ihexenyliphenol

; -: n-ll> dro \\ phen> ll-

(ι 2-lp-! l><iro \\ phenyllbcnzciihi.izol
(15 m

R, - CO H

CH ₅ COC

120 gi

CH ₁ COCH ..

I'd μ!

CH, COC _; H>
iftS gl

CH ₁ COCH ₁

CH ₃ COCH,

IXOgI

^ Mo-H> dro. \> Phcnyll ι CH, C () C, H «
bcn / oihia / oi I ilMlul

; lo-H> dro \\ phen> ll- _; CIl ₁ COC
ben / oxa / iil i IM) μι

X.iOli

RAW

114.6 ι; ι

KOH
12V.4 Ui

KOH

KOH

KOH

15h al

NaOH
(16.4 μ)

CHCi,

ü 12 hours

■ o bi-35 C] ι (Hückltiül

7.2 a 16 hours

[35 C] i reflux l

13.7 vi; 22 hours
up to 40 C], reflux Bi

a 27 p

[35 hl- 45 Cj ι reflux ι

2 (1 μ 26 hours

[35 to 40 C]: (reflux i

.'Og

up to 4s egg

10.5 μ i [35 hi- 4 (1 C] ? I hours
(Reflux)

M.5 hours
ckückliuUl ι

j ■ OC COOH
R;

Ig!

p-l1-Cyclohe \ en \ llpher -.xyisobulter-

IiI.5 Hi

p - (; - C \ clohexen \ l> -

phenoxvisobuttcr-

acid

(5 el

.i- [p- (2-C> clohe \ en \ U-

phcnoxy] -i-mcihyl-

butyric acid c

2-12 -Benzothnizolyl-

phenoxyisobutter

säiirc

IS gl

4-l2-benzothiazolyD-

phcnoxyisobutter-

fäurc

.i- [2- (2'-t! en / olhiazole \ l ! -phenoxy] - ■ i-methylbutyric acid

12 (1 gl

2 (2 -Bcnz-OxazolyD-

phenoxyisobutter

siiure

(May be

plusi kisses

I liien.sclKiiten

1- 85 to W C

1 · ". S7 to X9 C

"- 1.5WO

F. 106 his IDS C

F. 190 to 192 C.

? = 1.6398

F. 107 to lld C

Example 9

3 g of a 50% dispersion of sodium hydride in mineral oil are added to a mixture of 5 g of p- (2-cyclohexenyl-phenol and 50 ml of anhydrous toluene). 21.6 g of ethyl 2-bromoisobutyl ester in toluene are then added to the mixture while stirring The mixture is heated to 50 to 60 ° C. for 1 hour, then the toluene is distilled off and the residue is purified by chromatography on aluminum oxide, eluting first with n-hexane and then with mixtures of η-hexane and benzene with decreasing hexane content is eluted with benzene. 2.3 g of p- (2-cyclohexenyl) -phenovyisobutyric acid ethyl ester are obtained: n ² '= 1.5161.

According to example 9 the in the examples :! OK and 1! obtained compounds mentioned.

Example 10

ο - (2 - Cyclohexeny!) - phenoxyisobutyric acid ethyl ester: "fif = 1.5 * 110.

Example 11

2-ι 2'-Benzothiazole!) - phenoxyisobutyric acid ethyl ester: F. 51 to 54 C.

Example 12

τ, -io η C-CyclopentenyD-phenoxyisobutyric acid η 30 ml * 99% ethanol and 20 ml benzene are oeiöst The mixture is mixed with 2 drops of Schwele !, ure and heated under reflux for 1 ^ hours. Here, the reaction water formed during the esterification is distilled off together with the solvents, with corresponding amounts of the solvent being fed back in at the same time. After the reaction is complete, water is added to the reaction mixture, the solvents are removed and the residue is washed with ether. The ether solution is washed with water, dried over anhydrous sodium sulphate and evaporated. d chromatographically cleaned. 2.0 g _r - -Cv-

■ i "- (

dopentenyil-pheiio'xyisobuuer. "ureäthylester
ien: »i?> = 1-5132.

Example 1.3

According to Example 12, 1.7 becomes g ο
hexyl-phenoxyisobutyric acid 0.7 g of the c
corresponding ethyl ester: HV =! .MOS.

Examples 14-18

According to example 12 the in table
guided connections established.

- ■ hal-

Tabclle I!

Ausiianüsverhindunien

Hey
game Phenoxy carboxylic acid alcohol benzene Hours. 20 hours
(Reflux) (G) iml) iml) (Drops I (Tp.l 12 hours
(Reflux) 14th .i- [p - (- Cyclopente-!
nyl! -phenoxy] -:
Ί-methvl butleric acid
11.5 gl ' Ethanol
(60 ml) 2] 19 hours
' (Back nut) 2 hours
(Reflux) 1? ^] .i- [p- (2-C velohexe-
nyl) -phenoxy] - ■
> im: lhvlbutt <; räure
(5 g) W%
Ethanol
1100 mil -> 6 hours
(Reflux) lh i 2-f2-benzothiazole> l) -
phenoxyisobutter,
acid i
(10.5 g) W. 5 ° 'o
Ethanol
170 ml) benzene
(iOmll 3 17th
i 4- (2'-Benzothiazolyl) - '■
nheroxyisobulter-;
acid I
(log) 99.5%
Ethanol
1100 ml) benzene
CmI) I mi IX .i- [2- (2'-Benzoihia-!
/ ol \ l) -phenoxy] -]
n-methyl butyric acid |
110.5 g) "! 99.5%
Ethanol
(70 ml) benzene
(30 ml) 3

Produki
Reaction / L-it. :

■ phenoxycarboxylic acid ester! ph>> ik .:
i (?)

! / [- [p-C-CyclopentenyD-i phcnoxy] -ii-methyl-

butyric acid ethyl ester
j (0.8 g)

rf-rp- (2-cyclohexenyl) - j π- '= I.?; ¹
I phenoxy] -ii-methyl-I bulleric acid ester
I (3.2 g)

2- {2'-Benzothiazoly]) - F. 53 bi ^

phenoxyisobutyric acid

ethyl ester

(7g) ^!

4- (2'-benzolhiazolyl) - | F. 119 his ICi;

phenoxyisobutyric acid

ethyl ester

(Sg)

.i- [2- (2'-Benzothiazolyl) -j n? = 1,615;

phenoxy] -n-methyl-

butyric acid ethyl ester

(6.8 g)

The compounds prepared according to the invention can, for. B. administered orally. Usually the oral daily dose for adults is 0.01 to 10 g. preferably 0.05 to 3 g. The drugs can be formulated in the usual form for oral administration, e.g. B. in capsules, in liquid Form, as tablets ^ or as powder. For the production The medicinal substance can be mixed with conventional pharmaceutically acceptable carriers be mixed.

The activity of the compounds prepared according to the invention in lowering the blood cholesterol level was studied in mice given 500 mg / kg "Triton WR 1339" intravenously (i.e. a oxyethylated tert. - octylphenol - formaldehyde condensate). The test compounds were orally in doses of 50 mg / kg immediately after the injection of the "Triton" solution and 24 hours later administered. The mice were then sacrificed for serum cholesterol analysis. The reduction the cholesterol level was calculated using the following equation:

Cholesterol Lowering (%) =

C-T

C-N

Γ = serum cholesterol level (mg / 1 (X) ml)

the control group,
T = serum cholesterol level (mg / ICXl ml)

the group treated with the test compound. N - serum cholesterol level of the untreated group.

The results are summarized in Table IU

represents. connection of Table III Cholesterol picgcl-
lowering. % 1 example 80 2 50 3 40 4th 26th 5 52 6th 41

Connection of licispicl (hcilcNterinspiqic
scnkunj !. % 5 7th 34 S. 17th 9 35 K) 20th IO Il 50 12th 41 13th 20th 14th 64 15th 15th 60 16 50 17th 27 18th 36 20th p-chlorophenoxyisobutyric acid 14th ethyl ester (see Nature. Vol. 194 [1962]. P. 948)

Claims (1)

Patent claims: 1. Pheno ^ ycarbon-iiure - derivatives de. general Formula I. BR ₅ O - () —C —COA (I! in which B has the preceding meaning. either with Chloroform 'and a carbonyl compound of the general Formula III