DE3042091A1 - 2-XANTHONOXY-2-METHYL PROPIONIC ACIDS, THEIR ESTERS AND SALTS, A METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS CONTAINING THE SAME - Google Patents

Description

B. Evil 2l rc. 1 b u η j \

The invention relates to xanthone derivatives in general Formula:

CH.

(I)

where R is hydrogen or halogen and R is in the 6- or 7-position, the group

CH.

-O-C-COQR

CH.

in one of the positions 1, 2, 3 or A, R is hydrogen or represents a lower alkyl group or a pharmaceutically acceptable cation. The connections show anticholesteremic and anti-hyperlipidemic activity. The invention also relates to a method for their Manufacturing.

The invention relates to xanthone derivatives and in particular to xanthone derivatives containing an oxy-2-methylpropionic acid group, their esters and salts of the general formula:

CH.

(D

130025/05

ORIGINAL IMSPEGTED

where R is hydrogen or halogen, preferably chlorine, and R is in the 6- or 7-position of the xanthone ring stands. The group

-O-C-COOR

can be in any position 1, 2, 3 or 4 of the xanthone

-1

stand core. R means hydrogen or a lower alkyl group with 1 to 4 carbon atoms, preferably ethyl, or a pharmaceutically acceptable cation. The invention further relates to pharmaceutical agents or preparations, which contain at least one compound of formula I as an active ingredient.

The present invention also relates to a method for the use of the compounds of the formula I and the pharmaceutical agents which the compounds of the formula I as antihyperlipidemic agents for the treatment of atheromatous conditions.

The salts of the compounds of general formula I contain a metal ion as a cation, which is a pharmaceutical acceptable metal or which is the cation of an organic base, for example dialkylaminoalkanol, is. Because of the very high activity are the salts that are derived from dimethylaminoethanol or diethylaminoethanol derive, particularly preferred. The compounds according to the invention show a very high antihyperlipidemic Activity. Some of the compounds according to the invention

130 025/0542 ° ™ GINAL INSPECTED

fertilizers are better known in this regard antihyperlipidemic agent i.e. clofibrate. For example, the compound of the formula:

-C-COOC-H-j 25th

lipolysis induced by epinephrine in vitro, inhibit to a degree of 53? ό. On the same terms clofibrate shows an inhibition of only 46sS.

The compounds of formula I are therefore useful in the therapy of states of atheromatosis, and in particular are they are suitable as pharmaceuticals for the control of β-lipoproteins, in particular antherogenic lipoproteins.

The invention thus also relates to a method for using the compounds of general formula I as antihyperlipidemic agents.

The active substances of the invention can be in any pharmaceutically acceptable form, either as such or together with suitable excipients or together with pharmaceutically acceptable diluents, administered.

The present invention further relates to the pharmaceutical agents which contain one or more of the active ingredients

1 30025/0542

ingredients of formula I either alone or together with excipients and pharmaceutically acceptable carriers contain.

The invention further relates to a process for the preparation of compounds of the general formula I, according to the a hydroxyxanthone of the general formula II:

(II)

in front of R is hydrogen or halogen, in particular chlorine, and R is in the 6- or 7-position, the group OH in one of the positions 1, 2, 3 or 4, with acetone and chloroform and in the presence of a base after one well known procedures are implemented. The products are the corresponding 2-xanthoneoxy-2-methylporpionic acids, i.e. compounds of formula I in which R is hydrogen.

The above reaction is carried out with an alkali base, preferably sodium hydroxide. Acetone is preferred im Excess used so that it acts as both a reagent and a diluent. The usage of however, other diluents or solvents are not excluded. The reaction mixture is in itself Treated in a known manner to isolate the reaction products. The free acids are then optionally in the esters or converted into the salts.

1 3 Ü 0 2 _5/0 S h 2 Oni GmL

The compounds according to the invention in which R is a lower alkyl group, preferably an ethyl group, are from the corresponding acids in which R is hydrogen, by reacting the acids with an excess of one lower alkanol, preferably of ethanol, in the presence of a catalyst containing a strong acid, for example Sulfuric acid is obtained. Other longitudinal esterification processes, which are well known per se can also be used and give very satisfactory results. Corresponding a preferred embodiment according to the invention

form R means hydrogen or ethyl and R means hydrogen or chlorine.

The following examples illustrate the invention. Example 1 2- (3-xanthoneoxy) -2-methyl propionic acid

A solution of 10.6 g (0.05 mol) of 3-hydroxyxanthone in 300 ml Acetone is treated with 20 g of powdered sodium hydroxide and then with 20 ml of chloroform. After a short incubation period the reaction begins with considerable heat development. After the exothermic reaction has ended the reaction mixture heated to reflux for 4 h. The solution thus obtained becomes dry under reduced pressure evaporated. The residue is taken up in water, filtered and the filtrate is then washed with dilute hydrogen chloride acidified. The solid which separates out is isolated by filtration, washed well with water, dried and recrystallized from ethanol. 8.5 g (60% yield) of product are obtained in the form of white crystals.

130025/0542

Mp: 205 Ms 208 ^° C
Analysis for C ₁₇ H ₁ ^ O ₅ :

Found: C 68.32 H 4.58 Calculated: C 68.45 H 4.70.

Example 2

2- (7-chloro-2-xanthoneoxy) -2-methyl propionic acid

A solution of 12.3 g (0.05 mol) of 7-chloro-2-hydroxyxanthone in 300 ml of acetone is treated with 20 g of powdered NaOH and then with 20 ml of chloroform. After a short incubation period an exothermic reaction is observed. After the evolution of heat has ceased, the reaction mixture is refluxed for 4 hours. The reaction mixture is then evaporated to dryness under reduced pressure. The residue is treated with water, filtered and the so obtained liquid is acidified with dilute hydrochloric acid. The precipitate that forms is filtered off, washed with water, dried and recrystallized from ethanol. 8.3 g are obtained (yield 50% whiter Crystals.

Mp: 200 to 202 ^° C

Analysis for C ₁₇ H ₁₃ ClO ₅ :

Found %: C 61.41 H 3.85 Cl 10.40 calcd #: C 61.44 H 3.92 Cl 10.54.

Example 3 Ethyl 2- (3-xanthoneoxy) -2-methylpropionate

The material of Example 1, 5.7 g of 2- (3-xanthoneoxy) -2-

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methylpropionic acid in 100 ml of anhydrous ethanol is treated with a few drops of concentrated sulfuric acid and the mixture is refluxed for 10 hours. The solvent, ie the excess ethanol, is evaporated in vacuo and the residue is dissolved in chloroform. The solution thus obtained is washed with water, then with a saturated solution of sodium bicarbonate, again with water and dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is recrystallized from ethanol. In the form of white crystals, the product has a melting point of 97 to 99 ^° C., yield 5.0 g (8090.

Analysis for C ^ glLjgO, -:

Found %: C 69.84 H 5.60 calcd 96: C 69.94 H 5.52.

Example 4 Ethyl 2- (7-chloro-2-xanthoneoxy) ~ 2-ethyl propionate

A solution of 4.15 g of 2- (7-chloro-2-xanthoneoxy) -2-methylpropionic acid, prepared as described in Example 2, in 100 ml of anhydrous ethanol is prepared. To After adding a few drops of dilute sulfuric acid, the mixture is refluxed for 12 hours. The reaction mixture is evaporated to dryness under reduced pressure and the residue is dissolved in chloroform. The solution thus obtained is saturated with water, then with Sodium bicarbonate solution and finally again with Water washed. After drying over anhydrous sodium sulfate, the solvent is evaporated. Of the The residue is recrystallized from ethanol. White crystals are obtained in a yield of 2.7 g (6096).

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Mp: 127 to 129 ° C analysis for C ₁ QH ₁₇ found %: calculated %:

C 63.51 H 4.65 Cl 9.61 C 63.33 H 4.72 Cl 9.73.

In the following table, examples of compounds of the general formula I according to the invention are listed, which according to Processes which have been prepared analogously to the processes of Examples 1 to 4:

Tabel

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- ο ο φ - Φ O cn ο CJ CM • ΙΓ \ - I. 3Ϊ0 2 l £> CM O O C-CM ; H £ ■ νί- I. J COC- ε> ft O VO C— VO IfA O ν} "UN x> c— ^ 4 "UN O ^ UN Ir-J Γ? Cja'oN cf§ * Ϋ
HO tu J κ Vf Vf UN UN co ro Ö ' UN IfN LfN ΙΓ> β ei ö i ο U ο (ϋ U Y
• Po - A T "* C- C- - τ— ί β V-OJ aTi7 ^ ~ ——-—. 0? 'D _, ν - IfN ΓΟ vf O Vf ^ O vf t- vf ΙΛ OJ VOC JD-H Φ I. vf vt CO OA OA OA O ON 3Α cn r * H> W I. Γ CO CO OA ON O UN ON OA CO CO O ON no ro * "Ή φ O O UH Φ U 1" VO VO VO VO tCN νί- VO VO VO VO C- VO (Γ) ί "Ό . Φ CO CJ -P MH ο CO CO ο UN vt rn
CO * « T) -PO Φβ J) VO VO CO UN Vt O Pj ΙΟΉ ¹ O 3-P «Α v— τ— VO νονό Φ O) • Η · Η -P Ü Kl-P Τ— VO VO VD ω, α Φ? Η CO Φ | Ο · Η χ » Γ O Φ IfN Ι
ON CM . I -P O ' U.N. \ Γ \ U.N. VO I.
-J- ■ p Q) O O O O O LTv τ— U.N. CO vf CO U.N. CM O V-
ν ~ ΓΟ O »Γ
OA ν— ON CM O ι— \ ο O vf Λ - -
O O ο " O r- \ O \ - ' ^y c- ί ' O I.
O V- ΓΟ O ,H C- O \ - ; O ¹ O O 'r; | —I 'ß , Cj β <\ J O (d ^; (d H id Ü , Γ] O Λ
Jl & Γ-, j ^ id : M O O O UI ■ Ρ ΙΓ \ VO *>. O O VO VO VO vf ΙΓΝ IfN IfN OT t— C— C- rO I.
CM I.
ro VO IfN OJ ON U.N. <^ Ο I.
CM -ι- Ό tr \ Vf OJ CM W. O U.N. CM O V * OJ Vf - CM 1 L. C) VO

Biological tests

The antihyperlipidemic activity of the compounds of the formula I according to the invention was tested in Vitra in fat cells which had been isolated from the epididymal tissue of rats, as a criterion for the enzymatic hydrolysis of the triglycerides. The release of glycerol induced by epinephrine at a concentration of 10 "M is used as a criterion for the enzymatic hydrolysis of the triglycerides. The active compounds according to the invention are tested at a concentration of 10 M. The well-known antihyperlipidemic is used as a comparison Agent Clofibrate in the same concentration of 10 "M. The values obtained show that ethyl 2- (7-chloro-2-xanthoneoxy) -2-methylpropionate can inhibit lypolysis to a degree of 38% , while clofibrate can inhibit lypolysis in can inhibit a degree of 46% and ethyl 2- (3-xanthoneoxy) -2-methylpropionate can inhibit the lipolysis to a degree of 53% . These values show the superiority of the compounds according to the invention compared with the known antihyperlipidemic agents.

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Claims (12)

KRAUS & WEISERT PATENTATMWALTE DR. WALTER KRAUS DIPLOMA CHEMIST DR.-ING. ANNLKÄTE WEISERT DIPL.-ING. SPECIALIZATION CHEMISTRY IRMGARDSTRASSE 15 D BOOO MÜNCHEN 71 TELEFON OBB / 797O Γ7-797078 TFLEX O5-212156 kpatd TELEGRAM CRAUS PATENT 27 ^ 2 AW / rm IIEDEA RESEARCHES S.R.L. Milanο / Italy 2-Xanthono; <y - 2-iiethylpropionic acids, their esters and salts, a process for their preparation and pharmaceutical preparations containing them Claims Xanthone derivatives of the general formula: CII
J ³ ι 3 - o-c-cooir I. CH (I) ORIGINAL INSPECTED where R is hydrogen or halogen and R is in the 6- or 7-position, the group -O-C-COOB CH is in one of the positions 1, 2, 3 or 4, R is a hydrogen atom or represents a lower alkyl group or a pharmaceutically acceptable cation. 2. xanthone derivatives according to claim 1, characterized in that R is hydrogen or chlorine means and R means hydrogen. 3. xanthone derivatives according to claim 1, characterized in that R is hydrogen or chlorine 1 ··
means and R means ethyl. 4. Ethyl 2- (3-xanthoneoxy) -2-methylpropionate. 5. xanthone derivatives according to claim 1, characterized in that g e - -1 indicates that R is the cation of Dimethylam.inoäthanol or diethylaminoethanol. 6. Pharmaceutical agent used as an anticholesteremic and antihyperlipidemic agent is suitable, characterized in that it is at least one of the compounds according to claim 1 in an amount sufficient to produce an anticholesteremic and to provide anti-hyperlipidemic activity in the patient in need of treatment. 5 30026/0542 OR _{) Q (NAL INSPECTED} 7. Composition according to claim 6, characterized in that there is also a medicament carrier or contains a pharmaceutically acceptable carrier. 8. A method for the treatment of a patient suffering from atherone dosis, characterized in that a virksame Henge of a compound according to claim 1 or an agent according to claim 6 is administered to mz-n. 9. Process for the preparation of a compound of the formula: where R is hydrogen or halogen and R in the 6- or 7-position, the group 0 - C-COOR ¹ "1 in one of the positions 1, 2, 3 or 4, R is hydrogen or a lower alkyl group or a pharmaceutically acceptable cation, characterized in that a hydroxyxanthone of the formula: ORIGiWAL INSPECTED 130025/0542 _ ■ 4 - wherein R has the meaning given above and the OH group is in one of the positions 1, 2, 3 or 4 with Acetone and chloroform in the presence of a base under BiI conversion of an acid of the formula I, in which R is hydrogen and, if R has a meaning other than ¥ as possesses hydrogen, the acid in the corresponding ester or the corresponding salt transferred. 10. The method according to claim 9, characterized in that the reaction in the presence of an excess of acetone is carried out. 11. The method according to claim 9, characterized in that the acid is converted into an ester Reaction is converted with an excess of lower alkanol. 12. The method according to claim 11, characterized in that the reaction in the presence of a strong acid is carried out as a catalyst. 130025/0542