DE2534453C2 - Phenoxyalkanecarboxylic acid esters of oxyalkyl salicylates, processes for their preparation and pharmaceuticals containing them - Google Patents

Description

in which Ri is a hydrogen atom or a p-chlorophenoxyalkanecarboxylic acid radical of the general formula (H)

in which Ri is a hydrogen atom or a p-chlorophenoxyalkanecarboxylic acid radical of the general formula (II)

R ₃

oc-c-o- R ₄

(H)

OC-C-O

Cl

(ID

R _{2 is} a hydrogen atom, an acetyl radical or a p-chlorophenoxyalkanecarboxylic acid radical of the general formula (II), and π is 2 to 4, where at least one of the radicals Ri and R _{2 is} a p-chlorophenoxyalkanecarboxylic acid radical and Rj is a hydrogen atom, a methyl group or a p-chlorophenoxy radical, R _{4 denotes} a hydrogen atom or a methyl group.

2. Process for the preparation of the compounds according to claim 1, characterized in that one in a manner known per se either a phenoxyalkanecarboxylic acid of the general formula (IH)

R _{2 represents} a hydrogen atom, an acetyl radical or a p-chlorophenoxyalkanecarboxylic acid radical of the general formula (H), and η has the value 2 to 4, where

at least one of the radicals Ri and R _{2 is} a p-chlorophenoxyalkanecarboxylic acid radical and Rj is a hydrogen atom, a methyl group or a p-chlorophenoxy radical, R _{4 is} a hydrogen atom or a methyl group.

The invention also relates to a process for the preparation of the phenoxyalkanecarboxylic acid esters general formula (1), which is characterized in that in a known manner either one Phenoxyalkanecarboxylic acid of the general formula (III)

■ Ο — C-COOH

(III)

35 Ο — C — COOH (III)
R4

in which Rj and R _{4 have} the aforementioned meaning, or a reactive derivative of this acid with a

in which R ₃ and R ₄ are the 40 oxyalkyl esters of salicylic acid of the general formula (IV) specified in claim 1

Have meaning or a reactive derivative of these acids with an oxyalkyl ester of Salicylic acid of the general formula (I V)

COO (CH ₂ ) _B OH

(IV)

45

COO (CH ₂ ) "OH

(IV)

in which R ₂ and η have the meaning given in claim 1, reacts, or reacts an oxyalkyl ester of phenoxyalkanecarboxylic acid of the general formula (III) with salicylic acid or acetylsalicylic acid or their reactive derivatives and optionally subsequently acetylating them.

3. Medicines, characterized by a content of one or more compounds according to claim I, optionally together with customary pharmaceutical carriers and auxiliaries.

The invention relates to phenoxyalkanecarboxylic acid esters of oxyalkylsalicylates of the general type in which R ₂ and π have the aforementioned meaning, reacts or reacts an oxyalkyl ester of phenoxyalkanecarboxylic acid of the general formula HI with salicylic acid or acetylsalicylic acid, or its reactive derivative, and optionally subsequently acetylated.
The following process variants are preferred for the preparation of the phenoxyalkanecarboxylic acid esters of the general formula (1):

If R _{2 is} a hydrogen atom, the esterification takes place starting from salicylic acid with an oxyalkyl ester of phenoxyalkanecarboxylic acid (variant A), or by esterifying the oxyalkyl ester of salicylic acid with phenoxyalkanecarboxylic acid (variant B).

Ri means a hydrogen atom. so will first the salicylic acid with a reactive derivative de Phenoxyalkanecarboxylic acid reacted and the resulting compound with an alkanediol direk esterified (variant C), their alkali salt with a haloalkane! implemented (variant D), or derei

Acid chloride reacted with an alkanediol (variant E).

If Ri and R _{2 are} identical or different phenoxyalkanecarboxylic acid residues, the oxyalkyl ester of salicylic acid is reacted with a reactive G derivative of phenoxyalkanecarboxylic acid (variant E), or the monoester resulting from process variants A and B with a reactive derivative of the corresponding phenoxyalkanecarboxylic acid (variant G) or the hydroxy ester resulting from process variants C and D with the phenoxyalkanecarboxylic acid, respectively. their reactive derivative (variant H) implemented.

If R2 is an acetyl radical, then acetylsalicylic acid is preferably their acid chloride, with an oxyalkyl ester of phenoxyalkanecarboxylic acid (variant J) implemented, or the monoesters obtained according to variant A and B subsequently with acetic anhydride or acetyl chloride esterified (variant K).

Suitable acid derivatives of both the salicylic acid and the phenoxyalkanecarboxylic acid component are z. B. acid chlorides, acid anhydrides or esters.

The direct esterification of the acids with the oxyalkyl ester is carried out with the addition of a catalyst, such as Hydrogen chloride, sulfuric acid, sulfonyl chloride, p-toluene sulfonic acid or, particularly preferred, with kieselguhr carried out in aromatic hydrocarbons at temperatures between 100 ° and 150 ° C, the Water of reaction can be removed azeotropically. In the same way, the implementation in halogenated hydrocarbons, such as chloroform or dichloroethane, with sulfuric acid as the dehydrating agent be performed.

The molar ratio between the reactants is preferably 1: 1 to 1.3. The time to Completion of the reaction takes about 2 to 16 hours.

The invention also relates to medicaments which contain the compounds described in more detail above contain.

The production of the connection according to the invention is explained in more detail using the following examples:

example 1
(Variant B)

18.2 g (0.1 mol) of salicylic acid mono-glycol ester are dissolved in 200 ml of xylene and, after the addition of 4.0 g of kieselguhr and 18.6 g (0.1 mol) of p-chlorophenoxyacetic acid, heated on a water separator for 16 hours with saturated sodium bicarbonate solution! »like xylene solution washed with water i. V. evaporated and crystallized from a little ethanol. There are 21.6 g (61.4% of theory.). 1 - (salicyloyl-oxy) -2- (p-chlorophenoxyacetyl-oxy) -ethane of melting obtained from 85 to 86 ⁰ C..

JR (KBr): 3200.1769.1670.1615 / cm.
Elemental analysis: Ci7Hi5CIO ₆ (350.7):

Calculated: C 58.22, H 4.31, CIlO ₁ II;

Found: C 58.35, H 4.38, Ci 10.07.

Example 2
(Variant B)

36.4 g (0.2 mol) of salicylic acid mono-glycol ester Dissolved in 400 ml of xylene and after the addition of 8.0 g of kieselguhr and 40.4 g (0.2 mol) of 2- (p-chlorophenoxy) propionic acid Heated for 16 hours on a water separator. The filtered reaction solution is saturated with Bicarbonate solution and water washed and i. V.

evaporated The distillation residue is distilled on a thin film evaporator at 130 ⁰ C and 4 - 10 ² Torr, whereby 46.0 g (63% & th.) 1 (Salicyloyl-oxy) -2- [2- (p-ch! orphenoxy) - propionyl-oxy] ethane can be obtained as a colorless to slightly yellowish oil.

JR (FiIm): 3200, 1750, 1675, i615 / cm. Elemental analysis: Ci8H ₁₇ C! O6 (364.8):

Calculated: C 59.26, H 4.69. C110.72; found: C 59.26, H 4.77, el 10.16.

Example 3 (variant B)

Preparation according to Example 2 using 42.8 g (0.2 mol) of 2- (p-chlorophenoxy) -2-methyl-propionic acid.

The distillation in the thin film evaporator at 180 ⁰ C and 4 × 10 ^-2 Torr yields 33.0 g (43.3% d. Th.) L- (Saücyloyl-oxy) -2- [2- (p-chlorophenoxy) -2 -methyl-propionyl-oxy] -ethane as a yellowish oil.

JR (film): 3200.1740.1625.1615 / cm. Elemental analysis: Ci9H ₁₉ ClO6 (378.8):

Calculated: C 60.24, H 5.05, Cl 9.36; found: C 60.40, H 5.11, Cl 9.17.

Example 4 (variant B)

31.5 g (0.15 mol) 1- (salicyloyl-oxy) -butan-4-ol is in 250 ml of xylene dissolved and with the addition of 12.0 g of kieselguhr and 63.0 g (0.3 mol) of 2 (p-chlorophenoxy) -2-methyl-propionic acid, as described under Example 3, implemented and worked up.

The distillation thin film evaporator at 180 "C and 4 × 10 ^-3 Torr yields 28.8 g (47.2% of theory..) - (Salixyloyl-oxyH ^ ip-chlorphenoxyJ - ^ - methyl-propionyl-oxy] butane as a pale yellow oil.

JR (film): 3190.1735.1670.1615 / cm. Elemental analysis: C _{2 (} H ₂₃ CIO ₆ (406.8):

Calculated: C 61.99, H 5.69, Cl 8.71; found: C62.29, H 6.17, Cl 862.

Example 5 (Variant E)

32.0 g (0.1 mol) 2- [2- (p-chlorophenoxy-2-methyl-pro-

pionyl-oxy} -benzoic acid with a melting point of 130 ° to 132 ° C. is heated with 11 ml (0.15 mol) of thionyl chloride until the evolution of gas has ceased. After the excess thionyl chloride has been distilled off, the distillation residue is dissolved in 100 ml of chloroform and, after addition of 11.0 g (0.11 mol) of triethylamine, 12.4 g (0.2 mol) of ethylene glycol are slowly added. After the addition has ended, the batch is stirred for a further 2 hours until the exothermic reaction has subsided and shaken out with water. After the solvent has been distilled off, the residue is distilled on a thin-film evaporator at 185 ° C. and 2 × 10 ^-3 Torr, with 24.0 g (63.4% of theory) of 2- [2- (p-chlorophenoxy) -2 methylpropionyloxy] benzoic acid mono-glycol ester as

pale yellow oil et ^{1 will} hold.

JR (film): 3500, 1755, 1725, 1610 / cm. Elemental analysis: Ci ₉ H ₁ <, CIO 6 (378.8): Calculated: C 60.24, H 5.05, Cl 9.35; Found: C 60.86, H 5.16, Cl 8.66.

Example 6
(Variant F)

18.2 g (ü \ l MoI) salicylic acid mono-glycol ester are dissolved in 200 ml of chloroform and after adding 22.0 g (0.22 mol) of triethylamine slowly with 45.1 g (0.22 mol) of p- Chlorophenoxyacetylchloride added. The Ansav. is refluxed for 2 hours. The solution is washed with water, saturated sodium bicarbonate and water. After evaporation, the distillation residue in the thin film evaporator at 165 ° C and 2 - 10- ² Torr to incipient distillation. The remaining distillation residue is crystallized from a little diisopropyl ether and then from ethane. There are 35.1 g (67.5% of theory) 1 - [(2'-p - chlorophenoxy - acetoxy) - benzoy 1 - oxy] - 2 - (ρ - chlorophenoxyacetoxy) ethane with a melting point of 8 ° C.

JR (KBr): 1780.1765.1715.1610 / crn.
Elemental analysis: C2 _{5 H2oCl20 8} (519.3):

Calculated: C 57.83, H 3.88, Cl 13.65;

Found: C 57.78, H 3.99, Cl 13.52.

Example 7
(Variant F)

Preparation according to Example 6 using 523 g (0.21 mol) of 2- (p-chlorophenoxy) -2-methyl-propionyl chloride.

The distillation residue is distilled on a thin-film evaporator at 180 ^° C. and 2 · 10 " ³ Torr, 40.1 g (69.7% of theory) 1 - [2 '- (p-chlorophenoxy) -isobutyryl-oxy) -benzoyl-oxy] -2- [2- (p-chlorophenoxy) -isobutyryl-oxy] -älhan obtained.
Elemental analysis: C29H28Cl2O ₈ (575.4):

Calculated: C 60.54, H 4.91, CI 12.32;

Found: C 60.57, H 5.05, Cl 12.21.

Example 8
(Variant F)

12.6 g (0.033MoI) hydroxy ester according to Example 10 are dissolved in 100 ml of chloroform and after the addition of 6.6 g (0.066MoI) of triethylamine slowly with 15.3 g (0.066 mol) 2- (p-Chlorpher? Oxy) -2-methyl-propiony! -

chloride added and as described in Example 6.

worked up.

ίο There are 16.5 g (86.6% of theory) l- [2 '- (p-chlorophen

oxy) -isobutyryl-oxy) -benzoyi-oxy] -3- [2- (p-chlorophenoxy) -propionyl-oxy] -propane obtained as a yellowish oil.

JR (FiIm): 1820.5755.1725.1610 / cm.
Elemental analysis: C ₂ SH ₂ SCl ₂ O ₈ (575.4):
Calculated: C 60.53. H 4.90, Cl 12.32;
found: C. 60.58, H 5.06, Cl 12.80.

Example 9

• (variant J)

53.8 g (0.2 mol) l ^J [2- (p-chlorophenoxy) propionyloxy] -propane-3-ol are dissolved in 200 ml of chloroform and, after addition of 22.0 g (0.22 mol) of triethylamine slowly with 43.6 g (0.22 mol) Acetylsaüzyläurechlorid, dissolved in 50 ml chloroform, added. The reaction mixture worked up according to Example 6 is ^{distilled on a thin-film evaporator at 190 to 200 °} C. and 0.1 Torr. There are 43.7 g (51.9% of theory) 1 - [^ '- acetoxy) - benzoy 1 - oxy] - 3 - [2 - (ρ - chlorophenoxy) - propiony I-oxy] propane as almost colorless oil obtained.

JR (FiIm): 1755.1725.1610 / cm.
Elemental analysis: C ₂ IH _{2 ICIO 7} (420.8):
Calculated: C 59.83, H 5.03, Cl 8.42;
Found: C 60.46, H 5.14, Cl 9.24.

Example 10 to 22
In accordance with process variants A to K, the following additional compounds were established:

E.g.*) Vari η Ri • R2 JR (cm- ') 1612 the end ante OC-CH (CH ₃ ) O-CbHi-CI 1615 prey 10 A. 3 OC-CH (O-CeHi-Cl) ₂ H 3190, 1740, 1670, 1610 52.9 11th A. 2 H H 3160, 1770, 1674, 1610 67.8 12th E. 2 H OC-CH ₂ O-CeHi-CI 3500, 1755, 1725, 1610 69.5 13th D. 2 H OC-CH (CH ₃ P-CeHi-CI 3510, 1750, 1730, 1610 73.4 14th C. 3 H OC-qCH ^ O-CeHi-Ci 3490, 1752, 1728, 77.3 15th E. 4th R2 OC-qCH3) ₂ O-CeHi-CI 3400, 1748, 1725, 70.9 16 F. 2 R2 OC-CH (CH ₃ p-CeHi-Cl 1765, 1725, 1610 86.7 17th F. 2 OC-CH ₂ O-CbHi-CI OC-CH (O-CeHi-CI) J. 1765, 1725, 1612 67.9 18th G 2 OC-qCH3) 2O-CeHi-CI OC-C (CH ₃ J ₂ O-CeHi-Cl 1760, 1730, 1610 65.7 19th G 4th OC-qCH3) 2O-CeHi-Cr Ri 1765, 5725, 1610 62.8 20th K 2 OC-CH (CH3p-CeHi-Cl CH ₃ CO 1760, 1730, 1610 71.2 21 K 2 OC-qCH3) 2O-CeHi-Cl CH 3CO 1755, 1725, 1608 73.4 22nd 1 4th CH 3CO 1755, 1728, 1608 69.1

·) With the exception of the compounds of Example 11 (m.p. 89 ° C) and Example 17 (mp 131 ° C) are all compounds listed oily liquids at the thin-film evaporator at an oil circulation temperature of 160 ° to 200 ⁰ C and a vacuum of 10 ~ ² to 10 ^-3 torr were distilled.

The compounds according to the invention have an excellent anti-peresic wedge of activity with a good one Compatibility.

The therapeutic effectiveness of the invention Compounds according to Example 3, 7 and 20 were tested in animal experiments on female rats against the known Antilipaemica 2- (p-chlorophenoxy) -2-methyl-propionic acid (ciofibric acid), its ethyl ester (clofibrate) as well as against one consisting of equal weights Mixture of microencapsulated acetylsalicylic acid (ASA) and clofibrate tested.

Here, the compounds or the vehicle

(Polyethylene glycol 400) via a test cell administered by gavage for 14 days. 24 hours after the last dose, the Blood samples taken to determine scrum cholesterol and serum triglyceride levels.

In a first series, the effectiveness was tested on normolipemic rats with a body weight from bO to 95 g examined, which was a standardized, pelleted laboratory diet over the entire test period received (normal diet). The diet consisted essentially of crude proteins and carbohydrates a raw fat content of max. 3.9%, enriched with vitamins, minerals and amino acids.

In a second study, the effectiveness on hypercholesterolemic rats was determined according to the information von B e r g e r et al., Proc. Soc. Hxp. Biol. 132, 293 (1969) examined.

The animals that were initially normolipemic were given the above to produce artificial hyperlipidemia described standardized normal diet in powdered form, the one with 2% cholesterol and 1% cholic acid was moved.

The results of these two series are summarized in the table. The statistical significance ρ the results are included.

The test model used here under normal diet and hypercholesterol diet allows a reliable delimitation the activity in comparison with the known anilipaemics clofibric acid and clofibrate, as known is that the latter only intervene endogenously in the metabolic process, d. H. only a good one with a normal diet

ίο show activity while this activity is exogenous Metabolic influence ζ. Β. is completely lost through fat or massive cholesterol intake.

As the test results show, are according to the invention Compounds according to Example 3, 7 and

ι ;; 20, which or as direct descendants of Ciofibric acid can go from clofibrate, comparable to clofibrate in terms of lowering cholesterol.

However, this does not apply to lowering the triglyceride value on a hypocholesterol diet, as this is the case

ίο in contrast to clofibrate in particular the connection Genes according to Example 3 and 7 cause a significant reduction.

Tabel

Anti-lipemic activity under normal diet and hypochondriacal diet

E.g. mg / kg Normal diet
Chole
sterol
mg% %
Lowering Tri-
glyceride c
mg% %
Lowering Hypcrcholeslcrindiäl
Chole%
stcrin lowering
mg% - Tri-
glyceride c
mg% %
Sen
kung control - 96.4 - 66.7 - 453.4 - 54.2 - 3 100
250 85.4 *)
87.8 11.4
8.9 67.4
58.1 ! 2.9 469.8
625.9 - 47.3 ·)
52.1 12.7
3.9 7th 100
250 89.7
80.2 ···) 7.0
16.8 73.9
75.6 527.8
690.7 - 35.5 ·)
36.7) 34.5
32.3 20th 100
250 80.3 * ·)
76.9 *) 16.7
20.2 79.6
97.1 - 699.0
517.0 - 53.1
55.1 2.0 ASA / clofibrate 1: 1 100
250 87.6
104.0 9.1 65.8
51.4 1.3
29.9 483.6
565.8 - 51.1
54.3 5.7 control - 95.8 - 69.2 - 536.6 75.9 - Ciofibric acid 100
250 96.9
89.4 6.6 54.8
50.8 *) 20.8
26.5 572.8
587.8 - 69.7
62.7 8.2
17.4 control - 76.9 - 123.8 - 358.6 3.0 86.4 - Clofibrate 250 56.1 "*) 27.0 6b, 5 **) 46.3 347.Q 75, b 12.5 ") ρ <0.05.
· *) P-cO.OI.
***) p <0.00 !.

If you take into account. that in the tested compounds according to Example 3. 7 and 20 with respect to the Lipid lowering of the clofibric acid residue represents the active principle and that the compounds according to Example 3, 54%, according to Example 7, 70%. and according to Example 20, revealing 49% of this active principle, it results from this in comparison to Oofibrinsiiiirc rcsp. Cloiibrate a much higher therapeutic index.

The other compounds falling under the general formula have a comparable effect.

The acute oral to \ i / ii; il the criiiidungsgemeinschaft Connections were made according to the method of t ". S. Because. Biometrics K. 244-26 3rd H ") 2nd. M mice certainly.

r _v s connection according to example 3:

LD ₅₀ 1492 mg / kg (1276-1744)
Connection according to example 7:

l.Dio 1142 mg / kg (992-1 309)
Connection according to example 20:

LDw 1Π6 mg / kg (101 3- 122K)

/ in order to compare the oral Tnvi / iiai a
Mixture of the same (icuichtstcilen mikrovci kups
ter AccUlsaÜA Kinne and (lolibrai an der Kailc u
me the method of I. ι ι ch I'i c I d K W i I cο \ <
examined. Here I.ψ the permiiielie 7 1 .ige Ι.Π ,,, I
KdO mg / kg (W) 4- ^ 2 (I)

7ΙΙΊ CiW /. "

HE; ":"

The compounds according to the invention therefore show a significantly lower toxicity compared to the starting products.

The medicaments according to the invention contain one or more phenoxyalkanecarboxylic acid residues of the general kind Formula (I) as an active ingredient. It is preferably used orally, e.g. B. in the form of tablets or

ίο

Capsules, which optionally contain conventional pharmaceutical carriers and auxiliaries, e.g. B. lactose, starch, talc or magnesium stearate.

The compounds according to the invention are administered orally or rectally, depending on the case Daily doses of 100 to 1000 mg, preferably 250 to 750 mg. in the usual pharmaceutical forms.

Claims (1)

Formula (I) Pacentaji sayings: 1. Phenoxyalkanecarboxylic acid esters of oxyalkylsalieylates of the general formula (1) OR ₂ (D -COO (CH ₂ ), -O-R,
OR ₂