CZ121493A3 - Derivatives of 4-alkoxy-3-propyl-2-hydroxyacetophenone - Google Patents

Abstract

Derivatives of 4-alkyloxy-2-hydroxy-3-propylacetophenone of general formula I in which Y means O or S, Q means CH2COOR or COOR where R is hydrogen or a lower alkyl with 1 to 3 carbon atoms; if P is hydrogen or halogen then Z means (CH2)n, where n = 2 to 4, when P is hydrogen, Z may also be CH2CH(OH)CH2. The methods for preparing these compounds and pharmaceutical preparations containing these compounds as the active substance are described as well.<IMAGE>

Description

Technical field

The present invention relates to 4-alkyloxy-3-propyl-2-hydroxyacetophenone derivatives, to processes for their preparation and to pharmaceutical compositions having anti-inflammatory and anti-asthmatic activity.

BACKGROUND OF THE INVENTION

Influencing the enzymes that catalyzes the oxidative metabolism of arachidonic acid is a very fruitful basis for the development of effective drugs, especially with anti-inflammatory, if immunomodulatory activity. Initially, it was primarily cyclooxygenase inhibitors that prevent the biosynthesis of prostaglandins and thromboxanes, which are useful as anti-inflammatory agents and peripheral analgesics. Later, an alternative arachidonic acid biotransformation was discovered in which other important arachidonic acid metabolites, leukotrienes, are formed by S-lipoxygenase (Taylor GF, Clarke SR: Trends Phartaacol. Sci. 7, 100 <19863). The leukotrienes CLTJ C ₄ and D ₄ CSamuelsson B. * Science 220, 568 <19833 as a component of tz in the slow-reacting substance of CSRS-AJ inducing an anaphylactic reaction and known for nearly half a century <Bocklehurst VE: J. Physiol. 120, 16P ¢ 19533. SRS-A is a mediator of inflammation in bronchial constriction and causes vascular permeability in 'disease' associated with immediate hypersensitivity of CDahlen S. et al Nature <London3 288, 484 <19803. an important chemotactic agent for various cell types, including those involved in the development and development of an inflammatory process. trophies, is a mediator of lysosomal enzyme release and promotes superoxide formation <Ford-llutchinson AV et al .; J.

Immunol. 125, 1789 <19803, is therefore considered to be an important mediator of a number of inflammatory diseases <Bray H. A.: Agents Actions • 2

IP, 1 (19862.

and

In the last decade, significant progress has been made in the research of leukotriene antagonists. Discovery of FPL 55712

CXugstein J. et al., Nature (London J New Biol. 248, 215 (19732 _t derived from,, 4-dihydroxy-3-propylacetophenone) opened the way for the development of a number of potent antagonists of the so-called cysteine leukotrienes containing a hydroxyacetophenone fragment. modifications of the parent compound have yielded a number of significantly effective LT antagonists and the best known include LY 171,883 bearing a tetrazole skeleton molecule (Fleisck JH et al .: J. Pharmacgl. Exptl. Ther. 233, 148 C19853 and L 649,923, containing in addition to dihydroxyacetophenone fenylhydroxybutanové acid residue fragment (Jones et al .: TR Can.J.Physiol.Pharmacol. 64, 1068 (1986). One of the most recent _substances containing fragment _from dihydroxyacetof enone derivative CGP 45715 a, whose structure can be simultaneously considered analogous LT (von

Sprecher, A. et al., Drugs Fut. 16, 827 (19912). Although no drug has yet been developed in this class of substances, derivatives containing said hydroxyacetophenone fragment remain of interest in research into anti-inflammatory drugs and anti-asthmatics.

Most of these compounds are characterized primarily by a significant ahtagonist effect against cysteine leukotrienes with a low 5-lipoxygenase inhibitory effect. Exceptionally, antagonism to LTB ₄ has been reported, eg, for SC-41930.

(Djur.ic SV et al., J. Med. Chem. 32, 1145 (19892), but the dihydroxyacetophenone fragment is modified by methylation of free hydroxyl. Inhibition of 5-lipoxygenase has been rarely described for 2,4-dihydroxyacetophenone derivatives, e.g. , for WY-44329 (Levis AJ et al., Int.J. Immunopharmacol. 7, 384 (19862), which was also reported to have an LTD antagonist effect.

SUMMARY OF THE INVENTION

The present invention is based on novel 4-alkyloxy-3-propyl-β-hydroxyacetophenone derivatives of the general formula:

CD

wherein Y represents O or S, Q is CH _£ COOH or COOR wherein R is hydrogen or lower alkyl of 1 to 3 carbon atoms, followed if alkali metal cation or an organic base; if P is hydrogen or halogen / Z then represents CCH ^ j ^, where n »2-4 when P is hydrogen, may also denote CH Z CHCOHjCH _{g £.}

Organic synthesis methods may be used to prepare these compounds, with the reaction of 4-Co-haloalkyloxy-3-propyl-2-hydroxyacetophenone of formula II being preferred.

CID * wherein n is 2 to 4 and Hal is chlorine, bromine or iodine; or

4-C3-epoxypropoxy] -2-hydroxy-3-propyl acetophenone of the formula. TiT

with a mercaptobenzoic or hydroxyarylacetic acid derivative of the general formula IV

ΗΓ

CIV?

/ j

in which P. Q and Y are as defined above.

The reaction of II and IV usually takes place in a boiling lower ketone, e.g. acetone or 2-butanone, in the presence of a suitable base, preferably anhydrous potassium carbonate. The condensation of IV with epoxy derivative III is usually carried out in boiling lower alcohol, preferably methanol. The esters obtained can be converted to the free acids I (R = H 3 by conventional methods of hydrolysis, for example by treatment with an aqueous-alcoholic solution of an alkali hydroxide at 60-110 ° C, preferably at the boiling point of the alcohol / water mixture used. the free acid by acidification with a suitable organic or inorganic acid.

The Lize compounds are also preferably prepared by condensing 2,4-dihydroxy-3-propyl acetophenone / V

with a haloalkylthio- or haloalkyloxy derivative of the benzoic or arylacetic acid of the general formula VI

Hal (CEL) Y 4 Π

CVD,

P 'in which P. Q, Y and n are as defined above and Hal is chlorine, bromine or iodine. ^;

Compounds I, including pharmaceutically acceptable salts with inorganic or organic bases, which are the subject of the present invention, exhibit significant potency in inhibiting biosynthesis.

leukotrienes and also have considerable affinity for the binding sites of leukotriene receptors, in particular leukotrienes LTB4 and LTD4.

The combination of these effects is an important prerequisite for their λ

anti-inflammatory and anti-asthmatic activity in pharmaceutical compositions which are a further object of the invention. At the same time, these substances are characterized by low toxicity including the absence of ulcerogenic effect. They may be used to prepare therapeutic compositions which may contain the active ingredient in admixture with pharmaceutically acceptable excipients, liquid or solid, which are customary in the manufacture of dosage forms. Said biological activities of compounds I were evaluated in the following tests.

Inhibition of the LT B ₄ ex vivo

A considerably modified method was used for the evaluation (Palmer R.M.J. and Salmon J.A .; Immunology SO, 65 (1983), using a different source of cells).

1 ml of heat-inactivated rat serum was intrapleurally administered to Wistar female rats. After 4 h, the rats are sacrificed and the exudate is withdrawn. Dilute with 1: 1 balanced HEPES buffer and centrifuge at 150 g for 5 min. The cells are then washed with an equal volume of 0.87 µl of ammonium chloride and again centrifuged under the same conditions. Resuspend in an equal volume of buffer and centrifuge again. The procedure is repeated 2-3 times. The cell concentration is measured and adjusted to 10 million cells / ml with buffer. The cells were allowed to equilibrate for 15 minutes at 37 ° C. 450 µl of cell suspension was pipetted to 50 µl of test compound solution. A buffer-only sample serves to detect unaffected synthesis; sample with 100 µg of NDGA per ml to completely inhibit it. Incubate for 15 min at 37 ° C. Then, µL of Ca ionophore A 23187 solution is added to a final concentration of 0.5 µg / ml and incubation is continued for another 15 min. The reaction is. Centrifuge at 2000 g for 1 minute. Collect 500 µl of LTB 4 supernatant. The LT content of the samples is determined by the Amersham RIA kit.

Effect of LT B ₄ receptor binding

The work-based method (Cheng J.B. et al .: J.

Pharm. Exp. Ther. 236, 126 (1986) with minor modifications. Spleens were removed from male guinea pigs and prepared as usual

6 · membrane fraction. 2 mg wet C membranes C were incubated with 0.3 nM H LT for 30 min at 25 ° C in a 100 µl incubation mixture. Nonspecific binding is determined in the presence of 0.1 µM LTB 1. The membranes were filtered through a filter

Whatman GF / C, washed three times with buffer, radioactivity measured ka ^! _'W o arms scintillation spectrometry, and specific binding determined by H ^ LT B receptor.

Effect of LT receptor binding

A method based on the work of CBruns R.F. a spol .:

Life Sci. 33, 645, C19832. The lungs were removed from male guinea pigs and the membrane fraction was prepared in a conventional manner. 4 mg Cv membranes per wet tissue? were incubated with 0.4 nM H

LT for 60 min at 25 ° C in an incubation mixture with a total volume of 100 µl. Nonspecific binding is determined in the presence of 0.1 pM of LT D .. The membranes were processed as in the previous test, and ⁴ 3 H LT specific binding to the receptor was determined by measuring the radioactivity by liquid scintillation spectrometry.

Inhibition of carrageenin edema

CVinier J .: Why. Soc.Exptl. Biol. Copper. 111, 544 C19622 was evaluated by inducing edema by injecting a 0.5 µL carrageenin solution in Wistar Han rats. Test substances were administered p.o. in a single dose in suspension with acacia 1 hour prior to induction of edema. The volume of edema was measured with a CUgo Basel umolumometer at intervals of 1.5, 3.,

4.5 and 6 hours after carrageenin injection. The effect was expressed by inhibition of edema compared to the untreated control group. Each group contained at least 6 animals.

Inhibition of experimental pleuritis

Cttidaha, T .: J. Pharm. Pharmacol. 38, 242 C19862 was evaluated in a group of Wistar Han female rats injected with 0.5 µl carrageenin in saline. Test substances were administered p.o. in a single dose in suspension with acacia 1 hour before the injection of carrageenin. After 4 hours, the animals were killed, the pleural cavity exudate collected and its volume measured. Cell stamina and cell content were determined using a Sysmex cell counter compared to the untreated control group.

and

Inhibition of ear edema (Opas EE et al .: J.Invest.Dermatol. 84, 253 (19 & 53), induced in male mice by administration of arachidonic acid at a dose of 2 mg per ear C in a solution of 100 mg in 1 ml of acetone}. administered 1 hour prior to induction of edema After 1 hour, the animals were sacrificed and the degree of hyperlobia of the auricle and its weight compared to the control were determined.

Inhibition of LT-induced allergic bronchospasm was evaluated by a modified method (Kreutner, V. et al., Agents and Actions 28, 173 (1989)), in which a bronchoconstrictor response was induced in guinea pigs by administration of 1 pg / kg LT i.v. The animals were pretreated with indomethacin, mepyramine and propranolol and the test substance was administered at doses of 10, 30 and 100 mg / kg. after. 5 min before LT D ^ administration. The effect expressed by X inhibition of bronchospasm compared to the untreated control group.

The results of the evaluation of selected substances in the tests are summarized in Tables I, II and III. A number of substances that are subject to patent applications not only inhibit 5-lipoxygenase, but also have affinity for the binding sites of leukotrienes and D 2. The dichotomous nature of the effects of these compounds on biosynthesis. the biological function of leukotrienes is manifested by their anti-inflammatory and anti-asthmatic effect.

DETAILED DESCRIPTION OF THE INVENTION

The following examples illustrate the invention sufficiently, but do not limit it in any way.

Example 1: 4-C4-Bromobutoxy-3-propyl-2-hydroxyacetophenone. 39.0 g of C0.2 molyl-3-propyl-2,4-dihydroxyacetophenone, after dissolution in 230 ml of acetone, are added with stirring over a period of 2.5 hours to a boiling mixture of 172.4 g of CO, 8 moles of 1,4-dibromobutane, 3.0 g CO 2 O 2? of potassium iodide and 28.0 g of CO 2, 2 mol of potassium potassium carbonate in 390 ml of acetone. Boiling is continued for a further 9.5 h. Thereafter, the acetone is evaporated under vacuum and at about 70 ° C / 1.33 kPa. excess 1,4-dibromobutane is distilled off. The residue (which upon cooling below 0 ° C solidifies) is subjected to vacuum distillation; a product fraction of 175-180 ° C / 40 Pa was collected as a product. 57.8 g of C87.0 of the desired substance are obtained, which is 95% pure by GLC; ¹ H-NMR CC ² HCl ₃ ?:

HCO} 12.78 s; CH 8 CCO} 2.58 s; CH 2 CO 4.08 t; CH _g CBr} 3.50 t.

Example 2; 4-C3-Chloropropoxy-3-propyl-2-hydroxyacetophenone

15.5 g of CO, 08 molar) -3-propyl-2,4-dihydroxyacetophenone in 80 ml of acetone are slowly added to the boiling mixture of 50.4 g of CO, 32 mol of 1-chloro-3-bromopropane, 11.1 g of CO 2. .08 mol ^ uD bezv. potassium potassium carbonate and 1.2 g of potassium carbonate (0.008 mol) in 70 ml of acetone. After a total of 5 hours of boiling, the mixture is cooled to 20 ° C and poured into 300 ml of ice water with stirring. The precipitated oil is extracted into dichloromethane, dried over calcium chloride and evaporated under vacuum. The residue is dissolved by boiling in a minimum amount of 2-propanol, filtered with charcoal, and crystallized from the filtrate upon cooling. After filtration, wash

2-propanol and dried to give 14.6 g of C67.4.0 product s

mp 39-41 ° C, uniform according to GLC. For ^C 14 H 10 _{ug 3} C270.75} calculated: 62.10% C; H, 7.07; 13.10% Cl; Found: C, 62.36;

7.40% H; 12.82% Cl; ¹ H-NMR CC ² HCl ₃ }: HCOD 12.76 s; CH 8 CCO} 2.58 s; CHgCOD 4.10 t; CHgCCD 3.77 t.

Example 3: 4-C2-Chloroethoxy} -3-propyl-2-hydroxyacetophenone

A mixture of 54.7 g of 0.22 mol of 2-chloroethyl tosylate, 45.3 g of CO, 23 mol of 2,4-dihydroxy-3-propylacetophenone, 32.0 g of colorless salt. of potassium iodide in &gt; 300 ml of acetone is heated to boiling under stirring for 16 h. After cooling to 20 DEG C., the solid is filtered off and the filtrate is evaporated to dryness. The residue was dissolved in 400 mL of dichloromethane and the solution was washed with 100 mL of 2% sodium hydroxide and 2 x 100 mL of water. After drying over magnesium sulfate, the solution was concentrated in vacuo to a crystalline residue. The crude product was crystallized from methanol to give 21.0 g of C35.6 product, mp 72-73.5 ° C, uniform by GLC. For ^C 13 ^H 17 ¹⁰ 3 ^{73 C256 *;)} calculated: 60.81% C; H, 6.67; 13.81% Cl;

Found: C, 60.94; 6.72% H; 13.80% Cl; 1 H-NMR

CCHCtyj:

HCO 3 12.75 s; CH 2 CCO 2.59 s; CH _£ COD 4.30 t; CH _£ CCD 3.84 t.

and

Example 4: 4-C3-Epoxypropoxy-3-propyl-2-hydroxyacetophenone

To a solution of 19.4 g of 0.1 mole of 2,4-dihydroxy-3-propylacetophenone in 100 ml of 2-butanone was added 20.7 g <0.15 mol of aq. potassium carbonate followed by 27.8 g of 0.3 mol of epichlorohydrin in 30 ml of 2-butanone over 15 min. After heating to reflux for 10 h, the insoluble matter is filtered off and the filtrate is evaporated in vacuo. The partially crystalline residue is poured over 50 ml of water and 100 ml of chloroform, the organic layer is separated after shaking and the aqueous layer is washed with 100 ml of chloroform. The combined extracts were dried in magnesium sulfate and evaporated in vacuo and the residue was purified by crystallization from 25 ml of 2-propanol. 14.5 g of C62.0 are obtained of the desired substance having a mp of 54-56.5 ° C with a purity of Cdle GLO, 98, OD of it; ¹ H-NMR A Acig 3: HCO 3 12.75 s; CH 2 CO 2 2.55 s; CH ₂ CO 3 4.10 t; CH _g CepOXyj 3.77 t.

Example 5: 3-C-3-C4-Acetyl-3-hydroxy-2-propylphenyloxypropylthio-benzoic acid

To a mixture of 6.7 g of CO 2 026 mol of 4-C3-chloropropoxyC-2-hydroxy-3-propyl acetophenone, 7.2 g of CO.052 mol. potassium carbonate and 0.39 g of potassium iodide in 50 ml of 2-butanone are added a solution of 4.0 g of CO 2 O 2 molar 3-mercaptobenzoic acid under a nitrogen atmosphere. The reaction mixture is heated to boiling under stirring for 24 hours, then the solvent is evaporated and the slurry is dissolved in water.

100 tni of water. The cloudy solution was acidified with dilute hydrochloric acid while cooling in an ice bath after filtration with activated carbon. 1 - 1. Crystallization of the crude product from methanol yields

7.3 g <73.0 of the desired compound, mp: 136-138 ° C.

C388.473 calculated: 64.92% C; 6.83 KH; . 8.25 64.95 µ C; 6.48 µ H; 7.94 Ji, S; ¹ H-NMR CCl 2 HClgO: CH 3 CCO 3 2.56 s; CH _g CO 3 4.17 t; CH _g CS? 3,22 t.

For

She S; found: HCOD 12.86 s;

^C 21 ^H 24 ° 5 ^N

In a similar manner to Example 5, the following were prepared:

Example 6: 2-C 3 -C 4 -Acetyl-3-hydroxy-2-propyl-phenyloxy-propyl-thiobenzoic acid prepared in 41.0% yield with m.p. 1614 σ

O

«.

here

LLJ

C 388.473

-163 ° C after crystallization from methanol}, m.p .: 64.92 ° C; H, -83%; 8.25 µ

For

P Cp ^ω 7 ·

X f-> 9 0 3 m.

5, τ o

^C o ^C 21 ^H 24 ° 5 ^N

WITH; Found: 64.79 ° C;

6.41 µ H; 8.03 µS; 1 H-NMR CC ² HCl ₃ 3: CH ² Cl ₂ 2.56 s; CH 2 CO} 4.22 bt; CHgCS3 3.12 bt.

Example 7: 2-C 2 -C 4 -Acetyl-3-hydroxy-2-propyl-phenyloxyethyl-thio-benzoic acid prepared in 45.2% yield with m.p. 153-15 ° C (after crystallization from acetic acid). For

C, 374.443; Calculated: 64.15; 5.92 µ H; 8.56 µS; Found: 63.93 ° C; 5.88 µ H; 8.62 µ S; ¹ H-NMR CC ² HCl ₃ 3: HCO 3 12.85 s; CH ₃ CCO ₃ 2.58 s; CHgCO3 4.36 bt; CHgCS} 3.42 bt.

Example 8: 2-C4-C4-Acetyl-3-hydroxy-2-propyl-phenyloxy-3-butylthio-benzoic acid prepared in 4.5% yield with mp 111-113 ° C after crystallization from chloroform}. For _the C "H" 0_S dd C402,493 to about calculated: 65.64 II C; 6.51 µ H; 7.97 µ S; Found: 65.39 ° C; 6.51 µ H; 7.97 µ S; ¹ H-NMR CC ² HCl ₃ 3: CH ₃ CCO ₃ 2.56 s; CHgCO3 4.08 bt; CH ₂ (S) 3.05 bt.

Example 9: 3- (4-C4-Acetyl-3-hydroxy-2-propyl-phenyloxy-3-butylthiobenzoic acid) prepared in 47, m.p. 113-115 ° C after crystallization from methanol}. C CggHggOOSS C4022,4,493 (49.44) calculated: 65.64 ° C; 6.51 µ H; 7.97 µ S; Found: 65.81 ° C; 6.72 µ H; 7.33 XS; ^{Χ Η} ~ ^ ΝΜΚ cAlCl: CC03 _CH3 2.55 s; CH 3 CO 4.06 bt; CHgCS3 3.10 bt.

Example 10: Methyl 4-C-4-acetyl-3-hydroxy-2-propylphenyloxy-3-butoxy-3-chlorophenylacetate

To a solution of methyl 3-chloro-4-hydroxyphenyloctane (0.035 mol) in 50 ml of 2-butanone is added 0.32 g of potassium iodide and 9.7 g of CO 2 07 mol. A solution of 12.5 g of CO, 035 moles of 4-C4-bromobutoxy-3-hydroxy-3-propyl acetophenone in 50 ml of butanone is slowly added to the suspension with stirring. The mixture was then heated to reflux for 24 h. After cooling, the insoluble matter was filtered off, washed with acetone on the filter and the filtrate was evaporated to dryness. The residue was dissolved in 120 ml of dichloromethane, washed twice with 50 ml of water and, after drying with magnesium sulfate, the solvent was evaporated. under vacuum. The oily residue crystallized on standing to give crude product C in a yield of 33.0 XI with an m.p. 67.5-71.5 ° C, directly applicable to the preparation of the corresponding acid. Crystallization from methanol gave the product with m.p. 71-72.5 ° C in 58.6% yield.

For C ₂₄ H 10 _{2 g of} C448,940 calculated: 64.20% C; H, 6.51; 7.90 X Cl; found: 64.36 XC; 6.63 XH; 8.39% Cl; ¹ H-NMR CC ² HCl_O:

Z o

HCOO 12.76 s; CH 8 CCOO 2.58 s; CHgCOO 4.12 bm; CHgCCOOO 3.53 s.

In a similar manner to Example 10, the following were prepared:

Example 11: 4-C3-C4-Acetyl-3-hydroxy-2-propylphenyloxypropoxy-3-chlorophenylethyl methyl methanoate prepared in the crude state in a yield of 82.5%; after crystallization from 2-propanol, the product with m.p. -76.5 ° C in 58.0% yield. For C ^ HH ^ ClOOO: C, 434.910: Calculated: C, 63.52; 6.26% H; 8.15% Cl; found: C, 63.41;

6.40 XH; 8.13 'Λ Cl; ¹ H-NMR CC ² HCl ₃ O: CH ₃ COOOO 2.56 s; CHgCOO

4.20 t, 4.22 CHgCCOOO 3.54 s.

Example 12: 4-C 3 -C 4-Acetyl-3-hydroxy-2-propyl-phenyloxy-propoxy-methyl-phenylacetate prepared in crude form in yield

91.5%, after crystallization in methanol, the product was obtained with mp 64-65.5 ° C in 48.0X yield. For C 23 H 25 N 6 O 4 400.450 calculated: 68.98% C; 7.05 ϊί H; found: 68.85% C; 7.18% H; ¹ H-NMR

CC ² HCl ₃₀ : CH ₃ COOOO 2.55 s; CHgCOO 4.16 t, 4.22 t; CHgCCOOO

3,56 s.

Example 13: 4-C2-C4-Acetyl-3-hydroxy-2-propyl-phenyloxy-ethoxy-3-chloro-phenyloxy-acetic acid prepared in the crude state in a yield of 85.7%, after crystallization from 2-propanol,

mp 90-91.5 ° C. For C _oo H _C10_ _of C42O, 890 Calculated: C 62.78%;

cc what about

5.99% H; 8.42% Cl; Found: C, 62.87; 6.09 XH; 8.51 X Cl; ¹ H-NMR CC ² HCl ₃ O: HCOO 12.85 s; CH ₃ CCOO 2.56 s; CH _£ COO 4.40 s; CHgCCOOO 3.75 s.

Example 14; 4-C4-C4-Acetyl-4-hydroxy-2-propyl-phenyloxy-butoxy-phenylacetic acid

Charge the flask with 11.0 g of CO 2.04 mol-free potassium carbonate, 0.6 g of sodium iodide and 17.3 g of CO 3 08 mopd 5 1,4-dibromobutane in 35 ml of 2-butanone. The mixture is heated to boiling point and

A solution of 3.3 is added. g of CO 2.02 mol of 4-hydroxyphenylmethane methyltane in 35 ml of 2-butanone. The boiling is then continued for a total of 14 h, after cooling, the insoluble material is separated by filtration and the filtrate is concentrated in vacuo to an oily residue which crystallizes on cooling. 5.7 g of C95.0% th.3 of crude 4-C4-bromobutoxy-3-phenylmethane methylate, which is 95% pure by GLC, are obtained; ^ H-NMR HC1 CC ² ₃ 3: CHgCester) 3.68. with; CH _g CO 3 3.98 d; CHg CBr3 3.48

t. found:

26.71% Br.

The preceding product (5.5 g of C18-18 mol) was dissolved in 50 ml of 2-butanone and the solution was added to a mixture of 3.5 g of CO, 018 mol of 3-propyl-2,4-dihydroxyacetophenone, 0.16 g of sodium iodide. and 5.0 g perfect. of potassium carbonate in 50 ml of 2-butanone. After stirring for 24 hours with stirring, the insoluble matter is filtered off from the reaction mixture after cooling ^. The residue is dissolved in 100 ml of dichloromethane, washed with 50 ml of 2% sodium bicarbonate, 50 ml of water and dried over sodium sulfate. , / '..λ ,. ¹ . Evaporation of magnesium to an oily residue gave 6.4 g of C86.3% th3 / 4-C4-C4-acetyl-3-hydroxy-2-propylphenyloxy-3-butoxy-3-phenyloctane-1-methyltetra; ¹ H-NHR CC ² HCl 3: CH-CCOO 2.54 s; CH _O CO 3 ...,., _P 3 3 2

4.05 bm; CHgCCOO? .3,55 s

The preceding ester (C6.0 g, 0.014 mol) was dissolved in 35 ml of methanol and a solution of 3.9 g of CO 2 07 mol / d of potassium hydroxide in a mixture of 55 ml of methanol and 15 ml of water was added. The mixture was heated under stirring to boiling for 4 h and then cooled to 20 ° C and slowly. . Pour into 70 ml of ice water with stirring. The turbid solution is filtered with charcoal and the filtrate acidified to pH 1 with hydrochloric acid. The precipitate formed is filtered, washed with water and, after drying, crystallized from nitromethane. 3.3 g of C56.4% 3 of the desired acid are obtained with mp, 74-78 ° C. Calculated: C, 66.02; H, 7.22; Found: C, 66.12; H, 7.08; ¹ H-NMR CC ² HCl ₃ 3: CH 3 CCOD 2.54 s; CH ₂ CO 3 4.02 bm; CH _£ CC00H3 3.55 s.

In a similar way as in the example, they were prepared;

Example 15: 4-C4-C4-Acetyl-3-hydroxy-2-propyl-phenyloxy-butoxy-3-chloro-phenylacetic acid prepared in 56.4X yield of Smartolysis O mp 108-109 ° C after crystallization from methanol? For C ₂₃ H ₂₇ C 10 ₆ C .CH ₃ 0H 466.95? calculated: 61.73 XC; H, 6.69; 7.59 X Cl; Found: 62.02% C; 6.60 * H; 7.92 X Cl; ¹ H-NMR CC ² HCl ₃ ? 12.72 s; CHgCCO? 2.54 s; CHgCO? 4.10 m; CHg

CCOOH? 3,55 s.

Example 16: 4-C2-C4-Acetyl-3-hydroxy-2-propyl-phenyloxy-ethoxy

-3-chlorophenylacetic acid prepared in 70.5% yield with m.p.

128-130 C Cpo by crystallization from methanol ?. For C406,85? calculated: 62.00 [deg.] C; 5.70 µ H; 8.71 µ Cl;

CCHC1 ₃ ?:

^C 21 ^H 23 ^C10 6 found: 2.58

CH3CO3

C 420.88? calculated: 62.78 X C, 99 µ H; 8.43 µ Cl;

1 ,,.-2. 62.49; 6.03 µ H; 8.47 X Cl; @ 1 H-NMR (CDCl3 ₎ :

CHgC COD

62.16 X C; 5.92 µ H; 8.61 µ Cl; 1 H-NMR s; CHgCO? 4.41 s; CHgC COOH? 3,58 s.

Example 17: 4-C 3 -C 4 -Acetyl-3-hydroxy-2-propyl-phenyloxy-propoxy-3-chloro-phenylacetic acid prepared in 49.0% yield with m.p. M.p. 123-124 ° C after crystallization from 2-propanol? For CggHggClOg found: 2.56 s; CHgCO? 4.23 t, 4.28 t; CHgC COOH? 3,56 s.

Example 18:. 4-C3-C4-Acetyl-3-hydroxy-2-propyl-phenyloxy-propoxy-phenylacetic acid prepared in 75.3X yield with mp 110-112 ° C after crystallization from methanol? For C386,44? C, 68.38; 6.78 KH; Found: 68.21 ° C C; 6.73 Η; ¹ H-NMR CCCl 2:?

12.73 s;

ch _{3 what} ?

2.55 s;

CH _g CO?

4,16 t.

4,22 t; CHgC COOH? 3,58 s.

Example 19: 2-C3 ^, -C4-Acetyl-3-hydroxy-2-propyl-phenyloxy-2'-hydroxy-propylthio-benzoic acid • Mixture of 2.5 g of CO. 4-C3-epoxypropoxy-3-propyl-2-hydroxyacetophenone and 1.54 g (0.01 M) of thiosalicylic acid in 50 ml of methanol are heated under stirring for 20 h. After cooling to 20 ° C, the mixture was filtered with charcoal and the filtrate evaporated in vacuo to an oily residue which crystallized on standing. Crystallization from nitromethane gave the desired product with mp 108-110 ° C in 69.3X yield. For C ₂₁ Hg ₄ 0 ₆ S C404,47? calculated; 62.35 XC;

AND?

AND

I ·, 1

H, 5.98; 7.93 X Cl; found: 61.79 ° C; 5.95. 7.66% Cl; ¹ H-NMR CC ² HCl ₃ 3: HCO 3 arom. 12.80 s; HC03 alif. 6.42 d; CHgCCOj

2.57 s; CH 3 CO 3 + CHCO 3 4.15 m; CHgCSO 3.19 m.

AND·'

Example 20: 3-C3'-C4-Acetyl-3-hydroxy-2-propyl-phenyloxy-D-2'-hydroxy-propyl-thiobenzoic acid prepared in the same manner as in Example 19 in 52.2X yield with mp 132-134 ° C after double crystallization from nitromethane 0. For ^C 21 ^H 24 ° 6 ^S C 404.473 calculated: 62.35 XC; 5.98 X * H; 7.93% Cl; found:

61.91% C; H, 5.92; 7.72 µ Cl; ¹ H-NMR CC ² HCl ₃ 3: HCO 3 arom. 12.72 s; HC03 alif. 6.41 d; CH ^ CO? 2.55 s; CH C03 + _£ CHC0H3

4.12 bs; CHgCS3 3.26 bt.

*

Example 21: Preparation of hard gelatin capsules

Gelatin capsules are prepared from a mixture of the following ingredients:

marriage: active substance \ 15 parts amylum maydis 4 parts sácharum láctis 37 parts cellulosum. microcryst. 45 parts silicii oxydum 0.3 part magnesii stearas 0.7 part Example 22: Preparation of obduktet OF the previously prepared lenticular cores are coated with water- The composition of: hypromellosum 67.13 parts · Macrogolum 6000 9.7 part pigment 2,23 part anti-foam additive 0.87 part - aqua purificata q.s.

tn O tn tn O cn tn O CM τ- 0 4 O « 0 -O 0 4 β ο r i st st <n w sf tn tn cn tn WHAT CM 1 "

d O O O O O O O O O O O O O O O O O O O O O Τ ' t— t— T ν ' T ^- Τ ' r- T ' T ' r · X X X X X X X X X X X 1 b- <0 st VO O <0 WHAT in tn O cn tn t- cn cn O T ” cn st VD cn O t- • Φ

O O O cn tn > CD O O 0 O »» 0 « 0 I ( 1 9 1 1 o M CM VO O b- cn T * 00 r * Τ ' T ” • r- CM

O O O O O O O O O O O O T ' t— CM CM CM CM cm T * CM CM T ” X X X X X X X X X X X t b- .. : · .M * vo 00 tn tn and CM 00 tn in VO in cn tn 00 r- m tn

O CM tn O tn cn CM rn tn vo vo VO st b- CM m m Ό CM tn st what 4 0 »» 0 0 4 4 4 4 4 i t 4 CM O O Τ ' O O O O O O O

O O O O. O O O O O O O O O in- IN* n Τ ' <n m rn T— tn tn in* m X X X X X X X X X X X X b- O cn O VO O tn WHAT O O O tn <n O b- O cn O cn cn O O b * cn

Table I In vitro biological activities

CX <A. AND.

O r-4> o tn o

O

8 and and Q W 8 Q O O O O O O O O O O O O O O O

ffl 8- a- a a o o o o o

CM CM a

CM CM o

O Q O O 8 8 O 8 9 8 9 8 Q 8 Ό 8 Q O 9 AND CM X 1 tn AND with#· 1 M · Ύ St 1 st AND st 1 St 1 CM H l * S H H r-t 8 8 8- 8 8 8 7 7 T 8 CM CM CM CM it ra m ra O O O O O O ra CM 8 O cn CM m sf m sf CM CM st st E of-\ z-x z * x OF'. z-s O, XX of"·" z “x z-X O CM CM CM CM CM CM CM CM CM CM x ^ 8 8 8 8 8 8 8 8 8 8 8 O O O O O O O O O O O X-Z x-z x-z x_z x_z xz s ^ · - O CM <n st · tn VO b- WHAT cn O CM

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Table II Anti-inflammatory activity in vivo

Number Carragedema ^and (% inh® Pleuritis (% inh.) ^And 0bj _e e3: udocell / cell Ear inflammation (% inh.) ^And Edema Hyperemia 1 22nd 12 ₇ n _{/ 2} n 10 4 ⁿ 2 6 ⁿ 17 28/17 ^u 8 3 ⁿ 3 30 34 37/3 "’ ’25 0 4 14 20 May 20/3 ⁿ 9 7 ⁿ 5 25 '..38. . 33 Z9 ⁿ 18 0 6 56 32. 54/33 18 0 7 39 23 17/7 " 7 ⁿ 5 ⁿ 8 26 18 36/32 0 0 9 21 15/8 ⁿ 16 ₂ n 10 36 20 May 41/26 3 ⁿ 3 ⁿ 11. 34 25 26/8 ⁿ 5 ⁿ 2 ⁿ 12 34 0 37/38 10 5 " 14 ° , 68 l · ' 54 41/13 22nd 68

Substances were evaluated at a dose of 100 mg / kg i ⁰ n indicates not statistically significant (level of significance Q © 05) evaluated at doses of 10 mg / kg _o

Table III Inhibition of bronchospasm in guinea pigs

Number Dose (mg / kg) % inhibition ^a ' ^b 3 10 0 30 0 (0-73) 100 ALIGN! 8 (0-15) « 4 30 15 (6-25) 100 ALIGN! 8 (0-15) 5 .10. 23 30 74 (58-85) Ř .100 95 (90-100) 6 30 77 (68-100) 40 95 (90-100) 9 30 91 (83-100) 100 ALIGN! 73 (34-94) 4i 10 10 88 (79-97) 30 83 (48-100) 100 ALIGN! 85 (60-100) 13 ° 30 92 (85-100)

inhibition of bronchospasm calculated with - Jp _t (MD,) - 4p _t (X)% inh »--- X .-- 2 —_ χ 100

4p _t (izm ₄ ) where Ap ^ (LTD ^) is the increase in tracheal pressure after LTD ^ j ^ρ ^ (Χ) is the increase in tracheal pressure after substance administration. The limits of experimental values are given in brackets) ^c standard LY 171) 883

Claims (6)

PATENT CLAIMS ΊΙ & ί CLAIMS 1. 4-Alkoxy-2-hydroxy-3-propyl acetophenone derivatives of the formula I HO ^ Lo-Z-i CHJCO '* ^ p JAUiNiSVlA ΟΗ ^ ΛΠΊΞ * Cvíd ci. i wherein Y is O or .S, Q is CH 2 COOR or COOR, wherein R is hydrogen or lower alkyl 9 0 8 8 f ____ to 3 carbon atoms; after the event of an alkali metal cation or an organic base, if P is hydrogen or a halo, then Z represents _F CCH _£ 3kde n = 2-4, where P is hydrogen, may also denote CH Z _£ CHCOH3CHg. Compounds according to claim 1, selected from the group consisting of: 4-C 4 -C 4 -acetyl-3-hydroxy-2-propylphenyloxy-3-propoxy-3-phenylacetic acid, 4-C 4 -C 4 -acetyl-3-hydroxy-2-propylphenyloxy-3-butoxy-3-chlorophenylacetic acid, 3- C 4 -C 4 -acetyl-3-hydroxy-2-propylphenyloxy-3-butylthio-benzoic acid, ¹ 2-C3-C4-acetyl-3-hydroxy-2-propylphenyloxy-3-propylthio-benzoic acid, 4-C 2 -C 4 -acetyl-3-hydroxy-2-propylphenyloxy-3-ethoxy-3-chlorophenyl} acetic acid, 2- C 3 * - C 4 -acetyl-3-hydroxy-2-propylphenyloxy 3-2 '-hydroxy for pylthio-benzoic acid,' * Methyl 4-C4-C4-acetyl-3-hydroxy-2-propylphenyloxy-3-butoxy-3-chlorophenylacetate. fc 3. A process for the preparation of compounds according to claim 1, wherein the 4-C0-haloalkoxy-3-propyl-2-hydroxyacetophenone of the formula: .20 · HIM CH3CO 0CCH ₂ ) _n Hal cm in which n = 2 to 4 a Hal represents chlorine, bromine or iodine, or 4-C3-epoxypropoxy-3-propyl-2-hydroxyacetophenone. of formula III to react with a mercaptobenzoic or hydroxyacetic acid derivative of formula IV ΗΪ CIV 3 _Z wherein P, Q and Y have the same meaning _; as in claim 1. Process for the preparation of compounds according to claim 1, characterized in that 2,4-dihydroxy-3-propyl acetophenone of the formula V CVD is reacted with a haloalkoxy- or haloalkylthio derivative of the benzoic or arylacetic acid of formula VI HalCCH ₂ ) _n Y-O wherein P, Q and Y have the same meaning as in claim 1. CVD, prvtosein A pharmaceutical composition having an anti-inflammatory activity as claimed in claim 1, comprising as active ingredient a compound of formula (I) or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable excipients. The pharmaceutical composition with anti-asthmatic activity according to claim 1, characterized in that it is a pharmaceutical composition. comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable excipients. ή ». and; 4 » 1 / Annotation- Ù derivatives of 4-alkoxy-2-hydroxy-3-propyl-acetophenone of formula I wherein Y is 0 or S, Q is CH, COOR _g or COOR wherein R is hydrogen or lower alkyl having 1-3 carbon atoms; when P is hydrogen or halogen _; then Z is CCH 3, where n = 2 to 4, when P is hydrogen, Z may also be CH _g CHCOH 3 CH _g . Also described are processes for the preparation of these compounds and pharmaceutical compositions containing them as active ingredient.