FI63928C - PROCEDURE FOR THE FRAMEWORK OF THERAPEUTIC EQUIPMENT IN THE SUBSTANCE OF FENYLALKANSYROR - Google Patents

Description

5Sr * l ΓβΊ «« ANNOUNCEMENT.

LJ (11) uTLAGGN INGSSKKIFT 639 2 8 ^ T ^ (51) K ».ik? / I« .a3 C 07 C 59/68, 69/736 FINLAND —FINLAND (21) Pt »nttlh» k «mu» - - Ptt * ncana6kning 762250. (22) Hukumtapllv · - Amttknlngadag O5.O8.76 '^ (23) AlkupiM — GlMghMafag 15.08.69 (41) Tullut lulkksaksl - MMt effantilg 05. 08.76

Patmttt · ia Registry Board '. . (44) NlhtlvUulpunon and the Moon |

Patent · och reglsterstyreleen '; AmMcm utkgd odi utUkrtftM puMi ^ rad 31.05.83 (32) (33) (31) * yy4 "* r« uofc * i «—Buglrd priortm 15.08.68 15.08.68, 28.05.69 USA (US) 752800, 752801 828756 (71) Eli Lilly and Company, 307 East McCarty Street, Indianapolis,

Indiana, USA (72) Winston Stanley Marshall, Indianapolis, Indiana, USA (7U) Oy Kolster Ab (5M Method for the preparation of therapeutically useful new substituted phenylalanine acids - Förfarande för framställ-Ning av therapeutiskt användbara nya substituer The present invention relates to a process for the preparation of substituted phenylalkane compounds of formula (I): wherein O 2 and Y 2 denote by subheading 2392/69 (patent 5 ^ 099) -Avdelad frän ansökan 2392/69 (patent 5 0 099) hydrogen, halogen, methyl, ethyl or (C 1 -C 4 alkoxy; R 1 is hydrogen (C 1 -C 4 alkyl), or (C 1 -C 4) cycloalkyl; Z is -COOR 2 where R 2 is hydrogen, (C 1 -C 4) alkyl, an alkali metal cation, an alkaline earth metal cation or an ammonium cation, and pharmaceutically acceptable acid addition salts thereof.

2 <3 r 2 8

Many people and animals suffer from rheumatic diseases that include inflammation, swelling, fragility, decreased mobility, pain and fever. Although a number of anti-inflammatory agents are now known to be effective in treating diseases such as rheumatoid arthritis, rheumatoid arthritis and osteoarthritis, such agents have a number of undesirable side effects. For this reason, better anti-inflammatory agents are still being sought.

The present invention provides novel compounds which are excellent anti-inflammatory agents and which, in addition to their anti-inflammatory effect, have a mild, asperin-like analgesic and antipyretic effect.

The novel 2- (3- or 4-phenoxyphenyl) alkanoic acids, their pharmaceutically acceptable cationic salts and their esters, are useful as pharmaceutical compositions for the treatment of inflammation, pain and fever in humans and animals. A few compounds of the invention also potently enhance the analgesic effect of several analgesic agents.

The above "alkali metal" means sodium, potassium and lithium. Alkaline earth metal means calcium, magnesium and barium.

The expression "acid addition salts" means those salts which are prepared by reacting a free amine with an organic or inorganic or inorganic acid. Examples of these salts are the hydrochloride, hydrobromide, sulphate, bisulphite, acetate, valerate, oleate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthalene (2-naphthalene) ) and the like.

"(C 1 -C 4) alkyl" means both straight and branched alkyls such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-amyl, isoamyl -neopentyl and the like.

Halogen means chlorine, fluorine, bromine and iodine.

"(C 1 -C 4 alkoxy" means methoxy, ethoxy and propoxy.

The compounds of the formula I are excellent anti-inflammatory agents and several of them have an ED 2 value of 0.2-1.0 mg / kg in experiments against erythema 3,63928. All of the compounds of the invention are useful in the treatment of inflammatory diseases in mammals, with acids and amines being preferred. In addition to their anti-inflammatory effect, the compounds have a mild analgesic and antipyretic effect. Therapeutic compositions comprise as active ingredient one or more compounds of formula I in association with a pharmaceutically acceptable diluent. The compounds are generally administered to mammals in doses of 0.2 to 50 mg / kg body weight daily in either single or divided doses over a period of 24 hours.

The d- and 1-isomers of the oC-alkyl compounds of the invention are also within the scope of the invention. Thus, e.g., alkyl acids can be decomposed into d- and 1-isomers according to methods known per se. Both the d- and 1-isomers have been found to have substantially identical effects. Thus, either a racemic mixture or the d- or 1-isomer can be used to treat inflammation, pain and fever.

Certain compounds of the invention, especially those in which and Y 1 is hydrogen, is hydrogen, methyl or ethyl and Z is COOH, or salts thereof, have surprisingly been found to potentiate known substances such as 1,2-diphenyl-2-hydroxy-3-methyl esters of (substituted-4-amino) butanes, especially esters of? -d-propoxyphenene (chemically? -d-1,2-diphenyl-2-propionoxy-3-methyl-4-dimethylaminobutane) and certain narcotic analgesics such as the analgesic effect of morphine, codeine and the like when co-administered with them.

The enhancement of analgesics is provided when about 1 part by weight of a compound of the invention is administered substantially simultaneously or 1 hour before or 1 hour after administration together with 0.005 to 20 parts by weight of the analgesic. Generally, to provide greater analgesia, 0.5 to 50 mg / kg of a compound of the invention is administered with the usual therapeutic dose of the analgesic agent. The compounds of the invention are as follows: 2- (4-ethoxy-3-phenoxyphenyl) propionic acid, d-2- (3-phenoxyphenyl) propionic acid, 2- (3-phenoxyphenyl) propionic acid sodium salt dihydrate, 2- (3-phenoxyphenyl) propionic acid calcium salt dihydrate, 4 63928 2- (4-chloro-3-phenoxyphenyl) propionic acid, 1- [2- (3-phenoxyphenyl) propionic acid sodium salt, 2- (2-methyl-5-phenoxyphenyl) acetic acid, 2 - (3-phenoxyphenyl) propionic acid, 2- (2-ethyl-3-phenoxyphenyl) propionic acid calcium salt, 2- (5-chloro-3-phenoxyphenyl) propionic acid, methyl 2- (3-phenoxyphenyl) propionate, ethyl 2- (3-phenoxyphenyl) propionate, 2- (3-phenoxyphenyl) butyric acid, 2- (3-phenoxyphenyl) valeric acid, 2- (phenoxyphenyl) caproic acid, ethyl 3- (3-phenoxyphenyl) butyrate, 2- (3-phenoxyphenyl) propyl propionate, 2- (2,3-dimethyl-4-phenoxyphenyl) propionic acid, sodium salt of 2- (3,5-dimethyl-4-phenoxyphenyl) propionic acid, 2- (3-methoxy-4-phenoxyphenyl) propionic acid, t-butyl 2- (2-methyl-4-phenoxyphenyl) propionate, ethyl 2- (3-bromo-4-phenoxyphenyl) propionate, 2- (3-methyl-4-phenoxyphenyl) acetic acid, 2- (2-fluoro-4-phenoxyphenyl) propionic acid, methyl 2- (2- fluoro-4-phenoxyphenyl) propionate,

Compounds of formula (I) may be prepared as follows: To obtain a compound of formula (I) wherein Z is -COOH; dicarboxylic acid of formula

Ar-C (COOH) I * R1 wherein and are as defined above and Ar is Y2 / = S / Y1 wherein and Y2 are as defined above are decarboxylated to give a substituted phenylalkanoic acid, and that the acid obtained is, if desired, converted into the corresponding salts or esters mentioned above.

5,63928

ESTERS

lilac. Ar-CH- (CEL) COOH R-OH / HCl Ar-CH- (CH ~) COOR „I z n z ^ I z n z R1 R1

IIIb. Ar- ^ H- (CH2) nCOOH SOCl2 Ar- <j: H- (CH2) nCOCl.

R1 * R., R2OH

t

Ar-CH- (CH ~ C00Ro | z n 2 R1

The carboxylic acids prepared as described above are converted to the corresponding ester according to known methods, such as heating the acid with an alcohol in the presence of a mineral acid (IIIa) or converting the acid to the corresponding acid chloride and then reacting the resulting acid chloride with an alcohol, preferably an HCl binder (IIIb).

The starting materials used in the reactions described above are readily obtained by Ullman's diaryl ether synthesis as described by Bacon and Steward, J. Am. Chem. Soc., 87, 4953 (1965) and described by the following reaction equation:

Ar '-OH + Ar "X- ^ Ar' -O-Ar" wherein Ar 'is unsubstituted phenyl and Ar "is substituted phenyl

Yi Yj's general formula I.

Typical intermediates prepared according to the above reaction include: 3-phenoxyacetophenone, b.p. 117-126 ° C / 0.08 mm; n-R = 1.5865 4-chloro-5-methyldiphenyl ether, b.p. 105-113 ° C / 0.06 mm; n-R = 1.5850, 2-chloro-5-methyldiphenyl ether, b.p. 120 mm -123 ° C / 0.08 mm; n ^ 5'5 = 1.5850 4-fluoro-5-methyldiphenyl ether, b.p. 75-85 ° C / 0.05 mm; n ^ = 1.5565, 4-methyl -5-phenoxyacetophenone, b.p. 120-132 ° C / 0.05 mm; n = 1.5828, 2-methoxy-5-phenoxyacetophenone, b.p. 132-140 ° C / 0.15 mm, n = 5 = 1.5864.

63928

The following examples illustrate the present invention.

EXAMPLE I

Ethyl 2- (3-phenoxyphenyl) acetate

Dry HCl gas was introduced into a solution of 275 g of 2- (3-phenoxyphenyl) acetic acid prepared according to Example 1 and 1500 ml of ethanol until the solution was saturated. The solution was refluxed for 3 hours and the solution was again saturated with HCl gas. The solution was refluxed overnight. The reaction mixture was allowed to cool and partially evaporated to dryness in vacuo and poured into ice water. the oily product was extracted with ether. The ether solution was washed with water and 5% sodium bicarbonate solution and dried over sodium sulfate. The ether was evaporated in vacuo and the oily residue was distilled to give 256 g of ethyl 2- (3-phenoxyphenyl) acetate, b.p. 140-146 ° C / 10.1 mm; n £ 3'5 = 1.5520.

Calculated: C 16 H 18 O 3: C 74.98; H 6.29 Found: C 75.16; H 6.21

EXAMPLE II

Diethyl-2-methyl-2- (3-phenoxyphenyl) malonate

A mixture of 128 g of ethyl 2- (3-phenoxyphenyl) acetate and 300 ml of diethyl carbonate was stirred and heated to about 110 ° C, and 11.5 g of sodium metal was added to the mixture in pea-sized pieces over 1 hour. Some ethanol and diethyl carbonate were distilled off from the reaction mixture during the addition of sodium. After the addition of sodium was complete, the reaction temperature was raised until the temperature of the steam above the reaction mixture was 130 ° C. The reaction mixture was cooled to 15 ° C in an ice bath, and 60 ml of methyl iodide was added to the reaction mixture over 1/4 hour. The reaction mixture was heated to 80 ° C for one hour. The reaction mixture was cooled, a little water was added to the reaction mixture and the reaction mixture was poured into ice water, acidified with HCl and extracted with ether. The ether extract was dried over sodium sulfate and evaporated to dryness in vacuo. The resulting liquid residue was distilled on a 15 cm Vigreux column to give 100.2 g of diethyl 2-methyl-2- (3-phenoxyphenyl) malonate. mp. 155-175 ° C / 10.1 mm; n £ 3'5 = 1.5337.

K

7,63928

Analysis:

Calculated: C 20 H 22 O 5: C 70.16; H 6.48 Found: C 70.40; H 6.27

EXAMPLE III

2-Methyl-2- (3-phenoxyphenyl) Malo acid

A solution of 57 g of diethyl 2- (3-phenoxyphenyl) malonate and 40 g of sodium hydroxide and 300 ml of a 50% (v / v) aqueous ethanol solution was stirred and refluxed overnight. The reaction mixture was poured into ice water and washed with ether to remove the unhydrolyzed ester. The aqueous layer was acidified with concentrated HCl and extracted with ether, the ether extract was dried over sodium sulfate and evaporated to dryness in vacuo to give 44 g of 2-methyl-2- (3-phenoxyphenyl) malonic acid, m.p. 138-143 ° C (decomposes on evolution of gas).

Analysis:

Calculated: C 16 H 14 O 5: C, 67.13; H 4.93 Found: C 67.37; H 5.23.

EXAMPLE IV

2- (3-Phenoxyphenyl) propionic acid 15 g of 2-methyl-2- (3-phenoxyphenyl) malonic acid prepared according to Example III were heated to 130-160 ° C and stirred until vigorous evolution of CO 2 ceased. The reaction mixture was cooled to room temperature to give 12.2 g of 2- (3-phenoxyphenyl) propionic acid, n = 1.5729; The NMR spectrum is the same as that of the compound prepared in Example I.

Analysis:

Calculated for C 15 H 14 Cl 3: C, 74.36; H 5.82 Found: C 74.07; H 5.81

The following compounds were prepared in a similar manner:

Melting point

2- (2-methyl-4-phenoxyphenyl) acetic acid 71.5-74 ° C

2- (3-methyl-4-phenoxyphenyl) acetic acid 89/0-91 ° C

2- (2,3-dimethyl-4-phenoxyphenyl) acetic acid 124/0-126 ° C 2- (3,5-dimethyl-4-phenoxyphenyl) acetic acid 106/0 -108 ° C

8,63928 2- (2-ethyl-4-phenoxyphenyl) acetic acid 82.0-84 ° C

2- (2-methoxy-4-phenoxyphenyl) acetic acid 105.0-107 ° C

2- (3-methoxy-4-phenoxyphenyl) acetic acid 83.0-85 ° C

2- (2-fluoro-4-phenoxyphenyl) acetic acid 85.0-87 ° C

2- (2-chloro-4-phenoxyphenyl) acetic acid 102.0-103 ° C

2- (3-chloro-4-phenoxyphenyl) acetic acid 84.0-88 ° C

2- (3,5-Dichloro-4-phenoxy-phenyl) -acetic acid 167.0-168 ° C

2- (2-methyl-4-phenoxyphenyl) propionic acid 123.5-125 ° C

2- (2-fluoro-4-phenoxyphenyl) propionic acid 92.0-94 ° C

2- (3-methoxy-4-phenoxyphenyl) propionic acid 242.0-250 ° C

2- (3,5-dimethyl-4-phenoxyphenyl) butyric acid 73.0-75 ° C

2- (4-chloro-3-phenoxyphenyl) acetic acid 77.0-80 ° C

2- (6-chloro-3-phenoxyphenyl) acetic acid 88.0-90 ° C

2- (6-fluoro-3-phenoxyphenyl) acetic acid 80.0-82 ° C

EXAMPLE V

2- (3-Phenoxyphenylpropionic acid sodium salt dihydrate 2- (3-Phenoxyphenyl) propionic acid (6460 g) was converted to the sodium salt by the dropwise addition of 26.7 mol of 2N sodium hydroxide with stirring and cooling, after which the aqueous solution was evaporated to near dryness in vacuo. the residue was mixed with ethyl acetate and re-evaporated in vacuo The white solid residue was distilled off with as little boiling ethyl acetate as possible, filtered into a large tank (about 18 liters of solution) and allowed to stand at 7 ° C overnight.

The resulting crystalline mass was filtered and dried in vacuo at room temperature to give 6954 g of pure sodium 2- (3-phenoxyphenyl) propionate dihydrate, m.p. 76-78 ° C.

Analysis:

Calculated: C 15 H 17 ClO 5 Na: C, 59.99; H 5.70 Found: C 59.93; H 5.97 9 63928

EXAMPLE VI

2- (2,3-Dimethyl-4-phenoxyphenyl) propionic acid 2-Methyl-2- (2,3-dimethyl-4-phenoxyphenyl) malonic acid prepared from ethyl 2- (2,3-dimethyl-4-phenoxyphenyl ) acetate, diethyl carbonate and methyl iodide according to Examples II and III, was heated to 130-160 ° C and stirred until vigorous evolution of carbon dioxide ceased. The reaction mixture was cooled to room temperature to give 2- (2,3-dimethyl-4-phenoxyphenyl) propionic acid, m.p. 100-101 ° C.

EXAMPLE VII

2-Cyclohexyl-2- (4-phenoxyphenyl) acetic acid 2-Cyclohexyl-2- (4-phenoxyphenyl) malonic acid prepared from ethyl 2- (4-phenoxyphenyl) acetate, diethyl carbonate and cyclohexyl iodide was heated to room temperature according to Examples II and III. , where the strong development of carbon dioxide began. After the evolution of carbon dioxide ceased, the reaction mixture was cooled to room temperature to give 2-cyclohexyl-2- (4-phenoxyphenyl) acetic acid, m.p. 146-149 ° C.

EXAMPLE VIII

2- (3-methyl-4-phenoxyphenyl) propionic acid 2-methyl-2- (3-methyl-4-phenoxyphenyl) malonic acid prepared from ethyl 2- (3-methyl-4-phenoxyphenyl) acetate, diethyl carbonate and methyl iodide according to Examples II and III, was heated to 130-160 ° C and stirred until the strong evolution of carbon dioxide ceased. The reaction mixture was cooled to room temperature to give 2- (3-methyl-4-phenoxyphenyl) -propionic acid, b.p. 185-188 ° C at 0.08 mm Hg.

10 63928

PHARMACOLOGICAL EXPERIMENTS

The anti-inflammatory activity of the compounds according to the invention was studied with a modified Winder et al. method.

Male and female albino guinea pigs weighing 225-300 g were used as experimental animals, and their hair was shaved and chemically depilated for 18-20 h before being exposed to UV light. Animals were fasted overnight and immediately thereafter were treated with test compounds. Test compounds were administered orally to experimental animals in a 1% aqueous suspension of methylcellulose. Animals in the control group received only a 1% suspension of methylcellulose at 1.0 cm 2 / kg.

Reinforcements from glued flipchart paper were placed on the backs of the experimental animals, and the animals were irradiated with high-intensity UV light for 7 s. The UV light source was a Hanovia lamp (Kromayer model 10), which was contacted with guinea pig spinal cord. After irradiation, the reinforcements were removed and the backs of the animals were wiped clean with a gauze swab dipped in water. The non-irradiated areas under the reinforcements were a good contrast to judge the intensity of the erythema. The experimental animals were placed in 10 x 20 cm wide and 15 cm high compartments in a transparent plastic box. First, 1 h after irradiation and then at i h intervals, the erythema formed was evaluated on a scale based on contrast and redness. Anti-inflammatory agents prolong the formation of erythema and their effect is most effective in the initial periods of monitoring, which is why coefficients 4, 3, 2 and 1 were used in monitoring after 1.0, 1.5, 2.0 and 2.5 h. The erythema was rated according to the following scale

Score Appearance of irradiated surface 0 no braiding and no contrast 1 weak braiding and weak border with reinforcement 2 braiding from weak to moderate and clear border 3 strong reddening and clear circular border 11 63928

The total score of the guinea pigs formed by five or six guinea pigs was compared with the control group and the inhibitory effect was calculated as a percentage. The dose (ED 2 q) that produced a 50% inhibitory effect against erythema was calculated. The results are shown in the following table.

63928 12 ANTI-INFLAMMATORY ACTIVITY O in para position

Il i h z ^ 0 2- CH3 H H COOH k 3- CH3 H H COOH 12 2- CH3 3-CH3 H COOH 1 3- CH3 5-CH3 H COOH 1 2-CgH H H COOH 22

2- OCH3 H H COOH U

3- OCH3 HH COOH k 2-F1 HH COOH 20 2- C1 HH COOH 8 3- C1 HH COOH 2.5 3-C1 5-C1 H COOH 0.5 HH CH3 COOH 0.5 2- CH3 H CH3 COOH 0 .9 3- CH3 H CH3 COOH 1 2- CH3 3-CH3 CH3 COOH 2 3- CH3 5-CH3 CH3 COOH 0.9 3-OCH3 H CH3 COOH 0.7 HH CgH COOH il HH C3Ht COOH 9 HH CH3 COONa 0 .7 HH CH3 CONH2 3 O in para position Y1 Y2 R1 Z ED50 HH CH3 COONa 0.9 HH CH3 COOCa 1.0 HH CH3 COOC2H5 1.5 HH CH3 COOCH3 1.0

Comparison of 2- (4-phenoxyphenyl) acetic acid from U.S. Patent 3,385,886 29 aspirin 50

Claims (2)

A process for the preparation of therapeutically useful novel substituted phenylalkane compounds of formula (I) wherein Y 1 and Y 2 represent hydrogen, halogen, methyl, ethyl or (C 1 -C 3) alkoxy, R 1 is hydrogen, (C 1 -C 3) -C 1-4 alkyl or (C 1 -C 6) -cycloalkyl, Z is -COOR 2, wherein R 2 is hydrogen, (C 1 -C 4) -alkyl, ammonium, alkali metal or alkaline earth metal, and pharmaceutically acceptable acid addition salts thereof, characterized in that for the preparation of a compound of formula (I) wherein Z is -COOH; dicarboxylic acid of formula Ar-C (COOH) Λ I 2 R1 wherein R1 is as defined above and Ar is O ** wherein Y1 and Y2 are as defined above are decarboxylated to give a substituted phenylalkanoic acid, and that the acid obtained is, if desired, converted into the corresponding salts or esters mentioned above.