FI57592C - ANALOGIFICATION OF THERAPEUTIC ACTIVATION OF THERAPEUTIC ACTIVE 5- (3-PHENOXYBENYL) -1H-TETRAZOLER - Google Patents

Description

R3FH M (11) * ^ U ULUTUSJ UL KAISU ς? ς g 9 fäK (© lJ '' UTLÄGGNI NGSSKRIFT O f O 7 L · • J ^ St C (45) Fal-hUi, -. 'ji: ·.: ·. tty 10 0v 1' '0 (S1) MJuVa3 O 07 D 257/04 FINLAND —FINLAND (21) P «t * irttlh« k * mu · - P «* nt» n * eknlnX TÖ08U6 (22) Htk «ml * pUvl - Anvttknlnpdtf 17.03-78 '(23) Alkiipftlvt - GiKlfh «tsd * (15-08.69 (41) Tullut JulklMlal - Bllvlt off * ntll | 17.03 · 7Ö

Patent and Registration Office .... ., ,, , , , , _ . . (44) Date of issue of the notice and other information. - "_ n"

Patent · oeh registerstyrelsen '1 Arattkan utlagd och utl. * Krift # n publicerad 30.05.80 (32) (33) (31) Claim privilege —B «jird priority 15 · 08.68 15.08.68, 28.05.69 USA (US) 7528ΟΟ , 752801, 828756 (71) Eli Lilly and Company, 307 East McCarty Street, Indianapolis,

Indiana, USA (72) Winston Stanley Marshall, Indianapolis, Indiana, USA (7 ^) Oy Kolster Ab (5 * 0 Analog method for the preparation of therapeutically active 5- (3-phenoxybenzyl) -1H-tetrazoles - Analogiförfarande för framställning of therapeutically active 5- (3-phenoxybenzyl) -1H-tetrazoler (62) Separated from application 2392/69 (patent 5 * + 099) -Avdelad fr & n trap 2392/69 (patent 5 099)

The invention relates to an analogous process for the preparation of novel 3-phenoxyphenylalketrazoles and their acid addition salts having anti-inflammatory activity and a mild, aspirin-like analgesic and antipyretic effect.

Many people and animals suffer from rheumatic diseases, which include inflammation whose symptoms include swelling, tenderness, 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.

2 57592

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

More specifically, an analogous process for the preparation of therapeutically active 5- (3-phenoxybenzyl) -1H-tetrazoles of the formula Y1 / K I1 Ϊ-! W y is O-O having a hydrogen atom or a (C 1 -C 3) alkyl group and Y 1 is a halogen or hydrogen atom, and for the preparation of pharmaceutically acceptable acid addition salts thereof

The invention is characterized in that the nitrile of formula K) -CH-CH

wherein and have the same meaning as above, are reacted with sodium azide in the presence of an organic polar solvent, and that the resulting tetrazole is, if desired, converted into the corresponding acid addition salt.

The novel tetrazoles prepared according to the invention are useful as pharmaceutical compositions for the treatment of inflammation, pain, 3,57592 and fever in humans and animals. A few compounds of the invention also potently enhance the analgesic effect of several analgesic agents.

It is an advantage of the invention to provide therapeutic compositions for treating inflammation and the pain, swelling, fever and the like caused in humans and animals.

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

"C 1-6 alkyl" means both straight and branched alkyls such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, isobutyl-n-amyl , isoamyl, neopentyl and the like.

Halogen means chlorine, fluorine, bromine and iodine.

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 novel compounds together with a pharmaceutically acceptable diluent or carrier. The compounds are generally administered to mammals in doses of 0.5 to 5.0 mg / kg body weight daily, either as a single dose or in divided doses over a period of 2M · one hour.

Comparing the erythema inhibitory effect of the compound of the present invention wherein R1 is methyl and Y1 is hydrogen (Compound A) to the corresponding effect of the compound known from the U.S. patent p-phenoxyphenylacetic acid (Compound B), the following results were obtained:

Compound Inhibition of erythema ED * 0 A 10 B 29 m 57592

It is to be understood that both the di- and 1-isomers of the novel οί-alkyl compounds are within the scope of the invention. Thus, for example, C 1-4 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.

Enhancement of analgesia is achieved when about 1 part by weight of a compound of the invention is administered substantially simultaneously with the analgesic agent or one hour before or one hour after administration of 0. 005 to 20 parts by weight of the analgesic agent. To achieve greater analgesia, 0.5-5.0 mg / kg of a compound of the invention is generally administered with a typical therapeutic dose of an analgesic agent.

The novel compounds can be prepared by methods known in the art for the preparation of phenylalkyltetrazoles. The preparation of nitrile compounds used as starting materials is described in FI patent publication 54,099.

The following are preferred reaction sequences. In the following, R 1 and Y have the same meaning as above and "Ar" is the following part of the above formula: * 1

Ar-CH 2 N-bromosuccinimide Ar-C 1 -Br NaCN Ar-C 1 -CN

The methyl group of the appropriate meta-methyl diaryl ether is halogenated with N-bromosuccinimide, N-chlorosuccinimide, sulfuryl chloride or the like halogenating agent using a suitable catalyst such as benzoyl peroxide or azo-bis-isobutyronitrile in an inert solvent such as carbon tetrachloride. The resulting halomethyl diaryl ether is reacted with sodium or potassium cyanide, preferably in dimethyl sulfoxide solution. The resulting nitrile is used to prepare tetrazole.

s 57592

II. Ar-CH2-CN NaNH2 / NH3 Ar-CH-CN

R ~ X2 * R1

The nitrile prepared as described above can be alkylated with an aliphatic halide or tosylate (R 2) in liquid ammonia in the presence of sodium amide to produce a β-aliphatic substituted nitrile.

III. Ar-CH.-CN HCOOC.H, Ar-C-CN PhCOCl Ar-CN H./Pd Ar-CH-CN

* ‘0 II __V II * _S. I

-> CHOH> CHOC-Ph -> CH3 0

The nitrile prepared according to Reaction Series I may optionally be methylated according to the following method (Reaction Equation III): "The nitrile is condensed with ethyl formate under basic conditions, for example in the presence of sodium hydride or sodium methoxide the benzoic acid ester is then hydrogenated in the presence of a noble metal catalyst to give the desired od-methylarylgetonitrile.

IV. Ar-C-CH3 NaBH4 Ar-CH-CH3 PBr3 Ar-CH-CH3 NaCN Ar-CH-CN

- '«3

The desired o-methylarylacetonitrile can be prepared by the following series of reactions (Series IV). Aryloxyacetophenone (prepared by Ullman's ether synthesis) is reduced to either hydrogen in the presence of a noble metal catalyst or a metal hydride such as lithium aluminum hydride, lithium or sodium borohydride or the like to the corresponding carbinol. This carbinol is converted to equivalent! to the bromide by treating the carbinol with phosphorus tribromide, preferably in an inert solvent such as chloroform, benzene, carbon tetrachloride or the like. The resulting bromide is then reacted with sodium cyanide, preferably in dimethyl sulfoxide solution, to give the nitrile.

V. Ar-CsO / PhOP- (CHO) -CN7 + Br "Ar-C = CH- (CH_) -CN Η, / Pt Ar-CH- (CH) -CH

, 3 z n _. , z n-j. i v t * n R -> *! > KO-tert.-Bu 6 57592 The nitriles used as starting materials can be prepared in a known manner by the Wittig reaction, as shown in Reaction Scheme V.

N-N

l I

VI. Ar-CH (CHO) -CN NaNO Ar-CH- (CHO) -C N * 2 n 3, 2 n y.

R1 -> R1 V

B

Nitriles prepared by the methods described above or by methods known per se can be converted to the corresponding tetrazoles by treatment with, for example, sodium azide using dimethylformamide as the reaction solvent, as described in Finnigan, W.G., Henry, R.A. and Lofquist, R., J. Am. Chem. Soc., 80, 3908 (1958).

The following examples illustrate the present invention, Examples 1 and 2 illustrate the preparation of the starting materials.

Example 1 2- (4-Chloro-3-phenoxyphenyl) acetonitrile To 1.200 ml of carbon tetrachloride were added 232.7 g of 3-phenoxy-4-chlorotoluene, 196 g of N-bromosuccinimide and 1.0 g of benzoyl peroxide. The reaction mixture was stirred and refluxed for 24 hours, after which the reaction mixture was filtered and the solids were washed with carbon tetrachloride. The filtrate was evaporated to an oil and distilled to give crude A-B and C of crude 4-chloro-3-phenoxy-benzyl bromide.

Fraction Kp. ° C Weight (g) A 140-150 (0.08) 118.5 g 1.5960 B 145-153 (0.07) 190.6 g 1.6152 C 145-160 (0.07) 79.4 g 1.6250

Fractions B and C were combined and analyzed.

Analysis: Calculated for C 21 H 25 BrClO 2: C 52.46 H 3.38 Found: C 52.25 H 3.44 7 57592

The combined fractions B and C were redistilled through a Vigreux column to give fractions A, B, C, D and E.

2 S

Fractions Kp. ° C Weight (g) n ^ A 105-145 (0.009) 24.2 1.5951 B 145-155 (0.009) 29.6 1.6114 C 130-136 (0.007) 79.4 1.6228 D 128- 135 (0.007) 52.9 1.6218 E 136-149 (0.006) 29.8 1.6274 1 H NMR studies showed that fractions C and D contained 91 and 92% 4-chloro-3-phenoxyphenyl bromide, respectively:

22.2 g of 95% sodium cyanide was dissolved in about 400 ml of dimethyl sulfoxide and the reaction mixture was heated to about 50 ° C. Crude 4-chloro-3-phenoxybenzyl bromide (125 g) was added dropwise with stirring. The temperature was maintained at 50-60 ° C during the addition. Immediately after the addition of bromide, a red color formed. When the addition of bromide was complete, the reaction mixture was heated to 60 ° C and stirred for three hours. The mixture was then allowed to cool to room temperature and stirred overnight, after which it was poured onto ice and extracted with ethyl ether and then hexane. The extracts were washed with water and dried over sodium sulfate. The solvents were evaporated to give a reddish brown viscous oil which was distilled to give fractions A, B and C of 2- (4-chloro-3-phenoxyphenyl) acetonitrile.

Fraction Kp ° C Weight (g) n ^ 5 A 170 (0.4) - 170 (0.1 5) 51, 6 1, 5916 B 163-174 (0.08) 16.3 1.5917 C 174- 190 (0.1 0) 2.2 1, 591 7

Analysis: Calculated for C 12 H 12 ClNO: C 68.99 H 4.13 N 5.74 Found: C 68.72 H 4.20 N 5.50.

8 57592

Example 2 Preparation of 2- (3-phenoxyphenyl) propionitrile A. 3-Phenoxyacetophenone. A mixture of 906 g (6.68 moles) of m-hydroxyacetophenone, 4,500 g (28.6 moles) of bromobenzene, 996 g (7.2 moles) of anhydrous potassium carbonate and 300 g of copper bronze was heated to reflux with stirring. until hydrogen formation was complete using a Dean-Stark water separator. The mixture was then stirred and refluxed for 24 hours. After cooling to room temperature, the reaction mixture was diluted with an equal volume of CHCl 3 and filtered. The filtrate was washed with 5% HCl, then 5% NaOH, water, dried over sodium sulfate and evaporated in vacuo. The residual oil was distilled through a 15 cm Vigreux column to give 918 g of 3-phenoxyacetophenone, b.p. 120-121 ° C. (0.09 mm), n = 5 = 1.5868.

Analysis: Calculated ^ 79> 22 H 5.70 Found: C 79.39 H 5.79 B. (k-Methyl-3-phenoxybenzyl alcohol. A stirred solution of 700 g of m-phenoxyacetophenone in 3,000 ml of anhydrous metal). 136 g (3.6 moles) of sodium borohydride was added to this solution in small portions at such a rate that the temperature never rose above 10. After completion of the addition of borohydride, the reaction mixture was allowed to warm to room temperature and stirred for 18 hours. It was then stirred and refluxed for 8 hours, about 400 ml of methanol were distilled off and the remaining solution was evaporated to about 1/3 of its original volume in vacuo and poured into ice water. The mixture was extracted twice with ether, acidified with 6N hydrochloric acid and re-extracted with ether. , washed with saturated NaCl solution, dried over anhydrous sodium sulfate and evaporated in vacuo. was distilled through a 15 cm Vigreux column to give 666 g of O (methyl-3-phenoxybenzyl alcohol, b.p. 132-134 ° C. (0.35 mm), n = 1.5809. Analysis: Calculated C 78.48 H 6.59 Found: C 78.75 H 6.31.

9,57592 C. cis-methyl-3-phenoxybenzyl bromide. A stirred solution of 1,357 g of <X-methyl-3-phenoxybenzyl alcohol in 5,000 ml of anhydrous CCl 4 (pre-dried with a molecular sieve) was cooled to 0 ° C. To this was added 1760 g of PBr 2, stirred and cooled so that the temperature remained at 0-5 ° C during the addition. The reaction mixture was then allowed to warm to room temperature and stirred at room temperature overnight (about 12 hours). The reaction mixture was then poured into ice water and the organic phase was separated. The aqueous phase was extracted with CCl 4 and the combined extracts were washed three times with water, dried over anhydrous sodium sulphate and evaporated to dryness in vacuo to give 1,702 g of (-methyl-3-phenoxybenzyl bromide as a heavy viscous oil); , 5993.

Analysis: Calculated for C 12 H 12 N 2 O: C 60.44 H 4.71 Br 28.73 Found: C 60.62 H 4.89 Br 28.47.

D. 2- (3-phenoxyphenyl) propionitrile. A well-stirred suspension of 316 g of 98% sodium cyanide in 5,000 ml of anhydrous dimethyl sulfoxide (pre-dried with a molecular sieve) was heated to 50-60 ° C and maintained at this temperature while slowly adding 1,702 g of O <- methyl-3-fenoksibent-bromide. After the addition of bromide was complete, the temperature was raised to 75 ° C and the mixture was stirred at this temperature for 1.5 hours. The mixture was then allowed to cool to room temperature and stirred overnight at room temperature and then poured into ice water.

The resulting aqueous suspension was extracted twice with ethyl acetate and then with ether. The organic extract was washed twice with brine, once with water and dried over anhydrous sodium sulfate. Evaporation of the solvent in vacuo left an oily residue which was distilled through a 15 cm Vigreux column to give 1,136 g of 2- (3-phenoxyphenyl) propionitrile, b.p. 141-148 ° C. (0.1 mm), n ^ 5 = 1.5678.

Analysis: Calculated for C 12 H 12 NO: C 80.69 H 5.87 N 6.27 Found: C 80.89 H 6.10 N 6.14 10 57592

Example 3 5- (4-chloro-3-phenoxybenzyl) -1H-tetrazole

A mixture of 17.0 g of 4-chloro-3-phenoxyphenylacetonitrile, 5.0 g of sodium azide, 4.15 g of ammonium chloride and a small amount of lithium chloride in 80 ml of dimethylformamide (dried on a molecular sieve) was stirred and heated to 125 ml. At 12 ° C. The reaction mixture was filtered and the solvent was evaporated until a brown oil was obtained. the oil was suspended in about 400 ml of water. After stirring, the pH of the suspension was adjusted to 2 by the dropwise addition of 3N HCl. The resulting precipitate was cooled, filtered, washed with ice-water and dried in vacuo. The precipitate was then taken up in boiling 1,2-dichloroethane and allowed to crystallize slowly overnight to give 14.5 g of 5- (4-chloro-3-phenoxybenzyl) -1H-tetrathol Sol fine white needles, m.p. 157-158 ° C, pK'a = 5.7.

Analysis: Calculated for C 18 H 19 ClNO 2: C 58.64 H 3.86 N 19.54 Found: C 58.66 H 4.07 N 19.84

Example 4 5- (° (-methyl-3-phenoxybenzyl) -1H-tetrazole)

A well-stirred mixture of 10 g of 2- (3-phenoxyphenyl) propionitrile, 3.9 g of sodium azide, 3.2 g of ammonium chloride, a few milligrams of lithium chloride and 200 ml of dry dimethylformamide was heated at 125 ° C for about 18 hours. The reaction mixture was cooled and the dimethylformamide was partially evaporated in vacuo and the rest of the reaction mixture was poured into water. The pH of the aqueous mixture was adjusted to 4 with dilute HCl, whereupon the product precipitated as an oil. After the aqueous solution was removed by decantation, the oil became solid. The product was crystallized from a mixture of ethyl acetate and n-hexane to give 4.7 g of 5- (° (-methyl-3-phenoxybenzyl) -1H-tetrazole, mp 92-95 ° C, pK'a = 5.8.

Analysis: Calculated for C 28 H 18 N 2 O 2: C 67.65 H 5.30 N 21.04 Found: C 67.41 H 5.33 N 21.05.

Claims (1)

Claim: Analogous process for the preparation of therapeutically active 5- (3-phenoxybenzyl) -1H-tetrazoles of the formula Y1 NN CH'V "having a hydrogen atom or a (C1-C1) alkyl group and Yj being a halogen or hydrogen atom , and their pharmaceutically acceptable acid addition salts, characterized in that the nitrile of the formula Λ R 1 O- * "wherein and have the same meaning as above is reacted with sodium azide in the presence of an organic polar solvent, and that the resulting tetrazole is modified if desired. to the corresponding acid addition salt.