FI57933C - FRAMEWORK FOR ACTIVATION OF THERAPEUTIC ACTIVITIES OLEFINA ARYLKETONER - Google Patents

Description

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C ^ Patent oyonnetty 10 11 1930 uttpy Patent meddelat (51) K ».ik .- / im.a. c 07 D 211/52, 295/10, 401/04 ENGLISH —Ff N LAN D (21) hwiellH ^ -NiBWiiWiii 3573/72 (22) HaJcwnlipCIvi — 15.12.72 (FI) (23) AlkuptM — Giltl (h «Tsdi (15.12.72 (41) Tellut JulktMkd - BllWt offtntllg 19.06.73

National Board of Patents and Registration of Finland / 44) Date of issue of NUitivilulpan. -

Patent · och registerstyrelsen Anatkin utlagd oeh utUkrHten publishedurtd 31.07. Θ0 (32) (33) (31) Requested Kuolkwt — Bugftrd prlorltut 18.12.71 18.12.71, 15.02.72, 17.02.72, 28.01 + .72, 28.06.72 12.07.72, 12.07.72, 22.09.72 Japan -Japan (JP) 102851 + / 71, 102855/71, I6169 / 72, 16752/72, I + 3125/72, 65208/72, 70265/72, 70266/72, 95720/72 (71) Sumitomo Chemical. Company, Limited, No. 15, Kitahama 5-chome, Higashi-ku, Osaka-shi, Osaka-fu, Japan-Japan (JP) (72) Junki Katsube, Osaka-fu, Masaru Nakao, Osaka-fu, Kikuo Sasajima,

Osaka-fu, Isamu Maruyama, 0saka-fu, Masaharu Takayama, 0saka-fu,

Keiichi Ono, Osaka-fu, Shigenari Katayama, Hyogo-ken, Yoshihiro Tanaka, Hyogo-ken, Shigeho Inaba, Hyogo-ken, Hisao Yamamoto, Hyogo-ken, Izumi Yanagihara, Osaka-fu, Japan-Japan (JP) (7I + ) Leitzinger Oy (51+) Method for the preparation of therapeutically active olefinic aryl ketones - Förfarande för framställning av terapeutiskt aktiva olefina arylketoner

The invention relates to a process for the preparation of therapeutically active olefinic aryl ketones of the formula RV = Z \ _ (I) <V /) - c-ch * ch-ch9a \ // I! 2 '-' o wherein H "* · is halogen and A is a cyclic amino group having one of the following formulas

/ \ 0H

(Wherein R and R are each hydrogen, ha- / sfR logene, C1-C4-alkyl or trifluoromethyl).

R3 57933 -ou

N NH

(wherein R is hydrogen, halogen or C 1 -C 4 alkyl).

X u \ v (with (C 1 -C 4 alkoxy) wx + y R 5 and their acid addition salts.

The aryl ketones (I) prepared according to the invention are useful as depressants of the central nervous system.

The process according to the invention is characterized by a) reducing an acetylene aryl ketone of the formula: wherein R 1 and A are as defined above or an acid addition salt thereof, or h) oxidizing an olefinic aryl alcohol of the formula: = \

/) - CH-CH = CH-CH-A

\ / I 2

'-' OH

57933 wherein and A are as defined above or an acid addition salt thereof.

It has now been found that olefinic aryl ketones (I) have a number of useful properties and are in themselves useful as analgesic, anti-inflammatory, psychotropic, autonomotropic and / or emtifungal agents. In particular, it should be noted that compounds (I) have a pronounced depressive activity on the central nervous system, which is higher than that of the corresponding saturated aryl ketones.

The compounds of the invention contain at least one basic nitrogen atom and can readily form acid addition salts. If desired, these acid addition salts can be subjected as such to any of the above reactions.

Pharmaceutically acceptable salts are formed by the reaction of a free base with an acid having a pharmaceutically acceptable anion. The term "pharmaceutically acceptable anion" is intended for those skilled in the art. It is defined as the non-toxic anion of any simple acid used therapeutically to neutralize basic drugs when its salts are to be used therapeutically. These acids include both inorganic and organic acids, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, succinic acid, phosphoric acid, maleic acid, tartaric acid, citric acid, glycolic acid and other acids.

Each of these compounds may be formulated for administration according to a method known per se. For the preparation of pharmaceutical compositions, they can be mixed with carriers, diluents, lubricants, excipients and / or binders, such as lactose, sucrose, calcium phosphate, starch, talc, casein, magnesium stearate, methylcellulose, polyglycols, tragacanth and the like, The resulting mixture can be processed in the usual manner into tablets, capsules, pills, ampoules and the like. The usual oral dose of the active ingredient is between about 0.1 mg and about 100 mg daily.

Animal experiments have shown that the compounds of the invention are pharmacologically active and show various depressant effects on the central nervous system. They also have a stronger antiapomorphine effect than known compounds, as shown in the following comparison table.

11 57933

Well. Compound Anti-apomorphic effect *) ED50 (mg / kg) (s.c.) 1 / - = \ / —s. / OH 0.29 2 / = r \ / V / OK 0.55 * s

Cl 5 / = \ /—\.0H 0.10 0 ζ_ ^ 3 4 / - \ / r ~~ \ / OH 0 · 28 ** F \ Jhfl-®2ra2CT2-lJ <r 0 0 ^ 3 5 '0 · 0.047

° Q

6 '0 0.068 »f-Q-r ^' Qu51 7 <> ^^ - 0-0 1.3 0 CH., 0 ^ 3.

8 / = \ / - \ / = \ 3 * 0 «F- \ J> * || 'OT2CK2CH2-V / N · ^

0 CH 2

*) Arzneimittel Forschung, 1_5, 104-117 (1965) P.A.J. Janssen et al.

Rats were used as experimental animals. M) Reference compounds known from the prior art 5,57933

The present invention is illustrated by the following examples, of which Examples A-E illustrate the preparation of the starting material and Examples 1 and 2 illustrate the preparation of the compounds of the invention.

Example A

To a solution of ethylmagnesium bromide (820 mg) prepared from magnesium (150 mg) and ethyl bromide (300 mg) in a conventional manner in anhydrous tetrahydrofuran (5 ml) was added a solution · of 1-propargyl-1 + - (p- chlorophenyl) -1 * -hydroxypiperidine (3.0 g) in anhydrous tetrahydrofuran (15 ml) at 6 ° C and the mixture was stirred for 15 minutes at 35 ° C. To the resulting solution was added dropwise a solution of p-chlorobenzaldehyde (385 mg) in anhydrous tetrahydrofuran (5 ml) under ice-cooling. The resulting mixture was kept at 5 '9 ° C for 20 minutes and stirred at 60-65 ° C for 1 hour. The cooled reaction mixture was diluted with ethyl acetate and added to the cooled aqueous ammonium chloride solution. The organic layer was separated, washed with water and dried over magnesium sulfate. After evaporation of the solvent, the residual oil was chromatographed on silica gel to give 1- (1- + - (p-chlorophenyl) -1 + -hydroxy-2-butynyl) -1 + - (p-chlorophenyl) -U-hydroxypiperidine as an oily liquid (350 mg). vf £ 3350 cm -1, vg £ 2250 cm -1.

In a similar manner the following compounds were obtained: 1-A- (p-fluorophenyl) -1 + -hydroxy-2-butynyl / -1 + - (p-chlorophenyl) -piperazine, 3300 cm -1.

1- [N- (p-fluorophenyl) -1 + -hydroxy-2-butynyl] -1 + - (p-chlorophenyl) -1 + -hydroxypiperidine, m.p. Il * 5 - ll + 5.2 ° C.

1- [1 + - (p-fluorophenyl) -1 + -hydroxy-2-butynyl] -1 + - (m-trifluoromethyl-phenyl) -1 + -hydroxypiperidine, m.p. 3350 cm-1.

1-N- (p-fluorophenyl) -1 + -hydroxy-2-butynyl] -N- (keto-1-benzimidazolinyl) -piperidine, v or J 3 of 3200 cm-1, 166 cm-1 "1.

1 - [(p-fluorophenyl) -1 + -hydroxy-2-butynyl] -1 + - (m-chloro-p-methylphenyl) -1H-hydroxypiperidine, ν max 33 50 cm -1.

1- [1 + - (p-fluorophenyl) -1 + -hydroxy-2-butynyl] -1- (m-trifluoromethyl-2-chlorophenyl) -1 + -hydroxypiperidine, m.p. 3300 cm-1.

1- [4- (p-fluorophenyl) -4-hydroxy-2-butynyl] -4- (m, p-dichlorophenyl) -4-hydroxypiperidine, mp 3360 cm -1.

6,57933 1- [4- (p-fluorophenyl) -4-hydroxy-2-butynyl] -4- (p-methylphenyl) -4-hydroxypiperidine, λmax 3320 cm-1.

Example B

To a solution of 4- (p-chlorophenyl) -4-hydroxypiperidine (4.0 g), dioxane (25 mL), water (10 mL) and 37% formalin (2.06 g) was added a mixture of contained a solution of 3- (p-fluorophenyl) -3-hydroxy-1-propyne (2.38 g) and dioxane (5 ml) and copper sulphate (pentahydrate) (127 mg) and water (4 ml) under ice-cooling. The resulting mixture was heated at 80-90 ° C for 4 hours and, after cooling, poured into concentrated aqueous ammonia. The resulting mixture was extracted with ether, and the ether extraction was chromatographed to give 1- [4- (p-fluorophenyl) -4-hydroxy-2-butynyl] -4- (p-chlorophenyl) -4-hydroxypiperidine (5.15 g) as crystals. as a substance having a m.p. was 145-146.2 ° C.

In a similar manner the following compounds were obtained: 1- [4- (p-chlorophenyl) -4-hydroxy-2-butynyl] -4- (p-chlorophenyl) -4-hydroxypiperidine, ν ^ ά & δ 3350 cm-1, v ^ daS 2250 cm "1.

1- [4- (p-fluorophenyl) -4-hydroxy-2-butynyl] -4- (o-methoxyphenyl) piperazine, λmax 3300 cm-1.

1- [4- (p-fluorophenyl) -4-hydroxy-2-butynyl] -4- (2-keto-1-benzimidazolinyl) -piperidine, or 3200 cm -1, or 1680 cm -1.

1- [4- (p-fluorophenyl) -4-hydroxy-2-butynyl] -4- (m-trifluoromethylphenyl) -4-hydroxypiperidine, m.p. 3350 cm-1.

1- [4- (p-fluorophenyl) -4-hydroxy-2-butynyl] -4- (m-chloro-p-methylethylphenyl) -4-hydroxypiperidine, m.p. 3350 cm-1.

1- [4- (p-fluorophenyl) -4-hydroxy-2-butynyl] -4- (m-trifluoromethyl-p-chlorophenyl) -4-hydroxypiperidine, m.p. 3300 cm-1.

1- [4- (p-fluorophenyl) -4-hydroxy-2-butynyl] -4- (m, p-dichlorophenyl) -4-hydroxypiperidine, m.p. 3360 cm-1.

1- [4- (p-fluorophenyl) -4-hydroxy-2-butynyl] -4- (p-methylphenyl) -4-hydroxypiperidine, δHhda S ^ 320 cm -1 757933

Example C

A mixture of 1-A- (p-chlorophenyl) -N-hydroxy-2-butynyl / A- (p-chlorophenyl) A-hydroxypiperidine (0.25 g) in chloroform (5 ml) and manganese dioxide (2, 5 g), stirred at room temperature for 8 hours. The mixture was filtered and the filtrate was concentrated to give 1-N- (p-chlorophenyl) -N-oxo-2-butynyl / -N- (p-chlorophenyl) -A-hydroxypiperidine (0.15 g) as a crystalline substance.

Sp. A3 - A6 ° C (from chloroform).

In the same manner as above, the following compounds were obtained: 1-N- (p-fluorophenyl) -A-oxo-2-butynyl / N- (o-methoxyphenyl) -piperazine, g 2200 cm -1, 161.5 m -1.

1- [1- (p-fluorophenyl) -A-oxo-2-butynyl] -N- (chlorophenyl) -A-hydroxypiperidine, m.p. 139 ~ Al ° C (from chloroform).

1- [N- (p-fluorophenyl) -A-oxo-2-butynyl] -N- (2-keto-1-benzimidazolinyl) -piperidine, m.p. 182.5-187 ° C (from chloroform).

1- [N- (p-fluorophenyl) -A-oxo-2-butynyl] -N- (m-trifluoromethylphenyl) -A-hydroxypiperidine, m.p. 82.5-85 ° C (from n-hexanebenzene).

Example D

To an ethereal solution of lithium aluminum hydride (0.35 g) (7 ml) was added a solution of 1-N- (p-fluorophenyl) -N-hydroxy-2-butynyl / N- (p-chlorophenyl) -A-hydroxypiperidine (1.20 g) in ether. (13 ml) under ice-cooling. After stirring at 25 ° C for U hours, acetone was added to consume excess lithium aluminum hydride. The resulting mixture was poured into aqueous ammonium chloride solution and extracted with ether. The ether extracts were washed with water, dried over anhydrous magnesium sulfate and concentrated to give 1-A- (p-fluorophenyl) -U-hydroxy-2-butenyl / A- (p-chlorophenyl) A-hydroxypiperidine as a crystalline solid, m.p. was IU9 - 151 ° C.

In the same manner, the following compounds were obtained: 1-A- (p-fluorophenyl) -U-hydroxy-2-butenyl-N- (o-methoxyphenyl) piperazine, m.p. 93-95 ° C.

1-N '(p-fluorophenyl) N-hydroxy-2-butenyl / N- (2-keto-1-benzimidazolinyl) piperidine, m.p. 188-191 ° C.

57933 8 (1- (N-fluorophenyl) -N-hydroxy-2-butenyl) - (N-chloro-p-methylphenyl) -U-hydroxypiperidine, m.p. 108-110 ° C.

1- (M-p-fluorophenyl) -N-hydroxy-2-butenyl] -N- (m-trifluoromethyl-p-chlorophenyl) -U-hydroxypiperidine, ν max 3330 cm-1.

OH

1- [1 * - (p-fluorophenyl) -1 + -hydroxy-2-butenyl] -U- (m, p-dichlorophenyl) -N-hydroxypiperidine, 3360 cm-1.

There is 1- [N- (p-fluorophenyl) -N-hydroxy-2-butenyl] -N- (p-methylphenyl) -1 + -hydroxypiperidine, m.p. 3325 cm-1.

Example E

To a deactivated palladium catalyst prepared from 5% palladium on barium sulfate (20 mg) and quinoline (7 mg) in methanol (3 mL) with stirring for 15 minutes under hydrogen was added 1-Λ- (p-fluorophenyl) -U- a solution of hydroxy-2-butynyl-N- (p-chlorophenyl) -1H-hydroxypiperidine (0.60 g) in methanol (15 ml) and the resulting mixture was stirred under hydrogen at 25 ° C until an equimolar amount of hydrogen (38, 5 ml) was consumed. The catalyst was filtered off and the filtrate was concentrated in vacuo to give 1- (U- (p-fluorophenyl) -H-hydroxy-2-butenyl) -U- (p-chlorophenyl) -1H-hydroxypiperidine (0.60 g) as white prisms, m.p. Mp 9-150 ° C (from methanol).

In a similar manner the following compounds were obtained: 1- [1 + - (p-fluorophenyl) -1 + -hydroxy-2-butenyl] -1- (m-trifluoromethylphenyl) -U-hydroxypiperidine, m.p. 135-138 ° C.

1-N- (p-fluorophenyl) -N-hydroxy-2-butenyl] -h- (2-keto-1-benzimidazolyl) piperidine, m.p. 188-191 ° C.

Example 1

A mixture of N- [n- (p-fluorophenyl) -1 * -hydroxy-2-butenyl] -N- (m-trifluoromethylphenyl) -hydroxypiperidine (0.39 g) in chloroform (20 ml) and manganese dioxide (1.55 g) was stirred at room temperature for k hours. When the inorganics were filtered off and the filtrate was concentrated, crystals of 1- [U- (p-fluorophenyl) -U-oxo-2-butenyl] - (m-trifluoromethylphenyl) -h-hydroxypiperidine were obtained, m.p. was 97-97.5 ° C.

In a similar manner the following compounds were obtained: 1- [1 + - (p-fluorophenyl) -1 + -oxo-2-butenyl] -1 + - (p-chlorophenyl) -1 + - hydroxypiperidine, m.p. 111.5 - 113 ° C.

9,57933 1-N - (p-fluorophenyl) -1 + -oxo-2-butenyl] -1 + - (o-methoxyphenyl) -piperazine, m.p. 89.5 - 91.5 ° C.

1- [N- (p-fluorophenyl) -1 + -oxo-2-butenyl] -1 + - (2-keto-1-benzimidazolinyl) piperidine, m.p. 167-170 ° C.

1- [N- (p-fluorophenyl) -1H-oxo-2-butyl] -1 '- (m-chloro-p-methyl-phenyl) -1 + -hydroxypiperidine, m.p. 113-115 ° C.

1- [1 »- (p-fluorophenyl) -1 + -oxo-2-butenyl] -1 + - (m-trifluoromethyl-p-chlorophenyl) -1 + -hydroxypiperidine, m.p. 137-138 ° C (decomposes) (hydrochloride).

1- [1 + - (p-fluorophenyl) -U-oxo-2-butenyl] -1 * - (m, p-dichlorophenyl) -1 + -hydro Sipi peridine, v ^ a® = c I670, 1620 can ” 1.

1- [1 + - (p-fluorophenyl) -1 + -oxo-2-butenyl] -1 + - (p-methylphenyl) -1 + -hydroxy-piperidine, m.p. 115-117 ° C.

Example 2

To a deactivated palladium-on-catalyst prepared from 5% palladium on barium sulfate (15 mg) and quinoline (5 mg) with methanol (3 ml) under stirring for 15 minutes under hydrogen was added 1- [1 + - (p-fluorophenyl) -1 + -oxo-2 A solution of -butynyl / -1 + - (p-chlorophenyl) -1 + -hydroxypiperidine (0.30 g) in methanol (8 ml) and the resulting mixture was stirred under hydrogen at 25 ° C until an equimolar amount of hydrogen (20 ml) was absorbed. The catalyst was filtered off and the filtrate was concentrated in vacuo to give 1- [1 + - (p-fluorophenyl) -1 + -oxo-2-butenyl] -1 + - (p-chlorophenyl) -1 + -hydroxypiperidine (0.28 g). , sp. 111.5 - 113 ° C.

Claims (1)

A process for the preparation of therapeutically active olefinic aryl ketones of the formula -h-C-CH = CH-CH2A (I) '-' o which is halogen and A is a cyclic amino group having one of the following formulas / \ / 0H "NX (wherein R * and R · 3 are each hydrogen, halo-C 1-2 alkyl, C 1-4 alkyl or trifluoromethyl-R 3 -N 2 H, (wherein R 4 is hydrogen, halogen or C -N NH (where R 5 is -C 4 a 1 coke) -op R 5 and their acid addition salts, characterized in that a) the reduction of the acetylenic aryl chain P011 ^ 3 ^ a is: 57933 11 <Γ ^ Λ - cc * c-ch9a j wherein and A are as defined above or an acid addition salt thereof, or b) oxidizing an olefinic aryl alcohol of the formula: wherein R 1 and A are as defined above 12 57933 For the preparation of a therapeutically active olefin aryl ketone with the formula Elv = \ /) - C-CH * CH-CHO A (I) with R 1 is halogen and A is a cyclic amino group med nägon av följande formler / \ 0H 2. o> _v 2 (där R och R räda är väte, halogen, / ^ ^ ^ C1-CU eller trifluoromethyl) R3 - »y j? '-f \ (from R 1 is C 1, halogen or N NH \ _ / C 1 -C 4 alkyl) / - \ / —ς \ (from R 5 or C 1 -C 4 alkoxy) NN - / \ at R 5 and derivative , kännetecknat därav, att a) en arylketon av acetylen med formuleln V = \ ^ Λ— j-ch «c-ch2a