JPS607606B2 - Novel benzophenone derivatives and pharmaceuticals comprising the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the following formula 1 [where X and x2 are hydrogen atoms or halogen atoms (
R, represents a methyl group, and R2 represents -(C ratio)a-CH=CH-(CH2
)b day type or -(CH2)a-C is one C ratio one (C&)
aliphatic carbonization containing 4 to 7 carbon atoms of the b-day type (where a and b are integers varying from 0 to 5, such that the sum is 2 to 5); The subject of this paper is a novel benzophenone derivative of [representing a hydrogen chain].

When X and x2 represent a halogen atom, this is preferably a chlorine atom or a fluorine atom. Among the compounds of the present invention, those described in the Preparation Examples may be particularly mentioned.

Compounds of formula 1 have interesting pharmacological properties, in particular they exhibit very distinct analgesic activity.

The compounds of formula 1 can therefore be used in the treatment of humans and animals, in particular as medicaments in the treatment of muscle, joint and neuralgia, toothache, migraine.

They can be administered by oral, lingual, parenteral, rectal or topical routes. For this they are tablets,
Sublingual tablets, dragees, capsules, gelatin capsules, solutions or emulsions for drinking, solutions or suspensions for injection, suppositories,
It can be provided in the form of a cream, ointment or lotion.

The products of formula 1 can be used to prepare pharmaceutical compositions containing at least one thereof as an active ingredient. Pharmaceutical forms are manufactured according to conventional methods.

The active ingredients may be supplemented by the adjuvants commonly used in these compositions, such as aqueous or non-aqueous vehicles, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, fatty substances of animal or vegetable origin, paraffin derivatives. , glycol, various wetting, dispersing or emulsifying agents, and preservatives. Dosages vary depending on, inter alia, the route of administration and the desired therapeutic effect.

It is, for example, between 50 and 9 to 2 evenings per day for adults by oral administration. Compounds of formula 1 have the following formula D, where X, , X2, R, and a are as defined above.
A compound of the following formula m (C6 stop〉3-P=CH-(C ratio) b day (m), where b is as defined above) is condensed by Witschig reaction to give the following formula It is produced by a method characterized by obtaining a compound of the following formula and, if desired, reacting this compound with a reducing agent to obtain a compound of the following formula.

In a preferred method of carrying out the above manufacturing method, "formula m
The reagent has the following formula W(C6 ratio)3-P-(CH2)b-
The quaternary phosphonium halide of CH3.ya19(N) (where b is as defined above and Hal represents a halogen atom, preferably a bromine or iodine atom) is prepared in advance by the action of a strong base. can get.

The Witzig reaction takes place in a solvent such as benzene, toluene, tetrahydrofuran or dimethyl sulfoxide.

In a preferred method of practice, it takes place in an anhydrous mixture of tetrahydrofuran and dimethyl sulfoxide.

Reduction is hydrogenation in an alkanol such as methanol, ethanol or isopropanol in the presence of a catalyst such as Raney nickel or platinum oxide.

The compound of formula 0 used as a starting material in the above production method can be produced by the following method.

'11 When it is desired to produce a substance of formula 0 where a is equal to 0, a compound of the following general formula (where X, , X2 and R, are as defined above) (this compound can be used as (which can be obtained by a method similar to that described in No. 1) is converted into its acid chloride, which is catalytically reduced in the presence of palladium-supported barium sulfate according to the Rosemund method (described in the production example) to obtain the following formula: (Here X,,
X2 and R are as defined above).

{When it is desired to obtain a substance of formula B where 2'a is equal to 1, a compound of the following formula (where X, , X2 and R have the same meanings as above) (as described in French Pharmaceutical Special Patent No. 8440M) (obtained according to a method analogous to the method) is treated in the same manner as described above to obtain the product of formula 0 in which a is equal to 1.

{3' When we obtain the substance of formula (b) where a is an integer that can vary from 2 to 5, we first obtain the following formula (where X, , X2 and R,
is as defined above) is added to a compound of the following formula (G)31P=CH-(C ratio)p-C02R3 (where p is an integer that can vary from 0 to 5 and R3 is an alkali metal (representing an atom or an alkyl group), the resulting product is converted into an acid by saponification when R3 is an alkyl group, and the resulting acid is converted into an acid of the formula 0 where a is equal to 0.
Treated in the same manner as described above for the compound a
Compounds of formula 0 are obtained, where is an integer that can vary from 2 to 5.

Compounds of formula W can be prepared by reacting triphenylphosphine with a compound of formula V(CH2)b-CQ(V) in an anhydrous solvent such as ether, benzene, toluene or xylene or without the use of a solvent. You can get it by doing this.

Examples of the preparation of these compounds are given in the experimental section. Examples of the present invention are shown here, but are not intended to limit the present invention in any way.

Preparation 1: 2-Methyl-3-(p-chlorobenzoyl)penzaldehyde 2-Methyl- used as starting material
3-(p-chlorobenzoyl)penzaldehyde can be obtained from 2-methyl-3-(p-chlorobenzoyl)benzoic acid chloride (this is French Patent No. 2085) by the following method.
No. 638).

43.92 2-methyl-(p-chlorobenzoyl)benzoic acid chloride, 450' xylene 4.5
A solution obtained by refluxing 1 day of 10% barium sulfate on palladium and 6 days of quinoline with sulfur, cooling and diluting to 70% with xylene.
4 secretes were heated for 45 minutes under a hydrogen stream, at a temperature of 13
Set to 0oo.

The mixture was allowed to stand at this temperature until the evolution of hydrogen chloride had ceased, then kept under inert gas, cooled to about 30 mil, the catalyst chopped, the solvent removed, and the residual oil removed from isopropyl. Dissolve in ether, add sodium bisulfite, and stir the whole for 1 hour.The precipitated bisulfite compound is filtered in a vacuum oven, washed, and then immersed in inert gas in the presence of dilute sulfuric acid and ether. The ether is decanted, the aqueous phase is re-extracted with ether, the ether phase is collected, washed with water, dehydrated, and the ether is evaporated under vacuum. After recrystallization from propyl ether, 2-methyl-31 (p
-Chlorbenzoyl)penzaldehyde is recovered.

M yen = 68oo. Production 2: 2-methyl-3-(p-chlorobenzoyl)phenylacetaldehyde Step A: 2-methyl-3-(p-chlorobenzoyl)phenylacetic acid 5
The mixture of 2-methyl-3-(p-chlorobenzoyl)benzoic acid and 50 cc of thionyl chloride is heated for 2 hours.

Excess thionyl chloride is removed by vacuum distillation. The acid chloride produced is dissolved in 50 cc of methylene chloride, and the resulting solution is gradually added to 370 cc of diazomethane methylene chloride solution at 0°C. After standing overnight at ambient temperature,
The solvent is removed under reduced pressure. 30% of the obtained diazoketone
silver oxide, dissolved in cc of dioxane,
14.5 minutes of sodium carbonate and 9.6 hours of sodium thiosulfate are added slowly to a mixture of 70 cc of water at 7000 ml. After 2 hours at 70 oo, the whole is filtered and the oven liquor is acidified by addition of concentrated hydrochloric acid.

The precipitate is separated by furnace, washed with water and recrystallized from isopropyl ether. 2-Methyl-3-(p-chlorobenzoyl)phenylacetic acid is obtained.

Mm=15〆0. Step B: 2-methyl-3-(p-chlorobenzoyl)phenylacetic acid chloride 5.8 hours of 2-methyl-3-(p-chlorobenzoyl)phenylacetic acid
Dissolve in 5 cc of thionyl chloride and heat under reflux for 1.5 hours.

Excess thionyl chloride was removed and 2-methyl-3-(p-
chlorobenzoyl) phenyl acetic acid chloride is obtained. M yen = 62~63q○. Step C: 2-Methyl-3-(p-chlorobenzoyl)phenylacetaldehyde 2-Methyl-3-(p-chlorobenzoyl)phenylacetaldehyde by carrying out in the same manner as Preparation 1 starting from 2-methyl-3-(p-chlorobenzoyl)phenylacetic acid chloride. 3-(p-chlorobenzoyl)phenylacetaldehyde is obtained in the form of an oil.

Analysis C, 6th, 3CI02 Calculation: ○ Tsutomu 70.46 Nitsutsumi 4-8 01*13.0 Actual measurement: 70.5 4.6 13.6 Production 3: n-hexyltriphenylphosphonium iodide 28
．． Add 82 hours of triphenylphosphine and 21.2 hours of 1-iodohexane to 200 cc of xylene.

The solution so obtained is heated under reflux for 5 hours and, after cooling, the solvent is decanted and the gummy residue is triturated with ether. 90~100 under reduced pressure
Dry at 100 ℃ to obtain n-hexyltriphenylphosphonium iodide in 44.53 min. M yen = 10600. Preparation 4: n-Benzyltriphenylphosphonium iodide Proceeding in the same manner as Preparation 3 starting from n-bentyltrifhenylphosphine iodide, n-bentyltriphenylphosphonium iodide is obtained.

MP=17400. Example 1 4-chloro-3'-(r-n-heptenyl)-2-methylbenzophenone 9.955 days n-hexyltriphenylphosphonium iodide, 5.17 days 2-methyl-3
1 p-chlorobenzoylbenzaldehyde and 100c
20 cc of 1:1 dimethyl sulfoxide/tetrahydrofuran mixture and a solution containing a suspension of 60% sodium hydride in mineral oil at 0°C, previously washed with petroleum ether. Add to sulfoxide/tetrahydrofuran mixture.

Continue to incubate the entire thing at 0°C for 1 minute, then at ambient temperature for 4 minutes.
Time 3: Worship the female fly. Evacuate the solvent under vacuum. The residue is heated to reflux with isopropyl ether. Decant the whole thing and repeat this operation three times under the same conditions. Drying of the extract yields an oily residue of 12.4%. After chromatography on silica in benzene, 4-chloro-3'-(1"-heptenyl)-12-methylbenzofluoride of 5.645% is obtained. Enon is obtained in the form of an oil.
Chromatography on silica (reagent: benzene):
Rf=0.5 & Analysis: C2, Day 23 CIO Calculation: ○ Tsutomu 77.16 Day% 7.09 01 Multi 10.8
5 Actual measurement: 78.2 7.5 10.
Example 7 Example 2 4-chloro-3'-n-heptyl-2-methylbenzophenone 5.57 ml of 4-chloro-3- was added to a suspension containing 60 cc of ethanol and 110 parts of platinum oxide.
Add to (1″-heptenyl)-2-methylbenzophenone.

Place the whole thing in a hydrogen atmosphere and continue to worship the hawk for about 2 minutes.
It is filtered to drive off the solvent. After chromatography on silica in benzene, 4-chloro-3'-n'-hephage was obtained for 4.87 min. Chil-2'-methylbenzophenone is recovered in the form of an oil. Chromatography on silica (eluent: benzene): Rf=0.61. Analysis: C
2, Sun 23 CIO Calculation: ○ Tsutomu 76.69 H*7.66 01 many 10.7
8 Actual measurement: 76.5 7.7 10.
Example 8 34-Chloro-3-(1″-hexenyl)-2-methylbenzophenone Produced in the same manner as Example 1, yielding 9.66
5
．． Starting from 17 hours of 2-methyl-3-p-chlorobenzoylbenzaldehyde, 5.785 hours of 4-chloro-go(r-hexenyl)-2'-methylbenzophenone are obtained in the form of an oil.

Chromatography on silica (eluent: methylene chloride): Rf=0.72. Analysis: C2 Rainbow 2, CIO calculation:○
Tsutomu 76.78 Hita 6.77 01*11.33 actual measurement:
77.1 6.9 11.2 Example 44
-Chloro-3'-1n-hexyl-2'-methylbenzophenone Proceed in the same manner as in Example 2, starting from 4-chloro-3'-(1''-hexenyl)-2'-methylbenzophenone on 5.7 night. Then, 3.73 evening 4-Kurorou 3'-
n-hexyl-2'-methylbenzophenone is obtained in the form of an oil.

Chromatography on silica (eluting agent: methylene chloride-petroleum ether (4:6)) Rf = 0.34. analysis:
C2 phantom 23 CIO calculation: ○ grandson 76.29 H% 7.36 01 shot 11.2
Actual measurement: 76.2 7.4 11.3 Example 54-Chlor-3-(3″-putenyl)-2′-methylbenzophenone Produced in the same manner as Example 1, 3-(p-chlorobenzoyl)- Starting from 2-methylphenylpropionaldehyde and triphenylmethylphosphonium bromide, 4-chloro-3-(3''-butenyl)-2'-methylbenzophenone is obtained.

Chromatography on silica (eluent: methylene chloride-petroleum ether (4:6)) Rf = 0.3 Mr. analysis: C,
8th, 7CIO Calculation: ○Grandchild 75.91 Japan Association 6.02 01*12.4
5 Actual measurement: 76.0 6.2 12.5
Example 6 4-Chlor-3-n-butyl-2'-1-methylbenzophenone 9.01 evening 4-chloro-3
Starting from 1(3''-butenyl)-2'-1-methylbenzophenone, 7.09 hours of 4-chloro-3'-1-n-butyl-2-methylbenzophenone are obtained.

Chromatography on silica (eluent: benzene):
Rf=0.9 Analysis: C, 8th, 9CIO Calculation: ○ Tsutomu 75.38 H*6.68 01 Multi 12.3
6 Actual measurement: 75.5 6.9 12.
Example 4 74-Chloro-3'-(2''-butenyl)-2'-
Methylbenzophenone Produced as in Example 1, 8.065
Starting from 3-(p-chlorobenzoyl)-2-methylphenylacetaldehyde at 1 pm and triphenylethylphosphonium bromide at 11 pm, 4-chloro- at 2.54 pm.
3-(2''-butenyl)-2-methylbenzophenone is obtained in the form of an oil.

Chromatography on silica (eluent: cyclohexane ether (8:2)): Rf=0.5. Analysis: C,
8th, 7CIO Calculation: ○ Tsutomu 75.91 H% 6.02 01 Son 12.4
5 Actual measurement: 76.2 6.1 12.4
Example 84 - Fluoro-31 n-butyl-2'-methylbenzophenone Working in the same manner as Examples 1 and 2, 31 (p
Starting from 2-methylbenzaldehyde and n-propyltriphenylphosphonium iodide, 4-fluoro-3'-1-n-butyl-Z.1-methylbenzophenone is obtained in the form of an oil.

Analysis: C, 8 days 2, FO Calculation: ○ Tsutomu 79.97 H% 7.08 F% 7.03 Actual measurement; 80.3 7.1 7.0 Example of pharmaceutical composition Gelatin capsule corresponding to the following formulation was manufactured.

Compound of Example 7 9 of 50 Polyoxyethylene Glycol per gelatin capsule Required amount Pharmacological studies Studies of analgesic activity The tests used were as follows: by Mr. Koster (Fed.
Proc. , 18, 412 (1959)) is an acetic acid test based on the facts pointed out.

Intraperitoneal injection of acetic acid induces repetitive stretching and twisting movements in mice that can last for more than 6 hours. Analgesics prevent or reduce this symptom. Therefore, this can be considered an episode of generalized abdominal pain. It was a 1% solution in acetic acid with 10% gum arabic added.

The dose at which the above symptoms start to appear is 0.0 under these conditions.
It is 100% of acetic acid, or 100% of acetic acid. Test compounds are administered orally half an hour before injection of acetic acid.

Mice were fasted the day before the test. Stretching movements are observed and counted for each mouse during a 15 minute observation period starting immediately before the injection of acetic acid.

Results are expressed as AD5o, ie the dose that reduces the number of days of stretching exercise by 50% compared to control animals.

The results are summarized in the table below. The lethal dose (LDo) was determined after oral administration of the compounds of Acute Toxicity Examples 3 and 5 to mice.

LDo is the highest dose that causes all-cause mortality at the end of 8 days. The LDo of the two compounds is shown in the table below. 1st dream division (Z) Correct False Table (Showa et al. Issued on April 4th) Patent Publication Number Rahi Wara Lala Classification Identification Symbol Place Meaning
Positive C07C 49/76
1st column 18 x 3 x 1 line
Heptyl column 1 24 Hebutyl row

Claims (1)

[Claims] Primary formula I ▲ Numerical formulas, chemical formulas, tables, etc. Expressed, R_2 is -(CH_2)_a-CH=
CH-(CH_2)_b-H type or -(CH_2)_a
-CH_2-CH_2-(CH_2)_b-H type (where a and b are integers that can vary from 0 to 5, and their sum is 2 to 5) 4 to 7 pieces represents an aliphatic hydrocarbon chain containing carbon atoms. 2. The compound according to claim 1, which is a compound corresponding to formula I in which X_3 represents a hydrogen atom and X_2 represents a halogen atom. 3 4-chloro-3'-(1''-n-heptenyl)-2
The compound according to claim 1, which is '-methylbenzophenone. 4. The compound according to claim 1, which is 4-chloro-3'-n-heptyl-2'-methylbenzophenone. 5 4-chloro-3'-(1''-hexenyl)-2'-
The compound according to claim 1, which is methylbenzophenone. 6 4-chloro-3'-n-hexyl-2'-
The compound according to claim 1, which is methylbenzophenone. 7 The compound according to claim 1 which is 4-chloro-3'-(3''-butenyl)-2-methylbenzophenone.8 4-chloro-3'-(2''-butenyl)-2'
-Methylbenzophenone. 9. The compound according to claim 1, which is 4-chloro-3'-n-butyl-2'-methylbenzophenone. 10 The compound according to claim 1, which is 4-fluoro-3'-n-butyl-2'-methylbenzophenone. 11 4-fluoro-3'-(1''-butenyl)-2'
-Methylbenzophenone. 12 Formula I ▲ Contains mathematical formulas, chemical formulas, tables, etc. ▼ [Where, CH_2)_a-CH=
CH-(CH_2)_b-H type or -(CH_2)_a
-CH_2-CH_2-(CH_2)_b-H type (where a and b are integers that can vary from 0 to 5, and their sum is 2 to 5) 4 to 7 pieces an aliphatic hydrocarbon chain containing carbon atoms.