Method of producing 2,3-diaryl-5-haloidthiophene

专利摘要:
Certain 2,3-diaryl-5-halo thiophenes are useful in the treatment of inflammation and/or pain.
公开号:SU1250172A3
申请号:SU833552852
申请日:1983-02-16
公开日:1986-08-07
发明作者:Бэрри Хабер Стивен
申请人:Е.И.Дюпон Де Немур Энд Компани (Фирма)；
IPC主号:

专利说明:

This invention relates to organic chemistry, namely to thiophene derivatives of the general formula. (I)
% P
B,
where R and R are independently from each other - 4 fluorophenyl, 4-alkyl (C-C) -phenyl ,. 4-methylthiophenyl, 4-methylsulfonylphenyl, 4-alkoxy (, j,) phenyl; Y - chlorine, bromine or iodine, which have anti-inflammatory and / or analgesic effects and can be used in medicine. The purpose of the invention is to develop an accessible method for the preparation of 2,3-diaryl-5-halotiophenes.
Example 1. 5-Bromo-2,3-bis (4-fluorophenyl) thiophene.
A solution of 2,3-bis (4-fluorophenyl) thiophene (13.6 g, 50 mmol) in 120 ml of methylene chloride and 150 ml of acetic acid is cooled to 5 ° C and treated with bromine (2.8 ml, 55 mmol) . After 4 hours, the reaction mixture is evaporated in vacuo. The residue after evaporation is dissolved in ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate and brine, dried and evaporated in vacuo. Recrystallization from ethanol afforded the desired compound (14.7 g), m.p. .
The data of the NMR spectrum in the analysis of similar drugs correspond to a given structure. Mass spectrum 350,
352 (M).
EXAMPLE 2. 5-Chloro-2,3-bis (4-methoxyphenyl) thiophene.
A solution of N-chlorosuccinimide (2.92 g, 22 mmol) in 50 ml of methylene chloride is introduced into a solution of 2,3-bis (4-methoxyphenyl) thiophene (5.92 g, 20 mmol) in 7.0 ml of methylene chloride and 75 ml of acetic acid. After 45 minutes at room temperature, the reaction mixture is heated under reflux for 18 hours. Then the cooled reaction mixture is evaporated in vacuo.
The residue was dissolved in ethyl acetate, followed by saturation
an aqueous solution of sodium bicarbonate and brine, dried and rotated in vacuo. Recrystallization from methanol gives the desired compound (4.27 g) with m.p. 89-92 ° C. The infrared and NMR data correspond to a given compound structure. Mass Spectrum 330, 332 (M), 315, 317
(M-CHj).
Froze 5-Iodine-2,3-bis (4- methoxyphenyl) thiophene.
A solution of 2,3-bis (4-methoxyphenyl) thiophene (5.92 g 20 mmol) in 70 ml
methylene chloride is cooled in an ice bath and treated with individual portions of iodine (5.6 g, 20 mmol) and red oxide of mercury (4.32 g, 20 mmol). The reaction mixture is stirred at
room temperature for 4 hours and then treated with additional portions of iodine (2.8 g, 10 mmol) and mercuric oxide (2.16 g, 10 mmol). After another two hours the reaction mixture
filtered through a celite filter.
The filter is diluted with methylene chloride, washed with 10% aqueous sodium thiosulfate solution and brine, dried and evaporated in vacuo. Recrystallization from methanol affords the desired compound (6.9 g) with m. Mp. 83-87 0. The infrared and NMR spectrum data correspond to a given compound structure. Mass spectrum 422 (M), 407 (M-SSC). Table 1 lists the proposed compounds.
I
Dosage forms of drugs.
Anti-inflammatory and / or analgesic agents can be administered to the body for treatment of inflammation and / or pain relief by any means that ensure contact of the active agent with the causative agent of the mammalian animal. They can be administered by any well-known methods suitable for use in combination with pharmaceutical preparations; as in the form of individual therapeutic devices, so. and in combination with therapeutic agents. They can be administered individually but are usually administered together with a therapeutic carrier of a drug, the choice of which is determined by the method of drug administration into the body and standard pharmaceutical practice.
The dose of the drug administered varies depending on the known factors such as the pharmacodynamic characteristics of the drug, the nature and method of administration; age, health, and weight of the recipient; the nature and extent of the symptom, the type of concurrent treatment, the frequency of treatment and the desired effect. Typically, the daily dose of active ingredient should be about 0.1-100 mg per kg patient weight. Typically, a dose of 0.5-50, and preferably 1-10 mg per kg patient weight per day, given as divided doses 1-6 times a day or as a long-term preparation, effective for obtaining the desired results. tatov.
Dosage forms (formulations) suitable for oral administration contain about 1-500 mg of active ingredient per dosage. In these pharmaceutical compositions, the active ingredient will typically be present in an amount of about 0.5-93% by weight, based on the total weight of the composition.
The active ingredient can be administered through the mouth in a solid dosage form, such as capsules, tablets and powders, or in a liquid dosage form, such as elixirs, syrups, suspensions. It may also be administered parenterally, in the form of sterile liquid dosage forms.
Gelatin capsules contain the active ingredient and powdered carriers such as lactose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. Similar solvents can be used to make compressed tablets. Both tablets and capsules can be prepared in the form of long-term release drugs in the body to ensure an unalloyed balance. medication within a few hours. Extruded tablets may be sugar coated or film coated to mask the unpleasant taste and protect the tablet from the atmosphere, or may be coated specifically for selective disintegration in the gastrointestinal tract.
0
Liquid dosage forms for oral administration may contain coloring and cushioning agents to improve patient susceptibility to them.
Typically, carriers suitable for parenterally administered solutions are water, an appropriate oil, saline, an aqueous solution of dextrose (glucose) and related solutions of sugar and glycols, such as propylene glycols or polyethylene glycols. Solutions intended for parenteral administration into the body contain the active ingredient, appropriate stabilizing agents, and, if necessary, buffering substances. Stabilizing agents suitable for this purpose are anti-oxidant or anti-oxidant agents such as sodium bisulfite, sodium sulfite or ascorbic acid, used alone or in combination. Citric acid and ethylene diamine tetra-acetic acid sodium salt can also be used. In addition, the parenteral solutions administered may contain preservatives such as benzalkonium chloride, methyl-. or propyl-paraben and chlorbutanol.
Pharmaceutical dosage forms suitable for the administration of the proposed compounds.
Capsules
B. A large number of single capsules are prepared by filling each standard gelatin capsule consisting of two compartments, 50 mg of powdered active ingredient, 175 mg of lactose, 24 mg of talc and 6 mg of magnesium stearate.
Soft gelatin capsules.
A mixture of the active ingredient and soybean oil is prepared, and this mixture is injected into a gelatin by means of an injection piston pump, to form soft gelatin capsules containing 50 mg of the active ingredient. Capsules are washed in
0 petroleum ether and dried. Pills. : A large number of tablets prepared. It is cast by conventional means so that the unit dosage form contains 50 mg of active ingredient, 6 mg of magnesium stearate, 70 mg of microcrystalline cellulose, 11 mg of corn starch and 225 mg
five
0
five
lactose. Appropriate coatings may be applied to the tablets to improve their taste for delayed absorption.
Injectable composition.
A parenteral composition suitable for administration by injection is prepared by mixing 1.5% by weight of the active ingredient in 10% by volume of propylene glycol and in 10 by subcutaneous injection of 0.1 ml of styede. The solution is sterilized by conventional methods.
Suspension.
The aqueous suspension to be administered through the mouth is prepared in such a way that every 5 ml of this suspension contains 25 mg of finely divided active ingredient, 200 mg of sodium carboxymethylcellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution. US Pharmacopoeia, and 0.025 ml of vanillin.
Introduced by injection of the composition.
A parenteral composition suitable for administration by injection is prepared by dissolving 1% by weight of the active ingredient in an injection solution of sodium chloride, USP XX, and the regumulator (killed by Difco heated lyophilized Mycobacterium butyricum, suspended in mineral oil in 5 mg
15 to 1 ml). In the body of 20 control rats that are not infected; arthritis, mineral oil is given by subcutaneous injection. Allow arthritis to develop within two
20 weeks. The foot volume of the Hzad-n-left foot, through which, not injection, is measured), and the rats into whose body the stimulant is injected, are selected and distributed to the treated groups of 10 pieces, so that each group has the same degree of disease. Control rats not charged with arthritis are divided into 2 groups of 10 each. In the body
The solution is subjected to sterilization of the proposed compound or PVA-conventional methods .. Acacia (polyvinyl alcohol 1%, arapplication. Uv stone. US Pharmacopoeia, 5%,
Dp is the detection and comparison of methylparaben 0.5%) on the same day and the anti-inflammatory effect of soy-35 in six consecutive days. After one test of this series and the standard day after the last dose,
foot volume (through which no injection takes place, rear left) using the Ugo Basile Model 7101 differential volume meter.
 -chg
Processing group
medication is being tested based on a standard arthritis model that shows good correlation with the effectiveness of
Infected with arthritis
(control) Average volume of a pad, ml
The average volume of the legs, ml
100
Infected with arthritis (cont & ampliol)
Not infected with arthritis (control)
The average volume of the legs, ml The average volume of the legs, ml
 The percentage reduction as compared to the control average foot volume.
The dose-sensitive regression lines of the percent reduction are built on semi-log paper by visual adjustment, and by visual control it is determined to reduce the AU 50% compared to the control connection on the human body. This model is arthritis induced by stimulants in rats.
Established triggered arthritis in rats.
Charles River Lenis male rats (weighing 130-150 g) are injected through the sole of the hind right foot.
five
Multicore (killed by heating Difco lyophilized Mycobacterium butyricum, suspended in mineral oil in an amount of 5 mg
5 to 1 ml). In the body of 20 control rats that are not infected; arthritis, mineral oil is given by subcutaneous injection. Allow arthritis to develop within two
0 weeks. The foot volume of the Hzad-n-left foot, through which, not injection, is measured), and the rats into whose body the stimulant is injected, are selected and distributed to the treated groups of 10 pieces, so that each group has the same degree of disease. Control rats not charged with arthritis are divided into 2 groups of 10 each. In the body
100
lm volume paws, data for some compounds are summarized in table 2.
The proposed compounds are also compared with indomethacin, phenylbutazone, ibuprofen and aspirin.
7
Writhing test using phenylquinone. .
The standard technique for determining and comparing the analgesic effect of compounds for which a good ratio to human efficacy is obtained is a standard Writhing test using phenylquinone, a modification of the test by Siegmunol, etc. The compound being tested, suspended in 1% methylcellulose, is administered through mouth in the body of bound female white mice (17-21 h), 5-20 mice per double blind test. 6 minutes before the observation, an aqueous (0.01% phenyl-para-benzoquinone) is injected by intraperitoneal injection. Phenylquinone 0.20 ml per ml. Through the appropriate period of time after entering 4epfe3 the mouth of the test compound
4-F F4-F f
(f t 4-СН
4-CHjO / 4-CHjO
t -pf4-CH3
4-SNS S 4 4-F f
4-СНз 4-СНз
4-CHjOjii4-CHjS
4-F 4-CH3SOj #; H
4-Fi 4-CH SOg - H
4-СНзО (й4-CH O H
4-CH Sqji # 4-Fj (# phenyl)
ten
501728
Observe a smaller person for 10 minutes for characteristic stretching or Writhing syndrome, which is an indication of pain caused by 5 phenylquinone. The effective analgesic dose for 50% of the smaller (AU gg) is calculated by the average Thompson displacement method, the moment of maximum activity is determined for many of these compounds. The data obtained for some compounds are summarized in Table 2 along with the data obtained for some standard anesthetics of anti-inflammatory drugs.
1% reduction compared to control foot volume at the indicated daily dose.
Thus, the proposed method: it is possible to obtain compounds possessing anti-inflammatory drugs and / or analgesic effects.
: Table 1
15
20
g1250172
table 2
 60
4.5
46% with 81 - 1.4
0.25 81
6.8
2.1
15
108
108
2.9
Editor S.Patrusheva
Compiled by V.M. Kusheva
Tehred: N. Bonkapo Proofreader S.Mekmar
Order 43А1 / 60 Circulation 379 Subscription
VNIIPI USSR State Committee
for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
“Production and printing company, Uzhgorod, ul. Project, 4

ten
. Continued table. 2 d
eight
9
10 25 26
Ibuprofen
I
Aspirin
2.9 0.4 0.5
13 0.21
..Indometagnn 0.3 Phenylbutazone
ten
100
305
.15
108 108
3.6 VI08 0.35
80 10 135

权利要求:
Claims (4)
[1]
METHOD FOR PRODUCING
[2]
2
[3]
3-DIARIL-5-HALOIDTHIOPHENES of the general formula where Rj and Rj are independently 4-fluorophenyl, 4-alkyl. (C _d -C ₂ ) phenyl,
[4]
4-methipthiophenyl, 4-methyl · sulfonylphenyl, 4-alkoxy (C ₄ -C ^) - phenyl;
. Y is chlorine, bromine or iodine, characterized in that the compound of the general formula where and R ₂ have the indicated meanings, are reacted with an equimolecular * amount of a halogenating agent.
SU 1250172 AZ

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引用文献:

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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US35430082A| true| 1982-03-03|1982-03-03|

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