GB2055820A - 2-amino-3-(alkylthiobenzoyl)- phenylacetic acids and esters - Google Patents
2-amino-3-(alkylthiobenzoyl)- phenylacetic acids and esters Download PDFInfo
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- GB2055820A GB2055820A GB8022968A GB8022968A GB2055820A GB 2055820 A GB2055820 A GB 2055820A GB 8022968 A GB8022968 A GB 8022968A GB 8022968 A GB8022968 A GB 8022968A GB 2055820 A GB2055820 A GB 2055820A
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- methylthiobenzoyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C321/00—Thiols, sulfides, hydropolysulfides or polysulfides
- C07C321/24—Thiols, sulfides, hydropolysulfides, or polysulfides having thio groups bound to carbon atoms of six-membered aromatic rings
- C07C321/28—Sulfides, hydropolysulfides, or polysulfides having thio groups bound to carbon atoms of six-membered aromatic rings
Abstract
Compounds of the general formula <IMAGE> (wherein R represents a hydrogen atom or a lower alkyl group, R<1> represents hydrogen atom or a lower alkyl group or pharmaceutically acceptable metal cation, R<2> represents a hydrogen or halogen atom or a lower alkyl or lower alkoxy group, Am represents an amino, methylamino or dimethylamino group and the lower groups contain 1-6-carbon atoms) have anti-inflammatory and analgesic activity and inhibit blood platelet aggregation. They are prepared by the following route: <IMAGE>
Description
SPECIFICATION 2-Amino-3-(alkylthiobenzoyl)-phenylacetic acids
The present invention relates to certain novel 2-amino-3-benzoylphenylacetic acids having alkylthio substitution on the benzoyl moiety, their alkylesters and metal salts, pharmaceutical compositions incorporating such compounds, uses of such compounds and certain intermediates for the preparation of such compounds.
Certain 2-amino-3-(5 and 6) benzoylphenylacetic acids having the benzoyl moiety substituted by lower alkyl, halogen, nitro and trifluoromethyl groups and methods of preparing and using the same are disclosed in U.S. Patent 4,045,576. The compounds of the present invention cannot be prepared by the procedures disclosed therein.
The invention is more specifically concerned with 2-amino-3-(alkylthiobenzoyl)phenylacetic acids, alkylesters and metal salts having the formula:
wherein:
R represents a hydrogen atom or a lower alkyl group,
R1 represents a hydrogen atom or a lower alkyl group of a pharmaceutically acceptable metal cation,
R2 represents a hydrogen or a halogen atom or a lower alkyl or lower alkoxy group, and
Am represents a primary amino (-NH2), methylamino or dimethylamino group.
The novel compounds of Formula I possess valuable pharmacological properties and are useful as pharmaceutical agents. The compounds exhibit anti-inflammatory and analgesic activity and inhibit blood platelet aggregation in warm-blooded animals.
Certain novel intermediates, the 7-(S-loweralkyl-thiobenzoyl)indolin-2-ones may be represented by
Formula II:
wherein R, R' and R2 are as hereinabove defined.
The anti-inflammatory activity has been demonstrated in laboratory animals using a modification of the
Evans Blue Carrageenan Pleural Effusion Assay of Sancilio, L.F.,J. Pharmacol. Exp.Ther. Ther.168,199-204 (1969).
The compounds of Formula I have been demonstrated to be inhibitors of blood platelet aggregation by use of the test of reduction of platelet aggregation as described by Born, J. of Phys. 162,67-68 p. (1962) and
Evans et al, J. of Expt. Med. 128,877-894(1968). Rats were orally administered test drugs and after 2 hrs the rats were bled and platelet rich plasma obtained. Collagen was added to the platelet rich plasma to induce platelet aggregation and comparisons were made between control and treated samples.
The compounds of Formula I also act as analgetics as determined by the Bradykinin Analgetic Test Method of Dickerson et al, Life Sci. 4,2063-2069 (1965) as modified by Sancilio and Cheung, Fed. Proc. 35,774(1976).
It is an object of the present invention to provide novel compounds and compositions. Another object is to provide methods for the preparation of the novel compounds. A still further object is to provide a novel method for the treatment of a living animal body and especially mammalian bodies for purposes of alleviating inflammation and pain and inhibiting blood platelet aggregation with a minimum of undesirable side effects.
The present invention encompasses the compounds of Formula I set forth above with accompanying definitions as composition of matter and the utilization of these novel compounds in living animals for their pharmacological effects as set forth herein.
In the definition of the symbols of the formulae hereof and where they appear elsewhere throughout this specification, the terms have the following significance.
The term "lower alkyl" as used herein includes straight and branched chain groups of up to six carbons inclusive, and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, tertiary butyl, amyl, isoamyl and hexyl. Preferably lower alkyl groups having no more than four carbon atoms are used. The term "lower alkoxy" has the formula -O-lower alkyl.
The term "halogen" when referred to herein means Cl, F, Br and I.
Illustrative of pharmaceutically acceptable metal cations are sodium, potassium, calcium, magnesium, zinc, copper and the hydrates thereof.
The starting fluorobenzoylindolin-2-ones used to prepare the compounds of this invention may be prepared by one or more of the methods disclosed in U.S. Patent 4,045,576. One method disclosed therein begins by reacting 2-amino-4'-halobenzoylbenzophenone with ethyl methylthioacetate, t-BuOCI (tertiary butyl oxychloride) and Et3N (triethylamine) to give 7-(halobenzoyl)-3-methylthioindolin-2-ones which are then reduced using a Raney nickel catalyst to produce the 7-(halobenzoyl)-3-indolin-2-one. A modification of this procedure was used wherein the Raney nickel was replaced by tin powder in alcohol and concentrated
hydrochloric acid.The following equation is representative of the preparation of 7-(fluorobenzoyl)-indolin-2- ones used to prepare the compounds of the invention:
The preparation of the compounds of this invention is accomplished by reacting fluorobenzoyl indolin-2-ones with alkalimetal alkylsulphide, followed by acid hydrolysis to obtain the 7 (alkylthiobenzoyl)indolin-2-ones and hydrolyzing with an alkali-metal base to give the alkali-metal salt of the 2-amino-3-(alkylthiobenzoyl)phenylacetic acids. The following reaction sequence illustrates the preparation of the alkali-metal salts of the compounds of Formula I:
To obtain the free acid (R' = H) from the alkali metal salt, acetic acid is carefully added to an aqueous solution of the salt which causes the free acid to precipitate.The free acid is then separated by filtration, washed with water and dried. To obtain the ester (R1 = lower alkyl), the alkali metal salt is treated in a suitable solvent such as dry dimethylformamidewith a lower alkyl iodide. Water is added and the ester extracted from the mixture with a suitable solvent such as diethyl ether, dried over sodium sulphate and the solvent removed by evaporation.
The compounds of Formula I wherein Am is dimethylamino are prepared by reacting a 2aminophenylacetic acid ester of Formula I wherein Am is -NH2 with formaldehyde and sodium cyanoborohydride in a solvent such as acetonitrile under mildly acidic conditions as provided by the use of glacial acetic acid.
The invention may be put into practice in various ways and a number of specific embodiments will be described to illustrate the invention with reference to the accompanying preparations 1 to 10 of starting materials, Examples 1 to 8 of the compound of the invention and Examples 9 to 11 of pharmaceutical compositions in accordance with the invention.
PREPARATION 1 7-(4-Fluorobenzoyl)-3-meth ylthioin do lin -2-one.
A solution of 42.2 g (0.196 mole) of 2-amino-4'-fluorobenzophenone in 2 litres of methylene chloride was cooled to -65 C and 26.5 g (0.198 mole) of ethyl methylthioacetate was added. A solution of 23.0 g (0.21 mole) of 95% tertiary butoxychloride in 50 ml of methylene chloride was added dropwise, keeping the temperature below -65 C. One hour after the addition was complete, 22.2 g (0.22 mol) of triethylamine was added dropwise and the mixture was allowed to warm to room temperature. The solution was concentrated to 700 ml and then washed with water. The organic solution was concentrated and the residue dissolved in 400 ml of methanol containing 30 ml of concentrated hydrochloric acid. The mixture was heated at reflux for one hour followed by cooling.The mixture was allowed to stand overnight, the crystals collected and washed with methanol to yield 31.4 g (53%) as bright yellow solid, m.p. 165-167.5"C.
Analysis:
Calculated for C16H12NO2FS: C, 63.77; H, 4.01; N, 4.65 Found: C, 63.58; H,4.11; N,4.67 PREPARATIONS 2A to 2G Utilizing the procedure of Preparation 1 but substituting for 2-amino-4'-fluorobenzophenone, equal molar amounts of the following: 2-amino-4'-fluoro-4-methylbenzophenone, 2-amino-4'-fluoro-5-methylbenzophenone, 2-amino-4'-fluoro-6-methylbenzophenone, 2-amino-4'-fluoro-4-chlorobenzophenone,
2-amino-4'-fluoro-5-chlorobenzophenone,
2-amino-4'-fluoro-6-chlorobenzophenone,
2-amino-4'-fluoro-5-methoxybenzophenone, there are obtained::
(2A) 7-(4-fluorobenzoyl )-4-methyl-3-methylthioindolin-2-one, (2B) 7-(4-fluorobenzoyl)-5-methyl-3-methylthioindolin-2-one,
(2C) 7-(4-fluorobenzoyl)-6-methyl-3-methylthioindolin-2-one, (2D) 7-(4-fluorobenzoyl )-4-chloro-3-methylthioindolin-2-one, (2E) 7-(4-fluorobenzoyl )-5-chloro-3-methylthioindolin-2-one, (2F) 7-(4-fluorobenzoyl )-6-chloro-3-methylthioindolin-2-one, (2G) 7-(4-fluorobenzoyl )-5-methoxy-3-methylthioindolin-2-one.
PREPARATION 3 7-(2-Fluorohenzo yI)-3-meth ylthioin do /in -2-one.
A solution of 86 g (0.4 mole) of 2-amino-2'-fluorobenzophenone in 3 litres of methylene chloride was cooled to -650C and 54 g (0.4 mole) of ethyl methylthioacetate was added. A solution of 46 g (0.42 mole) of 95% tertiary butyoxychloride in 100 ml of methylene chloride was added dropwise keeping the temperature below -65 C. One hour after the addition was complete, 41 g (0.4 mole) of triethylamine was added dropwise and the mixture allowed to warm up to room temperature. The solution was concentrated to about 1400 ml and then washed with water. The organic solution was concentrated and the residue dissolved in 800 ml methanol containing 60 ml of concentrated hydrochloric acid. The mixture was heated at reflux for one hr followed by cooling. The mixture stood overnight, then the crystals were collected and recrystallized from 20% aqueous ethanol to give 66 g (55%) pale yellow needles, m.p. 147.0-148.5"C.
Analysis:
Calculated for C16H12NO2FS: C, 63.77; H, 4.01; N, 4.65
Found: C, 63.97; H, 4.19; N, 4.66 PREPARATION 4
Utilizing the procedure of Preparation 3 but substituting for 2-amino-2'-fluorobenzophenone, equal molar amounts of
2-amino-3'-fluorobenzophenone, there is obtained: 7-(3-fluorobenzoyl)-3-methylthioindolin-2-one.
PREPARATION 5 7- (4-Huornbenwyl)indolln-2-one.
This is the starting material for Example 1.
A mixture of 40.0 9 (0.133 mole) of 7-(4-fluorobenzoyl)-3-methylthioindolin-2-one and 40.0 g (0.34 mole) of tin powder in one litre of 95% ethanol was heated to reflux and 100 ml of concentrated hydrochloric acid was added. The mixture was heated for 6 hrs, then filtered while hot. The fiitrate was cooled and the precipitate was collected and recrystallized from isopropyl alcohol to yield 24.5 g (72%) as off-white needles, m.p.
185-187.0"C.
Analysis:
Calculated for C15H10NO2F: C, 70.58; H, 3.95; N, 5.49
Found: C, 70.80; H, 4.12; N, 5.51 PREPARATIONS 6Ato 6G
Utilizing the procedure of Preparation 5 but substituting for 7-(4-fluorobenzoyl)-3-methylthioindolin-2-one, equal molar amounts of the following: 7-(4-fluorobenzoyl)-4-methyl-3-methylthioindolin-2-one, 7-(4-fluorobenzoyl )-5-methyl-3-methylth ioindolin-2-one,
7-(4-fluorobenzoyl )-6-methyl-3-methylthioindol in-2-one,
7-(4-fluorobenzoyl)-4-ch loro-3-methylthioindol in-2-one, 7-(4-fluorobenzoyl )-5-ch loro-3-methylthioindolin-2-one, 7-(4-fluorobenzoyl)-6-chloro-3-methylthioindolin-2-one, 7-(4-flu orobenzoyl )-5-methoxy-3-methylthioindol in-2-one, there are obtained::
(6A) 7-(4-fluorobenzoyl)-4-methylindolin-2-one,
(6B) 7-(4-fluorobenzoyl)-5-methylindolin-2-one, (6C) 7-(4-fluorobenzoyl)-6-methylindolin-2-one, (6D) 7-(44luorobenzoyl)-4-chloroindolin-2-one, (6E) 7-(4-fluorobenzoyl)-5-chloroindolin-2-one, (6F) 7-(4-fluorobenzoyl)-6-chloroindolin-2-one,
(6G) 7-(4-fluorobenzoyl)-5-methoxyindolin-2-one.
PREPARATION 7 7- (2-Fluorob enzo yI)-in do lin -2-one.
A mixture of 60 g (0.2 mole) of 7-(2-fluorobenzoyl)-3-methylthioindolin-2-one and 60 g (0.5 mol) of tin powder in one litre of 95% ethanol was heated to reflux and 150 ml of concentrated hydrochloric acid was added. Heating was continued for 18 hrs then the mixture was cooled and the precipitate was collected by decanting the slurry from the remaining tin and filtering the slurry. The filter cake was recrystallized twice from absolute ethanol to give 31 g (60%) white needles, m.p. 209-210"C.
Analysis:
Calculated for C15H10NO2F: C, 70.58; H, 3.95; N, 5.49 Found: C, 70.31; H, 4.08; N, 5.56 PREPARATION 8
Utilizing the procedure of Preparation 7 but substituting for 7-(24luorobenzoyl)-3-methylthioindolin-2-one, equal molar amounts of the following: 7-(3-fluorobenzoyl)-3-methylthioindolin-2-one, there is obtained:
7-(3-fluorobenzoyl)-indolin-2-one.
PREPARATION 9
Utilizing the procedure of Preparation 1 but substituting equal molar amounts of ethyl a-(methylthio) propionate for ethyl methylthioacetate, there is obtained 7-(44luornbenzoyl )-3-methyl-3-methylthioindolin-2-one.
PREPARATION 10
Utilizing the procedure of Preparation 5 but substituting equal molar amount of 7-(4-fluorobenzoyl)-3methyl-3-methylthioindolin-2-one, there is obtained
7-(4-fluorobenzoyl )-3-methylindol in-2-one.
The reaction conditions employed for preparing the novel intermediates and compounds of the invention are more fully illustrated in the examples which follow.
EXAMPLE 1 7- (4-Meth ylthiobenzo yI)in do lin -2-one.
(R2=R=H; lower alkyl =CH3)
A solution of sodium methyl mercaptide, prepared from 400 ml of 3N sodium hydroxide and 24 g (0.5 mole) of methyl sulphide, was mixed with 25.5 g (0.1 mole) of 7-(44luorobenzoyl)indolin-2-one (see
Preparation 5). The mixture was refluxed for 1.5 hr, cooled and acidified with caution since much methyl sulphide evolves rapidly. The resulting precipitate was collected and recrystallized twice from benzene to give 17.8 g (70%) as yellow crystals, m.p. 167.0-169.0"C.
Analysis:
Calculated for C16H13NO2S: C, 67.82; H, 4.63; N, 4.94 Found: C,67.65; H, 4.63; N, 4.91
EXAMPLES 2Ato 21
Utilizing the procedure of Example 1 but substituting for 7-(4-fluorobenzoyl)indolin-2-one, equal molar amounts of the following:: 7-(4-fluorobenzoyl)-4-methylindolin-2-one, (see Preparation 6A) 7-(4-fluorobenzoyl)-5-methylindolin-2-one, (see Preparation 6B) 7-(4-fluorobenzoyi )-6-methyl indol in-2-one, (see Preparation 6C) 7-(4-fluorobenzoyl)-4-chloroindolin-2-one, (see Preparation 6D) 7-(4-fluorobenzoyl)-5-chloroindolin-2-one, (see Preparation 6E) 7-(4-fl uorobenzoyl)-6-ch loroi ndolin-2-one, (see Preparation 6F)
7-(4-fluorobenzoyl)-5-methoxyindolin-2-one, (see Preparation 6G)
7-(2-fluorobenzoyl)-indolin-2-one, (see Preparation 7)
7-(3-fluorobenzoyl)indolin-2-one, (see Preparation 8) there are obtained:: 7-(4-methylthiobenzoyl)-4-methylindolin-2-one, (Example 2A) 7-(4-methylthiobenzoyl)-5-methylindolin-2-one, (Example 2B) 7-(4-methylthiobenzoyl)-6-methylindolin-2-one, (Example 2C) 7-(4-methylthiobenzoyl)-4-ch loroindolin-2-one, (Example 2D) 7-(4-methylthiobenzoyl )-5-chloroindolin-2-one, (Example 2E) 7-(4-methylthiobenzoyl )-6-chloroindolin-2-one, (Example 2F)
7-(4-methylthiobenzoyl)-5-methoxyindolin-2-one, (Example 2G)
7-(2-methylthiobenzoyl)indolin-2-one (Example 2H)
7-(3-methylthiobenzoyl)indolin-2-one (Example 21).
EXAMPLES 3A to 3C
Utilizing the procedure of Example 1 but substituting for sodium methyl mercaptide, equal molar amounts of the following:
sodium ethylmercaptide,
sodium isopropylmercaptide,
sodium-n-butylmercaptide, there are obtained the following:
7-(4-ethylthiobenzoyl)indolin-2-one, (Example 3A) 7-(4-isopropylthiobenzoyl)indolin-2-one, (Example 3B)
7-(4-n-butylthiobenzoyl)indolin-2-one (Example 3C).
EXAMPLE 4
Sodium 2-amino-3-(4-meth ylthiobenzo yI)phenylacetic acid monoh ydrate)
A mixture of 5.2 g (0.018 mole) of 7-(4-methylthiobenzoyl)indolin-2-one (see Example 1) in 75 ml of 3N sodium hydroxide was heated at reflux for 20 hrs. The red solution was cooled and a yellow precipitate formed. The precipitate was collected by filtration and washed with a small amount of cold water and then triturated with tetrahydrofuran. The precipitate was again separated by filtration, dried, and recrystallized from 95% ethanol to give 4.9 g (83%) of bright yellow needles, m.p. 244-247"C.
Analysis:
Calculated for C16H16NO4SNa: C, 56.30; H, 4.72; N, 4.10
Found: C, 56.38; H, 4.62; N, 4.17 EXAMPLES SAto 5L Utilizing the procedure of Example 4 but substituting for 7-(4-methylthiobenzoyl)indolin-2-one, equal molar amounts of the following::
7-(4-methylthiobenzoyl)-4-methylindolin-2-one, (see Example 2A) 7-(4-methylthiobenzoyl)-S-methylindolin-2-one, (see Example 2B) 7-(4-methylthiobenzoyl)-6-methylindolin-2.one, (see Example 2C)
7-(4-methylthiobenzoyl)-4-chloroindolin-2-one, (see Example 2D) 7-(4-methylthiobenzoyl)-S-chloroindolin-2-one, (see Example 2E)
7-(4-methylthiobenzoyl)-6-chloroindolin-2-one, (see Example 2F) 7-(4-methylthiobenzoyl)-5-methoxyindolin-2-one, (see Example 2G)
7-(2-methylthiobenzoyl)indolin-2-one, (see Example 2H)
7-(3-methylthiobenzoyl)indolin-2-one, (see Example 21)
7-(4-ethylthiobenzoyl)indolin-2-one, (see Example 3A)
7-(4-isopropylthiobenzoyl)indolin-2-one, (see Example 3B)
7-(4-n-butylthiobenzoyl)indolin-2-one, (see Example 3C) there are obtained,
Sodium 2-amino-3-(4-methylthiobenzoyl)-6-methylphenylacetic acid, (Example 5A)
Sodium 2-amino-3-(4-methylthiobenzoyl)-5-methylphenylacetic acid, (Example 5B) Sodium 2-amino-3-(4-methylthiobenzoyl)-4-methylphenylacetic acid, (Example 5C) Sodium 2-amino-3-(4-methylthiobenzoyl)-6-chlornphenylacetic acid, (Example 5D) Sodium 2-amino-3-(4-methylthiobenzoyl)-5-chlorophenylacetic acid, (Example 5E) Sodium 2-amino-3-(4-methylthiobenzoyl)-4-chlorophenylacetic acid, (Example 5F) Sodium 2-amino-3-(4-methylthiobenzoyl)-5-methoxyphenylacetic acid (Example 5G) Sodium 2-amino-3-(2-methylthiobenzoyl)-phenylacetic acid, (Example 5H) Sodium 2-amino-3-(3-methylthiobenzoyl)-phenylacetic acid, (Example 51) Sodium 2-amino-3-(4-ethylthiobenzoyl)-phenylacetic acid, (Example 5J) Sodium 2-amino-3-(4-isopropylthiobenzoyl)-phenylacetic acid, (Example 5K)
Sodium 2-amino-3-(4-n-butylthiobenzoyl)-phenylacetic acid, (Example 5L) EXAMPLE 6 7-/4-Meth ylthiobenzo yl/3-meth ylin dolin-i-one.
Utilizing the procedure of Example 1 but substituting 7-(4-fluorobenzoyl)-3-methylindolin-2-one (see
Preparation 10) for 7-(4-fluorobenzoyl)indolin-2-one, the titled compound is obtained.
EXAMPLE 7
Sodium 2-amino-3-(4-methylthiobenzo yi)--meth ylphenylacetic acid.
A suspension of 7-(4-methylthiobenzoyll-3-methylindolin-2-one (see Example 6) in 3N sodium hydroxide is refluxed under nitrogen, stripped of water under vacuum, and the product is isolated by trituration with organic solvent.
EXAMPLE 8 EthyI2-amino-3-(4-meth ylthiob enzo yphen ylaceta te.
Seventeen grams (0.05 mole) of sodium 2-am,ino-3-(4-methylthiobenzoyl)phenylacetic acid monohydrate (see Example 4) are dissolved in approximately 150 ml of dimethylformamide and the solution treated with 33 g ethyl iodide. The solution is stirred at room temperature for 2.5 hrs and added to water and the mixture extracted several times with benzene. The combined benzene extracts are washed with dilute base and water, dried over sodium sulphate and concentrated to obtain the titled compound.
The present invention also contemplates novel compositions containing the compounds of the invention as active ingredients. Effective quantities of any of the foregoing pharmacologically active compounds may be administered to a living animal body in any one of various ways, for example, orally as in capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions. In forming the novel compositions of this invention, the active ingredient is incorporated in a suitable carrier, illustratively, a pharmaceutical carrier. Suitable pharmaceutical carriers which are useful in formulating the compositions of this invention include starch, gelatin, glucose, magnesium carbonate, lactose and malt.Liquid compositions are also within the purview of this invention and suitable liquid pharmaceutical carriers include ethyl alcohol, propylene glycol, glycerine and glucose syrup.
The pharmacologically active compounds may be advantageously employed in a unit dosage of from 0.1 to 150 milligrams. The unit dosage may be administered once daily or in multiple or divided daily doses. The daily dosages may vary from 0.3 to 450 milligrams. Five to 25 milligrams appears optimum per unit dose.
It is only necessary that the active ingredient constitute an effective amount, i.e. such that a suitable effective dosage will be obtained consistent with the dosage form employed. The exact individual dosages as well as daily dosages will, of course, be determined according to standard medical principles under the direction of a physician or veterinarian.
The active agents of the invention may be combined with other pharmacologically active agents, or with buffers, antacids or the like, for administration and the proportion of the active agent in the composition may be varied widely.
The following are examples of pharmaceutical compositions formed in accordance with this invention.
EXAMPLES 9Ato 9D
Capsules
Capsules of 5 mg. (Example 9A), 25 mg. (Example 9B), and 50 mg. (Example 9C) of active ingredient per capsule are prepared. With the higher amounts of active ingredient, adjustment may be made in the amount of lactose.
Typical blend for Per capsule,
encapsulation mg.
Active ingredient 5.0
Lactose 296.7
Starch 129.0
Magnesium stearate 4.3
Total 435.0 mg.
Additional capsule formulations preferably contain a higher dosage of active ingredient and are as follows:
EXAMPLE 9D
Per capsule,
Ingredients mg.
Active ingredient 25.0
Lactose 306.5
Starch 99.2
Magnesium stearate 4.3
Total 435.0 mg.
In Each of Examples 9A to 9D the selected active ingredients are uniformly blended with lactose, starch, and magnesium stearate and the blend is encapsulated.
EXAMPLE 10
Tablets
A typical formulation for a tablet containing 5.0 mg. of active ingredient per tablet follows. The formulation may be used for other strengths of active ingredient by adjustment of weight of dicalcium phosphate.
Per tablet, mg.
(1) Active ingredient 5.0
(2) Corn starch 13.6
(3) Corn starch (paste) 3.4
(4) Lactose 79.2
(5) Dicalcium phosphate 68.0
(6) Calciumstearate 0.9
170.1 mg
The procedure for making the tablets is to uniformly blend ingredients 1, 2,4 and 5. Ingredient 3 is formed into a 10 per cent paste in water. The blend is granulated with the starch paste and the wet mass is passed through an eight mesh screen. The wet granulation is dried and sized through a twelve mesh screen. The dried granules are blended with the calcium stearate and pressed.
EXAMPLE 11
Injectable - 2% sterile solutions
Per cc
Active ingredient . .. 20 mg.
Preservative, e.g., chlorobutanol .. 0.5% ......... . weightlvolume Water for injection q.s.
The procedure is to prepare the solution, clarify it by filtration, and fill it into vials, which are then sealed and autoclaved.
Claims (26)
1. Acompound having the formula:
wherein;
R represents a hydrogen atom or a lower alkyl group,
R' represents a hydrogen atom or a lower alkyl group or a pharmaceuticaliy acceptable metal cation,
R2 represents a hydrogen or halogen atom or a lower alkyl or lower alkoxy group and
Am represents a primary amino (-NH2), methylamino ordimethylamino group.
2. 2-Amino-3-(3-methylthiobenzoyl)-phenylacetic acid and pharmaceutically acceptable esters and salts thereof.
3. Sodium 2-amino-3-(4-methylthiobenzoyl)-phenylacetic acid monohydrate.
4. A compound as claimed in claim 1 and as specifically described with reference to Example 4, 5A to 5L, 7 or8.
5. A compound as claimed in claim 1,2,3 or 4 for use in alleviating inflammation in a living animal body.
6. A compound as claimed in claim 1, 2, 3 or 4 for use in alleviating pain in a living animal body.
7. A compound as claimed in claim 1, 2,3 or 4 for use in platelet aggregation in a warm-blooded animal.
8. Atherapeutic pharmaceutical composition suitable for alleviating inflammation and pain and inhibiting blood platelet aggregation in a living animal body comprising an effective amount of a compound having the formula:
wherein;
R represents a hydrogen atom or a loweralkyl group,
R1 represents a hydrogen atom or a loweralkyl group or a pharmaceutically acceptable metal cation,
R2 represents a hydrogen or a halogen atom or a loweralkyl or lower alkoxy group and
Am represents a primary amino (-NH2), methylamino or dimethylamino group and a pharmaceutically acceptable carrier or diluent.
9. A composition as claimed in claim 8 in which the compound is present in an amount in the range 0.1 to 150 milligrams.
10. A composition as claimed in claim 8 or claim 9 in which compound is 2-amino-3-(4 methylthiobenzoyl)-phenylacetic acid.
11. A composition as claimed in claim 8 or claim 9 in which compound is sodium 2-amino-3-(4 methylthiobenzoyl)-phenyl-acetic acid monohydrate.
12. A pharmaceutical composition as claimed in claim 8 substantially as specifically described herein with reference to Example 9,10 or 11.
13. 7-(S-loweralkylthiobenzoyl) indolin-2-ones having the formula
wherein;
R represents a hydrogen atom or a lower alkyl group,
R1 represents a hydrogen atom or a lower alkyl group or a pharmaceutically acceptable metal cation, and
R2 represents a hydrogen or a halogen atom or a lower alkyl or lower alkoxy group.
14. 7-(4-Methylthiobenzoyl) indolin-2-one.
15. 7-(4-Methylthiobenzoyl)-4-methylindolin-2-one.
16. 7-(4-Methylthiobenzoyl)-5-methylindol in-2-one.
17. 7-(4-Methylthiobenzoyl)-6-methylindolin-2-one.
18. 7-(4-Methylthiobenzoyl)-4-chloroindolin-2-one.
19. 7-(4-Methylthiobenzoyl)-5-chloroindolin-2-one.
20. 7-(4-Methylthiobenzoyl)-6-chloroindolin-2-one.
21. 7-(4-Methylth iobenzoyl )-5-methoxyindol in-2-one.
22. 7-(2-Methylthiobenzoyl) indolin-2-one.
23. 7-(3-Methylthiobenzoyl) indolin-2-one.
24. 7-(4-Ethylthiobenzoyl) indolin-2-one.
25. 7-(4-lsopropylthiobenzoyl)indolin-2-one.
26. 7-(4-n-Butylthiobenzoyl) indolin-2-one.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SG5484A SG5484G (en) | 1979-08-01 | 1984-01-21 | 2-amino-3-(alkylthiobenzoyl)-phenylacetic acids |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US6302979A | 1979-08-01 | 1979-08-01 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2055820A true GB2055820A (en) | 1981-03-11 |
| GB2055820B GB2055820B (en) | 1983-06-02 |
Family
ID=22046443
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8022968A Expired GB2055820B (en) | 1979-08-01 | 1980-07-14 | 2-amino -3- (alkylthiobenzoyl)-phenylacetic acids and esters |
| GB08214848A Expired GB2105708B (en) | 1979-08-01 | 1982-05-21 | 2-amino-3-(alkylthiobenzoyl)-phenylacetic acids |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08214848A Expired GB2105708B (en) | 1979-08-01 | 1982-05-21 | 2-amino-3-(alkylthiobenzoyl)-phenylacetic acids |
Country Status (37)
| Country | Link |
|---|---|
| JP (1) | JPS5629568A (en) |
| KR (1) | KR840000605B1 (en) |
| AR (1) | AR226855A1 (en) |
| AT (1) | AT369648B (en) |
| AU (1) | AU532247B2 (en) |
| BE (1) | BE884556A (en) |
| BR (1) | BR8004546A (en) |
| CA (1) | CA1147746A (en) |
| CH (1) | CH648295A5 (en) |
| CS (1) | CS214716B2 (en) |
| DE (1) | DE3026964A1 (en) |
| DK (1) | DK330380A (en) |
| EG (1) | EG14771A (en) |
| ES (1) | ES8106702A1 (en) |
| FI (1) | FI74457C (en) |
| FR (1) | FR2463124A1 (en) |
| GB (2) | GB2055820B (en) |
| GR (1) | GR69714B (en) |
| HK (2) | HK37584A (en) |
| HU (1) | HU181728B (en) |
| IE (1) | IE50293B1 (en) |
| IL (1) | IL60444A (en) |
| IN (1) | IN151542B (en) |
| IT (1) | IT1132273B (en) |
| KE (2) | KE3368A (en) |
| LU (1) | LU82672A1 (en) |
| MX (1) | MX6175E (en) |
| NL (1) | NL8004397A (en) |
| NO (1) | NO150080C (en) |
| NZ (1) | NZ194515A (en) |
| PH (1) | PH18030A (en) |
| PL (1) | PL127122B1 (en) |
| PT (1) | PT71632B (en) |
| SE (1) | SE447247B (en) |
| SG (1) | SG19884G (en) |
| YU (1) | YU41725B (en) |
| ZA (1) | ZA804703B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7186745B2 (en) | 2001-03-06 | 2007-03-06 | Astrazeneca Ab | Indolone derivatives having vascular damaging activity |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0723478U (en) * | 1993-10-08 | 1995-05-02 | 有限会社伊藤商店 | Collar cover |
| FR2711076B1 (en) * | 1993-10-13 | 1995-12-08 | Robatel Slpi | Waterproof and elastically deformable device for the deburring of the residual layer. |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE400966B (en) * | 1975-08-13 | 1978-04-17 | Robins Co Inc A H | PROCEDURE FOR PREPARING 2-AMINO-3- (OR 5-) BENZOYL-PHENYLETIC ACIDS |
-
1980
- 1980-06-30 IL IL60444A patent/IL60444A/en unknown
- 1980-07-02 IN IN761/CAL/80A patent/IN151542B/en unknown
- 1980-07-11 AR AR281743A patent/AR226855A1/en active
- 1980-07-14 EG EG420/80A patent/EG14771A/en active
- 1980-07-14 GB GB8022968A patent/GB2055820B/en not_active Expired
- 1980-07-16 DE DE19803026964 patent/DE3026964A1/en active Granted
- 1980-07-18 FI FI802282A patent/FI74457C/en not_active IP Right Cessation
- 1980-07-19 GR GR62503A patent/GR69714B/el unknown
- 1980-07-22 BR BR8004546A patent/BR8004546A/en unknown
- 1980-07-23 PH PH24330A patent/PH18030A/en unknown
- 1980-07-23 YU YU1870/80A patent/YU41725B/en unknown
- 1980-07-24 IE IE1537/80A patent/IE50293B1/en unknown
- 1980-07-24 CA CA000356926A patent/CA1147746A/en not_active Expired
- 1980-07-28 SE SE8005425A patent/SE447247B/en not_active IP Right Cessation
- 1980-07-28 AU AU60840/80A patent/AU532247B2/en not_active Ceased
- 1980-07-29 JP JP10423980A patent/JPS5629568A/en active Granted
- 1980-07-30 CS CS805349A patent/CS214716B2/en unknown
- 1980-07-30 BE BE0/201593A patent/BE884556A/en not_active IP Right Cessation
- 1980-07-30 LU LU82672A patent/LU82672A1/en unknown
- 1980-07-30 KR KR1019800003043A patent/KR840000605B1/en active
- 1980-07-31 DK DK330380A patent/DK330380A/en unknown
- 1980-07-31 PT PT71632A patent/PT71632B/en unknown
- 1980-07-31 NZ NZ194515A patent/NZ194515A/en unknown
- 1980-07-31 CH CH5844/80A patent/CH648295A5/en not_active IP Right Cessation
- 1980-07-31 IT IT23840/80A patent/IT1132273B/en active
- 1980-07-31 HU HU801919A patent/HU181728B/en not_active IP Right Cessation
- 1980-07-31 PL PL1980225990A patent/PL127122B1/en unknown
- 1980-07-31 MX MX808949U patent/MX6175E/en unknown
- 1980-07-31 NO NO802306A patent/NO150080C/en unknown
- 1980-07-31 ES ES493880A patent/ES8106702A1/en not_active Expired
- 1980-07-31 FR FR8016939A patent/FR2463124A1/en active Granted
- 1980-07-31 NL NL8004397A patent/NL8004397A/en not_active Application Discontinuation
- 1980-08-01 ZA ZA00804703A patent/ZA804703B/en unknown
- 1980-08-04 AT AT0403580A patent/AT369648B/en not_active IP Right Cessation
-
1982
- 1982-05-21 GB GB08214848A patent/GB2105708B/en not_active Expired
-
1984
- 1984-01-18 KE KE3368A patent/KE3368A/en unknown
- 1984-03-03 SG SG198/84A patent/SG19884G/en unknown
- 1984-03-30 KE KE3390A patent/KE3390A/en unknown
- 1984-05-03 HK HK375/84A patent/HK37584A/en unknown
- 1984-06-14 HK HK490/84A patent/HK49084A/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7186745B2 (en) | 2001-03-06 | 2007-03-06 | Astrazeneca Ab | Indolone derivatives having vascular damaging activity |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19920714 |