IE50293B1 - 2-amino-3-(alkylthiobenzoyl)phenylacetic acids - Google Patents
2-amino-3-(alkylthiobenzoyl)phenylacetic acidsInfo
- Publication number
- IE50293B1 IE50293B1 IE1537/80A IE153780A IE50293B1 IE 50293 B1 IE50293 B1 IE 50293B1 IE 1537/80 A IE1537/80 A IE 1537/80A IE 153780 A IE153780 A IE 153780A IE 50293 B1 IE50293 B1 IE 50293B1
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- IE
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- Prior art keywords
- amino
- compound
- hydrogen
- loweralkyl
- methylthiobenzoyl
- Prior art date
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Classifications
-
- 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
-
- 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
-
- 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
-
- 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]
-
- 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
-
- 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 (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:
Description
2-AMINO-3-(ALKYLTHIOBENZOYL)-PHENYLACETIC ACIDS
BACKGROUND OF THE INVENTION
1. FIELD OF INVENTION
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 and uses thereof and certain intermediates for the preparation thereof.
2. DESCRIPTION OF THE PRIOR ART
Certain 2-amino-3-(5 and 6) benzoylphenylacetic acids having the benzoyl moiety substituted by lower alkyl, halogen, nitro and trifluoromethyl and methods of preparing and using the same are disclosed in U. S. Patent 4,0^5,576· The compounds of the present invention cannot be prepared by the procedures disclosed therein.
SUMMARY OF THE INVENTION
The invention is more specifically concerned with
2-amino-3-(alkylthiobenzoyl)phenylacetic acids, alkylesters and metal salts having the formula:
wherein;
R is hydrogen or lower alkyl,
R1 is hydrogen, lower alkyl or pharmaceutically acceptable metal cation,
Re is hydrogen, halogen, lower alkyl or lower alkoxy,
Am is primary amino(-NHa), methylamino or dimethylamino .
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-loweralkylthiobenzoyl)indolin-2-ones are represented by Formula II:
Formula II wherein R, R1 and R2 are as hereinabove defined.
The anti-inflammatory activity was demonstrated in laboratory animals using a modification of the Evans Blue Carrageenan Pleural Effusion Assay of Sancilio, L. F.,
J. Pharmacol. Exp. Ther. 168, 199-204 (1969)·
The compounds of Formula I as inhibitors of blood platelet aggregation illustrate this property by the 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
5Θ293 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, 77^ (1976).
It is therefore 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 non-human animal body and especially non-human manmalian bodies for purposes of alleviating inflammation and pain and inhibiting blood platelet aggregation with a minimun of undesirable side effects.
Additional objects will be apparent to one skilled in the art and still other objects will become apparent hereinafter.
DETAILED DESCRIPTION OF THE INVENTION
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 hereinabove and below.
In the definition of symbols in the formulas hereof and where they appear elsewhere throughout this spscification, the terms have the following significance.
The term lower alkyl as used herein includes straight and branched chain radicals of up to six carbons inclusive, preferably no more than four carbon atoms, and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, butyl,
JO sec. butyl, tertiary butyl, amyl, isoamyl and hexyl. The term lower alkoxy has the formula -O-lower alkyl.
The term halogen when referred to herein is Cl, Fl,
Br and I.
Illustrative of pharmaceutically acceptable salts are sodium, potassium, calcium, magnesium, zinc, copper and the hydrates thereof.
Methods of Preparation
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-BuOCl and Et3N to give 7-(halobenzoyl)-3methylthioindolin-2-ones which are then reduced with Raney nickel to produce the 7-(halobenzoyl)-j5-indolin-2-one. A modification of this procedure was used wherein 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:
293
The preparation of the compounds of this invention is accomplished by reacting fluorobenzoyl indolin-2-ones with alkalimetal alkylsulfide, followed by acid hydrolysis to obtain the 7-(alkylthiobenzoyl)indolin-2-ones and hydrolyzing with alkali-metal base to give the alkalimetal 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:
C=O Formula la
To obtain the free acid (r1 = 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 = loweralkyl), the alkali metal salt is treated in a suitable solvent such as dry dimethylformamide with lower alkyl iodide. Water is added and the ester extracted from the mixture with a suitable solvent such as diethyl ether, dried over sodium sulfate and solvent removed by evaporation.
The compounds of Formula X wherein Am is dimethylamino are prepared by reacting a 2-aminophenylacetic acid ester of Formula I wherein Am is -NHa 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 reaction conditions employed for the preparation of the fluorobenzoylindolin-2-one starting materials is more specifically illustrated in the preparations which follow.
S0293
Preparation 1
7-(4-Fluorobenzoyl)-3-roethylthioindolin-2-one.
A solution of 42.2 g (0.196 mole) of 2-amino-4’-fluorobenzophenone in 2 liters 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 triethylemine 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 3θ 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. l65-l67.5°C·
Analysis: Calculated for CieHi2N0aFS: C,63*77? H,4.01; 11,4.65
Found : ΰ,63·5θ? H,4.11; N,4.67
Preparation 2
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 1-fluoro-4-chlorobenzophenone,
2-amino-4'-fluoro-5-chlorobenzophenone,
2-amino-4'-fluoro-6-chlorobenzophenone,
2-amino-4'-fluoro-5-methoxybenzophenone, there are obtained:
7-(4-fluorobenzoyl)-4-methyl-3-methylthioindolin-2-one,
7-(4-fluorobenzoyl)-5-methyl-3-methylthioindolin-2-one,
7-(4-fluorobenzoyl)-6-methyl-3-methylthioindolin-2-one,
7-(4-fluorobenzoyl)-4-chloro-3-methylthioindolin-2-one,
7-(4-chlorobenzoyl)~5-chloro-3-methylthioindolin-2-one,
7-(4-fluorobenzoyl)-6-chloro-3-methylthioindolin-2-one,
7-(4-fluorobenzoyl)-5-methoxy-3-methylthioindolin-2-one. Preparation 3
7-(2-Fluorobenzoyl)-3-methylthioindolin-2-one.
A solution of 86 g (0.4 mole) of 2-amino-2'-fluorobenzophenone in 3 liters of methylene chloride was cooled to -65°C. and 54 g (0.4 mole) of ethyl methylthioacetate was added. A solution of 46 g (0.42 mole) of 955^ tertiary butoxychloride in 100 ml of methylene chloride was added dropwise keeping the temperature below -65°C. One hour after addition was complete, 41 g (0.4 mole) of triethylamine was added dropwise and the mixture allowed to warm 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 6θ 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 200 aqueous ethanol to give 66 g (550) pal® yellow needles, m.p. 147.0-148.5°c.
Analysis: Calculated for CieHi2N0gFS: 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 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-Fluorobenzoyl)indolin-2-one,
A mixture of 40.0 g (0.133 mole) of 7-(4-fluorobenzoyl)3-methylthioindolin-2-one and 40.0 g (0.34 mole) of tin powder in one liter of 950 ethanol was heated to reflux and
S0293
100 ml of concentrated hydrochloric acid was added. The mixture was heated for 6 hrs, then filtered while hot.
The filtrate was cooled and the precipitate was collected and recrystallized from isopropyl alcohol to yield 24.5 9 (72^) as off-white needles, m.p. l85-l87-0°C.
Analysis: Calculated for C15Hi0N02F: Ο,70.5θ>· Η,3·95? Ν,5·49
Found : C,70.80; H,4.12; N,5-51
Preparation 6
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-methylthioindolin-2-one, 7-(4-fluorobenzoyl)-6-methyl-3-methylthioindolin-2-one,
7-(4-fluorobenzoyl)-4-chloro-5-methylthioindolin-2-one,
7-(4-fluorobenzoyl)-5~chloro-3-methylthioindolin-2-one, 7-(4-fluorobenzoyl)-6-chloro-3-methylthioindolin-2-one, 7-( 4-fluorobenzoyl)-5-methoxy-3-methylthioindolin-2-one, there are obtained:
7-(4-fluorobenzoyl)-4-methylindolin-2-one,
7-(4-fluorobenzoyl)-5-methylindo1in-2-one,
7-(4-fluo robenzoy1)-6-methy1indolin-2-one,
7-(4-fluorobenzoyl)-4-chioro indolin-2-one,
7-(4-fluorobenzoyl)-5-chloroindolin-2-one,
7-(4-fluorobenzoyl)-6-chloro indolin-2-one,
7-( 4-fluorobenzoyl)-5-methoxyindolin-2-one.
Preparation 7
7-(2-Fluorobenzoyl)-indolin-2-one.
A mixture of 60 g (0.2 mole) of 7-(2-fluorobenzoy1)-330 methylthioindolin-2-one and 60 g (0.5 mol) of tin powder in one liter 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
50283 was recrystallized twice from absolute ethanol to give 31 g (60^) white needles, m.p. 209-210°C.
Analysis: Calculated for Ci5HioN0gF: ¢,70.58: Η,3·95: Ν,5·49 Found : c,70-31: Η,4.θ8; Ν,5·5ό
Preparation 8
Utilizing the procedure of Preparation 7 but substituting for 7-(2-fluorobenzoyl)-3-methylthioindolin2-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 ¢-(methylthio) propionate for ethyl methylthioacetate, there is obtained
7-(4-fluorobenzoyl)-3-methyl-3-methylthioindolin2-one.
Preparation 10
Utilizing the procedure of Preparation 5 hut substituting equal molar amount of 7-( 4-fluorobenzoyl)-3me thyl-3-methylthio indo1in-2-one, there is obtained
7-(4-fluorobenzoyl)-3-methylindolin-2-one.
The reaction conditions employed for preparing novel intermediates and compounds of the invention are more fully illustrated in the examples which follow.
Example 1
7-(4-Methylthiobenzoyl)indolin-2-one
A solution of sodium methyl mercaptide, prepared from 400 ml of 3N sodium hydroxide and 24 g (0-5 mole) of methyl sulfide, was mixed with 25.5 9 (0.1 mole) of
7-(4-fluorobenzoyl)indolin-2-one. The mixture was refluxed for 1.5 hr, cooled and acidified (caution: much methyl sulfide 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 CieHj.3H02S: C,67-82; H,4.63? N,4.94 Found : C,67-65? H,4.63? N,4.91
Example 2
Utilizing the procedure of Example 1 but substituting for 7-(4-fluorobenzoyl)indolin-2-one, equal molar amounts lc, of the following:
7-(4-fluorobenzoyl)-4-methylindolin-2-one,
7-(4-fluorobenzoyl)-5-methylindolin-2-one,
7-(4-fluorobenzoyl)-6-methylindolin-2-one,
7-(4-fluorobenzoyl)-4-chloroindolin-2-one,
7-(4-fluorobenzoyl)-5~chloroindolin-2-one,
7-(4-fluorobenzoyl)-6-chloroindolin-2-one,
7-( 4-fluorobenzoyl)-5-methoxyindolin-2-one,
7-(2-fluorobenzoyl)-indolin-2-one,
7-(3-fluorobenzoyl)indolin-2-one, there are obtained:
7-(4-methylthiobenzoyl)-4-methylindolin-2-one,
7-(4-methylthiobenzoyl)-5~methylindolin-2-one, 7-(4-methylthiobenzoyl)-6-methylindolin-2-one,
7-(4-methylthiobenzoyl)-4-chloroindolin-2-one,
7-(4-methylthiobenzoyl)-5~chloroindolin-2-one,
7-(4-methylthiobenzoyl)-6-chloroindolin-2-one,
7-(4-methylthiobenzoyl)-5-methoxyindolin-2-one, 7-(2-methylthiobenzoyl)indolin-2-one.
7-( 3-»ethylthiobenzoyl)indolin-2-one.
Example 3
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,
7-(4-isopropylthiobenzoyl)indolin-2-one,
7-(4-n-butylthiobenzoyl)indolin-2-one.
Example 4
Sodium 2-amino-3-(4-methylthiobenzoyl)phenylacetic
Acid Monohydrate.
A mixture of 5.2 g (0.018 mole) of 7-(4-methylthiobenzoyl)indolin-2-one in 75 ml of 3N sodium hydroxide was heated at reflux for 20 hr. 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#) bright yellow needles, m.p. 244-247°C.
Analysis: Calculated for CxeHieN04SNa: C,56.30; H,4.72;
N,4.10
Found : Ο,56·3θ, H, 4.62;
N,4.17
Example 5
Utilizing the procedure of Example 4 but substituting for 7-(4-methylthiobenzoyl)indolin-2-one, equal molar amounts of the following:
7-(4-methylth iobenzoyl)-4-methylindo1in-2-one,
7-(4-methylth iobenzoyl)-5-methylindolin-2-one,
7-(4-methylthiobenzoyl)-6-methylindolin-2-one,
7-(4-methylthiobenzoyl)-4-chloroindolin-2-one,
S0293
7-(4-methy1th iobenzoyl)-5-chloroindo1in-2-one,
7-(4-methylthiobenzoyl)-6-chloroindolin-2-one,
7-(4-methylthiobenzoyl)-5-methoxyindolin-2-one,
7-(2-methylthiobenzoyl)indolin-2-one,
7-(3-methylthiobenzoyl)indolin-2-one,
7-(4-ethylthiobenzoyl)indolin-2-one,
7-(4-isopropylthiobenzoyl)indolin-2-one,
7-(4-n-butylthiobenzoyl)indolin-2-one, there are obtained,
Sodium 2-amino-3-(4-methylthiobenzoyl)-6-methylphenylacetic acid,
Sodium 2-amino-3-(4-methylthiobenzoyl)-5-methylphenylacetic acid,
Sodium 2-amino-j5-(4-methylthiobenzoyl)-4-methylphenylacetic acid,
Sodium 2-amino-3-(4-methylthiobenzoyl)-6-chlorophenylacetic acid,
Sodium 2-amino-3-(4-methylthiobenzoyl)-5-chlorophenylacetic acid,
Sodium 2-amino-3-(4-methylthiobenzoyl)-4-chlorophenylacetic acid,
Sodium 2-amino-J-(4-methylthiobenzoyl)-5-methoxyphenyl acetic acid,
Sodium 2-amino-3-(2-methylthiobenzoyl)-phenylacetic acid,
Sodium 2-amino-3-(3-methylthiobenzoyl)-phenylacetic acid,
Sodium 2-amino-3-(4-ethylthiobenzoyl)-phenylacetic acid.
Sodium 2-amino-3-(4-isopropy1th iobenzoyl)-phenylacetic acid,
Sodium 2-amino-3-(4-n-butylthiobenzoyl)-phenylacetic acid.
Example 6
7-(4-Methylthiobenzoyl)-3-methylindolin-2-one.
Utilizing the procedure of Example 1 but substituting
7-(4-fluorobenzoyl-3-methyl)indolin-2-one for 7-(4-fluorobenzoyl) indolin-2-one, the titled compound is obtained.
Example 7
Sodium 2-amino-3-(4-methylthiobenzoyl)-methylphenylacetic acid.
A suspension of 7-(4-methylthiobenzoyl)-3-methylindolin-2-one 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
Ethyl 2-amino-3-(4-methylthiobenzoyl)phenylacetate.
Seventeen grams (0.05 mole) of sodium 2-amino~3-(415 methylthiobenzoyl)phenylacetic acid monohydrate 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 lo benzene extracts are washed with dilute base and water, dried over sodium sulfate and concentrated to obtain the titled compound.
Formulation and Administration
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 adminis5 tered 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, malt and the like. Liquid compositions are also within the purview of this invention and suitable liquid pharmaceutical carriers include ethyl alcohol, propylene glycol, glycerine, glucose syrup and the like.
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 dosage 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 compositions formed in accordance with this invention.
1. Capsules
Capsules of 5 mg., 25 mg., and 5θ mg. °f active ingredient per capsule are prepared. With the higher amounts of active ingredient, adjustment may be made in the amount of lactose.
Per capsule,
Typical blend for encapsulat ion
Active ingredient
Lactose
Starch
Magnesium stearate mg.
Total
-0
296-7
129.0
4-3
435-0 mg.
Additional capsule formulations preferably contain a higher dosage of active ingredient and are as follows:
Per capsule,
Ingredients mg._
Active ingredient 25-0
Lactose 306.5
Starch 99-2
Magnesium stearate 4-3
Total
435-0 mg.
In each case, uniformly blend the selected active ingredient with lactose, starch, and magnesium stearate and encapsulate the blend.
2. 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 phoshpate.
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) Calcium stearate 0.9
170.1 mg
Uniformly blend 1, 2, 4 and 5· Prepare 5 as a 10 per cent paste in water. Granulate the blend with starch paste and pass the wet mass 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.
3· Injectable -2% sterile solutions
Per cc
Active ingredient............ 20 mg.
Preservative, e.g., cholorobutanol............ 0-5% weight/volume
Water for injection .........q.s.
Prepare solution, clarify by filtration, fill into vials, seal and autoclave.
various modifications and equivalents will be apparent to one skilled in the art and may be made in the compounds, compositions, and methods of the present invention without departing from the spirit or scope thereof and it is therefore to be understood that the invention is to be limited only by the scope of the appended claims.
50283
- 18 The term “animal” as used in the appended Claims excludes man.
Claims (6)
1. Α compound selected from the group having the formula» wherein; R is hydrogen or lower alkyl, r 1 is hydrogen, loweralkyl, or pharmaceutically acceptable metal cation, R 8 is hydrogen, halogen, loweralkyl or lower alkoxy, Am is primary amino (~NHs), methylamino or dimethylamino . - 2 The compound of claim 1 which is 2-amino-3-(4-methylthiobenzoyl)-phenylacetic acid. - 3 The compound of claim 1 which is sodium 2-amino-3(4-methylthiobenzoyl)-phenylacetic acid monohydrate. - 4 A method of alleviating inflammation in a living animal body comprising internally administering to said living animal body an effective amount of a compound selected from the group having the formula: wherein; 10 R is selected from hydrogen or lower alkyl, R 1 is selected from hydrogen, loweralkyl or pharmaceutically acceptable metal cation, R e is hydrogen, halogen, loweralkyl or lower alkoxy, Am is primary amino (-NH2), methylamino or dimethylamino. 15 -5The method of claim 4 wherein the compound is 2-amino-3-(4-methylthiobenzoyl)-phenylacetic acid. - 6 The method of claim 4 wherein the compound is sodium 20 2-amino-3-(4-methylthiobenzoyl)-phenylacetic acid monohydrate. - 7 A method of alleviating pain in a living animal body comprising internally administering to said living animal body an effective amount of a compound selected from the 25 group having the formula: .CHRCOOR 1 •Am R s C=O S-loweralkyl wherein; R is selected from hydrogen or loweralkyl, R 1 is selected from hydrogen, loweralkyl or pharmaceutically acceptable metal cation, R® is hydrogen, halogen, loweralkyl or lower alkoxy, Am is primary amino (-1}¾), methylamino or dimethylamino . - 8 A method of claim 7 wherein the compound is 2-amino-3-(4-methylthiobenzoyl)-phenylacetic acid. - 9 _ A method of claim 7 wherein the compound is sodium 2-amino-3-(4-methylthiobenzoyl)-phenylacetic acid monohydrate. - 10 A method of producing an inhibitory effect on blood platelet aggregation which comprises administering to a warm-blooded animal a blood platelet inhibitory effective amount of a compound having the formula; wherein; R is selected from hydrogen or loweralkyl, R 1 is selected from hydrogen loweralkyl or pharmaceutically acceptable metal cation, R 2 is hydrogen, halogen, loweralkyl or lower alkoxy, Am is primary amino (-11¾), methylamino or dimethylamino . Ζ -lift method of claim 10 wherein the compound is
2. -amino-
3. -(
4. -me thylth iobenzoyl)-phenylacet ic acid. - 12 5 A method of claim 10 wherein the compound is sodium 2-amino-3-(4-methylthiobenzoyl)-phenylacetic acid monohydrate. - 13 A therapeutic composition suitable for alleviating inflammation, pain and inhibiting blood platelet aggregation 10 in a living animal or human body comprising an effective amount of a compound selected from the group having the formula: wherein; R is selected from hydrogen or loweralkyl, 15 R 1 is selected from hydrogen, loweralkyl or pharmaceutically acceptable metal cation, R 2 is hydrogen, halogen, loweralkyl or lower alkoxy, Am is primary amino (-NHs), methylamino or dimethylamino . 20 - 14 The composition as defined in claim 13 wherein the compound is present in an amount of between about 0.1 and 150 milligrams. - 15 25 The composition as defined in claim 14 wherein the compound is 2-amino-3-(4-methylthiobenzoyl)phenylacetic acid. - 16 The composition as defined in claim 14 wherein the compound is sodium 2-amino-3-( 1 )-methylthiobenzoyl)-phenylacetic acid monohydrate.
5. - 17 A therapeutic composition according to claim 13, substantially as herein described. - 18 A method of treatment according to any of claims 4 to 12,
6. 10 substantially as herein described. - 19 A process for the preparation of a compound according to claim 1, substantially as herein described.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US6302979A | 1979-08-01 | 1979-08-01 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE801537L IE801537L (en) | 1981-02-01 |
| IE50293B1 true IE50293B1 (en) | 1986-03-19 |
Family
ID=22046443
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE1537/80A IE50293B1 (en) | 1979-08-01 | 1980-07-24 | 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) | ES493880A0 (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) |
Families Citing this family (3)
| 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. |
| US7186745B2 (en) | 2001-03-06 | 2007-03-06 | Astrazeneca Ab | Indolone derivatives having vascular damaging activity |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH577461A5 (en) * | 1975-08-13 | 1976-07-15 | Robins Co Inc A H |
-
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 YU YU1870/80A patent/YU41725B/en unknown
- 1980-07-23 PH PH24330A patent/PH18030A/en unknown
- 1980-07-24 CA CA000356926A patent/CA1147746A/en not_active Expired
- 1980-07-24 IE IE1537/80A patent/IE50293B1/en unknown
- 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 BE BE0/201593A patent/BE884556A/en not_active IP Right Cessation
- 1980-07-30 LU LU82672A patent/LU82672A1/en unknown
- 1980-07-30 CS CS805349A patent/CS214716B2/en unknown
- 1980-07-30 KR KR1019800003043A patent/KR840000605B1/en active
- 1980-07-31 MX MX808949U patent/MX6175E/en unknown
- 1980-07-31 NO NO802306A patent/NO150080C/en unknown
- 1980-07-31 DK DK330380A patent/DK330380A/en unknown
- 1980-07-31 PL PL1980225990A patent/PL127122B1/en unknown
- 1980-07-31 FR FR8016939A patent/FR2463124A1/en active Granted
- 1980-07-31 ES ES493880A patent/ES493880A0/en active Granted
- 1980-07-31 NL NL8004397A patent/NL8004397A/en not_active Application Discontinuation
- 1980-07-31 NZ NZ194515A patent/NZ194515A/en unknown
- 1980-07-31 HU HU801919A patent/HU181728B/en not_active IP Right Cessation
- 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 PT PT71632A patent/PT71632B/en unknown
- 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
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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
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