NZ194515A - 2-amino-3-(alkylthiobenzoyl)-phenylacetic acid, esters and salts; therapeutic compositions - Google Patents
2-amino-3-(alkylthiobenzoyl)-phenylacetic acid, esters and salts; therapeutic compositionsInfo
- Publication number
- NZ194515A NZ194515A NZ194515A NZ19451580A NZ194515A NZ 194515 A NZ194515 A NZ 194515A NZ 194515 A NZ194515 A NZ 194515A NZ 19451580 A NZ19451580 A NZ 19451580A NZ 194515 A NZ194515 A NZ 194515A
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- amino
- compound
- loweralkyl
- hydrogen
- 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
-
- 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
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- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
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- General Chemical & Material Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Animal Behavior & Ethology (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
New Zealand Paient Spedficaiion for Paient Number 1 94515
1945 1 5
Pri criiy
, Cosv>p!at9 Sp£oi^c2tion Fsiad. ...•■■• i C1MS■
U~ ,:OT. rta .....»?«
Patents Form No. 5
NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION 2-AMINO-3-(ALKYLTHIOBENZOYL)-PHENYLACETIC ACIDS
i
*/we a.h. robins company, inc.
a corporation organized under the laws of the State of Virginia, of 1407 Cummings Drive, Richmond,
Virginia 23220, United States of America,
hereby declare the invention, for which #/we pray that a patent may be granted to at/us, and the method by which it is to be performed, to be particularly described in and by the following statement
(Followed by page lA.)
194515
if*
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 5 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 10 and using the same are disclosed in Not Zealand Patent Specification No. 178622. 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;
Formula I
C=0
S-loweraIky1
PuiPATgr>n"(FF'''
1:^ 6DEC 1982
1 -V*:
RECf*
1945*1:
2
wherein;
R is hydrogen or lower alkyl,
R1 is hydrogen, lower alkyl or pharmaceutical^ acceptable metal cation,
R2 is hydrogen, halogen, lower alkyl or lower alkoxy,
Am is primary amino(-NH2), methylamino or dimethyl-am ino.
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-loweralkylthio-benzoyl)indolin-2-ones are represented by Formula II:
Formula II
loweralkyl
wherein R, R1 and R2 are as hereinabove defined.
The anti^inflamitiatory 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). 30 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, 877-89^ (1968). Rats were orally administered test drugs and after 35 2 hrs. the rats were bled and platelet rich plasma obtained. Collagen was added to the platelet rich plasma to induce
1945 1 5
•283-
3
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 5 Dickerson et al, Life Sci. 4_, 206j>-2069 (1965) as modified by Sancilio and Cheung, Fed. Proc. 35, 774 (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 10 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 minimun of undesirable side effects. 15 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 1 set forth above with accompanying definitions 20 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 specification, 25 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, 30 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 35 sodium, potassium, calcium, magnesium, zinc, copper and the hydrates thereof.
194515
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 New Zealand patent Specification No. 178622. One method disclosed therein begins by reacting 5 2-amino-4'-halobenzoylbenzophenone with ethy] methylthio-acetate, t-BuOCl and Et3N to give J-(halobenzoyl)-J-methylthioindolin-2-ones which are then reduced with Raney nickel to produce the 7~(halobenzoyl)-3-indolin-2-one. A modification of this procedure was used wherein Raney nickel 10 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:
c=o
(1) t-BuOCl
C=0 H
F
C=0 H
6 DEC5982
rsEcer/^
^945Jk5
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 J-(alkylthiobenzoyl)indolin-2-ones and hydrolyzing with 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:
H
**40
-R
1) Na alkylsulfide
I ^ ~
H
2) H
^^-1— S-lower alkyl
Formula II
NaOH
CHRCOONa
•Am
Formula la
S-loweralkyl
To obtain the free acid (R1 = h) from the alkali metal salt, acetic acid is carefully added to an aqueous solution of the 35 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
1945 iy5
6
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 5 sulfate and solvent removed by evaporation.
The compounds of Formula I wherein Am is dimethylamino are prepared by reacting a 2-aminophenylacetic acid ester of Formula I wherein Am is -NH2 with formaldehyde and sodium cyanoborohydride in a solvent such as acetonitrile 10 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
^ r- f0ll0W.
J 945 I 5
-5S3-
7
Preparation 1
7-(4-Fluorobenzoyl)-3-methylthioindolin-2-one■
A solution of 42.2 g (0.196 mole) of 2-amino-4'-fluoro-benzophenone in 2 liters of methylene chloride was cooled to -65°C. and 26.5 <3 (O.I98 mole) of ethyl methylthioacetate 5 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 10 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 15 cooling. The mixture was allowed to stand overnight, the crystals collected and washed with methanol to yield 31-4 g (53$) as bright yellow solid, m.p. 165-167-5°C-Analysis: Calculated for Ci6Hi2N02FS: C,63-77; H,4.01; N,4.65 Found : c,63-58; h,4.11? n,4.67
Preparation 2
Utilizing the procedure of Preparation 1 but substituting for 2-amino-4'-fluorobenzophenone, equal molar amounts of the following:
2-amino-4'-fluoro-4-methylbenzophenone, 25 2-amino-4'-fluoro-5-methylbenzophenone,
2-amino-41-fluoro-6-methylbenzophenone, 2-amino-4'-fluoro-4-chlorobenzophenone, 2-amino-4'-fluoro-5-chlorobenzophenone, 2-amino-4'-fluoro-6-chlorobenzophenone, 30 2-amino-4'-fluoro-5-methoxybenzophenone,
there are obtained:
7-(4-fluorobenzoyl)-4-methyl-3-methylthioindolin-2-one, 7-(4-fluorobenzoyl)-5-methyl-3-methylthioindolin-2-one, 7-(4-fluorobenzoyl)-6-methyl-3-methylthioindolin-2-one,
1.945-1 5
8
7-(4-fluorobenzoyl)-4-chloro-3-methylthioindolin-2-one, 7-(4-chlorobenzoyl)-5-chloro-3-methylthioindolin-2-one, 7-( 4-fluorobenzoyl)-6-chloro-3-methy1thioindolin-2-one, 7-( 4-fluorobenzoyl)-5-methoxy-J-methylthioindolin-2-one.
Preparation 3
7-(2-Fluorobenzoyl)-3-methylthioindolin-2-one.
A solution of 86 g (0.4 mole) of 2-amino-2'-fluoro-benzophenone in 3 liters of methylene chloride was cooled to -65°c. and 54 g (0.4 mole) of ethyl methylthioacetate was 10 added. A solution of 46 g (0.42 mole) of 95$ tertiary butoxy-chloride in 100 ml of methylene chloride was added drop-wise keeping the temperature below -65°C. One hour after addition was complete, 4l g (0.4 mole) of triethylamine was added dropwise and the mixture allowed to warm to room 15 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. 20 The mixture stood overnight, then the crystals were collected and recrystallized from 20$ aqueous ethanol to give 66 g (55$) pale yellow needles, m.p. 147.0-148.5°C.
Analysis: Calculated for Ci6Hi2n02FS: C,63-77; h,4.01; n,4.65 Found : c,63-97; h,4.19; n,4.66
Preparation 4
Utilizing the procedure of Preparation 3 but substituting for 2-amino-2'-fluorobenzophenone, equal molar amounts of
2-amino-3'-fluorobenzophenone,
there is obtained: 30 7~(3-fluorobenzoyl)-3~methylthioindolin-2-one.
Preparation 5 7-(4-Fluorobenzoyl)indolin-2-one.
A mixture of 40.0 g (0.133 mole) of 7-(4-fluorobenzoyl)-3-methylthioindolin-2-one and 40.0 g (0-34 mole) of tin 35 powder in one liter of 95$ ethanol was heated to reflux and
194 5
9
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 5 (72$) as off-white needles, m.p. l85-l87-0°C.
Analysis: Calculated for C15H10NO2F: C,70.58; H,3-95? N,5.49 Found : C, 70.80; H,4.12; N,5-51
preparation 6
Utilizing the procedure of Preparation 5 but substituting 10 for 7-( 4-fluorobenzoyl)-3-methylthioindolin-2-one, equal molar amounts of the following:
7-( 4-fluorobenzoyl)-4-methyl-3-methylthioindolin-2-one, 7-(4-fluorobenzoyl)-5-methyl-3-methylthioindolin-2-one, 7-(4-fluorobenzoyl)-6-methyl-3-methylthioindolin-2-one, 15 7-(4-fluorobenzoyl)-4-chloro-3-methylthioindolin-2-one,
7-(4-fluorobenzoyl)-5-chloro-3-methylthioindolin-2-one, 7-(4-fluorobenzoyl)-6-chloro-3-methy1thioindolin-2-one, 7-( 4-fluorobenzoyl)-5-methoxy-3-methylthio indolin-2-one, there are obtained: 20 7-(4-fluorobenzoyl)-4-methylindolin-2-one,
7-(4-fluorobenzoyl)-5-methylindolin-2-one, 7-(4-fluorobenzoyl)-6-methylindolin-2-one, 7-(4-fluorobenzoyl)-4-chloroindolin-2-one, 7-(4-fluorobenzoyl)-5-chloro indo1in-2-one, 25 7-(4-fluorobenzoyl)-6-chloro indolin-2-one,
7-(4-fluorobenzoyl)-5-methoxyindolin-2-one.
Preparation 7 7-(2-Fluorobenzoyl)-indolin-2-one.
A mixture of 60 g (0.2 mole) of 7-(2-fluorobenzoyl)-3-30 methylthioindolin-2-one and 60 g (0.5 mol) of tin powder in one liter of 95$ 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 35 precipitate was collected by decanting the slurry from the remaining tin and filtering the slurry. The filter cake
194S-1
was recrystallized twice from absolute ethanol to give 31 g (60$) white needles, m.p. 209-210°c.
Analysis: Calculated for c15h10no2F: c,70.58; h,3-95; n,5.49 Found : C,70-31; H,4.08; N,5-56
Preparation 8
Utilizing the procedure of Preparation 7 but substituting for 7-(2-fluorobenzoyl)-3-methylthioindolin-2-one, equal molar amounts of the following:
7-( 3-fluorobenzoyl)-3-methylthioindolin-2-one,
there is obtained:
7-( 3-fluorobenzoyl)indolin-2-one.
Preparation 9 Utilizing the procedure of preparation 1 but substituting equal molar amounts of ethyl ^-(methylthio) propionate for ethyl methylthioacetate,
there is obtained
7-(4-fluorobenzoyl)-3-methyl-3-methylthioindolin-2-one.
Preparation 10
Utilizing the procedure of Preparation 5 but substituting equal molar amount of 7~(4-fluorobenzoyl)-J-methy1-3-methylthioindolin-2-one,
there is obtained
7-( 4-fluorobenzoyl)-3-methylindolin-2-one.
The reaction conditions employed for preparing novel intermediates and compounds of the invention are more fully illustrated in the examples which follow.
19 4^ 1 5
11
Example 1
7-(4-Methylthiobenzoyl)indolin-2-one.
A solution of sodium methyl mercaptide, prepared from 400 ml of JN sodium hydroxide and 24 g (0.5 mole) of methyl sulfide, was mixed with 25-5 9 (0.1 mole) of 5 7~(4-fluorobenzoyl)indolin-2-one. The mixture was refluxed for 1.5 hr, cooled and acidified (caution: much methyl sulfide evolves rapidly). The resulting precipitate was collected and recrystallized twice from benzene to give 17.8 g (70$) as yellow crystals, m.p. 167.0-169.0°c. 10 Analysis: Calculated for CisHi3N02S: C,67-82; h,4.6j; N,4.94 Found : c,67-65; h,4.63; N,4.9l
Example 2
Utilizing the procedure of Example 1 but substituting for 7-(4-fluorobenzoyl)indolin-2-one, equal molar amounts 1c, 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, 20 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 7-(4-methylthiobenzoyl 7-(4-methylthiobenzoyl 7-(4-methylthiobenzoyl 30 7-(4-methylthiobenzoyl
7-(4-methylthiobenzoyl 7-(4-methylthiobenzoyl 7-(2-methylthiobenzoyl
-4-methylindo1in-2-one, -5-methylindolin-2-one, -6-methylindolin-2-one, -4-chloro indo1in-2-one, -5-chloroindolin-2-one, -6-chloroindolin-2-one, -5-methoxy indolin-2-one, indo1in-2-one.
7-( 3-n>ethylthiobenzoyl)indol in-2-one.
194S 1 5
12
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, 10 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-methylthio-15 benzoyl)indolin-2-one in 75 ml °f 5N 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 20 precipitate was again separated by filtration, dried, and recrystallized from 95$ ethanol to give 4-9 9 (83$) bright yellow needles, m.p. 244-247°C.
Analysis: Calculated for Ci6Hi6N04SNa: C,56-30; H,4.72;
N,4.10
Found : C,56-38; 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 iobenzoy1)-4-methylindo1in-2-one,
7-(4-methylthiobenzoyl)-5-methylindolin-2-one, 7-(4-methy1th iobenzoyl)-6-methylindolin-2-one, 7-(4-methylthiobenzoyl)-4-chloroindolin-2-one,
19 AS 1 5
13
7-( 4-methylthiobenzoyl)-5-chloroindolin-2-one, 7-(4-methylthiobenzoyl)-6-chloroindolin-2-one, 7-(4-methylthiobenzoyl)-5~methoxyindolin-2-one, 7-(2-methy1th iobenzoyl)indo1in-2-one, 7-( 3-niethylthiobenzoyl) indol in-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~
acetic acid,
Sodium 2-amino-3-
acetic acid,
Sodium 2-amino-3-15 acetic acid,
Sodium 2-amino-3~ acetic acid,
Sodium 2-amino-3-acetic acid, 20 Sodium 2-amino-3-
acetic acid,
Sodium 2-amino-3-acetic acid.
Sodium 2-amino-3~
acid,
Sodium 2-amino-3~
acid,
Sodium 2-amino-3~
acid,
Sodium 2-amino-3-
acid,
Sodium 2-amino-3~
acid.
4-methylth iobenzoy1 4-methylthiobenzoyl 4-methylthiobenzoyl 4-methylthiobenzoy1 4-methy1th iobenz oy1 4-methylthiobenzoyl 4-methy1th iobenzoy1 2-methylthiobenzoyl
-6-methylphenyl--5-methylphenyl--4-methylphenyl--6-chlorophenyl--5-chlorophenyl--4-chlorophenyl--5-me thoxypheny1 --phenylacet ic -phenylacet ic
3-methylthiobenzoyl
4-ethylthiobenzoy1)-phenylacetic 4-isopropylthiobenzoyl)-phenylacetic 4-n-butylthiobenzoyl)-phenylacetic
19 4*5-1 5
14
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-(^-fluoro-benzoyl)indolin-2-one, the titled compound is obtained.
Example 7
Sodium 2-amino-3-f4-methylthiobenzoyl) -ry-methylphenyl-acetic acid.
A suspension of J-(4-methylthiobenzoyl)-3-methyl-indolin-2-one in 3N sodium hydroxide is refluxed under 10 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-(4-methylthiobenzoyl)phenylacetic acid monohydrate are dissolved in approximately I50 ml of dimethylformamide and the solution treated with 33 9 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 sulfate and concentrated to obtain the titled compound.
1945S5
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 adminis-^ 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 10 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 15 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. 20 The unit dosage may be administered once daily or in multiple or divided daily doses. The daily dosage may vary from O.J to 450 milligrams. Five to 25 milligrams appears optimum per unit dose.
It is only necessary that the active ingredient 25 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 30 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.
1
16
The following are examples of compositions formed in accordance with this invention.
1. capsules
Capsules of 5 m<3 • * 25 mg., and 50 m9- 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 29§-7
Starch 129-0
Magnesium stearate 4.3
Total 435.0 mg.
Additional capsule formulations preferably contain a 15 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.
l) 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
Claims (3)
1945A-5 17
Uniformly blend 1, 2, 4 and 5. Prepare 3 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 5 screen. The dried granules are blended with the calcium stearate and pressed.
3. Injectable -2% sterile solutions Per cc Active ingredient 20 mg . 10 Preservative, e.g., cholorobutanol 0.5$ weight/volume Water for injection q.s. Prepare solution, clarify by filtration, fill into vials, seal and autoclave. 15 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 20 limited only by the scope of the appended claims. 194515 .> 18 WHAT WE CLAM IS." - 1 - A compound selected from the group having the formula: wherein; R is selected from hydrogen and lower alkyl, R1 is selected from hydrogen, loweralkyl, and a pharmaceutically acceptable metal cation, R2 is hydrogen, halogen, loweralkyl or lower alkoxy, Am is primary amino (-NHe), methylamino or dimethylamino . - 2 - The compound of claim 1 which is 2-amino-3-(4-methyl-thiobenzoyl)-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 non-human animal body comprising internally administering to said living non-human animal body an effective amount of a compound selected from the group having the formula: 194515 19 C=0 —S-loweralkyl CHRCOOR1 5 wherein; 10 R is selected from hydrogen and lower alkyl, R1 is selected from hydrogen, loweralkyl and a pharmaceutically acceptable metal cation, R2 is hydrogen, halogen, loweralkyl or lower alkoxy, Am is primary amino (-NHs), methylamino or dimethylamino. _ 5 _ The method of claim 4 wherein the compound is 2-amino-3-(4-methylthiobenzoyl)-phenylacetic acid. 20 2-amino-3-(4-methylthiobenzoyl)-phenylacetic acid monohydrate. - 7 - A method of alleviating pain in a living non-human animal body comprising internally administering to said living non-human animal body an effective amount of a compound selected from the 2^ group having the formula: - 6 - The method of claim 4 wherein the compound is sodium C=0 30 S-loweralkyl 194515 20 10 15 wherein; R is selected from hydrogen and loweralkyl, R1 is selected from hydrogen, loweralkyl and a pharmaceutically acceptable metal cation, Rs is hydrogen, halogen, loweralkyl or lower alkoxy, Am is primary amino (-NHs), methylamino or dimethylamino . - 8 - A method of claim J wherein the compound is 2-amino~3-(4-methylthiobenzoyl)-phenylacetic acid. - 9 - A method of claim 7 wherein the compound is sodium 2-amino-J-(4-methylthiobenzoyl)-phenylacetic acid monohydrate. - 10 - A method of producing an inhibitory effect on blood platelet aggregation which comprises administering to a warmblooded non-human animal a blood platelet inhibitory effective amount of a compound having the formula: 20 R2 25 30 wherein; R is selected from hydrogen and loweralkyl, R1 is selected from hydrogen,loweralkyl and a pharmaceutically acceptable metal cation, R2 is hydrogen, halogen, loweralkyl or lower alkoxy, 35 Am is primary amino (-NH2), methylamino or dimethyl amino . 194515 21 -lift method of claim 10 wherein the compound is 2-amino-3-(4-methylthiobenzoyl)-phenylacetic acid. - 12 - 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 and' pain and inhibiting blood platelet aggregation in a living animal body comprising an effective amount of a compound selected from the group having the formula: wherein; R is selected from hydrogen and loweralkyl, R1 is selected from hydrogen, loweralkyl and a pharmaceutically acceptable metal cation, R2 is hydrogen, halogen, loweralkyl or lower alkoxy, Am is primary amino (-NHg), methylamino or dimethylamino . - 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 - The composition as defined in claim 14 wherein the compound is 2-amino-3-(4-methylthiobenzoyl)phenylacetic acid. 6 DEC 1982 1945 1 5 22 - 16 - The composition as defined in claim 14 wherein the compound is sodium 2-amino-3-(4-methylthiobenzoyl)-phenyl-acetic acid monohydrate. ,, - 17 - A compound as claimed in claim 1 as particularly described herein. - 18 - A composition as claimed in claim 13 substantially as herein described with reference to the formulation examples. - 19 - A method as claimed in any one of claims 4, 7 and 10 substantially as herein described. - 20 - A process for preparing compounds as claimed in claim 1 substantially as herein described. BALDWIN, SON & CAREY Attorneys for the applicants
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US6302979A | 1979-08-01 | 1979-08-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ194515A true NZ194515A (en) | 1984-05-31 |
Family
ID=22046443
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ194515A NZ194515A (en) | 1979-08-01 | 1980-07-31 | 2-amino-3-(alkylthiobenzoyl)-phenylacetic acid, esters and salts; therapeutic compositions |
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. |
| JP2004529110A (en) | 2001-03-06 | 2004-09-24 | アストラゼネカ アクチボラグ | Indole derivatives with vascular damage activity |
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 GB GB8022968A patent/GB2055820B/en not_active Expired
- 1980-07-14 EG EG420/80A patent/EG14771A/en active
- 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 PT PT71632A patent/PT71632B/en unknown
- 1980-07-31 ES ES493880A patent/ES493880A0/en active Granted
- 1980-07-31 DK DK330380A patent/DK330380A/en unknown
- 1980-07-31 MX MX808949U patent/MX6175E/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 FR FR8016939A patent/FR2463124A1/en active Granted
- 1980-07-31 NO NO802306A patent/NO150080C/en unknown
- 1980-07-31 NL NL8004397A patent/NL8004397A/en not_active Application Discontinuation
- 1980-07-31 NZ NZ194515A patent/NZ194515A/en unknown
- 1980-07-31 PL PL1980225990A patent/PL127122B1/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
-
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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