US2390555A - Antispasmodic agents - Google Patents
Antispasmodic agents Download PDFInfo
- Publication number
- US2390555A US2390555A US497263A US49726343A US2390555A US 2390555 A US2390555 A US 2390555A US 497263 A US497263 A US 497263A US 49726343 A US49726343 A US 49726343A US 2390555 A US2390555 A US 2390555A
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- Prior art keywords
- compound
- diphenylthioacetate
- thio
- compounds
- ether
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Definitions
- This invention relates to new compounds having useful antispasmodic properties.
- the invention embraces di-N-substituted aminoethyl esters of diphenylthioacetic acid of the formula in which It represents a disubstituted amino radi;
- the creation of spasmolytic or antispasmodic drugs by organic synthesis has been the subject of much research in the past 'decade.
- the purpose of a spasmolytic drug is to relieve spasms of smooth muscles. Smooth muscles line most of the visceral organs. The peristalsis and muscular activity of the stomach, intestines, gall bladder, urinary bladder, the uterus, and to a degree the heart are all largely controlled b'y.smooth muscles. Smooth muscles are innervated by the autonomic nervous system.- The autonomic nervous system consists of two antagonistic branches-the sympathetic branch, and the 40 parasympathetic branch.
- a musculotropic efiect is acknowledged to be superior to a neurotropic effect.
- a neurotropic effect cannot relieve spasms intrinsic in the smooth muscle itself, while a musculotropic effect, by relaxing and decreasing the irritability and responsiveness of smooth muscle to stimulation from the autonomic nervous system, can help to relieve a smooth muscle spasm even when it is dueto exaggerated impulses from tne autonomic nervous system.
- a clinical difliculty with atropine is that of undesirable side-reactions.
- Atropine when given in effective doses, serves to break or partly break all the parasympathetic nerve-smooth muscle connections all over the body.
- atropine when given in suflicient dosage to relieve a spasm in a specific visceral organ, such as a gastric or intestinal spasm- (the spasm caused by exaggerated nerve impulses from the parasympathetic nervous system) undesirable sideactions due to the breaking of the parasympathetic nerve-muscle connections elsewhere in the body may occur.
- the most easily recognized of these undesirable side reactions are dilation of the pupil and dryness of the mouth; caused by the breaking of the parasympathetic connections to the oculomotor muscles and the saliva producing mechanism respectively.
- My invention is based upon my discovery that the thio analogs of certain disubstituted acetic acid esters of amino alcohols have desirable antispasmodic properties.- I have prepared the following closely related specific compounds'of this group andhave found each of them to be useful as antispasmodics and superior to the corresponding compounds in which the acid group of the diphenyl acetic acid is a simple carboxyl group instead of the thio carboxylic acid group.
- the hydrochloride is preferred for use as a drug because of its greater water solubility than the basic ester.
- Example 2 A mixture of 0.1 mole of B-chloroethyl diphenylthioacetate prepared as described in Example 1, and 0.3 mole of morpholine were heated in a sealed bottle for three days at 40 C. in a constant temperature oven. After cooling the reaction mixture was suspended in water and'extracted with ether. The ether extract was then evaporated and the residue purified by recrystallization from ethanol. The basic ester, B-morpholinoethyl diphenylthioacetate, thus obtained was dried, dissolved in anhydrous ether and treated with dry hydrogen chloride whereupon the ester hydrochloride precipitated. This was collected and recrystallized from a mixture of ethanol and ether. Melting point of the hydrochloride: 194-196 C.
- Example 3.-B-piperidinoethyl diphenylthioacetate hydrochloride was prepared in exactly the same Way as the morpholino derivative from 0.1 mole of B-chloroethyl diphenylthioacetate and 0.3 mole of piperidine. Melting point of the hydrochloride: 210-212 C.
- the thioacetate compound presumably has some neurotropic action but it is so weak or small as to be of little or no consequence in the use of the drug and has not been accurately measured.
- thio and non-thio compounds are approximately the same.
- the minimum lethal dose was found to vary considerably with the age of the rats, being 1.5 grams per kilogram of body weight for rats 4 months old and only about 0.5 gram per kilogram body weight for rats 45 days old. This low toxicity of the thio compound was contrary to logical expectation.
- the antispasmodic action of the morpholino and piperidino thioacetate compounds .of Examples 2 and 3 was found to be approximately equal to that of the B-diethylaminoethyl diphenylthioacetate compound of Example 1 and their neurotropic action and toxicity well within the permissible range of-tolerance for the use of the compounds as antispasmodic drugs.
- the thio compounds have been found to have a distinct advantage over the non-thio compounds with respect to stability. This result, like the discovery of the low toxicity of the thio compounds, was contrary to logical expectation.
- thio compound was found to be stable in aqueous solution for a period of at least two weeks.
- a compound of the formula on-cos-omcm-rr 3.
Description
Patented Dec. 11, 1945 PATENT orirlcs ANTISPASMODIO AGENTS Andrew G. Richardson, Richmond, Va., assignor to William P. Poythross & Company, Inc., Richmond, Va... a corporation of Virginia No Drawing. Application August 3, 1943, Serial No. 497,263
4 Claims. (Cl. zoo-239) This invention relates to new compounds having useful antispasmodic properties. The invention embraces di-N-substituted aminoethyl esters of diphenylthioacetic acid of the formula in which It represents a disubstituted amino radi;
cal of the group consisting of the diethylamino group CHz CHI The creation of spasmolytic or antispasmodic drugs by organic synthesis has been the subject of much research in the past 'decade. The purpose of a spasmolytic drug is to relieve spasms of smooth muscles. Smooth muscles line most of the visceral organs. The peristalsis and muscular activity of the stomach, intestines, gall bladder, urinary bladder, the uterus, and to a degree the heart are all largely controlled b'y.smooth muscles. Smooth muscles are innervated by the autonomic nervous system.- The autonomic nervous system consists of two antagonistic branches-the sympathetic branch, and the 40 parasympathetic branch. ,On all visceral organs except the heart'the parasympathetic nerve impulses increase the irritability and tension of the smooth muscles; contrariwise, the sympathetic nerve impulses increase the tension and irritability of the muscles of the heart muscle and relax the parasympathetic branch of the autonomic nervous system may often be corrected by administering atropine (an active-alkaloid of belladonna) which serves to break a connection between the parasympathetic nerve and the smooth muscle. This ability and effect of atropine is called a neurotropic efiect. A spasm intrinsic in the smooth muscle itself may often be corrected by papaverine (a derivative of opium which is classed as a narcotic). Papaverine has an ability to decrease intrinsically the contractility of smooth muscle; it has the ability to relax smooth muscles directly. This ability and effect of papaverine is called a ,mu'sculotropic effect.
In relieving spasms of smooth muscles generally, a musculotropic efiect is acknowledged to be superior to a neurotropic effect. A neurotropic effect cannot relieve spasms intrinsic in the smooth muscle itself, while a musculotropic effect, by relaxing and decreasing the irritability and responsiveness of smooth muscle to stimulation from the autonomic nervous system, can help to relieve a smooth muscle spasm even when it is dueto exaggerated impulses from tne autonomic nervous system.
A clinical difliculty with atropine is that of undesirable side-reactions. Atropine, when given in effective doses, serves to break or partly break all the parasympathetic nerve-smooth muscle connections all over the body. Thus when atropine is given in suflicient dosage to relieve a spasm in a specific visceral organ, such as a gastric or intestinal spasm- (the spasm caused by exaggerated nerve impulses from the parasympathetic nervous system) undesirable sideactions due to the breaking of the parasympathetic nerve-muscle connections elsewhere in the body may occur. The most easily recognized of these undesirable side reactions are dilation of the pupil and dryness of the mouth; caused by the breaking of the parasympathetic connections to the oculomotor muscles and the saliva producing mechanism respectively.
Atropine'is acknowledged to have also a musculotropic effect, but its neurotropic efiect is so saturated with hydrogen sulfide.
tropic effect. If successful, such substitution would permit the giving of the synthesized compound in much greater dosage before encountering the undesirable side reactions due to excessive neurotropic effect. The greater dosage would, of course, multiply the musculotropic effect preserved from the atropine molecule until it reached an intensity sufficient for therapeutic usefulness.
My invention is based upon my discovery that the thio analogs of certain disubstituted acetic acid esters of amino alcohols have desirable antispasmodic properties.- I have prepared the following closely related specific compounds'of this group andhave found each of them to be useful as antispasmodics and superior to the corresponding compounds in which the acid group of the diphenyl acetic acid is a simple carboxyl group instead of the thio carboxylic acid group.
B-diethylaminoethyl diphenylthioacetate CH-COS-CHrCHrv CHz-CH:
B-piperidinoethyl diphenylthioacetate CHrCHz B-morpholinoethyl diphenylthioacetate The procedure followed to carry out the above reactions is as follows:
22.4 gm. of potassium hydroxide were dissolved in 400 cc. of ethanol contained in a 1-liter flask equipped with a mechanical stirrer. The flask was immersed in an ice-salt bath and the solution 46.1 gm. of diphenylacetyl chloride previously dissolved in benzene was then added slowly to the potassium hydrosulfide solution while stirring. Stirring was continued for thirty minutes. was filtered with suction and the filtrate evaporated slowly under reduced pressure. The residue was then dissolved in distilled water and dilute hydrochloric acid added slowly until precipitation was complete. precipitate was collected on a filter, dissolved in dilute alkali and reprecipitatedwith dilute hydrochloric acid: The purified solid was filtered with suction, washed thoroughly with distilled water and dried by means of a vacuum pump and then by letting it stand in a desiccator over sodium Then the mixture The yellowish-white ture on a water bath, not over 40 C. The mixture was then filtered and the filtrate evaporated under reduced pressure. The residue, B-chloroethyl diphenylthioacetate, was recrystallized from a mixture of diethyl ether and petroleum ether. Melting point: 4547 C.
A mixture of 20 gm. of B-chloroethyl diphenylthioacetate and 20 gm. (excess) of diethylamine were heated in a sealed bottle for three days at 40 C. in a constant temperature oven. After cooling the reaction mixture was suspended in water and extracted by shaking with diethyl ether. The ether extract was dried over calcium chloride and the solvent evaporated. The B- diethylaminoethyl diphenylthioacetate thus obtained was dissolved in anhydrous ether and hydrogen chloride passed into the solution. Whereupon the ester hydrochloride precipitated. This was collected by filtration, and recrystallized from a mixture of alcohol and ether. Melting point: 82-85 C.
The hydrochloride is preferred for use as a drug because of its greater water solubility than the basic ester.
Example 2.A mixture of 0.1 mole of B-chloroethyl diphenylthioacetate prepared as described in Example 1, and 0.3 mole of morpholine were heated in a sealed bottle for three days at 40 C. in a constant temperature oven. After cooling the reaction mixture was suspended in water and'extracted with ether. The ether extract was then evaporated and the residue purified by recrystallization from ethanol. The basic ester, B-morpholinoethyl diphenylthioacetate, thus obtained was dried, dissolved in anhydrous ether and treated with dry hydrogen chloride whereupon the ester hydrochloride precipitated. This was collected and recrystallized from a mixture of ethanol and ether. Melting point of the hydrochloride: 194-196 C.
Example 3.-B-piperidinoethyl diphenylthioacetate hydrochloride was prepared in exactly the same Way as the morpholino derivative from 0.1 mole of B-chloroethyl diphenylthioacetate and 0.3 mole of piperidine. Melting point of the hydrochloride: 210-212 C.
It will be noted that the procedure described "above in Examples 2 and 3 for the preparation of the morpholino and the piperidino-compounds difiers from the method for the preparation of the diethylamino compound described in Example 1 with respect to therecovery of the compounds from the reaction mixtures in which the B-chloroethyl diphenylthioacetate is combined with the morpholine, piperidine and diethylamine. This difference in the procedures is due to the fact that the morpholino and piperidino basic esters are crystalline solids whereas the diethylamino basic ester is a liquid andrequires a different treatment for its recovery and purification.
Comparativepharmacological tests on the excised rat uterus, the excised rabbit intestine, and the excised human uterus have demonstrated that the B-diethylaminoethyl diphenylthioacetate administered as the hydrochloride has a musculotropic action about twice that of the corresponding non-thio or simple acetate compound, that is, the same antispasmodic effect is obtained by the use of a, concentration of the thioacetate compound equal to half of the concentration of the simple acetate compound required to give the specified antispasmodic eiiect.
The thioacetate compound presumably has some neurotropic action but it is so weak or small as to be of little or no consequence in the use of the drug and has not been accurately measured.
Tests made to determine the toxicity of the thioacetate compound indicate that its toxicity is very low and practically negligible. In tests made on white rats both young and mature, the
'minimum lethal doses of the thio and non-thio compounds are approximately the same. The minimum lethal dose was found to vary considerably with the age of the rats, being 1.5 grams per kilogram of body weight for rats 4 months old and only about 0.5 gram per kilogram body weight for rats 45 days old. This low toxicity of the thio compound was contrary to logical expectation.
The antispasmodic action of the morpholino and piperidino thioacetate compounds .of Examples 2 and 3 was found to be approximately equal to that of the B-diethylaminoethyl diphenylthioacetate compound of Example 1 and their neurotropic action and toxicity well within the permissible range of-tolerance for the use of the compounds as antispasmodic drugs.
The thio compounds have been found to have a distinct advantage over the non-thio compounds with respect to stability. This result, like the discovery of the low toxicity of the thio compounds, was contrary to logical expectation.
This greater stability of the thio compounds appears as a factor in their preparation and use. For instance, in the preparation of B-diethylaminoethyl diphenylacetate it was found thatthe hydrochloride salt could not be mad in the usual way by dissolving the basic ester in ether and passing hydrogen chloride into the solution because hydrolysis of the ester occurs under these conditions. This customary procedure may, ,however, be applied for the production of the corresponding thio compound without hydrolysis. Moreover, when it was attempted to purify the non-thio compound by recrystallization from alcohol hydrolysis occurred whereas th thio compound was stable under these conditions. The
thio compound was found to be stable in aqueous solution for a period of at least two weeks. i
So far as I am aware, the thre compounds described in Examples 1, 2 and 3 are new and no one heretofore has suggested their use a drugs.
I claim:
1. A di-N-substituted aminoethyl ester of diphenylthioacetic acid of the formula CH-COS-CHr-CHzR in which R represents a disubstituted amino radical of the group consisting of the diethylamino group, the morpholino group and the piperidino group.
2. A compound of the formula on-cos-omcm-rr 3. A compound of the formula CH-00S-CH:CH|N\ on, O CHr-Ca 4. A compound of the formula ore-cos-cr-ncrn-- o O CHr-Ca ANDREW c. RICHARDSON.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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US497263A US2390555A (en) | 1943-08-03 | 1943-08-03 | Antispasmodic agents |
Applications Claiming Priority (1)
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US497263A US2390555A (en) | 1943-08-03 | 1943-08-03 | Antispasmodic agents |
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US2390555A true US2390555A (en) | 1945-12-11 |
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US497263A Expired - Lifetime US2390555A (en) | 1943-08-03 | 1943-08-03 | Antispasmodic agents |
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Cited By (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2474651A (en) * | 1944-02-26 | 1949-06-28 | Univ Michigan | Basic-alkyl esters and their salts |
US2483671A (en) * | 1947-06-02 | 1949-10-04 | Parke Davis & Co | Aminoalkyl benzhydryl thioethers and their preparation |
US2488253A (en) * | 1946-05-20 | 1949-11-15 | Upjohn Co | Basic thio esters |
US2510773A (en) * | 1946-05-18 | 1950-06-06 | Sterling Drug Inc | Process for preparing a tertiary amino-alkyl thiol-ester hydrochloride |
US2589937A (en) * | 1947-05-23 | 1952-03-18 | Geigy Ag J R | Manufacture of new basic esters of 1-aryl-cyclopentane-1-monothiocarboxylic acids |
US2642428A (en) * | 1950-02-08 | 1953-06-16 | Merck & Co Inc | Quaternary ammonium ethyl thiocarbamates |
US2684370A (en) * | 1951-07-21 | 1954-07-20 | Warner Hudnut Inc | Certain aminoalkyl-2-thienyl-cycloalkenyl thiolacetates |
US4390542A (en) * | 1980-12-02 | 1983-06-28 | Schachar Ronald A | Method for inhibiting contraction of opthalmic wounds or incisions |
EP0102554A1 (en) * | 1982-08-27 | 1984-03-14 | United Pharmaceuticals, Inc. | Compounds for dilating the smooth muscles of the upper urinary tract |
EP0125508A1 (en) * | 1983-04-14 | 1984-11-21 | United Pharmaceuticals, Inc. | Method for stabilizing a detrusor muscle while increasing detrusor muscle strength |
US4510145A (en) * | 1980-12-02 | 1985-04-09 | Schachar Ronald A | Method for inhibiting contraction of ophthalmic wounds or incisions |
US4647562A (en) * | 1985-02-20 | 1987-03-03 | United Pharmaceuticals, Inc. | Anti-spasmodic agents having three branch chains |
US4707480A (en) * | 1983-04-14 | 1987-11-17 | United Pharmaceuticals, Inc. | Method for stabilizing a detrusor muscle while increasing detrusor muscle strength |
US4721783A (en) * | 1986-01-09 | 1988-01-26 | United Pharmaceuticals, Inc. | Anti-spasmodic agents having a heterocyclic ring |
US4721722A (en) * | 1985-07-12 | 1988-01-26 | United Pharmaceuticals, Inc. | Anti-spasmodic agents containing quaternary nitrogen |
US4725593A (en) * | 1985-02-20 | 1988-02-16 | United Pharmaceuticals, Inc. | Method of treating smooth muscle spasm |
EP0267319A1 (en) * | 1986-11-14 | 1988-05-18 | United Pharmaceuticals, Inc. | Anti-spasmodic agents having a ring in the main chain |
US4766119A (en) * | 1985-02-20 | 1988-08-23 | United Pharmaceuticals, Inc. | Antispasmodic alkylated aminothioester derivatives |
EP0289262A2 (en) * | 1987-04-27 | 1988-11-02 | Syntex Pharmaceuticals International Limited | Omega-quaternary ammonium alkyl esters and thioesters of acidic nonsteroidal antiinflammatory drugs |
US4857535A (en) * | 1986-01-09 | 1989-08-15 | United Pharmaceuticals | Anti-spasmodic agents having a heterocyclic ring |
US4918082A (en) * | 1985-07-12 | 1990-04-17 | United Pharmaceuticals, Inc. | Anti-spasmodic agents containing quaternary nitrogen |
USRE33907E (en) * | 1986-01-09 | 1992-04-28 | United Pharmaceuticals, Inc. | Anti-spasmodic agents having a heterocyclic ring |
-
1943
- 1943-08-03 US US497263A patent/US2390555A/en not_active Expired - Lifetime
Cited By (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2474651A (en) * | 1944-02-26 | 1949-06-28 | Univ Michigan | Basic-alkyl esters and their salts |
US2510773A (en) * | 1946-05-18 | 1950-06-06 | Sterling Drug Inc | Process for preparing a tertiary amino-alkyl thiol-ester hydrochloride |
US2488253A (en) * | 1946-05-20 | 1949-11-15 | Upjohn Co | Basic thio esters |
US2589937A (en) * | 1947-05-23 | 1952-03-18 | Geigy Ag J R | Manufacture of new basic esters of 1-aryl-cyclopentane-1-monothiocarboxylic acids |
US2483671A (en) * | 1947-06-02 | 1949-10-04 | Parke Davis & Co | Aminoalkyl benzhydryl thioethers and their preparation |
US2642428A (en) * | 1950-02-08 | 1953-06-16 | Merck & Co Inc | Quaternary ammonium ethyl thiocarbamates |
US2684370A (en) * | 1951-07-21 | 1954-07-20 | Warner Hudnut Inc | Certain aminoalkyl-2-thienyl-cycloalkenyl thiolacetates |
US4510145A (en) * | 1980-12-02 | 1985-04-09 | Schachar Ronald A | Method for inhibiting contraction of ophthalmic wounds or incisions |
US4390542A (en) * | 1980-12-02 | 1983-06-28 | Schachar Ronald A | Method for inhibiting contraction of opthalmic wounds or incisions |
EP0102554A1 (en) * | 1982-08-27 | 1984-03-14 | United Pharmaceuticals, Inc. | Compounds for dilating the smooth muscles of the upper urinary tract |
US4707480A (en) * | 1983-04-14 | 1987-11-17 | United Pharmaceuticals, Inc. | Method for stabilizing a detrusor muscle while increasing detrusor muscle strength |
EP0125508A1 (en) * | 1983-04-14 | 1984-11-21 | United Pharmaceuticals, Inc. | Method for stabilizing a detrusor muscle while increasing detrusor muscle strength |
US4766119A (en) * | 1985-02-20 | 1988-08-23 | United Pharmaceuticals, Inc. | Antispasmodic alkylated aminothioester derivatives |
US4725593A (en) * | 1985-02-20 | 1988-02-16 | United Pharmaceuticals, Inc. | Method of treating smooth muscle spasm |
US4647562A (en) * | 1985-02-20 | 1987-03-03 | United Pharmaceuticals, Inc. | Anti-spasmodic agents having three branch chains |
US4721722A (en) * | 1985-07-12 | 1988-01-26 | United Pharmaceuticals, Inc. | Anti-spasmodic agents containing quaternary nitrogen |
US4918082A (en) * | 1985-07-12 | 1990-04-17 | United Pharmaceuticals, Inc. | Anti-spasmodic agents containing quaternary nitrogen |
US4721783A (en) * | 1986-01-09 | 1988-01-26 | United Pharmaceuticals, Inc. | Anti-spasmodic agents having a heterocyclic ring |
US4857535A (en) * | 1986-01-09 | 1989-08-15 | United Pharmaceuticals | Anti-spasmodic agents having a heterocyclic ring |
USRE33907E (en) * | 1986-01-09 | 1992-04-28 | United Pharmaceuticals, Inc. | Anti-spasmodic agents having a heterocyclic ring |
EP0267319A1 (en) * | 1986-11-14 | 1988-05-18 | United Pharmaceuticals, Inc. | Anti-spasmodic agents having a ring in the main chain |
EP0289262A2 (en) * | 1987-04-27 | 1988-11-02 | Syntex Pharmaceuticals International Limited | Omega-quaternary ammonium alkyl esters and thioesters of acidic nonsteroidal antiinflammatory drugs |
EP0289262A3 (en) * | 1987-04-27 | 1989-05-31 | Syntex Pharmaceuticals International Limited | Omega-quaternary ammonium alkyl esters and thioesters of acidic nonsteroidal antiinflammatory drugs |
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