US3558641A - Certain pyridyl salicylic acid derivatives - Google Patents

Certain pyridyl salicylic acid derivatives Download PDF

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US3558641A
US3558641A US673273A US3558641DA US3558641A US 3558641 A US3558641 A US 3558641A US 673273 A US673273 A US 673273A US 3558641D A US3558641D A US 3558641DA US 3558641 A US3558641 A US 3558641A
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salicylic acid
acid derivatives
pyridyl
heterocyclic
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Lewis H Sarett
William V Ruyle
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Merck and Co Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • This invention relates to new salicylic acid compounds and processes for producing the same, particularly the 5-(heterocyclic)-salicylic acid derivatives. These compounds are useful in that. they have anti-inflammatory activity and are effective in the prevention and inhibition of edema and granuloma tissue formation. In addition, some of them have a useful degree of ,anti-pyretic and analgesic activity.
  • This invention relates to new heterocyclic phenyl conipounds and to processes for producing the same. More specifically, it relates to 5-(heterocyclic)-salicylic acid compounds (2-hydroxy-5-heterocyclic benzoic acids). Still R2 coon wherein:
  • hetero atoms are either nitrogen, sulphur, or oxygen;
  • this invention relates to compounds having the following general formula:
  • 6-membered ring structure containing from 1-3 hetero atoms are 2,3 or 4-pyridyl, 2 or 3-pyrazinyl, 2,4 or 5-pyrimid1yl, 3 or 4-pyridazinyl, s-triazinyl, 3,4 or 6-as-triazinyl (1,2,3-triazinyl; 1,3,5'-triazinyl; 1,2,4-triazinyl).
  • S-membered heterocyclic ring structures containing from 1-4 hetero atoms are:
  • the R substituent on the heterocyclic nucleus can be in any available position and may be in one or more positions.
  • the compounds described above have anti-inflammatory activity and are effective in the prevention and inhibition of edema and granuloma tissue formation.
  • some of them have a useful degree of anti-pyretic and analgesic activity.
  • they are normally administered orally in tablets or capsules, the optimum dosage depending on the particular compound being used and the type and severity of the condition being treated.
  • oral dose levels of preferred compounds in the range of 50 mg. to 10 g. per day are useful in the control of said conditions, depend ing on the activity of the specific compound and the reaction sensitivity of the patient.
  • the compounds of the instant invention are generally prepared by a carboxylation reaction wherein the appropriate starting material is reacted with carbon dioxide, preferably in the presence of potassium carbonate.
  • the reaction is usually carried out in a pressurized vessel at a wide range of temperatures especially from about 50 C. to 200 C., preferably at about C'. at 800 p.s.i. initial pressure. The pressure can also vary from atmospheric pressure on up.
  • the reaction is caried out for a sufficient time to consume the stoichiometric amount of carbon dioxide.
  • the desired product can be isolated by extraction with water, the water layer then acidified and the precipitated product recrystallized.
  • EXAMPLE 1 Preparation of 5-(2-thienyl)-salicylic acid A mixture of 5 g. of 2-(p-hydroxyphenyl)thiophene and 12 g. of anhydrous potassium carbonate in glass lined bomb is heated under a carbon dioxide atmosphere (800 p.s.i. initial pressure) at 175 C. for 8 hours. The material from the bomb is partitioned between water and methylene chloride, and the aqueous layer is acidified.
  • a carbon dioxide atmosphere 800 p.s.i. initial pressure
  • the precipitated product is dried and recrystallized from benzene/methanol, using charcoal to remove impurities, to obtain pure -(2-thienyl)-salicylic acid.
  • EXAMPIJE 2 Preparation of 5-(2-pyridyl)-salicylic acid An intimate mixture of 8 g. of 2-(p-hydroxyphenyl) pyridine and 20 g. of anhydrous potassium carbonate is subjected to 800 p.s.i. of carbon dioxide in a glass liner in a pressure bomb, and the temperature raised to 200 C. for 6 hours. Maximum pressure during this time is 1,400 p.s.i. After cooling and venting, the contents of the bomb are taken up in 100 ml. of water and filtered. The filtrate is carefully treated with dilute hydrochloric acid until the pH is 7.5. The precipitated dark brown material is filtered and discarded. Upon careful acidification of the filtrate, the desired product precipitates. It is collected by filtration, taken up in dilute potassium bicarbonate solution and re-precipitated by careful neutralization. The product is recrystallized from methanol, yield 3.8 g., M.P. 266267 C.
  • EXAMPLE 3 Preparation of 5-(3-pyridyl)-salicylic acid An intimate mixture of 1.6 g. of 3-(p-hydroxyphenyl)- pyridine, and 4 g. of anhydrous potassium carbonate is heated in a carbon dioxide atmosphere as described in the previous example. The 5-(3-pyridyl)-salicylic acid recrystallized from dimethyl formamide weighs 0.52 g., M.P. 263-265 C.
  • EXAMPLE 4 Preparation of 2-hydroxy-5-(4-pyrimidyl)-benzoic acid ⁇ A mixture of 5 g. of 4-(p-hydroxyphenyl)pyrimidine (as prepared below) and 12 g. of anhydrous potassium carbonate is heated at 200 C. for 6 hours, under carbon dioxide at an initial pressure of 800 p.s.i. The product is Worked up in the usual way to obtain pure 2-hydroxy- 5-(4'-pyrimidyl)-benzoic acid.
  • the mixture is cooled, and is neutralized by the gradual addition of sodium bicarbonate, with the addition of more water if necessary to keep the inorganic salts in solution.
  • the crude product is filtered and washed with a little cold water. Recrystallization from benzene/hexane furnishes pure 4-(p-hydroxyphenyl)-pyrimidine.
  • R is hydrogen, lower alkyl, lower alkoxy, halogen or haloloweralkyl
  • R is hydrogen, lower alkyl, halo, amino, loweralkylamino, diloweralkylamino, hydroxy or lower alkoxy.

Abstract

NEW SALICYCLIC ACID COMPOUNDS, PARTICULARLY 5-(HETEROCYCLIC)-SALICYCLIC ACID DERIVATIVES AND PROCESS FOR THEIR PREPARATION ARE CLAIMED. THE NEW 5-(HETEROCYCLIC)SALICYCLIC ACID COMPOUNDS DESCRIBED HAVE ANIT-INFLAMMATORY, ANTI-PYRETIC AND ANALGESIC ACTIVITY.

Description

U te S ate Patent Q iw ABSTRACT OF THE DISCLOSURE New salicylic acid compounds, particularly S-(heterocyclic)-salicylic acid derivatives and process for their preparation are claimed. The new S-(heterocyclic)salicylic acid compounds described have anti-inflammatory, anti-pyretic and analgesic activity.
BACKGROUND OF THE INVENTION The development of anti-inflammatory compounds in the past two decades has seen the growth of a great many new drugs. Most of these have been steroids of the 11- oxygenated pregnane series. These, while highly effective, have the drawback of causing many side effects. There is a need in the market for equally effective compounds of much simpler structure and having less side effects.
SUMMARY OF THE INVENTION This invention relates to new salicylic acid compounds and processes for producing the same, particularly the 5-(heterocyclic)-salicylic acid derivatives. These compounds are useful in that. they have anti-inflammatory activity and are effective in the prevention and inhibition of edema and granuloma tissue formation. In addition, some of them have a useful degree of ,anti-pyretic and analgesic activity.
DESCRIPTION AND PREFERRED EMBODIMENTS This invention relates to new heterocyclic phenyl conipounds and to processes for producing the same. More specifically, it relates to 5-(heterocyclic)-salicylic acid compounds (2-hydroxy-5-heterocyclic benzoic acids). Still R2 coon wherein:
is a 6-membered ring structure containing from 1-3 hetero atoms or a S-mernbered ring structure containing from 1-4 hetero atoms. The hetero atoms are either nitrogen, sulphur, or oxygen;
more specifically, this invention relates to compounds having the following general formula:
Patented Jan. 26, 1971 Preferable examples of the 6-membered ring structure containing from 1-3 hetero atoms are 2,3 or 4-pyridyl, 2 or 3-pyrazinyl, 2,4 or 5-pyrimid1yl, 3 or 4-pyridazinyl, s-triazinyl, 3,4 or 6-as-triazinyl (1,2,3-triazinyl; 1,3,5'-triazinyl; 1,2,4-triazinyl).
Preferred examples of S-membered heterocyclic ring structures containing from 1-4 hetero atoms are:
2 or 3 furyl,
2 or 3 thienyl,
2,3 or 4-thiazolyl,
3 or 4-(1,2,5-thiadiazolyl), 2 or 5-( 1,3,4-thiadiazolyl), 3 or 5-(1,2,4-thiadiazolyl), 2,4 or S-oxazolyl,
3,4 or S-isooxazolyl,
1,2 or 3-pyrrolyl,
1,2 or 4-imidazolyl.
In all the above structures, the R substituent on the heterocyclic nucleus can be in any available position and may be in one or more positions.
Representative compounds of this invention are as follows:
5- Z-thienyl -salicylic acid,
5- Z-pyridyl -salicylic acid, 5-(3-pyridyl)-salicylic acid,
2-hydroxy-5- (4'-pyrimidyl) -benzoic acid, 2-hydroxy-5-(2'-thiazolyl) -benzoic acid.
We have found that the compounds described above have anti-inflammatory activity and are effective in the prevention and inhibition of edema and granuloma tissue formation. In addition, some of them have a useful degree of anti-pyretic and analgesic activity. For these purposes, they are normally administered orally in tablets or capsules, the optimum dosage depending on the particular compound being used and the type and severity of the condition being treated. Although the optimum quantities to be used will depend on the compound employed and the particular type of disease treated, oral dose levels of preferred compounds in the range of 50 mg. to 10 g. per day are useful in the control of said conditions, depend ing on the activity of the specific compound and the reaction sensitivity of the patient.
The compounds of the instant invention are generally prepared by a carboxylation reaction wherein the appropriate starting material is reacted with carbon dioxide, preferably in the presence of potassium carbonate. The reaction is usually carried out in a pressurized vessel at a wide range of temperatures especially from about 50 C. to 200 C., preferably at about C'. at 800 p.s.i. initial pressure. The pressure can also vary from atmospheric pressure on up. The reaction is caried out for a sufficient time to consume the stoichiometric amount of carbon dioxide. When the reaction is complete, the desired product can be isolated by extraction with water, the water layer then acidified and the precipitated product recrystallized.
Various methods for preparing the end products are shown in the following examples. Also, the following examples should be construed as illustrations of the invention and not limitations thereof.
EXAMPLE 1 Preparation of 5-(2-thienyl)-salicylic acid A mixture of 5 g. of 2-(p-hydroxyphenyl)thiophene and 12 g. of anhydrous potassium carbonate in glass lined bomb is heated under a carbon dioxide atmosphere (800 p.s.i. initial pressure) at 175 C. for 8 hours. The material from the bomb is partitioned between water and methylene chloride, and the aqueous layer is acidified.
The precipitated product is dried and recrystallized from benzene/methanol, using charcoal to remove impurities, to obtain pure -(2-thienyl)-salicylic acid.
The preparation of the starting material shown above, namely Z-(p-hydroxyphenyl)-thiophene is shown in I. Gotze (German Pat. 1,051,115).
EXAMPIJE 2 Preparation of 5-(2-pyridyl)-salicylic acid An intimate mixture of 8 g. of 2-(p-hydroxyphenyl) pyridine and 20 g. of anhydrous potassium carbonate is subjected to 800 p.s.i. of carbon dioxide in a glass liner in a pressure bomb, and the temperature raised to 200 C. for 6 hours. Maximum pressure during this time is 1,400 p.s.i. After cooling and venting, the contents of the bomb are taken up in 100 ml. of water and filtered. The filtrate is carefully treated with dilute hydrochloric acid until the pH is 7.5. The precipitated dark brown material is filtered and discarded. Upon careful acidification of the filtrate, the desired product precipitates. It is collected by filtration, taken up in dilute potassium bicarbonate solution and re-precipitated by careful neutralization. The product is recrystallized from methanol, yield 3.8 g., M.P. 266267 C.
The preparation of the starting material used above, namely 5-(2-pyridyl)-salicylic acid is shown in Forsyth and Pyman, J. Chem. Soc. 1926, page 2916.
EXAMPLE 3 Preparation of 5-(3-pyridyl)-salicylic acid An intimate mixture of 1.6 g. of 3-(p-hydroxyphenyl)- pyridine, and 4 g. of anhydrous potassium carbonate is heated in a carbon dioxide atmosphere as described in the previous example. The 5-(3-pyridyl)-salicylic acid recrystallized from dimethyl formamide weighs 0.52 g., M.P. 263-265 C.
i The preparation of the starting material shown above, namely 3-(p-hydroxyphenyl)-pyridine is shown in Forsyth and Pyman, J. Chem. Soc. 1926, page 2916.
EXAMPLE 4 Preparation of 2-hydroxy-5-(4-pyrimidyl)-benzoic acid \A mixture of 5 g. of 4-(p-hydroxyphenyl)pyrimidine (as prepared below) and 12 g. of anhydrous potassium carbonate is heated at 200 C. for 6 hours, under carbon dioxide at an initial pressure of 800 p.s.i. The product is Worked up in the usual way to obtain pure 2-hydroxy- 5-(4'-pyrimidyl)-benzoic acid.
To a stirred solution of 3.0 g. of 4-(p-aminophenyl)- pyrimidine (preparation shown in Lythgoe and Rayner, J. Chem. Soc. 1951, page 2323) in 15 ml. of glacial acetic acid kept at 10-12 C. is added slowly a solution of 1.2 g. of sodium nitrite in 10 ml. of water. After stirring for an additional 0.25 hour, the diazotized solution is poured slowly into a boiling mixture of 10 ml. of concentrated sulfuric acid and 20 ml. of water. The mixture is boiled until a negative coupling test with ot-naphthol solution is obtained. The mixture is cooled, and is neutralized by the gradual addition of sodium bicarbonate, with the addition of more water if necessary to keep the inorganic salts in solution. The crude product is filtered and washed with a little cold water. Recrystallization from benzene/hexane furnishes pure 4-(p-hydroxyphenyl)-pyrimidine.
EXAMPLE 5 Preparation of 2-hydroxy-5-(2'-thiazolyl)- benzoic acid We claim: 1. A compound of the formula:
R2 R1 0 O OH -01; wherein:
R is hydrogen, lower alkyl, lower alkoxy, halogen or haloloweralkyl; and
R is hydrogen, lower alkyl, halo, amino, loweralkylamino, diloweralkylamino, hydroxy or lower alkoxy.
References Cited Prelog et al.: Chem. Abstracts, vol. 41, par. 4133 (1947).
Baine et al.: Chem. Abstracts, vol. 49, par. 4577-78 (1955).
Nandi et al.: Chem. Abstracts, vol. 55, par. 22-219 (1961).
The Merck Index, seventh edition, p. 1444 (1960).
ALAN L. ROTMAN, Primary Examiner US. Cl. X.R.
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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3676451A (en) * 1970-06-09 1972-07-11 Merck & Co Inc Thiazolylsalicylic acids
US3682968A (en) * 1969-06-25 1972-08-08 Merck & Co Inc Anti-inflammatory salicylic acid derivatives
FR2128292A1 (en) * 1971-03-12 1972-10-20 Berlin Chemie Veb Imidazole derivs - with hypotensive, mao-inhibitory, anticonvulsant antiinflammatory, choleretic and antiviral activity prepn
FR2128285A1 (en) * 1971-03-11 1972-10-20 Berlin Chemie Veb Imidazole derivs - with hypotensive mao-inhibitory, anticonvulsant antiinflammatory choleretic and antiviral activity prepn
US3860640A (en) * 1972-04-12 1975-01-14 Nippon Shinyaku Co Ltd 3-alkoxy-5-substituted phenylacetic acids
US3929833A (en) * 1970-10-30 1975-12-30 Sandoz Ag Organic compounds
US3993763A (en) * 1969-03-18 1976-11-23 Ciba-Geigy Corporation Tertiary aminoacids as anti-inflammatory agents
US4001420A (en) * 1968-12-12 1977-01-04 Science Union Et Cie, Societe Francaise De Recherche Medical Thiazolyl benzoic acid compounds
US4111935A (en) * 1975-01-02 1978-09-05 Smith Kline & French Laboratories Limited 3-chloro-6-phenylpyridazine compounds
US4152341A (en) * 1975-12-29 1979-05-01 Imperial Chemical Industries Limited Triaryl or diarylpyridyl methanes
US4305950A (en) * 1978-04-28 1981-12-15 Basf Aktiengesellschaft Pharmaceutical agent containing amino derivatives of 2-methyl-5-(2-hydroxystyryl)-1,3,4-thiadiazole
USRE31467E (en) * 1975-12-29 1983-12-20 Imperial Chemical Industries Plc Triaryl or diarylpyridyl methanes
EP0195582A1 (en) * 1985-03-14 1986-09-24 SMITH KLINE DAUELSBERG GmbH 5-Aminosalicylic acid derivatives of non-steroidal antiinflammatory acids
US5541219A (en) * 1992-03-04 1996-07-30 Rhone-Poulenc Rorer Limited 1-Alkoxy-2-(alkoxy- or cycloalkoxy-)-4-(cyclothioalkyl- or cyclothioalkenyl-) benzenes as inhibitors of cyclic AMP phosphodiesterase and tumor necrosis factor
EP3593803A4 (en) * 2017-03-10 2020-04-08 Universidad de Granada Compounds for the treatment of diseases caused by oxalate accumulation

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1308028A (en) * 1970-06-12 1973-02-21 Science Union & Cie Thiazolylbenzoic acid derivatives and a process for their manufactur
US3687971A (en) * 1970-06-22 1972-08-29 Merck & Co Inc 4-(pyrrolyl)-salicylic acid derivatives
US3865839A (en) * 1973-03-01 1975-02-11 Hoechst Co American Thiopyranopyrrolylsalicyclic acids and derivatives thereof

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4001420A (en) * 1968-12-12 1977-01-04 Science Union Et Cie, Societe Francaise De Recherche Medical Thiazolyl benzoic acid compounds
US3993763A (en) * 1969-03-18 1976-11-23 Ciba-Geigy Corporation Tertiary aminoacids as anti-inflammatory agents
US3682968A (en) * 1969-06-25 1972-08-08 Merck & Co Inc Anti-inflammatory salicylic acid derivatives
US3676451A (en) * 1970-06-09 1972-07-11 Merck & Co Inc Thiazolylsalicylic acids
US3929833A (en) * 1970-10-30 1975-12-30 Sandoz Ag Organic compounds
FR2128285A1 (en) * 1971-03-11 1972-10-20 Berlin Chemie Veb Imidazole derivs - with hypotensive mao-inhibitory, anticonvulsant antiinflammatory choleretic and antiviral activity prepn
FR2128292A1 (en) * 1971-03-12 1972-10-20 Berlin Chemie Veb Imidazole derivs - with hypotensive, mao-inhibitory, anticonvulsant antiinflammatory, choleretic and antiviral activity prepn
US3860640A (en) * 1972-04-12 1975-01-14 Nippon Shinyaku Co Ltd 3-alkoxy-5-substituted phenylacetic acids
US4111935A (en) * 1975-01-02 1978-09-05 Smith Kline & French Laboratories Limited 3-chloro-6-phenylpyridazine compounds
US4152341A (en) * 1975-12-29 1979-05-01 Imperial Chemical Industries Limited Triaryl or diarylpyridyl methanes
USRE31467E (en) * 1975-12-29 1983-12-20 Imperial Chemical Industries Plc Triaryl or diarylpyridyl methanes
US4305950A (en) * 1978-04-28 1981-12-15 Basf Aktiengesellschaft Pharmaceutical agent containing amino derivatives of 2-methyl-5-(2-hydroxystyryl)-1,3,4-thiadiazole
EP0195582A1 (en) * 1985-03-14 1986-09-24 SMITH KLINE DAUELSBERG GmbH 5-Aminosalicylic acid derivatives of non-steroidal antiinflammatory acids
US5541219A (en) * 1992-03-04 1996-07-30 Rhone-Poulenc Rorer Limited 1-Alkoxy-2-(alkoxy- or cycloalkoxy-)-4-(cyclothioalkyl- or cyclothioalkenyl-) benzenes as inhibitors of cyclic AMP phosphodiesterase and tumor necrosis factor
EP3593803A4 (en) * 2017-03-10 2020-04-08 Universidad de Granada Compounds for the treatment of diseases caused by oxalate accumulation

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BR6802728D0 (en) 1973-05-10
NL6813639A (en) 1969-04-09
CH502981A (en) 1971-02-15
NL161759C (en) 1980-03-17
DE1801303A1 (en) 1969-06-19
NL161759B (en) 1979-10-15
FR1585315A (en) 1970-01-16
GB1214079A (en) 1970-12-02

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