Classifications

• • 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.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Pyridine Compounds (AREA)

Applications Claiming Priority (1)

Publications (1)

Family

ID=24701969

Family Applications (1)

Country Status (7)

Cited By (15)

Families Citing this family (3)

• 1967
  • 1967-10-06 US US673273A patent/US3558641A/en not_active Expired - Lifetime
• 1968
  • 1968-09-24 NL NL6813639.A patent/NL161759C/xx not_active IP Right Cessation
  • 1968-09-30 BR BR202728/68A patent/BR6802728D0/pt unknown
  • 1968-10-01 GB GB46606/68A patent/GB1214079A/en not_active Expired
  • 1968-10-04 FR FR1585315D patent/FR1585315A/fr not_active Expired
  • 1968-10-04 DE DE19681801303 patent/DE1801303A1/de active Pending
  • 1968-10-07 CH CH1494368A patent/CH502981A/de not_active IP Right Cessation

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