US3687971A - 4-(pyrrolyl)-salicylic acid derivatives - Google Patents

4-(pyrrolyl)-salicylic acid derivatives Download PDF

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Publication number
US3687971A
US3687971A US48479A US3687971DA US3687971A US 3687971 A US3687971 A US 3687971A US 48479 A US48479 A US 48479A US 3687971D A US3687971D A US 3687971DA US 3687971 A US3687971 A US 3687971A
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United States
Prior art keywords
gms
salicylic acid
mixture
pyrrolyl
thiazolyl
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US48479A
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Tsung-Ying Shen
Howard Jones
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Merck and Co Inc
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Merck and Co Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
    • C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C07D207/327—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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C331/00—Derivatives of thiocyanic acid or of isothiocyanic acid
    • C07C331/02—Thiocyanates
    • C07C331/10—Thiocyanates having sulfur atoms of thiocyanate groups bound to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen 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
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole 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
    • 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
    • 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

  • the new 4-(hetero cyclic)salicyclic acid compounds described have antiinflammatory, anti-pyretic and analgesic activity.
  • This invention relates to new heterocyclic phenyl compounds and to processes for producing the same. More specifically, it relates to 4-(heterocyclic)-salicylic acid compounds (2-hdroxy -4-heterocyclic benzoic acids). Still more specifically, this invention relates to compounds having the following general formula:
  • Het is a 6- membered ring structure containing from one to three hetero atoms or a five-membered ring structure containing from one to four hetero atoms.
  • the hetero atoms are either nitrogen, sulphur, or oxygen;
  • R is hydrogen, lower alkyl, lower alkoxy, halogen, or
  • R is hydrogen, alkyl (preferably lower alkyl, such as methyl, ethyl, propyl, isopropyl, butyl or pentyl), halo (such as, chlorine, bromine or iodine or fluorine), amino, alkyl amino, (preferably lower alkyl amino, such as methyl amino or isopropyl amino), dialkyl amino, (preferably diloweralkyl amino such as dimethyl amino or diethyl amino), hydroxy or alkoxy (preferably lower alkoxy, such as methoxy or ethoxy).
  • alkyl preferably lower alkyl, such as methyl, ethyl, propyl, isopropyl, butyl or pentyl
  • halo such as, chlorine, bromine or iodine or fluorine
  • dialkyl amino preferably diloweralkyl amino such as di
  • the six-membered ring structure containing from one to three hetero atoms are 2,3 or 4-pyridyl, 2 or 3 pyrazinyl, 2,4 or S-pyrimidyl, 3 or 4 pyridazinyl, s-triazinyl, 3,4 or b-as-triazinyl (1,2,3- triazinyl; 1,3,5-Triazinyl; l ,2,4-triazinyl).
  • Preferred examples of five-membered heterocyclic ring structures containing from one to four hetero atoms are:
  • heterocyclic ring structures are the oxazole, thiazolyl and pyrole rings in that order of importance.
  • 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, depending on the activity of the specific compound and the reaction sensitivity of the patient.
  • the compounds of the instant invention can be 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 to 200 C., preferably at about 175 C. at 800 p.s.i. initial pressure. The pressure can also vary from atmospheric pressure on up.
  • the reaction mixture is carried out for a sufficient time to consume the stoimetric 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 EXAMPLE Preparation of 4-(2-oxazolyl-salicylic acid A. m-(Diethoxy ethylaminomethyl)-nitrobenzene 22.7 Gms. (0.15 moles) of 3-nitro-benzaldehyde and 20.0 gms. (0.15 moles) of diethoxyethyl amine were mixed together and heated in an oil bath for about 1 hour until no more water is given off. The mixture was then cooled and diluted with an ether-hexane mixture at which time a solid material crystallized. The solid material was filtered and dried yielding 34.3 gms. of m- (diethoxy ethylaminomethyl)-nitrobenzene, m.p.
  • This solid was a boron complex of 2-chloro-4-(mhydroxyphenyl)-thiazole. It was decomposed by heating it with a saturated sodium bicarbonate solution for about one-half hour on a steam bath. The crude solid was filtered, dried and crystallized from petroleum ether. A yield of 0.9 g. of 2-chloro-4-(m-hydroxyphenyl)-thiazole was obtained, n1.p. 89-90 C. D. 4-[4-(2-chlorotl'iiazolyl)]-salicylic acid 2,3 gms. of 2-chloro-4-( m-hydroxyphenyl)-thiazole and 5.1 gms.
  • R is hydrogen, lower alkyl, lower alkoxy, halogen or haloloweralkyl
  • R is hydrogen, lower alkyl, halo, amino, lower alkylamino, di( lower a1kyl)amino, hydroxy or lower alkoxy.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
US48479A 1970-06-22 1970-06-22 4-(pyrrolyl)-salicylic acid derivatives Expired - Lifetime US3687971A (en)

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US4847970A 1970-06-22 1970-06-22

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US (1) US3687971A (enrdf_load_stackoverflow)
CA (1) CA952116A (enrdf_load_stackoverflow)
DE (1) DE2130709A1 (enrdf_load_stackoverflow)
FR (1) FR2100810B1 (enrdf_load_stackoverflow)
GB (1) GB1295570A (enrdf_load_stackoverflow)
NL (1) NL7107784A (enrdf_load_stackoverflow)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3878225A (en) * 1973-03-01 1975-04-15 Hoechst Co American Condensed pyrroles bearing an N-phenyl substituent
US3904761A (en) * 1974-01-25 1975-09-09 Hoechst Co American Method of preventing thrombosis
US3931407A (en) * 1973-03-01 1976-01-06 American Hoechst Corporation Method of treatment with and compositions containing condensed pyrroles bearing an N-phenyl substituent
US4111935A (en) * 1975-01-02 1978-09-05 Smith Kline & French Laboratories Limited 3-chloro-6-phenylpyridazine compounds
US4122275A (en) * 1977-08-08 1978-10-24 American Cyanamid Company Imidazolinyl benzamides as herbicidal agents
US4166911A (en) * 1977-02-02 1979-09-04 Farmitalia Carlo Erba S.P.A. Pyridazinyl-ergoline compounds having neuroleptic activity
US4242351A (en) * 1979-05-07 1980-12-30 Imperial Chemical Industries Limited Antisecretory oxadiazoles and pharmaceutical compositions containing them
US5208251A (en) * 1986-05-09 1993-05-04 Warner-Lambert Company Styryl pyrazoles, isoxazoles and analogs thereof having activity as 5-lipoxygenase inhibitors, pharmaceutical compositions and methods of use therefor
US20040116427A1 (en) * 2002-11-21 2004-06-17 New York Blood Center Compounds for inhibition of HIV infection by blocking HIV entry

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL55064A (en) * 1977-08-08 1983-06-15 American Cyanamid Co 5,5-disubstituted-4-oxo-2-imidazolin-2-yl benzoic acid esters,their preparation and herbicidal compositions comprising them
US7790720B2 (en) 2005-03-31 2010-09-07 Ucb Pharma, S.A. Compounds comprising an oxazole or thiazole moiety, processes for making them, and their uses

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3185689A (en) * 1965-05-25 Tolyl-x-(jh)-pyrimidones
DE896047C (de) * 1951-09-12 1953-11-09 Basf Ag Verfahren zur Herstellung von Salicylsaeurederivaten
NL6515006A (enrdf_load_stackoverflow) * 1964-11-27 1966-05-31
US3558641A (en) * 1967-10-06 1971-01-26 Merck & Co Inc Certain pyridyl salicylic acid derivatives

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3878225A (en) * 1973-03-01 1975-04-15 Hoechst Co American Condensed pyrroles bearing an N-phenyl substituent
US3931407A (en) * 1973-03-01 1976-01-06 American Hoechst Corporation Method of treatment with and compositions containing condensed pyrroles bearing an N-phenyl substituent
US3904761A (en) * 1974-01-25 1975-09-09 Hoechst Co American Method of preventing thrombosis
US4111935A (en) * 1975-01-02 1978-09-05 Smith Kline & French Laboratories Limited 3-chloro-6-phenylpyridazine compounds
US4166911A (en) * 1977-02-02 1979-09-04 Farmitalia Carlo Erba S.P.A. Pyridazinyl-ergoline compounds having neuroleptic activity
US4252948A (en) * 1977-02-02 1981-02-24 Farmitalia Carlo Erba S.P.A. Ergoline derivatives
US4122275A (en) * 1977-08-08 1978-10-24 American Cyanamid Company Imidazolinyl benzamides as herbicidal agents
US4242351A (en) * 1979-05-07 1980-12-30 Imperial Chemical Industries Limited Antisecretory oxadiazoles and pharmaceutical compositions containing them
US5208251A (en) * 1986-05-09 1993-05-04 Warner-Lambert Company Styryl pyrazoles, isoxazoles and analogs thereof having activity as 5-lipoxygenase inhibitors, pharmaceutical compositions and methods of use therefor
US20040116427A1 (en) * 2002-11-21 2004-06-17 New York Blood Center Compounds for inhibition of HIV infection by blocking HIV entry
US7241803B2 (en) * 2002-11-21 2007-07-10 New York Blood Center Compounds for inhibition of HIV infection by blocking HIV entry
US20070232684A1 (en) * 2002-11-21 2007-10-04 New York Blood Center Compounds for inhibition of HIV infection by blocking HIV entry

Also Published As

Publication number Publication date
NL7107784A (enrdf_load_stackoverflow) 1971-12-24
CA952116A (en) 1974-07-30
FR2100810A1 (enrdf_load_stackoverflow) 1972-03-24
GB1295570A (enrdf_load_stackoverflow) 1972-11-08
DE2130709A1 (de) 1971-12-23
FR2100810B1 (enrdf_load_stackoverflow) 1975-06-06

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