US3551571A - Methods for reducing pain,reducing fever and alleviating inflammatory syndromes with heteroaromatic pyrrol-3-yl ketones - Google Patents

Methods for reducing pain,reducing fever and alleviating inflammatory syndromes with heteroaromatic pyrrol-3-yl ketones Download PDF

Info

Publication number
US3551571A
US3551571A US639620A US3551571DA US3551571A US 3551571 A US3551571 A US 3551571A US 639620 A US639620 A US 639620A US 3551571D A US3551571D A US 3551571DA US 3551571 A US3551571 A US 3551571A
Authority
US
United States
Prior art keywords
ketone
dimethylpyrrol
furyl
benzene
added
Prior art date
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.)
Expired - Lifetime
Application number
US639620A
Other languages
English (en)
Inventor
Irwin J Pachter
David L Nicholas
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ENDO LAB Inc
EIDP Inc
Original Assignee
ENDO LAB
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by ENDO LAB filed Critical ENDO LAB
Application granted granted Critical
Publication of US3551571A publication Critical patent/US3551571A/en
Assigned to E.I. DU PONT DE NEMOURS AND COMPANY reassignment E.I. DU PONT DE NEMOURS AND COMPANY ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: ENDO LABORATORIES, INC., A CORP. OF DEL.
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • 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
    • C07D207/33—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 ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention relates to a method for the use of certain chemical compounds having valuable pharmacodynamic activity, and to therapeutic compositions incorporating such compounds. More particularly, the invention relates to a method for administering certain heteroaromatic pyrrol-3-y1 ketones having antiinflammatory, analgetic and antipyretic properties and to therapeutically useful compositions incorporating such materials.
  • R I C Het R -L lRa N
  • R may be hydrogen; lower alkyl, lower alkenyl or cycloalkyl having not more than six carbon atoms; or benzyl or phenyl, including halo, lower alkoxyor lower alkylsubstituted benzyl or phenyl groups, the lower alkoxy or lower alkyl substituents of which have not more than four carbon atoms;
  • R R and R may each be hydrogen; lower alkyl, lower alkenyl, lower alkynyl, or cycloalkyl, having not more than six carbon atoms; halo; or phenyl or phenyl lower alkyl, the alkyl substituent of which has not more than four carbon atoms, and including lower alkoxyor lower alkyl-substituted phenyl or phenyl lower alkyl groups, the lower alkoxy or lower alkyl substituents of which have not more than four carbon atoms; and
  • Het is a fiveor six-membered heteroaromatic monocyclic radical, viz, a fully unsaturated monocyclic heterocyclic radical wherein the hetero atoms are nitrowherein:
  • Patented Dec. 29, 1970 gen, oxygen or sulfur or combinations of two or more of such moieties.
  • the noted class of compounds has outstanding antiinflammatory, analgetic and antipyretic properties.
  • Such compounds are of particular value in alleviating the symptoms of rheumatic, arthritic, allergic and other inflammatory conditions.
  • the compounds employed in accordance with the present invention are remarkable for their potency, for their ability to alleviate deep pain as evidenced by their activity on the hot plate test for analgesia, and for their ability to reverse an experimentally induced inflammatory condition in animals.
  • Z-furyl 2,5-dimethylpyrrol-3-yl ketone (see Example 1 below) may be cited as an illustration of efficacy.
  • This compound is three times as potent as phenylbutazone in the carrageenin edema assay in the rat.
  • As an antipyretic it is equal in potency to indomethacin, ten times as potent as phenylbutazone and 40 times as potent as aspirin.
  • In the hot plate test for analgesia it is approximately equal to codeine phosphate and is much more potent than aspirin, indomethacin or phenylbutazone, which are essentially inactive in this test.
  • Z-furyl 2,5-dimethylpyrrol-3-yl ketone furthermore, has the ability to reverse an experimentally induced infiammation.
  • Indomethacin, phenylbutazone and aspirin suppress inflammation, but only the compounds of the present in- "vention reverse inflammations already produced.
  • many compounds of this invention are equal in potency to hydrocortisone.
  • the compounds are therapeutically useful when administered to mammals orally, parenterally or rectally.
  • the oral route is preferred. Although they may be administered as pure compounds, the limited solubility in water of many of the compounds employed in the practice of this invention makes it advantageous to combine them with pharmaceutically acceptable carriers such as starch, sugar, talc and the like to form powder-s which can be used directly or inserted into gelatin capsules or converted into tablets.
  • pharmaceutically acceptable carriers such as starch, sugar, talc and the like to form powder-s which can be used directly or inserted into gelatin capsules or converted into tablets.
  • Suitable lubricants like magnesium stearate, binders such as gelatin and disintegrating agents like sodium carbonate in combination with citric acid can be used to form tablets. They may also be formulated as suspensions or emulsions in suitable liquid carriers.
  • heterocyclic moiety of the therapeutically active compounds utilized in the practice of the present invention may incorporate any suitable 5- or 6-membered heteroaromatic monocyclic radical.
  • heteroaromatic groups which may thus be utilized are furyl, pyrryl, thienyl, oxadiazolyl, pyrazolyl, thiadiazolyl, oxazolyl, thiazolyl, pyrazinyl, pyridyl, imidazolyl, tetrazolyl, isoxazolyl, pyrirnidinyl, triazolyl and isothiazolyl.
  • radicals may be unsubstituted or, alternatively, substituted, for example, by halogen, nitro, amino, hydroxy, phenyl, sulfamoyl, carbamoyl, cyano, trifluoromethyl, mercapto, lower alkyl, lower,
  • alkylthio lower alkoxy, lower alkylamino, di-lower alkylamino, lower .alkanoylamino, carb-lower alko'xy, and
  • phenyl lower alkyl the carbon chains of the aliphatic substituted substituents having not more than six carbon atoms.
  • heteroaromatic monocyclic radical Het is a 2- or 3-furyl group, whether unsubstituted or substituted as aforesaid, the preferred substituents on such radical being selected from the group consisting of halo, nitro, amino, or lower alkyl, lower alkoxy or lower alkylthio having no more than four carbon atoms in their aliphatic chains.
  • R is hydrogen and R R and R may each be selected from the group of hydrogen, halogen, or lower alkyl or cycloalkyl having not more than six carbon atoms. It is particularly desirable to incorporate such substituents in the active compounds utilized in accordance herewith when the heterocyclic moiety of the compound is constituted of the preferred 2- or 3-furyl; 2- or 3-thienyl; pyrrol-2-yl or pyrrol-3-yl; or 1,2,5-oxadiazol-3- yl or 1,2,4-oxadiazol-3-yl radicals.
  • the boron trifluoride catalyst is preferably utilized in the form of a suitable complex such as an etherate complex, which is understood to mean a complex of boron trifluoride with dialkyl ethers such as diethyl ether, dimethyl ether, dipropyl ether, and the like, as well as cyclic ethers such as tetrahydrofuran or dioxan.
  • etherate complex a complex of boron trifluoride with dialkyl ethers such as diethyl ether, dimethyl ether, dipropyl ether, and the like, as well as cyclic ethers such as tetrahydrofuran or dioxan.
  • the pyrrole which is to form the pyrrole moiety of the ketone, the heteroaromatic acid halide, and the boron trifluoride complex are mixed in an anhydrous reaction-inert organic solvent, suitably a hydrocarbon solvent such as an aliphatic hydrocarbon solvent, for example, hexane, heptane, octane, cyclohexane, cycloheptane or the like, or an aromatic solvent such as benzene or toluene.
  • Benzene is the solvent of choice, since undesirable side reactions are thereby minimized.
  • reaction temperature is not critical, ambient temperatures, say from about to about 30, suitably about are preferred. At the lower temperatures the reaction proceeds too slowly, and at higher temperatures undesirable side reactions will occur.
  • boron trifluoride is employed as the catalyst herein.
  • This reagent has many advantages over other Friedel-Crafts catalysts in the process of this invention.
  • Boron trifluoride, particularly in its etherate form is a far more convenient reagent to employ in large scale syntheses than other Friedel-Crafts catalysts such as magnesium bromide.
  • boron trifluoride is readily purified and does not leave solid residues.
  • the boron trifluoride Friedel-Crafts process of the present invention is also superior to the Grignard process mentioned hereinabove in that the use of ether or similar solvents required in Grignard reactions is kept to a mini mum, it being well known that the use of large volumes of ether in industrial processes gives rise to problems involving extraordinary precautions against fire and explo- $1011.
  • the compounds utilized in the present invention may, as noted above, be compounded into tablets or capsules.
  • dosage forms contain from about 5 to 500 mg., preferably 15 to mg., of active material per tablet or capsule.
  • the therapeutically active compounds are incorporated in such dosage forms in the proportion of therapeutically active material to carrier of between 1:30 and 1:0.33, preferably 1:10 to 121.5.
  • solutions, emulsions or suspensions of the active materials containing between 0.1 mg. and 100 mg. per ml. of liquor, preferably 5 to 25 mg. per ml. of liquor.
  • non-therapeutically active material used in preparing the aforementioned capsules, tablets, solutions, suspensions or emulsions may consist of any of the pharmaceutically acceptable carriers, suspendants, additives and the like usually used in the preparation of the dosage forms specified hereinabove.
  • the active compounds may also be admixed with cocoa butter or the like to form suppositories containing from 1 mg. to 250 mg., suitably from 10 to 100 mg., of the active compound per suppository, that is to say the ratio of active material to carrier in the suppository falls within the range of from about 1:2000 to about 1:8, preferably from about 1:200 to 1:20.
  • R is hydrogen; lower alkyl, lower alkenyl or cycloalkyl, having not more than six carbon atoms; benzyl; or phenyl;
  • R R and R are each hydrogen; lower alkyl, lower alkenyl, lower alkynyl or cycloalkyl, having not more than six carbon atoms; phenyl, phenyl lower alkyl in which the alkyl group has not more than four carbon atoms; halo;
  • H is furyl, pyrryl, thienyl, oxadiazolyl, pyrazolyl, thiadiazolyl, oxazolyl, thiazolyl, pyrazinyl, pyridyl, imidazolyl, tetrazolyl, isoxazolyl, pyrimidinyl, triazolyl or isothiazolyl;
  • Z in the group (Z) is hydrogen, halogen, nitro, amino,
  • moieties Z may be the same or dillerent
  • R and R are lower alkyl and H, is furyl or thienyl, at least one member of the group (Z) is other than hydrogen and n is other than zero.
  • EXAMPLE 1 Capsules containing 2-puryl 2,5-dimethylpyrrol- 3-yl ketone The indicated compound is prepared by reaction of the Grignard derivative of 2,5-dimethylpyrrol with 2- furoyl chloride. Initially, the Grignard reagent is prepared by placing magnesium (3.6 g.) in a round-bottom flask in an anhydrous system, and the system then flushed with dry nitrogen. Suflicient anhydrous ether to cover the magnesium ml.) is then added.
  • the reaction mixture is then cooled in an ice bath and 30 ml. of 25% aqueous ammonium chloride is added dropwise, followed by 100 ml. of water.
  • the layers are then separated and the organic layer washed successively with water, two 50 ml. portions of 10% aqueous sodium hydroxide, and again with H O. After drying, the solvent is removed at diminished pressure and the residue triturated with five 20 ml. portions of hexane and then filtered.
  • the product is dissolved in benzene and decolorized by passage through a short column of alumina. Concentration of the benzene eluate aifords 14 g. of pure product, M.P. 9899.
  • the above mixture is well mixed, screened through a #60 mesh sieve and 'filled into two-piece, hard gelatin capsules.
  • Similar antiinflammatory compounds are prepared employing the procedure of the preceding example by reaction of other appropriate acid halides in place of the 2- furoyl chloride reactant. In such manner the following compounds are prepared for capsule or other mode of administration.
  • EXAMPLE 3 Suppositories containing S-furyl 2,5-dimethylpyrrol-3-yl ketone
  • the above product is prepared by reaction of 3-furoyl chloride with the Grignard reagent of 2,5-dimethylpyrrole. Initially, the 3-furoyl chloride is prepared by heating a mixture of 20 g. of 3-furoic acid and 30 g. of thionyl chloride on a steam bath for eight hours. The excess thionyl chloride is evaporated and the residue is extracted twice with benzene and then distilled to give the 3-furoyl chloride, B.P. 475 at 15 mm.
  • the active compound thus prepared is thoroughly admixed with cocoa butter to provide 2 g. suppositories of the following composition:
  • the Grignard reagent is initially prepared by adding 16.14 g. of 2,5-dimethylpyrrole to a Grignard solution prepared from 4.12 g. of magnesium and 18.7 g. of ethylbromide in 150 ml. of anhydrous ether. The mixture is stirred for 30 minutes after the addition is completed.
  • the dispersion is prepared by initially dissolving the methyl and propylparabens in boiling water, allowing the solution to cool, adding the sorbitan monooleate and mixing well.
  • the PVP and CMC are separately dissolved in water, after which the active ketone product is dispersed in the PVP solution and the two solutions well mixed. Q.s.
  • the acid chloride reactant is initially obtained by adding 60 g. of thionyl chloride with stirring to a solution of 58 g. of l-methylpyrrole-Z-carboxylic acid and 102 g. of triethylamine in ml. of anhydrous benzene. The mixture is refluxed for one hour and then is filtered and evaporated to remove solvents. On distillation, 40 g. of l-methylpyrrole-Z- carbonyl chloride, -B.P. 7274, at 1.0 mm., is obtained.
  • the compound thus prepared is emulsified in the following composition:
  • the active drug is initially dissolved in the corn oil with the aid of gentle heat.
  • the oil is then mixed with the polyoxyethylene sorbitan monostearate and the sorbitan monooleate and warmed to 50 C.
  • the sucrose and paraben mixture is dissolved in water heated to 60 C; and the resulting water phase added to the oil phase with stirring.
  • the sorbitol solution is then added and the emulsion allowed to cool, after which the flavor is added. Q.s. and mix well.
  • butylated hydroxyanisole may be added to the corn oil as an antioxidant.
  • 1-cyclohexyl-2,5-dimethylpyrrole, M.P. 47- 48 is converted into 1-cyclohexyl-2,S-dimethylpyrrole- 3-y1 Z-furyl ketone;
  • 1-benzyl-2,5-dimethylpyrrole M.P. 48-49 is converted into l-benzyl-Z,5-dimethylpyrrol-3- yl 2-furyl ketone;
  • 1-allyl-2,S-dimethylpyrrole is converted into 1-allyl-2,5-dimethylpyrrol-3-yl 2-furyl ketone by related procedures.
  • anyhdrous benzene at 0 is added, with stirring, to a solution of 67.65 g. of isonicotinic acid and 56.1 g. of triethylamine in 100 ml. of anhydrous benzene.
  • the mixture is stirred at 0 for 20 minutes and then filtered.
  • the collected pyridine-4-carboxylic acid carbonic acid anhydride, ethyl ester is dissolved in 15 ml. of anhydrous benzene and reserved.
  • pyrazinoic acid produces 2,5-dimethylpyrrol-3-yl pyrazinyl ketone
  • 3-pyridinecarboxylic acid produces 2,5-dimethylpyrrol-3-yl 3-pyridyl ketone
  • pyrimidine-Z-carboxylic acid produces, 2,5- dimethylpyrrol-3-yl pyrimidin-Z-yl ketone.
  • EXAMPLE 14 3-(2-chlorophenyl)-5-methyl-4-isoxazolyl 2,5-dimethylpyrrol-3-yl ketone 28.5 g. of 2,5-dimethylpyrrole is added to a Grignard solution prepared from 8.5 g. of magnesium and 38.5 g. of ethyl bromide in 300 ml. of anhydrous ether. The mixture is stirred for 30 minutes after the addition is completed. 87 g. of 3 -(2 chlorophenyl) 5-methyl-4- isoxazole carbonyl chloride is added and the reaction mixture is stirred for two hours, then refluxed for 30 minutes. 50 ml. of 25% aqueous ammonium chloride is added to quench the reaction.
  • M.P. 130143 Upon concentration a total of 14.2 g. (83%) of solid, M.P. 130143, is obtained.
  • the product is decolorized on an alumina column, recrystallized from benzene twice and dried in vacuo to give yellow plates, M.P. 144145.
  • a method for relieving pain, reducing fever and alleviating inflammatory syndromes in a mammal which comprises administering to a mammal in need of such treatment an effective amount of a compound of the formula:
  • R represents hydrogen; lower alkyl, lower alkenyl or cycloalkyl, having not more than six carbon atoms; benzyl or phenyl;
  • R R and R individually represent hydrogen; lower alkyl, lower alkenyl, lower alkynyl or cycloalkyl, having not more than six carbon atoms; phenyl, phenyl lower alkyl in which the alkyl group has not more than four carbon atoms or halo; and
  • Het represents furyl, thienyl, or pyrrolyl.
  • R and R individually are hydrogen, halogen, lower alkyl of not more than six carbon atoms, or cycloalkyl of not more than six carbon atoms; and Het is a 2-furyl or 3- 4.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)
US639620A 1967-05-19 1967-05-19 Methods for reducing pain,reducing fever and alleviating inflammatory syndromes with heteroaromatic pyrrol-3-yl ketones Expired - Lifetime US3551571A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US63962067A 1967-05-19 1967-05-19

Publications (1)

Publication Number Publication Date
US3551571A true US3551571A (en) 1970-12-29

Family

ID=24564871

Family Applications (1)

Application Number Title Priority Date Filing Date
US639620A Expired - Lifetime US3551571A (en) 1967-05-19 1967-05-19 Methods for reducing pain,reducing fever and alleviating inflammatory syndromes with heteroaromatic pyrrol-3-yl ketones

Country Status (9)

Country Link
US (1) US3551571A (enrdf_load_stackoverflow)
AT (1) AT279602B (enrdf_load_stackoverflow)
CH (1) CH500188A (enrdf_load_stackoverflow)
DE (1) DE1770459A1 (enrdf_load_stackoverflow)
ES (1) ES354069A1 (enrdf_load_stackoverflow)
FR (1) FR8209M (enrdf_load_stackoverflow)
IL (1) IL29977A0 (enrdf_load_stackoverflow)
LU (1) LU56103A1 (enrdf_load_stackoverflow)
NL (1) NL6806962A (enrdf_load_stackoverflow)

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3966739A (en) * 1971-03-13 1976-06-29 Societa' Farmaceutici Italia S.P.A. Pyrrole-carboxylic acids lumilysergol esters
US4194003A (en) * 1977-10-10 1980-03-18 Albert Rolland S.A. New pyrrole derivatives, process for their preparation and therapeutic applications thereof
US4233309A (en) * 1977-12-06 1980-11-11 Teijin Limited Novel 1-substituted-3-acylpyrrole derivatives, platelet aggregation inhibitors containing them, as active ingredients, and processes for production of said derivatives
US4808601A (en) * 1984-09-19 1989-02-28 Pfizer Inc. Analgesic and antiinflammatory 1,3-diacyl-2-oxindole compounds
US4935440A (en) * 1986-11-25 1990-06-19 Syntex (U.S.A.) Inc. 3-[ω-(3,5-Di-t-butyl-4-hydroxyphenyl)alkyl]pyrroles, and anti-inflammatory uses thereof
US5015651A (en) * 1988-01-07 1991-05-14 E. I. Du Pont De Nemours And Company Treatment of hypertension with 1,2,4-angiotensin II antagonists
US5043349A (en) * 1988-01-07 1991-08-27 E. I. Du Pont De Nemours And Company Substituted pyrrole angiotensin II antagonists
US5081127A (en) * 1988-01-07 1992-01-14 E. I. Du Pont De Nemours And Company Substituted 1,2,3-triazole angiotensin II antagonists
US5093346A (en) * 1988-01-07 1992-03-03 E. I. Du Pont De Nemours And Company Substituted 1,2,4-triazole angiotensin II antagonists
US5189048A (en) * 1988-01-07 1993-02-23 E. I. Du Pont De Nemours And Company Substituted 1,2,3 triazole angiotensin II antagonists
US5288776A (en) * 1990-06-07 1994-02-22 Ciba-Geigy Corporation Substituted pyrroles as stabilisers for chlorinated polymers
US5315013A (en) * 1988-01-07 1994-05-24 E. I. Du Pont De Nemours And Company Substituted pyrazole angiotensin II antagonists
US6573293B2 (en) 2000-02-15 2003-06-03 Sugen, Inc. Pyrrole substituted 2-indolinone protein kinase inhibitors
US6642232B2 (en) 2001-10-10 2003-11-04 Sugen, Inc. 3-[4-Substituted heterocyclyl)-pyrrol-2-ylmethylidene]-2- indolinone derivatives as kinase inhibitors
US6653308B2 (en) 2001-02-15 2003-11-25 Sugen, Inc. 3-(4-amidopyrrol-2-ylmethylidene)-2-indolinone derivatives as protein kinase inhibitors
DE10261131A1 (de) * 2002-12-20 2004-07-01 Grünenthal GmbH Substituierte 5-Aminomethyl-1H-pyrrol-2-carbonsäureamide
USRE39420E1 (en) 1996-04-05 2006-12-05 Sankyo Company, Limited 1,2-Diphenylpyrrole derivatives, their preparation and their therapeutic uses
US20090036421A1 (en) * 2006-02-20 2009-02-05 Astellas Pharma Inc Pyrrole Derivative or Salt Thereof
US8247423B2 (en) 2007-07-12 2012-08-21 Tragara Pharmaceuticals, Inc. Methods and compositions for the treatment of cancer, tumors, and tumor-related disorders

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE792042A (fr) * 1971-11-30 1973-05-29 Ciba Geigy Procede de preparation de nouvelles alcenylene-amines substituees en 3

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3966739A (en) * 1971-03-13 1976-06-29 Societa' Farmaceutici Italia S.P.A. Pyrrole-carboxylic acids lumilysergol esters
US4194003A (en) * 1977-10-10 1980-03-18 Albert Rolland S.A. New pyrrole derivatives, process for their preparation and therapeutic applications thereof
US4233309A (en) * 1977-12-06 1980-11-11 Teijin Limited Novel 1-substituted-3-acylpyrrole derivatives, platelet aggregation inhibitors containing them, as active ingredients, and processes for production of said derivatives
US4808601A (en) * 1984-09-19 1989-02-28 Pfizer Inc. Analgesic and antiinflammatory 1,3-diacyl-2-oxindole compounds
US4935440A (en) * 1986-11-25 1990-06-19 Syntex (U.S.A.) Inc. 3-[ω-(3,5-Di-t-butyl-4-hydroxyphenyl)alkyl]pyrroles, and anti-inflammatory uses thereof
US5093346A (en) * 1988-01-07 1992-03-03 E. I. Du Pont De Nemours And Company Substituted 1,2,4-triazole angiotensin II antagonists
US5043349A (en) * 1988-01-07 1991-08-27 E. I. Du Pont De Nemours And Company Substituted pyrrole angiotensin II antagonists
US5081127A (en) * 1988-01-07 1992-01-14 E. I. Du Pont De Nemours And Company Substituted 1,2,3-triazole angiotensin II antagonists
US5189048A (en) * 1988-01-07 1993-02-23 E. I. Du Pont De Nemours And Company Substituted 1,2,3 triazole angiotensin II antagonists
US5315013A (en) * 1988-01-07 1994-05-24 E. I. Du Pont De Nemours And Company Substituted pyrazole angiotensin II antagonists
US5015651A (en) * 1988-01-07 1991-05-14 E. I. Du Pont De Nemours And Company Treatment of hypertension with 1,2,4-angiotensin II antagonists
US5288776A (en) * 1990-06-07 1994-02-22 Ciba-Geigy Corporation Substituted pyrroles as stabilisers for chlorinated polymers
USRE39420E1 (en) 1996-04-05 2006-12-05 Sankyo Company, Limited 1,2-Diphenylpyrrole derivatives, their preparation and their therapeutic uses
US7125905B2 (en) 2000-02-15 2006-10-24 Agouron Pharmaceuticals, Inc. Pyrrole substituted 2-indolinone protein kinase inhibitors
US6573293B2 (en) 2000-02-15 2003-06-03 Sugen, Inc. Pyrrole substituted 2-indolinone protein kinase inhibitors
US7572924B2 (en) 2000-02-15 2009-08-11 Sugen, Inc. Pyrrole substituted 2-indolinone protein kinase inhibitors
US20070010569A1 (en) * 2000-02-15 2007-01-11 Sugen, Inc. & Pharmacia & Upjohn Co. Pyrrole substituted 2-indolinone protein kinase inhibitors
US20050176802A1 (en) * 2000-02-15 2005-08-11 Sugen, Inc. & Pharmacia & Upjohn Co. Pyrrole substituted 2-indolinone protein kinase inhibitors
US6653308B2 (en) 2001-02-15 2003-11-25 Sugen, Inc. 3-(4-amidopyrrol-2-ylmethylidene)-2-indolinone derivatives as protein kinase inhibitors
US20070027149A1 (en) * 2001-02-15 2007-02-01 Sugen, Inc. 3-(4-amidopyrrol-2-ylmethylidene)-2-indolinone der derivatives as protein kinase inhibitors
US7179910B2 (en) 2001-02-15 2007-02-20 Agouron Pharmaceuticals, Inc. 3-(4-amidopyrrol-2-ylmethlidene)-2-indolinone derivatives as protein kinase inhibitors
US7256189B2 (en) 2001-02-15 2007-08-14 Sugen, Inc. 3-(4-amidopyrrol-2-ylmethylidene)-2-indolinone der derivatives as protein kinase inhibitors
US20080045709A1 (en) * 2001-02-15 2008-02-21 Sugen, Inc. 3-(4-amidopyrrol-2-ylmethylidene)-2-indolinone derivatives as protein kinase inhibitors
US7582756B2 (en) 2001-02-15 2009-09-01 Sugen, Inc. 3-(4-amidopyrrol-2-ylmethylidene)-2-indolinone derivatives as protein kinase inhibitors
US6642232B2 (en) 2001-10-10 2003-11-04 Sugen, Inc. 3-[4-Substituted heterocyclyl)-pyrrol-2-ylmethylidene]-2- indolinone derivatives as kinase inhibitors
US20050288342A1 (en) * 2002-12-20 2005-12-29 Gruenenthal Gmbh Substituted 5-aminomethyl-1H-pyrrole-2-carboxamides
DE10261131A1 (de) * 2002-12-20 2004-07-01 Grünenthal GmbH Substituierte 5-Aminomethyl-1H-pyrrol-2-carbonsäureamide
US7229991B2 (en) 2002-12-20 2007-06-12 Gruenenthal Gmbh Substituted 5-aminomethyl-1H-pyrrole-2-carboxamides
US20090036421A1 (en) * 2006-02-20 2009-02-05 Astellas Pharma Inc Pyrrole Derivative or Salt Thereof
US8222274B2 (en) * 2006-02-20 2012-07-17 Astellas Pharma Inc. Pyrrole derivative or salt thereof
US8247423B2 (en) 2007-07-12 2012-08-21 Tragara Pharmaceuticals, Inc. Methods and compositions for the treatment of cancer, tumors, and tumor-related disorders

Also Published As

Publication number Publication date
FR8209M (enrdf_load_stackoverflow) 1970-09-21
ES354069A1 (es) 1970-02-16
NL6806962A (enrdf_load_stackoverflow) 1968-11-20
DE1770459A1 (de) 1971-10-14
LU56103A1 (enrdf_load_stackoverflow) 1969-02-10
CH500188A (fr) 1970-12-15
IL29977A0 (en) 1968-07-25
AT279602B (de) 1970-03-10

Similar Documents

Publication Publication Date Title
US3551571A (en) Methods for reducing pain,reducing fever and alleviating inflammatory syndromes with heteroaromatic pyrrol-3-yl ketones
CA2291065C (en) Raf kinase inhibitors
EP0525197B1 (en) 3-benzylidene-1-carbamoyl-2-pyrrolidone analogs
DE602004011239T2 (de) Biaryloxymethylarenecarbonsäure
US20010006975A1 (en) Raf kinase inhibitors
US4267184A (en) Antiinflammatory 4,5-diaryl-2-(substituted-thio)pyrroles and their corresponding sulfoxides and sulfones
WO1999019303A1 (fr) Derives de pyrazole
KR20080012304A (ko) 피라졸 화합물 및 이들 피라졸 화합물을 포함하여이루어지는 당뇨병 치료약
US5302724A (en) Antitumor compositions and methods of treatment
EP0593761A1 (en) New thiophene derivatives
JP2005538183A (ja) 薬剤耐性細菌による感染症の治療方法
JPH06500557A (ja) ロイコトリエン生合成を阻害するインドール誘導体
CN110049978A (zh) 作为选择性hdac1,2抑制剂的哌嗪衍生物
AU2012221800A1 (en) Heteroaryl derivatives as alpha7 nAChR modulators
WO2000066562A1 (en) Pyrazoles having antiinflammatory activity
US20020032230A1 (en) Novel compounds having antiinflamatory activity: process for their preparation and pharmaceutical compositions containing them
DE2710902A1 (de) Cephemderivate und verfahren zu ihrer herstellung
AU2005311533A1 (en) Biaryloxymethylarene carboxylic acids
US3655693A (en) Anti-inflammatory salicyclic acid derivatives
AU2004218260A1 (en) N-aryl heteroaromatic products, compositions containing same and use thereof
US3997539A (en) 3-(4-Acylaminopiperazin-1-yl alkyl)indoles, precursors and processes for the preparation thereof
US4434175A (en) Nonsteroidal compounds as anti-inflammatory and analgesic agents
CA2004754A1 (en) Alpha-cyano-beta-oxopropionamides
US5041554A (en) Novel aryl-or heteroaryl-1-alkyl-pyrrole-2-carboxylic acid compounds useful in treating interleukin-1 mediated conditions
DE3786507T2 (de) Heterocyclische Propenamid-Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel.

Legal Events

Date Code Title Description
AS Assignment

Owner name: E.I. DU PONT DE NEMOURS AND COMPANY, 1007 MARKET S

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:ENDO LABORATORIES, INC., A CORP. OF DEL.;REEL/FRAME:004063/0107

Effective date: 19821110