WO1990004393A1 - Prodrugs of antiinflammatory 3-acyl-2-oxindole-1-carboxamides - Google Patents

Prodrugs of antiinflammatory 3-acyl-2-oxindole-1-carboxamides Download PDF

Info

Publication number
WO1990004393A1
WO1990004393A1 PCT/US1988/003658 US8803658W WO9004393A1 WO 1990004393 A1 WO1990004393 A1 WO 1990004393A1 US 8803658 W US8803658 W US 8803658W WO 9004393 A1 WO9004393 A1 WO 9004393A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
carbon atoms
calcd
yield
found
Prior art date
Application number
PCT/US1988/003658
Other languages
French (fr)
Inventor
Lawrence A. Reiter
Thomas C. Crawford
Original Assignee
Pfizer Inc.
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 Pfizer Inc. filed Critical Pfizer Inc.
Priority to HU886740A priority Critical patent/HU208421B/en
Priority to PCT/US1988/003658 priority patent/WO1990004393A1/en
Priority to SK5906-89A priority patent/SK590689A3/en
Priority to MX1802188A priority patent/MX18021A/en
Priority to RO147347A priority patent/RO109195B1/en
Priority to US07/675,883 priority patent/US5118703A/en
Priority to IS3509A priority patent/IS1598B/en
Priority to CA000614317A priority patent/CA1339558C/en
Priority to PH39329A priority patent/PH27554A/en
Priority to AT89310319T priority patent/ATE125794T1/en
Priority to IL9196089A priority patent/IL91960A/en
Priority to YU200589A priority patent/YU48070B/en
Priority to BG90022A priority patent/BG50834A3/en
Priority to APAP/P/1989/000141A priority patent/AP118A/en
Priority to MYPI89001415A priority patent/MY104238A/en
Priority to PT92000A priority patent/PT92000B/en
Priority to KR1019890014914A priority patent/KR910007237B1/en
Priority to CN89107943A priority patent/CN1022241C/en
Priority to OA59665A priority patent/OA09140A/en
Priority to AU42956/89A priority patent/AU606819B2/en
Priority to MA21909A priority patent/MA21657A1/en
Priority to PL89296831A priority patent/PL163112B1/en
Priority to IE333289A priority patent/IE66586B1/en
Priority to NZ231044A priority patent/NZ231044A/en
Priority to AR89315179A priority patent/AR246519A1/en
Priority to DD89333653A priority patent/DD285604A5/en
Priority to PL89281871A priority patent/PL162316B1/en
Priority to JP1270174A priority patent/JPH07597B2/en
Priority to DK514989A priority patent/DK514989A/en
Priority to EG49689A priority patent/EG19887A/en
Priority to CS895906A priority patent/CZ278983B6/en
Publication of WO1990004393A1 publication Critical patent/WO1990004393A1/en
Priority to NO911512A priority patent/NO178027C/en
Priority to SU914895525A priority patent/RU2036905C1/en
Priority to FI911855A priority patent/FI95253C/en

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom

Definitions

  • the present invention is concerned with anti- inflammatory agents and, in particular, with enol esters and ether prodrugs of 3-acyl-2-oxindole-l- carboxamides, a class of known nonsteroidal antiinflam- matory agents.
  • oxindoles as antiinflammatory agents was first reported in U.S. 3,634,453, and consisted of l-substituted-2-oxindole-3-carboxamides.
  • a series of 3-acyl-2-oxindole-l-carboxamides was dis ⁇ closed in U.S. 4,556,672 to be inhibitors of the cyclooxygenase (CO) and lipoxygenase (LO) enzymes and to be useful as analgesic and antiinflammatory agents in mammalian subjects.
  • CO cyclooxygenase
  • LO lipoxygenase
  • X and Y are each hydrogen, fluoro or chloro;
  • R is 2-thienyl or benzyl; and R is alkanoyl of two to ten carbon atoms, cycloalkylcarbonyl of five to seven carbon atoms, phenylalkanoyl of seven to ten carbon atoms, chlorobenzoyl, methoxybenzoyl, thenoyl, omega- alkoxycarbonylalkanoyl said alkoxy having one to three carbon atoms and said alkanoyl having three to five carbon atoms; alkoxy carbonyl of two to ten carbon atoms?
  • phenoxycarbonyl 1-(acyloxy)alkyl said acyl having one to four carbon atoms and said alkyl having two to four carbon atoms; 1-(alkoxycarbonyloxy)alkyl said alkoxy having two to five carbon atoms and said alkyl having one to four carbon atoms; alkyl of one to three carbon atoms; alkylsulfonyl of one to three carbon atoms; methylphenylsulfonyl or dialkylphos ⁇ phonate said alkyl each of one to three carbon atoms.
  • R is 2-thienyl
  • X is chloro
  • Y is hydrogen
  • R is alkanoyl of two to ten carbon atoms.
  • R is acetyl, propionyl and jl-butyryl.
  • a second preferred group of compounds of formula (I) are those where R is 2-thienyl, X is chloro, Y is hydrogen and R is phenylalkanoyl of seven to ten carbon atoms. Especially preferred within this group is the compound where R is phenylacetyl.
  • a third preferred group of compounds are those of formula (I) where R is 2-thienyl, X is chloro, Y is hydrogen and R is omega alkoxycarbonylalkanoyl, said alkoxy having one to three carbon atoms and said alkanoyl having three to five carbon atoms.
  • R is omega ethoxycarbonylpropionyl.
  • (I) are those where R is 2-thienyl, X is chloro, Y i hydrogen and R is alkoxycarbonyl of two to ten carbon ato s. Especially preferred within this group are compounds where R is methoxycarbonyl, ethoxycarbonyl and n-hexoxycarbonyl.
  • (I) are those where R is 2-thienyl, X is chloro, Y is hydrogen and R is 1- (alkoxycarbonyloxy) alkyl said alkoxy having two to five carbon atoms and said alkyl having one to four carbon atoms. Especially preferred within this group is the compound where R is 1- (ethoxy- carbonyloxy) ethyl.
  • a sixth group of preferred compounds of formula (I) are those where R is 2-thienyl, X is chloro, Y is hydrogen and R is alkylsulfonyl of one to three carbon atoms. Especially preferred within this group is the compound where R is methylsulfonyl.
  • a seventh group of preferred compounds of formula (I) are those where R ' is 2-thienyl, X is fluoro, Y is chloro and R is alkanoyl of two to ten carbon atoms. Especially preferred within this group are the com ⁇ pounds where R is acetyl, propionyl and _i-butyryl.
  • An eighth group of preferred compounds of formula (I) are those where R 1 is 2-thienyl, X is fluoro, Y is chloro and R is alkoxycarbonyl of two to ten carbon atoms. Especially preferred within this group are the compounds where R is methoxycarbonyl, ethoxycarbonyl and n-hexoxycarbonyl.
  • (I) are those where R is benzyl, X is hydrogen, Y is fluoro and R is alkanoyl having two to ten carbon atoms. Especially preferred within this group is the compound where R is acetyl.
  • the tenth group of preferred compounds of formula (I) are those where R is benzyl, X is hydrogen, Y is fluoro and R is alkoxycarbonyl of two to ten carbon atoms. Especially preferred with this group is the compound where R is methoxycarbonyl.
  • the present invention also comprises a method for treating inflammation in a mammal which comprises administering to said mammal an antiinflammatory effective amount of a compound selected from those of formula (I) .
  • the enol ethers and esters of the present invention are not enolic acids as the parent compounds are and show reduced gastric irritation when compared to said parent compounds.
  • prodrug refers to compounds which are drug precursors which, following administration and absorption, release the drug in vivo via some metabolic process. While all of the usual routes of administration are useful with the invention compounds, the preferred route of administration is oral. After gastro ⁇ intestinal absorption, the present compounds are hydrolyzed _in vivo, to the corresponding compounds of formula (I) where R is hydrogen, or a salt thereof. Since the prodrugs of the invention are not enolic acids, exposure of the gastrointestinal tract to the acidic parent compound is thereby minimized.
  • the first method comprises treating a solution of the appropriate 3-acyl-2-oxindole-l-carboxamide and an eguimolar amount of triethylamine in a reaction-inert solvent such as chloroform, at 0°C with an eguimolar amount, plus a slight excess of the requisite acid chloride, chloro- formate, oxonium salt or alkylating agent.
  • a reaction-inert solvent such as chloroform
  • the mixture is cooled to 0°C, additional acylating or alkylating agent is added and the process repeated until all the starting oxindole is consumed.
  • the product is isolated from the reaction solvent after it has been washed with IN hydrochloric acid followed by a saturated sodium bicarbonate solution extraction. The residual product, remaining after the solvent has been removed _in vacuo, is purified by recrystallization or chromatography.
  • the second procedure useful in the preparation of the products of the present invention, consists of contacting, in an anhydrous reaction-inert solvent such as acetone, the appropriate 3-acyl-2-oxindole-l- carboxamide a three-fold molar excess of the requisite alpha-chloroalkylcarbonate, a five fold molar excess of sodium iodide and a two fold molar excess of anhydrous potassium carbonate and heating said reaction mixture at reflux for 16 hours.
  • the reaction mixture is diluted with water and the product extracted with a water-immiscible solvent, such as diethyl ether or chloroform. Concentration of the solvent containing the product provides the crude material, which can be purified by recrystallization and/or chromatography.
  • 3-acyl-2-oxindole-l-carboxamides required as starting materials are available by methods well known in the art, see, for example, the reference to these compounds cited above.
  • the other starting reagents noted above are available commercially, or are prepared by well known methods.
  • the prodrugs of formula (I) are evaluated for their antiinflammatory and analgesic activity according to known methods such as the rat foot edema test, rat adjuvant-induced arthritis test or phenylbenzoquinone- induced writhing test in mice, as previously used in the evaluation of the parent compounds and described in the references cited above and elsewhere in the litera- ture; see e.g., C. A. Winter, in "Progress in Drug Research” edited by E. Jucker, Birkhauser Verlag, Basel, Vol. 10, 1966, pp. 139-192.
  • novel prodrugs of formula (I) are found to have reduced ability to inhibit prostaglandin synthesis from arachidonic acid in tests carried out by a modification of the method of T. J. Carty ejt al. , Prostaglandins, 19, 51-59 (1980) .
  • cultures of rat basophilic leukemic cells (RBL-1) prepared by the method of Jakschik e_t al. , ibid. , 16, 733 (1978), are employed in place of mouse fibroblast (MC5-5) and rabbit synovial cell cultures.
  • the invention compounds themselves are relatively inactive as antiinflammatory agents, but they give rise to an active antiinflammatory compound upon hydrolysis in vivo. Since the compounds (I) are not enolic acids and it is known that the hydrolysis takes place after the prodrug leaves the stomach, they will significantly reduce the gastric irritation caused by oral adminis- tration of the parent enolic compounds.
  • the present prodrugs are generally dosed at the same level and frequency as the known 3-acyl-2-oxindole-l-carboxamides from which they are derived.
  • the non-enolic nature of the present compounds will generally permit higher tolerated oral doses, when such higher dosage is required in the control of pain and inflammation.
  • the present prodrugs are also formulated in the same manner, and administered by the same routes as the known parent compounds, as described in the above cited reference.
  • the preferred route of administration is oral, thus taking particular advantage of the non- enolic nature of the present compounds.
  • EXAMPLE 1 General Procedures Method A To a slurry of a 3-acyl-2-oxindole-l-carboxamide in chloroform is added an eguimolar amount of triethyl- amine. The resulting solution is cooled to 0°C and a slight excess of the appropriate acid chloride, chloroformate, oxonium salt or alkylating agent added. After stirring for 2 hours at 0°C and then at room temperature for 2 hours, if the 3-acyloxindole-l- carboxamide has not been consumed, then the mixture is again cooled to 0°C and additional acid chloride chloroformate or oxonium salt is added and the mixture stirred at 0°C for 2 hours and then at room temperature for 2 hours.

Abstract

Certain enol ethers and esters of formula (I), where X and Y are each hydrogen, fluoro or chloro; R1 is 2-thienyl or benzyl and R is alkanoyl, cycloalkylcarbonyl, phenylalkanoyl, chlorobenzoyl, methoxybenzyl, phenyl, thenoyl, omega-alkoxycarbonylalkanoyl, alkoxycarbonyl, phenoxycarbonyl, 1-alkoxyalkyl, 1-alkoxy-carbonyloxyalkyl, alkyl, alkylsulfonyl, methylphenyl-sulfonyl or dialkylphosphonate are useful as prodrug forms the known 3-acyl-2-oxindole-1-carboxamide antiinflammatory and analgesic agents.

Description

PRODRUGS OP ANTIINFLAMMATORY 3-ACYL-2- OXINDOLE-1-CARBOXAMIDES
Background of the Invention The present invention is concerned with anti- inflammatory agents and, in particular, with enol esters and ether prodrugs of 3-acyl-2-oxindole-l- carboxamides, a class of known nonsteroidal antiinflam- matory agents. The use of oxindoles as antiinflammatory agents was first reported in U.S. 3,634,453, and consisted of l-substituted-2-oxindole-3-carboxamides. Recently, a series of 3-acyl-2-oxindole-l-carboxamides was dis¬ closed in U.S. 4,556,672 to be inhibitors of the cyclooxygenase (CO) and lipoxygenase (LO) enzymes and to be useful as analgesic and antiinflammatory agents in mammalian subjects.
Summary of the Invention The present invention provides antiinflammatory ether and ester prodrugs of the formula
Figure imgf000003_0001
wherein X and Y are each hydrogen, fluoro or chloro; R is 2-thienyl or benzyl; and R is alkanoyl of two to ten carbon atoms, cycloalkylcarbonyl of five to seven carbon atoms, phenylalkanoyl of seven to ten carbon atoms, chlorobenzoyl, methoxybenzoyl, thenoyl, omega- alkoxycarbonylalkanoyl said alkoxy having one to three carbon atoms and said alkanoyl having three to five carbon atoms; alkoxy carbonyl of two to ten carbon atoms? phenoxycarbonyl; 1-(acyloxy)alkyl said acyl having one to four carbon atoms and said alkyl having two to four carbon atoms; 1-(alkoxycarbonyloxy)alkyl said alkoxy having two to five carbon atoms and said alkyl having one to four carbon atoms; alkyl of one to three carbon atoms; alkylsulfonyl of one to three carbon atoms; methylphenylsulfonyl or dialkylphos¬ phonate said alkyl each of one to three carbon atoms.
Particularly preferred are compound of formula (I) where R is 2-thienyl, X is chloro, Y is hydrogen and R is alkanoyl of two to ten carbon atoms. Preferred within this group are compounds where R is acetyl, propionyl and jl-butyryl.
A second preferred group of compounds of formula (I) are those where R is 2-thienyl, X is chloro, Y is hydrogen and R is phenylalkanoyl of seven to ten carbon atoms. Especially preferred within this group is the compound where R is phenylacetyl.
A third preferred group of compounds are those of formula (I) where R is 2-thienyl, X is chloro, Y is hydrogen and R is omega alkoxycarbonylalkanoyl, said alkoxy having one to three carbon atoms and said alkanoyl having three to five carbon atoms. Especially preferred within this group is the compound where R is omega ethoxycarbonylpropionyl.
A fourth group of preferred compounds of formula
(I) are those where R is 2-thienyl, X is chloro, Y i hydrogen and R is alkoxycarbonyl of two to ten carbon ato s. Especially preferred within this group are compounds where R is methoxycarbonyl, ethoxycarbonyl and n-hexoxycarbonyl. A fifth group of preferred compounds of formula
(I) are those where R is 2-thienyl, X is chloro, Y is hydrogen and R is 1- (alkoxycarbonyloxy) alkyl said alkoxy having two to five carbon atoms and said alkyl having one to four carbon atoms. Especially preferred within this group is the compound where R is 1- (ethoxy- carbonyloxy) ethyl.
A sixth group of preferred compounds of formula (I) are those where R is 2-thienyl, X is chloro, Y is hydrogen and R is alkylsulfonyl of one to three carbon atoms. Especially preferred within this group is the compound where R is methylsulfonyl.
A seventh group of preferred compounds of formula (I) are those where R' is 2-thienyl, X is fluoro, Y is chloro and R is alkanoyl of two to ten carbon atoms. Especially preferred within this group are the com¬ pounds where R is acetyl, propionyl and _i-butyryl.
An eighth group of preferred compounds of formula (I) are those where R 1 is 2-thienyl, X is fluoro, Y is chloro and R is alkoxycarbonyl of two to ten carbon atoms. Especially preferred within this group are the compounds where R is methoxycarbonyl, ethoxycarbonyl and n-hexoxycarbonyl.
The ninth group of preferred compounds of formula
(I) are those where R is benzyl, X is hydrogen, Y is fluoro and R is alkanoyl having two to ten carbon atoms. Especially preferred within this group is the compound where R is acetyl. The tenth group of preferred compounds of formula (I) are those where R is benzyl, X is hydrogen, Y is fluoro and R is alkoxycarbonyl of two to ten carbon atoms. Especially preferred with this group is the compound where R is methoxycarbonyl.
The present invention also comprises a method for treating inflammation in a mammal which comprises administering to said mammal an antiinflammatory effective amount of a compound selected from those of formula (I) .
The enol ethers and esters of the present invention are not enolic acids as the parent compounds are and show reduced gastric irritation when compared to said parent compounds.
The term "prodrug" refers to compounds which are drug precursors which, following administration and absorption, release the drug in vivo via some metabolic process. While all of the usual routes of administration are useful with the invention compounds, the preferred route of administration is oral. After gastro¬ intestinal absorption, the present compounds are hydrolyzed _in vivo, to the corresponding compounds of formula (I) where R is hydrogen, or a salt thereof. Since the prodrugs of the invention are not enolic acids, exposure of the gastrointestinal tract to the acidic parent compound is thereby minimized. Further, since gastrointestinal complications have been noted as a major adverse reaction of acid non-steroidal anti- inflammatory drugs [see e.g., DelFavero in "Side Effects of Drugs Annual 7", Dukes and Elis, Eds. Excerpta Medica, Amsterdam, 1983, p. 104-115], the invention compounds (I) have a distinct advantage over the parent enolic compounds.
In converting the 3-acyl-2-oxindole-l-carboxamideε to the compounds of formula I, the substituents on the exocyclic double bond at the 3-position can be syn, anti or a mixture of both. Thus the compounds of the structures
Figure imgf000007_0001
or mixtures thereof are depicted as
Figure imgf000007_0002
All forms of these isomers are considered part of the present invention.
Detailed Description of the Invention There are two methods employed in the synthesis of the compounds of the present invention; the first method comprises treating a solution of the appropriate 3-acyl-2-oxindole-l-carboxamide and an eguimolar amount of triethylamine in a reaction-inert solvent such as chloroform, at 0°C with an eguimolar amount, plus a slight excess of the requisite acid chloride, chloro- formate, oxonium salt or alkylating agent. The reaction is allowed to warm to room temperature and remain for about 2-3 hours. If the starting oxindole is not completely reacted the mixture is cooled to 0°C, additional acylating or alkylating agent is added and the process repeated until all the starting oxindole is consumed. The product is isolated from the reaction solvent after it has been washed with IN hydrochloric acid followed by a saturated sodium bicarbonate solution extraction. The residual product, remaining after the solvent has been removed _in vacuo, is purified by recrystallization or chromatography.
The second procedure, useful in the preparation of the products of the present invention, consists of contacting, in an anhydrous reaction-inert solvent such as acetone, the appropriate 3-acyl-2-oxindole-l- carboxamide a three-fold molar excess of the requisite alpha-chloroalkylcarbonate, a five fold molar excess of sodium iodide and a two fold molar excess of anhydrous potassium carbonate and heating said reaction mixture at reflux for 16 hours. The reaction mixture is diluted with water and the product extracted with a water-immiscible solvent, such as diethyl ether or chloroform. Concentration of the solvent containing the product provides the crude material, which can be purified by recrystallization and/or chromatography. The 3-acyl-2-oxindole-l-carboxamides required as starting materials are available by methods well known in the art, see, for example, the reference to these compounds cited above. The other starting reagents noted above are available commercially, or are prepared by well known methods.
The prodrugs of formula (I) are evaluated for their antiinflammatory and analgesic activity according to known methods such as the rat foot edema test, rat adjuvant-induced arthritis test or phenylbenzoquinone- induced writhing test in mice, as previously used in the evaluation of the parent compounds and described in the references cited above and elsewhere in the litera- ture; see e.g., C. A. Winter, in "Progress in Drug Research" edited by E. Jucker, Birkhauser Verlag, Basel, Vol. 10, 1966, pp. 139-192.
In comparison with the parent 3-acyl-2-oxindole-l- carboxamides the novel prodrugs of formula (I) are found to have reduced ability to inhibit prostaglandin synthesis from arachidonic acid in tests carried out by a modification of the method of T. J. Carty ejt al. , Prostaglandins, 19, 51-59 (1980) . In the modified procedure cultures of rat basophilic leukemic cells (RBL-1) , prepared by the method of Jakschik e_t al. , ibid. , 16, 733 (1978), are employed in place of mouse fibroblast (MC5-5) and rabbit synovial cell cultures. Thus, the invention compounds themselves are relatively inactive as antiinflammatory agents, but they give rise to an active antiinflammatory compound upon hydrolysis in vivo. Since the compounds (I) are not enolic acids and it is known that the hydrolysis takes place after the prodrug leaves the stomach, they will significantly reduce the gastric irritation caused by oral adminis- tration of the parent enolic compounds.
On a molar basis, the present prodrugs are generally dosed at the same level and frequency as the known 3-acyl-2-oxindole-l-carboxamides from which they are derived. However, the non-enolic nature of the present compounds will generally permit higher tolerated oral doses, when such higher dosage is required in the control of pain and inflammation.
The present prodrugs are also formulated in the same manner, and administered by the same routes as the known parent compounds, as described in the above cited reference. The preferred route of administration is oral, thus taking particular advantage of the non- enolic nature of the present compounds.
The present invention is illustrated by the following examples, but is not limited to the specific details of these examples.
EXAMPLE 1 General Procedures Method A To a slurry of a 3-acyl-2-oxindole-l-carboxamide in chloroform is added an eguimolar amount of triethyl- amine. The resulting solution is cooled to 0°C and a slight excess of the appropriate acid chloride, chloroformate, oxonium salt or alkylating agent added. After stirring for 2 hours at 0°C and then at room temperature for 2 hours, if the 3-acyloxindole-l- carboxamide has not been consumed, then the mixture is again cooled to 0°C and additional acid chloride chloroformate or oxonium salt is added and the mixture stirred at 0°C for 2 hours and then at room temperature for 2 hours. This process may be repeated in order to ensure complete consumption of the 3-acyloxindole-l- carboxamide. Upon completion of the reaction, the mixture is filtered and the filtrate washed with IN hydrochloric acid (2X) and saturated sodium bicarbonate solution (2X) . The organic layer is dried with MgSO. , filtered and concentrated _in vacuo. The resulting product is purified by recrystallization or chroma¬ tography. Method B
A mixture of 3-acyl-2-oxindole-l-carboxamide, a 3-fold molar excess of the appropriate alpha- chloroalkyl- or alpha-chloro (aralkyl) carbonate, a 5-fold molar excess of sodium iodide, and a 2-fold molar excess of anhydrous potassium carbonate (dried under high vacuum at 165°C for 1 hour) in acetone (dried over molecular sieves) is refluxed for 16 hours. The cooled mixture is then diluted with water and extracted with ether. The combined ether extracts are dried with MgSO., filtered, and the filtrate concen¬ trated jLn vacuo. The resulting crude product is purified by chromatography and/or recrystallization.
EXAMPLE 2 Following the indicated procedure, and starting with the requisite reagents the indicated prodrugs were prepared:
Figure imgf000012_0001
Esters;
(R = -COCH-) - Method A; yield 53% after recrys¬ tallization from 2-propanol; mp 173-176°C; mass spectrum m/e (relative intensity) M , 362 (<1.0), 322 (4.2) , 320 (11.0), 296 (1.8), 279 (18.2), 277 (44.4) , 248 (10.6), 195 (77.7), 193 (100), 185 (12.3), 165 (13.4), 137 (42.8), 111 (88.2), 102 (20.0), 83 (23.9); 1H-NMR (CDC13) delta 2.39, 2.53 (3H, 2s), 5.31 (IH, br s) , 7.2-7.35 (2E, m) , 7.48, 7.55 (IH, 2d, J=2.lHz), 7.6-8.3 (3H, m) , 8.54 (IH, br s) . Anal, calcd for
C16H11C1N2°4S (362-79); c' 52.97; H, 3.06; N, 7.72. Found: C, 52.91; H, 2.95; N, 7.97. (R = -COCH2CH3) - Method A; yield 18% after recrystallization from 2-propanol; mp 183-185°C; mass spectrum m/e (relative intensity) M , 378, 376 (<1, g 1.2), 333 (0.7), 322 (6.4), 320 (18.4), 279 (17.8), 277 (44.3) , 250 (2.3), 248 (9.0), 195 (27.0), 193 (100), 137 (7.8), 111 (24.1), 57 (30.0); 1H-NMR (dg-Me^O) delta 1.0-1.3 (3H, m) , 2.7-3.0 (2H, q, J=7.5Hz) , 6.9-7.6 (3H, m) , 7.9-8.4 (5H, m) . Anal, calcd for C17H13C1N204S (376.68) : C, 54.18; H, 3.48; N, 7.43. Found: C, 53.86; H, 3.33; N, 7.28.
(R = -CO(CH2)5CH3) - Method A; yield 29% after recrystallization from 2-propanol; mp 189-190°C; mass
4. spectrum m/e (relative intensity) M , 432 (0.8), 322 (13.8), 320 (37.5), 279 (34.8), 277 (87.0), 250 (5.0), 248 (17.3) , 195 (26.6), 193 (100); 1H-NMR (CDC1-.) delta 0.95 (3H, m) , 1.32-1.55 (6H, ) , 1.85 (2H, pentet, J=8Hz) , 2.83 (2H, t, J=8Hz) , 5.35 (IH, br s) , 7.25 (IH, m) , 7.32 (IH, m) , 7.60 (IH, d) , 7.72 (IH, m) , 8.27 (IH, m) , 8.31 (IH, d, J=10Hz) , 8.62 (IH, br s) . Anal, calcd for C22H21C1 204S (432.91) : C, 58.26; H, 4.89; N, 6.47. Found: C, 58.18; H, 4.87; N, 6.42.
(R = -C0(CH2) gCH3) - Method A; yield 8% after recrystallization from 2-propanol; mp 120-122°C; mass spectrum m/e (relative intensity) M , 431 (< 1) , 322 (2.9) , 320 (8.6) , 279 (16.8) , 277 (42.6) , 262 (0.9) , 260 (2.1), 250 (2.4), 248 (9.0) , 195 (26.4), 193 (100), 155 (7.4) , 137 (6.3) , 111 (18.2); -"-H-NMR (dg- e^O) delta 0.87 (3H, s) , 1.30 (13H, br s) , 1.50 (IH, ) , 1.65 (IH, m) , 2.20 (IH, t, J=7.2Hz), 2.70 (IH, t, J=7.3Hz), 7.1-8.5 (7H, m) . Anal, calcd for C24H27C1N2°4S (474-75) : c' 60.68; H, 5.73; N, 5.90. Found: C, 60.64; H, 5.76; N, 5.88.
(R = -COCH(CH3)2) - Method A; yield 37% after recrystallization from 2-propanol; mp 189-191°C; mass spectrum m/e (relative intensity) M , 392, 390 (1.2, 3.5), 322, 320 (11.7, 30.2), 279, 277 (19.2, 48.7), 250, 248 { . t 15.5) , 195, 193 (28.7, 100); 1H-NMR (CDC13) delta 1.35 (3H, d, J=8Hz, isomer A) , 1.45 (3H, d, J=8Hz, isomer B) , 2.93 (IH, septet, J=8Hz, isomer A), 3.05 (IH, septet, J=8Hz, isomer B) , 5.38 (IH, br s, isomer A), 5.45 (IH, .br s, isomer B) , 7.2-7.4 (2H, m) , 7.54 (IH, d) , 7.7-7.8 (2H, m) , 8.2-8.3 (IH, m) , 8.48 (IH, br s, isomer B) , 8.55 (IH, br s, isomer A) (note: isomer ratio of A to B is approximately 80:20) . Exact mass calcd for C.gH-jςClN-O.S: 390.0449. Found: 390.0462.
(R = -COC(CH3)3) - Method A; yield 51% after recrystallization from 2-propanol; mp 198-200°C; mass spectrum m/e (relative intensity) M , 404 (0.3), 320 (2.4), 277 (22.0) , 259 (1.1), 248 (8.3), 193 (66.6) , 137 (6.6), 111 (19.1), 102 (2.4), 85 (21.1) , 57 (100); 1H-NMR (CDC13) delta 1.39 (9H, s) , 5.47 (IH, br s) , 7.23 (2H, m) , 7.50 (IH, d, J=2.2Hz), 7.71 (IH, dd, J=l.l, 5.0Hz), 7.77 (IH, dd, J=l.l, 3.8Hz), 8.25 (IH, d, J=8.8Hz), 8.57 (IH, br s) . Anal, calcd for C. C1K O S (404.85) : C, 56.36; H, 4.23; N, 6.92. Found: C, 56.05; H, 4.23; N, 6.86.
(R = -CO(cyclohexyl) ) - Method A; yield 10% after recrystallization from 2-propanol; mp 189-190°C; mass spectrum m/e (relative intensity) M , 430 (0.7), 381 (<1), 322 (2.3) , 320 (6.5), 279 (8.0), 277 (19.8) -" 195 (16.3) , 193 (60.0) , 111 (67.1) , 83 (100) , 55 (25.8); 1H-NMR (d6-Me2SO) delta 1.05-1.70 (11H, set of m) , 6.95-7.10 (IH, ) , 7.18 (IH, t, J=4.4Hz) , 7.31 (IH, dd, J=2.2, 8.8Hz), 7.4 (IH, m) , 7.70-8.15 (4H, set of m) . Anal, calcd for C21HιgCl 204S (429.72): C, 58.53; H, 4.44; N, 6.50. Found: C, 58.34; H, 4.32; N, 6.43.
(R = -COPh) - Method A; yield 44% after recrystal¬ lization from acetic acid; mp 228-230°C; mass spectrum m/e (relative intensity) M+, 424 (3.0), 381 (1.9), 277 (3.9), 260 (6.9) , 248 (10.2) , 232 (0.9) , 212 (2.3) , 185 (4.7), 168 (24.1), 140 (6.5), 105 (100) , 77 (27.1); 1H-NMR (CDC13) delta 5.55 (IH, br s) , 7.30 (3H, m) , 7.55 (3H, m) , 7.65 (IH, m) , 7.74 (IH, dd, J=1.0, 5.0Hz), 7.84 (IH, dd, J=l.0, 3.8Hz), 8.2-8.3 (3H, m) , 8.45 (IH, br s) . Anal, calcd for C2-,H13C1 20.S«H20 (442.87) : C, 56.95; H, 3.41; N, 6.32. Found: C, 57.24; H, 3.08; N, 6.09.
(R = -COCH-.Ph) - Method A; yield 3% after filtra- tion through silica gel (10:90 - methanol/chloroform) and two recrystallizations from 2-propanol; mp 207-208°C; mass spectrum m/e (relative intensity) M , 438 (< 1) , 395 (< 1), 322 (9.6), 320 (26.4) , 279 (17.1) , 277 (43.1) , 195 (14.6), 193 (54.3) , 91 (100); 1H-NMR (CDCl3/dg-Me2SO) delta 3.96 (2H, s) , 6.20 (IH, br s) , 7.02 (IH, dd, J=4.0, 5.1Hz), 7.15 (IH, dd,
J=2.2, 8.8Hz), 7.3-7.4 (6H, m) , 7.57 (IH, dd, J=1.2,
5.1Hz), 7.90 (IH, dd, J=1.2, 4.0Hz), 8.15 (IH, d,
J=8.8Hz), 8.30 (IH, br s) . Anal, calcd for (438.87) : C, 60.20; H, 3.45; N, 6.38.
Figure imgf000015_0001
Found: C, 60.53; H, 3.38; N, 6.18. (R = -CO(CH2)3Ph) - Method A; yield 13% after recrystallization from 2-propanol; mp 168-171°C; mass spectrum m/e (relative intensity) M , not observed, 423 (<1), 322 (1.0), 320 (2.9), 279 (10.2), 277 (25.7),
250 (1.5), 248 (5.6), 195 (26.7), 193 (100), 158 (0.7),
147 (72.1), 91 (99.5); 1H-NMR (do--Me SO) delta
1.75-2.05 (2H, m) , 2.22 (IH, t, J=7.4Hz), 2.55-3.00 (3H, ) , 6.90-7.65 (9H, m) , 7.85-8.50 (4H, m) . Anal. calcd for C24H19C1N204S (466.75) : C, 61.73; H, 4.10; N, 5.99. Found: C, 61.74; H, 4.02; N, 5.89.
(R = -CO(3-Cl-Ph) - Method A; yield 26% after recrystallization from 2-propanol/dimethylformamide; mp 210-218°C; mass spectrum m/e (relative intensity) M , 460, 458 (0.5, 0.6), 279 (1.5), 277 (3.9), 250 (0.9),
248 (2.8), 195 (1.3), 193 (4.6), 141 (43.0), 139 (100), 113 (8.8), 111 (32.8); ■'n- MR (CDC1-.) delta 5.28 (IH, br s) , 7.25 (2H, m) , 7.51 (2H, ) , 7.62 (IH, m) , 7.74 (IH, dd, J=l.l, 5.0Hz), 7.84 (IH, dd, J=l.l, 3.8Hz), 8.07 (IH, m) , 8.16 (IH, m) , 8.27 (IH, d, J=8.8Hz), 8.41 (IH, br s) . Anal, calcd for C21H12C12N204S (459.29): C, 54.91; H, 2.63; N, 6.10. Found: C, 54.85; H, 2.59; N, 6.04.
(R = -CO(4-MeO-Ph) - Method A; yield 11% after filtration through silica gel (5:95 - methanol/ chloroform) and recrystallization from 2-propanol; mp 198-199°C; mass spectrum m/e (relative intensity) M , 454 (0.3) , 411 (0.3), 279 (0.3) , 277 (0.6) , 250 (1.3), 248 (4.2) , 195 (1.1), 193 (4.0) , 135 (100); 1H-NMR (CDC13) delta 4.05, 4.10 (3H, 2s), 5.35, 5.46 (IH, 2 br s) , 7.15 (2H, m) , 7.40 (3H, m) 7.68 (IH, d, J=2.lHz), 7.86 (IH, dd, J=l.l, 5.0Hz), 7.97 (IH, dd, J=l.l, 3.8Hz), 8.29 (IH, m) , 8.41 (IH, m) , 8.60, 8.77 (IH, 2 br s) . Anal, calcd for C22H15C1N205S (454.87) : C, 58.09; H, 3.32; N, 6.16. Found: C, 57.99; H, 3.22; N, g 6.07.
(R = -CO (2-thienyl) ) - Method A; yield 16% after being twice flash chromatographed (1st: chloroform; 2nd: 0.5:99.5 - ethanol/chloroform) ; mp 220-222°C; mass spectrum m/e (relative intensity) M , 432, 430 (0.4, 1.1) , 389 (0.4) , 387 (0.7), 279 (0.6), 277 (1.7) , 113 (5.1) , 111 (100); 1H-NMR (dg-Me-jSO) delta 7.3-7.5 (4H, m) , 7.8-8.4 (7H, m) . Exact mass calcd for
C19H11C1N2°4S2:429'9849* Found: 429.9825.
(R = -COCH2CH2C02Et) - Method A; yield 72% after recrystallization from 2-propanol; mp 132-140°C; mass spectrum m/e (relative intensity) M , 448 (< 1) , 405 (<1) , 360 (<1) , 305 (1.3) , 303 (3.7), 279 (2.4), 277 (6.4), 195 (8.9), 193 (32.9), 129 (100), 111 (12.6), 101 (74.3); 1H-NMR ( g-Me2S0) delta 1.15 (3H, ) , 2.5 (2H, m) , 2.55-3.2 (2H, complex set of m) , 4.05 (2H, m) , 6.90-7.45 (3H, complex set of ) , 7.70 (IH, ) , 7.85-8.45 (4H, complex set of m) . Anal, calcd for C20H17Cl -,O6 (448.87) : C, 53.51; H, 3.82; N, 6.24.
Found: C, 53.49; H, 3.70; N, 6.23.
Carbonates:
(R = -C00CH3) - Method A; yield 29% after recrys¬ tallization from 2-propanol/chloroform; mp 180°C g softens, melts 200°C; mass spectrum m/e (relative intensity) M+, 380, 378 (8.5, 23.8), 337 (7.2) , 335 (21.2), 293 (17.3), 291 (39.8), 250 (28.3), 248 (100), 195 (24.9), 193 (86.2), 111 (88.6); 1H-N R (dg-Me^O) delta 3.90, 3.95 (3H, 2s), 7.3-7.5 (3H, m) , 7.95-8.05 (2H, m) , 8.15-8.25 (3H, ) . Anal, calcd for
C16H11C1N2°5S f378-22) : c' 50.73; H, 2.93; N, 7.39. Found: C, 50.84; H, 2.93; N, 7.34.
(R = -C00CH2CH3) - Method A; yield 24% after recrystallization from 2-propanol; mp 170-175°C; mass 5 spectrum m/e (relative intensity) M , 392 (<1.0), 320 (1.2) , 305 (3.9), 277 (22.5), 259 (2.6), 248 (17.0), 193 (100), 185 (7.2) , 165 (4.0), 111 (18.8); 1H-NMR (CDC13) delta 1.42 (3H, t, J=7.1Hz), 4.39 (2H, q, J=7.lHz), 5.41 (IH, br s) , 7.25 (2H, m) , 7.48, 7.66 0 (IH, 2d, J=2.1 and 2.2Hz) 7.75 (IH, m) , 8.25 (2H, m) , 8.57 (IH, br s) . Anal, calcd for C17H13C1N205S (392.79) : C, 51.98; H, 3.34; N, 7.13. Found: C, 51.90; H, 3.26; N, 6.93.
(R = -C00CH(CH3)2) - Method A; yield 37% after 5 recrystallization from 2-propanol; mp 185-186°C; mass spectrum m/e (relative intensity) M , 322, 320 (1.8, 6.5), 303 (1.6), 279 (15.2), 277 (41.3) , 250 (2.2) , 248 (8.5), 193 (100), 167 (1.7), 165 (2.6), 139 (1.3), 137 (4.3), 111 (12.4) , 102 (8.0); 1H-NMR (dg-Me2S0) delta 0 1.34, 1.37 (6H, 2s) , 5.00 (IH, heptet, J=6.2Hz) , 7.35
(IH, t, J=4.3Hz), 7.50 (IH, dd, J=8.7Hz), 7.55 (IH, m) , 7.96, 8.05 (2H, 2 br s) , 8.17 (2H, m) , 8.25 (IH, m) . Anal. calcd for C^H^CIN^S (406.69) : C, 53.14; H,
3.72; N, 6.89. Found: C, 52.93; H, 3.65; N, 6.82.
(R = -C00(CH2)5CH3) - Method A; yield 39% after g recrystallization from 2-propanol; mp 110-144°C; mass spectrum m/e (relative intensity) M , 448 (0.3) , 405
(<1), 322 (1.7), 320 (4.5), 279 (15.9) , 277 (39.9) ,
195 (29.8) , 193 (100) , 111 (14.8); 1H-NMR (dg-Me2SO) delta 0.85 (3H, br t, J=6.6Hz), 1.3 (6H, m) , 1.6 (2H, m) , 4.35 (2H, t, J=6.2Hz), 7.35 (IH, t, J=4.3),
7.4-7.55 (2H, m) , 7.95-8.05 (2H, ) , 8.15-8.25 (3H, m) .
Anal, calcd for C^H^CI ^S (448.91) : C, 56.18; H,
4.72; N, 6.24. Found: C, 56.11; H, 4.60; N, 6.16.
(R = -C00(CH2)gCH3) - Method A; yield 21% after recrystallization from 2-propanol; mp 118-120°C; mass
4. spectrum m/e (relative intensity) M , 490 (0.6), 368
(0.5), 322 (4.9) , 320 (2.2), 279 (32.6) , 277 (79.3),
250 (4.9), 248 (16.1), 195 (28.5), 193 (100); 1H-NMR
(CDC13) delta 0.89 (3H, m) , 1.2-1.5 (12H, m) , 1.76 (2H, m) , 4.34 (2H, t, J=6.6Hz), 5.33 (IH, br s) , 7.24 (IH, m) , 7.32 (IH, dd, J=2.2, 8.8Hz), 7.68 (IH, d, J=2.1Hz) ,
7.74 (IH, dd, J=1.2, 5.1Hz), 8.20 (IH, dd, J=l.2,
4.0Hz), 8.29 (IH, d, J=8.8Hz) , 8.58 (IH, br s) . Anal. calcd for C __!4.H Δ„Δ„C1N_„_,03--S (490.99) : C, 58.71; H, 5.54; N, 5.71. Found: C, 58.87; H, 5.48; N, 5.64.
(R = -COOPh) - Method A; yield 8% after recrystal¬ lization from 2-propanol; mp 212-214°C; mass spectrum m/e (relative intensity) M+, 442, 440 (1.7, 5.7), 399 (4.4), 397 (9.7), 355 (<1), 354 (<1), 353 (2.9), 352 (1.7), 338 (< 1), 336 (2.5), 250 (13.4) , 248 (44.3), 234 (9.7) , 232 (24.0) , 195 (8.1) , 193 (27.7) , 111 (100); 1H-NMR (CDC1-.) delta 5.90 (IH, br s) , 7.1-7.4 (7H, m) , 7.74 (2H, m) , 8.22 (2H, m) , 8.39 (IH, br s) . Anal, calcd for C21H13C1 205S (440.84) : C, 57.21; H, 2.97; N, 6.36. Found: C, 56.99; H, 2.98; N, 6.38. Acetal-esters:
(R = -CH(CH3)0C0CH3) - Method A with the exceptions that silver nitrate (1 molar equivalent was also included in the reaction mixture and that the reaction mixture was refluxed for 24 hours; yield 9% after twice being flash chromatographed (first: 1:99 - methanol/chloroform, second: 0.5:99.5 - ethanol/ chloroform) and recrystallization from cyclohexane/ ethyl acetate; mp 175-180°C; mass spectrum m/e (relative intensity) M+, 408, 406 (<1, <1), 364 (2.9), 362 (1.2) , 322 (12.1), 320 (40.2), 279 (25.8), 277 (62.6), 195 (43.3), 193 (100); 1H-NM (CDC13) delta 1.70 (3H, d, J=5.4Hz), 1.94 (3H, s) , 5.16 (IH, br, s) , 6.31 (IH, q, J=5.4Hz), 7.23 (IH, dd, J=3.9, 5.2Hz), 7.27 (IH, d, J=2.2Hz), 7.52 (IH, dd, 1.2, 3.7Hz), 7.69 (IH, dd, J=l.l, 5.1Hz), 7.98 (IH, d, J=2.2Hz), 8.21 (IH, d, J=8.8Hz), 8.47 (IH, br s) . Anal, calcd for
C18H15C1N2°5S (406-83) : c' 53.14; H, 3.72; N, 6.89. Found: C, 53.40; H, 3.61; N, 6.85. Acetal-carbonates: (R = -CH(CH3)OCOOCH2CH3) - Method B; yield 32% after flash chromatography (25:75 - ethyl acetate/ hexane) and recrystallization from 2-propanol; mp 159-162°C; mass spectrum m/e (relative intensity) M , 438, 436 (< 1.0, 1.0), 393 (<1.0), 322 (1.9), 320 (5.3) , 307 (2.0) , 305 (6.3) , 279 (9.9), 277 (26.9), 195 (42.5), 193 (100); 1H-NMR (CDC1- delta 1.21 (3H, t, J=7.1Hz) , 1.73 (3H, d, J=5.3Hz), 4.10 (2H, q, J=5.3Hz) , 5.19 (IH, br s) , 7.26 (2H, m) , 7.52 (IH, dd, J=l.l, 3.7Hz), 7.71 (IH, dd, J=l.1, 5.0Hz), 7.97 (IH, d, J=2.2Hz) , 8.22 (IH, d, J=8.7Hz) , 8.47 (IH, br s) . Anal, calcd for ClgH17ClN20gS (436.86) : C, 52.23; H, 3.92; N, 6.41. Found: C, 52.57; H, 4.44; N, 6.03.
(R = -CH(CH3)OCOOC(CH3)3) - Method B; yield 25% after flash chromatography (25:75 - ethyl acetate/ hexane) and recrystallization from 2-propanol; mp 184-187°C; mass spectrum m/e (relative intensity) M , 347 (0.8) , 322 (4.1) , 320 (2.0) , 279 (16.2) , 277 (53.8), 196 (11.3), 195 (34.5), 194 (13.3), 193 (100); 1H-NMR (CDC13) delta 1.33 (9H, s) , 1.71 (2H, d, J=5.4Hz), 5.21 (IH, br s) , 6.14 (IH, q, J=5.2Hz), 7.26 (2H, m) , 7.54 (IH, dd, J=1.2, 3.7Hz), 7.70 (IH, dd, J=1.2, 5.0Hz), 8.00 (IH, d, J=2.2Hz), 8.21 (IH, d, J=8.7Hz), 8.49 (IH, br s) . Anal, calcd. for
C21H21C1N2°6S (464-91): c' 54.25; H, 4.55; N, 6.03. Found, 54.38; H, 4.58; N, 6.09. (R = -CH(CH3)OCOOCH-,Ph) - Method B; yield 11% after flash chromatography (25:75 - ethyl acetate/ hexane) and recrystallization from ethyl acetate/ hexane; mp 140-145°C, softens 130°C; mass spectrum m/e (relative intensity) M+, 498 (< 1.0), 455 (< 1.0) , 410 (<1.0) , 195 (10.3) , 193 (32.2) , 111 (62.9) , 91 (100); 1H-NMR (CDC13) delta 1.72 (3H, d, J=5Hz) , 5.00 (IH, d, J=llHz) , 5.04 (IH, d, J=llHz) , 5.28 (IH, br s) , 6.20 (IH, q, J=5Hz) , 7.1-7.3 (7H, m) , 7.44 (IH, m) , 7.61 (IH, m) , 7.93 (IH, d, J=2Hz) , 8.20 (IH, d, J=9Hz) , 8.40 (IH, br s) . Anal, calcd for C24H19Cl 20gS (498.92) : C, 57.77; H, 3.84; N, 5.62. Found: C, 57.78; H, 3.80; N, 5.59. Ethers:
(R = -CH- - Method A using trimethyloxonium tetrafluoroborate; yield 27% after recrystallization from 2-propanol; mp 186-188°C; mass spectrum m/e
(relative intensity) M+, 335 (2.0), 334 (4.7), 291 (29.7), 277 (18.0), 260 (21.7), 248 (12.6), 193 (100), 185 (14.5), 157 (8.7), 111 (52.5); 1H-NMR (CDC13) delta 3.88 (3H, s) , 5.25 (IH, br s) , 7.27 (3H, ) , 7.69 (IH, d, J=5.7Hz), 7.88 (IH, d, J=2.2Hz), 8.21 (IH, d, J=8.7Hz), 8.49 (IH, br s) . Anal, calcd for
C15H11C1N2°3S (334-76) : c' 53.81; H, 3.31; N, 8.37. Found: C, 54.15; H, 3.48; N, 8.10.
(R = CH-,CH_j) - Method A using triethyloxonium tetrafluoroborate; yield 22% after recrystallization from 2-propanol; mp 202-205°C; mass spectrum m/e (relative intensity) M÷, 350, 348 (1.5, 4.6), 320 (<1) , 307 (7.3), 305 (19.6), 250 (2,2), 248 (7.4), 195 (27.0) , 193 (100), 187 (1.2), 185 (4.7), 167 (1.3) , 165 (3.2) , 139 (2.8), 137 (8.1), 111 (24.0); •'"H-NMR
(dg-Me2SO) delta 1.40 (3H, t, J=7.0Hz), 4.15 (2H, q, J=7.0Hz), 7.30 (IH, m) , 7.35 (IH, dd, J=2.3, 8.7), 7.50 (IH, m) , 7.65 (IH, s) , 7.90 (IH, d, J=2.3Hz), 8.00 (IH, dd, J=1.0, 5.0Hz), 8.05 (IH, s) , 8.15 (IH, d, J=8.7Hz). Anal, calcd for C^H-^CI ^S (348.67): C, 55.09; H, 3.76; N, 8.03. Found:, 54.87; H, 3.62; N, 7.79. S lfonates:
(R = -S02CH3) - Method A; yield 4% after being twice filtered through silica gel (5:95 - methanol/ chloroform) and recrystallization from 2-propanol; mp 180-182°C; mass spectrum m/e (relative intensity) M , 400, 398 (2.8, 5.6), 357 (6.8), 355 (2.6), 261 (15.3), 259 (45.3), 250 (31.0) , 248 (100), 141 (15.4) , 139
(42.9) , 113 (6.1) , 111 (37.7); 1H-NMR (CDClg) delta
3.02 (3H, s) , 5.23 (IH, br s) , 7.23 (IH, ) , 7.37 (IH, g dd, J=2.2, 8.8Hz), 7.76 (2H, m) , 8.16 (IH, d, J=2.lHz),
8.26 (IH, d, J=8.8Hz), 8.33 (IH, br s) . Anal, calcd for C15H11C1N205S2 (398.83) : C, 45.17; H, 2.78; N,
7.03. Found: C. 45.30; H, 2.60; N, 6.78.
(R = -S02(4-Me-Ph) - Method A; yield 6% after recrystallization from 2-propanol; mp 200-202°C; mass
_j- spectrum m/e (relative intensity) M , 474 (<1) , 433
(1.6) , 431 (4.0), 404 (1.6), 402 (3.3), 250 (32.0) , 248
(100) , 195 (4.4), 193 (15.8), 155 (27.7), 111 (47.8),
91 (42.2); 1H-NMR (dg-Me^O) delta 2.40 (3H, s) , 7.05 (IH, t, J=4.5Hz), 7.35-7.50 (4H, m) , 7.65 (3H, m) , 7.90
(3H, m) , 8.12 (IH, d, J=8.7Hz) . Anal, calcd for
C21H15C1N2°5S2 < 74-78): c' 53.10; H, 3.18; N, 5.89. Found: C, 53.09; H, 3.22; N, 5.66. Phosphonates:
(R = -PO(OCH2CH3)2) - Method A; yield 14% after being filtered through silica gel (5:95 - methanol/ chloroform) and recrystallization from cyclohexane/ ethyl acetate; mp 180-183°C; mass spectrum m/e (relative intensity) M+, 458, 456 (1.2, 3.8), 415 (7.4), 413 (17.4), 261 (31.7), 259 (100), 250 (3.1), 248 (9.2) , 196 (17.1) , 195 (12.5) , 193 (44.6) ; 1H-NMR (CDC1-) delta 1.33 (6H, dt, J=1.2, 7.1Hz) , 4.14 (4H, m) , 5.23 (IH, br s) , 7.32 (IH, dd, J=2.2, 8.8Hz) , 7.70 (IH, dd, J=1.2, 5.0Hz) , 7.83 (IH, dd, J=1.2, 3.8Hz), 8.06 (IH, d, J=2.2Hz), 8.25 (IH, d, J=8.8Hz) , 8.46 (IH, br s) . Anal, calcd for C^H-^Cl^OgPS (456.83): C, 47.32; H, 3.97; N, 6.13. Found: C, 47.25; H, 3.83; N, 6.08.
EXAMPLE 2 Starting with the appropriate reagents and using the indicated procedure the following compounds were prepared:
Figure imgf000024_0001
Esters:
(R = -COCH-.) - Method A; yield 16% after recrys¬ tallization from 2-propanol; mp 190-203°C; mass spectrum m/e (relative intensity) M , 382, 380 (1.6, 7.7), 340 (36.8), 338 (98.1), 297 (16.5), 295 (43.4), 279 (<1) , 277 (2.1), 268 (3.4), 266 (8.3) , 256 (1.4), 254 (5.2) , 213 (38.6), 211 (100), 111 (26.7); 1H-NMR (d,-Me SO) delta 1.9, 2.4 (3H, 2s), 7.09-7.40 (2H, set of m) , 7.55-7.80 (IH, set of m) , 7.95-8.50 (4H, set of m) . Anal, calcd for C^H^CIF ^S (380.66) : C, 50.47; H, 2.65; N, 7.36. Found: C, 50.13; H, 2.52; N, 7.19. (R = -COCH2CH3) - Method A; yield 10% after filtration through silica gel (5:95 - ethanol/ chloroform) and recrystallization from 2-propanol; mp 182-188°C; mass spectrum m/e (relative intensity) M , 396, 394 (< 1, 1.3), 340 (7.2), 338 (16.2), 297 (12.1), 295 (32.5) , 268 (2.7), 266 (7.1), 213 (26.1), 211 (100) , 111 (40.8) , 57 (94.2); ^Η-NMR (dg-Me2SO) delta 1.18 (3H 3. ψ-,D, m) 2.22 (2H3. , q, J=7.5Hz), 2.71 (2HJ,O, q,
J=7.5Hz) , 7.09-7.70 (2H cL f, ID, m) , 7.95-8.48 (5H cL f, f m) .
Anal, calcd for C17H12C1FN204S (394.80): C, 51.71; H, 3.06; N, 7.10. Found, 51.67; H, 3.01; N, 6.97.
(R = -COCH(CH3)2) - Method A; yield 11% after filtration through silica gel and recrystallization from 2-propanol; mp 204-206°C; mass spectrum m/e (relative intensity) M+, 410, 408 (1.1, 4.1), 340 (11.5) , 338 (27.2) , 297 (13.2) , 295 (33.6), 268 (5.6) , 266 (15.0), 213 (25.8), 211 (100), 111 (36.4); 1H-NMR (d.-Me_SO) delta 1.34 (6H, d, J=7.0Hz), 3.25 (IH, heptet, J=7.0Hz), 7.33 (IH, dd, J=4.0, 5.1Hz), 7.48 (IH, d, J=9.6Hz), 8.00 (IH, br s) , 8.03 (IH, br s) , 8.13 (IH, dd, J=1.2, 5.0Hz). Anal, calcd for
C18H14C1FN2°4S (408 ' 83) : c' 52.88; H, 3.45; N, 6.85. Found: C, 52.48; H, 3.32; N, 6.86. (R = -C0CH2Ph) - Method A; yield 22% after recrys¬ tallization from 2-propanol; mp 189-199°C; mass spectrum m/e (relative intensity) M , not observed, 340 (18.9) , 338 (42.1), 297 (20.7), 295 (54.4) , 268 (5.8) , 266 (19.6) , 213 (17.9) , 211 (53.7) , 91 (100); -""H-NMR (dg-Me2SO) delta 3.98 (2Ha, s) , 4.02 (2Hb, s) , 5.35 (IH, br s) , 6.99-7.45 (7H, m) , 7.68, 8.00 (2H, 2m), 8.42 (IH, dd, J=5.1, 6.9Hz) , 8.50 (IH, br s) . Anal, calcd for C22H14C1FN204S (456.86) : C, 57.83; H, 3.09; N, 6.13. Found: C, 57.53; H, 2.98; N, 6.15. g (R = -COCH2CH2COOEt) - Method A; yield 26% after recrystallization from 2-propanol; mp 153-155°C; mass spectrum m/e (relative intensity) M , not observed, 321 (3.1) , 295 (3.1) , 266 (4.5), 213 (8.8), 211 (23.4), 155 (5.2) , 129 (100), 111 (12.4), 101 (75.0), 91 (2.7); 1H-NMR (dg-Me2S0) delta 1.12 (3H, 2t, J=7.lHz), 2.5-3.5 (4H, complex set of m) , 4.05 (2H, 2q, J=7.3Hz), 7.15-7.40 (2H, complex set of m) , 7.70 (IH, ) , 7.95-8.43 (4H, complex set of m) . Anal, calcd for C20H16C1FN2°6_. (466.70) : C, 51.45; H, 3.45; N, 6.00. Found: C, 51.28; H, 3.26; N, 5.99. Carbonates:
(R = -COOCH3) - Method A; yield 25% after recrys¬ tallization from 2-propanol; mp 203-205°C; mass spectrum m/e (relative intensity) M , 398, 396 (7.5, 0 24.5) , 355 (4.5) , 353 (10.6), 311 (23.8), 309 (49.1),
280 (26.3), 278 (27.9), 268 (30.5), 266 (100), 252
(3.5) , 250 (6.9), 240 (3.4) , 238 (7.2), 213 (25.2) , 211
(56.9), 203 (29.4), 197 (5.6) , 182 (6.8), 169 (6.1),
157 (4.5), 155 (12.4), 142 (2.1), 111 (45.4) , 97 (5.3), 5 83 (5 . 5 ) ; 1H-NMR (d --Me_SO) delta 3 . 89 , 3 . 95 (3H , 2s ) , b Δ
7.38 (2H, m) , 8.00 (3H, m) , 8.19 (IH, m) , 8.29 (IH, t, J=6.7Hz) . Anal, calcd for C1gH1()ClFN20-.S (396.71): C, 48.43; H, 2.54; N, 7.06. Found: C, 48.41; H, 2.47; N, 6.95. 0 (R = -COOCH-,CH3) - Method A; yield 57% after recrystallization from 2-propanol; mp 164-166°C; mass spectrum m/e (relative intensity) M , 410 (1.4) , 325 (1.8), 323 (5.8) , 297 (8.0) , 295 (20.5), 268 (6.1), 266 (13.7), 213 (37.6), 211 (100), 203 (7.9) , 155 (7.5) , 111 (21.0); 1H-NMR (dg-Me2SO) delta 1.30 (3H, t, J=7.lHz) , 4.32 (2H, q, J=7.1Hz), 7.35 (2H, ) , 8.0 (3H, m) , 8.20-8.35 (2H, m) . Anal, calcd for C17H12C1FN205S (410.67) : C, 49.70; H, 2.94; N, 6.82. Found: C, 49.76; H, 2.85; N, 6.77.
(R = -COO(CH2)5CH3) - Method A; yield 85% after recrystallization from 2-propanol; mp 128-135°C; mass spectrum m/e (relative intensity) M , 468, 466 (0.3, 0.7), 425 (0.3), 424 (0.3), 423 (1.1) , 340 (7.0) , 338 (14.1) , 297 (28.5) , 295 (74.5), 213 (34.3), 211 (100); 1H-NMR (CDC13) delta 0.85-0.92 (3H, m) , 1.22-1.48 (6H, m) , 1.72 (2H, pentet, J=9Hz) , 4.31 (2Ha b, t) , 5.40 (lHa b, br s) , 7.21 (lHa fa, m) , 7.30 (lHa, d, J=9Hz) ,
7.47 (lHb , J=9Hz) , 7.77 (2Ha, lHfa, m) , 8.19 (lHj., m) ,
8.42 (IHa, d, J=8Hz) , 8.46 (IH, , d, J=8Hz) , 8.49 (IHa, br s) , 8.52 (IH, , br s) . Anal, calcd for
C21H20C1FN2°5S (466*91) : c' 54.02; H, 4.32; N, 6.00. Found: C, 53.93; H, 4.26; N, 6.02. Sulfonates:
(R = -S02CH3) - Method A; yield 9% after filtra¬ tion through silica gel and recrystallization from cyclohexane/ethyl acetate; mp 180-185°C; mass spectrum m/e (relative intensity) M+, 418, 416 (3.4, 7.2), 375 (8.4), 373 (21.8), 296 (6.8) , 294 (6.8), 294 (16.0), 279 (7.0), 277 (18.5) , 268 (42.7) , 266 (100) , 111 (65.4) . Anal, calcd for C15H10ClF 2O-.S2 (416.85) : C, 43.22; H, 2.42; N, 6.72. Found: C, 43.37; H, 2.30; N, 6.72. EXAMPLE 3
Using the indicated procedure and starting with the requisite reagents, the following compounds were prepared:
Figure imgf000028_0001
Esters:
(R = -COCH3) - Method A; yield 56% after recrystallization from 2-propanol; mp 195-197°C; mass spectrum m/e (relative intensity) M , 354 (<1), 312 (32.5), 269 (38.6), 251 (4.8) , 221 (12.2), 194 (1.6), 178 (100) , 121 (11.1) , 91 (23.9) , 65 (5.9); 1H-NMR (dg-Me2SO) delta 2.31 (3H, s) , 4.51 (2H, s) , 7.02 (IH, dt, J=2.6, 8.9Hz), 7.33 (6H, s) , 7.63 (IH, dd, J=5.8, 8.6Hz), 7.95 (2H, m) . Anal, calcd for C.,-.H15F 204 (354.19) : C, 64.40; H, 4.27; N, 7.91. Found: C, 64.30; H, 4.21; N, 7.89.
(R = -C0CH2CH3) - Method A; yield 23% after recrystallization from 2-propanol; mp 196-198°C; mass spectrum m/e (relative intensity) M , 368 (2) , 325 (5) , 312 (25), 269 (70), 251 (7) , 240 (4), 221 (5), 178 (100), 150 (8), 121 (10), 91 (37), 65 (12) , 57 (83); ■"•H-NMR (dg-Me2S0) delta 1.02 (3H, t, J=7.4Hz), 2.61 (2H, q, J=7.4Hz) , 4.53 (2H, s) , 7.02 (IH, dt, J=2.6, 9.2Hz), 7.32 (6H, m) , 7.61 (IH, dd, J=5.8, 8.6Hz), 7.95 (2H, m) . Anal, calcd for C20H17FN2O4 (368.20) : C, 65.21; H, 4.65; N, 7.61. Found: C, 64.98; H, 4.44; N, 7-54'
(R = -C0CH(CH3)2) - Method A; yield 28% after recrystallization from 2-propanol; mp 182-184°C; mass spectrum m/e (relative intensity) M , 382 (3.5), 339
(<1), 312 (18.6), 269 (18.1), 178 (46.2), 177 (17.4), 91 (31.8) , 71 (100); 1H-NMR (dg-Me2SO) delta 1.09 (3H, d, J=7.0Hz) , 2.64 (IH, dq, J=7.0Hz) , 4.65 (2H, s) , 5.36 (IH, br s) , 6.83 (IH, dt, J=2.5, 8.7Hz), 7.18-7.33 (5H, m) , 7.50 (IH, dd, J=5.6, 8.6Hz) , 8.10 (IH, dd, J=2.5, 10.3Hz), 8.59 (IH, br s) . Anal, calcd for C2iHi9FN2° (382.38) : C, 65.96; H, 5.01; N, 7.33. Found: C, 65.76; H, 4.94; N, 7.33.
(R = -COPh) - Method A; yield 68% after recrystal¬ lization from 2-propanol; mp 188-190°C; mass spectrum m/e (relative intensity) M+, 416 (2.7), 373 (3.0), 242 (6.1), 177 (6.4), 121 (5.2) , 105 (100) , 77 (17.8); •"•H-NMR (CDC13) delta 4.71 (2H, d) , 5.41 (IH, br s) , 6.71 (IH, dt, J=2.5, 8.7Hz), 7.26 (5H, m) , 7.42 (IH, dd, J=5.6, 8.6), 7.52 (2H, m) , 7.66 (IH, m) , 8.03 (2H, d) , 8.10 (IH, dd, J=2.5, 10.3Hz), 8.63 (IH, br s) . Anal, calcd for C24H17FN204 «H20 (434.41): C, 66.35; H, 4.40; N, 6.44. Found: C, 66.14; H, 3.92; N, 6.41.
(R = -COCH-Ph) - Method A; yield 27% after recrys¬ tallization from 2-propanol; mp 201-202°C; mass spectrum m/e (relative intensity) M , 430 (0.9), 387 (0.6), 312 (87.5), 269 (100), 178 (64.7), 91 (65.6); 1H-NMR (dg-Me2SO) delta 3.99 (2H, s) , 4.48 (2H, s) , 6.85 (2H, dt, J=2.6, 8.9Hz), 7.28 (10H, m) , 7.91 (IH, dd, J=2.5, 10.7Hz), 7.97 (IH, br s) , 8.07 (IH, br s) . Anal, calcd for C25HιgFN204 (430.25) : C, 69.76; H, 4.45; N, 6.51. Found: C, 69.35; H, 4.38; N, 6.62. (R = -C0CH2CH2C00Et) - Method A; yield 46% after recrystallization from 2-propanol; mp 159-161°C; mass spectrum m/e (relative intensity) M , not observed, 395 (0.4) , 352 (0.8), 331 (0.3) , 289 (0.6), 269 (6.4), 252 (9.4), 234 (1.9), 222 (6.8), 212 (1.5) , 196 (1.1), 178 (24.8) , 177 (10.6), 168 (1.5), 130 (7.7), 129 (100), 121 (5.3), 101 (65.8) , 91 (10.0); 1H-NMR (dg-Me2SO) delta 1.15 (3H, t, J=7.lHz), 2.61 (2H, t, J=6.0Hz), 2.88 (2H, t, J=6.0Hz), 4.06 (2H, q, J=7.1Hz), 4.46 (2H, s) , 6.98 (IH, dt, J=2.6, 8.9Hz), 7.32 (5H, m) , 7.67 (IH, dd, J=5.8, 8.6Hz), 7.93 (IH, dd, J=2.5, 10.7Hz), 7.98 (IH, br s) , 8.08 (IH, br s) . Anal, calcd for
C23H21FN2°6 <440-23) : c' 62.72; H, 4.81; N, 6.36. Found: C, 62.75; H, 4.79; N, 6.29. Carbonates: (R = -COOCH-.) - Method A; yield 45% after recrys¬ tallization from 2-propanol; mp 178-180°C; mass spectrum m/e (relative intensity) M , 370 (16.7), 327 (3.7) , 294 (24.0), 251 (100) , 235 (11.7), 222 (32.9), 205 (0.4), 204 (3.8), 192 (29.8), 178 (42.5), 164 (2.2), 149 (5.8); 1H-NMR (dg-Me2SO) delta 3.86 (3H, s) , 4.58 (2H, s) , 7.08 (IH, dt, J=2.6, 9.1Hz), 7.32 (5H, s) , 7.55 (IH, dd, J=5.9, 8.7Hz), 7.95 (IH, dd, J=2.5, 10.6Hz), 7.99 (IH, br s) , 8.07 (IH, br s) . Anal, calcd for c 19 Hi5FN2°5 (370.19): C, 61.62; H, 4.08; N, 7.56. Found: C, 61.64; H, 4.07; N, 7.55. (R = -COOCH2CH3) - Method A; yield 52% after recrystallization from 2-propanol; mp 189-190°C; mass spectrum m/e (relative intensity) M , 384 (8.8) , 340 g (3.4), 312 (33.2), 297 (57.0), 269 (71.1), 251 (47.1), 240 (14.9), 221 (33.6), 212 (7.1), 206 (10.1), 178 (100), 150 (10.6) , 121 (14.3), 91 (51.5); 1H-NMR (dg-Me2S0) delta 1.23 (3H, t, J=7.lHz), 4.26 (2H, q, J=7.lHz), 4.58 (2H, s) , 7.08 (IH, dt, J=2.5, 8.9Hz), 7.32 (5H, m) , 7.53 (IH, dd, J=5.8, 8.6Hz) , 7.94 (IH, dd, J=2.6, 10.7Hz), 7.99 (IH, br s) , 8.07 (IH, br s) .
Anal, calcd for C20H17FN2°5 <384-19) * ' 62.52; H, 4.42; N, 7.29. Found: C, 62.59) H, 4.41; N, 6.98. (R = -COO(CH2)5CH3) - Method A; yield 31% after recrystallization from 2-propanol; mp 144-145°C; mass spectrum m/e (relative intensity) M , 440 (<1), 397 (0.6), 378 (<1) , 353 (<1) , 312 (18.1) , 294 (1.9), 269 (69.7), 251 (16.7), 240 (4.3), 221 (16.4), 212 (2.1), 194 (2.0), 178 (100), 164 (0.9) , 149 (5.7) , 121 (9.2), 103 (1.1), 91 (29.2); 1H-NMR (dg-Me2S0) delta 0.85 (3H, br t,J=6.6Hz), 1.24 (6H, m) , 1.58 (2H, m) , 4.21 (2H, t, J=6.4Hz), 4.59 (2H, s) , 7.06 (IH, dt, J=2.5, 9.0Hz), 7.31 (5H, m) , 7.54 (IH, dd, =5.8, 8.6Hz) , 7.96 (IH, dd, J=2.5, 10.6Hz), 8.00 (IH, br s) , 8.07 (IH, br s) . Anal, calcd for C 24H25FN2°5 <440-24) : C' 65.44; H, 5.72; N, 6.36. Found: C, 65.31; H, 5.62; N, 6.38.

Claims

1. A compound of the formula
Figure imgf000032_0001
wherein X and Y are each selected from the group consisting of hydrogen, fluoro and chloro; R is selected from the group consisting of 2-thienyl and benzyl; and R is selected from the group consisting of alkanoyl having two to ten carbon atoms, cycloalkyl¬ carbonyl having five to seven carbon atoms, phenyl¬ alkanoyl having seven to ten carbon atoms, chloro¬ benzoyl, methoxybenzoyl, thenoyl, omega-alkoxycarbonyl- alkanoyl said alkoxy having one to three carbon atoms and said alkanoyl having three to five carbon atoms, alkoxycarbonyl having two to ten carbon atoms, phenoxycarbonyl, 1-(acyloxy)alkyl said acyl having two to four carbon atoms and said alkyl having one to four carbon atoms, 1-(alkoxycarbonyloxy)alkyl said alkoxy having two to five carbon atoms and said alkyl having one to four carbon atoms, alkylsulfonyl having one to three carbon atoms, meth lphenylsulfonyl and dialkylphosphonate said alkyl each having from one to three carbon atoms.
2. A compound of claim 1, wherein R is 2-thienyl, X is chloro and Y is hydrogen.
3. A compound of claim 2, wherein R is alkanoyl having two to ten carbon atoms.
4. The compound of claim 3, wherein R is acetyl.
5. The compound of claim 3, wherein R is propionyl.
6. The compound of claim 3, wherein R is isobutyryl.
7. A compound of claim 2, wherein R is phenyl¬ alkanoyl having seven to ten carbon atoms.
8. The compound of claim 7, wherein R is phenyl- acetyl.
9. A compound of claim 2, wherein R is omega- alkoxycarbonylalkanoyl said alkoxy having one to three carbon atoms and said alkanoyl having three to five carbon atoms.
10. The compound of claim 9, wherein R is omega- ethoxycarbonylpropionyl.
11. A compound of claim 2, wherein R is alkoxy¬ carbonyl having two to ten carbon atoms.
12. The compound of claim 11, wherein R is methoxycarbonyl.
13. The compound of claim 11, wherein R is ethoxycarbonyl.
14. The compound of claim 11, wherein R is n-hexoxycarbonyl.
15. A compound of claim 2, wherein R is 1-alkoxy- carbonylox}')alkyl said alkoxy having two to five carbon atoms and said alkyl having one to four carbon atoms.
16. The compound of claim 15, wherein R is 1-(ethoxycarbonyloxy)ethyl.
17. A compound of claim 2, wherein R is alkyl- g sulfonyl having one to three carbon atoms.
18. The compound of claim 17, wherein R is methylsulfonyl.
19. A compound of claim 1, wherein R is 2-thienyl, X is fluoro and Y is chloro.
20. A compound of claim 19, wherein R is alkanoyl having two to ten carbon atoms.
21. A compound of claim 20, wherein R is acetyl.
22. The compound of claim 20, wherein R is propionyl. 5
23. The compound of claim 20, wherein R is isobutyryl.
24. A compound of claim 19, wherein R is alkoxy¬ carbonyl having two to ten carbon atoms.
25. The compound of claim 24, wherein R is 0 methoxycarbonyl.
26. The compound of claim 24, wherein R is ethoxycarbonyl.
27. The compound of claim 24, wherein R is n-hexoxycarbonyl. 5
28. A compound of claim 1, wherein R is benzyl, X is hydrogen and Y is fluoro.
29. A compound of claim 28, wherein R is alkanoyl having two to ten carbon atoms.
30. The compound of claim 29, wherein R is 0 acetyl.
31. A compound of claim 28, wherein R is alkoxy¬ carbonyl having two to ten carbon atoms.
32. The compound of claim 31, wherein R is methoxycarbonyl.
33. A method for treating inflammation in a mammal which comprises administering to said mammal an antiinflammatory effective amount of a compound selected from claim 1.
PCT/US1988/003658 1988-10-18 1988-10-18 Prodrugs of antiinflammatory 3-acyl-2-oxindole-1-carboxamides WO1990004393A1 (en)

Priority Applications (34)

Application Number Priority Date Filing Date Title
HU886740A HU208421B (en) 1988-10-18 1988-10-18 Process for producing starting materials for producing 3-acyl-2-oxindol-carboxamides ofantiphlogistic activity
PCT/US1988/003658 WO1990004393A1 (en) 1988-10-18 1988-10-18 Prodrugs of antiinflammatory 3-acyl-2-oxindole-1-carboxamides
SK5906-89A SK590689A3 (en) 1988-10-18 1988-10-18 3-aryl-2-oxindole-1-carboxamides and method of their preparation
MX1802188A MX18021A (en) 1988-10-18 1988-10-18 PRO-DRUGS OF 3-ACIL-2-OXINDOL-1-CARBOXAMIDASANTI-INFLAMMATORIAS
RO147347A RO109195B1 (en) 1988-10-18 1988-10-18 3-acyl-2-oxindole-1-carboxamide derivates
US07/675,883 US5118703A (en) 1988-10-18 1988-10-18 Prodrugs of antiinflammatory 3-acyl-2-oxindole-1-carboxamides
IS3509A IS1598B (en) 1988-10-18 1989-09-20 Method of producing a prodrug for inflammation, ie. 3-acyl-2-oxindole-1-carboxamide
CA000614317A CA1339558C (en) 1988-10-18 1989-09-28 Prodrugs of antiinflammatory 3-acyl-2-oxindole-1-carboxamides
PH39329A PH27554A (en) 1988-10-18 1989-10-04 Prodrugs of antiinflammatory-3-acyl-2-oxindole-1-carboxamides
AT89310319T ATE125794T1 (en) 1988-10-18 1989-10-09 PRODROGEN OF ANTI-INFLAMMATORY 3-ACYL-2-OXINDOL-1-CARBOXAMIDES.
IL9196089A IL91960A (en) 1988-10-18 1989-10-12 Prodrugs of antiinflammatory 3-acyl-2-oxindole-1-carboxamides
YU200589A YU48070B (en) 1988-10-18 1989-10-16 PROCEDURE FOR THE PREPARATION OF 3-ACYL-2-OXINDOL-1-CARBOXAMIDE ENOL ESTERS AND ETARS
BG90022A BG50834A3 (en) 1988-10-18 1989-10-16 Method for the preparation of 3- acyl- 2- oxindole- 1- carboxamides
APAP/P/1989/000141A AP118A (en) 1988-10-18 1989-10-16 Prodrugs of antiflammatory 3-acyl-2-oxindole-1-carboxamides
MYPI89001415A MY104238A (en) 1988-10-18 1989-10-16 Prodrugs of antiinflammatory 3-acyl-2-oxindole-1 -carboxamides.
PT92000A PT92000B (en) 1988-10-18 1989-10-16 PROCESS FOR THE PREPARATION OF ANTI-INFLAMMATORY 3-ACYL-2-OXINDOLE-1-CARBOXAMID PRODUCTS
DD89333653A DD285604A5 (en) 1988-10-18 1989-10-17 PROCESS FOR THE PREPARATION OF ENOL ETHERS AND ESTERS
KR1019890014914A KR910007237B1 (en) 1988-10-18 1989-10-17 Products of anti inflammatory 3-acyl-2-oxidole-1-carboxamides
OA59665A OA09140A (en) 1988-10-18 1989-10-17 Process for the preparation of anti-inflammatory 3-acyl-2-oxindole-1-carboxamides precursors.
AU42956/89A AU606819B2 (en) 1988-10-18 1989-10-17 Prodrugs of antiinflammatory 3-acyl-2-oxindole-1-carboxamides
MA21909A MA21657A1 (en) 1988-10-18 1989-10-17 PROCESS FOR THE PREPARATION OF PRECURSORS OF 3-ACYL-2- OXINDOLE-1- CARBOXAMIDES SELF-INFLAMMATORY.
PL89296831A PL163112B1 (en) 1988-10-18 1989-10-17 Method of obtaining 3-acyl-2-oxyindolo-1-carbonamides
IE333289A IE66586B1 (en) 1988-10-18 1989-10-17 Prodrugs of antiinflammatory 3-acyl-2-oxindole-1-carboxamides
NZ231044A NZ231044A (en) 1988-10-18 1989-10-17 3-acyl-2-oxindole-1-carboxamide derivatives
AR89315179A AR246519A1 (en) 1988-10-18 1989-10-17 Preparation of anti-inflammatory agents such as esters and intermediate enolic esters of the 3-acyl-2-oxindol-1-carboxamides.
CN89107943A CN1022241C (en) 1988-10-18 1989-10-17 Prodrugs of antiinflammatory 3-acyl-2-oxindole-1-carboxamides
PL89281871A PL162316B1 (en) 1988-10-18 1989-10-17 Method of obtaining 3-acyl-2-oxyindolo-1-carbonamides
JP1270174A JPH07597B2 (en) 1988-10-18 1989-10-17 Anti-inflammatory 3-acyl-2-oxindole-1-carboxamide precursors
DK514989A DK514989A (en) 1988-10-18 1989-10-17 ENOLESTERS AND ETHERS OF 3-ACYL-2-OXINDOL-1-CARBOXAMIDES AND THEIR USE FOR THE PREPARATION OF MEDICINAL PRODUCTS
EG49689A EG19887A (en) 1988-10-18 1989-10-18 Prodrugs of antiinflammatory 3-acyl-2-oxindole-1-carboxamides
CS895906A CZ278983B6 (en) 1988-10-18 1989-10-18 3-acyl-2-oxindole-1-carboxamides, and process for preparing thereof
NO911512A NO178027C (en) 1988-10-18 1991-04-17 Analogous Process of Preparation of Precursors for Anti-Inflammatory 3-Acyl-2-Oxindole-1-Carboxamides
SU914895525A RU2036905C1 (en) 1988-10-18 1991-04-17 3-acyl-2-oxoindole-1-carboxamides and methods of their synthesis
FI911855A FI95253C (en) 1988-10-18 1991-04-17 Process for the preparation of 3-acyl-2-oxindole-1-carboxamide prodrug with anti-inflammatory effect

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1988/003658 WO1990004393A1 (en) 1988-10-18 1988-10-18 Prodrugs of antiinflammatory 3-acyl-2-oxindole-1-carboxamides

Publications (1)

Publication Number Publication Date
WO1990004393A1 true WO1990004393A1 (en) 1990-05-03

Family

ID=22208957

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1988/003658 WO1990004393A1 (en) 1988-10-18 1988-10-18 Prodrugs of antiinflammatory 3-acyl-2-oxindole-1-carboxamides

Country Status (33)

Country Link
US (1) US5118703A (en)
JP (1) JPH07597B2 (en)
KR (1) KR910007237B1 (en)
CN (1) CN1022241C (en)
AP (1) AP118A (en)
AR (1) AR246519A1 (en)
AT (1) ATE125794T1 (en)
AU (1) AU606819B2 (en)
BG (1) BG50834A3 (en)
CA (1) CA1339558C (en)
CZ (1) CZ278983B6 (en)
DD (1) DD285604A5 (en)
DK (1) DK514989A (en)
EG (1) EG19887A (en)
FI (1) FI95253C (en)
HU (1) HU208421B (en)
IE (1) IE66586B1 (en)
IL (1) IL91960A (en)
IS (1) IS1598B (en)
MA (1) MA21657A1 (en)
MX (1) MX18021A (en)
MY (1) MY104238A (en)
NO (1) NO178027C (en)
NZ (1) NZ231044A (en)
OA (1) OA09140A (en)
PH (1) PH27554A (en)
PL (2) PL163112B1 (en)
PT (1) PT92000B (en)
RO (1) RO109195B1 (en)
RU (1) RU2036905C1 (en)
SK (1) SK590689A3 (en)
WO (1) WO1990004393A1 (en)
YU (1) YU48070B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0984012A2 (en) * 1998-08-31 2000-03-08 Pfizer Products Inc. Nitric oxide releasing oxindole prodrugs with analgesic and anti-inflammatory properties

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5059693A (en) * 1989-10-06 1991-10-22 Pfizer Inc. Process for making 3-aroyl-2-oxindole-1-carboxamides
AU670454B2 (en) * 1992-11-23 1996-07-18 Pfizer Inc. Regioselective synthesis of 4-chloro-2-thiophenecarboxylic acid
US5270331A (en) * 1993-01-26 1993-12-14 Pfizer, Inc. Prodrugs of antiinflammatory 3-acyl-2-oxindole-1-carboxamides
JP2709530B2 (en) * 1993-02-09 1998-02-04 ファイザー・インク． Oxindole 1- [N- (alkoxycarbonyl)] carboxamides and 1- (N-carboxamide) carboxamides as anti-inflammatory agents
US5449788A (en) * 1994-01-28 1995-09-12 Catalytica, Inc. Process for preparing 2-oxindole-1-carboxamides
CN1094819C (en) * 1997-04-30 2002-11-27 大兴株式会社 Apparatus of making annular blank
EP1223809A4 (en) * 1999-10-26 2004-03-03 Univ Texas Southwestern Med Ct Methods of treating hair loss comprising administering indoline compound

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2872372A (en) * 1956-06-08 1959-02-03 Ici Ltd New indole derivatives
US3634453A (en) * 1969-10-15 1972-01-11 Pfizer Oxindole carboxamides
US3923996A (en) * 1972-07-31 1975-12-02 Sandoz Ag 3-Substituted-oxindoles in compositions and methods of treating obesity
US4556672A (en) * 1984-03-19 1985-12-03 Pfizer Inc. 3-Substituted 2-oxindole-1-carboxamides as analgesic and anti-inflammatory agents

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3564009A (en) * 1966-01-13 1971-02-16 Sumitomo Chemical Co Process for producing 1-acylindole derivatives
IE53102B1 (en) * 1981-05-12 1988-06-22 Ici Plc Pharmaceutical spiro-succinimide derivatives
EP0076606B1 (en) * 1981-10-06 1986-02-05 Imperial Chemical Industries Plc Biochemical process
US4752609A (en) * 1985-06-20 1988-06-21 Pfizer Inc. Analgesic and antiinflammatory 1,3-diacyl-2-oxindole compounds
RO105052B1 (en) * 1987-02-02 1994-12-01 Pfizer Producing process for the crystalline sodium salt, anhydre, of 5-chlorine-3-(2-tenoil)-2-oxindol-1-carboxamide
EP0365194B1 (en) * 1988-10-18 1995-08-02 Pfizer Inc. Prodrugs of antiinflammatory 3-acyl-2-oxindole-1-carboxamides
US5047554A (en) * 1989-04-18 1991-09-10 Pfizer Inc. 3-substituted-2-oxindole derivatives
US5059693A (en) * 1989-10-06 1991-10-22 Pfizer Inc. Process for making 3-aroyl-2-oxindole-1-carboxamides

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2872372A (en) * 1956-06-08 1959-02-03 Ici Ltd New indole derivatives
US3634453A (en) * 1969-10-15 1972-01-11 Pfizer Oxindole carboxamides
US3923996A (en) * 1972-07-31 1975-12-02 Sandoz Ag 3-Substituted-oxindoles in compositions and methods of treating obesity
US4556672A (en) * 1984-03-19 1985-12-03 Pfizer Inc. 3-Substituted 2-oxindole-1-carboxamides as analgesic and anti-inflammatory agents

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0984012A2 (en) * 1998-08-31 2000-03-08 Pfizer Products Inc. Nitric oxide releasing oxindole prodrugs with analgesic and anti-inflammatory properties
EP0984012A3 (en) * 1998-08-31 2001-01-10 Pfizer Products Inc. Nitric oxide releasing oxindole prodrugs with analgesic and anti-inflammatory properties

Also Published As

Publication number Publication date
CZ590689A3 (en) 1994-04-13
NZ231044A (en) 1990-12-21
CZ278983B6 (en) 1994-11-16
YU200589A (en) 1991-02-28
IL91960A0 (en) 1990-07-12
MY104238A (en) 1994-02-28
CN1041938A (en) 1990-05-09
KR910007237B1 (en) 1991-09-24
SK278175B6 (en) 1996-03-06
AR246519A1 (en) 1994-08-31
HU208421B (en) 1993-10-28
PL162316B1 (en) 1993-09-30
DK514989A (en) 1990-04-19
CN1022241C (en) 1993-09-29
IS1598B (en) 1996-05-20
RU2036905C1 (en) 1995-06-09
HUT58052A (en) 1992-01-28
DK514989D0 (en) 1989-10-17
ATE125794T1 (en) 1995-08-15
DD285604A5 (en) 1990-12-19
KR900006285A (en) 1990-05-07
US5118703A (en) 1992-06-02
YU48070B (en) 1997-01-08
AU4295689A (en) 1990-04-26
JPH02149559A (en) 1990-06-08
NO178027C (en) 1996-01-10
PT92000A (en) 1990-04-30
PL163112B1 (en) 1994-02-28
RO109195B1 (en) 1994-12-30
IE66586B1 (en) 1996-01-24
OA09140A (en) 1991-10-31
SK590689A3 (en) 1996-03-06
PT92000B (en) 1995-06-30
AU606819B2 (en) 1991-02-14
FI911855A0 (en) 1991-04-17
IL91960A (en) 1994-04-12
NO911512L (en) 1991-06-12
BG50834A3 (en) 1992-11-16
IS3509A7 (en) 1990-04-19
AP8900141A0 (en) 1989-10-31
MX18021A (en) 1993-11-01
MA21657A1 (en) 1990-07-01
AP118A (en) 1991-02-22
FI95253C (en) 1996-01-10
NO911512D0 (en) 1991-04-17
IE893332L (en) 1990-04-18
JPH07597B2 (en) 1995-01-11
PH27554A (en) 1993-08-18
FI95253B (en) 1995-09-29
EG19887A (en) 1996-03-31
NO178027B (en) 1995-10-02
CA1339558C (en) 1997-11-25
HU886740D0 (en) 1991-07-29

Similar Documents

Publication Publication Date Title
US4943587A (en) Hydroxamate derivatives of selected nonsteroidal antiinflammatory acyl residues and their use for cyclooxygenase and 5-lipoxygenase inhibition
US4752613A (en) Sulphonamidothienylcarboxylic acid compounds
KR20010041343A (en) Inhibitors of phospholipase enzymes
CA2195420A1 (en) Compounds useful as antiproliferative agents and garft inhibitors
MX2007001539A (en) Heterocyclic compounds as pharmaceutical agents.
US4695571A (en) Tricyclic oxindole antiinflammatory agents
WO1990004393A1 (en) Prodrugs of antiinflammatory 3-acyl-2-oxindole-1-carboxamides
HU192868B (en) Process for producing particularly antiasthmatic medicine preparations
US5112868A (en) Hydroxamate derivatives of selected nonsteroidal antiinflammatory acyl residues having cyclooxygenase and 5-lipoxygenase inhibition
EP0365194B1 (en) Prodrugs of antiinflammatory 3-acyl-2-oxindole-1-carboxamides
HU193274B (en) Process for preparing phenthiazines
US3564008A (en) Process for preparing 1-acyl-2-phenyl-3-indolylaliphatic acid derivatives
JPS60184077A (en) Antiinflammatory oxime precursor drug
KR920006785B1 (en) Anti-inflammatory 1-heteroaryl-3-acyl-2-oxindoles
EP0284069B1 (en) Benzopyranopyridineacetic acid ester compounds and their pharmaceutical uses
KR920006784B1 (en) Anti-inflammatory 1-heteroaryl oxindole-3-carboxamides
EP0145304B1 (en) Tetrahydro-beta-carboline derivatives and process for the preparation thereof
US4169147A (en) Novel transient pro-drug forms of phenylbutazone and oxyphenbutazone in compositions and methods of use
US20070173535A1 (en) Oxadiazoles having antiproliferative activity
JPH07119202B2 (en) Phenylsulfinylalkylcarboxylic acid derivative
JPS5936679A (en) 5-oxo-5h-(1)benzopyrano(2,3-b)pyridine derivative, its preparation, and drug composition
JPH03193756A (en) Naphthyl sulfonyl alkylcarboxylic acid derivative
JPH07119198B2 (en) Phenylsulfonylalkylcarboxylic acid derivative

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): FI HU NO RO SU US

WWE Wipo information: entry into national phase

Ref document number: 147347

Country of ref document: RO

WWE Wipo information: entry into national phase

Ref document number: 911855

Country of ref document: FI

WWG Wipo information: grant in national office

Ref document number: 911855

Country of ref document: FI