AP118A - Prodrugs of antiflammatory 3-acyl-2-oxindole-1-carboxamides - Google Patents

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

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Publication number
AP118A
AP118A APAP/P/1989/000141A AP8900141A AP118A AP 118 A AP118 A AP 118A AP 8900141 A AP8900141 A AP 8900141A AP 118 A AP118 A AP 118A
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compound
carbon atoms
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Thomas C Crawford
Lawrence Alan Reiter
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Pfizer
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    • 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 Table
    • 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

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  • Rheumatology (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

Certain enol ethers and esters of the formula where x and y are each hydrogen, fluoro or chloro; r1 is 2-thienyl or benzyl and r is alkanoyl, cycloalkyl-carbonyl, phenylalkanoyl, chlorobenenzoyl, methoxybenzyl, phenyl, thenoyl, omega-alkoxycarbonylalkanoyl, alkoxy-carbonyl, phenoxycarbonyl, 1-alkoxyalkyl, 1-alkoxy-carbonyloxyalkyl, alkyl, alkylsulfonyl, methylphenyl-sulfonyl or dialkylphosphonate are useful as prodrug forms the known 3-acyl-2-oxindole010carboxamide anti-inflammatory and analgestic agents.

Description

j The present invention is concerned with antiinflammatory agents and, in particular, with enol esters and ether prodrugs of 3-acyl-2-oxindole-lcarboxamides, a class of known nonsteroidal antiinflammatory 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 disclosed 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.
The present invention provides antiinflammatory 20 ether and ester prodrugs of the formula
AP 0 0 0 1 1 8 wherein X and Y are each hydrogen, fluoro or chloro; R1 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
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2atoms, chlorobenzoyl, methoxybenzoyl, thenoyl, omegaalkoxycarbonylalkanoyl 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 dialkylphosphonate said alkyl each of one to three carbon atoms.
Particularly preferred are compound of formula (I) where R3 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 i-butyryl.
A second preferred group of compounds of formula (I) are those where R3, 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 R3, 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 ethoxycarbonylpropicnyl.
A fourth group of preferred compounds of formula (I) are those where R3- is 2-thienyl, X is chloro, Y is hydrogen and R is alkoxycarbonyl of two to ten carbon
-3atoms. Especially preferred within this group are compounds where R is methoxycarbonyl, ethoxycarbonyl and n-hexoxycarbonyl.
. A fifth group of preferred compounds of formula * I (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 l-(ethoxycarbonyloxy)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 compounds where R is acetyl, propionyl and ^-butyryl.
An eighth group* of preferred compounds of formula (I) are those where R^ 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 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.
APO 00 1 1 8
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I
4The 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 l0 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 ail of the usual routes of administration are useful with the invention compounds, the preferred route of administration is oral. After gastrointestinal 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 antiinflammatory drugs (see e.g., DelFavero in Side Effects of Drugs Annual 7, Dukes and Elis, Eds.
-5Excerpta 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-carboxamides 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
or mixtures thereof are depicted as
AP 0 0 0 1 1 8
All forms of these isomers are considered part of the present 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-cxindole-l-carboxamide ar.d an equimolar amount of triethylamine in a reaction-inert solvent such as chloroform, at 0°C with an equimolar amount, plus a
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-6slight excess of the requisite acid chloride, chloroformate, 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-l20 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.
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-7The 3-acyl-2-oxindole-l-carboxamides required as starting materials are available by methods veil known in the art, see, for example, the reference to these 5 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
IQ to known methods such as the rat foot edema test, rat adjuvant-induced arthritis test or phenylbenzoquinoneinduced 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 literals ture; see e.g., C. A. Winter, in Progress in Drug Research edited by E. Jucker, Birkhaaser Verlag,
Basel, Vol. 10, 1966, pp. 139-192.
In comparison with the parent 3-acyl-2-oxindole-lcarboxamides 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 et al. , Prostaglandins, 19, 51-59 (1980). In the modified procedure cultures of rat basophilic leukemic cells (RBL-1), prepared by the method of Jakschik et 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
AP 0 0 0 1 1 8
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-8and it is known that the hydrolysis takes place after the prodrug leaves the stomach, they will significantly reduce the gastric irritation caused by oral adminis5 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
IQ 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 nonenolic 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-carboxaau.de in chloroform is added an equimolar amount of triethylamine. The resulting solution is cooled to 0*C and a slight excess of the appropriate acid chloride, chloroformate, oxonium salt or alkylating agent added.
IO After stirring for 2 hours at 0*C and then at room temperature for 2 hours, if the 3-acyloxindole-lcarboxamide 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-lcarboxamide. 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 chromatography.
Method B
A mixture of 3-acyl-2-oxindole-l-carbcxamide, a
3-fold molar excess of the appropriate alphachloroalkyl- 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.
AP 0 0 0 1 1 8
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I
-10The cooled mixture is then diluted with water and extracted with ether. The combined ether extracts are dried with MgSO^, filtered, and the filtrate concentrated in 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:
I o nh2
Esters:
(R » -COCHj) -.Method A; yield 53¾ after recrystallization 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); ^H-NMR (CDCl-j) delta 2.39 , 2.53 (3H, 2s), 5.31 (1H, br s), 7.2-7.35 (2H, m, , 7.48, 7.55 (13, 2d, J=2.lHz),
7.6-8.3 (3H, m), 8.54 (1H, br s). Anal, calcd for C16H11C1N2O4S (362.79): C, 52.97; H, 3.06; N, 7.72. Found: C, 52.91; H, 2.95; N, 7.97.
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I
-1110
IS (R » -COCHjCHj) - Method A; yield 181 after recrystallization from 2-propanol; mp 183-185*C; mass spectrum m/e (relative intensity) M+, 378, 376 (<1, 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-Me2SO) delta 1.0-1.3 (3H, m) , 2.7-3.0 (2H, q, J-7.5H2, ,
6.9-7.6 (3H, m) , 7.9-8.4 (5H, m) . Anal, calcd for C17H13C1N2O4S (376.68): C, 54.18; B, 3.48; N, 7.43. Found: C, 53.86; H, 3.33; N, 7.28.
(R » -CO(CHj) gCHj) - Method A; yield 291 after recrystallization from 2-propanol; mp 189-190*C; mass 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); 1fl-NMR (CDClj) delta 0.95 (3H, m) , 1.32-1.55 (6H, m) , 1.85 (2H, pentet, J»8Hz), 2.83 (2H, t, J»8Hz), 5.35 (lH, br s) , 7.25 (1H, m), 7.32 <1H, m) , 7.60 (1H, d), 7.72 (1H, m), 8.27 (1H, m), 8.31 (1H, d, J-lOHz) , 8.62 (1H, br s) . Anal, calcd for C22H21C1N2O4S (432.91): C, 58.26; H, 4.89; N,
6.47. Found: C, 53’.18; H, 4.87; N, 6.42.
(R -CO(CH2) gCH3) - Method A; yield 81 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), 243 (9.0), 195 (26.4), 193 (100), 155 (7.4), 137 (6.3), 111 (18.2); ^H-NMR (dg-Me^O) delta 0.87 (3H, s) , 1.30 (13H, br s) , 1.50 (1.H, m) ,
1.65 (1H, m) , 2.20 ilfl, t, J=7.2Hz), 2.70 (1H, t, J=7.3Hz), 7.1-8.5 (7H, m) . Anal, calcd for
AP 0 0 0 1 1 8
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-1210
IS
2S
C24H27C1N2O4S (474.75): C, 60.68; H, 5.73; N, 5.90. Found: C, 60.64; H, 5.76; tt, 5.88.
(R - -COCH(CH3)2) - Method A; yield 371 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 (4.6, 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 (1H, septet, J»8Hz, isomer A), 3.05 (1H, septet, J«8Hz, isomer B), 5.38 (1H, br s isomer A), 5.45 (1H, br s, isomer B, , 7.2-7.4 (2H, m) , 7.54 (1H, d), 7.7-7.8 (2H, m), 8.2-8.3 (1H, m), 8.48 (1H, br s, isomer B), 8.55 (1H, br s, isomer A) (note:
isomer ratio of A to B is approximately mass calcd for C^gH^jClNjO^S: 390.0449. 390.0462.
80:20) . Found:
Exact (R » -COC(CH3)3, - Method A; yield 51% after recrystallization from 2-propanol; mp 198-200eC; 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 (1H, br s) ,
7.23 (2H, m), 7.50 (1H, d, J»2.2Hz), 7.71 (1H, dd,
J-l.l, 5.0Hz), 7.77 (1H, dd, J-l.l, 3.8Hz), 8.25 (1H, d, J=8.8Hz), 8.57 (1H, br s). Anal, calcd for
C.aH.-C1N.O.S (404.85): C, 56.36; H, 4.23; N, 6.92.
17 24
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 (3.0), 277 (19.8), 19 bad
I
-1310 (16.3), 193 (60.0), 111 (67.1), 83 (100), 55 (25.8); ^H-NMR (dg-Me2SO) delta 1.05-1.70 (11H, set of m), 6.95-7.10 (1H, m), 7.18 (1H, t, J»4.4Hz), 7.31 (1H, dd, J»2.2, 8.8Hz), 7.4 (1H, m) , 7.70-8.15 (4H, set of m) . Anal, calcd for C^B^ClNjO^S (429.72); C, 58.53; H, 4.44; N, 6.50. Found; C, 58.34; H, 4.32; H, 6.43.
(R » -COPh) - Method A; yield 441 after recrystallization 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 (1H, br s), 7.30 (3H, m) ,
7.55 (3H, ra) , 7.65 (1H, a), 7.74 (1H, dd, J-1.0,
5.0Hz), 7.84 (1H, dd, J-1.0, 3.8Hz), 8.2-8.3 (3H, m) , 8.45 (1H, br s). Anal, calcd for c2lHl3ClN2°4S·Η2Ο (442.87); C, 56.95; H, 3.41; N, 6.32. Found: C,
57.24; H, 3.08; N, 6.09.
(R - -COCHjPh) - Method A; yield 3% after filtration through silica gel (10:90 - methanol/chloroform) and two recrystallizations from 2-propanol; mp , 4.
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 (1H, br s), 7.02 (1H, dd, J=4.0, 5.1Hz), 7.15 (1H, dd,
J-2.2, 8.8Hz), 7.3-7.4 (6H, m), 7.57 (1H, dd, J-1.2, 5.1Hz), 7.90 (1H, dd, J=1.2, 4.0Hz), 8.15 (1H, d, J=8.8Hz), 8.30 (1H, br s). Anal, calcd for C22H15C1N2°4S <438·87>: c' 60.20; H, 3.45; N, 6.38. Found: C, 80.53; H, 3.38; N, 6.18.
AP 0 0 0 1 1 8
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-14(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 5 (<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)? lH-NMR (dg-Me^O, delta 1.75-2.05 (2H, m,, 2.22 (1H, t, J-7.4HZ), 2.55-3.00 (3H, m,, 6.90-7.65 (9H, m,, 7.85-8.50 (4H, m). Anal.
l0 calcd for C24H19C1N2°4S (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)? ^H-NMR (CDCip delta 5.28 (1H, br s), 7.25 (2H, m) , 7.51 (2H, m), 7.62 (1H, m), 7.74 (1H, dd, J-l.l, 5.0Hz), 7.84 (1H, dd, J-l.l, 3.8Hz),
8.07 (1H, m), 8.16 (1H, m), 8.27 (1H, d, J-8.8Hz), 8.41 (1H, br s,. Anal, calcd for (459.29):
C, 54.91? H, 2.63? M, 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)? lH-NMR (CDC13) delta 4.05, 4.10 (3H, 2s), 5.35, 5.46 (1H, 2 br
s), 7.15 (2H, m), 7.40 (3H, m) 7.68 (1H, d, J=2.1Hz), 7.36 (1H, dd, J-l.l, 5.0Hz), 7.97 (13, dd, J-l.l, baDo»q’nM·
I
153.8Hz), 8.29 (1H, m) , 8.41 (1H, m) , 8.60, 8.77 (1H, 2 br s). Anal, calcd for C22H15ClN2O5S (454.87): C, 58.09; H, 3.32; N, 6.16. Found: C, 57.99; H, 3.22; N, 5 6.07.
(R -CO (2-thienyl)) - Method A; yield 16% after being twice flash chromatographed (1st: chloroform; 2nd: 0.5:99.5 - methanol/chloroform); mp 220-222*C; mass spectrum m/e (relative intensity) M+, 432, 430 l0 (0.4, 1.1), 389 (0.4), 387 (0.7), 279 (0.6), 277 (1.7), 113 (5.1), 111 (100); XH-NMR (dg-Me^O) delta 7.3-7.5 (4H, m), 7.8-8.4 (7H, m). Exact mass calcd for Ci9H11clN204S2:429.9849. Found: 429.9825.
(R ® -COCHjCHjCOjEt) - 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 (dg-Me2SO) delta 1.15 (3H, m) , 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 m), 7.70 (1H, m) , 7.85-8.45 (4H, complex set of m). Anal, calcd for C20H17C1N2°6 <448·87)·· c' 53.51; H, 3.82; N, 6.24. Found: C, 53.49; H, 3.70; N, 6.23.
^AD ORIGINAL
-1610
Carbonates
C16H11Clii2O5S (378.22):
(R -COOCHj) - Method A; yield 291 after recrystallization from 2-propanol/chloroform; mp 180”C 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-NMR (dg-MejSO) delta 3.90, 3.95 (3H, 2s,, 7.3-7.5 (3H, m,, 7.95-8.05 (2H, m) , 8.15-8.25 (3R, a). Anal, calcd for
C, 50.73; H, 2.93; N, 7.39.
Found: C, 50.84; H, 2.93; N, 7.34.
(R » -COOCHjCHj, - Method A; yield 241 after recrystallization from 2-propanol; mp 170-175*C; mass 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-7.1HZ), 5.41 (1H, br s), 7.25 (2H, a), 7.48, 7.66 (1H, 2d, J»2.1 and 2.2Hz) 7.75 (IB, m,, 8.25 (2H, m, , 8.57 (1H, br s).
(392.79): C, 51.98; *H, 3.34; ii, 7.13. Found: C, 51.90; H, 3.26; N, 6.93.
(R » -COOCH(CH3)2) - Method A; yield 371 after 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 (12.4), 102 (3.0),· L
Anal, calcd for 3ClN20jS (4.3), 111 1.34, 1.37 (6H, 2s), 5
H-NMR (dg-Me2SO) delta (1H, heptet, J=6.2Hz), 7.35 (1H, t, J=4.3Hz), 7.50 (1H, dd , J=8.7Hz), 7.55 (1H, m) , 7.96, 8.05 (2H, 2 br s) , 8.17 (2H, m), 8.25 (1H, m) .
OR'<
-17Anal. calcd for ci8H15C1N2°5S (406.69): C, 53.14; H, 3.72; If, 6.89. Found: C, 52.93; H, 3.65; N, 6.82.
(R » -COO(CH2)5CH3, - Method A; yield 39% after s 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); XH-NMR (dg-MejSO) delta 0.85 (3H, br t, J»6.6Hz), 1.3 (6H, m), 1.6 (2H, l0 m) , 4.35 (2H, t, J-6.2Hz), 7.35 (1H, t, J-4.3),
7.4-7.55 (2H, m), 7.95-8.05 (2H, m) , 8.15-8.25 (3H, m) . Anal, calcd for C2iH21ClN2°5S (448.91): C, 56.18; H, 4.72; N, 6.24. Found: C, 56.11; H, 4.60; N, 6.16.
(R ’ -COO(CH2)gCH3) - Method A; yield 21% after recrystallization from 2-propanol; mp 118-120*C; mass 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 (1H, br s), 7.24 (1H,
m) , 7.32 (1H, dd, J=«2.2, 8.8Hz), 7.68 (1H, d, J=»2.lHz), 7.74 (1H, dd, J-l.2,’ 5.1Hz), 8.20 (1H, dd, J»1.2, 4.0Hz), 8.29 (1H, d, J»8.8Hz), 8.58 (1H, br s). Anal, calcd for C24H22ClN2°5S (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 recrystallization from 2-propanol; mp 212-214’C; mass spectrum m/e (relative intensity) M+, 442, 440 (1.7, 5.7), 399
APO00 1 1 8
(4.4), 397 (9.7), 355 (< 1) , 354 (< 1) , 353 (2.9) , 352
30 (1.7, , 338 (< 1, , 336 (2.5), 250 (13.4), 248 (44.3) f
234 (9.7), 232 (24.0) , 195 (8.1) , 193 (27.7) , 111
(100); 1H- NMR (CDC13) delta 5.90 (1H, br s) , 7.1-7. 4
BAD ORIGINAL
-18(7H, m), 7.74 (2H, m), 8.22 (2H, m) , 8.39 (1H, br s). Anal, calcd for C2iHi3C1N2°5S (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)OCOCH3) - 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 91 after twice being flash chromatographed (first: 1:99 methanol/chloroform, second: 0.5:99.5 - methanol/ 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-NMR (CDC13) delta
1.70 (3H, d, J-5.4HZ), 1.94 (3H, s), 5.16 (1H, br, s),
6.31 (1H, q, J»5.4Hz>, 7.23 (1H, dd, J-3. 9, 5.2Hz),
7.27 (1H, d, J’2.2Hz), 7.52 (1H, dd, 1.2, 3.7Hz), 7.69
(1H, dd, J-l.l, 5.1Hz), 7.98 (1H, d, J-2. 2Hz), 8.21
(1H, d, J—8.8Hz), 8.47 (1H, br s) . Anal. calcd for
C18H 1 ,-ΟίΝ,Οςδ (406.83): C, 53.14; H , 3.72; M, 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 159-162eC; 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); ^H-NMR (CDCl-j, delta 1.21 (3H, t, J=7.lHz), 1.73 (3H, d, J=«5.3Hz), 4.10 (2H, q, J=5.3Hz),
I
195.19 (1H, br s), 7.26 (2H, m) , 7.52 (1H„ dd, J-l.l, 3.7Hz), 7.71 (1H, dd, J-l.l, 5.0Hz), 7.97 (1H, d, J-2.2Hz), 8.22 (1H, d, J»8.7Hz), 8.47 (1H, br s).
Anal, calcd for C^H^ClNjOgS (436.86): C, 52.23? H, 3.92; N, 6.41. Found: C, 52.57? H, 4.44? M, 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 (1H, br s) , 6.14 (1H, q, J-5.2HZ), 7.26 (2H, m) , 7.54 (1H, dd, J-1.2, 3.7Hz), 7.70 (1H, dd,
J-1.2, 5.0Hz), 8.00 (1H, d, J-2.2HZ), 8.21 (1H, d, J»8.7Hz), 8.49 (1H, 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)OCOOCHjPh) - Method B; yield 11» after flash chromatography (25:75 - ethyl acetate/ hexane) and recrystdllization 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 (1H, d, J=llHz), 5.04 (1H, d, J=llHz), 5.28 (1H, br s), 6.20 (1H, q, J=5Hz), 7.1-7.3 (7H, m), 7.44 (1H, m) , 7.61 (1H, m) , 7.93 (1H, d, J=2Hz) , 8.20 (1H, d, J=9Hz) , 8.40 30 (1H, br s) . Anal, calcd for jH^ClJ^OgS (498.92): C,
57.77? H, 3.84; N, 5.62. Found: C, 57.78? H, 3.80; N, 5.59.
AP 0 0 0 1 1 8 ’BAD ORIGINAL ά
-20Ethers:
(R -CH^) - Method A using triune thy loxoni uni tetrafluoroborate; yield 27t 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 (CDClj) delta 3.88 (3H, s), 5.25 (1H, br s), 7.27 (3H, m) , 7.69 (1H, d, J-5.7HZ), 7.88 (1H, d, J-2.2H2), 8.21 (1H, d, J»8.7Hz), 8.49 (1H, br s). Anal, calcd for C15HUClN2°3S {334-76); C, 53.81; H, 3.31; N, 8.37. Found: C, 54.15; H, 3.48; N, 8.10.
(R » CHjCHj) - Method A using triethyloxonium tetrafluoroborate; yield 221 after recrystallization from 2-propanol; mp 202-205eC (relative intensity) M+, 350, (< 1), 307 (7.3) , 305 (19.6), (27.0), 193 (100), 187 (1.2), (3.2), 139 (2.8) , 137 (8.1) , (d6-Me2SO) delta 1.40 (3H, t, J-7.0HZ), 7.30 (1H, A), 7.35 (1H, m), 7.65 (1H, s), 7.90 ( dd, J =»1.0, 5.0Hz), 8.05 (1H, Anal, calcd for C^gH^^ClNjO^S 3.76; N, 8.03. Found:, 54.87 Sulfonates :
mass spectrum m/e
348 (1.5, 4.6), 320
250 (2.2), 248 (7.4) , 195
185 (4.7), 167 (1.3) , 165
111 (24.0); 1H-NMR
J-7 .0Hz), 4.15 (2H, q,
(1H, dd, J-2.3, 8.7), 7.50
1H, d, J»2.3Hz), 8.00 (1H,
s) , 8.15 (1H, d, J-8. 7Hz) .
(34 8.67): C, 55.09; H,
3.62; N, 7.79.
after being - methanol/ (R = -SO2CH3) - Method A; yield 4¾ twice filtered through silica gel (5:95 chloroform) and recrystallizaticn 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),
I
-21259 (45.3) , 250 (31.0), 248 (100), 141 (15.4), 139 (42.9), 113 (6.1, , 111 (37.7); 1H-NMR (CDCip delta
3.02 (3H, 3), 5.23 (1H, br s), 7.23 (1H, m), 7.37 (1H, dd, J»2.2, 8.8Hz), 7.76 (2H, m) , 8.16 (1H, d, J»2.lHz),
8.26 (1H, d, J»8.8Hz), 8.33 (1H, br s). Anal, calcd for C15H11C1N2O5S2 (398.83): C, 45.17; H, 2.78; N,
7.03. Found: C. 45.30; H, 2.60; N, 6.78.
(R » -SO2(4-Me-Ph) - Method A; yield 61 after recrystallization from 2-propanol;. mp 200-202’C; mass spectrum ra/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), (42.2); 1H-NMR (dg-Me2SO) delta 2.40 (3H, s), 7.05 (1H, t, J»4.5HZ), 7.35-7.50 (4H, m), 7.65 (3H, m), 7.90 qq (3H, m) , 8.12 (1H, d, J«8.7Hz). Anal, calcd for *— C21H15C1N2°5S2 <474·78)* c' 53.10; H, 3.18; N, 5.89. x~
Found: C, 53.09; H, 3.22; N, 5.66. ° o
Phosphonates: o (R » -PO(OCH2CH3)2) - Method A; yield 141 after fX, 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); ^-NMR (CDCip delta 1.33 (6H, dt, J=1.2, 7.1Hz), 4.14 (4H, m) , 5.23 (1H, br s), 7.32 (1H, dd, J=2.2, 8.8Hz), 7.70 (1H, dd, J=1.2, 5.0Hz), 7.83 (1H, dd, J»1.2, 3.8Hz),
BAD ORIGINAL i
228.06 (1H, d, J-2.2HZ), 8.25 (1H, d, J»8.8Hz), 8.46 (1H, br s). Anal, calcd for C18H18C1N2O6PS (456.83): C, 47.32; H, 3.97; N, 6.13. Pound: 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:
I
NH2
Esters:
(R » -COCHj) - Method A; yield 16% after recrystallization from 2-propanol; mp 190-203eC; 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 (dg-Me2SO) delta 1.9, 2.4 (3H, 2s), 7.C9-7.40 (2H, set of m), 7.55-7.80 (1H, set of m) , 7.95-3.50 (4H, set of m) . Anal, calcd for C^H^CIFN^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 - methanol/ 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)? ^H-NMR (dg-Me2SO) delta
1.18 (3Ha b, m) 2.22 (2H*, q, J-7.5HZ), 2.71 (2Hb, q, ,0 J«7.5Hz),*7.09-7.70 (2H ., m), 7.95-8.48 (5H . m) .
Anal, calcd for C17H12C1FN2O4S (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)? XH-NMR (d6-Me2SO, delta 1.34 (6H, d, J»7.0Hz), 3.25 (1H, heptet, J»7.0Hz), 7.33 (1H, dd, J-4.0, 5.1Hz), 7.48 (1H, d, J-9.6HZ), 8.00 (1H, br s), 8.03 (1H, br s) ,
8.13 (1H, dd, J-1.2,’ 5.0Hz). Anal, calcd for C18H14C1FN2°4S (4θθ·83)ί c' 52.88? H, 3.45; N, 6.85. Found: C, 52.48; H, 3.32? N, 6.86.
(R = -COCH2Ph, - Method A? yield 22% after recrystallization from 2-propanol? mp 189-199eC? mass spectrum m/e (relative intensity) M , not observed, 340
APO 00 1 1 0
(18.9), 338 (42.1), 297 (20.7), 295 (54.4), 268 (5.3) ,
266 (19.6), 213 (17.9), 211 (53.7), 91 (100); 1 H-NMR
30 (dg-Me2SO) delta 3.98 (2Ha, s), 4.02 (2Hfa, s), 5.35
(1H, br s) , 6.99-7.45 (7H, m), 7.68, 8.00 (2H, 2m) ,
BAD ORIGINAL
-248.42 (1H, dd, J»5.1, 6.9Hz), 8.50 (1H, br s) . Anal, calcd for C22H14C1FN2O4S (456.86): C, 57.83; H, 3.09? N, 6.13. Pound: C, 57.53; H, 2.98; N, 6.15.
(R
-COCH2CH2COOEt) - Method A; yield 264 after recrystallization from 2-propanol; mp 153-155^0: 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); ^H-NMR (d6-Me2SO) delta 1.12 (3H, 2t, J-7.1HZ), 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 (1H, m), 7.95-8.43 (4H, complex set of m). Anal, calcd for C20H16C1FN2°6S <466·7θ): c· 51.45; H, 3.45; N, 6.00. Found: C, 51.28; H, 3.26; N, 5.99.
Carbonates:
(R » -COOCH^) - Method A; yield 254 after recrystallization from 2-propanol; mp 203-205*C; mass spectrum m/e (relative intensity) M , 398, 396 (7.5, 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), 83 (5.5); 1H-NMR (dg-Me2SO) delta 3.89, 3.95 (3H, 2s), 7.38 (2H, m) , 8.00 (3H, m) , 8.19 (1H, m) , 8.29 (1H, t, J=6.7Hz). Anal, calcd for ClgH1()ClFN2O5S (396.71): C, 48.43; H, 2.54; N, 7.06. Found: C, 48.41; H, 2.47; N, 6.95.
(R = -COCCH2CH2) - Method A; yield 57% after recrystallization from 2-propar.ol; 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
I
-25(13.7), 213 (37.6), 211 (100), 203 (7.9), 155 (7.5),
111 (21.0); XH-NMR (dg-Me^O) delta 1.30 (3H, t, J-7.1HZ), 4.32 (2H, q, J»7.1Hz), 7.35 (2H, m) , 8.0 (3H, m) , 8.20-8.35 (2H, m) . Anal, calcd for ci7Hi2CXFN2°5S (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 85¾ 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);
XH-NMR (CDC13) delta 0.85-0.92 (3H, m), 1.22-1.48 (6H,
m), 1.72 (2H, pentet, J»9Hz), 4.31 (2Ha fe, t), 5.40 (1H ., br s), 7.21 (1H ., m), 7.30 (1H . d, J-9Hz), a, o a f o a
7.47 (lHb d, J=9Hz), 7.77 (2H*, lHb, m, , 8.19 (lHb, m),
8.42 (1H d, J»8Hz), 8.46 (1H., d, J-8Hz) , 8.49 (1H , a o a br s) , 8.52 (lHy br s) . Anal, calcd for C21H20Cli,N2°5S ί466·91>! c» 54.02; H, 4.32; N, 6.00. Found: C, 53.93; H, 4.26; N, 6.02.
Sulfonates:
(R =* -SOjCHj) -’Method A; yield 9¾ after filtration through silica gel and recrystallization from cyclohexane/ethyl acetate; mp 180-185eC; 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 ClsH10ClFN2OsS2 (416.85): C, 43.22; H, 2.42; N, 6.72. Found: C, 43.37; H, 2.30; N, 6.72.
AP 0 0 0 1 1 8 'BAD ORIGINAL
-26EXAMPLE 3
Using the indicated procedure and starting with the requisite reagents, the following compounds were prepared:
Esters:
(R ” -COCHj) - 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); 3H-NMR (d-.-Me-.SO) delta 2.31 (3H, s), 4.51 (2H, s), 7.02 (1H,
O 4 · 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 (354.19): C, 64.40; H, 4.27; N, 7.91. Found: C, 64.30; H, 4.21; N, 7.89.
(R = -COCH2CH2) - Method A; yield 23% after recrystallization from 2-propanol; mp 196-198’C; mass spectrum m/e (relative intensity) M+, 363 (2), 325 (5), 312 (25), 269 (70), 251 (7), 240 (4), 221 (5), 178 (100), 150 (3), 121 (10), 91 (37), 65 (12), 57 (03); 1H-NMR (d6-Me2SO) delta 1.02 (3H, t, J=7.4Hz), 2.61 (2H, q, J=7.4Hz), 4.53 (2H, s), 7.02 (1H, dt, J=2.6,
9.2Hz), 7.32 (6H, m), 7.61 (1H, dd, J»5.8, 8.6Hz), 7.95 (2H, m). Anal, calcd for C2QH17FN2O4 (368.20): C, 65.21; H, 4.65; N, 7.61. Found: C, 64.98; H, 4.44; N,
^.54.
(R - -COCH(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), l0 91 (31.8), 71 (100); XH-NMR (dg-MejSO) delta 1.09 (3H, d, J-7.0HZ), 2.64 (1H, dq, J»7.0Hz), 4.65 (2H, s), 5.36 (1H, br s), 6.83 (1H, dt, J»2.5, 8.7Hz), 7.18-7.33 (5H, m, , 7.50 (1H, dd, J»5.6, 8.6Hz), 8.10 (1H, dd, J-2.5, 10.3Hz), 8.59 (1H, br s) . Anal, calcd for C21H19FN2°4 (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 recrystallization 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);
1H-NMR (CDC13) delta 4.71 (2H, d), 5.41 (1H, br s),
6.71 (1H, dt, J»2.5,’ 8.7Hz), 7.26 (5H, m) , 7.42 (1H, dd, J»5.6, 8.6), 7.52 (2H, m), 7.66 (1H, m), 8.03 (2H, d), 8.10 (1H, dd, J»2.5, 10.3Hz), 8.63 (1H, br s) .
Anal, calcd for C24H1?FN2O4«HjO (434.41): C, 66.35; H, 4.40; N, 6.44. Found: C, 66.14; H, 3.92; N, 6.41.
(R = -COCH2Ph) - Method A; yield 27% after recrystallization 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), 4.43 (2H, s),
6.85 (2H, dt, J=2.6, 3.9Hz), 7.28 (10H, m), 7.91 (1H,
APO00 1 1 8
BAD ORIGINAL
A dd, J»2.5, 10.7Hz), 7.97 (1H, br s), 8.07 (1H, br s). Anal, calcd for C25H19FN2O4 (430.25,: C, 69.76; H, 4.45; N, 6.51. Found: C, 69.35; H, 4.38; N, 6.62.
(R » -COCH2CH2COOEt, - 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); *H-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 (1H, dt, J-2.6, 8.9Hz), 7.32 (5H, m), 7.67 (1H, dd, J»5.8, 8.6Hz), 7.93 (1H, dd, J-2.5, 10.7Hz), 7.98 (1H, br s), 8.08 (1H, br s). Anal, calcd for C23H21FN2Og (440.23): C, 62.72; H, 4.81; N, 6.36.
Found: C, 62.75; H, 4.79; N, 6.29.
Carbonates:
(R - -COOCHj, - Method A; yield 45% after recrystallization 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); ^H-NMR (dg-Me2SO) delta 3.86 (3H, s) , 4.58 (2H, s), 7.08 (1H, dt, J-2.6, 9.1Hz), 7.32 (5H, s), 7.55 (1H, dd, J=5.9, 8.7Hz), 7.95 (1H, dd, J=2.5, 10.6H2), 7.99 (1H, br s), 8.07 (1H, br s). Anal, calcd for C19H15FN2O5 (370.19): C, 61.62; H, 4.08; N, 7.56. Found; C, 61,64; H, 4.07; N, 7.55.
-29(R - -COCCH2CH3) - Method A; yield 52% after recrystallization from 2-propanol; mp 189-190’C; mass spectrum m/e (relative intensity) M , 384 (8.8), 340 5 (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-Me2SO, delta 1.23 (3H, t, J-7.1Hz,, 4.26 (2H, q, J-7.lHz), 4.58 (2H, s,, 7.08 (1H, dt, J-2.5, 8.9Hz), l0 7.32 (5H, m,, 7.53 (1H, dd, J-5.8, 8.6Hz), 7.94 (1H, dd, J-2.6, 10.7Hz), 7.99 (1H, br s,, 8.07 (1H, br s). Anal, calcd for C20H1?FN2O5 (384.19): C, 62.52; H, 4.42; N, 7.29. Found: C, 62.59; H, 4.41; N, 6.98.
(R - -COO(CHj)gCHj) - 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-Me2SO) 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 (1H, dt, J-2.5, 9.0Hz), 7.31 (5H, m) , 7.54 (1H, dd, J-5.8, 8.6Hz), 7.96 (1H, dd, J-2.5, 10.6Hz), 8.00 (1H, br s), 8.07 (1H, br s,.
Anal, calcd for C24H25FN2O5(440.24): C, 65.44; H,
5.72; N, 6.36. Found: C, 65.31; H, 5.62; N, 6.38.
BAD ORIGINAL

Claims (2)

  1. A compound of the formula 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, cycloalkylcarbonyl having five to seven carbon atoms, phenylalkanoyl having seven to ten carbon atoms, chlorobenzoyl, 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, methylphe.ny Isui fcnyl and dialkylphosphonate said alkyl each having from one to three carbon atoms.
    PAD
    ORIGINAL
    I
    -312. A compound of claim 1, wherein R^ 2-thienyl, X is chloro and Y is hydrogen.
    3. A compound of claim 2, wherein R having two to ten carbon atoms.
    4. The compound of claim 3, wherein
    5. The compound of claim 3, wherein propionyl.
    is is alkanoyl
    R is acetyl. R is
    6. The compound of claim 3, wherein R is isobutyryl.
    7. A compound of claim 2, wherein R is phenylalkanoyl having seven to ten carbon atoms.
    8. The compound of claim 7, wherein R is phenylacetyl.
    9. A compound of claim 2, wherein R is omegaalkoxycarbonylalkanoyl 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 omegaethoxycarbonylpropionyl.
    11. A compound of claim 2, wherein R is alkoxycarbonyl having two’ to ten carbon atoms.
    12. The compound of claim n, wherein R is methoxycarbonyl. 13. The compound of claim 11, wherein R is ethoxycarbonyl. 14. The compound of claim 11, wherein R is
    n-hexoxycarbcnyl.
    15. A compound of claim 2, wherein R is 1-alkoxycarbonyloxy) alky1 said alkoxy having two to five carbon atoms and said alkyl having one to four carbon atoms.
    :bad original $
    APO 00 1 1 8
    -3216. The compound of claim 15, wherein R is
    1- {ethoxycar bonyloxy)ethyl.
    17. A compound of claim 2, wherein R is alkyl3 sulfonyl having one to three carbon atoms.
    18. The compound of claim 17, wherein R is methylsulfonyl.
    19. A compound of claim 1, wherein is
  2. 2- thienyl, X is fluoro and Y is chloro.
    IQ 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.
    IS 23. The compound of claim 20, wherein R is isobutyryl.
    24. A compound of claim 19, wherein R is alkoxycarbonyl having two to ten carbon atoms.
    25. The compound of claim 24, wherein R is 20 methoxycarbonyl.
    26. The compound of claim 24, wherein R is ethoxycarbcnyl.
    27. The compound of claim 24, wherein R is n-hexoxycarbonyl.
    2S 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 30 acetyl.
    31. A compound of claim 28, wherein R is alkoxycarbcnyl having two to ten carbon atoms.
    -3332. The compound of claim 31, wherein R is me thoxycarbony1.
    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.
    AP 0 0 0 1 1 8
    BAD ORIGINAL
    -3U-
APAP/P/1989/000141A 1988-10-18 1989-10-16 Prodrugs of antiflammatory 3-acyl-2-oxindole-1-carboxamides AP118A (en)

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US5059693A (en) * 1989-10-06 1991-10-22 Pfizer Inc. Process for making 3-aroyl-2-oxindole-1-carboxamides
ATE146181T1 (en) * 1992-11-23 1996-12-15 Pfizer REGIOSELECTIVE SYNTHESIS OF 4-CHLORINE-2-THIOPHENE CARBOXYLIC ACID
US5270331A (en) * 1993-01-26 1993-12-14 Pfizer, Inc. Prodrugs of antiinflammatory 3-acyl-2-oxindole-1-carboxamides
CA2155664C (en) * 1993-02-09 1999-06-15 Ralph P. Robinson Oxindole 1-[n-(alkoxycarbonyl)]carboxamides and 1-(n-carboxamido)carboxamides as antiinflammatory 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
EP0984012A3 (en) * 1998-08-31 2001-01-10 Pfizer Products Inc. Nitric oxide releasing oxindole prodrugs with analgesic and anti-inflammatory properties
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