US2013316953A1PendingUtilityA1

New uses for amino acid anticonvulsants

Individually held — no corporate assignee on recordPriority: Aug 25, 2000Filed: Jul 29, 2013Published: Nov 28, 2013
Est. expiryAug 25, 2020(expired)· nominal 20-yr term from priority
A61P 43/00A61P 25/00A61P 25/04A61P 25/28A61P 29/00A61P 25/06A61P 25/14A61P 25/18A61K 31/40A61K 38/05A61K 38/04A61K 31/44A61K 31/165A61K 31/195A61K 31/16
60
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Claims

Abstract

The present invention is directed to the use of compounds of the formula: for treating pain, in particular neuropathic pain, bipolar disease and migraine headaches.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A method for alleviating pain in a patient suffering from chronic pain comprising administering to said patient an analgesic effective amount of a compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, and R is unsubstituted or is substituted with at least one electron withdrawing group or electron donating group; 
 R 1  is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, heterocyclic, lower alkyl heterocyclic, lower cycloalkyl, lower, cycloalkyl lower alkyl, each unsubstituted or substituted with an electron donating group or an electron withdrawing group; and 
 R 2  and R 3  are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, halo, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, or Z—Y wherein R 2  and R 3  may be unsubstituted or substituted with at least one electron withdrawing group or electron donating group wherein the electron donating group or electron withdrawing group is acyclic; and wherein heterocyclic in R 2  and R 3  is furyl, thienyl, pyrazolyl, pyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl, pyrrolinyl, piperazinyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl, morpholinyl, benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, purinyl, indolinyl, pyrazolindinyl, imidazolinyl, imidazolindinyl, pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, epoxy, aziridino, oxetanyl or azetidinyl; 
 Z is O, S, S(O) a , NR 6 ′, or PR 4 ; 
 Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, heterocyclic, heterocyclic lower alkyl, and Y may be unsubstituted or substituted with an electron donating group or an electron withdrawing group, or 
 ZY taken together is NR 4 NR 5 R 7 , NR 4 OR 5 , ONR 4 R 7 , OPR 4 R 5 , PR 4 OR 5 , SNR 4 R 7 , NR 4 SR 7 , SPR 4 R 5 , PR 4 SR 7 , NR 4 PR 5 R 6  or PR 4 NR 5 R 7 , 
 
       
         
           
           
               
               
           
         
         R 6 ′ is hydrogen, lower alkyl, lower alkenyl, or lower alkynyl and R 4  may be unsubstituted or substituted with an electron withdrawing group or electron donating group; 
         R 4 , R 5  and R 6  are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R 4 , R 5  and R 6  may be unsubstituted or substituted with an electron withdrawing group or an electron donating group; and 
         R 7  is COOR 8 , COR 8 , hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl or lower alkynyl, which R 7  may be unsubstituted or substituted with an electron withdrawing group or electron donating group; 
         R 8  is hydrogen or lower alkyl, or aryl lower alkyl, and the aryl or alkyl group may be unsubstituted or substituted with an electron withdrawing group or an electron donating group; and 
         n is 1-4; and 
         a is 1-3. 
       
     
     
         2 . The method according to  claim 1  wherein one of R 2  and R 3  is hydrogen. 
     
     
         3 . The method according to  claim 1  wherein n is 1. 
     
     
         4 . The method according to  claim 1  wherein one of R 2  and R 3  is hydrogen and n is 1. 
     
     
         5 . The method according to  claim 1  wherein R is aryl lower alkyl and R 1  is lower alkyl. 
     
     
         6 . The method according to  claim 1  wherein
 R 2  and R 3  are independently hydrogen, lower alkyl, heterocyclic, heterocyclic loweralkyl, or ZY; 
 Z is O, NR 4  or PR 4 ; 
 Y is hydrogen or lower alkyl; or 
 ZY is NR 5 R 6 R 7 , NR 5 OR 6 , ONR 5 R 7 , 
 
       
         
           
           
               
               
           
         
       
     
     
         7 . The method according to  claim 6  wherein
 R 2  is hydrogen and R 3  is hydrogen, lower alkyl, heterocyclic, heterocyclic loweralkyl or ZY; 
 Z is O, NR 4  or PR 4 ; 
 Y is hydrogen, lower alkyl; or 
 ZY is NR 5 NR 6 R 7 , NR 5 OR 6 , ONR 5 R 7 , 
 
       
         
           
           
               
               
           
         
       
     
     
         8 . The method according to  claim 6  wherein
 R 2  is hydrogen and R 3  is lower alkyl, which may be unsubstituted or substituted with an electron donating or electron withdrawing group, NR 4 OR 5 , or ONR 4 R 7 . 
 
     
     
         9 . The method according to  claim 8  wherein R 3  is lower alkyl which is unsubstituted or substituted with hydroxy or loweralkoxy, NR 4 OR 6  or ONR 4 R 7 , wherein R 4 , R 5  and R 7  are independently hydrogen or lower alkyl, R is aryl loweralkyl, which aryl group may be unsubstituted or substituted with an electron withdrawing group and R 1  is lower alkyl. 
     
     
         10 . The method according to  claim 9  wherein aryl is phenyl. 
     
     
         11 . The method according to  claim 6  wherein one of R 2  and R 3  is heterocyclic. 
     
     
         12 . The method according to  claim 11  wherein heterocyclic is heteroaromatic. 
     
     
         13 . The method according to  claim 11  wherein R 3  is furyl, pyridyl, thienyl or thiazolyl. 
     
     
         14 . The method according to  claim 9  wherein aryl is phenyl and is unsubstituted or substituted with halo. 
     
     
         15 . The method according to  claim 1  wherein the compound is
 (R)—N-Benzyl-2-acetamide-3-methoxy-propionamide; 
 O-methyl-N-acetyl-D-serine-m-fluorobenzylamide; 
 O-methyl-N-acetyl-D-serine-p-fluorobenzylamide; 
 N-acetyl-D-phenylglycinebenzylamide; 
 D-1,2-(N,O-dimethylhydroxylamino)-2-acetamide acetic acid benzylamide; 
 D-1,2-(O-methylhydroxylamino)-2-acetamido acetic acid benzylamide. 
 
     
     
         16 . The method according to  claim 1  wherein the pain is neuropathic pain. 
     
     
         17 . The method according to  claim 6  wherein the pain is neuropathic pain. 
     
     
         18 . The method according to  claim 1  wherein the pain is nociceptive pain. 
     
     
         19 . The method according to  claim 6  wherein the pain is nociceptive pain. 
     
     
         20 . A method for the prophylaxis or treatment of migraine headaches in a subject, comprising administering to said patient a headache relieving effective amount of a compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, and R is unsubstituted or is substituted with at least one electron withdrawing group or electron donating group; 
 R 1  is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, heterocyclic, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, each unsubstituted or substituted with an electron donating group or an electron withdrawing group; and 
 R 2  and R 3  are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, halo, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower alkyl heterocyclic lower cycloalkyl, lower cycloalkyl lower alkyl, or Z—Y wherein R 2  and R 3  may be unsubstituted or substituted with at least one electron withdrawing group or electron donating group; 
 Z is O, S, S(O) a , NR 4 , or PR 4 ; 
 Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, heterocyclic, heterocyclic lower alkyl, and Y may be unsubstituted or substituted with an electron donating group or an electron withdrawing group, or 
 ZY taken together is NR 4 NR 5 R 7 , NR 4 OR 5 , ONR 4 R 7 , OPR 4 R 5 , PR 4 OR 5 , SNR 4 R 7 , NR 4 SR 7 , SPR 4 R 5  or PR 4 SR 7 , NR 4 PR 5 R 6  or PR 4 NR 5 R 7 , 
 
       
         
           
           
               
               
           
         
         R 4 , R 5  and R 6  are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R 4 , R 5  and R 6  may be unsubstituted or substituted with an electron withdrawing group or an electron donating group; and 
         R, is COOR 8  or COR 8 , hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl or lower alkynyl, which R 7  may be unsubstituted or substituted with an electron withdrawing group or electron donating group; 
         R 8  is hydrogen or lower alkyl, or aryl lower alkyl, and the aryl or alkyl group may be unsubstituted or substituted with an electron withdrawing group or an electron donating group; and 
         n is 1-4; 
         a is 1-3; 
       
       wherein
 heterocyclic contains from 3 up to 18 ring atoms and up to a total of 17 ring carbon atoms containing 1 to 4 hetero ring atoms selected from the group consisting of nitrogen, oxygen and sulfur. 
 
     
     
         21 . The method according to  claim 20  wherein one of R 2  and R 3  is hydrogen. 
     
     
         22 . The method according to  claim 20  wherein n is 1. 
     
     
         23 . The method according to  claim 20  wherein one of R 2  and R 3  is hydrogen and n is 1. 
     
     
         24 . The method according to  claim 20  wherein R is aryl lower alkyl and R 1  is lower alkyl. 
     
     
         25 . The method according to  claim 20  wherein R 2  and R 3  are independently hydrogen, lower alkyl, aryl, aryllower alkyl, heterocyclic, heterocyclic loweralkyl or ZY;
 Z is O, NR 4  or PR 4 ; 
 Y is hydrogen, lower alkyl, aryl, aryl loweralkyl, heterocyclic or heterocyclic lower alkyl; or 
 ZY taken together is NR 4 NR 5 R 7 , NR 4 OR 5 , ONR 4 R 7 , 
 
       
         
           
           
               
               
           
         
          and 
         R 4 , R 5  and R 7  are independently hydrogen, lower alkyl, aryl or aryl lower alkyl. 
       
     
     
         26 . The method according to  claim 25  wherein R 2  is hydrogen and R 3  is lower alkyl, aryl, aryllower alkyl, heterocyclic or heterocyclic lower alkyl, or ZY;
 Z is O, NR 4  or PR 4 ; 
 Y is hydrogen, lower alkyl, aryl, aryl loweralkyl, heterocyclic or heterocyclic lower alkyl; or 
 ZY taken together is NR 4 R 5 R 7 , NR 4 OR 5 , ONR 4 R 7 , 
 
       
         
           
           
               
               
           
         
          and 
         R 4 , R 5  and R 7  are independently hydrogen, lower alkyl, aryl or aryl lower alkyl. 
       
     
     
         27 . The method according to  claim 26  wherein
 R 2  is hydrogen and R 3  is lower alkyl, which may be unsubstituted or substituted with an electron donating or electron withdrawing group, NR 5 OR 6 , or ONR 5 R 7 . 
 
     
     
         28 . The method according to  claim 26  wherein R 3  is lower alkyl which is unsubstituted or substituted with hydroxy or loweralkoxy, NR 4 OR 5  or ONR 4 R 7 , wherein R 4 , R 5  and R 7  are independently hydrogen or lower alkyl, R is aryl loweralkyl, which aryl group may be unsubstituted or substituted with an electron withdrawing group and R 1  is lower alkyl. 
     
     
         29 . The method according to  claim 26  wherein R 3  is heterocyclic. 
     
     
         30 . The method according to  claim 29  wherein heterocyclic is heteroaromatic. 
     
     
         31 . The method according to  claim 30  wherein R 3  is furyl, pyridyl, thienyl or thiazolyl. 
     
     
         32 . The method according to  claim 28  wherein aryl is phenyl. 
     
     
         33 . The method according to  claim 28  wherein aryl is phenyl and is unsubstituted or substituted with halo. 
     
     
         34 . The method according to  claim 20  wherein the compound is
 (R)—N-Benzyl-2-acetamide-3-methoxy-propionamide; 
 O-methyl-N-acetyl-D-serine-m-fluorobenzylamide; 
 O-methyl-N-acetyl-D-serine-p-fluorobenzylamide; 
 N-acetyl-D-phenylglycinebenzylamide; 
 D-1,2-(N,O-dimethylhydroxylamino)-2-acetamide acetic acid benzylamide; or 
 D-1,2-(O-methylhydroxylamino)-2-acetamido acetic acid benzylamide. 
 
     
     
         35 . A method of treating a patient suffering from bipolar disease comprising administering thereto a therapeutically effective amount of a compound for treating bipolar disease, said compound having the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, and R is unsubstituted or is substituted with at least one electron withdrawing group or electron donating group; 
 R 1  is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, heterocyclic, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, each unsubstituted or substituted with an electron donating group or an electron withdrawing group; and 
 R 2  and R 3  are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, halo, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, or Z—Y wherein R 2  and R 3  may be unsubstituted or substituted with at least one electron withdrawing group or electron donating group; 
 Z is O, S, S(O) a , NR 4 , or PR 4 ; 
 Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, heterocyclic, heterocyclic lower alkyl, and Y may be unsubstituted or substituted with an electron donating group or an electron withdrawing group, or 
 ZY taken together is NR 4 NR 5 R 7 , NR 4 OR 5 , ONR 4 R 7 , OPR 4 R 5 , PR 4 OR 5 , SNR 4 R 7 , NR 4 SR 7 , SPR 4 R 5  or PR 4 SR 7 , NR 4 PR 5 R 6  or PR 4 NR 5 R 7 , 
 
       
         
           
           
               
               
           
         
         R 4 , R 5  and R 6  are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R 4 , R 5  and R 6  may be unsubstituted or substituted with an electron withdrawing group or an electron donating group; and 
         R 7  is COOR 8 , COR 8 , hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl or lower alkynyl wherein R 7  may be unsubstituted or substituted with an electron withdrawing group or electron donating group; 
         R 8  is hydrogen or lower alkyl, or aryl lower alkyl, and the aryl or alkyl group may be unsubstituted or substituted with an electron withdrawing group or an electron donating group; and 
         n is 1-4; and 
         a is 1-3. 
       
     
     
         36 . The method according to  claim 35  wherein one of R 2  and R 3  is hydrogen. 
     
     
         37 . The method according to  claim 35  wherein n is 1. 
     
     
         38 . The method according to  claim 35  wherein one of R 2  and R 3  is hydrogen and n is 1. 
     
     
         39 . The method according to  claim 35  wherein R is aryl lower alkyl and R 1  is lower alkyl. 
     
     
         40 . The method according to  claim 35  wherein R 2  and R 3  are independently lower alkyl, aryl, aryllower alkyl, heterocyclic, heterocyclic lower alkyl, or ZY;
 Z is O, NR 4  or PR 4 ; 
 Y is hydrogen, lower alkyl, aryl, aryl loweralkyl, heterocyclic or heterocyclic lower alkyl; or 
 ZY taken together is NR 4 NR 5 R 7 , NR 4 OR 5 , ONR 4 R 7 , 
 
       
         
           
           
               
               
           
         
          and 
         R 4 , R 5  and R 7  are independently hydrogen, lower alkyl, aryl or aryl lower alkyl. 
       
     
     
         41 . The method according to  claim 40  wherein R 2  is hydrogen and R 3  is lower alkyl, aryl, aryllower alkyl, heterocyclic, heterocyclic lower alkyl or ZY;
 Z is O, NR 4  or PR 4 ; 
 Y is hydrogen, lower alkyl, aryl, aryl loweralkyl, heterocyclic or heterocyclic lower alkyl; or 
 ZY taken together is NR 4 NR 5 R 7 , NR 4 OR 5 , ONR 4 R 7 , 
 
       
         
           
           
               
               
           
         
          and 
         R 4 , R 5  and R 7  are independently hydrogen, lower alkyl, aryl or aryl lower alkyl. 
       
     
     
         42 . The method according to  claim 41  wherein
 R 2  is hydrogen and R 3  is lower alkyl, which may be unsubstituted or substituted with an electron donating or electron withdrawing group, NR 4 OR 5 , or ONR 4 R 7 . 
 
     
     
         43 . The method according to  claim 41  wherein R 3  is lower alkyl which is unsubstituted or substituted with hydroxy or loweralkoxy, NR 4 OR 5  or ONR 4 R 7 , wherein R 4 , R 5  and R 7  are independently hydrogen or lower alkyl, R is aryl loweralkyl, which aryl group may be unsubstituted or substituted with an electron withdrawing group and R 1  is lower alkyl. 
     
     
         44 . The method according to  claim 41  wherein R 3  is heterocyclic. 
     
     
         45 . The method according to  claim 44  wherein heterocyclic is heteroaromatic. 
     
     
         46 . The method according to  claim 45  wherein R 3  is furyl, pyridyl, thienyl or thiazolyl. 
     
     
         47 . The method according to  claim 43  wherein aryl is phenyl. 
     
     
         48 . The method according to  claim 43  wherein aryl is phenyl and is unsubstituted or substituted with halo. 
     
     
         49 . The method according to  claim 35  wherein the compound is (R)—N-Benzyl-2-acetamide-3-methoxy-propionamide;
 O-methyl-N-acetyl-D-serine-m-fluorobenzylamide; 
 O-methyl-N-acetyl-D-serine-p-fluorobenzylamide; 
 N-acetyl-D-phenylglycinebenzylamide; 
 D-1,2-(N,O-dimethylhydroxylamino)-2-acetamide acetic acid benzylamide; 
 D-1,2-(O-methylhydroxylamino)-2-acetamido acetic acid benzylamide. 
 
     
     
         50 . A method for treating a disorder in a mammal resulting from abnormal activity at the glycine b  site of the NMDA receptor in neurons of said mammal comprising administering to said mammal a therapeutically effective amount of a compound to interact with the glycine b  site of the NMDA receptor, said compound having the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, and R is unsubstituted or is substituted with at least one electron withdrawing group or electron donating group; 
 R 1  is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, heterocyclic, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, each unsubstituted or substituted with an electron donating group or an electron withdrawing group; and 
 R 2  and R 3  are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, halo, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, or Z—Y wherein R 2  and R 3  may be unsubstituted or substituted with at least one electron withdrawing group or electron donating group; 
 Z is O, S, S(O) a , NR 4 , or PR 4 ; 
 Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, heterocyclic, heterocyclic lower alkyl, and Y may be unsubstituted or substituted with an electron donating group or an electron withdrawing group, or 
 ZY taken together is NR 4 NR 5 R 7 , NR 4 OR 5 , ONR 4 R 7 , OPR 4 R 5 , PR 4 OR 5 , SNR 4 R 7 , NR 4 SR 7 , SPR 4 R 5  or PR 4 SR 7 , NR 4 PR 5 R 6  or PR 4 NR 5 R 7 , 
 
       
         
           
           
               
               
           
         
         R 4 , R 5  and R 6  are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R 4 , R 5  and R 6  may be unsubstituted or substituted with an electron withdrawing group or an electron donating group; and 
         R 7  is COOR 8  or COR 8 , hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl or lower alkynyl, which R 7  may be unsubstituted or substituted with an electron withdrawing group or electron donating group; 
         R 8  is hydrogen or lower alkyl, or aryl lower alkyl, and the aryl or alkyl group may be unsubstituted or substituted with an electron withdrawing group or an electron donating group; and 
         n is 1-4; and 
         a is 1-3. 
       
     
     
         51 . The method according to  claim 1  wherein the electron withdrawing group and electron donating group are selected from the group consisting of halo, nitro, carboxy, lower alkenyl, lower alkynyl, formyl, carboxyamido, trifluoromethyl, lower alkoxy carbonyl, hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, diloweralkylamino, mercapto, loweralkylthio, and lower alkyldithio. 
     
     
         52 . The method according to  claim 20  wherein the electron withdrawing group and electron donating group are selected from the group consisting of halo, nitro, carboxy, loweralkoxy carbonyl, lower alkenyl, lower alkynyl, formyl, aryl, arylloweralkanoyl, carboxyamido, hydroxy, loweralkoxy, lower alkyl, amino, lower alkylamino, diloweralkylamino, aryl, aryl lower alkanoyl, trifluoromethyl, aryloxy, lower alkylthio, mercapto, and lower alkyldithio. 
     
     
         53 . The method according to  claim 35  wherein the electron withdrawing group and electron donating group are selected from the group consisting of halo, nitro, carboxy, loweralkoxy carbonyl, lower alkenyl, lower alkynyl, formyl, aryl, arylloweralkanoyl, carboxyamido, hydroxy, loweralkoxy, lower alkyl, amino, lower alkylamino, diloweralkylamino, aryl, aryl lower alkanoyl, trifluoromethyl, aryloxy, lower alkylthio, mercapto, and lower alkyldithio. 
     
     
         54 . The method according to  claim 50  wherein the electron withdrawing group and electron donating group are selected from the group consisting of halo, nitro, carboxy, lower alkenyl, lower alkynyl, formyl, carboxyamido, trifluoromethyl, lower alkoxy carbonyl, hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, diloweralkylamino, mercapto, loweralkylthio, and lower alkyldithio. 
     
     
         55 . The method according to  claim 1  wherein the carbon atom which is substituted by R 2  and R 3  is in the D configuration. 
     
     
         56 . The method according to  claim 20  wherein the carbon atom which is substituted by R 2  and R 3  is in the D configuration. 
     
     
         57 . The method according to  claim 35  wherein the carbon atom which is substituted by R 2  and R 3  is in the D configuration. 
     
     
         58 . The method of  claim 1  wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 Ar is aryl which is unsubstituted or substituted with an electron donating or electron withdrawing group, and 
 Q is loweralkoxy. 
 
     
     
         59 . The method according to  claim 56  wherein Ar is unsubstituted aryl or aryl substituted with halo. 
     
     
         60 . The method according to  claim 56  wherein Q is methoxy. 
     
     
         61 . The method according to  claim 56  wherein Q is methoxy and Ar is unsubstituted aryl or aryl substituted with halo. 
     
     
         62 . The method according to  claim 56  wherein the carbon atom which is bonded to CH 2 Q is in the D configuration. 
     
     
         63 . The method according to  claim 20  wherein Ar is unsubstituted aryl or aryl substituted with halo wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
       and Q is lower alkoxy. 
     
     
         64 . The method according to  claim 63  wherein Q is methoxy. 
     
     
         65 . The method according to  claim 63  wherein Q is methoxy and Ar is unsubstituted aryl or aryl substituted with halo. 
     
     
         66 . The method according to  claim 63  wherein the carbon atom which is bonded to CH 2 Q is in the D configuration. 
     
     
         67 . The method according to  claim 63  wherein the carbon atom which is bonded to CH 2 Q is in the D configuration. 
     
     
         68 . The method of  claim 35  wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 Ar is aryl which is unsubstituted or substituted with an electron donating or electron withdrawing group, and 
 Q is loweralkoxy. 
 
     
     
         69 . The method according to  claim 68  wherein Ar is unsubstituted aryl or aryl substituted with halo. 
     
     
         70 . The method according to  claim 68  wherein Q is methoxy. 
     
     
         71 . The method according to  claim 68  wherein Q is methoxy and Ar is unsubstituted aryl or aryl substituted with halo. 
     
     
         72 . The method according to  claim 68  wherein the carbon atom which is bonded to CH 2 Q is in the D configuration.

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