Methods of preventing and treating gastrointestinal dysfunction

Abstract

Methods of preventing and treating gastrointestinal dysfunction, particularly postoperative ileus and post-partum ileus, in a patient undergoing surgery or other biological stress by administering 4-aryl-piperidine derivatives are disclosed.

What is claimed is: 
     
         1 . A method of treating or preventing non-opioid induced gastrointestinal dysfunction in a patient undergoing surgery, comprising the step of:
 administering to said patient in need thereof about 0.5 mg/day to about 18 mg/day of an effective amount of at least one 4-aryl-piperidine derivative or a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate, an acid salt hydrate, an N-oxide or an isomorphic crystalline form thereof;   in a manner so as to obtain a pharmacokinetic profile wherein the free concentration in the plasma of said patient of said 4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof is sufficient to achieve substantially saturate the μ opioid receptors in the gastrointestinal tract of said patient;   wherein said patient is not receiving chronic or periodic exogenous opioids;   wherein said gastrointestinal dysfunction is postoperative ileus; and   wherein said 4-aryl-piperidine derivative is [[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpropanoyl]amino]acetic acid.   
     
     
         2 . A method of treating or preventing gastrointestinal dysfunction in a patient undergoing surgery, comprising the step of:
 administering to said patient an effective amount of at least one 4-aryl-piperidine derivative or a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate, an acid salt hydrate, an N-oxide or an isomorphic crystalline form thereof;   in a manner so as to obtain a pharmacokinetic profile wherein the plasma or whole blood concentration of 4-aryl-piperidine of said 4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof reaches a maximum concentration from about 30 minutes to about 120 minutes prior to said surgery;   wherein said gastrointestinal dysfunction is postoperative ileus; and   wherein said 4-aryl-piperidine derivative is [[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpropanoyl]amino]acetic acid.   
     
     
         3 . A method of treating or preventing gastrointestinal dysfunction in a patient undergoing surgery, comprising the step of:
 administering to said patient an effective amount of at least one 4-aryl-piperidine derivative or a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate, an acid salt hydrate, an N-oxide or an isomorphic crystalline form thereof;   in a manner so as to obtain a pharmacokinetic profile wherein the plasma or whole blood concentration of 4-aryl-piperidine of said 4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof reaches a maximum concentration from about 30 minutes to about 120 minutes after said administration;   wherein said gastrointestinal dysfunction is postoperative ileus; and   wherein said 4-aryl-piperidine derivative is [[24[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpropanoyl]aminolacetic acid.   
     
     
         4 . A method according to  claim 1 ,  2 , or  3 ,
 further comprising the step of administering at least one opioid to said patient.   
     
     
         5 . A method according to  claim 4 ,
 wherein said 4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof is administered to said patient from about 30 minutes prior to surgery to less than about 120 minutes prior to said administration of said opioid.   
     
     
         6 . A method according to  claim 1 ,  2 , or  3 ,
 wherein said 4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof is administered to said patient from about 30 minutes prior to surgery to less than about 120 minutes prior to surgery.   
     
     
         7 . A method according to  claim 1 ,  2 , or  3 ,
 wherein said 4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof is administered orally.   
     
     
         8 . A method according to  claim 1 ,  2 , or  3 ,
 wherein said 4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof is administered parenterally.   
     
     
         9 . A method according to  claim 8 ,
 wherein said 4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof is administered intravenously.   
     
     
         10 . A method according to  claim 1 ,  2 , or  3 ,
 wherein said [[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpropanoyl]amino]acetic acid is in hydrate form.   
     
     
         11 . A method according to  claim 10 ,
 wherein said [[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpropanoyl]amino]acetic acid is [[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpropanoyl]amino]acetic acid dihydrate.   
     
     
         12 . A method according to  claim 11 ,
 wherein said compound is a substantially pure stereoisomer.   
     
     
         13 . A method according to  claim 12 ,
 wherein said [[2-[[-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpropanoyl]amino]acetic acid is [[(2S)-2-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl]-3-phenylpropanoyl]amino]acetic acid dihydrate.   
     
     
         14 . A method of treating or preventing gastrointestinal dysfunction in a patient undergoing surgery, comprising the step of:
 administering to said patient an effective amount of at least one 4-aryl-piperidine derivative or a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate, an acid salt hydrate, an N-oxide or an isomorphic crystalline form thereof;   in a manner so as to obtain a pharmacokinetic profile wherein the free concentration in the plasma of said patient of 4-aryl-piperidine of said 4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof is sufficient to substantially saturate the μ opioid receptors in the gastrointestinal tract of said patient;   wherein said gastrointestinal dysfunction is postoperative ileus; and   wherein said 4-aryl-piperidine derivative is a compound of formula (IA):   
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is hydrogen or alkyl; 
         R 2  is hydrogen, alkyl or alkenyl; 
         R 3  is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl, heteroaryl, or heteroarylalkyl; 
         R 4  is hydrogen, alkyl or alkenyl; 
         A is OR 5  or NR 6 R 7 ; 
         R 5  is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or heteroarylalkyl; 
         R 6  is hydrogen or alkyl; 
         R 7  is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, cycloalkyl-substituted alkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, heteroarylalkyl, aralkyl, B, or alkylene substituted B or, together with the nitrogen atom to which they are attached, R 6  and R 7  form a heterocyclic ring; 
         B is 
       
       
         
           
           
               
               
           
         
         C(═O)W or NR 8 R 9 ; 
         R 8  is hydrogen or alkyl; 
         R 9  is hydrogen, alkyl, alkenyl, cycloalkyl-substituted alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl, or aralkyl or, together with the nitrogen atom to which they are attached, R 8  and R 9  form a heterocyclic ring; 
         W is OR 10 , NR 11 R 12 , or OE; 
         R 10  is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl; 
         R 11  is hydrogen or alkyl; 
         R 12  is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, heteroarylalkyl, aralkyl or alkylene substituted C(═O)Y or, together with the nitrogen atom to which they are attached, R 11  and R 12  form a heterocyclic ring; 
         E is 
       
       
         
           
           
               
               
           
         
       
       alkylene substituted (C═O)D, or —R 13 OC(═O)R 14 ;
 R 13  is alkyl substituted alkylene; 
 R 14  is alkyl; 
 D is OR 15  or NR 16 R 17 ; 
 R 15  is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or heteroarylalkyl; 
 R 16  is hydrogen, alkyl, alkenyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl or cycloalkenyl-substituted alkyl; 
 R 17  is hydrogen or alkyl or, together with the nitrogen atom to which they are attached, R 16  and R 17  form a heterocyclic ring; 
 Y is OR 18  or NR 19 R 20 ; 
 R 18  is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or heteroarylalkyl; 
 R 19  is hydrogen or alkyl; 
 R 20  is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or heteroarylalkyl, or, together with the nitrogen atom to which they are attached, R 19  and R 20  form a heterocyclic ring; 
 R 21  is hydrogen or alkyl; 
 n is 0 to 4; and 
 p is 0 or 1. 
 
     
     
         15 . A method of treating or preventing gastrointestinal dysfunction in a patient undergoing surgery, comprising the step of:
 administering to said patient an effective amount of at least one 4-aryl-piperidine derivative or a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate, an acid salt hydrate, an N-oxide or an isomorphic crystalline form thereof;   in a manner so as to obtain a pharmacokinetic profile wherein the plasma or whole blood concentration of 4-aryl-piperidine of said 4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof reaches a maximum concentration from about 30 minutes to about 120 minutes prior to said surgery;   wherein said gastrointestinal dysfunction is postoperative ileus; and   wherein said 4-aryl-piperidine derivative is a compound of formula (IA):   
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is hydrogen or alkyl; 
         R 2  is hydrogen, alkyl or alkenyl; 
         R 3  is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or heteroarylalkyl; 
         R 4  is hydrogen, alkyl or alkenyl; 
         A is OR 5  or NR 6 R 7 ; 
         R 5  is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or heteroarylalkyl; 
         R 6  is hydrogen or alkyl; 
         R 7  is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, cycloalkyl-substituted alkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, heteroarylalkyl, B, or alkylene substituted B or, together with the nitrogen atom to which they are attached, R 6  and R 7  form a heterocyclic ring; 
         B is 
       
       
         
           
           
               
               
           
         
         C(═O)W or NR 8 R 9 ; 
         R 8  is hydrogen or alkyl; 
         R 9  is hydrogen, alkyl, alkenyl, cycloalkyl-substituted alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl or, together with the nitrogen atom to which they are attached, R 8  and R 9  form a heterocyclic ring; 
         W is OR 10 , NR 11 R 12 , or OE; 
         R 10  is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl; 
         R 11  is hydrogen or alkyl; 
         R 12  is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, heteroarylalkyl, or alkylene substituted C(═O)Y or, together with the nitrogen atom to which they are attached, R 11  and R 12  form a heterocyclic ring; 
         E is 
       
       
         
           
           
               
               
           
         
       
       alkylene substituted (C═O)D, or —R 13 OC(═O)R 14 ;
 R 13  is alkyl substituted alkylene; 
 R 14  is alkyl; 
 D is OR 15  or NR 16 R 17 ; 
 R 15  is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or heteroarylalkyl; 
 R 16  is hydrogen, alkyl, alkenyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl or cycloalkenyl-substituted alkyl; 
 R 17  is hydrogen or alkyl or, together with the nitrogen atom to which they are attached, R 16  and R 17  form a heterocyclic ring; 
 Y is OR 18  or NR 19 R 20 ; 
 R 18  is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or heteroarylalkyl; 
 R 19  is hydrogen or alkyl; 
 R 20  is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or heteroarylalkyl or, together with the nitrogen atom to which they are attached, R 19  and R 20  form a heterocyclic ring; 
 R 21  is hydrogen or alkyl; 
 n is 0 to 4; and 
 p is 0 or 1. 
 
     
     
         16 . A method of treating or preventing gastrointestinal dysfunction in a patient undergoing surgery, comprising the step of:
 administering to said patient an effective amount of at least one 4-aryl-piperidine derivative or a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate, an acid salt hydrate, an N-oxide or an isomorphic crystalline form thereof;   in a manner so as to obtain a pharmacokinetic profile wherein the plasma or whole blood concentration of 4-aryl-piperidine of said 4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof reaches a maximum concentration from about 30 minutes to about 120 minutes after said administration;   wherein said gastrointestinal dysfunction is postoperative ileus; and   wherein said 4-aryl-piperidine derivative is a compound of formula (IA):   
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is hydrogen or alkyl; 
         R 2  is hydrogen, alkyl or alkenyl; 
         R 3  is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or heteroarylalkyl; 
         R 4  is hydrogen, alkyl or alkenyl; 
         A is OR 5  or NR 6 R 7 ; 
         R 5  is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or heteroarylalkyl; 
         R 6  is hydrogen or alkyl; 
         R 7  is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, cycloalkyl-substituted alkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, heteroarylalkyl, B, or alkylene substituted B or, together with the nitrogen atom to which they are attached, R 6  and R 7  form a heterocyclic ring; 
         B is 
       
       
         
           
           
               
               
           
         
         C(═O)W or NR 8 R 9 ; 
         R 8  is hydrogen or alkyl; 
         R 9  is hydrogen, alkyl, alkenyl, cycloalkyl-substituted alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl or, together with the nitrogen atom to which they are attached, R 8  and R 9  form a heterocyclic ring; 
         W is OR 10 , NR 11 R 12 , or OE; 
         R 10  is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl; 
         R 11  is hydrogen or alkyl; 
         R 12  is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, heteroarylalkyl, or alkylene substituted C(═O)Y or, together with the nitrogen atom to which they are attached, R 11  and R 12  form a heterocyclic ring; 
         E is 
       
       
         
           
           
               
               
           
         
       
       alkylene substituted (C═O)D, or —R 13 OC(═O)R 14 ;
 R 13  is alkyl substituted alkylene; 
 R 14  is alkyl; 
 D is OR 15  or NR 16 R 17 ; 
 R 15  is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or heteroarylalkyl; 
 R 16  is hydrogen, alkyl, alkenyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl or cycloalkenyl-substituted alkyl; 
 R 17  is hydrogen or alkyl or, together with the nitrogen atom to which they are attached, R 16  and R 17  form a heterocyclic ring; 
 Y is OR 18  or NR 19 R 20 ; 
 R 18  is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or heteroarylalkyl; 
 R 19  is hydrogen or alkyl; 
 R 20  is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl, heteroaryl, or heteroarylalkyl or, together with the nitrogen atom to which they are attached, R 19  and R 20  form a heterocyclic ring; 
 R 21  is hydrogen or alkyl; 
 n is 0 to 4; and 
 p is 0 or 1. 
 
     
     
         17 . A method according to  claim 14 ,  15 , or  16 , further comprising the step of administering at least one opioid to said patient. 
     
     
         18 . A method according to  claim 17 ,
 wherein said 4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof is administered to said patient from about 30 minutes to less than about 120 minutes prior to said administration of said opioid.   
     
     
         19 . A method according to  claim 14 ,  15 , or  16 ,
 wherein said 4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof is administered to said patient from about 30 minutes to less than about 120 minutes prior to surgery.   
     
     
         20 . A method according to  claim 14 ,  15 , or  16 ,
 wherein said 4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof is administered orally.   
     
     
         21 . A method according to  claim 14 ,  15 , or  16 ,
 wherein said 4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof is administered parenterally.   
     
     
         22 . A method according to  claim 21 ,
 wherein said 4-aryl-piperidine derivative or stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof is administered intravenously.   
     
     
         23 . A method according to  claim 14 ,  15 , or  16 ,
 wherein the compound of formula (IA) is a trans 3,4-isomer.   
     
     
         24 . A method according to  claim 14 ,  15 , or  16 ,
 wherein:   R 1  is hydrogen;   R 2  is alkyl;   n is 1 or 2;   R 3  is benzyl, phenyl, cyclohexyl, or cyclohexylmethyl; and   R 4  is alkyl.   
     
     
         25 . A method according to  claim 14 ,  15 , or  16 ,
 wherein:   A is OR 5 ; and   R 5  is hydrogen or alkyl.   
     
     
         26 . A method according to  claim 14 ,  15 , or  16 ,
 wherein:   A is NR 6 R 7 ;   R 6  is hydrogen;   R 7  is alkylene substituted B; and   B is C(O)W.   
     
     
         27 . A method according to  claim 14 ,  15 , or  16 ,
 wherein:   R 7  is (CH 2 ) q —B;   q is about 1 to about 3;   W is OR 10 ; and   R 10  is hydrogen, alkyl, phenyl-substituted alkyl, cycloalkyl or cycloalkyl-substituted alkyl.   
     
     
         28 . A method according to  claim 14 ,  15 , or  16 ,
 wherein:   W is NR 11 R 12      R 11  is hydrogen or alkyl; and   R 12  is hydrogen, alkyl or alkylene substituted C(═O)Y.   
     
     
         29 . A method according to  claim 14 ,  15 , or  16 ,
 wherein:   R 12  is (CH 2 ) m C(O)Y;   m is 1 to 3;   Y is OR 18  or NR 19 R 20 ; and   R 18 , R 19  and R 20  are independently hydrogen or alkyl.   
     
     
         30 . A method according to  claim 14 ,  15 , or  16 ,
 wherein:   W is OE;   E is CH 2 C(═O)D;   D is OR 15  or NR 16 R 17 ;   R 15  is hydrogen or alkyl;   R 16  is methyl or benzyl; and   R 17  is hydrogen.   
     
     
         31 . A method according to  claim 14 ,  15 , or  16 ,
 wherein:   W is OE;   E is R 13 OC(═O)R 14 ;   R 13  is —CH(CH 3 )— or —CH(CH 2 CH 3 )—; and   R 14  is alkyl.   
     
     
         32 . A method according to  claim 14 ,  15 , or  16 ,
 wherein p is 1.   
     
     
         33 . A method according to  claim 14 ,  15 , or  16 ,
 wherein the configuration at positions 3 and 4 of the piperidine ring is each R.   
     
     
         34 . A method according to  claim 14 ,  15 , or  16 ,
 wherein said compound is selected from the group consisting of:   Q-CH 2 CH(CH 2 (C 6 H 5 ))C(O)OH,   Q-CH 2 CH 2 CH(C 6 H 5 )C(O)NHCH 2 C(O)OCH 2 CH 3 ,   Q-CH 2 CH 2 CH(C 6 H 5 )C(O)NHCH 2 C(O)OH,   Q-CH 2 CH 2 CH(C 6 H 5 )C(O)NHCH 2 C(O)NHCH 3 ,   Q-CH 2 CH 2 CH(C 6 H 5 )C(O)NHCH 2 C(O)NHCH 2 CH 3 ,   G-NH(CH 2 ) 2 C(O)NH 2 ,   G-NH(CH 2 ) 2 C(O)NHCH 3 ,   G-NHCH 2 C(O)NH 2 ,   G-NHCH 2 C(O)NHCH 3 ,   G-NHCH 2 C(O)NHCH 2 CH 3 ,   G-NH(CH 2 ) 3 C(O)OCH 2 CH 3 ,   G-NH(CH 2 ) 3 C(O)NHCH 3 ,   G-NH(CH 2 ) 2 C(O)OH,   G-NH(CH 2 ) 3 C(O)OH,   Q-CH 2 CH(CH 2 (C 6 H 11 ))C(O)NHCH 2 C(O)OH,   Q-CH 2 CH(CH 2 (C 6 H 11 ))C(O)NH(CH 2 ) 2 C(O)OH,   Q-CH 2 CH(CH 2 (C 6 H 11 ))C(O)NH(CH 2 ) 2 C(O)NH 2 ,   Z—NHCH 2 C(O)OCH 2 CH 3 ,   Z—NHCH 2 C(O)OH,   Z—NHCH 2 C(O)NH 2 ,   Z—NHCH 2 C(O)N(CH 3 ) 2 ,   Z—NHCH 2 C(O)NHCH(CH 3 ) 2 ,   Z—NHCH 2 C(O)OCH 2 CH(CH 3 ) 2 ,   Z—NH(CH 2 ) 2 C(O)OCH 2 (C 6 H 5 ),   Z—NH(CH 2 )C(O)OH,   Z—NH(CH 2 ) 2 C(O)NHCH 2 CH 3 ,   Z—NH(CH 2 ) 3 C(O)NHCH 3 ,   Z—NHCH 2 C(O)NHCH 2 C(O)OH,   Z—NHCH 2 C(O)OCH 2 C(O)OCH 3 ,   Z—NHCH 2 C(O)O(CH 2 ) 4 CH 3 ,   Z—NHCH 2 C(O)OCH 2 C(O)NHCH 3 ,   Z—NHCH 2 C(O)O-(4-methoxycyclohexyl),   Z—NHCH 2 C(O)OCH 2 C(O)NHCH 2 (C 6 H 5 ) and   Z—NHCH 2 C(O)OCH(CH 3 )OC(O)CH 3 ;   wherein:   
       Q represents 
       
         
           
           
               
               
           
         
       
       G represents 
       
         
           
           
               
               
           
         
       
       and 
       Z represents 
       
         
           
           
               
               
           
         
       
     
     
         35 . A method according to  claim 34 ,
 wherein said compound is selected from the group consisting of:   (+)-Z—NHCH 2 C(O)OH,   (−)-Z—NHCH 2 C(O)OH,   (3R,4R)—Z—NHCH 2 C(O)NHCH 2 (C 6 H 5 ) and   (3R,4R)-G-NH(CH 2 ) 3 C(O)OH.   
     
     
         36 . A method according to  claim 35 ,
 wherein said compound is selected from the group consisting of:   (+)-Z—NHCH 2 C(O)OH, and   (−)-Z—NHCH 2 C(O)OH.   
     
     
         37 . A method according to  claim 36 ,
 wherein said compound is selected from the group consisting of:   (+)-Z—NHCH 2 C(O)OH.   
     
     
         38 . A method according to  claim 35 ,
 wherein said compound is Q-CH 2 CH(CH 2 (C 6 H 5 ))C(O)OH.   
     
     
         39 . A method according to  claim 38 ,
 wherein said compound is (3R,4R, S)-Q-CH 2 CH(CH 2 (C 6 H 5 ))C(O)OH.   
     
     
         40 . A method according to  claim 14 ,  15 , or  16 ,
 wherein said compound is a substantially pure stereoisomer.