Abstract:
The present invention relates to a compound represented as formula (I):                          
 
wherein
       A is R2-N(R3R4),                          
 
wherein Ar is a substituted or unsubstituted phenyl group, m is an integer between 0 to 4, Het is a substituted or unsubstituted 4 to 8 member heterocyclic group, n is an integer between 0 to 4; R 3  and R 4  are independently H,                          
 
or                          
 
R 2  is                          
                         
                         
                         
 
or                          
 
wherein X is (CH 2 ) y —Ar′, R 6 , or (CH 2 ) z -Het′, wherein Ar′ is a substituted or unsubstituted phenyl group, y is an integer between 0 to 2, R 6  is a substituted or unsubstituted linear or a branched C 1-10  alkyl group, z is an integer between 0 to 2, and Het′ is a 6 to 12 member heterocyclic group;
   B is OR 1  or                          
 
wherein R 1  is H or C 2-5  alkyl group.

Description:
BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     The present invention relates to a compound or derivatives of gabapentin, especially a compound or derivatives of gabapentin for medical purposes. 
     2. Description of Related Art 
     Gabapentin is used widely in the treatment of epilepsy and in pain syndrome therapy and in 2001; its global sales reached US$1.47 billion. However, the drug has poor oral bioavailability, and 900 to 4800 mg in dosage for three times per day is required to approach the desired efficacy. However, it was found that the greater dosage in administration did not result in relative adsorption enhancement. Moreover, the change of the administration method did not increase the oral bioavailability. Therefore, according to the prodrug concepts, if the gabapentin can be designed as a highly bioavailable prodrug to reduce the dosage amount and regime such that it need be taken only one time per day, then the convenience for the patients will be largely promoted. 
     Previously, the cyclic amino acid (gabaperitin) was used to conjugate with the twenty natural amino acids to produce its derivatives and increase its standing time in the body. The related art is achieved by chemical synthesis, which describes the synthesis pathway, yet the related tests were not extended to prove the efficacy of the designed derivative. 
     SUMMARY OF THE INVENTION 
     The object of the present invention is to provide a compound derived from gabapentin, which can be used as a prodrug of gabapentin to increase its bioavailability in vivo. 
     To achieve the object, the present gabapentin derivative is a compound of a formula (I): 
                                
wherein
         A is R2-N(R3R4),       
                                
or
 
                                
wherein Ar is a substituted or unsubstituted phenyl group, m is an integer between 0 to 4, Het is a substituted or unsubstituted 4 to 8 member heterocyclic group, n is an integer between 0 to 4; R 3  and R 4  are independently H,
 
                                
or
 
                                
R 2  is
 
     
       
                 
         
             
             
         
      
     
     
       
                 
         
             
             
         
      
     
     
       
                 
         
             
             
         
      
     
                                
or
 
                                
wherein X is (CH 2 ) y —Ar′, R 6 , or (CH 2 ) n -Het′, wherein Ar′ is a substituted or unsubstituted phenyl group, y is an integer between 0 to 2, R 6  is a substituted or unsubstituted linear or branched C 1-10  alkyl group, z is an integer between 0 to 2, and Het′ is a 6 to 12 member heterocyclic group;
         B is OR 1  or       
                                
wherein R 1  is H or C 2-5  alkyl group.
 
     In the present invention, one or several specific unnatural amino acids are conjugated with a gabapentin moeity to produce new compounds whose hydrophorbility is better than that of the original gabapentin. The new compounds are tested in the Caco-2 cell model, and the best transmission rate of the examples is ten fold more than the parent. Therefore, the compound with gabapentin moiety of the present invention increases the oral bioavailability in human patients. Moreover, the new structure of the compounds with gabapentin moiety of the present invention is a specific achievement of the novel concept in drug design. 
     In the present compound, A is R 2 —N(R 3 R 4 ), 
                                
or
 
                                
wherein Ar is a substituted or unsubstituted phenyl group, preferably
 
                                
or
 
                                
In the present compound, Het is a substituted or unsubstituted 4 to 8 member heterocyclic group, preferably
 
     
       
                 
         
             
             
         
      
     
     
       
                 
         
             
             
         
      
     
     
       
                 
         
             
             
         
      
     
                                
or
 
                                
and R 5  is H or
 
                                
In the present compound, X preferably is (CH 2 ) y —Ar′, R 6 , or (CH 2 ) n -Het′, wherein Ar′ is a substituted or unsubstituted phenyl group, preferably
 
                                
or
 
                                
and R 6  is a substituted or unsubstituted linear or branched C 1-10  alkyl group, preferably
 
                                
Het′ is a 6 to 12 member heterocyclic group, preferably
 
     
       
                 
         
             
             
         
      
     
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT 
     For the greater understanding of the present art by those skilled in the art, there are thirty-eight preferred embodiments specifically described as follows. 
     In the present invention, the preparing method of each embodiment is represented by the synthesis pathways in Scheme 1. 
     
       
                 
         
             
             
         
      
     
     The establishment of the intestinal absorption model in vitro is processed by an activity selection in vitro and showed as follows: 
     
       
                 
         
             
             
         
      
     
     The activity selection in vitro is used to select the gabapentin derivative. 
     The common use of the activity selection model for the in vitro intestinal absorption comprises: (1) Carcinoms (Caco-2); (2) Using Chamber; (3) Everted Gut Sac. Basically, there is no difference for those three drug-activity-selection models when they are used for evaluating the activity selection. However, in terms of the cell source from human, a cell line is predominant. Moreover, with the cellular metabolism being similar to human intestines, Caco-2 becomes an excellent tool in the study of intestine absorption. Therefore, in the comparison of the in vitro transmission rate between gabapentin and gabapentin derivatives, the Caco-2 system is still the favorable model. 
     The research for studying gabapentin and the derivatives thereof in the present invention includes: Caco-2 cell activation, Caco-2 monolayer cell cultivation, resistance value measurement, effect of time to gabapentin transmission rate, and comparison of transmission rate between gabapentin and gabapentin derivatives. In constructing the Caco-2 monolayer, the original cell line is the human colon adenocarcinoma cell (Caco-2), and its data sheet is listed as Table 2. 
     The Caco-2 cell is activated appropriately, and seeded in the transwell at 37° C. in an amount of about 1×10 5 . The aliquot is cultivated in 5% CO 2  at 37° C. and replaced with a fresh medium every 3 to 4 days, and then the monolayer cell is obtained by the 21 days cultivation. The integrity of the Caco-2 cell is further characterized by tissue section and resistance value measurement. 
     Embodiment 1 
     Preparation of the NBoc-D-Leu.GBP.OH 
     In the present embodiment, the chemicals and solvents are commercially available from Aldrich®, Lancaster®, or TEDIA® chemical degree products and never purified before usage; the (1-Aminomethyl-cyclohexyl)-acetic acid ethyl ester (GBPOEt) is synthesized according to the conventional methods. The IUPAC chemical nomenclature of the NBoc-D-Leu.GBP.OH is {1-[(2R-tert-Butoxycarbonylamino-4-methyl-pentanoylamino)-methyl]-cyclohexyl}-acetic acid. 
     0.8 g (3.4 mmol) of 2R-tert-Butoxycarbonylamino-4-methyl-pentanoic acid (BocN-D-LeuOH) is mixed with 0.8 g (3.41 mmol) of (1-Aminomethyl-cyclohexyl)-acetic acid ethyl ester (GBPOEt) and then dissolved in THF (6 mL) and DMA (2 mL). Then 460 μl (3.74 mmol) of N-ethylmorpholine (N-EM) and 0.52 g (3.74 mmol) of 1-hydroxybenzotriazole hydrate (HOBT) are further added. After dissolving completely, the solvent is cooled to 0° C., then 0.76 g (3.74 mmol) of 1,3-dicyclohexylcarbodiimide (DCC) is added and stirred for 1 hr. After the temperature is returned to 25 to 27° C., the mixture is stirred for another 10 to 15 hr. Then, the solid portion is filtrated, and the filtrate is diluted with 25 ml of ethyl acetate, and further washed individually and orderly with 10 ml of saturated NaHCO 3 , 10% of citric acid, and saturated NaHCO 3 . The organic layer is dried, filtrated, and concentrated to remove the solvent fraction and obtain the crude product. The crude product is further chromatographically filtrated by alumina oxide with the elute solvent of ethyl acetate/hexane 2:1 to obtain 0.69 g of a viscous liquid product (yield: 49.3%). 
       1 H NMR (200 MHz, CDCl 3 ): δ 0.94 (d, J=5.29 Hz, 6H), 1.30 (t, J=7.12 Hz, 3H), 1.21–1.72 (m, 15H, cyclohexyl, Leucine-CH2CH2CH—), 1.43 (9H, t-butyl), 2.29 (s, 2H), 3.25–3.31 (m, 2H), 4.06–4.20 (m, 4H), 4.96 (br d, J=7.80 Hz, 2H), 6.85 (br s, 2H). 
     Further, 0.69 g of {1-[(2-tert-Butoxycarbonylamino-4-methyl-pentanoylamino)-methyl]-cyclohexyl}-acetic acid ethyl ester and 10 ml of MeOH are added in the 50-ml bottle, then 2.5 ml of 2N NaOH is added and heated to 60° C. for 1 hr. After cooling, the mixture is neutralized to around pH 7.0 by 3N HCl and then vacuum concentrated to a nearly viscous state. Then, 10 ml of H 2 O is added and adjusted to pH ˜1.0 by 3N HCl and extracted twice with 10 ml of ethyl acetate. The organic layer is further washed with 10 ml of saturated salt solution, dried with magnesium sulfate anhydrate, filtrated and concentrated to obtain 0.52 g of product (yield: 80.8%). 
       1 H NMR (200 MHz, CDCl 3 ): δ 0.94 (d, J=5.26 Hz, 6H), 1.32–1.92 (m, 15H, cyclohexyl, Leucine-CH2CH2CH—), 1.44 (9H, t-butyl), 2.17 (s, 2H), 3.30 (s, 2H), 4.96 (br m, 1H), 7.29–7.34 (br m, 2H). 
     Embodiment 2 
     Preparation of the NH 2  GBP-GBPOEt 
     The IUPAC chemical nomenclature of the NH 2  GBP-GBPOEt is (1-{[2-(1-Aminomethyl-cyclohexyl)-acetylamino]-methyl}-cyclohexyl)-acetic acid ethyl ester. 
     1.6 g (5.9 mmol) of [1-(tert-Butoxy-carbonylamino-methyl)-cyclohexyl]-acetic acid (BocN-GBPOH) is mixed with 1.39 g (5.9 mmol) of (1-Aminomethyl-cyclohexyl)-acetic acid ethyl ester (GBPOEt) and then dissolved in THF (8 mL) and DMA (4 mL). Then 820 μl (6.49 mmol) of N-ethylmorpholine (N-EM) and 0.8 g (6.49 mmol) of 1-hydroxybenzotriazole hydrate (HOBT) are further added. After dissolving completely, the solvent is cooled to 0–5° C.; then 1.33 g (6.49 mmol) of 1,3-dicyclohexylcarbodiimide (DCC) is added and stirred for 1 hr. After the temperature is returned to 25 to 27° C., the mixture is stirred for another 18 hr. Then, the solid portion is filtrated, and the filtrate is diluted with 25 ml ethyl acetate, and further washed individually and orderly with 15 ml of saturated NaHCO 3 , 10% of citric acid, and saturated NaHCO 3 . The organic layer is dried, filtrated, and concentrated to remove the solvent fraction and obtain the crude product. The crude product is further chromatographically filtrated by alkali aluminum oxide with the elute consisting of ethyl acetate/hexane (1:3) to obtain 2.06 g of a white viscous liquid product [1-({2-[1-(tert-Butoxy-carbonylamino-methyl)-cyclohexyl]-acetylamino}-methyl)-cyclohexyl]-acetic acid ethyl ester. 
       1 H NMR (200 MHz, CDCl 3 ): δ 1.26 (t, J=7.10 Hz, 3H), 1.25–1.82 (m, 20H, cyclohexyl), 1.43 (9H, t-butyl), 2.15 (s, 2H), 2.32 (s, 2H), 3.13 (d, J=6.80 Hz, 2H), 3.30 (d, J=6.20 Hz, 2H) 4.08–4.20 (m, 2H), 5.46–5.52 (br m, 1H), 7.02 (br s, 1H). 
     Further, 2.06 g of [1-({2-[1-(tert-Butoxycarbonylamino-methyl)-cyclohexyl]-acetylamino}-methyl)-cyclohexyl]-acetic acid ethyl ester (the productivity of 77.1%) and 13 ml of CH 2 Cl 2  are added in the 50-ml bottle. Then, 2.5 ml of trifluoroacetatic acid is added under 25° C., and stirred at 25 to 28° C. for 3 hr. The mixture is further vacuum concentrated to a nearly viscous state and diluted with 20 ml ethyl acetate. Then, the mixture is extracted twice with 10 ml of saturated NaHCO 3 . The organic layer is further washed with 10 ml of a saturated salt solution, dried with magnesium sulfate anhydrate, filtrated and concentrated to obtain 1.6 g of a final product (yield: 99%). 
       1 H NMR (200 MHz, CDCl 3 ): δ 1.26 (t, J=7.10 Hz, 3H), 1.25–1.72 (m, 20H, cyclohexyl x2), 2.32 (s, 2H), 2.45 (s, 2H), 2.97 (s, 2H), 3.26 (d, J=6.00 Hz, 2H), 4.14-(q, J=7.10 Hz, 2H), 6.8 (br s, 1H), 7.21–7.28 (m, 1H). 
     Embodiments 3 to 38 
     Embodiments 3 to 38 are similar methods wherein the products are prepared as Table 1. 
     The results of the cell transmission rate in the products of embodiments 3 to 38 are further listed in Table 1. 
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 The results of products and cell transmission rate in the 
               
               
                 embodiments 
               
             
          
           
               
                   
                   
                   
                   
                 Caco-2 
                   
               
               
                   
                   
                   
                   
                 Cell 
                   
               
               
                   
                   
                   
                   
                 Mean 
                 gbp- 
               
               
                   
                   
                   
                   
                 Total 
                 prodrug/ 
               
               
                   
                   
                   
                   
                 Trans- 
                 gbp 
               
               
                   
                   
                   
                   
                 mission 
                 Trans- 
               
               
                 No. of 
                 Sample Name and IUPAC 
                   
                 Analysis 
                 rate 
                 mission 
               
               
                 Embodiment 
                 Nomenclature 
                 MW. 
                 Method 
                 4 h (%) 
                 Fold 
               
               
                   
               
             
          
           
               
                 Control 1 
                 GBP.HCl 
                 171 + 36.45 
                 ELSD 
                 1.1 
                 1 
               
               
                 Embodiment 1 
                 NBoc-D-Leu.GBP.OH 
                 384 
                 ELSD 
                 29 
                 26.4 
               
               
                   
                 {1-[(2-tert-Butoxycarbonyl- 
               
               
                   
                 amino-4-methyl-pentanoylamino)- 
               
               
                   
                 methyl]-cyclohexyl}-acetic 
               
               
                   
                 acid 
               
               
                 Embodiment 2 
                 NH 2 GBP-GBPOEt(1-{[2-(1- 
                 352 
                 ELSD 
                 10.25 
                 9.3 
               
               
                   
                 Aminomethyl-cyclohexyl)- 
               
               
                   
                 acetylamino]-methyl}-cyclohexyl)- 
               
               
                   
                 acetic acid ethyl ester 
               
               
                 Embodiment 3 
                 NBoc-D-PhG.GBP.OH 
                 404 
                 ELSD 
                 3.1 
                 2.8 
               
               
                   
                 {1-[(2-tert-Butoxycarbonyl- 
               
               
                   
                 amino-2-phenyl-acetylamino)- 
               
               
                   
                 methyl]-cyclohexyl}-acetic 
               
               
                   
                 acid 
               
               
                 Embodiment 4 
                 NBoc-D-Phe.GBP.OH 
                 418 
                 ELSD 
                 10 
                 9.1 
               
               
                   
                 {1-[(2-tert-Butoxycarbonyl- 
               
               
                   
                 amino-3-phenyl-propionylamino)- 
               
               
                   
                 methyl]-cyclohexyl}-acetic 
               
               
                   
                 acid 
               
               
                 Embodiment 5 
                 NBoc-D-Met.GBP.OH 
                 402 
                 ELSD 
                 26 
                 23.6 
               
               
                   
                 {1-[(2-tert-Butoxycarbonyl- 
               
               
                   
                 amino-4-methylsulfanyl-butyryl- 
               
               
                   
                 amino)-methyl]-cyclohexyl}- 
               
               
                   
                 acetic acid 
               
               
                 Embodiment 6 
                 NBoc.GBP.GBP.OH 
                 424 
                 ELSD 
                 27 
                 24.5 
               
               
                   
                 [1-({2-[1-(tert-Butoxycarbonyl- 
               
               
                   
                 amino-methyl)-cyclohexyl]- 
               
               
                   
                 acetylamino}-methyl)-cyclo- 
               
               
                   
                 hexyl]-acetic acid 
               
               
                 Embodiment 7 
                 NH2.INP.GBP.OEt 
                 310 
                 ELSD 
                 1 
                 0.9 
               
               
                   
                 (1-{[(Piperidine-4-carbonyl)- 
               
               
                   
                 amino]-methyl}-cyclohexyl)- 
               
               
                   
                 acetic acid ethyl ester 
               
               
                 Embodiment 8 
                 Tol-NHGBP.OEt 
                 317 
                 ELSD 
                 21.4 
                 19.5 
               
               
                   
                 [1-(Benzoylamino-methyl)- 
               
               
                   
                 cyclohexyl]-acetic acid ethyl 
               
               
                   
                 ester 
               
               
                 Embodiment 9 
                 NH2-ACHC.GBP.OEt 
                 324 
                 ELSD 
                 10.4 
                 9.5 
               
               
                   
                 (1-{[(1-Amino-cyclohexane- 
               
               
                   
                 carbonyl)-amino]-methyl}- 
               
               
                   
                 cyclohexyl)-acetic acid ethyl 
               
               
                   
                 ester 
               
               
                 Embodiment 10 
                 NBocD-Ser-GBPOH 
                 358 
                 ELSD 
                 20.7 
                 18.8 
               
               
                   
                 {1-[(2-tert-Butoxycarbonyl- 
               
               
                   
                 amino-3-hydroxy-propionyl- 
               
               
                   
                 amino)-methyl]-cyclohexyl}- 
               
               
                   
                 acetic acid 
               
               
                 Embodiment 11 
                 NH2.D-Ala-GBPOEt 
                 270 
                 ELSD 
                 17.6 
                 16.0 
               
               
                   
                 {1-[(2-Amino-propionylamino)- 
               
               
                   
                 methyl]-cyclohexyl}-acetic 
               
               
                   
                 acid ethyl ester 
               
               
                 Embodiment 12 
                 NH2.GBP-D-Ala-L-PheOEt 
                 417 
                 ELSD 
                 2.83 
                 2.6 
               
               
                   
                 2-{2-[2-(1-Aminonethyl-cyclo- 
               
               
                   
                 hexyl)-acetylamino]-propionyl- 
               
               
                   
                 amino}-3-phenyl-propionic 
               
               
                   
                 acid ethyl ester 
               
               
                 Embodiment 13 
                 NH 2 D-Leu-GBPOEt 
                 312 
                 ELSD 
                 12.37 
                 11.2 
               
               
                   
                 {1-[(2-Amino-4-methyl-pentanoyl- 
               
               
                   
                 amino)-methyl]-cyclo- 
               
               
                   
                 hexyl}-acetic acid ethyl ester 
               
               
                 Embodiment 14 
                 NH 2 D-Ser-GBPOEt 
                 292 
                 ELSD 
                 10.95 
                 10.0 
               
               
                   
                 {1-[(2-Amino-3-hydroxy- 
               
               
                   
                 propionylamino)-methyl]-cyclo- 
               
               
                   
                 hexyl}-acetic acid ethyl ester 
               
               
                 Embodiment 15 
                 NBocD-Phe-GBPOH 
                 418 
                 ELSD 
                 0.93 
                 0.8 
               
               
                   
                 {1-[(2-tert-Butoxycarbonyl- 
               
               
                   
                 amino-3-phenyl-propionylamino)- 
               
               
                   
                 methyl]-cyclohexyl}-acetic 
               
               
                   
                 acid 
               
               
                 Embodiment 16 
                 NH 2 D-Phe-GBPOEt 
                 346 
                 ELSD 
                 10.30 
                 9.4 
               
               
                   
                 {1-[(2-Amino-3-phenyl-propionyl- 
               
               
                   
                 amino)-methyl]-cyclohexyl}- 
               
               
                   
                 acetic acid ethyl ester 
               
               
                 Embodiment 17 
                 NH 2 L-Ile-GBPOEt 
                 312 
                 ELSD 
                 9.47 
                 8.6 
               
               
                   
                 {1-[(2-Amino-3-methyl-pentanoyl- 
               
               
                   
                 amino)-methyl]-cyclo- 
               
               
                   
                 hexyl}-acetic acid ethyl ester 
               
               
                 Embodiment 18 
                 NH 2 -2-MePhe-GBPOEt 
                 360 
                 ELSD 
                 2.13 
                 1.9 
               
               
                   
                 {1-[(2-Aminomethyl-benzoyl- 
               
               
                   
                 amino)-methyl]-cyclohexyl}- 
               
               
                   
                 acetic acid ethyl ester 
               
               
                 Embodiment 19 
                 NH 2 —CH2-4-Cyhexl-GBPOEt 
                 338 
                 ELSD 
                 11.14 
                 10.1 
               
               
                   
                 (1-{[(4-Aminomethyl-cyclo- 
               
               
                   
                 hexanecarbonyl)-amino]-methyl}- 
               
               
                   
                 cyclohexyl)-acetic acid 
               
               
                   
                 ethyl ester 
               
               
                 Embodiment 20 
                 NH 2 GBP.D-Leu-GBPOEt 
                 465 
                 ELSD 
                 12.22 
                 11.1 
               
               
                   
                 [1-({2-[2-(1-Aminomethyl- 
               
               
                   
                 cyclohexyl)-acetylamino]-4- 
               
               
                   
                 methyl-pentanoylamino}-methyl)- 
               
               
                   
                 cyclohexyl]-acetic acid 
               
               
                   
                 ethyl ester 
               
               
                 Embodiment 21 
                 NH 2 GBP.D-Phg-GBPOEt 
                 485 
                 ELSD 
                 8.58 
                 7.8 
               
               
                   
                 [1-({2-[2-(1-Aminomethyl- 
               
               
                   
                 cyclohexyl)-acetylamino]-2- 
               
               
                   
                 phenyl-acetylamino}-methyl)- 
               
               
                   
                 cyclohexyl]-acetic acid ethyl 
               
               
                   
                 ester 
               
               
                 Embodiment 22 
                 NH 2 GBP.D-Phe-GBPOEt 
                 499 
                 ELSD 
                 9.26 
                 8.4 
               
               
                   
                 [1-({2-[2-(1-Aminomethyl- 
               
               
                   
                 cyclohexyl)-acetylamino]-3- 
               
               
                   
                 phenyl-propionylamino}-methyl)- 
               
               
                   
                 cyclohexyl]-acetic acid 
               
               
                   
                 ethyl ester 
               
               
                 Embodiment 23 
                 NH 2 GBP.L-Pro-GBPOEt 
                 449 
                 ELSD 
                 10.73 
                 9.8 
               
               
                   
                 {1-[({1-[2-(1-Aminomethyl- 
               
               
                   
                 cyclohexyl)-acetyl]-pyrrolidine- 
               
               
                   
                 2-carbonyl}-amino)-methyl]- 
               
               
                   
                 cyclohexyl}-acetic acid 
               
               
                 Embodiment 24 
                 (3-OMe4OH)Ph-GBPOEt{1- 
                 349 
                 ELSD 
                 13.59 
                 12.4 
               
               
                   
                 [(4-Hydroxy-3-methoxy-benzoyl- 
               
               
                   
                 amino)-methyl]-cyclohexyl}- 
               
               
                   
                 acetic acid ethyl ester 
               
               
                 Embodiment 25 
                 Pydone-GBPOEt(1-{[(5-Oxo- 
                 310 
                 ELSD 
                 5.68 
                 5.2 
               
               
                   
                 pyrrolidine-2-carbonyl)-amino]- 
               
               
                   
                 methyl}-cyclohexyl)-acetic 
               
               
                   
                 acid ethyl ester 
               
               
                 Embodiment 26 
                 NH 2 D-Met-GBPOEt{1-[(2- 
                 330 
                 ELSD 
                 9.02 
                 8.2 
               
               
                   
                 Amino-4-methylsulfanyl-butyryl- 
               
               
                   
                 amino)-methyl]-cyclohexyl}- 
               
               
                   
                 acetic acid ethyl ester 
               
               
                 Embodiment 27 
                 3pyridine-GBPOEt(1-{[(Pyridine- 
                 304 
                 ELSD 
                 9.39 
                 8.5 
               
               
                   
                 3-carbonyl)-amino]- 
               
               
                   
                 methyl}-cyclohexyl)-acetic acid 
               
               
                   
                 ethyl ester 
               
               
                 Embodiment 28 
                 NH 2 D-Ala-GBPOEt{1-[(2- 
                 270 
                 ELSD 
                 8.11 
                 7.4 
               
               
                   
                 Amino-propionylamino)-methyl]- 
               
               
                   
                 cyclohexyl}-acetic acid 
               
               
                   
                 ethyl ester 
               
               
                 Embodiment 29 
                 NH 2 D-Val-GBPOEt{1-[(2- 
                 298 
                 ELSD 
                 8.73 
                 7.9 
               
               
                   
                 Amino-3-methyl-butyrylamino)- 
               
               
                   
                 methyl]-cyclohexyl}-acetic 
               
               
                   
                 acid ethyl ester 
               
               
                 Embodiment 30 
                 NH 2 L-Phg-GBPOEt{1-[(2- 
                 332 
                 ELSD 
                 11.87 
                 10.8 
               
               
                   
                 Amino-2-phenyl-acetylamino)- 
               
               
                   
                 methyl]-cyclohexyl}-acetic 
               
               
                   
                 acid ethyl ester 
               
               
                 Embodiment 31 
                 NH 2 D-hPhe-GBPOEt{1-[(2- 
                 358 
                 ELSD 
                 12.30 
                 11.2 
               
               
                   
                 Amino-4-phenyl-butyrylamino)- 
               
               
                   
                 methyl]-cyclohexyl}-acetic 
               
               
                   
                 acid ethyl ester 
               
               
                 Embodiment 32 
                 NH 2 L-hPhe-GBPOEt{1-[(2- 
                 358 
                 ELSD 
                 1.76 
                 1.6 
               
               
                   
                 Amino-4-phenyl-butyrylamino)- 
               
               
                   
                 methyl]-cyclohexyl}-acetic 
               
               
                   
                 acid ethyl ester 
               
               
                 Embodiment 33 
                 NH 2 D-Try-GBPOEt 
                 385 
                 ELSD 
                 9.97 
                 9.1 
               
               
                   
                 (1-{[2-Amino-2-(1H-indol-2- 
               
               
                   
                 yl)-acetylamino]-methyl}- 
               
               
                   
                 cyclohexyl)-acetic acid ethyl 
               
               
                   
                 ester 
               
               
                 Embodiment 34 
                 NH 2 L-Thz-GBPOEt(1- 
                 314 
                 ELSD 
                 4.50 
                 4.1 
               
               
                   
                 {[(Thiazolidine-4-carbonyl)- 
               
               
                   
                 amino]-methyl}-cyclohexyl)- 
               
               
                   
                 acetic acid ethyl ester 
               
               
                 Embodiment 35 
                 NH 2 L-Tyr-GBPOEt 
                 362 
                 ELSD 
                 10.33 
                 9.4 
               
               
                   
                 (1-{[2-Amino-2-(4-hydroxy- 
               
               
                   
                 phenyl)-acetylamino]-methyl}- 
               
               
                   
                 cyclohexyl)-acetic acid ethyl 
               
               
                   
                 ester 
               
               
                 Embodiment 36 
                 (3-Py)CH2CH2GBPOEt 
                 375 
                 ELSD 
                 9.00 
                 8.2 
               
               
                   
                 [1-({3-[(Pyridine-3-carbonyl)- 
               
               
                   
                 amino]-propionylamino}- 
               
               
                   
                 methyl)-cyclohexyl]-acetic 
               
               
                   
                 acid ethyl ester 
               
               
                 Embodiment 37 
                 NBocL-Thz-GBPOEt 
                 414 
                 ELSD 
                 6.13 
                 5.6 
               
               
                   
                 4-[(1-Ethoxycarbonylmethyl- 
               
               
                   
                 cyclohexylmethyl)-carbamoyl]- 
               
               
                   
                 thiazolidine-3-carboxylic 
               
               
                   
                 acid tert-butyl ester 
               
               
                 Embodiment 38 
                 NBocL-Tyr-GBPOEt 
                 462 
                 ELSD 
                 5.05 
                 4.6 
               
               
                   
                 (1-{[2-tert-Butoxycarbonyl- 
               
               
                   
                 amino-2-(4-hydroxy-phenyl)- 
               
               
                   
                 acetylamino]-methyl}-cyclo- 
               
               
                   
                 hexyl)-acetic acid ethyl ester 
               
               
                   
               
             
          
         
       
     
     HPLC Analysis: Intersil ODS-3V 250*4.6 mm column, Solvent: MeOH/H 2 O=10:90 to 70:30 with 0.1% of NH4OAc, Flow rate=1.0 ml/min, ELSD: Evaporative Light Scattering Detector. Every derivative has been repeated for 3 times in analysis, 4 hr later, the sample is analyzed for the transmission rate and then averaged to account its transmission fold. 
     
       
         
               
             
               
               
             
               
               
               
               
             
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                 Human Colon Adenocarcinoma Cell Line Strain Data Sheet 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Strain Code No. 
                 CCRC60018 
               
               
                 Cell Line 
                 Caco-2 
               
               
                 Cell Strain Source 
                 ATCC HTB-37 
               
               
                 Tissue Source 
                 Colon, adenocarcinoma, human 
               
             
          
           
               
                 Frozen Tube Volume 
                 1 ml 
                 Concentration 
                 1.3 × 10 6   
               
               
                 Frozen Date 
                 12.31.1999 
                 Subculture No. 
                 P23 
               
             
          
           
               
                 Survival Rate 
                 82.5% 
               
               
                 Medium 
                 80% MEM (Eagle) with non-essential amino 
               
               
                   
                 acids and Earle&#39;s BSS + 20% FBS 
               
               
                 Cultivation Condition 
                 37° C., 5% CO 2   
               
               
                 Frozen Medium 
                 90% culture medium + 10% DMSO 
               
               
                 Medium Replacement 
                 2 to 3 times per week 
               
               
                 Subculture Dilution Ratio 
                 1:2 to 1:3 
               
               
                 Contamination Test 
                 Negative for bacteria, fungi and mycoplasma 
               
               
                   
               
             
          
         
       
     
     Furthermore, for increasing the efficiency of drug-absorption through oral administration, these drugs are designed to pass the epithelium cells in small intestines by passive diffusion can enter the “body circulation”. For facilitating the passive diffusion of drugs through the epithelium cells in small intestines, several biochemical features of the drugs are adjusted. These biochemical features of the suitable drugs comprise low molecular weight (such as &lt;500 Da), water solubility, and proper hydrophilicity/hydrophobicity ratio (1.5&lt;log P&lt;4.0, with reference: Navia, chaturvedi, P. R.  Drug Discovery Today,  1996, 1, 179–189). On the other hand, because gabapentin is a compound with high polarity and high hyrophilicity (log P=−1.1), gabapentin or its derivative is hard to pass the lipid layer of the small intestines epithelium cells. Therefore, compounds modified from the structure of gabapentin or its derivatives (as listed in Table 1) for functioning as prodrugs facilitate the passive diffusion through the epithelium cells in small intestines for entering blood circulation. 
     Embodiment 39 
     Oral Drug Absorption Test 
     Rats (3 male, Winstar rats) are fed with 300 mg/kg dosage of compounds. Plural blood samples are collected at different times (0, 0.5, 1, 2, 3, 8, 12, 24 hrs). The blood samples are centrifuged, and the concentration of gabapentin in the serum are analyzed with LC/MS/MS (MRM method, limitation of instruments 0.005 μg/mL). The results are listed in Table 3. 
     
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 Gabapentin prodrug concentration in rat blood (passive diffusion 
               
               
                 passage) 
               
             
          
           
               
                   
                   
                 C max ***   
                 AUC ****   
               
               
                 Compound 
                 Tmax **  (hr) 
                 (mg/mL) 
                 (mg.hr/mL) 
               
               
                   
               
             
          
           
               
                 Embodiment 2 
                 1.0 
                 34.4 
                 198.56 
               
               
                 NH 2 .GBP.GBPOEt 
               
               
                 Embodiment 29 
                 3.5 
                 0.46 
                 2.66 
               
               
                 NH 2 .D-ValGBPOEt 
               
               
                 Gabapentin HCl *   
                 2.0 
                 2.53 
                 13.30 
               
               
                   
               
               
                   * Gabapentin HCl is synthesized by the inventor; 
               
               
                   ** Tmax: the timing of maximum concentration of Gabapentin; 
               
               
                   *** Cmax: the maximum concentration of Gabapentin in blood; 
               
               
                   **** AUC: the area sum under the Gabapentin concentration curve, the higher value means the better absorption by intestine, calculated by WinNonLin ®. 
               
             
          
         
       
     
     The AUC value of the compound from Embodiment 2 is 14.9 times higher than Gabapentin HCl. The fact means that compound prepared in embodiment 2 enters blood circulation easily. 
     After reducing the dosage, compounds of gabapentin prodrugs were selected for further pharmacodynamic analysis. The rats are fed with 50 mg/kg dosage of gabapentin equivalency individually. The results are listed in Table 4. The results showed gabapentin prodrugs could be absorbed in animal intestine and degraded by intestinal enzymes to release gabapentin. 
     
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                 Gabapentin released by prodrug blood analysis results in Rat 
               
             
          
           
               
                 Compound 
                 Tmax (hr) 
                 Cmax (mg/mL) 
                 AUC(μg.hr/mL) 
               
               
                   
               
             
          
           
               
                 Embodiment 2 
                 2.0 
                 1.00 
                 4.27 
               
               
                 NH 2 .GBP.GBP.OEt 
               
               
                 NH 2 .Gly GBPOH 
                 1.0 
                 22.0 
                 81.40 
               
               
                 NH 2 .L-Phe.GBPOH 
                 2.0 
                 2.71 
                 44.37 
               
               
                 Gabapentin HCl 
                 1.0 
                 32.3 
                 122.26 
               
               
                   
               
             
          
         
       
     
     NH 2 .Gly.GBPOH prodrug can release gabapentin in the animal blood with an AUC value of 81.4, which is 0.67 times higher than that of gabapentin. On the other hand, although the maximum concentration Cmax of prodrug is lower than that of gabapentin, which also means lower side effect while still having effective concentration. 
     The experiments illustrated above in Embodiment 39 prove that the gabapentin derivatives in a prodrug form can ease the absorption of gabapentin derivatives by intestinal diffusion, and the gabapentin prodrugs in the blood promise the releasing of gabapentin. The prodrug idea can be further applied to other drugs. 
     From the above embodiments, it is found that the present gabapentin derivatives certainly enhance the cell transmission rate and promote the bioavailability of the prodrug for the better potency. 
     Although the present invention has been explained in relation to its preferred embodiment, it is to be understood that many other possible modifications and variations can be made without departing from the spirit and scope of the invention as hereinafter claimed.