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,  
                         
 
     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  
         [0001]    1. Field of the Invention  
           [0002]    The present invention relates to a compound or derivatives of gabapentin, especially a compound or derivatives of gabapentin for medical purposes.  
           [0003]    2. Description of Related Art  
           [0004]    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.  
           [0005]    Previously, the cyclic amino acid (gabapentin) 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  
         [0006]    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.  
           [0007]    To achieve the object, the present gabapentin derivative is a compound of a formula (I):  
                         
 
           [0008]    wherein  
           [0009]    A is R2-N(R3R4),  
                         
 
           [0010]    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,  
                         
 
           [0011]    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 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  
                         
 
           [0012]    wherein R 1  is H or C 2-5  alkyl group.  
           [0013]    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.  
           [0014]    In the present compound, A is R 2 —N(R 3 R 4 ),  
                         
 
           [0015]    wherein Ar is a substituted or unsubstituted phenyl group, preferably  
                         
 
           [0016]    In the present compound, Het is a substituted or unsubstituted 4 to 8 member heterocyclic group, preferably  
                         
 
           [0017]    and R 5  is H or  
                         
 
           [0018]    In the present compound, X preferably is (CH 2 ) y —Ar′, R 6 , or (CH 2 ) z -Het′, wherein Ar′ is a substituted or unsubstituted phenyl group, preferably  
                         
 
           [0019]    and R 6  is a substituted or unsubstituted linear or branched C 1-10  alkyl group, preferably  
                         
 
           [0020]    Het′ is a 6 to 12 member heterocyclic group, preferably  
                         
 
       
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT  
       [0021]    For the greater understanding of the present art by those skilled in the art, there are thirty-eight preferred embodiments specifically described as follows.  
         [0022]    In the present invention, the preparing method of each embodiment is represented by the synthesis pathways in Scheme 1.  
                         
 
         [0023]    The establishment of the intestinal absorption model in vitro is processed by an activity selection in vitro and showed as follows:  
                         
 
         [0024]    The activity selection in vitro is used to select the gabapentin derivative.  
         [0025]    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.  
         [0026]    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.  
         [0027]    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.  
         [0028]    Embodiment 1 Preparation of the NBoc-D-Leu.GBP.OH  
         [0029]    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.  
         [0030]    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%).  
         [0031]    [0031] 1 H NMR (200 MHz, CDCl3): 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).  
         [0032]    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%).  
         [0033]    [0033] 1 H NMR (200 MHz, CDCl3): 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).  
         [0034]    Embodiment 2 Preparation of the NH 2  GBP-GBPOEt  
         [0035]    The IUPAC chemical nomenclature of the NH 2 GBP-GBPOEt is (1-{[2-(1-Aminomethyl-cyclohexyl)-acetylamino]-methyl}-cyclohexyl)-acetic acid ethyl ester.  
         [0036]    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.  
         [0037]    [0037] 1 H NMR (200 MHz, CDCl3): 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).  
         [0038]    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 2° 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%).  
         [0039]    [0039] 1 H NMR (200 MHz, CDCl3): 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).  
         [0040]    Embodiments 3 to 38  
         [0041]    Embodiments 3 to 38 are similar methods wherein the products are prepared as Table 1.  
         [0042]    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/                       Transmission   gbp       No. of   Sample Name and IUPAC       Analysis   rate   Transmission       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-Butoxycarbonylamino-           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-Butoxycarbonylamino-           2-phenyl-acetylamino)-           methyl]-cyclohexyl}-acetic           acid       Embodiment 4   NBoc-D-Phe.GBP.OH   418   ELSD   10   9.1           {1-[(2-tert-Butoxycarbonylamino-           3-phenyl-propionylamino)-           methyl]-cyclohexyl}-acetic           acid       Embodiment 5   NBoc-D-Met.GBP.OH   402   ELSD   26   23.6           {1-[(2-tert-Butoxycarbonylamino-           4-methylsulfanyl-butyrylamino)-           methyl]-cyclohexyl}-           acetic acid       Embodiment 6   NBoc.GBP.GBP.OH   424   ELSD   27   24.5           [1-({2-[1-(tert-Butoxycarbonylamino-           methyl)-cyclohexyl]-           acetylamino}-methyl)-cyclohexyl]-           acetic acid       Embodiment 7   NH2.INP.GBP.OEt   310   ELSD   1   0.9           (1-{[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-cyclohexanecarbonyl)-           amino]-methyl}-cyclohexyl)-           acetic acid ethyl           ester       Embodiment 10   NBocD-Ser-GBPOH   358   ELSD   20.7   18.8           {1-[(2-tert-Butoxycarbonylamino-           3-hydroxy-propionylamino)-           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-Aminomethyl-cyclohexyl)-           acetylamino]-propionylamino}-           3-phenyl-propionic           acid ethyl ester       Embodiment 13   NH 2 D-Leu-GBPOEt   312   ELSD   12.37   11.2           {1-[(2-Amino-4-methyl-pentanoylamino)-           methyl]-cyclohexyl}-           acetic acid ethyl ester       Embodiment 14   NH 2 D-Ser-GBPOEt   292   ELSD   10.95   10.0           {1-[(2-Amino-3-hydroxy-propionylamino)-           methyl]-cyclohexyl}-           acetic acid ethyl ester       Embodiment 15   NBocD-Phe-GBPOH   418   ELSD   0.93   0.8           {1-[(2-tert-Butoxycarbonylamino-           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-propionylamino)-           methyl]-cyclohexyl}-           acetic acid ethyl ester       Embodiment 17   NH 2 L-Ile-GBPOEt   312   ELSD   9.47   8.6           {1-[(2-Amino-3-methyl-pentanoylamino)-           methyl]-cyclohexyl}-           acetic acid ethyl ester       Embodiment 18   NH 2 -2-MePhe-GBPOEt   360   ELSD   2.13   1.9           {1-[(2-Aminomethyl-benzoylamino)-           methyl]-cyclohexyl}-           acetic acid ethyl ester       Embodiment 19   NH 2 -CH2-4-Cyhexl-GBPOEt   338   ELSD   11.14   10.1           (1-{[(4-Aminomethyl-cyclohexanecarbonyl)-           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-benzoylamino)-           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-Amino-   330   ELSD   9.02   8.2           4-methylsulfanyl-butyrylamino)-           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-Amino-   270   ELSD   8.11   7.4           propionylamino)-methyl]-           cyclohexyl}-acetic acid           ethyl ester       Embodiment 29   NH 2 D-Val-GBPOEt{1-[(2-Amino-   298   ELSD   8.73   7.9           3-methyl-butyrylamino)-           methyl]-cyclohexyl}-acetic           acid ethyl ester       Embodiment 30   NH 2 L-Phg-GBPOEt{1-[(2-Amino-   332   ELSD   11.87   10.8           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-{[(Thiazolidine-   314   ELSD   4.50   4.1           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-Butoxycarbonylamino-           2-(4-hydroxy-phenyl)-acetylamino]-           methyl}-cyclohexyl)-           acetic acid ethyl ester                  
 
         [0043]    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                  
 
         [0044]    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.  
         [0045]    Embodiment 39 Oral Drug Absorption Test  
         [0046]    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                                                                      
 
         [0047]    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.  
         [0048]    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                  
 
         [0049]    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.  
         [0050]    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.  
         [0051]    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.  
         [0052]    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.