TW200823172A - GABA analogs, compositions and method for manufacturing thereof - Google Patents

Abstract

The invention provides novel compounds of Formula (I), pharmaceutical compositions and synthesis methods thereof.

Description

200823172 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to a method for synthesizing γ-filament acid sensitizers. [Prior Art] Gama-amino butyric acid (GABA) is a non-essential product, which is mainly found in the brain of the human body, and is an inhibitory neurotransmitter of the central nervous system. It regulates the degree of nerve excitation by binding specific membrane proteins (ie, gamma-aminobutyric acid-gabaa receptor) to open the ion channel. When the cadaverine I is low / _ _ wei, there will be _, movement disorders (such as multiple sclerosis, motion tremor, tardive dyskinesia), panic, anxiety, depression, and Symptoms such as madness; therefore, the development of medical analogues superior to butylbutyric acid will be of great benefit for the treatment of related diseases. A number of pharmacologically active aminobutyric acid analogs (GABA anal〇gs) have been synthesized by hydrazine (e.g., U.S. Patent Nos. 4,024,175, 5,563,175 and 6,028,214; U.S. Patent Publication Nos. 20, 4,775,753 and 20, 5〇2〇9319; International Patent Application No. (WIPO) WO 00/31020, WO 02/00209, WO 05/027850 and WO 04/089289); in addition to the above gamma-aminobutyric acid analogs, gabapentin ( Gabapentin), pregabalin 2, algaenoic acid (vigabatrin) and baclofen have been used to treat different diseases; for example, gabapentin and pregabalin are used to treat epilepsy, neuropathic pain, etc.; The sales amount has exceeded 20 million US dollars. Clinical studies have shown that gamma-aminobutyric acid analogs are easily eliminated by the body; many γ-aminobutyric acid 5 200823172 acid analogs are often too late to be expelled, leading to frequent medications for therapeutic purposes (Bryans et al) ·, Med. Res Rev, 1999, 19, 149-177); for example, gabapentin is used for anti-caries treatment at least three times a day, 300-600 mg each time; if used for neuropathic pain, daily dose Up to 1800-3600 mg. Sustained-release dosage forms are commonly used in pharmacy to solve the problem of easy removal of gamma-aminobutyric acid analogues; however, most gamma-aminobutyric acid analogues, including gabapentin and pregabalin, are absorbed in the large intestine and rectum. Not as good as the small intestine, and cannot be absorbed by the transporter-lar@ neutral amino acid transporter (Jezyk et al? Pharm. Res., 1999, 16, 519-526). For most gamma-aminobutyric acid analogs, the use of sustained release dosage forms is limited. It is therefore necessary to provide an aminobutyric acid analog or a prodrug thereof which can be effectively absorbed in the intestinal tract (including the large and small intestines), and the compound is applied to a sustained release dosage form to solve the problem. SUMMARY OF THE INVENTION The present invention relates to novel gamma-aminobutyric acid analogs, pharmaceutical compositions thereof, and methods of synthesis. First, the present invention discloses a compound of the formula (I):

(I), a hydrate or a solvate; wherein, or a pharmaceutically acceptable salt thereof, R1 is

Constructed from an oxygen atom or an alkyl group; phantoms, phantoms are independently selected from the group consisting of hydrogen alkyl groups, C6-C8 aromatic groups or CrC6 burns 6 200823172 V. oxy (alkoxyl group); , γ is independently selected from a hydrogen atom, a chlorophenyl group, a 2-methylpropyl group, or a cyclohexyl group (4) by selective bonding with an X and Y bond. Secondly, the invention also discloses a pharmaceutical composition comprising one or more compounds of the invention and a pharmaceutically acceptable pour ((iv) (four). This! X Ming also provides - a preparation of a composition for treatment or Epilepsy, sorrow, anxiety, dizziness, exercise loss, skeletal disease, neurodegenerative disease, panic, [pain (especially (four) sexual lag, muscle and her pain), inflammatory response (ie arthritis), insomnia, gastrointestinal disease Or riding a withdrawal syndrome; administering a combined amount of the pharmaceutical composition to a patient having the above symptoms for the purpose of prevention or treatment. The compound of the present invention has a non-toxic protective group, and 丫-aminobutyric acid The amine or silk of the analog is ligated; the protecting group can be removed by an enzyme or a chemical reaction to produce a γ-amino butyl group. The present invention can be metabolized to a γ_月女基 in a living towel. Butyric acid analogs, in turn, are precursors to gamma-aminobutyric acid analogs.

I Definitions: "Alkyl" alone or as a substituent refers to a saturated or unsaturated, branched, linear or cyclic hydroxyl group. Typical hydrocarbon groups include, but are not limited to, methyl (methyl); ethyl (ethanyl), ethenyi, ethynyl, propyl (pr〇pyi) Such as n-propanyl (pr〇pan-1_yl), isopropanyl (piOpan-2-yl), J-propyl propyl group (cyCi〇pr0pan-1 -y|), n-propyl group ^pr〇p_ ι _ Qiu _ ι, isopropenyl (pr〇Pl-en_2-yl), second n-propenyl (prop_2_en_4_y allyl 7 200823172 (Allyl)), 1-cyclopropenyl (cycloprop^^; ^), 2-ring Propyl group (cydoprop-kn-l-yl), 1-propynyl group (prop small rush + state, 2-propynyl hydrazone 1) 2_Ke Xiaozhou, etc. Butyl (butyl) such as n-butane (butan -1-yl), second butanyl (butan_2_yl), isobutyl (2-methyl-propan small yl), tert-butyl (2-methyl-propan_2-yl), cyclobutan (cyclobutan) -1-yl), 1·butenyl (but-l-en-i-yi), second-μ butenyl (but-1-en-2-yl), isobutyl fluorenyl (2-methyl) -prop-l-en-1-yl), 2-butenyl (but-2-en-l-yl), second-2·butenyl (bm_2-en-2-yl), 1,3 - butadienyl f (bu^1,3".1·^1), 2-1,3-butadienyl (buta-l,3-dien-2-yl), Butyryl (cydobut-1-en-l-yl), 3-cyclobutenyl, cyclobuta-U-dien-1-yl, 1-butynyl (but+yn-; Uyl), 3_μ butynyl (but-l-yn-3-yl), 1-3-butynyl (but-3-yn-l-yl), etc.; and other hydrocarbon groups. 4 alkoxy (Alkoxy Or a singly or as a substituent refers to a group, wherein hydrazine is an oxygen atom, and R represents a hydrocarbon group or a cyclic hydrocarbon group as defined in the present invention; representative examples include the following but are not limited thereto: methoxy group (meth〇Xy), ethoxy (eth〇xy), propoxy 0 ❻Γ〇Ρ〇Χβ, butoxy_0矽), cyclohexyl〇xy and other alkoxy groups. Cycloalky's part alone or as a substituent refers to a saturated or unsaturated cyclic hydrocarbon group; depending on the degree of saturation, it can be named as cydalkanyl (cydoalkenyl). . Common cyclic hydrocarbon groups include, but are not limited to, those derived from cyclopropane, cyclohexene, cyclopentane, cyclohexane, and other cyclic hydrocarbons. The term "Aryl" alone or as a substituent refers to a monovalent aromatic chlorooxyl group 200823172 ι, which is removed from a single hydrogen atom derived from a single carbon atom of the original aromatic ring. Typical 曰: base package § the following but not limited to: derived from the wrong 浠 浠 (aCean, such as coffee), acenaphthylene, acephenanthlylene, anthracene, azulene, benzene Benzene, M (chrysene), coronene, fluoranthene, fluorine, hexacene, hexaphene, as-indacene, symmetry Province (s-indacene), indane, indene, naphthalene, ovaiene, pentacene, penteneene 〇Pentalene ), pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, py Rene), pyranthrene, mbicene, triphenylene, trinaphthalene, hexalene, octacene, octaphene, octalene, penta-2,4-diene and other aromatic hydrocarbons. Ideal aromatic hydrocarbon groups More preferably, 6 to 6 carbon atoms, more preferably 6 to 8 carbon atoms. "Pharmaceutically acceptable salt" means a salt of the compound of the present invention which is not only pharmaceutically acceptable but also active as the original compound. The salts include: (1) acid addition {^j salts, which may be formed by inorganic acids such as hydrochloric acid, hydrogen desert acid, sulfuric acid, citric acid, acid-breaking and other inorganic acids; or from organic acids such as acetic acid. (acetic acid), propionic acid, hexanoic acid, cyclopentane propionic acid, glycolic acid, pyrignic acid, lactic acid, Malonic acid, succinic acid, malic acid, maleic acid, fUmaric acid, tartaric acid, citric acid ), benzoic acid, 3-(4-pyrimidin® b ) benzoic acid (3-(4-hydroxybenzoyl) 9 200823172 benzoic acid), cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 , 2-, 2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid (4 -chloiObenzenesulfonic acid), 2_naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 3-phenylpropionic acid (3) -phenylpropionic acid), trimethylacetic acid, 3,3-dimethyl-1-butyric acid (tertiary butylacetic acid), lauryl sulfuric acid, gluconic acid, Glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, 4-methylbicyclo [2.2. 2]-oc1>2-ene-l-carboxylic acid and other organic acids; or (2) pro-compounds a salt formed by the replacement of an acidic proton by a metal ion, such as an alkali metal ion, an alkaline earth ion, or a sulphur ion; or an organic component such as an ethanolamine, Diethanolamine, triethanolamine, N_methylglucamine and other organic molecules are substituted. "Prodrng" refers to a derivative of a drug molecule that undergoes transformation in an organism to release the active molecule; the precursor drug is usually inactive unless converted to an effective drug, but not absolute. "Promoiety" is a protective group used to mask functional groups in a drug, converting the drug into a prodrug; the protecting group is bonded to the 200823172 ws drug molecule in a bond. This bond can be removed by enzyme or non-enzyme in the organism. "Protecting group" means a group of atoms that, when attached to a molecule's function, can mask, reduce or prevent the activity of a functional group. A commercially acceptable carrier (10) armaceutically earner) By means of a diluent, adjuvant, excipient or carrier, the patient can be administered with the compounds of the invention. "Compound" means a compound prepared synthetically in the present invention or a compound produced by administering a different η to a living organism. The compound does not contain metabolites of the parent drug. Compound of the invention: The compound of the invention is a compound of formula 1: 0, ^r^CNH2 (I)

Or a salt, hydrate or paper-soluble substance acceptable to them;

R2, R3 are independently selected from a hydrogen atom or an alkyl group; are an alkyl gr0Up, q_c8 aromatic hydrocarbon group (aryi gr〇Up^ crC6 alkoxyl group; X ' Y is independently selected from hydrogen Atom, chlorophenyl, 2-methylpropyl, or optionally bonded to X, γ by a carbon atom to form a cyclohexyl group 11 200823172 (cyclohexyl) 〇 in one embodiment, The compound of the formula (I) may be a compound of the formula (II), (in), (IV):

Or a pharmaceutically acceptable salt, hydrate or solvate thereof (IV) wherein

Ri is

R2, R3 are independently selected from a hydrogen atom or a hydrocarbon group (alkyl)

R4 is a CrC6 alkyl group, a C6-C8 aromatic aryl group or a CrC6 alkoxyl group. In a preferred embodiment of the formula (II), it is a general formula (V). Compound:

Or /, accepting a salt, hydrate or solvate; wherein 2 represents a hydrogen source 200823172, a sub or an alkyl group; a more suitable & A further-touch wire-like compound of the formula (II), which is a compound of the formula (VI):

Or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein, the phantom is independently selected from a nitrogen atom or: an alkyl group; the R4 is a CrC6 hydrocarbon group (al_r〇up), and the C6_C8 aromatic smoki group (four) Or CrC6 alkoxy (alkoxyl g_p). Use of the compound of the present invention: The compound of the present invention can be mixed with a pharmaceutically acceptable thief to form a pharmaceutical composition for providing a noodle preparation; the group extract comprises a compound of the present invention and at least one pharmaceutically acceptable The acceptable carrier may be in the form of a solution, a suspension, an emulsion, a tablet, a pellet, a capsule, a powder, a __, a plug, or other suitable dosage form. (The pharmaceutical composition referred to in the invention may use any literature. A common method of manufacture. The compound and/or pharmaceutical composition referred to in the present invention is suitable for use in mammals for treating or preventing diseases associated with γ-aminobutyric acid, such as epilepsy, neuropathic pain, post-therapy neuropathic pain, and sleeping feet. Motility, sorrow, anxiety, psychosis, skeletal disease, neurodegenerative disease, pain, inflammatory response and gastrointestinal disease, etc. Suitable dosage ranges depend on the potency of the compound, and the compound H of the present invention is about the weight of the mother.杈 and 0.001 home to 200 3⁄4 grams; any two people familiar with the art can easily determine the dosage range in a variety of ways. 13 200823172 Compound drug (pharmac The okinetic or pharmacodynamic properties can be determined by animal experiments, and any skilled artisan can easily design and perform experiments. For example, to understand the pharmacokinetic properties of a compound, the compound is first dissolved in Tween 80 or PEG 400 as a co-solvent. In the solution, the rats are directly fed with an appropriate amount of the compound; the blood sample is collected at a fixed time point, the blood macromolecular protein is removed, and then the blood sample is analyzed by liquid chromatography tandem mass spectrometry (LC/MS/MS) or other means. The maximum mean concentration (Cmax) in the blood of the compound of the invention, the area under the curve (AUC) and the half-life (half-life; T1/2) can be calculated using professional software. [Embodiment] Table 1 Summary The present invention is intended to be illustrative of the invention and not to limit the invention. Other embodiments of the invention and their methods of synthesizing are described in the specification or are apparent to those skilled in the art.

14 200823172 PGB-03 0 I 0 〈”-〇人. people.尺~Y^NH2 C17H31NO5 X Mol. Wt.: 329.43, Formula (II) 〇 R3 幻=!^人. Human R3 = methyl (methyl) R4 = cyclohexyl - oxy-yl 3.9796 PGB-04 0 0 ^Λ〇^〇^_^ΝΗ2 V ν 1 TFA salt C14H27NO4 A Mol. Wt.: 273.37 Formula (II) 〇R3 R1 = R4 person. Human R3 = hydrogen (hydrogen) R4 = isobutyl group 2.931 PGB-05 0 0 gossip A_^Nh2 C14H27N〇4 eight TFA salt Mol. Wt. :273.37 Formula (II) 〇R3 R1=R4 person . Human R3 = methyl (R) = isopropyl (isopropyl) 2.841 PGB-06 0 V 0 , 0 in. Person 1^nh2 —»—1 ] TFA salt C15H29N〇4 Eight Mol. Wt.: 287.40 Formula (II) 〇 R3 Magic = R4 person. Human R3 = isopropyl (isopropyl) R4 = ethyl (ethyl) 3.46 PGB-07 0 〇^lT〇A^pNH2 〇' Λ _t ^13^21 NO5 Mol. Wt.: 271.31 Formula (II) 〇κ° ΐΓ Rl= ° R2 R2 = methyl group 1.018 PGB-08 〇/〇t^nh2 ; 1 butyl FA salt C15H29NO4 Mol. Wt.: 287.40 Formula (II) 〇R3 R1 =R4 person σ person R3 = ethyl (ethyl) R4 = isopropyl (isopropyl) 3.37 15 200823172 Example 1 Synthesis of PGB-02 (3-Aminomethyl-5-mercapto-hexanoic acid-1-ethoxycarbonate-ethyl ester (3-Aminomethyl-) 5-methyl-hexanoic ac^ 1-ethoxycarbonyloxy-ethyl ester)

4 5 Procedure: Dissolve sodium iodide (3.93 g, 22.6 mmol) in 20 ml of anhydrous methyl cyanide (CH3CN). Then add compound 1 (1·〇〇 pre-dissolved in 8 ml of anhydrous methyl cyanide). Gram, 6.55 Torr, and reacted at 60 ° C for 6 hours. The residue after filtration and concentration was diluted with diethyl ether and concentrated again to give 1·4 g of Compound 2: Carbonic acid ethyl ester 1-iodo-ethyl ester; Yield: 64% ); 'HNMR (CDC13? 500MHz) 51.32 (t? J=7.0Hz? 3H)? 2.22(d? J=6.〇Hz, 3H)5 4.25 (q, J=7.0Hz5 2H), 6.75 (q, J = 6-0 Hz, 1H); 13C NMR (CDC 135 125 MHz) δ 14.14, 30.10, 52.34, 152.48.

319·319 g of cesium carbonate was dissolved in 7 ml of decyl alcohol, and then s_f〇rm compound 3 (〇·924 g, 3.57 mmol) was added, stirred at room temperature for 4 hours, and concentrated by filtration to dryness; (7 ml) and compound 2 (1.74 g, 7.04 mmol) were stirred at room temperature for one night; the residue after filtration was concentrated on a silica gel column (7 〇-230 mesh, solution: EA/hexane = l: 4) Chromatographically purified hydrazine in 0.815 g of compound compound 4 in the form of slightly palm oil: 3-(tertiary butoxymethylamino-indenyl)-5-mercapto-hexanoic acid ethoxylated _ ethyl ester (3_( tert_But〇xycarb〇nylamin〇_metW 16 200823172 5-methyl-hexanoic acid 1-ethyloxycarbonyloxy-ethylester ; Yield: 23%); iHNMRCCDCB, 500MHz) δ 0.87~0.90(m,6H),1_11 〜1.20(m,2H ), 1.33 (t, J = 7.0 Hz, 3H), 1.44 (s5 9H), 1.52 (d, J = 5.5 Hz, 3H), 1.60 to 1.68 (m, 1H), 2.03 to 2.13 (m, 1H), 2.32~2.38(m,2H), 2.96~3.08(m,1H), 3.13~3.22(m,1H), 4.23(q,J=7.0Hz,2H), 4.71~4.75(m,1H)5 6.76( q·J=5.5 Hz, 1H); 13CNMR (CDC13, 125MHz) δ14·08, 19.50, 22.52, 22.62, 22.66, 22.72, 25.09, 28.35 , 33.42, 33.61, 36.90, 37.10, 41.23, 41.25, 43.74, 43.81, 64.23, 79.12, 91.23, 153.05, 156.06, 171·(Π. 0.407 g (1.08 mmol) of compound 4 and 2.85 ml of dichloromethane ( The mixed solution of CH2C12) was placed in ice water, and then 6.5 ml of Trifluoroacetic acid was added, followed by ice bath for 30 minutes; the solution was warmed to room temperature and stirred for 4 hours, and the reaction solution was concentrated and dried. 0.50 g of compound 5: 3-aminomethyl-6-methyl-hexanoic acid 1-ethoxycarbonyloxy-ethyl ester TFA salt; yield: 99%); iHNMRCCDCB, 500MHz) δ 0.87~0.91 (m, 6H), 1.23~1.39 (m, 6H), 1.51 (6rs, 3H), 1.61 (S, 1H), 2·20 ~ 2.38 (m, 1H), 2·40~2.61 (m, 2H), 2.98~3.21 (m, 2H), 4.2 (br s, 2H), 6.75 (br s 1H), 7.51 to 7.80 (br s, 2H), 9.35~9.80 (br s, 1H); 13C NMR (CDC13, 125MHz) 513.86, 13.87, 19.16, 19.19, 21.70? 21.74? 22.38, 22.40, 24.83, 30.95, 31.02, 36.48, 36.69, 41.07, 41.32, 44.25, 44.36, 64.82, 9L41, 91.45, 153.38, 153.40, 171.87 , 172.08. Example 2 Synthesis of PGB-03 (3-Aminomethyl-5-methyl-hexanoic acid 1-cyclohexyloxycarbonyloxy-ethyl ester) 17 200823172

Procedure: Dissolve 1 · 4 g of cyclohexanol (CyCl〇hexy alcohol) in 15 liters of dichloromethane (CHfl2) under nitrogen treatment at 0 to ·5 C, and then slowly add chloroethyl chlorohydrazine. A mixture of 1-chloroethyl chloroformate (2 gram) and methylene chloride (1 liter) was stirred for 15 minutes; then pyridine (pyridine, 1.22 g) and dichloromethane were slowly added dropwise. 2 ml) of the mixture was reacted at room temperature for one night; the reaction solution was added with 20 ml of dichloromethane and 20 Torr of pure water, and the product was extracted with dichloromethane and washed twice with 20 ml of pure water, and the residue was dried and concentrated. 2.64 g of compound 6: cyclohexyl carbonate chloro-ethyl ester (Carbonic acid cyclohexyl ester l-chl-1 ester; yield: 94 ° /.); 5 (8)) δ 1.22-1.3 〇 (m, 1H), 1.32-1.41 (m, 2H), l·42'1·58^ 3H^? L71-L8〇(in, 2H), 1.83(d, J=6.0Hz, 3H), 1.89-2.00 (Gua 2, 4.65_4. 72 (m, 1H), 6.43 (q, household 6.0112, between. 4.48 g of sodium iodide lacquered in 3 ml of anhydrous methyl nitrogen (CH3CN)' and then added to compound 6 pre-dissolved in 3 ml of anhydrous cyanide ( 1.2G grams, 5.98 millimoles 18 200823172 觚 ears) And reacting at 50 ° C for 5, 5 hours. The residue after filtration and concentration is diluted with ethyl acetate and concentrated again to obtain 1 · 21 g of compound 7 : Carbonic acid cyclohexyl ester 1-iodo-ethyl ester; yield: 69%); 'HNMRCCDC^, 500MHz) δ i.25-i.40(m? 3H)? i.4i-i.58(m? 3H), 1.70-1.78 (m5 2H)? 1.85-1.95(m? 2H)? 2.22(d? J=7.0Hz? 3H)? 4.66-4.71(m? 1H), 6.77(q,(1=7·0Ηζ,1H). 0.319 The ruthenium carbonate was dissolved in 5 ml of methanol, and 0.5 g (1·28 mmol) of S-form compound 3 was added. The solution was stirred at room temperature for 4 hours and then concentrated by filtration to dryness. Cyanide and 1·g (3.39 mmol) of compound 10 were mixed at room temperature for one night; after the reaction solution was concentrated by filtration, the residue was chromatographed on a silica gel column (70-230 mesh, solution: EA/hexane=l: 4). Purification afforded 0.339 g of compound 8: 3-(tert-Butoxycarbonylamino-methyl)-(3-(tert-Butoxycarbonylamino-methyl)-(3-(tert-Butoxycarbonylamino-methyl)- 5-methyl-hexanoic acid 1-cyclohexyloxycarbonyloxy-ethyl ester ; Yield: 23%); 1HNMR (CDC13, 500MHz) δ0·87-0.90, (m 6H), U〇-1.21 (m, 2H), 1.25-1.42 (m, 3H), 2.04 (s, ς 9H), 1.55 (d, 々5·0Ηζ, 3H), L41-1.56 (m, 3H) , 1.6 (M.64 (m, 1H), 1.72-L78 (m, 2H), 1.88-1.92 (m, 2H), 2.04-2.15 (m, 1H), 2.23-2.34 (m, 2H), 2.95- 3.08 (m, 1H), 3.11-3.23 (m, 1H), 4.61-4.75 (m, 2H), 6.75 (q, / = 5.03⁄4 1H); 13CNMR (CDC13, 125MHz) δ14·17, 19.56, 20.99, 22.57, 22.64, 22.69, 22.74, 23.56, 25.15, 28.38, 31.38, 31.39, 33.53, 33.73, 37.G1, 37.16, 41.28, 41.32, 43.86, 60.35, 77.44, 79.13, 91.18, 91.19, 152.55, 156.07, 170.97. A mixed solution of 0.172 g (0.40 mmol) of compound 8 and 2.85 ml of dichloromethane was placed in an ice water bath, and 2.85 ml of trifluoroacetic acid was added thereto, followed by ice bath for 30 minutes; the solution was warmed to room temperature and stirred for 5 hours. The reaction solution was concentrated to dryness 19 200823172. After drying, 0.165 g of compound 5: 3-aminomethyl-5-methyl-hexanoic acid-1-cyclohexyloxycarbonate-ethyl ester trifluorocurate (3-Aminomethyl) was obtained. -6-methyl-tiexanoic acid 1-cyclohexyloxycarbonyloxy-ethyl ester TFA salt ; Yield: 93%); iHNMR (CDCl3? 500MHz) 50.87-0.91 (m? 6H)? 1.21-L40 (m? 6H)? 1.41-1.56 (m,6H),1.60-1.63 (m,1H),1.70-1.78 (m,2H),1.82-1.93 (m,2H), 2.23-2.64 (m,3H),3.01-3.3l (m,2H) ), 4.58-4.63 (br s, 1H), 6.77 (br s, 1H), 8.00 (br s, 2H); 13CNMR (CDC13, 125MHz) δ 19.01, 21.52, 21.58, 22.19, 23.16, 24.67, 24.82, 30.89 , 31.03, 36·68, 36.87, 41.07, 41.30, 44.20, 65.51, 77.76, 91.32, 91.36, 152.63, 152.69, 172.02, 172.08; LC/MS: ESI positive mode (M+H): 330.36. Example 3 Synthesis of PGB-04 (3-Aminomethyl-5-methyl-hexanoic acid 2?2- Dimethyl-propionyloxymethyl ester)

Procedure: Dissolve 2.5 g of sodium iodide in 13 ml of acetone, then add a mixture of Chloromethyl tert-butyl ester (1.0 g) and propionate 1 (2 ml) under nitrogen treatment at 50 ~5 5 °C reaction 5 · 5 hours. The residue after filtration and concentration was diluted with 10 ml of diethyl ether and then concentrated to yield 1.354 g of brown liquid compound 20 200823172 4 1 〇: 2'2-dimethyl-propionic acid methyl ester (2,2"〇^1161: 11}4-卩1*(^〇111〇&〇丨(1丨〇<1〇11101:]1}4 ester; yield esycO^HNMRCCDCUOOMHzM U9(s.9H), 5.93(s, 2H) 0.344 g of cesium carbonate was dissolved in 5 ml of decyl alcohol, and 0.50 g of S-form compound 3 was added thereto, and mixed at room temperature for 4 hours, and then concentrated by filtration to dryness. The dried product was dissolved in 5 ml of decyl cyanide, and then added to contain 0.948 g. A solution of compound 10 and 5 ml of decyl cyanide was stirred at room temperature for one night; after concentration by filtration, the residue was purified by a silica gel column (70-230mesh, solution: EA/hexane = 1 : 4) to obtain 0.689 g of a viscous liquid compound. 11:3-(tertiary-butoxycarbonylamino-methyl-methyl)-5 -methyi-hexanoic acid 2,2-dimethyl-propionyloxymethyl ester; Yield: 95%); 1HNMR (CDC13? 500MHz) 52.87-0.91 (m? 6H)5 1.06-1.23 (m9 2H)? 1.19 (S? 9H) 1.43(S? 9H)? 1.63-1.68(m? 2H)9 2.12-2.17(m9 1H)? 2.30-2 .38(m, 2H), 2.96_3.06(m, 1HX 3.16-3.22(m,1H), 4.62-4.70(m,1H),5·73, 5.76(dd, J=4.5, 9·0Ηζ, 2H); 13CNMR (CDC13, 125MHz) δ 14.16, 22.59, 22.69, 25.15, 26.85, 28.37, 33.63, 36.95, 38.74, 41.29, 43.82, 60.58, 79.20, 79.57, 156.05, 171.67, 177.12 (0.345 g of compound 11 Dissolved in 6 ml of dichloromethane, then slowly added 2.8 ml of trifluoroacetic acid, and then ice bathed for 30 minutes; the solution was warmed to room temperature and stirred for 4.5 hours. The reaction solution was concentrated and dried to obtain 0.220 g of yellowish Solid compound 12: 3-aminomethyl-5-mercapto-hexanoic acid·2,2-dimercapto-propoxymethyl trifluoroacetate (3-^丨11〇11^]^1-5- 11^1别-1^Parent&11〇&(^2,2-(1丨11^1171-propionyloxymethyl ester TFA salt; yield: 93%); iHNMR^CDCls, 500MHz) δ0·98- 1·00(ηι5 6H), 1.26(s,9H), 1.32(t, “7=7.5, 2H), 1.70-1.79 (m, 1H), 2.28-2.35 (m, 1H), 2.53-3.02 (m , 2H), 3.03 (d, J = 8.0 Hz, 2H), 3.07 (s, 21 200823172 2H), 5.82, 5.84 (dd, J = 2.0, 7·0Ηζ, 2H); 13CNMR (CDC13, 125MHz) Δ21·86, 22.43, 24·92, 26·73, 27.02, 31 .18, 36.23, 38.76, 41.05, 43.84, 79.84, 171.94, 177.44. LC/MS: ESI positive mode (M+H): 274.30 ° Example 4 Synthesis of PGB-05 (3-Aminomethyl-5-A 3-Aminomethyl-5-methyl-hexanoic acid 1-isobutyryloxy-ethyl ester Η

15 16 Procedure: Add 2.40g of ethylbenzene to 5.94g of isobutyryl chloride for 30 minutes under nitrogen treatment at 0~-5°C; transfer to room temperature for 4 hours, at 35-40°C Distillation under vacuum yielded 1.91 g of colorless compound 13: Isobutyric acid 1-chloro-ethyl ester (yield: 23%); 1HNMR (CDC13? 500 MHz) 61.19 (t? J=6.0 Hz, 6H)5 1.79 (d? J=5.5 Hz? 3H)? 2.55-2.60 (m, 1H), 0.54 (q, J=5.5 Hz, 1H); 13HNMR (CDC13, 125 MHz) δ 18.14, 18.22, 24.85, 33.55, 80.41, 171.31. 4.5 g of sodium iodide was dissolved in 13 ml of methyl cyanide (CH3CN), followed by the addition of compound 13 (2.16 g, 14.4 mmol) pre-dissolved in 5 ml of methyl cyanide and mixed for 6.5 hours. The residue after filtration and concentration was diluted with 10 ml of diethyl ether and concentrated again to give 1.597 g of compound 14···················· %); iHNMR^CDCls, 500MHz) 5U6-i.2l(m 6H), 2.20 (d, J=5.5Hz, 3H), 2.45-2.61 (m, 1H), 6.86 (q, J=6.〇Hz , 1H). 0.365 g of citric acid shavings were dissolved in 5 ml of decyl alcohol, and then 0.5 g (ΐ·28 mmol) of S-form compound 4 was added, mixed at room temperature for 4 hours, and concentrated by filtration to dryness; The mixture was diluted with methyl cyanide, and a mixture of compound 14 (0.945 g, 3.56 mmol) and hydrazine-based gas (5 ml) was added, and the mixture was reacted at room temperature for one night; and concentrated by filtration to obtain 1 g of a mixture, followed by a stone tube The column (70-230 mesh, solution: EA/hexane = 1 : 4) was purified by chromatography to give a compound of the compound 15: 3-(tris-butoxycarbonylamino-methyl)-5-methyl-hexanoic acid- Μ-(terl>Butoxycarbonylaminomethyl-5-methyl-hexanoic add 1-isobutyryloxy-ethyl ester; yield: 27%); iHNMR^CDCl, 500MHz) δ0.87-0·92(πι ,6H),1·10-1·21(πι,2H),1.55(d,/=5Hz,6H), 1.44(s,9H), 1.48(d,/=5·5Ηζ,3H),1.52- 1.59 (m, 2H), 2.06-2.12 (m, 1H), 2.28-2.35 (m, 2H), 2.49-2.57 (m, 1H), 2.93-3.06 (m, 1H), 3.12-3.22 (m, 1H) ), 4.62-4.73 (m, lH), 6.84 (q, J = 5.5 Hz, lH. 0.13 g (0.35 mmol) of compound 15 dissolved in 2.5 ml of dichloromethane, ϋ After 83 ml of trifluoroacetic acid, the mixture was ice-cooled for 1 hour; the solution was warmed to room temperature and stirred for further 5 hours, and the reaction solution was concentrated to dryness to obtain 0.12 g of compound 16: 3-aminomethyl-5-fluorenyl group. 1-Aminomethyl-5-methyl-hexanoic acid 1-isobutyryloxy-ethyl ester TFA salt; Yield: 62%; 1HNMR (CDC13, 500MHz) δ0·87 -0·91(ιη,6H), U4-U6(m,6H),1.21-1.29(m,2H),1·46-1·48(ιη,3H),1.51-1.63(m, 1H), 2.20-2.33(m,1H), 2.39-2.46(m,1H), 2.50-2.60(m, 2H), 2.96-3.06(m, 1H), 3.08-3.10(m,1H), 5.67(br s, 2H), 6.83 (br s, 1H); 13CNMR (CDC13, 23 200823172 i 125MHz) δ 18.44? 18.46, 19.16, 19.19, 21.82, 22.46, 24.93, 31.09, 31.14, 33.82, 33.84, 36.75, 37.02, 41.23, 41.51 , 44.40, 44.57, 88.82, 88.90, 172.11, 172.21, 175.96. LC/MS: ESI positive mode (M+H): 274.30. Example 5 Synthesis of PGB-06 (3-Aminomethyl-5-methyl-hexanoic acid 2-methyl_ 3-aminomethyl-5-methyl-hexanoic acid 2-methyl_

1-propionyloxy-propyl ester)

CS2CO3

Add 3 g of isobutyric acid (Isobutylaldehyde) to 3·85 g of propionyl chloride, treat with 〇~-5 °C nitrogen and mix for 4 hours, then vacuum distillation at 50 °C to obtain 2.59克 colorless liquid compound 17: propionic acid l-chloro-2-methyl-propyl ester; yield: 38%; iHNMRCCDCL 500MHz) δ1.06 (ΐ J=7.0Hz? 6H)? 7.60(t5 J=7.5Hz5 3H)? 2.13-2.17(m? 1H)? 2.39(q? >7·5Ηζ,2H)5 6.31(d,/=4·5Ηζ , 1H); 13CNMR (CDC13, 125MHz) δ8·66, 17.25, 17.36, 27.49, 35.19, 88.61, 172.16. 0.348 g of cesium carbonate was dissolved in 5 ml of decyl alcohol, followed by S-forai compound 3 (0.5 g, 1.228 mmol), and the solution was stirred at room temperature for 4 hours, then concentrated by filtration to dryness; and the dried product was added to 0.68 g of propionic acid - a mixture of 1-chloro-2-methylpropanopurine (propionic acid l-chloro-2-methyl-propyl 24 200823172 ester) and 3 ml of dimethyl decylamine (DMF), stirred and mixed at 5 ° C for 5 hours; After filtration, the filtrate was extracted three times with ethyl acetate (EtOAc) and purified water. The concentrated mixture of the organic layer was purified by chromatography on a gum column (70-230mesh 'solution: EA/hexane^l: 4) to obtain 0.196 g of a yellowish viscous liquid compound 18: 3-(tertiary butoxycarbonylamine) Base-methyl)_5_mercapto-hexanoic acid·2_methyl-1-propoxypropyl ester (3-plus 11_3111; 〇乂}^1*13〇11}^111^1〇-11^1113^ 5 -methyl-hexanoic acid 2-methyl-1-propionyloxy-propyl ester; Yield: 40%); 1HNMR (CDC 135 500 MHz) 80.86-0.94 (m3 9H)5 0.96 (d? J=7.0Hz9 3H)5 1.10-1.22 (m, 3H), 1.44 (s, 9H), 1.56-1.60 (m, 1H), 1.61-1.70 (m, 1H), 1.98-2.14 (m, 2H), 2.31 (q, J = 7.0 Hz, 1H) ), 2.35 (q, /=7·5Ηζ, lH), 2.96-3.06 (m, 1H), 3.16-3.25 (m, 1H), 4.26-4.71 (m5 1H), 6.65 (d, J = 5.5 Hz, 1H). 0.196 g (0.51 mmol) of compound 18 was dissolved in 2 ml of dichloromethane, and 3.25 ml of trifluoroacetic acid was added thereto, followed by ice bath for 30 minutes; the solution was warmed to room temperature and stirred for 5 hours, and the reaction solution was concentrated and dried. 0.194 g of compound 19: 3-aminomethylsulfonyl-5-mercapto-hexanoic acid-2-mercapto-1-propoxypropane g-3-Aminomethyl-5-methyl-hexanoic acid 2-methyl-1-propionyloxy-propyl ester TFA salt; Yield: 95°/〇); iHNMI^CDsOD, 500MHz) δ0·88-0·92(ιη, 6H), 0.94 (d, J=6.5Hz, 3H), 1.08 (t, J = 7.5 Hz, 2H), 1.20-1.28 (m, 2H), 1.60-1.69 (m, 1H), 1.95-2.02 (m, 1H), 2.16-2.23 (m, 1H) , 2.29-2.46 (m, 3H), 2.89-2.98 (m, 2H), 3.27 (s, lH), 6.59 (d, J = 5 Hz, 1H); 13CNMR (CDC13, 125MHz) δ9·29, 9.31, 16.74 , 16.84, 16.86, 22.58, 22.59, 23.25, 23.27, 23.31, 26.28, 26.32, 28.28, 32.83, 32.90, 32.95, 36.85, 36.93, 37.28, 41.80, 41.89, 42.24, 44.31, 44.34, 44.71, 49.66, 94.54 , 94.57, 172.16, 172.18, 174.46· LC/MS: ESI positive mode (M+H): 288.30. 25 200823172 Example 6 Synthesis of PGB-07 (3-Aminomercapto-5-methyl-hexanoic acid_5_methyl_2_ Oxygen (1 3) Oxo-4 Methotrexate (3-Aminomethyl-5- Inet}iyl_hexaiic)ic acid 5-methyl-2-ox〇-[l 53]diox〇l-4-ylmethyl ester)

Procedure: Compound 20 is configured according to the steps disclosed in Sakamoto et al. (c/2(10)

Pharm· Bull, View 4, 32, 224V) 〇〇·20g of cesium carbonate dissolved in methanol, then add ο% gram of Sf〇rm compound 3, stir in chamber/irrigation for 2 hours' then remove the solvent by means of reduced pressure The residue was diluted with 3.8 ml of N,N-dimethylacetamide, and then compound 20 (0.2 g, 0·0032 I mole) was added with 1 house liter n, N- thiol A mixture of amines was reacted overnight. The reaction solution was diluted with 50 ml of pure water, extracted with ethyl acetate, and then washed with brine, and then concentrated under reduced pressure to give an oily mixture of 63 g. The mixture was purified by chromatography on a silica gel column (7 〇 _ 23 〇mesh, solution: EA/hexane = 1: 4) to give 33·33 g of compound 21: 3-(tertiary butoxycarbonyl fe-yl) -5-Mercapto-hexanoic acid-2-methyl-2-oxo-(1,3)dioxo-4-methyl ester (tert B^t〇xycarbonylamino-methyl)-5-methyl-hexanoic acid 5-methyl -2-oxo-[l,3]diox〇l-4-ylmethyl ester; yield: 72%); iHNM^CDCls, 500MHz) δ 0.87-0.91 (m, 6H), 1.07-1.15 (m, 1H) , 1.16-1.21(m,1H), 1.43(s,9H), 1.59-1.67(m,1H),2.09-2.12(m,1H),2.18(s,3H),2.23-2.36(m,2H) , 26 200823172 4 2.96-3.03(m? 1H)5 3.17-3.23(m? 1H)5 4.68(br s, 1H)5 4.85(s? 2H). ; 13HNMR (CDC13, 125MHz) δ 9.25, 22.57, 22.60 , 25.13, 28.29, 29.59, 33.62 6.2, 4.38 43.79, 53.56, 79·7, 13·51, 13.9, 152.00, 5·02, 172.38. 150 mg of compound 21 was dissolved in 2.5 ml of dichloromethane, and 2 ml of a mixture of 4 hydrazine hydrochloride/dioxane was added and mixed at room temperature for 5 hours. The solvent was concentrated under reduced pressure to obtain 110 mg of a yellowish liquid compound. 22: 3-aminomercapto-5-methyl-hexanoic acid-5-methyl-2-oxo-(1,3)dioxo-4-decyl ester (3-Aminomethyl-5-methyl- hexanoic acid 5- Methyl-2-oxo-[l53]dioxol-4-[' ylmethyl ester TFA salt ; # : 89%) ; 1HNMR (CDC13? 500MHz) δ 0.88_0.92 (m, 6H), 1.18-1.29 (m, 1H) ), 1.31-1.40 (m, 1H), 1.58-1.68 (m, 1H), 2.19 (s, 3H), 2.37 (br s, 1H), 2.50-2.69 (m, 2H), 3.01-3.18 (m, 2H), 4.89 (s, 2H), 8.22 (br s, 2H)V; 13CNMR (CDC13, 125MHz) δ 9.34, 22.38, 22.46, 25.04, 29.61, 31.21, 36.02, 40.92, 42.98, 53.99, 133.34, 140.21, 152.14, 171.76. LC/MS: ESI positive mode (M+H): 272.20 o Example 7 Synthesis of PGB-08 (3-aminomethyl-5-methyl-hexanoic acid-1-isobutenyloxypropanone) 3-Aminomethyl-5-methyl-hexanoic acid 1 -isobutyryloxy-propyl l ester)

24 25 27 200823172 Procedure: Propionic acid (Propionaldehyde, 1.60 g) was mixed with isobutylbutene chloride (3.0 g) and stirred at 5 (TC for 4 hours; after the reaction, the solution was diluted with 15 ml of dichloromethane). Then, it is washed with saturated sodium hydrogencarbonate (15 ml twice) and pure water. The solvent is removed under vacuum (4 Torr) and 4 Torr to 45 to obtain 1.22 g of a colorless liquid compound. 23: Isobutyric acid l_chloro-ethyl ester; Yield: 27%; 1HNMR (CDCl3, p 500MHz) δ1·06 (ΐ, household 7·5Ηζ, 3H), 1.20- L22 (m, 6H), 2.04-2.07 (m, 2H), 2.59_2.63 (m, 1 Η), 6.40 (t, / = 5 · 5 Ηζ, 1 Η). 0.5 g of cesium carbonate dissolved in 8 ml of sterol, Further, 8 g of s_f〇rm compound 3 was added, and the mixture was stirred at room temperature for 75 minutes. After the reaction, the solution was added with a liquid compound 23 (1.1 g, 6.68 Å) pre-dissolved in 6·5 ml of N,N-:mercaptoethylamine. Mohr), stirred at 50 ° C for 5 hours. The reaction solution was filtered, diluted with 25 liters of EA, then washed three times with 25 ml of pure water, and finally concentrated to dryness; product 1.39 g of Shixi rubber column (70-230mes h, solution: EA / hexane = l : 4) Purification by chromatography I gave 71 g of compound 24: 3 - (tertiary butoxycarbonylamino-methyl)-5-mercapto-hexanoic acid-1-isobutenol 3-(tert-Butoxycarbonylamino-methyl)-5-methyl-hexanoic acid 1-isobutyryloxy-propyl ester; Yield: 89〇/〇); iHNMRCCDCls, 500MHz) δ0·87-0·95(ιη,6H ), 0.98 (t, J = 5.0 Hz, 3H), 1.15 - 1.21. (m, 8H), L26 (s, 9H), 1.61-1.69 (m, 1H), L78-1.82 (m, 2H), 2.06- 2.13 (m, 1H), 2.22 - 2.35 (m, 2H), 2.51-2.60 (m, 1H), 2.90-3.05 (m, 1H), 3.16-3.23 (m, 1H), 4.63-4_73 (br s, 1H), 6.73 (t, J = 5.5 Hz, 1H); 13CNMR (CDC13, 125MHz) δ7·58, 7.60, 18.65, 18.68, 22.56, 22.59, 22.68, 25.12, 26.39, 28.35, 33.52, 33.68, 33.86, 36.98 , 37.12, 41.24, 43.87, 79·09, 91.24, 156.07, 171.11, 175.09. 28 200823172 〇·3 g (0.77 mmol) of compound 24 dissolved in 5 liters of dichloromethane and 4.5 liters of diethanol, followed by ice bath for 30 minutes, the solution was warmed to room temperature and disturbed for 5 hours. After the reaction solution is concentrated and dried, 0.25 g of the compound 25: 3-aminomercapto-5-methyl-hexanoic acid-1-isobutyloxypropyl trifluorophosphate (3-Aminomethyl-S-methyl-) can be obtained. Hexanoic acid 1 -isobutyryloxy-propyl ester TFAsalt; yield: 80%); iHNMRCCDCUOOMHzMO.ST-OSSCmJH), 1.15-1.65 (m, 4H), 1.18-1.28 (m, 2H), 1.52-1.67 (m, 1H) , 1.71-1.82 (m, 2H), 2.18_2.31 (m, 1H), 2.39-2.46 (m, 1H), 2.51-2.62 (m, 2H), 3.02 (brs, 1H), 3.19 (br s, 1H), 6.89 (t, /=5·5Ηζ, 1H), 7.48 (br s, 2H); 13CNMR (CDC13, 125MHz) δ 7.29? 7.35, 14.69, 18.39? 18.42? 18.48, 18.52, 21.70, 21.73? , 24.9G, 26.18, 31.G5, 31.13, 33.93, 36.92, 37.08, 41.26, 41.47, 44.73, 44.79, 66.05, 91.73, 91.83, 172.58, 172.69, 176.43. Example 8 Pharmacokinetic Test The test compounds PGB-03, PGB-05, PGB-06, PGB-07 and pregabalin were dissolved in 2% Tween 80 to give final concentrations of 丨.25, 3, respectively. 45, 3〇5, 31.5, and 2.4 mg/ml; male SD rats (280-320 g, 3/group) were administered the above compounds in a feeding manner, and their doses were 34.5, 30.5, 31.5, and 24, respectively. And 12.5 mg/kg (equivalent to 12.5 mg/kg of pregabalin); after feeding, blood was collected at 〇, 〇·25, 〇·5, 〇·75, 卜, 5, 8, 12 and 24 hours, respectively, and Immediately treated with methyl cyanide/methanol (5〇/5〇) and stored in the generation. Finally, the concentration of the above test compound and pregabalin in the blood sample was measured by LC/MS/MS. Results: The presence of the above test compounds was not detected in all blood samples. After administration of the test compound, the bioavailability (Beivailavailability) and the average maximum blood concentration ratio of pregabalin (c fiber 29 200823172 annihilation) turned to touch A New Zealand _ (7 shun) __ recorded two . As shown in Table 2, after the 'PGM3 is administered, the bioavailability is compared with the average maximum blood concentration compared with = Bahrain is 56 er (four) s; p_ is for the coffee; the ship is secret and 0.666, and the PGB-G7 is 75.8% 舆_5. The results showed that the test compound was changed into the Bahrain for entering the body, and therefore the living towel could be used as a precursor drug for pregabalin. Table II

The area under the pregabalin curve (AUC) of the test compound group/the area under the pregabalin curve of the pregabalin group (AUC) The mean maximum blood concentration ratio (Cmaxratio): the mean maximum blood of pregabalin in the test compound group The average maximum blood concentration of pregabalin in the medium concentration/preribin group. Other embodiments of the invention disclosed in the invention are only a few preferred embodiments of the invention. Any of the skilled in the art can The contents of the specification and the contents of the modified examples are used to synthesize other compounds of the present invention. For example, compound 3 can be easily used in the synthesis process.

The compound of the formula (III) or the formula (IV) of the present invention is substituted, and thus the scope of the invention is not limited to the examples. [Simple diagram description] None [Main component symbol description] None

31

Claims (1)

200823172 X. Patent application scope: 1. A compound of formula (I) 〇X Y or a pharmaceutically acceptable salt, hydrate or solvate thereof; R2, R3 are independently selected from a hydrogen atom or a hydrocarbon group; R4 is a CrC6 hydrocarbon group, a C6-C8 aromatic hydrocarbon group or a CrC6 alkoxy group; X, Y is independently selected from a hydrogen atom, a chlorophenyl group, a 2-methylpropyl group, or a choice The bond is formed by carbon atoms and X, Y to form a cyclohexyl group. 2. The compound of claim 1, which has the formula (II): (II). 3. The compound of claim 1, which has the formula (III): 4. The compound of claim 1, which has the formula (IV): 200823172 5. The compound of claim 2, which has the formula (V): 6. The compound of claim 5, wherein R2 is methyl. 7. The compound of claim 2, which has the formula (VI): (VI) 〇 8. The compound of claim 7, wherein R 4 is a CrC 6 alkoxy group. 9. The compound of claim 8 wherein R4 is ethoxy or cyclohexyloxy. 10. The compound of claim 7, wherein R4 is Q-C6 alkyl. 11. The compound of claim 7, wherein R4 is isobutylene, isopropylene or ethyl. 12. The compound of claim 7, wherein R3 is a hydrogen atom, a methyl group, an ethyl group or an isopropane. 13. The compound of claim 2, wherein the compound is selected from the group consisting of: 3 -aminomercapto-5-methylhexanoic acid-1 -ethoxycarbonic acid-ethyl hydrazine, 3-amino hydrazine 5--5-mercapto-hexanoic acid_1_cyclohexyloxycarbonate-ethyl ester; 3-aminomercapto-5-mercapto-hexanoic acid-2,2-dimethyl-propoxymethyl ester; 3 - Aminomethyl-5-mercapto-hexanoic acid-1-isobutyl fine oxygen i-ethyl, 3-aminomercapto-5-methyl-hexanoic acid-2-methyl-1-propoxypropene , 3-aminomethyl-5-methyl-hexanoic acid-5-mercapto-2-lacto-[1,3]-4-indenyl, and 3-aminomethyl-5-methyl- Caproic acid-1-isobutyl milk-propyl vinegar. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier. A pharmaceutical composition for treating a disease associated with γ-aminobutyric acid, which comprises the compound of claim 1. The pharmaceutical composition according to claim 15, wherein the disease associated with γ-aminobutyric acid comprises epilepsy, neuropathic pain, post-constrained neuralgia, sleep-induced analgesia, depression, anxiety, psychosis , skull disease, neurodegenerative diseases, pain, inflammatory reactions and gastrointestinal diseases. 17. The pharmaceutical composition according to claim 15, wherein the disease associated with gamma-aminobutyric acid comprises epilepsy, neuropathic pain, post-herpetic neuralgia and sleep alopecia. A pharmaceutical composition comprising a pregabalin precursor drug, wherein the pregabalin precursor drug is the compound of claim 13. 200823172 VII. Designated representative map: (1) The representative representative of the case is: ( ). (2) A brief description of the symbol of the representative figure: Benefits 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: