CN1753673A

CN1753673A - Prodrugs of gaba analogs, compositions and uses thereof

Info

Publication number: CN1753673A
Application number: CN02814572.0A
Authority: CN
Inventors: M·A·盖络普; K·C·坎迪; C·X·周; 丘法扬; 姚棼梅; 祥佳宁; I·R·奥尔曼
Original assignee: XenoPort Inc
Current assignee: XenoPort Inc
Priority date: 2001-06-11
Filing date: 2002-06-11
Publication date: 2006-03-29
Anticipated expiration: 2022-06-11
Also published as: CN101381339A; CN1753673B; CN101434572B; CN101381339B; CN101434572A

Abstract

The present invention provides prodrugs of GABA analogs, pharmaceutical compositions of prodrugs of GABA analogs and methods for making prodrugs of GABA analogs. The present invention also provides methods for using prodrugs of GABA analogs and methods for using pharmaceutical compositions of prodrugs of GABA analogs for treating or preventing common diseases and/or disorders.

Description

The prodrug of GABA analog and compositions thereof and application

The application requires 35 U.S.C. § 119 (e) to require the U.S. Provisional Application 60/297 of application on June 11 calendar year 2001,521, the U.S. Provisional Application 60/298 of application on June 14 calendar year 2001, the U.S. Provisional Application 60/366 of application on March 19th, 514 and 2002,090 interests, this paper quotes these and offers as a reference.

1. Invention field

The present invention relates generally to the prodrug of GABA analog, the pharmaceutical composition of GABA analog prodrug, the preparation method of the prodrug of GABA analog, the application process of the pharmaceutical composition of GABA analog prodrug and GABA analog prodrug.More specifically, the present invention relates to the prodrug of gabapentin and pregabalin, the pharmaceutical composition of the prodrug of gabapentin and pregabalin, the preparation method of the prodrug of gabapentin and pregabalin, the application process of the pharmaceutical composition of the prodrug of the prodrug of gabapentin and pregabalin and gabapentin and pregabalin.

2. Background of invention

Gamma (" γ ")-aminobutyric acid (" GABA ") is a kind of main inhibitory transmitter in the mammalian central nervous system.GABA is not transported to brain (being that GABA does not stride across blood-brain barrier effectively) effectively from blood flow.Therefore, brain cell provides all GABA that finds (BABA is biosynthetic by the decarboxylation of glutamic acid and pyridoxal 5-phosphate) in fact in brain.

GABA is by combining and regulate neuronic irritability with specific memebrane protein (being the GABAA receptor), thereby causes ion channel open.Chloride ion enters and causes the hyperpolarization of recipient cell by ion channel, thereby prevents from Nerve impulse is delivered to other cell.In epilepsy, movement disorders (as multiple sclerosis, kinetic tremor, tardive dyskinesia), fear, anxiety, depression, alcoholism and manic behavior) individuality in observe low-level GABA.

Excited great interest about the prompting of the low GABA level of multiple common disease and/or common medical conditions to GABA analog preparation with the pharmaceutical property (for example seeing through the ability of blood brain barrier) that is better than GABA.Therefore, synthesized in the art multiple GABA analog with important pharmaceutical property (for example referring to people such as Satzinger, United States Patent (USP) 4,024,175; People such as Silverman, United States Patent (USP) 5,563,175; People such as Horwell, United States Patent (USP) 6,020,370; People such as Silverman, United States Patent (USP) 6,028,214; People such as Horwell, United States Patent (USP) 6,103,932; People such as Silverman, United States Patent (USP) 6,117,906; Silverman, international open WO 92/09560; People such as Silverman, international open WO93/23383; People such as Horwell, international open WO 97/29101, people such as HORWELL, international open WO 97/33858; People such as Horwell, international open WO 97/33859; People such as Bryans, international open WO 98/17627; People such as Guglietta, international open WO 99/08671; People such as Bryans, international open WO 99/21824; People such as Bryans, international open WO99/31057; People such as Belliotti, international open WO 99/31074; People such as Bryans, international open WO 99/31075; People such as Bryans, international open WO 99/61424; People such as Bryans, international open WO 00/15611; Bryans, international open WO 00/31020; People such as Bryans,

International open WO 00/50027; With people such as Bryans, international open WO 02/00209).

For example pharmaceutically important GABA analog comprises gabapentin (1), pregabalin (2), vigabatrin (3) and the baclofen (4) shown in above.Gabapentin is a kind of lipotropy GABA analog that can pass through blood brain barrier, and its exhibition since nineteen ninety-four is used for the clinical treatment epilepsy.Gabapentin also may have the useful therapeutical effect to following disease: chronic pain disease (for example neuropathic pain, muscle and skeleton pain), psychosis (for example fear, anxiety, depression, alcoholism and manic behavior), movement disorders (Magnus such as (for example multiple sclerosis, kinetic tremor, tardive dyskinesias), Epilepsia, 1999,40:S66-S72).At present, gabapentin also is used for the clinic control neuropathic pain.The pregabalin that has than the bigger curative effect of gabapentin in the clinical model of pain and epilepsy now is in the III clinical trial phase stage.

A major issue of many GABA analog is that gamma-amino and carboxyl functional group generation inner molecular reaction form gamma-lactam, the example such as following gabapentin.Because the toxicity of gamma-lactam (5), its formation brings serious difficulty to gabapentin formulation.Toxicity (the LD of gabapentin for example ₅₀, mice) and greater than 8000mg/kg, and the toxicity (LD of corresponding lactams (5) ₅₀, mice) and be 300mg/kg.Therefore, because safety, the formation of in the preparation of the compositions of synthetic and/or the GABA analog or the GABA analog of GABA analog and/or storage process by-product such as lactams is minimized (particularly exist

Under the situation of gabapentin).

By use specific additional purification step, to the accurate selection of the promoter material in the pharmaceutical composition and careful controlled step (people such as Augurt, United States Patent (USP) 6,054,482) part has overcome the lactams pollution problem, particularly the lactams pollution problem under the situation of gabapentin of GABA analog.But, prevent trial not achieving success fully aspect the synthetic or storage of GABA analog such as gabapentin or its compositions that lactams pollutes.

The System Cleaning rate is many GABA analog, comprises another important problem of gabapentin fast, therefore need take medicine continually with keep treatment in the systemic circulation and prevention concentration (people such as Bryans, Med.Res.REV., 1999,19,149-177).The scheme of taking medicine of using the gabapentin of three 300-600mg dosage every day generally is used for the convulsion treatment.Higher dosage (dosage that separated in 1800-3600mg/ days) generally is used for the treatment of neuropathic pain disease.

Extended release preparation is a conventional solution of System Cleaning rate fast, it is known to those skilled in the art (for example referring to " Remington ' sPharmaceutical Sciences; " Philadelphia College of Pharmacyand Science, 17TH Edition, 1985).Osmotic delivery system also be the known drug method that continues to send (for example referring to people such as Verma, Drug Dev.Ind.Pharm., 2000,26:695-708).Many GABA analog, comprise gabapentin and the obstructed excessive intestinal absorption of pregabalin.On the contrary, these chemical compounds generally in small intestinal, absorbed by big neutral amino acid transporter agent (" LNAA ") (people such as Jezyk, Pharm.RES., 1999,16,519-526).The express passway of passing through gastrointestinal near-end absorption region of regular dosage form has hindered and will continue release tech and successfully be applied to many GABA analog.

Therefore, be starved of the lasting release embodiments of effective GABA analog, minimize with the increase of the frequency of taking medicine that will cause owing to the rapid system clearance rate of these chemical compounds.Also need pure GABA analog pure basically and unautogenous ground lactamize in preparation or storage process, (particularly gabapentin and pregablin analog).

3. summary of the invention

The preparation method of the pharmaceutical composition of the prodrug of the prodrug of the present invention by the GABA analog is provided, GABA analog and the prodrug of GABA analog is devoted to these and other needs.The present invention also provide the GABA analog prodrug application process and the pharmaceutical composition of the prodrug of GABA analog is used for the treatment of or prevents the method for common disease and/or disease.

Importantly, prodrug provided by the invention can have the pharmacy advantage that specifically is applied to medical science significantly.At first, the primitive of the prodrug of GABA analog provided by the invention generally is unsettled (promptly producing a large amount of GABA analog by enzymatic or chemical method cracking before removing prodrug from the patient) in vivo.The second, the primitive derivant and its any metabolite that provide by cracking primitive from prodrug are generally nontoxic when being applied to mammal according to the scheme of taking medicine of generally following the GABA analog.

Chemical compound of the present invention has an amino primitive that links to each other of the γ with the GABA analog.This primitive can directly link to each other with the γ of GABA analog is amino, and perhaps optional can linking to each other with the amino of a-amino acid primitive or the hydroxyl of 'alpha '-hydroxy acids primitive, described primitive self links to each other with the γ of GABA analog is amino.

Chemical compound of the present invention can also have the primitive that links to each other with the carboxyl of GABA analog.The carboxyl primitive is generally ester or thioester substrate.A large amount of esters or thioester substrate can be used to form the carboxyl primitive.

Therefore, chemical compound of the present invention can comprise 4 primitives of as many as, comprises successively and amino 1 the carboxyl primitive that links to each other of γ and 3 amino primitives (that is, so make each primitive successively from the N-end cracking of GABA analog) at the most.Chemical compound of the present invention can comprise 2 amino primitives and 1 carboxyl primitive, 2 amino primitives, 1 amino primitive and 1 carboxyl primitive or 1 amino primitive.Preferably in the chemical compound of the present invention that comprises amino primitive and carboxyl primitive, the carboxyl primitive was hydrolyzed before the complete cracking of the primitive that links to each other with amino.

First aspect present invention provides the chemical compound of formula (I), formula (II) or formula (III):

Or its pharmaceutically acceptable salt, hydrate or solvate, wherein:

M, n, t and u are 0 or 1 independently;

X is O or NR ¹⁶

W is O or NR ¹⁷

Y is O or S;

R ¹Be selected from hydrogen, R ²⁴C (O)-, R ²⁵OC (O)-, R ²⁴C (S)-, R ²⁵OC (S)-, R ²⁵SC (O)-, R ²⁵SC (S)-, (R ⁹O) (R ¹⁰O) P (O)-, R ²⁵S-,

Each R ²Be independently selected from hydrogen; alkyl; the alkyl that replaces; alkoxyl; the alkoxyl that replaces; acyl group; the acyl group that replaces; acyl amino; the acyl amino that replaces; alkyl amino; the alkyl amino that replaces; alkyl sulphinyl; the alkyl sulphinyl that replaces; alkyl sulphonyl; the alkyl sulphonyl that replaces; alkylthio group; the alkylthio group that replaces; alkoxy carbonyl; the alkoxy carbonyl that replaces; aryl; the aryl that replaces; aryl alkyl; the aryl alkyl that replaces; aryloxy group; the aryloxy group that replaces; carbamoyl; cycloalkyl; the cycloalkyl that replaces; the assorted alkyl of ring; the assorted alkyl of the ring that replaces; dialkyl amido; the dialkyl amido that replaces; halogen; assorted alkyl; the assorted alkyl that replaces; heteroaryl; the heteroaryl that replaces; heteroaryl alkyl; the heteroaryl alkyl that replaces; assorted alkoxyl; the assorted alkoxyl that replaces; the heteroaryloxy of heteroaryloxy and replacement, perhaps optional R ²And R ¹⁶Form the assorted alkyl ring of the ring that encircles assorted alkyl or replacement with their bonded atoms;

R ³And R ⁶Be independently selected from the heteroaryl alkyl of heteroaryl, heteroaryl alkyl and replacement of the assorted alkyl of ring, heteroaryl, the replacement of aryl alkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring, the replacement of aryl, aryl alkyl, the replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement;

R ⁴And R ⁵Be independently selected from the heteroaryl alkyl of ring assorted alkyl, heteroaryl alkyl and replacement of aryl alkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring, the replacement of acyl group, aryl alkyl, the replacement of alkyl, acyl group, the replacement of hydrogen, alkyl, replacement, perhaps optional R ⁴And R ⁵Form the assorted alkyl of cycloalkyl, ring of cycloalkyl, replacement, the assorted alkyl of ring or the bridged ring alkyl ring of replacement with their bonded carbon atoms;

R ⁸And R ¹²Be independently selected from the heteroaryl alkyl of heteroaryl, heteroaryl alkyl and replacement of assorted alkyl, heteroaryl, the replacement of aryl alkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring of aryl, aryl alkyl, the replacement of alkyl, aryl, the replacement of alkoxy carbonyl, alkyl, the replacement of acyl group, alkoxy carbonyl, the replacement of hydrogen, acyl group, replacement, the assorted alkyl of ring of replacement, assorted alkyl, replacement, perhaps optional R ⁸And R ¹²Form the assorted alkyl of cycloalkyl, ring of cycloalkyl, replacement or the assorted alkyl ring of ring of replacement with their bonded carbon atoms;

R ¹¹Be selected from hydrogen, alkyl, the alkyl that replaces, acyl group, the acyl group that replaces, aryl, the aryl that replaces, aryl alkyl, the aryl alkyl that replaces, carbamoyl, cyano group, cycloalkyl, the cycloalkyl that replaces, Heterocyclylalkyl, the Heterocyclylalkyl that replaces, heteroaryl, the heteroaryl that replaces, heteroaryl alkyl, the heteroaryl alkyl that replaces, alkoxy carbonyl, the alkoxy carbonyl that replaces, the assorted alkoxy carbonyl of ring, the assorted alkoxy carbonyl of the ring that replaces, aryloxycarbonyl, the aryloxycarbonyl that replaces, the heteroaryloxy carbonyl, the heteroaryloxy carbonyl and the nitro that replace;

R ⁷, R ⁹, R ¹⁰, R ¹⁵, R ¹⁶And R ¹⁷Be independently selected from the heteroaryl alkyl of heteroaryl, heteroaryl alkyl and replacement of assorted alkyl, heteroaryl, the replacement of aryl alkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring of aryl, aryl alkyl, the replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement, the assorted alkyl of ring of replacement, assorted alkyl, replacement;

R ¹³And R ¹⁴Be independently selected from the heteroaryl alkyl of heteroaryl, heteroaryl alkyl and replacement of cyclo alkoxy carbonyl, heteroaryl, the replacement of cycloalkyl, cyclo alkoxy carbonyl, the replacement of aryl alkyl, carbamoyl, cycloalkyl, the replacement of aryl, aryl alkyl, the replacement of alkoxy carbonyl, aryl, the replacement of alkyl, alkoxy carbonyl, the replacement of hydrogen, alkyl, replacement, perhaps optional R ¹³And R ¹⁴Form the assorted alkyl of cycloalkyl, ring of cycloalkyl, replacement or the assorted alkyl ring of ring of replacement with their bonded carbon atoms;

R ²⁰And R ²¹Be independently selected from the heteroaryl alkyl of heteroaryl, heteroaryl alkyl and replacement of assorted alkyl, heteroaryl, the replacement of aryl alkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring of aryl, aryl alkyl, the replacement of alkyl, aryl, the replacement of acyl group, alkyl, the replacement of hydrogen, acyl group, replacement, the assorted alkyl of ring of replacement, assorted alkyl, replacement, perhaps optional R ²⁰And R ²¹Form the assorted alkyl of cycloalkyl, ring of cycloalkyl, replacement or the assorted alkyl ring of ring of replacement with their bonded carbon atoms;

R ²²And R ²³Be independently selected from the aryl alkyl of aryl, aryl alkyl and replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement, perhaps optional R ²²And R ²³Form the assorted alkyl of cycloalkyl, ring of cycloalkyl, replacement or the assorted alkyl ring of ring of replacement with their bonded carbon atoms;

R ²⁴Be selected from the heteroaryl alkyl of heteroaryl, heteroaryl alkyl and replacement of assorted alkyl, heteroaryl, the replacement of aryl alkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring of aryl, aryl alkyl, the replacement of alkyl, aryl, the replacement of acyl group, alkyl, the replacement of hydrogen, acyl group, replacement, the assorted alkyl of ring of replacement, assorted alkyl, replacement; And

R ²⁵Be selected from the heteroaryl alkyl of heteroaryl, heteroaryl alkyl and replacement of assorted alkyl, heteroaryl, the replacement of aryl alkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring of aryl, aryl alkyl, the replacement of alkyl, aryl, the replacement of acyl group, alkyl, the replacement of acyl group, replacement, the assorted alkyl of ring of replacement, assorted alkyl, replacement.

In second aspect, the invention provides the pharmaceutical composition of chemical compound of the present invention.Described pharmaceutical composition generally comprises one or more chemical compounds of the present invention and pharmaceutically acceptable excipient.

In the third aspect, the invention provides treatment or prevent the method for following disease: epilepsy, depression, anxiety, psychosis, faintness outbreak, hypocinesis, cranium are unusual, neurodegenerative disease, fear, pain (particularly neuropathic pain and muscle and skeleton pain), inflammatory diseases (being arthritis), insomnia, gastrointestinal disease or ethanol withdrawal symptom.Described method generally comprises the chemical compound of the present invention to patient's administering therapeutic effective dose of this treatment of needs or prevention.

In fourth aspect, the invention provides the pharmaceutical composition of following disease that is used for the treatment of or prevents the patient of this treatment of needs or prevention: epilepsy, depression, anxiety, psychosis, faintness outbreak, hypocinesis, cranium are unusual, neurodegenerative disease, fear, pain (particularly neuropathic pain and muscle and skeleton pain), inflammatory diseases (being arthritis), insomnia, gastrointestinal disease or ethanol withdrawal symptom.Described method generally comprises the pharmaceutical composition of the present invention to patient's administering therapeutic effective dose of this treatment of needs or prevention.

Aspect the 5th, the present invention includes and be used for the GABA analog derivative compound that the patient to needs treatments carries out administration, M-G, wherein M be primitive and G by the GABA analog, H-G (wherein H is a hydrogen) derives.Primitive M is in case go up cracking from G, and its any metabolite shows carcinogenic toxicity dosage (TD greater than 0.2mmol/kg/ days to rat ₅₀).And when rat is carried out colon administration primitive M in vivo with the cracking from the G of competent speed, to produce:

(i) obtain being at least the C of blood plasma H-G by the H-G of molar doses such as colonic administration _MaxThe Cmax (C of 120% blood plasma H-G _Max); With

(ii) the H-G by molar doses such as colonic administration obtains being at least 120% the AUC of AUC.

Preferred M-G is the derivant of formula (XIV):

Or its pharmaceutically acceptable salt, hydrate or solvate, wherein:

R is a hydrogen, or R and R ⁶Form the pyrrolidine ring of azetidine, pyrrolidine or the replacement of azetidine, replacement with their bonded atoms; With

Y, R ³, R ⁴, R ⁵, R ⁶And R ⁷For defining as the front.

Most preferably M is the derivant of formula (XV):

Wherein: n, X, R ¹And R ²Define as the front.

4. Detailed Description Of The Invention

4.1 Definition

" Active transport or active transport method" refer to the following molecular motion that strides across cell membrane:

A) depend on the method (promptly by drivings such as ATP hydrolysis, ion gradients) that energy mediates directly or indirectly;

Or

B) take place to spread by the facilitation that the interaction with specific transport protein mediates

" Alkyl" refer to by removing a hydrogen atom deutero-saturated or unsaturated, straight chain, side chain or ring monovalence alkyl from the single carbon atom of parent alkane, alkene or alkynes.Typical alkyl includes but not limited to methyl; Ethyl such as ethyl group, vinyl, acetenyl; Propyl group is as third-1-base, third-2-base, ring third-1-base, third-1-alkene-1-base, third-1-alkene-2-base, third-2-alkene-1-base (pi-allyl), ring third-1-alkene-1-base; Ring third-2-alkene-1-base, third-1-alkynes-1-base, third-2-alkynes-1-base etc.; Butyl such as fourth-1-base, fourth-2-base, 2-methyl-third-1-base, 2-methyl-third-2-base, ring fourth-1-base, but-1-ene-1-base, but-1-ene-2-base, 2-methyl-third-1-alkene-1-base, but-2-ene-1-base, but-2-ene-2-base, fourth-1,3-diene-1-base, fourth-1,3-diene-2-base, ring but-1-ene-1-base, ring but-1-ene-3-base, ring fourth-1,3-diene-1-base, fourth-1-alkynes-1-base, fourth-1-alkynes-3-base, fourth-3-alkynes-1-base or the like.

Term " Alkyl" specifically mean and comprise group with any degree of saturation or level, promptly have the single bonded group of exclusive carbon-to-carbon, have one or more carbon-to-carbon double bonds group, have the group of one or more carbon-to-carbon three keys and have the group of the mixture of carbon-to-carbon singly-bound, two key and three key.When meaning specific saturated level, use statement " alkyl group ", " alkenyl " and " alkynyl ".Preferred alkyl comprises 1-20 carbon atom, more preferably 1-10 carbon atom.

" Alkyl group" refer to by removing a hydrogen atom and deutero-saturated side chain, straight chain or cycloalkyl from the single carbon atom of parent alkane.Typical alkyl group includes but not limited to that methyl, ethyl, propyl group are as third-1-base, third-2-base (isopropyl), ring third-1-base etc.; Butyl such as fourth-1-base, fourth-2-base (sec-butyl), 2-methyl-third-1-base (isobutyl group), 2-methyl-third-2-base (tert-butyl group), ring fourth-1-base etc.

" Alkenyl" refer to by removing a hydrogen atom and deutero-unsaturated side chain, straight chain or cycloalkyl with at least one carbon-to-carbon double bond from the single carbon of parent alkene is former.Two keys of described group can cis or transoid conformation.Typical alkenyl includes but not limited to vinyl; Acrylic is as third-1-alkene-1-base, third-1-alkene-2-base, third-2-alkene-1-base (pi-allyl), third-2-alkene-2-base, ring third-1-alkene-1-base; Ring third-2-alkene-1-base; Cyclobutenyl such as but-1-ene-1-base, but-1-ene-2-base, 2-methyl-third-1-alkene-1-base, but-2-ene-1-base, but-2-ene-1-base, but-2-ene-2-base, fourth-1,3-diene-1-base, fourth-1,3-diene-2-base, ring but-1-ene-1-base, ring but-1-ene-3-base, ring fourth-1,3-diene-1-base or the like.

" Alkynyl" refer to by removing a hydrogen atom and deutero-unsaturated side chain, straight chain or cycloalkyl with at least one carbon-to-carbon three key from the single carbon atom of parent alkynyl.Typical alkynyl includes but not limited to acetenyl; Propinyl is as third-1-alkynes-1-base, third-2-alkynes-1-base etc.; Butynyl such as fourth-1-alkynes-1-base, fourth-1-alkynes-3-base, fourth-3-alkynes-1-base or the like.

" Acyl group" refer to group-C (O) R, wherein R is the assorted alkyl of hydrogen, alkyl, cycloalkyl, ring, aryl, aryl alkyl, assorted alkyl, heteroaryl, the heteroaryl alkyl of this paper definition.Representational example includes but not limited to formoxyl, acetyl group, cyclohexyl-carbonyl, cyclohexyl methyl carbonyl, benzoyl, benzyloxycarbonyl group etc.

" Acyl amino" (or selectable " acyl group acylamino-") refer to group-NR ' C (O) R, wherein R ' and R are as defined herein the assorted alkyl of hydrogen, alkyl, cycloalkyl, ring, aryl, aryl alkyl, assorted alkyl, heteroaryl, heteroaryl alkyl independently of one another.Representational example includes but not limited to formoxyl amino, acetyl-amino (being acetylamino), cyclohexyl-carbonyl amino, cyclohexyl methyl-carbonylamino, benzoyl-amido (being benzamido), benzyloxycarbonyl group amino etc.

" Acyloxy" refer to group-OC (O) R, wherein R is as defined herein the assorted alkyl of hydrogen, alkyl, cycloalkyl, ring, aryl, aryl alkyl, assorted alkyl, heteroaryl or heteroaryl alkyl.Representational example includes but not limited to acetoxyl group (or acetate), butoxy (butyloxy or butoxy), benzoyloxy etc.

" Alkyl amino" mean group-NHR, wherein R represents alkyl or cycloalkyl as defined herein.Representational example includes but not limited to methylamino, ethylamino, 1-Methylethyl amino, cyclohexyl amino etc.

" Alkoxyl" refer to group-OR, wherein R represents the alkyl or cycloalkyl of this paper definition.Representational example includes but not limited to methoxyl group, ethyoxyl, propoxyl group, butoxy, cyclohexyloxy etc.

" Alkoxy carbonyl" refer to group-C (O)-alkoxyl, wherein alkane hydrogen base is as defined herein.

" Alkyl sulphonyl" refer to group-S (O) ₂R, wherein R is the alkyl or cycloalkyl of this paper definition.Representational example includes but not limited to methyl sulphonyl, ethylsulfonyl, sulfonyl propyl base, butyl sulfonyl etc.

" Alkyl sulphinyl" refer to group-S (O) R, wherein R is the alkyl or cycloalkyl of this paper definition.Representational example includes but not limited to methylsulfinyl, ethyl sulfinyl, propyl group sulfinyl, butyl sulfinyl etc.

" Alkylthio group" refer to group-SR, wherein R can choose substituted alkyl or cycloalkyl as described herein wantonly for what this paper defined.Representational example includes but not limited to methyl mercapto, ethylmercapto group, rosickyite base, butylthio etc.

" Amino" refer to group-NH ₂-.

" Aryl" refer to by remove single carbon in the parent aromatic ring system on former a hydrogen atom and deutero-monovalence aryl radical.Typical aryl includes but not limited to by following deutero-group: aceanthrylene, acenaphthene, acephenanthrylene, anthracene, azulene, benzene, guan, fluoranthene, fluorenes, hexacene, hexaphene, hexalene, trans benzo two indenes, cis benzo two indenes, indane, indenes, naphthalene, and eight benzene (octacene), and eight benzene (octaphene), octalene, ovalene, penta-2, the 4-diene, Benzo[b, pentalene, pentaphene (phetaphene) perylene, anthracene (phenalene), luxuriant and rich with fragrance Pi, pleiadene, pyrene, pyranthrene, rubicene, benzophenanthrene, trinaphthylene etc.Preferred aryl groups contains 6-20 carbon atom, more preferably 6-12 carbon atom.

" Aryl alkyl" refer to non-cycloalkyl wherein with carbon atom, be generally end or SP ³The bonded hydrogen atom of carbon atom is replaced by aryl.Typical aryl alkyl includes but not limited to benzyl, 2-phenyl second-1-base, 2-phenyl ethylene-1-base, naphthyl methyl, 2-naphthyl second-1-base, 2-naphthyl ethylene-1-base, naphtho-benzyl, 2-naphtho-phenyl second-1-base etc.If wherein desire is specified specific moieties, use term aryl alkyl group, aromatic yl alkenyl and/or aromatic yl polysulfide yl.The preferred aryl groups alkyl is (C ₆-C ₃₀) aryl alkyl, for example the alkyl group of aryl alkyl, alkenyl or alkynyl partly are (C ₁-C ₁₀), and aryl moiety is (C ₆-C ₂₀), more preferably aryl alkyl is (C ₆-C ₂₀) aryl alkyl, for example the alkyl group of aryl alkyl, alkenyl or alkynyl partly are (C ₁-C ₈), and aryl moiety is (C ₆-C ₁₂).

" Alkoxy aryl" refer to wherein aryl alkyl as defined herein-the O-aryl alkyl.

" Aryloxycarbonyl" refer to group-C (O)-O-aryl, wherein aryl is as defined herein.

" AUC" be the area under the plasma drug level-right-time graph from the zero-time to infinitely great extrapolation.

" The bridged ring alkyl" refer to be selected from following group:

Wherein:

A is (CR ³⁵R ³⁶) _b

R ³⁵And R ³⁶Be independently selected from hydrogen and methyl;

R ³³And R ³⁴Be independently selected from hydrogen and methyl;

B is the integer of 1-4; With

C is the integer of 0-2.

" Carbamoyl" refer to group-C (O) N (R) ₂, wherein each R group is hydrogen, alkyl, cycloalkyl or the aryl of this paper definition independently, described group can be chosen wantonly and be substituted, as defined herein.

" Carboxyl" mean group-C (O) OH.

" carcinogenic potency (TD ₅₀) " (referring to people such as Peto; Environmental HealthPerspectives 1984; 58, what 1-8) be defined as that the animal species that causes determining has when its standard end-of-life that the half animal subject suffers from tumor is the chronic dose-grade of unit with the mg/kg body weight/day.Because relevant tumor often occurs on one's body the control animal TD ₅₀More clearly be defined as: with the mg/kg body weight/day is the dosage-grade of unit, if this dosage-grade chronic the using of standard life period of described kind, may keep no tumor during this period.Can calculate the tumor of any particular type, the TD of any particular organization or their any combination ₅₀

" C _Max" be the highest drug level of observed blood plasma after the medicine of using the blood vessel external dose.

" Chemical compound of the present invention" referring to the chemical compound that comprises by general formula described herein, it comprises the specific compound within any general formula scope that discloses its structure at this paper.Chemical compound of the present invention can be identified by their chemical constitution and/or chemical name.When chemical constitution and chemical name conflict, the identity of chemical constitution decision chemical compound.Chemical compound of the present invention can comprise one or more chiral centres and/or two key, therefore can be used as stereoisomer such as double bond isomer (being geometric isomer), optical antimer or diastereomer and exists.Therefore, the all possible optical antimer and the stereoisomer of chemical compound shown in chemical constitution as herein described comprises comprise the pure form of stereoisomer (for example geometry is pure, optical antimer is pure or diastereisomericallypure pure) and enantiomer and stereoisomer mixture.Can use isolation technics well known by persons skilled in the art or chirality synthetic technology enantiomer and stereoisomer mixture to be split into their composition optical antimer or stereoisomer.Chemical compound of the present invention can also multiple tautomeric forms exist, and comprises enol form, ketone form or their mixture.Therefore, all possible tautomeric forms of chemical compound shown in structural formula as herein described comprises.Chemical compound of the present invention also comprises isotope-labeled chemical compound, and the atomic weight of wherein one or more atoms is different from the atomic weight of finding usually in nature.The isotopic example that can be included in the chemical compound of the present invention includes but not limited to ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl.And when should be appreciated that the part-structure when the illustration The compounds of this invention, square brackets are represented the binding site of the remainder of this part-structure and molecule.

" Compositions of the present invention" refer at least a chemical compound of the present invention and pharmaceutically acceptable excipient, by it with described compound administration in the people.Chemical compound of the present invention is used with isolating form being applied to man-hour, and it means from synthetic organic reaction mixture and separates.

" Cyano group" mean group-CN.

" Cycloalkyl" refer to saturated or unsaturated cycloalkyl.If wherein desire is specified specific saturated level, use term " cycloalkyl " or " cycloalkenyl.Typical cycloalkyl includes but not limited to by deutero-groups such as cyclopropane, Tetramethylene., Pentamethylene., cyclohexane extraction.Preferred cycloalkyl is (C ₃-C ₁₀) cycloalkyl, more preferably (C ₃-C ₇) cycloalkyl.

" The assorted alkyl of ring" refer to saturated or unsaturated alkyl, wherein one or more carbon atoms (with any hydrogen atom that links to each other) are replaced by identical or different hetero atom independently.The hetero atom of typical alternate c atoms includes but not limited to N, P, O, S, Si etc., if wherein desire is specified specific saturated level, uses term " ring heterochain alkyl " or " ring heterochain thiazolinyl ".The assorted alkyl of typical ring includes but not limited to epoxide, imidazolidine, morpholine, piperazine, piperidines, pyrazolidine, pyrrolidine, quinuclidine etc.

" The assorted alkoxy carbonyl of ring" refer to that base closes-C (O)-OR, wherein R is as the assorted alkyl of the ring of above definition.

" Derive by bile acid" refer on the structure and formula (XVII) or the relevant part of chemical compound (XVIII):

Wherein each D, E and F are H or OH independently.

The structure of described part is identical with above-claimed cpd, except 1 or 2.In these positions, the covalent bond that has been used as the binding site of another part with the bonded hydrogen atom of the hydroxylic moiety of hydroxyl and/or carboxyl replaces, and this another part is preferably GABA analog or GABA analog derivant.

" Derive by the GABA analog" refer on the structure part beautiful mutually with the GABA analog.The structure of described part is identical with described chemical compound, except 1 or 2.In these positions, the covalent bond that has been used as the binding site of another part with the bonded hydrogen atom of hydroxylic moiety amino and (choosing wantonly) carboxyl replaces.

" Dialkyl amido" mean group-NRR ', wherein R and R ' represent the alkyl or cycloalkyl that this paper defines independently.Representational example includes but not limited to dimethylamino, Methylethyl amino, two (1-Methylethyl) amino, (cyclohexyl) (methyl) amino, (cyclohexyl) (ethyl) amino, (cyclohexyl) (propyl group) amino etc.

Unless otherwise noted, " The GABA analog" chemical compound that refers to have following structure:

Wherein:

R is a hydrogen, perhaps R and R ⁶With the pyrrolidine ring that forms azetidine, pyrrolidine or the replacement of azetidine, replacement with their bonded atoms;

R ³And R ⁶Be independently selected from the heteroaryl alkyl of heteroaryl, heteroaryl alkyl and replacement of the assorted alkyl of ring, heteroaryl, the replacement of aryl alkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring, the replacement of aryl, aryl alkyl, the replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement; With

R ⁴And R ⁵Be independently selected from the heteroaryl alkyl or the optional R of heteroaryl, heteroaryl alkyl and replacement of the assorted alkyl of ring, heteroaryl, the replacement of aryl alkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring, the replacement of aryl, aryl alkyl, the replacement of acyl group, aryl, the replacement of alkyl, acyl group, the replacement of hydrogen, alkyl, replacement ⁴And R ⁵Assorted alkyl of ring or bridged ring alkyl ring with the cycloalkyl that forms cycloalkyl, replacement with their bonded carbon atoms, the assorted alkyl of ring, replacement.

" Halogen" mean fluorine, chlorine, bromine or iodine.

" Assorted alkoxyl" mean-the assorted alkyl of O-, wherein assorted alkyl is as defined herein.

" Assorted alkyl, heterochain alkyl, heterochain thiazolinyl, assorted alkynyl" referring to alkyl, alkyl group, alkenyl and alkynyl respectively, wherein one or more carbon atoms (with any hydrogen atom that links to each other) are replaced by identical or different hetero atom independently of one another.Typical heteroatom group includes but not limited to :-O-,-S-,-O-O-,-S-S-,-O-S-,-NR '-,=N-N=,-N=N-,-N=N-NR ' ,-PH-,-P (O) ₂-,-O-P (O) ₂-,-S (O)-,-S (O) ₂-,-S _nH ₂-etc., wherein R ' is the aryl of cycloalkyl, aryl or replacement of alkyl, cycloalkyl, the replacement of hydrogen, alkyl, replacement.

" Heteroaryl" refer to the assorted aromatic group of deutero-monovalence by hydrogen atom on the single atom that removes roguing aromatic ring system.Typical heteroaryl includes but not limited to by following deutero-group: acridine, arsindole, carbazole, B-carboline, benzodihydropyran, .alpha.-5:6-benzopyran, cinnolines, furan, imidazoles, indazole, indole, indoline, indolizine, isobenzofuran, different .alpha.-5:6-benzopyran, iso-indoles, isoindoline, isoquinolin, isothiazole isoxazole, naphthyridines oxadiazole oxazole, the  pyridine, phenanthridines, phenanthroline, azophenlyene, phthalazines, pteridine, purine, pyrans, pyrazine, pyrazoles, pyridazine, pyridine, pyrimidine, the pyrroles, pyrroles's piperazine (pyrrolizine), quinazoline, quinoline, quinolizine, quinoxaline, tetrazolium, thiadiazoles, thiazole, thiophene, triazole, cluck ton etc.Preferred heteroaryl is a 5-20 unit heteroaryl, more preferably 5-10 unit heteroaryl.Preferred heteroaryl is by thiophene, pyrroles, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazoles, oxazole and the deutero-heteroaryl of pyrazine.

" The heteroaryloxy carbonyl" refer to group-C (O)-OR, wherein R is the heteroaryl of this paper definition.

" Heteroaryl alkyl" refer to acyclic alkyl wherein with carbon atom, be generally end or SP ³The bonded hydrogen atom of carbon atom is replaced by heteroaryl.If wherein desire is specified specific moieties, use term heteroaryl alkyl group, heteroaryl alkenyl and/or heteroaryl alkynyl.In preferred embodiments, heteroaryl alkyl is a 6-30 unit heteroaryl alkyl, for example the alkyl group of heteroaryl alkyl, alkenyl or alkynyl partly are 1-10 unit, and heteroaryl moieties is a 5-20 unit heteroaryl, more preferably 6-20 unit heteroaryl alkyl, for example the alkyl group of heteroaryl alkyl, alkenyl or alkynyl partly are 1-8 unit, and heteroaryl moieties is a 5-12-unit heteroaryl.

" Passive diffusion" refer to can't help the absorption of reagent of specific transport protein mediation.Basically reagent that can not passive diffusion have one external less than 5 * 10 ^-6Cm/ second is usually less than 1 * 10 ^-6Cm/ strides across the permeability of standard cell lines monolayer (for example Caco-2) second (lack and flow out mechanism).

" Pharmaceutically acceptable" mean that the approval of federation or national government maybe can ratify, perhaps American Pharmacopeia or other generally acknowledge be used for animal, more specifically be that people's pharmacopeia is listed.

" Pharmaceutically acceptable salt" referring to the salt of The compounds of this invention, it is pharmaceutically acceptable and has the pharmacological activity of the parent compound of expectation.These salt comprise: (1) acid-addition salts, and it is and forms such as following mineral acid: example hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid etc.; Perhaps with such as following organic acid form: acetic acid, propanoic acid, caproic acid, the Pentamethylene. propanoic acid, glycolic, acetone acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxy benzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, 1, the 2-ethionic acid, the 2-ethylenehydrinsulfonic acid, benzenesulfonic acid, the 4-chlorobenzenesulfonic acid, the 2-LOMAR PWA EINECS 246-676-2, the 4-toluenesulfonic acid, camphorsulfonic acid, 4-methyl bicycle 2.2.2-oct-2-ene-1-formic acid, glucoheptonic acid, the 3-phenylpropionic acid, trimethylace tonitric, butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid etc.; Or (2) salt of when the acid proton that exists in the parent compound is replaced by metal ion such as alkali metal ion, alkaline earth ion or aluminium ion, forming; The perhaps coordination compound that forms with organic base such as ethanolamine, diethylamine amine, triethanolamine, N-methylglucosamine etc.

" Pharmaceutically acceptable excipient" refer to diluent, auxiliary agent, excipient or the carrier used with chemical compound of the present invention.

" The patient" comprise the people.Term " people " and " patient " can exchange use in this article." Prevention (Dreventing or prevention)" refer to the risk of disease or disease reduce (promptly make at least a clinical disease symptom not at contact or susceptible disease but as yet not the patient of the symptom of experience or performance disease form on one's body).

" Prodrug" refer to transform in vivo the derivant of the drug molecule that discharges active medicine.Prodrug usually (though be not must) did not have pharmacological activity before changing into parent drug.

" Primitive" referring to a kind of protecting group form, this protecting group is converted into prodrug with medicine when the functional group that is used to shield in the drug molecule.Usually primitive combines with medicine by key, and this key is in vivo by enzymatic or the cracking of non-enzymatic mode.

" Protecting group" referring to one group of atom, it reduces or prevents the reactivity of functional group when reactive functional groups in the molecule screen combines.The example of protecting group can see people such as Green, " Protective Groups in Organic Chemistry (protecting group in the organic chemistry) ", (Wiley, 2 ^NdED.1991) and people such as Harrison, " Compendium ofSynthetic Organic Methods (methodology of organic synthesis summary) ", the 1-8 volume (JohnWiley and Sons, 1971-1996).Representational amino protecting group includes but not limited to trityl, allyloxycarbonyl, 9-fluorenyl methyl oxygen carbonyl (" FMOC "), nitro-veratryl oxygen carbonyl (" NVOC ") of formoxyl, acetyl group, trifluoroacetyl group, benzyl, benzyloxycarbonyl (" CBZ "), tert-butoxycarbonyl (" Boc "), trimethyl silyl (" TMS "), 2-trimethyl silyl-ethylsulfonyl (" SES "), trityl and replacement etc.Representational hydroxyl protecting group includes but not limited to that wherein hydroxyl is by acyl groupization or alkylating group such as benzyl and trityl ether and alkyl ether, THP trtrahydropyranyl ether, trialkylsilyl ethers and allyl ether.

" replacement " refers to the group that one or more hydrogen atom is replaced by identical or different substituent group independently of one another.Typical substituent group includes but not limited to-X ,-R ²⁹,=O ^-,-OR ²⁹,-SR ²⁹,-S ^-,=S ,-NR ²⁹R ³⁰,=NR ²⁹,-CX ₃,-CF ₃,-CN ,-OCN ,-SCN ,-NO ,-NO ₂,=N ₂,-N ₃,-S (O) ₂O ,-S (O) ₂OH ,-S (O) ₂R ²⁹,-OS (O ₂) O ^-,-OS (O) ₂R ²⁹,-P (O) (O ^-) ₂,-P (O) (OR ²⁹) (O ^-) ,-OP (O) (OR ²⁹) (OR ³⁰) ,-C (O) R ²⁹,-C (S) R ²⁹,-C (O) OR ²⁹,-C (O) NR ²⁹R ³⁰,-C (O) O-,-C (S) OR ²⁹,-NR ³¹C (O) NR ²⁹R ³⁰,-NR ³¹C (S) NR ²⁹R ³⁰,-NR ³¹C (NR ²⁹) NR ²⁹R ³⁰With-C (NR ²⁹) NR ²⁹R ³⁰, wherein each X is halogen independently; Each R ²⁹And R ³⁰Be independently heteroaryl, heteroaryl alkyl, the replacement of assorted alkyl, heteroaryl, the replacement of aryl alkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring of aryl, aryl alkyl, the replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement, the assorted alkyl of ring of replacement, assorted alkyl, replacement heteroaryl alkyl ,-NR ³¹R ³²,-C (O) R ³¹Or-S (O) ₂R ³¹, perhaps optional R ²⁹And R ³⁰Form the assorted alkyl ring of the ring that encircles assorted alkyl or replacement with their bonded atoms of while; And R ³¹And R ³²Be the heteroaryl alkyl of heteroaryl, heteroaryl alkyl or replacement of assorted alkyl, heteroaryl, the replacement of aryl alkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring of aryl, aryl alkyl, the replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement, the assorted alkyl of ring of replacement, assorted alkyl, replacement independently.

" Transport protein" refer to molecule transhipment is entered and/or by cell processes in play the albumen of direct or indirect effect.For example, transport protein can be but be not limited to solute and carry transport agents, common transport agents, antiport agent (counter transporter), single transport agents, co-transport agent, antiport agent (antiporter), pump, balance transport agents, concentrate transport agents and other albumen that their are regulated active transport, rely on the transhipment of energy, promote diffusion, exchanging mechanism and specific mechanism of absorption.Transport protein can also be but be not limited to discern substrate and influence the embrane-associated protein that it entered and left cell by the transport agents of carrier adjusting or the transport agents of receptor adjusting.Transport protein can also be but be not limited to participate in by with substrate transhipment by or leave the albumen of the cell inner expression of cell.Transport protein can also be but be not limited to directly not transport substrate but combine near albumen that is exposed to cell surface or the glycoprotein that holds it in the receptor with substrate, influences perhaps that substrate enters or the transport protein by cell.The carrier protein example comprises: the agent of intestinal regulating liver-QI bile acid transport, dipeptides transport agents, oligopeptide transport agents, monosaccharide transport agents (for example SGLT1), phosphate cotransporter agent, monocarboxylic acid transport agents, β-glycoprotein transport agents, organic anion transport agents (OAT) and organic cation transporter agent.The example of the transport protein that receptor is regulated comprises: virus receptor, immunoglobulin receptor, bacteriotoxin receptor, phytohemagglutinin receptor, bacterial adhesion receptor, vitamin transport agents and cytokine growth factor receptors.

Any disease or disease " Treatment (treating or treatment)" refer to improve disease or disease (promptly stopping or reducing the development of disease or its at least a clinical symptoms) in one embodiment.In another embodiment, " treat (treating or treatment) " and refer to improve the body parameter that at least one patient may can not distinguish.In further another embodiment, " treatment (treating or treatment) " refers to be suppressed on the health and (for example stablizes recognizable symptom), (for example stablizes physical parameter) on the physiology or suppresses disease or disease simultaneously.In further another embodiment, " treatment (treating or treatment) " refers to postpone the generation of disease or disease.

" The treatment effective dose" mean chemical compound and be enough to carry out the quantity of this treatment of diseases during disease with treatment being applied to the patient." treatment effective dose " will become with chemical compound, disease and its order of severity and patient's age to be treated, body weight etc.

Now in more detail with reference to embodiment preferred of the present invention.Though describe the present invention in conjunction with described embodiment preferred, be appreciated that this and do not mean that the present invention is defined in these embodiment preferred.On the contrary, the application's scheme of being intended to cover the design of the present invention that can be included in the definition of appended claim and the replacement within the scope, revising and be equal to.

4.2 chemical compound of the present invention

Those skilled in the art will recognize that formula (I), (II) and chemical compound (III) have common ground on some architectural feature.These chemical compounds all are in conjunction with the GABA analog (being gamma-aminobutyric acid derivative) of primitive.Particularly, R ², R ³, R ⁴, R ⁵, R ⁶, X and Y be the common substituent group of finding in formula (I), (II) and the chemical compound (III).

Chemical compound of the present invention comprises the chemical compound of formula (I), formula (II) or formula (III)

Or its pharmaceutically acceptable salt, hydrate or solvate, wherein:

N, t, u, X, Y, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ²⁰, R ²¹, R ²²And R ²³Definition as described above.

In a preferred embodiment, formula (I), (II) and chemical compound (III) do not comprise following chemical compound:

Work as R ³And R ⁶When all being hydrogen, R ⁴And R ⁵Not all be hydrogen or not all for methyl;

In the chemical compound of formula (I), when n be O or when n be 1, and X is NR ¹⁶The time, R then ¹Be not hydrogen;

In the chemical compound of formula (I), R ¹, R ⁷O-, R ²⁴C (O)-, R ²⁵C (O)-and R ²⁵O-is not by the deutero-part of bile acid;

In the chemical compound of formula (I), work as R ¹Be R ²⁴C (O)-and n is 0 o'clock, R ²⁴It is not methyl, the tert-butyl group, 2-amino-ethyl, 3-aminopropyl, benzyl, phenyl or 2-(benzoyloxy methyl) phenyl;

In the chemical compound of formula (I), work as R ¹Be R ²⁵OC (O)-time, R ²⁵Be not R ²⁶C (O) CR ¹³R ¹⁴-, R wherein ²⁶Be selected from the heteroaryl alkyl of heteroaryl, heteroaryl alkyl and replacement of assorted alkyl, heteroaryl, the replacement of aryl alkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring of aryl, aryl alkyl, the replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement, the assorted alkyl of ring of replacement, assorted alkyl, replacement;

In the chemical compound of formula (I), work as R ¹Be R ²⁵OC (O)-and n is 0 o'clock, R ²⁵Be not methyl, the tert-butyl group or benzyl;

In the chemical compound of formula (I), when n is 0 and R ¹Be R ²⁵C (O) OCR ¹³R ¹⁴OC (O)-time, if R ¹³Or R ¹⁴Arbitrary be the cyclo alkoxy carbonyl of alkoxy carbonyl, carbamoyl, cyclo alkoxy carbonyl or the replacement of hydrogen, alkoxy carbonyl, replacement, then R ¹³Or R ¹⁴In another be not hydrogen;

In the chemical compound of formula (I), when n is 1, X is NH, R ³, R ⁵And R ⁶The hydrogen of respectively doing for oneself, and R ⁴During for cyclohexyl, R then ²It is not benzyl;

In the chemical compound of formula (II), when t is 1, u is 0 o'clock, R ²⁰Or R ²¹It is not 2-hydroxy-3-methyl-5-chlorphenyl; With

In the chemical compound of formula (II), when u is 1 and X when being 0, t is 1.

In an embodiment of formula (I), (II) and chemical compound (III), work as R ³And R ⁶When respectively doing for oneself hydrogen, R ⁴And R ⁵Not all be hydrogen or not all for methyl.

In an embodiment of the chemical compound of formula (I), when n be 0 or when n be 1 and X is NR ¹⁶The time, R ¹Be not hydrogen.In another embodiment of the chemical compound of formula (I), R ¹, R ⁷O-, R ²⁴C (O)-, R ²⁵C (O)-or R ²⁵O-is not by the deutero-part of bile acid.In another embodiment of the chemical compound of formula (I), work as R ¹Be R ²⁴C (O)-and n is 0 o'clock, R ²⁴It is not the aryl of alkyl, aryl alkyl, aryl or the replacement of alkyl, replacement.In another embodiment of the chemical compound of formula (I), work as R ¹Be R ²⁴C (O)-and n is 0 o'clock, then R ²⁴Be not C _1-4The phenyl of alkyl group, benzyl, phenyl or replacement.In another embodiment of the chemical compound of formula (I), work as R ¹Be R ²⁴C (O)-and n is 0 o'clock, R ²⁴It is not methyl, the tert-butyl group, 2-amino-ethyl, 3-aminopropyl, benzyl, phenyl or 2-(benzoyloxy methyl)-phenyl.In another embodiment of the chemical compound of formula (I), work as R ¹Be R ²⁵OC (O)-time, R ²⁵Be not R ²⁶C (O) CR ¹³R ¹⁴-.In another embodiment of the chemical compound of formula (I), work as R ¹Be R ²⁵OC (O)-and n is 0 o'clock, R ²⁵It is not the alkyl or aryl alkyl.In another embodiment of the chemical compound of formula (I), work as R ¹Be R ²⁵OC (O)-and n is 0 o'clock, R ²⁵Be not C _1-4Alkyl group or benzyl.In another embodiment of the chemical compound of formula (I), work as R ¹Be R ²⁵OC (O)-and n is 0, R ²⁵Be not methyl, the tert-butyl group or benzyl.In another embodiment of the chemical compound of formula (I), when n is 0 and R ¹Be R ²⁵C (O) OCR ¹³R ¹⁴OC (O)-time, if R ¹³Or R ¹⁴Arbitrary be the cyclo alkoxy carbonyl of alkoxy carbonyl, carbamoyl, cyclo alkoxy carbonyl or the replacement of hydrogen, alkoxy carbonyl, replacement, then R ¹³Or R ¹⁴In another be not hydrogen.In another embodiment of the chemical compound of formula (I), work as R ³, R ⁵And R ⁶When respectively doing for oneself hydrogen, R ⁴It is not cyclohexyl.In another embodiment of the chemical compound of formula (I), when n is 1, X is NH, R ³, R ⁵, R ⁶Hydrogen and R respectively do for oneself ²During for benzyl, R ⁴It is not cyclohexyl.

In an embodiment of the chemical compound of formula (II), R ²⁰And R ²¹It is not 2-hydroxy-3-methyl-5-chlorphenyl.In an embodiment of the chemical compound of formula (II), when u is 1 and X when being 0, t is 1.

In an embodiment of formula (I), (II) and chemical compound (III), n is 0.In another embodiment, n is 1.When n is 1, and X is NR ⁶The time, preferred a-amino acid is the L-three-dimensional chemical configuration.

In another embodiment of formula (I) and chemical compound (II), R ⁷Be selected from the ring heterochain alkyl of cycloalkyl, ring heterochain alkyl and replacement of aryl alkyl group, cycloalkyl, the replacement of aryl, aryl alkyl group, the replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement.In a preferred embodiment, Y is O and R ⁷Be hydrogen.In another embodiment, Y is O and R ⁷Aryl for alkenyl, aryl or the replacement of the alkyl group of alkyl group, replacement, alkenyl, replacement.Preferred R ⁷For methyl, ethyl, benzyl ,-C (CH ₃)=CH ₂,-CH ₂C (O) N (CH ₃) ₂,

Or

Wherein V is O or CH ₂

In an embodiment preferred of formula (I), (II) and chemical compound (III), R ²Be selected from the heteroaryl alkyl of heteroaryl, heteroaryl alkyl and replacement of assorted alkyl, heteroaryl, the replacement of aryl alkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring of aryl, aryl alkyl, the replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement, the assorted alkyl of ring of replacement, assorted alkyl, replacement.Preferred R ²Be selected from the heteroaryl alkyl group of aryl alkyl group, cycloalkyl, heteroaryl alkyl and replacement of aryl, aryl alkyl group, the replacement of alkyl group, aryl, the replacement of hydrogen, alkyl group, replacement.

In another embodiment of formula (I), (II) and chemical compound (III), X is NH, and R ²Be hydrogen, cycloalkyl or alkyl group.Preferred R ²Be hydrogen, methyl, isopropyl, isobutyl group, sec-butyl, the tert-butyl group, cyclopenta or cyclohexyl.In another embodiment, X is NH, and R ²Be the alkyl group that replaces.Preferred R ²For-CH ₂OH ,-CH (OH) CH ₃,-CH ₂CO ₂H ,-CH ₂CH ₂CO ₂H ,-CH ₂CONH ₂,-CH ₂CH ₂CONH ₂,-CH ₂CH ₂SCH ₃, CH ₂SH ,-CH ₂(CH ₂) ₃NH ₂Or-CH ₂CH ₂CH ₂NHC (NH) NH ₂In another embodiment, X is NH, and R ²Be selected from the aryl alkyl group and the heteroaryl alkyl group of aryl, aryl alkyl group, replacement.

Preferred R ²Be phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazole radicals or 2-indyl.In another embodiment, X is NR ¹⁶, and R ²And R ¹⁶With the assorted alkyl ring of ring that forms assorted alkyl of ring or replacement with their bonded atoms.

Preferred R ²And R ¹⁶With form azetidine, pyrrolidine or piperidine ring with their bonded atoms.

In another embodiment of formula (I), (II) and chemical compound (III), R ³Be hydrogen.In another embodiment, R ⁶Be hydrogen.In another embodiment, R ³And R ⁶Be independently selected from the cycloalkyl of aryl, cycloalkyl and replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement.Preferred R ³And R ⁶Be independently selected from hydrogen and alkyl group.More preferably R ³Be hydrogen or alkyl group, and R ⁶Be hydrogen.

In another embodiment preferred of formula (I), (II) and chemical compound (III), R ⁴And R ⁵Be independently selected from the assorted alkyl of ring of alkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring and the replacement of hydrogen, alkyl, replacement.Preferred R ⁴And R ⁵Be independently selected from the alkyl group of hydrogen, alkyl group and replacement.

In another embodiment of formula (I), (II) and chemical compound (III), R ⁴And R ⁵Form the cycloalkyl ring of cycloalkyl or replacement with their bonded carbon atoms.Preferred R ⁴And R ⁵Cyclohexyl ring with cyclopenta, cyclohexyl or the replacement of the cyclobutyl that forms cyclobutyl, replacement with their bonded carbon atoms, cyclopenta, replacement.In another embodiment, R ⁴And R ⁵With the assorted alkyl ring of ring that forms assorted alkyl of ring or replacement with their bonded carbon atoms.In another embodiment, R ⁴And R ⁵Form bridged ring alkyl ring with their bonded carbon atoms.

In an embodiment of the chemical compound of formula (I), n is 1, R ¹Be R ²⁴C (O)-or R ²⁴C (S)-, and R ²⁴Heteroaryl for aryl, heteroaryl or the replacement of the assorted alkyl of the alkyl of alkyl, replacement, assorted alkyl, replacement, aryl, replacement.Preferred R ²⁴For methyl, ethyl, 2-propyl group, the tert-butyl group ,-CH ₂OCH (CH ₃) ₂, phenyl or 3-pyridine radicals.

In another embodiment of the chemical compound of formula (I), n is 1, R ¹Be R ²⁵OC (O)-or R ²⁵SC (O)-, and R ²⁵Heteroaryl for aryl, heteroaryl or the replacement of the alkyl of alkyl, replacement, assorted alkyl, aryl, replacement.Preferred R ²⁵For ethyl, 2-propyl group, neopentyl ,-CH ₂OCH (CH ₃) ₂, phenyl or 2-pyridine radicals.

An embodiment preferred of the chemical compound of formula (I) comprises the chemical compound of formula (IV):

Or its pharmaceutically acceptable salt, hydrate or solvate, wherein:

N, Y, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ¹³, R ¹⁴, R ¹⁶And R ²⁵Definition as described above.

In a preferred embodiment, the chemical compound of formula (IV) does not comprise following chemical compound: work as R ¹³Or R ¹⁴During for the cyclo alkoxy carbonyl of alkoxy carbonyl, carbamoyl, cyclo alkoxy carbonyl or the replacement of hydrogen, alkoxy carbonyl, replacement, R ¹³Or R ¹⁴In another be not hydrogen; And R ²⁵C (O) is not by the deutero-part of bile acid.

In an embodiment of the chemical compound of formula (IV), R ¹³And R ¹⁴Be that alkyl, alkoxy carbonyl, aryl, aryl alkyl, carbamoyl, the cycloalkyl of hydrogen, alkyl, replacement, cycloalkyl, cyclo alkoxy carbonyl or the heteroaryl of replacement (are preferably worked as R independently ¹³During for alkoxy carbonyl, cyclo alkoxy carbonyl or carbamoyl, R ¹⁴Be methyl).More preferably R ¹³And R ¹⁴Be hydrogen, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, cyclopenta, cyclohexyl, methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, isobutoxy carbonyl, sec-butoxy carbonyl, tert-butoxycarbonyl, cyclohexyloxy carbonyl, phenyl, benzyl, phenethyl or 3-pyridine radicals independently.

In another embodiment of the chemical compound of formula (IV), R ¹³And R ¹⁴Be the cycloalkyl of alkyl group, cycloalkyl or the replacement of hydrogen, alkyl group, replacement independently.Preferred R ¹³And R ¹⁴Be hydrogen, alkyl group or cycloalkyl.More preferably R ¹³And R ¹⁴Be hydrogen, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, cyclopenta or cyclohexyl independently.Even more preferably R ¹³Be methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, cyclopenta or cyclohexyl R ¹⁴Be hydrogen, perhaps R ¹³Be methyl R ¹⁴Be methyl.

In another embodiment of chemical compound of formula (IV), R ¹³And R ¹⁴Be hydrogen, aryl, aryl alkyl or heteroaryl independently.More preferably R ¹³And R ¹⁴Be hydrogen, phenyl, benzyl, phenethyl or 3-pyridine radicals independently.Even more preferably R ¹³Be phenyl, benzyl, phenethyl or 3-pyridine radicals and R ¹⁴Be hydrogen.

In another embodiment of chemical compound of formula (IV), R ¹³And R ¹⁴Be alkyl, alkoxy carbonyl, carbamoyl or the cyclo alkoxy carbonyl of hydrogen, alkyl, replacement independently.Preferably work as R ¹³During for alkoxy carbonyl, cyclo alkoxy carbonyl or carbamoyl, R ¹⁴Be methyl.More preferably R ¹³Be methoxycarbonyl, ethoxy carbonyl, isopropoxy carbonyl, butoxy carbonyl, isobutoxy carbonyl, sec-butoxy carbonyl, tert-butoxycarbonyl or cyclohexyloxy carbonyl, and R ¹⁴Be methyl.

In another embodiment of chemical compound of formula (IV), R ¹³And R ¹⁴The assorted alkyl ring of ring with the cycloalkyl that forms cycloalkyl, replacement with their bonded carbon atoms, the assorted alkyl of ring or replacement.Preferred R ¹³And R ¹⁴With form cycloalkyl ring with their bonded carbon atoms.More preferably R ¹³And R ¹⁴With form cyclobutyl, cyclopenta or cyclohexyl ring with their bonded carbon atoms.

In another embodiment of chemical compound of formula (IV), R ²⁵Heteroaryl alkyl for heteroaryl, heteroaryl alkyl or the replacement of the assorted alkyl of the aryl alkyl of the aryl of the alkyl of the acyl group of acyl group, replacement, alkyl, replacement, aryl, replacement, aryl alkyl, replacement, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring, the assorted alkyl of ring of replacement, assorted alkyl, replacement, heteroaryl, replacement.Preferred R ²⁵Alkyl, aryl, aryl alkyl, cycloalkyl or heteroaryl for the acyl group of acyl group, replacement, alkyl, replacement.More preferably R ²⁵Be methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl or 3-pyridine radicals.

In another embodiment of chemical compound of formula (IV), R ²⁵Acyl group for acyl group or replacement.More preferably R ²⁵Be acetyl group, propiono, bytyry, benzoyl or phenylacetyl group.

In another embodiment of chemical compound of formula (IV), R ²⁵Alkyl group for alkyl group or replacement.Preferred R ²⁵Be methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, amyl group, isopentyl, sec-amyl, neopentyl, 1, the 1-dimethoxy-ethyl, 1,1-diethoxy ethyl, 1-(1,3-dioxolanes-2-yl)-ethyl, 1-(1,3-diox-2-yl)-ethyl, 1,1-dimethoxy propyl group, 1,1-diethoxy propyl group, 1-(1,3-dioxolanes-2-yl)-propyl group, 1-(1,3-diox-2-yl)-propyl group, 1,1-dimethoxy butyl, 1,1-diethoxy butyl, 1-(1,3-dioxolanes-2-yl)-butyl, 1-(1,3-diox-2-yl)-butyl, 1, the 1-dimethoxy-benzyl, 1,1-diethoxy benzyl, 1-(1,3-dioxolanes-2-yl)-benzyl, 1-(1,3-diox-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolanes-2-yl)-2-phenethyl or 1-(1,3-diox-2-yl)-2-phenethyl.More preferably R ²⁵Be methyl, ethyl, propyl group, isopropyl, butyl, 1,1-dimethoxy-ethyl or 1,1-diethoxy ethyl.

In another embodiment of chemical compound of formula (IV), R ²⁵Be aryl, aryl alkyl or heteroaryl.Preferred R ²⁵Be phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridine radicals.

In another embodiment of chemical compound of formula (IV), R ²⁵Cycloalkyl for cycloalkyl or replacement.More preferably R ²⁵Be cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl.

In another embodiment of chemical compound of formula (IV), R ²⁵Heteroaryl alkyl for heteroaryl, heteroaryl alkyl or the replacement of the assorted alkyl of the aryl alkyl of the aryl of the alkyl of the acyl group of acyl group, replacement, alkyl, replacement, aryl, replacement, aryl alkyl, replacement, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring, the assorted alkyl of ring of replacement, assorted alkyl, replacement, heteroaryl, replacement; And R ¹³And R ¹⁴The heteroaryl of cyclo alkoxy carbonyl, heteroaryl or replacement that is cycloalkyl, cyclo alkoxy carbonyl, the replacement of aryl alkyl, carbamoyl, cycloalkyl, the replacement of aryl, aryl alkyl, the replacement of alkoxy carbonyl, aryl, the replacement of alkyl, alkoxy carbonyl, the replacement of hydrogen, alkyl, replacement independently (is preferably worked as R ¹³During for the cyclo alkoxy carbonyl of the alkoxy carbonyl of alkoxy carbonyl, replacement, cyclo alkoxy carbonyl, replacement or carbamoyl, R ¹⁴Be methyl).Preferred R ²⁵Be alkyl, aryl, aryl alkyl, cycloalkyl or the heteroaryl of the acyl group of acyl group, replacement, alkyl, replacement, and R ¹³And R ¹⁴The alkyl, alkoxy carbonyl, aryl, aryl alkyl, carbamoyl, cycloalkyl, cyclo alkoxy carbonyl or the heteroaryl that are hydrogen, alkyl, replacement independently (are preferably worked as R ¹³During for the cyclo alkoxy carbonyl of the alkoxy carbonyl of alkoxy carbonyl, replacement, cyclo alkoxy carbonyl, replacement or carbamoyl, R ¹⁴Be methyl).More preferably R ²⁵Be methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl or 3-pyridine radicals, and R ¹³And R ¹⁴Be hydrogen, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, cyclopenta, cyclohexyl, methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, isobutoxy carbonyl, sec-butoxy carbonyl, tert-butoxycarbonyl, cyclohexyloxy carbonyl, phenyl, benzyl, phenethyl or 3-pyridine radicals independently.Even more preferably R ²⁵Be methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, 1; 1-dimethoxy-ethyl, 1; 1-diethoxy ethyl, 1; 1-dimethoxy-benzyl, 1; 1-diethoxy benzyl, 1; 1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, acetyl group, propiono, bytyry, benzoyl, phenylacetyl group, phenyl, 4-methoxyphenyl, benzyl, phenethyl, cyclohexyl or 3-pyridine radicals, and R ¹³And R ¹⁴Be hydrogen, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, cyclopenta, cyclohexyl, methoxycarbonyl, ethoxy carbonyl, isopropoxy carbonyl, cyclohexyloxy carbonyl, phenyl, benzyl, phenethyl or 3-pyridine radicals independently.

In another embodiment of chemical compound of formula (IV), R ²⁵Be the heteroaryl alkyl of heteroaryl, heteroaryl alkyl or the replacement of the assorted alkyl of the aryl alkyl of the aryl of the alkyl of the acyl group of acyl group, replacement, alkyl, replacement, aryl, replacement, aryl alkyl, replacement, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring, the assorted alkyl of ring of replacement, assorted alkyl, replacement, heteroaryl, replacement, and R ¹³And R ¹⁴The assorted alkyl ring of ring with the cycloalkyl that forms cycloalkyl, replacement with their bonded atoms, the assorted alkyl of ring or replacement.Preferred R ²⁵Be alkyl, aryl, aryl alkyl, cycloalkyl or the heteroaryl of the acyl group of acyl group, replacement, alkyl, replacement, and R ¹³And R ¹⁴Form the cycloalkyl ring of cycloalkyl or replacement with their bonded atoms.More preferably R ²⁵Be methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; in cyclohexyl or the 3-pyridine radicals, and R ¹³And R ¹⁴With form cyclobutyl, cyclopenta or cyclohexyl ring with their bonded atoms.

In another embodiment of chemical compound of formula (IV), R ²⁵Be the acyl group of acyl group or replacement, and R ¹⁴And R ¹⁴The heteroaryl of cyclo alkoxy carbonyl, heteroaryl or replacement that is cycloalkyl, cyclo alkoxy carbonyl, the replacement of aryl alkyl, carbamoyl, cycloalkyl, the replacement of aryl, aryl alkyl, the replacement of alkoxy carbonyl, aryl, the replacement of alkyl, alkoxy carbonyl, the replacement of hydrogen, alkyl, replacement independently (is preferably worked as R ¹³During for the cyclo alkoxy carbonyl of the alkoxy carbonyl of alkoxy carbonyl, replacement, cyclo alkoxy carbonyl, replacement or carbamoyl, R ¹⁴Be methyl).Preferred R ²⁵Be acetyl group, propiono, bytyry, benzoyl or phenylacetyl group, and R ¹³And R ¹⁴The heteroaryl of cyclo alkoxy carbonyl, heteroaryl or replacement that is cycloalkyl, cyclo alkoxy carbonyl, the replacement of aryl alkyl, carbamoyl, cycloalkyl, the replacement of aryl, aryl alkyl, the replacement of alkoxy carbonyl, aryl, the replacement of alkyl, alkoxy carbonyl, the replacement of hydrogen, alkyl, replacement independently (is preferably worked as R ¹³During for alkoxy carbonyl, cyclo alkoxy carbonyl or carbamoyl, R ¹⁴Be methyl).

In another embodiment of chemical compound of formula (IV), R ²⁵Be the alkyl group of alkyl group or replacement, and R ¹³And R ¹⁴The heteroaryl of cyclo alkoxy carbonyl, heteroaryl or replacement that is cycloalkyl, cyclo alkoxy carbonyl, the replacement of aryl alkyl, carbamoyl, cycloalkyl, the replacement of aryl, aryl alkyl, the replacement of alkoxy carbonyl, aryl, the replacement of alkyl, alkoxy carbonyl, the replacement of hydrogen, alkyl, replacement independently (is preferably worked as R ¹³During for the cyclo alkoxy carbonyl of the alkoxy carbonyl of alkoxy carbonyl, replacement, cyclo alkoxy carbonyl, replacement or carbamoyl, R ¹⁴Be methyl).Preferred R ²⁵Be methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, amyl group, isopentyl, sec-amyl, neopentyl, 1, the 1-dimethoxy-ethyl, 1,1-diethoxy ethyl, 1-(1,3-dioxolanes-2-yl)-ethyl, 1-(1,3-diox-2-yl)-ethyl, 1,1-dimethoxy propyl group, 1,1-diethoxy propyl group, 1-(1,3-dioxolanes-2-yl)-propyl group, 1-(1,3-diox-2-yl)-propyl group, 1,1-dimethoxy butyl, 1,1-diethoxy butyl, 1-(1,3-dioxolanes-2-yl)-butyl, 1-(1,3-diox-2-yl)-butyl, 1, the 1-dimethoxy-benzyl, 1,1-diethoxy benzyl, 1-(1,3-dioxolanes-2-yl)-benzyl, 1-(1,3-diox-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolanes-2-yl)-2-phenethyl or 1-(1,3-diox-2-yl)-2-phenethyl, and R ¹³And R ¹⁴The heteroaryl of cyclo alkoxy carbonyl, heteroaryl or replacement that is cycloalkyl, cyclo alkoxy carbonyl, the replacement of aryl alkyl, carbamoyl, cycloalkyl, the replacement of aryl, aryl alkyl, the replacement of alkoxy carbonyl, aryl, the replacement of alkyl, alkoxy carbonyl, the replacement of hydrogen, alkyl, replacement independently (is preferably worked as R ¹³During for alkoxy carbonyl, cyclo alkoxy carbonyl or carbamoyl, R ¹⁴Be methyl).

In another embodiment of chemical compound of formula (IV), R ²⁵Be the heteroaryl of aryl alkyl, heteroaryl or the replacement of the aryl of aryl, replacement, aryl alkyl, replacement, and R ¹³And R ¹⁴The heteroaryl of cyclo alkoxy carbonyl, heteroaryl or replacement that is cycloalkyl, cyclo alkoxy carbonyl, the replacement of aryl alkyl, carbamoyl, cycloalkyl, the replacement of aryl, aryl alkyl, the replacement of alkoxy carbonyl, aryl, the replacement of alkyl, alkoxy carbonyl, the replacement of hydrogen, alkyl, replacement independently (is preferably worked as R ¹³During for the cyclo alkoxy carbonyl of the alkoxy carbonyl of alkoxy carbonyl, replacement, cyclo alkoxy carbonyl, replacement or carbamoyl, R ¹⁴Be methyl).Preferred R ²⁵Be phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridine radicals, and R ¹³And R ¹⁴The heteroaryl of cyclo alkoxy carbonyl, heteroaryl or replacement that is cycloalkyl, cyclo alkoxy carbonyl, the replacement of aryl alkyl, carbamoyl, cycloalkyl, the replacement of aryl, aryl alkyl, the replacement of alkoxy carbonyl, aryl, the replacement of alkyl, alkoxy carbonyl, the replacement of hydrogen, alkyl, replacement independently (is preferably worked as R ¹³During for alkoxy carbonyl, cyclo alkoxy carbonyl or carbamoyl, R ¹⁴Be methyl).

In another embodiment of chemical compound of formula (IV), R ²⁵Be the cycloalkyl of cycloalkyl or replacement, and R ¹³And R ¹⁴The heteroaryl of cyclo alkoxy carbonyl, heteroaryl or replacement that is cycloalkyl, cyclo alkoxy carbonyl, the replacement of aryl alkyl, carbamoyl, cycloalkyl, the replacement of aryl, aryl alkyl, the replacement of alkoxy carbonyl, aryl, the replacement of alkyl, alkoxy carbonyl, the replacement of hydrogen, alkyl, replacement independently (is preferably worked as R ¹³During for the cyclo alkoxy carbonyl of the alkoxy carbonyl of alkoxy carbonyl, replacement, cyclo alkoxy carbonyl, replacement or carbamoyl, R ¹⁴Be methyl).Preferred R ²⁵Be cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl, and R ¹³And R ¹⁴The heteroaryl of cyclo alkoxy carbonyl, heteroaryl or replacement that is cycloalkyl, cyclo alkoxy carbonyl, the replacement of aryl alkyl, carbamoyl, cycloalkyl, the replacement of aryl, aryl alkyl, the replacement of alkoxy carbonyl, aryl, the replacement of alkyl, alkoxy carbonyl, the replacement of hydrogen, alkyl, replacement independently (is preferably worked as R ¹³During for alkoxy carbonyl, cyclo alkoxy carbonyl or carbamoyl, R ¹⁴Be methyl).

In another embodiment of chemical compound of formula (IV), R ²⁵Be the heteroaryl alkyl of heteroaryl, heteroaryl alkyl or the replacement of the assorted alkyl of the aryl alkyl of the aryl of the alkyl of the acyl group of acyl group, replacement, alkyl, replacement, aryl, replacement, aryl alkyl, replacement, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring, the assorted alkyl of ring of replacement, assorted alkyl, replacement, heteroaryl, replacement, and R ¹³And R ¹⁴Be alkyl, aryl, aryl alkyl, cycloalkyl or the heteroaryl of hydrogen, alkyl, replacement independently.Preferred R ²⁵Be alkyl, aryl, aryl alkyl, cycloalkyl or the heteroaryl of the acyl group of acyl group, replacement, alkyl, replacement, and R ¹³And R ¹⁴Be the cycloalkyl of alkyl group, cycloalkyl or the replacement of hydrogen, alkyl group, replacement independently.More preferably R ²⁵Be alkyl, aryl, aryl alkyl, cycloalkyl or the heteroaryl of the acyl group of acyl group, replacement, alkyl, replacement, and R ¹³And R ¹⁴Be hydrogen, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, cyclopenta or cyclohexyl independently.In above embodiment, R ²⁵Be preferably methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl or 3-pyridine radicals.

In another embodiment of chemical compound of formula (IV), R ²⁵Be alkyl, aryl, aryl alkyl, cycloalkyl or the heteroaryl of the acyl group of acyl group, replacement, alkyl, replacement, and R ¹³And R ¹⁴Be alkyl, aryl, aryl alkyl, cycloalkyl or the heteroaryl of hydrogen, alkyl, replacement independently.Preferred R ²⁵Be alkyl, aryl, aryl alkyl, cycloalkyl or the heteroaryl of the acyl group of acyl group, replacement, alkyl, replacement, and R ¹³And R ¹⁴Be hydrogen, aryl, aryl alkyl or heteroaryl independently.More preferably R ²⁵Be alkyl, aryl, aryl alkyl, cycloalkyl or the heteroaryl of the acyl group of acyl group, replacement, alkyl, replacement, and R ¹³And R ¹⁴Be hydrogen, phenyl, benzyl, phenethyl or 3-pyridine radicals independently.In above embodiment, R ²⁵Be preferably methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl or 3-pyridine radicals.

In another embodiment of chemical compound of formula (IV), R ²⁵Be alkyl, aryl, aryl alkyl, cycloalkyl or the heteroaryl of the acyl group of acyl group, replacement, alkyl, replacement, and R ¹³And R ¹⁴Be alkyl, aryl, aryl alkyl, cycloalkyl or the heteroaryl of hydrogen, alkyl, replacement independently.Preferred R ²⁵Be alkyl, aryl, aryl alkyl, cycloalkyl or the heteroaryl of the acyl group of acyl group, replacement, alkyl, replacement, and R ¹³And R ¹⁴The cyclo alkoxy carbonyl of alkoxy carbonyl, carbamoyl, cyclo alkoxy carbonyl or replacement that is alkyl, alkoxy carbonyl, the replacement of hydrogen, alkyl, replacement independently (is preferably worked as R ¹³During for the cyclo alkoxy carbonyl of alkoxy carbonyl, carbamoyl, cyclo alkoxy carbonyl or the replacement of alkoxy carbonyl, replacement, R ¹⁴Be methyl; More preferably R ¹³Be methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, isobutoxy carbonyl, sec-butoxy carbonyl, tert-butoxycarbonyl or cyclohexyloxy carbonyl, and R ¹⁴Be methyl).In above embodiment, R ²⁵Be preferably methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl or 3-pyridine radicals.

In another embodiment of chemical compound of formula (IV), R ²⁵Be alkyl, aryl, aryl alkyl, cycloalkyl or the heteroaryl of the acyl group of acyl group, replacement, alkyl, replacement, and R ¹³And R ¹⁴The assorted alkyl ring of ring with the cycloalkyl that forms cycloalkyl, replacement with their bonded atoms, the assorted alkyl of ring or replacement.Preferred R ²⁵Be alkyl, aryl, aryl alkyl, cycloalkyl or the heteroaryl of the acyl group of acyl group, replacement, alkyl, replacement, and R ¹³And R ¹⁴With the cycloalkyl ring that forms cycloalkyl or replacement with their bonded atoms.More preferably R ²⁵Be alkyl, aryl, aryl alkyl, cycloalkyl or the heteroaryl of the acyl group of acyl group, replacement, alkyl, replacement, and R ¹³And R ¹⁴With form cyclobutyl, cyclopenta or cyclohexyl ring with their bonded atoms.In above embodiment, R ²⁵Be preferably methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl or 3-pyridine radicals.

In another embodiment of formula (I) and chemical compound (III), R ¹For

M is 0, and R ⁸, R ¹¹And R ¹²Define as the front.

In an embodiment of formula (I) and chemical compound (III), R ¹¹Be acyl group, alkoxy carbonyl, aryloxycarbonyl, cyclo alkoxy carbonyl or carbamoyl, R ⁸Be hydrogen, alkoxy carbonyl, alkyl, aryl, aryl alkyl or cyano group, and R ¹²Alkyl, aryl or aryl alkyl for hydrogen, alkoxy carbonyl, alkyl, replacement.

In another embodiment of formula (I) and chemical compound (III), R ¹¹Be selected from acetyl group; propiono; bytyry; isobutyryl; valeryl; the Pentamethylene. carbonyl; the cyclohexane extraction carbonyl; benzoyl; phenylacetyl group; methoxycarbonyl; ethoxy carbonyl; propoxycarbonyl; isopropoxy carbonyl; butoxy carbonyl; isobutoxy carbonyl; the sec-butoxy carbonyl; tert-butoxycarbonyl; cyclopenta oxygen carbonyl; cyclohexyloxy carbonyl; phenyloxycarbonyl; benzyloxycarbonyl; carbamoyl; N-methylamino formoxyl; N-ethylamino formoxyl; N-propyl group carbamoyl; N-isopropyl carbamoyl; N-butyl carbamoyl; N-isobutylamino formoxyl; N-sec-butyl carbamoyl; N-tert-butyl group carbamoyl; N-cyclopenta carbamoyl; N-cyclohexyl carboxyamide base; N-phenyl amino formoxyl; N-benzylamino formoxyl; N; the N-formyl-dimethylamino; N; N-diethylamino formoxyl; N; N-dipropyl carbamoyl; N; N-diisopropylaminoethyl formoxyl; N; N-dibutylamino formoxyl; N, N-dibenzyl amino formoxyl; N-pyrrolidinyl carbamoyl; N-piperidyl amino formoxyl and N-morpholinyl carbamoyl.More preferably R ¹¹Be selected from acetyl group; propiono; bytyry; isobutyryl; the cyclohexane extraction carbonyl; benzoyl; phenylacetyl group; methoxycarbonyl; ethoxy carbonyl; propoxycarbonyl; isopropoxy carbonyl; butoxy carbonyl; cyclohexyloxy carbonyl; phenyloxycarbonyl; benzyloxycarbonyl; carbamoyl; N-methylamino formoxyl; N-ethylamino formoxyl; N-propyl group carbamoyl; N-isopropyl carbamoyl; N-phenyl amino formoxyl; N-benzylamino formoxyl; N; the N-formyl-dimethylamino; N; N-diethylamino formoxyl; N, N-dipropyl carbamoyl; N-pyrrolidinyl carbamoyl; N-piperidyl amino formoxyl and N-morpholinyl carbamoyl.

In another embodiment of formula (I) and chemical compound (III), R ⁸Be selected from hydrogen, methyl, ethyl, propyl group, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, phenyloxycarbonyl, benzyloxycarbonyl and cyano group.More preferably R ⁸Be selected from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxy carbonyl and butoxy carbonyl.

In another embodiment of formula (I) and chemical compound (III), R ¹²Be selected from hydrogen, methyl, ethyl, propyl group, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, phenyloxycarbonyl and benzyloxycarbonyl.More preferably R ¹²Be selected from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxy carbonyl and butoxy carbonyl.

In another embodiment of formula (I) and chemical compound (III), R ¹¹Be selected from alkyl, aryl, the aryl alkyl of hydrogen, alkoxy carbonyl, alkyl, replacement, and R ⁸And R ¹²Form the assorted alkyl of cycloalkyl, ring of cycloalkyl, replacement or the assorted alkyl ring of ring of replacement with their bonded carbon atoms.Preferred R ¹¹Be selected from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxy carbonyl and butoxy carbonyl, and R ⁸And R ¹²The assorted alkyl ring of ring with the cycloalkyl that forms cycloalkyl, replacement with their bonded carbon atoms, the assorted alkyl of ring or replacement.More preferably R ¹¹Be hydrogen or methyl, and R ⁸And R ¹²Encircle penta-1-alkene, hexamethylene-1-alkene, 2-cyclopentenes-1-ketone, 2-cyclohexene-1-ketone, 2-(5H)-furanone or 5,6-dihydro-pyran-2-one ring with forming with their bonded carbon atoms.

In another embodiment of formula (I) and chemical compound (III), R ¹²Be selected from alkyl, aryl, the aryl alkyl of hydrogen, alkoxy carbonyl, alkyl, replacement, and R ⁸And R ¹¹Form the assorted alkyl of cycloalkyl, ring of cycloalkyl, replacement or the assorted alkyl ring of ring of replacement with their bonded carbon atoms.Preferred R ¹²Be selected from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxy carbonyl and butoxy carbonyl, and R ⁸And R ¹¹Form the assorted alkyl of cycloalkyl, ring of cycloalkyl, replacement or the assorted alkyl ring of ring of replacement with their bonded carbon atoms.More preferably R ¹²Be selected from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxy carbonyl and butoxy carbonyl, and R ⁸And R ¹¹Form gamma-butyrolacton, δ-Wu Neizhi or 2 with their bonded carbon atoms, 2-dimethyl-1,3-diox-4,6-diketone ring.

In another embodiment of formula (I) and chemical compound (III), R ¹For

And R ¹⁵Be selected from the heteroaryl of aryl, heteroaryl and replacement of cycloalkyl, aryl, the replacement of alkyl, cycloalkyl, the replacement of alkyl, replacement.Preferred R ¹⁵Be methyl, ethyl, propyl group, isopropyl, cyclopenta, cyclohexyl, phenyl, 4-hydroxy phenyl, benzyl, 4-hydroxybenzyl or 3-pyridine radicals.

In formula (I) and another embodiment (III), R ¹For

R wherein ³⁷Heteroaryl alkyl for heteroaryl, heteroaryl alkyl or the replacement of the assorted alkyl of ring of the aryl alkyl of the aryl of the alkyl of hydrogen, alkyl, replacement, acyl group, aryl, replacement, aryl alkyl, replacement, cycloalkyl, Heterocyclylalkyl, replacement, heteroaryl, replacement;

Z is O, N or S; With

Ar is the heteroaryl of aryl, heteroaryl or the replacement of aryl, replacement.

Preferred Z and CH ₂OC (O)-each other conjugation continuous (for example being correlated with) with 1,4 or 1,2 of hexatomic ring system.

In formula (I) and another embodiment (III), R ¹For

Or

Wherein q is 0 or 1;

R ³⁸And R ³⁹Be the heteroaryl of aryl, heteroaryl and replacement of alkyl, aryl, the replacement of alkyl, cycloalkyl, the replacement of hydrogen, alkyl, replacement independently;

R ⁴⁰And R ⁴¹Be the heteroaryl of aryl, heteroaryl and replacement of alkyl, aryl, the replacement of alkyl, cycloalkyl, the replacement of hydrogen, alkyl, replacement independently; Or and form cycloalkyl ring with their bonded carbon atoms;

R ⁴²And R ⁴³Independently for the aryl of aryl, heteroaryl and the replacement of the alkyl of the alkyl of alkyl, replacement, cycloalkyl, replacement, aryl, replacement or and form the aryl rings of aryl, heteroaryl or the replacement of aryl, replacement with their bonded carbon atoms;

And R ³⁷Define as the front.

In an embodiment preferred of the chemical compound of formula (I)-(IV), Y is O, R ³, R ⁶And R ⁷Be hydrogen, and R ⁴And R ⁵Form the bridged ring alkyl ring of ring assorted alkyl, bridged ring alkyl or replacement of cycloalkyl, the assorted alkyl of ring, the replacement of cycloalkyl, replacement with their bonded carbon atoms.

In another embodiment preferred of the chemical compound of formula (I)-(IV), R ⁴And R ⁵With the cycloalkyl ring that forms cycloalkyl or replacement with their bonded carbon atoms.In one embodiment, n is 0, and t is 0 and u is 0.In another embodiment, n is 1, and R ²For hydrogen, methyl, 2-propyl group, 2-butyl, isobutyl group, the tert-butyl group, cyclopenta, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazole radicals, 2-indyl ,-CH ₂OH ,-CH (OH) CH ₃,-CH ₂CO ₂H ,-CH ₂CH ₂CO ₂H ,-CH ₂CONH ₂,-CH ₂CH ₂CONH ₂,-CH ₂SCH ₃, CH ₂SH ,-CH ₂(CH ₂) ₃NH ₂Or-CH ₂CH ₂CH ₂NHC (NH) NH ₂In another embodiment, n is 1, and R ²And R ¹⁶Form pyrrolidine ring with their bonded atoms.

In another embodiment preferred of the chemical compound of formula (I)-(IV), R ⁴And R ⁵With the cyclobutyl ring that forms cyclobutyl or replacement with their bonded carbon atoms.The cyclobutyl ring of preferred described replacement is selected from following substituent group by one or more and replaces: the alkyl group of alkyl group, replacement, halogen, hydroxyl, carboxyl and alkoxy carbonyl.

In another embodiment preferred of the chemical compound of formula (I)-(IV), R ⁴And R ⁵With the cyclopenta ring that forms cyclopenta or replacement with their bonded carbon atoms.Preferred described cyclopenta ring is replaced by the alkyl group of alkyl group, replacement, halogen, hydroxyl, carboxyl or alkoxy carbonyl.More preferably described cyclopenta ring is replaced by alkyl group.Even more preferably described cyclopenta ring is selected from

With

Preferably at one of above embodiment more specifically in the version, R ⁷Be hydrogen.

In another embodiment preferred of the chemical compound of formula (I)-(IV), R ⁴And R ⁵With the cyclohexyl ring that forms cyclohexyl or replacement with their bonded carbon atoms.Preferred described cyclohexyl ring is replaced by the alkyl group of alkyl group, replacement, halogen, hydroxyl, carboxyl or alkoxy carbonyl.More preferably described cyclohexyl ring is replaced by alkyl group.Even more preferably described cyclohexyl ring is selected from

With

In another embodiment preferred of the chemical compound of formula (I)-(IV), R ⁴And R ⁵Form the assorted alkyl ring of the ring that encircles assorted alkyl or replacement with their bonded carbon atoms.

In one embodiment, n is 0.In another embodiment, n is 1, and R ²For hydrogen, methyl, 2-propyl group, 2-butyl, isobutyl group, the tert-butyl group, cyclopenta, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazole radicals, 2-indyl ,-CH ₂OH ,-CH (OH) CH ₃,-CH ₂CO ₂H ,-CH ₂CH ₂CO ₂H ,-CH ₂CONH ₂,-CH ₂CH ₂CONH ₂,-CH ₂CH ₂SCH ₃, CH ₂SH ,-CH ₂(CH ₂) ₃NH ₂Or-CH ₂CH ₂CH ₂NHC (NH) NH ₂In another embodiment, n is 1, and R ²And R ¹⁶With form pyrrolidine ring with their bonded atoms.Preferred R ⁴And R ⁵Encircle heterochain alkyl ring with forming with their bonded carbon atoms.More preferably described ring heterochain alkyl ring is selected from

Or

Wherein Z is O, S (O) _pOr NR ¹⁸

P is 0,1 or 2; With

R ¹⁸Be selected from alkyl, acyl group and the alkoxy carbonyl of hydrogen, alkyl, replacement.More preferably described ring heterochain alkyl ring is selected from

With

Preferably, at one of above embodiment more specifically in the version, R ⁷Be hydrogen.

In another embodiment of the chemical compound of formula (I)-(IV), R ⁴And R ⁵With form bridged ring alkyl ring with their bonded carbon atoms.In one embodiment, n is 0.In another embodiment, n is 1, and R ²For hydrogen, methyl, 2-propyl group, 2-butyl, isobutyl group, the tert-butyl group, cyclopenta, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazole radicals, 2-indyl ,-CH ₂OH ,-CH (OH) CH ₃,-CH ₂CO ₂H ,-CH ₂CH ₂CO ₂H ,-CH ₂CONH ₂,-CH ₂CH ₂CONH ₂,-CH ₂CH ₂SCH ₃, CH ₂SH ,-CH ₂(CH ₂) ₃NH ₂Or-CH ₂CH ₂CH ₂NHC (NH) NH ₂In another embodiment, n is 1 and R ²And R ¹⁶Form pyrrolidine ring with their bonded atoms.Preferred described bridged ring alkyl is

Or

In another embodiment of the chemical compound of formula (I)-(IV), Y is O, R ⁶And R ⁷Be hydrogen, R ⁴Be alkyl or cycloalkyl, R ⁵Be hydrogen or alkyl, and R ³Be hydrogen or alkyl.In one embodiment, n is 0.In another embodiment, n is 1 and R ²For hydrogen, methyl, 2-propyl group, 2-butyl, isobutyl group, the tert-butyl group, cyclopenta, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazole radicals, 2-indyl ,-CH ₂OH ,-CH (OH) CH ₃,-CH ₂CO ₂H ,-CH ₂CH ₂CO ₂H ,-CH ₂CONH ₂,-CH ₂CH ₂CONH ₂,-CH ₂CH ₂SCH ₃, CH ₂SH ,-CH ₂(CH ₂) ₃NH ₂Or-CH ₂CH ₂CH ₂NHC (NH) NH ₂In another embodiment, n is 1 and R ²And R ¹⁶Form pyrrolidine ring with their bonded atoms.Preferred R ⁴Be cycloalkyl, R ⁵Be hydrogen or methyl, and R ³Be hydrogen or methyl.Preferred R ³Be hydrogen, R ⁴Be isobutyl group R ⁵Be hydrogen.

In another embodiment of the chemical compound of formula (I)-(IV), Y is O, R ⁵And R ⁷Be hydrogen or alkyl group, R ³And R ⁶Be hydrogen, and R ⁴Be the assorted alkyl that replaces.

Preferred R ⁴For

A is NR ¹⁹, O or S;

B is alkyl, alkoxyl, halogen, hydroxyl, carboxyl, alkoxy carbonyl or the amino of alkyl, replacement;

R ¹⁹Be hydrogen, alkyl, cycloalkyl or aryl;

J is the integer of 0-4;

K is the integer of 1-4; With

L is the integer of 0-3.

More preferably k is 1.

In another embodiment of the chemical compound of formula (I)-(IV), Y is O, R ⁵And R ⁷Be hydrogen or alkyl group, R ³And R ⁶Be hydrogen, and R ⁴Cycloalkyl for the alkyl group, cycloalkyl or the replacement that replace.Preferred R ⁴Be selected from

Preferred R ⁴For

With

H is the integer of 1-6; With

I is the integer of 0-6.

More preferably h is 1,2,3 or 4, and i is 0 or 1.Even more preferably R ⁴Be selected from

With

The chemical compound of preferred formula (I)-(IV) is derived by the GABA analog of formula (XIII):

The GABA analog of its Chinese style (XIII) is selected from:

1-aminomethyl-1,2-Cyclohexaneacetic acid;

1-aminomethyl-1,2-(3-hexahydrotoluene) acetic acid;

1-aminomethyl-1,2-(4-hexahydrotoluene) acetic acid;

1-aminomethyl-1,2-(4-isopropyl cyclohexane) acetic acid;

1-aminomethyl-1,2-(4-tert-butyl group cyclohexane extraction) acetic acid;

1-aminomethyl-1,2-(3, the 3-dimethyl cyclohexane) acetic acid;

1-aminomethyl-1,2-(3,3,5,5-tetramethyl-ring hexane) acetic acid;

1-aminomethyl-1,2-Pentamethylene. acetic acid;

1-aminomethyl-1,2-(3-methyl cyclopentane) acetic acid;

1-aminomethyl-1,2-(3, the 4-dimethylcyclopentane) acetic acid;

7-amino methyl-bicyclo-[2.2.1] heptan-7-guanidine-acetic acid;

9-amino methyl-bicyclo-[3.3.1] ninth of the ten Heavenly Stems-9-guanidine-acetic acid;

4-amino methyl-4-(tetrahydropyran-4-base) acetic acid;

3-amino methyl-3-(tetrahydropyran-3-base) acetic acid;

4-amino methyl-4-(tetrahydrochysene sulfo-pyrans-4-yl) acetic acid;

3-amino methyl-3-(tetrahydrochysene sulfo-pyrans-3-yl) acetic acid;

3-amino methyl-5-methyl-caproic acid;

3-amino methyl-5-methyl-enanthic acid;

3-amino methyl-5-methyl-sad;

3-amino methyl-5-methyl-n-nonanoic acid;

3-amino methyl-5-methyl-capric acid;

3-amino methyl-5-cyclopropyl-caproic acid;

3-amino methyl-5-cyclobutyl-caproic acid;

3-amino methyl-5-cyclopenta-caproic acid;

3-amino methyl-5-cyclohexyl-caproic acid;

3-amino methyl-5-phenyl-caproic acid;

3-amino methyl-5-phenyl-pentanoic acid;

3-amino methyl-4-cyclobutyl-butanoic acid;

3-amino methyl-4-cyclopenta-butanoic acid;

3-amino methyl-4-cyclohexyl-butanoic acid;

3-amino methyl-4-phenoxy group-butanoic acid;

3-amino methyl-5-phenoxy group-caproic acid; With

3-amino methyl-5-dibenzylsulfide. alkyl-valeric acid.

The embodiment of particularly preferred formula (I) comprises formula V and chemical compound (VI):

R wherein ¹, R ², R ⁷And R ¹⁶Define as the front.

In an embodiment of formula V and chemical compound (VI), n is 0.In another embodiment, n is 1, and R ²For hydrogen, methyl, 2-propyl group, 2-butyl, isobutyl group, the tert-butyl group, cyclopenta, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazole radicals, 2-indyl ,-CH ₂OH ,-CH (OH) CH ₃,-CH ₂CO ₂H ,-CH ₂CH ₂CO ₂H ,-CH ₂CONH ₂,-CH ₂CH ₂CONH ₂,-CH ₂CH ₂SCH ₃,-CH ₂SH ,-CH ₂(CH ₂) ₃NH ₂Or-CH ₂CH ₂CH ₂NHC (NH) NH ₂Preferably in above embodiment, R ⁷Be hydrogen.

In another embodiment of formula V and chemical compound (VI), n is 1, R ¹Be R ²⁴C (O)-or R ²⁴C (S)-; And R ²⁴Heteroaryl for aryl, heteroaryl or the replacement of the alkyl of alkyl, replacement, assorted alkyl, aryl, replacement.Preferred R ²⁴For methyl, ethyl, 2-propyl group, the tert-butyl group ,-CH ₂OCH (CH ₃) ₂, phenyl or 3-pyridine radicals.Preferably in this embodiment, R ⁷Aryl for alkenyl, aryl or the replacement of the alkyl group of hydrogen, alkyl group, replacement, alkenyl, replacement.More preferably R ⁷For hydrogen, methyl, ethyl, benzyl ,-C (CH ₃)=CH ₂,-CH ₂C (O) N (CH ₃) ₂,

Or

Wherein V is O or CH ₂

R most preferably ⁷Be hydrogen.

In another embodiment of formula V and chemical compound (VI), n is 1, R ¹Be R ²⁵OC (O)-or R ²⁵SC (O)-; And R ²⁵Heteroaryl for aryl, heteroaryl or the replacement of the alkyl of alkyl, replacement, assorted alkyl, aryl, replacement.Preferred R ²⁵For ethyl, 2-propyl group, neopentyl ,-CH ₂OCH (CH ₃) ₂, phenyl or 2-pyridine radicals.Preferred R in this embodiment ⁷Aryl for alkenyl, aryl or the replacement of the alkyl group of hydrogen, alkyl group, replacement, alkenyl, replacement.More preferably R ⁷For hydrogen, methyl, ethyl, benzyl ,-C (CH ₃)=CH ₂,-CH ₂C (O) N (CH ₃) ₂,

Or

Wherein V is O or CH ₂

R most preferably ⁷Be hydrogen.

In another embodiment of formula V and (VI) chemical compound, R ¹For

And R ¹⁵Be selected from the heteroaryl of aryl, heteroaryl and replacement of cycloalkyl, aryl, the replacement of alkyl, cycloalkyl, the replacement of alkyl, replacement.

Preferred R ¹⁵Be methyl, ethyl, propyl group, isopropyl, cyclopenta, cyclohexyl, phenyl, 4-hydroxy phenyl, benzyl, 4-hydroxybenzyl or 3-pyridine radicals.At one of this embodiment more specifically in the version, R ⁷Aryl for alkenyl, aryl or the replacement of the alkyl group of hydrogen, alkyl group, replacement, alkenyl, replacement.More preferably R ⁷Be hydrogen, methyl, ethyl, benzyl ,-C (CH ₃)=CH ₂,-CH ₂C (O) N (CH ₃) ₂,

Or

Wherein V is O or CH ₂

Preferred R ⁷Be hydrogen.

The particularly preferred embodiment of formula V and chemical compound (VI) is to be selected from following chemical compound: 1-{[((5-methyl-2-oxo-1,3-dioxy ring penta-4-alkene-4-yl) carbonyl methoxyl group)] amino methyl }-1-Cyclohexaneacetic acid and 3-{[((5-methyl-2-oxo-1,3-dioxy ring penta-4-alkene-4-yl) methoxyl group) carbonyl] amino methyl }-5-methyl-caproic acid.

In another embodiment of formula V and chemical compound (VI), R ¹For

M is 0, and R ⁸, R ¹¹And R ¹²Define as the front.In an embodiment of formula V and chemical compound (VI), R ¹¹Be the carbamoyl of acyl group, alkoxy carbonyl, aryloxycarbonyl, cyclo alkoxy carbonyl, carbamoyl or replacement, R ⁸Be hydrogen, alkoxy carbonyl, alkyl, aryl, aryl alkyl or cyano group, and R ¹²Alkyl, aryl or aryl alkyl for hydrogen, alkoxy carbonyl, alkyl, replacement.In another embodiment of formula V and chemical compound (VI), R ¹¹Be selected from acetyl group; propiono; bytyry; isobutyryl; valeryl; the Pentamethylene. carbonyl; the cyclohexane extraction carbonyl; benzoyl; phenylacetyl group; methoxycarbonyl; ethoxy carbonyl; propoxycarbonyl; isopropoxy carbonyl; butoxy carbonyl; isobutoxy carbonyl; the sec-butoxy carbonyl; tert-butoxycarbonyl; cyclopenta oxygen carbonyl; cyclohexyloxy carbonyl; phenyloxycarbonyl; benzyloxycarbonyl; carbamoyl; N-methylamino formoxyl; N-ethylamino formoxyl; N-propyl group carbamoyl; N-isopropyl carbamoyl; N-butyl carbamoyl; N-isobutylamino formoxyl; N-sec-butyl carbamoyl; N-tert-butyl group carbamoyl; N-cyclopenta carbamoyl; N-cyclohexyl carboxyamide base; N-phenyl amino formoxyl; N-benzylamino formoxyl; N; the N-formyl-dimethylamino; N; N-diethylamino formoxyl; N; N-dipropyl carbamoyl; N; N-diisopropylaminoethyl formoxyl; N; N-dibutylamino formoxyl; N, N-dibenzyl amino formoxyl; N-pyrrolidinyl carbamoyl; N-piperidyl amino formoxyl and N-morpholinyl carbamoyl.In another embodiment of formula V and (VI) chemical compound, R ¹¹Be selected from acetyl group; propiono; bytyry; isobutyryl; the cyclohexane extraction carbonyl; benzoyl; phenylacetyl group; methoxycarbonyl; ethoxy carbonyl; propoxycarbonyl; isopropoxy carbonyl; butoxy carbonyl; cyclohexyloxy carbonyl; phenyloxycarbonyl; benzyloxycarbonyl; carbamoyl; N-methylamino formoxyl; N-ethylamino formoxyl; N-propyl group carbamoyl; N-isopropyl carbamoyl; N-phenyl amino formoxyl; N-benzylamino formoxyl; N; the N-formyl-dimethylamino; N; N-diethylamino formoxyl; N, N-dipropyl carbamoyl; N-pyrrolidinyl carbamoyl; N-piperidyl amino formoxyl and N-morpholinyl carbamoyl.

In an embodiment of formula V and chemical compound (VI), R ⁸Be selected from hydrogen, methyl, ethyl, propyl group, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, phenyloxycarbonyl, benzyloxycarbonyl and cyano group.Preferred R ⁸Be selected from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxy carbonyl and butoxy carbonyl.

In another embodiment of formula V and chemical compound (VI), R ¹²Be selected from hydrogen, methyl, ethyl, propyl group, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, phenyloxycarbonyl and benzyloxycarbonyl.Preferred R ¹²Be selected from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxy carbonyl and butoxy carbonyl.

In another embodiment of formula V and chemical compound (VI), R ¹¹Be selected from alkyl, aryl, the aryl alkyl of hydrogen, alkoxy carbonyl, alkyl, replacement, and R ⁸And R ¹²Form the assorted alkyl of cycloalkyl, ring of cycloalkyl, replacement or the assorted alkyl ring of ring of replacement with their bonded carbon atoms.Preferred R ¹¹Be selected from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxy carbonyl and butoxy carbonyl, and R ⁸And R ¹²Form the assorted alkyl of cycloalkyl, ring of cycloalkyl, replacement or the assorted alkyl ring of ring of replacement with their bonded carbon atoms.More preferably R ¹¹Be hydrogen or methyl, and R ⁸And R ¹²With form 2-cyclopentenes-1-ketone, 2-cyclohexene-1-ketone, 2-(5H)-furanone or 5,6-dihydro-pyran-2-one ring with their bonded carbon atoms.

In another embodiment of formula V and chemical compound (VI), R ¹²Be selected from alkyl, aryl, the aryl alkyl of hydrogen, alkoxy carbonyl, alkyl, replacement, and R ⁸And R ¹¹The assorted alkyl ring of ring with the cycloalkyl that forms cycloalkyl, replacement with their bonded carbon atoms, the assorted alkyl of ring or replacement.Preferred R ¹²Be selected from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxy carbonyl and butoxy carbonyl, and R ⁸And R ¹¹Form the assorted alkyl of cycloalkyl, ring of cycloalkyl, replacement or the assorted alkyl ring of ring of replacement with their bonded carbon atoms.More preferably R ¹²Be selected from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxy carbonyl and butoxy carbonyl, and R ⁸And R ¹¹With form gamma-butyrolacton, δ-Wu Neizhi or 2 with their bonded carbon atoms, 2-dimethyl-1,3-diox-4,6-diketone ring.

At one of the embodiment of above formula V and (VI) chemical compound more specifically in the version, R ⁷Aryl for alkenyl, aryl or the replacement of the alkyl group of hydrogen, alkyl group, replacement, alkenyl, replacement.More preferably R ⁷For hydrogen, methyl, ethyl, benzyl ,-C (CH ₃)=CH ₂,-CH ₂C (O) N (CH ₃) ₂,

Or

Wherein V is O or CH ₂

R most preferably ⁷Be hydrogen.

The particularly preferred embodiment of formula V and chemical compound (VI) is to be selected from following chemical compound:

1-{ (1-methyl-3-oxo-but-1-ene base) amino methyl }-1-Cyclohexaneacetic acid piperidines;

1-{1-[(2-oxo-oxolane-3-base subunit) ethylamino methyl }-1-Cyclohexaneacetic acid piperidines;

1-{ (2-carbon methoxyl group (carbomethoxy)-ring penta-1-thiazolinyl) amino methyl }-1-Cyclohexaneacetic acid piperidines; With

1-{ (1-methyl-2-(ethoxy carbonyl)-3-ethyoxyl-3-oxo third-1-thiazolinyl) amino methyl }-1-Cyclohexaneacetic acid piperidines.

In an especially preferred embodiment, the chemical compound of formula (IV) has formula (VII) or structure (VIII):

Or its pharmaceutically acceptable salt, hydrate or solvate, wherein:

N, R ², R ⁷, R ¹³, R ¹⁴, R ¹⁶And R ²⁵Define as the front.

In a preferred embodiment, formula (VII) and chemical compound (VIII) do not comprise following chemical compound:

If R ¹³Or R ¹⁴Arbitrary be the cyclo alkoxy carbonyl of alkoxy carbonyl, carbamoyl, cyclo alkoxy carbonyl or the replacement of hydrogen, alkoxy carbonyl, replacement, then R ¹³Or R ¹⁴In another be not hydrogen; With

R ²⁵C (O) is not by the deutero-part of bile acid.

In an embodiment of formula (VII) and chemical compound (VIII), n is 0.In another embodiment, n is 1.When n was 1, preferred a-amino acid was the L-three-dimensional chemical configuration.

In another embodiment of formula (VII) and chemical compound (VIII), R ⁷Aryl for alkenyl, aryl or the replacement of the alkyl group of hydrogen, alkyl group, replacement, alkenyl, replacement.Preferred R ⁷For hydrogen, methyl, ethyl, benzyl ,-C (CH ₃)=CH ₂,-CH ₂C (O) N (CH ₃) ₂,

Or

Wherein V is O or CH ₂

R most preferably ⁷Be hydrogen.

In another embodiment of formula (VII) and chemical compound (VIII), n is 0.In another embodiment of formula (VII) and chemical compound (VIII), n is 1, R ¹⁶Be hydrogen R ²For hydrogen, methyl, 2-propyl group, 2-butyl, isobutyl group, the tert-butyl group, cyclopenta, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazole radicals, 2-indyl ,-CH ₂OH ,-CH (OH) CH ₃,-CH ₂CO ₂H ,-CH ₂CH ₂CO ₂H ,-CH ₂CONH ₂,-CH ₂CH ₂CONH ₂,-CH ₂CH ₂SCH ₃,-CH ₂SH ,-CH ₂(CH ₂) ₃NH ₂Or-CH ₂CH ₂CH ₂NHC (NH) NH ₂Preferred R ¹⁶Be hydrogen, and R ²Be hydrogen, methyl, 2-propyl group, 2-butyl, isobutyl group, the tert-butyl group, cyclohexyl, phenyl or benzyl.In another embodiment, n is 1, and R ²And R ¹⁶With form pyrrolidine ring with their bonded atoms.

In another embodiment of formula (VII) and chemical compound (VIII), R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals, R ¹³Be methyl R ¹⁴Be hydrogen.

In another embodiment of formula (VII) and chemical compound (VIII), R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals, R ¹³Be ethyl R ¹⁴Be hydrogen.

In another embodiment of formula (VII) and chemical compound (VIII), R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals, R ¹³Be propyl group R ¹⁴Be hydrogen.

In another embodiment of formula (VII) and chemical compound (VIII), R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals, R ¹³Be isopropyl R ¹⁴Be hydrogen.

In another embodiment of formula (VII) and chemical compound (VIII), R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals, R ¹³Be butyl R ¹⁴Be hydrogen.

In another embodiment of formula (VII) and chemical compound (VIII), R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals, R ¹³Be isobutyl group R ¹⁴Be hydrogen.

In another embodiment of formula (VII) and chemical compound (VIII), R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals, R ¹³Be sec-butyl and R ¹⁴Be hydrogen.

In another embodiment of formula (VII) and chemical compound (VIII), R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals, R ¹³Be tert-butyl group R ¹⁴Be hydrogen.

In another embodiment of formula (VII) and chemical compound (VIII), R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals, R ¹³Be cyclopenta R ¹⁴Be hydrogen.

In another embodiment of formula (VII) and chemical compound (VIII), R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals, R ¹³Be cyclohexyl R ¹⁴Be hydrogen.

In another embodiment of formula (VII) and chemical compound (VIII), R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals, R ¹³Be methyl R ¹⁴Be methyl.

In another embodiment of formula (VII) and chemical compound (VIII), R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals, R ¹³Be methoxycarbonyl R ¹⁴Be methyl.

In another embodiment of formula (VII) and chemical compound (VIII), R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals, R ¹³Be ethoxy carbonyl R ¹⁴Be methyl.

In another embodiment of formula (VII) and chemical compound (VIII), R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals, R ¹³Be propoxycarbonyl R ¹⁴Be methyl.

In another embodiment of formula (VII) and chemical compound (VIII), R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals, R ¹³Be isopropoxy carbonyl R ¹⁴Be methyl.

In another embodiment of formula (VII) and chemical compound (VIII), R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals, R ¹³Be butoxy carbonyl R ¹⁴Be methyl.

In another embodiment of formula (VII) and chemical compound (VIII), R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals, R ¹³Be isobutoxy carbonyl R ¹⁴Be methyl.

In another embodiment of formula (VII) and chemical compound (VIII), R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals, R ¹³Be sec-butoxy carbonyl R ¹⁴Be methyl.

In another embodiment of formula (VII) and chemical compound (VIII), R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals, R ¹³Be tert-butoxycarbonyl R ¹⁴Be methyl.

In another embodiment of formula (VII) and chemical compound (VIII), R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals, R ¹³Be cyclohexyloxy carbonyl R ¹⁴Be methyl.

In another embodiment of formula (VII) and chemical compound (VIII), R ²⁵For being selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals, R ¹³Be phenyl R ¹⁴Be hydrogen.

In another embodiment of formula (VII) and chemical compound (VIII), R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals, R ¹³Be benzyl R ¹⁴Be hydrogen.

In another embodiment of formula (VII) and chemical compound (VIII), R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals, R ¹³Be phenethyl R ¹⁴Be hydrogen.

In another embodiment of formula (VII) and chemical compound (VIII), R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals, R ¹³Be 3-pyridine radicals R ⁴Be hydrogen.

The particularly preferred embodiment of formula (VII) and chemical compound (VIII) comprises and is selected from following chemical compound:

1-{[(α-acetate ethyoxyl) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;

1-{[(α-propionyloxy ethyoxyl) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;

1-{[(α-butyryl acyloxy ethyoxyl) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;

1-{[(α-isobutyl acyl-oxygen base oxethyl) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;

1-{[(α-new pentane acyloxy ethyoxyl) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;

1-{[(α-benzoyloxy ethyoxyl) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;

1-{[(α-acetate butoxy) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;

1-{[(α-butyryl acyloxy butoxy) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;

1-{[(α-isobutyl acyloxy butoxy) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;

1-{[(α-benzoyloxy butoxy) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;

1-{[(α-acetate isobutoxy) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;

1-{[(α-propionyloxy isobutoxy) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;

1-{[(α-butyryl acyloxy isobutoxy) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;

1-{[(α-isobutyl acyloxy isobutoxy) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;

1-{[(α-new pentane acyloxy isobutoxy) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;

1-{[(α-2,2-diethoxy propionyloxy isobutoxy) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;

1-{[(α-2-(1,3-dioxolanes-2-yl) propionyloxy isobutoxy) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;

1-{[(α-(2-amino-2-methyl propiono) oxygen isobutoxy) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;

1-{[(α-benzoyloxy isobutoxy) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;

1-{[(α-nicotinylsalicylic oxygen isobutoxy) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;

1-{[(α-acetate isopropoxy) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;

1-{[(α-butyryl acyloxy isopropoxy) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;

1-{[(α-isobutyl acyloxy isopropoxy) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;

1-{[(α-benzoyloxy isopropoxy) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;

1-{[(α-acetate benzyloxy) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;

1-{[(α-benzoyloxy benzyloxy) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;

1-{[(1-(3-methylbutyryl oxygen base)-2-phenyl ethoxy) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;

1-{[(1-benzoyloxy-2-phenyl ethoxy) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;

1-{[N-(α-isobutyl acyl-oxygen base oxethyl) carbonyl]-4-bromophenyl alanyl (ananinyl)-amino methyl }-the 1-Cyclohexaneacetic acid;

3-{[(α-isobutyl acyl-oxygen base oxethyl) carbonyl] amino methyl }-the 5-methylhexanoic acid;

3-{[(α-isobutyl acyloxy isobutoxy) carbonyl] amino methyl }-the 5-methylhexanoic acid; With

3-{[(α-benzoyloxy isobutoxy) carbonyl] amino methyl }-the 5-methylhexanoic acid.

In one embodiment, chemical compound of the present invention has the structure of formula (II):

In an embodiment of the chemical compound of formula (II), work as R ³, R ⁵And R ⁶Be hydrogen, R ⁴It is not the phenyl of phenyl or replacement.More preferably R ⁴It is not the 4-chlorphenyl.

In a preferred embodiment, the chemical compound of formula (II) has formula (IX) and structure (X):

In an embodiment of formula (IX) and chemical compound (X), t is 0.In another embodiment, t is 1 and R ²For hydrogen, methyl, 2-propyl group, 2-butyl, isobutyl group, the tert-butyl group, cyclopenta, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazole radicals, 2-indyl ,-CH ₂OH ,-CH (OH) CH ₃,-CH ₂CO ₂H ,-CH ₂CH ₂CO ₂H ,-CH ₂CONH ₂,-CH ₂CH ₂CONH ₂,-CH ₂CH ₂SCH ₃,-CH ₂SH ,-CH ₂(CH ₂) ₃NH ₂Or-CH ₂CH ₂CH ₂NHC (NH) NH ₂

In another embodiment of formula (IX) and chemical compound (X), R ²⁰And R ²¹Be independently selected from the heteroaryl of aryl, heteroaryl and replacement of alkyl, aryl, the replacement of alkyl, replacement.Preferred R ²⁰And R ²¹Be independently selected from the aryl and the heteroaryl of alkyl, replacement.In one embodiment, R ²⁰Be methyl R ²¹Be methyl.Preferably in this last embodiment, R ⁷For hydrogen, methyl, ethyl, benzyl ,-C (CH ₃)=CH ₂,-CH ₂C (O) N (CH ₃) ₂,

Or

Wherein V is O or CH ₂

R most preferably ⁷Be hydrogen.

In another embodiment of formula (IX) and chemical compound (X), R ²⁰And R ²¹With the cycloalkyl ring that forms cycloalkyl or replacement with their bonded carbon atoms.In one embodiment, R ²⁰And R ²¹With form cyclohexyl ring with their bonded carbon atoms.Preferably in this last embodiment, R ⁷For hydrogen, methyl, ethyl, benzyl ,-C (CH ₃)=CH ₂,-CH ₂C (O) N (CH ₃) ₂,

Or

Wherein V is O or CH ₂

R most preferably ⁷Be hydrogen.

In one embodiment, chemical compound of the present invention has the structure of formula (III):

In an embodiment of the chemical compound of formula (III), n is 1, R ¹Be hydrogen R ²Be aryl alkyl.Preferred R ²Be benzyl.In another embodiment of the chemical compound of formula (III), n is 0, and R ¹Be R ²⁵OC (O)-.Preferred R ²⁵Alkyl for alkyl or replacement.More preferably R ²⁵Be ethyl.In another embodiment of the chemical compound of formula (III), R ²²And R ²³Be hydrogen.In another embodiment, R ²²And R ²³Alkyl for alkyl or replacement.Preferred R ²²And R ²³Be methyl.

In a preferred embodiment, the chemical compound of formula (III) has the structure of formula (XI):

In an embodiment of the chemical compound of formula (XI), n is 1, and X is NH, and Y is 0, R ¹Be hydrogen, R ²Be benzyl, R ²²Be methyl R ²³Be methyl.In another embodiment, n is 0, and Y is 0, R ¹Be R ²⁵OC (O)-, R ²⁵Be ethyl, R ²²Be hydrogen R ²³Be hydrogen.

In another embodiment, the chemical compound of formula (III) has the structure of formula (XII):

In an embodiment of the chemical compound of formula (XII), n is 1, and X is NH, and Y is 0, R ¹Be hydrogen, R ²Be benzyl, R ²²Be methyl and R ²³Be methyl.In another embodiment, n is 0, and Y is 0, R ¹Be R ²⁵OC (O)-, R ²⁵Be ethyl, R ²²Be hydrogen R ²³Be hydrogen.

The present invention also comprises the GABA analog derivant that is used for patient's row administration of needs treatment, M-G, and wherein M is a primitive, and G is the GABA analog, the derivant of H-G (wherein H is a hydrogen).Primitive M is in case cracking on G and its any metabolite shows the carcinogenic toxicity dosage (TD to rat ₅₀) greater than 0.2mmol/kg/ days.And when rat was carried out colon administration, primitive M went up cracking with competent speed from G in vivo and produces:

(i) be at least the Cmax (C of the blood plasma H-G that the H-G by molar doses such as colonic administration obtains _Max) the C of 120% blood plasma H-G _MaxWith

(ii) be at least 120% the AUC of AUC that the H-G by molar doses such as colonic administration obtains.

Preferred M-G has the structure of formula (XIV):

Or its pharmaceutically acceptable salt, hydrate or solvate, wherein:

M is a primitive;

Y is O or S;

R ⁴And R ⁵Be independently selected from the heteroaryl alkyl of heteroaryl, heteroaryl alkyl and replacement of the assorted alkyl of ring, heteroaryl, the replacement of aryl alkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring, the replacement of aryl, aryl alkyl, the replacement of acyl group, aryl, the replacement of alkyl, acyl group, the replacement of hydrogen, alkyl, replacement, perhaps optional R ⁴And R ⁵Assorted alkyl of ring or bridged ring alkyl ring with the cycloalkyl that forms cycloalkyl, replacement with their bonded carbon atoms, the assorted alkyl of ring, replacement; With

R ⁷Be selected from the heteroaryl alkyl of heteroaryl, heteroaryl alkyl and replacement of assorted alkyl, heteroaryl, the replacement of aryl alkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring of aryl, aryl alkyl, the replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement, the assorted alkyl of ring of replacement, assorted alkyl, replacement.

In a preferred embodiment, M has the structure of formula (XV):

Wherein:

N, X, R ¹And R ²Define as the front.

In one embodiment, M-G comprises such chemical compound: wherein H-G is not in case from upward cracking of M, exist any lactams with structure of formula (XVI) basically:

Wherein R is a hydrogen, and R ³, R ⁴, R ⁵And R ⁶Define as the front.

Preferred primitive M or any metabolite that is formed by M do not form formaldehyde or neopentanoic acid when the G-M cracking.In one embodiment, when rat was carried out colon administration, primitive M went up cracking with competent speed from G in vivo and produces the C that is at least the blood plasma H-G that the H-G by molar doses such as colonic administration obtains _Max200%, the C of at least 1000% blood plasma H-G most preferably _MaxPreferably when rat is carried out colon administration, primitive M goes up cracking with competent speed from G in vivo and produces 200% of the AUC that is at least the blood plasma that the H-G by molar doses such as colonic administration obtains, the most preferably AUC of at least 500% blood plasma H-G.In another embodiment, after giving the dosage of the normal H-G/kg of Canis familiaris L. oral (for example using the mini pumping unit of permeability) about 60 μ mol, primitive M goes up cracking with competent speed from H-G in vivo and produces 200% the back 12 hours plasma concentration of taking medicine that is at least carrying out the same way as administration after by the blood plasma H-G concentration of the H-G acquisition that waits molar dose.

4.3 The compounds of this invention is synthetic

The synthetic method of chemical compound of the present invention shown in can pass course 1-17 obtains.The preferred route of synthesis that those skilled in the art will recognize that chemical compound of the present invention is that primitive is combined with the GABA analog.In the synthetic technology of GABA analog, described several different methods (for example referring to people such as Satzinger, United States Patent (USP) 4,024,175; People such as Silverman, United States Patent (USP) 5,563,175; People such as Horwell, United States Patent (USP) 6,020,370; People such as Silverman, United States Patent (USP) 6,028,214; People such as Horwell, United States Patent (USP) 6,103,932; People such as Silverman, United States Patent (USP) 6,117,906; Silverman, international open WO92/09560; People such as Silverman, international open WO 93/23383; People such as Horwell, international open WO 97/29101, people such as Horwell, international open WO 97/33858; People such as Horwell, international open WO 97/33859; People such as Bryans, international open WO98/17627; People such as Guglietta, international open WO 99/08671; People such as Bryans, international open WO 99/21824; People such as Bryans, international open WO 99/31057; People such as Belliotti, international open WO 99/31074; People such as Bryans, international open WO 99/31075; People such as Bryans, international open WO 99/61424; People such as Bryans, international open WO00/15611; Bryans, international open WO 00/31020; With people such as Bryans, international open WO 00/50027).Other method is known in GABA analog synthetic technology, and those skilled in the art can easily obtain.Primitive as herein described is well known in the art, and can by the method preparation of determining and be attached to the GABA analog be (for example referring to people such as Green, " Protective Groups in Organic Chemistry (protecting group in the organic chemistry) ", (Wiley, second edition, 1991); People such as Harrison, " Compendium ofSynthetic Organic Methods (methodology of organic synthesis summary) ", the 1-8 volume (JohnWiley and Sons, 1971-1996); " Beilstein Handbook of OrganicChemistry (Beilstein organic chemistry handbook), " Beilstein Institute ofOrganic Chemistry (Beilstein organic chemistry institute), Frankfort, Germany; People such as Feiser, " Reactions for Organic Synthesis (organic synthesis), " 1-17 volume, Wiley Interscience; People such as Trost, " ComprehensiveOrganic Synthesis (comprehensive organic synthesis) ", Pergamon Press, 1991; " Theilheimer ' s Synthetic Methods of OrganicChemistry (Theilheimer organic chemistry synthetic method), " 1-45 volume, Karger, 1991; March, " Advanced Organic Chemistry (Advanced Organic Chemistry), " Wiley Interscience, 1991; Larock " Comprehensive Organic Transformations (comprehensive organic transformation), " VCH publisher, 1989; Paquette, " Encyclopedia of Reagents for Organic Synthesis (organic synthesis reagent encyclopedia), " John Wiley ﹠amp; Sons, 1995, Bodanzsky, " Principlesof Peptide Synthesis (peptide composition principle), " Springer Verlag, 1984; Bodanzsky, " Practice of Peptide Synthesis (peptide is synthetic to be put into practice) " Springer Verlag, 1984).

Therefore, the raw material that is used to prepare chemical compound of the present invention and intermediate product thereof can be commercially available or can be by known synthetic method preparation.Other is used for being very conspicuous those skilled in the art of the reference material that provides more than considering perhaps, and can being used for synthetic chemical compound of the present invention described in the method such as this area of synthetic prodrug as herein described.Therefore, the method shown in this paper route is to carry out illustration rather than carry out comprehensive.

In following arbitrary route, after the aminofunctional with the GABA analog, can hydroxy-acid group be converted into ester or thioesters by many synthetic methods well known by persons skilled in the art with primitive or other protecting group.In a preferred embodiment, GABA analog and alcohol or mercaptan can be reacted in the presence of coupling agent (for example carbodiimides and dimethyl aminopyridine) and obtain ester.In another preferred embodiment, GABA analog and alkyl halide can be reacted in the presence of alkali and obtain ester.Other method that GABA analog is transformed into ester or thioesters is in the reference material scope provided herein that those skilled in the art were familiar with.

Shown in above route 1, carboxylic acid directly can be combined with terminal amino group (or hydroxyl) group of GABA analog derivant (6) and obtain adduct (7).The reagent that carries out this reaction is known for a person skilled in the art, and includes but not limited to carbodiimides, ammonium salt, phosphonium salt etc.Selectively, the reaction in the presence of alkali (for example hydroxide, tertiary amine etc.) of carboxylic acid derivates such as acyl chlorides, symmetrical anhydride or mixed anhydride and GABA analog (6) can be used to synthesize (7).

Route 2

As shown in Figure 2, can be by in the presence of alkali (for example hydroxide, tertiary amine etc.), handling and GABA analog derivant (6) being converted into carbamate (8) with multiple carbonic acid derivative.Selectively, known pure addition to isocyanates (9) or (10) can be used to synthesize (8).

As shown in Scheme 3, can be by in the presence of coupling agent, handling and GABA analog derivant (6) being converted into thioamides (11) with thio-acid.The reagent that is used to carry out this reaction is known for a person skilled in the art, and includes but not limited to carbodiimides, ammonium salt, phosphonium salt etc.Selectively, thio-acid derivant such as sulfo-acyl chlorides, symmetrical anhydride or mixed anhydride and (6) reaction in the presence of alkali (as hydroxide, tertiary amine etc.) can be used for synthetic thioamides (11).In another method, can be by in the presence of Phosphoric sulfide (as n=0 time), heating and amide (7) is converted into thioamides (11).

Can in the presence of alkali, react synthesizing thiocarbamate (12) and (13) with GABA analog derivant (6) by the thiocarbonic acid ester derivant (promptly being respectively P=O, Q=S and P=SQ=O) (wherein W is chloride, imidazole radicals or 4-nitrophenoxy) of correspondence.Can also be by mercaptan and isocyanates (9) or (10) reaction formation thiocarbamate (13).Can in the presence of alkali, react by GABA analog derivant (6) and dithiocarbonic acids ester derivant (being P and Q=S) (wherein W is chloride, imidazole radicals or 4-nitrophenoxy) and prepare dithiocarbamate (14) (P=S, Q=S) (referring to route 4).

Route 4

A kind of method such as route 5 illustrations that are used for the chemical compound of synthesis type (IV).

Route 5

In the presence of alkali, handle chloro-formate (15) and obtain p-nitrophenyl carbonic ester (16) with fragrant leaving group such as paranitrophenol.Halid mutual exchange obtains iodide (17), and the tetra-allkylammonium reactant salt of these iodide and metal or carboxylic acid is obtained chemical compound (18).Choose wantonly in the presence of trimethylsilyl chloride and handle the chemical compound that (18) obtain formula (IV) with GABA analog derivant (19).The method of the acyloxy alkyl carbamate chemical compound that preparation is relevant is described (Alexander, United States Patent (USP) 4,760,057 in the art; Alexander, United States Patent (USP) 4,916,230; Alexander, United States Patent (USP) 5,466,811; Alexander, United States Patent (USP) 5,684,018).

Selectively, the chemical compound of formula (IV) can substep mode as shown in Scheme 6 be prepared by carbonic ester (18).Here (18) obtain intermediate product (21) with the reaction of choosing the a-amino acid of protecting as ester (20) wantonly; described intermediate product (if necessary) when deprotection provides chemical compound (22), uses standard peptide coupling agent as known in the art with itself and GABA analog (23) coupling then.

Route 6

Carry out by intermediate product carbamic acid class by GABA analog derivant (19) carbonyl is turned to for the method for the chemical compound of another kind of synthesis type (IV), it is to carry out (the Butcher that alkylated reaction is on the spot collected in the remodeling by disclosed method in the art, Synlett, 1994,825-6; People such as Ferres, U.S.Patent 4,036, and 829).The carbon dioxide bubbling is entered in solvent such as DMF or NMP, contain (19) and alkali (CS for example ₂CO ₃, Ag ₂CO ₃Or AgO) solution.Choose wantonly and add activatory halogenide in the presence of as the iodide ion of catalyst, and continue carbonylation and finish up to reaction.The method as route 7 about by shown in the chemical compound of halogenide (24) preparation formula (IV).

Route 7

Selectively, the mode of the substep that the chemical compound of formula (IV) can be as shown in Scheme 8 prepares.The carbonylation of the a-amino acid of carboxy protective (20) and alkylation provide intermediate product (21), and it is when deprotection and GABA analog (23) coupling, shown in front route 6.

Route 8

But the method for the chemical compound of another one synthesis type (IV) relies on the oxidation (people such as Gallop, title be the common unsettled U.S. Patent application of " Methods forSynthesis of prodrug from 1-Acyl-Alkyl Derivatives andCompositions Thereof (method of synthesizing prodrug by 1-acyl group-alkyl derivative and derivant thereof) ") of the ketone carbamate derivatives of GABA analog.As shown in Scheme 9, the oxidation of ketone carbamate (25) obtains the chemical compound of formula (IV).Preferred solvent includes but not limited to the tert-butyl alcohol, Anaesthetie Ether, acetic acid, hexane, dichloroethanes, dichloromethane, ethyl acetate, acetonitrile, methanol, chloroform and water.Usually, oxidant can be organism (for example yeast or an antibacterial), perhaps chemical reagent (for example enzyme or peroxide).Preferred oxidant package is successfully used to ketone Baeyer-Villager is oxidized to oxidant (Strukul, Angnew.Chem.Int.ED., 1998,37,1198 of ester or lactone; People such as Renz, Eur.J.Org.Chem.1999,737; People such as Beller, in " Transition Metals in Organic Synthesis " Chapter 2, Wiley VCH; Stewart, Current Organic Chemistry, 1998,2,195; People such as Kayser, Synlett, 1999,1,153).

Route 9

Other chemical compound of the present invention can be synthetic by the oxidation of Baeyer-Villager type by suitable ketone carbamate derivatives, and condition is that they do not contain the chemical functional group who decomposes or transform easily under reaction condition.

Ketone carbamate (25) can be prepared by the following method by the alpha-hydroxyacetone compounds (26) of correspondence: directly by reacting with isocyanates (9), perhaps at first alpha-hydroxyacetone compounds is converted into halo chloro-formate or activatory carbonic ester intermediate product (27), then with chemical compound (19) reaction, as route 10 illustrations.

Route 10

Selectively, can be according to above-mentioned couling process, the a-amino acid carbamate (28) by as shown in Scheme 11 prepares ketone carbamate (25) in the substep mode.

Route 11

A kind of preparation method of noticing the isocyanate derivates (being chemical compound (9)) of the GABA analog that above route 10 is used is from as shown in Scheme 12 suitable hexa-atomic acid anhydride (29) beginning.By opening anhydro ring, obtain carboxylic acid (30) with alcohol or the reaction of mercaptan nucleopilic reagent.With 2 steps orders (promptly at first activated carboxylic is become mixed anhydride, acyl halide or synthetic equivalent, replace with azide then) or directly (for example by using PH ₂P (O) N ₃Handle) this chemical compound is converted into the intermediate product acyl azide.By thermal decomposition and the acyl azide intermediate product is carried out Ku Ertisi reset under 0 ℃ to 120 ℃ temperature in The suitable solvent (for example toluene), obtain isocyanates (9).Optional isocyanates is not separated, but forms on the spot, and by with its formation of alpha-alcohol ketone (26) reaction terminating, obtain target product (25).

Route 12

A kind of method that is used for synthesizing oxo dioxolyl (oxodioxolenyl) methyl carbamate prodrug (36) is disclosed in route 13.In the presence of alkali, handle hydroxy-ketone (31) and obtain cyclic carbonate ester (32) with phosgene or carbonyl dimidazoles.With N-bromine butanimide and azo isobutyronitrile the free radical bromination is obtained bromide (33), be translated into alcohol (34).By alcohol (34) being changed into two carbonic esters (dicarbonate) (35), make itself and GABA analog derivant (19) reaction obtain prodrug (36) then with the reaction of 4-chloroformate nitrophenyl ester.Selectively, chemical compound (34) obtains chemical compound (36) with isocyanates (9) reaction, and wherein n is 0.

Route 13

Can the synthetic prodrug (41) of pass course 14 disclosed methods.Carboxylic acid (37) and the coupling of alcohol (38) (for example dicyclohexyl carbodiimide and pyridine) are obtained ester (39).By ester (39) being converted into activated carbon acid esters (40), obtain prodrug (41) with GABA analog derivant (19) reaction then with the reaction of 4-chloroformate nitrophenyl ester.

Route 14

Can be by choosing wantonly in the presence of secondary amine as catalyst, under the dehydration conditions shown in the route 15, make active carbonyl compound (42) and GABA analog derivant (19) (R wherein ¹⁶=H) reaction and synthetic simply enamine prodrug be as (43).

Route 15

Approach synthetic compound (III) shown in can pass course 16.

GABA analog (23) obtains amino ester (45) with α-activatory ester derivant (44) reaction.

By amino-terminated obtain (46) (for example use above-mentioned method) of acyl groupization, and under standard conditions, the free acid esterification obtained diester (47) with (45).Carry out the Dieckman condensation, carry out decarboxylation then and obtain ketone (48).Carry out the peroxy acid oxidation then and obtain lactone (III).

Route 16

Can be as described in the route 17, by under dehydration conditions, handling ketone or ketone derivatives (49) and synthesizing imine prodrug (II) with GABA analog derivant (50).

Route 17

Can be by the synthetic phosphorus prodrug of conventional method as known in the art.Similarly, can be by using the synthetic prodrug of the method described in this area with S-N key.

4.4 the treatment of The compounds of this invention is used

According to the present invention, chemical compound of the present invention and/or compositions are applied to the patient who suffers from following disease, preferred people: epilepsy, depression, anxiety, psychosis, faintness outbreak, hypocinesis, cranium are unusual, neurodegenerative disease, fear, pain (particularly neuropathic pain and muscle and skeleton pain), inflammatory diseases (being arthritis), insomnia, gastrointestinal disease or ethanol withdrawal symptom.And in certain embodiments, can give the patient, preferred people uses chemical compound of the present invention and/or compositions as the preventive measure to multiple disease or disease.Therefore, chemical compound of the present invention and/or compositions can be used as the patient that a kind of preventive measure is applied to the following disease of easy trouble: epilepsy, depression, anxiety, psychosis, faintness outbreak, hypocinesis, cranium are unusual, neurodegenerative disease, fear, pain (particularly neuropathic pain and muscle and skeleton pain), inflammatory diseases (being arthritis), insomnia, gastrointestinal disease and ethanol withdrawal symptom.Therefore, chemical compound of the present invention and/or compositions can be used to prevent a kind of disease or disease, treat another kind of disease and disease simultaneously and (for example prevent psychosis and treat gastrointestinal disease; The prevention neuropathic pain is also treated the ethanol withdrawal symptom).

Can determine that chemical compound of the present invention and/or combination treatment epilepsy, depression, anxiety, psychosis, faintness outbreak, hypocinesis, cranium are unusual by method as known in the art, the well-formedness of neurodegenerative disease, fear, pain (particularly neuropathic pain and muscle and skeleton pain), inflammatory diseases (being arthritis), insomnia, gastrointestinal disease and ethanol withdrawal symptom is (for example referring to people such as Satzinger, United States Patent (USP) 4,024,175; People such as Satzinger, United States Patent (USP) 4,087,544; Woodruff, United States Patent (USP) 5,084,169; People such as Silverman, United States Patent (USP) 5,563,175; Singh, United States Patent (USP) 6,001,876; People such as Horwell, United States Patent (USP) 6,020,370; People such as Silverman, United States Patent (USP) 6,028,214; People such as Horwell, United States Patent (USP) 6,103,932; People such as Silverman, United States Patent (USP) 6,117,906; Silverman, international open WO 92/09560; People such as Silverman, international open WO 93/23383; People such as Horwell, international open WO 97/29101, people such as Horwell, international open WO 97/33858; People such as Horwell, international open WO 97/33859; People such as Bryans, international open WO 98/17627; People such as Guglietta, international open WO99/08671; People such as Bryans, international open WO 99/21824; People such as Bryans, international open WO 99/31057; People such as Magnus-Miller, international open WO 99/37296; People such as Bryans, international open WO 99/31075; People such as Bryans, international open WO99/61424; Pande, international open WO 00/23067; Bryans, international open WO00/31020; People such as Bryans, international open WO 00/50027; With people such as Bryans, international open WO 02/00209).That chemical compound of the present invention and/or compositions can be used for is unusual by the method described in this area (referring to above-mentioned) treatment or prevention epilepsy, depression, anxiety, psychosis, faintness outbreak, hypocinesis, cranium, neurodegenerative disease, fear, pain (particularly neuropathic pain and muscle and skeleton pain), inflammatory diseases (being arthritis), insomnia, gastrointestinal disease and ethanol withdrawal symptom.Therefore, those skilled in the art can analyze and use that chemical compound of the present invention and/or compositions are unusual with treatment or prevention epilepsy, depression, anxiety, psychosis, faintness outbreak, hypocinesis, cranium, neurodegenerative disease, fear, pain (particularly neuropathic pain and muscle and skeleton pain), inflammatory diseases (being arthritis), insomnia, gastrointestinal disease and ethanol withdrawal symptom.

4.5 treatment/prevention administration

Chemical compound of the present invention and/or compositions can be advantageously used in people's medical science.As with as described in the top 4.4, chemical compound of the present invention or compositions be used for the treatment of or prevent that epilepsy, depression, anxiety, psychosis, faintness outbreak, hypocinesis, cranium are unusual, neurodegenerative disease, fear, pain (particularly neuropathic pain and muscle and skeleton pain), inflammatory diseases (being arthritis), insomnia, gastrointestinal disease or ethanol withdrawal symptom.

Chemical compound of the present invention or compositions can single, the co-administered or application with other reagent when being used for the treatment of or prevent above-mentioned disease or disease.Chemical compound of the present invention and/or compositions can also be single, with other pharmaceutically active agent, comprise that other chemical compound of the present invention is co-administered or use.

The invention provides by compositions of the present invention of giving patient's administering therapeutic effective dose or the method that chemical compound is treated and prevented.Described patient can be an animal, and more preferably mammal most preferably is the people.

Chemical compound of the present invention or compositions comprise one or more chemical compounds of the present invention, preferably carry out oral.Chemical compound of the present invention and/or compositions can also be passed through other conventional route administration, for example by inculcating or pill injection, carry out administration by epithelium or mucosa and skin lining (for example oral mucous membrane, rectum and intestinal mucosa etc.).Administration can be to be administered systemically or topical.Multiple delivery system is known can be used to use chemical compound of the present invention and or the delivery system (for example capsule Bao Shu is in liposome, microgranule, microcapsule, capsule etc.) of compositions.Medication includes but not limited in Intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, mouth, Sublingual, intranasal, the brain, intravaginal, transdermal, rectum, suction or topical, especially ear, nose, eye or skin is carried out administration.

In particularly preferred embodiments, chemical compound of the present invention and/or compositions can be passed through sustained release system, and the preferred oral sustained release system is sent.In one embodiment, can use pump (referring to Langer, supra; Sefton, 1987, CRC Crit Ref BiomedEng.14:201; People such as Saudek, 1989, N.Engl.J Med.321:574).

In another embodiment, can use polymeric material (referring to " MedicalApplications of Controlled Release (controlled release pharmaceutical application), " Langer and Wise (eds.), CRC Pres., Boca Raton, Florida (1974); " Controlled Drug Bioavailability (controlled drug bioavailability), " Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J Macromol.Sci.Rev.Macromol Chem.23:61; Also referring to people such as Levy, 1985, Science 228:190; People such as During, 1989, Ann.Neurol.25:351; People such as Howard, 1989, J.Neurosurg.71:105).In a preferred embodiment, polymeric material is used for oral lasting release delivery.Preferred polymer comprises sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose and hydroxyethyl-cellulose (most preferably HYDROXY PROPYL METHYLCELLULOSE).Other preferred cellulose ether is described (Alderman, Int.J.Pharm.Tech.﹠amp; Prod.Mfr., 1984,5 (3) 1-9).The factor that influences drug release it is known to the person skilled in the art that and describe (people such as Bamba, Int.J.Pharm., 1979,2,307) in the art.

In another embodiment, the casing preparation can be used for oral sustained release administration.Preferred coating material comprises the polymer with the stability (being the release of pH control) that depends on pH, the polymer that has slowly or depend on expansion, dissolving or the erosion rate (being the release of time control) of pH, by the polymer and the polymer that forms the destroyed thin layer (being the pressure sustained release) by supercharging of enzymatic degradation (being that the enzyme controlled release is put).

In another embodiment, with osmotic delivery system be used for oral release administration (people such as Verma, Drug Dev.Ind.Pharm., 2000,26:695-708).In a preferred embodiment, with OROS ^TMPermeability apparatus is used for oral lasting release delivery device (people such as Theeuwes, United States Patent (USP) 3,845,770; People such as Theeuwes, United States Patent (USP) 3,916,899).

In another embodiment, controlled release system can be placed near the target body of chemical compound of the present invention and/or compositions, thereby only need part system dosage (for example referring to Goodson, in " Medical Applications of Controlled Release (medical application of controlled release); " supra, vol.2, pp.115-138 (1984)).Can also be applied in Langer, 1990, other controlled release system described in the Science 249:1527-1533.

Chemical compound of the present invention and/or compositions preferably provide GABA analog (for example gabapentin and pregablin) when the patient is carried out vivo medicine-feeding.Though be not intended to bound by theory, the primitive of chemical compound of the present invention and/or compositions can be through chemistry and/or enzymatic lysis.One or more enzymes that exist in mammiferous stomach, enteric cavity, intestinal tissue, blood, liver, brain or any suitable tissue can enzymatic lysis chemical compound of the present invention or the primitive of compositions.Splitting mechanism is not important for the present invention.Preferably do not contain a large amount of lactams pollutant (preferably less than 0.5wt%, being more preferably less than 0.2wt%) most preferably less than 0.1wt% by the GABA analog that forms from chemical compound cracking prodrug of the present invention.The degree that is discharged the lactams pollutant by prodrug of the present invention can be used the evaluation of standard body outer analysis method.

Though be not intended to bound by theory, the primitive of chemical compound of the present invention and/or compositions can be before by gastrointestinal absorption (for example in stomach or enteric cavity) and/or after by gastrointestinal absorption (for example at intestinal tissue, blood, liver or other suitable mammiferous tissue) cleaved.If the primitive of chemical compound of the present invention is cleaved before by intestinal absorption, then the GABA analog of gained can absorb routinely and enter systemic circulation (for example by being positioned at the big neutral amino acid transporter agent of small intestinal).If the cracking after by gastrointestinal absorption of the primitive of chemical compound of the present invention, then these GABA analog prodrugs can have an opportunity by passive diffusion, active transport or carry out passive diffusion and active transport simultaneously to be absorbed and to enter systemic circulation.

If the cracking after by gastrointestinal absorption of the primitive of chemical compound of the present invention, then these GABA analog prodrugs can have an opportunity to enter systemic circulation from big intestinal absorption.In this case, chemical compound of the present invention or compositions are preferably as the sustained release system administration.In a preferred embodiment, chemical compound of the present invention or compositions are sent by oral sustained release administration.Preferably in this embodiment, chemical compound of the present invention or compositions secondary every day administration (more preferably once a day).

4.6 compositions of the present invention

Compositions of the present invention comprise the treatment effective dose one or more be preferably the chemical compound of the present invention of purified form and an amount of pharmaceutically acceptable excipient, so that suitable form of medication to be provided to the patient.When the patient was carried out administration, chemical compound of the present invention and pharmaceutically acceptable excipient were preferably aseptic.When intravenous was used chemical compound of the present invention, water was a kind of preferred excipient.Can also be with saline solution and dextrose and glycerine water solution as liquid excipient, especially for injection.Suitable pharmaceutical excipient also comprises such as following excipient: starch, glucose, lactose, sucrose, gelatin, Fructus Hordei Germinatus, rice, flour, Chalk, silica gel, sodium stearate, glyceryl monostearate, Talcum, sodium chloride, anhydrous skimmed milk, glycerol, propylene glycol, water, ethanol etc.If necessary, compositions of the present invention can also comprise a spot of wetting agent and emulsifying agent or pH buffer agent.In addition, can make used additives, stabilizing agent, thickening agent, lubricant and coloring agent.

In one embodiment, compositions of the present invention does not contain the lactams by-product that forms by intramolecular cyclization.In a preferred embodiment, compositions of the present invention is stable for long term storage (being preferably greater than 1 year) also, can't form a large amount of lactams (preferably be less than the 0.5wt% lactams,, most preferably be less than the 0.1wt% lactams) more preferably less than the 0.2wt% lactams.

Contain chemical compound of the present invention pharmaceutical composition can by the mixing of routine, dissolving, granulation, system dragee, grinding, emulsifying, encapsulated, hold back (entrapping) or freeze drying process preparation.Described pharmaceutical composition can be conventional mode, use one or more physiologys to go up acceptable carrier, diluent, excipient or auxiliary agent preparation, thus help with chemical compound of the present invention make can be medicinal preparation.Suitable preparation depends on selected route of administration.

The dosage form of compositions of the present invention can be solution, suspension, emulsion, tablet, pill, pill, capsule, the capsule that contains liquid, powder, extended release preparation, suppository, emulsion, aerosol, spray, suspension or any form that other is suitable for using.In one embodiment, pharmaceutically acceptable excipient is capsule (for example referring to people such as Grosswald, United States Patent (USP) 5,698,155).The example of other appropriate drug excipient is described in this area (referring to Remington ' s Pharmaceutical Sciences (Remington pharmaceutical science), Philadelphia College of Pharmacy and Science (Philadelphia materia medica and science institute), the 17th edition, 1985).Preferred preparation of compositions of the present invention is used for oral delivery, especially for oral sustained release administration.

For example, the compositions of oral delivery can be tablet, lozenge, moisture or contain oil suspensions, granule, powder, emulsion, capsule, syrup or elixir.Orally administered composition can comprise one or more optional reagent, and for example sweeting agent such as fructose, aspartame or glucide, flavoring agent such as Herba Menthae, wintergreen oil or Fructus Pruni pseudocerasi coloring agent and antiseptic are to provide pharmaceutically good to eat preparation.And under the situation of tablet or pill, described compositions coating can be degraded and absorption at gastrointestinal tract with delay, thereby secular continuous action is provided.The selectively penetrating film that surrounds osmotically active driving chemical compound also is applicable to the chemical compound of the present invention and the compositions of oral administration.In these platforms afterwards, be driven chemical compound from the liquid of capsule surrounding and absorb, described chemical compound expands to replace reagent or reagent composition by the aperture.These delivery platforms are compared with the cone shaped pattern of instant speed preparation can provide zero level delivery curves basically.Can also use time-delay material such as glyceryl monostearate or tristerin.Orally administered composition can comprise standard excipients such as mannitol, lactose, starch, magnesium stearate, saccharin sodium, cellulose, magnesium carbonate etc.These excipient are preferably pharmaceutical grades.

For oral liquid, for example suspension, elixir and solution, suitable carrier, excipient or diluent comprise subacidity buffer agent between water, saline, alkylene glycol (for example propylene glycol), ployalkylene glycol (for example Polyethylene Glycol) oil, alcohol, pH4 and the pH6 (for example approximately 5mM to approximately acetate, citrate, the Ascorbate of 50mM) etc.In addition, can add flavoring agent, antiseptic, coloring agent, cholate, acyl group endogenous toxin alkali etc.

It is also conceivable that by other approach compositions is carried out administration.For the cheek administration, the dosage form of compositions can be with the tablet of conventional method preparation, lozenge etc.Be suitable for generally comprising chemical compound of the present invention and pharmaceutically acceptable excipient with the liquid pharmaceutical formulation that aerosol apparatus and liquid dispensing apparatus and EHD aerosol device are used.Preferred pharmaceutically acceptable excipient is that liquid is as alcohol, water, Polyethylene Glycol or perfluocarbon.The optional solution of another kind of substance change chemical compound of the present invention or the aerosol performance of suspension of adding.Preferred this material is that liquid is as alcohol, ethylene glycol, Polyethylene Glycol or fatty acid.Other be applicable to the preparation method of the liquid medicine solution of aerosol device or suspension be for a person skilled in the art known (for example referring to Biesalski, United States Patent (USP) 5,112,598; Biesalski, United States Patent (USP) 5,556,611).Chemical compound of the present invention can also be made rectum or vaginal compositions such as suppository or keep enema, and for example it comprises conventional suppository bases such as cupu oil or or other glyceride.Except aforesaid preparation, chemical compound of the present invention can also be made the precipitation preparation.This long term preparation can be by implanting (for example subcutaneous or intramuscular) or carrying out administration by intramuscular injection.Therefore, chemical compound for example of the present invention can prepare with suitable polymerization or hydrophobic material (for example emulsion in acceptable oil) or ion exchange resin, perhaps makes the derivant of minimal amounts of dissolved, for example the salt of minimal amounts of dissolved.

When chemical compound of the present invention was acidity, it can be used as free acid, pharmaceutically acceptable salt, solvate or hydrate and is included in any above-mentioned preparation.The activity that has kept free acid on the pharmaceutically acceptable salt base tincture, can by with alkali reaction preparation, and be tending towards more water-soluble and other proton solvent than the free acid form of correspondence.

4.7 application process and dosage

Chemical compound of the present invention or its compositions are generally used to realize the purpose of expectation with effective dose.Be used for the treatment of or prevent following application such as following disease or disease: epilepsy, depression, anxiety, psychosis, faintness outbreak, hypocinesis, cranium are unusual, neurodegenerative disease, fear, pain (particularly neuropathic pain and muscle and skeleton pain), inflammatory diseases (being arthritis), insomnia, gastrointestinal disease or ethanol withdrawal symptom, and chemical compound of the present invention or its compositions are used or used with the treatment effective dose.

Quantity for the treatment of the chemical compound of the present invention of specified disease or disease effectively disclosed herein depends on the character of disease or disease, and can be determined by aforesaid standard clinical techniques as known in the art.In addition, external or in vivo test can be chosen wantonly and be used for helping to identify the optimal dose scope.The administration quantity of chemical compound of the present invention depends on experimenter, the experimenter's of treatment weight, the ailing order of severity, administering mode and prescriber's judgement certainly.

For example, can by single administration, repeatedly application or controlled release and in pharmaceutical composition dosage delivered.In a preferred embodiment, chemical compound of the present invention is sent by oral sustained release administration.Preferably in this embodiment, chemical compound of the present invention is used secondary (more preferably once a day) every day.Dosage can repeat discontinuously, can be separately or unite with other medicines and to provide, and can continuous and effective ground treatment disease or the required time span of disease.

Suitable oral dose scope depends on the effectiveness of parent GABA analog medicine, but is generally about 0.001mg to about 200mg chemical compound/kg body weight of the present invention.When the GABA analog was gabapentin, the daily dose of typical adult's parent drug was 900mg/ days to 3600mg/ days, and the dosage of gabapentin prodrug can be adjusted to the gabapentin that equimolar amounts is provided.Other GABA analog can be more more effective than gabapentin (for example pregabalin), and be (the measuring on equimolar basis) that suits than low dosage to parent drug and any prodrug.Can easily determine dosage range by method known to those skilled in the art.

Chemical compound of the present invention preferably carried out the test of goal treatment in vitro and in vivo or prophylactic activity before being used for the people.For example, in vitro tests can be used for determining whether the administration of specific compound of the present invention or compound compositions of the present invention is preferred for reducing convulsions.Use animal model system can also prove that chemical compound of the present invention is effective and safe.

The chemical compound as herein described of the present invention of preferred therapeutic effective dose will provide the treatment benefit not cause toxicity simultaneously basically.The toxicity of chemical compound of the present invention can use standard pharmaceutical procedures to measure, and can easily be determined by those skilled in the art.Toxicity is therapeutic index with the dosage ratio of therapeutical effect.Chemical compound of the present invention preferably shows extra high treatment disease and treatment of conditions index.

The dosage of chemical compound of the present invention as herein described is comprising within the circulation composition scope that has a small amount of toxicity or do not have toxic effective dose.

4.8. therapeutic alliance

In certain embodiments of the invention, chemical compound of the present invention can be used for therapeutic alliance with at least a other therapeutic agent.Chemical compound of the present invention and therapeutic agent can play adduction, more preferably synergism.In a preferred embodiment, contain the administration simultaneously of compound compositions of the present invention and other therapeutic agent, described therapeutic agent can be the same with chemical compound of the present invention as the part of compositions or as different compositionss.In another embodiment, comprising compound compositions of the present invention can administration before or after another kind is treated administration.

5. embodiment

Further define the present invention with reference to following examples, described embodiment describes the application test of describing chemical compound of the present invention and preparation of compositions and chemical compound of the present invention and compositions in detail.Those skilled in the art can obviously find out under the situation that does not deviate from protection scope of the present invention can implement multiple remodeling to raw material and method.

In following embodiment, following abbreviation has following implication.If not definition abbreviation, then it has its implication of accepting usually.

AIBN=2,2 '-azo two (isopropyl cyanide)

Atm=atmospheric pressure

Boc=tert-butoxy carbonyl

Cbz=benzyloxy (carbobenzyloxy)

CPM=count per minute

DCC=dicyclohexyl carbodiimide

DMAP=4-N, the N-dimethyl aminopyridine

DMEM=limit eagl e culture medium

DMF=N, dinethylformamide

DMSO=dimethyl sulfoxine

Fmoc=9-fluorenylmethyloxycarbonyl

G=gram

H=hour

HBSS=Hanks buffer salt solution

L=liter

LC/MS=liquid chromatography/mass spectrometry

M=mole

Min=minute

Ml=milliliter

Mmol=mM

NBS=N-bromine butanimide

NHS=N-hydroxy-succinamide

PBS=phosphate buffered saline (PBS)

THF=oxolane

TFA=trifluoroacetic acid

TMS=trimethyl silyl

μ L=microlitre

μ M=micromole

V/v=volume by volume

Embodiment 1

1-{[(α-new pentane acyloxy methoxyl group) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (51)

Steps A: P-nitrophenyl carbonic acid chloromethyl ester (52)

(100g 0.72moles) is dissolved in anhydrous tetrahydro furan (3L) and vigorous stirring with paranitrophenol.(70mL 0.79moles), adds triethylamine (110mL) then to add chloro-methyl-chloroformate toward this solution under the room temperature.After stirring 1h, reactant mixture is filtered and filtrate is concentrated, use ethyl acetate (1L) dilution then.With 10% potassium carbonate (3 * 500mL) and 1NHCl (2 * 300mL), (2 * 300mL) washing organic solutions and are used anhydrous sodium sulfate drying to saline.Remove the title compound (52) that desolvates and obtain 157g (95%), be a kind of solid.Described chemical compound is to the LC-MS instability. ¹H NMR(CDCl ₃，400MHz)：5.86(s，2H)，7.44(d，J＝9Hz，2H)，8.33(d，J＝9Hz，2H)。

Step B: P-nitrophenyl carbonic acid iodine methyl ester (53)

Under blanket of nitrogen with p-nitrophenyl carbonic acid chloromethyl ester (52) (100g, 0.43moles), sodium iodide (228g, 1.30moles) and the anhydrous molecular sieve of 50g (4 ) be added to 2L acetone, carry out mechanical agitation simultaneously.Under 40 ℃, the mixture of gained stirred 5h (by ¹H NMR monitoring).When stirring is finished, the solids removed by filtration material, and under reduced pressure remove and desolvate.Residue is dissolved in dichloromethane (1L) again and washs secondary with saturated aqueous sodium carbonate (300mL), water (300mL) washing then.Separate organic layer and use anhydrous sodium sulfate drying.Removing the title compound (53) that desolvates and obtain 123.6g (89%), is a kind of solid when leaving standstill.Find that described chemical compound is to the LC-MS instability. ¹H NMR(CDCl ₃，400MHz)：6.06(s，2H)，7.42(d，J＝9Hz，2H)，8.30(d，J＝9Hz，2H). ¹³C NMR(CDCl ₃，100MHz)：155.1，151.0，146.0，125.8，125.7，121.9，33.5。

Step C: Trimethylace tonitric silver (54)

With neopentanoic acid (50g 0.49moles) is dissolved in acetonitrile (1.3L), add then silver oxide (70g, 0.29moles), and vigorous stirring.Under blanket of nitrogen, add 660mL water then.The suspension of gained is in the dark stirred 1h under 70 ℃.After the filtration of celite filter bed, remove the title compound (54) that desolvates and obtain 86g (82%), be a kind of pale solid, it is used for next step reaction without being further purified.Prepare other silver salt described in the application according to similar method.

Step D: Oxy acid methyl neopentyl carbonic acid p-nitrophenyl ester (55)

To the p-nitrophenyl carbonic acid iodine methyl ester (53) in dry toluene (1L) (62g, 0.19moles) solution add trimethylace tonitric silver (80g, 0.38moles).After under 55 ℃ and blanket of nitrogen, stirring 3h, reactant mixture is cooled to room temperature, and filters with the celite filter bed.With 10% potassium carbonate (500mL) wash filtrate.Remove the title compound (55) that desolvates and obtain 43g (75%), be a kind of xanchromatic oil. ¹H NMR(CDCl ₃，400MHz)：1.25(s，9H)，5.88(s，2H)，7.40(d，J＝9Hz，2H)，8.29(d，J＝9HZ，2H). ¹³CNMR(CDCl ₃，100MHz)：177.0，155.3，151.6，145.8，125.6，121.9，83.1，39.1，27.0。

Step e: 1-{[(α-new pentane acyloxy methoxyl group) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid

(51)

In anhydrous methylene chloride (100mL) with the gabapentin free alkali (24g, 0.14moles) slurrying, use respectively then the chlorine trimethyl silane (18.6mL, 0.28moles) and triethylamine (10mL 0.15moles) handles.With the suspension heating of gained, and be stirred to any solid dissolving fully of realization.Add funnel by balanced (equalizing) above gabapentin solution is added to slow backflow, and under blanket of nitrogen oxy acid methyl neopentyl carbonic acid p-nitrophenyl ester (the 55) (20g of mechanical agitation in dichloromethane (100mL), 67mmol) and triethylamine (10mL, solution 0.15moles).The yellow solution of gained is stirred 1.5h.(by 1,2,3-indantrione monohydrate dyeing monitoring) filtered mixture, and filtrate concentrated when stirring was finished.Residue is dissolved in ethyl acetate (500mL), with 1N HCl (3 * 100mL), saline (2 * 100mL) washings, and use anhydrous sodium sulfate drying.Except that after desolvating, crude product is dissolved in ethanol (300mL), add 1g 5%Pd/C then.The mixture of gained was stirred 15 minutes under the 50psi hydrogen atmosphere, filter with the celite filter bed then.After concentrating, residue is dissolved in ethyl acetate, uses 5%H ₂SO ₄Washing, and use anhydrous sodium sulfate drying.Under reduced pressure remove desolvate after, with silica gel residue is carried out chromatogram purification (4: 1 hexanes: ethyl acetate) obtain the title compound (51) of 15g (68%), be a kind of solid.M.p.：79-81℃； ¹HNMR(CDCl ₃，400MHz)：1.21(s，9H)，1.3-1.5(m，10H)，2.32(s，2H)，3.26(s，2H)，5.33(M，1H)，5.73(s，2H). ¹³C NMR(CDCl ₃，400MHz)：21.7，26.2，27.3，34.3，38.2，39.2，80.6，155.9，176.8，178.0.MS(ESI)m/z 328.36(M-H) ^-，330.32(M+H) ⁺，352.33(M+Na) ⁺。

Embodiment 2

1-{[(α-acetate ethyoxyl) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (56)

Steps A: 1-chloroethyl-p-nitrophenyl carbonic ester (57)

To ice-cold contain paranitrophenol in dichloromethane (60mL) (1.39g, 10mmol) and pyridine (0.81g, reactant mixture 10mmol) add chloro-carbonic acid 1-chloroethene ester (1.2mL, 11mmol).Mixture was stirred 30 minutes down in 0 ℃, at room temperature stir 1h then.Under reduced pressure, residue is dissolved in ether, water, 10% citric acid and water washing except that after desolvating.Use Na ₂SO ₄Dry ether layer, and vapourisation under reduced pressure obtains the title compound (57) of 2.4g (97%), is a kind of beige solid. ¹H NMR(CDCl ₃)：1.93(d，3H)，6.55(q，1H)，7.42(d，2H)，8.28(d，2H)。

Step B: α-acetate ethyl-p-nitrophenyl carbonic ester (58)

Will the 1-chloroethyl in the acetic acid (15mL)-p-nitrophenyl carbonic ester (57) (0.5g, 2mmol) and mercuric acetate (1.5g, mixture 4.4mmol) stirs 24h under room temperature.After under reduced pressure removing acetic acid, residue is dissolved in ether, and water, 0.5% (v/v) NaHCO ₃Aqueous solution and water washing.Use Na ₂SO ₄Dry ether layer, and be concentrated into dried.Handle the residue (hexane: ethyl acetate (95: 5)) obtain the title compound (58) of 0.45g (84%) of gained with silica gel chromatography. ¹H NMR(CDCl ₃，400MHz)：1.55(d，J＝5.6Hz，3H)，2.07(s，3H)，6.78(q，J＝5.6Hz，1H)，7.36(d，J＝9.6Hz，2H)，8.22(d，J＝9.6Hz，2H)。

Step C: 1-{[(α-acetate ethyoxyl) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (56)

To contain gabapentin in dichloromethane (20mL) (633mg, 3.7mmol) and triethylamine (1.03mL, mixture 7.4mmol) add trim,ethylchlorosilane, and (0.93mL 7.4mmol), and stirs mixture until forming clear solutions.Add the α-acetate ethyl-p-nitrophenyl carbonic ester (58) contain in dichloromethane (10mL) (1g, solution 3.7mmol), and the mixture of gained stirred 30 minutes.With 10% citric acid (20mL) washing reaction mixture, and separate organic layer.(3 * 10mL) extract water-bearing layers, and use MgSO further to use ether ₄The dry organic extract that merges.After the filtration, under reduced pressure remove organic solvent.Handle the residue (hexane: ethyl acetate (4: 1)) obtain the title compound (56) of 700mg (63%) of gained with silica gel chromatography. ¹H NMR(CDCl ₃，400MHz)：1.27-1.60(m，10H)，1.55(d，3H)，2.08(s，3H)，2.38(s，2H)，3.25(m，2H)，5.31(t，1H)，6.81(q，1H).MS(ESI)m/z 302.22(M+H) ⁺。By water-soluble (5mL), add the 0.5N NaHCO of equimolar amounts ₃, lyophilizing and be corresponding sodium salt then with sour form Quantitative yield.

Embodiment 3

1-{[(α benzoyloxy benzyloxy) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (59)

Steps A: α-benzoyl benzyl carbonic acid p-nitrophenyl ester (60)

Under the room temperature at 60mL CH ₂Cl ₂In Benzoinum (2.0g, solution 9.4mmol) add respectively DMAP (1.21g, 9.9mmol) and p-nitrophenyl-chloro-formate (1.99g, 9.9mmol).After stirring 3h under the room temperature, the water cessation reaction, and with ethyl acetate/hexane (2 * 100mL) extract.Organic extract with the anhydrous sodium sulfate drying merging.Under reduced pressure removing desolvates obtains title compound (60), and it is purified and be used for next step reaction.

Step B:1-{[(α-benzoyl benzyloxy) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid

(61)

Under 0 ℃ at CH ₂Cl ₂In gabapentin (1.70g, 9.9mmol) suspension add triethylamine (2.76mL, 19.8mmol) and TMSCl (2.51mL, 19.8mmol).Under the room temperature reactant was stirred 30 minutes.In this mixture, be added in CH ₂Cl ₂In chemical compound (60) (in above steps A, preparing), and the mixture of gained stirred 5h under room temperature.Use the dichloromethane diluted reaction mixture, use the salt water washing, and use Na ₂SO ₄Dry organic layer.Under reduced pressure,, be used in CH with silica gel chromatography purification residue except that after desolvating ₂Cl ₂In 5% methanol-eluted fractions obtain the title compound (61) of 3.78g (90%, through two step). ¹H NMR(CDCl ₃，400MHz)：δ1.48-1.35(m，10H)，2.30(s，2H)，3.24(d，J＝7.2Hz，2H)，5.58(t，J＝6.8Hz，1H)，6.85(s，1H)，7.50-7.33(m，8H)，7.93(d，J＝7.2Hz，2H)。

Step C: 1-{[(α-benzoyloxy benzyloxy) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid

(59)

Under the room temperature at 40mLCH ₂Cl ₂In 1-{[(α-benzoyl benzyloxy) carbonyl] amino methyl-1-Cyclohexaneacetic acid (61) (1.89g, solution 4.6mmol) add respectively 77%mCPBA (2.07g, 9.2mmol) and NaHCO ₃(O.78g, 9.2mmol), and the mixture of gained stirred under room temperature spend the night.With 10% citric acid acidify reactant mixture, and use CH ₂Cl ₂Extraction.With salt water washing organic extract, and use Na ₂SO ₄Dry.Decompression by anti-phase preparation HPLC (acetonitrile-water, 0.1% formic acid) purification residue, obtains the title compound (59) of 960mg (49%) after removing down and desolvating. ¹H NMR(CDCl ₃，400MHz)：δ1.58-1.35(m，LOH)，2.34(s，2H)，3.26(dd，J＝6.8，0.8Hz，2H)，5.38(t，J＝6.8Hz，1H)，7.46-7.26(M，5H)，7.63-7.55(M，3H)，7.89(s，1H)，8.08(dd，J＝8.8，1.2Hz，2H)。

Embodiment 4

1-{[(α-acetate benzyloxy) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (62)

According to the method for embodiment 3, and replace Benzoinum, obtain the title compound (62) of 300mg with 1-hydroxyl-1-phenyl-third-2-ketone. ¹H NMR(CDCl ₃，400MHz)：δ1.41(m，10H)，2.19(s，3H)，2.33(s，2H)，3.27(dd，J＝6.6，1.6Hz，2H)，5.36(t，J＝6.6Hz，1H)，7.40(M，3H)，7.52(M，2H)，7.63(s，1H)。

Embodiment 5

1-{[(α-benzoyloxy ethyoxyl) carbonylamino methyl }-1-Cyclohexaneacetic acid (63)

According to the method for embodiment 3, and replace Benzoinum, be able to the title compound (63) of 5mg with 2-hydroxyl-1-phenyl-1-acetone. ¹H NMR(CDCl ₃，400MHz)：δ1.44-1.36(m，10H)，1.62(d，J＝5.6Hz，3H)，2.34(s，2H)，3.24(d，J＝6.8Hz，2H)，5.28(t，J＝6.8Hz，1H)，7.06(q.J＝5.6Hz，1H)，7.44(M，2H)，7.56(M，1H)，8.03(dd，J＝8.4，1.6Hz，2H)。

Embodiment 6

1-{[(1-benzoyloxy-2-phenyl ethoxy) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid

(64)

Steps A: 2-phenyl-1,3-dithiane (65)

Under the room temperature at CH ₂Cl ₂(10.6g, 100mmol) with 1, the solution of 3-propane two mercaptan drips BF to benzaldehyde (150mL) ₃With Et ₂(6.3mL, 50mmol) mixture with gained stirs 2h to O under room temperature.Use CH then ₂Cl ₂Diluted reaction mixture filters and with saline, saturated NaHCO ₃, the saline wash filtrate, and use Na ₂SO ₄Dry.Under reduced pressure removing desolvates obtains-kind of white solid, with the mixture of 1: 1 ether and hexane its recrystallization is obtained the title compound (65) of 17.0g (87%), is the white crystals pin. ¹H NMR(CDCl ₃，400MHz)：δ1.91(M，1H)，2.14(M，1H)，2.89(M，2H)，3.04(M，2H)，5.16(s，1H)，7.35-7.28(M，3H)，7.46(M，2H)。

Step B: 2-phenyl-1-(2-phenyl-[1,3]-dithiane-2-yl)-ethanol (66)

To the 2-phenyl-1 in THF, (4.0g, solution 20.4mmol) are added in THF (15.3mL, 24.4mmol) solution of the 1.6M n-BuLi in to 3-dithiane (65) under-30 ℃.After stirring 30 minutes under-30 ℃, at-30 ℃ of phenyl acetyl aldehyde (2.45g, solution 20.4mmol) that drip down in oxolane.With the reactant mixture of gained in 0 ℃ of following restir 1h.Use saturated NH ₄Cl solution cessation reaction, and use ethyl acetate extraction.Use saturated NH ₄The organic extract that Cl solution, salt water washing merge, and use Na ₂SO ₄Dry.After filtering and concentrating, obtain the title compound (66) of 2.63g (71%) by flash chromatography on silica gel method purification crude product (25% ethyl acetate in hexane). ¹H NMR(CDCl ₃，400MHz)：δ1.97(m，2H)，2.23(dd，J＝4.0，1.2Hz，1H)，2.43(dd，J＝13.6，10.2Hz，1H)，2.77(M，4H)，3.02(d，J＝13.6Hz，1H)，4.07(M，1H)，7.44-7.13(M，8H)，8.02(dd，J＝8.4，1.4Hz，2H)。

Step C: 2-hydroxyl-1,3-diphenyl-third-1-ketone (67)

To the 2-phenyl-1-in the mixture of 9: 1 acetonitrile of 100mL and water (2-phenyl-[1,3]-dithiane-2-yl)-ethanol (66) (2.50g, 7.9mmol) solution add the mercuric perchlorate hydrate (4.1g, 10.3mmol).The mixture of gained was stirred under room temperature 5 minutes, and the reaction of thin layer chromatography processes and displays is finished.With ethyl acetate diluted mixture thing, filter with the celite filter bed, use saturated NaHCO ₃, the saline wash filtrate, and use Na ₂SO ₄Dry.Under reduced pressure remove and desolvate, and obtain the title compound (67) of 1.32g (74%) by flash chromatography on silica gel method purification crude product (20% ethyl acetate in hexane). ¹H NMR(CDCl ₃，400MHz)：δ2.90(dd，J＝14.4，7.0Hz，1H)，3.20(dd，J＝14.4，4.0Hz，1H)，3.70(d，J＝6.8Hz，1H)，5.35(M，1H)，7.28-7.11(M，5H)，7.53(m，2H)，7.65(M，1H)，7.93(d，J＝7.2HZ，2H)。

Step D: 1-{[(1-benzoyloxy-2-phenyl ethoxy) carbonyl] amino methyl }-the 1-hexamethylene

Alkane acetic acid (64)

According to the method for embodiment 3, and with 2-hydroxyl-1,3-diphenyl-third-1-ketone replaces Benzoinum, obtains the title compound (64) of 181mg. ¹H NMR(CDCl ₃，400MHz)：δ1.45-1.29(m，10H)，2.24(d，J＝13.6Hz，1H)，2.28(d，J＝13.6Hz，1H)，3.22(M，4H)，5.26(t，J＝6.6Hz，1H)，7.16(t，J＝5.6Hz，1H)，7.33-7.25(M，5H)，7.40(M，2H)，7.57(m，1H)，8.02(M，2H)。

Embodiment 7 1-{[(1-(3-methylbutyryl oxygen base)-2-phenyl ethoxy) carbonyl] amino first

Base }-1-Cyclohexaneacetic acid (68)

According to the method for embodiment 6, and replace benzaldehyde in the steps A, obtain the title compound (68) of 95mg with 3-methyl butyraldehyde. ¹H NMR(CDCl ₃，400MHz)：δ0.88-0.90(M，6H)，1.16-1.29(m，10H)，2.06(M，1H)，2.16(M，2H)，2.26(M，2H)，3.08(d，J＝6.8Hz，2H)，3.19(M，2H)，5.22(t，J＝6.8Hz，1H)，6.93(t，J＝6Hz，1H)，7.31-7.23(M，5H)。

Embodiment 8

1-{[(α-benzoyloxy butoxy) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (69)

According to the method for embodiment 6, and replace phenyl acetaldehyde among the step B, obtain the title compound (69) of 240mg with butyraldehyde. ¹H NMR(CDCl ₃，400MHz)：δ0.99(t，J＝7.6Hz，3H)，1.52-1.38(M，12H)，1.89(M，2H)，2.31(s，2H)，3.24(M，2H)，5.34(t，J＝6.6Hz，1H)，6.70(t，J＝5.6Hz，1H)，7.42(M，2H)，7.56(M，1H)，8.04(M，2H)。

Embodiment 9

1-{[(α-acetate butoxy) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (70)

According to the method for embodiment 6, and replace the benzaldehyde in the steps A and replace phenyl acetaldehyde among the step B with acetaldehyde respectively, obtain the title compound (70) of 42mg with butyraldehyde. ¹HNMR(CD ₃OD，400MHz)：δ0.95(M，3H)，1.52-1.31(M，12H)，1.72(M，2H)，2.02(s，3H)，2.27(s，2H)，3.20(s，2H)，6.67(t，J＝5.6Hz，1H)。

Embodiment 10

1-{[(α-butyryl acyloxy butoxy) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (71)

According to the method for embodiment 3, and replace Benzoinum, obtain the title compound (71) of 210mg with butyroin. ¹H NMR(CDCl ₃，400MHz)；80.93(M，6H)，1.37-1.76(M，16H)，2.30(M，4H)，3.23(M，2H)，5.25(broad triplet，1H)，6.73(M，1H).MS(ESI)m/z 356.45(M-H) ⁺。

Embodiment 11

1-{[(α-propionyloxy ethyoxyl) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (72)

Steps A: 1-iodine ethyl-p-nitrophenyl carbonic ester (73)

1-chloroethyl-p-nitrophenyl carbonic ester that will be in anhydrous propanone (0.5g, 2mmol) and NaI (0.6g, mixture 4mmol) stirs 3h down in 40 ℃.After the filtration, under reduced pressure filtrate is concentrated, be able to the title compound (73) of 480mg (72%), it is used for next step reaction without being further purified.

Step B: α-propionyloxy ethyl-p-nitrophenyl carbonic ester (74)

Will the 1-iodine ethyl in the toluene (20mL)-p-nitrophenyl carbonic ester (73) (0.51g, 1.5mmol) and silver propionate (0.54g, mixture 3mmol) stirs down 24h in 50 ℃.With the reactant mixture solids removed by filtration, and concentrated filtrate under reduced pressure.The residue of gained is carried out silica gel chromatography processing (20%CH ₂Cl ₂/ hexane is used 40%CH then ₂Cl ₂/ hexane), obtain the title compound (74) of 0.39g (92%). ¹H NMR(CDCl ₃，400MHz)：1.16(t，J＝7.6Hz，3H)，1.61(d，J＝5.6Hz，3H)，2.41(q，J＝7.6Hz，2H)，6.84(q，1H，J＝5.6Hz)，7.39(d，J＝9.2Hz，2H)，8.28(d，J＝9.2Hz，2H)。

Step C: 1-{[(α-propionyloxy ethyoxyl) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid

(72)

To the gabapentin in dichloromethane (30mL) (160mg, 2.76mmol) and triethylamine (0.77mL, 5.5mmol) mixture add trim,ethylchlorosilane, and (0.71mL 5.5mmol), and stirs the mixture of gained until forming settled solution.Be added in α-propionyloxy ethyl-p-nitrophenyl carbonic ester (74) (0.39g, solution 1.4mmol) in the dichloromethane (10mL) to above solution.Stir after 30 minutes with 10% citric acid (20mL) washing reaction mixture, and separate organic layer.(3 * 10mL) extract water-bearing layers, and use MgSO further to use ether ₄The dry organic extract that merges.After decompression removes down and desolvates, residue purified is obtained the title compound (72) of 190mg (44%) with anti-phase preparation HPLC (acetonitrile, water, 1% formic acid). ¹HNMR(CD ₃OD，400MHz)：1.09(t，J＝7.6Hz，3H)，1.36-1.54(m，10H)，1.44(d，J＝5.6Hz，3H)，2.28(s，2H)，2.31(q，J＝7.6Hz，2H)，3.22(s，2H)，6.67(q，J＝5.6Hz，1H).MS(ESI)m/z 316.25(M+H) ⁺。

Embodiment 12

1-{[(α-butyryl acyloxy ethyoxyl) carbonyl] amino methyl } Cyclohexaneacetic acid (75)

Steps A: α-butyryl acyloxy ethyl-p-nitrophenyl carbonic ester (76)

Will (1.5g, 4.5mmol) (1.3g, mixture 6.7mmol) stir 24h in oil bath under 90 ℃ with butanoic acid silver at the 1-iodine ethyl in the toluene (40mL)-p-nitrophenyl carbonic ester (73).Under reduced pressure reactant mixture is filtered and filtrate is concentrated.The residue of gained is carried out silica gel chromatography processing (20%CH ₂Cl ₂/ hexane is used 40%CH then ₂Cl ₂/ hexane), obtain the title compound (76) of 0.46g (36%). ¹H NMR(CDCl ₃，400MHz)：0.95(t，J＝7.6Hz，3H)，1.61(d，J＝5.6Hz，3H)，1.67(m.2H)，2.41(t，J＝7.6Hz，2H)，6.84(q，1H，J＝5.6Hz)，7.39(d，J＝9.2Hz，2H)，8.28(d，J＝9.2Hz，2H).MS(ESI)m/z 298.28(M+H) ⁺。

Step B: 1-{[(α-butyryl acyloxy ethyoxyl) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid

(75)

To contain gabapentin in dichloromethane (30mL) (530mg, 3.1mmol) and triethylamine (0.89mL, mixture 6.4mmol) add trim,ethylchlorosilane, and (0.83mL 6.4mmol), and stirs the mixture of gained until forming settled solution.Be added in α-butyryl acyloxy ethyl-p-nitrophenyl carbonic ester (76) in the dichloromethane (10mL) (0.46g, solution 1.6mmol), and the mixture of gained stirred 30 minutes toward this solution.With 10% citric acid (20mL) washing reaction mixture, and separate organic facies.(3 * 10mL) extractions contain water, and use MgSO further to use ether ₄The dry organic facies that merges, vacuum concentration then.The residue purified of gained is obtained the title compound (75) of 70mg (21%) by anti-phase preparation HPLC (acetonitrile, water, 1% formic acid). ¹H NMR(CD ₃OD，400MHz)：0.95(t，J＝7.6Hz，3H)，1.32-1.58(m，10H)，1.42(d，J＝5.6Hz，3H)，1.67(M，2H)，2.24(s，2H)，2.30(t，J＝7.6Hz，2H)，3.24(s，2H)，6.74(q，J＝5.6Hz，1H).MS(ESI)m/z 330.28(M+H) ⁺。

Be corresponding sodium salt by the following method with sour form Quantitative yield: water-soluble (5mL), the 0.5N NaHCO of adding equimolar amounts ₃, lyophilizing then.

Embodiment 13

1-{[(α-isobutyl acyl-oxygen base oxethyl) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (77)

According to the method for embodiment 2, and replace butanoic acid silver, obtain the title compound (77) of 70mg (21%) with isopropylformic acid. silver. ¹H NMR(CD ₃OD，400MHz)：1.12(d，J＝7.2Hz，3H)，1.14(d，J＝7.2Hz，3H)，1.32-1.58(m，10H)，1.44(d，J＝5.6Hz，3H)，2.28(s，2H)，2.56(M，1H)，3.25(m，2H)，6.73(q，J＝5.6Hz，1H).MS(ESI)m/z 330.30(M+H) ⁺。

Embodiment 14

1-{[(α-new pentane acyloxy ethyoxyl) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (78)

According to the method for embodiment 12, and replace butyrate, obtain the title compound (78) of 80mg (36%) with trimethylace tonitric silver. ¹H NMR(CDCl ₃，400MHz)：1.13(s，9H)，1.32-1.58(m，10H)，1.41(d，J＝5.6Hz，3H)，2.27(s，2H)，3.25(M，2H)，5.41(t，1H)，6.73(q，J＝5.6Hz，1H).MS(ESI)m/z344.20(M+H) ⁺。

Embodiment 15

1-{ (α-acetate isobutoxy) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (79)

According to the method for embodiment 2, and replace chloro-carbonic acid 1-chloroethene ester, obtain the title compound (79) of 212mg (38%) with chloro-carbonic acid 1-chloro-2-methyl-propyl ester. ¹H NMR(CD ₃OD，400MHz)：0.99(M，6H)，1.32-1.58(m，10H)，1.88(M，1H)，2.08(s，3H)，2.38(s，2H)，3.25(s，2H)，6.52(d，J＝4.4Hz，1H)；MS(ESI)mlz330.30(M+H) ⁺。

Embodiment 16

1-{[(α-propionyloxy isobutoxy) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (80)

According to the method for embodiment 11, and replace 1-chloroethyl-p-nitrophenyl carbonic ester, obtain the title compound (80) of 190mg (44%) with 1-chloro-2-methyl-propyl-p-nitrophenyl carbonic ester. ¹H NMR(CD ₃OD，400MHz)：0.90(d，J＝6.6Hz，3H)，0.91(d，J＝6.6Hz，3H)，0.98(T，J＝7.6Hz，3H)，1.32-1.58(m，10H)，1.83(m，1H)，2.18(s，2H)，2.28(q，J＝7.6Hz，2H)，3.25(s，2H)，6.52(d，J＝4.4Hz，1H).MS(ESI)mlz 344.34(M+H) ⁺。

Embodiment 17

1-{[(α-butyryl acyloxy isobutoxy) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (81)

According to the method for embodiment 2, and replace chloro-carbonic acid 1-chloro-ethyl ester and mercuric acetate with chloro-carbonic acid 1-chloro-2-methyl-propyl ester and butanoic acid hydrargyrum respectively, obtain the title compound (81) of 95mg (36%). ¹H NMR(CD ₃0D，400MHz)：1.12(t，J＝7.6Hz，3H)，1.13(d，J＝6.6Hz，3H)，1.14(d，J＝6.6Hz，3H)，1.32-1.58(m，10H)，1.87(m，2H)，2.22(m，1H)，2.42(s，2H)，2.46(t，J＝7.6Hz，2H)，3.44(m，2H)，6.78(d，J＝4.8Hz，1H).MS(ESI)m/z 358.30(M+H) ⁺。

Embodiment 18

1-{[(α-isobutyl acyloxy isobutoxy) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (82)

According to the method for embodiment 2, and replace chloro-carbonic acid 1-chloroethene ester and mercuric acetate with chloro-carbonic acid 1-chloro-2-methyl-propyl ester and isopropylformic acid. hydrargyrum respectively, obtain the title compound (82) of 95mg (36%). ¹H NMR(CD ₃OD，400MHz)：0.95(d，J＝7.2Hz，3H)，0.97(d，J＝7.2Hz，3H)，1.05(d，J＝6.6Hz，3H)，1.06(d，J＝6.6Hz，3H)，1.32-1.58(m，10H)，1.98(m，1H)，2.24(s，2H)，2.45(m，1H)，3.24(m，2H)，6.42(d，J＝4.8Hz，1H).MS(ESI)m/z 358.27(M+H) ⁺。

Embodiment 19

1-{[(α-new pentane acyloxy isobutoxy) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (83)

According to the method for embodiment 12, and replace 1-chloroethyl-p-nitrophenyl carbonic ester and butanoic acid silver with 1-chloro-2-methyl-propyl-p-nitrophenyl carbonic ester and trimethylace tonitric silver respectively, obtain the title compound (83) of 10mg (9%). ¹H NMR(CD ₃OD，400MHz)：0.98(d，J＝6.6Hz，3H)，0.99(d，J＝6.6Hz，3H)，1.19(s，9H)，1.32-1.58(m，10H)，2.08(m，1H)，2.28(s，2H)，3.21(m，2H)，6.49(d，1H)；MS(ESI)m/z 372.31(M+H) ⁺。

Embodiment 20

1-{[(α-benzoyloxy isobutoxy) carbonyl] aminomethyl-1,2-Cyclohexaneacetic acid (84)

According to the method for embodiment 11, and replace 1-p-nitrophenyl carbonic acid 1-chloro-ethyl ester and silver propionate with 1-chloro-2-methyl-propyl-p-nitrophenyl carbonic ester and silver benzoate respectively, obtain the title compound (84) of 109mg (40%). ¹H NMR(CD ₃OD，400MHz)：1.18(d，J＝7.2Hz，6H)，1.32-1.58(m，10H)，2.42(M，1H)，2.28(s，2H)，3.45(s，2H)，6.99(d，J＝4.8Hz，1H)，7.76(M，2H)，7.92(M，1H)，8.26(M，2H)。MS(ESI)m/z 392.22(M+H) ⁺。

Embodiment 21

1-{[(α-acetate isopropoxy) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (85)

Steps A: Isopropenyl-p-nitrophenyl carbonic ester (86)

(5.76g, 41.5mmol) (5g, mixture 41.5mmol) are added in pyridine (3.4mL, solution 42mmol) in the dichloromethane (50mL) with chloro-carbonic acid isopropenyl ester to the paranitrophenol in dichloromethane (200mL) under 0 ℃.The mixture of gained was stirred 30 minutes down in 0 ℃, at room temperature stir 1h then.Decompression is dissolved in ether with residue after removing down and desolvating, and water, 10% citric acid and wash with water once more.Use Na ₂SO ₄Dry ether layer, and vapourisation under reduced pressure obtains the title compound (86) of 8.7g (94%), this a kind of beige solid. ¹H NMR(CDCl ₃，400MHz)：2.05(s，3H)，4.81(M，1H)，4.95(d，J＝2Hz，1H)，7.42(d，J＝9.2Hz，2H)，8.28(d，J＝9.2Hz，2H)。

Step B: 2-chloro isopropyl-p-nitrophenyl carbonic ester (87)

(8.7g 39mmol) is dissolved in 4M hydrogen chloride/diox in sealed container with isopropenyl-p-nitrophenyl carbonic ester (86).Mixture is stirred 16h under room temperature.Under reduced pressure remove the title compound (87) that desolvates and obtain 10g (100%), it is used for next step reaction without being further purified. ¹H NMR(CDCl ₃，400MHz)：2.10(s，6H)，7.42(d，2H，J＝9.2Hz)，8.28(d，J＝9.2Hz，2H)。

Step C: α-acetate isopropyl-p-nitrophenyl carbonic ester (88)

Will the 2-chloro isopropyl in the dichloromethane (20mL)-p-nitrophenyl carbonic ester (87) (0.5g, 1.93mmol) and mercuric acetate (1.0g, mixture 3.13mmol) stirs 24h under room temperature.With the reactant mixture solids removed by filtration, and concentrated filtrate under reduced pressure.Handle the residue (20%CH of gained with silica gel chromatography ₂Cl ₂/ hexane is used 40%CH then ₂Cl ₂/ hexane), obtain the title compound (88) of 227mg (50%). ¹H NMR(CDCl ₃，400MHz)：1.90(s，6H)，2.07(s，3H)，7.28(d，2H，J＝9.2Hz)，8.28(d，J＝9.2Hz，2H)。

Step D: 1-{ (α-acetate isopropoxy) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (85)

Gabapentin in being included in dichloromethane (30mL) (257mg, 1.5mmol) and triethylamine (0.46mL, 3.3mmol) mixture add trim,ethylchlorosilane, and (0.38mL 3mmol), and will stir the mixture to clarification.Add the α-acetate isopropyl-p-nitrophenyl carbonic ester (88) contain in dichloromethane (10mL) (0.23g, solution 0.8mmol), and stirring 30 minutes.With saline (10mL) washing reaction mixture, and separate organic layer.(3 * 10mL) extract water-bearing layers, and use MgSO further to use ether ₄The dry organic extract that merges, vacuum concentration.With silica gel to the residue chromatography of gained (hexane: ethyl acetate (4: 1)) obtain the title compound (85) of 40mg (16%). ¹H NMR(CD ₃OD，400MHz)：1.32-1.58(m，10H)，1.80(s，6H)，2.02(s，3H)，2.27(s，2H)，3.30(s，2H).MS(ESI)m/z 316.21(M+H) ⁺。

Embodiment 22

1-{[(α-butyryl acyloxy isopropoxy) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (89)

According to the method for embodiment 21, and replace mercuric acetate, obtain the title compound (89) of 5mg (5%) with butanoic acid hydrargyrum. ¹H NMR(CD ₃OD，400MHz)：0.99(t，J＝7.6Hz，3H)，1.32-1.58(m，10H)，1.60(M，2H)，1.85(s，6H)，2.22(t，J＝7.6，2H)，2.27(s，2H)，3.20(s，2H).MS(ESI)m/z 344.24(M+H) ⁺，366.30(M+Na) ⁺。

Embodiment 23

1-{[(α-isobutyl acyloxy isopropoxy) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (90)

According to the method for embodiment 21, and replace mercuric acetate, obtain the title compound (90) of 109mg (43%) with isopropylformic acid. hydrargyrum. ¹H NMR(CD ₃OD，400MHz)：1.19(d.J＝7.2Hz，6H)，1.32-1.58(m，10H)，1.82(s，6H)，2.38(s，2H)，3.25(s，2H).MS(ESI)344.22(M+H) ⁺，366.24(M+Na) ⁺。

Embodiment 24

1-{[(α-benzoyloxy isopropoxy) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (91)

According to the method for embodiment 21, and replace mercuric acetate, obtain the title compound (91) of 170mg (58%) with mercuric benzoate. ¹H NMR(CDCl ₃，400MHz)：1.32-1.58(m，10H)，1.95(s，6H)，2.30(s，2H)，3.20(d，J＝6.8，2H)，5.41(t，J＝6.8Hz，1H)，7.40(M，2H)，7.52(m，1H)，7.98(m，2H).MS(ESI)m/z400.29(M+Na) ⁺。

Embodiment 25

1-{[(α-nicotinylsalicylic oxygen isobutoxy) carbonyl] the oxygen ylmethyl }-1-Cyclohexaneacetic acid (92)

Steps A: 1-{[(α-chlorine isobutoxy) carbonylamino methyl isophthalic acid-Cyclohexaneacetic acid (93)

To contain gabapentin in dichloromethane (150mL) (1.71g, 10mmol) and triethylamine (3.06mL, mixture 22mmol) add trim,ethylchlorosilane, and (1.4mL 11mmol), and stirs to clarify the mixture of gained (about 20 minutes).Add down the 1-chloro-2-methyl-propyl chloro-formate that contains in dichloromethane (10mL) (1.27mL, solution 11mmol), and at room temperature stirring 60 minutes at 0 ℃ then.With 10% citric acid (30mL) washing reaction mixture, and separate organic layer.(3 * 20mL) extract water-bearing layers, and use MgSO further to use ether ₄The dry organic facies that merges, vacuum concentration then.Handle residue with silica gel chromatography, use hexane: ethyl acetate (1: 4) eluting obtains the title compound of 2.37g (77%). ¹HNMR(CDCl ₃，400MHz)：δ1.04(d，J＝6.4Hz，3H)，1.06(d，J＝6.4Hz，3H)，1.36-1.53(m，10H)，2.15(M，1H)，2.34(s，2H)，3.24(M，2H)，5.39(t，1H)，6.32(d，J＝5.6Hz)，1H)。MS(ESI)m/z306.34(M+H ⁺)。

Step B: 1-{[(α-nicotinylsalicylic oxygen isobutoxy) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid

(92)

(93) that will be in acetone under the room temperature (268mg, 0.88mmol), 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU) (158 μ L, 1.01mmol) and nicotinic acid (637mg, mixture 5.2mmol) stirs 48h.After the filtration,, and, obtain the title compound of 50mg (14%) by the anti-phase residue for preparing HPLC method purification gained with the filtrate vacuum concentration. ¹HNMR(CD ₃OD，400MHz)：δ1.07(d，J＝6.8Hz，3H)，1.09(d，J＝6.8Hz，3H)，1.32-1.58(m，10H)，2.19(M，1H)，2.26(s，2H)，3.23(M，2H)，6.78(d，J＝4.8Hz，1H)，7.58(m，1H)，8.39(d，J＝6.4Hz，1H)，8.76(d，J＝4.4Hz，1H)，9.10(s，1H).MS(ESI)m/z393.42(M+H ⁺)。

Embodiment 26

1-{[(α-2,2-diethoxy propionyloxy isobutoxy) carbonyl] amino methyl }-the 1-cyclohexane extraction

Acetic acid (94)

Steps A: 1-{[(α-chlorine isobutoxy) carbonyl] amino methyl }-1-Cyclohexaneacetic acid benzyl ester

(95)

To (93) in dichloromethane (1.02g, 3.34mmol) solution adds 1, the 3-dicyclohexyl carbodiimide (758mg, 3.67mmol).Stir under the room temperature after 30 minutes, add benzylalcohol (380 μ L, 3.67mmol) and 4-(dimethylamino) pyridine (catalytic amount).The mixture of gained is stirred 16h under room temperature.After the filtration,, use Na with 10% citric acid wash filtrate ₂SO ₄Dry and concentrated.Handle residue with silica gel chromatography, obtain the title compound of 820mg (62%) with 10% ethyl acetate/hexane eluting. ¹H NMR(CDCl ₃，400MHz)：δ1.03(d，J＝6.4Hz，3H)，1.05(d，J＝6.4Hz，3H)，1.36-1.53(m，10H)，2.13(M，1H)，2.35(s，2H)，3.22(M，2H)，5.11(s，2H)，5.49(t，1H)，6.32(d，J＝4.8Hz)，1H)，7.34(m，5H).MS(ESI)m/z396.24(M+H ⁺)。

Step B: 2,2-diethoxy propanoic acid caesium (96)

In the solution of 14mL (0.2mol) acetone acid that stirs and 80ml triethyl orthoformate, add the 1mL concentrated sulphuric acid under 10 ℃.The mixture of gained is stirred 1h under 5-10 ℃, then with the dilution of 200mL dichloromethane.Continuously water (3 * 80mL) and saturated nacl aqueous solution (80mL) washing organic solution, use anhydrous sodium sulfate drying then.Mixture is filtered, concentrate and obtain 2 of quantitative yield, 2-diethoxy propanoic acid is a kind of oil. ¹H NMR(CDCl ₃，400MHz)：δ1.30(t，6H)，1.61(s，3H)，3.57(q，4H)，8.62(s，1H)。By the following method sour form Quantitative yield is become its cesium salt:, handle lyophilizing subsequently with the cesium carbonate of equimolar amounts then with acid water-soluble (25mL). ¹H NMR(D ₂O，400MHz)：δ0.98(t，6H)，1.28(s，3H)，3.22(q，2H)，3.47(q，2H)。

Step C: 1-{[(α-2,2-diethoxy propionyloxy isobutoxy) carbonyl] amino first

Base }-1-Cyclohexaneacetic acid benzyl ester (97)

(95) that will be in acetone under the room temperature (200mg, 0.51mmol) and sodium iodide (114mg, mixture 0.76mmol) stirs 1h.Add 2,2-diethoxy propanoic acid caesium (96) (300mg, 1.02mmol) and DMF (20mL), and with the mixture of gained in 40 ℃ of stirring 18h down.After the filtration, filtrate concentrated and with the residue of silica gel flash column chromatography purification gained, obtain the title compound of 100mg (37%) with 10% ethyl acetate/hexane eluting.MS(ESI)m/z522.34(M+H ⁺)。

Step D: 1-{[(α-2,2 diethoxy propionyloxy isobutoxy) carbonyl] amino first

Base }-1-Cyclohexaneacetic acid (94)

Under nitrogen atmosphere and the room temperature with (97) (200mg, 0.38mmol) and the mixture of 5%Pd-C (catalytic amount) stir 16h.After the filtration, filtrate is concentrated, and obtain the title compound of 98mg (60%) by the residue of anti-phase preparation HPLC method purification gained. ¹H NMR(CDCl ₃，400MHz)：δ0.97(D，J＝6.8Hz，6H)，1.19(t，J＝6.4Hz，3H)，1.21(t，J＝6.4Hz，3H)，1.32-1.58(m，10H，)，1.51(s，3H)，2.06(M，1H)，2.30(s，2H)，3.23(M，2H)，3.46(M，2H)，3.56(M，2H)，5.30(t，1H，NH)，6.59(d，J＝4.8Hz，1H).MS(ESI)m/z 432.24(M+H ⁺)。

Embodiment 27

1-{[(α-(2-amino-2-methyl propiono) oxygen isobutoxy) carbonyl] amino methyl }-the 1-ring

Hexane acetic acid (98)

According to the method for embodiment 26, and replace 2 with 2-amino-2-methyl propanoic acid, 2-diethoxy propanoic acid obtains title compound. ¹H NMR(CDCl ₃，400MHz)：δ0.97(d，J＝6.8Hz，6H)，1.44(s，3H)，1.45(s 3H)，1.32-1.58(m，10H，)，2.05(M，1H)，2.30(s，2H)，3.23(m，2H)，5.50(t，1H，NH)，6.58(d，J＝4.8Hz，1H).MS(ESI)m/z 373.48(M+H ⁺)。

Embodiment 28

1-{[(α-isobutyl acyloxy butoxy) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (99)

Steps A: 2-isopropyl-1,3-dithiane (100)

Under 0 ℃ to the isobutylaldehyde in dichloromethane (9.1mL, 100mmol) and 1, the 3-propane diol (10mL, add in mixture 100mmol) boron trifluoride Anaesthetie Ether compound (6.4mL, 50mmol).The mixture of gained was stirred 30 minutes down in 0 ℃, and under room temperature, stirred 30 minutes.With saline, 5%NaHCO ₃Use saline washing reaction mixture once more.Separate organic facies, and use Na ₂SO ₄Drying concentrates the title compound that obtains 16g (100%) then, is a kind of yellow liquid.Bring it into next step without being further purified. ¹H NMR(CDCl ₃，400MHz)：δ1.057(D，J＝7.2Hz，3H)，1.059(d，J＝7.2Hz，3H)，1.80(M，1H)，1.97-2.08(m，2H)，2.82(M，4H)，4.00(d，J＝5.2Hz，1H)。

Step B: 2-isopropyl-2-(Alpha-hydroxy butyl)-1,3-dithiane (101)

Under-20 ℃ to (100) in anhydrous tetrahydro furan (50mL) (4g, 24.7mmol) solution drip n-BuLi (1.6M in hexane, 18.5mL, 29.6mmol).Stirred mixture is at room temperature heated 4h, and then is cooled to-20 ℃.Toward this solution slowly be added in hutanal solution in the anhydrous tetrahydro furan (10mL) (2.7mL, 29.6mmol).The mixture of gained is stirred 16h under the temperature between-20 ℃ and the room temperature, use the saturated ammonium chloride solution cessation reaction, and use the ethyl acetate extraction mixture.Separate organic layer and use Na ₂SO ₄Dry.Decompression is carried out flash column chromatography with silica gel to residue and is handled after removing down and desolvating, and obtains the title compound of 5g (85%) with 5% ethyl acetate/hexane eluting, is a kind of xanchromatic oil. ¹HNMR(CDCl ₃，400MHz)：δ0.96(t，J＝7.2Hz，3H)，1.11(d，J＝6.8，Hz，3H)，1.17(d，J＝6.8Hz，3H)，1.42-1.52(M，2H)，1.76(M，1H)，1.87-1.95(M，2H)，2.04(M，2H)，2.62(M，4H)，2.94(M，2H)，4.03(d，J＝5.2HZ，1H)。

Step C: 4-hydroxy-2-methyl heptane-3-ketone (102)

(5.0g, solution 21.4mmol) are added in the Hg (ClO in the methanol (30mL) to (101) in acetonitrile (270mL) under vigorous stirring ₄) ₂Solution.Under the room temperature with the stirring 2h of the mixture of gained.After the filtration, under situation about not heating, filtrate decompression is concentrated.Obtain the title compound of 2.8g (91%) with silica gel flash column chromatography (10% ethyl acetate/hexane) purification residue, be a kind of colourless liquid. ¹H NMR(CDCl ₃，400 MHz)：S 0.91(t，J＝7.2Hz，3H)，1.09(d，J＝7.2Hz，3H)，1.10(d，J＝7.2Hz，3H)，1.35-1.46(M，4H)，1.75(M，1H)，2.80(M，1H)，3.45(d，J＝5.2Hz，1H)，4.29(M，1H)。

Step D: 2-methyl heptane-3-ketone-4-p-nitrophenyl carbonic ester (103)

Under 0 ℃ to (102) in anhydrous methylene chloride (1.1g, 7.6mmol), (1.84g slowly is added in 4-dimethylaminopyridine (1.12g, solution 9.2mmol) in the dichloromethane to chloro-carbonic acid p-nitrophenyl ester in mixture 9.2mmol).0 ℃ is descended to stir 1h and at room temperature stirs after the 4h, with 10% citric acid cessation reaction.Separate organic facies, use Na ₂SO ₄Drying, and vacuum concentration.Flash column chromatography is handled residue, with 30% dichloromethane/hexane eluting, obtains the title compound of 2g (85%), is a kind of beige solid. ¹H NMR(CDCl ₃，400MHz)：δ0.99(t，J＝7.6Hz，3H)，1.12(d，J＝6.8Hz，3H)，1.18(d，J＝6.8Hz，3H)，1.51(M，2H)，1.84(M，2H)，2.82(M，1H)，5.17(M，1H)，7.42(d，J＝6.8Hz，2H)，8.25(d，J＝6.8Hz，2H)。

Step e: 1-{[(α-isobutyryl butoxy) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid

(104)

To contain gabapentin in dichloromethane (20mL) (820mg, 4.8mmol) and triethylamine (1.35mL, mixture 9.6mmol) add trim,ethylchlorosilane, and (1.22mL 9.6mmol), and stirs the mixture of gained 20 minutes.(1g 3.2mmol), and stirs the mixture of gained 60 minutes to be added in (103) in the dichloromethane (10mL) in this solution.With 10% citric acid (20mL) washing reaction mixture, and separate organic layer.(3 * 10mL) further extract the water-bearing layer, and use MgSO with ether ₄The dry organic extract that merges concentrates under vacuum then.Handle residue with silica gel chromatography, use hexane: ethyl acetate (4: 1) eluting is removed paranitrophenol, and then uses hexane: ethyl acetate (1: 4) eluting obtains the title compound of (72%). ¹H NMR(CDCl ₃，400MHz)：δ0.91(t，J＝7.2Hz，3H)，1.04(d，J＝6.8Hz，3H)，1.12(d，J＝6.8HZ，3H)，1.36-1.53(m，12H)，1.74(M，2H)，2.33(s，2H)，2.78(M，1H)，3.22(M，2H)，5.11(M，1H)，5.48(t，1H，NH).MS(ESI)m/z 342.24(M+H ⁺)。

Step F: 1-{[(α-isobutyl acyloxy butoxy) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid

(99)

To (104) in dichloromethane (20mL) (780mg, 2.3mmol) solution add metachloroperbenzoic acid (1.03g, 4.6mmol) and NaHCO ₃(386mg, 4.6mmol).After stirring 16h under the room temperature, add again a collection of metachloroperbenzoic acid (791mg, 4.6mmol) and NaHCO ₃(386mg, 4.6mmol).Mixture restir 8h with gained uses 10% citric acid treatment then.After the filtration, separate organic layer, use Na ₂SO ₄Dry and concentrated.Obtain the title compound of 79mg (11%) by anti-phase preparation HPLC method purification residue. ¹HNMR(CDCl ₃，400MHz)：δ0.94(t，J＝7.2Hz，3H)，1.153(d，J＝7.2Hz，3H)，1.150(d，J＝7.2Hz，3H)，1.32-1.58(M，12H)，1.74(M，2H)，2.28(s，2H)，2.56(m，1H)，3.23(m，2H)，5.27(t，J＝6.8Hz，1H，NH)，6.71(t，J＝5.6Hz，1H).MS(ESI)MLZ 358.30(M+H ⁺)。

By the following method above acid cut amount is converted into corresponding sodium salt:, add the 0.5N NaHCO of equimolar amounts then with acid water-soluble (5mL) ₃And lyophilizing.

Embodiment 29

1-{[(α-isobutyl acyloxy isobutoxy) carbonyl] amino methyl }-1-Cyclohexaneacetic acid methyl ester

(105)

Steps A: 1-{[(α-chlorine isobutoxy) carbonyl] amino methyl }-1-Cyclohexaneacetic acid methyl ester

(106)

With (93) (1.0g, 3.3mmol), the mixture of benzene (90mL) and methanol (10mL) is cooled to 0 ℃.Slowly add trimethyl silyl two azomethanes down until keeping yellow color at 0 ℃.Mixture is stirred 30 minutes down until react completely (monitoring with TLC) in 0 ℃.After decompression removes down and desolvates,, obtain the title compound of 760mg (72%) with 10% ethyl acetate/hexane eluting with the residue of silica gel chromatography processing gained.MS(ESI)m/z 320.24(M+H ⁺)。

Step B: 1-{{[(α-isobutyl acyloxy isobutoxy) carbonyl] amino methyl }-1-cyclohexane extraction second

Acid methyl ester (105)

(106) that will be in chloroform (760mg, 2.38mmol), Disilver carbonate (394mg, 1.4mmol) and isopropylformic acid. (442 μ l, mixture 4.76mmol) at room temperature stirs 24h.Add another batch Disilver carbonate (394mg, 1.4mmol) and isopropylformic acid. (442 μ L, 4.76mmol), and with the mixture restir of gained 24 hours.After the filtration, filtrate concentrated and with the residue of silica gel flash column chromatography purification gained, obtain the title compound of 560mg (63%) with 10% ethyl acetate/hexane eluting. ¹H NMR(CDCl ₃，400MHz)：δ0.94(d，J＝6.8Hz，3H)，0.96(D，J＝6.8Hz，3H)，1.15(d，J＝7.2HZ，3H)，1.17(d，J＝7.2HZ，3H)，1.32-1.58(m，10H)，2.01(m，1H)，2.19(s，2H)，2.55(m，1H)，3.18(m，2H)，3.67(s，3H)，5.33(t，1H)，6.56(d，J＝4.8Hz，1H)。MS(ESI)m/z 372.38(M+H ⁺)。

Embodiment 30

1-{[(α-benzoyloxy isobutoxy) carbonyl] amino methyl }-1-Cyclohexaneacetic acid methyl ester

(107)

With 1-{[(α-benzoxy isobutoxy) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (84) (150mg, 0.38mmol), the mixture of benzene (18mL) and methanol (2mL) is cooled to 0 ℃.Slowly add trimethyl silyl two azomethanes down until keeping yellow color at 0 ℃.Mixture is stirred 30 minutes down until react completely (by the TLC monitoring) at 0 ℃.Decompression is handled residue with silica gel chromatography after removing down and desolvating, and obtains the title compound of 98mg (64%) with 5% ethyl acetate/hexane eluting. ¹H NMR(CDCl ₃，400MHz)：δ1.02(d，J＝6.4Hz，3H)，1.03(d，J＝6.4Hz，3H)，1.32-1.52(m，10H)，2.14(M，1H)，2.27(s，2H)，3.17(M，2H)，3.62(s，3H)，5.40(t，1H)，6.81(d，J＝4.8Hz，1H)，7.40(M，2H)，7.54(M，1H)，8.12(m，2H).MS(ESI)m/z 406.29(M+H ⁺)。

Embodiment 31

1-{ (N-[(α-isobutyl acyl-oxygen base oxethyl) carbonyl]-4-bromophenyl alanyl] amino methyl

-1-Cyclohexaneacetic acid (108)

Steps A: 1-{ (4-bromophenyl alanyl) amino methyl }-1-Cyclohexaneacetic acid ester (109)

In the 40mL bottle, add N-Boc-4-bromophenyl alanine (1.72g, 5mmol), dicyclohexyl carbodiimide (1.24g, 6mmol), N-hydroxy-succinamide (0.7g, 6mmol) and acetonitrile (20mL).With reactant mixture vibration 4h under 25 ℃.Remove by filter sedimentary 1,3-Dicyclohexylurea.Add in the filtrate gabapentin (1.04g, 6mmol) and sodium hydroxide (0.4g, aqueous solution 10mmol) (30mL).Reactant is stirred 16h down in 22-25 ℃.With ethyl acetate (100mL) diluted reaction mixture, and with the 0.5M aqueous citric acid solution (2 * 100mL) and water (2 * 100mL) washing.Separate organic facies, dry (MgSO ₄), filter and concentrating under reduced pressure.Residue is dissolved in trifluoroacetic acid (40mL), and under 22-25 ℃, leaves standstill 2h.Decompression removes down and desolvates.With residue water-soluble (4mL), and filter with 0.25 μ M nylon membrane filter, then by HPLC (Phenomenex 250 * 21.2mm, with 5 μ m LUNAC18 posts, 100% water elution 5 minutes is used in 0-60% acetonitrile in the water and 0.05%TFA then with the speed eluting of 20mL/min 20 minutes) purification.Merge pure fraction, and under reduced pressure remove the title compound (109) that desolvates and obtain 1.7g (70%), be a kind of white solid.MS(ESI)m/z 397.02，399.01(M+H ⁺)。

Step B: 1-{[N-[(α-isobutyl acyl-oxygen base oxethyl) carbonyl]-4-bromophenyl alanine amino

Methyl }-1-Cyclohexaneacetic acid (108)

Under 0 ℃ to (109) in dichloromethane (200mg, add in the suspension of stirring 0.51mmol) triethylamine (141 μ L, 1.01mmol) and trim,ethylchlorosilane (129mL, 1.01mmol).The mixture of gained was stirred 15 minutes down in 0 ℃, be added in α-isobutyl acyloxy ethyl-p-nitrophenyl carbonic ester (111) (144mg, solution 0.51mmol) in the dichloromethane.Mixture is stirred 7h (by the LC/MS monitoring) under room temperature, use the dichloromethane diluted reaction mixture then, use the citric acid acidify.Separate organic layer, use the salt water washing, and use Na ₂SO ₄Dry.After filtering and concentrating, obtain the title compound of 92mg with preparation LC/MS method purification crude product. ¹H-NMR(CD ₃OD，400MHz)：δ1.10(M，6H)，1.46-1.25(m，13H)，2.20(m，2H)，2.48(M，1H)，2.84(m，1H)，3.06(M，1H)，3.17(M，1H)，4.36(m，1H)，6.67(q，J＝5.6Hz，1H)，7.17(d，J＝2.0，8.0Hz，2H)，7.42(DD，J＝2.0，8.0Hz，2H)。

Embodiment 32

3-{[(α-isobutyl acyl-oxygen base oxethyl) carbonyl] amino methyl }-5-methylhexanoic acid (110)

Steps A: α-isobutyl acyloxy ethyl-p-nitrophenyl carbonic ester (111)

Will the 1-chloroethyl in the dichloromethane (10mL)-p-nitrophenyl carbonic ester (57) (2.0g, 8.14mmol) and isopropylformic acid. hydrargyrum (6.13g, solution 16.29mmol) stirs down 24h in 45 ℃.Then reactant is cooled to room temperature, and dilutes with the precipitation mercury salt with hexane.With celite filter bed filtering precipitate, and under vacuum and with filtrate concentrating, obtain the 2.5g crude product.Handle residue with silica gel chromatography, carry out the title compound that gradient elution obtains 1.2g (52%) with 10% dichloromethane/hexane to 20% dichloromethane/hexane. ¹H-NMR(CDCl ₃，400MHz)：δ1.21-1.99(M，6H)，1.62(d，J＝5.6Hz，3H)，2.61(M，1H)，6.84(q，J＝5.6Hz，1H)，7.41(dt，J＝6.8，2.4Hz，2H)，8.29(dt，J＝6.8，2.4Hz，2H)。

Step B: 3-{[(α-isobutyl acyl-oxygen base oxethyl) carbonyl] amino methyl-5-methylhexanoic acid

(110)

Under 0 ℃ to the pregabalin (2) in anhydrous methylene chloride (10mL) (150mg, the suspension of stirring 0.94mmol) add triethylamine (0.26mL, 1.88mmol) and trim,ethylchlorosilane (0.24mL, 1.88mmol).After stirring 15 minutes under 0 ℃, be added in α-isobutyl acyloxy ethyl-p-nitrophenyl carbonic ester (111) (267mg, solution 0.94mmol) in the dichloromethane (3mL).The mixture of gained is stirred 1.5h under room temperature.With the reactant mixture acidify, and use dichloromethane extraction with citric acid.With the organic extract of salt water washing merging, and use Na ₂SO ₄Dry.After filtration and the evaporation, with silica gel chromatography purification crude product, at first removing nitrophenol with the dichloromethane eluting, be used in the title compound that 30% eluent ethyl acetate in the dichloromethane obtains 130mg (48%) then, is the mixture of two kinds of diastereomers. ¹H-NMR(CDCI ₃，400MHz)：δ0.90(m，6H)，1.70(M，8H)，1.46(d，J＝5.6HZ，3H)，1.66(1H，M)，2.15(M，1H)，2.33(M，2H)，2.53(m，1H)，3.12(m，1H)，3.29(M，1H)，5.08(t，J＝6.0Hz，1H)，6.79(M，1H)。

Embodiment 33

3-{[(α-isobutyl acyloxy isobutoxy) carbonyl] amino methyl }-5-methyl-caproic acid (112)

Steps A: 1-chloro-2-methyl-propyl-p-nitrophenyl carbonic ester (113)

To the paranitrophenol (4.06g that contains in dichloromethane (200mL), 29mmol) with 1-chloro-2-methyl-propyl chloro-formate (5.0g, be added in pyridine (2.78mL, solution 32mmol) in the dichloromethane (50mL) in ice-cold reactant mixture 29mmol).Mixture is stirred 30min under 0 ℃, at room temperature stir 1h then.Behind the vapourisation under reduced pressure solvent, residue is dissolved in ether, and water, 10% citric acid and wash with water once more.Separate the ether layer, use Na ₂SO ₄Drying, and reduction vaporization obtains the title compound of 7.9g (100%), is a kind of beige solid. ¹H NMR(CDCl ₃，400MHz)：δ1.12(d，J＝6.6Hz，3H)，1.13(d，J＝6.6Hz，3H)，2.29(M，1H)，6.24(d，J＝4.8Hz，1H)，7.42(d，J＝9.2Hz，2H)，8.28(d，J＝9.2Hz，2H)。

Step B: α-isobutyl acyloxy isobutyl group-p-nitrophenyl carbonic ester (114)

According to the preparation method of (111), and replace (57), obtain productive rate and be 15% title compound, and the response rate of its raw material is 70% with (113). ¹H-NMR(CDCl ₃，400MHz)：δ1.07(d，J＝6.8Hz)，1.21(M，6H)，2.18(M，1H)，2.26(M，1H)，6.60(d，J＝5.2Hz，1H)，7.42(M，2H)，8.28(M，2H)。

Step C: 3-{[(α-isobutyl acyloxy isobutoxy) carbonyl] the oxygen ylmethyl }-5-methyl-caproic acid

(112)

According to the preparation method of (110), and with (114) replacements (111), obtaining title compound, is the mixture of two kinds of diastereomers, and productive rate is 51%. ¹H-NMR(CDCl ₃，400MHz)：δ0.89(m，12H)，1.17(m，8H)，1.65(m，1H)，2.02(m，1H)，2.16(m，1H)，2.33(m，2H)，2.56(m，1H)，3.13(m，1H)，3.30(m，1H)，5.00(m，1H)，6.57-6.56(m，1H)。

Embodiment 34

3-{[(α-benzoyloxy isobutoxy) carbonyl] amino methyl-5-methyl-caproic acid (115)

Steps A: α-benzoyloxy isobutyl group-p-nitrophenyl carbonic ester (116)

According to the preparation method of (111), replace (57) and replace isopropylformic acid. hydrargyrum with (113) with mercuric benzoate, obtain title compound, productive rate is 11%, and the response rate of raw material is 50%. ¹H-NMR(CDCl ₃，400MHz)：δ1.15(d，J＝3.2Hz，3H)，1.16(d，J＝3.2Hz，3H)，2.30(m，1H)，6.87(d，J＝4.4Hz，1H)，7.42(dd，J＝7.2，2.0Hz，2H)，7.48(t，J＝7.6Hz，2H)，7.62(t，J＝7.6Hz，1H)，8.09(dd，J＝8.0，1.0Hz，2H)，8.27(dd，J＝7.2，2.0Hz，2H)。

Step B: 3-{[(α-benzoyloxy isobutoxy) carbonyl] amino methyl }-5-methyl-caproic acid

(115)

According to the preparation method of (110), and with (116) replacements (111), obtaining title compound, is the mixture of two kinds of diastereomers, and productive rate is 58%. ¹H-NMR(CDCl ₃，400MHz)：δ0.87(m，6H)，1.05(m，6H)，1.16(m，2H)，1.64(m，1H)，2.17(m，2H)，2.32(m，2H)，3.12(m，1H)，3.29(m，1H)，5.01(br s，1H)，6.82(m，1H)，7.44(m，2H)，7.57(m，1H)，8.05(m，2H)。

Embodiment 35

1-{[((5-methyl-2-oxo-1,3-dioxy ring penta-4-alkene-4-yl) methoxyl group) carbonyl] ammonia

Ylmethyl }-1-Cyclohexaneacetic acid (117)

Steps A: Benzyl 2-two azos-3-oxo-butanoic acid (118)

Under 0 ℃ to the acetoacetic acid benzyl ester in acetonitrile (200mL) (5.0g, 26.01mmol) and 4-acetylaminohydroxyphenylarsonic acid benzenesulfonyl azide (6.25g, drip in solution 26.01mmol) triethylamine (10.9mL, 78.03mmol).The mixture of gained is stirred 30min under 0 ℃, and at room temperature stir 4h.Behind the concentrating under reduced pressure, (3 * 100mL) ground with 2: 1 ether/petroleum ether with residue.Celite filter bed in order to the silica gel butt filters the organic extract that merges.Obtain the title compound of 4.74g in removal of solvent under reduced pressure, be a kind of cream-coloured crystallization. ¹H-NMR(CDCl ₃，400MHz)：δ2.49(s，3H)，5.27(s，2H)，7.38(M，5H)。

Step B: Benzyl 2-hydroxyl-3-oxo-butanoic acid (119)

Will be at THF (110mL) and H ₂Two azo-compounds (118) (4.74g, solution 21.74mmol) and Rh among the O (50mL) ₂(OAc) ₂(77mg, 0.17mmol) reflux 4 hours together, and be cooled to room temperature.Mixture is concentrated under vacuum, and with ethyl acetate extraction residue aqueous solution.With the organic extract that the salt water washing merges, use Na ₂SO ₄Drying filter, and vacuum concentration obtains the 4.5g crude product. ¹H-NMR(CDCl ₃，400MHz)：δ2.28(s，3H)，3.90(s，1H)，4.82(s，1H)，5.26(m，2H)，7.37(m.5H)。

Step C: 4-benzyloxycarbonyl 5-methyl-2-oxo-1.3-dioxy ring penta-4-alkene (120)

(6.88g, suspension 42.45mmol) are added in alcohol (119) (4.50g, solution 21.22mmol) among the anhydrous THF (50mL) to the carbonyl dimidazoles in THF (50mL) under 0 ℃.The mixture of gained was stirred 5 hours down at 0 ℃, at room temperature stir and spend the night.With the mixture vacuum concentration, and water and ethyl acetate/hexane distribution residue.Separate organic layer, use saturated NH ₄Cl, salt water washing, and use Na ₂SO ₄Dry.After filtering and concentrating,, be used in the title compound that 20% eluent ethyl acetate in the hexane obtains 2.6g with flash chromatography on silica gel method purification crude product. ¹H-NMR(CDCl ₃，400MHz)：δ2.48(s，3H)，5.27(s，2H)，7.37(br.s，5H)。

Step D: 5-methyl-2-oxo-1.3-dioxy ring penta-4-thiazolinyl-4-formic acid (121)

(2.6g, solution 10.92mmol) adds 260mg PD/C (5%), and the mixture of gained is stirred 1h under hydrogen atmosphere to the chemical compound in 50mL ethanol (120).Filter and under reduced pressure remove to desolvate and obtain the title compound of 1.62g. ¹H-NMR(CD ₃OD，400MHz)：δ2.41(s，3H)。

Step e: 4-hydroxymethyl-5-methyl-2-oxo-1.3-dioxy ring penta-4-alkene (122)

Under 0 ℃ to the acid (121) in anhydrous methylene chloride (50mL) (1.62g, 11.10mmol) and the solution of dry DMF (112 μ L) drip oxalyl chloride (6.1mL, 2M solution, 12.2mmol).After stirring 30 minutes under 0 ℃ and at room temperature stirring 1h, under reduced pressure remove and desolvate.Residue is dissolved in anhydrous methylene chloride (65mL), and is cooled to-78 ℃.Drip Bu toward this solution in 10 minutes ₄NBH ₄The solution of (3.14g, 12.2mmol is in the 20mL dichloromethane).After stirring 1h under-78 ℃, use the reaction of 0.1N HCl (30mL) termination mix carefully, and be heated to room temperature.Separate the water-bearing layer, (3 * 50mL) extractions with the organic extract of salt water washing merging, and are used Na with EtOAc ₂SO ₄Dry.Decompression is carried out column chromatography with silica gel and is handled after removing down and desolvating, and is used in the title compound that 50%EtOAc eluting in the dichloromethane obtains 767mg. ¹H-NMR(CD ₃OD，400MHz)：δ2.09(s，3H)，4.34(s，2H)。

Step F: 1-{[((5-methyl-2-oxo-1,3-dioxy ring penta-4-alkene-4-yl) methoxyl group)

Carbonyl]-amino methyl }-1-Cyclohexaneacetic acid benzyl ester (123)

Alcohol (122) that will be in toluene (767mg, 5.9mmol) and the suspension returning of 1-isocyanate group methyl isophthalic acid-Cyclohexaneacetic acid benzyl ester (5.9mmol) spend the night.After decompression removed down and desolvates, with flash column chromatography purification residue, the eluting that is used in the 30%EtOAc in the hexane obtained the title compound of 510mg. ¹H-NMR(CD ₃OD，400MHz)：δ1.58-1.30(m，10H)，2.18(s，3H)，2.35(s，2H)，3.17(d，J＝6.8Hz，2H)，4.80(s，2H)，5.11(s，2H)，5.44(t，J＝6.8Hz，1H)，7.36(m，5H)。

Step G: 1-{[((5-methyl-2-oxo-1.3-dioxy ring penta-4-alkene-4-yl) carbonyl methoxyl group)

Base]-amino methyl }-1-Cyclohexaneacetic acid (117)

(510mg, solution 1.41mmol) adds 59mg PD/C (5%), and the mixture of gained is stirred 1h under hydrogen atmosphere to the chemical compound (123) in ethanol (20mL).Filter and remove volatile matter under the decompression and obtain crude product, obtain the title compound of 105mg by preparation LC/MS method purification crude product. ¹H-NMR(CD ₃OD，400MHz)：δ1.52-1.36(m，10H)，2.16(s，3H)，2.27(s，2H)，3.22(s，2H)，4.86(s，2H)。

Embodiment 36

1-{ (1-methyl-3-oxo-Ding-1-carbonyl) amino methyl }-1-Cyclohexaneacetic acid piperidines

(124)

With 2, the 4-pentanedione (103 μ L, 1mmol), gabapentin (171mg, 1mmol) and piperidines (99 μ L 1mmol) sneak into absolute methanol (10mL).Mixture heated backflow 4h with gained.Decompression removes down to desolvate and obtains purity greater than 90% title compound ¹H NMR (CDCl ₃, 400MHz): δ 1.34-1.62 (M, 12H), 1.71 (M, 4H), 1.94 (s, 3H), 1.96 (s, 3H), 2.26 (s, 2H), 2.98 (M, 4H), 3.38 (d, J=6Hz, 2H), 4.90 (s, 1H), 5.20 (s, br, 2H), 8.64 (t, J=6Hz, 1H) .MS (ESI) m/z252.35 (M-H ^-).

Embodiment 37

1-1-{[(2-oxo-oxolane-3-base subunit) ethyl] amino methyl }-the 1-Cyclohexaneacetic acid

Piperidines (125)

With 2-acetyl group butyrolactone (108 μ L, 1mmol), gabapentin (171mg, 1mmol) and piperidines (99 μ L 1mmol) sneak into absolute methanol (10mL).Behind the reflux 6h, under reduced pressure removing desolvates obtains purity greater than 90% title compound. ¹H NMR(CDCl ₃，400MHz)：δ1.34-1.62(m，12H)，1.71(m，4H)，1.94(s，3H)，2.24(s，2H)，2.81(T，J＝7.6Hz，2H)，2.99(M，4H)，3.31(d，J＝6.4Hz，2H)，4.23(t，J＝7.6Hz，2H)，5.17(s，br，2H)，8.64(t，J＝6.4Hz，1H).MS(ESI)m/z 280.34(M-H-)。

Embodiment 38

1-{ (2-carbon methoxyl group-ring penta-1-thiazolinyl) amino methyl }-1-Cyclohexaneacetic acid piperidines

(126)

With 2-oxo-cyclopentane methyl formate (124 μ L, 1mmol), gabapentin (171mg, 1mmol) and piperidines (99 μ L 1mmol) sneak into absolute methanol (10mL).Behind the reflux 16h, under reduced pressure removing desolvates obtains purity greater than 90% title compound. ¹H NMR(CDCl ₃，400MHz)：δ1.29-1.60(M，12H)，1.72(M，4H)，1.79(M，J＝7.6Hz，2H)，2.24(s，2H)，2.49(t，J＝7.6Hz，2H)，2.55(t，J＝7.6Hz，2H)，2.99(M，4H)，3.24(d，J＝6.8Hz，2H)，3.63(s，3H)，5.06(s，br，2H)，7.93(s，br，1H).MS(ESI)m/z 294.36(M-H-)。

Embodiment 39

The amino first of 1-{ (1-methyl-2-(ethoxy carbonyl)-3-ethyoxyl-3-oxo third-1-thiazolinyl)

Base }-1-Cyclohexaneacetic acid piperidines (127)

With the acetyl group diethyl malonate (202mg, 1mmol), gabapentin (171mg, 1mmol) and piperidines (99 μ L 1mmol) sneak into dehydrated alcohol (10mL).Behind the reflux 16h, under reduced pressure removing desolvates obtains purity greater than 90% title compound. ¹H NMR(CDCl ₃，400MHz)：δ1.28(t，J＝7.2Hz，6H)，1.38-1.64(m，12H)，1.75(m，4H)，1.96(s，3H)，2.23(s，2H)，2.99(m，4H)，3.24(d，J＝5.2Hz，2H)，4.20(q，J＝7.2Hz，4H)，4.35(s，br，2H)，7.79(t，J＝5.2Hz，1H).MS(ESI)m/z 354.38(M-H ^-)。

Embodiment 40

1-{[(α-(2-(2-methyl isophthalic acid, 3-dioxolanes-2-yl) carboxyl isobutoxy) carbonyl]-amino

Methyl }-1-Cyclohexaneacetic acid (128)

Steps A: The 2-methyl isophthalic acid, 3-dioxolanes-2-formic acid (129)

Under 0 ℃ to contain ethyl pyruvate in anhydrous methylene chloride (100mL) (11.1mL, 0.1mol) and ethylene glycol (5.6mL, add in stirred mixture 0.1mol) boron trifluoride two etherates (6.4mL, 0.05mol) and the acetic acid of catalytic amount.The mixture of gained is stirred 16h at 40 ℃, then with the dilution of 100mL dichloromethane.Use saturated nacl aqueous solution (2 * 80mL) washing organic solutions continuously.Separate organic layer, and concentrate the organic extract that merges.Use 1N naoh treatment residue under the room temperature.After stirring 3h (by the TLC monitoring) under the room temperature, add citric acid pH is transferred to 4.Use the dichloromethane extraction product, use Na ₂SO ₄Drying, and concentrate the title compound (129) that obtains 5.1g (38%), be a kind of clarifying liquid.This material is used for next step reaction without being further purified. ¹HNMR(CDCl ₃，400MHz)：51.55(s，3H)，4.03(m，4H)。

Step B: Benzyl 1-{[(α-(2-(2-methyl isophthalic acid, 3-dioxolanes-2-yl) carboxyl isobutyl oxygen

Base) carbonyl] amino methyl }-1-Cyclohexaneacetic acid benzyl ester (130)

To contain the 1-{[(α-chlorine isobutoxy in chloroform under the room temperature) the carbonylamino methyl }-1-Cyclohexaneacetic acid benzyl ester (95) (1g, 2.53mmol), (129) (673mg, 5.1mmol), Disilver carbonate (557mg, 2.53mmol) and triethylamine (709 μ l, mixture stirring 16h 5.1mmol).After the filtration, filtrate is concentrated.With the residue of silica gel chromatography purification gained, obtain the title compound (130) of 510mg (41%) with 15% ethyl acetate/hexane eluting.MS(ESI)m/z 492.40(M+H ⁺)。

Step C: 1-{[(α-(2-(2-methyl isophthalic acid, 3-dioxolanes-2-yl) carboxyl isobutoxy) carbonyl

Base]-amino methyl }-1-Cyclohexaneacetic acid (128)

(130) that will be in ethanol under nitrogen atmosphere and room temperature (470mg, 0.96mmol) and the mixture of 5%Pd-C (catalytic amount) stir 16h.Filter and concentrate the title compound (128) that obtains 382mg (100%). ¹H NMR(CDCl ₃，400MHz)：δ0.96(d，J＝6.8Hz，3H)，0.97(d，J＝6.8Hz，3H)，1.32-1.58(m，10H)，1.59(s，3H)，2.06(M，1H)，2.32(s，2H)，3.26(m，2H)，4.08(M，4H)，5.29(t，1H，NH)，6.55(d，J＝4.8Hz，1H).MS(ESI)m/z 402.32(M+H ⁺)。Be corresponding sodium salt by the following method with sour form Quantitative yield: water-soluble (5mL), the 0.5N NaHCO of adding equimolar amounts ₃, lyophilizing then.

Embodiment 41

The Caco-2 cell permeability of external test prodrug

Can use method as known in the art that the passive permeability of prodrug of the present invention is carried out in-vitro evaluation (for example referring to people such as Stewart, PHARM.RES., 1995,12,693).For example, can estimate by permeability by checking the polarization cell monolayer (for example Caco-2 cell) that prodrug flows through cultivation.The Caco-2 cell (go down to posterity and be less than 28) that derives from continuous culture is inoculated into the Transwell polycarbonate filter to high-density.With DMEM/10% fetal bovine serum+0.1mM non essential amino acid+2mM L-GLn, 5% CO ₂Support cell until testing the same day for/95%, 37 ℃.Overflowing pump inhibitor (250 μ M MK-571,250 μ M verapamils, 1mM ofloxacin) existence down, under pH6.5 and at the top, (containing 1mM CaCl ₂, 1MM MgCl ₂, 150mM NaCl, 3mM KCl, 1mM NaH ₂PO ₄, the 5mM glucose 50mM MES buffer in) and under pH7.4, (containing in the Hanks average salt solution of 10mM HEPES) and carrying out penetration study in the bottom side.Insert is placed 12 holes or the 24 hole flat boards that contain buffer, and cultivate 30min down at 37 ℃.(200 μ M) is added to top and bottom side compartment (donor) with prodrug, and uses LC/MS/MS with 1 hour the measuring space prodrug in relative compartment (receiver) and/or the concentration of the parent drug of release.See osmotic value (Papp) in order to following equation computer chart:

P _app＝V _r(dC/dt)//(AC ₀)

The V here _rFor with mL being the volume of accepting compartment of unit; DC/dt is the circulation (μ M/S) of prodrug and parent drug, and it is measured the slope of a curve of time according to the concentration of accepting in the compartment; C ₀For being the initial concentration of the prodrug of unit with μ M; A is with cm ²Film surface area for unit.Preferably has the P that the infiltrative prodrug that passes cell significantly shows _AppValue 〉=1 * 10 ^-6Cm/s, more preferably P _AppValue 〉=1 * 10 ^-65cm/s, further more preferably P _AppValue 〉=5 * 10 ^-5Cm/s.Typical P about the prodrug gained of GABA analog _AppValue is shown in following table:

Chemical compound	P _app(top is to the bottom side) (cm/s)	P _app(bottom side is to the top) (cm/s)	Ratio A-B/B-A
Chemical compound	P _app(top is to the bottom side) (cm/s)	P _app(bottom side is to the top) (cm/s)	Ratio A-B/B-A	(51)	1.06×10 ^-4	1.25×10 ^-5	8.5
(56)	3.1×10 ^-5	2.0×10 ^-6	15.5	(51)	1.06×10 ^-4	1.25×10 ^-5	8.5
(56)	3.1×10 ^-5	2.0×10 ^-6	15.5	(62)	2.10×10 ^-5	6.40×10 ^-6	3.3
(68)	8.43×10 ^-5	2.26×10 ^-5	3.7	(62)	2.10×10 ^-5	6.40×10 ^-6	3.3
(68)	8.43×10 ^-5	2.26×10 ^-5	3.7	(69)	1.84×10 ^-4	5.22×10 ^-6	35.2
(70)	1.78×10 ^-5	1.68×10 ^-6	10.6	(69)	1.84×10 ^-4	5.22×10 ^-6	35.2
(70)	1.78×10 ^-5	1.68×10 ^-6	10.6	(71)	8.10×10 ^-5	1.99×10 ^-5	4.1
(72)	2.51×10 ^-5	1.26×10 ^-6	2.0	(71)	8.10×10 ^-5	1.99×10 ^-5	4.1
(72)	2.51×10 ^-5	1.26×10 ^-6	2.0	(77)	7.41×10 ^-5	1.43×10 ^-5	5.2
(78)	1.37×10 ^-4	2.46×10 ^-6	5.6	(77)	7.41×10 ^-5	1.43×10 ^-5	5.2
(78)	1.37×10 ^-4	2.46×10 ^-6	5.6	(80)	6.62×10 ^-5	8.75×10 ^-6	7.6
(81)	8.65×10 ^-5	1.27×10 ^-5	6.8	(80)	6.62×10 ^-5	8.75×10 ^-6	7.6
(81)	8.65×10 ^-5	1.27×10 ^-5	6.8	(82)	1.25×10 ^-4	1.82×10 ^-6	6.9
(83)	1.29×10 ^-5	4.48×10 ^-5	0.3	(82)	1.25×10 ^-4	1.82×10 ^-6	6.9
(83)	1.29×10 ^-5	4.48×10 ^-5	0.3	(84)	1.26×10 ^-4	1.57×10 ^-5	8.1
(89)	5.85×10 ^-5	2.34×10 ^-6	25.0	(84)	1.26×10 ^-4	1.57×10 ^-5	8.1
(89)	5.85×10 ^-5	2.34×10 ^-6	25.0	(90)	9.22×10 ^-5	5.75×10 ^-6	16.0

Data in this table show that prodrug disclosed herein has high cell permeability, and should be well by intestinal absorption.Except chemical compound (83), prodrug top to bottom side permeability surpasses their bottom side to top permeability.This shows that these chemical compounds can be the substrates (though this infiltrative some composition that passes cell is regulated by passive diffusion) of the active transport mechanism that exists in Caco cell teleblem.(83) although bottom side to top permeability big more showing have efflux pump inhibitor MK-571, verapamil and ofloxacin, this chemical compound can flow through the bottom side film.

Embodiment 42

Gabapentin after the colonic administration of rat being carried out gabapentin or gabapentin prodrug

Absorption

The peroral dosage form that discharged the lasting release of medicine in 6-24 hour lentamente generally discharges a large amount of dosage at colonic.Therefore the medicine that is applicable to this dosage form preferably shows good colon absorption.Carry out this experiment to estimate the application of gabapentin prodrug in oral sustained release forms.

Steps A: dosage regimen

Be commercially available rat and at ascending colon and the pre-cannulate of jugular vein.Animal regains consciousness when experiment.All animal overnight fastings are until taking medicine back 4 hours.With the dosage that is equivalent to 25mg gabapentin/kg the solution (in water or PEG 400) of gabapentin or gabapentin prodrug (59), (63), (69), (72), (77), (79), (85), (117) and (126) directly is applied to colon by intubate.The compartment of terrain obtains blood sample (0.5mL) from jugular vein in 8 hours, and by adding acetonitrile/methanol cessation reaction immediately, transforms to prevent the prodrug back.As following analysis blood sample.

Step B: the sample preparation that colon absorbs the drug

1. in blank 1.5mL eppendorf pipe, add 300 μ L, 50/50 acetonitrile/methanol and 20 μ L DL-3-alanine as interior mark.

2. collect rat blood at different time points, immediately 100 μ L blood are added to the eppendorf pipe, and mix.

3. with 10 μ L gabapentin standard solution (0.04,0.2,1,5,25,100 μ g/ml) be added to the blank rat blood of 90 μ L to form final calibration criterion (0.004,0.02,0.1,0.5,2.5,10 μ g/ml), then 300 μ L, 50/50 acetonitrile/methanol is added in each pipe, adds 20 μ L DL-3-alanine subsequently.

4. sample is stirred and with 14 centrifugal 10 minutes of 000rpm speed.

5. get supernatant and be used for the LC/MS/MS analysis.

Step C: LC/MS/MS analyzes

The API 2000 LC/MS/MS spectrometers that are equipped with Shidmadzu 10ADVp binary pump and CTC HTS-PAL Autosampler are used for analyzing.During analyzing, Zorbax XDB C84.6 * 150mm post is heated to 45 ℃.Mobile phase is 0.1% formic acid (A) and acetonitrile and 0.1% formic acid (B).Gradient condition is: 5%B stream took off 1 minute, and the 98%B eluting is 3 minutes then, kept using 98%B eluting 2.5 minutes then.Mobile phase was reset into the 5%B eluting 2 minutes.The TurboIonSpray source is used for API 2000.Finish analysis in the cation mode, and MRM transformation 172/137 is used to analyze gabapentin, and (it is 426/198 that used MRM changes for (59), for (63) is 364/198, for (69) is 392/198, for (72) is 316/198, for (77) is 330/198, is 330/198 for (79), for (85) be 316/198 and for (117) for 327.7/153.8).Inject 20 μ L samples.Use the Analyst1.1 quantitation software with the peak integration.After in these prodrugs each is carried out colon administration, gabapentin maximal plasma concentration (C _Max) and gabapentin plasma concentration ground time graph area (AUC) down obviously greater than the area under a curve of the colon administration generation of (＞2 times) gabapentin own.For example, the gabapentin C that provides of prodrug (77) _MaxBigger 10 times with the AUC value than gabapentin itself.These data show that chemical compound of the present invention can make the compositions that is suitable for promoting absorbing and/or continuing to discharge effectively the GABA analog, thus because the rapid system clearance rate of GABA analog and the frequency of will taking medicine minimizes.

Embodiment 43

In the lasting release of using the gabapentin after mini pump is used prodrug to hunting dog

Gabapentin or gabapentin prodrug (77) and (82) (to equal the dosage of 10mg gabapentin/kg) are dissolved in The suitable solvent (for example water, PEG 400 etc.), and it is filled to the mini osmotic pumps device of preweighted Alzet  (model 2001D) (Durect Corp., Cupertino, CA).By under 37 ℃ the Alzet  that fills soaked 3 hours in infiltration saline and under 4 ℃ in sealed container store overnight carry out pre-equilibration.Allow the male hunting dog of four fasting oral then (approximately 6.5kg).Animal is in the feed in back 4 hours of taking medicine at every turn.Compartment of terrain blood sampling (1.0mL) in 48 hours, and immediately blood plasma is handled.With the plasma sample lyophilizing, and under-80 ℃, store until using above-mentioned method to analyze.The plasma concentration of two kinds of back 12 hours gabapentins of taking medicine that prodrug provided is used gabapentin, and originally the concentration of being seen gabapentin is big 2 times after one's death than in Alzet  device.These data further proof chemical compound of the present invention can be made the compositions that is suitable for continuing effectively release GABA analog.

Embodiment 44

Pregabalin's in the rat colon after pregabalin or the administration of pregabalin prodrug

Absorb

Scheme with pregabalin and pregabalin prodrug (110) and (112) repetition embodiment 41.After each of these prodrugs is carried out colon administration, the maximal plasma concentration (C of pregabalin _Max) and pregabalin plasma concentration area under curve (＞2 times) that the area under the time graph (AUC) is obviously produced greater than the colon administration of pregabalin own.

At last, should be noted that the selectable mode of the present invention of implementing that exists.Therefore, the present embodiment is considered to illustration rather than qualification, and the present invention do not limit by details provided herein, but can make an amendment within the scope of appended claim and equivalent.

All be incorporated herein the open and patent of all of citation as a reference.

Claims

1. the chemical compound of formula (I), formula (II) or formula (III)

Or its pharmaceutically acceptable salt, hydrate or solvate, wherein:

M, n, t and u are 0 or 1 independently;

X is O or NR ¹⁶

W is O or NR ¹⁷

Y is O or S;

With

Each R ²Be independently selected from hydrogen; alkyl; the alkyl that replaces; alkoxyl; the alkoxyl that replaces; acyl group; the acyl group that replaces; acyl amino; the acyl amino that replaces; alkyl amino; the alkyl amino that replaces; alkyl sulphinyl; the alkyl sulphinyl that replaces; alkyl sulphonyl; the alkyl sulphonyl that replaces; alkylthio group; the alkylthio group that replaces; alkoxy carbonyl; the alkoxy carbonyl that replaces; aryl; the aryl that replaces; aryl alkyl; the aryl alkyl that replaces; aryloxy group; the aryloxy group that replaces; carbamoyl; cycloalkyl; the cycloalkyl that replaces; the assorted alkyl of ring; the assorted alkyl of the ring that replaces; dialkyl amido; the dialkyl amido that replaces; halogen; assorted alkyl; the assorted alkyl that replaces; heteroaryl; the heteroaryl that replaces; heteroaryl alkyl; the heteroaryl alkyl that replaces; assorted alkoxyl; the assorted alkoxyl that replaces; the heteroaryloxy of heteroaryloxy and replacement, perhaps optional R ²And R ¹⁶With the assorted alkyl ring of ring that forms assorted alkyl of ring or replacement with their bonded atoms;

R ⁴And R ⁵Be independently selected from the heteroaryl alkyl of ring assorted alkyl, heteroaryl alkyl and replacement of aryl alkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring, the replacement of acyl group, aryl alkyl, the replacement of alkyl, acyl group, the replacement of hydrogen, alkyl, replacement, perhaps optional R ⁴And R ⁵Assorted alkyl of ring or bridged ring alkyl ring with the cycloalkyl that forms cycloalkyl, replacement with their bonded carbon atoms, the assorted alkyl of ring, replacement;

R ⁸And R ¹²Be independently selected from the heteroaryl alkyl of heteroaryl, heteroaryl alkyl and replacement of assorted alkyl, heteroaryl, the replacement of aryl alkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring of aryl, aryl alkyl, the replacement of alkyl, aryl, the replacement of alkoxy carbonyl, alkyl, the replacement of acyl group, alkoxy carbonyl, the replacement of hydrogen, acyl group, replacement, the assorted alkyl of ring of replacement, assorted alkyl, replacement, perhaps optional R ⁸And R ¹²The assorted alkyl ring of ring with the cycloalkyl that forms cycloalkyl, replacement with their bonded carbon atoms, the assorted alkyl of ring or replacement;

R ¹³And R ¹⁴Be independently selected from the heteroaryl alkyl of heteroaryl, heteroaryl alkyl and replacement of cyclo alkoxy carbonyl, heteroaryl, the replacement of cycloalkyl, cyclo alkoxy carbonyl, the replacement of aryl alkyl, carbamoyl, cycloalkyl, the replacement of aryl, aryl alkyl, the replacement of alkoxy carbonyl, aryl, the replacement of alkyl, alkoxy carbonyl, the replacement of hydrogen, alkyl, replacement, perhaps optional R ¹³And R ¹⁴The assorted alkyl ring of ring with the cycloalkyl that forms cycloalkyl, replacement with their bonded carbon atoms, the assorted alkyl of ring or replacement;

R ²⁰And R ²¹Be independently selected from the heteroaryl alkyl of heteroaryl, heteroaryl alkyl and replacement of assorted alkyl, heteroaryl, the replacement of aryl alkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring of aryl, aryl alkyl, the replacement of alkyl, aryl, the replacement of acyl group, alkyl, the replacement of hydrogen, acyl group, replacement, the assorted alkyl of ring of replacement, assorted alkyl, replacement, perhaps optional R ²⁰And R ²¹The assorted alkyl ring of ring with the cycloalkyl that forms cycloalkyl, replacement with their bonded carbon atoms, the assorted alkyl of ring or replacement;

R ²²And R ²³Be independently selected from the aryl alkyl of aryl, aryl alkyl and replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement, perhaps optional R ²²And R ²³The assorted alkyl ring of ring with the cycloalkyl that forms cycloalkyl, replacement with their bonded carbon atoms, the assorted alkyl of ring or replacement;

R ²⁴Be selected from the heteroaryl alkyl of heteroaryl, heteroaryl alkyl and replacement of assorted alkyl, heteroaryl, the replacement of aryl alkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring of aryl, aryl alkyl, the replacement of alkyl, aryl, the replacement of acyl group, alkyl, the replacement of hydrogen, acyl group, replacement, the assorted alkyl of ring of replacement, assorted alkyl, replacement;

R ²⁵Be selected from the heteroaryl alkyl of heteroaryl, heteroaryl alkyl and replacement of assorted alkyl, heteroaryl, the replacement of aryl alkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring of aryl, aryl alkyl, the replacement of alkyl, aryl, the replacement of acyl group, alkyl, the replacement of acyl group, replacement, the assorted alkyl of ring of replacement, assorted alkyl, replacement; And

Collateral condition is:

In the chemical compound of formula (I), when n be 0 or when n be 1, and X is NR ¹⁶The time, R ¹Be not hydrogen;

In the chemical compound of formula (I), work as R ¹Be R ²⁴C (O)-and n is 0 o'clock, R ²⁴It is not methyl, the tert-butyl group, 2-amino-ethyl, 3-aminopropyl, benzyl, phenyl or 2-(benzoxy methyl) phenyl;

In the chemical compound of formula (I), when n is 1, X is NH, R ³, R ⁵And R ⁶The hydrogen of respectively doing for oneself, and R ⁴During for cyclohexyl, R ²It is not benzyl;

2. the chemical compound that has the claim 1 of formula (I):

3. the chemical compound of claim 1, wherein R ⁷Be selected from the heteroaryl alkyl of heteroaryl, heteroaryl alkyl and replacement of assorted alkyl, heteroaryl, the replacement of aryl alkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring of aryl, aryl alkyl, the replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement, the assorted alkyl of ring of replacement, assorted alkyl, replacement.

4. the chemical compound of claim 1, wherein Y is O, and R ⁷Be hydrogen.

5. the chemical compound of claim 1, wherein Y is O, and R ⁷Aryl for alkenyl, aryl or the replacement of the alkyl group of alkyl group, replacement, alkenyl, replacement.

6. the chemical compound of claim 5, wherein R ⁷For methyl, ethyl, benzyl ,-C (CH ₃)=CH ₂,-CH ₂C (O) N (CH ₃) ₂, Or

Wherein V is O or CH ₂

7. the chemical compound of claim 1, wherein n is 0.

8. the chemical compound of claim 1, wherein n is 1, and X is NH.

9. the chemical compound of claim 8, wherein R ²Be selected from the heteroaryl alkyl group of aryl alkyl group, cycloalkyl, heteroaryl alkyl and replacement of aryl, aryl alkyl group, the replacement of alkyl group, aryl, the replacement of hydrogen, alkyl group, replacement.

10. the chemical compound of claim 8, wherein R ²Be selected from hydrogen, alkyl group and cycloalkyl.

11. the chemical compound of claim 10, wherein R ²Be selected from hydrogen, methyl, isopropyl, isobutyl group, sec-butyl, the tert-butyl group, cyclopenta and cyclohexyl.

12. the chemical compound of claim 8, wherein R ²Be selected from the alkyl group of replacement.

13. the chemical compound of claim 12, wherein R ²Be selected from-CH ₂OH ,-CH (OH) CH ₃,-CH ₂CO ₂H ,-CH ₂CH ₂CO ₂H ,-CH ₂CONH ₂,-CH ₂CH ₂CONH ₂,-CH ₂CH ₂SCH ₃, CH ₂SH ,-CH ₂(CH ₂) ₃NH ₂With-CH ₂CH ₂CH ₂NHC (NH) NH ₂

14. the chemical compound of claim 8, wherein R ²Be selected from the aryl alkyl group and the heteroaryl alkyl group of aryl, aryl alkyl group, replacement.

15. the chemical compound of claim 14, wherein R ²Be selected from phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazole radicals and 2-indyl.

16. the chemical compound of claim 1, wherein n is 1, and X is NR ¹⁶, and R ²And R ¹⁶With the assorted alkyl ring of ring that forms assorted alkyl of ring or replacement with their bonded atoms.

17. the chemical compound of claim 16, wherein R ²And R ¹⁶With form azetidine, pyrrolidine or piperidine ring with their bonded atoms.

18. the chemical compound of claim 1, wherein R ³And R ⁶Be independently selected from the cycloalkyl of aryl, cycloalkyl and replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement.

19. the chemical compound of claim 1, wherein R ³And R ⁶Be independently selected from hydrogen and alkyl group.

20. the chemical compound of claim 1, wherein R ³And R ⁶All be hydrogen.

21. the chemical compound of claim 1, wherein R ⁴And R ⁵Be independently selected from the heteroaryl of ring assorted alkyl, heteroaryl and replacement of aryl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring, the replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement.

22. the chemical compound of claim 1, wherein R ⁴And R ⁵Be independently selected from the alkyl group of hydrogen, alkyl group and replacement.

23. the chemical compound of claim 1, R wherein ⁴Be hydrogen, and R ⁵Be selected from C _1-6Alkyl group.

24. the chemical compound of claim 1, wherein R ⁴And R ⁵With the cycloalkyl that is cycloalkyl or replacement with their bonded carbon atoms.

25. the chemical compound of claim 1, wherein R ⁴And R ⁵With with their bonded carbon atoms for being selected from following group: the cyclohexyl of the cyclopenta of the cyclobutyl of cyclobutyl, replacement, cyclopenta, replacement, cyclohexyl and replacement.

26. the chemical compound of claim 1, wherein R ⁴And R ⁵With the ring assorted alkyl of their bonded carbon atoms for assorted alkyl of ring or replacement.

27. the chemical compound of claim 1, wherein R ⁴And R ⁵Be the bridged ring alkyl with their bonded carbon atoms.

28. chemical compound by the deutero-claim 1 of the GABA analog of formula (XIII) or 2:

The GABA analog of its Chinese style (XIII) is selected from:

1-aminomethyl-1,2-Cyclohexaneacetic acid;

1-aminomethyl-1,2-(3-hexahydrotoluene) acetic acid;

1-aminomethyl-1,2-(4-hexahydrotoluene) acetic acid;

1-aminomethyl-1,2-(4-isopropyl cyclohexane) acetic acid;

1-aminomethyl-1,2-(4-tert-butyl group cyclohexane extraction) acetic acid;

1-aminomethyl-1,2-(3, the 3-dimethyl cyclohexane) acetic acid;

1-aminomethyl-1,2-(3,3,5,5-tetramethyl-ring hexane) acetic acid;

1-aminomethyl-1,2-Pentamethylene. acetic acid;

1-aminomethyl-1,2-(3-methyl cyclopentane) acetic acid;

1-aminomethyl-1,2-(3, the 4-dimethylcyclopentane) acetic acid;

7-amino methyl-dicyclo [2.2.1] heptan-7-guanidine-acetic acid;

9-amino methyl-dicyclo [3.3.1] ninth of the ten Heavenly Stems-9-guanidine-acetic acid;

4-amino methyl-4-(tetrahydropyran-4-base) acetic acid;

3-amino methyl-3-(tetrahydropyran-3-base) acetic acid;

4-amino methyl-4-(tetrahydrochysene sulfo-pyrans-4-yl) acetic acid;

3-amino methyl-3-(tetrahydrochysene sulfo-pyrans-3-yl) acetic acid;

3-amino methyl-5-methyl-caproic acid;

3-amino methyl-5-methyl-enanthic acid;

3-amino methyl-5-methyl-sad;

3-amino methyl-5-methyl-n-nonanoic acid;

3-amino methyl-5-methyl-capric acid;

3-amino methyl-5-cyclopropyl-caproic acid;

3-amino methyl-5-cyclobutyl-caproic acid;

3-amino methyl-5-cyclopenta-caproic acid;

3-amino methyl-5-cyclohexyl-caproic acid;

3-amino methyl-5-phenyl-caproic acid;

3-amino methyl-5-phenyl-pentanoic acid;

3-amino methyl-4-cyclobutyl-butanoic acid;

3-amino methyl-4-cyclopenta-butanoic acid;

3-amino methyl-4-cyclohexyl-butanoic acid;

3-amino methyl-4-phenoxy group-butanoic acid;

3-amino methyl-5-phenoxy group-caproic acid; With

3-amino methyl-5-dibenzylsulfide. alkyl-valeric acid.

29. the chemical compound of formula (IV):

Or its pharmaceutically acceptable salt, hydrate or solvate, wherein:

Y, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ¹³, R ¹⁴, R ¹⁶And R ²⁵Define as claim 1;

Collateral condition is if R ¹³Or R ¹⁴Arbitrary be the cyclo alkoxy carbonyl of alkoxy carbonyl, carbamoyl, cyclo alkoxy carbonyl or the replacement of hydrogen, alkoxy carbonyl, replacement, then R ¹³Or R ¹⁴In another be not hydrogen; With

R ²⁵C (O) is not by the deutero-part of bile acid.

30. the chemical compound of claim 29, wherein Y is O, and R ⁷Be hydrogen.

31. the chemical compound of claim 29, wherein Y is O and R ⁷Aryl for alkenyl, aryl or the replacement of the alkyl group of alkyl group, replacement, alkenyl, replacement.

32. the chemical compound of claim 31, wherein R ⁷Be methyl, ethyl, benzyl ,-C (CH ₃)=CH ₂,-CH ₂C (O) N (CH ₃) ₂,

Or

Wherein V is O or CH ₂

33. the chemical compound of claim 29, wherein n is 0.

34. the chemical compound of claim 29, wherein n is 1, and X is NH.

35. chemical compound by the deutero-claim 29 of GABA analog of formula (XIII):

The GABA analog of its Chinese style (XIII) is selected from:

1-aminomethyl-1,2-Cyclohexaneacetic acid;

1-aminomethyl-1,2-(3-hexahydrotoluene) acetic acid;

1-aminomethyl-1,2-(4-hexahydrotoluene) acetic acid;

1-aminomethyl-1,2-(4-isopropyl cyclohexane) acetic acid;

1-aminomethyl-1,2-(4-tert-butyl group cyclohexane extraction) acetic acid;

1-aminomethyl-1,2-(3, the 3-dimethyl cyclohexane) acetic acid;

1-aminomethyl-1,2-(3,3,5,5-tetramethyl-ring hexane) acetic acid;

1-aminomethyl-1,2-Pentamethylene. acetic acid;

1-aminomethyl-1,2-(3-methyl cyclopentane) acetic acid;

1-aminomethyl-1,2-(3, the 4-dimethylcyclopentane) acetic acid;

7-amino methyl-dicyclo [2.2.1] heptan-7-guanidine-acetic acid;

4-amino methyl-4-(tetrahydropyran-4-base) acetic acid;

3-amino methyl-3-(tetrahydropyran-3-base) acetic acid;

4-amino methyl-4-(tetrahydrochysene sulfo-pyrans-4-yl) acetic acid;

3-amino methyl-3-(tetrahydrochysene sulfo-pyrans-3-yl) acetic acid;

3-amino methyl-5-methyl-caproic acid;

3-amino methyl-5-methyl-enanthic acid;

3-amino methyl-5-methyl-sad;

3-amino methyl-5-methyl-n-nonanoic acid;

3-amino methyl-5-methyl-capric acid;

3-amino methyl-5-cyclopropyl-caproic acid;

3-amino methyl-5-cyclobutyl-caproic acid;

3-amino methyl-5-cyclopenta-caproic acid;

3-amino methyl-5-cyclohexyl-caproic acid;

3-amino methyl-5-phenyl-caproic acid;

3-amino methyl-5-phenyl-pentanoic acid;

3-amino methyl-4-cyclobutyl-butanoic acid;

3-amino methyl-4-cyclopenta-butanoic acid;

3-amino methyl-4-cyclohexyl-butanoic acid;

3-amino methyl-4-phenoxy group-butanoic acid;

3-amino methyl-5-phenoxy group-caproic acid; With

3-amino methyl-5-dibenzylsulfide. alkyl-valeric acid.

36. formula (VII) or chemical compound (VIII):

Or its pharmaceutically acceptable salt, hydrate or solvate, wherein:

N, R ², R ⁷, R ¹³, R ¹⁴, R ¹⁶And R ²⁵Define as claim 1;

R ²⁵C (O) is not by the deutero-part of bile acid.

37. the chemical compound of claim 36, wherein R ⁷Be hydrogen.

38. the chemical compound of claim 36, wherein R ⁷Aryl for alkenyl, aryl or the replacement of the alkyl group of alkyl group, replacement, alkenyl, replacement.

39. the chemical compound of claim 38, wherein R ⁷For methyl, ethyl, benzyl ,-C (CH ₃)=CH ₂,-CH ₂C (O) N (CH ₃) ₂,

Or

Wherein V is O or CH ₂

40. the chemical compound of claim 36, wherein n is 0.

41. the chemical compound of claim 36, wherein n is 1.

42. the chemical compound of claim 40, wherein R ¹³Be methyl, R ⁷And R ¹⁴Be hydrogen, and R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals.

43. the chemical compound of claim 40, wherein R ¹³Be ethyl, R ⁷And R ¹⁴Be hydrogen, and R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals.

44. the chemical compound of claim 40, wherein R ¹³Be propyl group, R ⁷And R ¹⁴Be hydrogen, and R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals.

45. the chemical compound of claim 40, wherein R ¹³Be isopropyl, R ⁷And R ¹⁴Be hydrogen, and R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals.

46. the chemical compound of claim 40, wherein R ¹³Be butyl, R ⁷And R ¹⁴Be hydrogen, and R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1,3-dioxolanes-2-yl)-2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals.

47. the chemical compound of claim 40, wherein R ¹³Be isobutyl group, R ⁷And R ¹⁴Be hydrogen, and R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals.

48. the chemical compound of claim 40, wherein R ¹³Be sec-butyl, R ⁷And R ¹⁴Be hydrogen, and R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals.

49. the chemical compound of claim 40, wherein R ¹³Be the tert-butyl group, R ⁷And R ¹⁴Be hydrogen, and R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals.

50. the chemical compound of claim 40, wherein R ¹³Be cyclopenta, R ⁷And R ¹⁴Be hydrogen, and R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals.

51. the chemical compound of claim 40, wherein R ¹³Be cyclohexyl, R ⁷And R ¹⁴Be hydrogen, and R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals.

52. the chemical compound of claim 40, wherein R ¹³Be phenyl, R ⁷And R ¹⁴Be hydrogen, and R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals.

53. the chemical compound of claim 40, wherein R ¹³Be benzyl, R ⁷And R ¹⁴Be hydrogen, and R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals.

54. the chemical compound of claim 40, wherein R ¹³Be phenethyl, R ⁷And R ¹⁴Be hydrogen, and R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals.

55. the chemical compound of claim 40, wherein R ¹³Be 3-pyridine radicals, R ⁷And R ¹⁴Be hydrogen, and R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals.

56. the chemical compound of claim 40, wherein R ¹³Be methyl, R ¹⁴Be methyl, R ⁷Be hydrogen, and R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals.

57. the chemical compound of claim 40, wherein R ¹³Be methoxycarbonyl, R ¹⁴Be methyl, R ⁷Be hydrogen, and R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals.

58. the chemical compound of claim 40, wherein R ¹³Be ethoxy carbonyl, R ¹⁴Be methyl, R ⁷Be hydrogen, and R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals.

59. the chemical compound of claim 40, wherein R ¹³Be propoxycarbonyl, R ¹⁴Be methyl, R ⁷Be hydrogen, and R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals.

60. the chemical compound of claim 40, wherein R ¹³Be isopropoxy carbonyl, R ¹⁴Be methyl, R ⁷Be hydrogen, and R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals.

61. the chemical compound of claim 40, wherein R ¹³Be butoxy carbonyl, R ¹⁴Be methyl, R ⁷Be hydrogen, and R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals.

62. the chemical compound of claim 40, wherein R ¹³Be isobutoxy carbonyl, R ¹⁴Be methyl, R ⁷Be hydrogen, and R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals.

63. the chemical compound of claim 40, wherein R ¹³Be sec-butoxy carbonyl, R ¹⁴For methyl, R are hydrogen, and R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals.

64. the chemical compound of claim 40, wherein R ¹³Be tert-butoxycarbonyl, R ¹⁴Be methyl, R ⁷Be hydrogen, and R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals.

65. the chemical compound of claim 40, R wherein ¹³Be cyclohexyloxy carbonyl, R ¹⁴Be methyl, R ⁷Be hydrogen, and R ²⁵Be selected from methyl; ethyl; propyl group; isopropyl; butyl; isobutyl group; sec-butyl; amyl group; isopentyl; sec-amyl; neopentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolanes-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolanes-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolanes-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolanes-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-phenethyl; 1; 1-diethoxy-2-phenethyl; 1-(1; 3-dioxolanes-2-yl)-the 2-phenethyl; 1-(1,3-diox-2-yl)-2-phenethyl; acetyl group; propiono; bytyry; benzoyl; phenylacetyl group; phenyl; the 4-methoxyphenyl; benzyl; phenethyl; styryl; cyclopropyl; cyclobutyl; cyclopenta; cyclohexyl and 3-pyridine radicals.

66. the chemical compound of claim 41, wherein R ¹⁶Be hydrogen, and R ²Be selected from hydrogen, methyl, 2-propyl group, 2-butyl, isobutyl group, the tert-butyl group, cyclopenta, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazole radicals, 2-indyl ,-CH ₂OH ,-CH (OH) CH ₃,-CH ₂CO ₂H ,-CH ₂CH ₂CO ₂H ,-CH ₂CONH ₂,-CH ₂CH ₂CONH ₂,-CH ₂CH ₂SCH ₃,-CH ₂SH ,-CH ₂(CH ₂) ₃NH ₂With-CH ₂CH ₂CH ₂NHC (NH) NH ₂

67. the chemical compound of claim 66, wherein R ⁷Be hydrogen.

68. the chemical compound of claim 66, wherein R ⁷For methyl, ethyl, benzyl ,-C (CH ₃)=CH ₂,-CH ₂C (O) N (CH ₃) ₂,

Or

Wherein V is O or CH ₂

69. the chemical compound of claim 41, wherein R ⁷Be hydrogen, and R ²And R ¹⁶With their a bonded atoms-formation pyrrolidine ring.

70. formula V or chemical compound (VI):

Or its pharmaceutically acceptable salt, hydrate or solvate, wherein:

R ¹For

M is 0; With

N, R ², R ⁷, R ⁸, R ¹¹, R ¹²And R ¹⁶Define as claim 1.

71. the chemical compound of claim 70, wherein n is 0, R ⁷Be hydrogen, R ¹Be R ¹¹-K-, wherein R ¹¹Be selected from acetyl group, propiono, bytyry, isobutyryl, the cyclohexane extraction carbonyl, benzoyl, phenylacetyl group, methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, cyclohexyloxy carbonyl, phenyloxycarbonyl, benzyloxycarbonyl, carbamoyl, N-methylamino formoxyl, N-ethylamino formoxyl, N-propyl group carbamoyl, N-isopropyl carbamoyl, N-phenyl amino formoxyl, N-benzylamino formoxyl, N, the N-formyl-dimethylamino, N, N-diethylamino formoxyl, N, N-dipropyl carbamoyl, N-pyrrolidinyl carbamoyl, N-piperidyl amino formoxyl and N-morpholinyl carbamoyl; With

K is selected from following alkylene group: 1, the 2-ethenylidene, 1,2-acrylic-1-alkene, 1, crotyl-1-alkene, the 3-methyl isophthalic acid, crotyl-1-alkene, 2-phenyl-1,2-vinyl-1-alkene, 3-phenyl-1,2-acrylic-1-alkene, 2-methoxycarbonyl-1,2-vinyl-1-alkene, 2-ethoxy carbonyl-1,2-vinyl-1-alkene, 2-butoxy carbonyl-1,2-vinyl-1-alkene, the 1-methyl isophthalic acid, 2-vinyl-1-alkene, the 1-methyl isophthalic acid, 2-acrylic-1-alkene, the 1-methyl isophthalic acid, crotyl-1-alkene, 1,3-dimethyl-1, crotyl-1-alkene, 1-methyl-2-phenyl-1,2-vinyl-1-alkene, 1-methyl-3-phenyl-1,2-acrylic-1-alkene, 1-methyl-2-methoxycarbonyl-1,2-vinyl-1-alkene, 1-methyl-2-ethoxy carbonyl-1,2-vinyl-1-alkene, 1-methyl-2-butoxy carbonyl-1,2-vinyl-1-alkene, 1-ethyl-1,2-vinyl-1-alkene, 1-ethyl-1,2-acrylic-1-alkene, 1-ethyl-1, crotyl-1-alkene, 1-ethyl-3-methyl isophthalic acid, crotyl-1-alkene, 1-ethyl-2-phenyl-1,2-vinyl-1-alkene, 1-ethyl-3-phenyl-1,2-acrylic-1-alkene, 1-ethyl-2-methoxycarbonyl-1,2-vinyl-1-alkene, 1-ethyl-2-ethoxy carbonyl-1,2-vinyl-1-alkene, 1-ethyl-2-butoxy carbonyl-1,2-vinyl-1-alkene, 1-isopropyl-1,2-vinyl-1-alkene, 1-isopropyl-1,2-acrylic-1-alkene, 1-isopropyl-1, crotyl-1-alkene, 1-isopropyl-3-methyl isophthalic acid, crotyl-1-alkene, 1-isopropyl-2-phenyl-1,2-vinyl-1-alkene, 1-isopropyl-3-phenyl-1,2-acrylic-1-alkene, 1-isopropyl-2-methoxycarbonyl-1,2-vinyl-1-alkene, 1-isopropyl-2-ethoxy carbonyl-1,2-vinyl-1-alkene, 1-isopropyl-2-butoxy carbonyl-1,2-vinyl-1-alkene, 1-phenyl-1,2-vinyl-1-alkene, 1-phenyl-1,2-acrylic-1-alkene, 1-phenyl-1, crotyl-1-alkene, 1-phenyl-3-methyl isophthalic acid, crotyl-1-alkene, 1,2-diphenyl-1,2-vinyl-1-alkene, 1,3-diphenyl-1,2-acrylic-1-alkene, 1-phenyl-2-methoxycarbonyl-1,2-vinyl-1-alkene, 1-phenyl-2-ethoxy carbonyl-1,2-vinyl-1-alkene, 1-phenyl-2-butoxy carbonyl-1,2-vinyl-1-alkene, 1-benzyl-1,2-vinyl-1-alkene, 1-benzyl-1,2-acrylic-1-alkene, 1-benzyl-1, crotyl-1-alkene, 1-benzyl-3-methyl isophthalic acid, crotyl-1-alkene, 1-benzyl-2-phenyl-1,2-vinyl-1-alkene, 1-benzyl-3-phenyl-1,2-acrylic-1-alkene, 1-benzyl-2-methoxycarbonyl-1,2-vinyl-1-alkene, 1-benzyl-2-ethoxy carbonyl-1,2-vinyl-1-alkene, 1-benzyl-2-butoxy carbonyl-1,2-vinyl-1-alkene, 1-methoxycarbonyl-1,2-vinyl-1-alkene, 1-methoxycarbonyl-1,2-acrylic-1-alkene, 1-methoxycarbonyl-1, crotyl-1-alkene, 1-methoxycarbonyl-3-methyl isophthalic acid, crotyl-1-alkene, 1-methoxycarbonyl-2-phenyl-1,2-vinyl-1-alkene, 1-methoxycarbonyl-3-phenyl-1,2-acrylic-1-alkene, 1,2-dimethoxy carbonyl-1,2-vinyl-1-alkene, 1-methoxycarbonyl-2-ethoxy carbonyl-1,2-vinyl-1-alkene, 1-methoxycarbonyl-2-butoxy carbonyl-1,2-vinyl-1-alkene, 1-ethoxy carbonyl-1,2-vinyl-1-alkene, 1-ethoxy carbonyl-1,2-acrylic-1-alkene, 1-ethoxy carbonyl-1, crotyl-1-alkene, 1-ethoxy carbonyl-3-methyl isophthalic acid, crotyl-1-alkene, 1-ethoxy carbonyl-2-phenyl-1,2-vinyl-1-alkene, 1-ethoxy carbonyl-3-phenyl-1,2-acrylic-1-alkene, 1-ethoxy carbonyl-2-methoxycarbonyl-1,2-vinyl-1-alkene, 1,2-di ethoxy carbonyl-1,2-vinyl-1-alkene, 1-ethoxy carbonyl-2-butoxy carbonyl-1,2-vinyl-1-alkene, 1-butoxy carbonyl-1,2-vinyl-1-alkene, 1-butoxy carbonyl-1,2-acrylic-1-alkene, 1-butoxy carbonyl-1, crotyl-1-alkene, 1-butoxy carbonyl-3-methyl isophthalic acid, crotyl-1-alkene, 1-butoxy carbonyl-2-phenyl-1,2-vinyl-1-alkene, 1-butoxy carbonyl-3-phenyl-1,2-acrylic-1-alkene, 1-butoxy carbonyl-2-methoxycarbonyl-1,2-vinyl-1-alkene, 1-butoxy carbonyl-2-ethoxy carbonyl-1,2-vinyl-1-alkene and 1,2-dibutoxy carbonyl-1,2-vinyl-1-alkene.

72. the chemical compound of claim 70, wherein n is 1, R ¹⁶Be hydrogen, and R ²Be selected from hydrogen, methyl, 2-propyl group, 2-butyl, isobutyl group, the tert-butyl group, cyclopenta, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazole radicals, 2-indyl ,-CH ₂OH ,-CH (OH) CH ₃,-CH ₂CO ₂H ,-CH ₂CH ₂CO ₂H ,-CH ₂CONH ₂,-CH ₂CH ₂CONH ₂,-CH ₂CH ₂SCH ₃,-CH ₂SH ,-CH ₂(CH ₂) ₃NH ₂With-CH ₂CH ₂CH ₂NHC (NH) NH ₂

73. the chemical compound of claim 72, wherein R ⁷Be hydrogen.

74. the chemical compound of claim 72, wherein R ⁷For methyl, ethyl, benzyl ,-C (CH ₃)=CH ₂,-CH ₂C (O) N (CH ₃) ₂,

Or

Wherein V is O or CH ₂

75. the chemical compound of claim 70, wherein n is 1, R ⁷Be hydrogen, and R ²And R ¹⁶With form pyrrolidine ring with their bonded atoms.

76. the chemical compound of claim 70, wherein n is 0, R ⁷Be hydrogen, and R ⁸And R ¹²The assorted alkyl ring of ring with the cycloalkyl that forms cycloalkyl, replacement with their bonded carbon atoms, the assorted alkyl of ring or replacement.

77. the chemical compound of claim 76, wherein R ⁸And R ¹²Encircle penta-1-alkene, hexamethylene-1-alkene, 2-cyclopentenes-1-ketone, 2-cyclohexene-1-ketone, 2-(5H)-furanone or 5,6-dihydro-pyran-2-one ring with forming with their bonded carbon atoms.

78. the chemical compound of claim 77, wherein R ¹¹Be selected from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxy carbonyl and butoxy carbonyl.

79. the chemical compound of claim 70, wherein n is 0, R ⁷Be hydrogen, and R ⁸And R ¹¹The assorted alkyl ring of ring with the cycloalkyl that forms cycloalkyl, replacement with their bonded carbon atoms, the assorted alkyl of ring or replacement.

80. the chemical compound of claim 79, wherein R ⁸And R ¹¹With form gamma-butyrolacton, 6-valerolactone or 2 with their bonded carbon atoms, 2-dimethyl-1,3-diox-4,6-diketone ring.

81. the chemical compound of claim 80, wherein R ¹²Be selected from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxy carbonyl and butoxy carbonyl.

82. formula V or chemical compound (VI):

Or its pharmaceutically acceptable salt, hydrate or solvate, wherein:

R ¹For

And n, R ², R ⁷, R ¹⁵And R ¹⁶Define as claim 1.

83. the chemical compound of claim 82, wherein n is 0, R ⁷Be hydrogen, and R ¹⁵Be selected from methyl, ethyl, propyl group, isopropyl, cyclopenta, cyclohexyl, phenyl, 4-hydroxy phenyl, benzyl, 4-hydroxybenzyl and 3-pyridine radicals.

84. the chemical compound of claim 82, wherein n is 1, R ¹⁵Be hydrogen, and R ²Be selected from hydrogen, methyl, 2-propyl group, 2-butyl, isobutyl group, the tert-butyl group, cyclopenta, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazole radicals, 2-indyl ,-CH ₂OH ,-CH (OH) CH ₃,-CH ₂CO ₂H ,-CH ₂CH ₂CO ₂H ,-CH ₂CONH ₂,-CH ₂CH ₂CONH ₂,-CH ₂CH ₂SCH ₃,-CH ₂SH ,-CH ₂(CH ₂) ₃NH ₂With-CH ₂CH ₂CH ₂NHC (NH) NH ₂

85. the chemical compound of claim 84, wherein R ⁷Be hydrogen.

86. the chemical compound of claim 84, wherein R ⁷For methyl, ethyl, benzyl ,-C (CH ₃)=CH ₂,-CH ₂C (O) N (CH ₃) ₂,

Or

Wherein V is O or CH ₂

87. the chemical compound of claim 82, wherein n is 1, R ⁷Be hydrogen, and R ²And R ¹⁶With form pyrrolidine ring with their bonded atoms.

88. have the chemical compound of the claim 1 of formula (IX) or structure (X),

Or its pharmaceutically acceptable salt, hydrate or solvate, wherein: t, R ², R ⁷, R ²⁰And R ²¹Define as claim 1.

89. the chemical compound of claim 88, wherein t is 0.

90. the chemical compound of claim 88, wherein t is 1, and R ²Be selected from hydrogen, methyl, 2-propyl group, 2-butyl, isobutyl group, the tert-butyl group, cyclopenta, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazole radicals, 2-indyl ,-CH ₂OH ,-CH (OH) CH ₃,-CH ₂CO ₂H ,-CH ₂CH ₂CO ₂H ,-CH ₂CONH ₂,-CH ₂CH ₂CONH ₂,-CH ₂CH ₂SCH ₃,-CH ₂SH ,-CH ₂(CH ₂) ₃NH ₂With-CH ₂CH ₂CH ₂NHC (NH) NH ₂

91. the chemical compound of claim 89 or 90, wherein R ²⁰And R ²¹Be independently selected from the heteroaryl of aryl, heteroaryl and replacement of alkyl, aryl, the replacement of alkyl, replacement.

92. the chemical compound of claim 89 or 90, wherein R ²⁰And R ²¹The assorted alkyl ring of ring with the cycloalkyl that forms cycloalkyl, replacement with their bonded carbon atoms, the assorted alkyl of ring or replacement.

93. the chemical compound of claim 91 and 92, wherein R ⁷For hydrogen, methyl, ethyl, benzyl ,-C (CH ₃)=CH ₂,-CH ₂C (O) N (CH ₃) ₂,

Or

Wherein V is O or CH ₂

94. have the chemical compound of formula (XI) or claim 1 (XII):

Or its pharmaceutically acceptable salt, hydrate or solvate, wherein:

N, R ¹, R ², R ²²And R ²³Define as claim 1.

95. the chemical compound of claim 94, wherein n is 1, and X is NH, R ¹Be hydrogen, and R ²Be aryl alkyl.

96. the chemical compound of claim 95, wherein R ²Be benzyl.

97. the chemical compound of claim 94, wherein n is 0, and R ¹Be R ²⁵OC (O)-.

98. the chemical compound of claim 97, wherein R ²⁵Be selected from the heteroaryl of aryl, heteroaryl and replacement of alkyl, aryl, the replacement of alkyl, replacement.

99. the chemical compound of claim 98, wherein R ²⁵Be ethyl.

100. the chemical compound of claim 94, wherein R ²²And R ²³Be independently selected from the alkyl of hydrogen, alkyl and replacement.

101. the chemical compound of each of claim 94-100, wherein R ²²Be methyl, and R ²³Be hydrogen.

102. the chemical compound of each of claim 94-100, wherein R ²²Be methyl, and R ²³Be methyl.

103. treatment or prevention patient's the method for following disease: epilepsy, depression, anxiety, psychosis, faintness outbreak, hypocinesis, cranium are unusual, neurodegenerative disease, fear, pain, inflammatory diseases, insomnia, gastrointestinal disease or ethanol withdrawal symptom, described method comprise to patient's administering therapeutic effective dose of this treatment of needs according to claim 1,29,36,70,82,88 or 94 each chemical compound.

104. treatment or prevention patient's the method for neuropathic pain, myalgia or skeleton pain, described method comprise to patient's administering therapeutic effective dose of this treatment of needs according to claim 1,29,36,70,82,88 or 94 each chemical compound.

105. an epilepsy that is used for the treatment of or prevents the patient, depression, anxiety, psychosis, faintness outbreak, hypocinesis, cranium are unusual, the pharmaceutical composition of neurodegenerative disease, fear, pain, inflammatory diseases, insomnia, gastrointestinal disease or ethanol withdrawal symptom, described compositions comprise the treatment effective dose according to claim 1,29,36,70,82,88 or 94 each chemical compound and pharmaceutically acceptable excipient.

106. the pharmaceutical composition of a neuropathic pain that is used for the treatment of or prevents the patient, myalgia or skeleton pain, described compositions comprise the treatment effective dose according to claim 1,29,36,70,82,88 or 94 each chemical compound and pharmaceutically acceptable excipient.

107. GABA analog derivant that the patient who is used for to needs treatments uses, M-G, wherein M is a primitive, and G is derived by GABA analog H-G, wherein H is a hydrogen, and wherein primitive M is in case cracking from any metabolite of G and it shows the carcinogenic toxicity dosage (TD to rat greater than 0.2mmol/kg/ days ₅₀), and when rat is carried out colon administration primitive M in vivo with the cracking from the G of competent speed, to produce:

(i) be at least the C of the blood plasma H-G that the H-G by molar doses such as colonic administration obtains _MaxThe Cmax C of 120% blood plasma H-G _MaxWith

108. the GABA analog derivant that the patient who is used for to needs treatments uses, M-G, wherein M is a primitive, and G is derived by GABA analog H-G, and wherein H is a hydrogen, wherein M-G has the structure of formula (XIV):

Or the pharmaceutically acceptable salt of described chemical compound, hydrate or solvate, wherein:

Y is O or S;

R ⁴And R ⁵Be independently selected from the heteroaryl alkyl of heteroaryl, heteroaryl alkyl and replacement of the assorted alkyl of ring, heteroaryl, the replacement of aryl alkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring, the replacement of aryl, aryl alkyl, the replacement of acyl group, aryl, the replacement of alkyl, acyl group, the replacement of hydrogen, alkyl, replacement, perhaps optional R ⁴And R ⁵Assorted alkyl of ring or bridged ring alkyl ring with the cycloalkyl that forms cycloalkyl, replacement with their bonded carbon atoms, the assorted alkyl of ring, replacement;

R ⁷Be selected from the heteroaryl alkyl of heteroaryl, heteroaryl alkyl and replacement of assorted alkyl, heteroaryl, the replacement of aryl alkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring of aryl, aryl alkyl, the replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement, the assorted alkyl of ring of replacement, assorted alkyl, replacement; With

Wherein primitive M is in case cracking from any metabolite of G and it shows the carcinogenic toxicity dosage (TD to rat greater than 0.2mmol/kg/ days ₅₀), and when rat is carried out colon administration primitive M in vivo with the cracking from the G of competent speed, to produce:

109. a GABA analog derivant of using to the patient who needs treatment, M-G, wherein M is a primitive, and G is derived by GABA analog H-G, wherein H is a hydrogen, and wherein M-G has the structure of formula (XIV), and M has the structure of formula (XV):

Wherein: n, X, R ¹And R ²Define as claim 1; With

And wherein primitive M is in case cracking from any metabolite of G and it shows the carcinogenic toxicity dosage (TD to rat greater than 0.2mmol/kg/ days ₅₀), and when rat is carried out colon administration primitive M in vivo with the cracking from the G of competent speed, to produce:

(i) be at least the C of the blood plasma H-G that the H-G by molar doses such as colonic administration obtains _Max120% blood plasma H-G Cmax C _MaxWith

110. the GABA analog derivant of each of claim 107-109, M-G, wherein H-G is in case go up cracking from M, is substantially devoid of the lactams of (XVI) structure that has formula;

Wherein R is a hydrogen.

111. the GABA analog derivant of each of claim 107-109, M-G wherein is substantially devoid of formaldehyde during cracking as M from any metabolite of G and it.

112. the GABA analog derivant of each of claim 107-109, M-G wherein is substantially devoid of neopentanoic acid during cracking as M from any metabolite of G and it.

113. the GABA analog derivant of each of claim 107-109, M-G, wherein primitive M is at least the C of the blood plasma H-G that the H-G by molar doses such as colonic administration reaches in vivo with the cracking from the G of competent speed with generation when rat is carried out colon administration _MaxThe C of 200% blood plasma H-G _Max

114. the GABA analog derivant of each of claim 107-109, M-G, wherein primitive M is at least the C of the blood plasma H-G that the H-G by molar doses such as colonic administration reaches in vivo with the cracking from the G of competent speed with generation when rat is carried out colon administration _MaxThe C of 1000% blood plasma H-G _Max

115. the GABA analog derivant of each of claim 107-109, M-G, wherein primitive M is at least the AUC of 200% blood plasma H-G of the AUC of the blood plasma H-G that the H-G by molar doses such as colonic administration reaches in vivo with the cracking from the G of competent speed with generation when rat is carried out colon administration.

116. the GABA analog derivant of each of claim 107-109, M-G, wherein primitive M is at least the AUC of 500% blood plasma H-G of the AUC of the blood plasma H-G that the H-G by molar doses such as colonic administration reaches in vivo with the cracking from the G of competent speed with generation when rat is carried out colon administration.

117. the GABA analog derivant of each of claim 107-109, M-G, wherein after the dosage that uses lasting releasing device with the normal H-G/kg of about 60 μ mol carries out oral administration to Canis familiaris L., primitive M goes up cracking with competent speed from G in vivo, is at least 200% the blood plasma H-G concentration that is obtained blood plasma H-G concentration according to identical administering mode by the H-G that waits molar dose to produce at the back 12h that takes medicine.