CN101434572A - Prodrugs of GABA analogs, compositions and uses thereof - Google Patents

Prodrugs of GABA analogs, compositions and uses thereof Download PDF

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CN101434572A
CN101434572A CNA2008101693558A CN200810169355A CN101434572A CN 101434572 A CN101434572 A CN 101434572A CN A2008101693558 A CNA2008101693558 A CN A2008101693558A CN 200810169355 A CN200810169355 A CN 200810169355A CN 101434572 A CN101434572 A CN 101434572A
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replacement
alkyl
compound
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cycloalkyl
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CN101434572B (en
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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
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XenoPort Inc
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Abstract

The invention provides prodrugs of GABA analogs, pharmaceutical compositions of prodrugs of GABA analogs and methods for making prodrugs of GABA analogs. The 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 analogue and composition thereof and application
The present invention is to be the dividing an application of Chinese patent application 02814572.0 on June 11st, 2002 applying date, and the invention exercise question of original application is " prodrug of GABA analogue and composition 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 analogue, the pharmaceutical composition of GABA analogue prodrug, the preparation method of the prodrug of GABA analogue, the application method of the pharmaceutical composition of GABA analogue prodrug and GABA analogue 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 method 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 L-glutamic acid and pyridoxal phosphate) in fact in brain.
GABA is by combining and regulate neuronic excitability with specific membranin (being the GABAA acceptor), thereby causes ionic channel open.Chloride ion enters and causes the hyperpolarization of recipient cell by ionic channel, thereby prevents from Nerve impulse is delivered to other cell.In epileptic seizures, movement disorders (as multiple sclerosis, action 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 analogue preparation with the pharmaceutical property (for example seeing through the ability of hemato encephalic barrier) that is better than GABA.Therefore, synthesized in the art multiple GABA analogue 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 WO9 8/17627; 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,
G gabapentin Pregabalin
(1) (2)
Figure A200810169355D00052
Figure A200810169355D00053
The vigabatrin baclofen
(3) (4)
International open WO 00/50027; With people such as Bryans, international open WO 02/00209).
For example pharmaceutically important GABA analogue comprises gabapentin (1), pregabalin (2), vigabatrin (3) and the baclofen (4) shown in above.Gabapentin is a kind of lipotropy GABA analogue that can pass through hemato encephalic barrier, and since nineteen ninety-four it has been used for the clinical treatment epilepsy.Gabapentin also may have the useful therapeutic action 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, action 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 analogues is that gamma-amino and carboxyl functional group generation intramolecular 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, mouse) and greater than 8000mg/kg, and the toxicity (LD of corresponding lactan (5) 50, mouse) and be 300mg/kg.Therefore, because safety, the formation of in the preparation of the composition of synthetic and/or the GABA analogue or the GABA analogue of GABA analogue and/or storage process by product such as lactan is minimized (particularly exist
Figure A200810169355D00061
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 lactan pollution problem, particularly the lactan pollution problem under the situation of gabapentin of GABA analogue.But, prevent trial not achieving success fully aspect the synthetic or storage of GABA analogue such as gabapentin or its composition that lactan pollutes.
The System Cleaning rate is many GABA analogues, 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 anticonvulsion 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 analogues, comprise gabapentin and the obstructed excessive intestinal absorption of pregabalin.On the contrary, these compounds generally in small intestine, absorbed by big neutral amino acid transporter agent (" LNAA ") (people such as Jezyk, Pharm.RES., 1999,16,519-526).The rapid passage of passing through GI near-end absorption region of regular dosage form has hindered and will continue release tech and successfully be applied to many GABA analogues.
Therefore, be starved of the lasting release embodiments of effective GABA analogue, minimize with the increase of the frequency of taking medicine that will cause owing to the rapid system clearance rate of these compounds.Also need pure GABA analogue pure basically and unautogenous ground lactamize in preparation or storage process, (particularly gabapentin and pregablin analogue).
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 analogue is provided, GABA analogue and the prodrug of GABA analogue is devoted to these and other needs.The present invention also provide the GABA analogue prodrug application method and the pharmaceutical composition of the prodrug of GABA analogue is used for the treatment of or prevents the method for common disease and/or illness.
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 analogue provided by the invention generally is unsettled (promptly producing a large amount of GABA analogues by enzymatic or chemical process cracking before removing prodrug from the patient) in vivo.The second, the primitive derivative and its any metabolite that provide by cracking primitive from prodrug are generally nontoxic when being applied to Mammals according to the scheme of taking medicine of generally following the GABA analogue.
Compound of the present invention has an amino primitive that links to each other of the γ with the GABA analogue.This primitive can directly link to each other with the γ of GABA analogue is amino, and perhaps optional can linking to each other with the amino of a-amino acid primitive or the hydroxyl of alpha hydroxy acid primitive, described primitive self links to each other with the γ of GABA analogue is amino.
Compound of the present invention can also have the primitive that links to each other with the carboxyl of GABA analogue.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, 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 analogue) at the most.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 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 compound of formula (I), formula (II) or formula (III):
Figure A200810169355D00081
Or its pharmacy 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-,
With
Figure A200810169355D00092
Each R 2Be independently selected from hydrogen; alkyl; the alkyl that replaces; alkoxyl group; the alkoxyl group that replaces; acyl group; the acyl group that replaces; acyl amino; the acyl amino that replaces; alkylamino; the alkylamino that replaces; alkyl sulphinyl; the alkyl sulphinyl that replaces; alkyl sulphonyl; the alkyl sulphonyl that replaces; alkylthio; the alkylthio that replaces; alkoxy carbonyl; the alkoxy carbonyl that replaces; aryl; the aryl that replaces; arylalkyl; the arylalkyl that replaces; aryloxy; the aryloxy that replaces; formamyl; 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; heteroarylalkyl; the heteroarylalkyl that replaces; assorted alkoxyl group; the assorted alkoxyl group 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 heteroarylalkyl of heteroaryl, heteroarylalkyl and replacement of the assorted alkyl of ring, heteroaryl, the replacement of arylalkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring, the replacement of aryl, arylalkyl, the replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement;
R 4And R 5Be independently selected from the heteroarylalkyl of ring assorted alkyl, heteroarylalkyl and replacement of arylalkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring, the replacement of acyl group, arylalkyl, 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 heteroarylalkyl of heteroaryl, heteroarylalkyl and replacement of assorted alkyl, heteroaryl, the replacement of arylalkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring of aryl, arylalkyl, 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, arylalkyl, the arylalkyl that replaces, formamyl, cyano group, cycloalkyl, the cycloalkyl that replaces, Heterocyclylalkyl, the Heterocyclylalkyl that replaces, heteroaryl, the heteroaryl that replaces, heteroarylalkyl, the heteroarylalkyl 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 heteroarylalkyl of heteroaryl, heteroarylalkyl and replacement of assorted alkyl, heteroaryl, the replacement of arylalkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring of aryl, arylalkyl, 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 heteroarylalkyl of heteroaryl, heteroarylalkyl and replacement of cyclo alkoxy carbonyl, heteroaryl, the replacement of cycloalkyl, cyclo alkoxy carbonyl, the replacement of arylalkyl, formamyl, cycloalkyl, the replacement of aryl, arylalkyl, 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 heteroarylalkyl of heteroaryl, heteroarylalkyl and replacement of assorted alkyl, heteroaryl, the replacement of arylalkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring of aryl, arylalkyl, 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 arylalkyl of aryl, arylalkyl 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 heteroarylalkyl of heteroaryl, heteroarylalkyl and replacement of assorted alkyl, heteroaryl, the replacement of arylalkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring of aryl, arylalkyl, 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 heteroarylalkyl of heteroaryl, heteroarylalkyl and replacement of assorted alkyl, heteroaryl, the replacement of arylalkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring of aryl, arylalkyl, 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 compound of the present invention.Described pharmaceutical composition generally comprises one or more compounds of the present invention and pharmaceutically acceptable vehicle.
In the third aspect, the invention provides treatment or prevent the method for following disease: epilepsy, depression, anxiety, psychosis, faintness outbreak, hypokinesis, cranium are unusual, neurodegenerative disease, fear, pain (particularly neuropathic pain and muscle and skeleton pain), inflammatory diseases (being sacroiliitis), insomnia, gastrointestinal illness or ethanol withdrawal symptom.Described method generally comprises the compound of the present invention to patient's administering therapeutic significant quantity 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, hypokinesis, cranium are unusual, neurodegenerative disease, fear, pain (particularly neuropathic pain and muscle and skeleton pain), inflammatory diseases (being sacroiliitis), insomnia, gastrointestinal illness or ethanol withdrawal symptom.Described method generally comprises the pharmaceutical composition of the present invention to patient's administering therapeutic significant quantity of this treatment of needs or prevention.
Aspect the 5th, the present invention includes and be used for the GABA analogue derivative compound that the patient to needs treatments carries out administration, M-G, wherein M be primitive and G by the GABA analogue, H-G (wherein H is a hydrogen) derives.Primitive M is in case go up cracking from G, and its any meta-bolites 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 peak concentration (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 derivative of formula (XIV):
Figure A200810169355D00121
Or its pharmacy acceptable salt, hydrate or solvate, wherein:
R is a hydrogen, or R and R 6Form the pyrrolidine ring of azetidine, tetramethyleneimine 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 derivative of formula (XV):
Figure A200810169355D00131
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 cytolemma: 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 translocator mediates
" Alkyl" refer to that deutero-is saturated or unsaturated by removing a hydrogen atom from the single carbon atom of parent alkane, alkene or alkynes, straight chain, side chain or ring monovalence alkyl.Typical alkyl includes but not limited to methyl; Ethyl such as ethyl group, vinyl, ethynyl; 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 (allyl group), 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 saturated side chain, straight chain or the cycloalkyl of deutero-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 (sec.-propyl), ring third-1-base etc.; Butyl such as fourth-1-base, fourth-2-base (sec-butyl), 2-methyl-third-1-base (isobutyl-), 2-methyl-third-2-base (tertiary butyl), ring fourth-1-base etc.
" Alkenyl" refer to by removing a hydrogen atom and deutero-has unsaturated side chain, straight chain or the cycloalkyl of 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; Propenyl is as third-1-alkene-1-base, third-1-alkene-2-base, third-2-alkene-1-base (allyl group), third-2-alkene-2-base, ring third-1-alkene-1-base; Ring third-2-alkene-1-base; Butenyl 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 that deutero-has unsaturated side chain, straight chain or the cycloalkyl of at least one carbon-to-carbon three key by removing a hydrogen atom from the single carbon atom of parent alkynyl.Typical alkynyl includes but not limited to ethynyl; Proyl 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, arylalkyl, assorted alkyl, heteroaryl, the heteroarylalkyl of this paper definition.Representational example includes but not limited to formyl radical, ethanoyl, cyclohexyl-carbonyl, cyclohexyl methyl carbonyl, benzoyl, benzyloxycarbonyl group etc.
" Acyl amino" (or selectable " acyl group amido ") refer to group-NR ' C (O) R, wherein R ' and R are as defined herein the assorted alkyl of hydrogen, alkyl, cycloalkyl, ring, aryl, arylalkyl, assorted alkyl, heteroaryl, heteroarylalkyl independently of one another.Representational example includes but not limited to formyl radical amino, acetylamino (being kharophen), 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, arylalkyl, assorted alkyl, heteroaryl or heteroarylalkyl.Representational example includes but not limited to acetoxyl group (or acetoxyl), butoxy (butyloxy or butoxy), benzoyloxy etc.
" Alkylamino" 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 group" refer to group-OR, wherein R represents the alkyl or cycloalkyl of this paper definition.Representational example includes but not limited to methoxyl group, oxyethyl group, propoxy-, butoxy, cyclohexyloxy etc.
" Alkoxy carbonyl" refer to group-C (O)-alkoxyl group, wherein alkoxyl group 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 alkylsulfonyl 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" 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 methylthio group, 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 hydrogen atom and deutero-monovalence aryl radical.Typical aryl includes but not limited to by following deutero-group: aceanthrylene, acenaphthene, acephenanthrylene, anthracene,
Figure A200810169355D0015155855QIETU
, benzene,
Figure A200810169355D0015173829QIETU
, cool, 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-2,4-diene, pentacene, pentalene, pentaphene (phetaphene), perylene, anthracene (phenalene), Fei, Pi, pleiadene, pyrene, pyranthrene, rubicene, benzophenanthrene, trinaphthylene etc.Preferred aryl groups contains 6-20 carbon atom, more preferably 6-12 carbon atom.
" Arylalkyl" refer to non-cycloalkyl wherein with carbon atom, be generally end or SP 3Carbon atom bonded hydrogen atom is replaced by aryl.Typical arylalkyl includes but not limited to benzyl, 2-phenyl second-1-base, 2-phenyl ethene-1-base, naphthyl methyl, 2-naphthyl second-1-base, 2-naphthyl ethene-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) arylalkyl, for example the alkyl group of arylalkyl, alkenyl or alkynyl partly are (C 1-C 10), and aryl moiety is (C 6-C 20), more preferably arylalkyl is (C 6-C 20) arylalkyl, for example the alkyl group of arylalkyl, alkenyl or alkynyl partly are (C 1-C 8), and aryl moiety is (C 6-C 12).
" Alkoxy aryl" refer to wherein arylalkyl as defined herein-the O-arylalkyl.
" 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 curve from the zero-time to infinitely great extrapolation.
" The bridged ring alkyl" refer to be selected from following group:
Figure A200810169355D00161
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.
" Formamyl" 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 tumour is the chronic dose-grade of unit with the mg/kg body weight/day.Because relevant tumour 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 tumour during this period.Can calculate the knurl 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.
" Compound of the present invention" referring to the 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.Compound of the present invention can be identified by their chemical structure and/or chemical name.When chemical structure and chemical name conflict, the identity of chemical structure decision compound.Compound of the present invention can comprise one or more chiral centres and/or two key, therefore can be used as steric isomer such as double bond isomer (being geometrical isomer), optically active enantiomorph or diastereomer and exists.Therefore, the all possible optically active enantiomorph and the steric isomer of compound shown in chemical structure as herein described comprises comprise the pure form of steric isomer (for example geometry is pure, optically active enantiomorph is pure or diastereisomericallypure pure) and enantiomer and stereoisomer mixture.Can use isolation technique well known by persons skilled in the art or chirality synthetic technology enantiomer and stereoisomer mixture to be split into their composition optically active enantiomorph or steric isomer.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 compound shown in structural formula as herein described comprises.Compound of the present invention also comprises isotope-labeled compound, and the nucleidic mass of wherein one or more atoms is different from the nucleidic mass of finding usually in nature.The isotopic example that can be included in the 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.
" Composition of the present invention" refer at least a compound of the present invention and pharmaceutically acceptable vehicle, by it with described compound administration in the people.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, hexanaphthenes.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 heteroatoms independently.The heteroatoms 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, tetramethyleneimine, rubane etc.
" The assorted alkoxy carbonyl of ring" refer to group-C (O)-OR, wherein R is as the assorted alkyl of the ring of above definition.
" Derive by bile acide" refer on the structure and formula (XVII) or the relevant part of 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 linkage that has been used as the binding site of another part with the hydroxylic moiety bonded hydrogen atom of hydroxyl and/or carboxyl replaces, and this another part is preferably GABA analogue or GABA analogue derivative.
" Derive by the GABA analogue" refer to part relevant on the structure with the GABA analogue.The structure of described part is identical with described compound, except 1 or 2.In these positions, the covalent linkage that has been used as the binding site of another part with hydroxylic moiety bonded hydrogen atom 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 analogue" compound that refers to have following structure:
Wherein:
R is a hydrogen, perhaps R and R 6With the pyrrolidine ring that forms azetidine, tetramethyleneimine or the replacement of azetidine, replacement with their bonded atoms;
R 3And R 6Be independently selected from the heteroarylalkyl of heteroaryl, heteroarylalkyl and replacement of the assorted alkyl of ring, heteroaryl, the replacement of arylalkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring, the replacement of aryl, arylalkyl, the replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement; With
R 4And R 5Be independently selected from the heteroarylalkyl or the optional R of heteroaryl, heteroarylalkyl and replacement of the assorted alkyl of ring, heteroaryl, the replacement of arylalkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring, the replacement of aryl, arylalkyl, 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 group" 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 heteroatoms 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 impurity elimination aromatic ring system.Typical heteroaryl includes but not limited to by following deutero-group: acridine, arsindole, carbazole, β-Ka Lin, chroman, chromene, cinnolines, furans, imidazoles, indazole, indoles, indoline, indolizine, isobenzofuran, different chromene, isoindole, isoindoline, isoquinoline 99.9, isothiazole, isoxazole, naphthyridines, oxadiazole, oxazole,
Figure A200810169355D0020112800QIETU
Pyridine, phenanthridines, phenanthroline, azophenlyene, phthalazines, pteridine, purine, pyrans, pyrazine, pyrazoles, pyridazine, pyridine, pyrimidine, 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, thionaphthene, cumarone, indoles, pyridine, quinoline, imidazoles, oxazole and pyrazine deutero-heteroaryl.
" The heteroaryloxy carbonyl" refer to group-C (O)-OR, wherein R is the heteroaryl of this paper definition." Heteroarylalkyl" refer to acyclic alkyl wherein with carbon atom, be generally end or SP 3Hydrogen atom of carbon atom bonded 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, heteroarylalkyl is a 6-30 unit heteroarylalkyl, for example the alkyl group of heteroarylalkyl, alkenyl or alkynyl partly are 1-10 unit, and heteroaryl moieties is a 5-20 unit heteroaryl, more preferably 6-20 unit heteroarylalkyl, for example the alkyl group of heteroarylalkyl, 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 translocator 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 rate of permeation of standard cell lines individual layer (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.
" Pharmacy 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 salt, and it is and forms such as following mineral acid: example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc.; Perhaps with such as following organic acid form: acetate, propionic acid, caproic acid, the pentamethylene propionic acid, oxyacetic acid, pyruvic acid, lactic acid, propanedioic acid, succsinic acid, oxysuccinic acid, toxilic acid, fumaric acid, tartrate, citric acid, phenylformic acid, 3-(4-hydroxy benzoyl) phenylformic acid, styracin, tussol, methylsulfonic acid, ethyl sulfonic acid, 1, the 2-ethionic acid, the 2-ethylenehydrinsulfonic acid, Phenylsulfonic acid, the 4-chlorobenzenesulfonic acid, the 2-naphthene sulfonic acid, the 4-toluenesulphonic acids, camphorsulfonic acid, 4-methyl bicycle 2.2.2-oct-2-ene-1-formic acid, glucoheptonic acid, the 3-phenylpropionic acid, trimethylacetic acid, tert.-butylacetic acid, lauryl sulfate, glyconic acid, L-glutamic acid, hydroxynaphthoic acid, Whitfield's ointment, 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 alkalimetal ion, alkaline earth ion or aluminum ion, forming; The perhaps title complex that forms with organic bases such as thanomin, diethylamine amine, trolamine, N-methylglucosamine etc.
" Pharmaceutically acceptable vehicle" refer to thinner, auxiliary agent, vehicle or the carrier used with compound of the present invention.
" The patient" comprise the people.Term " people " and " patient " can exchange use in this article.
" Prevention (preventing or prevention)" refer to the risk of disease or illness 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 derivative 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 shield 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 formyl radical, ethanoyl, 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 acylations or alkylating group such as benzyl and trityl ether and alkyl oxide, THP trtrahydropyranyl ether, trialkylsilyl ethers and allyl ethers.
" Replace" refer to that one or more hydrogen atom is independently of one another by the group of identical or different substituting group replacement.Typical substituting 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, heteroarylalkyl, the replacement of assorted alkyl, heteroaryl, the replacement of arylalkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring of aryl, arylalkyl, the replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement, the assorted alkyl of ring of replacement, assorted alkyl, replacement heteroarylalkyl ,-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 while bonded atoms; And R 31And R 32Be the heteroarylalkyl of heteroaryl, heteroarylalkyl or replacement of assorted alkyl, heteroaryl, the replacement of arylalkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring of aryl, arylalkyl, the replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement, the assorted alkyl of ring of replacement, assorted alkyl, replacement independently.
" Translocator" refer to molecule transhipment is entered and/or by cell processes in play the albumen of direct or indirect effect.For example, translocator 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.Translocator 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 acceptor adjusting.Translocator 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.Translocator 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 acceptor with substrate, influences perhaps that substrate enters or the translocator by cell.The carrier proteins example comprises: intestines and the agent of hepatic bile acid transporter, dipeptides transport agents, oligopeptides transport agents, monose 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 translocator that acceptor is regulated comprises: virus receptor, immunoglobulin receptor, bacteriotoxin acceptor, phytohemagglutinin acceptor, bacterial adhesion acceptor, VITAMIN transport agents and cytokine growth factor receptors.
Any disease or illness " Treatment (treating or treatment)" refer to improve disease or illness (promptly stopping or reducing the development of disease or its at least a clinical symptom) 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 illness simultaneously.In further another embodiment, " treatment (treating or treatment) " refers to postpone the generation of disease or illness.
" The treatment significant quantity" mean compound and be enough to carry out the quantity of this treatment of diseases during disease with treatment being applied to the patient." treatment significant quantity " will become with compound, disease and its 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 compound of the present invention
Those skilled in the art will recognize that formula (I), (II) and compound (III) have common ground on some constitutional features.These compounds all are in conjunction with the GABA analogue (being gamma-aminobutyric acid derivative) of primitive.Particularly, R 2, R 3, R 4, R 5, R 6, X and Y be the common substituting group of finding in formula (I), (II) and the compound (III).
Compound of the present invention comprises the compound of formula (I), formula (II) or formula (III)
Figure A200810169355D00241
Or its pharmacy 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 compound (III) do not comprise following compound:
Work as R 3And R 6When all being hydrogen, R 4And R 5Not all be hydrogen or not all for methyl;
In the compound of formula (I), when n be 0 or when n be 1, and X is NR 16The time, R then 1Be not hydrogen;
In the compound of formula (I), R 1, R 7O-, R 24C (O)-, R 25C (O)-and R 25O-is not by bile acide deutero-part;
In the compound of formula (I), work as R 1Be R 24C (O)-and n is 0 o'clock, R 24It is not methyl, the tertiary butyl, 2-amino-ethyl, 3-aminopropyl, benzyl, phenyl or 2-(benzoyloxy methyl) phenyl;
In the 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 heteroarylalkyl of heteroaryl, heteroarylalkyl and replacement of assorted alkyl, heteroaryl, the replacement of arylalkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring of aryl, arylalkyl, the replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement, the assorted alkyl of ring of replacement, assorted alkyl, replacement;
In the compound of formula (I), work as R 1Be R 25OC (O)-and n is 0 o'clock, R 25Be not methyl, the tertiary butyl or benzyl;
In the 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, formamyl, cyclo alkoxy carbonyl or the replacement of hydrogen, alkoxy carbonyl, replacement, then R 13Or R 14In another be not hydrogen;
In the 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 compound of formula (II), when t is 1, u is 0 o'clock, R 20Or R 21It is not 2-hydroxy-3-methyl-5-chloro-phenyl-; With
In the compound of formula (II), when u is 1 and X when being O, t is 1.
In an embodiment of formula (I), (II) and 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 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 compound of formula (I), R 1, R 7O-, R 24C (O)-, R 25C (O)-or R 25O-is not by bile acide deutero-part.In another embodiment of the 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, arylalkyl, aryl or the replacement of alkyl, replacement.In another embodiment of the 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 compound of formula (I), work as R 1Be R 24C (O)-and n is 0 o'clock, R 24It is not methyl, the tertiary butyl, 2-amino-ethyl, 3-aminopropyl, benzyl, phenyl or 2-(benzoyloxy methyl)-phenyl.In another embodiment of the 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 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 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 compound of formula (I), work as R 1Be R 25OC (O)-and n is 0, R 25Be not methyl, the tertiary butyl or benzyl.In another embodiment of the 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, formamyl, 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 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 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 compound of formula (II), R 20And R 21It is not 2-hydroxy-3-methyl-5-chloro-phenyl-.In an embodiment of the compound of formula (II), when u is 1 and X when being 0, t is 1.
In an embodiment of formula (I), (II) and 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 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,
Figure A200810169355D00271
Or
Figure A200810169355D00272
Wherein V is O or CH 2
In an embodiment preferred of formula (I), (II) and compound (III), R 2Be selected from the heteroarylalkyl of heteroaryl, heteroarylalkyl and replacement of assorted alkyl, heteroaryl, the replacement of arylalkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring of aryl, arylalkyl, 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, heteroarylalkyl 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 compound (III), X is NH, and R 2Be hydrogen, cycloalkyl or alkyl group.Preferred R 2Be hydrogen, methyl, sec.-propyl, isobutyl-, sec-butyl, the tertiary butyl, cyclopentyl 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-imidazolyl 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, tetramethyleneimine or piperidine ring with their bonded atoms.
In another embodiment of formula (I), (II) and 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 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 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 cyclopentyl, cyclohexyl or the replacement of the cyclobutyl that forms cyclobutyl, replacement with their bonded carbon atoms, cyclopentyl, 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 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 tertiary butyl ,-CH 2OCH (CH 3) 2, phenyl or 3-pyridyl.
In another embodiment of the 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, neo-pentyl ,-CH 2OCH (CH 3) 2, phenyl or 2-pyridyl.
An embodiment preferred of the compound of formula (I) comprises the compound of formula (IV):
Figure A200810169355D00281
Or its pharmacy 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 compound of formula (IV) does not comprise following compound: work as R 13Or R 14During for the cyclo alkoxy carbonyl of alkoxy carbonyl, formamyl, 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 bile acide deutero-part.
In an embodiment of the compound of formula (IV), R 13And R 14Be that alkyl, alkoxy carbonyl, aryl, arylalkyl, formamyl, 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 formamyl, R 14Be methyl).More preferably R 13And R 14Be hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, isobutoxy carbonyl, sec-butoxy carbonyl, tert-butoxycarbonyl, cyclohexyloxy carbonyl, phenyl, benzyl, styroyl or 3-pyridyl independently.
In another embodiment of the 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, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, cyclopentyl or cyclohexyl independently.Even more preferably R 13Be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, cyclopentyl or cyclohexyl R 14Be hydrogen, perhaps R 13Be methyl R 14Be methyl.
In another embodiment of compound of formula (IV), R 13And R 14Be hydrogen, aryl, arylalkyl or heteroaryl independently.More preferably R 13And R 14Be hydrogen, phenyl, benzyl, styroyl or 3-pyridyl independently. even more preferably R 13Be phenyl, benzyl, styroyl or 3-pyridyl and R 14Be hydrogen.
In another embodiment of compound of formula (IV), R 13And R 14Be alkyl, alkoxy carbonyl, formamyl or the cyclo alkoxy carbonyl of hydrogen, alkyl, replacement independently.Preferably work as R 13During for alkoxy carbonyl, cyclo alkoxy carbonyl or formamyl, 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 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, cyclopentyl or cyclohexyl ring with their bonded carbon atoms.
In another embodiment of compound of formula (IV), R 25Heteroarylalkyl for heteroaryl, heteroarylalkyl or the replacement of the assorted alkyl of the arylalkyl of the aryl of the alkyl of the acyl group of acyl group, replacement, alkyl, replacement, aryl, replacement, arylalkyl, 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, arylalkyl, cycloalkyl or heteroaryl for the acyl group of acyl group, replacement, alkyl, replacement.More preferably R 25Be methyl; ethyl; propyl group; sec.-propyl; butyl; isobutyl-; sec-butyl; amyl group; isopentyl; sec.-amyl sec-pentyl secondary amyl; neo-pentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolane-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolane-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolane-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolane-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-styroyl; 1; 1-diethoxy-2-styroyl; 1-(1; 3-dioxolane-2-yl)-the 2-styroyl; 1-(1,3-diox-2-yl)-2-styroyl; ethanoyl; propionyl; butyryl radicals; benzoyl; phenylacetyl; phenyl; the 4-p-methoxy-phenyl; benzyl; styroyl; styryl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl or 3-pyridyl.
In another embodiment of compound of formula (IV), R 25Acyl group for acyl group or replacement.More preferably R 25Be ethanoyl, propionyl, butyryl radicals, benzoyl or phenylacetyl.
In another embodiment of compound of formula (IV), R 25Alkyl group for alkyl group or replacement.Preferred R 25Be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, amyl group, isopentyl, sec.-amyl sec-pentyl secondary amyl, neo-pentyl, 1, the 1-dimethoxy-ethyl, 1,1-diethoxy ethyl, 1-(1,3-dioxolane-2-yl)-ethyl, 1-(1,3-diox-2-yl)-ethyl, 1,1-dimethoxy propyl group, 1,1-diethoxy propyl group, 1-(1,3-dioxolane-2-yl)-propyl group, 1-(1,3-diox-2-yl)-propyl group, 1,1-dimethoxy butyl, 1,1-diethoxy butyl, 1-(1,3-dioxolane-2-yl)-butyl, 1-(1,3-diox-2-yl)-butyl, 1, the 1-dimethoxy-benzyl, 1,1-diethoxy benzyl, 1-(1,3-dioxolane-2-yl)-benzyl, 1-(1,3-diox-2-yl)-benzyl, 1,1-dimethoxy-2-styroyl, 1,1-diethoxy-2-styroyl, 1-(1,3-dioxolane-2-yl)-2-styroyl or 1-(1,3-diox-2-yl)-2-styroyl.More preferably R 25Be methyl, ethyl, propyl group, sec.-propyl, butyl, 1,1-dimethoxy-ethyl or 1,1-diethoxy ethyl.
In another embodiment of compound of formula (IV), R 25Be aryl, arylalkyl or heteroaryl.Preferred R 25Be phenyl, 4-p-methoxy-phenyl, benzyl, styroyl, styryl or 3-pyridyl.
In another embodiment of compound of formula (IV), R 25Cycloalkyl for cycloalkyl or replacement.More preferably R 25Be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
In another embodiment of compound of formula (IV), R 25Heteroarylalkyl for heteroaryl, heteroarylalkyl or the replacement of the assorted alkyl of the arylalkyl of the aryl of the alkyl of the acyl group of acyl group, replacement, alkyl, replacement, aryl, replacement, arylalkyl, 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 arylalkyl, formamyl, cycloalkyl, the replacement of aryl, arylalkyl, 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 formamyl, R 14Be methyl).Preferred R 25Be alkyl, aryl, arylalkyl, cycloalkyl or the heteroaryl of the acyl group of acyl group, replacement, alkyl, replacement, and R 13And R 14The alkyl, alkoxy carbonyl, aryl, arylalkyl, formamyl, 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 formamyl, R 14Be methyl).More preferably R 25Be methyl; ethyl; propyl group; sec.-propyl; butyl; isobutyl-; sec-butyl; amyl group; isopentyl; sec.-amyl sec-pentyl secondary amyl; neo-pentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolane-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolane-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolane-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolane-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-styroyl; 1; 1-diethoxy-2-styroyl; 1-(1; 3-dioxolane-2-yl)-the 2-styroyl; 1-(1,3-diox-2-yl)-2-styroyl; ethanoyl; propionyl; butyryl radicals; benzoyl; phenylacetyl; phenyl; the 4-p-methoxy-phenyl; benzyl; styroyl; styryl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl or 3-pyridyl, and R 13And R 14Be hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, isobutoxy carbonyl, sec-butoxy carbonyl, tert-butoxycarbonyl, cyclohexyloxy carbonyl, phenyl, benzyl, styroyl or 3-pyridyl independently.Even more preferably R 25Be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, 1; 1-dimethoxy-ethyl, 1; 1-diethoxy ethyl, 1; 1-dimethoxy-benzyl, 1; 1-diethoxy benzyl, 1; 1-dimethoxy-2-styroyl, 1,1-diethoxy-2-styroyl, ethanoyl, propionyl, butyryl radicals, benzoyl, phenylacetyl, phenyl, 4-p-methoxy-phenyl, benzyl, styroyl, cyclohexyl or 3-pyridyl, and R 13And R 14Be hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxy carbonyl, isopropoxy carbonyl, cyclohexyloxy carbonyl, phenyl, benzyl, styroyl or 3-pyridyl independently.
In another embodiment of compound of formula (IV), R 25Be the heteroarylalkyl of heteroaryl, heteroarylalkyl or the replacement of the assorted alkyl of the arylalkyl of the aryl of the alkyl of the acyl group of acyl group, replacement, alkyl, replacement, aryl, replacement, arylalkyl, 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, arylalkyl, 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; sec.-propyl; butyl; isobutyl-; sec-butyl; amyl group; isopentyl; sec.-amyl sec-pentyl secondary amyl; neo-pentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolane-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolane-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolane-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolane-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-styroyl; 1; 1-diethoxy-2-styroyl; 1-(1; 3-dioxolane-2-yl)-the 2-styroyl; 1-(1,3-diox-2-yl)-2-styroyl; ethanoyl; propionyl; butyryl radicals; benzoyl; phenylacetyl; phenyl; the 4-p-methoxy-phenyl; benzyl; styroyl; styryl; cyclopropyl; cyclobutyl; cyclopentyl; in cyclohexyl or the 3-pyridyl, and R 13And R 14With form cyclobutyl, cyclopentyl or cyclohexyl ring with their bonded atoms.
In another embodiment of 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 arylalkyl, formamyl, cycloalkyl, the replacement of aryl, arylalkyl, 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 formamyl, R 14Be methyl).Preferred R 25Be ethanoyl, propionyl, butyryl radicals, benzoyl or phenylacetyl, and R 13And R 14The heteroaryl of cyclo alkoxy carbonyl, heteroaryl or replacement that is cycloalkyl, cyclo alkoxy carbonyl, the replacement of arylalkyl, formamyl, cycloalkyl, the replacement of aryl, arylalkyl, 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 formamyl, R 14Be methyl).
In another embodiment of 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 arylalkyl, formamyl, cycloalkyl, the replacement of aryl, arylalkyl, 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 formamyl, R 14Be methyl).Preferred R 25Be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, amyl group, isopentyl, sec.-amyl sec-pentyl secondary amyl, neo-pentyl, 1, the 1-dimethoxy-ethyl, 1,1-diethoxy ethyl, 1-(1,3-dioxolane-2-yl)-ethyl, 1-(1,3-diox-2-yl)-ethyl, 1,1-dimethoxy propyl group, 1,1-diethoxy propyl group, 1-(1,3-dioxolane-2-yl)-propyl group, 1-(1,3-diox-2-yl)-propyl group, 1,1-dimethoxy butyl, 1,1-diethoxy butyl, 1-(1,3-dioxolane-2-yl)-butyl, 1-(1,3-diox-2-yl)-butyl, 1, the 1-dimethoxy-benzyl, 1,1-diethoxy benzyl, 1-(1,3-dioxolane-2-yl)-benzyl, 1-(1,3-diox-2-yl)-benzyl, 1,1-dimethoxy-2-styroyl, 1,1-diethoxy-2-styroyl, 1-(1,3-dioxolane-2-yl)-2-styroyl or 1-(1,3-diox-2-yl)-2-styroyl, and R 13And R 14The heteroaryl of cyclo alkoxy carbonyl, heteroaryl or replacement that is cycloalkyl, cyclo alkoxy carbonyl, the replacement of arylalkyl, formamyl, cycloalkyl, the replacement of aryl, arylalkyl, 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 formamyl, R 14Be methyl).
In another embodiment of compound of formula (IV), R 25Be the heteroaryl of arylalkyl, heteroaryl or the replacement of the aryl of aryl, replacement, arylalkyl, replacement, and R 13And R 14The heteroaryl of cyclo alkoxy carbonyl, heteroaryl or replacement that is cycloalkyl, cyclo alkoxy carbonyl, the replacement of arylalkyl, formamyl, cycloalkyl, the replacement of aryl, arylalkyl, 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 formamyl, R 14Be methyl).Preferred R 25Be phenyl, 4-p-methoxy-phenyl, benzyl, styroyl, styryl or 3-pyridyl, and R 13And R 14The heteroaryl of cyclo alkoxy carbonyl, heteroaryl or replacement that is cycloalkyl, cyclo alkoxy carbonyl, the replacement of arylalkyl, formamyl, cycloalkyl, the replacement of aryl, arylalkyl, 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 formamyl, R 14Be methyl).
In another embodiment of 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 arylalkyl, formamyl, cycloalkyl, the replacement of aryl, arylalkyl, 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 formamyl, R 14Be methyl).Preferred R 25Be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and R 13And R 14The heteroaryl of cyclo alkoxy carbonyl, heteroaryl or replacement that is cycloalkyl, cyclo alkoxy carbonyl, the replacement of arylalkyl, formamyl, cycloalkyl, the replacement of aryl, arylalkyl, 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 formamyl, R 14Be methyl).
In another embodiment of compound of formula (IV), R 25Be the heteroarylalkyl of heteroaryl, heteroarylalkyl or the replacement of the assorted alkyl of the arylalkyl of the aryl of the alkyl of the acyl group of acyl group, replacement, alkyl, replacement, aryl, replacement, arylalkyl, 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, arylalkyl, cycloalkyl or the heteroaryl of hydrogen, alkyl, replacement independently.Preferred R 25Be alkyl, aryl, arylalkyl, 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, arylalkyl, cycloalkyl or the heteroaryl of the acyl group of acyl group, replacement, alkyl, replacement, and R 13And R 14Be hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, cyclopentyl or cyclohexyl independently.In above embodiment, R 25Be preferably methyl; ethyl; propyl group; sec.-propyl; butyl; isobutyl-; sec-butyl; amyl group; isopentyl; sec.-amyl sec-pentyl secondary amyl; neo-pentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolane-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolane-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolane-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolane-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-styroyl; 1; 1-diethoxy-2-styroyl; 1-(1; 3-dioxolane-2-yl)-the 2-styroyl; 1-(1,3-diox-2-yl)-2-styroyl; ethanoyl; propionyl; butyryl radicals; benzoyl; phenylacetyl; phenyl; the 4-p-methoxy-phenyl; benzyl; styroyl; styryl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl or 3-pyridyl.
In another embodiment of compound of formula (IV), R 25Be alkyl, aryl, arylalkyl, cycloalkyl or the heteroaryl of the acyl group of acyl group, replacement, alkyl, replacement, and R 13And R 14Be alkyl, aryl, arylalkyl, cycloalkyl or the heteroaryl of hydrogen, alkyl, replacement independently.Preferred R 25Be alkyl, aryl, arylalkyl, cycloalkyl or the heteroaryl of the acyl group of acyl group, replacement, alkyl, replacement, and R 13And R 14Be hydrogen, aryl, arylalkyl or heteroaryl independently.More preferably R 25Be alkyl, aryl, arylalkyl, cycloalkyl or the heteroaryl of the acyl group of acyl group, replacement, alkyl, replacement, and R 13And R 14Be hydrogen, phenyl, benzyl, styroyl or 3-pyridyl independently.In above embodiment, R 25Be preferably methyl; ethyl; propyl group; sec.-propyl; butyl; isobutyl-; sec-butyl; amyl group; isopentyl; sec.-amyl sec-pentyl secondary amyl; neo-pentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolane-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolane-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolane-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolane-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-styroyl; 1; 1-diethoxy-2-styroyl; 1-(1; 3-dioxolane-2-yl)-the 2-styroyl; 1-(1,3-diox-2-yl)-2-styroyl; ethanoyl; propionyl; butyryl radicals; benzoyl; phenylacetyl; phenyl; the 4-p-methoxy-phenyl; benzyl; styroyl; styryl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl or 3-pyridyl.
In another embodiment of compound of formula (IV), R 25Be alkyl, aryl, arylalkyl, cycloalkyl or the heteroaryl of the acyl group of acyl group, replacement, alkyl, replacement, and R 13And R 14Be alkyl, aryl, arylalkyl, cycloalkyl or the heteroaryl of hydrogen, alkyl, replacement independently.Preferred R 25Be alkyl, aryl, arylalkyl, 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, formamyl, 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, formamyl, 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; sec.-propyl; butyl; isobutyl-; sec-butyl; amyl group; isopentyl; sec.-amyl sec-pentyl secondary amyl; neo-pentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolane-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolane-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolane-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolane-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-styroyl; 1; 1-diethoxy-2-styroyl; 1-(1; 3-dioxolane-2-yl)-the 2-styroyl; 1-(1,3-diox-2-yl)-2-styroyl; ethanoyl; propionyl; butyryl radicals; benzoyl; phenylacetyl; phenyl; the 4-p-methoxy-phenyl; benzyl; styroyl; styryl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl or 3-pyridyl.
In another embodiment of compound of formula (IV), R 25Be alkyl, aryl, arylalkyl, 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, arylalkyl, 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, arylalkyl, cycloalkyl or the heteroaryl of the acyl group of acyl group, replacement, alkyl, replacement, and R 13And R 14With form cyclobutyl, cyclopentyl or cyclohexyl ring with their bonded atoms.In above embodiment, R 25Be preferably methyl; ethyl; propyl group; sec.-propyl; butyl; isobutyl-; sec-butyl; amyl group; isopentyl; sec.-amyl sec-pentyl secondary amyl; neo-pentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolane-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolane-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolane-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolane-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-styroyl; 1; 1-diethoxy-2-styroyl; 1-(1; 3-dioxolane-2-yl)-the 2-styroyl; 1-(1,3-diox-2-yl)-2-styroyl; ethanoyl; propionyl; butyryl radicals; benzoyl; phenylacetyl; phenyl; the 4-p-methoxy-phenyl; benzyl; styroyl; styryl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl or 3-pyridyl.
In another embodiment of formula (I) and compound (III), R 1For
Figure A200810169355D00381
M is 0, and R 8, R 11And R 12Define as the front.
In an embodiment of formula (I) and compound (III), R 11Be acyl group, alkoxy carbonyl, aryloxycarbonyl, cyclo alkoxy carbonyl or formamyl, R 8Be hydrogen, alkoxy carbonyl, alkyl, aryl, arylalkyl or cyano group, and R 12Alkyl, aryl or arylalkyl for hydrogen, alkoxy carbonyl, alkyl, replacement.
In another embodiment of formula (I) and compound (III), R 11Be selected from ethanoyl; propionyl; butyryl radicals; isobutyryl; valeryl; the pentamethylene carbonyl; the hexanaphthene carbonyl; benzoyl; phenylacetyl; methoxycarbonyl; ethoxy carbonyl; propoxycarbonyl; isopropoxy carbonyl; butoxy carbonyl; isobutoxy carbonyl; the sec-butoxy carbonyl; tert-butoxycarbonyl; cyclopentyl oxygen carbonyl; cyclohexyloxy carbonyl; phenyloxycarbonyl; benzyloxycarbonyl; formamyl; N-methylamino formyl radical; N-ethylamino formyl radical; N-propyl group formamyl; N-sec.-propyl formamyl; N-butyl formamyl; N-isobutylamino formyl radical; N-sec-butyl formamyl; N-tertiary butyl formamyl; N-cyclopentyl formamyl; N-cyclohexyl carboxyamide base; N-phenyl amino formyl radical; N-benzylamino formyl radical; N; the N-formyl-dimethylamino; N; N-diethylamino formyl radical; N; N-dipropyl formamyl; N; N-diisopropylaminoethyl formyl radical; N; N-dibutylamino formyl radical; N, N-dibenzyl amino formyl radical; N-pyrrolidyl formamyl; N-piperidyl amino formyl radical and N-morpholinyl formamyl.More preferably R 11Be selected from ethanoyl; propionyl; butyryl radicals; isobutyryl; the hexanaphthene carbonyl; benzoyl; phenylacetyl; methoxycarbonyl; ethoxy carbonyl; propoxycarbonyl; isopropoxy carbonyl; butoxy carbonyl; cyclohexyloxy carbonyl; phenyloxycarbonyl; benzyloxycarbonyl; formamyl; N-methylamino formyl radical; N-ethylamino formyl radical; N-propyl group formamyl; N-sec.-propyl formamyl; N-phenyl amino formyl radical; N-benzylamino formyl radical; N; the N-formyl-dimethylamino; N; N-diethylamino formyl radical; N, N-dipropyl formamyl; N-pyrrolidyl formamyl; N-piperidyl amino formyl radical and N-morpholinyl formamyl.
In another embodiment of formula (I) and compound (III), R 8Be selected from hydrogen, methyl, ethyl, propyl group, sec.-propyl, phenyl, benzyl, methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, phenyloxycarbonyl, benzyloxycarbonyl and cyano group.More preferably R 8Be selected from hydrogen, methyl, ethyl, sec.-propyl, phenyl, benzyl, methoxycarbonyl, ethoxy carbonyl and butoxy carbonyl.
In another embodiment of formula (I) and compound (III), R 12Be selected from hydrogen, methyl, ethyl, propyl group, sec.-propyl, phenyl, benzyl, methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, phenyloxycarbonyl and benzyloxycarbonyl.More preferably R 12Be selected from hydrogen, methyl, ethyl, sec.-propyl, phenyl, benzyl, methoxycarbonyl, ethoxy carbonyl and butoxy carbonyl.
In another embodiment of formula (I) and compound (III), R 11Be selected from alkyl, aryl, the arylalkyl 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, sec.-propyl, 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-tetrahydrobenzene-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 compound (III), R 12Be selected from alkyl, aryl, the arylalkyl 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, sec.-propyl, 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, sec.-propyl, phenyl, benzyl, methoxycarbonyl, ethoxy carbonyl and butoxy carbonyl, and R 8And R 11Form gamma-butyrolactone, 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 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, sec.-propyl, cyclopentyl, cyclohexyl, phenyl, 4-hydroxy phenyl, benzyl, 4-hydroxybenzyl or 3-pyridyl.
In formula (I) and another embodiment (III), R 1For
Figure A200810169355D00402
R wherein 37Heteroarylalkyl for heteroaryl, heteroarylalkyl or the replacement of the assorted alkyl of ring of the arylalkyl of the aryl of the alkyl of hydrogen, alkyl, replacement, acyl group, aryl, replacement, arylalkyl, 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 six-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 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 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-, the tertiary butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 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 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 substituting 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 compound of formula (I)-(IV), R 4And R 5With the cyclopentyl ring that forms cyclopentyl or replacement with their bonded carbon atoms.Preferred described cyclopentyl ring is replaced by the alkyl group of alkyl group, replacement, halogen, hydroxyl, carboxyl or alkoxy carbonyl.More preferably described cyclopentyl ring is replaced by alkyl group.Even more preferably described cyclopentyl ring is selected from
Figure A200810169355D00421
With
Preferably at one of above embodiment more specifically in the version, R 7Be hydrogen.
In another embodiment preferred of the 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
Figure A200810169355D00423
Figure A200810169355D00424
With
Figure A200810169355D00425
Preferably at one of above embodiment more specifically in the version, R 7Be hydrogen.
In another embodiment preferred of the 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-, the tertiary butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 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
Figure A200810169355D00431
Or
Figure A200810169355D00432
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
Figure A200810169355D00434
With
Figure A200810169355D00435
Preferably, at one of above embodiment more specifically in the version, R 7Be hydrogen.
In another embodiment of the 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-, the tertiary butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 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
Figure A200810169355D00441
Or
Figure A200810169355D00442
Preferably at one of above embodiment more specifically in the version, R 7Be hydrogen.
In another embodiment of the 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-, the tertiary butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 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-R 5Be hydrogen.
In another embodiment of the 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
Figure A200810169355D00443
A is NR 19, O or S;
B is alkyl, alkoxyl group, 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 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
Figure A200810169355D00451
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
Figure A200810169355D00453
With
The compound of preferred formula (I)-(IV) is derived by the GABA analogue of formula (XIII):
Figure A200810169355D00461
The GABA analogue of its Chinese style (XIII) is selected from:
1-aminomethyl-1,2-Cyclohexaneacetic acid;
1-aminomethyl-1,2-(3-methylcyclohexane) acetate;
1-aminomethyl-1,2-(4-methylcyclohexane) acetate;
1-aminomethyl-1,2-(4-normenthane) acetate;
1-aminomethyl-1,2-(4-tertiary butyl hexanaphthene) acetate;
1-aminomethyl-1,2-(3, the 3-dimethyl cyclohexane) acetate;
1-aminomethyl-1,2-(3,3,5,5-tetramethyl-ring hexane) acetate;
1-aminomethyl-1,2-pentamethylene acetate;
1-aminomethyl-1,2-(3-methylcyclopentane) acetate;
1-aminomethyl-1,2-(3, the 4-dimethylcyclopentane) acetate;
7-amino methyl-two ring [2.2.1] heptan-7-guanidine-acetic acid;
9-amino methyl-two ring [3.3.1] ninth of the ten Heavenly Stems-9-guanidine-acetic acid;
4-amino methyl-4-(tetrahydropyran-4-base) acetate;
3-amino methyl-3-(tetrahydropyran-3-base) acetate;
4-amino methyl-4-(tetrahydrochysene sulfo-pyrans-4-yl) acetate;
3-amino methyl-3-(tetrahydrochysene sulfo-pyrans-3-yl) acetate;
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-cyclopentyl-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-butyric acid;
3-amino methyl-4-cyclopentyl-butyric acid;
3-amino methyl-4-cyclohexyl-butyric acid;
3-amino methyl-4-phenoxy group-butyric 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 compound (VI):
Figure A200810169355D00471
R wherein 1, R 2, R 7And R 16Define as the front.
In an embodiment of formula V and compound (VI), n is 0.In another embodiment, n is 1, and R 2For hydrogen, methyl, 2-propyl group, 2-butyl, isobutyl-, the tertiary butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 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 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 tertiary butyl ,-CH 2OCH (CH 3) 2, phenyl or 3-pyridyl.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,
Figure A200810169355D00481
Or
Figure A200810169355D00482
Wherein V is O or CH 2
R most preferably 7Be hydrogen.
In another embodiment of formula V and 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, neo-pentyl ,-CH 2OCH (CH 3) 2, phenyl or 2-pyridyl.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,
Figure A200810169355D00483
Or
Figure A200810169355D00484
Wherein V is O or CH 2
R most preferably 7Be hydrogen.
In another embodiment of formula V and (VI) compound, R 1For
Figure A200810169355D00491
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, sec.-propyl, cyclopentyl, cyclohexyl, phenyl, 4-hydroxy phenyl, benzyl, 4-hydroxybenzyl or 3-pyridyl.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,
Figure A200810169355D00492
Or
Wherein V is O or CH 2
Preferred R 7Be hydrogen.
The particularly preferred embodiment of formula V and compound (VI) is to be selected from following 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 compound (VI), R 1For
M is 0, and R 8, R 11And R 12Define as the front.In an embodiment of formula V and compound (VI), R 11Be the formamyl of acyl group, alkoxy carbonyl, aryloxycarbonyl, cyclo alkoxy carbonyl, formamyl or replacement, R 8Be hydrogen, alkoxy carbonyl, alkyl, aryl, arylalkyl or cyano group, and R 12Alkyl, aryl or arylalkyl for hydrogen, alkoxy carbonyl, alkyl, replacement.In another embodiment of formula V and compound (VI), R 11Be selected from ethanoyl; propionyl; butyryl radicals; isobutyryl; valeryl; the pentamethylene carbonyl; the hexanaphthene carbonyl; benzoyl; phenylacetyl; methoxycarbonyl; ethoxy carbonyl; propoxycarbonyl; isopropoxy carbonyl; butoxy carbonyl; isobutoxy carbonyl; the sec-butoxy carbonyl; tert-butoxycarbonyl; cyclopentyl oxygen carbonyl; cyclohexyloxy carbonyl; phenyloxycarbonyl; benzyloxycarbonyl; formamyl; N-methylamino formyl radical; N-ethylamino formyl radical; N-propyl group formamyl; N-sec.-propyl formamyl; N-butyl formamyl; N-isobutylamino formyl radical; N-sec-butyl formamyl; N-tertiary butyl formamyl; N-cyclopentyl formamyl; N-cyclohexyl carboxyamide base; N-phenyl amino formyl radical; N-benzylamino formyl radical; N; the N-formyl-dimethylamino; N; N-diethylamino formyl radical; N; N-dipropyl formamyl; N; N-diisopropylaminoethyl formyl radical; N; N-dibutylamino formyl radical; N, N-dibenzyl amino formyl radical; N-pyrrolidyl formamyl; N-piperidyl amino formyl radical and N-morpholinyl formamyl.In another embodiment of formula V and (VI) compound, R 11Be selected from ethanoyl; propionyl; butyryl radicals; isobutyryl; the hexanaphthene carbonyl; benzoyl; phenylacetyl; methoxycarbonyl; ethoxy carbonyl; propoxycarbonyl; isopropoxy carbonyl; butoxy carbonyl; cyclohexyloxy carbonyl; phenyloxycarbonyl; benzyloxycarbonyl; formamyl; N-methylamino formyl radical; N-ethylamino formyl radical; N-propyl group formamyl; N-sec.-propyl formamyl; N-phenyl amino formyl radical; N-benzylamino formyl radical; N; the N-formyl-dimethylamino; N; N-diethylamino formyl radical; N, N-dipropyl formamyl; N-pyrrolidyl formamyl; N-piperidyl amino formyl radical and N-morpholinyl formamyl.
In an embodiment of formula V and compound (VI), R 8Be selected from hydrogen, methyl, ethyl, propyl group, sec.-propyl, phenyl, benzyl, methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, phenyloxycarbonyl, benzyloxycarbonyl and cyano group.Preferred R 8Be selected from hydrogen, methyl, ethyl, sec.-propyl, phenyl, benzyl, methoxycarbonyl, ethoxy carbonyl and butoxy carbonyl.
In another embodiment of formula V and compound (VI), R 12Be selected from hydrogen, methyl, ethyl, propyl group, sec.-propyl, phenyl, benzyl, methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, phenyloxycarbonyl and benzyloxycarbonyl.Preferred R 12Be selected from hydrogen, methyl, ethyl, sec.-propyl, phenyl, benzyl, methoxycarbonyl, ethoxy carbonyl and butoxy carbonyl.
In another embodiment of formula V and compound (VI), R 11Be selected from alkyl, aryl, the arylalkyl 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, sec.-propyl, 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-tetrahydrobenzene-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 compound (VI), R 12Be selected from alkyl, aryl, the arylalkyl 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, sec.-propyl, 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, sec.-propyl, phenyl, benzyl, methoxycarbonyl, ethoxy carbonyl and butoxy carbonyl, and R 8And R 11With form gamma-butyrolactone, 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) 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,
Figure A200810169355D00511
Or
Figure A200810169355D00512
Wherein V is O or CH 2
R most preferably 7Be hydrogen.
The particularly preferred embodiment of formula V and compound (VI) is to be selected from following compound:
1-{ (1-methyl-3-oxo-but-1-ene base) amino methyl }-1-Cyclohexaneacetic acid piperidines;
1-{1-[(2-oxo-tetrahydrofuran (THF)-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-oxyethyl group-3-oxo third-1-thiazolinyl) amino methyl }-1-Cyclohexaneacetic acid piperidines.
In an especially preferred embodiment, the compound of formula (IV) has formula (VII) or structure (VIII):
Figure A200810169355D00521
Or its pharmacy 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 compound (VIII) do not comprise following compound:
If R 13Or R 14Arbitrary be the cyclo alkoxy carbonyl of alkoxy carbonyl, formamyl, 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 bile acide deutero-part.
In an embodiment of formula (VII) and 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 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,
Figure A200810169355D00531
Or
Figure A200810169355D00532
Wherein V is O or CH 2
R most preferably 7Be hydrogen.
In another embodiment of formula (VII) and compound (VIII), n is 0.In another embodiment of formula (VII) and compound (VIII), n is 1, R 16Be hydrogen R 2For hydrogen, methyl, 2-propyl group, 2-butyl, isobutyl-, the tertiary butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 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-, the tertiary butyl, 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 compound (VIII), R 25Be selected from methyl; ethyl; propyl group; sec.-propyl; butyl; isobutyl-; sec-butyl; amyl group; isopentyl; sec.-amyl sec-pentyl secondary amyl; neo-pentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolane-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolane-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolane-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolane-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-styroyl; 1; 1-diethoxy-2-styroyl; 1-(1; 3-dioxolane-2-yl)-the 2-styroyl; 1-(1,3-diox-2-yl)-2-styroyl; ethanoyl; propionyl; butyryl radicals; benzoyl; phenylacetyl; phenyl; the 4-p-methoxy-phenyl; benzyl; styroyl; styryl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl and 3-pyridyl, R 13Be methyl R 14Be hydrogen.
In another embodiment of formula (VII) and compound (VIII), R 25Be selected from methyl; ethyl; propyl group; sec.-propyl; butyl; isobutyl-; sec-butyl; amyl group; isopentyl; sec.-amyl sec-pentyl secondary amyl; neo-pentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolane-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolane-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolane-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolane-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-styroyl; 1; 1-diethoxy-2-styroyl; 1-(1; 3-dioxolane-2-yl)-the 2-styroyl; 1-(1,3-diox-2-yl)-2-styroyl; ethanoyl; propionyl; butyryl radicals; benzoyl; phenylacetyl; phenyl; the 4-p-methoxy-phenyl; benzyl; styroyl; styryl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl and 3-pyridyl, R 13Be ethyl R 14Be hydrogen.
In another embodiment of formula (VII) and compound (VIII), R 25Be selected from methyl; ethyl; propyl group; sec.-propyl; butyl; isobutyl-; sec-butyl; amyl group; isopentyl; sec.-amyl sec-pentyl secondary amyl; neo-pentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolane-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolane-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolane-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolane-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-styroyl; 1; 1-diethoxy-2-styroyl; 1-(1; 3-dioxolane-2-yl)-the 2-styroyl; 1-(1,3-diox-2-yl)-2-styroyl; ethanoyl; propionyl; butyryl radicals; benzoyl; phenylacetyl; phenyl; the 4-p-methoxy-phenyl; benzyl; styroyl; styryl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl and 3-pyridyl, R 13Be propyl group R 14Be hydrogen.
In another embodiment of formula (VII) and compound (VIII), R 25Be selected from methyl; ethyl; propyl group; sec.-propyl; butyl; isobutyl-; sec-butyl; amyl group; isopentyl; sec.-amyl sec-pentyl secondary amyl; neo-pentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolane-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolane-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolane-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolane-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-styroyl; 1; 1-diethoxy-2-styroyl; 1-(1; 3-dioxolane-2-yl)-the 2-styroyl; 1-(1,3-diox-2-yl)-2-styroyl; ethanoyl; propionyl; butyryl radicals; benzoyl; phenylacetyl; phenyl; the 4-p-methoxy-phenyl; benzyl; styroyl; styryl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl and 3-pyridyl, R 13Be sec.-propyl R 14Be hydrogen.
In another embodiment of formula (VII) and compound (VIII), R 25Be selected from methyl; ethyl; propyl group; sec.-propyl; butyl; isobutyl-; sec-butyl; amyl group; isopentyl; sec.-amyl sec-pentyl secondary amyl; neo-pentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolane-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolane-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolane-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolane-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-styroyl; 1; 1-diethoxy-2-styroyl; 1-(1; 3-dioxolane-2-yl)-the 2-styroyl; 1-(1,3-diox-2-yl)-2-styroyl; ethanoyl; propionyl; butyryl radicals; benzoyl; phenylacetyl; phenyl; the 4-p-methoxy-phenyl; benzyl; styroyl; styryl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl and 3-pyridyl, R 13Be butyl R 14Be hydrogen.
In another embodiment of formula (VII) and compound (VIII), R 25Be selected from methyl; ethyl; propyl group; sec.-propyl; butyl; isobutyl-; sec-butyl; amyl group; isopentyl; sec.-amyl sec-pentyl secondary amyl; neo-pentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolane-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolane-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolane-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolane-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-styroyl; 1; 1-diethoxy-2-styroyl; 1-(1; 3-dioxolane-2-yl)-the 2-styroyl; 1-(1,3-diox-2-yl)-2-styroyl; ethanoyl; propionyl; butyryl radicals; benzoyl; phenylacetyl; phenyl; the 4-p-methoxy-phenyl; benzyl; styroyl; styryl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl and 3-pyridyl, R 13Be isobutyl-R 14Be hydrogen.
In another embodiment of formula (VII) and compound (VIII), R 25Be selected from methyl; ethyl; propyl group; sec.-propyl; butyl; isobutyl-; sec-butyl; amyl group; isopentyl; sec.-amyl sec-pentyl secondary amyl; neo-pentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolane-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolane-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolane-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolane-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-styroyl; 1; 1-diethoxy-2-styroyl; 1-(1; 3-dioxolane-2-yl)-the 2-styroyl; 1-(1,3-diox-2-yl)-2-styroyl; ethanoyl; propionyl; butyryl radicals; benzoyl; phenylacetyl; phenyl; the 4-p-methoxy-phenyl; benzyl; styroyl; styryl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl and 3-pyridyl, R 13Be sec-butyl and R 14Be hydrogen.
In another embodiment of formula (VII) and compound (VIII), R 25Be selected from methyl; ethyl; propyl group; sec.-propyl; butyl; isobutyl-; sec-butyl; amyl group; isopentyl; sec.-amyl sec-pentyl secondary amyl; neo-pentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolane-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolane-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolane-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolane-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-styroyl; 1; 1-diethoxy-2-styroyl; 1-(1; 3-dioxolane-2-yl)-the 2-styroyl; 1-(1,3-diox-2-yl)-2-styroyl; ethanoyl; propionyl; butyryl radicals; benzoyl; phenylacetyl; phenyl; the 4-p-methoxy-phenyl; benzyl; styroyl; styryl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl and 3-pyridyl, R 13Be tertiary butyl R 14Be hydrogen.
In another embodiment of formula (VII) and compound (VIII), R 25Be selected from methyl; ethyl; propyl group; sec.-propyl; butyl; isobutyl-; sec-butyl; amyl group; isopentyl; sec.-amyl sec-pentyl secondary amyl; neo-pentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolane-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolane-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolane-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolane-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-styroyl; 1; 1-diethoxy-2-styroyl; 1-(1; 3-dioxolane-2-yl)-the 2-styroyl; 1-(1,3-diox-2-yl)-2-styroyl; ethanoyl; propionyl; butyryl radicals; benzoyl; phenylacetyl; phenyl; the 4-p-methoxy-phenyl; benzyl; styroyl; styryl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl and 3-pyridyl, R 13Be cyclopentyl R 14Be hydrogen.
In another embodiment of formula (VII) and compound (VIII), R 25Be selected from methyl; ethyl; propyl group; sec.-propyl; butyl; isobutyl-; sec-butyl; amyl group; isopentyl; sec.-amyl sec-pentyl secondary amyl; neo-pentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolane-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolane-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolane-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolane-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-styroyl; 1; 1-diethoxy-2-styroyl; 1-(1; 3-dioxolane-2-yl)-the 2-styroyl; 1-(1,3-diox-2-yl)-2-styroyl; ethanoyl; propionyl; butyryl radicals; benzoyl; phenylacetyl; phenyl; the 4-p-methoxy-phenyl; benzyl; styroyl; styryl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl and 3-pyridyl, R 13Be cyclohexyl R 14Be hydrogen.
In another embodiment of formula (VII) and compound (VIII), R 25Be selected from methyl; ethyl; propyl group; sec.-propyl; butyl; isobutyl-; sec-butyl; amyl group; isopentyl; sec.-amyl sec-pentyl secondary amyl; neo-pentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolane-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolane-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolane-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolane-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-styroyl; 1; 1-diethoxy-2-styroyl; 1-(1; 3-dioxolane-2-yl)-the 2-styroyl; 1-(1,3-diox-2-yl)-2-styroyl; ethanoyl; propionyl; butyryl radicals; benzoyl; phenylacetyl; phenyl; the 4-p-methoxy-phenyl; benzyl; styroyl; styryl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl and 3-pyridyl, R 13Be methyl R 14Be methyl.
In another embodiment of formula (VII) and compound (VIII), R 25Be selected from methyl; ethyl; propyl group; sec.-propyl; butyl; isobutyl-; sec-butyl; amyl group; isopentyl; sec.-amyl sec-pentyl secondary amyl; neo-pentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolane-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolane-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolane-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolane-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-styroyl; 1; 1-diethoxy-2-styroyl; 1-(1; 3-dioxolane-2-yl)-the 2-styroyl; 1-(1,3-diox-2-yl)-2-styroyl; ethanoyl; propionyl; butyryl radicals; benzoyl; phenylacetyl; phenyl; the 4-p-methoxy-phenyl; benzyl; styroyl; styryl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl and 3-pyridyl, R 13Be methoxycarbonyl R 14Be methyl.
In another embodiment of formula (VII) and compound (VIII), R 25Be selected from methyl; ethyl; propyl group; sec.-propyl; butyl; isobutyl-; sec-butyl; amyl group; isopentyl; sec.-amyl sec-pentyl secondary amyl; neo-pentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolane-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolane-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolane-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolane-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-styroyl; 1; 1-diethoxy-2-styroyl; 1-(1; 3-dioxolane-2-yl)-the 2-styroyl; 1-(1,3-diox-2-yl)-2-styroyl; ethanoyl; propionyl; butyryl radicals; benzoyl; phenylacetyl; phenyl; the 4-p-methoxy-phenyl; benzyl; styroyl; styryl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl and 3-pyridyl, R 13Be ethoxy carbonyl R 14Be methyl.
In another embodiment of formula (VII) and compound (VIII), R 25Be selected from methyl; ethyl; propyl group; sec.-propyl; butyl; isobutyl-; sec-butyl; amyl group; isopentyl; sec.-amyl sec-pentyl secondary amyl; neo-pentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolane-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolane-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolane-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolane-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-styroyl; 1; 1-diethoxy-2-styroyl; 1-(1; 3-dioxolane-2-yl)-the 2-styroyl; 1-(1,3-diox-2-yl)-2-styroyl; ethanoyl; propionyl; butyryl radicals; benzoyl; phenylacetyl; phenyl; the 4-p-methoxy-phenyl; benzyl; styroyl; styryl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl and 3-pyridyl, R 13Be propoxycarbonyl R 14Be methyl.
In another embodiment of formula (VII) and compound (VIII), R 25Be selected from methyl; ethyl; propyl group; sec.-propyl; butyl; isobutyl-; sec-butyl; amyl group; isopentyl; sec.-amyl sec-pentyl secondary amyl; neo-pentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolane-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolane-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolane-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolane-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-styroyl; 1; 1-diethoxy-2-styroyl; 1-(1; 3-dioxolane-2-yl)-the 2-styroyl; 1-(1,3-diox-2-yl)-2-styroyl; ethanoyl; propionyl; butyryl radicals; benzoyl; phenylacetyl; phenyl; the 4-p-methoxy-phenyl; benzyl; styroyl; styryl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl and 3-pyridyl, R 13Be isopropoxy carbonyl R 14Be methyl.
In another embodiment of formula (VII) and compound (VIII), R 25Be selected from methyl; ethyl; propyl group; sec.-propyl; butyl; isobutyl-; sec-butyl; amyl group; isopentyl; sec.-amyl sec-pentyl secondary amyl; neo-pentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolane-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolane-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolane-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolane-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-styroyl; 1; 1-diethoxy-2-styroyl; 1-(1; 3-dioxolane-2-yl)-the 2-styroyl; 1-(1,3-diox-2-yl)-2-styroyl; ethanoyl; propionyl; butyryl radicals; benzoyl; phenylacetyl; phenyl; the 4-p-methoxy-phenyl; benzyl; styroyl; styryl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl and 3-pyridyl, R 13Be butoxy carbonyl R 14Be methyl.
In another embodiment of formula (VII) and compound (VIII), R 25Be selected from methyl; ethyl; propyl group; sec.-propyl; butyl; isobutyl-; sec-butyl; amyl group; isopentyl; sec.-amyl sec-pentyl secondary amyl; neo-pentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolane-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolane-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolane-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolane-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-styroyl; 1; 1-diethoxy-2-styroyl; 1-(1; 3-dioxolane-2-yl)-the 2-styroyl; 1-(1,3-diox-2-yl)-2-styroyl; ethanoyl; propionyl; butyryl radicals; benzoyl; phenylacetyl; phenyl; the 4-p-methoxy-phenyl; benzyl; styroyl; styryl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl and 3-pyridyl, R 13Be isobutoxy carbonyl R 14Be methyl.
In another embodiment of formula (VII) and compound (VIII), R 25Be selected from methyl; ethyl; propyl group; sec.-propyl; butyl; isobutyl-; sec-butyl; amyl group; isopentyl; sec.-amyl sec-pentyl secondary amyl; neo-pentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolane-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolane-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolane-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolane-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-styroyl; 1; 1-diethoxy-2-styroyl; 1-(1; 3-dioxolane-2-yl)-the 2-styroyl; 1-(1,3-diox-2-yl)-2-styroyl; ethanoyl; propionyl; butyryl radicals; benzoyl; phenylacetyl; phenyl; the 4-p-methoxy-phenyl; benzyl; styroyl; styryl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl and 3-pyridyl, R 13Be sec-butoxy carbonyl R 14Be methyl.
In another embodiment of formula (VII) and compound (VIII), R 25Be selected from methyl; ethyl; propyl group; sec.-propyl; butyl; isobutyl-; sec-butyl; amyl group; isopentyl; sec.-amyl sec-pentyl secondary amyl; neo-pentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolane-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolane-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolane-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolane-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-styroyl; 1; 1-diethoxy-2-styroyl; 1-(1; 3-dioxolane-2-yl)-the 2-styroyl; 1-(1,3-diox-2-yl)-2-styroyl; ethanoyl; propionyl; butyryl radicals; benzoyl; phenylacetyl; phenyl; the 4-p-methoxy-phenyl; benzyl; styroyl; styryl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl and 3-pyridyl, R 13Be tert-butoxycarbonyl R 14Be methyl.
In another embodiment of formula (VII) and compound (VIII), R 25Be selected from methyl; ethyl; propyl group; sec.-propyl; butyl; isobutyl-; sec-butyl; amyl group; isopentyl; sec.-amyl sec-pentyl secondary amyl; neo-pentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolane-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolane-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolane-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolane-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-styroyl; 1; 1-diethoxy-2-styroyl; 1-(1; 3-dioxolane-2-yl)-the 2-styroyl; 1-(1,3-diox-2-yl)-2-styroyl; ethanoyl; propionyl; butyryl radicals; benzoyl; phenylacetyl; phenyl; the 4-p-methoxy-phenyl; benzyl; styroyl; styryl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl and 3-pyridyl, R 13Be cyclohexyloxy carbonyl R 14Be methyl.
In another embodiment of formula (VII) and compound (VIII), R 25For being selected from methyl; ethyl; propyl group; sec.-propyl; butyl; isobutyl-; sec-butyl; amyl group; isopentyl; sec.-amyl sec-pentyl secondary amyl; neo-pentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolane-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolane-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolane-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolane-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-styroyl; 1; 1-diethoxy-2-styroyl; 1-(1; 3-dioxolane-2-yl)-the 2-styroyl; 1-(1,3-diox-2-yl)-2-styroyl; ethanoyl; propionyl; butyryl radicals; benzoyl; phenylacetyl; phenyl; the 4-p-methoxy-phenyl; benzyl; styroyl; styryl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl and 3-pyridyl, R 13Be phenyl R 14Be hydrogen.
In another embodiment of formula (VII) and compound (VIII), R 25Be selected from methyl; ethyl; propyl group; sec.-propyl; butyl; isobutyl-; sec-butyl; amyl group; isopentyl; sec.-amyl sec-pentyl secondary amyl; neo-pentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolane-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolane-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolane-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolane-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-styroyl; 1; 1-diethoxy-2-styroyl; 1-(1; 3-dioxolane-2-yl)-the 2-styroyl; 1-(1,3-diox-2-yl)-2-styroyl; ethanoyl; propionyl; butyryl radicals; benzoyl; phenylacetyl; phenyl; the 4-p-methoxy-phenyl; benzyl; styroyl; styryl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl and 3-pyridyl, R 13Be benzyl R 14Be hydrogen.
In another embodiment of formula (VII) and compound (VIII), R 25Be selected from methyl; ethyl; propyl group; sec.-propyl; butyl; isobutyl-; sec-butyl; amyl group; isopentyl; sec.-amyl sec-pentyl secondary amyl; neo-pentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolane-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolane-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolane-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolane-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-styroyl; 1; 1-diethoxy-2-styroyl; 1-(1; 3-dioxolane-2-yl)-the 2-styroyl; 1-(1,3-diox-2-yl)-2-styroyl; ethanoyl; propionyl; butyryl radicals; benzoyl; phenylacetyl; phenyl; the 4-p-methoxy-phenyl; benzyl; styroyl; styryl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl and 3-pyridyl, R 13Be styroyl R 14Be hydrogen.
In another embodiment of formula (VII) and compound (VIII), R 25Be selected from methyl; ethyl; propyl group; sec.-propyl; butyl; isobutyl-; sec-butyl; amyl group; isopentyl; sec.-amyl sec-pentyl secondary amyl; neo-pentyl; 1; the 1-dimethoxy-ethyl; 1; 1-diethoxy ethyl; 1-(1; 3-dioxolane-2-yl)-ethyl; 1-(1; 3-diox-2-yl)-ethyl; 1; 1-dimethoxy propyl group; 1; 1-diethoxy propyl group; 1-(1; 3-dioxolane-2-yl)-propyl group; 1-(1; 3-diox-2-yl)-propyl group; 1; 1-dimethoxy butyl; 1; 1-diethoxy butyl; 1-(1; 3-dioxolane-2-yl)-butyl; 1-(1; 3-diox-2-yl)-butyl; 1; the 1-dimethoxy-benzyl; 1; 1-diethoxy benzyl; 1-(1; 3-dioxolane-2-yl)-benzyl; 1-(1; 3-diox-2-yl)-benzyl; 1; 1-dimethoxy-2-styroyl; 1; 1-diethoxy-2-styroyl; 1-(1; 3-dioxolane-2-yl)-the 2-styroyl; 1-(1,3-diox-2-yl)-2-styroyl; ethanoyl; propionyl; butyryl radicals; benzoyl; phenylacetyl; phenyl; the 4-p-methoxy-phenyl; benzyl; styroyl; styryl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl and 3-pyridyl, R 13Be 3-pyridyl R 4Be hydrogen.
The particularly preferred embodiment of formula (VII) and compound (VIII) comprises and is selected from following compound:
1-{[(α-acetoxyl oxyethyl group) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;
1-{[(α-propionyloxy oxyethyl group) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;
1-{[(α-butyryl acyloxy oxyethyl group) 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 oxyethyl group) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;
1-{[(α-benzoyloxy oxyethyl group) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;
1-{[(α-acetoxyl 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-acetoxyl 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-dioxolane-2-yl) propionyloxy isobutoxy) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid;
1-{[(α-(2-amino-2-methyl propionyl) 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-acetoxyl 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-acetoxyl 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, compound of the present invention has the structure of formula (II):
Figure A200810169355D00661
In an embodiment of the 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-chloro-phenyl-.
In a preferred embodiment, the compound of formula (II) has formula (IX) and structure (X):
Figure A200810169355D00662
In an embodiment of formula (IX) and compound (X), t is 0.In another embodiment, t is 1 and R 2For hydrogen, methyl, 2-propyl group, 2-butyl, isobutyl-, the tertiary butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 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 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,
Figure A200810169355D00671
Or
Figure A200810169355D00672
Wherein V is O or CH 2
R most preferably 7Be hydrogen.
In another embodiment of formula (IX) and 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,
Figure A200810169355D00673
Or
Figure A200810169355D00674
Wherein V is O or CH 2
R most preferably 7Be hydrogen.
In one embodiment, compound of the present invention has the structure of formula (III):
In an embodiment of the compound of formula (III), n is 1, R 1Be hydrogen R 2Be arylalkyl.Preferred R 2Be benzyl.In another embodiment of the 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 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 compound of formula (III) has the structure of formula (XI):
Figure A200810169355D00682
In an embodiment of the compound of formula (XI), n is 1, and X is NH, and Y is O, R 1Be hydrogen, R 2Be benzyl, R 22Be methyl R 23Be methyl.In another embodiment, n is 0, and Y is O, R 1Be R 25OC (O)-, R 25Be ethyl, R 22Be hydrogen R 23Be hydrogen.
In another embodiment, the compound of formula (III) has the structure of formula (XII):
Figure A200810169355D00683
In an embodiment of the compound of formula (XII), n is 1, and X is NH, and Y is O, R 1Be hydrogen, R 2Be benzyl, R 22Be methyl and R 23Be methyl.In another embodiment, n is 0, and Y is O, R 1Be R 25OC (O)-, R 25Be ethyl, R 22Be hydrogen R 23Be hydrogen.
The present invention also comprises the GABA analogue derivative that is used for patient's row administration of needs treatment, M-G, and wherein M is a primitive, and G is the GABA analogue, the derivative of H-G (wherein H is a hydrogen).Primitive M is in case cracking on G and its any meta-bolites 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 peak concentration (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):
Figure A200810169355D00691
Or its pharmacy acceptable salt, hydrate or solvate, wherein:
M is a primitive;
Y is O or S;
R is a hydrogen, perhaps R and R 6With the pyrrolidine ring that forms azetidine, tetramethyleneimine or the replacement of azetidine, replacement with their bonded atoms;
R 3And R 6Be independently selected from the heteroarylalkyl of heteroaryl, heteroarylalkyl and replacement of the assorted alkyl of ring, heteroaryl, the replacement of arylalkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring, the replacement of aryl, arylalkyl, the replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement;
R 4And R 5Be independently selected from the heteroarylalkyl of heteroaryl, heteroarylalkyl and replacement of the assorted alkyl of ring, heteroaryl, the replacement of arylalkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring, the replacement of aryl, arylalkyl, 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 heteroarylalkyl of heteroaryl, heteroarylalkyl and replacement of assorted alkyl, heteroaryl, the replacement of arylalkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring of aryl, arylalkyl, 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):
Figure A200810169355D00701
Wherein:
N, X, R 1And R 2Define as the front.
In one embodiment, M-G comprises such compound: wherein H-G is not in case from upward cracking of M, exist any lactan with structure of formula (XVI) basically:
Figure A200810169355D00702
Wherein R is a hydrogen, and R 3, R 4, R 5And R 6Define as the front.
Preferred primitive M or any meta-bolites that is formed by M do not form formaldehyde or PIVALIC ACID CRUDE (25) 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 dog oral (for example using the mini pumping unit of perviousness) 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 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 compound of the present invention is that primitive is combined with the GABA analogue.In the synthetic technology of GABA analogue, 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 analogue 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 analogue 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 OrganicTransformations (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 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 bibliography that provides more than considering perhaps, and can being used for synthetic 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 analogue, 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 analogue and alcohol or mercaptan can be reacted in the presence of coupler (for example carbodiimide and dimethyl aminopyridine) and obtain ester.In another preferred embodiment, GABA analogue and alkylogen can be reacted in the presence of alkali and obtain ester.Other method that GABA analogue is transformed into ester or thioesters is in the bibliography scope provided herein that those skilled in the art were familiar with.
Figure A200810169355D00731
Shown in above route 1, carboxylic acid directly can be combined with terminal amino group (or hydroxyl) group of GABA analogue derivative (6) and obtain adducts (7).The reagent that carries out this reaction is known for a person skilled in the art, and includes but not limited to carbodiimide, ammonium salt, phosphonium salt etc.Selectively, the reaction in the presence of alkali (for example oxyhydroxide, tertiary amine etc.) of carboxylic acid derivative such as acyl chlorides, symmetrical anhydride or mixed anhydride and GABA analogue (6) can be used to synthesize (7).
Route 2
Figure A200810169355D00732
As shown in Scheme 2, can be by in the presence of alkali (for example oxyhydroxide, tertiary amine etc.), handling and GABA analogue derivative (6) being converted into carbamate (8) with multiple carbonic acid derivatives.Selectively, known pure addition to isocyanic ester (9) or (10) can be used to synthesize (8).
As shown in Scheme 3, can be by in the presence of coupler, handling and GABA analogue derivative (6) being converted into thioamides (11) with thioic acid sulfoacid.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 carbodiimide, ammonium salt, phosphonium salt etc.Selectively, thioic acid sulfoacid derivative such as sulfo-acyl chlorides, symmetrical anhydride or mixed anhydride and (6) reaction in the presence of alkali (as oxyhydroxide, tertiary amine etc.) can be used for synthetic thioamides (11).In another method, can be by in the presence of thiophosphoric anhydride (as n=0 time), heating and acid amides (7) is converted into thioamides (11).
Can in the presence of alkali, react synthesizing thiocarbamate (12) and (13) with GABA analogue derivative (6) by the thiocarbonic acid SOH ester derivative (promptly being respectively P=O, Q=S and P=SQ=O) (wherein W is muriate, imidazolyl or 4-nitrophenoxy) of correspondence.Can also be by mercaptan and isocyanic ester (9) or (10) reaction formation thiocarbamate (13).Can in the presence of alkali, react by GABA analogue derivative (6) and dithiocarbonic acid ester derivative (being P and Q=S) (wherein W is muriate, imidazolyl or 4-nitrophenoxy) and prepare dithiocarbamate (14) (P=S, Q=S) (referring to route 4).
Route 4
Figure A200810169355D00751
A kind of method such as route 5 illustrations that are used for the compound of synthesis type (IV).
Route 5
Figure A200810169355D00752
In the presence of alkali, handle chloro-formic ester (15) and obtain p-nitrophenyl carbonic ether (16) with fragrant leavings group such as p-NP.Halid mutual exchange obtains iodide (17), and the tetra-allkylammonium reactant salt of these iodide and metal or carboxylic acid is obtained compound (18).Choose wantonly in the presence of trimethylsilyl chloride and handle the compound that (18) obtain formula (IV) with GABA analogue derivative (19).The method of the acyloxy alkyl carbamate 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 compound of formula (IV) can substep mode as shown in Scheme 6 be prepared by carbonic ether (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 compound (22), uses standard peptide coupler as known in the art with itself and GABA analogue (23) coupling then.
Route 6
Figure A200810169355D0076151308QIETU
Carry out by intermediate product carboxylamine class by GABA analogue derivative (19) carbonyl is turned to for the method for the 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 catalyzer, and continue carbonylation and finish up to reaction.This method as route 7 about by shown in the compound of halogenide (24) preparation formula (IV).
Route 7
Figure A200810169355D00771
Selectively, the mode of the substep that the 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 analogue (23) coupling, shown in front route 6.
Route 8
Figure A200810169355D00772
But the method for the 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 derivative thereof) ") of the ketone carbamate derivatives of GABA analogue.As shown in Scheme 9, the oxidation of ketone carbamate (25) obtains the compound of formula (IV).Preferred solvent includes but not limited to the trimethyl carbinol, Anaesthetie Ether, acetate, hexane, ethylene dichloride, methylene dichloride, ethyl acetate, acetonitrile, methyl alcohol, chloroform and water.Usually, oxygenant can be organism (for example yeast or a bacterium), perhaps chemical reagent (for example enzyme or superoxide).Preferred oxidant package is successfully used to ketone Baeyer-Villager is oxidized to oxygenant (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
Figure A200810169355D00781
Other 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 conditions.
Ketone carbamate (25) can be prepared by the following method by the alpha-hydroxyacetone compounds (26) of correspondence: directly by reacting with isocyanic ester (9), perhaps at first alpha-hydroxyacetone compounds is converted into halo chloro-formic ester or activatory carbonic ether intermediate product (27), then with compound (19) reaction, as route 10 illustrations.
Route 10
Figure A200810169355D00791
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
Figure A200810169355D00792
A kind of preparation method who notices the isocyanate derivates (being compound (9)) of the GABA analogue 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 nucleophilic reagent.With 2 steps orders (promptly at first activated carboxylic is become mixed anhydride, acyl halide or synthetic equivalent, replace with trinitride then) or directly (for example by using PH 2P (O) N 3Handle) this compound is converted into the intermediate product acyl azide.By thermolysis 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 isocyanic ester (9).Optional isocyanic ester 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
Figure A200810169355D00801
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 hydroxyketone (31) and obtain cyclic carbonate ester (32) with phosgene or carbonyl dimidazoles.With N-bromine succinimide and azo isobutyronitrile the free radical bromination is obtained bromide (33), be translated into alcohol (34).By alcohol (34) being changed into two carbonic ethers (dicarbonate) (35), make itself and GABA analogue derivative (19) reaction obtain prodrug (36) then with the reaction of 4-chloroformate nitrophenyl ester.Selectively, compound (34) obtains compound (36) with isocyanic ester (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 analogue derivative (19) reaction then with the reaction of 4-chloroformate nitrophenyl ester.
Route 14
Figure A200810169355D00811
Can be by choosing wantonly in the presence of secondary amine as catalyzer, under the dehydration conditions shown in the route 15, make active carbonyl compound (42) and GABA analogue derivative (19) (R wherein 16=H) reaction and synthetic simply enamine prodrug be as (43).
Route 15
Figure A200810169355D00812
Approach synthetic compound (III) shown in can pass course 16.
GABA analogue (23) obtains amino ester (45) with α-activatory ester derivative (44) reaction.By amino-terminated obtain (46) (for example use above-mentioned method) of acylations, 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
Figure A200810169355D00821
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 analogue derivative (50).
Route 17
Figure A200810169355D00831
Can be by the synthetic phosphorus prodrug of ordinary 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, compound of the present invention and/or composition are applied to the patient who suffers from following disease, preferred people: epilepsy, depression, anxiety, psychosis, faintness outbreak, hypokinesis, cranium are unusual, neurodegenerative disease, fear, pain (particularly neuropathic pain and muscle and skeleton pain), inflammatory diseases (being sacroiliitis), insomnia, gastrointestinal illness or ethanol withdrawal symptom.And in certain embodiments, can give the patient, preferred people uses compound of the present invention and/or composition as the preventive measures to multiple disease or illness.Therefore, compound of the present invention and/or composition can be used as the patient that a kind of preventive measures are applied to the following disease of easy trouble: epilepsy, depression, anxiety, psychosis, faintness outbreak, hypokinesis, cranium are unusual, neurodegenerative disease, fear, pain (particularly neuropathic pain and muscle and skeleton pain), inflammatory diseases (being sacroiliitis), insomnia, gastrointestinal illness and ethanol withdrawal symptom.Therefore, compound of the present invention and/or composition can be used to prevent a kind of disease or illness, treat another kind of disease and illness simultaneously and (for example prevent psychosis and treat gastrointestinal illness; The prevention neuropathic pain is also treated the ethanol withdrawal symptom).
Can determine that compound of the present invention and/or combination treatment epilepsy, depression, anxiety, psychosis, faintness outbreak, hypokinesis, 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 sacroiliitis), insomnia, gastrointestinal illness 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 WO97/29101, 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 compound of the present invention and/or composition 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, hypokinesis, cranium, neurodegenerative disease, fear, pain (particularly neuropathic pain and muscle and skeleton pain), inflammatory diseases (being sacroiliitis), insomnia, gastrointestinal illness and ethanol withdrawal symptom.Therefore, those skilled in the art can analyze and use that compound of the present invention and/or composition are unusual with treatment or prevention epilepsy, depression, anxiety, psychosis, faintness outbreak, hypokinesis, cranium, neurodegenerative disease, fear, pain (particularly neuropathic pain and muscle and skeleton pain), inflammatory diseases (being sacroiliitis), insomnia, gastrointestinal illness and ethanol withdrawal symptom.
4.5 treatment/prevention administration
Compound of the present invention and/or composition can be advantageously used in people's medical science.As with as described in the top 4.4, compound of the present invention or composition be used for the treatment of or prevent that epilepsy, depression, anxiety, psychosis, faintness outbreak, hypokinesis, cranium are unusual, neurodegenerative disease, fear, pain (particularly neuropathic pain and muscle and skeleton pain), inflammatory diseases (being sacroiliitis), insomnia, gastrointestinal illness or ethanol withdrawal symptom.
Compound of the present invention or composition can single, the co-administered or application with other reagent when being used for the treatment of or prevent above-mentioned disease or illness.Compound of the present invention and/or composition can also be single, with other pharmaceutically active agent, comprise that other compound of the present invention is co-administered or use.
The invention provides by the composition of the present invention of giving patient's administering therapeutic significant quantity or the method that compound is treated and prevented.Described patient can be an animal, and more preferably Mammals most preferably is the people.
Compound of the present invention or composition comprise one or more compounds of the present invention, preferably carry out oral.Compound of the present invention and/or composition can also pass through other conventional route administration, for example by inculcating or pill injection, carry out administration by epithelium or mucous membrane 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 compound of the present invention and or the delivery system (for example capsule Bao Shu is in liposome, particulate, microcapsule, capsule etc.) of composition.Medication includes but not limited in intracutaneous, intramuscular, intraperitoneal, intravenously, subcutaneous, the nose, in the epidural, mouth, hypogloeeis, nose, interior, the intravaginal of brain, transdermal, rectum, suction or topical, especially ear, nose, eye or skin are carried out administration.
In particularly preferred embodiments, compound of the present invention and/or composition can pass 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 polymkeric substance comprises Xylo-Mucine, hydroxypropylcellulose, Vltra tears and Natvosol (most preferably HYDROXY PROPYL METHYLCELLULOSE).Other preferred ether of cellulose 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 polymkeric substance with the stability (being the release of pH control) that depends on pH, the polymkeric substance that has slowly or depend on expansion, dissolving or the erosion rate (being the release of time control) of pH, by the polymkeric substance and the polymkeric substance that forms by supercharging destroyed thin film layer (being that pressure-controlling discharges) of enzyme liberating (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 TMPermeator 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 compound of the present invention and/or composition, thereby only need part system dosage (for example referring to Goodson, in " Medical Applications of Controlled Release (medical use 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.
Compound of the present invention and/or composition preferably provide GABA analogue (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 compound of the present invention and/or composition 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 compound of the present invention or the primitive of composition.Splitting mechanism is not important for the present invention.Preferably do not contain a large amount of lactan pollutent (preferably less than 0.5wt%, being more preferably less than 0.2wt%) most preferably less than 0.1wt% by the GABA analogue that forms from compound cracking prodrug of the present invention.The degree that is discharged the lactan pollutent 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 compound of the present invention and/or composition 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 compound of the present invention is cleaved before by intestinal absorption, then the GABA analogue of gained can absorb routinely and enter systemic circulation (for example by being positioned at the big neutral amino acid transporter agent of small intestine).If the cracking after by gastrointestinal absorption of the primitive of compound of the present invention, then these GABA analogue 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 compound of the present invention, then these GABA analogue prodrugs can have an opportunity to enter systemic circulation from big intestinal absorption.In this case, compound of the present invention or composition are preferably as the sustained release system administration.In a preferred embodiment, compound of the present invention or composition are sent by oral sustained release administration.Preferably in this embodiment, compound of the present invention or composition secondary every day administration (more preferably once a day).
4.6 composition of the present invention
Composition of the present invention comprise the treatment significant quantity one or more be preferably the compound of the present invention of purified form and an amount of pharmaceutically acceptable vehicle, so that suitable form of medication to be provided to the patient.When the patient was carried out administration, compound of the present invention and pharmaceutically acceptable vehicle were preferably aseptic.When intravenously was used compound of the present invention, water was a kind of preferred vehicle.Can also be with salt brine solution and dextrose and aqueous glycerin solution as liquid excipient, especially for injection liquid.Suitable pharmaceutical excipient also comprises such as following vehicle: starch, glucose, lactose, sucrose, gelatin, Fructus Hordei Germinatus, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talcum, sodium-chlor, anhydrous skimming milk, glycerine, propylene glycol, water, ethanol etc.If necessary, composition of the present invention can also comprise a spot of wetting agent and emulsifying agent or pH buffer reagent.In addition, can make used additives, stablizer, thickening material, lubricant and tinting material.
In one embodiment, composition of the present invention does not contain the lactan by product that forms by intramolecular cyclization.In a preferred embodiment, composition of the present invention is stable for standing storage (being preferably greater than 1 year) also, can't form a large amount of lactan (preferably be less than the 0.5wt% lactan,, most preferably be less than the 0.1wt% lactan) more preferably less than the 0.2wt% lactan.
Contain compound of the present invention pharmaceutical composition can by the mixing of routine, dissolving, granulation, system drageeing, grinding, emulsification, encapsulated, hold back (entrapping) or freeze drying process preparation.Described pharmaceutical composition can be conventional mode, use acceptable carrier on one or more physiology, thinner, vehicle or auxiliary agent preparation, thus help with compound of the present invention make can be medicinal preparation.Suitable preparation depends on selected route of administration.
The formulation of composition 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, sprays, suspension or any form that other is suitable for using.In one embodiment, pharmaceutically acceptable vehicle is capsule (for example referring to people such as Grosswald, United States Patent (USP) 5,698,155).The example of other appropriate drug vehicle is described in this area (referring to Remington ' s Pharmaceutical Sciences (Remington pharmaceutical science), Philadelphia College of Pharmacy and Science (Philadelphia pharmacology 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 composition of oral delivery can be tablet, lozenge, moisture or contain oil suspensions, granule, powder, emulsion, capsule, syrup or elixir.Oral compositions can comprise one or more optional reagent, and for example sweeting agent such as fructose, aspartame or asccharin, seasonings such as peppermint, wintergreen oil or cherry tinting material and sanitas are to provide pharmaceutically good to eat preparation.And under the situation of tablet or pill, described composition dressing can be degraded and absorption at gi tract with delay, thereby secular continuous action is provided.The selective permeation film that surrounds osmotically active driving compound also is applicable to the compound of the present invention and the composition of oral administration.In these platforms afterwards, be driven compound from the liquid of capsule surrounding environment and absorb, described 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 stearin.Oral compositions can comprise standard excipients such as N.F,USP MANNITOL, lactose, starch, Magnesium Stearate, soluble saccharin, Mierocrystalline cellulose, magnesiumcarbonate etc.These vehicle are preferably pharmaceutical grades.
For oral liquid, for example suspension, elixir and solution, suitable carrier, vehicle or thinner comprise subacidity buffer reagent between water, salt solution, alkylene glycol (for example propylene glycol), polyalkylene glycol (for example polyoxyethylene glycol) oil, alcohol, pH 4 and the pH 6 (for example approximately 5mM to approximately acetate, Citrate trianion, the ascorbate salt of 50mM) etc.In addition, can add seasonings, sanitas, tinting material, cholate, acylcarnitines etc.
It is also conceivable that by other approach composition is carried out administration.For the cheek administration, the formulation of composition can be with the tablet of ordinary method preparation, lozenge etc.Be suitable for generally comprising compound of the present invention and pharmaceutically acceptable vehicle with the liquid pharmaceutical formulation that atomizer and liquid dispensing apparatus and EHD aerosol device are used.Preferred pharmaceutically acceptable vehicle is that liquid is as alcohol, water, polyoxyethylene glycol or perfluoro-carbon.The optional solution of another kind of substance change compound of the present invention or the aerosol performance of suspension of adding.Preferred this material is that liquid is as alcohol, ethylene glycol, polyoxyethylene glycol or lipid 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).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 theobroma oil or or other glyceryl ester.Except aforesaid preparation, 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 intramuscularly.Therefore, 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 derivative of minimal amounts of dissolved, for example the salt of minimal amounts of dissolved.
When compound of the present invention was acidity, it can be used as free acid, pharmacy acceptable salt, solvate or hydrate and is included in any above-mentioned preparation.The activity that has kept free acid on the pharmacy acceptable salt base tincture, can by with alkali reaction preparation, and be tending towards more water-soluble and other protonic solvent than the free acid form of correspondence.
4.7 application method and dosage
Compound of the present invention or its composition are generally used to realize the purpose of expectation with significant quantity.Be used for the treatment of or prevent following application such as following disease or illness: epilepsy, depression, anxiety, psychosis, faintness outbreak, hypokinesis, cranium are unusual, neurodegenerative disease, fear, pain (particularly neuropathic pain and muscle and skeleton pain), inflammatory diseases (being sacroiliitis), insomnia, gastrointestinal illness or ethanol withdrawal symptom, and compound of the present invention or its composition are used or used with the treatment significant quantity.
Quantity for the treatment of the compound of the present invention of specified disease or illness effectively disclosed herein depends on the character of disease or illness, 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 compound of the present invention depends on experimenter, the experimenter's of treatment weight, ailing 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, compound of the present invention is sent by oral sustained release administration.Preferably in this embodiment, 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 illness.
Suitable oral dosage scope depends on the effectiveness of parent GABA analogue medicine, but is generally about 0.001mg to about 200mg compound/kg body weight of the present invention.When the GABA analogue was gabapentin, the per 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 amount is provided.Other GABA analogue 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.
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 compound of the present invention is effective and safe.
The 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 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 therapeutic action.Compound of the present invention preferably shows extra high treatment disease and treatment of conditions index.
The dosage of 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. combination therapy
In certain embodiments of the invention, compound of the present invention can be used for combination therapy with at least a other therapeutical agent.Compound of the present invention and therapeutical agent can play adduction, more preferably synergy.In a preferred embodiment, contain the administration simultaneously of compound compositions of the present invention and other therapeutical agent, described therapeutical agent can be the same with compound of the present invention as the part of composition or as different compositions.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 compound of the present invention and preparation of compositions and compound of the present invention and composition 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=normal atmosphere
Boc=tert.-butoxy carbonyl
Cbz=benzyloxy (carbobenzyloxy)
CPM=count per minute
DCC=dicyclohexyl carbodiimide
DMAP=4-N, the N-dimethyl aminopyridine
DMEM=limit eagle substratum
DMF=N, dinethylformamide
DMSO=methyl-sulphoxide
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=mmole
NBS=N-bromine succinimide
NHS=N-hydroxy-succinamide
PBS=phosphate buffered saline (PBS)
THF=tetrahydrofuran (THF)
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 p-NP.(70mL 0.79moles), adds triethylamine (110mL) then to add chloromethylchloroformate toward this solution under the room temperature.After stirring 1h, reaction mixture is filtered and filtrate is concentrated, use ethyl acetate (1L) dilution then.With 10% salt of wormwood (3 * 500mL) and 1NHCl (2 * 300mL), (2 * 300mL) washing organic solutions and are used anhydrous sodium sulfate drying to salt solution.Remove the title compound (52) that desolvates and obtain 157g (95%), be a kind of solid.Described 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 esters (53)
Under nitrogen atmosphere with p-nitrophenyl carbonic acid chloromethyl ester (52) (100g, 0.43moles), sodium iodide (228g, 1.30moles) and the anhydrous molecular sieve of 50g ( ) be added to 2L acetone, carry out mechanical stirring 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.Resistates is dissolved in methylene dichloride (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 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: Trimethylacetic acid silver (54)
With PIVALIC ACID CRUDE (25) (50g 0.49moles) is dissolved in acetonitrile (1.3L), add then silver suboxide (70g, 0.29moles), and vigorous stirring.Under nitrogen atmosphere, add 660mL water then.The suspension of gained is in the dark stirred 1h under 70 ℃.After the filtration of C salt 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 esters (53) in dry toluene (1L) (62g, 0.19moles) solution add trimethylacetic acid silver (80g, 0.38moles).After under 55 ℃ and nitrogen atmosphere, stirring 3h, reaction mixture is cooled to room temperature, and filters with C salt filter bed.With 10% salt of wormwood (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 heating of the suspension of gained, and be stirred to and realize that any solid dissolves fully.Add funnel by balanced (equalizing) above gabapentin solution is added to slow backflow, and under nitrogen atmosphere oxy acid methyl neopentyl carbonic acid p-nitrophenyl ester (the 55) (20g of mechanical stirring in methylene dichloride (100mL), 67mmol) and triethylamine (10mL, solution 0.15moles).The yellow solution of gained is stirred 1.5h.(by triketohydrindene hydrate dyeing monitoring) filtered mixture, and filtrate concentrated when stirring was finished.Resistates is dissolved in ethyl acetate (500mL), with 1N HCl (3 * 100mL), salt solution (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 C salt filter bed then.After concentrating, resistates 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 resistates is carried out chromatogram purification (4:1 hexane: 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-acetoxyl oxyethyl group) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (56)
Steps A: 1-chloroethyl-p-nitrophenyl carbonic ether (57)
To ice-cold contain p-NP in methylene dichloride (60mL) (1.39g, 10mmol) and pyridine (0.81g, reaction mixture 10mmol) add chloroformic acid 1-chloroethene ester (1.2mL, 11mmol).Mixture was stirred 30 minutes down in 0 ℃, at room temperature stir 1h then.Under reduced pressure, resistates 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-acetoxyl ethyl-p-nitrophenyl carbonic ether (58)
Will the 1-chloroethyl in the acetate (15mL)-p-nitrophenyl carbonic ether (57) (0.5g, 2mmol) and mercuric acetate (1.5g, mixture 4.4mmol) stirs 24h under room temperature.After under reduced pressure removing acetate, resistates is dissolved in ether, and water, 0.5% (v/v) NaHCO 3The aqueous solution and water washing.Use Na 2SO 4Dry ether layer, and be concentrated into dried.Handle the resistates (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-acetoxyl oxyethyl group) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (56)
To contain gabapentin in methylene dichloride (20mL) (633mg, 3.7mmol) and triethylamine (1.03mL, mixture 7.4mmol) add trimethylchlorosilane, and (0.93mL 7.4mmol), and stirs mixture until forming clear soln.Add the α-acetoxyl ethyl-p-nitrophenyl carbonic ether (58) contain in methylene dichloride (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 waterbearing stratums, and use MgSO further to use ether 4The dry organic extract that merges.After the filtration, under reduced pressure remove organic solvent.Handle the resistates (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 amount 3, freeze-drying 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 st-yrax (2.0g, solution 9.4mmol) add respectively DMAP (1.21g, 9.9mmol) and p-nitrophenyl-chloro-formic ester (1.99g, 9.9mmol).After stirring 3h under the room temperature, the water termination 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 compound (60) (in above steps A, preparing), and the mixture of gained stirred 5h under room temperature.Use the methylene dichloride 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 purifying resistates 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(0.78g 9.2mmol), and stirs the mixture of gained and to spend the night under room temperature.With 10% citric acid acidifying reaction 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) purifying resistates, obtains the title compound (59) of 960mg (49%) after removing down and desolvating. 1H NMR (CDCl 3, 400MHz): δ 1.58-1.35 (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-acetoxyl benzyloxy) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (62)
According to the method for embodiment 3, and replace st-yrax, obtain the title compound (62) of 300mg with 1-hydroxyl-1-phenyl-third-2-ketone. 1H NMR(CDCl 3，400MHz)：δ 1.41(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 oxyethyl group) carbonylamino methyl }-1-Cyclohexaneacetic acid (63)
According to the method for embodiment 3, and replace st-yrax, be able to the title compound (63) of 5mg with 2-hydroxyl-1-phenyl-1-acetone. 1H NMR(CDCl 3，400MHz)：δ 1.44-1.36(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 phenyl aldehyde (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 salt solution, saturated NaHCO 3, the salt solution wash filtrate, and use Na 2SO 4Dry.Under reduced pressure removing desolvates obtains a kind of white solid, with the mixture of the ether of 1:1 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-Butyl Lithium 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 tetrahydrofuran (THF).With the reaction mixture of gained in 0 ℃ of following restir 1h.Use saturated NH 4Cl solution termination 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 purifying crude product (25% ethyl acetate in hexane). 1H NMR(CDCl 3，400MHz)：δ 1.97(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-phenylbenzene-third-1-ketone (67)
To 2-phenyl-1-(2-phenyl-[1,3]-dithiane-2-the yl)-ethanol (66) in the mixture of the acetonitrile of 100mL 9:1 and water (2.50g, solution 7.9mmol) 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 C salt filter bed, use saturated NaHCO 3, the salt solution 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 purifying 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 acetate (64)
According to the method for embodiment 3, and with 2-hydroxyl-1,3-phenylbenzene-third-1-ketone replaces st-yrax, 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 phenyl aldehyde in the steps A, obtain the title compound (68) of 95mg with 3-methyl butyraldehyde. 1H NMR(CDCl 3，400MHz)：δ 0.88-0.90(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)：δ 0.99(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-acetoxyl butoxy) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (70)
According to the method for embodiment 6, and replace the phenyl aldehyde 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)：δ 0.95(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 st-yrax, 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 oxyethyl group) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (72)
Steps A: 1-iodine ethyl-p-nitrophenyl carbonic ether (73)
1-chloroethyl-p-nitrophenyl carbonic ether 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 ether (74)
Will the 1-iodine ethyl in the toluene (20mL)-p-nitrophenyl carbonic ether (73) (0.51g, 1.5mmol) and silver propionate (0.54g, mixture 3mmol) stirs down 24h in 50 ℃.With the reaction mixture solids removed by filtration, and concentrated filtrate under reduced pressure.The resistates 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 oxyethyl group) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid (72)
To the gabapentin in methylene dichloride (30mL) (160mg, 2.76mmol) and triethylamine (0.77mL, 5.5mmol) mixture add trimethylchlorosilane, and (0.71mL 5.5mmol), and stirs the mixture of gained until forming settled solution.Be added in α-propionyloxy ethyl-p-nitrophenyl carbonic ether (74) (0.39g, solution 1.4mmol) in the methylene dichloride (10mL) to above solution.Stir after 30 minutes with 10% citric acid (20mL) washing reaction mixture, and separate organic layer.(3 * 10mL) extract waterbearing stratums, 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 oxyethyl group) carbonyl] amino methyl } Cyclohexaneacetic acid (75)
Steps A: α-butyryl acyloxy ethyl-p-nitrophenyl carbonic ether (76)
Will (1.5g, 4.5mmol) (1.3g, mixture 6.7mmol) stir 24h in oil bath under 90 ℃ with butyric acid silver at the 1-iodine ethyl in the toluene (40mL)-p-nitrophenyl carbonic ether (73).Under reduced pressure reaction mixture is filtered and filtrate is concentrated.The resistates 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 oxyethyl group) carbonyl] amino methyl }-the 1-Cyclohexaneacetic acid (75)
To contain gabapentin in methylene dichloride (30mL) (530mg, 3.1mmol) and triethylamine (0.89mL, mixture 6.4mmol) add trimethylchlorosilane, 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 ether (76) in the methylene dichloride (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 phase.(3 * 10mL) extractions contain water, and use MgSO further to use ether 4The dry organic phase 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 amount 3, freeze-drying 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 butyric 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) +。
Be corresponding sodium salt by the following method with sour form Quantitative yield: water-soluble (5mL), the 0.5N NaHCO of adding equimolar amount 3, freeze-drying then.
Embodiment 14
1-{[(α-new pentane acyloxy oxyethyl group) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (78)
According to the method for embodiment 12, and replace butyrates, obtain the title compound (78) of 80mg (36%) with trimethylacetic acid 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) +。
Be corresponding sodium salt by the following method with sour form Quantitative yield: water-soluble (5mL), the 0.5N NaHCO of adding equimolar amount 3, freeze-drying then.
Embodiment 15
1-{ (α-acetoxyl isobutoxy) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (79)
According to the method for embodiment 2, and replace chloroformic acid 1-chloroethene ester, obtain the title compound (79) of 212mg (38%) with chloroformic 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 ether, obtain the title compound (80) of 190mg (44%) with 1-chloro-2-methyl-propyl-p-nitrophenyl carbonic ether. 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 chloroformic acid 1-chloro-ethyl ester and mercuric acetate with chloroformic acid 1-chloro-2-methyl-propyl ester and butyric acid mercury respectively, obtain the title compound (81) of 95mg (36%). 1H NMR(CD 3OD，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 chloroformic acid 1-chloroethene ester and mercuric acetate with chloroformic acid 1-chloro-2-methyl-propyl ester and isopropylformic acid mercury 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 ether and butyric acid silver with 1-chloro-2-methyl-propyl-p-nitrophenyl carbonic ether and trimethylacetic acid 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 ether 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-acetoxyl isopropoxy) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (85)
Steps A: Pseudoallyl-p-nitrophenyl carbonic ether (86)
(5.76g, 41.5mmol) (5g, mixture 41.5mmol) are added in pyridine (3.4mL, solution 42mmol) in the methylene dichloride (50mL) with chloroformic acid pseudoallyl ester to the p-NP in methylene dichloride (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 resistates 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 ether (87)
(8.7g 39mmol) is dissolved in 4M hydrogenchloride/diox in sealed vessel with pseudoallyl-p-nitrophenyl carbonic ether (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-acetoxyl sec.-propyl-p-nitrophenyl carbonic ether (88)
Will the 2-chloro isopropyl in the methylene dichloride (20mL)-p-nitrophenyl carbonic ether (87) (0.5g, 1.93mmol) and mercuric acetate (1.0g, mixture 3.13mmol) stirs 24h under room temperature.With the reaction mixture solids removed by filtration, and concentrated filtrate under reduced pressure.Handle resistates (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-acetoxyl isopropoxy) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (85)
Gabapentin in being included in methylene dichloride (30mL) (257mg, 1.5mmol) and triethylamine (0.46mL, 3.3mmol) mixture add trimethylchlorosilane, and (0.38mL 3mmol), and will stir the mixture to clarification.Add the α-acetoxyl sec.-propyl-p-nitrophenyl carbonic ether (88) contain in methylene dichloride (10mL) (0.23g, solution 0.8mmol), and stirring 30 minutes.With salt solution (10mL) washing reaction mixture, and separate organic layer.(3 * 10mL) extract waterbearing stratums, and use MgSO further to use ether 4The dry organic extract that merges, vacuum concentration.With silica gel to the resistates 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 butyric acid mercury. 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 mercury. 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] amino methyl }-1-Cyclohexaneacetic acid (92)
Steps A: 1-{[(α-chlorine isobutoxy) carbonylamino methyl isophthalic acid-Cyclohexaneacetic acid (93)
To contain gabapentin in methylene dichloride (150mL) (1.71g, 10mmol) and triethylamine (3.06mL, mixture 22mmol) add trimethylchlorosilane, and (1.4mL 11mmol), and stirs to clarify the mixture of gained (about 20 minutes).Add down the 1-chloro-2-methyl-propyl chloro-formic ester that contains in methylene dichloride (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 waterbearing stratums, and use MgSO further to use ether 4The dry organic phase that merges, vacuum concentration then.Handle resistates with silica gel chromatography, use hexane: ethyl acetate (1:4) wash-out obtains the title compound of 2.37g (77%). 1HNMR(CDCl 3，400MHz)：δ 1.04(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 resistates for preparing HPLC method purifying gained with the filtrate vacuum concentration. 1HNMR(CD 3OD，400MHz)：δ 1.07(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-hexanaphthene Acetate (94)
Steps A: 1-{[(α-chlorine isobutoxy) carbonyl] amino methyl }-1-Cyclohexaneacetic acid benzyl ester (95)
To (93) in methylene dichloride (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 resistates with silica gel chromatography, obtain the title compound of 820mg (62%) with 10% ethyl acetate/hexane wash-out. 1H NMR(CDCl 3，400MHz)：δ 1.03(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 propionic acid caesium (96)
In the solution of 14mL (0.2mol) pyruvic acid that stirs and 80ml triethyl orthoformate, add the 1mL vitriol oil under 10 ℃.The mixture of gained is stirred 1h under 5-10 ℃, then with the dilution of 200mL methylene dichloride.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 propionic 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 freeze-drying subsequently with the cesium carbonate of equimolar amount then with acid water-soluble (25mL). 1H NMR(D 2O，400MHz)：δ 0.98(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 propionic 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 resistates of silica gel flash column chromatography purifying gained, obtain the title compound of 100mg (37%) with 10% ethyl acetate/hexane wash-out.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 resistates of anti-phase preparation HPLC method purifying gained. 1H NMR(CDCl 3，400MHz)：δ 0.97(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 propionyl) 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 propionic acid, 2-diethoxy propionic acid obtains title compound. 1H NMR(CDCl 3，400MHz)：δ 0.97(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-sec.-propyl-1,3-dithiane (100)
Under 0 ℃ to the isobutyric aldehyde in methylene dichloride (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 salt solution, 5% NaHCO 3Use salt solution washing reaction mixture once more.Separate organic phase, 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)：δ 1.057(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-sec.-propyl-2-(Alpha-hydroxy butyl)-1,3-dithiane (101)
Under-20 ℃ to (100) in anhydrous tetrahydro furan (50mL) (4g, 24.7mmol) solution drip n-Butyl Lithium (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 butyraldehyde-n 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 termination 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 resistates and is handled after removing down and desolvating, and obtains the title compound of 5g (85%) with 5% ethyl acetate/hexane wash-out, is a kind of xanchromatic oil. 1HNMR(CDCl 3，400MHz)：δ 0.96(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 methyl alcohol (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) purifying resistates, be a kind of colourless liquid. 1H NMR(CDCl 3，400MHz)：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-methylheptane-3-ketone-4-p-nitrophenyl carbonic ether (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 methylene dichloride to chloroformic 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 termination reaction.Separate organic phase, use Na 2SO 4Drying, and vacuum concentration.Flash column chromatography is handled resistates, with 30% dichloromethane/hexane wash-out, obtains the title compound of 2g (85%), is a kind of beige solid. 1H NMR(CDCl 3，400MHz)：δ 0.99(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 methylene dichloride (20mL) (820mg, 4.8mmol) and triethylamine (1.35mL, mixture 9.6mmol) add trimethylchlorosilane, 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 methylene dichloride (10mL) in this solution.With 10% citric acid (20mL) washing reaction mixture, and separate organic layer.(3 * 10mL) further extract the waterbearing stratum, and use MgSO with ether 4The dry organic extract that merges concentrates under vacuum then.Handle resistates with silica gel chromatography, use hexane: ethyl acetate (4:1) wash-out is removed p-NP, and then uses hexane: ethyl acetate (1:4) wash-out obtains the title compound of (72%). 1H NMR(CDCl 3，400MHz)：δ 0.91(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 methylene dichloride (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 purifying resistates. 1HNMR(CDCl 3，400MHz)：δ 0.94(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 amount then with acid water-soluble (5mL) 3And freeze-drying.
Embodiment 29
1-{[(α-isobutyl acyloxy isobutoxy) carbonyl] amino methyl }-1-Cyclohexaneacetic acid methyl esters (105)
Steps A: 1-{[(α-chlorine isobutoxy) carbonyl] amino methyl }-1-Cyclohexaneacetic acid methyl esters (106)
With (93) (1.0g, 3.3mmol), the mixture of benzene (90mL) and methyl alcohol (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 wash-out with the resistates 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-hexanaphthene second Acid methyl esters (105)
(106) that will be in chloroform (760mg, 2.38mmol), silver carbonate (394mg, 1.4mmol) and isopropylformic acid (442 μ l, mixture 4.76mmol) at room temperature stirs 24h.Add another batch silver 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 resistates of silica gel flash column chromatography purifying gained, obtain the title compound of 560mg (63%) with 10% ethyl acetate/hexane wash-out. 1H NMR(CDCl 3，400MHz)：δ 0.94(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 esters (107)
With 1-{[(α-benzoyloxy isobutoxy) carbonyl] amino methyl }-1-Cyclohexaneacetic acid (84) (150mg, 0.38mmol), the mixture of benzene (18mL) and methyl alcohol (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 resistates with silica gel chromatography after removing down and desolvating, and obtains the title compound of 98mg (64%) with 5% ethyl acetate/hexane wash-out. 1H NMR(CDCl 3，400MHz)：δ 1.02(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 L-Ala (1.72g, 5mmol), dicyclohexyl carbodiimide (1.24g, 6mmol), N-hydroxy-succinamide (0.7g, 6mmol) and acetonitrile (20mL).With reaction mixture vibration 4h under 25 ℃.Remove by filter sedimentary dicyclohexylurea (DCU).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 phase, dry (MgSO 4), filter and concentrating under reduced pressure.Resistates is dissolved in trifluoroacetic acid (40mL), and under 22-25 ℃, leaves standstill 2h.Decompression removes down and desolvates.With resistates water-soluble (4mL), and filter with 0.25 μ M nylon membrane strainer, 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 wash-out of 20mL/min 20 minutes) purifying.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 L-Ala amino Methyl }-1-Cyclohexaneacetic acid (108)
Under 0 ℃ to (109) in methylene dichloride (200mg, add in the suspension of stirring 0.51mmol) triethylamine (141 μ L, 1.01mmol) and trimethylchlorosilane (129mL, 1.01mmol).The mixture of gained was stirred 15 minutes down in 0 ℃, be added in α-isobutyl acyloxy ethyl-p-nitrophenyl carbonic ether (111) (144mg, solution 0.51mmol) in the methylene dichloride.Mixture is stirred 7h (by the LC/MS monitoring) under room temperature, use the methylene dichloride diluted reaction mixture then, use the citric acid acidifying.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 purifying crude product. 1H-NMR(CD 3OD，400MHz)：δ 1.10(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 ether (111)
Will the 1-chloroethyl in the methylene dichloride (10mL)-p-nitrophenyl carbonic ether (57) (2.0g, 8.14mmol) and isopropylformic acid mercury (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 C salt filter bed filtering precipitate, and under vacuum and with filtrate concentrating, obtain the 2.5g crude product.Handle resistates 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 trimethylchlorosilane (0.24mL, 1.88mmol).After stirring 15 minutes under 0 ℃, be added in α-isobutyl acyloxy ethyl-p-nitrophenyl carbonic ether (111) (267mg, solution 0.94mmol) in the methylene dichloride (3mL).The mixture of gained is stirred 1.5h under room temperature.With the reaction mixture acidifying, 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 purifying crude product, at first removing nitrophenols with the methylene dichloride wash-out, be used in the title compound that 30% eluent ethyl acetate in the methylene dichloride obtains 130mg (48%) then, is the mixture of two kinds of diastereomers. 1H-NMR(CDCI3，400MHz)：δ 0.90(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 ether (113)
To the p-NP (4.06g that contains in methylene dichloride (200mL), 29mmol) with 1-chloro-2-methyl-propyl chloro-formic ester (5.0g, be added in pyridine (2.78mL, solution 32mmol) in the methylene dichloride (50mL) in ice-cold reaction mixture 29mmol).Mixture is stirred 30min under 0 ℃, at room temperature stir 1h then.Behind the vapourisation under reduced pressure solvent, resistates 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)：δ 1.12(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--p-nitrophenyl carbonic ether (114)
According to the preparation method of (111), and replace (57), obtain productive rate and be 15% title compound, and the rate of recovery 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] amino methyl }-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)：δ 0.89(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--p-nitrophenyl carbonic ether (116)
According to the preparation method of (111), replace (57) and replace isopropylformic acid mercury with (113) with mercuric benzoate, obtain title compound, productive rate is 11%, and the rate of recovery of raw material is 50%. 1H-NMR(CDCl 3，400MHz)：δ 1.15(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-butyric acid (118)
Under 0 ℃ to the etheric acid benzyl ester in acetonitrile (200mL) (5.0g, 26.01mmol) and 4-acetylaminohydroxyphenylarsonic acid benzenesulfonyl trinitride (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) grind with 2:1 ether/sherwood oil with resistates.C salt 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)：δ 2.49(s，3H)，5.27(s，2H)，7.38(M，5H)。
Step B: Benzyl 2-hydroxyl-3-oxo-butyric 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 the ethyl acetate extraction resistates 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)：δ 2.28(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 resistates.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 purifying crude product. 1H-NMR(CDCl 3，400MHz)：δ 2.48(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 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)：δ 2.41(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.Resistates 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 methylene dichloride).After stirring 1h under-78 ℃, use the reaction of 0.1N HCl (30mL) termination mix carefully, and be heated to room temperature.Separate the waterbearing stratum, (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 wash-out in the methylene dichloride obtains 767mg. 1H-NMR(CD 3OD，400MHz)：δ 2.09(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-isocyanato methyl isophthalic acid-Cyclohexaneacetic acid benzyl ester (5.9mmol) spend the night.After decompression removed down and desolvates, with flash column chromatography purifying resistates, the wash-out that is used in 30% EtOAc in the hexane obtained the title compound of 510mg. 1H-NMR(CD 3OD，400MHz)：δ 1.58-1.30(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) methoxyl group) carbonyl 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 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 purifying crude product. 1H-NMR(CD 3OD，400MHz)：δ 1.52-1.36(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-but-1-ene base) amino methyl }-1-Cyclohexaneacetic acid piperidines (124)
With 2, the 4-diacetylmethane (103 μ L, 1mmol), gabapentin (171mg, 1mmol) and piperidines (99 μ L 1mmol) sneak into anhydrous methanol (10mL).Mixture heating up 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-tetrahydrofuran (THF)-3-base subunit) ethyl] amino methyl }-the 1-Cyclohexaneacetic acid Piperidines (125)
With 2-ethanoyl butyrolactone (108 μ L, 1mmol), gabapentin (171mg, 1mmol) and piperidines (99 μ L 1mmol) sneak into anhydrous methanol (10mL).Behind the reflux 6h, under reduced pressure removing desolvates 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)，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-formiate (124 μ L, 1mmol), gabapentin (171mg, 1mmol) and piperidines (99 μ L 1mmol) sneak into anhydrous methanol (10mL).Behind the reflux 16h, under reduced pressure removing desolvates obtains purity greater than 90% title compound. 1H NMR(CDCl 3，400MHz)：δ 1.29-1.60(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-oxyethyl group-3-oxo third-1-thiazolinyl) Base }-1-Cyclohexaneacetic acid piperidines (127)
With the ethanoyl 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)：δ 1.28(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-dioxolane-2-yl) carboxyl isobutoxy) carbonyl]-amino Methyl }-1-Cyclohexaneacetic acid (128)
Steps A: The 2-methyl isophthalic acid, 3-dioxolane-2-formic acid (129)
Under 0 ℃ to contain Pyruvic Acid Ethyl ester 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 acetate of catalytic amount.The mixture of gained is stirred 16h at 40 ℃, then with the dilution of 100mL methylene dichloride.Use saturated nacl aqueous solution (2 * 80mL) washing organic solutions continuously.Separate organic layer, and concentrate the organic extract that merges.Use 1N sodium-hydroxide treatment resistates 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-dioxolane-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), silver carbonate (557mg, 2.53mmol) and triethylamine (709 μ l, mixture stirring 16h 5.1mmol).After the filtration, filtrate is concentrated.With the resistates of silica gel chromatography purifying gained, obtain the title compound (130) of 510mg (41%) with 15% ethyl acetate/hexane wash-out.MS(ESI)m/z 492.40(M+H +)。
Step C:1-{[(α-(2-(2-methyl isophthalic acid, 3-dioxolane-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)：δ 0.96(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 amount 3, freeze-drying then.
Embodiment 41
The Caco-2 cell permeability of external test prodrug
Can use method as known in the art that the passive perviousness 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 perviousness 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 Ofloxacine USP 23) existence down, under pH6.5 and at the top, (containing 1mM CaCl 2, 1MM MgCl 2, 150mM NaCl, 3mM KCl, 1mM NaH 2PO 4, 5mM glucose 50mM MES damping fluid in) and (containing in the Hanks average salt solution of 10mM HEPES) in the bottom side pH 7.4 times and to carry out penetration study.Inset is placed 12 holes or the 24 hole flat boards that contain damping fluid, 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 (recipient) and/or the concentration of the parent drug of release.See penetration number (Papp) in order to following equation reckoner:
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 analogue AppValue is shown in following table:
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
(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
(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 -5 5.6
(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 -5 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
(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 compound (83), prodrug top to bottom side perviousness surpasses their bottom side to top perviousness.This shows that these 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 perviousness big more showing have efflux pump inhibitor MK-571, verapamil and Ofloxacine USP 23, this 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 oral 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 formulation 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 the 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 PEG400) 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 termination reaction immediately, transforms to prevent the prodrug back.As following analysis blood sample.
Step B: the specimen 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 standardized 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 liquor 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 self-actuated sampler are used for analyzing.During analyzing, Zorbax XDB C84.6 * 150mm post is heated to 45 ℃.Moving 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 98% B wash-out is 3 minutes then, kept then with 98% B wash-out 2.5 minutes.Moving phase is reset into 5% B wash-out 2 minutes.The TurboIonSpray source is used for API 2000.Finish analysis in the positive ion 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 curve under area (AUC) obviously greater than (〉 2 times) area under a curve that produces of the colon administration of 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 compound of the present invention can make the composition that is suitable for promoting absorbing and/or continuing to discharge effectively the GABA analogue, thus because the rapid system clearance rate of GABA analogue 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, PEG400 etc.), and it are filled to preweighted
Figure A200810169355D01271
Mini osmotic pump device (model 2001D) (Durect Corp., Cupertino, CA).By what will fill down at 37 ℃
Figure A200810169355D01272
In infiltration salt solution, soaked 3 hours and under 4 ℃ in sealed vessel store overnight and 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 freeze-drying, and under-80 ℃, store until using above-mentioned method to analyze.The plasma concentration ratio of the back 12 hours gabapentin of taking medicine that two kinds of prodrugs provided exists
Figure A200810169355D01273
Originally the concentration of being seen gabapentin is big 2 times after one's death to use gabapentin in the device.These data further proof compound of the present invention can be made the composition that is suitable for continuing effectively release GABA analogue.
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 2 times of pregabalin plasma concentration area under curve (〉 that the area under the time curve (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 (13)

1. formula (VII) compound
Figure A200810169355C00021
Or its pharmacy acceptable salt, hydrate or solvate, wherein:
N is 0;
R 7Be selected from the heteroaralkyl of heteroaryl, heteroaralkyl and replacement of assorted alkyl, heteroaryl, the replacement of aralkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring of aryl, aralkyl, 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 heteroaralkyl of heteroaryl, heteroaralkyl and replacement of cycloalkyl, heteroaryl, the replacement of aralkyl, cycloalkyl, the replacement of aryl, aralkyl, the replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement, or R randomly 13And R 14Form the assorted alkyl of cycloalkyl, ring of cycloalkyl, replacement or the assorted alkyl ring of ring of replacement with the carbon atom that is connected with them; And
R 25Be selected from the heteroaralkyl of heteroaryl, heteroaralkyl and replacement of assorted alkyl, heteroaryl, the replacement of aralkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring of aryl, aralkyl, 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.
2. according to compound or its pharmacy acceptable salt, hydrate or the solvate of claim 1, wherein:
R 7Represent hydrogen,
R 25Represent the heteroaryl of aryl, heteroaryl or the replacement of the alkyl of alkyl, replacement, assorted alkyl, aryl, replacement; And
R 13And R 14Be independently selected from the heteroaryl of aryl, heteroaryl and the replacement of hydrogen, alkyl, aryl, replacement, or randomly, R 13And R 14Form cycloalkyl ring with the carbon that is connected with them.
3. according to compound or its pharmacy acceptable salt, hydrate or solvate, the wherein R of claim 2 13And R 144 on the spot is the aryl of hydrogen, alkyl, aryl, replacement, or randomly, forms cycloalkyl ring with the carbon that is connected with them.
4. pharmaceutical composition, it comprises each defined compound or its pharmacy acceptable salt, hydrate or solvate and pharmaceutically acceptable carrier among the claim 1-3.
5. according to the pharmaceutical composition of claim 4, it is applicable to oral sustained release administration.
6. according to each defined compound or its pharmacy acceptable salt, hydrate or solvate among the claim 1-3, be used for the treatment of.
7. be used to prepare the purposes of the medicine for the treatment of epilepsy, depression, anxiety, psychosis, faintness outbreak, hypokinesis, cranium disease, neurodegenerative disease, fear, pain, inflammatory disease, gastrointestinal tract disease or ethanol withdrawal symptom according to each defined compound or its pharmacy acceptable salt, hydrate or solvate among the claim 1-3.
8. according to the purposes of claim 7, be used for the treatment of pain.
9. purposes according to Claim 8 is used for the treatment of neuropathic pain and muscle and skeleton pain.
10. according to the purposes of claim 7, be used for the treatment of alcohol withdrawal syndrome.
11. the purposes according to claim 7 is used for the treatment of anxiety.
12. the purposes according to claim 7 is used for the treatment of epilepsy.
13. according to each purposes of claim 7-12, wherein said medicine is applicable to oral lasting release.
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