CN1753673B - Prodrugs of GABA analogs, compositions and uses thereof - Google Patents

Abstract

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

Description

Prodrugs of GABA analogs, compositions and uses thereof

This application claims 35u.s.c. § 119(e) the benefit of U.S. provisional application 60/297,521 filed on 11/6/2001, U.S. provisional application 60/298,514 filed on 14/6/2001 and U.S. provisional application 60/366,090 filed on 19/3/2002, which documents are incorporated herein by reference.

1. Field of the invention

The present invention relates generally to prodrugs of GABA analogs, pharmaceutical compositions of prodrugs of GABA analogs, methods of making prodrugs of GABA analogs, methods of using prodrugs of GABA analogs and pharmaceutical compositions of prodrugs of GABA analogs. More particularly, the present invention relates to prodrugs of gabapentin and pregabalin, pharmaceutical compositions of prodrugs of gabapentin and pregabalin, methods of making prodrugs of gabapentin and pregabalin, methods of using prodrugs of gabapentin and pregabalin and pharmaceutical compositions of prodrugs of gabapentin and pregabalin.

2. Background of the invention

Gamma ("γ") -aminobutyric acid ("GABA") is a major inhibitory transmitter in the mammalian central nervous system. GABA is not transported efficiently from the bloodstream to the brain (i.e., GABA does not cross the blood-brain barrier efficiently). Thus, brain cells provide virtually all of the GABA found in the brain (BABA is biosynthesized by decarboxylation of glutamate with pyridoxal phosphate).

GABA regulates neuronal excitability by binding to specific membrane proteins (i.e., GABAA receptors), resulting in the opening of ion channels. Chloride ions enter and pass through the ion channel causing hyperpolarization of the recipient cell, thereby preventing the transmission of nerve impulses to other cells. Low levels of GABA have been observed in individuals with seizures, movement disorders (such as multiple sclerosis, action tremor, tardive dyskinesia), panic, anxiety, depression, alcoholism and manic behavior.

The suggestion of low GABA levels for a variety of common conditions and/or common medical disorders has stimulated a great interest in the preparation of GABA analogs with superior pharmaceutical properties (e.g., ability to cross the blood brain barrier) over GABA. Thus, a variety of GABA analogs have been synthesized in the art having important pharmaceutical properties (see, e.g., Satzinger et al, U.S. Pat. No. 4,024,175, Silverman et al, U.S. Pat. No. 5,563,175, Horwell et al, U.S. Pat. No. 6,020,370, Silverman et al, U.S. Pat. No. 6,028,214, Horwell et al, U.S. Pat. No. 6,103,932, Silverman et al, U.S. Pat. No. 6,117,906, Silverman, International publication WO92/09560, Silverman et al, International publication WO93/23383, Horwell et al, International publication WO 97/29101, HORWELL et al, International publication WO 97/33858, Horwell et al, International publication WO 97/33859, Bryans et al, International publication WO98/17627, Guglietta et al, International publication WO99/08671, Bryans et al, International publication WO 99/21824, Bryans et al, International publication WO99/31057, International publication WO 99/31074, international publication WO 99/61424; bryans et al, International publication No. WO 00/15611; bryans, international publication WO 00/31020; the Bryans et al, in,

international publication WO 00/50027; and Bryans et al, International publication WO 02/00209).

For example, pharmaceutically important GABA analogs include gabapentin (1), pregabalin (2), vigabatrin (3) and baclofen (4) as shown above. Gabapentin is a lipophilic GABA analog that can pass through the blood brain barrier, and has been used clinically for the treatment of epilepsy since 1994. Gabapentin may also have useful therapeutic effects on: chronic pain conditions (e.g., neuropathic pain, muscular and skeletal pain), psychiatric conditions (e.g., panic, anxiety, depression, alcoholism, and manic behavior), movement disorders (e.g., multiple sclerosis, action tremor, tardive dyskinesia), and the like (Magnus, epilepisia, 1999, 40: S66-S72). Gabapentin is also currently used clinically to control neuropathic pain. Pregabalin, which has greater efficacy than gabapentin in clinical models of pain and epilepsy, is now in phase III clinical trials.

An important problem with many GABA analogs is the intramolecular reaction of the gamma amino group with the carboxyl function to form the gamma lactam, such as gabapentin below. The formation of gamma-lactam (5) poses serious difficulties in gabapentin formulations due to its toxicity. Toxicity (LD) of gabapentin, for example₅₀Mouse) is greater than 8000mg/kg, and the toxicity (LD) of the corresponding lactam (5)₅₀Mouse) was 300 mg/kg. Therefore, for safety reasons, it is necessary to minimize the formation of by-products such as lactams during the synthesis of GABA analogs and/or the formulation and/or storage of GABA analogs or compositions of GABA analogs (particularly during storage)

In the case of gabapentin).

The problem of lactam contamination of GABA analogs, particularly in the case of gabapentin, has been partially overcome by the application of specific additional purification steps, precise selection of adjuvant materials in pharmaceutical compositions, and careful control procedures (augert et al, U.S. patent 6,054,482). However, attempts to prevent lactam contamination have not been entirely successful in the synthesis or storage of GABA analogs such as gabapentin or compositions thereof.

Rapid systemic clearance is another important issue for many GABA analogs, including gabapentin, and therefore frequent dosing is required to maintain therapeutic and prophylactic concentrations in the systemic circulation (Bryans et al, med. res. rev., 1999, 19, 149-177). Dosing regimens of 300-600mg doses of gabapentin administered three times a day are generally used for anticonvulsant therapy. Higher doses (1800-.

Sustained release formulations are a conventional solution to rapid systemic clearance and are known to those skilled in the art (see, for example, "Remington's pharmaceutical Sciences," Philadelphia College of pharmacy and Science, 17TH Edition, 1985). Osmotic delivery systems are also known for sustained Drug delivery (see, e.g., Verma et al, Drug Dev. Ind. pharm., 2000, 26: 695-. Many GABA analogs, including gabapentin and pregabalin, are not absorbed through the large intestine. In contrast, these compounds are generally absorbed in the small intestine by large neutral amino acid transporters ("LNAA") (Jezyk et al, pharm. RES., 1999, 16, 519-526). The rapid passage of conventional dosage forms through the proximal absorption region of the gastrointestinal tract prevents the successful application of sustained release techniques to many GABA analogs.

Therefore, there is a great need for effective sustained release regimens of GABA analogs to minimize the increase in dosing frequency due to the rapid systemic clearance of these compounds. There is also a need for pure GABA analogs, (particularly gabapentin and pregablin analogs), which are substantially pure and which do not spontaneously lactamise during formulation or storage.

3. Summary of the invention

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

Importantly, the prodrugs provided by the present invention may have significant pharmaceutical advantages that have particular application in medicine. First, the promoiety of prodrugs of GABA analogs provided herein is generally unstable in vivo (i.e., large amounts of GABA analogs are produced by enzymatic or chemical cleavage prior to removal of the prodrug from the patient). Second, the promoiety derivative provided by cleavage of the promoiety from the prodrug, and any metabolites thereof, are generally non-toxic when administered to a mammal according to a dosing regimen generally following GABA analogs.

The compounds of the present invention have a promoiety attached to the gamma amino group of GABA analogs. This promoiety may be attached directly to the gamma amino group of a GABA analog, or optionally may be attached to the amino group of an alpha-amino acid promoiety or the hydroxyl group of an alpha-hydroxy acid promoiety, which itself is attached to the gamma amino group of a GABA analog.

The compounds of the present invention may also have a promoiety attached to the carboxyl group of GABA analogs. The carboxyl moiety is typically an ester or thioester group. A large number of ester or thioester groups may be used to form the carboxyl moiety.

Thus, the compounds of the present invention may include up to 4 motifs, including 1 carboxy motif and up to 3 amino motifs, which are in turn linked to a gamma amino group (i.e., thus allowing each motif to be cleaved from the N-terminus of a GABA analog in turn). The compounds of the invention may contain 2 amino moieties and 1 carboxy moiety, 2 amino moieties, 1 amino moiety and 1 carboxy moiety or 1 amino moiety. Preferably, in the compounds of the invention comprising an amino moiety and a carboxyl moiety, the carboxyl moiety is hydrolyzed prior to complete cleavage of the moiety attached to the amino group.

In a first aspect the invention provides a compound of formula (I), formula (II) or formula (III):

or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:

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

x is O or NR¹⁶；

W is O or NR¹⁷；

Y is O or S;

R¹selected from hydrogen, R²⁴C(O)-、R²⁵OC(O)-、R²⁴C(S)-、R²⁵OC(S)-、R²⁵SC(O)-、R²⁵SC(S)-、(R⁹O)(R¹⁰O)P(O)-、R²⁵S-、

And

each R²Independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alkylsulfinyl, substituted alkylsulfinyl, alkylsulfonyl, substituted alkylsulfonyl, alkylthio, substituted alkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, or substituted alkoxycarbonyl,Aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryloxy, substituted aryloxy, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino, halogen, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkoxy, substituted heteroalkoxy, heteroaryloxy, and substituted heteroaryloxy, or optionally R²And R¹⁶Together with the atoms to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

R³and R⁶Independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;

R⁴and R⁵Independently selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroarylalkyl and substituted heteroarylalkyl, or optionally R⁴And R⁵Together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, or bridged cycloalkyl ring;

R⁸and R¹²Independently selected from hydrogen, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally R⁸And R¹²Together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring;

R¹¹selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cyano, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, alkoxycarbonyl, substituted alkoxycarbonyl, cycloheteroalkoxycarbonyl, substituted cycloheteroalkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, heteroaryloxycarbonyl, substituted heteroaryloxycarbonyl, and nitro;

R⁷、R⁹、R¹⁰、R¹⁵、R¹⁶and R¹⁷Independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;

R¹³and R¹⁴Independently selected from hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl, or optionally R¹³And R¹⁴Together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring;

R²⁰and R²¹Independently selected from hydrogen, acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl, or optionally R²⁰And R²¹Are connected with themThe carbon atoms that are combined together form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring;

R²²and R²³Independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl and substituted arylalkyl, or optionally R²²And R²³Together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring;

R²⁴selected from the group consisting of hydrogen, acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; and is

R²⁵Selected from the group consisting of acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

In a second aspect, the present invention provides pharmaceutical compositions of the compounds of the invention. The pharmaceutical compositions generally comprise one or more compounds of the invention and a pharmaceutically acceptable excipient.

In a third aspect, the present invention provides a method of treating or preventing: epilepsy, depression, anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain (particularly neuropathic pain and muscular and skeletal pain), inflammatory disease (i.e., arthritis), insomnia, gastrointestinal disorders, or ethanol withdrawal syndrome. The methods generally comprise administering to a patient in need of such treatment or prevention a therapeutically effective amount of a compound of the present invention.

In a fourth aspect, the present invention provides a pharmaceutical composition for treating or preventing the following diseases in a patient in need of such treatment or prevention: epilepsy, depression, anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain (particularly neuropathic pain and muscular and skeletal pain), inflammatory disease (i.e., arthritis), insomnia, gastrointestinal disorders, or ethanol withdrawal syndrome. The methods generally comprise administering to a patient in need of such treatment or prevention a therapeutically effective amount of a pharmaceutical composition of the invention.

In a fifth aspect, the invention includes a GABA analog derivative compound, M-G, wherein M is a promoiety and G is derived from a GABA analog, H-G (wherein H is hydrogen) for administration to a patient in need of treatment. Promoiety M, once cleaved from G, and any metabolites thereof, exhibits a carcinogenic Toxic Dose (TD) of greater than 0.2 mmol/kg/day in rats₅₀). And promoiety M is cleaved from G in vivo at a sufficient rate to yield:

(i) obtaining a C of at least plasma H-G by colonic administration of an equimolar dose of H-G_max120% of plasma H-G maximum concentration (C)_max) (ii) a And

(ii) AUC of at least 120% of AUC was obtained by colonic administration of equimolar doses of H-G.

Preferably M-G are derivatives of formula (XIV):

or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:

r is hydrogen, or R and R⁶Together with the atoms to which they are bound form an azetidine, substituted azetidine, pyrrolidine or substituted pyrrolidine ring; and

Y、R³、R⁴、R⁵、R⁶and R⁷As defined above.

Most preferably, M is a derivative of formula (XV):

wherein: n, X, R¹And R²As previously defined.

4. Detailed description of the invention

4.1Definition of

“Active transport or active transport method"refers to the following molecular movements across the cell membrane: a) directly or indirectly dependent on energy-mediated methods (i.e., driven by ATP hydrolysis, ion gradients, etc.);

or

b) Facilitated diffusion mediated by interaction with specific transporters occurs

“Alkyl radical"refers to a saturated or unsaturated, straight chain, branched or cyclic monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne. Typical alkyl groups include, but are not limited to, methyl; ethyl groups such as ethyl, vinyl, and ethynyl; propyl such as prop-1-yl, prop-2-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-1-en-1-yl; cyclopropyl-2-en-1-yl, prop-1-yn-1-yl, prop-2-yn-1-yl, and the like; butyl radicals such as but-1-yl, but-2-yl, 2-methyl-prop-1-yl, 2-methyl-prop-2-yl, cyclobut-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-2-yl, but-1, 3-dien-1-yl, but-1, 3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobut-1, 3-dien-1-yl, but-1-yn-3-yl, but-3-yn-1-yl and the like.

Term "Alkyl radical"specifically means including having any saturationAnd degrees or levels of groups, i.e., groups having exclusively single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds, and groups having mixtures of single, double, and triple carbon-carbon bonds. When referring to a particular saturation level, the expressions "alkanyl", "alkenyl" and "alkynyl" are used. Preferably, the alkyl group contains 1 to 20 carbon atoms, more preferably 1 to 10 carbon atoms.

“Chain alkyl radical"refers to a saturated branched, straight chain, or cyclic alkyl group derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl such as prop-1-yl, prop-2-yl (isopropyl), cycloprop-1-yl, and the like; butyl groups such as but-1-yl, but-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl), 2-methyl-propan-2-yl (tert-butyl), cyclobut-1-yl, and the like.

“Alkenyl radical"refers to an unsaturated branched, straight chain, or cyclic alkyl group having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent olefin. The double bond of the group may be in either the cis or trans conformation. Typical alkenyl groups include, but are not limited to, vinyl; propenyl, such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, prop-1-en-1-yl; cyclopropyl-2-en-1-yl; butenyl groups such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-2-yl, but-1, 3-dien-1-yl, but-1, 3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobut-1, 3-dien-1-yl and the like.

“Alkynyl radical"refers to an unsaturated branched, straight chain, or cyclic alkyl group having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkynyl group. Typical alkynyl groups include, but are not limited to, ethynyl; propynyl groups such as prop-1-yn-1-yl, prop-2-yn-1-yl and the like; butynyl such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl and the like.

“Acyl radical"refers to the group-C (O) R, wherein R isHydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, and the like.

“Acylamino group"(or alternatively" acylamido ") refers to the group-NR 'c (o) R, wherein R' and R are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein. Representative examples include, but are not limited to, formylamino, acetylamino (i.e., acetylamino), cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino (i.e., benzoylamino), benzylcarbonylamino, and the like.

“Acyloxy radical"refers to the group-OC (O) R, where R is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl, as defined herein. Representative examples include, but are not limited to, acetoxy (or acetoxy), butoxy (butyloxy or butyloxy), benzoyloxy, and the like.

“Alkylamino radical"means a group-NHR, wherein R represents alkyl or cycloalkyl as defined herein. Representative examples include, but are not limited to, methylamino, ethylamino, 1-methylethylamino, cyclohexylamino, and the like.

“Alkoxy radical"refers to the group-OR, wherein R represents an alkyl OR cycloalkyl group as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy and the like.

“Alkoxycarbonyl radical"refers to the group-C (O) -alkoxy, wherein alkoxy is as defined herein.

“Alkyl sulfonyl radical"means a group-S (O)₂R, wherein R is alkyl or cycloalkyl as defined herein. Representative examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, and the like.

“Alkyl sulfinyl radical"refers to the group-S (O) R, wherein R is alkyl or cycloalkyl as defined herein. Representative examples include, but are not limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, and the like.

"alkylthio" refers to the group-SR, where R is alkyl or cycloalkyl as defined herein which may be optionally substituted as described herein. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, and the like.

“Amino group"means a group-NH₂-。

“Aryl radicals"refers to monovalent aromatic hydrocarbon radicals derived by the removal of one hydrogen atom from a single carbon atom in a parent aromatic ring system. Typical aryl groups include, but are not limited to, groups derived from: aceanthrylene, acenaphthylene, acephynthrylene, anthracene, azulene, benzene, coronene, fluoranthene, fluorene, hexacene, naphthotetracene, hexaene, trans-benzindene, cis-benzindene, indane, indene, naphthalene, octacene, pentacene, ovalene, penta-2, 4-diene, pentacene, pentalene, pentaphene, perylene, triphenylene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, binaphthalene, and the like. Preferably, the aryl group contains 6 to 20 carbon atoms, more preferably 6 to 12 carbon atoms.

“Aryl alkyl radical"refers to an acyclic alkyl group in which a hydrogen atom bonded to a carbon atom, typically the terminal or SP3 carbon atom, is replaced with an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenyleth-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthyleth-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenyleth-1-yl, and the like. Wherein the terms arylalkanyl, arylalkenyl and/or arylalkynyl are used if a particular alkyl moiety is to be specified. Preferably arylalkyl is (C)₆-C₃₀) Arylalkyl, e.g. arylalkyl, having an alkyl, alkenyl or alkynyl moiety of (C)₁-C₁₀) And the aromatic base is (C)₆--C₂₀) More preferably, the arylalkyl group is (C)₆-C₂₀) Arylalkyl, e.g. arylalkyl, having an alkyl, alkenyl or alkynyl moiety of (C)₁-C₈) And the aromatic base is (C)₆--C₁₂)。

“Arylalkoxy radical"refers to an-O-arylalkyl group wherein the arylalkyl group is as defined herein.

“Aryloxy carbonyl group"refers to the group-C (O) -O-aryl, wherein aryl is as defined herein.

“AUC"is the area under the plasma drug concentration-versus-time curve extrapolated from zero time to infinity.

“Bridged cycloalkyl radicals"refers to a group selected from:

wherein:

a is (CR)³⁵R³⁶)b；

R³⁵And R³⁶Independently selected from hydrogen and methyl;

R³³and R³⁴Independently selected from hydrogen and methyl;

b is an integer of 1 to 4; and

c is an integer of 0 to 2.

“Carbamoyl radical"means a group-C (O) N (R)₂Wherein each R group is independently hydrogen, alkyl, cycloalkyl or aryl as defined herein, which groups may be optionally substituted as defined herein.

“Carboxyl group"means the group-C (O) OH.

"carcinogenic potency (TD)₅₀) "(see Peto et al, Environmental health perspective)s1984, 58, 1-8) is defined as the chronic dose-grade in mg/kg body weight/day which results in half the tumor of the tested animals in the defined animal species at the end of their standard life. TD since associated tumors frequently occur in control animals₅₀More specifically defined as: dose-scale in mg/kg body weight/day, which if administered chronically over the standard life span of the species, will likely remain tumor-free during that period. The TD for any particular type of tumor, any particular tissue, or any combination thereof may be calculated₅₀。“C _max "is the highest plasma drug concentration observed after administration of an extravascular dose of drug.

“Compounds of the invention"refers to compounds encompassed by the formulae described herein, including any particular compound within the scope of the formulae for which structures are disclosed herein. The compounds of the present invention may be identified by their chemical structure and/or chemical name. When a chemical structure and a chemical name conflict, the chemical structure determines the identity of the compound. The compounds of the present invention may contain one or more chiral centers and/or double bonds and thus may exist as stereoisomers such as double bond isomers (i.e., geometric isomers), enantiomers or diastereomers. Thus, the chemical structures described herein encompass all possible optical antipodes and stereoisomers of the indicated compounds, including stereomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomers and stereoisomeric mixtures can be resolved into their constituent optical enantiomers or stereoisomers using separation techniques or chiral synthesis techniques known to those skilled in the art. The compounds of the present invention may also exist in a variety of tautomeric forms, including the enol form, the keto form, or mixtures thereof. Thus, the structural formulae described herein include all possible tautomeric forms of the compounds shown. The compounds of the present invention also include isotopically-labeled compounds in which one or more atoms have an atomic mass different from the atomic mass usually found in nature. May be included in the compounds of the inventionExamples of isotopes in matter include, but are not limited to²H、³H、¹³C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F and³⁶and (4) Cl. Furthermore, it should be understood that when a partial structure of a compound of the invention is exemplified, the brackets indicate the point of attachment of the partial structure to the remainder of the molecule.

“Compositions of the invention"refers to at least one compound of the invention and a pharmaceutically acceptable excipient by which the compound is administered to a human. The compounds of the invention are administered in isolated form when administered to a human, which means separated from the synthetic organic reaction mixture.

“Cyano radical"means the group-CN.

“Cycloalkyl radicals"refers to a saturated or unsaturated cycloalkyl group. Wherein the term "cycloalkyl" or "cycloalkenyl" is used if a particular saturation level is intended. Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like. Preferably cycloalkyl is (C)₃-C₁₀) Cycloalkyl, more preferably (C)₃-C₇) A cycloalkyl group.

“Cycloheteroalkyl radicals"refers to a saturated or unsaturated alkyl group in which one or more carbon atoms (and any attached hydrogen atoms) are independently substituted with the same or different heteroatoms. Typical heteroatoms substituted for carbon atoms include, but are not limited to N, P, O, S, Si, etc., wherein the term "cycloheteroalkenyl" or "cycloheteroalkenyl" is used if a particular saturation level is to be specified. Typical cycloheteroalkyl groups include, but are not limited to, epoxide, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, and the like.

“Cycloheteroalkoxycarbonyl"refers to the group-C (O) -OR, wherein R is cycloheteroalkyl as defined above.

“Derived from bile acids"refers to a compound structurally related to formula (XVII) or (XVIII)The relevant part is:

wherein each of D, E and F is independently H or OH.

The moiety has the same structure as the above compound except for the 1 or 2 position. At these positions, the hydrogen atom bound to the hydroxyl group and/or the hydroxyl moiety of the carboxyl group has been replaced by a covalent bond that serves as a binding site for another moiety, which is preferably a GABA analog or a GABA analog derivative.

“Derived from GABA analogues"refers to a moiety structurally related to a GABA analog. The moiety has the same structure as the compound, except for position 1 or 2. At these positions, the hydrogen atom bound to the hydroxyl moiety of the amino and (optionally) carboxyl group has been replaced by a covalent bond that serves as a binding site for another moiety.

“Dialkylamino radical"means a group-NRR 'where R and R' independently represent alkyl or cycloalkyl as defined herein. Representative examples include, but are not limited to, dimethylamino, methylethylamino, bis (1-methylethyl) amino, (cyclohexyl) (methyl) amino, (cyclohexyl) (ethyl) amino, (cyclohexyl) (propyl) amino, and the like.

Unless otherwise indicated "GABA analogs"refers to a compound having the structure:

wherein:

r is hydrogen, or R and R⁶And together with the atoms to which they are bound form an azetidine, substituted azetidine, pyrrolidine or substituted pyrrolidine ring;

R³and R⁶Independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; and

R⁴and R⁵Independently selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl, or optionally R⁴And R⁵And together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, or bridged cycloalkyl ring.

“Halogen element"means fluorine, chlorine, bromine or iodine.

“Heteroalkoxy radical"means an-O-heteroalkyl group, wherein heteroalkyl is as defined herein.

“Heteroalkyl, heteroalkenyl, heteroalkynyl"independently" refers to alkyl, alkanyl, alkenyl, and alkynyl groups in which one or more carbon atoms (and any attached hydrogen atoms) are each independently substituted with the same or different heteroatoms. Typical heteroatom groups include, but are not limited to: -O-, -S-, -O-, -S-, -O-S-, -NR '-, ═ N-N ═ N-, -N ═ N-NR', -PH-, -p (O)₂-、-O-P(O)₂-、-S(O)-、-S(O)₂-、-S_nH₂-and the like, wherein R' is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl or substituted aryl.

“Heteroaryl radical"refers to a monovalent heteroaromatic group derived by the removal of one hydrogen atom from a single atom of a heteroaromatic ring system. Typical heteroaryl groups include, but are not limited to, groups derived from: acridine, arsanilide, carbazole, beta-carboline, chroman, benzopyran, cinnoline, furanPyran, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isobenzopyran, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, pyridine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine (pyrrolizine), quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like. Preferably, the heteroaryl group is a 5-20 membered heteroaryl group, more preferably a 5-10 membered heteroaryl group. Preferred heteroaryl groups are heteroaryl groups derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.

“Heteroaryloxycarbonyl radicals"refers to the group-C (O) -OR, wherein R is heteroaryl as defined herein.

“Heteroaryl alkyl radical"refers to an acyclic alkyl group, with a carbon atom, typically terminal or SP³One of the hydrogen atoms bonded to the carbon atom is replaced by a heteroaryl group. Wherein the terms heteroarylalkanyl, heteroarylalkenyl and/or heteroarylalkynyl are used if a particular alkyl moiety is intended. In a preferred embodiment, the heteroarylalkyl is a 6-30 membered heteroarylalkyl, e.g., the alkyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-10 membered and the heteroaryl moiety is a 5-20 membered heteroaryl, more preferably a 6-20 membered heteroarylalkyl, e.g., the alkyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-8 membered and the heteroaryl moiety is a 5-12-membered heteroaryl.

“Passive diffusion"refers to the uptake of an agent that is not mediated by a particular transporter. The agent substantially incapable of passive diffusion has an in vitro volume of less than 5X 10^-6cm/sec, usually less than 1X 10^-6Permeability across a standard cell monolayer (e.g., Caco-2) in cm/sec (lacking efflux mechanism).

“Pharmaceutically acceptable"means approved or approvable by a federal or national government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

“Pharmaceutically acceptable salts"refers to salts of the compounds of the present invention which are pharmaceutically acceptable and possess the desired pharmacological activity of the parent compound. These salts include: (1) acid addition salts formed with inorganic acids such as: such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as: acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo 2.2.2-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, hexadiene diacid, and the like; or (2) a salt formed when an acidic proton present in the parent compound is replaced with a metal ion such as an alkali metal ion, an alkaline earth ion, or an aluminum ion; or complexes with organic bases such as ethanolamine, diethylamine, triethanolamine, N-methylglucamine, and the like.

“Pharmaceutically acceptable excipients"refers to a diluent, adjuvant, excipient, or carrier with which a compound of the invention is administered.

“Patient's health"includes a human. The terms "human" and "patient" are used interchangeably herein.

“Prevention (prevention or prevention)By "is meant a reduced risk of acquiring a disease or disorder (i.e., such that at least one clinical disease symptom is not developed in a patient who is exposed to or predisposed to the disease but does not yet experience or exhibit symptoms of the disease).

“Prodrugs"refers to derivatives of a drug molecule that require conversion in vivo to release the active drug. Prodrugs are generally, although not necessarily, pharmacologically inactive until converted to the parent drug.

“Primitive"refers to a form of a protecting group that when used to mask a functional group within a drug molecule converts the drug into a prodrug. Typically, the motif is bound to the drug via a bond that is cleaved enzymatically or non-enzymatically in vivo.

“Protecting group"refers to a group of atoms that, when combined with reactive functional groups in a molecular shield, reduces or prevents the reactivity of the functional groups. Examples of protecting Groups can be found in Green et al, "Protective Groups in Organic Chemistry" (Wiley, 2)^ndED.1991) and Harrison et al, "Compendium of synthetic Organic Methods (short description of Organic Synthesis Methods)", Vol.1-8 (John Wiley and Sons, 1971-1996). Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("SES"), trityl and substituted trityl, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitro-veratryloxycarbonyl ("NVOC"), and the like. Representative hydroxy protecting groups include, but are not limited to, groups in which the hydroxy group is acylated or alkylated such as benzyl, and trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.

“Substituted by"refers to a group in which one or more hydrogen atoms are each independently substituted by the same or different substituents. Typical substituents include, but are not limited to, -X, -R²⁹、＝O-、-OR²⁹、-SR²⁹、-S^-、＝S、-NR²⁹R³⁰、＝NR²⁹、-CX₃、-CF₃、-CN、-OCN、-SCN、-NO、-NO₂、＝N₂、-N₃、-S(O)₂O、-S(O)₂OH、-S(O)₂R²⁹、-OS(O₂)O^-、-OS(O)₂R²⁹、-P(O)(O^-)₂、-P(O)(OR²⁹)(O^-)、-OP(O)(OR²⁹)(OR³⁰)、-C(O)R²⁹、-C(S)R²⁹、-C(O)OR²⁹、-C(O)NR²⁹R³⁰、-C(O)O-、-C(S)OR²⁹、-NR³¹C(O)NR²⁹R³⁰、-NR³¹C(S)NR²⁹R³⁰、-NR³¹C(NR²⁹)NR²⁹R³⁰and-C (NR)²⁹)NR²⁹R³⁰Wherein each X is independently halogen; each R is²⁹And R³⁰Independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, -NR³¹R³²、-C(O)R³¹or-S (O)₂R³¹Or optionally R²⁹And R³⁰Together with the atoms to which they are simultaneously attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and R³¹And R³²Independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl.

“Transporter proteins"refers to proteins that play a direct or indirect role in the transport of molecules into and/or through cells. For example, the transporter protein may be, but is not limited to, solute-bearing transporters, co-transporters, counter transporters, single transporters, co-transporters, antiporters, pumps, equilibrium transporters, focused transporters, and other proteins that regulate active transport, energy-dependent transport, facilitate diffusion, exchange mechanisms, and specific absorption mechanisms. The transporter protein may also be, but is not limited to, a membrane-bound protein that recognizes a substrate and affects its entry into and exit from a cell via a carrier-regulated transporter or a receptor-regulated transporter. The transporter may also be, but is not limited to, one involved in the passage of a substrateAn intracellularly expressed protein that is transported through or out of the cell. The transport protein may also be, but is not limited to, a cell surface-exposed protein or glycoprotein that does not directly transport the substrate but binds to the substrate to keep it in the vicinity of the receptor, or a transport protein that affects the entry of the substrate into or through the cell. Examples of carrier proteins include: intestinal and hepatic bile acid transporters, dipeptide transporters, oligopeptide transporters, monosaccharide transporters (e.g., SGLT1), phosphate transporters, monocarboxylic acid transporters, beta-glycoprotein transporters, Organic Anion Transporters (OAT), and organic cation transporters. Examples of receptor-modulated transporters include: viral receptors, immunoglobulin receptors, bacterial toxin receptors, lectin receptors, bacterial adhesion receptors, vitamin transporters, and cytokine growth factor receptors.

Of any disease or disorder "Treatment (treating or treating)"in one embodiment refers to ameliorating a disease or disorder (i.e., arresting or reducing the development of the disease or at least one of its clinical symptoms). In another embodiment, "treating" or "treatment" refers to improving at least one physical parameter that may not be discernible by the patient. In yet another embodiment, "treating" or "treatment" refers to inhibiting the disease or disorder physically (e.g., stabilizing a discernible symptom), physiologically (e.g., stabilizing a physical parameter), or both. In yet another embodiment, "treating" or "treatment" refers to delaying the onset of a disease or disorder.

“A therapeutically effective amountBy "is meant the amount of a compound that, when administered to a patient to treat a disease, is sufficient to effect treatment of such disease. The "therapeutically effective amount" will vary with the compound, the disease and its severity, as well as the age, weight, etc., of the patient to be treated.

Reference will now be made in detail to the preferred embodiments of the present invention. While the invention will be described in conjunction with the preferred embodiments, it will be understood that they are not intended to limit the invention to these preferred embodiments. On the contrary, the application is intended to cover alternatives, modifications and equivalents, which may be included within the spirit and scope of the invention as defined by the appended claims.

4.2 Compounds of the invention

One skilled in the art will recognize that the compounds of formula (I), (II) and (III) have some structural features in common. These compounds are GABA analogs (i.e., gamma aminobutyric acid derivatives) to which promoieties have been attached. Specifically, R²、R³、R⁴、R⁵、R⁶X and Y are of the formula (I),

Common substituents found in the compounds of (II) and (III).

The compounds of the present invention include compounds of formula (I), formula (II) or formula (III)

Or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:

n、t、u、X、Y、R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R²⁰、R²¹、R²²and R²³As defined above.

In a preferred embodiment, the compounds of formulae (I), (II) and (III) do not include the following compounds:

when R is³And R⁵When both are hydrogen, R⁴And R⁵Not all hydrogen or not all methyl;

in the compounds of formula (I), when n is 0 or when n is 1, X is NR¹⁶When then R is¹Is not hydrogen;

in the compounds of formula (I), R¹、R⁷O-、R²⁴C(O)-、R²⁵C (O) -and R²⁵None of the O-is a moiety derived from a bile acid;

in the compounds of formula (I), when R is¹Is R²⁴C (O) -and when n is 0, R²⁴Is not methyl, t-butyl, 2-aminoethyl, 3-aminopropyl, benzyl, phenyl or 2- (benzoyloxymethyl) phenyl;

in the compounds of formula (I), when R is¹Is R²⁵OC (O) -or R²⁵Is not R²⁶C(O)CR¹³R¹⁴-, wherein R²⁶Selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;

in the compounds of formula (I), when R is¹Is R²⁵OC (O) -and when n is 0, R²⁵Is not methyl, t-butyl or benzyl;

in the compounds of formula (I), when n is 0 and R¹Is R²⁵C(O)OCR¹³R¹⁴OC (O) -if R¹³Or R¹⁴Any of which is hydrogen, alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl, cycloalkoxycarbonyl or substituted cycloalkoxycarbonyl, then R is¹³Or R¹⁴Is not hydrogen;

in the compound of formula (I), when n is 1, X is NH, R³、R⁵And R⁶Each is hydrogen, and R⁴When it is cyclohexyl, then R²Is not benzyl;

in the compound of formula (II), when t is 1 and u is 0, R²⁰Or R²¹Neither is 2-hydroxy-3-methyl-5-chlorophenyl; and

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

In one embodiment of the compounds of formulae (I), (II) and (III), when R is³And R⁶Each being hydrogen, R⁴And R⁵Not all hydrogen or not all methyl.

In one embodiment of the compounds of formula (I), when n is 0 or when n is 1 and X is NR¹⁶When R is¹Is not hydrogen. In another embodiment of the compounds of formula (I), R¹、R⁷O-、R²⁴C(O)-、R²⁵C (O) -or R²⁵Neither O-is a moiety derived from bile acids. In another embodiment of the compounds of formula (I), when R is¹Is R²⁴C (O) -and when n is 0, R²⁴Not an alkyl, substituted alkyl, arylalkyl, aryl or substituted aryl group. In another embodiment of the compounds of formula (I), when R is¹Is R²⁴C (O) -and when n is 0, then R²⁴Is other than C_1-4Alkanyl, benzyl, phenyl or substituted phenyl. In another embodiment of the compounds of formula (I), when R is¹Is R²⁴C (O) -and when n is 0, R²⁴Is not methyl, tert-butyl, 2-aminoethyl, 3-aminopropyl, benzyl, phenyl or 2- (benzoyloxymethyl) -phenyl. In another embodiment of the compounds of formula (I), when R is¹Is R²⁵OC (O) -or R²⁵Is not R²⁶C(O)CR¹³R¹⁴-. In another embodiment of the compounds of formula (I), when R is¹Is R²⁵OC (O) -and when n is 0, R²⁵Is not alkyl or arylalkyl. In another embodiment of the compounds of formula (I), when R is¹Is R²⁵OC (O) -and when n is 0, R²⁵Is other than C_1-4Alkanyl or benzyl. In another embodiment of the compounds of formula (I), when R is¹Is R²⁵OC (O) -and n is 0, R²⁵Not methyl, tert-butyl or benzyl. In another embodiment of the compounds of formula (I), when n is 0 and R¹Is R²⁵C(O)OCR¹³R¹⁴OC (O) -if R¹³Or R¹⁴Any of which is hydrogen, alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl, cycloalkoxycarbonyl or substituted cycloalkoxycarbonyl, then R is¹³Or R¹⁴Is not hydrogen. In another embodiment of the compounds of formula (I), when R is³、R⁵And R⁶Each being hydrogen, R⁴Is not cyclohexyl. In another embodiment of the compounds of formula (I), when n is 1, X is NH, R³、R⁵、R⁶Each is hydrogen and R²When it is benzyl, R⁴Is not cyclohexyl.

In one embodiment of the compound of formula (II), R²⁰And R²¹Are not 2-hydroxy-3-methyl-5-chlorophenyl. In one embodiment of the compounds of formula (II), when u is 1 and X is 0, t is 1.

In one embodiment of the compounds of formulae (I), (II), and (III), n is 0. In another embodiment, n is 1. When n is 1 and X is NR⁶When used, the α -amino acids preferably have an L-stereochemical configuration.

In another embodiment of the compounds of formulas (I) and (II), R⁷Selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl and substituted cycloheteroalkyl. In a preferred embodiment, Y is 0 and R⁷Is hydrogen. In another embodiment, Y is 0 and R⁷Is alkanyl, substituted alkanyl, alkenyl, substituted alkenyl, aryl or substituted aryl. Preferably R⁷Is methyl, ethyl, benzyl, -C (CH)₃)＝CH₂、-CH₂C(O)N(CH₃)₂、

Or

Wherein V is O or CH₂。

In a preferred embodiment of the compounds of formulae (I), (II) and (III), R²Selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. Preferably R²Selected from the group consisting of hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkyl, heteroarylalkyl and substituted heteroarylalkanyl.

In another embodiment of the compounds of formulas (I), (II), and (III), X is NH and R²Is hydrogen, cycloalkyl or alkanyl. Preferably R²Hydrogen, methyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl or cyclohexyl. In another embodiment, X is NH and R²Is a substituted alkanyl radical. Preferably R²is-CH₂OH，-CH(OH)CH₃、-CH₂CO₂H、-CH₂CH₂CO₂H、-CH₂CONH₂、-CH₂CH₂CONH₂、-CH₂CH₂SCH₃，CH₂SH、-CH₂(CH₂)₃NH₂or-CH₂CH₂CH₂NHC(NH)NH₂. In another embodiment, X is NH and R²Selected from the group consisting of aryl, arylalkanyl, substituted arylalkanyl and heteroarylalkanyl.

Preferably R²Is phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl or 2-indolyl. In another embodiment, X is NR¹⁶And R is²And R¹⁶And together with the atoms to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring.

Preferably R²And R¹⁶And together with the atoms to which they are bound form an azetidine, pyrrolidine or piperidine ring.

In another embodiment of the compounds of formulas (I), (II) and (III), R³Is hydrogen. In another embodiment, R⁶Is hydrogen. In another embodiment, R³And R⁶Independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl and substituted cycloalkyl³And R⁶Independently selected from hydrogen and alkanyl. More preferably R³Is hydrogen or alkanyl, and R⁶Is hydrogen.

In another preferred embodiment of the compounds of formulae (I), (II) and (III), R⁴And R⁵Independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, and substituted cycloheteroalkyl. Preferably R⁴And R⁵Independently selected from the group consisting of hydrogen, alkanyl and substituted alkanyl.

In another embodiment of the compounds of formulas (I), (II) and (III), R⁴And R⁵Together with the carbon atom to which they are attached form a cycloalkyl or substituted cycloalkyl ring. Preferably R⁴And R⁵And together with the carbon atom to which they are attached form a cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, cyclohexyl or substituted cyclohexyl ring. In another embodiment, R⁴And R⁵And together with the carbon atoms to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring. In another embodiment, R⁴And R⁵Together with the carbon atoms to which they are attached form a bridged cycloalkyl ring.

In one embodiment of the compounds of formula (I), n is 1 and R¹Is R²⁴C (O) -or R²⁴C (S) -, and R²⁴Is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkylA group, aryl, substituted aryl, heteroaryl or substituted heteroaryl. Preferably R²⁴Is methyl, ethyl, 2-propyl, tert-butyl, -CH₂OCH(CH₃)₂Phenyl or 3-pyridyl.

In another embodiment of the compounds of formula (I), n is 1 and R¹Is R²⁵OC (O) -or R²⁵SC (O) -, and R²⁵Is alkyl, substituted alkyl, heteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl. Preferably R²⁵Is ethyl, 2-propyl, neopentyl, -CH₂OCH(CH₃)₂Phenyl or 2-pyridyl.

A preferred embodiment of the compounds of formula (I) includes compounds of formula (IV):

or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:

n、Y、R²、R³、R⁴、R⁵、R⁶、R⁷、R¹³、R¹⁴、R¹⁶and R²⁵As defined above.

In a preferred embodiment, the compounds of formula (IV) do not include the following compounds:

when R is¹³Or R¹⁴When it is hydrogen, alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl, cycloalkoxycarbonyl or substituted cycloalkoxycarbonyl, R¹³Or R¹⁴Is not hydrogen; and R is²⁵C (O) is not a moiety derived from a bile acid.

In one embodiment of the compound of formula (IV), R¹³And R¹⁴Independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, aryl, arylalkyl, carbamoyl, cycloAlkyl, substituted cycloalkyl, cycloalkoxycarbonyl or heteroaryl (preferably when R is¹³When it is alkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl, R¹⁴Is methyl). More preferably R¹³And R¹⁴Independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl or 3-pyridyl.

In another embodiment of compounds of formula (IV), R¹³And R¹⁴Independently hydrogen, alkanyl, substituted alkanyl, cycloalkyl or substituted cycloalkyl. Preferably R¹³And R¹⁴Is hydrogen, alkanyl or cycloalkyl. More preferably R¹³And R¹⁴Independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl or cyclohexyl. Even more preferably R¹³R is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl or cyclohexyl¹⁴Is hydrogen, or R¹³Is methyl and R¹⁴Is methyl.

In another embodiment of compounds of formula (IV), R¹³And R¹⁴Independently hydrogen, aryl, arylalkyl or heteroaryl. More preferably R¹³And R¹⁴Independently hydrogen, phenyl, benzyl, phenethyl or 3-pyridyl, even more preferably R¹³Is phenyl, benzyl, phenethyl or 3-pyridyl and R¹⁴Is hydrogen.

In another embodiment of compounds of formula (IV), R¹³And R¹⁴Independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, carbamoyl or cycloalkoxycarbonyl. Preferably when R is¹³When it is alkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl, R¹⁴Is methyl. More preferably R¹³Is methoxycarbonyl, ethoxycarbonyl or isoPropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl or cyclohexyloxycarbonyl, and R¹⁴Is methyl.

In another embodiment of compounds of formula (IV), R¹³And R¹⁴And together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring. Preferably R¹³And R¹⁴And together with the carbon atom to which they are attached form a cycloalkyl ring. More preferably R¹³And R¹⁴And together with the carbon atom to which they are attached form a cyclobutyl, cyclopentyl or cyclohexyl ring.

In another embodiment of compounds of formula (IV), R²⁵Is acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl. Preferably R²⁵Is acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl. More preferably R²⁵Is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, neopentyl, or mixtures thereof, 1- (1, 3-dioxan-2-yl) -butyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-phenylethyl, 1-diethoxy-2-phenylethyl, 1- (1, 3-dioxolan-2-yl) -2-phenylethyl, 1- (1, 3-dioxan-2-yl) -2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methyloxan-2-ylOxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl.

In another embodiment of compounds of formula (IV), R²⁵Is acyl or substituted acyl. More preferably R²⁵Is acetyl, propionyl, butyryl, benzoyl or phenylacetyl.

In another embodiment of compounds of formula (IV), R²⁵Is alkanyl or substituted alkanyl. Preferably R²⁵Is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, neopentyl, or mixtures thereof, 1- (1, 3-dioxan-2-yl) -butyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-phenylethyl, 1-diethoxy-2-phenylethyl, 1- (1, 3-dioxolan-2-yl) -2-phenylethyl or 1- (1, 3-dioxan-2-yl) -2-phenylethyl. More preferably R²⁵Is methyl, ethyl, propyl, isopropyl, butyl, 1-dimethoxyethyl or 1, 1-diethoxyethyl.

In another embodiment of compounds of formula (IV), R²⁵Is aryl, arylalkyl or heteroaryl. Preferably R²⁵Is phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl.

In another embodiment of compounds of formula (IV), R²⁵Is cycloalkyl or substituted cycloalkyl. More preferably R²⁵Is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In another embodiment of compounds of formula (IV), R²⁵Is acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl; and R is¹³And R¹⁴Independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl or substituted heteroaryl (preferably when R is¹³When it is alkoxycarbonyl, substituted alkoxycarbonyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl or carbamoyl, R¹⁴Is methyl). Preferably R²⁵Is acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, and R is¹³And R¹⁴Independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, aryl, arylalkyl, carbamoyl, cycloalkyl, cycloalkoxycarbonyl or heteroaryl (preferably when R is¹³When it is alkoxycarbonyl, substituted alkoxycarbonyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl or carbamoyl, R¹⁴Is methyl). More preferably R²⁵Is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, neopentyl, or mixtures thereof, 1- (1, 3-dioxan-2-yl) -butyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-phenylethyl, 1-diethoxy-2-phenylethyl, 1- (1, 3-dioxolan-2-yl) -2-phenylethyl, 1- (1, 3-dioxan-2-yl) -2-phenylethylAlk-2-yl) -2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenylethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl, and R¹3 and R¹4 is independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl or 3-pyridyl. Even more preferably R²⁵Is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1-dimethoxy-2-phenylethyl, 1-diethoxy-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, cyclohexyl or 3-pyridyl, and R is¹³And R¹⁴Independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl or 3-pyridyl.

In another embodiment of compounds of formula (IV), R²⁵Is acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, and R is¹³And R¹⁴And together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring. Preferably R²⁵Is acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, and R is¹³And R¹⁴In combination with themTogether form a cycloalkyl or substituted cycloalkyl ring. More preferably R²⁵Is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, neopentyl, or mixtures thereof, 1- (1, 3-dioxan-2-yl) -butyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-phenylethyl, 1-diethoxy-2-phenylethyl, 1- (1, 3-dioxolan-2-yl) -2-phenylethyl, 1- (1, 3-dioxan-2-yl) -2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, n-butyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl, and R is¹³And R¹⁴And together with the atoms to which they are attached form a cyclobutyl, cyclopentyl or cyclohexyl ring.

In another embodiment of compounds of formula (IV), R²⁵Is acyl or substituted acyl, and R¹⁴And R¹⁴Independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl or substituted heteroaryl (preferably when R is¹³R 'when it is alkoxycarbonyl, substituted alkoxycarbonyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl or carbamoyl'¹⁴Is methyl). Preferably R²⁵Is acetyl, propionyl, butyryl, benzoyl or phenylacetyl, and R¹³And R¹⁴Independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted arylArylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl or substituted heteroaryl (preferably when R is¹³When it is alkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl, R¹⁴Is methyl).

In another embodiment of compounds of formula (IV), R²⁵Is alkanyl or substituted alkanyl, and R¹³And R¹⁴Independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl or substituted heteroaryl (preferably when R is¹³When it is alkoxycarbonyl, substituted alkoxycarbonyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl or carbamoyl, R¹⁴Is methyl). Preferably R²⁵Is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, neopentyl, or mixtures thereof, 1- (1, 3-dioxan-2-yl) -butyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-phenylethyl, 1-diethoxy-2-phenylethyl, 1- (1, 3-dioxolan-2-yl) -2-phenylethyl or 1- (1, 3-dioxan-2-yl) -2-phenylethyl, and R is¹³And R¹⁴Independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl or substituted heteroAryl (preferably when R is¹³When it is alkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl, R¹⁴Is methyl).

In another embodiment of compounds of formula (IV), R²⁵Is aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl or substituted heteroaryl, and R is¹³And R¹⁴Independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl or substituted heteroaryl (preferably when R is¹³When it is alkoxycarbonyl, substituted alkoxycarbonyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl or carbamoyl, R¹⁴Is methyl). Preferably R²⁵Is phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, and R¹³And R¹⁴Independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl or substituted heteroaryl (preferably when R is¹³When it is alkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl, R¹⁴Is methyl).

In another embodiment of compounds of formula (IV), R²⁵Is cycloalkyl or substituted cycloalkyl, and R¹³And R¹⁴Independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl or substituted heteroaryl (preferably when R is¹³When it is alkoxycarbonyl, substituted alkoxycarbonyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl or carbamoyl, R¹⁴Is methyl). Preferably R²⁵Is a ringPropyl, cyclobutyl, cyclopentyl or cyclohexyl, and R¹³And R¹⁴Independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl or substituted heteroaryl (preferably when R is¹³When it is alkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl, R¹⁴Is methyl).

In another embodiment of compounds of formula (IV), R²⁵Is acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, and R is¹³And R¹⁴Independently hydrogen, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl. Preferably R²⁵Is acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, and R is¹³And R¹⁴Independently hydrogen, alkanyl, substituted alkanyl, cycloalkyl or substituted cycloalkyl. More preferably R²⁵Is acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, and R is¹³And R¹⁴Independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl or cyclohexyl. In the above embodiments, R²⁵Preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl-dioxolan-2-yl) -butyl, 1- (1, 3-dioxan-2-yl) -butyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-phenethyl, 1-diethoxy-2-phenethyl, 1- (1, 3-dioxolan-2-yl) -2-phenethyl, 1- (1, 3-dioxan-2-yl) -2-phenethyl, acetyl, propionyl, butyryl, and a pharmaceutically acceptable salt thereof, Benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl.

In another embodiment of compounds of formula (IV), R²⁵Is acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, and R is¹³And R¹⁴Independently hydrogen, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl. Preferably R²⁵Is acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, and R is¹³And R¹⁴Independently hydrogen, aryl, arylalkyl or heteroaryl. More preferably R²⁵Is acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, and R is¹³And R¹⁴Independently hydrogen, phenyl, benzyl, phenethyl or 3-pyridyl. In the above embodiments, R²⁵Preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, neopentyl, isopentyl, neopentyl, and neopentyl, 1- (1, 3-dioxan-2-yl) -butyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-phenethyl, 1-diethoxy-2-phenylethyl, 1- (1, 3-dioxolan-2-yl) -2-phenylethyl, 1- (1, 3-dioxan-2-yl) -2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl.

In another embodiment of compounds of formula (IV), R²⁵Is acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, and R is¹³And R¹⁴Independently hydrogen, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl. Preferably R²⁵Is acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, and R is¹³And R¹⁴Independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl, cycloalkoxycarbonyl or substituted cycloalkoxycarbonyl (preferably when R is¹³When it is alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl, cycloalkoxycarbonyl or substituted cycloalkoxycarbonyl, R¹⁴Is methyl; more preferably R¹³Is methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl or cyclohexyloxycarbonyl, and R is¹⁴Is methyl). In the above embodiments, R²⁵Preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, neopentyl, isopentyl, neopentyl, and neopentyl, 1- (1, 3-dioxan-2-yl) -butyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethylOxy-2-phenylethyl, 1-diethoxy-2-phenylethyl, 1- (1, 3-dioxolan-2-yl) -2-phenylethyl, 1- (1, 3-dioxan-2-yl) -2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl.

In another embodiment of compounds of formula (IV), R²⁵Is acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, and R is¹³And R¹⁴And together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring. Preferably R²⁵Is acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, and R is¹³And R¹⁴And together with the atoms to which they are attached form a cycloalkyl or substituted cycloalkyl ring. More preferably R²⁵Is acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, and R is¹³And R¹⁴And together with the atoms to which they are attached form a cyclobutyl, cyclopentyl or cyclohexyl ring. In the above embodiments, R²⁵Preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, neopentyl, isopentyl, neopentyl, and neopentyl, 1- (1, 3-dioxan-2-yl) -butyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-phenylethyl, 1-diethoxy-2-phenylethyl, 1- (1, 3-dioxolan-2-yl) -2-phenylethyl, 1- (1, 3-dioxan-2-yl) -2-phenylethyl, acetyl, propionyl, butyryl, benzoylPhenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl.

In another embodiment of the compounds of formulas (I) and (III), R¹Is composed of

m is 0 and R⁸、R¹¹And R¹²As previously defined.

In one embodiment of the compounds of formulae (I) and (III), R¹¹Is acyl, alkoxycarbonyl, aryloxycarbonyl, cycloalkoxycarbonyl or carbamoyl, R⁸Is hydrogen, alkoxycarbonyl, alkyl, aryl, arylalkyl or cyano, and R is¹²Is hydrogen, alkoxycarbonyl, alkyl, substituted alkyl, aryl or arylalkyl.

In another embodiment of the compounds of formulas (I) and (III), R¹¹Selected from the group consisting of acetyl, propionyl, butyryl, isobutyryl, pivaloyl, cyclopentanecarbonyl, cyclohexanecarbonyl, benzoyl, phenylacetyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-isobutylcarbamoyl, N-sec-butylcarbamoyl, N-tert-butylcarbamoyl, N-cyclopentylcarbamoyl, N-cyclohexylcarbamoyl, N-phenylcarbamoyl, pivaloyl, cyclopentylcarbamoyl, N-cyclohexylcarbonyl, N-phenylcarbamoyl, N-ethyloxycarbonyl, N, N-benzylcarbamoyl, N-dimethylcarbamoyl, N-diethylcarbamoyl, N-dipropylcarbamoyl, N-diisopropylcarbamoyl, N-dibutylcarbamoyl, N-dibenzylcarbamoylN-pyrrolidinylcarbamoyl, N-piperidinyl carbamoyl and N-morpholinylcarbamoyl. More preferably R¹¹Selected from the group consisting of acetyl, propionyl, butyryl, isobutyryl, cyclohexanecarbonyl, benzoyl, phenylacetyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, cyclohexyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-phenylcarbamoyl, N-benzylcarbamoyl, N-dimethylcarbamoyl, N-diethylcarbamoyl, N-dipropylcarbamoyl, N-pyrrolidinylcarbamoyl, N-piperidinylcarbamoyl and N-morpholinylcarbamoyl.

In another embodiment of the compounds of formulas (I) and (III), R⁸Selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, and cyano. More preferably R⁸Selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl.

In another embodiment of the compounds of formulas (I) and (III), R¹²Selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, phenoxycarbonyl, and benzyloxycarbonyl. More preferably R¹²Selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl.

In another embodiment of the compounds of formulas (I) and (III), R¹¹Selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, substituted alkyl, aryl, arylalkyl, and R⁸And R¹²Together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring. Preferably R¹¹Selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl, and R⁸And R¹²And together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring. More preferably R¹¹Is hydrogen or methyl, and R⁸And R¹²And together with the carbon atom to which they are attached form a cyclopent-1-ene, cyclohex-1-ene, 2-cyclopenten-1-one, 2-cyclohexen-1-one, 2- (5H) -furanone or 5, 6-dihydro-pyran-2-one ring.

In another embodiment of the compounds of formulas (I) and (III), R¹²Selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, substituted alkyl, aryl, arylalkyl, and R⁸And R¹¹Together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring. Preferably R¹²Selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl, and R⁸And R¹¹Together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring. More preferably R¹²Selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl, and R⁸And R¹¹Together with the carbon atoms to which they are bound, form a γ -butyrolactone, δ -valerolactone or 2, 2-dimethyl-1, 3-dioxane-4, 6-dione ring.

In another embodiment of the compounds of formulae (I) and (III), R¹Is composed of

And R is¹⁵Selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. Preferably R¹⁵Is methyl, ethyl, propyl, isopropyl, cyclopentyl or cycloHexyl, phenyl, 4-hydroxyphenyl, benzyl, 4-hydroxybenzyl or 3-pyridyl.

In another embodiment of formulas (I) and (III), R¹Is composed of

Wherein R is³⁷Is hydrogen, alkyl, substituted alkyl, acyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, heterocycloalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl;

z is O, N or S; and

ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl.

Preferably Z and CH₂OC (O) -are linked in conjugation to each other (e.g.in relation to 1, 4 or 1, 2 of a six-membered ring system).

In another embodiment of formulas (I) and (III), R¹Is composed of

Or

Wherein q is 0 or 1;

R³⁸and R³⁹Independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R⁴⁰and R⁴¹Independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or and in combination with themThe carbon atoms together form a cycloalkyl ring;

R⁴²and R⁴³Independently are alkyl, substituted alkyl, cycloalkyl, substituted alkyl, aryl, substituted aryl, heteroaryl and substituted aryl or together with the carbon atom to which they are bound form an aryl, substituted aryl, heteroaryl or substituted aryl ring;

and R³⁷As previously defined.

In a preferred embodiment of the compounds of formulae (I) - (IV), Y is 0 and R is³、R⁶And R⁷Is hydrogen, and R⁴And R⁵Together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, bridged cycloalkyl or substituted bridged cycloalkyl ring.

In another preferred embodiment of the compounds of formulae (I) - (IV), R⁴And R⁵And together with the carbon atom to which they are attached form a cycloalkyl or substituted cycloalkyl ring. In one embodiment, n is 0, t is 0 and u is 0. In another embodiment, n is 1 and R is²Is hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 2-indolyl, -CH₂OH、-CH(OH)CH₃、-CH₂CO₂H、-CH₂CH₂CO₂H、-CH₂CONH₂、-CH₂CH₂CONH₂、-CH₂SCH₃、CH₂SH、-CH₂(CH₂)₃NH₂or-CH₂CH₂CH₂NHC(NH)NH₂. In another embodiment, n is 1 and R is²And R¹⁶Together with the atoms to which they are bonded, form a pyrrolidine ring.

In another preferred embodiment of the compounds of formulae (I) - (IV), R⁴And R⁵And together with the carbon atom to which they are bound form a cyclobutyl or substituted cyclobutylA base ring. Preferably the substituted cyclobutyl ring is substituted by one or more substituents selected from: alkanyl, substituted alkanyl, halo, hydroxy, carboxy, and alkoxycarbonyl.

In another preferred embodiment of the compounds of formulae (I) - (IV), R⁴And R⁵And together with the carbon atom to which they are attached form a cyclopentyl or substituted cyclopentyl ring. Preferably the cyclopentyl ring is substituted with alkanyl, substituted alkanyl, halogen, hydroxy, carboxy or alkoxycarbonyl. More preferably, the cyclopentyl ring is substituted with an alkanyl group. Even more preferably said cyclopentyl ring is selected from

And

preferably in a more particular version of the above embodiment, R⁷Is hydrogen.

In another preferred embodiment of the compounds of formulae (I) - (IV), R⁴And R⁵And together with the carbon atom to which they are attached form a cyclohexyl or substituted cyclohexyl ring. Preferably the cyclohexyl ring is substituted with alkanyl, substituted alkanyl, halogen, hydroxy, carboxy or alkoxycarbonyl. More preferably the cyclohexyl ring is substituted by an alkanyl group. Even more preferably said cyclohexyl ring is selected from

And

preferably in a more particular version of the above embodiment, R⁷Is hydrogen.

In another preferred embodiment of the compounds of formulae (I) - (IV), R⁴And R⁵Together with the carbon atoms to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring.

In one embodiment, n is 0. In another embodiment, n is 1 and R is²Is hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 2-indolyl, -CH₂OH、-CH(OH)CH₃、-CH₂CO₂H、-CH₂CH₂CO₂H、-CH₂CONH₂、-CH₂CH₂CONH₂、-CH₂CH₂SCH₃、CH₂SH、-CH₂(CH₂)₃NH₂or-CH₂CH₂CH₂NHC(NH)NH₂. In another embodiment, n is 1 and R is²And R¹⁶And together with the atoms to which they are bonded form a pyrrolidine ring. Preferably R⁴And R⁵And together with the carbon atom to which they are attached form a cycloheteroalkyl ring. More preferably the cycloheteroalkanyl ring is selected from

Or

Wherein Z is O, S (O)_pOr NR¹⁸

P is 0, 1 or 2; and

R¹⁸selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, and alkoxycarbonyl. More preferably the cycloheteroalkanyl ring is selected from

And

preferably, in a more specific version of the above embodiment, R⁷Is hydrogen.

In another embodiment of the compounds of formulas (I) - (IV), R⁴And R⁵And together with the carbon atom to which they are attached form a bridged cycloalkyl ring. In one embodiment, n is 0. In another embodiment, n is 1 and R is²Is hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 2-indolyl, -CH₂OH、-CH(OH)CH₃、-CH₂CO₂H、-CH₂CH₂CO₂H、-CH₂CONH₂、-CH₂CH₂CONH₂、-CH₂CH₂SCH₃、CH₂SH、-CH₂(CH₂)₃NH₂or-CH₂CH₂CH₂NHC(NH)NH₂. In another embodiment, n is 1 and R²And R¹⁶Together with the atoms to which they are bonded, form a pyrrolidine ring. Preferably the bridged cycloalkyl group is

Or

Preferably in a more particular version of the above embodiment, R⁷Is hydrogen.

In another embodiment of the compounds of formulas (I) - (IV), Y is 0 and R⁶And R⁷Is hydrogen, R⁴Is alkyl or cycloalkyl, R⁵Is hydrogen or alkyl, and R³Is hydrogen or alkyl. In one embodiment, n is 0. In another embodiment, n is 1 and R²Is hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 2-indolyl, -CH₂OH、-CH(OH)CH₃、-CH₂CO₂H、-CH₂CH₂CO₂H、-CH₂CONH₂、-CH₂CH₂CONH₂、-CH₂CH₂SCH₃、CH₂SH、-CH₂(CH₂)₃NH₂or-CH₂CH₂CH₂NHC(NH)NH₂. In another embodiment, n is 1 and R²And R¹⁶Together with the atoms to which they are bonded, form a pyrrolidine ring. Preferably R⁴Is cycloalkyl, R⁵Is hydrogen or methyl, and R³Is hydrogen or methyl. Preferably R³Is hydrogen, R⁴Is isobutyl and R⁵Is hydrogen.

In another embodiment of the compounds of formulas (I) - (IV), Y is 0 and R⁵And R⁷Is hydrogen or alkanyl, R³And R⁶Is hydrogen, and R⁴Is a substituted heteroalkyl group.

Preferably R⁴Is composed of

A is NR¹⁹O or S;

b is alkyl, substituted alkyl, alkoxy, halogen, hydroxy, carboxy, alkoxycarbonyl or amino;

R¹⁹is hydrogen, alkyl, cyclicAn alkyl or aryl group;

j is an integer of 0 to 4;

k is an integer of 1 to 4; and

1 is an integer of 0 to 3.

More preferably, k is 1.

In another embodiment of the compounds of formulas (I) - (IV), Y is 0 and R⁵And R⁷Is hydrogen or alkanyl, R³And R⁶Is hydrogen, and R⁴Is substituted alkanyl, cycloalkyl or substituted cycloalkyl. Preferably R⁴Is selected from

Preferably R⁴Is composed of

And

h is an integer of 1 to 6; and

i is an integer of 0 to 6.

More preferably, h is 1, 2,3 or 4 and i is 0 or 1. Even more preferably R⁴Is selected from

And

preferably, the compounds of formulae (I) - (IV) are derived from GABA analogs of formula (XIII):

wherein the GABA analogue of formula (XIII) is selected from:

1-aminomethyl-1-cyclohexaneacetic acid;

1-aminomethyl-1- (3-methylcyclohexane) acetic acid;

1-aminomethyl-1- (4-methylcyclohexane) acetic acid;

1-aminomethyl-1- (4-isopropylcyclohexane) acetic acid;

1-aminomethyl-1- (4-tert-butylcyclohexane) acetic acid;

1-aminomethyl-1- (3, 3-dimethylcyclohexane) acetic acid;

1-aminomethyl-1- (3, 3, 5, 5-tetramethylcyclohexane) acetic acid;

1-aminomethyl-1-cyclopentaneacetic acid;

1-aminomethyl-1- (3-methylcyclopentane) acetic acid;

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

7-aminomethyl-bicyclo [2.2.1] hept-7-ylacetic acid;

9-aminomethyl-bicyclo [3.3.1] non-9-ylacetic acid;

4-aminomethyl-4- (tetrahydro-pyran-4-yl) -acetic acid;

3-aminomethyl-3- (tetrahydropyran-3-yl) acetic acid;

4-aminomethyl-4- (tetrahydrothiopyran-4-yl) acetic acid;

3-aminomethyl-3- (tetrahydrothiopyran-3-yl) acetic acid;

3-aminomethyl-5-methyl-hexanoic acid;

3-aminomethyl-5-methyl-heptanoic acid;

3-aminomethyl-5-methyl-octanoic acid;

3-aminomethyl-5-methyl-nonanoic acid;

3-aminomethyl-5-methyl-decanoic acid;

3-aminomethyl-5-cyclopropyl-hexanoic acid;

3-aminomethyl-5-cyclobutyl-hexanoic acid;

3-aminomethyl-5-cyclopentyl-hexanoic acid;

3-aminomethyl-5-cyclohexyl-hexanoic acid;

3-aminomethyl-5-phenyl-hexanoic acid;

3-aminomethyl-5-phenyl-pentanoic acid;

3-aminomethyl-4-cyclobutyl-butyric acid;

3-aminomethyl-4-cyclopentyl-butyric acid;

3-aminomethyl-4-cyclohexyl-butyric acid;

3-aminomethyl-4-phenoxy-butyric acid;

3-aminomethyl-5-phenoxy-hexanoic acid; and

3-aminomethyl-5-benzylsulfanyl-pentanoic acid.

Particularly preferred embodiments of formula (I) include compounds of formulae (V) and (VI):

wherein R is¹、R²、R⁷And R¹⁶As previously defined.

In one embodiment of the compounds of formulae (V) and (VI), n is 0. In another embodiment, n is 1 and R is²Is hydrogen,Methyl, 2-propyl, 2-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 2-indolyl, -CH₂OH、-CH(OH)CH₃、-CH₂CO₂H、-CH₂CH₂CO₂H、-CH₂CONH₂、-CH₂CH₂CONH₂、-CH₂CH₂SCH₃、-CH₂SH、-CH₂(CH₂)₃NH₂or-CH₂CH₂CH₂NHC(NH)NH₂. Preferably in the above embodiments, R⁷Is hydrogen.

In another embodiment of the compounds of formulas (V) and (VI), n is 1 and R¹Is R²⁴C (O) -or R²⁴C (S) -; and R is²⁴Is alkyl, substituted alkyl, heteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl. Preferably R²⁴Is methyl, ethyl, 2-propyl, tert-butyl, -CH₂OCH(CH₃)₂Phenyl or 3-pyridyl. Preferably in this embodiment, R⁷Is hydrogen, alkanyl, substituted alkanyl, alkenyl, substituted alkenyl, aryl or substituted aryl. More preferably R⁷Is hydrogen, methyl, ethyl, benzyl, -C (CH)₃)＝CH₂、-CH₂C(O)N(CH₃)₂、

Or

Wherein V is O or CH₂。

Most preferred is R⁷Is hydrogen.

In another embodiment of the compounds of formulas (V) and (VI), n is 1 and R¹Is R²⁵OC (O) -or R²⁵SC (O) -; and R is²⁵Is alkyl, substitutedAlkyl, heteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl of (a). Preferably R²⁵Is ethyl, 2-propyl, neopentyl, -CH₂OCH(CH₃)₂Phenyl or 2-pyridyl. Preferably in this embodiment R⁷Is hydrogen, alkanyl, substituted alkanyl, alkenyl, substituted alkenyl, aryl or substituted aryl. More preferably R⁷Is hydrogen, methyl, ethyl, benzyl, -C (CH)₃)＝CH₂、-CH₂C(O)N(CH₃)₂、

Or

Wherein V is O or CH₂。

Most preferred is R⁷Is hydrogen.

In another embodiment of the compounds of formulas (V) and (VI), R¹Is composed of

And R is¹⁵Selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.

Preferably R¹⁵Is methyl, ethyl, propyl, isopropyl, cyclopentyl, cyclohexyl, phenyl, 4-hydroxyphenyl, benzyl, 4-hydroxybenzyl or 3-pyridyl. In a more specific version of this embodiment, R⁷Is hydrogen, alkanyl, substituted alkanyl, alkenyl, substituted alkenyl, aryl or substituted aryl. More preferably R⁷Is hydrogen, methyl, ethyl, benzyl, -C (CH)₃)＝CH₂、-CH₂C(O)N(CH₃)₂、

Or

Wherein V is O or CH₂。

Preferably R⁷Is hydrogen.

Particularly preferred embodiments of the compounds of formulae (V) and (VI) are compounds selected from the group consisting of: 1- { [ ((5-methyl-2-oxo-1, 3-dioxolan-4-en-4-yl) methoxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid and 3- { [ ((5-methyl-2-oxo-1, 3-dioxolan-4-en-4-yl) methoxy) carbonyl ] aminomethyl } -5-methyl-hexanoic acid.

In another embodiment of the compounds of formulas (V) and (VI), R¹Is composed of

m is 0 and R⁸、R¹¹And R¹²As previously defined. In one embodiment of the compounds of formulae (V) and (VI), R¹¹Is acyl, alkoxycarbonyl, aryloxycarbonyl, cycloalkoxycarbonyl, carbamoyl or substituted carbamoyl, R⁸Is hydrogen, alkoxycarbonyl, alkyl, aryl, arylalkyl or cyano, and R is¹²Is hydrogen, alkoxycarbonyl, alkyl, substituted alkyl, aryl or arylalkyl. In another embodiment of the compounds of formulas (V) and (VI), R¹¹Selected from acetyl, propionyl, butyryl, isobutyryl, pivaloyl, cyclopentanecarbonyl, cyclohexanecarbonyl, benzoyl, phenylacetyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, cyclopentyloxycarbonyl, and the like,Cyclohexyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-isobutylcarbamoyl, N-sec-butylcarbamoyl, N-tert-butylcarbamoyl, N-cyclopentylcarbamoyl, N-cyclohexylcarbamoyl, N-phenylcarbamoyl, N-benzylcarbamoyl, N-dimethylcarbamoyl, N-diethylcarbamoyl, N-dipropylcarbamoyl, N-diisopropylcarbamoyl, N-dibutylcarbamoyl, N-dibenzylcarbamoyl, N-ethylcarbamoyl, N-isopropylcarbamoyl, N-cyclohexylcarbamoyl, N-phenylcarbamoyl, N-benzylcarbamoyl, N-isopropylcarbamoyl, N-ethylcarbamoyl, N, N-pyrrolidinylcarbamoyl, N-piperidinylcarbamoyl and N-morpholinylcarbamoyl. In another embodiment of the compounds of formulas (V) and (VI), R¹¹Selected from the group consisting of acetyl, propionyl, butyryl, isobutyryl, cyclohexanecarbonyl, benzoyl, phenylacetyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, cyclohexyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-phenylcarbamoyl, N-benzylcarbamoyl, N-dimethylcarbamoyl, N-diethylcarbamoyl, N-dipropylcarbamoyl, N-pyrrolidinylcarbamoyl, N-piperidinylcarbamoyl and N-morpholinylcarbamoyl.

In one embodiment of the compounds of formulae (V) and (VI), R⁸Selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, and cyano. Preferably R⁸Selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl.

In another embodiment of the compounds of formulas (V) and (VI), R¹²Selected from hydrogen, methyl, ethyl, propyl, isopropyl, phenyl, benzylMethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, phenoxycarbonyl and benzyloxycarbonyl. Preferably R¹²Selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl.

In another embodiment of the compounds of formulas (V) and (VI), R¹¹Selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, substituted alkyl, aryl, arylalkyl, and R⁸And R¹²Together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring. Preferably R¹¹Selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl, and R⁸And R¹²Together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring. More preferably R¹¹Is hydrogen or methyl, and R⁸And R¹²And together with the carbon atom to which they are attached form a 2-cyclopenten-1-one, 2-cyclohexen-1-one, 2- (5H) -furanone or 5, 6-dihydro-pyran-2-one ring.

In another embodiment of the compounds of formulas (V) and (VI), R¹²Selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, substituted alkyl, aryl, arylalkyl, and R⁸And R¹¹And together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring. Preferably R¹²Selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl, and R⁸And R¹¹Together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring. More preferably R¹²Selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl, and R⁸And R¹¹And together with the carbon atom to which they are bound form a gamma-butyrolactone, delta-valerolactone or 2, 2-dimethyl-1, 3-dioxane-4, 6-dione ring.

In a more particular version of the embodiments of the compounds of formulae (V) and (VI) above, R⁷Is hydrogen, alkanyl, substituted alkanyl, alkenyl, substituted alkenyl, aryl or substituted aryl. More preferably R⁷Is hydrogen, methyl, ethyl, benzyl, -C (CH)₃)＝CH₂、-CH₂C(O)N(CH₃)₂、

Or

Wherein V is O or CH₂。

Most preferred is R⁷Is hydrogen.

Particularly preferred embodiments of the compounds of formulae (V) and (VI) are compounds selected from the group consisting of:

1- { (1-methyl-3-oxo-but-1-enyl) aminomethyl } -1-cyclohexaneacetic acid piperidinium salt;

1- {1- [ (2-oxo-tetrahydrofuran-3-ylidene) ethylaminomethyl } -1-cyclohexaneacetic acid piperidinium salt;

1- { (2-carbomethoxy) -cyclopent-1-enyl) aminomethyl } -1-cyclohexaneacetic acid piperidinium; and

1- { (1-methyl-2- (ethoxycarbonyl) -3-ethoxy-3-oxoprop-1-enyl) aminomethyl } -1-cyclohexaneacetic acid piperidinium salt.

In a particularly preferred embodiment, the compound of formula (IV) has the structure of formula (VII) or (VIII):

or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:

n、R²、R⁷、R¹³、R¹⁴、R¹⁶and R²⁵As previously defined.

In a preferred embodiment, the compounds of formulae (VII) and (VIII) do not include the following compounds:

if R is¹³Or R¹⁴Any of which is hydrogen, alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl, cycloalkoxycarbonyl or substituted cycloalkoxycarbonyl, then R is¹³Or R¹⁴Is not hydrogen; and

R²⁵c (O) is not a moiety derived from a bile acid.

In one embodiment of the compounds of formulae (VII) and (VIII), n is 0. In another embodiment, n is 1. When n is 1, the preferred alpha-amino acid is in the L-stereochemical configuration.

In another embodiment of the compounds of formulas (VII) and (VIII), R⁷Is hydrogen, alkanyl, substituted alkanyl, alkenyl, substituted alkenyl, aryl or substituted aryl. Preferably R⁷Is hydrogen, methyl, ethyl, benzyl, -C (CH)₃)＝CH₂、-CH₂C(O)N(CH₃)₂、

Or

Wherein V is O or CH₂。

Most preferred is R⁷Is hydrogen.

In another embodiment of the compounds of formulae (VII) and (VIII), n is 0. In another embodiment of the compounds of formulas (VII) and (VIII), n is 1 and R¹⁶Is hydrogen and R²Is hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 2-indolyl, -CH₂OH、-CH(OH)CH₃、-CH₂CO₂H、-CH₂CH₂CO₂H、-CH₂CONH₂、-CH₂CH₂CONH₂、-CH₂CH₂SCH₃、-CH₂SH、-CH₂(CH₂)₃NH₂or-CH₂CH₂CH₂NHC(NH)NH₂. Preferably R¹⁶Is hydrogen, and R²Is hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, tert-butyl, cyclohexyl, phenyl or benzyl. In another embodiment, n is 1 and R is²And R¹⁶And together with the atoms to which they are bonded form a pyrrolidine ring.

In another embodiment of the compounds of formulas (VII) and (VIII), R²⁵Selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, neopentyl, and mixtures thereof, 1- (1, 3-dioxan-2-yl) -butyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-phenylethyl, 1-diethoxy-2-phenylethyl, 1- (1, 3-dioxolan-2-yl) -2-phenylethyl, 1- (1, 3-dioxan-2-yl) -2-phenylethyl, acetyl, propionyl, butyryl, benzylAcyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³Is methyl and R¹⁴Is hydrogen.

In another embodiment of the compounds of formulas (VII) and (VIII), R²⁵Selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, neopentyl, and mixtures thereof, 1- (1, 3-dioxan-2-yl) -butyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-phenylethyl, 1-diethoxy-2-phenylethyl, 1- (1, 3-dioxolan-2-yl) -2-phenylethyl, 1- (1, 3-dioxan-2-yl) -2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, n-butyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³Is ethyl and R¹⁴Is hydrogen.

In another embodiment of the compounds of formulas (VII) and (VIII), R²⁵Selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, neopentyl, and mixtures thereof, 1- (1, 3-dioxan-2-yl) -butyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1-(1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-phenethyl, 1-diethoxy-2-phenethyl, 1- (1, 3-dioxolan-2-yl) -2-phenethyl, 1- (1, 3-dioxan-2-yl) -2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³Is propyl and R¹⁴Is hydrogen.

In another embodiment of the compounds of formulas (VII) and (VIII), R²⁵Selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, neopentyl, and mixtures thereof, 1- (1, 3-dioxan-2-yl) -butyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-phenylethyl, 1-diethoxy-2-phenylethyl, 1- (1, 3-dioxolan-2-yl) -2-phenylethyl, 1- (1, 3-dioxan-2-yl) -2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, n-butyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³Is isopropyl and R¹⁴Is hydrogen.

In another embodiment of the compounds of formulas (VII) and (VIII), R²⁵Selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxyPropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, 1- (1, 3-dioxan-2-yl) -butyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-phenethyl, 1-diethoxy-2-phenethyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-dimethoxybenzyl, 1-diethoxyb, 1- (1, 3-dioxolan-2-yl) -2-phenylethyl, 1- (1, 3-dioxan-2-yl) -2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³Is butyl and R¹⁴Is hydrogen.

In another embodiment of the compounds of formulas (VII) and (VIII), R²⁵Selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, neopentyl, and mixtures thereof, 1- (1, 3-dioxan-2-yl) -butyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-phenylethyl, 1-diethoxy-2-phenylethyl, 1- (1, 3-dioxolan-2-yl) -2-phenylethyl, 1- (1, 3-dioxan-2-yl) -2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, n-butyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³Is isobutyl and R¹⁴Is hydrogen.

In another embodiment of the compounds of formulas (VII) and (VIII), R²⁵Selected from methyl, ethyl, propylIsopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, neopentyl, or neopentyl, 1- (1, 3-dioxan-2-yl) -butyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-phenylethyl, 1-diethoxy-2-phenylethyl, 1- (1, 3-dioxolan-2-yl) -2-phenylethyl, 1- (1, 3-dioxan-2-yl) -2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, n-butyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³Is sec-butyl and R¹⁴Is hydrogen.

In another embodiment of the compounds of formulas (VII) and (VIII), R²⁵Selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, neopentyl, and mixtures thereof, 1- (1, 3-dioxan-2-yl) -butyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-phenylethyl, 1-diethoxy-2-phenylethyl, 1- (1, 3-dioxolan-2-yl) -2-phenylethyl, 1- (1, 3-dioxan-2-yl) -2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, n-butyl, benzyl, phenethyl, styryl, cyclopropylCyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl radical, R¹³Is tert-butyl and R¹⁴Is hydrogen.

In another embodiment of the compounds of formulas (VII) and (VIII), R²⁵Selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, neopentyl, and mixtures thereof, 1- (1, 3-dioxan-2-yl) -butyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-phenylethyl, 1-diethoxy-2-phenylethyl, 1- (1, 3-dioxolan-2-yl) -2-phenylethyl, 1- (1, 3-dioxan-2-yl) -2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, n-butyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³Is cyclopentyl and R¹⁴Is hydrogen.

In another embodiment of the compounds of formulas (VII) and (VIII), R²⁵Selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, neopentyl, and mixtures thereof, 1- (1, 3-dioxan-2-yl) -butyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-Phenethyl, 1-diethoxy-2-phenylethyl, 1- (1, 3-dioxolan-2-yl) -2-phenylethyl, 1- (1, 3-dioxan-2-yl) -2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³Is cyclohexyl and R¹⁴Is hydrogen.

In another embodiment of the compounds of formulas (VII) and (VIII), R²⁵Selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, neopentyl, and mixtures thereof, 1- (1, 3-dioxan-2-yl) -butyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-phenylethyl, 1-diethoxy-2-phenylethyl, 1- (1, 3-dioxolan-2-yl) -2-phenylethyl, 1- (1, 3-dioxan-2-yl) -2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, n-butyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³Is methyl and R¹⁴Is methyl.

In another embodiment of the compounds of formulas (VII) and (VIII), R²⁵Selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dioxan-2-ylMethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, 1- (1, 3-dioxan-2-yl) -butyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-phenylethyl, 1-diethoxy-2-phenylethyl, 1- (1, 3-dioxolan-2-yl) -2-phenylethyl, 1- (1, 3-dioxan-2-yl) -2-phenylethyl, Acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³Is methoxycarbonyl and R¹⁴Is methyl.

In another embodiment of the compounds of formulas (VII) and (VIII), R²⁵Selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, neopentyl, and mixtures thereof, 1- (1, 3-dioxan-2-yl) -butyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-phenylethyl, 1-diethoxy-2-phenylethyl, 1- (1, 3-dioxolan-2-yl) -2-phenylethyl, 1- (1, 3-dioxan-2-yl) -2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, n-butyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³Is ethoxycarbonyl and R¹⁴Is methyl.

In another embodiment of the compounds of formulas (VII) and (VIII), R²⁵Selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-butylPentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, 1- (1, 3-dioxan-2-yl) -butyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -propyl, neopentyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1,1, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-phenylethyl, 1-diethoxy-2-phenylethyl, 1- (1, 3-dioxolan-2-yl) -2-phenylethyl, 1- (1, 3-dioxan-2-yl) -2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenylethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, r¹³Is propoxycarbonyl and R¹⁴Is methyl.

In another embodiment of the compounds of formulas (VII) and (VIII), R²⁵Selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, neopentyl, and mixtures thereof, 1- (1, 3-dioxan-2-yl) -butyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-phenylethyl, 1-diethoxy-2-phenylethyl, 1- (1, 3-dioxolan-2-yl) -2-phenylethyl, 1- (1, 3-dioxan-2-yl) -2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, n-butyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³Is isopropoxycarbonyl group and R¹⁴Is methyl.

In another embodiment of the compounds of formulas (VII) and (VIII), R²⁵Selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, neopentyl, and mixtures thereof, 1- (1, 3-dioxan-2-yl) -butyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-phenylethyl, 1-diethoxy-2-phenylethyl, 1- (1, 3-dioxolan-2-yl) -2-phenylethyl, 1- (1, 3-dioxan-2-yl) -2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, n-butyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³Is butoxycarbonyl and R¹⁴Is methyl.

In another embodiment of the compounds of formulas (VII) and (VIII), R²⁵Selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, neopentyl, and mixtures thereof, 1- (1, 3-dioxan-2-yl) -butyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-phenethyl, 1-diethoxy-2-phenethyl1- (1, 3-dioxolan-2-yl) -2-phenylethyl, 1- (1, 3-dioxan-2-yl) -2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³Is isobutoxycarbonyl and R¹⁴Is methyl.

In another embodiment of the compounds of formulas (VII) and (VIII), R²⁵Selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, neopentyl, and mixtures thereof, 1- (1, 3-dioxan-2-yl) -butyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-phenylethyl, 1-diethoxy-2-phenylethyl, 1- (1, 3-dioxolan-2-yl) -2-phenylethyl, 1- (1, 3-dioxan-2-yl) -2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, n-butyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³Is sec-butoxycarbonyl group and R¹⁴Is methyl.

In another embodiment of the compounds of formulas (VII) and (VIII), R²⁵Selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, n-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, and neopentyl,1, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, 1- (1, 3-dioxan-2-yl) -butyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-phenylethyl, 1-diethoxy-2-phenylethyl, 1- (1, 3-dioxolan-2-yl) -2-phenylethyl, 1- (1, 3-dioxan-2-yl) -2-phenylethyl, 1- (1, 3-dioxolan-2-yl) -2-phenylethyl, Acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³Is tert-butoxycarbonyl and R¹⁴Is methyl.

In another embodiment of the compounds of formulas (VII) and (VIII), R²⁵Selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, neopentyl, and mixtures thereof, 1- (1, 3-dioxan-2-yl) -butyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-phenylethyl, 1-diethoxy-2-phenylethyl, 1- (1, 3-dioxolan-2-yl) -2-phenylethyl, 1- (1, 3-dioxan-2-yl) -2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, n-butyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³Is cyclohexyloxycarbonyl and R¹⁴Is methyl.

In another embodiment of the compounds of formulas (VII) and (VIII), R²⁵Is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, methyl, ethyl, propyl, isobutyl, pentyl, hexyl, and hexyl,Neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, 1- (1, 3-dioxan-2-yl) -butyl, methyl ethyl, propyl, butyl, 1, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-phenylethyl, 1-diethoxy-2-phenylethyl, 1- (1, 3-dioxolan-2-yl) -2-phenylethyl, 1- (1, 3-dioxan-2-yl) -2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenylethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, r¹³Is phenyl and R¹⁴Is hydrogen.

In another embodiment of the compounds of formulas (VII) and (VIII), R²⁵Selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, neopentyl, and mixtures thereof, 1- (1, 3-dioxan-2-yl) -butyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-phenylethyl, 1-diethoxy-2-phenylethyl, 1- (1, 3-dioxolan-2-yl) -2-phenylethyl, 1- (1, 3-dioxan-2-yl) -2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, n-butyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³Is benzyl and R¹⁴Is hydrogen.

In another embodiment of the compounds of formulas (VII) and (VIII), R²⁵Selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, neopentyl, and mixtures thereof, 1- (1, 3-dioxan-2-yl) -butyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-phenylethyl, 1-diethoxy-2-phenylethyl, 1- (1, 3-dioxolan-2-yl) -2-phenylethyl, 1- (1, 3-dioxan-2-yl) -2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, n-butyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³Is phenethyl and R¹⁴Is hydrogen.

In another embodiment of the compounds of formulas (VII) and (VIII), R²⁵Selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1-dimethoxyethyl, 1-diethoxyethyl, 1- (1, 3-dioxolan-2-yl) -ethyl, 1- (1, 3-dioxan-2-yl) -ethyl, 1-dimethoxypropyl, 1-diethoxypropyl, 1- (1, 3-dioxolan-2-yl) -propyl, 1- (1, 3-dioxan-2-yl) -propyl, 1-dimethoxybutyl, 1-diethoxybutyl, 1- (1, 3-dioxolan-2-yl) -butyl, neopentyl, and mixtures thereof, 1- (1, 3-dioxan-2-yl) -butyl, 1-dimethoxybenzyl, 1-diethoxybenzyl, 1- (1, 3-dioxolan-2-yl) -benzyl, 1- (1, 3-dioxan-2-yl) -benzyl, 1-dimethoxy-2-phenylethyl, 1-diethoxy-2-phenylethyl, 1- (1, 3-dioxolan-2-yl) -2-phenylethyl1- (1, 3-dioxan-2-yl) -2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³Is 3-pyridyl and R⁴Is hydrogen.

Particularly preferred embodiments of the compounds of formulae (VII) and (VIII) include compounds selected from the group consisting of:

1- { [ (α -acetoxyethoxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid;

1- { [ (α -propionyloxyethoxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid;

1- { [ (α -butyryloxyethoxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid;

1- { [ (α -isobutanoyloxyethoxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid;

1- { [ (α -pivaloyloxyethoxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid;

1- { [ (α -benzoyloxyethoxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid;

1- { [ (α -acetoxybutoxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid;

1- { [ (α -butyryloxybutoxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid;

1- { [ (α -isobutanoyloxybutoxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid;

1- { [ (α -benzoyloxybutoxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid;

1- { [ (α -acetoxyisobutoxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid;

1- { [ (α -propionyloxy isobutoxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid;

1- { [ (α -butyryloxy-isobutoxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid;

1- { [ (α -isobutyryloxy-isobutoxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid;

1- { [ (α -pivaloyloxy isobutoxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid;

1- { [ (α -2, 2-diethoxypropionyloxy-isobutoxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid;

1- { [ (α -2- (1, 3-dioxolan-2-yl) propionyloxy-isobutoxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid;

1- { [ (α - (2-amino-2-methylpropanoyl) oxoisobutoxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid;

1- { [ (α -benzoyloxy isobutoxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid;

1- { [ (α -nicotinoyloxy isobutoxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid;

1- { [ (α -acetoxyisopropoxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid;

1- { [ (α -butyryloxy-isopropoxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid;

1- { [ (α -isobutanoyloxyethoxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid;

1- { [ (α -benzoyloxy isopropoxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid;

1- { [ (α -acetoxybenzyloxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid;

1- { [ (α -benzoyloxybenzyloxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid;

1- { [ (1- (3-methylbutanoyloxy) -2-phenylethoxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid;

1- { [ (1-benzoyloxy-2-phenylethoxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid;

1- { [ N- (α -isobutanoyloxyethoxy) carbonyl ] -4-bromophenylallylaminyl (ananinyl) -aminomethyl } -1-cyclohexaneacetic acid;

3- { [ (α -isobutanoyloxyethoxy) carbonyl ] aminomethyl } -5-methylhexanoic acid;

3- { [ (α -isobutyryloxy isobutoxy) carbonyl ] aminomethyl } -5-methylhexanoic acid; and 3- { [ (α -benzoyloxy isobutoxy) carbonyl ] aminomethyl } -5-methylhexanoic acid.

In one embodiment, the compounds of the present invention have the structure of formula (II):

in one embodiment of the compounds of formula (II), when R is³、R⁵And R⁶Is hydrogen, R⁴Not phenyl or substituted phenyl. More preferably R⁴Is not 4-chlorophenyl.

In a preferred embodiment, the compounds of formula (II) have the structures of formulae (IX) and (X):

in one embodiment of the compounds of formulae (IX) and (X), t is 0. In another embodiment, t is 1 and R²Is hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 2-indazoleIndole radical, -CH₂OH、-CH(OH)CH₃、-CH₂CO₂H、-CH₂CH₂CO₂H、-CH₂CONH₂、-CH₂CH₂CONH₂、-CH₂CH₂SCH₃、-CH₂SH、-CH₂(CH₂)₃NH₂or-CH₂CH₂CH₂NHC(NH)NH₂。

In another embodiment of the compounds of formulae (IX) and (X), R²⁰And R²¹Independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. Preferably R²⁰And R²¹Independently selected from alkyl, substituted aryl and heteroaryl. In one embodiment, R²⁰Is methyl and R²¹Is methyl. Preferably in this last embodiment, R⁷Is hydrogen, methyl, ethyl, benzyl, -C (CH)₃)＝CH₂、-CH₂C(O)N(CH₃)₂、

Or

Wherein V is O or CH₂。

Most preferred is R⁷Is hydrogen.

In another embodiment of the compounds of formulae (IX) and (X), R²⁰And R²¹And together with the carbon atom to which they are attached form a cycloalkyl or substituted cycloalkyl ring. In one embodiment, R²⁰And R²¹And together with the carbon atom to which they are attached form a cyclohexyl ring. Preferably in this last embodiment, R⁷Is hydrogen, methyl, ethyl, benzyl, -C (CH)₃)＝CH₂、-CH₂C(O)N(CH₃)₂、

Or

Wherein V is O or CH₂。

Most preferred is R⁷Is hydrogen.

In one embodiment, the compounds of the present invention have the structure of formula (III):

in one embodiment of the compounds of formula (III), n is 1 and R¹Is hydrogen and R²Is an arylalkyl group. Preferably R²Is benzyl. In another embodiment of the compounds of formula (III), n is 0 and R¹Is R²⁵OC (O) -. Preferably R²⁵Is alkyl or substituted alkyl. More preferably R²⁵Is ethyl. In another embodiment of the compounds of formula (III), R²²And R²³Is hydrogen. In another embodiment, R²²And R²³Is alkyl or substituted alkyl. Preferably R²²And R²³Is methyl.

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

in one embodiment of the compounds of formula (XI), n is 1, X is NH, Y is 0, R¹Is hydrogen, R²Is benzyl, R²²Is methyl and R²³Is methyl. In another embodiment, n is 0, Y is 0, R¹Is R²⁵OC(O)-，R²⁵Is ethyl, R²²Is hydrogen and R²³Is hydrogen.

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

in one embodiment of the compounds of formula (XII), n is 1, X is NH, Y is 0, R¹Is hydrogen, R²Is benzyl, R²²Is methyl and R²³Is methyl. In another embodiment, n is 0, Y is 0, R¹Is R²⁵OC(O)-，R²⁵Is ethyl, R²²Is hydrogen and R²³Is hydrogen.

The invention also includes GABA analog derivatives, M-G, wherein M is a promoiety and G is a GABA analog, derivatives of H-G (wherein H is hydrogen) for administration to a patient in need of treatment. Promoiety M, once cleaved from G and any metabolites thereof, exhibits a carcinogenic Toxic Dose (TD) to rats₅₀) More than 0.2 mmol/kg/day. Furthermore, when administered to rats in the colon, promoiety M is cleaved from G in vivo at a sufficient rate to yield:

(i) at least the maximum plasma H-G concentration (C) obtained by colonic administration of an equimolar dose of H-G_max) 120% of plasma H-G C_max(ii) a And

(ii) AUC that is at least 120% of the AUC obtained by colonic administration of an equimolar dose of H-G.

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

or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:

m is a motif;

y is O or S;

r is hydrogen, or R and R⁶And together with the atoms to which they are bound form an azetidine, substituted azetidine, pyrrolidine or substituted pyrrolidine ring;

R³and R⁶Independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;

R⁴and R⁵Independently selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally R⁴And R⁵And together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, or bridged cycloalkyl ring; and

R⁷selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

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

wherein:

n、X、R¹and R²As previously defined.

In one embodiment, M-G includes compounds that: wherein H-G, once cleaved from M, is substantially absent any lactam having the structure of formula (XVI):

wherein R is hydrogen and R³、R⁴、R⁵And R⁶As previously defined.

Preferably, the motif M or any metabolite formed by M does not form formaldehyde or pivalic acid upon G-M cleavage. In one embodiment, when administered to rats in the colon, promoieties M are cleaved from G in vivo at a sufficient rate to yield C that is at least the plasma H-G obtained by colonic administration of an equimolar dose of H-G_max200%, most preferably at least 1000%, of plasma H-G C_max. Preferably, upon colonic administration to rats, the promoiety M cleaves in vivo from G at a sufficient rate to yield an AUC for plasma H-G that is at least 200%, most preferably at least 500%, of the AUC for plasma obtained by colonic administration of an equimolar dose of H-G. In another embodiment, after oral administration (e.g., using an osmotic mini-pump device) to a dog at a dose of about 60 μmol equivalent of H-G/kg, promoiety M is cleaved from H-G in vivo at a sufficient rate to yield a plasma concentration 12 hours post-administration that is at least 200% of the plasma H-G concentration obtained from an equimolar dose of H-G following administration in the same manner.

4.3 Synthesis of Compounds of the invention

The compounds of the present invention can be obtained by the synthetic methods shown in schemes 1-17. One skilled in the art will recognize that a preferred synthetic route for the compounds of the present invention is to bind a promoiety to a GABA analog. Various methods have been described in the art for the synthesis of GABA analogs (see, for example, Satzinger et al, U.S. Pat. No. 4,024,175, Silverman et al, U.S. Pat. No. 5,563,175, Horwell et al, U.S. Pat. No. 6,020,370, Silverman et al, U.S. Pat. No. 6,028,214, Horwell et al, U.S. Pat. No. 6,103,932, Silverman et al, U.S. Pat. No. 6,117,906, Silverman, International publication WO92/09560, Silverman et al, International publication WO93/23383, Horwell et al, International publication WO 97/29101, Horwell et al, International publication WO 97/33858, Horwell et al, International publication WO 97/33859, Bryans et al, International publication WO98/17627, Guglietta et al, International publication WO99/08671, Bryans et al, International publication WO 99/21824, Bryans publication WO99/31057, Bryalins et al, WO 99/31074, International publication WO 99/31075, international publication WO 99/61424; bryans et al, International publication No. WO 00/15611; bryans, international publication WO 00/31020; and Bryans et al, International publication WO 00/50027). Other methods are known in the art of GABA analog synthesis and are readily available to those skilled in the art. The motifs described herein are known in the art and can be prepared by established Methods and bound to GABA analogs (see, for example, Green et al, "Protective Groups in Organic Chemistry" "(Wiley, second edition, 1991); Harrison et al," Complex of Synthetic Organic Methods (short description of Methods of Organic Synthesis), "volumes 1-8 (John Wiley and Sons, 1971-1996)," Beilstein Handbook of Organic Chemistry, "" Beilstein Organic Chemistry (research institute of Beilstein), Frankfurt, Germany; Feiser et al, "Organic for Organic Synthesis," Chemistry, "volumes 1-17, Chemistry," Synthesis of Chemistry, "Methods of Organic Chemistry," Reinship, 1991-17, Methods of Organic Chemistry, "Synthesis of organics Synthesis of metals (Reilsberg 1991; Reinship, Synthetic Methods of Organic Chemistry," Reinship, 1991, "Advanced Organic Chemistry," Wiley Interscience, 1991; larock "Comprehensive organic transformations," VCH publishers, 1989; paquette, "Encyclopedia of Reagents for Organic Synthesis," John Wiley & Sons, 1995, Bodanzsky, "Prinipsof Peptide Synthesis," Springer Verlag, 1984; bodanzsky, "Practice of Peptide Synthesis," Springer Verlag, 1984).

Thus, the starting materials for preparing the compounds of the present invention and intermediates thereof are commercially available or can be prepared by known synthetic methods. Other methods for synthesizing the prodrugs described herein are as described in the art, or are readily apparent to those of skill in the art in view of the references provided above, and may be used to synthesize the compounds of the present invention. Thus, the methods shown in the schemes herein are exemplary rather than comprehensive.

In either of the following routes, after functionalization of the amino group of the GABA analog with a promoiety or other protecting group, the carboxylic acid group can be converted to an ester or thioester by a number of synthetic methods known to those skilled in the art. In a preferred embodiment, the GABA analog can be reacted with an alcohol or thiol in the presence of coupling agents (e.g., carbodiimides and dimethylaminopyridines) to give an ester. In another preferred embodiment, the GABA analogs can be reacted with alkyl halides in the presence of a base to give esters. Other methods of converting GABA analogs to esters or thioesters are within the scope of the references provided herein that are familiar to those skilled in the art.

Route 1

As shown in scheme 1 above, the carboxylic acid can be directly bound to the terminal amino (or hydroxyl) group of GABA analog derivative (6) to give adduct (7). Reagents for carrying out such reactions are known to those skilled in the art and include, but are not limited to, carbodiimides, ammonium salts, phosphonium salts, and the like. Alternatively, the reaction of a carboxylic acid derivative such as an acid chloride, a symmetrical anhydride or a mixed anhydride with GABA analog (6) in the presence of a base (e.g., hydroxide, tertiary amine, etc.) can be used for the synthesis of (7).

Route 2

As shown in fig. 2, GABA analog derivative (6) can be converted into carbamate (8) by treatment with various carbonic acid derivatives in the presence of a base (e.g., hydroxide, tertiary amine, etc.). Alternatively, known alcohol addition to the isocyanate (9) or (10) may be used for the synthesis of (8).

As shown in scheme 3, GABA analog derivatives (6) can be converted to thioamides (11) by treatment with thioacids in the presence of coupling agents. Reagents for carrying out such reactions are known to those skilled in the art and include, but are not limited to, carbodiimides, ammonium salts, phosphonium salts, and the like. Alternatively, the reaction of a thioacid derivative such as a thioacyl chloride, a symmetrical anhydride or a mixed anhydride with (6) in the presence of a base such as a hydroxide, a tertiary amine, etc. can be used to synthesize the thioamide (11). In another method, amide (7) may be converted to thioamide (11) by heating in the presence of phosphorus pentasulfide (when n ═ 0).

Thiocarbamates (12) and (13) can be synthesized from the corresponding thiocarbonate derivatives (i.e., P ═ O, Q ═ S, and P ═ SQ ═ O, respectively, where W is chloride, imidazolyl, or 4-nitrophenoxy) and GABA analog derivative (6) by reaction in the presence of a base. Thiourethanes (13) may also be formed by the reaction of thiols with isocyanates (9) or (10). The dithiocarbamate (14) (P ═ S, Q ═ S) can be prepared by reacting GABA analog derivative (6) with a dithiocarbonate derivative (i.e., P and Q ═ S) where W is chloride, imidazolyl or 4-nitrophenoxy, in the presence of a base (see scheme 4).

Route 4

One method for synthesizing the compound of formula (IV) is illustrated in scheme 5.

Route 5

Treatment of chloroformate (15) with an aromatic leaving group such as p-nitrophenol in the presence of a base affords p-nitrophenyl carbonate (16). The interchange of halides gives iodide (17), which is reacted with a tetraalkylammonium salt of a metal or carboxylic acid to give compound (18). Treating (18) with a GABA analogue derivative (19) optionally in the presence of trimethylsilyl chloride to give a compound of formula (IV). Methods for preparing related acyloxyalkyl carbamate compounds have been described in the art (Alexander, U.S. Pat. No. 4,760,057; Alexander, U.S. Pat. No. 4,916,230; Alexander, U.S. Pat. No. 5,466,811; Alexander, U.S. Pat. No. 5,684,018).

Alternatively, the compound of formula (IV) may be prepared from carbonate (18) in a stepwise manner as shown in scheme 6. Reaction of here (18) with an α -amino acid (20) optionally protected as an ester gives intermediate (21) which, when deprotected (if necessary) provides compound (22) which is then coupled with a GABA analogue (23) using standard peptide coupling reagents known in the art.

Another method for synthesizing the compound of formula (IV) is by carbonylating a GABA analog derivative (19) to an intermediate carbamate, which is collected by in situ alkylation in a variation of the methods disclosed in the art (Butcher, Synlett, 1994, 825-6; Ferres et al, U.S. Patent4,036, 829). Bubbling carbon dioxide gas into a mixture containing (19) and a base (e.g., CS) in a solvent such as DMF or NMP₂CO₃，Ag₂CO₃Or AgO). The activated halide is optionally added in the presence of iodide ion as a catalyst and carbonylation is continued until the reaction is complete. This process is shown in scheme 7 for the preparation of compounds of formula (IV) from halide (24).

Route 7

Alternatively, the compounds of formula (IV) may be prepared in a stepwise manner as shown in scheme 8. Carbonylation and alkylation of the carboxy-protected α -amino acid (20) provides an intermediate (21) which, upon deprotection, couples with a GABA analog (23), as shown previously in scheme 6.

Route 8

Yet another method for synthesizing compounds of formula (IV) relies on the oxidation of ketocarbamate Derivatives of GABA analogs (Gallop et al, co-pending U.S. patent application entitled "methods for Synthesis of prodrugs from 1-Acyl-Alkyl Derivatives and Derivatives Thereof" and methods for synthesizing prodrugs from 1-Acyl-Alkyl Derivatives and Derivatives Thereof). As shown in scheme 9, oxidation of the ketocarbamate (25) affords compounds of formula (IV). Preferred solvents include, but are not limited to, t-butanol, diethyl ether, acetic acid, hexane, dichloroethane, dichloromethane, ethyl acetate, acetonitrile, methanol, chloroform and water. Generally, the oxidizing agent may be an organism (e.g., yeast or bacteria), or a chemical agent (e.g., an enzyme or peroxide). Preferred oxidizing agents include oxidizing agents that are successfully used to oxidize the ketone Baeyer-Villager to esters or lactones (Strukul, Angnew. chem. int. ED., 1998, 37, 1198; Renz et al, Eur. J. org. chem.1999, 737; Beller et al, in "Transmission Metal Organic Synthesis" Chapter2, Wiley VCH; Stewart, Current Organic Chemistry, 1998, 2, 195; Kayser et al, Synlett, 1999, 1, 153).

Route 9

Other compounds of the invention can be synthesized from suitable ketocarbamate derivatives by Baeyer-Villager type oxidation, provided that they do not contain chemical functional groups that are readily decomposed or converted under the reaction conditions.

The ketone carbamate (25) can be prepared from the corresponding α -hydroxyketone compound (26) by the following method: either directly by reaction with isocyanate (9) or by first converting the alpha-hydroxyketone compound to a halochloroformate or activated carbonate intermediate (27) and then reacting with compound (19), as illustrated in scheme 10.

Route 10

Alternatively, the ketocarbamate (25) can be prepared in a stepwise manner by the α -amino acid carbamate (28) as shown in scheme 11 according to the coupling method described above.

Route 11

It is noted that one method for preparing the isocyanate derivative of the GABA analog, i.e., compound (9), used in scheme 10 above is to start with the appropriate six-membered anhydride (29) as shown in scheme 12. Opening of the anhydride ring by reaction with an alcohol or thiol nucleophile affords carboxylic acid (30). In 2-step sequence (i.e., activation of the carboxyl group first to a mixed anhydride, acid halide or synthetic equivalent, followed by azide substitution) or directly (e.g., by use of pH)₂P(O)N₃Treatment) to convert this compound to the intermediate acyl azide. The acyl azide intermediate is subjected to a curtius rearrangement by thermal decomposition in a suitable solvent (e.g., toluene) at a temperature of 0 ℃ to 120 ℃ to give isocyanate (9). Optionally, the isocyanate is not isolated, but formed in situ and its formation is terminated by reaction with the alpha-hydroxy ketone (26) to give the desired product (25).

Route 12

A method for synthesizing oxodioxolyl (oxoxolenyl) methylcarbamate prodrugs (36) is disclosed in scheme 13. Treatment of hydroxy ketone (31) with phosgene or carbonyldiimidazole in the presence of a base gives cyclic carbonate (32). The free radical is brominated with N-bromosuccinimide and azoisobutyronitrile to give the bromide (33), which is converted to the alcohol (34). Alcohol (34) is converted to a dicarbonate (dicarbanate) (35) by reaction with 4-nitrophenylchloroformate, which is then reacted with GABA analog derivative (19) to give prodrug (36). Alternatively, compound (34) is reacted with isocyanate (9) to provide compound (36), wherein n is 0.

Route 13

Prodrugs (41) can be synthesized by the methods disclosed in scheme 14. Coupling of carboxylic acid (37) with alcohol (38) (e.g., dicyclohexylcarbodiimide and pyridine) affords ester (39). The ester (39) is converted to the active carbonate (40) by reaction with 4-nitrophenylchloroformate, which is then reacted with GABA analog derivatives (19) to give the prodrug (41).

Route 14

The active carbonyl compound (42) can be reacted with the GABA analog derivative (19) (wherein R is¹⁶H) to synthesize simple enamine prodrugs such as (43).

Route 15

Compound (III) can be synthesized by the pathway shown in scheme 16.

GABA analogs (23) are reacted with α -activated ester derivatives (44) to give amino esters (45). Capping the amino group of (45) by acylation gives (46) (e.g., using the methods described above), and esterifying the free acid under standard conditions gives diester (47). Dieckman condensation followed by decarboxylation gives ketone (48). The peroxyacid oxidation is then carried out to give the lactone (III).

Route 16

Imine prodrugs (II) can be synthesized by treating a ketone or ketone derivative (49) with a GABA analog derivative (50) under dehydrating conditions, as described in scheme 17.

Route 17

Phosphorus prodrugs can be synthesized by conventional methods known in the art. Similarly, prodrugs having an S-N bond can be synthesized by using methods described in the art.

4.4 therapeutic applications of the Compounds of the invention

According to the invention, the compounds and/or compositions of the invention are administered to a patient, preferably a human, suffering from: epilepsy, depression, anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain (particularly neuropathic pain and muscular and skeletal pain), inflammatory disease (i.e., arthritis), insomnia, gastrointestinal disorders, or ethanol withdrawal syndrome. Also, in certain embodiments, the compounds and/or compositions of the present invention may be administered to a patient, preferably a human, as a prophylactic measure against a variety of diseases or conditions. Thus, the compounds and/or compositions of the present invention may be administered as a prophylactic measure to a patient susceptible to: epilepsy, depression, anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain (particularly neuropathic pain and muscular and skeletal pain), inflammatory disease (i.e., arthritis), insomnia, gastrointestinal disorders, and ethanol withdrawal syndrome. Thus, the compounds and/or compositions of the present invention may be used for the prevention of one disease or condition while treating another (e.g., the prevention of psychosis and treatment of gastrointestinal disease; the prevention of neuropathic pain and the treatment of ethanol withdrawal syndrome).

The suitability of the compounds and/or compositions of the present invention for the treatment of epilepsy, depression, anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain (particularly, neuropathic pain and muscular and skeletal pain), inflammatory disorders (i.e., arthritis), insomnia, gastrointestinal disorders, and ethanol withdrawal syndrome may be determined by methods known in the art (see, e.g., Satzinger et al, U.S. patent No. 4,024,175, Satzinger et al, U.S. patent4,087,544, Woodruff, U.S. patent No. 5,084,169, Silverman et al, U.S. patent No. 5,563,175, Singh, U.S. patent No. 6,001,876, Horwell et al, U.S. patent No. 6,020,370, Silverman et al, U.S. patent 6,028,214, Horwell et al, U.S. patent No. 6,103,932, Silverman et al, U.S. patent No. 6,117,906, Silverman, international publication No. WO92/09560, Silverman et al, international publication No. 93/23383, Horwell et al, international publication No. 97/29101, horwell et al, International publication WO 97/33858; horwell et al, International publication WO 97/33859; bryans et al, International publication No. WO 98/17627; guglietta et al, International publication WO 99/08671; bryans et al, International publication No. WO 99/21824; bryans et al, International publication No. WO 99/31057; Magnus-Miller et al, International publication WO 99/37296; bryans et al, International publication No. WO 99/31075; bryans et al, International publication WO 99/61424; pande, international publication WO 00/23067; bryans, International publication WO 00/31020; bryans et al, International publication No. WO 00/50027; and Bryans et al, International publication WO 02/00209). The compounds and/or compositions of the invention may be used to treat or prevent epilepsy, depression, anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain (particularly, neuropathic pain and muscular and skeletal pain), inflammatory disorders (i.e., arthritis), insomnia, gastrointestinal disorders, and ethanol withdrawal syndrome by methods described in the art (see above). Thus, one skilled in the art is able to analyze and use the compounds and/or compositions of the present invention to treat or prevent epilepsy, depression, anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain (particularly, neuropathic pain and muscular and skeletal pain), inflammatory disorders (i.e., arthritis), insomnia, gastrointestinal disorders, and ethanol withdrawal syndrome.

4.5 therapeutic/prophylactic administration

The compounds and/or compositions of the present invention may be advantageously used in human medicine. As described in section 4.4 above, the compounds or compositions of the invention are useful in the treatment or prevention of epilepsy, depression, anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain (particularly, neuropathic pain and muscular and skeletal pain), inflammatory disorders (i.e., arthritis), insomnia, gastrointestinal disorders, or ethanol withdrawal syndrome.

The compounds or compositions of the present invention may be administered or applied singly, in combination with other agents, when used to treat or prevent the above-mentioned diseases or conditions. The compounds and/or compositions of the present invention may also be administered or applied singly, in combination with other pharmaceutically active agents, including other compounds of the present invention.

The present invention provides methods of treatment and prevention by administering to a patient a therapeutically effective amount of a composition or compound of the present invention. The patient may be an animal, more preferably a mammal, most preferably a human.

The compounds or compositions of the invention, comprising one or more compounds of the invention, are preferably administered orally. The compounds and/or compositions of the present invention may also be administered by other conventional routes, such as by infusion or bolus injection, through epithelial or mucosal and skin lining (e.g., oral, rectal and intestinal mucosa, etc.). Administration may be systemic or topical. A variety of delivery systems are known (e.g., encapsulated in liposomes, microparticles, microcapsules, capsules, etc.) that can be used to administer the compounds and or compositions of the invention. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectal, inhalation, or topical administration, particularly to the ear, nose, eye, or skin.

In a particularly preferred embodiment, the compounds and/or compositions of the present invention may be delivered by a sustained release system, preferably an oral sustained release system. In one embodiment, a pump may be used (see Langer, supra; Sefton, 1987, CRC Crit Ref biomedEng.14: 201; Saudek et al, 1989, N.Engl. JMed.321: 574).

In another embodiment, polymeric materials may be used (see "medical applications of Controlled Release Release," Langer and Wise (eds.), CRCPres, Boca Raton, Florida (1974), "Controlled Drug Bioavailability," Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984), "Ranger and Peppas, 1983, JMacromol. Sci. Rev. Macromol. Chem.23: 61; see also Levy et al, 1985, Science 228: 190; Dug ring et al, 1989, Ann. Neurol.25: 351; Howard et al, 1989, J.Neuror.71: 71). In a preferred embodiment, the polymeric material is used for oral sustained release delivery. Preferred polymers include sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and hydroxyethylcellulose (most preferably hydroxypropylmethylcellulose). Other preferred cellulose ethers have been described (Alderman, int.j.pharm.tech. & prod.mfr., 1984, 5(3) 1-9). Factors that influence drug release are known to those skilled in the art and are described in the art (Bamba et al, int.j.pharm., 1979, 2, 307).

In another embodiment, enteric coated formulations may be used for oral sustained release administration. Preferred coating materials include polymers having pH-dependent stability (i.e. pH controlled release), polymers having slow or pH-dependent rates of swelling, dissolution or erosion (i.e. time controlled release), polymers that are degraded by enzymes (i.e. enzyme controlled release) and polymers that form a film layer that is disrupted by pressurization (i.e. pressure controlled release).

In another embodiment, the osmotic delivery system is used for oral delivery (Verma et al, Drug Dev. Ind. pharm., 2000, 26: 695-. In a preferred embodiment, the OROSTM osmotic device is used in an oral sustained release delivery device (Theeuwes et al, U.S. Pat. No. 3,845,770; Theeuwes et al, U.S. Pat. No. 3,916,899).

In another embodiment, a Controlled Release system may be placed in proximity to the target of the compounds and/or compositions of the invention, such that only a partial systemic dose is required (see, e.g., Goodson, in "Medical Applications of Controlled Release Release," supra, vol.2, pp.115-138 (1984)). It can also be applied to Langer, 1990, Science 249: 1527 and 1533.

The compounds and/or compositions of the present invention preferably provide GABA analogs (e.g., gabapentin and pregablin) when administered to a patient in vivo. While not intending to be bound by theory, the moieties of the compounds and/or compositions of the invention may be chemically and/or enzymatically cleaved. One or more enzymes present in the stomach, intestinal lumen, intestinal tissue, blood, liver, brain or any suitable tissue of a mammal can enzymatically cleave the moiety of the compound or composition of the invention. The cleavage mechanism is not important to the present invention. Preferably, the GABA analogs formed by cleaving prodrugs from the compounds of this invention do not contain significant amounts of lactam contaminants (preferably less than 0.5 wt%, more preferably less than 0.2 wt%, most preferably less than 0.1 wt%). The extent of lactam contamination released from the prodrugs of the invention can be assessed using standard in vitro assays.

While not intending to be bound by theory, the moieties of the compounds and/or compositions of the invention may be cleaved prior to absorption by the gastrointestinal tract (e.g., in the stomach or intestinal lumen) and/or after absorption by the gastrointestinal tract (e.g., in intestinal tissue, blood, liver, or other suitable mammalian tissue). If the promoiety of the compounds of the invention is cleaved prior to absorption by the intestinal tract, the resulting GABA analogs can be routinely absorbed into the systemic circulation (e.g., via large neutral amino acid transporters located in the small intestine). If the promoiety of the compounds of the present invention is cleaved after absorption from the gastrointestinal tract, these GABA analog prodrugs may have the opportunity to be absorbed into the systemic circulation by passive diffusion, active transport or both passive diffusion and active transport.

These GABA analog prodrugs may have the opportunity to be absorbed from the large intestine into the systemic circulation if the promoiety of the compounds of this invention is cleaved after absorption from the gastrointestinal tract. In such cases, the compounds or compositions of the present invention are preferably administered as a sustained release system. In a preferred embodiment, the compounds or compositions of the invention are delivered by oral sustained release administration. Preferably in this embodiment, the compound or composition of the invention is administered twice daily (more preferably once daily).

4.6 compositions of the invention

The compositions of the invention comprise a therapeutically effective amount of one or more compounds of the invention, preferably in purified form, and appropriate amounts of pharmaceutically acceptable excipients to provide the patient with a suitable form of administration. When administered to a patient, the compounds of the invention and pharmaceutically acceptable excipients are preferably sterile. Water is a preferred excipient when administering the compounds of the invention intravenously. Saline solutions and aqueous dextrose and glycerol solutions may also be employed as liquid excipients, particularly for injectable solutions. Suitable pharmaceutical excipients also include excipients such as: starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, anhydrous skim milk, glycerol, propylene glycol, water, ethanol and the like. The compositions of the present invention may also contain minor amounts of wetting and emulsifying agents or pH buffering agents, if desired. In addition, auxiliaries, stabilizers, thickeners, lubricants and colorants may be used.

In one embodiment, the compositions of the present invention do not contain lactam by-products formed by intramolecular cyclization. In a preferred embodiment, the composition of the invention is also stable to long term storage (preferably for more than 1 year) and does not form significant amounts of lactam (preferably less than 0.5 wt% lactam, more preferably less than 0.2 wt% lactam, most preferably less than 0.1 wt% lactam).

Pharmaceutical compositions containing the compounds of the present invention may be prepared by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping (entropping) or lyophilizing processes. The pharmaceutical compositions may be prepared in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries, which facilitate the formulation of the compounds of the invention into preparations which can be used pharmaceutically. Suitable formulations depend on the chosen route of administration.

The dosage form of the composition of the present invention may be a solution, suspension, emulsion, tablet, pill, capsule, liquid-containing capsule, powder, sustained-release formulation, suppository, emulsion, aerosol, spray, suspension or any other form suitable for the application. In one embodiment, the pharmaceutically acceptable excipient is a capsule (see, e.g., GrosSwald et al, U.S. patent No. 5,698,155). Examples of other suitable Pharmaceutical excipients are described in the art (see Remington's Pharmaceutical Sciences, Philadelphia College of Pharmacy and Science, 17th edition, 1985). Preferred compositions of the invention are prepared for oral delivery, particularly for oral sustained release administration.

For example, compositions for oral delivery may be tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups or elixirs. Oral compositions may contain one or more optional agents, for example sweetening agents such as fructose, aspartame or saccharin, flavouring agents such as peppermint, oil of wintergreen or cherry colouring agents and preservatives, to provide pharmaceutically palatable preparations. Also in the case of tablets or pills, the composition may be coated to delay degradation and absorption in the gastrointestinal tract, thereby providing a long lasting effect. Selectively permeable membranes surrounding osmotically active driver compounds are also suitable for use with the compounds and compositions of the present invention for oral administration. In these latter platforms, liquid from the environment surrounding the capsule is absorbed by the driving compound, which expands through the pore size to displace the agent or agent composition. These delivery platforms may provide a substantially zero order delivery profile compared to the tapered pattern of the immediate rate formulation. A time delay material such as glyceryl monostearate or glyceryl stearate may also be used. Oral compositions may include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. These excipients are preferably of pharmaceutical grade.

For oral liquid preparations such as suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, saline, alkylene glycols (e.g., propylene glycol), polyalkylene glycol (e.g., polyethylene glycol) oils, alcohols, slightly acidic buffers between pH4 and pH6 (e.g., acetate, citrate, ascorbate, from about 5mM to about 50 mM), and the like. In addition, flavoring agents, preservatives, coloring agents, bile salts, acylcarnitines, and the like may be added.

Administration of the composition by other routes is also contemplated. For buccal administration, the dosage form of the composition may be in the form of tablets, lozenges and the like prepared in a conventional manner. Liquid pharmaceutical formulations suitable for use with nebulizers and liquid spray devices and EHD aerosol devices generally comprise a compound of the invention and a pharmaceutically acceptable excipient. Preferably the pharmaceutically acceptable excipient is a liquid such as an alcohol, water, polyethylene glycol or a perfluorocarbon. Optionally, the addition of another substance alters the aerosol properties of a solution or suspension of the compound of the invention. Preferably the substance is a liquid such as an alcohol, glycol, polyglycol or a fatty acid. Other methods of preparing liquid drug solutions or suspensions suitable for use in aerosol devices are known to those skilled in the art (see, for example, Biesalski, U.S. Pat. No. 5,112,598; Biesalski, U.S. Pat. No. 5,556,611). The compounds of the invention may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. In addition to the aforementioned formulations, the compounds of the present invention may also be formulated as a precipitated formulation. Such long-acting formulations may be administered by implantation (e.g. subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention may be prepared with suitable polymeric or hydrophobic materials (e.g., emulsions in acceptable oils) or ion exchange resins, or made as sparingly soluble derivatives, e.g., sparingly soluble salts.

When the compound of the present invention is acidic, it may be included in any of the above-described formulations as a free acid, a pharmaceutically acceptable salt, solvate or hydrate. Pharmaceutically acceptable salt-based tints retain the activity of the free acid, can be prepared by reaction with a base, and tend to be more soluble in water and other protic solvents than the corresponding free acid form.

4.7 methods of use and dosages

The compounds of the present invention or compositions thereof are generally employed in an effective amount to achieve the desired purpose. Use for the treatment or prevention of a disease or condition such as: epilepsy, depression, anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain (particularly neuropathic pain and muscular and skeletal pain), inflammatory disease (i.e., arthritis), insomnia, gastrointestinal disorders, or ethanol withdrawal syndrome, a compound of the invention, or a composition thereof, is administered or used in a therapeutically effective amount.

The amount of a compound of the invention disclosed herein that is effective to treat a particular disease or condition depends on the nature of the disease or condition and can be determined by standard clinical techniques known in the art as previously described. In addition, in vitro or in vivo assays may optionally be used to help identify optimal dosage ranges. The amount of the compound of the invention administered will, of course, depend on the subject being treated, the weight of the subject, the severity of the affliction, the mode of administration and the judgment of the prescribing physician.

For example, the dose may be delivered in a pharmaceutical composition by single administration, multiple applications or controlled release. In a preferred embodiment, the compounds of the invention are delivered by oral sustained release administration. Preferably in this embodiment, the compounds of the invention are administered twice daily (more preferably once daily). The dosage may be repeated intermittently, may be provided alone or in combination with other agents, and may be continued for a length of time necessary to effectively treat the disease or condition.

The appropriate oral dosage range depends on the potency of the parent GABA analog drug, but is generally from about 0.001mg to about 200mg of the compound of the present invention per kilogram of body weight. When the GABA analog is gabapentin, the typical daily dosage of the parent drug in an adult is 900 mg/day to 3600 mg/day, and the dosage of the gabapentin prodrug can be adjusted to provide an equimolar amount of gabapentin. Other GABA analogs may be more potent than gabapentin (e.g., pregabalin), and lower doses are appropriate for the parent drug and any prodrug (as determined on an equimolar basis). Dosage ranges can be readily determined by methods known to those skilled in the art.

The compounds of the invention are preferably tested for the targeted therapeutic or prophylactic activity in vitro and in vivo prior to use in humans. For example, in vitro assays may be used to determine whether administration of a particular compound of the invention or a composition of compounds of the invention is preferred for reducing convulsions. The compounds of the invention may also be demonstrated to be effective and safe using animal model systems.

Preferably, a therapeutically effective dose of a compound of the invention as described herein will provide therapeutic benefit while causing substantially no toxicity. Toxicity of the compounds of the present invention can be determined using standard pharmaceutical procedures and can be readily determined by one skilled in the art. The dose ratio of toxic to therapeutic effect is the therapeutic index. The compounds of the present invention preferably exhibit a particularly high therapeutic index for the treatment of diseases and conditions.

The dosages of the compounds of the invention described herein are within the range of circulating concentrations that include effective dosages with little or no toxicity.

4.8. Combination therapy

In certain embodiments of the invention, the compounds of the invention may be used in combination therapy with at least one other therapeutic agent. The compounds of the invention and the therapeutic agents may act additively, more preferably synergistically. In a preferred embodiment, the composition containing the compound of the invention is administered concurrently with other therapeutic agents, which may be part of the same composition as the compound of the invention or a different composition. In another embodiment, a composition comprising a compound of the invention may be administered before or after administration of another treatment.

5. Examples of the embodiments

The invention is further defined by reference to the following examples describing in detail the preparation of the compounds and compositions of the invention and the application testing of the compounds and compositions of the invention. It will be apparent to those skilled in the art that various modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

In the examples below, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.

AIBN ═ 2, 2' -azobis (isobutyronitrile)

Atms ═ atmospheric pressure

Boc ═ tert-butoxycarbonyl

Cbz-benzyloxy (carbobenzozyloxy)

CPM counts per minute

DCC-dicyclohexylcarbodiimide

DMAP ═ 4-N, N-dimethylaminopyridine

DMEM ═ extreme eagle Medium

DMF ═ N, N-dimethylformamide

DMSO ═ dimethyl sulfoxide

Fmoc ═ 9-fluorenylmethoxycarbonyl

g is g ═ g

h is hour

HBSS Hanks buffered saline solution

L is liter

LC/MS liquid chromatography/mass spectrometry

M is equal to mole

min is divided into

ml to ml

mmol ═ mmol

NBS ═ N-bromosuccinimide

NHS ═ N-hydroxysuccinimide

PBS-phosphate buffered saline

THF ═ tetrahydrofuran

TFA ═ trifluoroacetic acid

TMS ═ trimethylsilyl

μ L ═ microliter

Micromolar (μ M)

v/v-volume to volume ratio

Example 1

1- { [ (alpha-pivaloyloxymethoxy) carbonyl]Aminomethyl } -1-cyclohexane acetic acid (51)

Step A:p-nitrophenyl chloromethyl carbonate (52)

P-nitrophenol (100g, 0.72moles) was dissolved in anhydrous tetrahydrofuran (3L) and stirred vigorously. To this solution was added chloromethyl chloroformate (70mL, 0.79moles) at room temperature followed by triethylamine (110 mL). After stirring for 1h, the reaction mixture was filtered and the filtrate was concentrated, then diluted with ethyl acetate (1L). The organic solution was washed with 10% potassium carbonate (3X 500mL) and 1N Cl (2X 300mL), brine (2X 300mL), and dried over anhydrous sodium sulfate. Removal of the solvent gave 157g (95%) of the title compound (52) as a solid. The compounds are unstable to LC-MS.¹H NMR(CDCl₃，400MHz)：5.86(s，2H)，7.44(d，J＝9Hz，2H)，8.33(d，J＝9Hz，2H)。

And B:methyl p-nitrophenylcarbonate (53)

Chloromethyl p-nitrophenyl carbonate (52) (100g, 0.43moles), sodium iodide (228g, 1.30moles), and 50g of anhydrous molecular sieves (4) were added to 2L of acetone under a nitrogen atmosphere while mechanically stirring. The resulting mixture was stirred at 40 ℃ for 5h (by¹H NMR monitoring). Upon completion of the stirring, the solid matter was removed by filtration, and the solvent was removed under reduced pressure. The residue was redissolved in dichloromethane (1L) and washed twice with saturated aqueous sodium carbonate (300mL) and then with water (300 mL). The organic layer was separated and dried over anhydrous sodium sulfate. Removal of the solvent gave 123.6g (89%) of the title compound (53) as a solid on standing. The compound was found to be unstable to LC-MS.¹HNMR(CDCl₃，400MHz)：6.06(s，2H)，7.42(d，J＝9Hz，2H)，8.30(d，J＝9Hz，2H).¹³CNMR(CDCl₃，100MHz)：155.1，151.0，146.0，125.8，125.7，121.9，33.5。

And C:trimethylsilver acetate (54)

Pivalic acid (50g, 0.49moles) was dissolved in acetonitrile (1.3L) and silver oxide (70g, 0.29moles) was added and stirred vigorously. 660mL of water were then added under nitrogen. The resulting suspension was stirred at 70 ℃ for 1h in the dark. After filtration through a pad of celite, the solvent was removed to give 86g (82%) of the title compound (54) as an off-white solid, which was used in the next reaction without further purification. Other silver salts described herein were prepared according to similar methods.

Step D:pivaloyloxymethyl p-nitrophenyl carbonate (55)

To a solution of iodomethyl p-nitrophenylcarbonate (53) (62g, 0.19moles) in anhydrous toluene (1L) was added silver trimethylacetate (80g, 0.38 moles). After stirring at 55 ℃ under nitrogen for 3h, the reaction mixture was cooled to room temperatureAnd filtered through a celite pad. The filtrate was washed with 10% potassium carbonate (500 mL). Removal of the solvent gave 43g (75%) of the title compound (55) as a yellow oil.¹H NMR(CDCl₃，400MHz)：1.25(s，9H)，5.88(s，2H)，7.40(d，J＝9Hz，2H)，8.29(d，J＝9HZ，2H).¹³CNMR(CDCl₃，100MHz)：177.0，155.3，151.6，145.8，125.6，121.9，83.1，39.1，27.0。

Step E:1- { [ (alpha-pivaloyloxymethoxy) carbonyl]Aminomethyl-1-cyclohexaneacetic acid

(51)

Gabapentin free base (24g, 0.14moles) was slurried in anhydrous dichloromethane (100mL) and then treated with chlorotrimethylsilane (18.6mL, 0.28moles) and triethylamine (10mL, 0.15moles), respectively. The resulting suspension was heated and stirred until complete dissolution of any solids was achieved. The gabapentin solution above was added to slow reflux via an equalizing addition funnel and a solution of p-nitrophenyl pivaloyloxymethylcarbonate (55) (20g, 67mmol) and triethylamine (10mL, 0.15moles) in dichloromethane (100mL) was mechanically stirred under nitrogen. The resulting yellow solution was stirred for 1.5 h. When stirring was complete (monitored by ninhydrin staining), the mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate (500mL), washed with 1N HCl (3X 100mL), brine (2X 100mL), and dried over anhydrous sodium sulfate. After removal of the solvent, the crude product was dissolved in ethanol (300mL) and 1g 5% Pd/C was added. The resulting mixture was stirred under 50psi of hydrogen atmosphere for 15 minutes and then filtered through a pad of celite. After concentration, the residue was dissolved in ethyl acetate and washed with 5% H₂SO₄Washed and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the residue was chromatographed on silica gel (4: 1 hexane: ethyl acetate) to give 15g (68%) of the title compound (51) as a solid. M.p.: 79 to 81 ℃;¹HNMR(CDCl₃，400MHz)：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).¹³CNMR(CDCl₃，400MHz)：21.7，26.2，27.3，34.3，38.2，39.2，80.6，155.9，176.8，178.0.MS(ESI)m/z328.36(M-H)^-，330.32(M+H)⁺，352.33(M+Na)⁺。

example 2

1- { [ (alpha-acetoxyethoxy) carbonyl]Aminomethyl } -1-cyclohexane acetic acid (56)

Step A:1-chloroethyl-p-nitrophenyl carbonate (57)

To an ice-cooled reaction mixture containing p-nitrophenol (1.39g, 10mmol) and pyridine (0.81g, 10mmol) in dichloromethane (60mL) was added 1-chloroethyl chloroformate (1.2mL, 11 mmol). The mixture was stirred at 0 ℃ for 30 minutes and then at room temperature for 1 h. After removal of the solvent under reduced pressure, the residue was dissolved in ether, washed with water, 10% citric acid and water. With Na₂SO₄The ether layer was dried and evaporated under reduced pressure to give 2.4g (97%) of the title compound (57) as a beige solid.¹HNMR(CDCl₃)：1.93(d，3H)，6.55(q，1H)，7.42(d，2H)，8.28(d，2H)。

And B:alpha-acetoxyethyl-p-nitrophenyl carbonate (58)

A mixture of 1-chloroethyl-p-nitrophenyl carbonate (57) (0.5g, 2mmol) and mercury acetate (1.5g, 4.4mmol) in acetic acid (15mL) was stirred at room temperature for 24 h. After removal of acetic acid under reduced pressure, the residue was dissolved in ether and washed with water, 0.5% (v/v) NaHCO₃Aqueous solution and water wash. With Na₂SO₄The ether layer was dried and concentrated to dryness. The resulting residue (hexane: ethyl acetate (95: 5)) was chromatographed on silica gel to give 0.45g (84%) of the title compound (58).¹HNMR(CDCl₃，400MHz)：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)。

And C:1- { [ (alpha-acetoxyethoxy) carbonyl]Aminomethyl } -1-cyclohexane acetic acid (56)

To a mixture containing gabapentin (633mg, 3.7mmol) and triethylamine (1.03mL, 7.4mmol) in dichloromethane (20mL) was added chlorotrimethylsilane (0.93mL, 7.4mmol) and the mixture was stirred until a clear solution formed. A solution containing α -acetoxyethyl-p-nitrophenyl carbonate (58) (1g, 3.7mmol) in dichloromethane (10mL) was added and the resulting mixture was stirred for 30 min. The reaction mixture was washed with 10% citric acid (20mL) and the organic layer was separated. The aqueous layer was further extracted with ether (3X 10mL) and MgSO₄The combined organic extracts were dried. After filtration, the organic solvent was removed under reduced pressure. The resulting residue was chromatographed on silica gel (hexane: ethyl acetate (4: 1)) to give 700mg (63%) of the title compound (56).¹HNMR(CDCl₃，400MHz)：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/z302.22(M+H)⁺. By dissolving in water (5mL), an equimolar amount of 0.5N naHCO was added₃And then lyophilized to quantitatively convert the acid form to the corresponding sodium salt.

Example 3

1- { [ (alpha-benzoyloxybenzyloxy) carbonyl]Aminomethyl } -1-cyclohexane acetic acid (59)

Step A:alpha-benzoylbenzylcarbonate p-nitrophenyl ester (60)

Room temperature at 60mLCH₂Cl₂DMAP (1.21g, 9.9mmol) and p-nitrophenyl-chloroformate (1.99g, 9.9mmol) were added to a solution of benzoin (2.0g, 9.4mmol), respectively. After stirring at room temperature for 3h, the reaction was quenched with water and extracted with ethyl acetate/hexane (2X 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound (60), which was used in the next reaction without purification.

And B: 1- { [ (alpha-benzoylbenzyloxy) carbonyl]Aminomethyl-1-cyclohexaneacetic acid

(61)

At 0 ℃ in the direction of CH₂Cl₂To the suspension of gabapentin (1.70g, 9.9mmol) was added triethylamine (2.76mL, 19.8mmol) and TMSCl (2.51mL, 19.8 mmol). The reaction was stirred at room temperature for 30 minutes. To this mixture was added CH₂Cl₂Compound (60) in (a) (prepared in step a above), and the resulting mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with dichloromethane, washed with brine, and washed with Na₂SO₄The organic layer was dried. After removal of the solvent under reduced pressure, the residue is purified by chromatography on silica gel on CH₂Cl₂Elution with 5% methanol afforded 3.78g (90%, over two steps) of the title compound (61).¹HNMR(CDCl₃，400MHz)：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)。

And C:1- { [ (alpha-benzoyloxybenzyloxy) carbonyl]Aminomethyl-1-cyclohexaneacetic acid

(59)

Room temperature reaction at 40mLCH₂Cl₂1- { [ (alpha-benzoylbenzyloxy) carbonyl in (A)]A solution of aminomethyl } -1-cyclohexaneacetic acid (61) (1.89g, 4.6mmol) was added 77% mCPBA (2.07g, 9.2mmol) and NaHCO, respectively₃(0.78g, 9.2mmol), and the resulting mixture was stirred at room temperature overnight. Acidifying the reaction mixture with 10% citric acid and CH₂Cl₂And (4) extracting. The organic extracts were washed with brine and Na₂SO₄And (5) drying. After removal of the solvent under reduced pressure, the residue was purified by reverse phase preparative HPLC (acetonitrile-water, 0.1% formic acid) to give 960mg (49%) of the title compound (59).¹H NMR(CDCl₃，400MHz)：δ1.58-1.35(m，LOH)，2.34(s，2H)，3.26(dd，J＝6.8，0.8Hz，2H)，5.38(t，J＝6.8Hz，1H)，7.46-7.26(M，5H)，7.63-7.55(M，3H)，7.89(s，1H)，8.08(dd，J＝8.8，1.2Hz，2H)。

Example 4

1- { [ (alpha-acetoxybenzyloxy) carbonyl]Aminomethyl } -1-cyclohexane acetic acid (62)

Following the procedure of example 3, and substituting 1-hydroxy-1-phenyl-propan-2-one for benzoin, 300mg of the title compound (62) was obtained.¹HNMR(CDCl₃，400MHz)：δ1.41(m，10H)，2.19(s，3H)，2.33(s，2H)，3.27(dd，J＝6.6，1.6Hz，2H)，5.36(t，J＝6.6Hz，1H)，7.40(M，3H)，7.52(M，2H)，7.63(s，1H)。

Example 5

1- { [ (α -Benzoyloxyethoxy) carbonylaminomethyl } -1-cyclohexane acetic acid (63)

Following the procedure of example 3, and substituting 2-hydroxy-1-phenyl-1-propanone for benzoin, 5mg of the title compound (63) was obtained.¹H NMR(CDCl₃，400MHz)：δ1.44-1.36(m，10H)，1.62(d，J＝5.6Hz，3H)，2.34(s，2H)，3.24(d，J＝6.8Hz，2H)，5.28(t，J＝6.8Hz，1H)，7.06(q.J＝5.6Hz，1H)，7.44(M，2H)，7.56(M，1H)，8.03(dd，J＝8.4，1.6Hz，2H)。

Example 6

1- { [ (1-benzoyloxy-2-phenylethoxy) carbonyl]Aminomethyl-1-cyclohexaneacetic acid

(64)

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

At room temperature to CH₂Cl₂A solution of benzaldehyde (10.6g, 100mmol) and 1, 3-propanedithiol in (150mL) was added BF dropwise₃. Adding Et₂O (6.3mL, 50mmol) and the resulting mixture were stirred at room temperature for 2 h. Then using CH₂Cl₂The reaction mixture was diluted, filtered and washed with brine, saturated NaHCO₃And brine washingWashing the filtrate with Na₂SO₄And (5) drying. Removal of the solvent under reduced pressure gave a white solid which was recrystallized from a 1: 1 mixture of ether and hexane to give 17.0g (87%) of the title compound (65) as a white crystalline needle.¹H NMR(CDCl₃，400MHz)：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)。

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

To a solution of 2-phenyl-1, 3-dithiane (65) (4.0g, 20.4mmol) in THF at-30 deg.C was added a solution of 1.6M n-butyllithium in THF (15.3mL, 24.4 mmol). After stirring at-30 ℃ for 30 minutes, a solution of phenylacetylaldehyde (2.45g, 20.4mmol) in tetrahydrofuran was added dropwise at-30 ℃. The resulting reaction mixture was stirred at 0 ℃ for a further 1 h. With saturated NH₄The reaction was quenched with Cl solution and extracted with ethyl acetate. With saturated NH₄The combined organic extracts were washed with Cl solution, brine and Na₂SO₄And (5) drying. After filtration and concentration, the crude product was purified by flash chromatography on silica gel (25% ethyl acetate in hexanes) to give 2.63g (71%) of the title compound (66).¹HNMR(CDCl₃，400MHz)：δ1.97(m，2H)，2.23(dd，J＝4.0，1.2Hz，1H)，2.43(dd，J＝13.6，10.2Hz，1H)，2.77(M，4H)，3.02(d，J＝13.6Hz，1H)，4.07(M，1H)，7.44-7.13(M，8H)，8.02(dd，J＝8.4，1.4Hz，2H)。

And C:2-hydroxy-1, 3-diphenyl-propan-1-one (67)

To a mixture of water at 100mL 9: 1 mixture of acetonitrile and water 2-phenyl-1- (2-phenyl- [1, 3)]A solution of-dithian-2-yl) -ethanol (66) (2.50g, 7.9mmol) was added mercuric perchlorate hydrate (4.1g, 10.3 mmol). The resulting mixture was stirred at room temperature for 5 minutes and thin layer chromatography indicated that the reaction was complete. The mixture was diluted with ethyl acetate, filtered through a pad of celite, and filtered through saturated NaHCO₃The filtrate was washed with brine and Na₂SO₄And (5) drying. Under reduced pressureThe solvent was removed and the crude product purified by flash chromatography on silica gel (20% ethyl acetate in hexanes) to give 1.32g (74%) of the title compound (67).¹HNMR(CDCl₃，400MHz)：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-phenylethoxy) carbonyl]Aminomethyl-1-cyclohexyl

Alkaneacetic acid (64)

Following the procedure of example 3, and substituting 2-hydroxy-1, 3-diphenyl-propan-1-one for benzoin, 181mg of the title compound (64) was obtained.¹H NMR(CDCl₃，400MHz)：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)。

Example 71- { [ (1- (3-methylbutyryloxy) -2-phenylethoxy) carbonyl]Amino-methyl

1-Cyclohexaneacetic acid (68)

Following the procedure of example 6, and substituting 3-methylbutanal for benzaldehyde in step A, 95mg of the title compound was obtained (68).¹H NMR(CDCl₃，400MHz)：δ0.88-0.90(M，6H)，1.16-1.29(m，10H)，2.06(M，1H)，2.16(M，2H)，2.26(M，2H)，3.08(d，J＝6.8Hz，2H)，3.19(M，2H)，5.22(t，J＝6.8Hz，1H)，6.93(t，J＝6Hz，1H)，7.31-7.23(M，5H)。

Example 8

1- { [ (alpha-benzoyloxy butoxy) carbonyl]Aminomethyl } -1-cyclohexane acetic acid (69)

The process of example 6 was followed, with butyraldehyde replacingPhenylacetaldehyde in step B, to give 240mg of the title compound (69).¹HNMR(CDCl₃，400MHz)：δ0.99(t，J＝7.6Hz，3H)，1.52-1.38(M，12H)，1.89(M，2H)，2.31(s，2H)，3.24(M，2H)，5.34(t，J＝6.6Hz，1H)，6.70(t，J＝5.6Hz，1H)，7.42(M，2H)，7.56(M，1H)，8.04(M，2H)。

Example 9

1- { [ (alpha-acetoxybutoxy) carbonyl]Aminomethyl } -1-cyclohexane acetic acid (70)

Following the procedure of example 6 and substituting acetaldehyde for benzaldehyde in step A and butyraldehyde for phenylacetaldehyde in step B, respectively, 42mg of the title compound (70) was obtained.¹HNMR(CD₃OD，400MHz)：δ0.95(M，3H)，1.52-1.31(M，12H)，1.72(M，2H)，2.02(s，3H)，2.27(s，2H)，3.20(s，2H)，6.67(t，J＝5.6Hz，1H)。

Example 10

1- { [ (alpha-butyryloxy-butoxy) carbonyl]Aminomethyl } -1-cyclohexane acetic acid (71)

Following the procedure of example 3, and substituting benzoin with butyroin, 210mg of the title compound (71) was obtained.¹H NMR(CDCl₃，400MHz)；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/z356.45(M-H)⁺。

Example 11

1- { [ (alpha-propionyloxyethoxy) carbonyl]Aminomethyl } -1-cyclohexane acetic acid (72)

Step A:1-iodoethyl-p-nitrophenyl carbonate (73)

A mixture of 1-chloroethyl-p-nitrophenyl carbonate (0.5g, 2mmol) and NaI (0.6g, 4mmol) in anhydrous acetone was stirred at 40 ℃ for 3 h. After filtration, the filtrate was concentrated under reduced pressure to yield 480mg (72%) of the title compound (73), which was used in the next reaction without further purification.

And B:alpha-propionyloxyethyl-p-nitrophenyl carbonate (74)

A mixture of 1-iodoethyl-p-nitrophenyl carbonate (73) (0.51g, 1.5mmol) and silver propionate (0.54g, 3mmol) in toluene (20mL) was stirred at 50 ℃ for 24 h. The reaction mixture was filtered to remove solids, and the filtrate was concentrated under reduced pressure. The residue obtained is chromatographed on silica gel (20% CH)₂Cl₂Hexane, then with 40% CH₂Cl₂Hexane) to yield 0.39g (92%) of the title compound (74).¹H NMR(CDCl₃，400MHz)：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)。

And C:1- { [ (alpha-propionyloxyethoxy) carbonyl]Aminomethyl-1-cyclohexaneacetic acid

(72)

To a mixture of gabapentin (160mg, 2.76mmol) and triethylamine (0.77mL, 5.5. mu.l) in dichloromethane (30mL) was added chlorotrimethylsilane (0.71mL, 5.5mmol) and the resulting mixture was stirred until a clear solution formed. To the above solution was added a solution of α -propionyloxyethyl-p-nitrophenyl carbonate (74) (0.39g, 1.4. mu.l) in dichloromethane (10 mL). After stirring for 30 minutes, the reaction mixture was washed with 10% citric acid (20mL), and the organic layer was separated. The aqueous layer was further extracted with ether (3X 10mL) and MgSO₄The combined organic extracts were dried. After removal of the solvent under reduced pressure, the residue was purified by reverse phase preparative HPLC (acetonitrile, water, 1% formic acid) to yield 190mg (44%) of the title compound (72).¹HNMR(CD₃0D，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/z316.25(M+H)⁺。

Example 12

1- { [ (alpha-butyryloxyethoxy) carbonyl]Aminomethyl } cyclohexaneacetic acid (75)

Step A:alpha-butyryloxyethyl-p-nitrophenyl carbonate (76)

A mixture of 1-iodoethyl-p-nitrophenyl carbonate (73) (1.5g, 4.5mmol) and silver butyrate (1.3g, 6.7mmol) in toluene (40mL) was stirred in an oil bath at 90 ℃ for 24 h. The reaction mixture was filtered under reduced pressure and the filtrate was concentrated. The residue obtained is chromatographed on silica gel (20% CH)₂Cl₂Hexane, then with 40% CH₂Cl₂Hexane) to yield 0.46g (36%) of the title compound (76).¹HNMR(CDCl₃，400MHz)：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/z298.28(M+H)⁺。

And B:1- { [ (alpha-butyryloxyethoxy) carbonyl]Aminomethyl-1-cyclohexaneacetic acid

(75)

To a mixture containing gabapentin (530mg, 3.1mmol) and triethylamine (0.89mL, 6.4mmol) in dichloromethane (30mL) was added chlorotrimethylsilane (0.83mL, 6.4mmol) and the resulting mixture was stirred until a clear solution formed. To this solution was added a solution of α -butyryloxyethyl-p-nitrophenyl carbonate (76) (0.46g, 1.6mmol) in dichloromethane (10mL) and the resulting mixture was stirred for 30 min. The reaction mixture was washed with 10% citric acid (20mL) and the organic phase was separated. The aqueous phase was further extracted with ether (3X 10mL) and MgSO₄The combined organic phases were dried and then concentrated in vacuo. The resulting residue was purified by reverse phase preparative HPLC (acetonitrile, water, 1% formic acid) to yield 70mg (21%) of the title compound (75).¹HNMR(CD₃OD，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/z330.28(M+H)⁺。

The acid form was quantitatively converted to the corresponding sodium salt by the following method: dissolved in water (5mL) and an equimolar amount of 0.5N naHCO was added₃And then lyophilized.

Example 13

1- { [ (alpha-isobutanoyloxyethoxy) carbonyl]Aminomethyl } -1-cyclohexane acetic acid (77)

Following the procedure of example 2, and substituting silver butyrate with silver isobutyrate, 70mg (21%) of the title compound (77) was obtained.¹H NMR(CD₃OD，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/z330.30(M+H)⁺。

The acid form was quantitatively converted to the corresponding sodium salt by the following method: dissolved in water (5mL) and an equimolar amount of 0.5N naHCO was added₃And then lyophilized.

Example 14

1- { [ (alpha-pivaloyloxyethoxy) carbonyl]Aminomethyl } -1-cyclohexane acetic acid (78)

Following the procedure of example 12, and substituting silver pivalate for the butyrate salt, 80mg (36%) of the title compound (78) was obtained.¹H NMR(CDCl₃，400MHz)：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)⁺。

The acid form was quantitatively converted to the corresponding sodium salt by the following method: dissolved in water (5mL) and an equimolar amount of 0.5N naHCO was added₃And then lyophilized.

Example 15

1- { (α -acetoxyisobutoxy) carbonyl]Aminomethyl 1-1-cyclohexaneacetic acid (79)

Following the procedure of example 2 and substituting 1-chloro-2-methylpropyl chloroformate for 1-chloroethyl chloroformate, 212mg (38%) of the title compound (79) was obtained.¹H NMR(CD₃OD，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)⁺。

Example 16

1- { [ (alpha-propionyloxy-isobutoxy) carbonyl]Aminomethyl } -1-cyclohexane acetic acid (80)

Following the procedure of example 11 and substituting 1-chloro-2-methylpropyl-p-nitrophenyl carbonate for 1-chloroethyl-p-nitrophenyl carbonate, 190mg (44%) of the title compound (80) was obtained.¹H NMR(CD₃OD，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)mlz344.34(M+H)⁺。

Example 17

1- { [ (alpha-butyryloxy-isobutoxy) carbonyl]Aminomethyl } -1-cyclohexane acetic acid (81)

Following the procedure of example 2 and substituting 1-chloro-2-methylpropyl chloroformate and mercury butyrate for 1-chloroethyl chloroformate and mercury acetate, respectively, 95mg (36%) of the title compound (81) was obtained.¹HNMR(CD₃OD，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/z358.30(M+H)⁺。

Example 18

1- { [ (alpha-Isobutyryloxy-isobutoxy) carbonyl]Aminomethyl } -1-cyclohexane acetic acid (82)

Following the procedure of example 2 and substituting 1-chloro-ethyl chloroformate and mercury acetate with 1-chloro-2-methylpropyl chloroformate and mercury isobutyrate, respectively, 95mg (36%) of the title compound (82) was obtained.¹H NMR(CD₃OD，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/z358.27(M+H)⁺。

Example 19

1- { [ (alpha-pivaloyloxy isobutoxy) carbonyl]Aminomethyl } -1-cyclohexane acetic acid (83)

Following the procedure of example 12 and substituting 1-chloro-2-methylpropyl-p-nitrophenylcarbonate and silver pivalate for 1-chloroethyl-p-nitrophenylcarbonate and silver butyrate, respectively, 10mg (9%) of the title compound was obtained (83).¹HNMR(CD₃OD，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/z372.31(M+H)⁺。

Example 20

1- { [ (alpha-benzoyloxy isobutoxy) carbonyl]Aminomethyl-1-cyclohexaneacetic acid (84)

Following the procedure of example 11, and substituting 1-chloroethyl 1-p-nitrophenylcarbonate and silver propionate with 1-chloro-2-methylpropyl-p-nitrophenylcarbonate and silver benzoate, respectively, 109mg (40%) of the title compound (84) was obtained.¹H NMR(CD₃OD，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/z392.22(M+H)⁺。

Example 21

1- { [ (alpha-acetoxyisopropoxy) carbonyl]Aminomethyl } -1-cyclohexane acetic acid (85)

Step A:isopropenyl-p-nitrophenyl carbonate (86)

To a mixture of p-nitrophenol (5.76g, 41.5mmol) and isopropenyl chloroformate (5g, 41.5mmol) in dichloromethane (200mL) was added a solution of pyridine (3.4mL, 42mmol) in dichloromethane (50mL) at 0 deg.C. The resulting mixture was stirred at 0 ℃ for 30 minutes and then at room temperature for 1 h. After removal of the solvent under reduced pressure, the residue was dissolved in ether and washed with water, 10% citric acid and again with water. With Na₂SO₄The ether layer was dried and evaporated under reduced pressure to give 8.7g (94%) of the title compound (86) as a beige solid.¹HNMR(CDCl₃，400MHz)：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)。

And B:2-chloroisopropyl-p-nitrophenyl carbonate (87)

Isopropenyl-p-nitrophenyl carbonate (86) (8.7g, 39mmol) was dissolved in 4M hydrogen chloride/dioxane in a sealed vessel. The mixture was stirred at rt for 16 h. Removal of the solvent under reduced pressure gave 10g (100%) of the title compound (87), which was used in the next reaction without further purification.¹H NMR(CDCl₃，400MHz)：2.10(s，6H)，7.42(d，2H，J＝9.2Hz)，8.28(d，J＝9.2Hz，2H)。

And C:alpha-acetoxyisopropyl-p-nitrophenyl carbonate (88)

Will be in dichloromethane (20mL)A mixture of 2-chloroisopropyl-p-nitrophenyl carbonate (87) (0.5g, 1.93mmol) and mercury acetate (1.0g, 3.13mmol) was stirred at room temperature for 24 h. The reaction mixture was filtered to remove solids, and the filtrate was concentrated under reduced pressure. The residue obtained is chromatographed on silica gel (20% CH)₂Cl₂Hexane, then with 40% CH₂Cl₂Hexane) to yield 227mg (50%) of the title compound (88).¹HNMR(CDCl₃，400MHz)：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 -acetoxyisopropoxy) carbonyl]Aminomethyl } -1-cyclohexane acetic acid (85)

To a mixture comprising gabapentin (257mg, 1.5mmol) and triethylamine (0.46mL, 3.3mmol) in dichloromethane (30mL) was added chlorotrimethylsilane (0.38mL, 3mmol) and the mixture was stirred to clear. A solution containing α -acetoxyisopropyl-p-nitrophenyl carbonate (88) (0.23g, 0.8mmol) in dichloromethane (10mL) was added and stirred for 30 min. The reaction mixture was washed with brine (10mL), and the organic layer was separated. The aqueous layer was further extracted with ether (3X 10mL) and MgSO₄The combined organic extracts were dried and concentrated in vacuo. Chromatography of the resulting residue on silica gel (hexane: ethyl acetate (4: 1)) afforded 40mg (16%) of the title compound (85).¹H NMR(CD₃OD，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/z316.21(M+H)⁺。

Example 22

1- { [ (alpha-Butyloxy-isopropoxy) carbonyl]Aminomethyl } -1-cyclohexane acetic acid (89)

Following the procedure of example 21, substituting mercuric butyrate for mercuric acetate, 5mg (5%) of the title compound (89) was obtained.¹H NMR(CD₃OD，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/z344.24(M+H)⁺，366.30(M+Na)⁺。

Example 23

1- { [ (alpha-isobutanoyloxyethoxy) carbonyl]Aminomethyl } -1-cyclohexane acetic acid (90)

Following the procedure of example 21, substituting mercury isobutyrate for mercury acetate, 109mg (43%) of the title compound (90) was obtained.¹H NMR(CD₃OD，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)⁺。

Example 24

1- { [ (alpha-benzoyloxy-isopropoxy) carbonyl]Aminomethyl } -1-cyclohexane acetic acid (91)

Following the procedure of example 21 and substituting mercury benzoate for mercury acetate, 170mg (58%) of the title compound (91) was obtained.¹HNMR(CDCl₃，400MHz)：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)⁺。

Example 25

1- { [ (alpha-nicotinoyloxy isobutoxy) carbonyl]Aminomethyl } -1-cyclohexane acetic acid (92)

Step A:1- { [ (α -Chlorobutoxy) carbonylaminomethyl-1-cyclohexane acetic acid (93)

To a mixture containing gabapentin (1.71g, 10mmol) and triethylamine (3.06mL, 22mmol) in dichloromethane (150mL) was added chlorotrimethylsilane (1.4mL, 11mmol) and the resulting mixture was stirred to clear (about 20 min). A solution containing 1-chloro-2-methylpropyl chloroformate (1.27mL, 11mmol) in methylene chloride (10mL) was then added at 0 deg.C and stirred at room temperature for 60 minutes.The reaction mixture was washed with 10% citric acid (30mL) and the organic layer was separated. The aqueous layer was further extracted with ether (3X 20mL) and MgSO₄The combined organic phases were dried and then concentrated in vacuo. The residue was chromatographed on silica gel with hexane: ethyl acetate (1: 4) gives 2.37g (77%) of the title compound.¹HNMR(CDCl₃，400MHz)：δ1.04(d，J＝6.4Hz，3H)，1.06(d，J＝6.4Hz，3H)，1.36-1.53(m，10H)，2.15(M，1H)，2.34(s，2H)，3.24(M，2H)，5.39(t，1H)，6.32(d，J＝5.6Hz)，1H)。MS(ESI)m/z306.34(M+H⁺)。

And B:1- { [ (alpha-nicotinoyloxy isobutoxy) carbonyl]Aminomethyl-1-cyclohexaneacetic acid

(92)

(93) (268mg, 0.88mmol), 1, 8-diazabicyclo [5.4.0 ] in acetone at room temperature]A mixture of undec-7-ene (DBU) (158. mu.L, 1.01mmol) and nicotinic acid (637mg, 5.2mmol) was stirred for 48 h. After filtration, the filtrate was concentrated in vacuo and the resulting residue was purified by reverse phase preparative HPLC to give 50mg (14%) of the title compound.¹HNMR(CD₃OD，400MHz)：δ1.07(d，J＝6.8Hz，3H)，1.09(d，J＝6.8Hz，3H)，1.32-1.58(m，10H)，2.19(M，1H)，2.26(s，2H)，3.23(M，2H)，6.78(d，J＝4.8Hz，1H)，7.58(m，1H)，8.39(d，J＝6.4Hz，1H)，8.76(d，J＝4.4Hz，1H)，9.10(s，1H).MS(ESI)m/z393.42(M+H⁺)。

Example 26

1- { [ (alpha-2, 2-diethoxypropionyloxy-isobutoxy) carbonyl]Aminomethyl-1-cyclohexane

Acetic acid (94)

Step A:1- { [ (alpha-chloro-isobutoxy) carbonyl]Benzyl aminomethyl } -1-cyclohexaneacetic acid

(95)

To a solution of (93) (1.02g, 3.34mmol) in dichloromethane was added 1, 3-dicyclohexylcarbodiimide (758mg, 3.67. mu.l). After stirring for 30min at room temperature, benzyl alcohol (380. mu.L, 3.67mmol) and 4- (dimethylamino) pyridine (catalytic amount) were added. The resulting mixture was stirred at room temperature for 16 h. After filtration, the filtrate was washed with 10% citric acid, Na₂SO₄Dried and concentrated. Chromatography on silica gel eluting with 10% ethyl acetate/hexanes provided 820mg (62%) of the title compound.¹HNMR(CDCl₃，400MHz)：δ1.03(d，J＝6.4Hz，3H)，1.05(d，J＝6.4Hz，3H)，1.36-1.53(m，10H)，2.13(M，1H)，2.35(s，2H)，3.22(M，2H)，5.11(s，2H)，5.49(t，1H)，6.32(d，J＝4.8Hz)，1H)，7.34(m，5H).MS(ESI)m/z396.24(M+H⁺)。

And B:2, 2-Cesium diethoxypropionate (96)

To a stirred solution of 14mL (0.2mol) of pyruvic acid and 80mL of triethyl orthoformate was added 1mL of concentrated sulfuric acid at 10 ℃. The resulting mixture was stirred at 5-10 ℃ for 1h, then diluted with 200mL of dichloromethane. The organic solution was washed successively with water (3X 80mL) and a saturated sodium chloride solution (80mL), and then dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to give 2, 2-diethoxypropionic acid in quantitative yield as an oil.¹HNMR(CDCl₃400 MHz): δ 1.30(t, 6H), 1.61(s, 3H), 3.57(q, 4H), 8.62(s, 1H). The acid form is quantitatively converted to its cesium salt by the following method: the acid was dissolved in water (25mL) and then treated with an equimolar amount of cesium carbonate, followed by lyophilization.¹H NMR(D₂O，400MHz)：δ0.98(t，6H)，1.28(s，3H)，3.22(q，2H)，3.47(q，2H)。

And C:1- { [ (alpha-2, 2-diethoxypropionyloxy-isobutoxy) carbonyl]Amino-methyl

Base } -1-cyclohexane acetic acid benzyl ester (97)

A mixture of (95) (200mg, 0.51mmol) and sodium iodide (114mg, 0.76mmol) in acetone was stirred at room temperature for 1 h.Cesium 2, 2-diethoxypropionate (96) (300mg, 1.02mmol) and DMF (20mL) were added, and the resulting mixture was stirred at 40 ℃ for 18 h. After filtration, the filtrate was concentrated and the resulting residue was purified by flash column chromatography on silica gel, eluting with 10% ethyl acetate/hexanes to give 100mg (37%) of the title compound. MS (ESI) M/z522.34(M + H)⁺)。

Step D:1- { [ (alpha-2, 2-diethoxypropionyloxy-isobutoxy) carbonyl]Amino-methyl

Base } -1-cyclohexane acetic acid (94)

A mixture of (97) (200mg, 0.38mmol) and 5% Pd-C (catalytic amount) was stirred under hydrogen atmosphere at room temperature for 16 h. After filtration, the filtrate was concentrated and the resulting residue was purified by reverse phase preparative HPLC to give 98mg (60%) of the title compound.¹H NMR(CDCl₃，400MHz)：δ0.97(D，J＝6.8Hz，6H)，1.19(t，J＝6.4Hz，3H)，1.21(t，J＝6.4Hz，3H)，1.32-1.58(m，10H，)，1.51(s，3H)，2.06(M，1H)，2.30(s，2H)，3.23(M，2H)，3.46(M，2H)，3.56(M，2H)，5.30(t，1H，NH)，6.59(d，J＝4.8Hz，1H).MS(ESI)m/z432.24(M+H⁺)。

Example 27

1- { [ (alpha- (2-amino-2-methylpropanoyl) oxy isobutoxy) carbonyl]Aminomethyl } -1-ring

Hexane acetic acid (98)

The title compound was obtained by following the procedure of example 26 and substituting 2-amino-2-methylpropionic acid for 2, 2-diethoxypropionic acid.¹HNMR(CDCl₃，400MHz)：δ0.97(d，J＝6.8Hz，6H)，1.44(s，3H)，1.45(s3H)，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/z373.48(M+H⁺)。

Example 28

1-{[(α-Isobutyryloxybutoxy) carbonyl]Aminomethyl } -1-cyclohexane acetic acid (99)

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

To a mixture of isobutyraldehyde (9.1mL, 100mmol) and 1, 3-propanediol (10mL, 100mmol) in dichloromethane was added boron trifluoride diethyl etherate (6.4mL, 50mmol) at 0 ℃. The resulting mixture was stirred at 0 ℃ for 30 minutes and at room temperature for 30 minutes. With brine, 5% NaHC0₃And the reaction mixture was washed again with brine. Separating the organic phase and adding Na₂SO₄Drying and then concentration gave 16g (100%) of the title compound as a yellow liquid. It was carried to the next step without further purification.¹HNMR(CDCl₃，400MHz)：δ1.057(D，J＝7.2Hz，3H)，1.059(d，J＝7.2Hz，3H)，1.80(M，1H)，1.97-2.08(m，2H)，2.82(M，4H)，4.00(d，J＝5.2Hz，1H)。

And B:2-isopropyl-2- (. alpha. -hydroxybutyl) -1, 3-dithiane (101)

To a solution of (100) (4g, 24.7mmol) in anhydrous tetrahydrofuran (50mL) was added n-butyllithium (1.6M in hexane, 18.5mL, 29.6mmol) dropwise at-20 ℃. The stirred mixture was heated at room temperature for 4h and then cooled again to-20 ℃. To this solution was slowly added a solution of n-butyraldehyde (2.7mL, 29.6mmol) in anhydrous tetrahydrofuran (10 mL). The resulting mixture was stirred at a temperature between-20 ℃ and room temperature for 16h, quenched with saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was separated and washed with Na₂S0₄And (5) drying. After removal of the solvent under reduced pressure, the residue was subjected to flash column chromatography on silica gel eluting with 5% ethyl acetate/hexane to give 5g (85%) of the title compound as a yellow oil.¹HNMR(CDCl₃，400MHz)：δ0.96(t，J＝7.2Hz，3H)，1.11(d，J＝6.8，Hz，3H)，1.17(d，J＝6.8Hz，3H)，1.42-1.52(M，2H)，1.76(M，1H)，1.87-1.95(M，2H)，2.04(M，2H)，2.62(M，4H)，2.94(M，2H)，4.03(d，J＝5.2HZ，1H)。

And C:4-hydroxy-2-methylheptan-3-one (102)

To a solution of (101) (5.0g, 21.4mmol) in acetonitrile (270mL) was added Hg (Cl 0) in methanol (30mL) with vigorous stirring₄)₂The solution of (1). The resulting mixture was stirred at room temperature for 2 h. After filtration, the filtrate was concentrated under reduced pressure without heating. The residue was purified by flash column chromatography on silica gel (10% ethyl acetate/hexane) to give 2.8g (91%) of the title compound as a colorless liquid.¹HNMR(CDCl₃，400MHz)：S0.91(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-one-4-p-nitrophenyl carbonate (103)To a mixture of (102) (1.1g, 7.6mmol), p-nitrophenylchloroformate (1.84g, 9.2mmol) in dry dichloromethane was slowly added a solution of 4-dimethylaminopyridine (1.12g, 9.2mmol) in dichloromethane at 0 ℃. After stirring at 0 ℃ for 1h and at room temperature for 4h, the reaction was quenched with 10% citric acid. Separating the organic phase with Na₂SO₄Dried and concentrated in vacuo. Flash column chromatography of the residue, eluting with 30% dichloromethane/hexanes, afforded 2g (85%) of the title compound as a beige solid.¹HNMR(CDCl₃，400MHz)：δ0.99(t，J＝7.6Hz，3H)，1.12(d，J＝6.8Hz，3H)，1.18(d，J＝6.8Hz，3H)，1.51(M，2H)，1.84(M，2H)，2.82(M，1H)，5.17(M，1H)，7.42(d，J＝6.8Hz，2H)，8.25(d，J＝6.8Hz，2H)。

Step E:1- { [ (α -isobutyrylbutoxy) carbonyl]Aminomethyl-1-cyclohexaneacetic acid

(104)

To a mixture containing gabapentin (820mg, 4.8mmol) and triethylamine (1.35mL, 9.6mmol) in dichloromethane (20mL) was added chlorotrimethylsilane (1.22mL,9.6mmol) and the resulting mixture was stirred for 20 minutes. To this solution was added (103) (1g, 3.2mmol) in dichloromethane (10mL) and the resulting mixture was stirred for 60 minutes. The reaction mixture was washed with 10% citric acid (20mL) and the organic layer was separated. The aqueous layer was further extracted with ether (3X 10mL) and MgSO₄The combined organic extracts were dried and then concentrated in vacuo. The residue was chromatographed on silica gel with hexane: p-nitrophenol was removed by elution with ethyl acetate (4: 1) and then with hexane: ethyl acetate (1: 4) gave (72%) of the title compound.¹HNMR(CDCl₃，400MHz)：δ0.91(t，J＝7.2Hz，3H)，1.04(d，J＝6.8Hz，3H)，1.12(d，J＝6.8HZ，3H)，1.36-1.53(m，12H)，1.74(M，2H)，2.33(s，2H)，2.78(M，1H)，3.22(M，2H)，5.11(M，1H)，5.48(t，1H，NH).MS(ESI)m/z342.24(M+H⁺)。

Step F:1- { [ (α -isobutanoyloxybutoxy) carbonyl]Aminomethyl-1-cyclohexaneacetic acid

(99)

To a solution of (104) (780mg, 2.3mmol) in dichloromethane (20mL) was added m-chloroperoxybenzoic acid (1.03g, 4.6mmol) and NaHCO₃(386mg, 4.6 mmol). After stirring for 16h at room temperature, a further batch of m-chloroperoxybenzoic acid (791mg, 4.6mmol) and NaHCO was added₃(386mg, 4.6 mmol). The resulting mixture was stirred for a further 8h and then treated with 10% citric acid. After filtration, the organic layer was separated and washed with Na₂SO₄Dried and concentrated. The residue was purified by reverse phase preparative HPLC to give 79mg (11%) of the title compound.¹HNMR(CDCl₃，400MHz)：δ0.94(t，J＝7.2Hz，3H)，1.153(d，J＝7.2Hz，3H)，1.150(d，J＝7.2Hz，3H)，1.32-1.58(M，12H)，1.74(M，2H)，2.28(s，2H)，2.56(m，1H)，3.23(m，2H)，5.27(t，J＝6.8Hz，1H，NH)，6.71(t，J＝5.6Hz，1H).MS(ESI)MLZ358.30(M+H⁺)。

The above acid was quantitatively converted to the corresponding sodium salt by the following method: dissolve the acid in water (5mL) then add etcMolar amount of 0.5N naHCO₃And freeze-dried.

Example 29

1- { [ (alpha-Isobutyryloxy-isobutoxy) carbonyl]Aminomethyl } -1-cyclohexaneacetic acid methyl ester

(105)

Step A:1- { [ (alpha-chloro-isobutoxy) carbonyl]Aminomethyl } -1-cyclohexaneacetic acid methyl ester

(106)

A mixture of (93) (1.0g, 3.3mmol), benzene (90mL) and methanol (10mL) was cooled to 0 ℃. Trimethylsilyl diazomethane was added slowly at 0 ℃ until the yellow color remained. The mixture was stirred at 0 ℃ for 30min until the reaction was complete (monitored by TLC). After removal of the solvent under reduced pressure, the resulting residue was chromatographed on silica gel, eluting with 10% ethyl acetate/hexane to give 760mg (72%) of the title compound. MS (ESI) M/z320.24(M + H)⁺)。

And B:1- { [ (α -Isobutyryloxy-isobutoxy) carbonyl]Aminomethyl-1-cyclohexaneethanes Acid methyl ester (105)

A mixture of (106) (760mg, 2.38mmol), silver carbonate (394mg, 1.4mmol) and isobutyric acid (442. mu.l, 4.76mmol) in chloroform was stirred at room temperature for 24 h. Another batch of silver carbonate (394mg, 1.4mmol) and isobutyric acid (442. mu.L, 4.76mmol) was added and the resulting mixture was stirred for an additional 24 hours. After filtration, the filtrate was concentrated and the resulting residue was purified by flash column chromatography on silica gel, eluting with 10% ethyl acetate/hexanes to give 560mg (63%) of the title compound.¹HNMR(CDCl₃，400MHz)：δ0.94(d，J＝6.8Hz，3H)，0.96(D，J＝6.8Hz，3H)，1.15(d，J＝7.2HZ，3H)，1.17(d，J＝7.2HZ，3H)，1.32-1.58(m，10H)，2.01(m，1H)，2.19(s，2H)，2.55(m，1H)，3.18(m，2H)，3.67(s，3H)，5.33(t，1H)，6.56(d，J＝4.8Hz，1H)。MS(ESI)m/z372.38(M+H⁺)。

Example 30

1- { [ (alpha-benzoyloxy isobutoxy) carbonyl]Aminomethyl } -1-cyclohexaneacetic acid methyl ester

(107)

Coupling 1- { [ (alpha-benzoyloxy isobutoxy) carbonyl]A mixture of aminomethyl } -1-cyclohexane acetic acid (84) (150mg, 0.38mmol), benzene (18mL) and methanol (2mL) was cooled to 0 ℃. Trimethylsilyl diazomethane was added slowly at 0 ℃ until the yellow color remained. The mixture was stirred at 0 ℃ for 30min until the reaction was complete (monitored by TLC). After removal of the solvent under reduced pressure, the residue was chromatographed on silica gel, eluting with 5% ethyl acetate/hexane to give 98mg (64%) of the title compound.¹H NMR(CDCl₃，400MHz)：δ1.02(d，J＝6.4Hz，3H)，1.03(d，J＝6.4Hz，3H)，1.32-1.52(m，10H)，2.14(M，1H)，2.27(s，2H)，3.17(M，2H)，3.62(s，3H)，5.40(t，1H)，6.81(d，J＝4.8Hz，1H)，7.40(M，2H)，7.54(M，1H)，8.12(m，2H).MS(ESI)m/z406.29(M+H⁺)。

Example 31

1- { (N- [ (α -isobutanoyloxyethoxy) carbonyl]-4-bromophenylallylaminyl radical]Aminomethyl group

-1-Cyclohexaneacetic acid (108)

Step A:1- { (4-bromophenyl alanyl) aminomethyl } -1-cyclohexane acetate (109)

A40 mL vial was charged with N-Boc-4-bromophenylalanine (1.72g, 5mmol), dicyclohexylcarbodiimide (1.24g, 6mmol), N-hydroxysuccinimide (0.7g, 6mmol) and acetonitrile (20 mL). The reaction mixture was shaken at 25 ℃ for 4 h. The precipitated dicyclohexylurea was removed by filtration. To the filtrate was added gabapentin hydrochloride (1.04g, 6mmol) and aqueous solution (30mL) of sodium hydroxide (0.4g, 10 mmol). The reaction was stirred at 22-25 ℃ for 16 h. The reaction was diluted with ethyl acetate (100mL)The mixture was washed with 0.5M aqueous citric acid (2X 100mL) and water (2X 100 mL). The organic phase was separated and dried (MgSO)₄) Filtered and concentrated under reduced pressure. The residue was dissolved in trifluoroacetic acid (40mL) and allowed to stand at 22-25 ℃ for 2 h. The solvent was removed under reduced pressure. The residue was dissolved in water (4mL) and filtered through a 0.25 μ M nylon membrane filter and then purified by HPLC (Phenomenex250 × 21.2mm, 5 μ M lunac18 column, 100% water for 5 min, then 0-60% acetonitrile in water and 0.05% TFA for 20 mL/min). The pure fractions were combined and the solvent was removed under reduced pressure to give 1.7g (70%) of the title compound (109) as a white solid. MS (ESI) M/z397.02, 399.01(M + H)⁺)。

And B:1- { [ N- [ (α -isobutanoyloxyethoxy) carbonyl]-4-bromophenylalanineamino

Methyl } -1-cyclohexane acetic acid (108)

To a stirred suspension of (109) (200mg, 0.51mmol) in dichloromethane was added triethylamine (141. mu.L, 1.01mmol) and chlorotrimethylsilane (129mL, 1.01mmol) at 0 ℃. The resulting mixture was stirred at 0 ℃ for 15 minutes and a solution of α -isobutyryloxyethyl-p-nitrophenyl carbonate (111) (144mg, 0.51mmol) in dichloromethane was added. The mixture was stirred at room temperature for 7h (monitored by LC/MS), then the reaction mixture was diluted with dichloromethane and acidified with citric acid. The organic layer was separated, washed with brine and Na₂SO₄And (5) drying. After filtration and concentration, the crude product was purified by preparative LC/MS to yield 92mg of the title compound.¹H-NMR(CD₃OD，400MHz)：δ1.10(M，6H)，1.46-1.25(m，13H)，2.20(m，2H)，2.48(M，1H)，2.84(m，1H)，3.06(M，1H)，3.17(M，1H)，4.36(m，1H)，6.67(q，J＝5.6Hz，1H)，7.17(d，J＝2.0，8.0Hz，2H)，7.42(DD，J＝2.0，8.0Hz，2H)。

Example 32

3- { [ (alpha-isobutanoyloxyethoxy) carbonyl]Aminomethyl } -5-methylhexanoic acid (110)

Step A: alpha-isobutanoyloxyethyl-p-nitrophenyl carbonate (111)

A solution of 1-chloroethyl-p-nitrophenyl carbonate (57) (2.0g, 8.14mmol) and mercury isobutyrate (6.13g, 16.29mmol) in dichloromethane (10mL) was stirred at 45 ℃ for 24 h. The reaction was then cooled to room temperature and diluted with hexane to precipitate the mercury salt. The precipitate was filtered through a pad of celite and concentrated under vacuum to give 2.5g of crude product. Chromatography of the residue on silica gel with a gradient of 10% dichloromethane/hexane to 20% dichloromethane/hexane afforded 1.2g (52%) of the title compound.¹H-NMR(CDCl₃，400MHz)：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)。

And B:3- { [ (alpha-isobutanoyloxyethoxy) carbonyl]Aminomethyl-5-methylhexanoic acid

(110)

To a stirred suspension of pregabalin (2) (150mg, 0.94mmol) in dry dichloromethane (10mL) at 0 deg.C was added triethylamine (0.26mL, 1.88mmol) and chlorotrimethylsilane (0.24mL, 1.88 mmol). After stirring at 0 ℃ for 15 min, a solution of α -isobutyryloxyethyl-p-nitrophenyl carbonate (111) (267mg, 0.94mmol) in dichloromethane (3mL) was added. The resulting mixture was stirred at room temperature for 1.5 h. The reaction mixture was acidified with citric acid and extracted with dichloromethane. The combined organic extracts were washed with brine and Na₂SO₄And (5) drying. After filtration and evaporation, the crude product is purified by chromatography on silica gel, eluting first with dichloromethane to remove nitrophenol and then with 30% ethyl acetate in dichloromethane to give 130mg (48%) of the title compound as a mixture of the two diastereomers.¹H-NMR(CDCI3，400MHz)：δ0.90(m，6H)，1.70(M，8H)，1.46(d，J＝5.6HZ，3H)，1.66(1H，M)，2.15(M，1H)，2.33(M，2H)，2.53(m，1H)，3.12(m，1H)，3.29(M，1H)，5.08(t，J＝6.0Hz，1H)，6.79(M，1H)。

Example 33

3- { [ (alpha-isobutyryloxy-isobutoxy) carbonyl]Aminomethyl } -5-methyl-hexanoic acid (112)

Step A:1-chloro-2-methylpropyl-p-nitrophenyl carbonate (113)

To an ice-cold reaction mixture containing p-nitrophenol (4.06g, 29mmol) and 1-chloro-2-methylpropyl chloroformate (5.0g, 29mmol) in dichloromethane (200mL) was added a solution of pyridine (2.78mL, 32mmol) in dichloromethane (50 mL). The mixture was stirred at 0 ℃ for 30min and then at room temperature for 1 h. After evaporation of the solvent under reduced pressure, the residue was dissolved in ether and washed with water, 10% citric acid and again with water. Separating the ether layer with Na₂SO₄Drying and evaporation under reduced pressure gave 7.9g (100%) of the title compound as a beige solid.¹HNMR(CDCl₃，400MHz)：δ1.12(d，J＝6.6Hz，3H)，1.13(d，J＝6.6Hz，3H)，2.29(M，1H)，6.24(d，J＝4.8Hz，1H)，7.42(d，J＝9.2Hz，2H)，8.28(d，J＝9.2Hz，2H)。

And B:alpha-isobutanoyloxyethyl-p-nitrophenyl carbonate (114)

According to the production method of (111) and replacement of (57) with (113), the title compound was obtained in a yield of 15% and a recovery rate of the starting material thereof was 70%.¹H-NMR(CDCl₃，400MHz)：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)。

And C:3- { [ (alpha-isobutyryloxy-isobutoxy) carbonyl]Aminomethyl-5-methyl-hexanoic acid

(112)

According to the preparation method of (110) and replacement of (111) with (114), the compound (I) is obtainedThe title compound was obtained as a mixture of two diastereomers in 51% yield.¹H-NMR(CDCl₃，400MHz)：δ0.89(m，12H)，1.17(m，8H)，1.65(m，1H)，2.02(m，1H)，2.16(m，1H)，2.33(m，2H)，2.56(m，1H)，3.13(m，1H)，3.30(m，1H)，5.00(m，1H)，6.57-6.56(m，1H)。

Example 34

3- { [ (alpha-benzoyloxy isobutoxy) carbonyl]Aminomethyl-5-methyl-hexanoic acid (115)

Step A:alpha-benzoyloxyisobutyl-p-nitrophenyl carbonate (116)

According to the production method of (111), replacing (57) with (113) and replacing mercury isobutyrate with mercury benzoate to obtain the title compound in a yield of 11% with a recovery of the starting material of 50%.¹H-NMR(CDCl₃，400MHz)：δ1.15(d，J＝3.2Hz，3H)，1.16(d，J＝3.2Hz，3H)，2.30(m，1H)，6.87(d，J＝4.4Hz，1H)，7.42(dd，J＝7.2，2.0Hz，2H)，7.48(t，J＝7.6Hz，2H)，7.62(t，J＝7.6Hz，1H)，8.09(dd，J＝8.0，1.0Hz，2H)，8.27(dd，J＝7.2，2.0Hz，2H)。

And B:3- { [ (alpha-benzoyloxy isobutoxy) carbonyl]Aminomethyl-5-methyl-hexanoic acid

(115)

The preparation according to (110) and replacing (111) with (116) gave the title compound as a mixture of two diastereomers in 58% yield.¹H-NMR(CDCl₃，400MHz)：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(brs，1H)，6.82(m，1H)，7.44(m，2H)，7.57(m，1H)，8.05(m，2H)。

Example 35

1- { [ ((5-methyl-2-oxo-1, 3-dioxolan-4-en-4-yl) methoxy) carbonylBase of]Ammonia

Ylmethyl } -1-cyclohexane acetic acid (117)

Step A:benzyl 2-diazo-3-oxo-butanoic acid (118)

To a solution of benzyl acetoacetate (5.0g, 26.01mmol) and 4-acetamido-benzenesulfonyl azide (6.25g, 26.01mmol) in acetonitrile (200mL) was added dropwise triethylamine (10.9mL, 78.03mmol) at 0 ℃. The resulting mixture was stirred at 0 ℃ for 30min and at room temperature for 4 h. After concentration under reduced pressure, the residue was triturated with 2: 1 diethyl ether/petroleum ether (3X 100 mL). The combined organic extracts were filtered through a pad of celite truncated on silica gel. The solvent was removed under reduced pressure to give 4.74g of the title compound as beige crystals.¹H-NMR(CDCl₃，400MHz)：δ2.49(s，3H)，5.27(s，2H)，7.38(M，5H)。

And B:benzyl 2-hydroxy-3-oxo-butyric acid (119)

Will be in THF (110mL) and H₂A solution of the disazo compound (118) (4.74g, 21.74mmol) in O (50mL) was mixed with Rh₂(OAc)₂(77mg, 0.17mmol) were heated together under reflux for 4 hours and cooled to room temperature. The mixture was concentrated in vacuo and the aqueous residue was extracted with ethyl acetate. The combined organic extracts were washed with brine, Na₂SO₄Drying, filtration and concentration in vacuo gave 4.5g of crude product.¹H-NMR(CDCl₃，400MHz)：δ2.28(s，3H)，3.90(s，1H)，4.82(s，1H)，5.26(m，2H)，7.37(m.5H)。

And C:4-benzyloxycarbonyl 5-methyl-2-oxo-1, 3-dioxolan-4-ene (120)

To a suspension of carbonyldiimidazole (6.88g, 42.45mmol) in THF (50mL) at 0 deg.C was added a solution of alcohol (119) (4.50g, 21.22mmol) in dry THF (50 mL). The resulting mixture was stirred at 0 ℃ for 5 hours and at room temperature overnight. The mixture was concentrated in vacuo and the residue partitioned with water and ethyl acetate/hexane. Separating the organic layer with saturated NH₄Cl, brine, and Na₂SO₄And (5) drying. After filtration and concentration, the crude product is purified by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane to give 2.6g of the title compound.¹H-NMR(CDCl₃，400MHz)：δ2.48(s，3H)，5.27(s，2H)，7.37(br.s，5H)。

Step D:5-methyl-2-oxo-1, 3-dioxolan-4-enyl-4-carboxylic acid (121)

To a solution of compound (120) (2.6g, 10.92mmol) in 50mL ethanol was added 260mg PD/C (5%), and the resulting mixture was stirred under a hydrogen atmosphere for 1 h. Filtration and removal of the solvent under reduced pressure gave 1.62g of the title compound.¹H-NMR(CD₃OD，400MHz)：δ2.41(s，3H)。

Step E: 4-hydroxymethyl-5-methyl-2-oxo-1, 3-dioxolan-4-ene (122)

To a solution of acid (121) (1.62g, 11.10mmol) and anhydrous DMF (112 μ L) in anhydrous dichloromethane (50mL) was added oxalyl chloride (6.1mL, 2M solution, 12.2mmol) dropwise at 0 ℃. After stirring at 0 ℃ for 30 minutes and at room temperature for 1h, the solvent was removed under reduced pressure. The residue was dissolved in anhydrous dichloromethane (65mL) and cooled to-78 ℃. Bu was added dropwise to this solution over 10 minutes₄NBH₄(3.14g, 12.2mmol in 20mL of dichloromethane). After stirring at-78 ℃ for 1h, the mixture was carefully quenched with 0.1N HCl (30mL) and warmed to room temperature. The aqueous layer was separated, extracted with EtOAc (3X 50mL), and the combined organic extracts were washed with brine and Na₂SO₄And (5) drying. After removal of the solvent under reduced pressure, column chromatography on silica gel eluting with 50% EtOAc in dichloromethane afforded 767mg of the title compound.¹H-NMR(CD₃OD，400MHz)：δ2.09(s，3H)，4.34(s，2H)。

Step F:1- { [ ((5-methyl-2-oxo-1, 3-dioxolan-4-en-4-yl) methoxy) Carbonyl radical]-aminomethyl } -1-cyclohexaneacetic acid benzyl ester (123)

A suspension of alcohol (122) (767mg, 5.9mmol) and benzyl 1-isocyanatomethyl-1-cyclohexaneacetate (5.9mmol) in toluene was refluxed overnight. After removal of the solvent under reduced pressure, the residue was purified by flash column chromatography eluting with 30% EtOAc in hexane to give 510mg of the title compound.¹H-NMR(CD₃OD，400MHz)：δ1.58-1.30(m，10H)，2.18(s，3H)，2.35(s，2H)，3.17(d，J＝6.8Hz，2H)，4.80(s，2H)，5.11(s，2H)，5.44(t，J＝6.8Hz，1H)，7.36(m，5H)。

Step G:1- { [ ((5-methyl-2-oxo-1, 3-dioxolan-4-en-4-yl) methoxy) carbonyl

Base of]-aminomethyl } -1-cyclohexaneacetic acid (117)

To a solution of compound (123) (510mg, 1.41mmol) in ethanol (20mL) was added 59mg pd/C (5%), and the resulting mixture was stirred under a hydrogen atmosphere for 1 h. Filtration and removal of volatiles under reduced pressure gave the crude product, which was purified by preparative LC/MS to give 105mg of the title compound.¹H-NMR(CD₃OD，400MHz)：δ1.52-1.36(m，10H)，2.16(s，3H)，2.27(s，2H)，3.22(s，2H)，4.86(s，2H)。

Example 36

1- { (1-methyl-3-oxo-but-1-enyl) aminomethyl } -1-cyclohexaneacetic acid piperidinium salt

(124)

2, 4-pentanedione (103. mu.L, 1mmol), gabapentin (171mg, 1mmol) and piperidine (99. mu.L, 1mmol) were mixed with anhydrous methanol (10 mL). The resulting mixture was heated to reflux for 4 h. The solvent was removed under reduced pressure to give the title compound in a purity of greater than 90%¹HNMR(CDCl₃，400MHz)：δ1.34-1.62(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^-)。

Example 37

1-1- { [ (2-oxo-tetrahydrofuran-3-ylidene) ethyl]Aminomethyl-1-cyclohexaneacetic acid

Piperidinium (125)

2-acetylbutyrolactone (108. mu.L, 1mmol), gabapentin (171mg, 1mmol) and piperidine (99. mu.L, 1mmol) were mixed with anhydrous methanol (10 mL). After heating at reflux for 6h, the solvent was removed under reduced pressure to give the title compound in a purity of greater than 90%.¹H NMR(CDCl₃，400MHz)：δ1.34-1.62(m，12H)，1.71(m，4H)，1.94(s，3H)，2.24(s，2H)，2.81(T，J＝7.6Hz，2H)，2.99(M，4H)，3.31(d，J＝6.4Hz，2H)，4.23(t，J＝7.6Hz，2H)，5.17(s，br，2H)，8.64(t，J＝6.4Hz，1H).MS(ESI)m/z280.34(M-H-)。

Example 38

1- { (2-Carbomethoxy-cyclopent-1-enyl) aminomethyl } -1-cyclohexaneacetic acid piperidinium salt

(126)

Methyl 2-oxocyclopentanecarboxylate (124. mu.L, 1mmol), gabapentin (171mg, 1mmol) and piperidine (99. mu.L, 1mmol) were mixed with dry methanol (10 mL). After heating under reflux for 16h, the solvent was removed under reduced pressure to give the title compound in a purity of greater than 90%.¹HNMR(CDCl₃，400MHz)：δ1.29-1.60(M，12H)，1.72(M，4H)，1.79(M，J＝7.6Hz，2H)，2.24(s，2H)，2.49(t，J＝7.6Hz，2H)，2.55(t，J＝7.6Hz，2H)，2.99(M，4H)，3.24(d，J＝6.8Hz，2H)，3.63(s，3H)，5.06(s，br，2H)，7.93(s，br，1H).MS(ESI)m/z294.36(M-H-)。

Example 39

1- { (1-methyl-2- (ethoxycarbonyl) -3-ethoxy-3-oxoprop-1-enyl) aminomethyl 1-Cyclohexaneacetic acid piperidinium salt radical (12)7)

Diethyl acetylmalonate (202mg, 1mmol), gabapentin (171mg, 1mmol) and piperidine (99. mu.L, 1mmol) were mixed with absolute ethanol (10 mL). After heating under reflux for 16h, the solvent was removed under reduced pressure to give the title compound in a purity of greater than 90%.¹HNMR(CDCl₃，400MHz)：δ1.28(t，J＝7.2Hz，6H)，1.38-1.64(m，12H)，1.75(m，4H)，1.96(s，3H)，2.23(s，2H)，2.99(m，4H)，3.24(d，J＝5.2Hz，2H)，4.20(q，J＝7.2Hz，4H)，4.35(s，br，2H)，7.79(t，J＝5.2Hz，1H).MS(ESI)m/z354.38(M-H^-)。

Example 40

1- { [ (alpha- (2- (2-methyl-1, 3-dioxolan-2-yl) carboxy-isobutoxy) carbonyl]-amino group

Methyl } -1-cyclohexane acetic acid (128)

Step A:2-methyl-1, 3-dioxolane-2-carboxylic acid (129)

To a stirred mixture containing ethyl pyruvate (11.1mL, 0.1mol) and ethylene glycol (5.6mL, 0.1mol) in anhydrous dichloromethane (100mL) was added boron trifluoride diether (6.4mL, 0.05mol) and a catalytic amount of acetic acid at 0 ℃. The resulting mixture was stirred at 40 ℃ for 16h, then diluted with 100mL of dichloromethane. The organic solution was washed successively with saturated sodium chloride solution (2X 80 mL). The organic layer was separated and the combined organic extracts were concentrated. The residue was treated with 1N sodium hydroxide at room temperature. After stirring at room temperature for 3h (monitored by TLC), the pH was adjusted to 4 by addition of citric acid. The product was extracted with dichloromethane and Na₂SO₄Drying and concentration gave 5.1g (38%) of the title compound (129) as a clear liquid. This material was used in the next reaction without further purification.¹HNMR(CDCl₃，400MHz)：51.55(s，3H)，4.03(m，4H)。

And B:benzyl 1- { [ (alpha- (2- (2-methyl-1, 3-dioxolan-2-yl) carboxyisobutoxy

Yl) carbonyl]Aminomethyl } -1-cyclohexane acetic acid benzyl ester (130)

A mixture containing benzyl 1- { [ (α -chloroisobutoxy) carbonylaminomethyl } -1-cyclohexane acetate (95) (1g, 2.53mmol), (129) (673mg, 5.1mmol), silver carbonate (557mg, 2.53mmol) and triethylamine (709 μ l, 5.1mmol) in chloroform was stirred at room temperature for 16 h. After filtration, the filtrate was concentrated. The resulting residue was purified by silica gel chromatography, eluting with 15% ethyl acetate/hexanes to provide 510mg (41%) of the title compound (130). MS (ESI) M/z492.40(M + H)⁺)。

And C:1- { [ (alpha- (2- (2-methyl-1, 3-dioxolan-2-yl) carboxy-isobutoxy) carbonyl

Base of]-aminomethyl } -1-cyclohexaneacetic acid (128)

A mixture of (130) (470mg, 0.96mmol) and 5% Pd-C (catalytic amount) in ethanol was stirred under hydrogen atmosphere at room temperature for 16 h. Filtration and concentration gave 382mg (100%) of the title compound (128).¹HNMR(CDCl₃，400MHz)：δ0.96(d，J＝6.8Hz，3H)，0.97(d，J＝6.8Hz，3H)，1.32-1.58(m，10H)，1.59(s，3H)，2.06(M，1H)，2.32(s，2H)，3.26(m，2H)，4.08(M，4H)，5.29(t，1H，NH)，6.55(d，J＝4.8Hz，1H).MS(ESI)m/z402.32(M+H⁺). The acid form was quantitatively converted to the corresponding sodium salt by the following method: dissolved in water (5mL) and an equimolar amount of 0.5N naHCO was added₃And then lyophilized.

EXAMPLE 41

In vitro determination of Caco-2 cell Permeability of prodrugs

Passive permeability of the prodrugs of the invention can be assessed in vitro using methods known in the art (see, e.g., Stewart et al, arm. For example, permeability may be assessed by examining the flow of the prodrug through a polarized monolayer of cells in culture (e.g., Caco-2 cells). Will be obtained from a continuous cultureCaco-2 cells (passage less than 28) were seeded at high density onto a Transwel1 polycarbonate filter. DMEM/10% fetal bovine serum +0.1mM non-essential amino acids +2mML-GLn, 5% CO₂Per 95%, cells were fed at 37 ℃ until the day of the experiment. In the presence of a spill pump inhibitor (250. mu. MMK-571, 250. mu.M verapamil, 1mM ofloxacin), at pH6.5 and at the top (in a solution containing 1mM CaCl)₂、1MMMgCl₂、150mMNaCl、3mMKCl、1mMNaH₂PO₄5mM glucose in 50mM MES buffer) and at pH7.4 on the bottom side (in Hanks mean salt solution containing 10mM HEPES). Inserts were placed in 12-well or 24-well plates containing buffer and incubated at 37 ℃ for 30 min. Prodrug (200 μ M) was added to the top and bottom compartments (donors) and the concentration of prodrug and/or released parent drug in the opposite compartment (recipient) was determined at 1 hour intervals using LC/MS. The apparent permeability value (Papp) was calculated using the following equation:

P_app＝Vr(dC/dt)//(AC₀)

here V_rIs the volume of the receiving compartment in mL; dC/dt is the prodrug and parent drug flux (μ M/S), which is determined from the slope of the concentration versus time curve in the receiving compartment; c₀Is the initial concentration of the prodrug in μ M; a is in cm²Is the surface area of the membrane in units. P exhibited by prodrugs that preferably have significant permeability through cells_appValue of ≥ 1X 10^-6cm/s, more preferably P_appValue of ≥ 1X 10^-65cm/s, more preferably P_appValue of ≥ 5X 10^-5cm/s. Typical P obtained for prodrugs of GABA analogs_appThe values are shown in the following table:

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

The data in this table indicate that the prodrugs disclosed herein have high cell permeability and should be well absorbed from the intestine. With the exception of compound (83), the top-to-bottom permeability of prodrugs exceeded their bottom-to-top permeability. This suggests that these compounds may be substrates for active transport mechanisms present in Caco cell apical membranes (although some of this permeability through the cell is regulated by passive diffusion). (83) The greater the bottom-to-top permeability of (a) indicates that this compound can flow through the bottom-side membrane despite the presence of efflux pump inhibitors MK-571, verapamil and ofloxacin.

Example 42

Gabapentin following intracolonic administration of gabapentin or a gabapentin prodrug to rats

Absorption of

Sustained release oral dosage forms that slowly release drug over 6-24 hours typically release large doses in the colon. Thus, drugs suitable for use in such dosage forms preferably exhibit good colonic absorption. This experiment was conducted to evaluate the use of gabapentin prodrugs in oral sustained release dosage forms.

Step A: dosing regimens

Rats were purchased commercially and cannulae were pre-inserted in the ascending colon and jugular vein. The animals were awake at the time of the experiment. All animals were fasted overnight until 4 hours post dosing. Solutions of gabapentin or gabapentin prodrugs (59), (63), (69), (72), (77), (79), (85), (117), and (126) (in water or PEG 400) were administered directly to the colon via intubation at a dose equivalent to 25mg gabapentin/kg. Blood samples (0.5mL) were obtained from the jugular vein at intervals of 8 hours and the reaction was immediately stopped by adding acetonitrile/methanol to prevent further conversion of the prodrug. Blood samples were analyzed as follows.

And B: sample preparation of colonic absorption of drugs

1. In a blank 1.5mLeppendorf tube, 300. mu.L of 50/50 acetonitrile/methanol and 20. mu.L of p-chlorophenylalanine were added as internal standards.

2. Rat blood was collected at different time points and 100. mu.L of blood was immediately added to the eppendorf tube and mixed with stirring.

3. mu.L of gabapentin standard solution (0.04, 0.2, 1, 5, 25, 100. mu.g/ml) was added to 90. mu.L of blank rat blood to make up the final calibration standard (0.004, 0.02, 0.1, 0.5, 2.5, 10. mu.g/ml), then 300. mu.L of 50/50 acetonitrile/methanol was added to each tube followed by 20. mu.L of p-chlorophenylalanine.

4. The sample was stirred and centrifuged at 14,000 rpm for 10 minutes.

5. The supernatant was taken for LC/MS/MS analysis.

And C:LC/MS/MS analysis

An API2000LC/MS/MS spectrometer equipped with a Shidmadzu10ADVp binary pump and a CTC HTS-PAL autosampler was used for analysis. The Zorbax XDB C84.6X 150mm column was heated to 45 ℃ during the analysis. The mobile phase was 0.1% formic acid (a) and acetonitrile with 0.1% formic acid (B). The gradient conditions were: the 5% B flow was off for 1 minute, then 98% B was eluted for 3 minutes, then the elution with 98% B was maintained for 2.5 minutes. The mobile phase was restored to 5% B for 2 minutes. A turbolonspray source was used for API 2000. The analysis was done in positive ion mode and MRM transition 172/137 was used to analyze gabapentin (the MRM transition used was 426/198 for (59), 364/198 for (63), 392/198 for (69), 316/198 for (72), 330/198 for (77), 330/198 for (79), 316/198 for (85) and 327.7/153.8 for (117)). 20 μ L of sample was injected. Peaks were integrated using analyst1.1 quantification software. Maximum plasma concentration (C) of gabapentin following colonic administration of each of these prodrugs_max) And the area under the time curve of gabapentin plasma concentration (AUC) is significantly greater than: (A)>2-fold) the area under the curve generated by colonic administration of gabapentin itself. For example, gabapentin C provided by prodrug (77)_maxAnd AUC values 10 times greater than gabapentin itself. This data demonstrates that the compounds of the present invention can be formulated into compositions suitable for promoting absorption and/or effective sustained release of GABA analogs, thereby minimizing dosing frequency due to rapid systemic clearance of GABA analogs.

Example 43

Sustained release of gabapentin following prodrug administration to hounds using mini-pump

Gabapentin or gabapentin prodrugs (77) and (82) (at a dose equal to 10mg gabapentin/kg) were dissolved in a suitable solvent (e.g., water, PEG400, etc.) and filled into a pre-weighed Alzet mini osmotic pump device (model 2001D) (durect corp., Cupertino, CA). Pre-equilibration was performed by soaking the filled Alzet in osmotic saline for 3 hours at 37 ℃ and storing overnight in a sealed container at 4 ℃. Four fasted male hounds were then given orally (approximately 6.5 kg). Animals were fed 4 hours after each dose. Blood samples (1.0mL) were taken at 48 hour intervals and plasma was immediately processed. Plasma samples were lyophilized and stored at-80 ℃ until analyzed using the methods described above. The two prodrugs provided plasma concentrations of gabapentin 12 hours after dosing that were 2-fold greater than the concentration of gabapentin seen after administration of gabapentin itself in an Alzet device. This data further demonstrates that the compounds of the present invention can be formulated into compositions suitable for effective sustained release of GABA analogs.

Example 44

Pregabalin following administration of Dregabalalin or pregabalin prodrug in rat colonIs/are as follows

Absorption of

The protocol of example 41 is repeated with pregabalin and pregabalin prodrugs (110) and (112). Maximum plasma concentration (C) of pregabalin after colonic administration of each of these prodrugs_max) And the area under the plasma concentration versus time curve (AUC) of pregabalin is significantly greater than the area under the curve resulting from colonic administration of pregabalin per se ((C))>2 times).

Finally, it should be noted that there are alternative ways of implementing the invention. Accordingly, the present embodiments are to be considered as illustrative and not restrictive, and the invention is not to be limited to the details given herein, but may be modified within the scope and equivalents of the appended claims.

All publications and patents cited herein are incorporated by reference in their entirety.

Claims (10)

1. A compound of formula (VII):

or a pharmaceutically acceptable salt or hydrate thereof,

wherein,

n is 0;

R¹³is methyl, R⁷And R¹⁴Is hydrogen, and R²⁵Selected from methyl, ethyl, isopropylAnd a phenyl group.

2. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, selected from 1- { [ (α -isobutanoyloxyethoxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid, or a pharmaceutically acceptable salt or hydrate thereof.

3. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, selected from 1- { [ (α -isobutanoyloxyethoxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid, or a sodium salt thereof.

4. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, which is 1- { [ (α -isobutanoyloxyethoxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid.

5. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, which is the sodium salt of 1- { [ (α -isobutanoyloxyethoxy) carbonyl ] aminomethyl } -1-cyclohexane acetic acid.

6. A pharmaceutical composition comprising a compound of any one of claims 1-5, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

7. The pharmaceutical composition of claim 6, which is an oral sustained release dosage form.

8. Use of a compound of any one of claims 1-5, or a pharmaceutically acceptable salt or hydrate thereof, for the manufacture of a medicament for treating or preventing epilepsy, depression, anxiety, neurodegenerative disorders, pain, gastrointestinal disorders, or insomnia in a patient.

9. The use of claim 8, wherein said pain is selected from the group consisting of neuropathic pain, muscular pain and skeletal pain.

10. The use according to claim 8, wherein the medicament is a pharmaceutical composition as defined in claim 6 or 7.