CN101898977A - GABA (Gamma-Aminobutyric Acid) conjugates and using method thereof - Google Patents

Abstract

On the one hand, the invention provides a composite of covalent conjugates of GABA (Gamma-Aminobutyric Acid) analogues and medicaments, and on the other hand, the invention provides a method for treating pain and neurological disorder by adopting the conjugates of the GABA analogues.

Description

GABA conjugates and using method thereof

Technical field

The present invention relates to GABA conjugates and using method thereof.

Background technology

At present, the methods of treatment of single medicament administration is proposed as and is slowed down the many pain that comprise neurodynia.Narcotic analgesic, γ-An Jidingsuan (GABA) analogue such as gabapentin, lyrica and baclofen, antidepressive and non-steroidal anti-inflammatory medicine (NSAIDs) individually dosed all shows the character of slowing down pain in clinical with different animal models.

Although the pain scheme of slowing down of the single medicament that uses has advantage at present, also there are a lot of defectives in these schemes.Wherein, the zone of a concern is exactly that existing many pain therapy schemes can cause not wishing the side effect that produces.Narcotic analgesic such as morphine are because its known habituation effect and central nervous system (CNS) side effect and because their the individually dosed stomach side effect that causes seldom is used for the treatment of chronic pain.

Another focus of existing pain therapy scheme is exactly their curative effect.Slow down the many single-activity compositions such as antidepressive or the GABA analogue that use in the treatment of pain scheme at present, under the situation of some serious pain, even under their certified maximum therapeutic doses, can not obtain and reach the effect that eases the pain fully.Except can not reaching the effect that eases the pain, improve dosage and also can cause undesirable side effect such as cognitive impairment, feel sick and the increase of constipation.

In addition, other focus of GABA analogue and many anaesthetic class pain killers are exactly that their pharmacokinetics and physiological characteristics is relatively poor.The opiates molecule of many oral medicines is before arriving systemic circulation, just by a large amount of metabolism of digestion organs.And some GABA analogues also can be saturated than the absorptions of short and some GABA analogues owing to their transformation period, thereby limited the potentiality of these medicines when treatment pain and other nervus centralis disease.These suboptimum character often can cause patient can't obtain sufficient drug effect in therapeutic process and produce undesirable side effect.

Slow release formulation is to solve a too short conventional solution of transformation period in the medicine body, this be these those skilled in the art known (as, " Remingtion ' s Pharmaceutical Sciences; " Philadelphia College of Pharmacy and Science, 17th Edition, 1985).The GABA analogue is not absorbed at large intestine as baclofen, gabapentin and lyrica.On the contrary, these compounds generally in small intestine by neutral amino acid transporter albumen system absorb (Jezyk et al., Pharm.Res., 1999,16,519-526).Because these GABA analogues fast therefore can't the successful Application release method by upper digestive tract.

Because these existing weak points, clearly, in the process of treatment pain disease, reducing side effect simultaneously will be to the patient with a lot of benefit if raising result of treatment (that is, reducing the severity and/or the frequency of pain) can be arranged.In addition, the improvement to GABA analogue pharmacokinetics also makes its easier needs according to patient formulate therapeutic regimen.

Summary of the invention

On the one hand, the invention provides a kind of compound, described compound comprises first part and second section, described first part is by holding amino or the acidic endgroups except that carboxyl and second section covalently bound, and wherein said first part is analogue or the derivative of γ-An Jidingsuan (GABA) or GABA.On the other hand; the invention provides a kind of compound; described compound comprises first part and second section; described first part is covalently bound by carboxyl and second section; the end of described first part is amino to be connected analogue or the derivative of wherein said GABA of first part or GABA with blocking group.The present invention has also specifically described a kind of pharmaceutical composition, and described composition comprises compound disclosed by the invention and pharmaceutically acceptable carrier.

On the other hand, the invention provides the method for a kind of prevention or treatment disease, described method comprises the compound of the present invention to patient's administering therapeutic significant quantity of needs.In some specific embodiments, used compound comprises first part and second section in the described methods of treatment, described first part is by holding amino or the acidic endgroups except that carboxyl and second section covalently bound, and wherein said first part is analogue or the derivative of GABA or GABA.In other specific embodiments; used compound comprises first part and second section in the described methods of treatment; described first part is covalently bound by carboxyl and second section; the end of described first part is amino to be connected with blocking group, and wherein said first part is GABA or GABA analogue or derivative.In other specific embodiments, described method comprises the pharmaceutical composition of the present invention to patient's administering therapeutic significant quantity of needs.Described pharmaceutical composition comprises compound of the present invention and pharmaceutically acceptable carrier.

On the other hand, the invention provides a kind of method that reduces the side effect that disease treatment brings, described method comprises the compound of the present invention that applies the treatment significant quantity to the patient of needs.In some specific embodiments, described compound comprises first part and second section, described first part is by holding amino or the acidic endgroups except that carboxyl and second section covalently bound, and wherein said first part is GABA or GABA analogue or derivative.In other specific embodiments; described compound comprises first part and second section; described first part is covalently bound by carboxyl and second section, and the end of described first part is amino to be connected with blocking group, and wherein said first part is GABA or GABA analogue or derivative.In other specific embodiments, the method for the side effect that described reduction disease treatment is brought comprises the pharmaceutical composition of the present invention that applies the treatment significant quantity to the patient of needs.Described pharmaceutical composition comprises compound of the present invention and pharmaceutically acceptable carrier.

On the other hand, the invention provides a kind of method that improves the curative effect of disease treatment, described method comprises that the patient to needs treats the compound of the present invention of significant quantity.In some specific embodiments, described compound comprises first part and second section, described first part is by holding amino or the acidic endgroups except that carboxyl and second section covalently bound, and wherein said first part is GABA or GABA analogue or derivative.In other specific embodiments; described compound comprises first part and second section; described first part is covalently bound by carboxyl and second section, and the end of described first part is amino to be connected with blocking group, and wherein said first part is GABA or GABA analogue or derivative.In other specific embodiments, the method that improves the treatment of diseases effect comprises the pharmaceutical composition of the present invention that applies the treatment significant quantity to the patient of needs.Described pharmaceutical composition comprises compound of the present invention and pharmaceutically acceptable carrier.

In the time of aspect enforcement is more disclosed in this invention, the first part of described compound is the GABA analogue.In some specific embodiments, described first part is baclofen, vigabatrin, gabapentin or lyrica or gamma-amino phosphonate derivative.In some specific embodiments, described second section is an anodyne, includes but not limited to non-steroidal anti-inflammatory medicine (NSAID), opiates medicament, narcotic, muscle relaxant, antidepressive.In other specific embodiments, described second section is analogue, derivative or the variant of gamma-hydroxybutyric acid (GHB) or GHB.Described first part preferably is connected by covalent linkage with second section.This covalent linkage can be ester bond, amido linkage, imine linkage, amino-formate bond, carbonic acid ester bond, thioester bond, acyloxy amino-formate bond, acyloxy carbonic acid ester bond, phosphoric acid ester bond, acyloxy phosphoric acid ester bond or list, dialkyl amido phosphoric acid ester bond.In some specific embodiments, the present invention further comprises the covalently bound connection base to second section with described first part.Described connection base is preferably on the physiology unsettled.In some specific embodiments, the present invention further comprises ion or covalently bound to the first part of described compound or the third part of second section.In other specific embodiments, described compound can with the coupling of at least a other treatment medicament, described other treatment medicament can be antipsychotic agent, anxiolytic, antidepressive, anticonvulsive drug, anti-Parkinson medicine, acetylcholinesterase depressant, MAO inhibitor, selective serotonin reuptake inhibitor (SSRI), N-methyl-D-aspartate (NMDA) antagonist or the selectivity norepinephrine replaces inhibitor.These other treatment medicaments can be before compound administration of the present invention, simultaneously or administration afterwards.In some specific embodiments, the present invention also provides a kind of end with first part's (as GABA analogue) the amino blocking group that is connected.That described blocking group can be is amino acid based, imino-, carbamate groups, N-dithiosuccinimide base, list or dialkyl amido is phosphate-based or the acyloxy carbamate groups.Preferably, after to patient's administration, described blocking group disconnects from the amino of first part.

Embodiment

All publications, patent and the patent application mentioned in this specification sheets are all included the present invention in the form of quoting, its scope and each publication, patent and patent application quote particularly, individually include in when of the present invention the same.

On the one hand, the invention provides a kind of GABA-medicament conjugates, described conjugates comprises at least two parts that connect by covalent linkage.The first part of described conjugates preferably includes the GABA analogue.In some specific embodiments, the second section of described conjugates comprises anodyne.In some specific embodiments, the second section of described conjugates comprises gamma-hydroxybutyric acid (GHB).The anodyne of the second section of conjugates comprises, but be not limited to any pharmaceutical composition of narcotics, NSAID, antidepressive, narcotic, muscle relaxant, gamma-hydroxybutyric acid, dual function opiates medicament agonist, N-methyl-D-aspartate (NMDA) receptor antagonist and medicament as herein described.The present invention also provides the method that is used for synthesizing and preparing these GABA-medicament conjugates.In addition, the present invention includes the pharmaceutical composition that adopts GABA-conjugates of the present invention and GABA-conjugates, treat and/or prevent the method for disease.

GABA-medicament conjugates of the present invention preferably provides the pharmaceutics advantage in medicinal application.First, these GABA-medicament conjugates are unsettled in vivo, in case reach the body circulation, just can be cut off by enzyme or chemistry route, to produce the GABA analogue and the medicament of slowly-releasing amount, described medicament can be selected from the anodyne of narcotics, NSAID, antidepressive, dual function opiates medicament, narcotic, muscle relaxant and gamma-hydroxybutyric acid.The second, in case be cut off in vivo, that each independent part of GABA-medicament conjugates can aim at is different or nonoverlapping, with the relevant physiology target of therapeutic purpose (as treatment pain or nervous system disorders).Like this, GABA-medicament conjugates in case be cut off in vivo, can aim at and surpasses more than one physiology target, produce add and or collaborative physiologic effect, thereby curative effect is improved.The connection base that discharges by GABA-medicament conjugates, to the suitable administration of patient the time, normally atoxic.

The example of acidic-group comprises, but is not only limited to phosphorous acid (phosphic acid), phosphonic acids, sulfonic acid,-sulfinic acid or carboxylic acid etc.End amino also is known, N-end group, NH2-end group, N-end or amine-end group.These terms are used interchangeably.End amino comprises by having free amino (end capped protein of amino acid NH2) or polypeptide.

The example of GABA analogue includes but not limited to following structure:

Wherein:

R is the atom that the heteroaralkyl of heteroaryl, heteroaralkyl and replacement of the assorted alkyl of ring, heteroaryl, replacement of aralkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring, the replacement of aryl, aralkyl, the replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement or R and R4 are connected with them, the ring of the tetramethyleneimine of azetidine, tetramethyleneimine or the replacement of formation azetidine, replacement;

R4 and R5 are independently from each other the aralkyl as heteroaryl, heteroaralkyl and the replacement of the assorted alkyl of ring of: the cycloalkyl of the aralkyl of the aryl of the alkyl of hydrogen, alkyl, replacement, aryl, replacement, aralkyl, replacement, cycloalkyl, replacement, the assorted alkyl of ring, replacement, heteroaryl, replacement;

R2 and R3 select the heteroaralkyl as heteroaryl, heteroaralkyl and the replacement of the assorted alkyl of ring of: the cycloalkyl of the aralkyl of the aryl of the acyl group of the alkyl of hydrogen, alkyl, replacement, acyl group, replacement, aryl, replacement, aralkyl, replacement, cycloalkyl, replacement, the assorted alkyl of ring, replacement, heteroaryl, replacement independently of one another; or randomly; R4 and R5 be with the carbon atom that they were connected, and forms the ring of the cycloalkyl of the assorted alkyl of ring of the assorted alkyl of cycloalkyl, ring, replacement of cycloalkyl, replacement and bridge joint.

R1 and R23 are independently from each other as follows: the heteroaralkyl of heteroaryl, heteroaralkyl and the replacement of the assorted alkyl of ring of the cycloalkyl of the aralkyl of the aryl of the alkyl of hydrogen, alkyl, replacement, aryl, replacement, aralkyl, replacement, cycloalkyl, replacement, the assorted alkyl of ring, replacement, heteroaryl, replacement.

Compound of the present invention can contain one or more chiral centres and/or two key, thereby can exist with the form of steric isomer such as double bond isomer (being geometrical isomer), enantiomer or diastereomer.Therefore, the all possible enantiomer and the steric isomer of compound shown in chemical structure described in the invention has contained, comprising, but be not limited to the form of stereoisomerism pure compound (as pure rotamerism, pure enantiomerism or pure diastereo-isomerism) and corresponding isomery and three-dimensional heterogeneous mixture.Enantiomerism and three-dimensional heterogeneous mixture can adopt separation method well-known to those skilled in the art or chirality synthetic method, split into the enantiomer or the steric isomer of each component.Compound of the present invention also can exist with the form of several tautomers, includes, but not limited to enol form, keto-acid and mixed form thereof.Therefore, all possible tautomeric form of compound shown in chemical structure described in the invention has contained.Compound of the present invention also can include, but not limited to isotope-labeled compound, and the atomic mass of wherein one or more atoms is different from the atomic mass of finding usually at nature.The isotopic example that can introduce compound of the present invention includes, but not limited to ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl.In addition, when signal compound of the present invention had only part-structure, what bracket was represented was the tie point of described part-structure and other molecule.

On the one hand, second section of the present invention such as medicament are connected on the gamma-amino of first part such as GABA analogue in general.These two portions can directly connect by the gamma-amino of GABA analogue, to form following connection base, described connection base comprises, but be not limited to carboxamide groups, phosphinylidyne amido, phosphono amido, sulfoamido, sulfonamido and imido grpup or randomly connect by can cutly being connected base " X " in vivo.On the other hand, second section of the present invention and first part such as GABA analogue is connected that the acidic-group that is by first part carries out.Acidic-group used herein includes, but not limited to carboxyl, phosphate and sulfino.The second section of conjugates is covalently bound to the acidic-group of first part, forms following connection base, and described connection base includes, but not limited to carboxylic acid ester groups, thioester substrate, phosphonous acid ester group,-sulfinic acid ester group and carboxamide groups.In addition, these two portions can be chosen wantonly by connecting by cut in vivo connection base " Z ".

In some specific embodiments, the invention provides chemical formula (I) and GABA-medicament conjugates (II):

As W=-S-or-P (R ₂₃)-, { } chooses wantonly

Or its pharmacy acceptable salt, hydrate, solvate and isotropic substance, wherein:

T is 0 or 1;

X is other medicament and the direct linking group of GABA analogue, is selected from following group:

Z is the linking group between other medicament and the GABA analogue, is selected from following group:

R1 is independently selected from following group: the heteroaralkyl of heteroaryl, heteroaralkyl and the replacement of the assorted alkyl of the cycloalkyl of the aralkyl of the aryl of the alkyl of hydrogen, alkyl, replacement, aryl, replacement, aralkyl, replacement, cycloalkyl, replacement, the assorted alkyl of ring, the assorted alkyl of ring of replacement, assorted alkyl, replacement, heteroaryl, replacement;

R2 and R3 are independently selected from following group: the heteroaralkyl of the cycloalkyl of the aralkyl of the acyl group of the alkyl of hydrogen, alkyl, replacement, acyl group, replacement, aralkyl, replacement, cycloalkyl, replacement, the assorted alkyl of ring, substituted aralkyl, heteroaralkyl and replacement or randomly, R2 and R3 be with the carbon atom that they were connected, and forms the ring of the cycloalkyl of the assorted alkyl of ring of the assorted alkyl of cycloalkyl, ring, replacement of cycloalkyl, replacement or bridge joint;

R4 and R5 are independently selected from as follows: the heteroaralkyl of heteroaryl, heteroaralkyl and the replacement of the assorted alkyl of ring of the cycloalkyl of the aralkyl of the aryl of the alkyl of hydrogen, alkyl, replacement, aryl, replacement, aralkyl, replacement, cycloalkyl, replacement, the assorted alkyl of ring, replacement, heteroaryl, replacement;

R6 and R7 are independently selected from as follows: hydrogen, alkyl, the alkyl that replaces, acyl group, the alkoxy carbonyl that replaces, the alkoxy carbonyl that replaces, aryl, the aryl that replaces, aralkyl, the aralkyl that replaces, carbamyl, cycloalkyl, the cycloalkyl that replaces, cyclo alkoxy carbonyl, the cyclo alkoxy carbonyl that replaces, heteroaryl, the heteroaryl that replaces, aralkyl, the aralkyl that replaces, the heteroaralkyl of heteroaralkyl and replacement or randomly, R4 and R5 form cycloalkyl with the carbon atom that they were connected, the cycloalkyl that replaces, the assorted alkyl of ring, the ring of the cycloalkyl of assorted alkyl of the ring that replaces or bridge joint;

R20 is independently selected from as follows: hydrogen, alkyl, the alkyl that replaces, alkoxyl group, the alkoxyl group that replaces, acyl group, the acyl group that replaces, acyl amino, the acyl amino that replaces, alkylamino, the alkylamino that replaces, alkyl sulphinyl, the alkyl sulphinyl that replaces, alkyl sulphonyl, the alkyl sulphonyl that replaces, alkyl thiol, the alkyl thiol that replaces, alkoxy carbonyl, the alkoxy carbonyl that replaces, aryl, the aryl that replaces, aralkyl, the aralkyl that replaces, aryloxy, the aryloxy that replaces, carbamyl, cycloalkyl, the cycloalkyl that replaces, the assorted alkyl of ring, the assorted alkyl of the ring that replaces, dialkyl amido, the dialkyl amido that replaces, halogen, assorted alkyl, the assorted alkyl that replaces, heteroaryl, the heteroaryl that replaces, heteroaralkyl, the heteroaralkyl that replaces, assorted alkoxyl group, the assorted alkoxyl group that replaces, the heteroaryloxy of heteroaryloxy and replacement, or randomly;

R21 and R22 are independently selected from as follows: the heteroaralkyl of heteroaryl, heteroaralkyl and the replacement of the assorted alkyl of the cycloalkyl of the aralkyl of the aryl of the alkyl of the acyl group of hydrogen, acyl group, replacement, alkyl, replacement, aryl, replacement, aralkyl, replacement, cycloalkyl, replacement, the assorted alkyl of ring, the assorted alkyl of ring of replacement, assorted alkyl, replacement, heteroaryl, replacement; or randomly R20 and R21 form the ring of the assorted alkyl of ring of the assorted alkyl of cycloalkyl, ring of cycloalkyl, replacement or replacement with the carbon atom that they were connected.

On the other hand, second section of the present invention connects by the carboxyl terminal on the GABA analogue of first part, and the aminoterminal of first part is connected with blocking group " P ".In some specific embodiments, GABA-medicament conjugates of the present invention has the structure of chemical formula (III):

Wherein

R2 and R3 are independently from each other as follows: the heteroaralkyl of aralkyl, heteroaralkyl and the replacement of the cycloalkyl of the aralkyl of the acyl group of the alkyl of hydrogen, alkyl, replacement, acyl group, replacement, aralkyl, replacement, cycloalkyl, replacement, the assorted alkyl of ring, replacement or randomly, R2 and R3 be with the carbon atom that they were connected, and forms the ring of the cycloalkyl of the assorted alkyl of ring of the assorted alkyl of cycloalkyl, ring, replacement of cycloalkyl, replacement and bridge joint;

R4 and R5 are independently selected from following group: the heteroaralkyl of heteroaryl, heteroaralkyl and the replacement of the assorted alkyl of ring of the cycloalkyl of the aralkyl of the aryl of the alkyl of hydrogen, alkyl, replacement, aryl, replacement, aralkyl, replacement, cycloalkyl, replacement, the assorted alkyl of ring, replacement, heteroaryl, replacement;

Z is the defined covalent linkage of connection base between other medicament and the GABA analogue, is selected from following group:

P is amino acid, imines, carbamate, N-dithiosuccinimide, list or dialkyl amido phosphoric acid ester, the acyloxy carbamate.

I. first part: GABA and GABA analogue

On the one hand, the invention provides a kind of composition that is used for the treatment of pain or neurological disorder.In some specific embodiments, the first part of described composition is the GABA analogue.

γ-An Jidingsuan (GABA) is the conduction mediator of a kind of inhibitory nerve in the mammalian central nervous system.It is to work by combining with specific transmembrane receptor in the plasma membrane of the forward and backward neurone process of cynapse (pre-and postsynaptic neuronalprocesses).This combination causes ionic channel to be opened, and makes electronegative chlorion enter cell, and perhaps positively charged potassium ion flows out from cell.This effect causes the negative charge in the transmembrane potential to change, and can cause hyperpolarization usually.Three kinds of common GABA acceptors have been confirmed, GABA _A, GABA _BAnd GABA _CGABA _AAnd GABA _CIonized acceptor, wherein GABA _BIt is the protein-coupled metabotropic receptor of G.The GABA of lower concentration is relevant with numerous disease in the body, include but not limited to, epileptic seizures, multiple sclerosis, action tremor, in alarm, anxiety and depression.

Because GABA lacks the hemato encephalic barrier penetrance, while role in different symptom, it is a very active pharmacy field that preparation GABA analogue has the research of pharmaceutical properties preferably.Therefore, a lot of GABA analogues (Satzinger et al., U.S. Patent No. 4,04,175 have been synthesized in the prior art; Silverman et al., U.S. Patent No. 5,563,175; 6,028,214; 6,117,906; International publication number No.WO92/09560; 93/23383; Horwell et al., U.S. Patent No. 6,020,370; International publication number No.WO97/29101,97/33858; 97/33859; Bryans et al., international publication number No.WO 99/31057; 99/31075; 99/61424; 00/15511; 00/31020; 00/50027; 02/00209; Guglietta et al. international publication number No.WO 99/08671).

Many GABA analogues are identified.These GABA analogues include but not limited to that baclofen [Formula I V (a)], vigabatrin [Formula I V (b)], gabapentin [Formula I V (c)] and lyrica [Formula I V (d)] are shown in hereinafter.Unlike GABA itself, these GABA derivatives can not only pass hemato encephalic barrier (might be by protein transport mechanism), also are proved it and have the clinical pharmaceutics way.Baclofen is GABA _BAgonist is used to treat the spasm type motion or slows down pain, particularly Spinal injury, spastic diplegia, multiple sclerosis and trigeminal neuralgia in clinical.Vigabatrin is a kind of anticonvulsive drug, has been used as the assisting therapy such as the disease of epilepsy and complex partial seizure.In the GABA analogue, the initial exploitation of gabapentin and lyrica is used as the treatment epilepsy, but is proved to be slowing down chronic pain, and particularly the neuropathic pain of neuropathic pain such as diabetes and herpes zoster neuralgia are effective.Clinical trial shows that also gabapentin and lyrica are that good effect is arranged in the treatment to fibromyalgia.Gabapentin and lyrica generally have tolerance in most patient, Wen He side effect relatively, and there are not metabolic problems in they yet, when drug combination, also can't cause simultaneously and other medicines between interaction.Though it is the derivative of GABA that gabapentin and lyrica look, their main biological activity is not to produce with the effect of GABA acceptor.Studies show that the effect that slows down of neuropathic pain is α by voltage-dependent N type calcium channel ₂δ subunit (binding site of the high affinity in the neu) mediation (Rose, M.A.et al, Anesthesia, 2002,57 (5), 451-462).This subunit works in the keeping of the mechanics hypersensitivity (mechanical hypersensitivity) of the model of neuropathic pain.Calcium ion merges the vesicle and the presynaptic membrane that contain neurotransmitter, and this effect has promoted to suppress the release of the neurotransmitter of synaptic cleft.Gabapentin and lyrica may all be via α by blocking-up ₂The inflow of the calcium ion of δ acceptor, thus the release of the neurotransmitter between the neurone reduced and the transmission that reduces pain signal produces result of treatment.External discovery shows that gabapentin can reduce the presynaptic release of excitatoty neurotransmitter such as glutamate and norepinephrine.

The vigabatrin of baclofen-(a)-(b)

The lyrica of gabapentin-(c)-(d)

The combination therapy of the opium analgesics of employing GABA analogue (as gabapentin, lyrica and baclofen) and other anodyne such as narcotics, dual function, NSAID, antidepressive, nmda antagonist can improve the control to chronic pain.When administration together, GABA analogue and these anodyne can with collaborative or add and mode interact, with the control chronic pain.This synergy may reduce every kind of dosage that compound is required, thereby reduces side effect, and the clinical application that improves these compounds.Analgesic effect can improve (Keskinbora K.J.of Pain andSymptom Management 2007,34 (2), 183-189 by the Combined Preparation of GABA analogue (gabapentin, lyrica and baclofen) and opiates medicament such as morphine; Kazi, J.A., Gee, C.F.J.Mol.Neurosci.2007,32,47-52; Berger, A.; Et al.Clinical Therapeutics 2003,25 (11), 2809-2821; Eckhardt, K.et al.Anesth Analg 2000,91,185-191; Granados-Soto, V.et al.Pharmacology 2005,74,200-208; Tiippana, E.M.; Et al.Anesthesia﹠amp; Analgesia 2007,104 (6), 1545-1556; Codd.E.E.; Et al.Pain 2008,134,254-262.).In the past, also have with the present invention and similarly report, promptly analgesic effect can pass through GABA analogue (gabapentin, lyrica) (Anesthesiology 1999 for Yoon, M.H.et al. to be improved curative effect with the Combined Preparation of NSAID or nmda receptor antagonist, 91 (4), 1006-1013; Hurley, R.W., et al., 2002,97 (5), 1263-1273; Durmus, M.et al., Acta Anaesthesiol Scand2007,51,299-304; Ryan, M.et al., International Patent No.WO99/12537).

Although the Combined Preparation of GABA analogue and other anodyne has lot of advantages, but these medicines have defective in various degree in use: 1) the GABA analogue (comprises, but be not limited to gabapentin, lyrica and baclofen) in vivo the transformation period shorter, thereby need often take medicine to keep treatment or the prevention concentration in the body circulation; 2) under higher dosage (1.8-3.6g/d, three times dosage), cause its bioavailability to reduce greatly owing to the absorption of gabapentin can reach capacity, thereby cause interpatient curative effect that bigger otherness is arranged; 3) in large intestine, can not absorb preferably, limit the use of slow release formulation; 4) by intestines and stomach toxicity that anodyne such as NSAID caused; 5) internal metabolism of some narcotic analgesics such as morphine.

On the one hand, the invention provides a kind of new GABA-medicament conjugates, it has new chemical entities, compares with treatment plan mentioned above, has the advantage of some uniquenesses.When some clinical uses, described GABA-medicament conjugates can be by big intestinal absorption.As a result, by adopting slow release formulation can reduce administration frequency.In other embodiments, GABA-medicament conjugates has changed the mechanism of absorption of GABA analogue, and having can be by passive diffusion, thus pharmacokinetic difference between the patient can improve clinical use the time.In other specific embodiments, pass through first part, it is the GABA analogue, with second section, be the covalent coupling of the connection base between anodyne, active agents (being the GABA analogue of activity form and the anodyne of activity form) can be optimised from the speed of GABA-medicament conjugates release in vivo.Compare with its former medicine, some intestines and stomach side effects can be lowered.The present invention also comprises GABA-anodyne conjugates, for example GABA-NSAID conjugates.The administration of GABA-NSAID conjugates of the present invention can prevent, reduces and/or treat the gastrointestinal damage that is caused by NSAID.

II. second section

In some specific embodiments, the second section of composition of the present invention is an anodyne.

A. anodyne

Anodyne is that to be used for slowing down the medicament of pain any.Anodyne works by different modes in periphery and central nervous system.There are some class anodyne, include, but not limited to Paracetamol (acetaminophen), non-steroidal anti-inflammatory medicine (NSAID) as Naproxen Base, narcotic such as morphine and opiate, synthetic medicament such as U-26225A and other treatment medicament with anesthesia character.

The selection of analgesia is by the reaction decision of severity and other drug treatment, also by the type decided of pain.For example, to neuropathic pain, traditional analgesia effect is relatively poor, does not think that simultaneously usually the medicament of anodyne such as tricyclics and anticonvulsive drug often also can tell on.

B. gamma-hydroxybutyric acid

In other specific embodiments, the second section of composition of the present invention is any analogue, the derivative of gamma-hydroxybutyric acid (GHB) or GHB.GHB is found in central nervous system, wine, ox, little citrus fruit and the nearly all animal, and it is a small amount of crude substance that exists.GHB is natural generation in human body cell, and its structure is relevant with the ketoboidies beta-hydroxy-butanoic acid ester.It still is a kind of neuroprotective therapeutic nutrient element, is listed in illegal medicament in many countries.Be subjected to control in the U.S. at present, and be used to treat the excessive daytime sleepiness of dampinging off and suffering from the patient of narcolepsy.GHB uses with the form of salt, and it can be produced by fermentation.

GHB has at least two tangible binding sites in central nervous system.GHB is the agonist of GHB acceptor, have excitability (Wu Y, et.al., 2004, Neuropharmacology 47 (8): 1146-56.).Simultaneously, it also has more weak to GABA _BThe exciting function of acceptor has inhibition to nervus centralis.GHB is by the institute of the GABA in GABA serotonergic neuron synthetic, and discharges when neurone discharges.

When medicine for oral use, GABA itself is difficult to pass hemato encephalic barrier, carries out effective function and reach higher GABA concentration and GABA acceptor at brain.Because GABA is natural synthetic in brain, if when concentration in the brain reaches higher than normal concentration, GABA will be very fast by metabolism.But, be under the pharmaceutical doses when GHB can reach higher concentration at brain,, it will activate GABA _BAcceptor, just it has major cause (Dimitrijevic N, et.al.2005, the Eur.J.Pharmacol.519 (3): 246-52) of calming effects for this.

GHB acceptor and GABA _BActivation be the addicted reason of GHB.The influence that GHB discharges Dopamine HCL is two stages (biphasic), passes through the release of GHB receptor for stimulating Dopamine HCL when lower concentration.And under higher concentration, can pass through GABA _BAcceptor suppresses the release of Dopamine HCL, this and other GABA _BAgonist such as baclofen identical (Maitre M, et.al.1990, J.Pharmacol.Exp.Ther.255 (2): 657-63 with phenibut; Smolders I, et.al., 1995Eur.J.Pharmacol.284 (1-2): 83-91).In the initial inhibition stage, the release of Dopamine HCL increases by the GHB acceptor.Inhibition and increase by the Dopamine HCL that GHB caused discharges all are subjected to the inhibition of opiates medicament antagonist such as naloxone and TREXUPONT.

The GHB prodrug of ester-formin includes, but not limited to 1,4-diacetoxy butane, methyl-4-acetoxyl group butyric ester and ethyl-4-acetoxyl group butyric ester.The prodrug of these GHB may all have time-lag action and long-acting.Midbody compound 4-acetaldol also is the prodrug of GHB.The present invention will be understood that it is to comprise GHB, any analogue of GHB, derivative, prodrug or any other suitable variant.

Synthesizing of III.GABA-medicament conjugates

GABA-medicament conjugates of the present invention can be obtained by the synthetic method shown in the synoptic diagram 1-8.Being engaged in those skilled in the art can understand and understand, the preferred route of synthesis of GABA-medicament conjugates of the present invention comprises anodyne is connected on the GABA analogue that described anodyne is selected from narcotics, NSAID, dual function opiates medicament anodyne, antidepressive, γ-Ding Suan and nmda receptor antagonist.Method (Satzinger et al., U.S. Patent No. 4,024,175 of a lot of synthetic GABA analogues have been described in the prior art; Silverman et al., U.S. Patent No. 5,563,175; No.6,028,214; No.6,117,906; Silverman et al., open publication number WO 92/09560; No.WO 93/23383; Horwell et al., U.S. Patent No. 6,020,370; No.6,103,932; Horwellet al., international publication number No.WO 97/29101; WO 97/33858; WO 97/33859; Bryans etal., international publication number No.WO 98/17627; WO 99/21824; WO 99/31057; WO99/31075; WO 99/61424; WO 00/15611; WO 00/31020; WO 00/50027; Guglietta et al., international publication number No.WO 99/08671; Belliotti et al., international publication number No.WO 99/31074).The additive method that is used for synthetic GABA analogue in the prior art also is to understand easily and obtain to those skilled in the art.Anodyne of the present invention is being known in the art, and can prepare according to known method.To contain the anodyne molecule of various functional groups (as carboxyl, hydroxyl, sulfydryl, amido, sulfahydantoin) and being connected of GABA analogue, also be method well known in the art (referring to, as, Green et al., " Protective Groups in Organic Chemistry ", (Wiley, 2nd ed.1991); Harrison et al., " Compendium of Synthetic Organic Methods ", Vols.1-8 (John Wiley and Sons, 1971-1996); " Beilstein Handbook of OrganicChemistry, " Beilstein Institute of Organic Chemistry, Frankfurt, Germany; Feiser et al., " Reagents for Organic Synthesis, " Volumes 1-17, WileyInterscience; Trost et al., " Comprehensive Organic Synthesis, " Pergamon Press, 1991; " Theilheimer ' s Synthetic Methods of Organic Chemistry, " Volumes 1-45, Karger, 1991; March, " Advanced Organic Chemistry, " Wiley Interscience, 1991; Larock " Comprehensive Organic Transformations, " VCH Publishers, 1989; Paquette, " Encyclopedia of Reagents for Organic Synthesis, " John Wiley﹠amp; Sons, 1995, Bodanzsky, " Principles of Peptide Synthesis, " Springer Verlag, 1984; Bodanzsky, " Practice of Peptide Synthesis, " Springer Verlag, 1984).

The initial substance that is used to prepare compound of the present invention and intermediate can be by commercially available, perhaps with known synthetic method preparation.Other synthetic methods of GABA-medicament conjugates of the present invention are existing in the prior art to be described, and perhaps to those skilled in the art, with reference to after the content mentioned above, is conspicuous.These methods all can be used to synthetic GABA-medicament conjugates of the present invention.Therefore, the method described in these synoptic diagram of the present invention is schematic reference, rather than comprehensively.

On the one hand, the invention provides a kind of GABA-medicament conjugates, the first part of wherein said conjugates as the GABA analogue by as described in the amino (nitrogen end group) or the acidic endgroups except that carboxyl of first part, be connected with second section such as medicament.In some specific embodiments, described first part is connected with second section by aminoterminal.In other specific embodiments, described first part is by including but not limited to that the acidic-group of phosphate and sulfino is connected with second section.In some cases, GABA analogue experience gamma-amino circularizes into gamma-lactam (these lactan are cyclic amide) with the intramolecularly of carboxyl functional group, particularly when carboxyl be when protecting by ester group.This by product is the formation meeting toxigenicity in vivo of lactan.Therefore, in some specific embodiments, connect this two portions, will reduce or avoid in vivo to form lactan in the building-up process with conjugates, thereby the potential side effect is reduced by amino.

In the synoptic diagram hereinafter; when the amino of GABA analogue with after second section (can be anodyne or other blocking groups) is connected; carboxyl can be converted into ester group or thioester substrate by many synthetic methods, and these methods are known the pharmacy field technician.Under a concrete reaction scheme of selecting in advance, the GABA analogue can with alcohol or mercaptan, the coupling catalyzer (as, carbodiimide and dimethyl aminopyridine) catalysis reaction down, thereby obtain ester.In another preferred specific embodiments, the GABA analogue can react in the presence of alkali with alkylogen, thereby obtains ester.After reference content provided by the invention, the pharmacy field technician also can have the ability to utilize other synthetic method that the GABA analogue is converted into ester or thioesters.

Synoptic diagram 1

(among the figure, coupling agent=coupling catalyzer, Base=alkali, drug=medicament, fromdrug=are from other medicament, and the translator annotates)

As illustrate shown in Figure 1ly, the medicament that contains carboxylic acid can directly be coupled on the end amino of derivative (1) of GABA analogue, thereby obtains affixture (2).The reagent that is used to carry out this reaction is known to those skilled in the art, includes but not limited to carbodiimide, ammonium salt, phosphonium salt etc.In addition, come from medicament carboxyl reaction can by form acyl chlorides, acid anhydrides activate, then alkali (as, oxyhydroxide, tertiary amine etc.) existence react with GABA analogue (1) down, this also can be used for synthesizing (2).

Synoptic diagram 2

(among the figure, drug=medicament, from drug=be from medicament, base=alkali, and the imidazolyl=imidazolyl, the 4-nitrophenoxy=4-nitro-phenoxy, the translator annotates)

As illustrate shown in Figure 2, the derivative of GABA analogue (1) can be connected base by carbamate or thiocarbamate with the medicament that contains hydroxylic moiety and connect: at first with alcohol and phosgene, diimidazole aminocarbamic acid ester or two p-nitrophenyl carbonic ethers, under the condition of alkalescence, react, under alkaline environment, add the GABA analogue then.In addition, also can adopt other commonly used with alcohol and isocyanic ester (4) isothiocyanic acid ester (5), to synthesize (3) and (6).

Synoptic diagram 3

(Base=alkali, from drug=are from medicament, and the translator annotates)

Illustrate that shown in Figure 3 is a kind of method of GABA-medicament conjugates of synthesis type (8).At first, in the presence of alkali, handle chloro-formic ester with aromatics leavings group such as p-NP, obtain the p-nitrophenyl carbonic ether, the p-nitrophenyl carbonic ether reacts with the medicament that contains carboxylic acid in the presence of sodium iodide and alkali (tertiary amine, Cs2CO3, Ag2CO3), obtains compound (7).In the presence of alkali, handle intermediate (7) with the GABA analogue, obtain the GABA-medicament conjugates of formula (8).

Synoptic diagram 4

(Base=alkali, drug=medicament, from drug=are from medicament, and the translator annotates)

Illustrate that shown in Figure 4 is the synthetic method of the GABA-medicament conjugates of formula (10).At first, in the presence of alkali, handle chloro-formic ester, obtain intermediate (9) with the GABA analogue, intermediate (9) then in the presence of sodium iodide and alkali with the medicament reaction of hydroxyl, obtain final GABA-medicament conjugates (10).

Synoptic diagram 5

(among the figure, drug=medicament, from drug=be from medicament, base=alkali, and the imidazolyl=imidazolyl, the 4-nitrophenoxy=4-nitro-phenoxy, acetone=acetone, the translator annotates)

Illustrate that shown in Figure 5 is the method for the GABA-medicament conjugates of synthesis type (14).The medicament that contains hydroxy functional group at first reacts under the condition of alkali with chloro-formic ester (or other active amino manthanoate or carbonic ethers).Adopt halogen exchange reaction to obtain intermediate (13), intermediate (13) in the presence of carbonic acid gas, with the reaction of GABA analogue, obtains the GABA-medicament conjugates of formula (14) under alkaline environment.

Synoptic diagram 6

(among the figure, from drug=is from medicament, base=alkali, and the imidazolyl=imidazolyl, the 4-nitrophenoxy=4-nitro-phenoxy, deprotection=separates protection, the translator annotates)

Illustrate that shown in Figure 6 is GABA-medicament conjugates synthetic of formula (17).Activatory chloro-formic ester (or other active amino manthanoate or carbonic ethers) derived from medicament reacts in the presence of alkali with the Alpha-hydroxy alkyl acetates, obtains carbonic ether.Ester is removed then, obtains intermediate (15).Compound (15) reacts in the presence of alkali and sodium iodide with the carbonic ether that halogen replaces, and forms compound (16).Compound (16) then with the coupling under alkaline environment of GABA analogue, obtain the final compound of formula (17).

Synoptic diagram 7

(among the figure, from drug=is from medicament, base=alkali, and the imidazolyl=imidazolyl, the 4-nitrophenoxy=4-nitro-phenoxy, coupling agent=coupling catalyzer, the translator annotates)

Illustrate that shown in Figure 7 is GABA-medicament conjugates synthetic of formula (18).Activatory chloro-formic ester (or other active amino manthanoate or carbonic ethers) derived from medicament reacts under alkaline environment with the Alpha-hydroxy alkyl acetates, removes ester then, obtains compound (15).Ester in the compound (15) then with the coupling of GABA analogue, obtain the final compound of formula (18).

On the other hand, the invention provides a kind of GABA-medicament conjugates, the first part of described conjugates, as the GABA analogue, the carboxyl by first part is a hydroxy-acid group, is connected with the medicament of second section; The amino of first part is that the N-end group is connected with blocking group.This structure of conjugates is avoided or has been reduced the formation that can increase side effect and toxic lactan.

That described blocking group comprises is amino acid based, imido grpup, carbamate groups, N-dithiosuccinimide base, list or dialkyl amido phosphoric acid ester or acyloxy carbamate groups.

Synoptic diagram 8

(among the figure, base=alkali, deprotection=separates protection, the drug=medicament, the translator annotates)

Illustrate that shown in Figure 8 is that the GABA-medicament conjugates of formula (21) is by carboxyl synthetic method.Initial GABA analogue at first reacts under alkaline condition with the chlorination dialkyl phosphate.After ester (19) was separated protection, free carboxylic acid (20) reacted under alkaline environment with chlorine then, obtained final amino protected final medicament conjugates to prevent that lactan from forming.

Connect base

Among the present invention, first part and second section are covalently bound.In some specific embodiments, these two portions connect by connecting base.Can be used for connection base of the present invention and include, but are not limited to following radicals:

Physiological unstable the connection can be under the physiological condition near physiological fluid such as blood plasma unsettled any suitable connection base.Described connection base can be direct key (connecting as, amide group, ester group, carbonate group, carbamate groups, acyloxy carbamate groups, sulfonate group or sulphamate group) or can be linking group (as C1-C12 glycol, C1-C12 hydroxyl alkane acid, C1-C12 hydroxyalkyl amine, C1-C12 diacid, C1-C12 amino acid or C1-C12 diamines).Particularly preferred connection base is the direct base that is connected of amide group, ester group, carbonate group, carbamate groups and sulfamate; And by being connected that succsinic acid, Whitfield's ointment, diglycollic acid, oxygen acid (oxa acids), oxygen methylene radical (oxamethylene) and their halogenide carry out.Described be connected under the physiological condition (meaning that usually the pH value is about 6～8) is unsettled.The unstable of this connection depend on the accurate pH value of connection base, physiological fluid of used particular type and ionic strength and can catalytic body in hydrolysis reaction enzyme existence whether.Usually, describedly be connected intravital unstable,, can measure with respect to the stable connection of the compound that is not dissolved in physiological fluid.Like this, although compounds more of the present invention are relatively stable in some physiological fluid, but with they for pure form or be dissolved in and compare in the non-physiological fluid (as non-aqueous solvent such as acetone), they are (or external in vivo, in being dissolved in physiological fluid, spontaneous generation or simulate) relatively easy hydrolysis.Thereby, described unsettled such connection that is connected to, when medicament was dissolved in aqueous solvent, particularly in physiological fluid such as the blood plasma, reaction was actuated to obtain hydrolysate.

Although diacid mentioned above, glycol, amino acid etc. are suitable connection bases, other connect base and are also contained within the present invention.For example, although the hydrolysate of compound of the present invention can contain diacid, be used to form the basic actual reagent of connection and can be, for example two carboxylic acid halides (as succinyl dichloride) or acid anhydrides (as succinyl oxide or anhydride diethylene glycol).One skilled in the art will realize that other possible acid, pure, amine, sulfato and sulfonamide also can be used as preparation and be connected basic reagent accordingly.

IV. pharmaceutical composition of the present invention

Another aspect of the present invention relate to contain GABA-medicament covalent coupling thing of the present invention or with formulation, route of administration and the effective dose of the pharmaceutical composition of other treatment medicament.

Compound of the present invention can administration the form of pharmaceutical formulation comprise that those are suitable for the formulation of oral cavity (comprise and sucking and the hypogloeeis), rectum, nose, part, transdermal patch, lung, vagina, suppository or non-enteron aisle (comprise in intramuscular, intra-arterial, the sheath, intracutaneous, intraperitoneal, subcutaneous and intravenously) administration, or to be suitable for atomizing, sucking or be blown into the formulation of administration.The general information of drug delivery system can be referring to Ansel et al., Pharmaceutical DosageForms and Drug Delivery Systems (Lippencott Williams﹠amp; Wilkins, Baltimore Md. (1999).

In different specific embodiments, described pharmaceutical composition comprises that carrier and vehicle (comprise, but be not limited to, buffer reagent, carbohydrate, N.F,USP MANNITOL, protein, polypeptide or amino acid such as glycine, antioxidant, fungistat, sequestrant, suspension agent, thickening material and/or sanitas), water, oil (comprises, but be not limited to, derive from oil, animal, those of plant or synthetic oil, as peanut oil, soybean oil, mineral oil, the sesame wet goods), salts solution, glucose and aqueous glycerin solution, perfume compound, tinting material, release agent and other acceptable additive, auxiliary agent or binding agent are used for other pharmaceutically acceptable auxiliary agent near physiological condition (as the pH buffer reagent, tension regulator, emulsifying agent, wetting agent etc.).The general method of pharmaceutical formulation is referring to Ansel et al., Pharmaceutical Dosage Formsand Drug Delivery Systems (Lippencott Williams﹠amp; Wilkins, Baltimore Md. (1999)).Will be appreciated that although any appropriate carriers well known by persons skilled in the art all can be used for the administration of composition of the present invention, the type of carrier still can change along with administering mode.

In general, pharmacy acceptable salt is those inorganic salt, for example, and sodium, potassium, calcium, magnesium ion etc.Described salt comprises and mineral acid or organic acid salt, example hydrochloric acid, Hydrogen bromide, phosphoric acid, nitric acid, sulfuric acid, methylsulfonic acid, tosic acid, acetate, fumaric acid, succsinic acid, lactic acid, amygdalic acid, oxysuccinic acid, citric acid, tartrate or toxilic acid.In addition, if contain carboxyl or other acidic-groups in the medicament, described medicament can react with inorganic or organic bases, and changes into the acceptable salt of medication.The example of suitable alkali includes, but not limited to sodium hydroxide, potassium hydroxide, ammonia, hexahydroaniline, dicyclohexylamine, thanomin, diethanolamine, trolamine etc.

Described medicament (or its pharmacy acceptable salt, ester or acid amides) can be with itself or with the form administration of pharmaceutical composition, and the active agents in the described composition is the mixture with one or more pharmaceutically acceptable carriers.Pharmaceutical compositions for use of the present invention can be the composition of any patient's administrable.Pharmaceutical compositions for use can adopt one or more pharmaceutically acceptable carriers among the present invention, composition according to the ordinary method preparation, described carrier comprises vehicle, thinner and/or auxiliary agent, for example, helps active agents is sneaked into auxiliary agent in the preparation of administration.Suitable formulation depends in part on selected route of administration at least.Used medicament among the present invention, or its pharmacy acceptable salt, ester or acid amides, can adopt multiple route of administration or mode to give patient, include but not limited to, the oral cavity, suck, part, rectum, transdermal, use, and suck through mucous membrane, subcutaneous, intravenously and intramuscular.

Preferred composition of the present invention is to be used for orally administering, particularly the formulation of oral cavity sustained-release administration.For orally administering, GABA-medicament conjugates can mix active GABA-medicament conjugates with pharmaceutically acceptable carrier well known in the art, thereby is easy to preparation.Described carrier can make GABA-medicament conjugates of the present invention make tablet, include but not limited to, chewable tablet, pill, dragee, capsule, lozenge, hard candy, liquid, gel, syrup, paste, powder, suspension, elixir, thin slice etc., patient can be from orally administer when treatment.These formulations can comprise pharmaceutically acceptable carrier, and described carrier includes but not limited to, solid diluent or filler, sterile liquid medium and various atoxic organic solvent.Solid carrier can be one or more materials, and it also can play thinner, perfume compound, solubilizing agent, lubricant, suspension agent, tackiness agent, sanitas, tablet disintegrant or packing material.

When the orally administering formulation of preparation compound of the present invention, the stomach resorting agent is adopted in expectation, to improve the absorption from stomach and intestine (GI) road.The formulation of being detained a few hours at stomach can slowly discharge compound of the present invention, and the preferred slowly-releasing of institute in specific embodiments more of the present invention is provided.This stomach resorting agent is at Klausner, E.A.; Lavy, E.; Barta, M.; Cserepes, E.; Friedman, M.; Hoffman, " Novel gastroretentive dosage forms:evaluation ofgastroretentivity and its effect on levodopa in humans. " Pharm.Res.20 A.2003,1466-73, Hoffman, A.; Stepensky, D.; Lavy, E.; Eyal, S.Klausner, E.; Friedman, " Pharmacokinetic and pharmacodynamic aspects of gastroretentivedosage forms " Int.J.Pharm.11 M.2004,141-53, Streubel, A.; Siepmann, J.; Bodmeier, R.; 2006 " Gastroretentive drug delivery systems " Expert Opin.Drug Deliver.3,217-3, and Chavanpatil, M.D.; Jain, P.; Chaudhari, S.; Shear, R.; Vavia, open among P.R. " Novel sustained release, swellable and bioadhesive gastroretentive drugdelivery system for olfoxacin " the Int.J.Pharm.2006 epub March 24.Expansible, buoyant and bioadhesion technology can make compound of the present invention obtain maximum absorption in vivo.

Compound of the present invention can be mixed with the various dissimilar parenterai administrations (as by injection, for example bolus injection or lasting infusion) that are used for, for example: unit dosage form, be pre-charged with the syringe form, and they can contain sanitas.Described composition also can be following form: the suspension in oiliness or aqueous medium, solution or emulsion, for example solution in the water-based polyoxyethylene glycol.

V. methods of treatment

The invention provides prevention and methods of treatment, treat the compound of the present invention or the pharmaceutical composition of significant quantity to the patient of needs.In some specific embodiments, compound of the present invention comprises first part and second section, and described first part is amino covalently bound with second section by end, and wherein said first part is γ-An Jidingsuan (GABA) or GABA analogue or derivative.In other specific embodiments; the compound of the present invention that is used to prevent and/or treat disease comprises first part and second section; described first part is covalently bound by end carboxyl and second section; the end of described first part is amino to be connected with blocking group, and wherein said first part is analogue or the derivative of γ-An Jidingsuan (GABA) or GABA.

Suitable patient can be, people for example, non-human primate's (including but not limited to gorilla, chimpanzee, orangutan or monkey), rodent (including but not limited to mouse, rat, cavy or gerbil jird), dog, cat, horse, ox, pig, sheep, rabbit or goat.The patient is preferably Mammals, most preferably is the people.

In some specific embodiments, GABA-medicament conjugates of the present invention and/or pharmaceutical composition are to Mammals, people preferably, (described pain includes but not limited to treatment neurological disorder, epilepsy or pain in administration, the pain of the pain of maincenter mediation, periphery mediation, with the pain (that is oncology) and the neuropathic pain of structural or the pain that soft tissue injury is relevant, gradual disease-related; It is acute that all these pain all comprise (is before acute injury or wound, the art and postoperative, headache is as migraine), chronic (being neuropathic pain such as diabetes peripheral nerve obstacle and postherpetic neuralgia) and inflammatory (promptly, the sequela of osteoarthritis or rheumatoid arthritis, acute injury or wound) pain), depression, anxiety, psychosis, faint, hypokinesia, head disease, neurodegenerative disease, alarmed, insomnia, gastrointestinal disorder, addictive disorders (as, alcohol, Cocaine), restless leg syndrome.

In other specific embodiments, GABA-medicament conjugates of the present invention and/or composition are to animal, preferably be the people, can be used as preventing/preventive measures of various diseases, described disease includes but not limited to that (described pain includes but not limited to for neurological disorder, epilepsy or pain, the pain of the pain of maincenter mediation, periphery mediation, with the pain (that is oncology) and the neuropathic pain of structural or the pain that soft tissue injury is relevant, gradual disease-related; It is acute that all these neuropathic pains all comprise (is before acute injury or wound, the art and postoperative, headache is as migraine), chronic (being neuropathic pain such as diabetes peripheral nerve obstacle and postherpetic neuralgia) and inflammatory diseases (promptly, the sequela of osteoarthritis or rheumatoid arthritis, acute injury or wound) pain), depression, anxiety, psychosis, faint, hypokinesia, head disease, neurodegenerative disease, alarmed, insomnia, gastrointestinal disorder, addictive disorders (as, alcohol, Cocaine), restless leg syndrome.

In other specific embodiments, GABA-medicament conjugates of the present invention and/or composition are used to prevent a kind of disease, are used for the treatment of other diseases mentioned above simultaneously, for example, GABA-medicament conjugates can be used as and prevents from psychosis or habituation to be used for the treatment of pain simultaneously.

Administration

GABA-medicament conjugates of the present invention and/or composition can be individually dosed, or with one or more pharmaceutically active substances Combined Preparation, described pharmaceutically active substances includes but not limited to other compounds of the present invention.

Contain one or more GABA-medicament conjugates of the present invention and/or compositions, preferably pass through orally administering.GABA-medicament conjugates of the present invention and/or composition also can be by any parenteral route administrations, for example infusion or bolus injection, the absorption (as oral mucosa, rectum and intestinal mucosa etc.) by epithelium or mucocutaneous system.Administration can be whole body administration or topical.The known drug delivery system that is used for GABA-medicament conjugates of the present invention and/or composition as, liposome encapsulation, particulate, microcapsule, capsule etc.Medication comprises, but be not limited to, in intracutaneous, intramuscular, intraperitoneal, intravenously, subcutaneous, the nose, in the epidural, oral cavity, hypogloeeis, brain, intravaginal, transdermal, rectum, suction, impose on ear, nose, eye or skin partly, especially, the IV part is described such as mentioned.GABA-medicament conjugates of the present invention and/or composition can be individually dosed, or with one or more pharmaceutically active substances Combined Preparation, described pharmaceutically active substances includes but not limited to other compounds of the present invention.

In some preferred specific embodiments, GABA-medicament conjugates of the present invention and/or composition can pass through the slow-released system administration, are preferably the oral cavity slow-released system.In a specific embodiments, can adopt pump (referring to, Langer, supra; Sefton, 1987, CRC Crit Ref Biomed Eng.14,201; Saudek et al., 1989, N.Engl.J.Med.321,574).In another embodiment, can adopt polymkeric substance (referring to " Medical Applications of Controlled Release, " Langer andWise (eds.), CRC Pres., Boca Raton, Florida (1974); " Controlled DrugBioavailability, " Drug Product Design and Performance, Smoln and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J.Macromol.Sci.Rev.Macromol Chem.23:61; See also Levy et al., 1985, Science 228:190; During etal., 1989, Ann.Neurol.25:351; Howard et al., 1989, J.Neurosurg.71:105).In a preferred specific embodiments, polymkeric substance can be used to the oral cavity sustained-release administration.Preferred polymkeric substance includes but not limited to that Xylo-Mucine, hydroxypropylcellulose, Vltra tears and Natvosol are most preferably Vltra tears.Also existing (Alderman, the Int.J.Pharm.Tech.﹠amp of describing of other preferred ether of cellulose; Prod.Mfr., 1984,5 (3) 1-9).The factor that influences medicament release is known to those skilled in the art, and existing in the prior art describe (Bamba et al., Int.J.Pharm., 1979,2,307).

In other specific embodiments, the casing preparation can be used to the oral cavity sustained-release administration.Preferred coating material includes but not limited to, has the deliquescent polymkeric substance (being the pH controlled release) that pH relies on, have polymkeric substance low or the dependent swelling of pH, dissolving or erosion rate (being the time controlled release), form the polymkeric substance (being the pressure controlled release) of the upborne pressure of energy institute destructive dura mater.

GABA-medicament conjugates of the present invention and/or composition can be cut off by chemistry and/or enzyme effect.But one or more enzyme enzymes that exist in mammiferous stomach, enteric cavity, intestinal tissue, blood, liver, brain or any other suitable tissue cut off the connection base of GABA-medicament conjugates of the present invention and/or composition.The cut-out mechanism of GABA-medicament conjugates may be known in the art, and is perhaps unknown or to association area and Yan Shixin.The connection base of GABA-medicament conjugates of the present invention and/or composition can be cut off before by gastrointestinal absorption and/or by (as in mammiferous intestinal tissue, blood, liver or other suitable tissues) after the gastrointestinal absorption.If the connection base of GABA-medicament conjugates of the present invention was cut off before being absorbed by intestines and stomach, medicament and GABA analogue can be entered in the body circulation by active transport and/or passive diffusion absorption usually.

Dosage

Be suitable for pharmaceutical composition used in this invention and comprise that activeconstituents is the composition that exists with significant quantity, described significant quantity promptly can obtain to treat and/or prevent the effective content of effect in the host of the pain of suffering from least a type or neurological disorder.The significant quantity of GABA-medicament conjugates of the present invention is in order to treat or preventing disease, described disease includes but not limited to, pain (relaxing tumor pain) and neuropathic pain, (comprise acute pain, be acute injury or wound, preceding and the postoperative of art, headache is as migraine, or chronic pain, be that neuropathic pain is as diabetes peripheral nerve obstacle and postherpetic neuralgia and inflammatory, be osteoarthritis or rheumatoid arthritis, the pain of the sequela of acute injury or wound), depressed, anxiety, psychosis, faint, hypokinesia, the head disease, neurodegenerative disease, in alarm, insomnia, gastrointestinal disorder, addictive disorders (as, alcohol, Cocaine), restless leg syndrome.

Those skilled in the art can monitor the effect of patient after the particular agent administration.For example, pain scores (pain scale) can be measured according to the standard method of this area.

VII. using method

Combination therapy

In some specific embodiments of the present invention, GABA-medicament conjugates of the present invention can be used in the combination therapy with at least a other treatment medicament.The effect of GABA-medicament conjugates of the present invention and medicament can add up, more preferably synergy.

Combination therapy comprises with a part of administration as a concrete treatment plan of conjugates of the present invention and at least a second medicament, with the effect that obtains to obtain after these medicament actings in conjunction.The beneficial effect of combination therapy includes, but not limited to by the pharmacokinetics of the combination acquisition of these medicaments or the common result of pharmacodynamics.

B. reduce side effect and improve curative effect

The present invention has also specifically described a kind of method that reduces the side effect that disease treatment brings and/or improve curative effect, and described method is conjugates of the present invention or the pharmaceutical composition that applies the treatment significant quantity to the patient of needs.

The method of pharmacy of the toxicity of conjugates of the present invention and curative effect available standards is measured on experimental animal, as measures the IC50 of tested compound and LD50 (lethal dose that causes 50% death in tested animal).

In a specific embodiments, compound of the present invention has reduced the generation of the undesirable side effect that is brought owing to various pain therapy schemes, and described side effect includes, but not limited to stomach side effect, cognitive impairment, feels sick and constipation.In another embodiment, with each not the independent medicament administration of coupling compare, composition of the present invention can obtain sufficient pain and slow down effect under lower dosage.In another embodiment, composition of the present invention has the pharmacokinetics and the physiological characteristics of improvement, include but not limited to, the absorption of slower whole body removing and the GABA analogue that improves, thus make these medicaments when treatment pain or other nervus centralis diseases, can reach the effect of their the best.In another embodiment, adopt slow release formulation that composition of the present invention is carried out administration, further reduced the whole body fast of active agents and removed, described active agents is the GABA analogue.Because GABA analogue such as baclofen, gabapentin and lyrica, in small intestine, by the absorption of neutral amino transporter system, rather than in large intestine, absorb, composition of the present invention makes the GABA analogue can successfully adopt release method.

Although this paper describes and listed preferred specific embodiments of the present invention, clearly, to those skilled in the art, these specific embodiments only are that the mode with example provides.To those skilled in the art, without departing from the scope of the present invention, can carry out various changes, variation and replacement.Will be understood that, also can implement the present invention the various changes of specific embodiments of the present invention.Below the purpose of claims be to limit scope of the present invention, with and cover method and structure within these claim scopes.

Embodiment

Embodiment 1: lyrica-Naproxen Base conjugates synthetic

The invention provides a kind of method that is used for synthetic GABA-medicament conjugates.Embodiment has hereinafter described the synthetic of GABA analogue-NSAID conjugates, the lyrica of saying so more specifically-Naproxen Base conjugates prevailingly.

Embodiment 2: gabapentin-GHB conjugates synthetic

Present embodiment provides GABA analogue-gamma-hydroxybutyric acid (GHB) conjugates, the synthetic method of the gabapentin of saying so more specifically-GHB conjugates prevailingly.

Embodiment 3:GABA _BSynthesizing of agonist-morphine conjugates

Present embodiment provides the synthetic method of GABA receptor stimulant-opiate anodyne conjugates, and GABA more specifically says so _BAgonist-morphine conjugates.

Above the embodiment that is provided should be considered to schematically, rather than restrictive, and the present invention should not be limited to the various details that provide herein, can change within the scope of the invention and is equivalent of the present invention.

Embodiment 5: chemical stability

In order to carry out the chemically stable Journal of Sex Research, prepared pH 2.0 (adopting 0.1M potassiumphosphate and 0.5MNaCl), the damping fluid of pH 7.4 and pH 8.0 (adopting 0.1M Tris-HCl and 0.5M NaCl).Compound (5 μ M) was cultivated 1 hour down at 37 ℃ with damping fluid, and temperature is controlled by the HPLC self-actuated sampler.After adding 0 and 1 hour, inject sample.Sample is analyzed with LC/MS/MS, and is as mentioned below.

Embodiment 6: metabolic stability

Plasma stability: compound (5 μ M) in 90% rat or human plasma, was cultivated 1 hour down at 37 ℃.Sampling after adding 0 and 1 hour, and use the methyl alcohol cancellation immediately, to prevent further conversion.Before the analysis, the sample of cancellation is frozen, and is kept under-80 ℃.Sample is analyzed with LC/MS/MS, and is as mentioned below.

Liver homogenate: in rat or people's liver S9, under 0.5mg protein/mL, there is 1mM NADPH in compound (5 μ M), under pH 7.4 and the 37oC, was cultivating 1 hour.Sampling after adding 0 and 1 hour, and use the methyl alcohol cancellation immediately, to prevent further conversion.Before the analysis, the sample of cancellation is frozen, and is kept under-80 ℃.Sample is analyzed with LC/MS/MS, and is as mentioned below.

The Caco-2 cell homogenates: the Caco-2 cell was grown in flask 21 days.To be cleaned/to scrape ice-cold pH value be in 10mM sodium phosphate/0.15M Repone K of 7.4 to cell then.Cell carries out ultrasonic dissolution with probe ultrasonic disruption instrument down at 4 ℃, at 4 ℃, 9, centrifugation is 20 minutes under the 000x g, the supernatant liquor that obtains (Caco-2 cell homogenates S9 composition) aliquots containig is transferred in the bottle of 0.5mL, is kept under-80 ℃ before using.In order to carry out stability study, (0.5mg protein/mL) was cultivated 1 hour down pH 7.4 and 37 ℃ with Caco-2S9 with compound (5 μ M).Sampling after adding 0 and 1 hour, and use the methyl alcohol cancellation immediately, to prevent further conversion.Before the analysis, the sample of cancellation is frozen, and is kept under-80 ℃.Sample is analyzed with LC/MS/MS, and is as mentioned below.

Pancreas enzyme: compound (5 μ M) in pig pancreas enzyme (10mg/mL is in the damping fluid of pH 7.5), was cultivated 1 hour down at 37 ℃.Sampling after adding 0 and 1 hour, and use the methyl alcohol cancellation immediately, to prevent further conversion.Before the analysis, the sample of cancellation is frozen, and is kept under-80 ℃.Sample is analyzed with LC/MS/MS, and is as mentioned below.

Embodiment 7:GABA analogue, anodyne or GABA-medicament conjugates are after carrying out the colonic administration to rat, the oral cavity slow release formulation of the absorption of the anodyne of GABA analogue and coupling slow release medicine in 6-24 hour, the general dosage that in colon, discharges considerable part.Like this, the pharmacy optimization that is applicable to this formulation has good colon absorptivity.This test is whether to be applicable to the oral cavity slow release formulation in order to assess GABA-medicament conjugates.

Steps A: dosage regimen

Rat is by commercially available, and inserts conduit in ascending colon and jugular vein in advance.At the trial, animal should be conscious.All animals all are one nights of fasting, until administration after 4 hours.Compound with designed dosage, directly enters colon by conduit with the form of solution (in water or in other solvents as PEG 400).Obtain 8 hours blood sample (0.5mL) by the neck conduit, add acetonitrile/methanol then immediately, to prevent the further conversion of GABA-medicament conjugates.The analysis of blood vide infra.

Step B: colon absorbs the specimen preparation of medicament

In the 1.5mL of sky eppendorf test tube, add 50/50 acetonitrile/methanol of 300 μ L and the fenclonine of 20 μ L, as interior mark.

Gather rat blood at different time points, immediately 100 μ L blood are added in the eppendorf test tube, rotation mixes.

GABA analogue or the anodyne standardized solution (0.04,0.2,1,5,25,100 μ g/mL) of 10 μ L are added in the blank rat blood of 90 μ L, make final calibration standard (0.004,0.02,0.1,0.5,2.5,10 μ g/mL).50/50 acetonitrile/methanol that adds 300 μ L then in each test tube adds the fenclonine of 20 μ L again.

The rotation sample, 14, centrifugation is 10 minutes under the 000rpm.

Take out supernatant liquor, analyze with LC/MS/MS.

Step C:LC/MS/MS analyzes.

In analysis, adopt the LC/MS/MS spectrograph that 10ADVp double pump and CTC HTS-PAL self-actuated sampler are housed.In analytic process, used separator column is heated to 45 ℃.Mobile phase can be different solvent mixtures, the formic acid as 0.1% (A) and contain the acetonitrile (B) of 0.1% formic acid.Can change the concentration of solvent according to the compound of being analyzed with gradient condition.On LC/MS/MS, can adopt TurboIonSpray source such as API 2000.Described analysis can be carried out under positively charged ion and negatively charged ion pattern, and the MRM monitoring can be selected according to the compound of being analyzed.Inject the sample of 20 μ L.Can quadrature with Analyst 1.1 quantitative analysis softwares in the peak.After the colon administration of these GABA-medicament conjugates, with the maximal plasma concentration (Cmax) of GABA analogue and anodyne, and the area under a curve of the plasma concentration of GABA analogue and anodyne and time (AUC) compares with female medicine.The conjugates of expectation should have higher Cmax separately than GABA analogue and anodyne, and bigger AUC value.This digital proof compound of the present invention can be by compositions formulated, said composition has the absorptivity of raising and/or the anodyne of GABA analogue and selection is had effective slow releasing function, so that because the quick whole body of GABA analogue is removed the frequency of taking medicine that is caused minimizes.

Embodiment 8: after to the macaque intravenous administration, and the pharmacokinetics of the GABA analogue of coupling or the anodyne of coupling

To 4 male rhesus macaques, apply the GABA analogue or the anodyne of aqueous solution form, administration is that the dosage that will design enters the saphena blood vessel by an intravenous shot.After administration, surpass 24 hours at interval, blood sampling from all animals.Blood is processed into blood plasma immediately under 4 ℃.All blood plasma samples adopt LC/MS/MS method mentioned above to analyze GABA analogue or anodyne subsequently.

Embodiment 9: after GABA analogue or GABA-medicament conjugates carry out the colonic administration to macaque,

The absorption of the anodyne of GABA analogue or coupling

To 4 male rhesus macaque groups, apply the aqueous solution form of design dosage or GABA analogue, anodyne and the GABA-medicament conjugates of suspensoid form, administration is to carry out disposable injection by the intubate of keeping somewhere, and directly enters colon.For colon administration, the legal system conduit of flexibility is inserted the rectum of every monkey, adopt fluoroscopy to extend to PC (about 16 inches) then.In the administration process, monkey is applied the Telazol/ ketamine, make its mild sedation.Between two treatments, can there be at least 5～7 days removing phase.After the administration, surpass 24 hours at interval, blood sampling, and cancellation immediately are processed into blood plasma under 4 ℃.Adopt LC/MS/MS method mentioned above to analyze the GABA analogue of all blood samples, anodyne and unchanged GABA-medicament conjugates.After the colon administration of GABA-medicament conjugates, the maximal plasma concentration of GABA analogue and anodyne (Cmax), and the area under a curve of the plasma concentration of GABA analogue and anodyne and time (AUC), be far longer than GABA analogue self separately to the value behind the colon administration.These GABA-medicament conjugates of this digital proof can be by compositions formulated, said composition has the absorptivity of raising and/or the GABA analogue is had effective slow releasing function, so that because the quick whole body of GABA analogue is removed the frequency of taking medicine that is caused minimizes.

Embodiment 10:GABA-medicament conjugates carries out macaque after the orally administering,

The absorption of the anodyne of GABA analogue and coupling

To 4 male rhesus macaque groups, apply the GABA-medicament conjugates of aqueous solution form or suspensoid form respectively, administration is that through port lumen feeding is carried out.After the administration, surpass 24 hours at interval, blood sampling, and under 4 ℃, be processed into blood plasma immediately.Adopt LC/MS/MS method mentioned above to analyze the GABA analogue of all blood samples, anodyne and unchanged GABA-medicament conjugates subsequently.

Although preferred specific embodiments of the present invention has been described in this article, to those skilled in the art, clearly, these specific embodiments only are that the form with example provides.To those skilled in the art, without departing from the scope of the present invention, can carry out various changes, variation and replacement.Will be understood that, also can implement the present invention the various changes of specific embodiments of the present invention.Below the purpose of claims be to limit scope of the present invention, it has covered method and structure within these claim scopes and their equivalent.

Claims (62)

1. a compound comprises first part and second section, and described first part is by holding amino or the acidic endgroups except that carboxyl and second section covalently bound, and wherein said first part is γ-An Jidingsuan or gamma-aminobutyric acid analog or derivative.

2. compound; comprise first part and second section; described first part is covalently bound by carboxyl and second section, and the end of described first part is amino to be connected with blocking group, and wherein said first part is γ-An Jidingsuan or gamma-aminobutyric acid analog or derivative.

3. compound as claimed in claim 1 or 2, wherein said first part is a gamma-aminobutyric acid analog.

4. compound as claimed in claim 3, wherein said first part is baclofen, vigabatrin, gabapentin or lyrica or gamma-amino-phosphonate derivative.

5. compound as claimed in claim 1 or 2, wherein said second section is an anodyne.

6. compound as claimed in claim 5, wherein said second section are on-steroidal antiphlogistic drug, opiates medicament or antidepressive.

7. compound as claimed in claim 1 or 2, wherein said second section are analogue, derivative or the variants of gamma-hydroxybutyric acid or gamma-hydroxybutyric acid.

8. compound as claimed in claim 1 or 2, wherein said first part and second section are to be connected by the covalent linkage that is selected from following group: ester bond, amido linkage, imine linkage, amino-formate bond, carbonic acid ester bond, thioester bond, acyloxy amino-formate bond, acyloxy carbonic acid ester bond, phosphoric acid ester bond, acyloxy phosphoric acid ester bond.

9. compound as claimed in claim 1 or 2 further comprises being connected base with what described first part and second section covalency linked.

10. compound as claimed in claim 9, wherein said connection base is unsettled on the physiology.

11. compound as claimed in claim 1 or 2 further comprises ion or covalently bound to the first part of described compound or the third part of second section.

12. compound as claimed in claim 1 or 2, wherein said compound can with the coupling of at least a other treatment medicament.

13. compound as claimed in claim 12, wherein said healing potion are selected from following group: antipsychotic agent, anxiolytic, antidepressive, anticonvulsive drug, anti-Parkinson medicine, acetylcholinesterase depressant, MAO inhibitor, selective serotonin reuptake inhibitor, N-methyl-D-aspartate antagonist and selectivity norepinephrine replace inhibitor.

14. compound as claimed in claim 1, wherein said acidic endgroups comprises phosphate or sulfino.

15. that compound as claimed in claim 2, wherein said blocking group comprise is amino acid based, imido grpup, carbamate groups, N-dithiosuccinimide base, list or dialkyl amido phosphoric acid ester or acyloxy carbamate groups.

16. compound as claimed in claim 2, wherein said blocking group can cut off from the amino of described first part.

17. a pharmaceutical composition contains claim 1 or 2 described compounds and pharmaceutically acceptable carrier.

18. pharmaceutical composition as claimed in claim 17 further comprises at least a other treatment medicament.

19. pharmaceutical composition as claimed in claim 17, wherein said composition is used for the treatment of pain and/or neurological disorder.

20. method of preventing or treating disease, described method comprises the compound that applies the treatment significant quantity to the patient of needs, described compound comprises first part and second section, described first part is by holding amino or the acidic endgroups except that carboxyl and second section covalently bound, and wherein said first part is γ-An Jidingsuan or gamma-aminobutyric acid analog or derivative.

21. method of preventing or treating disease; described method comprises the compound that applies the treatment significant quantity to the patient of needs; described compound comprises first part and second section; described first part is covalently bound by carboxyl and second section; the end of described first part is amino to be connected with blocking group, and wherein said first part is γ-An Jidingsuan or gamma-aminobutyric acid analog or derivative.

22. as claim 20 or 21 described methods, wherein said first part is a gamma-aminobutyric acid analog.

23. as claim 20 or 21 described methods, wherein said first part is baclofen, vigabatrin, gabapentin, lyrica or gamma-amino-phosphonate derivative.

24. as claim 20 or 21 described methods, wherein said second section is an anodyne.

25. as claim 20 or 21 described methods, wherein said second section is on-steroidal antiphlogistic drug, opiates medicament or antidepressive.

26. as claim 20 or 21 described methods, wherein said second section is analogue, derivative or the variant of gamma-hydroxybutyric acid or gamma-hydroxybutyric acid.

27. as claim 20 or 21 described methods, wherein said first part and second section are to be connected by the covalent linkage that is selected from following group: ester bond, amido linkage, imine linkage, amino-formate bond, carbonic acid ester bond, thioester bond, acyloxy amino-formate bond, acyloxy carbonic acid ester bond, phosphoric acid ester bond, acyloxy phosphoric acid ester bond.

28. as claim 20 or 21 described methods, further comprise with described first part and second section covalently bound be connected base.

29. method as claimed in claim 28, wherein said connection base is unsettled on the physiology.

30., further comprise ion ground or covalently be connected to the first part of described compound or the third part of second section as claim 20 or 21 described methods.

31. as claim 20 or 21 described methods, wherein said compound can with the coupling of at least a other treatment medicament.

32. method as claimed in claim 31, wherein said healing potion are selected from following group: antipsychotic agent, anxiolytic, antidepressive, anticonvulsive drug, anti-Parkinson medicine, acetylcholinesterase depressant, MAO inhibitor, selective serotonin reuptake inhibitor, N-methyl-D-aspartate antagonist and selectivity norepinephrine replace inhibitor.

33. as claim 20 or 21 described methods, further comprise the pharmaceutical composition that applies the treatment significant quantity to the patient of needs, described composition comprises described compound and pharmaceutically acceptable carrier.

34. as claim 20 or 21 described methods, wherein said disease is pain or neurological disorder.

35. method as claimed in claim 34, wherein said pain are acute, chronic or inflammatory.

36. method as claimed in claim 34, wherein said patient is the people.

37. as claim 20 or 21 described methods, compare with each several part is individually dosed, it is a kind of that the administration of described compound or pharmaceutical composition causes side effect to be reduced by at least.

38. as claim 20 or 21 described methods, compare with each several part is individually dosed, the administration of described compound or pharmaceutical composition causes therapeutic activity to improve.

39. as claim 20 or 21 described methods, wherein said compound or pharmaceutical composition and other treatment medicament Combined Preparation.

40. method that is used to reduce the side effect that disease treatment brings, described method comprises the compound that applies the treatment significant quantity to the patient of needs, described compound comprises first part and second section, described first part is by holding amino or the acidic endgroups except that carboxyl and second section covalently bound, and wherein said first part is γ-An Jidingsuan or gamma-aminobutyric acid analog or derivative.

41. method that is used to reduce the side effect that disease treatment brings; described method comprises the compound that applies the treatment significant quantity to the patient of needs; described compound comprises first part and second section; described first part is covalently bound by carboxyl and second section; the end of described first part is amino to be connected with blocking group, and wherein said first part is γ-An Jidingsuan or gamma-aminobutyric acid analog or derivative.

42. as claim 40 or 41 described methods, further comprise the pharmaceutical composition that applies the treatment significant quantity to the patient of needs, described composition comprises described compound and pharmaceutically acceptable carrier.

43. as claim 40 or 41 described methods, described disease is pain or nervous system disorders or obstacle.

44. method as claimed in claim 43, described pain are acute, chronic or inflammatory.

45. method as claimed in claim 43, wherein said neurological disorder are selected from following group: pain, anxiety, depression, the disease of dissociating, personality disorder, cognitive illnesses, mood disorder, alternating insanity, neurodegenerative disease, spasm illness, Parkinson's disease, Alzheimer's, epilepsy, schizophrenia, paranoia, psychosis, Huntington Chorea, Tourette syndrome, faint, hypokinesia, head disease, neurodegenerative disease, alarmed, insomnia, addictive disorders, restless leg syndrome.

46. as claim 40 or 41 described methods, wherein said patient is the people.

47. method that is used to improve the curative effect of disease treatment, described method comprises the compound that applies the treatment significant quantity to the patient of needs, described compound comprises first part and second section, described first part is connected with second section by end amino or the acidic endgroups except that carboxyl, and wherein said first part is γ-An Jidingsuan or gamma-aminobutyric acid analog or derivative.

48. method that is used to improve the curative effect of disease treatment; described method comprises the compound that applies the treatment significant quantity to the patient of needs; described compound comprises first part and second section; described first part is connected with second section by carboxyl; the end of described first part is amino to be connected with blocking group, and wherein said first part is γ-An Jidingsuan or gamma-aminobutyric acid analog or derivative.

49. as claim 47 or 48 described methods, wherein said first part is a gamma-aminobutyric acid analog.

50. as claim 47 or 48 described methods, wherein said first part is baclofen, vigabatrin, gabapentin or lyrica.

51. as claim 47 or 48 described methods, wherein said second section is an anodyne.

52. as claim 47 or 48 described methods, wherein said second section is on-steroidal antiphlogistic drug, opiates medicament or antidepressive.

53. as claim 47 or 48 described methods, wherein said second section is gamma-hydroxybutyric acid or gamma-hydroxybutyric acid analogue, derivative or variant.

54. as claim 47 or 48 described methods, wherein said first part and second section are to be connected by the covalent linkage that is selected from following group: ester bond, amido linkage, imine linkage, amino-formate bond, carbonic acid ester bond, thioester bond, acyloxy amino-formate bond, acyloxy carbonic acid ester bond, phosphoric acid ester bond, acyloxy phosphoric acid ester bond.

55. method as claimed in claim 54, wherein said connection base is unsettled on the physiology.

56. as claim 47 or 48 described methods, wherein said compound can with the coupling of at least a other treatment medicament.

57. method as claimed in claim 56, wherein said healing potion are selected from following group: antipsychotic agent, anxiolytic, antidepressive, anticonvulsive drug, anti-Parkinson medicine, acetylcholinesterase depressant, MAO inhibitor, selective serotonin reuptake inhibitor, N-methyl-D-aspartate antagonist and selectivity norepinephrine replace inhibitor.

58. as claim 47 or 48 described methods, further comprise the pharmaceutical composition that applies the treatment significant quantity to the patient of needs, described composition comprises described compound and pharmaceutically acceptable carrier.

59. as claim 47 or 48 described methods, wherein said disease is pain or nervous system disorders or obstacle.

60. method as claimed in claim 59, wherein said pain are acute, chronic or inflammatory.

61. method as claimed in claim 59, wherein said neurological disorder are selected from following group: pain, anxiety, depression, the disease of dissociating, personality disorder, cognitive illnesses, mood disorder, alternating insanity, neurodegenerative disease, spasm illness, Parkinson's disease, Alzheimer's, epilepsy, schizophrenia, paranoia, psychosis, Huntington Chorea, Tourette syndrome, faint, hypokinesia, head disease, neurodegenerative disease, alarmed, insomnia, addictive disorders, restless leg syndrome.

62. as claim 60 or 61 described methods, wherein said patient is the people.