CN1893954A

CN1893954A - Oral administration of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)alkyl]phosphonic acid and derivatives

Info

Publication number: CN1893954A
Application number: CN 200480037340
Authority: CN
Inventors: E·J·本杰明; W·F·克劳德; M·阿什拉夫; M·伊斯拉姆; M·R·布兰德特; G·F·特伦布莱
Original assignee: Wyeth LLC
Current assignee: Wyeth LLC
Priority date: 2003-10-15
Filing date: 2004-10-14
Publication date: 2007-01-10
Also published as: AR046544A1; ZA200603035B

Abstract

Solid, pharmaceutical dosage forms of [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0]non1(7)-en-2-yl)alkyl]phosphonic acid and derivatives thereof are disclosed. In addition, methods of use are disclosed for the treatment, inter alia, of cerebral vascular disorders, anxiety disorders; mood disorders; schizophrenia; schizophreniform disorder; schizoaffective disorder; cognitive impairment; chronic neurodegenerative disorders; inflammatory diseases; fibromyalgia; complications from herpes zoster; prevention of tolerance to opiate analgesia; withdrawal symptoms from addictive drugs; and pain.

Description

[2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene (EN)-2-yl) alkyl] phosphoric acid and derivant thereof Orally administered

The cross reference of related application

[0001] the application require the U. S. application submitted on October 8th, 2,004 the _ _ number priority, the rights and interests that it requires No. the 60/511st, 560, the U. S. application submitted on October 15th, 2003 are incorporated herein by reference its whole disclosures.No. the 10/820th, 216, No. the 10/820th, 215, the U. S. application that the application relates on April 7th, 1 and submits to and the U. S. application common co-pending of submission on April 7th, 2004 are incorporated herein by reference its whole disclosures.

Technical field

[0002] the present invention relates to the solid pharmaceutical dosage formulation and the using method thereof of [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] phosphoric acid and derivant thereof.

Background technology

[0003] a lot of clinical before and clinical evidence show that N-methyl-D-aspartate (NMDA) acceptor inhibitor has a lot of treatment of conditions potential of treatment.Be considered to suppress to have the disease of response to comprise that cerebrovascular disease for example can cause a series of diseases for example cerebral ischemia (for example apoplexy) or the cerebral infarction of thromboembolia type or hemorrhagic apoplexy to nmda receptor, or cerebral vasospasm; Cerebral trauma; Muscular spasm; And convulsive disorder, for example epilepsy or status epilepticus.Nmda receptor antagonist can also be used to prevent to the tolerance of OA or help to control the withdrawal symptom of addictive drug.

[0004] screening compound has in recent years identified many nmda receptor antagonists, has used them so that the Proof of Concept (proof of concept) for the treatment of multiple disease is proved in animal and human's clinical research.The shown difficulty of clinical practice nmda receptor antagonist normally when oral administration antagonist lack selectivity and/or biological activity to the nmda receptor hypotype.

[0005] [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] phosphoric acid and derivant thereof have shown the effectiveness as nmda receptor antagonist.For example referring to US-A-5,168,103 and WO03/031,416, its whole disclosures are incorporated herein by reference.This chemical compound is very easily dissolving in the scope of pH4 to 8.A little less than apparent capryl alcohol/lipid low (the log partition coefficient is-1.37) and the Caco-2 cell permeability, thereby show low and incomplete oral absorption.Based on its highly dissoluble and hypotonicity, [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] phosphoric acid can be categorized as BCSClass 3.The animal Absorption Study shows that in the rat body this chemical compound has about 1% bioavailability with the dosage of 100mg/kg, has about 2.5% bioavailability in the monkey body with 100mg/kg dosage.Low bioavailability in this scope may increase the cost of dosage and this product.The absorption effect of food in addition, in the people, may also have the problem that blood plasma level changes between the curee, owing to may make it further complicated.

[0006] [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] phosphoric acid is crystal powder, has extremely low bulk density, flowability and poor compressibility, cause preparing capsule or tablet existing problems, comprise mixture separation, content uniformity difference and filling weight difference by dried mixing method.Can not address these problems even comprise direct compressibility excipient, especially when the needs active pharmaceutical ingredient accounts for vast scale in preparation, for example, greater than about 70% weight, in the gross weight of preparation.And, because this chemical compound has extremely low bulk density, therefore do not fill by the dry blending side of routine and contain 300mg[2-(8 through densification steps, 9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] the preparation mixture of phosphoric acid or derivatives thereof is difficult.

Summary of the invention

[0007] the invention provides pharmaceutical composition and the dosage form that comprises [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] phosphoric acid or derivatives thereof.We are surprised to find that said composition shows the oral administration biaavailability of improvement.

[0008] in one embodiment, the present invention relates to solid pharmaceutical dosage formulation, comprising:

The chemical compound of at least a formula (I) or its pharmaceutically acceptable salt:

Wherein:

R ₁Be hydrogen, C ₁To C ₆Alkyl, C ₂To C ₇Acyl group, C ₁To C ₆Alkane sulfonyl (alkanes-ulfonyl), or C ₆To C ₁₄Aroyl;

A is the alkylidene (alkylenyl) of 1 to 4 carbon atom or the alkenylene (alkenylenyl) of 2 to 4 carbon atoms;

R ₂And R ₃Independently be selected from hydrogen,

Condition is R ₂And R ₃Have at least one not to be hydrogen;

R ₄And R ₅Be independently selected from hydrogen, C ₁To C ₄Alkyl, C ₅To C ₇Aryl, have the C of 5 to 7 carbon atoms on the aromatic ring ₆To C ₁₅Aralkyl, C ₂To C ₇Thiazolinyl, or C ₂To C ₇Alkynyl, or R ₄And R ₅Can form spiral shell C jointly ₃To C ₈Carbocyclic ring;

R ₆Be C ₁To C ₁₂The alkyl of straight or branched, C ₂To C ₇The alkenyl or alkynyl of straight or branched, C ₅To C ₁₃Aryl, partly have the C of 5 to 13 carbon atoms at aromatic ring ₆To C ₂₁Aralkyl, 5 yuan to 13 yuan heteroaryl has 6 yuan to 21 yuan heteroarylalkyl of 5 to 13 atoms, C on heteroaryl moieties ₄To C ₈Cycloalkyl, have the C of 4 to 8 carbon atoms at cycloalkyl ring ₅To C ₁₆Cycloalkyl-alkyl;

R ₇And R ₈Be independently selected from hydrogen, C ₁To C ₁₂The alkyl of straight or branched, C ₂To C ₇The alkenyl or alkynyl of straight or branched, C ₅To C ₁₃Aryl, have the C of 5 to 13 carbon atoms at aryl moiety ₆To C ₂₁Aralkyl, 5 as far as 13 yuan heteroaryl, has 6 yuan to 21 yuan heteroarylalkyl of 5 to 13 atoms or R at heteroaryl moieties ₇And R ₈Can form jointly and have 4 to 8 carbon atoms on the ring and randomly be selected from nitrogen, the cycloalkyl of one or two atom or Heterocyclylalkyl in oxygen or the sulfur;

Wherein has aryl, heteroaryl, the R of cycloalkyl or Heterocyclylalkyl part ₁To R ₈Group can be chosen wantonly at aryl, heteroaryl, and cycloalkyl or Heterocyclylalkyl part independently are selected from halogen, cyano group, nitro or hydroxyl, C by 1 to about 5 ₁To C ₆Alkyl, C ₁To C ₆The substituent group of alkoxyl replace; With

At least a pharmaceutically acceptable absorption enhancer.

[0009] in another embodiment, the present invention relates to solid pharmaceutical dosage formulation, comprising: the chemical compound of at least a general formula (I) or its pharmaceutically acceptable salt:

Wherein:

R ₁Be hydrogen;

A is-(CH ₂) _n-, n is 2; With

R ₂And R ₃Be hydrogen; With

At least a pharmaceutically acceptable absorption enhancer.

[0010] in another embodiment, the present invention relates at least a method that is selected from the disease of cerebrovascular disease of treatment in mammal, described disease is selected from cerebral ischemia, cerebral infarction or cerebral vasospasm; Cerebral trauma; Muscular spasm; Be selected from the convulsive disorder of epilepsy or status epilepticus; Hypoglycemia; Asystole; Perinatal asphyxia disease; Or chorda dorsalis injury, comprise step:

Give the above-mentioned solid pharmaceutical dosage formulation that the Orally administered effective dose of mammal that needs is arranged.

[0011] in another embodiment, the present invention relates at least a method that is selected from the disease of glaucoma or diabetes end-organ complication of treatment in mammal, comprise step:

[0012] in another embodiment, the present invention relates at least a anxiety disorder that is selected from of treatment in mammal; Mood disorders; Schizophrenia; Schizophreniform disorder; Or the method for the disease of schizoaffective disorder, comprise step:

[0013] in another embodiment, the present invention relates at least a Huntington's disease that is selected from of treatment in mammal, Alzheimer, amyotrophic lateral sclerosis, chronic dementia, or the method for the neurodegenerative disease of cognitive impairment comprise step:

[0014] in another embodiment, the present invention relates to treat Parkinsonian method,

Comprise step:

[0015] in another embodiment, the present invention relates at least a inflammatory diseases that is selected from of treatment in mammal; Fibromyalgia; The herpes zoster complication; The method of the disease of the prevention of the tolerance of OA or the withdrawal symptom of addictive drug comprises step:

[0016] in another embodiment, the present invention relates to the method for treatment pain in mammal, comprise step:

[0017] in another embodiment, the present invention relates to solid, the instant-free pharmaceutical composition comprises:

Wherein:

R ₁Be hydrogen, C ₁To C ₆Alkyl, C ₂To C ₇Acyl group, C ₁To C ₆Alkane sulfonyl or C ₆To C ₁₄Aroyl;

A is the alkylidene of 1 to 4 carbon atom or the alkenylene of 2 to 4 carbon atoms;

R ₂And R ₃Be independently selected from hydrogen,

Condition is R ₂And R ₃In at least one is not a hydrogen;

R ₄And R ₅Be independently selected from hydrogen, C ₁To C ₄Alkyl, C ₅To C ₇Aryl, on aromatic ring, have the C of 5 to 7 carbon atoms ₆To C ₁₅Aralkyl, C ₂To C ₇Thiazolinyl, or C ₂To C ₇Alkynyl, or R ₄And R ₅Can form spiral shell C jointly ₃To C ₈Carbocyclic ring;

R ₆Be C ₁To C ₁₂The alkyl of straight or branched, C ₂To C ₇The alkenyl or alkynyl of straight or branched, C ₅To C ₁₃Aryl, have the C of 5 to 13 carbon atoms at aryl moiety ₆To C ₂₁Aralkyl, 5 yuan to 13 yuan heteroaryl has 6 yuan to 21 yuan heteroarylalkyl of 5 to 13 atoms, C at heteroaryl moieties ₄To C ₈Cycloalkyl, on cycloalkyl ring, have the C of 4 to 8 carbon atoms ₅To C ₁₆Cycloalkyl-alkyl;

R ₇And R ₈Be independently selected from hydrogen, C ₁To C ₁₂The alkyl of straight or branched, C ₂To C ₇The alkenyl or alkynyl of straight or branched, C ₅To C ₁₃Aryl, have the C of 5 to 13 carbon atoms at aryl moiety ₆To C ₂₁Aralkyl, 5 yuan to 13 yuan heteroaryl has 6 yuan to 21 yuan heteroarylalkyl of 5 to 13 atoms or R at heteroaryl moieties ₇And R ₈Can be formed on jointly and have 4 to 8 carbon atoms and optional one to two on the ring and be selected from nitrogen, the cycloalkyl of the atom of oxygen or sulfur or Heterocyclylalkyl;

Wherein has aryl, heteroaryl, the R of cycloalkyl or Heterocyclylalkyl part ₁To R ₈In the group any one can be chosen wantonly at aryl, heteroaryl, and cycloalkyl or Heterocyclylalkyl part independently are selected from halogen, cyano group, nitro or hydroxyl, C by 1 to about 5 ₁To C ₆Alkyl, C ₁To C ₆The substituent group of alkoxyl replace;

Wherein above-mentioned composition has the 0.5g/cm of being at least about ³Bulk density.

[0018] in another embodiment, the present invention relates to solid instant-free pharmaceutical composition, comprising:

Wherein:

R ₁Be hydrogen;

A is-(CH ₂) _n-, n is 2; With

R ₂And R ₃Be hydrogen; With

[0019] in other embodiment, the present invention relates to the single dose form.In other embodiment, the present invention relates to the multiple dose form.

[0020] in further embodiment, the present invention relates to capsule.In further embodiment, the invention still further relates to tablet.

[0021] in another embodiment, the present invention relates to method, comprise step:

Form wet granular, it comprises:

At least a binding agent;

Randomly at least a filler;

Randomly at least a disintegrating agent; With

The chemical compound of at least a formula (I) or its pharmaceutically acceptable salt; With

Form solid dosage forms.

[0022] in another embodiment, the present invention relates to product by method for preparing.

The accompanying drawing summary

[0023] Fig. 1 is accepting 200,400,800 or 1600mg [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] behind the phosphoric acid in the health volunteer as time function (hour) average single dose [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] mean plasma concentration (ng/mL) curve of phosphoric acid.

[0024] Fig. 2 is accepting 200,400,800, or 1600mg [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] behind the phosphoric acid in the health volunteer as the C of [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] phosphoric acid of the single dose of dose function (mg) _Max(ng/mL) curve.

[0025] Fig. 3 is accepting 200,400,800, or 1600mg [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] behind the phosphoric acid in the health volunteer as the single dose of dose function (mg) [2-(and 8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] AUC (ngh/mL, t=0 to the ∞) curve of phosphoric acid.

[0026] Fig. 4 is accepting 200,400,800, or 1600mg [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] behind the phosphoric acid in the health volunteer as time function (hour) average steady state plasma concentration (ng/mL) curve of [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] phosphoric acid.

[0027] Fig. 5 is accepting 200,400,800, or 1600mg [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] behind the phosphoric acid in the health volunteer as the stable state C of [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] phosphoric acid of dose function (mg) _Max(ng/mL) curve.

[0028] Fig. 6 accepts 200,400,800, or 1600mg [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] behind the phosphoric acid in the health volunteer as dose function (mg) [2-(and 8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] stable state AUC (ngh/mL, t=0 to tau (12 hours)) curve of phosphoric acid.

Detailed Description Of The Invention

[0029] as mentioned and used in running through the disclosure, following term should be appreciated that to have following implication except as otherwise noted.

[0030] as used herein, " alkyl " refers to have the aliphatic alkyl of 1 to 12 carbon atom, and the chain that includes but not limited to straight or branched is methyl for example, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, Zhong Dingji, the tert-butyl group, n-pentyl, isopentyl, neopentyl, positive hexyl, and isohesyl. " low alkyl group " refers to have the alkyl of 1 to 3 carbon atom.

[0031] as used herein, " alkylidene " refers to have the aliphatic hydrocarbon diradical of 1 to 12 carbon atom, and the chain that includes but not limited to straight or branched is methylene for example, ethylidene, positive propylidene, isopropylidene, positive butylidene, isobutylene, secondary butylidene, uncle's butylidene, positive pentylidene, isopentylidene, new pentylidene, positive hexylidene, and isohexylidene. " low-grade alkylidene " refers to have the alkylidene of 1 to 3 carbon atom.

[0032] as used herein, " thiazolinyl " refers to have the alkyl of the straight or branched that comprises 1 to 3 two key of 2 to 7 carbon atoms. The example of thiazolinyl be straight or branched list-, two-, or many unsaturated groups vinyl for example, third-1-thiazolinyl, pi-allyl, methylallyl, but-1-ene base, but-2-ene base and fourth-3-thiazolinyl.

[0033] as used herein, " alkenylene " refers to have the hydrocarbon diradical of the aliphatic straight or branched that comprises 1 to 3 two key of 2 to 7 carbon atoms. The example of alkenylene be straight or branched list-, two-, or many unsaturated groups ethenylidene for example, third-1-alkenylene (enylenyl), acrol, methylene be for pi-allyl, fourth-1-alkenylene, fourth-2-alkenylene and fourth-3-alkenylene.

[0034] as used herein, " alkynyl " refers to have the hydrocarbon chain of the aliphatic straight or branched that comprises 1 to 3 triple bond of 2 to 7 carbon atoms.

[0035] as used herein, " acyl group " refer to radicals R-C (=O)-, wherein R is the alkyl of 1 to 5 carbon atom. For example, C₂To C₇Acyl group refer to R-C (=O)-group, wherein R is the alkyl of 1 to 6 carbon atom.

[0036] as used herein, " alkane sulfonyl " refers to R-S (O)₂-, wherein R is the alkyl of 1 to 6 carbon atom.

[0037] as used herein, " aryl " refers to for example phenyl or naphthyl of aromatic 5 yuan to 13 yuan monocyclic carbocyclic ring or bicyclic carbocyclic ring. Preferably, the group that comprises aryl moiety is the monocycle that has 5 to 7 carbon atoms at ring. As used herein, " assorted aryl ", (Het Ar) refer to aromatic the having to five and independently being selected from nitrogen, heteroatomic monocycle or the dicyclo of oxygen or sulphur of 5 to 13 carbon atoms of containing. Preferably, the group that comprises heteroaryl moieties is the monocycle that has 5 to 7 atoms at ring, and wherein one or two ring element independently is selected from nitrogen, oxygen or sulphur. Comprise the group of aryl or heteroaryl moieties optional can by as give a definition and be substituted or do not replace.

[0038] as used herein, " aroyl " refer to group Ar-C (=O)-, wherein Ar is aryl as defined above. For example, C₆To C₁₄Aroyl partly refer to group Ar-C (=O)-, wherein Ar is aromatic 5 yuan to 13 yuan carbocyclic ring.

[0039] as used herein, " aralkyl " refers to group-R-Ar, and wherein Ar is aryl as defined above, and R has 1 to 8, and be preferred 1 to 6, more preferably the alkylene moiety of 1 to 4 carbon atom. The example of aralkyl comprises benzyl, phenethyl, 3-phenylpropyl and 4-benzene butyl.

[0040] as used herein, " assorted aralkyl " refers to group-R-hetAr, and wherein hetAr is the aryl of mixing as defined above, and R has 1 to 8, and be preferred 1 to 6, more preferably the alkylene moiety of 1 to 4 carbon atom.

[0041] as used herein, " cycloalkyl " refers to have the monocyclic carbocyclic ring of 3 to 8 carbon atoms. The group of the cycloalkyl that comprises is optional can be by being substituted as giving a definition or not replacing.

[0042] as used herein, " Heterocyclylalkyl " refers to have the monocyclic carbocyclic ring of 3 to 8 ring elements, and one of them independently is selected from nitrogen, oxygen or sulphur to two annular atomses. Comprise the group of Heterocyclylalkyl part optional can by as following definition is substituted or do not replace.

[0043] as used herein, " cycloalkyl-alkyl " refers to group-R-cycloalk, and wherein cycloalk is cycloalkyl as defined above, and R has 1 to 8, preferred 1 to 6 and the more preferably alkylene moiety of 1 to 4 carbon atom.

[0044] as used herein, " halogen " refers to fluorine, chlorine, bromine or iodine.

[0045] as used herein, " pharmaceutically acceptable " refers to be suitable for using in medicinal application and not having disadvantageous interactional material with active component according to toxicologic viewpoint.

[0046] as used herein, " replacement " refers to for example aryl of certain part, assorted aryl, and cycloalkyl or Heterocyclylalkyl partly have 1 to about 5 substituting groups, and more preferably 1 to about 3 substituting groups, and substituting group is independently selected from halogen, cyano group, nitro or hydroxyl, C₁To C₆Alkyl, or C₁To C₆Alkoxyl. Preferred substituting group is halogen, hydroxyl, or C₁To C₆Alkyl.

[0047] " the C of this paper report_max”，“T _max" and " AUC " value, unless be indicated as being outside " mean value ", all refer to the observation in single patient. And, unless otherwise indicated, " C_max”， “T _max" and " AUC " value can be that the value observed in stable state when with Fixed Time Interval (for example per 12 hours) administration many days (for example multiple dose is used) maybe can be the observed value of single dose when using.

[0048] therefore, in one embodiment, the invention provides solid pharmaceutical dosage formulation, comprising:

The compound of at least a formula (I) or its pharmaceutically acceptable salt:

Wherein:

R ₁Hydrogen, C₁To C₆Alkyl, C₂To C₇Acyl group, C₁To C₆The alkane sulfonyl, or C₆To C₁₄Aroyl;

R ₂And R₃Be independently selected from hydrogen,

Condition is R₂And R₃In at least one is not hydrogen;

R ₄And R₅Be independently selected from hydrogen, C₁To C₄Alkyl, C₅To C₇Aryl, have the C of 5 to 7 carbon atoms at aromatic ring₆To C₁₅Aralkyl, C₂To C₇Thiazolinyl, or C₂To C₇Alkynyl, or R₄And R₅Can jointly form spiral shell C₃To C₈Carbocyclic ring.

R ₆C₁To C₁₂The alkyl of straight or branched, C₂To C₇The alkenyl or alkynyl of straight or branched, C₅To C₁₃Aryl, have the C of 5 to 13 carbon atoms at aryl moiety₆To C₂₁Aralkyl; 5 yuan to 13 yuan assorted aryl has 6 yuan to 21 yuan assorted aralkyl of 5 to 13 atoms, C at heteroaryl moieties₄To C₈Cycloalkyl, have the C of 4 to 8 carbon atoms in cycloalkyl₅To C₁₆Cycloalkyl-alkyl;

R ₇And R₈Be independently selected from hydrogen, C₁To C₁₂The alkyl of straight or branched, C₂To C₇The alkenyl or alkynyl of straight or branched, C₅To C₁₃Aryl, have the C of 5 to 13 carbon atoms at aryl moiety₆To C₂₁Aralkyl, 5 yuan to 13 yuan assorted aryl has 6 yuan to 21 yuan assorted aralkyl of 5 to 13 atoms or R at heteroaryl moieties₇And R₈Can jointly form and have 4 to 8 carbon atoms and optional one to two on the ring and be selected from nitrogen, the cycloalkyl of the atom of oxygen or sulphur or Heterocyclylalkyl;

Wherein has arbitrarily aryl, assorted aryl, the R of cycloalkyl or Heterocyclylalkyl part₁To R₈Group optionally at aryl, assorted aryl, cycloalkyl or Heterocyclylalkyl part are independently selected from halogen, cyano group, nitro or hydroxyl, C by 1 to about 5₁To C₆Alkyl, or C₁To C₆The substituting group of alkoxyl replace; With

At least a pharmaceutically acceptable sorbefacient.

[0049] in another embodiment, the present invention relates to solid pharmaceutical dosage formulation, comprising:

The compound of at least a formula (I) or its pharmaceutically acceptable salt:

Wherein:

R ₁Hydrogen;

A is-(CH₂) _n-, wherein n is 2; With

R ₂And R₃Hydrogen; With

At least a pharmaceutically acceptable sorbefacient.

[0050] in another embodiment, the present invention relates to solid instant-free pharmaceutical composition, comprising:

The compound of at least a formula (I) or its pharmaceutically acceptable salt:

Wherein:

R ₁Hydrogen, C₁To C₆Alkyl, C₂To C₇Acyl group, C₁To C's₆Alkane sulfonyl, or C₆To C₁₄Aroyl;

R ₂And R₃Be independently selected from hydrogen,

Condition is R₂And R₃In at least one is not hydrogen;

R ₆C₁To C₁₂The alkyl of straight or branched, C₂To C₇The alkenyl or alkynyl of straight or branched, C₅To C₁₃Aryl, have the C of 5 to 13 carbon atoms at aryl moiety₆To C₂₁Aralkyl; 5 yuan to 13 yuan assorted aryl has 6 yuan to 21 yuan assorted aralkyl of 5 to 13 atoms, C at heteroaryl moieties₄To C₈Cycloalkyl, have the C of 4 to 8 carbon atoms at cycloalkyl ring₅To C₁₆Cycloalkyl-alkyl;

Wherein has aryl, assorted aryl, arbitrary R of cycloalkyl or Heterocyclylalkyl part₁To R₈Group is optionally at aryl, assorted aryl, and cycloalkyl or Heterocyclylalkyl part are independently selected from halogen, cyano group, nitro or hydroxyl, C by 1 to about 5₁To C's₆Alkyl, or C₁To C₆The substituting group of alkoxyl replace;

Wherein said composition has the 0.5g/cm of being at least about³, preferably be at least about 0.8g/cm³Bulk density.

[0051] in another embodiment, the present invention relates to solid instant-free pharmaceutical composition, comprising:

The compound of at least a formula (I) or its pharmaceutically acceptable salt:

Wherein:

R ₁Hydrogen;

A is-(CH₂) _n-, wherein n is 2; With

R ₂And R₃Hydrogen; With

[0052] in other embodiments, the present invention relates to the single dose form. In other embodiments, the present invention relates to the multiple dose form.

[0053] in further embodiment, the present invention relates to capsule. In further embodiment, the invention still further relates to tablet.

[0054] in certain embodiments, the present invention relates to solid instant-free pharmaceutical composition,

The plasma C of the compound of the formula (I) that wherein said composition shows when using for the curee that needs are arranged_maxFor about 80ng/mL to about 4200ng/mL, preferred at least about 200ng/mL, more preferably at least about 270ng/mL, even more preferably at least about 2940ng/mL.

[0055] in certain embodiments, the present invention relates to solid instant-free pharmaceutical composition,

The blood plasma T of the compound of the formula (I) that wherein said composition shows when using for the curee that needs are arranged_maxBe about 0.5 hour to about 4.0 hours.

[0056] in certain embodiments, the present invention relates to solid instant-free pharmaceutical composition,

Wherein the AUC (t=0 to 12 hour) of the chemical compound of the formula (I) that said composition shows when using for the curee that needs are arranged is that about 250ngh/mL is to about 6,000ngh/mL, preferably at least about 510ngh/mL, more preferably at least about 1215ngh/mL, even more preferably at least about 1280ngh/mL, and even more preferably at least about 2850ngh/mL.In preferred embodiments, when with fixed interval (for example per 12 hours) during with said composition administration one day or many days, total exposure every day (t=0 to 24 hour) of AUC is that about 500ngh/mL is to about 12,000ngh/mL, preferably at least about 1020ngh/mL, more preferably at least about 2430ngh/mL, even more preferably 2560ngh/mL, and even more preferably at least about 5700ngh/mL.

[0057] solid pharmaceutical dosage formulation of the present invention can be any Orally administered solid dosage forms that is suitable for.Suitable solid dosage forms example comprises powder, capsule, tablet, pill, lozenge, cachet and piller.Preferably, being suitable for Orally administered solid dosage forms is capsule or tablet.These dosage forms can be enteric coated or be prepared into the form of instant-free.In preferred embodiments, capsule or tablet are enteric coated.

[0058] as skilled in the art to understand, capsule material can be hard capsule material or soft capsule material, generally includes tastelessly, is easy to use and water miscible chemical compound, for example gelatin, starch or fibrous material.Capsule preferably seals, and for example uses gelatin band or analog.For example, referring to Remiragtorn:The Science and Practice of Plzarmacy, the 20th edition (Easton, PA:Mack Publishing Company, 2000), it has described the material and the method for preparation encapsulate medicine capsule.

[0059] though optional, enteric coating is generally polymeric material.Preferred enteric coating material comprises bioerodible, gradually hydrolysis and/or water-soluble gradually polymer." coat weight ", or the relative quantity of every capsules coating material, the interval between control picked-up and the drug release usually.Any coating should be applied to enough thickness so that whole coating does not dissolve in pH is lower than about 5 gastro-intestinal Fluid, but pH be about 5 and above gastro-intestinal Fluid in dissolve.Expect that any anionic polymer that shows pH-dependency solubility curve in practice of the present invention all can be used as enteric coating to realize that active substance is delivered to lower gastrointestinal tract.Following character is depended in the selection of concrete enteric coating material: to stripping and disintegrate opposing under one's belt; When under one's belt to the impermeability of gastric juice and drug/vehicle/enzyme; In dissolving of target intestinal position or quickly disintegrated ability; Physics between the storage life and chemical stability; Nontoxic; Easy screening characteristics (substrate affinity) as coating; And it is economical and practical.

[0060] Shi Yi enteric coating material includes but not limited to: cellulosic polymer, hydroxypropyl cellulose for example, hydroxyethyl-cellulose, hydroxypropyl emthylcellulose, methylcellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, acetic acid-1,2,4-benzenetricarboxylic acid cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropyl methyl cellulose succinate (hydroxypropylme-thyl cellulose succinate) and sodium carboxymethyl cellulose; Acrylic polymers and copolymer, preferably by acrylic acid, methacrylic acid, acrylic acid methyl ester., acrylic acid methyl ester. ammonium, ethyl acrylate, polymer that methyl methacrylate and/or ethyl methacrylate form and copolymer (for example, those copolymers of selling with trade name EUDRAGIT); Ethene polymers and copolymer, polyvinylpolypyrrolidone (PVP) for example, polyvinyl acetate, polyvinyl acetate phthalate, vinylacetate .beta.-methylacrylic acid copolymer, and ethylene-vinyl acetate copolymer; And Lac (Refined shellac).Also can use the combination of different coating materials to come the single capsule of coating.

[0061] enteric coating provides the sustained release to active substance, makes medicine some to finish drug release in the position of precognition usually in lower gastrointestinal tract like this, will take place under the situation at no enteric coating at the following drug release of this point.Enteric coating can prevent that also hydrophilic therapeutic agent and carrier are exposed to the oral cavity, pharynx, and esophagogastric epithelial tissue and mucosal tissue, and organize relevant enzyme with these.Therefore enteric coating helps to protect activating agent and patient's intestinal to avoid any adverse events before the position that needs are sent discharges medicine.In addition, coating capsule of the present invention makes drug absorption, activating agent protection and safety optimization.Being that the multiple enteric clothing of purpose will be more effective and continue improvement and run through sending of lower gastrointestinal tract at lower gastrointestinal tract different parts release bioactive agent.

[0062] coating can, and preferably include plasticizer to prevent to form space and the crack that allows the gastric juice infiltration.Suitable plasticizer includes but not limited to; triethyl citrate (GITROFLEX 2); glyceryl triacetate (triacetin), CitroflexA-2 (CITROFLEC A2), CARBOWAX 400 (PEG400); diethyl phthalate; tributyl citrate, single-acetyl triglyceride, glycerol; fatty acid ester, propylene glycol and dibutyl phthalate.Especially, gross weight in coating, the coating that comprises anion carboxy acrylic polymer comprises usually less than about 50% weight, preferably less than about 30% weight, more preferably about 10% weight is to the plasticizer of about 25% weight, particularly dibutyl phthalate, Polyethylene Glycol, triethyl citrate and glyceryl triacetate.Coating can also comprise other coating excipient, antitack agent for example, and defoamer, lubricant (for example, magnesium stearate) and stabilizing agent (for example, hyprolose, bronsted lowry acids and bases bronsted lowry) are with dissolving or disperse coating material, and improve the product of coating performance and coating.

[0063] in preferred embodiments, enteric coated capsule or enteric coated tablet comprise the coating that is formed by anionic polymer, anionic polymer is selected from by methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate (hydroxpropylmet-hylcellulose phthalate), polyvinyl acetate phthalate, Lac, hydroxypropyl emthylcellulose succinic acid acetate (hydroxpropylmethylcellulose acetatesuccina-

-te) and carboxymethyl cellulose.In particularly preferred embodiments, enteric coating is a methacrylic acid copolymer.

[0064] can use conventional coating method and equipment that coating is coated on capsule or tablet.For example, can use coating pan, the airless spraying technology, fluidized bed coating equipment or analog are coated on capsule with enteric coating.Material about the preparation coated dosage form, the details of equipment and method can be at Pharmaceu-tical Dosage Forms:Tablets, people such as eds.Liebermanden. (New York: Marcel Dekker, 1989), and people such as Ansel, PharnzaceuticalDosage Forms and Drug Delivery Systems, the 6th edition (Media, PA:WilliamsWilkins, 1995) find in.As noted above, the thickness of coating must be enough to guarantee that peroral dosage form was kept perfectly before arriving the local position that discharges of lower intestinal tract needs.

[0065] in another embodiment of the invention, solid pharmaceutical dosage formulation is unit dosage form or multiple dose form.In this dosage form, compositions can be subdivided into the single dose or the multiple dose form that comprise an amount of active component.This dosage form can be a packaged composition.Therefore, the present invention also provides and has comprised at least a formula (I) chemical compound or its pharmaceutically acceptable salt that is suitable for Orally administered effective unit dosage or multiple dose; At least a pharmaceutically acceptable absorption enhancer; And the unit dosage form of the optional at least a additive that is used to form solid dosage forms or the solid pharmaceutical dosage formulation of multiple dose form.

[0066] it will be recognized by those skilled in the art that preferred effectively unit dose or multiple dose will depend on, for example the chemical compound of the disease that will treat and selected specific formula I.For example, it is believed that, with respect to R ₂And R ₃Be formula (I) chemical compound of hydrogen, R ₂And/or R ₃Be B, formula (I) chemical compound of C or D part has the bioavailability of improvement, therefore can be with the low dosage administration.Yet, preferably, the dosage (no matter being unit dose or multiple dose) of useful in the present invention formula (I) chemical compound that every day is Orally administered at about 400mg (200mg BID) to about 4000mg (2000mg BID) scope, more preferably at about 400mg (200mg BID) extremely in about 3200mg (1600mg BID) scope.In certain embodiments, the dosage of the chemical compound of the useful in the present invention formula (I) that every day is Orally administered (no matter being unit dose or multiple dose) will be at about 800mg (400mg BID) to about 3200mg (1600mg BID) scope, more preferably at about 800mg (400mg BID) extremely in about 1200mg (600mg BID) scope.

[0067] in above-mentioned formula (I):

R ₁Be hydrogen, C ₁To C ₆Alkyl, C ₂To C ₇Acyl group, C ₁To C ₆The alkane sulfonyl, or C ₆To C ₁₄Aroyl;

R ₂And R ₃Independently be selected from hydrogen,

R ₆Be C ₁To C ₁₂The alkyl of straight or branched, C ₂To C ₇The alkenyl or alkynyl of straight or branched, C ₅To C ₁₃Aryl, have the C of 5 to 13 carbon atoms at aryl moiety ₆To C ₂₁Aralkyl; 5 yuan to 13 yuan heteroaryl has 6 yuan to 21 yuan heteroarylalkyl of 5 to 13 atoms, C at heteroaryl moieties ₄To C ₈Cycloalkyl has the C of 4 to 8 carbon atoms on cycloalkyl ring ₅To C ₁₆Cycloalkyl-alkyl;

R ₇And R ₈Be independently selected from hydrogen, C ₁To C ₁₂The alkyl of straight or branched, C ₂To C ₇The alkenyl or alkynyl of straight or branched, C ₅To C ₁₃Aryl, have the C of 5 to 13 carbon atoms at aryl moiety ₆To C ₂ ₁Aralkyl, 5 yuan to 13 yuan heteroaryl has 6 yuan to 21 yuan heteroarylalkyl of 5 to 13 atoms or R at heteroaryl moieties ₇And R ₈Can be formed on jointly and have 4 to 8 carbon atoms and optional one to two on the ring and be selected from nitrogen, the cycloalkyl of the atom of oxygen or sulfur or Heterocyclylalkyl;

Wherein has aryl, heteroaryl, arbitrary R of cycloalkyl or Heterocyclylalkyl part ₁To R ₈Group can be randomly at aryl, heteroaryl, and cycloalkyl or Heterocyclylalkyl part are independently selected from halogen, cyano group, nitro or hydroxyl, C by 1 to about 5 ₁To C ₆Alkyl, or C ₁To C ₆The substituent group of alkoxyl replace.

[0068] in one embodiment of the invention, the R of formula (I) ₁Preferably hydrogen or C ₁To C ₄Alkyl and be more preferably H.

[0069] in another embodiment of the invention, the A of formula (I) is alkylidene preferably ,-(CH ₂) _n-, wherein n is 1 to 3, more preferably 1 to 2 and most preferably 2.

[0070] in another embodiment, when needs form the derivant of [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] phosphoric acid, preferred R ₂And R ₃In at least one is not H.

[0071] in other embodiment, the R of formula (I) ₂And R ₃Being H or (B) or (D) part, more preferably is H or (B) part, and most preferably two all is (B) part, wherein R ₄, R ₅And R ₆As above-mentioned definition.Work as R ₂And R ₃When being not hydrogen, preferably they are same group.

[0072] in another embodiment preferred of the present invention, R ₂And R ₃All be preferably hydrogen.

[0073] for (B), (C) and (D) part, R ₄And R ₅Preferably H or C ₁To C ₄Alkyl, more preferably H or methyl.R ₆C preferably ₃To C ₁₀The alkyl of straight or branched, C ₅To C ₇Aryl, 5 yuan to 7 yuan heteroaryl, or on ring, have the cycloalkyl of 5 to 7 carbon atoms.In preferred embodiments, R ₆Be C ₅To C ₇Aryl.

[0074] in another preferred embodiment of the present invention, R ₁Be H or C ₁To C ₄Alkyl; A has formula-(CH ₂) _n-alkylidene, wherein n is 1 to 3; R ₂And R ₃Be independently H or:

R ₄And R ₅Be H or C independently ₁To C ₄Alkyl; And R ₆Be C ₃To C ₁₀The alkyl of straight or branched, C ₅To C ₇Aryl, 5 yuan to 7 yuan heteroaryl has the cycloalkyl of 5 to 7 carbon atoms on ring.

[0075] instantiation of useful in the present invention chemical compound comprises following chemical compound:

[2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] phosphoric acid;

3-{2-[8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl] ethyl }-3-epoxy-7-oxo-7-phenyl-2,4,6-trioxa-3-phospha seven (phospha-hept)-1-yl benzoic acid ester;

3-{2-[8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl] ethyl }-3-epoxy-7-oxo-8-propyl group-2,4,6-trioxa-3-phospha 11 (phosphaundec)-1-base 2-Propylpentanoic ester;

2,2-dimethyl-propanoic acid (2,2-dimethyl-propionyloxy methoxyl group (propionyloxymet-hoxy))-[2-(8,9-dioxo-2,6-diaza-dicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl)-ethyl]-phosphine oxygen ylmethyl (phosphinoyloxymethyl) ester;

7-cyclohexyl-3-{2-[8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl] ethyl }-1,5-dimethyl-3-epoxy-7-oxo-2,4,6-trioxa-3-phospha seven-1-basic ring cyclohexane carboxylic-acid ester (cyclohexanecarboxylate);

7-cyclohexyl-3-{2-[8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl] ethyl }-3-epoxy-7-oxo-2,4,6-trioxa-3-phospha seven-1-basic ring cyclohexane carboxylic-acid ester;

[2-(8,9-dioxo-2,6-diaza-dicyclo [5.2.0] ninth of the ten Heavenly Stems-1-(7)-alkene-2-yl)-ethyl]-di(2-ethylhexyl)phosphate isopropoxy carbonyl oxygen ylmethyl (diisopropoxycarbonyloxymethyl) ester;

[2-[8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl] ethyl]-two [1-(benzoyloxy group) ethyl] esters of phosphoric acid;

Benzoic acid [2-(8,9-dioxo-2,6-diaza-dicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl)-ethyl]-hydroxyl-phosphine oxygen ylmethyl ester; With

[2-(8,9-dioxo-2,6-diaza-dicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl)-ethyl]-di(2-ethylhexyl)phosphate dimethyl methyl aminoacyl methoxyl group (didimethyl carbamoyloxymethyl) ester;

Or its pharmaceutically acceptable salt.

[0076] useful in the present invention chemical compound can comprise asymmetric carbon atom and/or phosphorus atoms, therefore produces optical isomer and diastereomer.Though spatial chemistry is not considered in demonstration in formula (I), the present invention includes such optical isomer and diastereomer; Raceme and fractionation, the R of enantiomeric pure and S stereoisomer; Other mixture and the pharmaceutically acceptable salt thereof of R and S stereoisomer.

[0077] be under the preferred situation in a kind of enantiomer, it can be substantially devoid of corresponding enantiomer in certain embodiments.Therefore, the enantiomer that is substantially devoid of corresponding enantiomer refers to the chemical compound that does not contain corresponding enantiomer by isolation technics segregation or isolated compound or preparation.As used herein, " not containing substantially " refers to the multi-form mixture of enantiomers be made up of a kind of enantiomer of larger proportion.In preferred embodiments, this mixture comprises the preferred enantiomer at least about 90% weight.In other embodiments of the present invention, this mixture comprises the preferred enantiomer at least about 99% weight.The formation that preferred enantiomer can comprise high performance liquid chromatography (HPLC) and chirality salt by any method known to those skilled in the art and crystallization separate or are prepared by method as herein described from racemic mixture.For example,, wait the people, Enayitiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981) referring to Jacques; Wilen, S.H. waits the people, Tetrahedron, 33:2725 (1977); Eliel, E.L.Stereochemistry of Carbon Cornpounds, (McGraw-Hill, NY, 1962); Wilen, S.H.Tables of Resolving Agents and OpticalResolutions, p.268 (E.L.Eliel, Ed., Univ.of Notre Dame Press, NotreDame, IN 1972).

[0078] those of skill in the art also will appreciate that the tautomer that may have formula (I).Although the present invention includes the application of all this tautomers does not show in formula (I).

[0079] useful in the present invention chemical compound also comprises formula (I) chemical compound pharmaceutically acceptable salt.With regard to the salt of " pharmaceutically acceptable salt ", it is meant any chemical compound that forms by the chemical compound that adds pharmaceutically acceptable alkali and the formula (I) that forms corresponding salt.With regard to term " pharmaceutically acceptable ", it is meant according to toxicologic viewpoint and is suitable for using in medicinal application and not having disadvantageous interactional material with active component.Preferably, pharmaceutically acceptable salt is the alkali metal salt (sodium, potassium, lithium) or alkaline-earth metal (calcium, the magnesium) salt of formula (I) chemical compound, or has the salt of pharmaceutically acceptable cationic formula (I) chemical compound that is obtained by ammonia or basic amine.The latter's example includes but not limited to, ammonium, single first ammonium, dimethylammonium or trimethylammonium, single second ammonium, diethyl ammonium or three second ammoniums, single third ammonium, dipropyl ammonium or 3 third ammoniums (different and just), ethyl Dimethyl Ammonium, the benzyl dimethyl ammonium, hexamethylene ammonium, benzyl ammonium, the benzhydryl ammonium, pyridine , morpholine , pyrrolidine , piperazine , 1-picoline , 1-isopropyl pyrrolidine , 1,4-lupetazin , 1-normal-butyl pyridine , 2-picoline , 1-ethyl-2-picoline , monoethanol ammonium, diethanol ammonium or triethanol ammonium, three (methylol) ammonium methyls or phenyl monoethanol ammonium.Preferably, work as R ₂Or R ₃In one can form salt during for hydrogen.

[0080] useful in the present invention chemical compound can be according to US-A-5, and 168,103, US-A-5,240,946, US-A-5,990,307 and US-A-6,011,168 described method prepares by the chemical compound of synthesis type (II), wherein A and R ₁Definition is suc as formula (I):

Its full content is incorporated herein by reference.Preferred synthetic route is at US-A-5, and 990,307 and US-A-6, on the books among 011,168 the embodiment 5.

[0081] in order to form R in the formula (I) ₂Or R ₃In at least one is not the chemical compound of hydrogen, subsequently with the compound dissolution of the formula (II) that obtains in appropriate solvent, dimethyl formamide for example.As used herein, " appropriate solvent " refers to that the chemical compound of formula (II) can dissolve and can not react with it therein.Preferably, preferably in room temperature with plumper (with the byproduct reaction of carboxylic acid halides reaction) amine for example, add in the reactant mixture.Preferably, amine is sterically hindered secondary amine or tertiary amine, more preferably tertiary amine diisopropylethylamine for example.The halogen ester of the following formula that suitably replaces is added in the reactant mixture,

R wherein ₄, R ₅And R ₆Suc as formula definition in (I), and Y is a halogen atom.Reactant mixture from about 50 ℃ to about 80 ℃, is more preferably heated enough response time so that the chemical compound of chemical compound reaction formation formula (I) of halogen ester and formula (II) from about 65 ℃ to about 75 ℃.Usually in order to obtain better yield, the response time is about 20 hours to about 40 hours, more preferably from about 25 hours to about 35 hours.After reaction is finished, preferably reactant mixture is cooled to room temperature, and uses the compound separation of routine techniques well known by persons skilled in the art formula (I).Preferred separation method be with reactant mixture at weak base, for example sodium bicarbonate aqueous solution and organic solvent for example distribute between the ethyl acetate.Preferably re-extract water several times with an organic solvent wash the organic layer of merging once more with weak base.With the organic layer drying, for example use saline and drying, filtration and evaporation on magnesium sulfate then.Preferably use routine techniques that residue is carried out the flash chromatography chromatography then on silica gel and come separating compound.

[0082] chemical compound of formula (I) exists to be suitable for Orally administered effective dose in solid pharmaceutical dosage formulation.As used herein, " effective dose " is the chemical compound of formula (I) or the minimum of being treated the disease of discussing by its pharmaceutically-acceptable salts that forms in mammal at least.Effective dose depends on the particular composition that such variable for example uses, the order of severity of symptom and specific treatment patient.In order to determine the effective dose of administered compound, the doctor can be for example by increasing the effect that dosage comes estimator (I) specific compound up to the remission level that reaches needs gradually.Can adjust the result that lasting dosage regimen acquisition needs then.For Orally administered, preferably in the patient, increase chemical compound of the present invention gradually until reaching the remission level that needs with amount from 1mg/kg to 10mg/kg.Can adjust the result of lasting dosage regimen then need to obtain, the scope of oral dose is preferably about 200mg/ days to about 4000mg/ days, more preferably be about 400mg/ days to about 3200mg/ days, even more preferably at least about 800mg/ days, even also more preferably at least about 1600mg/ days, further even more preferably at least about 3200mg/ days.Chemical compound of the present invention can be with single oral dose (for example, the tablet of a 600mg or capsule) or oral dose (for example, the tablet of three 200mg or capsule repeatedly; The tablet of two 300mg or capsule) form use to the patient, preferably use to the patient with tablet or capsular form.

[0083] in preferred embodiments, the chemical compound of formula (I) in solid pharmaceutical dosage formulation in the gross weight of described pharmaceutical composition, exist with the level of about 25% weight to about 99.5% weight, more preferably in the gross weight of described pharmaceutical composition, exist with the level of about 50% weight to about 99.5% weight, even more preferably in the gross weight of described solid pharmaceutical dosage formulation, exist with the level of about 60% weight to about 99.5% weight, even, exist with the level of about 67% weight to about 99.5% weight also more preferably in the gross weight of described solid pharmaceutical dosage formulation.

[0084] except that the chemical compound of at least a formula (I) that comprises effective dose; solid pharmaceutical dosage formulation of the present invention preferably includes at least a pharmaceutically acceptable absorption enhancer; it is selected from surfactant; cholate; fatty acid, soap, chelating agent; acylcarnitines, acyl group choline or its mixture.In preferred embodiments, absorption enhancer in the gross weight of described solid pharmaceutical dosage formulation, exists with the amount of about 0.25% weight to about 50% weight in solid pharmaceutical dosage formulation.

[0085] Shi Yi surfactant comprises, for example, ionic surfactant, nonionic surfactant or and composition thereof.Typical ionic surfactant comprises sodium lauryl sulphate, aerosol OT or its mixture.Typical nonionic surfactant comprises polyoxyethylene alkyl ether, polyxyethylated ester, polysorbate or its mixture.

[0086] Shi Yi polyxyethylated ester comprises, for example, and with Polyethylene Glycol-20 sorbitan monooleate of trade name TWEEN 80 sale.

[0087] Shi Yi cholate comprises, for example, and sodium cholate, sodium deoxycholate or its mixture.

[0088] Shi Yi fatty acid comprises, for example, and oleic acid.Suitable soap comprises, for example, and Capric acid sodium salt.

[0089] Shi Yi chelating agent comprises, for example, ethylenediaminetetraacetic acid (EDTA) and salt thereof comprise its sodium salt.

[0090] Shi Yi acylcarnitines comprises, for example, and palmitoyl carnitine.Suitable acyl group choline comprises, for example, and the lauroyl choline.

[0091] solid pharmaceutical dosage formulation of the present invention can randomly comprise at least a additive that is used to form the solid dosage forms of described pharmaceutical composition.Suitable optional additives comprises filler, disintegrating agent, binding agent, lubricant or and composition thereof.Absorption enhancer also can be used as a kind of in the unique additive that is used to form solid dosage forms or the additive.

[0092] typical filler comprises, for example, lactose, microcrystalline Cellulose, mannitol, calcium phosphate, pregelatinized Starch, pregelatinated sucrose or and composition thereof.Preferably microcrystalline cellulose is especially as in the granule and the outer composition of granule.

[0093] typical disintegrating agent comprises, for example, and cross-linked carboxymethyl cellulose sodium, starch, carboxymethyl starch sodium, pregelatinized Starch, polyvinylpolypyrrolidone and composition thereof.Preferred cross-linked carboxymethyl cellulose sodium is especially as in the granule and the outer composition of granule.

[0094] typical binding agent comprises, for example, and polyvidone (also being called polyvinylpyrrolidone or PVP), hydroxypropyl emthylcellulose, polyvinyl alcohol, gelatin, natural gum and composition thereof.Preferred polyvidone.Preferably,, then in compositions, comprise preferably about 0.5% weight, more preferably at least about 1.5% weight, most preferably at least about the binding agent of the amount of 2.5% weight, in the gross weight of compositions to about 10% weight if binding agent exists.

[0095] typical lubricants comprises, for example, and magnesium stearate, sodium stearyl fumarate and composition thereof.

[0096] preferably, in the gross weight of compositions, the additive that is used to form solid dosage forms accounts for altogether at least about 0.25% weight, and more preferably from about 0.25% weight is to about 95% weight, and most preferably about 0.25% weight is to about 33% weight.

[0097] can include but not limited to wet method by the production technology that is used to form oral dosage form of routine, dry method, fluidized bed granulation and direct compression technology prepare solid pharmaceutical dosage formulation.This type of technology is at Remington:The Science and Practice of Pharmacy, and the 20th edition (Easton, PA:MackPublishingCompany, 2000) are on the books in the 858-893 page or leaf, and its disclosure all is incorporated herein by reference.In example 1 and 2, use the wet granular technology that the density of mixture of powders is increased to 0.59g/ml from 0.33g/ml, ([2-(8 to make the active component can encapsulate 300mg in the HPMC of #0 size capsule, 9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] phosphoric acid).

[0098] solid pharmaceutical dosage formulation of the present invention also can be chosen wantonly and comprise one or more antimicrobial preservatives and storing and multiple dose microbial growth between the operating period with prevention.The example of suitable antiseptic is a benzalkonium chloride, thimersal, chlorobutanol or p-Hydroxybenzoate or and compositions.Though the concentration of antiseptic in compositions depends on employed antiseptic, in the gross weight of compositions, the total amount of antiseptic in compositions preferably in about 0.1% weight to the scope of about 2.0% weight.

[0099] in another embodiment of the invention, solid pharmaceutical dosage formulation can comprise one or more other pharmaceutically active agents, and for example those are used for the treatment of the medicament of any other medical conditions (medical condition) that exists in mammal.The example of this type of pharmaceutically active agents comprises the pain relief medicine, angiogenesis inhibitor (anti-angiogenic) medicine, antineoplastic agent, antidiabetic drug, anti-infective or gastrointestinal tract medicine, or its combination.The inventory of more complete pharmaceutically active agents can be at Physicians ' Desk Reference, and the 55th edition, 2001, published byMedical Economics Co., Inc. finds among the Montvale.These medicines can be used according to treatment effective dose known in the art and dosage regimen separately, for example Physicians ' Desk Reference, the 55th edition, 2001, published by Medical Economics Co., Inc., those that put down in writing among the Montvale.

[0100] the present invention also is included as the test kit or the packing of the pharmaceutical preparation that is used for dosage regimen described herein and method and designs.It is Orally administered and design that these test kits are preferably in specific period or cycle every day, be preferably the quantity of Orally administered regulation every day, and with its combination so that indicate dosage regimen or the associating of the single oral formulations that takes every day in the cycle or oral formulations and designing.Preferably, each test kit comprises the oral tablet that take specific every day, and an oral tablet contains each associating daily dose that has illustrated in some embodiments, in other embodiments so that independently preparation or compositions are carried out using of independent compound.Have in most preferred packing or the test kit to relate to and use the schedule of appropriate combination thing or the calendar of every day in the week in suitable date (day) or time.

[0101] in another embodiment of the invention, the invention provides the method for one or more diseases relevant of treatment with glutamate abnormality, comprise chemical compound at least a formula (I) of the Orally administered treatment effective dose of the mammal that needs are arranged.As used herein, " with ... relevant " refer to the disease that directly or indirectly causes by glutamate abnormality." glutamate abnormality " refers to by relating to glutamic acid and/or its receptor as the influence factor's of disease or imbalance disease or imbalance and any disease that causes.Be considered to the disease relevant with glutamate abnormality including, but not limited to, the angiopathy relevant with glutamate abnormality, for example cerebrovascular disease including, but not limited to, cause a series of diseases for example thromboembolia type or hemorrhagic apoplexy cerebral ischemia (for example, or cerebral vasospasm apoplexy) or cerebral infarction; Cerebral trauma; Muscular spasm; Convulsive disorder is epilepsy or status epilepticus for example; Glaucoma; Pain; Anxiety disorder is panic attack for example, agoraphobia, panic disorder, specific phobia, social phobia, obsessive compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, separation anxiety disorder, or the anxiety disorder that causes of material; Mood disorders for example bipolar disorder (as, two-phase I type obstacle, two-phase II type obstacle, and cyclothymic disorder), depression (as, major depressive disorder, dysthymic disorder, the mood disorders of or material-cause), the emotion outbreak (shows effect as severe depression, manic episode, Combination outbreak, and hypomania); Schizophrenia; Schizophreniform disorder; Schizoaffective disorder; Cognitive impairment is the loss of memory for example; And chronic neurodegenerative disease parkinson disease for example, Huntington Chorea, Alzheimer, amyotrophic lateral sclerosis, or the chronic dementia relevant disease, for example, Louis corpusculum disease (Lewy body disease), Alzheimer, frontotemporal dementia (fronto temporal dementia) or AIDS.For above cited psychotic disorders such as schizophrenia, mood disorders and anxiety disorder, can be with reference to Diagnostic and Statistical Manual of mental disorders, the 4th edition, Washington, DC, American Psychiatric Association (1994) is to the more complete description of various mental sickness.The disease that is considered to other relevant with glutamate abnormality comprises inflammatory diseases; Hypoglycemia; Diabetes end-organ complication; Asystole; Perinatal asphyxia disease, for example by near drowning, the perinatal asphyxia disease that pulmonary surgery and cerebral trauma cause; And spinal cord injury.Chemical compound of the present invention also can be used to treat fibromyalgia, irritable bowel syndrome, and for example prevention of postherpetic neuralgia of herpes zoster (herpes zoster (shingles)) complication.Pharmaceutical composition of the present invention also can be used for preventing to the tolerance of OA or helps to control the withdrawal symptom of addictive drug.Therefore, the invention provides the method that is used for the treatment of above-mentioned various diseases, comprise chemical compound at least a general formula (I) of the Orally administered treatment effective dose of the mammal that needs are arranged.

[0102] in a preferred embodiment, useful chemical compound is used for the treatment of pain among the present invention.Pain can be, for example, and acute pain (persistent period is short) or chronic pain (recurrence or lasting).Pain can also be central or periphery.

[0103] can be acute or chronic and can comprise inflammatory pain according to the pain example of method of the present invention treatment, musculoskeletal pain, boniness pain (bony pain), lumbosacral pain, cervical region or last back pain, Encelialgia, somatalgia, neuropathic pain, cancerous pain, for example burn or have a toothache by damage or the pain that causes of operation, or headache for example migraine or tonicity headache, or the combination of these pain.It will be recognized by those skilled in the art that these pain are can be overlapped.For example, the pain that is caused by inflammation can also be Encelialgia or musculoskeletal pain in nature.

[0104] in a preferred embodiment of the invention, give chemical compound useful among administration the present invention, for example with periphery or the central nervous system is impaired or pathological changes is relevant neuropathic pain with the treatment chronic pain; Cancerous pain; Visceral pain, for example with abdominal part, the visceral pain that pelvis and/or perineal region or pancreatitis are relevant; Musculoskeletal pain is for example with back of the body bottom or top, spinal column, muscle fiber pain (fibromylagia), the musculoskeletal pain that remporomandibular joint or myofasical pain syndrome are relevant; Boniness pain is for example with bone or degenerative joint disease osteoarthritis for example, rheumatoid arthritis (rheumatiod arthitis), or the relevant boniness pain of spinal stenosis; Headache, for example migraine or tension headache; Or with infect for example HIV, reaping hook cell anemia disease, autoimmune sexual disorders, multiple sclerosis, or inflammation for example osteoarthritis or the relevant pain of rheumatoid arthritis.

[0105] in a more preferred embodiment, according to methods described herein chemical compound useful among the present invention is used for the treatment of chronic pain, it is a neuropathic pain, visceral pain, musculoskeletal pain, boniness pain, cancerous pain or inflammatory pain or its associating.Inflammatory pain can with multiple medical conditions osteoarthritis for example, rheumatoid arthritis is performed the operation or is damaged relevant.Neuropathic pain comprises peripheral nervous pain, nervus centralis pain or its associating.Neuropathic pain can with for example diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, compound regional pain syndrome, waist or cervix uteri radiculopathy, fibromyalgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, causalgia, thalamic syndrome, nerve root avulsion, MG (MGUS) neuropathy that meaning is uncertain, the sarcoid polyneuropathy, by multiple reason for example by the relevant neuropathy of the drug-induced HIV that is used for the treatment of HIV, peripheral neurophaty is the peripheral neurophaty of connective tissue disease for example, paraneoplastic sensory nerve pathological changes, the familial amyloid polyneuropathy, acquired starch polyneuropathy, hereditary neuropathy becomes, the neuropathy of renal failure, heredity sensation autonomic neuropathy, the Fa Bulishi disease, celiac disease or cause periphery and/or maincenter sensitization and the nerve injury that causes by damage, phantom limb pain for example, reflex sympathetic dystrophy or thoracotomy postoperative pain (postthoracotomypain), comprise by chemotherapeutics or other and be used for the treatment of the cancer of the caused neuropathy of medicament of this disease, chemical injury, toxin be the arsenic neuropathy for example, malnutrition, or virus or bacterial infection be as the neuropathy relevant with herpes zoster or HIV, or its associating is relevant.The using method of The compounds of this invention further comprises treatment, and wherein neuropathic pain is to be soaked into by transitivity, and adiposis dolorosa is burnt or the disease of the central pain disease institute secondary relevant with the thalamus disease.

[0106] aforesaid in some cases neuropathic pain can also be divided into " pain fine fibre neuropathy ", for example constitutional fine fibre pain perception neuropathy, or " the big fiber nerve pathological changes of pain " for example demyelinating (demylinating) neuropathy or aixs cylinder neuropathy or its associating.For example, this type of neuropathy is people such as J.Mendell, and N.Engl.J.Med.2003 has more specifically record, thus with its complete being incorporated herein by reference among the 348:1243-1255.

[0107] as previously mentioned, method of the present invention can be used for the treatment of body and/or visceral pain in nature.For example can comprise according to the body pain of method of the present invention treatment with operation, dental procedure, burn or traumatic body injury process in the structure or the relevant pain of soft tissue injury that stand.Can comprise that those diseases with the internal are relevant or by pain that it caused according to the example of the visceral pain of method of the present invention treatment, described disease is ulcerative colitis for example, irritable intestine syndrome, irritable bladder, clone disease, rheumatism (arthralgia), tumor, gastritis, pancreatitis, organ infection, or biliary tract, or its associating.Those skilled in the art also will appreciate that all right and hyperpathia according to the pain of method treatment of the present invention, allodynia or relevant with the both.In addition, chronic pain can exist or not exist periphery or maincenter sensitization.

[0108] useful in the present invention chemical compound also can be used for treating the acute and/or chronic pain relevant with women's disease, and it may also be referred to as the distinctive pain into the women.This type of pain comprises the pain of having only or mainly being suffered by the women, comprises and menstruation ovulation, gestation or childbirth, miscarriage, ectopic pregnancy, retrograde menstruation, breaking of follicle or corpus lutein cyst, pelvic viscera stimulates, leiomyoma of uterus, endometriosis, endometriosis, infect and inflammation, pelvic organs's ischemia is blocked, adhesion in the abdomen, the anatomy deformity of pelvic viscera, ovarian abscess, the forfeiture that pelvis is supported, tumor, the pain that pain that pelvis is congested relevant or non-gynecological reason cause.

[0109] as used herein, term " treatment " or " treatment " also comprise completely or partially the generation that suppresses (for example prevention) pain except that alleviating the pain that has taken place in the mammal partially or completely.Therefore, can stand pain mammal gave administration chemical compound of the present invention with the generation of inhibition of pain partially or completely in the past.

[0110] in one embodiment, useful in the present invention chemical compound can be used before operation or in operation technique to suppress the generation of the pain relevant with operation technique partially or completely.In preferred embodiments, useful in the present invention chemical compound was preferably used before operation in about 0.25 hour to about 4 hours.For longer operation technique of persistent period, preferably in operation technique, press approximately and half-life (T in the body of chemical compound _1/2) each suitable interval repeat administration.In preferred embodiments, for preparation, in operation technique, press per approximately 4 to 8 hours repeat administrations according to embodiment 1.

[0111] in another embodiment of the invention, useful in the present invention chemical compound can increase the opium sample analgesic (as morphine) that other pain relief agents for example uses behind operation technique effectiveness and/or effect used in discovery before operation technique, and/or reduces the amount of the needed pain relief agents of treatment postoperative pain.Therefore, the invention provides the method for the treatment pain relevant with operation technique, be included in before the operation or use useful chemical compound of the present invention in the operation technique and at least a pain relief agents of administering therapeutic effective dose, for example opium sample analgesic after operation or in the operation technique.In preferred embodiments, also can behind operation technique, give administration chemical compound of the present invention, preferably with itself and one or more pain relief agents combined administration.As used herein, " operation technique " is included in any tissue, all treatments in organ or the body system, diagnosis, and/or beauty treatment operation, division is moved, radiation, excision, the change of chemistry or physics, tissue, organ or body system include but not limited to blood, blood vessel, fat, skin, connective tissue, muscle, internal organs, body of gland, skeleton, cartilage, nerve, bone marrow, fascia, meninges, sensory organ, brain or spinal cord.Except that more conventional technology, operation technique for example comprises also that use surgical technic more recently is laser for example, the ultrasonic operation of carrying out on mammal with radiation.

[0112] in another embodiment, can use useful in the present invention chemical compound to suppress the generation of neuropathic pain disease wholly or in part.For example, can give and have the administration chemical compound of the present invention that mammal that the danger of neuropathic pain disease takes place for example infects herpes zoster or carries out treatment of cancer.

[0113] in another embodiment of the invention, can give chemical compound useful among administration the present invention and one or more other pharmaceutically active agents, for example be used for the treatment of those medicaments of any other medical conditions that exists in the mammal.The example of this type of pharmaceutically active agents comprises that pain relief invites angiogenesis inhibitor medicine, antineoplastic agent, antidiabetic drug, anti-infective, or gastrointestinal tract medicine, or its combination.

[0114] one or more other medicines activating agents of treatment effective dose can be used (for example simultaneously use separately or use) simultaneously with one or more chemical compounds of the present invention in pharmaceutical composition, and/or continuous administration.

[0115] application process of other medicines activating agent can be identical or different with the route of administration that The compounds of this invention uses.For example, the other medicines activating agent can be by oral or parenteral administration, for example, by intramuscular, intraperitoneal, epidural, in the sheath, intravenous, in the mucosa, for example by intranasal or Sublingual, subcutaneous or applied dermally.Preferred route of administration depends on selected specific pharmaceutically active agents and its approach of using of recommendation well known by persons skilled in the art.

[0116] inventory of more complete pharmaceutically active agents can be at Physicians ' DeskReference, and the 55th edition, 2001, published by Medical Economics Co., Inc. finds among the Montvale.These medicines can be used according to treatment effective dose known in the art and scheme separately, and for example those are Physicians ' Desk Reference, the 55th edition, 2001, published by Medical Economics Co., Inc., the product of putting down in writing among the Montvale.

[0117] in a preferred embodiment of the invention, can give administration to treat mammiferous pain with one or more other pain relief agents chemical compound useful among the present invention.With regard to " pain relief agents ", it is meant the medicine of any direct or indirect treatment pain symptom.The example of pain relief agents comprises for example anti-inflammatory agent indirectly, for example the resisting rheumatoid disease medicine.

[0118] one or more other pain relief agents can be used (for example simultaneously use separately or use) simultaneously with chemical compound of the present invention in pharmaceutical composition, and/or continuous administration.Preferably, chemical compound of the present invention and one or more pain relief agents use by this way so that above-mentioned both in mammalian body, exist a period of time with treatment pain.

[0119] application process of other pain relief agents can be identical or different with the employed route of administration of The compounds of this invention.For example, opioid is oral administration preferably, intravenous, and intranasal, or the intramuscular administration approach is used.

[0120] one of ordinary skill in the art will recognize that the dosage to other pain relief agents of administration will depend on described specific pain relief agents and required route of administration.Therefore, other pain relief agents can be put into practice administration and uses according to well known by persons skilled in the art, for example be disclosed in list of references such as Physicians ' Desk Reference, the 55th edition, 2001, published by Medical Economics Co., Inc., Montvale, those among the NJ.

[0121] example of the pain relief agents that can use with The compounds of this invention comprises analgesic for example non-narcotic analgesics or narcosis analgesic; Anti-inflammatory agent is NSAID (non-steroidal anti-inflammatory drug) (NSAID) for example, steroid or antirheumatic; Migraine formulation example such as beta-adrenergic blocking agent, ergot derivative, or isometheptene; Tricyclics is amitryptyline for example, desipramine, or the miaow handkerchief is bright; Antuepileptic is gabapentin for example, kappa rice piperazine, topiramate, sodium valproate or phenytoin; α ₂Agonist; Or selectivity 5-hydroxy tryptamine uptake inhibitor/selectivity norepinephrine uptake inhibitors, or its combination.Some medicines performance that it will be recognized by those skilled in the art the following stated alleviates for example effect of pain and inflammation of various disease conditions, and other drug only can alleviate for example pain of a kind of symptom.An instantiation with medicine of multiple character is an aspirin, and aspirin is anti-inflammatory agent when giving with high dose, but only is analgesics when low dosage.Pain relief agents can comprise any combination of said medicine, and for example, pain relief agents can be the combination of non-narcotic analgesics and narcosis analgesic.

[0122] in the preferred embodiment of the invention, at least a chemical compound of the present invention and at least a opioid analgesic can be used with treatment pain according to the aforesaid method of this paper.Have been found that when The compounds of this invention when for example morphine is used with at least a opioid analgesic The compounds of this invention has such beneficial effect and for example reduces the pain sensation, increases the time of pain relief and/or compare with other comparable nmda antagonists and reduce side effect to a greater degree.

[0123] referring now to following concrete, limiting examples is set forth the present invention.The technical staff in organic synthesis field also can know other synthetic route of The compounds of this invention.At reagent used herein with intermediate is available commercially or can be according to the preparation of the literature method of routine.

[0124] in another embodiment, the present invention relates to form the method for the preparation that comprises formula (I) chemical compound.The method comprising the steps of: form wet granular; With the formation solid dosage forms.Wet granular comprises:

At least a binding agent, preferred polyvidone;

Randomly at least a filler, preferably microcrystalline cellulose;

Randomly at least a disintegrating agent, preferred cross-linked carboxymethyl cellulose sodium; With

The chemical compound of at least a formula (I) or its pharmaceutically acceptable salt, preferred [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] phosphoric acid or its pharmaceutically acceptable salt.

[0125] in certain preferred aspects, the formation of wet granular is by with at least a filler or disintegrating agent and described formula (I) chemical compound or its pharmaceutically acceptable salt dry mixed; With the binder solution of at least a formation wet granular dry mixture is granulated then and form.

[0126] in certain preferred aspects, this method further comprises step: dry wet particle; The dried granule of milling; Randomly above-mentioned dried granule of milling and the outer component of one or more granules are mixed then, preferably include the filler and/or the disintegrating agent that add the formation wet granular.

[0127] in certain embodiments, the present invention relates to product by method for preparing.

[0128] referring now to following concrete, limiting examples is set forth the present invention.The technical staff in organic synthesis field also can know other synthetic route of The compounds of this invention.At reagent used herein with intermediate is available commercially or can be according to the preparation of the literature method of routine.

Embodiment

[0129] further definition the present invention in following examples, except as otherwise noted, wherein all umbers and percentage number average are calculated by weight and temperature is a Celsius temperature.Though should be appreciated that these embodiment expression preferred embodiment of the invention, only be that these embodiment are provided for explanation.According to above discussion and these examples, those skilled in the art can determine essential feature of the present invention, and those skilled in the art can carry out different variations and revise the present invention so that it is suitable for different purposes and situation and can break away from the spirit and scope of the present invention the present invention.

Embodiment 1:

Capsule preparations (69.4%[2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] phosphoric acid)

[0130] by the capsule (100,200, the capsule of 300mg) of three kinds of concentration of common wet granular preparation.Particulate batch is 1297.8g.[2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] capsular prescription of phosphoric acid of all concentration is as shown in table 1.

[0131] preparation microcrystalline Cellulose, the mixture that the granule interior of [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] phosphoric acid and cross-linked carboxymethyl cellulose sodium is divided.By polyvidone being dissolved in the pure water solution of preparation polyvidone in the purified water.Mixture and povidone solution are granulated in high shear granulator.When needs, add pure water in addition to reach the granulation terminal point of needs.Then that granule is dry in suitable exsiccator, grind, and be transferred in the blender.Be added in the granule microcrystalline Cellulose and cross-linking sodium carboxymethyl cellulose and mixing.Add magnesium stearate and mixing.The capsular parts of #0 are filled in assembling to capsule filling machine.[2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] phosphoric acid (69.35% weight is in the total formulation weight amount) uses the target filling weight with opaque hydroxypropyl emthylcellulose (HPMC) the #0 capsule of brown.

[0132] these capsular analytical data are as shown in table 2.

Table 1

Component	100mg	200mg	300mg
Component	100mg	200mg	300mg		The mg/ capsule	The mg/ capsule	The mg/ capsule
In the granule					The mg/ capsule	The mg/ capsule	The mg/ capsule
In the granule				[2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] phosphoric acid	100.00	200.00	300.00
Microcrystalline Cellulose (AVICEL PH101)	13.91	27.82	41.73		100.00	200.00	300.00
Microcrystalline Cellulose (AVICEL PH101)	13.91	27.82	41.73	Polyvidone USP, 17PF	3.61	7.22	10.83
Cross-linking sodium carboxymethyl cellulose	5.77	11.54	17.31	Polyvidone USP, 17PF	3.61	7.22	10.83
Cross-linking sodium carboxymethyl cellulose	5.77	11.54	17.31	Outside the granule
Microcrystalline Cellulose (AVICEL PH101)	14.42	28.84	43.26	Outside the granule
Microcrystalline Cellulose (AVICEL PH101)	14.42	28.84	43.26	Cross-linking sodium carboxymethyl cellulose	5.77	11.54	17.31
Magnesium stearate (vegetable grade)	0.72	1.44	2.16	Cross-linking sodium carboxymethyl cellulose	5.77	11.54	17.31
Magnesium stearate (vegetable grade)	0.72	1.44	2.16	Amount to	144.20	288.40	432.60

Table 2

Detection		The result		The result		The result
Detection		The result		The result		The result				100mg		200mg		300mg
Concentration (HPLC)		98.3％LC		97.5％LC		98.9％LC				100mg		200mg		300mg
Concentration (HPLC)		98.3％LC		97.5％LC		98.9％LC		Content uniformity		On average: 96.8% cv=3.8% scope: 89.9-101.2%		On average: 98.0% cv=2.7% scope: 94.5-101.8%		On average: 99.7% cv=2.7% scope: 94.5-101.8%
Dissolution	Time	Average %	Scope %	Average %	Scope %	Average %	Scope %	Content uniformity		On average: 96.8% cv=3.8% scope: 89.9-101.2%		On average: 98.0% cv=2.7% scope: 94.5-101.8%		On average: 99.7% cv=2.7% scope: 94.5-101.8%
	Time	Average %	Scope %	Average %	Scope %	Average %	Scope %	15 minutes	97.0	95-99	98.6	97-102	96.2	89-100
	30 minutes	98.8	96-102	99.7	98-102	99.1	93-102	15 minutes	97.0	95-99	98.6	97-102	96.2	89-100
	30 minutes	98.8	96-102	99.7	98-102	99.1	93-102	45 minutes	99.5	96-102	99.8	98-102	99.6	95-103

LC=labelled amount (label claim) RL=method report limit (Method reporting limit)

Embodiment 2:

Capsule preparations (86.7%[2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2 base) ethyl] phosphoric acid)

[0133] use following component to repeat the preparation process of embodiment 1:

Component	200mg
Component	200mg		The mg/ capsule
In the granule			The mg/ capsule
In the granule		[2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] phosphoric acid	200.00
Polyvidone USP, 17PF	3.53		200.00
Polyvidone USP, 17PF	3.53	Cross-linking sodium carboxymethyl cellulose	7.05
Microcrystalline Cellulose (AVICEL PH101)	14.1	Cross-linking sodium carboxymethyl cellulose	7.05
Microcrystalline Cellulose (AVICEL PH101)	14.1	Outside the granule
Cross-linking sodium carboxymethyl cellulose	4.7	Outside the granule
Cross-linking sodium carboxymethyl cellulose	4.7	Magnesium stearate (vegetable grade)	1.18
Amount to	230.56	Magnesium stearate (vegetable grade)	1.18

Embodiment 3:

Capsule preparations (69.35%[2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] phosphoric acid)

[0134] use following component to repeat the preparation process of embodiment 1:

Component	300mg
Component	300mg		The mg/ capsule
In the granule			The mg/ capsule
In the granule		[2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] phosphoric acid	208.05
Polyvidone USP, 17PF	7.5		208.05
Polyvidone USP, 17PF	7.5	Cross-linking sodium carboxymethyl cellulose	12.00
Microcrystalline Cellulose (AVICEL PH101)	28.95	Cross-linking sodium carboxymethyl cellulose	12.00
Microcrystalline Cellulose (AVICEL PH101)	28.95	Outside the granule
Microcrystalline Cellulose (AVICEL PH101)	30.00	Outside the granule
Microcrystalline Cellulose (AVICEL PH101)	30.00	Cross-linking sodium carboxymethyl cellulose	12.00
Magnesium stearate (vegetable grade)	1.5	Cross-linking sodium carboxymethyl cellulose	12.00
Magnesium stearate (vegetable grade)	1.5	Amount to	300

[0135] prepares the common granule that comprises 69.35% active component by wet granulation.The capsule for preparing 100mg or 300mg concentration by the final mixture of in the #0 capsule, filling 144.20mg and 432.6mg respectively.

Embodiment 4:

The tablet formulation of enteric coating

[0136] carries out the preparation research of tablet by wet granulation.Use 30 POVIDONE K 30 BP/USP 17 (USP) as binding agent and cross-linking sodium carboxymethyl cellulose (Ac-Di-Sol ^TM, can obtain from FMC Corp.) and prepare [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] phosphoric acid tablet of 200mg as disintegrating agent.Use enteric coating solution to tablet coating then.With the base formulation of this tablet as [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] phosphoric acid 200mg tablet.

Component	Inventory/sheet (mg)	Effect
Component	Inventory/sheet (mg)	Effect	[2-(8 in the granule, 9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] phosphoric acid cross-linking sodium carboxymethyl cellulose polyvidone USP, outer microcrystalline Cellulose (AVICEL PH101) the cross-linking sodium carboxymethyl cellulose magnesium stearate of 17PF granule	? 200.00 ? 7.05 3.53 ? 14.10 4.70 1.18	Active component disintegrant adhesive diluent and disintegrant disintegrant lubricant

[0137] tablet was kept perfectly in 0.01N HCL in 2 hours.Tablet disintegrate fully within 26 minutes in phosphate buffer (pH6.8).

Embodiment 5:

The tablet formulation that comprises the enteric coating of sodium lauryl sulphate

[0138] comprise the tablet formulation of the enteric coating of sodium lauryl sulphate according to following table preparation:

Component	Inventory/sheet (mg)	Effect
Component	Inventory/sheet (mg)	Effect	[2-(8 in the particle; 9-dioxo-2; 6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] phosphoric acid Ac-Di-Sol PVP USP, outer microcrystalline cellulose (AVICEL PH101) the Ac-Di-Sol lauryl sodium sulfate dolomol of 17PF particle	? 200.00 ? 7.05 3.53 ? 14.10 4.70 5.88 1.18	Active component disintegrant adhesive diluent and disintegrant disintegrant sorbefacient lubricant

[0139] carry out Visulution2 hour of tablet in 0.01N HCL, carry out until the complete disintegrate of tablet in phosphate buffer (pH 6.8) then, the visulution time is 24 minutes in buffer.

Embodiment 6:

The tablet formulation that comprises the enteric coating of EDTA four sodium

[0140] comprise the tablet formulation of the enteric coating of EDTA four sodium according to following table preparation:

Component	Inventory/sheet (mg)	Effect
Component	Inventory/sheet (mg)	Effect	[2-(8 in the particle; 9-dioxo-2; 6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] phosphoric acid Ac-Di-Sol PVP USP, outer microcrystalline cellulose (AVICEL PH101) the Ac-Di-Sol EDTA four sodium dolomols of 17PF particle	? 200.00 ? 7.05 3.53 ? 14.10 4.70 7.05 1.18	Active component disintegrant adhesive diluent and disintegrant disintegrant sorbefacient lubricant

[0141] carry out Visulution2 hour of tablet in 0.01N HCL, carry out until the complete disintegrate of tablet in phosphate buffer (pH 6.8) then, the visulution time is 26 minutes in buffer.

Embodiment 7: the tablet formulation that comprises the enteric coating of TWEEN80

[0142] comprise the tablet formulation of the enteric coating of TWEEN80 according to following table preparation:

Component	Inventory/sheet (mg)	Effect
Component	Inventory/sheet (mg)	Effect	[2-(8 in the particle; 9-dioxo-2; 6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] phosphoric acid microcrystalline cellulose (AVICEL PH101) cross-linked carboxymethyl cellulose sodium polyethylene glycol-20 sorbitol monooleate (TWEEN-80) PVP USP that anhydrates, outer microcrystalline cellulose (AVICEL PH101) cross-linked carboxymethyl cellulose sodium dolomol of 17PF particle	? 200.00 ? 29.00 9.00 15.00 ? 10.50 ? 29.00 6.00 1.50	Active component diluent and disintegrant disintegrant sorbefacient adhesive diluent and disintegrant disintegrant lubricant

[0143] carry out Visulution2 hour of tablet in 0.01N HCL, carry out until the complete disintegrate of tablet in phosphate buffer (pH 6.8) then, the visulution time is 15 minutes in buffer.

Embodiment 8: the tablet formulation that comprises the enteric coating of Capric acid sodium salt

[0144] comprise the tablet formulation of the enteric coating of Capric acid sodium salt according to following table preparation:

Component	Inventory/sheet (mg)	Effect
Component	Inventory/sheet (mg)	Effect	[2-(8 in the granule, 9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] phosphoric acid microcrystalline Cellulose (AVICEL PH101) cross-linked carboxymethyl cellulose sodium Capric acid sodium salt polyvidone USP, 17PF	? 200.00 ? 20.00 20.00 50.00 18.00	Active component diluent and disintegrating agent disintegrating agent absorption enhancer binding agent
Component	Inventory/sheet (mg)	Effect		? 200.00 ? 20.00 20.00 50.00 18.00
Component	Inventory/sheet (mg)	Effect	Outer microcrystalline Cellulose (AVICEL PH101) cross-linked carboxymethyl cellulose sodium magnesium stearate of granule	? 82.00 8.00 2.00	Diluent and disintegrating agent disintegrating agent lubricant

Embodiment 9: comprise the tablet formulation of enteric coating and the capsule preparations of palmitoyl carnitine

[0145] preparation comprises the tablet formulation of enteric coating and the capsule preparations of palmitoyl carnitine according to following table:

Component	％(W/W)	The mg/ sheet
Component	％(W/W)	The mg/ sheet	[2-(8 in the granule, 9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] phosphoric acid cross-linking sodium carboxymethyl cellulose polyvidone USP, 17PF granule external crosslinking sodium carboxymethyl cellulose microcrystalline Cellulose (AVICEL PH101) magnesium stearate	? 86.75 ? 3.06 1.53 ? 2.04 6.11 0.51	? 200.00 ? 7.05 3.53 ? 4.70 14.10 1.18
Core tablet weight	100.00	230.56		? 86.75 ? 3.06 1.53 ? 2.04 6.11 0.51	? 200.00 ? 7.05 3.53 ? 4.70 14.10 1.18
Core tablet weight	100.00	230.56	Enteric film coat weight	8.00	18.44
Final sheet is heavy		249.00	Enteric film coat weight	8.00	18.44
Final sheet is heavy		249.00	Palmitoyl carnitine HGC#1		200 1 capsules (TIC)

Embodiment 10:

[2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] phosphoric acid bioavailability in the Beagle dog: the evaluation of oral formulations

[0146] this research gets down to [2-8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] phosphoric acid bioavailability in the Beagle dog is studied.Test preparation relatively comprised instant-free capsule preparations and 7 kinds of enteric coating preparations.

[0147] 12 female Beagle dogs is divided into four groups (3/group).This research comprises the crossing research in two weeks.Each treatment was separated by with the clean phase in a week.Every group of [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] phosphoric acid of using single dose 200 or 400mg.

[0148] all preparations is used with 10ml water.Gather blood sample at the testing program official hour by jugular puncture; Separated plasma, freezing and-70 ℃ of storages up to analyzing.HPLC assay determination [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] concentration of phosphoric acid by checking.

[0149] blood plasma [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] phosphoric acid concentration-time graph is carried out non-compartment analysis.Curve according to single dog directly writes down C _MaxAnd t _MaxValue and use linear trapezoid method calculate AUC (0-24) value.The result is as shown in table 3.

[0150] result shows that the enteric coating preparation that comprises absorption enhancer compares with the instant-free capsule that does not comprise absorption enhancer, provide that bigger [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] exposure of phosphoric acid.The enteric coating preparation that comprises absorption enhancer when the result is further illustrated in same dose is compared with the capsule of the enteric coating that does not comprise absorption enhancer and is provided that bigger [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] exposure of phosphoric acid.The capsular mean dose normalization of enteric coating preparation and instant-free ratio (AUC _0-24) scope is 1.20 to 2.51.

Table 3

Preparation	Absorption enhancer	AUC _0-24 (μg？·hr/mL)	The AUC ratio ^a	C _max (μg/mL)	C _maxRatio ^a	t _max(hour)	T _lag(hour)
Preparation	Absorption enhancer	AUC _0-24 (μg？·hr/mL)	The AUC ratio ^a	C _max (μg/mL)	C _maxRatio ^a	t _max(hour)	T _lag(hour)	2 * 200mg instant-free capsule (comparison) (embodiment 2)	Do not have	18.6(6.17) ? ? ?	- ? ? ?	6.20 (4.53) ? ?	- ? ? ?	1.33 (0.76) ? ?	0 ? ? ?
1 * 200mg ECT (comparison)	Do not have	5.24(5.06) ? ?	0.56 ? ?	2.55 (2.34) ?	0.82 ? ?	2.50 (1.50) ?	0.83 (0.58) ?	2 * 200mg instant-free capsule (comparison) (embodiment 2)	Do not have	18.6(6.17) ? ? ?	- ? ? ?	6.20 (4.53) ? ?	- ? ? ?	1.33 (0.76) ? ?	0 ? ? ?
1 * 200mg ECT (comparison)	Do not have	5.24(5.06) ? ?	0.56 ? ?	2.55 (2.34) ?	0.82 ? ?	2.50 (1.50) ?	0.83 (0.58) ?	2 * 200mg ECT (comparison)	Do not have	22.3(9.14) ? ?	1.20 ? ?	12.7 (6.89) ?	2.04 ? ?	2.67 (1.15) ?	1.67 (0.76) ?
2 * 200mg ECT	Polyethylene Glycol-20 sorbitol monooleate (TWEEN-80) that anhydrates	24.0(14.0) ? ?	1.29 ? ?	14.5 (9.30) ?	2.34 ? ?	1.67 (1.15) ?	0.67 (1.15) ?	2 * 200mg ECT (comparison)	Do not have	22.3(9.14) ? ?	1.20 ? ?	12.7 (6.89) ?	2.04 ? ?	2.67 (1.15) ?	1.67 (0.76) ?
2 * 200mg ECT		24.0(14.0) ? ?	1.29 ? ?	14.5 (9.30) ?	2.34 ? ?	1.67 (1.15) ?	0.67 (1.15) ?	2 * 200mg ECT	Sodium lauryl sulphate	36.9(31.4) ?	1.98 ?	17.6 (16.2)	2.84 ?	1.00 (0.00)	0 ?
2 * 200mg ECT	Capric acid sodium salt	46.7(28.9) ?	2.51 ?	24.8 (20.4)	4.00 ?	1.67 (1.26)	0.17 (0.29)	2 * 200mg ECT	Sodium lauryl sulphate	36.9(31.4) ?	1.98 ?	17.6 (16.2)	2.84 ?	1.00 (0.00)	0 ?
2 * 200mg ECT	Capric acid sodium salt	46.7(28.9) ?	2.51 ?	24.8 (20.4)	4.00 ?	1.67 (1.26)	0.17 (0.29)	2 * 200mg ECT	EDTA ?	24.6(14.1) ?	1.32 ?	13.5 (9.99)	2.18 ?	2.17 (1.61)	1.18 (0.75)
2 * 200mg ECT	Palmitoyl carnitine	29.5(25.9) ?	1.59 ?	15.5 (16.4)	2.51 ?	2.50 (1.32)	1.17 (2.02)	2 * 200mg ECT	EDTA ?	24.6(14.1) ?	1.32 ?	13.5 (9.99)	2.18 ?	2.17 (1.61)	1.18 (0.75)

A: for the meansigma methods of the capsular dosage normalization of instant-free ratio

Embodiment 11:

The 2-of single dose (8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] the pharmacokinetics research of phosphoric acid

[0151] carried out the tolerance studies of the single dose that increases progressively, the oral dose that fasting is used is 500,1000,2000, and 4000mg.In every group, 8 experimenters or accept placebo (2 experimenters) or accept 2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl of prescribed dose] phosphoric acid (6 experimenters).In the 2nd cycle of research, the experimenter's intersection in the 1000mg of the fasting group is accepted the dosage after meal of 1000mg.In addition, in old subject group, repeat the dosage level of 2000mg.

[0152] table 4 has been summarized in this research all groups at the Orally administered 2-of fasting state (8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] pharmacokinetics curve behind the phosphoric acid capsule.2-(8,9-dioxo-2,6 diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl in using back 1 to 2 hour] phosphoric acid is by fast Absorption, reaches peak plasma concentration.2-(8,9-dioxo-2,6 diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl subsequently] plasma concentration of phosphoric acid descends, and it is eliminated to single index and eliminates or be two indexes eliminations, on average t once in a while _1/2Be 6 to 16 hours, but t _1/2Estimated value always not reliable.For first group of experimenter, the average absolute bioavailability is estimated as 4.3%.

[0153] for second group experimenter, standardized higher fatty acid, use 2-(8 after the high heat food, 9-dioxo-2,6 diazabicyclos [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] phosphoric acid delayed 2-(8,9-dioxo-2,6 diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] absorption of phosphoric acid, prolong average t _MaxAbout 2 hours (from 0.88 to 2.92 hours) and reduce average C _Max67% (from 1179 to 392ng/ml).In addition, use with food reduce 2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] the average A UC 57% of phosphoric acid (from 5132 to 2210ngh/mL).

[0154] 2-(8 that is accepting 2000mg, 9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2 base) ethyl] old experimenter's (fasting of phosphoric acid, single dose) in, average oral administration clearance rate (Cl/F) is than low about 10% (3.14 than the 3.50L/h/kg) of the healthy adult experimenter who accepts same dosage.Therefore, 2-in old experimenter (8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] the average A UC high slightly (8891 than 7644ngh/mL) of phosphoric acid.

Table 4

Use separately the back health volunteer in 2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-

Alkene-2-yl) ethyl] meansigma methods ± SD (%CV) (every group of n=6) of phosphoric acid PK parameter

Dosage	C _max (ng/mL)	T _max (h)	T _1/2 (h)	AUC _0-24 (ng·h/mL)
Dosage	C _max (ng/mL)	T _max (h)	T _1/2 (h)	AUC _0-24 (ng·h/mL)	500mg is oral, fasting	320±63 (20％)	1.9±0.7 (39％)	6.7±6.4 (96％)	2140±542 (25％)
100mg 1-hour, injection	4007±512 (13％)	0.95±0.11 (12％)	8.3±8.8 (106％)	10226±1719 (17％)	500mg is oral, fasting	320±63 (20％)	1.9±0.7 (39％)	6.7±6.4 (96％)	2140±542 (25％)
100mg 1-hour, injection	4007±512 (13％)	0.95±0.11 (12％)	8.3±8.8 (106％)	10226±1719 (17％)	1000mg is oral, fasting	1179±618 (52％)	0.88±0.59 (67％)	14.6±9.3 (64％)	5132±1420 (28％)
1000mg is oral, feed	392±236 (60％)	2.92±1.20 (41％)	16.0±10.0 (63％)	2210±578 (26％)	1000mg is oral, fasting	1179±618 (52％)	0.88±0.59 (67％)	14.6±9.3 (64％)	5132±1420 (28％)
1000mg is oral, feed	392±236 (60％)	2.92±1.20 (41％)	16.0±10.0 (63％)	2210±578 (26％)	2000mg is oral, fasting	1786±1364 (76％)	1.42±0.96 (68％)	6.4±2.0 (32％)	7644±1828 (25％)
2000mg is oral, fasting (old age)	1606±628 (39％)	1.25±0.61 (49％)	14.1±11.1 (79％)	8891±1437 (16％)	2000mg is oral, fasting	1786±1364 (76％)	1.42±0.96 (68％)	6.4±2.0 (32％)	7644±1828 (25％)
2000mg is oral, fasting (old age)	1606±628 (39％)	1.25±0.61 (49％)	14.1±11.1 (79％)	8891±1437 (16％)	4000mg is oral, fasting	1488±436 (29％)	2.60±1.08 (42％)	9.1±4.6 (51％)	8982±1981 (22％)

The AUC of report is t=0 to ∞ in the table 4

Embodiment 12:

The pharmacokinetics research of [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] phosphoric acid of multiple dose

[0155] carried out the multiple dose tolerance studies that increases progressively of [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) ethyl] phosphoric acid, in 14 days cycle, use 200 to the health volunteer, 400,800 and the oral dose of 1600mg.

[0156] table 5 has been described repeatedly the pharmacokinetic data behind the ascending-dose.Fig. 1 to 6 is as follows:

Fig. 1 is accepting 200,400,800 or 1600mg [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] behind the phosphoric acid in the health volunteer as time function (hour) single dose [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] mean plasma concentration (ng/mL) curve of phosphoric acid.

Fig. 2 is accepting 200,400,800, or 1600mg [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] behind the phosphoric acid in the health volunteer as the C of single dose [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] phosphoric acid of dose function (mg) _Max(ng/mL) curve.

Fig. 3 is accepting 200,400,800, or 1600mg [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] behind the phosphoric acid in the health volunteer as the single dose of dose function (mg) [2-(and 8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] AUC (ngh/mL, t=0 to the ∞) curve of phosphoric acid.

Fig. 4 is accepting 200,400,800, or 1600mg [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] behind the phosphoric acid in the health volunteer as time function (hour) average steady state plasma concentration (ng/mL) curve of [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] phosphoric acid.

Fig. 5 is accepting 200,400,800, or 1600mg [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] behind the phosphoric acid in the health volunteer as the stable state C of [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] phosphoric acid of dose function (mg) _Max(ng/mL) curve.

Fig. 6 accepts 200,400,800, or 1600mg [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] behind the phosphoric acid in the health volunteer as stable state AUC (ngh/mL) curve of [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] phosphoric acid of dose function (mg).

Table 5

[2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) in the health volunteer

Ethyl] meansigma methods ± SD (%CV) (every group of n=6) of phosphoric acid PK parameter

Dosage	C _max (ng/mL)	T _max (h)	T _1/2 (h)	AUC ^** (ng·h/mL)
Dosage	C _max (ng/mL)	T _max (h)	T _1/2 (h)	AUC ^** (ng·h/mL)	It is oral that single dose is used 200mg, fasting	172±90 (52％)	1.3±0.5 (40％) ?	3.5±0.6 (18％) ?	699±201 (29％) ?
400mg is oral, fasting	346±282 (82％)	2.0±1.6 (79％)	4.5±1.2 (27％)	1487±371 (25％)	It is oral that single dose is used 200mg, fasting	172±90 (52％)	1.3±0.5 (40％) ?	3.5±0.6 (18％) ?	699±201 (29％) ?
400mg is oral, fasting	346±282 (82％)	2.0±1.6 (79％)	4.5±1.2 (27％)	1487±371 (25％)	800mg is oral, fasting	715±524 (73％)	1.4±0.7 (47％)	8.3±1.3 (16％)	3188±800 (25％)
1600mg is oral, fasting	962±592 (62％)	1.3±1.3 (98％)	6.9±1.7 (24％)	4057±1316 (32％)	800mg is oral, fasting	715±524 (73％)	1.4±0.7 (47％)	8.3±1.3 (16％)	3188±800 (25％)
1600mg is oral, fasting	962±592 (62％)	1.3±1.3 (98％)	6.9±1.7 (24％)	4057±1316 (32％)	It is oral that multiple dose is used (14 days) 200mg q 12h, feed	153±75 (49％) ?	1.2±0.3 (27％) ?	6.6±3.9 (60％) ?	817±265 (32％) ? ?
400mg q 12h is oral, fasting	398±209 (53％)	1.6±1.3 (83％)	11.9±10.4 (87％)	1811±747 (41％)		153±75 (49％) ?	1.2±0.3 (27％) ?	6.6±3.9 (60％) ?	817±265 (32％) ? ?
400mg q 12h is oral, fasting	398±209 (53％)	1.6±1.3 (83％)	11.9±10.4 (87％)	1811±747 (41％)	800mg q 12h is oral, fasting	436±151 (35％)	1.4±0.6 (40％)	16.9±8.8 (52％)	2175±644 (30％)
1600mg q 12h is oral, fasting	1509±842 (56％)	1.4±1.3 (90％)	10.5±6.6 (63％)	4909±1211 (25％)	800mg q 12h is oral, fasting	436±151 (35％)	1.4±0.6 (40％)	16.9±8.8 (52％)	2175±644 (30％)

The AUC that the single dose of report is used in the table 5 is t=0 to ∞

The AUC that the multiple dose of report is used is t=0 to 12 hour (tau)

[0157] use for example scope of molecular weight of physical property in this article, or chemical property is for example during the scope of chemical formula, is intended to comprise therein the specific embodiments of the combination and time combination of all scopes.

[0158] every part of patent will quoting in presents or describe, the disclosure of patent application and publication is all complete to be incorporated herein by reference.

[0159] one skilled in the art will appreciate that and can carry out many variations and modification the preferred embodiment of the invention, and this variation and revise and can carry out not breaking away under the spirit of the present invention.Therefore, additional claim is intended to comprise the variation that falls into all these equivalences in true spirit of the present invention and the scope.

Claims

1. solid pharmaceutical dosage formulation comprises:

Wherein:

R ₂And R ₃Independently be selected from hydrogen,

Condition is R ₂And R ₃Have at least one not to be hydrogen;

R ₇And R ₈Be independently selected from hydrogen, C ₁To C ₁₂The alkyl of straight or branched, C ₂To C ₇The alkenyl or alkynyl of straight or branched, C ₅To C ₁₃Aryl, have the C of 5 to 13 carbon atoms at aryl moiety ₆To C ₂₁Aralkyl, 5 yuan to 13 yuan heteroaryl has 6 yuan to 21 yuan heteroarylalkyl of 5 to 13 atoms or R at heteroaryl moieties ₇And R ₈Can form jointly and have 4 to 8 carbon atoms on the ring and randomly be selected from nitrogen, the cycloalkyl of one or two atom or Heterocyclylalkyl in oxygen or the sulfur;

Wherein has aryl, heteroaryl, arbitrary R of cycloalkyl or Heterocyclylalkyl part ₁To R ₈Group can be chosen wantonly at aryl, heteroaryl, and cycloalkyl or Heterocyclylalkyl part independently are selected from halogen, cyano group, nitro or hydroxyl, C by 1 to about 5 ₁To C ₆Alkyl, C ₁To C ₆The substituent group of alkoxyl replace; With

At least a pharmaceutically acceptable absorption enhancer.

2. solid pharmaceutical dosage formulation comprises:

The chemical compound of at least a general formula (I) or its pharmaceutically acceptable salt:

Wherein:

R ₁Be hydrogen;

A is-(CH ₂) _n-, n is 2; With

R ₂And R ₃Be hydrogen; With

At least a pharmaceutically acceptable absorption enhancer.

3. according to the dosage form of claim 1 or 2, it is a powder, capsule or tablet.

4. according to the dosage form of claim 1 or 2, it is the capsule of enteric coating or the tablet of enteric coating.

5. according to the dosage form of claim 4, it comprises and is selected from methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate, Lac, hydroxypropyl methyl cellulose succinate, the anionic polymer of carboxymethyl cellulose.

6. according to the dosage form of claim 1 or 2, it is instant-free capsule or immediate release tablet.

7. according to the dosage form of claim 1 or 2, it comprises the chemical compound of about 25% weight to the described formula (I) of about 99.5% weight, in the gross weight of described dosage form.

8. according to the dosage form of claim 7, it comprises the chemical compound of about 50% weight to the described formula (I) of about 99.5% weight, in the gross weight of described dosage form.

9. dosage form according to Claim 8, it comprises the chemical compound of about 60% weight to the described formula (I) of about 99.5% weight, in the gross weight of described dosage form.

10. according to the dosage form of claim 9, it comprises the chemical compound of about 70% weight to the described formula (I) of about 99.5% weight, in the gross weight of described dosage form.

11. according to the dosage form of claim 1, wherein R ₁Be hydrogen or C ₁To C ₄Alkyl.

12. according to each dosage form in claim 1 or the claim 3 to 11, wherein A has formula-(CH ₂) _n-alkylidene, wherein n is 1 to 3.

13. according to each dosage form in claim 1 or the claim 3 to 12, wherein R ₂Be hydrogen.

14. according to each dosage form in claim 1 or the claim 3 to 13, wherein R ₄And R ₅Be hydrogen independently, C ₁To C ₄Alkyl, and R ₆Be C ₃To C ₁₀The alkyl of straight or branched, C ₅To C ₇Aryl, 5 yuan to 7 yuan heteroaryl has the cycloalkyl of 5 to 7 carbon atoms on ring.

15. according to the dosage form of claim 14, wherein R ₆Be C ₅To C ₇Aryl.

16. according to each dosage form in the claim 1 to 15, wherein R ₂And R ₃All be hydrogen.

17. according to the dosage form of claim 1, the chemical compound of wherein at least a described formula (I) is:

3-{2-[8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl] ethyl }-3-epoxy-7-oxo-7-phenyl-2,4,6-trioxa-3-phospha seven-1-yl benzoic acid ester;

3-{2-[8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl] ethyl }-3-epoxy-7-oxo-8-propyl group-2,4,6-trioxa-3-phospha 11-1-base 2-Propylpentanoic ester;

2, and 2-dimethyl-propanoic acid (2,2-dimethyl-propionyloxy methoxyl group-[2-(8,9-dioxo-2,6-diaza-dicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl)-ethyl]-phosphine oxygen ylmethyl ester;

7-cyclohexyl-3-{2-[8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl] ethyl }-1,5-dimethyl-3-epoxy-7-oxo-2,4,6-trioxa-3-phospha seven-1-basic ring cyclohexane carboxylic-acid ester;

[2-(8,9-dioxo-2,6-diaza-dicyclo [5.2.0] ninth of the ten Heavenly Stems-1-(7)-alkene-2-yl)-ethyl]-di(2-ethylhexyl)phosphate isopropoxy carbonyl oxygen ylmethyl ester;

[2-(8,9-dioxo-2,6-diaza-dicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl)-ethyl]-di(2-ethylhexyl)phosphate dimethyl methyl aminoacyl methoxyl group ester;

Or its pharmaceutically acceptable salt.

18. according to each dosage form in the claim 1 to 17, it comprises the described absorption enhancer of about 0.25% weight to about 50% weight, in the gross weight of described dosage form.

19. according to each dosage form in the claim 1 to 18, wherein pharmaceutically acceptable absorption enhancer is a surfactant, cholate, fatty acid, soap, chelating agent, acylcarnitines, acyl group choline or its mixture.

20. according to the dosage form of claim 19, wherein surfactant is an ionic surfactant, nonionic surfactant or and composition thereof.

21. according to the dosage form of claim 20, wherein said ionic surfactant is a sodium lauryl sulphate, aerosol OT or its mixture.

22. according to the dosage form of claim 20, wherein said nonionic surfactant is a polyoxyethylene alkyl ether, polyxyethylated ester, polysorbate or its mixture.

23. according to the dosage form of claim 22, wherein said polyoxyethylene alkyl ether is Polyethylene Glycol-20 sorbitan monooleate

24. according to the dosage form of claim 19, wherein said cholate is a sodium cholate, sodium deoxycholate or its mixture.

25. according to the dosage form of claim 19, wherein fatty acid is an oleic acid.

26. according to the dosage form of claim 19, wherein soap is Capric acid sodium salt.

27. according to the dosage form of claim 19, wherein said chelating agent is an ethylenediaminetetraacetic acid.

28. according to the dosage form of claim 19, wherein said is the acylcarnitines palmitoyl carnitine.

29. according to the dosage form of claim 19, wherein the acyl group choline is the lauroyl choline.

30. according to each dosage form in the claim 1 to 29, it further comprises filler, disintegrating agent, binding agent, lubricant or and composition thereof.

31. according to the dosage form of claim 30, wherein said filler is a lactose, microcrystalline Cellulose, mannitol, calcium phosphate, pregelatinized Starch, pregelatinated sucrose or and composition thereof.

32. according to the dosage form of claim 30, wherein said disintegrating agent is cross-linked carboxymethyl cellulose sodium, starch, carboxymethyl starch sodium, pregelatinized Starch, polyvinylpolypyrrolidone and composition thereof.

33. according to the dosage form of claim 30, wherein said binding agent is a polyvidone, hydroxypropyl emthylcellulose, polyvinyl alcohol, gelatin, natural gum and composition thereof.

34. according to the dosage form of claim 30, wherein said lubricant is a magnesium stearate, sodium stearyl fumarate and composition thereof.

35. the single dose form comprises in the claim 1 to 34 each dosage form.

36. the multiple dose form comprises in the claim 1 to 34 each dosage form.

37. at least a method that is selected from the disease of cerebrovascular disease of treatment in mammal, described disease is selected from cerebral ischemia, cerebral infarction or cerebral vasospasm; Cerebral trauma; Muscular spasm; Be selected from the convulsive disorder of epilepsy or status epilepticus; Hypoglycemia; Asystole; Perinatal asphyxia disease; Or chorda dorsalis injury, comprise step:

Give have the Orally administered effective dose of mammal that needs according to each dosage form in the claim 1 to 36.

38. at least a method that is selected from the disease of glaucoma or diabetes end-organ complication of treatment in mammal comprises step:

39. at least a anxiety disorder that is selected from of treatment in mammal; Mood disorders; Schizophrenia; Schizophreniform disorder; Or the method for the disease of schizoaffective disorder, comprise step:

40. as the method for claim 39, wherein anxiety disorder is selected from panic attack, agoraphobia, panic disorder, specific phobia, social phobia, obsessive compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, separation anxiety disorder, or the anxiety disorder that causes of material; Or mood disorders is selected from bipolar disorder, is selected from major depressive disorder, the dysthymic disorder, and the depression of the mood disorders of or material-cause, or be selected from the severe depression outbreak, manic episode, Combination outbreak, or the outbreak of the emotion of hypomania.

41. at least a Huntington's disease that is selected from of treatment in mammal, Alzheimer, amyotrophic lateral sclerosis, chronic dementia, or the method for the neurodegenerative disease of cognitive impairment comprise step:

42. treat Parkinsonian method, comprise step:

43. at least a inflammatory diseases that is selected from of treatment in mammal; Fibromyalgia; The herpes zoster complication; The prevention of the tolerance of OA; Or the method for the disease of the withdrawal symptom of addictive drug, comprise step:

44. the method for treatment pain in mammal comprises step:

45., further comprise at least a pain relief agents of administering therapeutic effective dose according to the method for claim 44.

46. according to the method for claim 44, wherein pain is neuropathic pain; Cancerous pain; With pancreatitis or abdominal part, pelvis or perineal region or relevant visceral pain; With back of the body bottom or top, spinal column, muscle fiber pain, the musculoskeletal pain that remporomandibular joint or myofasical pain syndrome are relevant; The boniness pain relevant with bone or degenerative joint disease; Headache; With infection, reaping hook cell anemia disease, autoimmune sexual disorders, multiple sclerosis, dental procedure, burn or the pain of inflammation-related at least a.

47. method according to claim 44, wherein pain comprise neuropathic pain and and diabetic neuropathy, peripheral neurophaty, postherpetic neuralgia, trigeminal neuralgia, waist or cervix uteri radiculopathy, fibromyalgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, causalgia, thalamic syndrome, nerve root avulsion, or by being selected from phantom limb pain, the nerve injury that the damage of reflex sympathetic dystrophy or thoracotomy postoperative pain causes, cancer, chemical injury, toxin, malnutrition, or at least a relevant in virus or the bacterial infection.

48. according to the method for claim 46, wherein said pain is the fine fibre neuropathy.

49. according to the method for claim 46, wherein said pain is big fiber nerve pathological changes.

50. according to the method for claim 46, wherein said pain is peripheral neurophaty.

51. according to the method for claim 46, wherein said pain is the nervus centralis disease.

52. according to the method for claim 46, wherein said pain is postherpetic neuralgia.

53. according to the method for claim 46, wherein said pain is postoperative pain.

54. solid instant-free pharmaceutical composition comprises:

At least a as claim 12 or claim 11 to 17 in chemical compound or its pharmaceutically acceptable salt of formula (I) of each definition,

Wherein said compositions has the 0.5g/cm of being at least about ³Bulk density.

55. according to the solid instant-free pharmaceutical composition of claim 54, wherein said compositions has the 0.8g/cm of being at least about ³Bulk density.

56. according to the solid instant-free pharmaceutical composition of claim 54 or 55, wherein said compositions is a granule.

57. according to each solid instant-free pharmaceutical composition of claim 54 to 56, wherein said compositions further comprises at least a binding agent.

58. according to the solid instant-free pharmaceutical composition of claim 57, wherein said binding agent is a polyvidone.

59. according to the solid instant-free pharmaceutical composition of claim 58, wherein said polyvidone exists with the level of 1.5% weight at least, in described composition total weight.

60. according to the solid instant-free pharmaceutical composition of claim 59, wherein said polyvidone exists with the level of 2.5% weight at least, in described composition total weight.

61. according to each solid instant-free pharmaceutical composition in the claim 54 to 60, wherein said compositions further comprises at least a disintegrating agent or filler.

62. according to the solid instant-free pharmaceutical composition of claim 61, wherein said filler is a microcrystalline Cellulose.

63. according to the solid instant-free pharmaceutical composition of claim 61, wherein said disintegrating agent is a cross-linking sodium carboxymethyl cellulose.

64. solid pharmaceutical dosage formulation comprises: according to each solid instant-free pharmaceutical composition in the claim 54 to 63.

65. according to the dosage form of claim 64, it is capsule or tablet.

66. the single dose form comprises the dosage form according to claim 64 or 65.

67. the multiple dose form comprises the dosage form according to claim 64 or 65.

68. capsule comprises: comprise granule according to each solid instant-free pharmaceutical composition in the claim 54 to 63.

69. tablet comprises: comprise granule according to each solid instant-free pharmaceutical composition in the claim 54 to 63.

70. at least a method that is selected from the disease of cerebrovascular disease of treatment in mammal, described disease is selected from cerebral ischemia, cerebral infarction or cerebral vasospasm; Cerebral trauma; Muscular spasm; Be selected from the convulsive disorder of epilepsy or status epilepticus; Hypoglycemia; Asystole; Perinatal asphyxia disease; Or chorda dorsalis injury, comprise step:

Give have the Orally administered effective dose of mammal that needs according to each solid instant-free pharmaceutical composition in the claim 54 to 63.

71. at least a method that is selected from the disease of glaucoma or diabetes end-organ complication of treatment in mammal comprises step:

72. at least a anxiety disorder that is selected from of treatment in mammal; Mood disorders; Schizophrenia; Schizophreniform disorder; Or the method for the disease of schizoaffective disorder, comprise step:

73. as the method for claim 72, wherein anxiety disorder is selected from panic attack, agoraphobia, panic disorder, specific phobia, social phobia, obsessive compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, separation anxiety disorder, or the anxiety disorder that causes of material; Or mood disorders is selected from bipolar disorder, is selected from major depressive disorder, the dysthymic disorder, and the depression of the mood disorders of or material-cause, or be selected from the severe depression outbreak, manic episode, Combination outbreak, or the outbreak of the emotion of hypomania.

74. at least a Huntington's disease that is selected from of treatment in mammal, Alzheimer, amyotrophic lateral sclerosis, chronic dementia, or the method for the neurodegenerative disease of cognitive impairment comprise step:

75. treat Parkinsonian method, comprise step:

76. at least a inflammatory diseases that is selected from of treatment in mammal; Fibromyalgia; The herpes zoster complication; The prevention of the tolerance of OA; Or the method for the disease of the withdrawal symptom of addictive drug, comprise step:

77. the method for treatment pain in mammal comprises step:

78., further comprise at least a pain relief agents of administering therapeutic effective dose according to the method for claim 77.

79. according to the method for claim 77, wherein pain is neuropathic pain; Cancerous pain; With pancreatitis or abdominal part, pelvis or perineal region or relevant visceral pain; With back of the body bottom or top, spinal column, muscle fiber pain, the musculoskeletal pain that remporomandibular joint or myofasical pain syndrome are relevant; The boniness pain relevant with bone or degenerative joint disease; Headache; With infection, reaping hook cell anemia disease, autoimmune sexual disorders, multiple sclerosis, dental procedure, burn or the pain of inflammation-related at least a.

80. method according to claim 79, wherein pain comprise neuropathic pain and and diabetic neuropathy, peripheral neurophaty, postherpetic neuralgia, trigeminal neuralgia, waist or cervix uteri radiculopathy, fibromyalgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, causalgia, thalamic syndrome, nerve root avulsion, or by being selected from phantom limb pain, the nerve injury that the damage of reflex sympathetic dystrophy or thoracotomy postoperative pain causes, cancer, chemical injury, toxin, malnutrition, or at least a relevant in virus or the bacterial infection.

81. according to the method for claim 79, wherein said pain is the fine fibre neuropathy.

82. according to the method for claim 79, wherein said pain is big fiber nerve pathological changes.

83. according to the method for claim 79, wherein said pain is peripheral neurophaty.

84. according to the method for claim 79, wherein said pain is the nervus centralis disease.

85. according to the method for claim 79, wherein said pain is postherpetic neuralgia.

86. according to the method for claim 79, wherein said pain is postoperative pain.

87. according to each solid instant-free pharmaceutical composition in the claim 54 to 63, wherein when the plasma C of the chemical compound of giving the formula (I) that described compositions table reveals when having the curee who needs to use _MaxFor about 80ng/mL to about 4200ng/mL.

88. according to each solid instant-free pharmaceutical composition in the claim 54 to 63, wherein as the blood plasma T of the chemical compound of giving the formula (I) that described compositions table reveals when having the curee who needs to use _MaxBe about 0.5 hour to about 4.0 hours.

89. according to each solid instant-free pharmaceutical composition in the claim 54 to 63, wherein as the AUC of the chemical compound of giving the formula (I) that described compositions table reveals when having the curee who needs to use _{T=0 to 12 hour}For about 250ngh/mL to about 6,000ngh/mL.

90. according to each solid instant-free pharmaceutical composition in the claim 54 to 63, wherein said compositions is the form of capsule or tablet.

91. according to the solid instant-free pharmaceutical composition of claim 90, wherein said capsule or tablet comprise the chemical compound of the formula (I) of about 200mg to 4000mg.

92. according to the solid instant-free pharmaceutical composition of claim 90, wherein said compositions is single dose unit or the unitary form of multiple dose.

93. according to the solid instant-free pharmaceutical composition of claim 92, wherein said single dose unit or multiple dose unit comprise the chemical compound of formula (I) of about 200mg or its pharmaceutically acceptable salt chemical compound or its pharmaceutically acceptable salt to the formula (I) of 4000mg.

94. according to the solid instant-free pharmaceutical composition of claim 93, wherein said single dose unit or multiple dose unit comprise chemical compound or its pharmaceutically acceptable salt of the formula (I) at least about 400mg.

95. according to the solid instant-free pharmaceutical composition of claim 93, wherein said single dose unit or multiple dose unit comprise chemical compound or its pharmaceutically acceptable salt of the formula (I) at least about 600mg.

96. method comprises step:

Form wet granular, it comprises:

At least a binding agent;

Randomly at least a filler;

Randomly at least a disintegrating agent; With

At least a as claim 1 or 2, or the chemical compound of the formula of each definition in the claim 11 to 17 (I) or its pharmaceutically acceptable salt; With

Form solid dosage forms.

97. according to the method for claim 96, wherein said wet granular passes through at least a filler or disintegrating agent and described formula (I) chemical compound or its pharmaceutically acceptable salt dry mixed; With the binder solution of at least a formation wet granular dry mixture is granulated then and form.

98. according to the method for claim 96, wherein said binding agent is a polyvidone.

99. according to the method for claim 96, wherein said filler is a microcrystalline Cellulose.

100. according to the method for claim 96, wherein said disintegrating agent is a sodium carboxymethyl cellulose.

101., further comprise step: dry described wet granular according to each method in the claim 96 to 100; The described dried granule of milling; Randomly the outer component of described dried granule of milling and one or more granules is mixed.

102. according to each method in the claim 96 to 101, wherein said solid dosage forms is a tablet.

103. according to each method in the claim 96 to 101, wherein said solid dosage forms is a capsule.

104. product by each method preparation in the claim 96 to 101.

105. the instant-free solid composite medicament of single dose unit or multiple dose unit form, comprise that [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] phosphoric acid or its pharmaceutically acceptable salt, the wherein plasma C of the chemical compound of the formula (I) that described compositions table reveals when using for the curee that needs are arranged _MaxFor about 80ng/mL to about 4200ng/mL.

106. the instant-free solid composite medicament of single dose unit or the unitary form of multiple dose, comprise that [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] phosphoric acid or its pharmaceutically acceptable salt, the AUC of the chemical compound of the formula (I) that described compositions table reveals when using for the curee that needs are arranged _{T=0 to 12 hour}For about 250ngh/mL to about 6,000ngh/mL.

107. the method for treatment pain, comprise that Orally administered [2-(8 to the mammal that needs are arranged, 9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] phosphoric acid or its pharmaceutically acceptable salt, its amount provide [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] plasma C of phosphoric acid _MaxFor about 80ng/mL to about 4200ng/mL.

108. the method for treatment pain, comprise that Orally administered [2-(8 to the mammal that needs are arranged, 9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] phosphoric acid or its pharmaceutically acceptable salt, its amount provide [2-(8,9-dioxo-2,6-diazabicyclo [5.2.0] ninth of the ten Heavenly Stems-1 (7)-alkene-2-yl) alkyl] AUC of phosphoric acid _{T=0 to 12 hour}For about 250ngh/mL to about 6,000ngh/mL.