CN101505741A - A cyclohexane polyalcohol formulation for treatment of disorders of protein aggregation - Google Patents

Abstract

The invention provides formulations, dosage forms, and treatments comprising cyclohexane polyalcohol compounds that provide beneficial pharmacokinetic profiles in the treatment of a disorder and/or disease including a disorder in protein folding and/or aggregation, and/or amyloid formation, deposition, accumulation, or persistence. In aspects of the invention, a dosage form is provided comprising an amount of a cyclohexane polyalcohol compound suitable for administration to a subject to provide a therapeutically effective concentration of the compound in plasma, brain and/or cerebral spinal fluid and a pharmaceutically acceptable carrier, diluent or excipient. The formulation can be administered in a dose of 500, 1000, 2000, 3500, 5000 or 7000 mg of cyclohexane polyalcohol compound to achieve a mean plasma concentration profile having a mean AUC0-INF in [mu].h/mL of, respectively, 43+-20%, 130+-20%, 215+-20%, 467+-20%, 507+-20% or 885+-20%, and having a mean Cmax in [mu]mL of, respectively, 5.8+-20%, 17+-20%, 33+-20%, 75+-20%, 110+-20% or 155+-20%.

Description

The cyclohexane polyalcohol formulation that is used for the treatment of disorders of protein aggregation

Invention field

The present invention relates generally to be suitable for producing preparation, dosage form, drug delivery system or technology and the method for the useful characteristics of pharmacokinetics of the cyclohexane polyalcohol chemical compound that is used for the treatment of disorders of protein aggregation.

Background of invention

The probability that is keeping the disease adjustment of treatment of Alzheimer (AD) for the cyclohexane polyalcohol chemical compound.When to the transgene mouse model oral administration of Alzheimer (AD), amyloid beta-peptide (A β's) gathers in the inositol stereoisomer inhibition brain, and improve several AD-sample phenotypes in the model, comprise that cognitive synapse physiology, brain amyloid beta and mortality rate impaired, that change improve.No matter be to give before AD-sample phenotype takes place or after taking place, these effects all can occur.These chemical compounds are the solubility oligomer of preferential targeting A β in vitro and in vivo, and processing does not have influence (referring to the application 20040204387 of US publication) for amyloid precursor protein.

Summary of the invention

The present invention relates generally to produce the cyclohexane polyalcohol chemical compound, particularly dosage form, preparation and the method for the useful characteristics of pharmacokinetics (pharmacokinetic profile) of scyllitol (scyllo-cyclohexanehexol) chemical compound and epi-inositol (epi-cyclohexanehexol) chemical compound, described cyclohexane polyalcohol chemical compound can be used for treating disease described herein and/or disease, particularly protein folding and/or gather and/or amyloid forms, deposition, the disease of assembling or continuing wherein.

In some respects, the invention provides preparation, described preparation comprises one or more cyclohexane polyalcohol chemical compounds (for example scyllitol chemical compound or epi-inositol chemical compound), and described preparation provides useful characteristics of pharmacokinetics, includes but not limited to treat the characteristics of pharmacokinetics that the back continues.

The present invention also provides and has been used for individual administration so that useful characteristics of pharmacokinetics to be provided, include but not limited to the preparation of the characteristics of pharmacokinetics that continues, described preparation comprises pure or pure basically cyclohexane polyalcohol chemical compound, particularly pure or pure basically scyllitol chemical compound or epi-inositol chemical compound, and optional one or more pharmaceutically suitable carrier, excipient or the adjuvant of comprising.

The present invention also provides the preparation that is used for the treatment of disease disclosed herein and/or disease, described preparation comprises the cyclohexane polyalcohol chemical compound of effective dose in pharmaceutically suitable carrier, excipient or adjuvant, particularly scyllitol chemical compound or epi-inositol chemical compound, so that useful characteristics of pharmacokinetics to be provided, include but not limited to the characteristics of pharmacokinetics that continues.

In one aspect, the invention provides and comprise the cyclohexane polyalcohol chemical compound, the preparation of scyllitol chemical compound or epi-inositol chemical compound particularly, described preparation is and is suitable for individual administration so that useful characteristics of pharmacokinetics to be provided, and includes but not limited to that the characteristics of pharmacokinetics that continues treats the form of disease disclosed herein and/or disease or be adjusted to be suitable for described purpose.In one embodiment, dosage form is provided, make and to provide useful characteristics of pharmacokinetics to the individual administration of suffering from disease disclosed herein and/or disease this dosage form, include but not limited to the characteristics of pharmacokinetics that continues, during administration, bring curative effect, include but not limited to suppress, alleviate or reverse following one or more: A β fibril assembles or gathers; A β toxicity; Paraprotein folds, gathers, amyloid forms, deposition, assemble or lasting, and/or the amyloid lipid interacts; With the fibriilar decomposition of accelerating to form in the past.Particularly, compositions is such form, it is suitable for the characteristics of pharmacokinetics that provides useful, includes but not limited to the characteristics of pharmacokinetics that continues produce one or more following effects in the persistent period during administration in individuality: the division of accumulative A β or A beta oligomers; The long-term reinforcement that improves or recover; Keep the synapse function; The brain of the amyloid beta that reduces gathers; The deposition of brain amyloid plaque alleviates; The minimizing of solubility A beta oligomers in the brain; Reduce the neuroglia activity; Reduce inflammation; And/or alleviate cognitive decline or improve cognitive competence.

In one aspect, the present invention relates to comprise the dosage form of a certain amount of cyclohexane polyalcohol chemical compound, described dosage form is suitable for individual administration so that valid density to be provided in environment for use, particularly treat the chemical compound of valid density, or prevention, treatment or control disease protein folding and/or gather and/or amyloid forms, deposition, assemble or lasting aspect symptom in produce the effective dose of curative effect.In some respects, environment for use is a brain, particularly an extracellular or a matter cerebral tissue.In other respects, environment for use is blood plasma and/or cerebrospinal fluid (CSF).

In one aspect, the present invention relates to comprise the dosage form of a certain amount of cyclohexane polyalcohol chemical compound, described dosage form is suitable for individual administration to provide valid density in blood plasma, brain and/or cerebrospinal fluid, particularly treat the chemical compound of valid density, or prevention, treatment or control disease protein folding and/or gather and/or amyloid forms, deposition, assemble or lasting aspect symptom in produce the effective dose of curative effect.In one aspect, the present invention relates to comprise the dosage form of a certain amount of cyclohexane polyalcohol chemical compound, described dosage form is suitable for individual administration so that the chemical compound of treatment valid density to be provided in blood plasma, brain and/or cerebrospinal fluid, or provide at least one prevention, treatment or control disease protein folding and/or gather and/or amyloid forms, deposition, assemble or lasting aspect symptom in therapeutic effect.

In yet another aspect, the invention provides dosage form, wherein curative effect is in one or more following effects during the administration: in individuality, suppress, alleviate or reverses below one or more: A β fibril assembles and/or gathers; A β toxicity; Paraprotein is folding, paraprotein gathers, amyloid forms, deposit, assemble and/or lastingly, the amyloid lipid interacts; With the fibriilar decomposition of accelerating to form in the past.Aspect special, dosage form of the present invention remains in chemical compound in the effective plasma level or CSF concentration that brings curative effect in individuality.

In yet another aspect, the invention provides and comprise a certain amount of cyclohexane polyalcohol chemical compound and pharmaceutically suitable carrier, the dosage form of diluent or excipient, described dosage form is suitable for individual administration to provide chemical compound at blood plasma, treatment valid density in brain and/or the cerebrospinal fluid, wherein work as preparation with 500,1000,2000,3500,5000 or during the dosed administration of the described cyclohexane polyalcohol of 7000mg, obtained mean plasma concentration feature (mean plasma concentration profile), the mean plasma concentration feature has and is respectively 43 ± 20% μ gh/mL, 130 ± 20% μ gh/mL, 215 ± 20% μ gh/mL, 467 ± 20% μ gh/mL, the AUC of 507 ± 20% μ gh/mL or 885 ± 20% μ gh/mL _0-INF, and have the average C that is respectively 5.8 ± 20% μ g/mL, 17 ± 20% μ g/mL, 33 ± 20% μ g/mL, 75 ± 20% μ g/mL, 110 ± 20% μ g/mL or 155 ± 20% μ g/mL _Max

In yet another aspect, the present invention relates to comprise the cyclohexane polyalcohol chemical compound, the preparation of scyllitol chemical compound or epi-inositol chemical compound particularly, described preparation is in the particularly disease and/or the disease of amyloid beta deposition, more especially provide useful characteristics of pharmacokinetics in the treatment of Alzheimer, included but not limited to the characteristics of pharmacokinetics that continues.

In one aspect, the present invention relates to be suitable for be administered once every day or twice preparation or dosage form to treat the preparation or the dosage form of disease described herein in the individuality and/or disease, described preparation or dosage form comprise its amount can effectively provide useful characteristics of pharmacokinetics during administration, include but not limited to one or more cyclohexane polyalcohol chemical compounds of the characteristics of pharmacokinetics that continues.

In yet another aspect, the present invention relates to comprise one or more cyclohexane polyalcohol chemical compounds, the dosage form of one or more scyllitol chemical compounds or epi-inositol chemical compound particularly, the amount of wherein said chemical compound can effectively remain on the effective plasma level drug level that brings curative effect in the individuality.

In yet another aspect, the invention provides and comprise one or more cyclohexane polyalcohol chemical compounds, the dosage form of one or more scyllitol chemical compounds or epi-inositol chemical compound particularly, the amount of wherein said chemical compound can effectively remain on the effective CSF drug level that brings curative effect in the individuality.

In yet another aspect, the invention provides and comprise one or more cyclohexane polyalcohol chemical compounds, the dosage form of one or more scyllitol chemical compounds or epi-inositol chemical compound particularly, the amount of wherein said chemical compound can effectively remain on active drug concentration in the brain that brings curative effect in the individuality.

In yet another aspect, the present invention relates to the sustained release forms of cyclohexane polyalcohol chemical compound, described dosage form provides useful characteristics of pharmacokinetics.

The release characteristic of dosage form (release profile) can show different rate of release and persistent period, and can be continuous or pulsating.Release characteristic comprises such release characteristic continuously, and wherein a certain amount of one or more medical compoundss discharge continuously with constant or variable velocity during whole dosing interval.The pulsating release characteristic comprises such release characteristic, and wherein one or more medical compoundss of at least two discontinuous quantities discharge with friction speed and/or via the different time framework.For any given medical compounds or such combination of compounds, the release characteristic of given dosage form brings relevant blood plasma feature (plasma profile) in the patient.When two or more components of dosage form had different release characteristic, the release characteristic of making as a whole dosage form was the combination of independent release characteristic, generally can be described as " multimodal ".Wherein release characteristic with bi-component dosage form of different release characteristics of every kind of component can be described as " double mode ", and wherein release characteristic with three component dosage forms of different release characteristics of every kind of component can be described as " three-mode ".The whole effect of these dosage forms provides the release characteristic that continues basically, because do the combination that the release characteristic of as a whole dosage form is independent release characteristic.

With the variable class that is applicable to release characteristic seemingly, the relevant blood plasma feature among the patient duration can show constant or variable medical compounds plasma concentration level in effect, and can be continuously or pulsating.The blood plasma feature comprises the blood plasma feature of all speed and persistent period continuously, it shows a plasma concentration maximum, this maximum depends in part on the pharmacokinetics character of the medical compounds that comprises in the dosage form at least, and the release characteristic of each independent component of dosage form, after being administered to the patient, the multi-mode release characteristic can bring continuously or pulsating blood plasma feature.From the preferred release characteristic of pulsating delivery formulations is those of release characteristic continuously basically.

The present invention relates to the dosage form of cyclohexane polyalcohol chemical compound, described dosage form provides zero level or near the release characteristic of zero level.

The invention still further relates to the dosage form of cyclohexane polyalcohol chemical compound, described dosage form provides the release characteristic of following the mechanism beyond zero level or the first order kinetics, such as but not limited to, also relate to the square root of time release characteristic (time release profile).

In yet another aspect, the present invention relates to the dosage form of cyclohexane polyalcohol chemical compound, described dosage form provides the release characteristic by the combination results of any above-mentioned release characteristic.

In yet another aspect, the present invention relates to the dosage form of cyclohexane polyalcohol chemical compound, described dosage form provides zero level or near the release characteristic of zero level.

The invention still further relates to preparation and comprise one or more cyclohexane polyalcohol chemical compounds, the particularly stabilization formulations of scyllitol chemical compound or epi-inositol chemical compound or the method for dosage form, described preparation is suitable for providing useful characteristics of pharmacokinetics, the particularly characteristics of pharmacokinetics of Chi Xuing after treatment.In yet another aspect, the invention provides the method for preparing stabilizer type, described method comprises a certain amount of cyclohexane polyalcohol chemical compound and pharmaceutically suitable carrier, excipient or mixing diluents, and the mean plasma concentration feature that provides feature following is provided described mixture: the AUC that is respectively 43 ± 20% μ gh/mL, 130 ± 20% μ gh/mL, 215 ± 20% μ gh/mL, 467 ± 20% μ gh/mL, 507 ± 20% μ gh/mL or 885 ± 20% μ gh/mL _O-INF, and the average C that is respectively 5.8 ± 20% μ g/mL, 17 ± 20% μ g/mL, 33 ± 20% μ g/mL, 75 ± 20% μ g/mL, 110 ± 20% μ g/mL or 155 ± 20% μ g/mL _MaxAfter making preparation, they can be placed in the suitable containers, and stick the label of relevant treatment indication.For administration preparation of the present invention, such label will comprise amount, frequency and the method for administration.

In yet another aspect, the invention provides preparation and contain the cyclohexane polyalcohol chemical compound, the method of the commercial preparation of scyllitol chemical compound or epi-inositol chemical compound particularly, described preparation provides useful characteristics of pharmacokinetics, the particularly characteristics of pharmacokinetics of Chi Xuing in disease described herein and/or treatment of diseases.

In yet another aspect, the present invention relates at least a cyclohexane polyalcohol chemical compound, particularly scyllitol chemical compound or epi-inositol chemical compound are used to provide useful characteristics of pharmacokinetics in preparation, and particularly the characteristics of pharmacokinetics of Chi Xuing is with the application in the medicine that prevents and/or treats disease described herein and/or disease.

In yet another aspect, the present invention relates to the application of at least a cyclohexane polyalcohol chemical compound in the preparation medicine, wherein when described medicine with 500,1000,2000,3500,5000 or during the dosed administration of the described cyclohexane polyalcohol of 7000mg, described medicine provides the mean plasma concentration feature, and this mean plasma concentration feature has the AUC that is respectively 43 ± 20% μ gh/mL, 130 ± 20% μ gh/mL, 215 ± 20% μ gh/mL, 467 ± 20% μ gh/mL, 507 ± 20% μ gh/mL or 885 ± 20% μ gh/mL _0-INF, and have the average C that is respectively 5.8 ± 20% μ g/mL, 17 ± 20% μ g/mL, 33 ± 20% μ g/mL, 75 ± 20% μ g/mL, 110 ± 20% μ g/mL or 155 ± 20% μ g/mL _Max, prevent and/or treat protein folding wherein thus and/or gather and/or amyloid forms, deposition, the disease of assembling or continuing.

Preparation of the present invention can therapeutic or prophylactically administration particularly form, assemble or deposit relevant disease and/or disease to treat disease described herein and/or disease with amyloid.

Therefore, the invention provides the method that treats and/or prevents disease described herein in the individuality and/or disease, described method comprises preparation of the present invention or the dosage form of using effective dose to individuality.

In yet another aspect, the invention provides the method that treats and/or prevents disease in the individuality and/or disease, described method comprise use to individuality one or more, the preparation of two dosage particularly, described preparation comprises one or more cyclohexane polyalcohol chemical compounds, particularly one or more scyllitol chemical compounds or epi-inositol chemical compound, the amount of described chemical compound can effectively keep chemical compound to bring the effective plasma level drug level of curative effect in individuality.

In yet another aspect, the invention provides the method that treats and/or prevents disease in the individuality and/or disease, described method comprise use to individuality one or more, the preparation of two dosage particularly, described preparation comprises one or more cyclohexane polyalcohol chemical compounds, particularly one or more scyllitol chemical compounds or epi-inositol chemical compound, the amount of described chemical compound can effectively keep chemical compound to bring the effective CSF or the brain drug level of curative effect in individuality.

In yet another aspect, the invention provides the method that treats and/or prevents disease in the individuality and/or disease, described method comprises to individuality uses one or more cyclohexane polyalcohol chemical compounds, particularly the sustained release forms of one or more scyllitol chemical compounds or epi-inositol chemical compound.

In yet another aspect, the invention provides the method that treats and/or prevents disease in the individuality and/or disease, described method comprises uses one or more cyclohexane polyalcohol chemical compounds, the dosage form of one or more scyllitol chemical compounds or epi-inositol chemical compound particularly, described dosage form provide zero level or near the release characteristic of zero level.More generally, the invention provides the method for treatment Alzheimer in this patient who needs is arranged, described method comprises uses one or more cyclohexane polyalcohol chemical compounds, the dosage form of one or more scyllitol chemical compounds or epi-inositol chemical compound particularly, described dosage form provides the continuous release characteristic and the pulsating release characteristic of constant or variable velocity.

In yet another aspect, the invention provides medicine box, described medicine box comprises one or more cyclohexane polyalcohol chemical compounds, particularly scyllitol chemical compound or epi-inositol chemical compound, or be suitable for providing the preparation of the present invention of useful characteristics of pharmacokinetics, the particularly characteristics of pharmacokinetics of Chi Xuing.In one aspect, the invention provides the medicine box that is used to prevent and/or treat disease described herein and/or disease, described medicine box comprises preparation of the present invention or dosage form, container and the description about using.

By following accompanying drawing and detailed description, to those skilled in the art, these and other aspects of the present invention, feature and advantage should be conspicuous.

Accompanying drawing is described

The present invention may be better understood with reference to accompanying drawing, wherein:

Fig. 1 has shown 15,50 and the log plasma concentration of scyllitol (AZD103) in rat of 150mg/kg single dose.

Fig. 2 has shown 15,50 and the log plasma concentration of scyllitol (AZD103) in Canis familiaris L. of 150mg/kg single dose.

Fig. 3 has shown in Canis familiaris L. with 80mg/kg the log plasma concentration of scyllitol behind the oral and intravenous administration.

Fig. 4 shown in rat with 15,50 and twice administration 150mg/kg every day, after 28 days, and the log plasma concentration of scyllitol.

Fig. 5 shown in Canis familiaris L. with 15,50 and twice administration 150mg/kg every day, after 14 days, and the log plasma concentration of scyllitol.

Fig. 6 has shown that single oral gives after the 240mg/kg in Canis familiaris L., the log concentration of scyllitol in blood plasma and CSF.

Fig. 7 shown with the administration after 1 month arbitrarily of scyllitol or myo-inositol (myo-cyclohexanehexol), and in untreated animal, the CSF of scyllitol and myo-inositol and brain level.

Fig. 8 shows is to detect the representative micro constitutent that the GCMS of the inositol composition of phosphatidylinositols lipid analyzes, and described phosphatidylinositols lipid derives from one month the mice of scyllitol of accepting any administration and the brain of not treating mice.

Fig. 9 has shown the dose response effect of scyllitol for the cognitive function of TgCRND8 mice.Use indicated dosage level for the mice at 3-4 monthly age.

Figure 10: alleviated to the scyllitol therapeutic A β-dependency cognitive impairment.In the transgenic (Tg) of the acceptance at 5-6 monthly age indication treatment and non-transgenic (nTg) animal, be evaluated at the swimming path length of MorrisWater Maze in testing.Assessment animal in the time of 6 months.

Figure 11: the dose response of scyllitol in cognitive impairment treatment and reduction speckle load (speckle load).For the swimming path length in the Morris Water Maze test, the administration data are historical datas arbitrarily.

Figure 12: the scyllitol dose response confirms: amyloid reduces.The TgCRND8 mice was treated 5-6 month with the scyllitol of dose indicating level.

Figure 13: scyllitol treatment has reduced TgCRND8 speckle (plaque) level effectively, for spot size without any preferentially.Use 2 months scyllitol, begin treatment when 5 monthly ages for the TgCRND8 mice.(a) in the animal of scyllitol treatment, compare with matched group, the brain area percentage that is covered by speckle significantly reduces.*＝p<0.0001。(b) compare with control animal (black bar), scyllitol treatment (grey bar) has reduced the number of viewed speckle, no matter spot size.Speckle is categorized as dimensionally＜100,100-250,250-500 or 500 μ m2.

Figure 14: in CSF (a) that does not treat or use arbitrarily the treatment of myo-inositol (myo-inositol) or scyllitol and myo-inositol and the scyllitol concentration in the brain (b).The interior mark that uses D-chirality-inositol (D-chiro-inositol) to measure as GC/MS.(a) myo-inositol treatment does not arbitrarily have significantly to change inositol (black bar) or scyllitol (grey bar) level among the CSF, yet the scyllitol treatment has significantly improved the CSF scyllitol.(b) compare with not treatment group, myo-inositol treatment has arbitrarily significantly reduced the scyllitol level in the brain.On the contrary, compare with not treatment group, scyllitol has significantly improved brain scyllitol level.*, *=p＜0.001 (treating n=5 animal) at every turn.

Figure 15: the scyllitol concentration among the CSF of the mice of treatment, scyllitol treatment arbitrarily or once a day.Treatment is to give 10mg/kg, 30mg/kg or 100mg/kg scyllitol by gavage once a day, and mice is treated execution in back 8 hours the last time.When every other group is compared, the treatment remarkable increase that brings scyllitol concentration in CSF and the brain arbitrarily.Compare *=p＜0.001 (every group of n=4) with every other group.

Figure 16: the scyllitol (solid line) and the bioavailability of myo-inositol (dotted line) in blood plasma and brain that contain tritium inositol picked-up test determination of using orally give.The blood plasma level of myo-inositol and scyllitol reached peak value respectively in 2 hours and 12 hours rapidly after administration.The brain level also increases sharply, and reaches maximum at 8 hours and 32 hours respectively.

Figure 17: the competition assay of myo-inositol and scyllitol (scyllo-inositol) competition behind the mensuration single oral tube feed dosage.(A) give the blood plasma level of 3H-scyllitol behind 0,50, the 200 or 400 μ g myo-inositols jointly.As if inositol load change the kinetics of oral scyllitol in the dose dependent mode.(B) the brain level of administration myo-inositol scyllitol after 4 hours.The scyllitol level does not significantly change behind the administration myo-inositol.

Figure 18: the derivatization and the detection of GC/MS. myo-inositol, scyllitol and chiro-inositol (chiro-inositol).

Figure 19: treatment, arbitrarily or the once a day brain of the mice of treatment and the scyllitol concentration among the CSF.Treatment is to give 10mg/kg, 30mg/kg or 100mg/kg scyllitol by gavage once a day, and mice is treated execution in back 8 hours the last time.When every other group is compared, the treatment remarkable increase that brings scyllitol level in CSF and the brain arbitrarily.Compare *=p＜0.001 with every other group.

Figure 20: in not treating the mice (B) of mice (A), from the GC/MS feature of isolating myo-inositol of phosphatidylinositols and scyllitol to the scyllitol treatment.With the inositol compound derivingization, add chiro-inositol as interior mark, and use simple substance amount ion m/z 168 to come the quantitative assay inositol.Detect myo-inositol at an easy rate, but in any sample, all can not detect scyllitol.

Figure 21 shown single rising dosage of 1 phase of being used at the AZD-103 of healthy male volunteers assessment oral dose, double blinding, at random, the mean concentration-temporal characteristics of the test of placebo.

Figure 22 shown single rising dosage of 1 phase of being used at the AZD-103 of healthy male volunteers assessment oral dose, double blinding, at random, the average log concentration-temporal characteristics of the test of placebo.

The detailed description of embodiment

Terminology

The numerical range that this paper describes by terminal point comprises all numeral and marks (for example 1-5 comprises 1,1.5,2,2.75,3,3.90,4 and 5) that are included in this scope.It is also understood that all numerals and mark thereof the supposition all modify by term " about ".Term " about " be meant its numerical value of modifying ± 0.1-50%, ± 5-50% or ± 10-40%, preferred ± 10-20%, more preferably ± 10% or 15%.In addition, should be appreciated that " one ", " a kind of " and " being somebody's turn to do " comprise plural number, unless content is clearly pointed out.Therefore, when containing the compositions of " a kind of chemical compound " when mentioning, it comprises the mixture of two or more chemical compounds.

Term " administration " and " using " are meant the preparation described herein of treatment effective dose or dosage form are delivered to individuality with treatment, comprise the method for preventing purpose.Compositions and preparation are according to good medical practice, consider that known other factors of individual clinical disease, age, sex, body weight and doctor give.

Term " treatment " is meant reverse, alleviates or one or more symptoms of inhibitor disease described herein and/or disease or one or more symptoms of applied disease of this term and/or disease.According to the disease of individuality, this term also refers to prevent disease, and comprises prophylactic beginning, perhaps the prevention symptom relevant with disease.Treatment can be carried out with acute or chronic approach.This term also refers to be subjected to the order of severity that palliates a disease before this disease torment or alleviating the symptom relevant with such disease.The such prevention or the order of severity that palliates a disease are not meant and use preparation of the present invention or dosage form at the administration time that tormented by disease to individuality before tormenting." prevention " also refers to the recurrence of prevent disease or one or more symptoms relevant with such disease.Term " treatment " and " therapeutic ground " are meant the behavior of treatment, and wherein treatment as defined above.Term " treatment " and " prevention " can also be used in this article independently, to refer to reverse, alleviate or the progress or the symptom of inhibitor disease and/or disease perhaps prophylactic beginning or symptom respectively.

Term " curee ", " individuality " or " patient " are to use interchangeably in this article, and are meant animal, comprise for example mammal of homoiothermic animal, and it is suffered from or suspects and suffer from or suffer from just easily disease described herein and/or disease.Mammal includes but not limited to mammiferous any member.Aspect more of the present invention, term is meant the people.This term also comprises and is used for edible or as the performing animal of house pet, comprises horse, cow, sheep, poultry, fish, pig, cat, Canis familiaris L. and zoo animal, goat, ape (for example gorilla or chimpanzee), and rodent for example rat and mice.For treatment, typical individual comprises easily the people who suffers from, suffering from or suffering from disease described herein and/or disease.The patient can have or can not have the genetic factor for disease described herein and/or disorders such as alzheimer s disease.In embodiments of the invention, individuality suffers from or suffers from Alzheimer easily.In some aspects, individuality shows conscientious defective symptom and amyloid plaque neuro pathology.

Term " useful characteristics of pharmacokinetics " is meant the level of cyclohexane extraction polyol compound in blood plasma and/or the cerebrospinal fluid, the amount or the dosage of the cyclohexane polyalcohol chemical compound of certain level chemical compound are provided in blood plasma and/or cerebrospinal fluid, perhaps in prevention, treatment or the control of the symptom of disease described herein and/or disease, bring the required dosage of curative effect.Term used herein " lasting characteristics of pharmacokinetics " is meant the time span that the effect level of biological activity cyclohexane polyalcohol chemical compound is kept in its environment for use.The characteristics of pharmacokinetics that continues is preferably such, and once a day or twice administration, preferred twice administration every day enough prevents, treats or control the symptom of disease described herein and/or disease.Also preferably, the effect level of chemical compound kept in blood plasma, brain and/or CSF about 12 hours-Yue 36 hours, and more preferably 12 hours-Yue 24 hours, most preferably from about 20 hours-Yue 24 hours.

" curative effect " is meant the effect of preparation disclosed herein, dosage form, medicine delivery technique or method, comprises the biological activity and the effectiveness of improvement.Curative effect can be during drug treatment, particularly during the drug treatment of Chi Xuing with the concentration dependent lasting curative effect of blood plasma, brain and/or CSF of the substantial constant of cyclohexane polyalcohol chemical compound.According to the cyclohexane polyalcohol chemical compound, particularly the effect of scyllitol chemical compound or epi-inositol chemical compound is to the statistical analysis of the effect that do not have chemical compound, and curative effect can be that statistics significantly acts on." statistics is significant " or " significantly different " effect or level can be represented the level more high or low than standard.In embodiments of the invention, difference can be that the effect that obtains with there not being the cyclohexane polyalcohol chemical compound is compared high or low 1.5,2,3,4,5,6,7,8,9,10,15,20,25 or 50 times.

In one embodiment, wherein disease is an Alzheimer, the curative effect of preparation of the present invention, dosage form or method can show as at least 1,2,3,4,5,6,7,8,9,10,12,13,14,15 or all following performances, particularly 5 or 10 or more a plurality of, more especially 15 or more a plurality of following performance:

A) after to individual administration, stop, increase or recover the long-term enhancing of the level when not having preparation disclosed herein or dosage form with Alzheimer disease symptoms.Aspect more of the present invention, preparation or dosage form are induced the long-term enhanced increase at least about 0.05%, 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%, 20%, 30%, 33%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 95% or 99% in individuality.

B) after to individual administration, stop, increase or keep the synapse function of the synapse functional level when not having preparation disclosed herein or dosage form with Alzheimer disease symptoms.Aspect more of the present invention, preparation or dosage form induce the synapse function at least about 0.05%, 0.1%, 0.5%, 1%, 2%, 5%, 10%, 15%, 20%, 30%, 33%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 100%, 125%, 150%, 175% or 200% to improve in individuality.

C) increase of synaptophysin (synaptophysin).Aspect more of the present invention, outstanding element has increased at least about 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 100%, 125%, 150%, 175% or 200%.

D) increase of outstanding plain reaction knot and cyton.Aspect more of the present invention, outstanding plain reaction knot and cyton have increased at least about 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 100%, 125%, 150%, 175% or 200% more especially about 100-150% or 140-150%.

E) to after the individual administration with Alzheimer disease symptoms, prevent, alleviate or diminish inflammation, particularly the symptom of the beta induced inflammatory reaction of A.

F) in the individuality with Alzheimer disease symptoms, with respect to the level of measuring under the situation that does not have preparation of the present invention or dosage form to exist, A β's gathers in prevention, the reduction brain.Aspect more of the present invention, preparation or dosage form make that gathering of A β reduced at least about 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% in the brain.

G) in individuality, with respect to the level of under the situation that does not have preparation of the present invention or dosage form to exist, measuring, stop, reduce the deposition of amyloid plaque in the brain with Alzheimer disease symptoms.Aspect more of the present invention, preparation or dosage form make that the deposition of amyloid plaque has reduced at least about 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% in the brain.

H) number of minimizing speckle.Aspect more of the present invention, preparation of the present invention or dosage form make the speckle decreased number at least about 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%.Aspect special, preparation of the present invention or dosage form make speckle decreased number 5-15% or 10-15%.

I) size of reduction speckle.Aspect more of the present invention, preparation of the present invention or dosage form make the size of speckle reduce at least about 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%.Aspect special, preparation of the present invention or dosage form make the size of speckle reduce 5-15% or 10-15%.

J) reduce the brain area percentage that is covered by speckle.Aspect more of the present invention, preparation of the present invention or dosage form make the brain area percentage that is covered by speckle reduce at least about 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%.Aspect special, preparation of the present invention or dosage form make the brain area percentage that is covered by speckle reduce 5-15% or 10-15%.

K) in individuality,, reduce solubility A beta oligomers in the brain with respect to the level of under the situation that does not have preparation of the present invention or dosage form to exist, measuring with Alzheimer disease symptoms.Aspect more of the present invention, preparation of the present invention or dosage form make solubility A beta oligomers reduce about 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%.

1) the brain level of reduction A β 40.Aspect more of the present invention, preparation of the present invention or dosage form make A β 40 reduce at least about 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%.Aspect special, preparation of the present invention or dosage form make the brain level of A β 40 reduce 10-50%, 20-45% or 25-35%.

M) the brain level of reduction A β 42.Aspect more of the present invention, preparation of the present invention or dosage form make A β 42 reduce at least about 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%.Aspect special, preparation of the present invention or dosage form make the brain level of A β 42 reduce 10-50%, 15-40% or 20-25%.

N) in individuality,, reduce the neuroglia activity in the brain with respect to the level of under the situation that does not have preparation of the present invention or dosage form to exist, measuring with Alzheimer disease symptoms.Preferably, preparation of the present invention or dosage form make the neuroglia activity reduce about 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%.

O) after treatment, the synapse function is remained on normal level in long-time, particularly at least 5 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 20 weeks, 24 weeks, 30 weeks, 40 weeks, 52 week or 78 weeks after treatment, more especially 2 to 4 weeks, 2 to 5 weeks, 3 to 5 weeks, 2 to 6 weeks, 2 to 8 weeks, 2 to 10 weeks, 2 to 12 weeks, 2 to 16 weeks, 2 to 20 weeks, 2 to 24 weeks, 2 thoughtful 12 months or 2 thoughtful 24 months.

P) alleviate or slow down the speed of progression of disease in the individuality of suffering from Alzheimer.Particularly alleviate or slow down the cognitive function decline in the individuality of suffering from Alzheimer.

Q) prevent, alleviate or slow down the cognitive function defective or improve cognitive competence.

R) prevent, alleviate or slow down amyloid blood vessel disease.

S) reduce the mortality rate that improves.

T) improve survival in the individuality with Alzheimer disease symptoms.

Aspect more of the present invention, the curative effect of preparation of the present invention, dosage form or treatment can show as (a) and (b); (a) and (b) and (c); (a) and (b), (e), (f) and (g); (a) and (b), (e), (f) are to (h); (a) and (b), (e), (f) are to (i); (a) and (b), (e), (f) are to Q); (a) and (b), (e), (f) are to (k); (a) and (b), (e), (f) are to (l); (a) and (b), (e), (f) are to (m); (a) and (b), (e), (f) are to (n); (a) and (b), (e), (f) are to (o); (a) and (b), (e), (f) are to (p); (a) and (b), (e), (f) are to (q); (a) and (b), (e), (f) are to (r); (a) and (b), (e), (f) are to (s); (a) and (b), (e), (f) are to (t); (a) to (d); (a) to (e); (a) to (f); (a) to (g); (a) to (h); (a) to (i); (a) to q); (a) to (k); (a) to (1); (a) to (m); (a) to (n); (a) to (o); (a) to (p); (a) to (q); (a) to (r); (a) to (s); (a) to (t).

" treatment effective dose " is meant will provide or bring useful characteristics of pharmacokinetics, more especially the dosage of cyclohexane extraction polyol compound in the preparation of the characteristics of pharmacokinetics of Chi Xuing or the dosage form.

" treatment valid density " be meant useful characteristics of pharmacokinetics can be provided, the characteristics of pharmacokinetics of Chi Xuing more especially, or be the level of cyclohexane extraction polyol compound in a kind of blood plasma, brain and/or the cerebrospinal fluid of curative effect.

Term " pure " generally is meant the purity greater than 90%, 92%, 95%, 97%, 98% or 99%, " pure basically " is meant synthetic chemical compound, described chemical compound can be considered for preparation of the present invention or dosage form, and only have can not be by conventional purification process easily or the impurity of suitably removing.

Be to be understood that, " cyclohexane polyalcohol chemical compound " is meant any chemical compound, it wholly or in part, directly or indirectly provides one or more beneficial effects described herein, and comprises formula I described herein, II, III or IV chemical compound, or its analog or derivant.Aspect more of the present invention, the cyclohexane polyalcohol chemical compound is an inositol.The cyclohexane polyalcohol chemical compound comprises officinal salt.

" officinal salt " is meant such salt, and it is pharmaceutically useful, and has desirable pharmacokinetics character.Officinal salt is meant that the tissue that is suitable for individuality or patient contacts, and does not have unsuitable toxicity, stimulation, allergy etc., and matches with rational interests/risk ratio.Officinal salt is described in for example S.M.Berge, waits the people, J.Pharmaceutical Sciences, and 1977, among the 66:1.Suitable salt comprises that wherein the interior acid proton of chemical compound can react and the salt of formation with inorganic base or organic base.Suitable inorganic salt comprises and the alkali metal salt that forms of sodium and potassium, magnesium, calcium and aluminum for example.Suitable organic salt comprises the salt that forms with organic base, and described organic base is for example ethanolamine, diethanolamine, triethanolamine, Apiroserum Tham, N-methylglucosamine etc.Suitable salt also comprises the acid-addition salts with mineral acid (for example hydrochloric acid) and organic acid (for example acetic acid, citric acid, maleic acid and alkane-and aromatic hydrocarbons-sulfonic acid for example methanesulfonic acid and benzenesulfonic acid) formation.When having two acidic-groups, officinal salt can be single acid-single salt or disalt; And similarly, when having two above acidic-groups, some or all such groups can salinization.

The cyclohexane polyalcohol chemical compound comprises functional deriv." functional deriv " is meant such chemical compound, and it has the biological activity substantially similar with the biological activity of chemical compound disclosed herein (on function or structure).Term " functional deriv " comprises " modification ", " analog " or " chemical derivative " of cyclohexane polyalcohol chemical compound.Term " modification " is meant on 26S Proteasome Structure and Function and cyclohexane polyalcohol chemical compound or the substantially similar molecule of its part.If two molecules have substantially similar structure or if two molecules have similar biological activity, then this molecule and cyclohexane polyalcohol chemical compound " substantially similar ".Term " analog " is meant on function goes up similarly molecule substantially with the cyclohexane polyalcohol chemical compound.The molecule of other chemical part that contains the part that usually is not basic molecule described in term " chemical derivative ".

The cyclohexane polyalcohol chemical compound comprises the crystal form that can be used as the polymorph existence.This term also comprises the solvate that chemical compound and water or conventional organic solvent form.In addition, the present invention includes the hydrate forms of chemical compound and salt thereof.This term also comprises the prodrug of cyclohexane polyalcohol chemical compound.

Term " solvate " be meant chemical compound and one or more solvent molecules the physics associated complex or by solute (for example The compounds of this invention) and solvent for example water, ethanol or acetic acid form have different stereochemical complex.This physics association can relate to ion and covalent bonding in various degree, comprises hydrogen bond.In some cases, solvate can be separated, for example, and when one or more solvent molecules are incorporated in the lattice of crystalline solid.Selected solvent does not generally disturb the biological activity of solute.Solvate comprises solution phase and separable solvate.The representative solvents thing comprises hydrate, ethanol compound, methanol compound etc.The dehydrated form, eutectic form, anhydrous form or the amorphism that also comprise The compounds of this invention.Term " hydrate " is meant such solvate, and wherein solvent molecule is H ₂O comprises its monohydrate, dihydrate and various polyhydrate.Solvate can use solvate known in the art to form.Solvate can use various distinct methods known in the art to form.

Crystalline compounds of the present invention can be free alkali, salt or eutectiferous form.Free alkali compound can be in the presence of suitable solvent crystallization to form solvate.The acid salt of The compounds of this invention (for example HCl, HBr, benzoic acid) can be used to prepare solvate.For example, solvate can form by using acetic acid or ethyl acetate.The solvate molecule can be via hydrogen bond, Van der Waals force or dispersion force, or the combination of any two kinds or all three kinds of power.

The amount that is used to prepare the solvent of solvate can be determined by conventionally test.For example, the monohydrate of The compounds of this invention will have about 1 equivalent solvent (H ₂O)/the equivalent The compounds of this invention.Yet, select according to required solvent, can use more or less solvent.

The compounds of this invention can be an amorphism, perhaps can have different crystalline polymorphs, may exist with different solventsization or hydration status.By changing medicament forms, can change its physical property.For example, crystalline polymorph has the dissolubility that differs from one another usually, and like this, the dissolubility of the polymorph that thermodynamics is more stable is less than the more unsettled polymorph of thermodynamics.Can also be for example different aspect storage life, bioavailability, morphology, vapour pressure, density, color and the compressibility as the polymorph of medicine in character.

Term " prodrug " is meant the derivant or the carrier of the covalent bonding of parent compound or active medicine, and prodrug experienced some biotransformation at least before showing pharmacological action.But such prodrug generally has the cracked group of metabolism, and transforms to produce parent compound rapidly in vivo, for example transforms by hydrolysis in blood, and generally includes the ester and the amide analogue of parent compound.The purpose of preparation prodrug is the raising chemical stability, improves patient's acceptance and compliance, raising bioavailability, prolongs acting duration, improves the organ selectivity, improves the property prepared (for example improving water solublity) and/or reduce side effect (for example toxicity).Prodrug self generally has weak biological activity or does not have biological activity, and is stable under normal condition.Prodrug can easily use methods known in the art to make by parent compound, the method of in following document, describing for example: A Textbook of Drug Design and Development, Krogsgaard-Larsen and H.Bundgaard (eds.), Gordon ﹠amp; Breach, 1991, particularly Chapter 5: " Design and Applications of Prodrugs "; Design ofProdrugs, H.Bundgaard (ed.), Elsevier, 1985; Prodrugs:Topical andOcular Drug Delivery, K.B.Sloan (ed.), Marcel Dekker, 1998; Methodsin Enzymology, people such as K.Widder (eds.), Vol.42, Academic Press, 1985, pp.309-396 particularly; Burger ' s Medicinal Chemistry and Drug Discovery, 5th Ed., M.Wolff (ed.), John Wiley ﹠amp; Sons, 1995, particularly Vol.1 andpp.172 178 and pp.949 982; Pro-Drugs as Novel Delivery Systems, T.Higuchi and V.Stella (eds.), Am.Chem.Soc, 1975; With BioreversibleCarriers in Drug Design, E.B.Roche (ed.), Elsevier, 1987, each document all is incorporated herein by reference.

The example of prodrug includes but not limited to the ester (for example acetas, formic acid esters and benzoate derivatives), carbamate (for example N, N-dimethylamino carbonyl) of the hydroxy functional group on the The compounds of this invention etc.

Usually, all physical form all within the scope of the present invention.

Aspect more of the present invention, the cyclohexane polyalcohol chemical compound comprises the chemical compound of the basic structure with formula I, pure especially basically formula I chemical compound.

Formula I

Wherein X is a cyclohexane extraction, especially myo-inositol, scyllitol, table-inositol, chirality-inositol and other-inositol (allo-inositol) group, wherein R ¹, R ², R ³, R ⁴, R ⁵And R ⁶In one or more be hydroxyl independently; alkyl; thiazolinyl; alkynyl; alkylidene; alkenylene; alkoxyl; alkene oxygen base; cycloalkyl; cycloalkenyl group; cycloalkyloxy; cycloalkynyl radical; aryl; aryloxy; alkoxy aryl; aroyl; heteroaryl; heterocyclic radical; acyl group; acyloxy; sulfoxide; sulfuric ester; sulfonyl; organic sulfenyl (sulfenyl); sulphonic acid ester; sulfinyl; amino; imino group; azido; mercaptan; alkylthio; thio alkoxy; thioaryl; nitro; cyano group; isocyanato-; halogen; seleno; silicyl; silyloxy; first silicon sulfenyl; carboxyl; carboxylate; carbonyl; carbamoyl; or amide, and officinal salt; isomer; solvate or prodrug.Aspect more of the present invention, R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In 4 or 5 or be hydroxyl all.Of the present invention special aspect, using wherein, X is the formula I cyclohexane polyalcohol chemical compound of the group of scyllitol or table-inositol.

The cyclohexane polyalcohol chemical compound of formula II is used in aspects more of the present invention, especially isolating and pure, pure formula II chemical compound especially basically:

Formula II

R wherein ¹, R ², R ³, R ⁴, R ⁵And R ⁶Be hydroxyl, perhaps R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In one or morely be independently; alkyl; thiazolinyl; alkynyl; alkylidene; alkenylene; alkoxyl; alkene oxygen base; cycloalkyl; cycloalkenyl group; cycloalkyloxy; aryl; aryloxy; alkoxy aryl; aroyl; heteroaryl; heterocyclic radical; acyl group; acyloxy; sulfoxide; sulfuric ester; sulfonyl; organic sulfenyl; sulfinyl; sulphonic acid ester; amino; imino group; azido; mercaptan; alkylthio; thio alkoxy; thioaryl; nitro; cyano group; isocyanato-; halogen; seleno; silicyl; silyloxy; first silicon sulfenyl; carboxyl; carboxylate; carbonyl; carbamoyl; or amide, and other R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶Be hydroxyl, perhaps its officinal salt.

Aspect more of the present invention, the cyclohexane polyalcohol chemical compound is the formula I or the II chemical compound of pure basically this paper definition, and condition is if (a) R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In one be alkyl or fluorine, other R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In to be no more than 4 be hydroxyl, (b) R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In one be amino or azide, R ¹, R ², R ³, R ⁴, R ⁵And R ⁶In to be no more than 4 be hydroxyl, (c) R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In 2 be amino, R ¹, R ², R ³, R ⁴, R ⁵And R ⁶In to be no more than 3 be hydroxyl, and (d) R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In 3 be amino, carboxyl, carbamoyl, sulfonyl, isoxazolyl, imidazole radicals or thiazolyl, other R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶Can not all be hydroxyl.

Aspect more of the present invention, the cyclohexane polyalcohol chemical compound is pure basically formula III chemical compound,

Formula III

Wherein X is a cyclohexane ring, wherein R ¹, R ², R ³, R ⁴, R ⁵And R ⁶Be hydroxyl, perhaps R ¹, R ², R ³, R ⁴, R ⁵And R ⁶In at least one be independently selected from hydrogen, C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₁-C ₆Alkoxyl, C ₂-C ₆Alkene oxygen base, C ₃-C ₁₀Cycloalkyl, C ₄-C ₁₀Cycloalkenyl group, C ₃-C ₁₀Cycloalkyloxy, C ₆-C ₁₀Aryl, C ₆-C ₁₀Aryloxy, C ₆-C ₁₀Aryl-C ₁-C ₃Alkoxyl, C ₆-C ₁₀Aroyl, C ₆-C ₁₀Heteroaryl, C ₃-C ₁₀Heterocyclic radical, C ₁-C ₆Acyl group, C ₁-C ₆Acyloxy ,-NH ₂,-NHR ⁷,-NR ⁷R ⁸,=NR ⁷,-S (O) ₂R ⁷,-SH ,-SO ₃H, nitro, cyano group, halogen, haloalkyl, halogenated alkoxy, hydroxy alkyl ,-Si (R ⁷) ₃,-OSi (R ⁷) ₃,-CO ₂H ,-CO ₂R ⁷, the oxo base ,-PO ₃H ,-NHC (O) R ⁷,-C (O) NH ₂,-C (O) NHR ⁷,-C (O) NR ⁷R ⁸,-NHS (O) ₂R ⁷,-S (O) ₂NH ₂,-S (O) ₂NHR ⁷With-S (O) ₂NR ⁷R ⁸, R wherein ⁷And R ⁸Be independently selected from C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₃-C ₁₀Cycloalkyl, C ₄-C ₁₀Cycloalkenyl group, C ₆-C ₁₀Aryl, C ₆-C ₁₀Aryl C ₁-C ₃Alkyl, C ₆-C ₁₀Heteroaryl and C ₃-C ₁₀Heterocyclic radical, and residue R ¹, R ², R ³, R ⁴, R ⁵Or R ⁶In at least one be hydroxyl; Perhaps its officinal salt.Aspect special, the present invention uses the isomer of formula III chemical compound, more specifically scyllo-or epi-isomer.

Aspect more of the present invention, the cyclohexane polyalcohol chemical compound is pure basically formula IV chemical compound,

Formula IV

R wherein ¹, R ², R ³, R ⁴, R ⁵And R ⁶Define as formula III, perhaps its officinal salt.

The term about group of used herein comprising " alkyl ", " alkoxyl ", " thiazolinyl ", " alkynyl ", " hydroxyl " etc. is meant group unsubstituted or that replace.Any one or the selecteed group of a plurality of part that the ＂ that term ＂ used herein replaces means on the specified atom (for example hydroxyl) substitute, and condition is the normal quantivalence that is no more than this specified atom, and described replacement causes stable chemical compound.Uniting of substituent group and/or group allows, and condition is that such uniting causes stable chemical compound." stable chemical compound " is meant enough sane, exists after the purity that is separated into useful degree from reactant mixture, and is mixed with effective therapeutic agent.

" alkyl ", no matter separately or at other terms for example within " aryl alkyl ", meaning can be straight chain (being straight chain) or the unit price of side chain, saturated alkyl.Aspect more of the present invention, alkyl comprises about 1-24 or 1-20 carbon atom, preferred about 1-10,1-8,3-8, a 1-6 or 1-3 carbon atom.The example of alkyl comprise methyl, ethyl, n-pro-pyl, normal-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl group, isopentyl, amyl group, sec-butyl, the tert-butyl group, tertiary pentyl, n-heptyl,, n-octyl, n-nonyl, positive decyl, undecyl, dodecyl, n-tetradecane base, pentadecyl, n-hexadecyl, heptadecyl, n-octadecane base, nonadecyl, eicosyl, dosyl, n-tetracosane base etc., and side chain mutation.In some embodiments of the present invention, alkyl is to comprise or be selected from following C ₁-C ₆Low alkyl group: methyl, ethyl, n-pro-pyl, normal-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl group, isopentyl, amyl group, tributyl, sec-butyl, the tert-butyl group, tertiary pentyl and n-hexyl.Alkyl can significantly not disturb the preparation of cyclohexane polyalcohol chemical compound and significantly not reduce optional being substituted on the position of effect of chemical compound.Alkyl can be chosen wantonly and be substituted.In certain methods; alkyl is replaced by one or more substituent groups, amino, carboxyl, sulfonyl, organic sulfenyl, sulfinyl, sulfuric ester, sulfoxide that described substituent group comprises halogen, lower alkoxy, halogenated alkoxy, alkyl alkoxy, halogenated alkoxy alkyl, hydroxyl, cyano group, nitro, thio group, amino, replaced, the carboxyl that has replaced, junior alkyl halides (CF for example ₃), halogenated lower alkoxy, hydroxycarbonyl group, elementary alkoxy carbonyl, lower alkylcarbonyl oxygen base, lower alkylcarbonyl amino, aryl (for example phenyl methyl (being benzyl)), heteroaryl (for example pyridine radicals) and heterocycle (for example piperidyl, morpholinyl).

Aspect more of the present invention; the alkyl that has replaced " be meant by for example 1-5 substituent group and the alkyl that preferred this substituent group of 1-3 replaces that described substituent group is alkyl, alkoxyl, oxo base, alkanoyl, aryl, aralkyl, aryloxy, alkanoyl oxygen base, cycloalkyl, acyl group, amino, hydroxyl amino, alkyl amino, arylamino, alkoxy amino, aryl alkyl amino, cyano group, halogen, hydroxyl, carboxyl, carbamoyl, carboxyalkyl, ketone group, thioketone, sulfur for example , alkyl hydrosulfide, artyl sulfo, aromatic alkyl sulfurio, sulfonamide, thio alkoxy and nitro.

Term " thiazolinyl " is meant unsaturated acyclic side chain or the straight-chain alkyl that contains at least one two key.Thiazolinyl can contain have an appointment 2-24 or 2-10 carbon atom, preferably about 3-8 carbon atom and more preferably from about 3-6 or 2-6 carbon atom.The example of suitable thiazolinyl comprises vinyl, and acrylic is third-1-alkene-1-base, third-1-alkene-2-base, third-2-alkene-1-base (pi-allyl), third-2-alkene-2-base for example, butene-1-Ji, but-1-ene-2-base, 2-methyl-third-1-alkene-1-base, but-2-ene-1-base, but-2-ene-2-base, fourth-1,3-diene-1-base, fourth-1,3-two-2-base, hexene-1-base, 3-hydroxyl thiazolinyl-1-base, heptene-1-base, and octene-1-Ji etc.Preferred thiazolinyl comprises vinyl (CH=CH ₂), positive acrylic (CH ₂CH=CH ₂), isopropenyl (C (CH ₃)=CH ₂) etc.Thiazolinyl and alkyls are substituted like choosing wantonly.

Aspect more of the present invention; " replace thiazolinyl " is meant by for example 1-3 substituent group; especially the thiazolinyl that replaces of 1-2 substituent group, described substituent group is alkyl for example; alkoxyl; halogenated alkoxy; alkyl alkoxy; halogenated alkoxy alkyl; alkanoyl; alkanoyl oxygen base; cycloalkyl; cycloalkyloxy; acyl group; acyl amino; acyloxy; amino; alkyl amino; alkanoylamino; aminoacyl; amino acyloxy; cyano group; halogen; hydroxyl; carboxyl; carboxyalkyl; carbamoyl; ketone group; thioketone; mercaptan; the alkyl sulfenyl; sulfonyl; sulfonamido; thio alkoxy; aryl; nitro etc.

Term " alkynyl " is meant and contains one or more triple-linked unsaturated side chains or straight-chain alkyl.Alkynyl can contain the 1-20 that has an appointment, 1-15 or 2-10 carbon atom, preferably about 3-8 carbon atom and more preferably 3-6 carbon atom.Aspect more of the present invention, " alkynyl " is meant the straight or branched alkyl that contains 1-4 triple bond, a 2-6 carbon atom.The example of suitable alkynyl comprises acetenyl, propinyl is third-1-alkynes-1-base, third-2-alkynes-1-base for example, butynyl is fourth-1-alkynes-1-base, fourth-1-alkynes-3-base and fourth-3-alkynes-1-base for example, pentynyl is pentyne-1-base, pentyne-2-base and 4-methoxyl group pentyne-2-base and 3-methyl butine-1-base for example, the hexin base is hexin-1-base, hexin-2-base and hexin-3-base and 3 for example, 3-dimethyl butine-1-base etc.Described alkynyl and alkyls are substituted like choosing wantonly.Term " cycloalkynyl radical " is meant the ring-type alkynyl.

Aspect more of the present invention; " replace alkynyl " is meant and is substituted the alkynyl that base replaces, and described substituent group is alkyl, alkoxyl, alkanoyl, alkanoyl oxygen base, cycloalkyl, cycloalkyloxy, acyl group, acyl amino, acyloxy, amino, alkyl amino, alkanoylamino, aminoacyl, amino acyloxy, cyano group, halogen, hydroxyl, carboxyl, carboxyalkyl, carbamoyl, ketone group, thioketone, mercaptan, alkyl sulfenyl, sulfonyl, sulfonamido, thio alkoxy, aryl, nitro etc. for example.

Term " alkylidene " is meant side chain or the branched group that has about 1-10,1-8, a 1-6 or 2-6 carbon atom and have two or more covalent bond junction points.Such examples of groups is methylene, ethylidene, ethylidene, methyl ethylidene and isopropylidene.

Term " alkenylene " be meant have about 2-10,2-8 or 2-6 carbon atom, at least one two key and have the straight or branched group of two or more covalent bond junction points.Such examples of groups is 1,1-ethenylidene (CH ₂=C), (CH=CH-) and 1, the 4-butadienyl is (CH=CH-CH=CH-) for vinylene.

As used herein, " halogen " or " halogeno-group " is meant fluorine, chlorine, bromine, iodine, especially fluorine or chlorine.

Term " hydroxyl " is meant single-OH group.

Term " cyano group " is meant carbon-based group, shared by nitrogen-atoms for three in the middle of its four covalent bonds, particularly-CN.

Term " alkoxyl " be meant have about 10 carbon atoms of 1-can substituted moieties, straight or branched contains the group of aerobic base.Special alkoxyl is " lower alkoxy " with about 1-6,1-4 or 1-3 carbon atom.Alkoxyl with about 1-6 carbon atom comprises C ₁-C ₆Alkyl-O-group, wherein C ₁-C ₆Alkyl has the connotation of this paper definition.The alkoxyl illustrative example include but not limited to methoxyl group,, ethyoxyl, propoxyl group, butoxy, isopropoxy and tert-butoxy.＂ alkoxyl ＂ can choose wantonly further and be replaced by one or more substituent groups described herein, and described substituent group comprises that alkyl (especially low alkyl group) is to form " alkyl alkoxy "; Halogen atom, for example fluorine, chlorine, bromine, iodine are to form " halogenated alkoxy " (for example fluorine methoxyl group, chlorine methoxyl group, trifluoromethoxy, difluoro-methoxy, trifluoro ethoxy, fluorine ethyoxyl, tetrafluoro ethyoxyl, five fluorine ethyoxyls and fluorine propoxyl group) and " halogenated alkoxy alkyl " (for example fluorine methoxy, chlorine methoxy ethyl, trifluoromethoxy methyl, difluoro-methoxy ethyl and trifluoro ethoxy methyl).

Term " acyl group "; separately or associating; mean and be selected from for example carbonyl or the thiocarbonyl of the optional following groups bonding that replaces: hydrogen (hydrido); alkyl (for example haloalkyl); thiazolinyl; alkynyl; (" acyloxy " comprises acetoxyl group to alkoxyl; butyryl acyloxy; the isoamyl acyloxy; the phenyl acetoxyl group; benzoyloxy; to methoxybenzoyl oxygen base and the acyloxy that replaced for example alkoxyalkyl and halogenated alkoxy); aryl; halogen; heterocyclic radical; heteroaryl; sulfinyl (for example alkyl sulphinyl alkyl); sulfonyl (for example alkyl sulphonyl alkyl); cycloalkyl; cycloalkenyl group; alkylthio; thioaryl; amino (for example alkyl amino or dialkyl amido) and aralkoxy.The illustrative example of " acyl group " comprises formoxyl, acetyl group, 2-chloracetyl, 2-acetyl bromide, benzoyl, trifluoroacetyl group, phthalyl, malonyl, nicotinoyl etc.

Aspect more of the present invention, " acyl group " is meant group-C (O) R ¹⁰, R wherein ¹⁰Be hydrogen, alkyl, cycloalkyl, the assorted alkyl of ring, aryl, aryl alkyl, assorted alkyl, heteroaryl and heteroaryl alkyl.Example includes but not limited to formoxyl, acetyl group, cyclohexyl-carbonyl, cyclohexyl methyl carbonyl, benzoyl, benzyloxycarbonyl group etc.

Term " cycloalkyl " is meant the group that has about 3-16 or 3-15 carbon atom and contain 1,2,3 or 4 ring, and wherein said ring can side be hung that (pendant) mode connects or can is condensed.Aspect more of the present invention, " cycloalkyl " is meant to have the saturated hydrocarbons ring system that 1-2 ring and each ring contain the optional replacement of this carbon atom of 3-7, and described ring can be further and undersaturated C ₃-C ₇Carbocyclic fused.The example of cycloalkyl comprises single ring architecture for example cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, ring octyl group, ring nonyl, ring decyl, cyclo-dodecyl etc., perhaps multiring structure adamantyl etc. for example.Aspect some, cycloalkyl is " low-grade cycloalkyl " with about 3-10,3-8,3-6 or 3-4 carbon atom, especially cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and suberyl of the present invention.Term " cycloalkyl " comprises that also wherein cycloalkyl is and aryl or the condensed group of heterocyclic radical.Cycloalkyl can be chosen wantonly and be substituted.

Aspect more of the present invention; " cycloalkyl of replacement " is meant to have the substituent cycloalkyl of 1-5 individual (especially 1-3), and described substituent group includes but not limited to cycloalkyl, acyl group, acyl amino, acyloxy, amino, aminoacyl, amino acyloxy, oxygen base acyl amino, cyano group, halogen, hydroxyl, carboxyl, carboxyalkyl, ketone group, thioketone, mercaptan, thio alkoxy, aryl, aryloxy, heteroaryl, heteroaryl oxygen base, hydroxyl amino, alkoxy amino and the nitro of alkyl, thiazolinyl, alkoxyl, cycloalkyl, replacement.

Term " cycloalkenyl group " is meant and contains the 2-16 that has an appointment, 4-16,2-15,2-10,4-10,3-8, a 3-6 or 4-6 carbon atom, one or more carbon-to-carbon double bonds, with the group of 1,2,3 or 4 ring, it maybe can be condensed that wherein said ring can side extension mode links together.Aspect more of the present invention, cycloalkenyl group is " lower alkenyl ring " with 3-7 carbon atom, especially cyclobutane base, cyclopentenyl, cyclohexenyl group and cycloheptenyl.Cycloalkenyl group can be chosen wantonly by group described herein and replace.

Term " cycloalkyloxy " is meant the cycloalkyl (cycloalkyl that especially has 3-15, a 3-8 or 3-6 carbon atom) that is connected with the oxygen base.The example of cycloalkyloxy comprises cyclohexyloxy and ring propoxyl group.Cycloalkyloxy can be chosen wantonly by group described herein and replace.

Term " aryl " separately or associating, is meant the carbocyclic aromatic system of containing 1,2 or 3 ring, and it maybe can be condensed that wherein said ring can side extension mode links together.Term " condensed " is meant that second ring is by total with first ring or share two adjacent atoms and have (promptly be connected or form).Aspect more of the present invention, aryl contains 4-24 carbon atom, especially 4-10, a 4-8 or 4-6 carbon atom.Term " aryl " includes but not limited to aromatic hydrocarbon group for example phenyl, naphthyl, indenyl, benzo cyclo-octene base, benzocyclohepta thiazolinyl, pentalene base, Flos Chrysanthemi cyclic group, tetralyl, indanyl, xenyl, diphenyl, acephthylenyl, fluorenyl, phenalenyl, phenanthryl and anthryl, preferred phenyl.Aryl can be chosen wantonly by 1-4 substituent group and replace, and described substituent group is alkyl for example; the alkyl that replaces; thiazolinyl; the thiazolinyl that replaces; alkynyl; the alkynyl that replaces; aryl; the aryl that replaces; aralkyl; halogen; trifluoromethoxy; trifluoromethyl; hydroxyl; alkoxyl; alkanoyl; alkanoyl oxygen base; aryloxy; aralkyl oxy; amino; alkyl amino; arylamino; aryl alkyl amino; dialkyl amido; alkanoylamino; mercaptan; the alkyl sulfenyl; urea groups; nitro; cyano group; carboxyl; carboxyalkyl; carbamoyl; alkoxy carbonyl; the alkyl sulfide carbonyl; the aryl thiocarbonyl group; aryl sulfonyl amine; sulfonic acid; alkyl sulphonyl; sulfonamido; aryloxy group etc.Substituent group can further be replaced by hydroxyl, halogen, alkyl, alkoxyl, thiazolinyl, alkynyl, aryl or aralkyl.Aspect more of the present invention, aryl is replaced by hydroxyl, alkyl, carbonyl, carboxyl, mercaptan, amino and/or halogen.Term " aralkyl " is meant aryl or the aryl of replacement, for example benzyl that directly connects by alkyl.Other special examples of the aryl that replaces comprise benzyl chloride base aminobenzyl.

Term " aryloxy group " is meant the aryl defined above that is connected with oxygen atom.Exemplary aryloxy group comprises naphthoxy, quinolyl oxygen base, different quinolizinyl oxygen base etc.

Term used herein " alkoxy aryl " is meant the aryl that is connected with alkoxyl.The representative example of alkoxy aryl includes but not limited to 2-phenyl ethoxy, 3-naphthalene-2-base propoxyl group and 5-phenyl amoxy.

Term " aroyl " is meant the aryl of this paper definition that is connected with the carbonyl of this paper definition, includes but not limited to benzoyl and toluyl.Aroyl can be chosen wantonly by group described herein and replace.

Term " heteroaryl " be meant have 3-15, the complete undersaturated of annular atoms that 3-10,5-15,5-10 or 5-8 are selected from carbon, nitrogen, sulfur and oxygen contain heteroatomic ring-type aromatic hydrocarbon group, wherein at least one annular atoms is a hetero atom.The heteroaryl ring atom can contain 1,2 or 3 ring, and described ring can be surveyed the extension mode and connects or condense.The example of " heteroaryl " includes but not limited to contain unsaturated 5-6 unit heteromonocyclic group, especially pyrrole radicals, pyrrolinyl, imidazole radicals, pyrazolyl, 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, triazolyl, the tetrazole radical of 1-4 nitrogen-atoms etc.; Contain unsaturated annelated heterocycles base, especially indyl, isoindolyl, indolizine base, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazole base, tetrazole radical of 1-5 nitrogen-atoms etc.; The unsaturated 3-6 first heteromonocyclic group, especially 2-furyl, the 3-furyl etc. that contain oxygen atom; The unsaturated 5-6 first heteromonocyclic group, especially 2-thienyl, the 3-thienyl etc. that contain sulphur atom; The first heteromonocyclic group of unsaturated 5-6 that contains 1-2 oxygen atom and 1-3 nitrogen-atoms, Qi Shi oxazolyl of You, Yi Evil Zuo oxadiazole base etc.; The unsaturated annelated heterocycles base that contains 1-2 oxygen atom and 1-3 nitrogen-atoms, for example thiazolyl thiadiazolyl group etc.; The unsaturated annelated heterocycles base that contains 1-2 sulphur atom and 1-3 nitrogen-atoms is benzothiazolyl, diazosulfide base etc. for example.This term comprises that also wherein heterocyclic radical is and aryl-fused group, especially for example benzofuran, benzothiophene etc. of bicyclic group.Heteroaryl can be chosen wantonly by group described herein and replace.

Term " heterocycle " be meant have about 3-15,3-10,5-15,5-10 or 3-8 be selected from carbon, nitrogen, sulfur and oxygen annular atoms, saturated and fractional saturation, contain heteroatomic cyclic group.Heterocyclic radical can contain 1,2 or 3 ring, and the mode that wherein said ring can be surveyed extension connects or can condense.The example of saturated heterocyclyl includes but not limited to contain the assorted monocycle [for example pyrrolidinyl, imidazolidinyl, piperidyl and piperazinyl] of saturated 3-6 unit of 1-4 nitrogen-atoms; The first heteromonocyclic group [for example morpholinyl] of saturated 3-6 that contains 1-2 oxygen atom; With, contain 3-6 unit's heteromonocyclic group [for example thiazolidinyl] of a 1-2 sulphur atom 1-3 nitrogen-atoms etc.The example of fractional saturation heterocyclic radical includes but not limited to dihydro-thiophene, dihydropyran, oxolane and thiazoline.Exemplary heterocyclic radical includes but not limited to 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, 2H-pyranose, 4H-pyranose, piperidyl, 1,4-alkyl dioxin, morpholinyl, 1,4-dithiane base, thio-morpholinyl etc.

Term " sulfuric ester " separately or with the use that connects together of other terms, be known in the art, and comprise the group that is expressed from the next:

R wherein ¹⁶Be electron pair, hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl, heterocyclic radical, carbohydrate, peptide or peptide derivant.

Term " sulfonyl ", separately or with for example alkyl sulphonyl or the aryl sulfonyl use that connects together of other terms, be meant divalent group-SO ₂-.Aspect more of the present invention, R wherein ¹, R ³, R ⁴, R ⁵Or R ⁶In one or more are sulfonyls, described sulfonyl can be connected with following group: replacement or unsubstituted alkyl, thiazolinyl, alkynyl, aryl, cycloalkyl, cycloalkenyl group, cycloalkynyl radical or heterocyclic radical, carbohydrate, peptide or peptide derivant.

Term " sulphonic acid ester " is known in the art, and comprises the group that is expressed from the next:

R wherein ¹⁶Be electron pair, hydrogen, alkyl, cycloalkyl, aryl, thiazolinyl, alkynyl, cycloalkenyl group, cycloalkynyl radical, heterocyclic radical, carbohydrate, peptide or peptide derivant.

The example of sulfonated alkyl comprises ethyl sulfuric acid, ethyl sulfonic acid, the amino second of 2--1-bright sulfur acid, 1-propane sulfonic acid, 2-propane sulfonic acid, 1,2-two ethane disulfonic acid, 1 two sulphuric acid, 1,3-third disulfonic acid, 1-propanol sulphuric acid.1, ammediol two sulphuric acid, 1-fourth sulfonic acid, 1,4-butanediol two sulphuric acid, 1 two sulphuric acid, 3-amino-1-propane sulfonic acid, 3-hydroxy-propanesulfonic acid sulfuric ester, 1,4-fourth sulfonic acid, 1,4-butanediol one sulphuric acid, 1-penta sulfonic acid, 1,5-penta disulfonic acid, 1,5-pentanediol sulphuric acid, 4-sulfonic acid in heptan, 1,3,5-triol in heptan three sulfuric esters, 2-hydroxymethyl-1,3 propylene glycol three sulfuric esters, 2-hydroxymethyl-2-methyl isophthalic acid, ammediol three sulfuric esters, 1,3,5,7-tetrol in heptan four sulfuric esters, 1,3,5,7,9-pentathionic acid in ninth of the ten Heavenly Stems ester, 1-hendecane sulfonic acid, and officinal salt.

The example of cycloalkyl sulfonation group comprises 1,3-cyclohexane diol di-sulfate and 1,3,5-triol in heptan three sulfuric esters.

The example of aryl sulfonation group comprises 1,3-benzenedisulfonic acid, 2,5-dimethoxy-1,4-benzenedisulfonic acid, 4-amino-3-hydroxyl-1-naphthalene sulfonic aicd, 3,4-diaminostilbene-LOMAR PWA EINECS 246-676-2, and officinal salt.

The example of heterocycle sulfonated compound comprises 3-(N-morpholino) propane sulfonic acid and Tetramethylene sulfide-1,1-dioxide-3,4-disulfonic acid, and officinal salt.

The sulfonation examples of carbohydrates is sucrose eight sulphonic acid esters, 5-deoxidation-1,2-O-isopropylidene-α-D-furyl xylose-5-sulfonic acid or seven alkali salts, methyl-α-D-pyranglucoside 2,3-di-sulfate, methyl 4,-O-benzal-α-D-pyranglucoside 2,3-di-sulfate, 2,3,4,3 ', 4 '-sucrose pentathionic acid ester, 1,3:4,6-two-O-benzal-D-mannitol 2,5-di-sulfate, D-mannitol 2,5-di-sulfate, 2,5-two-O-benzyl-D-mannitol four sulfuric esters, and officinal salt.

Term " sulfinyl ", separately or with for example alkyl sulphinyl (promptly-S (O)-alkyl) or the aryl sulfonyl kia use that connects together of other terms, be meant divalent group-S (O)-.

Term " sulfoxide " is meant group-S=O.

Term " amino ", separately or associating, be meant the group that nitrogen (N) wherein is connected with three substituent groups, described three substituent groups are any combinations of hydrogen, hydroxyl, alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl or silicyl, and have general chemical formula-NR ¹⁰R ¹¹, wherein ¹⁰And R ¹¹Can be any combination of following group: hydrogen, hydroxyl, alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, silicyl, heteroaryl or heterocycle, described group can or cannot be substituted.Randomly, a substituent group on the nitrogen-atoms can be that hydroxyl (OH) is known as hydroxyl with formation.Amino illustrative example is amino (NH ₂), alkyl amino, acyl amino, ring amino, cycloalkyl amino, arylamino, aryl-alkyl amino and low alkyl group silicyl amino, especially methylamino, ethylamino, dimethylamino, 2-third amino, fourth amino, isobutyl amino, cyclopropylamino, benzylamino, allyl amino, hydroxyl amino, cyclohexyl amino, piperidines, benzylamino, diphenyl methyl amino, trityl amino, trimethyl silyl amino and dimethyl tert-butyl group silicyl amino.

Term " mercaptan " is meant-SH.

Term " organic sulfenyl (sulfenyl) " is meant group-SR ⁹, R wherein ⁹Not hydrogen.R ⁹Can be alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, silicyl, heterocyclic radical, heteroaryl carbonyl or carboxyl.

Term " alkylthio " separately or associating, is meant sulphur atom (S) wherein and the chemical functional group who can substituted alkyl be connected.The example of alkylthio is sulphomethyl, thio-ethyl and sulfo-propyl group.

Term " thioaryl " separately or associating, is meant the chemical functional group that sulphur atom (S) wherein is connected with aryl, and has general chemical formula-SR ¹², R wherein ¹²Be can substituted aryl.The thioaryl illustrative example of thioaryl and replacement is thio-phenyl, to chlorothio phenyl, sulfo-benzyl, 4-methoxyl group-thio-phenyl, 4-nitro-thio-phenyl with to nitro sulfo-benzyl.

Term " thio alkoxy " separately or associating, is meant the chemical functional group that sulphur atom (S) wherein is connected with alkoxyl, and has general chemical formula-SR ¹³, R wherein ¹³Be can substituted alkoxyl.Aspect more of the present invention, " thio alkoxy " has 1-6 carbon atom, and refers to-S-(O)-C ₁-C ₆Alkyl, wherein C ₁-C ₆Alkyl has connotation defined above.Have 1-6 carbon atom, also be known as C ₁-C ₆The illustrative example of the straight or branched thio alkoxy of thio alkoxy comprises sulfo-methoxyl group and thio ethoxy.

Term " carbonyl " is meant carbon-based group, and two in the middle of its four covalent bonds are shared with oxygen.

Term " carboxyl ", independent or associating is meant-C (O) OR ¹⁴-, R wherein ¹⁴Be hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, amino, mercaptan, aryl, heteroaryl, alkylthio, thioaryl, thio alkoxy or heterocyclic radical, described group can be chosen wantonly and be substituted.Aspect more of the present invention, the form that carboxyl is esterification, and can contain the esterified group low-grade alkyl group.Of the present invention special aspect ,-C (O) OR ¹⁴Form ester or amino acid derivativges.The form of esterification also is meant this paper alleged " carboxylate " especially.Aspect more of the present invention, " carboxyl " can be substituted, and especially replaced by the optional alkyl that is replaced by one or more following groups: amino, amine, halogen, alkyl amino, aryl, carboxyl or heterocyclic radical.Of the present invention special aspect, carboxyl is a methoxycarbonyl, butoxy carbonyl, uncle's alkoxy carbonyl is tert-butoxycarbonyl for example, aryl methoxy carbonyl with one or two aryl, described aryl includes but not limited to optional by for example low alkyl group, lower alkoxy, hydroxyl, halogen, and/or the phenyl of nitro replacement, for example benzyl oxygen base carbonyl, methoxyl group benzyloxy base carbonyl, diphenyl methoxy base carbonyl, 2-bromine oxethyl carbonyl, 2-iodine ethoxy carbonyl tert-butyl group carbonyl, 4-nitrobenzyl oxygen base carbonyl, diphenyl methoxy base-carbonyl, benzyloxycarbonyl, two-(4-methoxyphenyl-methoxycarbonyl, 2-bromine oxethyl carbonyl, 2-iodine ethoxy carbonyl, 2-trimethylsilylethoxy) carbonyl or 2-triphenyl silicyl ethoxy carbonyl.The carboxyl of other esterified form is a silicyl oxygen base carbonyl, comprises Organosilyl oxygen base carbonyl.Silicon substituent group in such chemical compound can be replaced by low alkyl group (for example methyl), alkoxyl (for example methoxyl group) and/or halogen (for example chlorine).The substituent example of silicon comprises trimethyl silyl and dimethyl tert-butyl group silicyl.

Term " amide ", separately or associating, be meant with carbonyl in two amino that is connected, an alkyl amino, dialkyl amido, a cycloalkyl amino, alkyl-cycloalkyl amino and bicyclic alkyl aminos of sharing in the keys.

Term " nitro " is meant-NO ₂-.

Group in the cyclohexane polyalcohol chemical compound can be replaced by one or more substituent groups that it will be apparent to those skilled in the art, described substituent group includes but not limited to alkyl; thiazolinyl; alkynyl; alkanoyl; alkylidene; alkenylene; hydroxy alkyl; haloalkyl; the halo alkylidene; haloalkenyl group; alkoxyl; alkene oxygen base; alkene oxygen base alkyl; alkoxyalkyl; aryl; alkylaryl; halogenated alkoxy; haloalkene oxygen base; heterocyclic radical; heteroaryl; sulfonyl; organic sulfenyl; alkyl sulphonyl; sulfinyl; alkyl sulphinyl; aralkyl; heteroarylalkyl; cycloalkyl; cycloalkenyl group; cycloalkyloxy; cyclenes oxygen base; amino; the oxygen base; halogen; azido; organic sulfenyl; cyano group; hydroxyl; phosphonate radical closes (phosphonato); the phosphinic acid root closes (phosphinato); alkylthio; alkyl amino; arylamino; aryl sulfonyl; alkyl-carbonyl; aryl carbonyl; the heteroaryl carbonyl; the heteroaryl sulfinyl; heteroarylsulfonyl; heteroaryl amino; heteroaryl oxygen base; heteroaryl oxygen base alkyl; aryl acetylamino (arylacetamidoyl); aryloxy; aroyl; aralkanoyl; aralkoxy; aromatic yloxy yl alkyl; halogenated aryl oxygen base alkyl; 4-hetaroylpyrazol; assorted aralkanoyl; assorted aralkoxy; assorted sweet-smelling alkoxy alkyl; thioaryl; the aryl alkylthio; alkoxyalkyl and acyl group.In embodiments of the invention, substituent group comprises alkyl, alkoxyl, alkynyl, halogen, amino, organic sulfenyl, oxygen base and hydroxyl.

Be used for the present invention although this paper has described the generality definition of cyclohexane polyalcohol chemical compound, can describe especially some chemical compounds of formula I, II, III or IV.In embodiments of the invention, the cyclohexane polyalcohol chemical compound is isolating, especially pure, more specifically pure basically formula I chemical compound, and wherein X is scyllitol, table-inositol or its configurational isomer, wherein

(a) R ¹, R ², R ³, R ⁴, R ⁵And R ⁶Be hydroxyl, perhaps

(b) R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In one or more; two or more; three or more is the optional independently alkyl that replaces; thiazolinyl; alkynyl; alkylidene; alkenylene; alkoxyl; alkene oxygen base; cycloalkyl; cycloalkenyl group; cycloalkyloxy; aryl; aryloxy; alkoxy aryl; aroyl; heteroaryl; heterocyclic radical; acyl group; acyloxy; sulfoxide; sulfuric ester; sulfonyl; organic sulfenyl; sulphonic acid ester; sulfinyl; amino; imino group; azido; mercaptan; alkylthio; thio alkoxy; thioaryl; nitro; cyano group; isocyanato-; halogen; seleno; silicyl; silyloxy; first silicon sulfenyl; carboxyl; carboxylate; carbonyl; carbamoyl or amide, and other R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶It is hydroxyl.

Aspect more of the present invention, the cyclohexane polyalcohol chemical compound is the scyllitol chemical compound, especially pure or pure basically scyllitol.Chemical compound " scyllitol " also refers to AZD-103 or the ELND005 of this paper.

" scyllitol chemical compound " comprises the chemical compound with formula Va or Vb structure:

In embodiments, with scyllitol chemical compound, salt or derivatives thereof, especially pure or pure basically scyllitol chemical compound is used for preparation described herein, dosage form, methods and applications.The scyllitol chemical compound comprises formula Va or Vb chemical compound, and wherein 1,2,3 or 4, especially 1,2 or 3, more preferably 1 or 2 hydroxyl under the situation that keeps configuration, is substituted base, especially unit price substituent group replacement.Suitable substituent group includes but not limited to hydrogen, alkyl, acyl group, thiazolinyl, cycloalkyl, halogen ,-NHR ¹R wherein ¹Be hydrogen, acyl group, alkyl, or-R ²R ³R wherein ²And R ³Be identical or different and expression acyl group or alkyl;-PO ₃H ₂-SR ⁴R wherein ⁴Be hydrogen, alkyl, or-O ₃H; With-OR ³R wherein ³Be hydrogen, alkyl, or-SO ₃H.Aspect more of the present invention, the scyllitol chemical compound does not comprise the scyllitol that is replaced by one or more bound phosphate groups.

The scyllitol chemical compound of formula Va or Vb is used in special aspect of the present invention, and wherein one or more hydroxyls are replaced by following group: alkyl, acyl group, thiazolinyl ,-NHR ¹R wherein ¹Be hydrogen, acyl group, alkyl, or-R ²R ³R wherein ²And R ³Be identical or different and expression acyl group or alkyl;-SR ⁴R wherein ⁴Be hydrogen, alkyl, or-O ₃H; With-OR ₃R wherein ³Be hydrogen, alkyl, or-SO ₃H, more specifically-SR ⁴R wherein ⁴Be hydrogen, alkyl, or-O ₃H or-SO ₃H.In embodiments of the invention, will show-inositol, the salt or derivatives thereof, especially pure or pure basically table-inositol chemical compound is used for preparation, dosage form, methods and applications that the present invention describes.

Aspect more of the present invention, the cyclohexane polyalcohol chemical compound is a table-inositol chemical compound, especially pure or pure basically table-inositol chemical compound.

" table-inositol chemical compound " comprises the chemical compound of the basic structure with formula VI:

Table-inositol chemical compound comprises formula VI chemical compound, and wherein 1,2,3 or 4, preferred 1,2 or 3, more preferably 1 or 2 hydroxyl under the situation that keeps configuration, is substituted base, especially unit price substituent group replacement.Suitable substituent group includes but not limited to hydrogen, alkyl, acyl group, thiazolinyl, cycloalkyl, halogen ,-NHR ¹R wherein ¹Be hydrogen, acyl group, alkyl, or-R ²R ³R wherein ²And R ³Be identical or different and expression acyl group or alkyl;-PO ₃H ₂-SR ⁴R wherein ⁴Be hydrogen, alkyl, or-O ₃H; With-OR ³R wherein ³Be hydrogen, alkyl, or-SO ₃H,

Table-inositol chemical compound of formula VI is used in special aspect of the present invention, and wherein one or more hydroxyls are replaced by following group: alkyl, acyl group, thiazolinyl ,-NHR ¹R wherein ¹Be hydrogen, acyl group, alkyl, or-R ²R ³R wherein ²And R ³Be identical or different and expression acyl group or alkyl;-SR ⁴R wherein ⁴Be hydrogen, alkyl, or-O ₃H; With-OR ³R wherein ³Be hydrogen, alkyl, or-SO ₃H, more specifically-SR ⁴R wherein ⁴Be hydrogen, alkyl, or-O ₃H or-SO ₃H.

Aspect more of the present invention, the cyclohexane polyalcohol chemical compound is table-cyclohexanhexanol (i.e. a table-inositol), especially pure or pure basically table-inositol.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is isolating, especially pure, more specifically pure basically formula II chemical compound, wherein

(a) R ¹, R ², R ³, R ⁴, R ⁵And R ⁶Be hydroxyl, perhaps

(b) R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In one or more; two or more; three or more is the optional independently alkyl that replaces; thiazolinyl; alkynyl; alkylidene; alkenylene; alkoxyl; alkene oxygen base; cycloalkyl; cycloalkenyl group; cycloalkyloxy; aryl; aryloxy; alkoxy aryl; aroyl; heteroaryl; heterocyclic radical; acyl group; acyloxy; sulfoxide; sulfuric ester; sulfonyl; organic sulfenyl; sulfinyl; sulphonic acid ester; amino; imino group; azido; mercaptan; alkylthio; thio alkoxy; thioaryl; nitro; cyano group; isocyanato-; halogen; seleno; silicyl; silyloxy; first silicon sulfenyl; carboxyl; carboxylate; carbonyl; carbamoyl or amide, and other R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶It is hydroxyl.

Of the present invention one special aspect, the cyclohexane polyalcohol chemical compound does not comprise wherein (a) if R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In one be alkyl or fluorine, other R so ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In be hydroxyl more than 4, if (b) R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In one be amino or azide, R so ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In be hydroxyl more than 4, if (c) R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In two be amino, R so ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In be hydroxyl and (d) R more than three ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶Be the formula I or the II chemical compound of isopropylidene.

Aspect more of the present invention, use wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In one or more be alkyl, alkoxy or halogen, and other R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶It is the cyclohexane polyalcohol chemical compound of hydrogen.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I or II chemical compound, and the one or more locational hydrogen in the position 1,2,3,4,5 or 6 of its Chinese style I or II is by R described herein ¹, R ², R ³, R ⁴, R ⁵And R ⁶Substituent group replace; described substituent group comprises the optional alkyl that replaces; thiazolinyl; alkynyl; alkylidene; alkenylene; alkoxyl; alkene oxygen base; cycloalkyl; cycloalkenyl group; cycloalkyloxy; aryl; aryloxy; alkoxy aryl; aroyl; heteroaryl; heterocyclic radical; acyl group; acyloxy; sulfoxide; sulfuric ester; sulfonyl; organic sulfenyl; sulfinyl; sulphonic acid ester; amino; imino group; azido; mercaptan; alkylthio; thio alkoxy; thioaryl; nitro; cyano group; isocyanato-; halogen; seleno; silicyl; silyloxy; first silicon sulfenyl; carboxyl; carboxylate; carbonyl; carbamoyl; or amide, the especially optional alkyl that replaces; thiazolinyl; alkoxyl; amino; imino group; mercaptan; nitro; cyano group; halogen or carboxyl.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I or II chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In one or more; two or more or three or more be thiazolinyl independently; alkynyl; alkylidene; alkenylene; alkoxyl; alkene oxygen base; cycloalkenyl group; cycloalkyloxy; aryl; aryloxy; alkoxy aryl; aroyl; heteroaryl; heterocyclic radical; acyl group; acyloxy; sulfonyl; organic sulfenyl; sulfinyl; sulphonic acid ester; sulfoxide; sulfuric ester; nitro; cyano group; isocyanato-; thioaryl; thio alkoxy; seleno; silicyl; silyloxy; first silicon sulfenyl; Cl; I; Br; carboxyl; carboxylate; carbonyl; carbamoyl or amide, and other R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶It is hydroxyl.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is isolating, especially pure, more specifically pure basically formula I or II chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In one or more, two or more or three or more be C independently ₁-C ₆Alkyl, C ₃-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₂-C ₆Alkylidene, C ₂-C ₈Alkenylene, C ₁-C ₆Alkoxyl, C ₂-C ₆Alkene oxygen base, C ₃-C ₈Cycloalkyl, C ₃-C ₈Cycloalkenyl group, C ₃-C ₈Cycloalkyloxy, C ₃-C ₈Cycloalkyloxy, acyloxy, sulfonyl, organic sulfenyl, sulfinyl, sulphonic acid ester, sulfoxide, sulfuric ester, isocyanato-, thioaryl, thio alkoxy, selene, silicyl, silyloxy, silylthio, aryl, aroyl, aryloxy, aryl C ₁-C ₆Alkoxyl, acetyl group, heteroaryl, heterocyclic radical, amino, mercaptan, alkylthio, thio alkoxy, nitro, cyano group, halogen (for example Cl, I or Br), carboxyl, carboxylate, carbonyl, carbamoyl, or amide, and other R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶It is hydroxyl.Aspect special, if (a) R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In one be alkyl or fluorine, other R so ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In at the most 4 be hydroxyl, if (b) R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In one be amino, R so ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In at the most 4 be hydroxyl, if (c) R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In two be amino, R so ¹, R ², R ³, R ⁴, R ⁵And R ⁶In at the most 3 be hydroxyl and (d) R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶It or not isopropylidene.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I chemical compound, wherein R ²At equatorial position is hydroxyl, R ¹, R ³, R ⁴, R ⁵And/or R ⁶In at least 1; 2; 3 or 4 is alkyl independently; thiazolinyl; alkynyl; alkylidene; alkenylene; alkoxyl; alkene oxygen base; cycloalkyl; cycloalkenyl group; cycloalkyloxy; aryl; aryloxy; alkoxy aryl; aroyl; heteroaryl; heterocyclic radical; acyl group; acyloxy; sulfoxide; sulfuric ester; organic sulfenyl; sulfonyl; sulphonic acid ester; sulfinyl; amino; imino group; azido; mercaptan; alkylthio; thio alkoxy; thioaryl; nitro; cyano group; isocyanato-; halogen; seleno; silicyl; silyloxy; first silicon sulfenyl; carboxyl; carboxylate; carbonyl; carbamoyl; or amide, especially C ₁-C ₆Alkyl, C ₃-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₂-C ₆Alkylidene, C ₂-C ₈Alkenylene, C ₁-C ₆Alkoxyl, C ₂-C ₆Alkene oxygen base, C ₃-C ₈Cycloalkyl, C ₃-C ₈Cycloalkenyl group, C ₃-C ₈Cycloalkyloxy, aryl C ₁-C ₆Alkoxyl, Cl, I or Br, and other R ¹, R ³, R ⁴, R ⁵And/or R ⁶It is hydroxyl.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I chemical compound, wherein R ²At equatorial position is hydroxyl, R ¹, R ³, R ⁴, R ⁵And/or R ⁶In at least two be alkyl independently; thiazolinyl; alkynyl; alkylidene; alkenylene; alkoxyl; alkene oxygen base; cycloalkyl; cycloalkenyl group; cycloalkyloxy; aryl; aryloxy; alkoxy aryl; aroyl; heteroaryl; heterocyclic radical; acyl group; acyloxy; sulfoxide; sulfuric ester; sulfonyl; organic sulfenyl; sulphonic acid ester; sulfinyl; amino; imino group; azido; mercaptan; alkylthio; thio alkoxy; thioaryl; nitro; cyano group; isocyanato-; halogen; seleno; silicyl; silyloxy; first silicon sulfenyl; carboxyl; carboxylate; carbonyl; carbamoyl; or amide, especially C1-C6 alkyl; C ₃-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₂-C ₆Alkylidene, C ₂-C ₈Alkenylene, C ₁-C ₆Alkoxyl, C ₂-C ₆Alkene oxygen base, C ₃-C ₈Cycloalkyl, C ₃-C ₈Cycloalkenyl group, C ₃-C ₈Cycloalkyloxy, aryl C ₁-C ₆Alkoxyl, Cl, I or Br, and other R ¹, R ³, R ⁴, R ⁵And/or R ⁶It is hydroxyl.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I or II chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In be hydroxyl at least, and R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In 1; 2; 3; or 4 be alkyl; thiazolinyl; alkynyl; alkylidene; alkenylene; alkoxyl; alkene oxygen base; cycloalkyl; cycloalkenyl group; cycloalkyloxy; aryl; aryloxy; alkoxy aryl; aroyl; heteroaryl; heterocyclic radical; acyl group; acyloxy; sulfoxide; sulfuric ester; sulfonyl; organic sulfenyl; sulphonic acid ester; sulfinyl; amino; imino group; azido; mercaptan; alkylthio; thio alkoxy; thioaryl; nitro; cyano group; isocyanato-; halogen; seleno; silicyl; silyloxy; first silicon sulfenyl; carboxyl; carboxylate; carbonyl; carbamoyl; or amide, especially C ₁-C ₆Alkyl, C ₃-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₂-C ₆Alkylidene, C ₂-C ₈Alkenylene, C ₁-C ₆Alkoxyl, C ₂-C ₆Alkene oxygen base, C ₃-C ₈Cycloalkyl, C ₃-C ₈Cycloalkenyl group, C ₃-C ₈Cycloalkyloxy, aryl C ₁-C ₆Alkoxyl, Cl, I or Br.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I or II chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In at least two be hydroxyl, and other R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In two or more be alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, alkylidene, alkenylene, alkoxyl, alkene oxygen base, cycloalkyloxy, aryl, aryloxy, alkoxy aryl, aroyl, heteroaryl, heterocyclic radical, acyl group or acyloxy, sulfonyl, organic sulfenyl, sulfinyl, amino, imino group, cyano group, isocyanato-, seleno, silicyl, silyloxy, first silicon sulfenyl, mercaptan, alkylthio, thio alkoxy, halogen, carboxyl, carboxylate, carbonyl, carbamoyl and amide, especially C ₁-C ₆Alkyl, C ₃-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₂-C ₆Alkylidene, C ₂-C ₈Alkenylene, C ₁-C ₆Alkoxyl, C ₂-C ₆Alkene oxygen base, C ₃-C ₈Cycloalkyl, C ₃-C ₈Cycloalkenyl group, C ₃-C ₈Cycloalkyloxy, aryl C ₁-C ₆Alkoxyl, Cl, I or Br.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I or II chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In at least two be hydroxyl, and other R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In three or more be alkyl independently; thiazolinyl; alkynyl; alkylidene; alkenylene; alkoxyl; alkene oxygen base; cycloalkyl; cycloalkenyl group; cycloalkyloxy; aryl; aryloxy; alkoxy aryl; aroyl; heteroaryl; heterocyclic radical; acyl group; acyloxy; sulfoxide; sulfuric ester; sulfonyl; organic sulfenyl; sulphonic acid ester; sulfinyl; amino; imino group; azido; mercaptan; alkylthio; thio alkoxy; thioaryl; azido; nitro; cyano group; isocyanato-; halogen; seleno; silicyl; silyloxy; first silicon sulfenyl; carboxyl; carbonyl; carbamoyl; or amide, especially C ₁-C ₆Alkyl, C ₃-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₂-C ₆Alkylidene, C ₂-C ₈Alkenylene, C-C ₆Alkoxyl, C ₂-C ₆Alkene oxygen base, C ₃-C ₈Cycloalkyl, C ₃-C ₈Cycloalkenyl group, C ₃-C ₈Cycloalkyloxy, aryl C ₁-C ₆Alkoxyl, Cl, I or Br.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I or II chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In at least three be hydroxyl, and other R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In 1; 2 or 3 is alkyl; thiazolinyl; alkynyl; alkylidene; alkenylene; alkoxyl; alkene oxygen base; cycloalkyl; cycloalkenyl group; cycloalkyloxy; aryl; aryloxy; alkoxy aryl; aroyl; heteroaryl; heterocyclic radical; acyl group; acyloxy; sulfoxide; sulfuric ester; sulfonyl; organic sulfenyl; sulphonic acid ester; sulfinyl; amino; imino group; azido; mercaptan; alkylthio; thio alkoxy; thioaryl; nitro; cyano group; isocyanato-; halogen; seleno; silicyl; silyloxy; first silicon sulfenyl; carboxyl; carboxylate; carbonyl; carbamoyl; or amide, especially C ₁-C ₆Alkyl, C ₃-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₂-C ₆Alkylidene, C ₂-C ₈Alkenylene, C ₁-C ₆Alkoxyl, C ₂-C ₆Alkene oxygen base, C ₃-C ₈Cycloalkyl, C ₃-C ₈Cycloalkenyl group, C ₃-C ₈Cycloalkyloxy, aryl C ₁-C ₆Alkoxyl, Cl, I or Br.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I or II chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In at least one be hydroxyl, and other R ¹, R ³, R ⁴, R ⁵And/or R ⁶In one or two be alkyl; thiazolinyl; alkynyl; alkylidene; alkenylene; alkoxyl; alkene oxygen base; cycloalkyl; cycloalkenyl group; cycloalkyloxy; aryl; aryloxy; alkoxy aryl; aroyl; heteroaryl; heterocyclic radical; acyl group; acyloxy; sulfoxide; sulfuric ester; sulfonyl; sulphonic acid ester; organic sulfenyl; sulfinyl; amino; imino group; azido; mercaptan; alkylthio; thio alkoxy; thioaryl; azido; nitro; cyano group; isocyanato-; halogen; seleno; silicyl; silyloxy; first silicon sulfenyl; carboxyl; carboxylate; carbonyl; carbamoyl; or amide, especially C ₁-C ₆Alkyl, C ₃-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₂-C ₆Alkylidene, C ₂-C ₈Alkenylene, Q-C ₆Alkoxyl, C ₂-C ₆Alkene oxygen base, C ₃-C ₈Cycloalkyl, C ₃-C ₈Cycloalkenyl group, C ₃-C ₈Cycloalkyloxy, aryl C ₁-C ₆Alkoxyl, Cl, I or Br.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I or II chemical compound, wherein R ¹, R ², R ⁴, R ⁵And R ⁶Be hydroxyl, and R ³It is alkyl; thiazolinyl; alkynyl; alkylidene; alkenylene; alkoxyl; alkene oxygen base; cycloalkyl; cycloalkenyl group; cycloalkyloxy; aryl; aryloxy; alkoxy aryl; aroyl; heteroaryl; heterocyclic radical; acyl group; acyloxy; sulfoxide; sulfuric ester; sulfonyl; organic sulfenyl; sulphonic acid ester; sulfinyl; amino; imino group; azido; mercaptan; alkylthio; thio alkoxy; thioaryl; azido; nitro; cyano group; isocyanato-; halogen; seleno; silicyl; silyloxy; first silicon sulfenyl; carboxyl; carboxylate; carbonyl; carbamoyl or amide.In one embodiment, R ³Be selected from thiazolinyl, alkynyl, alkylidene, alkenylene, alkoxyl, alkene oxygen base, cycloalkyl, cycloalkenyl group, cycloalkyloxy, aryl, aryloxy, alkoxy aryl, aroyl, imino group, heteroaryl, heterocyclic radical, acyl group, acyloxy, sulfonyl, organic sulfenyl, sulfinyl, sulfoxide, sulfuric ester, thio alkoxy, thioaryl, carboxyl, carbonyl, carbamoyl or amide, especially alkoxyl, sulfonyl, organic sulfenyl, sulfinyl, sulfoxide, sulfuric ester, thio alkoxy, carboxyl, carbonyl, carbamoyl or amide.In special embodiment, R ³Be selected from C ₁-C ₆Alkyl, C ₃-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₂-C ₆Alkylidene, C ₂-C ₈Alkenylene, C ₁-C ₆Alkoxyl, C ₂-C ₆Alkene oxygen base, C ₃-C ₈Cycloalkyl, C ₃-C ₈Cycloalkenyl group, C ₃-C ₈Cycloalkyloxy, aryl, aryloxy, aryl C ₁-C ₆Alkoxyl, acetyl group, halogen and carboxylate, especially C ₁-C ₆Alkyl, C ₃-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₂-C ₆Alkylidene, C ₂-C ₈Alkenylene, C ₁-C ₆Alkoxyl, C ₂-C ₆Alkene oxygen base, C ₃-C ₈Cycloalkyl, C ₃-C ₈Cycloalkenyl group, C ₃-C ₈Cycloalkyloxy, aryl C ₁-C ₆Alkoxyl, Cl, I or Br.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I or II chemical compound, wherein R ¹, R ³, R ⁴, R ⁵And R ⁶Be hydroxyl, and R ²It is alkyl; thiazolinyl; alkynyl; alkylidene; alkenylene; alkoxyl; alkene oxygen base; cycloalkyl; cycloalkenyl group; cycloalkyloxy; aryl; aryloxy; alkoxy aryl; aroyl; heteroaryl; heterocyclic radical; acyl group; acyloxy; sulfoxide; sulfuric ester; sulfonyl; organic sulfenyl; sulphonic acid ester; sulfinyl; amino; imino group; azido; mercaptan; alkylthio; thio alkoxy; thioaryl; azido; nitro; cyano group; isocyanato-; halogen; seleno; silicyl; silyloxy; first silicon sulfenyl; carboxyl; carboxylate; carbonyl; carbamoyl or amide.In embodiments, R ²Be selected from C ₁-C ₆Alkyl, C ₃-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₂-C ₆Alkylidene, C ₂-C ₈Alkenylene, C ₁-C ₆Alkoxyl, C ₂-C ₆Alkene oxygen base, C ₃-C ₈Cycloalkyl, C ₃-C ₈Cycloalkenyl group, C ₃-C ₈Cycloalkyloxy, aryl, aryloxy, aryl C ₁-C ₆Alkoxyl, acetyl group, halogen and carboxylate.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In 1,2,3,4 or 5 be independently of one another:

(a) have 1-24 carbon atom, especially the alkyl of a 1-10 or 1-6 carbon atom;

(b) have 3-16 carbon atom, especially the cycloalkyl of 3-10 or 3-6 carbon atom;

(c) has the 2-24 carbon atom, especially the thiazolinyl of 2-10 or 2-6 carbon atom;

(d) have 4-16 carbon atom, especially the cycloalkenyl group of 4-10 or 4-6 carbon atom;

(e) have 4-24 carbon atom, especially the aryl of 4-10,4-8 or 6 carbon atoms;

(f) aralkyl, alkaryl, arylalkenyl or alkenyl aryl;

(g) contain 3-10, especially a 3-8 or 3-6 annular atoms and at least one are selected from the heterocyclic radical of the atom of oxygen, nitrogen and sulfur;

(h) have the alkoxyl of this carbon atom of 1-6 or 1-3 carbon atom, especially methoxyl group, ethyoxyl, propoxyl group, butoxy, isopropoxy or tert-butoxy, particularly methoxyl group, or

(i) halogen, especially fluorine, chlorine or bromine, particularly chlorine.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ²Be hydroxyl, and R ¹, R ³, R ⁴, R ⁵And/or R ⁶In 1,2,3,4 or 5 is methyl independently of one another, ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, dodecyl, myristyl, pentadecyl, cetyl, heptadecyl, octadecyl, eicosyl, docosyl, methoxyl group, ethyoxyl, propoxyl group, butoxy, isopropoxy, tert-butoxy, chlorine, cyclopropyl, cyclopenta, cyclohexyl, vinyl, pi-allyl, acrylic, octadienyl, octenyl, the decene base, dodecenyl succinic, the tetradecene base, the hexadecene base, the vaccenic acid base, 18 carbon dialkylenes, 19 carbene bases, 18 carbon trialkenyl, arachidonic base (arachidonyl), cyclopentenyl, cyclopentadienyl group, cyclohexenyl group, cyclohexadienyl, phenyl, xenyl, terphenyl, naphthyl, anthryl, phenanthryl, pyridine radicals, furyl or thiazolyl.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹Be hydroxyl, and R ², R ³, R ⁴, R ⁵And/or R ⁶In 1,2,3,4 or 5 is methyl independently of one another, ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, dodecyl, myristyl, pentadecyl, cetyl, heptadecyl, octadecyl, eicosyl, docosyl, methoxyl group, ethyoxyl, propoxyl group, butoxy, isopropoxy, tert-butoxy, chlorine, cyclopropyl, cyclopenta, cyclohexyl, vinyl, pi-allyl, acrylic, octadienyl, octenyl, the decene base, dodecenyl succinic, the tetradecene base, the hexadecene base, the vaccenic acid base, 18 carbon dialkylenes, 19 carbene bases, 18 carbon trialkenyl, arachidonic base (arachidonyl), cyclopentenyl, cyclopentadienyl group, cyclohexenyl group, cyclohexadienyl, phenyl, xenyl, terphenyl, naphthyl, anthryl, phenanthryl, pyridine radicals, furyl or thiazolyl.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶1 or 2 be carboxyl, carbamoyl, sulfonyl or the heterocyclic radical that contains the N atom, more specifically N-methylamino formoxyl, N-propyl group carbamoyl, N-cyano group carbamoyl, amino-sulfonyl, isoxazolyl, imidazole radicals and thiazolyl.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ²It is hydroxyl; And R ¹, R ³, R ⁴, R ⁵And R ⁶Be independently selected from C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₁C ₆Alkoxyl, C ₂-C ₆Alkene oxygen base, C ₃-C ₁₀Cycloalkyl, C ₄-C ₁₀Cycloalkenyl group, C ₃-C ₁₀Cycloalkyloxy, C ₆-C ₁₀Aryl, C ₆-C ₁₀Aryloxy, C ₆-C ₁₀Aryl-C ₁-C ₃Alkoxyl, C ₆-C ₁₀Aroyl, C ₆-C ₁₀Heteroaryl, C ₃-C ₁₀Heterocyclic radical, C ₁-C ₆Acyl group, C ₁-C ₆Acyloxy, hydroxyl ,-NH ₂,-NHR ⁷,-NR ⁷R ⁸-,=NR ⁷,-S (O) ₂R ⁷,-SH ,-SO ₃H, nitro, cyano group, halogen, haloalkyl, halogenated alkoxy, hydroxy alkyl ,-Si (R ⁷) ₃,-OSi (R ⁷) ₃,-CO ₂H ,-CO ₂R ⁷, the oxo base ,-PO ₃H ,-NHC (O) R ⁷,-C (O) NH ₂,-C (O) NHR ⁷,-C (O) NR ⁷R ⁸,-NHS (O) ₂R ⁷,-S (O) ₂NH ₂,-S (O) ₂NHR ⁷With-S (O) ₂NR ⁷R ⁸, R wherein ⁷And R ⁸Be independently selected from C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₃-C ₁₀Cycloalkyl, C ₄-C ₁₀Cycloalkenyl group, C ₆-C ₁₀Aryl, C ₆-C ₁₀Aryl C ₁-C ₃Alkyl, C ₆-C ₁₀Heteroaryl and C ₃-C ₁₀Heterocycle; Condition is R ¹, R ², R ³, R ⁴, R ⁵And R ⁶It not all is hydroxyl.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ²It is hydroxyl; R ¹, R ³, R ⁴, R ⁵And R ⁶In one be hydroxyl; And R ¹, R ³, R ⁴, R ⁵And R ⁶In four be independently selected from C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₁-C ₆Alkoxyl, C ₂-C ₆Alkene oxygen base, C ₃-C ₁₀Cycloalkyl, C ₄-C ₁₀Cycloalkenyl group, C ₃-C ₁₀Cycloalkyloxy, C ₆-C ₁₀Aryl, C ₆-C ₁₀Aryloxy, C ₆-C ₁₀Aryl-C ₁-C ₃Alkoxyl, C ₆-C ₁₀Aroyl, C ₆-C ₁₀Heteroaryl, C ₃-C ₁₀Heterocyclic radical, C ₁-C ₆Acyl group, C ₁-C ₆Acyloxy ,-NH ₂,-NHR ⁷,-NR ⁷R ⁸-,=NR ⁷,-S (O) ₂R ⁷,-SH ,-SO ₃H, nitro, cyano group, halogen, haloalkyl, halogenated alkoxy, hydroxy alkyl ,-Si (R ⁷) ₃,-OSi (R ⁷) ₃,-CO ₂H ,-CO ₂R ⁷, the oxo base ,-PO ₃H ,-NHC (O) R ⁷,-C (O) NH ₂,-C (O) NHR ⁷,-C (O) NR ⁷R ⁸,-NHS (O) ₂R ⁷,-S (O) ₂NH ₂,-S (O) ₂NHR ⁷With-S (O) ₂NR ⁷R ⁸, R wherein ⁷And R ⁸Be independently selected from C-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₃-C ₁₀Cycloalkyl, C ₄-C ₁₀Cycloalkenyl group, C ₆-C ₁₀Aryl, C ₆-C ₁₀Aryl C ₁-C ₃Alkyl, C ₆-C ₁₀Heteroaryl and C ₃-C ₁₀Heterocycle.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ²It is hydroxyl; R ¹, R ³, R ⁴, R ⁵And R ⁶In two be hydroxyl; And R ¹, R ³, R ⁴, R ⁵And R ⁶In three be independently selected from C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₁C ₆Alkoxyl, C ₂-C ₆Alkene oxygen base, C ₃-C ₁₀Cycloalkyl, C ₄-C ₁₀Cycloalkenyl group, C ₃-C ₁₀Cycloalkyloxy, C ₆-C ₁₀Aryl, C ₆-C ₁₀Aryloxy, C ₆-C ₁₀Aryl-C ₁-C ₃Alkoxyl, C ₆-C ₁₀Aroyl, C ₆-C ₁₀Heteroaryl, C ₃-C ₁₀Heterocyclic radical, C ₁-C ₆Acyl group, C ₁-C ₆Acyloxy ,-NH ₂,-NHR ⁷,-NR ⁷R ⁸-,=NR ⁷,-S (O) ₂R ⁷,-SH ,-SO ₃H, nitro, cyano group, halogen, haloalkyl, halogenated alkoxy, hydroxy alkyl ,-Si (R ⁷) ₃,-OSi (R ⁷) ₃,-CO ₂H ,-CO ₂R ⁷, the oxo base ,-PO ₃H ,-NHC (O) R ⁷,-C (O) NH ₂,-C (O) NHR ⁷,-C (O) NR ⁷R ⁸,-NHS (O) ₂R ⁷,-S (O) ₂NH ₂,-S (O) ₂NHR ⁷And-S (O) ₂NR ⁷R ⁸, R wherein ⁷And R ⁸Be independently selected from C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₃-C ₁₀Cycloalkyl, C ₄-C ₁₀Cycloalkenyl group, C ₆-C ₁₀Aryl, C ₆-C ₁₀Aryl C ₁-C ₃Alkyl, C ₆-C ₁₀Heteroaryl and C ₃-C ₁₀Heterocycle.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula III or IV chemical compound, wherein R ²It is hydroxyl; R ¹, R ³, R ⁴, R ⁵And R ⁶In three be hydroxyl; And R ¹, R ³, R ⁴, R ⁵And R ⁶In two be independently selected from C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₁Q alkoxyl, C ₂-C ₆Alkene oxygen base, C ₃-C ₁₀Cycloalkyl, C ₄-C ₁₀Cycloalkenyl group, C ₃-C ₁₀Cycloalkyloxy, C ₆-C ₁₀Aryl, C ₆-C ₁₀Aryloxy, C ₆-C _J0Aryl-C ₁-C ₃Alkoxyl, C ₆-C ₁₀Aroyl, C ₆-C ₁₀Heteroaryl, C ₃-C ₁₀Heterocyclic radical, C ₁-C ₆Acyl group, C ₁-C ₆Acyloxy ,-NH ₂,-NHR ⁷,-NR ⁷R ⁸-,=NR ⁷,-S (O) ₂R ⁷,-SH ,-SO ₃H, nitro, cyano group, halogen, haloalkyl, halogenated alkoxy, hydroxy alkyl ,-Si (R ⁷) ₃,-OSi (R ⁷) ₃)-CO ₂H ,-CO ₂R ⁷, the oxo base ,-PO ₃H ,-NHC (O) R ⁷,-C (O) NH ₂,-C (O) NHR ⁷,-C (O) NR ⁷R ⁸,-NHS (O) ₂R ⁷,-S (O) ₂NH ₂,-S (O) ₂NHR ⁷With-S (O) ₂NR ⁷R ⁸, R wherein ⁷And R ⁸Be independently selected from C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₃-C ₁₀Cycloalkyl, C ₄-C ₁₀Cycloalkenyl group, C ₆-C ₁₀Aryl, C ₆-C ₁₀Aryl CrC ₃Alkyl, C ₆-C ₁₀Heteroaryl and C ₃-C ₁₀Heterocycle.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula III or IV chemical compound, wherein R ²It is hydroxyl; R ¹, R ³, R ⁴, R ⁵And R ⁶In four be hydroxyl; And R ¹, R ³, R ⁴, R ⁵And R ⁶In one be independently selected from C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₁-C ₆Alkoxyl, C ₂-C ₆Alkene oxygen base, C ₃-C ₁₀Cycloalkyl, C ₄-C ₁₀Cycloalkenyl group, C ₃-C ₁₀Cycloalkyloxy, C ₆-C ₁₀Aryl, C ₆-C ₁₀Aryloxy, C ₆-C ₁₀Aryl-C ₁-C ₃Alkoxyl, C ₆-C ₁₀Aroyl, C ₆-C ₁₀Heteroaryl, C ₃-C ₁₀Heterocyclic radical, C ₁-C ₆Acyl group, C ₁-C ₆Acyloxy ,-NH ₂,-NHR ⁷,-NR ⁷R ⁸-,=NR ⁷,-S (O) ₂R ⁷,-SH ,-SO ₃H, nitro, cyano group, halogen, haloalkyl, halogenated alkoxy, hydroxy alkyl ,-Si (R ⁷) ₃,-OSi (R ⁷) ₃,-CO ₂H ,-CO ₂R ⁷, the oxo base ,-PO ₃H ,-NHC (O) R ⁷,-C (O) NH ₂,-C (O) NHR ⁷,-C (O) NR ⁷R ⁸,-NHS (O) ₂R ⁷,-S (O) ₂NH ₂,-S (O) ₂NHR ⁷With-S (O) ₂NR ⁷R ⁸, R wherein ⁷And R ⁸Be independently selected from C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₃-C ₁₀Cycloalkyl, C ₄-C ₁₀Cycloalkenyl group, C ₆-C ₁₀Aryl, C ₆-C ₁₀Aryl CrC ₃Alkyl, C ₆-C ₁₀Heteroaryl and C ₃-C ₁₀Heterocycle.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula III or IV chemical compound, wherein R ¹, R ³, R ⁴, R ⁵And R ⁶In one be C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl, C ₁-C ₆Acyl group, halogen, oxo base ,=NR ⁷,-NHC (O) R ⁷,-C (O) NH ₂,-C (O) NHR ⁷,-C (O) NR ⁷R ⁸, CO ₂R ⁷Or-SO ₂R ⁷, R wherein ⁷R ⁸As hereinbefore defined; And R ¹, R ², R ³, R ⁴, R ⁵And R ⁶In at the most four be hydroxyl.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula III or IV chemical compound, wherein R ¹, R ³, R ⁴, R ⁵And R ⁶In two be C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl, C ₁-C ₆Acyl group, halogen, oxo base ,=NR ⁷,-NHC (O) R ⁷,-C (O) NH ₂,-C (O) NHR ⁷,-C (O) NR ⁷R ⁸, CO ₂R ⁷Or-SO ₂R ⁷, R wherein ⁷R ⁸As hereinbefore defined; And R ¹, R ², R ³, R ⁴, R ⁵And R ⁶In at the most three be hydroxyl.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula III or IV chemical compound, wherein R ¹, R ³, R ⁴, R ⁵And R ⁶In three be C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl, C ₁-C ₆Alkyl, halogen, oxo base ,=NR ⁷,-NHC (O) R ⁷,-C (O) NH ₂,-C (O) NHR ⁷,-C (O) NR ⁷R ⁸, CO ₂R ⁷Or-SO ₂R ⁷, R wherein ⁷R ⁸As hereinbefore defined; And R ¹, R ², R ³, R ⁴, R ⁵And R ⁶In at the most two be hydroxyl.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In 1,2,3,4 or 5 be hydroxyl, other R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶Be hydrogen independently; alkyl; thiazolinyl; alkynyl; alkylidene; alkenylene; alkoxyl; alkene oxygen base; cycloalkyl; cycloalkenyl group; cycloalkyloxy; aryl; aryloxy; alkoxy aryl; aroyl; heteroaryl; heterocyclic radical; acyl group; acyloxy; sulfoxide; sulfuric ester; sulfonyl; organic sulfenyl; sulphonic acid ester; sulfinyl; amino; imino group; azido; mercaptan; alkylthio; thio alkoxy; thioaryl; nitro; cyano group; isocyanato-; halogen; seleno; silicyl; silyloxy; first silicon sulfenyl; carboxyl; carboxylate; carbonyl; carbamoyl; or amide; especially alkyl; alkoxyl; acetyl group; halogen; carboxylate; amino; imino group; azido; mercaptan; alkylthio; nitro; thio alkoxy; cyano group or halogen, especially C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl, acetyl group, halogen or carboxylate, and R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In at least one be alkoxyl, especially the alkoxyl that has about 1-6 carbon atom, more specifically methoxyl group, ethyoxyl, propoxyl group, butoxy, isopropoxy and tert-butoxy, it can be replaced by following groups: alkyl (for example alkyl halide, haloalkyl halogen, halogenated alkyl alkyl), cyano group, amino, nitro or cycloalkyl, the more specifically CF of alkyl, halogen (for example fluorine), replacement ₃, CF ₃CF ₂, CF ₃CH ₂, CH ₂NO ₂, CH ₂NH ₂, C (CH ₂) ₃Or 3-4 unit cycloalkyl (for example cyclopropyl).

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In two be hydroxyl, other R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶Be hydrogen independently; alkyl; thiazolinyl; alkynyl; alkylidene; alkenylene; alkoxyl; alkene oxygen base; cycloalkyl; cycloalkenyl group; cycloalkyloxy; aryl; aryloxy; alkoxy aryl; aroyl; heteroaryl; heterocyclic radical; acyl group; acyloxy; sulfoxide; sulfuric ester; sulfonyl; organic sulfenyl; sulphonic acid ester; sulfinyl; amino; imino group; azido; mercaptan; alkylthio; thio alkoxy; thioaryl; nitro; cyano group; isocyanato-; halogen; seleno; silicyl; silyloxy; first silicon sulfenyl; carboxyl; carboxylate; carbonyl; carbamoyl; or amide; especially alkyl; alkoxyl; acetyl group; halogen; carboxylate; amino; imino group; azido; mercaptan; alkylthio; nitro; thio alkoxy; cyano group or halogen, preferred C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl, acetyl group, halogen or carboxylate, and R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In at least one be alkoxyl, especially the alkoxyl that has this carbon atom of 1-6, more specifically methoxyl group, ethyoxyl, propoxyl group, butoxy, isopropoxy and tert-butoxy, it can be replaced by following groups: alkyl (for example alkyl halide, haloalkyl halogen, halogenated alkyl alkyl), cyano group, amino, nitro or cycloalkyl, the more specifically CF of alkyl, halogen (for example fluorine), replacement ₃, CF ₃CF ₂, CF ₃CH ₂, CH ₂NO ₂, CH ₂NH ₂, C (CH ₂) ₃Or 3-4 unit cycloalkyl (for example cyclopropyl).

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In three be hydroxyl, other R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶Be hydrogen independently; alkyl; thiazolinyl; alkynyl; alkylidene; alkenylene; alkoxyl; alkene oxygen base; cycloalkyl; cycloalkenyl group; cycloalkyloxy; aryl; aryloxy; alkoxy aryl; aroyl; heteroaryl; heterocyclic radical; acyl group; acyloxy; sulfoxide; sulfuric ester; sulfonyl; organic sulfenyl; sulphonic acid ester; sulfinyl; amino; imino group; azido; mercaptan; alkylthio; thio alkoxy; thioaryl; nitro; cyano group; isocyanato-; halogen; seleno; silicyl; silyloxy; first silicon sulfenyl; carboxyl; carboxylate; carbonyl; carbamoyl; or amide; especially alkyl; alkoxyl; acetyl group; halogen; carboxylate; amino; imino group; azido; mercaptan; alkylthio; nitro; thio alkoxy; cyano group or halogen, especially C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl, acetyl group, halogen or carboxylate, and R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In at least one be alkoxyl, especially the alkoxyl that has about 1-6 carbon atom, more specifically methoxyl group, ethyoxyl, propoxyl group, butoxy, isopropoxy and tert-butoxy, it can be replaced by following groups: alkyl (for example alkyl halide, haloalkyl halogen, halogenated alkyl alkyl), cyano group, amino, nitro or cycloalkyl, the more specifically CF of alkyl, halogen (for example fluorine), replacement ₃, CF ₃CF ₂, CF ₃CH ₂, CH ₂NO ₂, CH ₂NH ₂, C (CH ₂) ₃Or 3-4 unit cycloalkyl (for example cyclopropyl).

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In four be hydroxyl, other R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶Be hydrogen independently; alkyl; thiazolinyl; alkynyl; alkylidene; alkenylene; alkoxyl; alkene oxygen base; cycloalkyl; cycloalkenyl group; cycloalkyloxy; aryl; aryloxy; alkoxy aryl; aroyl; heteroaryl; heterocyclic radical; acyl group; acyloxy; sulfoxide; sulfuric ester; sulfonyl; organic sulfenyl; sulphonic acid ester; sulfinyl; amino; imino group; azido; mercaptan; alkylthio; thio alkoxy; thioaryl; nitro; cyano group; isocyanato-; halogen; seleno; silicyl; silyloxy; first silicon sulfenyl; carboxyl; carboxylate; carbonyl; carbamoyl; or amide; especially alkyl; alkoxyl; acetyl group; halogen; carboxylate; amino; imino group; azido; mercaptan; alkylthio; nitro; thio alkoxy; cyano group or halogen, especially C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl, acetyl group, halogen or carboxylate, and R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In at least one be alkoxyl, especially the alkoxyl that has about 1-6 carbon atom, more specifically methoxyl group, ethyoxyl, propoxyl group, butoxy, isopropoxy and tert-butoxy, it can be chosen wantonly by alkyl (for example alkyl halide, haloalkyl halogen, halogenated alkyl alkyl), cyano group, amino, nitro or cycloalkyl, the more specifically CF of alkyl, halogen (for example fluorine), replacement ₃, CF ₃CF ₂, CF ₃CH ₂, CH ₂NO ₂, CH ₂NH ₂, C (CH ₂) ₃Or 3-4 unit cycloalkyl (for example cyclopropyl).

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In five be hydroxyl, and other R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶It is alkoxyl, especially the alkoxyl that has about 1-6 carbon atom, more specifically methoxyl group, ethyoxyl, propoxyl group, butoxy, isopropoxy and tert-butoxy, it can be replaced by following groups: alkyl (for example alkyl halide, haloalkyl halogen, halogenated alkyl alkyl), cyano group, amino, nitro or cycloalkyl, the more specifically CF of alkyl, halogen (for example fluorine), replacement ₃, CF ₃CF ₂, CF ₃CH ₂, CH ₂NO ₂, CH ₂NH ₂, C (CH ₂) ₃Or 3-4 unit cycloalkyl (for example cyclopropyl).

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In 1,2 or 3 be independently of one another-OR ¹⁵, R wherein ¹⁵It is alkyl; thiazolinyl; alkynyl; alkylidene; alkenylene; alkoxyl; alkene oxygen base; cycloalkyl; cycloalkenyl group; cycloalkyloxy; aryl; aryloxy; alkoxy aryl; aroyl; heteroaryl; heterocyclic radical; acyl group; acyloxy; sulfoxide; sulfuric ester; sulfonyl; organic sulfenyl; sulphonic acid ester; sulfinyl; amino; imino group; azido; mercaptan; alkylthio; thio alkoxy; thioaryl; nitro; cyano group; isocyanato-; halogen; seleno; silicyl; silyloxy; first silicon sulfenyl; carboxyl; carboxylate; carbonyl; carbamoyl or amide carbohydrate.In one aspect, R wherein ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In 1,2 or 3 be independently of one another-OR ¹⁵, R wherein ¹⁵Be C ₁-C ₆Alkyl, more specifically C ₁-C ₃Alkyl.

In the cyclohexane polyalcohol chemical compound of the selection of formula I, II, III or IV, R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In at least one be-OR ²⁰, R wherein ²⁰Be-CF ₃, CF ₃CF ₂, CF ₃CH ₂, CH ₂NO ₂, CH ₂NH ₂, C (CH ₂) ₃Or cyclopropyl.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴And R ⁵Be hydroxyl, and R ⁶It is alkoxyl, especially the alkoxyl that has about 1-6 carbon atom, more specifically methoxyl group, ethyoxyl, propoxyl group, butoxy, isopropoxy and tert-butoxy, it can be by alkyl (for example alkyl halide, haloalkyl halogen, halogenated alkyl alkyl), cyano group, amino, nitro or cycloalkyl, the more specifically CF of alkyl, halogen (for example fluorine), replacement ₃, CF ₃CF ₂, CF ₃CH ₂, CH ₂NO ₂, CH ₂NH ₂, C (CH ₂) ₃Or 3-4 unit cycloalkyl (for example cyclopropyl).In the special embodiment of the present invention, R ¹, R ², R ³, R ⁴And R ⁵Be hydroxyl, and R ⁶Be-OR ²⁰, R wherein ²⁰Be CF ₃, CF ₃CF ₂, CF ₃CH ₂, CH ₂NO ₂, CH ₂NH ₂, C (CH ₂) ₃Or cyclopropyl.In another special embodiment of the present invention, R ¹, R ², R ³, R ⁴And R ⁵Be hydroxyl, and R ⁶It is methoxyl group.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, H, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴And R ⁶Be hydroxyl, and R ⁵It is alkoxyl, especially the alkoxyl that has about 1-6 carbon atom, more specifically methoxyl group, ethyoxyl, propoxyl group, butoxy, isopropoxy and tert-butoxy, it can be replaced by following groups: alkyl (for example alkyl halide, haloalkyl halogen, halogenated alkyl alkyl), cyano group, amino, nitro or cycloalkyl, the more specifically CF of alkyl, halogen (for example fluorine), replacement ₃, CF ₃CF ₂, CF ₃CH ₂, CH ₂NO ₂, CH ₂NH ₂, C (CH ₂) ₃, or 3-4 unit cycloalkyl (for example cyclopropyl).In special embodiment of the present invention, R ¹, R ², R ³, R ⁴And R ⁶Be hydroxyl, and R ⁵Be-OR ²⁰, R wherein ²⁰Be CF ₃, CF ₃CF ₂, CF ₃CH ₂, CH ₂NO ₂, CH ₂NH ₂, C (CH ₂) ₃Or cyclopropyl.In another special embodiment of the present invention, R ¹, R ², R ³, R ⁴And R ⁶Be hydroxyl, and R ⁵It is methoxyl group.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁵And R ⁶Be hydroxyl, and R ⁴It is alkoxyl, especially the alkoxyl that has about 1-6 carbon atom, more specifically methoxyl group, ethyoxyl, propoxyl group, butoxy, isopropoxy and tert-butoxy, it can be replaced by following groups: alkyl (for example alkyl halide, haloalkyl halogen, halogenated alkyl alkyl), cyano group, amino, nitro or cycloalkyl, the more specifically CF of alkyl, halogen (for example fluorine), replacement ₃, CF ₃CF ₂, CF ₃CH ₂, CH ₂NO ₂, CH ₂NH ₂, C (CH ₂) ₃, or 3-4 unit cycloalkyl (for example cyclopropyl).In special embodiment of the present invention, R ¹, R ², R ³, R ⁵And R ⁶Be hydroxyl, and R ⁴Be-OR ²⁰, R wherein ²⁰Be CF ₃, CF ₃CF ₂, CF ₃CH ₂, CH ₂NO ₂, CH ₂NH ₂, C (CH ₂) ₃Or cyclopropyl.In another special embodiment of the present invention, R ¹, R ², R ³, R ⁵And R ⁶Be hydroxyl, and R ⁴It is methoxyl group.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ⁴, R ⁵And R ⁶Be hydroxyl, and R ³It is alkoxyl, especially the alkoxyl that has about 1-6 carbon atom, more specifically methoxyl group, ethyoxyl, propoxyl group, butoxy, isopropoxy and tert-butoxy, it can be replaced by following groups: alkyl (for example alkyl halide, haloalkyl halogen, halogenated alkyl alkyl), cyano group, amino, nitro or cycloalkyl, the more specifically CF of alkyl, halogen (for example fluorine), replacement ₃, CF ₃CF ₂, CF ₃CH ₂, CH ₂NO ₂, CH ₂NH ₂, C (CH ₂) ₃, or 3-4 unit cycloalkyl (for example cyclopropyl).In special embodiment of the present invention, R ¹, R ², R ⁴, R ⁵And R ⁶Be hydroxyl and R ³Be-OR ²⁰R wherein ²⁰Be CF ₃, CF ₃CF ₂, CF ₃CH ₂, CH ₂NO ₂, CH ₂NH ₂, C (CH ₂) ₃Or cyclopropyl.In another special embodiment of the present invention, R ¹, R ², R ⁴, R ⁵And R ⁶Be hydroxyl and R ³It is methoxyl group.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ³, R ⁴, R ⁵And R ⁶Be hydroxyl, and R ²It is alkoxyl, especially the alkoxyl that has about 1-6 carbon atom, more specifically methoxyl group, ethyoxyl, propoxyl group, butoxy, isopropoxy and tert-butoxy, it can be replaced by following groups: alkyl (for example alkyl halide, haloalkyl halogen, halogenated alkyl alkyl), cyano group, amino, nitro or cycloalkyl, the more specifically CF of alkyl, halogen (for example fluorine), replacement ₃, CF ₃CF ₂, CF ₃CH ₂, CH ₂NO ₂, CH ₂NH ₂, C (CH ₂) ₃, or 3-4 unit cycloalkyl (for example cyclopropyl).In special embodiment of the present invention, R ¹, R ³, R ⁴, R ⁵And R ⁶Be hydroxyl and R ²Be-OR ²⁰R wherein ²⁰Be CF ₃, CF ₃CF ₂, CF ₃CH ₂, CH ₂NO ₂, CH ₂NH ₂, C (CH ₂) ₃Or cyclopropyl.In another special embodiment of the present invention, R ¹, R ³, R ⁴, R ⁵And R ⁶Be hydroxyl, and R ²It is methoxyl group.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ², R ³, R ⁴, R ⁵And R ⁶It is hydroxyl, and R1 is an alkoxyl, especially the alkoxyl that has about 1-6 carbon atom, more specifically methoxyl group, ethyoxyl, propoxyl group, butoxy, isopropoxy and tert-butoxy, it can be replaced by following groups: alkyl (for example alkyl halide, haloalkyl halogen, halogenated alkyl alkyl), cyano group, amino, nitro or cycloalkyl, the more specifically CF of alkyl, halogen (for example fluorine), replacement ₃, CF ₃CF ₂, CF ₃CH ₂, CH ₂NO ₂, CH ₂NH ₂, C (CH ₂) ₃, or 3-4 unit cycloalkyl (for example cyclopropyl).In special embodiment of the present invention, R ², R ³, R ⁴, R ⁵And R ⁶Be hydroxyl, and R ¹Be-OR ²⁰R wherein ²⁰Be CF ₃, CF ₃CF ₂, CF ₃CH ₂, CH ₂NO ₂, CH ₂NH ₂, C (CH ₂) ₃Or cyclopropyl.In another special embodiment of the present invention, R ², R ³, R ⁴, R ⁵And R ⁶Be hydroxyl, and R ¹It is methoxyl group.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵Or R ⁶In 2,3,4 or 5 be hydroxyl, R ¹, R ², R ³, R ⁴, R ⁵Or R ⁶In at least one be the optional alkoxyl that replaces; And remaining R ¹, R ², R ³, R ⁴, R ⁵Or R ⁶(if any) be independently selected from C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₁-C ₆Alkoxyl, C ₂-C ₆Alkene oxygen base, C ₃-C ₁₀Cycloalkyl, C ₁-C ₆Acyl group, C ₁-C ₆Acyloxy, hydroxyl ,-NH ₂,-NHR ⁷,-NR ⁷R ⁸-,=NR ⁷,-S (O) ₂R ⁷,-SH, nitro, cyano group, halogen, haloalkyl, halogenated alkoxy, hydroxy alkyl ,-CO ₂R ⁷, the oxo base ,-PO ₃H-NHC (O) R ⁷,-C (O) NH ₂,-C (O) NHR ⁷,-C (O) NR ⁷R ⁸,-NHS (O) ₂R ⁷,-S (O) ₂NH ₂,-S (O) ₂NHR ⁷With-S (O) ₂NR ⁷R ⁸R wherein ⁷And R ⁸Be independently selected from C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₃-C ₁₀Cycloalkyl, C ₄-C ₁₀Cycloalkenyl group, C ₆-C ₁₀Aryl, C ₆-C ₁₀Aryl C ₁-C ₃Alkyl, C ₆-C ₁₀Heteroaryl and C ₃-C ₁₀Heterocycle.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵Or R ⁶In 5 be hydroxyl; And R ¹, R ², R ³, R ⁴, R ⁵Or R ⁶In one be C ₁-C ₆Alkoxyl; R for example ¹, R ², R ³, R ⁴, R ⁵Or R ⁶In at least one be methoxyl group.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula IV chemical compound, wherein R ², R ³, R ⁴, R ⁵Or R ⁶In 2,3 or 4 be hydroxyl; R ¹It is the optional alkoxyl that replaces; And remaining R ², R ³, R ⁴, R ⁵Or R ⁶Be independently selected from C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₁-C ₆Alkoxyl, C ₂-C ₆Alkene oxygen base, C ₃-C ₁₀Cycloalkyl, C ₁-C ₆Acyl group, C ₁-C ₆Acyloxy, hydroxyl ,-NH ₂,-NHR ⁷,-NR ⁷R ⁸-,=NR ⁷,-S (O) ₂R ⁷,-SH, nitro, cyano group, halogen, haloalkyl, halogenated alkoxy, hydroxy alkyl ,-CO ₂R ⁷, the oxo base ,-PO ₃H-NHC (O) R ⁷,-C (O) NH ₂,-C (O) NHR ⁷,-C (O) NR ⁷R ⁸,-NHS (O) ₂R ⁷,-S (O) ₂NH ₂,-S (O) ₂NHR ⁷With-S (O) ₂NR ⁷R ⁸, R wherein ⁷And R ⁸Be independently selected from C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₃-C ₁₀Cycloalkyl, C ₄-C ₁₀Cycloalkenyl group, C ₆-C ₁₀Aryl, C ₆-C ₁₀Aryl C ₁-C ₃Alkyl, C ₆-C ₁₀Heteroaryl and C ₃-C ₁₀Heterocycle.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula IV chemical compound, wherein R ¹Be C ₁-C ₆Alkoxyl; And R ², R ³, R ⁴, R ⁵And R ⁶It is hydroxyl; R for example ¹It is methoxyl group.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In 5 be hydroxyl, and other R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶Be the alkoxyl that replaces, especially have the alkoxyl of about 1-6 carbon atom, more specifically methoxyl group, ethyoxyl, propoxyl group, butoxy, isopropoxy and tert-butoxy, it is by alkyl, especially C ₁-C ₆Alkyl, more specifically C ₁-C ₃Alkyl replaces.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In 5 be hydroxyl, and other R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶Be alkoxyl, especially have the alkoxyl of about 1-6 carbon atom, more specifically methoxyl group, ethyoxyl, propoxyl group, butoxy, isopropoxy and tert-butoxy, it can be replaced by substituted halogen (for example fluorine, chlorine or bromine).In special embodiment, R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In 5 be hydroxyl, other R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶Be fluorine methoxyl group, chlorine methoxyl group, trifluoromethoxy, difluoro-methoxy, trifluoro ethoxy, fluorine ethyoxyl, tetrafluoro ethyoxyl, five fluorine ethyoxyls or fluorine propoxyl group.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In 5 be hydroxyl, and other R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶Be halogenated alkoxy alkyl, especially fluorine methoxy, chlorine methoxy ethyl, trifluoromethoxy methyl, difluoro-methoxy ethyl or trifluoro ethoxy methyl.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴And R ⁵Be hydroxyl and R ⁶Be the alkoxyl that replaces, especially have the alkoxyl of about 1-6 carbon atom, more specifically methoxyl group, ethyoxyl, propoxyl group, butoxy, isopropoxy and tert-butoxy, its substituted alkyl, especially low alkyl group replacement.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴And R ⁶Be hydroxyl, and R ⁵Be the alkoxyl that replaces, especially have the alkoxyl of about 1-6 carbon atom, more specifically methoxyl group, ethyoxyl, propoxyl group, butoxy, isopropoxy and tert-butoxy, it is by alkyl, especially low alkyl group, C more specifically ₁-C ₃Alkyl replaces.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁵And R ⁶Be hydroxyl, and R ⁴Be the alkoxyl that replaces, especially have the alkoxyl of about 1-6 carbon atom, more specifically methoxyl group, ethyoxyl, propoxyl group, butoxy, isopropoxy and tert-butoxy, it is by alkyl, especially low alkyl group, C more specifically ₁-C ₃Alkyl replaces.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ⁴, R ⁵And R ⁶Be hydroxyl, and R ³Be the alkoxyl that replaces, especially have the alkoxyl of about 1-6 carbon atom, more specifically methoxyl group, ethyoxyl, propoxyl group, butoxy, isopropoxy and tert-butoxy, it is by alkyl, especially low alkyl group, C more specifically ₁-C ₃Alkyl replaces.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ³, R ⁴, R ⁵And R ⁶Be hydroxyl, and R ²Be the alkoxyl that replaces, especially have the alkoxyl of about 1-6 carbon atom, more specifically methoxyl group, ethyoxyl, propoxyl group, butoxy, isopropoxy and tert-butoxy, it is alkyl, especially low alkyl group, C more specifically also ₁-C ₃Alkyl replaces.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ², R ³, R ⁴, R ⁵And R ⁶Be hydroxyl, and R ¹Be the alkoxyl that replaces, especially have the alkoxyl of about 1-6 carbon atom, more specifically methoxyl group, ethyoxyl, propoxyl group, butoxy, isopropoxy and tert-butoxy, it is by alkyl, especially low alkyl group, C more specifically ₁-C ₃Alkyl replaces.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴And R ⁵Be hydroxyl, and R ⁶Be alkoxyl, especially have the alkoxyl of about 1-6 carbon atom, more specifically methoxyl group, ethyoxyl, propoxyl group, butoxy, isopropoxy and tert-butoxy, it is replaced by halogen (for example fluorine, chlorine or bromine).In special embodiment, R ¹, R ², R ³, R ⁴And R ⁵Be hydroxyl, and R ⁶Be fluorine methoxyl group, chlorine methoxyl group, trifluoromethoxy, difluoro-methoxy, trifluoro ethoxy, fluorine ethyoxyl, tetrafluoro ethyoxyl, five fluorine ethyoxyls or fluorine propoxyl group.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴And R ⁶Be hydroxyl, and R ⁵Be alkoxyl, especially have the alkoxyl of 1-6 carbon atom, more specifically methoxyl group, ethyoxyl, propoxyl group, butoxy, isopropoxy and tert-butoxy, it is replaced by halogen (for example fluorine, chlorine or bromine).In special embodiment, R ¹, R ², R ³, R ⁴And R ⁶Be hydroxyl, and R ⁵Be fluorine methoxyl group, chlorine methoxyl group, trifluoromethoxy, difluoro-methoxy, trifluoro ethoxy, fluorine ethyoxyl, tetrafluoro ethyoxyl, five fluorine ethyoxyls or fluorine propoxyl group.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R5 and R ⁶Be hydroxyl, and R ⁴Be alkoxyl, especially have the alkoxyl of about 1-6 carbon atom, more specifically methoxyl group, ethyoxyl, propoxyl group, butoxy, isopropoxy and tert-butoxy, it is replaced by halogen (for example fluorine, chlorine or bromine).In special embodiment, R ¹, R ², R ³, R ⁴And R ⁶Be hydroxyl, and R ⁵Be fluorine methoxyl group, chlorine methoxyl group, trifluoromethoxy, difluoro-methoxy, trifluoro ethoxy, fluorine ethyoxyl, tetrafluoro ethyoxyl, five fluorine ethyoxyls or fluorine propoxyl group.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ⁴, R ⁵And R ⁶Be hydroxyl, and R ³Be alkoxyl, especially have the alkoxyl of about 1-6 carbon atom, more specifically methoxyl group, ethyoxyl, propoxyl group, butoxy, isopropoxy and tert-butoxy, it is replaced by halogen (for example fluorine, chlorine or bromine).In special embodiment, R ¹, R ², R ⁴, R ⁵And R ⁶Be hydroxyl, and R ³Be fluorine methoxyl group, chlorine methoxyl group, trifluoromethoxy, difluoro-methoxy, trifluoro ethoxy, fluorine ethyoxyl, tetrafluoro ethyoxyl, five fluorine ethyoxyls or fluorine propoxyl group.

In embodiment of the present invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ³, R ⁴, R ⁵And R ⁶Be hydroxyl, and R ²Be alkoxyl, especially have the alkoxyl of about 1-6 carbon atom, more specifically methoxyl group, ethyoxyl, propoxyl group, butoxy, isopropoxy and tert-butoxy will be replaced by halogen (for example fluorine, chlorine or bromine).In special embodiment, R ¹, R ³, R ⁴, R ⁵And R ⁶Be hydroxyl, and R ²Be fluorine methoxyl group, chlorine methoxyl group, trifluoromethoxy, difluoro-methoxy, trifluoro ethoxy, fluorine ethyoxyl, tetrafluoro ethyoxyl, five fluorine ethyoxyls or fluorine propoxyl group.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ², R ³, R ⁴, R ⁵And R ⁶Be hydroxyl, and R ¹Be alkoxyl, especially have the alkoxyl of about 1-6 carbon atom, more specifically methoxyl group, ethyoxyl, propoxyl group, butoxy, isopropoxy and tert-butoxy, it is replaced by halogen (for example fluorine, chlorine or bromine).In special embodiment, R ², R ³, R ⁴, R ⁵And R ⁶Be hydroxyl, and R ¹Be fluorine methoxyl group, chlorine methoxyl group, trifluoromethoxy, difluoro-methoxy, trifluoro ethoxy, fluorine ethyoxyl, tetrafluoro ethyoxyl, five fluorine ethyoxyls or fluorine propoxyl group.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is methyl-scyllitol

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In 1,2,3,4 or 5 be hydroxyl, other R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶Be hydrogen independently; alkyl; thiazolinyl; alkynyl; alkylidene; alkenylene; alkoxyl; alkene oxygen base; cycloalkyl; cycloalkenyl group; cycloalkyloxy; aryl; aryloxy; alkoxy aryl; aroyl; heteroaryl; heterocyclic radical; acyl group; acyloxy; sulfoxide; sulfuric ester; sulfonyl; organic sulfenyl; sulphonic acid ester; sulfinyl; amino; imino group; azido; mercaptan; alkylthio; thio alkoxy; thioaryl; nitro; cyano group; isocyanato-; halogen; seleno; silicyl; silyloxy; first silicon sulfenyl; carboxyl; carboxylate; carbonyl; carbamoyl; or amide; especially alkyl; amino; imino group; azido; mercaptan; alkylthio; nitro; thio alkoxy; cyano group or halogen, especially C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl, acetyl group, halogen or carboxylate, and R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In at least one be carboxylate.Aspect more of the present invention, R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶At least one be-C (O) OR ¹⁴, R wherein ¹⁴Be hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, amino, mercaptan, aryl, heteroaryl, alkylthio, thioaryl, thio alkoxy or heterocycle, it can be chosen wantonly and be substituted, especially substituted alkyl replaces, and described alkyl is replaced by the one or more groups in the following groups: alkyl, amino, halogen, alkyl amino, aryl, carboxyl, aryl or heterocycle.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In two be hydroxyl, other R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶Be hydrogen independently; alkyl; thiazolinyl; alkynyl; alkylidene; alkenylene; alkoxyl; alkene oxygen base; cycloalkyl; cycloalkenyl group; cycloalkyloxy; aryl; aryloxy; alkoxy aryl; aroyl; heteroaryl; heterocyclic radical; acyl group; acyloxy; sulfoxide; sulfuric ester; sulfonyl; organic sulfenyl; sulphonic acid ester; sulfinyl; amino; imino group; azido; mercaptan; alkylthio; thio alkoxy; thioaryl; nitro; cyano group; isocyanato-; halogen; seleno; silicyl; silyloxy; first silicon sulfenyl; carboxyl; carboxylate; carbonyl; carbamoyl; or amide; especially alkyl; amino; imino group; azido; mercaptan; alkylthio; nitro; thio alkoxy; cyano group or halogen, preferred C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl, acetyl group, halogen or carboxylate, and R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In at least one be carboxylate.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In three be hydroxyl, other R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶Be hydrogen independently; alkyl; thiazolinyl; alkynyl; alkylidene; alkenylene; alkoxyl; alkene oxygen base; cycloalkyl; cycloalkenyl group; cycloalkyloxy; aryl; aryloxy; alkoxy aryl; aroyl; heteroaryl; heterocyclic radical; acyl group; acyloxy; sulfoxide; sulfuric ester; sulfonyl; organic sulfenyl; sulphonic acid ester; sulfinyl; amino; imino group; azido; mercaptan; alkylthio; thio alkoxy; thioaryl; nitro; cyano group; isocyanato-; halogen; seleno; silicyl; silyloxy; first silicon sulfenyl; carboxyl; carboxylate; carbonyl; carbamoyl; or amide; especially alkyl; amino; imino group; azido; mercaptan; alkylthio; nitro; thio alkoxy; cyano group or halogen, preferred C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl, acetyl group, halogen or carboxylate, and R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In at least one be carboxylate.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In four be hydroxyl, other R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶Be hydrogen independently; alkyl; thiazolinyl; alkynyl; alkylidene; alkenylene; alkoxyl; alkene oxygen base; cycloalkyl; cycloalkenyl group; cycloalkyloxy; aryl; aryloxy; alkoxy aryl; aroyl; heteroaryl; heterocyclic radical; acyl group; acyloxy; sulfoxide; sulfuric ester; sulfonyl; organic sulfenyl; sulphonic acid ester; sulfinyl; amino; imino group; azido; mercaptan; alkylthio; thio alkoxy; thioaryl; nitro; cyano group; isocyanato-; halogen; seleno; silicyl; silyloxy; first silicon sulfenyl; carboxyl; carboxylate; carbonyl; carbamoyl; or amide; especially alkyl; amino; imino group; azido; mercaptan; alkylthio; nitro; thio alkoxy; cyano group or halogen, preferred C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl, acetyl group, halogen or carboxylate, and R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In at least one be carboxylate.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵Or R ⁶In 5 be hydroxyl, and other R ¹, R ², R ³, R ⁴, R ⁵Or R ⁶It is carboxylate.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In at least one be-C (O) OR ¹⁴, R wherein ¹⁴Be hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, amino, mercaptan, aryl, heteroaryl, alkylthio, thioaryl, thio alkoxy or heterocycle, it can be chosen wantonly and be substituted, especially replaced by alkyl, described alkyl is by the one or more replacements in the following groups: alkyl, amino, halogen, alkyl amino, aryl, carboxyl, aryl or heterocycle.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴And R ⁵Be hydroxyl, and R ⁶It is carboxylate.Aspect more of the present invention, R ⁶Be-C (O) OR ¹⁴, R wherein ¹⁴Be hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, amino, mercaptan, aryl, heteroaryl, alkylthio, thioaryl, thio alkoxy or heterocycle, it can be chosen wantonly and be substituted, especially replaced by alkyl, described alkyl is replaced by one or two group in the following groups: alkyl, amino, halogen, alkyl amino, aryl, carboxyl, aryl or heterocycle.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴And R ⁶Be hydroxyl, and R ⁵It is carboxylate.Aspect more of the present invention, R ⁵Be-C (O) OR ¹⁴, R wherein ¹⁴Be hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, amino, mercaptan, aryl, heteroaryl, alkylthio, thioaryl, thio alkoxy or heterocycle, it can be chosen wantonly and be substituted, especially replaced by alkyl, described alkyl is replaced by one or two group in the following groups: alkyl, amino, halogen, alkyl amino, aryl, carboxyl, aryl or heterocycle.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁵And R ⁶Be hydroxyl, and R ⁴It is carboxylate.Aspect more of the present invention, R ⁴Be-C (O) OR ¹⁴, R wherein ¹⁴Be hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, amino, mercaptan, aryl, heteroaryl, alkylthio, thioaryl, thio alkoxy or heterocycle, it can be chosen wantonly and be substituted, especially replaced by alkyl, described alkyl is replaced by one or two group in the following groups: alkyl, amino, halogen, alkyl amino, aryl, carboxyl, aryl or heterocycle.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ⁴, R ⁵And R ⁶Be hydroxyl, and R ³It is carboxylate.Aspect more of the present invention, R ³Be-C (O) OR ¹⁴, R wherein ¹⁴Be hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, amino, mercaptan, aryl, heteroaryl, alkylthio, thioaryl, thio alkoxy or heterocycle, it can be chosen wantonly and be substituted, especially replaced by alkyl, described alkyl is replaced by one or two group in the following groups: alkyl, amino, halogen, alkyl amino, aryl, carboxyl, aryl or heterocycle.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ³, R ⁴, R ⁵And R ⁶Be hydroxyl, and R ²It is carboxylate.Aspect more of the present invention, R ²Be-C (O) OR ¹⁴, R wherein ¹⁴Be hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, amino, mercaptan, aryl, heteroaryl, alkylthio, thioaryl, thio alkoxy or heterocycle, it can be chosen wantonly and be substituted, especially replaced by alkyl, described alkyl is replaced by one or two group in the following groups: alkyl, amino, halogen, alkyl amino, aryl, carboxyl, aryl or heterocycle.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ², R ³, R ⁴, R ⁵And R ⁶Be hydroxyl and R ¹It is carboxylate.Aspect more of the present invention, R ¹Be-C (O) OR ¹⁴, R wherein ¹⁴Be hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, amino, mercaptan, aryl, heteroaryl, alkylthio, thioaryl, thio alkoxy or heterocycle, it can be chosen wantonly and be substituted, especially replaced by alkyl, described alkyl is replaced by one or two group in the following groups: alkyl, amino, halogen, alkyl amino, aryl, carboxyl, aryl or heterocycle.In special embodiment, select R ¹⁴To produce amino acid derivativges or ester derivant.In the preferred embodiment of the invention, R ¹⁴Be one of following groups:

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In 1,2 or 3 be independently of one another:

R wherein ³⁰It is alkyl; thiazolinyl; alkynyl; alkylidene; alkenylene; alkoxyl; alkene oxygen base; cycloalkyl; cycloalkenyl group; cycloalkyloxy; aryl; aryloxy; alkoxy aryl; aroyl; heteroaryl; heterocyclic radical; acyl group; acyloxy; sulfoxide; sulfuric ester; sulfonyl; organic sulfenyl; sulphonic acid ester; sulfinyl; amino; imino group; azido; mercaptan; alkylthio; thio alkoxy; thioaryl; nitro; cyano group; isocyanato-; halogen; seleno; silicyl; silyloxy; first silicon sulfenyl; carboxyl; carboxylate; carbonyl; carbamoyl; or amide, and other R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶It is hydroxyl.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ³, R ⁴, R ⁵And/or R ⁶In at least 1,2,3 or 4 be hydroxyl, and other R ¹, R ³, R ⁴, R ⁵And/or R ⁶Be alkyl, halogen, alkoxyl, sulfonyl, sulfinyl, mercaptan, alkylthio, thio alkoxy, carboxyl, especially C ₁-C ₆Alkyl, Q-C ₆Alkoxy or halogen.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶Be independently of one another-CH ₃,-OCH ₃, F, N ₃, NH ₂, SH, NO ₂, CF ₃, OCF ₃, SeH, Cl, Br, I or CN, condition is R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In 4 or 5 be hydroxyl.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In 5 be hydroxyl, and R ¹, R ², R ³, R ⁴, R ⁵Or R ⁶In one, and R especially ²Or R ³, be selected from-CH ₃,-OCH ₃, CF ₃, F, SeH, Cl, Br, I and CN.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In 4 be hydroxyl, and R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In two be selected from-CH ₃,-OCH ₃, CF ₃, F ,-NO ₂, SH, SeH, Cl, Br, I and CN.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵Or R ⁶In 4 be hydroxyl; And R ¹, R ², R ³, R ⁴, R ⁵Or R ⁶In one be selected from CH independently of one another ₃, OCH ₃, NO ₂, CF ₃, OCF ₃, F, Cl, Br, I and CN.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵Or R ⁶In 5 be hydroxyl; And R ¹, R ², R ³, R ⁴, R ⁵Or R ⁶In one be selected from CH ₃, OCH ₃, NO ₂, CF ₃, OCF ₃, F, Cl, Br, I and CN.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In 4 be hydroxyl, and R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In other two are low alkyl groups, especially methyl, ethyl, butyl, propyl group, preferable methyl.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In 4 be hydroxyl, and R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In other 2 are low-grade cycloalkyls, especially cyclopropyl, cyclobutyl and cyclopenta.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In 2,3,4 or 5 be hydroxyl, other R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶Be hydrogen independently; alkyl; thiazolinyl; alkynyl; alkylidene; alkenylene; alkoxyl; alkene oxygen base; cycloalkyl; cycloalkenyl group; cycloalkyloxy; aryl; aryloxy; alkoxy aryl; aroyl; heteroaryl; heterocyclic radical; acyl group; acyloxy; sulfoxide; sulfuric ester; sulfonyl; organic sulfenyl; sulphonic acid ester; sulfinyl; amino; imino group; azido; mercaptan; alkylthio; thio alkoxy; thioaryl; nitro; cyano group; isocyanato-; halogen; seleno; silicyl; silyloxy; first silicon sulfenyl; carboxyl; carboxylate; carbonyl; carbamoyl; or amide; especially alkyl; amino; imino group; azido; mercaptan; alkylthio; nitro; thio alkoxy; cyano group; or halogen, preferred C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl, acetyl group, halogen or carboxylate, and R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In at least one be halogen, especially fluorine, chlorine or bromine, more specifically chlorine.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In two be hydroxyl, other R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶Be hydrogen independently; alkyl; thiazolinyl; alkynyl; alkylidene; alkenylene; alkoxyl; alkene oxygen base; cycloalkyl; cycloalkenyl group; cycloalkyloxy; aryl; aryloxy; alkoxy aryl; aroyl; heteroaryl; heterocyclic radical; acyl group; acyloxy; sulfoxide; sulfuric ester; sulfonyl; organic sulfenyl; sulphonic acid ester; sulfinyl; amino; imino group; azido; mercaptan; alkylthio; thio alkoxy; thioaryl; nitro; cyano group; isocyanato-; halogen; seleno; silicyl; silyloxy; first silicon sulfenyl; carboxyl; carboxylate; carbonyl; carbamoyl; or amide; especially alkyl; amino; imino group; azido; mercaptan; alkylthio; nitro; thio alkoxy; cyano group or halogen, preferred C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl, acetyl group, halogen or carboxylate, and R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In at least one be halogen, especially fluorine, chlorine or bromine, more specifically chlorine.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In 3 be hydroxyl, other R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶Be hydrogen independently; alkyl; thiazolinyl; alkynyl; alkylidene; alkenylene; alkoxyl; alkene oxygen base; cycloalkyl; cycloalkenyl group; cycloalkyloxy; aryl; aryloxy; alkoxy aryl; aroyl; heteroaryl; heterocyclic radical; acyl group; acyloxy; sulfoxide; sulfuric ester; sulfonyl; organic sulfenyl; sulphonic acid ester; sulfinyl; amino; imino group; azido; mercaptan; alkylthio; thio alkoxy; thioaryl; nitro; cyano group; isocyanato-; halogen; seleno; silicyl; silyloxy; first silicon sulfenyl; carboxyl; carboxylate; carbonyl; carbamoyl; or amide; especially alkyl; amino; imino group; azido; mercaptan; alkylthio; nitro; thio alkoxy; cyano group or halogen, preferred C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl, acetyl group, halogen or carboxylate, and R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In at least one be halogen, especially fluorine, chlorine or bromine, more specifically chlorine.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In 4 be hydroxyl, other R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶Be hydrogen independently; alkyl; thiazolinyl; alkynyl; alkylidene; alkenylene; alkoxyl; alkene oxygen base; cycloalkyl; cycloalkenyl group; cycloalkyloxy; aryl; aryloxy; alkoxy aryl; aroyl; heteroaryl; heterocyclic radical; acyl group; acyloxy; sulfoxide; sulfuric ester; sulfonyl; organic sulfenyl; sulphonic acid ester; sulfinyl; amino; imino group; azido; mercaptan; alkylthio; thio alkoxy; thioaryl; nitro; cyano group; isocyanato-; halogen; seleno; silicyl; silyloxy; first silicon sulfenyl; carboxyl; carboxylate; carbonyl; carbamoyl; or amide; especially alkyl; amino; imino group; azido; mercaptan; alkylthio; nitro; thio alkoxy; cyano group or halogen, preferred C ¹-C ⁶Alkyl, C ₁-C ₆Alkoxyl, acetyl group, halogen or carboxylate, and R ¹, R ², R ³, R ⁴, R ⁵Or R ⁶In at least one be halogen, especially fluorine, chlorine or bromine, more specifically chlorine.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵Or R ⁶In 2,3,4 or 5 be hydroxyl; R ¹, R ², R ³, R ⁴, R ⁵Or R ⁶In at least one be halogen; And remaining R ¹, R ², R ³, R ⁴, R ⁵Or R ⁶(if any) be C independently ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₁-C ₆Alkoxyl, C ₂-C ₆Alkene oxygen base, C ₃-C ₁₀Cycloalkyl, C ₁-C ₆Acyl group, C ₁-C ₆Acyloxy ,-NH ₂,-NHR ⁷,-NR ⁷R ⁸-,=NR ⁷,-S (O) ₂R ⁷,-SH, nitro, cyano group, halogen, haloalkyl, halogenated alkoxy, hydroxy alkyl ,-CO ₂R ⁷, the oxo base ,-PO ₃H-NHC (O) R ⁷,-C (O) NH ₂,-C (O) NHR ⁷,-C (O) NR ⁷R ⁸,-NHS (O) ₂R ⁷,-S (O) ₂NH ₂,-S (O) ₂NHR ⁷With-S (O) ₂NR ⁷R ⁸, R wherein ⁷And R ⁸Be independently selected from C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₃-C ₁₀Cycloalkyl, C ₄-C ₁₀Cycloalkenyl group, C ₆-C ₁₀Aryl, C ₆-C ₁₀Aryl C ₁-C ₃Alkyl, C ₆-C ₁₀Heteroaryl and C ₃-C _{10 B}Heterocycle.

Also on the other hand, the cyclohexane polyalcohol chemical compound is formula III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵Or R ⁶In 4 be hydroxyl; R ¹, R ², R ³, R ⁴, R ⁵Or R ⁶In one be halogen; And R ¹, R ², R ³, R ⁴, R ⁵Or R ⁶In one be selected from C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₁-C ₆Alkoxyl, C ₂-C ₆Alkene oxygen base, C ₃-C ₁₀Cycloalkyl, C ₁-C ₆Acyl group, C ₁-C ₆Acyloxy, hydroxyl ,-NH ₂,-NHR ⁷,-NR ⁷R ⁸-,=NR ⁷,-S (O) ₂R ⁷,-SH, nitro, cyano group, halogen, haloalkyl, halogenated alkoxy, hydroxy alkyl ,-Si (RP ^7P) B _3B,-CO ₂R ⁷, the oxo base ,-PO ₃H-NHC (O) R ⁷,-C (O) NH ₂,-C (O) NHR ⁷,-C (O) NR ⁷R ⁸,-NHS (O) ₂R ⁷,-S (O) ₂NH ₂,-S (O) ₂NHR ⁷With-S (O) ₂NR ⁷R ⁸, R wherein ⁷And R ⁸Be independently selected from C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₃-C ₁₀Cycloalkyl, C ₄-C ₁₀Cycloalkenyl group, C ₆-C ₁₀Aryl, C ₆-C ₁₀Aryl C ₁-C ₃Alkyl, C ₆-C ₁₀Heteroaryl and C ₃-C ₁₀Heterocyclic radical, and R ¹, R ², R ³, R ⁴, R ⁵Or R ⁶In at least one be halogen.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶In 5 be hydroxyl, and other R ¹, R ², R ³, R ⁴, R ⁵And/or R ⁶Be halogen, especially fluorine, chlorine or bromine, more specifically chlorine.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴And R ⁵Be hydroxyl, and R ⁶Be halogen, especially fluorine, chlorine or bromine, more specifically chlorine.In special embodiment of the present invention, R ¹, R ², R ³, R ⁴And R ⁵Be hydroxyl, and R ⁶Be chlorine.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁴And R ⁶Be hydroxyl, and R ⁵Be halogen, especially fluorine, chlorine or bromine, more specifically chlorine.In special embodiment of the present invention, R ¹, R ², R ³, R ⁴And R ⁶Be hydroxyl, and R ⁵Be chlorine.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ³, R ⁵And R ⁶Be hydroxyl, and R ⁴Be halogen, especially fluorine, chlorine or bromine, more specifically chlorine.In special embodiment of the present invention, R ¹, R ², R ³, R ⁵And R ⁶Be hydroxyl, and R ⁴Be chlorine.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ², R ⁴, R ⁵And R ⁶Be hydroxyl, and R ³Be halogen, especially fluorine, chlorine or bromine, more specifically chlorine.In special embodiment of the present invention, R ¹, R ², R ⁴, R ⁵And R ⁶Be hydroxyl and R ³Be chlorine.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ¹, R ³, R ⁴, R ⁵And R ⁶Be hydroxyl, and R ²Be halogen, especially fluorine, chlorine or bromine, more specifically chlorine.In special embodiment of the present invention, R ¹, R ³, R ⁴, R ⁵And R ⁶Be hydroxyl, and R ²Be chlorine.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is formula I, II, III or IV chemical compound, wherein R ², R ³, R ⁴, R ⁵And R ⁶Be hydroxyl, and R ¹Be halogen, especially fluorine, chlorine or bromine, more specifically chlorine.In special embodiment of the present invention, R ², R ³, R ⁴, R ⁵And R ⁶Be hydroxyl, and R ¹Be chlorine.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound is 1-chloro-1-deoxidation-scyllitol.

Can be by the application's knowledge and open, reaction and the method for using those skilled in the art extensively to know, preparation is used for cyclohexane polyalcohol chemical compound of the present invention.This reaction is to be suitable for employed reagent and material and to be suitable for carrying out in the solvent of realization response.The technical staff in organic synthesis field will understand, and the functional group that exists on the chemical compound should be consistent with the reactions steps of plan.This needs to adjust the order of synthesis step sometimes or selects a special reaction scheme, to obtain required The compounds of this invention.Also will recognize, at design another main Consideration in the route of synthesis, be the selection that is used to protect the protecting group of the reactive functional groups that is present in the chemical compound that the present invention describes.Authority's argumentation of describing a lot of additive methods except that the technical staff is Greene and Wuts (Protective Groups In Organic Synthesis, Wileyand Sons, 1991).

The parent material and the reagent that are used to prepare the cyclohexane polyalcohol chemical compound both can derive from for example Aldrich Chemical Company (Milwaukee of supplier, Wis.), Bachem (Torrance, Calif.), Sigma (St.Louis, Mo.), or Lancaster Synthesis Inc. (Windham, N.H.), also can pass through method known to those skilled in the art, according to for example preparing: Fieser and Fieser ' s Reagents for OrganicSynthesis below with reference to document, vols.1-17, John Wiley and Sons, New York, N.Y., 1991; Rodd ' s Chemistry of Carbon Compounds, vols.1-5and supps., ElsevierScience Publishers, 1989; Organic Reactions, vols.1-40, John Wiley andSons, New York, N.Y., 1991; March J.:Advanced Organic Chemistry, 4th ed., John Wiley and Sons, New York, N.Y.; And Larock:Comprehensive Organic Transformations, VCH Publishers, New York, 1989.

Can use that routine techniques for example precipitates, filtration, distillation, crystallization, chromatography etc., parent material, intermediate and cyclohexane polyalcohol chemical compound are separated and purification.Chemical compound can use comprise physics constant and spectrographic technique especially the conventional method of HPLC characterize.

The cyclohexane polyalcohol chemical compound that is alkalescence in nature can be inorganic or organic acid form multiple different salt.In practice, preferably the form of the salt of at first the cyclohexane polyalcohol chemical compound not being accepted with pharmacy is separated from reactant mixture, by handling the latter is converted into free alkali then, then free alkali is converted into the acceptable acid-addition salts of pharmacy with base reagent.Can prepare the acid-addition salts of alkali compounds easily by for example in methanol or the ethanol, alkali compounds being handled with the inorganic or organic acid of the selection of a great deal of basically at hydrosolvent medium or at suitable organic solvent.Desolvate by evaporating carefully, obtain required solid salt.

Be that tart cyclohexane polyalcohol chemical compound can be accepted cation formation alkali salt with multiple pharmacology in nature.These salt can prepare by routine techniques: by corresponding acid compound can be accepted treated cation with required pharmacology, preferably under vacuum the gained solution evaporation is extremely done then.Perhaps, it can prepare like this: by lower alkane acid compound solution and required alkali metal alcoholates are mixed, then with top same condition under with the gained solution evaporation to doing.In both cases, use the reagent of stoichiometric amount to react completely and maximum product yield usually with assurance.

The scyllitol chemical compound can use conventional method to prepare, and perhaps can obtain by commercial source.For example, the scyllitol chemical compound can use chemistry and/or microbial process to obtain.Aspect more of the present invention, scyllitol is to use the method step of following document description to prepare: M.Sarmah and Shashidhar, M., Carbohydrate Research, 2003,338,999-100, Husson, C wait people, Carbohyrate Research 307 (1998) 163-165; Anderson R. and E.S.Wallis, J.American Chemical Society (US), 1948,70:2931-2935; Weissbach, A., J Org Chem (US), 1958,23:329-330; Chung, people such as S.K., Bioorg Med Chem.1999,7 (11): 2577-89; Or Kiely D.E., and Fletcher, H.G., J.American Chemical Society (US) 1968,90:3289-3290; Be described in JP09-140388, DE 3,405,663 (Merck PatentGMBH), JP04-126075, JP05-192163 or WO06109479, or be described in WO0503577, US20060240534, EP1674578, JP9140388, JP09140388, JP02-184912, JP03-102492 (Hokko Chemical Industries).Aspect the compositions and methods of the invention special, scyllitol is to use Husson, and C waits the people, the method preparation of describing among CarbohydrateResearch 307 (1998) 163-165.Aspect other of the present composition and method, scyllitol is to use and is similar to the microbial process step preparation described among WO05035774 (EP1674578 and US20060240534) JP2003102492 or the JP09140388 (HokkoChemicalIndustries).Derivant can use the well-known method of those skilled in the art to prepare by introducing scyllitol.

Aspect more of the present invention, table-inositol can use chemistry and/or microbial process to prepare.For example, table-inositol can pass through V.Pistara (Tetrahedron Letters41,3253,2000), Magasanik B. and Chargaff E. (J Biol Chem, 1948,174:173188), US patent 7,157,268, or the method that the disclosed application of PCT WO0075355 describes prepares.Derivant can use the well-known method of those skilled in the art to prepare by introducing table-inositol.The cyclohexane polyalcohol chemical compound can comprise carrier in addition, includes but not limited to one or more polymer, carbohydrate, peptide or derivatives thereof.Carrier can be replaced by substituent group described herein, and described substituent group includes but not limited to alkyl, amino, nitro, halogen, mercaptan, alkylthio, sulfuric ester, sulfonyl, organic sulfenyl, sulfinyl, sulfoxide, hydroxyl.Carrier directly or indirectly covalent bond is connected on the The compounds of this invention.Aspect more of the present invention, carrier is an aminoacid, comprises alanine, glycine, proline, methionine, serine, threonine or aspartic acid.In other respects, carrier is a peptide, comprises alanyl-alanyl, prolyl-methionyl or glycyl-glycyl.

Carrier also comprises the molecule that makes The compounds of this invention targeting particular organization or organ.Especially, by initiatively or passive transportation, carrier can promote or improve The compounds of this invention is transported to brain.

" polymer " used herein is meant the molecule that comprises two or more identical multiple subunits or different multiple subunits.Monomer comprises simple structure, low-molecular-weight carbonaceous molecule usually.Polymer can be chosen wantonly and be substituted.The example that can be used for polymer of the present invention is vinyl, acrylic acid, styrene, hydrocarbon derived polymers, Polyethylene Glycol (PEG), polyethylene glycol oxide, the polymethylene glycol, poly--the trimethylene triol, polyvinylpyrrolidone, polyethylene glycol oxide-polypropylene oxide block polymer, and copolymer, salt and derivant.Of the present invention special aspect, polymer is poly-(2-acrylamido-2-methyl isophthalic acid-propane sulfonic acid); Poly-(2-acrylamido-2-methyl isophthalic acid-propane sulfonic acid-copolymerized acrylonitrile, poly-(2-acrylamido-2-methyl isophthalic acid-propane sulfonic acid-copolymerization-styrene), poly-(vinyl sulfonic acid); Poly-(4-Sodium styrene sulfonate); And deutero-thus sulfuric ester and sulphonic acid ester; Poly-(acrylic acid), poly-(acrylic acid methyl ester .), poly-(methyl methacrylate) and poly-(vinyl alcohol).

" carbohydrate " used herein is meant polyhydroxy aldehyde or polyhydroxyketone and derivant thereof.The simplest carbohydrate is a monosaccharide, and it is little linear chain aldehyde and ketone, has the hydroxyl that much adds, except functional group, a hydroxyl is arranged on each carbon usually.The example of monosaccharide comprises tetrose, arabinose, allose, altrose, glucose, mannose, threose, xylose, gulose, idose, galactose, talose, aldohexose, fructose, ketohexose, ribose and aldopentose.Other carbohydrates are made of monosaccharide unit, comprise disaccharide, oligosaccharide or polysaccharide, and this depends on the number of monosaccharide unit.Disaccharide is to be made of two monosaccharide that connect by the covalency glycosidic bond.The example of disaccharide is sucrose, lactose and maltose.Oligosaccharide and polysaccharide are to be made of the monosaccharide unit that links together by glycosidic bond.Oligosaccharide contains 3-9 monosaccharide unit usually, and polysaccharide contains the monosaccharide unit more than 10.Carbohydrate group can be substituted on except locational 1,2,3 or 4 position that is connected with formula I, II, III or IV chemical compound.For example, carbohydrate can be replaced by one or more following groups: alkyl, amino, nitro, halogen, mercaptan, carboxyl or hydroxyl, described group is optional to be substituted.The carbohydrate of exemplary replacement is glucamine or galactosamine.

Aspect more of the present invention, carbohydrate is a sucrose sugar, especially hexose or pentose, and can be aldose or ketose.Sugar can be D or L series, and can comprise amino sugar, deoxysaccharide and uronic acid derivative thereof.Carbohydrate is in the embodiment of the present invention of hexose therein, hexose is selected from glucose, galactose or mannose, or the hexose remnants that replace for example hexosamine, galactosamine, glucamine, especially D-glucamine (2-amino-2-deoxy-D-glucose) or D-galactosamine (2-amino-2-deoxidation-D-galactose) of amino sugar remnants for example.Suitable pentose comprises arabinose, fucose and ribose.

Term " carbohydrate " also comprises for example for example cerebroside and ganglioside of external source clusterin (for example concanavalin A, wheat germ agglutinin, peanutagglutinin, orosomucoid, orosomucoid O ALPHA1-Acid glycoprotein AGP) and glycolipid class of glycoprotein.

" peptide " that be used as carrier in practice of the present invention comprises by peptide bond covalently bound 1,2,3,4 or 5 or above aminoacid.Peptide can comprise aminoacid and analog, derivant and the isoplassont that one or more natures exist.Peptide can be modified to improve its stability, bioavailability, dissolubility etc." peptide analogues " used herein and " peptide derivant " comprise the chemical constitution of imitating peptide and keep the molecule of the functional characteristic of peptide.Aspect more of the present invention, carrier is for example alanine, glycine, proline, methionine, serine, threonine, histidine or an agedoite of aminoacid.In other respects, carrier is for example alanyl-alanyl, prolyl-methionyl or glycyl-glycyl of peptide.Also aspect other, carrier is for example protein, antitrypsin, macroglobulin, hoptoglobin, caeruloplasm, transferrins, α-or beta lipoprotein, β-or gamma globulin or Fibrinogen of polypeptide.

Designed peptide analog, derivant and simulating peptide are known in the art.For example referring to following document: Farmer, P.S., Drug Design (E.J.Ariens, ed.) Academic Press, New York, 1980, vol.10, pp.119-143; Ball.J.B. and Alewood, P.F. (1990) J MoI.Recognition 3:55; Morgan, B.A. and Gainor, J.A. (1989) Ann.Rep.Med.Chem.24:243; With Freidinger, R.M. (1989) Trends Pharmacol.Sci.10:270.Also referring to Sawyer, T.K. (1995) " Peptidomimetic DesignandChemical Approaches to Peptide Metabolism ", Taylor, M.D. and Amidon, G.L. (eds.) Peptide-Based Drug Design:Controlling Transportand Metabolism, Chapter 17; Smith, A.B.3rd waits people (1995) J.Am.Chem.Soc.117:11113-1 1 123; Smith, A.B.3rd waits people (1994) J.Am.Chem.Soc.116:9947-9962; And Hirschman, R. wait people (1993) J.Am.Chem.Soc.115:12550-12568.

The example of peptide analogues, derivant and simulating peptide comprises by one or more benzodiazepines

The peptide (referring to for example James, people such as G.L. (1993) Science 260:1937-1942) that molecule replaces, the peptide with the amido link that methylates and " contrary-anti-(retro-inverso) " peptide are (referring to U.S. Patent No. 4,522,752, Sisto).

The example of peptide derivant comprise wherein amino acid side chain, peptidic backbone or amino-or carboxyl-end by deutero-peptide (peptide of the amido link that for example methylates).

Term simulation, and especially, simulating peptide means and comprises isostere.Term " isostere " is meant the chemical constitution that can be used to substitute second chemical constitution, because the three-dimensional conformation of first structure is fit to the specific binding site of second structure.This term specifically comprises the well-known peptide backbone modification of those skilled in the art (being the amido link simulation).Such modification comprises the modification of amide nitrogen, alpha-carbon, amidocarbonylation, amido link alternative fully, and extension, deletion or skeleton are crosslinked.Other examples of isostere comprise by one or more benzodiazepines

The peptide (referring to for example James, people such as G.L. (1993) Science 260:1937-1942) that molecule replaces.

Other possible modifications comprise that N-alkyl (or aryl) replaces ([CONR]), crosslinked with the skeleton of construction lactams and other circuluses, interior all the D-aminoacid of chemical compound replace all L-aminoacid (" counter-rotating " chemical compound) or contrary-counter-rotating aminoacid mixes ([NHCO]).So-called " counter-rotating " is meant D-aminoacid replacement L-aminoacid, and so-called " contrary-anti-" or " anti--contrary (enantio-retro) " are meant anti-(" contrary ") and the D-aminoacid replacement L-aminoacid of aminoacid sequence.For example, if female peptide is Thr-Ala-Tyr, so contrary form of modifying is Tyr-Ala-Thr, and anti-form is thr-ala-tyr, and contrary-anti-form is tyr-ala-thr (more rudimentary letter is meant D-aminoacid).Compare with female peptide, contrary-anti-peptide has the backbone who puts upside down, and keeps the luv space conformation of side chain simultaneously basically, causes the topological structure of similar female peptide substantially.The further argumentation of relevant " contrary-anti-" peptide is referring to people such as Goodman " Perspectives in Peptide Chemistry " pp.283-294 (1981).Also referring to U.S. Patent No. 4,522,752, Sisto.

Peptide can pass through functional group or other the suitable functional groups on some aminoacid (for example serine) side chain, is connected on the The compounds of this invention.In embodiments of the invention, carrier can comprise four or more a plurality of aminoacid, has via the functional group on the side chain to connect three or more amino acid whose groups.In another embodiment, carrier is an aminoacid, especially amino acid whose sulfonate derivatives, for example cysteine.

" disease and/or disease " is commutative use at this paper, and comprises folding or gather or unusual amyloid forms, deposition or lasting or amyloid lipid interact is the state of feature with abnormal protein.In some respects, this term comprises folding or gather or amyloid forms, deposition or be the disease of feature lastingly with abnormal protein.Aspect special, disease is the state of central or peripheral nervous system or whole body organ.Aspect more particularly, this term comprises and amyloid or the fibriilar formation of amyloid, deposition, accumulation or lasting relevant situation, and described amyloid comprises or is selected from A amyloid beta, AA amyloid, AL amyloid, IAPP amyloid, PrP amyloid, α ₂-microglobulin amyloid, transthyretin, prelbumin and Procalcitonin. be A amyloid beta and IAPP amyloid especially.Disease and/or disease can be wherein to need to dissociate unusual albumen and/or the dissolving of building up or divide the fibriilar state of preformed or sedimentary in advance amyloid amyloid.Aspect some, described disease is that amyloid is stored up disease in the part purpose." amyloid is stored up disease " is meant that obtain the day after tomorrow or from a kind of various disease of heredity, it is characterized in that the accumulation of one of proteinogen fiber that is called amyloid with similar characteristics that some are dissimilar.Amyloid can be built up in single organ, perhaps can scatter whole health.This disease can cause serious problem in the zone that is affected that comprises heart, brain, kidney and digestive tract.The fibrous formation of amyloid beta deposition is the diagnostic characteristics of various amyloids.Mainly by amyloid-beta peptide (in the brain that the fibril of β-AP) constitutes and the cerebrovascular deposition be the feature of Alzheimer (family and accidental generation type); Islet cells amyloid peptide (IAPP; Dextrin) is fibriilar feature in the islet cells amyloid beta deposition relevant with type ii diabetes; And beta-2-microglobulin is as the key component of the result's of chronic hemodialysis treatment amyloid beta deposition.The disease that Protein virus is relevant, for example Creutzfeld-Jacob disease, pruritus disease, Niu Haimian shape encephalitis etc. are that accumulation with the protease resistant of PrPC (being appointed as AScr ro PrP-27) is a feature.

Some disease is considered to wherein not have the primary amyloid degeneration of the evidence of preexist or simultaneous disease.Primary amyloid degeneration is typically with the fibriilar feature that exists for of " AL type " (AL-type) albumen.Store up in the disease at the Secondary cases amyloid, potential chronic inflammatory or infectious disease state (for example rheumatic arthritis, juvenile chronic arthritis, ankylosing spondylitis are arranged, psoriasis, Reiter ' s syndrome, adult Still ' s disease, Behcet ' s syndrome, Crohn disease, chronic infected by microbes is osteomyelitis, pulmonary tuberculosis and leprosy for example, and malignant tumor is Hodgkin ' s lymphoma for example, renal carcinoma, intestinal, lung and apparatus urogenitalis cancer, basel cell carcinoma and hair cell cancer).The Secondary cases amyloid is stored up disease with by the fibriilar feature (ApoSSA) that is deposited as of the deutero-AA type of serum amyloid protein.The Inheritance amyloidosis can have nerve, kidney or the cardiovascular deposit of relevant ATTR transthyretin type, and it comprises other syndromes (for example being the familial Mediterranean heating of feature with the AA fibril) with different amyloid components.Other forms of amyloid is stored up disease and is comprised localized forms, is characterised in that the focus that exists in separating organ, often is tumor sample deposit.In addition, amyloidosis is relevant with aging, and forms feature with speckle in heart or the brain usually.Amyloidosis comprises systemic disease for example diabetes, the complication that is derived from chronic hemodialysis and chronic inflammatory or the dyscrasic result of plasma cell of adult onset.

Can use The compounds of this invention, the amyloid disease that compositions and method are treated includes but not limited to Alzheimer, mongolism, the dementia pugilistica, multiple system atrophy, inclusion body myositis, the amyloid of Holland's type is stored up the hereditary cerebral hemorrhage of disease, the sick C type of Nieman-Pick, brain amyloid-beta angiopathy, with the relevant dementia of cortex basis degeneration, the amyloid of type ii diabetes is stored up disease, the amyloid of chronic inflammatory disease is stored up disease, the amyloid pernicious and heating of familial Mediterranean is stored up disease, the dyscrasic amyloid of multiple myeloma and cell is stored up disease, have rubella and deaf nephropathy (Muckle-Wells syndrome), the amyloid relevant with SIDA stored up disease, and the congenital constitutional amyloid relevant with myeloma or macroglobulinemia stored up disease; The amyloid relevant with the immunocyte dyscrasia stored up disease; MG; Recessive dyscrasia; The local warty amyloid relevant with chronic inflammatory disease stored up disease; The amyloid relevant with some immunocyte dyscrasias stored up disease; Familial amyloid sample albumen polyneuropathy; Have amyloid and store up disease, the hereditary cerebral hemorrhage of Alzheimer and other neurodegenerative diseases, the amyloid relevant with chronic hemodialysis stored up disease, type ii diabetes, insulinoma, the amyloid of prion disease is stored up disease, (transmissible spongiform encephalopathy prion disease), creutzfeldt-jakob disease, the Gerstmann-Straussler syndrome, Kuru disease, with the pruritus disease, the amyloid relevant with complication of wrist stored up disease, and old heart amyloid is stored up disease, familial amyloid sample albumen polyneuropathy and and endocrine tumors, especially the Alzheimer amyloid relevant with type ii diabetes stored up disease.

Aspect more of the present invention, disease and/or disease comprise fibriilar formation, deposition, accumulation or the lasting relevant state that with the amyloid fibril, especially is selected from following amyloid: A amyloid beta, AA amyloid, AL amyloid, IAPP amyloid, PrP amyloid, α 2-microglobulin amyloid, transthyretin, prelbumin and Procalcitonin., especially A amyloid beta and IAPP amyloid.The example of such disease comprises Alzheimer, mongolism, dementia pugilistica's disease, multiple system atrophy, inclusion body myositis, Holland's type amyloid is stored up the disease hereditary cerebral hemorrhage, C type Niemann-Pick disease, brain amyloid-beta angiopathy, with the relevant dementia of cortex basis degeneration, the amyloid of type ii diabetes is stored up disease, and the amyloid of chronic inflammatory disease is stored up disease, the amyloid pernicious and heating of familial Mediterranean is stored up disease, multiple myeloma and the dyscrasic amyloid of B-cell are stored up disease, and the amyloid of Puli's protein disease is stored up disease, creutzfeldt-jakob disease, Ge-Shi syndrome, Kuru disease and pruritus disease, the amyloid relevant with complication of wrist stored up disease, and old heart amyloid is stored up disease, familial amyloid sample albumen polyneuropathy and and endocrine tumors, especially the Alzheimer amyloid relevant with type ii diabetes stored up disease.

In other aspects of the present invention, the disease of the enough The compounds of this invention of energy, compositions and method treatment and/or the state that disease comprises central or peripheral nervous system or whole body organ, described shape body causes proteinic deposition, protein fragment, and the peptide of β-plait plate shape formula, fibril and/or accumulation or oligomer.Especially this disease is the Alzheimer of senilism and senile form; Amyloid blood vessel disease; Mild cognitive impairment; Alzheimer-relevant dementia (for example vascular dementia and dementia of the Alzheimer type); Tauopathy (argyrophilic grain dementia for example, corticobasal degeneration, dementia pugilistica's disease, calcific diffusivity nerve fiber is twined, the disease that Puli's protein is relevant, Ha-Shi disease, myotonic dystrophy, C type Ni-Pi disease, has the non-Guamanian Motor Neuron disease that nerve fiber is twined, Pick's disease, parkinson disease after the encephalitis, brain amyloid blood vessel disease, gliosis under the carrying out property cortex, benumb on the carrying out property nuclear, subacute sclerosing panencephalitis(SSPE) and entanglement type dementia), alpha-synapse nucleoprotein disease (Louis's body dementia for example, the multiple system of glial cell inclusion body atrophy, the Shy-Drager syndrome, spinocebellar ataxia (for example DRPLA or Machado-Joseph disease); Striatonigral degeneration, olivopontocerebellar atrophy, ferrum is built up neural degeneration, olfactory disorder and amyotrophic lateral sclerosis in the I type brain); Parkinson disease (for example familial or non-familial); Amyotrophic lateral sclerosis; The spastic paraplegia defective function and/or the three A albumen of chaperone (for example with); Huntington Chorea, spinocebellar ataxia, Freidrich ' s Ataxia; With assemble relevant neurodegenerative disease in the proteic cell and/or in the neuron, described albumen has polyglutamic amide, poly-alanine or from the corresponding gene three or other repetitives of tetranucleotide element; Cerebrovascular disease; Mongolism; The head trauma of building up after the amyloid beta peptide wound; Puli's protein disease (creutzfeldt-jakob disease, Ge-Shi-Sha disease and variant creutzfeldt-jakob disease); The English dementia of familial; Familial Denmark formula dementia; The presenile dementia of spasmodic ataxia; English brain amyloid blood vessel disease; The presenile dementia of Denmark's formula spasmodic ataxia brain amyloid blood vessel disease; The neural flat inclusion body of color (FENIB) familial encephalopathia; Amyloid polyneuropathy (for example senile amyloid polyneuropathy or systemic amyloidosis sample albumen are stored up disease); Inclusion body myositis owing to amyloid beta peptide; Familial and Finland's type amyloid are stored up disease; The systemic amyloidosis sample albumen relevant with multiple myeloma is stored up disease; The heating of familial Mediterranean; Chronic infection and inflammation; And with the relevant type ii diabetes of islet cells amyloid polypeptide (IAPP).

Aspect more of the present invention especially in the therapeutic alliance, disease and/or disease are neuron disease (Alzheimer for example, mongolism, parkinson disease, Huntington chorea, the pathogenicity psychotic state, schizophrenia, food intake is lowered, the sleep awakening, the metabolic stable state adjustment of ability is lowered, and autonomic nervous function lowers, and regulates disorderly, body fluid, hypertension, heating, dyssomnias, apositia, comprise the anxiety associated conditions of depression, comprise epilepsy, drug withdrawal and excessive drinking comprise cognitive disorder and dull-witted neural degeneration in interior outbreak);

The compounds of this invention also can play a part to suppress or prevention alpha-synapse nucleoprotein/NAC fibril forms, suppresses or prevention alpha-synapse nucleoprotein/NAC fibril growth, and/or preformed alpha-synapse nucleoprotein/NAC fibril and proteins deposited decomposition, destruction and/or the depolymerization relevant with alpha-synapse nucleoprotein/NAC fibril.Be suitable for the synapse nucleoprotein disease of The compounds of this invention or combination treatment or altogether the example of nucleoprotein disease (synucleinopathies) be and the fibriilar formation of fibril especially alpha-synapse nucleoprotein, deposition, accumulation or lasting diseases associated, include but not limited to parkinson disease, familial Parkinson's disease, thunder dimension corpusculum disease, the thunder dimension corpusculum mutation of Alzheimer, thunder dimension corpusculum dementia, multiple system atrophy, Fructus Canarii albi pons cerebellar atrophy, ferrum is built up neural degeneration, olfactory disorder and Guam parkinsonism-dementia complex in the I type brain.

Aspect more of the present invention, with filamentous (filaments) and neurofilament (neurofilaments) and/or the relevant motor neuron of the proteic accumulation of superoxide dismutase, with the defectiveness function and/or the relevant spastic paraplegia of three A albumen of chaperone, or spinocebellar ataxia for example DRPLA or Machado-Joseph disease.

In other aspects of the present invention, disease is Puli's protein disease, comprises creutzfeldt-jakob disease, Ge-Shi-Sha disease and variant creutzfeldt-jakob disease, and the amyloid polyneuropathy, comprises that old amyloid polyneuropathy or systemic amyloidosis sample albumen stores up disease.

In embodiments of the invention, disease is Alzheimer or parkinson disease, comprises familial and non-familial type.

Alzheimer (AD) only just influences about 4.5 hundred ten thousand men and womens in the U.S..The sickness rate of Alzheimer increased with the age, and its influence people more than 85 years old of 50% nearly, and risk increases with the age usually.Therefore, whether be that risk factor of considering when treating and/or preventing the suitable host of Alzheimer are ages assess patient or patient crowd.Certainly, the signal of disease and symptom are better forecasting index.Yet under a lot of situations in suffering from the people of Alzheimer, the variation in the brain had just begun before the 10-20 of any tangible dementia or symptom appearance.Therefore, early treatment, even before visible sign begins, just treat, must influence treating and/or preventing of Alzheimer, perhaps postpone its effect at least, perhaps reduce its seriousness.

There are a lot of available diagnostic tests can help practitioner's assess patient to suffer from or develop the probability of Alzheimer.These tests, except other tests as known in the art, comprise known test in for example following field: Mini-mental State Examination (MMSE), Clock Drawing Test, Clinical Dementia Rating (CDR) scale, Mini-Mental State Examination (MMSE), Functional Assessment, for example use Functional Assessment Staging (FAST) scoring, Alzheimer ' sAssessment Scale-Cognitive Subscale (ADAS-Cog).A lot of tests concentrate on memory test, deal with problems, vision-sports coordination, attention and abstract thinking, for example require mental skill and simply calculate.The doctor uses various assessments and experimental determination to diagnose.The brain of suffering from the individuality of AD shows the characteristic damage, is called (or amyloid) speckle in old age, and amyloid blood vessel disease (the amyloid beta deposition thing in the blood vessel) and nerve fiber are twined.These most damages, especially amyloid speckle and nerve fiber are twined, usually in suffering from the patient of AD for being found in some zones in memory and the cognitive vital human brain.Relatively small number of these damages are not found in major part has old people's the brain of clinical AD yet in stricter anatomic distribution.Amyloid speckle and amyloid blood vessel disease also become suffers from the feature of brain that Trisomy21 (mongolism) and Dutch type amyloid are stored up the individuality of disease (HCHWA-D) hereditary cerebral hemorrhage.Use MRI, CT, PET, the such damage of detections such as SPECT also can be used to diagnose AD.

Aspect more of the present invention, disease can be a feature owing to the inflammatory process by the existence of amyloidogenicogenic albumen or the activated macrophage of peptide.The inventive method can comprise and suppress macrophage activation and/or suppress inflammatory process.A kind of method can be included among the patient process or the degree that lowers, slows down, improves or reverse macrophage invasion and inflammation.

Disease can be and the state that can be disintegrated by The compounds of this invention or dissociated interaction of molecules is relevant.＂ can be disintegrated by The compounds of this invention or dissociated interaction of molecules ＂ comprises the interaction that contains amyloid and glycoprotein.The interaction that contains amyloid protein comprises that amyloid protein-amyloid protein interacts, amyloid-Dan Baijutang interacts, and amyloid-Dan Baijutang/mucopolysaccharide (GAG) interacts and/or amyloid protein-mucopolysaccharide interacts.Interacting protein can be cell surface, secreted or extracellular protein.

Can comprise the disease of disintegrating or decomposing benefit that to benefit from from the interaction of molecules that comprises amyloid and the interacting compounds that comprises protein and glycoprotein with the disease of The compounds of this invention or combination treatment or prevention.Can comprise by antibacterial, viral Protein virus and fungus-caused infectious disease with the example of the disease of The compounds of this invention or combination treatment.The such disease and/or the example of disease are disease and/or the diseases relevant with pathogen, and described pathogen comprises herpes simplex virus, rabies virus, people's cytomegalovirus, human immunodeficiency virus, Bordetella pertussis, chlamydia trachomatis, hemophilus influenza, helicobacter pylori, the Borrelia burgdoyferi bacterium, gonococcus, mycobacterium tuberculosis, staphylococcus aureus, Streptococcus mutans, Streptococcus suis, Plasmodium falciparum, Shi Liman protozoon amazonensi, the Trypanozoma trypanosomicide, monocyte hyperplasia Li Site bacterium, mycoplasma pneumoniae, enterotoxic Escherichia coli, pyelonephritis escherichia coli, and Pseudomonas aeruginosa.

＂ mgA ＂ or the milligram ＂ of the ＂ activating agent amount that is meant active cyclohexanhexanol polyol compound about the cyclohexane polyalcohol chemical compound used herein.

The ＂ kg ＂ of unit in mg/kg or mgA/hr/kg used herein is meant the kg body weight of individual preferred mammal.

" C _Max" be meant by giving preparation of the present invention or dosage form or producing the Cmax of the cyclohexane polyalcohol chemical compound in environment for use by method of the present invention.Term " C _Max" with " top level " be synonym.

＂ C _Min＂ is meant by giving preparation of the present invention or dosage form or producing the Cmin of the cyclohexane polyalcohol chemical compound in environment for use by method of the present invention.Term " C _Min" with " trough level " be synonym.

" IR " is meant immediately and discharges.

" t _Max" be meant time of the maximum observation concentration that produces by administration cyclohexane polyalcohol chemical compound.

" total blood substance exposes " is meant area under curve (" AUC "), determines by blood plasma Chinese medicine concentration (Y-axle) was drawn to the time (X-axle).AUC is meansigma methods normally, and for example is that in the research all are tried individual meansigma methods.The mensuration of AUC is well-known method, and is described in for example " Pharmacokinetics; Processes and Mathematics ＂ ", Peter Welling (ACS Monograph 185, Amer.Chem.Soc, Wash.D.C.:1986) among.

" bid " is meant during 24 hours drug-delivery preparation or dosage form twice.

" qd " is meant during 24 hours drug-delivery preparation or dosage form once.

" speed of release " of chemical compound or " rate of release " are meant the chemical compound that time per unit discharges from preparation or dosage form amount, for example milligram (mgA/hr) of the active medicine that per hour discharges.The rate of release of dosage form is normally as the velocity determination of dissolution in vitro, promptly under suitable condition and measure the amount of the chemical compound that time per unit discharges from dosage form in suitable liquid.For example, methods known in the art be can use, solubility test and preparation dissolution in vitro feature carried out.

" dissolution in vitro feature " is meant that the total amount of the cyclohexane polyalcohol chemical compound that wherein discharges is to use the solubility test of conventional U.S.Pharmacopeia (USP) the instrument mensuration that is used for solubility test.Referring to being described in United States Pharmacopoeia XXIII (USP) Dissolution TestChapter 711, the USP instrument among the Apparatus 2 or 3.In one aspect, the USP instrument is the USP-2 instrument, and it is at 37 ± 0.5 ℃ of 900ml acetate buffers that contain pH4.0, and contains the NaCl of concentration 0.75M.If dosage form is continuous release tablet or non-disintegrate Kronocap, so the USP instrument is equipped with blade usually and stirs with about 50rpm.If dosage form is many granules and is not tablet, so usually the USP instrument is equipped with blade and stirs with about 100rpm.Therefore, sustained release forms is granose aspect therein, the USP instrument, and perhaps example is the 2 type instrument (serosity) of 100rpm, 37 ± 0.5 ℃ of temperature, testing liquid is for containing the 900ml 0.05M phosphate buffer of 75mM sodium lauryl sulfate (pH5.5).

The dissolution in vitro feature is normally used in the preparation of medicine.Dissolving characteristic can use FDA (at www.usfda.gov) and United States Pharmacopeia (USP) Vol.23, the method exploitation that pp1791-1793 (1995) describes.The preparation or the dosage form that meet solubility parameter disclosed herein can provide favourable pharmacokinetics feature.

" dosage form " is meant compositions or the device that contains cyclohexane polyalcohol chemical compound and optional pharmaceutically suitable carrier, excipient or delivery agents.Dosage form can be immediate release dosage form or sustained release forms.

" immediate release dosage form " is meant not comprise and is used for continuing to discharge component, promptly be used to slow down the disintegrate of reactive compound and the dosage form of dissolved component.The compositions that these dosage forms depend on drug matrices usually realizes the rapid release of active component.

So-called " sustained release forms " is also referred to as " lasting effect is disengaged dosage form ", is meant the preparation at the time of some hrs release of active compounds.In one aspect, sustained release forms comprises disintegrate or the dissolved component that is used to slow down reactive compound.In embodiments of the invention, dosage form can be to adopt or do not adopt the lasting release in initial delay stage.(qd) or every day twice (bid) administration once a day, sustained release forms can show 2,4,6 or 8 hours or the longer time at least, and preferably reached most 48 hours T _MaxValue.Sustained release forms can continue to discharge at least about 4-6 hour or longer, preferred about 8 hours or longer and, in special embodiment, about 12 hours or longer, about 12 hours-24 hours, or about 20 hours-24 hours persistent period.

Sustained release forms can be mixed with multiple physical arrangement or form, include but not limited to, tablet, lozenge, gelcap, oral cavity patch, suspension liquor, solution, gel etc.Aspect more of the present invention, sustained release form causes the daily dose of administration minimum number, especially 1,2 or 3 daily dose, more preferably two daily doses (being bid).

Term " zero release characteristic " or " near zero release characteristic " are meant that certain drug in the environment for use (for example blood plasma, brain or CSF) the patient is in the fixed or constant basically amount of specified time interval.On the contrary, in the most drug preparation, drug releasing rate improves rapidly, and rate of release is index decreased then.Such drug release is that one-level discharges.

The cumulative release and the proportional situation of the square root of time of the medicine that term " square root of release characteristic (square root of time release profile) " is meant wherein to be discharged.Aspect more of the present invention, will have an appointment from an interval to next interval 30%, 20%, 10% or 5% the variation of zero release characteristic.Gave aspects more of the present invention of drug compound at least in one day twice therein, during administration, to next time point, zero release characteristic will have and be no more than about variation of 30%, 20%, 10% or 5% from a time point of administration.

Term " zero level rate of release " is meant the rate of release of substantial constant, and medicine is dissolved in the target environment of use with constant speed like this.More specifically, the drug releasing rate relevant with the time have less than about 30%, preferably less than about 20%, be more preferably less than about 10%, most preferably less than about 5% variation, wherein measuring is that cumulative release is preferably carried out between about 25% to about 90% dosage form Chinese medicine gross weight therein.

" many granules " is meant a plurality of granules, and wherein designing each granule is in order to produce the lasting release of cyclohexane polyalcohol chemical compound.Aspect more of the present invention, each granule in many granules constitutes the self-sustaining formula unit that continues release.In other respects, described granule is formed bigger unit.Preferred each granule of many granules comprises one or more preparations of cyclohexane polyalcohol chemical compound or the needed excipient of usefulness.Individual particle usually between about 40 microns-Yue 5mm, for example between the about 3mm of about 50mm-, perhaps as another example between the about 1mm of about 50mm-, perhaps as another example between the about 300mm of about 50mm-.Usually will be mainly be called powder by many granules of the granulometric composition of the low side of size range.Usually will be mainly be called pearl by many granules of the approaching high-end granulometric composition of size range.Comprise granose dosage form and comprise unit dose bag or bag and the powder that is used for oral suspension.Many granules can be able to be provided the release characteristic of treatment interests with realization with the sustained release polymer coating film.

" matrix system " is meant dosage form, wherein medicine and excipient mixed with the form of compacting or extruding, and the release of medicine from dosage form weathers and the control of the combination of spreading like this.Send and slowly remove host material from substrate, to expose and to discharge medicine gradually after being included in administration by corroding the control medicine.Comprise in check mode soluble drug diffusion by the substrate excipient by the DIFFUSION CONTROLLED drug release.Matrix system can be hydrophilic or hydrophobic.The case description of matrix system is in the U.S. disclosed application No.2003/0180360 and international disclosed application No.WO 05102272.

Preparation/dosage form

Medical compounds effect in prevention and treatment morbid state depends on multiple factor, comprises the speed and the persistent period that chemical compound are delivered to the patient by dosage form.The delivery rate of given dosage form in the patient and the combination of persistent period, can be described in the body of described dosage form release characteristic and, according to the medical compounds of administration, relevant with concentration and the persistent period of this medical compounds in blood plasma, be called the blood plasma feature.Because medical compounds is changing aspect the speed of its pharmacokinetic properties biological example availability, absorption and eliminating, be important element so release characteristic and consequent blood plasma feature are effectively treated for design.

The invention provides dosage form, preparation and the method for the pharmacokinetics feature that produces favourable, especially favourable pharmacokinetics feature, more specifically continues.Can be with the cyclohexane polyalcohol chemical compound with pure or pure basically form, with the form of its officinal salt, and comprise with other forms and to be used for the form of anhydrous or hydration the present invention and to carry out.All such forms all belong within the scope of the present invention.

In embodiments of the invention, the cyclohexane polyalcohol chemical compound can comprise pharmaceutically acceptable eutectic, eutectic salt, polymorph, solvate, derivant or its mixture.Pharmaceutically acceptable eutectic is meant and is applicable to and contacts with individuality or patient's tissue and do not have toxicity, zest, anaphylaxis improperly and have the eutectic of required pharmacokinetic properties.

Term used herein " eutectic " is meant in room temperature and comprises two or more independent solid crystalline materials that each independent solid has unique physical characteristic for example structure, fusing point and melting heat.Eutectic can pass through medicine activity component (API) and eutectic forms agent, and by hydrogen bond or other non-covalent interactions, for example pi piles up and Van der Waals interacts forms.Other embodiments provide wherein, and eutectic formation agent is the eutectic of the 2nd API.In another embodiment, eutectic is not API.In another embodiment, comprise more than one eutectics and form agent.For example, can in having the eutectic of API, mix two kinds, three kinds, four kinds, five kinds or more kinds of eutectic formation agent.Pharmaceutically acceptable eutectic for example is described in " Pharmaceuticalco-crystals, " Journal of Pharmaceutical Sciences, Volume95 (3) P.499-516, in 2006.Preparing eutectiferous method is described in the U.S. Patent application 20070026078.

Eutectic, it also must be pharmaceutically acceptable chemical compound, it can be benzoquinone for example, terephthalaldehyde, glucide, nicotiamide, acetic acid, formic acid, butanoic acid, 1,3, the 5-benzenetricarboxylic acid, 5-nitro isophthalic acid, diamantane (obsolete)-1,3,5, the 7-tetracarboxylic acid, Methanamide, succinic acid, fumaric acid, tartaric acid, malic acid, tartaric acid, malonic acid, Benzoylamide, mandelic acid, glycolic, Fumaric acid, maleic acid, urea, nicotinic acid, piperazine, terephthalaldehyde, 2, the 6-pyridine carboxylic acid, 5-nitro isophthalic acid, citric acid and alkane-and aromatic hydrocarbons-sulfonic acid methanesulfonic acid benzenesulfonic acid for example.

In each method of the present invention, API need be combined for crystal formation together dose nearly, comprise these two kinds of solids are ground together, perhaps with a kind of or two kinds of components fusing and make it recrystallization.This also can comprise the API dissolving and add eutectic formation agent, perhaps eutectic be formed the agent dissolving and add API.Crystallization condition is put on API and eutectic plate.This need change the characteristic of solution, for example pH or temperature, and can need solution concentration, usually by removing dissolving, typically dry by dissolving.The concentration that causes API and eutectic plate in the past that solvent was removed along with the time increases, so that promote crystallization.

Be suitable for once a day or twice, the preparation or the dosage form of preferred administration once a day by administration, the pharmacokinetics feature that can obtain favourable pharmacokinetics feature, especially continues, described preparation comprise to be enough to chemical compound with desired concn or dosage and are provided to one or more cyclohexane polyalcohol chemical compounds that the environment of use exists with the amount for the treatment of disease described herein and/or disease.In one aspect, the environment of use is a brain, especially an extracellular or a matter cerebral tissue.In one aspect, the environment of use is blood plasma and/or CSF.

Be suitable for once a day or twice, the preparation or the dosage form of preferred administration once a day by administration, can obtain favourable pharmacokinetics feature, especially the pharmacokinetics feature of Chi Xuing, described preparation or dosage form comprise one or more cyclohexane polyalcohol chemical compounds that the chemical compound with the blood plasma brain that is enough to provide required or CSF concentration or dosage (for example every day dosage) exists with the amount for the treatment of disease described herein and/or disease.

In one aspect, the cyclohexane polyalcohol chemical compound in CSF, brain or blood plasma is at least about 0.05 μ M-at least about 125 μ M.

In the embodiment of dosage form of the present invention, the concentration of chemical compound in CSF, brain or blood plasma is about 0.05 μ M-100 μ M, 0.05 μ M-90 μ M, 0.05 μ M-80 μ M, 0.05 μ M-70 μ M, 0.05 μ M-60 μ M, 0.05 μ M-50 μ M, 0.05 μ M-40 μ M, 0.05 μ M-30 μ M or 0.05 μ M-20 μ M.

In other embodiments of dosage form of the present invention, the concentration of chemical compound in CSF, brain or blood plasma is about 0.1 μ M-100 μ M, 0.1 μ M-90 μ M, 0.1 μ M-80 μ M, 0.1 μ M-70 μ M, 0.1 μ M-60 μ M, 0.1 μ M-50 μ M, 0.1 μ M-40 μ M, 0.1 μ M-30M, 0.1 μ M-20 μ M, or0.1 μ M-10 μ M.

In the other embodiments of dosage form of the present invention, the concentration of chemical compound in CSF, brain or blood plasma is about 0.125-50 μ M, 0.125-50 μ M, 0.125-40 μ M, 0.125-30 μ M, 0.125-20 μ M or 0.125-10 μ M.

In the embodiment of dosage form of the present invention, the concentration of chemical compound in CSF, brain or blood plasma is about 0.5-100 μ M, 0.5-50 μ M, 0.5-40 μ M, 0.5-30 μ M, 0.5-20 μ M or 0.5-10 μ M.

In the embodiment of dosage form of the present invention, the concentration of chemical compound in CSF, brain or blood plasma is about 0.8-100 μ M, 0.8-50 μ M, 0.8-40 μ M, 0.8-30 μ M, 0.8-20 μ M or 0.8-10 μ M.

In the embodiment of dosage form of the present invention, the concentration of chemical compound in CSF, brain or blood plasma is about 0.9-50 μ M, 0.9-40 μ M, 0.9-30 μ M, 0.9-20 μ M or 0.9-10 μ M.

In the embodiment of dosage form of the present invention, the concentration of chemical compound in CSF, brain or blood plasma is about 1-50 μ M, 1-40 μ M, 1-30 μ M, 1-20 μ M, 1-10 μ M or 1 μ M-5 μ M.

In the embodiment of dosage form of the present invention, the concentration of chemical compound in CSF, brain or blood plasma is about 1.25-50 μ M, 1.25-40 μ M, 1.25-30 μ M, 1.25-20 μ M, 1.25-10 μ M or 1.25-5 μ M.

In specific embodiment, the concentration of chemical compound in CSF, brain or blood plasma is about 1-50 μ M, 1-20 μ M, 1-10 μ M, 1-6 μ M or 1-5 μ M.

In other special embodiments, the concentration of chemical compound in CSF, brain or blood plasma is about 2-6 μ M, 3-6 μ M or 4-6 μ M or about 5 μ M.

In one aspect, every day 1,2 or 3 times or more than 3 times the required dosage of the cyclohexane polyalcohol chemical compound of administration be about 1-100mg/kg, 1-90mg/kg, 1-80mg/kg, 1-75mg/kg, 1-70mg/kg, 1-60mg/kg, 1-50mg/kg, 1-40mg/kg, 1-35mg/kg, 2-35mg/kg, 2.5-30mg/kg, 3-30mg/kg, 3-20mg/kg or 3-15mg/kg.

In one aspect, once a day or twice, especially the required dosage of the cyclohexane polyalcohol chemical compound of single administration is about 1-100mg/kg, 1-90mg/kg, 1-80mg/kg, 1-75mg/kg, 1-70mg/kg, 1-60mg/kg, 1-50mg/kg, 1-40mg/kg, 1-35mg/kg, 2-35mg/kg, 2.5-30mg/kg, 3-30mg/kg, 3-20mg/kg or 3-15mg/kg.

In embodiments of the invention, the required dosage of twice administration every day is about 1-50mg/kg, 1-40mg/kg, 2.5-40mg/kg, 3-40mg/kg, 3-35mg/kg, 3-30mg/kg most preferably.In embodiments of the invention, required dosage every day is about 1-80mg/kg, and in this scope 1-70mg/kg, 1-65mg/kg, 2-70mg/kg, 3-70mg/kg, 4-65mg/kg, 5-65mg/kg or 6-60mg/kg.

Be suitable for once a day or the preparation or the dosage form of twice administration, preferred twice administration every day by administration, can obtain favourable pharmacokinetics feature, described preparation or dosage form comprise one or more cyclohexane polyalcohol chemical compounds that the amount with the chemical compound that is enough to provide required dosage exists.In one aspect, once a day or to give the required dosage of drug compound for twice be about 1-100mg/kg, 1-90mg/kg, 1-80mg/kg, 1-75mg/kg, 1-70mg/kg, 1-60mg/kg, 1-50mg/kg, 1-40mg/kg, 1-35mg/kg, 2-35mg/kg, 2.5-30mg/kg, 3-30mg/kg, 3-20mg/kg or 3-15mg/kg.

In embodiments of the invention, the required dosage of twice administration every day is about 1-50mg/kg, 1-40mg/kg, 2.5-40mg/kg, 3-40mg/kg, 3-35mg/kg, most preferably 3-30mg/kg.

In other embodiments of the present invention, required dosage every day is about 1-80mg/kg, and in this scope 1-70mg/kg, 1-65mg/kg, 2-70mg/kg, 3-70mg/kg, 4-65mg/kg, 5-65mg/kg or 6-60mg/kg.

Aspect more of the present invention, dosage form and preparation are provided, so that make the crest of cyclohexane polyalcohol chemical compound (for example scyllitol chemical compound or table-inositol chemical compound) and the minimize variations of valley floor blood plasma and/or cerebrospinal fluid level, and especially provide the cyclohexane polyalcohol chemical compound of lasting treatment effective dose.

Aspect of the present invention relates to the preparation that comprises one or more cyclohexane polyalcohol chemical compounds (for example scyllitol chemical compound or table-inositol chemical compound), and said preparation is during the administration, especially produce the chemical compound of treatment effective dose during the administration in 24 hours.In one embodiment, the treatment effective dose of cyclohexane polyalcohol chemical compound is about 1-100mg/kg, 1-90mg/kg, 1-80mg/kg, 1-75mg/kg, 1-70mg/kg, 1-60mg/kg, 1-50mg/kg, 1-40mg/kg, 1-35mg/kg, 2-35mg/kg, 2.5-30mg/kg, 3-30mg/kg, 3-20mg/kg or 3-15mg/kg.One special aspect, the treatment effective dose of twice administration every day is about 1-50mg/kg, 1-40mg/kg, 2.5-40mg/kg, 3-40mg/kg, 3-35mg/kg, most preferably preferred 3-30mg/kg.The treatment effective dose of the cyclohexane polyalcohol chemical compound that is administered twice every day in one embodiment, is about 3-30mg/kg.In another embodiment, the treatment effective dose of the cyclohexane polyalcohol chemical compound of administration every day is about 1-80mg/kg, and in this scope 1-70mg/kg, 1-65mg/kg, 2-70mg/kg, 3-70mg/kg, 4-65mg/kg, 5-65mg/kg or 6-60mg/kg.

Additional aspects of the present invention relate to once a day or the unit dosage forms of twice administration, this unit dosage forms comprises one or more cyclohexane polyalcohol chemical compounds (for example scyllitol chemical compound or table-inositol chemical compound), and the peak concentration Cmax that does not have the remarkable different chemical compound on the statistics with the peak concentration of the dosage form acquisition that (during 24 hours) are administered twice above with every day is provided.

Embodiment of the present invention relate to the dosage form that comprises one or more cyclohexane polyalcohol chemical compounds (for example scyllitol chemical compound or table-inositol chemical compound), and described dosage form provides about 1-125 μ g/ml, 1-100 μ g/ml, 1-90 μ g/ml, 1-80 μ g/ml, 1-70 μ g/ml, 1-60 μ g/ml, 1-50 μ g/ml, 1-40 μ g/ml, 1-30 μ g/ml, 1-20 μ g/ml, 1-10 μ g/ml, 1-μ g/ml, 5-125 μ g/ml, 5-100 μ g/ml, 5-70 μ g/ml, 5-50 μ g/ml, 10-100 μ g/ml, 10-90 μ g/ml, 10-80 μ g/ml, 10-70 μ g/ml, 10-60 μ g/ml, 10-50 μ g/ml, 10-40 μ g/ml, the peak plasma concentrations C of the chemical compound of 10-30 μ g/ml or 10-20 μ g/ml _MaxIn embodiments, described C _MaxBe about 1-125 μ g/ml, 1-100 μ g/ml, 5-70 μ g/ml, 5-50 μ g/ml, 10-100 μ g/ml, 10-90 μ g/ml, 10-80 μ g/ml, 10-70 μ g/ml, 10-60 μ g/ml, 10-50 μ g/ml or 10-40 μ g/ml.In special embodiment, described C _MaxBe 5-70 μ g/ml, 5-65 μ g/ml, 5-50 μ g/ml, 5-40 μ g/ml, 5-30 μ g/ml or 5-20 μ g/ml.

Embodiment of the present invention relate to the dosage form that comprises one or more cyclohexane polyalcohol chemical compounds (for example scyllitol chemical compound or table-inositol chemical compound), and described dosage form provides about 20-80%, 25-75%, 25-70%, 25-65% or 30-65%, the preferred peak C SF concentration C of the chemical compound of about 30-60% _MaxEmbodiment of the present invention relate to the dosage form that comprises one or more cyclohexane polyalcohol chemical compounds (for example scyllitol chemical compound or table-inositol chemical compound), and described dosage form provides about 1-125 μ g/ml, 1-100 μ g/ml, 1-90 μ g/ml, 1-80 μ g/ml, 1-70 μ g/ml, 1-60 μ g/ml, 1-50 μ g/ml, 1-40 μ g/ml, 1-30 μ g/ml, 1-20 μ g/ml, 1-10 μ g/ml, 1-5 μ g/ml, 5-125 μ g/ml, 5-100 μ g/ml, 5-70 μ g/ml, 5-50 μ g/ml, 10-100 μ g/ml, 10-90 μ g/ml, 10-80 μ g/ml, 10-70 μ g/ml, 10-60 μ g/ml, 10-50 μ g/ml, 10-40 μ g/ml, the peak C SF of the chemical compound of 10-30 μ g/ml or 10-20 μ g/ml or brain concentration C _MaxIn special embodiment, described C _MaxBe about 5-70 μ g/ml, 5-65 μ g/ml, 5-50 μ g/ml, 5-40 μ g/ml, 5-30 μ g/ml or 5-20 μ g/ml.In special embodiment, the administration of chemical compound provides the peak C SF concentration C of chemical compound _MaxBe about 1-75 μ g/ml, 1-70 μ g/ml, 1-60 μ g/ml, 1-55 μ g/ml, 1-50 μ g/ml, 1-30 μ g/ml, 1-25 μ g/ml, 1-20 μ g/ml or 1-15 μ g/ml.

Aspect other, the present invention relates to comprise the preparation or the dosage form of one or more cyclohexane polyalcohol chemical compounds (for example scyllitol chemical compound or table-inositol chemical compound), the degree of absorption that the degree of absorption that area (AUC) is defined under said preparation or the dosage form offer curves with by chemical compound a day three times or four dosage forms produce equates.In special embodiment, AUC, AUC especially _0infBe about 20-600 μ g.h/ml, 50-600 μ g.h/ml, 100-600 μ g.h/ml, 100-300 μ g.h/ml, or 100-250 μ g.h/ml, 15-125 μ g.h/ml, 20-135 μ g.h/ml, 80-270 μ g.h/ml, 80-200 μ g.h/ml, 80-150 μ g.h/ml, 80-125 μ g.h/ml or 80-100 μ g.h/ml.Other aspects of the present invention relate to preparation or the dosage form that comprises one or more cyclohexane polyalcohol chemical compounds (for example scyllitol chemical compound or table-inositol chemical compound), and described preparation or dosage form provide the AUC of blood plasma to be about 20-600 μ g.h/ml, 50-600 μ g.h/ml, 100-600 μ g.h/ml, 100-300 μ g.h/ml, or100-250 μ g.h/ml, 15-125 μ g.h/ml or 20-135 μ g.h/ml, 80-270 μ g.h/ml, 80-200 μ g.h/ml, 80-150 μ g.h/ml, 80-125 μ g.h/ml or 80-100 μ g.h/ml.Also other aspect of the present invention relates to preparation or the dosage form that contains one or more cyclohexane polyalcohol chemical compounds (for example scyllitol chemical compound or table-inositol chemical compound), and described preparation or dosage form provide the AUC of CSF AUC for the blood plasma level of about 40-75%, 45-70%, 50-70%, 55-70%, 55-65%, or60-65%, preferred 30-60%.

Other aspects of the present invention relate to once a day or the preparation or the dosage form of twice administration, described preparation or dosage form comprise one or more cyclohexane polyalcohol chemical compounds (for example scyllitol chemical compound), and the peak concentration C that does not have the remarkable different chemical compound on the statistics with the peak concentration of the dosage form acquisition that (during 24 hours) are administered twice above with every day is provided _Max

Aspect other, the invention provides the preparation or the dosage form that comprise one or more cyclohexane polyalcohol chemical compounds (for example scyllitol chemical compound), described preparation or dosage form provide 1-100 hour, 1-80 hour, 1-70 hour, 1-50 hour, 1-42 hour, 1-33 hour or3-50,16-32,5-30 hour, 10-30 hour, 1-28 hour, 1-25 hour, 10-25 hour, 1-24 hour, 10-24 hour, 13-24 hour, 1-23 hour, 1-20 hour, 1-18 hour, 1-15 hour, 1-14 hour, 1-13 hour, 1-12 hour, 1-10 hour, 1-8 hour, 1-7 hour, 1-5 hour, 1-4 hour, the eliminating t of 1-3 hour or 3-5 hour _1/2

Aspect other, the invention provides the dosage form that is administered twice every day of comprising one or more cyclohexane polyalcohol chemical compounds (for example scyllitol chemical compound), described dosage form has the AUC of passing through _0-infMeasure, be at least 50%, 60%, 65%, 70%, 75%, 80%, 85% or 90% the relative bioavailability of bioavailability of single dosage forms every day, preferred every day single dosage forms 70%, 75%, 80%, 85% or 90% relative bioavailability of bioavailability.

Dosage form of the present invention and preparation can provide the release of the cyclohexane polyalcohol chemical compound that meets zero order kinetics, and promptly the blood plasma of chemical compound, brain and/or CSF level keep constant between whole delivery period, preferably the C of selection _MinOn.In one aspect, described dosage form is twice administration every day, and the C behind second dosage of administration _MinThe C that is higher than first dosage of administration _MinTherefore, dosage form, preparation and method can provide ring to make the peak value of chemical compound in blood plasma, brain or CSF and the zero level rate of release of the minimized hexane polyol compound of the difference between the peak valley.In one aspect, the invention provides the preparation or the dosage form that comprise one or more cyclohexane polyalcohol chemical compounds (for example scyllitol chemical compound), described preparation or dosage form produce the zero level release characteristic, in case reach steady state level, produce straight basically blood plasma, brain or the CSF level of chemical compound thus.

Zero level of the present invention or can reduce administration frequency near the zero level release dosage form is improved the consumption compliance with regard to individual.

The present invention relates to comprise the dosage form of cyclohexane polyalcohol chemical compound, described dosage form comprises first dosage and second dosage that is used for second time point administration during administration that is used in first time point administration during the administration, wherein said dosage form comprises the chemical compound of the amount that is enough to provide useful characteristics of pharmacokinetics, during administration, concentration or the peak concentration of chemical compound in blood plasma, brain or CSF significantly do not change thus.In one aspect, it is about 8,12,18,20,24 or 48 hours during the total administration.In the embodiment aspect this, second time point is behind first time point about 4-20 hour, 4-18 hour, 4-12 hour, 4-14 hour, especially 6-14,6-12,6-8,8-12 or 8-10 hour.On the other hand, at concentration among blood plasma, brain or CSFs or the peak concentration of second time point to the drug compound generation, compare with the concentration or the peak concentration of chemical compound in blood plasma, brain or CSF after first time point administration, do not have difference greater than 90%, 80%, 70%, 60%, 50%, 30%, 20%, 15%, 20%, 5% or 3%.In one aspect, favourable pharmacokinetics feature is the zero level release characteristic that does not have between first time point to the second time point of administration greater than about difference of 30%, 20%, 10% or 5%.In one aspect, the zero level release characteristic does not have greater than about difference of 20%, 10% or 5% between three time points of first time point to the, and described the 3rd time point is extremely at 2,4,6,8,10,12,14 or 16 hours behind second time point.In other respects, described chemical compound is a scyllitol.Aspect special, the dosage of chemical compound is about 1-100mg/kg, 1-90mg/kg, 1-80mg/kg, 1-70mg/kg, 1-60mg/kg, 1-50mg/kg, 1-40mg/kg, 2.5-40mg/kg, 3-40mg/kg, 3-35mg/kg or 3-30mg/kg.

The present invention relates to comprise the dosage form of cyclohexane polyalcohol chemical compound, described dosage form is used at first time point during the administration to individual administration be used for second time point during administration to individual administration, and wherein said dosage form comprises is enough to provide following C _MinThe chemical compound of dosage: the C in blood plasma, brain or CSF that after second time point, provides _MinGreater than the C after first time point _MinIn one aspect, the C behind second time point _MinThan the C behind first time point _MinHigh by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80% or 90%.In one aspect, it is about 8,12,18,20,24 or 48 hours during the total administration.In this working of an invention scheme, second time point is about 4-20 hour, 4-18 hour after the very first time, 4-14 hour, 4-12 hour, especially first time point 6-14,6-12,6-8,8-12 or 8-10 hour afterwards.In special embodiment, the dosage of chemical compound is about 1-100mg/kg, 1-90mg/kg, 1-80mg/kg, 1-70mg/kg, 1-60mg/kg, 1-50mg/kg, 1-40mg/kg, 2.5-40mg/kg, 3-40mg/kg, 3-35mg/kg or 3-30mg/kg.In the embodiment aspect this of the present invention, can be after second time point, especially after second time point 1,2,3,4,5,6,7 or more days, the cyclohexane polyalcohol chemical compound is regularly delivered medicine to individuality, with in blood plasma, brain or CSF, provide basically with first time point after C _Min, the C behind the second preferably time point _MinIdentical C _Min

First time point and second time point of the present invention relates to during medication deliver medicine to the individual dosage form that contains the cyclohexane polyalcohol chemical compound, wherein this dosage form comprises the compound concentrations of enough keeping in the individuality, so that the C among blood, brain or the CSF behind second time point _MinBe higher than the C behind first time point _MinThe chemical compound of dosage.In one aspect, the C behind second time point _MinThan the C behind first time point _MinHigh by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, or90%.In one aspect, it is about 8,12,18,20,24 or 48 hours during total administration.In the embodiment aspect this, second time point is about 4-20 hour, 4-18 hour after first time point, 4-14 hour, 4-12 hour, especially 6-14,6-12,6-8,8-12 or 8-10 hour.Aspect special, the dosage of chemical compound is about 1-100mg/kg, 1-90mg/kg, 1-80mg/kg, 1-70mg/kg, 1-60mg/kg, 1-50mg/kg, 1-40mg/kg, 2.5-40mg/kg, 3-40mg/kg, 3-35mg/kg or 3-30mg/kg.In the embodiment in this aspect of the invention, can be after second time point, especially after second time point 1,2,3,4,5,6,7 or more days, the cyclohexane polyalcohol chemical compound is regularly delivered medicine to individuality, so as with in blood plasma, brain or CSF, provide basically with first time point after C _Min, the C behind the second preferably time point _MinIdentical C _Min

The present invention relates to be suitable for once a day or the oral formulations of twice administration every day, preferred twice administration every day obtains to have the preparation or the dosage form of favourable pharmacokinetics feature by administration, described preparation or dosage form comprise usually cyclohexane polyalcohol chemical compound, scyllitol chemical compound or table-inositol chemical compound that the amount with the cyclohexane polyalcohol chemical compound that is enough to provide required blood plasma, brain and/or CSF drug level or required dosage (for example daily dose) exists, so that described preparation performance dissolution in vitro feature favourable or that improve.

In one aspect, the following dissolution in vitro feature of preparation or dosage form performance:

A) after measuring 3 hours, be released about 15%-about 30% of whole chemical compounds approximately;

B) after measuring 9 hours, discharged about 50%-about 70% of whole chemical compounds;

C) after measuring 12 hours, discharged about 65%-about 95% of whole chemical compounds; And

D) after measuring 18 hours, at least 88% of whole chemical compounds have been discharged.

In one aspect, the following dissolution in vitro feature of preparation or dosage form performance:

A) mensuration discharged about 15% about 25% of whole chemical compounds after 3 hours in instrument;

B) mensuration discharged about 45%-about 69% of whole chemical compounds after 9 hours in instrument;

C) mensuration discharged about 59%-90% of whole chemical compounds after 12 hours in instrument; And

D) mensuration discharged at least 90% of whole chemical compounds after 18 hours in instrument.

In one aspect, the following dissolution in vitro feature of preparation or dosage form performance:

A) after measuring 3 hours, discharged about 35%-50% of whole chemical compounds;

B) after measuring 9 hours, about 70% of whole chemical compounds have been discharged;

C) after measuring 12 hours, discharged about 80%-90% of whole chemical compounds; And

D) after measuring 18 hours, whole chemical compounds at least 99% have been discharged.

One aspect of the present invention relates to qd or the bid dosage form with dissolving characteristic disclosed herein.A kind of dosage form of the present invention also can produce cyclohexane polyalcohol chemical compound, especially whole absorptions of scyllitol chemical compound.

Another aspect of the present invention provides and comprises so that the cyclohexane polyalcohol chemical compound to be provided: the amyloid peptide is the dosage form of the cyclohexane polyalcohol chemical compound that exists of the amount of the stoichiometric relationship of about 40:1,35:1,30:1,25:1,20:1 or 15:1, preferred 25:1.

A kind of dosage form of the present invention or preparation can be immediate release dosage form or non-release delivery system immediately, include but not limited to that time-delay discharges or sustained release forms.Especially, this dosage form or preparation can show time-delay release release immediately or lasting release then.

Therefore, the invention provides the sustained release forms of cyclohexane polyalcohol compound or pharmaceutically acceptable salt thereof, described dosage form advantageously realizes more lasting medicine blood plasma, brain or the reaction of CSF level, simultaneously by along with the stable cyclohexane polyalcohol chemical compound that discharges of providing in the past basically of time, alleviate or eliminate the drug level peak.

In one aspect, lasting liberation port oral dosage form is provided, described lasting liberation port oral dosage form discharges chemical compound with the rate of release that is provided at substantial constant during the administration, produces the amount of the chemical compound plasma concentration of substantial constant, comprises one or more cyclohexane extraction, scyllitol chemical compound especially.The plasma concentration of substantial constant preferably has relation with one or more therapeutic effect disclosed herein.In embodiments, this plasma concentration is about 1-125 μ g/ml, 1-100 μ g/ml, 1-90 μ g/ml, 1-80 μ g/ml, 1-70 μ g/ml, 1-60 μ g/ml, 1-50 μ g/ml, 1-40 μ g/ml, 1-30 μ g/ml, 1-20 μ g/ml, 1-10 μ g/ml, 1-5 μ g/ml, 5-125 μ g/ml, 5-100 μ g/ml, 5-70 μ g/ml, 5-50 μ g/ml, 10-100 μ g/ml, 10-90 μ g/ml, 10-80 μ g/ml, 10-70 μ g/ml, 10-60 μ g/ml, 10-50 μ g/ml, 10-40 μ g/ml, 10-30 μ g/ml or 10-20 μ g/ml.In special embodiment, this plasma concentration is about 5-70 μ g/ml, 5-65 μ g/ml, 5-50 μ g/ml, 5-40 μ g/ml, 5-30 μ g/ml or 5-20 μ g/ml.

On the other hand, provide and continue the liberation port oral dosage form, described oral release dosage form discharges chemical compound with the rate of release that is provided at substantial constant during the administration, produces the chemical compound brain of substantial constant or the amount of CSF concentration, comprises one or more cyclohexane extraction, scyllitol chemical compound especially.The CSF concentration of substantial constant preferably has relation with one or more therapeutical effect disclosed herein, i.e. the therapeutic effect of chemical compound substantial constant during prolonged treatment.

In the embodiment that continues the liberation port oral dosage form, this dosage form provides about 1-125 μ g/ml, 1-100 μ g/ml, 1-90 μ g/ml, 1-80 μ g/ml, 1-70 μ g/ml, 1-60 μ g/ml, 1-50 μ g/ml, 1-40 μ g/ml, 1-30 μ g/ml, 1-20 μ g/ml, 1-10 μ g/ml, 1-5 μ g/ml, 5-125 μ g/ml, 5-100 μ g/ml, 5-70 μ g/ml, 5-50 μ g/ml, 10-100 μ g/ml, 10-90 μ/ml, 10-80 μ g/ml, 10-70 μ g/ml, 10-60 μ g/ml, 10-50 μ g/ml, 10-40 μ g/ml, the CSF concentration of 10-30 μ g/ml or 10-20 μ g/ml.

In the embodiment of the peroral dosage form that continues to discharge, this dosage form provides about 1-125 μ g/ml, 1-100 μ g/ml, 1-90 μ g/ml, 1-80 μ g/ml, 1-70 μ g/ml, 1-60 μ g/ml, 1-50 μ g/ml, 1-40 μ g/ml, 1-30 μ g/ml, 1-20 μ g/ml, 1-10 μ g/ml, 1-5 μ g/ml, 5-125 μ g/ml, 5-100 μ g/ml, 5-70 μ g/ml, 5-50 μ g/ml, 10-100 μ g/ml, 10-90 μ g/ml, 10-80 μ g/ml, 10-70 μ g/ml, 10-60 μ g/ml, 10-50 μ g/ml, 10-40 μ g/ml, the concentration of chemical compound in brain of 10-30 μ g/ml or 10-20 μ g/ml.

In the special embodiment of sustained release forms, this dosage form provides about 1-125 μ g/ml, 1-100 μ g/ml, 1-90 μ g/ml, 1-80 μ g/ml, 1-70 μ g/ml, 1-60 μ g/ml, 1-50 μ g/ml, 1-40 μ g/ml, 1-30 μ g/ml, 1-20 μ g/ml, 1-10 μ g/ml, 1-5 μ g/ml, 5-125 μ g/ml, 5-100 μ g/ml, 5-70 μ g/ml, 5-50 μ g/ml, 10-100 μ g/ml, 10-90 μ g/ml, 10-80 μ g/ml, 10-70 μ g/ml, 10-60 μ g/ml, 10-50 μ g/ml, 10-40 μ g/ml, the C of 10-30 μ g/ml or 10-20 μ g/ml _MaxIn special embodiment, C _MaxBe about 5-70 μ g/ml, 5-65 μ g/ml, 5-50 μ g/ml, 5-40 μ g/ml, 5-30 μ g/ml or 5-20 μ g/ml.

On the other hand, the present invention relates to be suitable for the sustained release forms that administration for example is administered orally in individual especially mammiferous Hexalin, described sustained release forms produces the highest cyclohexane polyalcohol Compound C SF concentration C _Max, it is less than the C that measures when the chemical compound of individual equal dose with the form administration of immediate release formulation _MaxAbout 95%, 90%, 85%, 80% or 75%.

Aspect other, the invention provides and be suitable for the sustained release forms that administration for example is administered orally in individual especially mammiferous Hexalin, described sustained release forms produces the highest cyclohexane polyalcohol chemical compound plasma concentration C _Max, it is less than the C that measures when the chemical compound of individual equal dose with the form administration of immediate release formulation _MaxAbout 95%, 90%, 85%, 80% or 75%.

In one embodiment, in picked-up and with 0.01-50mgA/hr at least, 0.1-50mgA/hr, 0.1-40mgA/hr, 0.1-35mgA/hr, 0.1-30mgA/hr, 0.1-20mgA/hr, 0.1-10mgA/hr, 0.1-5mgA/hr, 1-50mgA/hr, 1-40mgA/hr, 1-35mgA/hr, 1-30mgA/hr, 1-20mgA/hr, 1-10mgA/hr, 1-5mgA/hr, 2-50mgA/hr, 2-40mgA/hr, 2-35mgA/hr, 2-30mgA/hr, 2-20mgA/hr, 2-10mgA/hr, 2-5mgA/hr, 3-50mgA/hr, 3-40mgA/hr, 3-35mgA/hr, 3-30mgA/hr, 3-20mgA/hr, 3-10mgA/hr, 3-5mgA/hr, 1-3mgA/hr, 0.1-30mgA/hr speed, preferably to be no more than 0.01,0.1,1,2,3,4,5,10,15,20,25,30 or the speed of 35mgA/hr, more preferably to be no more than 20,25 or the speed of 30mgA/hr discharge in first hour after the chemical compound, sustained release forms discharges the cyclohexane polyalcohol chemical compound that is no more than about 70% or 80% weight.

Aspect of the present invention relates to the cyclohexane polyalcohol chemical compound is discharged into environment for use (blood plasma for example, brain or CSF) in dosage form, condition is that this dosage form (1) is after entering environment for use in first hour, release is no more than about 70%, the wherein contained cyclohexane polyalcohol chemical compound of 80% or 90% weight, (2) with at least about 0.01-40mgA/hr, 0.1-40mgA/hr, 1-40mgA/hr, 2-40mgA/hr, 3-40mgA/hr, 3-40mgA/hr, 3-35mgA/hr, 3-30mgA/hr, 3-20mgA/hr, 3-10mgA/hr, 3-5mgA/hr, 1-3mgA/hr, 0.1-30mgA/hr speed, preferably to be no more than 3,5,10,15,20,25,30 or the speed of 35mgA/hr, more preferably no more than 20,25 or the speed of 30mgA/hr, discharge the cyclohexane polyalcohol chemical compound.

The low velocity that is particularly useful for the light and/or auld patient's of body weight cyclohexane polyalcohol chemical compound discharges and belongs within the scope of the invention.Therefore, the representative of picked-up back about 1,2,3,5,10,15,20,25,30 or 35mgA/hr cyclohexane polyalcohol chemical compound rate of release belong to embodiment of the present invention within feature.Before dosage form was eliminated, this speed can be enough to the cyclohexane polyalcohol chemical compound of delivery treatments q.s.Therefore, in one embodiment, dosage form of the present invention with at least about 3,5,10,15,20,25 or the speed of 30mgA/hr discharge the cyclohexane polyalcohol chemical compound.

The invention provides and be applicable to that administration for example is administered orally in the sustained release forms of individual especially mammiferous cyclohexane polyalcohol chemical compound, described sustained release forms produces the highest cyclohexane polyalcohol chemical compound blood plasma or CSF concentration C _Max, it is less than the C that measures with the cyclohexane polyalcohol chemical compound of the form administration mammal equal dose of releasing pattern dosage form immediately the time _MaxAbout 80%.In one embodiment, the dosage form (1) that continue to discharge discharges the wherein contained cyclohexane polyalcohol chemical compound that is no more than about 70%, 80% or 90% weight in first hour after picked-up, and (2) are with at least about 3,5,10,15,20,25,30 or the speed release cyclohexane polyalcohol chemical compound of 35mgA/hr.

In one aspect, the present invention continued to discharge the cyclohexane polyalcohol compound dosage forms in 24 hours, preferably in 18 hours, more preferably be selected in 16 hours, in 8 hours or in 6 hours, discharge its contained cyclohexane polyalcohol chemical compound at least about 60%, 70%, 80% or 90% weight.In other respects, dosage form of the present invention before 24 hours be no more than about 3,5,10,15,20,25,30 or the speed of 35mgA/hr discharge all its cyclohexane polyalcohol chemical compounds.

In one aspect, sustained release cyclohexane polyalcohol chemical compound every day of the present invention twice dosage form, in 4 hours, preferably in 6 hours, most preferably in 8 hours, discharge its contained cyclohexane polyalcohol chemical compound at least about 70%, 80% or 90% weight.

In one embodiment, the invention provides the sustained release forms that is suitable for being administered orally in mammiferous cyclohexane polyalcohol chemical compound, described sustained release forms is once a day or twice, during preferred every day twice administration, produce about 1-125 μ g/ml, 1-100 μ g/ml, 1-90 μ g/ml, 1-80 μ g/ml, 1-70 μ g/ml, 1-60 μ g/ml, 1-50 μ g/ml, 1-40 μ g/ml, 1-30 μ g/ml, 1-20 μ g/ml, 1-10 μ g/ml, 1-5 μ g/ml, 5-125 μ g/ml, 5-100 μ g/ml, 5-70 μ g/ml, 5-50 μ g/ml, 10-100 μ g/ml, 10-90 μ g/ml, 10-80 μ g/ml, 10-70 μ g/ml, 10-60 μ g/ml, 10-50 μ g/ml, 10-40 μ g/ml, the highest cyclohexane extraction polyol compound plasma concentration C of 10-30 μ g/ml or 10-20 μ g/ml _MaxIn special embodiment, this C _MaxBe about 5-70 μ g/ml, 5-65 μ g/ml, 5-50 μ g/ml, 5-40 μ g/ml, 5-30 μ g/ml or 5-20 μ g/ml.

In one embodiment, the invention provides the dosage form of the lasting release that is suitable for being administered orally in mammiferous cyclohexane polyalcohol chemical compound, described sustained release forms is once a day or twice, during preferred every day twice administration, produce about 1-125 μ g/ml, 1-100 μ g/ml, 1-90 μ g/ml, 1-80 μ g/ml, 1-70 μ g/ml, 1-60 μ g/ml, 1-50 μ g/ml, 1-40 μ g/ml, 1-30 μ g/ml, 1-20 μ g/ml, 1-10 μ g/ml, 1-5 μ g/ml, 5-125 μ g/ml, 5-100 μ g/ml, 5-70 μ g/ml, 5-50 μ g/ml, 10-100 μ g/ml, 10-90 μ g/ml, 10-80 μ g/ml, 10-70 μ g/ml, 10-60 μ g/ml, 10-50 μ g/ml, 10-40 μ g/ml, 10-30 μ g/ml, the highest cyclohexane extraction polyol compound CSF concentration C of or10-20 μ g/ml _Max

In another embodiment, the invention provides the sustained release forms that is suitable for being administered orally in mammiferous cyclohexane polyalcohol chemical compound, described sustained release forms is once a day or twice, during preferred every day twice administration, produce about 1-125 μ g/ml, 1-100 μ g/ml, 1-90 μ g/ml, 1-80 μ g/ml, 1-70 μ g/ml, 1-60 μ g/ml, 1-50 μ g/ml, 1-40 μ g/ml, 1-30 μ g/ml, 1-20 μ g/ml, 1-10 μ g/ml, 1-5 μ g/ml, 5-125 μ g/ml, 5-100 μ g/ml, 5-70 μ g/ml, 5-50 μ g/ml, 10-100 μ g/ml, 10-90 μ g/ml, 10-80 μ g/ml, 10-70 μ g/ml, 10-60 μ g/ml, 10-50 μ g/ml, 10-40 μ g/ml, the highest cyclohexane extraction polyol compound plasma concentration C of 10-30 μ g/ml or 10-20 μ g/ml _MaxIn particularly preferred embodiments, the cyclohexane polyalcohol chemical compound discharges at 4-12,6-12 or during 8-12 hour.

In another embodiment, the invention provides and be suitable for being administered orally in mammiferous cyclohexane polyalcohol chemical compound sustained release forms, described sustained release forms is once a day or twice, during preferred every day twice administration, produce about 1-125 μ g/ml, 1-100 μ g/ml, 1-90 μ g/ml, 1-80 μ g/ml, 1-70 μ g/ml, 1-60 μ g/ml, 1-50 μ g/ml, 1-40 μ g/ml, 1-30 μ g/ml, 1-20 μ g/ml, 1-10 μ g/ml, 1-5 μ g/ml, 5-125 μ g/ml, 5-100 μ g/ml, 5-70 μ g/ml, 5-50 μ g/ml, 10-100 μ g/ml, 10-90 μ g/ml, 10-80 μ g/ml, 10-70 μ g/ml, 10-60 μ g/ml, 10-50 μ g/ml, 10-40 μ g/ml, the highest cyclohexane extraction polyol compound CSF concentration C of 10-30 μ g/ml or 10-20 μ g/ml _MaxIn special embodiment, the cyclohexane polyalcohol chemical compound discharges at 4-12,6-12 or during 8-12 hour.

In another embodiment, the invention provides and be suitable for being administered orally in mammiferous cyclohexane polyalcohol chemical compound sustained release forms, the highest cyclohexane extraction polyol compound plasma concentration C of the about 125 μ g/ml of the described sustained release forms about 5-of generation, the about 100 μ g/ml of 5-, the about 70 μ g/ml of 5-, the about 50 μ g/ml of 5-, the about 120 μ g/ml of 10-, the about 100 μ g/ml of 10-, the about 90 μ g/ml of 10-, the about 80 μ g/ml of 10-, the about 70 μ g/ml of 10-, the about 50 μ g/ml of 10-or the about 40 μ g/ml of 10- _Max, wherein at C _MaxBlood plasma level be no more than the twice of the blood plasma level of administration after 24 hours.

Aspect more of the present invention, with respect to the C of the immediate release dosage form that contains equal quantities cyclohexane polyalcohol chemical compound _Max, continue to discharge the C that the cyclohexane polyalcohol compound dosage forms provides reduction _MaxAspect special, sustained release forms shows C _Max, it is less than or equal to the C that the cyclohexane polyalcohol chemical compound by the equal quantities in immediate release dosage form provides _MaxAbout 70%, 75%, 80%, 85% or 90%.

Dosage form of the present invention can provide total blood substance to expose in addition, and it with respect to the cyclohexane polyalcohol chemical compound of the equal quantities in the immediate release dosage form, does not have image persistence to discharge C _MaxReduce pro rata like that muchly.In one embodiment, continue to discharge cyclohexane polyalcohol compound dosage forms performance C _Max, it is served as reasons and discharges the C that the cyclohexane polyalcohol compound dosage forms produces immediately _Max50%, 55%, 60%, 65% or 70%, and performance AUC, it is higher than 60%, 65%, 70%, 75% or 80% of the AUC that produced by immediate release dosage form.

Dosage form or preparation can adopt any form that is suitable for the administration individuality, include but not limited to be suitable for the form of oral, parenteral, vein (intravenous injection or transfusion), intraperitoneal, subcutaneous or intramuscular administration.Dosage form or preparation can adopt the form by individuality consumption, the powder of pill, tablet, capsule sheet, soft or hard gelatin capsule, lozenge, pouch, cachet, vegicap, drop agent, elixir, suspension liquor, emulsion agent, solution, syrup, aerosol (is medium with solid or liquid), suppository, aseptic parenteral solution and/or aseptic packaging for example, be used to suppress that amyloid forms, deposition, build up and/or lasting, no matter its clinical setting.

In one aspect of the invention, dosage form or preparation are oral formulations or dosage form, include but not limited to tablet, capsule sheet, soft or hard gelatin capsule, pill, powder agent, granule, elixir, tincture, suspension liquor, syrup and emulsion agent.In another aspect of this invention, dosage form or preparation parenteral dosage forms include but not limited to the active substance in sterilized water or nonaqueous solvent, for example water, etc. open saline, etc. ooze glucose solution, buffer solution or other conveniently are used for the solvent of parenteral.

Aspect more of the present invention, dosage form is the tablet that comprises compressed tablets, coated tablet, osmotic tablet and other tablets known in the art.In other aspects of the present invention, dosage form is a capsule well-known in the art.Of the present invention also aspect other, dosage form is the alkyl that comprises little, round solid dosage forms, described solid dosage forms comprise with the microgranule of bonding agent and other mixed with excipients [referring to for example received text, in Remington:The Science and Practiceof Pharmacy (21 ^StEdition.2005, University of the Sciences in Philadelphia (Editor), Mack Publishing Company), and in The United StatesPharmacopeia:The National Formulary (USP 24 NF19) published in1999.]

Can prepare the dosage form or the preparation of the pharmacokinetics feature that produces favourable pharmacokinetics feature, especially continues by suitable method known in the art.For example, solid drug administration oral administration immediate release dosage form is by Cima Labs, Fuisz Technologies Ltd., and Prographarm, R.P.Scherer, and Yamanouchi-Shaklee sells.Sustained release forms can use and include but not limited to that disclosed standard technique prepares in the following document: the U.S. Patent No. 5,980,942 of authorizing people such as Katzhendler; Development of aControlled Release Matrix Tablet Containing a Water-Soluble DrugUtilizing Hypromellose and Ethyl cellulose.Dasbach, people such as T, The DowChemical Company, Midland, Mich.48674; The Effect of ProcessConditions on Various Sustained Release Formulations During WetGranulation.Inbasekaran P.and Balwinski, K.The Dow ChemicalCompany, Midland, Mich.48674; Direct Compression ofSustained-Release Hydrophilic Matrix Tablets Containing Hypromelloseand MCC:Effects of a Lubricant T.D.Cabelka Technical Service andDevelopment for METHOCEL Cellulose Ethers Larkin Laboratory, TheDow Chemical Company, Midland, Mich.48674 USA; And, Lab-Scaleto Full Production Scale Evaluation of a Controlled-Release FormulationBased on Hypromellose and Manufactured Using Roll CompactionTechnology Sheskeyl, P. wait the people, The Dow Chemical Company LarkinLaboratory Midland, Mich.48674.2 The Vector Corporation Marion, Iowa52302.

Dosage form of the present invention or preparation comprise the not effect or the activity of interferon activity component usually, and for the nontoxic pharmaceutically suitable carrier of patient, diluent or excipient.Carrier, excipient or delivery materials include but not limited to diluent, bonding agent, binding agent, lubricant, disintegrating agent, extender, wetting agent or emulsifying agent, pH buffer agent, and buffer agent, and multiple material absorbent for example, need described material so that preparation or send preparation or the dosage form that favourable pharmacokinetics feature is provided.The case description of suitable carrier, diluent or excipient is as follows.

The diluent that is used to prepare dosage form of the present invention or preparation comprise microcrystalline Cellulose (AvicelFMC Corp. for example, Philadelphia, Pa.), for example to wherein adding for example various microcrystalline Cellulose of HYDROXY PROPYL METHYLCELLULOSE of bonding agent, wax is paraffin for example, modified vegetable oil, palm wax, hydrogenated castor wet goods, and polymer cellulose for example, cellulose esters, cellulose ether, poly-(vinyl chloride), poly-(vinyl acetate), the copolymer of vinyl acetate and ethylene, polystyrene etc.Aspect more of the present invention, the about 200 μ m of the little about 90 μ m-of the average particle size of microcrystalline Cellulose.Microcrystalline Cellulose can the about 70wt% of about 10wt%-amount, especially the amount with about 30-70wt% exists.

Dosage form of the present invention or preparation can be chosen wantonly and comprise water solublity bonding agent or release regulator, comprise sugar, salt, water-soluble polymer, cellulose ethyl cellulose for example for example, hydroxy-methyl cellulose, hydroxy propyl cellulose (HPC), HYDROXY PROPYL METHYLCELLULOSE HPMC), methylcellulose, gather (N-vinyl-2-Pyrrolidone) (PVP), gather (oxirane) (PEO), polypropylpyrrolidone, gather (vinyl alcohol) (PVA), Polyethylene Glycol, starch, natural and paragutta (arabic gum for example, alginic acid ester, and wax and arabic gum) and other so natural and synthetic materials.Suitable water-soluble material comprises lactose, sucrose, glucose and mannitol, and HPC, HPMC; And PVP.

The dosage form of the present invention of tablet form or preparation can be chosen wantonly and comprise lubricant and be bonded in the mould to prevent tablet or drift.The example of lubricant comprises calcium stearate, glyceryl monostearate, palmitic acid stearic acid ester of glycerol (glyceryl palmitostearate), hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, Polyethylene Glycol, sodium benzoate, sodium lauryl sulfate, octadecyl fumaric acid acid sodium, stearic acid, Talcum and zinc stearate.Lubricant exists with for example amount of the about 4.0%wt% of about 0.25wt%-.

The optional disintegrating agent that comprises of dosage form of the present invention or preparation is to dismiss dosage form and to discharge the cyclopolyol chemical compound.The example of disintegrating agent comprises hydroxy propyl cellulose, polacrilin potassium, starch, pregelatinized starch and the sodium alginate of sodium starch glycollate, sodium carboxy methyl cellulose, carboxy methyl cellulose calcium, cross-linked carboxymethyl cellulose sodium, polyvinyl pyrrolidone, methylcellulose, microcrystalline Cellulose, cellulose powder, low alkyl group-replacement.The amount of the disintegrating agent that comprises in the dosage form will depend on the factor of the characteristic that comprises dispersion characteristic and selected disintegrating agent.Disintegrating agent can comprise the 1wt%-15wt% of dosage form, preferred 1wt%-10wt% usually.

Dosage form of the present invention or preparation can be chosen wantonly and comprise the acid excipient of solubilising, to improve the rate of release of cyclohexane polyalcohol chemical compound, improve the total amount of the cyclohexane polyalcohol chemical compound that is discharged, and potential raising absorbs and therefore improves the bioavailability of cyclohexane polyalcohol chemical compound, especially from discharging the matrix preparation of cyclohexane polyalcohol chemical compound at six hours or longer time durations.The example of the acid excipient of solubilising comprises malic acid, citric acid, arabo-ascorbic acid, ascorbic acid, adipic acid, glutamic acid, maleic acid, equisetic acid and aspartic acid, and lyotropy the excipient for example copolymer and the Polyethylene Glycol of partial glyceride, glyceride, glyceride ester derivatives, macrogol ester, polypropylene glycol ester, polyhydroxy alkyl ester, polyoxyethylene ether, sorbitan ester, polyoxyethylene sorbitol acid anhydride ester, saccharide ester, phospholipid, poly(ethylene oxide)-poly(propylene oxide) block.

The dosage form that the present invention continues to discharge can be chosen wantonly and comprise reduced carbohydrate.Reduced carbohydrate normally contains can be by electronation and as the sugar and the derivant thereof of the free aldehydes or ketones base of Reducing agent.Suitable reduced carbohydrate comprises monosaccharide and disaccharide, and more particularly comprises similarly sugar of lactose, glucose, fructose, maltose and other.Dosage form or preparation can comprise to the reduced carbohydrate of 20% weight of saving your breath.

The excipient that can be used for dosage form of the present invention or preparation comprises starch, mannitol, Kaolin, calcium sulfate, inorganic salt (for example sodium chloride), cellulose powder derivant, tricalcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, poloxamer for example poly(ethylene oxide) and HYDROXY PROPYL METHYLCELLULOSE.

Dosage form of the present invention or preparation can also be included in the aqueous medium solvable and be thermoplastic polymer, i.e. the sustained release component of polymer-matrix.The example of such polymer comprises cellulose ether for example cellulose acetate, cellulose propionate, cellulose butyrate, cellulose acetate-butyrate, ethyl cellulose, HYDROXY PROPYL METHYLCELLULOSE etc.

The strategy of realizing the lasting release of hexane polyol compound is known in the art, and include but not limited to diffusion system (for example bank device and matrix device), for example encapsulated decomposing system of decomposing system (for example small timing pill) and substrate decomposing system, unite diffusion/decomposing system, osmosis system and at received text, Remington:The Science and Practiceof Pharmacy (21 ^StEdition.2005, University of the Sciences in Philadelphia (Editor), Mack Publishing Company) the middle exchange of particles resin system of describing.

One class sustained release forms comprises having or do not have granose tablet.Tablet can comprise the many granules with binding agent, disintegrating agent or other mixed with excipients known in the art, and uses compression stress that it is formed tablet afterwards.Suitable bonding comprises microcrystalline Cellulose, starch, and gelatin, polyvinylpyrrolidone, Polyethylene Glycol and sugar is sucrose, glucose, glucose and lactose for example.Suitable disintegrants comprises sodium starch glycolate, cross-linking sodium carboxymethyl cellulose, polyvidone and sodium carboxymethyl cellulose.In one embodiment, tablet comprises effervescent (Acid-Base combination), and it produces carbon dioxide after administration, to help disintegration of tablet.Before forming tablet, many granules, binding agent and other excipient can be granulated.Can use well-known wet method or dry granulation method, direct compression or non-compression method prepare many granules tablet.

Sustained release forms can be capsule form, and described capsule comprises solid dosage forms, and wherein many granules and optional excipient are included in hard or soft the solubility container or shell." capsule " also comprises dosage form, and wherein during being present in environment for use, the dosage form body is kept perfectly basically.After the administration, capsular shell is dissolving or disintegrate usually, the inclusions of release capsule.Can use method well-known in the art to produce capsule.

Sustained release forms can also be the form of pill, promptly comprises the granose little rounded solid dosage form with binding agent and other mixed with excipients.After administration, the pill disintegrate makes many Dispersion of Particles in wherein.Can use method well-known in the art to prepare pill.

The multicompartment dosage form

In one embodiment, the invention provides many particle modifications release composition, described compositions is sent the cyclohexane polyalcohol chemical compound with pulse mode, so that the blood plasma feature of the immediate release dosage form that is similar to first post dose to be provided.

In another embodiment, the invention provides many particle modifications release composition, described compositions is sent the cyclohexane polyalcohol chemical compound in a continuous manner.

In another embodiment, the invention provides many particle modifications release composition, wherein first's cyclohexane polyalcohol chemical compound discharges after administration immediately, and the cyclohexane polyalcohol chemical compound of one or more further parts postpones back release at initial time.

In one embodiment, the invention provides many particle modifications release composition, wherein granule can contain modification release coating as required and/or modify release matrix materials.

According to an aspect of the present invention, pharmaceutical composition is provided, described pharmaceutical composition has first assembly, described first assembly comprises the granule that contains active component, comprise the particulate subsequent components that contains active component with at least one, each subsequent components has rate of release and/or the persistent period different with first assembly, and wherein at least one described assembly comprises the granule that contains the cyclohexane polyalcohol chemical compound.The granule that contains medicine can be with modifying the release coating material coating.Alternately or in addition, the granule that contains medicine can comprise the modification release matrix materials.Behind the oral administration, compositions is sent the cyclohexane polyalcohol chemical compound with pulse mode.In one embodiment, first assembly provides the release immediately of cyclohexane polyalcohol chemical compound, and one or more subsequent components provide the lasting release of cyclohexane polyalcohol chemical compound.In such embodiments.Promptly release the assembly role and be by will adding fastoperation, and one or more subsequent components role is minimum to be reduced in the variation of plasma concentration level and/or keep treatment effective plasma level concentration during dosing interval from the time minimization that is administered between the treatment effective plasma level concentration level.

Modify to discharge coating and/or modify release matrix materials and can cause that active component discharges with active component contain the time delay between the release the granule of active component from the granule of active component is contained in first colony from follow-up colony.When the granule that contains active component of an above colony provided modification to discharge, modification discharged coating and/or modifies release matrix materials and can cause that active component is from the time delay between the particle release that contains active component of different colonies.The persistent period of these time delays can change by changing the composition and/or the amount of modifying composition and/or the amount that discharges coating and/or changing used modification release matrix materials.Therefore, the persistent period that can design time delay simulate required blood plasma feature for example from immediate release formulations every day twice administration feature.

Because the blood plasma feature that produces by modified release composition after administration is substantially similar to the blood plasma feature that is produced by giving two or more immediate release dosage form in proper order, modified release composition of the present invention can be used in particular for administration cyclohexane polyalcohol chemical compound.Therefore, in another aspect of the present invention, designed compositions and produced the blood plasma feature, described blood plasma feature reduces to minimum or elimination with giving the relevant plasma concentration level change of two or more immediate release dosage forms with order.In such embodiments, compositions can be provided, described compositions has promptly releases assembly with by adding fastoperation from the time minimization that is administered between the treatment effective plasma level concentration level, modify releasing unit to keep continuing release characteristic with at least one, during dosing interval, also have treatment effective plasma level concentration level.

Active component in each assembly can be identical or different.For example, compositions can comprise and only comprises the assembly of cyclohexane polyalcohol chemical compound as active component.Perhaps, compositions can comprise first assembly that contains the cyclohexane polyalcohol chemical compound, and comprise at least one subsequent components with the active component of cyclohexane polyalcohol chemical compound administering drug combinations of being suitable for except the cyclohexane polyalcohol chemical compound, perhaps contain first assembly of the active component except the cyclohexane polyalcohol chemical compound, and at least one subsequent components that comprises the cyclohexane polyalcohol chemical compound.When active component is compatible with each other, two or more active components can be incorporated in the same assembly.The active component that is present in the assembly of compositions can be followed for example reinforcing agent chemical compound in another assembly of compositions or enhanced sensitivity chemical compound, to modify its bioavailability or curative effect.

Term used herein " reinforcing agent " is meant such chemical compound, and it can be by promoting for example to cross absorption and/or the bioavailability that the clean transhipment of gastrointestinal improves active component among the people animal.Reinforcing agent includes but not limited to: medium-chain fatty acid, its salt, ester, ether and derivant comprise glyceride and triglyceride; Non-ionic surface active agent is those by ethylene oxide and fatty acid response are made for example, aliphatic alcohol, alkylphenol or fatty acid glyceride; Cytochrome P 450 inhibitors, P-glycoprotein inhibitors etc.; The mixture of the material that two or more are such.

Have the embodiment that contains the assembly of medicine more than therein, according to required dosage regimen, the ratio that is included in the cyclohexane polyalcohol chemical compound in each assembly can be identical or different.The cyclohexane polyalcohol chemical compound that is present in first assembly and the subsequent components can be to be enough to produce treatment effective plasma level concentration level, any amount of preferred constant level.

For cyclohexane polyalcohol chemical compound sending from each assembly, the time release characteristic can comprise that any excipient and/or coating that adjustment can exist change by adjusting the composition of each assembly.Particularly, if there is such coating, the release of cyclohexane polyalcohol chemical compound can be present in composition and/or the amount that modification on the granule discharges coating by change and control.If there is more than one decorative features assembly,, modify that to discharge coating can be identical or different then for each of these assemblies.Similarly, when helping modify when discharging by introduce modifying release matrix materials, the release that can control active component by the selection and the amount of used modification release matrix materials.Modify discharging coating can be present in each assembly with any amount of required time delay of being enough to produce each characteristics assembly.Modifying the release coating can be present in each assembly to be enough to any amount that required time lags behind between the generation component.

For the release of cyclohexane polyalcohol chemical compound from each assembly, lag time and/or time delay can also comprise that any excipient and coating that adjustment can exist change by adjusting the composition of each assembly.For example, first assembly can be promptly to release assembly, and wherein the cyclohexane polyalcohol chemical compound discharges after administration immediately.Second and subsequent components can be for example time delay promptly release assembly as mentioned above, perhaps, the lasting release of time delay or the releasing unit of prolongation, wherein the cyclohexane polyalcohol chemical compound discharges in the mode of control in the time durations that prolongs.

The definite character that it will be appreciated by those skilled in the art that the plasma concentration curve will influence by the combination of above-mentioned all of these factors taken together.Particularly, in containing each assembly of cyclohexane polyalcohol chemical compound, can control the lag time of sending and absorbing between the beginning of cyclohexane polyalcohol chemical compound by the composition and the coating (if having dialogue) that change each assembly.Therefore, the composition (amount and the character that comprise active component) by changing each assembly and by changing lag time can obtain multiple release and blood plasma feature.According to the persistent period of the lag time between the release of cyclohexane polyalcohol chemical compound from each assembly and cyclohexane polyalcohol chemical compound (promptly from the character of the release of each assembly, promptly release, continue to discharge etc.), the blood plasma feature can be successive (only promptly having a maximum) or pulsating, wherein the peak can be good separation and clear (for example when be length lag time) that limits or be superimposed to a certain degree (for example when be weak point lag time) in the blood plasma feature, is such situation for twice dosage regimen every day of immediate release dosage form.

Send the active component of two pulses when hope, when not needing simultaneously order to use two dosage units, the blood plasma feature that comprises the single dosage unit of the present composition from administration is favourable.

Can use any coating material of trimming loop hexane polyol compound release according to required mode.Particularly, be suitable for implementing coating material of the present invention and include but not limited to the polymer coating material, Cellacefate for example, acetic acid three maleic acid celluloses, Hydroxypropyl Methylcellulose Phathalate, polyvinyl acetate O-phthalic vinyl acetate, the ammonium methacrylate copolymer is for example with trade mark

Those that RS and RL sell, polyacrylic acid and polyacrylate and methacrylate copolymer are for example with trade mark

Those that S and L sell, polyvinyl acetal diethyl amino yl acetate, HPMC-AS, Lac; Hydrogel and gel formation material, CVP Carbopol ETD2050 for example, sodium alginate, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, carboxymethyl starch sodium, polyvinyl alcohol, hydroxyethyl-cellulose, methylcellulose, gelatin, starch, and based on the cellulose of cross linked polymer, wherein the degree of cross linking is low, absorbs and expansion hydroxypropyl cellulose with the water that promotes polymeric matrix, hydroxypropyl emthylcellulose, polyvinylpyrrolidone, crosslinked starch, microcrystalline Cellulose, chitin, aminoacrylic acid-methacrylate copolymer (

RS-PM, Rohm ﹠amp; Haas), amylopectin, collagen, casein, agar, Arab, sodium carboxymethyl cellulose (expandable hydrophilic polymer) gathers (methacrylic acid hydroxyl Arrcostab) (molecular weight～5k-5,000k), (molecular weight～10k-360k), anion and cationic water gel have the polyvinyl alcohol of low acetate ester residue to polyvinylpyrrolidone, the inflatable mixture of agar and carboxymethyl cellulose, maleic anhydride and styrene, ethylene, the copolymer of propylene or isobutene., (molecular weight～30k-300k), polysaccharide is agar for example for pectin, arabic gum, POLY-karaya, tragacanth, Algin, polyacrylamide

Polyethylene glycol oxide (molecular weight～100k-5,000k),

Acrylate polymer, the diester of glucosan, the pure and mild poly N-vinyl-2-Pyrrolidone of crosslinked polyethylene, the starch gluconic acid sodium salt is (for example

Edward Mandell C.Ltd.); Hydrophilic polymer is polysaccharide for example, methylcellulose, and sodium carboxymethyl cellulose or calcium, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, NC Nitroncellulose, carboxymethyl cellulose, cellulose ether, polyethylene glycol oxide are (for example

Union Carbide), methylethylcellulose, ethyl hydroxy ethyl cellulose, cellulose acetate, cellulose butyrate, cellulose propionate, gelatin, collagen, starch, maltodextrin, amylopectin, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, fatty acid glyceride, polyacrylamide, polyacrylic acid, with the copolymer of methacrylic acid, other acrylic acid derivatives, Isosorbide Dinitrate, natural gum, lecithin, pectin, alginate esters, ammonium alginate, sodium alginate, calcium alginate, potassium alginate, propylene glycol alginate, agar and natural gum is arabic gum for example, POLY-karaya, tracasol, tragacanth, carrageenin, guar gum, xanthan gum, sclerosis glucosan and composition thereof and blend.It will be appreciated by those skilled in the art that and in coating, to add excipient for example plasticizer, lubricant, solvent etc.Suitable manufacturing methods comprises for example acetylation monoglyceride; Glycolic butyl phthalyl butyl ester; Dibutyl tartrate; Diethyl phthalate; Dimethyl phthalate; Glycolic ethyl phthalyl ethyl ester; Glycerol; Propylene glycol; Glyceryl triacetate; Citrate; Tripropioin; Diacetin; Dibutyl phthalate; The acetyl group monoglyceride; Polyethylene Glycol; Oleum Ricini; Triethyl citrate; Polyhydric alcohol; Glycerol, acetas, glycerol triacetate, acetyl triethyl citrate; Dibenzyl phthalate, dihexylphthalate, the butyl phthalate monooctyl ester, diisononyl phthalate, butyl phthalate monooctyl ester, dioctyl azelate, epoxidized fatty acid ester, trimellitic acid three monooctyl esters, di (2-ethylhexyl) phthalate, dinoctyl phthalate, diisooctyl phthalate, diisooctyl phthalate, phthalic acid two n-undecane base esters, phthalic acid two n-tridecane base esters, trimellitic acid three-2-Octyl Nitrite, di-2-ethylhexyl adipate, Diisooctyl Sebacate, di 2-ethylhexyl azelate, dibutyl sebacate.

When the modification releasing unit comprises the modification release matrix materials, can use any suitable modification release matrix materials or the suitable combination of modification release matrix materials.Such material is well known by persons skilled in the art.Term described herein " modification release matrix materials " comprises hydrophilic polymer, hydrophobic polymer and composition thereof, and it can modify the release that is scattered in cyclohexane polyalcohol chemical compound wherein in external or body.Be suitable for implementing modification release matrix materials of the present invention and include but not limited to microcrystalline Cellulose, sodium carboxymethyl cellulose, hydroxy alkyl cellulose is hydroxypropyl emthylcellulose and hydroxypropyl cellulose for example, polyethylene glycol oxide, alkylcellulose is methylcellulose and ethyl cellulose for example, Polyethylene Glycol, polyvinylpyrrolidone, cellulose acetate, cellulose acetate-butyrate, Cellacefate, the inclined to one side benzene trimethyl cellulose of acetic acid, polyvinyl acetate O-phthalic vinyl acetate, polyalkyl methacrylate, polyvinyl acetate and composition thereof.

Modified release composition of the present invention can be incorporated in the dosage form of any appropriate, and described dosage form promotes that active component discharges with pulse mode.In one embodiment, dosage form comprises that formation promptly releases and modify the particulate mixture that contains active component of the different groups of releasing unit, and mixture is filled in for example hard or soft gelatine capsule of examples of suitable.Perhaps, the granule that contains active component (optional with other excipient) of different groups can be compressed into tabloid, tabloid can be filled in the capsule with suitable ratio subsequently.Another suitable dosage form is a multilayer tablet.In this case, first assembly of modified release composition can be compressed into one deck, afterwards the succeeding layer of subsequent components as multilayer tablet is added.The granule colony that constitutes the present composition may further include at Expidet for example in effervescent dosage form or the fast thawing dosage form.

In one embodiment, compositions comprises at least two assemblies that contain the cyclohexane polyalcohol chemical compound: first assembly and one or more subsequent components.In such embodiments, first assembly of compositions can show multiple release characteristic, comprise such feature, all the cyclohexane polyalcohol chemical compounds basically that wherein are included in first assembly all discharge rapidly after the dosage form administration, but after time delay, discharge (postponing to discharge) rapidly, perhaps along with the time discharges lentamente.In such embodiment, after to patient's administration, the cyclohexane polyalcohol chemical compound that is included in first assembly discharges rapidly." discharge rapidly " used herein comprises the release characteristic that the active component at least about 20%-60% of assembly wherein discharges in about 1 hour after administration, term " postpone discharge " comprises that wherein the active component of assembly discharges after the time delay release characteristic of (rapidly or lentamente), term " sustained release " and " prolong and discharge " comprise that wherein being included in the assembly is the release characteristic of slow release at least about the 40%-80% active component.

Second assembly of such embodiment can also show multiple different release characteristic, comprises promptly releasing feature, delay release characteristic or sustained release feature.In such embodiment, second component table reveals the delay release characteristic, and wherein the cyclohexane polyalcohol chemical compound is to discharge after time delay.

For such dosage form of the present invention, wherein said dosage form comprise contain the cyclohexane polyalcohol chemical compound promptly release assembly, or contain the microparticle of cyclohexane polyalcohol chemical compound, with at least one microparticle that contains the modification releasing unit of cyclohexane polyalcohol chemical compound or contain the cyclohexane polyalcohol chemical compound, the blood plasma feature that is produced by the described dosage form of the present invention of administration can be substantially similar to by giving the blood plasma feature that two or more IR dosage forms are produced in proper order, perhaps is similar to by administration independent IR and the modification blood plasma feature that release dosage form produced.Therefore, when keeping of pharmacokinetic parameters be wish but when complicated, dosage form of the present invention can be used in particular for administration cyclohexane polyalcohol chemical compound.

In one embodiment, compositions and the solid oral dosage form release cyclohexane polyalcohol chemical compound that contains compositions, all cyclohexane polyalcohol chemical compounds that are included in so basically in first assembly all discharged before the cyclohexane polyalcohol chemical compound discharges from least one subsequent components.When first assembly comprised the IR assembly, for example, preferably, the release of cyclohexane polyalcohol chemical compound from least one subsequent components was delayed, and all the cyclohexane polyalcohol chemical compounds basically in the IR assembly all discharge.The release of cyclohexane polyalcohol chemical compound from least one subsequent components can as above be described in detail, is delayed by using to modify to discharge coating and/or modify release matrix materials.

As described herein, the present invention also comprises various types of modification delivery systems, and by described delivery system, the cyclohexane polyalcohol chemical compound can be sent with pulsation or continuation mode.These systems include but not limited to: have the film of cyclohexane polyalcohol chemical compound or contain the microparticle of cyclohexane polyalcohol chemical compound, in polymeric matrix (single unit system); Wherein cyclohexane polyalcohol chemical compound or the microparticle that contains the cyclohexane polyalcohol chemical compound are aggregated system's (storage storehouse device) that thing comprises; The polymeric colloidal granule granule or the microcapsule (microparticle, microsphere or nano-particle) of storage storehouse and matrix means form; Wherein cyclohexane polyalcohol chemical compound or the microparticle that contains the cyclohexane polyalcohol chemical compound are aggregated the system that thing comprises, described polymer contains hydrophilic and/or can filter additive for example second polymer, surfactant or plasticizer etc., to form Multiple-Aperture Device, perhaps wherein the release of cyclohexane polyalcohol chemical compound can be the device (storage storehouse and matrix means) of infiltration control; Enteric coating (can in suitable pH ionizing and dissolving); (solubility) polymer with cyclohexane polyalcohol chemical compound of connection (covalently bound), and device, wherein rate of release is dynamically control: osmotic pumps for example.

It must be biocompatible being used for the lasting polymer that discharges coating, and is biodegradable reasoningly.The example of naturally occurring polymer, for example Aquacoat (FMCCorporation, Food ﹠amp; Pharmaceutical Products Division, Philadelphia, USA) (by mechanical means nodularization become submicron-scale, based on the ethyl cellulose of water, imitative latex dispersion), and synthetic polymer for example

(Rohm and Haas) is that poly-(acrylate, methacrylate) copolymer is known in the art.

Single unit system (matrix means)

Whole (matrix) device can be used for controlling the release of medicine.This is possible, because compare with storage storehouse device, they are easy to make, and does not have the unexpected high dose danger that can cause owing to the film rupture of storage storehouse device.In such device, activating agent is present in the polymeric matrix as dispersion, and they normally form by comperession polymer/medicinal mixture or by dissolving or fusing.The dosage release characteristic of single unit system can depend on the dissolubility of polymeric matrix Chinese medicine, perhaps for porous matrix, dissolubility in the percolating solution in the granule pore network, and the tortuosity of network (on the degree greater than permeability of the membrane), depend on that medicine is dispersed in the polymer or is dissolved in the polymer.For the medicine (0-5%W/V) of low load, medicine will discharge (under the situation that does not have the hole to exist) by the solution dispersal mechanism.At higher load (5-10%W/V), releasing mechanism is owing to existing cavity to become complicated, and described cavity forms near apparatus surface when medicine loses: such cavity will be filled the fluid from environment, improve the rate of release of medicine.

Usually in matrix means (with storage storehouse device), add plasticizer (for example poly-(ethylene glycol), be abbreviated as PEG), surfactant, adjuvant (promptly improving the component of effectiveness), as improving infiltrative means (though on the contrary, plasticizer can be migration, and only play auxiliary film formed effect, and reduce permeability thus).

Surfactant on (hydrophobicity) matrix means can may mechanism improve drug releasing rate by following three kinds: (i) improve dissolving, (ii) improve for " wettability " of dissolve medium and (iii) form the hole as the result of surfactant lixiviate.The example of suitable surfactant for example comprises Eudragit board surfactant

RL 100,

RS,

RL and by the plastifying RS 100 of sorbitol.Applied by surfactant for the maximum effect that discharges, owing to formed division in matrix, make dissolve medium enter in the matrix, surfactant has stronger dissolubility.The set composite that also exists the polymer matrix by coating in the polymer that does not contain medicine to constitute.Such device can be by moisture

Dot matrix forms, and spreads from core via shell by medicine successive release is provided.Similarly, can prepare the polymer core that contains medicine, and with can be by the erosive shell coating of gastric juice.The speed that medical compounds discharges from this shell can be comparison linearity (via the function of shell speed limit diffusion process), and is inversely proportional to the thickness of shell, may be along with the time reduces and discharge from independent described core.The sustained release forms that the present invention relates to comprises matrix system, wherein cyclohexane polyalcohol compound dissolution, embedding or be dispersed in the matrix of another material, and the matrix of described another material slows down and discharges in the body of cyclohexane polyalcohol chemical compound.Matrix system can be to continue the complete basically matrix tablet of deenergized period maintenance.The matrix tablet can be with hindering the polymer moieties coating that the cyclohexane polyalcohol chemical compound discharges.The matrix material that is used for the production dosage form comprise diluent for example microcrystalline Cellulose (AviceltE FMC Corp. for example, Philadelphia, Pa.).Sustained release forms can be not aggressive matrix system, and it comprises the cyclohexane polyalcohol chemical compound that is dispersed in the hydrogel matrix.The example that is used to form the material of hydrogel comprises hydrophilic ethylene base and acrylate copolymer, polysaccharide is calcium alginate for example, with poly-(ethylene oxide), particularly poly-(2-hydroxyethyl methacrylate), poly-(acrylic acid), poly-(methacrylic acid), poly-(N-vinyl-2-Pyrrolidone), poly-(vinyl alcohol), and copolymer each other and with the hydrophobic monomer copolymer of methyl methacrylate, vinyl acetate etc. for example; With the hydrophilic polyurethane that contains poly-(ethylene oxide) block.Hydrogel can comprise the mutual perforation network of polymer, and it can form or form by condensation polymerization by addition.The matrix tablet can prepare by this area tabletting method commonly used.

Matrix system can contain many granules, described granule comprises a plurality of granules that contain the cyclohexane polyalcohol chemical compound, and each granule contains the mixture of one or more excipient of cyclohexane polyalcohol chemical compound and selection to form the matrix that can limit collar hexane polyol compound be dissolved into the speed in the water-bearing media.Suitable matrix material comprises water-insoluble material for example wax, cellulose or other aqueous polymers, particularly microcrystalline Cellulose.Matrix system can also comprise water solublity release regulator, release regulator, lyotropy acid or surfactant type excipient etc.The many granules of matrix can use the methods known in the art preparation, and described method includes but not limited to extrude/nodularization processing or the processing of rotation granulation, or chemical compound, matrix formation excipient and other matrix materials are applied on kind of the nuclear; Perhaps form Wax particles.In case form, can with the many granules of cyclohexane polyalcohol chemical compound matrix and compressible excipient for example lactose, microcrystalline Cellulose, dicalcium phosphate etc. mix, and with the mixture compression with the formation tablet.In matrix system, can also adopt disintegrating agent.When placing water-bearing media, the disintegration of tablet by this method preparation exposes the many granules that discharge the cyclohexane polyalcohol chemical compound thus.Can also cyclohexane polyalcohol chemical compound matrix is how particles filled to capsule for example in the hard gelatin capsule.In one embodiment, provide hydrophilic matrix tablet, the combination of its diffusion, erosion or dissolving or these mechanism and from matrix, discharge the cyclohexane polyalcohol chemical compound by matrix, and optionally comprise many granules.

Can be with matrix system dosage form coatings or part coating to improve the rate of release of cyclohexane polyalcohol chemical compound.In one aspect, the matrix tablet is coated with impermeable coating, and hole or opening are provided, the content of tablet is exposed (referring to the U.S. patent 4,792,448 of for example Ranade by hole or opening, with people such as Hansson, J.Pharm.Sci.77 (1988) 322-324).The example of coating material comprises film forming polymer and wax, particularly thermoplastic polymer for example poly-(ethylene-copolymerization-vinyl acetate), poly-(vinyl chloride), ethyl cellulose and cellulose acetate.

Enteric film

Enteric film is by forming as pH sensitive polymer described in the prior.Polymer is carboxylation normally, and with the interaction of water very little under low pH, and under high pH, polymer ionsization causes swelling polymer or dissolving.Therefore, can design coating, to be kept perfectly in the sour environment of stomach, the protection medicine is not subjected to the influence of this environment or the influence that stomach is not subjected to medicine, but dissolves in the stronger intestinal environment of alkalescence.The core that can regulate tablet or dosage form is to continue release, and the rate of release of medicine was held along with the time like this.

Storage storehouse device

Cyclohexane polyalcohol chemical compound sustained release forms of the present invention can comprise the system or the storage storehouse system of film restriction.The typical method of adjustment release be with medicine (for example as nuclear) fully encapsulation be included in polymeric film or coating (being the nuclear that microcapsule or spraying/pot is coated with) in.The various technology that can influence diffusion process can easily be applied to store storehouse device (for example additive, polymer degree of functionality (with therefore percolating solution pH), porosity, casting film condition etc.), therefore, in the exploitation of storage storehouse device, the condition of polymer must be important consideration.To change the release characteristic of storage storehouse device (and single unit system), wherein the transhipment of cyclohexanhexanol is undertaken by solution diffusion, carries out modelling under the relevant border condition.When activating agent was saturated suspension, it is constant in installing not saturated that the driving force of release keeps, and successive basically release characteristic is provided.Perhaps, rate of release kinetics can be desorbing control and the subduplicate function of time, the release of another adjusting.The example of storage storehouse dosage form comprise the film coating based on capsule, the tablet of diffusion or comprise granose system.In this dosage form, the storage storehouse of cyclohexane polyalcohol chemical compound by the speed limit zona around.The cyclohexane polyalcohol chemical compound, for example is included in the film and dissolves by film via mass transportation mechanism, spreads by the film diffusion or via the liquid filling hole in the film then.System dosage form in individual storage storehouse can be big, for example contains the tablet in single big storage storehouse or comprises granose system, for example contains a plurality of storages storehouse granule, and each storage storehouse granule is the capsule of tunicle coating respectively.Be used to store that the coating of storehouse system can the right and wrong hole, and also be permeable (for example cyclohexane polyalcohol chemical compound can directly via the film diffusion) for the cyclohexane polyalcohol chemical compound, perhaps it can be porous.Film can be by lasting release coating known in the art, for example cellulose esters or ether, and acrylate copolymer, Eudragit board polymer is Eudragit RS for example Or mixture of polymers makes.

In one aspect of the invention, storage storehouse system is a tablet.The tablet core that contains the cyclohexane polyalcohol chemical compound can make by multiple pharmaceuticals industry standard technique.Core can be with speed controlling coating coating, and described coating allows that storage storehouse or tablet core cyclohexane polyalcohol chemical compound in the heart go out with required VELOCITY DIFFUSION via coating.

Another example of storage storehouse system is to comprise granose dosage form, and wherein each granule continues the polymer coating that discharges with design so that the cyclohexane polyalcohol chemical compound to be provided.According to producing and performance demands, each granose granule comprises cyclohexane polyalcohol chemical compound and one or more excipient.Can use lasting release coating known in the art, particularly polymer coating prepares film.The film coating can also be regulated by adding plasticizer known in the art.

The infiltration control device

Cyclohexane polyalcohol chemical compound sustained release forms comprises osmotic delivery device or " osmotic pumps ".Osmotic pumps comprises core, core comprise by semipermeable membrane around the infiltration compositions useful.Water passes film, but be dissolved in solute in the water with the speed that significantly is slower than water via membrane permeation.In the time of in being placed on water environment, because the osmotically active of core component, device absorbs water.As the result around the semi-permeable character of film, the content of device (comprising cyclohexane polyalcohol and any excipient) can not be by the non-bore region of film, and is driven with via opening in the dosage form or passage separating device by osmotic pressure.Passage can be incorporated in the device in process of production, form in position by breaking of the weakness of having a mind to mix in the coating under osmotic pressure influence, perhaps by dissolving and remove the water solublity pore former (porosigens) that in coating, mixes and form in position.The infiltration compositions useful generally comprises water-soluble substances and the water expandable polymer that produces the colloidal state osmotic pressure.The example that is used to form the material of semipermeable membrane comprises polyamide, polyester and cellulose derivative, preferred cellulose ether and ester.Preferable material is to form those of one or more exit passageways in process of production or when placing environment for use automatically, comprises in process of production by inversion of phases or the hole that forms by the dissolving that is present in the water soluble ingredient in the film.The osmotic delivery device can comprise the bilayer tablet of coating, with the many granules of cyclohexane polyalcohol chemical compound of asymmetric membrane coating, or the infiltration capsule.As the function of moisture flow around environment, rate of release keeps substantial constant, sends the volume that approximately equates with the solvent volume of absorbing.

The inflatable tablet of coating

Another cyclohexane polyalcohol chemical compound sustained release forms is the inflatable tablet of the coating described in EP 378404 A2 orUS5792471.Tablet comprises the tablet core that contains cyclohexane polyalcohol chemical compound and expandable material (for example hydrophilic polymer), tablet core film coating, described film comprises aperture or hole, and the cyclohexane polyalcohol chemical compound be extruded and be carried to expanding material can via described hole.Perhaps, film can comprise polymerization or low-molecular weight water-soluble pore former, and described pore former is dissolved in the water environment, and it provides the hole, can extrude via hole expanding material and cyclohexane polyalcohol chemical compound.Suitable pore former comprises for example glycerol, sucrose, glucose and sodium chloride and water-soluble polymer hydroxypropyl emthylcellulose (HPMC) for example of low molecular weight compound.Can in coating, form aperture or hole by using laser instrument or other machinerys in coating, to hole.Membrane material can comprise any film forming polymer, comprise the permeable or impermeable polymer of water, condition is to be porous or to contain the water solublity pore former at the sedimentary in the heart film of tablet core, perhaps has macroscopic hole and leaves with the cyclohexane polyalcohol chemical compound with water supply and discharge.Also relate to the many granules (or beadlet) with cyclohexane polyalcohol chemical compound/expandable material core, its coating has porous or contains the film of pore former.The inflatable Tabules of coating also can be multiwalled, described in EP 378404A2 or US5792471.

The invention still further relates to combination dosage forms, described combination dosage forms comprises lasting release characteristic and promptly releases combination of features.For example, preparation of the present invention or dosage form can be the form of oral tablet, described oral tablet comprises promptly releases part, this is promptly released part and comprises the cyclohexane polyalcohol chemical compound, the curative effect that begins rapidly is provided, with the lasting release portion of cyclohexane polyalcohol chemical compound so that the curative effect than long duration (combination dosage forms also is described in the application 2003009272 and US patent 6,908,626 that for example US publishes) to be provided.

Use

The present invention relates to preparation of the present invention or dosage form in treatment disease and/or disease, particularly prevent and/or improve the application in disease severity, disease symptoms and/or the recurrence period of disease described herein and/or disease.The invention still further relates to and use preparation of the present invention, dosage form or Therapeutic Method to prevent and/or treat disease and/or disease in the mammal.

In one aspect, the invention provides the method for the memory of the individuality that improves healthy individual memory or have old memory injury, comprise preparation of the present invention or the dosage form of using effective dose.

In yet another aspect, the present invention relates to improve memory, especially the method for impermanent memory and other moral function obstacles relevant with aging course comprises preparation of the present invention or the dosage form of using effective dose.

In one embodiment, the invention provides the mammiferous method that treatment need improve memory, wherein said mammal is without any the illness of disease, disease, weak or known infringement or the reduction memory of diagnosis, and described method comprises preparation of the present invention or the dosage form to effectively improvement amount of described administration memory.

In another aspect of the present invention, provide in the treatment individuality with protein folding or gather or amyloid forms, deposition, assemble or continue the relevant maincenter or the method for peripheral nervous system or whole body organ disease, described method comprises preparation of the present invention or the dosage form to individual administering therapeutic effective dose.

In yet another aspect, the invention provides method, comprise to individuality and use preparation of the present invention or dosage form, described preparation or dosage form suppress amyloid and form, deposit, assemble and/or continue, and/or the amyloid dissolving/decomposition that exists before causing.Therefore, preparation of the present invention or dosage form can be used for suppressing wherein taking place the amyloidosis in the individuality of amyloid beta deposition.

In yet another aspect, the invention provides the method for disease relevant in the treatment individuality with the amyloid interaction, described amyloid interacts and can interrupt or separation with the cyclohexane polyalcohol chemical compound, and described method comprises preparation of the present invention or the dosage form to individual administering therapeutic effective dose.

In yet another aspect, the invention provides in individuality and prevent, reverse, alleviate or suppress amyloid and assemble, promote the removing of amyloid beta deposition thing, the sedimentary method of amyloid beta deposition thing that perhaps slows down, described method comprise uses preparation of the present invention or dosage form.

In one aspect, the invention provides in individuality prevent, reverse, alleviate or suppress that the amyloid fibril forms, organ specificity dysfunction (for example neural degeneration) or Cytotoxic method, described method comprises preparation of the present invention or the dosage form to individual administering therapeutic effective dose.

In yet another aspect, the invention provides prevention or reverse the albumen assembling of conformational change in the animal or the method for gathering, described method comprises to the albumen of conformational change introduces preparation of the present invention or dosage form.

In another aspect of the present invention, the albumen assembling of conformational change in the treatment animal or the method for gathering are provided, described method comprises the preparation of the present invention or the dosage form of administering therapeutic effective dose.

In one aspect, the invention provides the method that improves or keep the synapse function in individuality, described method comprises the preparation of the present invention or the dosage form of administering therapeutic effective dose.

The present invention is characterised in that the disease and/or the disease, particularly amyloidosis of amyloid beta deposition more especially to have special application in the Alzheimer in treatment.Therefore, the present invention relates to Therapeutic Method, described method comprises preparation of the present invention or the dosage form to individual administering therapeutic effective dose, described individuality has the disease that is characterised in that amyloid beta deposition, the symptom of Alzheimer particularly, to produce useful characteristics of pharmacokinetics, the characteristics of pharmacokinetics of Chi Xuing particularly.In one embodiment, treatment proves by one or more following effects: the division of accumulative A β or A beta oligomers; The long-term reinforcement that improves or recover; Keep or raising synapse function; The brain of the A β that reduces gathers; The deposition of brain amyloid plaque alleviates; The minimizing of solubility A beta oligomers in the brain; Reduce the neuroglia activity; Reduce inflammation; And/or alleviate cognitive decline or improve cognitive competence.In one aspect, the invention provides the process of improving disease and/or disease in the individuality of suffering from such disease (for example Alzheimer) or the method that obtains the more not serious stage of disease, described method comprises the preparation of the present invention or the dosage form of administering therapeutic effective dose.

In yet another aspect.The present invention relates to postpone the method for the process of disease and/or disease (for example Alzheimer), described method comprises the preparation of the present invention or the dosage form of administering therapeutic effective dose.

In yet another aspect, the present invention relates to improve the method for the survival of the individuality of suffering from disease and/or disease, described method comprises the preparation of the present invention or the dosage form of administering therapeutic effective dose.In one embodiment, the present invention relates to improve the method for the natural duration of life of the individuality suffer from disease and/or disease (for example Alzheimer), described method comprises the preparation of the present invention or the dosage form of administering therapeutic effective dose.

In one aspect, the invention provides the method for treatment mild cognitive impairment (MCI), described method comprises the preparation of the present invention or the dosage form of administering therapeutic effective dose.

In one embodiment, the invention provides in individuality and to alleviate after cognitive defect and amyloid plaque neuropathy begin or reverse amyloid beta deposition and neuropathic method, described method comprises preparation of the present invention or the dosage form to individual administering therapeutic effective dose.

In another embodiment, the invention provides in individuality and after cognitive defect and amyloid plaque neuropathy begin, to alleviate or reverse amyloid beta deposition and neuropathic method, described method comprises to individuality uses a certain amount of preparation of the present invention or dosage form, and the preparation of the present invention of this amount or dosage form can be effectively alleviate after cognitive defect and amyloid plaque neuropathy begin or reverse amyloid beta deposition and neuropathy.

In one aspect, the present invention relates to treat the method for Alzheimer, described method comprises the A β in the individuality, A beta peptide aggregation thing or A beta oligomers, particularly A β 40 or A β 40 aggregations or oligomer and/or A β 42 or A β 42 aggregations or oligomer is contacted with the preparation of the present invention or the dosage form of treatment effective dose.

In yet another aspect, the present invention relates to treat the method for Alzheimer, described method comprises provides preparation of the present invention or the dosage form that comprises the cyclohexane polyalcohol chemical compound, the amount of described cyclohexane polyalcohol chemical compound is enough to produce useful characteristics of pharmacokinetics, thus accumulative A β of the long-time implosion after administration or A beta oligomers.

In yet another aspect, the invention provides the method for treatment Alzheimer in this patient who needs is arranged, described method comprises to individuality uses preparation of the present invention or dosage form, the form of described preparation or dosage form and amount are enough to produce useful characteristics of pharmacokinetics, bring the long-term enhancing that improves or recover and/or keep the synapse function.In yet another aspect, the invention provides the method for treatment Alzheimer, described method comprises to be used, preferred oral or systemic administration preparation of the present invention or dosage form, to produce useful characteristics of pharmacokinetics, alleviate one or more in following thus in long-time after administration: the brain of A β is assembled, the deposition of brain amyloid plaque, solubility A beta oligomers in the brain, neuroglia activity and/or inflammation.

In one aspect, the invention provides the method for treatment Alzheimer, described method comprises to the administration that these needs are arranged preparation of the present invention or dosage form, the amount of described preparation or dosage form is enough to produce useful characteristics of pharmacokinetics, alleviating cognitive competence thus descends, especially in long-time after administration, with the treatment Alzheimer.

In one aspect, the invention provides the method for treatment Alzheimer, described method comprises the compositions that comprises preparation of the present invention or dosage form to the administration that these needs are arranged, the amount of described preparation or dosage form is enough to produce useful characteristics of pharmacokinetics, improve thus or keep the synapse function, especially in long-time after administration, with the treatment Alzheimer.

In yet another aspect, the invention provides the method that prevents and/or treats Alzheimer, described method comprises the compositions that comprises preparation of the present invention or dosage form to the administration that these needs are arranged, and the amount of described preparation or dosage form is enough to accumulative A β of long-time implosion or the A beta oligomers after administration; And the amount of measuring accumulative A β or A beta oligomers, treatment treatment Alzheimer thus.The amount of accumulative A β or A beta oligomers can be used to be had specific antibody or measures with the scyllitol of detectable material labelling A β.

In one embodiment, the invention provides treatment disease disclosed herein or disease, protein folding and/or gather wherein particularly, and/or amyloid forms, deposition, the method of the disease of assembling or continuing, described method comprises the mammal to this treatment of needs, comprise the Orally administered treatment effective dose of people patient at the sustained release forms that comprises the cyclohexane polyalcohol compound or pharmaceutically acceptable salt thereof cyclohexane polyalcohol chemical compound in the peroral dosage form for example, described dosage form is according to rate of release described herein, for example about 0.01mgA/hr to 50mgA/hr is at environment for use as described herein blood plasma for example, discharge the cyclohexane polyalcohol chemical compound among brain or the CSF.In another embodiment, the invention provides the method for treatment Alzheimer, described method comprises the mammal to this treatment of needs, comprise the Orally administered treatment effective dose of people patient at the sustained release forms that comprises the cyclohexane polyalcohol compound or pharmaceutically acceptable salt thereof cyclohexane polyalcohol chemical compound in the peroral dosage form for example, described dosage form is according to rate of release described herein, for example about 0.01mgA/hr to 50mgA/hr for example discharges the cyclohexane polyalcohol chemical compound among blood plasma, brain or the CSF in environment for use as described herein.

Typically, in the methods of the invention, for the average one-tenth individual human of body weight for about 70kg, the preferred dosage scope is about 1mg-5mg cyclohexane polyalcohol chemical compound/sky, and can be as high as about 30-35mg cyclohexane polyalcohol chemical compound/sky.For example, dosage can be about 1 μ g/kg/ days-40 μ g/kg/ days, perhaps in comprising other scopes of 3 μ g/kg/ days-30 μ g/kg/ days.

The present invention relates to treat and/or prevent the method for disease described herein and/or disease, first time point and second time point that described method is included in during the administration are used the dosage form that comprises the cyclohexane polyalcohol chemical compound, the dosage between first time point and second time point and/or be enough to provide useful characteristics of pharmacokinetics at interval wherein, during administration, compound concentrations or peak concentration significantly do not change among blood plasma, brain or the CSF thus.In one aspect, during the administration be about 18,20 or 24 hours.In the embodiment aspect this, second time point is after first time point about 4-14 hour, particularly 6-14,6-12 or 8-12 hour.In yet another aspect, bring compound concentrations or peak concentration among blood plasma, brain or the CSF to drug compound at second time point, behind described concentration or peak concentration and first time point among blood plasma, brain or the CSF compound concentrations or peak concentration compare, changed and be no more than 30%, 20%, 15%, 20%, 5% or 3%.In one aspect, useful characteristics of pharmacokinetics is the zero level release characteristic, and from first time point to the second time point of administration, release characteristic has changed and is no more than about 20%, 10% or 5%.In one aspect, from three time points of first time point to the, the zero level release characteristic has changed and has been no more than approximately 20%, 10% or 5%, and described the 3rd time point is after second time point at least 2,4,6,8,10,12,14 or 16 hours.In other respects, chemical compound is the scyllitol chemical compound.In embodiments.Chemical compound dosage is about 1-50mg/kg, 1-40mg/kg, 2.5-40mg/kg, 3-40mg/kg, 3-35mg/kg, most preferably 3-30mg/kg.

The present invention relates to treat and/or prevent the method for disease described herein and/or disease, first time point and second time point that described method is included in during the administration are used the dosage form that comprises the cyclohexane polyalcohol chemical compound, the dosage between first time point and second time point and/or be enough to provide the C after second time point among blood plasma, brain or the CSF at interval wherein _MinGreater than the C after first time point _MinIn one aspect, second time point C afterwards _MinThan the C after first time point _MinBig by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50%.In one aspect, during the administration be about 18,20 or 24 hours.In the embodiment aspect this, second time point is after first time point about 4-14 hour, particularly 6-14,6-12 or 8-12 hour.Aspect special, chemical compound dosage is about 1-50mg/kg, 1-40mg/kg, 2.5-40mg/kg, 3-40mg/kg, 3-35mg/kg, most preferably 3-30mg/kg.

The present invention relates to treat and/or prevent the method for disease described herein and/or disease, first time point and second time point that described method is included in during the administration are used the dosage form that comprises the cyclohexane polyalcohol chemical compound, the dosage between first time point and second time point and/or be enough to keep the concentration of chemical compound in individuality at interval wherein makes the C among blood plasma, brain or the CSF after second time point _MinGreater than the C after first time point _MinIn one aspect, second time point C afterwards _MinThan the C after first time point _MinBig by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50%.In one aspect, during the administration be about 18,20 or 24 hours.In the embodiment aspect this, second time point is after first time point about 4-14 hour, particularly 6-14,6-12 or 8-12 hour.Aspect special, chemical compound dosage is about 1-50mg/kg, 1-40mg/kg, 2.5-40mg/kg, 3-40mg/kg, 3-35mg/kg, most preferably 3-30mg/kg.

The present invention also comprises preparation, dosage form and method and one or more other therapeutic agents are united use, described other therapeutic agent includes but not limited to beta-secretase inhibitor, inhibitors of gamma-secretase, ε-Secretase inhibitors, β-sheet gathering/fibril formation/ADDL forms other inhibitor of (for example Alzhemed), nmda antagonist (for example Memantine hydrochloride), non-steroid class anti-inflammatory compound (ibuprofen for example, celecoxib), antioxidant (for example vitamin E), hormone (for example estrogen), nutrient and food additive (for example Semen Ginkgo extrac (Gingko biloba)), statins (statins) and other anticholesteremic agents (for example lovastatin and simvastatin), acetylcholinesteraseinhibitors inhibitors (for example donezepil), muscarinic agonist (AF102B (Cevimeline for example, EVOXAC), AF1 50 (S) and AF267B), antipsychotic drug (haloperidol for example, clozapine, olanzapine), antidepressant drug, comprise tricyclic antidepressants and serotonin reuptake inhibitors (for example Sertraline and Citalopram Hbr), statins (statins) and other anticholesteremic agents (for example lovastatin and simvastatin), the antibody of immunotherapeutic agent and A β (for example ELAN AN-1792), vaccine, kinases (CDK5 with the TAU protein phosphorylation, GSK3 α, GSK3 β) inhibitor (for example lithium chloride), regulate kinases (the GSK3 α that A β generates, GSK3 β, the Rho/ROCK kinases) inhibitor (for example lithium chloride and Ibuprofen), the medicine of rise neprilysin (enzyme of a kind of A β that degrades); Raise the medicine of insulin-degrading enzyme (this enzymatic degradation A β), be used for the treatment of the complication that causes by disease or with the medicine of disease complications associated with arterial system, or be used for the treatment of or prevent the medicine of side effect.The present invention also comprises the method for uniting use preparation of the present invention and dosage form and one or more other treatments, described other treatment includes but not limited to raise the gene therapy of neprilysin (enzyme of a kind of A of degraded β) and/or based on the method for medicine, raise the medicine gene therapy of insulin-degrading enzyme (enzyme of a kind of A β that degrades) and/or based on the method for medicine, or based on the treatment of stem cell and other cells.Therapeutic alliance can give simultaneously and/or in proper order.

The combination that can select preparation of the present invention or dosage form and other therapeutic agent or treatment to be to provide unexpected superposition or greater than superposition, i.e. synergism.Other treatment agent and treatment can be worked via different mechanisms, and can have stack/synergism with the present invention.

In one aspect, the present invention relates to the application of cyclohexane polyalcohol chemical compound in the preparation medicine, described medicine has useful characteristics of pharmacokinetics in treatment disease and/or disease, particularly the characteristics of pharmacokinetics of Chi Xuing.The present invention also provides preparation of the present invention or dosage form to be used for the treatment of and/or to prevent application in the medicine of disease and/or disease in preparation.

In one embodiment, the invention provides preparation of the present invention or dosage form is used for prolonging or the application of the medicine of continued treatment Alzheimer in preparation.

In another embodiment, the invention provides preparation of the present invention or dosage form in the application of preparation in the medicine, wherein said medicine is that to be used for treating feature via oral administration be that paraprotein is folding and/or gather and/or amyloid forms, deposition, the disease of assembling or continuing.

The curative effect of preparation of the present invention or dosage form and toxicity can be passed through in cell culture or adopt the standard pharmacological method of laboratory animal to measure, and for example pass through for example ED of counting statistics mathematic(al) parameter ₅₀(the effective dosage of treatment in 50% colony) or LD ₅₀(for the lethal dosage of 50% colony) statistics.Therapeutic index is the dose ratio of treatment and toxic action, and can be used as ED ₅₀/ LD ₅₀Ratio is represented.It is preferred showing exponential preparation of big treatment and dosage form.One or more curative effects, lasting curative effect particularly disclosed herein can confirm in individuality or disease model.For example, confirm in the model that curative effect can be described that particularly, curative effect can be confirmed in having the TgCRND8 mice of Alzheimer disease symptoms in this paper embodiment.

Preparation of the present invention or dosage form can be to individual administration pacts or at least about 1 week, 2 week-4 weeks, 2 week-6 weeks, 2 week-8 weeks, 2 week-10 weeks, 2 week-12 weeks, 2 week-14 weeks, 2 week-16 weeks, 2 week-6 month, 2 week-12 month, 2 week-18 month, or 2 week-24 pact, the cycle carries out or carries out continuously.

By specific embodiment the present invention is described in more detail.Just explanation for example of the following example is provided, rather than limits the present invention by any way.Those skilled in the art should easily recognize, can change or adjust a plurality of non-key parameters to produce substantially the same result.

Embodiment 1

Just before giving birth preceding pharmacokinetics and metabolism

Carry out three tests and assess the pharmacokinetics (table 1) of oral scyllitol:

Single dose pharmacokinetics-rat

15,50 and the single port of 150mg/kg clothes dosage after, the blood plasma pharmacokinetics (PK) of assessment scyllitol in rat.Fig. 1 has shown the curve chart of mean plasma concentration to the time.Table 2 has been summed up the PK parameter that obtains.In rat after the single oral dose, maximal plasma concentration (C _Max) and expose (AUC _0t) value is along with the dosage level of scyllitol increases pro rata.Other parameters are along with dosage level changes.Scyllitol is absorbed rapidly, is observing average t after the administration between 1.0 hours and 2.2 hours _MaxScyllitol is eliminated quickly, and the half-life of estimation (t1/2) is 2.1-2.7 hour.The average retention time (MRT) of estimation is consistent.Volume of distribution (Vdss) is very big, this means that scyllitol has wider distribution in rat.

Canis familiaris L.

Carry out two tests and assess the single dose PK of scyllitol oral administration in Canis familiaris L..18 animals of 14 days test assessment.Fig. 2 has shown the curve chart of mean plasma concentration to the time.Table 3 has been summed up the PK parameter that obtains.First day of this test, C _MaxIncrease pro rata with the dosage level of AUC value along with scyllitol.Yet dosage standardization exposure value has shown the trend that increases along with dosage.Scyllitol is absorbed rapidly, is observing t between 1.2 hours and 2.2 hours after the administration _Max, and the estimated value of t1/2 is 1.7-2.2 hour.Dosage level does not influence t _MaxOr t1/2.At low dosage level (15mg/kg), Vdss and systemic clearance (Cl/F) are higher than Vdss and the systemic clearance of observing under higher dosage, and this has emphasized that scyllitol removes fast.The extensive brain of scyllitol penetrates (seeing below) may be relevant with this respect.

In the dosage range that in 5 beagles, carries out-discovery test, assess the PK of the scyllitol of single port clothes dosage in preliminary mode.In cross-over design (20,80 and 240mg/kg p.o., 80 and 240mg/kg i.v.), use the dosage that increases gradually.Table 4 has been summed up the PK parameter that obtains.AZD-103 is also absorbed rapidly, is observing t between 1.5 hours and 2 hours behind the oral administration _MaxC _MaxIncrease pro rata with the dosage level of AUC value along with scyllitol.C _MaxWith the AUC value along with dosage level increases pro rata, consistent with observed result in bigger test.The estimated value of t1/2 is 2-5 hour.Dosage and route of administration for t1/2, MRT, Cl/F or Vdss all without any appreciable impact.For these two route of administration, the AUC value has shown oral absorption very widely, and first pass effect can be ignored.At the 80mg/kg dosage level, the oral administration biaavailability of estimation〉90% (Fig. 3).

The repeated doses pharmacokinetics

Rat

Be administered twice every day, with 15,50 and the oral dose administration of 150mg/kg 28 days after, assessment scyllitol chemical compound in rat blood plasma PK.Fig. 4 has shown the curve chart of mean plasma concentration to the time.Table 5 has been summed up the PK parameter that obtains.After the administration 28 days, C _MaxAnd the increase pro rata between 50-150mg/kg dosage of AUC0-t value, with observed the same behind single dose.Yet administration was compared with single dose after 28 days, and low dosage level (15mg/kg) shows C _MaxRemarkable increase with the AUC0-t value.In fact, as if at this dosage level, Vdss, clearance rate and elimination speed reduce along with repeated doses.Yet,, do not observe C at higher dosage level _MaxWith the increase of AUC0-t, and there is not evidence to show, the gathering of scyllitol along with repeat administration.For single dose, scyllitol is absorbed rapidly, is observing average t after the administration between 1.2 hours and 1.3 hours _MaxThe t1/2 value is compared with single dose a little to be increased, and is 3.1-4.4 hour.The MRT of estimation is consistent.

Canis familiaris L.

Be administered twice every day, with 15,50 and the oral dose administration of 150mg/kg 14 days after, assessment scyllitol chemical compound in Canis familiaris L. blood plasma PK.Fig. 5 has shown the curve chart of mean plasma concentration to the time.Table 6 has been summed up the PK parameter that obtains.The 1st day of this test, C _MaxIncrease pro rata with the dosage level of AUC0-t value along with scyllitol.As if yet dosage standardization exposure value reduces along with dosage.This is opposite with observed positive trend after acute exposure.There is not evidence to show, the gathering of scyllitol along with repeat administration.For single dose, scyllitol is absorbed rapidly, is observing t between 1.1 hours and 1.8 hours after the administration _MaxThe t1/2 value is compared with single dose a little to be increased, and is 2.9-4.7 hour.The MRT of estimation is consistent.For all dosage levels, Vdss and Cl/F value are similar.

Brain penetrates

In single dose test (dosage of detection 20,80,240mg/kg), install conduit to Canis familiaris L. and collect cerebrospinal fluid (CSF) sample to allow series.CSF soaks the central nervous system, and is positioned at the inboard of blood brain barrier.Though still needing to penetrate cerebral tissue, the central action medicine realizes effect, the rough estimate that the quantitative assay of medicine in CSF can provide brain to penetrate.Fig. 6 has shown the curve chart of average CSF and plasma concentration behind the oral administration 240mg/kg.Table 7 has provided the relevant CSF that obtains and the PK parameter of blood plasma from identical Canis familiaris L..

It is extensively and fast that scyllitol penetrates in the brain.The t that in CSF, observes _MaxValue was for 2.8-4.0 hour.These values and the blood plasma t that derives from same animals _MaxValue (2.3-2.8 hour) is very similar.This has shown that scyllitol crosses very fast the passing through of blood brain barrier.Average C in CSF _MaxValue is the plasma C that observes in same animals _MaxThe 27-66% of value.Similarly, the AUC in CSF _0-InfBe the AUC in the blood plasma of in same animals, observing _0-infAverage 62% or 65%, this shows that scyllitol has high brain and sees through.

Also (last administration after about 24 hours) collects CSF from Canis familiaris L. when the repeat administration off-test performed an autopsy on sb in 14 days.The average level of scyllitol in these samples is listed in the table 8.The level of scyllitol in CSF increases along with dosage, and meets the feature that observes in blood plasma.

Pharmacokinetics is summed up

The PK of scyllitol is very consistent between rat and Canis familiaris L..Maximal plasma concentration and exposure value in rat and Canis familiaris L. all be widely with dose proportional.Every day twice, behind the repetition oral administration 150mg/kg, the AUC that in rat and Canis familiaris L., obtains _0tValue is respectively 573 and 523 μ g/h/mL.In rat and Canis familiaris L., scyllitol all is absorbed rapidly, has the short half-life, and has very large volume of distribution.All having observed linearity in rat and Canis familiaris L. departs from.For rat and Canis familiaris L., after this shows as the scyllitol of repeat administration low dosage level (15mg/kg), the reduction of clearance rate and volume of distribution.In rat and Canis familiaris L., all do not observe such variation in higher dosage.Do not observe any gathering after the long term exposure.

Compare the PK mark sheet of oral administration and intravenous administration and understand oral absorption very widely in Canis familiaris L., first pass effect can be ignored.The bioavailability of estimation〉90%.Therefore, scyllitol is very suitable for treating as oral administration in clinical.The every day of scyllitol, twice administration was only.

Scyllitol has been crossed blood brain barrier especially effectively in Canis familiaris L..Therefore, in patients with Alzheimer disease, scyllitol may arrive action site with high concentration, thereby can apply its target pharmacological action.

Valid density/dosage level

The stoichiometric relationship between amyloid kind and the required scyllitol level of efficient that in vitro study is verified.The 25:1 stoichiometric relationship (scyllitol: the amyloid peptide) be observed for synthetic A β fibril the minimum of any influence is arranged.When assessing the oligomer of natural expression with 1-2nM, (be considered to the level of relevant AD: Cleary, J.P., Deng the people, (2005), Nature Neuroscience, 8:79-84), the least concentration that shows the scyllitol of any effect is 125nM, and this shows that it is effective that 100:1 closes the oligomeric characteristic aspect that ties up to change A β.Yet at 5 μ M (0.9 μ g/mL), scyllitol shows bigger in this respect concordance.

More complicated system provides support as effective local concentration of scyllitol for 5 μ M (0.9 μ g/mL).Strengthen in the test long-term, 5 μ M are minimum maximum effective dose levels (same, the amyloid oligomer concentrations is 1-2nM).The effectiveness of this concentration has obtained confirmation in acute cognitive dysfunction rat test.

Clinically, effective local concentration of scyllitol need obtain behind oral administration.Three tests after measured the effective dosage ranges of scyllitol behind the oral administration.In young CRND8 mice (in the administration in age of 12-16 week, at this moment symptom is new), provided the effectiveness aspect gathering in 3.3mg/kg/ days at behavior and A β.In big slightly CRND8 mice of age (5-6 month), showing maximum effectiveness aspect the minimizing speckle in 30mg/kg/ days.In the rat of tricorn (icv) infusion A beta oligomers, approximately 30mg/kg/ days (minimum dose of oral administration) provides conscientious and handicappedly effectively alleviated.Therefore, consider 2 species, different animals age and different terminal points, 3-30mg/kg/ days dosage level has as one man shown effectiveness.

There is not the level of quantitative assay scyllitol in animal brain in these trials.Yet the test of the pharmacokinetics that carries out in Canis familiaris L. has shown that it is extensively and rapidly that scyllitol penetrates in the brain.Average C among the CSF _MaxAnd AUC _0-InfValue is average 60% of the value that observes in blood plasma.In accepting 14 days Canis familiaris L. of 30/mg/kg/ days mud crab inositols, the level of scyllitol in blood plasma and CSF is～4 μ g/mL (last administration after 12 and 24) hours.Usually, between the characteristics of pharmacokinetics feature of rat and Canis familiaris L., has big concordance.In the test of 28 days rats, after the last administration 12 hours, the mean plasma concentration of scyllitol was～6 μ g/mL.Therefore, render a service in the experiment, receive the CSF level that 30mg/kg/ days animal has similar scope above-mentioned rat.Expectation in CSF and brain between the drug level in the action site with variant.Even so, these levels are extensively consistent with the external estimated value of minimum effective drug concentration (0.9 μ g/mL).

Each preclinical test is considered together, looked that scyllitol provides the probability of effectiveness to reach maximum in the μ g/mL scope by the horizontal dimension of chemical compound in CSF is held in AD patient.3-30mg/kg/ days dosage level scope will be enough to obtain the μ M concentration of scyllitol in brain.

Embodiment 2

In the TgCRND8 mice, the administration scyllitol can prevent and limit the Alzheimer sample phenotype of these animal expressions.In this respect, scyllitol is more effective than relevant stereoisomer myo-inositol.The supposition action site of scyllitol in Alzheimer disease model is brain.Therefore assess with scyllitol or myo-inositol the therapeutic effect on the brain level of these molecules.In not treating animal, myo-inositol is more than scyllitol in brain and CSF.The administration scyllitol provides the remarkable increase of this molecular level in brain and CSF arbitrarily.On the contrary, the administration myo-inositol only makes the brain level of this molecule that less increase is arranged, and has significantly reduced the brain exposure of scyllitol.Therefore, in mice, as the central action pharmaceutically active agents, scyllitol has remarkable potential greater than myo-inositol.In brain, scyllitol is not incorporated in the phosphatidylinositols, and does not influence mixing of other inositols, this means that signal transduction path will can not be affected.

Target

The CSF of relevant scyllitol treatment for the TgCRND8 mice and the information of the influence of brain mysoinositol level are provided.

Material and method

Material

Mice: TgCRND8; Age: 4 months

Trial drug:

Scyllitol: provide by Hokko (Japan)

Myo-inositol: provide by Hokko (Japan)

Dosage:

Trial drug with 30mg/kg by oral gavage administration, perhaps by being dissolved in the drinking water administration arbitrarily.For administration in drinking water, trial drug is dissolved with 10mg/ml.The average magnitude of the water that every animal absorbs from bottle every day is 3ml.Average mice weight is 33g.Therefore, for any administration, the mean dose of trial drug has reached 900mg/kg after 24 hours.

Method

The quantitative assay of scyllitol and inositol (myo-inositol): use scyllitol and myo-inositol level among gas chromatography/analytical reagent composition brain and the CSF.Use D-chirality-inositol (D-chiro-inositol) as interior mark, because it does not exist in these biological specimens.

Derivatization: for volatility and the heat stability that improves these chemical compounds, and allow that suitable peak separates, these samples need at first carry out derivatization.Derivatization by art methods improve (Shetty, HU wait the people, 1995, Anal.Biochem.224:279-85), the hydroxyl of its mysoinositol substitutes with acetyl group.In brief, with the homogenize in 2 * 2ml methanol of half mouse brain.With gained suspension centrifugal (5min, 5000 * g), and the cerebral tissue of 30mg a great deal of placed the glass tubing with Teflon-lining plug.Similarly, with 5-15 μ l CSF sample and 1ml methanol mixed, and be allowed to condition at room temperature and left standstill 5 minutes.To make suspension centrifugal (5min, 5000 * g), and supernatant transferred in the glass tubing (Teflon-lining plug).Under each situation, all add D-chirality-inositol (D-chiro-inositol) of setting concentration (50ng/ μ l is for brain, and 1ng/ μ l is for CSF) afterwards.Then these samples are evaporated to dried fully (Speedvac; 60 ℃). residue is handled with 100 μ l pyridine reagent (solution of 1mg/ml 4-dimethylaminopyridine in pyridine) and 100 μ l acetic anhydrides.This mixture is purged with drying nitrogen, clog safely, and with (80 ℃ of glass tubing heating; 30min).

Analyze:

Behind the derivatization, sample is compiled (RT), and use stable nitrogen current that unreacted acetylation reagent is evaporated.The derivatization product is dissolved (4ml again; Hexane-ethyl acetate (80:20, v/v)), and wash with 1ml 5% sodium bicarbonate solution.Vortex (5 minutes) and centrifugal (3min after 1000 * g), transfers to organic layer in another pipe, and evaporation (Speedvac; 40 ℃).Residue is being dissolved in 100 μ l ethyl acetate again.1 this injection of solution of μ L is arrived in the GC/MS system.Scyllitol that use is stocked and myo-inositol concentrate carry out similar operations, use it for then to produce concentration curve (in this case, interior mark is independent derivatization and adds subsequently).

The Perkin Elmer TurboMassAutosystem XL that use has quadrupole mass spectrometer and electron ionization carries out GC/MS.Gas chromatogram is that using gases helium (1ml/min) carries out as carrier with 30m * 0.25mm * 0.25 μ mZB5 (5% biphenyl/95% dimethyl polysiloxane) post.The injection sample, shunting is set in 50 in the time of 1 minute, is set in 0 in the time of 5 minutes, and injector temperature is set at 300 ℃, and initial oven temperature is set in 80 ℃.Keep after 1 minute temperature being risen to 187 ℃ with 45 ℃/min, and kept 15 minutes in this temperature.Then oven temperature is risen to 295 ℃ with 45 ℃/min, and kept 1.5 minutes.Use the ion monitoring of selecting to come the analyzing samples peak,, use m/z168,, use m/z373, monitor the noise that bigger ion reduces for the mensuration of blood plasma mysoinositol level for the mensuration of brain and CSF mysoinositol level.Sample peak area and concentration curve are compared.

Method

Lipid extracts and hydrolysis

The method that is used for that lipid extracts and analyzes by art methods improve (Kersting, people such as MC, 2003, J.Eukaryot.Microbiol.50:164-168).In brief, with half mouse brain at 2ml dH ₂Homogenize among the O, and use this homogenize thing of 500 μ l to be used for lipid and separate.In order to separate lipid and polyphosphoinositide, the above-mentioned homogenize thing of 500 μ l placed contain 3.75ml chloroform/methanol/dense HCl (10:20:0.1 is in the glass tubing that vice is arranged v/v), and vortex.Add 1.25ml chloroform and 1.25ml 0.1M HCl, and with this solution vortex once more.Then with sample centrifugal (200g) to separate each phase.The organic facies that will contain lipid is dry under nitrogen, be resuspended in 200 μ l chloroform/methanol (6:1, v/v) in, and be added on the silica gel plate.With this silica gel plate place hexane/ether/acetic acid (70:30:1, v/v) in.In case solvent has moved in the 1cm from the top of silica gel plate, be about to silica gel plate and from the TLC groove, take out, and air-dry.Collection contains the initial eluting part of phospholipid, and (2:1:0.1 v/v) comes the eluting lipid to use 4 1ml chloroform/methanol/dense HCl.Lipid is dry under nitrogen, and be dissolved in again among the 1ml6N HCl.With sample carry out acid hydrolysis (110 ℃, 56h) to discharge inositol from the phospholipid that contains inositol.Hydrolysate is dry under nitrogen, and derivatization (as mentioned above), carry out GCMS then and analyze.Use the ion monitoring of selecting to come the analyzing samples peak, adopt m/z 168.

EXPERIMENTAL DESIGN

Brain and CSF level with scyllitol or any administration of myo-inositol scyllitol and myo-inositol after one month: mice was accepted the scyllitol of any administration or myo-inositol 1 month, obtain the CSF sample (animal that n=5 only treats with scyllitol then, 10 animals) and brain sample (n=5 is only with animal and 15 animals for the treatment of with myo-inositol of scyllitol treatment) with myo-inositol treatment.Also from untreated animal sampling (CSF n=10, brain n=17).

Scyllitol mixes in the phosphatidylinositols lipid in brain: accepted any administration 1 month in TgCRND8 hour for 5 and (provide the same animals of CSF and brain sample arbitrarily after the administration; Above).Gather in the crops cerebral tissue then and measure lipid.

The result

Brain and CSF level with scyllitol or any administration of myo-inositol scyllitol and myo-inositol after one month: mice was accepted the scyllitol of any administration (trial drug in drinking water) or myo-inositol 1 month.Measure the level (Fig. 7) of scyllitol and myo-inositol in CSF and the brain then.In untreated animal, scyllitol and myo-inositol can quantitative assay in CSF and cerebral tissue.In brain and CSF, the amount of myo-inositol is all than scyllitol height (high 7 times in brain, high 3 times in CSF).These observed results and observed result (Michaelis, the 1993) unanimity in the people.In 1 month animal of the scyllitol of accepting any administration, CSF (increases by 10 times; P＜0.001) and brain (increase by 7 times; P＜0.001) level in the scyllitol in significantly increases.The CSF level of myo-inositol and untreated animal do not have significant difference (p=0.7).The level of myo-inositol significantly is lower than the level (p＜0.001) that observes in the brain in not treating animal, though this change amplitude less (30% reduces).Opposite with the observed result behind the administration scyllitol, accepted any remarkable change (p=0.35) that 1 month the animal of myo-inositol of any administration does not show myo-inositol level in CSF.The level of myo-inositol in brain significantly improves (p＜0.001), though this change amplitude less (20% increases).The CSF level of scyllitol is not with not treat animal significantly different.The level of scyllitol in brain is than low 80% (p=0.008) of the level that observes in not treating animal.Therefore, myo-inositol has suppressed scyllitol and has been distributed in the cerebral tissue.

Scyllitol and myo-inositol all interact with amyloid-β external, and can prevent amyloid-beta induced neurotoxicity.Targeting amyloid-β is a brain with the effective function site of the medicine of treatment Alzheimer.Fig. 7 has shown that the administration scyllitol provides the main increase of the level of this medicine in brain and CSF, has therefore supported the further exploitation of this medicine.On the contrary, the administration myo-inositol only provides the less increase of the brain level of this molecule, and has significantly reduced the exposure of scyllitol brain.These observed results show that in mice, as the central action pharmaceutically active agents, scyllitol has remarkable potential greater than myo-inositol.

Scyllitol mixes in the phosphatidylinositols lipid in brain: the phosphatidylinositols lipid is the essential composition in the signal transduction path.Therefore, separating phospholipids acyl inositol lipid from the mouse brain of accepting any administration of scyllitol in 1 month is to determine whether scyllitol mixes (Fig. 8).Derive from the phosphatidylinositols lipid of not treating mice and contain a large amount of chirality-inositols (chiro-cyclohexanehexol) and myo-inositol.Yet, do not detect scyllitol.The feature of the phosphatidylinositols lipid that obtains from the mice of accepting any administration of scyllitol in 1 month is with not treat animal identical.There is not scyllitol to be incorporated in the lipid, although this molecule has high level in brain.In addition, the level of chirality-inositol (chiro-cyclohexanehexol) and myo-inositol is not affected in the lipid.These data show that the administration scyllitol does not influence the composition of phosphatidylinositols lipid, and therefore signal transduction path should be unaffected.

Conclusion

In not treating animal, the amount of myo-inositol is greater than scyllitol among brain and the CSF.

The administration scyllitol provides the main increase of this medicine level in brain and CSF arbitrarily.On the contrary, the administration myo-inositol only provides the less increase of the brain level of this molecule, and has significantly reduced the exposure of scyllitol brain.Therefore, in mice, as the central action pharmaceutically active agents, scyllitol has remarkable potential greater than myo-inositol.

In brain, scyllitol is not incorporated in the phosphatidylinositols lipid, and does not influence mixing of other inositols, this means that signal transduction path should be unaffected.

Embodiment 3

General introduction

Shown in the past that prevention and therapeutic ground administration scyllitol can be limited in the Alzheimer phenotype that develops in the TgCRND8 mice effectively.Twice dose form of 3.3mg/kg/ days by oral gavage administration revealed significant cognitive dysfunction and alleviated with speckle load and reduce every day.On the contrary, do not compare, showed part effectiveness, unobserved effect in 0.3mg/kg/ days in 1.0mg/kg/ days with treating animal.In this test, the scyllitol that gives higher dose levels in 4 monthly age TgCRND8 mices is to determine the most effective dose level of scyllitol.3.3,10 and 30mg/kg/ days dosage level all show significantly alleviating of cognitive dysfunction.Continue assessment speckle load.This test shows that in 4 monthly age TgCRND8 mices, 3.3mg/kg/ days can be the most effective dose of restriction Alzheimer sample pathology.

Purpose

In 4 monthly age TgCRND8 mices, determine the most effective dose of scyllitol.

Material and method

Mice:

Describe: expressing human amyloid protein precursor transgenic (APP ₆₉₅) the TgCRND8 mice, described transgenic carries two missense mutation (KM670/671NL and V717F) relevant with philtrum AD.At about 3 monthly ages, the TgCRND8 mice shows carrying out property space learning defective, be attended by the outer amyloid plaque number of the increase of brain A β level and brain cell increase (ChishtiMA, 2001, J.Biol.Chem.276:21562-21570).When 6 monthly ages, A β level and morphology in the TgCRND8 mouse brain, the density of amyloid plaque and distributional class are similar to observed result in the human brain of the AD with good foundation.As among the AD people patient, the biochemistry of mouse model, behavior and neuropathological feature are the increases that is attended by mortality rate.

Sample size:

Placebo n=9

3.3mg/kg/ it n=5

10mg/kg/ days n=8

30mg/kg/ days n=9

Age: 3 monthly ages when the beginning administration

Trial drug:

Scyllitol is provided by Hokko (Japan).

Placebo (sterilized water)

Dosage and scheme:

From 3 months to 4 months, the TgCRND8 mice is treated by oral gavage with scyllitol.The dosage level is 3.3,10 and 30mg/kg/ days, or placebo, and every day is as two equal dose administrations.Assessment animal when 4 monthly ages.

Method

Behavior test: carry out Morris Water Maze test (JanusC waits the people, 2000, Nature 408:979-982) according to description of the Prior Art.After the non-space training in advance, mice is carried out the position differentiate training 5 days, train every day 4 times.Data are measured variation analysis (ANOVA) repeatedly, adopt treatment (not treatment, scyllitol) as the factor between individuality.

Brain speckle load. take out brain, a brain hemisphere is fixed in 4% paraformaldehyde, and in plane, middle footpath, is embedded in the paraffin.For the evenly section at random of generation system, cross the section of whole brain hemisphere mobile phone 5 μ m series.Use 50 μ m section group at interval to analyze (10-14 section/group).Carry out the antigen rescue with formic acid, and cultivate, cultivate with second antibody (Dako StreptABCcomplex/ Radix Cochleariae officinalis test kit) then, identify speckle with initial resisting-A β antibody (Dako M-0872).Use DAB to manifest final product, and carry out enumerator dyeing with luxol fast blue.Use with the LecoIA-3001 image analysis software that the Leica microscope is connected with Hitachi KP-MlU ccd video camera and assess A β speckle load.(Improvision, Lexington MA) change into microphotograph in the binary photo to carry out speckle number and speckle area estimation to use the Openlab imaging software then.Blood vessel A β load is defined as from blood plasma and produces or around the A β speckle of blood vessel, and carries out similar analysis.

The result

The Morris Water Maze of spatial memory test: with the TgCRND8 mice with 3.3,10 and 30mg/kg/ days mud crab inositols or placebo treat from 3 monthly ages to 4 monthly ages.When treatment cycle finishes, use Morris Water Maze to assess conscientious function.In this test, animal is placed the pond with buried platform at continuous day.Total swimming path length of hiding platform is found in assessment.Along with empirical increase every day, the swimming path length can reduce usually.

Assess after 5 days, for the animal of accepting scyllitol (all dosage levels), compare with the animal of accepting placebo, the swimming path length significantly shortens (Fig. 9, for 3.3,10 and 30mg/kg/ days, p respectively=0.003,0.008,0.002).Aspect the swimming path length, 3.3-30mg/kg/ days dosage level shows equal effectiveness.Therefore, as (promptly 4 week age animal) this test is assessed under at experimental condition, 3.3mg/kg/ days most effective dose levels seemingly.This result with wherein showed in 3.3mg/kg/ days and test unanimity from the identical cognitive beneficial effect of any treatment animal of routine tests.

Conclusion

Aspect the cognitive dysfunction that scyllitol is observed in alleviating 4 monthly age TgCRND8 mices is effective.Every day, the dosage level of 3.3,10 and 30mg/kg/ days mud crab inositols of twice of oral administration showed similar effectiveness.At 3.3mg/kg/ days and more between the high dose level, without any the evidence of relevant difference on effect.Therefore, as (promptly 4 week age animal) this test is assessed under at experimental condition, 3.3mg/kg/ days most effective dose levels seemingly.

Embodiment 4

Can measure the dissolving of the unit dosage forms of scyllitol chemical compound by the following method: be placed in the USP-2 device that is equipped with oar, this device is equipped with the 900ml test solution that contains chemical compound at 37 ℃, and slurry stirs with 50rpm.If dosage form is a capsule, it is measured in the same way, but test solution also contains the 0.1mg/mL trypsin.Get the filtering sample aliquot (normally 2 or 10mL) of dissolve medium at different time or attraction (pull points).Filter sample aliquot, and use HPLC analysis or other suitable analyses to measure the content of cyclohexane polyalcohol chemical compound.Data are drawn, and wherein as the y-axle, the time is as the x-axle for the mg cyclohexane polyalcohol chemical compound of Shi Fanging (active cyclohexane polyalcohol chemical compound) (or cyclohexane polyalcohol chemical compound of % weight release).Record discharges the time of the selected amount (for example 80% weight) of cyclohexane polyalcohol chemical compound dosage.Should repeat independent solubility test, finding speed, and average.Described method provides the clear mensuration of drug releasing rate, and it is independent of the mechanism that the cyclohexane polyalcohol chemical compound discharges from dosage form.

Embodiment 5

Dosetest

TgCRND8 mice: treatment administration

Whether can eliminate the AD-sample phenotype of good foundation in order to measure the scyllitol chemical compound, will treat delay until 5 monthly ages, at this moment animal has significant cognitive defect usually, with abundant A β peptide and speckle load.Medicine is used in AZD-103 in the drinking water (10mg/ml, the treatment of about dosage of 24 hours=900mg/kg) 28 days.Cognitive function, the amyloid of assessment animal gather in the time of 6 months, speckle is loaded and synaptic density.

Improve cognitive function: compare with untreated contrast, treatment brought remarkable improvement behavior performance (the swimming path length shortens among the Morris Water Maze) (Figure 10, p=0.01).For using 28 days TgCRND8 mice of compounds for treating, actual swimming path length and non-transgenic animal as broad as long (p=0.11).

Alleviate that amyloid gathers in the brain: the level relevant (table 9 is distinguished p＜0.05) of the reduction of insoluble A β 40 and A β 42 in treatment dosage regimen and the brain.

The speckle load reduces: treatment dosage regimen relevant with significantly reduced speckle load (area and size, table 9, p＜0.05 respectively).

Synaptic density increases: treatment dosage regimen relevant with the synaptic density of raising (p＜0.001).

The observed result that will prevent to obtain in the administration extends to the treatment aspect.Owing to multiple reason, this is very important.At first, the alleviating of cognitive defect, the reduction of amyloid and speckle load can realize when these genius morbis fully make progress.Secondly, treat more relevantly,, will treat the patient in case be diagnosed with human diseases.The 3rd, on behalf of the accumulation pathology mechanism of disease, amyloid gathers with the reduction of speckle load be restricted.Therefore, chemical compound is to work as the disease regulator, and is not only to influence symptom.

TgCRND8 mice: effective dosage ranges

Use the scyllitol chemical compound of the highest possibility dosage level for the CRND8 mouse model.In case verified and reproduced the wide region of clinical related activity, just can seek the effective dosage ranges of this chemical compound.From 3 to 4 monthly ages are promptly when newly having set up disease phenotype, to TgCRND mice administration 28 days.Select the effectiveness (early dosage) of this EXPERIMENTAL DESIGN to improve test, and the information maximization (at the dosage when the change amplitude is enough to detect therapeutical effect) that obtains.Animal is used 0.3,1 or 3.3mg/kg/ days accumulated dose or carrier, be divided into 2 five equilibrium dosage through ports clothes gavages every day and use.Assessment cognitive function and speckle load.

Improve cognitive function: in the time of 4 months, use Morris Water Maze assessment animal (Figure 11).Compare with untreated contrast, at the 5th day of training, 3.3mg/kg/ days dosage groups showed the swimming path length (p=0.04) of remarkable shortening.This path length is similar to the result who is observed with the compound administration mice in the drinking water arbitrarily in the test of front.This means under these experimental conditions,, can reach maximum efficiency in 3.3mg/kg/ days as assessing by this terminal point.On the contrary, path length and the untreated contrast in 0.3mg/kg/ days groups is as broad as long.

The speckle load reduces: speckle load (speckle counting and the brain speckle area: Figure 11) of assessment animal.Accept speckle parameter in 0.3mg/kg/ days the animal with the treatment contrast is not as broad as long.On the contrary, by treating with 1mg/kg/ days (speckle counting p=0.02, speckle area p=0.011) and 3.3mg/kg/ days (speckle counting p＜0.0001, speckle area p＜0.001), two speckle parameters all significantly reduce.3.3mg/kg/ it provides maximum of speckle load to reduce, significantly greater than the reduction that was provided in 1mg/kg/ days (for two parameters, p=0.03).Therefore, observed clearly dose response.

Therefore, dose form revealed remarkable activity in 3.3mg/kg/ days, and described activity is consistent between two independent terminal points: cognitive and speckle load.So this low dosage level can be considered as the minimum effective dose in the early stage disease animal model.

The animal of from 5 to 6 monthly ages administration, further measure dose response.At this later stage time point, disease is more serious, and they can have bigger clinical correlation like this.The dosage level of assessment is 5,10 and 30mg/kg or carrier, and be administered once every day.Assessment A β 42 gathers.

The reduction that amyloid gathers in the brain: by the level of A β 42 in the ELISA assessment brain homogenate.Show dose response.Compare with carrier, 10 and 30mg/kg/ days chemical compound remarkable reduction (Figure 12,10mg/kg/ days: p=0.03 of solubility A β 42 levels in the brain all are provided; 30mg/kg/ days: p=0.02), wherein obviously showed in 30mg/kg/ days and pretend usefulness most.

Therefore, in two independent trialss, determine and reproduced dose response.

Embodiment 6

Inositol is a kind of simple polyhydric alcohol, has 8 kinds of naturally occurring stereoisomers.Measured myo-inositol, D-chiro-inositol and table-inositol, obtained satisfactory result, but scyllitol of no use is studied in the prior art at multiple disease.Shown that scyllitol suppresses cognitive defect in the TgCRND8 mice, and the condition of illness that significantly palliates a disease, meaned that it can treat Alzheimer (AD) effectively.Understand that at this test invading the exterior scyllitol has the continuous capability in the serious stage of treatment AD-sample pathological changes.With respect to untreated TgCRND8 mice, in the brain of treatment, observe the remarkable reduction that insoluble A β 40, A β 42 and speckle gather.The administration scyllitol has suppressed the growth of all size speckles.In order to confirm the scyllitol effect in the CNS, use gas chromatography/mass spectrography to measure myo-inositol and scyllitol concentration behind the oral administration.In addition, also measured scyllitol and myo-inositol in CNS, mutually regulate have how tight, and if in CNS, increase, whether scyllitol will mix in the phosphatidylinositols.After the scyllitol treatment, the cerebrospinal fluid level of scyllitol increases, but then can not with the myo-inositol treatment.Scyllitol treatment also having caused increase of scyllitol level in the brain.Even scyllitol at high level, also can not be incorporated in the lipid family of phosphatidylinositols.The result of these merging has confirmed that the scyllitol accumulation is up to 10 times of the endogenous level in the CNS, does not generate but do not influence the phosphatidylinositols lipid.

A purpose of this test be determine the scyllitol treatment amyloid and A β level equal latter stage sporadic A Erci and the time whether remain valid.Second purpose is to measure the oral administration inositol whether to increase scyllitol concentration in the brain.Myo-inositol is crucial for keeping in the CNS osmolarity and signal transduction path, and the physiological concentration of brain mysoinositol with and some regulatory mechanism be known, and should understand still very general [1].Interaction between myo-inositol and the scyllitol is not fully studied, and therefore can understand this system better by this test and how to be regulated and control subtly.More particularly, whether the treatment of myo-inositol or scyllitol will change the CNS concentration of these two kinds of polyhydric alcohol in mice, and change a kind of polyhydric alcohol concentration and whether can influence another kind of polyhydric alcohol concentration.In addition, measure when CNS concentration increases, whether scyllitol is incorporated in the lipid of phosphatidylinositols family, changes signal transduction path thus.Material and method in this test below the test.

Material and method

Mice remains on outbreed C3H/C57B16 background [2] with the TgCRND8 mice.Under the control of Syria hamster prion gene promoter, these mices cross and are expressed in Swedish (KM670/671NL) and Indiana (V717F) the APP sudden change that is cis on the APP695 copy.One group of mice was treated 2 months arbitrarily via its drinking water with the 10mg/ml scyllitol, at 5 monthly age begin treatments, and measured the influence of treatment for A β and speckle level.Second group of mice treated arbitrarily with myo-inositol or scyllitol, and the change of quantitative assay inositol level.Every mice consumes 2.5-3ml liquid common every day, is equivalent to the scyllitol of every animal 25-30mg dosage.All tests all are to carry out according to the guidance of Canadian Council on Animal Care.

Material except as otherwise noted, all reagent all be available from Sigma (St.Louis, MO, USA) or EMD (Merck, Darmstadt, Germany).Scyllitol derive from TransitionTherapeutics (Toronto, Ontario, Canada).

Brain A β load is fixing in 4% paraformaldehyde with a brain hemisphere, and is embedded in the paraffin.Use the section of 50-μ m at interval to organize and analyze (every group of 5 sections).(Dako M-0872) identifies speckle, and uses 3 that 3-diaminobenzidine (DAB) is shown one's color to use initial A β-s specific antibody 6F/3D.Use Openlab imaging software (Improvision) to assess A β speckle load.Microphotograph is changed into binary picture, and definite brain area percentage that is covered by speckle, and spot size distributes.

Blood plasma and brain A β content add half brain sample homogenize in buffered sucrose solution then 0.4% diethylamine and 100-mM NaCl and measure solubility A β level, perhaps add cold formic acid and measure total A β.With the sample neutralization, dilution, and use commercially available ELISA test kit (Biosource International) to analyze A β 40 and A β 42 levels.Sample is to analyze in triplicate.For blood plasma, use similar approach.

Scyllitol and myo-inositol concentration in gas chromatography/mass spectrography (GC/MS) quantitative assay brain, CSF and the blood plasma is used in the quantitative assay of myo-inositol and scyllitol.For volatility and the heat stability that improves these chemical compounds, and allow that the peak separates, these samples need at first carry out derivatization.Derivatization is next [3] of technical method improvement by people such as Shetty.In brief, with brain hemisphere homogenize in 2 * 2ml methanol, with gained suspension centrifugal 5 minutes with 5000 * g.The supernatant that will be equivalent to the volume of 30mg cerebral tissue (based on the weight of organizing before the homogenize) is analyzed.Similarly, for blood plasma and CSF, with 100 μ l blood plasma or 5 μ l CSF and 1ml methanol mixed, allow real-time 5 minutes of solution left standstill, with gained suspension with 5000 * g centrifugal 5 minutes, hemisphere took out supernatant.Mark D-chirality-inositol (Wako, Osaka, Japan) in all supernatant, adding, for brain and blood plasma, in be marked with 50ng/ml and add, for CSF, in be marked with the 1ng/ml adding.These samples are evaporated to dried (Speedvac; 60 ℃).Add 100 μ l pyridine reagent (solution of 1mg/ml4-dimethyl aminopyridine in pyridine) and 100 μ l acetic anhydrides, with effective nitrogen purging, and 80 ℃ of heating 30 minutes.Behind the derivatization, under stable nitrogen current, unreacted acetylation reagent is evaporated.The derivatization product is dissolved (4ml again; Hexane-ethyl acetate (80:20, v/v)), and wash with the 1ml5% sodium bicarbonate solution.Vortex (5 minutes) and centrifugal (3min is after 1000 * g), with organic layer evaporation (Speedvac; 40 ℃).Residue is dissolved again (100 μ l; Ethyl acetate), and 1 this injection of solution of μ L arrive in the GC/MS system.Scyllitol that use is stocked and myo-inositol concentrate carry out similar operations, use it for the generation concentration curve then.

The Perkin Elmer TurboMassAutosystem XL that use has quadrupole mass spectrometer and electron ionization carries out GC/MS.GC be with 30m * 0.25mm * 0.25 μ m ZB5 post (5% diphenyl/95% dimethyl polysiloxane, Phenomenex, Macclesfield, UK), using gases helium (1ml/min) carries out as carrier.The injection sample, shunting is set in 50 in the time of 1 minute, is set in 0 in the time of 5 minutes; Injector temperature is set at 300 ℃, and initial oven temperature is set in 80 ℃.Keep after 1 minute temperature being risen to 187 ℃ with 45 ℃/min, and kept 15 minutes in this temperature.Then temperature is risen to 295 ℃ with 45 ℃/min, and kept 1.5 minutes.Use the ion monitoring of selecting to come the analyzing samples peak, in m/z 168 monitorings.Sample peak area and normal concentration curve are compared.

Lipid extracts and hydrolysis is used for that lipid separates and the method analyzed is [4] by people's such as Kersting technical method improvement.In brief, with a brain hemisphere at 2ml dH ₂Homogenize among the O, and use this homogenize thing of 500 μ l to be used for lipid and separate.Carry out organic extraction of cephalopin by the following method: adding 3.75ml chloroform/methanol/HCl (10:20:0.1 v/v), adds 1.25ml chloroform and 1.25ml 0.1M HCl then, and with this solution vortex.Centrifugal (200 * g) to separate each phase with sample then.The organic facies that will contain lipid is dry under nitrogen, be resuspended in 200 μ l chloroform/methanol (6:1, v/v) in, be added to then silica gel 60F254 plate (EM Industries, Merck, Darmstadt, Germany) on.With this silica gel plate place hexane/ether/acetic acid (70:30:1, v/v) in.In case solvent has moved in the 1cm from the top of silica gel plate, be about to silica gel plate and from the thin layer chromatography groove, take out, and air-dry.Collection contains the initial eluting part of phospholipid, and (2:1:0.1 v/v) comes the eluting lipid to use 4 1ml chloroform/methanol/dense HCl.Lipid is dry under nitrogen, and be dissolved in again among the 1ml6N HCl.With sample carry out acid hydrolysis (110 ℃, 56h).Hydrolysate is dry under nitrogen, and derivatization (as mentioned above), carry out GC/MS then and analyze.Use the ion monitoring of selecting to come the analyzing samples peak, adopt m/z168.

Statistical analysis uses the StatisticalPackage of the Social Sciences 11 of relevant Mac OS X to carry out statistical analysis.Use relatively each group of unidirectional ANOVA.If observe significant F mark (P＜0.05), use then that hoc checks relatively each group behind the Bonferroni, significance,statistical is arranged on P＜0.05.

The result

Scyllitol treatment having alleviated AD condition of illness

In order to determine the effect of scyllitol treatment, the TgCRND8 mice at 5 monthly ages was treated 2 months arbitrarily with scyllitol for the terminal stage of AD-sample pathological changes.The terminal point of this test has and corresponding A β of philtrum terminal stage disease that suffers from sporadic AD and amyloid load [5-7].The outcome measurement of analyzing is, compares with untreated contrast, and the animal midbrain of treatment and the solubility in the blood plasma and insoluble A β 40 and A β 42, the brain area percentage that is covered by speckle, and spot size distributes.Compare with the contrast of age-matched, scyllitol treatment brings the remarkable reduction (F of insoluble A β 40 and A β 42 levels in the brain _1,14=12.012; P＜0.05; Table 10).After the treatment, solubility A β 40 in brain and the blood plasma and A β 42 levels all show non-remarkable reduction.The scyllitol treatment also significantly reduction brain area percentage (F that is covered by speckle _1,14=31.281; P=0.0001; Figure 13 a).Whether be result that new speckle form the reduction of the speckle growth that be suppressed and/or set up, the spot size of analyzing as therapeutic outcome distributes for the speckle of determining to reduce if loading.The result shows that the scyllitol treatment is being effective (Figure 13 b) aspect the speckle growth that suppresses all sizes.The quantitative assay of inositol

In order to measure oral administration myo-inositol and scyllitol is how to influence the concentration of these two kinds of materials in CSF and brain, uses GC/MS to analyze the change of myo-inositol and scyllitol level in CS and the cerebral tissue.Known sodium myo-inositol transport protein 1 (SMIT-I) and the transport protein of hydrogen myo-inositol are all at external transhipment scyllitol [15,25].Known SMIT-I is a constitutive activity, and all has affinity for myo-inositol and scyllitol, expresses at choroid plexus; Therefore, estimate that the scyllitol oral administration will change CNS inositol level, estimate that also the myo-inositol oral administration will change CNS inositol level.

Measure the increase of myo-inositol and scyllitol treatment back CSF and brain inositol level.Before death, isolate at least 5 μ l mice CSF from the ventriculus quartus by conventional method.In not treating animal, the CSF of myo-inositol and scyllitol and brain level and prior art in the literature less than level be more or less the same (Figure 14).The concentration of myo-inositol is 2-15mM in the brain of report, and the concentration of myo-inositol is 0.08-0.3mM[1 among the CSF], its with the brain of the 3mM that observes in the CSF concentration of concentration and 0.21mM be more or less the same.The concentration of scyllitol is the 8-20%[8 of myo-inositol level, 9] and, it is well relevant with the result.In addition, for untreated non-Tg young baby, myo-inositol does not have different (P=0.96) with scyllitol concentration with untreated TgCRND8 mice, this means the disease pathological changes for example the cerebrovascular amyloid do not change the inositol level.

For relatively the inositol administration is for the equilibrated influence of myo-inositol/scyllitol in the brain, the concentration of being applied in the drinking water for mice arbitrarily is myo-inositol or the scyllitol of 10mg/ml.Compare with not treating contrast, myo-inositol and scyllitol significantly do not change CSF myo-inositol concentration (P difference=0.35 and 0.7; Figure 14 a).Yet scyllitol has increased by 16 times of (F in scyllitol treatment the causing CSF _2.25=69.61; P＜0.001; Figure 13 a).Detected scyllitol increases representative and directly transports and from the balance between the outflow of cerebral tissue from blood plasma among the CSF.

Use full brain homogenate to assess the mice mysoinositol concentration of treatment.With respect to not treatment contrast, with myo-inositol arbitrarily treatment show that the myo-inositol level has increased by 1.2 times of (F in the brain _2,22=36.01; P＜0.001), and the scyllitol level reduced by 5.4 times of (F _2,23=247.57; P=0.008; Figure 14 b).On behalf of the inositol balance, the minimizing of following of myo-inositol treatment back scyllitol may move to stablize the homeostatic direction of brain to degraded.With respect to contrast, showing scyllitol with any treatment of scyllitol has increased by 7.6 times of (F _2,23=247.6; P＜0.001), myo-inositol has reduced by 0.7 times of (P＜0.001 and in the brain; Figure 13 b).These results show, increase in hindbrain and have reflected continuing to increase of inositol picked-up, and scyllitol shows the most remarkable change.The less change of myo-inositol may reflect that the strict control of needs keeps osmolarity and the signal transduction path in the CNS.

Relatively any administration of scyllitol and treatments in 10-100mg/kg/ days once a day are to determine being administered once whether be enough to improve CNS scyllitol level every day.After about 8 hours of the final treatment, mice is killed to analyze the analysis of CSF inositol.The CSF analytical table is understood, compares with control mice, and the non-remarkable dose dependent of scyllitol increases (Figure 15).After the treatment of administration scyllitol, the level of scyllitol is significantly higher than the level (F after the single dose administration scheme arbitrarily _4,17=30.1; P＜0.001).These results show that the single dose administration of scyllitol has improved the CSF level, but mean that the multiple dose administration scheme may be more favourable for the high CNS scyllitol concentration that continues.

Myo-inositol is the lipid of phosphatidylinositols family and the whole composition of signal transduction path.In order to get rid of the result who increases as scyllitol brain concentration, scyllitol is crossed myo-inositol and is incorporated in the phosphatidylinositols lipid, separates cephalin to analyze the composition of head group.Can not detect scyllitol in the isolated phosphatidylinositols lipid from the brain of control mice and scyllitol treatment mice, the elution time of scyllitol is 18.2, and the signal pointwise between 17-19 minute detects and do not detect scyllitol.Though scyllitol can not be excluded the following 0.25ng/ml that is limited to that detects in the brain sample than small concentration.These results mean that scyllitol substitutes myo-inositol when existing with the concentration that raises in CNS.

Discuss

Reported the endogenous levels [8-11,24] of the interior scyllitol of brain of a lot of species.Rat, rabbit and Medulla Bovis seu Bubali contain myo-inositol are changed into scyllitol epimerase [10,12,24].In addition, the administration myo-inositol shows 1% conversion to scyllitol [13] in the blood plasma in the women, and shows 0.06% conversion to scyllitol, preferential 60% conversion to chirality-inositol [14] with the myo-inositol treatment in rabbit.Scyllitol can use SMIT-I to enter brain, and known SMIT-I preferentially transports myo-inositol [15] at external transhipment myo-inositol and scyllitol, and at choroid plexus, expresses on blood-CSF barrier [16].This enters in the CNS around having studies confirm that myo-inositol and scyllitol clump.

The front has shown that treating the TgCRND8 mice with any administration of scyllitol causes cognitive function to improve, and the minimizing of the interior toxicity solubility A beta substance of CNS.Further shown for the dose-dependent effects and the pathological examination of cognition and measured.In A β load and the corresponding mice of people's final stage AD, the result after the scyllitol treatment has shown the lasting inhibition of speckle formation and the reduction of speckle load.In this test, measured treatment and do not treated spot size distribution change between the animal, and measured the change of the brain area percentage that is covered by speckle, with the mechanism of determining that scyllitol interacts and speckle forms and expands.This has relatively proved a main observed result, and promptly scyllitol effectively and indistinguishably suppresses the growth of all size speckles.Therefore, the scyllitol administration has suppressed the speckle growth by the structural interaction with speckle and A β subunit.Suppress the speckle growth for scyllitol, can propose a lot of hypothesis.Vitro data has shown the stable of A β 42 fibroplastic inhibition and little A β conformer, and its PC-12 cell for the nerve growth factor differentiation does not have toxicity [17].Vitro data has shown the minimizing of soluble high-molecular weight oligomers, and A beta monomers and trimerical increase.Two mechanism of not repelling have mutually been proposed: at first, in the aggregation that scyllitol can be by inserting growth and the beta structure of fiber, the growing surface of fiber is not induced with further adding A β peptide like this, perhaps, scyllitol can " cover " growing edge of A beta peptide aggregation body, to suppress further assembling.Based on other observed result, i.e. scyllitol treatment causes the minimizing of insoluble A β 40 and A β 42, and does not follow the increase of solubility A β level or blood plasma level, and the further consequence of scyllitol treatment is degraded and the removing of accelerating from brain.

Find based on this GC/MS, arbitrarily but be not the remarkable increase that the treatment of single dose scyllitol causes brain scyllitol level.These results show that scyllitol shows high CNS bioavailability, and this is an important consideration in design AD treatment.If the increase of supposition brain scyllitol level is that scyllitol is necessary as people AD therapeutic strategy, then the multiple dose administration scheme may be preferred with respect to the day single dose, because it will cause the more lasting raising of brain scyllitol level.Support this proposal, dosage has been found evidence, and aspect the cognitive defect that reverses the TgCRND8 mice, under equal dose, day twice oral gavage administration scyllitol is more effective than day single dose.For the treatment of TgCRND8 mice, myo-inositol does not show effectiveness, although external be effectively [17].This may be owing to myo-inositol in blood plasma changes into scyllitol and chirality-inositol mutually, and the low multiple of brain myo-inositol level improves, perhaps may mean the strictness regulation and control of myo-inositol in the CNS, as estimating for the chemical compound that relates to osmolarity and signal transduction path.On the contrary, do not participate in the report of signal transduction path in the brain, and in mice, do not see the evidence of detrimental effect about scyllitol.

Use proton magnetic resonance (PMR) spectrum in vivo detection type be similar to scyllitol [9,18] in the human brain of the level that relevant post-mortem tissue reported.Research of the prior art shows that scyllitol increases in some cerebral tumor and disease, and owing to astroglia reaction [9,19,20].On the contrary, in having the healthy individual of normal neural state, observed high-caliber scyllitol [8].In this individuality, do not observe any adverse side effect, although the ratio of myo-inositol scyllitol is 5:1, rather than 12:1 ratio [8] more generally.Such proposal has been supported in this test, and the scyllitol concentration that promptly continues to improve is not deleterious, because the animal of treatment does not show any cognition or pathology side effect.

Another purpose of this test is to determine in the brain whether the scyllitol increase causes scyllitol to cross myo-inositol and preferentially be incorporated in the phosphatidylinositols lipid, and therefore prediction for the secondary action of signal transduction path.Up to now, having only ciliate and barley seed to show scyllitol and be incorporated in the lipid, all is as the result who exposes increase and endogenous condition; On the contrary, in the mammal test, do not detect the endogenous scyllitol and be incorporated into [21-23] in the lipid.This test has confirmed that scyllitol is not incorporated in the lipid of phosphatidylinositols family after treating arbitrarily with scyllitol.At last, the result has confirmed that the scyllitol of oral administration has improved CSF and brain scyllitol level, and this has brought the amelioration of disease result in the AD mouse model.

Embodiment 7

The ability that the isomer of research inositol is crossed blood brain barrier and improved stable state brain inositol level subsequently.

Purpose:

1. determine that peripherally administered hindbrain mysoinositol concentration discharges change.The peripherally administered concentration of these chemical compounds in cerebrospinal fluid and brain that causes of inositol stereoisomer increases.

2. determine whether this causes the increase of mixing in the lipid of phosphoinositide or phosphatidylinositols family.

Method: in order to detect this hypothesis, use gas chromatography/mass spectrography is measured the inositol level in oral administration hindbrain and the cerebrospinal fluid.For volatility and the heat stability that improves these chemical compounds, and allow that suitable peak separates, with the hydroxyl acetyl group derivatization (by people such as Shetty HU, 1995, the method improvement of Anal Biochem 224:279-285) of inositol.By detecting the improved quantitative assay that mass ion 168 is set up inositol.By using thin layer chromatography to separate inositol and acid hydrolysis (people such as Kersting, 2003, J Eukaryot Microbiol), come inositol level among quantitative assay phosphatidylinositols lipid and the phosphoinositide by gas chromatography/mass spectrography then.

The result: the result is presented among Figure 14, the 16-20.The inositol of administration on every side shows increasing sharply of blood plasma inositol level, and this monitors by radiolabeled inositol chemical compound.The successive administration of some inositol chemical compound has improved the concentration in brain and CSF.The increase of inositol level does not change the phosphoinositide level, and the inositol of administration on every side is not incorporated in the lipid of phosphatidylinositols family yet.For the most effective inositol isomer, observed the dose response increase.Conclusion: these results show that dosage has improved brain stable state inositol level independently on every side.

Embodiment 8

Single ascending-dose of 1 phase of in healthy male volunteers, carrying out, double blinding, at random, placebo-controlled trial is with toleration and the characteristics of pharmacokinetics of the AZD-103 of assessment oral dose

Purpose:

1. when to the healthy male volunteers oral administration, assess safety and the toleration of the AZD-103 of single ascending-dose.

2. when to the healthy male volunteers oral administration, assess pharmacokinetics (PK) feature of the AZD-103 of single ascending-dose.

EXPERIMENTAL DESIGN:

With AZD-103 (scyllitol) to continuous 6 groups of healthy male volunteers administrations.Every winding is subjected to the AZD-103 of various dose level.Improve dosage level gradually between each group, such first winding is subjected to lowest dosage levels, dosage level in the middle of middle groups is accepted, and last winding is subjected to the highest proposal dosage level.The dosage increase depends on the data of safety assessment that derives from front administration group.

With 48 (48) healthy males with the random assortment of 3:1 pattern to accept AZD-103 or placebo (36 individualities are accepted medicine, and 12 individualities are accepted placebo).The AZD-103 of 6 ascending-doses of assessment in 6 Different Individual groups, every individuality is only accepted a trial drug dosage like this.Every group comprises 8 individualities, and AZD-103 is accepted in 6 individual random assortment, and placebo is accepted in 2 individual random assortment.Begin administration with lowest dose level, and be incremented to maximum dose level.Initial dose is 500mg, is following intended dose: 1000mg, 2000mg, 3500mg, 5000mg and 7000mg then.

In first day (the 1st day) of test, individuality is accepted the trial drug of its single dose.In the 1st day time all day, the safety that monitoring is individual, and extract the PK sample.At the 2nd day, the safety that monitoring is individual, and extract the PK sample.At the 3rd day, after last safety monitoring and PK sampling is finished, approximately after the trial drug of its single dose 48 hours, allow individuality withdraw from.

The 1st group finish after, carry out the comprehensive safety commentary of individual data of safety, and the 2nd group administration will be only commented by main research worker and the sponsor associating safety of being satisfied with.This program also will be carried out before the administration of organizing subsequently.

Test colony: 48 healthy male volunteers

Test of cure: individuality will be accepted placebo or AZD-103 capsule

The incidence rate of safety terminal point: AE and SAE

Laboratory safety test (hematology, biochemistry, urinalysis)

Vital sign

·ECG

The PK terminal point

The plasma concentration of AZD-103 (AUC, C _Max, t _Max, t _1/2, K _El) result: it is 5.82 μ g/mL (500mg) that the average peak in the 1st group exposes, in the 2nd group 16.99 μ g/mL (1000mg), in the 3rd group 33.11 μ g/mL (2000mg), in the 4th group 74.62 μ g/mL (3500mg), being 109.5 μ g/mL (5000mg) in the 5th group, is 154.56 μ g/mL (7000mg) in the 6th group.For the personal feature of the individuality of these 6 groups, behind the oral administration, observe average A ZD-103 T _Max(± SD) is 4.00 ± 1.55 hours (500mg), 3.25 ± 1.47h (1000mg), 2.75 ± 0.61h (2000mg), 2.75 ± 0.61h (3500mg), 2.42 ± 0.66h (5000mg) and 2.42 ± 0.67h (7000mg).

The elimination of AZD-103 is two-phase seemingly, and average final to eliminate the half-life be 18.37 hours to the pju of assessment in the 6th group (7000mg).

In the 1st group, from the zero-time to the end under the averaged curve of prediction concentrations area be 29.86 μ gh/mL (500mg), in the 2nd group 111.8 μ gh/mL (1000mg), in the 3rd group 194.21 μ gh/mL (2000mg), in the 4th group 440.63 μ gh/mL (3500mg), being 490.84 μ gh/mL (5000mg) in the 5th group, is 859.88 μ gh/mL (7000mg) in the 6th group.

For the 6th group (7000mg), from the time zero to infinitely-great averaged curve under area be 885.35 μ gh/mL, the average apparent volume of distribution is 213.98L, average total health clearance rate is 8.08L/h.

By with pharmacokinetic parameters (C _MaxAnd AUC _0-t) standardization assesses dose ratio.For 500mg, 1000,2000,3500,5000 and 7000mg dosage, mean dose standardization C _MaxValue is respectively 0.01,0.02,0.02,0.02,0.02 and 0.02 (μ g/mL)/mg.For 500mg, 1000,2000,3500,5000 and 7000mg dosage, mean dose standardized A UC _0-tValue is 0.06,0.112,0.1,0.13,0.10 and 0.12 (μ g/mL)/mg.These discoveries are consistent with the dose ratio of the AZD-103 of 1000-7000mg oral dose scope.

As shown in table 11, as if along with the increase of the dosage that is up to and comprises 3500mg, the PK parameter increases pari passu.At 5000mg dosage, C _MaxWith the increase of AUC less than pro rata increase; This means that absorption process is saturated.Average half-life (the t that eliminates _1/2) be 13-24 hour; Yet plasma concentration shows preceding 12 hours to time graph (Figure 21 and 22) and accounts for about 80-85% of AUC.

In concrete embodiment preferred illustrated with described principle of the present invention, it will be appreciated by those skilled in the art that can be under the situation that does not deviate from such principle arrange and details aspect make a change the present invention.All such changes are all in claims scope of the present invention.

All publications, patent and the patent application mentioned herein all are incorporated herein by reference, and the degree of introducing all is to introduce for your guidance fully independently just as each independent publication, patent or patent application.

Table 1

Pharmacokinetics test before clinical

Table 2

The average pharmacokinetic parameters of the AZD103 of single oral dose in rat (± SD)

^*P＜0.05 (variance analysis)

Table 3

The average pharmacokinetic parameters of the AZD103 of single oral dose in Canis familiaris L. (± SD)

^*P＜0.05 (variance analysis)

Table 4

The average pharmacokinetic parameters of the AZD103 of single oral and intravenous dosages in Canis familiaris L. (± SD)

ND: do not record

Table 5

The average pharmacokinetic parameters of twice administration every day AZD103 after 28 days in rat (± SD)

^*P＜0.05 (variance analysis)

Table 6

The average pharmacokinetic parameters of twice administration every day AZD103 after 14 days in Canis familiaris L. (± SD)

^*P＜0.05 (variance analysis)

Table 7

The average pharmacokinetic parameters among blood plasma and the CSF behind the AZD103 of single oral dose in Canis familiaris L. (± SD)

Blood plasma and CSF meansigma methods are to use the data that derive from identical animal to obtain.

For this reason, have little difference between the statistical data that blood plasma statistical data of listing herein and table 5 are listed, the statistical data that table 5 is listed is based on all animals of accepting oral administration.

Table 8

After the administration 14 days, AZD-103 in CSF and blood plasma respectively at 24 and 12 hours average level

Table 9

(5-6 monthly age) AZD-103 reduction A β and speckle gather when the treatment administration

ANOVA with Fisher ' s PLSD, ^*P＜0.05

Table 10

The scyllitol treatment reduces A β 40 and A β 42 levels

ANOVA with Fisher ' s PLSD, ^*P＜0.05

Table 11

Average (± SD) the pharmacokinetic parameters assessment of ELND005 in health adult behind the single port clothes dosage

The publication of quoting among the embodiment 6

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Claims (27)

1. the dosage form that comprises a certain amount of cyclohexane polyalcohol chemical compound, described dosage form is suitable for individual administration so that the chemical compound of treatment valid density to be provided in blood plasma, brain and/or cerebrospinal fluid, or prevention, treatment or control disease protein folding and/or gather and/or amyloid forms, deposition, assemble or lasting aspect symptom at least a curative effect is provided.

2. the dosage form of claim 1, wherein said dosage form remains on chemical compound in the treatment effective plasma level concentration.

3. the dosage form of claim 2, the plasma concentration of wherein said chemical compound is at least about 0.05 μ M.

4. each dosage form of aforementioned claim, the plasma concentration of wherein said chemical compound is at least about 1-50 μ M, 1-20 μ M, 1-10 μ M, 1-6 μ M or 1-5 μ M.

5. the dosage form of claim 1, wherein said dosage form remains on chemical compound in treatment effective cerebrospinal fluid (CSF) concentration.

6. the dosage form of claim 5, the CSF concentration of wherein said chemical compound is at least about 0.05 μ M.

7. the dosage form of claim 6, the concentration of the CSF of wherein said chemical compound is at least about 1-50 μ M, 1-20 μ M, 1-10 μ M, 1-6 μ M or 1-5 μ M.

8. each dosage form of aforementioned claim, described dosage form is to be used for that be administered once every day or twice, and the chemical compound that comprises doses, described dosage form provide with by the absorption region that is administered three times every day or the absorption that dosage form provided of more times this chemical compound equates, described absorption defines by area under curve (AUC).

9. each dosage form of aforementioned claim, described dosage form comprises the chemical compound of doses, and the Cmin C of chemical compound is provided _Min, the C of described chemical compound _MinWith by the C that above dosage form obtained that is administered twice every day during administration _MinThere is not statistics significantly different.

10. each dosage form of aforementioned claim, described dosage form comprises the chemical compound of doses, and 1-35 hour T is provided _1/2

11. each dosage form of aforementioned claim, described dosage form is to be used for being administered twice every day, and as by its bioavailability that AUC measures be every day the single-dose dosage form bioavailability at least 50%, 60%, 65%, 70%, 75%, 80%, 85% or 90%.

12. each dosage form of aforementioned claim, wherein the cyclohexane polyalcohol chemical compound is to provide about 40:1,35:1,30:1,25:1,20:1 or 15:1, the dosage existence of the cyclohexane polyalcohol chemical compound of preferred 25:1 and the stoichiometric relationship of amyloid peptide.

13. comprise a certain amount of cyclohexane polyalcohol chemical compound and pharmaceutically suitable carrier, the dosage form of diluent or excipient, described dosage form is suitable for individual administration to provide chemical compound at blood plasma, treatment valid density in brain and/or the cerebrospinal fluid, wherein work as dosage form with 500,1000,2000,3500,5000 or during the dosed administration of the described cyclohexane polyalcohol chemical compound of 7000mg, obtained to have and be respectively 43 ± 20% μ gh/mL, 130 ± 20% μ gh/mL, 215 ± 20% μ gh/mL, 467 ± 20% μ gh/mL, the AUC of 507 ± 20% μ gh/mL or 885 ± 20% μ gh/mL _0-INF, and have the average C that is respectively 5.8 ± 20% μ g/mL, 17 ± 20% μ g/mL, 33 ± 20% μ g/mL, 75 ± 20% μ g/mL, 110 ± 20% μ g/mL or 155 ± 20% μ g/mL _MaxThe mean plasma concentration feature.

14. the dosage form of claim 1, wherein said dosage form are suitable for that be administered once every day or twice.

15. each dosage form of aforementioned claim, wherein said dosage form is suitable for oral administration.

16. each dosage form of aforementioned claim, wherein said dosage form is a sustained release forms.

17. each dosage form of aforementioned claim, wherein said dosage form are suitable for that be administered once every day or twice, and chemical compound exists with the amount that is enough to make dosage form to show favourable or the dissolution in vitro feature improved.

18. each dosage form of aforementioned claim, wherein said dosage form is suitable for being administered once every day.

19. each dosage form of aforementioned claim, wherein said dosage form provide zero level or near the release characteristic of zero level.

20. each dosage form of aforementioned claim, wherein said dosage form is suitable for being administered twice every day.

21. comprise the dosage form of cyclohexane polyalcohol chemical compound, described dosage form comprises first dosage and second dosage that is used for second time point administration during administration that is used in first time point administration during the administration, wherein said dosage form comprises the chemical compound of the amount that is enough to provide useful characteristics of pharmacokinetics, and during administration, concentration or the peak concentration of chemical compound in blood plasma, brain or CSF significantly do not change.

22. comprise the dosage form of cyclohexane polyalcohol chemical compound, described dosage form comprises and being used at first time point during the administration to first dosage of individual administration be used for second time point during administration to second dosage of individual administration that wherein said dosage form comprises is enough to provide following C _MinThe chemical compound of amount: the C in blood plasma, brain or CSF that after second time point, provides _MinGreater than the C after first time point _Min

23. each dosage form of aforementioned claim, wherein said cyclohexane polyalcohol chemical compound is the scyllitol chemical compound.

24. each dosage form of aforementioned claim, wherein said cyclohexane polyalcohol chemical compound is a table-inositol chemical compound.

25. comprising to the patient that these needs are arranged, the method for treatment Alzheimer, described method use each dosage form of aforementioned claim.

26. the method for the stabilizer type of preparation claim 1, described method comprises that with a certain amount of cyclohexane polyalcohol chemical compound and pharmaceutically suitable carrier, excipient or mixing diluents, described mixture is suitable for providing described mean plasma concentration feature.

27. the application of at least a cyclohexane polyalcohol chemical compound in the preparation medicine, wherein when described medicine with 500,1000,2000,3500,5000 or during the dosed administration of the described cyclohexane polyalcohol chemical compound of 7000mg, obtained to have the AUC that is respectively 43 ± 20% μ gh/mL, 130 ± 20% μ gh/mL, 215 ± 20% μ gh/mL, 467 ± 20% μ gh/mL, 507 ± 20% μ gh/mL or 885 ± 20% μ gh/mL _0-INF, and have the average C that is respectively 5.8 ± 20% μ g/mL, 17 ± 20% μ g/mL, 33 ± 20% μ g/mL, 75 ± 20% μ g/mL, 110 ± 20% μ g/mL or 155 ± 20% μ g/mL _MaxThe mean plasma concentration feature, to prevent and/or treat protein folding wherein thus and/or to gather and/or amyloid forms, deposition, the disease of assembling or continuing.

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