CN101119714A - Sphingosine 1-phosphate agonists comprising cycloalkanes and 5-membered heterocycles substitued by amino and phenyl groups - Google Patents

Abstract

The present invention provides sphingosine-1-phosphate analogs that are potent, and selective agonists at one or more S1P receptors, specifically the S1P1 receptor type. The compounds invention include compounds having a phosphate moiety as well as compounds with hydrolysis-resistant phosphate surrogates such as phosphonates, alpha-substituted phosphonates, and phosphothionates.

Description

Contain by cycloalkyl and 5 yuan of exciting agent of heterocyclic 1-phosphoric acid sphingol amino and that phenyl replaces

The mutual reference of related application

The application requires the provisional application the 60/652nd of submission on February 14th, 2005, submit in No. 642 and on April 8th, 2005 60/669,60/692,760 the priority of submitting on June 22nd, 616 and 2005, the complete by reference the application that incorporates into of the content of all these applications.

The right of U.S. government

The present invention carries out under U.S.'s National Institutes of Health (National Institutes of Health) No.ROl GM067958 that authorizes and the support of the U.S. government of ROl GM052722 grubstake.U.S. government has some right among the present invention.

Technical field

The present invention relates to that one or more 1-phosphoric acid sphingol receptors are had active novel 1-phosphoric acid sphingol analog.

Background technology

1-phosphoric acid sphingol (S1P) is the lysophosphatide regulator that excites the various kinds of cell reaction by five members of stimulating endothelial cell differentiation gene (EDG) receptor family.Described EDG receptor is g protein coupled receptor (GPCR) and passes through to activate heterotrimeric G protein alpha (G when being upset _α) subunit and β-γ (G _{β γ}) dimer and transmit second message,second messenger's signal.

1-phosphoric acid sphingol (S1P) excites the many reactions from cell and tissue.Wherein be mainly anti-apoptotic, cellular morphology change, cell migration, cell division, blood vessel takes place and pass through change lymphocyte transportation adjusting immune system.Therefore, the S1P receptor is the target that is used for the treatment of for example neoplastic disease, autoimmune disease and organizes allograft rejection.1-phosphoric acid sphingol part is S1P by a group name ₁, S1P ₂, S1P ₃, S1P ₄And S1P ₅G protein coupled receptor and send signal to cell.These receptors have the identical aminoacid of 50-55% and with structure on three kinds of other receptors (LPA of relevant lysophosphatidic acid (LPA) ₁, LPA ₂And LPA ₃) cluster.

When part during in conjunction with described receptor, induce the conformation change in the g protein coupled receptor (GPCR), cause on associating G protein alpha subunit GDP to be replaced by GTP and subsequently G albumen be released in the Cytoplasm.Then, alpha subunit is from the disassociation of β γ subunit, and each subunit can associate with effect protein then, and this has activated the second message,second messenger who causes cell effect.At last, the GTP on the G albumen is hydrolyzed to GDP, and the proteic subunit of G associates mutually again and associates with described receptor then.Amplify to be reflected in the common GPCR approach and play a major role.A kind of part causes the proteic activation of many G with combining of a kind of receptor, and wherein each G albumen can associate with many effect proteins of the cell effect that causes amplifying.

The S1P receptor is the excellent drug target, because each receptor has tissue specificity and atopic simultaneously.The tissue specificity of S1P receptor is desirable, because the exploitation of a kind of selective agonist of receptor or antagonist concentrates on the tissue that contains this receptor with cell effect, has limited undesired side effect.The atopic of S1P receptor also is important, because it allow to start or suppresses some cell effect and do not influence the exploitation of the agonist or the antagonist of other reactions.For example, the atopic of S1P receptor can allow to start platelet aggregation and the exploitation that do not influence the S1P analogies of cellular morphology.

1-phosphoric acid sphingol forms as the metabolite of sphingol in the reaction of itself and E.C. 2.7.1.91, and has high-caliber E.C. 2.7.1.91 and lacking abundant storage the in the platelet aggregation thing of S1P lyases.S1P discharges in the platelet aggregation process, accumulates in serum, and is also shown in malignant ascite.Think S1P the reversibility biodegradation via outer phosphide enzyme for example the enzyme hydrolysis of S1P phosphoric acid hydrolysis carry out, S1P is degraded by S1P hydrolytic enzyme irreversibility.

The physiologic meaning that stimulates each S1P receptor is unknown to a great extent, and this part is owing to lack the acceptor type selective ligands.The S1P receptor is had effective agonist or antagonist activities the S1P analog separation and characterize because the synthetic complexity that S1P analog shortage dissolubility causes is restricted.

At present, novel, the effective optionally preparation that reaches that needs the S1P receptor stimulating agent.Also need to be used for the pharmacological tool of the physiological processes that further research is relevant with the excitement of S1P receptor.

Summary of the invention

The invention provides 1-phosphoric acid sphingol analog, it is one or more S1P receptors (S1P particularly ₁Acceptor type) effectively and optionally agonist.The phosphate radical substitute that The compounds of this invention comprises the chemical compound with phosphate radical part and has an anti-hydrolysis is the chemical compound of the phosphonate radical of phosphonate radical, alpha-substituted (special is the situation of halogen at the alpha-substituted base) and D2EHDTPA root for example.In addition, the invention provides prodrug, for example contain the chemical compound of primary alconol, by for example E.C. 2.7.1.91, especially 2 type E.C. 2.7.1.91 (SPHK2) activate or transform (for example phosphorylation) external for it.

Therefore, the invention provides have formula (I) or (II) 1-phosphoric acid sphingol analog or its pharmaceutically acceptable salt or ester:

Or

Wherein, R ⁴And R ⁷Be CH or CH independently ₂R ⁵Be C, CH or N, R ⁶Be CH, CH ₂, O, S or NR ³R ³Be hydrogen or alkyl;

X is selected from hydroxyl (OH), phosphate radical (OPO ₃H ₂), phosphonate radical (CH ₂PO ₃H ₂), the phosphonate radical of alpha-substituted;

R ¹Be selected from hydrogen, halogen, trifluoromethyl, (C ₁-C ₁₀) alkyl, by (the C of halogen, hydroxyl, alkoxyl or cyano group replacement ₁-C ₁₀) alkyl;

R ²Be selected from (C ₁-C ₂₀) alkyl, the alkyl of cycloalkyl substituted, (C ₂-C ₂₀) thiazolinyl, (C ₂-C ₂₀) group formed of the aralkyl that replaces of alkynyl, aryl, the alkyl aryl, aralkyl and the aryl that replace; R wherein ²In the group-individual or a plurality of carbon atoms can be independently by non-peroxide oxygen, sulfur or NR ⁸Replace; R wherein ⁸Be hydrogen or (C ₁-C ₁₀) alkyl;

R wherein ²In alkyl, thiazolinyl and alkynyl optional replaced by oxo; N is 0,1,2 or 3; And

Represent 1,2 or 3, optional two keys.

The present invention also provides the ester of any chemical compound of formula (1) or formula (II), and phosphate ester for example wherein can add the ester degree of functionality and forms the prodrug that increases oral availability.

The present invention also provides the formula (I) that is used for therapeutic treatment or the chemical compound of formula (II).

On the other hand, the present invention also provides:

Can be the The compounds of this invention of prodrug, promptly they can be activated by phosphorylation in the curee, for example form the analog of single phosphorylation after the administration of carrying out primary alconol.The activated form of some chemical compound of the present invention is the agonist of S1P1 receptor, and therefore can excite lymphopenia to reach about 7 days or the longer time when time in the introducing animal;

Can be S1P ₁, S1P ₄And S1P ₅The selective agonist of receptor also has long acting duration as than FTY-720 (Fen Gemode, fingolimod) The compounds of this invention of long action time;

The pharmaceutical composition that contains formula (I), formula (II) chemical compound or its mixture or its pharmaceutically acceptable salt or ester and pharmaceutically acceptable excipient;

The method of prevention or treatment autoimmune disease, described autoimmune disease is uveitis, type i diabetes, rheumatoid arthritis, inflammatory bowel for example, and more particularly, multiple sclerosis, described method comprise the formula (I) of mammal (as the people) effective dose that delivers medicine to this treatment of needs, chemical compound or its pharmaceutically acceptable salt of formula (II);

The method of prevention or treatment progressive dementia or brain degenerative diseases;

Change the lymphocyte transportation, as the method that is used to prolong allograft's time-to-live, for example be used for that the organa parenchymatosum transplants, the treatment of graft versus host disease, bone marrow transplantation etc.;

By suppressing self toxin prophylaxis of cancer progress, for example take place by the blood vessel in prevention or the inhibition tumor; Or

The chemical compound of formula (I), formula (II) or its pharmaceutically acceptable salt are used for preparation prevention or suppress the autoimmune disease of mammal (as the people) or the purposes of the medicine that the blood vessel of tumor takes place.

The present invention also provides new intermediate and the method that is used for the chemical compound of preparation formula (I) or formula (II) disclosed herein, comprises general and specific intermediate and the synthetic method of describing in the figure of this paper and embodiment.

The accompanying drawing summary

Fig. 1 provides the route of synthesis of preparation VPC01091 (6) and preparation VPC01211 (7).

Fig. 2 is explanation chemical compound VPC01091 does not have the measurement result of influence to the heart rate of mice a diagram.In this was measured, test-compound was by intravenously administrable, and carrier is 2% cyclodextrin.

Fig. 3 illustrates the total blood lymphocyte counting after single dose VPC01091 or carrier are delivered medicine to mice.Every group of 5 mices, age in 10-11 week, svl29 x C57B1/6 system.Vertical coordinate is represented lymphocyte (K/ μ l).The abscissa express time (my god).

Fig. 4 illustrates the VPC01091 (vehicle Control at the variable concentrations of oral administration (tube feed) in 2% hydroxypropyl, 0.1,0.3,1.0 and 3.0mg/kg) measurement result of lymphopenia afterwards, every group of 3 mices (with homology among Fig. 3) detect when 24 hours (every group left bar) and 48 hours (every group right bar).

Fig. 5 illustrates at the VPC01091 with single oral dose and delivers medicine to heterozygosis (SPHK2 ^+/tr) and (SPHK2 that isozygotys ^Tr/tr) total lymphocyte counting (k/ μ l) after the mice 24 hours, wild-type mice is only accepted carrier (hydroxypropyl).By being inserted two allele, the exon capturing element destroys the SPHK2 gene.

Fig. 6 illustrates broken GTP γ ³⁵The S cell is for people S1P ₁Receptor in conjunction with measurement result, detected S1P and three kinds of other chemical compounds.Chemical compound " CA5-P " is VPC01211.Chemical compound VPC01214 (CA6-P) and VPC01222 (CA4-P) are corresponding cyclohexyl and cyclobutyl chemical compound.Vertical coordinate is represented GTP γ ³⁵The bonded percent of S, abscissa are represented the log molar concentration of phospholipid.

Fig. 7 illustrates and uses express recombinant people S1P ₂The result that the calcium mobilization that the CHO-K1 cell of receptor carries out measures.Chemical compound " CA5-P " is VPC01211.Compound C A6-P and CA4-P are corresponding cyclohexyl and cyclobutyl chemical compound.Vertical coordinate is represented maximum calcium mobilization's percent, and abscissa is represented the log molar concentration of phospholipid.

Fig. 8 illustrates broken GTP γ ³⁵The S cell is for people S1P ₂Receptor in conjunction with measurement result.Chemical compound " CA5-P " is VPC01211.Compound C A6-P and CA4-P are corresponding cyclohexyl and cyclobutyl chemical compound.Vertical coordinate is represented GTP γ ³⁵The bonded percent of S, abscissa are represented the log molar concentration of phospholipid.

Fig. 9 illustrates and uses express recombinant people S1P ₃The result that the calcium mobilization that the CHO-K1 cell of receptor carries out measures.Chemical compound " CA5-P " is VPC01211.Compound C A6-P and CA4-P are corresponding cyclohexyl and cyclobutyl chemical compound.

Figure 10 illustrates broken GTP γ ³⁵The S cell is for people S1P ₄Receptor in conjunction with measurement result.Chemical compound " CA5-P " is VPC01211.Compound C A6-P and CA4-P are corresponding cyclohexyl and cyclobutyl chemical compound.

Figure 11 illustrates broken GTP γ ³⁵The S cell is for people S1P ₅Receptor in conjunction with measurement result.Chemical compound " CA5-P " is VPC01211.Compound C A6-P and CA4-P are corresponding cyclohexyl and cyclobutyl chemical compound.

Figure 12 has illustrated that the test-compound VPC01222 of prescribed concentration is to people S1P ₃The S1P dose response curve result's of receptor Schild curve.The moving to right of S1P dose response curve shows that VPC01222 is as the surmountable antagonist of this receptor type and work.

Figure 13 has illustrated that the test-compound VPC01211 of prescribed concentration is to S1P ₃The S1P dose response curve result's of receptor Schild curve.The moving to right of S1P dose response curve shows that VPC01211 is as the surmountable antagonist of this receptor type and work.

Figure 14 has illustrated that the test-compound VPC01214 of prescribed concentration is to S1P ₃The S1P dose response curve result's of receptor Schild curve.The moving to right of S1P dose response curve shows that VPC01214 is as the surmountable antagonist of this receptor type and work.

Figure 15 has illustrated in the reaction to S1P and the S1P that has 10 μ M VPC01211 and has crossed expressing human S1P ₃Calcium mobilization's measurement result in the T24 cell of receptor.Move to right and show that VPC01211 is to S1P ₃The surmountable antagonism of receptor.

Figure 16 has illustrated the exciting S1P of phosphorylation isomer VPC01211 (VPC01091 of phosphorylation) ₁The ability of receptor.

Figure 17 has illustrated the exciting S1P of phosphorylation isomer VPC01211 (VPC01091 of phosphorylation) ₃The ability of receptor.

Figure 18 has illustrated the SPHK2 activity with four kinds of VPC01091 isomers.

Figure 19 illustrates the total lymphocyte counting (k/ μ l) that VPC01091 isomer with oral dose delivers medicine to 24 hours (every group left bar) and 96 hours (every group right bar) behind the mice.

The specific embodiment

Abbreviation

This paper has used following abbreviation: S1P, 1-phosphoric acid sphingol; GPCR, g protein coupled receptor; SAR, structure-activity relation; EDG, the endothelial cell differentiation gene; EAE, experimental autoimmune encephalomyelitis; NOD, non-non-insulin-dependent diabetes mellitus; TNF α, tumor necrosis factor; HDL, high density lipoprotein; RT-PCR, reverse transcriptional PCR.

Unless otherwise, all technical terms used herein have the known identical implication with the general technical staff of the technical field of the invention with scientific terminology.Although those similar or identical methods any and described herein and material can be used for practice of the present invention or test, this paper has described preferable methods and material.As used herein, each following term has in the relative implication of this part.

In explanation the present invention with in to its prescription, following term will be used according to following definitions.

For purpose of the present invention is described, article herein (" a " and " an ") is used in reference to one (kind) or refers to thing more than the grammer of this article of one (kind) (being at least one (kind)).For instance, " element " meaning is (kind) element or more than a kind of element.

As used herein, " analog " of chemical compound is for example structurally similar to another kind of chemical compound but chemical compound not necessarily isomer (is the analog of thymus pyrimidine as 5-fluorouracil).

" contrast " cell, tissue, sample or curee are cell, tissue, sample or the curees with the cell that is tried, tissue, sample or curee's same type.For example, subject cell, tissue, sample or curee's accurately detection contrast simultaneously or almost simultaneously can detected.For example, can also the time detecting when the cell that is tried away from detection, tissue, sample or curee contrast, the testing result of record contrast is so that can compare record result and the result that the cell that is tried by detection, tissue, sample or curee obtain.Can be from another source or similar source but not be subjected to the examination group or the curee that tried obtains contrast, wherein given the test agent suffers from patient's acquisition that institute implements the disease or the disease of detection from suspection.

" being tried " cell, sample or curee is just examined cell, sample or curee.

" pathology indication " cell, tissue or sample are positioned at wherein cell, tissue or the sample that the animal of (or obtain tissue) is invaded by disease or disease for indication described cell, tissue or sample.For instance, the existence of one or more mammary glandular cells in the lung tissue of animal indicates this animal to be subjected to the infringement of metastatic breast cancer.

If one or more cells are present in the tissue of the animal that is not subjected to disease or disease infringement, tissue " comprising under the normal condition " cell.

As used herein, " derivant " of chemical compound is meant to have the chemical compound that the chemical compound of analog structure produces from another kind with a step or a plurality of step, and described step is as by alkyl, acyl group or the amino hydrogen that replaces.

The meaning of the version of word " detection " and grammer thereof is meant the measurement of non-quantitation ground to species, and the word " mensurations " that uses in conjunction with its grammatical variants or " measurement " look like and be meant quantitatively measurement to species.Term " detection " and " evaluation " are used interchangeably in this article.

As used herein, " detectable label " or " reporter molecules " are meant the atom or the molecule of permission specific detection chemical compound under the situation of the analogue compounds that have unmarked thing.Detectable label or reporter molecules include, but are not limited to radiosiotope, antigenic determinant, enzyme, the nucleic acid that can be used for hybridizing, chromophore, fluorophor, chemiluminescent molecule, the detectable molecule of electrochemistry and provide the fluorescence polarization of variation or the molecule of the light scattering of variation.

As used herein, " effective dose " is meant the amount of the selected effect of enough generations." the treatment effective dose " of chemical compound is the amount that enough curee who carries out described compound administration is provided the chemical compound of beneficial effect.

As used herein, " guiding material " comprises publication, record, chart or any other expression medium that can be used for passing at earmarking of the present composition its serviceability.The guiding material of test kit of the present invention can for example invest the container that comprises described compositions or transport with the container that contains described compositions.Alternatively, described guiding material can separate with container and transports, and purpose is that described guiding material and described compositions are by the use of receiver's co-operate.

As used herein, term " purification " and similar term be meant with normal condition under the molecule of other components relevant or the enrichment of chemical compound with respect to the molecule in the natural surroundings or chemical compound.Term " purification " not necessarily shows the complete purification that has obtained specific molecular in operating process.This paper employed " highly purified " chemical compound is meant that purity is greater than 90% chemical compound.

As used herein, term " pharmaceutically acceptable carrier " comprises the pharmaceutical carriers of any standard known in the art, for example phosphate buffered salt solution, water, Emulsion (for example oil/water or water/oil emulsion), and various types of wetting agent.This term also comprises the Federal Government administrative organization any preparation that is used for animal (comprising the people) approval or that American Pharmacopeia is listed.

As used herein, " sample " preferably is meant the biological sample from the curee, includes but not limited to normal tissue sample, ill tissue sample, biopsy, blood, saliva, stool, seminal fluid, tear and urine.Sample can also be the material in any other source of obtaining from the curee, and it contains interested cell, tissue or liquid.Sample also can obtain from the cell or tissue culture.

As used herein, term " standard " is meant the material that is used to compare.For example, it can be known standard preparation or the chemical compound that delivers medicine to or make an addition to control sample and be used for comparing result during described chemical compound in measuring given the test agent.Standard also can refer to " internal standard ", for example makes an addition to sample with known quantity and processed or stand to can be used for measuring when purification or extraction are operated preparation or chemical compound such as the project of the purification or the response rate when sample measuring before the interested label of institute.

" curee " that analyze, diagnose or treat is animal.Described animal comprises mammal, preferred people.

" curee " of diagnosis or treatment is animal, comprises the people.

" therapeutic " treatment is to deliver medicine to performance the curee of pathology sign to be arranged to alleviate or to eliminate the treatment of those signs.

" the treatment effective dose " of chemical compound is the amount of the chemical compound of beneficial effect to be provided enough for the curee who carries out described compound administration.

As used herein, term " treatment " comprises the prevention of particular disorder or illness, or the alleviation symptom relevant with particular disorder or illness, and/or prevention or alleviate described symptom." preventative " treatment is to deliver medicine to the curee that do not show the disease sign and only show the early stage sign of the disease danger with the pathology that reduces to develop described disease association.

As used herein, term " receptor stimulating agent " is defined as simulating S1P to the effect of its receptor but the chemical compound with different effectiveness and/or effect.

As used herein, term " pharmaceutically acceptable carrier " comprises the pharmaceutical carrier of any standard, for example phosphate buffered salt solution, hydroxypropyl (HO-propyl group beta cyclodextrin), water, Emulsion (for example oil/water or water/oil emulsion), and various types of wetting agent.This term also comprises the Federal Government administrative organization any preparation that is used for animal (comprising the people) approval or that American Pharmacopeia is listed.

As used in the present invention, term " pharmaceutically acceptable salt " is meant the biological effectiveness that keeps The compounds of this invention and character and is not biologically or the salt of other non-expectations.In many cases, The compounds of this invention can form hydrochlorate and/or alkali salt down by the existence of amino and/or carboxyl or its similar group.

As used herein, term " treatment " comprises the prevention of particular disorder or illness, or the alleviation symptom relevant with particular disorder or illness, and/or prevention or alleviate described symptom.

As used herein, " effective dose " is meant the amount of the selected effect of enough generations.For example, the S1P receptor stimulating agent of effective dose is the amount that reduces the cell signaling activity of S1P receptor.

As used herein, " guiding material " comprises the publication, record, chart or any other expression that can be used for passing at earmarking of The compounds of this invention its serviceability.The guiding material of test kit of the present invention can for example invest the container that comprises described compositions or transport with the container that contains described compositions.Alternatively, described guiding material can separate with container and transports, and purpose is that described guiding material and described compositions are by the use of receiver's co-operate.

Method of the present invention comprises test kit, and it contains in the present invention the inhibitor of identifying and describes the guiding material that described inhibitor or the compositions that contains described inhibitor is delivered medicine to cell or animal.This should be interpreted as comprising the test kit of other embodiments well known by persons skilled in the art, for example comprises being suitable for described compound administration being dissolved before cell or animal or the test kit of the solvent (preferably aseptic) of suspension The compounds of this invention.Preferably, described animal is behaved.

It will be understood by those skilled in the art that the The compounds of this invention with chiral centre can exist with separated with optical activity and racemic modification form.Some chemical compound can show pleomorphism.Should understand any raceme, optical activity, pleomorphism or the stereoisomer form that the present invention includes The compounds of this invention, or their mixture, it has useful quality as herein described, how to prepare the optical activity form (for example, by resolve racemic form, recrystallization technology, synthetic from the optical activity parent material, chirality is synthetic or by using chiral stationary phase chromatography to separate) with use standard method of test described herein or to use other similar test determines S1P agonist activities well known in the art be well known in the art.

At chemical compound enough acid or alkalescence with the situation that forms hydrochlorate or alkali salt in, be suitable as the use of the chemical compound of salt.The example of acceptable salt is and forms the organic acid addition salt that the physiology goes up acceptable anionic acid formation, for example toluene fulfonate, mesylate, acetate, citrate, malonate, tartrate, succinate, benzoate, Ascorbate, alpha-ketoglutarate, α-glycerophosphate.Suitable inorganic salt be can also form, hydrogen villaumite, sulfate, nitrate, bicarbonate and carbonate comprised.

Can prepare pharmaceutically-acceptable acid addition by mineral acid and organic acid.The mineral acid of salt derivative comprises hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid etc.The organic acid of salt derivative comprises acetic acid, propanoic acid, glycolic, acetone acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, salicylic acid etc.

Pharmaceutically acceptable base addition salts can be by inorganic base and organic base preparation.Comprise (only for instance) sodium, potassium, lithium, ammonium, calcium and magnesium salt by the deutero-salt of inorganic base.Salt derived from organic base comprises, but be not limited to primary amine, the salt of secondary amine and tertiary amine, described primary amine, secondary amine and tertiary amine be alkylamine for example, dialkylamine, trialkylamine, the alkylamine that replaces, two (alkyl of replacement) amine, three (alkyl of replacement) amine, alkenyl amine, dialkylene amine, trialkenyl amine, the alkenyl amine that replaces, two (thiazolinyl of replacement) amine, three (thiazolinyl of replacement) amine, Cycloalkyl amine, two (cycloalkyl) amine, three (cycloalkyl) amine, the Cycloalkyl amine that replaces, dibasic Cycloalkyl amine, trisubstituted Cycloalkyl amine, cycloalkenyl group amine, two (cycloalkenyl group) amine, three (cycloalkenyl group) amine, the cycloalkenyl group amine that replaces, dibasic cycloalkenyl group amine, trisubstituted cycloalkenyl group amine, arylamine, diaryl amine, triarylamine, heteroaryl amine, two heteroaryl amine, three heteroaryl amine, heterocyclic amine, two heterocyclic amines, three heterocyclic amines, blended diamidogen and triamine, at least two substituent groups differences on the wherein said amine also are selected from alkyl, the alkyl that replaces, thiazolinyl, the thiazolinyl that replaces, cycloalkyl, the cycloalkyl that replaces, cycloalkenyl group, the cycloalkenyl group that replaces, aryl, heteroaryl, the group that heterocycle etc. are formed.Comprise that also two or three substituent groups wherein form the amine of heterocycle or heteroaryl with amino nitrogen.The example of suitable amine comprises (only for instance), 2-aminopropane., trimethylamine, diethylamine, three (isopropyl) amine, three (n-pro-pyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethane, lysine, arginine, histidine, caffeine, procaine, Kazakhstan amine (hydrabamine), choline, betanin, ethylenediamine, glycosamine, N-alkyl glucose amine, theobromine, purine, piperazine, piperidines, morpholine, N-ethylpiperidine etc.Should also be appreciated that other carboxylic acid derivates can be used for enforcement of the present invention, for example carboxylic acid amide comprises carboxylic acid amides, low alkyl group carboxylic acid amides, dialkyl group carboxylic acid amides etc.

Acceptable salt can use standard operation well known in the art to obtain, for example the chemical compound by enough alkalescence for example amine with the physiology is provided upward acceptable anionic suitable acid reaction.The alkali metal (for example sodium, potassium or lithium) or alkaline-earth metal (for example calcium) salt that can also prepare organic acid (for example carboxylic acid).

The method of intermediate that preparation formula (I), the chemical compound of formula (II) or the chemical compound that preparation is used for preparation formula (I) or formula (II) are provided is as further embodiment of the present invention.The intermediate that the chemical compound that is used for preparation formula (I) or formula (II) also is provided is as further embodiment of the present invention.

The chemistry definition

As used herein, term " halogen " or " halogen " comprise bromine, chlorine, fluorine and iodine.

As used herein, term " alkylhalide group " is meant the alkyl that has at least one halogenic substituent, for example, and chloromethyl, methyl fluoride or trifluoromethyl etc.

As used herein, term " alkyl or C ₁-C ₁₀Alkyl " expression has the branched-chain or straight-chain alkyl of 1 to 6 carbon atom.Typically, C ₁-C ₁₀Alkyl includes, but are not limited to methyl, ethyl, n-pro-pyl, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, hexyl, heptyl, octyl group etc.

As used herein, term " thiazolinyl or C ₂-C ₁₀Thiazolinyl " expression has the olefinic unsaturated side chain or the straight chain group of the two keys of 2 to 10 carbon atoms and at least one.This class examples of groups includes, but are not limited to 1-acrylic, 2-acrylic, 1,3-butadiene base, 1-butylene base, hexenyl, pentenyl etc.

Term " alkynyl or C ₂-C ₁₀Alkynyl " be meant to have 2 to 10 carbon atoms and at least one triple-linked unsaturated side chain or straight chain group, this class examples of groups includes, but are not limited to 1-propinyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 1-pentynyl etc.

Term " C ₃-C ₈Cycloalkyl " representative ring propyl group, cyclobutyl, cyclopenta, cyclohexyl, suberyl, ring octyl group etc.

As used herein, term " the optional replacement " is nulling to four substituent group, and wherein said substituent group is respectively to be selected independently.Each substituent group of selecting independently can be identical or different with other substituent groups.

As used herein, term " aryl " is meant monocycle or the bicyclo-C with one or two aromatic ring ₅-C ₁₀Carbon-loop system includes, but are not limited to phenyl, benzyl, naphthyl, tetralyl, indanyl, indenyl etc.

As used herein, " optional replace aryl " comprises having zero to four substituent aryl compounds, and the aryl that replaces comprises having one to three substituent aryl compound, and wherein said substituent group comprises for example alkyl, halogen or amino substituent group.

Term " aralkyl " is meant any aryl that is connected to parent fraction by alkyl, for example, and aryl (C ₁-C ₈Alkyl).Therefore, term (C ₅-C ₆Aryl) (C ₅-C ₈Alkyl) is meant and passes through C ₅-C ₈Alkyl is connected to five yuan or hexa-atomic aromatic ring of parent fraction.

Term " heterocyclic group " be meant optional replace contain one to three heteroatomic monocycle or bicyclo-carbon-loop system, wherein said hetero atom is selected from the group that oxygen, sulfur and nitrogen are formed.

As used herein, term " heteroaryl " is meant monocycle or the bicyclo-carbon-loop system with the optional replacement that contains one to three heteroatomic one or two aromatic ring, includes but not limited to furyl, thienyl, pyridine radicals etc.

Stable 7 yuan to 12 yuan bridge joints or condensed bicyclo-carbocyclic ring that term " bicyclo-" expression is unsaturated or saturated.Described bicyclo-can connect providing on any carbon atom of rock-steady structure.This term includes, but not limited to naphthyl, dicyclohexyl, two cyclohexenyl groups etc.

Chemical compound of the present invention can contain one or more asymmetric centers in molecule.According to the present invention, do not specify any structure of stereochemical structure to be understood to include all multiple optical isomer and racemic mixture thereof.

Chemical compound of the present invention can exist with tautomeric form, and the present invention comprises mixture and the one tautomer that separates simultaneously.For example, following array structure:

Be understood that to represent the mixture of array structure down:

With

Term 16:0,18:0,18:1,20:4 or 22:6 hydrocarbon are meant branched-chain or straight-chain alkyl or thiazolinyl, the number of the two keys in the sum of the carbon in first integer representation group wherein, second integer representation group.

As used herein, " S1P regulator " be meant can be in vivo or the chemical compound of the detectable variation of external evoked S1P receptor active or compositions (for example, the active increase of S1P or be reduced by at least 10%), the detectable variation of described S1P receptor active by given assay method for example described in the embodiment and bioassay method known in the art measure.As used herein, " S1P receptor " is meant all S1P receptor subtypes (for example, S1P receptor S1P ₁, S1P ₂, S1P ₃, S1P ₄, S1P ₅), unless specify specific hypotype.

As used herein, the term " EC of preparation ₅₀" be meant in given activity and comprise the concentration of the functional activity (for example signaling activity) of the combination of the sphingol part of S1P receptor or other parts and/or S1P receptor for the preparation of 50% maximum activity of S1P receptor.EC is differently described ₅₀Provide the concentration of 50% active preparation, add multiple ligand/agonist more and amount that the S1P receptor active does not increase when 100% activity is set at, 0% is set to the active amount in the mensuration that does not have the part/agonist that is added.

As used herein, term " phosphate radical analog " and " phosphonate radical analog " comprise the phosphate radical that phosphorus atoms is wherein partly replaced by non-oxygen at+5 oxidation state and one or more oxygen atom and the analog of phosphonate radical, comprise, for example phosphate radical analog D2EHDTPA root, phosphordithiic acid root, seleno phosphate radical, two seleno-acid phosphate radicals, aniline D2EHDTPA root, aniline phosphate radical, phosphamide root, boron phosphate radical etc., comprise relevant equilibrium ion, for example hydrogen, NH ₄, Na etc. (if this class equilibrium ion exists).

The present invention relates to as receptor stimulating agent one or more S1P receptors (S1P particularly ₁, S1P ₄And S1P ₅Acceptor type) has active 1-phosphoric acid sphingol (S1P) analog.The phosphate radical substitute that The compounds of this invention comprises the chemical compound with phosphate radical part and has an anti-hydrolysis is the chemical compound of the phosphonate radical of phosphonate radical, alpha-substituted (especially when described alpha-substituted base be under the situation of halogen) and D2EHDTPA root for example.

In an embodiment of S1P receptor stimulating agent or its pharmaceutically acceptable salt, it has the general structure of following formula (IIA):

Wherein, n is 0,1,2 or 3; X is selected from hydroxyl (OH), phosphate radical (OPO ₃H ₂), phosphonate radical (CH ₂PO ₃H ₂), the phosphonate radical of alpha-substituted (comprises-CHFPO ₃H ₂,-CF ₂PO ₃H ₂,-CHOHPO ₃H ₂,-C=OPO ₃H ₂),

R wherein ¹Be selected from hydrogen, halogen (wherein F or C1 are preferred halogen), (C ₁-C ₆) group formed of alkyl, for example methyl, ethyl and propyl group, the or (C that replaces of halogen, hydroxyl, alkoxyl, cyano group ₁-C ₆) alkyl, for example trifluoromethyl.

R ²Group is selected from the group that aryl that aryl that alkyl, thiazolinyl, alkynyl, alkyl replace, cycloalkyl, aralkyl and aralkyl that alkyl replaces replace is formed.At R ²In, the chain length of 5-8 carbon atom is preferred.

The present invention also provides the ester of any chemical compound of formula (II), and for example phosphate ester wherein can add the ester degree of functionality to form the prodrug that increases oral availability.

In an embodiment preferred, the described chemical compound with formula (II) can have and is selected from following group R ¹: H, halogen (preferred F or Cl), methyl, trifluoromethyl, ethyl, propyl group or other low alkyl groups (C ₁-C ₆), or the low alkyl group that replaces of halogen, hydroxyl, alkoxyl, cyano group; And R ²The group that is selected from alkyl, thiazolinyl, alkynyl, alkyl (aryl of optional replacement), alkyl (the optional cycloalkyl that replaces), aralkyl and preferably has aralkyl (the optional aryl that the replaces) composition of 5-8 carbon atom length.

S1P receptor antagonist prodrugs (preferred S1P ₁The acceptor type selective antagonist) potential use includes, but are not limited to:

Change the lymphocyte transportation, as the Therapeutic Method of following autoimmune disease: for example uveitis, type i diabetes, rheumatoid arthritis, inflammatory bowel, and multiple sclerosis more particularly." treatment " of multiple sclerosis comprises the various ways of this disease, comprise recurrence remission form, chronic progress type etc., and the S1P receptor antagonist can use or unite other preparations use and preventative uses of the S﹠S of alleviating this disease separately.

In addition, The compounds of this invention can be used for changing lymphocyte transportation, and described change lymphocyte transportation is a kind of method that prolongs allograft's time-to-live, for example is used for that the organa parenchymatosum transplants, the treatment of graft versus host disease, bone marrow transplantation etc.

In addition, The compounds of this invention can be used for suppressing autocrine motility factor (autotaxin).Autocrine motility factor---a kind of serum phosphodiesterase has been proved to be and can have carried out the end-product inhibition.Several substrates of autocrine motility factor hydrolysis produce lysophosphatidic acid and 1-phosphoric acid sphingol, and relate to cancer progression and blood vessel generation.Therefore, S1P receptor stimulating agent prodrug for example VPC01091 can be used for suppressing autocrine motility factor.This activity can with to the excitement of S1P receptor associating or do not rely on this activity.

In addition, The compounds of this invention can be used for suppressing the S1P lyases.The S1P lyases is the desmoenzyme of irreversibility degraded S1P.The inhibition of S1P lyases destroys the lymphocyte transportation, and with lymphopenia.Therefore, the S1P lyase inhibitors can be used for regulating function of immune system.Therefore, prodrug for example VPC01091 can be used for suppressing the S1P lyases.This inhibitory action can be consistent with the S1P receptor active, maybe can not rely on the activity to any S1P receptor.

" treatment " of multiple sclerosis comprises the various ways of this disease, comprise recurrence remission form, chronic progress type etc., and the S1P receptor stimulating agent can use or unite other preparations use and preventative uses of the S﹠S of alleviating this disease separately.

The present invention also comprises the pharmaceutical composition that contains The compounds of this invention.More specifically, described chemical compound can use pharmaceutically acceptable carrier, filler, solubilizing agent and the stabilizing agent of standard well known by persons skilled in the art to be mixed with pharmaceutical composition.For example, the compositions that contains The compounds of this invention or its analog, derivant or modifier as described herein is used for suitable described compound administration in the curee.

The compounds of this invention can be used for treating disease or disease, but comprise to have in requisition for the curee treat the chemical compound of the formula (I) of receiving amount, or contain the chemical compound of the formula (I) for the treatment of effective dose and the pharmaceutical composition of pharmaceutically acceptable carrier.

The concrete value of low alkyl group is ethyl or propyl group.

The concrete value of halogen is a fluorine or chlorine.

The concrete value of X is hydroxyl or OPO ₃H ₂

The phosphonate radical of alpha-substituted comprises-CHFPO ₃H ₂,-CF ₂PO ₃H ₂,-CHOHPO ₃H ₂,-C=OPO ₃H ₂Or thiophosphate root (OPO ₂SH ₂).

R ¹Concrete value be hydrogen.

R ²Concrete value be alkyl with 5-8 carbon atom length.

R ²Value more specifically be heptyl, octyl group, nonyl ,-the O-heptyl ,-C (=O) heptyl or CH ₃-CH ₂-O-CH ₂-CH ₂-O-CH ₂-CH ₂-O-.

R ²In the value more specifically of alkyl be octyl group or-the O-heptyl.

R ²The value more specifically of middle alkyl is an octyl group.

The concrete value of n is 1 or 2.

Concrete cycloalkyl with two keys comprises:

Particular compound of the present invention has the R that is positioned at the cycloalkyl ring para-position ²Group.

Particular compound of the present invention has the R of being positioned at ²The R of an ortho position or a position ¹Group.

Particular compound of the present invention has the R of the para-position that is positioned at the benzyl rings alkyl (promptly 1,4) ²Group.

The limiting examples of the ester of The compounds of this invention comprises that wherein the X group is the chemical compound of following radicals:

Wherein Y is selected from O, CH ₂, CHOH, CHF, CF ₂With

The group that becomes; And

R ⁹And R ¹⁰Be independently selected from alkoxyl, alkene oxygen base, alkynyloxy group, aryloxy group,

O-R ¹¹,

And

The group of forming;

Wherein, R ¹¹Be selected from C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, C ₂-C ₄The group that alkynyl and the optional aryl that replaces are formed.Particularly preferred R ⁹And R ¹⁰Be alkoxyl,

And

The route of synthesis of preparation VPC01091 and VPC01211 is provided in the flow process in Fig. 1.Those skilled in the art can use and known the operational approach of described flow process and the improved technology of detailed description in this paper specific embodiment be come other chemical compounds of preparation formula (I) or formula (II).

The particular compound of formula of the present invention (II) is VPC01091, and wherein X is OH, R ¹Be hydrogen, R ²Be octyl group (C ₈H ₁₇), n is 2, and R ²Group is in the para-position of phenyl ring.This formula is:

The particular compound of formula of the present invention (II) is VPC02162, and wherein X is OH, R ¹Be hydrogen, R ²Be octyl group (C ₈H ₁₇), n is 2, and R ²Group is the position between phenyl ring, and this formula is:

The present invention also comprises following isomer:

And

These chemical compounds can be formulated as mixture and separate by chromatographic process.Isolating appropraite condition is as follows: post: Chiralpak AD 4.6 mmID x 250mm; Mobile phase: Hex/EtOH/MeOH/DEA=95/2.5/2.5/0.03; Flow velocity: 1mL/min; Detector: UV 220nm; Column temperature: 40 ℃; Or column temperature: 25 ℃.After separating, find two kinds of isomers external not by SPHK2 enzyme phosphorylation.Yet, before test, during phosphorylation, find that the chemical compound of phosphorylation is effective agonist of S1P receptor.

Another particular compound of formula of the present invention (II) is VPC01211, and wherein X is OPO ₃H ₂, R ¹Be hydrogen, R ²Be octyl group (C ₈H ₁₇), n is 2, and R ²Group is in the para-position of phenyl ring, and this formula is:

Another particular compound of formula of the present invention (II) is VPC02164, and wherein X is OPO ₃H ₂, R ¹Be hydrogen, R ²Be octyl group (C8H17) that n is 2, and R ²Group is the position between phenyl ring, and this formula is:

Other examples that comprise the The compounds of this invention of hetero atom (for example N, S, O) and/or two keys in cycloalkyl ring comprise following structure:

Or

Having the formula (I) of general formula (III) or other chemical compounds of formula (II) describes hereinafter.Concrete version is described in table 1:

Table 1

Chemical compound	Figure number	R	n	X
					VPC02004	-	C 7H 15	2	OH
VPC02007	-	C 7H 15	2	OPO 3H 2
					VPC01091	CA5	C 8H 17	2	OH
VPC01211	CA5-P	C 8H 17	2	OPO 3H 2
					VPC02031	-	C 9H 19	2	OH
VPC02033	-	C 9H 19	2	OPO 3H 2
					VPC01289	-	C 10H 21	2	OH
VPC01292	-	C 10H 21	2	OPO 3H 2
					VPC01220	CA4	C 8H 17	1	OH
VPC01222	CA4-P	C 8H 17	1	OPO 3H 2
					VPC01213	CA6	C 8H 17	3	OH
VPC01214	CA6-P	C 8H 17	3	OPO 3H 2

The present invention also provides the ester of the chemical compound of formula (I) or formula (II), and the formation of wherein said ester can be converted into described chemical compound the prodrug that strengthens administration, for example increases oral availability.In addition, the present invention also provides the pharmaceutically acceptable salt of the chemical compound of formula (I) or formula (II).In addition, the invention provides all possible isomer of formula (I) or the described structure of formula (II), note: when n is 1 (Tetramethylene. base), described chemical compound is symmetric, and lacks chiral centre, but has cis and trans forms.

The pharmaceutical composition that contains one or more chemical compounds of the present invention can deliver medicine to the curee who needs corresponding treatment by the approaches and methods of any number, described approaches and methods includes, but are not limited in part, oral, oral cavity, intravenous, intramuscular, intra-arterial, the marrow, in the sheath, in the ventricle, through skin, subcutaneous, intraperitoneal, intranasal, enteral, part, Sublingual, vagina, eye, lung or rectum approach.Oral route need in the most applications of The compounds of this invention to be applied to usually.Preferred intravenous injection or infusion are administered for acute treatment.For Concept of Maintenance, oral or parenteral, for example intramuscular or subcutaneous route are preferred.

According to an embodiment, provide and contained The compounds of this invention or its analog, derivant or modified form and albuminous compositions, more particularly, described compositions contains The compounds of this invention, pharmaceutically acceptable carrier and 0.1-1.0% albumin.Albumin works as buffer agent and improves the dissolubility of described chemical compound.On the one hand, do not add albumin.

In one embodiment, the administration that can be used for implementing pharmaceutical composition of the present invention is to send 1ng/kg/ days to 100mg/kg/ days dosage.In another embodiment, the administration that can be used for implementing pharmaceutical composition of the present invention is to send 1ng/kg/ days to 100g/kg/ days dosage.

Useful pharmaceutically acceptable carrier includes, but are not limited to glycerol, water, saline, ethanol and other pharmaceutically acceptable salt solution, for example phosphate and acylate.The example of these and other pharmaceutically acceptable carriers is described in Remington ' s Pharmaceutical Sciences (1991, MackPublication Co., New Jersey) to some extent.

Can be with form preparation, packing or the sale pharmaceutical composition of aseptic parenteral solution or oil suspension or solution.This suspension or solution can be prepared according to known technology, and except that active component, also contain other compositions, dispersant for example as herein described, wetting agent or suspending agent.This aseptic injection preparation can use avirulent parenteral acceptable diluent or solvent preparation, for example water or 1,3 butylene glycol.Other acceptable diluent and solvent include, but are not limited to for example synthetic monoglyceride of ringer's solution, isotonic sodium chlorrde solution, nonvolatile oil or diglyceride.

Can prepare to use any method compounds identified described herein and it is delivered medicine to the curee and be used for the treatment of any disease as herein described and disease.Yet the purposes of The compounds of this invention should not be construed as and only comprises disease as herein described and disease.Preferably, described curee behaves.

The preparation of pharmaceutical composition as herein described can any method known or exploitation in the future prepare by pharmaceutical field.In general, these preparation methoies comprise active component introducing and carrier or one or more other auxiliary elements are merged, and then, if necessary or need, described product is shaped or is packaged into required single dose or multiple dose unit.

Although the explanation of pharmaceutical composition provided herein is at the pharmaceutical composition that is suitable for delivering medicine to the people in principle with meeting ethics, it will be understood by those skilled in the art that these compositionss are suitable for delivering medicine to the animal of all kinds usually.

For being modified as of pharmaceutical composition that is suitable for delivering medicine to the people that described compositions is suitable for deliver medicine to various animals known, and the those of ordinary skill of veterinary pharmacology can design and only use common experiment to implement this modification.The curee of the administration of carried out the present invention pharmaceutical composition of being considered includes, but are not limited to people and other vertebratess and mammal, comprises commercial relevant mammal, for example cattle, pig, horse, sheep, cat and Canis familiaris L..

Pharmaceutical composition of the present invention can be used as single unit dose large volume or prepares, packs or sell as a plurality of single unit dose.As used herein, " unit dose " is the pharmaceutical composition of fractional dose of the active component that contains scheduled volume.The amount of described active component is generally equal to the suitable part of the dosage or this dosage of the active component that delivers medicine to the curee, and for example 1/2 of this dosage or 1/3.

The relative quantity of active ingredient in pharmaceutical of the present invention, pharmaceutically acceptable carrier and any other composition will be according to its character, size and the curee's who is treated the state of an illness and also according to the approach that gives described compositions and difference.For instance, described compositions can contain the active component of 0.1%-100% (w/w).

Except active component, pharmaceutical composition of the present invention also contains one or more other drug active component.Special other compositions of considering comprise antiemetic and scavenger for example cyanide scavenger and cyanate scavenger.

The controlled release of pharmaceutical composition of the present invention or slow releasing preparation can use the conventional art preparation.

In some cases, employed dosage form can be used as the slow release of one or more active component or controlled release forms and for example uses hydroxypropyl cellulose, other polymeric matrixs, gel, permeable film, osmosis system, multiple coatings, microgranule, liposome or microsphere or their combining form to provide so that the required release mode of different proportion to be provided.The known suitable controlled release preparation of those of ordinary skills (comprise as herein described those) can easily be selected for pharmaceutical composition of the present invention and use.Therefore, the present invention includes the single unit dosage form that is suitable for oral administration that is suitable for controlled release, for example tablet, capsule, soft capsule and Caplet.

Most of controlled release preparations are designed to the rapid medication amount that produces required therapeutical effect of initial release, and other measure medicines to keep the therapeutical effect of this level in the time period that prolongs with continuing release gradually.In order to keep this constant level of medicine in vivo, medicine must discharge from this dosage form just will replace by metabolism and from the speed of the amount of the excretory medicine of body.

The controlled release of active component can be stimulated by multiple inducement, for example pH, temperature, enzyme, water or other physiological conditions or chemical compound.

The powder of pharmaceutical preparation of the present invention and granular preparation can use the known method preparation.These preparations can directly deliver medicine to the curee, and described preparation can be used for for example forming tablet, filled capsules or passes through to add water carrier or oily preparing carriers water slurry or oil suspension or solution.These preparations can also further contain one or more dispersants or wetting agent, suspending agent and antiseptic separately.Other excipient, for example filler and sweeting agent, flavoring agent or coloring agent also can be included in these preparations.

As used herein, " oil " liquid is the liquid that contains the carbonaceous fluid molecule of bag and show the feature littler than aqueous polar.

The preparation that is suitable for the pharmaceutical composition of the present invention of oral administration can be used as discrete solid dosage unit preparation, packing or sale, described solid dosage unit comprises, but be not limited to tablet, hard capsule or soft capsule, cachet, buccal tablet or lozenge, contain the active component of scheduled volume separately.Other preparations that are suitable for oral administration include, but are not limited to powder or granular preparation, water or oil suspension, water or oil solution, paste, gel, toothpaste, collutory, coating, oral rinse or Emulsion.Term oral rinse and collutory are used interchangeably at this paper.

The tablet that contains described active component can be suppressed or molded the preparation with one or more other compositions by for example active component being chosen wantonly.Compressed tablets can be by will for example powder or optional being mixed together with one or more binding agents, lubricant, excipient, surfactant and dispersant of granular preparation prepare with the active component of free-flowing form in suitable device.Molded tablet can be by in suitable device, the liquid of the mixture of molded active component, pharmaceutically acceptable carrier and enough at least described mixture of moistening and preparing.The pharmaceutically acceptable excipient that is used to prepare tablet includes, but are not limited to inert diluent, granulating agent and disintegrating agent, binding agent and lubricant.Known dispersant includes, but are not limited to potato starch and Explotab.Known surfactant comprises, but is not limited to sodium lauryl sulphate.Known diluent includes but not limited to calcium carbonate, sodium carbonate, lactose, microcrystalline Cellulose, calcium phosphate, calcium hydrogen phosphate and sodium phosphate.Known granulating agent and disintegrating agent include but not limited to corn starch and alginic acid.Known binding agent includes, but are not limited to gelatin, arabic gum, pregelatinized corn starch, polyvinylpyrrolidone and hydroxypropyl emthylcellulose.Known lubricant includes but not limited to magnesium stearate, stearic acid, silicon dioxide and Talcum.

Tablet can be for non-coating, maybe can use the known method coating to reach the disintegrate of delay in curee's gastrointestinal tract, and the lasting release and the absorption of active component are provided thus.For instance, for example glyceryl monostearate or distearin can be used for tablet is carried out coating.Also for instance, tablet can use United States Patent (USP) the 4th, 256, and 108,4,160,452 and 4,265, No. 874 described method is carried out coating to form the tablet of infiltration controlled release.Tablet can also contain sweeting agent, flavoring agent, coloring agent, antiseptic or their some combination, so that agreeable to the taste preparation pharmaceutically attractive in appearance to be provided.

The hard capsule that contains described active component can use on the physiology degradable compositions for example gelatin prepare.This hard capsule contains active component, and can also contain other compositions, comprises, for example inert solid diluent, for example calcium carbonate, calcium phosphate or Kaolin.

The soft capsule that contains described active component can use on the physiology degradable compositions for example gelatin prepare.This soft capsule contains described active component, and it can for example Oleum Arachidis hypogaeae semen, liquid paraffin or olive oil be mixed together with water or oil matrix.

Being suitable for the liquid preparation of the pharmaceutical composition of the present invention of oral administration can be with liquid form or make water or the heavy molten dry products of other suitable carriers prepare, pack or sell before use.

Injection can unit dosage forms ampoule or contain a plurality of dose containers preparations, the packing of antiseptic or sell for example.The preparation of parenteral includes but not limited to suspending agent, solution, the Emulsion in oil or the water carrier, paste and implantable slow release or biodegradable preparation.Described preparation also can contain one or more other compositions, includes but not limited to suspending agent, stabilizing agent or dispersant.In an embodiment of the preparation that is used for parenteral, provide described active component with dried forms (being powder or granule), dried forms as described in use suitable carriers (as aseptic apirogen water) is heavily molten, parenteral gives the molten compositions that weighs then.

Pharmaceutical composition of the present invention can prepare with the form that is suitable for oral administration, pack or sell.Appropriate formulation can be used the preparation of administration traditional method with for example tablet or lozenge form, and for example can contain 0.1-20% (w/w) active component, contains the balance liquid of oral solubilized or degradable compositions and one or more other compositions as herein described randomly.Alternatively, the preparation that is suitable for oral administration can comprise powder or atomizing or spray solution or contain the suspension of described active component.These powder, atomizing or spray agent when being disperseed, preferably have about 0.1 average grain or droplet size to about 200 nanometer range, and also can contain one or more other compositions as herein described.

As used herein; " other compositions " includes, but are not limited to one or more following compositions: excipient; surfactant; dispersant; inert diluent; granulating agent and disintegrating agent; binding agent; lubricant; sweeting agent; flavoring agent; coloring agent; antiseptic; degradable compositions gelatin for example on the physiology; water carrier and solvent; oil carrier and solvent; suspending agent; dispersant or wetting agent; emulsifying agent; demulcent; buffer agent; salt; thickening agent; filler; emulsifying agent; antioxidant; antibiotic; antifungal; stabilizing agent and pharmaceutically acceptable polymerization or hydrophobic material.See Genaro, ed., 1985, Remington ' s Pharmaceutical Sciences, Mack Publishing Co., Easton, PA incorporates this paper by reference into.

Described chemical compound can deliver medicine to the curee every day several times continually, or its administration more continually, for example once a day, once in a week, whenever biweekly, every month once, or even more not frequent, for example every some months is once or even once a year or more not frequent.The frequency of administration will easily be that those skilled in the art are conspicuous, and will depend on any amount of factor, for example, but be not limited to the type and the seriousness of the disease of being treated, curee's kind and age, etc.

The present invention also provides drug packages or test kit, and it comprises one or more containers of one or more compositions that are filled with pharmaceutical composition of the present invention.According to an embodiment, provide a kind of test kit that is used for the treatment of the immunoregulatory curee of needs.Preferably, described curee is the people.In one embodiment, described test kit comprises one or more S1P analog of the present invention and can also comprise one or more known immunosuppressant.These pharmaceutical preparatioies can be packaged in the multiple container, for example phial, test tube, microtitration microwell plate, bottle etc.Other reagent can be included in the container separately and use test kit to provide, for example positive control sample, negative control sample, buffer agent, cell culture medium etc.Preferably, described test kit also comprises operation instructions.

Although it is similar or be equal to those methods as herein described and material and can be used for having described preferable methods and material herein in practice of the present invention or the test.

Those skilled in the art will understand easily that the present invention will be suitable for putting into practice described target well and the terminal point that obtains to be mentioned and advantage and wherein inherent those.The present invention can implement with other particular forms under the situation that does not deviate from its spirit or fundamental property.

Embodiment

Referring now to the following example the present invention is described.Provide these embodiment only for illustrative purposes, and the present invention never is interpreted as limiting these embodiment, and should be interpreted as comprising as instruction result provided herein and conspicuous any and all changes form.

Embodiment 1:(1-amino-3-(the hot phenyl of 4-) cyclopenta) methanol (6)

A:3-(4-iodine substituted phenyl) Ketocyclopentane (1)

At N ₂Under the atmosphere 0.23g palladium (II) (0.1 equivalent) and 0.23g antimony chloride (III) (0.1 equivalent) are added into the acetum that 80mL contains 0.82g (10mmol) 2-ring penta-1-ketone, 2.48g (10mmol) 4-iodobenzene boric acid and 1.6g (20mmol) sodium acetate.After 25 ℃ are stirred 24 hours down, filter and remove black precipitate and use 250mL saline dilute filtration liquid, use the 50mL dichloromethane extraction then twice.Use saturated NaHCO ₃Solution stirring organic extract 30min uses the salt water washing and then through MgSO ₄Dry.Remove solvent and obtain yellow oil, use quick post (chloroform) to be further purified and obtain 1.92g (67%) white solid product.J.Org.Chem.，1995，60，883-888。

¹H NMR (CDCl ₃) δ 7.63 (d, 2H, ArH), 7.00 (d, 2H, ArH), 3.35 (m, 1H, ArCHCC), 2.7-1.8 (m, 6H, cyclopenta);

¹³C NMR(CDCl ₃)δ218，143，138，129，95，46，42，39，31。

B.:3-(4-suffering-1-alkynyl) phenyl) Ketocyclopentane (2)

1.1g (10mmol) 1-octyne is added into is equipped with in the flame-dried 25mL flask of THF solution that 10mL contains 1.43g (5mmol) 1.After the degassing 30min, under the N2 protection, add 2mL triethylamine, 5mg CuI and 10mg Pd (PPh ₃) ₄Be reflected in 6 hours and finish, remove after solvent and the volatile reagent, use chloroform that mixture is carried out column purification and obtain 1.34g (99%) yellow oil.

¹H NMR (CDCl ₃) δ 7.35 (d, 2H, ArH), 7.15 (d, 2H, ArH), 3.37 (m, IH, ArCHCC), 2.7-2.2 (m, 6H, cyclopenta), 1.95 (m, 2H, CCCH ₂CH ₂), 1.6-1.2 (m, 8H, CH ₂), 0.89 (t, J=6Hz, 2H, CH ₃);

¹³C NMR(CDCl ₃)δ220，143，132，127，122，91，80，46，42，39，32，31，29，29，23，20，14。

C:3-(the hot phenyl of 4-) Ketocyclopentane (3)

Several formic acid and catalytic amount 5%Pd/C are added in the 25mL flask that 10mL methanol and 1.34g (5mmol) 2 are housed.Use H ₂Wash this reaction vessel 3 times, load onto H then ₂Air bag.After two days the hydrogenolysis,, concentrate then and obtain yellow oil by silicon dioxide pad filtration washing solute.Collect 1.32g (98%) product.

¹H NMR (CDCl ₃) δ 7.18 (s, 4H, ArH), 3.38 (m, IH, ArCHCC), 2.60 (t, 2H, CCCH ₂CH ₂), 2.45-1.91 (m, 6H, cyclopenta), 1.64-1.15 (m, 12H, CH ₂), 0.90 (t, 3H, CH ₃);

¹³C NMR(CDCl ₃)δ220，142，140，129，127，46，42，39，36，32，32，32，30，30，29，23，14。

D.:1-amino-3-(the hot phenyl of 4-) Pentamethylene. nitrile (4)

3.20g (11.8mmol), 1.15g (23.5mmol) Cyanogran. and 1.25g (23.5mmol) ammonium chloride are added in the 20mL ammonium hydroxide.Mixture uses the 10mL dichloromethane extraction twice after violent stirred overnight.Dry and concentrated organic extract obtains the 3.30g yellow oil.Crude product is used for next step under situation about not being further purified.J.Med.Chem.，1986，29，1988-1995。

E.:1-amino-3-(the hot phenyl of 4-) Cyclopentane carboxylic acid (5)

3.3g (11.2mmol) and 50mL concentrated hydrochloric acid are heated to 70 ℃ and stirred overnight.Resulting clear aqueous solution is evaporated to drying.Add 10mL water and after drying.Repeat this process several times.Make water and ethyl ketone washing crude product obtain the white fine powder end.Yield is 1.7g (45%).

¹H NMR (d ⁶-DMSO) δ 7.25-7.06 (m, 4H, ArH) ₉3.21 (m, IH, ArCHCC), 2.38-1.62 (m, 6H, cyclopenta), 1.49-1.20 (m, 14H, CH ₂), 0.81 (t, J=6Hz, 3H, CH ₃);

¹³C NMR(d ⁶-DMSO)δ175，141，140，64，51，46，45，44，36，35，35，34，32，32，29，29，23，15。

F.:(1-amino-3-(the hot phenyl of 4-) cyclopenta) methanol (6)

63.4mg (0.2mmol) 5 and 27mg (0.6mmol) sodium borohydride are dissolved in 3mLTHF.This solution is cooled to after 0 ℃, with 51mg (0.2mmol) I ₂Be dissolved in 1mL THF and dropwise interpolation.Then, to this container assembling condenser and at N ₂Following reaction mixture refluxed 5 hours.Use methanol cancellation excessive N aBH ₄Remove after the solvent, add 2mL water and 5mL dichloromethane, stir the mixture about 1 hour until organic layer change clarification.Collect organic facies, use dichloromethane to extract water again twice.The organic extract that merges is carried out drying and concentrated, obtain 43mg (71%) crude product.Upward use methanol/chloroform (5: 95) to be further purified in TLC and obtain 13mg clarification grease.J.Org.Chem.，1993，58，3568-3571.

¹H NMR (CD ₃OD) δ 7.11 (m, 4H, ArH), 3.80 (t, J=7.5Hz, IH, cyclopenta-CH ₂O), 3.67 (t, J=7.5Hz, IH, cyclopenta-CH ₂O), 3.01 (m, IH, ArCHCC) ₅2.55 (t, J=7.5Hz, 2H, ArCH ₂), 2.29-1.69 (m, 6H, cyclopenta), 1.57 (m, 2H, ArCH ₂CH ₂), 1.38-1.28 (m, 10H, CH ₂), 0.89 (t, J=7.5Hz, 3H, CH ₃);

¹³C NMR(CD ₃COCD ₃)δ141，128，127，96，45，44，43，35，35，33，33，32，32，29，29，29，23，13。

Embodiment 2:(1-amino-3-(the hot phenyl of 4-) cyclopenta) methyl dihydrogen phosphoric acid ester (7)

(1-amino-3-(the hot phenyl of 4-) cyclopenta) methyl dihydrogen phosphoric acid ester (7)

With 1mL 85%H ₃PO ₄Slowly be added dropwise to the P of 0.5g ₂O ₅, in, then at N ₂Protection down, in 100 ℃ with acid-acid anhydride mixture heated 1 hour.P with other 0.5g ₂O ₅Be added in the polyphosphoric acid with 30mg 6 and in 100 ℃ of heating 5 hours.After being cooled to room temperature, the 10mL frozen water is added in the reactant mixture.Product is settled out as white solid.Collect product and make and wash with water.Collect 31mg (82%) green product after the vacuum drying.MS is two peak: M+1=384.4 and 304.4 (hydrolysis returns 6) only.

Embodiment 3:GTP γ S-35 is in conjunction with mensuration

This mensuration has illustrated the agonist activity of g protein coupled receptor in separation (GPCR).The follow expression of this mensuration by using each proteic four kinds of plasmid DNA transfection HEK293T cell of coding to impel three kinds of subunits (being generally α 1, β 2, γ 3) of reorganization GPCR (as the S1P1-5 receptor) and heterotrimeric G protein as described in each is comfortable in the cell.After the transfection about 60 hours, results, smudge cells, and abandon nucleus.This permission prepares thick microsome from residue.The agonist of G protein receptor complex (for example S1P) stimulation causes in dosage dependence mode GTP being converted to GDP on the alpha subunit on the microsome.For detecting the bonded alpha subunit of GTP, used GTP analog (GTP γ S-35), it is the thiophosphate of radionuclide (Sulphur-35) labelling, is not hydrolyzed to GDP.Have the proteic microsome of the G that adheres to by filtering to collect, and in liquid scintillation counter, bonded GTP γ S-35 is carried out quantitatively.Mensuration obtains relative effectivenes (EC ₅₀Be worth) and maximum effect (effect, E _Max).In the presence of the antagonist of fixed amount, in the agonist dose-response curve, measure antagonist activities for moving to right.If antagonist works competitively, can measure the affinity of receptor/antagonist to (Kj).

In this was measured, (VPC01211, CA5-P) itself was negative, or is S1P for the phosphorylation form of all VPC01091 isomers and the VPC01091 of phosphorylation ₃The inverse agonist of receptor, and be S1P with respect to S1P ₁The partial agonist of receptor (promptly not exclusively effectively).Inverse agonist is an antagonist, that is, they will disturb the combination of agonist ligand, but does not excite the activation of receptor.

VPC01211 (CA5-P) and cyclohexyl (CA6-P) analog are S1P ₁The partial agonist of receptor (Fig. 6) is to S1P ₂Receptor (Fig. 7 and 8) and S1P ₃Receptor (Fig. 9) non-activity.These chemical compounds are S1P ₄The full agonist and the S1P of receptor (Figure 10) ₅The partial agonist of receptor (Figure 11).Cyclohexyl chemical compound (CA4-9) is to S1P ₁Receptor has very little agonist activity, but has the activity similar with the cyclohexyl chemical compound to cyclopenta.

Assessed 1-phosphoric acid sphingol (S1P), four kinds of component isomers of VPC01211 (VPC01091 of phosphorylation) and VPC01211 are to the people 1 type S1P (S1P of reorganization ₁) effect of receptor (Figure 16).This is measured according to Davis, M-D., JJ.Clemens, T.L.Macdonald and K.R.Lynch (2005) " S1P Analogs as Receptor Antagonists " Journal of BiologicalChemistry, vol.280 carries out described in the pp.9833-9841.Effectiveness rank order (the EC of the described chemical compound in this experiment ₅₀) be: isomer 1＞isomer 3＞isomer 4＞isomer 2＞S1P＞VPC01211.By being carried out chemical phosphorylation, each isomer of VPC01091 prepares isomer.

Assessed 1-phosphoric acid sphingol (S1P), four kinds of component isomers of VPC01211 (VPC01091 of phosphorylation) and VPC01211 are to the human 3-type S1P (S1P of reorganization ₃) effect of receptor (Figure 17).This is measured according to Davis, M.D., JJ.Clemens, T.L.Macdonald and K.R.Lynch (2005) " S1P Analogs as Receptor Antagonists " Journal of BiologicalChemistry, vol.280 carries out described in the pp.9833-9841.Effectiveness rank order (the EC of the described chemical compound in this experiment ₅₀) be: S1P＞isomer 2＞VPC01211＞isomer 4＞isomer 1＞isomer 3.By being carried out chemical phosphorylation, each isomer of VPC01091 prepares isomer.

Embodiment 4: lymphopenia is measured

Preceding drug compound (be primary alconol, for example VPC01091) is dissolved in 2% hydroxypropyl and through port lumen feeding and introduces mice with the dosage of 0.01-30mg/kg body weight.(or its multiple) afterwards, softly anaesthetized mice in 24 hours, and extracted 0.1ml blood from the socket of the eye hole.Use the Hemavet blood analyser to measure lymphocyte quantity (, normally being 4-11 thousand) with every ml blood thousands of expression.In rectangular histogram, shown four kinds of isomers of VPC01091,100% value of the mice of vehicle treated was 5 for being 7.5 at 24 hours at 96 hours.Every group of three mices, its kind are blended svl29 x C57BL/6.(as VPC01211) is dissolved in acidifying DMSO with 20mM with reactive compound, and under agitation to be diluted in 2% hydroxypropyl aqueous solution at 1: 20.This solution is introduced mice with the dosage of 0.01-10mg/kg body weight by intraperitoneal (i.p.) injection.

When being dissolved in 2% hydroxypropyl (carrier) aqueous solution and oral cavity (tube feed) when delivering medicine to mice, VPC01091 excites the lymphopenia for a long time (Fig. 3) of the degree of depth.Fig. 3 has described the total blood lymphocyte counting after VPC01091 or the carrier single dose.Single ED of VPC01091 ₉₅Dosage can cause one week or more of a specified duration of lymphopenia.Every group of five mices, male, 10-11 svl29/C57B16 system in age in week.

In lymphopenia is measured, provide among the dose response curve of VPC01091 such as Fig. 4.Fig. 4 illustrates the oral administration of having summed up the VPC01091 in 2% hydroxypropyl, every group of 3 mices (with homology among Fig. 3).

Think this phosphorylation of these chemical compounds in vivo by 2 type sphingol (SPHK2) catalysis, described 2 type sphingols in mice by the SPHK2 gene code.When VPC01091 is introduced into the mice of non-functional SPHK2 gene, do not observe lymphopenia (Fig. 5).

In Figure 18, the ability of four kinds of VPC01091 isomers of SPHK2 enzyme phosphorylation has been described.

In Figure 19, illustrate the measurement result that the phosphorylation isomer through port lumen that uses VPC01091 is raised administration.Write down after the total lymphocyte counting (k/ μ l) of 24 hours and 96 hours with the VPC01091 isomer IV administration of phosphorylation.

Embodiment 5: the sphingosine kinase enzymatic determination

By being gone into the HEK293T cell, relevant plasmid DNA transfection impel the expression of mice or people's recombinase to prepare 2 type E.C. 2.7.1.91 (SPHK2) of reorganization.After about 60 hours, results, smudge cells also keep no microsome (promptly soluble) part.Smudge cells suspension and test-compound (VPC01091, sphingol etc.) (5-50 micromole) and mixed 37 ℃ of cultivations 0.5-2.0 hour that be incorporated in of γ-32P-ATP that to contain recombinase.Liposome in the reactant mixture is extracted into organic solvent also to be showed by the thin layer chromatography of positive.By the band of autoradiography detection of radioactive labels, strike off described band and undertaken quantitatively by scinticounting from culture plate.In shown rectangular histogram, sphingol is 15 μ M, and VPC01091 and isomer thereof are 50 μ M, and incubation time is 0.5 hour.

Embodiment 6: the calcium mobilization measures

End user S1P ₂Or people S1P ₃Receptor dna transfection hamster CHOK1 cell, and the clonal population of separation and amplification demonstration ectopic expression receptor.For detecting the calcium mobilization that the response agonist stimulates, cell is spread into 96 well culture plates, use calcium sensing dyestuff Fluo-4AM to go up sample, and with the agonist 3-5min of cellular exposure in variable concentrations.Use FlexStation exometer detection to mobilize relevant change in fluorescence with intracellular Ca2+.Triplicate detects each agonist concentration.This scheme is in Davis, M.D., JJ.Clemens, T.L.Macdonald and K.R.LynchSphingosine 1-phosphate analogs asreceptor antagonists.J.Biological Chemistry 280,9833-9841 is described in detail in (2005).In Fig. 7 and 9, the result has been described.

Fig. 7: use S1P ₂The CHOK1 cell of receptor dna transfection.

Fig. 9: use S1P ₃The CHOK1 cell of receptor dna transfection.

Embodiment 7: heart rate measurement

Use VPC01091 (intravenous, 3mg/kg) or carrier (2% hydroxypropyl) mice is carried out administration, and after administration, at the appointed time detect heart rate.Use ECGenie ^TMThe heart rate of inhibition, conscious animal is caught by system.

The results are described in Fig. 2.

Comprise title in this article, be used for reference and help some part is positioned.The non-scope that is intended to limit the notion of describing its below of these titles, and these notions go for other parts of whole description.

Employed but additive method that this paper does not describe be the those of ordinary skill in field of clinical, medical science, cytology, histochemistry, biochemistry, molecular biology, microbiology and recombinant DNA technology known and in its limit of power.

The employed abbreviation of this paper has its conventional sense in the chemistry and biology field.All announcements, patent and the patent document quoted in the description are incorporated this paper by reference into, as incorporating this paper separately by reference into.Why not consistent in the situation in office, content of the present invention comprises that wherein any definition is with prior applicability.With reference to each concrete and embodiment preferred and technical description the present invention.Yet, should understand within the spirit and scope of the present invention, can make many changes and modification.

Claims (30)

1. chemical compound or its pharmaceutically acceptable salt or ester with following formula:

Or

Wherein, R ⁴And R ⁷Be CH or CH independently ₂R ⁵Be C, CH or N, R ⁶Be CH, CH ₂, O, S or SR ³R ³Be hydrogen or (C ₁-C ₁₀) alkyl;

X is selected from the phosphonate radical of hydroxyl, phosphate radical, phosphonate radical, alpha-substituted;

R ¹Be selected from hydrogen, halogen, trifluoromethyl, (C ₁-C ₁₀) alkyl, by halogen, hydroxyl, (C ₁-C ₁₀) (the C that replaces of alkoxyl or cyano group ₁-C ₁₀) group formed of alkyl; And

R ²Be selected from (C ₁-C ₂₀) alkyl, the alkyl of cycloalkyl substituted, (C ₂-C ₂₀) thiazolinyl, (C ₂-C ₂₀) group formed of the aralkyl that replaces of alkynyl, aryl, the alkyl aryl, aralkyl and the aryl that replace; R wherein ²One or more carbon atoms in the group can be independently by non-peroxide oxygen, sulfur or NR ⁸Replace;

R wherein ⁸Be hydrogen or (C ₁-C ₁₀) alkyl;

R wherein ²In alkyl, thiazolinyl and alkynyl optional replaced by oxo; N is 0,1,2 or 3; And Table 1,2 or 3 optional two keys.

2. chemical compound as claimed in claim 1 or its pharmaceutically acceptable salt, it has following formula (II):

Wherein, X is selected from the phosphonate radical of hydroxyl, phosphate radical, phosphonate radical, alpha-substituted;

R wherein ¹Be selected from hydrogen, halogen, (C ₁-C ₆) alkyl, by (the C of halogen, hydroxyl, alkoxyl, cyano group replacement ₁-C ₆) group formed of alkyl;

R ²Be selected from the group that aryl that aryl that alkyl, thiazolinyl, alkynyl, alkyl replace, cycloalkyl, aralkyl and aralkyl that alkyl replaces replace is formed; And n is 0,1,2 or 3.

3. chemical compound as claimed in claim 1 or 2, wherein said R ¹Be fluorine or chlorine.

4. as each described chemical compound of claim 1-3, wherein said X is hydroxyl or OPO ₃H ₂

5. chemical compound as claimed in claim 4, wherein said X is OPO ₃H ₂

6. chemical compound as claimed in claim 4, wherein said X is a hydroxyl.

7. chemical compound as claimed in claim 1 or 2, the phosphonate radical of wherein said alpha-substituted is-CHFPO ₃H ₂,-CF ₂PO ₃H ₂,-CHOHPO ₃H ₂,-C=OPO ₃H ₂Or-OPO ₂SH ₂

8. chemical compound as claimed in claim 7, the phosphonate radical of wherein said alpha-substituted is-CHFPO ₃H ₂,-CF ₂PO ₃H ₂,-CHOHPO ₃H ₂, or-C=OPO ₃H ₂

9. as each described chemical compound of claim 1-8, wherein said R ¹Be hydrogen.

10. as each described chemical compound of claim 1-9, wherein said R ²It is alkyl with 5,6,7 or 8 carbon atoms.

11. chemical compound as claimed in claim 10, wherein said R ²Be heptyl, octyl group, nonyl or-the O-heptyl.

12. chemical compound as claimed in claim 11, wherein said R ²It is octyl group.

13. as each described chemical compound of claim 1-12, wherein said n is 1 or 2.

14. as each described chemical compound of claim 1-13, wherein said R ²Group is positioned at the para-position of described cycloalkyl ring.

15. chemical compound as claimed in claim 1 or 2, wherein said cycloalkyl has following formula:

Or

16. as each described chemical compound of claim 1-15, wherein said R ¹Group is positioned at described R ²An ortho position or a position.

17. as each described chemical compound of claim 1-15, wherein said R ²Group is positioned at the para-position of described benzyl rings alkyl.

18. chemical compound as claimed in claim 1 or 2, it has following formula:

Or

19. method that is used to prevent or treat mammiferous pathologic conditions or symptom, the activity that wherein relates to 1-phosphoric acid sphingol receptor, and described active excitement expects, described method comprise deliver medicine to described mammal effective dose as each described chemical compound of claim 1-18.

20. method as claimed in claim 19, wherein said pathologic conditions is an autoimmune disease.

21. method as claimed in claim 20, wherein said autoimmune disease are uveitis, type i diabetes, rheumatoid arthritis, inflammatory bowel or multiple sclerosis.

22. method as claimed in claim 21, wherein said autoimmune disease is a multiple sclerosis.

23. being the lymphocyte transportations, method as claimed in claim 19, wherein said pathologic conditions change.

24. method as claimed in claim 23, wherein said treatment are to change the lymphocyte transportation.

25. method as claimed in claim 23, wherein said lymphocyte transportation provides the time-to-live of the allograft that prolongs.

26. method as claimed in claim 23, wherein said allograft is used for transplanting.

27. method that is used to prevent or treat mammiferous pathologic conditions or symptom, wherein relate to S1P lyases activity, and the inhibition of S1P lyases is required, it comprise deliver medicine to described mammal effective dose as each described chemical compound of claim 1-18.

28. each described chemical compound of claim 1-18 is used for the purposes of therapeutic treatment.

29. each described chemical compound of claim 1-18 is used to prepare the purposes that is used to prevent or treat the medicine of mammal pathology disease or symptom, wherein relates to the activity of 1-phosphoric acid sphingol receptor.

30. purposes as claimed in claim 28, wherein said medicine contains liquid-carrier.

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