CN102558022A - Substituted isoindoline-1,3-dione derivative - Google Patents

Substituted isoindoline-1,3-dione derivative Download PDF

Info

Publication number
CN102558022A
CN102558022A CN2010106205327A CN201010620532A CN102558022A CN 102558022 A CN102558022 A CN 102558022A CN 2010106205327 A CN2010106205327 A CN 2010106205327A CN 201010620532 A CN201010620532 A CN 201010620532A CN 102558022 A CN102558022 A CN 102558022A
Authority
CN
China
Prior art keywords
compound
deuterium
acceptable salt
pharmacy acceptable
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN2010106205327A
Other languages
Chinese (zh)
Other versions
CN102558022B (en
Inventor
J·F·刘
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Concert Pharmaceuticals Inc
Original Assignee
Concert Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Concert Pharmaceuticals Inc filed Critical Concert Pharmaceuticals Inc
Priority to CN201610327209.8A priority Critical patent/CN106008313B/en
Priority to CN201010620532.7A priority patent/CN102558022B/en
Publication of CN102558022A publication Critical patent/CN102558022A/en
Application granted granted Critical
Publication of CN102558022B publication Critical patent/CN102558022B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention relates to a novel substituted isoindoline-1,3-dione derivative and the pharmaceutically acceptable salts thereof. More particularly, the invention relates to a novel substituted isoindoline-1,3-dione derivative used as an analogue of apremilast. The invention further provides a composition containing the compound disclosed by the invention and a carrier, and the application of the disclosed compound and composition in a method for beneficially treating diseases and conditions by administering apremilast.

Description

Substituted isoindoline-1,3 derovatives
Background of invention
Many existing medicines are subject to bad absorption, distribution, metabolism and/or drainage (ADME) character, and this has stoped them to use or limit its purposes in specific adaptations disease more widely.Bad ADME character also is the major cause that drug candidate is failed in clinical trial.Though preparation technique and prodrug strategy can be used to improve some ADME character in some cases, these methods often can not solve the basic ADME problem that many medicines and drug candidate exist.A kind of such problem is to cause many medicines by the tachymetabolism from the too fast removing of health, otherwise this medicine is being very effective aspect the treatment disease.Possible the solution of removing for quick medicament be frequently or the high dosage administration reach sufficiently high medicine blood plasma level.Yet this has introduced many potential treatment problems, makes the violent more and medical expense of spinoff increase like the patient for poor, the higher dosage of the compliance of dosage regimen.The medicine of tachymetabolism also possibly make the patient be exposed to unwanted toxic or reactive metabolite.
The another kind of ADME restriction that influences many medicines is deleterious or the formation of the metabolite of biological reactivity.Therefore, some patients that accept this medicine may experience toxicity, or the safe dose of this type medicine may be restricted and make the patient accept time good promoting agent.In some cases, change dosing interval or formulation method and can help to reduce clinical adverse, but the formation of these the unwanted metabolites metabolism inherent of this compound normally.
Under the situation of some selection, metabolic poison will with used jointly by the medicine of too fast removing.Here it is is used to treat the situation of the proteinase inhibitor class medicine that HIV infects.The FDA suggestion; These medicines with use jointly as the suppressor factor ritonavir (ritonavir) of cytochrome P 450 enzymes 3A4 (CYP3A4), this kind of enzyme is responsible for the metabolism of these medicines usually (referring to, Kempf; D.J. wait the people; Antimicrobial agents and chemotherapy, 1997,41 (3): 654-60).Yet ritonavir causes untoward reaction, and increases HIV patient's's (it must take the combination of different pharmaceutical already) the burden of taking medicine (pill burden).Similarly, in order to reduce the metabolic purpose of quick CYP2D6 of Dextromethorphane Hbr in false oblongata mood (pseudobulbar affect) treatment, CYP2D6 suppressor factor Quinidine adds Dextromethorphane Hbr to.Yet Quinidine has deleterious spinoff, this greatly limit its use in the potential conjoint therapy (referring to Wang, people such as L, Clinical Pharmacology and Therapeutics, 1994,56 (6Pt 1): 659-67; With on www.accessdata.fda.gov for the FDA label of Quinidine).
In the ordinary course of things, not the strategy that gratifying minimizing medicine is removed with medicine and cytochrome P 450 inhibitors combination.The inhibition of CYP enzymic activity can influence by the metabolism of the other drug of this same enzymes metabolism and removing.CYP suppresses to cause other drug to be accumulated to toxic level in vivo.
The potential attractive strategy that is used to improve the metabolisming property of medicine is that deuterium is modified.In this way, the technician attempts through substitute the formation that one or more Wasserstoffatomss slow down the drug metabolism of CYP mediation or reduce unwanted meta-bolites with D atom.Deuterium is safety, stable, cold hydrogen isotopes.Than hydrogen, deuterium and carbon form stronger key.Under situation about selecting, the bonding strength that deuterium is given strengthens can influence the ADME character of medicine by forward, thereby produces the potentiality of the pharmaceutical efficacy, security and/or the tolerance that improve.Simultaneously, because the size of deuterium is identical with hydrogen basically with shape, therefore compare with only wrapping hydrogenous original chemical body, the expection of deuterium instead of hydrogen can not influence the biological chemistry of medicine and render a service and selectivity.
In the past in 35 years, for the approval drug report of very little per-cent deuterium substitute effect for metabolic rate (for example, referring to, Blake, people such as MI, J Pharm Sci, 1975,64:367-91; Foster, AB, Adv Drug Res 1985,14:1-40 (" Foster "); Kushner, people such as DJ, Can J Physiol Pharmacol 1999,79-88; Fisher, people such as MB, Curr Opin Drug Discov Devel, 2006,9:101-09 (" Fisher ")).These results are changeable with uncertain.For some compounds, deuterate causes intravital MCR to descend.For other compound, metabolism does not change.Other some compounds show the MCR raising again.The mutability of deuterium effect also makes the professional query or considers that no longer deuterium modifies as being used to suppress the metabolic feasible medicinal design strategy of adverse drug (referring to the 35th page of, Foster document with the Fisher document the 101st page).
Even when metabolic known site was mixed, deuterium is modified neither be predictable for the drug metabolism The properties at D atom.Have only through actual fabrication and test deuterated medicine, the technician could confirm whether metabolic speed is different from its non-deuterated counterpart and how different.Referring to, for example, and people such as Fukuto (J.Med.Chem.1991,34,2871-76).Many medicines have the contingent a plurality of sites of metabolism.Need carry out the substituted site of deuterium is different with observing for the necessary degree of deuterium of metabolic effect (if any) for various medicines.
Apremilast also is called as (+)-N-[2-[1 (S)-(3-oxyethyl group-4-p-methoxy-phenyl)-2-(methylsulfonyl) ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl] ethanamide, is the PDE4 suppressor factor, and performance reduces the effect of TNF-alpha levels.Apremilast is in the clinical trial that is used for treating psoriatic, psoriasis in plaques, psoriasis inveterata, skin tag disease, psoriatic arthritis, behcet disease (Behcet ' s Disease), prurigo nodularis, cutaneous lupus and uveitis etc.
The common adverse events relevant with the PDE4 suppressor factor generally includes headache, feels sick, vomiting and functional gastrointestinal disorder.
It is desirable to provide a kind of compound; It has the useful activity and other benefits of apremilast; The adverse side effect that for example reduces; Metabolism proneness with reduction is with its pharmacology validity period of further expansion, and the compliance that improves the patient is to reduce the population pharmacokinetics variability and/or to reduce the possibility of its dangerous drug-drug interactions potentially.
Summary of the invention
The present invention relates to new substituted isoindoline-1,3-derovatives and pharmacy acceptable salt thereof.
More particularly, the present invention relates to new substituted isoindoline-1, the 3-derovatives as the apremilast analogue.The present invention also provides the compsn that comprises compound of the present invention and carrier, and disclosed compound and compsn in treatment through the purposes in the method for the disease using apremilast and treat valuably and state.
Description of drawings
Fig. 1 shows the graphic representation with the plasma concentration versus time of each rat in 5 rats of apremilast, compound 114 (a) and compound 116 (a) co-administered.
Fig. 2 show as among 5 width of cloth figure of Fig. 1 for the graphic representation of the plasma concentration versus time of the mean+SD of the plasma concns value of apremilast, compound 114 (a) and compound 116 (a).
Embodiment
Term " treatment " means reduction, suppresses, weakens, reduces, stops the perhaps development or the process of stable disease (for example, disease described herein or obstacle), reduces the severity or the improvement symptom relevant with disease of disease.
" disease " is meant the state or the obstacle of the normal function of any infringement or interference cell, tissue or organ.
Can recognize: depend on the source of chemical material used in synthetic, in the synthetic compound, have some variation of natural isotopic abundance.Therefore, the preparation of apremilast comprises a spot of deuterated isotropic substance analogue (isotopologue) inherently.Although there is this variation, it is little of inessential that the stable hydrogen of natural abundance and the concentration of carbon isotope are compared with the substituted degree of the stable isotope of The compounds of this invention.Referring to, for example, people such as Wada E, Seikagaku 1994,66:15; People such as Ganes LZ, Comp Biochem Physiol Mol Integr Physiol 1998,119:725.
In compound of the present invention, any atom of clearly not being appointed as specific isotope means any stable isotope of representing this atom.Except as otherwise noted, when a locality specific was appointed as " H " or " hydrogen ", this position was appreciated that the hydrogen that has by its natural abundance isotopics.In addition, except as otherwise noted, when a locality specific was appointed as " D " or " deuterium ", this position was appreciated that the deuterium (that is, at least 50.1% deuterium mixes) for the abundance with at least 3340 times of natural abundances (it is 0.015%) according to deuterium.
As used herein, term " the isotopic enrichment factor " meaning is the ratio of specified isotopic isotopic abundance and natural abundance.
In other embodiments, compound of the present invention has the isotopic enrichment factor of at least 3500 (deuterium at each specified D atom place 52.5% mixes), at least 4000 (60% deuterium mixes), at least 4500 (67.5% deuterium mixes), at least 5000 (75% deuterium mixes), at least 5500 (82.5% deuterium mixes), at least 6000 (90% deuterium mixes), at least 6333.3 (95% deuterium mixes), at least 6466.7 (97% deuterium mixes), at least 6600 (99% deuterium mixes) or at least 6633.3 (99.5% deuterium mixes) for each specified D atom.
Term " isotropic substance analogue " refers to that its chemical structure only is different from the material of specific compound of the present invention in isotopics.
Term " compound " when referring to compound of the present invention, is meant the set that except possibly in the composed atom of molecule, having the isotropic substance variation, has the molecule of identical chemical structure.Therefore, those skilled in the art can be clear: the compound by the particular chemical structure representative that contains the D atom of indicating is also contained in the more a spot of isotropic substance analogue that has Wasserstoffatoms on the one or more specified deuterium position in this structure.The relative quantity of this isotropic substance analogue depends on many factors in the compound of the present invention, comprises the isotopic purity of the deuteration agents that is used for preparing this compound and at the doping efficiency of each synthesis step deuterium that is used to prepare this compound.But as noted above, this isotropic substance analogue all relative quantity of (in toto) is lower than 49.9% of compound.In other embodiments, the whole relative quantity of this isotropic substance analogue be lower than compound 47.5%, be lower than 40%, be lower than 32.5%, be lower than 25%, be lower than 17.5%, be lower than 10%, be lower than 5%, be lower than 3%, be lower than 1% or be lower than 0.5%.
The present invention also provides the salt of The compounds of this invention.
At the salt that forms The compounds of this invention between the basic group (like amido functional group) of acid and said compound or between the acidic-group (like carboxyl functional group) at alkali and said compound.Based on another kind of embodiment, this compound is a pharmaceutically-acceptable acid addition.
As used herein; Term " pharmaceutically acceptable " refers to and in the scope of rational medical judgment, is applicable to the composition that does not have over-drastic toxicity, pungency, anaphylaxis etc. with human the contact with other mammiferous tissues, and matches with rational interests/risk ratio." pharmacy acceptable salt " refers to any at the non-toxic salt that compound of the present invention can be provided when the recipient uses directly or indirectly." pharmaceutically acceptable gegenion " is in ion part from back atoxic salt when salt discharges to the recipient that use.
The acid that is generally used for forming pharmacy acceptable salt comprises mineral acid; Like disulfides other than hydrogen (hydrogen bisulfide), hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid and phosphoric acid; And organic acid; Like tosic acid, Whitfield's ointment, tartrate, acid tartrate, xitix, toxilic acid, Phenylsulfonic acid (besylic acid), fumaric acid, glucono-, glucuronic acid, formic acid, L-glutamic acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, lactic acid, oxalic acid, to bromo-benzene sulfonic acid, carbonic acid, succsinic acid, Hydrocerol A, phenylformic acid and acetic acid, and relevant inorganic and organic acid.Therefore this pharmacy acceptable salt comprises vitriol, pyrosulphate, hydrosulfate, sulphite, hydrosulphite, phosphoric acid salt, monohydric phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate salt, muriate, bromide, iodide, acetate, propionic salt, caprate, octylate, acrylate, formate, isobutyrate, caprate, enanthate, propiolate (propiolate), oxalate, malonate, SUMATRIPTAN SUCCINATE, suberate, sebacate, fumarate, PHENRAMINE MALEATE, butine-1; 4-diacid salt, hexin-1,6-diacid salt, benzoate, chloro benzoate, tolyl acid salt, dinitro-benzoate, hydroxy benzoate, methoxybenzoic acid salt, phthalate, terephthalate, sulphonate, xylenesulfonate, phenylacetic acid salt, phenylpropionic acid salt, phenylbutyric acid salt, Citrate trianion, lactic acid salt, beta-hydroxy-butanoic acid salt, glycollate, PHENRAMINE MALEATE, tartrate, mesylate, propanesulfonic acid salt, naphthalene-1-sulphonate, naphthalene-2-sulfonic acid salt, mandelate and other salt.In one embodiment, pharmaceutically-acceptable acid addition comprises the acid salt that forms with mineral acid example hydrochloric acid and Hydrogen bromide, especially those and the acid salt of organic acid such as toxilic acid formation.
Pharmacy acceptable salt also can be to have the The compounds of this invention of acidic functionality (like carboxylic acid functional) and the salt of alkali.Exemplary alkali includes but not limited to: the oxyhydroxide of basic metal (comprising sodium, potassium and lithium); The oxyhydroxide of earth alkali metal (like calcium and magnesium); The oxyhydroxide of other metals (like aluminum and zinc); Ammonia, organic amine, as do not replace or the substituted list of hydroxyl-, two-or three-alkylamine, dicyclohexyl amine; TBuA; Pyridine; The N-methyl, the N-ethylamine; Diethylamine; Triethylamine; Single-, two-or three-(2-OH-(C 1-C 6)-alkylamine), like N, N-dimethyl--N-(2-hydroxyethyl) amine or three (2-hydroxyethyl) amine; N-methyl D-glycamine; Morpholine; Thiomorpholine (thiomorpholine); Piperidines; Tetramethyleneimine; And amino acid, like l-arginine, Methionin etc.
Compound of the present invention (for example, formula I compound) possibly comprise unsymmetrical carbon, for example, because deuterium replaces or other reasons causes.Therefore, compound of the present invention can be used as the mixture existence of independent enantiomorph or two enantiomorphs.Thereby; Compound of the present invention maybe be as racemic mixture or non-racemize (scalemic) mixture (as mainly containing a kind of mixture of steric isomer), or exists as each the independent steric isomer that is substantially free of another kind of possible steric isomer).Term as used herein " be substantially free of other steric isomers " and refer to exist other steric isomers less than 25%, preferably less than other steric isomers of 10%, be more preferably less than other steric isomers of 5% and most preferably less than other steric isomers of 2%.The method of the single enantiomorph of acquisition or synthetic given compound is known in the art, and can be applied to final compound or starting raw material or midbody according to practical situation.
Except as otherwise noted, do not indicate its stereochemistry character when the name of disclosed compound or through structrual description, and when having one or more chiral centre, it is interpreted as representing all possible steric isomer of this compound.
As used herein; Term " stable compound " refers to have enough stability to allow its preparation and in the sufficiently long time that is used for the purpose that this paper details (for example, being mixed with treatment product, the midbody that is used for the production for treating compound, separable or storable midbody compound, treatment disease or the state to the medicine response), to keep the compound of the integrity of compound.
" D " and " d " all is meant deuterium." steric isomer " refers to enantiomorph and diastereomer." uncle " and " t-" respectively refers to uncle." US " refers to the U.S..
" deuterium replacement " is meant that one or more Wasserstoffatomss are substituted by the D atom of respective number.
In whole specification sheets, variable can be made a general reference (for example, " each R ") or refer in particular to (for example, R 1, R 2, R 3Deng).Except as otherwise noted, when variable was made a general reference, its meaning was all specific implementations that comprise this particular variables.
The treatment compound
The invention provides the compound of formula I:
Figure BSA00000407441900071
Formula I
Or its pharmacy acceptable salt, wherein:
R 1Be selected from CH 3, CH 2D, CHD 2And CD 3
R 2Be selected from methyl, sec.-propyl, cyclopentyl, cyclopropyl, 2-furyl, trifluoromethyl, methoxymethyl, amino methyl, dimethylamino methyl, dimethylamino-1-ethyl, 1-dimethylamino-ethyl and 2-dimethylamino-ethyl, wherein, R 2Randomly replaced by deuterium;
R 3Be selected from CH 3, CH 2D, CHD 2, CD 3, CF 3, CHF 2, CH 2F, CDF 2And CD 2F;
R 4By 0 to 5 substituted ethyl of deuterium, or by 0 to 9 substituted cyclopentyl of deuterium;
X is selected from CH 2, CHD, CD 2And C=O;
Y 1a, Y 1b, Y 2, Y 3, Y 4, Y 5, Y 7And Y 8Respectively be independently selected from H and D; With
Y 6Be selected from Cl, H and D;
Condition is if R 1Be CH 3, R 2Do not replaced R by deuterium 3Be CH 3, CF 3, CHF 2Or CH 2F, R 4Be not by the substituted ethyl of deuterium or not by the substituted cyclopentyl of deuterium, X is CH 2Or C=O and Y 6Be Cl or H, Y so 1a, Y 1b, Y 2, Y 3, Y 4, Y 5, Y 7And Y 8At least one be D.
In one embodiment, the compound of formula I is the compound of formula II:
Figure BSA00000407441900081
Formula II
Or its pharmacy acceptable salt, wherein:
R 1Be selected from CH 3And CD 3
R 2Be selected from methyl, sec.-propyl, cyclopentyl, cyclopropyl, 2-furyl, trifluoromethyl, methoxymethyl, amino methyl, dimethylamino methyl, dimethylamino-1-ethyl, 1-dimethylamino-ethyl and 2-dimethylamino-ethyl, wherein, R 2Randomly replaced by deuterium;
R 3Be selected from CH 3, CD 3, CF 3, CHF 2, CH 2F, CDF 2And CD 2F;
R 4Be selected from CH 2CH 3, CD 2CD 3, CD 2CH 3And CH 2CD 3With
Each Y is independently selected from H and D;
Condition is if R 1Be CH 3, R 2Do not replaced R by deuterium 3Be CH 3, CF 3, CHF 2Or CH 2F and R 4Be CH 2CH 3, at least one Y is D so.
In the embodiment of formula I or II, R 1Be CH 3Or CD 3
In the embodiment of formula I or II, R 2Be CH 3Or CD 3
In the embodiment of formula I or II, R 3Be CH 3Or CD 3
In the embodiment of formula I or II, Y 6, Y 7And Y 8Identical.On the one hand, Y 6, Y 7And Y 8The hydrogen of respectively doing for oneself.
In the embodiment of formula I or II, Y 1aAnd Y 1bIdentical.On the one hand, Y 1aAnd Y 1bAll be hydrogen.On the other hand, Y 1aAnd Y 1bIt all is deuterium.
In the embodiment of formula I or II, Y 3, Y 4And Y 5Identical.On the one hand, Y 3, Y 4And Y 5The hydrogen of respectively doing for oneself.
In the embodiment of formula I or II, R 4Be CD 2CD 3In the embodiment of formula I or II, R 2Be CH 3Or CD 3R 3Be CH 3Or CD 3Y 6, Y 7And Y 8Identical; Y 1aAnd Y 1bIdentical; And Y 3, Y 4And Y 5Identical.
In the embodiment of formula I or II, R 1Be CH 3Or CD 3R 2Be CH 3Or CD 3R 3Be CH 3Or CD 3R 4Be CD 2CD 3Y 6, Y 7And Y 8Identical; Y 1aAnd Y 1bIdentical; And Y 3, Y 4And Y 5Identical.
In one embodiment, the compound of formula I is compound or its pharmacy acceptable salt of formula Ia, and it is connected to Y 2Carbon mainly have (S) configuration:
Figure BSA00000407441900091
Formula Ia
Wherein remaining variable is as the definition for formula I.
In one embodiment, the compound of formula Ia is gone up basically and is not contained other steric isomers.
In one embodiment, the compound of formula I is compound or its pharmacy acceptable salt of formula Ib, and it is connected to Y 2Carbon mainly have (R) configuration:
Formula Ib
Wherein remaining variable is as the definition for formula I.
In one embodiment, the compound of formula Ib is gone up basically and is not contained other steric isomers.
In the embodiment of formula Ia or Ib, R 1Be CH 3Or CD 3
In the embodiment of formula Ia or Ib, R 2Be CH 3Or CD 3
In the embodiment of formula Ia or Ib, R 3Be CH 3Or CD 3
In the embodiment of formula Ia or Ib, Y 6, Y 7And Y 8Identical.On the one hand, Y 6, Y 7And Y 8The hydrogen of respectively doing for oneself.
In the embodiment of formula Ia or Ib, Y 1aAnd Y 1bIdentical.On the one hand, Y 1aAnd Y 1bAll be hydrogen.On the other hand, Y 1aAnd Y 1bIt all is deuterium.
In the embodiment of formula Ia or Ib, Y 3, Y 4And Y 5Identical.On the one hand, Y 3, Y 4And Y 5The hydrogen of respectively doing for oneself.
In the embodiment of formula Ia or Ib, R 4Be CD 2CD 3
In the embodiment of formula Ia or Ib, R 1Be CH 3Or CD 3R 2Be CH 3Or CD 3R 3Be CH 3Or CD 3R 4Be CD 2CD 3Y 6, Y 7And Y 8Identical; Y 1aAnd Y 1bIdentical; And Y 3, Y 4And Y 5Identical.
In one embodiment, the compound of formula I is selected from:
Figure BSA00000407441900111
The pharmacy acceptable salt of
Figure BSA00000407441900121
or above-mentioned any compound.
In one embodiment, the compound of formula I is selected from:
Figure BSA00000407441900122
Or the pharmacy acceptable salt of above-mentioned any compound.
In one embodiment, compound is the compound of formula Ia, and is selected from:
Figure BSA00000407441900123
Figure BSA00000407441900131
Or the pharmacy acceptable salt of above-mentioned any compound.
Embodiment provides a kind of compound of pharmacy acceptable salt of (S) enantiomorph or the above-mentioned any compound that mainly are compound 100,101,102,103,104,105,106,107,108,109,110,111 or 112.
Embodiment provides a kind of compound of pharmacy acceptable salt of (S) enantiomer or the above-mentioned any compound that mainly are compound 113,114,115,116.
Embodiment provides a kind of compound of pharmacy acceptable salt of (R) enantiomorph or the above-mentioned any compound that mainly are compound 100,101,102,103,104,105,106,107,108,109,110,111 or 112.
Embodiment provides a kind of compound of pharmacy acceptable salt of (R) enantiomorph or the above-mentioned any compound that mainly are compound 113,114,115,116.
In another group embodiment, any atom of not being appointed as deuterium for the compound of formula I, I (a) or I (b) in the listed embodiment of any preceding text exists with its natural isotopic abundance.
Synthetic can being easy to of the compound of formula I realized through common synthetic chemistry professional.Following document discloses relevant method and midbody: for example, and Man, people such as H.W., Journal of Medicinal Chemistry (2009), 52 (6), 1522-1524; Muller, people Journal of Medicinal Chemistry (1996) such as G.W., 39 (17), 3238-3240; WO2006/025991; AU2006/200033; WO2001/034606; USP the 6th, 020, No. 358; With USP the 6th, 667, No. 316.
Can utilize corresponding deuteration agents and optional other to contain isotopic reagent and/or midbody carries out this method with synthetic compound as herein described, or by means of standard synthetic schemes known in the art to introduce isotope atom to chemical structure.Some midbody can pass through or not purified (for example, filtration, distillation, distillation, crystallization, grinding, SPE and chromatography) used.
Exemplary is synthetic
The general route of scheme 1. formula I compounds.
Figure BSA00000407441900141
Scheme 1 has been described according to Man, HW; Deng people Journal of Medicinal Chemistry (2009), 52 (6), the general route of the general method preparation I compound of 1522-1524.Therefore, suitable substituted aldehyde 10 usefulness hexamethyl two silica-based amido lithiums (lithium hexamethyldisilazide) are handled, and then handle with MSM lithium and boron trifluoride ethyl ether complex, and to produce racemic amine 11, it is being connected to Y 2Carbon have three-dimensional center.If desired, can be through handle the amine 11 of resolution of racemic with (enantiopure) acid of the enantiomer-pure in the methyl alcohol.For example, handle the amine 11 that racemic amine 11 produces as the S enantiomorph, and handle the amine 11 that produces as the R enantiomorph with N-ethanoyl-D-leucine with N-ethanoyl-L-leucine.Amine 11 can be used as racemoid, S enantiomorph or R enantiomorph and uses, with the compound of production I when handling with acid anhydrides 12 purified or in solvent (like acetic acid).It will be appreciated by those skilled in the art that: in scheme 1, use suitable deuterated midbody and reagent to cause producing the compound of the formula I with various deuterium substitute modes.
scheme 2: the preparation of aldehyde 10.
Figure BSA00000407441900151
Scheme 2 has been described the preparation of aldehyde 10, and it is the useful parent material of scheme 1.As Li, people Hecheng Huaxue (1993) such as Juren, 1 (4), the 333-40 general description, under condition of phase transition, handle suitable deuterated glycol 13, to produce phenol 15 with suitable deuterated monobromethane 14.Phenol 15 produces aldehyde 16 with the Reimer-Tiemann reaction of chloroform.Deuterated reagent and solvent can be used for this step to maximize the isotopic level of mixing.Selectively, like Li, people such as Ying-chun, Yingyong Huagong (2004), 33 (1), it is 16 that the Tetrabutyl amonium bromide condition of 26-27 general description can be used for transforming 15.According to Kiehlmann, people such as E., Organic Preparations and Procedures International (1982), 14 (5), the general method of 337-42 is handled 16 with suitable deuterated methyl-sulfate 17 and is produced required midbody 10.
For example, commercially available methyl-sulfate-d6 can be as the reagent 17 in the scheme 2, finally to produce the compound of formula I, wherein R 3Be CD 3In another example, commercially available monobromethane-d5 can be used as the reagent 14 in the scheme 2, finally to produce the compound of formula I, wherein, R 4For-CD 2CD 3Equally, commercially available monobromethane-2,2,2-d3 and monobromethane-1,1-d2 also can be used for scheme 2 finally to be created in R 4On have the compound of the formula I of various other deuterium substitute modes.
scheme 3: the preparation of midbody 12a and 12b.
Figure BSA00000407441900161
Scheme 3 has been described midbody 12a (wherein X is the instance of the midbody 12 of C=O) and midbody 12b, and (wherein X is CH 2, CHD or CD 2The instance of midbody 12) preparation.The nitrated of acid anhydrides skeleton 18 is known in document, for example, and patented claim WO2005051870, CN 1740138 and CN 1405143; And comprise people such as Chen, Zhi-min, Hecheng Huaxue (2004), 12 (2), 167-169,173; Zhu, people such as Zhi-jia, Huaxue Shiji (2003), 25 (5), 306,308; Ma, people such as S.L., Polish Journal of Chemistry (2002), 76 (4), 511-517; And Culhane, people such as P.J., Organic Syntheses (1927), the document article of 7 (not providing the page number).Use suitable deuterated starting raw material and reagent can produce the deuterate form of compound 19.According to the general method of describing among the U.S. Patent application US 2008234359, the hydrogenation of compound 19 produces amine 20 in the presence of palladium carbon, and it is handled so that midbody 12a to be provided with suitable deuterated diacetyl oxide 21 then.According to Wamser, people such as C.C., J.Org.Chem. (1976), 41 (17), the general method of 2929-31 can reduce midbody 12a so that midbody 12b to be provided with zinc and acid.Commercially available DCL, acetic acid-d4 and acetic anhydride-d6 can be used to the alternating pattern to provide deuterium to mix in the final step.
For example, commercially available 3-aminophthalic acid can be used as midbody 20 and is used for scheme 3 with final generation Y wherein 6, Y 7And Y 8It all is the formula I compound of hydrogen.In another example, commercially available diacetyl oxide-d6 can be used as reagent 21 in scheme 3, with final generation R wherein 2Be CD 3Formula I compound.In another example again, commercially available phthalic acid-d4 acid anhydrides can be used as acid anhydrides 18 in scheme 3, with final generation Y wherein 6, Y 7And Y 8It all is the formula I compound of deuterium.
The substituting group of the present invention imagination and the combination of variable are those combinations that cause forming the substituting group and the variable of stable compound.
Compsn
The present invention also provides compound or the pharmacy acceptable salt of said compound and the compsn of acceptable carrier of the formula I (any chemical formula that for example, comprises this paper) that comprises significant quantity.Said carrier is saying it is " acceptable " on the used amount meaning harmless for the recipient in medicine under and the situation at pharmaceutically acceptable carrier compatible with other compositions of preparation.
Pharmaceutically acceptable carrier, assistant agent and the solvent that can be used for pharmaceutical composition of the present invention include but not limited to, material, polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, wax, Vilaterm-polyoxypropylene block polymer, polyoxyethylene glycol and the yolk of partial glycerol ester mixture, water, salt or the ionogen of ionite, aluminum oxide, StAl, Yelkin TTS, serum proteins such as human serum albumin, buffer substance such as phosphoric acid salt, glycocoll, Sorbic Acid, POTASSIUM SORBATE GRANULAR WHITE, saturated vegetable fatty acid such as protamine sulfate, Sodium phosphate, dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, silica gel, Magnesium Trisilicate, Vinylpyrrolidone polymer, cellulose base.
Pharmaceutical composition of the present invention comprises that those are suitable for the pharmaceutical composition that oral cavity, rectum, nasal cavity, part (comprising cheek and hypogloeeis), vagina or parenteral (comprising subcutaneous, intramuscular, intravenously and intracutaneous) are used.In some embodiments, the compound transdermal administration among this paper shown in the chemical formula (for example, using percutaneous plaster or iontophoresis (iontophoretic) technology).Other preparations can exist with unit dosage (like tablet, slow releasing capsule) and exist with liposome easily, and can be through any method preparation of knowing in the pharmaceutical field.Referring to, for example, Remington ' s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA (the 20th edition, 2000).
This type preparation method comprises makes some composition (like carrier) and molecule bonded step to be used that constitutes one or more ancillary components.Usually, combine with the solid carrier of liquid vehicle, liposome or segmentation or with the two through evenly and nearly making activeconstituents, then (if necessary) make product shaping and prepare compsn.
In some embodiments, compound oral administration.Be fit to Orally administered compsn of the present invention and can be used as discrete unit and exist, like capsule, cachet (sachets) or the tablet of the activeconstituents that respectively contains predetermined amount; Powder or particle; Solution in waterborne liquid or non-aqueous liquid or suspension-s; Oil-in-water liq emulsion; The water-in-oil-type liquid emulsion; Be packaged in the liposome; Or as bolus (bolus) etc.Soft capsule can be used to comprise this suspension-s, and this can advantageously improve the compound specific absorption.
In the situation of the tablet that orally uses, normally used carrier comprises lactose and W-Gum.Usually also add lubricant, like Magnesium Stearate.Orally administered for capsule form, useful thinner comprises lactose and exsiccant W-Gum.When the oral administration waterborne suspension, activeconstituents combines with emulsifying agent and suspension agent.If desired, can add some sweeting agent and/or seasonings and/or tinting material.
Be suitable for the pastille (pastilles) that Orally administered compsn is included in the lozenge (lozenges) that contains this composition in the flavoured base (normally sucrose and gum arabic or tragacanth gum) and in inert base (like gelatin and glycerine, or sucrose and gum arabic), contains activeconstituents.
The compsn that is suitable for administered parenterally comprises water-based and non-aqueous sterile solution for injection, and it possibly contain inhibitor, buffer reagent, fungistat and give preparation and the isoosmotic solute of intended recipient's blood; With comprise water-based and non-aqueous sterilization suspension-s, it possibly comprise suspending agent and thickening material.Said preparation possibly exist or be present in the container of multiple doses with unit dosage form; For example, the ampoule of sealing and bottle, and can under the condition of lyophilize (freeze-drying), preserve; Thereby only need before being about to use, add sterile liquid carrier (for example, water for injection).Can be by sterilized powder, particle and tablet prepn instant injection solution and suspension-s.
This injection liquid for example can be, the aseptic injectable water-based or the form of oily suspensions.Can use suitable dispersion agent or wetting agent (for example, tween 80) and suspension agent to prepare this suspension-s according to technology known in the art.Aseptic injectable formulation also can be sterile injectable solution or the suspension-s in non-toxicity parenteral acceptable diluent or solvent, for example, and the solution in the 1,3 butylene glycol.Operable acceptable carrier and solvent have N.F,USP MANNITOL, water, ringer's solution (Ringer ' s solution) and isotonic sodium chlorrde solution.In addition, adopt aseptic fixed oil as solvent or suspension medium usually.For this purpose, the fixed oil of any gentleness be can use, synthetic monoglyceride or triglyceride comprised.Lipid acid like oleic acid and glyceride derivative thereof, can be used for preparing injection, as natural pharmaceutically acceptable oil, and like sweet oil or Viscotrol C, their T 46155 form especially.These oil solutions or suspension-s can also comprise long-chain alcohol thinner or dispersion agent.
Pharmaceutical composition of the present invention possibly used with the suppository form that is used for rectal administration.Can be through compound of the present invention and suitable non-irritating excipient be mixed with these compsns, said non-irritating excipient at room temperature is a solid, but is liquid in rectal temperature, therefore in rectum fusing with release of active ingredients.These materials include but not limited to, theobroma oil, beeswax and polyoxyethylene glycol.
Pharmaceutical composition of the present invention can or suck through the nasal cavity aerosol and use.Such compsn is according to technique known preparation in the field of pharmaceutical preparations, and can adopt phenylcarbinol or other suitable sanitass, absorption enhancer, fluorocarbon and/or other solubilizing agent known in the art or the dispersion agent that improve bioavailability process salt brine solution.Referring to, for example: Rabinowitz JD and Zaffaroni AC, USP 6,803,031 is authorized Alexza Molecular Delivery Corporation.
When the treatment of needs relates to approaching easily zone of topical application or organ, the topical application particularly advantageous of pharmaceutical composition of the present invention.To the topical application of skin, pharmaceutical composition should be with containing the suitable ointment preparation that suspends or be dissolved in the activeconstituents in the carrier for partly.The carrier that is used for the The compounds of this invention topical application includes but not limited to MO, liquid petroleum, Vaseline (white petroleum), Ucar 35, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Selectively, pharmaceutical composition can be with containing suitable washing lotion or the emulsifiable paste preparation that suspends or be dissolved in the active compound in the carrier.Suitable carriers includes but not limited to, MO, sorbitan monostearate, polysorbate60, cetyl esters wax, cetostearyl alcohol, 2-Standamul G, phenylcarbinol and water.Pharmaceutical composition of the present invention also can be applied topically to lower intestinal tract through rectal suppository or suitable enema agent.Using of topical transdermal paster and iontophoresis is also included among the present invention.
The application of patient treatment medicine can be partial, so that be applied in the target location.Various technology are used in interested position said compsn are provided, as injecting, use conduit, trochar, projectile body, polyethers gel (pluronic gel), support, medicament slow release polymkeric substance or inner other devices that contact being provided.
Therefore, according to another embodiment, compound of the present invention can mix the compsn that is used to apply implantable medical device such as prosthese, artificial valve, artificial blood vessel, support or conduit.The general preparation of the implantable device of suitable coating compounds and coating is known in the art, and at USP 6,099,562,5,886,026 and 5,304,121 illustrated.Coating is the polymeric materials of biocompatibility normally, like aquogel polymer, gather methyl sily oxide, polycaprolactone, polyoxyethylene glycol, POLYACTIC ACID, ethylene vinyl acetate and composition thereof.Coating can be randomly covered by the top coating of suitable fluorosilicone, polysaccharide, polyoxyethylene glycol, phosphatide or its combination, to give the compsn release characteristics.The coating of intrusion apparatus is included within the definition of the pharmaceutically acceptable carrier of term, assistant agent or the solvent that use like this paper.
According to another kind of embodiment, the invention provides the method that applies implantable medical device, comprise the step that said device is contacted with coating composition mentioned above.The coating of device occurs in and implants Mammals is conspicuous for those skilled in the art before.
According to another kind of embodiment, the invention provides the method for the implantable drug release device of dipping, comprise the step that said drug release device is contacted with compound of the present invention or compsn.Implantable drug release device includes but not limited to, the diffustivity polymer capsule of biodegradable polymer capsule or bullet, non-degraded and biodegradable polymer membrane (wafer).
According to another kind of embodiment, the invention provides the implantable medical device that is coated with compound of the present invention or comprises the compsn of The compounds of this invention, so that said compound has therapeutic activity.
According to another kind of embodiment; The invention provides with compound of the present invention or comprise the compsn dipping of The compounds of this invention or contain compound of the present invention or comprise the implantable drug release device of the compsn of The compounds of this invention, so that said compound discharges and has a therapeutic activity from said device.
In organ or tissue owing to remove in patient's body under the come-at-able situation; Such organ or tissue can be bathed in the medium that contains compsn of the present invention; Compsn of the present invention can be coated on this organ, or compsn of the present invention can with any other easily mode use.
In another embodiment, compsn of the present invention further comprises second medicine.
Second medicine can be selected from known to having any compound or the medicine that has or demonstrate advantageous feature when using with the compound of the same mechanism of action of apremilast.Such medicine comprises that those show advantageously and apremilast bonded medicine that include but not limited to that those are used to treat the medicine of following disease: psoriatic comprises psoriasis in plaques and psoriasis inveterata; Sarcoidosis comprises that skin tag is sick; Psoriatic arthritis; Behcet disease; Prurigo nodularis; Lupus comprises cutaneous lupus; With uveitis etc.
In one embodiment, second medicine is to be used to treat psoriatic or sarcoid medicine.
In another embodiment, the invention provides the formulation of separating of The compounds of this invention and one or more any above-mentioned second medicines, wherein, the said compound and second medicine are associated with each other.Term used herein " associated with each other " meaning is that isolating formulation is packaging together or otherwise be bonded to each other so that said isolating formulation clearly is (within 24 hours, the using continuously or simultaneously each other) that is intended to sell together and use.
In pharmaceutical composition of the present invention, compound of the present invention exists with significant quantity.As used herein, term " significant quantity " refers to when using with suitable therapeutic regimen, to be enough to the amount of treatment (therapeutic ground or prophylactically) target disease.For example, reduce the order of severity, duration or the progress of disease to be treated, prevent advancing of disease to be treated, cause the reverse of disease to be treated, perhaps strengthen or improve the prevention or the result of treatment of another kind of treatment.
People such as Freireich, Cancer Chemother.Rep, 1966, the mutual relationship of the dosage (based on milligram/square metre body surface area) of animal and human's class has been described among the 50:219.Body surface area can be confirmed from patient's height and body weight approx.Referring to, for example, Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 1970,537.
In one embodiment, the significant quantity scope of compound of the present invention can be that treatment about 0.2 at every turn is to 2000mg.In embodiment more particularly, this scope be each treatment about 2 to 1000mg or 4 to 400mg, perhaps each treatment about 20 is to 200mg.Treatment is normally used with 0.625 to 1.25ng/kg/ minute speed.Preceding 4 all infusion rates can increase with the increment that is no more than 1.25ng/kg/ minute weekly, then for increasing with the increment that is no more than 2.5ng/kg/ minute weekly during the remaining infusion.
As those skilled the in art will appreciate that; Effective dose is also with severity, the route of administration of disease to be treated, disease, the use of patient's sex, age and general health situation, vehicle, the possibility of using (as using other drug) with the processing of other treatment property jointly and treatment doctor's judgement and changing.For example, select the guidance of effective dose to confirm with reference to prescription information for apremilast.
For the pharmaceutical composition that comprises second medicine, the significant quantity of second medicine be in only using the single therapy scheme of this medicine normal using dosage about 20% to 100%.Preferably, significant quantity is about 70% to 100% of normal single therapeutic dose.Normal single therapeutic dose of these second medicines is known in the art.For example, referring to, people such as Wells write, Pharmacotherapy Handbook, the 2nd edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), complete by reference each document of introducing of this paper.
Can expect some second medicine above-mentioned and compound of the present invention performance synergy.When this happens, allow the effective dose dosage more required of second medicine and/or compound of the present invention to reduce than single therapy.This has so that the toxic side effect of second medicine or The compounds of this invention minimizes, synergy, raising is used or the accessibility used and/or reduce the advantage of the whole cost of compound or preparation.
Treat-ment
In another embodiment, the invention provides a kind of method that in the experimenter, suppresses PDE4, comprise compound from the formula I of this paper to the experimenter or its pharmacy acceptable salt of using.
In another embodiment, the invention provides the method for the TNF-alpha levels among a kind of experimenter of reduction, comprise compound from the formula I of this paper to the experimenter or its pharmacy acceptable salt of using.
According to another kind of embodiment; The invention provides a kind of treatment can be advantageously by the method for the disease of apremilast treatment, comprise that patient to the needs treatment uses compound or the step of its pharmacy acceptable salt or compsn of the present invention of the formula I of significant quantity.Such disease is well known in the art; And be disclosed in (but being not limited to) following patent and the disclosed application: WO2006/025991, AU2006/200033, WO2001/034606, No. the 6th, 020,358, USP and USP the 6th; 667, No. 316.
These diseases include but not limited to: septic shock, Sepsis, endotoxin shock, haemodynamics shock and sepsis syndrome, postischemic reperfusion damage, malaria, mycobacterial infections, meningitis; Psoriatic comprises psoriasis in plaques and psoriasis inveterata; Sarcoidosis (sarcoidosis) comprises that skin tag is sick; Psoriatic arthritis; Behcet disease; Prurigo nodularis; Lupus comprises cutaneous lupus; Uveitis; Congestive heart failure; Fibrotic disease; Emaciation; Transplant rejection; Cancer; Autoimmune disorder; The AIDS opportunistic infection; Rheumatoid arthritis; The similar rheumatism spondylitis; Osteo-arthritis; Other arthritis diseases; Crohn's disease; Ulcerative colitis; Multiple sclerosis; Systemic lupus erythematous; The ENL of leprosy; Radiation injury; Hyperoxic alveolar injury; Bad vasculogenesis; Inflammatory diseases; Sacroiliitis; Inflammatory bowel; Stomatocace; Asthma; Adult respiratory distress syndrome and AIDS.
In a special embodiment, method of the present invention is used to treat psoriatic or sarcoidosis.
Method as herein described comprises that also patient wherein confirms as the method for the treatment that need show especially.Affirmation needs the patient of this treatment to be judged by patient or health care professional, and can be subjective (like suggestion) or objective (as measuring through check or diagnostic method).
In another embodiment, any above-mentioned treat-ment comprises the other step of using one or more second medicines to said patient jointly.Second medicine can be selected from any known second medicine that can be used for using jointly with apremilast.Specified disease to be treated or state are also depended in the selection of second medicine.The example that can be used for second medicine of method of the present invention is second medicine that comprises preceding text being used for of proposing the combined group compound of the compound of the present invention and second medicine.
Especially, combination therapy of the present invention comprises compound or its pharmacy acceptable salt and second medicine that is used to treat following disease of using formula I jointly: psoriatic comprises psoriasis in plaques and psoriasis inveterata; Sarcoidosis comprises that skin tag is sick; Psoriatic arthritis; Behcet disease; Prurigo nodularis; Lupus comprises cutaneous lupus; And uveitis.
The meaning " used " jointly in term used herein is that second medicine can be with as the part of the single formulation compsn of the present invention of the compound of the present invention and above-mentioned second medicine (as comprise) or use as isolating multi-form and compound of the present invention.Selectively, can or, use The compounds of this invention other medicine after using before The compounds of this invention is used, with The compounds of this invention order of applying ground.In this conjoint therapy treatment, use the compound of the present invention and second medicine through ordinary method.Use another time that the present composition that comprises the compound of the present invention and second medicine is not precluded within the course of treatment to the patient and use same medicine, any other second medicine or any compound of the present invention separately to said patient.
The significant quantity of these second medicines is that those skilled in the art is well-known; And patent and patent application publication that the guidance that is used for administration can be quoted at this paper, and write Pharmacotherapy Handbook people such as Wells; The 2nd edition; Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda finds in Calif. (2000) and other medical literature.Yet the scope of confirming the best significant quantity of second medicine is within those of skill in the art's limit of power.
Using to the experimenter in one embodiment of the present invention of second medicine, the significant quantity of compound of the present invention is lower than its significant quantity in the situation of not using second medicine.In another embodiment, the significant quantity of second medicine is lower than its significant quantity in the situation of not using compound of the present invention.Like this, relevant with the high dosage of any medicine unwanted spinoff can minimize.Other potential advantages (including but not limited to that dosage regimen is improved and/or the medicine expense reduces) are conspicuous for those skilled in the art.
In more other one side, the invention provides formula I compound or its pharmacy acceptable salt and be used for treating the purposes of medicine (as single compsn or as isolating formulation) of patient's above-mentioned disease, obstacle or symptom in manufacturing separately or with one or more above-mentioned second medicines.Another aspect of the present invention is formula I compound or its pharmacy acceptable salt that is used to treat patient's disease described herein, obstacle or symptom.
Embodiment
Embodiment 1: (S)-and N-(2-(1-d-2-(methylsulfonyl)-1-(3-(oxyethyl group-d 5 )-4-(methoxyl group-d 3 ) phenyl) ethyl)-1,3-dioxoisoindolin-4-yl) ethanamide (compound 113a) synthetic.
scheme 4: the preparation of compound 113a.
Step 1:3-hydroxyl-4-(methoxyl group-d 3 )-ethyl benzoate (23).
(10g is 55mmol) with CD in DMF with commercially available ester 22 3I (99 atom %D, Cambridge Isotopes; 8.1g, 55mol) and K 2CO 3(7.59g) mix, and at room temperature stir a weekend.LCMS demonstrates the product 23 (55%) of quality and parent material (20%), required monoalkylation and 3 consistent peaks of sub product (23%) of dialkylated.Filter this reactant through Celite pad, with the EtOAc washing, and concentrating filter liquor is to almost dry.Residue is dissolved in CH 2Cl 2(300mL), and water (5x 50mL), this solution of brine wash, dry (Na 2SO 4) and concentrate.Through the chromatography purification crude product on the silica gel,, further grind to produce the compound 23 that 4.1g (36%) needs then with heptane with EtOAc/ heptane (1: 9 to 1: 6) wash-out.
Step 2:3-(oxyethyl group-d 5 )-4-(methoxyl group-d 3 )-ethyl benzoate (24).
(4.1g 20mmol) is dissolved among the DMF (10mL) compound 23, and adds K 2CO 3(2.5g) and CD 3CD 2Br (99 atom %D, Cambridge Isotopes; 4.7g, 41mmol).The sealed reaction bottle, and at room temperature stirred 24 hours.LCMS shows the reaction completion.Filter this mixture through Celite pad, wash with MTBE.Concentrating filter liquor to be removing volatile matter, and adds entry (100mL).Under vacuum state, collect solid, water (50mL) washing.Solid is dissolved among the MTBE (200mL) again, and uses brine wash solution, dry (Na 2SO 4) and concentrate, with the compound 24 that produces about 3.8g (81%) (confirm through LCMS about 90% purity).
Step 3: (3-(oxyethyl group-d 5 )-4-(methoxyl group-d 3 )-phenyl)-1,1-d 2 -methyl alcohol (25).
(3.8g 16.3mmol) is dissolved among the MTBE (50mL) compound 24, and adds LiAlD 4(98 atom %D, Cambridge Isotopes; 0.7g, 17mmol).At room temperature stirred reaction mixture spends the night.LCMS shows the reaction completion.Add NH carefully 4The Cl aqueous solution (20mL) reacts with cancellation, and filters this mixture through Celite pad.Separate mutually, and with EtOAc (2x 20mL) aqueous phase extracted.Dry (Na 2SO 4) organic phase that merges, and concentrate to produce the compound 25 as light yellow oil of 2.8g.This material directly is used for next step.
Step 4:3-(oxyethyl group-d 5 )-4-(methoxyl group-d 3 )-phenyl aldehyde-d (10a).
(2.8g 16mmol) is dissolved among the EtOAc (30mL) compound 25.Add MnO 2(14g 160mmol), and at room temperature stirs black mixture and spends the night.LCMS shows the parent material completely consumed.This mixture is through Celite pad, and with the EtOAc washing, and concentrating filter liquor is to produce xanchromatic oil.This oil carries out purifying through chromatography on silica gel, with 20%EtOAc/ heptane wash-out, to produce the compound 10a as white solid of 2.05g (is 68% for 2 steps).
Step 5:1-(3-(oxyethyl group-d 5 )-4-(methoxyl group-d 3 )-phenyl)-1-d-2-(methylsulfonyl) ethamine (11a).
(1g 10.7mmol) is suspended among the THF (70mL) the methyl sulfone, and in acetone/the dry ice bath, is cooled to and is lower than-70 ℃.(2.5M is in hexane, and 4.6mL 11.5mmol), and stirred the mixture 30 minutes to add n-BuLi.In independent flask, (1.9g, 10.0mmol) solution in THF (20mL) is cooled to 0 ℃ with compound 10a.(1M is in THF, 12mL) to add hexamethyl two silica-based amido lithiums (LHMDS).After 15 minutes, (2.8mL 22mmol), and proceeded to stir other 5 minutes to add boron trifluoride ethyl ether complex.Add methyl sulfone/n-BuLi solution through syringe to this solution then, the while is cooled in acetone/the dry ice bath and is lower than-70 ℃.Observe heat release.Make this mixture be warmed up to room temperature, and stirred overnight.After cooling in ice-water bath, add K 2CO 3(8g), then be water (50mL).Layering takes place, and with EtOAc (2x 20mL) aqueous phase extracted.Dry (Na 2SO 4) organic solution that merges, and concentrate to produce the oil of viscosity.(4N 30mL), and at room temperature stirs the mixture 2 hours to produce clarifying two phase liquid to add MTBE (30mL) and aqueous hydrochloric acid.Be separated, and with aqueous hydrochloric acid (4N, 25mL) extraction organic solution.Add the NaOH aqueous solution (24%) until pH＞12 to the water that merges.With EtOAc (3x 50mL) aqueous phase extracted.Dry (Na 2SO 4) organic phase, and concentrate to produce yellow solid.This solid suspension and stirred 1 hour in MTBE (20mL).Filter the compound 11a that produces 1.2g (36%) under the vacuum.
Step 6: (S)-1-(3-(oxyethyl group-d 5 )-4-(methoxyl group-d 3 )-phenyl)-1-d-2-(methylsulfonyl)-ethamine N-ethanoyl leucine salt ((S)-11a).
(1.2g, 4.25mmol) (0.44g 2.55mmol) mixes compound 11a with N-ethanoyl-L-leucine in MeOH (10mL).At 70 ℃ of following these mixtures of heating 3 hours, stirred overnight at room temperature then.Collect solid through vacuum filtration, and be suspended among the MeOH (15mL).Down stirred these mixtures 2 hours at 70 ℃, then stirred overnight at room temperature.Collect solid, and repeat methyl alcohol and grind.Ee with＞99% separates compound (the S)-11a of 600-mg part (31%).
Step 7: (S)-N-(2-(1-d-1-(3-(oxyethyl group-d 5 )-4-(methoxyl group-d 3 )-phenyl)-and the 2-methylsulfonyl) ethyl)-1,3-dioxoisoindolin-4-yl) ethanamide (compound 113a).
Compound (S)-11a (380mg, 0.88mmol) in acetate (6mL) with compound known 12a (200mg, 1mmol; Referring to US 20080234359) mix, and reflux 24 hours is to promote reaction to accomplish.Enriched mixture, and colourless oil is dissolved among the EtOAc (100mL) again.Use saturated NaHCO 3The aqueous solution (20mL) washs this solution, dry (Na 2SO 4) and concentrate.Through column chromatography purifying crude product in the Analogix system, use 0-3% MeOH/CH 2Cl 2Wash-out is to produce the compound 113a of 360mg (87%). 1H-NMR (300MHz, CDCl 3): δ 1.58 (s, 1H), 2.27 (s, 3H), 2.87 (s, 3H), 3.72 (d, J=14.31H), 4.55 (d, J=14.5; 1H), 6.84 (d, J=9.8,1H), 7.11 (d, J=9.2,2H), 7.49 (d, J=6.5; 1H), 7.66 (s, J=7.7,1H), 8.77 (d, J=7.7,1H), 9.46 (s, 1H). 13C-NMR (75MHz, CDCl 3): δ 24.97,41.67, and 54.47,111.45,112.38; 115.14,118.25,120.28,124.99,129.18; 131.07,136.14,137.66,148.70; 167.51 (method: 50mm 3 μ m Waters Atlantis T3 2.1 posts-gradient method 5-95% ACN+0.1% formic acid 14 minutes, remained 95%ACN+0.1% formic acid in 4 minutes to 169.16.HPLC; Wavelength: 305nm): RT: 5.96 minutes; 99.5% purity.MS(M+H)：470.3。Ultimate analysis (C 22H 15D 9N 2O 7SH 2O): calculated value: C=54.20, H=5.38, N=5.75. measured value: C=54.15, H=4.98, N=5.60.
Embodiment 2: (S)-and N-(2-(2-((methylsulfonyl)-1-(3-(oxyethyl group-d 5 )-4-(methoxyl group-d 3 ) phenyl) ethyl)-1,3-dioxoisoindolin-4-yl) ethanamide (compound 107a) synthetic.
scheme 5: the preparation of compound 107a.
Figure BSA00000407441900281
Figure BSA00000407441900291
Step 1:3-hydroxyl-4-(methoxyl group-d 3 )-phenyl aldehyde (27).
With commercially available 3, (10g 80mmol) is dissolved among the DMF (50mL) 4-dihydroxyl-phenyl aldehyde 26.Add K 2CO 3(10g), and at ice-water bath cool off this solution.Slowly add CD 3I (99 atom %D, Cambridge Isotopes; 12.4g 84mmol), and at room temperature reaction stirred is spent the night.With EtOAc (200mL) diluting reaction thing, and through the Celite pad filtration.Concentrating filter liquor is to produce the oil of black.Add EtOAc (150mL) and water (50mL), and carry out layer and separate.Adjust water to pH 6 through slow adding 1N HCl, and extract this mixture with EtOAc (2x 100mL).Dry (Na 2SO 4) organic solution that merges and concentrating.Through the thick material of chromatography purifying on silica gel,, be approximately the compound 27 greater than 5g of 90% purity with generation with EtOAc/ heptane (1: 6 to 1: 2) wash-out.This material is purifying on the Analogix chromatographic system further, with the EtOAc/ heptane wash-out of 0-30%, to produce the compound 27 of 4.3g (35%).
Step 2:3-(oxyethyl group-d 5 )-4-(methoxyl group-d 3 )-phenyl aldehyde (10b).
(4.3g is 27.7mmol) with Cs in acetone for compound 27 2CO 3(15g 46mmol) mixes, and in ice-water bath, cools off.Add monobromethane-d 5(99 atom %D, Cambridge Isotopes; 3.8g 33.6mmol), and reaction stirred is spent the night.Add MTBE, and filter this mixture through Celite pad.Through after concentrating, through chromatography purifying crude product on silica gel, with 1: 4 EtOAc/ heptane wash-out, with the compound 10b of the needs of generation 2g (38%).
Step 3:1-(3-(oxyethyl group-d 5 )-4-(methoxyl group-d 3 )-phenyl)-2-(methylsulfonyl) ethamine (11b).
(1g 10.7mmol) is suspended among the THF (70mL) the methyl sulfone, and in acetone/the dry ice bath, is cooled to and is lower than-70 ℃.(2.5M is in hexane, and 4.8mL 11.9mmol), and stirred the mixture about 30 minutes to add n-BuLi.In flask independently, (2g, 10.6mmol) solution in THF (20mL) is cooled to 0 ℃ with aldehyde 10b.Add LHMDS (1M in THF, 12 mL).After 15 minutes, (2.8mL 22mmol), and continues to stir other 5 minutes to add boron trifluoride ethyl ether complex.Through syringe this solution is added in methyl sulfone/n-BuLi solution then, the while is cooled in acetone/the dry ice bath and is lower than-70 ℃.Observe heat release.Make this mixture be warmed up to room temperature, and stirred overnight.After cooling in ice-water bath, add K 2CO 3(8g), then add entry (50mL).Layer separates, and with EtOAc (2x 20mL) aqueous phase extracted.Dry (Na 2SO 4) organic solution that merges, and concentrate to produce the oil of viscosity.(4N 30mL), and at room temperature stirs this mixture 2 hours to produce clarifying two phase liquid to add MTBE (30mL) and aqueous hydrochloric acid.Be separated, and with aqueous hydrochloric acid (4N, 25mL) extracted organic phase.To the aqueous phase that merges add the NaOH aqueous solution (24%) with rising pH to＞12.With EtOAc (3x 50mL) extraction solution.Dry (Na 2SO 4) organic solution that merges, and concentrate to produce yellow solid.Solid suspension is in MTBE (20mL), and stirs 1 hour.Vacuum filtration produces the compound 11b as faint yellow solid of 1.2g (38%).
Step 4: (S)-1-(3-(oxyethyl group-d 5 )-4-(methoxyl group-d 3 )-phenyl)-2-(methylsulfonyl) ethamine N-ethanoyl-L-leucine salt ((S)-11b).
(1.05g, 3.73mmol) (0.39g 2.24mmol) mixes compound 11b with N-ethanoyl-L-leucine in MeOH (6mL).At 70 ℃ of following these mixtures of heating 3 hours, stirred overnight at room temperature then.Collect solid through vacuum filtration, and be suspended among the MeOH (15mL).Down stirred these suspension-s 2 hours at 70 ℃, then stirred overnight at room temperature.Collect solid, and repeat methyl alcohol and grind.Ee with＞98% obtains (the S)-11b N-ethanoyl-L-leucine salt of 400-mg part (23%).
Step 5: (S)-N-(2-(1-(3-(oxyethyl group-d 5 )-4-(methoxyl group-d 3 )-phenyl)-and the 2-methylsulfonyl) ethyl)-1,3-dioxoisoindolin-4-yl) ethanamide (compound 107a).
(S)-(220mg, 0.5mmol) (123mg 0.6mmol) mixes 11b N-ethanoyl-L-leucine salt, and reflux 24 hours is to promote reaction near accomplishing with compound known 12a in acetate (5mL).Concentrate this mixture, colourless oil is dissolved among the EtOAc (100mL), and uses saturated NaHCO 3The aqueous solution (20mL) washs this solution.Dry (Na 2SO 4) organic phase and concentrated.Through column chromatography purifying crude product in the Analogix system, with 0-70%EtOAc/ heptane wash-out, to produce the compound 107a of 210mg (89%). 1H-NMR (300MHz, CDCl 3): δ 1.59 (s, 1H), 2.27 (s, 3H), 2.87 (s, 3H), 3.72 (dd, J=4.6,14.4; 1H), 3.85 (s, 3H), 4.56 (dd, J=10.8,14.4,1H), 5.87 (dd, J=4.4; 10.6), 6.84 (d, J=8.8,1H), 7.10 (d, J=7.0,2H), 7.49 (d, J=6.6; 1H), 7.65 (t, J=7.3,1H), 8.76 (d, J=8.0,1H), 9.46 (s, 1H). 13C-NMR (75MHz, CDCl 3): δ 24.97,41.66, and 48.60,54.55,55.96,76.58,77.01; 77.43,111.48,112.40,115.14,118.25,120.29; 125.00,129.26,131.07,136.14,137.66,148.70; 149.79,167.51,169.17, (method: 50mm 3 μ m Waters Atlantis T32.1 post-gradient method 5-95%ACN+0.1% formic acid 14 minutes, remained 95%ACN+0.1% formic acid in 4 minutes to 169.53.HPLC; Wavelength: 305nm): RT: 6.02 minutes;＞98.0% purity.Chirality HPLC (method: Chiralpak AD 25cm post-78% hexane such as method such as degree of grade/22% Virahol/0.01% diethylamine, 40 minutes, 1.00mL/ minute; Wavelength: 254nm): RT: 12.73 minutes (main enantiomorph);＞99%ee purity.MS(M+Na)：488.1。Ultimate analysis (C 22H 21D 3N 2O 7S): calculated value: C=56.76, H=5.20, N=6.02, S=6.89. measured value: C=56.74, H=5.43, N=5.70, S=6.51.
Embodiment 3: (S)-and N-(2-(2-((methylsulfonyl)-1-(3-oxyethyl group-4-(methoxyl group-d 3 ) phenyl) ethyl)-1,3-dioxoisoindolin-4-yl) ethanamide (compound 114a) synthetic.
scheme 6: the preparation of compound 114a.
Figure BSA00000407441900311
Figure BSA00000407441900321
Step 1:3-oxyethyl group-4-(methoxyl group-d 3 )-phenyl aldehyde (10c).
(5g is 30mmol) with Cs in acetone for the commercially available compound 16a of cooling in ice-water bath 2CO 3(15g, mixture 46mmol).Add (CD 3) 2SO 4(99 atom %D, Cambridge Isotopes; 2.7mL, 30mmol), make reactant slowly be warmed up to room temperature, and stirred overnight.Filter this mixture through Celite pad, and concentrate to produce the compound 10c of 5.7g (about 100%).
Step 2:1-(3-oxyethyl group-4-(methoxyl group-d 3 )-phenyl)-2-(methylsulfonyl)-ethamine (11c).
(3g 32.1mmol) is suspended among the THF (280mL) the methyl sulfone, and in acetone/the dry ice bath, is cooled to and is lower than-70 ℃.(2.5M is in hexane, and 13.6mL 35.7mmol), and stirred the mixture about 30 minutes to add n-BuLi.In flask independently, (5.7g, 30.2mmol) solution in THF (60mL) is cooled to 0 ℃ with compound 10c.(1M is in THF, 34.4mL) to add LHMDS.After 15 minutes, (8mL 62.9mmol), and stirred this mixture 5 minutes to add boron trifluoride ethyl ether complex.Through syringe this solution is added in methyl sulfone/n-BuLi solution then, the while is cooled in acetone/the dry ice bath and is lower than-70 ℃.Observe heat release.Make this mixture be warmed up to room temperature, and stirred overnight.After cooling in ice-water bath, add K 2CO 3(24g), then add entry (150mL).Layer separates, and with EtOAc (3x 60mL) aqueous phase extracted.Dry (Na 2SO 4) organic solution that merges, and concentrate to produce the oil of viscosity.(4N 90mL), and at room temperature stirs this mixture 2 hours to produce clarifying two phase liquid in residue, to add MTBE (90mL) and aqueous hydrochloric acid.Be separated, and with aqueous hydrochloric acid (4N, 75mL) extracted organic phase.Add the NaOH aqueous solution (24%) to improve pH to the aqueous phase that merges to＞12.With EtOAc (3x 150mL) aqueous layer extracted.Dry (Na 2SO 4) organic solution that merges, and concentrate to produce yellow solid.Solid suspension and stirred 1 hour in MTBE (60mL).Vacuum filtration is to produce the compound 11c as faint yellow solid of 2.7g (31.4%).
Step 3: (S)-1-(3-oxyethyl group-4-(methoxyl group-d 3 )-phenyl)-2-(methylsulfonyl)-ethamine N-ethanoyl-L-leucine salt ((S)-11c).
(2.3g, 8.17mmol) (0.78g 4.48mmol) mixes compound 11c with N-ethanoyl-L-leucine in MeOH (12mL).At 70 ℃ of following these mixtures of heating 3 hours, stirred overnight at room temperature then.Collect solid through vacuum filtration, be suspended among the MeOH (12mL), and stirred 2 hours down, then stirred overnight at room temperature at 70 ℃.Collect solid, and repeat methyl alcohol and grind.Ee with＞98% obtains (the S)-11c N-ethanoyl-L-leucine salt of 1-g part (28.8%).
Step 4: (S)-N-(2-(1-(3-oxyethyl group-4-(methoxyl group d 3 )-phenyl)-and 2-(methylsulfonyl) ethyl)-1,3-dioxoisoindolin-4-yl) ethanamide (114a).
(0.97g, 2.2mmol) (470mg 2.5mmol) mixes compound (S)-11c, and reflux 24 hours, to promote reaction near accomplishing with compound known 12a in acetate (20mL).Enriched mixture, colourless oil are dissolved among the EtOAc (200mL), and use saturated NaHCO 3(40mL) wash this solution.Dry (Na 2SO 4) organic phase and concentrated.Through column chromatography purifying crude product in the Analogix system, with 0-70%EtOAc/ heptane wash-out, to produce the compound 114a of 0.7g (68%). 1H-NMR (300MHz, CDCl 3): δ 1.47 (t, J=7.0,3H), 1.61 (s, 1H), 2.26 (s, 3H), 2.87 (s, 3H), 3.72 (dd, J=4.6; 14.4,1H), 4.11 (q, J=6.9,14.0,2H), 4.55 (dd, J=10.5,14.4,1H), 5.87 (dd; J=4.4,10.6,1H), 6.84 (d, J=8.7,1H), 7.10 (d, J=6.5,2H), 7.49 (d; J=7.3,1H), 7.65 (t, J=7.7,1H), 8.76 (d, J=8.5,1H), 9.46 (s, 1H). 13C-NMR (75MHz, CDCl 3): δ 14.70,24.96, and 41.65,48.59,54.54,64.55; 111.46,112.44,115.14,118.25,120.32,125.00; 129.24,131.07,136.14,137.66,148.67,149.79; 167.51,169.17, (method: 50mm 3 μ m Waters Atlantis T32.1 post-gradient method 5-95%ACN+0.1% formic acid 14 minutes, remained on 95%ACN+0.1% formic acid in 4 minutes to 169.53.HPLC; Wavelength: 305nm): RT: 6.03 minutes;＞97.4% purity.Chirality HPLC (method: Chiralpak AD 25cm post-78% hexane such as method such as degree of grade/22% Virahol/0.01% diethylamine, 40 minutes, 1.00mL/ minute; Wavelength: 254nm): RT: 12.69 minutes (main enantiomorph); Minute 39.03 (less important enantiomorph); The purity of＞99%ee.MS(M+Na)：486.0.
Ultimate analysis (C 22H 21D 3N 2O 7S): calculated value: C=57.01, H=5.22, N=6.04, S=6.92.
Measured value: C=57.68, H=5.63, N=5.52, S=6.33.
Embodiment 4: (S)-and N-(2-(2-(methylsulfonyl)-1-(3-(oxyethyl group-d 5 )-4-(methoxyl group) phenyl) ethyl)-1,3-dioxoisoindolin-4-yl) ethanamide (compound 110a) is synthetic.
scheme 7: the preparation of compound 110a.
Step 1:3-(oxyethyl group-d 5 )-4-methoxyl group-phenyl aldehyde (10d).
(5g is 30mmol) with Cs in acetone for commercially available compound 29 2CO 3(15g 46mmol) mixes, and in ice-water bath, cools off.Add monobromethane-d 5(99 atom %D, Cambridge Isotopes; 3.8g, 33.6mmol), make reactant slowly be warmed up to room temperature, and stirred overnight.With MTBE diluting reaction thing, filter through Celite pad, and concentrate to produce the compound 10d of 5.5g (about 100%).
Step 2:1-(3-(oxyethyl group-d 5 )-4-methoxyl group-phenyl)-2-(methylsulfonyl) ethamine (11d).
(2.76g 29.5mmol) is suspended among the THF (250mL) the methyl sulfone, and in acetone/the dry ice bath, is cooled to and is lower than-70 ℃.(2.5M is in hexane, and 12.5mL 31mmol), and stirred this mixture about 30 minutes to add n-BuLi.In flask independently, (5.25g, 27.6mmol) solution in THF (50mL) is cooled to 0 ℃ with aldehyde 10d.(1M is in THF, 31.7mL) to add LHMDS.After 15 minutes, (7.36mL 57.8mmol), and stirred this mixture other 5 minutes to add boron trifluoride ethyl ether complex.Through syringe this solution is added methyl sulfone/n-BuLi solution then, the while is cooled in acetone/the dry ice bath and is lower than-70 ℃.Observe heat release.Make this mixture be warmed up to room temperature, and stirred overnight.After cooling in ice-water bath, add K 2CO 3(24g), then add entry (150mL).Layer separates, and with EtOAc (3x 60mL) aqueous phase extracted.Dry (Na 2SO 4) organic solution that merges, and concentrate to produce the oil of viscosity.(4N 90mL), and at room temperature stirs this mixture 2 hours to produce clarifying two phase liquid to add MTBE (90mL) and aqueous hydrochloric acid.Be separated, and with aqueous hydrochloric acid (4N, 75mL) extracted organic phase.Add the NaOH aqueous solution (24%) to improve pH to the water that merges to＞12.With EtOAc (3x 150mL) extraction mixture.Dry (Na 2SO 4) organic solution that merges, and concentrate to produce yellow solid.This solid suspension and stirred 1 hour in MTBE (60mL).Vacuum filtration produces the compound 11d as faint yellow solid of 2.7g (34.2%).
Step 3: (S)-1-(3-(oxyethyl group-d 5 )-4-methoxyl group-phenyl)-2-(methylsulfonyl) ethamine N-ethanoyl-L-leucine salt ((S)-11d).
(2.6g, 9.33mmol) (0.98g 5.6mmol) mixes compound 11d with N-ethanoyl-L-leucine in MeOH (15mL).At 70 ℃ of following these mixtures of heating 3 hours, stirred overnight at room temperature then.Collect solid through vacuum filtration, and be suspended among the MeOH (15mL).Down stirred these suspension-s 2 hours at 70 ℃, then stirred overnight at room temperature.Collect solid, and repeat methyl alcohol and grind.Ee with＞98% obtains (the S)-11d N-ethanoyl-L-leucine salt of 1-g part (23%).
Step 4: (S)-N-(2-(1-(3-(oxyethyl group-d 5 )-4-methoxyl group-phenyl)-and 2-(methylsulfonyl) ethyl)-1,3-dioxoisoindolin-4-yl) ethanamide (110a).
(1.4g, 3.2mmol) (0.77g 3.84mmol) mixes compound (S)-11d, and reflux 24 hours, to promote reaction near accomplishing with compound known 12a in acetate (20mL).Enriched mixture, colourless oil are dissolved among the EtOAc (200mL), and use saturated NaHCO 3(40mL) wash this solution.Dry (Na 2SO 4) organic layer and concentrated.Through column chromatography purifying crude product in the Analogix system, with 0-70%EtOAc/ heptane (in 1 hour) wash-out, to produce the compound 110a of 1.2g (80%). 1H-NMR (300MHz, CDCl 3): δ 1.59 (s, 1H), 2.27 (s, 3H), 2.87 (s, 3H), 3.72 (dd, J=4.6,14.4; 1H), 3.85 (s, 3H), 4.56 (dd, J=10.8,14.4,1H), 5.87 (dd, J=4.4; 10.6), 6.84 (d, J=8.8,1H), 7.10 (d, J=7.0,2H), 7.49 (d, J=6.6; 1H), 7.65 (t, J=7.3,1H), 8.76 (d, J=8.0,1H), 9.46 (s, 1H). 13C-NMR (75MHz, CDCl 3): δ 24.97,41.66, and 48.60,54.55,55.96,76.58,77.01; 77.43,111.48,112.40,115.14,118.25,120.29; 125.00,129.26,131.07,136.14,137.66,148.70; 149.79,167.51,169.17, (method: 50mm 3 μ m Waters Atlantis T32.1 post-gradient method 5-95%ACN+0.1% formic acid 14 minutes, remained on 95%ACN+0.1% formic acid in 4 minutes to 169.53.HPLC; Wavelength: 305nm): RT: 6.02 minutes;＞98.0% purity.Chirality HPLC (method: Chiralpak AD 25cm post-78% hexane such as method such as degree of grade/22% Virahol/0.01% diethylamine, 40 minutes, 1.00mL/ minute; Wavelength: 254nm): RT: 12.73 minutes (main enantiomorph);＞99%ee purity.MS(M+Na)：488.1。Ultimate analysis (C 22H 21D 3N 2O 7S): calculated value: C=56.76, H=5.20, N=6.02, S=6.89. measured value: C=56.74, H=5.43, N=5.70, S=6.51.
embodiment 5: midbody 12b's is synthetic.
The preparation of scheme 8:12b.
Figure BSA00000407441900361
N-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl) ethanamide-d3 (12b).
The amino isobenzofuran-1 of commercially available 4-, (5g 30.6mmol) is suspended in acetic anhydride-d to 3-diketone 30 6(98 atom %D, Cambridge Isotopes; 10g), and reflux 3 hours, stirred overnight at room temperature then.Solution is cooled to 0 ℃ and filtration, then with MTBE wash solids and dry so that the compound 12b of 2.5g to be provided.
Embodiment 6: (S)-and N-(2-1-(3-(oxyethyl group-d 5 )-4-(methoxyl group-d 3 )-phenyl)-and 2-(methylsulfonyl) ethyl)-1,3-dioxoisoindolin-4-yl) acetyl-d 3 Synthesizing of-amine (compound 115a).
The preparation of scheme 8:115a.
Figure BSA00000407441900371
(S)-N-(2-1-(3-(oxyethyl group-d 5 )-4-(methoxyl group-d 3 Phenyl)-and 2-(methylsulfonyl) ethyl)-1,3-dioxoisoindolin-4-yl) acetyl-d 3 -amine (115a)
Compound (S)-11b N-ethanoyl-L-leucine salt (200mg, 0.44mmol; Referring to scheme 5) and the compound 12b (130mg in acetate (5mL); Referring to scheme 8) mix, and heated this solution 20 hours down at 80 ℃.Enriched mixture, and colourless oil is dissolved among the EtOAc (100mL) again.Use saturated NaHCO 3The aqueous solution (20mL) washs this solution, dry (Na 2SO 4) and concentrate.Through column chromatography purifying crude product in the Analogix system, with 0-70%EtOAc/ heptane wash-out, to produce the compound 115a of 174mg (73%). 1H-NMR (300MHz, CDCl 3): δ 1.55 (s, 1H), 2.87 (s, 3H), 3.72 (dd, J=4.4,14.3,1H), 4.56 (dd; J=10.5,14.4,1H), 5.87 (dd, J=4.4,10.5,1H), 6.84 (d; J=8.5,1H), 7.10 (d, J=7.0,2H), 7.49 (d, J=7.3,1H); 7.66 (t, J=7.5,1H), 8.76 (d, J=8.3,1H), 9.46 (s, 1H). 13C-NMR (75MHz, CDCl 3): δ 41.66,48.61, and 54.56,76.58,77.00,77.21; 77.43,111.45,112.40,115.14,118.26,120.29; 125.01,129.24,131.07,136.15,137.66; 148.70,167.52, (method: 50mm 3 μ mWaters Atlantis T32.1 post-gradient method 5-95%ACN+0.1% formic acid 14 minutes, remained on 95%ACN+0.1% formic acid in 4 minutes to 169.54.HPLC; Wavelength: 305nm): RT: 5.96 minutes; 99.1% purity.MS(M+H)：472.0。Ultimate analysis (C 22H 16D 8N 2O 7S): calculated value: C=56.04, H=5.13, N=5.94. measured value: C=55.90, H=5.23, N=5.85.
Embodiment 7: (S)-and N-(2-1-(3-(oxyethyl group-d 5 )-4-(methoxyl group-d 3 ) phenyl)-2-((methyl-d 3 ) alkylsulfonyl)-2,2-d 2 -ethyl)-1,3-dioxoisoindolin-4-yl) ethanamide (compound 116a) is synthetic.
scheme 9: the preparation of compound 116a.
Figure BSA00000407441900381
Step 1:1-(3-(oxyethyl group-d 5 )-4-(methoxyl group-d 3 ) phenyl)-2-((methyl-d 3 ) alkylsulfonyl)-2,2-d 2 -ethamine (11e)
Methyl sulfone-d 6(99 atom %D, Isotec; 1g 10.0mmol) is suspended among the THF (70mL), and in acetone/the dry ice bath, is cooled to and is lower than-70 ℃.(2.5M is in hexane, and 4.4mL 11mmol), and stirred the mixture about 30 minutes to add n-BuLi.In flask independently, with aldehyde 10b (1.91g, 10.0mmol; Referring to scheme 5) solution in THF (20mL) is cooled to 0 ℃.(1M is in THF, 11mL) to add LHMDS.After 15 minutes, (2.8mL 22mmol), and continued to stir other 5 minutes to add boron trifluoride ethyl ether complex.Through syringe this solution is added methyl sulfone-d then 6In/n-BuLi the solution, the while is cooled in acetone/the dry ice bath and is lower than-70 ℃.Observe heat release.Make this mixture be warmed up to room temperature, and stirred overnight.After cooling in ice-water bath, add K 2CO 3(8g), then add entry (50mL).Layer separates, and with EtOAc (2x 20mL) aqueous phase extracted.Dry (Na 2SO 4) organic solution that merges, and concentrate to produce the oil of viscosity.(4N 30mL), and at room temperature stirs the mixture 2 hours to produce clarifying two phase liquid to add MTBE (30mL) and aqueous hydrochloric acid.Be separated, and with aqueous hydrochloric acid (4N, 25mL) extracted organic phase.Add the NaOH aqueous solution (24%) to improve pH to the aqueous phase that merges to＞12.With EtOAc (3x 50mL) extraction solution.Dry (Na 2SO 4) organic solution that merges, and concentrate to produce yellow solid.This solid suspension and stirred 1 hour in MTBE (20mL).Vacuum filtration produces the compound 11e as faint yellow solid of 1.2g (37%).
1The loss of some isotopic purity of the α position of H NMR and LCMS demonstration sulfone.This D-possibly occur in acid/alkali extraction process to the exchange of-H.Preferably in entire operation, use the deuterate solvent.
The material of low isotopic purity is dissolved in MeOD (99% atom D, Cambridge Isotopes; 30mL), and add K 2CO 3(0.5g).Heat this mixture 6 hours down at 70 ℃, be concentrated into drying then.Add new MeOD (30mL), and mixture heating up to 70 ℃ is spent the night.With EtOAc (100mL) dilution refrigerative solution, and filtering mixt.Concentrating filter liquor, and be dissolved in again among the EtOAc (100mL).Use D 2O (99.9 atom %D, Cambridge Isotopes; 20mL) wash this solution.Organic phase is through dry (Na 2SO 4), and concentrate the compound 11e of about 1g that has the high isotopic purity of recovery with generation.
Step 2: (S)-1-(3-(oxyethyl group-d 5 )-4-(methoxyl group-d 3 ) phenyl)-2-((methyl-d 3 )-alkylsulfonyl)-2,2-d 2 -ethamine N-ethanoyl-L-leucine salt ((S)-11e)
Compound 11e (630mg, 2.2mmol) with at MeOD (99 atom %D, Cambridge Isotopes; (0.23g 1.32mmol) mixes N-ethanoyl-L-leucine 6mL).At 70 ℃ of following these mixtures of heating 3 hours, stirred overnight at room temperature then.Collect solid through vacuum filtration, and be suspended among the MeOH (6mL).Down stirred these mixtures 2 hours at 70 ℃, then stirred overnight at room temperature.Collect solid, and repeat methyl alcohol and grind.Ee with＞99% obtains (the S)-11e N-ethanoyl-L-leucine salt of 300-mg part (29%).
Step 3: (S)-N-(2-(1-(3-(oxyethyl group-d 5 )-4-(oxyethyl group-d 3 )-phenyl)-2-((methyl-d 3 )-alkylsulfonyl)-2,2-d 2 -ethyl)-1, ethanamide (116a) 3-dioxoisoindolin-4-yl).
Compound (S)-11e N-ethanoyl-L-leucine salt (280mg, 0.62mmol) with at acetate-d (99 atom %D, Aldrich; (145mg, 0.7mmol) mixing, and reflux 24 hours is to promote reaction near accomplishing for compound known 12a 5mL).Concentrate this mixture, and colourless oil is dissolved among the EtOAc (100mL).Use NaHCO 3(20mL) wash this solution, dry (Na 2SO 4) and concentrate.Through column chromatography purifying crude product in the Analogix system, use 0-3%MeOH/CH 2Cl 2Wash-out is to produce the compound 116a of 245mg (84%).
1H-NMR (300MHz, CDCl 3): δ 1.57 (s, 1H), 2.26 (s, 3H), 5.86 (s, 1H), 6.84 (d, J=6.8,1H), 7.10 (d, J=6.8,2H), 7.49 (d, J=6.4,1H), 7.65 (t, J=7.9,1H), 8.76 (d, J=8.5,1H), 9.46 (s, 1H). 13C-NMR (75MHz, CDCl 3): δ 24.97,48.43, and 111.45,112.40,115.14; 118.25,120.28,125.00,129.22,131.07; 136.14,137.66,148.70,149.79,167.52; 169.17 (method: 50mm 3 μ m Waters Atlantis T32.1 post-gradient method 5-95%ACN+0.1% formic acid 14 minutes, remained on 95%ACN+0.1% formic acid in 4 minutes to 169.54.HPLC; Wavelength: 305nm): RT: 5.97 minutes; 99.7% purity.MS(M+H)：474.3。Ultimate analysis (C 22H 11D 13N 2O 7S): calculated value: C=55.80, H=5.11, N=5.92. measured value: C=52.73, H=4.73, N=5.43.
Embodiment. the evaluation of metabolic stability
Microsome is analyzed: people's hepatomicrosome (20mg/mL) is from Xenotech, and (Lenexa KS) obtains LLC.β-Triphosphopyridine nucleotide, reduced reduced form (NADPH), magnesium chloride (MgCl 2) and methyl-sulphoxide (DMSO) all available from Sigma-Aldrich.
The mensuration of metabolic stability: the stoste of the test compounds of preparation 7.5mM in DMSO.The stoste of dilution 7.5mM is to 12.5-50 μ M in acetonitrile (ACN).In pH value 7.4, contain 3mM MgCl 2The 0.1M potassium phosphate buffer in, the dilution 20mg/mL people's hepatomicrosome to 0.625mg/mL.Microsome with dilution adds in the hole of 96 hole depth hole polypropylene boards in triplicate.Add the 12.5-50 μ M test compounds of 10 μ L aliquots containigs to microsome, and preheated mixture 10 minutes.NADPH solution through adding preheating starts reaction.The end reaction volume is 0.5mL, and comprises people's hepatomicrosome of 0.5mg/mL, test compounds and 2mM NADPH in 0.1M potassium phosphate buffer (pH 7.4) and the MgCl of 3mM of 0.25-1.0 μ M 2Incubate reaction mixture 37 ℃ of following temperature, took out the aliquots containig of 50 μ L at 0,5,10,20 and 30 minute, and add in shallow bore hole 96 orifice plates that contain the ACN that target 50 μ L are ice-cold in the band with stopped reaction.Plate was preserved 20 minutes at 4 ℃, in the hole of plate, added 100 μ L water afterwards, and is centrifugal then so that sedimentary protein is agglomerating.Supernatant is transferred to another 96 orifice plate, and use Applied Bio-systems API 4000 mass spectrographs to analyze the amount of residual parent (parent remaining) through LC-MS/MS.For apremilast and positive control (7-ethoxy coumarin (1 μ M)), carry out same program.Test in triplicate.
Data analysis: the relation of incubating the slope of time from the linear regression (ln) of residual parent % with respect to temperature is calculated the external t of test compounds 1/2
External t 1/2=0.693/k
K=-[slope of time is incubated in the linear regression of residual parent % (ln) with respect to temperature]
Use the Excel of Microsoft software to carry out data analysis.
Internal metabolism stability:
Carry out following research to test representative compound 114a and compound 116a with respect to the metabolic stability of apremilast in rat.5 male rat (the mouse age when beginning to handle: 7-9 weeks; Body weight when beginning to handle: 300g-350g) overnight fasting before administration.Shown in following Table I, pass through gavage to oral 3 kinds of compound a premilast, compound 114a and the compound 116a of using jointly of rat.After administration, collect blood sample (～200 μ L) in the following time: 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours through great saphenous vein.
Experiment
Table I
The research explanation: above-mentioned three kinds of compounds add in the drug administration carrier an amount of in the vial, to obtain to comprise the drug solns of giving of each compound of 2mg/mL.Through the oral gavage application dosage.Confirm the administration volume of each test animal based on the body weight of administration each animal on the same day.Above-mentioned time point with the blood collecting of about 250 μ L to comprising in the pipe of K2EDTA as anti-coagulant.Blood sample is placed on ice up to centrifugal to obtain blood plasma.Branches such as blood plasma are added in 96 orifice plates, and preserve down at-80 ℃.Through LC-MS/MS analysed for plasma sample.
Result: Fig. 1 shows the graphic representation with the plasma concentration versus time of each rat in 5 rats of apremilast, compound 114a and compound 116a co-administered.In each case, be easy to find out: compound 114a and compound 116a are obvious more stable than apremilast.In each case, compound 116a is more stable than compound 114a.Fig. 2 shows as 5 width of cloth figure among Fig. 1 for the graphic representation of the plasma concentration versus time of the mean+SD of the plasma concns value of apremilast, compound 114a and compound 116a.
Table 2 is presented at the C of each compound in each rat MaxAnd AUC 0-6Value; C for each compound MaxAnd AUC 0-6MV; With respect to apremilast, the C of compound 114a and 116a MaxAnd AUC 0-6The increased value of MV.As shown in table 2, for compound 114a and compound 116a, C MaxAnd AUC 0-6The increase of MV all is significant.
Table 2
Figure BSA00000407441900431
Do not need further explanation, believe that those of ordinary skill in the art can use above-mentioned explanation and illustrative embodiment preparation and utilize compound of the present invention, and implement method required for protection.Should be realized that the discussion of front and example just propose some detailed description of the preferred embodiment.It is obvious that for those of ordinary skill in the art: under the situation that does not deviate from the spirit and scope of the present invention, can make various modifications and be equal to replacement.

Claims (26)

1. the compound of formula I:
Or its pharmacy acceptable salt, wherein:
R 1Be selected from CH 3, CH 2D, CHD 2And CD 3
R 2Be selected from methyl, sec.-propyl, cyclopentyl, cyclopropyl, 2-furyl, trifluoromethyl, methoxymethyl, amino methyl, dimethylamino methyl, dimethylamino-1-ethyl, 1-dimethylamino-ethyl and 2-dimethylamino-ethyl, wherein, R 2Randomly replaced by deuterium;
R 3Be selected from CH 3, CH 2D, CHD 2, CD 3, CF 3, CHF 2, CH 2F, CDF 2And CD 2F;
R 4By 0 to 5 substituted ethyl of deuterium, or by 0 to 9 substituted cyclopentyl of deuterium;
X is selected from CH 2, CHD, CD 2And C=O;
Y 1a, Y 1b, Y 2, Y 3, Y 4, Y 5, Y 7And Y 8Respectively be independently selected from H and D; With
Y 6Be selected from Cl, H and D;
Condition is if R 1Be CH 3, R 2Do not replaced R by deuterium 3Be CH 3, CF 3, CHF 2Or CH 2F, R 4Be not by the substituted ethyl of deuterium or not by the substituted cyclopentyl of deuterium, X is CH 2Or C=O, and Y 6Be Cl or H, Y so 1a, Y 1b, Y 2, Y 3, Y 4, Y 5, Y 7And Y 8At least one be D.
2. according to the compound of claim 1, wherein, R 2Be CH 3Or CD 3R 3Be CH 3Or CD 3Y 6, Y 7And Y 8Identical; Y 1aAnd Y 1bIdentical; And Y 3, Y 4And Y 5Identical.
3. according to the compound of claim 1, wherein, the compound of said formula I is the compound of formula II:
Or its pharmacy acceptable salt, wherein:
R 1Be selected from CH 3And CD 3
R 2Be selected from methyl, sec.-propyl, cyclopentyl, cyclopropyl, 2-furyl, trifluoromethyl, methoxymethyl, amino methyl, dimethylamino methyl, dimethylamino-1-ethyl, 1-dimethylamino-ethyl and 2-dimethylamino-ethyl, wherein, R 2Randomly replaced by deuterium;
R 3Be selected from CH 3, CD 3, CF 3, CHF 2, CH 2F, CDF 2And CD 2F;
R 4Be selected from CH 2CH 3, CD 2CD 3, CD 2CH 3And CH 2CD 3With
Each Y is independently selected from H and D;
Condition is if R 1Be CH 3, R 2Do not replaced R by deuterium 3Be CH 3, CF 3, CHF 2Or CH 2F, and R 4Be CH 2CH 3, at least one Y is D so.
4. according to the compound of claim 1, wherein, the compound of said formula I is compound or its pharmacy acceptable salt of formula Ia, and it is connected to Y 2On carbon mainly have (S) configuration:
Figure FSA00000407441800031
5. according to the compound of claim 1, wherein, the described compound of claim 1 is compound or its pharmacy acceptable salt of formula Ib, and it is connected to Y 2On carbon mainly have (R) configuration:
Figure FSA00000407441800032
6. according to the compound of claim 1 or 2, wherein, R 2Be CH 3Or CD 3
7. according to the compound of claim 1 or 2, wherein, R 3Be CH 3Or CD 3
8. according to claim 1 or 2 compounds, wherein, Y 6, Y 7And Y 8Identical.
9. according to the compound of claim 1 or 2, wherein, Y 1aAnd Y 1bIdentical.
10. according to the compound of claim 1 or 2, wherein, Y 3, Y 4And Y 5Identical.
11. according to each compound of aforementioned claim, wherein, R 1Be CH 3Or CD 3
12. according to each compound of aforementioned claim, wherein, R 4Be CD 2CD 3
13. be selected from following compound:
Figure FSA00000407441800041
Figure FSA00000407441800051
Or the pharmacy acceptable salt of above-mentioned any compound.
14. the described compound of claim 13, it mainly has (S) configuration.
15. the described compound of claim 13, it mainly has (R) configuration.
16. be selected from following compound:
Figure FSA00000407441800052
Figure FSA00000407441800061
Or the pharmacy acceptable salt of above-mentioned any compound.
17. according to each compound of aforementioned claim, wherein, any atom of not being appointed as deuterium exists with its natural isotopic abundance.
18. the described compound of claim 1 or the pharmacy acceptable salt of said compound and compsn of acceptable carrier that comprises significant quantity.
19. the described compound of claim 1 or the pharmacy acceptable salt of said compound and pharmaceutical composition of acceptable carrier that comprises significant quantity; Wherein, said compsn is suitable for treating and is selected from following disease: the ENL of septic shock, Sepsis, endotoxin shock, haemodynamics shock and sepsis syndrome, postischemic reperfusion damage, malaria, mycobacterial infections, meningitis, psoriatic, sarcoidosis, psoriatic arthritis, behcet disease, prurigo nodularis, lupus, uveitis, congestive heart failure, fibrotic disease, emaciation, transplant rejection, cancer, autoimmune disorder, AIDS opportunistic infection, rheumatoid arthritis, similar rheumatism spondylitis, osteo-arthritis, other arthritis diseases, Crohn's disease, ulcerative colitis, multiple sclerosis, systemic lupus erythematous, leprosy, radiation injury, hyperoxic alveolar injury, bad vasculogenesis, inflammatory diseases, sacroiliitis, inflammatory bowel, stomatocace, asthma, adult respiratory distress syndrome and AIDS.
20. a method that in the experimenter of needs, suppresses PDE4 comprises the described compound of claim 1 from significant quantity to the experimenter or its pharmacy acceptable salt of using.
21. a method that reduces the TNF-alpha levels among the experimenter who needs comprises the described compound of claim 1 from significant quantity to the experimenter or its pharmacy acceptable salt of using.
22. one kind in the patient of needs treatments treatment be selected from the method for following disease, comprise the described compound of claim 1 from significant quantity to the patient or its pharmacy acceptable salt of using: the ENL of septic shock, Sepsis, endotoxin shock, haemodynamics shock and sepsis syndrome, postischemic reperfusion damage, malaria, mycobacterial infections, meningitis, psoriatic, sarcoidosis, psoriatic arthritis, behcet disease, prurigo nodularis, lupus, uveitis, congestive heart failure, fibrotic disease, emaciation, transplant rejection, cancer, autoimmune disorder, AIDS opportunistic infection, rheumatoid arthritis, similar rheumatism spondylitis, osteo-arthritis, other arthritis diseases, Crohn's disease, ulcerative colitis, multiple sclerosis, systemic lupus erythematous, leprosy, radiation injury, hyperoxic alveolar injury, bad vasculogenesis, inflammatory diseases, sacroiliitis, inflammatory bowel, stomatocace, asthma, adult respiratory distress syndrome and AIDS.
23. according to the method for claim 22, wherein, said disease is psoriatic or sarcoidosis.
24. according to the method for claim 23, wherein, said psoriatic is psoriasis in plaques or psoriasis inveterata.
25. according to the method for claim 23, wherein, said sarcoidosis is that skin tag is sick.
26. according to the method for claim 22, wherein, said lupus is a cutaneous lupus.
CN201010620532.7A 2010-12-22 2010-12-22 Isoindoline-1,3 derovatives replaced Active CN102558022B (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201610327209.8A CN106008313B (en) 2010-12-22 2010-12-22 Substituted -1,3 derovatives of isoindoline
CN201010620532.7A CN102558022B (en) 2010-12-22 2010-12-22 Isoindoline-1,3 derovatives replaced

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201010620532.7A CN102558022B (en) 2010-12-22 2010-12-22 Isoindoline-1,3 derovatives replaced

Related Child Applications (1)

Application Number Title Priority Date Filing Date
CN201610327209.8A Division CN106008313B (en) 2010-12-22 2010-12-22 Substituted -1,3 derovatives of isoindoline

Publications (2)

Publication Number Publication Date
CN102558022A true CN102558022A (en) 2012-07-11
CN102558022B CN102558022B (en) 2016-06-15

Family

ID=46404789

Family Applications (2)

Application Number Title Priority Date Filing Date
CN201610327209.8A Active CN106008313B (en) 2010-12-22 2010-12-22 Substituted -1,3 derovatives of isoindoline
CN201010620532.7A Active CN102558022B (en) 2010-12-22 2010-12-22 Isoindoline-1,3 derovatives replaced

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CN201610327209.8A Active CN106008313B (en) 2010-12-22 2010-12-22 Substituted -1,3 derovatives of isoindoline

Country Status (1)

Country Link
CN (2) CN106008313B (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105218428A (en) * 2015-10-20 2016-01-06 南京美嘉宁逸医药研究开发有限公司 A kind of preparation method of Apremilast of high chiral purity
CN105294534A (en) * 2014-07-15 2016-02-03 上海优拓医药科技有限公司 Industrial method for preparing apremilast and intermediate thereof
WO2016066116A1 (en) * 2014-10-29 2016-05-06 南京安源生物医药科技有限公司 Preparation method of apremilast and intermediate thereof
CN106278992A (en) * 2016-08-05 2017-01-04 温州大学 A kind of synthetic method of 2 replacement iso-indoles 1,3 derovatives
CN110746376A (en) * 2018-07-22 2020-02-04 上海星叶医药科技有限公司 Benzoisoselenazolone amine compound and preparation method and application thereof
CN113527179A (en) * 2020-04-13 2021-10-22 苏州璞正医药有限公司 Chain hydrocarbon substituted isoindoline-1, 3-diketone PDE4 inhibitor and pharmaceutical application thereof
CN110746376B (en) * 2018-07-22 2024-04-30 上海星叶医药科技有限公司 Benzisoselenazolone amine compound and preparation method and application thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6020358A (en) * 1998-10-30 2000-02-01 Celgene Corporation Substituted phenethylsulfones and method of reducing TNFα levels
WO2003080048A1 (en) * 2002-03-20 2003-10-02 Celgene Corporation (-)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione: methods of using and compositions thereof
CN1802353A (en) * 2002-12-30 2006-07-12 细胞基因公司 Fluoroalkoxy-substituted 1,3-dihydro-isoindolyl compounds and their pharmaceutical uses
CN101031546A (en) * 2004-07-28 2007-09-05 细胞基因公司 Isoindoline compounds and methods of making and using the same
CN101389330A (en) * 2005-12-29 2009-03-18 细胞基因公司 Methods for treating cutaneous lupus using aminoisoindoline compounds

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6020358A (en) * 1998-10-30 2000-02-01 Celgene Corporation Substituted phenethylsulfones and method of reducing TNFα levels
WO2003080048A1 (en) * 2002-03-20 2003-10-02 Celgene Corporation (-)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione: methods of using and compositions thereof
CN1802353A (en) * 2002-12-30 2006-07-12 细胞基因公司 Fluoroalkoxy-substituted 1,3-dihydro-isoindolyl compounds and their pharmaceutical uses
CN101031546A (en) * 2004-07-28 2007-09-05 细胞基因公司 Isoindoline compounds and methods of making and using the same
CN101389330A (en) * 2005-12-29 2009-03-18 细胞基因公司 Methods for treating cutaneous lupus using aminoisoindoline compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HON-WAH MAN等: "Discovery of (S)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide (Apremilast), a Potent and Orally Active Phosphodiesterase 4 and Tumor Necrosis Factor-α Inhibitor", 《J. MED. CHEM.》 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105294534A (en) * 2014-07-15 2016-02-03 上海优拓医药科技有限公司 Industrial method for preparing apremilast and intermediate thereof
CN105294534B (en) * 2014-07-15 2020-04-10 上海优拓医药科技有限公司 Industrialized method for preparing aplidine and intermediate thereof
WO2016066116A1 (en) * 2014-10-29 2016-05-06 南京安源生物医药科技有限公司 Preparation method of apremilast and intermediate thereof
CN105218428A (en) * 2015-10-20 2016-01-06 南京美嘉宁逸医药研究开发有限公司 A kind of preparation method of Apremilast of high chiral purity
CN106278992A (en) * 2016-08-05 2017-01-04 温州大学 A kind of synthetic method of 2 replacement iso-indoles 1,3 derovatives
CN106278992B (en) * 2016-08-05 2018-12-11 温州大学 A kind of synthetic method of 2- substitution-iso-indoles -1,3- derovatives
CN110746376A (en) * 2018-07-22 2020-02-04 上海星叶医药科技有限公司 Benzoisoselenazolone amine compound and preparation method and application thereof
CN110746376B (en) * 2018-07-22 2024-04-30 上海星叶医药科技有限公司 Benzisoselenazolone amine compound and preparation method and application thereof
CN113527179A (en) * 2020-04-13 2021-10-22 苏州璞正医药有限公司 Chain hydrocarbon substituted isoindoline-1, 3-diketone PDE4 inhibitor and pharmaceutical application thereof
CN113527179B (en) * 2020-04-13 2023-07-07 苏州璞正医药有限公司 Chain hydrocarbon substituted isoindoline-1, 3-diketone PDE4 inhibitor and pharmaceutical application thereof

Also Published As

Publication number Publication date
CN106008313A (en) 2016-10-12
CN102558022B (en) 2016-06-15
CN106008313B (en) 2018-11-13

Similar Documents

Publication Publication Date Title
ES2469849T3 (en) Deuterated isoindolin-1,3-dione derivatives as PDE4 and TNF-alpha inhibitors
AU2014235462C1 (en) Deuterated palbociclib
CN102558022A (en) Substituted isoindoline-1,3-dione derivative
EP2616467A1 (en) Substituted azaindoles
US20130109707A1 (en) Fluorouracil derivatives
CN104725380A (en) Ruxolitinib deuteration derivative
WO2012154728A1 (en) Deuterated n-butyl bumetanide
CN106459056A (en) Substituted triazolobenzodiazepines
KR101900498B1 (en) Substituted isoindoline-1,3-dione derivatives
AU2013263763B2 (en) Deuterated isoindoline-1,3-dione derivatives as PDE4 and TNF-alpha inhibitors
CA2828251A1 (en) 2-amino-naphthyridine derivatives
CA2824626A1 (en) 2-amino-naphthyridine derivatives

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant