CN104725380A - Ruxolitinib deuteration derivative - Google Patents

Ruxolitinib deuteration derivative Download PDF

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Publication number
CN104725380A
CN104725380A CN201310700192.2A CN201310700192A CN104725380A CN 104725380 A CN104725380 A CN 104725380A CN 201310700192 A CN201310700192 A CN 201310700192A CN 104725380 A CN104725380 A CN 104725380A
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compound
deuterium
hydrogen
acid
solution
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CN104725380B (en
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I·R·西尔弗曼
J·F·刘
A·J·摩根
B·潘德雅
S·L·哈比森
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Sun Pharmaceutical Industry Co ltd
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Concert Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a ruxolitinib deuteration derivative. An enforcement scheme in the invention provides a compound of formula A or a pharmaceutically acceptable salt thereof, a medicinal composition containing the compound, and an indication treatment method.

Description

Lu Suo is for the deuterated derivative of Buddhist nun
background of invention
There is the problem of bad absorption, distribution, metabolism and/or excretion (ADME) performance in current many medicines, which prevent its widespread use or limit its purposes in some indication.Bad ADME performance is also the major cause failed in clinical trial of drug candidate.Although preparation technique and prodrug strategies may be used for improving some ADME performance in some cases, these approach often can not solve the essence ADME problem of many medicines and drug candidate existence.Such problem is tachymetabolism, and it causes some to remove in body too quickly many medicines of efficient disease therapy.The possible solution that quick medicament is removed is frequent or heavy dose takes medicine to reach sufficiently high drug blood plasma level.But, which introduce many potential treatment problems, under as poor in the compliance of patient to dosage regimen, higher dosage, become the increase of side effect more sharply and treatment cost.The medicine of rapid metabolization also may make patient be exposed to undesirable toxicity or reactive metabolite.
Another ADME limitation affecting many medicines is the formation of toxicity or biological reactivity metabolite.Therefore, some patients accepting medicine may occur poisoning, or the safe dose of this medicine may be restricted to make patient accept the promoting agent of suboptimum amount.In some cases, change dosing interval or preparation way and can help to reduce clinical adverse, but the formation of usual this undesirable metabolite is intrinsic for the metabolism of compound.
When some is selected, the medicine with too fast removing is used by metabolic poison jointly.The proteinase inhibitor class medicine being used for the treatment of HIV is exactly such situation.FDA (food and drug administration) recommends these medicines and cytochrome P 450 enzymes 3A4(CYP3A4) the inhibitor ritonavir co-administered of the metabolism of these medicines (be usually responsible for) is (see Kempf, D.J. etc., Antimicrobial agents and chemotherapy, 1997,41 (3): 654-60).But ritonavir causes untoward reaction, and increase the weight of the former drug burden must taking the HIV patient of the different pharmaceutical of combination.Similarly, in order to be reduced in the quick CYP2D6 metabolism of Dextromethorphane Hbr in treatment pseudobulbar mood (pseudobulbar affect), CYP2D6 inhibitor Quinidine is added in Dextromethorphane Hbr.But Quinidine has harmful side effect, this greatly limits its purposes in potential combination therapy (see Wang, L etc., ClinicalPharmacology and Therapeutics, 1994,56 (6Pt1): 659-67; And the FDA label of Quinidine on www.accessdata.fda.gov).
Generally speaking, being combined with cytochrome P 450 inhibitors by medicine is not gratifying strategy for reducing Drug total clearance.Suppress the activity of CYP enzyme may affect by the metabolism of the other drug of this same enzymes metabolism and removing.CYP suppresses to cause other drug to accumulate toxic level in vivo.
The one strategy of potential magnetism that has improving drug metabolism performance is that deuterium is modified.In this approach, people attempt by substitute with D atom one or more hydrogen atom slow down CYP mediation drug metabolism or reduce the formation of undesirable metabolite.Deuterium is safety, stable, inactive hydrogen isotope.Compared with hydrogen, deuterium and carbon form stronger key.When selecting, the bonding strength increase of being given by deuterium actively can affect the ADME character of medicine, thus produces the potential improving efficacy of drugs, security and/or tolerance.Meanwhile, because the size and shape of deuterium is substantially identical with the size and shape of hydrogen, compared with the original chemical entity only comprising hydrogen, substitute by deuterium biochemical activity and the selectivity that hydrogen estimates to affect medicine.
Between in the past 35 years, the deuterium of the approval drug report on considerably less ratio replace impact on metabolic rate (see, such as, Blake, MI etc., J Pharm Sci, 1975,64:367-91; Foster, AB, Adv Drug Res, 1985,14:1-40 (" Foster "); Kushner, DJ etc., Can J Physiol Pharmacol, 1999,79-88; Fisher, MB etc., Curr Opin DrugDiscov Devel, 2006,9:101-09 (" Fisher ")).Many examples in these documents report the deuterium isotope effect (impact on the metabolic rate in deuterated site specific in substrate) of local instead of deuterate for the impact of this medicine overall metabolic stability, namely via the overall base consumption of metabolism.Reported on measuring deuterium, to replace results of those researchs of the impact of overall metabolic stability be changeable with unpredictable.To some compounds, deuterate causes internal metabolism clearance rate to reduce.To other compounds, there is no metabotic change.The compounds exhibit also had goes out the increase of metabolic clearance rate.The variability of deuterium effect also causes technician to suspect or abandons deuterium modification as the feasible drug design strategies (see 35 pages of Foster and 101 pages of Fisher) suppressing unfavorable metabolism.
It is not predictable that deuterium is modified the impact of pharmacokinetic properties, even if when D atom mixes known metabolism site.By the medicine of reality preparation and test deuterate, people only can determine whether and how metabolic rate is different from the counterpart of its non-deuterate.See, such as, Fukuto etc. (J.Med.Chem., 1991,34,2871-76).Many medicines have multiple sites of possibility generation metabolism.Need to carry out the site of deuterium replacement and see that impact (if any) the necessary degree of deuterium on metabolism will be different for various medicine.
Lu Suo is the pyrrolo-[2 that heteroaryl replaces for Buddhist nun (Ruxolitinib) phosphoric acid salt, 3-d] pyrimidine, also referred to as 3 (R)-cyclopentyl-3-[4-(7H-pyrrolo-es [2,3-d] pyrimidine-4-yl)-1H-pyrazol-1-yl] propionitrile phosphoric acid salt, and (R)-3-(4-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-1H-pyrazol-1-yl)-3-cyclopentyl propionitrile phosphoric acid salt, it suppresses Janus associated kinase (JAK) JAK1 and JAK2.These kinase mediated intracellular signaling for hematopoiesis and the important cytokine profiles of immunologic function and somatomedin.JAK intracellular signaling relates to STAT(signal transducer and transcriptional activator) to the raising of cytokine receptor, to activate and STAT, to nuclear location, thus causes the adjustment of genetic expression subsequently.
During existing approved Lu rope is used for the treatment of for Buddhist nun's phosphoric acid salt or the patient of excessive risk myelofibrosis, to comprise after PMF, polycythemia vera myelofibrosis after myelofibrosis and primary thrombocytosis.Lu Suo is now also used for the treatment of primary thrombocytosis, carcinoma of the pancreas, prostate cancer, mammary cancer, leukemia, non-Hodgkin lymphoma, multiple myeloma and psoriatic for Buddhist nun's phosphoric acid salt in clinical trial.
The three kinds of metabolites produced by the hydroxylation on cycloalkyl moieties 2-position, hydroxylation on cycloalkyl moieties 3-position and the ketone that produced by the further oxidation on cycloalkyl moieties 3-position in human body have been identified as active (see Shilling; A.D. etc.; Drug Metabolism andDisposition; 2010,38 (11): 2023-2031; FDA provisioning information and US20080312258).
The modal hematology untoward reaction replacing Buddhist nun's administration relevant to Lu's rope is thrombopenia and anaemia.Modal non-blood untoward reaction is bruise, dizziness and headache.
Although Lu's rope has useful activity for Buddhist nun, but there are the lasting needs to the novel cpd for the treatment of above-mentioned disease and situation.
summary of the invention
The present invention relates to pyrrolo-[2,3-d] pyrimidine and its pharmacy acceptable salt of novel heteroaryl replacement.Present invention also offers the composition containing the compounds of this invention, and said composition in treatment by using hypotype 1 and 2 (JAK1/JAK2) selectively Janus associated kinase inhibitor and by the purposes in the disease of favourable therapeutic and situation.
Accompanying drawing explanation
The result of the metabolic stability test of accompanying drawing display indication compound.
detailed Description Of The Invention
Definition
Term " treatment " refers to reduction, suppress, alleviate, eliminate, contain or the development of stable disease (disease such as summarized herein or disorder) or progress, the severity palliated a disease or improve the symptom relevant with disease.
" disease " refers to any illness or the disorder of the normal function of infringement or interference cell, tissue or organ.
It should be understood that the source depending on the chemical material used in synthesis, in the compound of synthesis, there are some changes of natural isotopic abundance.Therefore, Lu's rope will comprise the coordination ferritic (isotopologue) of a small amount of deuterate inherently for the goods of Buddhist nun.Although there is this variation, compared with the degree replaced with the stable isotope of the compounds of this invention, the stable hydrogen of this natural abundance and the concentration of carbon isotope are still very low with inessential.See such as Wada, E etc., Seikagaku, 1994,66:15; Gannes, LZ etc., Comp Biochem Physiol MolIntegr Physiol, 1998,119:725.
In compound of the present invention, any atom do not specified as specific isotope means any stable isotope representing this atom.Except as otherwise noted, when a position is designated specifically as " H " or " hydrogen ", this position is interpreted as having the hydrogen according to its natural abundance isotopics.Equally, except as otherwise noted, when a position is designated specifically as " D " or " deuterium ", this position is interpreted as having the deuterium (that is, the deuterium of at least 45% mixes) of the abundance of the natural abundance (it is 0.015%) at least 3000 times being greater than deuterium.
Term used herein " Isotope enrichment factor " refers to the ratio between the isotopic abundance of specific isotope and natural abundance.
In other embodiments, the Isotope enrichment factor of the D atom that compound of the present invention is specified for each is that at least 3500(mixes at the deuterium at the D atom place 52.5% that each is specified), at least the deuterium of 4000(60% mixes), at least the deuterium of 4500(67.5% mixes), at least the deuterium of 5000(75% mixes), at least the deuterium of 5500(82.5% mixes), at least the deuterium of 6000(90% mixes), at least the deuterium of 6333.3(95% mixes), at least the deuterium of 6466.7(97% mixes), at least the deuterium of 6600(99% mixes) or the deuterium of at least 6633.3(99.5% mix).
Term " coordination ferritic " refers to the material that wherein chemical structure is only different in its isotopics from specific compound of the present invention.
Term " compound ", when relating to compound of the present invention, refers to the set except may have isotropic substance change in the middle of the composed atom of molecule except with the molecule of identical chemical structure.Therefore those skilled in the art are very clear, and the compound represented by the particular chemical containing the D atom indicated also comprises the coordination ferritic in one or more appointment deuterium positions of this structure with hydrogen atom of small amount.The relative quantity of coordination ferritic such in the compounds of this invention will depend on many factors, comprise the deuteration agents for manufacturing described compound isotopic purity and in each synthesis step being used for preparing described compound the doping efficiency of deuterium.But as described above, the overall relative quantity of such coordination ferritic is by lower than 49.9% of compound.In other embodiments, the overall relative quantity of such coordination ferritic by lower than 47.5% of compound, lower than 40%, lower than 32.5%, lower than 25%, lower than 17.5%, lower than 10%, lower than 5%, lower than 3%, lower than 1% or lower than 0.5%.
Present invention also offers the salt of the compounds of this invention.The salt of the compounds of this invention is formed between acid and the basic group (such as amido functional group) of described compound or between the acidic-group (such as carboxyl functional group) of alkali and described compound.According to another kind of embodiment, described compound is pharmaceutically acceptable acid salt.
Term used herein " pharmaceutically acceptable " refers within the scope of rational medical judgment, be suitable for and people and other mammiferous contact tissue and there is no excessive toxicity, stimulation, transformation reactions etc., and the component matched with rational interests/Hazard ratio." pharmacy acceptable salt " refers to any non-toxic salt that directly or indirectly can provide the compounds of this invention when being applied to recipient." pharmaceutically acceptable gegenion " is the ionic portions of atoxic salt when being and discharging from salt being applied to recipient.
The acid being commonly used to be formed pharmacy acceptable salt comprises mineral acid as hydrogen sulfide, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid and phosphoric acid, and organic acid as tosic acid, Whitfield's ointment, tartrate, liquor epinephrinae bitartratis ophthalmicus, xitix, toxilic acid, Phenylsulfonic acid, fumaric acid, gluconic acid, 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, citric acid, phenylformic acid and acetic acid, and relevant mineral acid and organic acid.Therefore such 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, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butine-Isosorbide-5-Nitrae-diacid salt, alkynes-1,6-diacid salt, benzoate, chloro-benzoate, tolyl acid salt, dinitro-benzoate, hydroxy benzoate, methoxybenzoic acid salt, phthalate, terephthalate, sulfonate, xylenesulfonate, phenyl acetate salt, phenylpropionic acid salt, PB, Citrate trianion, lactic acid salt, beta-hydroxy-butanoic acid salt, oxyacetate, maleate, tartrate, mesylate, propanesulfonic acid salt, naphthalene-1-sulfonate, naphthalene-2-sulfonic acid salt, mandelate and other salt.In one embodiment, pharmaceutically acceptable acid salt comprises the acid salt formed with mineral acid such as hydrochloric acid and Hydrogen bromide, the acid salt especially formed as toxilic acid with organic acids.
Compound of the present invention (compound such as formula I or formula A) may due to such as deuterium replacement or other reasons containing unsymmetrical carbon.Therefore, compound of the present invention can exist as the mixture of single enantiomer or two enantiomers.Therefore, compound of the present invention can exist as racemic mixture or non-racemic mixture (scalemic mixture), or as substantially not existing containing the corresponding single steric isomer of another possible steric isomer.Term used herein " substantially not containing other steric isomers " refer to exist be less than 25% other steric isomers, be preferably less than other steric isomers of 10%, other steric isomers more preferably less than 5% and be most preferably less than 2% other steric isomers.Acquisition known in the art or synthesize the method for single enantiomer of given compound, and in the light of actual conditions can be applied to final compound or raw material or intermediate.
Except as otherwise noted, when disclosed compound is not by when specifying stereochemical structure to name or describe and have one or more chiral centre, it is understood to represent all possible steric isomer of this compound.
Term used herein " Mammals " comprises people or non-human animal, as mouse, rat, cavy, dog, cat, horse, ox, pig, monkey, chimpanzee, baboon or macaque.In one embodiment, described Mammals is non-human animal.In another embodiment, described Mammals is people.
Term used herein " stable compound " refer to the stability that has and be enough to allow them to manufacture and keep the integrity of the described compound sufficient time so that the object that can be used for describing in detail herein (such as, be mixed with treatment product, for for the production of the intermediate of therapeutic compound, separable or storable midbody compound, treat disease in response to therapeutical agent or illness) compound.
" D " and " d " all refers to deuterium." steric isomer " refers to enantiomer and diastereomer." Tert " and " t-" all refers to " uncle "." US " refers to the U.S..
" replace with deuterium " to refer to and substitute one or more hydrogen atom with the D atom of respective numbers.
In whole specification sheets, variable can be that general reference (such as, " each R ") refers in particular to (such as R 1, R 2, R 3deng).Except as otherwise noted, when variable is made a general reference, it means all specific specific form comprising this concrete variable.
Therapeutic compound
A kind of embodiment of the present invention provides the compound of formula A:
Or its pharmacy acceptable salt, wherein:
Y 1be selected from hydrogen and deuterium;
Each Y 2independently selected from hydrogen and deuterium, condition is each Y be connected on common carbon 2identical;
Each Y 3independently selected from hydrogen and deuterium, condition is each Y be connected on common carbon 3identical;
Y 4be selected from hydrogen and deuterium;
Each Y 5be identical and be selected from hydrogen and deuterium; And
Y 6, Y 7, Y 8, Y 9and Y 10be selected from hydrogen and deuterium independently of one another;
Condition works as Y 1hydrogen, each Y 2with each Y 3hydrogen, Y 4be hydrogen and Y 6, Y 7, Y 8, Y 9and Y 10during each hydrogen naturally, each Y 5it is deuterium.
In an embodiment of formula A, each Y 2identical, each Y 3identical, and each Y 5identical.In of this embodiment, each Y 2it is deuterium.Further, each Y 3it is deuterium.In another is further, each Y 3hydrogen.In the another aspect of this embodiment, each Y 2hydrogen.Further, each Y 3it is deuterium.In another is further, each Y 3hydrogen.Arbitrary aforementioned in an embodiment in, Y 1it is deuterium.Arbitrary aforementioned in another embodiment in, Y 1hydrogen.Arbitrary aforementioned in embodiment particularly in, Y 1deuterium, Y 4deuterium, and each Y 5it is deuterium.Arbitrary aforementioned in another embodiment particularly in, Y 1deuterium, Y 4deuterium, and each Y 5hydrogen.Arbitrary aforementioned in another embodiment particularly in, Y 1deuterium, Y 4hydrogen, and each Y 5hydrogen.Arbitrary aforementioned in another embodiment particularly in, Y 1hydrogen, Y 4hydrogen, and each Y 5hydrogen.Arbitrary aforementioned in another embodiment particularly in, Y 1hydrogen, Y 4hydrogen, and each Y 5it is deuterium.Arbitrary aforementioned in another embodiment particularly in, Y 1hydrogen, Y 4deuterium, and each Y 5it is deuterium.Arbitrary aforementioned in another embodiment particularly in, Y 1hydrogen, Y 4deuterium, and each Y 5hydrogen.
In one embodiment, Y 6it is deuterium.In of this embodiment, Y 7and Y 8each deuterium naturally.In the another aspect of this embodiment, Y 7and Y 8each hydrogen naturally.
In one embodiment, Y 6hydrogen.In of this embodiment, Y 7and Y 8each deuterium naturally.In the another aspect of this embodiment, Y 7and Y 8each hydrogen naturally.
A kind of embodiment of the present invention provides the compound of a kind of formula I:
Or its pharmacy acceptable salt, wherein:
Y 1be selected from hydrogen and deuterium;
Each Y 2independently selected from hydrogen and deuterium, condition is each Y be connected on common carbon 2identical;
Each Y 3independently selected from hydrogen and deuterium, condition is each Y be connected on common carbon 3identical;
Y 4be selected from hydrogen and deuterium;
Each Y 5be identical and be selected from hydrogen and deuterium; And
Y 6, Y 7and Y 8be selected from hydrogen and deuterium independently of one another; Condition works as Y 1hydrogen, each Y 2with each Y 3hydrogen, Y 4be hydrogen and Y 6, Y 7and Y 8during each hydrogen naturally, each Y 5it is deuterium.
In one embodiment, each Y 2identical, each Y 3identical, and each Y 5identical.In of this embodiment, each Y 2it is deuterium.Further, each Y 3it is deuterium.In another is further, each Y 3hydrogen.In the another aspect of this embodiment, each Y 2hydrogen.Further, each Y 3it is deuterium.In another is further, each Y 3hydrogen.Arbitrary aforementioned in an embodiment in, Y 1it is deuterium.Arbitrary aforementioned in another embodiment in, Y 1hydrogen.Arbitrary aforementioned in embodiment particularly in, Y 1deuterium, Y 4deuterium, and each Y 5it is deuterium.Arbitrary aforementioned in another embodiment particularly in, Y 1deuterium, Y 4deuterium, and each Y 5hydrogen.Arbitrary aforementioned in another embodiment particularly in, Y 1deuterium, Y 4hydrogen, and each Y 5hydrogen.Arbitrary aforementioned in another embodiment particularly in, Y 1hydrogen, Y 4hydrogen, and each Y 5hydrogen.Arbitrary aforementioned in another embodiment particularly in, Y 1hydrogen, Y 4hydrogen, and each Y 5it is deuterium.Arbitrary aforementioned in another embodiment particularly in, Y 1hydrogen, Y 4deuterium, and each Y 5it is deuterium.Arbitrary aforementioned in another embodiment particularly in, Y 1hydrogen, Y 4deuterium, and each Y 5hydrogen.
In one embodiment, Y 6it is deuterium.In of this embodiment, Y 7and Y 8each deuterium naturally.In the another aspect of this embodiment, Y 7and Y 8each hydrogen naturally.
In one embodiment, Y 6hydrogen.In the one side of this embodiment, Y 7and Y 8each deuterium naturally.In the another aspect of this embodiment, Y 7and Y 8each hydrogen naturally.
In one embodiment, this compound is the compound of formula I, wherein Y 6, Y 7and Y 8each hydrogen naturally, and this compound to be selected from table 1(as follows) listed by arbitrary compound (Cmpd):
The exemplary of table 1: formula I
Compound Y 1 Each Y 2 Each Y 3 Y 4 Each Y 5
100 H H H D H
101 H H H H D
102 H H H D D
103 H H D H H
104 H H D D H
105 H H D H D
106 H H D D D
107 H D H H H
108 H D H D H
109 H D H H D
110 H D H D D
111 H D D H H
112 H D D D H
113 H D D H D
114 H D D D D
115 D H H H H
116 D H H D H
117 D H H H D
118 D H H D D
119 D H D H H
120 D H D D H
121 D H D H D
122 D H D D D
123 D D H H H
124 D D H D H
125 D D H H D
126 D D H D D
127 D D D H H
128 D D D D H
129 D D D H D
130 D D D D D
Or its pharmacy acceptable salt, wherein any atom not being designated as deuterium exists with its natural isotopic abundance.
In one embodiment, this compound is the compound of formula I, wherein Y 6, Y 7and Y 8each deuterium naturally, and this compound to be selected from table 2(as follows) listed by arbitrary compound (Cmpd):
The exemplary embodiment of table 2: formula I
Compound Y 1 Each Y 2 Each Y 3 Y 4 Each Y 5
200 H H H D H
201 H H H H D
202 H H H D D
203 H H D H H
204 H H D D H
205 H H D H D
206 H H D D D
207 H D H H H
208 H D H D H
209 H D H H D
210 H D H D D
211 H D D H H
212 H D D D H
213 H D D H D
214 H D D D D
215 D H H H H
216 D H H D H
217 D H H H D
218 D H H D D
219 D H D H H
220 D H D D H
221 D H D H D
222 D H D D D
223 D D H H H
224 D D H D H
225 D D H H D
226 D D H D D
227 D D D H H
228 D D D D H
229 D D D H D
230 D D D D D
231 H H H H H
Or its pharmacy acceptable salt, wherein any atom not being designated as deuterium exists with its natural isotopic abundance.
In another group embodiment, in above-mentioned arbitrary embodiment, any atom not being designated as deuterium exists with its natural isotopic abundance.
Following compounds can be used for preparing various compound of the present invention:
Or its salt, wherein any atom not being designated as deuterium exists with its natural isotopic abundance.
The synthesis of the compound of formula I or formula A can easily be realized with reference to exemplary synthesis disclosed herein and embodiment by the synthetic chemistry worker of common skill.The methods involving similar with the method for preparation I compound and intermediate thereof of being used for is disclosed in, such as United States Patent (USP) 7, and 598,257 and Organic Letters, 2009, in 11 (9): 1999-2009.
Can utilize corresponding deuterate and optional other containing isotopic reagent and/or intermediate to synthesize compound described herein or to quote the standard synthetic protocols for isotope atom being introduced chemical structure known in the art to perform such method.
Exemplary synthesis
The compound of formula I or formula A can by being similar to United States Patent (USP) 7,598, and 257 and OrganicLetters, 2009, the modes of those synthesis shown in 11 (9): 1999-2009 use suitable deuterate raw material to prepare.
The compound of formula I or formula A can also be prepared by scheme as follows.
The preparation of the compound of scheme 1: formula I
Scheme 1 discloses the exemplary preparation of the compound of formula I, wherein Y 1, each Y 2with each Y 3deuterium, and Y 4, each Y 5, Y 6, Y 7and Y 8hydrogen.To be similar to the mode described in WO2010/083283, commercially available 4-chloro-7H-pyrrolo-[2,3-d] pyrimidine 11(Aldrich) obtain 12 through sodium hydride and chlorination SEM process, itself and commercially available 13 be obtained by reacting 14.Replace 11,4-bromo-7H-pyrrolo-[2,3-d] pyrimidine also can be used to the 4-providing SEM to protect bromo-7H-pyrrolo-[2,3-d] pyrimidine (being similar to 12) in the first step, it can react to obtain 14 with 13.14 with as preparation disclosed in scheme 2a below 15 reaction be by with the Org.Lett.2009 such as Lin, Q., the similar mode described in 11,1999 carries out obtaining 16.Carry out under the existence of the chiral ligand 27 of the preparation that this reaction describes at such as Lin, Q etc.16 by using NH 4oH and I 2process and be converted into 17.The SEM blocking group of 17 uses LiBF subsequently 4and NH 4oH goes to protect and provides the compound of formula I.
Scheme 2a: the preparation of compound 15
As shown in scheme 2a, 18 commercially available Yong Phosphonium ylide 20 and DCl/D 2o process to generate 19, its with 20 and DiBAl-H process to obtain 15.
Scheme 2b: the preparation of compound 23
Scheme 2c: the preparation of compound 26
The compound of similar 15 can also be prepared.Such as, as shown in scheme 2b, commercially available 21 can by being converted into 23 with similar fashion disclosed in scheme 2a.For another example, as shown in scheme 2c, commercially available 24 can by being converted into 26 with similar fashion disclosed in scheme 2a and scheme 2b.23 can by being converted into the compound of formula I, wherein Y with similar fashion disclosed in scheme 1 1with each Y 3deuterium, and Y 4, each Y 2, each Y 5, Y 6, Y 7and Y 8hydrogen.Similarly, 26 can by being converted into the compound of formula I, wherein Y with similar fashion disclosed in scheme 1 1with each Y 2deuterium, and Y 4, each Y 3, each Y 5, Y 6, Y 7and Y 8hydrogen.
Particular approach as implied above and compound are not intended to be restrictive.No matter whether pass through identical variable name (that is, R 1, R 2, R 3deng) identify, the chemical structure in diagram herein depicts carries out the suitable variable limited with chemical group definition (part, atom etc.) of corresponding position in this paper Formula at this.In the compound structure for the synthesis of another kind of compound, the suitability of chemical group is within the ken of those of ordinary skill in the art.
The additive method of the compound of synthesis type I or formula A and synthesis precursor thereof (be included in the path clearly do not shown in diagram herein those) is within the means scope of the chemist of this area common skill.The synthetic chemistry that can be used for synthesizing applicable compound transforms and protecting group method (protect and go to protect) is known in the art, and comprise, such as, those methods are in the following documents described: Larock R, Comprehensive Organic Transformations, VCHPublishers (1989); Greene, TW etc., Protective Groups in Organic Synthesis, 3 rded., John Wiley and Sons (1999); Fieser, L etc., Fieser and Fieser ' sReagents for Organic Synthesis, John Wiley and Sons (1994); With Paquette, L write, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and later release thereof.
The substituting group of the present invention's imagination and the combination of variable are the combination that those cause being formed stable compound.
Composition
The present invention also provides pyrogen-free pharmaceutical composition, includes the compound (such as comprise formula described herein any one) of the formula I of effective amount or formula A or the pharmacy acceptable salt of described compound, and pharmaceutically acceptable carrier.Described carrier compatible with other compositions of preparation and, pharmaceutically when acceptable carrier, the meaning that can not be harmful to its recipient under the amount in medicine is " acceptable ".
The pharmaceutically acceptable carrier of pharmaceutical composition used in the present invention, assistant agent and medium include, but are not limited to: ion-exchanger, aluminum oxide, aluminum stearate, Yelkin TTS, serum protein is human serum albumin such as, buffer substance is phosphoric acid salt such as, glycine, Sorbic Acid, potassium sorbate, the partial glyceride mixture of saturated vegetable fatty acid, water, salt or ionogen such as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloidal silica, Magnesium Trisilicate, Polyvinylpyrolidone (PVP), cellulose base materials, polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, wax, polyethylene-polyoxypropylene segmented copolymer, polyoxyethylene glycol and lanolin.
If necessary, solubleness and the bioavailability of the compounds of this invention in pharmaceutical composition can be improved by method well-known in the art.One method comprises and uses lipid excipients in the formulation.Edit see " Oral Lipid-Based Formulations:Enhancing theBioavailability of Poorly Water-Soluble Drugs (Drugs and thePharmaceutical Sciences) " David J.Hauss, Informa Healthcare, 2007; " Role of Lipid Excipients in Modifying Oral and Parenteral DrugDelivery:Basic Principles and Biological Examples " Kishor M.Wasan edits, Wiley-Interscience, 2006.
The another kind of currently known methods improving bioavailability is the compounds of this invention using the amorphous form optionally prepared together with oxypropylene block copolymer with poloxamer (such as LUTROLTM with PLURONICTM (BASF Corporation)) or ethylene oxide.See United States Patent (USP) 7,014,866 and U.S. Patent Publication 20060094744 and 20060079502.
Pharmaceutical composition of the present invention comprises those pharmaceutical compositions being suitable for oral, rectum, nose, locally (comprise cheek and sublingual), vagina or parenteral (comprising subcutaneous, intramuscular, intravenously and intradermal) and using.In certain embodiments, the compound transdermal administration (such as, using percutaneous plaster or iontophoretic technology) of this paper structural formula.Other preparations can be provided as unit dosage easily, such as tablet, sustained releasing type capsule and in liposome, and can be prepared by any method known in pharmaceutical field.See, such as, Remington:The Science andPractice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (the 20th edition, 2000).
Such preparation method comprises the step molecule preparing to use and the composition (such as carrier) forming one or more ancillary components being carried out combining.Usually, by by the solid carrier of activeconstituents and liquid vehicle, liposome or segmentation or both are all even is closely combined, then if necessary, product is shaped and prepares composition.
In some embodiments, described compound is Orally administered.Being applicable to the Orally administered present composition can with the capsule of discrete unit such as separately containing predetermined amount activeconstituents, sachet or tablet; Powder or particle; Solution in waterborne liquid or non-aqueous liquid or suspension; Oil-in-water liq emulsion; Water-in-oil liquid emulsion; Filled liposome; Or as existence such as bolus.Soft gelatin capsule may be used for comprising such suspension, and it can advantageously improve compound specific absorption.
In the tablet situation orally used, normally used carrier comprises lactose and W-Gum.Lubricant such as Magnesium Stearate is also usually add.For for capsules per os administration, useful thinner comprises lactose and dried corn starch.When oral application of water suspension, activeconstituents and emulsifying agent and suspending agents.If needed, some sweeting agent and/or seasonings and/or tinting material can be added.
Be suitable for the pastille that Orally administered composition is included in the dragee that comprises described composition in flavoured base (normally sucrose and gum arabic or tragacanth gum) and comprises activeconstituents in inert base (such as gelatin and glycerine or sucrose and gum arabic).
The composition that applicable parenteral is used comprises water-based and nonaqueous aseptic parenteral solution, its solute that can comprise antioxidant, buffer reagent, fungistat and make the blood of preparation and intended recipient isotonic; And water-based and nonaqueous sterile suspension, it can comprise suspension agent and thickening material.Described preparation can be provided in unitary dose or multi-dose container, the ampoule such as sealed and bottle, and under can being stored in lyophilize (freeze-drying) condition, only needs to add aseptic liquid vehicle, such as water for injection before being about to use.Instant injection solution and suspension can be prepared from aseptic powder, particle and tablet.
Such injection solution can be the form of aseptic water-based or oily injection suspension.This suspension can, according to technology known in the art, utilize suitable dispersion or wetting agent (such as tween 80) and suspension agent to prepare.Aseptic injection preparation also can be aseptic injectable solution in the acceptable non-toxic thinner of parenteral or solvent or suspension, such as, as the solution in 1,3 butylene glycol.Operablely accepting medium and solvent can comprise mannitol, water, Ringer's solution and isotonic sodium chlorrde solution.In addition, aseptic fixed oil is conventionally used as solvent or suspension medium.To this, the fixed oil of any gentleness can be used, comprise glyceryl monoacetate or the diglyceride of synthesis.Lipid acid, such as oleic acid and glyceride derivative thereof, can be used for preparing injection, and natural pharmaceutically acceptable oil, such as sweet oil or Viscotrol C, especially their polyoxyethylated versions.These oil solutions or suspension also can comprise long-chain alcohol diluents or dispersion agent.
Pharmaceutical composition of the present invention can adopt the suppository form for rectal administration to use.These compositions can be prepared by being mixed with suitable nonirritant excipient by compound of the present invention, and described vehicle is at room temperature solid but is liquid under rectal temperature, therefore melts in the rectum to discharge active ingredient.Such material includes, but are not limited to theobroma oil, beeswax and polyoxyethylene glycol.
Pharmaceutical composition of the present invention can be used by nose aerosol or suction.Such composition is prepared according to the known technology of technical field of medicine, and can use phenylcarbinol or other sanitass be applicable to, improves the solution that other known solubilisings of the absorption enhancer of bioavailability, fluorohydrocarbon and/or this technical field or dispersion agent are prepared into salt solution.See, such as, Rabinowitz JD and Zaffaroni AC, United States Patent (USP) 6,803,031, has transferred AlexzaMolecular Delivery Corporation.
When required treatment relates to the readily accessible region of topical application or organ, the topical application of pharmaceutical composition of the present invention is particularly useful.For the topical application of local skin, pharmaceutical composition should be prepared with the ointment be applicable to containing the active ingredient suspending or dissolve in the carrier.Carrier for topical application the compounds of this invention includes, but are not limited to: mineral oil, Albolene, white vaseline, propylene glycol, PULLRONIC F68 compound, emulsifying wax and water.Or described pharmaceutical composition can be prepared by the washing lotion or breast frost containing suspension or dissolving active compound in the carrier.The carrier be applicable to includes, but are not limited to: mineral oil, Stearinsaeure anhydrosorbitol, polysorbate 60, cetyl ester wax, cetostearyl alcohol, 2-Standamul G, phenylcarbinol and water.Pharmaceutical composition of the present invention also can be applied topically to lower intestine by rectal suppository formulation or with the enema agent be applicable to.The present invention also comprises topical transdermal paster and iontophoresis is used.
The application of this therapeutical agent can be local, to use in object site.Various technology can be used to provide this composition in object site, such as, inject, use conduit, trochar, projectile body, pluronic gel, support, Sustained drug release polymers or be provided for arriving other inner devices.
Therefore, according to another embodiment again, the compounds of this invention can be added in composition such as, for coating implantable medical treatment device, prosthese, artificial valve, blood vessel graft, support or conduit.Known in the art and at United States Patent (USP) 6 through the suitable coating of the implantable device of coating and general preparation, 099,562; 5,886,026 and 5,304, illustrate in 121.The normally biocompatible polymeric material of coating, such as aquogel polymer, poly-tetramethyldisiloxane, polycaprolactone, polyoxyethylene glycol, poly(lactic acid), ethane-acetic acid ethyenyl ester and composition thereof.Described coating can optionally be covered by suitable fluorosilicone, polysaccharide, polyoxyethylene glycol, phosphatide or its external coating (EC) combined further, thus gives composition Co ntrolled release characteristic.Coating for intrusion apparatus is included in the definition of pharmaceutically acceptable carrier, assistant agent or medium, as used herein those terms.
According to another embodiment, the invention provides the method for coating implantable medical device, comprise the step that described device is contacted with above-described coating composition.Those skilled in the art it is evident that being coated in of device implants generation before in Mammals.
According to another embodiment, the invention provides the method for flooding implantable drug release device, comprise the step that described drug release device is contacted with compound of the present invention or composition.Implantable drug release device includes but not limited to biodegradable polymer capsule or bullet, nondegradable diffusible polymer capsule and biodegradable polymer flake.
According to another embodiment, the invention provides the implantable medical device scribbling the compounds of this invention or the composition containing the compounds of this invention, to make described compound, there is therapeutic activity.
According to another embodiment, the invention provides dipping or containing compound of the present invention or the implantable drug release device of composition comprising the compounds of this invention, discharge from described device to make described compound and be therapeutic activity.
When organ or tissue because from patient remove and can close to time, this organ or tissue can be bathed in the medium containing the present composition, composition of the present invention can be coated on organ or the present composition can with any other easily mode apply.
In another embodiment, composition of the present invention comprises the second therapeutical agent further.Described second therapeutical agent can be selected from any known when with compound or the therapeutical agent or show when having and use together for the compound of the identical mechanism of action of Buddhist nun with Lu's rope with favourable character.These reagent comprise those that be shown as and can be combined for Buddhist nun with Lu's rope.
Preferably, described second therapeutical agent can be used for treatment or prevention is selected from following disease or the reagent of situation: myelofibrosis (comprise myelofibrosis after PMF, polycythemia vera, polycythemia vera, chronic idiopathic myelofibrosis, primary thrombocytosis after myelofibrosis and primary thrombocytosis), carcinoma of the pancreas, prostate cancer, mammary cancer, leukemia, non-Hodgkin lymphoma, multiple myeloma, psoriatic and alopecia areata.
In one embodiment, described second therapeutical agent is selected from Revlimid, LBH589, capecitabine, Exemestane and combination thereof.
In another embodiment, the invention provides the independent formulation of the compounds of this invention and one or more above-mentioned any second therapeutical agents, wherein this compound and the second therapeutical agent are associated with each other.Term as used herein " is associated with each other " and refers to that independent formulation is packed together or to be connected with each other to otherwise thus this independent formulation intention of easy understand is sold together and used (be separated by be less than and sequentially use within 24 hours or side by side use).
In pharmaceutical composition of the present invention, the compounds of this invention exists with significant quantity.The amount of as used herein, term " significant quantity " refers to be enough to when using with correct dosage regimen to treat (therapeutic or prophylactically) target conditions.
Mutual relationship for the dosage (based on the every square meter body area of milligram) of animal and human is described in Freireich etc., in (1966) Cancer Chemother.Rep50:219.Body surface area can be determined approx from the height of patient and body weight.See, such as, ScientificTables, Geigy Pharmaceuticals, Ardsley, N.Y., 1970,537.
In one embodiment, the significant quantity scope of the compounds of this invention can from 1mg to 500mg, such as 5mg to 100mg, such as 5mg to 50mg.The example of scope is from 40mg to 50mg, from 25mg to 40mg, from 25mg to 50mg, from 20mg to 40mg, from 20mg to 50mg, from 10mg to 25mg, from 10mg to 20mg, from 5mg to 25mg, from 5mg to 20mg, and from 5mg to 10mg.In one embodiment, the dosage of 10mg, 20mg, 40mg and 50mg daily once.In one embodiment, the dosage of 5mg, 10mg, 20mg, 40mg and 50mg daily twice.
As those skilled in the art recognize that, effective dose also can change, this depend on the severity of treated disease, disease, the approach of administration, the sex of experimenter, age and general health, vehicle use, share the judgement as the possibility and doctor in charge using other reagent with other treatment treatment process.Such as, select the guidance of effective dose by determining with reference to the provisioning information of Lu's rope for Buddhist nun.
For the pharmaceutical composition comprising the second therapeutical agent, the significant quantity of the second therapeutical agent is about 20% to 100% of the dosage being generally used for the monotherapy only using this medicament.Preferably, significant quantity is about 70% to 100% of normal monotherapy dosage.The normal monotherapy dosage of these the second therapeutical agents well known to a person skilled in the art, for example, see Wells etc. write, and PharmacotherapyHandbook, the 2nd edition, Appleton and Lange, Stamford, Conn. (2000); PDRPharmacopoeia, Tarascon Pocket Pharmacopoeia2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), this reference is respectively herein incorporated in full with way of reference.
Expect that more above-mentioned second therapeutical agent will play a role with the compounds of this invention is collaborative.When this happens, the effective dose of permission second therapeutical agent and/or the compounds of this invention is reduced relative to the dosage needed for monotherapy.This have make the collaborative improvement of the minimize toxic side effects of the second therapeutical agent or the compounds of this invention, effect, improvement use or ease of use and/or compound preparation or preparation whole cost reduce advantage.
Methods for the treatment of
In another embodiment, the invention provides a kind of one or more method in Janus associated kinase (JAK) JAK1 and JAK2 in T suppression cell, comprise and make cell herein the compound of Chinese style I or formula A or its pharmacy acceptable salt contact with one or more.
According to another embodiment, the invention provides the method for the disease that treatment Lu's rope is treated valuably for Buddhist nun in the experimenter needed, comprise and the compound of the present invention of significant quantity or the step of composition are used to this experimenter.In one embodiment, this experimenter is the patient needing this treatment.This kind of disease is well known in the art, and open in following (but being not limited to) patent: United States Patent (USP) 7,598,257.This kind of disease includes but not limited to relate to immune disease, comprises such as organ transplant rejection (such as allograft rejection and graft versus host disease (GVH disease)); Autoimmune disorder is as multiple sclerosis, rheumatoid arthritis, juvenile arthritis, type i diabetes, lupus, psoriatic, inflammatory bowel, ulcerative colitis, Crohn's disease, myasthenia gravis, immunoglobulin (Ig) ephrosis, autoimmune thyroid disease; Allergic conditions is as asthma, food anaphylaxis, allergic dermatitis and rhinitis; Virus disease is as epstein-Barr virus (EBV), hepatitis B, hepatitis C, HIV, HTLV1, varicella zoster virus (VZV) and human papillomavirus (HPV); Dermatosis is as psoriatic (such as psoriasis vulgaris), allergic dermatitis, fash, skin irritation, sensitization of skin reaction (such as contact dermatitis or allergic contact dermatitis); Cancer, (example comprises Sai Zharui syndromes and mycosis fungoides to comprise cancer (cancer, thyroid carcinoma, glioblastoma multiforme, Kaposi's sarcoma, castleman's disease, the melanoma of such as prostate cancer, kidney, liver cancer, carcinoma of the pancreas, cancer of the stomach, mammary cancer, lung cancer, incidence) that those take noumenal tumour as feature, hematologic cancers (if lymphoma, leukemia are as acute lymphoblastic leukemia or multiple myeloma) and skin carcinoma such as cutaneous T cell lymphoma (CTCL) and cutaneous B-cell lymphoma; Myeloproliferative disease (MPD) is as polycythemia vera (PV), primary thrombocytosis (ET), myeloid metaplasia myelofibrosis (MMM), chronic myelomonocytic leukemia (CMML), hypereosinophilia syndrome (HES), systemic mast cell disease (SMCD); (the such as upper respiratory tract comprises the diseases associated with inflammation of nose, nasal sinus for inflammation and inflammatory diseases such as the diseases associated with inflammation of ocular inflammatory disease (such as iritis, uveitis, scleritis, conjunctivitis or relevant disease), respiratory tract, as rhinitis or sinusitis paranasal sinusitis, or the diseases associated with inflammation of lower respiratory tract comprises bronchitis, chronic obstructive pulmonary disease etc.), inflammatory myopathy is as myocarditis; Systemic inflammatory response syndrome (SIRS) and septic shock; Ischemical reperfusion injury or the disease relevant to inflammatory ischemic events or situation are as apoplexy or sudden cardiac arrest; Apositia; Emaciation; Tired as that caused by cancer or relevant to cancer fatigue; Restenosis; Sclerodermatitis (sclerodermitis); Fibrosis; The situation relevant to anoxic or proliferation of astrocytes, such as diabetic retinopathy, cancer or nerve degenerative diseases; Gout; Because the prostate gland of such as benign prostatauxe or benign prostatic hyperplasia increases.
In one particular embodiment, method of the present invention is used to treatment in the experimenter needed and is selected from myelofibrosis, comprise myelofibrosis after myelofibrosis after PMF, polycythemia vera, primary thrombocytosis, primary thrombocytosis or its combination; Carcinoma of the pancreas; Prostate cancer; Mammary cancer; Leukemia; Non-Hodgkin lymphoma; Multiple myeloma; The disease of psoriatic and combination thereof or situation.
In another particular, method of the present invention is used to treatment in the experimenter needed and is selected from myelofibrosis, comprises disease or the situation of myelofibrosis after myelofibrosis and primary thrombocytosis after PMF, polycythemia vera.
Need the discriminating of the experimenter of this treatment to be undertaken by the judgement of experimenter or health care professional, and can be subjective (such as suggestion) or objective (measuring by inspection or diagnostic method).
In another embodiment, any above methods for the treatment of comprises the step further experimenter of needs being used jointly to one or more the second therapeutical agents.Second therapeutical agent can be selected from any known the second therapeutical agent that can be used for jointly using for Buddhist nun with Lu's rope.Specified disease to be treated or situation are also depended in the selection of the second therapeutical agent.In the inventive method, the example of adoptable second therapeutical agent is those in above-mentioned composition of combining for comprising compound of the present invention and the second therapeutical agent.
Especially, conjoint therapy of the present invention comprises and jointly uses the compound of formula I or formula A and the second therapeutical agent to treat conditions (specific second therapeutical agent is shown in the bracket after this indication) to the experimenter of needs: myelofibrosis (Revlimid or LBH589); Carcinoma of the pancreas (capecitabine) and mammary cancer (Exemestane).
Term used in the present invention " is jointly used " and is referred to that the part that the second therapeutical agent can be used as single formulation (present composition such as containing the compounds of this invention and above-described second therapeutical agent) is used together with the compounds of this invention, or uses together with the compounds of this invention as independent multi-form.Or, other medicaments can before using the compounds of this invention, simultaneously or use afterwards.In the treatment of this conjoint therapy, the compounds of this invention and the second therapeutical agent are all used by ordinary method.This identical therapeutical agent, any other second therapeutical agent or any compound of the present invention is used separately another time be not precluded within therapeutic process by being applied to patient containing the compounds of this invention and the present composition of the second therapeutical agent.
The significant quantity of these the second therapeutical agents is known in those skilled in the art; and administration instructs the patent that can mention in this article and disclosed patent application and Wells etc. to write; Pharmacotherapy Handbook; 2nd edition; Appleton and Lange; Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia2000, finds in DeluxeEdition, Tarascon Publishing, Loma Linda, Calif. (2000) and other medical articles.But those skilled in the art are easy to the best significant quantity scope determining the second therapeutical agent.
Second therapeutical agent is applied in the embodiment of the present invention of experimenter wherein, and the significant quantity of the compounds of this invention is less than its significant quantity when not using the second therapeutical agent.In another embodiment, the significant quantity of the second therapeutical agent is less than its significant quantity when not using the compounds of this invention.In this way, the undesirable side effect relevant to the high dosage of any one medicament can be minimized.Other possible advantages (including but not limited to the medicine cost of dosage regimen and/or the reduction improved) will be apparent to those skilled in the art.
More on the other hand, the compound that the invention provides formula I or formula A prepare as single composition or independent formulation for treating or prevent the purposes in the medicine of disease described above, imbalance or symptom in experimenter separately or together with one or more above-mentioned second therapeutical agents.Another aspect of the present invention is that the compound of formula I or formula A for treating or preventing disease described herein, imbalance or symptom in experimenter.
Embodiment
Embodiment 1. (R)-3-(4-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-1H-pyrazol-1-yl)-3-(2,2,5,5-d 4-cyclopentyl) synthesis of propionitrile (compound 107).
The preparation of scheme 3. compound 107
step 1.2,2,5,5-d 4 -pentamethylene-1,1-diethyl dicarboxylate (32).At diethyl malonate (6.57mL, add the ethanolic soln (32.3mL, 86.6mmol) of the sodium ethylate of 21 % by weight in ethanol (40mL) solution 43.3mmol), add 1 subsequently, 1,4,4-, tetra-deuteriums-Isosorbide-5-Nitrae-dibromobutane (31,5.53mL, 45.5mmol, CDN Isotopes, 98 atom % deuteriums).Gained solution stirs 2 hours under reflux, is then cooled to room temperature and dilutes with excessive water.Subsequently by the most of ethanol of distillation removing, and obtained aqueous solution ethyl acetate (3x75mL) extracts.Organic layer merges, and uses salt water washing, dry (Na 2sO 4), also concentrating under reduced pressure is to obtain 32 of yellow oil in filtration, and it is not purified and enter subsequent step (9.45g, 100%).
step 2.2,2,5,5-d 4 -pentamethylene-1-carboxylic acid (33).The sodium hydroxide solution (20mL) of 5M is added in ethanol (20mL) solution of 32 (9.45g, 43.3mmol).Add other water (15mL) subsequently again, reaction is stirred 3 hours under reflux.After being cooled to room temperature, this reaction excessive water dilutes and passes through the most of ethanol of distillation removing.Make this aqueous solution aobvious acid (pH<2) with 1N hydrochloric acid, use diethyl ether (3x50mL) to extract subsequently.Organic layer merges, dry (Na 2sO 4), filter and concentrating under reduced pressure.Gained orange solid is transferred in pressure flask, and adds water (140mL).This pressure flask is sealed, and reacts and stirs 15 hours at 160 DEG C, be then cooled to room temperature.This reaction 1N hydrochloric acid also extracts with diethyl ether (3x50mL).Organic layer merges, dry (Na 2sO 4), also concentrating under reduced pressure is to obtain 33 (4.37g, 86%) of amber oily in filtration, and it is not purified and use.
step 3.2,2,5,5-d 4 -N-methoxy-. N-methyl cyclopentane formamide (34).At 0 DEG C, to 33 (4.37g, N is added in acetonitrile (60mL) solution 37.0mmol), hydrochloride (the 4.33g of O-dimethyl hydroxylamine, 44.4mmol), TBTU (12.5g, 38.9mmol) with DIPEA (19.0mL, 111mmol).Reaction is at room temperature stirred 15 hours, then also uses ethyl acetate (3x50mL) extraction with 1N hydrochloric acid.Organic phase merges, and uses saturated NaHCO 3washing, dry (Na 2sO 4), filter and concentrating under reduced pressure.Products therefrom column chromatography (SiO 2, 0-50% ethyl acetate/hexane) and purifying to be to obtain 34 (2.22g, 37%) of clear oil.MS(ESI)162.3[(M+H) +]。
step 4.2,2,5,5-d 4 -pentamethylene-1-formaldehyde (35).At 0 DEG C, in THF (50mL) solution of 34 (2.22g, 13.8mmol), dropwise add the LiAlH of 1M 4tHF (24.8mL, 24.8mmol) solution.Reaction at 0 DEG C stir 1 hour, then by order drip water (940 μ L), 15% NaOH (940 μ L) and water (2.82mL) carry out cancellation.The reactant of cancellation at room temperature stirs 30 minutes, then passes through filter and concentrating under reduced pressure.Gained oily matter 1N hydrochloric acid also extracts with diethyl ether (3x50mL).Organic layer merges, dry (Na 2sO 4), also concentrating under reduced pressure is to obtain 35 (850mg, 60%) of clear oil thing in filtration, and it is not purified and use.
step 5.3-(2,2,5,5-d 4 -cyclopentyl) vinyl cyanide (36).At 0 DEG C, in THF (8.74mL, the 8.74mmol) solution of the potassium tert.-butoxide of 1M, dropwise add THF (12mL) solution of cyanogen methyl-phosphorous acid diethyl ester (1.48mL, 9.15mmol).Reaction is heated to room temperature, stirs 15 minutes, then is cooled to 0 DEG C.Aldehyde 35 (850mg, 8.32mmol) adds as the dropwise of THF (3mL).Reaction is at room temperature stirred 48 hours, then dilutes with excessive water and uses diethyl ether (1x50mL) and ethyl acetate (3x50mL) extraction.Organic layer merges, dry (Na 2sO 4), also concentrating under reduced pressure is to obtain 36 (1.17g, >100%) of light orange oily in filtration, and it is not purified and use.
step 6. (+/-)-(4-(1-(2-cyano group-1-(2,2,5,5-d 4 -cyclopentyl) ethyl)-1H-pyrazoles-4- base)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl) methyl pivalate ((+/-) 38).To 37, (400mg, 1.34mmol, at Org.Lett. such as Lin, Q., the preparation described in 2009,11,1999-2002) acetonitrile (10mL) solution in add 36 (418mg, 3.34mmol), DBU (421 μ L, 2.81mmol) is then added.Reaction is at room temperature stirred 15 hours, then concentrating under reduced pressure.Gained crude mixture dilute with water also extracts by ethyl acetate (3x50mL).Organic layer merges, with 1N salt acid elution, and dry (Na 2sO 4), filter and concentrating under reduced pressure.First use normal phase column chromatogram (SiO 2, 0-60% ethyl acetate/hexane) and purifying, then use reverse column chromatography (C18, the 5-70% acetonitrile/water containing 0.1% formic acid) purifying to obtain (+/-) 38 (68mg, 12%) of white foam.1H NMR(DMSO-d 6,400MHz)8.84(s,1H),8.79(s,1H),8.40(s,1H),7.74(d,J=3.8Hz,1H),7.12(d,J=3.8Hz,1H),6.24(s,2H),4.54(td,J=9.7,4.3Hz,1H),3.30-3.15(m,2H),2.39(d,J=9.8Hz,1H),1.68–1.36(m,4H),1.08(s,9H);MS(ESI)425.3[(M+H) +].
step 7. (R)-(4-(1-(2-cyano group-1-(the deuterated cyclopentyl of 2,2,5,5-tetra-) ethyl)-1H-pyrazoles-4- base)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl) methyl pivalate ((R)-38).Racemic compound (+/-) 38 (62mg) is dissolved in acetonitrile with the concentration of 30mg/mL, and with per injection 500 μ L (+/-) 38 solution at Daicel ChiralPak AD post (20x250mm, 10 μm) above use method such as degree such as grade to carry out chiral separation by preparation HPLC: 30% Virahol (+0.1% diethylamine)/70% hexane (+0.1% diethylamine), flow velocity is 17mL/min.In these cases, to locate wash-out (S)-38 at 15.0 minutes and to locate wash-out (R)-38 at 20.2 minutes to realize baseline separation.
Fraction containing each enantiomer merges and concentrates, and produces the colorless film of (S)-38 of 28mg and the colorless film of (R)-38 of 29mg.
step 8. (R)-3-(4-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-1H-pyrazoles-1- base)-3-(the deuterated cyclopentyl of 2,2,5,5-tetra-) propionitrile (compound 107).Compound (R)-38 (28mg, 0.066mmol, 1 equivalent) is dissolved in methyl alcohol (1mL) in the scintillation vial of 20mL.Add sodium hydroxide (the 1M solution of 0.13mL, 0.13mmol, 2 equivalents), and reaction is at room temperature stirred 18 hours.Reaction use water (10mL) and salt solution (20mL) dilution.This aqueous mixture ethyl acetate (2x20mL) extracts.Organic layer washed with brine (20mL) washing merged, by dried over sodium sulfate, filters and evaporates.Crude material Analogix automatization chromatographic system is purified, by the 0-6% methanol-eluted fractions in methylene dichloride.Product fraction merges and evaporates, and produces the compound 107 of white foam.Chiral purity is >99%ee (Chiralpak OD4.6x250mm, 10um, 70% (hexane+0.1% diethylamine)+30% (Virahol+0.1% diethylamine), 1mL/min, 254nm retention time=8.85min).
Embodiment 2. (R)-3-(4-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-1H-pyrazol-1-yl)-3-(3,3,4,4-d 4-cyclopentyl) synthesis of propionitrile (compound 103).
The preparation of scheme 4. compound 103
step 1.3,3,4,4-d 4 -pentamethylene-1,1-diethyl dicarboxylate (40).To diethyl malonate (3.25mL, add the ethanolic soln (16.0mL, 42.8mmol) of the sodium ethylate of 21 % by weight in ethanol (20mL) solution 21.4mmol), then add 2,2,3,3-tetra-is deuterated-Isosorbide-5-Nitrae-dibromobutane (39,4.95g, 22.5mmol, CDN Isotopes, 98 atom % deuteriums).Gained solution stirs 2 hours under reflux, is then cooled to room temperature and dilutes with excessive water.Subsequently by the most of ethanol of distillation removing, and obtained aqueous solution ethyl acetate (3x75mL) extracts.Organic layer merges, and uses salt water washing, dry (Na 2sO 4), also concentrating under reduced pressure is to obtain 40 of yellow oil in filtration, and it is not purified and enter subsequent step (4.67g, 100%).
step 2.3,3,4,4-d 4 -pentamethylene-1-carboxylic acid (41).The sodium hydroxide solution (10mL) of 5M is added in ethanol (10mL) solution of 40 (4.67g, 21.4mmol).Add other water (10mL) subsequently again, and reaction is stirred 3 hours under reflux.After being cooled to room temperature, this reaction excessive water dilutes and passes through the most of ethanol of distillation removing.Make this aqueous solution in acid (pH<2) with 1N hydrochloric acid, use diethyl ether (3x50mL) to extract subsequently.Organic layer merges, dry (Na 2sO 4), filter and concentrating under reduced pressure.Gained orange solid is transferred in pressure flask, and adds water (70mL).This pressure flask is sealed, and reaction is stirred 15 hours at 160 DEG C, is then cooled to room temperature.This reaction 1N hydrochloric acid also extracts with diethyl ether (3x50mL).Organic layer merges, dry (Na 2sO 4), also concentrating under reduced pressure is to obtain 41 (1.93g, 76%) of amber oily in filtration, and it is not purified and use.
step 3.3,3,4,4-d 4 -N-methoxy-. N-methyl cyclopentane formamide (42).At 0 DEG C, to 41 (1.93g, N is added in acetonitrile (30mL) solution 16.3mmol), O-dimethyl hydroxylamine hydrochloride (1.91g, 19.6mmol), TBTU (5.50g, 17.1mmol) with DIPEA (8.52mL, 48.9mmol).Reaction is at room temperature stirred 15 hours, then also uses ethyl acetate (3x50mL) extraction with 1N hydrochloric acid.Organic phase merges, and uses saturated NaHCO 3washing, dry (Na 2sO 4), filter and concentrating under reduced pressure.Products therefrom column chromatography (SiO 2, 0-40% acetone/hexane) and purifying to be to obtain 42 (1.47g, 56%) of clear oil.MS(ESI)162.3[(M+H) +]。
step 4.3,3,4,4-d 4 -pentamethylene-1-formaldehyde (43).At 0 DEG C, in THF (35mL) solution of 42 (1.47g, 9.12mmol), dropwise add the LiAlH of 1M 4tHF (16.4mL, 16.4mmol) solution.Reaction at room temperature stir 1 hour, then at 0 DEG C by order drip water (623 μ L), 15% NaOH (623 μ L) and water (1.87mL) carry out cancellation.The reaction of cancellation at room temperature stirs 30 minutes, then passes through filter and concentrating under reduced pressure.Gained oily matter 1N hydrochloric acid also extracts with diethyl ether (3x50mL).Organic layer merges, dry (Na 2sO 4), also concentrating under reduced pressure is to obtain 43 (767mg, 82%) of clear oil in filtration, and it is not purified and use.
step 5.3-(3,3,4,4-d 4 -cyclopentyl) vinyl cyanide (44).At 0 DEG C, in THF (10mL) solution of cyano methyl diethyl phosphonate (0.607mL, 3.75mmol), dropwise add THF (3.75mL, the 3.75mmol) solution of the potassium tert.-butoxide of 1M.Reaction is stirred 1 hour at 0 DEG C.THF (3mL) solution of aldehyde 43 (767mg, 7.51mmol) is dropwise added.Reaction is at room temperature stirred 15 hours, then dilutes with excessive 1:1 water/salt solution and uses MTBE (3x50mL) to extract.Organic layer merges, dry (Na 2sO 4), filter and concentrating under reduced pressure.Gained oily matter is dissolved in CH 2cl 2(100ml) NaHSO is used in 3(3x25mL) wash.Dried (the Na of organic phase 2sO 4), filter and obtain 44 (537mg, 57%) of light orange oily after concentrating under reduced pressure, it is not purified and use.
step 6. (+/-)-(4-(1-(2-cyano group-1-(3,3,4,4-d 4 -cyclopentyl) ethyl)-1H-pyrazoles-4- base)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl) methyl pivalate ((+/-) 45).To 37, (514mg, 1.72mmol, as Org.Lett. such as Lin, Q., the preparation described in 2009,11,1999-2002) acetonitrile (15mL) solution in add 44 (537mg, 4.29mmol), DBU (540 μ L, 3.61mmol) is then added.Reaction is at room temperature stirred 15 hours, then concentrated under reduced vacuum.Gained crude mixture dilute with water also extracts by ethyl acetate (3x50mL).Organic layer merges, with 1N salt acid elution, and dry (Na 2sO 4), filter and concentrating under reduced pressure.With normal phase column chromatogram (SiO 2, 0-60% ethyl acetate/hexane) and obtain (+/-) 45 (368mg, 50%) of white foam after purifying.1H NMR(DMSO-d 6,400MHz)δ8.84(s,1H),8.79(s,1H),8.40(s,1H),7.75(d,J=3.7Hz,1H),7.12(d,J=3.7Hz,1H),6.24(s,2H),4.53(td,J=9.7,4.2Hz,1H),3.32–3.14(m,2H),2.41(q,J=8.7Hz,1H),1.79(dd,J=12.6,7.6Hz,1H),1.36–1.11(m,3H),1.08(s,9H).;MS(ESI)425.2[(M+H) +]。
step 7. (R)-(4-(1-(2-cyano group-1-(3,3,4,4-d 4 -cyclopentyl) ethyl)-1H-pyrazoles-4- base)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl) methyl pivalate ((R)-45).Racemic compound (+/-) 45 (151mg) is dissolved in acetonitrile with the concentration of 30mg/mL, and with per injection 1000 μ L (+/-) 45 solution at Daicel ChiralPak AD post (20x250mm, 10 μm) above carry out chiral separation by method such as degree such as grade by preparation HPLC: 30% Virahol (+0.1% diethylamine)/70% hexane (+0.1% diethylamine), flow velocity is 17mL/min.In these cases, baseline separation is realized at 15.5 minutes place's wash-outs and (R)-45 at 20.7 minutes place's wash-outs with (S)-45.
Fraction containing each enantiomer merges individually and concentrates the colorless film of the colorless film of (S)-45 to produce 51mg and (R)-45 of 53mg.
step 8. (R)-3-(4-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-1H-pyrazoles-1- base)-3-(3,3,4,4-d 4 -cyclopentyl) propionitrile (compound 103).(R)-45 (53mg, 0.13mmol, 1 equivalents) are dissolved in methyl alcohol (2mL) in the scintillation vial of 20mL.Add sodium hydroxide (the 1M solution of 0.25mL, 0.25mmol, 2 equivalents), reaction mixture at room temperature stirs 18 hours.This reaction mixture use water (10mL) and salt solution (20mL) dilution.This aqueous mixture ethyl acetate (2x20mL) extracts.Organic layer washed with brine (20mL) washing merged, by dried over sodium sulfate, filters and concentrates.Thick material Analogix automatization chromatographic system purifying, by the 0-6% methanol-eluted fractions in methylene dichloride.Product fraction merges and evaporates with the compound 103 producing white foam, and purity is ~ 90%, and incomplete de-protected methylol intermediate is major impurity.Further stratographic analysis cannot improve its purity further.This 90% pure material is dissolved in THF (2mL), and at 40 DEG C, processes 8 hours with the aqueous NaOH of several 10%, causes being converted into compound 103 completely.This reaction mixture use water (10mL) dilutes and uses ethyl acetate (2x10mL) to extract.The organic layers with sodium sulfate merged is dry, filters and is condensed into white foam.This foam is dissolved in minimum acetonitrile, dilute with water, and freeze-drying is to provide the compound 103 (14mg, 35% productive rate) of white solid.Chiral purity is >99%ee (Chiralpak OD4.6x250mm, 10um, 70% (hexane+0.1% diethylamine)+30% (Virahol+0.1% diethylamine), 1mL/min, 254nm retention time=7.56min).
Embodiment 3. (R)-3-(4-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-1H-pyrazol-1-yl)-3-(cyclopentyl-d 9) synthesis of propionitrile (compound 127).
The preparation of scheme 5. compound 127
step 1.2,2,3,3,4,4,5,5-d 8 -pentamethylene-1,1-diethyl dicarboxylate (47).The ethanolic soln (30.7mL, 82.2mmol) of the sodium ethylate of 21 % by weight is added in ethanol (40mL) solution of diethyl malonate (6.24mL, 41.1mmol), then 1 is added, 1,2,2,3,3,4,4-eight is deuterated-Isosorbide-5-Nitrae-dibromobutane (46,9.67g, 43.2mmol, CDN Isotopes, 98 atom % deuteriums).Gained solution stirs 2 hours under reflux, is then cooled to room temperature and dilutes with excessive water.Subsequently by the most of ethanol of distillation removing, and obtained aqueous solution ethyl acetate (3x75mL) extracts.Organic layer merges, and uses salt water washing, dry (Na 2sO 4), also concentrating under reduced pressure is to obtain 47 (9.12g, 100%) of yellow oily in filtration, and it is not purified and enter subsequent step.
the complete deuterated pentamethylene-1-carboxylic acid (48) of step 2..The sodium hydroxide solution (20mL) of 5M is added in ethanol (20mL) solution of 47 (9.12g, 41.1mmol).Add other water (15mL) subsequently again, reaction is stirred 3 hours under reflux.After being cooled to room temperature, reaction excessive water dilutes and passes through the most of ethanol of distillation removing.Make this aqueous solution in acid (pH<2) with 1N hydrochloric acid, use diethyl ether (3x50mL) to extract subsequently.Organic layer merges, dry (Na 2sO 4), filter and concentrating under reduced pressure.Gained orange solid is transferred in pressure flask, and adds D 2o (120mL).This pressure flask is sealed, and reaction is stirred 15 hours at 160 DEG C, is then cooled to room temperature.Reaction 1N hydrochloric acid also extracts with diethyl ether (3x50mL).Organic layer merges, dry (Na 2sO 4), also concentrating under reduced pressure is to obtain 48 (4.58g, 90%) of yellow oily in filtration, and it is not purified and use.
step 3.N-methoxy-. N-methyl (pentamethylene-d 9 ) methane amide (49).At 0 DEG C, to 48 (4.58g, N is added in acetonitrile (60mL) solution 37.2mmol), O-dimethyl hydroxylamine hydrochloride (4.35g, 44.6mmol), TBTU (12.5g, 39.1mmol) with DIPEA (19.4mL, 112mmol).Reaction is at room temperature stirred 15 hours, then also uses ethyl acetate (3x50mL) extraction with 1N hydrochloric acid.Organic phase merges, and uses saturated NaHCO 3washing, dry (Na 2sO 4), filter and concentrating under reduced pressure.Products therefrom column chromatography (SiO 2, 0-50% ethyl acetate/hexane) and purifying to be to obtain 49 (3.41g, 55%) of clear oil.MS(ESI)167.2[(M+H) +]。
the complete deuterated pentamethylene-1-formaldehyde (50) of step 4..At 0 DEG C, in THF (80mL) solution of 49 (3.41g, 20.5mmol), dropwise add the LiAlH of 1M 4tHF (37.0mL, 37.0mmol) solution.Reaction is at room temperature stirred 1 hour, then at 0 DEG C, drips D by order 2o (1.41mL), 15% NaOD/D 2o (1.41mL) and D 2o (4.23mL) carrys out cancellation.The reaction of this cancellation at room temperature stirs 30 minutes, then passes through filter and concentrating under reduced pressure.Gained oily matter 1N DCl/D 2o dilutes and uses diethyl ether (3x50mL) to extract.Organic layer merges, dry (MgSO 4), also concentrating under reduced pressure is to obtain 50 (1.79g, 82%) of clear oil in filtration, and it is not purified and use.
step 5.3-(complete deuterated cyclopentyl) vinyl cyanide (51).At 0 DEG C, in THF (25mL) solution of cyano methyl diethyl phosphonate (1.35mL, 8.34mmol), dropwise add THF (8.34mL, the 8.34mmol) solution of the potassium tert.-butoxide of 1M.Reaction is stirred 1 hour at 0 DEG C.Then THF (5mL) solution of aldehyde 50 (1.79g, 16.7mmol) is dropwise added.Reaction is at room temperature stirred 15 hours, then dilutes with excessive 1:1 water/salt solution and uses MTBE (3x50mL) to extract.Organic layer merges, dry (Na 2sO 4), filter and concentrating under reduced pressure.Organic phase merges, dry (Na 2sO 4), also concentrating under reduced pressure is to obtain 51 (1.61g, 74%) of light orange oily in filtration, and it is not purified and use.
step 6. (+/-)-(4-(1-(2-cyano group-1-(cyclopentyl-d 9 ) ethyl)-1H-pyrazoles-4-base)-7H-pyrrole cough up also [2,3-d] pyrimidin-7-yl) methyl pivalate ((+/-) 52).To 37, (619mg, 2.07mmol, at Org.Lett. such as Lin, Q., the preparation described in 2009,11,1999-2002) acetonitrile (15mL) solution in add 51 (673mg, 5.17mmol), DBU (650 μ L, 4.35mmol) is then added.Reaction is at room temperature stirred 15 hours, then concentrating under reduced pressure.Gained crude mixture dilute with water also extracts by ethyl acetate (3x50mL).Organic layer merges, with 1N salt acid elution, and dry (Na 2sO 4), filter and concentrating under reduced pressure.With normal phase column chromatogram (SiO 2, 0-60% ethyl acetate/hexane) and purifying obtains (+/-) 52 (447mg, 50%) of white foam.1H NMR(DMSO-d 6,400MHz)δ8.84(s,1H),8.79(s,1H),8.39(s,1H),7.75(d,J=3.7Hz,1H),7.12(d,J=3.7Hz,1H),6.24(s,2H),4.53(dd,J=9.6,4.2Hz,1H),3.32–3.13(m,2H),1.08(s,9H).;MS(ESI)430.3[(M+H) +]。
step 7. (R)-(4-(1-(2-cyano group-1-(cyclopentyl-d 9 ) ethyl)-1H-pyrazoles-4-base)-7H-pyrrole cough up also [2,3-d] pyrimidin-7-yl) methyl pivalate ((R)-52).Racemic compound (+/-) 52 (162mg) is dissolved in acetonitrile with the concentration of 30mg/mL, and with per injection 1000 μ L (+/-) 52 solution at Daicel ChiralPak AD post (20x250mm, 10 μm) above carry out chiral separation by method such as degree such as grade by preparation HPLC: 30% Virahol (+0.1% diethylamine)/70% hexane (+0.1% diethylamine), flow velocity is 17mL/min.In these cases, baseline separation is realized at 15.4 minutes place's wash-outs and (R)-52 at 20.5 minutes place's wash-outs with (S)-52.
Fraction containing each enantiomer merges separately and concentrates the colorless film of the colorless film of (S)-52 to produce 61mg and (R)-52 of 63mg.
step 8. (R)-3-(4-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-1H-pyrazol-1-yl)-3-(ring penta base-d 9 ) propionitrile (compound 127).(R)-52 (60mg, 0.14mmol, 1 equivalents) are dissolved in methyl alcohol (2mL) in the scintillation vial of 20mL.Add sodium hydroxide (the 1M solution of 0.28mL, 0.28mmol, 2 equivalents), and reaction mixture at room temperature stirs 18 hours.This reaction mixture use water (10mL) and salt solution (20mL) dilution.This aqueous mixture ethyl acetate (2x20mL) extracts.Organic layer washed with brine (20mL) washing merged, by dried over sodium sulfate, filters and concentrates.Thick material Analogix automatization chromatographic system purifying, with the 0-6% methyl alcohol/wash-out in methylene dichloride.Product fraction merges and evaporates with the compound 127 (34mg) producing white foam, and purity is ~ 90%, and incomplete de-protected methylol intermediate is major impurity.Further stratographic analysis cannot improve its purity further.90% pure substance dissolves in THF (2mL), and processes 8 hours with the aqueous NaOH of several 10% at 40 DEG C, causes being converted into compound 127 completely.This reaction mixture use water (10mL) dilutes and uses ethyl acetate (2x10mL) to extract.Organic layers with sodium sulfate after merging is dry, filters and is condensed into white foam.This foam is dissolved in minimum acetonitrile, dilute with water, and freeze-drying is to provide the compound 127 (19mg, 42% productive rate) of white solid.Chiral purity is >99%ee (Chiralpak OD4.6x250mm, 10um, 70% (hexane+0.1% diethylamine)+30% (Virahol+0.1% diethylamine), 1mL/min, 254nm retention time=7.55min).
Embodiment 4.CYP3A4Supersomes tMthe assessment of middle metabolic stability
People CYP3A4Supersomes tMthe assessment of the metabolic stability of middle compound 103,107 and 127
SUPERSOMES tManalyze.In DMSO, prepare test-compound, compound 103,107,127 and Lu Suo replace the 10mM stock solution of Buddhist nun.This 10mM stock solution is diluted to 15.6 μMs in acetonitrile (ACN).People CYP3A4supersomes tM(1000pmol/mL, purchased from BD Gentest tMproducts and Services) at potassium phosphate buffer (pH7.4, the MgCl containing 3mM of 0.1M 2) in be diluted to 62.5pmol/mL.The supersomes of dilution is added in the hole of 96-hole polypropylene board in triplicate.10 μ L equal portions of these 15.6 μMs of test-compounds are added in described supersomes, and mixture is preheated 10 minutes.By adding the NADPH solution of preheating with initiation reaction.Final reaction volume is 0.5mL, and is included in the potassium phosphate buffer (MgCl of pH7.4,3mM of 0.1M 2) in the CYP3A4supersomes of 50pmol/mL tM, the test-compound of 0.25 μM and the NADPH of 2mM.This reaction mixture is incubation at 37 DEG C, and 0,5,10,20 and 30 minute time, pipette 50 μ L equal portions, and adds to and have in the 96-orifice plate of the ice-cold CAN of interior target with stopped reaction containing 50 μ L.This plate is stored 20 minutes at 4 DEG C, and after this 100mL water is added in the hole of plate, centrifugal to make the protein balling-up of precipitation afterwards.Supernatant liquor is transferred in another 96-orifice plate, and by using the mass spectrometric LC-MS/MS of Applied Bio-systems API4000 to analyze residual size of population.
Data analysis: the vitro half-lives (t calculating test-compound from LN (parent that % is residual) the linear regression slope to incubative time relation 1/2value):
External t 1/2=0.693/k, wherein k=-[% remains parent (ln) to the slope of the linear regression of incubative time].
The result of this experiment is presented in table 3 and Fig. 1.As shown in table 3, calculate Lu's rope and replace the transformation period of Buddhist nun to be 14.5 minutes.On the contrary, each compound 103,107 and 127 is more stable in described supersomes, and the transformation period calculated is respectively 16.9,17.9 and 32.0 minutes.The transformation period of this representation compound 103 improves 17%, and the transformation period of compound 107 improves 23%, and the transformation period of compound 127 improves 121%.
Table 3: at people CYP3A4Supersomes tMmiddle compound 103,107 Lu rope relative to 127 is for the metabolic stability of Buddhist nun
* % Δ=[(deuterated material)-(non-deuterated material)] (100)/(non-deuterated material)
The metabolic stability evaluation of embodiment 5. in human liver's microsome
Microsomal assay: people's liver microsomes (20mg/mL) is available from Xenotech, LLC (Lenexa, KS).β-the Triphosphopyridine nucleotide, reduced (NADPH) of reduction form, magnesium chloride (MgCl 2) and methyl-sulphoxide (DMSO) purchased from Sigma-Aldrich.
The mensuration of metabolic stability: the test-compound stock solution preparing 7.5mM in DMSO.The stock solution acetonitrile (ACN) of this 7.5mM is diluted to 12.5-50 μM.(pH7.4, containing 3mM MgCl at the potassium phosphate buffer of 0.1M for people's liver microsomes of 20mg/mL 2) in be diluted to 0.625mg/mL.The microsome of this dilution is added in the hole of 96-hole deep well polypropylene plate in triplicate.10 μ L equal portions of the test-compound of 12.5-50 μM are added in microsome, and mixture is preheated 10 minutes.Add the NADPH solution of preheating with initiation reaction.Final reaction volume is 0.5mL, and is included in the potassium phosphate buffer (MgCl of pH7.4,3mM of 0.1M 2) in 0.5mg/mL people's liver microsomes, the test-compound of 0.25-1.0 μM and the NADPH of 2mM.This reaction mixture is incubation at 37 DEG C, and 0,5,10,20 and 30 minute time, pipette 50 μ L equal portions, adds to and has in the shallow bore hole 96-orifice plate of the ice-cold CAN of interior target with stopped reaction containing 50 μ L.This plate is stored 20 minutes at 4 DEG C, and after this 100 μ L water are added in the hole of plate, centrifugal to make the protein balling-up of precipitation afterwards.Supernatant liquor is transferred in another 96-orifice plate, and by analyzing residual size of population with the mass spectrometric LC-MS/MS of Applied Bio-systems API4000.Same program is followed to the compound of non-deuterated formula I or formula A and positive control CYP1A (1 μM).Test in triplicate.
Data analysis: the external t from % residual parent (ln), the linear regression slope of incubative time relation being calculated to test-compound 1/2:
External t 1/2=0.693/k
K=-[% remains parent (ln) to the slope of the linear regression of incubative time]
Data analysis is carried out with Microsoft Excel Software.
Without the need to further illustrating, it is believed that those of ordinary skill in the art can utilize description above and illustrative embodiment to prepare and use compound of the present invention and the method for enforcement request protection.Should be appreciated that, above-mentioned discussion and embodiment just illustrate some detailed description of preferred embodiments.Various improvement and Equivalent can be made without departing from the spirit and scope of the invention, and this will be apparent for those of ordinary skill in the art.

Claims (11)

1. the compound of formula I:
Or its pharmacy acceptable salt, wherein:
Y 6, Y 7and Y 8be hydrogen separately, and described compound is selected from arbitrary compound listed in Table:
Compound Y 1 Each Y 2 Each Y 3 Y 4 Each Y 5 100 H H H D H 101 H H H H D 102 H H H D D 103 H H D H H 104 H H D D H 105 H H D H D 106 H H D D D 107 H D H H H 108 H D H D H 109 H D H H D 110 H D H D D 111 H D D H H 112 H D D D H 113 H D D H D 114 H D D D D
115 D H H H H 116 D H H D H 117 D H H H D 118 D H H D D 119 D H D H H 120 D H D D H 121 D H D H D 122 D H D D D 123 D D H H H 124 D D H D H 125 D D H H D 126 D D H D D 128 D D D D H 129 D D D H D 130 D D D D D
Wherein any atom not being designated as deuterium exists with its natural isotopic abundance.
2. the compound of formula I:
Or its pharmacy acceptable salt, wherein:
Y 6, Y 7and Y 8be deuterium separately, and described compound is selected from arbitrary compound listed in Table:
Compound Y 1each Y 2each Y 3y 4each Y 5
200 H H H D H 201 H H H H D 202 H H H D D 203 H H D H H 204 H H D D H 205 H H D H D 206 H H D D D 207 H D H H H 208 H D H D H 209 H D H H D 210 H D H D D 211 H D D H H 212 H D D D H 213 H D D H D 214 H D D D D 215 D H H H H 216 D H H D H 217 D H H H D 218 D H H D D 219 D H D H H 220 D H D D H 221 D H D H D 222 D H D D D 223 D D H H H 224 D D H D H 225 D D H H D 226 D D H D D 227 D D D H H 228 D D D D H
229 D D D H D 230 D D D D D 231 H H H H H
Wherein any atom not being designated as deuterium exists with its natural isotopic abundance.
3. comprise the compound of claim 1 and the pharmaceutical composition of pharmaceutically acceptable carrier.
4. comprise the compound of claim 2 and the pharmaceutical composition of pharmaceutically acceptable carrier.
5. inclusion compound 127
With the pharmaceutical composition of pharmaceutically acceptable carrier.
6. the composition any one of claim 3-5, comprises the therapeutical agent being selected from Revlimid, LBH589, capecitabine, Exemestane and combination thereof further.
7. the purposes in the medicine of the compound of claim 1 or 2 or its pharmaceutically acceptable one or more activity in for the preparation of T suppression cell in JAK1 or JAK2.
8. the purposes in the medicine of compound 127 or its pharmacy acceptable salt one or more activity in for the preparation of T suppression cell in JAK1 or JAK2
9. the compound of claim 1 or 2 or the pharmaceutical composition of any one of claim 3-5 are for the preparation of the purposes in treatment myelofibrosis, carcinoma of the pancreas, prostate cancer, mammary cancer, leukemia, non-Hodgkin lymphoma, multiple myeloma, psoriatic or its medicine combined.
10. the purposes of claim 9, wherein said myelofibrosis is myelofibrosis after myelofibrosis after PMF, polycythemia vera, primary thrombocytosis, primary thrombocytosis or its combination.
The purposes of 11. claims 9, described medicine be selected from Revlimid, LBH589, capecitabine, Exemestane and combination thereof therapeutic agent use.
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