CN104086551B - Compound and its production and use - Google Patents
Compound and its production and use Download PDFInfo
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- CN104086551B CN104086551B CN201410251204.2A CN201410251204A CN104086551B CN 104086551 B CN104086551 B CN 104086551B CN 201410251204 A CN201410251204 A CN 201410251204A CN 104086551 B CN104086551 B CN 104086551B
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- 0 C=CC(Nc1nc(NC2(CC3C4)*3I4CC2)nc2c1nc[n]2C(CC1)CCN1C(C=C)=O)=O Chemical compound C=CC(Nc1nc(NC2(CC3C4)*3I4CC2)nc2c1nc[n]2C(CC1)CCN1C(C=C)=O)=O 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
Abstract
The invention provides compound and its production and use, this compound is the stereoisomer of compound, tautomer, pharmaceutical active metabolite, officinal salt, hydrate, solvate or prodrug shown in compound shown in Formulas I or Formulas I, wherein, X, R1、R2It is defined as in the description.This compound can be as inhibitors of kinases.
Description
Technical field
The present invention relates to field of medicaments, concrete, the present invention relates to compound and its production and use, more specifically
, the present invention relates to compound and preparation method thereof, pharmaceutical composition, compound and the pharmaceutical composition use in preparing medicine
On the way.
Background technology
Bruton tyrosine kinase (Bruton's tyrosine kinase, BTK) is that the one of Tec kinase families is non-to be subject to
Body tyrosine kinase is B cell growth, activate, signal conducts and the key regulators of survival, at B-cell receptor (BCR) signal
Transduction plays a significant role.When activating BCR, first BTK is activated by other tyrosine kinase (such as Lyn and SYK), causes B
Cell proliferation obtains activation with the required transcription factor of differentiation.In addition, BTK has also assisted in and has migrated with B cell and stick phase
The receptors signal transduction closed, including Chemokine receptor CXCR4, CXCR5 and adhesion molecule (integrin).BTK kinases is lived
Jump out of control, cause the random breeding of cell cause or promote canceration.
BTK inhibitor ibrutinib obtains FDA in November, 2013 to be ratified for treating lymphoma mantle cell, in February, 2014
Granted treatment chronic lymphocytic leukemia.Ibrutinib can be with the cysteine residues selectivity on BTK, irreversibility
The strong covalent bond of formation, suppression malignant B cell in overacfivity cells survival signal transmission thus reach anticancer
Effect, ibrutinib is also the BTK inhibitor of a currently the only listing.But ibrutinib dissolubility is low and blood plasma egg
White combination rate (PPB) is high, oral administration biaavailability is low, directly results in the oral rear curative effect of patient the highest.
Therefore, current BTK inhibitor still haves much room for improvement.
Summary of the invention
It is contemplated that solve one of above-mentioned technical problem the most to a certain extent or provide at a kind of useful business
Industry selects.To this end, it is an object of the present invention to propose a kind of compound as inhibitors of kinases.
It is a further object to provide compound shown in formula I or its stereoisomer, tautomer,
The method of pharmaceutical active metabolite, officinal salt, hydrate, solvate or prodrug and intermediate.
It is a further object to provide the pharmaceutical composition of a kind of compound comprising the present invention, described medicine group
Compound comprises the change of at least one present invention of one or more pharmaceutically acceptable excipient and therapeutically effective amount further
Compound or its stereoisomer, tautomer, pharmaceutical active metabolite, officinal salt, hydrate, solvate or prodrug.
It is a further object to provide compound or its stereoisomer, tautomer, the medicine of the present invention
Active metabolite, officinal salt, hydrate, solvate or the prodrug purposes in preparing medicine.Enforcement according to the present invention
Example, described medicine as BTK inhibitor, can be treated the disease mediated by B cell, is used for preparing treatment tumor disease, proliferative
The medicine of disease, allergic disease, autoimmune disease and diseases associated with inflammation.
The these and other objects of compound shown in the present invention, feature and advantage are describing in detail disclosed in this patent subsequently
Middle disclosure.
The present invention is described below in detail:
In a first aspect of the present invention, the present invention proposes a kind of compound.According to embodiments of the invention, described chemical combination
Thing is the stereoisomer of compound shown in compound shown in Formulas I or Formulas I, tautomer, pharmaceutical active metabolite, pharmaceutically acceptable
Salt, hydrate, solvate or prodrug,
Wherein, X is selected from one of following: substituted or unsubstituted phenyl, substituted or unsubstituted 3 yuan to 7 yuan saturated or
Unsaturated carbocyclic, substituted or unsubstituted 8 yuan to 10 yuan saturated or unsaturated dicyclos or aryl rings, substituted or unsubstituted have
1 to 4 heteroatomic 5 yuan to 6 yuan bicyclic heteroaryl rings, substituted or unsubstituted there are 1 to 3 heteroatomic 4 yuan to 7 yuan satisfy
With or unsaturated heterocycle, substituted or unsubstituted have 1 to 5 heteroatomic 7 yuan to 10 yuan saturated or unsaturated bicyclic heterocycle,
Substituted or unsubstituted have 1 to 5 heteroatomic 8 yuan to 10 yuan bicyclic heteroaryl rings；R1For selected from-R, halogen ,-OR ,-O
(CH2)aOR、-CN、-NO2、-SO2R、-SO2N(R)2、-SOR、-C(O)R、-CO2R、-C(O)N(R)2、-NRC(O)R、-NRC(O)
NR2、-NRSO2R and-N (R)2In any one；R2For selected from-R, halogen ,-OR ,-O (CH2)aOR、-CN、-NO2、-SO2R、-
SO2N(R)2、-SOR、-C(O)R、-CO2R、-C(O)N(R)2、-NRC(O)R、-NRC(O)NR2、-NRSO2R and-N (R)2In appoint
Meaning one；Wherein, a is the integer of 1 to 5, and R group is each independently selected from one of following: hydrogen, substituted or unsubstituted C1-6
Fatty group, substituted or unsubstituted phenyl, substituted or unsubstituted there are 1 to 2 heteroatomic 4 yuan to 7 yuan heterocycles, replacements
Or unsubstituted there are 1 to 4 heteroatomic 5 yuan to 6 yuan bicyclic heteroaryl rings, described hetero atom be each independently selected from nitrogen,
Any one of oxygen and sulfur.
Further, according to embodiments of the invention,For selected from one of following:
It will be understood by those skilled in the art that according to convention used in the art, in the structural formula of the application,For describing chemical bond, described chemical bond is part or the point that is connected with core texture or framing structure of substituent group.
Thus, this specification in the whole text in, those skilled in the art can be rightGroup and substituent group thereof are carried out
Select, to provide compound or its stereoisomer, tautomerism shown in described in embodiments of the invention, stable Formulas I
Body, pharmaceutical active metabolite, officinal salt, hydrate, solvate or prodrug.
The term used in the present invention, by all stereoisomers (either mixture shape of the compounds of this invention
Formula or pure form or the purest form) all take into account.The term " stereoisomer " used in the present invention can
It is the compound of optical isomer including by having one or more chiral atom, and by around one or more keys
Limited rotation and be the compound of optical isomer.The definition of the compounds of this invention contain all possible stereoisomer and it
Mixture.The most specifically contain racemic form and there is the separated optical isomer of given activity.Can pass through
Physical method resolution of racemic form, described physical method include but not limited to fractional crystallization, diastereo-isomerism derivant point
From or crystallization or separated by chiral column chromatography.Single optical isomer can be obtained by racemic modification by conventional method,
Described conventional method includes but not limited to form salt with optical activity acid, then crystallizes.
The term used in the present invention, compound shown in Formulas I and salt thereof can be existed by their tautomeric form,
In described tautomeric form, Hydrogen transfer is to the chemical bond between the other parts of molecule, and molecule Atom therefore
Reset.It should be understood that all tautomeric forms (as long as they can exist), be just included in the invention.This
Outward, shown in formula I, compound can have transisomer and cis-isomer.
The term used in the present invention, " officinal salt " is that compound shown in formula I is anti-with mineral acid or organic acid
The conventional nontoxic salts that should be formed.Such as, the nontoxic salts of described routine can be by compound and mineral acid or organic shown in formula I
Acid reaction prepares, and described mineral acid includes hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, amidosulfonic acid and phosphoric acid etc., and described organic
Acid include citric acid, tartaric acid, lactic acid, acetone acid, acetic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid, methanesulfonic acid, LOMAR PWA EINECS 246-676-2, ethyl sulfonic acid,
Naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propanoic acid, oxalic acid, trifluoroacetic acid, stearic acid, flutter acid, hydroxyl
Base maleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, para-anilinesulfonic acid, Aspirin and
Isethionic acid etc.；Or compound shown in formula I and propanoic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, Herba Marsileae Quadrifoliae
Sodium salt that fruit acid, tartaric acid, citric acid, aspartic acid or glutamic acid are formed with inorganic base after forming ester again, potassium salt, calcium salt, aluminum
Salt or ammonium salt；Or methylamine salt, ethylamine salt or the ethanolamine salt that compound shown in formula I is formed with organic base；Or formula I institute
Show compound and lysine, arginine, ornithine formed after ester again with hydrochloric acid, hydrobromic acid, Fluohydric acid., sulphuric acid, nitric acid, phosphoric acid shape
The corresponding inorganic acid salt become or the corresponding acylate formed with formic acid, acetic acid, picric acid, methanesulfonic acid and ethyl sulfonic acid.
The term used in the present invention, described compound is once given experimenter, described chemical combination by " prodrug " expression
Thing just carries out chemical conversion by metabolic process or chemical process, thus obtain compound shown in Formulas I and/or its salt and/or
Solvate.Any compound that can convert to provide bioactive substance (i.e. compound shown in Formulas I) in vivo is at this
The bright prodrug in scope and spirit.Such as, the compound containing carboxyl can hydrolyzable ester on physiology, it is by body
Interior hydrolysis serves as prodrug to obtain compound shown in Formulas I itself.Described prodrug preferred oral is administered, this is because hydrolysis is being permitted
Main generation under the influence of digestive enzyme in the case of Duo.When ester itself is active or hydrolysis occurs in blood, can use
Parenteral.
Should also be understood that the hydrate of compound shown in formula I, solvate (such as methylate, DMSO
Compound) also within the scope of the invention.The method of solvation is well known in the art.
In a second aspect of the present invention, the present invention proposes compound shown in a kind of formula Ι or its stereoisomer, mutually
The method of tautomeric, pharmaceutical active metabolite, officinal salt, hydrate, solvate or prodrug and intermediate.
According to embodiments of the invention, compound shown in formula Ι or its stereoisomer, tautomer, medicine work
Property metabolite, officinal salt, hydrate, the method for solvate or prodrug include: (1) makes compound shown in described formula 1 and formula 2
Shown compound contacts, in order to obtain compound shown in formula 3；(2) compound shown in described formula 3 and chemical combination shown in formula 4 are made
Thing (acryloyl chloride) contacts, in order to obtain compound shown in formula 5；(3) compound shown in described formula 5 and formula 6a shownization are made
Compound contacts, in order to obtain compound shown in Formulas I.
Wherein, X, R1And R2For as defined above.
Inventor finds, the method utilizing the present invention can fast and effeciently compound shown in formula I or it is three-dimensional
Isomer, tautomer, pharmaceutical active metabolite, officinal salt, hydrate, solvate or prodrug, and synthetic route is short,
Environmental friendliness, the yield of target product and purity are higher, and raw material is easy to get, operates and post processing industrialized production simple, applicable.
Below the conventional method of compound shown in formula I employed in embodiments of the invention is described:
1) preparation of compound (intermediate) shown in formula 3
Compound shown in formula 1 is made to contact with compound shown in formula 2, in order to obtain compound shown in formula 3；
Specifically, there-necked flask adds compound and oxolane (THF) shown in compound, formula 2 shown in formula 1, then
Add cesium carbonate, reflux 12～24 hours, after reaction terminates, be concentrated to give oily liquid, first dissolve with methanol, more heavily tie with acetone
Crystalline substance, separates out solid, filters, and is dried to obtain compound shown in formula 3, it is not necessary to be further purified.
2) preparation of compound (intermediate) shown in formula 5
Compound shown in described formula 3 is made to contact with compound shown in formula 4, in order to obtain compound shown in formula 5；
Specifically, compound shown in formula 3 is mixed with N-Methyl pyrrolidone (NMP) at-5 DEG C～5 DEG C, is slowly added to
Compound shown in formula 4, and at 0 DEG C, insulated and stirred is reacted 60 minutes, is subsequently adding water and continues to stir half an hour, is subsequently added into full
And NaHCO3Basified aqueous solution, is extracted with ethyl acetate 3 times subsequently.The ethyl acetate that successively use water, saline washing merge
Extract, Na2SO4It is dried and under reduced pressure concentrates, obtaining compound shown in formula 5.
3) preparation of compound shown in Formulas I
Compound shown in described formula 5 is made to contact with compound shown in formula 6a, in order to obtain compound shown in Formulas I；
Specifically, by compound shown in compound, formula 6a shown in formula 5 (compound shown in formula 5 and compound shown in formula 6a
Mol ratio is 1:1.5) add N-Methyl pyrrolidone solution in, carry out microwave irradiation (100 DEG C～200 DEG C, 5～30 points
Clock).Cooling reactant mixture, dilute with water, and it is extracted with ethyl acetate 3 times.The acetic acid second that successively use water, saline washing merge
Ester extract, Na2SO4It is dried and under reduced pressure concentrates, then dissolving with isopropanol, recrystallization at-5 DEG C～5 DEG C, filtering, obtain white
Color solid, drying under reduced pressure, obtain compound shown in Formulas I.
In an embodiment of the present invention, compound shown in described Formulas I can be: compound shown in Formulas I or its stereoisomer,
Tautomer, pharmaceutical active metabolite, officinal salt, hydrate, solvate or prodrug.
It was found by the inventors of the present invention that the compound of the present invention also demonstrates the dissolubility of raising and is less susceptible to from cell
The character of middle outflow, thus improve bioavailability.
In a third aspect of the present invention, the present invention provides a kind of pharmaceutical composition, chemical combination shown in the contained I of described compositions
In thing or its stereoisomer, tautomer, pharmaceutical active metabolite, officinal salt, hydrate, solvate or prodrug
At least one.According to embodiments of the invention, described pharmaceutical composition may further include pharmaceutically acceptable excipient.
This Pharmaceutical composition can also comprise the conventional additives such as odorant agent, flavouring agent further.
Pharmaceutical composition provided by the present invention preferably comprises compound shown in the Formulas I that weight ratio is 0.1%～99% and makees
For active ingredient, it is further preferred that compound shown in Formulas I as active component account for pharmaceutical composition gross weight 10%～
40%, remainder is pharmaceutically acceptable carrier and/or conventional additives.
Compound provided by the present invention and pharmaceutical composition can be various ways, such as tablet, capsule, injection, note
Penetrate with powder pin, powder, syrup, solution shape, suspension and aerosol etc., it is possible to be present in the carrier of suitable solid or liquid
Or in diluent and suitable in injection or the disinfector that instils.
The various dosage forms of the pharmaceutical composition of the present invention can be prepared according to the customary preparation methods of pharmaceutical field.The present invention's
Compound and pharmaceutical composition can be to mammal Clinical practice, including humans and animals, can pass through mouth, nose, skin, lung or
The administration of gastrointestinal tract etc..No matter using which kind of instructions of taking, the optimal dose of individual should be according to concrete therapeutic scheme
Fixed.It is to be gradually increased dosage until finding optimal dosage under normal circumstances from the beginning of low dose.Most preferably it is administered way
Footpath is oral.
In a fourth aspect of the present invention, the present invention proposes compound shown in formula Ι or its stereoisomer, tautomerism
Body, pharmaceutical active metabolite, officinal salt, hydrate, solvate or the prodrug purposes in preparing medicine.According to the present invention
Embodiment, described medicine be used as inhibitors of kinases.According to embodiments of the invention, the compound scalable kinases of the present invention is lived
Property, including BTK is adjusted, can be used as inhibitors of kinases, the other type of kinases that can be regulated by the compounds of this invention is lived
Property includes but not limited to the member of Tec family, such as BMX, BTK, ITK, Txk and Tec and their mutant.Therefore, above-mentioned medicine
Thing effectively as BTK inhibitor, and then can treat the disease mediated by B cell, is used for treating tumor disease, proliferative disease
Disease, allergic disease, autoimmune disease and diseases associated with inflammation.
Further, compound shown in Formulas I of the present invention has higher BTK according to Shandong for Buddhist nun than existing BTK inhibitor
Kinase inhibiting activity.And, after the restructuring BTK of compound pretreatment shown in the Formulas I of the present invention, with the cultivation basic weight without inhibitor
After backwashing is washed, and its activity will not be recovered, and shows that BTK is by the irreversible suppression of the compound of the present invention.
Concrete, medicine of the present invention is applicable to treat one or more diseases relevant with BTK activity, described
Disease includes but not limited to solid tumor, lymphoma, soft tissue sarcoma, lymphocytic lymphoma, lymphoma mantle cell, melanin
Tumor, multiple myeloma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic bone
Myelogenous leukemia, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus (sle), psoriasis, rheumatoid
Property spondylitis, gouty arthritis etc..
Further, in Mus arthritis model (CIA) experiment that bovine collagen is protein induced, the chemical combination of the embodiment of the present invention
Thing shows and replaces the more preferable curative effect of Buddhist nun than according to Shandong.
Of the present invention as compound shown in the Formulas I of inhibitors of kinases, it, as BTK inhibitor, successfully overcomes
The defect that the existing BTK inhibitor dissolubility of ibrutinib medicine own is low, oral administration biaavailability is low, has good clinic
Application and medical usage.
The additional aspect of the present invention and advantage will part be given in the following description, and part will become from the following description
Obtain substantially, or recognized by the practice of the present invention.
Detailed description of the invention
Embodiments of the invention are described below in detail.The embodiments described below is exemplary, is only used for explaining this
Bright, and be not considered as limiting the invention.Unreceipted concrete technology or condition in embodiment, according to the literary composition in this area
Offer described technology or condition or carry out according to product description.Agents useful for same or instrument unreceipted production firm person, all
For can by city available from conventional products.
The embodiment provides compound shown in Formulas I or its stereoisomer, tautomer, pharmaceutically active generation
Thank thing, officinal salt, hydrate, solvate or prodrug, compound shown in formula Ι or its stereoisomer, tautomerism
The method of body, pharmaceutical active metabolite, officinal salt, hydrate, solvate or prodrug and intermediate, pharmaceutical composition, with
And the purposes that the compound of the present invention and pharmaceutical composition are in preparing medicine.
Embodiment 1: compound (intermediate) shown in formula 3
There-necked flask adds compound shown in compound (17.0 grams, 0.1 mole), formula 2 shown in formula 1 (11.1 grams, 0.11
Mole) and oxolane (800 milliliters), adding cesium carbonate (39.1 grams, 0.12 mole), reflux 15 hours, reaction terminates
After, it is concentrated to give oily liquid, first dissolves with methanol (60 milliliters), then stir recrystallization with acetone (180 milliliters), separate out solid, mistake
Filter, is dried to obtain compound (18.7 grams, yield 74.0%) shown in formula 3, it is not necessary to be further purified.
Embodiment 2: compound (intermediate) shown in formula 3
There-necked flask adds compound shown in compound (17.0 grams, 0.1 mole), formula 2 shown in formula 1 (15.2 grams, 0.15
Mole) and oxolane (800 milliliters), adding cesium carbonate (48.9 grams, 0.15 mole), reflux 12 hours, reaction terminates
After, it is concentrated to give oily liquid, first dissolves with methanol (60 milliliters), then stir recrystallization with acetone (180 milliliters), separate out solid, mistake
Filter, is dried to obtain compound (18.2 grams, yield 72.1%) shown in formula 3, it is not necessary to be further purified.
Embodiment 3: compound (intermediate) shown in formula 3
There-necked flask adds compound shown in compound (17.0 grams, 0.1 mole), formula 2 shown in formula 1 (10.6 grams,
0.105 mole) and oxolane (800 milliliters), add cesium carbonate (39.1 grams, 0.12 mole), reflux 24 hours, instead
After should terminating, it is concentrated to give oily liquid, first dissolves with methanol (60 milliliters), then stir recrystallization with acetone (180 milliliters), separate out solid
Body, filters, and is dried to obtain compound (18.4 grams, yield 72.8%) shown in formula 3, it is not necessary to be further purified.
Embodiment 4: compound (intermediate) shown in formula 5
By compound shown in formula 3 (25.3 grams, 0.1 mole) and N-Methyl pyrrolidone (300 milliliters) at-5 DEG C～5 DEG C
Mixing, is slowly added to compound shown in formula 4 (19.9 grams, 0.22 mole), and insulated and stirred reaction 60 minutes at 0 DEG C, then
Add water (50 milliliters) to continue to stir half an hour, be subsequently added into saturated NaHCO3Basified aqueous solution, uses ethyl acetate subsequently
Extract 3 times, each 300 milliliters.The acetic acid ethyl ester extract that successively use water, saline washing merge, Na2SO4Be dried and under reduced pressure
Concentrate, obtain compound shown in formula 5 (23.9 grams, yield 66.3%).
Embodiment 5: compound shown in formula I-1
According to compound shown in scheme described below, step formula I-1.Specific as follows:
Compound (15.2 grams, 0.15 mole) shown in compound shown in formula 5 (36.1 grams, 0.1 mole), formula 6a-1 is added
In the solution of N-Methyl pyrrolidone (600 milliliters), carry out microwave irradiation (100 DEG C, 30 minutes).Cooling reactant mixture, uses
The dilution of 500 milliliters of water, and be extracted with ethyl acetate 3 times, each 400 milliliters.The ethyl acetate that successively use water, saline washing merge
Extract, Na2SO4It is dried and under reduced pressure concentrates, then by isopropanol 300 milliliters dissolving, recrystallization at-5 DEG C～5 DEG C, mistake
Filter, obtains white solid, drying under reduced pressure, obtains compound shown in Formulas I-1 (must measure 34.5 grams, yield 78.0%).
Embodiment 6: compound shown in formula I-2
Compound (25.1 grams, 0.15 mole) shown in compound shown in formula 5 (36.1 grams, 0.1 mole), formula 6a-2 is added
In the solution of N-Methyl pyrrolidone (600 milliliters), carry out microwave irradiation (160 DEG C, 10 minutes).Post processing, with embodiment 5, obtains
Compound shown in Formulas I-2 (must measure 40.2 grams, yield 81.6%).
Embodiment 7: compound shown in formula I-3
Compound (30.8 grams, 0.15 mole) shown in compound shown in formula 5 (36.1 grams, 0.1 mole), formula 6a-2 is added
In the solution of N-Methyl pyrrolidone (500 milliliters), carry out microwave irradiation (200 DEG C, 5 minutes).Post processing, with embodiment 5, obtains
Compound shown in Formulas I-3 (must measure 38.1 grams, yield 72.0%).
According to embodiments of the invention, in like manner, compound shown in Formulas I-4 is same to the preparation method of compound shown in Formulas I-26
In embodiment 5 to embodiment 7, compound shown in formula I-1 is to the method for compound shown in Formulas I-3.Chemical combination shown in its Chinese style 5
Thing is 1:1.5 with the molar ratio of compound shown in formula 6a.Such as, with compound shown in formula 6a-15 as initiation material, formula is used
Compound shown in 5 contacts with compound shown in formula 6a-15, and finally obtain is compound shown in corresponding Formulas I-15.Tool
Body compound and data see table 1.
Table 1:
Embodiment 8: the scheme that human B cell stimulates
Human B cell is from 150ml Blood purification.Specifically, blood with PBS dilute 1/2, through Ficoll density gradient from
The heart.The B cell separating kit II from Milenyi (Auburn, CA) is used to separate B by Solid phase from mononuclear cell
Cell.Then, every hole 50000B cell 10 μ g/ml goat F (ab ') 2 anti-human IgM antibodies (Jackson in 96 orifice plates
ImmunoResearch Laboratories, West Grove, PA) stimulate.The Formulas I-1 prepared in embodiment 1-7～formula
Compound DMSO shown in I-26 (dimethyl sulfoxide) dilutes and adds to cell.Final concentration of the 0.5% of DMSO.Make after 3 days
Propagation is measured with PromegaCellTiter-Glo (Madison, WI).Found that compound quilt shown in Formulas I of the present invention
Test is all activated.
Embodiment 9: people's recombinant BTK enzymatic determination
Test compound, people recombinant BTK (1nM, Invitrogen is added in V-Bottom 384 orifice plate
Corporation), Fluoresceinated peptide (fluoresceinated peptide) (1.5 μMs), ATP (20 μMs) and mensuration buffer
(20mM HEPES(pH 7.4)、10mM MgCl2, 0.015%Brij35 and 4mM DTT solution in 1.6%DMSO), its
Middle final volume is 30 μ L.After incubated at room 60 minutes, terminate by adding 45 μ l35mM EDTA in each sample
Reaction.By to fluorogenic substrate and Phosphorylated products on Caliper LabChip3000 (Caliper, Hopkinton, MA)
Carry out electrophoretic separation reactant mixture is analyzed.By with as 100% suppression control reaction without enzyme and as 0%
The no inhibitor control of suppression is compared to calculate suppression data.Generate dose response curve to determine that suppression 50% kinases is lived
Concentration (IC50) needed for property.Compound is dissolved in dimethyl sulfoxide (DMSO) with 10 mM, then comments with 11 concentration
Valency.Use this mensuration, determine that compound of the present invention and existing BTK inhibitor compound replace the IC50 value of Buddhist nun according to Shandong.Knot
Fruit is shown in Table 2.
Table 2 shows the activity in selected the compounds of this invention BTK kinase inhibition in vitro mensuration.Compound number pair
Compound number in Ying Yubiao 1.Activity is appointed as IC50≤10 nM that the compound of " A " provides；Activity is appointed as " B's "
The IC50 that compound provides is 10-100 nM；The IC50 of the compound offer that activity is appointed as " C " is 100-1000 nM；Activity
The IC50 of the compound offer being appointed as " D " is 1000-10000 nM；And activity is appointed as the IC50 that the compound of " E " provides
≥10000 nM.Compound shown in Formulas I of the present invention has higher BTK kinase inhibiting activity than according to Shandong for Buddhist nun.And, this
After the compound pretreatment restructuring BTK of invention, with the culture medium repeated washing without inhibitor, its activity will not be recovered, show
BTK is by the irreversible suppression of these compounds.
Table 2:BTK suppresses data
| Compound number | The IC50 (μM) of suppression BTK | Activity is specified |
| I-1 | 0.018 | A |
| I-2 | 0.025 | A |
| I-3 | 0.016 | A |
| I-4 | 0.54 | A |
| I-5 | 1.2 | A |
| I-6 | 0.41 | A |
| I-7 | 0.94 | A |
| I-8 | 1.2 | A |
| I-9 | 1.7 | A |
| I-10 | 0.45 | A |
| I-11 | 0.58 | A |
| I-12 | 0.028 | A |
| I-13 | 0.049 | A |
| I-14 | 0.80 | A |
| I-15 | 1.7 | A |
| I-16 | 2.3 | A |
| I-17 | 0.44 | A |
| I-18 | 0.050 | A |
| I-19 | 0.045 | A |
| I-20 | 0.39 | A |
| I-21 | 0.038 | A |
| I-22 | 1.3 | A |
| I-23 | 0.50 | A |
| I-24 | 0.80 | A |
| I-25 | 0.016 | A |
| I-26 | 0.48 | A |
| According to Shandong for Buddhist nun | 2.5 | A |
Embodiment 10: the Mus arthritis model (CIA) that bovine collagen is protein induced
1, Emulsion preparation: weigh bovine collagen and be dissolved in acetic acid, be made into the bovine collagen solution that concentration is 8mg/ml, 4 degrees Celsius
Overnight.In bovine collagen solution, add isopyknic complete Freund's adjuvant (CFA, 1mg/ml), be made into final concentration of 4mg/ml's
Bovine collagen CFA mixed liquor, then be homogenized with high speed homogenizer on ice wet, until forming white Emulsion.
At the 0th day, by rat with II type bovine collagen in complete Freund's adjuvant (CFA) Emulsion injection, on back
Several positions intradermal injection (i.d.) 50 microlitre.Collagen emulsion is provided in the about the 7th day alternative site at tail base portion or back
Booster injection (i.d.) 50 microlitre.Initial collagen inject after within 12 days, be generally observed arthritis to 14 days.From the 14th
It rises, and (arthritic evaluation) as described below can evaluate the arthritic progress of animal.
Arthritic evaluation:
In two kinds of models, marking system is used to carry out quantitatively to the inflammatory development in pawl and limb joint, described scoring system
System includes the assessment to 4 pawls of the standard as described below, and standards of grading are shown in Table 3.
Table 3: standards of grading
| Score value | Corresponding symptom |
| 0 point | Without erythema and redness/or rubescent |
| 1 point | Near nearly shank or erythema or mild redness, pawl or the swelling of a toe and/or rubescent occur in ankle joint or metatarsal |
| 2 points | Ankle joint and metatarsal slight erythema and swelling, or two or more arthroncuss |
| 3 points | Ankle, carpal joint and metatarsal moderate erythema and swelling, or the overall swelling of pawl, relate to more than two joint |
| 4 points | Whole pawl and toe are all serious red and swollen, severe arthritic |
21st day, being grouped all animals, (i.e. animal morbidity number accounts for sum to make every treated animal body weight, sickness rate
Percentage ratio) basically identical.Starting oral administration gavage at the 21st day to be administered, once a day (QD), every treated animal dosage is shown in Table
4.After being administered 14 days, calculate each group of medicine suppression ratio to rats with arthritis.
Table 4:
| Group | Number of animals | It is administered | Dosage | Administration time | Dosage rate | Suppression ratio |
| 1 | 10 | Normal saline | 10mg/kg | 14 days | QD | / |
| 2 | 10 | Formula I-2 compound | 5mg/kg | 14 days | QD | 58.22% |
| 3 | 10 | Formula I-11 compound | 3mg/kg | 14 days | QD | 42.78% |
| 4 | 10 | Formula I-11 compound | 10mg/kg | 14 days | QD | 72.31%* |
| 5 | 10 | Formula I-18 compound | 10mg/kg | 14 days | QD | 54.46% |
| 6 | 10 | According to Shandong for Buddhist nun | 10mg/kg | 14 days | QD | 56.20% |
Note: * p ＜ 0.01
As can be seen from Table 4, the 6th group (according to Shandong for Buddhist nun, 10mg/kg) and the 2nd group of (formula I-2 compound, the 5mg/ of the present invention
Kg), the 5th group of (formula I-18 compound, 10mg/kg) suppression ratio is suitable.But the 4th of the present invention the group (formula I-11 compound,
Suppression ratio 10mg/kg) is apparently higher than the 6th group (according to Shandong for Buddhist nun, 10mg/kg).
Embodiment 11: water-soluble measures
As a example by compound I-2, the water solubility of compound I-2 of the present invention is made comparisons for Buddhist nun with according to Shandong.Measure
Method is as follows:
Equilbrium solubility is measured in the aqueous buffer solution that pH is 7.4.PH be 7.4 buffer solution by with 10 moles/
The sodium hydroxide risen is by the pH regulator of the sodium dihydrogen phosphate of 0.07M to 7.4, and the ionic strength of this solution is 0.15.Near
The powder of few 1 milligram and the buffer mixing of 1 milliliter, preparation concentration is more than the mixture of 1 mg/ml.These samples are shaken
Swing more than 2 hours, and at room temperature stand overnight.Then the nylon syringe passing through 0.45 first saturated with sample μm filters
Device filtered sample, continuous sampling 2 times from filtrate.Make reference with the standard solution of preparation in 50% methanol, surveyed by HPLC
Determine filtrate.The dissolubility of compound I-2 is 44 mg/ml, and the dissolubility replacing Buddhist nun according to Shandong is 12 mg/ml.
Embodiment 12: for the capsule of oral administration
| Composition | % w/w |
| Active component | 20.0% |
| Lactose | 79.5% |
| Magnesium stearate | 0.5% |
Composition in upper table is mixed, and active component (compound of the present invention) distributes in capsule, is prepared as altogether
1000 grams of powder, fill becomes capsule, the active component of every seed lac capsule to be 200mg.
Embodiment 13: for the capsule of oral administration
| Composition | % w/w |
| Active component | 40.0% |
| Pregelatinized corn starch | 59.5% |
| Magnesium stearate | 0.5% |
Composition in upper table is mixed, and active component (compound of the present invention) distributes in capsule, is prepared as altogether
1000 grams of powder, fill becomes capsule, the active component of every seed lac capsule to be 400mg.
Embodiment 14: tablet for oral administration
| Composition | % w/w |
| Active component | 20.0% |
| Lactose | 75.5% |
| Cross-linking sodium carboxymethyl cellulose | 3.0% |
| Polyvinylpyrrolidone | 1.0% |
| Magnesium stearate | 0.5% |
Composition in upper table is mixed, and uses solvent such as alcohol granulation.Then preparation is dried, is prepared as 1000 altogether
Gram powder, and be formed as tablet with suitable tablet machine, the active component (compound of the present invention) of every is 200mg.
Embodiment 15: for the injection of drug administration by injection
| Composition | % w/w |
| Active component | 0.20 gram |
| Sodium chloride | Appropriate with isotonic |
| Cross-linking sodium carboxymethyl cellulose | 100 milliliters |
Active component (compound of the present invention) is dissolved in partial syringe water.The most under agitation add q.s
Sodium chloride so that solution is isotonic.With remaining water for injection, this solution is supplied weight, filters with 0.2 mum membrane filter,
And aseptically pack, obtain injection.
In the description of this specification, reference term " embodiment ", " some embodiments ", " example ", " specifically show
Example " or the description of " some examples " etc. means to combine this embodiment or example describes specific features, structure, material or feature
It is contained at least one embodiment or the example of the present invention.In this manual, the schematic representation of above-mentioned term is differed
Surely identical embodiment or example are referred to.And, the specific features of description, structure, material or feature can be any
One or more embodiments or example combine in an appropriate manner.
Although above it has been shown and described that embodiments of the invention, it is to be understood that above-described embodiment is example
Property, it is impossible to be interpreted as limitation of the present invention, those of ordinary skill in the art is without departing from the principle of the present invention and objective
In the case of above-described embodiment can be changed within the scope of the invention, revise, replace and modification.
Claims (10)
1. a compound, it is characterised in that described compound is that shown in compound shown in Formulas I or Formulas I, the solid of compound is different
Structure body or tautomer,
Wherein,
For selected from one of following:
2. the method for the compound prepared described in claim 1, it is characterised in that including:
(1) compound shown in formula 1 is made to contact with compound shown in formula 2, in order to obtain compound shown in formula 3；
(2) compound shown in described formula 3 is made to contact with compound shown in formula 4, in order to obtain compound shown in formula 5；
(3) compound shown in described formula 5 is made to contact with compound shown in formula 6a, in order to obtain compound shown in Formulas I,
Wherein,As defined in claim 1.
3. a pharmaceutical composition, it is characterised in that including:
Compound described in claim 1.
Pharmaceutical composition the most according to claim 3, it is characterised in that farther include:
Pharmaceutically acceptable excipient.
5. the compound described in claim 1 or the pharmaceutical composition described in claim 3 or 4 purposes in preparing medicine,
Described medicine is used as inhibitors of kinases.
Purposes the most according to claim 5, it is characterised in that described medicine is used as BTK inhibitor.
Purposes the most according to claim 5, it is characterised in that the disease that described medicine is mediated by B cell for treatment.
Purposes the most according to claim 5, it is characterised in that described medicine be used for treating tumor disease, proliferative disease,
At least one of allergic disease, autoimmune disease and diseases associated with inflammation.
Purposes the most according to claim 5, it is characterised in that described medicine is used for treating solid tumor, acute lymphoblastic
Leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, rheumatoid arthritis, silver
In the sick arthritis of bits, osteoarthritis, systemic lupus erythematosus (sle), psoriasis, rheumatoid spondylitis and gouty arthritis extremely
Few one.
Purposes the most according to claim 9, it is characterised in that described solid tumor be selected from lymphoma, soft tissue sarcoma,
At least one in lymphocytic lymphoma, lymphoma mantle cell, melanoma, multiple myeloma.
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| HUE031334T2 (en) * | 2006-09-22 | 2017-07-28 | Pharmacyclics Llc | Inhibitors of bruton's tyrosine kinase |
| WO2008116064A2 (en) * | 2007-03-21 | 2008-09-25 | Bristol-Myers Squibb Company | Fused heterocyclic compounds useful for the treatment of proliferative, allergic, autoimmune or inflammatory diseases |
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