CN107445981B - A kind of reactive compound for anti-treating cervicitis - Google Patents
A kind of reactive compound for anti-treating cervicitis Download PDFInfo
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- CN107445981B CN107445981B CN201710741192.5A CN201710741192A CN107445981B CN 107445981 B CN107445981 B CN 107445981B CN 201710741192 A CN201710741192 A CN 201710741192A CN 107445981 B CN107445981 B CN 107445981B
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- XRABUNLIQNAVDO-UHFFFAOYSA-N CCOc(c1c2CCC(SC(CNC(NCC3=C=C=CCC3)=O)=NC3)=C3N1)cnc2OC Chemical compound CCOc(c1c2CCC(SC(CNC(NCC3=C=C=CCC3)=O)=NC3)=C3N1)cnc2OC XRABUNLIQNAVDO-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
- C07D513/14—Ortho-condensed systems
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Abstract
The present invention relates to a kind of for treating the reactive compound of inflammatory disease such as cervicitis, the compound has the structure shown in formula (I).Body outer suppressioning test shows that reactive compound of the present invention has good inhibiting effect for Btk, in the prevention that can be consequently used for inflammatory disease such as cervicitis.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to a kind of reactive compound for anti-treating cervicitis, the present invention
Further relate to the preparation method of the reactive compound and the reactive compound be used to prepare anti-treating cervicitis drug use
On the way.
Background technology
Cervicitis is one of gynaecology's common disease, often because give a birth, miscarry or surgical injury uterine neck after, pathogen intrusion and
Cause infection.Hygienic bad or estrogen deficiency, local anti-infective energy force difference can also cause.If Cervicitis cannot be thorough in time
The treatment at bottom can cause genital inflammation, and severe patient's cause is infertile, may also be further development of cervical lesions.Therefore, actively
Anti- treating cervicitis is to preventing cervical lesions, improving WomanHealth level and family social harmony being promoted to be of great significance.
At present, treatment cervicitis has many methods, can be divided into physical therapy and medicinal treatment, physical therapy is with laser irradiation
For using carbon dioxide laser defocus irradiation, 70 watts of power, irradiation 10-15 minutes every time, 10 times are as a treatment course.This treatment
The method time is long, costly.Oral medicine treatment time is long, and body is adversely affected.Known externally applied drug is although effective in cure, but
It is that some medicine therapeutic effects are not high, easily recurs.
It can be seen that there is clearly disadvantageous and defects for therapy and medicine of the tradition to cervicitis, it would be highly desirable to
It is further improved.
Bruton's tyrosine kinase (Bruton ' s tyrosine kinase, Btk), is nonreceptor tyrosine kinase Tec
The member of family.Btk plays the role of crucial Information Conduction in hematopoietic cell, especially in autoimmunity and inflammatory disease
The B cell to play an important role in pathogenesis.Btk inflammatory disease effect by rat basophilic from blood disease cell
(RBL-2H3) model is proven.RBL-2H3 is the common model for studying mast-cell inflammatory condition.Mast cell is rich in thermophilic
Alkali grain plays a leading role in the allergic reaction of immunoglobulin E (IgE)-mediation.Small molecule disturbance ribonucleic acid
(small interfering RNA, siRNA) and LFM-A13 (an effective Btk inhibitor), can be by reducing the work of Btk
Property is come inflammatory reaction caused by reducing mast cell：In the RBL-2H3 mast cells handled through siRNA and LFM-A13, discharged
Proinflammatory mediation agent --- the content of histamine reduces 20-25%.
The present invention provides a kind of novel B tk inhibitor, can be used in the prevention of inflammatory disease such as cervicitis.
Invention content
The object of the present invention is to provide a kind of new for preventing the reactive compound of inflammatory disease such as cervicitis, specifically
Ground, the present invention relates to the compounds of formula (I) or its pharmaceutically acceptable salt, tautomer, optical isomer, solvent to close
Object, pro-drug：
In formula (I),
R、R1、R2Can be identical or different, it each independently represents：Hydrogen, halogen, C1-4 alkyl, nitro, hydroxyl, amino,
Carboxyl, C4-7 cycloalkyl, C1-4 alkoxies, C1-4 alkyl-carbonyls, C1-4 alkoxy carbonyls, C1-4 alkyl aminos or two (C1-4
Alkyl) amino, wherein, the C1-4 alkyl, C1-4 alkoxies, C1-4 alkyl-carbonyls, C1-4 alkoxy carbonyls, C1-4 alkyl ammonia
Alkyl in base, two (C1-4 alkyl) amino is also optional a selected from halogen, hydroxyl, amino, C1-4 alkoxies, C6-10 by 1-3
Aryl, C2-10 heterocycles group replaced；
R3It represents：Hydrogen, C1-4 alkyl or C4-7 cycloalkyl, wherein, the C1-4 alkyl is also optional to be selected from halogen by 1-3
Element, hydroxyl, amino, C1-4 alkoxies, C6-10 aryl group replaced；
L is represented：Singly-bound or C1-6 alkylidenes, wherein, one or more CH in the C1-6 alkylidenes2It can be optional
Ground is substituted by O, S or NH.
In an example of the compounds of this invention, the M is represented：N or CH.
In an example of the compounds of this invention, the R1It represents：Hydrogen, amino, C1-4 alkyl aminos or C1-4 alcoxyls
Base.
In an example of the compounds of this invention, the R2It represents：Hydrogen, C1-4 alkyl, C2-10 heterocycles replace
C1-4 alkyl or C1-4 alkoxies.
In an example of the compounds of this invention, the L is represented：Singly-bound or-CH2-。
In an example of the compounds of this invention, the R3It represents：C1-4 alkyl or the C1-4 alkane of C6-10 aryl substitution
Base.
Currently preferred compound is：
Compound provided by the invention is hereinafter referred to as " the compounds of this invention ".The compounds of this invention includes any form
Compound, such as free form, salt form, solvate forms and salt and solvate forms.
On the other hand, the present invention provides the compounds of this invention of salt form.
This kind of salt preferably includes pharmaceutically acceptable salt, but also includes pharmaceutically unacceptable salt, such as be used to prepare/
The salt of separation/purifying purpose.
The pharmaceutically acceptable salt of the compounds of this invention includes its acid-addition salts, and appropriate acid-addition salts are nontoxic by being formed
The acid of salt is formed.The example of the salt includes organic salt, such as acetate, aspartate, benzoate, benzene sulfonate, lemon
Lemon hydrochlorate, ethanedisulphonate, esilate, formates, fumarate, gluconate, glucuronate, lactate, malic acid
Salt, trifluoroacetate, maleate, inorganic salts, such as hydrochloride, hydrobromate, disulfate, nitrate.Appropriate alkali salt
It is formed by the alkali for forming nontoxic salts.
The compounds of this invention of free form can be converted into the respective compound of salt form；And vice versa.Trip
From the free shape that form or salt form and the compounds of this invention of solvate forms can be converted into non-solvate form
The respective compound of formula or salt form；And vice versa.
The compounds of this invention can exist in the form of isomers and its mixture；Such as tautomer, optics are different
Structure body, enantiomter, diastereoisomer.The compounds of this invention can be for example comprising asymmetric carbon atom, and therefore can be with
Enantiomter or the form of diastereoisomer and its mixture exist, such as in the form of racemate.Chemical combination of the present invention
Object can with (R)-, (S)-or (R, S)-configuration exist, be (R)-or (S)-configuration preferably on the specific position of compound.
The compounds of this invention can be given as prodrug form.Therefore, itself may have seldom pharmacological activity
Or certain derivatives without pharmacological activity are converted into when being administered on internal or body for example, by hydrolytic rupture
The compound of the present invention with required activity.This derivative is referred to as " pro-drug ".About using for pro-drug
Details can be found in Pro-drugs as Novel Delivery Systems, Vol.14, ACS Symposium Series
(T.Higuchi and W.Stella) and Bioreversible Carriers in Drug Design, Pergamon
Press, 1987 (editors：E.B.Roche,American Pharmaceutical Association).
Group definition
Terms used herein " halogen " should refer to fluorine, chlorine, bromine and iodine.Halogen is preferably fluorine, chlorine or bromine, more preferably chlorine or
Bromine.
Terms used herein " alkyl " no matter individually or as substituent group part using include straight chain and branch, alkyl
1-6 carbon atom, further preferably 1-4 carbon atom are preferably comprised, the example of alkyl such as C1-4 alkyl includes, for example, first
Base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl and tertiary butyl.
Terms used herein " alkylidene " refers to that alkyl removes the remaining group after a hydrogen, no matter individually or as
The part of substituent group preferably comprises 1-6 carbon atom, alkylidene such as C1-6 alkyl using straight chain and branch, alkylidene is included
Example include, for example,-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH(CH3)-、-CH2CH(CH3)CH2-、-
CH2CH2CH2CH2Etc..
No matter terms used herein " cycloalkyl " individually or as the part use of substituent group refers both to cyclic saturated hydrocarbon base, ring
Alkyl preferably comprises 4-7 carbon atom, and the example of cycloalkyl such as C4-7 cycloalkyl includes, for example, cyclobutyl, cyclopenta, ring
Hexyl and suberyl.
Terms used herein " aryl " represents isocyclic aryl or biaryl.Isocyclic aryl is preferred containing 6-18 carbon atom
The aromatics of 6-10 carbon atom.It can be monocyclic, bicyclic or tricyclic, such as phenyl or naphthyl etc..
Terms used herein " C2-10 heterocycles " can enumerate following (1) or (2)：
(1) containing the 1-4 selected from nitrogen-atoms, oxygen atom and sulphur atom preferably 1,2,3 or 4 hetero atoms, simultaneously
And containing the aromatic ring yl or their benzene fused rings of 2-10 preferably 2-8 more preferably 2-5 carbon atoms, described is cyclic former
When son is nitrogen-atoms or sulphur atom, the nitrogen-atoms, sulphur atom can form oxide.For example, pyrrole radicals, Yin can be enumerated
Diindyl base, furyl, benzofuranyl, thienyl, benzothienyl, thiazolyl, benzothiazolyl, imidazole radicals, benzimidazolyl,
Triazole, pyridyl group, pyrazolyl, pyrimidine radicals, pyrazinyl, triazine radical.
(2) containing the 1-4 selected from nitrogen-atoms, oxygen atom and sulphur atom preferably 1,2,3 or 4 hetero atoms, simultaneously
It is described when the ring member nitrogen atoms are nitrogen-atoms or sulphur atom and containing the saturation ring group of 2-10 preferably 2-5 carbon atoms
Nitrogen-atoms, sulphur atom can form oxide.For example, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, pyrroles can be enumerated
Alkyl, tetrahydrofuran base.
The present invention also provides pharmaceutical composition, described pharmaceutical composition includes the compound of formula as defined above (I)
Or its pharmaceutically acceptable salt, tautomer, optical isomer, solvate, pro-drug with it is pharmaceutically acceptable
The combination of diluent or carrier.
Described pharmaceutical composition can be used as unit dosage forms to there is or can pass through any known method system in pharmaceutical field
It is standby.All methods all include making reactive compound with forming the carrier-bound step of one or more ingredients.
The term as used herein " pharmaceutically acceptable " refer to the biological activity of not eliminating compound as described herein or
The substance of property, such as carrier or diluent.This kind of substance, which is applied to individual, does not lead to undesirable biological action or not
With harmful way with interacting comprising any component in its composition.
Term " pharmaceutically acceptable carrier " as used herein includes any and all solvent, decentralized medium, packet
Clothing material, surfactant, antioxidant, preservative (such as antiseptic, antifungal agent), isotonic agent, absorption delaying agent, salt,
Preservative, drug stabilizing agent, adhesive, excipient, disintegrant, lubricant, dyestuff etc. and a combination thereof, this is people in the art
Member known to (for example, see Remington ' s Pharmaceutical Sciences, 18th Ed.Mack Printing
Company,1990,pp.1289-1329).Other than the carrier incompatible with active constituent, in treatment or pharmaceutical composition
Consider using any conventional carrier.
The drug of specific embodiments of the present invention can be given by enteral or parenteral approach, including it is intravenous,
It intramuscular, intraperitoneal, subcutaneous, percutaneous, rectum, vagina and administers locally to.
The present invention also provides the methods of prevention inflammatory disease, and the method includes giving subject's effective quantity of needs
The compounds of this invention or pharmaceutical composition.
Another example of the present invention is the purposes of the compounds of this invention in medicine preparation, and the drug is used for need
Subject prevent inflammatory disease.
Inflammatory disease described herein includes but not limited to cervicitis, colitis, cystitis, oaritis, rectitis, defeated
Oviduct inflammation, vaginitis and vulvitis.
It is another object of the present invention to provide a kind of methods for the compound for preparing above-mentioned formula (I), can pass through
Following reaction equations 1 such steps manufactures：
[reaction equation 1]
In above-mentioned reaction equation, M, R1、R2、R3, L is as described above, X1、X2Can be identical or different, independently represent halogen, it is excellent
Select chlorine or bromine.
Advantageous effect
The compounds of this invention has good inhibiting effect for Btk, can be consequently used for inflammatory disease such as cervicitis
Prevention in.
Specific embodiment
The following examples are for the present invention will be described rather than the limitation present invention.
Those skilled in the art will realize that：Chemical reaction described in the invention can be used for suitably preparing perhaps
Other compounds of more present invention, and the other methods for being used to prepare the compound of the present invention are considered as the model in the present invention
Within enclosing.In addition, reaction disclosed in this invention or known reaction condition are also admittedly suitable for other compounds of the invention
Preparation.
Embodiment 1：The synthesis of compound 1
In round-bottomed flask, by the bromo- 2- bromomethyls -4- nitrothiazoles of 2- (methylamino) pyridin-3-yl boric acid 15.2g, 5-
31.6g is dissolved in toluene 200ml, adds in the K of 150ml2CO3Pd (the PPh of (2M) and 2.9g3)4, then it is refluxed.
Confirmed by TLC and reacted, and add water, then terminate reaction.After organic layer is extracted with ethyl acetate and is filtered under diminished pressure, upper prop
It is refined, obtain the intermediate 1-1 of 24.1g, yield 73.2%.
The above-mentioned intermediate 1-1 of 16.5g is dissolved in chlorobenzene 150ml, then adds the P (OEt) of 100ml3, and returned
Stream stirring.After organic layer dichloromethane is extracted and is filtered under diminished pressure, upper prop refines, and obtains the intermediate 1-2 of 10.1g, yield
67.6%
By above-mentioned intermediate 1-2,4.5g KHCO of 8.9g3, 0.57g CuI and 250ml toluene mix, stir
Under be heated to 85 DEG C, then solution of the 3.3g 1- methylurea in 30ml toluene is slowly added dropwise into, is added dropwise within 1 hour,
It is being heated to reflux lower stirring 5 hours.Remove solvent under reduced pressure after reaction, residue ethyl alcohol recrystallization obtains 7.4g whites
The compound 1 of crystal, yield 85.4%.
ESI-MS：291.34[M+H]+
Elemental analysis：Theoretical value/measured value, C (49.64/49.54), H (4.86/4.93), N (28.95/28.82), O
(5.51/5.57), S (11.04/11.14)
1H NMR(400MHz,CDCl3)δ7.99(d,1H),7.87(s,1H),6.95(d,1H),6.72(s,1H),6.41
(s,1H),4.42(s,2H),4.03(s,1H),2.75(s,3H),2.68(s,3H)。
Embodiment 2：The synthesis of compound 2
According to the method for embodiment 1,2- (methylamino) pyridin-3-yl boric acid is replaced with 6- methyl pyridazine -4- ylboronic acids, three
Walk gross production rate 39.2%.
ESI-MS：277.32[M+H]+
Elemental analysis：Theoretical value/measured value, C (47.81/47.74), H (4.38/4.33), N (30.41/30.52), O
(5.79/5.77), S (11.60/11.59)
1H NMR(400MHz,CDCl3)δ9.09(s,1H),7.87(s,1H),6.72(s,1H),6.41(s,1H),4.43
(s,2H),2.73(s,3H),2.38(s,3H)。
Embodiment 3：The synthesis of compound 3
According to the method for embodiment 1, with 6- (pyrrolidines -1- methyl) pyridazine -4- ylboronic acids replace 2- (methylamino) pyridine -
3- ylboronic acids, three step gross production rates 38.4%.
ESI-MS：388.18[M+H]+
Elemental analysis：Theoretical value/measured value, C (55.79/55.74), H (6.50/6.33), N (25.30/25.42), O
(4.13/4.07), S (8.27/8.51)
1H NMR(400MHz,CDCl3)δ7.09(s,1H),6.78(s,1H),6.43(s,1H),6.03(s,1H),4.43
(s,2H),3.63(s,2H),2.58(t,4H),1.68(s,4H),1.63(s,9H),。
Embodiment 4：The synthesis of compound 4
According to the method for embodiment 1,2- (methylamino) pyridin-3-yl is replaced with 2,5- dimethoxy-pyridine -3- ylboronic acids
Boric acid replaces 1- methylurea, three step gross production rates 36.5% with 1- benzylureas.
ESI-MS：388.45[M+H]+
Elemental analysis：Theoretical value/measured value, C (57.42/57.54), H (4.82/4.73), N (17.62/15.52), O
(12.08/12.17), S (8.07/7.94)
1H NMR(400MHz,CDCl3)δ7.25-7.33(m,6H),6.73(s,1H),6.48(s,1H),6.43(s,1H),
4.43(s,2H),4.23(s,2H),4.08(s,3H),3.88(s,3H)。
Embodiment 5：The synthesis of compound 5
According to the method for embodiment 1,2- (methylamino) pyridin-3-yl boric acid is replaced with 2-aminopyridine -3- ylboronic acids, is used
2,5- bis- bromo- 4- nitrothiazoles replace the bromo- 2- bromomethyls -4- nitrothiazoles of 5-, and 1- methyl is replaced with 1- (2- phenylethyls) urea
Urea, three step gross production rates 37.9%.
ESI-MS：353.41[M+H]+
Elemental analysis：Theoretical value/measured value, C (57.94/57.84), H (4.58/4.53), N (23.85/23.77), O
(4.54/4.62), S (9.10/9.32)
1H NMR(400MHz,CDCl3)δ7.93(d,1H),7.28-7.40(m,5H),6.98(d,1H),6.78(s,2H),
6.53(s,1H),6.13(s,1H),6.03(s,1H),3.53(t,2H),2.93(t,2H)。
Test example：The external inhibitory activity analysis of Btk
In acellular kinase assays, the Btk of the compounds of this invention can be measured with method as described below or the like
IC50。
Usage time resolved fluorescent resonance energy transfer method (TR-FRET) measures Btk kinase activities.It is measured using 96 holes
Plate is measured in 50 μ L reaction volumes.By kinases, inhibitor, ATP and 1 μM of peptide substrates (biotin-
AVLESEEELYSSARQ-NH2) be incubated 1 hour in the reaction buffer (pH7.4), the reaction buffer by 20mM Tris,
50mM NaCl、MgCl2(5-25mM, depending on kinases), MnCl2 (0-10mM), 1mM DTT, 0.1mM EDTA, 0.01% N
Seralbumin, 0.005% Tween-20 and 10%DMSO compositions.By the 1x Lance buffer solutions (Perkin- for adding in 25 μ L
Elmer EDTA (relative to bivalent cation) the quenching reactants of 1.2 equivalents in).It is affine that strepto- is added in 25 μ L volumes
The 1x Lance buffer solutions of the p-Tyr100 antibody (Perkin-Elmer) of element-APC (Perkin-Elmer) and Eu labels, respectively
Final concentration of 100nM and 2.5nM is obtained, which is incubated 1 hour.Use multi-mode plate reader, the excitation wavelength of 330nm
And TR-FRET signals are measured under the Detection wavelength of 615nm and 665nm.By the fluorescence under 665nm and 615nm than determining activity.
To each compound, the enzymatic activity under various concentration compound is determined.Negative control reaction is lacking inhibitor
It carries out and (does six in duplicate), and baseline fluorescence level is determined without enzyme control with two.Use program Batch Ki
(Kuzmic etc. (2000), Anal.Biochem., 286：45-50) fitting obtains IC50。
Table 1：The Btk IC of compound of the embodiment of the present invention50Value
Result of the test shows that the compounds of this invention has good inhibiting effect for Btk, can be consequently used for inflammatory disease
In the prevention of case such as cervicitis.
It is understood that embodiment described herein be only used for the purpose illustrated, and accordingly with embodiment
Made various modifications or change can make enlightenment to those skilled in the art, and be included in apply herein spirit and
In the range of range and appended claims.Herein cited all publications, patents and patent applications all pass through reference
It is fully incorporated herein for all purposes.
Claims (8)
1. a kind of compound or its pharmaceutically acceptable salt of formula (I)：
In formula (I),
M is represented：N or CH；
R1It represents：Hydrogen, amino, C1 alkyl aminos or C1 alkoxies；
R2It represents：Hydrogen, C1 alkyl, C1 alkoxies or the C1 alkyl of pyrrolidinyl substitution；
R3It represents：The C1-4 alkyl of C1-4 alkyl or phenyls substitution；
L is represented：Singly-bound or-CH2-。
2. the compound or its pharmaceutically acceptable salt of formula (I) according to claim 1, are selected from：
3. a kind of method for preparing the compound according to the formula (I) described in claim 1, the method pass through following reaction equations
1 such step manufactures：
[reaction equation 1]
In above-mentioned reaction equation, M, R1、R2、R3, L as described in the appended claim 1, X1、X2Can be identical or different, independently represent halogen
Element.
4. the according to the method described in claim 3, it is characterized in that, X1、X2Can be identical or different, independently represent chlorine
Or bromine.
5. a kind of pharmaceutical composition, compound including formula according to claim 1 or 2 (I) or its can pharmaceutically connect
The salt received is combined with pharmaceutically acceptable diluent or carrier.
6. the compound of formula (I) according to claim 1 or 2 or its pharmaceutically acceptable salt in medicine preparation should
With the subject that the drug is used for need prevents inflammatory disease.
7. application according to claim 6, wherein the inflammatory disease is selected from cervicitis, colitis, cystitis, ovary
Inflammation, rectitis, salpingitis, vaginitis and vulvitis.
8. application according to claim 7, wherein the inflammatory disease is cervicitis.
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