CN105949180B - Treat compound and its application of central nervous system degenerative disease - Google Patents
Treat compound and its application of central nervous system degenerative disease Download PDFInfo
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- CN105949180B CN105949180B CN201610304191.XA CN201610304191A CN105949180B CN 105949180 B CN105949180 B CN 105949180B CN 201610304191 A CN201610304191 A CN 201610304191A CN 105949180 B CN105949180 B CN 105949180B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
The present invention relates to compound, pharmaceutical composition and its applications for the treatment of central nervous system degenerative disease, the compound has the structure of formula (I), these compounds can be used as ROCK inhibitor, and be made into appropriate pharmaceutical dosage form for treating neurodegenerative disease.
Description
Technical field
The invention belongs to field of medicaments, are related to treating the compound of central nervous system degenerative disease, pharmaceutical composition
And its application.The invention further relates to a series of preparation method and applications with multi-functional ROCK inhibitor, they can quilt
Appropriate pharmaceutical dosage form is made for treating neurodegenerative disease.
Background technology
Central nervous system degenerative disease（Including Alzheimer disease, Parkinson's disease, Huntington's chorea etc.）'s
Pathogenesis not yet illustrates completely, but it is believed that these diseases are facilitated by multifactor, mainly including various signal transductions
The disorder of access, the formation of oxidative stress and free radical, nerve excitability toxicity and inflammatory reaction, the false folding, more of albumen
Bar amine can nerve and choline neurotransmitter it is unbalance etc..This multifactor facilitating property so that central nervous system degenerative disease
Study of pathogenesis and medicament research and development are difficult.
With the continuous development of systems biology, it has been found that complex disease (such as maincenter degenerative disease, tumour) is simultaneously
It is not to be mediated by single signal access, but is regulated and controled by entire disease network.Network pharmacology based on disease
(Network pharmacology) is theoretical, and single target drug of the regulation and control a certain node of disease network cannot meet the complicated disease for the treatment of
The demand of disease.The conventional treatment model of " a sick target spot, one target spot of a medicine ", is not the available strategy for treating complex disease.Needle
The multiple target spots, the multiple node albumen that induce an illness are intervened simultaneously, so as to regulate and control the multiple target point medicine of entire disease mechanisms network
Object (MTDs) is expected to more preferably tactful as treatment central nervous system degenerative disease.
Multinomial result of study is shown in recent years, and Rho/ROCK signal paths are in the morbidity of central nervous system degenerative disease
Play the role of in the process it is very important, ROCK inhibitor be expected to become treatment nervous centralis degenerative disease novel drugs.
The study found that play a role may be mainly by following approach for ROCK inhibitor：Reduce the generation of A amyloid betas；Promote
Neuron regeneration and survival；Expansion of cerebral vascular improves cerebral blood flow distribution；Adjust the plasticity of neuronal synapse；Promote aixs cylinder
Growth；Promote the differentiation of Neural Stem Cells；In addition ROCK inhibitor can also adjust central nervous system oxidation and answer
Sharp and inflammatory reaction.Although ROCK inhibitor shows good prospect in pivot nervous system degenerative disease in the treatment,
But existing ROCK inhibitor therapy target is single, it is difficult to through blood-brain barrier, low blood pressure and hemorrhage of digestive tract etc. easily occur
Side effect limits its application in this respect.
Lipoic acid（Lipoic acid, LA）" omnipotent antioxidant " is known as, is that effect is most strong in known natural inhibitor
It is a kind of.It is the confactor of pyruvic dehydrogenase and metabolic antioxidant, can be converted into reduced form in vivo
Dihydrolipoic acid（Dihydrolipoic acid, DHLA）, its oxidation resistance includes：Remove free radical and active oxygen；Suppression
Lipid peroxidation processed；Chelated metal ions；Internal anti-oxidant action with other.Lipoic acid is low and amphiphilic with molecular weight
Feature readily penetrates through blood-brain barrier, can play antioxidation in central nervous system, therefore is considered as that treatment nerve moves back
The useful micromolecular compound of row disease.But lipoic acid is unstable in vivo, action target spot is more single, only with antioxygen
Change acts on, and mostly it is combined with other drugs or as the pharmacophore for designing multiple target point drug in recent years.
Invention content
It is theoretical based on above research and multiple target point medicament research and development, we by the pharmacophore with ROCK kinase inhibitory activities and
Lipoic acid is coupled, and has synthesized a series of multi-functional ROCK inhibitors.
A series of the characteristics of compounds of the present invention, is that there are two main units：Anti-oxidant part and ROCK kinases
Inhibit part, by coupling, by this two parts heterozygosis in a molecule, to reach multiple target point, while improve compound blood brain
The purpose of barrier permeability, so as to effectively treat central nervous system degenerative disease.
The present invention relates to the compound of formula (I) or its tautomer, pharmaceutical salts, prodrug or solvates：
Formula（I）
Wherein,
R1Selected from-H ,-F ,-Cl ,-Br ,-I ,-OCH3、-OCH2CH3、-OCH2CH2CH3、-OCH2CH2CH2CH3、、、、、、、With；
R2It is selected fromWith。
Another aspect of the present invention provides a kind of pharmaceutical composition, and it includes any compound of the present invention or its medicines
Acceptable salt and pharmaceutically acceptable carrier on.
Another aspect of the present invention provides any compound of the present invention or its pharmaceutically acceptable salt is preparing treatment
Application in the drug of central nervous system degenerative disease.Preferably, the central nervous system degenerative disease is A Er
Ci Haimo diseases, Parkinson's disease, amyotrophic lateral sclerosis or Huntington's chorea.
Another aspect of the present invention provides a kind of multi-functional ROCK inhibitor, and it includes any compounds of the present invention
Or its pharmaceutically acceptable salt.
Unless otherwise specified, the compound of the present invention is also meant to include differing only in rich in the presence of one or more isotopes
The compound of the atom of collection.For example, replace hydrogen, Huo Zheyong with deuterium or tritium13C or14C- enrichment carbon atom replace carbon atom or15The compound that the nitrogen-atoms of N- enrichments replaces nitrogen-atoms is within the scope of the present invention.
Belong to " pharmaceutical salts, derivative, solvate, prodrug " and refer to any pharmaceutical salts, ester, solvate or through application
It is capable of providing after recipient（Directly or indirectly）Other compounds of compound described herein.It is it is, however, to be understood that non-medicinal
Salt is also within the scope of the present invention, because those are possibly used for vegetation officinal salt, salt, the vegetation of prodrug and derivative can lead to
Cross methods known in the art progress.For example, the pharmaceutical salts of compound provided by the invention can be by conventional method by parent
Compound synthesis, the parent compound contain alkali or acid moieties.In general, the salt is for example by by these of free acid or alkali form
The appropriate alkali or acid of compound and stoichiometric amount are prepared in water or in organic solvent or in the mixture of the two.It is logical
Often, non-aqueous medium such as ether, ethyl acetate, ethyl alcohol, isopropanol or acetonitrile are preferred.The example of acid-addition salts includes inorganic
Acid-addition salts for example, hydrochloride, hydrobromate, hydriodate, sulfate, nitrate and organic acid addition salt, such as such as acetic acid
Salt, maleate, fumarate, citrate, oxalates, succinate, tartrate, malate, mandelate and right
Toluene fulfonate.The example of base addition salts includes inorganic salts such as sodium, potassium, calcium, ammonium, magnesium, aluminium and lithium salts；And organic base such as second two
Amine, ethanol amine, N, N- dialkyl ethanolamines, triethanolamine, aminoglucose and alkaline amino acid salt.
Preferred derivative or prodrug are relative to parent material, improve this hair when these compounds are used in patient
The bioavilability of bright compound（Such as the compound by being administered orally is easier to be absorbed into blood）Or enhancing
Parent compound is to biological compartment（Such as brain or lymphatic system）Transmission those.
Formula（Ⅰ）Any compound of compound prodrug is within the scope of the present invention, and term " prodrug " is widest with it
Meaning uses and those derivatives including being converted into the compounds of this invention in vivo.These derivatives are for art technology
Personnel be it will be apparent that and the functional group according to present in molecule, the following derivative including being not limited to the compounds of this invention
Object：Ester；Amino-acid ester；Phosphoric acid；Metal salt sulfuric acid；Carbamate and amide.
The compound of the present invention can be the crystal form as advantageous chemical compounds or as solvate, it is intended to by two kinds
Form is included within the scope of the invention.The method of solvation is well known in the art.Appropriate solvate is medicinal molten
Agent compound.In a specific embodiment, solvate is hydrate.
Reaction route lists the method for preparing the compound of the present invention.
Reaction route 1
Sodium hydrogen (60%) is added in the alcohol comprising substituent group under the conditions of 0 DEG C, reaction adds in compound a after 15 minutes, will
Reaction temperature is warmed to room temperature, and is stirred overnight, and reaction finishes, and adds water and organic solvent（Ethyl acetate or dichloromethane）It extracts
To crude product b；
By compound 2,4- pyridine boronic acid Knit-the-brows alcohol esters, K2CO3、Pd(pph3)4, mixed solvent（Toluene：Water：Ethyl alcohol=3：
2：1）It is added in 15ml tube sealings, vacuumizes, making mixture, reaction finished, and removes in vacuum, 100 DEG C of conditioned responses 6-10 hours
After removing solvent, compound c is obtained by purified by flash chromatography crude product；
For compound c by Raney's nickel, hydrazine hydrate reduction in methanol solution, reaction, which finishes, is obtained by filtration compound d；
Compound d and lipoic acid are in EDCI, DMAP, Et3N（Or HATU, DIEA）In dichloromethane under the conditions of existing（Or
DMF）Coupling reaction 6-12 hours in solution, reaction is finished obtains target compound by extraction, purified by flash chromatography crude product
1-8。
Reaction route 2
By compound b, N-BOC- pyrazoles pinacol borate, Cs2CO3, PdCl (dppf), mixed solvent（1,4- dioxies six
Ring：Water=10：1）It is added in 15ml tube sealings, vacuumizes, mixture is made to have reacted in vacuum, 70 DEG C of conditioned responses 6-8 hours
Finish, after removing solvent, compound e is obtained by purified by flash chromatography crude product；
For compound e by palladium carbon/hydrogen reducing in methanol solution, reaction, which finishes, is obtained by filtration compound f；
Compound f and lipoic acid under the conditions of existing for HATU, DIEA coupling reaction 4-12 hours in DMF solution, instead
It should finish and compound g is obtained by extraction, purified by flash chromatography crude product；
Compound g takes off BOC protecting groups, unsaturated carbonate hydrogen in dichloromethane solution under the conditions of trifluoroacetic acid is existing
Target compound 9-16 is obtained by extraction in sodium.
It if desired, can be by conventional method such as crystallisation or chromatography purifying reaction product.When being used to prepare this hair
When the above method of bright compound generates the mixture of stereoisomer, these isomers can such as prepare color by routine techniques
Spectrometry detaches.If there is chiral centre, compound may be prepared with racemic form or can be closed by enantiospecific
Into or be prepared by splitting single enantiomter.
A kind of preferred medicinal forms are crystal forms, including this form in pharmaceutical composition.If salt and molten
Agent compound, ion or solvent portion in addition should also be as being non-toxic.The compound of the present invention may have different polymorphics
Object, it is intended to which the present invention includes all these forms.
The typical compound represented by foregoing invention formula (I), salt, their solvate or prodrug show stronger blood
Brain barrier permeability, comparable ROCK inhibiting effect, the level for improving endogenous anti-oxidative albumen glutathione, neuroprotection are made
With and mild vasorelaxation action.Therefore, another aspect of the present invention is related to treating, ameliorating or preventing neurodegenerative disease
Method, this method includes the compound or its medicine group for the formula (I) that therapeutically effective amount is applied to the object for needing this treatment
Close object.In a preferred method, the object is mammal, such as people.
The compound of the present invention and composition can be used together to provide combination therapy with other medicines.Other medicines can
Using formed same combination a part or can be as simultaneously or the separated composition that is not administered simultaneously provides.
Description of the drawings
Fig. 1：Protective effect of the compound to L-glutamate induction HT22 cell deaths.###P<0.001, with normal group
Compare；* P<0.05,** P<0.01, * * *P<0.001 compared with glutamic acid group.
Fig. 2：Compound 15 is to intracellular ROS（A,B）And GSH（C）Horizontal influence.A (a) CT; (b) Glu; (c)
1µM 15 + Glu; (d) 3µM 15 + Glu; (e) 10µM 15 + Glu; (f) 10µM LA + Glu;Scale:
100 μm ###P<0.001, compared with normal group；*** P<0.001,** P<0.01 compared with glutamic acid group.
Fig. 3：Compound 15 acts on the diastole for shrinking vascular circle in advance.** P<0.01,*** P<0.001 compared with DMSO groups.
Specific embodiment
The following example is provided, the present invention is further illustrated, they should not be considered as the limit to the scope of the invention
It is fixed.
1-5- of embodiment (bis- sulphur pentamethylene-3- bases of 1,2-)-N- (4- (pyridin-4-yl) phenyl) pentanamide (1)
Compound 1 is synthesized according to said synthesis route 1, obtains faint yellow solid, three step gross production rates are 52%.1H NMR
(400 MHz, CDCl3) δ 8.62 (d, J = 4.7 Hz, 2H), 7.96 (s, 1H), 7.68 (d, J = 8.1
Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 5.2 Hz, 2H), 3.64 – 3.49 (m,
1H), 3.22 – 3.04 (m, 2H), 2.53 – 2.33 (m, 3H), 1.90 (dt, J = 19.7, 6.8 Hz,
1H), 1.84 – 1.62 (m, 4H), 1.61 – 1.43 (m, 2H). 13C NMR (100 MHz, CDCl3) δ
171.4, 150.1, 147.7, 139.2, 133.4, 127.6, 121.3, 120.2, 56.4, 40.3, 38.5,
37.4, 34.7, 28.9, 25.2. ESI-HRMS for [C19H23N2OS2]+,calcd: 359.1246; found:
359.1232. purity: 100% （HPLC）..
Embodiment 2-[5- (bis- sulphur pentamethylene-3- bases of 1,2-)-N- (2- fluoro- 4- (pyridin-4-yl) phenyl) pentanamide
(2)
Compound 2 is synthesized according to said synthesis route 1, obtains faint yellow solid, 3 step gross production rates are 32.8%.1H NMR
(400 MHz, CDCl3) δ 8.65 (d, J = 6.0 Hz, 2H), 8.48 (t, J = 8.2 Hz, 1H), 7.51 –
7.35 (m, 5H), 3.66 – 3.53 (m, 1H), 3.25 – 3.06 (m, 2H), 2.57 – 2.37 (m, 3H),
1.93 (td, J = 13.6, 6.9 Hz, 1H), 1.87 – 1.72 (m, 4H), 1.62 – 1.47 (m, 2H).13C
NMR (100 MHz, CDCl3) δ 170.16 (s), 151.50 (d, J = 243.8 Hz), 149.33 (s),
145.51 (d, J = 1.8 Hz), 133.04 (d, J = 7.5 Hz), 126.22 (d, J = 10.5 Hz),
122.13 (d, J = 3.0 Hz), 121.10 (s), 120.13 (s), 112.21 (d, J = 20.7 Hz),
55.32 (s), 39.24 (s), 37.49 (s), 36.43 (s), 33.64 (s), 27.80 (s), 24.07 (s).
ESI-HRMS for [C19H22FN2OS2]+,calcd: 377.1158; found:377.1151. purity: 99%（HPLC）.
3-5- of embodiment (bis- sulphur pentamethylene-3- bases of 1,2-)-N- (2- methoxyl groups-4- (pyridin-4-yl) phenyl) valeryl
Amine (3)
Compound 3 is synthesized according to said synthesis route 1, obtains faint yellow solid, three step gross production rates are 22%.1H NMR
(400 MHz, CDCl3) δ 8.62 (dd, J = 4.5, 1.6 Hz, 2H), 8.50 (d, J = 8.4 Hz, 1H),
7.83 (s, 1H), 7.47 (dd, J = 4.5, 1.6 Hz, 2H), 7.29 – 7.23 (m, 1H), 7.11 (d, J
= 1.8 Hz, 1H), 3.97 (s, 3H), 3.64 – 3.52 (m, 1H), 3.24 – 3.06 (m, 2H), 2.54 –
2.39 (m, 3H), 1.97 – 1.85 (m, 2H), 1.83 – 1.69 (m, 4H), 1.60 – 1.47 (m, 2H).13C NMR (100MHz, CDCl3) δ 170.0, 149.2, 147.1, 147.0, 132.3, 127.7, 120.3,
119.0, 107.3, 75.7, 55.4, 54.9, 39.3, 37.5, 36.7, 33.7, 27.8, 24.2. ESI-HRMS
for [C20H25N2O2S2]+,calcd: 389.1352; found:389.1350. purity: 99%.
4-5- of embodiment (bis- sulphur pentamethylene-3- bases of 1,2-)-N- (3- fluoro- 4- (pyridin-4-yl) phenyl) pentanamide
(4)
Compound 4, faint yellow solid are synthesized according to said synthesis route 1,3 step gross production rates are 45.2%.1H NMR (400
MHz, CDCl3) δ 8.66 (s, 1H), 8.63 (d, J = 5.8 Hz, 2H), 7.68 (d, J = 12.9 Hz,
1H), 7.47 (d, J = 4.7 Hz, 2H), 7.40 (t, J = 8.4 Hz, 1H), 7.33 (d, J = 8.4 Hz,
1H), 3.59 – 3.48 (m, 1H), 3.21 – 3.02 (m, 2H), 2.46 – 2.36 (m, 3H), 1.87 (td,
J = 13.6, 6.9 Hz, 1H), 1.81 – 1.61 (m, 4H), 1.56 – 1.43 (m, 2H). 13C NMR (100
MHz, CDCl3) δ 171.8, 161.3, 158.8, 149.7, 143.5, 140.8, 140.6, 130.3, 130.2,
123.5, 123.4, 121.1, 121.0, 115.6, 108.1, 107.8, 56.4, 40.3, 38.5, 37.3,
34.6, 28.9, 25.2. ESI-HRMS for [C19H22FN2OS2]+,calcd: 377.1152; found:
377.1136. purity: 98%.
5-5- of embodiment (bis- sulphur pentamethylene-3- bases of 1,2-)-N- (3- methoxyl groups-4- (pyridin-4-yl) phenyl) valeryl
Amine (5)
Compound 5 is synthesized according to said synthesis route 1, obtains yellow solid, 3 step gross production rates are 78.8%.1H NMR
(400 MHz, CDCl3) δ 8.59 (dd, J = 4.6, 1.6 Hz, 2H), 7.78 (s, 1H), 7.65 (s,
1H), 7.47 (dd, J = 4.5, 1.6 Hz, 2H), 7.28 (d, J = 8.3 Hz, 1H), 6.96 (dd, J =
8.3, 2.0 Hz, 1H), 3.84 (s, 3H), 3.58 (td, J = 12.7, 6.4 Hz, 1H), 3.26 – 3.06
(m, 2H), 2.51 – 2.39 (m, 3H), 1.91 (dt, J = 19.7, 6.9 Hz, 1H), 1.84 – 1.69
(m, 4H), 1.58 – 1.48 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 171.5, 157.2, 149.2,
146.2, 140.3, 130.5, 124.2, 122.9, 111.7, 103.4, 56.4, 55.6, 40.3, 38.5,
37.4, 34.7, 28.9, 25.2. ESI-HRMS for [C20H25N2O2S2]+,calcd: 389.1352; found:
389.1342. purity: 99%.
6-N- of embodiment (2- (2- (dimethylamino) ethyoxyl)-4- (pyridin-4-yl) phenyl)-5- (bis- sulphur of 1,2-
Pentamethylene base -3-) pentanamide (6)
Compound 6 is synthesized according to said synthesis route 1, obtains faint yellow solid, 4 step gross production rates are 67.8%.1H NMR
(400 MHz, CDCl3) δ 9.34 (s, 1H), 8.54 (dd, J = 4.5, 1.6 Hz, 2H), 8.40 (d, J =
8.5 Hz, 1H), 7.39 (dd, J = 4.5, 1.6 Hz, 2H), 7.24 (dd, J = 8.5, 2.0 Hz, 1H),
7.14 (d, J = 2.0 Hz, 1H), 4.12 (t, J = 5.2 , 2H), 3.57 – 3.48 (m, 1H), 3.17 –
2.99 (m, 2H), 2.63 (t , J = 5.2 , 2H), 2.41 – 2.34 (m, 3H), 2.29 (s, 6H),
1.85 (td, J = 13.8, 7.0 Hz, 1H), 1.76 – 1.62 (m, 4H), 1.53 – 1.40 (m, 2H). 13C
NMR (100 MHz, CDCl3) δ 170.7, 149.1, 147.0, 146.8, 132.2, 130.0, 120.2,
112.1, 67.0, 57.0, 55.4, 44.2, 39.2, 37.5, 36.2, 33.7, 28.0, 24.3. ESI-HRMS
for [C23H32N3O2S2]+,calcd: 446.1930; found: 446.1929. Purity: 99%.
Embodiment 7- 5- (bis- sulphur pentamethylene -3- bases of 1,2-)-N- (2- ((1- methyl piperidine -4- bases) methoxyl group) -4- (pyrroles
Pyridine -4- bases) phenyl) pentanamide (7)
Compound 7, yellow-brown solid are synthesized according to said synthesis route 1,4 step gross production rates are 64.8%.1H NMR (400
MHz, CDCl3) δ 8.62 (d, J = 4.6 Hz, 2H), 8.48 (d, J = 8.0 Hz, 1H), 7.81 (s,
1H), 7.47 (d, J = 4.7 Hz, 2H), 7.10 (s, 1H), 3.99 (d, J = 5.6 Hz, 2H), 3.64 –
3.53 (m, 1H), 3.21– 3.08 (m, 2H), 3.06 – 2.91 (m, 3H), 2.51– 2.43 (m, 3H),
2.33 (s, 3H), 2.08 – 1.72 (m, 17H). 13C NMR (100 MHz, CDCl3) δ 171.0, 150.2,
148.2, 147.5, 133.4, 128.7, 121.4, 120.2, 120.0, 109.4, 73.2, 56.4, 55.2,
46.2, 40.3, 38.5, 37.8, 35.2, 34.7, 29.0, 28.9, 25.3. ESI-HRMS for
[C26H36N3O2S2]+,calcd: 486.2243; found:486.2234. purity: 98%.
8-5- of embodiment (bis- sulphur pentamethylene-3- bases of 1,2-)-N- (4- pyridin-4-yls) 2- (2,2,2 ,-trifluoroethoxy
Base) phenyl) pentanamide (8)
Compound 8 is synthesized according to said synthesis route 1, obtains faint yellow solid, 4 step gross production rates are 40.4%.1H NMR
(400 MHz, CDCl3) δ 8.64 (d, J = 4.9 Hz, 2H), 8.52 (d, J = 8.3 Hz, 1H), 7.73
(s, 1H), 7.45 (d, J = 5.2 Hz, 2H), 7.36 (d, J = 8.1 Hz, 1H), 7.13 (s, 1H),
4.52 (dd, J = 15.7, 7.8 Hz, 2H), 3.69 – 3.52 (m, 1H), 3.29 – 3.04 (m, 2H),
2.59 – 2.37 (m, 3H), 1.92 (dt, J = 19.7, 6.8 Hz, 1H), 1.88 – 1.67 (m, 4H),
1.64 – 1.45 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 170.0, 149.3, 146.2, 145.2,
132.7, 128.2, 123.5, 121.2, 120.7, 120.2, 120.1, 109.7, 66.5, 66.1, 65.8,
65.4, 55.3, 39.2, 37.5, 36.7, 33.7, 27.8, 24.1. ESI-HRMS for [C21H24F3N2O2S2
]+,calcd: 457.1226; found:457.1225. purity: 99%.
9-N- of embodiment (4- (1H- pyrazoles-4- bases) phenyl)-5- (bis- sulphur pentamethylene-3- bases of 1,2-) pentanamide (9)
Compound 9 is synthesized according to said synthesis route 2, obtains white solid, 4 step gross production rates are 5.6%.1H NMR
(400 MHz, DMSO) δ 12.81 (s, 1H), 9.86 (s, 1H), 7.97 (s, 2H), 7.57 (d, J = 8.6
Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H), 3.74 – 3.56 (m, 1H), 3.26 – 3.05 (m, 2H),
2.41 (td, J = 12.5, 6.3 Hz, 1H), 2.30 (t, J = 7.3 Hz, 2H), 1.87 (dt, J =
19.7, 6.8 Hz, 1H), 1.77 – 1.55 (m, 4H), 1.46 – 1.37 (m, 2H). 13C NMR (100 MHz,
DMSO) δ 170.9, 137.2, 127.7, 125.3, 120.9, 119.4, 56.1, 38.1, 36.2, 34.1,
28.3, 24.9. ESI-HRMS for [C17H22N3OS2]+,calcd: 348.1199; found:It is 348.1195. pure
Degree: 97%.
10-5- of embodiment (bis- sulphur pentamethylene-3- bases of 1,2-)-N- (the fluoro- 4- of 2- (1H- pyrazoles-4- bases) phenyl) valeryl
Amine (10)
Compound 10 is synthesized according to said synthesis route 2, obtains faint yellow solid, 4 step gross production rates are 7%.1H NMR
(400 MHz, DMSO) δ 12.94 (s, 1H), 9.60 (s, 1H), 8.06 (s, 2H), 7.77 (t, J = 8.4
Hz, 1H), 7.49 (dd, J = 12.3, 1.8 Hz, 1H), 7.38 (dd, J = 8.3, 1.5 Hz, 1H),
3.62 (td, J = 12.3, 6.2 Hz, 1H), 3.22 – 3.05 (m, 2H), 2.45 - 2.31 (m, 3H),
1.87 (dq, J = 13.5, 6.8 Hz, 1H), 1.75 – 1.52 (m, 4H), 1.48 – 1.33 (m, 5H). 13C
NMR (100 MHz, DMSO) δ 171.41 (s), 154.14 (d, J = 243.8 Hz), 130.44 (d, J =
7.6 Hz), 124.73 (s), 123.62 (d, J = 12.2 Hz), 120.62 (d, J = 2.8 Hz), 119.98
(d, J = 1.9 Hz), 111.82 (d, J = 20.8 Hz), 56.10 (s), 38.07 (s), 35.52 (s),
34.08 (s), 28.23 (s), 24.87 (s). ESI-HRMS for [C17H21FN3OS2]+,calcd:
366.1105; found:366.1098. purity: 97%.
11-5- of embodiment (bis- sulphur pentamethylene-3- bases of 1,2-)-N- (2- methoxyl groups-4- (1H- pyrazoles-4- bases) phenyl)
Pentanamide (11)
Compound 11 is synthesized according to said synthesis route 2, obtains white solid, 4 step gross production rates are 14.3%.1H NMR
(400 MHz, DMSO) δ 12.90 (s, 1H), 9.02 (s, 1H), 8.34 – 7.76 (m, 3H), 7.23 (s,
1H), 7.13 (d, J = 8.2 Hz, 1H), 3.88 (s, 3H), 3.62 (td, J = 12.5, 6.2 Hz, 1H),
3.26 – 3.06 (m, 2H), 2.47 – 2.32 (m, 3H), 1.87 (dq, J = 13.5, 6.8 Hz, 1H),
1.77 – 1.50 (m, 4H), 1.48 – 1.33 (m, 2H).13C NMR (100 MHz, DMSO) δ 171.6,
150.5, 129.7, 125.8, 122.9, 121.7, 117.3, 108.6, 56.7, 56.2, 38.6, 36.3,
34.6, 28.8, 25.5. ESI-HRMS for [C18H24N3O2S2]+,calcd: 378.1304; found:
378.1306. Purity: 99%.
12-5- of embodiment (bis- sulphur pentamethylene-3- bases of 1,2-)-N- (the fluoro- 4- of 3- (1H- pyrazoles-4- bases) phenyl) valeryl
Amine (12)
Compound 12 is synthesized according to said synthesis route 2, obtains faint yellow solid, 4 step gross production rates are 15.3%.1H NMR
(400 MHz, DMSO) δ 13.00 (s, 1H), 10.08 (s, 1H), 7.98 (s, 2H), 7.73 – 7.57 (m,
2H), 7.28 (dd, J = 8.5, 1.8 Hz, 1H), 3.67 – 3.56 (m, 1H), 3.24 – 3.06 (m,
2H), 2.47 – 2.37 (m, 1H), 2.33 (dd, J = 18.4, 11.0 Hz, 2H), 1.87 (td, J =
13.4, 6.8 Hz, 1H), 1.74 – 1.52 (m, 4H), 1.46 – 1.35 (m, 2H).13C NMR (100 MHz,
DMSO) δ 171.8, 159.9, 157.4, 139.0, 138.9, 128.3, 128.2, 115.5, 115.5, 115.4,
115.3, 115.1, 115.0, 107.0, 106.7, 56.6, 38.6, 36.7, 34.6, 28.8, 25.2. ESI-
HRMS for [C17H21FN3OS2]+,calcd: 366.1105; found: 366.1090. Purity: 98%.
13-5- of embodiment (bis- sulphur pentamethylene-3- bases of 1,2-)-N- (3- methoxyl groups-4- (1H- pyrazoles-4- bases) phenyl)
Pentanamide (13)
Compound 13 is synthesized according to said synthesis route 2, obtains crocus solid, 4 step gross production rates are 4.3%.1H NMR
(400 MHz, DMSO) δ 12.78 (s, 1H), 9.89 (s, 1H), 7.96 (s, 2H), 7.50 (d, J = 8.3
Hz, 1H), 7.44 (d, J = 1.6 Hz, 1H), 7.15 (dd, J = 8.4, 1.8 Hz, 1H), 3.82 (s,
3H), 3.67 – 3.57 (m, 1H), 3.23 – 3.07 (m, 2H), 2.41 (dt, J = 18.7, 6.3 Hz,
1H), 2.30 (t, J = 7.3 Hz, 2H), 1.87 (td, J = 13.5, 6.8 Hz, 1H), 1.75 – 1.54
(m, 4H), 1.46 – 1.36 (m, 2H). 13C NMR (100 MHz, DMSO) δ 171.0, 155.4, 138.4,
127.0, 116.8, 116.2, 111.2, 102.7, 56.1, 55.2, 38.1, 36.3, 34.1, 28.3, 24.8.
ESI-HRMS for [C18H24N3O2S2]+,calcd: 378.1304; found: 378.1301. Purity: 98%.
Embodiment 14N- (2- (2- (dimethylamino) ethyoxyl) -4- (1H- pyrazoles -4- bases) phenyl) -5- (bis- sulphur of 1,2-
Pentamethylene -3- bases) pentanamide (14)
Compound 14 is synthesized according to said synthesis route 2, obtains faint yellow solid, 4 step gross production rates are 16.1%.1H NMR
(400 MHz, DMSO) δ 12.89 (s, 1H), 9.34 (s, 1H), 8.14 (s, 2H), 7.92 (d, J = 8.0
Hz, 1H), 7.31 (s, 1H), 7.18 (d, J = 7.9 Hz, 1H), 4.16 (t, J = 4.8 Hz, 2H),
3.71 – 3.53 (m, 1H), 3.22 – 3.11 (m, 2H), 2.63 (t, J = 4.8 Hz, 2H), 2.46 –
2.38 (m, 1H), 2.38 – 2.30 (m, 2H), 2.27 (s, 6H), 1.87 (dt, J = 19.2, 6.5 Hz,
1H), 1.80 – 1.50 (m, 4H), 1.50 – 1.30 (m, 2H).13C NMR (100 MHz, DMSO) δ 171.3,
149.4, 136.9, 129.6, 127.5, 125.9, 122.5, 121.5, 118.5, 112.3, 68.3, 58.0,
56.6, 55.4, 45.7, 38.6, 36.6, 34.7, 28.8, 25.5. ESI-HRMS for [C21H31N4O2S2]+,
calcd: 435.1883; found:435.1883. purity: 99%.
15-5- of embodiment (bis- sulphur pentamethylene-3- bases of 1,2-)-N- (2- ((1- methyl piperidine-4- bases) methoxyl group-4-
(1H- pyrazoles -4- bases) phenyl) pentanamide (15)
Compound 15 is synthesized according to said synthesis route 2, obtains white solid, 4 step gross production rates are 24.6%.1H NMR
(400 MHz, CDCl3) δ 8.34 (d, J = 8.2 Hz, 1H), 7.80 (s, 2H), 7.73 (s, 1H), 7.09
(dd, J = 8.3, 1.7 Hz, 1H), 6.97 (d, J = 1.7 Hz, 1H), 3.96 (d, J = 5.9 Hz,
2H), 3.64 – 3.52 (m, 1H), 3.24 – 3.08 (m, 2H), 3.06 – 2.96 (m, 2H), 2.50 –
2.41 (m, 4H), 2.36 (s, 3H), 2.15 – 2.05 (m, 3H), 1.96 – 1.82 (m, 5H), 1.82 –
1.68 (m, 5H), 1.66 – 1.50 (m, 5H). 13C NMR (100 MHz, CDCl3) δ 170.8, 147.6,
131.0, 128.3, 126.3, 122.5, 120.5, 118.5, 108.7, 73.1, 56.4, 55.2, 46.1,
40.3, 38.5, 37.7, 35.2, 34.7, 29.7, 28.9, 25.4. ESI-HRMS for [C24H35N4O2S2]+,
calcd: 475.2196; found:475.2179. purity: 99%.
16-N- of embodiment (4- (1H- pyrazoles-4- bases) phenyl)-2-（2,2,2- trifluoro ethoxies）Phenyl) -5- (1,
Bis- sulphur pentamethylene base -3- of 2-) pentanamide (16)
Compound 16 is synthesized according to said synthesis route 2, obtains white solid, 4 step gross production rates are 8.7%.1H NMR
(400 MHz, DMSO) δ 12.91 (s, 1H), 9.01 (s, 1H), 8.09 (s, 2H), 7.66 (d, J = 7.0
Hz, 1H), 7.40 (s, 1H), 7.25 (d, J = 7.8 Hz, 1H), 4.81 (d, J = 8.6 Hz, 2H),
3.68 – 3.60 (m, 1H), 3.25 – 2.98 (m, 2H), 2.46 – 2.22 (m, 3H), 1.88 (dd, J =
12.0, 6.2 Hz, 1H), 1.80 – 1.52 (m, 4H), 1.49 – 1.36 (m, 2H). 13C NMR (100 MHz,
DMSO) δ 171.7, 149.7, 130.7, 125.9, 125.8, 125.2, 123.1, 121.2, 119.2, 111.2,
66.6, 66.3, 65.9, 65.6, 56.6, 38.6, 36.3, 34.7, 28.7, 25.5. ESI-HRMS for
[C19H23F3N3O2S2]+,calcd: 446.1178; found:446.1161. purity: 98%.
17-compound of embodiment is to multiple protein kinase activity inhibiting effect
Using the Z '-LYTE kinase method kits based on fluorescence resonance energy transfer（Invitrogen, Carlsbad,
CA）Compound is measured to ROCK 2, PKA (protein kinase A, PKA), PKG (protein kinase G,
PKG) the IC of kinases50Value.Untested compound is configured to 10 mM, then step by step 3 times dilute down, 10 concentration are set altogether.
In 384 orifice plates per hole add in 10 μ L reaction solutions (be dissolved in 50mM HEPES, pH 7.5,0.01% Brij-35 comprising 2 μM,
10 mM MgCl2, the small peptide substrate of 1 mM EGTA and suitable ROCK 1, ROCK 2, PKA, PKG) and it is a series of 3 times it is dilute
The untested compound released.Final concentration of 75 μM of ATP.After the incubation of 1 h, reaction terminating calculates fluorescence ratio according to specification
Value.Amount effect curve is obtained, and calculate IC using the fittings of Prism 5.050Value.1 is the results are shown in Table, is changed it can be seen from experimental result
It closes object 7,14 and 15 and shows certain ROCK inhibiting effect, and compared with Fasudil, these compounds are to ROCK2's
Selectivity is more preferable.
1. untested compound of table is to the inhibiting effect of different protein kinases
| Compound | ROCK2 IC50(μM) | PKA IC50(μM) | PKG IC50(μM) |
| 1 | 156 | ＞ 5000 | 76 |
| 2 | 70 | ＞ 5000 | 60 |
| 3 | 92 | ＞ 5000 | 105 |
| 6 | 49 | ＞ 5000 | 14 |
| 7 | 5±1 | 252 | 5.9±0.8 |
| 9 | 64 | ＞ 5000 | 81 |
| 10 | 46 | ＞ 5000 | 168 |
| 11 | 37 | ＞ 5000 | 147 |
| 14 | 10±2 | 256±55 | 33±3 |
| 15 | 0.8±0.1 | 363±26 | 24±3 |
| fasudil | 0.46±0.06 | 5.3±1 | 2.5±0.7 |
18-compound of embodiment inhibits the effect of L-glutamate inducing cytotoxics
Mouse hippocampal neuron cell strain HT22, with the DMEM complete mediums containing 10% fetal calf serum, at 37 DEG C, saturation
Humidity is 5% CO containing volume fraction2, 95% air carbon dioxide incubator in routine culture.It takes the logarithm growth period cell,
After being digested with 0.25% pancreatin, complete medium is resuspended, under microscope cell counting board counts and adjust cell concentration be 10 ×
104A/ml, is inoculated with 96 porocyte culture plates, 100 μ L/ holes, and overnight incubation makes cell adherent.Culture medium in 96 orifice plates is inhaled
It walks, untested compound is dissolved with DMSO, is diluted with complete medium, is added in 96 orifice plates, 100 μ L/ holes.Preincubate 30min
Afterwards, 2 μ L 100mM L-glutamate are added in.Model group is not added with untested compound, is directly added into 2 μ L 100mM L-
glutamate.After being incubated 24 h, 10 μ L 5mg/mL MTT are added in per hole, 2h is incubated, discards supernatant, add 100 μ L/ of DMSO
Hole, oscillation make product formazan fully dissolve, and each hole absorbance value is measured in microplate reader, measure 570 nm of wavelength.It adopts
Promote survival rate (%)=100%* (A of cell with formula compoundUntested compound-AModel group) / (AModel group-ABlank) calculate cell survival
Rate.The result is shown in Figure 1, it can be seen that the neuroprotection of majority of compounds is all more preferable compared with lipoic acid, wherein compound 11,14
It can almost be reversed completely 10 μM when with 15 dead by the HT22 of glutamate induction.
Embodiment 19-in vitro blood-brain barrier transmitance
1) 4 μ L 2% are taken（PBL）Solution is added in the hydrophobic membrane of 96 orifice plates of MAIPn4550, pays attention to moving during being added dropwise
Liquid pipette tips do not contact film surface to prevent destroying membrane structure；
2) 200 μ L analyte sample fluids are quantitatively drawn (in 10 min) rapidly（0.1 mg/ml）The film being added in 96 orifice plates
As administration pond, it is acceptance pool that film opposite side, which adds in 200 μ L PBS (pH=7.4), pays attention to that holding acceptable solution and film fill for top
Tap is touched；
3) after the static 10h of room temperature, administration pond is carefully removed, 200ul is taken per hole, with chemical combination in UV spectrometers test acceptance pool
Object absorbance value（250-500 nm）；
4) 100 μ L analyte sample fluids and the 100 abundant mixings of μ L PBS are drawn, as Theoretical Equilibrium solution, test its suction
Shading value（250-500 nm）, need with acceptor board tests；
5) logP is calculated according to formulaeValue：
Vd is the volume of acceptance pool in formula, and Va is the volume of acceptance pool, and A is membrane area, and t is time of penetration,
[drug]acceptorIt is the absorbance of acceptance pool, [drug]equilibriumIt is Theoretical Equilibrium absorbance.
Note：P e×10-6 cm s-1Value is more than 5.3, then compound can penetrate blood-brain barrier, be defined as not less than 2.4
Blood-brain barrier can be penetrated.2. be the results are shown in Table by result it is found that majority of compounds can penetrate the blood-brain barrier of external model.
2 external PAMPA-BBB methods of table detect blood brain barrier transmissivity, are as a result represented with means standard deviation
Scavenging effect of the 20-compound of embodiment to free radical
The generation situation of detection oxygen radical is dyed using DHE.HT-22 cells+10% fetal calf serums of DMEM, are placed in
37 DEG C, containing 5% CO2In incubator.By cell with suitable density kind in coated 24 orifice plate of poly-D-lysine；Treat that cell is adherent
Afterwards, it is added in corresponding hole with the prepared PT243 of culture medium respectively, after handling 30 min, adds in 2 mM glutamic acid processing 10
h.Cell is collected, and uses 30 min of DHE dyestuffs incubated cell or so, clean DHE dyestuffs are glimmering with high intension system detectio DHE
Luminous intensity.Experimental result shows that compound 15 can significantly reduce the ROS raisings by glutamate induction, and lipoic acid is dense at 10 μM
The content of ROS is had no significant effect under degree.
21-compound of embodiment is to endogenous anti-oxidative albumen glutathione（Glutathione, GSH）Influence
Influence of the kit detection compound 15 measured using GSH to endogenous GSH.HT-22 cell various concentrations
Compound handle 30 min after, add in 2 mM glutamic acid handle 10 h.Cell is collected, method builds up GSH reagents with reference to Nanjing
Box is measured.As a result see that Fig. 2 can be seen that compound 15 and can significantly increase to be exhausted by the GSH of glutamate induction.And sulphur is pungent
Acid is under 10 μM of concentration without obvious effect.
The vasodilator effect of 22-vascular circle of embodiment experiment detection compound
Quick removal rat chest aorta, and on ice chest connective tissue is detached in the Krebs liquid of ice.It is passed through mixed gas
(95%O2, 5%CO2), gas velocity is adjusted, makes baseline held stationary, blood vessel is hung in the bath of 5mL Krebs liquid, often
15min changes a Krebs liquid.After ready to balance about 1h, KCl (60mM) 5ml is changed, blood vessel is made to reach maximum shrinkage value, and steady
Determine 15min, then change KCl (60mM) 5mL, repetition is done 2 times；After blood vessel is rebalanced, drug is added in accumulative（3 μM,
10 μM, 20 μM, 30 μM）.Maximum tension and each drug when recording pre- contraction add in after tension, to compare.
As a result see Fig. 3, it can be seen that compared with Fasudil, compound 15 shows more mild vasorelaxation action.
Claims (5)
1. the compound or pharmaceutically acceptable salt thereof of formula (I)：
Formula（I）
Wherein,
R1Selected from-H ,-F ,-Cl ,-Br ,-I ,-OCH3、-OCH2CH3、-OCH2CH2CH3、-OCH2CH2CH2CH3、、、、、、、With；
R2It is selected fromWith。
2. a kind of pharmaceutical composition it includes any compound or pharmaceutically acceptable salt thereof described in claim 1 and can pharmaceutically connect
The carrier received.
3. any compound or pharmaceutically acceptable salt thereof described in claim 1 is in the medicine for preparing treatment central nervous system degenerative disease
Application in object.
4. application according to claim 3, wherein the central nervous system degenerative disease is Alzheimer disease, pa
Golden Sen Shi diseases, amyotrophic lateral sclerosis or Huntington's chorea.
5. a kind of ROCK inhibitor, it includes any compound or pharmaceutically acceptable salt thereofs described in claim 1.
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|---|---|---|---|---|
| WO2000053601A1 (en) * | 1999-03-08 | 2000-09-14 | The University Of Mississippi | 1,2-dithiolane derivatives |
| CN1310712A (en) * | 1998-07-31 | 2001-08-29 | 日本曹达株式会社 | Phenylazole compound, process for producing the same and drugs for hyperlipemia |
| CN1349523A (en) * | 1999-04-02 | 2002-05-15 | 科学研究与运用咨询公司 | Novel lipoic acid derivatives, their prepn., and pharmaceutical compositions containing them |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1310712A (en) * | 1998-07-31 | 2001-08-29 | 日本曹达株式会社 | Phenylazole compound, process for producing the same and drugs for hyperlipemia |
| WO2000053601A1 (en) * | 1999-03-08 | 2000-09-14 | The University Of Mississippi | 1,2-dithiolane derivatives |
| CN1349523A (en) * | 1999-04-02 | 2002-05-15 | 科学研究与运用咨询公司 | Novel lipoic acid derivatives, their prepn., and pharmaceutical compositions containing them |
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