CN104370880A - Protease inhibitor and preparing method and use thereof - Google Patents
Protease inhibitor and preparing method and use thereof Download PDFInfo
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- CN104370880A CN104370880A CN201410031649.XA CN201410031649A CN104370880A CN 104370880 A CN104370880 A CN 104370880A CN 201410031649 A CN201410031649 A CN 201410031649A CN 104370880 A CN104370880 A CN 104370880A
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- compound
- ethanoyl
- represent hydrogen
- ethyl
- picolinoyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention discloses a compound and a pharmaceutical composition, a preparation method and use thereof; and the present invention relates to a compound for reducing or inhibiting dual leucine zipper kinase activity of cells or subjects, and use of the compound and a solvate, a hydrate or a pharmaceutically acceptable salt of the compound in prevention or treatment of disease or related diseases caused by dual leucine zipper kinase disorders of patients.
Description
Technical field
The invention discloses a compounds and pharmaceutical composition thereof and its production and use, the present invention relates to a kind of reduction or the compound of two leucine zipper kinase activities of T suppression cell or experimenter, the illness using compound of the present invention or its solvate, hydrate or pharmacologically acceptable salt to cause because two leucine zipper kinases exception in prevention or treatment sufferer or the purposes of associated conditions.
Background technology
DLK (Dual Leucine zipper Kinase) is two leucine zipper kinases, has another name called MAPK upstream kinases or leucine zipper protein kinases.It is that Holzman equals find when screening mice develop regulation and control kinases and identify out for 1994, and containing 1 catalyst structure domain, 2 leucine-zipper motif and N end hold the structural domain of Gly/Pro-rich with C, can be phosphorylated at Ser, Thr place.DLK is at apoptosis, propagation, differentiation and tissue reconstruction important role.DLK inhibitor can give extraordinary action effect on apoptosis, propagation, differentiation and tissue reconstruction.
The present inventor has prepared one group of compound and similar compound thereof or its pharmacologically acceptable salt, and this group compound and similar compound thereof or its pharmacologically acceptable salt have beyond thought outstanding effect as DLK inhibitor.
Summary of the invention
The invention provides one group of compound and similar compound or its pharmacologically acceptable salt thereof the novelty teabag as DLK inhibitor.
Technical scheme of the present invention is as follows:
One compounds or its pharmacologically acceptable salt and analogue thereof, the structure of described compound is as follows:
Wherein: R
1represent hydrogen, methyl; R
2represent hydrogen, methyl; R represent hydrogen, 2-methysulfonylethyl, 2-morpholinyl ethyl, 2-hydroxyethyl, 2-amino-ethyl, 2-cyano ethyl, carbamoyhnethyl, 2-picolyl, carboxymethyl, formamyl, 2-picolinoyl, 3-picolinoyl, 4-picolinoyl, ethanoyl, 2-dimethylamino acetyl, 2-hydroxyethylamino ethanoyl, 2-(
n-hydroxyethyl methylamino-) ethanoyl, 2-(2-imidazolyl) ethanoyl, 2,3-dihydroxyl propionyls.
Enumerate 3 preferred compounds below:
Compound (A), 4-cyano group-
n-[2-[3-[1-[2-(dimethylamino) ethanoyl] piperidin-4-yl] phenyl] cyclohexenyl-1-base]-1
h-imidazoles-2-methane amide
；
Compound (B), 4-cyano group-
n-[2-[3-[1-[2-(methyl sulphonyl) ethyl] piperidin-4-yl] phenyl] cyclohexenyl-1-base]-1
h-imidazoles-2-methane amide;
Compound (C), 4-cyano group-
n-[2-[3-[1-[2-morpholinyl ethyl] piperidin-4-yl] phenyl] cyclohexenyl-1-base]-1
h-imidazoles-2-methane amide;
The synthetic route of compound of the present invention is as follows:
Wherein: R
1represent hydrogen, methyl; R
2represent hydrogen, methyl; R represent hydrogen, 2-methysulfonylethyl, 2-morpholinyl ethyl, 2-hydroxyethyl, 2-amino-ethyl, 2-cyano ethyl, carbamoyhnethyl, 2-picolyl, carboxymethyl, formamyl, 2-picolinoyl, 3-picolinoyl, 4-picolinoyl, ethanoyl, 2-dimethylamino acetyl, 2-hydroxyethylamino ethanoyl, 2-(
n-hydroxyethyl methylamino-) ethanoyl, 2-(2-imidazolyl) ethanoyl, 2,3-dihydroxyl propionyls.
Compound of the present invention is a kind of reduction or the compound of two leucine zipper kinase activities of T suppression cell or sufferer, the illness using compound of the present invention or its solvate, hydrate or pharmacologically acceptable salt to cause because two leucine zipper kinases exception in prevention or treatment sufferer or the purposes of associated conditions.
Compound of the present invention and analogue thereof or its pharmacologically acceptable salt can be prepared into through topical, gastrointestinal administration or the various preparations of parenteral administration.Described preparation comprises ordinary preparation, controlled release preparation, targeting preparation etc.Described local administration preparation is powder injection, aqueous injection, microball preparation, nanometer formulation, Liposomal formulation, dendrimer preparation, polyethyleneglycol modified preparation, aqueogel etc. through administrations such as organ, head, eyes.Described parenterals is the formulation of suitable intravenous injection, intramuscular injection, subcutaneous injection, bone marrow injection, transdermal administration, mucosa delivery and inhalation.
The present inventor studies discovery: this compounds is as DLK inhibitor, and effect obviously.The exploitation of this new compound is by for going the disease for the treatment of to produce far reaching significance to applying DLK inhibitor future.
Accompanying drawing explanation
Fig. 1: the nuclear magnetic spectrum of compound (A).
Fig. 2: the nuclear magnetic spectrum of compound (B).
Fig. 3: the nuclear magnetic spectrum of compound (C).
Embodiment
preparation embodiment
The preparation of preparation embodiment 1(compd A and compd A 11)
Compd A 1 and A2 chemical combination generate compound A-13; A3 bromination obtains compd A 4; benzene replaces bromine and generates compound A-45; generate compd A 6 after deaminizing, nitro replaces generation compd A 7, and nitro is reduced generation compound A-28; under Boc protection; A8 is not generated compd A 9 by the amino-reactive that Boc protects, and trifluoroacetic acid takes off Boc and generates A10, and naphthene amino activation generates A11.
The preparation of preparation embodiment 2(compd B and compound B-11 1)
Compound B-11 and B2 chemical combination generate compd B 3; B3 bromination obtains compd B 4; benzene replaces bromine and generates compd B 5; generate compound B-26 after deaminizing, nitro replaces generation compd B 7, and nitro is reduced and generates compd B 8; under Boc protection; B8 is not generated compd B 9 by the amino-reactive that Boc protects, and trifluoroacetic acid takes off Boc and generates B10, and naphthene amino activation generates B11.
The preparation of preparation embodiment 3(Compound C and Compound C 11)
Compound C 1 and C2 chemical combination generate Compound C 3; C3 bromination obtains Compound C 4; benzene replaces bromine and generates Compound C 5; generate Compound C 6 after deaminizing, nitro replaces generation Compound C 7, and nitroreduction generates Compound C 8; under Boc protection; C8 is not generated Compound C 9 by the amino-reactive that Boc protects, and trifluoroacetic acid takes off Boc and generates C10, and naphthene amino activation generates C11.
Preparation containing compd A injection:
1. get common 50mg and 100mg formula (A) compound of N.F,USP MANNITOL, phosphatide, glycerine, cyclodextrin derivative, dimethyl sulfoxide (DMSO) and poloxamer mix in water for injection and make it to dissolve;
2. mixing first uses 0.45um millipore filtration coarse filtration after dissolving after stable, then uses 0.2um filtering with microporous membrane;
3. be distributed into little cillin bottle, add other freeze-drying therapeutical agent and auxiliary materials;
4. procedural freeze-drying is carried out;
5. pyrogen, aseptic, the corresponding inspection such as visible foreign matters, particulate matter is carried out, stand-by after all meeting the requirements.
Preparation containing compd B injection:
1. get common 50mg and 200mg formula (B) compound of N.F,USP MANNITOL, phosphatide, glycerine, cyclodextrin derivative, dimethyl sulfoxide (DMSO) and poloxamer mix in water for injection and make it to dissolve;
2. mixing first uses 0.45um millipore filtration coarse filtration after dissolving after stable, then uses 0.2um filtering with microporous membrane;
3. be distributed into little cillin bottle, add other freeze-drying therapeutical agent and auxiliary materials;
4. procedural freeze-drying is carried out;
5. pyrogen, aseptic, the corresponding inspection such as visible foreign matters, particulate matter is carried out, stand-by after all meeting the requirements.
Preparation containing Compound C injection:
1. get common 50mg and 400mg formula (C) compound of N.F,USP MANNITOL, phosphatide, glycerine, cyclodextrin derivative, dimethyl sulfoxide (DMSO) and poloxamer mix in water for injection and make it to dissolve;
2. mixing first uses 0.45um millipore filtration coarse filtration after dissolving after stable, then uses 0.2um filtering with microporous membrane;
3. be distributed into little cillin bottle, add other freeze-drying therapeutical agent and auxiliary materials;
4. procedural freeze-drying is carried out;
5. pyrogen, aseptic, the corresponding inspection such as visible foreign matters, particulate matter is carried out, stand-by after all meeting the requirements.
effect example
By medicine A, B, the injection of C is configured to the concentration of 0.01mg/ml, roll up according to paper A small molecule – kinase interaction map for clinical(NATURE BIOTECHNOLOGY: 23, number of pages: 329-336, 2005), and paper Activation State-Dependent Binding of Small Molecule Kinase Inhibitors:Structural Insights from Biochemistry kinase inhibitors(Chemistry & Biology rolls up: 17, number of pages: 1241 – 1249, 2010) described method measures the IC50 of DLK, wherein each drug determination 5 times, average, the scope being included into DLK inhibitor IC50 according to mean values (is less than 0.01um, 0.01um-0.1um, 0.1um-0.2um, 0.2um-0.5um, 0.5um-1um).Wherein see the following form in the IC50 interval of each medicine:
Table one: the IC50 of each Drug inhibition DLK is interval.(IC50 averages after measuring 5 times)
| The IC50 scope of Drug inhibition DLK (unit: micro-rub) | Medicine A | Medicine B | Medicine C |
| Below 0.01um | |||
| 0.01um-0.1um | |||
| 0.1um-0.2um | |||
| 0.2um-0.5um | √ | √ | |
| 0.5um-1um | √ |
Claims (8)
1. a compounds or its pharmacologically acceptable salt and analogue thereof, the structure of described compound is as follows:
Wherein: R
1represent hydrogen, methyl; R
2represent hydrogen, methyl; R represent hydrogen, 2-methysulfonylethyl, 2-morpholinyl ethyl, 2-hydroxyethyl, 2-amino-ethyl, 2-cyano ethyl, carbamoyhnethyl, 2-picolyl, carboxymethyl, formamyl, 2-picolinoyl, 3-picolinoyl, 4-picolinoyl, ethanoyl, 2-dimethylamino acetyl, 2-hydroxyethylamino ethanoyl, 2-(
n-hydroxyethyl methylamino-) ethanoyl, 2-(2-imidazolyl) ethanoyl, 2,3-dihydroxyl propionyls.
2. compound or pharmaceutically acceptable salt thereof according to claim 1 and analogue thereof, work as R
1, R
2represent hydrogen, R is when representing 2-dimethylamino acetyl, the various salt of this compound; Work as R
1, R
2represent hydrogen, R is when representing 2-methysulfonylethyl, the various salt of this compound; Work as R
1, R
2represent hydrogen, R is when representing 2-morpholinyl ethyl, the various salt of this compound.
3. compound or pharmaceutically acceptable salt thereof according to claim 1 and analogue thereof, it is selected from following compound:
Compound (A), 4-cyano group-
n-[2-[3-[1-[2-(dimethylamino) ethanoyl] piperidin-4-yl] phenyl] cyclohexenyl-1-base]-1
h-imidazoles-2-methane amide
；
Compound (B), 4-cyano group-
n-[2-[3-[1-[2-(methyl sulphonyl) ethyl] piperidin-4-yl] phenyl] cyclohexenyl-1-base]-1
h-imidazoles-2-methane amide;
Compound (C), 4-cyano group-
n-[2-[3-[1-[2-morpholinyl ethyl] piperidin-4-yl] phenyl] cyclohexenyl-1-base]-1
h-imidazoles-2-methane amide.
4. the preparation method of compound described in claim any one of claim 1-3, is characterized by and synthesize according to following route:
Wherein: R
1represent hydrogen, methyl; R
2represent hydrogen, methyl; R represent hydrogen, 2-methysulfonylethyl, 2-morpholinyl ethyl, 2-hydroxyethyl, 2-amino-ethyl, 2-cyano ethyl, carbamoyhnethyl, 2-picolyl, carboxymethyl, formamyl, 2-picolinoyl, 3-picolinoyl, 4-picolinoyl, ethanoyl, 2-dimethylamino acetyl, 2-hydroxyethylamino ethanoyl, 2-(
n-hydroxyethyl methylamino-) ethanoyl, 2-(2-imidazolyl) ethanoyl, 2,3-dihydroxyl propionyls.
5. compound described in any one of claim 1-4 or its solvate, hydrate, or its pharmaceutical salts and analogue thereof the purposes in the medicine of the two leucine zipper kinase inhibitor of preparation.
6. purposes according to claim 5, is characterized in that described compound is DLK inhibitor.
7. comprise the pharmaceutical composition of compound or pharmaceutically acceptable salt thereof any one of claim 1-6 and analogue thereof, it is characterized in that this pharmaceutical composition to be prepared into ordinary preparation, controlled release preparation or targeting preparation.
8. the pharmaceutical composition of claim 7, described compound and pharmacologically acceptable salt thereof are prepared into through topical with its analogue, gastrointestinal administration or the various preparations of parenteral administration.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410031649.XA CN104370880A (en) | 2013-01-24 | 2014-01-23 | Protease inhibitor and preparing method and use thereof |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310036091 | 2013-01-24 | ||
| CN201310036091X | 2013-01-24 | ||
| CN201410031649.XA CN104370880A (en) | 2013-01-24 | 2014-01-23 | Protease inhibitor and preparing method and use thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104370880A true CN104370880A (en) | 2015-02-25 |
Family
ID=52550115
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410031649.XA Pending CN104370880A (en) | 2013-01-24 | 2014-01-23 | Protease inhibitor and preparing method and use thereof |
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| Country | Link |
|---|---|
| CN (1) | CN104370880A (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1918162A (en) * | 2003-12-23 | 2007-02-21 | 赛福伦公司 | Novel fused pyrrolocarbazoles |
| CN101340909A (en) * | 2005-10-18 | 2009-01-07 | 詹森药业有限公司 | Method of inhibiting flt3 kinase |
| CN101437514A (en) * | 2004-10-22 | 2009-05-20 | 詹森药业有限公司 | Inhibidores of C-FMS cinasa |
| CN101610768A (en) * | 2006-04-20 | 2009-12-23 | 詹森药业有限公司 | Suppress the kinase whose method of C KIT |
| CN102573855A (en) * | 2009-10-22 | 2012-07-11 | 霍夫曼-拉罗奇有限公司 | Modulation of axon degeneration |
-
2014
- 2014-01-23 CN CN201410031649.XA patent/CN104370880A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1918162A (en) * | 2003-12-23 | 2007-02-21 | 赛福伦公司 | Novel fused pyrrolocarbazoles |
| CN101437514A (en) * | 2004-10-22 | 2009-05-20 | 詹森药业有限公司 | Inhibidores of C-FMS cinasa |
| CN101340909A (en) * | 2005-10-18 | 2009-01-07 | 詹森药业有限公司 | Method of inhibiting flt3 kinase |
| CN101610768A (en) * | 2006-04-20 | 2009-12-23 | 詹森药业有限公司 | Suppress the kinase whose method of C KIT |
| CN102573855A (en) * | 2009-10-22 | 2012-07-11 | 霍夫曼-拉罗奇有限公司 | Modulation of axon degeneration |
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Application publication date: 20150225 |
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