CN104387391A - Protease inhibitor and preparation method and application thereof - Google Patents
Protease inhibitor and preparation method and application thereof Download PDFInfo
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- CN104387391A CN104387391A CN201410021960.6A CN201410021960A CN104387391A CN 104387391 A CN104387391 A CN 104387391A CN 201410021960 A CN201410021960 A CN 201410021960A CN 104387391 A CN104387391 A CN 104387391A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 239000000137 peptide hydrolase inhibitor Substances 0.000 title description 2
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 44
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims abstract description 10
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 239000012453 solvate Substances 0.000 claims abstract description 4
- -1 sec.-propyl Chemical group 0.000 claims description 22
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 12
- 239000003112 inhibitor Substances 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 4
- 229940043355 kinase inhibitor Drugs 0.000 claims description 3
- 108090001035 mitogen-activated protein kinase kinase kinase 12 Proteins 0.000 claims description 3
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 3
- 102100025180 Mitogen-activated protein kinase kinase kinase 12 Human genes 0.000 claims description 2
- 239000003405 delayed action preparation Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 230000002496 gastric effect Effects 0.000 claims description 2
- 238000007911 parenteral administration Methods 0.000 claims description 2
- 230000008685 targeting Effects 0.000 claims description 2
- 230000000699 topical effect Effects 0.000 claims description 2
- 108091000080 Phosphotransferase Proteins 0.000 abstract description 10
- 102000020233 phosphotransferase Human genes 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 6
- 230000009977 dual effect Effects 0.000 abstract description 3
- 201000010099 disease Diseases 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- 208000024891 symptom Diseases 0.000 abstract 1
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 4
- 238000004108 freeze drying Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 3
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000012982 microporous membrane Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000013618 particulate matter Substances 0.000 description 2
- 229960000502 poloxamer Drugs 0.000 description 2
- 229920001983 poloxamer Polymers 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 239000002510 pyrogen Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 1
- LWLSVNFEVKJDBZ-UHFFFAOYSA-N N-[4-(trifluoromethoxy)phenyl]-4-[[3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl]methyl]piperidine-1-carboxamide Chemical compound FC(OC1=CC=C(C=C1)NC(=O)N1CCC(CC1)CC1=CC(=CC=C1)OC1=NC=C(C=C1)C(F)(F)F)(F)F LWLSVNFEVKJDBZ-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000000412 dendrimer Substances 0.000 description 1
- 229920000736 dendritic polymer Polymers 0.000 description 1
- 230000000547 effect on apoptosis Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000011806 microball Substances 0.000 description 1
- 102000004898 mitogen-activated protein kinase kinase kinase 12 Human genes 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a class of compounds and their pharmaceutical composition and a preparation method and an application thereof. The invention relates to a compound for reducing or inhibiting dual leucine zipper kinase activity of cells or a subject. The compound or its solvate, hydrate or pharmaceutical salt can be applied in preventing or treating diseases or related symptoms caused by dual leucine zipper kinase abnormity 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 R1 is selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, benzyl; R2 is selected from methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, propoxy-; R3 is selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, positive propoxy.
The present invention has specifically prepared following 2 compounds:
Compound (A);
Compound (B);
The synthetic route of compound of the present invention is as follows:
Wherein R1 is selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, benzyl; R2 is selected from methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, propoxy-; R3 is selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, positive propoxy.
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).
Embodiment
preparation embodiment
The preparation of preparation embodiment 1(compd A and compd A 6)
Compd A 1 and a1, K
2cO
3, CH
3cOCH
3backflow generates compd A 2, by A2 and a2, a3 is together placed in distilling flask at triethylamine, in ethanol, backflow generates compound A-13, compound A-13 normal-temperature reaction in the aqueous ethanolic solution of sodium hydroxide generates compd A 4 in 12 hours, compd A 4 is under sodium borohydride catalysis, and in ethanolic soln, normal temperature generates compound A-45, and compound A-45 and a4 generate A6 under 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and I-hydroxybenzotriazole catalysis.
The preparation of preparation embodiment 2(compd B and compound B-26)
Compound B-11 and b1, K
2cO
3, CH
3cOCH
3backflow generates compd B 2, by B2 and b2, b3 is together placed in distilling flask at triethylamine, in ethanol, backflow generates compd B 3, compd B 3 normal-temperature reaction in the aqueous ethanolic solution of sodium hydroxide generates compd B 4 in 12 hours, compd B 4 is under sodium borohydride catalysis, and in ethanolic soln, normal temperature generates compd B 5, and compd B 5 and b4 generate B6 under 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and I-hydroxybenzotriazole catalysis.
effect example
Compd A, B are to the restraining effect of two leucine zipper kinases (DLK).
Preparation is 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 is 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.
The injection of medicine A and B is configured to the concentration of 0.01mg/ml, according to paper A small molecule – kinase interaction map for clinical(NATURE BIOTECHNOLOGY VOLUME 23 NUMBER 3 MARCH 2005), and paper Activation State-Dependent Binding of Small Molecule Kinase Inhibitors:Structural Insights from Biochemistry kinase inhibitors(Chemistry & Biology 17, 1241 – 1249, November 24, 2010) method measures the IC50 of DLK, wherein the IC50 of A to be that 0.15um(is micro-rub), to be that 0.23um(is micro-rub the IC50 of B).
Claims (7)
1. a compounds or its pharmacologically acceptable salt and analogue thereof, the structure of described compound is as follows:
Wherein R
1be selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, benzyl; R
2be selected from methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, propoxy-; R3 is selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, positive propoxy.
2. compound or pharmaceutically acceptable salt thereof according to claim 1 and analogue thereof, it is selected from following compound:
Compound (A);
Compound (B).
3. the preparation method of compound described in claim any one of claim 1-2, is characterized by and synthesize according to following route:
Wherein R1 is selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, benzyl; R2 is selected from methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, propoxy-; R3 is selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, positive propoxy.
4. compound described in any one of claim 1-3 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.
5. purposes according to claim 4, is characterized in that described compound is DLK inhibitor.
6. comprise the pharmaceutical composition of compound or pharmaceutically acceptable salt thereof any one of claim 1-5 and analogue thereof, it is characterized in that this pharmaceutical composition to be prepared into ordinary preparation, controlled release preparation or targeting preparation.
7. the pharmaceutical composition of claim 6, 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 |
|---|---|---|---|
| CN201410021960.6A CN104387391A (en) | 2013-01-18 | 2014-01-18 | Protease inhibitor and preparation method and application thereof |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310024920 | 2013-01-18 | ||
| CN2013100249202 | 2013-01-18 | ||
| CN201410021960.6A CN104387391A (en) | 2013-01-18 | 2014-01-18 | Protease inhibitor and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104387391A true CN104387391A (en) | 2015-03-04 |
Family
ID=52605365
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410021960.6A Pending CN104387391A (en) | 2013-01-18 | 2014-01-18 | Protease inhibitor and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104387391A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104370913A (en) * | 2013-01-18 | 2015-02-25 | 韩冰 | Intraocular tension reducing compound and preparation method and use thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102573855A (en) * | 2009-10-22 | 2012-07-11 | 霍夫曼-拉罗奇有限公司 | Modulation of axon degeneration |
-
2014
- 2014-01-18 CN CN201410021960.6A patent/CN104387391A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102573855A (en) * | 2009-10-22 | 2012-07-11 | 霍夫曼-拉罗奇有限公司 | Modulation of axon degeneration |
Non-Patent Citations (2)
| Title |
|---|
| V.BAGGA ET AL.: "A three-dimensional pharmacophore modelling of ITK inhibitors and virtual screening for novel inhibitors", 《SAR AND QSAR IN ENVIRONMENTAL RESEARCH》 * |
| V.L.GEIN ET AL.: "Synthesis of 6-acyl-7-aryl-4,7-dihydrotetrazolo[1,5-α]pyrimidine-5-carboxylic acids and their methyl esters", 《RUSSIAN JOURNAL OF ORGANIC CHEMISTRY》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104370913A (en) * | 2013-01-18 | 2015-02-25 | 韩冰 | Intraocular tension reducing compound and preparation method and use thereof |
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Application publication date: 20150304 |
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