CN116082239A - PDE4/7 double-target inhibitor and preparation method and application thereof - Google Patents
PDE4/7 double-target inhibitor and preparation method and application thereof Download PDFInfo
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- CN116082239A CN116082239A CN202310105791.3A CN202310105791A CN116082239A CN 116082239 A CN116082239 A CN 116082239A CN 202310105791 A CN202310105791 A CN 202310105791A CN 116082239 A CN116082239 A CN 116082239A
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- 101100296720 Dictyostelium discoideum Pde4 gene Proteins 0.000 title claims abstract description 34
- 101100082610 Plasmodium falciparum (isolate 3D7) PDEdelta gene Proteins 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 239000003112 inhibitor Substances 0.000 title claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 48
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 239000003814 drug Substances 0.000 claims abstract description 6
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims abstract description 5
- 208000036824 Psoriatic arthropathy Diseases 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 206010002556 Ankylosing Spondylitis Diseases 0.000 claims abstract description 4
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims abstract description 4
- 201000004681 Psoriasis Diseases 0.000 claims abstract description 4
- 206010035664 Pneumonia Diseases 0.000 claims abstract description 3
- 230000001684 chronic effect Effects 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000013067 intermediate product Substances 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 238000001704 evaporation Methods 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 238000004440 column chromatography Methods 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 125000004429 atom Chemical group 0.000 claims description 8
- 125000000524 functional group Chemical group 0.000 claims description 8
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000004434 sulfur atom Chemical group 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- -1 amine compound Chemical class 0.000 claims description 7
- 239000000047 product Substances 0.000 claims description 7
- VFZRZRDOXPRTSC-UHFFFAOYSA-N 3,5-Dimethoxybenzaldehyde Chemical class COC1=CC(OC)=CC(C=O)=C1 VFZRZRDOXPRTSC-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 6
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 claims description 6
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- DZGWFCGJZKJUFP-UHFFFAOYSA-N tyramine Chemical compound NCCC1=CC=C(O)C=C1 DZGWFCGJZKJUFP-UHFFFAOYSA-N 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 230000002829 reductive effect Effects 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- 125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 239000000376 reactant Substances 0.000 claims description 4
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 4
- UHDFWGBBKSDYKJ-UHFFFAOYSA-N 1-[4-(diethoxymethyl)phenyl]ethanone Chemical class CCOC(OCC)C1=CC=C(C(C)=O)C=C1 UHDFWGBBKSDYKJ-UHFFFAOYSA-N 0.000 claims description 3
- ICGLPKIVTVWCFT-UHFFFAOYSA-N 4-methylbenzenesulfonohydrazide Chemical compound CC1=CC=C(S(=O)(=O)NN)C=C1 ICGLPKIVTVWCFT-UHFFFAOYSA-N 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 claims description 3
- DDRPCXLAQZKBJP-UHFFFAOYSA-N furfurylamine Chemical compound NCC1=CC=CO1 DDRPCXLAQZKBJP-UHFFFAOYSA-N 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- RWIVICVCHVMHMU-UHFFFAOYSA-N n-aminoethylmorpholine Chemical compound NCCN1CCOCC1 RWIVICVCHVMHMU-UHFFFAOYSA-N 0.000 claims description 3
- 230000007935 neutral effect Effects 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 229960003732 tyramine Drugs 0.000 claims description 3
- 101100296719 Caenorhabditis elegans pde-4 gene Proteins 0.000 claims description 2
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- 230000000694 effects Effects 0.000 abstract description 13
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- 230000003285 pharmacodynamic effect Effects 0.000 abstract description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract 1
- 230000005764 inhibitory process Effects 0.000 description 10
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 description 7
- 101100407335 Dictyostelium discoideum pde7 gene Proteins 0.000 description 6
- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 description 6
- 235000021283 resveratrol Nutrition 0.000 description 6
- 229940016667 resveratrol Drugs 0.000 description 6
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 5
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 5
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 description 5
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- 238000003786 synthesis reaction Methods 0.000 description 5
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- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 2
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 2
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- 229940079593 drug Drugs 0.000 description 2
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- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
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- IFIUFCJFLGCQPH-UHFFFAOYSA-N BRL-50481 Chemical compound CN(C)S(=O)(=O)C1=CC(N(=O)=O)=CC=C1C IFIUFCJFLGCQPH-UHFFFAOYSA-N 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
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- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 229940123304 Phosphodiesterase 7 inhibitor Drugs 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 244000153955 Reynoutria sachalinensis Species 0.000 description 1
- 235000003202 Reynoutria sachalinensis Nutrition 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
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- 235000012333 Vitis X labruscana Nutrition 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 235000014787 Vitis vinifera Nutrition 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- IMOZEMNVLZVGJZ-QGZVFWFLSA-N apremilast Chemical compound C1=C(OC)C(OCC)=CC([C@@H](CS(C)(=O)=O)N2C(C3=C(NC(C)=O)C=CC=C3C2=O)=O)=C1 IMOZEMNVLZVGJZ-QGZVFWFLSA-N 0.000 description 1
- 229960001164 apremilast Drugs 0.000 description 1
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- 238000005259 measurement Methods 0.000 description 1
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- UPSFMJHZUCSEHU-JYGUBCOQSA-N n-[(2s,3r,4r,5s,6r)-2-[(2r,3s,4r,5r,6s)-5-acetamido-4-hydroxy-2-(hydroxymethyl)-6-(4-methyl-2-oxochromen-7-yl)oxyoxan-3-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide Chemical compound CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](NC(C)=O)[C@H](OC=2C=C3OC(=O)C=C(C)C3=CC=2)O[C@@H]1CO UPSFMJHZUCSEHU-JYGUBCOQSA-N 0.000 description 1
- 230000004112 neuroprotection Effects 0.000 description 1
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- LUKBXSAWLPMMSZ-UHFFFAOYSA-N resveratrol Chemical compound C1=CC(O)=CC=C1C=CC1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-UHFFFAOYSA-N 0.000 description 1
- MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 description 1
- 229960002586 roflumilast Drugs 0.000 description 1
- HJORMJIFDVBMOB-UHFFFAOYSA-N rolipram Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OC1CCCC1 HJORMJIFDVBMOB-UHFFFAOYSA-N 0.000 description 1
- 229950005741 rolipram Drugs 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Dermatology (AREA)
- Pain & Pain Management (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a PDE4/7 double-target inhibitor and a preparation method and application thereof, the compound of the general formula (A), or a stereoisomer, a stable isotope derivative or a pharmaceutically acceptable salt thereof, provided by the invention, has good PDE4/7 double-inhibition activity, can show more excellent pharmacodynamic performance and small side effect compared with the traditional single PDEs inhibitor so as to overcome the side effect such as serious nausea, vomiting and gastrointestinal tract reaction, can be used for preparing medicaments for treating psoriasis, psoriatic arthritis, chronic obstructive pneumonia, ankylosing spondylitis, inflammatory bowel disease and the like,
Description
Technical Field
The invention belongs to the field of medicine synthesis, and in particular relates to a PDE4/7 inhibitor with diaryl pyrazole skeleton, and a preparation method and application thereof.
Background
Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are intracellular second messengers. They are found in many tissue cell structures, are responsible for intracellular signaling, are involved in the regulation of various physiological processes, and play an extremely important role in physiological activities of cells. Imbalance in cAMP and cGMP concentrations can lead to the development of a variety of diseases, and thus how to maintain their concentrations at normal levels, leaving the body in a healthy state, has become an important point of research. Phosphodiesterases (PDEs) are the only proteases that are able to selectively hydrolyze cAMP (cyclic adenosine monophosphate) and cGMP (cyclic guanosine monophosphate) in the body. PDEs can be classified into the 11 families (PDE 1-PDE 11) according to their specificity for substrates, enzymatic kinetic properties, etc. Among them, PDE4 plays an important role in degrading inflammatory cells, pulmonary and nervous system diseases, thus making PDE4 a very important target for drug development. In recent years, PDE4 inhibitors Roflumilast, apremilast, crisabanole have been approved by the FDA for the treatment of chronic obstructive pulmonary disease, psoriatic arthritis, and atopic dermatitis, respectively. However, these inhibitors, while achieving therapeutic effects, have unavoidable side effects such as severe nausea, vomiting, gastrointestinal reactions, etc. (front. Pharmacol.2018,9,1048), greatly restricting their use.
While drugs that have an inhibitory effect on multiple PDE subtypes at the same time are one of the strategies that have become possible to address these problems. Among these, more double-target PDEs inhibitors with one of the PDE4 targets, such as PDE3/4, PDE4/7 double-target inhibitors, are reported (Bioorganic & Medicinal Chemistry Letters,2013,23,375-381;European Journal of Medicinal Chemistry,2018,146,381-394;European Journal of Medicinal Chemistry,2018,158,517-533).
Resveratrol (Resveratrol) is a natural polyphenol compound widely existing in red wine, grape skin and Japanese giant knotweed, has various biological activities such as anti-inflammatory, antioxidant, antitumor and neuroprotection (Nutritional Neuroscience,2017,20,180-194), and also has a certain PDE4 inhibitory activity (Oncotarget, 2016,7,17380-17392). However, the inhibition of PDE4 by resveratrol is not strong enough, so that the resveratrol is subjected to pharmaceutical chemistry design, and a compound with strong inhibition of PDE4 and good PDE7 inhibition activity is developed, so that the compound has great significance and great clinical demands and market value.
Disclosure of Invention
In view of the deficiencies of the prior art, it is an object of the present invention to provide a compound having good PDE4/7 inhibitory activity.
To achieve the above object, the present invention provides a PDE4/7 dual-target inhibitor comprising a compound of general formula (a), or a stereoisomer, a stable isotope derivative or a pharmaceutically acceptable salt thereof, the general formula (a) being as follows:
in the general formula:
r is:
1-12C alkyl or 1-12C heteroalkyl or 3-12C cycloalkyl or 3-12C cycloheteroalkyl, said C1-12 heteroalkyl or 3-12C cycloheteroalkyl containing the following atoms or functional groups: n, O, S atoms or two of them;
or a benzene ring, an aromatic heterocycle, a benzene ring containing a substituent or an aromatic heterocycle containing a substituent, wherein the substituent is hydroxyl, 1-4C substituted alkyl or alkoxy, amino, 1-4C substituted alkylamino, nitro or cyano.
Preferably, the R is:
1-6C alkyl or 1-6C heteroalkyl or 3-6C cycloalkyl or 3-6C cycloheteroalkyl, said C1-6 heteroalkyl or 3-6C cycloheteroalkyl containing the following atoms or functional groups: n, O, S atoms or two of them.
Preferably, the PDE4/7 dual-target inhibitor is selected from the group consisting of:
the present invention also provides a pharmaceutical composition comprising the compound of general formula (a) as defined in any one of the above, or a stereoisomer, a stable isotope derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
The invention also provides a preparation method of the PDE4/7 double-target inhibitor, which comprises the following preparation steps:
(1) Dissolving substituted 3, 5-dimethoxy benzaldehyde and 1- [4- (diethoxymethyl) phenyl ] ethanone in methanol, adding 3M sodium hydroxide solution under ice bath condition for reaction, adjusting pH to neutral after the reaction is completed, adding ethyl acetate and water for layering, taking ethyl acetate layer, evaporating solvent under reduced pressure, and separating by column chromatography to obtain intermediate product 3;
(2) Dissolving the intermediate product 3, p-toluenesulfonyl hydrazine and catalytic amount of iodine in absolute ethyl alcohol, heating and refluxing, standing reactants after the reaction is completed, separating out pale yellow solid, and recrystallizing the pale yellow solid in DMF to obtain an intermediate product 4;
(3) Dissolving the intermediate product 4 and 2M hydrochloric acid in tetrahydrofuran at room temperature, stirring for reaction, adding ethyl acetate and water for layering after the reaction is finished, decompressing and evaporating the ethyl acetate layer to remove the solvent, and separating by column chromatography to obtain an intermediate product 5;
(4) Dissolving an intermediate product 5 and an amine compound in absolute ethyl alcohol, carrying out reflux reaction, cooling to room temperature after the reaction is completed, adding sodium borohydride in batches for continuous reaction, after the reaction is completed, evaporating the solvent under reduced pressure, dissolving the reactant by using ethyl acetate, filtering, washing by using saturated saline water, separating an ethyl acetate layer, evaporating the solvent under pressure, and separating by using column chromatography to obtain a target product, wherein the general formula (A) of the target product is as described above, and the amine compound is prepared byThe general formula (B) is RNH 2 In the general formula (B):
r is:
1-12C alkyl or 1-12C heteroalkyl or 1-12C cycloalkyl or 1-12C cycloheteroalkyl, said C1-12 heteroalkyl or 1-12C cycloheteroalkyl containing the following atoms or functional groups: n, O, S atoms or two of them;
or a benzene ring, an aromatic heterocycle, a benzene ring containing a substituent or an aromatic heterocycle containing a substituent, wherein the substituent is hydroxyl, 1-4C substituted alkyl or alkoxy, amino, 1-4C substituted alkylamino, nitro or cyano.
Preferably, the R is:
1-6C alkyl or 1-6C heteroalkyl or 3-6C cycloalkyl or 3-6C cycloheteroalkyl, said C1-6 heteroalkyl or 1-6C cycloheteroalkyl containing the following atoms or functional groups: n, O, S atoms or two of them.
Preferably, the amine compound is ethylamine, propylamine, cyclopentylamine, cyclohexylamine, benzylamine, tyramine, furfuryl amine, N- (2-aminoethyl) morpholine.
The invention further provides application of the PDE4/7 double-target inhibitor in preparing medicines for preventing and treating PDE4 related diseases.
Preferably, the PDE 4-related disease is psoriasis, psoriatic arthritis, chronic obstructive pulmonary disease, ankylosing spondylitis, inflammatory bowel disease.
The invention has the following advantages:
by carrying out pharmaceutical chemistry design on resveratrol, double bonds in the structure of resveratrol are changed into pyrazole rings, and PDE4 and PDE7 inhibitors with excellent activity are successfully discovered. The resveratrol derivative containing pyrazole rings, which has the structure shown in the general formula A, has good PDE4/7 double inhibition activity, and can show more excellent pharmacodynamic performance and small side effect compared with the traditional single PDEs inhibitor. To overcome the side effects such as serious nausea, vomiting and gastrointestinal reactions, the compounds can be used for preparing medicaments for treating psoriasis, psoriatic arthritis, chronic obstructive pneumonia, ankylosing spondylitis, inflammatory bowel diseases and the like.
Detailed Description
The present invention will be further described in detail with reference to examples and effect examples, without limiting the scope of the present invention.
EXAMPLE 1 preparation of Compound a Synthesis
(1) Preparation and Synthesis of intermediate 3
The structural formula of intermediate 3 is as follows:
to a round bottom flask was added 1.66g (10 mmol) of human 3, 5-dimethoxybenzaldehyde, 2.22g (10 mmol) of 1- [4- (diethoxymethyl) phenyl ] ethanone, 30mL of methanol, and 4.67mL (0.56 g of NaOH) of 3M sodium hydroxide solution in ice bath. The reaction was continued at room temperature for 12h. After the reaction is finished, the pH value of the diluted hydrochloric acid is adjusted to be neutral. Then adding proper amount of ethyl acetate and water for layering, decompressing and evaporating the ethyl acetate layer to remove the solvent, and separating by column chromatography to obtain the intermediate 3 (2.45 g, yield 66.3%).
1 H NMR(400MHz,DMSO-d 6 )δ7.53(d,J＝8.6Hz,2H),7.36(m,3H),6.93-6.82(m,3H),6.78(m,1H),6.11(s,1H),3.92(s,6H),3.81(m,4H),1.26(m,6H).HRMS calcd.for C 22 H 27 O 5 [M+H] + :371.1858,found371.1841.
(2) Preparation of intermediate 4
The structural formula of intermediate 4 is as follows:
3.70g (10 mmol) of Compound 3, 1.86g (10 mmol) of p-toluenesulfonyl hydrazide, a catalytic amount of iodine and 30mL of absolute ethanol were added to a round bottom flask, the reaction progress was monitored by TLC under heating reflux for 5h, after completion of the reaction, the reaction was left to stand overnight to precipitate a pale yellow solid, which was recrystallized in DMF to give Compound 4 (2.77 g, yield 72.6%).
1 H NMR(400MHz,DMSO-d 6 )δ7.55(d,J＝8.7Hz,2H),7.23(m,2H),7.13(d,J＝8.7Hz,2H),6.92(m,1H),6.78(m,1H),6.12(s,1H),3.91(s,6H),3.83(m,4H),1.25(m,6H).HRMS calcd.for C 22 H 27 N 2 O 4 [M+H] + :383.1971,found 383.1987.
(3) Preparation and Synthesis of intermediate 5
The intermediate 5 has the following structural formula:
to a round bottom flask was added human compound 4 (3.82 g,10 mmol), 2M hydrochloric acid 5mL and 30mL tetrahydrofuran at room temperature, and reacted for 2h. After the reaction, adding a proper amount of ethyl acetate and water for layering, decompressing and evaporating the ethyl acetate layer to remove the solvent, and separating by column chromatography to obtain the target product 5 (2.47 g, yield 80.2%).
1 H NMR(400MHz,DMSO-d 6 )δ9.92(s,1H),8.07(d,J＝8.5Hz,2H),7.62(d,J＝8.5Hz,2H),7.13(m,2H),6.97(m,1H),6.85(m,1H),3.89(s,6H).HRMS calcd.for C 18 H 17 N 2 O 3 [M+H] + :309.1239,found309.1226.
(4) Preparation of Compound a
In a round bottom flask was added human compound 5 (3.08 g,10 mmol), ethylamine (0.45 g,10 mmol) and 30mL absolute ethanol and reacted for 2h under reflux. After cooling to room temperature, sodium borohydride (0.19 g,5 mmol) was added in portions and the reaction was continued for 5 hours. After the reaction was completed, the solvent was distilled off under reduced pressure. The reaction mixture was dissolved in 50ml of ethyl acetate, filtered and washed with saturated brine. The ethyl acetate layer was separated, the solvent was distilled off under pressure, and the desired product a (2.47 g, yield 83.6%) was obtained by column chromatography.
1 H NMR(400MHz,DMSO-d 6 )δ7.56(d,J＝8.2Hz,2H),7.38(d,J＝16.1Hz,1H),7.16(d,J＝16.1Hz,1H),6.93(d,J＝8.2Hz,2H),6.81(s,1H),6.55(s,1H),3.91(s,3H),3.82(s,3H),3.71(s,2H),2.12(m,2H),1.35(m,3H).HRMS calcd.for C 20 H 24 N 3 O 2 [M+H] + :338.1869,found 338.1852。
EXAMPLE 2 preparation of Compound b Synthesis
The structural formula of the compound b is as follows:
compound b was synthesized by referring to the preparation method of compound a of example 1, except that propylamine was used instead of ethylamine, with a total yield of 31.3%.
1 H NMR(400MHz,DMSO-d 6 )δ7.53(d,J＝8.1Hz,2H),7.33(d,J＝16.3Hz,1H),7.17(d,J＝16.3Hz,1H),6.92(d,J＝8.1Hz,2H),6.86(s,1H),6.51(s,1H),3.91(s,3H),3.83(s,3H),3.77(s,2H),2.13(m,2H),1.49(m,2H),1.12(m,3H).HRMS calcd.for C 21 H 26 N 3 O 2 [M+H] + :352.2025,found 352.2039。
Example 3: preparation of Compound c
The structural formula of compound c is as follows:
compound c was synthesized according to the procedure for the preparation of compound a of example 1, using cyclopentylamine instead of ethylamine, with a total yield of 28.6%. 1 H NMR(400MHz,DMSO-d 6 )δ7.52(d,J＝8.3Hz,2H),7.37(d,J＝16.2Hz,1H),7.1l(d,J＝16.2Hz,1H),6.95(d,J＝8.3Hz,2H),6.81(s,1H),6.47(s,1H),3.92(s,3H),3.80(s,3H),3.77(s,2H),3.06(m,1H),1.71(m,2H),1.61(m,2H),1.45(m,2H),1.38(m,2H).HRMS calcd.for C 23 H 28 N 3 O 2 [M+H] + :378.2182,found378.2173。
Example 4: preparation of Compound d
The structural formula of compound d is as follows:
compound d was synthesized according to the procedure for the preparation of compound a of example 1, using cyclohexylamine instead of ethylamine, with a total yield of 26.1%. 1 HNMR(400MHz,DMSO-d 6 )δ7.51(d,J＝8.5Hz,2H),7.37(d,J＝16.3Hz,1H),7.11(d,J＝16.3Hz,1H),6.95(d,J＝8.5Hz,2H),6.80(m,1H),6.47(m,1H),3.80(s,3H),3.77(m,3H),3.76(s,2H),2.42(m,1H),1.84(m,2H),1.63(m,2H),1.05-1.22(m,6H).HRMS calcd.for C 24 H 30 N 3 O 2 [M+H] + :392.2338,found 392.2351。
Example 5: preparation of Compound e
The structural formula of compound e is as follows:
compound e was synthesized according to the procedure for the preparation of compound a of example 1, using benzylamine instead of ethylamine, with a total yield of 33.9%. 1 H NMR(400MHz,DMSO-d 6 )δ7.52-7.58(m,4H),7.45-7.48(m,3H),7.18(d,J＝8.7Hz,2H),6.98(d,J＝8.7Hz,2H),6.89(m,1H),6.55(m,1H),4.23(m,2H),4.11(m,2H),3.84(s,3H),3.80(s,3H),3.77(s,2H).HRMS calcd.for C 25 H 26 N 3 O 2 [M+H] + :400.2025,found400.2013。
Example 6: preparation of Compound f
The structural formula of the compound f is as follows:
compound f was synthesized according to the procedure for the preparation of compound a of example 1, using tyramine instead of ethylamine, with a total yield of 22.7%. 1 H NMR(400MHz,DMSO-d 6 )δ9.32(s,1H),7.49(d,J＝8.6Hz,2H),7.32(d,J＝16.2Hz,1H),7.10(d,J＝16.2Hz,1H),6.96(m,3H),6.82(m,2H),6.61(d,J＝8.6Hz,2H),6.45(m,1H),3.80(s,3H),3.78(s,3H),3.75(s,2H),2.71(m,2H),2.59(m,2H).HRMS calcd.for C 26 H 28 N 3 O 3 [M+H] + :430.2131,found 430.2147。
Example 7: preparation of Compound g
The structural formula of compound g is as follows:
compound g was synthesized according to the procedure for the preparation of compound a of example 1, using furfuryl amine instead of ethylamine, with a total yield of 30.2%. 1 H NMR(400MHz,DMSO-d 6 )δ7.58(m,1H),7.46(d,J＝8.6Hz,2H),7.25(m,1H),7.09(m,1H),6.96(d,J＝8.6Hz,2H),6.82(m,1H),6.48(m,1H),6.52(m,1H),6.28(m,1H),3.80(s,6H),3.73(m,4H).HRMS calcd.for C 23 H 24 N 3 O 3 [M+H] + :390.1818,found 390.1829。
Example 8: preparation of Compound h
The structural formula of the compound h is as follows:
compound g was synthesized according to the procedure for the preparation of compound a of example 1, using N- (2-aminoethyl) morpholine instead of ethylamine, with a total yield of 30.2%. 1 HNMR(400MHz,DMSO-d 6 )δ7.55(d,J＝8.7Hz,2H),7.32(m,1H),7.13(m,1H),6.95(d,J＝8.7Hz,2H),6.82(m,1H),6.48(m,1H),3.80(s,3H),3.81(s,3H),3.77(m,2H),3.40(m,4H),2.62(m,2H),2.35(m,2H),2.23(m,4H).HRMS calcd.for C 24 H 31 N 4 O 3 [M+H] + :423.2396,found 423.2381。
PDE4 inhibitory Activity studies on the products obtained in examples 1-8
The experimental method comprises the following steps: refer to the prior art(J.Nat. Prod.2014,77,955-962; eur. J. Med. Chem.2016,114,134-140; biochem. Pharmacol.2017,130, 51-59). Rolipram was used as PDE4 positive control and BRL-50481 was used as PDE7 positive control. Will contain 20mM Tris/HCl buffer (pH 7.5), 10mM MgCl 2 1mM DTT and 10-30nM specific fluorogenic substrate 3 Assay buffer of H-cAMP (20,000-30,000 c.p.m./assay, GE Healthcare) and test compound are incubated for 15 min at room temperature (25 ℃). Adding 0.2M ZnSO 4 The reaction was terminated. With 0.2M Ba (OH) 2 Allowing the reaction product to react 3 Precipitation of H-AMP, unreacted 3 H-cAMP remained in the supernatant. Radioactivity in the supernatant was measured using a liquid scintillation counter (PerkinElmer 2910liquid scintillation counter). For IC 50 At least 8 different concentrations of the test compound are used. Each measurement was repeated at least three times. IC calculation using nonlinear regression method 50 Values.
Inhibitory Activity of Compounds of Table 1 on PDE4 and PDE7
From the specific IC of the above table 50 As can be seen from the value data, the compounds of the general formula A show strong inhibition effects on PDE4 and PDE7<5 μm), which are substantially higher than resveratrol, wherein compounds a, b, c have stronger inhibition to PDE4 and PDE7 than the positive control, and compounds d, g have stronger inhibition to PDE4 than the positive control, and also have stronger inhibition to PDE 7; the compounds e, f and h have stronger inhibition effect on PDE7 than a positive control group, and have stronger inhibition effect on PDE4 at the same time, thus having potential medicinal value.
Finally, what is necessary here is: the above embodiments are only for further detailed description of the technical solutions of the present invention, and should not be construed as limiting the scope of the present invention, and some insubstantial modifications and adjustments made by those skilled in the art from the above description of the present invention are all within the scope of the present invention.
Claims (9)
1. A PDE4/7 dual-target inhibitor, characterized by: comprising a compound of the general formula (a), or a stereoisomer, a stable isotope derivative or a pharmaceutically acceptable salt thereof, formula (a) being as follows:
in the general formula:
r is:
1-12C alkyl or 1-12C heteroalkyl or 3-12C cycloalkyl or 3-12C cycloheteroalkyl, said C1-12 heteroalkyl or 3-12C cycloheteroalkyl containing the following atoms or functional groups: n, O, S atoms or two of them;
or a benzene ring, an aromatic heterocycle, a benzene ring containing a substituent or an aromatic heterocycle containing a substituent, wherein the substituent is hydroxyl, 1-4C substituted alkyl or alkoxy, amino, 1-4C substituted alkylamino, nitro or cyano.
2. The PDE4/7 dual-target inhibitor according to claim 2, wherein R is:
1-6C alkyl or 1-6C heteroalkyl or 3-6C cycloalkyl or 3-6C cycloheteroalkyl, said C1-6 heteroalkyl or 3-6C cycloheteroalkyl containing the following atoms or functional groups: n, O, S atoms or two of them.
3. A PDE4/7 dual-target inhibitor according to claim 1, which is selected from the group consisting of:
4. a pharmaceutical composition characterized by: a compound of the general formula (a) as defined in any one of claims 1 to 3, or a stereoisomer, a stable isotope derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
5. A method for preparing a PDE4/7 dual-target inhibitor, which is characterized in that: the preparation method comprises the following steps:
(1) Dissolving substituted 3, 5-dimethoxy benzaldehyde and 1- [4- (diethoxymethyl) phenyl ] ethanone in methanol, adding 3M sodium hydroxide solution under ice bath condition for reaction, adjusting pH to neutral after the reaction is completed, adding ethyl acetate and water for layering, taking ethyl acetate layer, evaporating solvent under reduced pressure, and separating by column chromatography to obtain intermediate product 3;
(2) Dissolving the intermediate product 3, p-toluenesulfonyl hydrazine and catalytic amount of iodine in absolute ethyl alcohol, heating and refluxing, standing reactants after the reaction is completed, separating out pale yellow solid, and recrystallizing the pale yellow solid in DMF to obtain an intermediate product 4;
(3) Dissolving the intermediate product 4 and 2M hydrochloric acid in tetrahydrofuran at room temperature, stirring for reaction, adding ethyl acetate and water for layering after the reaction is finished, decompressing and evaporating the ethyl acetate layer to remove the solvent, and separating by column chromatography to obtain an intermediate product 5;
(4) Dissolving an intermediate product 5 and an amine compound in absolute ethyl alcohol, carrying out reflux reaction, cooling to room temperature after the reaction is completed, adding sodium borohydride in batches for continuous reaction, after the reaction is completed, evaporating solvent under reduced pressure, dissolving reactants by ethyl acetate, filtering, washing by saturated saline water, separating an ethyl acetate layer, evaporating the solvent under pressure, and separating by column chromatography to obtain a target product, wherein the general formula (A) of the target product is as in claim 1, and the general formula (B) of the amine compound is RNH 2 In the general formula (B):
r is:
1-12C alkyl or 1-12C heteroalkyl or 1-12C cycloalkyl or 1-12C cycloheteroalkyl, said C1-12 heteroalkyl or 1-12C cycloheteroalkyl containing the following atoms or functional groups: n, O, S atoms or two of them;
or a benzene ring, an aromatic heterocycle, a benzene ring containing a substituent or an aromatic heterocycle containing a substituent, wherein the substituent is hydroxyl, 1-4C substituted alkyl or alkoxy, amino, 1-4C substituted alkylamino, nitro or cyano.
6. The method of claim 5, wherein R is:
1-6C alkyl or 1-6C heteroalkyl or 3-6C cycloalkyl or 3-6C cycloheteroalkyl, said C1-6 heteroalkyl or 1-6C cycloheteroalkyl containing the following atoms or functional groups: n, O, S atoms or two of them.
7. The method for preparing a PDE4/7 dual-target inhibitor according to claim 5, wherein said amine compound is ethylamine, propylamine, cyclopentylamine, cyclohexylamine, benzylamine, tyramine, furfuryl amine, N- (2-aminoethyl) morpholine.
8. Use of a PDE4/7 dual-target inhibitor according to any one of claims 1 to 3 in the manufacture of a medicament for the prophylaxis and treatment of PDE 4-related diseases.
9. Use according to claim 8, characterized in that: the PDE4 related disease refers to psoriasis, psoriatic arthritis, chronic obstructive pneumonia, ankylosing spondylitis and inflammatory bowel disease.
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