WO2024017366A1 - 一种调控15-pgdh活性的化合物及其制备方法 - Google Patents
一种调控15-pgdh活性的化合物及其制备方法 Download PDFInfo
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- WO2024017366A1 WO2024017366A1 PCT/CN2023/108559 CN2023108559W WO2024017366A1 WO 2024017366 A1 WO2024017366 A1 WO 2024017366A1 CN 2023108559 W CN2023108559 W CN 2023108559W WO 2024017366 A1 WO2024017366 A1 WO 2024017366A1
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- 238000005215 recombination Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 230000004648 relaxation of smooth muscle Effects 0.000 description 1
- 201000002793 renal fibrosis Diseases 0.000 description 1
- 230000008521 reorganization Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 108010027126 short chain trans-2-enoyl-CoA reductase Proteins 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 231100000019 skin ulcer Toxicity 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical class [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 208000003265 stomatitis Diseases 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- IBBLKSWSCDAPIF-UHFFFAOYSA-N thiopyran Chemical compound S1C=CC=C=C1 IBBLKSWSCDAPIF-UHFFFAOYSA-N 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 231100000886 tinnitus Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 230000003156 vasculitic effect Effects 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 231100000889 vertigo Toxicity 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- 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
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- 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
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- 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
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Definitions
- the present application relates to a compound that modulates the activity of 15-PGDH and a preparation method thereof. Specifically, it relates to a compound that modulates the activity of 15-PGDH that can be used as a drug, its pharmacologically acceptable salts, compositions containing the compound or its salts, and It is used for preparing medicines and belongs to the field of medicinal chemistry.
- 15-Hydroxyprostaglandin dehydrogenase belongs to the evolutionarily conserved superfamily of short-chain dehydrogenases/reductases (SDRs) and is named SDR36C1 according to the latest approved human enzyme nomenclature. According to current research results, most of the in vivo activity can be attributed to type I 15-PGDH encoded by the HPGD gene.
- 15-PGDH has strong effects on active prostaglandins (PGD2, PGE1, PGE2, PGF2 ⁇ , PGI2, etc.), hydroxyeicosatetraenoic acids (HETEs) and inflammation-reducing lipid mediators (RvD1, RvD2, RvE1, MaR1, LXA4, etc.) (below
- PGD2, PGE1, PGE2, PGF2 ⁇ , PGI2, etc. active prostaglandins
- HETEs hydroxyeicosatetraenoic acids
- RvD1, RvD2, RvE1, MaR1, LXA4, etc. The inactivation of the hydroxyl group at position 15 of PGF2 ⁇ plays an important role (for example, by catalyzing the oxidation of the 15-hydroxyl group of PGF2 ⁇ to 15-keto-PGF2 ⁇ ).
- prostaglandins PGE1, PGE2, PGF2 ⁇ , PGI2, etc.
- hydroxyeicosatetraenoic acid and inflammation-reducing lipid mediators RvD1, RvD2, RvE1, MaR1, LXA4, etc.
- PGE1, PGE2, PGF2 ⁇ , PGI2, etc. are commonly used to evaluate the activity of 15-PGDH.
- the activity of PGDH is evaluated by measuring the ketone metabolite of the 15-hydroxyl group of PGF2 ⁇ (Journal of Clinical Endocrinology and Metabolism, Vol84, No. 1, 291-299).
- Receptors for 15-PGDH substrates are widely and differentially distributed in the body, and the diversity of receptor types, signaling and expression distribution jointly create diversity of effects in the body.
- PGE1 acts on blood vessels and platelets to increase blood flow through vasodilation and platelet aggregation inhibition, so it is often used to treat chronic arterial occlusion (thromboangitis obliterans (TAO) or arteriosclerosis obliterans (ASO)). ), skin ulcers and other diseases;
- TAO thromboangitis obliterans
- ASO arteriosclerosis obliterans
- PGF2 ⁇ has uterine contraction and intraocular pressure-lowering effects, and its derivatives are used as therapeutic agents for glaucoma; while PGD2 can inhibit inflammation by enhancing the barrier function of pulmonary blood vessels.
- PGE2 has vasodilatory effects and has multiple functions including blood pressure, pain, bone formation and cell growth, stem cell differentiation, and anti-fibrotic and anti-inflammatory effects.
- PGI2 has an inhibitory effect on platelet activation and a relaxing effect on vascular smooth muscle, and its derivatives are used as therapeutic agents for chronic arterial occlusion and primary pulmonary hypertension.
- Inflammation resolution lipid mediators (RvD1, RvD2, RvE1, MaR1, LXA4, etc.) inhibit neutrophil migration/activation and accelerate neutrophil apoptosis.
- RvD1, RvD2, RvE1, MaR1, LXA4, etc. inhibit neutrophil migration/activation and accelerate neutrophil apoptosis.
- it is indispensable in increasing the phagocytic activity of macrophages to effectively remove apoptotic neutrophils/tissue debris remaining at the site of inflammation. These functions promote inflammation and maintain biological homeostasis.
- These inflammation-reducing lipid mediators have been reported to exhibit medicinal
- 15-PGDH inhibitors and 15-PGDH agonists may have therapeutic value.
- a recent study demonstrated increased expression of 15-PGDH in protection from thrombin-mediated cell death. It is known that 15-PGDH causes the inactivation of prostaglandin E2 (PGE2), a downstream product of COX-2 metabolism. Studies have shown that PGE2 is beneficial in a variety of biological processes, such as maintaining hair density, promoting skin wound healing and bone formation.
- 15-PGDH is an important enzyme in the inactivation of 15-PGDH substrates and is involved in a wide range of functions in the body. It is required for the prevention or treatment of diseases related to 15-PGDH and/or 15-PGDH substrates, and/or 15-PGDH inhibitors may be used to increase 15-PGDH substrate levels in a subject.
- 15-PGDH inhibitors can effectively treat or prevent fibrosis (such as pulmonary fibrosis (idiopathic pulmonary fibrosis, etc.), liver fibrosis, renal fibrosis, myocardial fibrosis, scleroderma and myelofibrosis), Inflammatory diseases (such as chronic obstructive pulmonary disease (COPD), acute lung injury, sepsis, asthma and lung diseases, inflammatory bowel diseases (such as ulcerative colitis and Crohn's disease), peptic ulcers (such as NSAID-induced ulcers), autoinflammatory diseases (such as Behcet's disease), vasculitic syndromes, acute liver injury, acute kidney injury, non-alcoholic fatty liver disease (NASH), atopic dermatitis, psoriasis, inter
- fibrosis such as pulmonary fibrosis (idiopathic pulmonary fibrosis, etc.), liver fibrosis, renal fibrosis, myocardial fibrosis, sc
- Metabolites and other anti-cancer chemotherapeutic agents, cellular or humoral immunotherapy or radiation therapy, or mucosal damage related to graft-versus-host disease such as mucositis or stomatitis
- autoimmune diseases such as multiple sclerosis or rheumatoid arthritis
- graft-versus-host disease GVHD
- hair growth disorders such as osteoporosis
- ear diseases such as hearing loss, tinnitus, vertigo and balance disorders
- eye diseases such as glaucoma and dry eye
- diabetes mellitus, underactive bladder, neutropenia, neurological disorders caused by stem cell, bone marrow or organ transplantation such as psychoneurological disorders, neuropathy, neurotoxic disorders, neuropathic pain and Neurodegenerative diseases
- muscle regenerative diseases such as muscle wasting, muscular dystrophy, and muscle damage
- 15-PGDH inhibitors can also be used to promote cervical ripening.
- the compounds and pharmaceutically acceptable salts thereof provided in this application further satisfy the demand for small molecules that inhibit the activity of 15-PGDH.
- One aspect of the present application is to provide a compound represented by formula (I), stereoisomers, tautomers or mixtures thereof, or their Pharmaceutically acceptable salts, or solvates (such as hydrates), or prodrugs thereof:
- Ring A is selected from the group consisting of an aromatic ring, an aromatic heterocycle, an unsaturated aliphatic heterocycle, a ring composed of an aromatic ring and an unsaturated aliphatic heterocycle, and a ring composed of an aromatic heterocycle and an unsaturated aliphatic heterocycle,
- Ring B is a 3-12 membered saturated aliphatic heterocyclic ring
- R A is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, cyano, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 1 to C 6 haloalkyl, 3 to 8 membered cycloalkyl,
- o is selected from 0, 1, 2, 3,
- the aromatic heterocyclic ring, saturated aliphatic heterocyclic ring, unsaturated aliphatic heterocyclic ring, aliphatic heterocyclic group, and cyclic ring each independently contain 1 to 3 heteroatoms, and the heteroatoms are independently selected from N, O, S , and ring B contains at least 1 nitrogen atom;
- the ring B is preferably a single ring or a double ring.
- the ring B is a 5-10-membered saturated aliphatic heterocyclic ring containing at least 1 nitrogen atom, such as a 5-8-membered or 5-7-membered saturated aliphatic heterocyclic ring.
- the aforementioned ring B is selected from
- X is selected from covalent bond, O, S, NH, (CH 2 ) n , SO 2 and Y is selected from covalent bond, S, NH, (CH 2 ) n and SO 2 ;
- n is selected from 0, 1, 2, 3;
- R 2 is each independently selected from deuterium, tritium, nitro, hydroxyl, sulfhydryl, cyano, halogen, amine, ester, aldehyde, carboxyl, amide, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 haloalkyl, C 1 ⁇ C 6 alkoxy, 3 to 8 membered cycloalkyl, 6 to 10 membered aryl, 5 to 10 membered heteroaryl; the n is selected Since 0, 1, 2, 3.
- the ring B is selected from Among them, the definitions of m and R2 are consistent with the aforementioned definitions in this application.
- the Ring B is selected from preferred Among them, the definitions of m and R2 are consistent with the aforementioned definitions in this application.
- each of the aforementioned R 2 is independently selected from deuterium, tritium, nitro, hydroxyl, mercapto, cyano, fluorine, chlorine, bromine, amine, ester, aldehyde, Carboxyl, amide, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, trifluoroethyl, trichloromethyl base, trichloroethyl, cyclobutyl, cyclopropyl, phenyl, pyridyl.
- each of the R 2 is independently selected from deuterium, tritium, hydroxyl, fluorine, chlorine, bromine, amine, methyl, ethyl; preferably deuterium, tritium.
- m is selected from 0, 1, 2, such as 0 or 1, with 0 being preferred.
- the RA is selected from hydrogen, deuterium, tritium, hydroxyl, fluorine, chlorine, bromine, cyano, C 1 to C 5 alkyl (e.g., C 1 to C 4 alkyl, C 1 to C 3 alkyl), C 1 to C 5 alkoxy (such as C 1 to C 4 alkoxy, C 1 to C 3 alkoxy), C 1 to C 5 haloalkyl (such as C 1 to C 4 haloalkyl , C 1 to C 3 haloalkyl; such as C 1 to C 5 fluoroalkyl, C 1 to C 5 chloroalkyl, C 1 to C 5 bromoalkyl), 3 to 6 membered cycloalkyl (for example 3-5 membered cycloalkyl, 3-4 membered cycloalkyl).
- C 1 to C 5 alkyl e.g., C 1 to C 4 alkyl, C 1 to C 3 alkyl
- C 1 to C 5 alkoxy such as
- the RA is selected from hydrogen, deuterium, tritium, hydroxyl, fluorine, chlorine, bromine, cyano, cyclopropyl, cyclobutyl, methyl, ethyl, propyl, butyl, pentyl group, methoxy group, ethoxy group, propoxy group, C 1 to C 3 fluoroalkyl group (such as trifluoromethyl, trifluoroethyl), C 1 to C 3 chloroalkyl group (such as trichloromethyl base, trichloroethyl), C 1 to C 3 bromoalkyl (such as tribromomethyl, tribromoethyl); preferably hydrogen, deuterium, tritium, fluorine, chlorine, bromine, cyano, cyclopropyl, Cyclobutyl, methyl, ethyl, propyl, butyl, methoxy, ethoxy, C 1 to C 3 fluoroalky
- the RA is selected from cyclopropyl. In certain embodiments, the RA is selected from bromine. In certain embodiments, the RA is selected from trifluoromethyl. In certain embodiments, the RA is selected from methoxy. In certain embodiments, the RA is selected from hydrogen, deuterium, tritium, cyano, methyl, ethyl, and propyl.
- the RA is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, cyano, cyclopropyl, cyclobutyl, methyl, ethyl, methoxy, ethoxy, and trifluoromethyl.
- the ring A is selected from a 6-10-membered aromatic ring, a 5-10-membered aromatic heterocyclic ring, a 3-8-membered unsaturated aliphatic heterocyclic ring, a 7-12-membered aromatic ring and an unsaturated aliphatic heterocyclic ring (for example, 8-10 membered) 7- to 12-membered cyclic ring, an aromatic heterocyclic ring and an unsaturated aliphatic heterocyclic ring; preferably, the aromatic ring and aromatic heterocyclic ring are monocyclic or bicyclic, and the unsaturated aliphatic heterocyclic ring It is a single ring, and the branched ring is a bicyclic ring, and the aromatic heterocycle, unsaturated aliphatic heterocycle, and branched ring each independently contain 1 to 3 heteroatoms, and the heteroatoms are independently selected from N, O, S .
- the ring A is selected from the group consisting of 6-10 membered aromatic rings (eg, 6-membered aromatic rings, 10-membered aromatic rings), 5-10-membered aromatic heterocycles (eg, 5-membered aromatic heterocycles, 6-membered aromatic heterocycles).
- 6-10 membered aromatic rings eg, 6-membered aromatic rings, 10-membered aromatic rings
- 5-10-membered aromatic heterocycles eg, 5-membered aromatic heterocycles, 6-membered aromatic heterocycles.
- ring 9-membered aromatic heterocycle, 10-membered aromatic heterocycle; containing 1-2 heteroatoms selected from N, O or S), 4-7-membered unsaturated aliphatic heterocycle (for example, containing 1-2 heteroatoms selected from N , heteroatoms of O or S), 8 to 12-membered rings composed of aromatic rings and unsaturated aliphatic heterocyclic rings (for example, containing 1-2 heteroatoms selected from N, O or S), aromatic heterocyclic rings and unsaturated An 8- to 12-membered paracyclic ring composed of an aliphatic heterocyclic ring (for example, containing 1-2 heteroatoms selected from N, O or S).
- the ring A is selected from the group consisting of a 6- to 10-membered aromatic ring, a 5- to 10-membered aromatic heterocyclic ring, a 5- to 6-membered unsaturated aliphatic heterocyclic ring, and a 9 to 10-membered aromatic ring and an unsaturated aliphatic heterocyclic ring.
- the aromatic heterocycle, the unsaturated aliphatic heterocycle, and the paracyclic ring each independently contain 1 to 2 heteroatoms selected from N, O, and S.
- the Ring A is selected from
- a base e.g., methyl
- the present application also provides a compound represented by formula (II), its stereoisomer, its tautomer or its mixture form, or its pharmaceutically acceptable salt, or its solvate substance (such as a hydrate), or its prodrug,
- Ring A is selected from the group consisting of an aromatic ring, an aromatic heterocycle, an unsaturated aliphatic heterocycle, a ring composed of an aromatic ring and an unsaturated aliphatic heterocycle, and a ring composed of an aromatic heterocycle and an unsaturated aliphatic heterocycle;
- R A is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, cyano, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 1 to C 6 haloalkyl, and 3 to 8-membered cycloalkyl;
- o is selected from 0, 1, 2, 3;
- X is selected from covalent bond, S, NH, CH 2 , (CH 2 ) 2 or (CH 2 ) 3 ;
- R 3 is each independently selected from deuterium, tritium, nitro, hydroxyl, thiol, cyano, halogen, amine group, ester group, aldehyde group, carboxyl group, amide group, C 1 to C 6 alkyl group, C 1 to C 6 haloalkyl group, C 1 to C 6 alkoxy group, C 3 to C 8 cycloalkyl group, 6 to 10 Yuanaryl group, 5-10 yuan heteroaryl group; p is selected from 0, 1;
- each of the R 3 is independently selected from deuterium, tritium, nitro, hydroxyl, mercapto, cyano, fluorine, chlorine, bromine, amine, ester, aldehyde, carboxyl, amide, methyl, ethanol. base, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclobutyl base, cyclopropyl, phenyl, pyridyl.
- the p is 0;
- the p is 0 and the X is CH 2 .
- the R A is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, cyano, cyclopropyl, cyclobutyl, methyl, ethyl, methoxy, ethoxy, tritium, Fluoromethyl.
- the RA is selected from hydrogen, deuterium, tritium, cyano, cyclopropyl, trifluoromethyl, halogen, methyl.
- the RA is selected from hydrogen, deuterium, tritium, hydroxyl, fluorine, chlorine, bromine, cyano, cyclopropyl, cyclobutyl, methyl, ethyl, propyl, butyl, pentyl group, methoxy group, ethoxy group, propoxy group, C 1 to C 3 fluoroalkyl group (such as trifluoromethyl, trifluoroethyl), C 1 to C 3 chloroalkyl group (such as trichloromethyl base, trichloroethyl), C 1 to C 3 bromoalkyl (such as tribromomethyl, tribromoethyl); preferably hydrogen, deuterium, tritium, fluorine, chlorine, bromine, cyano, cyclopropyl, Cyclobutyl, methyl, ethyl, propyl, butyl, methoxy, ethoxy, C 1 to C 3 fluoroalky
- the RA is selected from cyclopropyl. In certain embodiments, the RA is selected from bromine. In certain embodiments, the RA is selected from trifluoromethyl. In certain embodiments, the RA is selected from methoxy. In certain embodiments, the RA is selected from hydrogen, deuterium, tritium, cyano, methyl, ethyl, and propyl.
- the ring A is selected from a 6- to 10-membered aromatic ring, a 5- to 10-membered aromatic heterocyclic ring, a 3 to 8-membered unsaturated aliphatic heterocyclic ring, an aromatic ring and an unsaturated aliphatic heterocyclic ring.
- a 7- to 12-membered paracyclic ring, a 7- to 12-membered paracyclic ring composed of an aromatic heterocyclic ring and an unsaturated aliphatic heterocyclic ring.
- the aromatic ring and aromatic heterocyclic ring are preferably monocyclic or bicyclic
- the unsaturated aliphatic heterocyclic ring is preferably monocyclic
- the branched ring is preferably bicyclic
- the aromatic heterocycle, unsaturated aliphatic heterocyclic ring, and branched ring are preferably bicyclic.
- the ring A is selected from the group consisting of 6-10 membered aromatic rings (eg, 6-membered aromatic rings, 10-membered aromatic rings), 5-10-membered aromatic heterocycles (eg, 5-membered aromatic heterocycles, 6-membered aromatic heterocycles).
- 6-10 membered aromatic rings eg, 6-membered aromatic rings, 10-membered aromatic rings
- 5-10-membered aromatic heterocycles eg, 5-membered aromatic heterocycles, 6-membered aromatic heterocycles.
- ring 9-membered aromatic heterocycle, 10-membered aromatic heterocycle; containing 1-2 heteroatoms selected from N, O or S), 4-7-membered unsaturated aliphatic heterocycle (for example, containing 1-2 heteroatoms selected from N , heteroatoms of O or S), 8 to 12-membered rings composed of aromatic rings and unsaturated aliphatic heterocyclic rings (for example, containing 1-2 heteroatoms selected from N, O or S), aromatic heterocyclic rings and unsaturated An 8- to 12-membered paracyclic ring composed of an aliphatic heterocyclic ring (for example, containing 1-2 heteroatoms selected from N, O or S).
- the ring A is selected from the group consisting of a 6- to 10-membered aromatic ring, a 5- to 10-membered aromatic heterocyclic ring, a 5- to 6-membered unsaturated aliphatic heterocyclic ring, and a 9 to 10-membered aromatic ring and an unsaturated aliphatic heterocyclic ring.
- the aromatic heterocycle, the unsaturated aliphatic heterocycle, and the paracyclic ring each independently contain 1 to 2 heteroatoms selected from N, O, and S.
- the ring A is selected from
- the ring A is preferably selected from
- the Ring A is selected from
- the application provides a compound represented by formula (I), its stereoisomer or mixture form, or its pharmaceutically acceptable salt, or its solvate (such as hydrate), or Its prodrug,
- the ring A is selected from a 6-10-membered aromatic ring, a 5-10-membered aromatic heterocyclic ring containing 1-2 heteroatoms selected from N, O or S, and a 5-10-membered aromatic heterocyclic ring containing 1-2 heteroatoms selected from N, O or S.
- 4 to 7-membered unsaturated aliphatic heterocyclic ring with S heteroatom 8-12-membered paracyclic ring composed of aromatic ring and unsaturated aliphatic heterocyclic ring (containing 1-2 heteroatoms selected from N, O or S), aromatic ring
- the ring B is a 5-10-membered, such as 5-8-membered or 5-7-membered saturated aliphatic heterocyclic ring containing at least 1 nitrogen atom; preferably, the ring B is selected from
- R 2 is each independently selected from deuterium, tritium, nitro, hydroxyl, sulfhydryl, cyano, halogen, amine, ester, aldehyde, carboxyl, amide, C 1 ⁇ C 6 alkyl group, C 1 ⁇ C 6 haloalkyl group, C 1 ⁇ C 6 alkoxy group, 3-8 membered cycloalkyl group, 6-10 membered aryl group, 5-10 membered heteroaryl group;
- the R A is selected from hydrogen, deuterium, tritium, hydroxyl, fluorine, chlorine, bromine, cyano, C 1 to C 5 alkyl, C 1 to C 5 alkoxy, C 1 to C 5 haloalkyl, 3 ⁇ 6-membered cycloalkyl; preferably, the R A is selected from hydrogen, deuterium, tritium, hydroxyl, fluorine, chlorine, bromine, cyano, cyclopropyl, cyclobutyl, methyl, ethyl, propyl, butyl Base, pentyl, methoxy, ethoxy, propoxy, C 1 to C 3 fluoroalkyl, C 1 to C 3 chloroalkyl, C 1 to C 3 bromoalkyl;
- the application provides a compound represented by formula (I), its stereoisomer or mixture form, or its pharmaceutically acceptable salt, or its solvate (such as hydrate), or Its prodrugs, among which,
- the ring A is selected from
- the ring B is selected from
- n is selected from 0 and 1;
- R 2 is each independently selected from deuterium, tritium, hydroxyl, fluorine, chlorine, bromine, amino, methyl, ethyl; preferably deuterium and tritium;
- the R A is selected from hydrogen, deuterium, tritium, fluorine, chlorine, bromine, cyano, cyclopropyl, cyclobutyl, methyl, ethyl, propyl, butyl, methoxy, ethoxy, C 1 to C 3 fluoroalkyl (such as trifluoromethyl, trifluoroethyl); preferably hydrogen, bromine, cyano, cyclopropyl, methyl, ethyl, propyl, methoxy, trifluoromethyl .
- the compound shown below in the present application its stereoisomers, tautomers or mixture forms thereof, or its pharmaceutically acceptable salts, or its solvates (such as hydrated substance), or its prodrug:
- Another aspect of the present application is to provide a pharmaceutical composition
- a pharmaceutical composition comprising at least one of the aforementioned compounds, their stereoisomers, tautomers or mixtures thereof, or their pharmaceutically acceptable salts, or their solvates , or its prodrug, and at least one pharmaceutically acceptable excipient.
- Another aspect of the application is to provide a aforementioned compound, or its stereoisomer, tautomer or mixture form, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or Use of pharmaceutical compositions for the preparation of medicaments.
- the drug is a 15-PGDH inhibitor, which can be used to treat diseases related to unwanted increases in 15-PGDH activity levels.
- the application provides a aforementioned compound used as a medicine, or its stereoisomer, tautomer or mixture form thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug , or pharmaceutical compositions.
- the present application provides a method for treating or preventing 15-PGDH-related diseases, comprising administering the aforementioned compound, or its stereoisomer, tautomer, or mixture thereof, or its mixture to a subject in need thereof.
- the 15-PGDH-related diseases mentioned herein refer to diseases or their complications that achieve clinically beneficial effects such as remission, improvement, stopping of progression, reduction or no deterioration by inhibiting the activity of 15-PGDH.
- the medicaments, inhibitors or methods are used to treat or prevent fibrosis, oral ulcers, gum disease, colitis, ulcerative colitis, gastroduodenal ulcers, inflammatory diseases, Vascular insufficiency, Raynaud's disease, Buerger's disease, neuropathy, pulmonary hypertension, cardiovascular and renal diseases, cardiovascular disease, trauma, skin lesions, autoimmune diseases, graft versus host disease, osteoporosis, ear disease, Eye disease, neutropenia, diabetes, inactive bladder, or to promote hair growth, pigmentation, tissue repair, tissue regeneration, implants, neurogenesis and nerve cells in stem cell transplantation or bone marrow transplantation or organ transplantation death, muscle regeneration and cervical ripening, or to enhance resistance to the toxicity of radiation exposure, the toxicity of chemotherapy, the toxicity of immunosuppressants.
- Alkyl refers to a saturated aliphatic hydrocarbon group.
- the alkyl part can be a straight-chain alkyl group or a branched-chain alkyl group; the C 1 -C 6 alkyl group used in this application refers to 1 to 6 (for example, 1, 2, 3, 4, A linear or branched alkyl group composed of 5, 6 or a range of any two of the aforementioned values) carbon atoms.
- Typical alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, ppentyl, n-hexyl, etc.
- Alkoxy refers to -O-alkyl; C 1 -C 6 alkoxy used in this application refers to 1 to 6 (such as 1, 2, 3, 4, 5, 6 or a range consisting of any two of the aforementioned values), a straight-chain alkoxy group or a branched-chain alkoxy group composed of carbon atoms.
- Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentyloxy, isopentyloxy base, pylpentyloxy group, n-hexyloxy group, etc.
- Cycle refers to any cyclic covalently closed structure, including, for example, carbocyclic rings (such as aromatic rings or alicyclic rings) and heterocyclic rings (such as aromatic heterocyclic rings or alicyclic heterocyclic rings).
- a carbocyclic ring refers to a ring composed only of carbon atoms
- a heterocyclic ring refers to a closed structure formed by the covalent bonding of carbon atoms and heteroatoms.
- a "ring” may be monocyclic, bicyclic, tricyclic or polycyclic. When the rings are bicyclic, tricyclic or polycyclic, the relationship between each ring may include parallel rings, spiro rings, and bridged rings.
- Heteroatom refers to any atom other than carbon atom that can be covalently bonded to a carbon atom. Common heteroatoms include but are not limited to O, S, N, P, Si, etc.
- Element refers to the number of skeleton atoms constituting the ring.
- Typical 5-membered rings may include, but are not limited to, cyclopentane, pyrrole, imidazole, thiazole, furan, thiophene, etc.;
- typical 6-membered rings may include, but are not limited to, cyclohexane, pyridine, pyran, pyrazine, thiopyran, pyridine, etc. Azine, pyrimidine, benzene, etc.
- Alicyclic ring or “alicyclic group” refers to a saturated or partially unsaturated cyclic group with no aromaticity and a skeleton composed of carbon atoms.
- a saturated carbocyclic ring can be called, for example, a saturated alicyclic ring, and a partially unsaturated carbon ring.
- the ring can be called, for example, an unsaturated alicyclic ring.
- the alicyclic ring can be composed of 3 to 10 (such as 3, 4, 5, 6, 7, 8, 9 or 10) atoms, and can be a single ring.
- polycyclic, for example, a 3- to 8-membered alicyclic group refers to an alicyclic group composed of 3 to 8 skeleton atoms.
- Typical alicyclic structures include but are not limited to: wait.
- Aliphatic heterocyclic ring or aliphatic heterocyclic group refers to a non-aromatic cyclic group formed by one or more heteroatoms replacing carbon atoms in an alicyclic ring.
- Aliphatic heterocyclic ring or aliphatic heterocyclic group may include saturated aliphatic heterocyclic ring and unsaturated aliphatic heterocyclic ring.
- the 3- to 8-membered aliphatic heterocyclic group used in this application refers to a non-aromatic cyclic group composed of 3 to 8 skeleton atoms and containing one or more heteroatoms. It can be a saturated aliphatic heterocyclic group and Unsaturated aliphatic heterocyclic group.
- “Saturated aliphatic heterocyclic ring” or “saturated aliphatic heterocyclic group” means that the atoms constituting the ring skeleton in the aliphatic heterocyclic ring are all saturated.
- the 3-12 membered saturated aliphatic heterocycle used in this application refers to a non-aromatic cyclic group formed by 3-12 atoms constituting the ring skeleton, in which the atoms constituting the ring skeleton are composed of saturated carbon atoms and heteroatoms.
- Typical saturated aliphatic heterocycles include, but are not limited to: wait.
- Unsaturated aliphatic heterocyclic ring or “unsaturated aliphatic heterocyclic group” refers to a non-aromatic cyclic structure containing some unsaturated atoms as the ring skeleton in the alicyclic heterocyclic ring.
- "Unsaturated aliphatic heterocyclic ring” in this application means that the skeleton constituting the aliphatic heterocyclic ring contains unsaturated carbon atoms.
- Cycloalkyl refers to a saturated aliphatic carbocyclic group, and may also be referred to as, for example, a saturated alicyclic group.
- the cycloalkyl group can be a single ring, a spiro ring, a bridged ring or a bridged ring.
- the 3- to 8-membered cycloalkyl group used in this application refers to a cyclic alkyl group composed of 3 to 8 carbon atoms.
- Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2,1,1]hexyl, cycloheptyl, etc.
- Aromatic ring or “aryl” refers to a fully unsaturated carbocyclic ring with a planar ring having a delocalized pi electron system and containing 4n+2 pi electrons, where n is an integer.
- the aromatic ring can be composed of six, eight, ten or more than ten carbon atoms, and the aromatic ring can be single, bicyclic, tricyclic or polycyclic. Common aromatic rings include but are not limited to benzene ring, naphthalene ring, phenanthrene ring, anthracene ring, tetraphenyl, pyrene ring, pentaphenyl, etc.
- the 6- to 10-membered aromatic ring or 6- to 10-membered aryl group used in this application refers to an aromatic ring group composed of 6 to 10 skeleton carbon atoms.
- Aromatic heterocycle or “heteroaryl” refers to an aromatic cyclic structure formed by one or more heteroatoms replacing carbon atoms in an aromatic ring. Typical aromatic heterocycles or heteroaryl groups include but are not limited to: wait.
- the 5- to 10-membered aromatic heterocycle or 5- to 10-membered heteroaryl group used in this application refers to a group composed of 5 to 10 (such as 5, 6, 7, 8, 9 or 10) skeleton atoms.
- Parallel ring refers to a cyclic structure composed of two adjacent ring atoms shared between rings.
- the parallel rings can be double rings, three rings or multiple rings.
- the ring composed of an aromatic ring and an unsaturated aliphatic heterocycle refers to the ring structure formed by sharing two adjacent ring atoms between an aromatic ring and an unsaturated aliphatic heterocycle;
- an aromatic ring and an unsaturated aliphatic heterocycle refers to the joined-ring structure formed by an aromatic heterocyclic ring and an unsaturated aliphatic heterocyclic ring sharing two adjacent ring atoms.
- 7-12 membered ring composed of aromatic heterocyclic ring and unsaturated aliphatic heterocyclic ring refers to a 7-12 skeleton ring formed by an unsaturated aliphatic heterocyclic ring and an aromatic heterocyclic ring sharing two adjacent ring atoms.
- 7-12-membered parallel ring consisting of an aromatic ring and an unsaturated aliphatic heterocyclic ring refers to a ring with 7-12 skeleton ring atoms formed by an unsaturated aliphatic heterocyclic ring and an aromatic ring sharing two adjacent ring atoms. Parallel ring structure.
- aromatic rings and unsaturated aliphatic heterocycles include but are not limited to:
- aromatic heterocycles and unsaturated aliphatic heterocycles include but are not limited to:
- Halogen or halogen means fluorine, chlorine, bromine or iodine.
- Haloalkyl means that at least one hydrogen in the alkyl group is replaced by a halogen atom.
- the C 1 to C 6 haloalkyl used in this application refers to a linear or branched alkyl group composed of 1 to 6 carbon atoms, and At least one hydrogen on the alkyl group is optionally substituted by a halogen atom.
- Amino or " amine” refers to a chemical structure having the structure -NRURV , where each RURV is independently selected from hydrogen, deuterium, tritium, alkyl, cycloalkyl.
- amide or " amide group” refers to a chemical structure having -C ( O ) NR , alkyl group, cycloalkyl group, common amide groups include but are not limited to -CONH 2 , -CONHCH 3 , -CON(CH 3 ) 2 , -NHCOH, -NHCOCH 3 , -N(CH 3 )COCH 3 .
- Ester group refers to a chemical structure having the formula -COOR 0 , where R 0 is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.
- Substituted means that one or more hydrogen atoms in a group are independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art is able to determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
- Inhibitor refers to a substance that reduces enzyme activity.
- Optional or “optionally” means that the subsequently described event or circumstance can but does not necessarily occur, and that the description includes instances where the event or circumstance does or does not occur.
- “optionally substituted” includes substituted or unsubstituted, such as "a heterocyclic group optionally substituted by an alkyl group” means that an alkyl group may but does not have to be present, and this description includes a heterocyclic group substituted by an alkyl group. The case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group.
- “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or physiologically/pharmaceutically acceptable salts or prodrugs thereof, together with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients.
- the purpose of pharmaceutical compositions is to facilitate administration to living organisms and facilitate the absorption of active ingredients to exert biological activity.
- “Pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without undue toxicity , irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- Examples of pharmaceutically acceptable salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.
- Tautomers or “tautomeric forms” refer to structural isomers of different energies that can interconvert via a low energy barrier.
- proton tautomers also known as proton transfer tautomers
- proton migration such as keto-enol and imine-enamine isomerizations.
- a specific example of a proton tautomer is the imidazole moiety, where the proton can migrate between two ring nitrogens.
- Valence tautomers include tautomers by reorganization of some of the bonding electrons.
- Non-limiting examples of tautomers include, but are not limited to, "Stereoisomers” refer to isomers resulting from differences in the spatial arrangement of atoms in a molecule.
- Enantiomers refer to compounds with the same molecular formula and functional groups, isomerism caused by different spatial configurations of atoms. At the same time, the compounds form stereoisomers that are mirror images of each other and cannot be superimposed.
- Diastereomers refers to compounds with the same molecular formula and functional groups, which are isomers caused by different configurations of atoms in space. At the same time, the compounds are not stereoisomers in a mirror image relationship with each other. body.
- Step 2 Preparation of ethyl 7-amino-3-methoxythieno[2,3-b]pyrazine-6-carboxylate
- Step 3 Preparation of 7-iodo-3-methoxythieno[2,3-b]pyrazine-6-carboxylic acid ethyl ester
- Step 4 Preparation of 7-iodo-3-methoxythieno[2,3-b]pyrazine-6-carboxylic acid
- Step 5 Preparation of: (7-iodo-3-methoxythiophene[2,3-b]pyrazin-6-yl)(piperidin-1-yl)methanone
- Step 6 Preparation of: (7-cyclopropyl-3-methoxythieno[2,3-b]pyrazin-6-yl)(piperidin-1-yl)methanone
- Step 2 Preparation of ethyl 7-amino-3-phenylthieno[2,3-b]pyrazine-6-carboxylate
- Step 2 Preparation of 7-cyclopropyl-6-(piperidine-1-carbonyl)thieno[2,3-b]pyrazin-3-yl triflate
- Step 3 (7-Cyclopropyl-3-(2-methylpyridin-4-yl)thieno[2,3-b]pyrazin-6-yl)(piperidin-1-yl)methanone preparation
- Step 2 Preparation of ethyl 7-amino-3-phenylthieno[2,3-b]pyrazine-6-carboxylate
- Step 3 Preparation of 7-iodo-3-phenylthieno[2,3-b]pyrazine-6-carboxylic acid ethyl ester (BT-120-348-062)
- Step 5 Preparation of 3-phenyl-6-(piperidine-1-carbonyl)thieno[2,3-b]pyrazine-7-nitrile (BT-120-348-065)
- Step 3 Preparation of 3-(2-methoxypyrimidin-5-yl)-6-(piperidine-1-carbonyl)thieno[2,3-b]pyrazine-7-carbonitrile
- Step 2 Preparation of ethyl 7-amino-3-phenylthieno[2,3-b]pyrazine-6-carboxylate
- Step 3 Preparation of 7-iodo-3-phenylthieno[2,3-b]pyrazine-6-carboxylic acid ethyl ester (BT-120-348-062)
- Step 5 Preparation of 3-phenyl-6-(piperidine-1-carbonyl)thieno[2,3-b]pyrazine-7-nitrile (BT-120-348-065)
- Step 1 Preparation of: (3-hydroxy-7-(trifluoromethyl)thieno[2,3-b]pyrazin-6-yl)(piperidin-1-yl)methanone
- Step 2 Preparation of 6-(piperidin-1-carbonyl)-7-(trifluoromethyl)thieno[2,3-b]pyrazin-3-yl trifluoromethanesulfonate
- Test example 1 15-PGDH enzyme activity detection
- reaction buffer to prepare a 15-PGDH protein solution with a concentration of 5ng/ ⁇ L. Add 5 ⁇ L of 15-PGDH protein solution to the experimental wells and positive control wells. At the same time, add 5 ⁇ L of reaction buffer to the blank control well, and then Centrifuge plate at 2000rpm for 30 seconds;
- reaction buffer to prepare 5mM ⁇ -NAD and 2mM PGF2 ⁇ respectively, mix them at a volume of 1:1 to obtain a substrate mixture, and add 10 ⁇ L of the substrate mixture to the experimental wells, positive control wells, and blank control wells. , start to react;
- Inhibition rate % [1-(slope of experimental well-signal value of positive control well)/(signal value of blank control well-average signal value of positive control well)] ⁇ 100%.
- Y Bottom+(Top-Bottom)/(1+10 ⁇ ((LogIC50-X)*HillSlope)), where X is the log value of compound concentration and Y is the inhibition rate %.
- the IC 50 range of the compound of the present application for 15-PGDH enzyme inhibitory activity is less than or equal to 100 nM.
- the IC 50 range of the inhibitory activity of some compounds in this application against 15-PGDH enzyme is less than 50nM3nM; the IC 50 range of the inhibitory activity against 15-PGDH enzyme in some compounds in this application is less than 20nM; the IC 50 range of some compounds in this application against 15-PGDH enzyme inhibitory activity
- the range is less than 10 nM; the IC 50 range of the 15-PGDH enzyme inhibitory activity of certain compounds of the present application is less than 3 nM.
- Test Example 2 Determination of intracellular PGE2 up-regulation activity
- A549 cells were seeded in a 24-well plate. After the cells adhered, IL-1 ⁇ was added to stimulate for 16 hours to induce COX2 expression and PGE2 production.
- b) Use culture medium to prepare a solution of the compound to be tested and dilute it gradiently to a total of 3 concentrations of 5nM, 50nM, and 500nM.
- set up a positive control group (only IL-1 ⁇ is added to the cells for stimulation) and a negative control group (only IL-1 ⁇ is added to the wells). cells without any treatment), and the cell supernatants were collected after 8 hours of action.
- the positive control group was induced by IL-1 ⁇ without compound treatment, and the negative control group was not stimulated by IL-1 ⁇ and was not treated with compounds.
- PGE2 up-regulation ratio % (PGE2 concentration of sample group/PGE2 concentration of positive control group) ⁇ 100%.
- the compounds in the examples of the present application can up-regulate PGE2 in A549 cells at a rate of >100%.
- the compounds of the present application have good activity in up-regulating intracellular PGE2.
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Abstract
提供一种具有调控15-PGDH活性的式(I)化合物、其立体异构体、互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药、包含其的药物组合物,其制备方法以及它们用作15-PGDH抑制剂的用途。
Description
本申请涉及一种调控15-PGDH活性的化合物及其制备方法,具体涉及可用作药物的调控15-PGDH活性的化合物、及其药理上可接受的盐、含有化合物或其盐的组合物及其用于制备药物用途,属于医药化学领域。
15-羟基前列腺素脱氢酶(15-PGDH)属于短链脱氢酶/还原酶(SDR)的进化保守超家族,根据最新批准的人类酶命名法,其命名为SDR36C1。根据现有研究结果,大部分体内活性可归因于HPGD基因编码的I型15-PGDH。15-PGDH对活性前列腺素(PGD2,PGE1,PGE2,PGF2α,PGI2等)、羟基二十碳四烯酸(HETEs)和炎症消退脂质介质(RvD1,RvD2,RvE1,MaR1,LXA4等)(下文通称为15-PGDH底物)的失活具有重要作用(例如,通过催化PGF2α的15位羟基的氧化反应生成15-酮-PGF2α)。这些前列腺素(PGD2、PGE1、PGE2、PGF2α、PGI2等)、羟基二十碳四烯酸和炎症消退脂质介质(RvD1、RvD2、RvE1、MaR1、LXA4等)通过靶细胞上的特异性受体发挥其功能。其中,前列腺素PGE1、PGE2、PGF2α、PGI2等常用来评估15-PGDH的活性。例如通过测定PGF2α的15位羟基的酮代谢物来评估PGDH的活性(Journal of Clinical Endocrinology and Metabolism,Vol84,No.1,291-299)。
15-PGDH底物的受体在体内具有广泛且差异性地分布,并且受体类型、信号传递及表达分布的多样性共同造就了体内作用的多样性。例如,PGE1作用于血管和血小板,通过血管舒张作用和血小板聚集抑制作用表现出血流增加效果,因此常用于治疗慢性动脉闭塞(血栓闭塞性脉管炎(TAO)或闭塞性动脉硬化(ASO))、皮肤溃疡等疾病;PGF2α具有子宫收缩作用和降眼压作用,其衍生物被作为青光眼的治疗剂;而PGD2可通过增强肺血管的屏障功能来抑制炎症。此外,PGE2具有血管扩张作用,还具有包括涉及血压、疼痛、骨形成和细胞生长、干细胞分化、以及抗纤维化和抗炎作用的多种功能。PGI2对血小板活化具有抑制作用,对血管平滑肌具有松弛作用,其衍生物用作慢性动脉闭塞和原发性肺动脉高压的治疗剂。炎症消退脂质介质(RvD1、RvD2、RvE1、MaR1、LXA4等)抑制嗜中性粒细胞的迁移/活化,并加速嗜中性粒细胞的凋亡。此外,其在增加巨噬细胞的吞噬活性从而有效去除残留在炎症部位的凋亡嗜中性粒细胞/组织碎片的过程中不可或缺。这些功能可促进炎症并维持生物体内平衡。据报道,这些炎症消退脂质介质在各种类型的病理模型(例如小鼠肺炎模型、结肠炎模型和肝损伤模型)中均可表现出药用功效。
近期研究表明,15-PGDH抑制剂和15-PGDH激动剂可能具有治疗价值。最近的一项研究表明在保护凝血酶介导的细胞死亡中15-PGDH的表达增加。众所周知,15-PGDH导致前列腺素E2(PGE2)失活,前列腺素E2是COX-2代谢的下游产物。已有研究显示PGE2在多种生物过程中是有益的,例如维持头发密度、促进皮肤伤口愈合和骨形成。
15-PGDH作为15-PGDH的底物失活中一种重要的酶,所涉及的体内作用广泛,为预防或治疗与15-PGDH和/或15-PGDH底物相关的疾病,和/或需要增加受试者体内15-PGDH的底物水平时,可以使用15-PGDH抑制剂。
如上所述,15-PGDH的一些底物具有抗纤维化、抗炎、血流改善、促生长、促进干细胞增加、促平滑肌收缩/松弛、影响骨代谢和免疫抑制等作用。因此,15-PGDH抑制剂可有效治疗或预防纤维化(如肺纤维化(特发性肺纤维化等)、肝纤维化、肾纤维化、心肌纤维化、硬皮病和骨髓纤维化),炎性疾病(如慢性阻塞性肺病(COPD)、急性肺损伤、脓毒症、哮喘和肺病、炎症性肠病(如溃疡性结肠炎和克罗恩氏病)、消化性溃疡(如NSAID诱导的溃疡)、自身炎性疾病(如贝切特氏病)、血管炎综合征、急性肝损伤、急性肾损伤、非酒精性脂肪肝(NASH)、特应性皮炎、牛皮癣、间质性膀胱炎、前列腺炎综合征(如慢性前列腺炎/慢性骨盆疼痛综合征)),心血管疾病(如肺动脉高压、心绞痛、心肌梗死、心力衰竭、缺血性心脏病、慢性肾病、肾衰竭、脑卒中和周围循环障碍),创伤(如糖尿病性溃疡、烧伤、压迫性溃疡、急性粘膜损伤(包括斯-约二氏综合征,及与烷化剂、DNA合成抑制剂、DNA回旋酶抑制剂或抗代谢物等抗癌化疗剂有关的,与细胞或体液免疫治疗或放射线治疗有关的,或与移植物抗宿主疾病有关的粘膜损伤(如粘膜炎或口腔炎)),自身免疫性疾病(如多发性硬化或类风湿性关节炎),移植物抗宿主疾病(GVHD),毛发生长(hair growth)障碍,骨质疏松症,耳病(如听力损失,耳鸣,眩晕和平衡失调),眼病(如青光眼和干眼),糖尿病,膀胱活动低下症(underactive bladder),中性白细胞减少症,干细胞、骨髓或器官移植引起的神经系统疾病(如精神神经疾病,神经病,神经毒性疾病,神经性疼痛和神经变性疾病),肌肉再生性疾病(如肌肉萎缩,肌营养不良和肌肉损伤);此外,15-PGDH抑制剂还可用于促进宫颈成熟。
本申请提供的化合物及其可药用盐等进一步满足了对抑制15-PGDH活性的小分子的需求。
发明内容
本申请的一个方面是提供一种式(I)所示的化合物、立体异构体、互变异构体或其混合物形式、或其
可药用的盐、或其溶剂合物(例如水合物)、或其前药:
环A选自芳环、芳杂环、不饱和脂杂环、芳环与不饱和脂杂环构成的并环、芳杂环与不饱和脂杂环构成的并环,
环B为3~12元饱和脂杂环,
RA选自氢、氘、氚、羟基、卤素、氰基、C1~C6烷基、C1~C6烷氧基、C1~C6卤代烷基、3~8元环烷基,
o选自0、1、2、3,
R1各自独立地选自氘、氚、硝基、羟基、巯基、卤素、氰基、=O、亚胺基、胺基、酯基、醛基、羧基、酰胺基、C1~C6烷基、卤素取代的C1~C6烷基、C1~C6烷氧基、卤素取代的C1~C6烷氧基、3~8元环烷基、3~8元饱和脂杂环基;
其中,所述芳杂环、饱和脂杂环、不饱和脂杂环、脂杂环基、并环各自独立地包含1~3个杂原子,所述杂原子独立地选自N、O、S,并且环B包含至少1个氮原子;
所述环B、R1任选地被独立地选自氘、氚、硝基、羟基、-NH2、巯基、卤素、氰基、酯基、羧基、酰胺基、=O、=NH、C1~C6烷基、C1~C6烷氧基、3~8元环烷基、6~10元芳基、5~10元脂杂环基、5~10元杂芳基中的一个或多个取代;
进一步地,所述环B优选为单环或双环。
在一些实施方案中,所述环B为包含至少1个氮原子的5~10元饱和脂杂环,例如5~8元或5~7元饱和脂杂环。
进一步地,本申请某些实施方案中,前述环B选自
其中X选自共价键、O、S、NH、(CH2)n、SO2,Y选自共价键、S、NH、(CH2)n、SO2;
m选自0、1、2、3;R2各自独立地选自氘、氚、硝基、羟基、巯基、氰基、卤素、胺基、酯基、醛基、羧基、酰胺基、C1~C6烷基、C1~C6卤代烷基、C1~C6烷氧基、3~8元环烷基、6~10元芳基、5~10元杂芳基;所述n选自0、1、2、3。
进一步地,在某些具体实施方案中,所述环B选自
其中,m、R2定义与本申请前述定义相一致。
在一些优选的实施方案中,所述环B选自
优选
其中,m、R2定义与本申请前述定义相一致。
进一步地,在本申请某些具体实施方案中,前述R2各自独立地选自氘、氚、硝基、羟基、巯基、氰基、氟、氯、溴、胺基、酯基、醛基、羧基、酰胺基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、三氟甲基、三氟乙基、三氯甲基、三氯乙基、环丁基、环丙基、苯基、吡啶基。
在一些实施方案中,所述R2各自独立地选自氘、氚、羟基、氟、氯、溴、胺基、甲基、乙基;优选氘、氚。
在一些实施方案中,m选自0、1、2,如0或1,优选0。
在一些实施方案中,所述RA选自氢、氘、氚、羟基、氟、氯、溴、氰基、C1~C5烷基(例如C1~C4烷基、C1~C3烷基)、C1~C5烷氧基(例如C1~C4烷氧基、C1~C3烷氧基)、C1~C5卤代烷基(例如C1~C4卤代烷基、C1~C3卤代烷基;如C1~C5氟代烷基、C1~C5氯代烷基、C1~C5溴代烷基)、3~6元环烷基(例如3~5元环烷基、3~4元环烷基)。
在一些实施方案中,所述RA选自氢、氘、氚、羟基、氟、氯、溴、氰基、环丙基、环丁基、甲基、乙基、丙基、丁基、戊基、甲氧基、乙氧基、丙氧基、C1~C3氟代烷基(例如三氟甲基、三氟乙基)、C1~C3氯代烷基(例如三氯甲基、三氯乙基)、C1~C3溴代烷基(例如三溴甲基、三溴乙基);优选氢、氘、氚、氟、氯、溴、氰基、环丙基、环丁基、甲基、乙基、丙基、丁基、甲氧基、乙氧基、C1~C3氟代烷基(例如三氟甲基、三氟乙基)。在某些具体实施例中,所述RA选自环丙基。在某些具体实施例中,所述RA选自溴。在某些具体实施例中,所述RA选自三氟甲基。在某些具体实施例中,所述RA选自甲氧基。在某些具体实施例中,所述RA选自氢、氘、氚、氰基、甲基、乙基、丙基。
进一步地,所述RA选自氢、氘、氚、羟基、卤素、氰基、环丙基、环丁基、甲基、乙基、甲氧基、乙氧基、三氟甲基。
进一步地,所述环A选自6~10元芳环、5~10元芳杂环、3~8元不饱和脂杂环、芳环与不饱和脂杂环构成的7~12元(例如8-10元)并环、芳杂环与不饱和脂杂环构成的7~12元并环;优选地,所述芳环、芳杂环为单环或双环,所述不饱和脂杂环为单环,所述并环为双环,且所述芳杂环、不饱和脂杂环、并环各自独立地包含1~3个杂原子,所述杂原子独立地选自N、O、S。
在一些实施方案中,所述环A选自6~10元芳环(例如6元芳环、10元芳环)、5~10元芳杂环(例如5元芳杂环、6元芳杂环、9元芳杂环、10元芳杂环;含有1-2个选自N、O或S的杂原子)、4~7元不饱和脂杂环(例如含有1-2个选自N、O或S的杂原子)、芳环与不饱和脂杂环构成的8~12元并环(例如含有1-2个选自N、O或S的杂原子)、芳杂环与不饱和脂杂环构成的8~12元并环(例如含有1-2个选自N、O或S的杂原子)。
在一些实施方案中,所述环A选自6~10元芳环、5~10元芳杂环、5~6元不饱和脂杂环、芳环与不饱和脂杂环构成的9~10元并环,且所述芳杂环、不饱和脂杂环、并环各自独立地包含1~2个选自N、O、S的杂原子。
在一些实施方案中,所述的环A选自
在一些实施方案中,o选自0、1、2,并且R1各自独立地选自氘、氚、羟基、卤素、氰基、=O、亚胺基、胺基、C1~C6烷基、卤素取代的C1~C6烷基、C1~C6烷氧基、4~8元环烷基、4~8元饱和脂杂环基,所述R1任选地被C1~C6烷基取代。
在一些实施方案中,o选自0、1、2,并且R1各自独立地选自氘、氚、氟、氯、溴、氰基、=O、亚胺基、胺基、C1~C5烷基(例如C1~C4烷基、C1~C3烷基)、卤素取代的C1~C5烷基(例如卤素取代的C1~C4烷基、卤素取代的C1~C3烷基)、C1~C5烷氧基(例如C1~C4烷氧基、C1~C3烷氧基)、5~7元(例如5-6元)饱和脂杂环基(例如含有1-2个选自N、O或S的杂原子),所述亚胺基、胺基、饱和脂杂环基任选地被C1~C5烷基(例如C1~C4烷基、C1~C3烷基)取代。
在一些实施方案中,o选自0、1、2,并且R1各自独立地选自氟、氯、溴、氰基、=O、胺基、甲基、乙基、丙基、甲氧基、乙氧基、丙氧基、含有1-2个选自N或O的杂原子的5~7元(例如5-6元)饱和脂杂环基(例如),所述胺基任选地被甲基、乙基或丙基(例如甲基)取代。
在一些实施方案中,o选自0、1、2,并且R1各自独立地选自氟、氯、溴、氰基、=O、胺基、甲基、
乙基、丙基、甲氧基、乙氧基、丙氧基、吗啉基、硫代吗啉基、哌啶基、哌嗪基(例如R1各自独立地选自氟、氯、溴、氰基、=O、胺基、甲基、乙基、丙基、甲氧基、乙氧基、丙氧基、吗啉基),所述胺基任选地被甲基、乙基或丙基(例如甲基)取代。
在一些实施方案中,o选自0、1、2,并且R1各自独立地选自氟、氯、溴、氰基、=O、-NH2、-NHCH3、-N(CH3)2、-NHCH2CH3、-N(CH2CH3)2、甲基、乙基、丙基、甲氧基、乙氧基、丙氧基、吗啉基。
在本申请的实施方案中,本申请还提供如式(II)所示化合物、其立体异构体、其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物(例如水合物)、或其前药,
其中,环A选自芳环、芳杂环、不饱和脂杂环、芳环与不饱和脂杂环构成的并环、芳杂环与不饱和脂杂环构成的并环;
R1各自独立地选自氘、氚、硝基、羟基、巯基、卤素、氰基、=O、亚胺基、胺基、酯基、醛基、羧基、酰胺基、C1~C6烷基、C1~C6烷氧基、3~8元环烷基、3~8元饱和脂杂环基;
RA选自氢、氘、氚、羟基、卤素、氰基、C1~C6烷基、C1~C6烷氧基、C1~C6卤代烷基、3~8元环烷基;
o选自0、1、2、3;
X选自共价键、S、NH、CH2、(CH2)2或(CH2)3;R3各自独立地选自氘、氚、硝基、羟基、巯基、氰基、卤素、胺基、酯基、醛基、羧基、酰胺基、C1~C6烷基、C1~C6卤代烷基、C1~C6烷氧基、C3~C8环烷基、6~10元芳基、5~10元杂芳基;p选自0、1;
优选地,所述R3各自独立地选自氘、氚、硝基、羟基、巯基、氰基、氟、氯、溴、胺基、酯基、醛基、羧基、酰胺基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、三氟甲基、三氟乙基、三氯甲基、三氯乙基、环丁基、环丙基、苯基、吡啶基。
进一步,本申请的实施方案中,所述p为0;
进一步,本申请的实施方案中,所述p为0且所述X为CH2。
在本申请的实施方案中,所述RA选自氢、氘、氚、羟基、卤素、氰基、环丙基、环丁基、甲基、乙基、甲氧基、乙氧基、三氟甲基。在某些具体的实施方案中,所述RA选自氢、氘、氚、氰基、环丙基、三氟甲基、卤素、甲基。
在一些实施方案中,所述RA选自氢、氘、氚、羟基、氟、氯、溴、氰基、环丙基、环丁基、甲基、乙基、丙基、丁基、戊基、甲氧基、乙氧基、丙氧基、C1~C3氟代烷基(例如三氟甲基、三氟乙基)、C1~C3氯代烷基(例如三氯甲基、三氯乙基)、C1~C3溴代烷基(例如三溴甲基、三溴乙基);优选氢、氘、氚、氟、氯、溴、氰基、环丙基、环丁基、甲基、乙基、丙基、丁基、甲氧基、乙氧基、C1~C3氟代烷基(例如三氟甲基、三氟乙基)。在某些具体实施例中,所述RA选自环丙基。在某些具体实施例中,所述RA选自溴。在某些具体实施例中,所述RA选自三氟甲基。在某些具体实施例中,所述RA选自甲氧基。在某些具体实施例中,所述RA选自氢、氘、氚、氰基、甲基、乙基、丙基。
在本申请的实施方案中,所述的环A选自6~10元芳环、5~10元芳杂环、3~8元不饱和脂杂环、芳环与不饱和脂杂环构成的7~12元并环、芳杂环与不饱和脂杂环构成的7~12元并环。
进一步,所述芳环、芳杂环优选单环或双环,所述不饱和脂杂环优选单环,所述并环优选为双环,并且所述芳杂环、不饱和脂杂环、并环各自独立地包含1~3个杂原子,所述杂原子独立地选自N、O、S。
在一些实施方案中,所述环A选自6~10元芳环(例如6元芳环、10元芳环)、5~10元芳杂环(例如5元芳杂环、6元芳杂环、9元芳杂环、10元芳杂环;含有1-2个选自N、O或S的杂原子)、4~7元不饱和脂杂环(例如含有1-2个选自N、O或S的杂原子)、芳环与不饱和脂杂环构成的8~12元并环(例如含有1-2个选自N、O或S的杂原子)、芳杂环与不饱和脂杂环构成的8~12元并环(例如含有1-2个选自N、O或S的杂原子)。
在一些实施方案中,所述环A选自6~10元芳环、5~10元芳杂环、5~6元不饱和脂杂环、芳环与不饱和脂杂环构成的9~10元并环,且所述芳杂环、不饱和脂杂环、并环各自独立地包含1~2个选自N、O、S的杂原子。
在本申请某些实施方案中,所述的环A选自
在本申请某些具体实施方案中,所述的环A优选自
在一些实施方案中,所述的环A选自
在本申请的某些实施方案中,本申请所述的R1各自独立地选自氘、氚、硝基、羟基、巯基、卤素、氰基、=O、亚胺基、胺基、酯基、醛基、羧基、酰胺基、环丙基、环丙甲基、环丁基、三氟甲基、环己基、环戊基、甲基、乙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、特戊基、正己基、吗啉基、硫代吗啉基、哌啶基、哌嗪基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、二氧杂环戊基、二氧杂环己基、甲氧基、乙氧基、正丙氧基、异丙氧基、环丙氧基、环丙甲氧基、正丁氧基、异丁氧基、叔丁氧基、正戊氧基、异戊氧基、特戊氧基、正己氧基,其中所述R1任选地被独立地选自氘、氚、硝基、羟基、-NH2、巯基、卤素、氰基、酯基、羧基、酰胺基、=O、=NH、C1~C6烷基、卤素取代的C1~C6烷基、C1~C6烷氧基、卤素取代的C1~C6烷基、3~8元环烷基、6~10元芳基、5~10元脂杂环基、5~10元杂芳基中的一个或多个取代。
在本申请的某些具体实施方案中,本申请所述的R1各自独立地优选自氘、氚、硝基、羟基、巯基、氰基、=O、=NH、-NH2、-N(CH3)2、-NHCH3、=NCH3、酯基、醛基、羧基、酰胺基、环丙基、环丁基、环己基、环戊基、甲基、乙基、异丙基、环丙甲基、三氟甲基、三氟乙基、三氯甲基、三氯乙基、吗啉基、哌啶基、N-甲基哌嗪基、对甲基哌啶基、哌嗪基、甲氧基、乙氧基、异丙氧基、环丙氧基、环丙甲氧基、卤素、环丙氧基。
在一些实施方案中,本申请提供了一种式(I)所示的化合物、其立体异构体或混合物形式、或其可药用的盐、或其溶剂合物(例如水合物)、或其前药,
其中,所述环A选自6~10元芳环、含有1-2个选自N、O或S的杂原子的5~10元芳杂环、含有1-2个选自N、O或S的杂原子的4~7元不饱和脂杂环、芳环与不饱和脂杂环构成的8~12元并环(含有1-2个选自N、O或S的杂原子)、芳杂环与不饱和脂杂环构成的8~12元并环(含有1-2个选自N、O或S的杂原子);优选地,所述环A选自6~10元芳环、5~10元芳杂环、5~6元不饱和脂杂环、芳环与不饱和脂杂环构成的9~10元并环,且所述芳杂环、不饱和脂杂环、并环各自独立地包含1~2个选自N、O、S的杂原子;
所述环B为包含至少1个氮原子的5~10元、例如5~8元或5~7元饱和脂杂环;优选地,所述环B选自
m选自0、1、2、3;R2各自独立地选自氘、氚、硝基、羟基、巯基、氰基、卤素、胺基、酯基、醛基、羧基、酰胺基、C1~C6烷基、C1~C6卤代烷基、C1~C6烷氧基、3~8元环烷基、6~10元芳基、5~10元杂芳基;
所述RA选自氢、氘、氚、羟基、氟、氯、溴、氰基、C1~C5烷基、C1~C5烷氧基、C1~C5卤代烷基、3~6元环烷基;优选地,所述RA选自氢、氘、氚、羟基、氟、氯、溴、氰基、环丙基、环丁基、甲基、乙基、丙基、丁基、戊基、甲氧基、乙氧基、丙氧基、C1~C3氟代烷基、C1~C3氯代烷基、C1~C3溴代烷基;
o选自0、1、2,并且R1各自独立地选自氘、氚、羟基、卤素、氰基、=O、亚胺基、胺基、C1~C6烷基、卤素取代的C1~C6烷基、C1~C6烷氧基、4~8元环烷基、4~8元饱和脂杂环基,所述R1任选地被C1~C6烷基取代;优选,o选自0、1、2,并且R1各自独立地选自氘、氚、氟、氯、溴、氰基、=O、亚胺基、胺基、C1~C5烷基、卤素取代的C1~C5烷基、C1~C5烷氧基、5~7元饱和脂杂环基,所述亚胺基、胺基任选地被C1~C5烷基取代。
在一些实施方案中,本申请提供了一种式(I)所示的化合物、其立体异构体或混合物形式、或其可药用的盐、或其溶剂合物(例如水合物)、或其前药,其中,
所述的环A选自
所述环B选自
m选自0、1;
R2各自独立地选自氘、氚、羟基、氟、氯、溴、胺基、甲基、乙基;优选氘、氚;
所述RA选自氢、氘、氚、氟、氯、溴、氰基、环丙基、环丁基、甲基、乙基、丙基、丁基、甲氧基、乙氧基、C1~C3氟代烷基(例如三氟甲基、三氟乙基);优选氢、溴、氰基、环丙基、甲基、乙基、丙基、甲氧基、三氟甲基。
o选自0、1、2,并且R1各自独立地选自氟、氯、溴、氰基、=O、胺基、甲基、乙基、丙基、甲氧基、乙氧基、丙氧基、吗啉基、硫代吗啉基、哌啶基、哌嗪基,所述胺基任选地被甲基、乙基或丙基(例如甲基)取代。
在本申请的一些具体实施方案中,本申请如下所示的化合物、其立体异构体、互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物(例如水合物)、或其前药:
本申请还涵盖通过对上述各实施方案进行任意组合、删减或调换而得到的方案。
本申请的另一方面是提供一种药物组合物,包含至少一种前述化合物、其立体异构体、互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药,和至少一种药学上可接受的辅料。
本申请的另一方面是提供一种前述化合物、或其立体异构体、互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药、或药物组合物用于制备药物的用途。其中,所述药物是15-PGDH抑制剂,可用于治疗不需要的15-PGDH活性水平升高相关的疾病。或者,本申请提供了一种用作药物的前述化合物、或其立体异构体、互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药、或药物组合物。或者,本申请提供了一种治疗或预防15-PGDH相关疾病的方法,包括向有需要的受试者给予前述化合物、或其立体异构体、互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药、或药物组合物。本文中的所述15-PGDH相关疾病是指通过抑制15-PGDH活性而达到缓解、改善、停止进展、减轻或者不再恶化等临床上有益的疗效的疾病或其并发症。
在某些具体的实施方案中,所述药物、抑制剂或方法用于治疗或预防纤维化、口腔溃疡、龈疾病、结肠炎、溃疡性结肠炎、胃十二指肠溃疡、炎性疾病、血管功能不全、Raynaud病、Buerger病、神经病变、肺动脉高压、心血管病和肾病、心血管疾病、创伤、皮肤损伤、自身免疫性疾病、移植物抗宿主疾病、骨质疏松症、耳病、眼病、中性白细胞减少、糖尿病、膀胱活动低下症,或者用于促进毛发生长、色素沉着、组织修复、组织再生、在干细胞移植或骨髓移植或器官移植中的植入物、神经发生和神经细胞死亡、肌肉
再生和宫颈成熟,或者用于增强对辐射暴露的毒性、化疗的毒性、免疫抑制剂的毒性的抗性。
定义
除非有相反陈述,否则下列用在说明书和权利要求书中的术语具有下述含义。一个特定的术语在没有特别定义的情况下不应被认为是不明确或不清楚的,而应该按照本领域的常规含义去理解。
“烷基”是指饱和的脂肪族烃基团。烷基部分可以是直链烷基,亦可以是支链烷基;本申请中使用的C1-C6烷基指由1~6个(例如1个、2个、3个、4个、5个、6个或由任意两个前述数值组成的范围值)碳原子构成的直链烷基或支链烷基。典型的烷基包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、特戊基、正己基等。
“烷氧基”是指-O-烷基;本申请中使用的C1-C6烷氧基指由1~6个(例如1个、2个、3个、4个、5个、6个或由任意两个前述数值组成的范围值)碳原子构成的直链烷氧基或支链烷氧基。典型的烷氧基包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、正戊氧基、异戊氧基、特戊氧基、正己氧基等。
“环”是指任意的环状共价封闭结构,包括例如碳环(例如芳环或脂环)、杂环(例如芳杂环或脂杂环)。碳环是指仅由碳原子构成的环,杂环是指由碳原子、杂原子共价结合并形成的封闭结构。根据环的数量,“环”可以是单环、双环、三环或多环。环为双环、三环或多环时,各个环之间的关系可以包括并环、螺环、桥环。
“杂原子”是指除碳原子以外其他任意可与碳原子共价结合的原子。常见的杂原子包括但不限于O、S、N、P、Si等。
“元”是表示构成环的骨架原子的个数。典型的5元环可以包括但不限于环戊烷、吡咯、咪唑、噻唑、呋喃和噻吩等;典型的6元环包括但不限于环己烷、吡啶、吡喃、吡嗪、噻喃、哒嗪、嘧啶、苯等。
“脂环”或“脂环基”是指饱和或者部分不饱和的由碳原子构成骨架的没有芳香性的环状基团,饱和的碳环可以称为例如饱和脂环,部分不饱和的碳环可以称为例如不饱和脂环,脂环可以由3~10个(例如3个、4个、5个、6个、7个、8个、9个或10)原子构成,可以为单环或多环,例如3~8元脂环基即是指由3~8个骨架原子构成的脂环基。典型的脂环结构包括但不限于:
等。
“脂杂环”或”脂杂环基”是指由一个或多个杂原子置换脂环中碳原子形成的没有芳香性的环状基团。脂杂环或脂杂环基可以包括饱和脂杂环和不饱和脂杂环。例如本申请中使用的3~8元脂杂环基是指由3~8个骨架原子构成的含有一个或多个杂原子的没有芳香性的环状基团,可以是饱和脂杂环基和不饱和脂杂环基。
“饱和脂杂环”或“饱和脂杂环基”是指脂杂环中构成环骨架的原子均为饱和的。例如本申请中使用的3~12元饱和脂杂环是指由3~12个原子构成环骨架形成的没有芳香性的环状基团,其中构成环骨架的原子由饱和碳原子和杂原子组成。典型的饱和脂杂环包括但不限于:
等。
“不饱和脂杂环”或”不饱和脂杂环基”是指脂杂环中包含部分不饱和原子作为环骨架的不具有芳香性的环状结构。本申请中的“不饱和脂杂环”是指构成脂杂环的骨架中含有不饱和碳原子。本申请中使用的3~8元不饱和脂杂环指由3~8个(例如3个、4个、5个、6个、7个或8个)骨架原子构成的没有芳香性的环状基团,其中构成环骨架的原子包括饱和碳原子、不饱和碳原子和杂原子,典型的不饱和脂杂环包括但不限于:
等。
“环烷基”是指饱和的脂肪族碳环基团,也可以称为例如饱和脂环基。环烷基可以是单环、螺环、并环或桥环。本申请中使用的3~8元环烷基指由3~8个碳原子构成的环状烷基。典型的环烷基包括但不限于环丙基、环丁基、环戊基、环己基、双环[2,1,1]己烷基、环庚基等。
“芳环”或“芳基”是指完全不饱和的碳环,其平面环具有离域的π电子系统并且含有4n+2个π电子,其中n是整数。芳环可以由六、八、十或多于十个碳原子构成,芳环可以是单环也可以是双环、三环或多环。常见的芳环包括但不限于苯环、萘环、菲环、蒽环、四苯、芘环、五苯等。本申请中使用的6~10元芳环或6~10元芳基指由6~10个骨架碳原子构成的芳环基团。
“芳杂环”或“杂芳基”是指由一个或多个杂原子置换芳环中的碳原子形成的芳香性环状结构,典型的芳杂环或杂芳基包括但不限于:
等。
本申请中使用的5~10元芳杂环或5~10元杂芳基指由5~10个(例如5个、6个、7个、8个、9个或10个)骨架原子构成的含杂原子的芳香性环状基团。
“并环”是指环与环之间共用两个相邻的环原子构成的环状结构。并环可以为双环、三环或多环。
本申请中“芳环与不饱和脂杂环构成的并环”是指芳环与不饱和脂杂环共用两个相邻的环原子形成的并环结构;“芳杂环与不饱和脂杂环构成的并环”是指芳杂环与不饱和脂杂环共用两个相邻的环原子形成的并环结构。本申请中“芳杂环与不饱和脂杂环构成的7~12元并环”是指由不饱和脂杂环与芳杂环共用两个相邻环原子形成的具有7~12个骨架环原子的并环结构。本申请中“芳环与不饱和脂杂环构成的7~12元并环”是指由不饱和脂杂环与芳环共用两个相邻环原子形成的具有7~12个骨架环原子的并环结构。
常见的芳环与不饱和脂杂环构成的并环包括但不限于:
常见的芳杂环与不饱和脂杂环构成的并环包括但不限于:
“卤素”或“卤”是指氟、氯、溴或碘。
“卤代烷基”是指烷基中至少一个氢被卤素原子置换,本申请中使用的C1~C6卤代烷基指由1~6个碳原子构成的直链烷基或支链烷基,且烷基上至少一个氢被卤素原子任意取代。
“胺基”或”胺”是指具有-NRURV的化学结构,其中RURV各自独立地选自氢、氘、氚、烷基、环烷基。
“亚胺基”或”亚胺”是指具有=NRW的化学结构,其中RW选自氢、氘、氚、烷基、环烷基。
“酰胺”或“酰胺基”是指具有-C(O)NRXRY或-NRXC(O)RY的化学结构,其中RX、RY各自独立地选自氢、氘、氚、烷基、环烷基,常见的酰胺基包括但不限于-CONH2、-CONHCH3、-CON(CH3)2、-NHCOH、-NHCOCH3、-N(CH3)COCH3。
“酯基”是指具有式-COOR0的化学结构,其中R0选自烷基、环烷基、杂环烷基、芳基、杂芳基。
“取代”指基团中的一个或多个氢原子彼此独立地被相应数目的取代基所取代。不言而喻,取代基仅处在它们的可能的化学位置,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。各自并且独立地选自烷基、环烷基、芳基、杂芳基、杂环烷基、羟基、烷氧基、烷硫基、芳氧基、硝基、酰基、卤素、卤代烷基、氨基等等。
“抑制剂”是指使酶活性下降的物质。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必然发生,该说明包括该事件或环境发生或不发生地场合。例如,“任选地被取代的”包括取代或未取代的,如“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在,该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物,以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。
“可药用的”是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。
作为可药用的盐,例如可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。
“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如,质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变,如酮-烯醇及亚胺-烯胺异构化。质子互变异构体的具体实例是咪唑部分,其中质子可在两个环氮间迁移。价互变异构体包括通过一些成键电子的重组的互变。互变异构体的非限制性实例包括但不限于,“立体异构体”是指由于分子中的原子在空间上排列方式不同所产生的异构体。
“对映异构体”是指具有相同分子式、官能团的化合物,由于原子在空间配置不同而引起的同分异构现象,同时所述化合物形成互为镜像而不可重叠的立体异构体。
“非对映异构体”是指具有相同分子式、官能团的化合物,由于原子在空间配置不同而引起的同分异构现象,同时所述化合物彼此之间不呈实物与镜像关系的立体异构体。
除非另有说明,本文使用的术语“包含、包括和含有(comprise、comprises和comprising)”或其等
同物(contain、contains、containing、include、includes、including)为开放式表述,意味着除所列出的要素、组分和步骤外,还可涵盖其它未指明的要素、组分和步骤。
除非另有说明,本文所使用的表示成分的量、测量值或反应条件的所有数字应理解为在所有情况下均由术语“约”修饰。当与百分比相连时,术语“约”可以表示例如±1%、优选±0.5%、更优选±0.1%。
除非上下文另有明确指示,本文中的单数术语涵盖复数的指示对象,反之亦然。类似地,除非上下文另有明确指示,本文中的词语“或”意在包括“和”。
显然,根据本申请的上述内容,按照本领域的普通技术知识和手段,在不脱离本申请上述基本技术思想前提下,还可以做出其他多种形式的修改、替换或变更。
本申请中的缩写具有如下所示的意义:
下面通过举例说明本申请的化合物和中间体的合成方法,下述举例仅作为本申请的示例,而不应作为对本申请范围的限制。除特殊说明外,本申请中所涉及的原料和试剂均可通过商业化渠道获得,具体渠道来源并不影响本申请技术方案的实施。
制备例1:(7-环丙基-3-甲氧基噻吩并[2,3-b]吡嗪-6-基)(哌啶-1-基)甲酮的制备
步骤1:3-氯-5-甲氧基吡嗪-2-腈的制备
称取3,5-二氯吡嗪-2-腈(20.0g)溶于甲醇(100mL)中,0℃下加入甲醇钠(6.8g),在0℃下反应3h后,升至室温下搅拌1h。TLC显示原料消耗完毕,减压浓缩,加水淬灭,乙酸乙酯萃取两次,无水硫酸钠干燥,硅胶柱层析纯化得标题化合物(9.0g)。MS(ESI)m/z(M+H)+=170.0。
步骤2:7-氨基-3-甲氧基噻吩并[2,3-b]吡嗪-6-羧酸乙酯的制备
称取3-氯-5-甲氧基吡嗪-2-腈(9.0g)溶于N,N-二甲基甲酰胺(120mL)中,加入碳酸钾(16g)、巯基乙酸乙酯(7.0mL),于80℃反应过夜。TLC显示原料消耗完毕,加水淬灭,乙酸乙酯萃取两次,饱和食盐水洗涤两次,无水硫酸钠干燥,硅胶柱层析纯化得标题化合物(8.0g)。MS(ESI)m/z(M+H)+=254.0。
步骤3:7-碘-3-甲氧基噻吩并[2,3-b]吡嗪-6-甲酸乙酯的制备
称取7-氨基-3-甲氧基噻吩并[2,3-b]吡嗪-6-羧酸乙酯(9.0g)和碘化亚铜(12g)溶于120mL乙腈中,在60℃下滴加亚硝酸叔丁酯(7.58mL),在60℃下反应6h。TLC监控反应完全,EA稀释,硅藻土过滤,加水淬灭,乙酸乙酯萃取两次,无水硫酸钠干燥,硅胶柱层析纯化得标题化合物(6.47g)。MS(ESI)m/z(M+H)+=365.0。
步骤4:7-碘-3-甲氧基噻吩并[2,3-b]吡嗪-6-羧酸的制备
称取7-碘-3-甲氧基噻吩并[2,3-b]吡嗪-6-甲酸乙酯(6.47g),溶于四氢呋喃(30mL)、甲醇(10mL)、水(10mL)的混合溶剂中,加入氢氧化钾(3.0g),于80℃下反应3h。LCMS显示原料消耗完毕,加水淬灭,用2M盐酸调节PH值至酸性,乙酸乙酯萃取三次,无水硫酸钠干燥,减压浓缩得标题化合物(3.6g)。MS(ESI)m/z(M+H)+=336.9。
步骤5:(7-碘-3-甲氧基噻吩[2,3-b]吡嗪-6-基)(哌啶-1-基)甲酮的制备
称取7-碘-3-甲氧基噻吩并[2,3-b]吡嗪-6-羧酸(3.6g)溶于N,N-二甲基甲酰胺(50mL)中,0℃下依次加入N,N-二异丙基乙胺(3.72mL)、六氢吡啶(1.65mL)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(6.1g)后升至室温下反应3h。TLC显示原料消耗完毕,加水淬灭,乙酸乙酯萃取两次,饱和食盐水洗涤两次,无水硫酸钠干燥,硅胶柱层析纯化得标题化合物(2.5g)。MS(ESI)m/z(M+H)+=404.0。
步骤6:(7-环丙基-3-甲氧基噻吩并[2,3-b]吡嗪-6-基)(哌啶-1-基)甲酮的制备
称取(7-碘-3-甲氧基噻吩[2,3-b]吡嗪-6-基)(哌啶-1-基)甲酮(1.1g)、环丙基硼酸硼酸(0.46g)、碳酸钠(8mg)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(100mg),加入1,4-二氧六环(15mL)、水(5mL),氩气置换三次,于80℃下反应8h。LCMS监控原料反应完全,加水淬灭,乙酸乙酯萃取两次,无水硫酸钠干燥,硅胶柱纯化得标题化合物(0.62g)。MS(ESI)m/z(M+H)+=318.0。
制备例2:3-甲氧基-6-(哌啶-1-羰基)噻吩并[2,3-b]吡嗪-7-甲腈的制备
称取制备例1步骤5得到的(7-碘-3-甲氧基噻吩[2,3-b]吡嗪-6-基)(哌啶-1-基)甲酮(3.6g)、氰化亚铜(2.4g),加入N,N-二甲基甲酰胺(40mL),氩气置换三次,于110℃下反应6h。LCMS监控原料反应完全,减压蒸出溶剂,加入饱和硫化钠溶液,室温搅拌30min,过滤,滤饼用乙酸乙酯洗涤,合并滤液,浓缩后硅胶柱纯化得标题化合物(2.2g)。MS(ESI)m/z(M+H)+=303.1。
制备例3:(3-甲氧基-7-(三氟甲基)噻吩并[2,3-b]吡嗪-6-基)(哌啶-1-基)甲酮的制备
称取(7-碘-3-甲氧基噻吩[2,3-b]吡嗪-6-基)(哌啶-1-基)甲酮(1.0g)溶于N,N-二甲基甲酰胺(10mL)中,加入2,2-二氟-2-(氟磺酰基)乙酸甲酯(0.95mL)、碘化亚铜(95mg),氩气置换三次,于90℃下反应4h。加水淬灭,乙酸乙酯萃取两次,无水硫酸钠干燥,硅胶柱层析纯化得标题化合物(845mg)。MS(ESI)m/z(M+H)+=346.0。
实施例1:(7-环丙基-3-苯基噻吩并[2,3-b]吡嗪-6-基)(哌啶-1-基)甲酮的制备
步骤1:3-氯-5-苯基吡嗪-2-腈的制备
称取3,5-二氯吡嗪-2-腈(2.5g)、苯硼酸(1.95g)、碳酸钠(1.84g)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(0.53g)溶于1,4-二氧六环(20mL)和水(5mL)混合溶剂中,氮气置换三次后,80℃反应2h,TLC监测原料反应完全。冷却至室温,过滤,滤液加入水,乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,减压蒸出溶剂,残余物硅胶柱纯化得标题化合物粗品(3.1g)。MS(ESI)m/z(M+H)+=216.0。
步骤2:7-氨基-3-苯基噻吩并[2,3-b]吡嗪-6-羧酸乙酯的制备
称取3-氯-5-苯基吡嗪-2-腈(80mg)溶于N,N-二甲基甲酰胺中(2mL)中,加入碳酸钾(120mg)、巯基乙酸乙酯(54μL),80℃反应过夜,LC-MS监测反应完全。冷却至室温,加水淬灭,乙酸乙酯萃取三次,合并有机相,无水硫酸钠干燥,减压浓缩,硅胶柱纯化得标题化合物(90mg)。MS(ESI)m/z(M+H)+=300.1。
步骤3:(7-氨基-3-苯基噻吩并[2,3-b]吡嗪-6-基)(哌啶-1-基)甲酮的制备
(1)称取7-氨基-3-苯基噻吩并[2,3-b]吡嗪-6-羧酸乙酯(90mg)溶于四氢呋喃(2mL)、甲醇(0.6mL)和水(0.6mL)中,加入氢氧化钾(51mg),70℃反应2h,LCMS监测反应完全。冷却至室温,加入水,用乙酸乙酯萃取三次,舍去有机相,水相用2M稀盐酸调节pH至2,再用乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,减压蒸出溶剂后得7-氨基-3-苯基噻吩并[2,3-b]吡嗪-6-羧酸粗品。
(2)粗品溶于N,N-二甲基甲酰胺中(2mL)中,冰水浴下依次加入二异丙基乙胺(100μL)、哌啶(37μL)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(170mg),移至室温搅拌2h,LCMS监测反应完全。加水淬灭,乙酸乙酯萃取三次,合并有机相,无水硫酸钠干燥,减压浓缩,残余物反相制备纯化得标题化合物(9.5mg)。MS(ESI)m/z(M+H)+=339.1。
步骤4:(7-溴-3-苯基噻吩并[2,3-b]吡嗪-6-基)(哌啶-1-基)甲酮的制备
称取(7-氨基-3-苯基噻吩并[2,3-b]吡嗪-6-基)(哌啶-1-基)甲酮(130mg)溶于干燥乙腈(3mL)中,冰水浴下,氮气保护下加入溴化铜(100mg),再滴入叔丁基亚硝酸酯(57μL),移至室温反应1h,TLC监测反应完全。加入饱和碳酸氢钠溶液淬灭,过滤除去不溶物,滤液用乙酸乙酯萃取,合并有机相,无水硫酸钠干燥。减压蒸出溶剂,硅胶柱纯化得粗品,再用Prep-HPLC分离得到标题化和物(30mg)。MS(ESI)m/z(M+H)+=402.0。
步骤5:(7-环丙基-3-苯基噻吩并[2,3-b]吡嗪-6-基)(哌啶-1-基)甲酮的制备
称取(7-溴-3-苯基噻吩并[2,3-b]吡嗪-6-基)(哌啶-1-基)甲酮(30mg)、环丙基硼酸(8mg)、碳酸钠(16mg)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(6.5mg)溶于1,4-二氧六环(2mL)和水(0.6mL)中,氮气置换三次后,100℃反应3h,TLC监测原料反应完全。冷却至室温,过滤,滤液加入水,乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,减压蒸出溶剂,反相制备纯化得标题化合物(2.56mg)。
MS(ESI)m/z(M+H)+=364.1。1H NMR(400MHz,DMSO-d6)δ9.37(s,1H),8.23-8.20(m,2H),7.59-7.51(m,3H),3.66-3.45(m,4H),2.14-2.09(m,1H),1.64-1.56(m,6H),1.41-1.37(m,2H),1.02-0.98(m,2H)。
实施例2(7-环丙基-3-(2-甲基吡啶-4-基)噻吩并[2,3-b]吡嗪-6-基)(哌啶-1-基)甲酮的制备
步骤1:(7-环丙基-3-羟基噻吩并[2,3-b]吡嗪-6-基)(哌啶-1-基)甲酮的制备
称取(7-环丙基-3-甲氧基噻吩并[2,3-b]吡嗪-6-基)(哌啶-1-基)甲酮(0.62g)溶于N,N-二甲基甲酰胺(3mL)中,加入甲硫醇钠(20%水溶液,1.4mL)于100℃下,反应过夜。加水淬灭,2M盐酸调节PH值至酸性,乙酸乙酯萃取2次,饱和食盐水洗涤2次,无水硫酸钠干燥,硅胶柱层析纯化得标题化合物粗品(0.6g)。MS(ESI)m/z(M+H)+=304.0。
步骤2:7-环丙基-6-(哌啶-1-羰基)噻吩并[2,3-b]吡嗪-3-基三氟甲磺酸酯的制备
称取(7-环丙基-3-羟基噻吩并[2,3-b]吡嗪-6-基)(哌啶-1-基)甲酮(600mg)溶于二氯甲烷(12mL)中,加入N,N-二异丙基乙胺(0.62mL)、N-苯基双(三氟甲烷磺酰)亚胺(1.1g)于50℃下反应过夜。TLC及LCMS监控原料反应完全,加水淬灭,二氯甲烷萃取2次,无水硫酸钠干燥,硅胶柱层析纯化得标题化合物(0.8g)。MS(ESI)m/z(M+H)+=436.0。
步骤3:(7-环丙基-3-(2-甲基吡啶-4-基)噻吩并[2,3-b]吡嗪-6-基)(哌啶-1-基)甲酮的制备
称取7-环丙基-6-(哌啶-1-羰基)噻吩并[2,3-b]吡嗪-3-基三氟甲磺酸酯(30mg)、(2-甲基吡啶-4-基)硼酸(14mg)、碳酸钠(12mg)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(2mg),向其中加入1,4-二氧六环(1mL)、水(0.3mL),氩气置换三次,于80℃下反应1.5h。LCMS监控原料反应完全,加水淬灭,乙酸乙酯萃取2次,无水硫酸钠干燥,反相制备柱分离得标题化合物(9.05mg)。
MS(ESI)m/z(M+H)+=379.0。1H NMR(400MHz,DMSO-d6)δ9.46(s,1H),8.64-8.63(d,J=5.2Hz,1H),8.07(s,1H),7.99-7.97(d,J=5.9Hz,1H),3.67(m,2H),3.45(m,2H),2.59(s,3H),2.15-2.10(m,1H),1.67-1.55(m,6H),1.41-1.37(dt,J=5.9,3.0Hz,2H),1.03-0.99(dt,J=8.6,3.1Hz,2H)。
采用相应的商品化试剂及前述制备例与实施例中产物为原料,使用类似的制备方法,制备得到一类化合物,所述化合物的结构及表征数据见表1。
表1
实施例33(7-环丙基-3-(2-甲基吡啶-4-基)噻吩并[2,3-b]吡嗪-6-基)(哌啶-1-基)甲酮的制备
步骤1:3-氯-5-苯基吡嗪-2-腈的制备
称取3,5-二氯吡嗪-2-腈(2.5g)、苯硼酸(1.95g)、碳酸钠(1.84g)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(0.53g)溶于1,4-二氧六环(20mL)和水(5mL)混合溶剂中,氮气置换三次后,80℃反应2h,TLC监测原料反应完全。冷却至室温,过滤,滤液加入水,乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,减压蒸出溶剂,残
余物硅胶柱纯化得标题化合物粗品(3.1g)。MS(ESI)m/z(M+H)+=216.0。
步骤2:7-氨基-3-苯基噻吩并[2,3-b]吡嗪-6-羧酸乙酯的制备
称取3-氯-5-苯基吡嗪-2-腈(80mg)溶于N,N-二甲基甲酰胺中(2mL)中,加入碳酸钾(120mg)、巯基乙酸乙酯(54μL),80℃反应过夜,LC-MS监测反应完全。冷却至室温,加水淬灭,乙酸乙酯萃取三次,合并有机相,无水硫酸钠干燥,减压浓缩,硅胶柱纯化得标题化合物(90mg)。MS(ESI)m/z(M+H)+=300.1。
步骤3:7-碘-3-苯基噻吩并[2,3-b]吡嗪-6-羧酸乙酯(BT-120-348-062)的制备
称取碘(0.76g)、叔丁基亚硝酸酯(0.18mL)溶于干燥乙腈(10mL)中,氮气保护下加入7-氨基-3-苯基噻吩并[2,3-b]吡嗪-6-羧酸乙酯(300mg),加入溴化铜(490mg),再滴入叔丁基亚硝酸酯(0.3mL),45℃反应2h,TLC监测反应完全。冷却至室温,加入饱和亚硫酸氢钠溶液淬灭,再用饱和碳酸氢钠溶液调节pH至8,用乙酸乙酯萃取,合并有机相,无水硫酸钠干燥。减压蒸出溶剂,硅胶柱纯化得标题化合物(80mg)。MS(ESI)m/z(M+H)+=411.1。
步骤4:(7-碘-3-苯基噻吩并[2,3-b]吡嗪-6-基)(哌啶-1-基)甲酮(BT-120-348-063)的制备
称取7-碘-3-苯基噻吩并[2,3-b]吡嗪-6-羧酸乙酯(80mg)溶于四氢呋喃(1mL)、甲醇(0.3mL)和水(0.3mL)中,加入氢氧化钾(34mg),70℃反应2h,LCMS监测反应完全。冷却至室温,加入水,用乙酸乙酯萃取三次,舍去有机相,水相用2M稀盐酸调节pH至2,再用乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,减压蒸出溶剂后得粗品。粗品溶于N,N-二甲基甲酰胺(2mL)中,冰水浴下依次加入二异丙基乙胺(65μL)、哌啶(25μL)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(114mg),移至室温搅拌2h,LCMS监测反应完全。加水淬灭,乙酸乙酯萃取三次,合并有机相,无水硫酸钠干燥,减压浓缩,残余物硅胶柱纯化得标题化合物(30mg)。MS(ESI)m/z(M+H)+=449.9。
步骤5:3-苯基-6-(哌啶-1-羰基)噻吩并[2,3-b]吡嗪-7-腈(BT-120-348-065)的制备
称取(7-碘-3-苯基噻吩并[2,3-b]吡嗪-6-基)(哌啶-1-基)甲酮(30mg)溶于1,4-二氧六环(1mL)和水(0.3mL)的混合溶剂中,依次加入醋酸钾(15mg)、六氰合亚铁酸钾三水合物(16mg)、2-二环己基磷-2,4,6-三异丙基联苯(7mg)、甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(6mg),体系氮气置换3次,密封后110℃反应3h,LC-MS监测反应完全。冷却至室温,过滤,滤饼用乙酸乙酯洗涤多次,滤液加水后分出有机层,水相用乙酸乙酯萃取三次,合并有机相,无水硫酸钠干燥,减压浓缩至干,残余物Prep-HPLC分离得标题化合物(2.18mg)。
MS(ESI)m/z(M+H)+=349.0。1H NMR(400MHz,DMSO-d6)δ9.60(s,1H),8.30-8.27(m,2H),7.64-7.58(m,3H),3.68-3.51(m,4H),1.66-1.60(m,6H)。
实施例34(7-环丙基-3-(2-甲基吡啶-4-基)噻吩并[2,3-b]吡嗪-6-基)(哌啶-1-基)甲酮的制备
步骤1:3-羟基-6-(哌啶-1-羰基)噻吩并[2,3-b]吡嗪-7-甲腈的制备
称取3-甲氧基-6-(哌啶-1-羰基)噻吩并[2,3-b]吡嗪-7-甲腈(1.2g)溶于N,N-二甲基甲酰胺(5mL)中,加入甲硫醇钠(20%水溶液,3mL)于115℃下,反应1.5h。加水淬灭,2M盐酸调节PH值至酸性,乙酸乙酯萃取两次,饱和食盐水洗涤两次,无水硫酸钠干燥,硅胶柱层析纯化得标题化合物粗品(1.2g)。MS(ESI)m/z(M+H)+=289.0。
步骤2:7-氰基-6-(哌啶-1-羰基)噻吩并[2,3-b]吡嗪-3-基三氟甲磺酸酯的制备
称取(7-氰基-3-羟基噻吩并[2,3-b]吡嗪-6-基)(哌啶-1-基)甲酮(1.2g)溶于二氯甲烷(12mL)中,加入N,N-二异丙基乙胺(1.3mL)、N-苯基双(三氟甲烷磺酰)亚胺(2.9g)于50℃下反应过夜。TLC及LCMS监控原料反应完全,加水淬灭,二氯甲烷萃取两次,无水硫酸钠干燥,硅胶柱层析纯化得标题化合物(0.9g)。MS(ESI)m/z(M+H)+=421.1。
步骤3:3-(2-甲氧基嘧啶-5-基)-6-(哌啶-1-羰基)噻吩并[2,3-b]吡嗪-7-甲腈的制备
称取7-氰基-6-(哌啶-1-羰基)噻吩并[2,3-b]吡嗪-3-基三氟甲磺酸酯(30mg)、2-甲氧基-5-嘧啶硼酸(22mg),碳酸钠(12mg)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(2mg),向其中加入1,4-二氧六环(1mL)、水(0.3mL),氩气置换三次,于80℃下反应1.5h。LCMS监控原料反应完全,加水淬灭,乙酸乙酯萃取2次,无水硫酸钠干燥,反相制备柱分离得标题化合物(5.34mg)。
MS(ESI)m/z(M+H)+=381.1。1H NMR(400MHz,DMSO-d6)δ9.63(s,1H),9.44(s,2H),4.04(s,3H),3.68-3.51(m,4H),1.68-1.61(m,6H)。
采用相应的商品化试剂及前述制备例与实施例中产物为原料,使用上述类似的制备方法,制备得到一类化合物,所述化合物的结构及表征数据见表2。
表2
实施例63:(3-苯基-7-(三氟甲基)噻吩并[2,3-b]吡嗪-6-基)(哌啶-1-基)甲酮的制备
步骤1:3-氯-5-苯基吡嗪-2-腈的制备
称取3,5-二氯吡嗪-2-腈(2.5g)、苯硼酸(1.95g)、碳酸钠(1.84g)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(0.53g)溶于1,4-二氧六环(20mL)和水(5mL)混合溶剂中,氮气置换三次后,80℃反应2h,TLC监测原料反应完全。冷却至室温,过滤,滤液加入水,乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,减压蒸出溶剂,残余物硅胶柱纯化得标题化合物粗品(3.1g)。MS(ESI)m/z(M+H)+=216.0。
步骤2:7-氨基-3-苯基噻吩并[2,3-b]吡嗪-6-羧酸乙酯的制备
称取3-氯-5-苯基吡嗪-2-腈(80mg)溶于N,N-二甲基甲酰胺中(2mL)中,加入碳酸钾(120mg)、巯基乙酸乙酯(54μL),80℃反应过夜,LC-MS监测反应完全。冷却至室温,加水淬灭,乙酸乙酯萃取三次,合并有机相,无水硫酸钠干燥,减压浓缩,硅胶柱纯化得标题化合物(90mg)。MS(ESI)m/z(M+H)+=300.1。
步骤3:7-碘-3-苯基噻吩并[2,3-b]吡嗪-6-羧酸乙酯(BT-120-348-062)的制备
称取碘(0.76g)、叔丁基亚硝酸酯(0.18mL)溶于干燥乙腈(10mL)中,氮气保护下加入7-氨基-3-苯基噻吩并[2,3-b]吡嗪-6-羧酸乙酯(300mg),加入溴化铜(490mg),再滴入叔丁基亚硝酸酯(0.3mL),45℃反应2h,TLC监测反应完全。冷却至室温,加入饱和亚硫酸氢钠溶液淬灭,再用饱和碳酸氢钠溶液调节pH至8,
用乙酸乙酯萃取,合并有机相,无水硫酸钠干燥。减压蒸出溶剂,硅胶柱纯化得标题化合物(80mg)。MS(ESI)m/z(M+H)+=411.1。
步骤4:(7-碘-3-苯基噻吩并[2,3-b]吡嗪-6-基)(哌啶-1-基)甲酮(BT-120-348-063)的制备
称取7-碘-3-苯基噻吩并[2,3-b]吡嗪-6-羧酸乙酯(80mg)溶于四氢呋喃(1mL)、甲醇(0.3mL)和水(0.3mL)中,加入氢氧化钾(34mg),70℃反应2h,LCMS监测反应完全。冷却至室温,加入水,用乙酸乙酯萃取三次,舍去有机相,水相用2M稀盐酸调节pH至2,再用乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,减压蒸出溶剂后得粗品。粗品溶于N,N-二甲基甲酰胺(2mL)中,冰水浴下依次加入二异丙基乙胺(65μL)、哌啶(25μL)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(114mg),移至室温搅拌2h,LCMS监测反应完全。加水淬灭,乙酸乙酯萃取三次,合并有机相,无水硫酸钠干燥,减压浓缩,残余物硅胶柱纯化得标题化合物(30mg)。MS(ESI)m/z(M+H)+=449.9。
步骤5:3-苯基-6-(哌啶-1-羰基)噻吩并[2,3-b]吡嗪-7-腈(BT-120-348-065)的制备
称取(7-碘-3-苯基噻吩并[2,3-b]吡嗪-6-基)(哌啶-1-基)甲酮(15mg)、2,2-二氟-2-(氟磺酰基)乙酸甲酯(20mg)、碘化亚铜(1mg)溶于N,N-二甲基甲酰胺中(1mL),氮气保护,90℃反应3h,LCMS监测反应完全。冷却至室温,加水淬灭反应,用乙酸乙酯萃取三次,合并有机相,无水硫酸钠干燥,减压浓缩,Prep-HPLC纯化得标题化合物(2.27mg)。
MS(ESI)m/z(M+H)+:392.1。1H NMR(400MHz,DMSO-d6)δ9.58-9.56(t,J=2.3Hz,1H),8.28-8.26(d,J=7.0Hz,2H),7.64-7.60(m,3H),3.67-3.66(m,2H),3.35-3.33(m,2H),1.65-1.59(m,4H),1.48(m,2H)。
实施例64 3-(2-甲氧基嘧啶-5-基)-6-(哌啶-1-羰基)噻吩并[2,3-b]吡嗪-7-甲腈的制备
步骤1:(3-羟基-7-(三氟甲基)噻吩并[2,3-b]吡嗪-6-基)(哌啶-1-基)甲酮的制备
称取制备例3得到的(3-甲氧基-7-(三氟甲基)噻吩并[2,3-b]吡嗪-6-基)(哌啶-1-基)甲酮(845mg)溶于N,N-二甲基甲酰胺(10mL)中,加入甲硫醇钠(20%水溶液)(1.46mL)于100℃下反应过夜。加水淬灭,2M盐酸调节pH至酸性,乙酸乙酯萃取两次,饱和食盐水洗涤两次,无水硫酸钠干燥,硅胶柱层析纯化得标题化合物(800mg)。MS(ESI)m/z(M+H)+=332.0。
步骤2:6-(哌啶-1-羰基)-7-(三氟甲基)噻吩并[2,3-b]吡嗪-3-基三氟甲磺酸酯的制备
称取(3-羟基-7-(三氟甲基)噻吩并[2,3-b]吡嗪-6-基)(哌啶-1-基)甲酮(800mg)溶于二氯甲烷(12mL)中,加入N,N-二异丙基乙胺(0.84mL)、N-苯基双(三氟甲烷磺酰)亚胺(1.72g)于50℃下反应过夜。TLC及LCMS监
控原料反应完全,加水淬灭,二氯甲烷萃取两次,无水硫酸钠干燥,硅胶柱层析纯化得标题化合物(560mg)。MS(ESI)m/z(M+H)+=464.0。
步骤3:(3-(2-甲氧基嘧啶-5-基)-7-(三氟甲基)噻吩并[2,3-b]吡嗪-6-基)(哌啶-1-基)甲酮的制备
称取6-(哌啶-1-羰基)-7-(三氟甲基)噻吩并[2,3-b]吡嗪-3-基三氟甲磺酸酯(25mg)、2-甲氧基-5-嘧啶硼酸(9mg)、碳酸钠(8mg)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(2mg),向其中加入1,4-二氧六环(1.5mL)、水(0.3mL),氩气置换三次,于80℃下反应1.5h。LCMS监控原料反应完全,加水淬灭,乙酸乙酯萃取两次,无水硫酸钠干燥,反相制备柱分离得标题化合物(8.30mg)。
MS(ESI)m/z(M+H)+=424.1。1H NMR(400MHz,DMSO-d6)δ9.59(s,1H),9.43(s,2H),4.04(s,3H),3.66(t,J=5.3Hz,2H),3.32(m,2H),1.64(d,J=6.3Hz,2H),1.59(t,J=5.7Hz,2H),1.47(dd,J=10.5,5.6Hz,2H)。
采用相应的商品化试剂及前述制备例与实施例中产物为原料,使用类似的制备方法,制备得到一类化合物,所述化合物的结构及表征数据见表3。
表3
生物试验
测试例1:15-PGDH酶活性检测
1.实验材料:
2.实验方法:
a.用超纯水配制含有50mM Tris-HCl、0.01%吐温20,pH 7.5的溶液作为反应缓冲液;
b.用DMSO配制10mM的待测化合物母液,然后使用反应缓冲液将待测化合物母液溶液稀释得到浓度为40000nM的待测化合物溶液1,再将待测化合物溶液1以三倍作为梯度差连续稀释为9(或11)个浓度的待测化合物溶液2~9(或2~12)。将各浓度的待测化合物溶液分别取5μL加入到384孔板中作为实验孔;
c.再向384孔板的空白孔中分别加入5μL反应缓冲液作为阳性对照孔和空白对照孔。
d.使用反应缓冲液配制浓度为5ng/μL的15-PGDH蛋白溶液,取5μL 15-PGDH蛋白溶液加入实验孔和阳性对照孔中,同时向空白对照孔中再加入5μL反应缓冲液,然后以2000rpm离心板30秒;
e.使用反应缓冲液分别配制5mM的β-NAD和2mM PGF2α,将其按体积1:1混合得到底物混合液,取10μL底物混合液加入到实验孔、阳性对照孔、空白对照孔中,开始反应;
f.使用多功能酶标仪连续检测每孔荧光信号值(Ex/Em=340/450)。
3.数据分析:
a)使用PHERAstar Data analysis软件中的“kinetic calculations-slope calculation method”对连续荧光信号值进行分析,得到每个实验孔的斜率;
b)使用以下公式计算抑制率%:
抑制率%=[1-(实验孔斜率-阳性对照孔信号值)/(空白对照孔信号值-阳性对照孔平均信号值)]×100%。
c)计算IC50并绘制抑制率-剂量曲线:使用GraphPad Prism 6.0对化合物浓度和相应抑制率以非线性回归(剂量响应-可变斜率)进行拟合,计算得到IC50值。
公式如下:Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope)),其中X为化合物浓度log值,Y为抑制率%。
4.实验结果:
本申请中部分化合物对15-PGDH酶抑制活性如下:
表中,“/”代表未检测;“A”代表15-PGDH酶抑制活性的IC50范围小于3nM;“B”代表15-PGDH酶抑制活性的IC50范围大于等于3nM且小于10nM;“C”代表15-PGDH酶抑制活性的IC50范围大于等于10nM且小于20nM;“D”代表15-PGDH酶抑制活性的IC50范围大于等于20nM且小于等于50nM;“E”代表15-PGDH酶抑制活性的IC50范围大于等于50nM且小于等于100nM。
实验发现,本申请化合物对15-PGDH酶抑制活性IC50范围小于等于100nM。本申请某些化合物对15-PGDH酶抑制活性IC50范围小于50nM3nM;本申请某些化合物对15-PGDH酶抑制活性IC50范围小于20nM;本申请某些化合物对15-PGDH酶抑制活性IC50范围小于10nM;本申请某些化合物对15-PGDH酶抑制活性IC50范围小于3nM。
结果表明本申请的化合物、尤其是实施例的部分化合物可对15-PGDH酶抑制活性有较强的抑制活性。测试例2:细胞内PGE2上调活性测定
1.实验材料:
2.实验方法:
a)A549细胞接种于24孔板,待细胞贴壁后加入IL-1β刺激16h以诱导COX2表达和PGE2产生。
b)用培养基配制待测化合物溶液并梯度稀释为5nM、50nM、500nM共3个浓度,同时设置阳性对照组(仅向细胞中加入IL-1β进行刺激)及阴性对照组(孔中仅加入细胞而不进行任何处理),作用8h后收集细胞上清液,其中阳性对照组经IL-1β诱导后不加化合物处理,阴性对照组不加IL-1β刺激也不加化合物处理。
c)用Prostaglandin E2 Kit试剂盒测定样品PGE2含量,多功能酶标仪检测荧光信号(Ex/Em=337/620、337/665)。
3.数据分析:
a)用“Prostaglandin E2 Kit试剂盒”中的PGE2标准品绘制标准曲线,代入样品荧光信号求得PGE2浓度。
b)使用以下公式计算PGE2上调比率%:
PGE2上调比率%=(样品组PGE2浓度/阳性对照组PGE2浓度)×100%。
4.实验结果
本申请实施例的化合物在A549细胞中对PGE2的上调比率能够达到>100%,本申请化合物具有良好的上调细胞内PGE2的活性。
为了描述和公开的目的,以引用的方式将所有的专利、专利申请和其它出版物在此明确地并入本文。这些出版物仅因为它们的公开早于本申请的申请日而提供。所有关于这些文件的日期的声明或这些文件的内容的表述是基于申请者可得的信息,并且不构成任何关于这些文件的日期或这些文件的内容的正确性的承认。而且,在任何国家,在本中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。
本领域技术人员将认识到,本申请的范围并不限于上文描述的各种具体实施方案和实施例,而是能够在不脱离本申请的精神的情况下,进行各种修改、替换、或重新组合,这些调整后的方案都落入了本申请的保护范围内。
Claims (15)
- 一种式(I)所示的化合物、其立体异构体、互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药:
环A选自芳环、芳杂环、不饱和脂杂环、芳环与不饱和脂杂环构成的并环、芳杂环与不饱和脂杂环构成的并环,环B为3~12元饱和脂杂环,RA选自氢、氘、氚、羟基、卤素、氰基、C1~C6烷基、C1~C6烷氧基、C1~C6卤代烷基、3~8元环烷基,o选自0、1、2、3,R1各自独立地选自氘、氚、硝基、羟基、巯基、卤素、氰基、=O、亚胺基、胺基、酯基、醛基、羧基、酰胺基、C1~C6烷基、卤素取代的C1~C6烷基、C1~C6烷氧基、卤素取代的C1~C6烷氧基、3~8元环烷基、3~8元饱和脂杂环基;其中,所述芳杂环、饱和脂杂环、不饱和脂杂环、脂杂环基、并环各自独立地包含1~3个杂原子,所述杂原子独立地选自N、O、S,并且环B包含至少1个氮原子;所述环B、R1任选地被独立地选自氘、氚、硝基、羟基、醛基、胺基、亚胺基、卤素、氰基、酯基、羧基、酰胺基、=O、C1~C6烷基、C1~C6烷氧基、3~8元环烷基、6~10元芳基、5~10元脂杂环基、5~10元杂芳基中的一个或多个取代;优选地,所述环B为单环或双环。 - 根据权利要求1所述的化合物、其立体异构体、互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药,其中,环B选自其中,X选自共价键、O、S、NH、(CH2)n、SO2;Y选自共价键、S、NH、(CH2)n、SO2;m选自0、1、2、3;R2各自独立地选自氘、氚、硝基、羟基、巯基、氰基、卤素、胺基、酯基、醛基、羧基、酰胺基、C1~C6烷基、C1~C6卤代烷基、C1~C6烷氧基、3~8元环烷基、6~10元芳基、5~10元杂芳基;所述n选自0、1、2、3;优选地,所述环B选自
- 根据权利要求2所述的化合物、其立体异构体、互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药,其中,所述R2各自独立地选自氘、氚、硝基、羟基、巯基、氰基、氟、氯、溴、胺基、酯基、醛基、羧基、酰胺基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、三氟甲基、三氟乙基、三氯甲基、三氯乙基、环丁基、环丙基、苯基、吡啶基。
- 根据权利要求1~3中任一项所述的化合物,其互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药,其中,所述RA选自氢、氘、氚、羟基、卤素、氰基、环丙基、环丁基、甲基、乙基、甲氧基、乙氧基、三氟甲基;或者,所述RA选自氢、氘、氚、羟基、氟、氯、溴、氰基、环丙基、环丁基、甲基、乙基、丙基、丁基、戊基、甲氧基、乙氧基、丙氧基、C1~C3氟代烷基、C1~C3溴代烷基。
- 根据权利要求1所述的化合物、其立体异构体、互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药,其中,所述化合物具有如式II所示结构,
其中,X选自共价键、S、CH2、(CH2)2或(CH2)3;R3各自独立地选自氘、氚、硝基、羟基、巯基、氰基、卤素、胺基、酯基、醛基、羧基、酰胺基、C1~C6烷基、C1~C6卤代烷基、C1~C6烷氧基、C3~C8环烷基、6~10元芳基、5~10元杂芳基;p选自0、1;优选地,所述R3各自独立地选自氘、氚、硝基、羟基、巯基、氰基、氟、氯、溴、胺基、酯基、醛基、羧基、酰胺基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、三氟甲基、三氟乙基、三氯甲基、三氯乙基、环丁基、环丙基、苯基、吡啶基。 - 根据权利要求5所述的化合物、其立体异构体、互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药,其中,所述p为0;优选地,所述p为0且所述X为CH2。
- 根据权利要求5或6所述的化合物、其立体异构体、互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药,其中,所述RA选自氢、氘、氚、羟基、卤素、氰基、环丙基、环丁基、甲基、乙基、甲氧基、乙氧基、三氟甲基;优选地,所述RA选自氢、氘、氚、氰基、环丙基、三氟甲基、卤素、甲基;或者,所述RA选自氢、氘、氚、羟基、氟、氯、溴、氰基、环丙基、环丁基、甲基、乙基、丙基、丁基、戊基、甲氧基、乙氧基、丙氧基、C1~C3氟代烷基、C1~C3溴代烷基;优选地,所述RA选自氢、氘、氚、氰基、环丙基、环丁基、三氟甲基、氟、氯、溴、甲基、乙基、丙基、丁基、甲氧基、乙氧基。
- 根据权利要求1~7中任一项所述的化合物,其立体异构体、互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药,其中,环A选自6~10元芳环、5~10元芳杂环、3~8元不饱和脂杂环、芳环与不饱和脂杂环构成的7~12元并环、芳杂环与不饱和脂杂环构成的7~12元并环;优选地,所述芳环、芳杂环为单环或双环,所述不饱和脂杂环为单环,所述并环为双环,且所述芳杂环、不饱和脂杂环、并环各自独立地包含1~3个杂原子,所述杂原子独立地选自N、O、S。
- 根据权利要求8所述的化合物、其立体异构体、互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药,其中,环A选自
- 根据权利要求1~9中任一项所述的化合物、其立体异构体、互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药,其中,R1各自独立地选自氘、氚、硝基、羟基、巯基、卤素、氰基、=O、亚胺基、胺基、酯基、醛基、羧基、酰胺基、环丙基、环丙甲基、环丁基、环己基、环戊基、甲基、三氟甲基、乙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、特戊基、正己基、吗啉基、硫代吗啉基、哌啶基、哌嗪基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、二氧杂环戊基、二氧杂环己基、甲氧基、乙氧基、正丙氧基、异丙氧基、环丙氧基、环丙甲氧基、正丁氧基、异丁氧基、叔丁氧基、正戊氧基、异戊氧基、特戊氧基、正己氧基,其中所述R1任选地被独立地选自氘、氚、硝基、羟基、-NH2、巯基、卤素、氰基、酯基、羧基、酰胺基、=O、=NH、C1~C6烷基、卤素取代的C1~C6烷基、C1~C6烷氧基、卤素取代的C1~C6烷氧基、3~8元环烷基、6~10元芳基、5~10元脂杂环基、5~10元杂芳基中的一个或多个取代。
- 根据权利要求1所述的化合物、其立体异构体、互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药,其中,所述环A选自6~10元芳环、含有1-2个选自N、O或S的杂原子的5~10元芳杂环、含有1-2个选自N、O或S的杂原子的4~7元不饱和脂杂环、芳环与不饱和脂杂环构成的8~12元并环、芳杂环与不饱和脂杂环构成的8~12元并环,所述并环含有1-2个选自N、O或S的杂原子;所述环B为包含至少1个氮原子的5~10元饱和脂杂环,例如5~8元或5~7元饱和脂杂环;m选自0、1、2、3;R2各自独立地选自氘、氚、硝基、羟基、巯基、氰基、卤素、胺基、酯基、醛基、羧基、酰胺基、C1~C6烷基、C1~C6卤代烷基、C1~C6烷氧基、3~8元环烷基、6~10元芳基、5~10元杂芳基;所述RA选自氢、氘、氚、羟基、氟、氯、溴、氰基、C1~C5烷基、C1~C5烷氧基、C1~C5卤代烷基、3~6元环烷基;o选自0、1、2,并且R1各自独立地选自氘、氚、羟基、卤素、氰基、=O、亚胺基、胺基、C1~C6烷基、卤素取代的C1~C6烷基、C1~C6烷氧基、4~8元环烷基、4~8元饱和脂杂环基,所述R1任选地被C1~C6烷基取代。
- 根据权利要求1~4和8~11中任一项所述的化合物、其立体异构体、互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药,其中,所述的环A选自所述环B选自m选自0、1;R2各自独立地选自氘、氚、羟基、氟、氯、溴、胺基、甲基、乙基;所述RA选自氢、氘、氚、氟、氯、溴、氰基、环丙基、环丁基、甲基、乙基、丙基、丁基、甲氧基、乙氧基、C1~C3氟代烷基;o选自0、1、2,并且R1各自独立地选自氟、氯、溴、氰基、=O、胺基、甲基、乙基、丙基、甲氧基、乙氧基、丙氧基、吗啉基、硫代吗啉基、哌啶基、哌嗪基,所述胺基任选地被甲基、乙基或丙基取代。
- 根据权利要求1~12中任一项所述的化合物、其立体异构体、互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药,其中,选自如下化合物:
- 一种药物组合物,包含至少一种权利要求1~13中任一项所述的化合物、其立体异构体、互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药,和至少一种药学上可接受的辅料。
- 用作药物的根据权利要求1~13中任一项所述的化合物、其立体异构体、互变异构体或其混合物形式、或其可药用的盐、或其溶剂合物、或其前药、或根据权利要求14所述的药物组合物;优选地,所述药物为15-PGDH抑制剂;或者优选地,所述药物用于治疗或预防纤维化、口腔溃疡、龈疾病、结肠炎、溃疡性结肠炎、胃十二指肠溃疡、炎性疾病、血管功能不全、Raynaud病、Buerger病、神经病变、肺动脉高压、心血管病和肾病、心血管疾病、创伤、皮肤损伤、自身免疫性疾病、移植物抗宿主疾病、骨质疏松症、耳病、眼病、中性白细胞减少、糖尿病、膀胱活动低下症,或者用于促进毛发生长、色素沉着、组织修复、组织再生、在干细胞移植或骨髓移植或器官移植中的植入物促进、神经发生和神经细胞死亡或肌肉再生和宫颈成熟,或者用于增强对辐射暴露的毒性、化疗的毒性、免疫抑制剂的毒性的抗性。
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CN111132982A (zh) * | 2017-05-26 | 2020-05-08 | 卡斯西部储备大学 | 调节短链脱氢酶活性的组合物和方法 |
WO2020160151A1 (en) * | 2019-01-31 | 2020-08-06 | Kyorin Pharmaceutical Co., Ltd. | 15-pgdh inhibitors |
CN113226310A (zh) * | 2019-01-08 | 2021-08-06 | 杏林制药株式会社 | 15-pgdh抑制剂 |
CN113507931A (zh) * | 2018-11-21 | 2021-10-15 | 卡斯西部储备大学 | 调节短链脱氢酶活性的组合物和方法 |
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CN110582277A (zh) * | 2016-07-18 | 2019-12-17 | 卡斯西部储备大学 | 用于促进神经发生并抑制神经细胞死亡的短链脱氢酶活性的抑制剂 |
CN111132982A (zh) * | 2017-05-26 | 2020-05-08 | 卡斯西部储备大学 | 调节短链脱氢酶活性的组合物和方法 |
CN113507931A (zh) * | 2018-11-21 | 2021-10-15 | 卡斯西部储备大学 | 调节短链脱氢酶活性的组合物和方法 |
CN113226310A (zh) * | 2019-01-08 | 2021-08-06 | 杏林制药株式会社 | 15-pgdh抑制剂 |
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