WO2017148417A1 - 一种2,3-环氧丁二酰衍生物及其制备方法和用途 - Google Patents
一种2,3-环氧丁二酰衍生物及其制备方法和用途 Download PDFInfo
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- WO2017148417A1 WO2017148417A1 PCT/CN2017/075453 CN2017075453W WO2017148417A1 WO 2017148417 A1 WO2017148417 A1 WO 2017148417A1 CN 2017075453 W CN2017075453 W CN 2017075453W WO 2017148417 A1 WO2017148417 A1 WO 2017148417A1
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- 0 CCC*(C)(CC[C@@]1NC([C@@]2O[C@@]2C(OCC)=O)=O)C1=O Chemical compound CCC*(C)(CC[C@@]1NC([C@@]2O[C@@]2C(OCC)=O)=O)C1=O 0.000 description 5
- QFIMCZFUDBIVTP-WLUIXCMPSA-N CCC(CCCC1)N1C([C@H](CCSC)NC([C@H]1O[C@@H]1C(OCC)=O)=O)=O Chemical compound CCC(CCCC1)N1C([C@H](CCSC)NC([C@H]1O[C@@H]1C(OCC)=O)=O)=O QFIMCZFUDBIVTP-WLUIXCMPSA-N 0.000 description 1
- SZAFJWIGQOOJMH-ULQDDVLXSA-N CCOC([C@H]1O[C@@H]1C(N[C@@H](CCSC)C(NCCc1ccc(C)cc1)=O)=O)=O Chemical compound CCOC([C@H]1O[C@@H]1C(N[C@@H](CCSC)C(NCCc1ccc(C)cc1)=O)=O)=O SZAFJWIGQOOJMH-ULQDDVLXSA-N 0.000 description 1
- DUMUGAAGXCTVRM-PMXPPJISSA-N CCO[NH+]([C@H]1O[C@@H]1C(NC(C1)(C1SCc1ccccc1)C(N(CC1)CCC1c1ccccc1)=O)=O)[O-] Chemical compound CCO[NH+]([C@H]1O[C@@H]1C(NC(C1)(C1SCc1ccccc1)C(N(CC1)CCC1c1ccccc1)=O)=O)[O-] DUMUGAAGXCTVRM-PMXPPJISSA-N 0.000 description 1
- GBWKGMPEQISNDC-ZPODEYMZSA-N CCO[NH+]([C@H]1O[C@@H]1C(NC1([C@H](CSC)C1)C(N(CC1)CCC1c1ccccc1)=O)=O)[O-] Chemical compound CCO[NH+]([C@H]1O[C@@H]1C(NC1([C@H](CSC)C1)C(N(CC1)CCC1c1ccccc1)=O)=O)[O-] GBWKGMPEQISNDC-ZPODEYMZSA-N 0.000 description 1
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- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/48—Compounds containing oxirane rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. ester or nitrile radicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
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- C07D301/00—Preparation of oxiranes
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- 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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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the invention belongs to the field of medicine, in particular to a 2,3-epoxysuccinyl derivative and a preparation method and use thereof, the compound can be used as a cathepsin inhibitor for treating tumor, osteoporosis, Ebola Viral infections, rheumatoid arthritis and osteoarthritis, autoimmune diseases or degenerative diseases.
- Proteases are the main proteolysis participants in the human body. According to the proteolytic mechanism, they can be divided into serine proteases, cysteine proteases, aspartyl proteases, threonine proteases and metalloproteinases. Current research focuses on cysteine proteases, while papain-like cysteine proteases are the largest subfamily.
- the papain-like cysteine in mammals belongs to cathepsin. Most members of cathepsins are present in lysosomes and can be activated in acidic environments, including most cysteine proteases, small amounts of aspartic proteases (cathepsin D, E) and serine proteases (cathepsin). A, G).
- cathepsins include endopeptidases (cathepsin B, F, H, K, L, S, V), and peptide chain endolytic enzymes (cathepsin B, C, H, X). , aminopeptidase (Cathepsin C, H) and carboxypeptidase (Cathepsin B, X).
- Cathepsins are mainly composed of cathepsins B, C, F, H, K, L, O, S, V, W and X in humans, and various physiological and pathological processes of the human body are closely related to them.
- cathepsins are highly conserved in sequence, they are also composed of two almost identical domains, the L (Left) domain and the R (Right) domain, with a "V" shape in the middle.
- the active site groove, the Cys25 in the L domain and the active residues such as His159 and Asn175 in the R domain are exposed thereto.
- Cathepsin B is the most studied of all cysteine proteases. It is widely found in various tissues of mammals and is the first lysosomal protease to be found in breast cancer. It is closely related to the occurrence and development of various human tumors. Tumor cells can secrete cathepsin B. This secreted cathepsin B cannot be taken up into lysosomes due to the lack of mannose-6-phosphate receptor recognition marker, but is present in cytoplasm and cells in the form of zymogen. outer. Since the tumor cells can acidify the surrounding environment, they can activate the zymogen to form active cathepsin B.
- activated cathepsin B can also activate the proteolytic cascade to ultimately degrade.
- the activity of cathepsin B secreted by tumor cells in the neutral and alkaline environment is not affected or even increased, so in many human and animal tumors such as gastric cancer. Bladder cancer, colon cancer, glioma, melanoma, etc., all found elevated levels of cathepsin B expression and/or activity.
- cathepsin B has been reported that the expression of cathepsin B and its activity in cervical cancer, lung cancer, breast cancer, prostate cancer and other malignant tumor tissues are doubled or even 3 to 9 times higher than that of adjacent normal tissues, and it is considered that the activity and concentration of cathepsin B are increased.
- Bone resorption is a metabolic imbalance between bone resorption and bone formation. Bone resorption is greater than the disease caused by bone formation. It is the elderly, especially menopause. A common and frequently-occurring disease in postmenopausal women. During bone resorption, osteoclasts first attach to the bone surface, forming a relatively closed bone resorption microenvironment, secreting protons and proteolytic enzymes, first dissolving bone minerals, and then degrading the bone matrix, resulting in the formation of bone voids.
- cysteine protease and matrix metalloproteinase, the main role of which is cathepsin K in cysteine protease, which is selectively abundant. It is expressed in osteoclasts, and its physiological substrate is 95% of type I collagen in the organic bone matrix. In addition, it can degrade osteopontin and osteonectin in the bone matrix.
- a cysteine protease with the highest expression and the strongest osteolytic activity in cells, its degradation ability to osteogenic collagen is much higher than other matrix metalloproteinases, and is a key enzyme in bone resorption process. A hot spot in the study of osteoporosis in recent years.
- cathepsin L is also present in the microenvironment of osteoclast formation, which has a strong collagen solubilization and is directly involved in bone matrix degradation.
- cathepsins B and S show bone resorption in vivo and in vitro, and are also associated with the formation of osteoporosis.
- Rheumatoid arthritis is a chronic systemic autoimmune disease characterized by synovial inflammation of the joint. Sustained recurrent episodes of synovitis can lead to destruction of cartilage and bone in the joints, joint dysfunction, and even disability.
- Osteoarthritis is a common disease caused by degeneration of articular cartilage and new bone formation on the surface of the joint and the edge of the joint. Non-inflammatory lesions occur in the movable joint.
- Cartilage contains two main components: one is type II collagen, which can form a 3-D fiber network, which makes the tissue extensible; the other is a polymer that ensures the cartilage has toughness; two protein components Any type of excessive degradation will result in destruction of the cartilage in the joint.
- Cathepsin K is expressed at the joints of RA and OA patients, and can be further activated by inflammatory cytokines, indicating Cathepsin K may be a major player in cartilage destruction in RA and OA.
- the membrane fusion protein GP is composed of two subunits of GP1 and GP2.
- Ebola virus particles have a helical nucleocapsid with an outer envelope.
- Envelope viruses require the envelope protein to fuse with the host cell membrane or endosomal membrane before it can replicate its causative genes.
- Ebola virus invades cells when the virus adheres to the cell surface, its envelope fusion protein GP must be bound to cathepsin B and L to change its conformation to fuse with the host cell membrane.
- the genetic material carried by it is injected into the interior of the cell and replicated in large amounts within the infected cell.
- Cathepsin L can promote the invasion and metastasis of tumors by catalytically degrading the matrix membrane.
- cathepsin L has been found in various cancers such as kidney cancer, testicular cancer, breast cancer, ovarian cancer, colon cancer, bladder cancer and thyroid cancer. High expression; cathepsin S also plays an important role in the pathogenesis of degenerative diseases and autoimmune diseases. It participates in the antigen presentation of major histocompatibility complex class II molecules, and its overexpression and tumor Growth, angiogenesis and metastasis are closely related.
- the object of the present invention is to synthesize novel cathepsin inhibitors for the treatment of diseases such as tumor, osteoporosis, arthritis, Ebola virus infection, rheumatoid arthritis, osteoarthritis, autoimmune diseases or degenerative diseases. .
- the present invention has obtained a series of novel derivatives having an epoxy succinic acid structure, which have high inhibitory activity and/or selectivity of cathepsin (especially cathepsin B).
- the invention was completed based on the above findings.
- One aspect of the invention relates to a compound of formula 1, a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof,
- R 1 represents a hydrogen atom, a C 1 -C 10 linear or branched alkyl group, a C 3 -C 10 cycloalkyl group, a C 2 -C 10 linear or branched alkenyl group, a C 2 -C 10 straight chain or a branch. Alkynyl, aryl, aryl-C 1 -C 6 alkyl, heterocyclic or heterocyclic-C 1 -C 6 alkyl;
- R 2 represents a hydrogen atom, a C 1 -C 10 linear or branched alkyl group, a C 3 -C 10 cycloalkyl group, a C 1 -C 10 alkylthio group, a C 3 -C 10 cycloalkylthio group, a C 2 - C 10 straight or branched alkenyl, C 2 -C 10 straight or branched alkynyl, aryl, aryl-C 1 -C 6 alkyl, heterocyclic or heterocyclic-C 1 -C 6 alkane Or optionally, wherein said C 1 -C 10 straight or branched alkyl, C 3 -C 10 cycloalkyl, C 1 -C 10 alkylthio, C 3 -C 10 cycloalkylthio, C 2 -C 10 linear or branched alkenyl, C 2 -C 10 linear or branched alkynyl, aryl, aryl-C 1 -C
- X represents -O-, -N(R 5 )-;
- n is an integer selected from 0 to 5, preferably 1-3;
- R 3 and R 4 each independently represent a hydrogen atom, a C 1 -C 10 linear or branched alkyl group, a C 3 -C 10 cycloalkyl group, a C 2 -C 10 linear or branched alkenyl group, C 2 - C 10 linear or branched alkynyl, aryl, aryl-C 1 -C 6 alkyl, heterocyclyl, heterocyclo-C 1 -C 6 alkyl or benzene fused heterocyclyl, optionally, C 1 -C 10 straight or branched alkyl, C 3 -C 10 cycloalkyl, C 2 -C 10 straight or branched alkenyl, C 2 -C 10 straight or branched alkynyl, aromatic
- the aryl group, the aryl-C 1 -C 6 alkyl group, the heterocyclic group, the heterocyclic-C 1 -C 6 alkyl group or the benzene fused heterocyclic group
- R 3 and R 4 together with the attached N atom form a 5-8 membered heterocyclic ring.
- the 5-8 membered heterocyclic ring is substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, a C 1 -C 10 alkyl group, a C 1 -C 10 alkoxy group, a C 1 -C 10 alkylthio group, an aryl group, an oxy group or an ester group;
- R 5 represents a hydrogen atom, a C 1 -C 10 linear or branched alkyl group, an aryl group, an aryl-C 1 -C 6 alkyl group, a heterocyclic group or a heterocyclic group-C 1 -C 6 alkyl group.
- R 1 represents a hydrogen atom, a C 1 -C 10 linear or branched alkyl group, a C 3 -C 10 cycloalkyl group, a C 2 -C 10 linear or branched alkenyl group or a C 2 -C 10 linear or branched alkynyl group; preferably, R 1 represents a hydrogen atom, a C 1 -C 6 straight or branched alkyl group; preferably, R 1 represents a C 1 -C 4 straight chain or branch Alkenyl, such as methyl or ethyl.
- the compound of Formula 1 a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 represents a hydrogen atom.
- the compound of Formula 1 a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 represents a C 3 -C 10 ring alkyl.
- the compound of Formula 1 represents C 2 -C 10 straight Chain or branched alkenyl.
- the compound of Formula 1 represents C 2 -C 10 straight Chain or branched alkynyl.
- the compound of Formula 1 represents C 1 -C 6 straight Chain or branched alkyl.
- the compound of Formula 1 represents C 1 -C 4 straight Chain or branched alkyl.
- the compound of Formula 1 the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 represents an ethyl group.
- the compound of Formula 1 a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 represents a methyl group.
- the compound of Formula 1 a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 represents a propyl group.
- the compound of Formula 1 a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 represents an isopropyl group.
- the compound of Formula 1 the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 represents n-butyl.
- the compound of Formula 1 a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 represents an isobutyl group.
- the compound of Formula 1 the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 represents a t-butyl group.
- the compound of Formula 1 the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 represents n-pentyl.
- the compound of Formula 1 a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 represents an isopentyl group.
- the compound of Formula 1 the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 represents a neopentyl group.
- the compound of Formula 1 a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 represents an isopentyl group.
- the compound of Formula 1 a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 represents 1-methylbutyl .
- the compound of Formula 1 a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 represents 1-ethylpropyl .
- the compound of Formula 1 the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 represents 1,2-dimethyl Base propyl.
- the compound of Formula 1 a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 represents 2-methylbutyl .
- the compound of Formula 1, a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 2 represents a hydrogen atom, C 1 - C 6 straight or branched alkyl or aryl-C 1 -C 4 alkyl; preferably, R 2 represents a C 1 -C 4 straight or branched alkyl or aryl-C 1 -C 4 alkyl For example, methyl, ethyl or benzyl.
- the compound of Formula 1 a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 represents a hydrogen atom.
- the compound of Formula 1 a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 represents aryl-C 1 - C 6 alkyl.
- the compound of Formula 1 a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 represents a heterocyclic group.
- the compound of Formula 1 a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 represents a heterocyclic ring -C 1 - C 6 alkyl.
- the compound of Formula 1 a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 represents aryl-C 1 - C 4 alkyl.
- the compound of Formula 1 a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 represents aryl-C 1 - C 4 alkyl.
- the compound of Formula 1 a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 represents an isopropyl group.
- the compound of Formula 1 the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 represents n-butyl.
- the compound of Formula 1 a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 represents an n-pentyl group.
- the compound of Formula 1 a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 represents an isopentyl group.
- the compound of Formula 1 a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 represents a neopentyl group.
- the compound of Formula 1 a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 represents an isopentyl group.
- the compound of Formula 1 the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 represents 1-ethylpropyl .
- the compound of Formula 1 the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 represents 1,2-dimethyl Base propyl.
- the compound of Formula 1 a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 represents 2-methylbutyl .
- the compound of Formula 1 a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 is optionally one or more Hydroxyl substitution.
- a compound of Formula 1, a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 2 is optionally one or more C 1 -C 10 alkyl substituted.
- a compound of Formula 1, a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 2 is optionally one or more C 1 -C 10 alkylthio substituted.
- the compound of Formula 1, a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 and R 4 each independently represent C 1 -C 10 linear or branched alkyl, C 3 -C 10 cycloalkyl, aryl, aryl-C 1 -C 6 alkyl, heterocyclic, heterocyclic-C 1 -C 6 alkyl Or a benzene fused heterocyclyl, optionally wherein said C 1 -C 10 straight or branched alkyl, C 3 -C 10 cycloalkyl, aryl, aryl-C 1 -C 6 alkyl,
- the heterocyclic group, heterocyclic-C 1 -C 6 alkyl or benzene fused heterocyclic group are each independently substituted by one or more substituents selected from the group consisting of halogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy and C 1
- R 3 and R 4 together with the attached N atom form a 5-8 membered heterocyclic ring, optionally wherein the 5-8 membered heterocyclic ring is substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino a C 1 -C 10 alkyl group, a C 1 -C 6 alkoxy group, a C 1 -C 6 alkylthio group, an aryl group, an oxy group or an ester group;
- R 3 and R 4 each independently represent a C 1 -C 6 linear or branched alkyl, aryl-C 1 -C 6 alkyl group, optionally wherein said C 1 -C 6 straight chain Or a branched alkyl group and an aryl-C 1 -C 6 alkyl group are each independently substituted with one or more substituents selected from the group consisting of halogen, C 1 -C 4 alkyl and C 1 -C 4 alkoxy; ,
- R 3 and R 4 together with the attached N atom form a 5-8 membered heterocyclic ring, optionally substituted with one or more substituents selected from C 1 -C 4 alkane a group, a C 1 -C 4 alkoxy group and an aryl group;
- R 3 and R 4 each independently represent a C 1 -C 6 straight or branched alkyl group (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl) Base, isobutyl, n-pentyl, 3-methyl-butyl, 2-methyl-butyl, 1-methyl-butyl, 2,2-dimethyl-propyl, 1,1-di Methyl-propyl, 1,2-dimethyl-propyl, 1-ethyl-propyl, n-hexyl, 1-methyl-n-pentyl, 2-methyl-pentyl, 3-methyl- Pentyl, 4-methyl-pentyl, 1,1-dimethyl-butyl, 2,2-dimethyl-butyl, 3,3-dimethyl-butyl, 1,2-dimethyl Base-butyl, 1,3-dimethyl-butyl, 2,3-
- R 3 and R 4 together with the attached N form a 5-8 membered heterocyclic ring (for example, a pyrrolidine ring, a thiazolidine ring, an oxazolidine ring, a piperidine ring, a morpholine ring, a thiomorpholine ring, a piperazine ring or a homopiperazine ring, optionally wherein the 5-8 membered heterocyclic ring is substituted with one or more substituents selected from carbonyl, halo (eg, fluoro, chloro, bromo or iodo), C1 - C 4 alkyl (e.g. methyl, ethyl, propyl or isopropyl), C 1- C 4 alkoxy (e.g. methoxy, ethoxy or propoxy).
- a 5-8 membered heterocyclic ring for example, a pyrrolidine ring, a thiazolidine ring, an oxa
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents H, and R 4 represents a different Amyl, n-pentyl, 2-methylbutyl, n-propyl, n-butyl, n-hexyl, 1-methylbutyl, isobutyl, neopentyl, tert-amyl, sec-butyl, 1- Ethylpropyl, phenylpropyl, 4-methoxyphenethyl, p-methoxyphenethyl, 3-fluorophenethyl, 4-phenylbutyl; or,
- R 3 and R 4 form together with the N atom attached to 3-methylpiperidine, 2-ethylpiperidine, 3,5-dimethylpiperidine, 4-phenyl piperidine, pyrrolidine, morpholine, Tetrahydrothiazole, thiomorpholine.
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents a hydrogen atom, and R 4 represents C 1 -C 10 linear or branched alkyl, C 3 -C 10 cycloalkyl, aryl, aryl-C 1 -C 6 alkyl, heterocyclic, heterocyclic-C 1 -C 6 alkyl Or a benzene fused heterocyclyl, optionally wherein said C 1 -C 10 straight or branched alkyl, C 3 -C 10 cycloalkyl, aryl, aryl-C 1 -C 6 alkyl,
- the heterocyclic group, heterocyclic-C 1 -C 6 alkyl or benzene fused heterocyclic group are each independently substituted by one or more substituents selected from the group consisting of halogen, C 1 -C 10 alkyl, C 1 -C 10 alkoxy and C
- R 3 and R 4 together with the attached N atom form a 5-8 membered heterocyclic ring, optionally wherein the 5-8 membered heterocyclic ring is substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino C 1 -C 10 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, aryl, oxy or ester.
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents a hydrogen atom, and R 4 represents C 1 -C 6 straight or branched alkyl, aryl-C 1 -C 6 alkyl, optionally wherein said C 1 -C 6 straight or branched alkyl and aryl-C 1 -
- the C 6 alkyl groups are each independently substituted with one or more substituents selected from the group consisting of halogen, C 1 -C 4 alkyl and C 1 -C 4 alkoxy; or
- R 3 and R 4 together with the attached N atom form a 5-8 membered heterocyclic ring, optionally substituted with one or more substituents selected from C 1 -C 4 alkane a group, a C 1 -C 4 alkoxy group and an aryl group.
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents a hydrogen atom, and R 4 represents C 1 -C 6 straight or branched alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-pentyl, 3- Methyl-butyl, 2-methyl-butyl, 1-methyl-butyl, 2,2-dimethyl-propyl, 1,1-dimethyl-propyl, 1,2-dimethyl Base-propyl, 1-ethyl-propyl, n-hexyl, 1-methyl-n-pentyl, 2-methyl-pentyl, 3-methyl-pentyl, 4-methyl-pentyl, 1 , 1-dimethyl-butyl, 2,2-dimethyl-butyl,
- R 3 and R 4 together with the attached N form a 5-8 membered heterocyclic ring (for example, a pyrrolidine ring, a thiazolidine ring, an oxazolidine ring, a piperidine ring, a morpholine ring, a thiomorpholine ring, a piperazine ring or homopiperazine ring), optionally, wherein said 5-8 membered heterocyclic ring substituted with one or more substituents selected from: carbonyl, halo (e.g. fluoro, chloro, bromo or iodo), C 1- C 4 alkyl (e.g. methyl, ethyl, propyl or isopropyl), C 1- C 4 alkoxy (e.g. methoxy, ethoxy or propoxy).
- a 5-8 membered heterocyclic ring for example, a pyrrolidine ring, a thiazolidine ring, an oxazolidine
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents a hydrogen atom, and R 4 represents C 1 -C 6 straight or branched alkyl.
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents a hydrogen atom, and R 4 represents aryl -C 1 -C 6 alkyl group, said aryl group optionally substituted with one or more halogen (e.g. fluoro, chloro, bromo or iodo) substituents.
- R 3 represents a hydrogen atom
- R 4 represents aryl -C 1 -C 6 alkyl group, said aryl group optionally substituted with one or more halogen (e.g. fluoro, chloro, bromo or iodo) substituents.
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents a hydrogen atom, and R 4 represents aryl -C 1 -C 6 alkyl group, said aryl group optionally substituted with one or more C 1- C 4 alkyl (e.g. methyl, ethyl, propyl or isopropyl) groups.
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents a hydrogen atom, and R 4 represents aryl -C 1 -C 6 alkyl group, said aryl group optionally substituted with one or more C 1- C 4 alkoxy (e.g. methoxy, ethoxy or propoxy) group.
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents a hydrogen atom, and R 4 represents Tert-butyl.
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents a hydrogen atom, and R 4 represents Isobutyl.
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents a hydrogen atom, and R 4 represents 3-methyl-butyl.
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents a hydrogen atom, and R 4 represents 2-methyl-butyl.
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents a hydrogen atom, and R 4 represents 1-methyl-butyl.
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents a hydrogen atom, and R 4 represents 2,2-dimethyl-propyl.
- the compound of Formula 1 the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 3 represents a hydrogen atom, and R 4 represents 1,1-dimethyl-propyl.
- the compound of Formula 1 the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 3 represents a hydrogen atom, and R 4 represents 1,2-dimethyl-propyl.
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents a hydrogen atom, and R 4 represents 1-ethyl-propyl.
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents a hydrogen atom, and R 4 represents Is the base.
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents a hydrogen atom, and R 4 represents 1-methyl-n-pentyl.
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents a hydrogen atom, and R 4 represents 2-methyl-pentyl.
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents a hydrogen atom, and R 4 represents 3-methyl-pentyl.
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents a hydrogen atom, and R 4 represents 4-methyl-pentyl.
- the compound of Formula 1 the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 3 represents a hydrogen atom, and R 4 represents 1,1-dimethyl-butyl.
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents a hydrogen atom, and R 4 represents 2,2-dimethyl-butyl.
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents a hydrogen atom, and R 4 represents 3,3-Dimethyl-butyl.
- the compound of Formula 1 the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 3 represents a hydrogen atom, and R 4 represents 1,2-dimethyl-butyl.
- the compound of Formula 1 the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 3 represents a hydrogen atom, and R 4 represents 1,3-Dimethyl-butyl.
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents a hydrogen atom, and R 4 represents 2,3-Dimethyl-butyl.
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents a hydrogen atom, and R 4 represents 1-ethyl-butyl.
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents a hydrogen atom, and R 4 represents 2-ethyl-butyl.
- the compound of Formula 1 the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 3 represents a hydrogen atom, and R 4 represents 1,2,2-trimethyl-propyl.
- the compound of Formula 1 the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 3 represents a hydrogen atom, and R 4 represents 1,1,2-trimethyl-propyl.
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents a hydrogen atom, and R 4 represents Benzyl.
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents a hydrogen atom, and R 4 represents Phenylethyl.
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents a hydrogen atom, and R 4 represents Phenylpropyl.
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents a hydrogen atom, and R 4 represents 4-methoxyphenethyl.
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents a hydrogen atom, and R 4 represents P-methoxyphenethyl.
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents a hydrogen atom, and R 4 represents 3-fluorophenethyl.
- the compound of Formula 1, the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 represents a hydrogen atom, and R 4 represents 4-phenylbutyl.
- the compound of Formula 1, the racemate or optical isomer, a solvate thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 and R 4 are bonded to N Forming a 5-8 membered heterocyclic ring together (for example, a pyrrolidine ring, a thiazolidine ring, an oxazolidine ring, a piperidine ring, a morpholine ring, a thiomorpholine ring, a piperazine ring or a homopiperazine ring), optionally wherein said 5-8 membered heterocyclic ring substituted with one or more substituents selected from: carbonyl, halo (e.g.
- C 1- C 4 alkyl e.g. methyl, ethyl group, propyl or isopropyl
- C 1- C 4 alkoxy e.g. methoxy, ethoxy or propoxy
- the piperidine ring is formed together.
- the morpholine ring is formed together.
- the thiomorpholine ring is formed together.
- the piperazine ring is formed together.
- the compound of Formula 1 the racemate or optical isomer, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 3 and R 4 are bonded to N The atoms together form a tetrahydropyrrole.
- the compound of Formula 1 the racemate or optical isomer, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 3 and R 4 are bonded to N The atoms together form tetrahydrothiazole.
- the compound of Formula 1 the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof, wherein X is -O-.
- the compound of Formula 1 a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: n is an integer selected from 1 to 3 , preferably 1 or 2.
- the compound of Formula 1 the racemate or optical isomer, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: n is 0.
- the compound of Formula 1 the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: n is 1.
- the compound of Formula 1 the racemate or optical isomer, the solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: n is 2.
- the compound of Formula 1 a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 represents a hydrogen atom, C 1 - a C 10 linear or branched alkyl group, a C 3 -C 10 cycloalkyl group, a C 2 -C 10 linear or branched alkenyl group, a C 2 -C 10 linear or branched alkynyl group;
- R 2 represents a hydrogen atom, a C 1 -C 10 linear or branched alkyl group, a C 3 -C 10 cycloalkyl group, a C 1 -C 10 alkylthio group, a C 3 -C 10 cycloalkylthio group, a C 2 - C 10 straight or branched alkenyl, C 2 -C 10 straight or branched alkynyl, aryl, aryl-C 1 -C 6 alkyl, heterocyclic or heterocyclic-C 1 -C 6 alkane group, optionally, wherein said C 1 -C 10 straight chain or branched chain alkyl, C 3 -C 10 cycloalkyl, C 1 -C 10 alkylthio, C 3 -C 10 cycloalkyl group, C 2 -C 10 linear or branched alkenyl group, C 2 -C 10 linear or branched alkynyl group, aryl group, aryl-
- X is -O-
- n is an integer selected from 1 to 3, preferably 1 or 2;
- R 3 and R 4 each independently represent a hydrogen atom, a C 1 -C 10 linear or branched alkyl group, a C 3 -C 10 cycloalkyl group, a C 2 -C 10 linear or branched alkenyl group, C 2 - a C 10 linear or branched alkynyl group, an aryl group, an aryl-C 1 -C 6 alkyl group, a heterocyclic group, a heterocyclic-C 1 -C 6 alkyl group, or a benzene fused heterocyclic group, optionally, Wherein the C 1 -C 10 linear or branched alkyl group, C 3 -C 10 cycloalkyl group, C 2 -C 10 linear or branched alkenyl group, C 2 -C 10 linear or branched alkynyl group , aryl, aryl -C 1 -C 6 alkyl, heterocyclyl, heterocyclyl -C 1 -C
- R 3 and R 4 together with the attached N atom form a 5-8 membered heterocyclic ring, optionally wherein the 5-8 membered heterocyclic ring is substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 alkylthio, aryl, oxy or ester.
- the compound of Formula 1 the racemate or optical isomer, solvate thereof, or a pharmaceutically acceptable salt thereof, wherein:
- R 1 represents a hydrogen atom, a C 1 -C 6 linear or branched alkyl group
- R 2 represents a hydrogen atom, a C 1 -C 6 linear or branched alkyl group, an aryl-C 1 -C 4 alkyl group;
- X is -O-
- n 1 or 2;
- R 3 and R 4 each independently represent a C 1 -C 10 linear or branched alkyl group, a C 3 -C 10 cycloalkyl group, an aryl group, an aryl-C 1 -C 6 alkyl group, a heterocyclic group, a hetero a cyclo-C 1 -C 6 alkyl or benzene fused heterocyclic group, optionally wherein said C 1 -C 10 linear or branched alkyl group, C 3 -C 10 cycloalkyl group, aryl group, aryl group -C 1 -C 6 alkyl, heterocyclic, heterocyclic-C 1 -C 6 alkyl or benzene fused heterocyclic are each independently substituted by one or more substituents selected from halogen: C 1 - C 10 alkyl, C 1 -C 10 alkoxy and C 1 -C 10 alkylthio, optionally wherein said C 1 -C 10 alkyl, C 1 -C
- R 3 and R 4 together with the attached N atom form a 5-8 membered heterocyclic ring.
- the 5-8 membered heterocyclic ring is substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, C 1 -C 10 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio group, aryl group, an ester group or a group.
- the compound of Formula 1 the racemate or optical isomer, solvate thereof, or a pharmaceutically acceptable salt thereof, wherein:
- R 1 represents a C 1 -C 4 straight or branched alkyl group
- R 2 represents a C 1 -C 4 linear or branched alkyl or aryl-C 1 -C 4 alkyl
- X is -O-
- n 1 or 2;
- R 3 and R 4 each independently represent a C 1 -C 6 linear or branched alkyl, aryl-C 1 -C 6 alkyl group, optionally wherein said C 1 -C 6 is straight or branched
- the alkyl group and the aryl-C 1 -C 6 alkyl group are each independently substituted with one or more substituents selected from the group consisting of halogen, C 1 -C 4 alkyl and C 1 -C 4 alkoxy; or
- R 3 and R 4 together with the attached N atom form a 5-8 membered heterocyclic ring, optionally wherein the 5-8 membered heterocyclic ring is substituted by one or more substituents selected from C 1 -C 4 Alkyl, C 1 -C 4 alkoxy and aryl.
- a compound of Formula 1 a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein
- R 1 represents a C 1 -C 4 straight or branched alkyl group, such as an ethyl group
- R 2 represents a C 1 -C 4 linear or branched alkyl group (for example, methyl) or an aryl-C 1 -C 4 alkyl group (for example, benzyl);
- X is -O-
- n 1 or 2;
- R 3 represents H
- R 4 represents a C 1 -C 6 linear or branched alkyl group (e.g., isopentyl, n-pentyl, 2-methylbutyl, n-propyl, n-butyl, n-hexyl, 1- Methyl butyl, isobutyl, neopentyl, tert-amyl, sec-butyl, 1-ethylpropyl), aryl-C 1 -C 6 alkyl (eg phenylpropyl, phenethyl, 4 -Phenylbutyl), optionally wherein said C 1 -C 6 straight or branched alkyl and aryl-C 1 -C 6 alkyl are each independently selected from one or more halogens (eg Substituted with a substituent of a fluorine, a C 1 -C 4 alkyl group (for example, a methyl group) and a C 1
- R 3 and R 4 together with the attached N atom form a 5-8 membered heterocyclic ring (e.g., piperidine, tetrahydropyrrole, morpholine, tetrahydrothiazole, thiomorpholine), optionally wherein said 5-8
- the heterocyclic ring is substituted by one or more substituents selected from the group consisting of C 1 -C 4 alkyl (eg methyl, ethyl), C 1 -C 4 alkoxy and aryl (eg phenyl).
- a compound of Formula 1 a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein
- R 1 represents an ethyl group
- R 2 represents a methyl group or a benzyl group
- X is -O-
- n 1 or 2;
- R 3 represents H
- R 4 represents isopentyl, n-pentyl, 2-methylbutyl, n-propyl, n-butyl, n-hexyl, 1-methylbutyl, isobutyl, neopentyl, tert Pentyl, sec-butyl, 1-ethylpropyl, phenylpropyl, 4-methoxyphenethyl, p-methoxyphenethyl, 3-fluorophenethyl, 4-phenylbutyl; or ,
- R 3 and R 4 form together with the N atom attached to 3-methylpiperidine, 2-ethylpiperidine, 3,5-dimethylpiperidine, 4-phenyl piperidine, pyrrolidine, morpholine, Tetrahydrothiazole, thiomorpholine.
- the compound of Formula 1 the racemate or optical isomer thereof, a solvate thereof, or a pharmaceutically or physiologically acceptable salt thereof, wherein the compound is selected from the group consisting of:
- Another aspect of the invention relates to a process for the preparation of a compound of formula I, a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, according to any of the invention, which comprises the following steps :
- Compound A and Compound B are esterified or amidated to form Compound C;
- Compound A can be prepared by chiral resolution of (+/-)-trans-epoxysuccinic acid with arginine.
- esterification reaction of item (1) can be carried out in the presence of sulfuric acid.
- the condensation in the item (3) may be a DCC, HOBt, EDCI, HATU, HBTU, TBTU or PyBOP or the like as a condensing agent, and TEA, DIPEA or the like is a base.
- a third aspect of the invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula 1 according to any one of the first aspects of the invention, a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof And optionally one or more pharmaceutically acceptable carriers or excipients.
- a further aspect of the invention relates to a compound of formula 1 according to any one of the first aspects of the invention, a racemate thereof or an optical rotation Use of an isomer, a solvate thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any of the third aspects of the invention, for the preparation of a cathepsin inhibitor.
- the cathepsin is selected from the group consisting of cathepsins B, C, F, H, K, L, O, S, V, W and X, preferably the cathepsin is selected from the group consisting of cathepsins B, K, L and S.
- a further aspect of the invention relates to a compound of formula 1 according to any one of the first aspects of the invention, a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, or a third aspect of the invention
- the tumor is selected from the group consisting of kidney cancer, lymphoma, lung cancer, liver cancer, gastric cancer, testicular cancer, lung non-small cell carcinoma, breast cancer, ovarian cancer, colon cancer, bladder cancer, and thyroid cancer. .
- a further aspect of the invention relates to a compound of formula 1 according to any one of the first aspects of the invention, a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, or a third aspect of the invention
- the autoimmune disease is selected from the group consisting of chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, chronic ulcerative colitis, pernicious anemia with chronic atrophic gastritis, lung Hemorrhagic nephritis syndrome, pemphigoid, primary biliary cirrhosis and multiple sclerosis.
- the degenerative disease is selected from the group consisting of cardiovascular diseases (eg, hypertensive heart disease, cardiomyopathy, myocardial infarction, valvular heart disease), brain dysfunction (eg, Alzheimer's disease, Don) Syndrome, etc.) and cataracts.
- cardiovascular diseases eg, hypertensive heart disease, cardiomyopathy, myocardial infarction, valvular heart disease
- brain dysfunction eg, Alzheimer's disease, Don) Syndrome, etc.
- cataracts eg, cataracts.
- the invention further relates to a compound of the formula 1 according to any one of the first aspects of the invention, a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, or a third aspect of the invention
- the pharmaceutical composition for inhibiting cathepsin activity is not limited to any one of the first aspects of the invention, a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, or a third aspect of the invention.
- the cathepsin is selected from the group consisting of cathepsins B, C, F, H, K, L, O, S, V, W and X, preferably the cathepsin is selected from the group consisting of cathepsins B, K, L and S.
- the invention further relates to a compound of the formula 1 according to any one of the first aspects of the invention, a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, or a third aspect of the invention
- the pharmaceutical composition for treating/preventing/or adjuvant treatment of a tumor is not limited to any one of the first aspects of the invention, a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, or a third aspect of the invention.
- the tumor is selected from the group consisting of kidney cancer, lymphoma, lung cancer, liver cancer, gastric cancer, testicular cancer, lung non-small cell carcinoma, breast cancer, ovarian cancer, colon cancer, bladder cancer, and thyroid cancer. .
- the invention further relates to a compound of formula 1 according to any one of the first aspects of the invention, a racemate or an optical isomer thereof, A solvate thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any of the third aspects of the present invention for use in the prevention and/or treatment of osteoporosis, Ebola virus infection, rheumatoid Arthritis, osteoarthritis, autoimmune disease, or degenerative disease.
- the autoimmune disease is selected from the group consisting of chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, chronic ulcerative colitis, pernicious anemia with chronic atrophic gastritis, lung Hemorrhagic nephritis syndrome, pemphigoid, primary biliary cirrhosis and multiple sclerosis.
- the degenerative disease is selected from the group consisting of cardiovascular diseases (eg, hypertensive heart disease, cardiomyopathy, myocardial infarction, valvular heart disease), brain dysfunction (eg, Alzheimer's disease, Don) Syndrome, etc.) and cataracts.
- cardiovascular diseases eg, hypertensive heart disease, cardiomyopathy, myocardial infarction, valvular heart disease
- brain dysfunction eg, Alzheimer's disease, Don) Syndrome, etc.
- cataracts eg, cataracts.
- the present invention relates to a method of inhibiting cathepsin activity, which comprises administering to a subject in need thereof an effective amount of a compound of the formula 1 according to any one of the first aspects of the invention, a racemate or an optical isomer thereof, A solvate thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of the third aspects of the invention.
- the cathepsin is selected from the group consisting of cathepsins B, C, F, H, K, L, O, S, V, W and X, preferably the cathepsin is selected from the group consisting of cathepsins B, K, L and S.
- the subject is a mammal, such as a bovine, equine, ovine, porcine, canine, feline, rodent, primate An animal; among them, a particularly preferred subject is a human.
- the present invention relates to a method of treating/preventing or or adjunctively treating a tumor comprising administering to a subject in need thereof an effective amount of a compound of the formula 1 according to any one of the first aspects of the invention, a racemate thereof or an optical rotation Isomer, a solvate thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of the third aspects of the invention.
- the tumor is selected from the group consisting of kidney cancer, lymphoma, lung cancer, liver cancer, gastric cancer, testicular cancer, lung non-small cell carcinoma, breast cancer, ovarian cancer, colon cancer, bladder cancer, and thyroid cancer. .
- the subject is a mammal, such as a bovine, equine, ovine, porcine, canine, feline, rodent, primate An animal; among them, a particularly preferred subject is a human.
- the invention also relates to a method of preventing and/or treating osteoporosis, Ebola virus infection, rheumatoid arthritis, osteoarthritis, autoimmune disease or degenerative disease, comprising to a subject in need thereof An effective amount of a compound of formula 1 according to any one of the first aspects of the invention, a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, or any of the third aspect of the invention.
- the subject is a mammal, such as a bovine, equine, ovine, porcine, canine, feline, rodent, primate An animal; among them, a particularly preferred subject is a human.
- the autoimmune disease is selected from the group consisting of chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, chronic ulcerative colitis, pernicious anemia with chronic atrophic gastritis, lung Hemorrhagic nephritis syndrome, pemphigoid, primary biliary cirrhosis and multiple sclerosis.
- the degenerative disease is selected from the group consisting of cardiovascular diseases (eg, hypertensive heart disease, cardiomyopathy, myocardial infarction, valvular heart disease), brain dysfunction (eg, Alzheimer's disease, Don) Syndrome, etc.) and cataracts.
- cardiovascular diseases eg, hypertensive heart disease, cardiomyopathy, myocardial infarction, valvular heart disease
- brain dysfunction eg, Alzheimer's disease, Don) Syndrome, etc.
- cataracts eg, cataracts.
- C 1 -C 10 linear or branched alkyl as used in the present invention means a straight or branched alkyl group having 1 to 10 carbon atoms, for example, a C 1 -C 6 straight or branched alkyl group, C 1- C 4 straight or branched alkyl.
- Specific examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-pentyl, 3-methyl-butyl, 2- Methyl-butyl, 1-methyl-butyl, 2,2-dimethyl-propyl, 1,1-dimethyl-propyl, 1,2-dimethyl-propyl, 1-B -propyl, n-hexyl, 1-methyl-n-pentyl, 2-methyl-pentyl, 3-methyl-pentyl, 4-methyl-pentyl, 1,1-dimethyl-butyl Base, 2,2-dimethyl-butyl, 3,3-dimethyl-butyl, 1,2-dimethyl-butyl, 1,3-dimethyl-butyl, 2,3- Dimethyl-butyl, 1-ethyl-butyl, 2-ethyl-butyl, 1,
- C 1 -C 10 alkoxy as used in the present invention means a group having a "C 1 -C 10 alkyl-O-" structure, such as a C 1 -C 6 alkoxy group, a C 1 -C 4 alkane.
- An oxy group, wherein the C 1 -C 10 alkyl group has the same meaning as the "C 1- C 10 straight or branched alkyl group" described above.
- Specific examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, isobutoxy, pentyloxy, 2- Pentyloxy, 3-pentyloxy, isopentyloxy, neopentyloxy, sec-pentyloxy, hexyloxy, 2-hexyloxy and 3-hexyloxy and the like.
- C 1 -C 10 alkylthio as used in the present invention can be similarly understood as “C 1 -C 10 alkoxy", except that the oxygen atom is replaced by a sulfur atom.
- C 1- C 6 alkylthio, C 1- C 4 alkylthio group Specific examples include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, and the like.
- C 3 -C 10 cycloalkyl as used in the present invention means a saturated carbocyclic group having 3 to 10 carbon atoms.
- the cycloalkyl group may be a monocyclic or polycyclic fused system and may be fused to an aromatic ring, such as a C 3 -C 8 cycloalkyl group, a C 5 -C 8 cycloalkyl group, a C 5 -C 7 naphthenic ring.
- the group is a C 5 -C 6 cycloalkyl group or the like, and specific examples include, but are not limited to, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and the like.
- C 3 -C 10 cycloalkoxy as used in the present invention means a group having a "C 3 -C 10 cycloalkyl-O-" structure in which a C 3 -C 10 cycloalkyl group and the aforementioned C 3 -
- the C 10 cycloalkyl group has the same meaning.
- Specific examples include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
- C 3 -C 10 cycloalkylthio as used in the present invention can be similarly understood as C 3 -C 10 cycloalkoxy, except that the oxygen atom is replaced by a sulfur atom.
- a C 3 -C 8 cycloalkylthio group a C 5 -C 8 cycloalkylthio group, a C 5 -C 7 cycloalkylthio group, a C 5 -C 6 cycloalkylthio group or the like.
- Specific examples include, but are not limited to, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.
- C 2 -C 10 straight or branched alkenyl as used in the present invention means a straight or branched hydrocarbon group having 2 to 10 carbon atoms and at least one carbon-carbon double bond, for example, C 2 - C 8 straight A chain or branched alkenyl group, a C 2 -C 6 straight or branched alkenyl group, a C 2 -C 4 straight or branched alkenyl group. Specific examples include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like.
- C 2 -C 10 linear or branched alkynyl as used in the present invention means a straight or branched hydrocarbon group having 2 to 10 carbon atoms and at least one carbon-carbon triple bond, for example, C 2 - C 8 straight A chain or branched alkynyl group, a C 2 -C 6 linear or branched alkynyl group, a C 2 -C 4 linear or branched alkynyl group. Specific examples include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.
- halogen as used in the present invention means fluorine, chlorine, bromine and iodine.
- aryl as used in the present invention means a fused ring having a monocyclic ring (e.g., phenyl), a polycyclic ring (e.g., naphthyl), or at least one of which is aromatic (e.g., 1,2,3,4-tetrahydro)
- An anthranyl carbocyclyl group optionally substituted by one or more selected from the group consisting of halogen, amino, cyano, trifluoromethyl, hydroxy, nitro, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 alkylthio group, aryl group and heteroaryl group substituents.
- Specific examples include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, anthracenyl, fluorenyl, fluorenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methyl Phenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, biphenyl, and the like.
- arylalkyl refers to an alkyl group substituted with an aryl group substituted with one or more previously defined as previously defined, such aryl groups -C l -C 6 alkyl, aryl, -C l -C 4 alkyl. Specific examples include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl, and the like.
- heterocyclyl or “heterocycle” as used herein, denotes a 3-10 membered monocyclic or polycyclic ring containing at least one up to four heteroatoms selected from N, O or S, which may be divided into aliphatic heterocyclic groups.
- an aromatic heterocyclic group provided that the ring of the group does not contain two adjacent O or S atoms, preferably 3-8 members (for example, 3, 4, 5, 6, 7 or 8)
- An aliphatic heterocyclic group or an aromatic heterocyclic group, optionally, the heterocyclic group may also be selected from one or more selected from the group consisting of halogen, amino, cyano, trifluoromethyl, hydroxy, nitro, C 1 -C 10 Alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkylamino, di(C 1 -C 6 alkyl)amino, C 1 - Substituent substitution of C 10 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 10 alkylthio, aryl and heteroaryl.
- oxiranyl oxocyclobutane
- pyrrolidinyl tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, pyrrolyl, furyl, thienyl, imidazolyl, cacao Azyl, thiazolyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, pyridyl, pyranyl, pyrazinyl, pyrimidinyl, triazinyl, 2-methyl Piperidinyl, 3-methylpiperidinyl, 4-methylpiperidinyl, 2-ethylpiperidinyl, 3-ethylpiperidinyl, 4-ethylpiperidinyl, 3,5-di Methylpiperidinyl, 2-phenylpiperidinyl, 3-phenylpiperidinyl, 3-phenylpiperidinyl, 3-
- benzene fused heterocyclic group means a group obtained by condensing a benzene ring with a heterocyclic compound, such as benzofuran, anthracene, benzothiophene, benzoxazole, benzimidazole, Benzothiazole, benzoxazole, benzotriazole, benzothiadiazole, quinoline, benzotetrahydrofuran, benzotetrahydropyrrole, benzotetrahydropyran, benzopiperidine, Benzodioxane, benzodiimido or benzopiperazine.
- a heterocyclic compound such as benzofuran, anthracene, benzothiophene, benzoxazole, benzimidazole, Benzothiazole, benzoxazole, benzotriazole, benzothiadiazole, quinoline, benzotetrahydrofuran, benzotetrahydropyrrole, benzo
- oxy as used in the present invention specifically refers to It may be substituted for the formation of a carbonyl group on a carbon atom of a heterocyclic ring or in the form of an enol form, for example, a structure such as pyrrolidone, morpholinone or pyridin-2-one.
- ester group as used in the present invention means a substituent having a -COOR structure, wherein R represents an alkyl group, for example alkyl, Alkyl or Alkyl and the like.
- plurality includes two, three, four or five, and the like.
- an optical isomer as used in the present invention includes all possible optical isomers (e.g., enantiomers, diastereomers, etc.) of the compounds of the formula 1 of the present invention, for example, asymmetrical centers. R and S configurations.
- the compound of the formula 1 of the present invention or a pharmaceutically acceptable salt thereof may also form a solvate such as a hydrate, an alcoholate or the like, and generally, a solvate form and a non-solvent formed with a pharmaceutically acceptable solvent such as water, ethanol or the like.
- a pharmaceutically acceptable solvent such as water, ethanol or the like.
- the form of the compound is equivalent.
- the above compounds may also be in the form of prodrugs or which release the active ingredient after metabolic changes in the body. The selection and preparation of suitable prodrug derivatives are well known to those skilled in the art.
- an effective amount refers to an amount sufficient to achieve the desired prophylactic and/or therapeutic effect, for example, to achieve an amount that prevents or reduces the symptoms associated with the condition to be treated.
- treating refers to both therapeutic treatment and prophylactic measures, the purpose of which is to prevent or delay (reduce) the disease state or condition to which it is directed. If the subject receives a therapeutic amount of a compound, or an isomer, solvate, pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, as described herein, the subject has one or more indications and symptoms Subjects exhibit an observable and/or detectable reduction or improvement and the subject is successfully "treated”. It will also be understood that the prevention or treatment of the disease state or condition includes not only complete prevention or treatment, but also failure to achieve complete prevention or treatment, but achieving some biological or medical related results.
- autoimmune disease refers to a disease caused by an organism's immune response to an autoantigen to cause damage to its own tissues, particularly a disease associated with elevated expression or activity of cathepsins, such as chronic lymphocytic thyroiditis.
- cathepsins such as chronic lymphocytic thyroiditis.
- Hyperthyroidism insulin-dependent diabetes mellitus, myasthenia gravis, chronic ulcerative colitis, pernicious anemia with chronic atrophic gastritis, pulmonary hemorrhagic nephritis syndrome, pemphigoid, primary biliary cirrhosis, multiple Cerebral spinal sclerosis.
- degenerative disease means that humans produce oxidation by-products during metabolism, which cause extensive damage to deoxyribonucleic acids, proteins and other macromolecules, which promote degradation of diseases caused by aging.
- sexual diseases including cancer, cardiovascular diseases (such as hypertensive heart disease, cardiomyopathy, myocardial infarction, valvular heart disease), immune system decline, brain dysfunction (such as Alzheimer's disease, Down syndrome, etc.) Cataracts, etc.
- pharmaceutical composition denotes a compound, one or more of the compounds described herein, a racemate or an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
- the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
- the carriers described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human blood.
- Albumin buffer substances such as phosphate, glycerin, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated plant fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, chlorination Sodium, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic material, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, beeswax, lanolin.
- the excipient refers to an addenda other than the main drug in the pharmaceutical preparation.
- the compound of the present invention, its racemate or optical isomer, its solvate, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof can be administered by parenteral, topical, intravenous, oral, or the like.
- the composition may optionally be administered in combination with other agents that have at least some effect in the treatment of various diseases.
- the compound of the present invention can be formulated into various suitable dosage forms depending on the route of administration.
- the compounds of the invention can be formulated into any orally acceptable formulation including, but not limited to, tablets, capsules, aqueous solutions or aqueous suspensions.
- the carrier used for the tablet generally includes lactose and corn starch, and a lubricant such as magnesium stearate may also be added.
- the diluent used in the capsule formulation generally comprises lactose and dried cornstarch.
- Aqueous suspension formulations are usually prepared by admixing the active ingredient with a suitable emulsifier and suspension.
- some sweeteners, fragrances or colorants may also be added to the above oral formulation forms.
- the compounds of the present invention can be formulated into a suitable ointment, lotion or cream preparation wherein the active ingredient is suspended or dissolved in one or more carriers.
- Carriers which may be used in ointment preparations include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; and detergents or creams which may be used include, but are not limited to, minerals Oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
- the compounds of the present invention can also be administered in the form of a sterile injectable preparation, including sterile injectable aqueous or oily suspension or sterile injection solutions.
- a sterile injectable preparation including sterile injectable aqueous or oily suspension or sterile injection solutions.
- carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils may also be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.
- the pharmaceutical preparation of the present invention includes any preparation pharmaceutically acceptable, such as an oral preparation, a parenteral preparation, and the like.
- suitable in vitro or in vivo assays are performed to determine the efficacy of the compositions of the invention and whether the administration is suitable for treating a disease or medical condition in a subject. Examples of such assays are described below in connection with specific diseases or medical treatments in non-limiting embodiments.
- an effective amount of a composition of the invention sufficient to achieve a prophylactic or therapeutic effect is from about 0.001 mg/kg body weight/day to about 10,000 mg/kg body weight/day.
- the dosage is from about 0.01 mg/kg body weight/day to about 1000 mg/kg body weight/day.
- Dosage range can be daily, every two days Or about 0.01 to 1000 mg/kg of host body weight per three days, more typically 0.1 to 500 mg/kg of host body weight.
- An exemplary treatment regimen is once every two days or once a week or once a month.
- the agent is usually administered multiple times, and the interval between single doses can be daily, weekly, monthly or yearly.
- the agent can be administered in the form of a sustained release formulation, in which case less dosing frequency is required.
- the dose and frequency will vary depending on the half-life of the agent in the subject. It can also be different depending on whether it is a preventive treatment or a therapeutic treatment.
- relatively low doses are administered chronically at relatively low frequency intervals.
- the present invention provides a class of epoxy succinic acid derivatives which have high inhibitory activity and/or selectivity for cathepsins, especially for cathepsin B, and can be used for the treatment of cathepsins.
- Related diseases such as osteoporosis associated with cathepsin K, rheumatoid arthritis and osteoarthritis, and Ebola virus infection, degenerative diseases associated with cathepsin L, S and autoimmunity Disease, especially for cathepsin B related to tumor diseases, such as gastric cancer, cervical cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, colon cancer, glioma, melanoma and the like.
- the specific optical rotation of the compound was determined by an OA company polaar 3005 precision automatic polarimeter, and the 1H-NMR spectrum was measured by a Bruker ARX400 type nuclear magnetic apparatus; the FAB mass spectrum was measured by an Agilent 1260-G6230A high resolution mass spectrometer.
- (+/-)-trans-epoxysuccinic acid (178 g, 1.35 mol) was dissolved in 2600 ml of methanol. Add (234.9 g, 1.35 mol) L-arginine to 650 ml of water, heat to dissolve, and then add dropwise to the (+/-)-trans-epoxysuccinic acid in methanol while stirring. A large amount of insoluble matter appeared. After the addition, the mixture was stirred at room temperature overnight. The precipitate was obtained by suction filtration, and the precipitate was washed with a methanol/water (4:1) mixture solvent (1000 ml) to give 201.2 g of crude material. The crude product was recrystallized from about 3000 ml of methanolic water (2:1) to afford (y)-trans-epoxysuccinic acid 170.2 g, yield 82.5%.
- (+/-)-trans-epoxysuccinic acid (107.1 g, 0.35 mol) was added to a solution of 1050 ml of ethanol at room temperature, stirred, and then 95% concentrated sulfuric acid (102.9 g, 1.05 mol) was added dropwise. After the addition, the mixture was stirred and refluxed for 4.5 hours. After completion of the reaction, the solvent in the mixture was removed by rotary evaporation, and the residue was poured into 200 ml of ice water and extracted with ethyl acetate three times (300 ml*3). The combined ester layer was washed with saturated aqueous sodium bicarbonate (200 mL*2), brine (200*2). The column was obtained as a pure product, 50.4 g of a colorless oily liquid, yield 76.6%.
- Example 2 Using hexylamine and Intermediate 3 as starting materials, the same procedure as in Example 1 was carried out to obtain a white needle-like powder of Compound 5.
- Example 2 The same procedure as in Example 1 was carried out using 2-aminopentane and Intermediate 3 as a starting material to give Compound 6 as a white needle powder.
- Example 9 Using isobutylamine and Intermediate 3 as starting materials, the same procedure as in Example 1 was carried out to obtain Compound 9, a white acicular powder.
- Example 2 The same procedure as in Example 1 was carried out using 2-butylamine and Intermediate 3 as a starting material to obtain Compound 32 as a yellow needle powder.
- Example 2 The same procedure as in Example 1 was carried out using thiomorpholine and intermediate 3 as the starting material to afford compound 36 as a white solid.
- Example 1 The same procedure as in Example 1 was carried out using 4-phenylbutylamine and Intermediate 3 as the starting material to give Compound 40 as a white solid.
- Example 1 The same procedure as in Example 1 was carried out using 3,5-dimethylpiperidine and Intermediate 3 as the starting material to give Compound 41 as a colorless solid.
- Example 25 The same procedure as in Example 25 was carried out using propylamine and Intermediate 4 to give Compound 17 as a colorless oil.
- Example 25 The same procedure as in Example 25 was carried out using hexylamine and Intermediate 4 as the starting material to afford compound 18 as a yellow solid.
- Example 25 The same procedure as in Example 25 was carried out using 2-butylamine and Intermediate 4 to give Compound 19 as a white solid.
- Example 25 The same procedure as in Example 25 was carried out using 4-phenylbutylamine and Intermediate 4 as the starting material to afford Compound 20 as a colorless solid.
- Example 25 The same procedure as in Example 25 was carried out using p-methylphenylethylamine and Intermediate 4 as the starting material to afford Compound 21 as a yellow solid.
- Example 25 The same procedure as in Example 25 was carried out using tetrahydropyrrole and intermediate 4 as the starting material to afford compound 22 as a yellow oil.
- Example 25 The same procedure as in Example 25 was carried out using 4-phenylpiperidine and Intermediate 4 to give Compound 23 as a colorless oil.
- Example 25 The same procedure as in Example 25 was carried out using 3-fluorophenethylamine and Intermediate 4 to give Compound 24 as a yellow oil.
- Example 25 The same procedure as in Example 25 was carried out using morpholine and intermediate 4 as the starting material to afford compound 25 as a white solid.
- Example 25 The same procedure as in Example 25 was carried out using 4-methoxyphenethylamine and Intermediate 4 as the starting material to afford Compound 26 as a white powder.
- Example 25 The same procedure as in Example 25 was carried out using 2-aminopentane and Intermediate 4 to give Compound 42 as a white solid.
- Example 25 The same procedure as in Example 25 was carried out using 3-aminopentane and Intermediate 4 to give Compound 43 as a white solid.
- Example 25 The same procedure as in Example 25 was carried out using isobutylamine and Intermediate 4 as the starting material to afford Compound 44 as a yellow oil.
- Example 25 The same procedure as in Example 25 was carried out using 3-phenylpropylamine and Intermediate 4 as the starting material to afford Compound 45 as a yellow oil.
- Example 25 The same procedure as in Example 25 was carried out using thiomorpholine and intermediate 4 as the starting material to afford compound 46 as white oil.
- Example 25 The same procedure as in Example 25 was carried out using THF and Intermediate 4 to give Compound 47 as a colorless oil.
- Example 25 The same procedure as in Example 25 was carried out using 2-ethylpiperidine and Intermediate 4 to give Compound 49 as a yellow oil.
- Example 25 The same procedure as in Example 25 was carried out using 3,5-dimethylpiperidine and Intermediate 4 to give Compound 50 as a yellow oil.
- Example 25 The same procedure as in Example 25 was carried out using isoamylamine and Intermediate 4 as the starting material to afford Compound 51 as a white oil.
- Example 25 The same procedure as in Example 25 was carried out using pentylamine and Intermediate 4 to give Compound 52 as a white oil.
- the present invention relates to the evaluation of the activity of cathepsin inhibitors by the following method
- Cathepsin K screening was performed using Biovision's Cathepsin K Inhibitor Screening Kit kit (Cat. No. K150-100).
- test compound was prepared in the above examples, the positive compound FF-FMK was provided in the kit, and the positive compounds zxy-37 (E64d) and zxy-60 (CA-074) were purchased from Selleck.
- cathepsin K enzyme solution Take 40ul of cathepsin K enzyme and 80ul of cathepsin K reagent into 3.88ml cathepsin K buffer solution, mix well, and prepare a volume of 4ml of cathepsin K enzyme solution. Reserve on ice.
- the positive control drugs were zxy-37 (E64d) and zxy-60 (CA-074), respectively.
- cathepsin K substrate solution Take 160ul of cathepsin K substrate in 3.44ml of cathepsin K buffer solution, mix well, and prepare a volume of 3.6ml of cathepsin K enzyme solution, placed on ice. spare.
- cathepsin K inhibitor according to 10 ul / well cathepsin K enzyme solution (prepared in 1.1.1) was added to a 384-well plate (ProxiPlate-384Plus, Perkinelmer), centrifuged at 1000 rpm for 1 min; then added compound solution ( Prepared in 1.1.2, 2 ul / well, set each concentration in two parallels, centrifuge at 1000 rpm for 1 min, then place in a 25 ° C incubator for 15 min; then add cathepsin K substrate solution, 8 ul / well, centrifuge at 1000 rpm for 1 min Finally, the fluorescent signal was read in Enspire, 400 nm excitation light and 505 nm emission light were set, and the reading was continuously performed at 37 ° C for 120 min.
- the IC50 assay of the compound for cathepsin B was carried out using Biovision's Cathepsin B Inhibitor Screening Kit kit (Cat. No. K147-100);
- the IC50 assay of the compound for cathepsin K was carried out using Biovision's Cathepsin K Inhibitor Screening Kit kit (Cat. No. K150-100);
- the IC50 assay of the compound for cathepsin L was carried out using Biovision's Cathepsin L Inhibitor Screening Kit (Cat. No. K161-100);
- the IC50 assay of the compound for cathepsin S was carried out using Biovision's CathepsinS Inhibitor Screening Kit kit (Cat. No. K149-100).
- test compound was prepared in the above examples, and the positive compounds FF-FMK, FF-FMK, FF-FMK and Z-FF-FMK were provided in the kit, and the positive compounds zxy-37 (E64d) and zxy-60 (CA) were used. -074) Purchased from Selleck Corporation.
- cathepsin K solution Take 23ul of cathepsin K enzyme and 46ul of cathepsin K reagent into 2231ul of cathepsin K buffer solution, mix well and prepare into a volume of 2.3ml. The protease K enzyme solution was placed on ice for later use.
- cathepsin B solution Take 23ul of cathepsin B enzyme and 46ul of cathepsin B reagent into 2231ul of cathepsin B buffer solution, mix well, and prepare a volume of 2.3ml of cathepsin B enzyme solution. Alternate on ice.
- cathepsin L solution 3 ul of cathepsin L reagent was taken into 3 ul of cathepsin L enzyme, and uniformly mixed for 1 hour to obtain a 1 mU/ul cathepsin L enzyme solution. 24 ul of cathepsin L buffer solution was taken into 6 ul of 1 mU/ul of cathepsin L enzyme solution to obtain a 0.2 mU/ul cathepsin L enzyme solution.
- cathepsin S solution Take 46ul of cathepsin S enzyme into 2254ul cathepsin S buffer solution, mix well, and prepare a cathepsin S enzyme solution with a volume of 2.3ml, and put it on ice for use.
- the concentrations of the test compounds are 1000, 333.3, 111.1, 37, 12.3, 4.1, 1.4, 0.46, 0.15, 0.05 and 0uM, respectively.
- the concentration is 10%.
- Cathepsin K Take 90 ul of cathepsin K substrate in 1710 ul of cathepsin K buffer solution, mix well, and prepare a volume of 1.8 ml of cathepsin K enzyme solution, and place it on ice for later use.
- Cathepsin B 90 ul of cathepsin B substrate was mixed in 1710 ul of cathepsin B buffer solution, uniformly mixed, and prepared into a volume of 1.8 ml of cathepsin B enzyme solution, and placed on ice for use.
- Cathepsin L Take 45 ul of cathepsin L substrate in 1755 ul of cathepsin L buffer solution, mix well, and prepare a volume of 1.8 ml of cathepsin L enzyme solution, and place it on ice for later use.
- Cathepsin S Take 90 ul of cathepsin S substrate in 1710 ul of cathepsin S buffer solution, mix well, and prepare a volume of 1.8 ml of cathepsin S enzyme solution, and place it on ice for later use.
- cathepsin inhibitor activity indicates that the compound of formula 1 of the present invention, particularly compounds 5, 8, 13, 34, 39, 40 has a strong selective action on cathepsin B, as listed in the following table:
Abstract
Description
Claims (21)
- 式1所示化合物、其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐,其中,R1代表氢原子、C1-C10直链或支链烷基、C3-C10环烷基、C2-C10直链或支链烯基、C2-C10直链或支链炔基、芳基、芳基-C1-C6烷基、杂环基或杂环-C1-C6烷基;R2代表氢原子、C1-C10直链或支链烷基、C3-C10环烷基、C1-C10烷硫基、C3-C10环烷硫基、C2-C10直链或支链烯基、C2-C10直链或支链炔基、芳基、芳基-C1-C6烷基、杂环基或杂环-C1-C6烷基,任选地,其中所述C1-C10直链或支链烷基、C3-C10环烷基、C1-C10烷硫基、C3-C10环烷硫基、C2-C10直链或支链烯基、C2-C10直链或支链炔基、芳基、芳基-C1-C6烷基、杂环基或杂环-C1-C6烷基各自独立地被一个或多个选自以下的取代基取代:卤素、氨基、氰基、三氟甲基、羟基、硝基、C1-C10烷基、C1-C10烷氧基和C1-C10烷硫基,任选地,其中所述C1-C10烷基、C1-C10烷氧基或C1-C10烷硫基进一步被一个或多个选自上述的取代基取代;X代表-O-、-N(R5)-;n为选自0-5的整数,优选1-3;R3和R4各自独立地代表氢原子、C1-C10直链或支链烷基、C3-C10环烷基、C2-C10直链或支链烯基、C2-C10直链或支链炔基、芳基、芳基-C1-C6烷基、杂环基、杂环-C1-C6烷基或稠杂环基(例如苯并杂环基),任选地,其中所述C1-C10直链或支链烷基、C3-C10环烷基、C2-C10直链或支链烯基、C2-C10直链或支链炔基、芳基、芳基-C1-C6烷基、杂环基、杂环-与C1-C6烷基或稠杂环基各自独立地被一个或多个选自以下的取代基取代:卤素、氨基、氰基、三氟甲基、羟基、硝基、C1-C10烷基、C1-C10烷氧基、C1-C10烷硫基,任选地,其中所述C1-C10烷基、C1-C10烷氧基或C1-C10烷硫基进一步被一个或多个选自上述的取代基取代;或者,R3和R4与相连的N一起形成5-8元杂环,任选地,所述5-8元杂环被选自以下的一个或多个取代基取代:卤素、羟基、氨基、C1-C10烷基、C1-C10烷氧基、C1-C10烷硫基、芳基、氧基或酯基;R5代表氢原子、C1-C10直链或支链烷基、芳基、芳基-C1-C6烷基、杂环基或杂环基-C1-C6烷基。
- 权利要求1所述的式1化合物、其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐,其中,R1代表氢原子、C1-C10直链或支链烷基、C3-C10环烷基、C2-C10直链或支链烯基、C2-C10直链或支链炔基;R2代表氢原子、C1-C10直链或支链烷基、C3-C10环烷基、C1-C10烷硫基、C3-C10环烷硫基、C2-C10直链或支链烯基、C2-C10直链或支链炔基、芳基、芳基-C1-C6烷基、杂环基或杂环-C1-C6烷基,任选地,其中,所述的C1-C10直链或支链烷基、C3-C10环烷基、C1-C10烷硫基、C3-C10环烷硫基、C2-C10直链或支链烯基、C2-C10直链或支链炔基、芳基、芳基-C1-C6烷基、杂环基或杂环-C1-C6烷基各自独立地被一个或多个选自以下的取代基取代:卤素、氨基、氰基、三氟甲基、羟基、硝基、C1-C10烷基、C1-C10烷氧基和C1-C10烷硫基,任选地,其中所述C1-C10烷基或C1-C10烷氧基进一步被一个或多个选自上述的取代基取代;X为-O-;n为选自1-3的整数,优选1或2;R3和R4各自独立地代表氢原子、C1-C10直链或支链烷基、C3-C10环烷基、C2-C10直链或支链烯基、C2-C10直链或支链炔基、芳基、芳基-C1-C6烷基、杂环基、杂环-C1-C6烷基或苯稠杂环基,任选地,所述的C1-C10直链或支链烷基、C3-C10环烷基、C2-C10直链或支链烯基、C2-C10直链或支链炔基、芳基、芳基-C1-C6烷基、杂环基、杂环-C1-C6烷基或苯稠杂环基各自独立地被一个或多选自以下的取代基取代:卤素、氨基、氰基、三氟甲基、羟基、硝基、C1-C10烷基、C1-C10烷氧基或C1-C10烷硫基,任选地,其中所述C1-C10烷基、C1-C10烷氧基或C1-C10烷硫基进一步被一个或多个选自上述的取代基取代;或者,R3和R4与相连的N一起形成5-8元杂环,任选地,其中所述5-8元杂环被选自以下的一个或多个取代基取代:卤素、羟基、氨基、C1-C10烷基、C1-C10烷氧基、C1-C10烷硫基、 芳基、氧基或酯基。
- 权利要求1所述的式1化合物、其消旋体或旋光异构体、其溶剂化物、或其药学或生理学上可接受的盐,R1代表氢原子或C1-C5直链或支链烷基;R2代表氢原子、C1-C6直链或支链烷基或芳基-C1-C4烷基;X为-O-;n为1或2;R3和R4各自独立地代表C1-C10直链或支链烷基、C3-C10环烷基、芳基、芳基-C1-C6烷基、杂环基、杂环-C1-C6烷基或苯稠杂环基,任选地,其中所述C1-C10直链或支链烷基、C3-C10环烷基、芳基、芳基-C1-C6烷基、杂环基、杂环-C1-C6烷基或苯稠杂环基各自独立地被一个或多个选自以下的取代基取代:卤素、C1-C10烷基、C1-C10烷氧基和C1-C10烷硫基,任选地,其中所述C1-C10烷基、C1-C10烷氧基或C1-C10烷硫基进一步被一个或多个选自上述的取代基取代;或者,R3和R4与相连的N一起形成5-8元杂环,任选地,所述5-8元杂环被选自以下的一个或多个取代基取代:卤素、羟基、氨基、C1-C10烷基、C1-C6烷氧基、C1-C6烷硫基、芳基、氧基或酯基。
- 权利要求1所述的式1化合物、其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐,其中,R1代表C1-4烷基;R2代表C1-C4烷基或芳基-C1-C4烷基;X为-O-;n为1或2;R3和R4各自独立地代表C1-C6直链或支链烷基、芳基-C1-C6烷基,任选地,其中所述C1-C6直链或支链烷基和芳基-C1-C6烷基各自独立地被一个或多个选自卤素、C1-C4烷基和C1-C4烷氧基的取代基取代;或者,R3和R4与相连的N一起形成5-8元杂环,任选地,所述5-8元杂环被一个或多个选自以下的取代基取代:C1-C4烷基、C1-C4烷氧基和芳基。
- 权利要求1-4任一项所述的式1化合物、其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐,其中,R1为甲基或乙基。
- 权利要求1-4任一项所述的式1化合物、其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐,其中,R2为甲基、乙基或苄基。
- 权利要求1-4任一项所述的式1化合物、其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐,其中,X为-O-。
- 权利要求1-4任一项所述的式1化合物、其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐,其中,n为1或2。
- 药物组合物,其包含权利要求1-9任一项所述的式1化合物、其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐,以及任选的一种或多种药学可接受的 载体或赋形剂。
- 权利要求1-9任一项所述的式1化合物、其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐或权利要求11的药物组合物在制备组织蛋白酶抑制剂中的用途,优选地,所述组织蛋白酶选自组织蛋白酶B、C、F、H、K、L、O、S、V、W和X,更优选地,所述组织蛋白酶选自组织蛋白酶B、K、L和S。
- 权利要求1-9任一项所述的式1化合物、其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐或权利要求11的药物组合物在制备治疗/预防/或辅助治疗肿瘤的药物中的用途。
- 权利要求13的用途,其中所述肿瘤选自肾癌、淋巴瘤、肺癌、肝癌、胃癌、睾丸癌、肺非小细胞癌、乳腺癌、卵巢癌、结肠癌、膀胱癌和甲状腺癌。
- 权利要求1-9任一项所述的式1化合物、其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐或权利要求11的药物组合物在制备骨质疏松症、埃博拉病毒感染、类风湿性关节炎、骨关节炎、自身免疫疾病或退行性疾病的药物中的用途,优选地,所述自身免疫疾病选自慢性淋巴性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、慢性溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、类天疱疮、原发性胆汁性肝硬变和多发性脑脊髓硬化症,优选地,所述退行性疾病选自心血管疾病(例如高血压性心脏病、心肌病、心肌梗死、心脏瓣膜病)、脑功能障碍(例如阿尔兹海默症、唐氏综合症等)以及白内障等。
- 权利要求1-9任一项所述的式1化合物、其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐或权利要求11的药物组合物,其用于抑制组织蛋白酶活性,优选地,所述组织蛋白酶选自组织蛋白酶B、C、F、H、K、L、O、S、V、W和X,更优选地,所述组织蛋白酶选自组织蛋白酶B、K、L和S。
- 权利要求1-9任一项所述的式1化合物、其消旋体或旋光异构体、其溶剂化 物、或其药学上可接受的盐或权利要求11的药物组合物,其用于治疗/预防/或辅助治疗肿瘤,优选地,所述肿瘤选自肾癌、淋巴瘤、肺癌、肝癌、胃癌、睾丸癌、肺非小细胞癌、乳腺癌、卵巢癌、结肠癌、膀胱癌和甲状腺癌。
- 权利要求1-9任一项所述的式1化合物、其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐或权利要求11的药物组合物,其用于预防和/或治疗骨质疏松症、埃博拉病毒感染、类风湿性关节炎、骨关节炎、自身免疫疾病或退行性疾病,优选地,所述自身免疫疾病选自慢性淋巴性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、慢性溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、类天疱疮、原发性胆汁性肝硬变和多发性脑脊髓硬化症,优选地,所述退行性疾病选自心血管疾病(例如高血压性心脏病、心肌病、心肌梗死、心脏瓣膜病)、脑功能障碍(例如阿尔兹海默症、唐氏综合症等)以及白内障等。
- 一种抑制组织蛋白酶活性的方法,其包括向有需要的受试者施用有效量的权利要求1-9任一项所述的式1化合物、其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐或权利要求11的药物组合物,优选地,所述组织蛋白酶选自组织蛋白酶B、C、F、H、K、L、O、S、V、W和X,进一步优选地,所述组织蛋白酶选自组织蛋白酶B、K、L和S。
- 一种治疗/预防/或辅助治疗肿瘤的方法,其包含向有需要的受试者施用有效量的权利要求1-9任一项所述的式1化合物、其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐或权利要求11的药物组合物,优选地,所述肿瘤选自肾癌、淋巴瘤、肺癌、肝癌、胃癌、睾丸癌、肺非小细胞癌、乳腺癌、卵巢癌、结肠癌、膀胱癌和甲状腺癌。
- 一种预防和/或治疗骨质疏松症、埃博拉病毒感染、类风湿性关节炎、骨关节炎、自身免疫疾病或退行性疾病的方法,其包含向有需要的受试者施用有效量的权利 要求1-9任一项所述的式1化合物、其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐或权利要求11的药物组合物,优选地,所述自身免疫疾病选自慢性淋巴性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、慢性溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、类天疱疮、原发性胆汁性肝硬变和多发性脑脊髓硬化症,优选地,所述退行性疾病选自心血管疾病(例如高血压性心脏病、心肌病、心肌梗死、心脏瓣膜病)、脑功能障碍(例如阿尔兹海默症、唐氏综合症等)以及白内障等。
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4393228A (en) * | 1977-03-03 | 1983-07-12 | Taisho Pharmaceutical Co., Ltd. | Epoxysuccinic acid derivatives |
CN1112555A (zh) * | 1993-10-29 | 1995-11-29 | 武田药品工业株式会社 | 环氧琥珀酸衍生物 |
WO1995032954A1 (en) * | 1994-05-31 | 1995-12-07 | Takeda Chemical Industries, Ltd. | Epoxysuccinic acid derivatives, their production and use |
EP0808839A1 (en) * | 1995-12-12 | 1997-11-26 | Taiho Pharmaceutical Co., Ltd. | Epoxysuccinamide derivatives or salts thereof, and drugs containing the same |
CN1195343A (zh) * | 1995-07-13 | 1998-10-07 | 千寿制药株式会社 | 哌啶衍生物及其用途 |
CN101808634A (zh) * | 2006-06-13 | 2010-08-18 | 利兰·斯坦福青年大学托管委员会 | 半胱氨酸蛋白酶的环氧化物抑制剂 |
-
2016
- 2016-03-03 CN CN201610119872.9A patent/CN107151236B/zh active Active
-
2017
- 2017-03-02 JP JP2018545989A patent/JP6929866B2/ja active Active
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- 2017-03-02 WO PCT/CN2017/075453 patent/WO2017148417A1/zh active Application Filing
- 2017-03-02 EP EP17759268.0A patent/EP3424913B1/en active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4393228A (en) * | 1977-03-03 | 1983-07-12 | Taisho Pharmaceutical Co., Ltd. | Epoxysuccinic acid derivatives |
CN1112555A (zh) * | 1993-10-29 | 1995-11-29 | 武田药品工业株式会社 | 环氧琥珀酸衍生物 |
WO1995032954A1 (en) * | 1994-05-31 | 1995-12-07 | Takeda Chemical Industries, Ltd. | Epoxysuccinic acid derivatives, their production and use |
CN1195343A (zh) * | 1995-07-13 | 1998-10-07 | 千寿制药株式会社 | 哌啶衍生物及其用途 |
EP0808839A1 (en) * | 1995-12-12 | 1997-11-26 | Taiho Pharmaceutical Co., Ltd. | Epoxysuccinamide derivatives or salts thereof, and drugs containing the same |
CN101808634A (zh) * | 2006-06-13 | 2010-08-18 | 利兰·斯坦福青年大学托管委员会 | 半胱氨酸蛋白酶的环氧化物抑制剂 |
Non-Patent Citations (1)
Title |
---|
See also references of EP3424913A4 * |
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EP3424913B1 (en) | 2023-04-05 |
EP3424913A4 (en) | 2019-08-07 |
JP6929866B2 (ja) | 2021-09-01 |
CN107151236B (zh) | 2021-04-30 |
EP3424913A1 (en) | 2019-01-09 |
US20190062290A1 (en) | 2019-02-28 |
JP2019510755A (ja) | 2019-04-18 |
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