CN109730999A - Thiazole benzamide it is derivative prepare anti-osteoporosis, the application in Hyanalgese-D object - Google Patents
Thiazole benzamide it is derivative prepare anti-osteoporosis, the application in Hyanalgese-D object Download PDFInfo
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- 230000003262 anti-osteoporosis Effects 0.000 title claims description 16
- MUZRPGWJQGCNII-UHFFFAOYSA-N benzamide;1,3-thiazole Chemical compound C1=CSC=N1.NC(=O)C1=CC=CC=C1 MUZRPGWJQGCNII-UHFFFAOYSA-N 0.000 title description 5
- -1 thiazole heterocyclic carbamate derivatives Chemical class 0.000 claims abstract description 36
- 239000003814 drug Substances 0.000 claims abstract description 21
- 229940079593 drug Drugs 0.000 claims abstract description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 239000001257 hydrogen Substances 0.000 claims description 26
- 150000002431 hydrogen Chemical class 0.000 claims description 24
- 150000002148 esters Chemical class 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 150000001408 amides Chemical class 0.000 claims description 10
- 125000003178 carboxy group Chemical class [H]OC(*)=O 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 238000007363 ring formation reaction Methods 0.000 claims description 10
- XNVMFDGFXSZPDU-UHFFFAOYSA-N cyano nitroformate Chemical compound [O-][N+](=O)C(=O)OC#N XNVMFDGFXSZPDU-UHFFFAOYSA-N 0.000 claims description 8
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 150000002170 ethers Chemical class 0.000 claims description 6
- 125000004122 cyclic group Chemical group 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical class OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000002490 anilino group Chemical class [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000002915 carbonyl group Chemical class [*:2]C([*:1])=O 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000006574 non-aromatic ring group Chemical group 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 4
- 150000001735 carboxylic acids Chemical class 0.000 claims 3
- 150000001721 carbon Chemical group 0.000 claims 1
- HJMZMZRCABDKKV-UHFFFAOYSA-N carbonocyanidic acid Chemical compound OC(=O)C#N HJMZMZRCABDKKV-UHFFFAOYSA-N 0.000 claims 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 claims 1
- 210000002997 osteoclast Anatomy 0.000 abstract description 43
- 150000001875 compounds Chemical class 0.000 abstract description 39
- 208000001132 Osteoporosis Diseases 0.000 abstract description 11
- 230000004069 differentiation Effects 0.000 abstract description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 5
- 201000010099 disease Diseases 0.000 abstract description 4
- 239000003112 inhibitor Substances 0.000 abstract description 4
- 150000003016 phosphoric acids Chemical class 0.000 abstract description 2
- 239000003223 protective agent Substances 0.000 abstract description 2
- 230000001988 toxicity Effects 0.000 abstract description 2
- 231100000419 toxicity Toxicity 0.000 abstract description 2
- 101000942967 Homo sapiens Leukemia inhibitory factor Proteins 0.000 abstract 1
- 102100032352 Leukemia inhibitory factor Human genes 0.000 abstract 1
- 208000029725 Metabolic bone disease Diseases 0.000 abstract 1
- 206010049088 Osteopenia Diseases 0.000 abstract 1
- 102000003982 Parathyroid hormone Human genes 0.000 abstract 1
- 108090000445 Parathyroid hormone Proteins 0.000 abstract 1
- 229940011871 estrogen Drugs 0.000 abstract 1
- 239000000262 estrogen Substances 0.000 abstract 1
- 239000000199 parathyroid hormone Substances 0.000 abstract 1
- 229960001319 parathyroid hormone Drugs 0.000 abstract 1
- 231100000135 cytotoxicity Toxicity 0.000 description 22
- 230000003013 cytotoxicity Effects 0.000 description 22
- 230000001629 suppression Effects 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 19
- 230000002401 inhibitory effect Effects 0.000 description 15
- 230000005764 inhibitory process Effects 0.000 description 15
- 210000000988 bone and bone Anatomy 0.000 description 9
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 229960004424 carbon dioxide Drugs 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 150000001299 aldehydes Chemical class 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 102000014128 RANK Ligand Human genes 0.000 description 3
- 108010025832 RANK Ligand Proteins 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 description 3
- 239000001569 carbon dioxide Substances 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 239000006285 cell suspension Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000012894 fetal calf serum Substances 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 231100000636 lethal dose Toxicity 0.000 description 3
- 238000012423 maintenance Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- 231100000820 toxicity test Toxicity 0.000 description 3
- 208000010392 Bone Fractures Diseases 0.000 description 2
- 208000006386 Bone Resorption Diseases 0.000 description 2
- 102000003945 NF-kappa B Human genes 0.000 description 2
- 108010057466 NF-kappa B Proteins 0.000 description 2
- 208000035896 Twin-reversed arterial perfusion sequence Diseases 0.000 description 2
- 230000024279 bone resorption Effects 0.000 description 2
- 229910002090 carbon oxide Inorganic materials 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000006481 glucose medium Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 210000000963 osteoblast Anatomy 0.000 description 2
- 230000001599 osteoclastic effect Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 231100001274 therapeutic index Toxicity 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- UWSONZCNXUSTKW-UHFFFAOYSA-N 4,5-Dimethylthiazole Chemical compound CC=1N=CSC=1C UWSONZCNXUSTKW-UHFFFAOYSA-N 0.000 description 1
- 206010072395 Atypical fracture Diseases 0.000 description 1
- 229940078581 Bone resorption inhibitor Drugs 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 206010017076 Fracture Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- CZAFIFBJBFDMTP-UHFFFAOYSA-N N-[(4-bromophenyl)methyl]-2-[4-(2-phenylethylsulfamoyl)phenoxy]acetamide Chemical compound Brc1ccc(CNC(=O)COc2ccc(cc2)S(=O)(=O)NCCc2ccccc2)cc1 CZAFIFBJBFDMTP-UHFFFAOYSA-N 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000002424 anti-apoptotic effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- LJWIAZFZRNWQOL-UHFFFAOYSA-N benzene;1,3-thiazole Chemical compound C1=CSC=N1.C1=CC=CC=C1 LJWIAZFZRNWQOL-UHFFFAOYSA-N 0.000 description 1
- 230000037182 bone density Effects 0.000 description 1
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 description 1
- 229960005084 calcitriol Drugs 0.000 description 1
- 235000020964 calcitriol Nutrition 0.000 description 1
- 239000011612 calcitriol Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 238000005034 decoration Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 239000002834 estrogen receptor modulator Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001917 fluorescence detection Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 210000001721 multinucleated osteoclast Anatomy 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 230000004072 osteoblast differentiation Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000000197 pyrolysis Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 108010048734 sclerotin Proteins 0.000 description 1
- 238000003153 stable transfection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000816 toxic dose Toxicity 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
-
- 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
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D277/82—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Disclosure of the invention thiazole heterocyclic carbamate derivatives as osteoclast differentiation inhibitor are preparing the application in osteosporosis resistant medicament.The structural formula of the thiazole heterocyclic carbamate derivatives is as shown in the formula (I).Thiazole amide derivatives provided by the invention use the molecular skeletons of osteoporosises protective agents such as phosphoric acid salt, estrogen drugs and parathyroid hormone inhibitor different from Present clinical, and its osteoclast differentiation inhibitory activity is high, small toxicity.Therefore, such compound can be used as a kind of noval chemical compound type, for preventing and treating the related disease as caused by osteoclast disdifferentiation, especially osteoporosis or osteopenia.
Description
Technical field
The present invention relates to medicinal usage technical fields, are preparing anti-sclerotin more particularly, to thiazole benzamide derivative
Application loose, in Hyanalgese-D object.
Background technique
Osteoporosis and osteoarthritis are orthopaedics common diseases.Osteoporosis refers to due to bone amount reduction, the micro- knot of bone tissue
Structure degeneration leads to the increase of bone brittleness, the increased skeletal diseases of risk of bone fracture.As Chinese society aging aggravates, this disease disease incidence
In rising year by year trend.Epidemiological survey is shown, in 50 years old or more crowd, there are about the males of 50% women and 20% to have
The risk (Rachner, Khosla et al.2011) of fracture.National statistics office data is shown: to the year two thousand fifty, China 50 years old with
On the nearly national population of population half (49%), about 6.36 hundred million, it is contemplated that about to the year two thousand fifty China's sufferers of osteoporosis face number
For 300,000,000 people.As it can be seen that osteoporosis is very harmful to China's national health.However, solution is not yet received in osteoporosis problem, face
Still lack the drug that can effectively cure osteoporosis on bed.
There are mainly two types of the drugs that osteoporosis is prevented and treated on Present clinical, and one is include estrogen receptor modulator, double
The bone resorption inhibitor of phosphoric acid salt, another kind are the preparation such as Ah methods that there is bone resorption to inhibit to promote double action with bon e formation
Ostelin, calcitriol etc..Although cannot significantly be dropped however, said medicine can prevent bone density from declining to a certain extent
The risk of low atypical fracture, and the side effect of various degrees are not yet able to satisfy wanting for anti-osteoporosis treatment
Ask (Siris, Selby et al.2009).Therefore, at present there is an urgent need to develop a kind of specific drug of new anti-osteoporosis, with
Solve the problems, such as that Present clinical medication is unable to satisfy Treatment need.
Proportional imbalance between osteoclast (Osteoclast) and osteoblast (Osteoblast) is that osteoporosis produces
Raw pathologic basis (Rachner, Khosla et al.2011).Osteoclast differentiation phase is to increasing or osteoblast differentiation phase
To reduction, can all bone amount be caused to be lost, cause osteoporosis.Reducing bone resorption, promoting bone synthesis is that bone is treated on Present clinical
The loose essential therapeutic arsenals of matter.
Expression of nuclear factor kappa B (nuclear factor-kappa B, NF- κ B) is transcription factor particularly important in body,
Participate in the tune of the various functions such as the inflammation of body and the cycle regulating and development of immune response, apoptosis and anti-apoptotic and cell
Section.Non-classical NF- κ B signal access, i.e. RANKL-NF- κ B signal access mediate mononuclear macrophage to multinucleated osteoclast point
Change, is the important target (Boyle, Simonet et al.2003, Kim andKim 2016) of osteosporosis resistant medicament.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, provide a kind of thiazole benzamide it is derivative prepare anti-osteoporosis,
Application in Hyanalgese-D object.
Above-mentioned technical purpose is implemented with the following technical solutions in the present invention:
Thiazole heterocyclic carbamate derivatives prepare anti-osteoporosis, the application in Hyanalgese-D object, the thiazole benzene
Shown in the structural formula of carboxamides derivatives such as formula (I):
Wherein, R1For hydrogen, alkyl, hydroxyl, phenyl or substituted-phenyl, five yuan or hexa-atomic heteroaromatic, replace five yuan or six
First heteroaromatic；R2For hydrogen, alkyl, alkyl-substituted carbonyl or ester, phenyl or substituted-phenyl, five yuan or hexa-atomic heteroaromatic, substitution
Five yuan or hexa-atomic heteroaromatic, cycloaliphatic ring, heterocycle, substituted aniline or phenol；R1、R2Can be cyclic, R3For hydrogen, halogen atom, alkane
Oxygroup, alkylamino radical, hydroxyl, amino, cyano, nitro, carboxylic acid, alkyl-substituted carboxyl, amide or ester；R4For hydrogen, halogen atom,
Alkoxy, alkylamino radical, hydroxyl, amino, cyano, nitro, carboxylic acid, alkyl-substituted carboxyl, amide or ester；R5It is former for hydrogen, halogen
Son, alkoxy, alkylamino radical, hydroxyl, amino, cyano, nitro, carboxylic acid, alkyl-substituted carboxyl, amide or ester；R4、R5It can cyclization；
R6For hydrogen, alkyl, halogen atom, alkoxy, carboxylic acid, alkyl-substituted carboxyl, amide or ester, R5、R6Can be cyclic, R7For hydrogen, halogen
Plain atom, alkoxy, alkylamino radical, hydroxyl, amino, cyano, nitro, carboxylic acid, alkyl-substituted carboxyl, amide or ester.
As a preferred embodiment, R1For hydrogen, the alkyl of C1~C6；R2For hydrogen, C1~C6 alkyl, C1~C6 unsaturation alkane
Base, phenyl or substituted-phenyl, carboxylic acid and alkyl-substituted ester, alkyl-substituted aldehyde, alkyl-substituted ether.
As a preferred embodiment, R3For hydrogen, C1~C6 alkyl, C1~C6 alkoxy, halogen atom, hydroxyl, cyano, carboxylic
Sour and alkyl-substituted ester, alkyl-substituted aldehyde, alkyl-substituted ether.
As a preferred embodiment, R4For hydrogen, C1~C6 alkyl, C1~C6 alkoxy, hydroxyl, cyano, halogen atom, carboxylic
Sour and alkyl-substituted ester, alkyl-substituted aldehyde, alkyl-substituted ether.
As a preferred embodiment, R5For hydrogen, C1~C6 alkyl, C1~C6 alkoxy.
As a preferred embodiment, R6For hydrogen or methyl.
As a preferred embodiment, R1、R2Cyclization, R3、R4Cyclization, R4、R5Cyclization, cyclization are five yuan or hexa-atomic aromatic ring or non-
Aromatic ring.
As a preferred embodiment, the carbon atom number in ester, aldehyde and ether is 1~6.
As a preferred embodiment, the structural formula of the thiazole heterocyclic carbamate derivatives is one of following structural formula:
As a preferred embodiment, the drug includes pharmaceutically acceptable salt, carrier and/or excipient.
Thiazole benzamide derivatives of the present invention be as osteoclast differentiation inhibitor prepare anti-sclerotin dredge
Application in loose drug.
Compared with the existing technology, the present invention has the advantage that and effect:
Thiazole heterocyclic carbamate derivatives structure novel provided by the invention, the active testing equal energy of such compound as the result is shown
Inhibit osteoclast differentiation, thiazole amide derivatives structure provided by the invention is simple, is easily-synthesized；And such toxicity of compound
It is small, preparation treatment and/or pre- preventing bone rarefaction or the drug of bone amount reduction can be used safely in.
Detailed description of the invention
Fig. 1 is that 1a cytotoxicity and osteoclast break up suppression curve figure.
Fig. 2 is that 1b cytotoxicity and osteoclast break up suppression curve figure.
Fig. 3 is that 1c cytotoxicity and osteoclast break up suppression curve figure.
Fig. 4 is that 1d cytotoxicity and osteoclast break up suppression curve figure.
Fig. 5 is that 1e cytotoxicity and osteoclast break up suppression curve figure.
Fig. 6 is that 1f cytotoxicity and osteoclast break up suppression curve figure.
Fig. 7 is that 1g cytotoxicity and osteoclast break up suppression curve figure.
Fig. 8 is that 1h cytotoxicity and osteoclast break up suppression curve figure.
Fig. 9 is that 1i cytotoxicity and osteoclast break up suppression curve figure.
Figure 10 is that 1j cytotoxicity and osteoclast break up suppression curve figure.
Figure 11 is that 1k cytotoxicity and osteoclast break up suppression curve figure.
Figure 12 is that 1l cytotoxicity and osteoclast break up suppression curve figure.
Figure 13 is that 1m cytotoxicity and osteoclast break up suppression curve figure.
Figure 14 is that 1n cytotoxicity and osteoclast break up suppression curve figure.
Figure 15 is that 1o cytotoxicity and osteoclast break up suppression curve figure.
Figure 16 is that 1p cytotoxicity and osteoclast break up suppression curve figure.
Figure 17 is that 1q cytotoxicity and osteoclast break up suppression curve figure.
Figure 18 is that 1r cytotoxicity and osteoclast break up suppression curve figure.
Figure 19 is for 1o to the inhibition figure of osteoclast under various concentration.
Specific embodiment
Further illustrate the present invention below in conjunction with specific embodiments and the drawings, but embodiment the present invention is not done it is any
The restriction of form.Unless stated otherwise, the present invention uses reagent, method and apparatus is the art conventional reagents, method
And equipment.
Unless stated otherwise, agents useful for same and material of the present invention are commercially available.
Embodiment 1: thiazole heterocyclic carbamate derivatives synthesis
Embodiment 2:NF- κ B signal access Inhibition test
S1. cell culture.
The RAW264.7 cell of in vitro culture stable transfection height expression NF- κ B.Using contain 10% fetal calf serum, DMEM high
Sugar culture-medium carries out conventional maintenance culture and passage under the conditions of 37 DEG C, 5% gas concentration lwevel.
S2. compound intervention.
Logarithmic phase cell is collected, concentration of cell suspension is made into 5 × 105A/ml is added in 96 porocyte culture plates.In
After cultivating for 24 hours in carbon dioxide incubator, culture solution is changed into the culture medium containing different compound concentrations, co-incubation 6h.
Untested compound is configured to using DMSO the solution of various concentration.Each concentration sets 3 parallel multiple holes, and sets without compound
The control group of processing is compared.
S3. test method.
After experiment, using cell pyrolysis liquid lytic cell, according to fluorescence detection reagent kit specification to cell cracking
The fluorescence of liquid is detected, and gained values of chemiluminescence reflects NF- κ B signal access inhibitory activity situation.
S4. result treatment.
Each drug is calculated to the inhibiting effect of NF- κ B signal access by following formula:
Using inhibiting rate as ordinate, the log value of compound concentration is that abscissa draws each compound to NF- κ B signal access
Inhibiting effect curve graph finds out half effective percentage IC according to each compound to the inhibiting rate of access50, that is, inhibit signal path to reach
Drug concentration when 50%.
Embodiment 3: the toxicity test of Compound cellular
S1. cell culture.
In vitro culture RAW264.7 cell.Using contain 10% fetal calf serum, DMEM high glucose medium, at 37 DEG C, 5% 2
Conventional maintenance culture and passage are carried out under carbonoxide concentration conditions.
S2. compound intervention.
Logarithmic phase cell is collected, concentration of cell suspension is made into 1 × 105A/ml is added in 96 porocyte culture plates.In
After cultivating for 24 hours in carbon dioxide incubator, culture solution is changed into culture medium containing different compound concentrations, continuous culture 2 days,
In the 3rd day detection cytotoxicity.Untested compound is configured to using DMSO the solution of various concentration.Each concentration sets 3 and puts down
Row multiple holes, and set and be compared without the control group that compound is handled.
S3. test method.
Using the measurement of MTT [3- (4,5- dimethylthiazole -2) -2,5- diphenyltetrazolium bromide bromide] method through compound processing 6
Cell after it.A hole light absorption value (OD value) is measured using microplate reader (Detection wavelength 570nm, reference wavelength 630nm).
S4. result treatment.
Each drug is calculated to the growth inhibition ratio of RAW264.7 cell by following formula:
Using RAW264.7 inhibitory rate of cell growth as ordinate, it is that abscissa draws each chemical combination that compound concentration, which obtains log value,
The suppression curve figure that object grows cell finds out half toxic concentration CC according to each compound on intracellular inhibiting rate50, that is, inhibit
Drug concentration when cell growth is up to 50%.
Separately according to formula: selection inhibition constant (SI)=CC50/IC50The selection inhibition constant of each compound is calculated, to comment
The drug safety of each compound of valence.The selection inhibition constant of tetra- compounds of 1a, 1b, 1c and 1d the results are shown in Table 1.1a,1b,1c
FIG. 1 to FIG. 4 is shown in respectively to the toxicity test result of RAW264.7 cell with tetra- compounds of 1d.
Embodiment 4: osteoclast breaks up Inhibition test
S1. cell culture.
In vitro culture RAW264.7 cell.Using contain 10% fetal calf serum, DMEM high glucose medium, at 37 DEG C, 5% 2
Conventional maintenance culture and passage are carried out under carbonoxide concentration conditions.
S2. compound intervention.
Logarithmic phase cell is collected, concentration of cell suspension is made into 2 × 104A/mL is added in 96 porocyte culture plates.In
After cultivating for 24 hours in carbon dioxide incubator into, culture solution is changed to the training containing 100ng/ml RANKL and different compound concentrations
Base is supported, continuous culture 5 days is changed the culture medium of identical RANKL concentration and compound concentration for every 2 days, used in detection in the 5th day
TRAP decoration method dyes osteoclast.Each concentration sets 3 parallel multiple holes, and sets the control group handled without compound
It is compared.
S3. test method.
The osteoclast being differentiated to form is dyed using TRAP kit, Shuo≤3 Ji nuclear fusion it is osteoclastic
Cell number.
S4. result treatment.
Each drug is calculated by following formula, and inhibiting rate is broken up to the osteoclast that RANKL is induced:
Using osteoclast differentiation inhibiting rate as ordinate, the log value of compound concentration is that abscissa draws each compound pair
Osteoclast breaks up suppression curve figure and finds out half effective percentage IC according to the inhibiting rate that each compound breaks up osteoclast50,
Drug concentration when inhibiting osteoclast differentiation up to 50%.Wherein the osteoclast differentiation figure of 1o is shown in Figure 19
Separately according to formula: selection inhibition constant (SI)=CC50/IC50The selection inhibition constant of each compound is calculated, to comment
The drug safety of each compound of valence.The selection inhibition constant of tetra- compounds of 1a, 1b, 1c and 1d the results are shown in Table 1.1a,1b,1c
FIG. 1 to FIG. 4 is shown in respectively to the toxicity test result of host cell with tetra- compounds of 1d.
According to selectivity index SI=CC50/IC50Value, by the effect of the anti-osteoporosis differentiation of following standard evaluation compound
Fruit.SI < 1.0 show that compound is toxic invalid, and 1.0≤SI≤2.0 show the inefficient toxic i.e. weakly positive of compound, 2.0 < SI <
10.0 show that compound effectively low toxicity is i.e. positive, and SI >=10.0 show compound high-efficiency low-toxicity i.e. strong positive.
By the result of table 1 and Fig. 1~19 as it can be seen that the present invention breaks up Inhibition test by osteoclast, 4 compounds are found
There is different degrees of inhibiting effect to osteoclast differentiation, wherein 1o activity is best, therapeutic index highest, IC50It is 1.16, SI
For 328.29 (see Figure 15, table 1)；It secondly is 1q, IC50It is 6.36 (see Figure 17, table 1) for 3.94, SI；That activity is taken second place is 1p,
IC50It is 126.97 (see Figure 16, table 1) for 3.98, SI；Compound 1j, IC50It is 87.46 (see Figure 10, tables 1) for 4.00, SI；With
Other three compounds are compared, and 1c activity is poor, IC50It is 18.58 (see Fig. 3, table 1) for 11.43, SI.
The compound structure that 1 drug screening of table obtains and its inhibiting effect to osteoclast differentiation
The present invention has found a kind of thiazole amide derivatives by the method for Computer-Aided Drug Design similarity retrieval.And
Break up Inhibition test and cytotoxicity (MTT) experiment by osteoclast, find in such compound, 1o, 1p, 1q are to osteoclastic thin
Born of the same parents break up inhibitory activity and are respectively less than 10 μM, and cytotoxicity is small, and therapeutic index is high.1o breaks up 50 3nhibitory dose to osteoclast
(IC50) it is 1.16 μM, cell half lethal dose (CC50) it is 379.5 μM, select inhibition constant (SI) for 328.29 (table 1, figures
15)；1p breaks up 50 3nhibitory dose (IC to osteoclast50) it is 3.98 μM, cell half lethal dose (CC50) it is 505.6 μM,
Select inhibition constant (SI) for 126.97 (tables 1, Figure 16)；1q breaks up 50 3nhibitory dose (IC to osteoclast50) it is 3.98 μM,
Cell half lethal dose (CC50) it is 25.07 μM, select inhibition constant (SI) for 6.36 (tables 1, Figure 17)；1c is to osteoclast point
Change 50 3nhibitory dose (IC50) it is 11.43 μM, select inhibition constant (SI) for 18.58 (tables 1, Fig. 3).The result shows that suchization
The inhibitory activity that conjunction object breaks up osteoclast is high, cytotoxicity is small, can be used as a kind of osteoclast inhibitors and is used to prepare bone
Matter is loose or sclerotin reduces protective agents.
Claims (10)
1. thiazole heterocyclic carbamate derivatives prepare anti-osteoporosis, the application in Hyanalgese-D object, which is characterized in that institute
The structural formula for stating thiazole heterocyclic carbamate derivatives is as shown in the formula (I):
；
Wherein, R1It is miscellaneous for hydrogen, alkyl, hydroxyl, phenyl or substituted-phenyl, five yuan or hexa-atomic heteroaromatic, five yuan of substitution or hexa-atomic virtue
Ring；R2For hydrogen, alkyl, alkyl-substituted carbonyl or ester, phenyl or substituted-phenyl, five yuan or hexa-atomic heteroaromatic, replace five yuan
Or hexa-atomic heteroaromatic, cycloaliphatic ring, heterocycle, substituted aniline or phenol；R1、R2Can be cyclic, R3For hydrogen, halogen atom, alkoxy,
Alkylamino radical, hydroxyl, amino, cyano, nitro, carboxylic acid, alkyl-substituted carboxyl, amide or ester；R4For hydrogen, halogen atom, alcoxyl
Base, alkylamino radical, hydroxyl, amino, cyano, nitro, carboxylic acid, alkyl-substituted carboxyl, amide or ester；R5For hydrogen, halogen atom, alkane
Oxygroup, alkylamino radical, hydroxyl, amino, cyano, nitro, carboxylic acid, alkyl-substituted carboxyl, amide or ester；R4、R5It can cyclization；R6For
Hydrogen, alkyl, halogen atom, alkoxy, carboxylic acid, alkyl-substituted carboxyl, amide or ester, R5、R6Can be cyclic, R7It is former for hydrogen, halogen
Son, alkoxy, alkylamino radical, hydroxyl, amino, cyano, nitro, carboxylic acid, alkyl-substituted carboxyl, amide or ester.
2. thiazole heterocyclic carbamate derivatives are preparing anti-osteoporosis, in Hyanalgese-D object according to claim 1
Using, which is characterized in that R1For hydrogen, the alkyl of C1 ~ C6；R2For hydrogen, C1 ~ C6 alkyl, C1 ~ C6 unsaturated alkyl, phenyl or substitution
Phenyl, carboxylic acid and alkyl-substituted ester, alkyl-substituted aldehyde, alkyl-substituted ether.
3. thiazole heterocyclic carbamate derivatives are preparing anti-osteoporosis, in Hyanalgese-D object according to claim 1
Using, which is characterized in that R3It is taken for hydrogen, C1 ~ C6 alkyl, C1 ~ C6 alkoxy, halogen atom, hydroxyl, cyano, carboxylic acid and alkyl
The ester in generation, alkyl-substituted aldehyde, alkyl-substituted ether.
4. thiazole heterocyclic carbamate derivatives are preparing anti-osteoporosis, in Hyanalgese-D object according to claim 1
Using, which is characterized in that R4It is taken for hydrogen, C1 ~ C6 alkyl, C1 ~ C6 alkoxy, hydroxyl, cyano, halogen atom, carboxylic acid and alkyl
The ester in generation, alkyl-substituted aldehyde, alkyl-substituted ether.
5. thiazole heterocyclic carbamate derivatives are preparing anti-osteoporosis, in Hyanalgese-D object according to claim 4
Using, which is characterized in that R5For hydrogen, C1 ~ C6 alkyl, C1 ~ C6 alkoxy.
6. thiazole heterocyclic carbamate derivatives are preparing anti-osteoporosis, in Hyanalgese-D object according to claim 1
Using, which is characterized in that R6For hydrogen or methyl.
7. thiazole heterocyclic carbamate derivatives are preparing anti-osteoporosis, in Hyanalgese-D object according to claim 1
Using, which is characterized in that R1、R2Cyclization, R3、R4Cyclization, R4、R5Cyclization, cyclization are five yuan or hexa-atomic aromatic ring or non-aromatic ring.
8. the thiazole heterocyclic carbamate derivatives according to any one of claim 2 to 7 are preparing anti-osteoporosis, anti-bone pass
Save the application in scorching drug, which is characterized in that the carbon atom number in ester, aldehyde and ether is 1 ~ 6.
9. thiazole heterocyclic carbamate derivatives are preparing anti-osteoporosis, in Hyanalgese-D object according to claim 1
Using, which is characterized in that the structural formula of the thiazole heterocyclic carbamate derivatives is one of following structural formula:
。
10. application according to claim 1, which is characterized in that the drug includes pharmaceutically acceptable salt, carrier
And/or excipient.
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| CN117771226A (en) * | 2023-12-28 | 2024-03-29 | 山东博森医学工程技术有限公司 | Promoter for accelerating repair of osteoarthritis injury |
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| CN105228626A (en) * | 2013-03-15 | 2016-01-06 | 加州生物医学研究所 | For the Compounds and methods for that inducing cartilage is formed |
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| CN117771226A (en) * | 2023-12-28 | 2024-03-29 | 山东博森医学工程技术有限公司 | Promoter for accelerating repair of osteoarthritis injury |
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