WO2020258971A1 - 腙酰胺类衍生物及其在制备抗骨质疏松药物中的应用 - Google Patents

腙酰胺类衍生物及其在制备抗骨质疏松药物中的应用 Download PDF

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WO2020258971A1
WO2020258971A1 PCT/CN2020/083067 CN2020083067W WO2020258971A1 WO 2020258971 A1 WO2020258971 A1 WO 2020258971A1 CN 2020083067 W CN2020083067 W CN 2020083067W WO 2020258971 A1 WO2020258971 A1 WO 2020258971A1
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carboxy
compound
methyl
group
ring
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PCT/CN2020/083067
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French (fr)
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黄丹娥
赵超
顾琼
徐峻
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深圳市三启药物开发有限公司
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Priority to JP2021577960A priority Critical patent/JP7523480B2/ja
Priority to EP20831187.8A priority patent/EP3992184B1/en
Publication of WO2020258971A1 publication Critical patent/WO2020258971A1/zh
Priority to US17/562,040 priority patent/US20220153688A1/en

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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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    • C07C251/74—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
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    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
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    • 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
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    • 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
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    • 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
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Definitions

  • the present invention relates to the field of biomedicine. Specifically, the present invention relates to hydrazone amide derivatives and their application as osteoclast differentiation inhibitors in the preparation of anti-osteoporosis drugs.
  • Osteoprosis (Osteoprosis for short OP) is a systemic and systemic skeletal disease characterized by decreased bone mass and the destruction of the fine structure of bone tissue leading to increased bone fragility and increased fracture risk. The clinical manifestations and signs are mainly pain, followed by shortened body length, hunchback, fractures and respiratory disorders. Epidemiological research shows that among people over 50 years old, about 50% of women and 20% of men are at risk of fracture (Rachner, Khosla et al. 2011).
  • the imbalance of the ratio between osteoclasts and osteoblasts is the pathological basis of osteoporosis (Rachner, Khosla et al. 2011).
  • the relative increase in osteoclast differentiation or the relative decrease in osteoblast differentiation will cause bone loss and cause osteoporosis.
  • Reducing bone resorption and promoting bone synthesis are the main clinical treatments for osteoporosis.
  • Bone resorption inhibitors mainly include estrogen receptor modulators, such as tamoxifen, toremifene, droloxifene, raloxifene, azoxifene, apeledoxifene, eproflavones, etc., diphosphoric acid Esters/salts such as glycolic acid phosphonate, clodronate, pamidronate, halogen phosphate, allen phosphate, risedronate sodium, zoledron phosphate, ibandronate sodium, etc., and calcium reduction Vegetarian etc.
  • estrogen receptor modulators such as tamoxifen, toremifene, droloxifene, raloxifene, azoxifene, halifene, eproflavones, etc.
  • diphosphoric acid Esters/salts such as glycolic acid phosphonate, clodronate, pamidronate, halogen phosphate, allen phosphate, risedron
  • the drugs that promote bone synthesis mainly include Wnt signal regulators (AMG785, BHQ880), parathyroid hormone (PTH), calcium-sensitive receptor antagonists (such as: ATF936), and statins.
  • Wnt signal regulators AMG785, BHQ880
  • PTH parathyroid hormone
  • ATF936 calcium-sensitive receptor antagonists
  • statins preparations that both inhibit bone resorption and promote bone formation, such as Alfacalcidol, Calcitriol (Alfacalcidol, Calcitriol, RO-26-9228, ED-71) and so on.
  • Alfacalcidol Calcitriol
  • Calcitriol Alfacalcidol, Calcitriol, RO-26-9228, ED-71
  • the above-mentioned drugs can prevent the decline of bone density to a certain extent, they cannot significantly reduce the risk of atypical fractures, and there are different degrees of side effects, which have not yet met the requirements of anti-osteoporosis
  • Osteoclast is a terminally differentiated cell derived from the bone marrow macrophage cell line, and is the only cell known to have bone resorption.
  • Nuclear receptor activator of nuclear factor ligand (RANKL) is a transmembrane soluble protein necessary for osteoclasts to maintain their structure, function and survival.
  • RANK binds to its ligand, activates downstream NF- ⁇ B, Akt, mitogen activated protein kinase (MAPK), activates T cell nuclear receptor (NFAT), calcium ion channels, and calcium/calmodulin-dependent kinase signaling pathways, making Undifferentiated bone marrow macrophages differentiate into osteoclasts, which in turn causes osteoporosis (Boyle, Simonet et al. 2003). A large number of studies have confirmed that interference with the RANKL signaling pathway can inhibit osteoclast differentiation and produce anti-osteoporosis pharmacological effects (Kim and Kim 2016).
  • the present invention is based on the new target RANKL signaling pathway and discovered a new anti-osteoporosis drug to overcome the problem that the existing osteoporosis treatment drugs cannot reduce the risk of atypical fractures. Therefore, the present invention provides a new class of hydrazone amide derivatives and their application in the preparation of anti-osteoporosis drugs.
  • the present invention proposes compounds represented by formula (I), or stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrated compounds of formula (I) Substances, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • X and Y are each independently selected from C 1 -C 6 alkyl, hydroxyl, mercapto, amino, nitro or cyano, and the C 1 -C 6 alkyl, hydroxyl, mercapto, and amino are independently R 1 Or R 3 , said R 1 and R 3 are independently optionally hydrogen, cyano, nitro, alkoxy, alkylamino, hydroxyl, amino, fluorine, chlorine, bromine, linear alkyl, cycloalkane Group, cycloalkyl, alkenyl, five to ten membered heterocyclic ring, five to ten membered aromatic heterocyclic ring, benzene ring or R 1 together with Y or R 3 together with X to form a five to ten membered heterocyclic ring or five to ten membered aromatic heterocycle Ring, wherein the linear alkyl, cycloalkyl, alkenyl, five to ten membered heterocyclic ring, five to ten to
  • R 2 is a cyano group, a nitro group, an alkoxy group, an alkylamino group, a cycloalkyl group, a linear alkyl group, an alkenyl group, a five- to six-membered ring, a five- to six-membered aromatic heterocyclic ring, a benzene ring, wherein the straight Alkyl, cycloalkyl, alkenyl, five to six membered heterocyclic ring, five to six membered aromatic heterocyclic ring, and benzene ring are independently optionally substituted by R';
  • the R' is hydrogen, halo, C 1 ⁇ C 5 alkoxy, C 1 ⁇ C 5 alkyl, ester, nitro, hydroxyl, mercapto, carboxy, amino, cyano, alkynyl, trifluoromethyl Group, trifluoromethoxy.
  • X is a hydroxyl group or an amino group, and the X is substituted by R 3 ;
  • Y is a C 1 -C 4 alkyl group, a hydroxyl group, or an amino group, and the Y is substituted by R 1 .
  • R 1 is hydrogen or a C 1 -C 3 linear alkyl group.
  • R 2 is phenyl, 2-carboxyphenyl, 3-carboxyphenyl, 4-carboxyphenyl, 2-hydroxyphenyl, 2-methoxyphenyl, 2- Methylhydroxyphenyl, 2-aminophenyl, 2-amide phenyl, 2-methyl formate phenyl, 2-nitrophenyl, 2-cyanophenyl, 2,3-biscarboxyphenyl, 2 ,4-Biscarboxyphenyl, 2,6-biscarboxyphenyl, 2,5-biscarboxyphenyl, 2-carboxy-3methylphenyl, 2-carboxy-4-methylphenyl, 2-carboxy -5-methylphenyl, 2-carboxy-6-methylphenyl, 2-carboxy-3-fluorophenyl, 2-carboxy-4-fluorophenyl, 2-carboxy-5-fluorophenyl, 2 -Carboxy-6-fluorophenyl, 2-carboxy-3-hydroxyphen
  • R 3 is thiazole, 4-methylthiazole, 4-methyl-5-methyl thiazole, 4-methyl-5-methyl thiazole, 4-methyl-5-carboxylic acid thiazole , 4-methyl-5-formylmorpholine thiazole, 4-phenylthiazole, thiophene, imidazole, pyridine, 6-methyl pyridine, morpholine, 2-methylpyridine, 3-methylpyridine, 4-methyl Pyridine, 5-methylpyridine, 6-methylpyridine, 2-cyanopyridine, 3-cyanopyridine, 4-cyanopyridine, 5-cyanopyridine, 6-cyanopyridine, 2-nitropyridine , 3-nitropyridine, 4-nitropyridine, 5-nitropyridine, 6-nitropyridine, 2-hydroxypyridine, 3-hydroxypyridine, 4-hydroxypyridine, 5-hydroxypyridine, 6-hydroxypyridine, 2-methoxypyridine, 3-methoxypyridine, 4-methoxypyridine, 5-methoxypyridine, 6-methoxypyridine, 4-hydroisoquino
  • R 1 is hydrogen, a C 1 ⁇ C 4 alkyl group
  • R 2 is a benzene ring, a pyridine ring, a pyrimidine ring, or a pyrazine ring
  • R 3 is a five- to six-membered heterocyclic ring containing N or O , Five-membered aromatic heterocyclic ring contains N, O or S, six-membered aromatic heterocyclic ring contains 1 or 2 N, benzene ring, Or R 3 and X form a 5-10 membered heterocyclic ring containing N or O atoms.
  • R 1 is hydrogen;
  • R 2 is a benzene ring;
  • R 3 is a pyridine ring, a pyrimidine ring, a pyrazine ring, Or R 3 together with X to form
  • the compound does not include the compound represented by formula (1),
  • the present invention is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate of a compound having one of the following structures , Metabolite, pharmaceutically acceptable salt or its prodrug:
  • the compounds 3, 10, 12, 18 and 25 in the above structural formula have significant effects in terms of inhibitory activity and safety.
  • the present invention proposes a pharmaceutical composition. According to an embodiment of the present invention, it comprises the aforementioned compound.
  • the pharmaceutical composition further includes a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or any combination thereof.
  • the present invention proposes the use of the aforementioned compound or the aforementioned pharmaceutical composition in the preparation of a medicine for inhibiting osteoclast differentiation.
  • the present invention proposes the use of the aforementioned compound or the aforementioned pharmaceutical composition in the preparation of a kit for inhibiting osteoclast differentiation.
  • the present invention proposes the use of the aforementioned compound or the aforementioned pharmaceutical composition in the preparation of a medicine for the treatment or prevention of osteoporosis or osteopenia.
  • the present invention has the following advantages and effects:
  • the hydrazone amide derivatives provided by the present invention can inhibit osteoclast differentiation to a certain extent, and have good inhibitory activity and safety.
  • the hydrazone amide derivatives provided by the present invention are simple in structure and easy to synthesize; and the compounds have low toxicity and can be safely used to prepare medicines for the treatment and/or prevention of osteoporosis or osteopenia.
  • Figure 1 shows the inhibition curve of osteoclast differentiation by compound 1 and the cytotoxicity curve of RAW264.7.
  • Figure 2 is a graph showing the inhibition of osteoclast differentiation by compound 2 and a graph of RAW264.7 cytotoxicity.
  • Figure 3 is a graph of compound 3's inhibition of osteoclast differentiation and a graph of RAW264.7 cytotoxicity.
  • Figure 4 is a graph showing the inhibition of osteoclast differentiation by compound 4 and a graph of RAW264.7 cytotoxicity.
  • Figure 5 is a graph of compound 5's inhibition of osteoclast differentiation and a graph of RAW264.7 cytotoxicity.
  • Figure 6 is a graph showing the inhibition of osteoclast differentiation by compound 6 and a graph of RAW264.7 cytotoxicity.
  • Figure 7 is a graph showing the inhibition of osteoclast differentiation by compound 7 and a graph of RAW264.7 cytotoxicity.
  • Figure 8 is a graph showing the inhibition of osteoclast differentiation by compound 8 and a graph of RAW264.7 cytotoxicity.
  • Figure 9 is a graph of compound 9's inhibition of osteoclast differentiation and a graph of RAW264.7 cytotoxicity.
  • Figure 10 is a graph showing the inhibition of osteoclast differentiation by compound 10 and a graph of RAW264.7 cytotoxicity.
  • Figure 11 is a graph of compound 11's inhibition of osteoclast differentiation and a graph of RAW264.7 cytotoxicity.
  • Figure 12 is a graph showing the inhibition of osteoclast differentiation by compound 12 and a graph of RAW264.7 cytotoxicity.
  • Figure 13 is a graph showing the inhibition of osteoclast differentiation by compound 13 and a graph of RAW264.7 cytotoxicity.
  • Figure 14 is a graph showing the inhibition of osteoclast differentiation by compound 14 and a graph of RAW264.7 cytotoxicity.
  • Figure 15 is a graph showing the inhibition of osteoclast differentiation by compound 15 and a graph of RAW264.7 cytotoxicity.
  • Figure 16 is a graph showing the inhibition of osteoclast differentiation by compound 16 and a graph of RAW264.7 cytotoxicity.
  • Figure 17 shows the inhibition curve of osteoclast differentiation by compound 17 and the cytotoxicity curve of RAW264.7.
  • Figure 18 is a graph showing the inhibition of osteoclast differentiation by compound 18 and a graph of RAW264.7 cytotoxicity.
  • Figure 19 is a graph showing the inhibition of osteoclast differentiation by compound 19 and a graph of RAW264.7 cytotoxicity.
  • Figure 20 is a graph showing the inhibition of osteoclast differentiation by compound 20 and a graph of RAW264.7 cytotoxicity.
  • Figure 21 is a graph of compound 21's inhibition of osteoclast differentiation and a graph of RAW264.7 cytotoxicity.
  • Figure 22 is a graph showing the inhibition of osteoclast differentiation by compound 22 and a graph of RAW264.7 cytotoxicity.
  • Figure 23 is a graph showing the inhibition of osteoclast differentiation by compound 23 and a graph of RAW264.7 cytotoxicity.
  • Figure 24 is a graph showing the inhibition of osteoclast differentiation by compound 24 and a graph of RAW264.7 cytotoxicity.
  • Figure 25 is a graph showing the inhibition of osteoclast differentiation by compound 25 and a graph of RAW264.7 cytotoxicity.
  • Figure 26 is a graph showing the inhibition of osteoclast differentiation by compound 26 and a graph of RAW264.7 cytotoxicity.
  • Figure 27 shows the inhibition curve of osteoclast differentiation by compound 27 and the cytotoxicity curve of RAW264.7.
  • Figure 28 is a graph showing the inhibition of osteoclast differentiation by compound 28 and a graph of RAW264.7 cytotoxicity.
  • Figure 29 shows the inhibition curve of osteoclast differentiation by compound 29 and the cytotoxicity curve of RAW264.7.
  • Figure 30 is a graph showing the inhibition of osteoclast differentiation by compound 30 and a graph of RAW264.7 cytotoxicity.
  • Stereoisomers refer to compounds that have the same chemical structure but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
  • Chiral refers to a molecule that can not overlap with its mirror image; and “achiral” refers to a molecule that can overlap with its mirror image.
  • Enantiomers refer to two isomers of a compound that cannot be superimposed but are mirror images of each other.
  • Diastereoisomers refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting point, boiling point, spectral properties and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical operations such as electrophoresis and chromatography, such as HPLC.
  • optically active compounds that is, they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to one or more chiral centers.
  • the prefixes d and l or (+) and (-) are symbols used to specify the rotation of plane-polarized light caused by the compound, where (-) or l indicates that the compound is levorotatory.
  • Compounds prefixed with (+) or d are dextrorotatory.
  • a specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is called a racemic mixture or a racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
  • any asymmetric atom (for example, carbon, etc.) of the compound disclosed in the present invention can exist in a racemic or enantiomerically enriched form, such as (R)-, (S)- or (R,S)-configuration form exist.
  • each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess in the (R)- or (S)- configuration, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • the compounds of the present invention can be used as one of the possible isomers or their mixtures, such as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms).
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may have E or Z configuration; if the compound contains a disubstituted cycloalkyl, the substituent of the cycloalkyl may have a cis or trans configuration.
  • Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physical and chemical properties of the components, for example, by chromatography Method and/or fractional crystallization method.
  • racemate of any final product or intermediate obtained can be resolved into optical enantiomers by methods familiar to those skilled in the art by known methods, for example, by performing diastereomeric salts of the obtained Separate.
  • the racemic product can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • enantiomers can be prepared by asymmetric synthesis, for example, refer to Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert E.
  • tautomer or "tautomeric form” refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomers also called prototropic tautomers
  • keto-enol tautomerism include interconversion through the recombination of some bond-forming electrons.
  • keto-enol tautomerism are the tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerism is phenol-ketone tautomerism.
  • a specific example of phenol-ketone tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
  • C 1 -C 6 alkyl refers particularly to the disclosure independently methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • linking substituents are described.
  • the Markush variables listed for the group should be understood as the linking group.
  • the Markush group definition of the variable lists “alkyl” or “aryl” it should be understood that the “alkyl” or “aryl” respectively represents the attached Alkylene group or arylene group.
  • the compounds of the present invention can be optionally substituted by one or more substituents, such as the compounds of the general formula above, or the special examples, subclasses, and subclasses contained in the examples.
  • substituents such as the compounds of the general formula above, or the special examples, subclasses, and subclasses contained in the examples.
  • substituents such as the compounds of the general formula above, or the special examples, subclasses, and subclasses contained in the examples.
  • a class of compounds can be understood that the term “optionally substituted” and the term “substituted or unsubstituted” can be used interchangeably. Generally speaking, the term “optionally” whether or not preceded by the term “substituted” means that one or more hydrogen atoms in a given structure may be substituted or unsubstituted by a specific substituent. Unless otherwise indicated, an optional substituent group may have a substituent at each substitutable position of the group. When more than one position
  • alkyl as used in the present invention includes saturated linear or branched monovalent hydrocarbon groups of 1-20 carbon atoms, wherein the alkyl groups can be independently optionally substituted with one or more substituents described in the present invention.
  • the alkyl group contains 1-10 carbon atoms, in other embodiments, the alkyl group contains 1-8 carbon atoms, and in other embodiments, the alkyl group contains 1-6 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), 2-methylpropyl or isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), 1-methylpropyl or sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu , -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-
  • amino refers to -NH 2 .
  • alkoxy refers to an alkyl group, as defined in the present invention, connected to the main carbon chain through an oxygen atom.
  • alkyl group as defined in the present invention, connected to the main carbon chain through an oxygen atom.
  • examples include, but are not limited to, methoxy, ethoxy, propoxy and the like.
  • cycloalkyl refers to a monovalent or multivalent saturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms.
  • the bicyclic or tricyclic ring system may include fused rings, bridged rings, and spiro rings.
  • the cycloalkyl group contains 3-10 carbon atoms; in another embodiment, the cycloalkyl group contains 3-8 carbon atoms; in another embodiment, the cycloalkyl group contains 3-6 carbon atoms. carbon atom.
  • Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • the cycloalkyl group is optionally substituted with one or more substituents described in this invention.
  • aryl means a monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, at least one of which is aromatic of.
  • the aryl group is usually, but not necessarily, connected to the parent molecule through the aromatic ring of the aryl group.
  • aryl can be used interchangeably with the term “aromatic ring”. Examples of aryl groups may include phenyl, naphthyl, and anthracene.
  • the aryl group is optionally substituted with one or more substituents described in the present invention.
  • aromatic heterocyclic ring means a monocyclic, bicyclic and tricyclic ring system containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, at least one of which is aromatic, And at least one ring contains one or more heteroatoms.
  • the aromatic heterocyclic group is usually, but not necessarily, connected to the parent molecule through the aromatic ring of the aromatic heterocyclic group.
  • heteroaryl can be used interchangeably with the terms “heteroaromatic ring", “aromatic heterocycle” or “heteroaromatic compound”.
  • the heteroaryl group is optionally substituted with one or more substituents described in the present invention.
  • the 5-10 atom heteroaryl group contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.
  • heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-thi
  • the ring system formed by the substituent R'connected to the central ring by a bond represents that the substituent R'can be substituted at any substitutable or any reasonable position on the ring.
  • formula a represents that any position on the B'ring that may be substituted can be substituted by R', as shown in formula b, formula c and formula d.
  • each R 7 can be the same or different, and they are mutually expressing The specific items may also be the same or different; the specific options of each n1 may be the same or different, and the specific items expressed between each other may also be the same or different; for example, in formula (I), each R 2
  • the specific options of R 3 or R 4 may be the same or different, and the specific items expressed by R 2 , R 3 and R 4 may also be the same or different.
  • pharmaceutically acceptable refers to molecular entities and compositions that are physiologically tolerable when administered to humans and generally do not produce allergies or similar inappropriate reactions, such as gastrointestinal upset, dizziness, and the like.
  • pharmaceutically acceptable refers to those approved by a federal regulatory agency or a national government or listed in the US Pharmacopeia or other generally recognized pharmacopoeia for use in animals, more particularly in humans.
  • carrier refers to a diluent, adjuvant, excipient or base with which the compound is administered.
  • These pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like.
  • Water and aqueous solutions Saline solutions and aqueous dextrose and glycerol solutions are preferably used as carriers, especially injectable solutions. Suitable drug carriers are described in "Remington's Pharmaceutical Sciences” by E.W. Martin.
  • “Hydrate” in the present invention refers to the compound or its salt provided by the present invention, which also includes water bound by non-covalent intermolecular forces in chemical or non-chemical quantities. It can also be said that solvent molecules are formed by water. Associate.
  • solvate of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention.
  • Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • N-oxide in the present invention means that when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide.
  • N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms.
  • the corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or peracid (such as peroxycarboxylic acid) to form N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).
  • N-oxides can be prepared by the method of LWDeady (Syn. Comm. 1977, 7, 509-514), in which, for example, the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA) in an inert solvent such as methylene chloride .
  • MCPBA m-chloroperoxybenzoic acid
  • prodrug represents the conversion of a compound into a compound represented by formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the enzymatic conversion of the prodrug into the maternal structure in the blood or tissue.
  • the prodrug compounds of the present invention can be esters.
  • esters can be used as prodrugs including phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, and carbonates. , Carbamates and amino acid esters.
  • a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug.
  • prodrug forms include phosphate esters.
  • these phosphate ester compounds are obtained by phosphorylation of the parent hydroxyl group.
  • T. Higuchi and V. Stella Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J.
  • the structural formulas of the compounds described in the present invention include enriched isotopes of one or more different atoms.
  • the present invention includes isotopically-labeled compounds, which are equivalent to the compounds described in formula (I), but one or more of the atoms are replaced by atoms whose atomic mass or mass number is different from the common atomic mass or mass number in nature.
  • isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • the compounds of the present invention containing the above isotopes and/or other isotopes of other atoms, their prodrugs, and the compounds or pharmaceutically acceptable salts of the prodrugs all fall within the scope of the present invention.
  • the isotope-labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared in this way.
  • easily available isotope-labeled reagents are used instead Non-isotopically labeled reagents.
  • Metal refers to the product obtained by the metabolism of a specific compound or its salt in the body.
  • the metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by experimental methods as described in the present invention. Such products can be obtained by oxidizing, reducing, hydrolyzing, acylating, deamidating, esterifying, degreasing, enzymatic cleavage and the like of the administered compound.
  • the present invention includes the metabolites of the compound, including the metabolites produced by fully contacting the compound of the present invention with a mammal for a period of time.
  • compositions can be prepared by the active ingredient and a pharmaceutically acceptable carrier.
  • the "pharmaceutically acceptable salt” used in the present invention refers to the organic and inorganic salts of the compound of the present invention.
  • Pharmaceutically acceptable salts are well known to us in the field, as described in the literature: S.M. Berge et al., describe pharmaceutical acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19, 1977.
  • non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups include hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, Nitrate, etc., and organic acid salts such as acetate, propionate, glycolate, oxalate, maleate, malonate, succinate, fumarate, tartrate, citric acid Salt, benzoate, mandelate, methanesulfonate, ethanesulfonate, tosylate, sulfosalicylate, etc., or obtained by other methods described in books and literature such as ion exchange These salts.
  • salts include adipate, malate, 2-hydroxypropionic acid, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, Borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate Salt, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate , Laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, Pectinate, persul
  • the present invention also contemplates the quaternary ammonium salt formed by any compound containing the N group.
  • Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium salt, lithium salt, potassium salt, calcium salt, magnesium salt, iron salt, zinc salt, copper salt, manganese salt, aluminum salt and the like.
  • Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts, and amine cations that resist counterion formation, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, and C 1 -8 Sulfonates and aromatic sulfonates.
  • Amine salts such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methyl reduced glucose Amine, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidine-1'-ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine And tris(hydroxymethyl)aminomethane; alkaline earth metal salts such as but not limited to barium, calcium and magnesium; transition metal salts such as but not limited to zinc.
  • alkaline earth metal salts such as but not limited to barium, calcium and magnesium
  • transition metal salts such as but not limited to zinc.
  • One of the objectives of the present invention is to provide new compounds with significant osteoclast inhibitory activity.
  • the second objective of the present invention is to provide a new compound that can significantly treat or prevent osteoporosis or osteopenia.
  • the third object of the present invention is to provide a method for preparing the osteoclast inhibitory compound.
  • the fourth object of the present invention is to provide the application of the compound in the treatment or prevention of osteoporosis or osteopenia.
  • the compound provided by the present invention has significant osteoclast-inhibiting activity, and can be used as a lead compound for treating or preventing osteoporosis or osteopenia.
  • the present invention will be further described below with reference to specific embodiments and drawings, but the embodiments do not limit the present invention in any form.
  • the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the technical field.
  • Example 1 According to the method described in Example 1, 186 mg of ethyl 2-amino-4-methylthiazole-5-carboxylate, 206 mg of DCC, 10 mg of DMAP, and 102 mg of 3-oxobutyric acid were reacted together to obtain 200 mg Ethyl-4-methyl-2-acetoacetylthiazolamide-5-carboxylate with a yield of 74%.
  • Example 1 According to Example 1, 186 mg of ethyl 2-amino-4-methylthiazole-5-carboxylate, 206 mg of DCC, 10 mg of DMAP and 102 mg of 3-oxobutyric acid were reacted together to obtain 200 mg of Ethyl-4-methyl-2-acetoacetylthiazolamide-5-carboxylate, the yield is 74%.
  • Example 1 According to Example 1, 186 mg of ethyl 2-amino-4-methylthiazole-5-carboxylate, 206 mg of DCC, 10 mg of DMAP and 102 mg of 3-oxobutyric acid were reacted together to obtain 200 mg of Ethyl-4-methyl-2 acetoacetylthiazolamide-5-carboxylate, the yield is 74%.
  • Example 1 According to Example 1, 186 mg of ethyl 2-amino-4-methylthiazole-5-carboxylate, 206 mg of DCC, 10 mg of DMAP and 102 mg of 3-oxobutyric acid were reacted together to obtain 200 mg of Ethyl-4-methyl-2-acetoacetylthiazolamide-5-carboxylate, the yield is 74%.
  • Example 1 According to Example 1, 186 mg of ethyl 2-amino-4-methylthiazole-5-carboxylate, 206 mg of DCC, 10 mg of DMAP and 102 mg of 3-oxobutyric acid were reacted together to obtain 200 mg of Ethyl-4-methyl-2-acetoacetylthiazolamide-5-carboxylate, the yield is 74%.
  • Example 1 According to Example 1, 186 mg of ethyl 2-amino-4-methylthiazole-5-carboxylate, 206 mg of DCC, 10 mg of DMAP and 102 mg of 3-oxobutyric acid were reacted together to obtain 200 mg of Ethyl-4-methyl-2-acetoacetylthiazolamide-5-carboxylate, the yield is 74%.
  • Example 1 186 mg of ethyl 2-amino-4-methylthiazole-5-carboxylate, 206 mg of DCC, 10 mg of DMAP, and 102 mg of 3-oxobutyric acid were reacted together to obtain 200 mg Ethyl-4-methyl-2-acetoacetylthiazolamide-5-carboxylate with a yield of 74%.
  • Example 1 According to the method described in Example 1, 186 mg of ethyl 2-amino-4-methylthiazole-5-carboxylate, 206 mg of DCC, 10 mg of DMAP, and 102 mg of 3-oxobutyric acid were reacted together to obtain 200 mg Ethyl-4-methyl-2-acetoacetylthiazolamide-5-carboxylate with a yield of 74%.
  • Example 1 According to Example 1, 186 mg of ethyl 2-amino-4-methylthiazole-5-carboxylate, 206 mg of DCC, 10 mg of DMAP and 102 mg of 3-oxobutyric acid were reacted together to obtain 200 mg of Ethyl-4-methyl-2-acetoacetylthiazolamide-5-carboxylate, the yield is 74%.
  • Example 1 According to the method described in Example 1, 186 mg of ethyl 2-amino-4-methylthiazole-5-carboxylate, 206 mg of DCC, 10 mg of DMAP, and 102 mg of 3-oxobutyric acid were reacted together to obtain 200 mg Ethyl-4-methyl-2-acetoacetylthiazolamide-5-carboxylate with a yield of 74%.
  • 186 mg of ethyl 2-amino-4-methylthiazole-5-carboxylate, 206 mg of DCC, 10 mg of DMAP, and 102 mg of 3-oxobutyric acid are reacted together to obtain 200 mg of ethyl -4-Methyl-2-acetoacetylthiazolamide-5-carboxylate, the yield is 74%.
  • 186 mg of ethyl 2-amino-4-methylthiazole-5-carboxylate, 206 mg of DCC, 10 mg of DMAP, and 102 mg of 3-oxobutyric acid are reacted together to obtain 200 mg of ethyl -4-Methyl-2-acetoacetylthiazolamide-5-carboxylate, the yield is 74%.
  • Example 1 According to the method described in Example 1, 186 mg of ethyl 2-amino-4-methylthiazole-5-carboxylate, 206 mg of DCC, 10 mg of DMAP, and 102 mg of 3-oxobutyric acid were reacted together to obtain 200 mg Ethyl-4-methyl-2-acetoacetylthiazolamide-5-carboxylate with a yield of 74%.
  • Example 1 According to the method described in Example 1, 186 mg of ethyl 2-amino-4-methylthiazole-5-carboxylate, 206 mg of DCC, 10 mg of DMAP, and 102 mg of 3-oxobutyric acid were reacted together to obtain 200 mg Ethyl-4-methyl-2-acetoacetylthiazolamide-5-carboxylate with a yield of 74%.
  • Example 1 According to Example 1, 186 mg of ethyl 2-amino-4-methylthiazole-5-carboxylate, 206 mg of DCC, 10 mg of DMAP and 102 mg of 3-oxobutyric acid were reacted together to obtain 200 mg of Ethyl-4-methyl-2-acetoacetylthiazolamide-5-carboxylate, the yield is 74%.
  • Example 1 According to the method described in Example 1, 186 mg of ethyl 2-amino-4-methylthiazole-5-carboxylate, 206 mg of DCC, 10 mg of DMAP, and 102 mg of 3-oxobutyric acid were reacted together to obtain 200 mg Ethyl-4-methyl-2-acetoacetylthiazolamide-5-carboxylate with a yield of 74%.
  • Example 1 According to the method described in Example 1, 186 mg of ethyl 2-amino-4-methylthiazole-5-carboxylate, 206 mg of DCC, 10 mg of DMAP, and 102 mg of 3-oxobutyric acid were reacted together to obtain 200 mg Ethyl-4-methyl-2-acetoacetylthiazolamide-5-carboxylate with a yield of 74%.
  • Example 1 According to the method described in Example 1, 186 mg of ethyl 2-amino-4-methylthiazole-5-carboxylate, 206 mg of DCC, 10 mg of DMAP, and 102 mg of 3-oxobutyric acid were reacted together to obtain 200 mg Ethyl-4-methyl-2-acetoacetylthiazolamide-5-carboxylate with a yield of 74%.
  • Example 1 According to the method described in Example 1, 186 mg of ethyl 2-amino-4-methylthiazole-5-carboxylate, 206 mg of DCC, 10 mg of DMAP, and 102 mg of 3-oxobutyric acid were reacted together to obtain 200 mg Ethyl-4-methyl-2-acetoacetylthiazolamide-5-carboxylate with a yield of 74%.
  • Example 1 According to the method described in Example 1, 186 mg of ethyl 2-amino-4-methylthiazole-5-carboxylate, 206 mg of DCC, 10 mg of DMAP, and 102 mg of 3-oxobutyric acid were reacted together to obtain 200 mg Ethyl-4-methyl-2-acetoacetylthiazolamide-5-carboxylate with a yield of 74%.
  • Example 1 100 mg of 2-amino-thiazole, 206 mg of DCC, 10 mg of DMAP, and 102 mg of 3-oxobutyric acid were reacted together to obtain 139 mg of 2-acetoacetylthiazolamide, with a yield of 76% .
  • Example 1 According to the method described in Example 1, 88 mg of morpholine, 206 mg of DCC, 10 mg of DMAP, and 102 mg of 3-oxobutyric acid were reacted together to obtain 106 mg of acetoacetylmorpholinamide with a yield of 63%.
  • Collect the log phase cells adjust the cell suspension concentration to 1 ⁇ 10 5 cells/mL, and add them to a 96-well cell culture plate. After culturing in a carbon dioxide incubator for 24 hours, the culture medium was changed to a medium containing different compound concentrations, and the culture was continued for 2 days, and the cytotoxicity was detected on the third day.
  • the MTT [3-(4,5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide] method was used to determine the cells treated with the compound for 6 days. Use a microplate reader (detection wavelength 570nm, reference wavelength 630nm) to determine the absorbance value (OD value) of each hole.
  • the RAW264.7 cell growth inhibition rate is used on the ordinate and the compound concentration to obtain the log value as the abscissa to plot the inhibition curve of each compound on cell growth. According to the inhibition rate of each compound on the cell, the half-toxic concentration CC 50 is calculated, which is the cell inhibition The concentration of the drug when the growth reaches 50%.
  • Inhibition constants selected (SI) CC 50 / IC 50 calculated inhibition constants of each compound selected to evaluate the safety of each drug compound. The results of selection inhibition constants for all compounds are shown in Table 1.
  • Collect log phase cells adjust the cell suspension concentration to 2 ⁇ 10 4 cells/ml, and add them to a 96-well cell culture plate. After culturing in a carbon dioxide incubator for 24 hours, the culture medium was changed to a medium containing 100ng/ml RANKL and different compound concentrations. The culture was continued for 5 days, and the medium with the same RANKL concentration and compound concentration was replaced every 2 days. Day detection uses TRAP staining method to stain osteoclasts. Set up 3 parallel replicate holes for each concentration, and set up a control group without compound treatment for comparison.
  • TRAP kit to stain the differentiated osteoclasts and count the number of osteoclasts with ⁇ 3 nuclei fusion.
  • the osteoclast differentiation inhibition rate is used on the ordinate, and the log value of the compound concentration is plotted on the abscissa to plot the inhibition curve of each compound on osteoclast differentiation. According to the inhibition rate of each compound on osteoclast differentiation, the half effective rate IC 50 is calculated , That is, the concentration of the drug that inhibits osteoclast differentiation up to 50%.
  • Inhibition constants selected (SI) CC 50 / IC 50 calculated inhibition constants of each compound selected to evaluate the safety of each drug compound.
  • SI ⁇ 1.0 indicates that the compound is toxic and ineffective
  • 1.0 ⁇ SI ⁇ 2.0 indicates that the compound is inefficient and toxic, that is, weakly positive
  • 2.0 ⁇ SI ⁇ 10.0 indicates that the compound is effective and low-toxic, that is, positive
  • SI ⁇ 10.0 indicates that the compound is highly effective and low-toxic, that is, strong positive.
  • Table 1 The structure of the compound obtained by drug screening and its inhibitory effect on osteoclast differentiation
  • the invention finds a class of thiazolamide derivatives through a computer-aided drug design similarity search method. And through osteoclast differentiation inhibition experiments and cytotoxicity (MTT) experiments, it was found that among these compounds, 3, 10, 12, 18 and 25 had less than 0.5 ⁇ M osteoclast differentiation inhibitory activity, low cytotoxicity and high therapeutic index .
  • MTT cytotoxicity
  • Compound 3 has an inhibitory amount (IC 50 ) of osteoclast differentiation of 0.05 ⁇ M, a cell half-lethal dose (CC 50 ) of 81.24 ⁇ M, and a selective inhibition constant (SI) of 1625 (see Figure 1, Table 1); Compound 12
  • the inhibitory dose of osteoclast differentiation (IC 50 ) was 0.23 ⁇ M
  • the cell half-lethal dose (CC 50 ) was 391.2 ⁇ M
  • the selective inhibition constant (SI) was 1701 (see Figure 2, Table 1);
  • the half-differentiation inhibitor (IC 50 ) is 0.27 ⁇ M
  • the cell half-lethal dose (CC 50 ) is 81.24 ⁇ M
  • the selective inhibition constant (SI) is 301 (see Figure 3, Table 1); compound 10 inhibits osteoclast differentiation by half
  • the dose (IC 50 ) is 0.40 ⁇ M
  • the cell half-lethal dose (CC 50 ) is 123.3 ⁇ M

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Abstract

本发明提供了一类全新的腙酰胺类衍生物及其在制备抗骨质疏松药物中的应用，所述腙酰胺类衍生物的结构式如式(I)所示，是一类全新的具有抗骨质疏松效果的化合物。

Description

腙酰胺类衍生物及其在制备抗骨质疏松药物中的应用 技术领域
本发明涉及生物医药领域，具体地，本发明涉及腙酰胺类衍生物及其作为破骨细胞分化抑制剂在制备抗骨质疏松药物中的应用。
背景技术
骨质疏松症(Osteoprosis简称OP)是以骨量减少，骨组织微细结构破坏导致骨脆性增加和骨折危险性增加为特征的一种系统性、全身性骨骼疾病。临床表现和体征主要是疼痛，其次为身长缩短、驼背、骨折及呼吸系统障碍。流行病学调研显示，50岁以上的人群中，约有50％的女性和20％的男性有骨折的风险(Rachner,Khosla et al.2011)。
破骨细胞(Osteoclast)和成骨细胞(Osteoblast)之间的比例失衡是骨质疏松产生的病理基础(Rachner,Khosla et al.2011)。破骨细胞分化相对增多或成骨细胞分化相对减少，都会造成骨量流失，引起骨质疏松。降低骨吸收、促进骨合成是当前临床上治疗骨质疏松的主要治疗手段。骨吸收抑制剂主要有雌激素受体调控剂，如他莫昔芬，托瑞米芬，屈洛昔芬，雷洛昔芬，阿佐昔芬，巴多昔芬，依普黄酮等、双磷酸酯/盐类如乙醇酸膦酸盐，氯膦酸盐，帕米膦酸，卤素磷酸盐，磷酸艾伦，利塞膦酸钠，磷酸唑来膦，伊班膦酸钠等、以及降钙素等。促进骨合成药物主要有Wnt信号调控剂(AMG785,BHQ880)、甲状旁腺激素Parathyroid hormone(PTH)、钙敏感受体拮抗剂(如：ATF936)，和他汀类药物。还有既抑制骨吸收又促成骨的制剂，如阿法骨化醇，骨化三醇(Alfacalcidol,Calcitriol,RO-26-9228,ED-71)等。然而，上述药物虽然能在一定程度上阻止骨密度下降，但不能显著降低非典型性骨折的风险，而且存在着不同程度的副作用，尚未能满足抗骨质疏松治疗的要求(Siris,Selby et al.2009)。因此，目前迫切需要开发一种新的抗骨质疏松的特效药，以解决当前临床用药无法满足治疗需求的问题。
破骨细胞是来源于骨髓巨噬细胞系的一种末分化细胞，是目前所知唯一具有骨吸收作用的细胞。核受体活化因子配体(Receptor activator of nuclear factor kappa B ligand,RANKL)是破骨细胞维持其结构、功能和存活所必需的一种跨膜的可溶性蛋白。RANK与其配体结合，激活下游NF-κB、Akt，丝裂原激活蛋白激酶(MAPK)，激活T细胞核受体(NFAT)，钙离子通道，和钙/钙调蛋白依赖性激酶信号通路，使得未分化的骨髓巨噬细胞向破骨细胞分化，进而引起骨质疏松(Boyle,Simonet et al.2003)。大量的研究证实，干扰RANKL信号通路可抑制破骨细胞分化，产生抗骨质疏松的药理作用(Kim and Kim 2016)。近年来，通过干 扰RANKL信号通路研发新型抗骨质疏松药物成为热点。寻找具有抑制由RANKL诱导产生的破骨细胞抑制活性的药物，将有望解决当前骨质疏松治疗药物存在的问题。
发明内容
针对于现有技术的不足，本发明基于新靶标RANKL信号通路，发现了新的抗骨质疏松药物，以克服现有骨质疏松治疗药物不能降低非典型性骨折的风险的问题。因此，本发明提供一类新的腙酰胺类衍生物，及其在制备抗骨质疏松药物中的应用。
在本发明的第一方面，本发明提出了式(I)所示化合物，或式(I)所示化合物的立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，药学上可接受的盐或前药，
Figure PCTCN2020083067-appb-000001
其中，X、Y分别独立地选自C 1～C 6烷基、羟基、巯基、氨基、硝基或氰基，所述C 1～C 6烷基、羟基、巯基、氨基独立地被R 1或R 3所取代，所述R 1和R 3独立任选地为氢、氰基、硝基、烷氧基、烷氨基、羟基、氨基、氟、氯、溴、直链烷基、环烷基、环烷基、烯基、五～十元杂环、五～十元芳杂环、苯环或R 1连同Y或R 3连同X形成五～十元杂环或五～十元芳杂环，其中，所述直链烷基、环烷基、烯基、五～十元杂环、五～十元芳杂环、苯环独立任选地被R’所取代；
R 2为氰基、硝基、烷氧基、烷氨基、环烷基、直链烷基、烯基、五～六元环、五～六元芳杂环、苯环，其中，所述直链烷基、环烷基、烯基、五～六元杂环、五～六元芳杂环、苯环独立任选地被R’所取代；
所述R’为氢、卤基、C 1～C 5烷氧基、C 1～C 5烷基、酯基、硝基、羟基、巯基，羧基、氨基、氰基、炔基、三氟甲基、三氟甲氧基。
根据本发明的实施例，X为羟基或氨基，所述X被R 3所取代；Y为C 1～C 4烷基、羟基、氨基，所述Y被R 1所取代。
根据本发明的实施例，R 1为氢或C 1～C 3的直链烷基。
根据本发明的实施例，R 2为苯基，2-羧酸苯基，3-羧酸苯基，4-羧酸苯基，2-羟基苯基，2-甲氧基苯基，2-甲基羟基苯基，2-氨基苯基，2-酰胺苯基，2-甲酸甲酯苯基， 2-硝基苯基，2-氰基苯基，2,3-双羧基苯基，2,4-双羧基苯基，2,6-双羧基苯基，2,5-双羧基苯基，2-羧基-3甲基苯基，2-羧基-4-甲基苯基，2-羧基-5-甲基苯基，2-羧基-6-甲基苯基，2-羧基-3-氟苯基，2-羧基-4-氟苯基，2-羧基-5-氟苯基，2-羧基-6-氟苯基，2-羧基-3-羟基苯基，2-羧基-4-羟基苯基，2-羧基-5-羟基苯基，2-羧基-6-羟基苯基，2-羧基-3-氨基苯基，2-羧基-4-氨基苯基，2-羧基-5-氨基苯基，2-羧基-6-氨基苯基，2-羧基-6-三氟甲基苯基，2-羧基-3-三氟甲基苯基，2-羧基-4-三氟甲基苯基，2-羧基-5-三氟甲基苯基，2-羧基-6-三氟甲基苯基，2-羧基-6-甲氧基苯基，2-羧基-3-甲氧基苯基，2-羧基-4-甲氧基苯基，2-羧基-5-甲氧基苯基，2-羧基-6-甲氧基苯基，2-羧基-3-氯苯基，2-羧基-4-氯苯基，2-羧基-5-氯苯基，2-羧基-6-氯苯基，2-羧基-3-氰基苯基，2-羧基-4-氰基苯基，2-羧基-5-氰基苯基，2-羧基-6-氰基苯基，2-羧基-3-硝基苯基，2-羧基-4-硝基苯基，2-羧基-5-硝基苯基，2-羧基-6-硝基苯基。
根据本发明的实施例，R 3为噻唑，4-甲基噻唑，4甲基-5-甲酸乙酯噻唑，4甲基-5-甲酸甲酯噻唑，4-甲基-5-羧酸噻唑，4甲基-5-甲酰吗啉噻唑，4-苯基噻唑，噻吩，咪唑，吡啶，6-甲酸甲酯吡啶，吗啉，2-甲基吡啶，3-甲基吡啶，4-甲基吡啶，5-甲基吡啶，6-甲基吡啶，2-氰基吡啶，3-氰基吡啶，4-氰基吡啶，5-氰基吡啶，6-氰基吡啶，2-硝基吡啶，3-硝基吡啶，4-硝基吡啶，5-硝基吡啶，6-硝基吡啶，2-羟基吡啶，3-羟基吡啶，4-羟基吡啶，5-羟基吡啶，6-羟基吡啶，2-甲氧基吡啶，3-甲氧基吡啶，4-甲氧基吡啶，5-甲氧基吡啶，6-甲氧基吡啶，4-氢异喹啉，苯环，苯并噻唑。
根据本发明的实施例，R 1为氢、C 1～C 4的烷基；R 2为苯环、吡啶环、嘧啶环、吡嗪环；R 3为五～六元杂环包含N或O、五元芳杂环包含N、O或S，六元芳杂环包含1或2个N，苯环、
Figure PCTCN2020083067-appb-000002
或R 3连同X形成5～10元杂环包含N原子或O原子。
根据本发明的实施例，R 1为氢；R 2为苯环；R 3为吡啶环、嘧啶环、吡嗪环、
Figure PCTCN2020083067-appb-000003
或R 3连同X形成
Figure PCTCN2020083067-appb-000004
根据本发明的实施例，所述化合物不包括式(1)所示化合物，
Figure PCTCN2020083067-appb-000005
根据本发明的实施例，其为具有下列之一结构的化合物或具有下列之一结构的化合物的立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，药学上可接受的盐或它的前药：
Figure PCTCN2020083067-appb-000006
作为一种更优选方案，以上结构式中的化合物3、10、12、18和25无论在抑制活性上或者安全性上均具备显著的效果。
在本发明的第二方面，本发明提出了一种药物组合物。根据本发明的实施例，其包含前面所述的化合物。
根据本发明的实施例，所述药物组合物进一步包括药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物或它们的任意组合。
在本发明的第三方面，本发明提出了前面所述的化合物或前面所述的药物组合物在制备药物中的用途，所述药物用于抑制破骨细胞分化。
在本发明的第四方面，本发明提出了前面所述的化合物或前面所述的药物组合物在制备试剂盒中的用途，所述试剂盒用于抑制破骨细胞分化。
在本发明的第五方面，本发明提出了前面所述的化合物或前面所述的药物组合物在制备药物中的用途，所述药物用于治疗或预防骨质疏松或骨质减少。
相对于现有技术，本发明具有如下的优点及效果：
本发明提供的腙酰胺类衍生物均能一定程度上抑制破骨细胞分化，抑制活性和安全性较好。本发明提供的腙酰胺类衍生物结构简单、易合成；而且此类化合物毒性小，可安全用于制备治疗和/或预防骨质疏松或骨量减少的药物。
附图说明
图1为化合物1对破骨细胞分化抑制曲线图和RAW264.7细胞毒性曲线图。
图2为化合物2对破骨细胞分化抑制曲线图和RAW264.7细胞毒性曲线图。
图3为化合物3对破骨细胞分化抑制曲线图和RAW264.7细胞毒性曲线图。
图4为化合物4对破骨细胞分化抑制曲线图和RAW264.7细胞毒性曲线图。
图5为化合物5对破骨细胞分化抑制曲线图和RAW264.7细胞毒性曲线图。
图6为化合物6对破骨细胞分化抑制曲线图和RAW264.7细胞毒性曲线图。
图7为化合物7对破骨细胞分化抑制曲线图和RAW264.7细胞毒性曲线图。
图8为化合物8对破骨细胞分化抑制曲线图和RAW264.7细胞毒性曲线图。
图9为化合物9对破骨细胞分化抑制曲线图和RAW264.7细胞毒性曲线图。
图10为化合物10对破骨细胞分化抑制曲线图和RAW264.7细胞毒性曲线图。
图11为化合物11对破骨细胞分化抑制曲线图和RAW264.7细胞毒性曲线图。
图12为化合物12对破骨细胞分化抑制曲线图和RAW264.7细胞毒性曲线图。
图13为化合物13对破骨细胞分化抑制曲线图和RAW264.7细胞毒性曲线图。
图14为化合物14对破骨细胞分化抑制曲线图和RAW264.7细胞毒性曲线图。
图15为化合物15对破骨细胞分化抑制曲线图和RAW264.7细胞毒性曲线图。
图16为化合物16对破骨细胞分化抑制曲线图和RAW264.7细胞毒性曲线图。
图17为化合物17对破骨细胞分化抑制曲线图和RAW264.7细胞毒性曲线图。
图18为化合物18对破骨细胞分化抑制曲线图和RAW264.7细胞毒性曲线图。
图19为化合物19对破骨细胞分化抑制曲线图和RAW264.7细胞毒性曲线图。
图20为化合物20对破骨细胞分化抑制曲线图和RAW264.7细胞毒性曲线图。
图21为化合物21对破骨细胞分化抑制曲线图和RAW264.7细胞毒性曲线图。
图22为化合物22对破骨细胞分化抑制曲线图和RAW264.7细胞毒性曲线图。
图23为化合物23对破骨细胞分化抑制曲线图和RAW264.7细胞毒性曲线图。
图24为化合物24对破骨细胞分化抑制曲线图和RAW264.7细胞毒性曲线图。
图25为化合物25对破骨细胞分化抑制曲线图和RAW264.7细胞毒性曲线图。
图26为化合物26对破骨细胞分化抑制曲线图和RAW264.7细胞毒性曲线图。
图27为化合物27对破骨细胞分化抑制曲线图和RAW264.7细胞毒性曲线图。
图28为化合物28对破骨细胞分化抑制曲线图和RAW264.7细胞毒性曲线图。
图29为化合物29对破骨细胞分化抑制曲线图和RAW264.7细胞毒性曲线图。
图30为化合物30对破骨细胞分化抑制曲线图和RAW264.7细胞毒性曲线图。
发明详细描述
下面详细描述本发明的实施例，所述实施例的示例在附图中示出。下面通过参考附图描述的实施例是示例性的，旨在用于解释本发明，而不能理解为对本发明的限制。
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体，等等。
“手性”是具有与其镜像不能重叠性质的分子；而“非手性”是指与其镜像可以重叠的分子。
“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。
“非对映异构体”是指有两个或多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质，如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱，例如HPLC来分离。
本发明所使用的立体化学定义和规则一般遵循S.P.Parker，Ed.，McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company，New York；and Eliel，E.and Wilen，S.，“Stereochemistry of Organic Compounds”，John Wiley&Sons，Inc.，New York，1994。
许多有机化合物以光学活性形式存在，即它们具有使平面偏振光的平面发生旋转的能力。在描述光学活性化合物时，使用前缀D和L或R和S来表示分子关于其一个或多个手性中心的绝对构型。前缀d和l或(+)和(-)是用于指定化合物所致平面偏振光旋转的符号，其中(-)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。一种具体 的立体异构体是对映异构体，这种异构体的混合物称作对映异构体混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或过程中没有立体选择性或立体特异性时，可出现这种情况。
本发明公开化合物的任何不对称原子(例如，碳等)都可以以外消旋或对映体富集的形式存在，例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中，各不对称原子在(R)-或(S)-构型方面具有至少50％对映体过量，至少60％对映体过量，至少70％对映体过量，至少80％对映体过量，至少90％对映体过量，至少95％对映体过量，或至少99％对映体过量。
依据起始物料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物，例如外消旋体和非对映异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备，或使用常规技术拆分。如果化合物含有一个双键，取代基可能为E或Z构型；如果化合物中含有二取代的环烷基，环烷基的取代基可能有顺式或反式构型。
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。
可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体，如，通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离，如，使用手性吸附剂的高效液相色谱(HPLC)。特别地，对映异构体可以通过不对称合成制备，例如，可参考Jacques,et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2 nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本 发明的范围之内。
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C 1-C 6烷基”特别指独立公开的甲基、乙基、C 3烷基、C 4烷基、C 5烷基和C 6烷基。
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
像本发明所描述的，本发明的化合物可以任选地被一个或多个取代基所取代，如上面的通式化合物，或者像实施例里面特殊的例子，子类，和本发明所包含的一类化合物。应了解“任选取代的”这个术语与“取代或非取代的”这个术语可以交换使用。一般而言，术语“任选地”不论是否位于术语“取代的”之前，表示所给结构中的一个或多个氢原子可以被具体取代基所取代或不取代。除非其他方面表明，一个任选的取代基团可以有一个取代基在基团的各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。
本发明使用的术语“烷基”包括1-20个碳原子饱和直链或支链的单价烃基，其中烷基可以独立任选地被一个或多个本发明所描述的取代基所取代。其中一些实施例是，烷基基团含有1-10个碳原子，另外一些实施例是，烷基基团含有1-8个碳原子，另外一些实施例是，烷基基团含有1-6个碳原子，另外一些实施例是，烷基基团含有1-4个碳原子，另外一些实施例是，烷基基团含有1-3个碳原子，另外一些实施例是，烷基基团含有2-6个碳原子。烷基基团更进一步的实例包括，但并不限于，甲基(Me，-CH 3)，乙基(Et，-CH 2CH 3)，正丙基(n-Pr，-CH 2CH 2CH 3)，异丙基(i-Pr，-CH(CH 3) 2)，正丁基(n-Bu，-CH 2CH 2CH 2CH 3)，2-甲基丙基或异丁基(i-Bu，-CH 2CH(CH 3) 2)，1-甲基丙基或仲丁基(s-Bu，-CH(CH 3)CH 2CH 3)，叔丁基(t-Bu，-C(CH 3) 3)，正戊基(-CH 2CH 2CH 2CH 2CH 3)，2-戊基(-CH(CH 3)CH 2CH 2CH 3)，3-戊基(-CH(CH 2CH 3) 2)，2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)，3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)，3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)，2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)，正己基(-CH 2CH 2CH 2CH 2CH 2CH 3)，2-己基(-CH(CH 3)CH 2CH 2CH 2CH 3)，3-己基(-CH(CH 2CH 3)(CH 2CH 2CH 3))，2-甲基-2-戊基(-C(CH 3) 2CH 2CH 2CH 3)，3-甲基-2-戊基(-CH(CH 3)CH(CH 3)CH 2CH 3)，4-甲基-2-戊基(-CH(CH 3)CH 2CH(CH 3) 2)，3-甲基-3-戊基(-C(CH 3)(CH 2CH 3) 2)，2-甲基-3-戊基(-CH(CH 2CH 3)CH(CH 3) 2)，2,3-二甲基-2-丁基(-C(CH 3) 2CH(CH 3) 2)，3,3-二甲基-2-丁基(-CH(CH 3)C(CH 3) 3) ，正庚基，正辛基，等等。术语“烷基”和其前缀“烷”在此处使用，都包含直链和支链的饱和碳链。
术语“氨基”是指-NH 2。
本发明中所使用的术语“烷氧基”，涉及到烷基，像本发明所定义的，通过氧原子连接到主要的碳链上。这样的实施例包括，但并不限于，甲氧基，乙氧基，丙氧基等等。
术语“环烷基”表示含有3-12个碳原子的，单价或多价的饱和单环，双环或三环体系。双环或三环体系可以包括稠环、桥环和螺环。在一实施方案中，环烷基包含3-10个碳原子；在另一实施方案中，环烷基包含3-8个碳原子；在又一实施方案中，环烷基包含3-6个碳原子。环烷基基团的实例包括，但不限于，环丙基、环丁基、环戊基、环己基，等等。所述环烷基基团任选地被一个或多个本发明所描述的取代基所取代。
术语“芳基”表示含有6-14个环原子，或6-12个环原子，或6-10个环原子的单环、双环和三环的碳环体系，其中至少有一个环是芳香族的。芳基基团通常，但不必须地通过芳基基团的芳香性环与母体分子连接。术语“芳基”可以和术语“芳环”交换使用。芳基基团的实例可以包括苯基、萘基和蒽。所述芳基基团任选地被一个或多个本发明所描述的取代基所取代。
术语“芳杂环”表示含有5-12个环原子，或5-10个环原子，或5-6个环原子的单环、双环和三环体系，其中至少有一个环是芳香族的，且至少一个环包含一个或多个杂原子。芳杂环基团通常，但不必须地通过芳杂环基团的芳香性环与母体分子连接。术语“杂芳基”可以与术语“杂芳环”，“芳杂环”或“杂芳族化合物”交换使用。所述杂芳基基团任选地被一个或多个本发明所描述的取代基所取代。在一实施方案中，5-10个原子组成的杂芳基包含1，2，3或4个独立选自O，S和N的杂原子。
杂芳基基团的实例包括，但并不限于，2-呋喃基、3-呋喃基、N-咪唑基、2-咪唑基、4-咪唑基、5-咪唑基、3-异噁唑基、4-异噁唑基、5-异噁唑基、2-噁唑基、4-噁唑基、5-噁唑基、N-吡咯基、2-吡咯基、3-吡咯基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基、哒嗪基(如3-哒嗪基)、2-噻唑基、4-噻唑基、5-噻唑基、四唑基(如5-四唑基)、三唑基(如2-三唑基和5-三唑基)、2-噻吩基、3-噻吩基、吡唑基(如2-吡唑基)、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基；也包括以下的双环，但绝不限于这些双环：苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基(如2-吲哚基)、嘌呤基、喹啉基(如2-喹啉基，3-喹啉基，4-喹啉基)、异喹啉基(如1-异喹啉基、3-异喹啉基或4-异喹啉基)、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基，等等。
如本发明所描述，取代基R’由一个键连接到中心的环上形成的环体系代表取代基R’可 以在该环上任何可取代或任何合理的位置进行取代。例如，式a代表B’环上任何可能被取代的位置均可被R’取代，如式b，式c和式d所示。
Figure PCTCN2020083067-appb-000007
另外，需要说明的是，除非以其他方式明确指出，在本文中通篇采用的描述方式“各…和…独立地为”、“…和…各自独立地为”和“…和…分别独立地为”可以互换，应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。例如，“-(C(R 7) 2) n1-NR 8-(C(R 7) 2) n1-”中每个R 7的具体选项可以相同，也可以不同，且相互之间所表达的具体项也可以一样或不一样；每个n1的具体选项可以相同，也可以不同，且相互之间所表达的具体项也可以一样或不一样；又例如，式(I)中，各个R 2、R 3或R 4的具体选项可以相同，也可以不同，且R 2、R 3和R 4相互之间所表达的具体项也可以一样或不一样。
术语“药学上可接受的”是指当给人施用时生理上可耐受的并且一般不产生过敏或相似不适当的反应，例如肠胃不适、眩晕等的分子实体和组合物。优选地，本文所用的术语“药学上可接受的”是指联邦监管机构或国家政府批准的或美国药典或其他一般认可的药典上列举的在动物中、更特别在人体中使用的。
术语“载体”指与所述化合物一同施用的稀释剂、辅剂、赋形剂或基质。这些药物载体可以是无菌液体，例如水和油类，包括石油、动物、植物或合成来源的，例如花生油、大豆油、矿物油、芝麻油等。水和水性溶液盐水溶液和水性葡萄糖与甘油溶液优选用作载体、特别是可注射溶液。适宜的药物载体描述于E.W.Martin的“Remington′s Pharmaceutical Sciences”中。
本发明的“水合物”是指本发明所提供的化合物或其盐，其还包括化学量或非化学当量通过非共价分子间力结合的水，也可说是溶剂分子是水所形成的缔合物。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸，氨基乙醇。
本发明的“氮氧化物”是指当化合物含几个胺官能团时，可将1个或大于1个的氮原子氧化形成N-氧化物。N-氧化物的特殊实例是叔胺的N-氧化物或含氮杂环氮原子的N-氧化物。可用氧化剂例如过氧化氢或过酸(例如过氧羧酸)处理相应的胺形成N-氧化物(参见Advanced Organic Chemistry,Wiley Interscience,第4版,Jerry March,pages)。尤其是，N-氧化物可用L.W.Deady的方法制备(Syn.Comm.1977,7,509-514)，其中例如在惰性溶剂例如 二氯甲烷中，使胺化合物与间氯过氧苯甲酸(MCPBA)反应。
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C 1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14 of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51，2328-2345。
除非其他方面表明，本发明的化合物的所有互变异构形式都包含在本发明的范围之内。
另外，除非其他方面表明，本发明所描述的化合物的结构式包括一个或多个不同的原子的富集同位素。本发明包括同位素标记的化合物，它们等同于式(I)所述的化合物，但其中一个或多个原子被原子质量或质量数不同于自然界常见的原子质量或质量数的原子所代替。可以引入本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，分别例如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。含有上述同位素和/或其它原子的其它同位素的本发明化合物、其前体药物和所述化合物或所述前体药物的药学上可接受的盐都属于本发明的范围。同位素标记的本发明式(I)所示化合物及其前体药物一般可以这样制备，在进行下述流程和/或实施例与制备例所公开的工艺时，用容易得到的同位素标记的试剂代替非同位素标记的试剂。
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
本发明化合物的各种药学上可接受的盐形式都是有用的。术语“药学上可接受的盐”是指那些盐形式对于制药化学家而言是显而易见的，即它们基本上无毒并能提供所需的药代动力学性质、适口性、吸收、分布、代谢或排泄。其他因素，在性质上更加实用，对于选择也很重要，这些是：原材料的成本、结晶的容易、产率、稳定性、吸湿性和结果原料药的 流动性。简单地讲，药物组合物可以通过有效成分与药学上可接受的载体制备得到。
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,66:1-19,1977.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，硝酸盐等，和有机酸盐如乙酸盐，丙酸盐，乙醇酸盐，草酸盐，马来酸盐，丙二酸盐，琥珀酸盐，富马酸盐，酒石酸盐，枸橼酸盐，苯甲酸盐，扁桃酸盐，甲磺酸盐，乙磺酸盐，甲苯磺酸盐，磺基水杨酸盐等，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。
其他药学上可接受的盐包括己二酸盐、苹果酸盐、2-羟基丙酸、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、环戊基丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、反丁烯二酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖醛酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐、等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N +(C 1-4烷基) 4的盐。
本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠盐、锂盐、钾盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C 1-8磺酸化物和芳香磺酸化物。胺盐，例如但不限于N,N’-二苄基乙二胺，氯普鲁卡因，胆碱，氨，二乙醇胺和其它羟烷基胺，乙二胺，N-甲基还原葡糖胺，普鲁卡因，N-苄基苯乙胺，1-对-氯苄基-2-吡咯烷-1’-基甲基-苯并咪唑，二乙胺和其它烷基胺，哌嗪和三(羟甲基)氨基甲烷；碱土金属盐，例如但不限于钡，钙和镁；过渡金属盐，例如但不限于锌。
在本说明书中，如果在化学名称和化学结构间存在任何差异，结构是占优的。
本发明所使用的任何氨基酸和其它化合物的缩写，除非另有说明，都以它们通常使用的、公认的缩写为准，或参照IUPAC-IUBCommission on Biochemical Nomenclature(参见Biochem.1972，11：942-944)。
本发明的目的之一在于提供新的具有显著破骨细胞抑制活性的化合物。
本发明的目的之二在于提供新的具有显著治疗或预防骨质疏松或骨质减少的化合物。
本发明的目的之三在于提供所述破骨细胞抑制化合物的制备方法。
本发明的目的之四在于提供所述化合物在治疗或预防骨质疏松或骨质减少中的应用。
本发明提供的化合物具有显著的抑制破骨细胞活性，可作为治疗或预防骨质疏松或骨质减少的先导化合物。
以下结合具体实施例和附图来进一步说明本发明，但实施例并不对本发明做任何形式的限定。除非特别说明，本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
除非特别说明，本发明所用试剂和材料均为市购。
以下实施例所需要合成的化合物如下所示。
Figure PCTCN2020083067-appb-000008
实施例1 腙酰胺类衍生物的合成
Figure PCTCN2020083067-appb-000009
腙酰胺类衍生物的合成路线如上所示。含有取代的乙酰乙酸、二环己基碳二亚胺(DCC)、4-二甲氨基吡啶(DMAP)以及含有取代的醇或氨加入到二氯甲烷中，室温条件 下搅拌8h。使用旋转蒸发仪将溶剂除去，通过柱层析纯化得到相应的乙酰乙酰胺或乙酰乙酸酯。
含不同取代的氨加入到甲醇中，加入等量的盐酸和亚硝酸钠，室温搅拌0.5小时，随后加入含取代的乙酰乙酰胺或乙酰乙酸酯，室温搅拌10小时，过滤得到所需的腙酰胺类衍生物。
实施例2 化合物1的合成
根据实施例1方法所述，186毫克的2-氨基-4-甲基噻唑-5-羧酸乙酯、206毫克DCC、10毫克DMAP以及102毫克的3-氧丁酸共同反应，得到200毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯，产率74％。
135毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯、0.5毫升1M盐酸、34毫克亚硝酸钠及70毫克2-氨基苯甲酸共同反应，得到150毫克的化合物1，产率72％。
实施例3 化合物2的合成
根据实施例1所述，186毫克的2-氨基-4-甲基噻唑-5-羧酸乙酯、206毫克DCC、10毫克DMAP以及102毫克的3-氧丁酸共同反应，得到200毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯，产率74％。
135毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯、0.5毫升1M盐酸、34毫克亚硝酸钠及70毫克4-氨基苯甲酸共同反应，得到160毫克的化合物2，产率77％。
实施例4 化合物3的合成
根据实施例1所述，186毫克的2-氨基-4-甲基噻唑-5-羧酸乙酯、206毫克DCC、10毫克DMAP以及102毫克的3-氧丁酸共同反应，得到200毫克的乙基-4-甲基-2乙酰乙酰噻唑胺-5-甲酸酯，产率74％。
135毫克的乙基-4-甲基-2乙酰乙酰噻唑胺-5-甲酸酯、0.5毫升1M盐酸、34毫克亚硝酸钠及70毫克3-氨基苯甲酸共同反应，得到141毫克的化合物3，产率67％。
实施例5 化合物4的合成
根据实施例1所述，186毫克的2-氨基-4-甲基噻唑-5-羧酸乙酯、206毫克DCC、10毫克DMAP以及102毫克的3-氧丁酸共同反应，得到200毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯，产率74％。
135毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯、0.5毫升1M盐酸、34毫克亚硝酸钠及75毫克2-氨基苯甲酸甲酯共同反应，得到187毫克的化合物4，产率86％。
实施例6 化合物5的合成
根据实施例1所述，186毫克的2-氨基-4-甲基噻唑-5-羧酸乙酯、206毫克DCC、10毫克DMAP以及102毫克的3-氧丁酸共同反应，得到200毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯，产率74％。
135毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯、0.5毫升1M盐酸、34毫克亚硝酸钠及54毫克2-氨基苯酚共同反应，得到103毫克的化合物5，产率53％。
实施例7 化合物6的合成
根据实施例1所述，186毫克的2-氨基-4-甲基噻唑-5-羧酸乙酯、206毫克DCC、10毫克DMAP以及102毫克的3-氧丁酸共同反应，得到200毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯，产率74％。
135毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯、0.5毫升1M盐酸、34毫克亚硝酸钠及62毫克2-氨基苯甲醇共同反应，得到155毫克的化合物6，产率77％。
实施例8 化合物7的合成
根据是实施例1所述，186毫克的2-氨基-4-甲基噻唑-5-羧酸乙酯、206毫克DCC、10毫克DMAP以及102毫克的3-氧丁酸共同反应，得到200毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯，产率74％。
135毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯、0.5毫升1M盐酸、34毫克亚硝酸钠及76毫克2-氨基-3-甲基-苯甲酸共同反应，得到124毫克的化合物7，产率57％。
实施例9 化合物8的合成
根据实施例1方法所述，186毫克的2-氨基-4-甲基噻唑-5-羧酸乙酯、206毫克DCC、10毫克DMAP以及102毫克的3-氧丁酸共同反应，得到200毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯，产率74％。
135毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯、0.5毫升1M盐酸、34毫克亚硝酸钠及76毫克2-氨基-4-甲基-苯甲酸共同反应，得到132毫克的化合物8，产率61％。
实施例10 化合物9的合成
根据实施例1所述，186毫克的2-氨基-4-甲基噻唑-5-羧酸乙酯、206毫克DCC、10毫克DMAP以及102毫克的3-氧丁酸共同反应，得到200毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯，产率74％。
135毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯、0.5毫升1M盐酸、34毫克亚硝酸钠及76毫克2-氨基-5-甲基-苯甲酸共同反应，得到105毫克的化合物9，产率49％。
实施例11 化合物10的合成
根据实施例1方法所述，186毫克的2-氨基-4-甲基噻唑-5-羧酸乙酯、206毫克DCC、10毫克DMAP以及102毫克的3-氧丁酸共同反应，得到200毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯，产率74％。
135毫克的乙基-4-甲基--2乙酰乙酰噻唑胺-5-甲酸酯、0.5毫升1M盐酸、34毫克亚硝酸钠及77毫克2-氨基-5-氟-苯甲酸共同反应，得到108毫克的化合物10，产率50％。
实施例12 化合物11的合成
根据方法所述，186毫克的2-氨基-4-甲基噻唑-5-羧酸乙酯、206毫克DCC、10毫克DMAP以及102毫克的3-氧丁酸共同反应，得到200毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯，产率74％。
135毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯、0.5毫升1M盐酸、34毫克亚硝酸钠及77毫克2-氨基-4-氟-苯甲酸共同反应，得到136毫克的化合物11，产率62％。
实施例13 化合物12的合成
根据方法所述，186毫克的2-氨基-4-甲基噻唑-5-羧酸乙酯、206毫克DCC、10毫克DMAP以及102毫克的3-氧丁酸共同反应，得到200毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯，产率74％。
135毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯、0.5毫升1M盐酸、34毫克亚硝酸钠及81毫克2-氨基-3-氰基-苯甲酸共同反应，得到92毫克的化合物12，产率41％。
实施例14 化合物13的合成
根据实施例1方法所述，186毫克的2-氨基-4-甲基噻唑-5-羧酸乙酯、206毫克DCC、10毫克DMAP以及102毫克的3-氧丁酸共同反应，得到200毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯，产率74％。
135毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯、0.5毫升1M盐酸、34毫克亚硝酸钠及76毫克2-氨基-4-氰基-苯甲酸共同反应，得到172毫克的化合物13，产率78％。
实施例15 化合物14的合成
根据实施例1方法所述，186毫克的2-氨基-4-甲基噻唑-5-羧酸乙酯、206毫克DCC、10毫克DMAP以及102毫克的3-氧丁酸共同反应，得到200毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯，产率74％。
135毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯、0.5毫升1M盐酸、34毫克亚硝酸钠及91毫克2-氨基-5-硝基-苯甲酸共同反应，得到167毫克的化合物14，产率72％。
实施例16 化合物15的合成
根据实施例1所述，186毫克的2-氨基-4-甲基噻唑-5-羧酸乙酯、206毫克DCC、10毫克DMAP以及102毫克的3-氧丁酸共同反应，得到200毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯，产率74％。
135毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯、0.5毫升1M盐酸、34毫克亚硝酸钠及85毫克2-氨基-5-氯-苯甲酸共同反应，得到179毫克的化合物15，产率79％。
实施例17 化合物16的合成
根据实施例1方法所述，186毫克的2-氨基-4-甲基噻唑-5-羧酸乙酯、206毫克DCC、10毫克DMAP以及102毫克的3-氧丁酸共同反应，得到200毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯，产率74％。
135毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯、0.5毫升1M盐酸、34毫克亚硝酸钠及70毫克4-氨基-5-羧酸-吡啶共同反应，得到164毫克的化合物16，产率79％。
实施例18 化合物17的合成
根据实施例1方法所述，186毫克的2-氨基-4-甲基噻唑-5-羧酸乙酯、206毫克DCC、10毫克DMAP以及102毫克的3-氧丁酸共同反应，得到200毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯，产率74％。
135毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯、0.5毫升1M盐酸、34毫克亚硝酸钠及76毫克4-氨基-5-羟基-苯甲酸共同反应，得到133毫克的化合物17，产率61％。
实施例19 化合物18的合成
根据实施例1方法所述，186毫克的2-氨基-4-甲基噻唑-5-羧酸乙酯、206毫克DCC、10毫克DMAP以及102毫克的3-氧丁酸共同反应，得到200毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯，产率74％。
135毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯、0.5毫升1M盐酸、34毫克亚硝酸钠及91毫克2-氨基-间苯二甲酸共同反应，得到111毫克的化合物18，产率48％。
实施例20 化合物19的合成
根据实施例1方法所述，186毫克的2-氨基-4-甲基噻唑-5-羧酸乙酯、206毫克DCC、10毫克DMAP以及102毫克的3-氧丁酸共同反应，得到200毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯，产率74％。
135毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯、0.5毫升1M盐酸、34毫克亚硝酸钠及91毫克2-氨基-对苯二甲酸共同反应，得到141毫克的化合物19，产率61％。
实施例21 化合物20的合成
根据实施例1方法所述，186毫克的2-氨基-4-甲基噻唑-5-羧酸乙酯、206毫克DCC、10毫克DMAP以及102毫克的3-氧丁酸共同反应，得到200毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯，产率74％。
135毫克的乙基-4-甲基-2-乙酰乙酰噻唑胺-5-甲酸酯、0.5毫升1M盐酸、34毫克亚硝酸钠及76毫克2，5-二氨基-苯甲酸共同反应，得到130毫克的化合物20，产率62％。
实施例22 化合物21的合成
根据实施例1方法所述，114毫克的2-氨基-4-甲基噻唑、206毫克DCC、10毫克DMAP以及102毫克的3-氧丁酸共同反应，得到185毫克的4-甲基-2-乙酰乙酰噻唑胺，产率93％。
100毫克的4-甲基-2-乙酰乙酰噻唑胺、0.5毫升1M盐酸、34毫克亚硝酸钠及70毫克2-氨基-苯甲酸共同反应，得到102毫克的化合物21，产率59％。
实施例23 化合物22的合成
根据实施例1所述，100毫克的2-氨基-噻唑、206毫克DCC、10毫克DMAP以及102毫克的3-氧丁酸共同反应，得到139毫克的2-乙酰乙酰噻唑胺，产率76％。
91毫克的2-乙酰乙酰噻唑胺、0.5毫升1M盐酸、34毫克亚硝酸钠及70毫克2-氨基-苯甲酸共同反应，得到102毫克的化合物22，产率59％。
实施例24 化合物23的合成
根据实施例1方法所述，150毫克的2-氨基-苯并噻唑、206毫克DCC、10毫克DMAP以及102毫克的3-氧丁酸共同反应，得到158毫克的2-乙酰乙酰苯并噻唑胺，产率68％。
116毫克的2-乙酰乙酰苯并噻唑胺、0.5毫升1M盐酸、34毫克亚硝酸钠及70毫克2-氨基-苯甲酸共同反应，得到117毫克的化合物23，产率61％。
实施例25 化合物24的合成
根据实施例1方法所述，92毫克的苯胺、206毫克DCC、10毫克DMAP以及102毫克的3-氧丁酸共同反应，得到125毫克的2-乙酰乙酰苯胺，产率71％。
88毫克的2-乙酰乙酰苯胺、0.5毫升1M盐酸、34毫克亚硝酸钠及70毫克2-氨基-苯甲酸共同反应，得到97毫克的化合物24，产率59％。
实施例26 化合物25的合成
根据实施例1方法所述，93毫克的2-氨基-吡啶、206毫克DCC、10毫克DMAP以及102毫克的3-氧丁酸共同反应，得到104毫克的2-乙酰乙酰吡啶胺，产率59％。
88毫克的2-乙酰乙酰吡啶胺、0.5毫升1M盐酸、34毫克亚硝酸钠及70毫克2-氨基-苯甲酸共同反应，得到85毫克的化合物25，产率52％。
实施例27 化合物26的合成
根据实施例1方法所述，99毫克的4-氨基-哌啶、206毫克DCC、10毫克DMAP以及102毫克的3-氧丁酸共同反应，得到128毫克的3-氧-N-哌啶-4丁酰胺，产率70％。
91毫克的3-氧-N-哌啶-4丁酰胺、0.5毫升1M盐酸、34毫克亚硝酸钠及70毫克2-氨基-苯甲酸共同反应，得到75毫克的化合物26，产率45％。
实施例28 化合物27的合成
根据实施例1方法所述，133毫克的四氢异喹啉、206毫克DCC、10毫克DMAP以及102毫克的3-氧丁酸共同反应，得到129毫克的1-四氢异喹啉丁基-1,3-二酮，产率60％。
108毫克的1-四氢异喹啉丁基-1,3-二酮、0.5毫升1M盐酸、34毫克亚硝酸钠及70毫克2-氨基-苯甲酸共同反应，得到86毫克的化合物27，产率47％。
实施例29 化合物28的合成
根据实施例1方法所述，88毫克的吗啉、206毫克DCC、10毫克DMAP以及102毫克的3-氧丁酸共同反应，得到106毫克的乙酰乙酰吗啉胺，产率63％。
85毫克的乙酰乙酰吗啉胺、0.5毫升1M盐酸、34毫克亚硝酸钠及70毫克2-氨基-苯甲酸共同反应，得到89毫克的化合物28，产率56％。
实施例30 化合物29的合成
根据实施例1方法所述，119毫克的2-氨基-5-氰基-吡啶、206毫克DCC、10毫克DMAP以及102毫克的3-氧丁酸共同反应，得到137毫克的5-氰基吡啶-2-乙酰乙酰胺，产率67％。
101毫克的5-氰基吡啶-2-乙酰乙酰胺、0.5毫升1M盐酸、34毫克亚硝酸钠及70毫克2-氨基-苯甲酸共同反应，得到88毫克的化合物29，产率50％。
实施例31 化合物30的合成
根据方法所述，110毫克的2-氨基-6-羟基-吡啶、206毫克DCC、10毫克DMAP以及102毫克的3-氧丁酸共同反应，得到160毫克的6-羟基吡啶-2-乙酰乙酰胺，产率83％。
96毫克的6-羟基吡啶-2-乙酰乙酰胺、0.5毫升1M盐酸、34毫克亚硝酸钠及70毫克2-氨基-苯甲酸共同反应，得到106毫克的化合物30，产率62％。
实施例32 化合物细胞的毒性测定
S1.细胞培养
体外培养RAW264.7细胞。使用含有10％胎牛血清，DMEM高糖培养基，在37℃，5％二氧化碳浓度条件下进行常规维持培养和传代。
S2.化合物干预
收集对数期细胞，将细胞悬液浓度配成1×10 5个/mL，加入96孔细胞培养板中。于二氧化碳培养箱中培养24h后，将培养液换成含有不同化合物浓度的培养基，连续培养2天，于第3天检测细胞毒性。使用DMSO将待测化合物配置为不同浓度的溶液。每个浓度设3个平行复孔，并设不经化合物处理的对照组进行比较。
S3.测试方法
采用MTT[3-(4，5-二甲基噻唑-2)-2，5-二苯基四氮唑溴盐]法测定经化合物处理6天之后的细胞。应用酶标仪(检测波长570nm，参考波长630nm)测定个孔吸光值(OD值)。
S4.结果处理。
按下面的公式计算各个药物对RAW264.7细胞的生长抑制率：
Figure PCTCN2020083067-appb-000010
以RAW264.7细胞生长抑制率为纵坐标，化合物浓度得log值为横坐标绘制各化合物对细胞生长的抑制曲线图，根据各化合物对细胞抑制率，求出半数毒性浓度CC 50，即抑制细胞生长达50％时药物浓度。
另按照公式：选择抑制常数(SI)＝CC 50/IC 50计算各化合物的选择抑制常数，以评价各化合物的用药安全性。所有化合物的选择抑制常数结果见表1。
实施例33 破骨细胞分化抑制实验
S1.细胞培养
体外培养RAW264.7细胞。使用含有10％胎牛血清，DMEM高糖培养基，在37℃，5％二氧化碳浓度条件下进行常规维持培养和传代。
S2.化合物干预
收集对数期细胞，将细胞悬液浓度配成2×10 4个/ml，加入96孔细胞培养板中。于二氧化碳培养箱中培养24h后，将培养液换成含有100ng/ml RANKL及不同化合物浓度的培养基，连续培养5天，每2天换上相同RANKL浓度和化合物浓度的培养基，于第5天检测采用TRAP染色法对破骨细胞进行染色。每个浓度设3个平行复孔，并设不经化合物处理的对照组进行比较。
S3.测试方法
采用TRAP试剂盒对分化形成的破骨细胞进行染色，计数≧3个细胞核融合的破骨细胞数目。
S4.结果处理
按下面的公式计算各药物对RANKL诱导的破骨细胞分化抑制率：
Figure PCTCN2020083067-appb-000011
以破骨细胞分化抑制率为纵坐标，化合物浓度的log值为横坐标绘制各化合物对破骨细胞分化抑制曲线图，根据各化合物对破骨细胞分化的抑制率，求出半数有效率IC 50，即抑制破骨细胞分化达50％时药物浓度。
另按照公式：选择抑制常数(SI)＝CC 50/IC 50计算各化合物的选择抑制常数，以评价各化合物的用药安全性。
根据选择性指数SI＝CC 50/IC 50值，按以下标准评价化合物的抗骨质疏松分化的效果。SI<1.0表明化合物有毒无效，1.0≤SI≤2.0表明化合物低效有毒即弱阳性，2.0<SI<10.0表明化合物有效低毒即阳性，SI≥10.0表明化合物高效低毒即强阳性。
由表1的结果可见，本发明通过破骨细胞分化抑制实验，发现5个化合物对破骨细胞分化均有不同程度的抑制作用，其中化合物3活性最好，治疗指数最高，IC 50为0.05μM，SI为1625(见图1，表1)；其次为化合物12，IC 50为0.23μM，SI为1701(见图2，表1)；活性次之的是化合物25，IC 50为0.36μM，SI为301(见图3，表1)；活性再次之是化合物10和化合物18，IC 50分别为0.40μM和0.46μM，SI分别为308和271(见图4和图5，表1)。
表1：药物筛选获得的化合物结构及其对破骨细胞分化的抑制作用
Figure PCTCN2020083067-appb-000012
Figure PCTCN2020083067-appb-000013
本发明通过计算机辅助药物设计相似度检索的方法发现一类噻唑酰胺衍生物。并通过破骨细胞分化抑制实验和细胞毒性(MTT)实验，发现此类化合物中，3、10、12、18和25对破骨细胞分化抑制活性均小于0.5μM，细胞毒性小，治疗指数高。化合物3对破骨细胞分化半数抑制剂量(IC 50)为0.05μM，细胞半致死剂量(CC 50)为81.24μM，选择抑制常数(SI)为1625(见图1，表1)；化合物12对破骨细胞分化半数抑制剂量(IC 50)为0.23μM，细胞半致死剂量(CC 50)为391.2μM，选择抑制常数(SI)为1701(见图2，表1)；化合物25对破骨细胞分化半数抑制剂量(IC 50)为0.27μM，细胞半致死剂量(CC 50)为81.24μM，选择抑制常数(SI)为301(见图3，表1)；化合物10对破骨细胞分化半数抑制剂量(IC 50)为0.40μM，细胞半致死剂量(CC 50)为123.3μM，选择抑制常数(SI)为 308(见图4，表1)；化合物18对破骨细胞分化半数抑制剂量(IC 50)为0.46μM，细胞半致死剂量(CC 50)为124.8μM，选择抑制常数(SI)为271(见图5，表1)。结果表明，此类化合物对破骨细胞分化的抑制活性高、细胞毒性小，可作为一类破骨细胞抑制剂用于制备骨质疏松或骨质减少防治药物。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (15)

  1. 其为式(I)所示化合物，或式(I)所示化合物的立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，药学上可接受的盐或前药，
    Figure PCTCN2020083067-appb-100001
    其中，X、Y分别独立地选自C 1～C 6烷基、羟基、巯基、氨基、硝基或氰基，所述C 1～C 6烷基、羟基、巯基、氨基独立地被R 1或R 3所取代，所述R 1和R 3独立任选地为氢、氰基、硝基、烷氧基、烷氨基、羟基、氨基、氟、氯、溴、直链烷基、环烷基、环烷基、烯基、五～十元杂环、五～十元芳杂环、苯环或R 1连同Y或R 3连同X形成五～十元杂环或五～十元芳杂环，其中，所述直链烷基、环烷基、烯基、五～十元杂环、五～十元芳杂环、苯环独立任选地被R’所取代；
    R 2为氰基、硝基、烷氧基、烷氨基、环烷基、直链烷基、烯基、五～六元环、五～六元芳杂环、苯环，其中，所述直链烷基、环烷基、烯基、五～六元杂环、五～六元芳杂环、苯环独立任选地被R’所取代；
    所述R’为氢、卤基、C 1～C 5烷氧基、C 1～C 5烷基、酯基、硝基、羟基、巯基，羧基、氨基、氰基、炔基、三氟甲基、三氟甲氧基。
  2. 根据权利要求1所述的化合物，其特征在于，X为羟基或氨基，所述X被R 3所取代；Y为C 1～C 4烷基、羟基、氨基，所述Y被R 1所取代。
  3. 根据权利要求1所述的化合物，其特征在于，R 1为氢或C 1～C 3的直链烷基。
  4. 根据权利要求1所述的化合物，其特征在于，R 2为苯基，2-羧酸苯基，3-羧酸苯基，4-羧酸苯基，2-羟基苯基，2-甲氧基苯基，2-甲基羟基苯基，2-氨基苯基，2-酰胺苯基，2-甲酸甲酯苯基，2-硝基苯基，2-氰基苯基，2,3-双羧基苯基，2,4-双羧基苯基，2,6-双羧基苯基，2,5-双羧基苯基，2-羧基-3甲基苯基，2-羧基-4-甲基苯基，2-羧基-5-甲基苯基，2-羧基-6-甲基苯基，2-羧基-3-氟苯基，2-羧基-4-氟苯基，2-羧基-5-氟苯基，2-羧基-6-氟苯基，2-羧基-3-羟基苯基，2-羧基-4-羟基苯基，2-羧基-5-羟基苯基，2-羧基-6-羟基苯基，2-羧基-3-氨基苯基，2-羧基-4-氨基苯基，2-羧基-5-氨基苯基，2-羧基-6-氨基苯基，2-羧基-6-三氟甲基苯基，2-羧基-3-三氟甲基苯基，2-羧基-4-三氟甲基苯基，2-羧基-5-三氟甲基苯基，2-羧基-6-三氟甲基苯基，2-羧基-6-甲氧基苯基，2-羧基-3-甲氧基苯基，2-羧基-4-甲氧基苯基，2-羧基-5-甲氧基苯基，2-羧基-6-甲氧基苯基，2-羧基-3-氯苯基，2-羧基-4-氯苯基，2-羧基-5- 氯苯基，2-羧基-6-氯苯基，2-羧基-3-氰基苯基，2-羧基-4-氰基苯基，2-羧基-5-氰基苯基，2-羧基-6-氰基苯基，2-羧基-3-硝基苯基，2-羧基-4-硝基苯基，2-羧基-5-硝基苯基，2-羧基-6-硝基苯基。
  5. 根据权利要求1所述的化合物，其特征在于，R 3为噻唑，4-甲基噻唑，4甲基-5-甲酸乙酯噻唑，4甲基-5-甲酸甲酯噻唑，4-甲基-5-羧酸噻唑，4甲基-5-甲酰吗啉噻唑，4-苯基噻唑，噻吩，咪唑，吡啶，6-甲酸甲酯吡啶，吗啉，2-甲基吡啶，3-甲基吡啶，4-甲基吡啶，5-甲基吡啶，6-甲基吡啶，2-氰基吡啶，3-氰基吡啶，4-氰基吡啶，5-氰基吡啶，6-氰基吡啶，2-硝基吡啶，3-硝基吡啶，4-硝基吡啶，5-硝基吡啶，6-硝基吡啶，2-羟基吡啶，3-羟基吡啶，4-羟基吡啶，5-羟基吡啶，6-羟基吡啶，2-甲氧基吡啶，3-甲氧基吡啶，4-甲氧基吡啶，5-甲氧基吡啶，6-甲氧基吡啶，4-氢异喹啉，苯环，苯并噻唑。
  6. 根据权利要求1所述的化合物，其特征在于，R 1为氢、C 1～C 4的烷基；
    R 2为苯环、吡啶环、嘧啶环、吡嗪环；
    R 3为五～六元杂环包含N或O、五元芳杂环包含N、O或S，六元芳杂环包含1或2个N，苯环、
    Figure PCTCN2020083067-appb-100002
    或R 3连同X形成5～10元杂环包含N原子或O原子。
  7. 根据权利要求1所述的化合物，其特征在于，R 1为氢；
    R 2为苯环；
    R 3为吡啶环、嘧啶环、吡嗪环、
    Figure PCTCN2020083067-appb-100003
    或R 3连同X形成
    Figure PCTCN2020083067-appb-100004
    Figure PCTCN2020083067-appb-100005
  8. 根据权利要求1所述的化合物，其特征在于，所述化合物不包括式(1)所示化合物，
    Figure PCTCN2020083067-appb-100006
  9. 根据权利要求1所述的化合物，其特征在于，其为具有下列之一结构的化合物或具 有下列之一结构的化合物的立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，药学上可接受的盐或它的前药：
    Figure PCTCN2020083067-appb-100007
  10. 一种药物组合物，其包含权利要求1～9任一项所述的化合物。
  11. 根据权利要求10所述的药物组合物，其特征在于，其进一步包括药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物或它们的任意组合。
  12. 权利要求1～9任一项所述的化合物或权利要求10～11任一项所述的药物组合物在 制备药物中的用途，所述药物用于抑制破骨细胞分化。
  13. 权利要求1～9任一项所述的化合物或权利要求10～11任一项所述的药物组合物在制备试剂盒中的用途，所述试剂盒用于抑制破骨细胞分化。
  14. 权利要求1～9任一项所述的化合物或权利要求10～11任一项所述的药物组合物在制备药物中的用途，所述药物用于治疗或预防骨质疏松或骨质减少。
  15. 一种治疗或预防骨质疏松或骨质减少的方法，其特征在于，包括：给与患者权利要求1～9任一项所述的化合物或权利要求10～11任一项所述的药物组合物。
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DATABASE REGISTRY 10 August 2010 (2010-08-10), ANONYMOUS: "Butanamide, 2-[2-(4-methyl-2-nitrophenyl)hydrazinylidene]-N-(2- methylphenyl)-3-oxo- (CA INDEX NAME)", XP055885795, retrieved from STN Database accession no. 1235682-03-7 *
DATABASE REGISTRY 12 January 1985 (1985-01-12), ANONYMOUS: "Butanamide, 2-[(5-chloro-2-hydroxyphenyl)hydrazono]-3-oxo-N-phenyl- (9CI) (CA INDEX NAME)", XP055885828, retrieved from STN Database accession no. 94207-41-7 *
DATABASE REGISTRY 12 January 1985 (1985-01-12), ANONYMOUS: "Butyranilide, 2,3-dioxo-, 2-[(2-hydroxy-3,5-dinitrophenyl)hydrazone] (7CI) (CA INDEX NAME)", XP055885835, retrieved from STN Database accession no. 94206-41-4 *
DATABASE REGISTRY 12 January 1985 (1985-01-12), ANONYMOUS: "Butyranilide, 2,3-dioxo-, 2-[(5-chloro-2-hydroxy-3-nitrophenyl)hydrazone] (7CI) (CA INDEX NAME)", XP055885833, retrieved from STN Database accession no. 94207-07-5 *
DATABASE REGISTRY 16 April 2001 (2001-04-16), ANONYMOUS: "5-Thiazolecarboxylic acid, 4-methyl-2-[[2-[2-(3- nitrophenyl)hydrazinylidene]-1,3-dioxobutyl]amino]-, ethyl ester (CA INDEX NAME)", XP055885805, retrieved from STN Database accession no. 331416-65-0 *
DATABASE REGISTRY 16 November 1984 (1984-11-16), ANONYMOUS: "Benzoic acid, 4-[2-[1-[[(2,4-dimethylphenyl)amino]carbonyl]-2- oxopropylidene]hydrazinyl]- (CA INDEX NAME)", XP055885855, retrieved from STN Database accession no. 63239-94-1 *
DATABASE REGISTRY 16 November 1984 (1984-11-16), ANONYMOUS: "Benzoic acid, 4-[2-[1-[[(2,4-dimethylphenyl)amino]carbonyl]-2- oxopropylidene]hydrazinyl]-, ethyl ester (CA INDEX NAME)", XP055885853, retrieved from STN Database accession no. 63239-95-2 *
DATABASE REGISTRY 16 November 1984 (1984-11-16), ANONYMOUS: "Benzoic acid, 4-[2-[2-oxo-1-[(phenylamino)carbonyl]propylidene]hydrazinyl]- (CA INDEX NAME)", XP055885858, retrieved from STN Database accession no. 63239-81-6 *
DATABASE REGISTRY 16 November 1984 (1984-11-16), ANONYMOUS: "Benzoic acid, 4-[2-[2-oxo-1-[(phenylamino)carbonyl]propylidene]hydrazinyl]- , ethyl ester (CA INDEX NAME)", XP055885857, retrieved from STN Database accession no. 63239-82-7 *
DATABASE REGISTRY 16 November 1984 (1984-11-16), ANONYMOUS: "Butanamide, 2-[2-(4-methyl-2-nitrophenyl)diazenyl]-N-(4-methylphenyl)-3- oxo- (CA INDEX NAME)", XP055885865, retrieved from STN Database accession no. 57206-92-5 *
DATABASE REGISTRY 16 November 1984 (1984-11-16), ANONYMOUS: "Butanamide, 3-oxo-N-phenyl-2-[2-(3-pyridinyl)hydrazinylidene]- (CA INDEX NAME)", XP055885860, retrieved from STN Database accession no. 50599-23-0 *
DATABASE REGISTRY 16 November 1984 (1984-11-16), ANONYMOUS: "Butanamide, N-(2-methylphenyl)-2-[2-(2-methylphenyl)hydrazinylidene]-3-oxo- (CA INDEX NAME)", XP055885850, retrieved from STN Database accession no. 90422-20-1 *
DATABASE REGISTRY 17 December 1984 (1984-12-17), ANONYMOUS: "Butyranilide, 2,3-dioxo-, 2-[(3-chloro-2-hydroxy-5-nitrophenyl)hydrazone] (7CI) (CA INDEX NAME)", XP055885847, retrieved from STN Database accession no. 92873-78-4 *
DATABASE REGISTRY 18 December 1984 (1984-12-18), ANONYMOUS: "Butanamide, 2-[(2-hydroxy-5-nitrophenyl)hydrazono]-3-oxo-N-phenyl- (9CI) (CA INDEX NAME)", XP055885837, retrieved from STN Database accession no. 93021-19-3 *
DATABASE REGISTRY 18 December 1984 (1984-12-18), ANONYMOUS: "Butyranilide, 2,3-dioxo-, 2-[(2-hydroxy-3-nitrophenyl)hydrazone] (7CI) (CA INDEX NAME)", XP055885844, retrieved from STN Database accession no. 93021-17-1 *
DATABASE REGISTRY 18 December 1984 (1984-12-18), ANONYMOUS: "Butyranilide, 2,3-dioxo-, 2-[(2-hydroxy-4-nitrophenyl)hydrazone] (7CI) (CA INDEX NAME)", XP055885841, retrieved from STN Database accession no. 93021-18-2 *
DATABASE REGISTRY 18 January 2001 (2001-01-18), ANONYMOUS: "5-Thiazolecarboxylic acid, 4-methyl-2-[[2-[2-(2- methylphenyl)hydrazinylidene]-1,3-dioxobutyl]amino]-, ethyl ester (CA INDEX NAME)", XP055885807, retrieved from STN Database accession no. 314763-74-1 *
DATABASE REGISTRY 20 April 2001 (2001-04-20), ANONYMOUS: "5-Thiazolecarboxylic acid, 2-[[2-[2-(2-carboxyphenyl)hydrazinylidene]-1,3- dioxobutyl]amino]-4-methyl-, 5-ethyl ester (CA INDEX NAME) OTHER CA INDEX NAMES", XP055885802, retrieved from STN Database accession no. 331968-10-6 *
DATABASE REGISTRY 24 February 1985 (1985-02-24), ANONYMOUS: "Butyranilide, 2,3-dioxo-, 2-[(6-hydroxy-m-tolyl)hydrazone] (7CI) (CA INDEX NAME)", XP055885816, retrieved from STN Database accession no. 94959-92-9 *
DATABASE REGISTRY 26 September 2001 (2001-09-26), ANONYMOUS: "Butanamide, 2-[2-(4-hydroxyphenyl)hydrazinylidene]-3-oxo-N-2-pyridinyl- (CA INDEX NAME)", XP055885799, retrieved from STN Database accession no. 358718-99-7 *
DATABASE REGISTRY 4 June 2019 (2019-06-04), ANONYMOUS: "INDEX NAME NOT YET ASSIGNED", XP055885789, retrieved from STN Database accession no. 2324187-36-0 *
DATABASE REGISTRY 4 October 2013 (2013-10-04), ANONYMOUS: "2-Propenoic acid, 2,3-dimethyl-4-[2-[2-oxo-1- [(phenylamino)carbonyl]propylidene]hydrazinyl]phenyl ester (CA INDEX NAME)", XP055885792, retrieved from STN Database accession no. 1455518-21-4 *
DATABASE REGISTRY 5 April 2011 (2011-04-05), ANONYMOUS: "Butanamide, 2-[2-(3-chloro-4-methylphenyl)hydrazinylidene]-3-oxo-N-2- pyridinyl- (CA INDEX NAME)", XP055885794, retrieved from STN Database accession no. 1274906-03-4 *
DATABASE REGISTRY 8 March 1996 (1996-03-08), ANONYMOUS: "Butanamide, 2-[(4-ethylphenyl)hydrazono]-3-oxo-N-phenyl- (9CI) (CA INDEX NAME)", XP055885813, retrieved from STN Database accession no. 174011-05-3 *
DATABASE REGISTRY 8 March 1996 (1996-03-08), ANONYMOUS: "Butanamide, 3-oxo-2-[2-(4-pentylphenyl)hydrazinylidene]-N-phenyl- (CA INDEX NAME)", XP055885810, retrieved from STN Database accession no. 174011-08-6 *
DATABASE REGISTRY 9 February 1985 (1985-02-09), ANONYMOUS: "Butyranilide, 2,3-dioxo-, 2-[(6-hydroxy-5-nitro-m-tolyl)hydrazone] (7CI) (CA INDEX NAME)", XP055885818, retrieved from STN Database accession no. 94674-38-1 *
DIETRICH MODERHACK ET AL.: "1, 2, 5, 6-Tetrazocines from Nitrile Imines and tert-Butyl Isocyanide", J. PRAKT. CHEM., vol. 342, no. 7, 17 August 2000 (2000-08-17), XP055773385, ISSN: 1436-9966, DOI: 20200612155722X *
ELIEL, E.L.: "Stereochemistry of Carbon Compounds", 1962, MCGRAW-HILL
ELIEL, E.WILEN, S.: "Stereochemistry of Organic Compounds", 1994, JOHN WILEY & SONS, INC.
GREIG CHISHOLM ET AL.: "Comparison of the structural motifs of acetoacetanilides and related azo pigments", ACTA CRYSTALLOGRAPHICA SECTION B: STRUCTURAL SCIENCE, vol. B56, no. 6, 31 December 2000 (2000-12-31), XP055773374, ISSN: 0108-7681, DOI: 20200612141327X *
J. RAUTIO ET AL.: "Prodrugs: Design and Clinical Applications", NATURE REVIEW DRUG DISCOVERY, vol. 7, 2008, pages 255 - 270, XP055227338, DOI: 10.1038/nrd2468
JACQUES ET AL.: "Enantiomers, Racemates and Resolutions", 1981, WILEY INTERSCIENCE
K. M. DYUMAEV ET AL.: "Synthesis and structure of 2-(2-phenylhydrazono) acetoacetanilide and its derivatives", ZHURNAL ORGANICHESKOI KHIMII, vol. 14, no. 3, 31 December 1978 (1978-12-31), pages 562`569, XP009533330, ISSN: 0514-7492 *
KETTRUP ANTONIUS, GROTE MANFRED: "Die Fragmentierung der Azo- und Hydrazontautomeren von 2.3-Dioxobutyranilid-2-phenylhydrazonen in der Gasphase in Abhängigkeit von Substituenten = The fragmentation of azo and hydrazone tautomers of 2, 3-dioxobutyranilide-2-phenylhydrazones in the gaseous state in dependence of substituents", ZEITSCHRIFT FÜR NATURFORSCHUNG, vol. 32b, no. 8, 31 August 1977 (1977-08-31), DE , pages 863 - 868, XP009533295, ISSN: 0340-5087, DOI: 10.1515/znb-1977-0806 *
L. W. DEADY, SYN. COMM., vol. 7, 1977, pages 509 - 514
M. A. ABOUTABL ET AL.: "Polarographic behaviour of α- and γ-substituted acetoacetanilide derivatives in alcoholic aqueous media", MONATSHEFTE FÜR CHEMIE, vol. 123, no. 3, 31 March 1992 (1992-03-31), XP055773343, ISSN: 0026-9247, DOI: 20200611180842X *
M. A. ZAYED ET AL.: "The use of thermal and spectrometric analyses for the structure investigation of arylhydrazoneacetoacetylaminopyridines and their copper chelates", THERMOCHIMICA ACTA, vol. 146, 31 December 1989 (1989-12-31), XP055773368, ISSN: 0040-6031, DOI: 20200612125417X *
M. I. ALI ET AL.: "Reactions with acetoacetylaminopyridines", EGYPTIAN JOURNAL OF CHEMISTRY, vol. 30, no. 5, 31 December 1989 (1989-12-31), pages 357 - 368, XP009533332, ISSN: 0367-0422 *
MURAT ÇAĞLAR HAMZAÇEBI ET AL.: "Synthesis and structure elucidation of hydrazones derived from N-(2, 4-dimethylphenyl)-3-oxobutanamide", ARKIVOC, vol. 2008, no. 12, 21 May 2008 (2008-05-21), XP055773381, ISSN: 1551-7012, DOI: 20200617103153X *
POUL ERIK HANSEN ET AL.: "Long-range intrinsic and equilibrium deuterium isotope effects on 19F chemical shifts", ACTA CHEMICA SCANDINAVICA, vol. 51, no. 8, 31 August 1997 (1997-08-31), XP055773376, ISSN: 0904-213X, DOI: 20200617102722X *
PRATIBHA SHARMA ET AL.: "Studies on synthesis and evaluation of quantitative structure-activity relationship of 5-[(3'-chloro-4', 4'-disubstituted-2-oxoazetidinyl)(N-nitro) amino]-6-hydroxy-3-alkyl/aryl [1, 3] azaphospholo [1, 5-a] pyridin-1-yl-phosphorus dichlorides", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 15, no. 4,, 20 January 2005 (2005-01-20), XP027801875, ISSN: 0960-894X, DOI: 20200611173404X *
QIAN ZHANG ET AL.: "Formal [4+1] annulation of α-aryl hydrazone ketones and dimethylsulfoxonium methylide: one-pot synthesis of substituted pyrazoles and dihydropyrazoles", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 81, no. 14, 21 June 2016 (2016-06-21), XP055773353, ISSN: 0022-3263, DOI: 20200611171806X *
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RAJEEV JAIN ET AL.: "Synthesis of some new 1-carbamoyl-3-aminophenyl- and 1-carbamoyl-3-amino-(2-chlorophenyl)-5-methyl-4-arylazopyrazoles as possible potential antidiabetics", JOURNAL OF THE INDIAN CHEMICAL SOCIETY, vol. 66, no. 7, 31 July 1989 (1989-07-31), IN , pages 486 - 489, XP009533298, ISSN: 0019-4522 *
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RAJEEV, JAIN ET AL.: "Synthesis of some new isonicotinoylazopyrazoles", JOURNAL OF THE INDIAN CHEMICAL SOCIETY, vol. 66, no. 5, 31 May 1989 (1989-05-31), IN , pages 350 - 352, XP009533297, ISSN: 0019-4522 *
ROBERT E. GAWLEY: "Principles of Asymmetric Synthesis", 2012, ELSEVIER
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SUJIT SURESH KAMBLE ET AL.: "Room temperature diazotization and coupling reaction using a DES-ethanol system: a green approach towards the synthesis of monoazo pigments", CHEM. COMMUN., vol. 55, no. 42, 25 April 2019 (2019-04-25), XP055773348, ISSN: 1359-7345, DOI: 20200611163457X *
T. HIGUCHIV. STELLA: "A.C.S. Symposium Series", vol. 14, 1987, AMERICAN PHARMACEUTICAL ASSOCIATION AND PERGAMON PRESS, article "Pro-drugs as Novel Delivery Systems"
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JP2022540063A (ja) 2022-09-14
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US20220153688A1 (en) 2022-05-19
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CN110229118A (zh) 2019-09-13
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