WO2019128963A1 - 抗肺结核病的硝基咪唑衍生物 - Google Patents
抗肺结核病的硝基咪唑衍生物 Download PDFInfo
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- 0 CC(C)(C)N1*CNCC1 Chemical compound CC(C)(C)N1*CNCC1 0.000 description 4
- SGQKPVHSXGDPJB-UHFFFAOYSA-N CC(C)(C)N(CC1)CCN1c(nc1)ncc1O Chemical compound CC(C)(C)N(CC1)CCN1c(nc1)ncc1O SGQKPVHSXGDPJB-UHFFFAOYSA-N 0.000 description 2
- CPDQMRJHARPNIE-MRXNPFEDSA-N CC(C)(C)N(CC1)CCN1c(nc1)ncc1OC[C@@](C)(CO)O Chemical compound CC(C)(C)N(CC1)CCN1c(nc1)ncc1OC[C@@](C)(CO)O CPDQMRJHARPNIE-MRXNPFEDSA-N 0.000 description 1
- QUPYSDDHCXPIIK-LJQANCHMSA-N CC(C)(C)N(CC1)CCN1c(nc1)ncc1OC[C@]1(C)Oc2nc([N+]([O-])=O)c[n]2C1 Chemical compound CC(C)(C)N(CC1)CCN1c(nc1)ncc1OC[C@]1(C)Oc2nc([N+]([O-])=O)c[n]2C1 QUPYSDDHCXPIIK-LJQANCHMSA-N 0.000 description 1
- XGLICRLNBCXPDH-UHFFFAOYSA-N CC(C)(C)N(CC1)CCN1c(nc1)ncc1OCc1ccccc1 Chemical compound CC(C)(C)N(CC1)CCN1c(nc1)ncc1OCc1ccccc1 XGLICRLNBCXPDH-UHFFFAOYSA-N 0.000 description 1
- KOXBGKPTVXWSGT-UHFFFAOYSA-N CC(C)(C)[Si+](C)(C)OCC(Cc(cc1)ccc1Cl)(CC1)CCN1c(nc1)ncc1OCC(C)(C[n]1c(Cl)nc([IH][NH+]([O-])O)c1)O Chemical compound CC(C)(C)[Si+](C)(C)OCC(Cc(cc1)ccc1Cl)(CC1)CCN1c(nc1)ncc1OCC(C)(C[n]1c(Cl)nc([IH][NH+]([O-])O)c1)O KOXBGKPTVXWSGT-UHFFFAOYSA-N 0.000 description 1
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- BYBQPFFSEDPACU-RUZDIDTESA-N CC(C)(c(cc1)ccc1Cl)N(CC1)CCN1c(nc1)ncc1OC[C@]1(C)[O](C)c2nc([N+]([O-])=O)c[n]2C1 Chemical compound CC(C)(c(cc1)ccc1Cl)N(CC1)CCN1c(nc1)ncc1OC[C@]1(C)[O](C)c2nc([N+]([O-])=O)c[n]2C1 BYBQPFFSEDPACU-RUZDIDTESA-N 0.000 description 1
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- ATKLTTYLHNYOET-UHFFFAOYSA-N CC1(COCc2cnc(N(CC3)CCC3Oc(cc3)ccc3OC(F)(F)F)nc2)OC1 Chemical compound CC1(COCc2cnc(N(CC3)CCC3Oc(cc3)ccc3OC(F)(F)F)nc2)OC1 ATKLTTYLHNYOET-UHFFFAOYSA-N 0.000 description 1
- OTQBYYULYRNRAL-UHFFFAOYSA-N CC1(COCc2cnc(N(CC3)CCC3Oc(cc3)ccc3OC(F)(F)F)nc2)Oc2nc([N+]([O-])=O)c[n]2C1 Chemical compound CC1(COCc2cnc(N(CC3)CCC3Oc(cc3)ccc3OC(F)(F)F)nc2)Oc2nc([N+]([O-])=O)c[n]2C1 OTQBYYULYRNRAL-UHFFFAOYSA-N 0.000 description 1
- DTTWXSIEPHXICT-UHFFFAOYSA-N CC1(COc2cnc(N3CCNCC3)nc2)Oc2nc(C[NH+]([O-])OC)c[n]2C1 Chemical compound CC1(COc2cnc(N3CCNCC3)nc2)Oc2nc(C[NH+]([O-])OC)c[n]2C1 DTTWXSIEPHXICT-UHFFFAOYSA-N 0.000 description 1
- KJNIRSHAGCRIJK-UHFFFAOYSA-N CCOc1cnc(N(CC2)CCN2C(C)(C)C)nc1 Chemical compound CCOc1cnc(N(CC2)CCN2C(C)(C)C)nc1 KJNIRSHAGCRIJK-UHFFFAOYSA-N 0.000 description 1
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- MZTLTUWMKRDBRA-JOCHJYFZSA-N C[C@@]1(COc2cnc(N3CCN(Cc(cc4F)ccc4Cl)CC3)nc2)Oc2nc([N+]([O-])=O)c[n]2C1 Chemical compound C[C@@]1(COc2cnc(N3CCN(Cc(cc4F)ccc4Cl)CC3)nc2)Oc2nc([N+]([O-])=O)c[n]2C1 MZTLTUWMKRDBRA-JOCHJYFZSA-N 0.000 description 1
- YRQQIHKDYLSYLR-HSZRJFAPSA-N C[C@@]1(COc2cnc(N3CCN(Cc4ccccc4)CCC3)nc2)Oc2nc([N+]([O-])=O)c[n]2C1 Chemical compound C[C@@]1(COc2cnc(N3CCN(Cc4ccccc4)CCC3)nc2)Oc2nc([N+]([O-])=O)c[n]2C1 YRQQIHKDYLSYLR-HSZRJFAPSA-N 0.000 description 1
- CNHFWVASMVDEQT-UHFFFAOYSA-N Cc(nc1)ncc1OCc1ccccc1 Chemical compound Cc(nc1)ncc1OCc1ccccc1 CNHFWVASMVDEQT-UHFFFAOYSA-N 0.000 description 1
- FFYTTYVSDVWNMY-UHFFFAOYSA-N Cc1nc([N+]([O-])=O)c[nH]1 Chemical compound Cc1nc([N+]([O-])=O)c[nH]1 FFYTTYVSDVWNMY-UHFFFAOYSA-N 0.000 description 1
- KOLVCHCMDCAEJY-UHFFFAOYSA-N FC(Oc(cc1)ccc1OC(CC1)CCN1c(nc1)ncc1OCc1ccccc1)(F)F Chemical compound FC(Oc(cc1)ccc1OC(CC1)CCN1c(nc1)ncc1OCc1ccccc1)(F)F KOLVCHCMDCAEJY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Definitions
- the present invention relates to a substituted nitroimidazole derivative, and specifically discloses a compound of the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, a pharmaceutical composition comprising the above compound, and the same
- Treatment of related diseases caused by mycobacterial infection, such as Mycobacterium tuberculosis, is particularly suitable for diseases caused by drug resistance combined with mycobacteria.
- Mycobacterium tuberculosis is the causative agent of tuberculosis. As a globally widespread and fatal infectious disease, according to the World Health Organization, more than 8 million people are infected each year and 2 million die from tuberculosis. In the past decade, tuberculosis cases have grown at a rate of 20% worldwide, especially in poor areas. If this trend continues, tuberculosis cases are likely to continue to grow at a 41% increase over the next two decades. In the 50 years since the initial application of chemotherapy, tuberculosis has been the leading infection to adults, second only to AIDS. Complications of tuberculosis have led to the emergence of many drug-resistant strains and a symbiotic relationship with AIDS.
- the current treatment of tuberculosis uses a combination of multiple agents recommended by the US Department of Public Health, including the first use of isoniazid, rifampicin, pyrazinamide and ethambutol for two months, and then separately Haze and rifampin are combined for four months.
- the use of this combination of drugs needs to be extended to seven months.
- the drug combination also needs to add the remaining second-line agents, such as streptomycin, kanamycin, amikacin, capreomycin, ethionamide, cycloserine, cyclopropane Sand star and ofloxacin.
- Such combination therapies for patients with multidrug-resistant tuberculosis usually have lower activity and higher side effects compared to current first-line drugs on the market.
- TBA-354 is a nitroimidazolium derivative derived from PA-824. The mechanism of action of Delamanid is to inhibit the synthesis of methoxy and keto-mycolic acid, thereby killing bacteria, which are important components of the cell wall of Mycobacterium tuberculosis.
- Nitroimidazole derivatives and treatments for Mycobacterium tuberculosis have been previously reported in large numbers (US 5,668,127, US 6,087,358; Jiricek et al., WO 2007075872 A2; Tsubochi et al., WO 2005042542 A1 and WO 2004033463 Al; JP 2005330266 A; THOMPSON et Al., WO 2011014776; MUSONDA et al., WO 2013072903).
- Delamanid is a nitro-dihydroimidazolidinazole derivative that inhibits the biosynthesis of mycolic acid and exhibits high activity against MDR-TB in both in vitro and in vivo, November 2013.
- Deltyba (Delamanid) was conditionally approved by the European Committee for the Use of Medicine (CHMP), and a 50 mg film-coated tablet was used for the treatment of MDR-TB. It was officially launched in Europe on April 28, 2014. Deltyba was identified as an orphan drug on February 1, 2008.
- the present invention is directed to the invention of a novel nitroimidazole compound for use in the treatment of tuberculosis and multidrug-resistant tuberculosis.
- OPC-67683 has been proven to be clinically effective in the treatment of multidrug-resistant tuberculosis, there is room for further optimization in the course of treatment and cure. Based on this, the present invention designs a series of nitroimidazole derivatives. They have been shown to have better water solubility and pharmacokinetic properties. It is expected that this improvement will lead to better clinical performance.
- the invention provides a compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,
- R 1 , R 2 and R 3 are each independently H, -L 1 -R 4 or -L 2 -R 5 ;
- R 4 is C 3-6 cycloalkyl, 5-6 membered heteroaryl or 6-12 membered aryl, wherein said C 3-6 cycloalkyl, 5-6 membered heteroaryl and 6-12 membered aromatic
- the base is optionally substituted by 1, 2 or 3 R;
- R 5 is F, Cl, Br, I, -OH, -NH 2 , -CN or optionally 1, 2 , 3 or 4 independently selected from the group consisting of F, Cl, Br, I, -NH 2 , -OH, a C 1-6 alkyl group substituted with a substituent of -OCH 3 and -CN;
- p 1 or 2;
- q 0, 1 or 2;
- R 6 and R 7 are each independently H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 or -CH 2 (CH 3 ) 2 ;
- Each R is independently F, Cl, Br, I, -CN, -OH, C 1-6 alkoxy or C 1-6 alkyl, wherein said C 1-6 alkoxy and C 1-6 alkane
- the radicals are optionally independently substituted with 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, I, -NH 2 , -OH, -OCH 3 and -CN;
- n 1 is 1 or 2;
- n 2 and n 3 are each independently 0, 1, or 2;
- the 5-6 membered heteroaryl contains 1, 2, 3 or 4 heteroatoms or heteroatoms independently selected from -O-, -S-, N or -NH-.
- each of the above R is independently F, Cl, Br, I, -CN, -OH, -OCH 3 , -OCF 3 , -OCH 2 CH 3 , -OCH 2 CF 3 , -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 (CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 (CH 3 ) 3 , -CH 2 (CH 3 CH 2 CH 3 , -CH 2 CH 2 (CH 3 ) 2 , -CF 3 or -CH 2 CF 3 , other variables are as defined in the present invention.
- R 4 above is cyclopropyl, cyclobutyl, furanyl, pyridyl, pyrimidinyl or phenyl, wherein said cyclopropyl, cyclobutyl, furanyl, pyridyl, pyrimidine
- the base and phenyl are each independently optionally substituted by 1, 2 or 3 R, and R and other variables are as defined herein.
- R 4 is R and other variables are as defined by the present invention.
- R 5 above is F, Cl, Br, I, -OH, -NH 2 , -CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 (CH 3 ) 2 , -CH 2 CH 2 (CH 3 ) 2 , Other variables are as defined by the present invention.
- R 1 , R 2 and R 3 are each independently H, F, Cl, Br, I, -OH, -NH 2 , -CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 (CH 3 ) 2 , -CH 2 CH 2 (CH 3 ) 2 , R and other variables are as defined by the present invention.
- R 1 , R 2 and R 3 are each independently H, F, Cl, Br, I, -OH, -NH 2 , -CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 (CH 3 ) 2 , -CH 2 CH 2 (CH 3 ) 2 , Other variables are as defined by the present invention.
- the above compound, a pharmaceutically acceptable salt thereof or an isomer thereof has the structure represented by formula (II) to (IV):
- W is O or S; n 2 , n 3 , R 1 , R 2 and R 3 are as defined in the present invention.
- the above compound, a pharmaceutically acceptable salt thereof or an isomer thereof has the structure represented by the formula (IIa) to (IVa):
- W is O or S; n 2 , n 3 , R 1 , R 2 and R 3 are as defined in the present invention.
- the above compound, a pharmaceutically acceptable salt thereof or an isomer thereof has the structure represented by formula (V) to (VIII):
- W is O or S; and R 1 , R 2 and R 3 are as defined in the present invention.
- the above compound, a pharmaceutically acceptable salt thereof or an isomer thereof has the structure represented by formula (Va) to (VIIIa):
- W is O or S; and R 1 , R 2 and R 3 are as defined in the present invention.
- the above compound, a pharmaceutically acceptable salt thereof or an isomer thereof has the structure represented by formula (Vb) to (VIId):
- R 5 , L 1 and R are as defined in the present invention.
- the above compound, a pharmaceutically acceptable salt thereof or an isomer thereof has the structure represented by the formula (Vb-1) to (VIId-1):
- R 5 , L 1 and R are as defined in the present invention.
- the above compound is selected from the group consisting of
- a pharmaceutically acceptable salt thereof or a stereoisomer thereof is provided.
- the above compound is selected from the group consisting of
- a pharmaceutically acceptable salt thereof or a stereoisomer thereof is provided.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of the above compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.
- the present invention also provides the use of the above compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition as described above, for the preparation of a medicament for treating a disease associated with infection by mycobacteria.
- the mycobacterium is Mycobacterium tuberculosis.
- the related disease caused by the mycobacterial infection is tuberculosis.
- the invention provides a series of nitroimidazole derivatives which have good antibacterial activity, especially exhibit good inhibitory activity against mycobacteria; at the same time, they have been proved to have better water solubility and pharmacokinetic properties. . It is expected that this improvement will lead to better clinical performance.
- pharmaceutically acceptable as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues. Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
- a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
- Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
- an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
- pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
- the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
- such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
- the compounds provided herein also exist in the form of prodrugs.
- Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention.
- prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
- Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms.
- the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.
- the compounds of the invention may exist in specific geometric or stereoisomeric forms. All such compounds are contemplated by the present invention, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers , (D)-isomer, (L)-isomer, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to the present Within the scope of the invention. Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
- enantiomer or “optical isomer” refer to stereoisomers that are mirror images of one another.
- cis-trans isomer or “geometric isomer” is caused by the inability to freely rotate a single bond due to a double bond or a ring-forming carbon atom.
- diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirrored relationship.
- wedge-shaped dashed keys Represents the absolute configuration of a solid center with straight solid keys
- straight dashed keys Indicates the relative configuration of the stereocenter, using wavy lines Indicates a wedge solid key Or wedge-shaped dotted key Or with wavy lines Represents a straight solid key And straight dashed keys
- tautomer or “tautomeric form” mean that the different functional isomers are in dynamic equilibrium at room temperature and can be rapidly converted into each other. If tautomers are possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
- proton tautomers also known as prototropic tautomers
- prototropic tautomers include interconversions by proton transfer, such as keto-enol isomerization and imine-enes. Amine isomerization.
- the valence tautomer includes the mutual transformation of some of the bonding electrons.
- keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
- the terms "enriched in one isomer”, “isomer enriched”, “enriched in one enantiomer” or “enantiomeric enriched” refer to one of the isomers or pairs
- the content of the oligo is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or greater than or equal to 99.9%.
- the term “isomer excess” or “enantiomeric excess” refers to the difference between the two isomers or the relative percentages of the two enantiomers. For example, if one of the isomers or enantiomers is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomer or enantiomeric excess (ee value) is 80%. .
- optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
- a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art.
- the diastereomers are resolved and the pure enantiomer is recovered.
- the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
- the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
- radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C).
- hydrogen can be replaced by heavy hydrogen to form a deuterated drug.
- the bond composed of barium and carbon is stronger than the bond composed of common hydrogen and carbon.
- deuterated drugs have reduced side effects and increased drug stability. Enhance the efficacy and prolong the biological half-life of the drug. Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
- pharmaceutically acceptable carrier refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts.
- excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
- an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
- an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
- active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
- substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of.
- Oxygen substitution does not occur on the aromatic group.
- optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
- any variable eg, R
- its definition in each case is independent.
- the group may optionally be substituted with at most two R, and each case has an independent option.
- combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
- linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
- one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
- substituents When the listed substituents are not indicated by which atom is attached to the substituted group, such a substituent may be bonded through any atom thereof, for example, a pyridyl group as a substituent may be passed through any one of the pyridine rings. A carbon atom is attached to the substituted group.
- the listed linking group does not indicate its direction of attachment, its connection direction is arbitrary, for example, The medium linking group L is -MW-, and at this time, -MW- can be connected in the same direction as the reading order from left to right to form ring A and ring B. It is also possible to connect the ring A and the ring B in a direction opposite to the reading order from left to right. Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
- hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
- ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring” means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
- 5- to 7-membered ring includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
- ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
- heterocycle or “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring.
- the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2).
- the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
- the heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites.
- the nitrogen atom in the heterocycle is optionally quaternized.
- a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one.
- aromatic heterocyclic group or "heteroaryl” as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
- the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
- the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
- bridged rings are also included in the definition of heterocycles.
- a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
- Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
- heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl,
- hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, aryl, etc.), by itself or as part of another substituent, is meant to be straight-chain, branched or cyclic.
- the hydrocarbon atom group or a combination thereof may be fully saturated (such as an alkyl group), a unit or a polyunsaturated (such as an alkenyl group, an alkynyl group, an aryl group), may be monosubstituted or polysubstituted, and may be monovalent (such as Methyl), divalent (such as methylene) or polyvalent (such as methine), may include divalent or polyvalent radicals with a specified number of carbon atoms (eg, C 1 -C 12 represents 1 to 12 carbons) , C 1-12 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 ; C 3-12 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 .).
- C 1-12 is selected from C 1
- Hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members.
- An aromatic hydrocarbon group such as benzene, naphthalene or the like.
- hydrocarbyl refers to a straight or branched chain of atoms or a combination thereof, which may be fully saturated, mono- or polyunsaturated, and may include divalent and multivalent radicals.
- saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl).
- a homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl.
- the unsaturated hydrocarbon group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.
- cycloalkyl refers to any heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized “hydrocarbyl group” or “heterohydrocarbyl group”, respectively.
- a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule.
- cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
- heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
- heterocycloalkyl by itself or in conjunction with other terms, denotes a cyclized “heteroalkyl”, respectively, and further, in the case of the "heterocycloalkyl", a heteroatom may occupy a heterocycloalkyl group.
- the heterocycloalkyl group is a 4-6 membered heterocycloalkyl group; in other embodiments, the heterocycloalkyl group is a 5-6 membered heterocycloalkane.
- heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thioheterobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetra Hydropyranyl, piperidinyl, piperazinyl, morpholinyl, dioxoalkyl, dithiaalkyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2- Thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl or oxetanyl.
- alkyl is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH 2 F) or polysubstituted (eg, -CF 3 ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine).
- alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
- a cycloalkyl group includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom which is saturated, may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.
- Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cycloheptyl, cyclohexyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicycloindole Alkane, etc.
- halo or “halogen”, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom.
- haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
- halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
- examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
- alkoxy represents attached through an oxygen bridge
- C 1-6 alkoxy groups include C 1, C 2, C 3 , C 4, C 5 , and C 6 alkoxy groups.
- alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
- aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted or polysubstituted, which may be monovalent, divalent or polyvalent, which may be monocyclic or polycyclic ( For example, 1 to 3 rings; at least one of which is aromatic), they are fused together or covalently linked.
- heteroaryl refers to an aryl (or ring) containing one to four heteroatoms. In an exemplary embodiment, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
- a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
- aryl or heteroaryl groups include phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, phenyl-oxazolyl, isomerism Azyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, indolyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, quinolinyl, 1 -naphthyl, 2-naphthyl, 4-biphenylyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl
- leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction).
- substituent groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
- protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
- amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
- Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
- hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
- Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
- alkyl groups such as methyl, ethyl and t-butyl groups
- acyl groups such as alkanoyl groups (e.g., acetyl)
- arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
- the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
- the solvent used in the present invention is commercially available.
- the compounds of the present invention can be prepared by a variety of synthetic procedures well known to those skilled in the art, through a series of synthetic procedures.
- the compounds of the invention can be synthesized using synthetic methods as described below or alternatively.
- Preferred methods include, but are not limited to, the description below.
- the compound of formula (I) can be reacted with the reaction intermediate (II) with a suitable halohydrocarbyl group or with an aldehyde or ketone in a suitable base (such as Na 2 CO 3 and K 2 CO 3 ) or a reducing agent (eg, NaBH 3 In the presence of CN and NaBH(OAc) 3 ), in a suitable solvent (such as 1,2 dichloroethane, dichloromethane or methanol), according to reaction scheme 1, the reaction is more preferred at 20 ° C ⁇ 80 Under °C:
- a suitable base such as Na 2 CO 3 and K 2 CO 3
- a reducing agent eg, NaBH 3 In the presence of CN and NaBH(OAc) 3
- a suitable solvent such as 1,2 dichloroethane, dichloromethane or methanol
- intermediate (II) can be produced according to a conventional reaction by various synthetic methods well known to those skilled in the art.
- intermediate (II) can be prepared according to Reaction Scheme 2:
- variable LG 1 represents a suitable leaving group such as a halogen (e.g., chlorine, bromine or iodine), a methylsulfonyl group and the like.
- the variable LG 2 represents a suitable leaving group such as a halogen (e.g., chlorine, bromine or iodine), a methylsulfonyl group and the like.
- LG 3 represents a suitable leaving group such as a halogen such as chlorine, bromine or iodine.
- PG 1 represents a suitable protecting group such as benzyl, Cbz, TBDMS and the like.
- PG 2 represents a suitable protecting group such as t-butoxycarbonyl and the like. All other variables are as defined by the present invention.
- Step A of Reaction Scheme 2 is a pyrimidine ester with a suitable reducing agent (e.g., DIBAl-H LiAlH 4 , etc.) in a suitable solvent (e.g., tetrahydrofuran and DCM) at a suitable temperature.
- a suitable reducing agent e.g., DIBAl-H LiAlH 4 , etc.
- a suitable solvent e.g., tetrahydrofuran and DCM
- Step B is the reaction of a hydroxyl group with a suitable protecting agent such as a benzyl group.
- Step C is a hydroxy-protected pyrimidine and a protecting group-containing piperazine or the like in a suitable solvent (dioxane), and a suitable temperature is usually carried out at 40 ° C to 100 ° C.
- step D to deprotection is usually accomplished by hydrogenation at room temperature.
- Step E the insertion of the epoxy is usually in a suitable solvent (such as acetone, DMF) and a suitable base (such as t-BuONa, t-BuOK, K 2 CO 3, etc.) at a suitable temperature (usually between 40 ° C ⁇ 100 °C).
- a suitable solvent such as acetone, DMF
- a suitable base such as t-BuONa, t-BuOK, K 2 CO 3, etc.
- a ring closure reaction occurs in a suitable solvent (such as DMF) in the presence of a suitable base, followed by a protecting group in the presence of a suitable acid (such as hydrochloric acid, trifluoroacetic acid).
- a suitable solvent such as DMF
- a protecting group in the presence of a suitable acid (such as hydrochloric acid, trifluoroacetic acid).
- the intermediate (II) is obtained by removal, and the reaction is usually carried out at a temperature ranging from -20 ° C to 40 ° C.
- reaction product can be separated from the reaction medium, and if necessary, it can be further purified by purification methods well known to those skilled in the art, such as extraction, crystallization, and chromatography. More clearly, for the reaction product in which more than one enantiomer is present, the compound of formula (I) can be separated into its isoforms by separation methods well known to those skilled in the art, in particular preparative chromatography, such as preparative HPLC, SFC, and the like. Structure.
- LG 3 represents a suitable leaving group such as a halogen (e.g., chlorine, bromine, iodine, etc.).
- PG 2 represents a suitable protecting group such as t-butoxycarbonyl. All other variables are as defined by the present invention.
- the reaction of the epoxy nitroimidazole (III) with the alcoholic hydroxyl group in the nucleophile in step A requires a suitable base (such as sodium hydrogen) and a suitable solvent (such as DMF), and the reaction should be between -20 degrees Celsius and 20 degrees Celsius. The temperature range is carried out.
- the deprotection group is required to be carried out in a suitable acid such as hydrochloric acid and trifluoroacetic acid, and a suitable solvent such as dichloromethane or the like, and usually the reaction is carried out at normal temperature.
- the compound of formula (I) can also be prepared from reaction scheme 4:
- variable LG 1 represents a suitable leaving group such as a halogen (e.g., chlorine, bromine, iodine, methylsulfonyl, etc.).
- the variable LG 2 represents a suitable leaving group such as a halogen (e.g., chlorine, bromine, iodine, methylsulfonyl, etc.).
- LG 3 represents a suitable leaving group such as a halogen (e.g., chlorine, bromine, iodine, etc.).
- PG 1 represents a suitable protecting group such as benzyl, Cbz, TBDMS and the like. All other variables are as defined by the present invention.
- Reaction Scheme 4 comprises the pyrimidine protected in step A and a suitable nucleophile such as piperidine, phenanthrene or the like in a suitable solvent such as dioxane, usually at a temperature ranging from 40 degrees Celsius to 100 degrees Celsius.
- a suitable solvent such as dioxane
- the deprotecting group is carried out by hydrogenation at room temperature.
- the insertion of the epoxy is usually carried out in a suitable solvent such as acetone, DMF and a suitable base (eg t-BuONa, t-BuOK, K 2 CO). 3 , etc.), at a suitable temperature, usually between 40 degrees Celsius and 100 degrees Celsius.
- the nitroimidazole is heated with the previously obtained epoxy compound while having a suitable base such as K 2 CO 3 and a suitable solvent such as DMF, and the temperature is usually from 40 ° C to 100 ° C.
- the next step E is carried out by ring-closing in a suitable solvent such as DMF in the presence of a suitable base to give a compound of formula (I) which is usually carried out in a temperature range of from -20 ° C to 40 ° C.
- intermediate compounds in the previous schemes are either commercially available or can be prepared according to the general reaction scheme well known to those skilled in the art.
- an intermediate compound of formula (III) can be prepared according to reaction scheme 5:
- LG 2 , LG 3 represent a suitable leaving group, such as a halogen (e.g., chlorine, bromine, iodine), a methylsulfonyl group, and the like, respectively. All other variables are as defined by the present invention.
- a halogen e.g., chlorine, bromine, iodine
- Reaction Scheme 5 comprises the step A in which allyl alcohol is oxidized by cumene peroxide in the presence of the corresponding (+) diisopropyl tartrate or (-) diisopropyl tartrate and tetraisopropyl titanate. It is usually carried out in a suitable solvent such as dichloromethane or toluene.
- the upper protecting group p-nitrobenzenesulfonyl chloride requires a suitable base such as triethylamine, diisopropylethylamine, and nitrogen aziridine, and the reaction is usually carried out at a temperature ranging from -20 ° C to 0 ° C.
- the epoxy transfer to the nitroimidazole is carried out by heating the epoxy intermediate obtained above with the raw material nitroimidazole, and the reaction requires a suitable solvent such as ethanol, isopropanol, tert-butanol, acetic acid. Tert-butyl ester or the like, a suitable base such as diisopropylethylamine, sodium acetate or the like, the reaction is usually carried out at a temperature ranging from 40 ° C to 100 ° C.
- Step C likewise we can directly obtain the non-optically active intermediate compound of formula (III) by heating the epoxy group with the leaving group and the nitroimidazole, the reaction requires a suitable solvent such as ethanol, isopropanol, uncle Butanol, t-butyl acetate, etc., a suitable base such as diisopropylethylamine, sodium acetate, etc., the reaction is usually carried out at a temperature ranging from 40 ° C to 100 ° C.
- a suitable solvent such as ethanol, isopropanol, uncle Butanol, t-butyl acetate, etc.
- a suitable base such as diisopropylethylamine, sodium acetate, etc.
- step A allyl alcohol is oxidized by cumene peroxide in the presence of the corresponding (+) diisopropyl tartrate or (-) diisopropyl tartrate and tetraisopropyl titanate.
- the reaction is usually carried out in a suitable solvent such as dichloromethane or toluene.
- a suitable temperature is -20 degrees Celsius to 0 degrees Celsius.
- the epoxy compound can be obtained directly by oxidation of m-chloroperoxybenzoic acid, and the reaction temperature of the oxidation is between -20 degrees Celsius and 20 degrees Celsius.
- the obtained epoxy intermediate is subjected to an attack by a suitable nucleophile, which requires a suitable base such as sodium hydroxide, a suitable solvent such as toluene, etc., usually at a temperature of 40 ° C. Between 100 degrees Celsius.
- Step C the diol is regenerated into an epoxy, and a suitable solvent such as tetrahydrofuran, a suitable base such as sodium hydrogen and a suitable leaving group such as p-toluenesulfonyl chloride, methanesulfonyl chloride, p-nitrobenzenesulfonate are required.
- the acid chloride or the like is usually subjected to a reaction temperature of from 0 ° C to 30 ° C.
- the compound of the formula (I) can also be converted from a compound represented by the formula (I) by itself a functional group well known in the art.
- the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
- High performance liquid chromatography was performed using a Shimadzu LC20AB system equipped with a Shimadzu SIL-20A autosampler and a Shimadzu DAD: SPD-M20A detector, using a Xtimate C18 (3 ⁇ m packing, 2.1 x 300 mm) column.
- 0-60AB_6 min method Apply a linear gradient, start elution with 100% A (A is 0.0675% TFA in water), and end the elution with 60% B (B is 0.0625% TFA in MeCN solution). The whole process is 4.2 minutes, then eluted with 60% B for 1 minute.
- the column was equilibrated for 0.8 minutes to reach 100:0 with a total run time of 6 minutes.
- 10-80AB_6 min method Apply a linear gradient, start elution with 90% A (A is 0.0675% TFA in water), and end the elution with 80% B (B in 0.0625% TFA in acetonitrile). 4.2 minutes, then eluted with 80% B for 1 minute.
- the column was equilibrated for 0.8 minutes to 90:10 with a total run time of 6 minutes.
- the column temperature was 50 ° C and the flow rate was 0.8 mL/min.
- the diode array detector has a scanning wavelength of 200-400 nm.
- TLC Thin layer chromatography
- a common solvent for flash column chromatography or thin layer chromatography is a mixture of dichloromethane/methanol, ethyl acetate/methanol and hexane/ethyl acetate.
- AS-H_3_40_2.35ML Chromatographic conditions Chiralpak AS-H column (specification 250 ⁇ 4.6 mm ID, 5 ⁇ m packing); mobile phase 40% methanol (0.05% DEA)-CO 2 ; flow rate 2.35 mL / min, detection The wavelength is 220 nm.
- OD-H_3_40_2.35M Chromatographic conditions Chiralcel OD-H column (specification 250 ⁇ 4.6 mm ID, 5 ⁇ m packing), mobile phase 40% methanol (0.05% DEA)-CO 2 , flow rate 2.35mL / min, detection The wavelength is 220 nm.
- AD-H_2_50_2.35ML Chromatographic conditions Chiralpak AD-H column (specification 250 ⁇ 4.6 mm ID, 5 ⁇ m packing), mobile phase 50% methanol (0.1% MEA)-CO 2 , flow rate 2.35mL / min, detection The wavelength is 220 nm.
- Preparative SFC analysis was performed on a Waters Thar 80 Pre-SFC system using a Gilson UV detector using Chiralcel OD-H (250 x 4.6 mm ID, 5 ⁇ m packing) or Chiralpak AD-H (specification 250 x 4.6 mm ID, 5 ⁇ m filler).
- Chiralcel OD-H 250 x 4.6 mm ID, 5 ⁇ m packing
- Chiralpak AD-H specification 250 x 4.6 mm ID, 5 ⁇ m filler
- reaction mixture was separated and purified by preparative separation chromatography (Boston Green ODS 150 mm ⁇ 30 mm ⁇ 5 ⁇ m; acetonitrile 5%-35%; water (0.225% formic acid); 25 mL/min) to give Compound 25.
- Methylmagnesium bromide (3.0 M, 623.33 [mu]L, 1.10 eq.) was added to a solution of compound 44-1 (300.00 mg, 1.70 mmol, 1.00 eq) in tetrahydrofuran (3.00 mL). The mixture was reacted at 0 ° C for 1 hour. TLC showed the reaction was complete. The reaction mixture was quenched by aqueous EtOAc (20 mL)EtOAc. The combined organic layers were concentrated under reduced pressure to give compound 44-2.
- Part I Testing the anti-tuberculous mycobacterial compound in vitro efficacy using H37Rv strain
- the compound was dissolved in pure DMSO (Sigma 276855-2L) to a concentration of 10 mg/ml as a mother liquor of the compound.
- 30 ⁇ l of DMSO was added to the wells of columns 2 to 11 of the v-bottom 96-well plate (Axygen-wipp 02280).
- Add 30 ⁇ l of compound mother liquor to the wells of column 2 mix well, and take 30 ⁇ l from the second column of wells and add to the third column of wells and mix by pipetting. Take this to the 10th column.
- Column 11 was not administered and contained only 30 ⁇ l of DMSO. This is the compound "motherboard".
- the H37Rv strain in the glycerol cryotube was inoculated into 7H9 medium containing 0.05% Tween 80, and cultured at 37 ° C for 4 weeks in a shaker at 200 rpm.
- the bacterial solution was washed twice with 7H9 medium containing 0.05% Tween 80 and resuspended in the same medium.
- This bacterial solution was dispensed into a microcentrifuge tube and stored at -80 °C. Storage time is less than 1 month. On the day of the test, the dispensed bacteria were lyophilized.
- the lyophilized broth was diluted 20-fold with 7H9 medium and then diluted 50-fold, and diluted 1000 times. This broth was used to inoculate the daughter plate. 100 ⁇ l of the bacterial solution was inoculated into each well of the daughter plate, and the column 12 was added with 100 ⁇ l of 7H9 medium without adding a bacterial solution.
- test panels were placed in a 37 ° C incubator and the humidity was maintained at >80%. Starting one week later, add 12.5 ⁇ l of 7H9 medium containing 20% Tween 80 and 20 ⁇ l of Alamar Blue (Invitrogen DAL1100) to a column of bacteria-containing wells and a column 12 containing no bacteria. Observed after 24 hours of culture. When the bacterial solution in the first column of pores can reduce the added Alamar blue to pink within 24 hours, add 7H9 medium containing 20% Tween 80 and Alamar blue to all wells on the test plate, 37 ° C Fluorescence values were measured after 24 hours of continued incubation.
- 7H9 medium containing 20% Tween 80 and Alamar blue
- the minimum inhibitory concentration (MIC) is defined as the minimum drug concentration that can completely inhibit the discoloration of Alamar blue by visual observation, or the minimum drug concentration that can inhibit the formation of more than 90% reduced Alamar blue by fluorometer. The results of partial compound detection are shown in Table 1.
- Part II Method for testing in vitro efficacy of anti-tuberculous mycobacterial compounds using M. bovis BCG strain TMC1019 (ATCC35737)
- the compound was dissolved in pure DMSO (Sigma 276855-2L) to a concentration of 12.8 mg/ml as a mother liquor of the compound.
- 30 ⁇ l of DMSO was added to the wells of columns 1 to 12 of the v-bottom 96-well plate (Axygen-wipp 02280).
- Column 12 was free of compound and contained only 30 ⁇ l of DMSO. Only 30 ⁇ l of DMSO was added to all A and H rows of wells.
- the BCG strain in the glycerol cryotube was inoculated into 7H9 liquid medium containing 0.05% Tween 80, and cultured in a shaker at 37 ° C for 200 rpm for 4 weeks.
- the bacterial solution was washed twice with 7H9 medium containing 0.05% Tween 80 and resuspended in the same medium.
- This bacterial solution was dispensed into a microcentrifuge tube and stored at -80 °C. Storage time is less than 1 month. On the day of the test, the dispensed bacteria were lyophilized.
- the diluted broth was diluted 20-fold with 7H9 medium and then diluted 50-fold, and diluted 1000 times. This broth was used for inoculation. 100 ⁇ l of the bacterial solution was inoculated into each well of the A row on the daughter plate. Only 100 ⁇ l of 7H9 medium was added to the wells of row A, and no bacterial solution was added. The final concentrations of the drug tested were 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.0625 and 0 ⁇ g/ml. The test panels were placed in a 37 ° C incubator and the humidity was maintained at >80%.
- the minimum inhibitory concentration is defined as the minimum final drug concentration that can completely inhibit the discoloration of Alamar blue by visual observation, or the minimum final drug concentration that can inhibit the formation of more than 90% reduced Alamar blue by a fluorometer.
- the results of partial compound detection are shown in Table 1. It is apparent that the compounds of the present invention have excellent inhibitory activity against the M. bovis strain BCG strain or the M. tuberculosis H37Rv strain, the minimum inhibitory concentration is ⁇ 1 ⁇ g/mL, and the compound of the present invention is non-cytotoxic. .
- MDR1-MDCK cell bidirectional permeability evaluation experiment MDR1-MDCK cells permanently expressing human P-glycoprotein were planted in 96-well Insert cell plate (cell culture nesting plate), cultured 4-7 Converging monolayers formed after the day; using one-way (A ⁇ B) permeability to evaluate fenoterol (low permeability label) and propranolol (high permeability label), and Digoxin (a P-glycoprotein substrate) The two-way permeability is used to verify the quality of the monolayer cells. These three control compounds made two duplicate wells.
- test compound transfer assay The standard conditions for the test compound transfer assay are as follows:
- -Transport buffer HBSS, pH 7.4;
- the sample solutions in the donor wells and receiver wells were immediately mixed with the cold acetonitrile solution containing the internal standard.
- the amount of intracellular compound accumulated was measured by lysing the cells with a cold acetonitrile solution containing an internal standard.
- the concentration of the test compound in all samples was analyzed by the LC/MS/MS method.
- the concentration of the test compound is expressed by the ratio of the peak area to the internal standard peak area.
- Table 2 lists the in vitro kinetic solubility (Kinetic Solubility, KS) of some of the compounds of the invention and the permeability data in MDR1-MDCK monolayer cells. Obviously, both compounds are superior to OPC-67683 in both KS and permeability.
- KS Kinetic Solubility
- the rodent pharmacological profile of the compound after intravenous and oral administration was tested in a standard protocol. Specifically, the test compounds were intravenously administered and orally administered to CD-1 male mice of 7 to 10 weeks old.
- the oral preparation was a suspension of 0.5% methylcellulose; the intravenous preparation was a clear solution of ethanol/DMSO/polyethylene glycol 400/pure water (10/10/50/30).
- Plasma and lung samples were collected and analyzed by LC-MS/MS method and the pharmacokinetic parameters were calculated.
- the pharmacokinetic parameters of Compound 4A are shown in Table 3. It is obvious that the pharmacokinetic parameters of Compound 4A are superior to the reference compound (OPC-67683).
- the pulmonary drug concentration of 4A is far from 1 hour and 6 hours after administration. It is much higher than the reference compound (OPC-67683), which is more than three times that of the reference compound. For patients with pulmonary infection with tubercle bacilli, the higher the drug exposure means the better the drug, which is very important.
- the experimental principle is to use aerosols to produce mice with M. tuberculosis aerosol inhalation infection, then the infected mice are kept under normal conditions for 31 days to form chronic lung infection of Mycobacterium tuberculosis, and then the mice are orally administered. Medical treatment. At the end of the experiment, the amount of bacteria in the lungs of the mice was counted to test the bactericidal efficacy of the drugs.
- the strain used in the experiment was Mycobacterium tuberculosis Erdman, ATCC 35801.
- the expansion medium was a broth medium based on Middlebrook 7H9, and a final concentration of 0.2% glycerol, 0.05% Tween 80, and 10% OADC (oleic acid-albumin-dextrose-catalase) solution were added.
- the bacteria were inoculated into the expansion medium and cultured at 37 ° C for 1-2 weeks to reach the logarithmic growth phase. Thereafter, the bacterial liquid was collected by centrifugation at 3150 g for 15 minutes at 4 °C.
- the collected Mycobacterium tuberculosis was washed twice with PBS supplemented with 0.05% Tween 80, and then the bacterial solution was filtered using an 8 ⁇ m pore size filter to remove excessively large pieces, all at 4 °C.
- the bacterial solution was dispensed in 0.5 ml and stored in a -80 ° C ultra-low temperature freezer. The actual concentration of the prepared bacterial solution was counted from the colonies on the 7H11 plate.
- Animals are adapted for rearing for at least two days in animal feeding facilities.
- the absorbance of the tuberculosis Bacillus licheniformis solution contained approximately 0.5 ⁇ 10 6 CFU/ml to 1 ⁇ 10 6 CFU/ml. 100 ⁇ l of this bacterial solution was plated on a 7H11 plate to measure the actual CFU concentration of the bacterial solution, which was an inoculum.
- Aerosol inhalation infection of the animals was performed using an aerosol produced in a Middlebrook inhalation exposure system (IES) (Glas-Col, Terre Haure, IN, USA) using 10 ml of bacterial inoculum. Before infection, pre-heat the IES for 15 minutes, fix the mice, add the bacteria solution to the nebulizer, and inject the aerosol for 1.5 hours. The IES was thoroughly sterilized immediately and the time of infection was recorded as T0.
- IES Middlebrook inhalation exposure system
- mice in the CO 2 euthanasia T3 group and the T29 group were used to perform CFU counts on the whole lung tuberculosis: after the mice were euthanized by CO 2 , the lungs were placed in 3 ml HBSS (Hanks Balanced). Salt Solution was homogenized in buffer for 20-30 s, followed by sonication for 15 seconds. The homogenate was diluted 1:10 to 1:10000 with a 10-fold gradient using the same HBSS buffer. A 7H11 plate was prepared using a 6-well plate, and 50 ⁇ l of the homogenate was inoculated per well. CFU was counted after all 6-well plates were cultured for 18 days at 37 °C.
- HBSS Hors Balanced
- the drug control group and the treatment group were administered on the 29th day after infection until the 56th day. One day later, the experiment was completed on the 57th day, and the mice were subjected to CFU counts of the whole lung tuberculosis bacilli after being euthanized by CO 2 .
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Abstract
Description
Claims (21)
- 式(I)所示化合物、其药学上可接受的盐或其立体异构体,其中,X为-O-、-S-、-S(=O)-、-S(=O) 2-、-NR 1-或-C(R 2)(R 3)-;R 1、R 2和R 3各自独立地为H、-L 1-R 4或-L 2-R 5;L 1为-O-、-S-、-S(=O) 2-、-(CR 6R 7) p-或-(CR 6R 7) q-C(=O)-;R 4为C 3-6环烷基、5-6元杂芳基或6-12元芳基,其中所述C 3-6环烷基、5-6元杂芳基和6-12元芳基独立任选被1、2或3个R取代;L 2为单键或-C(=O)-O-;R 5为F、Cl、Br、I、-OH、-NH 2、-CN或任选被1、2、3或4个独立选自F、Cl、Br、I、-NH 2、-OH、-OCH 3和-CN的取代基所取代的C 1-6烷基;p为1或2;q为0、1或2;R 6和R 7各自独立地为H、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3或-CH 2(CH 3) 2;各R独立地为F、Cl、Br、I、-CN、-OH、C 1-6烷氧基或C 1-6烷基,其中所述C 1-6烷氧基和C 1-6烷基独立任选被1、2或3个独立选自F、Cl、Br、I、-NH 2、-OH、-OCH 3和-CN的取代基所取代;n 1为1或2;n 2和n 3各自独立地为0、1或2;所述5-6元杂芳基包含1、2、3或4个独立选自-O-、-S-、N或-NH-的杂原子或杂原子团。
- 根据权利要求1所述的化合物、其药学上可接受的盐或其立体异构体,其中所述L 1为-O-、-CH 2-、-(CH 2) 2-、-CH(CH 3)-、-C(CH 3) 2-、-C(=O)-或-CH 2-C(=O)-。
- 根据权利要求1所述的化合物、其药学上可接受的盐或其立体异构体,其中所述各R独立地为F、Cl、Br、I、-CN、-OH、-OCH 3、-OCF 3、-OCH 2CH 3、-OCH 2CF 3、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH 2(CH 3) 2、-CH 2CH 2CH 2CH 3、-CH 2(CH 3) 3、-CH 2(CH 3)CH 2CH 3、-CH 2CH 2(CH 3) 2、-CF 3或-CH 2CF 3。
- 根据权利要求1或3所述的化合物、其药学上可接受的盐或其立体异构体,其中所述R 4为环丙基、环丁基、呋喃基、吡啶基、嘧啶基或苯基,其中所述环丙基、环丁基、呋喃基、吡啶基、嘧啶基和苯基独立任选被1、2或3个R取代。
- 一种药物组合物,包括作为活性成分的治疗有效量的根据权利要求1~17任一项所述的化合物、其药学上可接受的盐或其立体异构体以及药学上可接受的载体。
- 根据权利要求1~17任一项所述的化合物、其药学上可接受的盐或其立体异构体或权利要求18所述的药物组合物在制备治疗分支杆菌感染引起的相关疾病的药物中的应用。
- 根据权利要求19所述的应用,其中所述的分支杆菌为结核分枝杆菌。
- 根据权利要求19所述的应用,其中所述的分支杆菌感染引起的相关疾病为肺结核。
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