WO2017071606A1 - Utilisation médicale d'un composé d'hydroxylpurine - Google Patents

Utilisation médicale d'un composé d'hydroxylpurine Download PDF

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WO2017071606A1
WO2017071606A1 PCT/CN2016/103486 CN2016103486W WO2017071606A1 WO 2017071606 A1 WO2017071606 A1 WO 2017071606A1 CN 2016103486 W CN2016103486 W CN 2016103486W WO 2017071606 A1 WO2017071606 A1 WO 2017071606A1
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mmol
methyl
dione
indole
group
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PCT/CN2016/103486
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English (en)
Chinese (zh)
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吴凌云
张鹏
张丽
陈誌中
陈曙辉
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南京明德新药研发股份有限公司
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Priority to CN201680063418.4A priority Critical patent/CN108348525B/zh
Publication of WO2017071606A1 publication Critical patent/WO2017071606A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms

Definitions

  • the present invention relates to the use of a series of hydroxy steroids in the preparation of a medicament for treating liver diseases, in particular to the use of a compound of the formula (I), a tautomer thereof or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating liver diseases .
  • Phosphodiesterase catalyzes the hydrolysis of cyclized nucleotides cGMP and cAMP, and regulates various physiological responses by controlling the intramolecular concentrations of these two important secondary signaling factors. Cyclization of nucleotides cGMP and cAMP intramolecular Abnormal regulation is the cause of many diseases. Several drugs have been used to improve and treat diseases by inhibiting PDE activity, such as PDE5 inhibitors for pulmonary hypertension and PDE4 inhibitors for arthritis caused by psoriasis. There are eleven major classes of phosphodiesterase genes, each of which can express several subtypes. There are more than 100 PDE subtypes in total. Different subtypes have different structures, different tissue distributions, and circularized nuclei. The activities of cGMP and cAMP of glucosinolates are also very different, and the physiological functions of regulation are also very different.
  • PDE2 phosphodiesterase can catalyze the hydrolysis of cyclized nucleotides cGMP and cAMP, while cAMP activity is regulated by cGMP, which plays a key role in the balance of cGMP and cAMP functions in cells.
  • PDE2 is widely expressed in human tissues and is mainly distributed in the heart, central nervous system, liver, adrenal gland, endothelial cells, and platelets. PDE2 is involved in the regulation of various physiological activities, such as central learning, memory and cognition, maintaining the basic rhythm of the heart, smooth muscle and endothelial cells, permeability of endothelial cells, and regulating inflammation.
  • PDE2 knockout mice directly cause embryonic death. It can be used in a variety of central, cardiovascular, and inflammatory responses by inhibiting PDE2 activity.
  • Non-selective PDE inhibitory activities of various natural and synthetic terpenoids have long been discovered, such as caffeine, theophylline, pentoxifylline and the like.
  • Pentoxifylline PDE2 activity
  • PDE2 activity is clinically approved for lower limb paralysis caused by peripheral vascular occlusion. The main role is to reduce blood viscosity, increase red blood cell deformation, and inhibit platelet aggregation.
  • Novel highly selective PDE2 inhibitors have also been reported to control endothelial cell division and angiogenesis, and to improve central cognitive impairment.
  • the development and application of the new novel selective PDE2 inhibitors are still very limited, and the discovery and application of new PDE2 inhibitors have broad prospects.
  • TNF- ⁇ Tumor necrosis factor alpha
  • IL-1 interleukon-l
  • IL-6 proinflammatory cytokines
  • IMID immune-mediated inflammatory diseases
  • RA rheumatoid arthritis
  • psoriatic arthritis psoriatic arthritis
  • JCA juvenile chronic arthritis
  • TNF- ⁇ is an ideal target for many of the above IMIDs, and for some diseases caused by chronic chronic inflammatory damage, such as steatohepatitis, chronic obstructive pneumonia, etc., using TNF- ⁇ inhibitors (TNF- ⁇ inhibitors) And excess TNF- ⁇ is also an effective prevention and treatment route.
  • TNF- ⁇ monoclonal antibody has been clinically proven to inhibit TNF- ⁇ as a very effective means of treating the aforementioned inflammation-related diseases.
  • PDE2 can be mechanically By regulating the expression of TNF- ⁇ , it is possible to control the level of TNF- ⁇ by regulating PDE2 activity, thereby achieving control of the inflammatory response.
  • the present invention provides a compound of the formula (I), a tautomer thereof or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for treating or preventing liver disease,
  • L 11 is selected from the group consisting of empty, C(R)(R');
  • R, R' are each independently selected from H, halogen, OH, NH 2 , CN, optionally substituted 1 to 6 alkyl or heteroalkyl;
  • R, R' may be cyclized to a 3-6 membered cycloalkyl or heterocycloalkyl group
  • A is empty or is selected from optionally substituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl;
  • L 12 is selected from an optionally substituted 1 to 6 membered alkyl or heteroalkyl group
  • R 1 is selected from an optionally substituted 1 to 6 membered alkyl group, a 3 to 6 membered cycloalkyl group or a heteroalkyl group;
  • the liver disease is selected from the group consisting of nonalcoholic fatty liver and liver fibrosis.
  • the substituents in the above R, R', A, L 12 and R 1 are each independently selected from the group consisting of halogen, OH, NH 2 , CN, optionally substituted 1 to 6 alkyl, 3 A 6-membered cycloalkyl or heteroalkyl group, the number of each group substituent being independently selected from 1, 2 or 3.
  • the substituents in the above R, R', A, L 12 and R 1 are each independently selected from the group consisting of halogen, CF 3 , CN, OH, Me, Et, n-propyl, isopropyl, and ring.
  • halogen CF 3 , CN, OH, Me, Et, n-propyl, isopropyl, and ring.
  • R and R' are each independently selected from the group consisting of H, Me, CF 3 , and Et.
  • the above L 11 is selected from
  • the above A is selected from the group consisting of: a 3 to 12 membered cycloalkyl or heterocycloalkyl group, a 5 to 12 membered aryl group or a heteroaryl group.
  • the above A is selected from the group consisting of: optionally substituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pentylpentyl, Phenyl, pyridyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, bicyclo[1.1.1]pentane, or a bicyclic ring or spiro ring selected from any two of the above groups Base or a cyclized group.
  • the above A is selected from the group consisting of:
  • the above A is selected from the group consisting of
  • the above L 12 is selected from the group consisting of methylene,
  • R 1 is selected from the group consisting of Me, CHF 2 , CF 3 , Et, CH 2 CF 3 , isopropyl, Cyclopropyl,
  • the invention is selected from the group consisting of the following compounds in the preparation of a medicament for treating or preventing liver diseases:
  • the present invention is selected from the group consisting of the following compounds in the preparation of a medicament for treating or preventing liver diseases:
  • 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 salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
  • a "pharmaceutically acceptable salt” is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, Bicarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydrogen Iodate, hydroxyl, hydroxynaphthalene, isethionate, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, Phenylacetic acid, phosphoric
  • 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.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • 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.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers 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.
  • 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 salt of a diastereomer is formed with a suitable optically active acid or base, and then by a conventional method 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). 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 base, wash Agent matrix, ointment base, and the like. 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. For additional information on vectors, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are hereby incorporated by reference.
  • 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, including variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable.
  • it means that two hydrogen atoms are substituted.
  • Ketone substitution does not occur on the aryl 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 a bond of a substituent can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring.
  • substituents do not indicate which atom is attached to a compound included in the chemical structural formula including but not specifically mentioned, such a substituent may be bonded through any atomic phase thereof.
  • Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, a structural unit or It is indicated that it can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • halo or halogen
  • 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.
  • haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • Alkoxy represents the above alkyl group having a specified number of carbon atoms attached through an oxygen bridge.
  • the C 1-6 alkoxy group includes a 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.
  • Cycloalkyl includes saturated cyclic groups such as cyclopropyl, cyclobutyl or cyclopentyl.
  • the 3-7 cycloalkyl group includes C 3 , C 4 , C 5 , C 6 and C 7 cycloalkyl groups.
  • Alkenyl includes hydrocarbon chains in a straight or branched configuration wherein one or more carbon-carbon double bonds, such as vinyl and propylene groups, are present at any stable site on the chain.
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • 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, phenylpyridine 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 means a straight or branched chain radical or a combination thereof, which may be fully saturated, unitary 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.
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom.
  • heterohydrocarbyl by itself or in conjunction with another term denotes a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the heteroatoms B, O, N and S can be located at any internal position of the heterohydrocarbyl group (including where the hydrocarbyl group is attached to the rest of the molecule).
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • alkoxy alkylamino and “alkylthio” (or thioalkoxy) are customary expressions and refer to those alkane which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Base group alkoxy
  • 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.
  • 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.
  • 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.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted, disubstituted or polysubstituted, may be monovalent, divalent or polyvalent, it may be monocyclic or Polycyclic (preferably 1 to 3 rings) which are fused together or covalently linked.
  • heteroaryl refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, 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, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyridyl Azyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxan Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, 5-
  • aryl groups when used in conjunction with other terms (eg, aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen.
  • alkyl groups substituted by an atom such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
  • 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 groups, Ethyl and tert-butyl; acyl, such as alkanoyl (such as acetyl); arylmethyl, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) And diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl groups, Ethyl and tert-butyl
  • acyl such as alkanoyl (such as acetyl)
  • arylmethyl such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenyl
  • 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.
  • Compound 1 is the isomer 2 of Example 51; Pen. is pentoxifylline; INT-747 is 6-ethyl chenodeoxycholic acid; aq stands for water; HATU stands for O- (7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; EDC stands for N-(3-dimethylaminopropyl)-N '-Ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for Diisopropyl azodicarboxylate; DMF stands for N,N-dimethyl
  • FIG. 1 Liver HE staining of MCD mice
  • Control group (STZ solvent control + normal diet)
  • Model group (STZ + high fat diet) + vehicle control (t.i.d.)
  • FIG. 10 Live picture of Sirius red staining in STZ+HFD mice
  • Figure 14 Liver HE staining of a model of cholestasis-induced liver fibrosis, 100-fold magnification.
  • A group-1, healthy control
  • B group-2, model control
  • C group-3INT-747-20 mg/kg, QD
  • D group-4, pentoxifylline-100 mg/kg, TID
  • E Group-5, compound 1-1 mg/kg, BID
  • F Group-6, compound 1-3 mg/kg, BID
  • G group-7, compound 1-10 mg/kg, BID.
  • Figure 16 Liver Sirius red staining of a model of cholestasis-induced liver fibrosis in rats, 50-fold magnification.
  • A group-1, healthy control
  • B group-2, model control
  • C group-3INT-747-20 mg/kg, QD
  • D group-4, pentoxifylline-100 mg/kg, TID
  • E Group-5, compound 1-1 mg/kg, BID
  • F Group-6, compound 1-3 mg/kg, BID
  • G group-7, compound 1-10 mg/kg, BID.
  • Figure 18 Liver HE staining picture of mice with liver fibrosis induced by CCl 4 , 100-fold magnification.
  • A group-1, healthy control
  • B group-2, model control
  • C group -3 INT-747-20 mg/kg, QD
  • D group-4, pentoxifylline - 100 mg/kg, TID
  • E Group-5, compound 1-1 mg/kg, BID
  • F Group-6, compound 1-3 mg/kg, BID
  • G Group-7, compound 1-10 mg/kg, BID.
  • FIG 24 CCl 4 liver fibrosis model mice induced by Sirius red staining images in liver of mice, 50-fold magnification.
  • A group-1, healthy control
  • B group-2, model control
  • C group-3INT-747-20 mg/kg, QD
  • D group-4, pentoxifylline-100 mg/kg, TID
  • E Group-5, compound 1-1 mg/kg, BID
  • F Group-6, compound 1-3 mg/kg, BID
  • G group-7, compound 1-10 mg/kg, BID.
  • Ethyl 5-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-indol-1-yl)pentanoic acid ethyl ester (0.500 g, 1.62)
  • Ethyl acetate was dissolved in anhydrous tetrahydrofuran (5 mL). N.sub.3.
  • the reaction solution was stirred at -78 ° C for 0.5 hour, then slowly raised to 0 ° C and reacted for 0.5 hour.
  • the reaction solution was poured into water and extracted with ethyl acetate (30 mL, 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and evaporated.
  • Ethylmagnesium bromide (3M ether solvent, 1.1 mL, 3.24 mmol) was added to ethyl 5-(3,7-dimethyl-2,6-dioxo-2,3 at -35 °C under nitrogen.
  • ,6,7-Tetrahydro-1H-indol-1-yl)pentanoic acid ethyl ester 500 mg, 1.62 mmol
  • tetraisopropyl titanate (461 mg, 1.62 mmol) in tetrahydrofuran (10 mL).
  • the reaction solution was slowly heated to 25 ° C and stirred for 2 hours.
  • the reaction was quenched by water (10 mL).
  • Methyl-3-oxocyclobutanecarboxylic acid (25.0 g, 195 mmol), ethylene glycol (35.0 g, 564 mmol) and p-toluenesulfonic acid (3.50 g, 20.0 mmol) were dissolved in toluene (250 mL).
  • the water separator was heated to reflux overnight.
  • the reaction solution was cooled to 25 ° C, washed sequentially with water (300 mL ⁇ 2) and saturated sodium hydrogen carbonate (500 mL ⁇ 2).
  • the organic phase was dried over anhydrous magnesium sulfate, filtered, and then filtered and evaporated tolulululululululululululululululululululululululu Rate: 90%.
  • Lithium tetrahydroaluminum (5.20 g, 136 mmol) was slowly dissolved in tetrahydrofuran (240 mL) under nitrogen at 0 ° C, then 5,8-dioxaspiro[3,4] dissolved in tetrahydrofuran (60 mL) Methyl octane-2-carboxylate (19.5 g, 113 mmol). The reaction was slowly raised to 25 ° C and stirred for 3.5 hours.
  • Methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (40.0 mg, 0.256 mmol) and triethylamine (39.0 mg, 0.384 mmol) were dissolved in dichloromethane (15 mL) Methanesulfonyl chloride (35.0 mg, 0.307 mmol) was slowly added dropwise at 0 °C. The reaction mixture was stirred at 0 ° C for 2 hours. The mixture was diluted with methylene chloride (10 mL). Methyl (((methylsulfonyl)oxy)methyl)-bicyclo[1.1.1]pentan-1-carboxylate (50.0 mg, yellow oil).
  • Methyl 3-oxo-cyclopentanoate (16.0 g, 110 mmol), p-toluenesulfonic acid (14.0 g, 220 mmol) and ethylene glycol (969 mg, 5.60 mmol) were dissolved in anhydrous toluene (160 mL). The water separator was heated and refluxed for 4 hours. The reaction was quenched with water (2OmL)EtOAc. The combined organic layers were washed with EtOAc EtOAc EtOAc.
  • Methyl 1,4-dioxaspiro[4.4]nonane-7-carboxylate (1.00 g, 10.7 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), and the mixture was stirred under nitrogen. (531 mg, 13.9 mmol). The reaction solution was slowly warmed to 25 ° C and stirred for 3 hours. Water (0.5 mL), 15% sodium hydroxide solution (0.5 mL), and water (1.5 mL) were sequentially added to the mixture. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give (4-dioxaspiro[4.4]decane-7-yl)-methanol (m.
  • the 1,4-dioxaspiro[4.4]decane-7-ylmethyl methanesulfonate (300 mg, 1.27 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL). Potassium carbonate (350 mg, 2.54 mmol), potassium iodide (21.0 mg, 0.130 mmol), 2,6-hydroxy-3,7-dimethylindole (275 mg, 1.52 mmol) were added at 25 °C. The reaction solution was heated to 130 ° C and stirred for 3 hours. The reaction mixture was cooled to 25 ° C, then quenched with water (40 mL).
  • Lithium tetrahydroaluminum (2.30 g, 61.0 mmol) was slowly added to tetrahydrofuran (60 mL) under nitrogen at 0 ° C, and ethyl 1,4-dioxaspiro[4,5]nonane-8-carboxyl was added dropwise.
  • 1,4-Dioxaspiro[4,5]decane-8-ylmethyl methanesulfonate (1.50 g, 6.00 mmol), 3,7-dimethyl-1H-indole-2,6 ( 3H,7H)-dione (1.00 g, 6.00 mmol) and potassium carbonate (2.50 g, 18.0 mmol), potassium iodide (100 mg, 0.600 mmol) dissolved in N,N-dimethylformamide (20 mL) Heat to 130 ° C and stir for 3 hours.
  • Triethyl phosphonoacetate (12.2 g, 54.4 mmol) was dissolved in tetrahydrofuran (100 mL), and sodium hydride (1.92 g, 48.0 mmol) was added portionwise at 0 ° C, and the reaction was stirred for 30 min under nitrogen atmosphere.
  • a solution of 1,4-cyclohexanedione monoethylene ketal (5.00 g, 32.0 mmol) dissolved in tetrahydrofuran (15 mL) was added dropwise to the reaction solution at 0 ° C, and the reaction solution was stirred at 25 ° C for 3 hours. .
  • the reaction was quenched with water (25 mL) andEtOAcEtOAc.
  • Methyl 2-(1,4-dioxaspiro[4.5]decane-8-ylidene)acetate (3.80 g, 17.9 mmol) was dissolved in methanol (50 mL) and dry palladium carbon (palladium 10%) , water 1%, 400 mg), the reaction solution was reacted under hydrogen (50 psi) for 18 hours at room temperature. The reaction mixture was filtered, and the filtrate was evaporated toluiserjjjjjjjjj .
  • Ethyl ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (5.00 g, 23.3 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL). A lithium diisopropylamide solution (2M tetrahydrofuran solution, 14.0 mL, 28.0 mmol) was added, and the mixture was stirred at -78 ° C for one hour. Methyl iodide (6.62 g, 46.7 mmol) was slowly added and stirring was continued for 1 hour. The reaction was quenched by the addition of water (100 mL). The reaction mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc.
  • Ethyl 8-methyl-1,4-dioxaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (5.00 g, 21.9 mmol) was dissolved in tetrahydrofuran (50 mL) and 1N hydrochloric acid was added dropwise at 0 °C. The aqueous solution (20 mL) was stirred at 20 ° C for 1 hour. The mixture was cooled to 0 ° C and quenched with sodium bicarbonate (50 mL). The mixture was extracted with ethyl acetate (100 mL x 3).
  • Ethyl ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (5.00 g, 23.3 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL). A lithium diisopropylamide solution (2M-hexane solution, 14.0 mL, 28.0 mmol) was added, and the mixture was stirred at -78 ° C for one hour. Methoxybromomethane (5.83 g, 46.7 mmol) was slowly added and stirring was continued for 1 hour. The reaction was quenched by the addition of water (100 mL). The reaction mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc.
  • Ethyl ethyl 8-(methoxymethyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate (5.00 g, 19.4 mmol) was dissolved in tetrahydrofuran (50 mL) at 0 ° C After 1N diluted hydrochloric acid (10 mL) was added dropwise, the mixture was stirred at 20 ° C for 1 hour. The mixture was cooled to 0 ° C and quenched with sodium bicarbonate (50 mL). The mixture was extracted with ethyl acetate (100 mL x 3).
  • Ethyl ethyl 1-(methoxymethyl)-4-oxocyclohexanecarboxylate (3.00 g, 14.0 mmol)
  • EtOAc EtOAc
  • EtOAc EtOAc
  • Trimethylsilyltrifluoromethyl (3.98 g, 28.0 mmol) was then added at 0 °C.
  • the reaction solution was reacted under nitrogen for 20 hours at 20 °C.
  • 4N dilute hydrochloric acid (7 mL) was added.
  • the mixture was reacted under nitrogen for 6 hours at room temperature.
  • Methyl 1,4-cyclohexanecarboxylate (1.20 g, 6.45 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and then filtered under nitrogen, and borane dimethyl sulfide (10 M, 1.0 mL) was slowly added dropwise at 0 ° C. 10.3 mmol), the reaction solution was stirred at 0 ° C for 0.5 hour, slowly raised to 25 ° C, and stirring was continued for 1 hour. The reaction was quenched by the addition of water (40 mL). The organic phase was combined, washed with EtOAc EtOAc (EtOAc m. : 91%.
  • Methyl 4-hydroxymethylcyclohexanecarboxylate (900 mg, 5.20 mmol) and triethylamine (1.58 g, 15.6 mmol) were dissolved in anhydrous dichloromethane (5 mL). Sulfonyl chloride (720 mg, 6.30 mmol). The reaction solution was raised to 25 ° C and stirred for 2 hours. The reaction was quenched by the addition of water (60 mL).
  • Methyl 4-methanesulfonyloxymethyl-cyclohexanecarboxylate (580 mg, 2.32 mmol) was dissolved in 5 mL of anhydrous N,N-dimethylformamide, and potassium carbonate was added at 25 ° C under nitrogen atmosphere ( 640 mg, 4.64 mmol), potassium iodide (38.0 mg, 0.230 mmol), 2,6-hydroxy-3,7-dimethylindole (501 mg, 2.80 mmol). The reaction solution was stirred at 130 ° C for 3 hours. The mixture was extracted with ethyl acetate.
  • Methyl 4-((3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-indol-1-yl)-cyclohexanecarboxylic acid (100 mg , 0.30 mmol) was dissolved in 5 mL of anhydrous tetrahydrofuran.
  • Ethyl magnesium bromide solution (3M diethyl ether solution, 1 mL, 3.00 mmol) was slowly added dropwise at -65 ° C under nitrogen atmosphere, and the reaction mixture was stirred at -65 ° C for 2 hours.
  • the trans-cyclohexane-1,4-dicarboxylic acid monomethyl ester (5.00 g, 26.8 mmol) was dissolved in tetrahydrofuran (100 mL), and borane dimethyl sulfide (3.06 g, 40.3 mmol) was added at 0 °C. The reaction was carried out for 2 hours at room temperature. The reaction was quenched by the addition of saturated MeOH (50 mL). After concentrating, water (50 mL) was evaporated (EtOAc m. Oily), yield: 87%.
  • Methyl trans-4-methanesulfonyloxymethyl-cyclohexanecarboxylate (1.00 g, 4.00 mmol), 3,7-dimethyl-1H-indole-2,6(3H,7H)- Diketone (719 mg, 4.00 mmol), potassium iodide (66.0 mg, 0.397 mmol) and potassium carbonate (1.10 g, 7.96 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction solution was warmed to 120 ° C and stirred for 3 hours. It was cooled to room temperature, filtered, and the filtrate was concentrated.
  • Ethyl 3-acetylbenzoate 500 mg, 2.60 mmol was dissolved in tetrahydrofuran (20 mL), and trifluoromethyltrimethylsilane (370 mg, 2.60 mmol) and cesium fluoride (79.0 mg, 0.520) were added at room temperature. Mm). After stirring at room temperature for 12 hours, the reaction mixture was diluted with ethyl acetate (30 mL). Ethyl ethyl 3-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoic acid ethyl ester (600 mg, yellow solid). 88%.
  • Ethyl ethyl 3-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoate (500 mg, 1.91 mmol) was dissolved in tetrahydrofuran (20 mL). Lithium aluminum hydride (108 mg, 2.87 mmol) was stirred at room temperature for 2 hours, and water (0.1 mL), 15% sodium hydroxide (0.1 mL) and water (0.3 mL) were added to the mixture and stirred for 20 min. The reaction mixture was diluted with ethyl acetate (30 mL). EtOAc. Methyl)phenyl)propan-2-ol (400 mg, yellow solid), yield: 95%.
  • 1,1,1-Trifluoro-2-(3-hydroxymethyl)phenyl)propan-2-ol 400 mg, 1.82 mmol
  • triethylamine 275 mg, 2.72 mmol
  • the reaction mixture was added with methanesulfonyl chloride (250 mg, 2.18 mmol) at 0 ° C, and stirred for 2 hr, diluted with dichloromethane (30 mL). Filtration and concentration of the filtrate under reduced pressure gave 3-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzyl methanesulfonate (500 mg, m.
  • MS-ESI calcd [M+H] + 299.
  • Lithium aluminum hydride (1.61 g, 42.3 mmol) was slowly added to methyl 4-(1,1,1-trifluoro-2-hydroxypropyl-2-yl)benzoate (7.00 g) under nitrogen at 0 °C. , 28.2 mmol) in tetrahydrofuran (150 mL).
  • the reaction solution was stirred at 0 ° C for 3 hours.
  • water (1.60 mL), 15% sodium hydroxide solution (1.60 mL) and water (4.80 mL) were added slowly.
  • 1,1,1-Trifluoro-2-(4-(hydroxymethyl)phenyl)propyl-2-ol (5.80 g, 26.3 mmol) and diisopropylethylamine (10.2 g, 79.0 mmol) Dissolved in dichloromethane (80 mL) and slowly added methanesulfonyl chloride (4.53 g, 39.5 mmol) at 0 °C. The reaction solution was stirred at 0 ° C for 0.5 hour.
  • EtOAc EtOAc
  • EtOAc EtOAc
  • EtOAc Drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure by high-performance liquid chromatography to obtain 3,7-dimethyl-1-((6-(1,1,1-trifluoro-2-hydroxypropane-2) -yl)pyridin-3-yl)methyl)-1H-indole-2,6(3H,7H)-dione (50 mg, white solid), yield: 27%.
  • N-Methoxy-N,5-dimethylpyrazine-2-carboxamide (1.50 g, 8.28 mmol) was dissolved in tetrahydrofuran (30 mL), and methylmagnesium bromide (3M diethyl ether solution) was added dropwise at 0 °C. 13.3 mL, 39.9 mmol), then stirred at 25 ° C for 1 hour. The mixture was cooled to 0 ° C and quenched by water (10 mL). The mixture was extracted with EtOAc (30 mLEtOAc) The residue was purified by EtOAc EtOAcjjjjjjj 62%. MS-ESI calcd for [M + H] + 137, found 137.
  • 1,4-Dioxaspiro[4,5]decane-8-ylmethyl methanesulfonate 200 mg, 0.800 mmol
  • 3-methyl-7-(2,2,2-trifluoroethyl -1H-indole-2,6(3H,7H)-dione 200 g, 0.800 mmol
  • potassium carbonate 334 mg, 2.42 mmol
  • potassium iodide 14.0 mg, 0.0800 mmol
  • N,N-dimethyl In the formamide (3 mL) the reaction solution was heated to 130 ° C and stirred for 3.5 hours.
  • 1,4-Dioxaspiro[4,5]decane-8-ylmethyl methanesulfonate (603 mg, 2.41 mmol), 3-methyl-7-(2,2,2-trifluoroethyl -1H-indole-2,6-(3H,7H)-dione (500 mg, 2.01 mmol) and potassium iodide (33.3 mg, 0.201 mmol) were dissolved in N,N-dimethylformamide (8 mL). Potassium carbonate (555 mg, 4.02 mmol) was added, and the mixture was heated to reflux at 130 ° C for 4 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated evaporated. (2,2,2-Trifluoroethyl)-1H-indole-2,6-(3H,7H)-dione (980 mg, yellow oil). MS-ESI calcd for [M+H] + 403.
  • 6-Amino-5-bromo-1-methylpyrimidine-2,4(1H,3H)-dione (2.19 g, 10.0 mmol) was dissolved in a mixed solvent of cyclopropylamine (20 mL) and water (5 mL). The reaction solution was heated to reflux for 5 hours. The reaction solution was filtered to remove the solvent to give the crude product 6-amino-5-(cyclopropylamine)-1-methylpyrimidine-2,4(1H,3H)-dione.
  • 6-Amino-5-(cyclopropylamine)-1-methylpyrimidine-2,4(1H,3H)-dione (1.96 g, 10.0 mmol), trimethyl orthoformate (2.12) under N2 g, 20.0 mmol) and p-toluenesulfonic acid (86.0 mg, 0.500 mmol) were dissolved in anhydrous N,N-dimethylformamide (20 mL). The reaction solution was heated to 100 ° C overnight. The reaction solution was filtered, and the solvent was evaporated to give the crude product 7-cyclopropyl-3-methyl-1H-indole-2, 6(3H,7H)-dione.
  • 1,4-Dioxaspiro[4.5]decane-8-ylmethyl methanesulfonate 250 mg, 1.00 mmol
  • 7-isopropyl-3-methyl-1H-indole-2,6 ( 3H,7H)-Dione 208 mg, 1.00 mmol
  • potassium iodide 15.8 mg, 0.100 mmol
  • potassium carbonate 276 mg, 2.00 mmol

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Abstract

La présente invention concerne une application d'une série de composés de hydroxylpurine dans la préparation d'un médicament pour le traitement ou la prévention d'une maladie hépatique, et en particulier, l'invention concerne une application d'un composé de formule (I) ou de son tautomère ou de son sel pharmaceutiquement acceptable dans la préparation d'un médicament pour le traitement d'une maladie hépatique.
PCT/CN2016/103486 2015-10-29 2016-10-27 Utilisation médicale d'un composé d'hydroxylpurine WO2017071606A1 (fr)

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WO2022042390A1 (fr) * 2020-08-25 2022-03-03 广东众生睿创生物科技有限公司 Utilisation de composés d'hydroxypurine pour le traitement de maladies de la peau

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WO1998055110A2 (fr) * 1997-06-05 1998-12-10 Dalhousie University NOUVELLES UTILISATIONS DES COMPOSES REDUISANT L'EXPRESSION DU GENE $i(c-jun)
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CA2915814A1 (fr) * 2013-06-18 2014-12-24 Imprimis Pharmaceuticals Inc. Preparations locales de pentoxifylline pour traiter la maladie de la peyronie

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WO2022042390A1 (fr) * 2020-08-25 2022-03-03 广东众生睿创生物科技有限公司 Utilisation de composés d'hydroxypurine pour le traitement de maladies de la peau

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