WO2016180247A1 - Composé bicyclique utilisé comme inhibiteur de la lp-pla2, et procédé de préparation et utilisation pharmaceutique de ce dernier - Google Patents

Composé bicyclique utilisé comme inhibiteur de la lp-pla2, et procédé de préparation et utilisation pharmaceutique de ce dernier Download PDF

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WO2016180247A1
WO2016180247A1 PCT/CN2016/080725 CN2016080725W WO2016180247A1 WO 2016180247 A1 WO2016180247 A1 WO 2016180247A1 CN 2016080725 W CN2016080725 W CN 2016080725W WO 2016180247 A1 WO2016180247 A1 WO 2016180247A1
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group
alkyl
compound
formula
alkoxy
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PCT/CN2016/080725
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Chinese (zh)
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沈建华
王逸平
陈鑫德
徐文伟
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中国科学院上海药物研究所
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Priority to CN201680016991.XA priority Critical patent/CN107709325B/zh
Publication of WO2016180247A1 publication Critical patent/WO2016180247A1/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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to novel bicyclic compounds and preparation methods thereof, pharmaceutical compositions using the compounds as active ingredients, and their use in the preparation of a medicament for treating diseases associated with Lp-PLA 2 enzyme activity .
  • Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ), also known as platelet-activating factor acetylhydrolase (PAF-AH), contains 441 amino acids with a relative molecular mass of 45 kD. 70% of Lp-PLA 2 in human plasma binds to low-density lipoprotein (LDL), and 30% of Lp-PLA 2 binds to high-density lipoprotein (HDL).
  • LDL low-density lipoprotein
  • HDL high-density lipoprotein
  • Lp-PLA 2 can rapidly hydrolyze oxidized phosphatidylcholine into lysophosphatidylcholine (1yso-PC) and oxidized non-esterified fatty acid (ox-NEFA), while lyso-PC and ox-NEFA are very strong. It promotes inflammation and activates the inflammatory/immune response of various cells including endothelial cells, smooth muscle cells, monocytes/macrophages, T cells, and neutrophils.
  • Lp-PLA 2 inhibitors may be universally applicable to any condition in which the lipid involved in oxidation is hydrolyzed into two inflammatory traits with the participation of Lp-PLA 2 .
  • These include atherosclerosis, diabetes, diabetic eye disease, diabetic brain disease, hypertension, angina pectoris, rheumatoid arthritis, stroke, myocardial infarction, ischemia and reperfusion, psoriasis, and brain inflammatory diseases (such as: Alzheimer's disease), various neuropsychiatric diseases (such as: schizophrenia), ischemia-reperfusion injury, sepsis, acute and chronic inflammatory diseases.
  • Atherosclerosis is not only related to abnormal blood lipid levels, but also an inflammation-related disease. Inflammatory factors that inhibit atherosclerosis are new ways to treat the disease. Studies have shown that lyso-PC can promote the development of atherosclerotic plaque and eventually form a necrotic core. Experiments conducted on a diabetic high cholesterol pig model confirmed that Lp-PLA 2 inhibitors can affect the arteriosclerotic plaque volume, composition and gene expression of diabetic high cholesterol pigs, and effectively inhibit the continued growth of atherosclerotic plaques.
  • Lyso-PC acts as a pro-inflammatory factor that induces the release of multiple cytotoxic inflammatory cytokines, whereas Lp-PLA 2 inhibitors attenuate inflammatory responses by inhibiting the production of lyso-PC.
  • Lp-PLA 2 inhibitors can improve blood brain barrier (BBB) function, reduce blood-brain barrier (BBB) permeability, and alleviate beta-like protein in the brain. precipitation.
  • BBB blood brain barrier
  • BBB blood-brain barrier
  • Lp-PLA 2 inhibitors can inhibit lyso- The production of PC is used to treat diabetes-related tissue damage. Considering that local inflammatory reactions play an important role in the development of diabetic retinopathy, it is speculated that Lp-PLA 2 inhibitors can be used for the treatment of diabetic eye diseases.
  • BRB blood-retinal barrier
  • DME diabetic macular edema
  • Lp-PLA 2 inhibitors can reduce BRB permeability
  • studies have shown that Lp-PLA 2 inhibitors may Used in the treatment of diabetic macular edema.
  • Glaucoma and age-related macular degeneration are retinal neurodegenerative diseases, and studies have shown that inflammatory responses, including: TNF- ⁇ signaling pathway may play an important role in these two diseases.
  • Lp-PLA 2 inhibitors can block the release of inflammatory cytokines, it is speculated that Lp-PLA 2 inhibitors can be used in the treatment of glaucoma and AMD.
  • GlaxoSmithKline has developed a class of potent reversible inhibitors of Lp-PLA 2 (WO 99/24420, WO 01/60805, WO 02/30911, WO 03/016287, WO 03/042179, WO 03/042206, WO 08/048867, etc., characterized by a bicyclo or pyridone group in the structure, and the representative compounds darapladib and rilapladib are currently in clinical research.
  • GlaxoSmithKline has also developed a class of Lp-PLA 2 inhibitors (US 2012/0142717, WO 2012/075917, WO 2012/037782, WO 2013/013503, WO 2013/014185, WO 2014/114248, WO 2014/114249 , WO 2014/114694), the structure is also characterized by a bicyclic group, which differs from the previous class of reversible inhibitors in that the structure is linear and the molecular weight is relatively small.
  • R 1 is C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl, -(CH 2 ) m -NR 4 R 5 , phenyl, -(CH 2 ) m -(3-8 membered heteroaryl) or halogen, wherein the C 1 -C 4 alkyl group, C 2 -C 4 alkenyl group a C 2 -C 4 alkynyl group, a C 3 -C 6 cycloalkyl group, a 3-8 membered heteroaryl group, a 3-6 membered heterocyclic group, and a phenyl group are optionally 1-4 groups selected from the group consisting of Substituted: -CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, halogenated C 1
  • R 1 is -(CH 2 ) m -NR 4 R 5 , phenyl, -(CH 2 ) m -(3-6 membered heteroaryl), wherein the 3-6 membered heteroaryl group
  • the phenyl group is optionally substituted by one to three groups selected from the group consisting of -CN, fluorine, chlorine, bromine, methoxy, trifluoromethyl, methyl, ethyl or propyl;
  • R 1 is -(CH 2 )-N(CH 3 ) 2 , phenyl, -(CH 2 )-pyrazolyl, pyrimidinyl, pyridyl, wherein the pyrazolyl, pyrimidinyl, Pyridyl, phenyl is optionally substituted with from 1 to 3 groups selected from the group consisting of -CN, fluorine, chlorine, bromine, methoxy, trifluoromethyl, methyl, ethyl or propyl;
  • R 2 is H or a C 1 -C 6 alkyl group, wherein said C 1 -C 6 alkyl group is optionally substituted with from 1 to 4 groups selected from the group consisting of -CN, C 1 - C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, halogenated C 1 -C 6 alkyl; more preferably R 2 is H or C 1 -C 4 alkyl, wherein said C 1- C 4 alkyl is optionally substituted with from 1 to 3 groups selected from the group consisting of -CN, fluorine, chlorine, bromine, methoxy, trifluoromethyl, methyl, ethyl or propyl; More preferably, R 2 is H or methyl;
  • R 3 is H or a C 1 -C 6 alkyl group, wherein said C 1 -C 6 alkyl group is optionally substituted with from 1 to 4 groups selected from the group consisting of -CN, C 1 - C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, halogenated C 1 -C 6 alkyl; more preferably R 3 is H or C 1 -C 4 alkyl, wherein said C 1- C 4 alkyl is optionally substituted with from 1 to 3 groups selected from the group consisting of -CN, fluorine, chlorine, bromine, methoxy, trifluoromethyl, methyl, ethyl or propyl; More preferably, R 3 is H;
  • X is O, S, -(CH 2 ) q - or -N(R 8 )-; preferably X is O or S;
  • n 0, 1, 2, 3 or 4; preferably n is 0, 1, 2 or 3; more preferably n is 0, 1 or 2;
  • Ar is a C 6 -C 10 aryl group or a 3-8 membered heteroaryl group, wherein the C 6 -C 10 aryl group or the 3-8 membered heteroaryl group is optionally 1-4 selected from the group consisting of Group substitution: -CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkoxy;
  • Ar is phenyl, naphthyl or 5-6 membered heteroaryl, wherein the phenyl, naphthyl, 5-6 membered heteroaryl is optionally substituted with from 1 to 4 groups selected from the group consisting of :-CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkoxy;
  • Ar is a phenyl group or a 5-6 membered heteroaryl group, wherein the phenyl group, a 5-6 membered heteroaryl group is optionally substituted with from 1 to 3 groups selected from the group consisting of -CN, C 1- C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxy, halogenated C 1 -C 4 alkyl, halogenated C 1 -C 4 alkoxy;
  • Ar is a phenyl group, wherein the phenyl group is optionally substituted with from 1 to 3 groups selected from the group consisting of -CN, fluorine, chlorine, bromine, trifluoromethyl, methyl, ethyl, Propyl;
  • Y is hydrogen, -A-(C 6 -C 10 aryl) or -A-(3-8 membered heteroaryl), wherein A is O, S, -(CH 2 ) o - or -N(R 9 )-, the C 6 -C 10 aryl, 3-8 membered heteroaryl is optionally substituted with 1-3 groups selected from the group consisting of -CN, C 1 -C 6 alkyl, C 1- C 6 alkoxy, halogen, halogenated C 1 -C 6 alkyl;
  • Y is -A-(C 6 -C 10 aryl) or -A-(5-6 membered heteroaryl), wherein A is O, said C 6 -C 10 aryl, 5-6
  • the heteroaryl group is optionally substituted by one to three groups selected from the group consisting of -CN, fluorine, chlorine, bromine, trifluoromethyl, methyl, ethyl, propyl;
  • Z is CH or N
  • R 4 to R 9 and R 1 ' to R 4 ' are each independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkanoyl, -(CH 2 ) p -(C 1 - C 6 alkoxy), C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and C 3 -C 8 cycloalkenyl; preferably, R 4 to R 9 And R 1 ' to R 4 ' are each independently selected from H, C 1 -C 3 alkyl;
  • the m, q, o, and p are each independently 0, 1, 2, or 3.
  • the compound of formula I has one or both of the following characteristics:
  • R 2 is H or C 1 -C 6 alkyl, preferably R 2 is H or C 1 -C 4 alkyl; most preferably, R 2 is H or methyl;
  • R 3 is H or C 1 -C 6 alkyl; preferably, R 3 is H or C 1 -C 4 alkyl; most preferably, R 3 is H;
  • n 0, 1, 2 or 3;
  • R 1 is C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocyclic , -(CH 2 ) m -NR 4 R 5 , phenyl, -(CH 2 ) m -(3-8 membered heteroaryl) or halogen, wherein
  • R 4 , R 5 , R 3 ' and R 4 ' are each independently selected from H, C 1 -C 6 alkyl, -(CH 2 ) p -(C 1 -C 6 alkoxy), C 3 -C 8 -cycloalkyl;
  • n and p are each independently 0, 1, 2 or 3.
  • the compound of formula I has one or both of the following characteristics:
  • Ar is a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted 5-6 membered heteroaryl group, and the substituent means a phenyl group, a naphthyl group or a 5-6 membered hetero
  • the aryl group has from 1 to 4 substituents selected from the group consisting of -CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, halogenated C 1 -C 6 alkyl, Halogenated C 1 -C 6 alkoxy;
  • Y is hydrogen, -A-(C 6 -C 10 aryl) or -A-(5-6 membered heteroaryl), wherein A is O or S; the C 6 -C 10 aryl group And the 5-6 membered heteroaryl group optionally has 1-3 substituents selected from the group consisting of C 1 -C 4 alkyl, -CN, halogen, halogenated C 1 -C 6 alkyl.
  • Ar is a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5-6 membered heteroaryl group, and the substituent means a phenyl group or a 5- to 6-membered heteroaryl group having 1-3 Substituents selected from the group consisting of -CN, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxy, halogenated C 1 -C 4 alkyl, halogenated C 1 -C 4 Alkoxy.
  • Ar is a substituted or unsubstituted phenyl group, and the substitution means having 1-3 substituents selected from the group consisting of -CN, fluorine, chlorine, bromine, trifluoromethyl Base, methyl, ethyl or propyl.
  • A is O.
  • the C 6 -C 10 aryl group, the 5-6 membered heteroaryl group optionally has 1-3 substituents selected from the group consisting of -CN, F, Cl, CF 3 .
  • the compound has the structure shown in formula (IA):
  • Ra and Rb are each independently H, halogen, -CN, trifluoromethyl or methyl;
  • Z is CH or N
  • n 0, 1, 2 or 3;
  • R 1 is -(CH 2 )-N(CH 3 ) 2 , phenyl, -(CH 2 )-pyrazolyl, pyrazolyl, pyrimidinyl, pyridyl, wherein the phenyl, pyrazolyl,
  • R 2 is hydrogen or methyl
  • Ar' is a phenyl group, a pyridyl group or a pyrimidinyl group, wherein the phenyl group, pyridyl group or pyrimidinyl group is optionally substituted with one to three groups selected from the group consisting of trifluoromethyl, fluorine, chlorine, Cyano, methyl.
  • the compound of formula I is any of the compounds shown in the following table.
  • the pharmaceutically acceptable salt is a hydrochloride, a hydrobromide, a sulfate, a nitrate, a phosphate, a citrate, a methanesulfonate, a trifluoroacetate, or a Acid salts, oxalates, succinates, malates, tosylates, tartrates, fumarates, glutamates, glucuronates, lactates, glutarate, fine Alkaloid or maleate.
  • Z in the general formula I is CH, that is, a compound of the formula II, obtained by reacting a compound of the formula Ic with R 1 W, wherein W is Cl, Br or I;
  • preparation method comprises the following steps:
  • preparation method comprises the following steps:
  • Z in the formula I is CH, it is a compound of the formula II, which is obtained by reacting a compound of the formula IId with Y-Ar-(CH 2 ) n XH in the presence of a base;
  • preparation method comprises the following steps:
  • R 1 , R 2 , R 3 , Y, Ar, n, and X are as described in the first aspect.
  • a pharmaceutical composition comprising a compound of formula I according to the first aspect, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier are provided.
  • a fourth aspect of the invention provides the use of a compound of formula I according to the first aspect, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the third aspect, for use in:
  • the disease associated with Lp-PLA 2 enzyme activity is atherosclerosis, stroke, myocardial infarction, ischemia-reperfusion injury, diabetic eye disease, diabetic encephalopathy, diabetic macular edema, various types Neurodegenerative diseases, Alzheimer's disease, acute inflammatory diseases, chronic inflammatory diseases, psoriasis or glaucoma macular degeneration.
  • the disease associated with Lp-PLA 2 enzyme activity is atherosclerosis, diabetic macular edema, diabetic encephalopathy or Alzheimer's disease.
  • R 2 , R 3 , Y, Ar, n, X are as defined in the first aspect.
  • R 2 , R 3 , Y, Ar, n, X are as defined in the first aspect.
  • R 2 , R 3 , Y, Ar, n, X are as defined in the first aspect.
  • R 1 , R 2 , and R 3 are as defined in the first aspect.
  • R 2 , R 3 , Y, Ar, n, X are as defined in the first aspect.
  • a method of inhibiting Lp-PLA 2 administering a safe and effective amount of a compound of formula I to a subject or to the environment.
  • a method of treating a condition associated with Lp-PLA 2 enzymatic activity wherein a safe and effective amount of a compound of formula I is administered to a subject in need thereof.
  • the desired subject comprises cells cultured in vitro, human or non-human mammals, preferably human, mouse or rat.
  • safety and effective amount means that the amount of the active ingredient (the compound of formula I) is sufficient to significantly improve the condition without causing serious side effects.
  • Figure 1 is a graph showing the activity of serum Lp-PLA 2 in rats after oral administration of the compounds of Examples 1 and 11 and the positive control compound darapladib to SD rats.
  • Figure 2 is a graph showing the activity of serum Lp-PLA 2 in rats after oral administration of the compounds of Examples 44 and 47 and the positive control compound darapladib to SD rats.
  • the inventors of the present application have extensively and intensively studied for the first time to develop a novel bicyclic compound which can be used as an Lp-PLA 2 inhibitor to prevent and/or treat and/or ameliorate Lp-PLA 2 enzyme activity.
  • Related diseases On the basis of this, the present invention has been completed.
  • C 1 -C 6 alkyl means a straight or branched alkyl group having 1 to 6 carbon atoms, and includes, without limitation, methyl, ethyl, propyl, isopropyl. And butyl and the like; the term “C 1 -C 4 alkyl” has a similar meaning.
  • C 2 -C 6 alkenyl refers to a straight or branched alkenyl group having 2 to 6 carbon atoms and having one double bond, and includes, without limitation, a vinyl group, a propenyl group, a butenyl group, an isobutenyl group. , pentynyl and hexynyl.
  • halo C 1 -C 6 alkyl refers to an alkyl group substituted with one or more halogen atoms, such as -CH 2 F, -CF 3 , -CH 2 CHF 3 and the like.
  • C 1 -C 6 alkoxy means a straight or branched alkoxy group having 1 to 6 carbon atoms, and includes, without limitation, a methoxy group, an ethoxy group, a propoxy group. Base, isopropoxy and butoxy, etc.; the term “C 1 -C 4 alkoxy” has a similar meaning.
  • C 3 -C 8 cycloalkyl means a cyclic alkyl group having 3 to 8 carbon atoms in the ring, and includes, without limitation, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group. , cyclohexyl, cycloheptyl, cyclooctyl, etc.; the term “C 3 -C 6 cycloalkyl” has a similar meaning.
  • C 3 -C 8 cycloalkenyl refers to a cyclic alkenyl group having from 3 to 8 carbon atoms in the ring, including, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl Wait.
  • aryl means a hydrocarbon group containing one or more aromatic rings such as a phenyl group or a naphthyl group and the like.
  • heteroaryl denotes an aromatic ring group containing from 1 to 4 heteroatoms selected from N, O, S, including, without limitation, pyrazolyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, Pyridazinyl, furyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, quinazolinyl, quinolyl, isoquinolyl and anthracenyl.
  • heterocyclyl means a cycloalkyl group containing from 1 to 4 hetero atoms selected from N, O, S, and includes, without limitation, pyrrolidinyl, morpholinyl, piperidinyl, thio. Morpholinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiazolyl.
  • the compound of the formula I according to the invention, its stereoisomer or a pharmaceutically acceptable salt thereof can be prepared by the following method:
  • the boric acid or boron ester of R 1 is selected from
  • the base in the step (a), (g), (k) or (1) is selected from the group consisting of inorganic bases, organic bases, and combinations thereof; preferably, the inorganic base is selected from the group consisting of sodium hydroxide, potassium hydroxide, and hydrogen.
  • the organic base is selected from the group consisting of sodium alkoxide, potassium alkoxide, butyl lithium, 1,8-diazacyclo[5,4,0]undecene-7, pyridine, piperidine, pyrrolidine, morpholine, N-methyl Morpholine, quinoline, 4-dimethylaminopyridine, triethylamine, diethylamine, tri-n-butylamine, tripropylamine, diisopropylamine, diisopropylethylamine, and combinations thereof; more preferably The base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium carbonate, sodium carbonate, barium carbon
  • the reaction solvent for the reaction is selected from the group consisting of aromatic hydrocarbons Solvent-like, ether soluble a halogenated hydrocarbon solvent and other solvents; preferably, the aromatic hydrocarbon solvent is selected from the group consisting of benzene, toluene, xylene, chlorobenzene, nitrobenzene, and combinations thereof; the ether solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, and ethyl Diol dimethyl ether, diethylene glycol dimethyl ether, ethylene glycol monomethyl ether, dioxane and combinations thereof; the halogenated hydrocarbon solvent is selected from the group consisting of dichloromethane, chloroform, carbon tetrachloride, and Eth
  • the compounds of the invention are Lp-PLA 2 inhibitors. These compounds are therefore useful in the treatment, for example, in the treatment of conditions associated with the activity of Lp-PLA 2 . Accordingly, another aspect of the present invention relates to the treatment associated with Lp-PLA 2 activity is a disorder.
  • a particular disorder or treatment thereof can involve one or more underlying mechanisms associated with Lp-PLA 2 activity, including one or more of the mechanisms described herein.
  • the compounds of the invention are useful in the treatment of any disease involving endothelial dysfunction, such as atherosclerosis, diabetes, hypertension, angina pectoris, and conditions following ischemia and reperfusion.
  • the compounds of the invention are useful in the treatment of any disease involving lipid oxidation associated with enzymatic activity, for example, in addition to conditions such as atherosclerosis and diabetes, such as rheumatoid arthritis, Stroke, brain inflammatory conditions such as Alzheimer's disease, various neuropsychiatric disorders such as schizophrenia, myocardial infarction, ischemia, reperfusion injury, sepsis, and acute and chronic inflammation.
  • the compounds of the invention are useful in the treatment of diseases involving activated monocytes, macrophages or lymphocytes, since all of these cell types express Lp-PLA 2 , including diseases involving activated macrophages, typically Conditions include, but are not limited to, psoriasis, rheumatoid arthritis, wound healing, chronic obstructive pulmonary disease, cirrhosis, atopic dermatitis, emphysema, chronic pancreatitis, chronic gastritis, aortic aneurysm, atherosclerosis, Multiple sclerosis, Alzheimer's disease, and autoimmune diseases such as lupus.
  • the invention provides a method of treating a disease associated with Lp-PLA 2 activity comprising treating a subject in need of treatment with an effective amount of an Lp-PLA 2 inhibitor.
  • the disease may be associated with increased involvement of monocytes, macrophages or lymphocytes; with the formation of lysophosphatidylcholine and oxidized free fatty acids; associated with lipid oxidation of associated Lp-PLA 2 activity; Or related to endothelial dysfunction.
  • the compounds of the invention may be used for primary or secondary prevention of acute coronary events, for the prevention of combination therapy for restenosis or for delaying the development of diabetes or hypertensive renal insufficiency. A subject having a risk of such a condition is prevented and treated.
  • the compounds of the invention are useful in combination with an antihyperlipidemic agent, an antiatherogenic agent, an anti-diabetic agent, an anti-angina or an antihypertensive agent, or an agent for lowering lipoprotein a to treat the present invention.
  • an antihyperlipidemic agent such as statins; antioxidants, such as probucol; insulin sensitizers; calcium channel antagonists and anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs.
  • the compounds of the invention are useful for treating a neurodegenerative disease in a subject.
  • the method comprises administering a pharmaceutical composition comprising a drug that inhibits Lp-PLA 2 activity to a subject in need of treatment.
  • exemplary neurodegenerative diseases include, but are not limited to, Alzheimer's disease, vascular dementia, Parkinson's disease, and Huntington's disease.
  • the neurodegenerative disease of the invention is associated with an abnormal blood-brain barrier.
  • the subject to whom the agent that inhibits Lp-PLA 2 activity is administered is a human.
  • the invention provides a method of treating a subject having or at risk of having vascular dementia.
  • the method comprises administering to a subject a pharmaceutical composition comprising an effective amount of a compound of the invention.
  • the vascular dementia is associated with Alzheimer's disease.
  • the invention provides a method of treating a neurological disorder associated with abnormal blood-brain barrier function, inflammation, or microglial activation in a subject in need of treatment.
  • the method comprises administering an effective amount of a compound of the invention to a subject.
  • the abnormal blood brain barrier is a permeable blood brain barrier.
  • the disease is a neurodegenerative disease.
  • Such neurodegenerative diseases are, for example but not limited to, vascular dementia, Alzheimer's disease, Parkinson's disease, and Huntington's disease.
  • the invention provides a method of treating a condition associated with blood-brain barrier leakage in a subject. Exemplary diseases include, but are not limited to, cerebral hemorrhage, cerebral amyloid angiopathy.
  • the neurodegenerative disease is Alzheimer's disease.
  • the neurodegenerative disease is vascular dementia.
  • the neurodegenerative disease is multiple sclerosis.
  • the invention provides a method of reducing beta amyloid accumulation in a brain of a subject.
  • the method comprises administering to a subject in need of treatment a pharmaceutical composition comprising an effective amount of a compound of the invention.
  • the amyloid beta protein is A[beta]-42.
  • the method can further comprise treating another neurodegenerative disease or possibly a comorbidity that can be used to treat the subject being treated
  • the therapeutic agent is administered to the subject or may also include the simultaneous use of other therapies.
  • the neurodegenerative disease is similar to Alzheimer's disease
  • the subject may be treated with other agents or other therapies that target Alzheimer's disease, such as donepezil, tacrine, and lifan Smectin, galantamine, anti-amyloid vaccine, A ⁇ reduction therapy, thinking practice or stimulation.
  • the invention relates to a method of treating metabolic bone disease by administering an effective amount of a compound of the invention to a subject in need of treatment.
  • exemplary metabolic bone diseases include diseases associated with loss of bone mass and bone density including, but not limited to, osteoporosis and osteopenia related diseases.
  • Exemplary osteoporosis and osteopenia related diseases include, but are not limited to, bone marrow abnormalities, dyslipidemia, Parkid's disease, type II diabetes, metabolic syndrome, insulin resistance, hyperparathyroidism, and related diseases.
  • the subject in need of treatment is a human.
  • some embodiments of the present invention provides a method of suppressing blocking activity of Lp-PLA 2 is.
  • a method of inhibiting Lp-PLA 2 by reducing and/or downregulating expression of Lp-PLA 2 RNA is provided.
  • bone loss and/or loss of bone density is prevented and/or reduced, thereby preventing or reducing symptoms associated with metabolic bone diseases such as osteoporosis and/or osteopenia.
  • the method further comprises administering to the subject in need of treatment additional therapeutic agents for treating metabolic bone disease.
  • additional therapeutic agents for treating metabolic bone disease.
  • the metabolic bone disease is osteoporosis
  • other therapeutic agents such as bisphosphonate therapeutic agents can be used.
  • One aspect of the invention provides a method of treating an ocular condition by administering an effective amount of a compound of the invention.
  • the eye disease to which the present invention is applicable may be related to the destruction of the blood retinal barrier.
  • Exemplary ocular diseases involve diabetic ocular diseases and conditions including macular edema, diabetic retinopathy, and the like.
  • the present invention relates to a method to inhibit the Lp-PLA 2 for treating eye diseases by administration of the compounds of the present invention.
  • Exemplary ocular diseases include, but are not limited to, central retinal vein occlusion, retinal branch vein occlusion, I-plus syndrome, retinitis pigmentosa, flattening inflammation, shotgun-like retinal choroidal lesion, retinal outer membrane, choroidal neoplasm, Cystic macular edema, paracentral telangiectasia, traction macular disease, vitreoma macular traction syndrome, retinal detachment, optic nerve retinitis, idiopathic macular edema, etc.
  • some embodiments of the invention provide methods for treating diabetic macular edema in a subject.
  • the method comprises administering an effective amount of a compound of the invention to a subject in need of treatment.
  • the invention provides methods for treating a subject having macular edema or having a risk of macular edema.
  • the method comprises administering an effective amount of a compound of the invention to a subject.
  • the macular edema is associated with a diabetic eye disease, such as diabetic retinopathy.
  • the macular edema is associated with posterior uveitis.
  • the invention provides a method of treating glaucoma or macular degeneration.
  • the method comprises administering an effective amount of a compound of the invention to a subject.
  • the invention provides a method of treating a condition associated with disruption of the blood retinal barrier in a subject in need of treatment.
  • the method comprises administering an effective amount of a compound of the invention to a subject.
  • systemic inflammatory diseases such as juvenile rheumatoid arthritis, inflammatory bowel disease, Kawasaki disease, multiple sclerosis, sarcoidosis, polyarteritis, psoriatic arthritis, reactive arthritis, system Lupus erythematosus, Fu-Koyanagi-Harada syndrome, Lyme disease, Behcet's disease, ankylosing spondylitis, inflammatory granulomatous disease, etc.
  • the present invention relates to a method of treating uveitis or any of these systemic inflammatory diseases by administering an effective amount of a compound of the present invention.
  • the compounds and pharmaceutical compositions provided by the present invention may be in various forms such as tablets, capsules, powders, syrups, solutions, suspensions, aerosols, and the like, and may be present in a suitable solid or liquid carrier or In the diluent.
  • the pharmaceutical compositions of the invention may also be stored in a suitable injectable or drip sterilizing device. Odorants, flavoring agents and the like may also be included in the pharmaceutical composition.
  • the pharmaceutical composition contains a safe or effective amount (e.g., 0.1 to 99.9 parts by weight, preferably 1 to 90 parts by weight) of the compound of the formula (I) or a pharmaceutically acceptable salt thereof; A quantity of a pharmaceutically acceptable excipient wherein the total weight of the composition is 100 parts by weight.
  • the pharmaceutical composition according to the invention contains from 0.1 to 99.9% by weight, based on the total weight, preferably from 1 to 90% by weight, based on the total weight of the compound of the formula (I) or a pharmaceutically acceptable salt thereof; A pharmaceutically acceptable excipient wherein the total weight of the composition is 100% by weight.
  • a preferred ratio of the compound of the formula (I) to a pharmaceutically acceptable carrier, excipient or sustained release agent is that the formula (I) as the active ingredient accounts for more than 60% by weight of the total weight, and the balance is 0-40% by weight of the total weight, the rest
  • the amount of the moiety is preferably from 1 to 20%, most preferably from 1 to 10%.
  • the compound of the formula (I) or the pharmaceutical composition comprising the compound of the formula (I) can be used clinically in mammals, including humans and animals, and the route of administration can include oral, nasal inhalation, transdermal absorption, and pulmonary administration. Medicine or gastrointestinal tract.
  • a preferred route of administration is oral.
  • it is a unit dosage form, and each dose contains 0.01 mg to 200 mg, preferably 0.5 mg to 100 mg, of the active ingredient, once or in divided doses.
  • the optimal dosage for the individual should be based on the particular treatment. Usually starting with a small dose, gradually increase the dose until the most appropriate dose is found.
  • the pharmaceutical composition of the present invention can be administered orally and intravenously, intramuscularly or subcutaneously.
  • preferred pharmaceutical compositions are solid compositions, especially tablets and solid filled or liquid filled capsules. Oral administration of the pharmaceutical composition is preferred.
  • the intermediate 1 (1.0 g, 1 eq.) was dissolved in dichloromethane, and then chlorosulfoxide (480 ⁇ l, 2 eq.) was added dropwise in an ice bath. After the addition was completed, the mixture was stirred at room temperature for 2 h, then evaporated and evaporated. Chlorosulfoxide gave 1.05 g of intermediate 2a which was used directly in the next step without purification.
  • Intermediate 10c was prepared by referring to the preparation method of Intermediate 1a, except that the starting material was Intermediate 10b and 4-chloro-3-trifluoromethylphenol.
  • the intermediate 11c was prepared by referring to the preparation method of the intermediate 1a, except that p-fluorobenzaldehyde was replaced with the intermediate 11b.
  • Intermediate 12 was prepared by referring to the preparation method of Intermediate 4, except that Intermediate 1a was used as a starting material.
  • N-methylpyrazole (1.0 g, 1 equivalent) was dissolved in N,N-dimethylformamide (2.8 ml, 3 eq.), and phosphorus oxychloride (1.3 ml, 1.2 eq.) was added dropwise at 90 ° C. The addition was completed in 1 h, and the reaction was continued for 2 h. After cooling, the reaction solution was poured into ice water, adjusted to pH 4 to 5 with 10% aqueous sodium hydroxide solution, extracted twice with dichloromethane, washed twice with water, dried over anhydrous sodium sulfate, filtered, evaporated and evaporated 600 mg of intermediate 60a.
  • Oxalyl chloride (428 ⁇ L, 1.5 eq.) was dissolved in methylene chloride, EtOAc (EtOAc) EtOAc (EtOAc) After the addition, the mixture was stirred for 5 min, then the intermediate 60 d of dichloromethane solution was added, and the addition was completed in about 10 min. After the addition, the mixture was stirred for 5 min, then triethylamine (1.67 mL, 4 equivalents) was added, and the addition was completed in about 3 min. After stirring for 5 min, the reaction flask was taken out from the cold mash and allowed to react at room temperature for 5 min. Add water to quench The methylene chloride layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated and evaporated.
  • the intermediate 1 was used as a raw material, and the preparation method of the intermediate 56 was referred. MS (ESI): 499 (M+1).
  • the intermediate 25 was used as a raw material, and the preparation method of the intermediate 56 was referred. MS (ESI): 513 (M+1).
  • the intermediate 14 was used as a raw material, and the preparation method of the intermediate 56 was referred to. MS (ESI): 524 (MH).
  • the intermediate 13 was used as a raw material, and the preparation method of the intermediate 56 was referred to. MS (ESI): 517 (M+1).
  • the intermediate 26 was used as a raw material, and the preparation method of the intermediate 56 was referred to. MS (ESI): 533 (M + 1).
  • the intermediate 27 was used as a raw material, and the preparation method of the intermediate 56 was referred. MS (ESI): 567 (M+1).
  • Example 2 The compound of Example 2 was prepared by referring to the production method of Example 1 except that Intermediate 28 and 2-methoxy-4-bromopyrimidine were used as starting materials.
  • Example 3 The compound of Example 3 was prepared by referring to the production method of Example 1 except that Intermediate 33 and 4-bromopyrimidine were used as starting materials.
  • Example 7 The compound of Example 7 was prepared by referring to the production method of Example 1 except that Intermediate 35 and 4-bromopyrimidine were used as starting materials.
  • Example 9 The compound of Example 9 was prepared by referring to the preparation method of Example 8 except that the intermediate 54 and p-methoxyphenylboronic acid were used as a starting material.
  • 1 H NMR 300 MHz, Chloroform-d
  • 7.63 - 7.28 m, 7H
  • 7.04 m, 5H
  • 5.49 s, 2H
  • Example 10 The compound of Example 10 was prepared by referring to the preparation method of Example 1 except that Intermediate 29 and 4-bromopyrimidine were used as starting materials.
  • Example 11 The compound of Example 11 was prepared by referring to the preparation method of Example 1 except that Intermediate 34 and 4-bromopyrimidine were used as the starting materials.
  • 1 H NMR 300 MHz, Chloroform-d
  • Example 12 The compound of Example 12 was prepared by referring to the preparation method of Example 1 except that Intermediate 36 and 4-bromopyrimidine were used as the starting materials.
  • Example 13 The compound of Example 13 was prepared by referring to the preparation method of Example 8 except that Intermediate 58 and 4-pyrimidineboronic acid were used as a starting material.
  • Example 14 was prepared by referring to the preparation method of Example 8 except that Intermediate 54 and 4-pyridine boronic acid were used as the starting materials.
  • Example 15 was prepared by referring to the preparation method of Example 1 except that Intermediate 28 and 3-bromopyridine were used as the starting materials.
  • 1 H NMR 400 MHz, Chloroform-d
  • Example 16 was prepared by referring to the preparation method of Example 8 except that Intermediate 59 and 4-pyrimidineboronic acid were used as a starting material.
  • Example 17 The compound of Example 17 was prepared by referring to the preparation method of Example 1 except that Intermediate 37 and 4-bromopyrimidine were used as the starting materials.
  • 1 H NMR 300 MHz, Chloroform-d
  • Example 18 was prepared by referring to the preparation method of Example 1 except that Intermediate 38 and 4-bromopyrimidine were used as starting materials.
  • Example 19 The compound of Example 19 was prepared by referring to the preparation method of Example 1 except that Intermediate 39 and 4-bromopyrimidine were used as starting materials.
  • Example 20 was prepared by referring to the preparation method of Example 1 except that Intermediate 40 and 4-bromopyrimidine were used as the starting materials.
  • Example 21 was prepared by referring to the preparation method of Example 1 except that Intermediate 41 and 4-bromopyrimidine were used as the starting materials.
  • Example 22 The compound of Example 22 was prepared by referring to the preparation method of Example 1 except that Intermediate 42 and 4-bromopyrimidine were used as starting materials.
  • Example 23 The compound of Example 23 was prepared by referring to the preparation method of Example 1 except that Intermediate 43 and 4-bromopyrimidine were used as starting materials.
  • Example 24 The compound of Example 24 was prepared by referring to the preparation method of Example 1 except that Intermediate 44 and 4-bromopyrimidine were used as starting materials.
  • Example 25 was prepared by referring to the preparation method of Example 1 except that Intermediate 31 and 4-bromopyrimidine were used as the starting materials.
  • Example 26 was prepared by referring to the preparation method of Example 6 except that Intermediate 8 and Intermediate 53 were used.
  • Example 27 was prepared by referring to the preparation method of Example 6 except that Intermediate 9 and Intermediate 53 were used.
  • Example 28 was prepared by referring to the preparation method of Example 6 except that Intermediate 10 and Intermediate 53 were used.
  • 1 H NMR 400 MHz, Chloroform-d
  • Example 8 was carried out to prepare the compound of Example 29.
  • 1 H NMR 400 MHz, Chloroform-d
  • Example 8 was carried out to prepare the compound of Example 30.
  • 1 H NMR 300 MHz, Chloroform-d
  • Example 31 was prepared by referring to the preparation method of Example 8 except that Intermediate 59 and 2-methoxy-4-pyrimidineboronic acid were used as a starting material.
  • Example 32 The compound of Example 32 was prepared by referring to the preparation method of Example 1 except that Intermediate 29 and 3-bromo-4-methylpyridine were used as starting materials.
  • 1 H NMR 400 MHz, Chloroform-d
  • Example 33 The compound of Example 33 was prepared by referring to the preparation method of Example 1 except that Intermediate 32 and 4-bromopyrimidine were used as a starting material.
  • Example 34 was prepared by referring to the preparation method of Example 1 except that Intermediate 30 and 4-bromopyrimidine were used as the starting materials.
  • Example 35 was prepared by referring to the preparation method of Example 8 except that Intermediate 57 and 4-pyrimidineboronic acid were used as a starting material.
  • Example 36 The compound of Example 36 was prepared by referring to the preparation method of Example 1 except that Intermediate 45 and 4-bromopyrimidine were used as starting materials.
  • Example 37 The compound of Example 37 was prepared by referring to the preparation method of Example 1 except that Intermediate 46 and 4-bromopyrimidine were used as starting materials.
  • Example 38 was prepared by referring to the preparation method of Example 6 except that Intermediate 2 and Intermediate 53 were used.
  • Example 39 The compound of Example 39 was prepared by referring to the preparation method of Example 1 except that Intermediate 47 and 4-bromopyrimidine were used as starting materials.
  • Example 40 The compound of Example 40 was prepared by referring to the preparation method of Example 8 except that Intermediate 56 and 4-pyrimidineboronic acid were used as starting materials.
  • Example 41 was prepared by referring to the preparation method of Example 6 except that Intermediate 5 and Intermediate 53 were used.
  • 1H NMR 400MHz, Chloroform-d
  • Example 42 The compound of Example 42 was prepared by referring to the preparation method of Example 6 except that Intermediate 6 and Intermediate 53 were used.
  • Example 43 The compound of Example 43 was prepared by referring to the preparation method of Example 1 except that Intermediate 48 and 4-bromopyrimidine were used as starting materials.
  • 1 H NMR 400 MHz, Chloroform-d
  • Example 8 The preparation method of Example 8 was referred to using Intermediate 61 and 4-pyrimidineboronic acid as raw materials.
  • Example 8 The preparation method of Example 8 was referred to using Intermediate 62 and 4-pyrimidineboronic acid as raw materials.
  • Example 8 The preparation method of Example 8 was referred to using Intermediate 63 and 4-pyrimidineboronic acid as raw materials.
  • Example 8 The preparation method of Example 8 was referred to using Intermediate 64 and 4-pyrimidineboronic acid as raw materials.
  • Example 8 The preparation method of Example 8 was referred to using Intermediate 65 and 4-pyrimidineboronic acid as raw materials.
  • Example 8 The preparation method of Example 8 was referred to using Intermediate 66 and 4-pyrimidineboronic acid as raw materials.
  • Example 1 The preparation method of Example 1 was referred to using Intermediate 67 as a raw material.
  • the reaction buffer was 0.1 M Tris-HCl, 1 mM EGTA, pH 7.2.
  • the concentration was 1.1 mg/ml with three distilled water, and an appropriate amount of 0.1 M NaOH was added until the DTNB just dissolved.
  • Lp-PLA 2 activity was determined using 2-sulfur-PAF as a substrate.
  • the thiol group produced after the hydrolysis of 2-sulfo-PAF can react with DTNB to form a yellow substance, and the optical density value can be detected at 414 nm to reflect the Lp-PLA 2 activity.
  • Inhibition rate 1 - (slope sample hole - slope blank hole) / (slope control hole - slope blank hole) ⁇ 100%
  • the compounds listed in Table 2 had an inhibition rate of Lp-PLA 2 of more than 50% at a concentration of 1 ⁇ M, and some compounds showed an inhibition rate of Lp-PLA 2 of more than 50% at a concentration of 100 nM, wherein Example 16 showed in rabbit serum.
  • the best in vitro activity, the inhibition rate of Lp-PLA 2 can reach more than 70% at 100nM concentration.
  • Inhibition rate 1 - (slope sample hole - slope blank hole) / (slope control hole - slope blank hole) ⁇ 100%
  • the compounds listed in Table 4 had an inhibition rate of Lp-PLA 2 of more than 50% at a concentration of 10 nM, wherein Example 16 and Example 31 showed the best in vitro activity in human recombinant enzyme at a concentration of 10 nM.
  • the inhibition rate to Lp-PLA 2 reached about 90%.
  • Inhibition rate 1 - (slope sample hole - slope blank hole) / (slope control hole - slope blank hole) ⁇ 100%
  • the compounds listed in Table 6 showed good in vitro activity in rat serum, and all compounds inhibited Lp-PLA 2 by more than 50% at a concentration of 100 nM.
  • TRIS tris-hydroxymethyl aminomethane
  • a solution of MgCl 2 (100 mM) was prepared in 0.1 M Tris/HCl buffer, and stored at -20 ° C after dispensing. The incubation concentration of MgCl 2 was 5.0 mM.
  • NADPH NADPH
  • Human S9 (purchased from Reid Liver Disease Research (Shanghai) Co., Ltd.) was diluted 10-fold with 0.1 M Tris/HCl, and rat S9 (purchased from Reid Liver Disease Research (Shanghai) Co., Ltd.) was diluted 5-fold.
  • the incubation concentration of human and rat S9 was equivalent to the incubation concentration of the corresponding species of liver microsomes (the incubation concentration of human and rat liver microsomes was 0.33 mg/mL).
  • the compound was dissolved in DMSO to obtain a stock solution having a concentration of 10 mM. After diluting to 1 mM in DMSO, it was diluted with 0.1% BSA-water to obtain a working solution having a concentration of 2 ⁇ M. In the incubation system, 2 ⁇ M of the working solution was diluted 20-fold to a final concentration of 0.1 ⁇ M. The concentration of DMSO in the incubation system was ⁇ 0.01%.
  • VIVID stock solution purchased from Shanghai Baili Biotechnology Co., Ltd.
  • 2 mM VIVID stock solution purchased from Shanghai Baili Biotechnology Co., Ltd.
  • the mixed working solution of VIVID and the analyte is diluted 20 times.
  • S9 was incubated in 96-well plates at 450 ⁇ L per incubation system, 0.1 M Tris buffer (pH 7.4), MgCl 2 , S9 and +NADPH/-NADPH pre-incubated for 10 min at 37 ° C (600 rpm)
  • the test drug was added to initiate the reaction, and the reaction was stopped by adding the same volume of ice methanol at 0, 7, 17, 30, 60 min.

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Abstract

La présente invention concerne un composé bicyclique utilisé comme inhibiteur de la Lp-PLA2, un procédé de préparation et une utilisation pharmaceutique de ce dernier, ainsi qu'une composition pharmaceutique contenant le composé. La structure du composé bicyclique est présentée dans la formule générale I. Les définitions de R1, R2, R3, X, Y, Z, Ar et n sont présentées dans la description et les revendications. Le composé présenté dans la formule générale I de la présente invention peut être utilisé comme inhibiteur de la Lp-PLA2 pour la prévention et/ou le traitement et/ou le soulagement de maladies liées à l'activité enzymatique de la Lp-PLA2.
PCT/CN2016/080725 2015-05-08 2016-04-29 Composé bicyclique utilisé comme inhibiteur de la lp-pla2, et procédé de préparation et utilisation pharmaceutique de ce dernier WO2016180247A1 (fr)

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