Cyano-substituted fused bicyclic derivatives, their preparation and use
阅读说明：本技术 氰基取代的稠合双环衍生物及其制备方法和用途 (Cyano-substituted fused bicyclic derivatives, their preparation and use ) 是由 杨新业 黄常伟 马发城 郝学良 王慧 王晓军 张英俊 于 2018-02-28 设计创作，主要内容包括：本发明涉及一类氰基取代的稠合双环衍生物,以及包含该化合物的药物组合物。所述化合物或药物组合物可用于抑制黄嘌呤氧化酶和尿酸盐阴离子转运体1,并降低血中尿酸水平。本发明还涉及制备这类化合物和药物组合物的方法,以及它们在治疗或预防哺乳动物,特别是人类,与血中尿酸值偏高有关的疾病中的用途。(The invention relates to a cyano-substituted fused bicyclic derivative and a pharmaceutical composition containing the compound. The compounds or pharmaceutical compositions are useful for inhibiting xanthine oxidase and urate anion transporter 1, and reducing uric acid levels in blood. The invention also relates to methods for preparing such compounds and pharmaceutical compositions, and their use in the treatment or prevention of diseases associated with elevated blood uric acid levels in mammals, particularly humans.)
A compound of formula (I) or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt of a compound of formula (I) or a prodrug thereof,
wherein:
x and Z are each independently-N (R)a)-、-O-、-S(O)t-、-C(Rb)＝、-CRcRd-or-N ═ N;
y is-C (R)e)＝、-CRfRg-or-N ═ N;
t is 0, 1 or 2;
each RaIndependently of one another is hydrogen, deuterium, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl or C3-6A cycloalkyl group;
each RbIndependently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Alkylamino or C1-6A haloalkoxy group;
each RcIndependently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Alkylamino or C1-6A haloalkoxy group;
each RdIndependently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Alkylamino or C1-6A haloalkoxy group;
Reis hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylamino radical, C1-6Halogenated alkylamidosBase, C3-8Cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl;
Rfis hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylamino radical, C1-6Haloalkylamino, C3-8Cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl;
Rgis hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylamino radical, C1-6Haloalkylamino, C3-8Cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl;
R1and R2Each independently is hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Alkylamino or C1-6A haloalkoxy group;
each R3Independently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy or C1-6A haloalkoxy group;
r is hydrogen, deuterium, C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl, 5-10 membered heteroaryl or Q, wherein said C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl, 5-10 membered heteroaryl and Q are independently optionally substituted with 1,2,3,4 or 5 substituents selected from deuterium, F, Cl, Br, I, hydroxy, amino, cyano, nitro, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C3-6Cycloalkyl or 3-6 membered heterocyclyl;
q is substituted or unsubstituted C1-6(ii) aliphatic hydrocarbyl wherein 0-3 methylene groups are independently optionally replaced by a group selected from-O-, -NH-, and-C (═ O) -;
L0is a bond, -O-, -NH-or-S-;
L1is-O-, -NH-or-S-;
L2is-C1-6Alkylene-, -C (═ O) -or-NH-;
L3is a bond, -O-, -NH-, -C (═ O) -, -C (═ NH) -, -C (═ O) -O-, -O-C (═ O) -, -C (═ O) -N (R)4)-、-N(R4) -C (═ O) -or-C1-6Alkylene-;
R4is hydrogen, deuterium, C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6Haloalkyl or C3-8A cycloalkyl group;
e is deuterium, F, Cl, Br, I, hydroxyl, amino, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl radical, C1-6Alkylamino radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-10 membered heteroaryl,
R5and R6Each independently is hydrogen, deuterium or Q;
R7is hydrogen, deuterium, methyl, hydroxymethyl, isopropyl, isobutyl, sec-butyl, benzyl, 4-hydroxybenzyl, methylthioethyl, carbamoylYlmethyl, carbamoylethyl, 1-hydroxyethyl, mercaptomethyl, carboxylmethyl, - (CH)2)4NH2、-(CH2)3NH-C(＝NH)-NH2Or
R8And R9Each independently of the other being hydrogen, deuterium, C1-6Alkyl or C1-6A haloalkyl group;
n is 0, 1,2 or 3.
The compound of claim 1, wherein each RaIndependently of one another is hydrogen, deuterium, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Hydroxyalkyl or C3-6A cycloalkyl group;
each RbIndependently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Alkylamino or C1-3A haloalkoxy group;
each RcIndependently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Alkylamino or C1-3A haloalkoxy group;
each RdIndependently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Alkylamino or C1-3A haloalkoxy group;
Reis hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-3Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy, C1-3Alkylamino radical, C1-3Haloalkylamino, C3-6Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
Rfis hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-3Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy, C1-3Alkylamino radical, C1-3Haloalkylamino, C3-6Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
Rgis hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-3Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy, C1-3Alkylamino radical, C1-3Haloalkylamino, C3-6Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl.
A compound according to claim 1 or 2, wherein each R isaIndependently hydrogen, deuterium, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
each RbIndependently hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, or dimethylamino;
each RcIndependently hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, or dimethylamino;
each RdIndependently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino,Nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, or dimethylamino;
Reis hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, dimethylamino, trifluoromethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl, thiazolyl, pyrazolyl, oxazolyl, pyridinyl, or pyrimidinyl;
Rfis hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, dimethylamino, trifluoromethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl, thiazolyl, pyrazolyl, oxazolyl, pyridinyl, or pyrimidinyl;
Rgis hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, methyl, ethyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, dimethylamino, trifluoromethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl, thiazolyl, pyrazolyl, oxazolyl, pyridinyl, or pyrimidinyl.
The compound of claim 1, wherein R1And R2Each independently is hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Alkylamino or C1-3A haloalkoxy group;
each R3Independently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy or C1-3A haloalkoxy group.
A compound according to claim 1 or 4, wherein R1And R2Each independently is hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy, trifluoromethoxy, methylamino or dimethylamino;
each R3Independently hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy or trifluoromethoxy.
The compound of claim 1, wherein R is hydrogen, deuterium, C1-4Alkyl radical, C1-3Hydroxyalkyl radical, C1-3Haloalkyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl, 5-6 membered heteroaryl or Q, wherein said C1-4Alkyl radical, C1-3Hydroxyalkyl radical, C1-3Haloalkyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl, 5-6 membered heteroaryl and Q are independently optionally substituted with 1,2,3,4 or 5 substituents selected from deuterium, F, Cl, Br, I, hydroxy, amino, cyano, nitro, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C3-6Cycloalkyl or 3-6 membered heterocyclyl.
A compound according to claim 1 or 6, wherein R is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, tert-butyl, hydroxymethyl, hydroxyethyl, 1, 2-dihydroxyethyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl, 2, 3-dihydro-1H-indene, thiazolyl, pyrazolyl, oxazolyl, pyridinyl, pyrimidinyl or Q, wherein said methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, 1, 2-dihydroxyethyl, difluoromethyl, 2-difluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, Morpholinyl, thiomorpholinyl, phenyl, 2, 3-dihydro-1H-indene, thiazolyl, pyrazolyl, oxazolyl, pyridinyl, pyrimidinyl and Q are independently optionally substituted with 1,2,3,4 or 5 substituents selected from deuterium, F, Cl, Br, I, hydroxy, amino, cyano, nitro, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl.
The compound of claim 1, wherein L2is-C1-3Alkylene-, -C (═ O) -or-NH-;
L3is a bond, -O-, -NH-, -C (═ O) -, -C (═ NH) -, -C (═ O) -O-, -O-C (═ O) -, -C (═ O) -N (R)4)-、-N(R4) -C (═ O) -or-C1-3Alkylene-;
R4is hydrogen, deuterium, C1-3Alkyl radical, C1-3Hydroxyalkyl radical, C1-3Haloalkyl or C3-6A cycloalkyl group.
The compound of claim 1 or 8, wherein L2Is methylene, ethylene, propylene, -C (═ O) -or-NH-;
L3is a bond, -O-, -NH-, -C (═ O) -, -C (═ NH) -, -C (═ O) -O-, -O-C (═ O) -, -C (═ O) -N (R)4)-、-N(R4) -C (═ O) -, methylene, ethylene orA propylene group;
R4hydrogen, deuterium, methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, 1, 2-dihydroxyethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The compound of claim 1, wherein E is deuterium, F, Cl, Br, I, hydroxy, amino, cyano, C1-4Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy, C1-3Hydroxyalkyl radical, C1-3Alkylamino radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl,
R5and R6Each independently is hydrogen, deuterium or Q;
R7is hydrogen, deuterium, methyl, hydroxymethyl, isopropyl, isobutyl, sec-butyl, benzyl, 4-hydroxybenzyl, methylthioethyl, carbamoylmethyl, carbamoylethyl, 1-hydroxyethyl, mercaptomethyl, carboxylmethyl, - (CH)2)4NH2、
R8And R9Each independently of the other being hydrogen, deuterium, C1-3Alkyl or C1-3A haloalkyl group.
The compound of claim 1 or 10, wherein E is deuterium, F, Cl, Br, I, hydroxy, amino, cyano, methyl, ethyl, n-propyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, hydroxyethyl, 1, 2-dihydroxyethyl, methylamino, ethylamino, dimethylamino, diethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl, thiazolyl, pyrazolyl, oxazolyl, pyridinyl, pyrimidinyl, o,-C(＝O)-CH(R7)-N(R8)(R9)、
R5and R6Each independently is hydrogen, deuterium or Q;
R7is hydrogen, deuterium, methyl, hydroxymethyl, isopropyl, isobutyl, sec-butyl, benzyl, 4-hydroxybenzyl, methylthioethyl, carbamoylmethyl, carbamoylethyl, 1-hydroxyethyl, mercaptomethyl, carboxylmethyl, - (CH)2)4NH2、
R8And R9Each independently of the others hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl or 2, 2-difluoroethaneAnd (4) a base.
The compound of claim 1, which is a compound of formula (II) or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt of a compound of formula (II) or a prodrug thereof,
the compound of claim 1, which is a compound of formula (III) or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt of a compound of formula (III) or a prodrug thereof,
a compound having the structure of one of the following or a stereoisomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:
a pharmaceutical composition comprising a compound of any one of claims 1-14.
The pharmaceutical composition of claim 15, further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or combination thereof.
The pharmaceutical composition according to claim 16, further comprising an agent for preventing or treating hyperuricemia, tophus, gouty arthritis, renal disorders associated with hyperuricemia, and urolithiasis, the active ingredient of the agent being different from the compound according to any one of claims 1 to 14, the agent being colchicine, a non-steroidal anti-inflammatory agent, a glucocorticoid, an uric acid production inhibitor, a uric acid excreting agent, a urinary alkalinizing agent, or any combination thereof.
Use of a compound according to any one of claims 1 to 14 or a pharmaceutical composition according to any one of claims 15 to 17 for the manufacture of a medicament for the prevention or treatment of hyperuricemia, tophus, gouty arthritis, renal disorders associated with hyperuricemia or urolithiasis in a mammal, including a human being.
Use of a compound according to any one of claims 1 to 14 or a pharmaceutical composition according to any one of claims 15 to 17 for the manufacture of a medicament for lowering blood uric acid levels.
Use of a compound according to any one of claims 1 to 14 or a pharmaceutical composition according to any one of claims 15 to 17 in the manufacture of a medicament for inhibiting xanthine oxidase and urate anion transporter 1.
A compound according to any one of claims 1 to 14 or a pharmaceutical composition according to any one of claims 15 to 17 for use in the prevention or treatment of hyperuricemia, tophus, gouty arthritis, a kidney disorder associated with hyperuricemia or urolithiasis in a mammal, including a human.
A compound according to any one of claims 1 to 14 or a pharmaceutical composition according to any one of claims 15 to 17 for use in lowering uric acid levels in blood.
A compound according to any one of claims 1 to 14 or a pharmaceutical composition according to any one of claims 15 to 17 for use in the inhibition of xanthine oxidase and urate anion transporter 1.
A method of preventing or treating hyperuricemia, tophus, gouty arthritis, a kidney disorder associated with hyperuricemia, or urolithiasis, the method comprising administering to a patient a therapeutically effective amount of a compound of any one of claims 1-14 or a pharmaceutical composition of any one of claims 15-17.
A method of lowering uric acid levels in blood, the method comprising administering to a patient a therapeutically effective amount of a compound of any one of claims 1-14 or a pharmaceutical composition of any one of claims 15-17.
A method of inhibiting xanthine oxidase and urate anion transporter 1 using a compound according to any one of claims 1 to 14 or a pharmaceutical composition according to any one of claims 15 to 17.
The following is a summary of some aspects of the invention only and is not intended to be limiting. These aspects and others are described more fully below. All references in this specification are incorporated herein by reference in their entirety. When the disclosure of the present specification differs from the cited documents, the disclosure of the present specification controls.
The invention provides a compound with dual inhibitory activities of xanthine oxidase and URAT1, which is used for preparing a medicine for preventing or treating diseases related to hyperuricemia in blood, such as hyperuricemia, tophus, gouty arthritis, kidney disorder related to hyperuricemia, urolithiasis and the like; the compound of the invention can well inhibit xanthine oxidase and URAT1, and has excellent physicochemical property and pharmacokinetic property.
The invention also provides processes for the preparation of these compounds, pharmaceutical compositions containing these compounds and methods of using these compounds or compositions in the treatment of the above-mentioned diseases in mammals, especially humans.
Specifically, the method comprises the following steps:
in one aspect, the invention relates to a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof of a compound of formula (I),
wherein:
x and Z are each independently-N (R)a)-、-O-、-S(O)t-、-C(Rb)＝、-CRcRd-or-N ═ N;
y is-C (R)e)＝、-CRfRg-or-N ═ N;
t is 0, 1 or 2;
each RaIndependently of one another is hydrogen, deuterium, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl or C3-6A cycloalkyl group;
each RbIndependently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Alkylamino or C1-6A haloalkoxy group;
each RcIndependently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Alkylamino or C1-6A haloalkoxy group;
each RdIndependently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Alkylamino or C1-6A haloalkoxy group;
Reis hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Halogenoalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylamino radical, C1-6Haloalkylamino, C3-8Cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl;
Rfis hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylamino radical, C1-6Haloalkylamino, C3-8Cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl;
Rgis hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylamino radical, C1-6Haloalkylamino, C3-8Cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl;
R1and R2Each independently is hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Alkylamino or C1-6A haloalkoxy group;
each R3Independently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy or C1-6A haloalkoxy group;
r is hydrogen, deuterium, C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl, 5-10 membered heteroaryl or Q, wherein said C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl, 5-10 membered heteroaryl and Q are independently optionally substituted with 1,2,3,4 or 5 substituents selected from deuterium, F, Cl, Br, I, hydroxy, amino, cyano, nitro, C1-3Alkyl, aryl, heteroaryl, and heteroaryl,C1-3Haloalkyl, C1-3Alkoxy radical, C3-6Cycloalkyl or 3-6 membered heterocyclyl;
q is substituted or unsubstituted C1-6(ii) aliphatic hydrocarbyl wherein 0-3 methylene groups are independently optionally replaced by a group selected from-O-, -NH-, and-C (═ O) -;
L0is a bond, -O-, -NH-or-S-;
L1is-O-, -NH-or-S-;
L2is-C1-6Alkylene-, -C (═ O) -or-NH-;
L3is a bond, -O-, -NH-, -C (═ O) -, -C (═ NH) -, -C (═ O) -O-, -O-C (═ O) -, -C (═ O) -N (R)4)-、-N(R4) -C (═ O) -or-C1-6Alkylene-;
R4is hydrogen, deuterium, C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6Haloalkyl or C3-8A cycloalkyl group;
e is deuterium, F, Cl, Br, I, hydroxyl, amino, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl radical, C1-6Alkylamino radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-10 membered heteroaryl,
R5and R6Each independently is hydrogen, deuterium or Q;
R7is hydrogen, deuterium, methyl, hydroxymethyl, isopropyl,Isobutyl, sec-butyl, benzyl, 4-hydroxybenzyl, methylthioethyl, carbamoylmethyl, carbamoylethyl, 1-hydroxyethyl, mercaptomethyl, carboxymethyl, carboxyethyl, - (CH)2)4NH2、
R8And R9Each independently of the other being hydrogen, deuterium, C1-6Alkyl or C1-6A haloalkyl group;
n is 0, 1,2 or 3.
In some embodiments, each RaIndependently of one another is hydrogen, deuterium, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Hydroxyalkyl or C3-6A cycloalkyl group;
each RbIndependently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Alkylamino or C1-3A haloalkoxy group;
each RcIndependently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Alkylamino or C1-3A haloalkoxy group;
each RdIndependently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Alkylamino or C1-3A haloalkoxy group;
Reis hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-3Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy, C1-3Alkylamino radical, C1-3Haloalkylamino, C3-6Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
Rfis hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-3Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy, C1-3Alkylamino radical, C1-3Haloalkylamino, C3-6Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
Rgis hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-3Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy, C1-3Alkylamino radical, C1-3Haloalkylamino, C3-6Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl.
In other embodiments, each RaIndependently hydrogen, deuterium, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
each RbIndependently hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, or dimethylamino;
each RcIndependently hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, or dimethylamino;
each RdIndependently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethylA group, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, or dimethylamino;
Reis hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, dimethylamino, trifluoromethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl, thiazolyl, pyrazolyl, oxazolyl, pyridinyl, or pyrimidinyl;
Rfis hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, dimethylamino, trifluoromethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl, thiazolyl, pyrazolyl, oxazolyl, pyridinyl, or pyrimidinyl;
Rgis hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, methyl, ethyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, dimethylamino, trifluoromethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl, thiazolyl, pyrazolyl, oxazolyl, pyridinyl, or pyrimidinyl.
In some embodiments, R1And R2Each independently is hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Alkylamino or C1-3A haloalkoxy group;
each R3Independently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy or C1-3A haloalkoxy group.
In other embodiments, R1And R2Each independently is hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy, trifluoromethoxy, methylamino or dimethylamino;
each R3Independently hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy or trifluoromethoxy.
In some embodiments, R is hydrogen, deuterium, C1-4Alkyl radical, C1-3Hydroxyalkyl radical, C1-3Haloalkyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl, 5-6 membered heteroaryl or Q, wherein said C1-4Alkyl radical, C1-3Hydroxyalkyl radical, C1-3Haloalkyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl, 5-6 membered heteroaryl and Q may be independently optionally substituted with 1,2,3,4 or 5 substituents selected from deuterium, F, Cl, Br, I, hydroxy, amino, cyano, nitro, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C3-6Cycloalkyl or 3-6 membered heterocyclyl.
In other embodiments, R is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, tert-butyl, hydroxymethyl, hydroxyethyl, 1, 2-dihydroxyethyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl, 2, 3-dihydro-1H-indene, thiazolyl, pyrazolyl, oxazolyl, pyridinyl, pyrimidinyl, or Q, wherein said methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, 1, 2-dihydroxyethyl, difluoromethyl, 2-difluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or Q, Phenyl, 2, 3-dihydro-1H-indene, thiazolyl, pyrazolyl, oxazolyl, pyridyl, pyrimidinyl, and Q are independently optionally substituted with 1,2,3,4, or 5 substituents selected from deuterium, F, Cl, Br, I, hydroxy, amino, cyano, nitro, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.
In some embodiments, L2is-C1-3Alkylene-, -C (═ O) -or-NH-;
L3is a bond, -O-, -NH-, -C (═ O) -, -C (═ NH) -, -C (═ O) -O-, -O-C (═ O) -, -C (═ O) -N (R)4)-、-N(R4) -C (═ O) -or-C1-3Alkylene-;
R4is hydrogen, deuterium, C1-3Alkyl radical, C1-3Hydroxyalkyl radical, C1-3Haloalkyl or C3-6A cycloalkyl group.
In other embodiments, L2Is methylene, ethylene, propylene, -C (═ O) -or-NH-;
L3is a bond, -O-, -NH-, -C (═ O) -, -C (═ NH) -, -C (═ O) -O-, -O-C (═ O) -, -C (═ O) -N (R)4)-、-N(R4) -C (═ O) -, methylene, ethylene or propylene;
R4hydrogen, deuterium, methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, 1, 2-dihydroxyethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
In some embodiments, E is deuterium, F, Cl, Br, I, hydroxy, amino, cyano, C1-4Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy, C1-3A hydroxyalkyl group,C1-3Alkylamino radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl,
R5and R6Each independently is hydrogen, deuterium or Q;
R7is hydrogen, deuterium, methyl, hydroxymethyl, isopropyl, isobutyl, sec-butyl, benzyl, 4-hydroxybenzyl, methylthioethyl, carbamoylmethyl, carbamoylethyl, 1-hydroxyethyl, mercaptomethyl, carboxymethyl, carboxyethyl, - (CH)2)4NH2、
R8And R9Each independently of the other being hydrogen, deuterium, C1-3Alkyl or C1-3A haloalkyl group.
In other embodiments, E is deuterium, F, Cl, Br, I, hydroxy, amino, cyano, methyl, ethyl, n-propyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, hydroxyethyl, 1, 2-dihydroxyethyl, methylamino, ethylamino, dimethylamino, diethylamino, cyclopropyl, cyclobutyl, and the like,Cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl, thiazolyl, pyrazolyl, oxazolyl, pyridinyl, pyrimidinyl, piperazinyl,
R5and R6Each independently is hydrogen, deuterium or Q;
R7is hydrogen, deuterium, methyl, hydroxymethyl, isopropyl, isobutyl, sec-butyl, benzyl, 4-hydroxybenzyl, methylthioethyl, carbamoylmethyl, carbamoylethyl, 1-hydroxyethyl, mercaptomethyl, carboxymethyl, carboxyethyl, - (CH)2)4NH2、
R8And R9Each independently hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl or 2, 2-difluoroethyl.
In some embodiments, the compound of formula (I) is a compound of formula (II), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt, or prodrug thereof of a compound of formula (II),
wherein, R, R1、R2、X、Z、Re、L1、L2、L3And E has the meaning as described in the present invention.
In some embodiments, the compound of formula (I) is a compound of formula (III), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt, or prodrug thereof of a compound of formula (III),
wherein, R, R1、R2、X、Z、Re、L1、L2、L3And E has the meaning as described in the present invention.
In another aspect, the invention relates to a pharmaceutical composition comprising a compound disclosed herein.
In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or combination thereof.
In other embodiments, the pharmaceutical composition of the present invention further comprises a drug for preventing or treating hyperuricemia, tophus, gouty arthritis, renal disorders associated with hyperuricemia, and urolithiasis, the active ingredient of the drug being different from the compound disclosed in the present invention, the drug being colchicine, a non-steroidal anti-inflammatory drug, a glucocorticoid, an uric acid production inhibitor, a uric acid excretion promoter, a urinary alkalinizing agent, or any combination thereof.
In another aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the preparation of a medicament for the prevention or treatment of hyperuricemia, tophus, gouty arthritis, renal disorders associated with hyperuricemia, or urolithiasis in a mammal, including a human.
In another aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the manufacture of a medicament for reducing uric acid levels in blood.
In another aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the preparation of a medicament for inhibiting xanthine oxidase and urate anion transporter 1.
In another aspect, the compounds or pharmaceutical compositions disclosed herein are used for preventing or treating hyperuricemia, tophus, gouty arthritis, renal disorders associated with hyperuricemia, or urolithiasis in a mammal, including a human.
In another aspect, the compounds or pharmaceutical compositions disclosed herein are used to reduce uric acid levels in blood.
In another aspect, the compounds or pharmaceutical compositions disclosed herein are useful for inhibiting xanthine oxidase and urate anion transporter 1.
In another aspect, the present invention relates to a method for preventing or treating hyperuricemia, tophus, gouty arthritis, a kidney disorder associated with hyperuricemia, or urolithiasis, the method comprising administering to a patient a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein.
In another aspect, the invention relates to a method of reducing uric acid levels in blood, comprising administering to a patient a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein.
In another aspect, the invention relates to a method of inhibiting xanthine oxidase and urate anion transporter 1 using a compound or pharmaceutical composition disclosed herein.
In another aspect, the invention relates to a process for the preparation, isolation and purification of a compound encompassed by formula (I), (II) or (III).
Biological test results show that the compound provided by the invention can be used as a better xanthine oxidase and urate anion transporter 1 inhibitor. Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict.
The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below.
Definitions and general terms
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.
It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be referred to as described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.
The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to articles of one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.
The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects, e.g., also primates (e.g., humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.
"stereoisomers" refers to compounds having the same chemical structure but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.
"chiral" is a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.
"enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.
"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.
The stereochemical definitions and rules used in the present invention generally follow the general definitions of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.
Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity during the chemical reaction.
Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.
Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.
Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.
The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., High Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemes and solutions (Wiley Interscience, New York, 1981); principles of Asymmetric Synthesis (2)nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
The compounds of the invention may be optionally substituted with one or more substituents, as described herein, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the invention.
In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a substituent described herein. Unless otherwise indicated, a substituted group may have one substituent substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently.
The term "unsubstituted" means that the specified group bears no substituents.
The term "optionally substituted with … …" is used interchangeably with the term "unsubstituted or substituted with … …", i.e., the structure is unsubstituted or substituted with one or more substituents described herein. Substituents described herein include, but are not limited to, D, F, Cl, Br, I, N3、CN、NO2、OH、SH、NH2Alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like.
In addition, unless otherwise explicitly indicated, the descriptions of the terms "… independently" and "… independently" and "… independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that the specific items expressed between the same symbols do not affect each other in different groups or that the specific items expressed between the same symbols in the same groups do not affect each other.
In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C1-6Alkyl "means in particular independently disclosed methyl, ethyl, C3Alkyl radical, C4Alkyl radical, C5Alkyl and C6An alkyl group.
In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.
The term "aliphatic hydrocarbon group" as used herein refers to a saturated or partially unsaturated chain or cyclic hydrocarbon group, wherein the aliphatic hydrocarbon group may be optionally substituted with one or more substituents as described herein. In some embodiments, the aliphatic hydrocarbyl group contains 1-12 carbon atoms; in other embodiments, the aliphatic hydrocarbyl group contains 1 to 6 carbon atoms; in some embodiments, 1-6 methylene groups in the aliphatic hydrocarbyl group may be replaced by-O-, -NH-, and-C (═ O) -, among others; in other embodiments, 1-3 methylene groups in the aliphatic hydrocarbyl group may be replaced by-O-, -NH-, and-C (═ O) -, among others. Examples include, but are not limited to, methoxymethyl, ethoxymethyl, ethylaminoethyl, n-propyloxymethyl, propionyloxymethyl, acetoxyethyl, acetamidomethyloxymethyl, and the like.
The term "alkyl" or "alkyl group" as used herein, denotes a saturated straight or branched chain monovalent hydrocarbon radical, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1 to 12 carbon atoms; in another embodiment, the alkyl group contains 3 to 12 carbon atoms; in another embodiment, the alkyl group contains 1 to 6 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 4 carbon atoms.
Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)3) Ethyl group (Et, -CH)2CH3) N-propyl (n-Pr, -CH)2CH2CH3) Isopropyl group (i-Pr, -CH (CH)3)2) N-butyl (n-Bu, -CH)2CH2CH2CH3) Isobutyl (i-Bu, -CH)2CH(CH3)2) Sec-butyl (s-Bu, -CH (CH)3)CH2CH3) Tert-butyl (t-Bu, -C (CH)3)3) N-pentyl (-CH)2CH2CH2CH2CH3) 2-pentyl (-CH (CH)3)CH2CH2CH3) 3-pentyl (-CH (CH)2CH3)2) 2-methyl-2-butyl (-C (CH)3)2CH2CH3) 3-methyl-2-butyl (-CH (CH)3)CH(CH3)2) 3-methyl-1-butyl (-CH)2CH2CH(CH3)2) 2-methyl-1-butyl (-CH)2CH(CH3)CH2CH3) N-hexyl (-CH)2CH2CH2CH2CH2CH3) 2-hexyl (-CH (CH)3)CH2CH2CH2CH3) 3-hexyl (-CH (CH)2CH3)(CH2CH2CH3) 2-methyl-2-pentyl (-C (CH))3)2CH2CH2CH3) 3-methyl-2-pentyl (-CH (CH)3)CH(CH3)CH2CH3) 4-methyl-2-pentyl (-CH (CH)3)CH2CH(CH3)2) 3-methyl-3-pentyl (-C (CH)3)(CH2CH3)2) 2-methyl-3-pentyl (-CH (CH)2CH3)CH(CH3)2)2, 3-dimethyl-2-butyl (-C (CH)3)2CH(CH3)2) 3, 3-dimethyl-2-butyl (-CH (CH)3)C(CH3)3) N-heptyl, n-octyl, and the like.
The term "alkylene" denotes a saturated divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a saturated straight or branched chain hydrocarbon. Unless otherwise specified, the alkylene group contains 1 to 12 carbon atoms. In one embodiment, the alkylene group contains 1 to 6 carbon atoms; in another embodiment, the alkylene group contains 1 to 4 carbon atoms; in yet another embodiment, the alkylene group contains 1 to 3 carbon atoms; in yet another embodiment, the alkylene group contains 1 to 2 carbon atoms. This is achieved byExamples of the same include methylene (-CH)2-, ethylene (-CH)2CH2-, isopropylidene (-CH (CH)3)CH2-) and the like.
The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical having at least one site of unsaturation, i.e. one carbon-carbon sp2A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 12 carbon atoms; in another embodiment, the alkenyl group contains 3 to 12 carbon atoms; in another embodiment, the alkenyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH)2) Allyl (-CH)2CH＝CH2) And so on.
The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. a carbon-carbon sp triple bond, wherein said alkynyl radical may optionally be substituted with one or more substituents as described herein. In one embodiment, alkynyl groups contain 3-12 carbon atoms; in another embodiment, alkynyl groups contain 2-6 carbon atoms; in yet another embodiment, alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH)2C.ident.CH), 1-propynyl (-C.ident.C-CH)3) And so on.
The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.
Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)3) Ethoxy (EtO, -OCH)2CH3) 1-propoxy (n-PrO, n-propoxy, -OCH)2CH2CH3) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)3)2) 1-butoxy (n-BuO, n-butoxy, -OCH)2CH2CH2CH3) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)2CH(CH3)2) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)3)CH2CH3) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)3)3) 1-pentyloxy (n-pentyloxy, -OCH)2CH2CH2CH2CH3) 2-pentyloxy (-OCH (CH)3)CH2CH2CH3) 3-pentyloxy (-OCH (CH))2CH3)2) 2-methyl-2-butoxy (-OC (CH))3)2CH2CH3) 3-methyl-2-butoxy (-OCH (CH)3)CH(CH3)2) 3-methyl-l-butoxy (-OCH)2CH2CH(CH3)2) 2-methyl-l-butoxy (-OCH)2CH(CH3)CH2CH3) And so on.
The term "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" in which the amino groups are each independently substituted with one or two alkyl groups; the alkyl group has the meaning described in the present invention. In some of these embodiments, the alkylamino group is one or two C1-6The alkyl group is attached to a nitrogen atom to form a lower alkylamino group. In other embodiments, the alkylamino group is one or two C1-4To the nitrogen atom to form an alkylamino group. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, and the like.
The terms "haloalkyl", "haloalkoxy" or "haloalkylamino" mean alkyl, alkoxy or alkylamino groups substituted with one or more halogen atoms, wherein alkyl, alkoxy or alkylamino groups have the meaning as described herein, examples of which include, but are not limited to, trifluoromethyl, 2,3, 3-tetrafluoropropyl, difluoromethoxy, trifluoromethoxy, trifluoromethylamino, and the like.
The term "hydroxyalkyl" denotes an alkyl group substituted with one or more hydroxyl groups, wherein alkyl has the meaning as described herein, examples of which include, but are not limited to, hydroxymethyl, hydroxyethyl, 2-hydroxyethyl, 1, 2-dihydroxyethyl, and the like.
The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic cyclic hydrocarbon radical containing from 3 to 12 carbon atoms. In one embodiment, cycloalkyl groups contain 7 to 12 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atoms. The cycloalkyl groups may be independently unsubstituted or substituted with one or more substituents described herein.
The term "carbocyclyl" denotes a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated monocyclic, bicyclic or tricyclic cyclic hydrocarbon radical containing from 3 to 12 carbon atoms. Carbobicyclic groups include spirocarbocyclic and fused carbocyclic groups, and suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl groups. In one embodiment, carbocyclyl contains 3 to 8 carbon atoms; in yet another embodiment, carbocyclyl contains 3 to 6 carbon atoms. Examples of carbocyclyl groups further include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. The carbocyclyl groups may independently be unsubstituted or substituted with one or more substituents described herein.
The term "carbocycle" denotes a non-aromatic, saturated or partially unsaturated monocyclic, bicyclic or tricyclic cyclic hydrocarbon containing 3 to 12 carbon atoms. Suitable carbocycles include, but are not limited to, cycloalkanes, cycloalkenes, and cycloalkynes. In one embodiment, carbocycles contain 3 to 8 carbon atoms; in yet another embodiment, carbocycles contain 3-6 carbon atoms. Examples of carbocycles further include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane, cyclododecane, and the like. The carbocycles may be independently unsubstituted or substituted with one or more substituents described herein.
The term "heterocyclyl" refers to a saturated or partially unsaturated, non-aromatic, monovalent or polyvalent, monocyclic, bicyclic, or tricyclic ring containing 3 to 12 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise indicated, a heterocyclyl group may be attached to other groups in the molecule through a carbon atom, may be attached to other groups in the molecule through a nitrogen atom, and-CH2-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, homopiperazinyl, homopiperidinyl, diazepanyl, oxepanyl, thiepanyl, oxazepanyl, thiazepanyl, oxazepanyl, and pyrrolidinyl
The term "heterocycle" refers to a saturated or partially unsaturated, non-aromatic, monocyclic, bicyclic, or tricyclic ring containing 3 to 12 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise indicated, the heterocycle may be attached to other groups in the molecule through a carbon atom, may be attached to other groups in the molecule through a nitrogen atom, and-CH2-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocycles include, but are not limited to: oxirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, pyrazoline, pyrazolidine, imidazoline, imidazolidine, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, 1, 3-dioxolane, dithiolane, tetrahydropyran, dihydropyran, 2H-pyran, 4H-pyran, tetrahydrothiopyran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiane, thioxane, homopiperazine, homopiperidine, diazepane, oxepane, thietane, oxazepane
The term "r-atom composed", wherein r is an integer, typically describes the number of ring-forming atoms in a molecule in which the number of ring-forming atoms is r. For example, piperidinyl is a heterocycloalkyl group of 6 atoms, and decahydronaphthyl is a carbocyclyl group of 10 atoms.
The term "unsaturated" as used herein means that the group contains one or more unsaturations.
The term "heteroatom" refers to O, S, N, P and Si, including N, S and any oxidation state form of P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or hydrogen on nitrogen atoms in the heterocycle substituted, e.g. N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR10(like NR in N-substituted pyrrolidinyl10)。
The term "halogen" or "halogen atom" means a fluorine atom (F), chlorine atom (Cl), bromine atom (Br) or iodine atom (I).
The term "cyano" or "CN" denotes a cyano structure, which group may be attached to another group.
The term "nitro" or "NO2"denotes a nitro structure, which may be linked to other groups.
The term "aryl" denotes a monovalent or polyvalent mono-, bi-, or tricyclic all carbocyclic ring system containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring is aromatic and has one or more attachment points to the rest of the molecule. In one embodiment, aryl is a monovalent or polyvalent carbocyclic ring system consisting of 6 to 10 ring atoms and containing at least one aromatic ring. Examples of the aryl group may include phenyl, naphthyl and anthracenyl. The aryl group may independently be optionally substituted with one or more substituents described herein.
The term "aromatic ring" means a monocyclic, bicyclic or tricyclic all-carbocyclic ring system containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring is aromatic. In one embodiment, the aromatic ring is a carbocyclic ring system consisting of 6 to 10 ring atoms, and wherein at least one ring is aromatic. Examples of the aromatic ring may include benzene, naphthalene, and anthracene. The aromatic rings may independently be optionally substituted with one or more substituents as described herein.
The term "heteroaryl" denotes a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring is aromatic and at least one aromatic ring contains one or more heteroatoms and has one or more attachment points to the rest of the molecule. The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, heteroaryl is a 5-12 atom heteroaryl comprising 1,2,3, or 4 heteroatoms independently selected from O, S and N; in another embodiment, heteroaryl is 5-6 atom consisting of 1,2,3, or 4 heteroatoms independently selected from O, S and N.
Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, oxadiazolyl (e.g., 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl), oxadiazolyl (e.g., 1,2,3, 4-oxadiazolyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, isothiazolyl, 2-thiadiazolyl (e.g., 1,3, 4-thiadiazolyl, 1,2, 3-thiadiazolyl, 1,2, 5-thiadiazolyl) Thiatriazolyl (e.g., 1,2,3, 4-thiatriazolyl), tetrazolyl (e.g., 2H-1,2,3, 4-tetrazolyl, 1H-1,2,3, 4-tetrazolyl), triazolyl (e.g., 2H-1,2, 3-triazolyl, 1H-1,2, 4-triazolyl, 4H-1,2, 4-triazolyl), 2-thienyl, 3-thienyl, 1H-pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl), N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), 2-pyrazinyl, triazinyl (e.g., 1,3, 5-triazine), tetrazinyl (e.g., 1,2,4, 5-tetrazine, 1,2,3, 5-tetrazine); the following bicyclic rings are also included, but are in no way limited to these: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridyl, and the like.
The terms "heteroaromatic ring" or "heteroaromatic compound" each refer to a monocyclic, bicyclic, or tricyclic ring containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring is aromatic and at least one aromatic ring contains one or more heteroatoms. The heteroaromatic ring or heteroaromatic compound is optionally substituted with one or more substituents as described herein. In one embodiment, the heteroaromatic ring or heteroaromatic compound is a 5-12 atom heteroaromatic ring or heteroaromatic compound comprising 1,2,3, or 4 heteroatoms independently selected from O, S and N; in another embodiment, the heteroaromatic ring or heteroaromatic compound is a 5-6 atom heteroaromatic ring or heteroaromatic compound comprising 1,2,3, or 4 heteroatoms independently selected from O, S and N.
Examples of heteroaromatic rings or heteroaromatic compounds include, but are not limited to, furan, imidazole, isoxazole, oxazole, oxadiazole, oxatriazole, thiazole, isothiazole, thiadiazole, thiatriazole, tetrazole, triazole, thiophene, 1H-pyrazole, pyrrole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, tetrazine; the following bicyclic rings are also included, but are in no way limited to these: benzimidazole, benzofuran, benzothiophene, indole, purine, quinoline, isoquinoline, imidazo [1,2-a ] pyridine, pyrazolo [1,5-a ] pyrimidine, imidazo [1,2-b ] pyridazine, [1,2,4] triazolo [4,3-b ] pyridazine, [1,2,4] triazolo [1,5-a ] pyrimidine, [1,2,4] triazolo [1,5-a ] pyridine, and the like.
As described herein, a ring system formed on a ring wherein a substituent is bonded to the center (as shown in formula b) represents that the substituent may be substituted at any substitutable position on the ring. For example, formula b represents a substituent R11May be mono-or polysubstituted at any possible substituted position on the C ring, as shown in formulae C1-C19.
As described herein, the ring system formed by a linker attached to the center of the ring (as shown in formula d) represents that the linker may be attached to the rest of the molecule at any available position on the ring system. Formula D represents that any possible attachment position on the D ring can be attached to the rest of the molecule.
The ring system formed by the ring in which the substituent R is bonded to the center represents the substituent R as described in the present invention12Substitution can only be made at any substitutable or any reasonable position on the ring to which it is attached. For example, formula e represents that any possible substituted position on the A ring may be substituted by R, as shown in formula f, formula g, formula h and formula i.
The term "protecting group" or "PG" refers to a substituent that, when reacted with other functional groups, is generally used to block or protect a particular functionality. For example, "amino protecting group" means a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to the functionality of a substituent of a hydroxyl group to block or protect the hydroxyl group, and suitable protecting groups include acetyl and silyl groups. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH2CH2SO2Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.
The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)1-C24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。
"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.
As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, description of the scientific acceptable salts in detail in J. pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, methanesulphonatesAcid salts, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N+(C1-4Alkyl radical)4A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8Sulfonates and aromatic sulfonates.
"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.
When the solvent is water, the term "hydrate" may be used. In some embodiments, a molecule of a compound of the present invention may be associated with a molecule of water, such as a monohydrate; in other embodiments, one molecule of the compound of the present invention may be associated with more than one molecule of water, such as a dihydrate, and in still other embodiments, one molecule of the compound of the present invention may be associated with less than one molecule of water, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the compound in its non-hydrated form.
The term "treating" any disease or condition, as used herein, means all that can slow, halt, arrest, control or halt the progression of the disease or condition, but does not necessarily mean that all the symptoms of the disease or condition have disappeared, and also includes prophylactic treatment of the symptoms, particularly in patients susceptible to such disease or disorder. In some of these embodiments, refers to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.
The term "therapeutically effective amount" or "therapeutically effective dose" as used herein refers to an amount of a compound of the invention that is capable of eliciting a biological or medical response (e.g., reducing or inhibiting enzyme or protein activity, or ameliorating symptoms, alleviating a disorder, slowing or delaying the progression of a disease, or preventing a disease, etc.) in a subject. In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount that, when administered to a subject, is effective for: (1) at least partially alleviating, inhibiting, preventing and/or ameliorating a condition or disease (i) mediated by xanthine oxidase or a urate anion transporter 1(URAT1), or (ii) associated with xanthine oxidase or urate anion transporter 1 activity, or (iii) characterized by abnormal activity of xanthine oxidase or urate anion transporter 1; or (2) reduces or inhibits the activity of xanthine oxidase or a urate anion transporter 1; or (3) reduces or inhibits expression of xanthine oxidase or urate anion transporter 1. In another embodiment, the term "therapeutically effective amount" means an amount that, when administered to a cell, or organ, or non-cellular biological substance, or vehicle, at least partially reduces or inhibits xanthine oxidase or urate anion transporter 1 activity; or an amount of a compound of the invention effective to at least partially reduce or inhibit expression of xanthine oxidase or urate anion transporter 1.
The terms "administration" and "administering" of a compound as used herein shall be understood as providing a compound of the invention or a prodrug of a compound of the invention to a subject in need thereof. It will be appreciated that the effect on the blood uric acid concentration may be effected by one skilled in the art by treating a patient currently suffering from such a disorder, or prophylactically treating a patient suffering from such a disorder, with an effective amount of a compound of the present invention.
The term "composition" as used herein refers to a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. The meaning of such terms in relation to pharmaceutical compositions includes products comprising the active ingredient(s) and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from mixing, complexation or aggregation of any two or more of the ingredients, or from decomposition of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention include any composition prepared by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
Description of the Compounds of the invention
The invention discloses a cyano-substituted fused bicyclic derivative, a stereoisomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, a pharmaceutical preparation and a composition thereof, which can be used as xanthine oxidase and urate anion transporter 1 inhibitors and have potential application to treatment of symptoms or diseases with high uric acid value in human blood, such as hyperuricemia, tophus, gouty arthritis, kidney disorder related to hyperuricemia and urolithiasis.
In one aspect, the invention relates to a compound of formula (I) or a stereoisomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt of a compound of formula (I) or a prodrug thereof,
wherein, R, R1、R2、R3、X、Y、Z、L0、L1、L2、L3E and n have the meanings given in the description of the invention.
In some embodiments, X and Z are each independently-N (R)a)-、-O-、-S(O)t-、-C(Rb)＝、-CRcRd-or-N ═ N; wherein, t and Ra、Rb、RcAnd RdHave the meaning as described in the present invention.
In some embodiments, Y is-C (R)e)＝、-CRfRg-or-N ═ N; wherein R ise、RfAnd RgHave the meaning as described in the present invention.
In some embodiments, t is 0, 1, or 2.
In some embodiments, each RaIndependently of one another is hydrogen, deuterium, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl or C3-6A cycloalkyl group.
In some embodiments, each RbIndependently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Alkylamino or C1-6A haloalkoxy group.
In some embodiments, each RcIndependently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Alkylamino or C1-6A haloalkoxy group.
In some embodiments, each RdIndependently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C1-6Haloalkyl group、C1-6Alkoxy radical, C1-6Alkylamino or C1-6A haloalkoxy group.
In some embodiments, ReIs hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylamino radical, C1-6Haloalkylamino, C3-8Cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl.
In some embodiments, RfIs hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylamino radical, C1-6Haloalkylamino, C3-8Cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl.
In some embodiments, RgIs hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Alkylamino radical, C1-6Haloalkylamino, C3-8Cycloalkyl, 3-8 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl.
In some embodiments, R1Is hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Alkylamino or C1-6A haloalkoxy group.
In some embodiments, R2Is hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Alkylamino or C1-6A haloalkoxy group.
In some embodimentsIn (1), each R3Independently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy or C1-6A haloalkoxy group.
In some embodiments, R is hydrogen, deuterium, C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl, 5-10 membered heteroaryl or Q, wherein said C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-10Aryl, 5-10 membered heteroaryl and Q are independently optionally substituted with 1,2,3,4 or 5 substituents selected from deuterium, F, Cl, Br, I, hydroxy, amino, cyano, nitro, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C3-6Cycloalkyl or 3-6 membered heterocyclyl; wherein Q has the meaning as described in the present invention.
In some embodiments, Q is substituted or unsubstituted C1-6An aliphatic hydrocarbon group in which 0 to 3 methylene groups are independently optionally replaced by a group selected from-O-, -NH-, and-C (═ O) -.
In some embodiments, L0Is a bond, -O-, -NH-or-S-.
In some embodiments, L1is-O-, -NH-or-S-.
In some embodiments, L2is-C1-6Alkylene-, -C (═ O) -or-NH-.
In some embodiments, L3Is a bond, -O-, -NH-, -C (═ O) -, -C (═ NH) -, -C (═ O) -O-, -O-C (═ O) -, -C (═ O) -N (R)4)-、-N(R4) -C (═ O) -or-C1-6Alkylene-; wherein R is4Have the meaning as described in the present invention.
In some embodiments, R4Is hydrogen, deuterium, C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6Haloalkyl or C3-8A cycloalkyl group.
In some embodiments, E is deuterium, F, Cl, Br, I, hydroxyRadical, amino, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl radical, C1-6Alkylamino radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-10 membered heteroaryl,
In some embodiments, R5And R6Each independently is hydrogen, deuterium or Q; wherein Q has the meaning as described in the present invention.
In some embodiments, R7Is hydrogen, deuterium, methyl, hydroxymethyl, isopropyl, isobutyl, sec-butyl, benzyl, 4-hydroxybenzyl, methylthioethyl, carbamoylmethyl, carbamoylethyl, 1-hydroxyethyl, mercaptomethyl, carboxymethyl, carboxyethyl, - (CH)2)4NH2、
In some embodiments, R8And R9Each independently of the other being hydrogen, deuterium, C1-6Alkyl or C1-6Alkyl halidesAnd (4) a base.
In some embodiments, n is 0, 1,2, or 3.
In some embodiments, the compound of the present invention is a compound of formula (I) or a stereoisomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt of a compound of formula (I) or a prodrug thereof, with the proviso that-L in formula (I)1-L2-L3-E is not hydroxy or difluoromethoxy.
In other embodiments, each RaIndependently of one another is hydrogen, deuterium, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Hydroxyalkyl or C3-6A cycloalkyl group.
Also in some embodiments, each RaIndependently hydrogen, deuterium, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
In other embodiments, each RbIndependently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Alkylamino or C1-3A haloalkoxy group.
Also in some embodiments, each RbIndependently hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino or dimethylamino.
In other embodiments, each RcIndependently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Alkylamino or C1-3A haloalkoxy group.
Also in some embodiments, each RcIndependently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, diFluoromethoxy, trifluoromethoxy, methylamino, ethylamino, or dimethylamino.
In other embodiments, each RdIndependently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Alkylamino or C1-3A haloalkoxy group.
Also in some embodiments, each RdIndependently hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino or dimethylamino.
In other embodiments, ReIs hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-3Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy, C1-3Alkylamino radical, C1-3Haloalkylamino, C3-6Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl.
Also in some embodiments, ReIs hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, methyl, ethyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, dimethylamino, trifluoromethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl, thiazolyl, pyrazolyl, oxazolyl, pyridinyl, or pyrimidinyl.
In other embodiments, RfIs hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-3Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy, C1-3Alkylamino radical, C1-3Haloalkylamino, C3-6Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl.
Also in some embodiments, RfIs hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, methyl, ethyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, dimethylamino, trifluoromethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl, thiazolyl, pyrazolyl, oxazolyl, pyridinyl, or pyrimidinyl.
In other embodiments, RgIs hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-3Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy, C1-3Alkylamino radical, C1-3Haloalkylamino, C3-6Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl.
Also in some embodiments, RgIs hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, methyl, ethyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, dimethylamino, trifluoromethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl, thiazolyl, pyrazolyl, oxazolyl, pyridinyl, or pyrimidinyl.
In other embodiments, R1Is hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Alkylamino or C1-3Alkyl halidesAn oxy group.
Also in some embodiments, R1Hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, methyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy, trifluoromethoxy, methylamino or dimethylamino.
In other embodiments, R2Is hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Alkylamino or C1-3A haloalkoxy group.
Also in some embodiments, R2Hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, methyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy, trifluoromethoxy, methylamino or dimethylamino.
In other embodiments, each R3Independently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy or C1-3A haloalkoxy group.
Also in some embodiments, each R3Independently hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy or trifluoromethoxy.
In other embodiments, R is hydrogen, deuterium, C1-4Alkyl radical, C1-3Hydroxyalkyl radical, C1-3Haloalkyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl, 5-6 membered heteroaryl or Q, wherein said C1-4Alkyl radical, C1-3Hydroxyalkyl radical, C1-3Haloalkyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl, 5-6 membered heteroaryl and Q are independently optionally substituted with 1,2,3,4 or 5 substituents selected from deuterium, F, Cl, Br, I, hydroxy, amino, cyano, nitro, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical,C3-6Cycloalkyl or 3-6 membered heterocyclyl; wherein Q has the meaning as described in the present invention.
In still other embodiments, R is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, t-butyl, hydroxymethyl, hydroxyethyl, 1, 2-dihydroxyethyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl, 2, 3-dihydro-1H-indene, thiazolyl, pyrazolyl, oxazolyl, pyridinyl, pyrimidinyl, or Q, wherein said methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, 1, 2-dihydroxyethyl, difluoromethyl, 2-difluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or Q, Phenyl, 2, 3-dihydro-1H-indene, thiazolyl, pyrazolyl, oxazolyl, pyridyl, pyrimidinyl, and Q are independently optionally substituted with 1,2,3,4, or 5 substituents selected from deuterium, F, Cl, Br, I, hydroxy, amino, cyano, nitro, methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl; wherein Q has the meaning as described in the present invention.
In other embodiments, L2is-C1-3Alkylene-, -C (═ O) -or-NH-.
Also in some embodiments, L2Is methylene, ethylene, propylene, -C (═ O) -or-NH-.
In other embodiments, L3Is a bond, -O-, -NH-, -C (═ O) -, -C (═ NH) -, -C (═ O) -O-, -O-C (═ O) -, -C (═ O) -N (R)4)-、-N(R4) -C (═ O) -or-C1-3Alkylene-; wherein R is4Have the meaning as described in the present invention.
Also in some embodiments, L3Is a bond, -O-, -NH-, -C (═ O) -, -C (═ NH) -, -C (═ O) -O-, -O-C (═ O) -, -C (═ O) -N (R)4)-、-N(R4) -C (═ O) -, methylene, ethylene or propylene; wherein R is4Have the meaning as described in the present invention.
In other embodiments, R4Is hydrogen, deuterium, C1-3Alkyl radical, C1-3Hydroxyalkyl radical, C1-3Haloalkyl or C3-6A cycloalkyl group.
Also in some embodiments, R4Hydrogen, deuterium, methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, 1, 2-dihydroxyethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
In other embodiments, E is deuterium, F, Cl, Br, I, hydroxy, amino, cyano, C1-4Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Haloalkoxy, C1-3Hydroxyalkyl radical, C1-3Alkylamino radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl,
In still other embodiments, E is deuterium, F, Cl, Br, I, hydroxy, amino, cyano, methyl, ethyl, n-propyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, hydroxyethyl, 1, 2-dihydroxyethyl, methylamino, ethylamino, dimethylamino, diethylamino, cyclopropyl, cyclobutyl, or a mixture thereofPentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl, thiazolyl, pyrazolyl, oxazolyl, pyridinyl, pyrimidinyl, piperazinyl,
In other embodiments, R5And R6Each independently is hydrogen, deuterium or Q; wherein Q has the meaning as described in the present invention.
In other embodiments, R7Is hydrogen, deuterium, methyl, hydroxymethyl, isopropyl, isobutyl, sec-butyl, benzyl, 4-hydroxybenzyl, methylthioethyl, carbamoylmethyl, carbamoylethyl, 1-hydroxyethyl, mercaptomethyl, carboxymethyl, carboxyethyl, - (CH)2)4NH2、
In other embodiments, R8And R9Each independently of the other being hydrogen, deuterium, C1-3Alkyl or C1-3A haloalkyl group.
Also in some embodiments, R8And R9Each independently hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl or 2, 2-difluoroethyl.
In some embodiments, the compound of formula (I) is a compound of formula (II) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt, or prodrug thereof of a compound of formula (II),
wherein, R, R1、R2、X、Z、Re、L1、L2、L3And E has the meaning as described in the present invention.
In some embodiments, the compound of formula (I) is a compound of formula (III) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt, or prodrug thereof of a compound of formula (III),
wherein, R, R1、R2、X、Z、Re、L1、L2、L3And E has the meaning as described in the present invention.
In another aspect, the present invention relates to a compound, or a stereoisomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, of one of the following, but in no way limited to these compounds:
in another aspect, the invention relates to a pharmaceutical composition comprising a compound disclosed herein.
In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or combination thereof.
In other embodiments, the pharmaceutical composition of the present invention further comprises a drug for preventing or treating hyperuricemia, tophus, gouty arthritis, renal disorders associated with hyperuricemia, and urolithiasis, the active ingredient of the drug being different from the compound disclosed in the present invention, the drug being colchicine, a non-steroidal anti-inflammatory drug, a glucocorticoid, an uric acid production inhibitor, a uric acid excretion promoter, a urinary alkalinizing agent, or any combination thereof.
In another aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the preparation of a medicament for the prevention or treatment of hyperuricemia, tophus, gouty arthritis, renal disorders associated with hyperuricemia, or urolithiasis in a mammal, including a human.
In another aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the manufacture of a medicament for reducing uric acid levels in blood.
In another aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the preparation of a medicament for inhibiting xanthine oxidase and urate anion transporter 1.
In another aspect, the compounds or pharmaceutical compositions disclosed herein are used for preventing or treating hyperuricemia, tophus, gouty arthritis, renal disorders associated with hyperuricemia, or urolithiasis in a mammal, including a human.
In another aspect, the compounds or pharmaceutical compositions disclosed herein are used to reduce uric acid levels in blood.
In another aspect, the compounds or pharmaceutical compositions disclosed herein are useful for inhibiting xanthine oxidase and urate anion transporter 1.
In another aspect, the present invention relates to a method for preventing or treating hyperuricemia, tophus, gouty arthritis, a kidney disorder associated with hyperuricemia, or urolithiasis, the method comprising administering to a patient a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein.
In another aspect, the invention relates to a method of reducing uric acid levels in blood, comprising administering to a patient a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein.
In another aspect, the invention relates to a method of inhibiting xanthine oxidase and urate anion transporter 1 using a compound or pharmaceutical composition disclosed herein.
In another aspect, the invention relates to a process for the preparation, isolation and purification of a compound encompassed by formula (I), (II) or (III).
Stereoisomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of formula (I), (II), (III) are included within the scope of the present invention unless otherwise specified.
The compounds of the present disclosure may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. The present invention contemplates that all stereoisomeric forms of the compounds of formula (I), (II), (III), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or conformational) isomers, and mixtures thereof, such as racemic mixtures, are integral to the invention.
In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated as within this invention and are included as disclosed compounds in this invention. When stereochemistry is indicated by a solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of the structure are so well-defined and defined.
The compounds of formula (I), (II), (III) may exist in different tautomeric forms, and all such tautomers are included within the scope of the invention.
The compounds of the formulae (I), (II), (III) may be present in the form of salts. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be compatible chemically and/or toxicologically with the other ingredients comprising the formulation and/or the mammal being treated therewith. In another embodiment, the salt need not be a pharmaceutically acceptable salt, but may be an intermediate useful in the preparation and/or purification of the compounds of formula (I), (II), (III) and/or in the isolation of the enantiomers of the compounds of formula (I), (II), (III).
Pharmaceutically acceptable acid addition salts may be formed from the disclosed compounds of the invention by the action of an inorganic or organic acid, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorotheyl salt, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/biphosphate/dihydrogen phosphate, phosphate, Polysilonolactates, propionates, stearates, succinates, sulfosalicylates, tartrates, tosylates and trifluoroacetates.
Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, and the like.
Pharmaceutically acceptable base addition salts may be formed from the disclosed compounds by reaction with an inorganic or organic base.
Inorganic bases from which salts can be derived include, for example, ammonium salts and metals of groups I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
Organic bases from which salts can be derived include primary, secondary and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Some organic amines include, for example, isopropylamine, benzathine (benzathine), choline salts (cholinate), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine, and tromethamine.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, Mack Publishing Company, Easton, Pa., (1985); and "handbook of pharmaceutically acceptable salts: properties, Selection and application (Handbook of Pharmaceutical Salts: Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) may find some additional lists of suitable Salts.
In addition, the compounds disclosed herein, including their salts, may also be obtained in the form of their hydrates or in the form of solvents containing them (e.g., ethanol, DMSO, etc.), for their crystallization. The compounds disclosed herein may form solvates with pharmaceutically acceptable solvents (including water), either inherently or by design; thus, the present invention is intended to include both solvated and unsolvated forms of the disclosed compounds.
Any formulae given herein are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H、3H、11C、13C、14C、15N、17O、18O、18F、31P、32P、35S、36Cl and125I。
in another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, e.g. wherein a radioisotope, e.g. is present3H、14C and18those compounds of F, or in which a non-radioactive isotope is present, e.g.2H and13those of C. The isotopically enriched compounds can be used for metabolic studies (use)14C) Reaction kinetics study (using, for example2H or3H) Detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution determination, or may be used in radiotherapy of a patient.18F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I) can be prepared by conventional techniques known to those skilled in the art or by the procedures and examples described in the present specification using a suitable isotopically labelled reagent in place of the original used unlabelled reagent.
In addition, heavier isotopes are, in particular, deuterium (i.e.,2the substitution of H or D) may provide certain therapeutic advantages which result fromHigher metabolic stability. For example, increased in vivo half-life or decreased dosage requirements or improved therapeutic index. It is to be understood that deuterium in the present invention is to be considered as a substituent of the compound of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined by isotopic enrichment factors. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic and natural abundance of a given isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g. D2O, acetone-d6、DMSO-d6Those solvates of (a).
In another aspect, the invention relates to intermediates for the preparation of compounds of formula (I), (II), (III).
In another aspect, the invention relates to methods for the preparation, isolation and purification of compounds of formula (I), (II), (III).
In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention. In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle or combination thereof. In another embodiment, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel, or spray dosage form.
Pharmaceutical compositions, formulations and administration of the compounds of the invention
The present invention provides a pharmaceutical composition comprising a compound disclosed herein, for example, as set forth in the examples; and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof.
The present invention provides methods of treating, preventing or ameliorating a disease or condition comprising administering a safe and effective amount of a combination comprising a compound of the present disclosure and one or more therapeutically active agents. Wherein the combination comprises one or more drugs for preventing or treating hyperuricemia, tophus, gouty arthritis, kidney disorders associated with hyperuricemia and urolithiasis, and the active ingredients of the drugs are different from the compounds disclosed by the invention.
Drugs for preventing or treating hyperuricemia, tophus, gouty arthritis, kidney disorders associated with hyperuricemia, and urolithiasis include, but are not limited to: colchicine, non-steroidal anti-inflammatory drugs, glucocorticoids, uric acid production-inhibiting drugs, uricosuric drugs, urinary alkalizing agents or any combination thereof.
The medicine for treating hyperuricemia, tophus, gouty arthritis, kidney disorder related to hyperuricemia and urolithiasis is colchicine, indomethacin, etoricoxib, diclofenac, ibuprofen, rofecoxib, celecoxib, meloxicam, prednisone, hydrocortisone succinate, allopurinol, probenecid, fensultone, benzbromarone, oxypurinol, febuxostat, recombinant aspergillus flavus urate oxidase, pegylated recombinant urate oxidase, sodium bicarbonate tablets, potassium sodium citrate mixture or any combination thereof.
The amount of compound in the pharmaceutical compositions disclosed herein is that amount which is effective to detect inhibition of xanthine oxidase and urate anion transporter 1 in a biological sample or patient. The dosage of the active ingredient in the composition of the present invention may vary, however, the amount of the active ingredient must be such that a suitable dosage form is obtained. The active ingredient may be administered to patients (animals and humans) in need of such treatment at dosages that provide optimal pharmaceutical efficacy. The selected dosage depends on the desired therapeutic effect, on the route of administration and on the duration of the treatment. The dosage will vary from patient to patient depending on the nature and severity of the disease, the weight of the patient, the particular diet of the patient, the concurrent use of drugs, and other factors that will be recognized by those skilled in the art. The dosage range is generally about 0.5mg to 1.0g per patient per day and may be administered in a single dose or in multiple doses. In one embodiment, the dosage range is from about 0.5mg to 500mg per patient per day; from about 0.5mg to 200mg per patient per day in another embodiment; and in yet another embodiment from about 5mg to 50mg per patient per day.
It will also be appreciated that certain compounds of the invention may be present in free form and used in therapy, or if appropriate in the form of a pharmaceutically acceptable derivative thereof. Pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any additional adduct or derivative that upon administration to a patient in need thereof provides, directly or indirectly, a compound of the present invention or a metabolite or residue thereof.
The medicaments or pharmaceutical compositions disclosed herein may be prepared and packaged in bulk (bulk) form, wherein a safe and effective amount of the compound of formula (I) may be extracted and then administered to a patient in the form of a powder or syrup. Typically, the administration to a patient is at a dosage level of between 0.0001 to 10mg/kg body weight per day to achieve effective antagonism of xanthine oxidase and urate anion transporter 1. Alternatively, the pharmaceutical compositions disclosed herein can be prepared and packaged in unit dosage forms, wherein each physically discrete unit contains a safe and effective amount of a compound of formula (I). When prepared in unit dosage form, the disclosed pharmaceutical compositions can generally contain, for example, from 0.5mg to 1g, or from 1mg to 700mg, or from 5mg to 100mg of the disclosed compounds.
When the pharmaceutical composition of the invention contains one or more other active ingredients in addition to the compound of the invention, the compound weight ratio of the compound of the invention to the second active ingredient may vary and depends on the effective dose of each ingredient. Generally, an effective dose of each is used. Thus, for example, when a compound of the present invention is mixed with another pharmaceutical agent, the weight ratio of the compound of the present invention to the other pharmaceutical agent typically ranges from about 1000: 1 to about 1: 1000, e.g., from about 200: 1 to about 1: 200. Mixtures of the compounds of the invention with other active ingredients are generally also within the above-mentioned ranges, but in each case an effective dose of each active ingredient should be used.
As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, mixture or vehicle, which is compatible with the dosage form or pharmaceutical composition to be administered. Each excipient, when mixed, must be compatible with the other ingredients of the pharmaceutical composition to avoid interactions that would substantially reduce the efficacy of the disclosed compounds and which would result in a pharmaceutical composition that is not pharmaceutically acceptable when administered to a patient. Furthermore, each excipient must be pharmaceutically acceptable, e.g., of sufficiently high purity.
Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, pharmaceutically acceptable excipients may be selected for their specific function in the composition. For example, certain pharmaceutically acceptable excipients may be selected to aid in the production of a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected to aid in the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be selected to facilitate carrying or transporting the disclosed compounds from one organ or portion of the body to another organ or portion of the body when administered to a patient. Certain pharmaceutically acceptable excipients may be selected that enhance patient compliance.
Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function, and provide alternative functions, depending on how many such excipients are present in the formulation and which other excipients are present in the formulation.
The skilled person is knowledgeable and skilled in the art to enable them to select suitable amounts of suitable pharmaceutically acceptable excipients for use in the present invention. Furthermore, there is a large amount of resources available to the skilled person, who describes pharmaceutically acceptable excipients and is used to select suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (The American Pharmaceutical Association and The Pharmaceutical Press).
Various carriers for The formulation of pharmaceutically acceptable compositions, and well known techniques for their preparation, are disclosed in Remington, The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988. Annu 1999, Marcel Dekker, New York, The contents of each of which are incorporated herein by reference. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention (e.g., exhibits any undesirable biological effect or otherwise interacts in a deleterious manner with any other component of a pharmaceutically acceptable composition), its use is contemplated as falling within the scope of the present invention.
The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. Some commonly used methods in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
Thus, in another aspect, the invention relates to a process for preparing a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof, which process comprises admixing the ingredients. Pharmaceutical compositions comprising the disclosed compounds may be prepared by mixing, for example, at ambient temperature and atmospheric pressure.
The compounds disclosed herein are generally formulated in a dosage form suitable for administration to a patient by a desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, e.g., suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.
In one embodiment, the compounds disclosed herein may be formulated in oral dosage forms. In another embodiment, the compounds disclosed herein may be formulated in an inhalation dosage form. In another embodiment, the compounds disclosed herein can be formulated for nasal administration. In yet another embodiment, the compounds disclosed herein can be formulated for transdermal administration. In yet another embodiment, the compounds disclosed herein may be formulated for topical administration.
The pharmaceutical compositions provided by the present invention may be provided as compressed tablets, milled tablets, chewable lozenges, fast-dissolving tablets, double-compressed tablets, or enteric-coated, sugar-coated or film-coated tablets. Enteric coated tablets are compressed tablets coated with a substance that is resistant to the action of gastric acid but dissolves or disintegrates in the intestine, thereby preventing the active ingredient from contacting the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can help to mask unpleasant tastes or odors and prevent oxidation of the tablet. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings are endowed with the same general characteristics as sugar coatings. A tabletted tablet is a compressed tablet prepared over more than one compression cycle, including a multi-layer tablet, and a press-coated or dry-coated tablet.
Tablet dosage forms may be prepared from the active ingredient in powder, crystalline or granular form, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents and/or colorants. Flavoring and sweetening agents are particularly useful in forming chewable tablets and lozenges.
The pharmaceutical composition provided by the present invention may be provided in soft or hard capsules, which may be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsules, also known as Dry Fill Capsules (DFC), consist of two segments, one inserted into the other, thus completely encapsulating the active ingredient. Soft Elastic Capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by the addition of glycerol, sorbitol or similar polyols. The soft gelatin shell may contain a preservative to prevent microbial growth. Suitable preservatives are those as described herein, including methyl and propyl parabens, and sorbic acid. The liquid, semi-solid and solid dosage forms provided by the present invention may be encapsulated in a capsule. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions may be as described in U.S. patent nos.4,328,245; 4,409,239 and 4,410,545. The capsules may also be coated as known to those skilled in the art to improve or maintain dissolution of the active ingredient.
The pharmaceutical compositions provided herein may be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. Emulsions are two-phase systems in which one liquid is dispersed throughout another in the form of globules, which can be either oil-in-water or water-in-oil. Emulsions may include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifiers and preservatives. Suspensions may include a pharmaceutically acceptable suspending agent and a preservative. The aqueous alcoholic solution may comprise pharmaceutically acceptable acetals, such as di (lower alkyl) acetals of lower alkyl aldehydes, e.g. acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugars, such as sucrose, and may also contain preservatives. For liquid dosage forms, for example, a solution in polyethylene glycol may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, for precise and convenient administration.
Other useful liquid and semi-solid dosage forms include, but are not limited to, those comprising the active ingredients provided herein and a secondary mono-or poly-alkylene glycol, including: 1, 2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, where 350, 550, 750 refer to the approximate average molecular weight of the polyethylene glycol. These formulations may further include one or more antioxidants, such as Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.
Dosage unit formulations for oral administration may be microencapsulated, where appropriate. They may also be prepared as extended or sustained release compositions, for example by coating or embedding the particulate material in a polymer, wax or the like.
The oral pharmaceutical composition provided by the invention can also be provided in the form of liposome, micelle, microsphere or nano system. Micellar dosage forms can be prepared using the methods described in U.S. Pat. No.6,350,458.
The pharmaceutical compositions provided herein can be provided as non-effervescent or effervescent granules and powders for reconstitution into liquid dosage forms. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders may include diluents, sweeteners and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders may include organic acids and sources of carbon dioxide.
Coloring and flavoring agents may be used in all of the above dosage forms.
The disclosed compounds may also be conjugated to soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol or polyoxyethylene polylysine substituted with palmitoyl residues. In addition, the disclosed compounds may be combined with a class of biodegradable polymers used in achieving controlled release of a drug, such as polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.
The pharmaceutical compositions provided by the present invention may be formulated into immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed release forms.
The pharmaceutical compositions provided by the present invention may be co-formulated with other active ingredients that do not impair the intended therapeutic effect, or with substances that supplement the intended effect.
The pharmaceutical compositions provided by the present invention may be administered parenterally by injection, infusion or implantation for local or systemic administration. Parenteral administration as used herein includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.
The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and solid forms suitable for solution or suspension in a liquid prior to injection. Such dosage forms may be prepared according to conventional methods known to those skilled in The art of pharmaceutical Science (see Remington: The Science and Practice of Pharmacy, supra).
Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives to inhibit microbial growth, stabilizers, solubility enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, thickening agents, pH adjusting agents, and inert gases.
Suitable aqueous carriers include, but are not limited to: water, saline, normal saline or Phosphate Buffered Saline (PBS), sodium chloride injection, Ringers injection, isotonic glucose injection, sterile water injection, dextrose and lactated Ringers injection. Non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and the medium chain triglycerides of coconut oil, and palm seed oil. Water-miscible vehicles include, but are not limited to, ethanol, 1, 3-butanediol, liquid polyethylene glycols (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol, N-methyl-2-pyrrolidone, N-dimethylacetamide, and dimethylsulfoxide.
Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, mercurial, benzyl alcohol, chlorobutanol, methyl and propyl parabens, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl and propyl parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerol and glucose. Suitable buffers include, but are not limited to, phosphate and citrate. Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Suitable emulsifiers include those described herein, including polyoxyethylene sorbitan monolaurate. Polyoxyethylene sorbitan monooleate 80 and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to, EDTA. Suitable pH adjusters include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrinRefined and sulfobutyl ether 7-beta-cyclodextrin (b)
The pharmaceutical compositions provided herein may be formulated for single or multiple dose administration. The single dose formulations are packaged in ampoules, vials or syringes. The multi-dose parenteral formulation must contain a bacteriostatic or fungistatic concentration of the antimicrobial agent. All parenteral formulations must be sterile, as is known and practiced in the art.
In one embodiment, the pharmaceutical composition is provided as a ready-to-use sterile solution. In another embodiment, the pharmaceutical compositions are provided as sterile dried soluble products, including lyophilized powders and subcutaneous injection tablets, which are reconstituted with a carrier prior to use. In yet another embodiment, the pharmaceutical composition is formulated as a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical composition is formulated as a sterile, dry, insoluble product that is reconstituted with a carrier prior to use. In yet another embodiment, the pharmaceutical composition is formulated as a sterile emulsion ready for use.
The pharmaceutical composition may be formulated as a suspension, solid, semi-solid, or thixotropic liquid for depot administration for implantation. In one embodiment, the disclosed pharmaceutical compositions are dispersed in a solid internal matrix surrounded by an outer polymeric membrane that is insoluble in body fluids but allows diffusion therethrough of the active ingredient in the pharmaceutical composition.
Suitable internal matrices include polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrogels of hydrophilic polymers such as esters of acrylic and methacrylic acid, collagen, crosslinked polyvinyl alcohol, and partially hydrolyzed polyvinyl acetate of the class of copolymers.
Suitable outer polymeric films include polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene, chlorinated polyethylene, polyvinyl chloride, copolymers of chlorinated ethylene and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomers polyethylene terephthalate, butyl rubber chlorohydrin rubber, ethylene/vinyl alcohol copolymers, ethylene/vinyl acetate/vinyl alcohol terpolymers, and ethylene/ethyleneoxyethanol copolymers.
In another aspect, the disclosed pharmaceutical compositions may be formulated in any dosage form suitable for administration to a patient by inhalation, such as a dry powder, aerosol, suspension, or solution composition. In one embodiment, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for inhalation administration to a patient as a dry powder. In yet another embodiment, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for inhalation administration to a patient via a nebulizer. Dry powder compositions for delivery to the lung by inhalation typically comprise a finely powdered compound disclosed herein and one or more finely powdered pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients that are particularly suitable for use as dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di-and polysaccharides. Fine powders may be prepared, for example, by micronization and milling. Generally, the size-reduced (e.g., micronized) compound may pass through a D of about 1 to 10 microns50Values (e.g., measured by laser diffraction).
Aerosols can be formulated by suspending or dissolving the disclosed compounds in a liquefied propellant. Suitable propellants include chlorinated hydrocarbons, hydrocarbons and other liquefied gases. Representative propellants include: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1-difluoroethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane, perfluoropentane, butane, isobutane and pentane. Aerosols comprising the compounds disclosed herein are typically administered to a patient via a Metered Dose Inhaler (MDI). Such devices are known to those skilled in the art
The aerosol may contain additional pharmaceutically acceptable excipients that may be used by MDIs, such as surfactants, lubricants, co-solvents, and other excipients, to improve the physical stability of the formulation, to improve valve characteristics, to improve solubility, or to improve taste.
Pharmaceutical compositions suitable for transdermal administration may be prepared as discrete patches intended to remain in intimate contact with the epidermis of the patient for an extended period of time. For example, the active ingredient may be delivered from a patch agent by iontophoresis, as generally described in Pharmaceutical Research,3(6),318 (1986).
Pharmaceutical compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For example, ointments, creams and gels may be formulated with a water or oil base, and suitable thickeners and/or gelling agents and/or solvents. Such bases may include, water, and/or oils such as liquid paraffin and vegetable oils (e.g., peanut oil or castor oil), or solvents such as polyethylene glycol. Thickeners and gelling agents used according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, carbopol and cellulose derivatives, and/or glyceryl monostearate and/or non-ionic emulsifiers.
Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents or thickening agents.
Powders for external use may be formed in the presence of any suitable powder base, for example talc, lactose or starch. Drops may be formulated with an aqueous or non-aqueous base containing one or more dispersing agents, solubilising agents, suspending agents or preservatives.
Topical formulations may be administered by application to the affected area one or more times per day; an occlusive dressing covering the skin is preferably used. Adhesive depot systems allow for continuous or extended administration.
Use of the Compounds and compositions of the invention
The compound or the pharmaceutical composition disclosed by the invention can be used for preparing a medicine for treating, preventing, improving, controlling or relieving hyperuricemia, tophus, gouty arthritis, kidney disorder related to hyperuricemia and urolithiasis in mammals including human beings, and can also be used for preparing other medicines for inhibiting xanthine oxidase and urate anion transporter 1.
Specifically, the amount of the compound in the composition of the present invention is effective to detectably inhibit xanthine oxidase and urate anion transporter 1, and the compound of the present invention can be used as a medicament for preventing or treating hyperuricemia, tophus, gouty arthritis, renal disorders associated with hyperuricemia, and urolithiasis in humans.
The compounds or compositions of the present invention may be used, but are in no way limited to, in preventing, treating or alleviating hyperuricemia, tophus, gouty arthritis, renal disorders associated with hyperuricemia, and urolithiasis in mammals, including humans, by administering to a patient an effective amount of the compounds or compositions of the present invention.
In addition to being beneficial for human therapy, the compounds and pharmaceutical compositions of the present invention may also find application in veterinary therapy for pets, animals of the introduced species and mammals in farm animals. Examples of other animals include horses, dogs, and cats. Herein, the compound of the present invention includes pharmaceutically acceptable derivatives thereof.
Method of treatment
In one embodiment, the presently disclosed methods of treatment comprise administering to a patient in need thereof a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention. Various embodiments of the present disclosure include methods of treating the above-mentioned diseases by administering to a patient in need thereof a safe and effective amount of a disclosed compound or a pharmaceutical composition comprising a disclosed compound.
In one embodiment, the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds may be administered by any suitable route of administration, including systemic and topical administration. Systemic administration includes oral, parenteral, transdermal and rectal administration. Typical parenteral administration refers to administration by injection or infusion, including intravenous, intramuscular, and subcutaneous injection or infusion. Topical administration includes application to the skin and intraocular, otic, intravaginal, inhalation, and intranasal administration. In one embodiment, a disclosed compound or a pharmaceutical composition comprising a disclosed compound may be administered orally. In another embodiment, a disclosed compound or a pharmaceutical composition comprising a disclosed compound may be administered by inhalation. In yet another embodiment, the presently disclosed compounds or compositions comprising the presently disclosed compounds may be administered intranasally.
In one embodiment, a disclosed compound or a pharmaceutical composition comprising a disclosed compound may be administered once or several times at different time intervals over a specified period of time according to a dosing regimen. For example, once, twice, three times or four times daily. In one embodiment, the administration is once daily. In yet another embodiment, the administration is twice daily. The administration may be carried out until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. Suitable dosing regimens for the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds depend on the pharmacokinetic properties of the compound, such as dilution, distribution and half-life, which can be determined by the skilled person. In addition, suitable dosing regimens for the compounds or pharmaceutical compositions comprising the disclosed compounds, including the duration of the regimen, will depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of concurrent therapy, the desired therapeutic effect, and other factors within the knowledge and experience of the skilled artisan. Such a skilled artisan will also appreciate that adjustments to the subject's response to the dosage regimen, or the need for changes in the subject's patient over time, may be required.
The compounds disclosed herein may be administered simultaneously, or before or after, one or more other therapeutic agents. The compounds of the present invention may be administered separately, or together with other therapeutic agents, by the same or different routes of administration, in the form of pharmaceutical compositions.
For an individual of about 50-70kg, the disclosed pharmaceutical compositions and combinations may be in unit dosage form containing from about 1-1000mg, or from about 1-500mg, or from about 1-250mg, or from about 1-150mg, or from about 0.5-100mg, or from about 1-50mg of the active ingredient. The therapeutically effective amount of the compound, pharmaceutical composition or combination thereof will depend on the species, weight, age and condition of the individual, the disease (disorder) or illness (disease) being treated, or the severity thereof. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient to prevent, treat or inhibit the progression of the disease (disorder) or condition (disease).
The above cited dose profiles have been demonstrated in vitro and in vivo tests using beneficial mammals (e.g., mice, rats, dogs, monkeys) or isolated organs, tissues and specimens thereof. The compounds disclosed herein are used in vitro in the form of solutions, e.g. aqueous solutions, and also enterally, parenterally, especially intravenously, in vivo, e.g. in the form of suspensions or aqueous solutions.
In one embodiment, a therapeutically effective dose of a compound of the present disclosure is from about 0.1mg to about 2,000mg per day. The pharmaceutical composition thereof should provide a dose of the compound of about 0.1mg to about 2,000 mg. In a particular embodiment, the pharmaceutical dosage unit form is prepared to provide from about 1mg to about 2,000mg, from about 10mg to about 1,000mg, from about 20mg to about 500mg, or from about 25mg to about 250mg of the principal active ingredient or a combination of principal ingredients per dosage unit form. In a particular embodiment, the pharmaceutical dosage unit form is prepared to provide about 10mg,20mg,25mg,50mg,100mg,250mg,500mg,1000mg or 2000mg of the primary active ingredient.
In addition, the compounds disclosed herein may be administered in the form of a prodrug. In the present invention, a "prodrug" of a disclosed compound is a functional derivative that, when administered to a patient, is ultimately released in vivo. When administering the compounds disclosed herein in the form of a prodrug, one skilled in the art can practice one or more of the following: (a) altering the in vivo onset time of the compound; (b) altering the duration of action of the compound in vivo; (c) altering the in vivo delivery or distribution of the compound; (d) altering the in vivo solubility of the compound; and (e) overcoming side effects or other difficulties faced by the compounds. Typical functional derivatives useful for preparing prodrugs comprise variants of the compounds which are cleaved in vivo either chemically or enzymatically. These variants, which involve the preparation of phosphates, amides, esters, thioesters, carbonates and carbamates, are well known to those skilled in the art.
General synthetic procedure
To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.
In general, the compounds of the invention can be prepared by the methods described herein, wherein the substituents are as defined in formulae (I), (II), (III), unless otherwise specified. The following reaction schemes and examples serve to further illustrate the context of the invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.
The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin Haojian Yunyu chemical Co., Ltd, Tianjin Shucheng chemical reagent factory, Wuhan Xin Huayuan scientific and technological development Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaolingyi factory.
The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were previously dried over anhydrous sodium sulfate.
The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.
The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants.
NMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer, CDC13、DMSO-d6、CD3OD or acetone-d6TMS (0ppm) or chloroform (7.26ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are expressed in hertz (Hz).
The conditions for determining low resolution Mass Spectrometry (MS) data were: agilent 6120 four-stage rod HPLC-M (column model: Zorbax SB-C18,2.1X 30mm,3.5 micron, 6min, flow rate 0.6 mL/min. mobile phase: 5% -95% (CH with 0.1% formic acid)3CN) in (H containing 0.1% formic acid)2Proportion in O)), adoptDetection was performed by electrospray ionization (ESI) at 210nm/254nm and UV.
The purity of the compound was determined by High Performance Liquid Chromatography (HPLC), using Agilent 1260HPLC (column model: Agilent zorbax Eclipse Plus C18) and detected by DAD detector, and finally calculated by area normalization to obtain the purity of the compound.
The following acronyms are used throughout the invention:
AcOH acetic acid
AIBN azobisisobutyronitrile
CDC13Deuterated chloroform
CD3OD deuterated methanol
DBU 1, 8-diazabicycloundec-7-enes
DCM dichloromethane
DMAP 4-dimethylaminopyridine
DMF N, N-dimethylformamide
DMSO dimethyl sulfoxide
DMSO-d6Deuterated dimethyl sulfoxide
g
h hours
min for
mmol millimole
M mol per liter of DEG C
H2SO4Sulfuric acid
HATU 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate
NBS N-bromosuccinimide
MeCN、CH3CN acetonitrile
MeOH methanol
mL, mL
NMP N-methylpyrrolidone
RT, RT, r.t. Room temperature
rpm rotation per minute
Rt Retention time
TFA trifluoroacetic acid
THF tetrahydrofuran
Preparation of the inventionTypical synthetic procedures for the disclosed compounds are shown in the following synthetic schemes. Wherein, L represents a leaving group including, but not limited to, a halogen atom and a trifluoromethanesulfonyloxy group; r0Represents a hydrogen atom or C1-4Alkyl, or two R0Joined together to form a ring; r, R unless otherwise stated1、R2、R3、X、Y、Z、L0、L1、L2、L3E and n have the meanings given in the description of the invention.
Synthesis scheme 1
The compound (I) can be prepared by the following processes:
the method comprises the following steps that (1) a fused bicyclic compound substituted by different substituents and a compound (2) containing a borate structure are subjected to coupling reaction under the catalysis of a [ palladium ] catalyst to obtain a compound (I);
synthesis scheme 2
Compound (I-1) can be prepared by the following procedure:
the compound (3) is subjected to ester hydrolysis reaction under the action of acid or alkali to generate a compound (4), and the compound (4) is subjected to substitution or acylation reaction to obtain a compound (I-1).
The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further illustrated below in connection with the examples.
EXAMPLE 1 methyl 4- (5-cyano-1-methyl-2- (trifluoromethyl) -1H-indol-7-yl) -2-hydroxybenzoate
First step 7-bromo-1-methyl-2- (trifluoromethyl) -1H-indole-5-carbonitrile
7-bromo-2- (trifluoromethyl) -1H-indole-5-carbonitrile (0.50g,1.73mmol) and DMF (10mL) were added to a 50mL two-necked flask. Sodium hydride (0.50g,1.95mmol, 60%) was added to the reaction flask at 0 ℃ and after addition was complete, the reaction mixture was stirred at 0 ℃ for 0.5h, then iodomethane (0.20mL,3.2mmol) was added to the reaction mixture and the reaction mixture was stirred at room temperature for an additional 12 h. The organic solvent was removed under reduced pressure, a saturated aqueous sodium chloride solution (80mL) and ethyl acetate (80mL) were added to the residue, and the organic phase was washed with a saturated sodium chloride solution (40 mL. times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/50) to give the title compound (yellow solid, 0.50g, 96%).
MS(ES-API,pos.ion)m/z:304.0[M+2]
Second step methyl 4- (5-cyano-1-methyl-2- (trifluoromethyl) -1H-indol-7-yl) -2-hydroxybenzoate
7-bromo-1-methyl-2- (trifluoromethyl) -1H-indole-5-carbonitrile (0.36g,1.19mmol), methyl 2-hydroxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate (0.30g,1.08mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (48mg,0.059mmol) and DMF (8mL) were added to a 50mL two-necked flask. An aqueous solution of potassium carbonate (1.1mL,2M) was added to the reaction flask under nitrogen and the reaction mixture was stirred at 90 ℃ for 0.5 h. The reaction mixture was cooled to room temperature, saturated brine (80mL) was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (40 mL. times.2), and the organic phases were combined. The organic phase was washed with saturated brine (60mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/15) to give the title compound (light yellow solid, 0.14g, 32%).
MS(ES-API,pos.ion)m/z:375.1[M+1]
1H NMR(400MHz,CDCl3)δ10.94(s,1H),8.06(d,J＝1.2Hz,1H),7.97(d,J＝8.1Hz,1H),7.38(d,J＝1.2Hz,1H),7.13(s,1H),7.06(d,J＝1.3Hz,1H),6.96(dd,J＝8.1,1.6Hz,1H),4.03(s,3H),3.47(s,3H)。
Example 2 tert-butyl 4- (6-cyanobenzofuran-4-yl) -2-hydroxybenzoate
First step 3- (ethoxycarbonyl) -4- (furan-2-yl) -3-butenoic acid
Potassium tert-butoxide (126g,1123mmol) and tert-butanol (350mL) were added to a 1000mL two-necked flask, a mixture of diethyl succinate (294g,1688mmol) and furan-2-carbaldehyde (36.0g,375mmol) was added dropwise to the reaction flask, and after the addition was complete, the reaction mixture was stirred at 110 ℃ for 3h under nitrogen. The reaction mixture was cooled to room temperature, tert-butanol was removed under reduced pressure, the residue was added to dilute hydrochloric acid (1000mL,6M), the aqueous phase was extracted with diethyl ether (200 mL. times.2), and the organic phases were combined. The organic phase was washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/1) to give the title compound (light yellow solid, 83.2g, 99%).
MS(ES-API,neg.ion)m/z:223.1[M-1]
Second step Ethyl 4-acetoxybenzofuran-6-carboxylate
3- (ethoxycarbonyl) -4- (furan-2-yl) -3-butenoic acid (84.1g,375mmol), sodium acetate (123g,1499mmol) and acetic anhydride (350mL) were added to a 1000mL single-necked flask and the reaction mixture was stirred at 180 ℃ for 5 h. The reaction mixture was cooled to room temperature, acetic anhydride was removed under reduced pressure, and the residue was adjusted to a slightly alkaline pH with 15% aqueous sodium carbonate solution. The aqueous phase was extracted with ethyl acetate (100 mL. times.2) and the organic phases were combined. The organic phase was washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/6) to give the title compound (pale yellow oily liquid, 55.6g, 60%).
MS(ES-API,pos.ion)m/z:249.1[M+1]
The third step is 4-hydroxybenzofuran-6-carboxylic acid
Ethyl 4-acetoxybenzofuran-6-carboxylate (24.8g,100mmol), methanol (100mL), tetrahydrofuran (100mL) and water (100mL) were added to a 1000mL one-neck flask, sodium hydroxide (12g,300mmol) was added to the reaction flask, and the reaction mixture was stirred at room temperature for 12 h. The organic solvent was removed under reduced pressure, water (600mL) was added to the residue, and the aqueous phase was washed once with diethyl ether (200 mL). The aqueous phase was then acidified to pH 1 with 2N dilute hydrochloric acid, the precipitated solid was filtered with suction, and the filter cake was washed with water (300 mL. times.2) and dried to give the title compound (white solid, 16.9g, 95%).
MS(ES-API,neg.ion)m/z:177.0[M-1]
Fourth step 4-Methoxybenzofuran-6-carboxylic acid methyl ester
4-hydroxybenzofuran-6-carboxylic acid (1.78g,10mmol), cesium carbonate (8.15g,25mmol) and DMF (20mL) were added to a 100mL single-neck flask, iodomethane (3.12g,22mmol) was added dropwise to the reaction flask, and after addition, the reaction mixture was stirred at room temperature for 24 h. To the reaction mixture was added saturated aqueous ammonium chloride (200mL), the aqueous phase was extracted with ethyl acetate (100 mL. times.2), and the organic phases were combined. The organic phase was washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/10) to give the title compound (white solid, 1.92g, 93%).
MS(ES-API,pos.ion)m/z:207.1[M+1]
Fifth step 4-Methoxybenzofuran-6-carboxylic acid
Methyl 4-methoxybenzofuran-6-carboxylate (2.06g,10mmol), methanol (10mL), tetrahydrofuran (10mL) and water (10mL) were added to a 100mL single-neck flask, sodium hydroxide (1.2g,30mmol) was added to the reaction flask, and the reaction mixture was stirred at room temperature for 12 h. The organic solvent was removed under reduced pressure, water (80mL) was added to the residue, and the aqueous phase was washed once with diethyl ether (80 mL). The aqueous phase was then acidified to pH 1 with 2N dilute hydrochloric acid, the precipitated solid was filtered under suction, and the filter cake was washed with water (60 mL. times.2) and dried to give the title compound as a white solid (1.75 g, 91%).
MS(ES-API,neg.ion)m/z:191.0[M-1]
Sixth step 4-Methoxybenzofuran-6-carbonyl chloride
4-Methoxybenzofuran-6-carboxylic acid (1.35g,7.05mmol) and thionyl chloride (20mL) were added to a 100mL one-neck flask and the reaction mixture was stirred at 90 ℃ for 12 h. Thionyl chloride was removed under reduced pressure to give the title compound (brown viscous liquid, 1.48g, 100%).
Seventh step 4-Methoxybenzofuran-6-carboxamide
Aqueous ammonia (20mL, 28%) was added to a 100mL single-neck flask, a solution of 4-methoxybenzofuran-6-carbonyl chloride (1.48g,7.05mmol) in dichloromethane (20mL) was added dropwise to the reaction flask, and after the addition was complete, the reaction mixture was stirred at room temperature for 2 h. Water (100mL) was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (80 mL. times.2), and the organic phases were combined. The organic phase was washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/dichloromethane (v/v) ═ 1/30) to give the title compound (pale yellow solid, 1.31g, 97%).
MS(ES-API,pos.ion)m/z:192.0[M+1]
Eighth step 4-Methoxybenzofuran-6-carbonitrile
4-Methoxybenzofuran-6-carboxamide (0.677g,3.54mmol) and toluene (20mL) were added to a 50mL single-neck flask, phosphorus oxychloride (2.71,17.7mmol) was added dropwise to the flask, and the reaction mixture was stirred at 120 ℃ for 12 h. The reaction mixture was cooled to room temperature, saturated brine (80mL) was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (40 mL. times.2), and the organic phases were combined. The organic phase was washed with saturated brine (60mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/3) to give the title compound (light yellow solid, 0.490g, 80%).
MS(ES-API,pos.ion)m/z:174.0[M+1]
Ninth step 4-Hydroxybenzofuran-6-carbonitrile
4-Methoxybenzofuran-6-carbonitrile (1.73g,10mmol) and DCM (20mL) were added to a 100mL single-neck flask, boron tribromide (7.5g,30mmol) was added dropwise to the reaction flask at-70 deg.C, and after the addition, the reaction mixture was stirred at room temperature for 24 h. Ice water (200mL) was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (100 mL. times.2), and the organic phases were combined. The organic phase was washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/6) to give the title compound (light yellow solid, 1.42g, 89%).
MS(ES-API,neg.ion)m/z:158.0[M-1]
Tenth step 6-Cyanobenzofuran-4-yl triflate
4-hydroxybenzofuran-6-carbonitrile (0.652g,4.1mmol), pyridine (0.97g,12.3mmol) and DCM (80mL) were added to a 250mL single-necked flask, trifluoromethanesulfonic anhydride (1.35g,4.8mmol) was added dropwise to the flask at 0 deg.C, and after addition, the reaction mixture was stirred at room temperature for 1 h. Concentrating under reduced pressure. The residue was subjected to silica gel column chromatography (dichloromethane/petroleum ether (v/v) ═ 1/5) to give the title compound (white solid, 0.991g, 83%).
MS(ES-API,pos.ion)m/z:291.9[M+1]
Eleventh step tert-butyl 4- (6-cyanobenzofuran-4-yl) -2-hydroxybenzoate
6-Cyanobenzofuran-4-yl trifluoromethanesulfonate (0.419g,1.44mmol), tert-butyl 2-hydroxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate (0.42g,1.31mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (53mg,0.065mmol), potassium carbonate (0.362g,2.62mmol) and anhydrous 1, 4-dioxane (15mL) were added to a 50mL two-necked flask and the reaction mixture was stirred at 90 ℃ for 7h under nitrogen. The reaction mixture was cooled to room temperature, saturated brine (80mL) was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (40 mL. times.2), and the organic phases were combined. The organic phase was washed with saturated brine (60mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (dichloromethane/petroleum ether (v/v) ═ 1/4) to give the title compound (white solid, 0.185g, 42%).
MS(ES-API,pos.ion)m/z:336.1[M+1]
1H NMR(600MHz,CDCl3)δ11.20(s,1H),7.94(d,J＝8.2Hz,1H),7.89–7.87(m,2H),7.62(d,J＝1.1Hz,1H),7.21(d,J＝1.5Hz,1H),7.09(dd,J＝8.2,1.7Hz,1H),7.05–7.03(m,1H),1.67(s,9H)。
Example 3 2-acetoxy-4- (5-cyano-2-fluorobenzofuran-7-yl) benzoic acid
First step 2, 3-dihydrobenzofuran-5-carbaldehyde
2, 3-dihydrobenzofuran (601g,5.0mol) and DMF (803g,10.98mol) were added to a 5L four-necked flask, phosphorus oxychloride (1527g,9.96mol) was slowly added dropwise to the flask at 10 ℃ while the temperature of the reaction system did not exceed 30 ℃ at the time of dropwise addition, and after the addition was completed, the reaction mixture was slowly heated to 70 ℃ and stirred for 8 hours. The reaction mixture was cooled to room temperature, the reaction mixture was slowly poured into 8L of an ice-water mixture, and the mixture was stirred at room temperature for 1 h. The aqueous phase was extracted with ethyl acetate (3L X2), the organic phases were combined, washed with saturated brine (1.5L X2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (black liquid, 741g, 100%).
MS(ES-API,pos.ion)m/z:149.0[M+1]
Second step 7-bromo-2, 3-dihydrobenzofuran-5-carbaldehyde
2, 3-Dihydrobenzofuran-5-carbaldehyde (741g,5.0mol) and DMF (1.5L) were added to a 5L four-necked flask, NBS (1157g,6.5mol) was added to the flask in portions at 0 ℃ and, after the addition, the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was slowly poured into 5L of an ice-water mixture, the aqueous phase was extracted with ethyl acetate (1L. times.2), the organic phases were combined, and the organic phase was washed with saturated brine (0.8L. times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from (ethyl acetate/petroleum ether (v/v) ═ 1/4) to give the title compound (light yellow solid, 704g, 62%).
1H NMR(400MHz,CDCl3)δ9.78(s,1H),7.82(s,1H),7.66(d,J＝0.8Hz,1H),4.79(t,J＝8.8Hz,2H),3.38(t,J＝8.8Hz,2H)；
The third step is 7-bromobenzofuran-5-carbaldehyde
7-bromo-2, 3-dihydrobenzofuran-5-carbaldehyde (341g,1.5mol), NBS (320g,1.8mol), AIBN (2.3g,75mmol) and chlorobenzene (1.5L) were charged into a 5L four-necked flask, and the reaction mixture was stirred for 4h while slowly warming to 85 ℃ under nitrogen. The reaction mixture was cooled to room temperature, saturated brine (2L) was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (0.5L. times.2), and the organic phases were combined. The organic phase was washed with saturated brine (0.5L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (dichloromethane/petroleum ether (v/v) ═ 1/6) to give the title compound (pale yellow solid, 162g, 48%).
MS(ES-API,pos.ion)m/z:225.9[M+2]
The fourth step is 3, 7-bromo-2-fluoro-2, 3-dihydrobenzofuran-5-carbaldehyde
7-bromobenzofuran-5-carbaldehyde (22.5g,100mmol), dibromohydantoin (18.6g,65mmol) and dichloromethane (150mL) were added to a 500mL teflon-sealed tube, and a solution of hydropyridine fluoride (125mL, 65%) was added to the reaction tube at 0 ℃ and, after completion of the addition, the reaction mixture was stirred at room temperature under a seal for 72 h. The reaction mixture was poured into 500mL of an ice-water mixture, the aqueous phase was extracted with ethyl acetate (200 mL. times.2), and the organic phases were combined. The organic phase was washed with saturated brine (200mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (dichloromethane/petroleum ether (v/v) ═ 1/4) to give the title compound (light yellow solid, 28.5g, 88%).
MS(ES-API,pos.ion)m/z:324.9[M+3]
The fifth step is 7-bromo-2-fluorobenzofuran-5-carbaldehyde
3, 7-bromo-2-fluoro-2, 3-dihydrobenzofuran-5-carbaldehyde (3.24g,10mmol), potassium fluoride (0.70g,12mmol), and DMF (20mL) were added to a 100mL single-neck flask and the reaction mixture was stirred at 100 ℃ for 48h under nitrogen. The reaction mixture was poured into saturated aqueous ammonium chloride (100mL), the aqueous phase was extracted with ethyl acetate (80 mL. times.2), and the organic phases were combined. The organic phase was washed with saturated brine (80mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (dichloromethane/petroleum ether (v/v) ═ 1/10) to give the title compound (white solid, 0.608g, 25%).
1H NMR(400MHz,CDCl3)δ9.99(s,1H),7.97(s,2H),6.09(d,J＝6.6Hz,1H)；
19F NMR(376MHz,CDCl3)δ-107.30(s,1F)。
Sixth step 7-bromo-2-fluorobenzofuran-5-carbaldehyde oxime
7-bromo-2-fluorobenzofuran-5-carbaldehyde (0.486g,2.0mmol), N-diisopropylethylamine (0.517g,4.0mmol), hydroxylamine hydrochloride (0.167g,2.4mmol), and DCM (10mL) were added to a 100mL one-neck flask and the reaction mixture was stirred at room temperature for 12h under nitrogen. To the reaction mixture was added saturated aqueous sodium chloride (60mL), the aqueous phase was extracted with ethyl acetate (40 mL. times.2), and the organic phases were combined. The organic phase was washed with saturated brine (60mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/4) to give the title compound (white solid, 0.490g, 95%).
MS(ES-API,pos.ion)m/z:258.9[M+2]
Seventh step 7-bromo-2-fluorobenzofuran-5-carbonitrile
7-bromo-2-fluorobenzofuran-5-carbaldehyde oxime (0.439g,1.7mmol) and acetic anhydride (8mL) were added to a 50mL one-neck flask and the reaction mixture was stirred at 150 ℃ for 24h under nitrogen. The reaction mixture was cooled to room temperature, saturated brine (80mL) was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (60 mL. times.2), and the organic phases were combined. The organic phase was washed with saturated brine (80mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (dichloromethane/petroleum ether (v/v) ═ 1/3) to give the title compound (white solid, 0.388g, 95%).
MS(ES-API,pos.ion)m/z:240.9[M+2]
1H NMR(400MHz,CDCl3)δ7.77(s,1H),7.71(s,1H),6.07(d,J＝6.6Hz,1H)；
19F NMR(376MHz,CDCl3)δ-106.46(s,1F)。
Eighth step tert-butyl 4- (5-cyano-2-fluorobenzofuran-7-yl) -2-hydroxybenzoate
7-bromo-2-fluorobenzofuran-5-carbonitrile (0.314g,1.31mmol), tert-butyl 2-hydroxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate (0.42g,1.31mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (53mg,0.065mmol) and DMF (8mL) were added to a 50mL two-necked flask. An aqueous solution of potassium carbonate (1.3mL,2M) was added to the reaction flask under nitrogen and the reaction mixture was stirred at 90 ℃ for 0.5 h. The reaction mixture was cooled to room temperature, saturated brine (80mL) was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (40 mL. times.2), and the organic phases were combined. The organic phase was washed with saturated brine (60mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/8) to give the title compound (white solid, 0.347g, 75%).
MS(ES-API,pos.ion)m/z:354.1[M+1]
Ninth step 4- (5-cyano-2-fluorobenzofuran-7-yl) -2-hydroxybenzoic acid
Tert-butyl 4- (5-cyano-2, 3-dihydrobenzofuran-7-yl) -2-hydroxybenzoate (0.347g,0.98mmol) and dichloromethane (15mL) were added to a 100mL one-neck flask, and trifluoroacetic acid (2mL) was added and stirred at room temperature for 12 h. The organic solvent was removed under reduced pressure, and the residue was subjected to silica gel column chromatography (methanol/dichloromethane (v/v) ═ 1/20) to give the title compound (white solid, 0.262g, 90%).
MS(ES-API,neg.ion)m/z:296.0[M-1]
Tenth step 2-acetoxy-4- (5-cyano-2-fluorobenzofuran-7-yl) benzoic acid
4- (5-cyano-2-fluorobenzofuran-7-yl) -2-hydroxybenzoic acid (0.892g,3.0mmol), N, N-diisopropylethylamine (2.33g,18.0mmol) and DCM (20mL) were added to a 100mL one-neck flask, acetyl chloride (0.707g,9.0mmol) was added dropwise to the reaction flask at 0 deg.C, and after completion of the addition, the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was slowly poured into 100mL of ice water, the aqueous phase was extracted with ethyl acetate (60 mL. times.2), and the organic phases were combined. The organic phase was washed with saturated brine (60mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/3) to give the title compound (white solid, 0.489g, 48%).
MS(ES-API,neg.ion)m/z:338.0[M-1]
1H NMR(400MHz,DMSO)δ8.21(d,J＝1.5Hz,1H),8.11–8.09(m,2H),7.91(dd,J＝8.2,1.7Hz,1H),7.76(d,J＝1.6Hz,1H),6.60(d,J＝6.4Hz,1H),2.30(s,3H)；
19F NMR(376MHz,DMSO)δ-109.04(s,1F)。
Biological activity assay
Test example 1XO (xanthine oxidase) inhibitory Activity measurement
1) Test method
Compounds were diluted 2.5-fold with buffer (50mM potassium dihydrogen phosphate solution) in a range of concentrations from 2000nM to 0.524nM, added to 384-well plates at 30 μ L/well; then adding 30 μ L of xanthine oxidase with concentration of 21mU/mL into each well, centrifuging at 3000rpm for 1min, and incubating at room temperature for 10min with shaking; then 30. mu.L of substrate (xanthine) was added to each well at a concentration of 600. mu.M; buffer treatment wells (no compound, same concentration of enzyme and substrate added) and negative control wells (no compound and enzyme, same concentration of substrate added) were also set. Incubating at room temperature for 5min, reading absorbance value at 290nm with PHERAstar FS microplate reader, calculating the inhibition rate of the compound for inhibiting xanthine oxidase activity by the following formula, and calculating IC with GraphPad Prism 550The value:
inhibition ratio (%) ([ 1- (OD)Drug treatment hole-ODNegative control well)/(ODBuffer treatment wells-ODNegative control well)]×100
2) Test results
And (4) conclusion: the compound of the invention has better inhibitory activity on XO.
Test example 2 assay of inhibitory Activity of URAT1 (Uroic anion Transporter 1)
1) Test method
Construction of hURAT1-stably expressing cell line
The human URAT1 plasmid was transfected into HEK-293T cells, and G418 (Geneticin) was used for selection to obtain a human URAT1 stably expressing cell line.
b. Uric acid absorption inhibition
Inoculating the human URAT1 stable expression cells obtained in the above step into a 96-well plate, incubating for at least 12h, removing the culture medium, and washing the cells with chloride-free HBSS (Hanks Balanced salt solution) buffer; the compounds were diluted four-fold with buffer to give a series of 200. mu. aliquotsM to 0.8nM concentration of compound solution, 5. mu.L of the compound solution prepared above and 45. mu.L of [8-14C]Mixing buffer solution of uric acid, adding into 96-well plate containing human URAT1 stable expression cells (final concentration of compound is 20 μ M-0.08 nM), and arranging buffer solution hole (human URAT1 stable expression cells without drug) and negative hole (HEK-293T cells without drug); after incubation at 37 ℃ for 5min, the buffer was removed and the cells were washed with buffer, 50. mu.L of lysis buffer (100mM NaOH solution) was added to each well, the cells were lysed and shaken at 600rpm for 10 min. Centrifuging at 1000rpm for 5min, transferring 45. mu.L of the supernatant to an Isoplate-96 microwell plate, adding 150. mu.L of Ultima Gold to each wellTMXR, and shake at 600rpm for 10 min. Read [8-14C]Residual amount of uric acid, and the inhibition of the compound [8-14C]IC was calculated by XLFit software after the inhibition of uric acid absorption50The value is obtained.
Inhibition rate (%) ([ 1- (drug well)14C uptake-negative well14C uptake)/(buffer wells14C uptake-negative well14C intake)]×100；
Wherein, the negative hole is a hole of a non-inoculated human URAT1 stable expression cell.
2) Test results
And (4) conclusion: the compound of the invention has better inhibitory activity to URAT 1.
Test example 3 uric acid lowering test
1) Test method
Male SD rats were fasted overnight before the experiment, randomly grouped according to body weight, each group was subjected to intragastric gavage for a single administration of vehicle (control group) and 20mg/kg of test compound, blood was taken from tail vein before and after 2,4, 6h, respectively, blood was centrifuged at 3000rpm for 15min, serum was separated and then uric acid level in serum was measured using roche biochemical analyzer, and percent uric acid reduction was calculated according to the following formula.
The blood uric acid decrease rate was [ (control group blood uric acid value-administration group blood uric acid value)/control group blood uric acid value ] × 100%
2) Test results
The compound of example 3 has a significant uric acid lowering effect within 10 hours after oral administration, and the maximum uric acid lowering rate can reach 65%.
The results show that the compound has good effect of reducing uric acid.
Test example 4 pharmacokinetic evaluation
1) Test method
SD rats were weighed after fasting overnight for 15 hours and randomly grouped according to body weight, and the test compounds were formulated in a vehicle of 5% DMSO + 5% Solutol (polyethylene glycol-12-hydroxystearate) + 90% Saline (normal Saline). (iii) for the test group administered intravenously (iv), the test animals were given a dose of 1 mg/kg; for the oral administration (po) test group, the test animals were given a dose of 5 mg/kg. Venous blood (approximately 0.2mL) was then removed at time points of 0, 0.083 (intravenous only group), 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24 hours and placed in the EDTAK2(ethylenediaminetetraacetic acid dipotassium salt) anticoagulation tube, at 11000rpm centrifugal 2 minutes, collect plasma, and at-20 degrees or-70 degrees C storage until LC/MS/MS analysis. The drug concentration in plasma was measured at each time point and pharmacokinetic parameters were calculated from the drug concentration-time curve.
The pharmacokinetic properties of the compounds of the invention were tested by the above assay.
2) Test results
And (4) conclusion: after oral administration, the compound of the invention has higher blood concentration and exposure water average in rats, low clearance rate and good pharmacokinetic characteristic.
Finally, it should be noted that there are other ways of implementing the invention. Accordingly, the embodiments of the present invention will be described by way of illustration, but not limitation to the description of the present invention, and modifications made within the scope of the present invention or equivalents added to the claims are possible. All publications or patents cited herein are incorporated by reference.
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