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WO2014198195A1 - Dérivé d'acide 4-aminobutyrique substitué par biaryle, procédé de préparation s'y rapportant et ses utilisations - Google Patents

Dérivé d'acide 4-aminobutyrique substitué par biaryle, procédé de préparation s'y rapportant et ses utilisations Download PDF

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WO2014198195A1
WO2014198195A1 PCT/CN2014/079278 CN2014079278W WO2014198195A1 WO 2014198195 A1 WO2014198195 A1 WO 2014198195A1 CN 2014079278 W CN2014079278 W CN 2014079278W WO 2014198195 A1 WO2014198195 A1 WO 2014198195A1
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group
substituted
alkyl
halogen
mmol
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PCT/CN2014/079278
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Chinese (zh)
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杨飞
王春娟
仝朝龙
喻红平
徐耀昌
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上海翰森生物医药科技有限公司
江苏豪森药业股份有限公司
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Priority to CN201480009596.XA priority Critical patent/CN105143183B/zh
Publication of WO2014198195A1 publication Critical patent/WO2014198195A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/18—Acyclic radicals, substituted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/22—Esters of monothiocarboxylic acids having carbon atoms of esterified thiocarboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the invention belongs to the field of pharmaceutical synthesis, and in particular relates to a biaryl substituted 4-aminobutyric acid derivative and a preparation method and use thereof. Background technique
  • Hypertension is one of the most common cardiovascular diseases and a major risk factor for morbidity and mortality in congestive heart failure, stroke, coronary heart disease, renal failure, and aortic aneurysm. According to a recent press release published by the International Society of Hypertension, there are 972 million people with high blood pressure or high blood pressure in the world, accounting for 26.4% of the world's adult population. With the increasing ageing population, the proportion of hypertensive patients has gradually increased. By 2025, the estimated number of patients will reach 1.56 billion. With the emergence and widespread application of a new generation of antihypertensive drugs, the mortality rate of various cardiovascular diseases has dropped significantly.
  • EP neutral endopeptidase, also known as Neprilysin
  • Neprilysin is a type II transmembrane glycoprotein of the Ml 3 zinc-dependent metalloproteinase family, also known as enkephalinase, which carries a zinc atom at the active site of the enzyme.
  • EP has a molecular weight of about 97 kDa and consists of 750 amino acids. It contains a signal peptide and two hydrophilic domains. The intracellular fragment has 26 amino acids and the extracellular fragment has 700 amino acids. EP can act on the amino terminus of the polypeptide to hydrolyze the polypeptide chain.
  • EP a neuropeptide degrading enzyme
  • endothelial cells vascular smooth muscle cells
  • cardiomyocytes vascular smooth muscle cells
  • renal epithelial cells vascular smooth muscle cells
  • fibroblasts which are also present in the lungs, intestines, Adrenal gland, brain, etc.
  • Natriuretic peptides are mainly degraded by EP, and EP also catalyzes the adrenal medulla and bradykinin.
  • EP-selective inhibitors inhibit EP activity, increase the concentration of natriuretic peptide and bradykinin, increase vasodilation, increase cardiac output, decrease aldosterone levels, and inhibit RAAS (renin-angiotensin-aldosterone system), reducing Pre- and post-loading of the heart delays myocardial remodeling and improves cardiac function in patients with heart failure.
  • RAAS renin-angiotensin-aldosterone system
  • EP/ACE dual inhibitors dual inhibitors of EP in the past decade, including EP/ACE dual inhibitors, dual inhibitors of EP/ARB (angiotensin receptor), and dual inhibition of EP/ECE (endothelin converting enzyme).
  • EP/APN aminopeptidase N
  • the antihypertensive effect of EP/ACE dual inhibitors is superior to that of single inhibitors, which increases the content of diastolic vasopeptides such as substance P, bradykinin and adrenomedullin, and reduces contractile blood vessels such as endothelin I and angiotensin II.
  • the peptide content and optimized to combine the dual effects of diuresis and blood pressure, to maintain organ blood supply.
  • Omapatrilat is a potent ACE/NEP double inhibitor developed by BMS, but due to side effects such as angioedema, the FDA declined to approve Omapatrilat for the treatment of hypertension in July 2002, even as a last resort for refractory patients.
  • Solvay has developed three EP/ECE (endothelin-converting enzyme) dual inhibitors, currently in the clinical phase II of daglutril (SLV-306, oral) and SLV-334 (intravenous) for the treatment of pulmonary hypertension and Brain injury, SLV-338 (intravenous administration) at the clinical stage is used to treat cardiovascular disease, metabolic disorders and neurological diseases.
  • the EP/APN (aminopeptidase N) double inhibitor PL-37 (Debio-0827, orally) developed by Pharmaleads is mainly used to treat pain, especially neuropathic pain.
  • LCZ-696 is an oral antihypertensive and cardioprotective drug developed by Novartis.
  • the object of the present invention is to solve the existing technical problems and provide a biaryl substituted 4-aminobutyric acid derivative which can be metabolized in vivo to produce compound LBQ657, which has EP inhibitory activity and can be used as an EP inhibitor. It can be used to treat related diseases such as high blood pressure, heart failure, pulmonary hypertension and kidney disease.
  • Z is selected from oxygen or sulfur;
  • R is selected from alkali metal, alkaline earth metal
  • Ri R 2 are each independently selected from hydrogen, halogen, hydroxy, cyano, nitro, D. 8 embankment group, C 2.
  • d. 8 fluorenyl, ⁇ . 8 cyclodecyl, 3-8 membered heterocyclic, C 5 .1Q aryl or 5-10 membered heteroaryl are each independently optionally further selected by one or more From halogen, hydroxy, cyano, nitro, d. 8 fluorenyl, halo substituted d. 8 fluorenyl, hydroxy substituted d. 8 fluorenyl, d. 8 decyloxy, 3 ⁇ 4 substituted d. 8 decyloxy, C 3.
  • R 3 is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, d. 8 fluorenyl. 2. 8 alkenyl, . 2.8 alkynyl group,
  • d. 8 fluorenyl, ⁇ . 8 cyclodecyl, 3-8 membered heterocyclic, C 5 .1Q aryl or 5-10 membered heteroaryl are each independently optionally further selected by one or more From halogen, hydroxy, cyano, nitro, d. 8 fluorenyl, halo substituted d. 8 fluorenyl, hydroxy substituted d. 8 fluorenyl, d. 8 decyloxy, halo substituted d. 8 decyloxy, C 3.
  • R 5 and Re are selected from the group consisting of hydrogen and C M thiol. 3. 8 ring sulfhydryl;
  • r 0, 1, and 2.
  • R is selected from the group consisting of sodium, potassium, magnesium, calcium, and ammonium.
  • the biaryl substituted 4-aminobutyric acid derivative is selected from the group consisting of compounds of formula (II):
  • R 3 , , R 5 , Re, r are as defined in formula (I).
  • R 3 is selected from the group consisting of hydrogen, halogen, d. 8 fluorenyl, halogen substituted d. 8 fluorenyl, . 3. 8 ⁇ ⁇ , -d 0-C(0)R 4 , -0-C(0)OR 4 , -C 1-4 -0-C(0)OR4; , R 5 , , r as (I) is defined.
  • Another object of the present invention is to provide an intermediate for preparing the biaryl-substituted 4-aminobutyric acid derivative having a structure represented by the formula (III):
  • Z is selected from oxygen or sulfur
  • R is selected from the group consisting of alkali metals, alkaline earth metals, ammonium or '3 ⁇ 4 R -
  • Ri R 2 are each independently selected from hydrogen, halogen, a hydroxyl group 2, cyano, nitro, alkyl with CL 8, C 2 8 alkenyl group,. 8 alkynyl group. Cyclic alkyl with 8, D 8 embankment group, C 3. 8 cycloalkyl group embankment, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 5. 1Q aryl group, C 5.
  • d. 8 fluorenyl, ⁇ . 8 cyclodecyl, 3-8 membered heterocyclic, C 5 .1Q aryl or 5-10 membered heteroaryl are each independently optionally further selected by one or more From halogen, hydroxy, cyano, nitro, d. 8 fluorenyl, halo substituted d. 8 fluorenyl, hydroxy substituted d. 8 fluorenyl, d. 8 decyloxy, 3 ⁇ 4 substituted d. 8 decyloxy, C 3.
  • R 3 is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, d. 8 fluorenyl. 2. 8 alkenyl, . 2.8 alkynyl group,
  • d. 8 fluorenyl, ⁇ . 8 cyclodecyl, 3-8 membered heterocyclic, C 5 .1Q aryl or 5-10 membered heteroaryl are each independently optionally further selected by one or more From halogen, hydroxy, cyano, nitro, d. 8 fluorenyl, halo substituted d. 8 fluorenyl, hydroxy substituted d. 8 fluorenyl, d. 8 decyloxy, halo substituted d. 8 decyloxy, C 3. 8 ring decyloxy, -
  • R 5 and Re are selected from the group consisting of hydrogen and C M thiol. 3. 8 ring sulfhydryl;
  • R 7 is selected from hydroxy, mercapto, d 8 embankment group, d 8 embankment thio group, C 3 8 cycloalkyl group embankment, C 3 8 cycloalkyl group embankment, -S (0) rR 12, - 0-C(0)Ri2 -NR 13 R 14 , -OM, the M is an alkali metal, an alkaline earth metal, an ammonium;
  • said d. 8 embankment group, c 3. 8 cycloalkyl are each independently alkyl with optionally further substituted with one or more substituents selected from halo, hydroxy, cyano, nitro, d. 8 alkyl with halogen substituent d.
  • r 0, 1, and 2.
  • R 7 is selected from the group consisting of sodium, potassium, magnesium, calcium, and ammonium.
  • the intermediate for preparing the biaryl substituted 4-aminobutyric acid derivative represented by the formula (I) is selected from the compound of the formula (IV):
  • Ri and R 2 are each independently selected from the group consisting of hydrogen, halogen, and d. 8 fluorenyl. 3. 8 fluorenyl, d. 8 decyloxy, C 3 .8 cyclodecyloxy; Z, R 3 , , R 5 , Re, r are as defined in formula (III).
  • R 3 is selected from hydrogen, halo, d. 8 alkyl with halogen substituent d. 8 embankment group, C 3. 8 cycloalkyl group embankment, -Ci -4 -0-C (0 ) R4 -0-C (0) OR4, -C 1-4 -0-C(0)OR4; Z, Ri R 2 , R 4 , R 5 , , r are as defined in the formula (III).
  • the intermediate is selected from the group consisting of:
  • the intermediate (III) has a similar pharmaceutical activity as the compound of the final product of the formula (I).
  • Another object of the present invention is to provide a process for preparing an intermediate of the biaryl substituted 4-aminobutyric acid derivative, which comprises the steps of:
  • R is the same as R of formula (III), but R is not hydrogen; and X is a halogen atom.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing and/or treating a disease associated with EP abnormalities, which comprises a therapeutically effective amount of said biaryl substituted 4-amino group.
  • Butyric acid derivative or an intermediate thereof, and at least one pharmaceutically acceptable carrier are examples of pharmaceutically acceptable carriers.
  • the diseases associated with EP abnormalities are hypertension, pulmonary hypertension, heart failure, and kidney disease.
  • the inventors have found through animal experiments that the compounds of the present invention have good pharmacokinetic activity. Detailed ways
  • d. 8 fluorenyl means a linear fluorenyl group having 1 to 8 carbon atoms and a branched fluorenyl group, and a fluorenyl group means a saturated aliphatic hydrocarbon group.
  • a fluorenyl group means a saturated aliphatic hydrocarbon group.
  • the fluorenyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano , nitro, CL 8 embankment group, a substituted 3 ⁇ 4 d. 8 embankment, hydroxy substituted d. 8 embankment group, d. 8 embankment group, a substituted 3 ⁇ 4 d. 8 embankment group, C 3.
  • Embankment ring group refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent group, "C 3 8 cycloalkyl group embankment.” Refers to a ring alkyl with 3-8 carbon atoms, for example:
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Alkenyl, cyclooctyl and the like.
  • Polycyclic fluorenyl groups include spiro, fused, and cyclic fluorenyl groups.
  • “Spirocyclic thiol” refers to a polycyclic group that shares a carbon atom (called a spiro atom) between the individual rings. These may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system.
  • the spirocyclic fluorenyl group is divided into a single spiro fluorenyl group, a bispirocyclic fluorenyl group or a polyspirocyclic fluorenyl group according to the number of shared snail atoms between the ring and the ring.
  • Non-limiting examples of the spiro fluorenyl group include: "Thick-ring thiol" means an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but None of the rings have a fully conjugated ⁇ -electron system. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused ring fluorenyl groups, and non-limiting examples of fused ring fluorenyl groups include:
  • Bridge ring thiol refers to an all-carbon polycyclic group in which two rings share two carbon atoms that are not directly bonded. These may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. . Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged fluorenyl groups. Non-limiting examples of bridged ring fluorenyl groups
  • the cyclononyl ring may be fused to an aryl, heteroaryl or heterocyclic indenyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydrogen Naphthyl, benzocycloheptyl and the like.
  • the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, d. 8 fluorenyl halogen-substituted alkyl with d 8, d 8 substituted alkyl with hydroxy, d 8 embankment group, a halogen-substituted alkoxy embankment d 8, C 3 8 cycloalkyl group embankment, -S (0) rR4,. ....
  • Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(0)i ⁇ where r is an integer 0, 1, 2 a hetero atom, but does not include a ring moiety of -0-0-, -0-S- or -SS-, and the remaining ring atoms are carbon.
  • the "3-8 membered heterocyclic group” means a ring group containing 3 to 8 ring atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like.
  • Polycyclic fluorenyl groups include spiro, fused, and bridged heterocyclic groups.
  • “Spiroheterocyclyl” refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S(0)r (where r is an integer) The heteroatoms of 0, 1, and 2), and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system.
  • the spirocyclic thiol group is classified into a monospiroheterocyclic group, a dispirocyclic heterocyclic group or a polyspiroheterocyclic group depending on the number of common snail atoms between the ring and the ring.
  • Non-limiting examples of spirocyclic thiol groups include: "Fused heterocyclic group” means that each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more double bonds, but none
  • the ring has a fully conjugated pi-electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(0)r (wherein r is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic fluorenyl groups, fused heterocyclic rings.
  • “Bridge heterocyclyl” refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly bonded, and these may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system, One or more of the ring atoms are selected from the group consisting of nitrogen, oxygen or a hetero atom of S(0)r (wherein r is an integer of 0, 1, 2), and the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged fluorenyl groups.
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cyclodecyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group,
  • the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, d. 8 fluorenyl halogen-substituted alkyl with d 8, d 8 substituted alkyl with hydroxy, d 8 embankment group, a halogen-substituted alkoxy embankment d 8, C 3 8 cycloalkyl group embankment, -S (0) rR4,. ....
  • Aryl means an all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms), a polycyclic ring having a conjugated ⁇ -electron system (ie, a ring with adjacent pairs of carbon atoms) ;) group, "C 5 . 1Q aryl” refers to an all-carbon aryl group containing 5-10 carbons, such as phenyl and naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cyclodecyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, d. 8 fluorenyl, halogen substituted . d 8 embankment group, a hydroxyl-substituted alkyl with d 8, d 8 embankment group, a halogen-substituted alkoxy embankment d 8, C 3 8 cycloalkyl group embankment, -S (0) r R4, -....
  • Heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms including nitrogen, oxygen and a hetero atom of S(0)r (wherein r is an integer 0, 1, 2), 5-
  • a 10-membered heteroaryl group means a heteroaromatic system having 5 to 10 ring atoms, such as furyl, thienyl, pyridyl, pyrrolyl, N-fluorenylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetra Azolyl and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring wherein the ring with the parent is a heteroaryl ring, non-limiting examples comprising:
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, d. 8 fluorenyl halogen-substituted alkyl with d 8, d 8 substituted alkyl with hydroxy, d 8 embankment group, a halogen-substituted alkoxy embankment d 8, C 3 8 cycloalkyl group embankment, -S (0) rR4,. ....
  • Alkenyl refers to at least two carbon atoms and at least one carbon - carbon double bond as defined above consisting of alkyl with, C 2 8 alkenyl group means a straight chain comprising 2-8 carbon atoms or a branched alkylene. base.
  • alkyl with, C 2 8 alkenyl group means a straight chain comprising 2-8 carbon atoms or a branched alkylene. base.
  • base for example, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, d. 8 fluorenyl, halo substituted . d 8 embankment group, a hydroxyl-substituted alkyl with d 8, d 8 embankment group, a halogen-substituted alkoxy embankment d 8, C 3 8 cycloalkyl group embankment, -S (0) r R4, -....
  • Alkynyl means at least two carbon atoms and at least one carbon - carbon triple bond group as embankment composition as defined,
  • C 2 8 alkynyl group means a straight chain comprising 2-8 carbon atoms or a branched alkynyl group.
  • the alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, d. 8 fluorenyl, halo substituted . d 8 embankment group, a hydroxyl-substituted alkyl with d 8, d 8 embankment group, a halogen-substituted alkoxy embankment d 8, C 3 8 cycloalkyl group embankment, -S (0) r R4, -....
  • the methoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent, preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, d. 8 ⁇ group, a halogen-substituted alkyl with d 8, d 8 substituted alkyl with hydroxy, d 8 embankment group, a halogen-substituted alkoxy embankment d 8, C 3 8 cycloalkyl group embankment,
  • Cyclopentoxy refers to and -O- (unsubstituted cyclodecyl), wherein cyclodecyl is as defined above.
  • 3.8 embankment cycloalkyl group refers to a 3-8 carbon cyclic embankment group, non-limiting embodiment includes cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.
  • the methoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, d. 8 fluorenyl halogen-substituted alkyl with d 8, d 8 substituted alkyl with hydroxy, d 8 embankment group, a halogen-substituted alkoxy embankment d 8, C 3 8 cycloalkyl group embankment, -S (0) rR4,. ....
  • Halogen means fluoro, chloro, bromo or iodo.
  • -Ci -4 -S(0)rR4" refers to an R4 substituted d. 4 mercaptosulfide, d. 4 mercaptosulfinyl, d. 4 mercaptosulfonyl.
  • R4 refers to R4 ⁇ 4 alkyl with butoxycarbonyl.
  • heterocyclic group optionally substituted by a thiol group means that a fluorenyl group may be, but is not necessarily, present, including the case where the heterocyclic group is substituted by a thiol group and the case where the heterocyclic group is not substituted by a thiol group.
  • Substituted means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms are independently substituted with each other by a corresponding number of substituents.
  • substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort.
  • an amino or hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote administration to an organism, to facilitate absorption of the active ingredient and to exert biological activity.
  • Ethyl carbonate chloromethyl ester (3.1 g, 22.4 mmol) was dissolved in 25 mL of acetonitrile, then sodium iodide (6.7 g, 44.7 mmol) was added and allowed to react at room temperature for 20 hours. Filtration and concentrating. The obtained crude material was taken from ethyl ether.
  • (2R,4S)-4-(3-Benzyloxycarbonyl-propionylamino)-5-biphenyl-4-yl-2-methylpentanoic acid isopropoxycarboxymethyl ester dissolved in 20 In methanol, add palladium on charcoal (400 mg), exchange gas, and hydrogenate at atmospheric pressure for 2 hours. Filtration, concentration, reverse phase column chromatography to give a colorless oily liquid (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methylpentanoic acid Isopropoxy carboxymethyl ester (166 mg, 49%).
  • 2,3,4,6-Tetrabenzyl-glucose (5407 mg, 10.0 mmol) was dissolved in 20 mL of dichloromethane, and trichloroacetonitrile (1.5 mL, 15.0 mmol) and 1 drop of DBU were added in an ice water bath. The mixture was naturally warmed to room temperature and allowed to react for 4 hours. The reaction was stopped, concentrated directly, and the resulting product was used in the next step.
  • the compound 1-chloroethyl chloroformate (3 ml, 27.8 mmol) was diluted with DCM (25 ml), cooled to 0 ° C, isopropyl alcohol (2.1 ml, 27.8 mmol) diluted with DCM (25 ml) Slowly add with a constant pressure dropping funnel, react for about 15 min, and slowly add pyridine (2.4 ml, 30.6 mmol) diluted with DCM (5 ml) with a constant pressure dropping funnel. After completion, the reaction was carried out at room temperature overnight, then diluted with water, extracted with DCM, and then dried and evaporated.
  • Cyclohexanol (2.6 mL, 25.0 mmol) was added to 25 mL of dichloromethane and cooled in an ice water bath; 1-chloroethyl chloroformate (2.2 mL, 25.0 mmol) was dissolved in 25 mL of dichloromethane and slowly added dropwise to the reaction system. Middle; pyridine (2.2 mL, 27.5 mmol) was diluted in 5 mL of dichloromethane and slowly added dropwise to the reaction system. Room Warm reaction overnight. Diluted with dichloromethane, washed 3 times with water and dried over anhydrous sodium sulfate. Concentrated to give a colorless liquid of 5.05 g.
  • the following in vitro assays can be used to determine the inhibitory activity of the compounds of the invention against EP enzymes in rat plasma, the activity of which can be expressed as IC 5Q values.
  • the half-inhibitory concentration of the compound IC 5Q (the concentration of the compound required to inhibit a certain concentration of the enzyme activity to 50%) is determined by mixing a certain amount of the enzyme with a specific substrate and a different concentration of the test compound.
  • the NEP enzyme system used in this experiment is fresh blood taken from normal SD rats, placed in a tube containing heparin sodium anticoagulant, collected at 5000 rpm, centrifuged at 4 ° C for 10 min, and plasma is collected; different concentrations of EP inhibitors are prepared.
  • the EP inhibitor had a maximum final concentration of 100 ⁇ and was diluted 10 times in a 3-fold gradient; 60 ⁇ L of fresh rat plasma was added to each well in a 384-well plate; then, 10 ⁇ of a gradient dilution of ⁇ was added to each well.
  • Inhibitor 37 ° C, after incubation for 30 min, add 10 ⁇ ⁇ substrate per well (SenoLyte 520 Neprilysin Activity Assay Kit, AnaSpec, 72223); incubate at 37 ° C for 18 h ( ⁇ lh); at excitation light 490 nm and emission The fluorescence signal was measured at a wavelength of 520 nm; and the IC 50 was determined using Prism 5.0 software.
  • the EP enzyme inhibitory activity of the compound of the present invention was measured by the above test, and the measured IC 5Q value is shown in the following table.
  • 0.1 ml of blood was collected, placed in a heparinized test tube, and centrifuged at 3,500 rpm for 10 min to separate the plasma, and stored at 20 ° C; Eat 2 h after administration. Because the test object is unstable in plasma, the blood sample is quickly placed in the ice water bath after collection, and the whole process of blood sample collection, processing and analysis is kept at a low temperature.
  • Simultaneous detection of prodrugs and metabolites LBQ657 Take 25 ⁇ l of rat plasma at each time after administration, add internal standard SHR133162 (200 ng/ml, methanol) 50 ⁇ l, methanol 175 ⁇ l, vortex for 3 min, centrifuge 10 Min (13500 rpm), the supernatant was taken 10 ⁇ for LC/MS/MS analysis.
  • Simultaneous detection of prodrugs and metabolites LBQ657 Take 25 ⁇ l of rat blank plasma, add 25 ⁇ l of mixed standard series solution, and make blood concentration 1.00, 2.00, 5.00, 25.0, 100, 500, 2000, 5000, 20000 and 40000 ng /ml , add internal standard SHR133162 (200 ng/ml, prepared in methanol) 50 ⁇ l, methanol 150 ⁇ 1, press
  • Example 11 y 0.000942x + 0.00116 0.9989
  • Rats were intragastrically administered with 30.0 mg/kg of prodrug 2, and the blood concentration of the compound of Example 2 was lower than the lower limit of quantification in rats at all times. It is speculated that the prodrug was rapidly hydrolyzed by the enzyme; the blood of metabolite LBQ657
  • the drug concentration peak time 1 is (0.67 ⁇ 0.29) 11, peak concentration. (8145 ⁇ 2101 3 ⁇ 4/1 ⁇ , the area under the blood concentration-time curve AUC 0-t is (20301 ⁇ 3404) ng/ml-h, and the elimination half-life t 1/2 is (1.63 ⁇ 1.56)h.
  • the blood concentration of the prodrug at each time after administration is less than 10 ng/ml, and it is speculated that the prodrug is rapidly enzyme-enzymed in rats.
  • Hydrolysis; the peak concentration t max of the metabolite LBQ657 is (0.50 ⁇ 0.00) h, the peak concentration C max is (30041 ⁇ 13427) ng/ml, and the area under the plasma concentration-time curve is AUC Q. t ( 78570 ⁇ 31469) ng/ml-h, elimination half-life t 1/2 is (2.36 ⁇ 0.39)h.
  • the test results showed that after the rats were administered with 30.0 mg/kg of the prodrug of the compound of Example 4 by intragastric administration, the blood concentration of the compound of Example 4 was lower than the lower limit of quantification in the rats at all times, and it was speculated that the prodrug was rapidly hydrolyzed by the enzyme.
  • the blood product concentration peak time t x of the metabolite LBQ657 is (0.833 ⁇ 0.289) h
  • peak concentration. nie ⁇ is (13308 ⁇ 3949) ng/ml
  • the area under the blood concentration-time curve is AUCo- t (35276 ⁇ 16283) ng/ml-h
  • the elimination half-life t 1/2 is (4.54 ⁇ 1.77)h.
  • the blood concentration of the compound of Example 13 at each time in the rat is lower than the lower limit of quantification, and the prodrug is presumed to be rapidly hydrolyzed by the enzyme; metabolite LBQ657
  • the blood concentration peak time t max was (0.83 ⁇ 0.29) h
  • the peak concentration C ⁇ was (12466 ⁇ 5106) ng/ml
  • the area under the plasma concentration-time curve was AUCo- t (33505 ⁇ 14118) ng/ Ml-h
  • elimination half-life t 1/2 is (1.91 ⁇ 1.50) h.
  • the compounds of the examples of the present invention can be metabolized into the active pharmaceutical ingredient LBQ657 in rats.

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Abstract

La présente invention porte sur un dérivé d'acide 4-aminobutyrique substitué par biaryle, sur un procédé de préparation s'y rapportant et sur ses utilisations. En particulier, elle porte sur un dérivé d'acide 4-aminobutyrique substitué par biaryle tel que représenté par la formule (I), sur un procédé de préparation s'y rapportant et sur ses utilisations, sur un intermédiaire d'un dérivé d'acide 4-aminobutyrique substitué par biaryle préparé par cyclisation et sur une composition pharmaceutique contenant un dérivé d'acide 4-aminobutyrique substitué par biaryle. Les présents dérivés d'acide 4-aminobutyrique substitué par biaryle ont une activité inhibitrice de la NEP et peuvent être utilisés comme inhibiteurs de la NEP.
PCT/CN2014/079278 2013-06-13 2014-06-05 Dérivé d'acide 4-aminobutyrique substitué par biaryle, procédé de préparation s'y rapportant et ses utilisations WO2014198195A1 (fr)

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WO2017033128A1 (fr) * 2015-08-25 2017-03-02 Novartis Ag Dérivés d'acide 4-aminé-butyrique substitués par le biphényle, et leur utilisation dans la synthèse d'inhibiteurs de nep
US10668035B2 (en) 2018-02-07 2020-06-02 Novartis Ag Substituted bisphenyl butanoic ester derivatives as NEP inhibitors
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KR20220035334A (ko) * 2020-09-09 2022-03-22 난징 헤론 파마슈티컬 사이언스 앤 테크놀로지 컴퍼니 리미티드 아릴프로피온산 유도체, 약학적 조성물 및 이의 제조방법과 응용

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