AR092031A1 - Inhibidores del canal de potasio medular externo renal - Google Patents

Inhibidores del canal de potasio medular externo renal

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Publication number
AR092031A1
AR092031A1 ARP130102534A ARP130102534A AR092031A1 AR 092031 A1 AR092031 A1 AR 092031A1 AR P130102534 A ARP130102534 A AR P130102534A AR P130102534 A ARP130102534 A AR P130102534A AR 092031 A1 AR092031 A1 AR 092031A1
Authority
AR
Argentina
Prior art keywords
alkyl
optionally substituted
bond
cycloalkyl
halo
Prior art date
Application number
ARP130102534A
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English (en)
Original Assignee
Merck Sharp & Dohme
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/CN2012/079184 external-priority patent/WO2014015495A1/en
Application filed by Merck Sharp & Dohme filed Critical Merck Sharp & Dohme
Publication of AR092031A1 publication Critical patent/AR092031A1/es

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/20—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, ***e
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • 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
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • 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
    • A—HUMAN NECESSITIES
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    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems

Abstract

Son inhibidores del canal de ROMK (Kir1.1). Los compuestos se pueden usar como agentes diuréticos y/o natriuréticos y para la terapia y la profilaxis de afecciones médicas que incluyen enfermedades cardiovasculares tales como hipertensión, insuficiencia cardíaca y afecciones asociadas con excesiva retención de sal y agua. ROMK (Kir1.1) canal Kir1.1 de Potasio Medular Externo Renal. Reivindicación 1: Un compuesto que tiene la fórmula estructural (1) o una sal farmacéuticamente aceptable del mismo en la que: R¹ es -H, halo, -OH o -O-alquilo C₁₋₃; m es un número entero seleccionado entre cero (R³ᵇ está ausente) y 1 (R³ᵇ está presente); n es un número entero seleccionado entre 1 ó 2; R² está seleccionado independientemente en cada aparición entre -H, =O (oxo), -OH, alquilo C₁₋₃ o -O-alquilo C₁₋₃, con la condición de que cuando n es 2, entonces al menos un R² es -H; R³ᵃ es -H, =O, cicloalquilo C₃₋₄ o alquilo C₁₋₃ opcionalmente sustituido con -OCH₃ o 1 a 3 de -F, con la condición de que sólo uno de R² o R³ᵃ pueden ser =O; R³ᵇ es -H o alquilo C₁₋₃, o R³ᵇ está ausente cuando R³ᵃ es =O ó cuando el enlace discontinuo es un doble enlace o un enlace aromático; o R³ᵃ y R³ᵇ están unidos junto con el carbono al que ambos están unidos para formar ciclopropilo o ciclobutilo; o cuando n es 1, R² y R³ᵃ pueden estar unidos junto con los carbonos a los que cada uno está unido para formar (i) un anillo de fenilo que está condensado con el anillo de pirrolidina, y m es cero, o (ii) un anillo de ciclopropilo condensado con el anillo de pirrolidina, y m es 1; R⁴ es -H o =O; R⁵ es (a) -H, (b) halo, (c) -alquilo C₁₋₃ opcionalmente sustituido con -O-alquilo C₁₋₃, (d) -cicloalquilo C₃₋₆ o (e) heterociclo opcionalmente sustituido con -alquilo C₁₋₃ o halo; R⁶ es -H o alquilo C₁₋₃; R⁷ᵃ es -H o alquilo C₁₋₃ opcionalmente sustituido con -OH, -OCH₃ o 1 a 3 de -F; R⁷ᵇ es -H o -alquilo C₁₋₃; o R⁷ᵃ y R⁷ᵇ están unido junto con el carbono al que ambos están unidos para formar -cicloalquilo C₃₋₄; R⁸ es -H, halo, o -alquilo C₁₋₃; R⁹ es -H, -F, -OH, -O-alquilo C₁₋₃, -CH₂OH, -NH-R¹³ o un resto de fórmula (2); R¹⁰ es -H, halo, -CN, cicloalquilo C₃₋₄, o alquilo C₁₋₃ opcionalmente sustituido con 1 a 3 de -F; o R⁹ es -O- y está unido junto con R¹⁰ para representar -CH₂-CH₂-O-; R¹¹ es -H, -CH₂OH, -CH₂OCH₃, o alquilo C₁₋₃ opcionalmente sustituido con 1 a 3 de -F; R¹² es -H, -CH₂OH, -CH₂OCH₃, o alquilo C₁₋₃ opcionalmente sustituido con 1 a 3 de -F; o R¹¹ y R¹² están unidos entre sí para representar -CH₂-CH₂-, -CH₂-N(CH₃)-CH₂- o -CH₂OCH₂-; R¹³ es -H, -(CH₂)₀₋₂-cicloalquilo C₃₋₆, -(CH₂)₁₋₂-O-cicloalquilo C₃₋₆, -(CH₂)₁₋₂-O-alquilo C₁₋₃, -(CH₂)₁₋₂-CN, -C(O)O-alquilo C₁₋₃, -SO₂CH₃ o alquilo C₁₋₃ opcionalmente sustituido con uno a tres de -F; y el enlace discontinuo (- - -) representa un enlace sencillo, doble o aromático, con la condición de que (A) cuando n es 2, entonces el enlace discontinuo es un enlace sencillo y m es 1; y (B) cuando n es 1 y (i) m es 1 (que incluye pero no se limita a compuestos en los que R² y R³ᵃ están unidos para representar ciclopropilo condensado con el anillo de pirrolidina), o (ii) R³ᵃ es =O y m es cero, entonces el enlace discontinuo es un enlace sencillo; y (C) cuando n es 1, m es cero, R² no es =O y R³ᵃ no es =O, entonces el enlace discontinuo es (i) un doble enlace, o (ii) un enlace aromático R² y R³ᵃ están unidos entre sí para formar el anillo de fenilo condensado con el anillo de pirrolidina.
ARP130102534A 2012-07-26 2013-07-16 Inhibidores del canal de potasio medular externo renal AR092031A1 (es)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
PCT/CN2012/079184 WO2014015495A1 (en) 2012-07-26 2012-07-26 Inhibitors of the renal outer medullary potassium channel
US201261691390P 2012-08-21 2012-08-21
US201361759040P 2013-01-31 2013-01-31

Publications (1)

Publication Number Publication Date
AR092031A1 true AR092031A1 (es) 2015-03-18

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ARP130102534A AR092031A1 (es) 2012-07-26 2013-07-16 Inhibidores del canal de potasio medular externo renal

Country Status (14)

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US (2) US8952166B2 (es)
EP (1) EP2877471B1 (es)
JP (1) JP6166783B2 (es)
KR (1) KR20150036142A (es)
CN (1) CN104540826B (es)
AR (1) AR092031A1 (es)
AU (1) AU2013295722B2 (es)
BR (1) BR112015001419A8 (es)
CA (1) CA2876508A1 (es)
ES (1) ES2606016T3 (es)
MX (1) MX365986B (es)
RU (1) RU2642066C2 (es)
TW (1) TW201410675A (es)
WO (1) WO2014018764A1 (es)

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CA2876508A1 (en) 2014-01-30
JP2015523399A (ja) 2015-08-13
TW201410675A (zh) 2014-03-16
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AU2013295722A1 (en) 2015-01-15
BR112015001419A8 (pt) 2019-07-30
ES2606016T3 (es) 2017-03-17
RU2642066C2 (ru) 2018-01-24
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US20150099729A1 (en) 2015-04-09
US8952166B2 (en) 2015-02-10
US20140031349A1 (en) 2014-01-30
RU2015106139A (ru) 2016-09-20
CN104540826A (zh) 2015-04-22
BR112015001419A2 (pt) 2017-07-04
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