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WO2007034846A1 - Agent tonicardiaque comprenant un inhibiteur de la grk - Google Patents

Agent tonicardiaque comprenant un inhibiteur de la grk Download PDF

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Publication number
WO2007034846A1
WO2007034846A1 PCT/JP2006/318666 JP2006318666W WO2007034846A1 WO 2007034846 A1 WO2007034846 A1 WO 2007034846A1 JP 2006318666 W JP2006318666 W JP 2006318666W WO 2007034846 A1 WO2007034846 A1 WO 2007034846A1
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WIPO (PCT)
Prior art keywords
group
amino
optionally substituted
ring
grk
Prior art date
Application number
PCT/JP2006/318666
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English (en)
Japanese (ja)
Inventor
Shota Ikeda
Manami Kaneko
Shuji Fujiwara
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Takeda Pharmaceutical Company Limited
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Publication of WO2007034846A1 publication Critical patent/WO2007034846A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to G protein-coupled receptor kinase, (G protein-coupled receptor phosphatase; GRK) inhibitory compound or a prodrug thereof (hereinafter sometimes abbreviated as GRK. Inhibitor). Concerning cardiotonic drugs (acute cardiac strength improving drugs). Background art
  • Heart failure is a general term for pathological conditions caused by the inability to beat blood that meets the demand for peripheral organ tissue due to abnormal cardiac function.
  • Very Umate prognosis among diseases of the circulatory system is one of the bad disease, the 5-year survival rate of about 50% (the American Heart Association Statistics
  • Heart failure treatment has two objectives: improving acute symptoms and improving chronic life prognosis.
  • catecholamines 'diuretics' digitalis Antibiotics such as PDE inhibitors are expected to improve chronic prognosis and survival.
  • the therapeutic effects of these drugs are far from satisfactory and the only radical treatment that can truly recover from a heart failure state is heart transplantation.
  • Drugs that act directly on the heart and improve the cardiac contractile force immediately after drug administration are called ⁇ cardiotonic drugs'', focusing on the aforementioned digitalis' catecholamines and PDE inhibitors, especially in the treatment of heart failure, especially in the acute phase A category is formed as an essential drug for the improvement of symptoms.
  • catecholamines, PDE inhibitors, etc. can It is known to increase life prognosis in the long run rather by accelerating and increasing the frequency of fatal cardiac arrhythmias.
  • digitalis has a known fatal serious side effect called “digitalis intoxication”, and placebo-controlled, soil-blind, other large-scale clinical trials in 6800 patients with heart failure.
  • GRK2 G protein-coupled receptor phosphorylase-2, also known as receptor phosphorylation enzyme
  • G protein-coupled receptor phosphorylase-2 also known as receptor phosphorylation enzyme
  • a compound having a triazole skeleton has a strong GRK inhibitory action in the enzyme assembly. It was found that GRK can be inhibited through the cell membrane even when applied from outside the cell. Furthermore, when this compound is applied directly to the isolated perfused heart preparation, the contractile force increases immediately after drug administration, and its effect is further increased in the presence of catecholamine, and the heart rate is almost increased. Not Was revealed. In addition, when the compound is administered intranasally to anesthetized rats, immediately after drug administration, only the systolic force is selectively enhanced with little effect on blood pressure and heart rate, and it can be recovered by administration interruption. Found ⁇
  • Ring A represents an optionally substituted aromatic ring.
  • Ring B represents an optionally substituted 5-membered ⁇ nitrogen aromatic heterocycle
  • Ring C represents an optionally substituted nitrogen-containing aromatic heterocycle
  • X represents an optionally substituted Ci-4 alkylene group
  • Y represents an optionally substituted imino group, 1 O— or 1 S (0) n— (n represents Q, 1 or 2). ]
  • a cardiotonic drug according to (2) which is a GRK2 inhibitor comprising a compound represented by the formula:
  • a method for treating heart failure in a mammal comprising administering an effective amount of the cardiotonic agent according to (1) to the mammal suffering from heart failure;
  • GRK inhibitors act as a “cardiac agent” that acts directly on the heart and improves cardiac contraction force immediately after drug administration.
  • cardiac agent acts directly on the heart and improves cardiac contraction force immediately after drug administration.
  • GRK inhibitors have been confirmed to have a ⁇ characteristic with little increase in heart rate, and are expected to have a chronic life prognostic effect as well as an action mechanism. That is, according to the present invention, an excellent “cardiotonic drug” is provided by the present invention, and the GRK inhibitor is based on its medicinal properties as a “cardiac drug” and heart failure (especially symptomatic heart failure). It has been demonstrated for the first time that it can be applied as: prevention, treatment, amelioration of symptoms of heart failure, left ventricular function improving agent in patients with heart failure, etc.
  • Figure 1 shows the results of observing the effect of acute GRK inhibition by the test compound (1) on rat cardiovascular dynamics. Best form for applying the invention to the cold
  • the GRK inhibitor J used in the present invention is not particularly limited as long as it is a compound having a GRK inhibitory action, but is a low molecular weight compound, a nucleic acid, a protein, a peptide, a prodrug thereof, or a compound thereof. Any of salt, etc. can be used, but it is advantageous in practice of the present invention to use one having a strong GRK inhibitory action, for example, by the method disclosed in Test Examples 1 and 8 described later.
  • the inhibitory activity of GRK2 is measured, it is recommended to use an IC of 5 or less, more preferably 0.3 iM or less, and still more preferably 0.1 M or less. This is advantageous in the practice of the invention, but is not limited thereto.
  • the “GRK inhibitor” used in the present invention may have a pharmacological action other than the GRK inhibitory action, but it has a high selectivity to the GRK inhibitory action, and in particular, it is selected for the GRK2 inhibitory action. It is advantageous in the practice of the present invention to use a material having high properties.
  • GRK inhibitor used in the present invention examples include International Application No. PCT / JP2005 / 005995 (W02005 / Ri 90328), a compound represented by the following formula (I), or the American Chemical Society, 231st National Meeting ), And the compounds represented by the formula (II) described later.
  • a GRK inhibitor can be appropriately selected from these to implement the present invention.
  • the following compounds are given as examples of GRK inhibitors only, and are not intended to be limiting. .
  • ring A represents an optionally substituted aromatic ring.
  • aromatic ring in the “optionally substituted aromatic ring” represented by ring A examples include (i) aromatic cyclic hydrocarbon, and (ii) nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom.
  • An aromatic heterocycle containing preferably 1 to 3 heteroatoms selected from 1 or 2 is mentioned.
  • aromatic cyclic hydrocarbon for example, benzene, naphthalene, C 6 etc. - include 1 4 aromatic cyclic hydrocarbons.
  • aromatic heterocycle examples include 5- to 6-membered aromatic monocyclic compounds such as furan, thiophene, pyridine, pyridazine, pyrimidine, pyrazine, and triazine. Treatment: For example, benzofuran, indole, etc., 8 to 16 membered. (Preferably 8 to 12 membered) aromatic condensed heterocycle (preferably 5 to 6 membered aromatic Monocyclic heterogeneous heterocycles of 1 to 2 (preferably: 1) fused with a benzene ring to 2 ⁇ ⁇ ⁇ ⁇ (preferably 1), or as described above. A heterocyclic ring in which the same ⁇ "of a cyclic heterocyclic ring or 2 to 3 different heterocyclic rings, preferably 2) are fused, and the like.
  • examples of the substituent that the aromatic ring in the “optionally substituted aromatic ring” represented by ring may have include a halogen atom, an optionally substituted hydrocarbon: group, and a substituted Mole, heterocyclic group, optionally substituted amino group, optionally substituted imidoyl group, optionally substituted amidino group, optionally substituted hydroxyl group, substituted Optionally substituted cyanore group: sia / group, nitro group, nitrozo group, sulfo group, optionally substituted rubamoyl group, .substituted samoyl group, esterified
  • the optional carboxyl group may be substituted with 1 to 5 (preferably 1 to 3) of these optional substituents at substitutable positions.
  • halogen atom as the substituent that the aromatic ring in the “optionally substituted aromatic ring” represented by ring A may have include fluorine, silicon, bromine, and iodine. It is done.
  • hydrocarbon group in the “optionally substituted hydrocarbon group” as the substituent that the ring may have in the “optionally substituted aromatic ring” represented by ring A is examples thereof include an aliphatic chain hydrocarbon group, an alicyclic hydrocarbon group (non-aromatic cyclic hydrocarbon group), and an aryl group (aromatic hydrocarbon group).
  • aliphatic chain hydrocarbon group examples include linear or branched aliphatic hydrocarbon groups such as an alkyl group, an alkenyl group, and an alkynyl group.
  • alkyl group examples include C 10 alkyl groups (preferably C ⁇ alkyl etc.) such as methyl, ethyl, n-propyl, isopropyl, etc. Leaking. ..,,
  • alkenyl group examples include vinyl, allyl, isopropenyl, etc.
  • alkynyl group for example,' Echuru, 1 Purobyuru, 2-propyl sulfonyl, C 2 etc. - include 6 alkynyl group.. -.
  • alicyclic hydrocarbon group examples include saturated or unsaturated alicyclic hydrocarbon groups such as a cycloalkyl group, a cycloalkenyl group, and a chloralkadienyl group. . .
  • cycloalkyl group J for example, Shikuropuropinore, Shikurobu chill, C 3 _ 9 cycloalkyl grave or the like and the like.
  • cycloalkenyl group for example, 2- Shikuropenchin one 1-I le, 3-cyclopentene -.. 1 I Le, C 3 _ 9 consequent equal Roaruke group, and the like.
  • cycloalkadienyl group examples include, for example, 2,4-cyclopentagen 1-yl, 2,4-cyclohexahexan 1-yl, 2,5-cyclopentahexagen 1 A C 4-6 cycloalkadienyl group such as —yl; .
  • aryl group examples include monocyclic or condensed polycyclic aromatic hydrocarbon groups, such as C 6-14 aryl groups such as phenyl, naphthyl, etc. Among them, a 'C 6:12 aryl group and the like are particularly preferable.
  • hydrocarbon group the same or different 2 to 3 groups constituting a group selected from the above-described alicyclic hydrocarbon group and aryl group, such as 1,2-di-7dronaphtyl, indanyl and the like.
  • aryl group such as 1,2-di-7dronaphtyl, indanyl and the like.
  • a bridged hydrocarbon group such as adamantyl is also included.
  • hydrocarbon group in the “optionally substituted hydrocarbon group” as the substituent that the aromatic ring in the “optionally substituted aromatic ring” represented by ring A may have Examples of the substituent that may be used include:
  • a halogen atom optionally halogenated C [1 -4 alkyl group, optionally halogenated C [Medicine 4 alkoxy groups, optionally substituted by human Dorokishi C,. 4 alkyl group and phenyl C optionally substituted with a substituent selected from the group 6 ” 12 reel base; ',:,...
  • human Dorokishiru may be substituted with a group C 3 - 10, down Roarukiru group, C. _ 10 Bicyclic hydrocarbon group condensed with cycloalkyl group and benzene (for example, indal etc.), Bridged hydrocarbon group (for example, adarnayl etc.);
  • (XV) halogenated expired they may Ji alkyl group, /, halogenated which may be C 2 _ 6 alkenyl group, an optionally C 1-4 alkylthio group which may be halogenated, substituted with human Dorokishi group It may be substituted with a d- 4 alkyl group or a hydroxy group. 4 alkylthio groups;
  • (XX) optionally halogenated C 1-4 anoleno ⁇ / sunorephoninole group, phenenolesnorephonyl group, phenylsenorephonyl-to- 4 arenoalkyl group;
  • (XXV) C 1-6 acyl group or benzoyl group each optionally substituted by a substituent selected from a halogen atom, a force / repoxyl group and a C 1-4 aroxy-carbonyl group ⁇ No,.
  • (XXX) a linear or branched C 1-4 alkylenedioxy group which may be halogenated;
  • the “hydrocarbon group” may have 1 to 5 (preferably 1 to 3, more preferably 1 or 2) of these substituents at substitutable positions.
  • the substituents may be the same or different.
  • heterocyclic group in the “optionally substituted heterocyclic group” as the substituent that the aromatic ring in the “optionally substituted aromatic ring” represented by ring A may have, for example,
  • the atoms that make up the ring system (ring atoms) are oxygen atoms, sulfur atoms And at least one (preferably 1 or 2) preferably 1 to 3 kinds of atom atoms selected from nitrogen insulators, etc.
  • An aromatic heterocyclic group, a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group) and the like can be mentioned. : ''
  • aromatic heterocyclic group examples include 5- to 6-membered aromatic monocyclic heterocyclic groups such as furyl, .cenyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, .triazinyl and the like.
  • aromatic monocyclic heterocyclic groups such as furyl, .cenyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, .triazinyl and the like.
  • non-aromatic heterocyclic group examples include pyrrolidinyl, piperidyl, tetrahydro, pyrael, morpholinyl, thiomorpholiel (the sulfur atom may be oxidized), piperazinyl and the like.
  • heterocyclic group in the “optionally substituted heterocyclic group” as the substituent that the aromatic ring in the “optionally substituted aromatic ring” represented by ring A may have.
  • substituent that may be included include, for example, the “hydrocarbon group” in the “optionally substituted hydrocarbon group” as the substituent of the “optionally substituted aromatic ring” represented by ring A. And the same number of the same groups as the substituents which may be present.
  • the “optionally substituted amino group” or the “optionally substituted amino group” as the substituent that the aromatic ring in the “optionally substituted aromatic ring” represented by ring A may have.
  • imidoyl group “ optionally substituted amidino, group ”,“ optionally substituted, hydroxyl group ”,“ optionally substituted thiol group ”, Examples of the substituent that each of the imidazole group, amidino, hydroxy, thione group and thiol group may have include:
  • the phenyl is halogen atom, Nono Gen of which may flicking 6 even if. Alkyl, Bruno, may be substituted with halogenated which may be C ⁇ e-alkoxy, etc.), it has been Nono port Gen of May be naphthyl and C 3 .
  • Cigroalkyl is selected; a lower alkyl group optionally substituted with a substituent, etc .;
  • Nzoiru base may be halogenated, Nono halogenated which may be ⁇ doctor 6 alkylsulfonyl group, Nono halogenated which may be benzenesulfonyl, torr ⁇ Nsuruho two les, etc.);
  • (V) Soso halogenated which may c be the 1 - 6 alkoxy - carbonyl group, a substituted c Medical 6 optionally alkoxy carbonyl group phenyl;
  • the “amino group” in the “optionally substituted amino group” as a substituent is an optionally substituted imidoyl group (for example, ⁇ 6 alkylimidoyl, C t 6 alkoxyimidoyl, alkylthioimidoyl). , Amidino and the like), an amino group which may be substituted with 1 to 2 alkyls, and the like.
  • an optionally substituted imidoyl group for example, ⁇ 6 alkylimidoyl, C t 6 alkoxyimidoyl, alkylthioimidoyl. , Amidino and the like
  • an amino group which may be substituted with 1 to 2 alkyls and the like.
  • two substituents are combined with the nitrogen atom.
  • examples of the cyclic amino group include 1-azedinyl, 1-pyrrolidinyl, piperidine, thiomorpholino, kirolino, 1-piperazinyl, and A cyclic amino group having a lower alkyl group, an aralkyl group, an aryl group, etc. at the 4-position, such as 1-pipera notede, 1 pyrolithule, 1 imidazolyl, etc., preferably 3 to 8 members.
  • Etc. : ..
  • Two or more substituents present adjacent to each other on the aromatic ring in the “optionally substituted aromatic ring” represented by ring A are combined to form a linear or branched C!
  • An alkylene dioxy group or the like may be formed.
  • the “optionally substituted strong rubermoyl group” as the substituent that the aromatic ring may have includes In addition to the / vamoyl group, N-mono.substitutional force ruberamoyl3 ⁇ 4 and N, N-disubstitutional force / levermoinole group are fisted.
  • N-mono-substituted rubamoyl group examples include, for example, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, and an optionally substituted amino.
  • Examples of the “optionally substituted hydrocarbon group” as an example of the substituent of “N-mono-substituted rubamoyl group” include substitution in the “optionally substituted aromatic ring” represented by ring A Examples thereof include the same groups as the “optionally substituted hydrocarbon group” as the group.
  • Examples of the “optionally substituted heterocyclic group” as an example of the substituent of “N-mono-substituted rubamoyl group” include substitution in the “optionally substituted aromatic ring” represented by ring A Examples thereof include the same groups as the “optionally substituted heterocyclic group” as the group.
  • the “optionally substituted amino group” as an example of the substituent of “N-mono-substituted rubamoyl group” is the “optionally substituted aromatic ring” represented by ring A.
  • substituents are the same groups such as “amino group which may be substituted and ⁇ ”.
  • ⁇ , ⁇ —di-substituted rubamoyl group means two force rubamoyl groups on the 3 ⁇ 4 atom (one example of such a substituent is as described above; etc.
  • two substituents may be combined with a nitrogen atom to form a cyclic amino group.
  • examples of the cyclic aminocarbamoinole group include .1.
  • Examples of the “optionally substituted sulfamoyl group” as the substituent that the aromatic ring in the optionally substituted aromatic ring J may have include an unsubstituted sulfamoyl group, as well as an N-monosubstituted sulfamoyl group. Groups and N, N-disubstituted sulfamoyl groups.
  • N-quino-substituted sulfamoyl group examples include the same groups as the substituent of “N-mono-substituted rubamoyl group”.
  • N, N-disubstituted sulfamoyl group means a sulfamoyl group having two substituents on the nitrogen atom, and one example of the substituent is the above-mentioned “N-mono substituted sulfamoyl group” include those similar to the substituents, it is in the other examples, for example, a lower alkyl group, C 3 _ 6 cycloalkyl group, such as C 7 _ 1 0 Ararukiru group. In some cases, two substituents together with a nitrogen atom form a cyclic amino group.
  • examples of the cyclic aminosulfamoyl group include 1-azetidylsulfonyl, 1 Monopyrrolidinylsulfonyl, piperidinosulfonyl, morpholinosulfonyl, thiomorpholinosulfoninole (sulfur atom may be oxidized), 1-piperazinylsulfonyl, and lower alkyl at position 4 A 3- to 8-membered (preferably 5- to 6-membered) cyclic amino-sulfonyl group, such as 1-piperazinylsulfonyl, which may have an alkyl group, an aralkyl group, an aryl group, etc.
  • the “optionally esterified carboxyl group” as the substituent that the aromatic ring in the “optionally substituted” ring represented by ring A may have is a free carboxyl
  • examples include lower alkoxycarbonyl group, aryl, oxycarbonyl group, aralkyloxycarbonyl group and the like.
  • lower alkoxycarbonyl ⁇ le group for example, main butoxy Rubo sulfonyl, E-butoxycarbonyl, propoxycarbonyl, C etc. -. 6 Anorekokishi one carbonylation Honoré, and among them C L - 3 alkoxy one Carbonyl and the like are preferred.
  • Aryl talented xycarbonyl groups include, for example, phenoxycarbonyl,
  • the " ⁇ Lal Kill O alkoxycarbonyl group" for example ', benzyl O propoxycarbonyl sulfonyl, phenethyl' O carboxymethyl Kano repo sulfonyl etc. C 7 - 1 () Ararukiru - O butoxycarbonyl, etc. (preferably, C 6 - 1 Aryl 1 C 4 alkoxy 1 carbonyl, etc.) are preferred.
  • the “lower alkoxycarbonyl group”, “aryloxycarbonyl group”, and “aralkyloxycarbonyl group” may have a substituent, and as the substituent, the “substituted alkoxy group represented by ring A”
  • the same number of the same groups as those mentioned as the substituents that the “hydrocarbon group” in the “optionally substituted hydrocarbon group” as the substituent in the “optionally aromatic ring” may have. Used.
  • acyl group as the substituent that the aromatic ring in the “optionally substituted aromatic ring” represented by ring A may have, a carboxylic acid-derived asil group, a sulfinic acid-derived acyl group And an acyl group derived from sulfonic acid and an acyl group derived from phosphonic acid.
  • a hydrogen atom which may be substituted A hydrocarbon group (for example, the same group as the “optionally substituted hydrocarbon group” as a substituent in the “optionally substituted aromatic ring” in ring A) or may be substituted A silicon ring group (for example, “optionally substituted heterocyclic group” as a substituent in the “optionally substituted aromatic ring” represented by ring A and similar groups) and carbonyl (-C (O)-) and a group bonded thereto, for example, formyl, acetyl, propionyl, butyryl, isotoptyl, norrelyl, isovaleryl, hydr.
  • a hydrocarbon group for example, the same group as the “optionally substituted hydrocarbon group” as a substituent in the “optionally substituted aromatic ring” in ring A
  • silicon ring group for example, “optionally substituted heterocyclic group” as a substituent in the “optionally substituted aromatic ring” represented by ring A and similar groups
  • the “sulfinic acid-derived acyl group” includes an optionally substituted hydrocarbon group (for example, a “substituted” as a g-substituted group in the “optionally substituted aromatic ring” represented by ring A.
  • an optionally substituted hydrocarbon group for example, a “substituted” as a g-substituted group in the “optionally substituted aromatic ring” represented by ring A.
  • the same group as “optionally substituted hydrocarbon group” or a heterocyclic group which may be substituted eg, ring. Indicated by A.
  • the “sulfonic acid-derived acyl group” is an optionally substituted hydrocarbon group (for example, “substituted” as a substituent in the “optionally substituted aromatic ring” represented by ring A.
  • hydrocarbon group or a heterocyclic group which may be substituted (for example, “substituted” as the substituent in the “optionally substituted aromatic ring” represented by ring A)
  • the phosphonic acid-derived acyl group includes, for example, 'dimethylphosphoso, jetylphosphono, diisopropylphosphono, dibutylphosphono, .2-oxide 1: 3,2-dioxaphosphinan-1
  • 'dimethylphosphoso jetylphosphono
  • diisopropylphosphono dibutylphosphono
  • .2-oxide 1 3,2-dioxaphosphinan-1
  • cocoons such as rutile, di-C 1-4 teralkyl, phosphoso and the like.
  • a neurogenic atom A neurogenic atom
  • C 6 alkyl group (wherein the c 1-6 alkyl group is a halogen atom, hydroxy, carbamoyl, mono- or di-benzylcarbamoinole, moso- or di-phenethylol-rubamoyl, carboxyl, di- 4 Anorekokishi one carbonylation Honoré.
  • Nono halogenated which may be C 1 -4 alkoxy, amino, mono- one or di- _C 1-4 Arukirua amino, C ⁇ alkanoyloxy noisy Rua amino, may be Nono halogenated Substituted with phenyl, optionally halogenated benzoyl, etc.);
  • C 2-6 alkenyl group (the C 2 _ 6 alkenyl group may be substituted with may be Benzoiru like halogenated) .;
  • a phenylol group (the phenylol is a hydrogen atom, a log atom, a hydroxyloxy, a canolamoyl, a carboxyl, a sulfo group, an alkoxy monocarbonyl, an optionally halogenated 4- alkoxy, an optionally halogenated d— 4 alkyl, amino, mono- one or di- one C ⁇ Arukiruamino may be substituted with C 1 -6 alkanoyloxy noisy Rua amino, etc.);
  • a non-aromatic heterocyclic group (preferably oxazoline, the non-aromatic heterocyclic group may be substituted with an oxo group or the like);
  • amino group (the amino group is an optionally halogenated C ⁇ alkyl, an optionally halogenated C 1-6 alkanol, an optionally halogenated ben; Zoyl, phenylacetyl (the phenyl may be substituted with a halogen atom, which may be halogenated, such as Ci-e alkyl), .. mono- or di-benzylcarbamoyl group, mono- or di- .
  • full energy chill carbamoylthiopheno group it may be replacement by phenylene Le - 6 alkoxy one carbonyl group, Bruno, halogenated which may be optionally C 1 - 6 alkylsulfonyl is substituted by an Izu, also 'Hydroxy group (the hydroxy block is phenyl, the phenyl is a halogen atom,
  • I be substituted with a halogenated or may be substituted by may be C i _ 6 alkyl such as optionally) and optionally halogenated selected from a naphthyl substituents: There C ⁇ alkyl, May be substituted with an optionally halogenated phenyl, etc.);
  • a thiol group (the thiol group may be substituted with a halogen atom or an optionally halogenated phenyl group, substituted with a 6- alkylenoleole, a nitrogenated L. or an optionally substituted phenyl group, etc.) It may be.);
  • N—C ⁇ e alkyl ' (wherein the alkyl may be substituted with a halogen atom, a hydride, etc.)
  • N-phenyl (wherein the phenyl may be substituted with a halogen atom, optionally halogenated C 1-4 alkyl, etc.) —strength rubamoyl group;
  • N—non-aromatic heterocycle preferably tetrahydrobiranyl
  • N—bi- or tricyclic hydrocarbon preferably tetrahydronaphthyl, indanolanol, fluorenyl, the dicyclic or tricyclic hydrocarbon may be substituted with hydroxy, etc.
  • N _ C 6 _ 1 2 aryl (the aryl is a halogen atom, optionally halogenated C 4 alkyl, optionally halogenated C 4 alkoxy, hydro May be substituted with xyl — 4 may be substituted with alkyl, phenyl, etc.) monoalkyl (the C 1-6 alkyl may be substituted with hydroxy, rubermoyl, etc.) ) —Force rubermoyl group;
  • N—5 to 10-membered heterocycle preferably pyridyl, furyl, chenyl, indolyl.
  • the heterocycle may be substituted with C anolole.kill, etc.) 1 C 6 azorequinole 1canole vamoire Group;
  • NC 3 10 cycloalkyl (said cycloalkyl may be replacement by such human Dorokishi.) Have one C, alkyl - force Rubamoiru group.;
  • N, N-, substituted rubermoyl groups eg, N—C 6 alkyl-N-phenyl-Cu arnolequinol / canolevamoi / re groups; to.
  • 5- to 6-membered cyclic amino preferably, forming a piperidine ring
  • monocarbonyl group preferably 1, 2, 3, 4-tetrahydroisoquinoline 1- 2-ylcarbonyl
  • N-monosubstituted snorefamoinole group for example, N-phenol (this phenyl may be substituted with a non-ogen atom, a hydrogenated Ci-alkyl, etc.) Ji 6 alkyl monosulfamoyl);
  • alkylsulfonyl group which may be halogenated; '' Benzinores norehoninole group ''; ⁇ ,. ' ⁇
  • Ring A is preferably an optionally substituted benzene ring or an optionally substituted pyridine ring, among which an optionally substituted benzene ring is more preferred, and a halogen atom (preferably , Silicon, bromine, etc.)
  • the 3-position is substituted with a benzene ring which may be substituted with, or a rubamoyl group which may be substituted with ⁇ .
  • a good benzene ring is particularly preferred.
  • a cisene ring which may be substituted at the 3 • position with a mono-substituted rubamoyl group, is most preferable. .. ..
  • X may be substituted.
  • An alkylene group is shown.
  • Examples thereof include linear or branched C ⁇ 4 alkylene groups such as propylene and dimethylenoethylene. Of these, methylene, methylmethylene, ethylmethylene and the like are preferable.
  • substituents that the o 4 alkylene group may have include “substitution” as the substituent that the aromatic ring in the “optionally substituted aromatic ring” represented by ring A may have.
  • the hydrocarbon group in “optionally substituted hydrocarbon group” includes the same group as the substituent which may have (however, it is preferably not an oxo group), and these substituents can be substituted. 1 to 3 (preferably 1) may be substituted at any position.
  • substituent that the Ci alkylene group may have include a halogen atom;
  • Mono- or di-C 1-4 alkylamino group (in addition, the C, ⁇ alkyl may be substituted with phenenyl, pyridyl, etc.);
  • Etc. are preferred.
  • an amino group, a mono- or C 1-4 alkylamino group (methylamino., Ethylamino; /, etc.) which may be substituted with phenyl or pyridyl is particularly preferable. .
  • X is preferably substituted and more preferably methylene, especially unsubstituted methylene.
  • ring B represents an optionally substituted 5-membered nitrogen-containing aromatic heterocycle.
  • the “5-membered nitrogen aromatic silicon ring” include, for example, roll, oxazole, isoxazol, thiazole, isothiazole, imidazole, pyrazole, oxadiazole (1, 2, 3-oxadiazole, 1, 2 , 4-Oxadiazole, 1, 3, 4 oxadiazole), furazane, thiadiazole (1, 2, 3-thiadiazole, 1, 2, 4-thiadiazole, 1, 3, 4-thiadiazole), triazole ( 1,2,3-triazole, .1,2,4-triazole), and tetrazole.
  • pyrrolinole pyrazole, imidazole, triazole, thiazole, isooxazole, oxadiazole and thiadiazole.
  • substituents in the “optionally substituted aromatic ring” represented by the above ring A, etc. 1 to 3 (preferably 1) of these substituents may be substituted at any substitutable position.
  • substituent that the “5-membered nitrogen-containing aromatic heterocycle” may have,
  • Alkyl group (the C ⁇ alkyl group, a halogen atom, arsenic Dorokishi, Cal Bamoinore, carboxyl, optionally phenyl optionally halogenated, C physician 4 Anoreko carboxymethyl Ichiriki Noreboninore, Surufamoinore, Sunoreho group may be Harogenihi C !: 4 alkoxy, Benjiruokishi, Amino, mono- one or di- one 4 Arukirua amino, C 1 - 6 alk Noi Rua amino, may be halogenated - 4 alkyl Chio, C doctor 4 Arukirusu be halogenated / Refinyl, optionally substituted with C 1-4 alkylsulfonyl which may be halogenated),
  • An optionally halogenated file;-and the like are preferable.
  • Ring B may be bonded to ring C and X at any substitutable position of the “5-membered nitrogen-containing aromatic heterocycle”:
  • R 1 represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an acyl group
  • R 2 and R 3 each independently represents a hydrogen atom, a halogen atom
  • Atom eg, fluorine, chlorine, bromine, iodine
  • X is as defined above. .
  • An optionally substituted hydrocarbon group represented by R 1 includes an optionally substituted aromatic ring in the “optionally substituted aromatic ring” represented by ring A. And the same groups as the “optionally substituted hydrocarbon group”. ..
  • the aromatic ring in the “optionally substituted aromatic ring” represented by ring A may be substituted.
  • Examples thereof include the same groups as the “optionally substituted heterocyclic group”.
  • the “acyl group” represented by R 1 is a substituent that the aromatic ring in the “optionally substituted aromatic ring” represented by ring A.
  • the group of the visitor is mentioned.
  • C ⁇ 6 alkyl group (the C 6 alkyl group is a halogen atom, hydroxy, strong rubamoyl, carboxyl, phenyl, optionally substituted phenyl, C 4 alkoxycarboninole, snolefa Moinole, Snorejo group, optionally halogenated C ⁇ 4 alkoxy, benzyloxy, amino, mono- or di C 1-4 alkylamino, C 6 alkanoylamino, optionally halogenated C 1 -4 alkylthio, optionally halogenated — optionally substituted with 4 alkylsulfinyl, optionally halogenated Ci-4 alkylsulfonyl, etc.);
  • hydrogen atom hydrogen atom, halogen atom (fluorine atom, etc.), alkoxy Shi (methoxy, etc.)
  • C 6 alkyl groups such as methylethyl
  • monocarbonyl such as ethoxycarbonyl
  • R 3 is a ring
  • aromatic ring in the “optionally substituted V, aromatic ring” represented by A may have. . ..
  • the “optionally substituted silicon ring group” represented by R 2 , R 2 and R 3 may have an aromatic ring in the “optionally substituted aromatic ring” represented by ring A. V, the same as the “optionally substituted heterocyclic group” as the substituted S, and the like.
  • the ⁇ optionally substituted amino group '' may have an aromatic ring in the ⁇ optionally substituted aromatic ring '' represented by ring A. Examples of good substituents include “optionally substituted amino group” and the like.
  • the “optionally substituted hydroxy group” represented by R 2 and R 3 may have an aromatic ring in the “optionally substituted aromatic ring” represented by ring A. Examples thereof include the same groups as the “optionally substituted hydroxy group” as a substituent.
  • the aromatic ring in the “optionally substituted aromatic ring” represented by ring A may be substituted.
  • Examples of the group include the same groups as the “optionally esterified carboxyl group”.
  • the aromatic ring in the “optionally substituted aromatic ring” represented by ring A may be The same groups as the “optionally substituted rubamoyl group” in the above are listed.
  • acyl group represented by R 2 and R 3 is an “acyl group” as a substituent that the aromatic ring in the “optionally substituted aromatic ring” represented by ring A may have. And the like groups.
  • R 2 and R 3 are each preferably a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, or the like.
  • An alkyl group (the C 1-6 alkyl group is a halo-gen atom, a hydroxy, a strong ruby moinole, a carboxyl, an optionally halogenated file, a C 4 alkoxy;
  • Alkylamino, C! -E ar canylamino, optionally halogenated C 1-4 alkylthio, optionally halogenated C 4 alkylsulfiel, optionally substituted with Ci-4 alkylsulfonyl, etc.).
  • Y represents an optionally substituted imino group, O— or one S (0) n— (n represents 0, 1, or 2).
  • the “optionally substituted imino group” represented by Y is represented by the formula: 1 N (R 4 ) 1 (wherein R 4 is a hydrogen atom, an optionally substituted hydrocarbon group, a substituted And a divalent group represented by the following: a preferable heterocyclic group, an optionally esterified carboxyl group, an optionally substituted rubamoyl group or an acyl group.
  • the aromatic ring in the “optionally substituted aromatic ring” represented by ring A is an optionally substituted aromatic ring. And the same groups as the “optionally substituted hydrocarbon group”. .
  • the “optionally substituted heterocyclic group” represented by R 4 the “optionally substituted aromatic ring” represented by ring A as “the optionally substituted aromatic ring” Examples thereof include the same groups as the “optionally substituted heterocyclic group”.
  • Examples of the “optionally esterified carboxyl group” represented by R 4 include a ring The same as the “optionally esterified carboxyl group” as the i substituent which the aromatic ring in the “optionally substituted aromatic ring” represented by ⁇ ⁇ And the like. ⁇ ——
  • R 4 is represented by ring A.
  • the aromatic ring in the “optionally substituted aromatic ring” may have And the like and the same group as the “optionally substituted rubamoyl group”.
  • R 4 is an “acyl group”, and is represented by ring A. “An acyl group in the aromatic ring that may be substituted” The same as above. .
  • the Y, optionally substituted Imino group (e.g., formula: _N (R) - is a group represented by) are preferred, among them, C - 4 Argyle groups are substitution with C 1-4 alkoxy ⁇ group May be phenyl group, rubamoyl group, norogenated,
  • An imino group optionally substituted by a C 2 L 8 arnoyl group, a benzoyl group or the like ie,
  • R 4 forces a hydrogen atom, d-4 alkyl group, alkoxy Hue Le group have be substituted with a group, the force Rubamoiru group, optionally halogenated and C 2 - 8
  • An alkanoyl group, a benzoyl group, and the like are more preferable, and R 4 , a hydrogen atom, and a 4- alkyl group are particularly preferable. Above all, R 4 .
  • Y is a substituted imi / group
  • the substituent of the imino group and the substituent of the “aromatic ring” in ring A may be combined to form a ring (eg, tetrahydroquinoline).
  • ring C represents an optionally substituted nitrogen-containing aromatic heterocycle.
  • Containing 8 to 16 members such as 2,4-triazolo [4,3-a] pyridine, 1,2,4-triazolo [4,3-, b] pyridazine, etc.
  • Examples thereof include nitrogen-aromatic fused complex rings, and 5 to 6-membered nitrogen-containing nitrogen-containing aromatic monocyclic heterocycles are preferable.
  • Examples of the substituent that the nitrogen-containing aromatic heterocyclic ring may have include the same groups as the substituent in the “optionally substituted aromatic ring” represented by the ring A described above. These substituents may be substituted at any substitutable position by 1 to 4 (preferably 1 or 2 are preferred).
  • substituent that the “nitrogen-containing aromatic heterogeneous prefecture” may have,
  • C, _ 6 alkyl group (the C t _ 6 alkyl group, a halogen atom, arsenic Dorokishi group, may be substituted by Cal Bamoiruokishi group);
  • Mono- or di-C ⁇ alkylamino group (the alkyl group, halogen atom, be halogenation C -! 6 alkoxy, optionally Nono halogenated C 6 alkylthio, phenyl (Fu, enyl may be substituted with a halogon atom, no, C ⁇ alkyl which may be genated, C 1-6 alkoxy which may be optionally halogenated, etc.), May be substituted with a substituent selected from C 3 10 ⁇ chloroalkyl);
  • Benzoylamino group which may be halogenated; Phenylorecetinoleamino group;
  • Aromatic heterocycles preferably thiophene—forced ruby groups
  • ring C when the “nitrogen-containing aromatic heterocycle” in the “optionally substituted nitrogen-containing aromatic heterocycle” represented by ring C has two or more substituents adjacent to each other, the substituents are bonded to each other.
  • ring e.g., cyclopentane, cyclohexane, C 4 cycloheptane, etc. - 8 cycloalkane ring, a benzene ring
  • ring e.g., cyclopentane, cyclohexane, C 4 cycloheptane, etc. - 8 cycloalkane ring, a benzene ring
  • ring. May be bonded to ring B at any substitutable position of the “nitrogen-containing aromatic heterocycle”, and in particular, is bonded to ring B at a constituent carbon atom of the “nitrogen-containing aromatic heterocycle”. It is preferable.
  • Ring C is preferably an optionally substituted pyridine ring, an optionally substituted pyrimidine ring, or an optionally substituted thiadiazole ring.
  • each of ring C ′ and ring C ′′ may have include the same groups as the substituent S that ring C may have:
  • the nitrogen atom constituting the pyridine ring may be oxidized and tau. .
  • R i represents a hydrogen atom, an optionally substituted alkyl group, an alkoxy group, a benzyloxy group, an alkylthio group, a sulfamoyl group, a halogen ⁇ atom, a nitro group, a cyano group, or an N-monosubstituted optionally substituted rubermoyl group.
  • alkyl group” in the “optionally substituted alkyl group” of C include, for example, C, ⁇ alkyl groups (preferably C 1-4 alkyl, etc.) such as methyl, ethyl, ⁇ -propyl, isopropyl, etc. Can be mentioned.
  • alkoxy group for example, main butoxy, etc. ⁇ I 4 ⁇ alkoxy groups ethoxy, and the like.
  • alkylthio group for example methylthio, C 1 such Echiruchio - like 4 ⁇ alkylthio group.
  • halogen atom examples include fluorine, chlorine, bromine, and iodine.
  • substituent of the “optionally substituted alkyl group” for R t include fluorine, Halogen atoms such as chlorine, bromine and iodine. .
  • Examples of the convertible group of “N-mono-substituted rubamoyl 3 ⁇ 4” of R t include, for example, a C 1-6 ′ alkyl group, a phenyl group, a pyridyl group and the like which may be substituted with a morpholino group. Can be mentioned.
  • the substituent of the “optionally substituted phenoxy group” in C may be a C 6 alkyl group, a halogen atom, a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), C ⁇ 4 alkoxy groups (for example: methoxy, edoxy, etc.) and the like. ',
  • an optionally esterified carboxyl group includes a free carboxyl group, for example, An alkoxycarbonyl group etc. are mentioned.
  • Ri is preferably a naroxy group, and most preferably a methoxy group.
  • the compounds of formula (I I) include 2 — [(3-methoxyphenyl) amino] — N ′
  • the GRK inhibitor used in the present invention in addition to the compound of the above formula (I) or the formula ( ⁇ I), for example, 3-amino-1-((4-monophenyl) amino] — 1— (3-morpholino 1 H—1, 2, 4—triazole 1-5-inole) Propane is preferred.
  • the salt of the compound (I) or (II) include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. Can be mentioned. Of these, pharmaceutically acceptable salts are preferred.
  • an alkali metal salt eg, sodium salt, strong rhodium salt, etc.
  • an alkaline earth metal salt eg, calcium salt, magnesium salt, barium
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. . salts or acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid,;:.
  • Compound (I) or ( ⁇ ) may be used as a prodrug.
  • Compounds ⁇ Prodrugs such as (I) or ( ⁇ ) are compounds that convert to compounds (I) or (II) by reaction with enzymes, gastric acid, etc. under physiological conditions in vivo, ie enzymatically oxidized , A compound that undergoes reduction, hydrolysis, etc. and changes to a compound (I) or ( ⁇ ), etc., or a compound that undergoes hydrolysis or the like by gastric acid ⁇ and changes to a ⁇ compound (I) or ( ⁇ ), etc.
  • the pharmacologically acceptable carrier is used alone or in accordance with conventional methods (for example, the method described in the Japanese Pharmacopoeia).
  • tablets including sugar-coated tablets, film-coating tablets
  • powders granules, capsules, liquids, emulsions, suspensions, injections, suppositories, sustained-release agents, As a patch, etc.
  • it can be safely administered orally or parenterally (eg, topical, rectal, intravenous administration, continuous intravenous administration, etc.).
  • the content of the GRK inhibitor in the pharmaceutical composition is about 0.01 to 11% by weight of the total composition, preferably about 2 to 8.5% by weight.
  • the dose of GRK inhibitor varies depending on the subject of administration, administration route, disease, etc.
  • a GRK inhibitor that is an active ingredient.
  • 1 to 1 00 Omg preferably about 3 to 300 mg, More preferably, it is about 10 to 2 , 0 O rag and can be administered in 1 to several times. These can be adjusted appropriately according to the strength of action and the molecular weight of the GRK inhibitor used. ',
  • the “cardiotonic drug containing a GRK inhibitor” of the present invention is a drug that is usually used for the treatment of heart failure, for example, digitalis, catecholamine (eg, dobutamine, 'nomin, denopamine, zamoterol, etc.) ,] 3 blockers (pisoprolol, carbegi, rolls, etc.), nitrates (nitronitroserine, etc.), seven doraradi, Ca antagonists (Am mouth dipine, etc.), ACE inhibitors (enalapril, etc.), Al antagonists (force) Ndesartan, etc.), diuretics (such as larosemide), PDE-inhibited cold (such as milrinone), Ca sensitizers (such as pimobendan), thrombolytic agents (such as t-PA), anticoagulants (heparin,. ⁇ Rufaline, etc.), anti-blood platelets (aspirin, etc.), antiarrhythmic drugs (amiodarone, etc, etc
  • the “cardiotonic drug containing a GRK inhibitor” of the present invention can be used in combination with a biologic (eg, antibody, vaccine preparation, etc.) when applied to each of the above diseases. It can also be applied as a combination therapy in combination with gene therapy.
  • a biologic eg, antibody, vaccine preparation, etc.
  • antibodies and vaccine preparations include vaccine preparations against angiotensin II, vaccine preparations against CETP, CETP antibodies, antibodies against TNFa antibodies and other site-in, amyloid] 3 vaccine preparations, type 1 diabetes vaccines ( In addition to Peptor's DIAPEP-277, etc.), site-in, renin angiotensin-based enzymes and their products or vaccines, enzymes involved in blood lipid metabolism Antibodies or mactin preparations for proteins, coagulation in blood, antibodies or vaccines for enzymes and proteins that contribute to the lysis system, antibodies to vaccines involved in glucose metabolism resistance, vaccine preparations, etc.
  • gene therapy methods include, for example, site force-in, renici 'angiotensin enzymes and their related products: gene therapy, ⁇ receptor: signal transmission such as duty cycle.
  • treatment using genes related to the system treatment using genes related to j3 ARKct, / 3 arrestin, etc.6, treatment using DNA decoys such as NF KB decoy, treatment using antisense,
  • DNA decoys such as NF KB decoy
  • Treatment using antisense Related to enzymes and proteins involved in blood lipid metabolism: for example, cholesterol or triglyceride or HDL-cholesterol Genes related to metabolism, excretion, and absorption of blood phospholipids). Enzymes and proteins involved in angiogenesis therapy for treatment, peripheral ductal obstruction, etc.
  • HGF vascular endothelial growth factor
  • VEGF vascular endothelial growth factor
  • various organ regeneration methods such as heart regeneration, kidney regeneration, sputum regeneration, and blood vessel regeneration, bone marrow cells (bone marrow mononuclear cells, bone marrow stem cells, etc.) and other cells that have the ability to differentiate into muscle (embryonic stem cells, myoblasts) It can also be used in combination with blood vessel and myocardial neoplasia using cell transplantation.
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the compounding ratio of GRK inhibitor and concomitant drug is determined according to the subject of administration, administration route, It can be selected as appropriate depending on the condition, symptom, combination, etc.
  • the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the GRK inhibitor.
  • test compound (1) used in the pharmacological test is shown below. .3 — [[[[4-Methyl-5- (4-Pyridyl) 1 4 H— 1, 2, 4-Triazole 1 3 _yl] methyl] Amino] — N— [2— (Trifluoromethyl Benzile] benzamide; test compound (1)...
  • test compound (13) used in the pharmacological test is shown below.
  • test compound (14)-used in the pharmacological test is shown below.
  • (2S) -2-phenylamine 3_ [N_ (tert-butoxycanoleboninole) -N- (2-pyridylmethyl) amino] methyl propionate (1.5 g) in ethanol (5 OmL) After adding drazine monohydrate (1.8 mL) and heating to reflux for 24 hours, the solvent was distilled off under reduced pressure, and (2 S) — 2-phenylaminomino 3 _ [N- (tert-butoxycarbonyl ) 1 N- (2-Pyridylmethinole) amino] Propionic acid hydrazide was obtained as a colorless oil.
  • test food used in the pharmacological test is shown below.
  • the reaction mixture was diluted with ethyl acetate (200 mL), washed successively with water (100 mL) and saturated brine (100 mL), dried over magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • a solution of the residue and acetic acid (15 mL) in ethanol (15 OmL) was heated to reflux for 12 hours.
  • the reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure.
  • the organic layer was washed with saturated brine (8 OmL), dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • test compound (16) used in the pharmacological test is shown below.
  • the reaction solution was diluted with ethyl acetate (80 mL), washed with water (5.0 mL) and saturated brine (5 OmL), dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the residue was heated under reflux for 12 hours in a solution of acetic acid (2.5 mL) and ethanol (25 mL).
  • the reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure.
  • the residue was diluted with water (5 OmL), adjusted to pH 8 by adding saturated aqueous sodium hydrogen carbonate solution, and extracted with black mouth form (3 X 5 OmL).
  • the organic layer was washed with saturated brine (10 OmL), dried over magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • test compound (18) used in the pharmacological test is shown below.
  • test compound (19) used in the pharmacological test is shown below.
  • diammonium cerium nitrate (IV) 80 g
  • 80 ° C 80 ° C
  • diammonium cerium nitrate (IV) 40 g
  • the organic layer was combined and washed with saturated brine (250 mL), dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give crude 1, 2, 5-thiadiazole 3-carbaldehyde (4 3 g) was obtained as a brown liquid.
  • N, N ′ monocarbodidiimidazole (12.2 g) was added to a solution of the obtained residue in THF (5 OmL), and the mixture was stirred at 60 ° C. for 3 hours.
  • the reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure.
  • Water (5 OmL) was added to the residue, and the mixture was extracted with ethyl acetate (5 OmL).
  • the organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure.
  • the resulting residue (crude 1, 2, 5-thiadiazole _ 3-carbonitryl) was dissolved in ethanol (5 OmL) and anhydrous hydrazine. (3.6 g) was added and the mixture was stirred at 60 ° C. for 3 hours.
  • the reaction solution is cooled to room temperature, and the resulting crystals are collected by filtration and washed with ethanol (5 mL). After purification, it was dried under reduced pressure to obtain 2.1 g (yield 21 ° / 0 ) of the title compound as pale yellow crystals. .. ..
  • Enzyme inhibitory activity against GRK2 was measured using tubulin as a substrate with reference to a report by Pitcher et al. (Journal 'Ob' Biological Chemistry, Vol. 273, pages 12316-12324). 0.15 / ⁇ purified ushi GRK2, 0.9 ⁇ M purified ushi tubulin, 0.5 ⁇ ⁇ (including 0.1 / iCi [ ⁇ - 32 P] ATP), 2 mM EDTA, lOraM MgCl 2 , A test compound of an appropriate concentration is added to 20 mM Tris-HCl (pH 7.5) containing ImM DTT to make a 25 L mixed solution, which is reacted at 30 ° (:, 1 hour.
  • TCA mouth acetic acid solution
  • the enzyme inhibitory activity against PKCc, PKA, and ROKa is 6 ⁇ g / mL purified human PKCa or 8 / g / m purified Ushi PKA catalyst subunit, or 0., 4 U / mL of purified rat ROKa was measured in the same manner as described above using 20 ⁇ g / mL purified ushimyelin basic protein as a substrate. The results are shown in Table 1.
  • the human i receptor to prepare a high expression was membrane preparation from Rex 16 cells, 5QmM containing Asukorubin acid 1.4 mM, 0.001% of ⁇ shea serum albumin, 1.5 mM CaCl 2, 5 m EDTA and 120 mM NaCl Tris- Incubate with 0.03 nM 125 1-Cyanopindolol in HC1 (pH 7.4) for 2 hours at 25 ° C. I did.
  • test compound (1) was dissolved in DMS0 (final concentration 1%) and added to a final concentration of 10 / ⁇ . After incubation, the reaction solution was filtered through a GF / B filter, and the radioactivity on the filter was measured using an inversion counter. Nonspecific binding was defined as the amount of binding in the presence of 100 / i M S (-) -Propranolol, and the inhibition rate for the specific binding amount in the absence of 5 test compounds was determined. ⁇ 2 receptor, receptor, D 21 _ receptor, D 2 S receptor, D 3 receptor, D receptor, ET A receptor, ET B .receptor .., affinity for CaCh and NaCh It measured by the method of.
  • the source of the specimen is human j3 2> D or D 2 D 2 S , D 3 , D 5 , ⁇ ⁇ ′, and CH0 cells or rat cerebrum highly expressing ET B receptors. And NaCh), and the label ligand is 0.2 nM 3 H- CGP-12177 (] 3 2 ), 1.4 nM 3 H-SCH-23390 (Dj) ⁇ 0. 16n 3H-Spiperone (D 2 2 S ), .0.7 nM 3 H Spiperone '(D 3 ), 2 nM 3 H-SCH-23390 (D 5 ), 0.03 nM 125 I-Endothelin-l (ET A ), 0.
  • InM 125 1 Endothelin-1 (ET B ), 2 nM 3H-: Diltiazem (CaCh) and 5riM 3H-Batrachotoxin (NaCh) were used. Incubation conditions were 25 ° C for 1 hour, (] 3 2 ), 37 ° C for 2 hours (D D D 5 , 5 ET A ), 25 ° C 2 h (D 2 D D 2 S , .ET B ), 4 ° C for 3 hours (CaCh) and 37 ° C for 1 hour (NaCh). Furthermore, non-specific binding is 10 / iM.
  • test compound (1) for adrenergic receptor, dopamine receptor ⁇ : and endoserine receptor
  • test compound (1) has no affinity for various receptors and ion channels involved in myocardial contractility.
  • Test example 3
  • test compound (1) was dissolved in DMS0 (final concentration 1%) and added to a final concentration of ⁇ .
  • Test compound (1) was dissolved in DMS0 (final concentration 1%) and added to a final concentration of 10 ⁇ . After the reaction time of 20 minutes, stop the reaction by heating at 100 ° C for 2 minutes, add snake venom, and incubate at 37 ° C for 10 minutes. Converted to 3H-Adenosine After removing unreacted cAMP with AG1 2 resin, the radioactivity in the reaction solution was measured, and the enzyme activity in the absence of the test compound was used as an index of enzyme activity. The inhibitory rate of the compound was calculated with PED4 and PDE5 as the enzyme source, and the enzyme source was hydrated U931 cells (PDE4) and human platelets (PDE5). Was measured in the same manner using 3 ⁇ -cGMP containing 3H-cGMP instead of 3H-cAMP / cAMP.
  • test compound (1) has no enzyme inhibitory activity against Na / K-ATPase and PDE involved in myocardial contractility.
  • Test example 4
  • HEK-B2 cells suspended in D_PBS (+) solution containing 3 -isobutyl-1-methyl-xantine (IBMX, ImM) and L-ascorbic acid (0.01%). Compounds were added and incubated at 37 ° C for 20 minutes. Then, add enough isoproterenol ⁇ ( ⁇ ) to induce a / 3 receptor desensitization reaction and incubate at 37 ° C for 20 minutes. Induced (Atsusy capacity 20 / L). The cAMP production reaction was stopped by adding the same volume of Tris-EDTA buffer (pH 8.0) and heating at 95 ° C.
  • Tris-EDTA buffer pH 8.0
  • the amount of cAMP produced was measured using an ALPHA-Screen cAMP detection kit (Perkin Elma). As a control, the same reaction was carried out by adding only the solvent (N, dimethylformamide, final concentration 0.3%) without ⁇ S test compound. The results are shown by normalizing the amount of cAMP accumulated with the amount of cAMP accumulated in the absence of the compound as 100%. The results are shown in Table 4.
  • test compound () shows concentration-dependent cAMP accumulation enhancing action, that is, for GRK inhibition, by extracellular application.
  • Test example 5
  • Test Example 4 To confirm that the inhibitory effect of the receptor desensitization by GRK inhibition of the test compound (1) confirmed in Test Example 4 also occurs at the heart organ level. The following experiment was conducted using this.
  • lysis buffer 25 raM Tris-HC1, 5 mM EDTA, 5 mM EGTA, pH 7.4 at 37 ° C
  • homogenize and centrifuge at 500 xg to obtain the nuclear fraction.
  • the supernatant obtained was centrifuged at 40,000 xg to precipitate the membrane fraction.
  • the obtained membrane fraction was resuspended in a binding buffer (75 mM Tris-HC1, 12.5 mM MgCl 2 , 2 raM EDTA, pH 7.4 at 37 ° C.).
  • Receptor reactivity of membrane specimens was measured using isoproterenol-dependent adenylate cyclase (AC) activity as an indicator.
  • AC isoproterenol-dependent adenylate cyclase
  • Add 0.12 mM ATP in the presence of sodium (NaF) CAMP was produced by incubation at 37 ° C.
  • the reaction was stopped by the addition of triclomouth oxalate, and after deproteinization and TCA removal, the cAMP produced was measured using the ALPHA-Screen cAMP detection kit.
  • the results were normalized with the amount of cAMP obtained in the presence of NaF as 100%, and are shown as the mean value and standard error of 8 cases. The results are shown in Table 5. ;
  • the reduction in receptor responsiveness (desensitization) caused by the application of high-concentration isoproterenol in rat isolated perfused heart specimens was 10 / M Was significantly inhibited by pretreatment with the test compound (1). This indicates that the inhibitory action of the 3 receptor desensitization by GRK inhibition of the test compound (1) confirmed in Test Example 4 occurs at the heart level.
  • test compound (1) In order to observe the effect of acute GRK inhibition using test compound (1) on the contractility of isolated perfused heart specimens, the following experiment was conducted.
  • the heart rate was measured from the left ventricular pressure using a tachometer (Nihon Kohden). After the stabilization period, the compound dissolved in N, N-dimethylformamide (1): was applied to the perfusate mixed at a rate of 0.1%. After 15 minutes of drug perfusion, isoproterenol InM dissolved in distillate was simultaneously perfused for 15 minutes to investigate the action of compound (1) in the presence of catecholamine. As a control, only the solvent was perfused for 15 minutes, and then the same observation was performed using InM isoproterenol for 15 minutes.
  • Test compound (1) 10 W M 45% 97% 2% 35%
  • Table 6 the cardiac contractile force depending on the compound concentration is shown by selective inhibition of cardiac GRK by test compound (1). It has been clarified that the potentiating effect appears immediately after drug administration, and that the effect increases in the presence of catecholamine. The working concentration of test compound (1) was not inconsistent with the effective concentration of GRK inhibitory action obtained in the cell line. Interestingly, this potentiation of cardiac contractility by acute GRK inhibition was hardly accompanied by an increase in heart rate.
  • test compounds (1) port containing iN HC1, triethylene glycol (PEG) 400 And then diluted with physiological saline to make a lOmg / mL solution (final PEG concentration 30%, HC1 concentration 0.02N), and administered intravenously at a dose of lmg / kg / min for 30 minutes. Cardiovascular changes were recorded until 20 minutes after the end of administration. In the control group, a compound-free solvent ( 30 % PEG / HC1 / saline) was administered in the same manner.
  • the data obtained in Fig. 1 is shown as the average change rate and standard error of the 4 cases as the rate of change from the value before starting drug administration. As shown in Fig.
  • the unit is nM (where ND indicates no data).
  • Test compounds (2) to (20) used in Test Example 8 were almost the same as Test Example 7. In the same way, an experiment was conducted to evaluate the strong effect of cardiac contraction force it in anesthetized rats. Each test compound was dissolved in polyethylene glycol (PEG) 400. containing IN HC1 and then diluted with physiological saline (final PEG concentration 30%, HC1 concentration. 0.02-0., 04N). Intravenous administration (ImL / kg): The results are shown in Table 8. The effect of enhancing cardiac contraction force in the table is the maximum LVdP / dt ra ax after each test compound administration when the maximum left ventricular pressure first derivative value (LVdP / d) immediately before the test compound administration is taken as the reference (100%). The amount of change (%) is shown. ;;;;
  • a cardiotonic drug containing a GRK inhibitor can be implemented, for example, in the form of a pharmaceutical group ⁇ 3 ⁇ 4 having the following specific formulation (however, Not limited).
  • components (additives) other than the active ingredient may be those listed in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Pharmaceutical Standards or the Pharmaceutical Additives Standard, etc. '
  • a GRK inhibitor has an excellent cardiotonic effect.
  • the agent of the present invention comprising a GRK inhibitor is useful as a cardiotonic drug,
  • the utility value in the field of industry is extremely high.

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Abstract

La présente invention concerne un agent tonicardiaque (médicament permettant d'améliorer la contraction cardiaque aiguë) innovant qui comprend un composé ayant un effet inhibiteur sur la kinase du récepteur couplé à la protéine G (G protein-coupled receptor kinase ; GRK), son promédicament ou un de ses sels (inhibiteur de la GRK).
PCT/JP2006/318666 2005-09-22 2006-09-14 Agent tonicardiaque comprenant un inhibiteur de la grk WO2007034846A1 (fr)

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US8067448B2 (en) 2008-02-22 2011-11-29 Radius Health, Inc. Selective androgen receptor modulators
US8268872B2 (en) 2008-02-22 2012-09-18 Radius Health, Inc. Selective androgen receptor modulators
US8642632B2 (en) 2010-07-02 2014-02-04 Radius Health, Inc. Selective androgen receptor modulators
US8987319B2 (en) 2010-02-04 2015-03-24 Radius Health, Inc. Selective androgen receptor modulators
US9133182B2 (en) 2010-09-28 2015-09-15 Radius Health, Inc. Selective androgen receptor modulators
WO2016210403A1 (fr) 2015-06-26 2016-12-29 The Regents Of The University Of Michigan Inhibiteurs de la kinase du récepteur couplé aux protéines g et méthodes d'utilisation de ceux-ci
US9555014B2 (en) 2010-05-12 2017-01-31 Radius Health, Inc. Therapeutic regimens
US10023564B2 (en) 2014-08-08 2018-07-17 The Regents Of The University Of Michigan G protein-coupled receptor kinase 2 inhibitors and methods for use of the same
WO2018130537A1 (fr) 2017-01-10 2018-07-19 ETH Zürich Composés protecteurs de cellules et leur utilisation
US10071066B2 (en) 2014-03-28 2018-09-11 Duke University Method of treating cancer using selective estrogen receptor modulators
US10385008B2 (en) 2017-01-05 2019-08-20 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCL
US10420734B2 (en) 2014-03-28 2019-09-24 Duke University Method of treating cancer using selective estrogen receptor modulators
US11578066B1 (en) 2019-12-20 2023-02-14 Tenaya Therapeutics, Inc. Fluoroalkyl-oxadiazoles and uses thereof
US11643385B2 (en) 2018-07-04 2023-05-09 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCl
US11771682B2 (en) 2016-06-22 2023-10-03 Ellipses Pharma Ltd. AR+ breast cancer treatment methods
US11819480B2 (en) 2015-04-29 2023-11-21 Radius Pharmaceuticals, Inc. Methods for treating cancer
EP4161917A4 (fr) * 2020-05-27 2024-08-28 Sonata Therapeutics, Inc. Inhibiteurs de grk2 et leurs utilisations
US12201617B2 (en) 2021-05-04 2025-01-21 Tenaya Therapeutics, Inc. HDAC6 inhibitors for treatment of metabolic disease and HFpEF

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US8268872B2 (en) 2008-02-22 2012-09-18 Radius Health, Inc. Selective androgen receptor modulators
US8455525B2 (en) 2008-02-22 2013-06-04 Radius Health, Inc. Selective androgen receptor modulators
US8629167B2 (en) 2008-02-22 2014-01-14 Radius Health, Inc. Selective androgen receptor modulators
US8067448B2 (en) 2008-02-22 2011-11-29 Radius Health, Inc. Selective androgen receptor modulators
US8987319B2 (en) 2010-02-04 2015-03-24 Radius Health, Inc. Selective androgen receptor modulators
US9555014B2 (en) 2010-05-12 2017-01-31 Radius Health, Inc. Therapeutic regimens
US8642632B2 (en) 2010-07-02 2014-02-04 Radius Health, Inc. Selective androgen receptor modulators
US9920044B2 (en) 2010-09-28 2018-03-20 Radius Pharmaceuticals, Inc. Selective androgen receptor modulators
US9133182B2 (en) 2010-09-28 2015-09-15 Radius Health, Inc. Selective androgen receptor modulators
US11951080B2 (en) 2014-03-28 2024-04-09 Duke University Method of treating cancer using selective estrogen receptor modulators
US10071066B2 (en) 2014-03-28 2018-09-11 Duke University Method of treating cancer using selective estrogen receptor modulators
US12263142B2 (en) 2014-03-28 2025-04-01 Duke University Method of treating cancer using selective estrogen receptor modulators
US10420734B2 (en) 2014-03-28 2019-09-24 Duke University Method of treating cancer using selective estrogen receptor modulators
US11779552B2 (en) 2014-03-28 2023-10-10 Duke University Method of treating cancer using selective estrogen receptor modulators
US10023564B2 (en) 2014-08-08 2018-07-17 The Regents Of The University Of Michigan G protein-coupled receptor kinase 2 inhibitors and methods for use of the same
US12263141B2 (en) 2015-04-29 2025-04-01 Radius Pharmaceuticals, Inc. Methods for treating cancer
US11819480B2 (en) 2015-04-29 2023-11-21 Radius Pharmaceuticals, Inc. Methods for treating cancer
US10329283B2 (en) 2015-06-26 2019-06-25 The Regents Of The University Of Michigan G protein-coupled receptor kinase inhibitors and methods for use of the same
WO2016210403A1 (fr) 2015-06-26 2016-12-29 The Regents Of The University Of Michigan Inhibiteurs de la kinase du récepteur couplé aux protéines g et méthodes d'utilisation de ceux-ci
US11771682B2 (en) 2016-06-22 2023-10-03 Ellipses Pharma Ltd. AR+ breast cancer treatment methods
US12329746B2 (en) 2016-06-22 2025-06-17 Ellipses Pharma Ltd AR+breast cancer treatment methods
US11708318B2 (en) 2017-01-05 2023-07-25 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCL
US10385008B2 (en) 2017-01-05 2019-08-20 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCL
US12398094B2 (en) 2017-01-05 2025-08-26 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCL
US11628159B2 (en) 2017-01-10 2023-04-18 Eth Zurich Cell-protective compounds and their use
WO2018130537A1 (fr) 2017-01-10 2018-07-19 ETH Zürich Composés protecteurs de cellules et leur utilisation
US11643385B2 (en) 2018-07-04 2023-05-09 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCl
US11926622B2 (en) 2019-12-20 2024-03-12 Tenaya Therapeutics, Inc. Fluoroalkyl-oxadiazoles and uses thereof
US11578066B1 (en) 2019-12-20 2023-02-14 Tenaya Therapeutics, Inc. Fluoroalkyl-oxadiazoles and uses thereof
US12312345B2 (en) 2019-12-20 2025-05-27 Tenaya Therapeutics, Inc. Fluoroalkyl-oxadiazoles and uses thereof
EP4161917A4 (fr) * 2020-05-27 2024-08-28 Sonata Therapeutics, Inc. Inhibiteurs de grk2 et leurs utilisations
US12201617B2 (en) 2021-05-04 2025-01-21 Tenaya Therapeutics, Inc. HDAC6 inhibitors for treatment of metabolic disease and HFpEF

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