JP7323913B2 - Heterocyclic compounds that are sleep-inducing agents - Google Patents

Description

The present invention relates to heterocyclic compounds that are positive allosteric modulators of adenosine _A2A receptors and useful as sleep-inducing agents. More particularly, the present invention relates to a sleep-inducing agent capable of providing slow-wave sleep that gives particularly deep sleep.

Insomnia is one of the most common sleep disorders, with an estimated prevalence of 10-15% in the general population and 30-60% in the elderly population. The most widely prescribed drugs for the treatment of insomnia are central nervous system antidepressants that enhance signaling of the inhibitory neurotransmitter gamma-aminobutyric acid, known as benzodiazepines (BDZs) and non-BDZs. is. However, these medications suffer from a wide range of side effects, including muscle relaxation, rebound insomnia, appetite changes, next day sedation, cognitive impairment, amnesic effects, and the development of drug tolerance and dependence. Also, orexin receptor antagonists have recently been developed and approved as therapeutic agents for insomnia (Non-Patent Document 1). However, the main problem with these drugs is next morning drowsiness with possible signs of muscle weakness, strange dreams, sleepwalking, other nocturnal behaviors or suicidal thoughts (2). In addition, orexin receptor antagonists mostly work by preventing awakening from sleep, and are therefore less effective for those who have trouble falling asleep.

CGS21680, a highly selective adenosine _A2A receptor ( _A2AR ) agonist, significantly increases sleep after injection into the rostral ventral subarachnoid space of the basal forebrain in rats or the lateral ventricle of mice. (Non-Patent Document 3; Non-Patent Document 4; Non-Patent Document 5). However, it is generally believed that administration of _A2A R agonists has no clinical potential to treat sleep disorders due to cardiovascular effects such as hypotension and tachycardia (6). Because the action of _A2A R allosteric modulators is limited to when adenosine is released and adenosine levels in the brain rise during wakefulness, in contrast to orthosteric _A2A R agonists, allosteric _A2A R modulation is associated with insomnia. It may be an alternative strategy for disease treatment (Non-Patent Document 7).

Patent Document 1 describes a method for treating or preventing septic shock, comprising administering a MEK inhibitor represented by the following formula to a patient.

(In the formula, each symbol is as described in the literature.)
Patent document 1 also specifically describes the following compound (compound X).

Patent Document 2 describes a compound represented by the following formula, which is a MEK inhibitor and useful for treating cancer, restenosis, psoriasis, atherosclerosis, and the like.

(In the formula, each symbol is as described in the literature.)
Patent Document 2 also specifically describes the following compound (compound Y), which is an intermediate of the above compound.

WO 98/37881 WO 02/06213

Cox et al, 2010, J Med Chem 53: 5320-5332. Jacobson et al, 2014, Expert Rev Clin Pharmacol 7: 711-730 Satoh et al, 1999, Eur J Neurosci 11: 1587-1597 Scammell et al, 2001, Neuroscience 107: 653-663 Urade et al, 2003, Neurology 61: S94-96 Lera Ruiz et al, 2014, J Med Chem 57: 3623-3650 Porkka-Heiskanen et al, 1997, Science 276: 1265-1268

The present invention provides a sleep-inducing agent, particularly a sleep-inducing agent that does not have side effects such as muscle relaxation, rebound insomnia, appetite changes, next-day sedation, cognitive impairment, amnestic effects, and development of drug tolerance and dependence. An object of the present invention is to provide a positive allosteric modulator (PAM) targeting the adenosine _A2A receptor, which is useful as a sleep-inducing agent capable of providing wave sleep.

In order to solve the above problems, the present inventors have conducted exploratory research on positive allosteric modulators (PAMs) targeting adenosine _A2A receptors, and found adenosine _A2A R PAMs (hereinafter sometimes collectively referred to as _A2A R PAMs). A series of novel compounds represented by the following formula (I) or a salt thereof (hereinafter sometimes collectively referred to as compound (I)) useful as a compound), and the compounds X and Y above are A _2A (hereinafter, compound (I), compounds X and Y, and salts thereof may be collectively referred to as compound (Ia)), and administration of the compound has The inventors succeeded in inducing slow-wave sleep (SWS) without causing side effects such as vasoactivity, and completed the present invention.
That is, the present invention is as follows.

(1) the following formula (I):

(In the formula,
Ring A is a 5- or 6-membered aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from nitrogen and sulfur atoms as ring-constituting atoms other than carbon atoms, or benzene;
R ₁ is a carboxy group;
m R ₂ are each independently a halogen atom, an alkyl group, an alkoxy group, a nitro group, a cyano group, an aryl group, or a 5- or 6-membered aromatic heterocyclic group;
Ring B is a 5- or 6-membered aromatic ring;
n R ₃ are each independently a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a nitro group, a cyano group, or an aryl group;
m is 0, 1, or 2; and n is 1 or 2.
However, 1) when ring A is benzene, a group represented by the following partial structural formula:

is 2-carboxy-5,6-difluorophenyl and a group represented by the following partial structural formula:

is 3-fluoro-4-iodophenyl, 3-biphenyl, 4-bromophenyl, 2-iodophenyl, 2,5-difluorophenyl, 2-fluoro-5-chlorophenyl, 2-fluoro-5-methylphenyl, 2 -fluoro-5-bromophenyl, 2-fluoro-5-methoxyphenyl, 2-fluoro-4-methoxyphenyl, 4-ethynylphenyl, or 3-bromophenyl; or 2) ring A is benzene In some cases, a group represented by the following partial structural formula:

is 2-carboxyphenyl or 3-carboxyphenyl, and a group represented by the following partial structural formula:

is 4-propylphenyl. )
A compound represented by or a salt thereof.
(2) ring A is pyridine, thiophene, or benzene;
R ₁ is a carboxy group,
m R ₂ are each independently a 5- or 6-membered aromatic heteroatom containing 1 to 4 heteroatoms selected from nitrogen and sulfur atoms as ring-constituting atoms other than halogen atoms or carbon atoms is a cyclic group;
Ring B is benzene; and n R ₃ are each independently a halogen atom, C ₁ -C ₆ alkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, C ₁ The compound or salt thereof according to (1) above, which is a —C ₆ alkoxy group or a C ₆ -C ₁₀ aryl group.
(3) The compound or salt thereof according to (1) or (2) above, wherein ring A is pyridine or thiophene.
(4) ring A is pyridine or thiophene;
Ring B is benzene,
each of the n R ₃ is independently a halogen atom, a C ₁ -C ₆ alkyl group, or a phenyl; and
The compound or salt thereof according to (1) above, wherein m is 0.
(5) The compound or salt thereof according to (4) above, which is selected from the following group of compounds:

(Where nPr is propyl and Ph is phenyl.)
(6) The compound or salt thereof according to (1) or (2) above, wherein ring A is benzene.
(7) A medicament containing compound (I) or a pharmaceutically acceptable salt thereof according to (1) above as an active ingredient.
(8) Compound (I) or a pharmaceutically acceptable salt thereof according to (1) above, for use as a medicament.
(9) the following formula (Ia):

(In the formula,
Ring A is a 5- or 6-membered aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from nitrogen and sulfur atoms as ring-constituting atoms other than carbon atoms, or benzene;
R ₁ is a carboxy group;
m R ₂ are each independently a halogen atom, an alkyl group, an alkoxy group, a nitro group, a cyano group, an aryl group, or a 5- or 6-membered aromatic heterocyclic group;
Ring B is a 5- or 6-membered aromatic ring;
n R ₃ are each independently a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a nitro group, a cyano group, or an aryl group;
m is 0, 1, or 2; and n is 1 or 2.
However, 1) when ring A is benzene, a group represented by the following partial structural formula:

is 2-carboxy-5,6-difluorophenyl and a group represented by the following partial structural formula:

is 3-fluoro-4-iodophenyl, 3-biphenyl, 4-bromophenyl, 2-iodophenyl, 2,5-difluorophenyl, 2-fluoro-5-chlorophenyl, 2-fluoro-5-methylphenyl, 2 -fluoro-5-bromophenyl, 2-fluoro-5-methoxyphenyl, 2-fluoro-4-methoxyphenyl, 4-ethynylphenyl, 3-bromophenyl, 2-methyl-4-iodophenyl, or 2-fluoro- 4-bromophenyl; or 2) when ring A is benzene, a group represented by the following partial structural formula:

is 2-carboxyphenyl or 3-carboxyphenyl, and a group represented by the following partial structural formula:

is 4-propylphenyl. )
A medicament that is a positive allosteric modulator (PAM) targeting the adenosine _A2A receptor, comprising the compound represented by or a pharmaceutically acceptable salt thereof as an active ingredient.
(10) A pharmaceutical for inducing slow-wave sleep, containing the compound (Ia) defined in (9) above or a pharmaceutically acceptable salt thereof as an active ingredient.
(11) A medicament for preventing or treating insomnia, containing the compound (Ia) defined in (9) above or a pharmaceutically acceptable salt thereof as an active ingredient.
(12) A method of inducing slow-wave sleep in a mammal, comprising administering compound (Ia) defined in (9) above or a pharmaceutically acceptable salt thereof to a mammal in need thereof.
(13) A method for treating or preventing insomnia in a mammal, which comprises administering compound (Ia) defined in (9) above or a pharmaceutically acceptable salt thereof to a mammal in need thereof.
(14) A compound (Ia) as defined in (9) above, or a pharmaceutically acceptable salt thereof, for use in inducing slow-wave sleep in a mammal.
(15) Compound (Ia) as defined in (9) above or a pharmaceutically acceptable salt thereof for use in treating or preventing insomnia.

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide adenosine A _2a R PAM, which is useful as a sleep-inducing agent, particularly as a sleep-inducing agent capable of providing slow-wave sleep that gives a feeling of deep sleep.

Effect of YNT-2167 treatment on adenosine A _2A R activity in mouse A _2A R-expressing CHO cells (A) co-treatment of mouse A _2A R-expressing CHO cells with adenosine and YNT-378, YNT-2167 (B) mouse A _2A Adenosine treatment of R-expressing CHO cells alone or co-treatment with different concentrations of YNT-2167 Effect of intraperitoneal administration of YNT-2167 on slow wave sleep in mice Time course (A) and total amount (B) of SWS, REM sleep and wakefulness in mice after intraperitoneal administration of saline or YNT-2167

The present invention will be described below. Terms used herein have meanings commonly used in the art unless otherwise specified.

A "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

"Alkyl group" means a linear or branched alkyl group having 1 to 10, preferably 1 to 6 carbon atoms, specific examples of which are methyl, ethyl, n-propyl, isopropyl, n- Butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, 2-pentyl, 3-pentyl, n-hexyl, 2-hexyl and the like. The alkyl group may have a substituent.

"Alkenyl group" means a linear or branched alkenyl group having 2 to 10, preferably 2 to 6 carbon atoms, specific examples thereof being vinyl, allyl, isopropenyl, butenyl, isobutenyl, 2 -pentenyl, 3-hexenyl and the like. The alkenyl group may have a substituent.

The "alkynyl group" means a linear or branched alkynyl group having 2 to 10, preferably 2 to 6 carbon atoms, specific examples thereof being ethynyl, 1-propynyl, propargyl, 2-butynyl, 3-pentynyl, 5-hexynyl and the like. The alkynyl group may have a substituent.

"Aryl group" means an aryl group having 6 to 10 carbon atoms, and specific examples include phenyl and naphthyl groups. The aryl group may have a substituent.

"Alkoxy group" means a linear or branched alkoxy group having 1 to 10, preferably 1 to 6 carbon atoms, specific examples of which are methoxy, ethoxy, n-propoxy, isopropoxy, n -butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, tert-pentyloxy, neopentyloxy, 2-pentyloxy, 3-pentyloxy, n-hexyloxy, 2-hexyloxy etc. The alkoxy group may have a substituent.

Examples of "5- or 6-membered aromatic heterocyclic group" include pyrrolyl, pyrazolyl, imidazolyl, triazolyl (1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl), tetrazolyl , oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, furyl, thienyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and ring-constituting atoms other than carbon atoms are preferably selected from nitrogen and sulfur atoms. 5- or 6-membered aromatic heterocyclic groups containing 1 to 4 heteroatoms, more preferably pyridyl and thienyl.

Examples of the "5- or 6-membered aromatic ring" include benzene, pyrrole, pyrazole, imidazole, triazole (1,2,3-triazole, 1,2,4-triazole, 1,3,4-triazole), tetrazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, furan, thiophene, pyridine, pyridazine, pyrimidine, pyrazine, triazine and the like, preferably benzene.

Examples of the 5- or 6-membered aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from nitrogen and sulfur atoms as ring-constituting atoms other than carbon atoms include pyrrole, imidazole, triazole ((1, 2,3-triazole, 1,2,4-triazole, 1,3,4-triazole), tetrazole, thiazole, isothiazole, thiadiazole, thiophene, pyridine, pyridazine, pyrimidine, pyrazine, triazine and the like, preferably , a 5- or 6-membered aromatic heterocyclic ring containing 1 to 2 heteroatoms selected from nitrogen and sulfur atoms as ring-constituting atoms other than carbon atoms (e.g., pyrrole, pyrazole, imidazole, thiazole, isothiazole , thiophene, pyridine, pyridazine, pyrimidine, pyrazine), more preferably pyridine and thiophene.

Substituents that the "alkyl group", "alkenyl group", "alkynyl group", "aryl group" and "alkoxy group" may have include:
(1) a halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, iodine atom; preferably fluorine atom),
(2) a lower alkyl group optionally substituted with a halogen atom (e.g., C _1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.; ),
(3) cycloalkyl groups (e.g., C _3-6 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.),
(4) lower alkynyl groups (e.g., _C2-6 alkynyl groups such as ethynyl, 1-propynyl, propargyl, etc.),
(5) lower alkenyl groups (e.g., _C2-6 alkenyl groups such as vinyl, allyl, isopropenyl, butenyl, isobutenyl, etc.),
(6) an aralkyl group optionally substituted with a C _1-6 alkoxy group (e.g., methoxy) (e.g., C _7-12 aralkyl group such as benzyl, α-methylbenzyl, phenethyl, etc.),
(7) an aryl group (e.g., a C _6-10 aryl group such as phenyl, naphthyl, etc., preferably a phenyl group),
(8) lower alkoxy groups optionally substituted by halogen atoms (e.g., C _1-6 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, trifluoromethoxy etc),
(9) aryloxy groups (for example, C _6-10 aryloxy groups such as phenoxy, etc.),
(10) optionally substituted with a halogen atom, a formyl group or a lower alkanoyl group (e.g., C _1-6 alkyl-carbonyl groups such as acetyl, propionyl, butyryl, isobutyryl, etc., C _3-6 cyclocyclohexylcarbonyl, etc.) alkyl-carbonyl group, etc.),
(11) arylcarbonyl groups (e.g., C _6-10 aryl-carbonyl groups such as benzoyl, naphthoyl, etc.),
(12) a formyloxy group or a lower alkanoyloxy group (e.g., a C _1-6 alkyl-carbonyloxy group such as acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, etc.),
(13) arylcarbonyloxy groups (e.g., C _6-10 aryl-carbonyloxy groups such as benzoyloxy, naphthoyloxy, etc.),
(14) a carboxy group,
(15) lower alkoxycarbonyl groups (e.g., C _1-6 alkoxy-carbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, etc.),
(16) aralkyloxycarbonyl groups (for example, C _7-12 aralkyloxy-carbonyl groups such as benzyloxycarbonyl, etc.),
(17) a carbamoyl group,
(18) mono-, di- or tri-halogeno lower alkyl groups (for example, mono-, di- or tri-halogeno C ₁ such as chloromethyl, dichloromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, etc.) _-6 alkyl group, etc.),
(19) an oxo group,
(20) an amidino group,
(21) an imino group,
(22) an amino group,
(23) mono-lower alkylamino group (e.g., mono-C _1-6 alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.),
(24) a di-lower alkylamino group (e.g., a di-C _1-6 alkylamino group such as dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, N-ethyl-N-methylamino, etc.),
(25) optionally having a substituent, in addition to a carbon atom and one nitrogen atom, optionally containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom; 8-membered nitrogen-containing heterocyclic group (e.g., halogen atom, nitro group, cyano group, hydroxy group, optionally halogenated C _1-6 alkyl group, optionally halogenated C _1-6 alkoxy group , amino group, mono-C _1-6 alkylamino group, di-C _1-6 alkylamino group, carboxyl group, C _{1-6 alkyl-carbonyl group, C 1-6 alkoxy} -carbonyl group, carbamoyl group, mono- C _1-6 alkyl-carbamoyl group, di-C _1-6 alkyl-carbamoyl group, C _6-10 aryl-carbamoyl group, C _6-10 aryl group, C _6-10 aryloxy group, and halogenated optionally having 1 to 5 substituents selected from a C _1-6 alkyl-carbonylamino group, an oxo group, etc., in addition to a carbon atom and one nitrogen atom, a nitrogen atom, an oxygen atom and 3- to 8-membered nitrogen-containing heterocyclic group optionally containing 1 to 3 heteroatoms selected from sulfur atoms; for example, aziridinyl, azetidinyl, pyrrolidinyl, pyridyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, imidazolidinyl, piperidyl , oxadiazolyl, isoxazolyl, morpholinyl, dihydropyridyl, tetrahydropyridyl, piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, etc.),
(26) an alkylenedioxy group (for example, a C _1-3 alkylenedioxy group such as methylenedioxy, ethylenedioxy, etc.),
(27) a hydroxy group,
(28) a nitro group,
(29) a cyano group,
(30) a mercapto group,
(31) a sulfo group,
(32) a sulfino group,
(33) a phosphono group,
(34) a sulfamoyl group,
(35) mono-lower alkylsulfamoyl groups (e.g., N-methylsulfamoyl, N-ethylsulfamoyl, N-propylsulfamoyl, N-isopropylsulfamoyl, N-butylsulfamoyl, etc.) mono-C _1-6 alkylsulfamoyl group, etc.),
(36) di-lower alkylsulfamoyl groups (e.g., N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N,N-dipropylsulfamoyl, N,N-dibutylsulfamoyl, etc.) such as a di-C _1-6 alkylsulfamoyl group of
(37) lower alkylthio groups (e.g., C _1-6 alkylthio groups such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, etc.),
(38) arylthio groups (e.g., _C6-10 arylthio groups such as phenylthio, naphthylthio, etc.),
(39) lower alkylsulfinyl groups (e.g., C _1-6 alkylsulfinyl groups such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, etc.),
(40) an arylsulfinyl group (e.g., a C _6-10 arylsulfinyl group such as phenylsulfinyl, naphthylsulfinyl, etc.),
(41) lower alkylsulfonyl groups (e.g., C _1-6 alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, etc.),
(42) arylsulfonyl groups (e.g., C _6-10 arylsulfonyl groups such as phenylsulfonyl, naphthylsulfonyl, etc.),
(43) a group consisting of lower alkylcarbonylamino groups (e.g., C _1-6 alkylcarbonylamino groups such as methylcarbonylamino, etc.) (referred to herein as substituent group A);
(44) aralkylamino (e.g., C _7-12 aralkylamino such as benzylamino), and (45) a substituent (e.g., a C _1-6 alkyl group optionally substituted with a halogen atom) A substituent selected from an arylsulfonylamino group (e.g., a C _6-10 arylsulfonylamino group such as phenylsulfonylamino, naphthylsulfonylamino, etc.) (referred to herein as [substituent group A]) Used.

Compound (I) and compound (Ia) are described below. Unless otherwise specified, the definition of each group is the same as above.

Ring A may have substituents at substitutable positions in addition to R ₁ and m R ₂ s. Ring B may have substituents at substitutable positions in addition to n R ₃ s. Examples of the substituent that ring A and ring B may further have include those exemplified for [substituent group A] above.

The "5- or 6-membered aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from a nitrogen atom and a sulfur atom as ring-constituting atoms other than carbon atoms" of ring A includes "a ring other than carbon atoms A 5- or 6-membered aromatic heterocyclic ring containing 1 to 2 heteroatoms selected from a nitrogen atom and a sulfur atom as constituent atoms is preferred. Of these, pyridine and thiophene are most preferred.

As the "5- or 6-membered aromatic ring" for ring B, a 6-membered aromatic ring (eg, benzene, pyridine, pyridazine, pyrimidine, pyrazine, triazine) is preferred. Of these, benzene is most preferred.

A fluorine atom is preferable as the halogen atom for R ₂ .
Preferred alkyl groups for R ₂ are C ₁ -C ₆ alkyl groups, and most preferred is methyl.
Preferred alkoxy groups for R ₂ are C ₁ -C ₆ alkoxy groups, and most preferred is methoxy.
Preferred aryl groups for R ₂ are C ₆ -C ₁₀ aryl groups, and most preferred is phenyl.
The 5- or 6-membered aromatic heterocyclic group for R ₂ is a 5- or 6-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen and sulfur atoms as ring-constituting atoms other than carbon atoms. A cyclic group is preferred. Of these, pyridyl and thienyl are most preferred.
R ₂ is preferably a halogen atom or a 5- or 6-membered aromatic heterocyclic group, more preferably a fluorine atom, pyridyl or thienyl.

As the halogen atom for _R3 , a fluorine atom, a chlorine atom, an iodine atom and a bromine atom are preferred.
Preferred alkyl groups for R ₃ are C ₁ -C ₆ alkyl groups, and most preferred are methyl and propyl.
The alkenyl group for R ₃ is preferably a C ₂ -C ₆ alkenyl group.
Preferred alkynyl groups for R ₃ are C ₂ -C ₆ alkynyl groups, and most preferred is ethynyl.
Preferred alkoxy groups for R ₃ are C ₁ -C ₆ alkoxy groups, and most preferred is methoxy.
Preferred aryl groups for R ₃ are C ₆ -C ₁₀ aryl groups, and most preferred is phenyl.
R ₃ is preferably a halogen atom, a C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group, a C ₂ -C ₆ alkynyl group, a C ₁ -C ₆ alkoxy group and a C ₆ -C ₁₀ aryl group. , more preferably fluorine atom, chlorine atom, iodine atom, bromine atom, methyl, propyl, ethynyl, methoxy and phenyl.

m is preferably 0, 1 or 2.
n is preferably 1 or 2.

Preferred examples of compound (I) include the following compounds.

[Compound A-1]
Ring A is a 5- or 6-membered aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from nitrogen and sulfur atoms as ring-constituting atoms other than carbon atoms;
R ₁ is a carboxy group;
m R ₂ are each independently a 5- or 6-membered aromatic heterocyclic group (preferably 1 to 4 heteroatoms selected from nitrogen and sulfur atoms as ring-constituting atoms other than carbon atoms 5- or 6-membered aromatic heterocyclic group containing
Ring B is a 5- or 6-membered aromatic ring;
n R ₃ are each independently a halogen atom, a C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group, a C ₂ -C ₆ alkynyl group, a C ₁ -C ₆ alkoxy group, or a C _{6 -C10} aryl;
m is 0 or 1; and n is 1 or 2,
Compound (I).

[Compound A-2]
each of m R ₂ is independently pyridyl or thienyl;
Ring B is benzene;
n R ₃ are each independently a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), C ₁ -C ₆ alkyl group (eg, methyl, propyl), C ₂ -C ₆ alkenyl groups (eg vinyl), C ₂ -C ₆ alkynyl groups (eg ethynyl), C ₁ -C ₆ alkoxy groups (eg methoxy) or C ₆ -C ₁₀ aryl (eg phenyl), more preferably , a halogen atom (eg fluorine atom), a C ₁ -C ₆ alkyl group (eg propyl), a C ₂ -C ₆ alkenyl group (eg vinyl), or a C ₆ -C ₁₀ aryl (eg phenyl) ,
[Compound A-1] above.
[Compound A-3]
A group represented by the following partial structural formula:

is a group represented by the following partial structural formula:

is
The compound described in [Compound A-1] or [Compound A-2] above.
[Compound A-4]
A compound selected from the following group of compounds.

[Compound B]
Among compounds (I), other preferred examples include compounds selected from the following compound groups:

(In the formula, Ph is phenyl, Me is methyl, nPr is propyl, and OMe is methoxy.)

Preferred examples of compound (Ia) include [compound A-1], [compound A-2], [compound A-3], [compound A-4] and [compound B]. In addition, the following compounds are exemplified as other preferred compounds of compound (Ia).

(In the formula, Me represents methyl.)

Salts of compound (I) or (Ia) include pharmaceutically acceptable salts. Examples included are trifluoroacetic acid, acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, cinnamic acid, fumaric acid, Phosphonic acid, hydrochloric acid, nitric acid, hydrobromic acid, hydroiodic acid, sulfamic acid, acid addition salts with acids such as sulfuric acid; metal salts such as sodium, potassium, magnesium, calcium; trimethylamine, triethylamine, pyridine, picoline, Examples thereof include salts with organic bases such as N-methylpyrrolidine, N-methylpiperidine and N-methylmorpholine.

When compound (I) or (Ia) has isomers such as optical isomers, stereoisomers, positional isomers, and rotational isomers, either one of the isomers or the mixture of isomers is the compound ( Included in I) or (Ia). For example, when compound (I) or (Ia) has an optical isomer, the optical isomer resolved from the racemate is also included in compound (I) or (Ia). These isomers can be obtained as single products by per se known synthesis techniques and separation techniques (concentration, solvent extraction, column chromatography, recrystallization, etc.). Compound (I) or (Ia) also has structural isomers such as tautomers and geometric isomers, and such isomers are also within the scope of the present invention.

Compound (I) or (Ia) may be crystalline or amorphous. When compound (I) or (Ia) is a crystal, it is included in compound (I) or (Ia) whether the crystal form is a single crystal form or a crystal form mixture. Crystals can be produced by applying a crystallization method known per se to crystallize.

Compound (I) or (Ia) may be a solvate (e.g., hydrate, etc.) or a non-solvate, both of which are included in compound (I) or (Ia). .

Compound (I) or (Ia) may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.).

Compound (I) or (Ia) has an action of activating adenosine _A2A receptor. Adenosine _A2A receptors are intimately involved in the sleep/wake cycle and sleep can be induced by activating the adenosine _A2A receptors. The action of activating the adenosine _A2A receptor can be measured according to a method commonly practiced in the art, or by modifying the method as necessary. For example, as shown in the Examples, using Chinese hamster ovary cells expressing _A2AR and measuring the amount of cAMP produced by _A2AR activation by fluorescence resonance energy transfer (FRET) immunoassay. can be evaluated by

While closely involved in the sleep/wake cycle, adenosine _A2A receptors are distributed in the cerebral cortex, hippocampus, striatum, coronary vessels, lungs, leukocytes, platelets, etc. , pain, and relaxation of visceral smooth muscle. Adenosine _A2A receptor activators are therefore concerned about cardiovascular side effects. However, compound (I) or (Ia) does not cause the above-mentioned side effects because it acts on a site different from the orthosteric site on which the endogenous ligand acts. Thus, compounds (I) or (Ia) act as positive allosteric modulators of adenosine _A2A receptors.

Compound (I) or (Ia) having excellent adenosine _A2A receptor activating action is used in mammals (e.g., humans, monkeys, cats, pigs, horses, cows, mice, rats, guinea pigs, dogs, rabbits, etc.). On the other hand, it is useful as a sleep inducer, particularly as a sleep inducer capable of providing slow-wave sleep that gives a feeling of deep sleep.

The content of compound (I) or (Ia) in a medicament containing the compound of the present invention as an active ingredient (for example, a sleep inducer) is usually about 0.01 to about 99.9% by weight, Preferably from about 0.1 to about 50% by weight.

The dose of compound (I) or (Ia) is determined according to age, body weight, general health, sex, diet, time of administration, method of administration, rate of excretion, combination of drugs, and the patient's current medical condition. Depending on the degree, these or other factors may be considered.
The dosage varies depending on the target disease, symptoms, administration subject, administration method, etc., but for example, the amount of compound (I) or (Ia) of the compound of the present invention is about 0.1 to 100 mg/kg (body weight), preferably about It is preferable to administer 1 to 10 mg/kg (body weight), more preferably about 1 to 3 mg/kg (body weight), once or in 2 to 3 divided doses per day.

For example, when compound (I) or (Ia) is used as a sleep-inducing agent, it can be used in combination with other agents depending on the degree of sleep disorder to be treated. These concomitant drugs may be low-molecular-weight compounds, or high-molecular-weight proteins, polypeptides, antibodies, vaccines, and the like. In this case, the timing of administration of compound (I) or (Ia) and the concomitant drug is not limited as long as compound (I) or (Ia) and the concomitant drug are combined at the time of administration.

Compound (I) or (Ia) is compounded with a pharmaceutically acceptable carrier to prepare solid formulations such as tablets, capsules, granules, and powders; liquid formulations such as syrups and injections; patches and ointments. , transdermal absorbers such as plasters; inhalants; and suppositories.
A drug containing compound (I) or (Ia) is administered orally or parenterally, and the above compounds may be used singly or in combination of two or more.

As a pharmaceutically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials can be used. Specifically, excipients, lubricants, binders, disintegrants in solid formulations, solvents, solubilizers, suspending agents, tonicity agents, buffers, pain relievers, etc. in liquid formulations. can do. In addition, formulation additives such as preservatives, antioxidants, coloring agents and sweetening agents can be used as necessary.

Examples of excipients include lactose, white sugar, glucose, starch, sucrose, crystalline cellulose, licorice powder, mannitol, sodium hydrogen carbonate, calcium phosphate, calcium sulfate and the like.

Examples of lubricants include magnesium stearate, stearic acid, calcium stearate, refined talc, colloidal silica, and the like.

Examples of binders include crystalline cellulose, white sugar, mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like.

Examples of disintegrants include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethylstarch sodium, and the like.

Preferable examples of solvents include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like.

Preferable examples of solubilizing agents include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.

Examples of suspending agents include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; polyvinyl alcohol, polyvinylpyrrolidone, Carboxymethyl cellulose sodium, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and the like.

Suitable examples of tonicity agents include sodium chloride, glycerin, D-mannitol and the like.

Suitable examples of buffers include buffers such as phosphate, acetate, carbonate and citrate.
Preferable examples of soothing agents include benzyl alcohol and the like.

Preferable examples of preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Suitable examples of antioxidants include sulfites, ascorbic acid, and the like.
Preferable examples of coloring agents include tar pigments, caramel, iron sesquioxide, titanium oxide, riboflavins and the like.
Suitable examples of sweeteners include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, simple syrup and the like.

Production method The compounds represented by the formula (I) of the present invention, compounds X and Y, their isomers, solvates and salts thereof are characterized by their basic skeletons or the types of substituents, and can be produced in various ways. It can be manufactured by applying a known synthesis method. For example, it can be produced according to the following synthetic methods, but it is not limited to these, and can be modified as desired. Such modifications include alkylation, acylation, amination, imination, halogenation, reduction, oxidation and the like, and reactions or methods commonly used in the art are utilized. At that time, depending on the type of functional group, it may be effective in terms of production technology to replace the functional group with an appropriate protective group (a group that can be easily converted to the functional group) at the raw material or intermediate stage. There is The chemical properties of protecting groups, techniques for their introduction, and their removal are described, for example, in T.W. Greene andP. Wuts "Protective Groups in Organic Synthesis" ( ^3rd ed.), John Wiley & Sons NY (1999).

Unless otherwise specified, starting compounds can be easily obtained from commercial sources, or can be produced according to methods known per se or methods analogous thereto.

In each reaction and each reaction in synthesizing starting compounds, a generally known solvent may be used during the reaction.
Examples of commonly known solvents include ethers such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane and 1,4-dioxane; esters such as ethyl acetate and butyl acetate; and aromatic hydrocarbons such as benzene and toluene. Hydrogen, aromatic heterocyclic compounds such as pyridine and lutidine, amides such as N,N-dimethylformamide and N-methylpyrrolidone, halides such as chloroform and methylene chloride, methanol, ethanol, 2-propanol, 2,2 -Alcohols such as dimethylethanol, hydrocarbon compounds such as hexane, heptane and petroleum ether, carboxylic acids such as formic acid and acetic acid, and water.
As for the solvent used in the reaction, a single solvent may be used, or a mixture of 2 to 6 solvents may be used.
In addition, the reaction may be carried out in the presence of amines such as triethylamine, N,N-diisopropylamine, pyridine, N-methylmorpholine, or a base.
Examples of bases include organic bases such as triethylamine, tri-n-butylamine, piperidine, pyridine and 4-dimethylaminopyridine; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; and sodium hydrogen carbonate. , carbonates such as sodium carbonate and potassium carbonate, phosphates such as dipotassium monohydrogen phosphate and trisodium phosphate, alkali metal hydrides such as sodium hydride, alkali metals such as sodium methoxide and sodium ethoxide Examples include alcoholates, organic lithiums such as n-butyllithium, Grignard reagents such as ethylmagnesium bromide, lithium amide, and lithium diisopropylamide.
Moreover, the reaction may be carried out in the presence of an acid such as hydrochloric acid, sulfuric acid, or acetic acid.

Synthetic schemes of the compounds of the present invention are shown below (detailed reactions are according to Examples). Although specific groups and compounds may be described in the schemes, it is obvious to those skilled in the art that substitutable groups and compounds can be used.

In the formula, L is a leaving group such as a halogen atom (eg, fluorine atom, bromine atom), and other symbols are defined as described above.
In a suitable solvent, in the presence of a suitable base, compound (1) is reacted with compound (2) in an amount generally two times the molar amount of compound (1) to give a compound represented by formula (I). is the process of obtaining
Although the solvent is not particularly limited, it may be used by appropriately selecting it within the range of 1 to 10-fold molar equivalents relative to compound (1).
Although the base is not particularly limited, it may be used by appropriately selecting it within the range of 0.01 to 5 times the molar equivalent of compound (1).
The reaction temperature is generally about 100 to about 250°C, preferably about 150 to about 220°C.
The reaction time is generally about 0.01 to about 20 hours.
Example

The present invention will be described in detail below using examples, but the present invention is not limited in any way. Reagents and materials used are commercially available unless otherwise specified.
All compounds except A _2A R PAM YNT-2221 or YNT-2224 are synthesized according to the general method.
General method

A 5 mL microwave vial was charged with benzoic acid, aniline, lithium amide and tetrahydrofuran or 1,4-dioxane. The vessel was microwave heated at 150-220° C. for 1-5 minutes. The reaction tube was then cooled to room temperature and the mixture was diluted with 1M aqueous hydrogen chloride and extracted with chloroform. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/10% acetic acid-methanol solution=100/0→90/10) to obtain the title compound.

Example 1: Synthetic Route of A _2A R PAM YNT-2137

2,3,4-fluorobenzoic acid (141.7 mg, 0.805 mmol), 4-chloro-2-methylaniline (206.4 mg, 0.886 mmol), and lithium amide (92.4 mg, 4.03 mmol) A solution in tetrahydrofuran (3 mL) was reacted according to the general method to give YNT-2137 (54.8 mg, 17%) as a brown solid. ¹ H NMR (400 MHz, acetone-d ₆ ) δ 9.23 (br, 1H), 7.96 (ddd, J = 8.9, 6.0, 1.8 Hz, 1H), 7.57 (d , J=1.8Hz, 1H, ), 7.47 (dd, J=8.5, 1.8Hz, 1H), 6.96 (ddd, J=9.2, 9.2, 7.1Hz, 1H), 6.73 (dd, J=8.2, 6.4 Hz, 1H), 2.32 (s, 3H).

Example 2: Synthetic Route of A _2A R PAM YNT-2138

2,3,4-fluorobenzoic acid (161.6 mg, 0.918 mmol), 4-bromo-2-fluoroaniline (191.9 mg, 1.01 mmol), and lithium amide (105.4 mg, 4.59 mmol) A solution in tetrahydrofuran (3 mL) was reacted according to the general method to give YNT-2138 (287.6 mg, 91%) as a brown solid. ¹ H NMR (400 MHz, acetone-d ₆ ) δ 9.33 (br, 1H), 7.96 (ddd, J = 9.2, 5.9, 2.1 Hz, 1H), 7.42 (dd , J=10.7, 2.3 Hz, 1H), 7.30 (ddd, J=8.6, 2.3, 1.2 Hz, 1H), 7.07 (ddd, J=8.1, 7 .3, 4.6 Hz, 1 H), 7.01 (ddd, J = 9.4, 8.8, 6.6 Hz, 1 H).

Example 3: Synthetic Route of A _2A R PAM YNT-2139

2,3,4-fluorobenzoic acid (142.5 mg, 0.809 mmol), 4-iodo-3-fluoroaniline (210.9 mg, 0.890 mmol), and lithium amide (92.8 mg, 4.05 mmol) A solution in tetrahydrofuran (3 mL) was reacted according to the general method to give YNT-2139 (276.5 mg, 70%) as a brown solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.89 (ddd, J=9.0, 5.8, 2.3 Hz, 1 H), 7.60 (dd, J=8.7, 7.3 Hz , 1H), 6.96 (ddd, J = 9.4, 7.3, 7.3 Hz, 1H), 6.72 (ddd, J = 10.1, 2.9, 2.9 Hz, 1H), 6.58 (ddd, J=8.7, 2.9, 2.9 Hz, 1 H).

Example 4: Synthetic Route of A _2A R PAM YNT-2167

The 1,4- A solution in dioxane (5 mL) was reacted according to the general procedure to give YNT-2167 (76.3 mg, 60%) as a brown solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.03 (d, J=7.3 Hz, 1 H), 7.55 (d, J=2.8 Hz, 1 H), 7.32 (d, J= 8.2Hz, 2H), 7.25 (d, J = 8.2Hz, 2H), 7.05 (dd, J = 7.3, 2.8Hz, 1H), 2.63 (dd, J = 7 .6 Hz, 2 H), 1.67 (tq, J=7.6, 7.3 Hz, 2 H), 0.97 (t, J=7.3 Hz, 3 H).

Example 5: Synthetic Route of A _2A R PAM YNT-2168

The 1,4- A solution in dioxane (5 mL) was reacted according to the general method to give YNT-2168 (82.3 mg, 64%) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.76 (dd, J = 8.6, 7.3 Hz, 1 H), 7.48 (d, J = 7.3 Hz, 1 H), 7.42 ( d, J = 8.6 Hz, 2H), 7.16 (m, 3H), 2.56 (dd, J = 7.6 Hz, 2H), 1.63 (tq, J = 7.6, 7.3 Hz , 2H), 0.94 (t, J=7.3 Hz, 3H).

Example 6: Synthetic Route of A _2A R PAM YNT-2224 1) Synthesis of Compound A (Intermediate of YNT-2224)

Cesium carbonate (642.3 mg, 3.33 mmol), palladium acetate (7.48 mg, 0.0333 mmol), rac-BINAP (33.2 mg, 0.0533 mmol), and 4-propylaniline (96.0 μL, 0.673 mmol) ) was added to a suspension of methyl 3-bromobenzoate (143.2 mg, 0.666 mmol) in toluene (10 mL) with stirring. The resulting mixture was stirred at 100° C. for 24 hours, diluted with saturated aqueous ammonium chloride at room temperature, and extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5→80/20) to give compound A (89.7 mg, 50%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.66 (t, J = 2.0 Hz, 1 H), 7.53 (dt, J = 7.6, 1.3 Hz, 1 H), 7.29 (t , J = 7.8Hz, 1H), 7.19 (ddd, J = 8.1, 2.5, 1.1Hz, 1H), 7.15-7.08 (m, 2H), 7.07- 6.98 (m, 2H), 5.72 (s, 1H), 3.89 (s, 3H), 2.55 (dd, J = 7.6Hz, 2H), 1.64 (tq, J = 7.6, 7.3 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H).
2) Synthesis of YNT-2224

A 5 mM aqueous sodium hydroxide solution (1 mL) was added to a stirred solution of Compound A (53.7 mg, 0.199 mmol) in tetrahydrofuran (1.0 mL) and methanol (1.0 mL). The resulting mixture was stirred at room temperature for 5 hours, diluted with 1M aqueous hydrogen chloride solution at 0° C., and extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/10% acetic acid-methanol solution=100/0→90/10) to give YNT-2224 (33.7 mg, 66%) as a white solid. ¹ H NMR (400 MHz, acetone-d ₆ ) δ 7.80-7.75 (m, 1H), 7.49 (dt, J = 7.3, 1.5 Hz, 1H), 7.38-7 .27 (m, 2H), 7.18-7.08 (m, 4H), 2.53 (dd, J = 7.6Hz, 2H), 1.63 (tq, J = 7.6, 7. 3 Hz, 2 H), 0.95 (t, J = 7.3 Hz, 3 H).

Example 7: Synthetic Route of A _2A R PAM YNT-2205

The 1,4- A solution in dioxane (5 mL) was reacted according to the general method to give YNT-2205 (54.8 mg, 30%) as a brown solid. ¹ H NMR (400 MHz, acetone-d ₆ ) δ 7.98 (ddd, J = 9.0, 6.0, 1.8 Hz, 1 H), 7.65 (dd, J = 8.2, 1. 4Hz, 2H,), 7.49-6.94 (m, 8H).

Example 8: Synthetic Route of A _2A R PAM YNT-2221 1) Synthesis of Compound B (Intermediate of YNT-2221)

Potassium carbonate (178.5 mg, 1.29 mmol), [1,1' _- bis ₍ diphenylphosphino)ferrocene]dichloropalladium(II).dichloromethane adduct ( _{PdCl2.dppf.CH2Cl2} ) (10.5 mg ₎ , 0.0129 mmol), and phenylboronic acid (63.0 mg, 0.516 mmol) to methyl 4-((2-fluoro-4-iodophenyl)amino)thiophene-3-carboxylate (97.4 mg, 0.516 mmol). 258 mmol) in water (1 mL) and 1,4-dioxane (5 mL) was added with stirring. The resulting mixture was refluxed for 2 hours, diluted with a saturated aqueous ammonium chloride solution at room temperature, and extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to preparative silica gel column chromatography (hexane/ethyl acetate=98/2→90/10) to give compound B (34.2 mg, 69%) as a brown solid. ¹ H NMR (400 MHz, acetone-d ₆ ) δ 8.72 (br, 1H), 8.09 (d, J = 3.2 Hz, 1H), 7.56 (m, 3H), 7.46- 7.31 (m, 5H), 6.75 (d, J=3.2Hz, 1H) 3.92 (s, 3H).
2) Synthesis of YNT-2221

A 5 mM aqueous sodium hydroxide solution (1 mL) was added to a stirred solution of compound B (26.5 mg, 0.0810 mmol) in tetrahydrofuran (1.0 mL) and methanol (1.0 mL). The resulting mixture was stirred at room temperature for 19 hours, diluted with 1M aqueous hydrogen chloride solution at 0° C., and extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by PTLC (chloroform/10% acetic acid-methanol solution=20/10) to give YNT-2221 (17.3 mg, 68%) as a white solid. ¹ H NMR (400 MHz, acetone-d ₆ ) δ 8.34 (d, J = 3.2 Hz, 1 H), 7.75 (dd, J = 8.2, 8.2 Hz, 1 H), 7.67 (m, 2H), 7.55-7.44 (m, 4H), 7.36-7.32 (m, 1H), 7.07 (d, J=3.2Hz, 1H).

Example 9: Synthetic Route for A _2A R PAM YNT-2222

2-fluorobenzoic acid (126.5 mg, 0.903 mmol), 4-propylaniline (141.4 μL, 0.993 mmol), and lithium amide (103.7 mg, 4.51 mmol) in 1,4-dioxane (5 mL) The medium solution was reacted according to the general method to give YNT-2222 (124.4 mg, 54%) as a brown solid. ¹ H NMR (400 MHz, acetone-d ₆ ) δ 8.03 (dd, J=8.0, 1.6 Hz, 1 H), 7.38 (ddd, J=8.7, 7.1, 1. 7Hz, 1H), 7.24-7.20 (m, 5H), 6.76 (dd, J = 7.5, 0.9Hz, 1H), 2.59 (dd, J = 7.6Hz, 2H ), 1.65 (tq, J=7.6, 7.3 Hz, 2H), 0.95 (t, J=7.3 Hz, 3H).

Example 10: Synthetic Route for A _2A R PAM YNT-2245

The 1,4- A solution in dioxane (5 mL) was reacted according to the general method to give YNT-2245 (401.5 mg, 80%) as a brown solid. ¹ H NMR (400 MHz, acetone-d ₆ ) δ 7.96 (ddd, J=8.9, 6.0, 1.8 Hz, 1 H), 7.46 (d, J=8.7 Hz, 2 H, ), 7.04-6.98 (m, 3H).

Example 11: Synthetic Route for A _2A R PAM YNT-2247

The 1,4- A solution in dioxane (5 mL) was reacted according to the general method to give YNT-2247 (103.9 mg, 62%) as a brown solid. ¹ H NMR (400 MHz, acetone-d ₆ ) δ 7.99 (ddd, J = 9.2, 6.0, 2.3 Hz, 1 H), 7.89 (d, J = 7.8, 1. 4Hz, 1H, ), 7.35 (ddd, J = 7.1, 7.1, 1.4Hz, 1H), 7.07-7.00 (m, 2H), 6.85 (ddd, J = 7.6, 7.6, 1.4Hz, 1H).

Example 12: Synthetic Route for A _2A R PAM YNT-2248

2,3,4-fluorobenzoic acid (84.1 mg, 0.478 mmol), 2,5-fluoroaniline (48.3 μL, 0.482 mmol), and lithium amide (54.8 mg, 2.39 mmol) in 1, A solution in 4-dioxane (5 mL) was reacted according to the general method to give YNT-2248 (97.2 mg, 71%) as a brown solid. ¹ H NMR (400 MHz, acetone-d ₆ ) δ 8.00 (ddd, J=9.0, 5.8, 2.3 Hz, 1 H), 7.23 (ddd, J=11.0, 9.00; 2, 5.0Hz, 1H,), 7.09 (ddd, J = 9.4, 9.4, 7.1Hz, 1H), 6.93-6.86 (m, 1H), 6.84- 6.77 (m, 1H).

Example 13: Synthetic Route for A _2A R PAM YNT-2249

2,3,4-fluorobenzoic acid (80.4 mg, 0.457 mmol), 5-chloro-2-fluoroaniline (50.5 μL, 0.461 mmol), and lithium amide (52.4 mg, 2.28 mmol). A solution in 1,4-dioxane (5 mL) was reacted according to the general method to give YNT-2249 (99.3 mg, 72%) as a brown solid. ¹ H NMR (400 MHz, acetone-d ₆ ) δ 9.36 (br, 1H), 7.99 (ddd, J = 9.0, 5.8, 2.3 Hz, 1H), 7.23 (dd , J=11.0, 8.7 Hz, 1H), 7.13-7.05 (m, 3H).

Example 14: Synthetic route for A _2A R PAM YNT-2251

2,3,4-fluorobenzoic acid (101.7 mg, 0.577 mmol), 2-fluoro-5-methylaniline (65.8 μL, 0.583 mmol), and lithium amide (66.3 mg, 2.89 mmol) A solution in 1,4-dioxane (5 mL) was reacted according to the general procedure to give YNT-2251 (73.9 mg, 45%) as a brown solid. ¹ H NMR (400 MHz, acetone-d ₆ ) δ 9.32 (br, 1H), 7.96 (ddd, J = 9.0, 5.8, 2.3 Hz, 1H), 7.08-6 .88 (m, 4H), 2.29 (s, 3H).

Example 15: Synthetic Route for A _2A R PAM YNT-2252

2,3,4-fluorobenzoic acid (115.5 mg, 0.656 mmol), 5-bromo-2-fluoroaniline (74.3 μL, 0.662 mmol), and lithium amide (75.3 mg, 3.28 mmol) A solution in 1,4-dioxane (5 mL) was reacted according to the general procedure to give YNT-2252 (130.6 mg, 58%) as a brown solid. ¹ H NMR (400 MHz, acetone-d ₆ ) δ 9.37 (br, 1H), 7.98 (ddd, J = 9.0, 5.8, 2.3 Hz, 1H), 7.27-7 .15(m, 3H), 7.06(ddd, J=9.9, 7.7, 7.7Hz, 1H).

Example 16: Synthetic Route for A _2A R PAM YNT-2307

2,3,4-fluorobenzoic acid (129.3 mg, 0.734 mmol), 2-fluoro-5-methoxyaniline (98.9 μL, 0.662 mmol), and lithium amide (84.2 mg, 3.67 mmol) A solution in 1,4-dioxane (5 mL) was reacted according to the general method to give YNT-2307 (159.6 mg, 73%) as a brown solid. ¹ H NMR (400 MHz, acetone-d ₆ ) δ 9.34 (br, 1H), 7.97 (ddd, J = 9.0, 5.8, 2.3 Hz, 1H), 7.10 (dd , J = 10.8, 8.9 Hz, 1H), 7.06 (ddd, J = 9.4, 7.1, 7.1 Hz, 1H), 6.68-6.60 (m, 2H), 3.76(s, 3H).

Example 17: Synthetic route for A _2A R PAM YNT-2308

2,3,4-fluorobenzoic acid (169.2 mg, 0.620 mmol), 2-fluoro-4-methoxyaniline (88.4 mg, 0.626 mmol), and lithium amide (71.1 mg, 3.10 mmol) A solution in 1,4-dioxane (5 mL) was reacted according to the general method to give YNT-2308 (99.2 mg, 54%) as a brown solid. ¹ H NMR (400 MHz, acetone-d ₆ ) δ 9.35 (br, 1H), 7.92 (ddd, J = 9.2, 5.9, 2.1 Hz, 1H), 7.12 (dd , J=9.3, 3.5 Hz, 1 H), 6.85-6.79 (m, 2 H), 6.74 (ddd, J=8.9, 2.8, 1.2 Hz, 1 H).

Example 18: Synthetic Route for A _2A R PAM YNT-2310

The 1,4- A solution in dioxane (5 mL) was reacted according to the general method to give YNT-2310 (15.4 mg, 8%) as a brown solid. ¹ H NMR (400 MHz, acetone-d ₆ ) δ 7.97 (ddd, J = 8.9, 6.0, 1.8 Hz, 1 H), 7.42 (d, J = 8.7 Hz, 2 H) , 7.04-7.00 (m, 3H), 3.56 (s, 1H).

Example 19: Synthetic Route for A _2A R PAM YNT-2311

The 1,4- A solution in dioxane (5 mL) was reacted according to the general method to give YNT-2311 (116.3 mg, 53%) as a brown solid. ¹ H NMR (400 MHz, acetone-d ₆ ) δ 9.28 (br, 1H), 7.97 (ddd, J = 8.9, 6.0, 1.8 Hz, 1H), 7.27-7 .17 (m, 3H), 7.07-7.00 (m, 2H).

Test example [Materials and methods]

(1) Reagents Various _A2A R PAMs were synthesized according to the above examples. Adenosine, DMSO (dimethylsulfoxide), DMEM (Dulbecco's Modified Eagle's Medium), and non-essential amino acids (NEAA) were purchased from Nacalai Tesque. FBS (fetal bovine serum) was purchased from Nichirei Biosciences. HBSS (Hanks Balanced Salt Solution) and HEPES (hydroxyethylpiperazineethanesulfonic acid) were purchased from Gibco. Hygromycin B, penicillin and streptomycin were purchased from Fuji Film Wako Pure Chemical Industries, Ltd. Pentobarbital (Somnopentyl) was purchased from Kyoritsu Pharmaceutical Co., Ltd. Puromycin was purchased from InvioGen. Physiological saline was purchased from Otsuka Pharmaceutical Co., Ltd. 3-isobutyl-1-methylxanthine (IBMX) was purchased from Tocris Biosciences.

(2) Animals Male C57BL/6 inbred mice weighing 21 to 27 g (10 to 15 weeks old) bred at the International Institute for Integrative Sleep Medicine were used for experiments. Animals were insulated and sound-insulated with a temperature of 23 ± 0.5°C, a relative humidity of 50 ± 5%, and a 12-hour light/12-hour dark cycle (lights on at 08:00, illuminance approximately 100 lux). They were kept in a well-equipped recording room. All animals had free access to water and food. Experiments were performed in strict accordance with the recommendations in the National Institutes of Health Guide for the Care and Use of Laboratory Animals (National Research Council, 2011). The experimental protocol complied with relevant Japanese and institutional laws and guidelines and was approved by the University of Tsukuba Animal Care and Use Committee (protocol number 14-322). Every effort was made to minimize the number of animals used and the pain and discomfort they experienced.

(3) Mouse A _2A R-expressing Chinese hamster ovary cell A _2A R FLAG epitope-tagged open reading frame was amplified by PCR from mouse brain total RNA. The resulting amplicons were cloned into the pMXs-IRES-Puro retroviral vector (Kitamura et al., 2003). The plasmid was then transfected into the retroviral packaging cell line Plat-E (Morita et al., 2000). Supernatants of transfected Plat-E cells were harvested 24 hours later and applied to Chinese Hamster Ovary (CHO) cells, which strongly express retroviral ecotropic receptors (Montminy et al., 1990). CHO cells expressing mouse A _2A R (mA _2A R-CHO) were treated with hygromycin B (250 μg ml ⁻¹ ) and puromycin (10 μg ml ⁻¹ ) supplemented with 5% FBS and 1% NEAA. Selections were made in DMEM. Subsequently, mA _2A R-CHO cells were cultured in DMEM supplemented with 5% FBS, 1% NEAA, 1% penicillin/streptomycin, and 250 μg ml ⁻¹ hygromycin B in an atmosphere of 5% CO ₂ 37 cells. °C.

(4) cAMP Assay _A2A receptor activation was quantified by the accumulation of cyclic adenosine monophosphate (cAMP) in CHO cells expressing mouse _A2A receptors. CHO cells were suspended in HBSS containing 1 M HEPES, 0.25 M IBMX in 384-well microplates (2×10 ³ cells per well), with adenosine and the indicated concentrations of A _2A R PAMs for 30 min. Incubated at 25°C. A detection mixture containing Eu-cAMP tracer and ULight-anti-cAMP antibody was added and incubated for 1 hour at 25°C. Forster resonance energy transfer (FRET) signals were measured using a microplate reader (ARVOX5; PerkinElmer, Waltham, Mass.; excitation: 340 nm; emission: 665 nm). All experiments were performed according to the manufacturer's instructions (LANCE Ultra cAMP kit, PerkinElmer). cAMP levels were determined based on the dynamic range (“linear portion”) of the cAMP standard curve and normalized to baseline or adenosine-treated groups.

(5) Stereotaxic Surgery to Place EEG/EMG Electrodes Mice were anesthetized with pentobarbital [50 mg kg ⁻¹ body weight, intraperitoneal (ip)] and then placed in a stereotaxic apparatus. Electroencephalographic (EEG) and electromyographic (EMG) electrodes for polysomnographic recording were chronically implanted in mice (Oishi et al., 2016). According to the Atlas of Paquinos and Franklin (2004), an implant consisting of two stainless steel screws (1 mm diameter) was inserted through the skull above the cortex (from bregma or lambda, anteroposterior, +1.0 mm; lateral, −1.0 mm). 5 mm) were used as EEG electrodes. Two insulated stainless steel Teflon-coated wires were placed bilaterally intramuscularly in both trapezius muscles and used as EMG electrodes. All electrodes were fitted with microconnectors and fixed to the skull with dental cement.

(6) Pharmacological treatment Mice were injected with saline or vehicle (10 ml kg ⁻¹ , ip) at exactly 22:00 for control data. Immediately prior to use, YNT-2167 was dissolved in saline and administered intraperitoneally at a dose of 75 mg kg ⁻¹ at exactly 22:00 on the day of the experiment. Mice were randomly assigned to groups receiving control or drug injections.

(7) Assessment of Vigilance Status Based on EEG/EMG Polygraphic Recordings Ten days post-surgery, mice were housed individually in transparent barrels in an insulated and soundproofed recording room and were placed for 3 days of habituation before polygraphic recordings were initiated. - Connected to an EEG-EMG recording cable for 5 days. Twenty-four hour (beginning at exactly 20:00, onset of dark phase) recordings were taken for each animal in order to examine spontaneous sleep-wake cycles. Animals then entered the pharmacological phase of the study in which sleep-wake parameters were recorded for 36 hours. Data collected during the first 24 hours were also used as baseline comparative data for the second day of the experiment. Cortical EEG/EMG signals were amplified and filtered (EEG 0.5-30 Hz; EMG 20-200 Hz), then digitized at a sampling rate of 128 Hz and processed with data acquisition software SleepSign® (Kissei Comtech, Matsumoto, Japan). was recorded using The vigilance state was measured by SleepSign® (ver 3.4) software according to standard criteria (Oishi et al., 2016) in 10 s epochs into three stages: wakefulness, rapid eye movement (REM) sleep, and SWS. was classified offline by As a final step, the defined vigilance status was visually examined and corrected if necessary.

(8) Results

(i) YNT-2167 enhances the activity of mouse A _2A R-expressing Chinese hamster ovary cells. We established CHO cells expressing mouse _A2A R using retrovirus-mediated gene transfer (Kitamura et al., 2003). Using these mA _2A R-CHO cells, we tested the activity of YNT-2167, a derivative of YNT-378, a previously identified A _2A R positive allosteric modulator, against A _2A R. . A _2A R activity in CHO cells was determined by measuring cAMP produced after addition of adenosine and small compounds using a fluorescence resonance energy transfer immunoassay. Percentage cAMP changes were calculated based on the reduction in FRET signal between adenosine-treated and adenosine- and compound-treated cell groups. Alternatively, the percentage of increased cAMP levels determined based on the decrease in FRET signal after adenosine or adenosine and compound treatment of the cell population was determined. Treatment of mA _2A R-CHO cells with YNT-2167 robustly increased cAMP production by approximately 50%. This result is highly significant compared to YNT-378, the first identified adenosine A _2A R positive allosteric modulator, which increased cAMP production by approximately 20% (FIG. 1A). Furthermore, co-treatment of cells with adenosine and different concentrations of YNT-2167 increased cellular cAMP production levels in a concentration-dependent manner (FIG. 1B).

(ii) Intraperitoneal administration of YNT-2167 induces slow-wave sleep in mice. As for the previously reported A _2A R positive allosteric modulator YNT-378, the slow-wave sleep-inducing activity of YNT-2167 was measured using a sleep bioassay. The vigilance stage of animals was determined by electroencephalographic (EEG) and electromyographic (EMG) signals recorded by SLEEPSIGN® software. YNT-2167 was administered intraperitoneally 2 hours after the onset of the dark period at 22:00, when animals were awake for most of the time. YNT-2167 significantly increased slow-wave sleep in animals during the last 5 hours of the dark period, while decreasing wakefulness (Fig. 2A). The total amount of slow-wave sleep increased by approximately 45 minutes over a 5-hour period with 75 mg·kg ⁻¹ YNT-2167 compared to saline treatment. On the other hand, wakefulness was reduced by approximately 50 minutes (Fig. 2B). Intraperitoneal injection of YNT-2167 did not significantly affect the animals' REM sleep profile compared to saline injection (FIGS. 2A and 2B).

reference:
(1) T. Kitamura, Y.; Koshino, F.; Shibata, T.; Oki, H. Nakajima, T.; Nosaka, H.; Kumagai. Retrovirus-mediated gene transfer and expression cloning: Powerful tools in functional genomics, Exp. Hematol. , 31 (2003), pp. 1007-1014 https://doi. org/10.1016/j. exhem. 2003.07.005
(2) Mustafa Korkutata, Tsuyoshi Saitoh, Yoan Cherasse, Shuji Ioka, Feng Duo, Rujie Qin, Nobuyuki Murakoshi, Shinya Fujii, Xuzhao Zhou, Fumihiro Sugiyama, Jiang-Fan Chen, Hidetoshi Kumagai, Hiroshi Nagase, Michael Lazarus. Enhancing endogenous adenosine A2A receptor signaling induces slow-wave sleep without affecting body temperature and cardiovascular function, europharmacolo gy, https://doi. org/10.1016/j. Neuropharm. 2018.10.022.
(3) National Research Council Guide for the Care and Use of Laboratory Animals
(eighth ed.). National Academy Press, Washington, D.C. (2011)
(4) Y. Oishi, Y.; Takata, Y.; Taguchi, S.; Kohtoh, Y.; Urade, M.; Lazarus. Polygraphic Recording Procedure for Measuring Sleep in Mice JoVE (2016) e53678 https://doi. org/10.3791/53678
(5) G.I. Paxinos, K.; B. J. Franklin. The Mouse Brain in Stereotaxic Coordinates (second ed.), Academic Press, Cambridge, Mass. (2004)

The present invention relates to heterocyclic compounds that are positive allosteric modulators of adenosine _A2A receptors and useful as sleep-inducing agents. More particularly, the present invention relates to a sleep-inducing agent capable of providing slow-wave sleep that gives particularly deep sleep.

Claims (3)

Formula (Ia) below:

(Wherein nPr is propyl .)
A medicament that is a positive allosteric modulator (PAM) targeting the adenosine _A2A receptor, comprising the compound represented by or a pharmaceutically acceptable salt thereof as an active ingredient. A pharmaceutical for inducing slow-wave sleep, comprising the compound (Ia) defined in claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. A medicament for preventing or treating insomnia, comprising the compound (Ia) defined in claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient .