RU2777915C2 - Imidazodiazepine compound - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: invention relates to a crystal form of 4-fluor-3-(2-oxo-2-{2-[4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-imidazo[1,2-a][1,4]diazepine-8(9H)-yl}ethyl)-1,3-benzoxazole-2(3H)-one, having characteristic peaks at angles 2θ(°) 7.0, 9.4, 12.3, 15.8, 17.4, 18.9, 19.6, 21.3, 23.8, 25.0.

EFFECT: 4-fluor-3-(2-oxo-2-{2-[4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-imidazo[1,2-a][1,4]diazepine-8(9H)-yl}ethyl)-1,3-benzoxazole-2(3H)-one in a crystal form, having positive allosteric modulating effect (PAM effect) on dopamine D1 receptor.

1 cl, 12 tbl, 14 ex

Description

The field of technology to which the invention belongs

[0001]

The present invention relates to an imidazodiazepine compound which has a positive allosteric modulating effect (hereinafter referred to as PAM action) on the dopamine D1 receptor, and which is intended as an active ingredient in pharmaceutical compositions, in particular pharmaceutical compositions for the prevention and/or treatment of cognitive impairment, negative symptoms of schizophrenia, cognitive impairment associated with schizophrenia (CIAS), Parkinson's disease, Alzheimer's disease, Huntington's disease, depression, attention deficit hyperactivity disorder (ADHD), drug dependence syndrome or the like.

Prerequisites for the creation of the invention

[0002]

Dopamine receptors are G-protein coupled receptors that are expressed in the central nervous system. Dopamine receptors are classified into the D1-like receptor family and the D2-like receptor family. Of the dopamine receptors, dopamine D1 and D5 receptors belong to the D1-like receptor family, and dopamine D2, D3 and D4 receptors belong to the D2-like receptor family.

[0003]

The dopamine D1 receptor has been reported to couple with Gs, which is a promoter G protein, to activate adenylate cyclase and increase cAMP production in the cell to stimulate protein kinase A activity, and also exhibit various functions (Medicinal Research Reviews, 2009, vol. 29(2) , pp. 272-294).

[0004]

There is a report suggesting that decreased levels of dopamine D1 receptors in the prefrontal cortex play a key role in cognitive impairment and the negative symptoms of schizophrenia. Because in patients with schizophrenia, levels of dopamine D1 receptors were significantly reduced in a part of the frontal lobe called the prefrontal cortex. Also, since the degree of reduction in dopamine D1 receptors correlated with the results of the Wisconsin Card Sorting Test, which is a measure of the intensity of negative symptoms of schizophrenia and frontal lobe function (Nature, 1997, vol. 385(6617), p. 634-636).

[0005]

It has been reported that even in patients with depression, as in patients with schizophrenia, there was a functional impairment in the prefrontal cortex (Psychiatry Research, 1999, vol. 89, p. 171-187).

[0006]

A dopamine D1 receptor agonist has been reported to be useful in a model of cognitive impairment (European Neuropsychopharmacology, 2009, vol. 19(6), p. 440-450; Psychopharmacology, 2010, vol. 210(3), p. 407-418; Molecular Pharmacology , 2007, vol. 71(6), pp. 1598-1609 and Annals of the New York Academy of Sciences, 1996, vol. 777, pp. 427-430).

[0007]

The dopamine D1 receptor has been reported to be associated with the negative symptoms of schizophrenia (The American Journal of Psychiatry, 2002, vol. 159(5), p. 761-767; and Pharmacopsychiatry, 2006, vol. 39(3), p. 115-116 ).

[0008]

Therefore, a dopamine D1 receptor agonist is proposed as a drug that stimulates the dopamine D1 receptor in the prefrontal cortex and can improve cognitive impairment, negative symptoms of schizophrenia, CIAS, and depression.

[0009]

There is a report suggesting that a dopamine D1 receptor agonist is believed to be useful in Parkinson's disease (Current Opinion in Investigational Drugs, 2001, vol. 2(11), p. 1582-1591) and Alzheimer's disease (The Journal of Biological Chemistry , 2011, vol.286(5), pp. 3270-3276).

[0010]

In addition, a dopamine D1 receptor agonist has been reported to be effective in every animal model of Huntington's disease (Neurodegenerative Diseases, 2011, vol. 8(4), p. 230-239) and drug dependence syndrome (Neuroscience Letters, 2012, vol. 513 (2), pp. 214-218).

[0011]

Moreover, it has been suggested that a dopamine agonist could potentially be used to treat cognitive impairment in ADHD (Neuropsychologia, 2013, vol. 51(2), p. 235-266; and Pharmacogenomics and Personalized Medicine, 2014, vol. 7, p 349-356).

[0012]

Therefore, it is hypothesized that a compound that stimulates the dopamine D1 receptor may be promising as an agent for the prevention and/or treatment of diseases such as cognitive impairment, negative symptoms of schizophrenia, CIAS, Parkinson's disease, Alzheimer's disease, Huntington's disease, depression, ADHD, syndrome drug addiction or the like.

[0013]

A dopamine D1 receptor agonist is also used as a peripherally acting antihypertensive agent (The New England Journal of Medicine, 2001, vol. 345(21), p. 1548-1557). Meanwhile, it has been reported, for example, that dihydrexidine, which is a dopamine D1 receptor agonist that has been developed for Parkinson's disease, causes a decrease in blood pressure as a side effect, although it is effective in Parkinson's disease (Clinical Neuropharmacology, 1998, vol. 21(6 ), pp. 339-343).

[0014]

Therefore, it is expected that there will be a compound that stimulates the dopamine D1 receptor but does not have a side effect such as lowering blood pressure.

[0015]

The G-protein coupled receptor has been studied for a long time as an important target for drug development. In recent years, it has become clear that many G-protein coupled receptors also have allosteric sites other than orthosteric ligand sites (ACS Chemical Biology, 2008, vol. 3(9), p. 530-541). In this regard, research has been actively carried out to search for new drugs, where the targets are allosteric sites in G-protein coupled receptors (British Journal of Pharmacology, 2012, vol. 165(6), p. 1659-1669).

[0016]

A positive allosteric modulator (hereinafter referred to as PAM) is a compound that binds to a site other than the endogenous ligand binding site to enhance receptor function. PAM does not enhance receptor function by itself, but enhances receptor function in the presence of a ligand.

[0017]

Therefore, it is proposed that dopamine D1 receptor PAM (hereinafter referred to as D1 PAM) has a PAM effect on the dopamine D1 receptor, can be used for the prevention and/or treatment of cognitive impairment, negative symptoms of schizophrenia, CIAS, Parkinson's disease, Alzheimer's disease, Huntington's disease, depression. , ADHD, drug dependence syndrome or the like, and is useful as a drug with fewer side effects compared to a dopamine D1 receptor agonist.

[0018]

Patent Document 1 reports that the compound of formula (A) has the action of a benzodiazepine ω ₃ receptor agonist. The claims describe a tranquilizer or antidepressant.

[0019]

[Chemical formula 1]

(In the formula, R ¹ and R ² form a saturated heterocyclic group, which may be substituted, together with the nitrogen atom to which they are attached. However, (1), in the case of (a) or (b) below, R ¹ and R ² do not form a saturated heterocyclic group which may be substituted together with the nitrogen atom to which they are bonded.In (a), all substituents R ⁵ , R ⁶ , R ⁷ and R ⁸ are hydrogen atoms.In (b), one or two of the substituents R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently halogen atoms and the rest are hydrogen atoms X is O, S, NR ¹⁰ or CR ¹¹ R ¹² See also in this post).

[0020]

Patent Document 2 reports that the compound of formula (B) has urotensin II antagonistic and inhibitory effects, and is useful in congestive heart failure or the like.

[0021]

[Chemical formula 2]

(See this post for other symbols.)

[0022]

Patent Document 3 reports that the compound of formula (C) has cannabinoid 1 antagonist and/or inverse agonist activities and is useful as a central functional agent or the like.

[0023]

[Chemical formula 3]

(In the formula, each of R ¹ and R ² is alkyl, cycloalkyl, aryl, aryl-alkyl, heteroaryl, heteroaryl-alkyl, or the like. See this publication for other symbols.)

[0024]

Patent Document 4 reports that the compound of formula (D) is useful in the treatment and/or prevention of dyskinesia and/or motor fluctuation.

[0025]

[Chemical formula 4]

(In the formula, each of R ³ and R ^3a is H or unsubstituted C _1-4 alkyl. See this publication for other symbols.)

[0026]

Patent Document 5 reports that the compound of formula (E) is useful in the treatment and/or prevention of schizophrenia.

[0027]

[Chemical Formula 5]

(See this post for other symbols.)

Prior Art

Patent Documents

[0028]

Patent Document 1: WO 2005/080334

Patent Document 2: WO 2008/011551

Patent document 3: WO 03/077847

Patent Document 4: WO 2005/118561

Patent Document 5: WO 2014/171528

Disclosure of the present invention

Problems Solved by the Present Invention

[0029]

Provided is a compound that has a PAM action on the dopamine D1 receptor and is intended as an active ingredient in pharmaceutical compositions, in particular pharmaceutical compositions for the prevention and/or treatment of cognitive impairment, negative symptoms of schizophrenia, CIAS, Parkinson's disease, Alzheimer's disease, Huntington's disease, depression, ADHD or drug dependence syndrome.

Ways to solve problems

[0030]

The present inventors have carefully studied a compound having a PAM effect on the dopamine D1 receptor. As a result, they found that the imidazodiazepine compound of the present invention has a PAM action on the dopamine D1 receptor, thereby completing the present invention.

Thus, the present invention relates to a compound of formula (I) or a salt thereof, as well as a pharmaceutical composition containing a compound of formula (I) or a salt thereof and an excipient:

[0031]

[Chemical formula 6]

(in the formula:

R ¹ , R ² and R ³ are the same or different from each other and represent H, halogen, lower alkyl or halogen-lower alkyl;

R ⁴ is H, halo, lower alkyl or halo-lower alkyl;

R ⁵ is H;

R ⁶ is phenyl which may be substituted; or

R ⁵ and R ⁶ may form a benzene ring, which may be substituted, together with the carbon atoms to which they are attached; and

---- represents a single bond or a double bond.)

In addition, unless otherwise indicated, when symbols used in a particular chemical formula in the present specification are also used in another chemical formula, the same symbol has the same meaning.

[0032]

In addition, the present invention relates to a pharmaceutical composition for the prevention and/or treatment of cognitive impairment, negative symptoms of schizophrenia, CIAS, Parkinson's disease, Alzheimer's disease, Huntington's disease, depression, ADHD or drug dependence syndrome, which contains a compound of formula (I) or its salt.

In addition, the specified pharmaceutical composition includes an agent for the prevention and/or treatment of cognitive impairment, negative symptoms of schizophrenia, CIAS, Parkinson's disease, Alzheimer's disease, Huntington's disease, depression, ADHD or drug dependence syndrome, which contains the compound of formula (I) or its salt .

In addition, the present invention relates to:

(1) the use of a compound of formula (I) or a salt thereof for the preparation of a pharmaceutical composition for the prevention and/or treatment of cognitive impairment, negative symptoms of schizophrenia, CIAS, Parkinson's disease, Alzheimer's disease, Huntington's disease, depression, ADHD, or drug dependence syndrome;

(2) the use of a compound of formula (I) or a salt thereof for the prevention and/or treatment of cognitive impairment, negative symptoms of schizophrenia, CIAS, Parkinson's disease, Alzheimer's disease, Huntington's disease, depression, ADHD, or drug dependence syndrome;

(3) a compound of formula (I) or a salt thereof for the prevention and/or treatment of cognitive impairment, negative symptoms of schizophrenia, CIAS, Parkinson's disease, Alzheimer's disease, Huntington's disease, depression, ADHD, or drug dependence syndrome; and

(4) a method for preventing and/or treating cognitive impairment, negative symptoms of schizophrenia, CIAS, Parkinson's disease, Alzheimer's disease, Huntington's disease, depression, ADHD, or a drug dependence syndrome, which comprises administering to a subject an effective amount of a compound of formula (I) or a salt thereof .

[0033]

As used herein, "subject" refers to a human or other animal in need of such prophylaxis or treatment, and, in a specific embodiment, a human in need of such prophylaxis or treatment.

Invention Effects

[0034]

The compound of formula (I) or a salt thereof has a PAM action at the dopamine D1 receptor and can be used as an agent for the prevention and/or treatment of cognitive impairment, negative symptoms of schizophrenia, CIAS, Parkinson's disease, Alzheimer's disease, Huntington's disease, depression, ADHD or drug dependence syndrome.

Embodiments of the invention

[0035]

Hereinafter, the present invention will be described in detail.

"Alkyl" and "alkylene" both mean a straight or branched saturated hydrocarbon chain and mean a monovalent group and a divalent group, respectively.

[0036]

"Lower alkyl" is an alkyl containing from 1 to 6 carbon atoms (hereinafter referred to as C _1-6 ), for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n -pentyl, n-hexyl or the like; in one embodiment, C _1-4 alkyl; in one embodiment, methyl or ethyl; and in one embodiment, methyl.

[0037]

"Lower alkylene" is C _1-6 alkylene, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, methylmethylene, ethylethylene, 1,2-dimethylethylene, 2,2-dimethylethylene, 1,1,2,2- tetramethylethylene or the like; in one embodiment, C _1-4 alkylene; in one embodiment, ethylene or 2,2-dimethylethylene; and in one embodiment, ethylene.

[0038]

"Halogen" means F, Cl, Br or I.

[0039]

"Halo-lower alkyl" is C _1-6 alkyl substituted with one or more halogen atoms; in one embodiment, C _1-6 alkyl substituted with one to five halogen atoms; and in one embodiment, CF ₃ .

[0040]

As used herein, the term "may be substituted" means that the compound is unsubstituted or has one to four substituents; and in one embodiment, the compound is unsubstituted or has one to three substituents. In case there are multiple substituents, these substituents may be the same or different from each other.

[0041]

In the term "phenyl" which may be substituted in R ⁶ , the substituent in one embodiment includes R ^A1 and in one embodiment R ^A2 . R ^A1 is a group selected from the group consisting of -OH, -O-lower alkyl, -CN, halogen, lower alkyl, halogen-lower alkyl, lower alkylene-O-lower alkyl, -C(=O)-lower alkyl and -C(=O)-lower alkylene-CN. R ^A2 is a group selected from the group consisting of halogen, lower alkyl and halogen-lower alkyl.

[0042]

In the term "may form a benzene ring, which may be substituted, together with the carbon atoms to which they are bonded" in R ⁵ and R ⁶ , in one embodiment the substituent includes R ^B1 and in one embodiment R ^B2 . R ^B1 is a group selected from the group consisting of -OH, -O-lower alkyl, -CN, halogen, lower alkyl, halogen-lower alkyl, lower alkylene-O-lower alkyl, -C(=O)-lower alkyl and -C(=O)-lower alkylene-CN. R ^B2 is a group selected from the group consisting of halogen, lower alkyl and halogen-lower alkyl.

[0043]

Embodiments of the present invention are given below.

(1) In one embodiment, a compound of formula (I) or a salt thereof, wherein R ¹ , R ² and R ³ are the same or different and are H or halogen.

(2) In one embodiment, a compound of formula (I) or a salt thereof, wherein R ¹ is H.

(3) In one embodiment, a compound of formula (I) or a salt thereof, wherein R ² is H or halogen; or in one embodiment, a compound of formula (I) or a salt thereof, wherein R ² is H, F, or Cl; or in one embodiment, a compound ^of formula (I) or a salt thereof, wherein R2 is H.

(4) In one embodiment, a compound of formula (I) or a salt thereof, wherein R ³ is H or halogen; or in one embodiment, a compound of formula (I) or a salt thereof, wherein R ³ is H or F; or in one embodiment, a compound of formula (I) or a salt thereof, wherein R ³ is halogen.

(5) In one embodiment, a compound of formula (I) or a salt thereof, wherein R ⁴ is H or halogen; or in one embodiment, a compound of formula (I) or a salt thereof, wherein R ⁴ is H or F; or in one embodiment, a compound of formula (I) or a salt thereof, wherein R ⁴ is H.

(6) In one embodiment, a compound of formula (I) or a salt thereof, wherein R ⁵ is H.

(7) In one embodiment, a compound of formula (I) or a salt thereof, wherein R ⁶ is phenyl which may be substituted with one to four R ^A1 substituents that are the same or different from each other; or in one embodiment, a compound of formula (I) or a salt thereof, wherein R ⁶ is phenyl which may be substituted with one R ^A2 substituent; or in one embodiment, a compound of formula (I) or a salt thereof, wherein R ⁶ is phenyl which may be substituted with one R A 2 ^substituent para from its bond.

(8) In one embodiment, a compound of formula (I), or a salt thereof, wherein R ⁵ and R ⁶ may form, together with the carbon atoms to which they are attached, a benzene ring which may be substituted with one to four R ^B1 substituents, which are the same or different from each other.

(9) In one embodiment, a compound of formula (I) or a salt thereof, wherein

---- represents a simple relationship.

(10) A compound of formula (I) or a salt thereof, which is a sequential combination of two or more of the groups described in (1) to (9) above.

[0044]

Examples of a compound that is a combination of embodiments like those in (10) above are illustrated as follows.

(11) In one embodiment, a compound of formula (I) or a salt thereof, wherein R ¹ is H, R ² is H or halogen, R ³ is halogen, R ⁴ is H, and ---- is is a simple connection.

(12) In one embodiment, a compound of formula (I) or a salt thereof, wherein R ¹ is H, R ² is H or halogen, R ³ is halogen, R ⁴ is H, R ⁵ is H, R ⁶ is phenyl which may be substituted and ---- is a single bond.

(13) In one embodiment, a compound of formula (I) or a salt thereof, wherein R ¹ is H, R ² is H, R ³ is halogen, R ⁴ is H, R ⁵ is H, R ⁶ is phenyl which may be substituted with one to four R ^A1 substituents that are the same or different from each other, and ---- is a single bond.

(14) In one embodiment, a compound of formula (I) or a salt thereof, wherein R ¹ is H, R ² is H or halogen, R ³ is halogen, R ⁴ is H, R ⁵ and R ⁶ may form a benzene ring, which may be substituted, together with the carbon atoms to which they are bonded, and ---- is a single bond.

(15) In one embodiment, a compound of formula (I) or a salt thereof, wherein R ¹ is H, R ² is halogen, R ³ is halogen, R ⁴ is H, R ⁵ and R ⁶ together with atoms the carbons to which they are bonded may form a benzene ring which may be substituted with one to four R ^B1 substituents that are the same or different from each other, and ---- is a single bond.

(16) In one embodiment, a compound of formula (I) or a salt thereof, wherein R ⁵ is H and R ⁶ is phenyl, which may be substituted.

(17) In one embodiment, the compound or salt thereof according to (16), wherein ---- is a single bond.

(18) In one embodiment, the compound or salt thereof according to (17), wherein R ⁴ is H.

(19) In one embodiment, the compound or salt thereof according to (18), wherein R ¹ is H, R ² is H or halogen, and R ³ is halogen.

(20) In one embodiment, the compound or salt thereof according to (19), wherein R ⁶ is phenyl which may be substituted with one to four R ^A1 substituents that are the same or different from each other, and R ^A1 is a group selected from the group consisting of -OH, -O-lower alkyl, -CN, halogen, lower alkyl, halogen-lower alkyl, lower alkylene-O-lower alkyl, -C(=O)-lower alkyl and -C( =O)-lower alkylene-CN.

(21) In one embodiment, the compound or salt thereof according to (20), wherein R ⁶ is phenyl which may be substituted with one substituent R ^A 2 , and R ^A 2 is a group selected from the group consisting of halo, lower alkyl and halo-lower alkyl.

(22) In one embodiment, the compound or salt thereof according to (21), wherein R ² is H.

(23) In one embodiment, the compound or salt thereof according to (22), wherein R ⁶ is phenyl which may be substituted with one R A 2 ^substituent para from its bond.

[0045]

Examples of specific compounds covered by the present invention include the following compounds and their salts:

4-fluoro-3-(2-oxo-2-{2-[4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-imidazo[1,2-a][1,4]diazepine-8( 9H)-yl}ethyl)-1,3-benzoxazol-2(3H)-one,

4-fluoro-3-{2-[2-(2-fluorophenyl)-6,7-dihydro-5H-imidazo[1,2-a][1,4]diazepin-8(9H)-yl]-2 -oxoethyl}-1,3-benzoxazol-2(3H)-one,

3-[2-(4,5-dihydro-1H-[1,4]diazepino[1,2-a]benzimidazol-2(3H)-yl)-2-oxoethyl]-4,5-difluoro-1, 3-benzoxazol-2(3H)-one,

4-fluoro-3-[2-(8-fluoro-4,5-dihydro-1H-[1,4]diazepino[1,2-a]benzimidazol-2(3H)-yl)-2-oxoethyl]- 1,3-benzoxazol-2(3H)-one,

4,5-difluoro-3-[2-oxo-2-(2-phenyl-6,7-dihydro-5H-imidazo[1,2-a][1,4]diazepin-8(9H)-yl) ethyl]-1,3-benzoxazol-2(3H)-one,

4-fluoro-3-{2-[2-(3-fluorophenyl)-6,7-dihydro-5H-imidazo[1,2-a][1,4]diazepin-8(9H)-yl]-2 -oxoethyl}-1,3-benzoxazol-2(3H)-one, and

3-{2-[2-(4-chlorophenyl)-6,7-dihydro-5H-imidazo[1,2-a][1,4]diazepin-8(9H)-yl]-2-oxoethyl}- 4-fluoro-1,3-benzoxazol-2(3H)-one.

[0046]

In the compound of formula (I), a tautomer may exist depending on the kind of substituents. In the present description, the compound of formula (I) is described in only one form of isomers, but the present invention includes other isomers and also includes compounds from which isomers are isolated, or mixtures thereof.

In addition, there is the case of a compound of formula (I) containing asymmetric carbon atoms. Based on this, optical isomers exist in the compound of formula (I). In the present invention, the compound of formula (I) also includes compounds from which optical isomers have been isolated, or mixtures thereof.

[0047]

In addition, the present invention includes a pharmaceutically acceptable prodrug of the compound of formula (I). A pharmaceutically acceptable prodrug is a compound containing a group that can be converted to an amino group, a hydroxyl group, a carboxyl group, or the like, by solvolysis or under physiological conditions. As a prodrug-forming group, for example, the group described in Progress in Medicine, 1985, vol. 5, p. 2157-2161 or "Pharmaceutical Research and Development" (Hirokawa Publishing Company), 1990, vol. 7 (Drug Design), p. 163-198.

[0048]

In addition, the salt of the compound of formula (I) is a pharmaceutically acceptable salt of the compound of formula (I), and the formation of acid addition salts or salts with a base is possible, depending on the kind of substituents. Specific examples of such salts include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid, and acid addition salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, para-toluenesulfonic acid, aspartic acid and glutamic acid; salts with alkali metals such as sodium or potassium; salts with alkaline earth metals such as calcium and magnesium; salts with metals such as aluminium; salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine and ornithine; salts with various amino acids such as acetyleucine and amino derivatives; and ammonium salts.

[0049]

In addition, the present invention also includes various hydrates, solvates and crystalline polymorphs of the compound of formula (I) and its salts. Moreover, the present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.

[0050]

"Positive allosteric modulating action (PAM action)" means an action that enhances the function of a receptor by binding to a site other than the site to which the endogenous ligand binds relative to the receptor.

"Positive allosteric modulator (PAM)" means a compound having a PAM action. For example, in Test Example 1, PAM means a compound that shifts the dopamine dose-response curve to the left.

PAM does not enhance receptor function by itself, but enhances receptor function in the presence of a ligand.

[0051]

The names of the diseases in this description correspond to the International Classification of Diseases " ^ICD10 " of the World Health Organization (WHO), 5th edition of the Diagnostic and Statistical Manual (DSM-5) of Mental Disorders of the American Psychiatric Association (APA) and/or the Japanese Society of Neurology.

[0052]

"Schizophrenia" is a disease characterized by deterioration in various mental functions such as cognition, emotions, motivation, behavior and self-awareness. Its symptoms are classified into positive and negative symptoms and cognitive impairment. A positive symptom, for example, is a symptom such as hallucination, delusion or the like. A negative symptom, for example, is social withdrawal or emotional flattening.

"Negative symptom of schizophrenia" is a negative symptom in schizophrenia.

"Cognitive impairment associated with schizophrenia (CIAS)" are cognitive impairments associated with schizophrenia.

[0053]

(Obtaining method)

The compound of formula (I) and its salt can be obtained by applying various known synthetic methods using characteristics based on the type of its basic structure or substituent. At present, there is a technologically efficient option in the preparation technology, when, according to the type of functional group, this functional group is replaced by a suitable protecting group (a group that can be easily converted into a functional group) from the starting material to the intermediate. As a protecting group, for example, examples of protecting groups are given in "Greene's Protective Groups in Organic Synthesis", published by Peter G. M. Wuts and Theodora W. Greene, fourth edition, 2006. These protecting groups can be selected and used depending on reaction conditions. In this method, after carrying out the reaction by introducing a protecting group, if necessary, the desired compound can be obtained by removing the protecting group.

In addition, the prodrug of the compound of formula (I), similar to the above protecting group, can be obtained by introducing a specific group or by carrying out a further reaction using the obtained compound of formula (I) from the starting material to the intermediate. The reaction can be carried out using a method known to those skilled in the art such as total esterification, amidation, dehydration, or the like.

In the following, standard methods for preparing compounds of formula (I) will be described. Each of the production methods can also be carried out by referring to the Reference Documents attached in the respective description. The production method of the present invention is not limited to the following Examples.

[0054]

In the present description, the following abbreviations are used.

DMF=N,N-dimethylformamide, DMSO=dimethyl sulfoxide, EtOAc=ethyl acetate, EtOH=ethanol, Hex=hexane, MeCN=acetonitrile, MeOH=methanol, THF=tetrahydrofuran.

nBuLi=n-butyllithium, CDI=1,1'-carbonyl bis(1H-imidazole), DCC=N,N'-dicyclohexylcarbodiimide, DBU=1,8-diazabicyclo[5.4.0]undeca-7-ene, DIPEA =N,N-diisopropylethylamine, DMAP=N,N-dimethyl-4-aminopyridine, DPPA=diphenylphosphoryl azide, HATU=O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, HOBt=1-hydroxybenzotriazole, KOtBu=potassium tert-butoxide, NaOtBu=sodium tert-butoxide, NMM=N-methylmorpholine, NMP=N-methyl-2-pyrrolidone, Pd/C=palladium on carbon, PPh ₃ =triphenylphosphine, Pd2dba3 =tris(dibenzylideneacetone)dipalladium(0), TBAB=tetrabutylammonium bromide, TEA=triethylamine, TFA=trifluoroacetic acid, WSC=N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide, WSC HCl=N-[3- (dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride, xantphos=9,9'-dimethyl-4,5-bis(diphenylphosphino)xanthene.

Silica gel CC=silica gel column chromatography.

Saturated saline = saturated aqueous NaCl, saturated aqueous sodium bicarbonate = saturated aqueous NaHCO ₃ , MgSO ₄ = anhydrous magnesium sulfate, Na ₂ SO ₄ = anhydrous sodium sulfate.

[0055]

The following abbreviations are used in the structural formulas and groups in the present specification.

Ac=acetyl, BOC=t-butoxycarbonyl, t-Bu=t-butyl, Et=ethyl, Halo=halogen, Me=methyl, MsO=methanesulfonyloxy, MOM=methoxymethyl, TBDMS=t-butyldimethylsilyl, TsO=p-toluenesulfonyloxy.

[0056]

(First way to get)

[0057]

[Chemical Formula 7]

The compound of formula (I) can be obtained from compound (1) and compound (2).

In this reaction, compound (1) and compound (2) are used in equivalent amounts, or both compounds in excess, and their mixture is usually stirred in a solvent inert to the reaction in the presence of a condensing agent for 0.1 hour to 5 days under conditions from cooling to heating, preferably from -20°C to 60°C. Examples of the solvent include aromatic hydrocarbons such as toluene or the like; halogenated hydrocarbons such as dichloromethane or the like; ethers such as THF or the like; DMF; NMP; DMSO; EtOAc; MeCN; water; and their mixtures. Examples of the condensing agent include HATU, WSC, WSC·HCl, DCC, CDI, DPPA and the like. Sometimes the use of an additive (eg HOBt) is preferred for the reaction. In some cases, this reaction is further smoothly carried out in the presence of an organic base such as TEA, DIPEA, NMM or the like, or an inorganic base such as K ₂ CO ₃ , Na ₂ CO ₃ , KOH or the like.

[0058]

In addition, a method of converting the compound (1) into a reactive derivative and then reacting the reactive derivative with the compound (2) can be used. Examples of the reactive carboxylic acid derivative include acid halides obtained by reaction with a halogenating agent such as POCl ₃ , SOCl ₂ , (COCl) ₂ or the like; mixed acid anhydrides obtained by reaction with isobutyl chloroformate and the like; and active esters obtained by condensation with HOBt and the like. If a small amount of DMF is used as an additive in the synthesis of the acid halide, the reaction proceeds more easily. As an additive, a base such as DMAP can be used. The reaction of the reactive derivative with the compound (2) can be carried out in a reaction-inert solvent such as halogenated hydrocarbons, aromatic hydrocarbons or ethers under cooling to heating conditions, preferably -78°C to 60°C.

[References] ʺOrganic Functional Group Preparationsʺ, edited by SR Sandler and W. Karo al., second edition, vol. 1, Academic Press Inc., 1991; ʺCourses in Experimental Chemistry (fifth edition)ʺ, edited by Japan Chemical Society, vol. March 16, 2005

[0059]

(Second way to get)

[0060]

[Chemical formula 8]

(In the formulas, Halo is a halogen. The same applies to what is described below).

Compound (I-1) can be obtained from compound (3).

This reaction is the halogenation of the hydroxyl group. In a solvent inert to the reaction, PPh ₃ and a halogen source are added to the compound (3), followed by stirring for 0.5 hour to 8 hours at 20°C-100°C. As the solvent, for example, an ether-based solvent such as THF or the like is exemplified. Examples of a halogen source include bis(2-methoxyethyl)aminosulfur trifluoride, CCl ₄ , CBr ₄ and I ₂ . Here, chlorination using PPh ₃ and CCl ₄ is also called the Appel reaction.

[Literature] Angewandte Chemie International Edition, p. 801, vol. 14, 1975.

[0061]

(Method 1 of obtaining the original substance)

[0062]

[Chemical formula 9]

(In the formulas, R ^4a is H, halogen, lower alkyl, halogen-lower alkyl, or —O-lower alkyl. As shown in formula (5a), R ^4a may be substituted at any carbon atom of the propylene chain. Pg ₁ is a protective each of the substituents Lv ₁ and Lv ₂ represents a leaving group.The same applies to the following).

The starting compound (2a) can be obtained from compound (4) and compound (5a). The starting compound (2b) can be obtained from compound (4) and compound (5b). Examples of the leaving group include Hal (hereinafter, Hal is Cl, Br, or I), an MsO group, a TsO group, and the like. Examples of Pg ₁ include a benzyl group and a BOC group.

In this reaction, compound (4) and compound (5a) are used in equivalent amounts, or both compounds are used in excess, and the mixture is usually stirred in a solvent inert to the reaction or without solvent for 0.1 hour to 5 days under conditions from cooling to heating at boiling under reflux, preferably at a temperature of from 0°C to 80°C. Examples of the solvent include aromatic hydrocarbons, ethers, halogenated hydrocarbons, DMF, DMSO, EtOAc, MeCN, and mixtures thereof. In some cases, this reaction is further smoothly carried out in the presence of an organic base such as TEA, DIPEA, NMM or the like, or an organic base such as KOtBu, K ₂ CO ₃ , Na ₂ CO ₃ , NaOH or the like.

[References] ʺOrganic Functional Group Preparationsʺ, SR Sandler and W. Karo, second edition, vol. 1, Academic Press Inc., 1991; "Courses in Experimental Chemistry", fifth edition, edited by Japan Chemical Society, vol. March 14, 2005

[0063]

(Method 2 of obtaining the original substance)

[0064]

[Chemical Formula 10]

(In the formula Hal is Cl, Br or I. Pg ₂ is a protecting group. The same applies to what is described below).

Compound (8) can be obtained from compound (6) and compound (7). As Pg ₂ , the BOC group or the like is exemplified.

This reaction can be carried out in the same manner as in Method 1 for preparing the starting material. Compound (6) is added to compound (7) in a solvent inert to the reaction, followed by stirring for 1 hour to 2 days at room temperature or higher in the presence of a base. An inorganic base is used as the base, and examples thereof include K ₂ CO ₃ , Na ₂ CO ₃ , Cs ₂ CO ₃ , KOH and the like. As the solvent, MeCN or the like is exemplified.

[0065]

[Chemical formula 11]

(In the formula R, ^L is lower alkyl. The same applies as described below).

Compound (4) can be obtained from compound (8) and compound (9).

In this reaction, compound (8) and compound (9) are stirred in a reaction-inert solvent for 12 hours to 3 days at 100° C. or higher or under reflux. Examples of the solvent include aromatic hydrocarbons such as toluene or the like.

[0066]

(Method 3 of obtaining the original substance)

[0067]

[Chemical Formula 12]

(In the formula, Lv is a leaving group. n is an integer from 1 to 4. The same applies to described below).

Compound (13) can be obtained from compound (11) and compound (12).

The leaving group Lv is, for example, halogen or —OSO ₂ CF ₃ .

In this reaction, a metal such as palladium or the like and a ligand such as PPh ₃ or the like are added as a catalyst to compound (11) and compound (12) in the presence of a base in a solvent inert to the reaction, followed by stirring for 5 hours to 4 days at 20°C to 140°C. Examples of the catalyst include Pd ₂ dba ₃ and the like. Examples of the base include bis(trimethylsilyl)sodium amide, NaOtBu and the like. Examples of the solvent include dioxane and the like. This is the so-called Buchwald-Hartwig cross-coupling reaction.

[References] Journal of the American Chemical Society, p. 5969, vol. 116, 1994; Journal of the American Chemical Society, p. 7901, vol. 116, 1994; Angewandte Chemie International Edition, p. 1348, vol. 34, 1995; Tetrahedron Letters, p.3609, vol. 36, 1995.

[0068]

[Chemical formula 13]

Compound (2c) is obtained by reduction of compound (13).

This reaction is a common way to reduce the nitro group. In this reaction, iron, tin or the like is added to the compound (13) in a solvent such as hydrochloric acid, acetic acid or the like, followed by stirring for 0.5 hour to 3 days at 50°C to 140°C .

[0069]

(Product method of starting material 4)

[0070]

[Chemical formula 14]

(In the formula (R ^P , R ^P' ) is a combination of (imidazolyl, imidazolyl), (Cl ₃ CO-, -O-CCl ₃ ), (Cl, -O-CCl ₃ ) (Cl, -O-phenyl) , (Cl, -O-p-nitrophenyl).)

Compound (16) can be obtained from compound (14) and compound (15).

In this reaction, the compound (14) is added to an equivalent amount or an excess amount of the compound (15) in a solvent inert to the reaction, and preferably the mixture is stirred for 0.1 hour to 1 day under cooling to heating conditions, preferably 50 °C to 150°C. Examples of the solvent include halogenated hydrocarbons, aromatic hydrocarbons, ethers, DMF, DMSO, EtOAc, MeCN, and mixed solvents including them. Compound (15) is also known as a carbonyl reagent, and examples thereof include 4-nitrophenyl chloroformate and phenyl chloroformate, as well as CDI, diphosgene, and triphosgene. When the phenyl carbonate form, which is an intermediate, is stable (for example, when 4-nitrophenyl chloroformate or phenyl chloroformate is used), the intermediate is immediately isolated and the reaction can be carried out again.

[Literature] ʺOrganic Functional Group Preparationsʺ published by S.R. Sandler and W. Karo, second edition, Academic Press Inc., vol. 2, 1991.

[0071]

[Chemical Formula 15]

(In the formula, Pg ₃ is a protecting group. The same applies to what is described below).

Compound (1) can be obtained from compound (16) and compound (17).

Pg ₃ The ester form of compound (1) can be obtained from compound (16) and compound (17). As the leaving group, for example, an MsO group, a TsO group, or the like, in addition to Hal, can be used. Examples of the Pg ₃ protecting group include a Me group, an Et group, a tBu group, and the like.

In this reaction, compound (16) and compound (17) are used in equivalent amounts, or both compounds are used in excess, and their mixture is stirred in the presence of a base. As the solvent, MeCN or the like is exemplified. In some cases, the reaction proceeds more smoothly when using a phase transfer catalyst such as TBAB or the like.

Compound (1) is obtained by removing Pg ₃ protection from the resulting Pg ₃ ester for compound (1). Deprotection can be done with reference to "Greene's Protective Groups in Organic Synthesis", Peter GM Wuts and Theodora W. Greene, fourth edition, 2006.

[0072]

The compound of formula (I) is purified by isolating the free compound or its salt, hydrate, solvate or crystalline polymorph. A salt of a compound of formula (I) can also be prepared by a general salt formation reaction.

Isolation and purification can be accomplished by general chemical procedures such as extraction, fractional crystallization, and various types of fractional chromatography.

Various isomers can be obtained by selecting an appropriate starting compound, or they can be separated using the difference in physicochemical properties between the isomers. For example, optical isomers can be obtained using a general method for separating optical isomers of a racemic compound (eg, fractional crystallization of a diastereomeric salt with an optically active base or acid, or chromatography using a chiral column), and they can be obtained from a suitable optically active starting compound.

In the powder X-ray diffraction pattern given in the present description, in order to confirm the identity of the crystals, due to the nature of the data, the intervals of the crystal lattice and the diagram as a whole are important, and regarding the angle of diffraction and the pattern of diffraction intensity, there may be some errors depending on the direction of crystal growth , particle size and measurement conditions. Therefore, a strict interpretation should not be required. In the present description, the diffraction angle (2θ(°)) in an X-ray powder diffraction pattern is interpreted in terms of the generally accepted error range in the corresponding measurement method, and in one aspect there may be an error range of ±0.2°. In addition, for example, in the case where the measurement is carried out in the state of mixture with the excipient, in the peak located on the slope of the baseline existing near the peak obtained from the excipient, there is obviously a possibility that the peak is shifted by about ±0.3 °.

[0073]

The pharmacological activity of the compound of formula (I) was evaluated using the following tests.

[0074]

(abbreviations)

In the present description, in particular in the Test Examples, the following abbreviations are used.

ATCC=American Type Culture Collection, CHO cell=Chinese hamster ovary cell, FBS=fetal bovine serum, IBMX=3-isobutyl-1-methylxanthine, MTX=methotrexate, αMEM=alpha-modified minimum required medium Needle containing ribonucleoside and free from deoxynucleoside L-glutamine, TR-FRET=time resolved fluorescence inductive resonance energy transfer, NMDA=N-methyl-D-aspartic acid, PCP=phencyclidine, WCST=Wisconsin card sorting test, SD2=simple discrimination 2, CD=mixed discrimination, ID=intradimensional shift, IDR=ID shift reversal, ED=extradimensional shift, EDR=ED shift reversal, CIAS=cognitive impairment associated with schizophrenia, ADHD=attention deficit hyperactivity disorder.

[0075]

(Material)

The composition of the buffer solution used in Test Example 1 is described.

Assay Buffer=αMEM containing 1 mM IBMX

Dilution buffer=αMEM containing 1 mM IBMX and 0.8 mM ascorbic acid

[0076]

Test Example 1

Assessment of Positive Allosteric Modulating Action (PAM action)

The PAM effect of the compound of the present invention was assessed by the degree of leftward shift in the dose-response curve for dopamine.

A left shift means that the dose-response curve of dopamine, in which the logarithm of dose is set on the abscissa (X-axis) and the response (in this trial, cAMP concentration) is set on the ordinate (Y-axis), is parallel shifted in the negative direction of the X-axis at adding PAM.

[0077]

(Determination of a cell stably expressing the human dopamine D1 receptor)

The human dopamine D1 receptor coding sequence (Access No: NM_000794.3) was amplified by PCR and subcloned into the pEF-BOS vector. The resulting construct was transfected into a CHO (dhfr-) cell (ATCC no: CRL-9096) using Lipofectamine 2000 (manufactured by Thermo Fisher Scientific Inc., Lipofectamine is a registered trademark). A stably transfected clone was obtained by selection using 100 nM MTX. The resulting cell clone was maintained in αMEM containing 10% FBS, penicillin and streptomycin.

[0078]

(test method)

(1) Dose-response curve of dopamine to which the compound of the present invention was added

A dose-response curve of dopamine to which the test drug was added was obtained by performing the following experiment.

A serially diluted test drug solution was prepared using assay buffer (concentration 0.49 μM - 40 μM, 3-fold dilution). The above serially diluted test drug solution was dispensed into a black 384-well plate (Corning Inc.) at 2.5 μl.

CHO cells stably expressing the human dopamine D1 receptor were seeded in each well at a density of about 5000 cells per well at a concentration of 5 μl, centrifuged in a plate centrifuge (05PR-22, Hitachi Koki Co., Ltd., 800 rpm) and then left to stand for 10 minutes.

A serially diluted dopamine solution was prepared by diluting a DMSO solution of dopamine (Sigma-Aldrich Co. LLC) with a buffer solution (concentration from 0.018 μM to 13.3 μM, 3-fold dilution). The above serially diluted dopamine solution was dispensed into each well of the plate at 2.5 μl.

The plate was stirred using a plate shaker (mx-5, Sanko Junyaku Co., Ltd.) and then left to stand for 15 minutes to 20 minutes at room temperature (final concentration: test drug 0 μM - 10 μM, dopamine 0 μM - 3.3 μM, 3-fold dilution).

For cAMP measurement, the LANCE Ultra cAMP kit (PerkinElmer Inc., LANCE is a registered trademark) was used. The reagents from the Eu-cAMP indicator solution kit and the ULight-anti-cAMP solution (ULight is a registered trademark), respectively, were added to each well of the above plate in an amount of 5 μl, and the reaction was stopped. The plate was incubated at room temperature for 1 hour, and then the fluorescence intensity at 665 nm and 620 nm (excitation wavelength: 320 nm, fluorescence wavelength: 665 nm, 620 nm) was measured by TR-FRET using a plate reader (2103 Multilabel Plate Reader (registered trademark of Envision, PerkinElmer, Inc.). The ratio of fluorescence intensity [(fluorescence intensity at 665 nm)/(fluorescence intensity at 620 nm) x 10 ⁴ ] of each well was calculated and used for analysis.

As a control group, a well in which no dopamine was added was set to 0%, and a well in which the final concentration of dopamine was 3.3 μM was set to 100%.

(2) Dopamine dose-response curve

A dose-response curve for dopamine was obtained by conducting the experiment without test drug in a manner similar to that described in paragraph (1).

[0079]

(Activity Score)

From the test results, it was found that the dose-response curve of dopamine (1), to which the compound of the example of the present invention was added, was shifted to the left based on the dose-response curve of dopamine (2). In addition, it was found that each shift value was calculated by changing the concentration of the test drug, and thus the dopamine dose-response curve shifted to the left in a dose-dependent manner.

Thus, in the case where the dose of dopamine was 0, the test drug showed no agonist effect.

As described above, the example compound of the present invention was found to have a PAM effect.

[0080]

The results for compounds of some representative Compound Examples of the present invention are shown in Table 1.

The activity value is expressed as a shift value used as an indicator of activity.

The shift value is a value indicating to what extent the EC ₅₀ value of dopamine in 1.1 μM of the test drug was increased based on the EC ₅₀ value of dopamine without the addition of the test drug [Shift value=(the EC ₅₀ value of dopamine without the addition of the test drug) /(EC ₅₀ value of dopamine in 1.1 μM of test drug)]. Therefore, if the value of the test drug is greater than 1, this indicates that the dopamine dose-response curve was shifted to the left when the test drug was added. The EC ₅₀ value of dopamine was calculated using a dose-response curve for each dopamine.

In the Table, No. represents a compound, Ex. represents the Connection Example number, and Data 1 represents the shift amount.

[0081]

Table 1 No. Data 1 No. Data 1 Ex 1 7.3 Ex 5 3.6 Ex 2 2.3 Ex 6 2.0 Ex 3 2.0 Ex 7 6.2 Ex 4 2.0

[0082]

Here, the 2-fold potentiation of EC ₅₀ Ex 1 was 0.061 μM. The 2-fold EC ₅₀ potentiation means the concentration of the test drug at which the EC ₅₀ in the dopamine dose-response curve (2) is potentiated by 2-fold. For example, this is the test drug concentration that increases the EC ₅₀ in the dopamine dose-response curve (2) from 1.0 μM to 0.5 μM (2-fold, in other words, half the numerical value).

[0083]

Test Example 2

Y-maze method

The improving effect of the compound of the present invention on cognitive impairment was evaluated using the Y-maze method, which is an experimental spontaneous alternation of behavior system.

[0084]

(Experimental setup)

As a Y-shaped labyrinth, a labyrinth was used in which three arms, each 40 cm long, 13 cm high, 3 cm wide at the floor, and 10 cm wide at the top, are attached to each other in a Y shape at an angle of 120°.

[0085]

(test method)

Single oral administration of test drug (0.01, 0.03, 0.1 and 0.3 mg/kg suspended in 0.5% methylcellulose solution) to a 5-6 week old male ddY mouse (n=8 Japan SLC , Inc.) was performed 1 hour prior to the start of the Y-maze test, and intraperitoneal administration of MK-801 (Sigma-Aldrich Co. LLC), which is an NMDA receptor antagonist that causes cognitive impairment, to mice at a dose of 0.15 mg/kg was performed 20 minutes before the start of the Y-maze test.

In this trial, mice from the control group received a vehicle (0.5% methylcellulose solution) instead of the test drug. Moreover, saline was used instead of MK-801.

Mice from the MK-801 control group were injected with vehicle (0.5% methylcellulose) instead of the test drug.

After the above mouse was placed at the end of any lane in the Y-maze, the mouse freely explored the maze for eight minutes. The number of times the mouse entered the track was counted, and this counted number was set as the total number of visits. The number of times the mouse repeatedly entered three different lanes was counted (for example, when the three arms of the maze were represented as a, b, and c, respectively, in the case where the order of entering the lanes was abccbacab, this was counted as 4), and this was set as the number of spontaneous alternations of behavior. The rate of spontaneous alternations of behavior was calculated using the equation: Rate of spontaneous alternations of behavior=[number of spontaneous alternations of behavior/(total number of visits - 2)] × 100. The calculated level of spontaneous alternations of behavior was used as an indicator of spontaneous alternations of behavior. It has been shown that with an increase in this indicator, short-term memory is preserved.

[0086]

(Data analysis)

The measured value was presented as the mean ± standard error for each group. Significant difference analysis between the control group and the MK-801 control group was performed using Student's t-test. In addition, an analysis of the significant difference between the test drug administration group and the MK-801 control group was performed using Dunnett's multiple comparison test to determine the improving effect of the test drug on learning disabilities. With a P value < 0.05 in each analysis, it was determined that there was a significant difference.

[0087]

The results of a significant improvement in spontaneous alternation behavior for compounds of some representative examples of the present invention are presented in the table below. In the table, No. represents the connection number, Ex. represents the Compound Example number, and Data 2 represents the minimum effective dose.

[0088]

table 2 No. Data 2 Ex 1 0.03 mg/kg

[0089]

Test Example 3

The task of switching attention

The compound of the present invention was evaluated in an attention-switching test.

[0090]

The Attention Switching Test, as in the WCST, is a test to measure flexibility with respect to rule change (clue(hint)). The effect on executive dysfunction, which is one of the higher brain function disorders, can be determined using this test.

After mice were allowed to learn the task that a food reward is achieved if there is a cue, in the event that the cue changes in size (e.g., the cue changes from one shape to another shape), both the normal animal and the pathological animal having the disorder in the prefrontal cortex of the brain (hereinafter referred to as "pathological animal"), could distinguish clues (cues) to achieve nutritional rewards. However, after mice were allowed to learn the task of achieving a food reward with a cue, when the cue change is not related to size (e.g., changing the cue from shape to smell), the normal animal can distinguish the food cue, but the pathological animal can't distinguish food clue. This test adds practical application to such behavior.

[0091]

The following experiments were carried out with reference to European Journal of Neuroscience, 2005, vol. 21, p. 1070-1076 which has been partially modified.

[0092]

(test method)

1. Test equipment and animal

As test equipment, a field was used, including a starting area and a selection area, separated by a guillotine door. The selection area has been partially split so that the left and right areas are the same size, as seen from the starting area. The containers filled with contents were placed in the left and right zones one after the other, and a food reward (grain pieces, General Mill Inc.) was enclosed in them. The left and right containers were changed randomly for each trial (from start to correct response or incorrect response in trial). The rats placed in the starting area moved to the selection area when the guillotine door was opened and they were free to operate between the left and right areas of the selection area.

Rats treated subchronically with PCP were used as a pathological model. 5-week-old male Long Evans rats (Japan SLC, Inc.) were intraperitoneally injected with 2 mg/ml/kg PCP-containing saline for 7 days twice a day. The tests were carried out after a washout period of 7 or 8 days. Food intake was limited during the washout period.

[0093]

2. Addictive

The rats were returned to the start zone after the start of the test by opening the guillotine door and allowing the rats to act freely for 4 minutes. Then the containers were placed respectively in the left and right areas of the selection zone. Each of the containers was filled with alpha dry food (Shepherd Specialty Papers, alpha dry is a registered trademark), one of the total two food rewards was placed on top of each of the containers, and the other of them was placed at the bottom of each of the containers. The rats were returned to their cage after the start of the trial and it was confirmed that the rats had completely eaten the food rewards (four food rewards).

[0094]

3. Training

On the same day that was used for habituation, a simple discrimination task (SD1) was performed as training. One container was filled with plastic balls and the rim was coated with aromatic nutmeg oil. Another container was filled with wooden beads and covered with lemon scented oil. The food reward was placed in the first container only and the trial started. The rats returned to the starting area (1) after they completely ate the food reward for a correct answer, or (2) immediately after they rummaged around in the container, which meant an incorrect answer. The rats were trained until they gave the correct answers five times in a row.

[0095]

4. Test

On the next day of training, the rats were allowed to search for a food reward using the content or scent as a clue. Six discriminatory tasks related to the combination of content and flavor were completed. It was allowed to move on to the next task when each discriminative task was correctly completed five times. The test was carried out in order from the first item (SD2) to the sixth item (EDR). After completion of the CD, a single oral administration of the test drug (0.001, 0.003 and 0.01 mg/kg suspended in 0.5% methylcellulose) to rats was performed. Rats in the control group received vehicle (0.5% methylcellulose) instead of the test drug.

Table 3 shows the combinations of content and flavor in each task. Table 4 shows specific examples (example). In the tables, underlines show the correct answers (hint of the container in which the food reward was placed).

[0096]

Table 3 one SSD2 Corn chips or wood chips/None 2 CD Corn chips or wood chips/mint or ginger 3 IID Pebbles or small balls/cinnamon or orange four IIDR Pebbles or small balls / cinnamon or orange 5 EED Plastic beads or cut paper / jasmine or vanilla 6 EEDR plastic beads or cut paper/jasmine or vanilla

[0097]

Table 4 Left selection area
(content/flavor) Right selection zone
(content/flavor) one SD2 Corn chips /none Wood shavings/none 2 CD wood shavings/mint Corn chips / ginger 3 ID Pebbles / cinnamon small balls/orange four IDR Pebble/cinnamon Small balls / orange 5 ED plastic beads / jasmine Cut paper/vanilla 6 EDR plastic beads/jasmine Cut paper / vanilla

[0098]

5. Results

Number of examples - 6 examples in each group. Carried out a statistical analysis of the number of attempts to obtain the correct answers five times in a row. Student's t-test was used for the control group and PCP for the control group. A significant difference (P<0.05) was observed only in ED, and executive dysfunction was found in the PCP control group. In addition, Dunnett's multiple comparison test was used for the test drug administration group and the PCP control group to determine the effect of the test drug in improving executive dysfunction. No significant difference was observed from the first item (SD2) to the fourth item (IDR) of the discrimination task, as well as at the sixth item (EDR), and a significant difference (P<0.05) was observed only at the fifth item (ED) of the discrimination task.

[0099]

The dosage of the drug at the time of administration of the compound of a representative example of the present invention, which improves the disorder of the executive function, is shown in the table below. Etc. means the number of the connection example. Data 3 means the minimum effective dose.

[0100]

Table 5 No. Data 3 Ex 1 0.003 mg/kg

[0101]

From the above test results, it is suggested that the compound of the present invention can be used to prevent and/or treat cognitive impairment, negative symptoms of schizophrenia, CIAS, Parkinson's disease, Alzheimer's disease, Huntington's disease, depression, ADHD, or drug dependence syndrome.

[0102]

A pharmaceutical composition containing as active ingredient one or two or more compounds of formula (I) or salts thereof can be prepared by a commonly used method with a commonly used excipient well known in the art, i.e. a pharmaceutical excipient or a pharmaceutical carrier.

Administration can be any form of oral administration using tablets, pills, capsules, granules, powders or solutions and parenteral administration using intra-articular, intravenous or intramuscular injections, suppositories, eye drops, eye ointments, transdermal liquids, ointments, transdermal patches, transmucosal solutions, transmucosal patches or inhalation preparations.

[0103]

As a solid composition for oral administration, tablets, powders, granules and the like are used. In this solid composition, one or two or more active ingredients are mixed with at least one inert excipient. The composition may contain inert additives such as lubricant, disintegrant, stabilizer and solubilizing agent, in accordance with the General method. The tablet or pill may, if necessary, be coated with a film of sugar or a gastric or intestinal soluble substance.

The liquid composition for oral administration contains a pharmaceutically acceptable emulsion, solution, suspension, syrup or elixir and contains a commonly used inert diluent such as purified water or EtOH. The liquid composition may contain an adjuvant such as a solubilizing agent, a humectant or suspending agent, a sweetener, flavoring, flavoring or antiseptic agent, in addition to an inert diluent.

[0104]

An injection for parenteral administration contains a sterile aqueous or non-aqueous solution, suspension or opacifying agent. As an aqueous solvent, for example, distilled water for injection or saline is included. Examples of the non-aqueous solvent include alcohols such as EtOH. Such a composition may further comprise a tonicity regulator, an antiseptic, a humectant, an emulsifier, a dispersant, a stabilizer, or a solubilizing agent. They are sterilized by filtration through a bacteria-retaining filter, a combination of germicides, or irradiation with light. In addition, they can also be used in dissolved or suspended form in sterile water or sterile injectable solvent before being formulated into a sterile solid composition and then used.

[0105]

The external preparation includes an ointment, a patch, a cream, a jelly, a poultice, a spray, a lotion, an eye drop, and an eye ointment. The external preparation contains a commonly used ointment base, lotion, aqueous solution or non-aqueous solution, suspension, emulsion or the like.

[0106]

The transmucosal agent, such as a preparation for inhalation or nasal administration, is used in a liquid or semi-solid state and can be prepared according to a conventional method. For example, a known excipient or pH adjuster, antiseptic, surfactant, lubricant, stabilizer or thickener may be added in a suitable manner. Upon administration, the device may be used for appropriate inhalation or insufflation. For example, the compound can be administered in powder form alone or as a powder formulated mixture or in the form of a solution or suspension of a combination of pharmaceutically acceptable carriers using a known device or nebulizer such as a metered inhalation device. The dry powder inhaler can be used for single or multiple administration, and a dry powder or powder-containing capsule can be used. Alternatively, the appropriate propellant may, for example, be in an aerosol spray bottle or the like. and is a suitable gas such as chlorofluoroalkane or carbon dioxide.

[0107]

In the case of conventional oral administration, the daily dose is from about 0.001 mg/kg to 100 mg/kg of body weight, and preferably from 0.0001 mg/kg to 0.01 mg/kg of body weight, and is administered as a single dose or divided into 2 -4 receptions. In the case of intravenous administration, the daily dose is from about 0.0001 mg/kg to 10 mg/kg body weight, and it is administered once or divided into several injections per day. In the case of a transmucosal agent, from about 0.001 mg/kg to 100 mg/kg of body weight is administered as a single or divided dose in multiple doses per day. The dose is appropriately determined taking into account symptoms, age, sex, or the like, as the case may be.

[0108]

Although it varies depending on the route of administration, dosage form, site of administration, or type of excipients or additives, in one aspect, the pharmaceutical composition of the present invention contains one or more compounds of formula (I) and their salts in an amount of from 0.01 wt.% to 100 wt.%, and from 0.01 wt.% to 50 wt.%, as active ingredients.

[0109]

The compound of formula (I) can be used in combination with various therapeutic agents or prophylactic agents for diseases in which the above compound of formula (I) is believed to be effective. Suitable combined use may be a simultaneous administration, separate continuous administration or administration at the required time intervals. The composition for simultaneous administration may be a combination drug, and may also be formulated separately.

Examples

[0110]

Hereinafter, a method for producing a compound of formula (I) will be described in detail with reference to Examples. However, the present invention is not limited to the compounds described in the following examples. Methods for obtaining the starting compounds are presented in the Preparation Examples. In addition, the method for producing the compound of formula (I) is not limited to the methods for obtaining specific examples below, and the compound of formula (I) can be obtained using a combination of these methods of preparation or using methods obvious to those skilled in the art.

[0111]

In the Examples, Production Examples, and Tables below, the following abbreviations may be used.

Mn=Production Example number, Ex=Example number, Synthesis=Production method (the corresponding compound is a compound obtained by a method similar to the preparation method of the compound with the Example number or Production Example number described in this column), Page=Structural formula, Data=physico-chemical data, ESI+=m/z value (represents (M+H) ⁺ unless otherwise noted) in ESI-MS, ESI-=m/z value (represents (MH) ^- unless otherwise indicated) otherwise stated) in ESI-MS, NMR1=δ(ppm) in ¹ H-NMR 500 MHz in DMSO-d ₆ and NMR 2=δ(ppm) in ¹ H-NMR 400 MHz in DMSO-d ₆ . In some cases, the peak area (integral value) of the chemical shift (δ) NMR is represented by the conformational isomerism fraction of the compound. For example, in Ex. 1, 7/5H is the peak area of the fifth part of 7H.

For example, in Ex. 2, the phrase Synthesis Ex. 1 indicates that the compound of Ex. Ex. 2, which is the target, was prepared in a manner similar to that described in Ex. 1. In addition, it is shown that HCl in the Structural formula is a hydrochloride.

2θ(°) is the diffraction angle of characteristic peaks in X-ray powder diffraction. Powder X-ray diffraction was measured using RINT-TTR II (RIGAKU Inc.) under the following conditions: tube: Cu, tube current: 300 mA, tube voltage: 50 kV, sample width: 0.020°, scan speed: 4°/min, length wavelength: 1.54056 Å, diffraction angle measurement range (2θ): 2.5°-40°.

[0112]

For convenience, the mol/L concentration is represented as M. For example, it means that 1M NaOH aqueous solution is 1 mol/L NaOH aqueous solution.

[0113]

Receiving example 1

To a mixture of NaOH (5 g), water (7 ml), TBAB (50 mg) and DMF (25 ml) was added 1-(4-phenyl-1H-imidazol-2-yl)methanamine monohydrochloride (1 g) under ice-cooling. and further, a DMF (25 ml) solution of 1,3-dibromopropane (1.98 g) was slowly added to this mixture, followed by stirring overnight at room temperature. Thereafter, the insoluble matter was removed by filtration, washing with toluene was carried out, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH-chloroform) to give 2-phenyl-6,7,8,9-tetrahydro-5H-imidazo[1,2-a][1,4]diazepine (200 mg).

[0114]

Receiving example 2

To a mixture of NaOH (1.1 g), water (2 ml), TBAB (15 mg) and DMF (5 ml) was added 1-(4-phenyl-1H-imidazol-2-yl)methanamine monohydrochloride (300 mg), followed by stirring for 10 minutes at the same temperature. Then, DMF (5 ml) 2-(chloromethyl)oxirane solution (230 μl) was added thereto, followed by stirring for 18 hours at room temperature and for 5 hours at 40°C. Thereafter, the insoluble matter was removed by filtration, washing with toluene was carried out, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH-chloroform) to give 2-phenyl-6,7,8,9-tetrahydro-5H-imidazo[1,2-a][1,4]diazepin-6-ol ( 85.3 mg).

[0115]

Receiving Example 3

To a mixture of NaOH (1.0 g), water (3 ml), TBAB (17 mg) and DMF (10 ml) was added 1-[4-(4-fluorophenyl)-1H-imidazol-2-yl) under ice-cooling methanamine dihydrochloride (446 mg), followed by stirring for 10 minutes at the same temperature. Then, DMF (10 ml) 1-bromo-3-chloropropane solution (250 μl) was added thereto, followed by stirring for 1 hour at room temperature and overnight at 50°C. Thereafter, the insoluble matter was removed by filtration, washing with toluene was carried out, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH-chloroform) to give 2-(4-fluorophenyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a][1,4]diazepine ( 20.8 mg).

[0116]

Receiving Example 4

1-bromo-3-chloropropane ( 0.95 ml) and K ₂ CO ₃ (3.64 g), followed by stirring overnight at 60°C. Thereafter, the reaction solution was filtered with celite and the solids were washed with DMF (15 ml). KOtBu (1.97 g) was added to the filtrate under ice-cooling, followed by stirring for 2 hours at the same temperature under argon. Thereafter, water was added to the reaction solution, followed by extraction with EtOAc, and the organic layer was washed with water and brine in that order, dried over MgSO ₄ and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc-hexane) to give 2-[4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-imidazo[1,2-a][1,4 ]diazepine-8(9H)-carboxylic acid (1.26 g).

[0117]

Receiving Example 5

Iron (286 mg) was added to a solution of 4-benzyl-1-(5-fluoro-2-nitrophenyl)-1,4-diazepan-2-one (440 mg) in acetic acid (9 ml), followed by stirring for 3 hours at 80°C. Thereafter, the reaction solution was filtered with Celite, the filtrate was diluted with EtOAc, and the organic layer was washed with aqueous saturated sodium bicarbonate and brine in that order, dried over MgSO ₄ and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc-hexane) to give 2-benzyl-8-fluoro-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]benzimidazole ( 150 mg).

[0118]

Receiving example 6

To a solution of 4-benzyl-1,4-diazepan-2-one (500 mg) in dioxane (15 ml) was added 2-bromo-4-fluoro-1-nitrobenzene (538 mg), Pd ₂ dba ₃ (67 mg) , xantphos (127 mg) and Cs ₂ CO ₃ (1 g), followed by stirring overnight at 100° C. under argon. This was followed by dilution with EtOAc and the organic layer was washed with water and brine in that order, dried over Na ₂ SO ₄ and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc-hexane) to give 4-benzyl-1-(5-fluoro-2-nitrophenyl)-1,4-diazepan-2-one (440 mg).

[0119]

Receiving Example 7

To a solution of 2-oxo-2-[4-(trifluoromethyl)phenyl]ethyl ester of [(tert-butoxycarbonyl)amino]acetic acid (3 g) in toluene (30 ml) was added ammonium acetate (3.2 g), then boiled reflux overnight. Thereafter, water was added to the reaction solution, followed by extraction with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc-hexane) to give ({4-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}methyl)-carbamic acid tert-butyl ester (2.6 g) .

[0120]

Receiving example 8

To a solution of N-(tert-butoxycarbonyl)glycine (3 g) in MeCN (60 ml) was added 2-bromo-1-[4-(trifluoromethyl)phenyl]ethanone (4.57 g) and K ₂ CO ₃ (2. 4 g), followed by stirring for 1 hour at room temperature. Thereafter, the reaction solution was filtered with Celite, and the filtrate was concentrated under reduced pressure to obtain [(t-butoxycarbonyl)amino]acetic acid 2-oxo-2-[4-(trifluoromethyl)phenyl]ethyl ester (6 g).

[0121]

Receiving example 9

To a solution of 2-[4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-imidazo[1,2-a][1,4]diazepine-8(9H)-carboxylic acid tert-butyl ester (1, 25 g) in dichloromethane (12.5 ml) was added a 4M solution of hydrogen chloride in dioxane (4.1 ml), followed by stirring overnight at room temperature. After that, concentration was carried out under reduced pressure to obtain 2-[4-(trifluoromethyl)phenyl]-6,7,8,9-tetrahydro-5H-imidazo[1,2-a][1,4]diazepine hydrochloride (1, 1 g).

[0122]

Receiving example 10

10 % Pd/C (50 mg), followed by stirring overnight in a hydrogen atmosphere. Thereafter, the reaction solution was filtered with Celite, and the filtrate was concentrated under reduced pressure to obtain 8-fluoro-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]benzimidazole (97 mg) .

[0123]

Receiving example 11

To a mixture of 2-amino-3,4-difluorophenol (6.9 g) and dioxane (70 ml) was added CDI (10 g) at room temperature, followed by stirring for 2 hours at 60°C. Thereafter, a 1M hydrochloric acid aqueous solution was added to the reaction mixture, followed by dilution with EtOAc, and the organic layer was washed with brine, dried over Na ₂ SO ₄ and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc-hexane) to give 4,5-difluoro-1,3-benzoxazol-2(3H)-one (3.65 g).

[0124]

Receiving example 12

K ₂ CO ₃ (105 mg) and bromoacetic acid tert-butyl ester ( 100 μl), followed by stirring for 2.5 hours at 50°C. Thereafter, EtOAc was added to the reaction mixture, the solid was collected by filtration, followed by washing with EtOAc and drying under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc-hexane) to give (4,5-difluoro-2-oxo-1,3-benzoxazol-3(2H)-yl)acetic acid tert-butyl ester (180 mg).

[0125]

Receiving example 13

To a mixture of 4-fluoro-1,3-benzoxazol-2(3H)-one (27.2 g) and MeCN (500 ml) at room temperature were added K ₂ CO ₃ (35.2 g) and bromoacetic acid (27.6 ml), followed by stirring overnight at 60°C. The reaction mixture was cooled to room temperature, the insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure. A mixed solvent of hexane-EtOAc (9:1) was added to the resulting residue, and then the resulting solid was collected by filtration, followed by washing with a mixed solvent of hexane-EtOAc (9:1) to obtain tert-butyl ether (4-fluoro-2 -oxo-1,3-benzoxazol-3(2H)-yl)-acetic acid (42.6 g).

[0126]

Receiving Example 14

TFA (400 μl ), followed by stirring for 3 hours at the same temperature. The reaction mixture was concentrated under reduced pressure, and hexane was added thereto. The solid was collected by filtration, washed with hexane and dried under reduced pressure to give (4,5-difluoro-2-oxo-1,3-benzoxazol-3(2H)-yl)acetic acid (128 mg).

[0127]

Receiving example 15

To a mixture of (4-fluoro-2-oxo-1,3-benzoxazol-3(2H)-yl)acetic acid tert-butyl ester (5 g) and dichloromethane (14 ml) was added TFA (7 ml) at room temperature, followed by stirring overnight at the same temperature. The reaction mixture was concentrated under reduced pressure, and the resulting solid was collected by filtration, washed with diethyl ether, and dried under reduced pressure to give (4-fluoro-2-oxo-1,3-benzoxazol-3(2H)-yl)acetic acid ( 3.65 g).

[0128]

Receiving Example 16

To a mixture of (4,5-difluoro-2-oxo-1,3-benzoxazol-3(2H)-yl)acetic acid (80 mg) and dichloromethane (1 ml) was added HATU (140 mg) and DIPEA (120 μl) and to this was added a mixture of 2-phenyl-6,7,8,9-tetrahydro-5H-imidazo[1,2-a][1,4]diazepin-6-ol (80 mg) and dichloromethane (2 ml), followed by stirring for 2 hours at room temperature. The reaction solution was diluted with chloroform, and a saturated sodium bicarbonate aqueous solution was added thereto. The resulting solid was collected by filtration and washed with water and chloroform to give 4,5-difluoro-3-[2-(6-hydroxy-2-phenyl-6,7-dihydro-5H-imidazo[1,2-a] [1,4]diazepin-8(9H)-yl)-2-oxoethyl]-1,3-benzoxazol-2(3H)-one (64 mg). The filtrate was washed with water and brine, in that order, and then dried over Na₂SO_fourand concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH-chloroform) to give 4,5-difluoro-3-[2-(6-hydroxy-2-phenyl-6,7-dihydro-5H-imidazo[1,2-a ][1,4]diazepin-8(9H)-yl)-2-oxoethyl]-1,3-benzoxazol-2(3H)-one (9.7 mg).

[0129]

Example 1

HATU (1.29 g) and DIPEA (1.9 ml), followed by stirring for 3 minutes at room temperature. Next, 2-[4-(trifluoromethyl)phenyl]-6,7,8,9-tetrahydro-5H-imidazo[1,2-a][1,4]diazepine hydrochloride (1 g) was added thereto, followed by stirring in overnight at room temperature. The reaction solution was then diluted with EtOAc, the organic layer was washed with water, saturated aqueous sodium bicarbonate and brine in that order, and then dried over MgSO_fourand concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH-chloroform) and then purified by silica gel column chromatography (EtOAc-hexane) to give 4-fluoro-3-(2-oxo-2-{2-[4-(trifluoromethyl )phenyl]-6,7-dihydro-5H-imidazo[1,2-a][1,4]diazepin-8(9H)-yl}ethyl)-1,3-benzoxazol-2(3H)-one ( 1.1 g).

4-Fluoro-3-(2-oxo-2-{2-[4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-imidazo[1,2-a][1,4]diazepine-8( 9H)-yl}ethyl)-1,3-benzoxazol-2(3H)-one obtained by the above method was crystallized by the following crystallization (1) or (2).

(1) 4-Fluoro-3-(2-oxo-2-{2-[4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-imidazo[1,2-a][1,4] solution diazepin-8(9H)-yl}ethyl)-1,3-benzoxazol-2(3H)-one (230 mg) in EtOH (1.6 ml) was stirred for 3 hours at room temperature. The precipitate was collected by filtration and dried under reduced pressure to obtain A01 crystal (Form A01) 4-fluoro-3-(2-oxo-2-{2-[4-(trifluoromethyl)phenyl]-6,7-dihydro- 5H-imidazo[1,2-a][1,4]diazepin-8(9H)-yl}ethyl)-1,3-benzoxazol-2(3H)-one (51 mg).

(2) 4-Fluoro-3-(2-oxo-2-{2-[4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-imidazo[1,2-a][1,4] solution diazepin-8(9H)-yl}ethyl)-1,3-benzoxazol-2(3H)-one (39.5 g) in EtOH (80 ml) was stirred for 30 minutes at room temperature. Thereafter, the solid obtained by slow concentration under reduced pressure was dried to obtain A02 crystal (Form A02) 4-fluoro-3-(2-oxo-2-{2-[4-(trifluoromethyl)phenyl]-6.7 -dihydro-5H-imidazo[1,2-a][1,4]diazepin-8(9H)-yl}ethyl)-1,3-benzoxazol-2(3H)-one (36 g).

[0130]

Example 11

To a solution of (5-chloro-2-oxo-1,3-benzoxazol-3(2H)-yl)acetic acid (230 mg) in dichloromethane (10 ml) 1,4]diazepino[1,2-a]benzimidazole (160 mg), WSC·HCl (220 mg) and HOBt (105 mg), followed by stirring for 12 hours at room temperature. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with brine and then dried over Na₂SO_fourand concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH-chloroform), and then the resulting crude product was solidified using EtOAc-hexane to give 5-chloro-3-[2-(4,5-dihydro-1H-[1,4] diazepino[1,2-a]benzimidazol-2(3H)-yl)-2-oxoethyl]-1,3-benzoxazol-2(3H)-one (70 mg).

[0131]

Example 12

To a solution of (5-chloro-2-oxo-1,3-benzoxazol-3(2H)-yl)acetic acid (530 mg) in dichloromethane (15 ml) was added oxalyl chloride (1.18 g) and a catalytic amount of DMF while cooling ice, followed by stirring for 3 hours at room temperature. The reaction solution was concentrated under reduced pressure, the residue was dissolved in dichloromethane (15 ml), 8,9-dimethyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]benzimidazole ( 400 mg) and TEA (1.6 ml) under ice-cooling, followed by stirring for 12 hours at room temperature. Thereafter, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH-chloroform) and solidified using EtOAc-hexane to obtain 5-chloro-3-[2-(8,9-dimethyl-4, 5-dihydro-1H-[1,4]diazepino[1,2-a]benzimidazol-2(3H)-yl)-2-oxoethyl]-1,3-benzoxazol-2(3H)-one (453 mg) .

[0132]

Examples 13 and 14

To a mixture of dichloromethane (1 ml) and 4,5-difluoro-3-[2-(6-hydroxy-2-phenyl-6,7-dihydro-5H-imidazo[1,2-a][1,4]diazepine -8(9H)-yl)-2-oxoethyl]-1,3-benzoxazol-2(3H)-one (40 mg) bis(2-methoxyethyl)aminosulfur trifluoride (80 µl) was added under ice-cooling, followed by stirring for 2 hours at the same temperature and for 19 hours at room temperature. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with brine and then dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH-chloroform) to give 4,5-difluoro-3-[2-(6-fluoro-2-phenyl-6,7-dihydro-5H-imidazo[1,2-a ][1,4]diazepin-8(9H)-yl)-2-oxoethyl-1,3-benzoxazol-2(3H)-one (11.1 mg) and 4,5-difluoro-3-[2- oxo-2-(2-phenyl-7H-imidazo[1,2-a][1,4]diazepin-8(9H)-yl)ethyl]-1,3-benzoxazol-2(3H)-one (17 .3 mg).

Table 6 No. Structural formula No. Structural formula Pp1

Pp5

Pp1-1

Pp6

Pp2

Pp7

Pp3

Pp7-1

Pp3-1

Pp7-2

Pp3-2

Pp8

Pp3-3

Pp8-1

Pp4

Pp8-2

[0134]

Table 7 No. Structural formula No. Structural formula Pp9

Pp11

Pp9-1

Pp12

Pp9-2

Pp13

Pp10

Pp14

Pp15

[0135]

Table 8 No. Structural formula Pp16

Ex 1

Ex 2

Ex 3

Ex 4

Ex 5

Ex 6

[0136]

Table 9 No. Structural formula Ex 7

Ex 8

Ex 9

Ex 10

Ex 11

Ex 12

[0137]

Table 10 No. Structural formula Ex 13

Ex 14

[0138]

Table 11 No. Synthesis Data No. Synthesis Data Pp1 Pp1 ESI+:214 Pp8 Pp8 ESI-:360[M-H]- Pp1-1 Pp1 ESI+:216 Pp8-1 Pp8 ESI+:334[M+Na]+ Pp2 Pp2 ESI+:230 Pp8-2 Pp8 ESI+:334[M+Na]+ Pp3 Pp3 ESI+:232 Pp9 Pp9 ESI+:282 Pp3-1 Pp3 ESI+:232 Pp9-1 Pp9 ESI+:192 Pp3-2 Pp3 ESI+:248 Pp9-2 Pp9 ESI+:192 Pp3-3 Pp3 ESI+:232 Pp10 Pp10 ESI+:206 Pp4 Pp4 ESI+:382 Pp11 Pp11 ESI-:170[M-H]- Pp5 Pp5 ESI+:296 Pp12 Pp12 ESI+:308[M+Na]+ Pp6 Pp6 ESI+:344 Pp13 Pp13 ESI+:290[M+Na]+ Pp7 Pp7 ESI+:342 Pp14 Pp14 ESI+:230 Pp7-1 Pp7 ESI+:292 Pp15 Pp15 ESI+:212 Pp7-2 Pp7 ESI+:292 Pp16 Pp16 ESI+:441

[0139]

Table 12 No. Synthesis Data Ex 1 Ex 1 ESI+:475
NMR1(ppm): 1.77-1.85(m.7/5H), 2.02-2.09(m.3/5H), 3.77-3.92(m.2H) .4.23-4.35(m, 2H), 4.71-5.08(m, 4H), 6.96-7.16(m, 2H), 7.19-7.28(m, 1H), 7.65-7.72(m, 2H), 7.81-7.95(m, 3H).
A01 shape: 2Θ(°)=6.7, 13.6, 15.2, 15.6, 18.5, 19.4, 20.4, 23.3,25.5, 26.6.
A02 form: 2Θ(°)=7.0, 9.4, 12.3, 15.8, 17.4, 18.9, 19.6, 21.3, 23.8, 25.0. Ex 2 Ex 1 ESI+:425
NMR1 (ppm): 1.75-1.83(m.7/5H), 1.99-2.06(m.3/5H), 3.77-3.91(m.2H) .4.27-4.36(m, 2H), 4.73-5.05(m, 4H), 6.96-7.15(m, 2H), 7.20-7.27(m, 4H), 7.51-7.60(m, 1H), 7.94-8.07(m, 1H). Ex 3 Ex 1 ESI+:399
NMR2 (ppm): 1.82-1.91(m.7/5H), 2.08-2.16(m.3/5H), 3.85-3.98(m.2H) .4.41-4.51(m,2H),4.92(s.3/5H),4.96(s.3/5H),5.06(s.14/5H),7.09 -7.31(m, 4H), 7.53-7.66(m, 2H). Ex 4 Ex 1 ESI+:399
NMR2 (ppm): 1.80-1.89(m.7/5H), 2.06-2.15(m.3/5H), 3.83-3.98(m.2H) .4.38-4.50(m, 2H), 4.86-5.08(m, 4H), 6.91-7.27(m, 4H), 7.49-7.67(m, 2H). Ex 5 Ex 1 ESI+:425
NMR2 (ppm): 1.76-1.84(m.7/5H), 2.00-2.08(m.3/5H), 3.77-3.90(m.2H) .4.20-4.29(m, 2H), 4.71-5.07(m, 4H), 7.10-7.38(m, 5H), 7.56-7.75(m, 3H). Ex 6 Ex 1 ESI+:425 Ex 7 Ex 1 ESI+:441 Ex 8 Ex 1 ESI+:443 Ex 9 Ex 1 ESI+:423 Ex 10 Ex 1 ESI+:425 Ex 11 Ex 11 ESI+:397 Ex 12 Ex 12 ESI+:425 Ex 13 Ex 13, Ex 14 ESI+:443 Ex 14 Ex 13, Ex 14 ESI+:423

Industrial Applicability

[0140]

The compound of formula (I) or a salt thereof has a PAM action at the dopamine D1 receptor and is contemplated as an agent for the prevention and/or treatment of cognitive impairment, negative symptoms of schizophrenia, CIAS, Parkinson's disease, Alzheimer's disease, Huntington's disease, depression, ADHD, drug addiction syndrome. dependencies or the like.

Claims (1)

Crystalline form of 4-fluoro-3-(2-oxo-2-{2-[4-(trifluoromethyl)phenyl]-6,7-dihydro-5H-imidazo[1,2-a][1,4]diazepin- 8(9H)-yl}ethyl)-1,3-benzoxazol-2(3H)-one having characteristic peaks at 2θ(°) angles of 7.0, 9.4, 12.3, 15.8, 17, 4, 18.9, 19.6, 21.3, 23.8, 25.0.