JP2008105963A - Dna damage checkpoint activator - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new DNA damage checkpoint activator useful as an antitumor agent. <P>SOLUTION: The effective ingredient of the DNA damage checkpoint activator is a compound having an imidazo[1,5-a]pyridine skeleton or its pharmaceutically acceptable salt. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a novel DNA damage checkpoint activator useful as an anticancer agent.

The DNA damage checkpoint, one of the control mechanisms for orderly cell cycle progression, senses DNA damage and replication delay, and pauses the cell cycle until the DNA is successfully repaired. It is known that a decrease or disappearance of the function causes various genetic changes leading to carcinogenesis. Therefore, in recent years, a substance having a DNA damage checkpoint activating action has attracted attention as an anticancer agent having a new mechanism of action. In this connection, Non-Patent Document 1 describes a G1 / S phase checkpoint mutation in yeast. A screening method for a substance that activates DNA damage checkpoints in higher eukaryotic cells including humans has been proposed by utilizing the high sensitivity of strains to DNA damage. Although not yet fully elucidated with respect to DNA damage checkpoint, this screening method, DNA damage checkpoint budding yeast is transmitted by signals through MEC1, Chk1 and RAD53 around the RAD9, enzyme DNA repair system By using yeast that has disrupted the RAD9 gene based on the activation of transcription and cell cycle arrest, substances that activate Chk1 and RAD53 associated with DNA damage checkpoint signals by bypassing the defective RAD9 In order to find a substance that can arrest the cell cycle instead of RAD9 (see Fig. 1), it is an antibiotic as a substance having a DNA damage checkpoint activation effect obtained from a culture solution of microorganisms in the same document. Borrelidin etc. are shown.
Hideko Tsuchiya, Development of anticancer drugs using yeast, FY 1998-2012 Research on advanced utilization of brewing microbial functions (Hiroshima Industrial Technology Promotion Organization), p53-p60, (2001)

However, the search for a substance having a novel DNA damage checkpoint activation action is very important in research and development of anticancer agents.
Accordingly, an object of the present invention is to provide a novel DNA damage checkpoint activator useful as an anticancer agent.

  As a result of intensive studies in view of the above points, the present inventors have found that a compound having an imidazo [1,5-a] pyridine skeleton, which is known as an organic EL material, has a DNA damage. It was found to have a checkpoint activation effect.

  The DNA damage checkpoint activator of the present invention made on the basis of the above findings comprises a compound having an imidazo [1,5-a] pyridine skeleton or a pharmaceutically acceptable salt thereof as described in claim 1. It is characterized by being an active ingredient.

  The DNA damage checkpoint activator according to claim 2 is the DNA damage checkpoint activator according to claim 1, wherein the compound having an imidazo [1,5-a] pyridine skeleton has a substituent. It is characterized by having an aryl group which may be substituted or a heteroaryl group which may have a substituent at the 3-position.

  The DNA damage checkpoint activator according to claim 3 is the DNA damage checkpoint activator according to claim 2, wherein the compound having an imidazo [1,5-a] pyridine skeleton is represented by the following general formula ( It is represented by 1).

[Wherein R ¹ represents a hydrogen atom, a lower alkyl group, a lower cycloalkyl group, a lower alkenyl group, a halogen atom, an aryl group which may have a substituent, or an aryl lower group which may have a substituent. An alkyl group, an optionally substituted heteroaryl group, —XR ¹¹ (X is S or Se, R ¹¹ is a lower alkyl group, a lower alkenyl group, a lower alkoxy group, a halogen atom, a substituent; An aryl group which may have a substituent, a heteroaryl group which may have a substituent, or a group represented by the following general formula (2)), -YR ¹² R ¹³ (Y is , B, N, or P, and R ¹² and R ¹³ may be the same or different and each may have a lower alkyl group, a lower alkenyl group, a lower alkoxy group, a halogen atom, or a substituent. Aryl group, heteroaryl optionally having substituent Group, the general formula is any of the groups represented by ^{(2)), - ZR 14} R 15 R 16 (Z is, Si, Ge, is any of ^{Sn, R 14, R 15,} R ¹⁶ are the same or different and are each a lower alkyl group, a lower alkenyl group, a lower alkoxy group, a halogen atom, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, -CR ¹⁷ R ¹⁸ R ¹⁹ (R ¹⁷ , R ¹⁸ , R ¹⁹ are the same or different, and each represents a lower alkenyl group or a lower alkoxy group). A group, a halogen atom, an optionally substituted heteroaryl group, or a group represented by the following general formula (2). R ² represents an aryl group which may have a substituent or a heteroaryl group which may have a substituent. R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and are each a hydrogen atom, a lower alkyl group, an aryl group optionally having a substituent, a hydroxyl group, a lower alkoxy group, an amino group, or a mono-lower group. An alkylamino group, a di-lower alkylamino group, a nitro group, a halogen atom, a carboxyl group, a lower alkoxycarbonyl group, or a trifluoromethyl group is shown. ]

[Wherein R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ have the same meanings as described above. ]

  Further, as described in claim 4, the anticancer agent of the present invention is characterized by comprising a compound having an imidazo [1,5-a] pyridine skeleton or a pharmaceutically acceptable salt thereof as an active ingredient.

  According to the present invention, a novel DNA damage checkpoint activator useful as an anticancer agent is provided.

  The DNA damage checkpoint activator of the present invention comprises a compound having an imidazo [1,5-a] pyridine skeleton or a pharmaceutically acceptable salt thereof as an active ingredient. It is well known to those skilled in the art that the imidazo [1,5-a] pyridine skeleton is a skeleton represented by the following chemical formula.

  In the present invention, among compounds having an imidazo [1,5-a] pyridine skeleton, a desirable compound as an active ingredient of a DNA damage checkpoint activator is an aryl group or substituent which may have a substituent. And a compound having a heteroaryl group which may have a 3-position. Specific examples include compounds represented by the following general formula (1).

[Wherein R ¹ represents a hydrogen atom, a lower alkyl group, a lower cycloalkyl group, a lower alkenyl group, a halogen atom, an aryl group which may have a substituent, or an aryl lower group which may have a substituent. An alkyl group, an optionally substituted heteroaryl group, —XR ¹¹ (X is S or Se, R ¹¹ is a lower alkyl group, a lower alkenyl group, a lower alkoxy group, a halogen atom, a substituent; An aryl group which may have a substituent, a heteroaryl group which may have a substituent, or a group represented by the following general formula (2)), -YR ¹² R ¹³ (Y is , B, N, or P, and R ¹² and R ¹³ may be the same or different and each may have a lower alkyl group, a lower alkenyl group, a lower alkoxy group, a halogen atom, or a substituent. Aryl group, heteroaryl optionally having substituent Group, the general formula is any of the groups represented by ^{(2)), - ZR 14} R 15 R 16 (Z is, Si, Ge, is any of ^{Sn, R 14, R 15,} R ¹⁶ are the same or different and are each a lower alkyl group, a lower alkenyl group, a lower alkoxy group, a halogen atom, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, -CR ¹⁷ R ¹⁸ R ¹⁹ (R ¹⁷ , R ¹⁸ , R ¹⁹ are the same or different, and each represents a lower alkenyl group or a lower alkoxy group). A group, a halogen atom, an optionally substituted heteroaryl group, or a group represented by the following general formula (2). R ² represents an aryl group which may have a substituent or a heteroaryl group which may have a substituent. R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and are each a hydrogen atom, a lower alkyl group, an aryl group optionally having a substituent, a hydroxyl group, a lower alkoxy group, an amino group, or a mono-lower group. An alkylamino group, a di-lower alkylamino group, a nitro group, a halogen atom, a carboxyl group, a lower alkoxycarbonyl group, or a trifluoromethyl group is shown. ]

[Wherein R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ have the same meanings as described above. ]

Here, the lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group. Tert-butyl group and the like.
The lower cycloalkyl group means a cycloalkyl group having 3 to 7 carbon atoms, and specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.
The lower alkenyl group means a linear or branched alkenyl group having 1 to 6 carbon atoms, and specifically includes a vinyl group, an allyl group, a 1-propenyl group, an isopropenyl group, a 1-butenyl group, and the like. Is mentioned.
Examples of the halogen atom include fluorine, chlorine, bromine and iodine.
Examples of the aryl group which may have a substituent include a phenyl group and a naphthyl group which may have a substituent.
As the aryl lower alkyl group which may have a substituent, the aryl part and the lower alkyl part have the same meanings as described above, and examples thereof include an optionally substituted benzyl group, phenethyl group and 3-phenylpropylene. Group, 1-naphthylmethyl group, 2-naphthylmethyl group and the like.
As the heteroaryl group which may have a substituent, for example, a 5- to 6-membered cyclic group having an optionally substituted carbon and 1 to 4 heteroatoms (oxygen, sulfur, nitrogen), Specifically, an optionally substituted pyrrolyl group, furyl group, thienyl group, oxazolyl group, isoxazolyl group, imidazolyl group, thiazolyl group, isothiazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, 1,3 , 5-Oxiadiazolyl group, 1,2,4-oxadiazolyl group, 1,2,4-thiadiazolyl group, pyridyl group, pyranyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, 1,2,4-triazinyl group, 1, Examples include 2,3-triazinyl group and 1,3,5-triazinyl group.
The lower alkoxy group means a linear or branched alkoxy group having 1 to 6 carbon atoms, and specifically includes a methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, tert -Butoxy group etc. are mentioned.
As the mono-lower alkylamino group, the lower alkyl part has the same meaning as described above, for example, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, tert-butylamino group Etc.
As the di-lower alkylamino group, the lower alkyl part has the same meaning as described above, and examples thereof include a dimethylamino group, a diethylamino group, an ethylmethylamino group, a dipropylamino group, a methylpropylamino group, and a diisopropylamino group. .
As the lower alkoxycarbonyl group, the lower alkoxy part has the same meaning as described above. For example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, tert-butoxycarbonyl Groups and the like.
Examples of the substituent in the aryl group which may have a substituent, the aryl lower alkyl group which may have a substituent, and the heteroaryl group which may have a substituent include a lower alkyl group and a substituent. Aryl group, hydroxyl group, lower alkoxy group, amino group, mono-lower alkylamino group, di-lower alkylamino group, nitro group, halogen atom, carboxyl group, lower alkoxycarbonyl group, trifluoromethyl group, etc. Is mentioned. A lower alkyl group, an aryl group which may have a substituent, a lower alkoxy group, a mono-lower alkylamino group, a di-lower alkylamino group, a halogen atom and a lower alkoxycarbonyl group have the same meanings as described above.

The compound represented by the above general formula (1) is, for example, “2B2-” published on March 27, 2005 at the International Publication No. 2006/088028 pamphlet and the 85th Annual Meeting of the Chemical Society of Japan (Kanagawa University). 10: Synthesis of azaindolizines by cyclization reaction with thioamide desulfurization: Fumitoshi Shibahara, Asumi Kitagawa, Toshiaki Murai, Proceedings of the 86th Annual Meeting of the Chemical Society of Japan (Funabashi Campus, Nihon University) The compound described in the proceedings of the lecture proceedings, such as “1J5-44: Expansion of Conjugated Systems Utilizing Transition Metal-Catalyzed Reactions of Azaindolizine: Fumitoshi Shibahara, Eiji Yamaguchi, Asumi Kitagawa, Toshiaki Murai” Or cyclization of N-2-pyridylmethylcarbothioamides described above (where R ² is bonded to thiocarbonyl in N-2-pyridylmethylcarbothioamide) in the presence of an oxidizing agent such as iodine. Manufacturing method by letting In addition to the method, it can be produced by a production method known per se (if necessary, see paragraph number 0006 of the specification of WO 2006/088028 pamphlet). In addition, when the compound represented by the general formula (1) has an asymmetric carbon, various stereoisomers and optical isomers may exist, and the present invention includes all of them within the scope of the right. It is.

  When the compound having an imidazo [1,5-a] pyridine skeleton can take the form of a salt, the pharmaceutically acceptable salt includes inorganic salts with sodium, potassium, magnesium, calcium, aluminum, etc., lower alkyl In addition to organic salts with amines, lower alcohol amines, etc., basic amino acid salts with lysine, arginine, ornithine and the like, and known salts such as ammonium salts.

  The compound having an imidazo [1,5-a] pyridine skeleton of the present invention or a pharmaceutically acceptable salt thereof can be used as an active ingredient of a DNA damage checkpoint activator. When administered to humans and animals as a pharmaceutical, the administration method may be an oral administration method or a parenteral administration method. Examples of parenteral administration methods include intravenous injection, intramuscular injection, subcutaneous injection, intraperitoneal injection, transdermal administration, pulmonary administration, nasal administration, enteral administration, buccal administration, and transmucosal administration. In this case, the DNA damage checkpoint activator of the present invention is formulated and administered by a method known per se into a form suitable for these administration methods. Examples of the dosage form include injections, suppositories, aerosols, transdermal absorption tapes, eye drops, nasal drops and the like. When preparing an injection, a pH adjuster, a buffer, a stabilizer, a solubilizing agent and the like are appropriately added to form an injection. Examples of oral preparations include tablets (including sugar-coated tablets, coated tablets, and buccal tablets), powders, capsules (including soft capsules), granules (including those coated), pills, troches, liquids, and the like. And a pharmaceutically acceptable sustained release preparation. Liquids include suspensions, emulsions, syrups (including dry syrups), elixirs and the like. For example, a tablet can be prepared with a pharmaceutically acceptable carrier, excipient, binder, disintegrant, lubricant, colorant and the like according to known pharmaceutical manufacturing methods. In this case, as the carrier or excipient, for example, lactose, glucose, sucrose, mannitol, potato starch, corn starch, calcium carbonate, calcium phosphate, calcium sulfate, crystalline cellulose, licorice powder, gentian powder and the like can be used. As the binder, for example, starch, tragacanth gum, gelatin, syrup, polyvinyl alcohol, polyvinyl ether, polyvinyl pyrrolidone, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, carboxymethyl cellulose and the like can be used. As the disintegrant, for example, starch, agar, gelatin powder, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, sodium alginate and the like can be used. As the lubricant, for example, magnesium stearate, talc, hydrogenated vegetable oil, macrogol and the like can be used. As the colorant, those allowed to be added to pharmaceuticals can be used. Tablets and granules are sucrose, gelatin, hydroxypropylcellulose, purified shellac, glycerin, sorbitol, ethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, cellulose phthalate acetate, hydroxypropylmethylcellulose phthalate, methyl methacrylate, methacrylic acid as required It may be coated with a polymer or the like, or may be coated with two or more layers. Further, it may be encapsulated using ethyl cellulose or gelatin.

  The disease in which the DNA damage checkpoint activator of the present invention acts effectively is cancer. When the DNA damage checkpoint activator of the present invention is administered to a patient as an anticancer agent, the dose may be appropriately set according to conditions such as the patient's age, weight, symptom level, health condition, etc. May be administered at a dose of about 10 mg to about 10 g per day for an adult, orally or parenterally, once to several times a day. In the case of eye drops, an eye drop having an active ingredient concentration of 0.003 to 5 (w / v)% may be administered once a day several times.

  In addition, the DNA damage checkpoint activator of the present invention may be eaten by adding an effective amount sufficient to exert the DNA damage checkpoint activation action to various forms of food (including supplements). Ingestion of 0.1 mg to 100 mg per kg is standard).

  EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is limited to the following description and is not interpreted at all.

In this example, the DNA damage checkpoint activation effect was evaluated according to the method described in Non-Patent Document 1. The yeast to be used is a yeast in which the RAD9 gene is disrupted as described above, but since this yeast is further temperature sensitive, DNA damage is induced when cultivated at 37 ° C, and the checkpoint control system does not work, so the cell cycle is changed. It has the characteristic of not being able to stop and having the property of rapidly dying and causing cell division. This is thought to be one of the modeling of cancer. A substance that bypasses RAD9 that was lost during culture and activates Chk1 and RAD53 involved in DNA damage checkpoint signals, and a substance that can arrest the cell cycle instead of RAD9. Then, this yeast grows with a lethal effect at 37 ° C. suppressed (see FIG. 2). That is, in the evaluation method described in Non-Patent Document 1, the anticancer activity is opposite to the activity of killing cancer cells so far, and the phenotype (= substance is impregnated) as a growth circle of growing yeast. This is a positive screening system in which yeast grows around the disk). Accordingly, it is possible to find an active substance with low toxicity and high specificity. In fact, since hydroxyurea and mycophenolic acid having anticancer activity show a growth circle, a substance having a DNA damage checkpoint activating action found by this method can be an effective anticancer agent for humans. Is. It is well known that anticancer drugs used in clinical settings today have a need for new chemical structures and mechanisms of action because of problems such as side effects and reduced drug sensitivity. However, according to this method, it is possible to provide a new anticancer agent having an action mechanism different from that of the existing anticancer agent.

Reference example 1: Details of screening system
A temperature-sensitive mutant of the yeast in which the RAD9 gene was disrupted (gene disrupted yeast: ΔRAD9 ) was grown overnight at 28 ° C in YPD medium (yeast extract 10 g / l, peptone 20 g / l, dextrose 20 g / 1, pH 6.5). Precultured, 1.75 ml of the obtained A ₅₉₀ = 0.8 culture solution and 48.25 ml of YPD agar medium were well suspended, and 12.5 ml each was dispensed into a petri dish. The test sample was soaked in a paper disc (8mm, thick) at 40μl so that its concentration would be 40μg / disc (concentration was adjusted with methanol) and placed on a petri dish. After inducing DNA damage at 37 ° C for 6 hours, After culturing at 28 ° C. for 2 days, the size of the growth circle was measured, and the effect of growing the above mutant strain by the DNA damage checkpoint activation action (= anticancer activity) was evaluated. The positive control was mycophenolic acid (average growth circle 17.6 mm, 50 μg / disc), which is an immunosuppressant and known to have anticancer activity.

Example 1: DNA damage checkpoint activation action of a compound having an imidazo [1,5-a] pyridine skeleton A compound having an imidazo [1,5-a] pyridine skeleton represented by the following general formula (3) ( R ^a and R ^b in the formula are as shown in Table 1) DNA damage checkpoint activating action (evaluation based on the size of the growth circle of the temperature-sensitive mutant of the gene-disrupted yeast (Δ RAD9 )) Shown in 1.

  As is clear from Table 1, it was found that the compound having an imidazo [1,5-a] pyridine skeleton exerted a DNA damage checkpoint activation effect equivalent to that of mycophenolic acid used as a positive control.

Example 2: Anticancer activity of a compound having an imidazo [1,5-a] pyridine skeleton
100 μl of human chronic myeloid leukemia cell K562 suspended in 10% FBS-RPMI1640 medium at 5 × 10 ⁴ cells / ml is seeded in a 96-well microwell, and expressed by the following general formula (3) at various concentrations. Add 5 μl of a compound having an imidazo [1,5-a] pyridine skeleton (wherein R ^a and R ^b are as shown in Table 2) (concentration adjustment with methanol), 37 ° C., 5% CO _The cells were cultured for 4 days in the presence of ₂ and examined for cytotoxicity by MTT assay to determine 50% inhibitory concentration (IC ₅₀ ). In addition, 100 μl of human prostate cancer cell LNCaP suspended in 10% FBS-RPMI1640 medium at 1 × 10 ⁵ cells / ml is seeded in a 96-well microwell, and expressed by the following general formula (3) at various concentrations. Add 5 μl of a compound having an imidazo [1,5-a] pyridine skeleton (wherein R ^a and R ^b are as shown in Table 2) (concentration adjustment with methanol), 37 ° C., 5% CO _The cells were cultured for 4 days in the presence of ₂ and examined for cytotoxicity by MTT assay to determine 50% inhibitory concentration (IC ₅₀ ). The results are shown in Table 2.

  As is apparent from Table 2, it was found that the compound having an imidazo [1,5-a] pyridine skeleton has an excellent anticancer activity.

Formulation Example 1: Injection
Dissolve 1.5 g of 3-phenylimidazo [1,5-a] pyridine in 100 ml of physiological saline containing ethanol as a solubilizer (total 1.5 g / 100 ml), fill the vial, and then heat sterilize, An intravenous injection was produced.

Formulation Example 2: Tablets Each component was mixed with the following composition and tableted to produce 400 500 mg tablets containing 50 mg of 3- (2-pyridyl) imidazo [1,5-a] pyridine.
3- (2-Pyridyl) imidazo [1,5-a] pyridine ... 20g
Potato starch ・ ・ ・ 6g
Talc stearate ・ ・ ・ 4g
6% HPC lactose ... 170g
(Total 200g)

Formulation Example 3: Granules Each component was mixed with the following composition, compression-molded, pulverized, and sized to produce 20-50 mesh 5% granules.
3- (2-Thienyl) imidazo [1,5-a] pyridine ... 10g
Lactose ... 187g
Magnesium stearate ・ ・ ・ 3g
(Total 200g)

Formulation Example 4: Capsules Each component was mixed well with the following composition, and the mixture was filled into No. 1 capsules to produce 300 capsules.
3-Phenylimidazo [1,5-a] pyridine ・ ・ ・ 5g
Lactose ・ ・ ・ 40g
Potato starch ... 50g
Hydroxypropyl methylcellulose ... 3.5g
Magnesium stearate ・ ・ ・ 1.5g
(Total 100g)

Formulation Example 5: Eye drops The following components were dissolved in 100 ml of sterilized purified water, and eye drops were produced by a conventional method.
3-Phenylimidazo [1,5-a] pyridine ・ ・ ・ 5g
Sodium chloride ... 0.9g
Benzalkonium chloride ・ ・ ・ Trace amount
1N sodium hydroxide
1N hydrochloric acid: appropriate amount ethanol: appropriate amount

Reference Example 1: Physicochemical properties of compounds having imidazo [1,5-a] pyridine skeleton described in Example 1 and Example 2 (Production is according to the method described in International Publication No. 2006/088028)
(Compound 1) 3-phenyl-imidazo [1,5-a] pyridine yellow solid; mp 100-103 ℃; IR (KBr ) 3035, 1601, 1505, 1458, 1354, 1002, 807, 769, 752, 688 cm - ¹ ; ¹ H NMR (CDCl ₃ ): δ 6.57 (td, J = 6.8, 1.0 Hz, 1H, Ar), 6.64 (ddd, J = 9.3, 6.3, 1.0 Hz, 1H, Ar), 7.33-7.49 (m , 5H, Ar), 7.01-7.73 (m, 2H, Ar), 8.18 (dd, J = 7.3, 1.0 Hz, 1H, Ar); ¹³ C NMR (CDCl ₃ ): δ 113.1, 118.7, 118.8, 120.6, 121.4, 127.9, 128.6, 129.0, 130.4, 131.6, 138.2 (Ar); MS (EI) m / z 194 (M ⁺ ); HRMS Calcd for C ₁₃ H ₁₀ N ₂ : 194.0844; Found: 194.0823.

(Compound 2) 3- (4-Methoxyphenyl) imidazo [1,5-a] pyridine Brown oil: IR (KBr) 1612, 1525, 1463, 1357, 1250, 1031, 837 cm ^-1 ; ¹ H NMR (CDCl ₃ ): δ 3.84 (s, 3H, OMe), 6.49 (td, J = 6.9, 1.0 Hz, 1H, Ar), 6.65 (dd, J = 9.3, 6.3 Hz, 1H, Ar), 7.02 (dq, J = 8.3, 4.7 Hz, 2H, Ar), 7.42 (dd, J = 9.3, 1.0 Hz, 1H, Ar), 7.49 (s, 1H, Ar), 7.68 (dq, J = 8.3, 4.7 Hz, 2H, Ar ), 8.13-8.15 (m, 1H, Ar); ¹³ C NMR (CDCl ₃ ): δ 55.4 (OMe), 112.8, 114.4, 118.4, 118.7, 120.2, 121.3, 122.9, 129.4, 131.3, 138.2, 159.8 (Ar ); MS (EI) m / z 224 (M ⁺ ); HRMS Calcd for C ₁₄ H ₁₂ N ₂ O: 224.0950; Found: 224.0955.

(Compound 3) 3- (4-Methylphenyl) imidazo [1,5-a] pyridine yellow solid; mp 86-87 ° C; IR (KBr) 3034, 1507, 1354 cm ^-1 ; ¹ H NMR (CDCl ₃ ) : δ 6.63 (t, J = 7.1 Hz, 1H, Ar), 6.82 (dd, J = 7.1, 9.1 Hz, 1H, Ar), 7.21-7.29 (m, 2H, Ar), 7.50 (d, J = 9.1 Hz, 1H, Ar), 7.58 (s, 1H, Ar), 7.77-7.82 (m, 2H, Ar), 8.14 (d, J = 7.1 Hz, 1H, Ar); ¹³ C NMR (CDCl ₃ ): δ 21.4 (Me), 112.9, 118.6, 118.7, 120.2, 121.4, 127.4, 127.8, 129.6, 131.4, 138.3, 138.6 (Ar); MS (EI) m / z 208 (M ⁺ ); HRMS (EI) Calcd for C ₁₄ H ₁₂ N ₂ (M ⁺ ) 208.1000, Found: 208.0988.

(Compound 4) 3- (2-pyridyl) imidazo [1,5-a] pyridine pale yellow solid; mp 99-100 ° C .; IR (KBr) 3417, 3114, 1585, 1495, 1419, 1353, 1251, 1146, 1009, 787, 686 cm ^-1 ; ¹ H NMR (CDCl ₃ ): δ 6.66 (td, J = 5.1, 1.0 Hz, 1H, Ar), 6.79 (ddd, J = 9.3, 6.3, 1.0 Hz, 1H, Ar ), 7.13 (ddd, J = 7.3, 4.9, 1.0 Hz, 1H, Ar), 7.46-7.48 (m, 1H, Ar), 7.55 (s, 1H, Ar), 7.72 (td, J = 7.8, 1.0 Hz , 1H, Ar), 8.28-8.30 (m, 1H, Ar), 8.57 (dd, J = 4.9, 1.0 Hz, 1H, Ar), 9.90 (d, J = 7.2 Hz, 1H Ar); ¹³ C NMR ( CDCl ₃ ): δ 113.4, 117.9, 120.0, 120.9, 121.5, 121.6, 125.9, 132.8, 135.3, 136.4, 148.0, 151.1 (Ar); MS (EI) m / z 195 (M ⁺ ); HRMS Calcd for C ₁₂ H ₉ N ₃ : 195.0796; Found: 195.0777.

(Compound 5) 1-allyl-3- (2-pyridyl) imidazo [1,5-a] pyridine Brown oil: IR (KBr) 1589, 1502, 1424, 1344, 1262, 783, 748 cm ^-1 ; ¹ H NMR (CDCl ₃ ): δ 3.76 (d, J = 6.4 Hz, 2H, CH ₂ ), 5.11 (dd, J = 10.0, 1.7 Hz, 1H, CH = C H ₂ ), 5.20 (dd, J = 17.1, 1.5 Hz, 1H, CH = C H ₂ ), 6.13 (ddt, J = 17.1, 10.2, 6.6 Hz, 1H, C H = CH ₂ ), 6.69 (t, J = 7.3 Hz, 1H, Ar), 6.79 ( ddd, J = 8.8, 6.3, 1.0 Hz, 1H, Ar), 7.16 (ddd, J = 7.3, 4.9, 1.0 Hz, 1H, Ar), 7.49 (d, J = 9.3 Hz, 1H, Ar), 7.75 ( td, J = 7.8, 2.0 Hz, 1H, Ar), 8.33 (d, J = 8.6 Hz, 1H, Ar), 8.62 (d, J = 4.9 Hz, 1H, Ar), 9.89 (d, J = 7.3 Hz , 1H, Ar); ¹³ C NMR (CDCl ₃ ): δ 32.5 (CH ₂ ), 113.4, 115.6 (C = C), 117.5, 118.9, 121.2, 121.6, 125.8, 129.6, 131.2, 133.9, 136.3, 136.3, 148.1, 151.0 (Ar); MS (EI) m / z 235 (M ⁺ ); HRMS Calcd for C ₁₅ H ₁₃ N ₃ : 235.1109; Found: 235.1115.

(Compound 6) bis- [3- (2-pyridyl) imidazo [1,5-a] pyridin-1-yl] sulfide light yellow solid; mp 161-164 ° C .; IR (KBr) 3113, 1586, 1089, 1029 cm ^-1 ; ¹ H NMR (CDCl ₃ ): δ 6.68 (ddd, J = 9.3, 7.6, 1.2 Hz, 2H, Ar), 6.88 (ddd, J = 8.8, 6.4, 1.2 Hz, 2H, Ar), 7.10 (ddd, J = 7.2, 4.4, 0.8 Hz, 2H, Ar), 7.69 (td, J = 8.0, 2.0 Hz, 2H, Ar), 7.96 (d, J = 8.8 Hz, 2H, Ar), 8.35 (d , J = 8.4 Hz, 2H, Ar), 8.51 (d, J = 7.6 Hz, 2H, Ar), 9.85 (d, J = 7.2 Hz, 2H, Ar); ¹³ C NMR (CDCl ₃ ): δ 113.9, 118.2, 121.4, 121.7, 122.1, 123.3, 126.3, 134.5, 134.9, 136.4, 147.9, 150.6 (Ar); MS (EI) m / z 420 (M ⁺ ); HRMS Calcd for C ₂₄ H ₁₆ N ₆ S: 420.1157 ; Found: 420.1154.

(Compound 7) 3- (2-thienyl) imidazo [1,5-a] pyridine light gray solid; mp 106-110 ° C; IR (KBr) 1631, 1505, 1466, 1404, 1351, 1306, 1247, 1224, 999, 839, 794, 729, 690 cm ^-1 ; ¹ H NMR (CDCl ₃ ): δ 6.56-6.59 (m, 1H, Ar), 6.67-6.69 (m, 1H, Ar), 7.08-7.11 (m, 1H, Ar), 7.32-7.33 (m, 1H, Ar), 7.40-7.43 (m, 2H, Ar), 7.46 (s, 1H, Ar), 8.24 (d, J = 6.8 Hz, 1H, Ar); ¹³ C NMR (CDCl ₃ ): δ 113.7, 118.8, 118.8, 120.8, 121.7, 124.3, 125.9, 127.6, 131.7, 132.6, 133.0 (Ar); MS (EI) m / z 200 (M ⁺ ); HRMS Calcd for C ₁₁ H ₈ N ₂ S: 200.0408; Found: 200.0391.

(Compound 8) 3- (4-Fluorophenyl) imidazo [1,5-a] pyridine yellow solid; mp 105-106 ° C; IR (KBr) 3074, 1520, 1230 cm ^-1 ; ¹ H NMR (CDCl ₃ ) : δ 6.63 (t, J = 7.1 Hz, 1H, Ar), 6.82 (dd, J = 7.1, 9.1 Hz, 1H, Ar), 7.21-7.29 (m, 2H, Ar), 7.50 (d, J = 9.1 Hz, 1H, Ar), 7.58 (s, 1H, Ar), 7.77-7.82 (m, 2H, Ar), 8.14 (d, J = 7.1 Hz, 1H, Ar); ¹³ C NMR (CDCl ₃ ): δ 113.2 (Ar), 115.9 (d, J = 21.8 Hz, FC C ), 118.7, 118.8, 120.4, 121.0, 126.4, 126.5 (Ar), 129.7 (d, J = 8.8 Hz, FCC C ), 131.5, 137.2 ( Ar), 162.7 (d, J = 249 Hz, F C ); ¹⁹ F NMR (CDCl ₃ ): δ -112.7 (CF); MS (EI) m / z 212 (M ⁺ ); HRMS (EI) Calcd for C ₁₃ H ₉ FN ₂ (M ⁺ ) 212.0750, Found: 212.0716.

(Compound 9) 3- (4-Bromophenyl) imidazo [1,5-a] pyridine yellow solid; mp 109-111 ° C; IR (KBr) 1505, 1454, 1434 1399, 1352, 1307, 1249, 1070, 999 , 826, 791, 763, 688 cm ^-1 ; ¹ H NMR (CDCl ₃ ): δ 6.57 (t, J = 6.6 Hz, 1H, Ar), 6.73 (dd, J = 9.0, 6.6 Hz, 1H, Ar) , 7.48 (d, J = 9.3 Hz, 1H, Ar), 7.55 (s, 1H, Ar), 7.62-7.68 (m, 4H, Ar), 8.19 (d, J = 7.3 Hz, 1H, Ar); ¹³ C NMR (CDCl ₃ ): δ 113.4, 118.9, 118.9, 120.9, 121.1, 122.5, 129.2, 129.3, 131.8, 132.1, 137.1 (Ar); MS (EI) m / z 272 (M ⁺ ), 274 (M ⁺ +2); HRMS Calcd for C ₁₃ H ₉ BrN ₂ : 271.9949; Found: 271.9966.

(Compound 10) 3- (1-Phenylethyl) imidazo [1,5-a] pyridine
¹ H NMR (CDCl ₃ ): δ 1.88 (d, J = 7.32 Hz, 3H, Me), 4.38 (q, J = 7.32 Hz, 1H, CH), 6.69 (dd, J = 6.34, 5.86 Hz, 1H, Ar), 7.07 (dd, J = 9.27, 6.34 Hz, 1H, Ar), 7.14 (d, J = 6.83 Hz 2H, Ar), 7.20 (d, J = 6.90 Hz, 1H, Ar), 7.26 (t, J = 6.84 Hz, 2H, Ar), 7.39 (d, J = 9.27 Hz, 1H, Ar), 7.46 (s, 1H, Ar), 7.47 (d, J = 5.86 Hz, 1H, Ar); ¹³ C NMR (CDCl ₃ ): δ 21.4 (Me), 38.3 (CH), 112.0, 118.0, 118.4, 118.5, 120.7, 126.8, 127.1, 128.9, 130.8, 140.5, 143.0 (Ar); MS (EI) m / z 222 ( M ⁺ ); HRMS Calcd for C ₁₅ H ₁₄ N ₂ : 222.1157; Found: 222.1159.

(Compound 11) 3- (1-methylethyl) imidazo [1,5-a] pyridine brown oil; IR (KBr) 1702, 1589, 1463, 1385, 1088, 1028, 745, 696 cm ^-1 ; ¹ H NMR (CDCl ₃ ): δ 1.44 (d, J = 6.8 Hz, 6H, Me), 3.30 (sep, J = 6.8 Hz, 1H, CH), 6.50-6.53 (m, 1H, Ar), 6.60-6.64 (m , 1H, Ar), 7.35 (s, 1H, Ar), 7.38-7.41 (m, 1H, Ar), 7.74 (d, J = 7.3 Hz, 1H, Ar); ¹³ C NMR (CDCl ₃ ): δ 20.4 (Me), 26.0 (CH), 112.1, 117.6, 118.2, 118.7, 120.5, 130.3, 143.4 (Ar); MS (EI) m / z 160 (M ⁺ ); HRMS Calcd for C ₁₀ H ₁₂ N ₂ : 160.1000 ; Found: 160.0993.

(Compound 12) 1-methyl-3- (2-pyridyl) imidazo [1,5-a] pyridine light yellow solid: mp 99-102 ° C; IR (KBr) 1589, 1501, 1415, 1334, 1256, 1074, 783, 746, 683 cm ^-1 ; ¹ H NMR (CDCl ₃ ): δ 2.52 (s, 3H, Me), 6.58-6.61 (m, 1H, Ar), 6.69 (ddd, J = 8.8, 6.3, 1.0 Hz , 1H, Ar), 7.07 (ddd, J = 7.3, 4.9, 1.0 Hz, 1H, Ar), 7.36-7.39 (m, 1H, Ar), 7.65-7.69 (m, 1H, Ar), 8.22-8.24 ( m, 1H, Ar), 8.54 (dq, J = 4.9, 1.0 Hz, 1H, Ar), 9.78-9.80 (m, 1H, Ar); ¹³ C NMR (CDCl ₃ ): δ 12.8 (Me), 113.4, 117.5, 118.5, 121.2, 121.5, 125.8, 129.5, 129.6, 133.7, 136.4, 148.2, 151.1 (Ar); MS (EI) m / z 209 (M ⁺ ); HRMS Calcd for C ₁₃ H ₁₁ N ₃ : 209.0953; Found: 209.0928.

  The present invention has industrial applicability in that it can provide a novel DNA damage checkpoint activator useful as an anticancer agent.

Schematic diagram of DNA damage checkpoint mechanism. The figure which shows the screening principle of the DNA damage checkpoint activation effect | action using gene disruption yeast.

Claims (4)

  A DNA damage checkpoint activator comprising a compound having an imidazo [1,5-a] pyridine skeleton or a pharmaceutically acceptable salt thereof as an active ingredient.   The compound having an imidazo [1,5-a] pyridine skeleton has an aryl group which may have a substituent or a heteroaryl group which may have a substituent in the 3-position. Item 2. A DNA damage checkpoint activator according to Item 1. 3. The DNA damage checkpoint activator according to claim 2, wherein the compound having an imidazo [1,5-a] pyridine skeleton is represented by the following general formula (1).
[Wherein R ¹ represents a hydrogen atom, a lower alkyl group, a lower cycloalkyl group, a lower alkenyl group, a halogen atom, an aryl group which may have a substituent, or an aryl lower group which may have a substituent. An alkyl group, an optionally substituted heteroaryl group, —XR ¹¹ (X is S or Se, R ¹¹ is a lower alkyl group, a lower alkenyl group, a lower alkoxy group, a halogen atom, a substituent; An aryl group which may have a substituent, a heteroaryl group which may have a substituent, or a group represented by the following general formula (2)), -YR ¹² R ¹³ (Y is , B, N, or P, and R ¹² and R ¹³ may be the same or different and each may have a lower alkyl group, a lower alkenyl group, a lower alkoxy group, a halogen atom, or a substituent. Aryl group, heteroaryl optionally having substituent Group, the general formula is any of the groups represented by ^{(2)), - ZR 14} R 15 R 16 (Z is, Si, Ge, is any of ^{Sn, R 14, R 15,} R ¹⁶ are the same or different and are each a lower alkyl group, a lower alkenyl group, a lower alkoxy group, a halogen atom, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, -CR ¹⁷ R ¹⁸ R ¹⁹ (R ¹⁷ , R ¹⁸ , R ¹⁹ are the same or different, and each represents a lower alkenyl group or a lower alkoxy group). A group, a halogen atom, an optionally substituted heteroaryl group, or a group represented by the following general formula (2). R ² represents an aryl group which may have a substituent or a heteroaryl group which may have a substituent. R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and are each a hydrogen atom, a lower alkyl group, an aryl group optionally having a substituent, a hydroxyl group, a lower alkoxy group, an amino group, or a mono-lower group. An alkylamino group, a di-lower alkylamino group, a nitro group, a halogen atom, a carboxyl group, a lower alkoxycarbonyl group, or a trifluoromethyl group is shown. ]
[Wherein R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ have the same meanings as described above. ]   An anticancer agent comprising a compound having an imidazo [1,5-a] pyridine skeleton or a pharmaceutically acceptable salt thereof as an active ingredient.