JP2020164521A - Antiviral drug - Google Patents
Antiviral drug Download PDFInfo
- Publication number
- JP2020164521A JP2020164521A JP2020056916A JP2020056916A JP2020164521A JP 2020164521 A JP2020164521 A JP 2020164521A JP 2020056916 A JP2020056916 A JP 2020056916A JP 2020056916 A JP2020056916 A JP 2020056916A JP 2020164521 A JP2020164521 A JP 2020164521A
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- JP
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- Prior art keywords
- group
- formula
- compound
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- hydroxy
- Prior art date
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- 239000003443 antiviral agent Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 179
- 150000003839 salts Chemical class 0.000 claims abstract description 57
- 208000002672 hepatitis B Diseases 0.000 claims abstract description 23
- 239000003814 drug Substances 0.000 claims description 80
- -1 phosphoryloxy group Chemical group 0.000 claims description 73
- 229940079593 drug Drugs 0.000 claims description 60
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 53
- 239000001257 hydrogen Substances 0.000 claims description 45
- 229910052739 hydrogen Inorganic materials 0.000 claims description 45
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 38
- 241000700721 Hepatitis B virus Species 0.000 claims description 25
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 25
- 150000002431 hydrogen Chemical class 0.000 claims description 25
- 201000010099 disease Diseases 0.000 claims description 24
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- 229910052736 halogen Inorganic materials 0.000 claims description 20
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- 231100000835 liver failure Toxicity 0.000 claims description 7
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Abstract
Description
本発明は、優れた抗ウィルス活性(特に抗B型肝炎ウィルス活性)を有する核酸アナログに関する。 The present invention relates to nucleic acid analogs having excellent antiviral activity (particularly anti-hepatitis B virus activity).
B型肝炎ウィルス(HBV)による慢性肝炎は肝硬変や肝臓癌の主要な原因の1つである。現在、全世界にはキャリアとして20億人、持続感染が4億人、日本でも100万人を超えるキャリアがいると言われている。90%以上のキャリアは自然治癒に至るが、5%以上の者が劇症化し、慢性肝炎、肝臓癌に移行し、死に至る。
HBV感染予防にはワクチンが開発されており、また既にいくつかの抗HBV薬も存在し、ラミブジン、アデホビル、そしてエンテカビル等の核酸アナログが上市されている。
核酸アナログは、逆転写機能を有するHBVのDNAポリメラーゼを標的として、抗HBV活性を示す。これらの使用により、血中のHBVは消失する。しかしながら、HBVは肝細胞内で安定な形のDNAとして存在するため、抗ウィルス薬による化学療法を中断すると、肝炎が再燃するおそれがある。また、既存の抗HBV薬に対する薬剤耐性ウィルスの出現も報告されている。このようなことから、既存の薬剤に加えて、新たな抗HBV薬の開発が望まれている。
Chronic hepatitis due to hepatitis B virus (HBV) is one of the major causes of liver cirrhosis and liver cancer. Currently, it is said that there are 2 billion carriers worldwide, 400 million persistent infections, and more than 1 million carriers in Japan. More than 90% of carriers lead to spontaneous healing, but more than 5% become fulminant, develop chronic hepatitis, liver cancer, and die.
Vaccines have been developed to prevent HBV infections, and some anti-HBV drugs already exist, with nucleic acid analogs such as ramibdin, adehovir, and entecavir on the market.
Nucleic acid analogs exhibit anti-HBV activity by targeting HBV DNA polymerase with reverse transcription function. With these uses, HBV in the blood disappears. However, since HBV exists as a stable form of DNA in hepatocytes, hepatitis may relapse if chemotherapy with antiviral drugs is interrupted. The emergence of drug-resistant viruses against existing anti-HBV drugs has also been reported. For these reasons, it is desired to develop a new anti-HBV drug in addition to the existing drug.
このような中核酸アナログの研究が進められているが、例えば、特許文献1、非特許文献1、非特許文献2は、2’位にフッ素原子、6’位にメチレン基を有する核酸アナログを開示している。特許文献2および特許文献3は、2’位にフッ素原子を有する核酸アナログを開示するが、本願発明の核酸アナログは具体的には開示していない。 Research on such medium nucleic acid analogs is underway. For example, Patent Document 1, Non-Patent Document 1, and Non-Patent Document 2 use nucleic acid analogs having a fluorine atom at the 2'position and a methylene group at the 6'position. It is disclosed. Patent Document 2 and Patent Document 3 disclose nucleic acid analogs having a fluorine atom at the 2'position, but do not specifically disclose the nucleic acid analogs of the present invention.
また、特許文献4および特許文献5は、2’位にフッ素原子を有する核酸アナログを開示するが、当該核酸アナログが抗B型肝炎ウィルス活性を有することについては開示しておらず、さらに後述される本願発明の化合物におけるR4が式(II)で表される基である化合物を具体的には開示していない。 Further, Patent Documents 4 and 5 disclose nucleic acid analogs having a fluorine atom at the 2'position, but do not disclose that the nucleic acid analogs have anti-hepatitis B virus activity, which will be described later. The compound in which R 4 is the group represented by the formula (II) in the compound of the present invention is not specifically disclosed.
他方、特許文献6は、クロファラビン(Clofarabine)が抗B型肝炎ウィルス活性を有することについて開示するが、後述される本願発明の化合物におけるR4が式(II)で表される基である化合物を具体的には開示していない。 On the other hand, Patent Document 6, although clofarabine (Clofarabine) is disclosed to have anti-hepatitis B virus activity, the compounds wherein R 4 is a group represented by the formula (II) in the compound of the present invention as described below Not specifically disclosed.
本発明は、より優れた抗ウィルス活性(特に抗B型肝炎ウイルス活性)を有する核酸アナログを提供することを課題とする。 An object of the present invention is to provide a nucleic acid analog having more excellent antiviral activity (particularly anti-hepatitis B virus activity).
本発明者らは、上記課題を解決するために鋭意研究した結果、下記式(I)で表される化合物が、優れた抗ウィルス活性(特に抗B型肝炎ウィルス活性)を有することを見出し、本発明を完成した。即ち、本発明は、以下の通りである。 As a result of diligent research to solve the above problems, the present inventors have found that the compound represented by the following formula (I) has excellent antiviral activity (particularly anti-hepatitis B virus activity). The present invention has been completed. That is, the present invention is as follows.
[1]下記の式(I): [1] The following formula (I):
[式中、R1は、置換されていてもよいプリン塩基を表し;
R2は、ヒドロキシ基またはアジド基を表し;
R3は、水素、置換されていてもよい(C1−C6)アルキル基、置換されていてもよい(C2−C6)アルキニル基、またはシアノ基を表し;および
R4は、ヒドロキシ基、ホスホリルオキシ基(−OPO3H)、または式(II):
[In the formula, R 1 represents a purine base that may be substituted;
R 2 represents a hydroxy or azide group;
R 3 represents hydrogen, a optionally substituted (C 1- C 6 ) alkyl group, optionally substituted (C 2- C 6 ) alkynyl group, or cyano group; and R 4 is hydroxy. group, phosphoryloxy group (-OPO 3 H), or formula (II):
(式中、Rは、エステル化されたカルボキシ(C1−C6)アルキル基を表し、およびArは置換されていてもよい(C6−C14)アリール基を表す)
で表される基を表す;
但し、R2が、ヒドロキシ基であり、R3が、水素である場合は、R1は、下記の式(IIIa)または(IIIb):
(In the formula, R represents an esterified carboxy (C 1- C 6 ) alkyl group, and Ar represents an optionally substituted (C 6- C 14 ) aryl group).
Represents a group represented by;
However, when R 2 is a hydroxy group and R 3 is hydrogen, R 1 is represented by the following formula (IIIa) or (IIIb):
(式中、R5は、水素またはハロゲンを表す)
で表される基を表し;および
R4は、上記の式(II)で表される基を表す。]
で表される化合物またはその塩(以下、本発明化合物(I)と称する場合がある)。
(In the formula, R 5 represents hydrogen or halogen)
In represents a group represented by; and R 4 represents a group represented by the formula (II). ]
Compound represented by (hereinafter, may be referred to as compound (I) of the present invention).
[2]下記の式(I): [2] The following formula (I):
[式中、R1は、置換されていてもよいプリン塩基を表し;
R2は、ヒドロキシ基またはアジド基を表し;
R3は、水素、置換されていてもよい(C1−C6)アルキル基、置換されていてもよい(C2−C6)アルキニル基、またはシアノ基を表し;および
R4は、ヒドロキシ基、ホスホリルオキシ基(−OPO3H)、または式(II):
[In the formula, R 1 represents a purine base that may be substituted;
R 2 represents a hydroxy or azide group;
R 3 represents hydrogen, a optionally substituted (C 1- C 6 ) alkyl group, optionally substituted (C 2- C 6 ) alkynyl group, or cyano group; and R 4 is hydroxy. group, phosphoryloxy group (-OPO 3 H), or formula (II):
(式中、Rは、エステル化されたカルボキシ(C1−C6)アルキル基を表し、およびArは置換されていてもよい(C6−C14)アリール基を表す)
で表される基を表す;
但し、R2が、ヒドロキシ基の場合は、R1は、下記の式(IIIa)または(IIIb):
(In the formula, R represents an esterified carboxy (C 1- C 6 ) alkyl group, and Ar represents an optionally substituted (C 6- C 14 ) aryl group).
Represents a group represented by;
However, when R 2 is a hydroxy group, R 1 is represented by the following formula (IIIa) or (IIIb):
(式中、R5は、水素またはハロゲンを表す)
で表される基を表し;および
R4は、上記の式(II)で表される基を表す。]
で表される化合物またはその塩。
[3]R1が、下記の式(IIIa)または(IIIb):
(In the formula, R 5 represents hydrogen or halogen)
In represents a group represented by; and R 4 represents a group represented by the formula (II). ]
A compound represented by or a salt thereof.
[3] R 1 is the following formula (IIIa) or (IIIb):
(式中、R5は、前記と同義である)
で表される基であり;
R3が、水素、ヒドロキシ(C1−C6)アルキル基、(C2−C6)アルキニル基、またはシアノ基であり;
Rが、(C1−C6)アルコキシカルボニル(C1−C6)アルキル基であり;および
Arが、フェニル基である、上記[1]または[2]に記載の化合物またはその塩。
[4]R1が、下記の式(IIIa):
(In the formula, R 5 is synonymous with the above)
It is a group represented by;
R 3 is a hydrogen, hydroxy (C 1- C 6 ) alkyl group, (C 2- C 6 ) alkynyl group, or cyano group;
The compound or salt thereof according to the above [1] or [2], wherein R is a (C 1- C 6 ) alkoxycarbonyl (C 1- C 6 ) alkyl group; and Ar is a phenyl group.
[4] R 1 is the following formula (IIIa):
で表される基である、上記[1]〜[3]のいずれかに記載の化合物またはその塩。
[5]R1が、下記の式(IIIb):
The compound according to any one of the above [1] to [3] or a salt thereof, which is a group represented by.
[5] R 1 is the following formula (IIIb):
(式中、R5は、水素を表す)
で表される基である、上記[1]〜[3]のいずれかに記載の化合物またはその塩。
[6]R1が、下記の式(IIIb):
(In the formula, R 5 represents hydrogen)
The compound according to any one of the above [1] to [3] or a salt thereof, which is a group represented by.
[6] R 1 is the following formula (IIIb):
(式中、R5は、ハロゲンを表す)
で表される基である、上記[1]〜[3]のいずれかに記載の化合物またはその塩。
(In the formula, R 5 represents halogen)
The compound according to any one of the above [1] to [3] or a salt thereof, which is a group represented by.
[7]上記[1]または[2]に記載の化合物またはその塩を有効成分として含有する医薬。
[8]ウィルス感染により誘発される疾患の予防または治療のための、上記[7]に記載の医薬。
[7] A drug containing the compound according to the above [1] or [2] or a salt thereof as an active ingredient.
[8] The medicament according to the above [7] for the prevention or treatment of a disease induced by a virus infection.
[9]上記[1]または[2]に記載の化合物(I)またはその塩の有効量を、哺乳動物に投与することを含む、当該哺乳動物におけるウィルス活性抑制方法。
[10]上記[1]または[2]に記載の化合物(I)またはその塩の予防または治療有効量を、その投薬を必要とする哺乳動物に投与することを含む、ウィルス感染により誘発される疾患の予防または治療方法。
[9] A method for suppressing virus activity in a mammal, which comprises administering to the mammal an effective amount of the compound (I) or a salt thereof according to the above [1] or [2].
[10] Induced by a viral infection, which comprises administering a prophylactic or therapeutically effective amount of the compound (I) or salt thereof according to the above [1] or [2] to a mammal in need thereof. How to prevent or treat a disease.
[11]医薬として使用するための、上記[1]または[2]に記載の化合物またはその塩。
[12]ウィルス感染により誘発される疾患の予防または治療に使用するための、上記[1]または[2]に記載の化合物またはその塩。
[13]ウィルス感染が、B型肝炎ウィルス(HBV)、C型肝炎ウィルス(HCV)、ヘルペスウィルス(HSB−1またはHSB−2)、サイトメガロウィルス(CMV)、水痘・帯状疱疹ウィルス(VZV)および/またはエプスタイン・バール・ウィルス(EBV)によるものである、上記[8]に記載の医薬、[9]に記載のウィルス活性抑制方法、[10]に記載の予防または治療方法、または上記[12]に記載の化合物またはその塩。
[11] The compound according to the above [1] or [2] or a salt thereof for use as a medicine.
[12] The compound according to the above [1] or [2] or a salt thereof for use in the prevention or treatment of a disease induced by a virus infection.
[13] Virus infections include hepatitis B virus (HBV), hepatitis C virus (HCV), herpes virus (HSB-1 or HSB-2), cytomegalovirus (CMV), varicella-zoster virus (VZV). And / or the drug according to [8] above, the method for suppressing virus activity according to [9], the preventive or therapeutic method according to [10], or the above [10], which is caused by Epstein-Barr virus (EBV). 12] The compound or a salt thereof.
[14]下記の式(Ia): [14] The following formula (Ia):
[式中、R1は、置換されていてもよいプリン塩基を表し;
R2は、ヒドロキシ基またはアジド基を表し;
R3は、水素、置換されていてもよい(C1−C6)アルキル基、置換されていてもよい(C2−C6)アルキニル基、またはシアノ基を表し;および
R4は、ヒドロキシ基、ホスホリルオキシ基、または式(II):
[In the formula, R 1 represents a purine base that may be substituted;
R 2 represents a hydroxy or azide group;
R 3 represents hydrogen, a optionally substituted (C 1- C 6 ) alkyl group, optionally substituted (C 2- C 6 ) alkynyl group, or cyano group; and R 4 is hydroxy. Group, phosphoryloxy group, or formula (II):
(式中、Rは、エステル化されたカルボキシ(C1−C6)アルキル基を表し、およびArは置換されていてもよいアリール基を表す)
で表される基を表す;
但し、R2が、ヒドロキシ基であり、R3が、水素である場合は、
1)R1が、下記の式(IIIa)または(IIIb):
(Wherein, R represents an esterified carboxy (C 1 -C 6) alkyl group, and Ar represents an aryl group which may be substituted)
Represents a group represented by;
However, when R 2 is a hydroxy group and R 3 is hydrogen,
1) R 1 is the following formula (IIIa) or (IIIb):
(式中、R5は、水素を表す)で表される基を表すか、または
2)R1が、下記の式(IIIb):
(In the formula, R 5 represents hydrogen), or 2) R 1 represents the following formula (IIIb):
(式中、R5は、ハロゲンを表す)で表される基であり、かつ
R4が、式(II):
(In the formula, R 5 represents a halogen), and R 4 is a group represented by the formula (II) :.
(式中、Rは、エステル化されたカルボキシ(C1−C6)アルキル基を表し、およびArは置換されていてもよい(C6−C14)アリール基を表す。)
で表される基を表す]
で表される化合物またはその塩(以下、本発明化合物(Ia)と称する場合がある)を、有効成分として含有するB型肝炎ウィルス感染により誘発される疾患の予防または治療のための医薬。
[15]下記の式(Ia):
(In the formula, R represents an esterified carboxy (C 1- C 6 ) alkyl group, and Ar represents an optionally substituted (C 6- C 14 ) aryl group.)
Represents a group represented by]
A drug for preventing or treating a disease induced by hepatitis B virus infection, which contains a compound represented by (1) or a salt thereof (hereinafter, may be referred to as a compound of the present invention (Ia)) as an active ingredient.
[15] The following formula (Ia):
[式中、R1は、置換されていてもよいプリン塩基を表し;
R2は、ヒドロキシ基またはアジド基を表し;
R3は、水素、置換されていてもよい(C1−C6)アルキル基、置換されていてもよい(C2−C6)アルキニル基、またはシアノ基を表し;および
R4は、ヒドロキシ基、ホスホリルオキシ基、または式(II):
[In the formula, R 1 represents a purine base that may be substituted;
R 2 represents a hydroxy or azide group;
R 3 represents hydrogen, a optionally substituted (C 1- C 6 ) alkyl group, optionally substituted (C 2- C 6 ) alkynyl group, or cyano group; and R 4 is hydroxy. Group, phosphoryloxy group, or formula (II):
(式中、Rは、エステル化されたカルボキシ(C1−C6)アルキル基を表し、およびArは置換されていてもよいアリール基を表す)
で表される基を表す;
但し、R2が、ヒドロキシ基の場合は、
1)R1が、下記の式(IIIa)または(IIIb):
(Wherein, R represents an esterified carboxy (C 1 -C 6) alkyl group, and Ar represents an aryl group which may be substituted)
Represents a group represented by;
However, when R 2 is a hydroxy group,
1) R 1 is the following formula (IIIa) or (IIIb):
(式中、R5は、水素を表す)で表される基を表すか、または
2)R1が、下記の式(IIIb):
(In the formula, R 5 represents hydrogen), or 2) R 1 represents the following formula (IIIb):
(式中、R5は、ハロゲンを表す)で表される基であり、かつ
a)R4が、式(II):
(In the formula, R 5 represents a halogen), and a) R 4 is the formula (II) :.
(式中、Rは、エステル化されたカルボキシ(C1−C6)アルキル基を表し、およびArは置換されていてもよい(C6−C14)アリール基を表す。)
で表される基を表す]
で表される化合物またはその塩を、有効成分として含有するB型肝炎ウィルス感染により誘発される疾患の予防または治療のための医薬。
[16]R1が、下記の式(IIIa)または(IIIb):
(In the formula, R represents an esterified carboxy (C 1- C 6 ) alkyl group, and Ar represents an optionally substituted (C 6- C 14 ) aryl group.)
Represents a group represented by]
A drug for the prevention or treatment of a disease induced by hepatitis B virus infection, which contains the compound represented by (1) or a salt thereof as an active ingredient.
[16] R 1 is the following formula (IIIa) or (IIIb):
(式中、R5は、前記と同義である)
で表される基であり;
R3が、水素、ヒドロキシ(C1−C6)アルキル基、(C2−C6)アルキニル基、またはシアノ基であり;
Rが、(C1−C6)アルコキシカルボニル(C1−C6)アルキル基であり;および
Arが、フェニル基である、上記[14]または[15]に記載の医薬。
[17]R1が、下記の式(IIIa):
(In the formula, R 5 is synonymous with the above)
It is a group represented by;
R 3 is a hydrogen, hydroxy (C 1- C 6 ) alkyl group, (C 2- C 6 ) alkynyl group, or cyano group;
The medicament according to the above [14] or [15], wherein R is a (C 1- C 6 ) alkoxycarbonyl (C 1- C 6 ) alkyl group; and Ar is a phenyl group.
[17] R 1 is the following formula (IIIa):
で表される基である、上記[14]〜[16]のいずれかに記載の医薬。
[18]R1が、下記の式(IIIb):
The medicament according to any one of the above [14] to [16], which is a group represented by.
[18] R 1 is the following formula (IIIb):
(式中、R5は、水素を表す)
で表される基である、上記[14]〜[16]のいずれかに記載の医薬。
[19]R1が、下記の式(IIIb):
(In the formula, R 5 represents hydrogen)
The medicament according to any one of the above [14] to [16], which is a group represented by.
[19] R 1 is expressed by the following equation (IIIb):
(式中、R5は、ハロゲンを表す)
で表される基である、上記[14]〜[16]のいずれかに記載の医薬。
[20]B型肝炎ウィルス感染により誘発される疾患が、肝炎、肝不全、肝硬変または肝臓癌である、上記[14]〜[19]のいずれかに記載の医薬。
(In the formula, R 5 represents halogen)
The medicament according to any one of the above [14] to [16], which is a group represented by.
[20] The medicament according to any one of the above [14] to [19], wherein the disease induced by hepatitis B virus infection is hepatitis, liver failure, liver cirrhosis or liver cancer.
[21]上記[14]または[15]に記載の化合物またはその塩の予防または治療有効量を、その投薬を必要とする哺乳動物に投与することを含む、B型肝炎ウィルス感染により誘発される疾患の予防または治療方法。
[22]B型肝炎ウィルス感染により誘発される疾患が、肝炎、肝不全、肝硬変または肝臓癌である上記[21]に記載の予防または治療方法。
[21] Induced by hepatitis B virus infection, which comprises administering a prophylactic or therapeutically effective amount of the compound or salt thereof according to the above [14] or [15] to a mammal in need thereof. How to prevent or treat a disease.
[22] The preventive or therapeutic method according to the above [21], wherein the disease induced by hepatitis B virus infection is hepatitis, liver failure, cirrhosis or liver cancer.
[23]B型肝炎ウィルス感染により誘発される疾患の予防または治療に使用するための、上記[14]または[15]に記載の化合物またはその塩。
[24]B型肝炎ウィルス感染により誘発される疾患が、肝炎、肝不全、肝硬変または肝臓癌である、上記[23]に記載の化合物またはその塩。
[23] The compound according to the above [14] or [15] or a salt thereof for use in the prevention or treatment of a disease induced by hepatitis B virus infection.
[24] The compound or salt thereof according to the above [23], wherein the disease induced by hepatitis B virus infection is hepatitis, liver failure, cirrhosis or liver cancer.
[25]上記[14]に記載の化合物(Ia)が、上記[1]に記載の化合物(I)である、上記[14]〜[20]に記載の医薬、上記[21]または[22]に記載の予防または治療方法、および上記[23]または[24]に記載の化合物またはその塩。
[26]R1が、下記の式(IIIa)または(IIIb):
[25] The medicament according to the above [14] to [20], wherein the compound (Ia) according to the above [14] is the compound (I) according to the above [1], the above [21] or [22]. ], And the compound or salt thereof according to the above [23] or [24].
[26] R 1 is the following formula (IIIa) or (IIIb):
(式中、R5は、水素を表す)で表される基であり;
R2が、ヒドロキシ基である、上記[14]〜[20]に記載の医薬、上記[21]または[22]に記載の予防または治療方法、および上記[23]または[24]に記載の化合物またはその塩。
(In the formula, R 5 represents hydrogen) is a group represented by;
R 2 is a hydroxy group, the above-mentioned [14] according to [20] a pharmaceutical, prophylactic or therapeutic method according to [21] or [22], and according to the above [23] or [24] Compound or salt thereof.
本発明化合物(I)および本発明化合物(Ia)は、優れた抗ウィルス活性(特に抗B型肝炎ウィルス活性)を有し、ウィルス感染により誘発される疾患(特に、B型肝炎ウィルス感染により誘発される疾患(例えば、肝炎、肝不全、肝硬変、肝臓癌等))の予防または治療に有用である。 The compound (I) of the present invention and the compound (Ia) of the present invention have excellent antiviral activity (particularly anti-hepatitis B virus activity) and are induced by a virus infection-induced disease (particularly, hepatitis B virus infection). It is useful for the prevention or treatment of diseases (for example, hepatitis, liver failure, cirrhosis, liver cancer, etc.).
以下、本明細書中で用いられる各用語の定義について詳述する。特記しない限り各用語は以下の定義を有する。 Hereinafter, the definitions of each term used in the present specification will be described in detail. Unless otherwise specified, each term has the following definitions.
本明細書中、特に限定しない限り、「プリン塩基」としては、グアニン、アデニン、およびその誘導体が挙げられる。当該プリン塩基は、プリン骨格の9位窒素原子を介して化合物(I)および化合物(Ia)のテトラヒドロフラン骨格に結合している。 In the present specification, unless otherwise specified, "purine base" includes guanine, adenine, and derivatives thereof. The purine base is attached to the tetrahydrofuran skeleton of compound (I) and compound (Ia) via the nitrogen atom at the 9-position of the purine skeleton.
当該「プリン塩基」は、プリン塩基を構成する酸素および/または窒素官能基が保護基により保護されていてもよい。好適な保護基としては、例えば、トリメチルシリル基、ジメチルヘキシルシリル基、t−ブチルジメチルシリル基またはt−ブチルジフェニルシリル基のようなシリル基、アセチル基またはプロプロニル基のようなアシル基、メタンスルホニル基またはp−トルエンスルホニル基のようなスルホニル基等が挙げられる。 In the "purine base", the oxygen and / or nitrogen functional groups constituting the purine base may be protected by a protecting group. Suitable protecting groups include, for example, a silyl group such as a trimethylsilyl group, a dimethylhexylsilyl group, a t-butyldimethylsilyl group or a t-butyldiphenylsilyl group, an acyl group such as an acetyl or propronyl group, a methanesulfonyl group. Alternatively, a sulfonyl group such as a p-toluenesulfonyl group can be mentioned.
当該「プリン塩基」は、適当な置換基により置換されていてもよく、このような置換基としては、例えば、ハロゲン原子、ヒドロキシ基、アミノ基、シアノ基、ニトロ基、(C1−C6)アルキル基、(C2−6)アルケニル基、(C2−C6)アルキニル基、(C1−6)アルコキシ基等が挙げられる。 The "purine base" may be substituted with an appropriate substituent, and examples of such a substituent include a halogen atom, a hydroxy group, an amino group, a cyano group, a nitro group, and (C 1- C 6). ) alkyl group, (C 2 - 6) alkenyl, (C 2 -C 6) alkynyl, (C 1 - include 6) alkoxy group.
本明細書中、特に限定しない限り、「(C1−C6)アルキル基」としては、例えば、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、sec−ブチル基、tert−ブチル基、ペンチル基、イソペンチル基、ネオペンチル基、1−エチルプロピル基、1,1−ジメチルプロピル基、2−メチルブチル基、ヘキシル基、イソヘキシル基、1,1−ジメチルブチル基、2,2−ジメチルブチル基、3,3−ジメチルブチル基、2−エチルブチル基等が挙げられる。 Herein, unless otherwise specified, as the "(C 1 -C 6) alkyl group", for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, butyl group, isobutyl group, sec- butyl group, tert -Butyl group, pentyl group, isopentyl group, neopentyl group, 1-ethylpropyl group, 1,1-dimethylpropyl group, 2-methylbutyl group, hexyl group, isohexyl group, 1,1-dimethylbutyl group, 2,2- Examples thereof include a dimethylbutyl group, a 3,3-dimethylbutyl group and a 2-ethylbutyl group.
本明細書中、特に限定しない限り、「(C2−C6)アルケニル基」としては、例えば、エテニル基、1−プロペニル基、2−プロペニル基、2−メチル−1−プロペニル基、1−ブテニル基、2−ブテニル基、3−ブテニル基、3−メチル−2−ブテニル基、1−ペンテニル基、2−ペンテニル基、3−ペンテニル基、4−ペンテニル基、4−メチル−3−ペンテニル基、1−ヘキセニル基、3−ヘキセニル基、5−ヘキセニル基等が挙げられる。 Herein, unless otherwise specified, as the "(C 2 -C 6) alkenyl group", for example, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl group, 1- Butenyl group, 2-butenyl group, 3-butenyl group, 3-methyl-2-butenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 4-methyl-3-pentenyl group , 1-hexenyl group, 3-hexenyl group, 5-hexenyl group and the like.
本明細書中、特に限定しない限り、「(C2−C6)アルキニル基」としては、例えば、エチニル基、1−プロピニル基、2−プロピニル基、1−ブチニル基、2−ブチニル基、3−ブチニル基、1−ペンチニル基、2−ペンチニル基、3−ペンチニル基、4−ペンチニル基、1−ヘキシニル基、2−ヘキシニル基、3−ヘキシニル基、4−ヘキシニル基、5−ヘキシニル基等が挙げられる。 Herein, unless otherwise specified, as the "(C 2 -C 6) alkynyl group", for example, ethynyl group, 1-propynyl, 2-propynyl, 1-butynyl group, 2-butynyl group, 3 − Butynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 1-hexynyl group, 2-hexynyl group, 3-hexynyl group, 4-hexynyl group, 5-hexynyl group, etc. Can be mentioned.
当該「(C1−C6)アルキル基」、「(C2−C6)アルケニル基」および「(C2−C6)アルキニル基」は、適当な置換基により置換されていてもよく、このような置換基としては、例えば、ハロゲン原子、ヒドロキシ基、アミノ基、シアノ基、ニトロ基、(C1−C6)アルコキシ基等が挙げられる。 The "(C 1- C 6 ) alkyl group", "(C 2- C 6 ) alkenyl group" and "(C 2- C 6 ) alkynyl group" may be substituted with an appropriate substituent. as such substituents, for example, a halogen atom, hydroxy group, an amino group, a cyano group, a nitro group, and (C 1 -C 6) alkoxy group.
本明細書中、特に限定しない限り、「(C1−C6)アルコキシ基」としては、例えば、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ブトキシ基、イソブトキシ基、sec−ブトキシ基、tert−ブトキシ基、ペンチルオキシ基、ヘキシルオキシ基等が挙げられる。 In the present specification, unless otherwise specified, the "(C 1- C 6 ) alkoxy group" includes, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, and the like. Examples thereof include a tert-butoxy group, a pentyloxy group, a hexyloxy group and the like.
本明細書中、特に限定しない限り、「エステル化されたカルボキシ(基)」としては、例えば、「(C1−C6)アルコキシ−カルボニル(基)」が挙げられ、その具体例としては、例えば、メトキシカルボニル(基)、エトキシカルボニル(基)、プロポキシカルボニル(基)、イソプロポキシカルボニル(基)、ブトキシカルボニル(基)、イソブトキシカルボニル(基)、sec−ブトキシカルボニル(基)、tert−ブトキシカルボニル(基)、ペンチルオキシカルボニル(基)、ヘキシルオキシカルボニル(基)等が挙げられる。 Herein, unless otherwise specified, as the "esterified carboxyl (group)", for example, - include "(C 1 -C 6) alkoxy carbonyl (group)", as specific examples thereof, For example, methoxycarbonyl (group), ethoxycarbonyl (group), propoxycarbonyl (group), isopropoxycarbonyl (group), butoxycarbonyl (group), isobutoxycarbonyl (group), sec-butoxycarbonyl (group), tert- Examples thereof include butoxycarbonyl (group), pentyloxycarbonyl (group), and hexyloxycarbonyl (group).
本明細書中、特に限定しない限り、「エステル化されたカルボキシ(C1−C6)アルキル基」とは、上記「エステル化されたカルボキシ」により置換された上記「(C1−C6)アルキル基」をいう。具体的には、メトキシカルボニルメチル基、エトキシカルボニルエチル基、プロポキシカルボニルプロピル基、イソプロポキシカルボニルプロピル基、ブトキシカルボニルエチル基、ブトキシカルボニルブチル基、イソブトキシカルボニルブチル基、イソブトキシカルボニルエチル基、sec−ブトキシカルボニルメチル基、sec−ブトキシカルボニルエチル基、tert−ブトキシカルボニルエチル基、ペンチルオキシカルボニルペンチル基、ヘキシルオキシカルボニルヘキシル基等が挙げられる。 In the present specification, unless otherwise specified, the "esterified carboxy (C 1- C 6 ) alkyl group" is referred to as the above "(C 1- C 6 )" substituted with the above "esterified carboxy". "Alkyl group". Specifically, methoxycarbonylmethyl group, ethoxycarbonylethyl group, propoxycarbonylpropyl group, isopropoxycarbonylpropyl group, butoxycarbonylethyl group, butoxycarbonylbutyl group, isobutoxycarbonylbutyl group, isobutoxycarbonylethyl group, sec- Examples thereof include a butoxycarbonylmethyl group, a sec-butoxycarbonylethyl group, a tert-butoxycarbonylethyl group, a pentyloxycarbonylpentyl group, and a hexyloxycarbonylhexyl group.
本明細書中、特に限定しない限り、「(C6−C14)アリール基」とは、例えば、フェニル基、1−ナフチル基、2−ナフチル基、1−アントリル基、2−アントリル基、9−アントリル基等が挙げられる。
当該「(C6−C14)アリール基」は、適当な置換基により置換されていてもよく、このような置換基としては、例えば、ハロゲン原子、ヒドロキシ基、アミノ基、シアノ基、ニトロ基、(C1−C6)アルキル基、(C2−6)アルケニル基、(C2−C6)アルキニル基、(C1−6)アルコキシ基等が挙げられる。
Herein, unless otherwise specified, the "(C 6 -C 14) aryl group", for example, a phenyl group, 1-naphthyl, 2-naphthyl, 1-anthryl group, 2-anthryl group, 9 -Anthryl groups and the like can be mentioned.
The "(C 6- C 14 ) aryl group" may be substituted with an appropriate substituent, and examples of such a substituent include a halogen atom, a hydroxy group, an amino group, a cyano group and a nitro group. , (C 1 -C 6) alkyl group, (C 2 - 6) alkenyl, (C 2 -C 6) alkynyl, - include (C 1 6) alkoxy group.
本明細書中、特に限定しない限り、「ハロゲン」としては、フッ素原子、塩素原子、臭素原子、およびヨウ素原子が挙げられる。 In the present specification, unless otherwise specified, "halogen" includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
本発明の一つの態様は、本発明化合物(I)に関する。以下、式(I)の各記号について説明する。 One aspect of the present invention relates to compound (I) of the present invention. Hereinafter, each symbol of the formula (I) will be described.
R1は、置換されていてもよいプリン塩基を表す。
R1は、好ましくは、プリン塩基であり、さらに好ましくは、下記の式(IIIa)または(IIIb):
R 1 represents a purine base which may be substituted.
R 1 is preferably a purine base, and more preferably the following formula (IIIa) or (IIIb):
(式中、R5は、水素またはハロゲンを表す)で表される基である。 (In the formula, R 5 represents hydrogen or halogen) is a group represented by.
R2は、ヒドロキシ基またはアジド基を表す。 R 2 represents a hydroxy group or an azide group.
R3は、水素、置換されていてもよい(C1−C6)アルキル基、置換されていてもよい(C2−C6)アルキニル基、またはシアノ基を表す。
R3は、好ましくは、水素、ヒドロキシ(C1−C6)アルキル基、(C2−C6)アルキニル基、またはシアノ基、より好ましくは、水素、ヒドロキシ(C1−C4)アルキル基、(C2−C4)アルキニル基、またはシアノ基である。
R 3 represents hydrogen, a optionally substituted (C 1- C 6 ) alkyl group, optionally substituted (C 2- C 6 ) alkynyl group, or a cyano group.
R 3 is preferably a hydrogen, hydroxy (C 1- C 6 ) alkyl group, (C 2- C 6 ) alkynyl group, or cyano group, more preferably a hydrogen, hydroxy (C 1- C 4 ) alkyl group. a (C 2 -C 4) alkynyl or cyano group.
R4は、ヒドロキシ基、ホスホリルオキシ基、または式(II): R 4 is hydroxy group, phosphoryloxy group, or a group of the formula, (II):
(式中、Rは、エステル化されたカルボキシ(C1−C6)アルキル基を表し、およびArは置換されていてもよい(C6−C14)アリール基を表す)
で表される基を表す。
R4は、好ましくは、ヒドロキシ基または式(II):
(In the formula, R represents an esterified carboxy (C 1- C 6 ) alkyl group, and Ar represents an optionally substituted (C 6- C 14 ) aryl group).
Represents a group represented by.
R 4 is preferably hydroxy group or a group represented by the formula (II):
(式中、Rは、(C1−C6)アルコキシ−カルボニル(C1−C6)アルキル基、より好ましくは、(C1−C4)アルコキシ−カルボニル(C1−C4)アルキル基であり、およびArは、(C6−C14)アリール基、より好ましくはフェニル基である)
で表される基である。
(In the formula, R is a (C 1- C 6 ) alkoxy-carbonyl (C 1- C 6 ) alkyl group, more preferably a (C 1- C 4 ) alkoxy-carbonyl (C 1- C 4 ) alkyl group. , and the and Ar, (C 6 -C 14) aryl group, more preferably a phenyl group)
It is a group represented by.
以下、化合物(I)の好適な具体例について説明する。 Hereinafter, suitable specific examples of compound (I) will be described.
[化合物A−1]
R1が、下記の式(IIIa)または(IIIb):
[Compound A-1]
R 1 is the following formula (IIIa) or (IIIb):
(式中、R5は、水素またはハロゲンを表す)
で表される基であり;
R2が、アジド基であり;
R3が、水素、ヒドロキシ(C1−C6)アルキル基、(C2−C6)アルキニル基、またはシアノ基であり;
R4が、ヒドロキシ基または式(II):
(In the formula, R 5 represents hydrogen or halogen)
It is a group represented by;
R 2 is the azide group;
R 3 is a hydrogen, hydroxy (C 1- C 6 ) alkyl group, (C 2- C 6 ) alkynyl group, or cyano group;
R 4 is a hydroxy group or formula (II):
(式中、Rは、エステル化されたカルボキシ(C1−C6)アルキル基を表し、およびArは置換されていてもよい(C6−C14)アリール基を表す)
で表される基である、
化合物(I)。
[化合物A−2]
R1が、下記の式(IIIa)または(IIIb):
(In the formula, R represents an esterified carboxy (C 1- C 6 ) alkyl group, and Ar represents an optionally substituted (C 6- C 14 ) aryl group).
Is a group represented by
Compound (I).
[Compound A-2]
R 1 is the following formula (IIIa) or (IIIb):
(式中、R5は、水素またはハロゲン(例、塩素原子)を表す)
で表される基であり;
R2が、アジド基であり;
R3が、水素、ヒドロキシ(C1−C4)アルキル基、(C2−C4)アルキニル基、またはシアノ基、より好ましくは水素、ヒドロキシメチル基、エチニル基、またはシアノ基であり;
R4が、ヒドロキシ基または式(II):
(In the formula, R 5 represents hydrogen or halogen (eg, chlorine atom))
It is a group represented by;
R 2 is the azide group;
R 3 is a hydrogen, hydroxy (C 1- C 4 ) alkyl group, (C 2- C 4 ) alkynyl group, or cyano group, more preferably a hydrogen, hydroxymethyl group, ethynyl group, or cyano group;
R 4 is a hydroxy group or formula (II):
(式中、Rは、(C1−C4)アルコキシ−カルボニル(C1−C4)アルキル基(例、イソブトキシカルボニルエチル基)であり、およびArは(C6−C14)アリール基(例、フェニル基)である)
で表される基である、
化合物(I)。
(In the formula, R is a (C 1- C 4 ) alkoxy-carbonyl (C 1- C 4 ) alkyl group (eg, isobutoxycarbonyl ethyl group), and Ar is a (C 6- C 14 ) aryl group. (Example, phenyl group))
Is a group represented by
Compound (I).
[化合物A−3]
R1が、下記の式(IIIa):
[Compound A-3]
R 1 is the following formula (IIIa):
で表される基である、[化合物A−1]または[化合物A−2]。 [Compound A-1] or [Compound A-2], which is a group represented by.
[化合物A−4]
R1が、下記の式(IIIb):
[Compound A-4]
R 1 is the following formula (IIIb):
(式中、R5は、水素を表す)
で表される基である、[化合物A−1]または[化合物A−2]。
(In the formula, R 5 represents hydrogen)
[Compound A-1] or [Compound A-2], which is a group represented by.
[化合物A−5]
R1が、下記の式(IIIb):
[Compound A-5]
R 1 is the following formula (IIIb):
(式中、R5は、ハロゲンを表す)
で表される基である、[化合物A−1]または[化合物A−2]。
(In the formula, R 5 represents halogen)
[Compound A-1] or [Compound A-2], which is a group represented by.
[化合物B−1]
R1が、下記の式(IIIa)または(IIIb):
[Compound B-1]
R 1 is the following formula (IIIa) or (IIIb):
(式中、R5は、水素またはハロゲンを表す)
で表される基であり;
R2が、ヒドロキシ基であり;
R3が、水素、ヒドロキシ(C1−C6)アルキル基、(C2−C6)アルキニル基、またはシアノ基であり;
R4が、式(II):
(In the formula, R 5 represents hydrogen or halogen)
It is a group represented by;
R 2 is a hydroxy group;
R 3 is a hydrogen, hydroxy (C 1- C 6 ) alkyl group, (C 2- C 6 ) alkynyl group, or cyano group;
R 4 is represented by the formula (II):
(式中、Rは、エステル化されたカルボキシ(C1−C6)アルキル基を表し、およびArは置換されていてもよい(C6−C14)アリール基を表す)
で表される基である、
化合物(I)。
(In the formula, R represents an esterified carboxy (C 1- C 6 ) alkyl group, and Ar represents an optionally substituted (C 6- C 14 ) aryl group).
Is a group represented by
Compound (I).
[化合物B−2]
R1が、下記の式(IIIa)または(IIIb):
[Compound B-2]
R 1 is the following formula (IIIa) or (IIIb):
(式中、R5は、水素またはハロゲン(例、塩素原子)を表す)
で表される基であり;
R2が、ヒドロキシ基であり;
R3が、水素、ヒドロキシ(C1−C4)アルキル基、(C2−C4)アルキニル基、またはシアノ基、より好ましくは水素、ヒドロキシメチル基、エチニル基、またはシアノ基であり;
R4が、式(II):
(In the formula, R 5 represents hydrogen or halogen (eg, chlorine atom))
It is a group represented by;
R 2 is a hydroxy group;
R 3 is a hydrogen, hydroxy (C 1- C 4 ) alkyl group, (C 2- C 4 ) alkynyl group, or cyano group, more preferably a hydrogen, hydroxymethyl group, ethynyl group, or cyano group;
R 4 is represented by the formula (II):
(式中、Rは、(C1−C4)アルコキシ−カルボニル(C1−C4)アルキル基(例、イソブトキシカルボニルエチル基)であり、およびArは(C6−C14)アリール基(例、フェニル基)である)
で表される基である、
化合物(I)。
(In the formula, R is a (C 1- C 4 ) alkoxy-carbonyl (C 1- C 4 ) alkyl group (eg, isobutoxycarbonyl ethyl group), and Ar is a (C 6- C 14 ) aryl group. (Example, phenyl group))
Is a group represented by
Compound (I).
[化合物B−3]
R1が、下記の式(IIIa):
[Compound B-3]
R 1 is the following formula (IIIa):
で表される基である、[化合物B−1]または[化合物B−2]。 [Compound B-1] or [Compound B-2], which is a group represented by.
[化合物B−4]
R1が、下記の式(IIIb):
[Compound B-4]
R 1 is the following formula (IIIb):
(式中、R5は、水素を表す)
で表される基である、[化合物B−1]または[化合物B−2]。
(In the formula, R 5 represents hydrogen)
[Compound B-1] or [Compound B-2], which is a group represented by.
[化合物B−5]
R1が、下記の式(IIIb):
[Compound B-5]
R 1 is the following formula (IIIb):
(式中、R5は、ハロゲンを表す)
で表される基である、[化合物B−1]または[化合物B−2]。
(In the formula, R 5 represents halogen)
[Compound B-1] or [Compound B-2], which is a group represented by.
[化合物C−1]
R1が、下記の式(IIIa)または(IIIb):
[Compound C-1]
R 1 is the following formula (IIIa) or (IIIb):
(式中、R5は、水素またはハロゲンを表す)
で表される基であり;
R2が、ヒドロキシ基であり;
R3が、ヒドロキシ(C1−C6)アルキル基、(C2−C6)アルキニル基、またはシアノ基であり;
R4が、ヒドロキシ基または式(II):
(In the formula, R 5 represents hydrogen or halogen)
It is a group represented by;
R 2 is a hydroxy group;
R 3 is a hydroxy (C 1- C 6 ) alkyl group, (C 2- C 6 ) alkynyl group, or cyano group;
R 4 is a hydroxy group or formula (II):
(式中、Rは、エステル化されたカルボキシ(C1−C6)アルキル基を表し、およびArは置換されていてもよい(C6−C14)アリール基を表す)
で表される基である、
化合物(I)。
ここでより好ましい化合物[C−1]は、R4が、ヒドロキシ基である化合物である。
(In the formula, R represents an esterified carboxy (C 1- C 6 ) alkyl group, and Ar represents an optionally substituted (C 6- C 14 ) aryl group).
Is a group represented by
Compound (I).
Here a more preferred compound, [C-1] is, R 4 is a compound which is a hydroxy group.
化合物(I)の特に好適な具体例としては、以下の化合物が挙げられる。
2−クロロ−9−(3’−アジド−2’3’−ジデオキシ−2’−フルオロ−β−D−アラビノフラノシル)アデニン(NUK−15)
9−(3’−アジド−2’3’−ジデオキシ−2’−フルオロ−β−D−アラビノフラノシル)グアニン(NUK−16)
2−クロロ−9−(2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)アデニン 5’−O−[α−フェニル−N−(イソブチル L−アラニル)]リン酸アミド(NUK−1)
2−クロロ−9−(2’−デオキシ−2’−フルオロ−4’−C−ヒドロキシメチル−β−D−アラビノフラノシル)アデニン(NUK−17)
Specific examples of the compound (I) that are particularly preferable include the following compounds.
2-Chloro-9- (3'-Azide-2'3'-Dideoxy-2'-Fluoro-β-D-Arabinofuranosyl) Adenine (NUK-15)
9- (3'-Azide-2'3'-dideoxy-2'-fluoro-β-D-arabinofuranosyl) guanine (NUK-16)
2-Chloro-9- (2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) adenine 5'-O- [α-phenyl-N- (isobutyl L-alanyl)] phosphate amide ( NUK-1)
2-Chloro-9- (2'-deoxy-2'-fluoro-4'-C-hydroxymethyl-β-D-arabinofuranosyl) adenine (NUK-17)
本発明の別の態様は、本発明化合物(Ia)を有効成分として含有するB型肝炎ウィルス感染により誘発される疾患の予防または治療のための医薬等に関する。ここで、式(Ia)の各記号としては、上記式(I)の各記号について説明されたものと同じものが挙げられる。 Another aspect of the present invention relates to a medicine for preventing or treating a disease induced by hepatitis B virus infection containing the compound (Ia) of the present invention as an active ingredient. Here, as each symbol of the formula (Ia), the same one as described for each symbol of the above formula (I) can be mentioned.
化合物(Ia)の好適な具体例としては、上記化合物(I)について説明された[化合物A−1]〜[化合物A−5]、[化合物B−1]〜[化合物B−5]および[化合物C−1]と同じ化合物が挙げられるが、加えて以下の化合物が挙げられる。 Preferable specific examples of the compound (Ia) include [Compound A-1] to [Compound A-5], [Compound B-1] to [Compound B-5], and [Compound B-5] described for the above compound (I). The same compounds as in Compound C-1] can be mentioned, but in addition, the following compounds can be mentioned.
[化合物D−1]
R1が、下記の式(IIIa)または(IIIb):
[Compound D-1]
R 1 is the following formula (IIIa) or (IIIb):
(式中、R5は、水素を表す)で表される基であり;
R2が、ヒドロキシ基であり;
R3が、水素、ヒドロキシ(C1−C6)アルキル基、(C2−C6)アルキニル基、またはシアノ基、より好ましくは水素、ヒドロキシ(C1−C4)アルキル基、(C2−C4)アルキニル基、またはシアノ基であり;
R4が、ヒドロキシ基である、
化合物(Ia)。
(In the formula, R 5 represents hydrogen) is a group represented by;
R 2 is a hydroxy group;
R 3 is a hydrogen, hydroxy (C 1- C 6 ) alkyl group, (C 2- C 6 ) alkynyl group, or cyano group, more preferably hydrogen, hydroxy (C 1- C 4 ) alkyl group, (C 2). -C 4 ) Alkynyl group or cyano group;
R 4 is a hydroxy group,
Compound (Ia).
化合物(I)および化合物(Ia)における塩としては、薬理学的に許容される塩が好ましく、このような塩としては、例えば、無機塩基との塩、有機塩基との塩、無機酸との塩、有機酸との塩、塩基性または酸性アミノ酸との塩が挙げられる。
無機塩基との塩の好適な例としては、ナトリウム塩、カリウム塩などのアルカリ金属塩;カルシウム塩、マグネシウム塩などのアルカリ土類金属塩;アルミニウム塩;アンモニウム塩が挙げられる。
有機塩基との塩の好適な例としては、トリメチルアミン、トリエチルアミン、ピリジン、ピコリン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、ジシクロヘキシルアミン、N,N−ジベンジルエチレンジアミンなどとの塩が挙げられる。
無機酸との塩の好適な例としては、塩酸、臭化水素酸、硝酸、硫酸、リン酸などとの塩が挙げられる。
有機酸との塩の好適な例としては、ギ酸、酢酸、トリフルオロ酢酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、リンゴ酸、メタンスルホン酸、ベンゼンスルホン酸、p−トルエンスルホン酸などとの塩が挙げられる。
塩基性アミノ酸との塩の好適な例としては、アルギニン、リジン、オルニチンなどとの塩が挙げられる。
酸性アミノ酸との塩の好適な例としては、アスパラギン酸、グルタミン酸などとの塩が挙げられる。
以上の塩の中で、好ましいものとしては、無機酸との塩および有機酸との塩が挙げられる。
As the salt in the compound (I) and the compound (Ia), a pharmacologically acceptable salt is preferable, and such a salt includes, for example, a salt with an inorganic base, a salt with an organic base, and an inorganic acid. Examples include salts, salts with organic acids, salts with basic or acidic amino acids.
Preferable examples of salts with inorganic bases include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt; ammonium salt.
Preferable examples of the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picolin, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine and the like.
Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
Preferable examples of salts with organic acids are formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-. Examples include salts with toluenesulfonic acid and the like.
Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like.
Preferable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like.
Among the above salts, preferred ones include a salt with an inorganic acid and a salt with an organic acid.
化合物(I)またはその塩、並びに化合物(Ia)またはその塩(以下、本発明化合物と称する場合がある)は、結晶であってもよく、結晶形が単一であっても結晶形混合物であっても本発明化合物に包含される。結晶は、自体公知の結晶化法を適用して、結晶化することによって製造することができる。本発明化合物は、薬学的に許容され得る共結晶または共結晶塩であってもよい。ここで、共結晶または共結晶塩とは、各々が異なる物理的特性(例えば、構造、融点、融解熱、吸湿性、溶解性および安定性等)を持つ、室温で二種またはそれ以上の独特な固体から構成される結晶性物質を意味する。共結晶または共結晶塩は、自体公知の共結晶化法に従い製造することができる。本発明化合物は、溶媒和物(例、水和物等)であっても、無溶媒和物(例、非水和物等)であってもよく、いずれも本発明化合物に包含される。 Compound (I) or a salt thereof, and compound (Ia) or a salt thereof (hereinafter, may be referred to as a compound of the present invention) may be crystalline, or may be a single crystalline form or a crystalline mixture. Even if there is, it is included in the compound of the present invention. Crystals can be produced by crystallization by applying a crystallization method known per se. The compound of the present invention may be a pharmaceutically acceptable co-crystal or co-crystal salt. Here, a co-crystal or a co-crystal salt is unique to two or more at room temperature, each having different physical properties (eg, structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a solid solid. The co-crystal or co-crystal salt can be produced according to a co-crystallization method known per se. The compound of the present invention may be a solvate (eg, hydrate, etc.) or a non-solvate (eg, non-hydrate, etc.), and both are included in the compound of the present invention.
本発明化合物には、その互変異性体が存在する場合があるが、このような互変異性体もまた本発明化合物に包含される。例えば、本発明化合物において、式(IIIa)で表される基が、式(IIIa’)で表される構造を有する基で存在する場合の化合物が、このような互変異性体の例として挙げられる。 The compound of the present invention may have a tautomer thereof, and such a tautomer is also included in the compound of the present invention. For example, in the compound of the present invention, a compound in which the group represented by the formula (IIIa) is present in a group having a structure represented by the formula (IIIa') is given as an example of such a tautomer. Be done.
本発明化合物は、哺乳動物(例、マウス、ラット、ハムスター、ウサギ、ネコ、イヌ、ウシ、ヒツジ、サル、ヒト等)に対して、優れた抗ウィルス活性を有し、これらの動物におけるウィルス感染(B型肝炎ウィルス(HBV)、C型肝炎ウィルス(HCV)、ヘルペスウィルス(HSB−1またはHSB−2)、サイトメガロウィルス(CMV)、水痘・帯状疱疹ウィルス(VZV)および/またはエプスタイン・バール・ウィルス(EBV)による感染、特に、B型肝炎ウィルスによる感染)により誘発される疾患の予防・治療薬として使用できる。「ウィルス感染(特に、B型肝炎ウィルス感染)により誘発される疾患」としては、例えば、肝炎(急性肝炎、劇症肝炎等)、肝不全、肝硬変、肝臓癌等が挙げられる。
本発明化合物は、毒性(例、急性毒性、慢性毒性、遺伝毒性、生殖毒性、心毒性、薬物相互作用、癌原性等)が低く、さらに、安定性及び体内動態(吸収性、分布、代謝、***等)にも優れているので、医薬品として有用である。
The compounds of the present invention have excellent antiviral activity against mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.) and viral infections in these animals. (Hepatitis B virus (HBV), hepatitis C virus (HCV), herpes virus (HSB-1 or HSB-2), cytomegalovirus (CMV), varicella / herpes zoster virus (VZV) and / or Epstein var -It can be used as a prophylactic / therapeutic agent for diseases induced by virus (EBV) infection, especially hepatitis B virus infection). Examples of the "disease induced by virus infection (particularly hepatitis B virus infection)" include hepatitis (acute hepatitis, fulminant hepatitis, etc.), liver failure, cirrhosis, liver cancer and the like.
The compounds of the present invention have low toxicity (eg, acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity, etc.), and also have stability and pharmacokinetics (absorption, distribution, metabolism, etc.). , Excretion, etc.), so it is useful as a medicine.
本発明化合物を含有する医薬(以下、本発明医薬と称する場合がある)は、医薬製剤の製造法として自体公知の方法(例、日本薬局方記載の方法等)に従って、本発明化合物を単独で、あるいは薬理学的に許容される担体と混合して、例えば錠剤(糖衣錠、フィルムコーティング錠、舌下錠、口腔内崩壊錠、バッカル錠等を含む)、丸剤、散剤、顆粒剤、カプセル剤(ソフトカプセル剤、マイクロカプセル剤を含む)、トローチ剤、シロップ剤、液剤、乳剤、懸濁剤、放出制御製剤(例、速放性製剤、徐放性製剤、徐放性マイクロカプセル剤)、エアゾール剤、フィルム剤(例、口腔内崩壊フィルム、口腔粘膜貼付フィルム)、注射剤(例、皮下注射剤、静脈内注射剤、筋肉内注射剤、腹腔内注射剤)、点滴剤、経皮吸収型製剤、軟膏剤、ローション剤、貼付剤、坐剤(例、肛門坐剤、膣坐剤)、ペレット、経鼻剤、経肺剤(吸入剤)、点眼剤等の医薬組成物とすることができる。
経口的または非経口的(例、静脈内、筋肉内、皮下、臓器内、鼻腔内、皮内、点眼、脳内、直腸内、膣内、腹腔内等)に安全に投与することができる。
本発明化合物の本発明医薬中の含有量は、医薬全体の約0.01〜99重量%である。本発明医薬の投与量は、投与対象、投与ルート、疾患、症状等により異なるが、例えばウィルス感染(特に、B型肝炎ウィルス感染)により誘発される疾患の治療の目的で成人患者に経口投与する場合、有効成分である本発明化合物として約0.001〜約100mg/kg体重、好ましくは約0.005〜約50mg/kg体重、さらに好ましくは約0.01〜約2mg/kg体重であり、これらの服用量を症状に応じて1日約1〜3回投与するのが望ましい。
A medicine containing the compound of the present invention (hereinafter, may be referred to as the medicine of the present invention) uses the compound of the present invention alone according to a method known per se as a method for producing a pharmaceutical preparation (eg, a method described in the Japanese Pharmacy). , Or mixed with a pharmacologically acceptable carrier, eg tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), suppositories, powders, granules, capsules (Including soft capsules and microcapsules), troches, syrups, liquids, emulsions, suspensions, controlled release formulations (eg, fast-release formulations, sustained-release formulations, sustained-release microcapsules), aerosols Agents, film preparations (eg, intraoral disintegration film, oral mucosal patch film), injections (eg, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections), drip, transdermal absorption type It can be used as a pharmaceutical composition such as preparations, ointments, lotions, patches, suppositories (eg, anal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary agents (inhalants), eye drops, etc. it can.
It can be safely administered orally or parenterally (eg, intravenous, intramuscular, subcutaneous, organ, intranasal, intradermal, eye drops, brain, rectum, vagina, intraperitoneal, etc.).
The content of the compound of the present invention in the medicine of the present invention is about 0.01 to 99% by weight of the whole medicine. The dose of the medicament of the present invention varies depending on the administration subject, administration route, disease, symptom, etc., but is orally administered to an adult patient for the purpose of treating a disease induced by, for example, a virus infection (particularly, hepatitis B virus infection). In this case, the compound of the present invention as an active ingredient has a body weight of about 0.001 to about 100 mg / kg, preferably about 0.005 to about 50 mg / kg body weight, and more preferably about 0.01 to about 2 mg / kg body weight. It is desirable to administer these doses about 1 to 3 times a day depending on the symptoms.
上記薬理学的に許容される担体としては、製剤素材として慣用の各種有機又は無機担体物質が挙げられ、例えば固形製剤における賦形剤、滑沢剤、結合剤及び崩壊剤、又は液状製剤における溶剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤及び無痛化剤等が挙げられる。更に必要に応じ、通常の防腐剤、抗酸化剤、着色剤、甘味剤、吸着剤、湿潤剤等の添加物を適宜、適量用いることもできる。
賦形剤としては、例えば乳糖、白糖、D−マンニトール、デンプン、コーンスターチ、結晶セルロース、軽質無水ケイ酸等が挙げられる。滑沢剤としては、例えばステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、コロイドシリカ等が挙げられる。結合剤としては、例えば結晶セルロース、白糖、D−マンニトール、デキストリン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、デンプン、ショ糖、ゼラチン、メチルセルロース、カルボキシメチルセルロースナトリウム等が挙げられる。崩壊剤としては、例えばデンプン、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム、L−ヒドロキシプロピルセルロース等が挙げられる。溶剤としては、例えば注射用水、アルコール、プロピレングリコール、マクロゴール、ゴマ油、トウモロコシ油、オリーブ油等が挙げられる。溶解補助剤としては、例えばポリエチレングリコール、プロピレングリコール、D−マンニトール、安息香酸ベンジル、エタノール、トリスアミノメタン、コレステロール、トリエタノールアミン、炭酸ナトリウム、クエン酸ナトリウム等が挙げられる。懸濁化剤としては、例えばステアリルトリエタノールアミン、ラウリル硫酸ナトリウム、ラウリルアミノプロピオン酸、レシチン、塩化ベンザルコニウム、塩化ベンゼトニウム、モノステアリン酸グリセリン等の界面活性剤;例えばポリビニルアルコール、ポリビニルピロリドン、カルボキシメチルセルロースナトリウム、メチルセルロース、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース等の親水性高分子等が挙げられる。等張化剤としては、例えばブドウ糖、D−ソルビトール、塩化ナトリウム、グリセリン、D−マンニトール等が挙げられる。緩衝剤としては、例えばリン酸塩、酢酸塩、炭酸塩、クエン酸塩等の緩衝液等が挙げられる。無痛化剤としては、例えばベンジルアルコール等が挙げられる。防腐剤としては、例えばパラオキシ安息香酸エステル類、クロロブタノール、ベンジルアルコール、フェネチルアルコール、デヒドロ酢酸、ソルビン酸等が挙げられる。抗酸化剤としては、例えば亜硫酸塩、アスコルビン酸、α−トコフェロール等が挙げられる。
Examples of the pharmacologically acceptable carrier include various organic or inorganic carrier substances commonly used as preparation materials, for example, excipients, lubricants, binders and disintegrants in solid preparations, or solvents in liquid preparations. , Dissolving aids, suspending agents, tonicity agents, buffers, soothing agents and the like. Further, if necessary, an appropriate amount of additives such as ordinary preservatives, antioxidants, colorants, sweeteners, adsorbents, and wetting agents can be used.
Examples of excipients include lactose, sucrose, D-mannitol, starch, cornstarch, crystalline cellulose, light anhydrous silicic acid and the like. Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methyl cellulose, sodium carboxymethyl cellulose and the like. Examples of the disintegrant include starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium croscarmellose, sodium carboxymethyl starch, L-hydroxypropyl cellulose and the like. Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like. Examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone, and carboxy. Examples thereof include hydrophilic polymers such as sodium methylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose. Examples of the tonicity agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like. Examples of the buffering agent include buffer solutions such as phosphates, acetates, carbonates and citrates. Examples of the pain-relieving agent include benzyl alcohol and the like. Examples of preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Examples of the antioxidant include sulfites, ascorbic acid, α-tocopherol and the like.
本発明化合物を上記各疾患に適用する際には、それら疾患に通常用いられる薬剤又は治療法と適宜併用することが可能である。以下、本発明化合物と併用薬物を併用して使用することを「本発明の併用剤」と称する。
併用薬物としては、例えば、ラミブジン、アデホビル、エンテカビル、テノホビル等の他の抗ウィルス剤が挙げられる。
When the compound of the present invention is applied to each of the above-mentioned diseases, it can be appropriately used in combination with a drug or a therapeutic method usually used for those diseases. Hereinafter, the combined use of the compound of the present invention and the concomitant drug is referred to as "the concomitant drug of the present invention".
Concomitant medications include, for example, other antiviral agents such as lamivudine, adefovir, entecavir, tenofovir.
本発明化合物と併用薬物とを組み合わせることにより、(1)本発明化合物、あるいは併用薬物を単独で投与する場合に比べて、その投与量を軽減することができる、(2)患者の症状(軽症、重症等)に応じて、併用薬物を選択することができる、(3)本発明化合物と作用機序が異なる併用薬物を選択することにより、治療期間を長く設定することができる、(4)本発明化合物と作用機序が異なる併用薬物を選択することにより、治療効果の持続を図ることができる、(5)本発明化合物と併用薬物とを併用することにより、相乗効果が得られる、等の優れた効果を得ることができる。 By combining the compound of the present invention and the concomitant drug, the dose can be reduced as compared with the case where (1) the compound of the present invention or the concomitant drug is administered alone, and (2) the patient's symptoms (mild). , Severity, etc.), the concomitant drug can be selected, (3) The treatment period can be set longer by selecting the concomitant drug having a different mechanism of action from the compound of the present invention, (4). By selecting a concomitant drug having a different mechanism of action from the compound of the present invention, the therapeutic effect can be sustained, (5) a synergistic effect can be obtained by using the compound of the present invention in combination with the concomitant drug, etc. Excellent effect can be obtained.
本発明の併用剤は、毒性が低く、例えば、本発明化合物、あるいは(及び)上記併用薬物を自体公知の方法に従って、薬理学的に許容される担体と混合して医薬組成物、例えば錠剤(糖衣錠、フィルムコーティング錠等も含む)、散剤、顆粒剤、カプセル剤、液剤、乳剤、懸濁剤、注射剤、坐剤、徐放剤(例、舌下錠、マイクロカプセル等)、貼布剤、口腔内崩壊錠、口腔内崩壊フィルム等として、経口的又は非経口的(例、皮下、局所、直腸、静脈投与等)に安全に投与することができる。本発明の併用剤の製造に用いられてもよい薬理学的に許容される担体としては、製剤素材として慣用の各種有機又は無機担体物質が挙げられ、例えば固形製剤における賦形剤、滑沢剤、結合剤及び崩壊剤、又は液状製剤における溶剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤及び無痛化剤等が挙げられる。更に必要に応じ、通常の防腐剤、抗酸化剤、着色剤、甘味剤、吸着剤、湿潤剤等の添加物を適宜、適量用いることもできる。 The concomitant drug of the present invention has low toxicity, for example, a pharmaceutical composition, for example, a tablet (and), in which the compound of the present invention or (and) the concomitant drug is mixed with a pharmacologically acceptable carrier according to a method known per se. (Including sugar-coated tablets, film-coated tablets, etc.), powders, granules, capsules, liquids, emulsions, suspensions, injections, suppositories, sustained-release agents (eg, sublingual tablets, microcapsules, etc.), patches , Orally disintegrating tablets, orally disintegrating films, etc., can be safely administered orally or parenterally (eg, subcutaneous, topical, rectal, intravenous administration, etc.). Examples of the pharmacologically acceptable carrier that may be used in the production of the concomitant drug of the present invention include various conventional organic or inorganic carrier substances as preparation materials, for example, excipients and lubricants in solid preparations. , Binders and disintegrants, or solvents, solubilizers, suspending agents, tonicity agents, buffers and soothing agents in liquid formulations and the like. Further, if necessary, an appropriate amount of additives such as ordinary preservatives, antioxidants, colorants, sweeteners, adsorbents, and wetting agents can be used.
本発明の併用剤の使用に際しては、本発明化合物と併用薬物の投与時期は限定されず、本発明化合物あるいはその医薬組成物と、併用薬物又はその医薬組成物とを、投与対象に対し、同時に投与してもよいし、時間差をおいて投与してもよい。併用薬物の投与量は、臨床上用いられている投与量に準ずればよく、投与対象、投与ルート、疾患、組み合わせ等により適宜選択することができる。 When using the concomitant drug of the present invention, the administration time of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention or the pharmaceutical composition thereof and the concomitant drug or the pharmaceutical composition thereof are simultaneously administered to the administration subject. It may be administered or may be administered at staggered times. The dose of the concomitant drug may be based on the dose clinically used, and can be appropriately selected depending on the administration target, administration route, disease, combination and the like.
本発明の併用剤の投与形態は、特に限定されず、投与時に、本発明化合物と併用薬物とが組み合わされていればよい。このような投与形態としては、例えば、(1)本発明化合物と併用薬物とを同時に製剤化して得られる単一の製剤の投与、(2)本発明化合物と併用薬物とを別々に製剤化して得られる2種の製剤の同一投与経路での同時投与、(3)本発明化合物と併用薬物とを別々に製剤化して得られる2種の製剤の同一投与経路での時間差をおいての投与、(4)本発明化合物と併用薬物とを別々に製剤化して得られる2種の製剤の異なる投与経路での同時投与、(5)本発明化合物と併用薬物とを別々に製剤化して得られる2種の製剤の異なる投与経路での時間差をおいての投与(例、本発明化合物;併用薬物の順序での投与、又は逆の順序での投与等)等が挙げられる。 The administration form of the concomitant drug of the present invention is not particularly limited, and the compound of the present invention and the concomitant drug may be combined at the time of administration. Such administration forms include, for example, (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the concomitant drug, and (2) separately formulating the compound of the present invention and the concomitant drug. Simultaneous administration of the two obtained preparations on the same route of administration, (3) Administration of the two preparations obtained by separately formulating the compound of the present invention and the concomitant drug on the same route of administration with a time lag. (4) Simultaneous administration of two preparations obtained by separately formulating the compound of the present invention and the concomitant drug by different routes of administration, (5) Obtaining by separately formulating the compound of the present invention and the concomitant drug 2 Examples thereof include administration of different kinds of preparations at different routes of administration at different times (eg, the compound of the present invention; administration of concomitant drugs in order, administration in reverse order, etc.).
本発明の併用剤における本発明化合物と併用薬物との配合比は、投与対象、投与ルート、疾患等により適宜選択することができる。
例えば、本発明の併用剤における本発明化合物の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約0.01〜99重量%、好ましくは約0.1〜50重量%、さらに好ましくは約0.5〜20重量%である。
本発明の併用剤における併用薬物の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約0.01〜99重量%、好ましくは約0.1〜50重量%、さらに好ましくは約0.5〜20重量%である。
本発明の併用剤における担体等の添加剤の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約1〜99重量%、好ましくは約10〜90重量%である。
また、本発明化合物及び併用薬物をそれぞれ別々に製剤化する場合も同様の含有量でよい。
The compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration target, administration route, disease and the like.
For example, the content of the compound of the present invention in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 99% by weight, preferably about 0.1 to 50% by weight, based on the whole preparation. More preferably, it is about 0.5 to 20% by weight.
The content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 99% by weight, preferably about 0.1 to 50% by weight, more preferably about the whole preparation. It is about 0.5 to 20% by weight.
The content of additives such as carriers in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 1 to 99% by weight, preferably about 10 to 90% by weight, based on the entire preparation.
Further, when the compound of the present invention and the concomitant drug are separately formulated, the same content may be used.
[製造方法]
以下、本発明化合物の製造方法について説明する。以下の製造方法における各工程で用いられた原料や試薬、ならびに得られた化合物は、それぞれ塩を形成していてもよい。このような塩としては、例えば、前述の本発明化合物の塩と同様のものが挙げられる。
[Production method]
Hereinafter, a method for producing the compound of the present invention will be described. The raw materials and reagents used in each step in the following production methods, and the obtained compounds may each form salts. Examples of such a salt include the same salts as those of the above-mentioned compound of the present invention.
製造方法1 Manufacturing method 1
製造方法2 Manufacturing method 2
[式中、R6は、置換されていてもよい、保護されたプリン塩基を表し;
R7は、保護されたヒドロキシ基を表し;
R8は、式(II):
[In the formula, R 6 represents a protected purine base that may be substituted;
R 7 represents a protected hydroxy group;
R 8 is the formula (II):
(式中、RおよびArは、それぞれ前記と同義である)で表される基を表し;
R1、R2およびR3は、それぞれ前記と同義であり;および
Xは、脱離基を表す]
Represents a group represented by (in the formula, R and Ar are synonymous with each other);
R 1 , R 2 and R 3 are synonymous with each other; and X represents a leaving group]
Xで表される「脱離基」としては、ハロゲン(例、塩素原子、臭素原子、ヨウ素原子)が挙げられ、好ましくは塩素原子が挙げられる。 Examples of the "leaving group" represented by X include halogens (eg, chlorine atom, bromine atom, iodine atom), and preferably chlorine atom.
以下に、上記製造方法について説明する。 The above manufacturing method will be described below.
製造方法1Manufacturing method 1
Step1
化合物(V)は、1)化合物(IV)のプリン塩基上のアミノ基を保護基により保護し、並びに2)化合物(IV)の5’位のヒドロキシ基を保護基により保護することにより製造することができる。
プリン塩基上のアミノ基の保護は、当技術分野で汎用される保護基導入方法により行うことができる。例えば、イソ酪酸無水物のようなアシル化試薬とピリジンのような適当な溶媒中で反応させることにより保護基を導入することができる。反応は、トリメチルシリルクロリドのような促進剤の存在下に行ってもよい。反応温度は特に限定されないが、例えば、室温〜加温下に行うことができる。
5’位のヒドロキシ基の保護は、当技術分野で汎用される保護基導入方法により行うことができる。例えば、t−ブチルジメチルシリルクロリドのようなシリル化試薬とDMFやイミダゾールのような適当な溶媒中で反応させることにより保護基を導入することができる。反応温度は特に限定されないが、例えば、室温〜加温下で行うことができる。
上記反応の諸条件は、当業者であれば、適宜決定することができる。
化合物(IV)は、公知化合物であるか、当業者であれば、公知化合物から出発して、後記の実施例に記載された方法、当分野で公知の方法、またはこれらに準じる方法により適宜製造して入手することができる。
Step1
Compound (V) is produced by 1) protecting the amino group on the purine base of compound (IV) with a protecting group, and 2) protecting the hydroxy group at the 5'position of compound (IV) with a protecting group. be able to.
Protection of amino groups on purine bases can be performed by protective group introduction methods commonly used in the art. For example, protecting groups can be introduced by reacting an acylating reagent such as isobutyric anhydride in a suitable solvent such as pyridine. The reaction may be carried out in the presence of an accelerator such as trimethylsilyl chloride. The reaction temperature is not particularly limited, but can be carried out, for example, from room temperature to warming.
Protection of the hydroxy group at the 5'position can be performed by a protecting group introduction method widely used in the art. For example, the protecting group can be introduced by reacting with a silylation reagent such as t-butyldimethylsilyl chloride in a suitable solvent such as DMF or imidazole. The reaction temperature is not particularly limited, but can be carried out, for example, from room temperature to heating.
The conditions of the above reaction can be appropriately determined by those skilled in the art.
Compound (IV) is a known compound, or if a person skilled in the art, the compound (IV) is appropriately produced by a method described in Examples below, a method known in the art, or a method similar thereto, starting from the known compound. Can be obtained.
Step2
化合物(VI)は、化合物(V)の2’位のヒドロキシ基の立体を反転させることにより製造することができる。
ヒドロキシ基の立体の反転化は、酸化と還元とを組み合わせることにより行うことができる。例えば、デス・マーチン試薬のような適当な酸化剤とジクロロメタンのような適当な溶媒中で反応させて酸化して、ヒドロキシ基をカルボニル基へと変換した後、水素化ホウ素ナトリウムのような適当な還元剤とイソプロパノールのような適当な溶媒中で反応させることにより行うことができる。
上記反応の諸条件は、当業者であれば、適宜決定することができる。
Step2
The compound (VI) can be produced by reversing the configuration of the hydroxy group at the 2'position of the compound (V).
The steric inversion of the hydroxy group can be performed by combining oxidation and reduction. For example, it is reacted with a suitable oxidizing agent such as Death Martin reagent in a suitable solvent such as dichloromethane to oxidize it to convert a hydroxy group to a carbonyl group, and then a suitable oxidizing agent such as sodium borohydride. This can be done by reacting the reducing agent with a suitable solvent such as isopropanol.
The conditions of the above reaction can be appropriately determined by those skilled in the art.
Step3
化合物(VII)は、化合物(VI)の2’位のヒドロキシ基をアジド基で置換することにより製造することができる。
本反応は、例えばジフェニル−2−ピリジルホスフィンのようなリン試薬とアゾジカルボキシレート剤によりヒドロキシ基を活性化した後、例えばアジ化ナトリウムのようなアジ化剤と反応させることにより行うことができる。反応はDMFのような適当な溶媒中で行うことができる。
上記反応の諸条件は、当業者であれば、適宜決定することができる。
Step3
Compound (VII) can be produced by substituting the hydroxy group at the 2'position of compound (VI) with an azide group.
This reaction can be carried out by activating the hydroxy group with a phosphorus reagent such as diphenyl-2-pyridylphosphine and an azodicarboxylate agent, and then reacting with an azizing agent such as sodium azide. .. The reaction can be carried out in a suitable solvent such as DMF.
The conditions of the above reaction can be appropriately determined by those skilled in the art.
Step4
化合物(Ib)は、化合物(VII)のプリン塩基上のアミノ基の保護基、並びに2)化合物(VII)の5’位のヒドロキシ基の保護基を脱保護することにより製造することができる。
プリン塩基上のアミノ保護基の脱保護は、当技術分野で汎用される方法により行うことができ、例えば、NaOMeのような試薬とジクロロメタン、メタノールのような適当な溶媒中で反応させてアミド結合を加水分解することにより行うことができる。反応温度は特に限定されないが、例えば、室温〜加温下に行うことができる。
5’位のヒドロキシ保護基の脱保護は、当技術分野で汎用される方法により行うことができ、例えば、3HF・Et3N、テトラブチルアンモニウムフロリド(TBAF)のような試薬とTHFのような適当な溶媒中で反応させてヒドロキシ基上のシリル保護基を除去することにより行うことができる。反応温度は特に限定されないが、例えば、室温〜加温下に行うことができる。
上記反応の諸条件は、当業者であれば、適宜決定することができる。
Step4
Compound (Ib) can be produced by deprotecting the protecting group of the amino group on the purine base of compound (VII) and 2) the protecting group of the hydroxy group at the 5'position of compound (VII).
Deprotection of the amino protecting group on the purine base can be carried out by a method commonly used in the art, for example, reacting with a reagent such as NaOMe in a suitable solvent such as dichloromethane or methanol to form an amide bond. Can be done by hydrolyzing. The reaction temperature is not particularly limited, but can be carried out, for example, from room temperature to warming.
5 Deprotection of 'position of the hydroxy protecting groups may be carried out by methods commonly used in the art, for example, 3HF · Et 3 N, as a reagent and THF as tetrabutylammonium fluoride (TBAF) It can be carried out by reacting in a suitable solvent to remove the silyl protecting group on the hydroxy group. The reaction temperature is not particularly limited, but can be carried out, for example, from room temperature to warming.
The conditions of the above reaction can be appropriately determined by those skilled in the art.
製造方法2Manufacturing method 2
Step1
化合物(Id)は、化合物(Ic)と化合物(VIII)とを反応させることにより製造することができる。
反応は、Cu(OTf)2、トリエチルアミンのような縮合促進剤の存在下、THFのような適当な溶媒中で行うことができる。反応温度は特に限定されないが、例えば、室温〜加温下に行うことができる。
上記反応の諸条件は、当業者であれば、適宜決定することができる。
Step1
Compound (Id) can be produced by reacting compound (Ic) with compound (VIII).
The reaction can be carried out in the presence of a condensation accelerator such as Cu (OTf) 2 or triethylamine in a suitable solvent such as THF. The reaction temperature is not particularly limited, but can be carried out, for example, from room temperature to warming.
The conditions of the above reaction can be appropriately determined by those skilled in the art.
本発明は、更に以下の実施例、試験例および製剤例によって詳しく説明されるが、これらは本発明を限定するものではなく、また本発明の範囲を逸脱しない範囲で変化させてもよい。 The present invention will be further described in detail by the following Examples, Test Examples and Formulation Examples, but these are not limited to the present invention and may be changed without departing from the scope of the present invention.
[本発明化合物の製造に関する実施例] [Examples relating to the production of the compound of the present invention]
参考例1 Reference example 1
step(1): 2−デオキシ−2−フルオロ−3,5−ジ−O−ベンゾイル−α−D−アラビノフラノシル ブロミド(compound(1−II))
2−デオキシ−2−フルオロ−1,3,5−トリ−O−ベンゾイル−α−D−アラビノフラノース(compound(1−I))2.5gをジクロロメタン(80mL)に溶解し、臭化亜鉛606mg,トリメチルシリルブロミド1.8mLを加えて、0℃にて20時間撹拌した。反応液を飽和炭酸水素ナトリウム水溶液50mLで希釈後、ジクロロメタンで抽出した。抽出液を水、飽和食塩水で順次洗浄後、硫酸マグネシウム乾燥した。溶媒を減圧下留去後、トルエンを加えて減圧下留去した。更なる精製操作を行わないで、白色シロップ状の生成物2.3g(収率99%)を得た。
step (1): 2-deoxy-2-fluoro-3,5-di-O-benzoyl-α-D-arabinofuranosyl bromide (compound (1-II))
2.5 g of 2-deoxy-2-fluoro-1,3,5-tri-O-benzoyl-α-D-arabinofuranose (compound (1-I)) was dissolved in dichloromethane (80 mL) and zinc bromide was added. 606 mg and 1.8 mL of trimethylsilyl bromide were added, and the mixture was stirred at 0 ° C. for 20 hours. The reaction solution was diluted with 50 mL of a saturated aqueous sodium hydrogen carbonate solution and then extracted with dichloromethane. The extract was washed successively with water and saturated brine, and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, toluene was added and distilled off under reduced pressure. Without further purification operation, 2.3 g (yield 99%) of white syrup-like product was obtained.
1HNMR (500MHz,CDCl3)δ4.73(dd,J=3.9,11.7Hz,1H),4.80−4.85(m,2H),5.56(dd,J=3.9,22.0Hz,1H),5.61(d,J=50.1Hz,1H),6.6(d,J=12.2Hz,1H),7.43−8.14(m,10H) 1 1 HNMR (500 MHz, CDCl 3 ) δ4.73 (dd, J = 3.9, 11.7 Hz, 1H), 4.80-4.85 (m, 2H), 5.56 (dd, J = 3. 9,22.0Hz, 1H), 5.61 (d, J = 50.1Hz, 1H), 6.6 (d, J = 12.2Hz, 1H), 7.43-8.14 (m, 10H) )
step(2): 2−アミノ−6−クロロ−9−(3’,5’−ジ−O−ベンゾイル−2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)−9H−プリン(compound(1−III))
2−アミノ−6−クロロプリン1.4gを1,2−ジメトキシエタン(100mL)に溶解し、カリウムtert−ブトキシド931mgを加えて、室温にて1時間撹拌した。溶媒を減圧下留去後、アセトニトリル175mL、2−デオキシ−2−フルオロ−3,5−ジ−O−ベンゾイル−α−D−アラビノフラノシル ブロミド2.3gのジクロロエタン(140mL)溶液を加えて、室温にて20時間撹拌した。反応液をろ過し、アセトニトリルで洗浄した。ろ液を減圧下留去後、残渣物をカラムクロマトグラフィー(展開溶媒: 酢酸エチルエステル:ヘキサン=1:2 to 1:1)で精製し、無色固体の生成物1.1g(収率36%)を得た。
step (2): 2-amino-6-chloro-9- (3', 5'-di-O-benzoyl-2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) -9H- Pudding (compound (1-III))
1.4 g of 2-amino-6-chloropurine was dissolved in 1,2-dimethoxyethane (100 mL), 931 mg of potassium tert-butoxide was added, and the mixture was stirred at room temperature for 1 hour. After distilling off the solvent under reduced pressure, a solution of 175 mL of acetonitrile and 2.3 g of 2-deoxy-2-fluoro-3,5-di-O-benzoyl-α-D-arabinofuranosyl bromide in dichloroethane (140 mL) was added. , Stirred at room temperature for 20 hours. The reaction was filtered and washed with acetonitrile. After distilling off the filtrate under reduced pressure, the residue was purified by column chromatography (developing solvent: ethyl acetate ester: hexane = 1: 2 to 1: 1), and 1.1 g of a colorless solid product (yield 36%). ) Was obtained.
1HNMR (500MHz,CDCl3)δ4.57−4.60(m,1H),4.77−4.83(m,2H),5.14(br.s,NH2),5.34(dd,J=2.7,50.0Hz,1H),5.78(dd,J=2.7,16.6Hz,1H),6.46(dd,J=2.9,22.5Hz,1H),7.45−7.69(m,6H),8・05(d,J=3.2Hz,1H),8.09−8.11(m,4H) 1 1 HNMR (500 MHz, CDCl 3 ) δ4.57-4.60 (m, 1H), 4.77-4.83 (m, 2H), 5.14 (br.s, NH 2 ), 5.34 ( dd, J = 2.7, 50.0Hz, 1H), 5.78 (dd, J = 2.7, 16.6Hz, 1H), 6.46 (dd, J = 2.9, 22.5Hz, 1H), 7.45-7.69 (m, 6H), 8.05 (d, J = 3.2Hz, 1H), 8.09-8.11 (m, 4H)
step(3)および(4): 9−(2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)グアニン(compound1;NUK−2)
2−アミノ−6−クロロ−9−(3’,5’−ジ−O−ベンゾイル−2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)−9H−プリン1.1gを酢酸(14mL)に溶解し、無水酢酸14mL,酢酸ナトリウム820mgを加えて、120℃にて3時間撹拌した。反応液を室温に戻し、メタノール(MeOH)50mLを加えた後、溶媒を減圧下留去した。残渣物を飽和炭酸水素ナトリウム水溶液50mLで希釈後、クロロホルムで抽出した。抽出液を水、飽和食塩水で順次洗浄後、硫酸マグネシウム乾燥した。溶媒を減圧下留去後、残渣物をアンモニアメタノール溶液(7N,100mL)に溶解し、室温にて2日間撹拌した。溶媒を減圧下留去後、ジクロロメタンとメタノールの混合溶液による再結晶より、白色固体の生成物256mg(収率45%)を得た。
steps (3) and (4): 9- (2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) guanine (compound1; NUK-2)
2-Amino-6-chloro-9- (3', 5'-di-O-benzoyl-2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) -9H-purine 1.1 g It was dissolved in acetic acid (14 mL), 14 mL of acetic anhydride and 820 mg of sodium acetate were added, and the mixture was stirred at 120 ° C. for 3 hours. The reaction solution was returned to room temperature, 50 mL of methanol (MeOH) was added, and then the solvent was evaporated under reduced pressure. The residue was diluted with 50 mL of saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The extract was washed successively with water and saturated brine, and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was dissolved in an ammonia-methanol solution (7N, 100 mL) and stirred at room temperature for 2 days. After distilling off the solvent under reduced pressure, 256 mg (yield 45%) of a white solid product was obtained by recrystallization from a mixed solution of dichloromethane and methanol.
1HNMR (500MHz,CD3OD)δ3.59−3.64(m,2H),3.79−3.82(m,1H),4.36(ddd,J=4.7,13.0,17.9Hz,1H),5.05−5.16(m,2H),5.93(d,J=4.9Hz,OH),6.12(dd,J=4.1,15.9Hz,1H),6.52(br.s,NH2),7.79(d,J=2.5Hz,1H),10.4(br.s,NH) 1 1 HNMR (500 MHz, CD 3 OD) δ3.59-3.64 (m, 2H), 3.79-3.82 (m, 1H), 4.36 (ddd, J = 4.7, 13.0) , 17.9Hz, 1H), 5.05-5.16 (m, 2H), 5.93 (d, J = 4.9Hz, OH), 6.12 (dd, J = 4.1, 15. 9Hz, 1H), 6.52 (br.s, NH 2 ), 7.79 (d, J = 2.5Hz, 1H), 10.4 (br.s, NH)
参考例2 Reference example 2
step(1): N 6 −ベンゾイル−9−(3’,5’−ジ−O−ベンゾイル−2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)アデニン(compound(2−II))
N6−ベンゾイルアデニン(216mg)を1,2−ジメトキシエタン(28mL)に溶解し、カリウムtert−ブトキシド100mgを加えて、0℃にて20分間撹拌した。溶媒を減圧下留去後、アセトニトリル8.8mL,CaH240mgを加えて10分間撹拌した。2−デオキシ−2−フルオロ−3,5−ジ−O−ベンゾイル−α−D−アラビノフラノシル ブロミド(compound(2−I))308mgのジクロロエタン(12mL)溶液を加えて、室温にて24時間撹拌した。反応液をろ過し、ジクロロメタンで洗浄した。ろ液を減圧下留去後、水50mLで希釈し、酢酸エチルで抽出した。抽出液を水で洗浄後、硫酸マグネシウム乾燥した。溶媒を減圧下留去後、カラムクロマトグラフィー(展開溶媒: 酢酸エチルエステル:ヘキサン=1:1 to酢酸エチルエステル:メタノール=10:1)で精製し、白色固体の生成物230mg(収率44%)を得た。
step (1): N 6 -benzoyl-9- (3', 5'-di-O-benzoyl-2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) adenine (2-) II)))
N 6 -benzoyladenine (216 mg) was dissolved in 1,2-dimethoxyethane (28 mL), 100 mg of potassium tert-butoxide was added, and the mixture was stirred at 0 ° C. for 20 minutes. The solvent was distilled off under reduced pressure, acetonitrile 8.8 mL, was added and stirred CaH 2 40 mg 10 minutes. 2-Deoxy-2-fluoro-3,5-di-O-benzoyl-α-D-arabinofuranosyl bromide (compound (2-I)) 308 mg solution of dichloroethane (12 mL) was added and 24 at room temperature. Stirred for hours. The reaction was filtered and washed with dichloromethane. The filtrate was evaporated under reduced pressure, diluted with 50 mL of water, and extracted with ethyl acetate. The extract was washed with water and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure and then purified by column chromatography (developing solvent: ethyl acetate ester: hexane = 1: 1 to ethyl acetate ester: methanol = 10: 1) to produce 230 mg of a white solid product (yield 44%). ) Was obtained.
1HNMR (500MHz,CD3Cl)δ4.62−4.64(m,1H),4.83(d,J=4.7Hz,2H),5.41(dd,J=2.7,49.8Hz,1H),5.79(dd,J=2.7,16.4Hz,1H),6.74(dd,J=2.7,2.2Hz,1H),7.44−8.12(m, 15H),8.32(d,J=2.9Hz, 1H),8.82(s,1H),9.21(br.s,NH) 1 1 HNMR (500 MHz, CD 3 Cl) δ4.62-4.64 (m, 1H), 4.83 (d, J = 4.7 Hz, 2H), 5.41 (dd, J = 2.7, 49) 8.8Hz, 1H), 5.79 (dd, J = 2.7, 16.4Hz, 1H), 6.74 (dd, J = 2.7, 2.2Hz, 1H), 7.44-8. 12 (m, 15H), 8.32 (d, J = 2.9Hz, 1H), 8.82 (s, 1H), 9.21 (br.s, NH)
step(2): 9−(2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)アデニン(compound2;NUK−3)
N6−ベンゾイル−9−(3’,5’−ジ−O−ベンゾイル−2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)アデニン230mgをアンモニアメタノール溶液(7N,15mL)に溶解し、室温にて2日間撹拌した。溶媒を減圧下留去後、ジクロロメタンとメタノールの混合溶液による再結晶より、白色固体の生成物85mg(収率80%)を得た。
step (2): 9- (2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) adenine (compound2; NUK-3)
N 6 -benzoyl-9- (3', 5'-di-O-benzoyl-2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) 230 mg of adenine in ammonia methanol solution (7N, 15 mL) Was dissolved in, and the mixture was stirred at room temperature for 2 days. After distilling off the solvent under reduced pressure, 85 mg (yield 80%) of a white solid product was obtained by recrystallization from a mixed solution of dichloromethane and methanol.
1HNMR (500MHz,d−DMSO)δ3.63−3.70(m,2H),3.83−3.86(m,1H),4.42−4.47(m,1H),5.11(t,J=5.6Hz,OH),5.20(dt,J=4.2,52.8Hz,1H),5.95(d,J=5.1Hz,OH),6.40(dd,J=4.6,14.7Hz,1H),7.33(br.s,NH2),8.16(s,1H),8.23(d,J=2.2Hz,1H) 1 1 HNMR (500 MHz, d-DMSO) δ3.63-3.70 (m, 2H), 3.83-3.86 (m, 1H), 4.42-4.47 (m, 1H), 5. 11 (t, J = 5.6Hz, OH), 5.20 (dt, J = 4.2,52.8Hz, 1H), 5.95 (d, J = 5.1Hz, OH), 6.40 (Dd, J = 4.6, 14.7Hz, 1H), 7.33 (br.s, NH 2 ), 8.16 (s, 1H), 8.23 (d, J = 2.2Hz, 1H) )
参考例3 Reference example 3
step(1): O 6 −(ベンゾトリアゾール−1H−イル)−9−(3’,5’−ジ−O−(tert−ブチルジメチルシリル)−2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)グアニン(compound(3−II))
9−(3’,5’−ジ−O−(tert−ブチルジメチルシリル)−2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)グアニン(compound(3−I))520mgをアセトニトリル(10mL)に溶解し、ベンゾトリアゾール−1−イルオキシ−トリスジメチルアミノホスホニウム(BOP)(884mg)、1,8−ジアザビシクロ[5.4.0]−7−ウンデセン(DBU)(300μL)を加えて、室温にて20時間撹拌した。反応液に水を加えてクロロホルムで抽出した。抽出液に飽和食塩水で洗浄後、硫酸マグネシウム乾燥した。溶媒を減圧下留去後、残渣物をカラムクロマトグラフィー(展開溶媒: 酢酸エチルエステル:ノルマルヘキサン=1:2)で精製し、生成物257mg(収率41%)を得た。
step (1): O 6- (benzotriazole-1H-yl) -9- (3', 5'-di-O- (tert-butyldimethylsilyl) -2'-deoxy-2'-fluoro-β- D-arabinofuranosyl) guanine (compound (3-II))
9- (3', 5'-di-O- (tert-butyldimethylsilyl) -2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) guanine (compound (3-I)) 520 mg In acetonitrile (10 mL), benzotriazole-1-yloxy-trisdimethylaminophosphonium (BOP) (884 mg), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) (300 μL) was added. In addition, it was stirred at room temperature for 20 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by column chromatography (developing solvent: ethyl acetate ester: normal hexane = 1: 2) to obtain 257 mg (yield 41%) of the product.
1HNMR (500MHz,CD3Cl)δ0.13(s,6H),0.17(s,3H),0.17(s,3H),0.94(s,9H),0.95(s,9H),3.82(d,J=4.2Hz,2H),3.97−3.99(m,1H),4.63(ddd,J=3.0,3.2,16.9Hz,1H),4.80(br.s,NH2),4.99(ddd,J=2.7,3.7,52.1Hz,1H),6.36(dd,J=3.7,17.9Hz,1H),7.44−7.54(m,3H),8.08(d,J=2.5Hz,1H),8.12(d,J=8.3Hz,1H) 1 1 HNMR (500MHz, CD 3 Cl) δ0.13 (s, 6H), 0.17 (s, 3H), 0.17 (s, 3H), 0.94 (s, 9H), 0.95 (s) , 9H), 3.82 (d, J = 4.2Hz, 2H), 3.97-3.99 (m, 1H), 4.63 (ddd, J = 3.0, 3.2, 16. 9Hz, 1H), 4.80 (br.s, NH 2 ), 4.99 (ddd, J = 2.7, 3.7, 52.1Hz, 1H), 6.36 (dd, J = 3. 7,17.9Hz, 1H), 7.44-7.54 (m, 3H), 8.08 (d, J = 2.5Hz, 1H), 8.12 (d, J = 8.3Hz, 1H) )
step(2): O 6 −アリル−9−(3’,5’−ジ−O−(tert−ブチルジメチルシリル)−2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)グアニン(compound(3−III))
O6−(ベンゾトリアゾール−1H−イル)−9−(3’,5’−ジ−O−(tert−ブチルジメチルシリル)−2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)グアニン257mgをアリルアルコール(5mL)に溶解し、CsCO3(265mg)を加えて、室温にて2時間撹拌した。溶媒を減圧下留去後、残渣物をカラムクロマトグラフィー(展開溶媒: 酢酸エチルエステル:ノルマルヘキサン=1:4)で精製し、白色シロップ状の生成物150mg(収率66%)を得た。
step (2): O 6 -allyl-9- (3', 5'-di-O- (tert-butyldimethylsilyl) -2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) Guanine (compound (3-III))
O 6- (benzotriazole-1H-yl) -9- (3', 5'-di-O- (tert-butyldimethylsilyl) -2'-deoxy-2'-fluoro-β-D-arabinofurano Sil) 257 mg of guanine was dissolved in allyl alcohol (5 mL), CsCO 3 (265 mg) was added, and the mixture was stirred at room temperature for 2 hours. After distilling off the solvent under reduced pressure, the residue was purified by column chromatography (developing solvent: ethyl acetate ester: normal hexane = 1: 4) to obtain 150 mg (yield 66%) of a white syrup-like product.
1HNMR (500MHz,CD3Cl)δ0.10(s,6H),0.16(s,3H),0.17(s,3H),0.93(s,9H),0.94(s,9H),3.82−3.83(m,2H),3.93−3.96(m,1H),4.63(ddd,J=2.7,3.9,17.1Hz,1H),4.83(br.s,NH2),4.95(ddd,J=2.5,3.7,52.1Hz,1H),5.03(ddd,J=1.7,3.2,5.6Hz,2H),5.28(ddd,J=1.2,2.7,10.5Hz,1H),5.44(ddd,J=1.7,3.2,17.4Hz,1H),6.14(ddt,J=5.6,10.5,17.1Hz,1H),6.34(dd,J=3.7,19.1Hz,1H),7.89(d,J=1.9Hz,1H) 1 1 HNMR (500MHz, CD 3 Cl) δ0.10 (s, 6H), 0.16 (s, 3H), 0.17 (s, 3H), 0.93 (s, 9H), 0.94 (s) , 9H), 3.82-3.83 (m, 2H), 3.93-3.96 (m, 1H), 4.63 (ddd, J = 2.7, 3.9, 17.1Hz, 1H), 4.83 (br.s, NH 2 ), 4.95 (ddd, J = 2.5, 3.7, 52.1Hz, 1H), 5.03 (ddd, J = 1.7, 3.2,5.6Hz, 2H), 5.28 (ddd, J = 1.2, 2.7, 10.5Hz, 1H), 5.44 (ddd, J = 1.7, 3.2, 2) 17.4Hz, 1H), 6.14 (ddt, J = 5.6, 10.5, 17.1Hz, 1H), 6.34 (dd, J = 3.7, 19.1Hz, 1H), 7 .89 (d, J = 1.9Hz, 1H)
step(3): O 6 −アリル−2−アジド−9−(3’,5’−ジ−O−(tert−ブチルジメチルシリル)−2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)グアニン(compound(3−IV))
O6−アリル−9−(3’,5’−ジ−O−(tert−ブチルジメチルシリル)−2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)グアニン150mgをジクロロメタン(3mL)に溶解し、トリメチルシリルアジド354μL,亜硝酸 tert−ブチル(tBuONO)(90%,356μL)を−20℃で加えて1時間撹拌した後、室温にて24時間撹拌した。反応液に水を加えてクロロホルムで抽出した。抽出液に飽和食塩水で洗浄後、硫酸マグネシウム乾燥した。溶媒を減圧下留去後、残渣物をカラムクロマトグラフィー(展開溶媒: 酢酸エチルエステル:ノルマルヘキサン=1:4)で精製し、黄色液状の生成物74mg(収率47%)を得た。
step (3): O 6 -allyl-2-azido-9- (3', 5'-di-O- (tert-butyldimethylsilyl) -2'-deoxy-2'-fluoro-β-D-arabi) Nofuranosyl) guanine (compound (3-IV))
O 6 -allyl-9- (3', 5'-di-O- (tert-butyldimethylsilyl) -2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) 150 mg of guanine in dichloromethane ( It was dissolved in 3 mL), 354 μL of trimethylsilyl azide and tert-butyl nitrite (tBuONO) (90%, 356 μL) were added at −20 ° C. and stirred for 1 hour, and then stirred at room temperature for 24 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by column chromatography (developing solvent: ethyl acetate ester: normal hexane = 1: 4) to obtain 74 mg (yield 47%) of a yellow liquid product.
1HNMR (500MHz,CD3Cl)δ0.11(s,6H),0.15(s,3H),0.16(s,3H),0.92(s,9H),0.94(s,9H),3.85(dd,J=1.5,4.9Hz,2H),3.96−3.98(m,1H),4.59−4.63(m,1H),4.97(ddd,J=2.7,3.9,52.1Hz,1H),5.12(ddd,J=1.5,3.5,5.9Hz,2H),5.33(ddd,J=1.2,2.4,10.3Hz,1H),5.49(ddd,J=1.5,3.0,17.6Hz,1H),6.14(ddt,J=5.9,10.5,17.1Hz,1H),6.45(dd,J=4.0,17.6Hz,1H),8.13(d,J=2.5Hz,1H) 1 1 HNMR (500 MHz, CD 3 Cl) δ0.11 (s, 6H), 0.15 (s, 3H), 0.16 (s, 3H), 0.92 (s, 9H), 0.94 (s) , 9H), 3.85 (dd, J = 1.5, 4.9Hz, 2H), 3.96-3.98 (m, 1H), 4.59-4.63 (m, 1H), 4 .97 (ddd, J = 2.7, 3.9, 52.1Hz, 1H), 5.12 (ddd, J = 1.5, 3.5, 5.9Hz, 2H), 5.33 (dddd) , J = 1.2, 2.4, 10.3Hz, 1H), 5.49 (ddd, J = 1.5, 3.0, 17.6Hz, 1H), 6.14 (ddt, J = 5) 9.9, 10.5, 17.1Hz, 1H), 6.45 (dd, J = 4.0, 17.6Hz, 1H), 8.13 (d, J = 2.5Hz, 1H)
step(4): O 6 −アリル−2−(4−(4−メトキシフェニル)−1,2,3−トリアゾール−1H−イル)−9−(3’,5’−ジ−O−(tert−ブチルジメチルシリル)−2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)グアニン(compound(3−V))
O6−アリル−2−アジド−9−(3’,5’−ジ−O−(tert−ブチルジメチルシリル)−2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)グアニン74mgをtert−ブタノール(tBuOH)/H2O(1:1,2mL)に溶解し、4−エチニルアニソール33μL、CuCl(3mg)を加えて、室温にて12時間撹拌した。反応液に水を加えてクロロホルムで抽出した。抽出液に飽和食塩水で洗浄後、硫酸マグネシウム乾燥した。溶媒を減圧下留去後、残渣物をカラムクロマトグラフィー(展開溶媒: 酢酸エチルエステル:ノルマルヘキサン=1:8to1:2)で精製し、白色固体の生成物62mg(収率67%)を得た。
step (4): O 6 - Allyl-2- (4- (4-methoxyphenyl) -1,2,3-triazol -1H- yl) -9- (3 ', 5'-di -O- (tert -Butyldimethylsilyl) -2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) guanine (compound (3-V))
O 6 -allyl-2-azido-9- (3', 5'-di-O- (tert-butyldimethylsilyl) -2'-deoxy-2'-fluoro-β-D-arabinoflanosyl) guanine 74 mg was dissolved in tert-butanol (tBuOH) / H 2 O (1: 1, 2 mL), 33 μL of 4-ethynylanisole and CuCl (3 mg) were added, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by column chromatography (developing solvent: ethyl acetate ester: normal hexane = 1: 8 to 1: 2) to obtain 62 mg (yield 67%) of a white solid product. ..
1HNMR (500MHz,CD3Cl)δ0.13(s,6H),0.18(s,3H),0.16(s,3H),0.96(s,18H),3.87−3.93(m,5H),3.99−4.00(m,1H),4.69(ddd,J=2.7,4.4,18.4Hz,1H),5.11(ddd,J=3.0,4.2,52.3Hz,1H),5.27(ddd,J=1.5,4.2,5.9Hz,2H),5.39(d,J=1.3,2.5,10.3Hz,1H),5.57(ddd,J=1.5,2.9,17.1Hz,1H),6.14(ddt,J=5.6,10.5,17.4Hz,1H),6.67(dd,J=4.2,16.4Hz,1H),7.02(d,J=8.8Hz,2H),7.90(d,J=8.8Hz,2H),8.30(d,J=2.5Hz,1H),8.66(s,1H) 1 1 HNMR (500MHz, CD 3 Cl) δ0.13 (s, 6H), 0.18 (s, 3H), 0.16 (s, 3H), 0.96 (s, 18H), 3.87-3 .93 (m, 5H), 3.99-4.00 (m, 1H), 4.69 (ddd, J = 2.7, 4.4, 18.4Hz, 1H), 5.11 (ddd, J = 3.0, 4.2, 52.3Hz, 1H), 5.27 (ddd, J = 1.5, 4.2, 5.9Hz, 2H), 5.39 (d, J = 1. 3,2.5, 10.3Hz, 1H), 5.57 (ddd, J = 1.5, 2.9, 17.1Hz, 1H), 6.14 (ddt, J = 5.6, 10. 5,17.4Hz, 1H), 6.67 (dd, J = 4.2,16.4Hz, 1H), 7.02 (d, J = 8.8Hz, 2H), 7.90 (d, J) = 8.8Hz, 2H), 8.30 (d, J = 2.5Hz, 1H), 8.66 (s, 1H)
step(5): O 6 −アリル−2−(4−(4−メトキシフェニル)−1,2,3−トリアゾール−1H−イル)−9−(2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)グアニン(compound(3−VI))
O6−アリル−2−(4−(4−メトキシフェニル)−1,2,3−トリアゾール−1H−イル)−9−(3’,5’−ジ−O−(tert−ブチルジメチルシリル)−2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)グアニン61mgをテトラヒドロフラン(THF)3mLに溶解し、トリエチルアミン三フッ化水素酸塩(3HF・Et3N)84μLを加えて、室温にて24時間撹拌した。溶媒を減圧下留去後、残渣物をカラムクロマトグラフィー(展開溶媒: 酢酸エチルエステル:ノルマルヘキサン=1:2)で精製し、白色固体の生成物38mg(収率91%)を得た。
step (5): O 6 - Allyl-2- (4- (4-methoxyphenyl) -1,2,3-triazol -1H- yl) -9- (2'-deoxy-2'-fluoro -β- D-arabinofuranosyl) guanine (compound (3-VI))
O 6 -allyl-2- (4- (4-methoxyphenyl) -1,2,3-triazole-1H-yl) -9- (3', 5'-di-O- (tert-butyldimethylsilyl)) the 2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl) guanine 61mg was dissolved in tetrahydrofuran (THF) 3 mL, was added triethylamine trihydrofluoride (3HF · Et 3 N) 84μL , Stirred for 24 hours at room temperature. After distilling off the solvent under reduced pressure, the residue was purified by column chromatography (developing solvent: ethyl acetate ester: normal hexane = 1: 2) to obtain 38 mg (yield 91%) of a white solid product.
1HNMR (500MHz,d−DMSO)δ3.68−3.75(m,2H),3.82(s,3H),3.91−3.94(m,1H),4.55(ddd,J=5.1,9.5,18.8Hz,1H),5.11(t,J=5.6Hz,OH),5.28−5.31(m,2H),5.37−5.40(m,1H),5.57(ddd,J=1.7,3.2,17.4Hz,1H),6.05(br.s,OH),6.14(ddt,J=5.6,10.3,17.1Hz,1H),6.59(dd,J=4.7,13.5Hz,1H),7.07(d,J=8.8Hz,2H),7.90(d,J=8.8Hz,2H),8.62(d,J=2.0Hz,1H),9.34(s,1H) 1 1 HNMR (500 MHz, d-DMSO) δ3.68-3.75 (m, 2H), 3.82 (s, 3H), 3.91-3.94 (m, 1H), 4.55 (ddd, J = 5.1,9.5,18.8Hz, 1H), 5.11 (t, J = 5.6Hz, OH), 5.28-5.31 (m, 2H), 5.37-5 .40 (m, 1H), 5.57 (ddd, J = 1.7, 3.2, 17.4Hz, 1H), 6.05 (br.s, OH), 6.14 (ddt, J = 5.6, 10.3, 17.1Hz, 1H), 6.59 (dd, J = 4.7, 13.5Hz, 1H), 7.07 (d, J = 8.8Hz, 2H), 7 .90 (d, J = 8.8Hz, 2H), 8.62 (d, J = 2.0Hz, 1H), 9.34 (s, 1H)
step(6): 2−(4−(4−メトキシフェニル)−1,2,3−トリアゾール−1H−イル)−9−(2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)グアニン(compound3;NUK−6)
O6−アリル−2−(4−(4−メトキシフェニル)−1,2,3−トリアゾール−1H−イル)−9−(2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)グアニン38mgをMeOH/THF(1:2)の混合溶液3mLに溶解し、ベンゼンスルフィン酸ナトリウム塩(PhSO2Na)16mg,テトラキス(トリフェニルホスフィン)パラジウム(Pd(Ph3)4)4mgを加えて、室温にて2時間撹拌した。溶媒を減圧下留去後、酢酸エチルエステルで洗浄し、析出した黄色固体の生成物30mg(収率86%)を得た。
step (6): 2- (4- (4-Methoxyphenyl) -1,2,3-triazole-1H-yl) -9- (2'-deoxy-2'-fluoro-β-D-arabinoflano) Sil) guanine (compound3; NUK-6)
O 6 -allyl-2- (4- (4-methoxyphenyl) -1,2,3-triazole-1H-yl) -9- (2'-deoxy-2'-fluoro-β-D-arabinofurano Dissolve 38 mg of syl) guanine in 3 mL of a mixed solution of MeOH / THF (1: 2), and add 16 mg of sodium benzenesulfinate (PhSO 2 Na) and 4 mg of tetrakis (triphenylphosphine) palladium (Pd (Ph 3 ) 4 ). In addition, it was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure and then washed with ethyl acetate ester to obtain 30 mg (86% yield) of the precipitated yellow solid product.
1HNMR (500MHz,d−DMSO)δ3.63−3.71(m,2H),3.81(s,3H),3.86−3.89(m,1H),4.55(ddd,J=4.9,9.1,13.7Hz,1H),5.08(t,J=5.6Hz,OH),5.19−5.31(m,1H),5.37−5.40(m,1H),6.01(d,J=4.9Hz,1H),6.43(dd,J=4.4,15.4Hz,1H),7.07(d,J=9.1Hz,2H),7.93(d,J=8.8Hz,2H),8.17(br.s,1H),9.34(s,1H) 1 1 HNMR (500 MHz, d-DMSO) δ3.63-3.71 (m, 2H), 3.81 (s, 3H), 3.86-3.89 (m, 1H), 4.55 (ddd, dd, J = 4.9, 9.1, 13.7Hz, 1H), 5.08 (t, J = 5.6Hz, OH), 5.19-5.31 (m, 1H), 5.37-5 .40 (m, 1H), 6.01 (d, J = 4.9Hz, 1H), 6.43 (dd, J = 4.4, 15.4Hz, 1H), 7.07 (d, J = 9.1Hz, 2H), 7.93 (d, J = 8.8Hz, 2H), 8.17 (br.s, 1H), 9.34 (s, 1H)
実施例1 Example 1
step(1): 2−クロロ−N 6 −イソブチリル−9−(2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)アデニン(compound(E1−II))
クロファラビン(compound(E1−I))(606mg)をピリジンに溶解し、ピリジンを減圧下留去する操作を3回行い、減圧下で乾燥した。残渣をピリジン(10mL)に溶解し、トリメチルシリルクロリド1.5mLを加えて、0℃にて2時間撹拌した。イソ酪酸無水物2mLを加えて、室温にて24時間撹拌した。反応液にアンモニア水(28%,3mL)、水(3mL)を加えて、ジクロロメタンで抽出した。抽出液を水で洗浄後、硫酸マグネシウム乾燥した。溶媒を減圧下留去後、カラムクロマトグラフィー(展開溶媒: ジクロロメタン:メタノール=95:5to90:10)で精製し、白色固体の生成物453mg(収率61%)を得た。
step (1): 2-chloro-N 6 -isobutyryl-9- (2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) adenine (compound (E1-II))
Clofarabine (compound (E1-I)) (606 mg) was dissolved in pyridine, and the operation of distilling off pyridine under reduced pressure was performed three times, and the mixture was dried under reduced pressure. The residue was dissolved in pyridine (10 mL), 1.5 mL of trimethylsilyl chloride was added, and the mixture was stirred at 0 ° C. for 2 hours. 2 mL of isobutyric anhydride was added, and the mixture was stirred at room temperature for 24 hours. Ammonia water (28%, 3 mL) and water (3 mL) were added to the reaction solution, and the mixture was extracted with dichloromethane. The extract was washed with water and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure and then purified by column chromatography (developing solvent: dichloromethane: methanol = 95: 5 to 90:10) to obtain 453 mg (yield 61%) of a white solid product.
1HNMR (500MHz,CD3Cl)δ1.32(d,J=6.9Hz,3H),1.32(d,J=6.9Hz,3H),3.26−3.28(m,1H),3.97−4.12(m,3H),4.77−4.83(m,1H),5.21(ddd,J=3.4,4.4,51.8Hz,1H),6.50(dd,J=4.4,15.2Hz,1H),8.28(d,J=2.0Hz,1H),8.53(br.s,NH) 1 HNMR (500MHz, CD 3 Cl) δ1.32 (d, J = 6.9Hz, 3H), 1.32 (d, J = 6.9Hz, 3H), 3.26-3.28 (m, 1H) ), 3.97-4.12 (m, 3H), 4.77-4.83 (m, 1H), 5.21 (ddd, J = 3.4, 4.4, 51.8Hz, 1H) , 6.50 (dd, J = 4.4, 15.2Hz, 1H), 8.28 (d, J = 2.0Hz, 1H), 8.53 (br.s, NH)
step(2): 2−クロロ−N 6 −イソブチリル−9−(5’−O−(tert−ブチルジメチルシリル)−2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)アデニン(compound(E1−III))
2−クロロ−N6−イソブチリル−9−(2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)アデニン(350mg)をN,N−ジメチルホルムアミド(DMF)7mLに溶解し、tert−ブチルジメチルシリルクロリド150mg,イミダゾール136mgを加えて、室温にて24時間撹拌した。溶媒を減圧下留去後、カラムクロマトグラフィー(展開溶媒: ジクロロメタン:メタノール=95:5)で精製し、白色固体の生成物453mg(収率99%)を得た。
step (2): 2-chloro-N 6 -isobutyryl-9- (5'-O- (tert-butyldimethylsilyl) -2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) adenine (Compound (E1-III))
2-Chloro-N 6 -isobutyryl-9- (2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) adenine (350 mg) was dissolved in 7 mL of N, N-dimethylformamide (DMF). 150 mg of tert-butyldimethylsilyl chloride and 136 mg of imidazole were added, and the mixture was stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure and then purified by column chromatography (developing solvent: dichloromethane: methanol = 95: 5) to obtain 453 mg (yield 99%) of a white solid product.
1HNMR (500MHz,CD3Cl)δ0.13(s,3H),0.13(s,3H),0.94(s,9H),1.32(d,J=6.9Hz,6H),3.28−3.30(m,1H),3.89(ddd,J=1.3,5.9,11.0Hz,1H),3.94(ddd,J=1.0,4.2,11.0Hz,1H),4.01−4.05(m,1H),4.66−4.72(m,1H),5.15(ddd,J=2.5,3.7,51.6Hz,1H),6.51(dd,J=3.7,17.1Hz,1H),8.23(d,J=2.5Hz,1H),8.37(br.s,NH) 1 1 HNMR (500MHz, CD 3 Cl) δ0.13 (s, 3H), 0.13 (s, 3H), 0.94 (s, 9H), 1.32 (d, J = 6.9Hz, 6H) , 3.28-3.30 (m, 1H), 3.89 (ddd, J = 1.3, 5.9, 11.0Hz, 1H), 3.94 (ddd, J = 1.0, 4) .2, 11.0Hz, 1H), 4.01-4.05 (m, 1H), 4.66-4.72 (m, 1H), 5.15 (ddd, J = 2.5, 3. 7,51.6Hz, 1H), 6.51 (dd, J = 3.7, 17.1Hz, 1H), 8.23 (d, J = 2.5Hz, 1H), 8.37 (br.s) , NH)
step(3): 2−クロロ−N 6 −イソブチリル−9−(5’−O−(tert−ブチルジメチルシリル)−2’−デオキシ−2’−フルオロ−β−D−リキソフラノシル)アデニン(compound(E1−IV))
2−クロロ−N6−イソブチリル−9−(5’−O−(tert−ブチルジメチルシリル)−2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)アデニン(456mg)をジクロロメタン3mLに溶解し、デス・マーチン・ペルヨージナン(Dess−Martin periodinate)594mgを0℃で加えて、1時間後撹拌後、室温にて3時間撹拌した。反応液を−60℃に冷却し、イソプロパノール3mL,水素化ホウ素ナトリウム(NaBH4)80mgを順次加えて、−60℃にて12時間撹拌した。反応液にアセトン3mLを加えた後、室温にした。反応液に飽和炭酸水素ナトリウム水溶液を加えて酢酸エチルエステルで抽出した。抽出液に飽和食塩水で洗浄後、硫酸マグネシウム乾燥した。溶媒を減圧下留去後、残渣物をカラムクロマトグラフィー(展開溶媒: ジクロロメタン:メタノール=95:5)で精製し、白色固体の生成物406mg(収率89%)を得た。
step (3): 2-chloro-N 6 -isobutyryl-9- (5'-O- (tert-butyldimethylsilyl) -2'-deoxy-2'-fluoro-β-D-lyxoflanosyl) adenine (compound) E1-IV)))
2-Chloro-N 6 -isobutyryl-9- (5'-O- (tert-butyldimethylsilyl) -2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) adenine (456 mg) in dichloromethane It was dissolved in 3 mL, and 594 mg of Dess-Martin periodinate was added at 0 ° C., and the mixture was stirred after 1 hour and then at room temperature for 3 hours. The reaction mixture was cooled to −60 ° C., 3 mL of isopropanol and 80 mg of sodium borohydride (NaBH 4 ) were sequentially added, and the mixture was stirred at −60 ° C. for 12 hours. After adding 3 mL of acetone to the reaction solution, the temperature was brought to room temperature. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by column chromatography (developing solvent: dichloromethane: methanol = 95: 5) to obtain 406 mg (yield 89%) of a white solid product.
1HNMR (500MHz,CD3Cl)δ0.12(s,3H),0.13(s,3H),0.93(s,9H),1.32(d,J=7.1Hz,6H),3.27−3.30(m,1H),4.03−4.28(m,3H),4.68−4.71(m,1H),5.15(dt,J=5.1,51.8Hz,1H),6.39(dd,J=5.1,11.5Hz,1H),8.36(d,J=2.0Hz,1H),8.39(br.s,NH) 1 HNMR (500MHz, CD 3 Cl) δ0.12 (s, 3H), 0.13 (s, 3H), 0.93 (s, 9H), 1.32 (d, J = 7.1Hz, 6H) , 3.27-3.30 (m, 1H), 4.03-4.28 (m, 3H), 4.68-4.71 (m, 1H), 5.15 (dt, J = 5. 1,51.8Hz, 1H), 6.39 (dd, J = 5.1, 11.5Hz, 1H), 8.36 (d, J = 2.0Hz, 1H), 8.39 (br.s) , NH)
step(4)および(5): 2−クロロ−9−(3’−アジド−2’3’−ジデオキシ−2’−フルオロ−β−D−アラビノフラノシル)アデニン(compoundE1;NUK−15)
2−クロロ−N6−イソブチリル−9−(5’−O−(tert−ブチルジメチルシリル)−2’−デオキシ−2’−フルオロ−β−D−リキソフラノシル)アデニン(300mg)をDMF2.5mLに溶解し、ジフェニル−2−ピリジルホスフィン197mg、アゾジカルボン酸ジイソプロピル(DIAD)(1.9M,395μL),アジ化ナトリウム(NaN3)96mgを加えて、室温にて8時間撹拌した。溶媒を減圧下留去後、残渣物をカラムクロマトグラフィー(展開溶媒: ジクロロメタン:メタノール=98:2)で精製した。得られた生成物をTHF2mLに溶解し、3HF・Et3N326μLを加えて、室温にて12時間撹拌した。溶媒を減圧下留去後、ジクロロメタン/メタノールの混合溶液(1:1,4mL)で溶解し、ナトリウムメトキシド(NaOMe)70mgを加えて、45℃にて20時間撹拌した。溶媒を減圧下留去後、残渣物をカラムクロマトグラフィー(展開溶媒: ジクロロメタン:メタノール=95:5to90:10)で精製し、白色固体の生成物30mg(収率16%)を得た。
steps (4) and (5): 2-chloro-9- (3'-azido-2'3'-dideoxy-2'-fluoro-β-D-arabinofuranosyl) adenine (compoundE1; NUK-15)
2-Chloro-N 6 -isobutyryl-9- (5'-O- (tert-butyldimethylsilyl) -2'-deoxy-2'-fluoro-β-D-lyxoflanosyl) adenine (300 mg) in 2.5 mL of DMF After dissolution, 197 mg of diphenyl-2-pyridylphosphine, diisopropyl azodicarboxylate (DIAD) (1.9 M, 395 μL) and 96 mg of sodium azide (NaN 3 ) were added, and the mixture was stirred at room temperature for 8 hours. After distilling off the solvent under reduced pressure, the residue was purified by column chromatography (developing solvent: dichloromethane: methanol = 98: 2). The obtained product was dissolved in 2 mL of THF, 326 μL of 3HF · Et 3 N was added, and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure, dissolved in a mixed solution of dichloromethane / methanol (1: 1,4 mL), 70 mg of sodium methoxide (NaOMe) was added, and the mixture was stirred at 45 ° C. for 20 hours. After distilling off the solvent under reduced pressure, the residue was purified by column chromatography (developing solvent: dichloromethane: methanol = 95: 5 to 90:10) to obtain 30 mg (yield 16%) of a white solid product.
1HNMR (300MHz,CD3OD)δ3.86−4.01(m,2H),4.13−4.18(m,1H),4.52−4.56(m,1H),4.61(br.s,OH),5.40(ddd,J=7.8,9.8,51.0Hz,1H),6.38(dd,J=6.5,7.0Hz,1H),8.36(d,J=1.2Hz,1H) 1 1 HNMR (300 MHz, CD 3 OD) δ3.86-4.01 (m, 2H), 4.13-4.18 (m, 1H), 4.52-4.56 (m, 1H), 4. 61 (br.s, OH), 5.40 (ddd, J = 7.8, 9.8, 51.0Hz, 1H), 6.38 (dd, J = 6.5, 7.0Hz, 1H) , 8.36 (d, J = 1.2Hz, 1H)
実施例2 Example 2
step(1): N 2 −イソブチリル−9−(2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)グアニン(compound(E2−II))
9−(2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)グアニン(compound(5−I))(900mg)をピリジン(15mL)に溶解し、トリメチルシリルクロリド2.4mLを加えて、0℃にて2時間撹拌した。イソ酪酸無水物3.2mLを加えて、室温にて24時間撹拌した。反応液にアンモニア水(28%,3mL)、水(3mL)を加えて、ジクロロメタンで抽出した。抽出液を水で洗浄後、硫酸マグネシウム乾燥した。溶媒を減圧下留去後、カラムクロマトグラフィー(展開溶媒: ジクロロメタン:メタノール=95:5to90:10)で精製し、白色固体の生成物680g(収率61%)を得た。
step (1): N 2 - isobutyryl-9- (2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl) guanine (Compound (E2-II))
9- (2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) guanine (compound (5-I)) (900 mg) was dissolved in pyridine (15 mL), and 2.4 mL of trimethylsilyl chloride was added. Then, the mixture was stirred at 0 ° C. for 2 hours. 3.2 mL of isobutyric acid anhydride was added, and the mixture was stirred at room temperature for 24 hours. Ammonia water (28%, 3 mL) and water (3 mL) were added to the reaction solution, and the mixture was extracted with dichloromethane. The extract was washed with water and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure and then purified by column chromatography (developing solvent: dichloromethane: methanol = 95: 5 to 90:10) to obtain 680 g (yield 61%) of a white solid product.
1HNMR (500MHz,d−DMSO)δ1.03(d,J=6.9Hz,6H),3.33−3.41(m,1H),3.62−3.68(m,2H),3.85−3.86(m,1H),4.39−4.44(m,1H),5.11−5.24(m,1H),6.22(dd,J=4.4,14.7Hz,1H),8.20(d,J=2.0Hz,1H) 1 1 HNMR (500 MHz, d-DMSO) δ1.03 (d, J = 6.9 Hz, 6H), 3.33-3.41 (m, 1H), 3.62-3.68 (m, 2H), 3.85-3.86 (m, 1H), 4.39-4.44 (m, 1H), 5.11-5.24 (m, 1H), 6.22 (dd, J = 4.4) , 14.7Hz, 1H), 8.20 (d, J = 2.0Hz, 1H)
step(2): N 2 −イソブチリル−9−(5’−O−(tert−ブチルジメチルシリル)−2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)グアニン(compound(E2−III))
N2−イソブチリル−9−(2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)グアニン(680mg)をDMF14mLに溶解し、tert−ブチルジメチルシリルクロリド302mg,イミダゾール272mgを加えて、室温にて24時間撹拌した。溶媒を減圧下留去後、カラムクロマトグラフィー(展開溶媒: ジクロロメタン:メタノール=95:5)で精製し、白色固体の生成物345mg(収率37%)を得た。
step (2): N 2 -isobutyryl-9- (5'-O- (tert-butyldimethylsilyl) -2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) guanine (E2) −III)))
N 2 -isobutyryl-9- (2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) guanine (680 mg) was dissolved in 14 mL of DMF, and 302 mg of tert-butyldimethylsilyl chloride and 272 mg of imidazole were added. , Stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure and then purified by column chromatography (developing solvent: dichloromethane: methanol = 95: 5) to obtain 345 mg (yield 37%) of a white solid product.
1HNMR (500MHz,CD3Cl)δ0.17(s,3H),0.18(s,3H),0.95(s,9H),1.30(d,J=7.1Hz,6H),2.63(sept, J=7.1Hz,1H),4.15−4.18(m,1H),4.33(dd,J=4.7,11.7Hz,1H),4.43(dd,J=5.6,11.7Hz,1H),4.47−4.52(m,1H),4.91(ddd,J=2.0,5.7,51.8Hz,1H),6.22(dd,J=3.4,20.0Hz,1H),7.88(d,J=2.5Hz,1H),8.10(br.s,NH) 1 1 HNMR (500MHz, CD 3 Cl) δ0.17 (s, 3H), 0.18 (s, 3H), 0.95 (s, 9H), 1.30 (d, J = 7.1Hz, 6H) , 2.63 (sept, J = 7.1Hz, 1H), 4.15-4.18 (m, 1H), 4.33 (dd, J = 4.7, 11.7Hz, 1H), 4. 43 (dd, J = 5.6, 11.7Hz, 1H), 4.47-4.52 (m, 1H), 4.91 (ddd, J = 2.0, 5.7, 51.8Hz, 1H), 6.22 (dd, J = 3.4, 20.0Hz, 1H), 7.88 (d, J = 2.5Hz, 1H), 8.10 (br.s, NH)
step(3): N 2 −イソブチリル−9−(5’−O−(tert−ブチルジメチルシリル)−2’−デオキシ−2’−フルオロ−β−D−リキソフラノシル)グアニン(compound(E2−IV))
N2−イソブチリル−9−(5’−O−(tert−ブチルジメチルシリル)−2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)グアニン(345mg)をジクロロメタン3mLに溶解し、Dess−Martin periodinate467mgを0℃で加えて、1時間後撹拌後、室温にて3時間撹拌した。反応液を−60℃に冷却し、イソプロパノール3mL,NaBH455mgを順次加えて、−60℃にて12時間撹拌した。反応液にアセトン3mLを加えた後、室温にした。反応液に飽和炭酸水素ナトリウム水溶液を加えて酢酸エチルエステルで抽出した。抽出液に飽和食塩水で洗浄後、硫酸マグネシウム乾燥した。溶媒を減圧下留去後、残渣物をカラムクロマトグラフィー(展開溶媒: ジクロロメタン:メタノール=95:5)で精製し、白色固体の生成物250mg(収率73%)を得た。
step (3): N 2 - isobutyryl -9- (5'-O- (tert- butyldimethylsilyl) -2'-deoxy-2'-fluoro-beta-D-lyxofuranosyl) guanine (compound (E2-IV) )
N 2 -isobutyryl-9- (5'-O- (tert-butyldimethylsilyl) -2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) guanine (345 mg) was dissolved in 3 mL of dichloromethane. , Dess-Martin periodinate 467 mg was added at 0 ° C., and the mixture was stirred after 1 hour and then stirred at room temperature for 3 hours. The reaction was cooled to -60 ° C., isopropanol 3 mL, added sequentially NaBH 4 55 mg, was stirred for 12 hours at -60 ° C.. After adding 3 mL of acetone to the reaction solution, the temperature was brought to room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate ester. The extract was washed with saturated brine and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by column chromatography (developing solvent: dichloromethane: methanol = 95: 5) to obtain 250 mg (yield 73%) of a white solid product.
1HNMR (500MHz,CD3Cl)δ0.11(s,3H),0.11(s,3H),0.91(s,9H),1.30(d,J=6.9Hz,6H),3.26(sept, J=6.9Hz,1H),4.03−4.15(m,3H),5.26(ddd,J=4.9,5.2,51.5Hz,1H),6.40(dd,J=5.4,10.5Hz,1H),8.40(d,J=2.0Hz,1H),8.71(br.s,NH) 1 1 HNMR (500MHz, CD 3 Cl) δ0.11 (s, 3H), 0.11 (s, 3H), 0.91 (s, 9H), 1.30 (d, J = 6.9Hz, 6H) , 3.26 (sept, J = 6.9Hz, 1H), 4.03-4.15 (m, 3H), 5.26 (ddd, J = 4.9, 5.2, 51.5Hz, 1H) ), 6.40 (dd, J = 5.4, 10.5Hz, 1H), 8.40 (d, J = 2.0Hz, 1H), 8.71 (br.s, NH)
step(4)および(5): 9−(3’−アジド−2’3’−ジデオキシ−2’−フルオロ−β−D−アラビノフラノシル)グアニン(compoundE2;NUK−16)
N2−イソブチリル−9−(5’−O−(tert−ブチルジメチルシリル)−2’−デオキシ−2’−フルオロ−β−D−リキソフラノシル)グアニン(150mg)をDMF2mLに溶解し、ジフェニル−2−ピリジルホスフィン126mg、DIAD(1.9M,250μL),NaN362mgを加えて、室温にて8時間撹拌した。溶媒を減圧下留去後、残渣物をカラムクロマトグラフィー(展開溶媒: 酢酸エチルエステル:ノーマルヘキサン=2:1)で精製した。得られた生成物をTHF2mLに溶解し、フッ化テトラ−n−ブチルアンモニウム(TBAF)(1M,300μL)を加えて、室温にて12時間撹拌した。溶媒を減圧下留去後、ジクロロメタン/メタノールの混合溶液(1:1,4mL)で溶解し、NaOMe10mg加えて、45℃にて20時間撹拌した。溶媒を減圧下留去後、残渣物をカラムクロマトグラフィー(展開溶媒: ジクロロメタン:メタノール=90:10to80:20)で精製し、白色固体の生成物5mg(収率5%)を得た。
steps (4) and (5): 9- (3'-azido-2'3'-dideoxy-2'-fluoro-β-D-arabinofuranosyl) guanine (compoundE2; NUK-16)
N 2 -isobutyryl-9- (5'-O- (tert-butyldimethylsilyl) -2'-deoxy-2'-fluoro-β-D-lyxoflanosyl) guanine (150 mg) was dissolved in 2 mL of DMF and diphenyl-2. - pyridylphosphine 126mg, DIAD (1.9M, 250μL) , added NaN 3 62 mg, and stirred at room temperature for 8 hours. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate ester: normal hexane = 2: 1). The obtained product was dissolved in 2 mL of THF, tetra-n-butylammonium fluoride (TBAF) (1M, 300 μL) was added, and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure, dissolved in a mixed solution of dichloromethane / methanol (1: 1,4 mL), 10 mg of NaOMe was added, and the mixture was stirred at 45 ° C. for 20 hours. After distilling off the solvent under reduced pressure, the residue was purified by column chromatography (developing solvent: dichloromethane: methanol = 90: 10 to 80:20) to obtain 5 mg (yield 5%) of a white solid product.
1HNMR (500MHz,CD3OD)δ3.84−3.97(m,2H),4.09−4.11(m,1H),4.51−4.53(m,1H),5.33(ddd,J=4.6,5.9,51.3Hz,1H),6.26(dd,J=6.1,7.6Hz,1H),8.05(d,J=1.5Hz,1H),8.55(bs.s,NH) 1 1 HNMR (500 MHz, CD 3 OD) δ3.84-3.97 (m, 2H), 4.09-4.11 (m, 1H), 4.51-4.53 (m, 1H), 5. 33 (ddd, J = 4.6, 5.9, 51.3Hz, 1H), 6.26 (dd, J = 6.1,7.6Hz, 1H), 8.05 (d, J = 1. 5Hz, 1H), 8.55 (bs.s, NH)
実施例3 Example 3
step(1): 2−クロロ−9−(2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)アデニン 5’−O−[α−フェニル−N−(イソブチル L−アラニル)]リン酸アミド(compoundE3;NUK−1)
クロファラビン(compound(E3−I))(60mg)をTHF(6mL)に溶解し、トリフルオロメタンスルホン酸銅(II)(Cu(OTf)2)(14mg),イソブチル (2S)−2−(クロロ(フェノキシ)ホスホリルアミノ)プロパノエート64mg,トリエチルアミン75μLを加えて、室温にて12時間撹拌した。溶媒を減圧下留去後、カラムクロマトグラフィー(展開溶媒: ジクロロメタン:メタノール=98:2to95:5)で精製し、白色シロップ状の生成物18mg(収率15%)を得た。
step (1): 2-Chloro-9- (2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) adenine 5'-O- [α-phenyl-N- (isobutyl L-alanyl)) ] Phosphate amide (compoundE3; NUK-1)
Copper (Compound (E3-I)) (60 mg) was dissolved in THF (6 mL), and copper (II) trifluoromethanesulfonate (Cu (OTf) 2 ) (14 mg), isobutyl (2S) -2- (chloro ( 64 mg of phenoxy) phosphorylamino) propanoate and 75 μL of triethylamine were added, and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure and then purified by column chromatography (developing solvent: dichloromethane: methanol = 98: 2to95: 5) to obtain 18 mg (yield 15%) of a white syrup-like product.
1HNMR (500MHz,CD3Cl)δ0.87−0.90(m,6H),1.38−1.40(m,3H),1.87−1.93(m,1H),3.72−4.39(m,6H),4.54−4.63(m,1H),5.10(ddd,J=2.3,3.2,51.6Hz,1H),6.43−6.48(m,1H),7.16−7.33(m,5H),7.98−8.04(m,1H) 1 1 HNMR (500 MHz, CD 3 Cl) δ0.87-0.90 (m, 6H), 1.38-1.40 (m, 3H), 1.87-1.93 (m, 1H), 3. 72-4.39 (m, 6H), 4.54-4.63 (m, 1H), 5.10 (ddd, J = 2.3, 3.2, 51.6Hz, 1H), 6.43 -6.48 (m, 1H), 7.16-7.33 (m, 5H), 7.98-8.04 (m, 1H)
実施例4 Example 4
step(1): 2−クロロ−N 6 −ベンゾイル−9−(2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)アデニン(compound(E4−II))
クロファラビン(compound(E1−I))(600mg)をピリジンに溶解し、ピリジンを減圧下留去する操作を3回行い、減圧下で乾燥した。残渣をピリジン(10mL)に溶解し、トリメチルシリルクロリド1.5mLを加えて、0℃にて30分間撹拌した。ベンゾイルクロリド(697μL)をゆっくり加えて、室温にて24時間撹拌した。反応液にアンモニア水(28%,3mL)、水(3mL)を加えて、酢酸エチルエステルで抽出した。抽出液を飽和炭酸水素ナトリウム水溶液で洗浄後、硫酸マグネシウム乾燥した。溶媒を減圧下留去後、カラムクロマトグラフィー(展開溶媒: ジクロロメタン:メタノール=95:5)で精製し、白色固体の生成物618mg(収率76%)を得た。
step (1): 2-chloro-N 6 -benzoyl-9- (2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) adenine (compound (E4-II))
Clofarabine (compound (E1-I)) (600 mg) was dissolved in pyridine, and the operation of distilling off pyridine under reduced pressure was performed three times, and the mixture was dried under reduced pressure. The residue was dissolved in pyridine (10 mL), 1.5 mL of trimethylsilyl chloride was added, and the mixture was stirred at 0 ° C. for 30 minutes. Benzoyl chloride (697 μL) was added slowly and stirred at room temperature for 24 hours. Ammonia water (28%, 3 mL) and water (3 mL) were added to the reaction solution, and the mixture was extracted with ethyl acetate ester. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure and then purified by column chromatography (developing solvent: dichloromethane: methanol = 95: 5) to obtain 618 mg (yield 76%) of a white solid product.
1HNMR (500MHz,CD3OD)δ3.28(dd,J=5.2,12.3Hz,1H),3.87(dd,J=2.7,12.0Hz,1H),4.03(q,J=4.2Hz,1H),4.53−4.58(m,2H),5.21(ddd,J=3.2,4.2,52.0Hz,1H),6.55(dd,J=4.2,15.2Hz,1H),7.55(t,J=7.8Hz,2H),7.63−7.67(m,1H),8.06(d,J=8.6Hz,2H),8.59(d,J=2.0Hz,1H) 1 1 HNMR (500 MHz, CD 3 OD) δ3.28 (dd, J = 5.2, 12.3 Hz, 1H), 3.87 (dd, J = 2.7, 12.0 Hz, 1H), 4.03 (Q, J = 4.2Hz, 1H), 4.53-4.58 (m, 2H), 5.21 (ddd, J = 3.2, 4.2, 52.0Hz, 1H), 6. 55 (dd, J = 4.2, 15.2Hz, 1H), 7.55 (t, J = 7.8Hz, 2H), 7.63-7.67 (m, 1H), 8.06 (d) , J = 8.6Hz, 2H), 8.59 (d, J = 2.0Hz, 1H)
step(2): 2−クロロ−N 6 −ベンゾイル−9−(3’−O−(tert−ブチルジメチルシリル)−2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)アデニン(compound(E4−III))
2−クロロ−N6−ベンゾイル−9−(2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)アデニン(560mg)をピリジン(5.5mL)に溶解し、ジメトキシトリチルクロリド674mgを加えて、室温にて3時間撹拌した。エタノールを加えて反応を止め、溶媒を減圧下留去後、水を加えて酢酸エチルエステルで抽出した。抽出液を飽和食塩水で洗浄後、硫酸マグネシウム乾燥した。カラムクロマトグラフィー(展開溶媒: ジクロロメタン:メタノール=95:5)で精製し、得られた生成物760mgをN,N−ジメチルホルムアミド(DMF)3mLに溶解し、tert−ブチルジメチルシリルクロリド289mg、イミダゾール158mgを加えて、室温にて24時間撹拌した。水を加えて酢酸エチルエステルで抽出した。抽出液を飽和食塩水で洗浄後、硫酸マグネシウム乾燥した。残渣物をクロロホルム/メタノールの混合溶液(2:1)に溶解し、p−トルエンスルホン酸・水和物262mgを加えて、室温にて15分間撹拌した。飽和炭酸水素ナトリウム水溶液を加えて、抽出液を飽和食塩水で洗浄後、硫酸マグネシウム乾燥した。溶媒を減圧下留去後、カラムクロマトグラフィー(展開溶媒: ジクロロメタン:メタノール=98:2)で精製し、白色固体の生成物442mg(収率62%)を得た。
step (2): 2-chloro-N 6 -benzoyl-9- (3'-O- (tert-butyldimethylsilyl) -2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) adenine (Compound (E4-III))
2-Chloro-N 6 -benzoyl-9- (2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) adenine (560 mg) was dissolved in pyridine (5.5 mL) and dimethoxytritylchloride 674 mg. Was added, and the mixture was stirred at room temperature for 3 hours. Ethanol was added to stop the reaction, the solvent was evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate ester. The extract was washed with saturated brine and dried over magnesium sulfate. Purification by column chromatography (developing solvent: dichloromethane: methanol = 95: 5), 760 mg of the obtained product was dissolved in 3 mL of N, N-dimethylformamide (DMF), tert-butyldimethylsilyl chloride 289 mg, imidazole 158 mg. Was added, and the mixture was stirred at room temperature for 24 hours. Water was added and the mixture was extracted with ethyl acetate ester. The extract was washed with saturated brine and dried over magnesium sulfate. The residue was dissolved in a mixed solution of chloroform / methanol (2: 1), 262 mg of p-toluenesulfonic acid / hydrate was added, and the mixture was stirred at room temperature for 15 minutes. A saturated aqueous sodium hydrogen carbonate solution was added, and the extract was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and then purified by column chromatography (developing solvent: dichloromethane: methanol = 98: 2) to obtain 442 mg (yield 62%) of a white solid product.
1HNMR (500MHz,CD3Cl)δ0.15(s,3H),0.16(s,3H),0.93(s,9H),3.82−4.01(m,3H),4.67(ddd,J=3.0,4.7,19.1Hz,1H),5.08(ddd,J=2.7,3.9,52.1Hz,1H),6.48(dd,J=3.9,16.1Hz,1H),7.53(t,J=7.4Hz,2H),7.62(t,J=7.3Hz,1H),8.02(d,J=8.1Hz,2H),8.27(d,J=2.2Hz,1H),9.10(br.s,NH) 1 HNMR (500MHz, CD 3 Cl) δ0.15 (s, 3H), 0.16 (s, 3H), 0.93 (s, 9H), 3.82-4.01 (m, 3H), 4 .67 (ddd, J = 3.0, 4.7, 19.1Hz, 1H), 5.08 (ddd, J = 2.7, 3.9, 52.1Hz, 1H), 6.48 (dd) , J = 3.9, 16.1Hz, 1H), 7.53 (t, J = 7.4Hz, 2H), 7.62 (t, J = 7.3Hz, 1H), 8.02 (d, J = 8.1Hz, 2H), 8.27 (d, J = 2.2Hz, 1H), 9.10 (br.s, NH)
step(3):2−クロロ−9−(3’−O−(tert−ブチルジメチルシリル)−2’−デオキシ−2’−フルオロ−4’−C−ヒドロキシメチル−β−D−アラビノフラノシル)アデニン(compound(E4−IV))
2−クロロ−N6−ベンゾイル−9−(3’−O−(tert−ブチルジメチルシリル)−2’−デオキシ−2’−フルオロ−β−D−アラビノフラノシル)アデニン(150mg)をトルエン/ジメチルスルホキシド(DMSO)の混合溶液(2:3)に溶解し、1−エチル−3−(3−ジメチルアミノプロピル)カルジイミド塩酸塩(85mg)、ピリジン20μM、トリフルオロ酢酸10μMを加えて、室温にて2時間撹拌した。反応液に水を加えて酢酸エチルエステルで抽出した。抽出液を飽和食塩水で洗浄後、硫酸マグネシウム乾燥した。溶媒を減圧下留去後、残渣物を1,4−ジオキサン1.0mLに溶解し、37%ホルムアルデヒド水溶液153μM、2NNaOH水溶液153μMを加えて、室温にて3時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えて酢酸エチルエステルで抽出した。抽出液を飽和食塩水で洗浄後、硫酸マグネシウム乾燥した。溶媒を減圧下留去後、残渣物をメタノール1mLに溶解し、水素化ホウ素ナトリウム22mgを氷冷下で加えて、30分間撹拌した。酢酸を加えた後、飽和炭酸水素ナトリウム水溶液を加えて酢酸エチルエステルで抽出した。抽出液を飽和食塩水で洗浄後、硫酸マグネシウム乾燥した。溶媒を減圧下留去後、カラムクロマトグラフィー(展開溶媒: ジクロロメタン:メタノール=95:5)で精製し、白色固体の生成物70mg(収率56%)を得た。
step (3): 2-chloro-9- (3'-O- (tert-butyldimethylsilyl) -2'-deoxy-2'-fluoro-4'-C-hydroxymethyl-β-D-arabinofurano Sill) Adenine (compound (E4-IV))
2-Chloro-N 6 -benzoyl-9- (3'-O- (tert-butyldimethylsilyl) -2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) Adenine (150 mg) in toluene / Dissolve in a mixed solution of dimethyl sulfoxide (DMSO) (2: 3), add 1-ethyl-3- (3-dimethylaminopropyl) cardiimide hydrochloride (85 mg), pyridine 20 μM, and trifluoroacetic acid 10 μM to room temperature. Was stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate ester. The extract was washed with saturated brine and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was dissolved in 1.0 mL of 1,4-dioxane, 153 μM of a 37% aqueous formaldehyde solution and 153 μM of a 2N NaOH aqueous solution were added, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate ester. The extract was washed with saturated brine and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was dissolved in 1 mL of methanol, 22 mg of sodium borohydride was added under ice-cooling, and the mixture was stirred for 30 minutes. After adding acetic acid, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate ester. The extract was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and then purified by column chromatography (developing solvent: dichloromethane: methanol = 95: 5) to obtain 70 mg (yield 56%) of a white solid product.
1HNMR (500MHz,CD3OD)δ0.16(s,3H),0.18(s,3H),0.96(s,9H),3.50(d,J=11.5Hz,1H),3.63(d,J=12.0Hz,1H),3.68(d,J=12.0Hz,1H),3.82(d,J=11.8Hz,1H),5.02(dd,J=5.9,24.7Hz,1H),5.55(dt,J=5.7,56.2Hz,1H),6.55(t,J=6.1Hz,1H),8.34(s,1H) 1 1 HNMR (500MHz, CD 3 OD) δ0.16 (s, 3H), 0.18 (s, 3H), 0.96 (s, 9H), 3.50 (d, J = 11.5Hz, 1H) , 3.63 (d, J = 12.0Hz, 1H), 3.68 (d, J = 12.0Hz, 1H), 3.82 (d, J = 11.8Hz, 1H), 5.02 ( dd, J = 5.9, 24.7Hz, 1H), 5.55 (dt, J = 5.7, 56.2Hz, 1H), 6.55 (t, J = 6.1Hz, 1H), 8 .34 (s, 1H)
step(4): 2−クロロ−9−(2’−デオキシ−2’−フルオロ−4’−C−ヒドロキシメチル−β−D−アラビノフラノシル)アデニン(compoundE4;NUK−17)
2−クロロ−9−(3’−O−(tert−ブチルジメチルシリル)−2’−デオキシ−2’−フルオロ−4’−C−ヒドロキシメチル−β−D−アラビノフラノシル)アデニン(30mg)をTHF2mLに溶解し、3HF・Et3N22μLを加えて、室温にて24時間撹拌した。溶媒を減圧下留去後、残渣物をカラムクロマトグラフィー(展開溶媒: ジクロロメタン:メタノール=80:20)で精製し、白色固体の生成物11mg(収率49%)を得た。
step (4): 2-chloro-9- (2'-deoxy-2'-fluoro-4'-C-hydroxymethyl-β-D-arabinofuranosyl) adenine (compoundE4; NUK-17)
2-Chloro-9- (3'-O- (tert-butyldimethylsilyl) -2'-deoxy-2'-fluoro-4'-C-hydroxymethyl-β-D-arabinofuranosyl) adenine (30 mg) ) Was dissolved in 2 mL of THF, 22 μL of 3HF · Et 3 N was added, and the mixture was stirred at room temperature for 24 hours. After distilling off the solvent under reduced pressure, the residue was purified by column chromatography (developing solvent: dichloromethane: methanol = 80:20) to obtain 11 mg (yield 49%) of a white solid product.
1HNMR (500MHz,CD3OD)δ3.57(d,J=11.7Hz,1H),3.69(s,2H),3.85(d,J=11.7Hz,1H),4.80(dd,J=5.6,24.5Hz,1H),5.51(dt,J=5.9,55.5Hz,1H),6.56(dd,J=6.1,7.6Hz,1H),8.34(d,J=1.0Hz,1H) 1 1 HNMR (500 MHz, CD 3 OD) δ3.57 (d, J = 11.7 Hz, 1H), 3.69 (s, 2H), 3.85 (d, J = 11.7 Hz, 1H), 4. 80 (dd, J = 5.6, 24.5Hz, 1H), 5.51 (dt, J = 5.9, 55.5Hz, 1H), 6.56 (dd, J = 6.1,7. 6Hz, 1H), 8.34 (d, J = 1.0Hz, 1H)
[本発明化合物の抗ウィルス活性に関する試験例]
1.試験方法
[Test Example on Antiviral Activity of Compound of the Present Invention]
1. 1. Test method
1−1.抗HBV活性の測定
抗HBV活性の評価は、ヒト肝癌細胞株HepG2にHBVゲノムの2倍長の遺伝子を導入したHBV産生細胞であるHepG2.2.15細胞株を用いて行い、薬剤(試験化合物)の添加後7日間当該細胞を培養した後、細胞内HBV DNA量あるいは細胞上清中のHBV DNA量をPCR法にて定量評価することにより行った。HBV DNAのPCRは、Forward Primer(HBV−S703R;5’−GAA CCA
CTG AAC AAA TGG CAC TAG TA−3’)(配列番号1)を用いた。PCRは95℃10秒、62℃10秒、72℃30秒を1サイクルとして35サイクル実施した。
各薬剤についてのより具体的な試験方法を以下に述べる。
(1)NUK−1
HepG2.2.15細胞を1×105cell/wellになるように播種した。24時間後にETV(entecavir),Clofarabine,Sofosbuvir及び薬剤NUK−1を1μMになるように希釈して細胞に添加した。7日間培養後、細胞質分画を回収し、フェノール・クロロホルム抽出にてDNAを精製した。精製されたDNA20ngを使用して、細胞内HBV DNA量を定量的PCR法にて評価した。
(2)NUK−2〜NUK−17
HepG2.2.15細胞を1×105cell/wellになるように播種した。24時間後に上記各NUK化合物を1μMと10μMになるように希釈して細胞に添加した。7日間培養後、細胞質分画を回収し、フェノール・クロロホルム抽出にてDNAを精製した。精製されたDNA20ngを使用して、細胞内HBV DNA量を定量的PCR法にて評価した。
1-1. Measurement of anti-HBV activity Evaluation of anti-HBV activity was performed using a HepG 2.2.15 cell line, which is an HBV-producing cell in which a gene twice as long as the HBV genome was introduced into the human hepatitis cell line HepG2, and a drug (test compound). ) Was cultured for 7 days, and then the amount of intracellular HBV DNA or the amount of HBV DNA in the cell supernatant was quantitatively evaluated by the PCR method. PCR of HBV DNA is performed by Forward Primer (HBV-S703R; 5'-GAA CCA).
CTG AAC AAA TGG CAC TAG TA-3') (SEQ ID NO: 1) was used. PCR was carried out for 35 cycles with 95 ° C. for 10 seconds, 62 ° C. for 10 seconds, and 72 ° C. for 30 seconds as one cycle.
More specific test methods for each drug are described below.
(1) NUK-1
HepG 2.2.15 cells were seeded at 1 × 10 5 cell / well. After 24 hours, ETV (entecavir), clofarabine, sofosbuvir and the drug NUK-1 were diluted to 1 μM and added to the cells. After culturing for 7 days, the cytoplasmic fraction was collected and DNA was purified by phenol / chloroform extraction. Using 20 ng of purified DNA, the amount of intracellular HBV DNA was evaluated by a quantitative PCR method.
(2) NUK-2 to NUK-17
HepG 2.2.15 cells were seeded at 1 × 10 5 cell / well. After 24 hours, each of the above NUK compounds was diluted to 1 μM and 10 μM and added to the cells. After culturing for 7 days, the cytoplasmic fraction was collected and DNA was purified by phenol / chloroform extraction. Using 20 ng of purified DNA, the amount of intracellular HBV DNA was evaluated by a quantitative PCR method.
1−2.エンテカビル耐性株に対する抗HBV活性の測定
薬剤耐性型HBVに対する薬剤感受性試験を以下の通り実施した。HepG2 NTCP−myc細胞に野生型(C_JPNAT wt)または、薬剤耐性型遺伝子(C_JPNAT mt)(mt: L180M, S202G, M204V)を導入し、24時間後にETV(entecavir)、Clofarabine、薬剤NUK−2、NUK−3、およびNUK−15を1μMになるように希釈して細胞に添加し、7日間培養した。細胞内HBV DNA量あるいは培養上清中のHBV DNA量をPCR法にて定量評価した。
1-2. Measurement of anti-HBV activity against entecavir-resistant strains A drug susceptibility test for drug-resistant HBV was performed as follows. Wild-type (C_JPNAT wt) or drug-resistant gene (C_JPNAT mt) (mt: L180M, S202G, M204V) was introduced into HepG2 NTCP-myc cells, and 24 hours later, ETV (entecavir), Clofarabine, drug NUK-2, NUK-3 and NUK-15 were diluted to 1 μM, added to cells, and cultured for 7 days. The amount of intracellular HBV DNA or the amount of HBV DNA in the culture supernatant was quantitatively evaluated by the PCR method.
1−3.細胞毒性の測定
HepG2 NTCP−myc細胞を2×104cell/wellになるように播種した。24時間後に薬剤NUK−2〜NUK−17を1μMと10μMになるように希釈して細胞に添加し、7日間培養した。培養後、premix WST−1 Cell Proliferation Assay System(TaTaRa)を10μL添加して37℃2時間培養後、450nmでマイクロプレートリーダーを用いて吸光度を測定して、細胞生存率を求めた。
1-3. Measurement of Cytotoxicity HepG2 NTCP-myc cells were seeded at 2 × 10 4 cell / well. After 24 hours, the drugs NUK-2 to NUK-17 were diluted to 1 μM and 10 μM, added to the cells, and cultured for 7 days. After culturing, 10 μL of premix WST-1 Cell Proflation Assay System (TaTaRa) was added, and the cells were cultured at 37 ° C. for 2 hours, and then the absorbance was measured at 450 nm using a microplate reader to determine the cell viability.
1−4.PXB−cellsでの抗HBV活性の測定
JFC(Caucasian,1Y,Male)を移植して作製されたPXBマウス(登録商標)から,コラゲナーゼ灌流法により分離されたヒト肝細胞(PXB−cells)を用いた抗HBV薬効評価試験を行った。PXB−cellsにHBV(gt C)を感染させて、12、17、22、27日間培養後、にETV(entecavir)、薬剤NUK−2(本試験においてComAと表記する場合がある)およびNUK−15(本試験においてComBと表記する場合がある)を2.5、25、250nMになるように希釈して細胞に添加した。実験期間中、培養開始日から12、17、22、27日後の上清中のHBV DNA量及びヒトアルブミン量を測定した。培養32日後に、上清中のHBV DNA量及びヒトアルブミン量、加えて細胞内のHBV DNA量とcccDNA量を測定した。
HBV DNAのPCRは、Forward Primer(5’−CAC ATC AGG ATT CCT AGG ACC−3’)(配列番号2)、Reverse primer(5’−AGG TTG GTG AGT GAT TGG AG−3’)(配列番号3)、TaqMan probe(5’−CAG AGT CTA GAC TCG TGG TGG ACT TC−3’)(配列番号4)(Dye:FAM for
5’, TAMRA for 3’)を用いた。PCRは50℃2秒を1サイクル、95℃20秒を1サイクル、95℃3秒、60℃32秒を53サイクル実施した。
1-4. Measurement of anti-HBV activity in PXB-cells Human hepatocytes (PXB-cells) isolated by collagenase perfusion from PXB mice (registered trademark) prepared by transplanting JFC (Caucasian, 1Y, Male) are used. An anti-HBV drug efficacy evaluation test was conducted. After infecting PXB-cells with HBV (gt C) and culturing for 12, 17, 22, and 27 days, ETV (entecavir), drug NUK-2 (sometimes referred to as ComA in this test) and NUK- 15 (sometimes referred to as ComB in this test) was diluted to 2.5, 25, 250 nM and added to the cells. During the experimental period, the amount of HBV DNA and the amount of human albumin in the supernatant 12, 17, 22, and 27 days after the start of culture were measured. After 32 days of culturing, the amount of HBV DNA and human albumin in the supernatant, as well as the amount of intracellular HBV DNA and cc cDNA were measured.
PCR of HBV DNA was performed by Forward Primer (5'-CAC ATC AGG ATT CCT AGG ACC-3') (SEQ ID NO: 2), Reverse primer (5'-AGG TTG GTG GTG AGT GAT TGG AG-3') (SEQ ID NO: 3). ), TaqMan probe (5'-CAG AGT CTA GAC TCG TGG TGG TGG ACT TC-3') (SEQ ID NO: 4) (Dye: FAM for
5', TAMRA for 3') was used. PCR was carried out at 50 ° C. for 2 seconds for one cycle, 95 ° C. for 20 seconds for one cycle, 95 ° C. for 3 seconds, and 60 ° C. for 32 seconds for 53 cycles.
1−5.PXBマウスでの抗HBV活性の測定
JFC(Caucasian,1Y,Male)を移植して作製されたPXBマウス(ヒト肝細胞キメラマウス)を用いた抗HBV薬効評価試験を行った。PXBマウスにHBV(gt C)を感染させたヒト肝細胞キメラマウス(4匹)へ0.02mg/kgのNUK−2を2週間経口投与し、血清HBVDNA量(HBsAg量、HBcrAg量)およびBW、hALB量を測定した。2週間の休薬後、1mg/kgのNUK−2を2週間経口投与し、血清HBVDNA量(HBsAg量、HBcrAg量)およびBW、hALB量を測定した。なお感染源は、野生群では感染キメラマウス由来血清を接種した。HBV DNAのPCRは、Forward Primer(5’−CAC ATC AGG ATT CCT AGG ACC−3’)(配列番号2)、Reverse primer(5’−AGG TTG GTG AGT GAT TGG AG−3’)(配列番号3)、TaqMan probe(5’−CAG AGT CTA GAC TCG TGG TGG ACT TC−3’)(配列番号4)(Dye:FAM for 5’, TAMRA for 3’)を用いた。PCRは50℃2秒を1サイクル、95℃20秒を1サイクル、95℃3秒、60℃32秒を53サイクル実施した。
1-5. Measurement of anti-HBV activity in PXB mice An anti-HBV drug efficacy evaluation test was conducted using PXB mice (human hepatocyte chimeric mice) prepared by transplanting JFC (Caucasian, 1Y, Male). 0.02 mg / kg NUK-2 was orally administered to human hepatocyte chimeric mice (4 animals) in which PXB mice were infected with HBV (gt C) for 2 weeks, and serum HBVDNA amount (HBsAg amount, HBcrAg amount) and BW , The amount of hALB was measured. After a 2-week washout, 1 mg / kg of NUK-2 was orally administered for 2 weeks, and the serum HBVDNA amount (HBsAg amount, HBcrAg amount), BW, and hALB amount were measured. In the wild group, the source of infection was inoculated with serum derived from infected chimeric mice. PCR of HBV DNA was performed by Forward Primer (5'-CAC ATC AGG ATT CCT AGG ACC-3') (SEQ ID NO: 2), Reverse primer (5'-AGG TTG GTG GTG AGT GAT TGG AG-3') (SEQ ID NO: 3). ), TaqMan probe (5'-CAG AGT CTA GAC TCG TGG TGG TGG ACT TC-3') (SEQ ID NO: 4) (Dye: FAM for 5', TAMRA for 3') was used. PCR was carried out at 50 ° C. for 2 seconds for one cycle, 95 ° C. for 20 seconds for one cycle, 95 ° C. for 3 seconds, and 60 ° C. for 32 seconds for 53 cycles.
2.薬剤(試験化合物)
上記試験で用いられた各種薬剤(試験化合物)(NUK−1〜NUK−17)の構造を図1に示す。これらの薬剤は、市販されているものは購入することにより、または、本明細書中に開示された方法もしくは公知の方法により合成することにより入手することができる。
2. Drug (test compound)
The structures of various drugs (test compounds) (NUK-1 to NUK-17) used in the above test are shown in FIG. These agents can be obtained by purchasing commercially available products, or by synthesizing them by the methods disclosed herein or by known methods.
3.実験結果 3. 3. Experimental result
試験1−1:抗HBV活性
NUK−1を薬剤として用いた試験での結果を図2に示す。
NUK−2〜NUK−17を薬剤として用いた試験での結果を図3に示す。
Test 1-1: Anti-HBV activity The results of a test using NUK-1 as a drug are shown in FIG.
The results of the test using NUK-2 to NUK-17 as drugs are shown in FIG.
試験1−2:エンテカビル耐性株に対する抗HBV活性
NUK−2、NUK−3、およびNUK−15を薬剤として用いた試験での結果を図4に示す。
Test 1-2: Anti-HBV activity against entecavir-resistant strains The results of a test using NUK-2, NUK-3, and NUK-15 as agents are shown in FIG.
試験1−3:細胞毒性
NUK−2〜NUK−17を薬剤として用いた試験での結果を図3に示す。
Test 1-3: Cytotoxicity The results of a test using NUK-2 to NUK-17 as drugs are shown in FIG.
試験1−4:PXB−cellsでの抗HBV活性
NUK−2およびNUK−15を薬剤として用いた試験での結果を図5に示す。
Test 1-4: Anti-HBV activity in PXB-cells The results of a test using NUK-2 and NUK-15 as drugs are shown in FIG.
試験1−5:PXBマウスでの抗HBV活性
NUK−2を薬剤として用いた試験での結果を図6に示す。
Test 1-5: Anti-HBV activity in PXB mice The results of a test using NUK-2 as a drug are shown in FIG.
[本発明医薬に関する製剤例]
製剤例1(カプセル剤の製造)
1)実施例1の化合物 30 mg
2)微粉末セルロース 10 mg
3)乳糖 19 mg
4)ステアリン酸マグネシウム 1 mg
計 60 mg
1)、2)、3)および4)を混合して、ゼラチンカプセルに充填する。
[Example of formulation related to the pharmaceutical product of the present invention]
Formulation Example 1 (Manufacturing of capsules)
1) Compound of Example 1 30 mg
2) Fine powdered cellulose 10 mg
3) Lactose 19 mg
4) Magnesium stearate 1 mg
60 mg in total
1), 2), 3) and 4) are mixed and filled in gelatin capsules.
製剤例2(錠剤の製造)
1)実施例3の化合物 30 g
2)乳糖 50 g
3)トウモロコシデンプン 15 g
4)カルボキシメチルセルロースカルシウム 44 g
5)ステアリン酸マグネシウム 1 g
1000錠 計 140 g
1)、2)、3)の全量および30gの4)を水で練合し、真空乾燥後、整粒を行う。この整粒末に14gの4)および1gの5)を混合し、打錠機により打錠する。このようにして、1錠あたり実施例1の化合物30mgを含有する錠剤1000錠を得る。
Formulation Example 2 (Manufacturing of tablets)
1) Compound 30 g of Example 3
2) Lactose 50 g
3) Corn starch 15 g
4) Carboxymethyl cellulose calcium 44 g
5) Magnesium stearate 1 g
1000 tablets total 140 g
The whole amount of 1), 2) and 3) and 30 g of 4) are kneaded with water, vacuum dried, and then sized. 14 g of 4) and 1 g of 5) are mixed with this sized powder and tableted with a tableting machine. In this way, 1000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained.
本発明化合物は、優れた抗ウィルス活性(特に抗B型肝炎ウィルス活性)を有し、ウィルス感染により誘発される疾患(特に、B型肝炎ウィルス感染により誘発される疾患(例えば、肝炎、肝不全、肝硬変、肝臓癌等))の予防または治療に有用である。 The compound of the present invention has excellent antiviral activity (particularly anti-hepatitis B virus activity) and is induced by virus infection (particularly, disease induced by hepatitis B virus infection (eg, hepatitis, liver failure). , Liver cirrhosis, liver cancer, etc.)) is useful for prevention or treatment.
Claims (11)
[式中、R1は、置換されていてもよいプリン塩基を表し;
R2は、ヒドロキシ基またはアジド基を表し;
R3は、水素、置換されていてもよい(C1−C6)アルキル基、置換されていてもよい(C2−C6)アルキニル基、またはシアノ基を表し;および
R4は、ヒドロキシ基、ホスホリルオキシ基(−OPO3H)、または式(II):
(式中、Rは、エステル化されたカルボキシ(C1−C6)アルキル基を表し、およびArは置換されていてもよい(C6−C14)アリール基を表す)
で表される基を表す;
但し、R2が、ヒドロキシ基であり、R3が、水素である場合は、R1は、下記の式(IIIa)または(IIIb):
(式中、R5は、水素またはハロゲンを表す)
で表される基を表し;およびR4は、上記の式(II)で表される基を表す。]
で表される化合物またはその塩。 The following formula (I):
[In the formula, R 1 represents a purine base that may be substituted;
R 2 represents a hydroxy or azide group;
R 3 represents hydrogen, a optionally substituted (C 1- C 6 ) alkyl group, optionally substituted (C 2- C 6 ) alkynyl group, or cyano group; and R 4 is hydroxy. group, phosphoryloxy group (-OPO 3 H), or formula (II):
(In the formula, R represents an esterified carboxy (C 1- C 6 ) alkyl group, and Ar represents an optionally substituted (C 6- C 14 ) aryl group).
Represents a group represented by;
However, when R 2 is a hydroxy group and R 3 is hydrogen, R 1 is represented by the following formula (IIIa) or (IIIb):
(In the formula, R 5 represents hydrogen or halogen)
In represents a group represented by; and R 4 represents a group represented by the formula (II). ]
A compound represented by or a salt thereof.
[式中、R1は、置換されていてもよいプリン塩基を表し;
R2は、ヒドロキシ基またはアジド基を表し;
R3は、水素、置換されていてもよい(C1−C6)アルキル基、置換されていてもよい(C2−C6)アルキニル基、またはシアノ基を表し;および
R4は、ヒドロキシ基、ホスホリルオキシ基(−OPO3H)、または式(II):
(式中、Rは、エステル化されたカルボキシ(C1−C6)アルキル基を表し、およびArは置換されていてもよい(C6−C14)アリール基を表す)
で表される基を表す;
但し、R2が、ヒドロキシ基の場合は、R1は、下記の式(IIIa)または(IIIb):
(式中、R5は、水素またはハロゲンを表す)
で表される基を表し;およびR4は、上記の式(II)で表される基を表す。]
で表される化合物またはその塩。 The following formula (I):
[In the formula, R 1 represents a purine base that may be substituted;
R 2 represents a hydroxy or azide group;
R 3 represents hydrogen, a optionally substituted (C 1- C 6 ) alkyl group, optionally substituted (C 2- C 6 ) alkynyl group, or cyano group; and R 4 is hydroxy. group, phosphoryloxy group (-OPO 3 H), or formula (II):
(In the formula, R represents an esterified carboxy (C 1- C 6 ) alkyl group, and Ar represents an optionally substituted (C 6- C 14 ) aryl group).
Represents a group represented by;
However, when R 2 is a hydroxy group, R 1 is represented by the following formula (IIIa) or (IIIb):
(In the formula, R 5 represents hydrogen or halogen)
In represents a group represented by; and R 4 represents a group represented by the formula (II). ]
A compound represented by or a salt thereof.
(式中、R5は、前記と同義である)
で表される基であり;
R3が、水素、ヒドロキシ(C1−C6)アルキル基、(C2−C6)アルキニル基、またはシアノ基であり;
Rが、(C1−C6)アルコキシカルボニル(C1−C6)アルキル基であり;および
Arが、フェニル基である、請求項1または2に記載の化合物またはその塩。 R 1 is the following formula (IIIa) or (IIIb):
(In the formula, R 5 is synonymous with the above)
It is a group represented by;
R 3 is a hydrogen, hydroxy (C 1- C 6 ) alkyl group, (C 2- C 6 ) alkynyl group, or cyano group;
The compound or salt thereof according to claim 1 or 2, wherein R is a (C 1- C 6 ) alkoxycarbonyl (C 1- C 6 ) alkyl group; and Ar is a phenyl group.
で表される基である、請求項1〜3のいずれか1項に記載の化合物またはその塩。 R 1 is the following formula (IIIa):
The compound according to any one of claims 1 to 3, or a salt thereof, which is a group represented by.
(式中、R5は、水素を表す)
で表される基である、請求項1〜3のいずれか1項に記載の化合物またはその塩。 R 1 is the following formula (IIIb):
(In the formula, R 5 represents hydrogen)
The compound according to any one of claims 1 to 3, or a salt thereof, which is a group represented by.
(式中、R5は、ハロゲンを表す)
で表される基である、請求項1〜3のいずれか1項に記載の化合物またはその塩。 R 1 is the following formula (IIIb):
(In the formula, R 5 represents halogen)
The compound according to any one of claims 1 to 3, or a salt thereof, which is a group represented by.
R2は、ヒドロキシ基またはアジド基を表し;
R3は、水素、置換されていてもよい(C1−C6)アルキル基、置換されていてもよい(C2−C6)アルキニル基、またはシアノ基を表し;および
R4は、ヒドロキシ基、ホスホリルオキシ基、または式(II):
(式中、Rは、エステル化されたカルボキシ(C1−C6)アルキル基を表し、およびArは置換されていてもよいアリール基を表す)
で表される基を表す;
但し、R2が、ヒドロキシ基であり、R3が、水素である場合は、
1)R1が、下記の式(IIIa)または(IIIb):
(式中、R5は、水素を表す)で表される基を表すか、または
2)R1が、下記の式(IIIb):
(式中、R5は、ハロゲンを表す)で表される基であり、かつ
R4が、式(II):
(式中、Rは、エステル化されたカルボキシ(C1−C6)アルキル基を表し、およびArは置換されていてもよい(C6−C14)アリール基を表す)
で表される基を表す]
で表される化合物またはその塩を、有効成分として含有するB型肝炎ウィルス感染により誘発される疾患の予防または治療のための医薬。 The following formula (Ia):
R 2 represents a hydroxy or azide group;
R 3 represents hydrogen, a optionally substituted (C 1- C 6 ) alkyl group, optionally substituted (C 2- C 6 ) alkynyl group, or cyano group; and R 4 is hydroxy. Group, phosphoryloxy group, or formula (II):
(Wherein, R represents an esterified carboxy (C 1 -C 6) alkyl group, and Ar represents an aryl group which may be substituted)
Represents a group represented by;
However, when R 2 is a hydroxy group and R 3 is hydrogen,
1) R 1 is the following formula (IIIa) or (IIIb):
(In the formula, R 5 represents hydrogen), or 2) R 1 represents the following formula (IIIb):
(In the formula, R 5 represents a halogen), and R 4 is a group represented by the formula (II) :.
(In the formula, R represents an esterified carboxy (C 1- C 6 ) alkyl group, and Ar represents an optionally substituted (C 6- C 14 ) aryl group).
Represents a group represented by]
A drug for the prevention or treatment of a disease induced by hepatitis B virus infection, which contains the compound represented by (1) or a salt thereof as an active ingredient.
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