JPWO2007069555A1 - Novel 16-membered ring 4 "-O-carbamoyl azalide derivative and method for producing the same - Google Patents

Novel 16-membered ring 4 "-O-carbamoyl azalide derivative and method for producing the same Download PDF

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JPWO2007069555A1
JPWO2007069555A1 JP2007550160A JP2007550160A JPWO2007069555A1 JP WO2007069555 A1 JPWO2007069555 A1 JP WO2007069555A1 JP 2007550160 A JP2007550160 A JP 2007550160A JP 2007550160 A JP2007550160 A JP 2007550160A JP WO2007069555 A1 JPWO2007069555 A1 JP WO2007069555A1
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知明 三浦
知明 三浦
憲一 兼本
憲一 兼本
里美 夏目
里美 夏目
尚志 渡邊
尚志 渡邊
吉田 卓史
卓史 吉田
鈴木 尚
尚 鈴木
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Abstract

一般式(1)[式中、R1は、水素原子又はC2〜6の直鎖状アルキルカルボニル基を表し、R2は、水素原子又はC2〜6のアルキルカルボニル基を表し、R3は、水酸基で置換されていてもよいC1〜6のアルキル基等を表し、R4は、水素原子、C1〜6のアルキル基、C2〜6のアルケニル基、Ar-B-基(Arはアリール基又は複素環基を表し、BはC1〜6のアルキル基又はC2〜6のアルケニル基を表す)等を表し、R5及びR6は、同一でも異なっていても良く、水素原子、又は水酸基で置換されていてもよいC1〜6のアルキル基若しくはC2〜6のアルケニル基である]で表される化合物又は薬学的に許容されるその塩、これらの製造方法、これらを含有する医薬組成物及び抗菌剤。General formula (1) [wherein R1 represents a hydrogen atom or a C2-6 linear alkylcarbonyl group, R2 represents a hydrogen atom or a C2-6 alkylcarbonyl group, and R3 is substituted with a hydroxyl group. Represents an optionally substituted C1-6 alkyl group or the like, and R4 represents a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, an Ar-B- group (Ar represents an aryl group or a heterocyclic group). And B represents a C1-6 alkyl group or a C2-6 alkenyl group), etc., and R5 and R6 may be the same or different and may be substituted with a hydrogen atom or a hydroxyl group. A -6 alkyl group or a C2-6 alkenyl group] or a pharmaceutically acceptable salt thereof, a production method thereof, a pharmaceutical composition containing them, and an antibacterial agent.

Description

本発明は、主としてロイコマイシン類16員環マクロライドから誘導される、グラム陽性菌及びグラム陰性菌に対して有効な新規16員環4”-O-カルバモイルアザライド誘導体及び薬理学的に許容されるその塩に関する。また、本発明は、それらの製造方法に関する。   The present invention relates to a novel 16-membered ring 4 "-O-carbamoyl azalide derivative that is effective against gram-positive and gram-negative bacteria, mainly derived from leucomycins 16-membered ring macrolides, and pharmacologically acceptable. The present invention also relates to a process for producing them.

マクロライド系抗生物質は、一般的に毒性が低く経口投与が可能であり、細菌感染症の治療において臨床上重要な抗菌薬の一つである。マクロライド系抗生物質は、アグリコン(非糖部位)であるラクトン環部分の構造原子数によって、14員環マクロライド及び16員環マクロライドに大別される。一方、化学修飾を施した抗菌剤としては、14員環マクロライドであるエリスロマイシンから誘導され、ラクトン環内に窒素原子が導入された市販の15員環マクロライドアジスロマイシン(特許文献1及び特許文献2参照)が知られている。また、エリスロマイシンの6位水酸基をメチル化した14員環マクロライドのクラリスロマイシン(非特許文献1参照)は、アジスロマイシンと共にニューマクロライドと呼ばれている。これらのニューマクロライドの登場により、臨床現場でのマクロライド系抗菌剤の使用が拡大してきた。それに伴い、エリスロマイシン耐性菌が増大し、臨床現場で問題になってきている。これら耐性菌に有効なマクロライド系抗生物質として、14員環マクロライドを出発原料とし、3位中性糖の代わりにカルボニル基を導入したケトライド系抗菌剤の研究が活発に行われている。ケトライド系経口抗菌剤としては、テリスロマイシン(特許文献3参照)が上市されている。   Macrolide antibiotics generally have low toxicity and can be administered orally, and are one of the clinically important antibacterial agents in the treatment of bacterial infections. Macrolide antibiotics are broadly classified into 14-membered macrolides and 16-membered macrolides depending on the number of structural atoms in the lactone ring portion, which is an aglycon (non-sugar moiety). On the other hand, as an antibacterial agent subjected to chemical modification, a commercially available 15-membered ring macrolide azithromycin derived from erythromycin which is a 14-membered ring macrolide and having a nitrogen atom introduced into the lactone ring (Patent Documents 1 and 2) See). In addition, clarithromycin (see Non-Patent Document 1), which is a 14-membered ring macrolide methylated at the 6-position hydroxyl group of erythromycin, is called a new macrolide together with azithromycin. With the advent of these new macrolides, the use of macrolide antibacterial agents in clinical settings has expanded. Along with this, erythromycin-resistant bacteria have increased and become a problem in clinical practice. As macrolide antibiotics effective against these resistant bacteria, ketolide antibacterial agents in which a 14-membered ring macrolide is used as a starting material and a carbonyl group is introduced instead of the 3-position neutral sugar are being actively studied. As a ketolide-type oral antibacterial agent, telithromycin (see Patent Document 3) is marketed.

近年、本発明者らは、ロイコマイシン類16員環マクロライドを出発原料として、それらのラクトン環に窒素原子を導入した後、種々化学修飾した新規アザライド及びアザラクタム誘導体を創製し、既存16員環マクロライド抗菌剤が無効であった耐性菌に対して抗菌力の改善が認められたことを報告した。(特許文献4及び特許文献5参照)。   In recent years, the present inventors have created novel azalides and azalactam derivatives that have been chemically modified after introducing nitrogen atoms into their lactone rings, starting from 16-membered macrolides of leucomycins, We reported that antibacterial activity was improved against resistant bacteria for which macrolide antibacterial agents were ineffective. (See Patent Document 4 and Patent Document 5).

これまで16員環マクロライドのうち臨床で使用されているものは、その誘導体を含めロイコマイシン類抗生物質である。ロイコマイシン類抗生物質については、北里研究所、東洋醸造株式会社(当時)、及び当社を含め多くのグループによりそれらの有効性向上を目的とした研究がなされ、ロキタマイシン(非特許文献2及び非特許文献3参照)、ミオカマイシン(非特許文献4及び非特許文献5参照)などが発売されている。   The 16-membered macrolides that have been used clinically so far are leucomycin antibiotics including their derivatives. With regard to leucomycin antibiotics, Kitasato Institute, Toyo Brewing Co., Ltd. (at that time), and many groups including our company have conducted research aimed at improving their effectiveness. Rokitamicin (Non-Patent Document 2 and Non-Patent Documents) Document 3), myokamycin (see Non-Patent Document 4 and Non-Patent Document 5), and the like are on the market.

ロイコマイシン類16員環マクロライドは、中性糖の4”位水酸基上にアシル基を有している。そのためミオカマイシンのような半合成マクロライドは生体内のエステレースによる代謝を受け易く、その結果として抗菌活性が血中において持続しにくいといった課題を有していた(非特許文献6)。上記の代謝に着目し、エステレースによる不活化を受け難い構造を有する16員環マクロライドとして、中性糖部分4”位のアシル基をアルキル基に変換した誘導体が報告されている(非特許文献7、非特許文献8及び非特許文献9参照)。   Leucomycin 16-membered macrolides have an acyl group on the 4 ”hydroxyl group of neutral sugars. Therefore, semi-synthetic macrolides such as myomycin are susceptible to metabolism by estelace in vivo, As a result, the antibacterial activity has a problem that it is difficult to sustain in the blood (Non-patent Document 6) As a 16-membered ring macrolide having a structure that is difficult to be inactivated by esterase, focusing on the above metabolism. Derivatives in which the acyl group at the 4 ″ position of the neutral sugar moiety is converted to an alkyl group have been reported (see Non-Patent Document 7, Non-Patent Document 8 and Non-Patent Document 9).

J. Antibiotics, 37, 187, 1984J. Antibiotics, 37, 187, 1984 J. Antibiotics, 34, 1001, 1981J. Antibiotics, 34, 1001, 1981 J. Antibiotics, 34, 1011, 1981J. Antibiotics, 34, 1011, 1981 J. Antibiotics, 29, 536, 1976J. Antibiotics, 29, 536, 1976 J. Antibiotics, 34, 436, 1981J. Antibiotics, 34, 436, 1981 薬学雑誌, 102, 781, 1982Pharmaceutical Journal, 102, 781, 1982 J. Antibiotics, 49, 582, 1996J. Antibiotics, 49, 582, 1996 J. Antibiotics, 50, 92, 1997J. Antibiotics, 50, 92, 1997 J. Antibiotics, 50, 32, 1997J. Antibiotics, 50, 32, 1997 米国特許第4474768号U.S. Pat. No. 4,474,768 米国特許第4517359号U.S. Pat.No. 4,517,359 米国特許第5635485号U.S. Pat.No. 5,635,485 国際公開WO2003/072589号International Publication WO2003 / 072589 国際公開WO2005/019238号International Publication WO2005 / 019238

テリスロマイシンは、クラリスロマイシンの3位の中性糖を除去して出現する水酸基を酸化してカルボニル基へと変換し、かつアグリコン部の11、12位にサイクリックカルバメートを構築し、その窒素原子に側鎖を導入した構造的特徴を有する化合物である。構造上、3位のケトンに特徴があることから、ケトライド系抗菌剤と呼ばれている。また、テリスロマイシンの作用機序は、細菌のリボソーム50SサブユニットのドメインII及びドメインVに作用して蛋白合成を阻害するものと考えられている。テリスロマイシンは、感受性菌のみならず耐性菌に対する抗菌活性が大きく改善されており、その作用機序からマクロライド系ではなくケトライド系抗菌剤として薬効区分されている。しかしながら、薬剤排出型耐性菌に対するテリスロマイシンの抗菌活性と、感受性菌に対するテリスロマイシンの抗菌活性との比較において大きな隔たりがあることから、既にテリスロマイシンにより、排出機構の遺伝子が影響を受けている可能性は否定しきれない。特に最近は、臨床現場において薬剤排出型耐性菌が増えていることも報告されている。また薬剤排出機構及びリボソームメチル化酵素産生機構の両方を有する複合型耐性菌の出現も確認されており、今後その割合が増加することも危惧され、これらに有効な抗菌剤の開発が期待されている。   Terithromycin removes the neutral sugar at position 3 of clarithromycin, oxidizes the hydroxyl group that appears and converts it to a carbonyl group, and constructs cyclic carbamates at positions 11 and 12 of the aglycon. It is a compound having structural characteristics in which a side chain is introduced into a nitrogen atom. It is called a ketolide antibacterial agent because it is characterized by the 3rd-position ketone. The mechanism of action of telithromycin is considered to act on the domain II and domain V of the bacterial ribosome 50S subunit to inhibit protein synthesis. Terithromycin is greatly improved in antibacterial activity against not only susceptible bacteria but also resistant bacteria, and is classified as a ketolide antibacterial agent instead of a macrolide based on its action mechanism. However, there is a big gap in the comparison of antibacterial activity of telithromycin against drug efflux resistant bacteria and that of susceptibility bacteria, so the gene of the excretion mechanism has already been affected by telithromycin. There is no denying the possibility. In particular, recently, it has been reported that drug excretion-resistant bacteria are increasing in clinical settings. In addition, the emergence of complex resistant bacteria having both a drug excretion mechanism and a ribosome methylase production mechanism has been confirmed, and there is concern that the ratio will increase in the future, and the development of antibacterial agents effective for these is expected. Yes.

ミオカマイシン、ロキタマイシン等のロイコマイシン類16員環マクロライドは、その高い安全性及び良好な服用性から、小児を中心として使用される臨床上有用なマクロライド系薬剤である。これまでのケトライド系誘導体はいずれも14員環マクロライドから化学変換により誘導されている。よって、ロイコマイシン類16員環マクロライドから化学変換により、現在問題となっているマクロライド耐性菌に有効なケトライド系抗菌剤様の性質を引き出すことができれば、きわめて有用な抗菌剤となり得る。その理由の一点目として、構造が全く異なることから14員環マクロライド耐性機構の影響を受け難い、全く新しいタイプのケトライド様抗菌剤としての期待が持たれる。二点目としては、14員環マクロライドがモチリン受容体に対して有する親和性のため胃腸に刺激を与えるのに対して、16員環マクロライドはそれを有していないこと、さらにこれまでの小児における臨床実績から、副作用が少なく安全性が高い薬剤として期待できるからである。   Leucomycin 16-membered ring macrolides such as myokamycin and rokitamycin are clinically useful macrolides used mainly in children because of their high safety and good dosage. All conventional ketolide derivatives are derived from 14-membered macrolides by chemical transformation. Therefore, if a ketolide antibacterial-like property effective against macrolide-resistant bacteria currently in question can be extracted by chemical conversion from 16-membered macrolides of leucomycin, it can be an extremely useful antibacterial agent. The first reason is that the structure is completely different, making it less susceptible to the 14-membered macrolide resistance mechanism, and it is expected to be a completely new type of ketolide-like antibacterial agent. Second, the 14-membered macrolide has a gastrointestinal irritation due to the affinity of the 14-membered macrolide for the motilin receptor, whereas the 16-membered macrolide does not have it. This is because it can be expected as a highly safe drug with few side effects based on the clinical results in children.

しかしながらロイコマイシン類16員環マクロライドは前述のように生体内で中性糖部分が代謝を受け易く、またロイコマイシン類16員環マクロライドから化学修飾により合成される誘導体は、中性糖部分4”位にアシル基を有している限り生体内エステレースによる代謝を受け易いことが予想される。これらのことから、ロイコマイシン類16員環マクロライドの特徴を有し、且つマクロライド耐性菌に有効で代謝的に安定な薬剤の創出が望まれる。   However, as described above, the 16-membered macrolides of leucomycin are susceptible to metabolism of the neutral sugar moiety in vivo, and the derivatives synthesized from the leucomycin 16-membered macrolide by chemical modification are neutral sugar moieties. As long as it has an acyl group at the 4 ″ position, it is expected to be easily metabolized by in vivo esterase. From these facts, it has the characteristics of a 16-membered ring macrolide and is resistant to macrolide. The creation of a drug that is effective against bacteria and metabolically stable is desired.

本発明者らは、前述したようにロイコマイシン類16員環マクロライドを出発原料として、それらのラクトン環内に窒素原子を導入した後、種々化学修飾した新規アザライド及びアザラクタム誘導体を創製し、既存16員環マクロライド抗菌剤が無効であった耐性菌に対して抗菌力の改善が認められたことを報告した(WO2005/019238)。   As described above, the inventors of the present invention created new azalides and azalactam derivatives with various chemical modifications after introducing nitrogen atoms into their lactone rings using leucomycin 16-membered macrolides as starting materials. It was reported that the antibacterial activity was improved against resistant bacteria for which the 16-membered macrolide antibacterial agent was ineffective (WO2005 / 019238).

さらに本発明者らは、ラクトン環15位に適当な側鎖を導入することに加えて、中性糖部分4”位プロピオニル基を3”位に転移させた後、4”位をカルバモイル化することにより、抗菌活性が改善されると共に代謝的に安定な化合物が得られることを見出した。ロイコマイシン類16員環マクロライドを化学修飾した誘導体において、4”位をカルバモイル化した例はこれまで報告されていない。   In addition to introducing an appropriate side chain at the 15-position of the lactone ring, the present inventors transferred the neutral sugar moiety 4 "-position propionyl group to the 3" -position, and then carbamoylated the 4 "-position. As a result, it was found that antibacterial activity was improved and a metabolically stable compound was obtained. Derivatives obtained by chemically modifying leucomycin 16-membered macrolides have been carbamoylated at the 4 ″ position. Not reported.

本発明者らは、本発明の化合物が、出発物質であるロイコマイシン類縁体と比較して、マクロライド耐性肺炎球菌である薬剤排出型耐性菌のみならず、メチラーゼ産生型耐性肺炎球菌に対しても抗菌活性が改善されることを見出し、本発明を完成させるに至った。   The inventors of the present invention compared not only drug excretion-resistant bacteria, which are macrolide-resistant pneumococci, but also methylase-producing resistant pneumococci, as compared with the starting leucomycin analog. Has also found that the antibacterial activity is improved, leading to the completion of the present invention.

第一の本発明により、新規化合物として、下記の一般式(1)

Figure 2007069555
[式中、R1は、水素原子又はC2〜6の直鎖状アルキルカルボニル基を表し、R2は、水素原子又はC2〜6のアルキルカルボニル基を表し、R3は、水酸基で置換されていてもよいC1〜6のアルキル基、C2〜6のアルケニル基又はC2〜6のアルキニル基を表し、R4は、水素原子、C1〜6のアルキル基、C2〜6のアルケニル基、C2〜6のアルキニル基又はAr-B-基(ここで、Arはアリール基又は複素環基を表し、BはC1〜6のアルキル基又はC2〜6のアルケニル基を表す)を表し、R5及びR6は、同一でも異なっていても良く、水素原子、又は水酸基で置換されていてもよいC1〜6のアルキル基若しくはC2〜6のアルケニル基である]で表される化合物又は薬学的に許容されるその塩が提供される。According to the first aspect of the present invention, as a novel compound, the following general formula (1)
Figure 2007069555
[In the formula, R 1 represents a linear alkyl group of hydrogen or C2-6, R 2 represents an alkyl group of hydrogen or C2-6, R 3 is substituted by a hydroxyl group C1-6 alkyl group, C2-6 alkenyl group or C2-6 alkynyl group may be represented, R 4 is a hydrogen atom, C1-6 alkyl group, C2-6 alkenyl group, C2-6 An alkynyl group or an Ar-B- group (wherein Ar represents an aryl group or a heterocyclic group, B represents a C1-6 alkyl group or a C2-6 alkenyl group), R 5 and R 6 May be the same or different and are a hydrogen atom, or a C1-6 alkyl group or a C2-6 alkenyl group optionally substituted with a hydroxyl group], or a pharmaceutically acceptable compound. The salt is provided.

第二の本発明により、新規製造方法として、一般式(2)

Figure 2007069555
〔式中、R1は、C2〜6の直鎖状アルキルカルボニル基を表し、R2は、C2〜6の直鎖状アルキルカルボニル基、又は水酸基の修飾基であり、R3は、C1〜6のアルキル基、C2〜6のアルケニル基、C2〜6のアルキニル基又は水酸基をシリル系保護基で修飾したヒドロキシエチル基を表し、R4は、C1〜6のアルキル基、C2〜6のアルケニル基、C2〜6のアルキニル基又はAr-B-基(ここで、Arはアリール基又は複素環基を表し、BはC1〜6のアルキル基、C2〜6のアルケニル基又はC2〜6のアルキニル基を表す)を表し、R7は、-CH(OR10)2(ここで、R10はC1〜5のアルキル基を表す)、下記の基(a)
Figure 2007069555
(ここで、nは2〜3の整数を表す)又はR1とR7を含んで下記の基(b)
Figure 2007069555
(ここで、R11は、シリル系保護基を表す)を表し、
R8は、C2〜C5の直鎖状アルキルカルボニル基、シリル系保護基、ベンジルオキシカルボニル基、4-メトキシベンジルオキシカルボニル基又は4-ニトロベンジルオキシカルボニル基を表し、
R9は、アセチル基、プロピオニル基、ノルマルブチリル基又はイソバレリル基を表す〕で表される化合物を、塩基存在下、アルキルイソシアネートと反応させ、一般式(2)におけるR9の3"位水酸基への転移を伴う、一般式(3)
Figure 2007069555
[式中、R1〜R4及びR7〜R9は前記一般式(2)で表されたものと同じ意味を表し、R5は水素原子を表し、R6はC1〜6のアルキル基を表す] で表される化合物の製造方法が提供される。According to the second aspect of the present invention, as a novel production method, the general formula (2)
Figure 2007069555
Wherein, R 1 represents a linear alkyl group of C2-6, R 2 is a linear alkyl group, or a hydroxyl-modifying group of C2-6, R 3 is C1 to 6 represents an alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group or a hydroxyethyl group in which a hydroxyl group is modified with a silyl protecting group, R 4 represents a C1-6 alkyl group, a C2-6 alkenyl A group, a C2-6 alkynyl group or an Ar-B- group (wherein Ar represents an aryl group or a heterocyclic group, B is a C1-6 alkyl group, a C2-6 alkenyl group or a C2-6 alkynyl group). R 7 represents —CH (OR 10 ) 2 (where R 10 represents a C1-5 alkyl group), the following group (a):
Figure 2007069555
(Where n represents an integer of 2 to 3) or R 1 and R 7 and the following group (b)
Figure 2007069555
(Wherein R 11 represents a silyl protecting group)
R 8 represents a C2-C5 linear alkylcarbonyl group, a silyl protecting group, a benzyloxycarbonyl group, a 4-methoxybenzyloxycarbonyl group or a 4-nitrobenzyloxycarbonyl group,
R 9 represents an acetyl group, a propionyl group, a normal butyryl group or an isovaleryl group] and is reacted with an alkyl isocyanate in the presence of a base to give a 3 "-position hydroxyl group of R 9 in the general formula (2). General formula (3) with transition to
Figure 2007069555
[Wherein R 1 to R 4 and R 7 to R 9 represent the same meaning as that represented by the general formula (2), R 5 represents a hydrogen atom, and R 6 represents a C 1-6 alkyl group. A method for producing a compound represented by:

第三の本発明により、新規製造方法として、一般式(2)

Figure 2007069555
〔式中、R1は、C2〜6の直鎖状アルキルカルボニル基を表し、R2は、C2〜6の直鎖状アルキルカルボニル基、又は水酸基の修飾基を表し、R3は、C1〜6のアルキル基、C2〜6のアルケニル基、C2〜6のアルキニル基又は水酸基をシリル系保護基で修飾したヒドロキシエチル基を表し、R4は、C1〜6のアルキル基、C2〜6のアルケニル基、C2〜6のアルキニル基、Ar-B-基(ここで、Arはアリール基又は複素環基を表し、BはC1〜6のアルキル基、C2〜6のアルケニル基又はC2〜6のアルキニル基を表す)を表し、R7は、-CH(OR10)2(ここで、R10はC1〜5のアルキル基を表す)、下記の基(a)
Figure 2007069555
(ここで、nは2〜3の整数を表す)、又はR1とR7を含んで下記の基(b)
Figure 2007069555
(ここで、R11は、シリル系保護基を表す)を表し、
R8は、C2〜C5の直鎖状アルキルカルボニル基を表し、
R9はアセチル基、プロピオニル基、ノルマルブチリル基又はイソバレリル基を表す〕で表される化合物を、塩基存在下、1,1 '-カルボニルジイミダゾールと反応させ、一般式(4)
Figure 2007069555
[式中、R1〜R4及びR7〜R9は、前記一般式(2)で表されたものと同じ意味を表す] とした後、さらに塩基の存在下又は非存在下、一級若しくは二級アミンであるR5R6NHと反応させる、一般式(3)
Figure 2007069555
[R1〜R4及びR7〜R9は、前記一般式(2)で表されたものと同じ意味を表し、R5及びR6は、同一でも異なっていても良く、水素原子又は水酸基で置換されていてもよいC1〜6のアルキル基を表す]で表される化合物の製造方法が提供される。According to the third aspect of the present invention, as a novel production method, the general formula (2)
Figure 2007069555
Wherein, R 1 represents a linear alkyl group of C2-6, R 2 represents a linear alkyl group, or a hydroxyl-modifying group of C2-6, R 3 is C1 to 6 represents an alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group or a hydroxyethyl group in which a hydroxyl group is modified with a silyl protecting group, R 4 represents a C1-6 alkyl group, a C2-6 alkenyl A group, a C2-6 alkynyl group, an Ar-B- group (wherein Ar represents an aryl group or a heterocyclic group, B is a C1-6 alkyl group, a C2-6 alkenyl group, or a C2-6 alkynyl group). R 7 represents —CH (OR 10 ) 2 (where R 10 represents a C1-5 alkyl group), the following group (a):
Figure 2007069555
(Where n represents an integer of 2 to 3), or R 1 and R 7 and the following group (b)
Figure 2007069555
(Wherein R 11 represents a silyl protecting group)
R 8 represents a C2-C5 linear alkylcarbonyl group,
R 9 represents an acetyl group, a propionyl group, a normal butyryl group or an isovaleryl group] and is reacted with 1,1′-carbonyldiimidazole in the presence of a base to give a compound of the general formula (4)
Figure 2007069555
[Wherein R 1 to R 4 and R 7 to R 9 represent the same meaning as that represented by the general formula (2)], and further, in the presence or absence of a base, primary or Reaction with secondary amine R 5 R 6 NH, general formula (3)
Figure 2007069555
[R 1 to R 4 and R 7 to R 9 represent the same meaning as that represented by the general formula (2), and R 5 and R 6 may be the same or different, and may be a hydrogen atom or a hydroxyl group. Represents a C1-6 alkyl group which may be substituted with a compound represented by the following formula:

さらに本発明により、細菌感染の治療を要するヒトを含む哺乳類動物に、治療有効量の一般式(1)で表される化合物、又は薬理学上許容されるその塩を投与する工程を含む、ヒトを含む哺乳類動物における細菌感染症の治療方法が提供される。   Furthermore, according to the present invention, the method comprises administering to a mammal, including a human in need of treatment for a bacterial infection, a therapeutically effective amount of a compound represented by the general formula (1), or a pharmacologically acceptable salt thereof. Methods of treating bacterial infections in mammals including are provided.

また、本発明により、上記一般式(1)で表される化合物又は薬理学的に許容されるその塩を含む医薬、好ましくは上記化合物又は薬理学的に許容されるその塩とともに薬理学上許容される担体を含む医薬組成物の形態の上記医薬が提供される。この医薬は抗菌剤として、細菌感染症の治療に有用である。さらに、本発明により、上記医薬の製造のための上記一般式(1)で表される化合物又は薬理学的に許容されるその塩の使用が提供される。   Further, according to the present invention, a pharmaceutical comprising the compound represented by the above general formula (1) or a pharmacologically acceptable salt thereof, preferably a pharmacologically acceptable together with the above compound or a pharmacologically acceptable salt thereof. There is provided a medicament as described above in the form of a pharmaceutical composition comprising a carrier. This medicine is useful as an antibacterial agent for the treatment of bacterial infections. Furthermore, the present invention provides the use of the compound represented by the above general formula (1) or a pharmacologically acceptable salt thereof for the manufacture of the above medicament.

本発明により、マクロライド耐性肺炎球菌である薬剤排出型耐性菌のみならず、メチラーゼ産生型耐性肺炎球菌に対しても抗菌活性が向上し、且つ代謝的に安定な化合物を提供することができる。また、本発明の製造方法は、16員環マクロライド基質の中性糖部分4”位を短工程でカルバモイル化する方法であり、本発明の化合物の効率的な製造方法を提供できる。   According to the present invention, it is possible to provide a metabolically stable compound that has improved antibacterial activity not only against drug efflux resistant bacteria that are macrolide-resistant pneumococci, but also against methylase-producing resistant pneumococci. In addition, the production method of the present invention is a method for carbamoylating the neutral sugar moiety 4 ″ position of a 16-membered ring macrolide substrate in a short process, and can provide an efficient method for producing the compound of the present invention.

以下に本発明を詳細に説明する。
本明細書において、アザライドとは、アグリコン(非糖部位)の11位が窒素原子であるラクトン環を含有する化合物であり、例えば一般式(1)で表される化合物を意味する。
The present invention is described in detail below.
In the present specification, azalide is a compound containing a lactone ring in which the 11th position of aglycone (non-sugar moiety) is a nitrogen atom, and means, for example, a compound represented by the general formula (1).

本明細書において、一般式中に記載した置換基中の数字(例えばR1やR2の数字)以外の数字は、その一般式における位置番号を意味する。In the present specification, numbers other than the numbers in the substituents described in the general formula (for example, the numbers of R 1 and R 2 ) mean position numbers in the general formula.

本明細書において、Meはメチル基、Etはエチル基、Prはプロピル基、Acはアセチル基、TBSはtert-ブチルジメチルシリル基を意味する。   In the present specification, Me represents a methyl group, Et represents an ethyl group, Pr represents a propyl group, Ac represents an acetyl group, and TBS represents a tert-butyldimethylsilyl group.

本明細書において、Arは、特に断らない限り、アリール基又は複素環基を意味する。   In the present specification, Ar means an aryl group or a heterocyclic group unless otherwise specified.

本明細書において、アルキル基及びアルキル基部分を含む置換基(例えばアルキルカルボニル基など)のアルキル部分は、特に断らない限り、メチル、エチル、プロピル、ブチル、ペンチル、ヘキシル、イソプロピル、イソブチル、tert−ブチル、イソペンチル、ネオペンチル、tert-ペンチル、シクロプロピル、シクロブチル、シクロペンチル等の直鎖状、分岐鎖状、環状、又はそれらの組み合わせのいずれであってもよく、好ましくはメチル、エチル、プロピル、ブチル、ペンチル、ヘキシル等の直鎖状、又はイソプロピル、イソブチル等の分岐鎖状である。   In the present specification, unless otherwise specified, an alkyl group and an alkyl part of a substituent containing an alkyl group part (such as an alkylcarbonyl group) are methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, tert- It may be any of linear, branched, cyclic, or combinations thereof such as butyl, isopentyl, neopentyl, tert-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, etc., preferably methyl, ethyl, propyl, butyl, They are linear such as pentyl and hexyl, or branched such as isopropyl and isobutyl.

アルケニル基、アルキニル基及びこれらの基部分を含む置換基のアルケニル又はアルキニル部分は、特に断らない限り、ビニル、1-プロペニル、2-プロペニル、イソプロペニル、1-ブテニル、2-ブテニル、1-プロピニル、2-プロピニル、プロパルギル、1-ブチニル、1-ペンチニル、2-ブチニル等の直鎖状、分岐鎖状、又はそれらの組み合わせのいずれであってもよく、好ましくは直鎖状である。アルケニル、アルキニル部分に含まれる二重結合又は三重結合の数と位置は特に限定されず、アルケニル部分に含まれる二重結合はシス配置又はトランス配置のいずれでもよい。さらに好ましくは、1-プロペニル、2-プロペニル、2-ブテニル、2-プロピニル等の直鎖状であり、アルケニル部分に含まれる二重結合はトランス配置である。   Unless otherwise specified, an alkenyl group, an alkynyl group, and an alkenyl or alkynyl part of a substituent containing these group parts are vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 1-propynyl. , 2-propynyl, propargyl, 1-butynyl, 1-pentynyl, 2-butynyl and the like may be linear, branched, or a combination thereof, and is preferably linear. The number and position of the double bond or triple bond contained in the alkenyl or alkynyl moiety is not particularly limited, and the double bond contained in the alkenyl moiety may be either cis configuration or trans configuration. More preferably, it is linear such as 1-propenyl, 2-propenyl, 2-butenyl, 2-propynyl, and the double bond contained in the alkenyl moiety is in the trans configuration.

本明細書において、アリール基とは、特に断らない限り、フェニル基、1-ナフチル基、2-ナフチル基等のヘテロ原子を含有しない6〜10員(単環式〜2環式)の芳香環を意味するが、好ましくは1-ナフチル基、2-ナフチル基等の10員(2環式)の芳香環である。ここで6〜10員のアリール基は、その環系中に6〜10個の炭素原子を有する。前記6〜10員のアリール基は、場合によりハロゲン原子、水酸基、アミノ基、ニトロ基、シアノ基、トリフルオロメチル基、C1〜6のアルキル基、C1〜6のアシル基、C1〜6のアルキルオキシカルボニル基、C1〜6のアシルオキシ基、ジメチルアミノ基、ジエチルアミノ基、C1〜6のアルコキシ基の中から選択した置換基1〜5個で置換されていてもよいが、好ましくはクロロ基、アミノ基、ニトロ基、メチル基、ジメチルアミノ基、メトキシ基の中から選択した置換基1個で置換されているものである。   In this specification, unless otherwise specified, an aryl group is a 6 to 10-membered (monocyclic to bicyclic) aromatic ring that does not contain a hetero atom such as a phenyl group, a 1-naphthyl group, and a 2-naphthyl group. However, it is preferably a 10-membered (bicyclic) aromatic ring such as a 1-naphthyl group and a 2-naphthyl group. Here, a 6-10 membered aryl group has 6-10 carbon atoms in its ring system. The 6- to 10-membered aryl group may optionally be a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, a trifluoromethyl group, a C1-6 alkyl group, a C1-6 acyl group, or a C1-6 alkyl group. It may be substituted with 1 to 5 substituents selected from oxycarbonyl group, C1-6 acyloxy group, dimethylamino group, diethylamino group, C1-6 alkoxy group, preferably chloro group, amino A group substituted with one substituent selected from a group, a nitro group, a methyl group, a dimethylamino group, and a methoxy group.

本明細書において、複素環基とは、特に断らない限り、ピリジン-3-イル基、ピリジン-4-イル基、ピリミジン-5 -イル基、キノリン-2-イル基、キノリン-3-イル基、キノリン-4-イル基、イソキノリン-1-イル基、イソキノリン-3-イル基、イソキノリン-4-イル基、キノキサリン-2-イル基、キノキサリン-6-イル基、1,5-ナフチリジン-3-イル基、1,6-ナフチリジン-8-イル基、イミダゾ[1,2-a]ピリジン-3-イル基、イミダゾ[1,2-a]ピリミジン-6-イル、ベンゾチアゾール-2-イル基、ベンゾチアゾール-6-イル基、ベンズオキサゾール-2-イル基、ベンズオキサゾール-5-イル基、ベンゾフラン-5-イル基、ベンゾチオフェン-5-イル基(ここで、結合位置は特にこれらに限定されない)等の、酸素原子、硫黄原子、及び窒素原子からそれぞれ選択したヘテロ原子1〜3個を含有する芳香族系の6〜10員(単環式〜2環式)の複素環を意味するが、好ましくは窒素原子1〜3個を含有する芳香族系の6〜10員(単環式〜2環式)の複素環である。さらに好ましくはピリジン-3-イル基、ピリジン-4-イル基、ピリミジン-5-イル基、キノリン-2-イル基、キノリン-3-イル基、キノリン-4-イル基、イソキノリン-1-イル基、イソキノリン-3-イル基、イソキノリン-4-イル基、キノキサリン-2-イル基、キノキサリン-6-イル基、1,5-ナフチリジン-3-イル基、1,6-ナフチリジン-8-イル基、イミダゾ[1,2-a]ピリジン-3-イル基、イミダゾ[1,2-a]ピリミジン-6-イルである。ここで6〜10員の複素環基は、その環系中に6〜10個の原子を有する。前記芳香族系の6〜10員の複素環基は、場合によりハロゲン原子、水酸基、アミノ基、ニトロ基、シアノ基、トリフルオロメチル基、C1〜6アルキル基、C1〜6アルキルカルボニル基、C1〜6アルキルオキシカルボニル基、C1〜6のアシルオキシ基、C1〜6のアシルアミノ基、ジメチルアミノ基、ジエチルアミノ基、C1〜6アルコキシ基の中から独立して選択した置換基1〜6個で置換されていてもよい。好ましくは、クロロ基、アミノ基、ニトロ基、メチル基、ジメチルアミノ基、メトキシ基、アセチルアミノ基の中から選択した置換基1〜2個で置換されているものである。   In the present specification, unless otherwise specified, the heterocyclic group means a pyridin-3-yl group, a pyridin-4-yl group, a pyrimidin-5-yl group, a quinolin-2-yl group, and a quinolin-3-yl group. Quinolin-4-yl group, isoquinolin-1-yl group, isoquinolin-3-yl group, isoquinolin-4-yl group, quinoxalin-2-yl group, quinoxalin-6-yl group, 1,5-naphthyridine-3 -Yl group, 1,6-naphthyridin-8-yl group, imidazo [1,2-a] pyridin-3-yl group, imidazo [1,2-a] pyrimidin-6-yl, benzothiazol-2-yl Group, benzothiazol-6-yl group, benzoxazol-2-yl group, benzoxazol-5-yl group, benzofuran-5-yl group, benzothiophen-5-yl group (where the bonding position is particularly Non-limiting) containing 1 to 3 heteroatoms each selected from oxygen, sulfur and nitrogen atoms Aromatic 6 to 10 membered (monocyclic to bicyclic) heterocycle, preferably aromatic 6 to 10 membered (monocyclic to 2) containing 1 to 3 nitrogen atoms (Cyclic) heterocycle. More preferably, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, isoquinolin-1-yl Group, isoquinolin-3-yl group, isoquinolin-4-yl group, quinoxalin-2-yl group, quinoxalin-6-yl group, 1,5-naphthyridin-3-yl group, 1,6-naphthyridin-8-yl A group, an imidazo [1,2-a] pyridin-3-yl group, an imidazo [1,2-a] pyrimidin-6-yl. Here, a 6-10 membered heterocyclic group has 6-10 atoms in its ring system. The aromatic 6-10 membered heterocyclic group is optionally a halogen atom, hydroxyl group, amino group, nitro group, cyano group, trifluoromethyl group, C1-6 alkyl group, C1-6 alkylcarbonyl group, C1 -6 alkyloxycarbonyl groups, C1-6 acyloxy groups, C1-6 acylamino groups, dimethylamino groups, diethylamino groups, C1-6 alkoxy groups independently substituted with 1-6 substituents It may be. Preferably, it is substituted with one or two substituents selected from chloro, amino, nitro, methyl, dimethylamino, methoxy, and acetylamino groups.

本明細書において、アシル基及びアシル基部分を含む置換基(例えばアセトキシ基等のアシルオキシ基)のアシル部分は、特に断らない限り、ホルミル基、アセチル基、プロピオニル基、ブチリル基、イソブチリル基、バレリル基、イソバレリル基等の、C2〜5の直鎖状又は分岐鎖状のアルキルカルボニル基を意味する。好ましくは、アセチル基、プロピオニル基、n-ブチリル基等である。   In this specification, unless otherwise specified, the acyl part of an acyl group and a substituent containing an acyl group part (for example, an acyloxy group such as an acetoxy group) is a formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group. Means a C2-5 linear or branched alkylcarbonyl group such as a group or an isovaleryl group. Preferred are acetyl group, propionyl group, n-butyryl group and the like.

本明細書において、水酸基の修飾基とは、1−エトキシエチル基の如きアセタール基等の水酸基の修飾基を意味する。   In the present specification, the hydroxyl modifying group means a hydroxyl modifying group such as an acetal group such as 1-ethoxyethyl group.

本明細書において、シリル系保護基とは、トリメチルシリル基、トリエチルシリル基、tert-ブチルジメチルシリル基、tert-ブチルジフェニルシリル基等の如く、水酸基を保護し、かつ選択的に除去し得ることが当該技術分野において公知である容易に除去可能な基を意味する。好ましくはtert-ブチルジメチルシリル基等である。   In the present specification, the silyl-based protecting group can protect and selectively remove a hydroxyl group such as a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, and the like. By means of an easily removable group known in the art. Preferred is a tert-butyldimethylsilyl group.

本明細書において、アセタール系保護基とは、特に断らない限り、ジメチルアセタール、ジエチルアセタール、ジイソプロピルアセタール等の非環状アセタール、又は、エチレンアセタール、プロピレンアセタール等の環状アセタールの如く、ホルミル基を保護し、かつ選択的に除去し得ることが当該技術分野において公知である容易に除去可能な基を意味する。好ましくは、ジメチルアセタール基等である。   In this specification, unless otherwise specified, an acetal-based protecting group protects a formyl group, such as acyclic acetals such as dimethyl acetal, diethyl acetal, and diisopropyl acetal, or cyclic acetals such as ethylene acetal and propylene acetal. And means an easily removable group known in the art to be selectively removable. Preferably, it is a dimethylacetal group or the like.

本明細書において、ハロゲン原子とは、特に断らない限り、フッ素、塩素、臭素又はヨウ素原子から選択した原子を意味する。好ましくは、塩素原子である。   In the present specification, a halogen atom means an atom selected from fluorine, chlorine, bromine or iodine atom unless otherwise specified. Preferably, it is a chlorine atom.

本発明による一般式(1)において、R1がアルキルカルボニル基で表される化合物は、下記工程図1に示す4工程を経て製造することができる。特に断らない限り、以下の工程図における(5a)〜(8a)で表される化合物のR2〜R6は、前記一般式(2)で表されたものと同じ意味を表す。これらの製造方法について、工程図1の第1〜第4工程に分けてそれぞれ工程毎にその詳細を説明する。In the general formula (1) according to the present invention, the compound in which R 1 is an alkylcarbonyl group can be produced through the four steps shown in the following process diagram 1. Unless otherwise specified, R 2 to R 6 of the compounds represented by (5a) to (8a) in the following process diagrams have the same meaning as that represented by the general formula (2). About these manufacturing methods, the detail is demonstrated for every process, dividing into the 1st-4th process of process drawing 1. FIG.

Figure 2007069555
Figure 2007069555

はじめに第1工程である式(5a)で表される化合物を出発原料として、式(6a)で表される化合物を製造する方法について述べる。式(5a)で表される化合物に対して、例えばジメチルホルムアミド溶媒中、モレキュラシーブス存在下、アミン類を加え、0〜50℃で1〜24時間撹拌した後、還元剤としてナトリウムボロヒドリドを用いた還元的アミノ化を実施することにより式(6a)で表される化合物が供給される。   First, a method for producing the compound represented by the formula (6a) using the compound represented by the formula (5a) as the starting material in the first step will be described. For example, an amine is added to the compound represented by the formula (5a) in a dimethylformamide solvent in the presence of molecular sieves and stirred at 0 to 50 ° C. for 1 to 24 hours, and then sodium borohydride is used as a reducing agent. By carrying out the reductive amination, the compound of formula (6a) is supplied.

本反応における還元剤は、ナトリウムボロヒドリド、ナトリウムトリアセトキシボロヒドリド又はナトリウムシアノボロヒドリド等が挙げられ、好ましくはナトリウムボロヒドリドを1〜5当量用いるとよい。本反応におけるアミン類とは、例えば(R)-7-メチルアミノ-1-ヘプテン-4-オール(WO2005/019238、参考例22)等が挙げられる。上記アミン類は、塩酸等の無機酸あるいは酢酸等の有機酸と塩を形成していてもよく、0.8〜7当量用いるとよい。モレキュラシーブスは、式(5a)で表される化合物に対して、1倍量(W/W)〜10倍量(W/W)用いるとよい。溶媒としては、メタノール、エタノール、イソプロパノール等の低級アルコール、アセトニトリル、テトラヒドロフラン、塩化メチレン、ジメチルホルムアミド等が挙げられ、好ましくはジメチルホルムアミドである。溶媒は、式(5a)で表される化合物に対して、1倍量(V/W)〜50倍量(V/W)用いるとよい。反応は0℃〜50℃の範囲で進行し、反応時間は0.5時間〜24時間である。   Examples of the reducing agent in this reaction include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like, and preferably 1 to 5 equivalents of sodium borohydride is used. Examples of amines in this reaction include (R) -7-methylamino-1-hepten-4-ol (WO2005 / 019238, Reference Example 22). The amines may form a salt with an inorganic acid such as hydrochloric acid or an organic acid such as acetic acid, and 0.8 to 7 equivalents are preferably used. Molecular sieves may be used in an amount of 1-fold (W / W) to 10-fold (W / W) with respect to the compound represented by formula (5a). Examples of the solvent include lower alcohols such as methanol, ethanol and isopropanol, acetonitrile, tetrahydrofuran, methylene chloride, dimethylformamide, and the like, and dimethylformamide is preferable. The solvent is preferably used in a 1-fold amount (V / W) to 50-fold amount (V / W) with respect to the compound represented by the formula (5a). The reaction proceeds in the range of 0 ° C. to 50 ° C., and the reaction time is 0.5 to 24 hours.

また、式(6a)で表される化合物は以下の方法でも製造することが可能である。式(5a)で表される化合物に対して、例えばモレキュラシーブス存在下又は非存在下、エタノール溶媒中、酢酸及びアミン類を加え、還元剤としてナトリウムシアノボロヒドリドを用いた還元的アミノ化を実施することにより式(6a)で表される化合物が供給される。   The compound represented by the formula (6a) can also be produced by the following method. The compound represented by formula (5a) is subjected to reductive amination using sodium cyanoborohydride as a reducing agent by adding acetic acid and amines in an ethanol solvent in the presence or absence of molecular sieves, for example. By doing so, the compound represented by the formula (6a) is supplied.

本反応における還元剤は、ナトリウムボロヒドリド、ナトリウムトリアセトキシボロヒドリド又はナトリウムシアノボロヒドリド等が挙げられ、好ましくはナトリウムトリアセトキシボロヒドリド又はナトリウムシアノボロヒドリドを1〜10当量用いるとよい。本反応におけるアミン類とは、例えば(R)-7-メチルアミノ-1-ヘプテン-4-オール(WO2005/019238、参考例22)等が挙げられる。上記アミン類は、塩酸等の無機酸又は酢酸等の有機酸と塩を形成していてもよく、0.8〜7当量用いるとよい。また添加する酸としては、酢酸、塩酸等が挙げられ、好ましくは酢酸を1〜30当量用いるとよい。溶媒としては、メタノール、エタノール、イソプロパノール等の低級アルコール、ジメチルホルムアミド、アセトニトリル、テトラヒドロフラン、塩化メチレン、1,2-ジクロロエタン等が挙げられ、好ましくはエタノール又は1,2-ジクロロエタン等である。溶媒は、式(5a)で表される化合物に対して、1倍量(V/W)〜50倍量(V/W)用いるとよい。反応は0℃〜50℃の範囲で進行し、反応時間は0.5時間〜48時間である。ここで上記還元的アミノ化反応の実施により、式(6a)においてR3が水素原子で表される化合物が生成する場合、上記還元的アミノ化反応に続いて以下の還元的アルキル化反応を実施することにより、式(5a)で表される化合物からone-potで水素原子以外の置換基R3を導入することが可能である。即ち上記還元的アミノ化反応を実施した後、反応液を後処理することなく、反応液にアルデヒド類を加え、還元剤としてナトリウムシアノボロヒドリドを用いた還元的アルキル化反応を実施することにより、式(6a)において水素原子以外の置換基R3が導入される。
還元的アルキル化反応における還元剤は、ナトリウムトリアセトキシボロヒドリド又はナトリウムシアノボロヒドリド等が挙げられ、好ましくはナトリウムシアノボロヒドリドを式(5a)で表される化合物に対して、1〜5当量用いるとよい。本反応におけるアルデヒド類とは、例えばtert-ブチル N-(2-オキソエチル)カーバメート、ホルムアルデヒド(水溶液)等が挙げられる。反応は0℃〜80℃の範囲で進行し、反応時間は0.5時間〜24時間である。
Examples of the reducing agent in this reaction include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, and the like. Preferably, 1 to 10 equivalents of sodium triacetoxyborohydride or sodium cyanoborohydride are used. Examples of amines in this reaction include (R) -7-methylamino-1-hepten-4-ol (WO2005 / 019238, Reference Example 22). The amines may form a salt with an inorganic acid such as hydrochloric acid or an organic acid such as acetic acid, and 0.8 to 7 equivalents are preferably used. Examples of the acid to be added include acetic acid and hydrochloric acid. Preferably, 1 to 30 equivalents of acetic acid is used. Examples of the solvent include lower alcohols such as methanol, ethanol and isopropanol, dimethylformamide, acetonitrile, tetrahydrofuran, methylene chloride, 1,2-dichloroethane, and the like, preferably ethanol or 1,2-dichloroethane. The solvent is preferably used in a 1-fold amount (V / W) to 50-fold amount (V / W) with respect to the compound represented by the formula (5a). The reaction proceeds in the range of 0 ° C to 50 ° C, and the reaction time is 0.5 to 48 hours. When the reductive amination reaction produces a compound in which R 3 is a hydrogen atom in formula (6a), the following reductive alkylation reaction is carried out following the reductive amination reaction. By doing so, it is possible to introduce a substituent R 3 other than a hydrogen atom in one-pot from the compound represented by the formula (5a). That is, after carrying out the above reductive amination reaction, aldehydes are added to the reaction solution without post-treatment of the reaction solution, and a reductive alkylation reaction using sodium cyanoborohydride as a reducing agent is performed. In the formula (6a), a substituent R 3 other than a hydrogen atom is introduced.
Examples of the reducing agent in the reductive alkylation reaction include sodium triacetoxyborohydride or sodium cyanoborohydride, and preferably 1 to 5 equivalents of sodium cyanoborohydride is used with respect to the compound represented by the formula (5a). Good. Examples of aldehydes in this reaction include tert-butyl N- (2-oxoethyl) carbamate and formaldehyde (aqueous solution). The reaction proceeds in the range of 0 ° C. to 80 ° C., and the reaction time is 0.5 hour to 24 hours.

続いて式(7a)で表される化合物を製造する第2工程について述べる。式(6a)で表される化合物に対して、例えばテトラヒドロフラン溶媒中、トリエチルアミン存在下、2,4,6-トリクロロベンゾイルクロライドを加え、0〜50℃で1〜24時間撹拌することで混合酸無水物を調製する。0〜50℃で4-ジメチルアミノピリジンのトルエン溶液に、先に調製した混合酸無水物を5分〜1時間かけて滴下し、閉環反応を実施することにより式(7a)で表される化合物が供給される。   Subsequently, the second step for producing the compound represented by the formula (7a) will be described. For example, 2,4,6-trichlorobenzoyl chloride is added to the compound represented by the formula (6a) in a tetrahydrofuran solvent in the presence of triethylamine, and the mixture is stirred at 0 to 50 ° C. for 1 to 24 hours to obtain a mixed acid anhydride. Prepare the product. The compound represented by the formula (7a) is obtained by dropping the previously prepared mixed acid anhydride into a toluene solution of 4-dimethylaminopyridine at 0 to 50 ° C. over 5 minutes to 1 hour, and carrying out a ring closure reaction. Is supplied.

混合酸無水物調製における溶媒としては、テトラヒドロフラン、塩化メチレン、トルエン、ベンゼン等が挙げられ、好ましくはテトラヒドロフランを式(6a)で表される化合物に対して、5〜50倍量(W/W)用いるとよい。トリエチルアミンは1〜5当量用いるとよい。2,4,6-トリクロロベンゾイルクロライドは、1〜2当量用いるとよい。続く閉環反応に用いる4-ジメチルアミノピリジンは、1〜5当量用いるとよい。溶媒としては、トルエン、ベンゼン等が挙げられ、好ましくはトルエンである。溶媒は、式(6a)で表される化合物に対して、50〜300倍量(W/W)用いるとよい。反応は0〜80℃の範囲で進行し、反応時間は0.5〜24時間である。   Examples of the solvent for preparing the mixed acid anhydride include tetrahydrofuran, methylene chloride, toluene, benzene and the like, and preferably 5 to 50 times (W / W) of tetrahydrofuran with respect to the compound represented by the formula (6a). Use it. It is recommended to use 1 to 5 equivalents of triethylamine. 1,2 to 6 equivalents of 2,4,6-trichlorobenzoyl chloride may be used. 4-Dimethylaminopyridine used in the subsequent ring closure reaction is preferably used in an amount of 1 to 5 equivalents. Examples of the solvent include toluene, benzene and the like, preferably toluene. The solvent is preferably used in an amount of 50 to 300 times (W / W) with respect to the compound represented by the formula (6a). The reaction proceeds in the range of 0 to 80 ° C., and the reaction time is 0.5 to 24 hours.

また、式(7a)で表される化合物は以下の方法でも製造することが可能である。例えば、2-メチル-6-ニトロ安息香酸無水物及び4-ジメチルアミノピリジンの塩化メチレン溶液に、式(6a)で表される化合物の塩化メチレン溶液をゆっくりと滴下し、閉環反応を実施することにより式(7a)で表される化合物が供給される。   The compound represented by the formula (7a) can also be produced by the following method. For example, a methylene chloride solution of the compound represented by formula (6a) is slowly dropped into a methylene chloride solution of 2-methyl-6-nitrobenzoic anhydride and 4-dimethylaminopyridine to carry out a ring-closing reaction. Supplies the compound represented by the formula (7a).

本反応における塩基としては、4-ジメチルアミノピリジン-1-オキシド、4-ピロリジノピリジン-1-オキシド等を単独で2〜5当量用いてもよく、又はトリエチルアミンの2〜5当量に加えて、4-ジメチルアミノピリジン、4-ジメチルアミノピリジン-1-オキシド、4-ピロリジノピリジン、4-ピロリジノピリジン-1-オキシド等を0.1〜0.5当量用いてもよいが、好ましくは4-ジメチルアミノピリジンを2〜5当量用いるとよい。2-メチル-6-ニトロ安息香酸無水物は1〜2当量用いるとよい。溶媒としては、塩化メチレン、テトラヒドロフラン、トルエン、ベンゼン等が挙げられ、好ましくは塩化メチレン又はテトラヒドロフランを式(6a)で表される化合物に対して10〜600倍量(W/W)用いるとよい。また、式(6a)で表される化合物の塩化メチレン又はテトラヒドロフラン溶液は、0〜50℃で20分〜5時間かけて滴下すればよく、滴下後の反応は0〜50℃の範囲で進行し、反応時間は0.5〜24時間である。   As a base in this reaction, 4-dimethylaminopyridine-1-oxide, 4-pyrrolidinopyridine-1-oxide and the like may be used alone in 2 to 5 equivalents, or in addition to 2 to 5 equivalents of triethylamine, 4-dimethylaminopyridine, 4-dimethylaminopyridine-1-oxide, 4-pyrrolidinopyridine, 4-pyrrolidinopyridine-1-oxide and the like may be used in an amount of 0.1 to 0.5 equivalents, preferably 4-dimethylaminopyridine. 2 to 5 equivalents should be used. It is recommended to use 1 to 2 equivalents of 2-methyl-6-nitrobenzoic anhydride. Examples of the solvent include methylene chloride, tetrahydrofuran, toluene, benzene and the like. Preferably, methylene chloride or tetrahydrofuran is used in an amount of 10 to 600 times (W / W) with respect to the compound represented by the formula (6a). Further, the methylene chloride or tetrahydrofuran solution of the compound represented by the formula (6a) may be dropped at 0-50 ° C. over 20 minutes to 5 hours, and the reaction after dropping proceeds in the range of 0-50 ° C. The reaction time is 0.5 to 24 hours.

次に式(8a)で表される化合物を製造する第3工程について述べる。封管中、式(7a)で表される化合物に対して、塩基存在下、アルキルイソシアネートと反応させることで中性糖部4”位をカルバモイル化した式(8a)で表される化合物が供給される。   Next, the third step for producing the compound represented by the formula (8a) will be described. In the sealed tube, the compound represented by the formula (7a) is supplied with the compound represented by the formula (8a) in which the neutral sugar part 4 ″ is carbamoylated by reacting with the alkyl isocyanate in the presence of a base. Is done.

本反応では、4”位プロピオニル基が3”位に転移した後、フリーとなった4”位水酸基にアルキルイソシアネートが反応する。   In this reaction, after the 4 ″ -propionyl group is transferred to the 3 ″ position, alkyl isocyanate reacts with the free 4 ″ position hydroxyl group.

本反応における塩基としては、1,4-ジアザビシクロ[2.2.2]オクタン、ピリジン、N-メチルモルホリン、N-メチルピペリジン、トリエチルアミン、N,N,N',N'-テトラメチル-1,3-プロパンジアミン、N,N-ジメチルシクロヘキシルアミン、キニン、1,2-ジメチルイミダゾール等が挙げられ、好ましくは1,4-ジアザビシクロ[2.2.2]オクタン又はピリジンを1〜50当量用いるとよい。アルキルイソシアネートは式(7a)で表される化合物に対して、5〜100当量用いるとよい。溶媒としては、ベンゼン、トルエン、アセトニトリル、テトラヒドロフラン等を式(7a)で表される化合物に対して、0〜50倍量(V/W)用いてもよいが、好ましくは無溶媒がよい。無溶媒の場合、式(7a)で表される化合物に対して、ピリジンを1〜50倍量(V/W)用いるのみでもよいが、好ましくは共塩基として1,4-ジアザビシクロ[2.2.2]オクタン等の上記塩基を式(7a)で表される化合物に対して、1〜50当量用いるとよい。反応は0℃〜115℃の範囲で進行し、反応時間は1時間〜72時間である。   As the base in this reaction, 1,4-diazabicyclo [2.2.2] octane, pyridine, N-methylmorpholine, N-methylpiperidine, triethylamine, N, N, N ′, N′-tetramethyl-1,3- Examples thereof include propanediamine, N, N-dimethylcyclohexylamine, quinine, 1,2-dimethylimidazole, and preferably 1 to 50 equivalents of 1,4-diazabicyclo [2.2.2] octane or pyridine is used. The alkyl isocyanate is preferably used in an amount of 5 to 100 equivalents with respect to the compound represented by the formula (7a). As the solvent, benzene, toluene, acetonitrile, tetrahydrofuran and the like may be used in an amount of 0 to 50 times (V / W) based on the compound represented by the formula (7a), but preferably no solvent is used. In the absence of a solvent, the pyridine may be used in an amount of 1 to 50 times (V / W) based on the compound represented by the formula (7a), but 1,4-diazabicyclo [2.2.2] It is good to use 1-50 equivalent of said bases, such as octane, with respect to the compound represented by Formula (7a). The reaction proceeds in the range of 0 ° C. to 115 ° C., and the reaction time is 1 hour to 72 hours.

また、式(8a)で表される化合物は以下の方法でも製造することが可能である。封管中、式(7a)で表される化合物に対して、塩基存在下、1,1'-カルボニルジイミダゾールと作用させることで以下の一般式(9)で表されるイミダゾライドとした後、アミン類を用いた求核置換反応により当該化合物が供給される。   The compound represented by the formula (8a) can also be produced by the following method. In a sealed tube, the compound represented by the formula (7a) is reacted with 1,1′-carbonyldiimidazole in the presence of a base to obtain an imidazolide represented by the following general formula (9). The compound is supplied by a nucleophilic substitution reaction using amines.

Figure 2007069555
Figure 2007069555

イミダゾライド化における塩基は、1,4-ジアザビシクロ[2.2.2]オクタン、N-メチルモルホリン、N-メチルピペリジン、トリエチルアミン、N,N,N',N'-テトラメチル-1,3-プロパンジアミン、N,N-ジメチルシクロヘキシルアミン、キニン、1,2-ジメチルイミダゾール等が挙げられ、好ましくは1,4-ジアザビシクロ[2.2.2]オクタンを式(7a)で表される化合物に対して、1〜50当量用いるとよい。1,1'-カルボニルジイミダゾールは式(7a)で表される化合物に対して、1〜30当量用いるとよい。溶媒としては、ベンゼン、トルエン、アセトニトリル、テトラヒドロフラン等が挙げられ、式(7a)で表される化合物に対して、1〜50倍量(V/W)用いてもよいが、好ましくは無溶媒がよい。無溶媒の場合、式(7a)で表される化合物に対して、ピリジンを1〜50倍量(V/W)用いるのみでもよいが、好ましくは共塩基として1,4-ジアザビシクロ[2.2.2]オクタン等の上記塩基を式(7a)で表される化合物に対して、1〜50当量用いるとよい。反応は0℃〜100℃の範囲で進行し、反応時間は0.5時間〜24時間である。   Bases in imidazolide formation are 1,4-diazabicyclo [2.2.2] octane, N-methylmorpholine, N-methylpiperidine, triethylamine, N, N, N ', N'-tetramethyl-1,3-propanediamine N, N-dimethylcyclohexylamine, quinine, 1,2-dimethylimidazole and the like, and preferably 1,4-diazabicyclo [2.2.2] octane is 1 to the compound represented by the formula (7a). It is good to use ~ 50 equivalents. 1,1′-carbonyldiimidazole is preferably used in an amount of 1 to 30 equivalents with respect to the compound represented by the formula (7a). Examples of the solvent include benzene, toluene, acetonitrile, tetrahydrofuran, and the like. The compound represented by the formula (7a) may be used in an amount of 1 to 50 times (V / W). Good. In the absence of a solvent, the pyridine may be used in an amount of 1 to 50 times (V / W) based on the compound represented by the formula (7a), but 1,4-diazabicyclo [2.2.2] It is good to use 1-50 equivalent of said bases, such as octane, with respect to the compound represented by Formula (7a). The reaction proceeds in the range of 0 ° C. to 100 ° C., and the reaction time is 0.5 hour to 24 hours.

次の求核置換反応におけるアミン類は、塩酸等の無機酸あるいは酢酸等の有機酸と塩を形成していてもよく、1〜30当量用いるとよい。アミン類とは、例えばメチルアミン、ジメチルアミン、2-ヒドロキシエチルアミン等が挙げられる。またアミン類が無機酸又は有機酸と塩を形成している場合、塩基を用いるとよい。この塩基としては、トリエチルアミン、ジイソプロピルエチルアミン等が挙げられ、好ましくはトリエチルアミンを1〜30当量用いるとよい。溶媒としては、ジメチルホルムアミド、アセトニトリル、テトラヒドロフラン、塩化メチレン、1,2-ジクロロエタン等が挙げられ、好ましくはジメチルホルムアミドを式(9)に対して、1倍量(V/W)〜50倍量(V/W)用いるとよい。反応は-30℃〜50℃の範囲で進行し、反応時間は1時間〜48時間である。   The amines in the next nucleophilic substitution reaction may form a salt with an inorganic acid such as hydrochloric acid or an organic acid such as acetic acid, and 1 to 30 equivalents are preferably used. Examples of amines include methylamine, dimethylamine, 2-hydroxyethylamine and the like. In the case where amines form a salt with an inorganic acid or an organic acid, a base may be used. Examples of the base include triethylamine, diisopropylethylamine and the like, and preferably 1 to 30 equivalents of triethylamine is used. Examples of the solvent include dimethylformamide, acetonitrile, tetrahydrofuran, methylene chloride, 1,2-dichloroethane, and the like. Preferably, dimethylformamide is used in an amount (V / W) to 50 times (V / W) to formula (9) ( V / W) should be used. The reaction proceeds in the range of −30 ° C. to 50 ° C., and the reaction time is 1 hour to 48 hours.

最後に、式(1)で表される本発明の化合物を製造する第4工程について述べる。式(8a)で表される化合物のマイカミノース部分における2'位アセチル基の脱保護は、メタノール又はメタノール-水の混合溶媒中で進行する。反応は0〜80℃の範囲で進行し、反応時間は1時間〜5日間である。ここで、式(8a)で表される化合物のR2がアセチル基である場合、反応条件によっては、2'位の脱アセチル化と同時に、R2の除去が可能である。Finally, the fourth step for producing the compound of the present invention represented by the formula (1) will be described. The deprotection of the 2′-position acetyl group in the micaminose moiety of the compound represented by formula (8a) proceeds in a methanol or methanol-water mixed solvent. The reaction proceeds in the range of 0 to 80 ° C., and the reaction time is 1 hour to 5 days. Here, when R 2 of the compound represented by the formula (8a) is an acetyl group, depending on the reaction conditions, R 2 can be removed simultaneously with deacetylation at the 2′-position.

次いでアセトニトリル及び水との混合溶媒中でジフルオロ酢酸との反応により式(8a)におけるアセタール系保護基を除去して、式(1)で表される本発明の化合物が供給される。溶媒として用いるアセトニトリル及び水の等量混合溶液は、式(8a)で表される化合物に対して、10〜300倍量(V/W)用いるとよい。酸としては、モノフルオロ酢酸、ジフルオロ酢酸、トリフルオロ酢酸、塩酸が挙げられ、好ましくはジフルオロ酢酸を1〜100当量、又は塩酸を1〜50当量用いるとよい。反応は0〜50℃の範囲で進行し、反応時間は1時間〜10日間である。ここで、式(8a)で表される化合物のR2が、1-エトキシエチル基の如きアセタール基等の水酸基の修飾基である場合、本反応により、R2の除去が可能である。Next, the acetal protecting group in formula (8a) is removed by reaction with difluoroacetic acid in a mixed solvent of acetonitrile and water to supply the compound of the present invention represented by formula (1). An equivalent mixed solution of acetonitrile and water used as a solvent is preferably used in an amount of 10 to 300 times (V / W) with respect to the compound represented by the formula (8a). Examples of the acid include monofluoroacetic acid, difluoroacetic acid, trifluoroacetic acid, and hydrochloric acid. Preferably, 1 to 100 equivalents of difluoroacetic acid or 1 to 50 equivalents of hydrochloric acid are used. The reaction proceeds in the range of 0 to 50 ° C., and the reaction time is 1 hour to 10 days. Here, when R 2 of the compound represented by the formula (8a) is a hydroxyl-modified group such as an acetal group such as 1-ethoxyethyl group, R 2 can be removed by this reaction.

次に一般式(1)で表される本発明の化合物において、R1が水素原子で表される化合物は、下記工程図2に示す7工程を経て製造することができる。特に断らない限り、以下の工程図におけるR2〜R6は、一般式(1)以外の化合物においては前記一般式(3)で表されたものと同じ意味を表す。これらの製造方法について、工程図2の第1〜第7工程に分けてそれぞれ工程毎にその詳細を説明する。Next, in the compound of the present invention represented by the general formula (1), the compound in which R 1 is a hydrogen atom can be produced through 7 steps shown in the following process diagram 2. Unless otherwise specified, R 2 to R 6 in the following process diagrams have the same meaning as that represented by the general formula (3) in the compounds other than the general formula (1). About these manufacturing methods, the detail is demonstrated for every process in 1st-7th process of process drawing 2. FIG.

Figure 2007069555
Figure 2007069555

はじめに式(11)で表される化合物を製造する第1工程について述べる。式(10)で表される化合物に対して、例えば触媒量の金属酸化剤存在下、アセトンと水の混合溶媒中、共酸化剤としてN-メチルモルホリン-N-オキシドを用いて反応させるとよい。用いる金属酸化剤としては、四酸化オスミウム、オスミウム(VI)酸カリウム二水和物等が挙げられ、好ましくは四酸化オスミウムを0.05〜1当量用いるのがよい。共酸化剤としては、トリメチルアミン-N-オキシド、ヘキサシアノ鉄(III)酸カリウム、酢酸テトラエチルアンモニウム等の4級アンモニウム塩存在下又は非存在下に、塩素酸ナトリウム、塩素酸銀、塩素酸バリウム等の塩素酸塩、過酸化水素、tert-ブチルヒドロペルオキシド、 N-メチルモルホリン-N-オキシド等を用いることができるが、好ましくは、N-メチルモルホリン-N-オキシドを1〜5当量用いるとよい。また溶媒としては、アセトンと水の混合溶媒の他、アセトニトリル、テトラヒドロフラン(THF)、塩化メチレン、tert-ブチルアルコール、ジエチルエーテル、tert-ブチルアルコールと水の混合溶媒、THFと水の混合溶媒等が挙げられ、好ましくはアセトンと水の混合溶媒を式(10)で表される化合物に対して、1倍量(V/W)〜50倍量(V/W)用いるとよい。反応は0℃〜50℃の範囲で進行し、反応時間は3時間〜3日間である。   First, the first step for producing the compound represented by the formula (11) will be described. The compound represented by formula (10) may be reacted with N-methylmorpholine-N-oxide as a co-oxidant in a mixed solvent of acetone and water, for example, in the presence of a catalytic amount of a metal oxidant. . Examples of the metal oxidizing agent to be used include osmium tetroxide, potassium osmium (VI) acid dihydrate and the like, and preferably 0.05 to 1 equivalent of osmium tetroxide is used. Co-oxidants include sodium chlorate, silver chlorate, barium chlorate, etc. in the presence or absence of quaternary ammonium salts such as trimethylamine-N-oxide, potassium hexacyanoferrate (III), and tetraethylammonium acetate. Although chlorate, hydrogen peroxide, tert-butyl hydroperoxide, N-methylmorpholine-N-oxide and the like can be used, 1 to 5 equivalents of N-methylmorpholine-N-oxide are preferably used. Solvents include mixed solvent of acetone and water, acetonitrile, tetrahydrofuran (THF), methylene chloride, tert-butyl alcohol, diethyl ether, mixed solvent of tert-butyl alcohol and water, mixed solvent of THF and water, etc. Preferably, a mixed solvent of acetone and water is used in an amount of 1-fold amount (V / W) to 50-fold amount (V / W) with respect to the compound represented by formula (10). The reaction proceeds in the range of 0 ° C. to 50 ° C., and the reaction time is 3 hours to 3 days.

次に、式(12)で表される化合物を製造する第2工程について述べる。式(11)で表される化合物に対して、例えばベンゼン溶媒中、無機塩基存在下、酸化剤として四酢酸鉛を用いて反応させるとよい。   Next, the second step for producing the compound represented by the formula (12) will be described. The compound represented by the formula (11) may be reacted with, for example, lead tetraacetate as an oxidizing agent in a benzene solvent in the presence of an inorganic base.

本反応に用いる酸化剤としては、メタ過ヨウ素酸ナトリウム等の過酸又は活性二酸化マンガン、ピリジニウムクロロクロメート、四酢酸鉛等が挙げられ、好ましくは四酢酸鉛を1〜5当量用いるとよい。四酢酸鉛による反応に用いる溶媒としては、ベンゼン、トルエン、キシレン、塩化メチレン等の非プロトン性溶媒が好ましい。またメタ過ヨウ素酸等の過酸による反応に用いる溶媒としては、水又はエーテル-水、塩化メチレン-水等の混合溶媒でもよい。本反応における塩基としては、炭酸水素ナトリウム、炭酸ナトリウム、炭酸水素カリウム、炭酸カリウム等の無機塩基を1〜15当量用いるとよい。反応は0℃〜50℃の範囲で進行し、反応時間は5分〜24時間である。なお本反応で供給される式(12)で表される化合物は、精製することなく以下の第3工程に用いる。   Examples of the oxidizing agent used in this reaction include peracids such as sodium metaperiodate, activated manganese dioxide, pyridinium chlorochromate, lead tetraacetate and the like, and preferably 1 to 5 equivalents of lead tetraacetate is used. As a solvent used for the reaction with lead tetraacetate, an aprotic solvent such as benzene, toluene, xylene, methylene chloride or the like is preferable. The solvent used for the reaction with a peracid such as metaperiodic acid may be water or a mixed solvent such as ether-water or methylene chloride-water. As a base in this reaction, it is good to use 1-15 equivalent of inorganic bases, such as sodium hydrogencarbonate, sodium carbonate, potassium hydrogencarbonate, potassium carbonate. The reaction proceeds in the range of 0 ° C. to 50 ° C., and the reaction time is 5 minutes to 24 hours. In addition, the compound represented by Formula (12) supplied by this reaction is used for the following 3rd processes, without refine | purifying.

続いて式(5b)で表される化合物を製造する第3工程について述べる。式(12)で表される化合物に対して、例えばベンゼンと酢酸エチルの混合溶媒中、塩基を作用させることにより式(5b)で表される化合物が供給される。   Subsequently, the third step for producing the compound represented by the formula (5b) will be described. For example, a compound represented by the formula (5b) is supplied to the compound represented by the formula (12) by allowing a base to act in a mixed solvent of benzene and ethyl acetate.

本反応における塩基は、1,8-ジアザビシクロ[5.4.0]-ウンデカン-7-エン、1,5-ジアザビシクロ[4.3.0]-ノナン-5-エン、1,4-ジアザビシクロ[2.2.2]-オクタン、4-ジメチルアミノピリジン等が挙げられ、好ましくは1,8-ジアザビシクロ[5.4.0]-ウンデカン-7-エンを1〜5当量用いるとよい。溶媒としては、ベンゼンと酢酸エチルの混合溶媒、メタノール、エタノール、イソプロパノール等の低級アルコール、テトラヒドロフラン、塩化メチレン、アセトニトリル、ベンゼン又は酢酸エチル等が挙げられ、好ましくはベンゼンと酢酸エチルの混合溶媒であり、式(12)で表される化合物に対して、5倍量(V / W)〜300倍量(V/W)用いるとよい。反応は0℃〜50℃の範囲で進行し、反応時間は0.5時間〜24時間である。   Bases in this reaction are 1,8-diazabicyclo [5.4.0] -undecan-7-ene, 1,5-diazabicyclo [4.3.0] -nonane-5-ene, 1,4-diazabicyclo [2.2.2]. -Octane, 4-dimethylaminopyridine and the like can be mentioned, and preferably 1 to 5 equivalents of 1,8-diazabicyclo [5.4.0] -undecan-7-ene is used. Examples of the solvent include a mixed solvent of benzene and ethyl acetate, lower alcohols such as methanol, ethanol, and isopropanol, tetrahydrofuran, methylene chloride, acetonitrile, benzene, and ethyl acetate, preferably a mixed solvent of benzene and ethyl acetate, It is good to use 5 times amount (V / W)-300 times amount (V / W) with respect to the compound represented by Formula (12). The reaction proceeds in the range of 0 ° C. to 50 ° C., and the reaction time is 0.5 to 24 hours.

工程図2に従って製造した式(5b)で表される化合物は、次の第4〜第6工程、即ち、前記工程図1の第1〜第3工程と同様の方法を用いて式(8b)で表される化合物へと誘導される。   The compound represented by the formula (5b) produced according to the process diagram 2 is represented by the formula (8b) using the same method as the following fourth to sixth steps, that is, the first to third steps of the process diagram 1 described above. It is induced | guided | derived to the compound represented by these.

最後に、第7工程であるが、前記工程図1の第4工程と同様の方法を用いて、式(8b)で表される化合物のマイカミノース部分における2'位アセチル基の脱保護(ここで、式(8b)で表される化合物のR2がアセチル基である場合、反応条件によっては、2'位の脱アセチル化と同時に、R2の除去が可能である)に続く、酸を用いたシリル系保護基の除去により式(1)で表される本発明の化合物が供給される。ここで、式(8b)で表される化合物のR2が、1-エトキシエチル基の如きアセタール基等の水酸基の修飾基である場合、シリル系保護基の除去と同時にR2の除去が可能である。Finally, in the seventh step, the deprotection of the 2′-position acetyl group in the micaminose moiety of the compound represented by the formula (8b) is carried out using the same method as in the fourth step of the above-mentioned process diagram 1 (here In the case where R 2 of the compound represented by the formula (8b) is an acetyl group, depending on the reaction conditions, R 2 can be removed at the same time as the 2′-position deacetylation). The compound of the present invention represented by the formula (1) is supplied by removing the silyl protecting group. Here, when R 2 of the compound represented by the formula (8b) is a hydroxyl modifying group such as an acetal group such as 1-ethoxyethyl group, it is possible to remove R 2 at the same time as removal of the silyl protecting group It is.

ここで工程図1あるいは2に示した製造方法に従って閉環反応に付すことで、下記に示したようなアリール基及び複素環基を有する式(17a)、式(18a)又は、式(17b)、式(18b)で表される化合物を製造することが可能である。また、後述する工程図3又は工程図4のごとく、閉環後にアリール基及び複素環基を導入することにより、式(17a)、式(18a)又は、式(17b)及び式(18b)で表される化合物へと誘導することもできる。特に断らない限り、以下の工程図におけるR1〜R3、 R5、R6、R11及びArは一般式(3)で表されたものと同じ意味を表す。これらの製造方法について、工程図3及び工程図4の第1〜第6工程に分けてそれぞれ工程毎にその詳細を説明する。Here, by subjecting to a ring-closing reaction according to the production method shown in the process diagram 1 or 2, the formula (17a), the formula (18a) or the formula (17b) having an aryl group and a heterocyclic group as shown below, It is possible to produce a compound represented by the formula (18b). In addition, as shown in Step 3 or Step 4 to be described later, by introducing an aryl group and a heterocyclic group after ring closure, it is represented by Formula (17a), Formula (18a), Formula (17b), or Formula (18b). Can also be derived into the compound. Unless otherwise specified, R 1 to R 3 , R 5 , R 6 , R 11 and Ar in the following process diagrams have the same meaning as that represented by the general formula (3). About these manufacturing methods, it divides into the 1st-6th process of process figure 3 and process figure 4, and explains the details for every process, respectively.

Figure 2007069555
Figure 2007069555

Figure 2007069555
Figure 2007069555

はじめに工程図3及び工程図4の第1工程について述べる。工程図1及び工程図2に従って製造した式(13a)および式(13b)で表される化合物から、工程図1の第3工程と同様の方法を用いて式(14a)または式(14b)で表される化合物へと誘導される。   First, the first step in the process diagrams 3 and 4 will be described. From the compound represented by the formula (13a) and the formula (13b) produced according to the process diagram 1 and the process diagram 2, using the same method as the third process of the process diagram 1, the formula (14a) or the formula (14b) To the compound represented.

次に、式(15a)及び式(15b)で表される化合物を製造する第2工程について述べる。式(14a)又は式(14b)で表される化合物に対して、塩基及びホスフィン配位子存在下、パラジウム触媒を用いたハロゲン化合物とのHeck反応(Acc. Chem. Res. 1995, 28, 2-7、J. Am. Chem. Soc. 2001, 123, 6989-7000)を実施することにより式(15a)及び式(15b)で表される化合物が供給される。Next, the second step for producing the compounds represented by formula (15a) and formula (15b) will be described. Heck reaction (Acc. Chem. Res. 1995, 28 , 2) with a halogen compound using a palladium catalyst in the presence of a base and a phosphine ligand for the compound represented by formula (14a) or (14b). -7, J. Am. Chem. Soc. 2001, 123 , 6989-7000), the compounds represented by formula (15a) and formula (15b) are supplied.

本反応には、トリス(ジベンジリデンアセトン)ジパラジウム(0)、テトラキス(トリフェニルホスフィン)パラジウム(0)、パラジウム(II)クロライド又はパラジウム(II)アセテート等、通常のHeck反応に用いることのできるパラジウム触媒を用いることが可能であるが、好ましくはトリス(ジベンジリデンアセトン)ジパラジウム(0)を0.05〜0.6当量用いるとよい。本反応で用いる塩基としては、ジシクロヘキシルメチルアミン、トリエチルアミン、炭酸水素ナトリウム、炭酸ナトリウム又は炭酸セシウム等が挙げられ、好ましくはジシクロヘキシルメチルアミンを1〜5当量用いるとよい。本反応で用いるホスフィン配位子は、トリ-t-ブチルホスフィン、トリ-o-トリルホスフィン、1,3-ビス(ジフェニルホスフィノ)プロパン、1,4-ビス(ジフェニルホスフィノ)ブタン又は1,1'-ビス(ジフェニルホスフィノ)フェロセン等、通常のHeck反応に用いることのできる配位子を用いることが可能であり、好ましくはトリ-t-ブチルホスフィンを0.1〜1.5当量用いるとよい。本反応で用いるハロゲン化物は、芳香環又は複素環上にハロゲン原子を有しており、1〜10当量用いるとよい。またハロゲン原子としては、臭素原子、塩素原子、ヨウ素原子等が挙げられ、好ましくは臭素原子がよい。溶媒としては、1,4-ジオキサン、ジメチルホルムアミド、アセトニトリル、テトラヒドロフラン、ジメチルスルホキシド、1-メチル-2-ピロリドン等が挙げられ、好ましくは1,4-ジオキサン又はジメチルホルムアミドを用いるとよい。反応は10〜130℃の範囲で進行し、反応時間は0.5時間〜10日間である。本反応はマイクロ波照射下で実施することも可能であり、この場合100℃から200℃の範囲で、反応時間は1分〜1時間である。   For this reaction, tris (dibenzylideneacetone) dipalladium (0), tetrakis (triphenylphosphine) palladium (0), palladium (II) chloride or palladium (II) acetate can be used for usual Heck reaction. Although a palladium catalyst can be used, 0.05 to 0.6 equivalent of tris (dibenzylideneacetone) dipalladium (0) is preferably used. Examples of the base used in this reaction include dicyclohexylmethylamine, triethylamine, sodium bicarbonate, sodium carbonate, cesium carbonate, and the like, and preferably 1 to 5 equivalents of dicyclohexylmethylamine is used. The phosphine ligand used in this reaction is tri-t-butylphosphine, tri-o-tolylphosphine, 1,3-bis (diphenylphosphino) propane, 1,4-bis (diphenylphosphino) butane or 1, A ligand that can be used in a normal Heck reaction, such as 1′-bis (diphenylphosphino) ferrocene, can be used, and preferably 0.1 to 1.5 equivalents of tri-t-butylphosphine is used. The halide used in this reaction has a halogen atom on the aromatic ring or heterocyclic ring, and it is good to use 1 to 10 equivalents. Moreover, as a halogen atom, a bromine atom, a chlorine atom, an iodine atom, etc. are mentioned, Preferably a bromine atom is good. Examples of the solvent include 1,4-dioxane, dimethylformamide, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, 1-methyl-2-pyrrolidone, and the like. Preferably, 1,4-dioxane or dimethylformamide is used. The reaction proceeds in the range of 10 to 130 ° C., and the reaction time is 0.5 hour to 10 days. This reaction can also be carried out under microwave irradiation. In this case, the reaction time ranges from 100 ° C. to 200 ° C., and the reaction time is 1 minute to 1 hour.

また、式(15a)又は式(15b)で表される化合物は以下の方法でも製造することが可能である。式(14a)又は式(14b)で表される化合物に対して、Grubbsの触媒を用いたオレフィン化合物とのオレフィンクロスメタセシス反応(J. Am. Chem. Soc. 2003, 125, 11360-11370、Org. Lett. 1999, 1, 1751-1753)を実施することにより式(15a)又は式(15b)で表される化合物が供給される。The compound represented by the formula (15a) or the formula (15b) can also be produced by the following method. Olefin cross-metathesis reaction with an olefin compound using a Grubbs catalyst (J. Am. Chem. Soc. 2003, 125 , 11360-11370, Org) for the compound represented by formula (14a) or formula (14b) Lett. 1999, 1 , 1751-1753), the compound represented by the formula (15a) or the formula (15b) is supplied.

本反応には、トリシクロヘキシルホスフィン〔1,3-ビス(2,4,6-トリメチルフェニル)-4,5-ジヒドロイミダゾール-2-イリデン〕〔ベンジリデン〕ルテニウム(IV)ジクロライド、(ベンジリデン)ビス(トリクロロヘキシルホスフィン)ルテニウム(IV)ジクロライド、2,6-ジイソプロピルフェニルイミドネオフィリデンモリブデナム(VI)ビス(ヘキサフルオロ-t-ブトキシド)等、通常のクロスメタセシス反応に用いることのできる金属触媒を用いることが可能であるが、好ましくはトリシクロヘキシルホスフィン〔1,3-ビス(2,4,6-トリメチルフェニル)-4,5-ジヒドロイミダゾール-2-イリデン〕〔ベンジリデン〕ルテニウム(IV)ジクロライドを0.05〜0.6当量用いるとよい。本反応で用いるオレフィン化合物は、適当なアリール基又は複素環上(ここで言う「アリール基又は複素環」とは、前記Arと同じ意味を表す。)にビニル基を有しており、1〜5当量用いるとよい。溶媒としては、塩化メチレン、ベンゼン、トルエン等が挙げられ、好ましくは塩化メチレンを式(14a)又は式(14b)で表される化合物に対して10〜50倍量(V/W)用いるとよい。反応は10℃〜100℃の範囲で進行し、反応時間は1時間〜2日間である。   In this reaction, tricyclohexylphosphine [1,3-bis (2,4,6-trimethylphenyl) -4,5-dihydroimidazol-2-ylidene] [benzylidene] ruthenium (IV) dichloride, (benzylidene) bis ( Use metal catalysts that can be used for ordinary cross-metathesis reactions such as trichlorohexylphosphine) ruthenium (IV) dichloride, 2,6-diisopropylphenylimide neophylidenemolybdenum (VI) bis (hexafluoro-t-butoxide) Preferably, tricyclohexylphosphine [1,3-bis (2,4,6-trimethylphenyl) -4,5-dihydroimidazol-2-ylidene] [benzylidene] ruthenium (IV) dichloride is added in an amount of 0.05. It is good to use ~ 0.6 equivalent. The olefin compound used in this reaction has a vinyl group on an appropriate aryl group or heterocycle (herein, “aryl group or heterocycle” has the same meaning as Ar), and 1 to 5 equivalents should be used. Examples of the solvent include methylene chloride, benzene, toluene and the like. Preferably, methylene chloride is used in an amount of 10 to 50 times (V / W) with respect to the compound represented by formula (14a) or formula (14b). . The reaction proceeds in the range of 10 ° C to 100 ° C, and the reaction time is 1 hour to 2 days.

続いて、式(16a)及び式(16b)で表される化合物を製造する第3工程について述べる。式(15a)又は式(15b)で表される化合物に対して、接触水素還元を実施することにより式(16a)又は式(16b)で表される化合物が供給される。   Subsequently, the third step for producing the compounds represented by formula (16a) and formula (16b) will be described. The compound represented by the formula (16a) or the formula (16b) is supplied by performing catalytic hydrogen reduction on the compound represented by the formula (15a) or the formula (15b).

本反応に用いる触媒は、パラジウム-カーボン(Pd-C)、パラジウム-黒、水酸化パラジウム等が挙げられ、好ましくはパラジウム-カーボン(Pd-C)を式(15a)又は式(15b)で表される化合物に対して5〜50%(W/W)用いるとよい。溶媒としては、メタノール、エタノール、イソプロパノール等の低級アルコール、酢酸エチル、ジオキサン、水、アセトニトリル、テトラヒドロフラン等を単一溶媒で用いてもよく、又これらの溶媒を組み合わせて混合溶媒として用いてもよいが、好ましくは酢酸エチル又はジオキサン-水の混合溶媒を用いるとよい。反応は0〜50℃の範囲で進行し、反応時間は1〜48時間である。   Examples of the catalyst used in this reaction include palladium-carbon (Pd-C), palladium-black, palladium hydroxide, and the like. Preferably, palladium-carbon (Pd-C) is represented by formula (15a) or formula (15b). It is good to use 5 to 50% (W / W) with respect to the compound to be made. As the solvent, lower alcohols such as methanol, ethanol and isopropanol, ethyl acetate, dioxane, water, acetonitrile, tetrahydrofuran and the like may be used as a single solvent, or a combination of these solvents may be used as a mixed solvent. It is preferable to use a mixed solvent of ethyl acetate or dioxane-water. The reaction proceeds in the range of 0 to 50 ° C., and the reaction time is 1 to 48 hours.

さらに式(17a)及び式(17b)で表される化合物を製造する第4工程であるが、工程図1の第4工程で記載したアセチル基の脱保護と同様の方法を用いて、式(16a)又は式(16b)で表される化合物から誘導される。   Furthermore, although it is the 4th process which manufactures the compound represented by Formula (17a) and Formula (17b), using the method similar to deprotection of the acetyl group described in the 4th process of process FIG. It is derived from the compound represented by 16a) or formula (16b).

ここで式(17a)及び式(17b)で表される化合物は、工程図3及び工程図4の第5工程に続く第6工程を経て製造することもできる。即ち、式(15a)又は式(15b)で表される化合物から、工程図1の第4工程で記載したアセチル基の脱保護により式(18a)又は式(18b)で表される化合物とした後、工程図3及び工程図4の第3工程における接触水素還元を実施することにより式(17a)又は式(17b)で表される化合物が供給される。   Here, the compounds represented by the formula (17a) and the formula (17b) can also be produced through a sixth step following the fifth step in the step diagrams 3 and 4. That is, from the compound represented by the formula (15a) or the formula (15b), the compound represented by the formula (18a) or the formula (18b) was obtained by deprotecting the acetyl group described in the fourth step of the process diagram 1. Thereafter, the catalytic hydrogen reduction in the third step of Process Diagram 3 and Process Diagram 4 is performed to supply the compound represented by Formula (17a) or Formula (17b).

工程図3に従って製造した式(17a)及び式(18a)で表される化合物、並びに工程図4に従って製造した式(17b)及び式(18b)で表される化合物は、前記工程図1の第4工程におけるアセタール系保護基の除去と同様の方法を用いて式(1)で表される化合物へと誘導可能である。   The compounds represented by formula (17a) and formula (18a) produced according to process diagram 3 and the compounds represented by formula (17b) and formula (18b) produced according to process diagram 4 The compound represented by the formula (1) can be derived using a method similar to the removal of the acetal protecting group in the four steps.

また工程図3或いは工程図4に従って製造した、式(18a)又は式(18b)で表される化合物に、前記工程図1の第4工程におけるアセタール系保護基の除去に続く、工程図3及び工程図4の第3工程における接触水素還元を実施することにより、式(1)で表される化合物が供給される。供給された式(1)で表される化合物は工程図3又は工程図4の式(17a)又は式(17b)で表される化合物から誘導される式(1)で表される化合物と同一のものである。   In addition, to the compound represented by the formula (18a) or the formula (18b) produced according to the process diagram 3 or the process diagram 4, following the removal of the acetal protecting group in the fourth process of the process diagram 1, By performing the catalytic hydrogen reduction in the third step of the process diagram 4, the compound represented by the formula (1) is supplied. The supplied compound represented by the formula (1) is the same as the compound represented by the formula (1) derived from the compound represented by the formula (17a) or the formula (17b) in the process diagram 3 or the process diagram 4 belongs to.

その他、式(17a)又は式(17b)で表される化合物は、工程図3又は工程図4に示した製造方法に従って製造することが可能であるが、工程図5又は工程図6のごとく、式(19a)又は式(19b)で表される化合物から誘導することもできる。特に断らない限り、以下の工程図におけるR1〜R3、R5、R6、R11及びArは一般式(3)で表されたものと同じ意味を表す。これらの製造方法について、工程図5及び工程図6の第1〜第4工程に分けてそれぞれ工程毎にその詳細を説明する。In addition, the compound represented by the formula (17a) or the formula (17b) can be produced according to the production method shown in the process diagram 3 or the process diagram 4, but as shown in the process diagram 5 or the process diagram 6, It can also be derived from a compound represented by formula (19a) or formula (19b). Unless otherwise specified, R 1 to R 3 , R 5 , R 6 , R 11 and Ar in the following process diagrams have the same meaning as that represented by the general formula (3). About these manufacturing methods, it divides into the 1st-4th process of process drawing 5 and process drawing 6, and explains the details for every process, respectively.

Figure 2007069555
Figure 2007069555

Figure 2007069555
Figure 2007069555

はじめに工程図5及び工程図6の第1工程であるが、工程図1又は工程図2に従って製造した式(19a)又は式(19b)で表される化合物から、工程図1の第3工程と同様の方法を用いて式(20a)又は式(20b)で表される化合物へと誘導される。   First, in the first step of the step diagrams 5 and 6, from the compound represented by the formula (19a) or the formula (19b) manufactured according to the step diagram 1 or the step diagram 2, the third step of the step diagram 1 and A similar method is used to derive the compound represented by formula (20a) or formula (20b).

次に式(21a)及び式(21b)で表される化合物を製造する第2工程について述べる。式(20a)又は式(20b)で表される化合物に対して、塩基及びホスフィン配位子存在下、パラジウム触媒を用いたハロゲン化合物との薗頭反応(Tetrahedron Lett. 1975, 16, 4467-4470、Synthesis 1980, 627-630、Org. Lett. 2003, 5, 4191-4194)を実施することにより式(21a)又は式(21b)で表される化合物が供給される。Next, the second step for producing the compounds represented by formula (21a) and formula (21b) will be described. Sonogashira reaction with a halogen compound using a palladium catalyst in the presence of a base and a phosphine ligand with respect to the compound represented by the formula (20a) or (20b) (Tetrahedron Lett. 1975, 16 , 4467-4470 Synthesis 1980, 627-630, Org. Lett. 2003, 5 , 4191-4194) provides a compound represented by formula (21a) or formula (21b).

本反応には、トリス(ジベンジリデンアセトン)ジパラジウム(0)、パラジウム(II)アセテート、ビス(ベンゾニトリル)ジクロロパラジウム(II)又はジクロロビス(トリフェニルホスフィン)パラジウム(II)等の通常の薗頭反応に用いることのできるパラジウム触媒を用いることが可能であるが、好ましくはトリス(ジベンジリデンアセトン)ジパラジウム(0)を0.05〜0.6当量用いるとよい。用いる塩基としては、1,4-ジアザビシクロ[2.2.2]オクタン、キナクリジン、ジイソプロピルエチルアミン、トリエチルアミン、ジシクロヘキシルメチルアミン、ピペリジン等が挙げられ、好ましくは1,4-ジアザビシクロ[2.2.2]オクタン又はキナクリジンを1〜5当量用いるとよい。条件によっては、添加物として通常の薗頭反応に用いられるヨウ化銅(I)を0.1〜1.2当量用いてもよい。用いるホスフィン配位子は、トリ-t-ブチルホスフィン、トリ-o-トリルホスフィン、1,3-ビス(ジフェニルホスフィノ)プロパン、1,4-ビス(ジフェニルホスフィノ)ブタン、1,1'-ビス(ジフェニルホスフィノ)フェロセン等を用いることが可能であるが、好ましくはトリ-t-ブチルホスフィンを0.1〜1.5当量用いるとよい。用いるハロゲン化物は、適当な芳香環又は複素環上にハロゲン原子を有し、1〜10当量用いるとよい。又、ハロゲン原子としては、臭素原子、塩素原子、ヨウ素原子等が挙げられ、好ましくは臭素原子である。溶媒としては、ジメチルホルムアミド、アセトニトリル、テトラヒドロフラン、1,4-ジオキサン、ベンゼン等が挙げられ、好ましくはジメチルホルムアミドを式(20a)又は式(20b)で表される化合物に対して1〜50倍量(V/W)用いるとよい。反応は20〜90℃の範囲で進行し、反応時間は1時間〜10日間である。   In this reaction, conventional buns such as tris (dibenzylideneacetone) dipalladium (0), palladium (II) acetate, bis (benzonitrile) dichloropalladium (II) or dichlorobis (triphenylphosphine) palladium (II) Although a palladium catalyst that can be used for the reaction can be used, 0.05 to 0.6 equivalent of tris (dibenzylideneacetone) dipalladium (0) is preferably used. Examples of the base to be used include 1,4-diazabicyclo [2.2.2] octane, quinacridine, diisopropylethylamine, triethylamine, dicyclohexylmethylamine, piperidine and the like. Preferably, 1,4-diazabicyclo [2.2.2] octane or quinacridine is used. It is recommended to use 1 to 5 equivalents. Depending on conditions, you may use 0.1-1.2 equivalent of copper (I) iodide used for a usual Sonogashira reaction as an additive. The phosphine ligand used is tri-t-butylphosphine, tri-o-tolylphosphine, 1,3-bis (diphenylphosphino) propane, 1,4-bis (diphenylphosphino) butane, 1,1'- Bis (diphenylphosphino) ferrocene or the like can be used, but 0.1 to 1.5 equivalents of tri-t-butylphosphine is preferably used. The halide to be used has a halogen atom on a suitable aromatic ring or heterocyclic ring, and 1 to 10 equivalents are preferably used. Moreover, as a halogen atom, a bromine atom, a chlorine atom, an iodine atom, etc. are mentioned, Preferably it is a bromine atom. Examples of the solvent include dimethylformamide, acetonitrile, tetrahydrofuran, 1,4-dioxane, benzene and the like, and preferably 1 to 50 times the amount of dimethylformamide with respect to the compound represented by formula (20a) or formula (20b). (V / W) should be used. The reaction proceeds in the range of 20 to 90 ° C., and the reaction time is 1 hour to 10 days.

続いて式(22a)及び式(22b)で表される化合物を製造する第3工程について述べる。式(21a)又は式(21b)で表される化合物から、工程図1の第4工程で記載したアセチル基の脱保護を実施することにより、式(22a)又は式(22b)で表される化合物が供給される。   Next, the third step for producing the compounds represented by formula (22a) and formula (22b) will be described. The compound represented by the formula (21a) or the formula (21b) is represented by the formula (22a) or the formula (22b) by carrying out deprotection of the acetyl group described in the fourth step of the process diagram 1 A compound is supplied.

最後に第4工程であるが、式(22a)又は式(22b)で表される化合物から、工程図3及び工程図4の第3工程における接触水素還元と同様の方法を用いて、式(17a)又は式(17b)で表される化合物が供給される。   Finally, in the fourth step, from the compound represented by the formula (22a) or the formula (22b), using the same method as the catalytic hydrogen reduction in the third step of the step diagrams 3 and 4, the formula (22 A compound represented by 17a) or formula (17b) is supplied.

工程図5又は工程図6に従って製造した式(17a)、式(17b)、又は式(22a)式(22b)で表される化合物は、工程図1の第4工程におけるアセタール系保護基の除去と同様の方法を用いて、式(1)で表される化合物へと誘導される。   The compound represented by the formula (17a), the formula (17b), or the formula (22a) or the formula (22b) produced according to the process diagram 5 or the process diagram 6 is the removal of the acetal protecting group in the fourth process of the process diagram 1 The compound represented by the formula (1) is derived using the same method as described above.

ここで工程図3又は工程図4に示した製造方法に従って、式(15a)又は式(15b)で表される化合物を製造することが可能であるが、以下の工程図7又は工程図8のごとく、中性糖部4”位をカルバモイル化する前に、アリール基及び複素環基を導入することで式(15a)又は式(15b)で表される化合物へと誘導することもできる。特に断らない限り、以下の工程図におけるR1〜R3、R5、R6、R11及びArは前記一般式(3)で表されたものと同じ意味を表す。これらの製造方法について、工程図7及び工程図8を用いて説明する。Here, it is possible to produce the compound represented by the formula (15a) or the formula (15b) according to the production method shown in the step diagram 3 or the step diagram 4, but the following step diagram 7 or step diagram 8 As described above, before the carbamoylation of the neutral sugar moiety 4 ″ position, an aryl group and a heterocyclic group can be introduced to give a compound represented by the formula (15a) or the formula (15b). Unless otherwise specified, R 1 to R 3 , R 5 , R 6 , R 11 and Ar in the following process diagrams represent the same meaning as those represented by the general formula (3). This will be described with reference to FIGS. 7 and 8.

Figure 2007069555
Figure 2007069555

Figure 2007069555
Figure 2007069555

はじめに式(23a)又は式(23b)で表される化合物を製造する第1工程について述べる。工程図1又は工程図2に従って製造した式(13a)又は式(13b)で表される化合物から、工程図3又は工程図4の第2工程と同様の方法を用いて式(23a)又は式(23b)で表される化合物へと誘導される。   First, the first step for producing the compound represented by the formula (23a) or the formula (23b) will be described. From the compound represented by formula (13a) or formula (13b) produced according to process diagram 1 or process diagram 2, formula (23a) or formula using the same method as the second process of process diagram 3 or process diagram 4 It is derived to the compound represented by (23b).

続いて第2工程であるが、式(23a)又は式(23b)で表される化合物から、工程図1の第3工程と同様の方法を用いて式(15a)又は式(15b)で表される化合物へと誘導される。   Subsequently, in the second step, the compound represented by the formula (15a) or the formula (15b) is obtained from the compound represented by the formula (23a) or the formula (23b) by using the same method as the third step in the step diagram 1. To the compound to be produced.

工程図2に示した製造方法に従って式(1)においてR1が水素原子でありR2がアセチル基で表される化合物を製造することが可能であるが、以下の工程図9の如く誘導することも可能である。特に断らない限り、以下の工程図におけるR1〜R6は式(1)と同じ意味を表す。工程図9の製造方法について以下に説明する。According to the production method shown in Process Diagram 2, it is possible to produce a compound in which R 1 is a hydrogen atom and R 2 is an acetyl group in Formula (1). It is also possible. Unless otherwise specified, R 1 to R 6 in the following process diagrams represent the same meaning as in formula (1). The manufacturing method of process drawing 9 is demonstrated below.

Figure 2007069555
Figure 2007069555

初めに、式(24b)で表される化合物を製造する第1工程について述べる。工程図2に従って製造した式(24a)で表される化合物に対して、溶媒中、無水酢酸を作用させることにより、式(24b)で表される化合物が供給される。   First, the first step for producing the compound represented by the formula (24b) will be described. The compound represented by the formula (24b) is supplied by allowing acetic anhydride to act on the compound represented by the formula (24a) produced according to the process diagram 2 in a solvent.

本反応に用いる無水酢酸は、2〜20当量用いるとよい。溶媒としては、アセトニトリル、テトラヒドロフラン、1,4-ジオキサン、ベンゼン、トルエン、塩化メチレン等が挙げられ、好ましくはアセトニトリルを式(24a)で表される化合物に対して1〜100倍量(V/W)用いるとよい。反応は20〜80℃の範囲で進行し、反応時間は1時間〜2日間である。   The acetic anhydride used in this reaction may be used in an amount of 2 to 20 equivalents. Examples of the solvent include acetonitrile, tetrahydrofuran, 1,4-dioxane, benzene, toluene, methylene chloride and the like. Preferably, acetonitrile is 1 to 100 times the amount of the compound represented by the formula (24a) (V / W ) It is good to use. The reaction proceeds in the range of 20 to 80 ° C., and the reaction time is 1 hour to 2 days.

続いて第2工程であるが、式(24b)で表される化合物から、工程図1の第4工程で記載したマイカミノース部分における2'位アセチル基の脱保護により、R1が水素原子でありR2がアセチル基である式(1)で表される化合物が供給される。本反応では、反応時間を短縮することでR2がアセチル基である式(1)で表される化合物へと誘導可能である。反応時間が長い場合、R1およびR2が水素原子である式(1)で表される化合物、即ち式(24a)で表される化合物が供給される。Subsequently, in the second step, R 1 is a hydrogen atom from the compound represented by the formula (24b) by deprotecting the 2′-position acetyl group in the micaminose moiety described in the fourth step of Process FIG. A compound represented by the formula (1) in which R 2 is an acetyl group is supplied. In this reaction, the reaction time can be shortened to lead to a compound represented by the formula (1) in which R 2 is an acetyl group. When the reaction time is long, a compound represented by the formula (1) in which R 1 and R 2 are hydrogen atoms, that is, a compound represented by the formula (24a) is supplied.

ここで式(1)においてR1がアセチル基で表される化合物は、以下のように製造することができる。Here, the compound in which R 1 is represented by an acetyl group in the formula (1) can be produced as follows.

初めに、工程図9に従って製造したR1が水素原子である式(24b)で表される化合物に対して、ピリジン溶媒中、無水酢酸を作用させることにより、R1がアセチル基である式(24b)で表される化合物が供給される。 First , by reacting the compound represented by the formula (24b) in which R 1 is a hydrogen atom produced according to the process diagram 9 with acetic anhydride in a pyridine solvent, the formula in which R 1 is an acetyl group ( The compound represented by 24b) is supplied.

本反応に用いる無水酢酸は、1〜30当量用いるとよい。ピリジンはR1が水素原子である式(24b)で表される化合物に対して1〜100倍量(V/W)用いるとよい。反応は20〜80℃の範囲で進行し、反応時間は1時間〜2日間である。Acetic anhydride used in this reaction is preferably used in an amount of 1 to 30 equivalents. Pyridine is preferably used in an amount of 1 to 100 times (V / W) the compound represented by the formula (24b) in which R 1 is a hydrogen atom. The reaction proceeds in the range of 20 to 80 ° C., and the reaction time is 1 hour to 2 days.

続いて、R1がアセチル基である式(24b)で表される化合物から、工程図1の第4工程で記載した2'位及び/又は9位アセチル基の脱保護によりR1がアセチル基である式(1)で表される化合物が供給される。Subsequently, a compound wherein R 1 is represented by the formula (24b) is an acetyl group, 2 described in the fourth step of Scheme 1 'position and / or 9-position R 1 is acetyl group by deprotection of the acetyl group A compound represented by the formula (1) is supplied.

本発明の化合物の製造方法は、上記に説明した方法又は実施例に具体的に示された方法に限定されることはない。また、本発明の化合物は、上記に説明した方法又は実施例に具体的に示された方法により製造されたものに限定されることはなく、いかなる方法により製造されたものも本発明の範囲に包含される。例えば上記の一般的な説明及び実施例の具体的説明に基づき、公知の手段を施してこれらを合成、生産、抽出、精製して得られる化合物も本発明に包含されることは言うまでもない。   The method for producing the compound of the present invention is not limited to the method described above or the method specifically shown in the examples. Further, the compounds of the present invention are not limited to those produced by the methods described above or specifically shown in the examples, and those produced by any method are within the scope of the present invention. Is included. For example, it goes without saying that compounds obtained by synthesizing, producing, extracting, and purifying these by applying known means based on the above general explanation and specific explanation of the examples are also included in the present invention.

本発明の化合物は多くの酸と塩を形成し、この性質は純物質製造及び医薬品としての提供形態に利用される。すなわち製造時にあっては例えば酸性とすることで水等の極性溶媒に可溶化、抽出精製がされ、好ましい物理化学的性状を示す塩の形態として単離され、医薬の用途においては、薬学的に許容される塩の形態をとることができる。本発明の医薬の有効成分としては、上記のいずれの形態の物質を用いてもよい。   The compound of the present invention forms a salt with many acids, and this property is utilized for the production of pure substances and the form of providing as pharmaceuticals. That is, at the time of production, it is solubilized and extracted and purified in a polar solvent such as water by making it acidic, and isolated as a salt form exhibiting preferable physicochemical properties. It can take the form of an acceptable salt. As an active ingredient of the medicament of the present invention, any of the above-mentioned substances may be used.

本発明の化合物がとりうる塩の形態は特に限定されないが、これらの化合物の薬学的に許容される塩の形態が好ましい。例えば、酸性付加塩として、ハロゲン化水素酸(フッ化水素酸、塩酸、臭化水素酸、ヨウ化水素酸等)塩、無機酸(硫酸塩、硝酸塩、リン酸塩、過塩素酸塩、炭酸塩等)塩、カルボン酸(酢酸、トリクロロ酢酸、トリフルオロ酢酸、ヒドロキシ酢酸、乳酸、クエン酸、酒石酸、シュウ酸、安息香酸、マンデル酸、酪酸、マレイン酸、プロピオン酸、蟻酸、リンゴ酸等)塩、アミノ酸(アルギン酸、アスパラギン酸、グルタミン酸塩等)塩、有機酸(メタンスルホン酸、パラトルエンスルホン酸等)塩等が挙げられる。   Although the salt form which the compound of this invention can take is not specifically limited, The form of the pharmaceutically acceptable salt of these compounds is preferable. For example, as an acid addition salt, hydrohalic acid (hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.) salt, inorganic acid (sulfate, nitrate, phosphate, perchlorate, carbonic acid) Salt, carboxylic acid (acetic acid, trichloroacetic acid, trifluoroacetic acid, hydroxyacetic acid, lactic acid, citric acid, tartaric acid, oxalic acid, benzoic acid, mandelic acid, butyric acid, maleic acid, propionic acid, formic acid, malic acid, etc.) Examples thereof include salts, amino acids (such as alginic acid, aspartic acid, and glutamate salts), organic acid (such as methanesulfonic acid and paratoluenesulfonic acid) salts, and the like.

本発明の化合物がとりうる溶媒和物の形態としては、溶媒の種類は特に限定されないが、例えば、水;メタノール、エタノール、イソプロパノール、等のアルコール類;テトラヒドロフラン等のエーテル類などが挙げられる。   The form of the solvate which the compound of the present invention can take is not particularly limited, and examples thereof include water; alcohols such as methanol, ethanol and isopropanol; ethers such as tetrahydrofuran and the like.

本発明の化合物中には多くの不斉炭素が存在するが、その立体配置は、絶対配置を示す(立体の表記は通常の表記に従ったものである)。また本発明の化合物は、前記一般式(1)に示された不斉炭素に加えて、置換基に不斉炭素を有する場合がある。置換基に存在する不斉炭素に基づく任意の立体異性体(光学活性体、ジアステレオ異性体)及びそれらの任意の混合物(ラセミ体、ジアステレオマー混合物)は、いずれも本発明の範囲に包含される。また前記一般式(1)で表される遊離形態の化合物又はその塩の他、それらの任意の水和物又はそれらの任意の溶媒和物も本発明の範囲に包含される。   Although many asymmetric carbons exist in the compound of the present invention, the configuration thereof shows an absolute configuration (the notation of the stereo conforms to the normal notation). In addition to the asymmetric carbon shown in the general formula (1), the compound of the present invention may have an asymmetric carbon as a substituent. Any stereoisomer (optically active form, diastereoisomer) based on the asymmetric carbon present in the substituent and any mixture thereof (racemate, diastereomer mixture) are all included in the scope of the present invention. Is done. In addition to the free form compound represented by the general formula (1) or a salt thereof, any hydrate or any solvate thereof is also included in the scope of the present invention.

本発明による化合物、薬学的に許容されるその塩及び溶媒和物は、経口または非経口(例えば、静注、筋注、皮下投与、腹腔内投与、直腸投与、経皮投与)のいずれかの投与経路で、ヒトおよびヒト以外の動物に投与することができる。
従って、本発明による化合物、薬学的に許容されるその塩及び溶媒和物は、投与経路に応じて適当な剤形とされ、具体的には主として静注、筋注等の注射剤、カプセル剤、錠剤、顆粒剤、散剤、丸剤、細粒剤、トローチ錠等の経口剤、直腸投与剤、油脂性坐剤、水性坐剤等のいずれかの製剤形態に調製することができる。
The compounds according to the present invention, pharmaceutically acceptable salts and solvates thereof are either oral or parenteral (eg, intravenous, intramuscular, subcutaneous, intraperitoneal, rectal, transdermal) It can be administered to humans and non-human animals by the route of administration.
Therefore, the compounds according to the present invention, pharmaceutically acceptable salts and solvates thereof are in suitable dosage forms depending on the route of administration, and specifically, injections such as intravenous injection and intramuscular injection, capsules. , Tablets, granules, powders, pills, fine granules, lozenges and other oral preparations, rectal administration agents, oily suppositories, aqueous suppositories and the like.

これらの各種製剤は通常用いられている賦形剤、増量剤、結合剤、浸潤化剤、崩壊剤、表面活性剤、滑沢剤、分散剤、緩衝剤、保存剤、溶解補助剤、防腐剤、矯味矯臭剤、無痛化剤、安定化剤等を用いて常法により製造することができる。
賦形剤としては、例えば乳糖、果糖、ブドウ糖、コーンスターチ、ソルビット、結晶セルロース等が、崩壊剤としては、例えば澱粉、アルギン酸ナトリウム、ゼラチン、炭酸カルシウム、クエン酸カルシウム、デキストリン、炭酸マグネシウム、合成ケイ酸マグネシウム等が、結合剤としては、例えばメチルセルロースまたはその塩、エチルセルロース、アラビアゴム、ゼラチン、ヒドロキシプロピルセルロース、ポリビニルピロリドン等が、潤沢剤としては、タルク、ステアリン酸マグネシウム、ポリエチレングリコール、硬化植物油等が、その他添加剤としてシロップ、ワセリン、グリセリン、エタノール、プロピレングリコール、クエン酸、塩化ナトリウム、亜硫酸ソーダ、リン酸ナトリウム等がそれぞれ挙げられる。
These various preparations are usually used excipients, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, solubilizers, preservatives. It can be produced by a conventional method using a flavoring agent, a soothing agent, a stabilizer and the like.
Examples of excipients include lactose, fructose, glucose, corn starch, sorbit, and crystalline cellulose. Examples of disintegrants include starch, sodium alginate, gelatin, calcium carbonate, calcium citrate, dextrin, magnesium carbonate, and synthetic silicic acid. Magnesium or the like as a binder, for example, methyl cellulose or a salt thereof, ethyl cellulose, gum arabic, gelatin, hydroxypropyl cellulose, polyvinyl pyrrolidone, etc., as a lubricant, talc, magnesium stearate, polyethylene glycol, hydrogenated vegetable oil, etc. Other additives include syrup, petrolatum, glycerin, ethanol, propylene glycol, citric acid, sodium chloride, sodium sulfite, sodium phosphate and the like.

本発明の医薬組成物中の本発明による化合物の含有量は、その製剤形態に応じて異なるが、通常は全組成物中10〜95重量%、好ましくは30〜80重量%程度である。投与量は、用法、患者の年齢、性別、疾患の相違、症状の程度等を考慮して適宜決定されるが、通常成人1日1人当たり本発明の化合物の重量として約1〜3000 mg、好ましくは10〜2000mgの投与量であり、これを1日1回または数回に分けて投与することができる。   The content of the compound according to the present invention in the pharmaceutical composition of the present invention varies depending on the preparation form, but is usually about 10 to 95% by weight, preferably about 30 to 80% by weight in the total composition. The dosage is appropriately determined in consideration of the usage, patient age, sex, disease difference, symptom level, etc., but is usually about 1 to 3000 mg as the weight of the compound of the present invention per adult per day, preferably Is a dose of 10 to 2000 mg, which can be administered once or divided into several times a day.

次に、実施例により本発明をさらに詳細に例示するが、下記実施例は本発明を例示するためのものであって、本発明の範囲はこれらによってなんら限定されるものではない。   Next, the present invention will be illustrated in more detail by way of examples. However, the following examples are for illustrating the present invention, and the scope of the present invention is not limited by these examples.

参考例1
2-ビニルキノリンの製造方法
2-ヨードキノリン117.5 mgを1,4-ジオキサン2.35 mlに溶解し、反応容器をアルゴン置換した後、[1,1'-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)ジクロロメタン錯体3.3 mgを加え、室温で20分間撹拌した。さらに炭酸カリウム56.2 mg、水0.7 ml、ビニルボロニックアンハイドライドピリジン錯体97.9 mgを順次加え、60℃で20. 5時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出し、有機層を硫酸マグネシウムで乾燥後、これを濾過した。濾液を減圧濃縮して得られた残渣を分取用TLC(ヘキサン−酢酸エチル(5:1))で精製して、標記化合物31.7 mgを得た。
Reference example 1
Method for producing 2-vinylquinoline
After dissolving 117.5 mg of 2-iodoquinoline in 2.35 ml of 1,4-dioxane and replacing the reaction vessel with argon, 3.3 mg of [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex was added. In addition, the mixture was stirred at room temperature for 20 minutes. Further, 56.2 mg of potassium carbonate, 0.7 ml of water and 97.9 mg of vinylboronic anhydride pyridine complex were sequentially added, followed by stirring at 60 ° C. for 20.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and then filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by preparative TLC (hexane-ethyl acetate (5: 1)) to obtain 31.7 mg of the title compound.

本化合物の理化学的性状
(1)マススペクトル(EI):m/z 155 (M)+
(2)1H NMRスペクトル(400MHz, CDCl3) δ(ppm):5.67(dd, CH=CH2), 6.28(dd, CH=CH2), 7.05(dd, CH=CH2), 7.51(ddd, quinoline), 7.62(d, quinoline), 7.70(ddd, quinoline), 7.79(d, quinoline), 8.07(d, quinoline), 8.12(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (EI): m / z 155 (M) +
(2) 1 H NMR spectrum (400 MHz, CDCl 3 ) δ (ppm): 5.67 (dd, CH = CH 2 ), 6.28 (dd, CH = CH 2 ), 7.05 (dd, CH = CH 2 ), 7.51 ( ddd, quinoline), 7.62 (d, quinoline), 7.70 (ddd, quinoline), 7.79 (d, quinoline), 8.07 (d, quinoline), 8.12 (d, quinoline).

参考例2
2-ビニルキノキサリンの製造方法
参考例1と同様の方法で、2-ヨードキノリンの代わりに2-ブロモキノキサリン174 mgを用いて、標記化合物94.4 mgを得た。
Reference example 2
Production method of 2-vinylquinoxaline In the same manner as in Reference Example 1, 174 mg of 2-bromoquinoxaline was used instead of 2-iodoquinoline to obtain 94.4 mg of the title compound.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 157 (M)+
(2)1H NMRスペクトル(400MHz, CDCl3) δ(ppm):5.73(d, CH=CH2), 6.40(d, CH=CH2), 6.98(dd, CH=CH2), 7.68(m, quinoxaline), 8.00(m, quinoxaline), 8.94(s, quinoxaline).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 157 (M) +
(2) 1 H NMR spectrum (400 MHz, CDCl 3 ) δ (ppm): 5.73 (d, CH = CH 2 ), 6.40 (d, CH = CH 2 ), 6.98 (dd, CH = CH 2 ), 7.68 ( m, quinoxaline), 8.00 (m, quinoxaline), 8.94 (s, quinoxaline).

参考例3
3-ブロモイソキノリンの製造方法
氷冷下、3-アミノイソキノリン500 mgを47%臭化水素酸−水(84:16)2.5 mlに溶解し、亜硝酸ナトリウム449.8 mgをゆっくり加え、室温まで昇温しつつ21時間撹拌した。反応容器に1N水酸化ナトリウム水溶液を加え、pHを13に調節後、ジエチルエーテルで抽出した。有機層を硫酸マグネシウムで乾燥後、これを濾過し、濾液を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン−酢酸エチル(9:1))で精製して、標記化合物289 mgを得た。
Reference example 3
Method for producing 3-bromoisoquinoline Under ice cooling, dissolve 500 mg of 3-aminoisoquinoline in 2.5 ml of 47% hydrobromic acid-water (84:16), slowly add 449.8 mg of sodium nitrite, and warm to room temperature The mixture was stirred for 21 hours. A 1N aqueous sodium hydroxide solution was added to the reaction vessel to adjust the pH to 13, followed by extraction with diethyl ether. The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate (9: 1)) to give 289 mg of the title compound. Obtained.

本化合物の理化学的性状
(1)マススペクトル(EI):m/z 207 (M)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):7.61(ddd, isoquinoline), 7.71(ddd, isoquinoline), 7.75(d, isoquinoline), 7.90(s, isoquinoline), 7.95(d, isoquinoline), 9.03(s, isoquinoline).
Physicochemical properties of this compound (1) Mass spectrum (EI): m / z 207 (M) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 7.61 (ddd, isoquinoline), 7.71 (ddd, isoquinoline), 7.75 (d, isoquinoline), 7.90 (s, isoquinoline), 7.95 (d, isoquinoline), 9.03 (s, isoquinoline).

参考例4
1-ヨードイソキノリンの製造方法
1-クロロイソキノリン257.4 mgをプロピオニトリル3. 86 mlに溶解し、よう化ナトリウム825 mg、57%よう化水素水128.7μlを順次加え、70℃で7時間撹拌した。反応液を室温まで戻し、28%アンモニア水を加え、pH9に調節した後、酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥後、これを濾過し、濾液を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン−アセトン(20:1〜4:1))で精製して、標記化合物350.8 mgを得た。
Reference example 4
Method for producing 1-iodoisoquinoline
257.4 mg of 1-chloroisoquinoline was dissolved in 3.86 ml of propionitrile, 825 mg of sodium iodide and 128.7 μl of 57% hydrogen iodide water were sequentially added, and the mixture was stirred at 70 ° C. for 7 hours. The reaction solution was returned to room temperature, 28% aqueous ammonia was added to adjust to pH 9, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-acetone (20: 1-4: 1)) to give the title compound. 350.8 mg was obtained.

本化合物の理化学的性状
(1)マススペクトル (EI):m/z 255 (M)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):7.57(d, isoquinoline), 7.72(m, isoquinoline), 8.11(d, isoquinoline), 8.25(d, isoquinoline).
Physicochemical properties of this compound (1) Mass spectrum (EI): m / z 255 (M) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 7.57 (d, isoquinoline), 7.72 (m, isoquinoline), 8.11 (d, isoquinoline), 8.25 (d, isoquinoline).

参考例5
(R)-7-アミノ-1-ヘプテン-4-オールの製造方法
(a)(R)-5-アミノ-2-ヒドロキシペンタン酸15.1 gを1,4-ジオキサン50 ml及び水130 mlの混合溶媒に溶解し、氷冷下5N水酸化ナトリウム水溶液でpHを約10に保ちながら、同時に1,4-ジオキサン50 mlに溶解したジ-tert-ブチルジカーボネート28 gを40分かけて加えた。氷冷下で45分間撹拌した後、pHを約10に保ちながらジ-tert-ブチルジカーボネート3 gを加え、さらに氷冷下で2時間15分間撹拌した。反応液をジエチルエーテル100 mlで2回洗浄し、水層を濃塩酸40 mlでpHを約3とした後、水層から酢酸エチル300 mlで2回、200 mlで2回抽出した。有機層を無水硫酸マグネシウムで乾燥、これを濾過した後、濾液を減圧濃縮して、(R)-5-tert-ブトキシカルボニルアミノ-2-ヒドロキシペンタン酸28 gを得た。
Reference Example 5
Method for producing (R) -7-amino-1-hepten-4-ol
(a) 15.1 g of (R) -5-amino-2-hydroxypentanoic acid is dissolved in a mixed solvent of 50 ml of 1,4-dioxane and 130 ml of water, and the pH is adjusted to about 10 with a 5N aqueous sodium hydroxide solution under ice cooling. At the same time, 28 g of di-tert-butyl dicarbonate dissolved in 50 ml of 1,4-dioxane was added over 40 minutes. After stirring for 45 minutes under ice cooling, 3 g of di-tert-butyl dicarbonate was added while maintaining the pH at about 10, and the mixture was further stirred for 2 hours and 15 minutes under ice cooling. The reaction solution was washed twice with 100 ml of diethyl ether, the aqueous layer was adjusted to pH 3 with 40 ml of concentrated hydrochloric acid, and extracted from the aqueous layer twice with 300 ml of ethyl acetate and twice with 200 ml. The organic layer was dried over anhydrous magnesium sulfate and filtered, and then the filtrate was concentrated under reduced pressure to obtain 28 g of (R) -5-tert-butoxycarbonylamino-2-hydroxypentanoic acid.

本化合物の理化学的性状
(1)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):1.44(s, C(CH3)3), 1.57-1.97(m, 3-H and 4-H), 3.16(br s, 5-H), 4.27(m, 2-H).
Physicochemical properties of this compound (1) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 1.44 (s, C (CH 3 ) 3 ), 1.57-1.97 (m, 3-H and 4-H) , 3.16 (br s, 5-H), 4.27 (m, 2-H).

(b)参考例5(a)の化合物300 mgをテトラヒドロフラン4.5 mlに溶解し、室温でジメチルスルフィドボラン250μlを加え、8時間撹拌した。反応液にジメチルスルフィドボラン250μlを加え、さらに室温で14時間撹拌した後、メタノール1.5 mlを加えた。室温で1時間撹拌した後、反応液を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム−メタノール(60:1〜30:1))で精製して、(+)-(R)-5-tert-ブトキシカルボニルアミノペンタン-1,2-ジオール30 mgを得た。 (b) 300 mg of the compound of Reference Example 5 (a) was dissolved in 4.5 ml of tetrahydrofuran, 250 μl of dimethyl sulfide borane was added at room temperature, and the mixture was stirred for 8 hours. To the reaction mixture was added 250 μl of dimethyl sulfide borane, and the mixture was further stirred at room temperature for 14 hours, and then 1.5 ml of methanol was added. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol (60: 1-30: 1)) to obtain (+)-(R) 30 mg of -5-tert-butoxycarbonylaminopentane-1,2-diol was obtained.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 220 (M+H) +
(2)比旋光度:[α]D 19 1.5°(c1.0, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm) :1.44(s, C(CH3)3), 1.50-1.74(m, 3-H and 4-H), 3.15(m, 5-H), 3.44(dd, 1-H), 3.58-3.78(m, 1-H and 2-H), 4.81(br s, NH).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 220 (M + H) +
(2) Specific rotation: [α] D 19 1.5 ° (c1.0, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 1.44 (s, C (CH 3 ) 3 ), 1.50-1.74 (m, 3-H and 4-H), 3.15 (m, 5 -H), 3.44 (dd, 1-H), 3.58-3.78 (m, 1-H and 2-H), 4.81 (br s, NH).

(c)参考例5(b)の化合物244 mgを塩化メチレン2.5 mlに溶解し、酸化ジブチルスズ 5.6 mg、トリエチルアミン170 μl、p-トルエンスルホニルクロライド223 mgを順次加え、氷冷下で2時間撹拌した。反応液を塩化メチレン15 mlで希釈し、水10 mlで2回、飽和食塩水10 mlで順次洗浄した。有機層を無水硫酸マグネシウムで乾燥後、これを濾過し、濾液を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン−酢酸エチル(3:2))で精製して、(-)-(R)-5-(N-tert-ブトキシカルボニルアミノ)-1-(p-トルエンスルホニルオキシ)-2-ペンタノール384 mgを得た。 (c) 244 mg of the compound of Reference Example 5 (b) was dissolved in 2.5 ml of methylene chloride, 5.6 mg of dibutyltin oxide, 170 μl of triethylamine, and 223 mg of p-toluenesulfonyl chloride were sequentially added, followed by stirring for 2 hours under ice cooling. . The reaction solution was diluted with 15 ml of methylene chloride, washed successively with 10 ml of water twice and 10 ml of saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate (3: 2)), and (-)- 384 mg of (R) -5- (N-tert-butoxycarbonylamino) -1- (p-toluenesulfonyloxy) -2-pentanol was obtained.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 374 (M+H) +
(2)比旋光度:[α]D 19 -3.1°(c1.0, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):1.40-1.59(m, 3-H and 4-H), 1.43(s, C(CH3)3), 2.46(s, CH3), 3.13(m, 5-H), 3.87(m, 2-H), 3.90(m, 1-H), 3.99(m, 1-H), 7.36 (d, C6H4), 7.80 (d, C6H4).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 374 (M + H) +
(2) Specific rotation: [α] D 19 -3.1 ° (c1.0, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 1.40-1.59 (m, 3-H and 4-H), 1.43 (s, C (CH 3 ) 3 ), 2.46 (s, CH 3 ), 3.13 (m, 5-H), 3.87 (m, 2-H), 3.90 (m, 1-H), 3.99 (m, 1-H), 7.36 (d, C 6 H 4 ), 7.80 (d, C 6 H 4 ).

(d)参考例5(c) の化合物23.4 gをメタノール90 mlに溶解し、1N ナトリウムメトキシドのメタノール溶液130 mlを加え、氷冷下で1時間撹拌した。反応液に20%塩化アンモニウム水溶液100 mlを加え、減圧下でメタノールを留去した後、水40 mlを加え、酢酸エチル150mlで2回抽出した。有機層を飽和食塩水60 mlで洗浄、無水硫酸ナトリウムで乾燥後、これを濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン−酢酸エチル(4:1〜2:1))で精製して、(+)-(R)-N-tert-ブトキシカルボニル-N-(4,5-エポキシペンチル)アミン11.4 gを得た。 (d) 23.4 g of the compound of Reference Example 5 (c) was dissolved in 90 ml of methanol, 130 ml of 1N sodium methoxide in methanol was added, and the mixture was stirred for 1 hour under ice cooling. To the reaction solution was added 100 ml of 20% aqueous ammonium chloride solution, methanol was distilled off under reduced pressure, 40 ml of water was added, and the mixture was extracted twice with 150 ml of ethyl acetate. The organic layer was washed with 60 ml of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate (4: 1-2: 1)) to give (+)-(R) -N-tert-butoxycarbonyl-N- (4,5 -Epoxypentyl) amine 11.4 g was obtained.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 202 (M+H) +
(2)比旋光度:[α]D 21 5.0°(c1.01, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):1.40-1.72(m, 2-H and 3-H), 1.44(s, C(CH3)3), 2.49(dd, 5-H), 2.77(dd, 5-H), 2.93(m, 4-H), 3.18(dt, 1-H), 4.62(br s, NH).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 202 (M + H) +
(2) Specific rotation: [α] D 21 5.0 ° (c1.01, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 1.40-1.72 (m, 2-H and 3-H), 1.44 (s, C (CH 3 ) 3 ), 2.49 (dd, 5 -H), 2.77 (dd, 5-H), 2.93 (m, 4-H), 3.18 (dt, 1-H), 4.62 (br s, NH).

(e)シアン化銅(I)1.2 gのテトラヒドロフラン30 ml懸濁液を-30℃に冷却し、1.0M ビニルマグネシウムブロマイドのテトラヒドロフラン溶液63 mlを10分かけて滴下後、10分間撹拌した。反応液に参考例5(d) の化合物5.0 gのテトラヒドロフラン45 ml溶液を20分かけて滴下した後、-30℃〜-20℃で2.5時間撹拌した。反応液を-30℃に冷却し、1.0M ビニルマグネシウムブロマイドのテトラヒドロフラン溶液13 mlを5分かけて滴下後、さらに-30℃〜-20℃で40分間撹拌した。反応液に20%塩化アンモニウム水溶液70 mlを加え、室温まで昇温した後、減圧下でテトラヒドロフランを留去した。水層から酢酸エチル100 mlで2回抽出し、有機層を飽和食塩水100 mlで洗浄、無水硫酸ナトリウムで乾燥後、これを濾過した。濾液を減圧濃縮して得られた残さをシリカゲルカラムクロマトグラフィー(ヘキサン−酢酸エチル(3:1〜2:1))で精製して、(+)-(R)-7-(N-tert-ブトキシカルボニルアミノ)-1-ヘプテン-4-オール5.29 gを得た。 (e) A suspension of 1.2 g of copper (I) cyanide in 30 ml of tetrahydrofuran was cooled to −30 ° C., and 63 ml of 1.0 M vinylmagnesium bromide in tetrahydrofuran was added dropwise over 10 minutes, followed by stirring for 10 minutes. A solution of 5.0 g of the compound of Reference Example 5 (d) in 45 ml of tetrahydrofuran was added dropwise to the reaction solution over 20 minutes, and the mixture was stirred at -30 ° C to -20 ° C for 2.5 hours. The reaction solution was cooled to −30 ° C., 13 ml of 1.0M vinylmagnesium bromide in tetrahydrofuran was added dropwise over 5 minutes, and the mixture was further stirred at −30 ° C. to −20 ° C. for 40 minutes. To the reaction solution was added 70 ml of 20% aqueous ammonium chloride solution, and the temperature was raised to room temperature, and then tetrahydrofuran was distilled off under reduced pressure. The aqueous layer was extracted twice with 100 ml of ethyl acetate, and the organic layer was washed with 100 ml of saturated brine, dried over anhydrous sodium sulfate, and then filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate (3: 1 to 2: 1)) to give (+)-(R) -7- (N-tert- Butoxycarbonylamino) -1-hepten-4-ol 5.29 g was obtained.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 230 (M+H) +
(2)比旋光度:[α]D 21 6.6°(c1.0, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):1.40-1.73(m, 5-H and 6-H), 1.44(s, C(CH3)3), 1.93(br s, OH), 2.15(m, 3-H), 2.29(m, 3-H), 3.15(m, 7-H), 3.67(m, 4-H), 4.66(br s, NH), 5.14(m, 1-H), 5.82(m, 2-H).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 230 (M + H) +
(2) Specific rotation: [α] D 21 6.6 ° (c1.0, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 1.40-1.73 (m, 5-H and 6-H), 1.44 (s, C (CH 3 ) 3 ), 1.93 (br s, OH), 2.15 (m, 3-H), 2.29 (m, 3-H), 3.15 (m, 7-H), 3.67 (m, 4-H), 4.66 (br s, NH), 5.14 (m , 1-H), 5.82 (m, 2-H).

(f)参考例5(e)の化合物5.29 gを1,4-ジオキサン26 mlに溶解し、4N塩酸1,4-ジオキサン溶液26 mlを加え室温で1.5時間攪拌した。反応液を減圧濃縮し、濃縮液に水40 mlを加え、ジエチルエーテル40 mlで2回洗浄した。水層をムロマチテクノス製DOWEX 50W-X2(H form)にて脱塩し、14%アンモニア水−メタノール(6:1)で溶出した後、溶出液を減圧濃縮して、標記化合物2.3 gを得た。この化合物はこれ以上の精製は行わず、そのまま次の行程に用いた。 (f) 5.29 g of the compound of Reference Example 5 (e) was dissolved in 26 ml of 1,4-dioxane, 26 ml of 4N hydrochloric acid 1,4-dioxane solution was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, 40 ml of water was added to the concentrate, and the mixture was washed twice with 40 ml of diethyl ether. The aqueous layer was desalted with DOWEX 50W-X2 (H form) manufactured by Muromachi Technos and eluted with 14% aqueous ammonia-methanol (6: 1). The eluate was concentrated under reduced pressure to give 2.3 g of the title compound. It was. This compound was used in the next step without further purification.

本化合物の理化学的性状
(1)マススペクトル(ESI):m/z 130 (M+H) +
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):1.47(m, 5-H), 1.70(m, 6-H and 6-H), 2.24(dt, 3-H), 2.65(m, 7-H), 2.90(m, 7-H), 3.627(m, 4-H), 5.10(m, 1-H), 5.87(ddt, 2-H).
Physicochemical properties of this compound (1) Mass spectrum (ESI): m / z 130 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 1.47 (m, 5-H), 1.70 (m, 6-H and 6-H), 2.24 (dt, 3-H), 2.65 (m, 7-H), 2.90 (m, 7-H), 3.627 (m, 4-H), 5.10 (m, 1-H), 5.87 (ddt, 2-H).

参考例6
3-アミノ-5-ブロモピリジンの製造方法
3N水酸化ナトリウム水溶液9 .95 mlに臭素301 μl、5-ブロモニコチン酸アミド1 gを順次加え、原料が溶解するまで室温で撹拌後、10分間加熱還流させた。反応液に10N塩酸水溶液でpH2とした後、水を加え、水層をジエチルエーテルで洗浄した。水層に5N水酸化ナトリウム水溶液を加え、pHを11に調節した後、ジエチルエーテルで抽出した。有機層を無水硫酸マグネシウムで乾燥後、これを濾過し、濾液を減圧濃縮して得られた残渣をアミノシリカゲルカラムクロマトグラフィー(ヘキサン−酢酸エチル(3:1))で精製して、標記化合物617 mgを得た。
Reference Example 6
Method for producing 3-amino-5-bromopyridine
To 9.95 ml of 3N sodium hydroxide aqueous solution, 301 μl of bromine and 1 g of 5-bromonicotinic acid amide were sequentially added, and the mixture was stirred at room temperature until the starting material was dissolved, and then heated to reflux for 10 minutes. The reaction mixture was adjusted to pH 2 with 10N aqueous hydrochloric acid solution, water was added, and the aqueous layer was washed with diethyl ether. A 5N aqueous sodium hydroxide solution was added to the aqueous layer to adjust the pH to 11, followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (hexane-ethyl acetate (3: 1)) to give the title compound 617. mg was obtained.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 173 (M+H)+
(2)1H NMRスペクトル(400MHz, CDCl3) δ(ppm):3.78(br s, NH2), 7.14(t, pyridine), 7.99(d, pyridine), 8.06(d, pyridine).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 173 (M + H) +
(2) 1 H NMR spectrum (400 MHz, CDCl 3 ) δ (ppm): 3.78 (br s, NH 2 ), 7.14 (t, pyridine), 7.99 (d, pyridine), 8.06 (d, pyridine).

参考例7
4-ブロモ-1-(2-トリメチルシリルエトキシカルボニルアミノ)イソキノリンの製造方法
(a)1-アミノイソキノリン500 mgを酢酸17.5 mlに溶解し、臭素554.3 mgの四塩化炭素35 ml溶液を加え、室温で2.5時間撹拌した。反応液を氷水125 mlに注ぎ、5N水酸化カリウムを加え、pH7に調節し、クロロホルムで抽出した。有機層を無水硫酸マグネシウムで乾燥後、これを濾過し、濾液を減圧濃縮して得られた残渣をアミノシリカゲルカラムクロマトグラフィー(ヘキサン−酢酸エチル(2:1))で精製して、1-アミノ-4-ブロモイソキノリン559.1 mgを得た。
Reference Example 7
Process for producing 4-bromo-1- (2-trimethylsilylethoxycarbonylamino) isoquinoline
(a) 1-Aminoisoquinoline 500 mg was dissolved in 17.5 ml of acetic acid, a solution of 554.3 mg of bromine in 35 ml of carbon tetrachloride was added, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was poured into 125 ml of ice water, 5N potassium hydroxide was added to adjust to pH 7, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (hexane-ethyl acetate (2: 1)) to give 1-amino 559.1 mg of -4-bromoisoquinoline was obtained.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 223 (M+H)+
(2)1H NMRスペクトル(400MHz, CDCl3) δ(ppm):5.17(br s, NH2), 7.57(dt, isoquinoline), 7.75(dt, isoquinoline), 7.79(d, isoquinoline), 8.08(d, isoquinoline), 8.13(s, isoquinoline).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 223 (M + H) +
(2) 1 H NMR spectrum (400 MHz, CDCl 3 ) δ (ppm): 5.17 (br s, NH 2 ), 7.57 (dt, isoquinoline), 7.75 (dt, isoquinoline), 7.79 (d, isoquinoline), 8.08 ( d, isoquinoline), 8.13 (s, isoquinoline).

(b)参考例7(a)の化合物202 mgを1,4-ジオキサン2 mlに溶解し、ジイソプロピルエチルアミン473 μl、1-(2-トリメチルシリルエトキシカルボニル)ピロリジン-2,5-ジオン704.5 mgを順次加え、100℃で22時間撹拌した。反応液を室温に戻し、飽和塩化アンモニウム水溶液を加え、水層を酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥後、これを濾過し、有機層を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン−酢酸エチル(10:1))で精製して、標記化合物95.9 mgを得た。 (b) 202 mg of the compound of Reference Example 7 (a) was dissolved in 2 ml of 1,4-dioxane, and 473 μl of diisopropylethylamine and 704.5 mg of 1- (2-trimethylsilylethoxycarbonyl) pyrrolidine-2,5-dione were sequentially added. The mixture was further stirred at 100 ° C. for 22 hours. The reaction solution was returned to room temperature, saturated aqueous ammonium chloride solution was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate (10: 1)) to give the title compound 95.9. mg was obtained.

本化合物の理化学的性状(1)マススペクトル(ESMS):m/z 367 (M+H)+
(2)1H NMRスペクトル(400MHz, CDCl3) δ(ppm):0.05(s, Si(CH3)3), 1.08(dd, CH2Si), 4.31(dd, OCH2), 7.66(t, isoquinoline), 7.81(t, isoquinoline), 8.04(d, isoquinoline), 8.16(d, isoquinoline), 8.50(s, isoquinoline).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 367 (M + H) +
(2) 1 H NMR spectrum (400 MHz, CDCl 3 ) δ (ppm): 0.05 (s, Si (CH 3 ) 3 ), 1.08 (dd, CH 2 Si), 4.31 (dd, OCH 2 ), 7.66 (t , isoquinoline), 7.81 (t, isoquinoline), 8.04 (d, isoquinoline), 8.16 (d, isoquinoline), 8.50 (s, isoquinoline).

Figure 2007069555
Figure 2007069555

実施例1
式(1)において、R1がプロピオニル基、R2が水素原子、R3がメチル基、R4がトランス-3-(キノリン-3-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)工程図10の式(13c)のアリル体(WO2005/019238実施例48(b))715 mg及び1,4-ジアザビシクロ[2.2.2]オクタン4 05 mg をピリジン2.2 mlに溶解し、エチルイソシアネート1.7 mlを加え、封管中、60℃で23時間撹拌した後、1,4-ジアザビシクロ[2.2.2]オクタン405 mg及びエチルイソシアネート1.2 mlを加え、さらに24時間撹拌した。反応液を室温まで戻した後、酢酸エチル50 mlで希釈し、水20 mlで3回、飽和食塩水20 mlで順次洗浄した。有機層を無水硫酸ナトリウムで乾燥後、これを濾過し、濾液を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン−アセトン−28%アンモニア水(35:10:0.1〜30:10:0.1))で精製して、カルバモイル化合物(工程図10の式(14c)において、R5が水素原子及びR6がエチル基で表される化合物)605 mgを得た。
Example 1
In the formula (1), R 1 is a propionyl group, R 2 is a hydrogen atom, R 3 is a methyl group, R 4 is a trans-3- (quinolin-3-yl) -2-propenyl group, R 5 is a hydrogen atom and Method for producing compound in which R 6 is represented by ethyl group
(a) 715 mg of the allyl derivative of the formula (13c) in Step 10 (WO2005 / 019238 Example 48 (b)) and 1,4-diazabicyclo [2.2.2] octane 4 05 mg were dissolved in 2.2 ml of pyridine, After adding 1.7 ml of ethyl isocyanate and stirring in a sealed tube at 60 ° C. for 23 hours, 405 mg of 1,4-diazabicyclo [2.2.2] octane and 1.2 ml of ethyl isocyanate were added and further stirred for 24 hours. The reaction solution was allowed to cool to room temperature, diluted with 50 ml of ethyl acetate, and washed successively with 20 ml of water and three times with 20 ml of saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane-acetone-28% aqueous ammonia (35: 10: 0.1 to 30:10: 0.1)) to obtain 605 mg of a carbamoyl compound (a compound in which R 5 is represented by a hydrogen atom and R 6 is an ethyl group in formula (14c) of Step 10).

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1060 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.91(d, 8-CH3), 1.11(d, 6”-H) , 1.13(t, 3-OCOCH2CH3), 1.13(t, 3”-OCOCH2CH3), 1.15(t, NHCH2CH3), 1.19(d, 6'-H), 1.46(s, 3”-CH3), 1.67(dd, 2”-Hax), 2.03(s, 9-OCOCH3), 2.04(s, 2'-OCOCH3), 2.22(s, NCH3), 2.41(s, 3'-N(CH3)2), 2.85(dd, 2-H), 3.12(t, 4 '-H), 3.14(s, CH(OCH3)2), 3.19(d, 2”-Heq), 3.23(m, 5'-H), 3.24(s, CH(OCH3)2), 3.61(s, 4-OCH3), 3.63(br d, 4-H), 3.91(br d, 5-H), 4.41(m, 4”-H), 4.41(m, 5”-H), 4.54(dd, CH(OCH3)2), 4.67(d, 1'-H), 4.78(d, 1"-H), 4.89(m, 9-H), 4.96(dd, 2'-H), 5.03(br dd, 3-H), 5.03(m, 15-H), 5.07(m, CH=CH2), 5.71(m, CH=CH2).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1060 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.91 (d, 8-CH 3 ), 1.11 (d, 6 ”-H), 1.13 (t, 3-OCOCH 2 CH 3 ), 1.13 (t, 3 ”-OCOCH 2 CH 3 ), 1.15 (t, NHCH 2 CH 3 ), 1.19 (d, 6'-H), 1.46 (s, 3” -CH 3 ), 1.67 (dd, 2 ” -Hax), 2.03 (s, 9-OCOCH 3 ), 2.04 (s, 2'-OCOCH 3 ), 2.22 (s, NCH 3 ), 2.41 (s, 3'-N (CH 3 ) 2 ), 2.85 ( dd, 2-H), 3.12 (t, 4 '-H), 3.14 (s, CH (OCH 3 ) 2 ), 3.19 (d, 2 ”-Heq), 3.23 (m, 5'-H), 3.24 (s, CH (OCH 3 ) 2 ), 3.61 (s, 4-OCH 3 ), 3.63 (br d, 4-H), 3.91 (br d, 5-H), 4.41 (m, 4 ”-H) , 4.41 (m, 5 ”-H), 4.54 (dd, CH (OCH 3 ) 2 ), 4.67 (d, 1'-H), 4.78 (d, 1" -H), 4.89 (m, 9-H ), 4.96 (dd, 2'-H), 5.03 (br dd, 3-H), 5.03 (m, 15-H), 5.07 (m, CH = CH 2 ), 5.71 (m, CH = CH 2 ) .

(b)実施例1(a)の化合物905 mg及びトリス(ジベンジリデンアセトン)ジパラジウム(0)117 mg を1,4-ジオキサン2.8 mlに懸濁し、反応容器をアルゴン置換した後、3−ブロモキノリン230μl、ジシクロヘキシルメチルアミン370μl及び0.5Mトリ−t−ブチルホスフィンの1,4-ジオキサン溶液510μlを加えた。50℃で25.5時間撹拌した後、トリス(ジベンジリデンアセトン)ジパラジウム(0)117 mg及び0.5Mトリ−t−ブチルホスフィンの1,4-ジオキサン溶液510μlを追加し、さらに25.5時間撹拌した。反応液を室温まで戻し、酢酸エチル60 mlを用いて触媒を濾過した。濾液を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン−アセトン−28%アンモニア水(20:10:0.1〜30:20:0.1))で精製して、カップリング化合物(工程図10の式(15c)において、Arがキノリン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)684 mgを得た。(b) 905 mg of the compound of Example 1 (a) and 117 mg of tris (dibenzylideneacetone) dipalladium (0) were suspended in 2.8 ml of 1,4-dioxane, the reaction vessel was purged with argon, and 3-bromo 230 μl of quinoline, 370 μl of dicyclohexylmethylamine and 510 μl of a 1,4-dioxane solution of 0.5 M tri-t-butylphosphine were added. After stirring at 50 ° C. for 25.5 hours, 117 mg of tris (dibenzylideneacetone) dipalladium (0) and 510 μl of 1,4-dioxane solution of 0.5M tri-t-butylphosphine were added, and the mixture was further stirred for 25.5 hours. The reaction solution was returned to room temperature, and the catalyst was filtered using 60 ml of ethyl acetate. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (hexane-acetone-28% aqueous ammonia (20: 10: 0.1 to 30: 20: 0.1)) to produce a coupling compound (step diagram 10). In the formula (15c), Ar is a quinolin-3-yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group) (684 mg).

本化合物の理化学的性状
(1)マススペクトル (FAB):m/z 1188 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.92(d, 8-CH3), 1.12(d, 6”-H), 1.13(t, 3-OCOCH2CH3), 1.20(d, 6'-H), 1.47(s, 3”-CH3), 1.62(dd, 2”- Hax), 2.04(s, 9-OCOCH3), 2.07(s, 2'-OCOCH3), 2.24(s, NCH3), 2.42(s, 3'-N(CH3)2), 2.86(dd, 2-H), 3.15(s, CH(OCH3)2), 3.19(d, 2”-Heq), 3.25(s, CH(OCH3)2), 3.59(s, 4-OCH3), 3.93(br d, 5-H), 4.41(m, 4”-H), 4.41(m, 5”-H), 4.55(dd, CH(OCH3)2), 4.68(d, 1'-H), 4.79(d, 1”-H), 4.92(m, 9-H), 4.97(dd, 2'-H), 5.07(br dd, 3-H), 5.15(m, 15-H), 6.37(dt, CH=CH), 6.61(d, CH=CH), 7.53(ddd, quinoline), 7.66(ddd, quinoline), 7.79(br d, quinoline), 8.02(d, quinoline), 8.06(br d, quinoline), 8.95(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1188 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.92 (d, 8-CH 3 ), 1.12 (d, 6 ”-H), 1.13 (t, 3-OCOCH 2 CH 3 ), 1.20 (d, 6'-H), 1.47 (s, 3 ”-CH 3 ), 1.62 (dd, 2” -Hax), 2.04 (s, 9-OCOCH 3 ), 2.07 (s, 2'-OCOCH 3 ), 2.24 (s, NCH 3 ), 2.42 (s, 3'-N (CH 3 ) 2 ), 2.86 (dd, 2-H), 3.15 (s, CH (OCH 3 ) 2 ), 3.19 (d, 2 ”-Heq), 3.25 (s, CH (OCH 3 ) 2 ), 3.59 (s, 4-OCH 3 ), 3.93 (br d, 5-H), 4.41 (m, 4” -H), 4.41 ( m, 5 ”-H), 4.55 (dd, CH (OCH 3 ) 2 ), 4.68 (d, 1'-H), 4.79 (d, 1” -H), 4.92 (m, 9-H), 4.97 (dd, 2'-H), 5.07 (br dd, 3-H), 5.15 (m, 15-H), 6.37 (dt, CH = CH), 6.61 (d, CH = CH), 7.53 (ddd, quinoline), 7.66 (ddd, quinoline), 7.79 (br d, quinoline), 8.02 (d, quinoline), 8.06 (br d, quinoline), 8.95 (d, quinoline).

(c)実施例1(b)の化合物129 mgにメタノール5.1 mlを加え溶解し、40℃で42時間攪拌した。反応液を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム−メタノール−28%アンモニア水(100:1:0.1〜60:1:0.1))で精製して、脱アセチル化合物(工程図10の式(18c)において、R2が水素原子、Arがキノリン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)60 mgを得た。(c) 5.1 ml of methanol was dissolved in 129 mg of the compound of Example 1 (b), and the mixture was stirred at 40 ° C. for 42 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform-methanol-28% aqueous ammonia (100: 1: 0.1 to 60: 1: 0.1)) to give a deacetylated compound (step diagram) In the formula (18c) of 10, R 2 is a hydrogen atom, Ar is a quinolin-3-yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group)).

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1103 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.87(d, 8-CH3), 1.10(d, 6”-H), 1.12(t, 3-OCOCH2CH3), 1.14(t, 3”-OCOCH2CH3), 1.17(t, NHCH2CH3), 1.20(d, 6'-H), 1.40(m, 8-H), 1.48(s, 3”-CH3), 1.69(dd, 2”-Hax), 2.31(s, NCH3), 2.53(s, 3'-N(CH3)2), 2.62(dd, 2-H), 2.82(dd, 2-H), 3.14(s, CH(OCH3)2), 3.21(d, 2”-Heq), 3.25(s, CH(OCH3)2), 3.47(dd, 2'-H), 3.66(s, 4-OCH3), 4.41(d, 1'-H), 4.48(m, 4”-H), 4.48(m, 5”-H ), 4.81(d, 1”-H), 5.13(m, 15-H), 5.50(m, 3-H), 6.36(dt, CH=CH), 6.59(d, CH=CH), 7.53(ddd, quinoline), 7.67(ddd, quinoline), 7.78(br d, quinoline), 8.01(d, quinoline), 8.06(br d, quinoline), 8.94(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1103 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.87 (d, 8-CH 3 ), 1.10 (d, 6 ”-H), 1.12 (t, 3-OCOCH 2 CH 3 ), 1.14 (t, 3 ”-OCOCH 2 CH 3 ), 1.17 (t, NHCH 2 CH 3 ), 1.20 (d, 6'-H), 1.40 (m, 8-H), 1.48 (s, 3” -CH 3 ), 1.69 (dd, 2 ”-Hax), 2.31 (s, NCH 3 ), 2.53 (s, 3'-N (CH 3 ) 2 ), 2.62 (dd, 2-H), 2.82 (dd, 2 -H), 3.14 (s, CH (OCH 3 ) 2 ), 3.21 (d, 2 ”-Heq), 3.25 (s, CH (OCH 3 ) 2 ), 3.47 (dd, 2'-H), 3.66 ( s, 4-OCH 3 ), 4.41 (d, 1'-H), 4.48 (m, 4 ”-H), 4.48 (m, 5” -H), 4.81 (d, 1 ”-H), 5.13 ( m, 15-H), 5.50 (m, 3-H), 6.36 (dt, CH = CH), 6.59 (d, CH = CH), 7.53 (ddd, quinoline), 7.67 (ddd, quinoline), 7.78 ( br d, quinoline), 8.01 (d, quinoline), 8.06 (br d, quinoline), 8.94 (d, quinoline).

(d)実施例1(c)の化合物21 mgにアセトニトリル-水の等量混合溶媒0.53 ml、ジフルオロ酢酸54μlを加え、室温で20時間攪拌した。反応液をクロロホルム20 mlで希釈し、飽和重曹水10 mlで2回、飽和食塩水10 mlで順次洗浄した。有機層を無水硫酸ナトリウムで乾燥後、これを濾過し、濾液を減圧濃縮して得られた残渣を分取用TLC(クロロホルム−酢酸エチル−メタノール−28%アンモニア水(4:4:1:0.1))で精製して、標記化合物11 mgを得た。 (d) To 21 mg of the compound of Example 1 (c), 0.53 ml of a mixed solvent of equal amounts of acetonitrile and water and 54 μl of difluoroacetic acid were added and stirred at room temperature for 20 hours. The reaction solution was diluted with 20 ml of chloroform and washed successively with 10 ml of saturated aqueous sodium hydrogen carbonate twice and 10 ml of saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to preparative TLC (chloroform-ethyl acetate-methanol-28% aqueous ammonia (4: 4: 1: 0.1 )) To give 11 mg of the title compound.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1057 (M+H)+
(2)比旋光度:[α]D 18 -58°(c0.3, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.89(d, 8-CH3), 1.13(d, 6”-H), 1.16(t, NHCH2CH3), 1.34(m, 8-H), 1.47(s, 3”-CH3), 1.69(dd, 2”-Hax), 2.31(s, NCH3), 2.53(s, 3'-N(CH3)2), 2.84(dd, 2-H), 2.90(dd, 6-CH2), 3.20(d, 2”-Heq), 3.25(q, NHCH2CH3), 3.39(dd, 2'-H), 3.66(s, 4-OCH3), 3.87(br d, 5-H), 3.98(br d, 4-H), 4.38(d, 1'-H), 4.41(m, 4”-H), 4.42(m, 5”-H), 4.82(d, 1”-H), 5.13(m, 15-H), 5.58(m, 3-H), 6.36(dt, CH=CH), 6.58(d, CH=CH), 7.53(ddd, quinoline), 7.67(ddd, quinoline), 7.78(br d, quinoline), 8.00(d, quinoline), 8.06(br d, quinoline), 8.94(d, quinoline), 9.65(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1057 (M + H) +
(2) Specific rotation: [α] D 18 -58 ° (c0.3, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.89 (d, 8-CH 3 ), 1.13 (d, 6 ”-H), 1.16 (t, NHCH 2 CH 3 ), 1.34 ( m, 8-H), 1.47 (s, 3 ”-CH 3 ), 1.69 (dd, 2” -Hax), 2.31 (s, NCH 3 ), 2.53 (s, 3'-N (CH 3 ) 2 ) , 2.84 (dd, 2-H), 2.90 (dd, 6-CH 2 ), 3.20 (d, 2 ”-Heq), 3.25 (q, NHCH 2 CH 3 ), 3.39 (dd, 2'-H), 3.66 (s, 4-OCH 3 ), 3.87 (br d, 5-H), 3.98 (br d, 4-H), 4.38 (d, 1'-H), 4.41 (m, 4 ''-H), 4.42 (m, 5 ''-H), 4.82 (d, 1 ''-H), 5.13 (m, 15-H), 5.58 (m, 3-H), 6.36 (dt, CH = CH), 6.58 (d , CH = CH), 7.53 (ddd, quinoline), 7.67 (ddd, quinoline), 7.78 (br d, quinoline), 8.00 (d, quinoline), 8.06 (br d, quinoline), 8.94 (d, quinoline), 9.65 (s, CHO).

実施例2
式(1)において、R1がプロピオニル基、R2がアセチル基、R3がメチル基、R4がトランス-3-(キノリン-3-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例1(b)の化合物74 mgにメタノール3 mlを加え溶解し、室温で22時間攪拌した。反応液を減圧濃縮して得られた残渣を分取用TLC(酢酸エチル−メタノール−28%アンモニア水(50:1:0.1))で精製して、2'位脱アセチル化合物(工程図10の式(18c)において、R2がアセチル基、Arがキノリン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)10.5 mgを得た。
Example 2
In the formula (1), R 1 is a propionyl group, R 2 is an acetyl group, R 3 is a methyl group, R 4 is a trans-3- (quinolin-3-yl) -2-propenyl group, R 5 is a hydrogen atom and Method for producing compound in which R 6 is represented by ethyl group
(a) To 74 mg of the compound of Example 1 (b), 3 ml of methanol was added and dissolved, followed by stirring at room temperature for 22 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by preparative TLC (ethyl acetate-methanol-28% aqueous ammonia (50: 1: 0.1)) to give a 2′-position deacetylated compound (step of FIG. 10). 10.5 mg of a compound represented by the formula (18c) in which R 2 is an acetyl group, Ar is a quinolin-3-yl group, R 5 is a hydrogen atom and R 6 is an ethyl group.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1145 (M+H)+
(2)比旋光度:[α]D 21 -36°(c1.0, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.93(d, 8-CH3), 1.17(t, NHCH2CH3), 1.20(d, 6'-H), 1.47(s, 3”-CH3), 1.70(dd, 2”-Hax), 2.07(s, 9-OCOCH3), 2.26(s, NCH3), 2.53(s, 3'-N(CH3)2), 2.65(dd, 2-H), 2.87(dd, 2-H), 3.18(s, CH(OCH3)2), 3.26(s, CH(OCH3)2), 3.52(dd, 2'-H), 3.64(s, 4-OCH3), 4.40(d, 1'-H), 4.43(m, 4”-H), 4.43(m, 5”-H), 4.50(dd, CH(OCH3)2), 4.82(d, 1”-H), 4.92(m, 9-H), 5.12(m, 3-H), 5.16(m, 15-H), 6.36(dt, CH=CH), 6.60(d, CH=CH), 7.53(ddd, quinoline), 7.66(ddd, quinoline), 7.78(br d, quinoline), 8.02(d, quinoline), 8.06(br d, quinoline), 8.94(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1145 (M + H) +
(2) Specific rotation: [α] D 21 -36 ° (c1.0, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.93 (d, 8-CH 3 ), 1.17 (t, NHCH 2 CH 3 ), 1.20 (d, 6'-H), 1.47 ( s, 3 ”-CH 3 ), 1.70 (dd, 2” -Hax), 2.07 (s, 9-OCOCH 3 ), 2.26 (s, NCH 3 ), 2.53 (s, 3'-N (CH 3 ) 2 ), 2.65 (dd, 2-H), 2.87 (dd, 2-H), 3.18 (s, CH (OCH 3 ) 2 ), 3.26 (s, CH (OCH 3 ) 2 ), 3.52 (dd, 2 ' -H), 3.64 (s, 4-OCH 3 ), 4.40 (d, 1'-H), 4.43 (m, 4 ”-H), 4.43 (m, 5” -H), 4.50 (dd, CH ( OCH 3 ) 2 ), 4.82 (d, 1 ”-H), 4.92 (m, 9-H), 5.12 (m, 3-H), 5.16 (m, 15-H), 6.36 (dt, CH = CH ), 6.60 (d, CH = CH), 7.53 (ddd, quinoline), 7.66 (ddd, quinoline), 7.78 (br d, quinoline), 8.02 (d, quinoline), 8.06 (br d, quinoline), 8.94 ( d, quinoline).

(b)実施例2(a)の化合物10.5 mgをアセトニトリル210 μlに溶解し、1N塩酸210 μlを加え、室温で1時間攪拌した。反応液に飽和重曹水5 mlを加え、酢酸エチル15 mlで抽出した後、有機層を飽和重曹水10 ml、飽和食塩水10 mlで順次洗浄した。有機層を無水硫酸ナトリウムで乾燥後、これを濾過し、濾液を減圧濃縮して得られた残渣を分取用TLC(クロロホルム−メタノール(14:1))で精製して、標記化合物8.6 mgを得た。 (b) 10.5 mg of the compound of Example 2 (a) was dissolved in 210 μl of acetonitrile, 210 μl of 1N hydrochloric acid was added, and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added 5 ml of saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with 15 ml of ethyl acetate. The organic layer was washed successively with 10 ml of saturated aqueous sodium hydrogen carbonate and 10 ml of saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative TLC (chloroform-methanol (14: 1)) to give 8.6 mg of the title compound. Obtained.

本化合物の理化学的性状
(1)マススペクトル (FAB):m/z 1057 (M+H)+
(2)比旋光度:[α]D 18 -58°(c0.3, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.92(d, 8-CH3), 1.16(t, NHCH2CH3), 1.47(s, 3”-CH3), 1.70(dd, 2”-Hax), 2.07(s, 9-OCOCH3), 2.24(s, NCH3), 2.54(s, 3'-N(CH3)2), 2.67(dd, 2-H), 2.90(dd, 2-H), 2.95(dd, 6-CH2), 3.21(d, 2”-Heq), 3.38(dd, 2'-H), 3.65(s, 4-OCH3), 4.39(d, 1'-H), 4.43(m, 4”-H), 4.43(m, 5”-H), 4.80(t, NH), 4.83(d, 1”-H), 5.19(m, 3-H), 5.19(m, 15-H), 6.36(dt, CH=CH), 6.60(d, CH=CH), 7.53(ddd, quinoline), 7.66(ddd, quinoline), 7.79(dd, quinoline), 8.01(d, quinoline), 8.06(br d, quinoline), 8.94(d, quinoline), 9.65(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1057 (M + H) +
(2) Specific rotation: [α] D 18 -58 ° (c0.3, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.92 (d, 8-CH 3 ), 1.16 (t, NHCH 2 CH 3 ), 1.47 (s, 3 ″ -CH 3 ), 1.70 (dd, 2 ”-Hax), 2.07 (s, 9-OCOCH 3 ), 2.24 (s, NCH 3 ), 2.54 (s, 3'-N (CH 3 ) 2 ), 2.67 (dd, 2-H) , 2.90 (dd, 2-H), 2.95 (dd, 6-CH 2 ), 3.21 (d, 2 ”-Heq), 3.38 (dd, 2'-H), 3.65 (s, 4-OCH 3 ), 4.39 (d, 1'-H), 4.43 (m, 4 ''-H), 4.43 (m, 5 ''-H), 4.80 (t, NH), 4.83 (d, 1 ''-H), 5.19 (m , 3-H), 5.19 (m, 15-H), 6.36 (dt, CH = CH), 6.60 (d, CH = CH), 7.53 (ddd, quinoline), 7.66 (ddd, quinoline), 7.79 (dd , quinoline), 8.01 (d, quinoline), 8.06 (br d, quinoline), 8.94 (d, quinoline), 9.65 (s, CHO).

実施例3
式(1)において、R1がプロピオニル基、R2が水素原子、R3がメチル基、R4がトランス-3-(ナフタレン-2-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例1(b)と同様の方法で、3-ブロモキノリンの代わりに2-ブロモナフタレンを用い、実施例1(a)の化合物258.8 mgから、カップリング化合物(工程図10の式(15c)において、Arがナフタレン-2-イル基、R5が水素原子及びR6がエチル基で表される化合物)151.9mgを得た。
Example 3
In the formula (1), R 1 is a propionyl group, R 2 is a hydrogen atom, R 3 is a methyl group, R 4 is a trans-3- (naphthalen-2-yl) -2-propenyl group, R 5 is a hydrogen atom and Method for producing compound in which R 6 is represented by ethyl group
(a) In the same manner as in Example 1 (b), using 2-bromonaphthalene instead of 3-bromoquinoline, from 258.8 mg of the compound of Example 1 (a), the coupling compound (formula of Step Diagram 10) (15c), Ar is a naphthalen-2-yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group) (151.9 mg).

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1186 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.91(d, 8-CH3), 1.11(d, 6”-H), 1.13(t, 3-OCOCH2CH3), 1.13(t, 3”-OCOCH2CH3), 1.15(t, NHCH2CH3), 1.18(d, 6'-H), 1.46(s, 3”-CH3), 1.67(dd, 2”-Hax), 2.02(s, 9-OCOCH3), 2.04(s, 2'-OCOCH3), 2.22(s, NCH3), 2.41(s, 3'-N(CH3)2), 2.82(dd, 2-H), 3.14(s, CH(OCH3)2), 3.19(d, 2”-Heq), 3.22(m, 5'-H), 3.24(s, CH(OCH3)2), 3.57(s, 4-OCH3), 3.62(br d, 4-H), 3.91(br d, 5-H), 4.41(m, 4”-H), 4.41(m, 5”-H), 4.54(dd, CH(OCH3)2), 4.66(d, 1'-H), 4.77(d, 1”-H), 4.90(m, 9-H), 4.95(dd, 2'-H), 5.06(br dd, 3-H), 5.12(m, 15-H), 6.23(dt, CH=CH), 6.59(d, CH=CH), 7.42(m, naphthalene), 7.54(dd, naphthalene),
7.67(s, naphthalene), 7.75(dt, naphthalene).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1186 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.91 (d, 8-CH 3 ), 1.11 (d, 6 ”-H), 1.13 (t, 3-OCOCH 2 CH 3 ), 1.13 (t, 3 ”-OCOCH 2 CH 3 ), 1.15 (t, NHCH 2 CH 3 ), 1.18 (d, 6'-H), 1.46 (s, 3” -CH 3 ), 1.67 (dd, 2 ” -Hax), 2.02 (s, 9-OCOCH 3 ), 2.04 (s, 2'-OCOCH 3 ), 2.22 (s, NCH 3 ), 2.41 (s, 3'-N (CH 3 ) 2 ), 2.82 ( dd, 2-H), 3.14 (s, CH (OCH 3 ) 2 ), 3.19 (d, 2 ”-Heq), 3.22 (m, 5'-H), 3.24 (s, CH (OCH 3 ) 2 ) , 3.57 (s, 4-OCH 3 ), 3.62 (br d, 4-H), 3.91 (br d, 5-H), 4.41 (m, 4 ”-H), 4.41 (m, 5” -H) , 4.54 (dd, CH (OCH 3 ) 2 ), 4.66 (d, 1'-H), 4.77 (d, 1 ”-H), 4.90 (m, 9-H), 4.95 (dd, 2'-H ), 5.06 (br dd, 3-H), 5.12 (m, 15-H), 6.23 (dt, CH = CH), 6.59 (d, CH = CH), 7.42 (m, naphthalene), 7.54 (dd, naphthalene),
7.67 (s, naphthalene), 7.75 (dt, naphthalene).

(b)実施例1(c)と同様の方法で、実施例3(a)の化合物151.9 mgから、脱アセチル化合物(工程図10の式(18c)において、R2が水素原子、Arがナフタレン-2-イル基、R5が水素原子及びR6がエチル基で表される化合物)70.7 mgを得た。(b) In the same manner as in Example 1 (c), from 151.9 mg of the compound of Example 3 (a), a deacetylated compound (in formula (18c) of process diagram 10, R 2 is a hydrogen atom, Ar is naphthalene, 2-0.7yl compound, a compound in which R 5 is a hydrogen atom and R 6 is an ethyl group) was obtained (70.7 mg).

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1102 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.86(d, 8-CH3), 1.11(d, 6”-H), 1.13(t, 3-OCOCH2CH3), 1.13(t, 3”-OCOCH2CH3), 1.15(t, NHCH2CH3), 1.19(d, 6'-H), 1.46(s, 3”-CH3), 1.67(dd, 2”-Hax), 2.30(s, NCH3), 2.51(s, 3'-N(CH3)2), 2.60(dd, 2-H), 2.80(dd, 2-H), 3.14(s, CH(OCH3)2), 3.20(d, 2”-Heq), 3.23(s, CH(OCH3)2), 3.47(dd, 2'-H), 3.62(s, 4-OCH3), 3,87(br d, 5-H), 3.98(br d, 4-H), 4.39(d, 1'-H), 4.41(d, 4”-H), 4.46(dq, 5”-H), 4.48(dd, CH(OCH3)2), 4.79(d, 1”-H), 5.11(m, 15-H), 5.47(m, 3-H), 6.22(dt, CH=CH), 6.56(d, CH=CH), 7.42(m, naphthalene), 7.51(dd, naphthalene), 7.65(s, naphthalene), 7.75(m, naphthalene).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1102 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.86 (d, 8-CH 3 ), 1.11 (d, 6 ”-H), 1.13 (t, 3-OCOCH 2 CH 3 ), 1.13 (t, 3 ”-OCOCH 2 CH 3 ), 1.15 (t, NHCH 2 CH 3 ), 1.19 (d, 6'-H), 1.46 (s, 3” -CH 3 ), 1.67 (dd, 2 ” -Hax), 2.30 (s, NCH 3 ), 2.51 (s, 3'-N (CH 3 ) 2 ), 2.60 (dd, 2-H), 2.80 (dd, 2-H), 3.14 (s, CH (OCH 3 ) 2 ), 3.20 (d, 2 ”-Heq), 3.23 (s, CH (OCH 3 ) 2 ), 3.47 (dd, 2'-H), 3.62 (s, 4-OCH 3 ), 3 , 87 (br d, 5-H), 3.98 (br d, 4-H), 4.39 (d, 1'-H), 4.41 (d, 4 ”-H), 4.46 (dq, 5” -H) , 4.48 (dd, CH (OCH 3 ) 2 ), 4.79 (d, 1 ”-H), 5.11 (m, 15-H), 5.47 (m, 3-H), 6.22 (dt, CH = CH), 6.56 (d, CH = CH), 7.42 (m, naphthalene), 7.51 (dd, naphthalene), 7.65 (s, naphthalene), 7.75 (m, naphthalene).

(c)実施例1(d)と同様の方法で、実施例3(b)の化合物70.7 mgから、標記化合物59.7 mgを得た。 (c) In the same manner as in Example 1 (d), 59.7 mg of the title compound was obtained from 70.7 mg of the compound of Example 3 (b).

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1056 (M+H)+
(2)比旋光度:[α]D 26 -55°(c1.00, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.89(d, 8-CH3), 1.11(d, 6”-H), 1.13(t, 3-OCOCH2CH3), 1.13(t, 3”-OCOCH2CH3), 1.15(t, NHCH2CH3), 1.16(d, 6'-H), 1.46(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.30(s, NCH3), 2.51(s, 3'-N(CH3)2), 2.63(dd, 2-H), 2.82(dd, 2-H), 2.90(dd, 6-CH2), 3.22(m, 5'-H), 3.21(d, 2”-Heq), 3.39(dd, 2'-H), 3.63(s, 4-OCH3), 3.85(br d, 5-H), 3.98(br d, 4-H), 4.36(d, 1'-H), 4.41(m, 4”-H), 4.44(m, 5”-H), 4.81(d, 1”-H), 5.12(m, 15-H), 5.55(m, 3-H), 6.22(dt, CH=CH), 6.57(d, CH=CH), 7.42(m, naphthalene), 7.53(dd, naphthalene), 7.65(s, naphthalene), 7.76(m, naphthalene), 9.63(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1056 (M + H) +
(2) Specific rotation: [α] D 26 -55 ° (c1.00, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.89 (d, 8-CH 3 ), 1.11 (d, 6 ”-H), 1.13 (t, 3-OCOCH 2 CH 3 ), 1.13 (t, 3 ”-OCOCH 2 CH 3 ), 1.15 (t, NHCH 2 CH 3 ), 1.16 (d, 6'-H), 1.46 (s, 3” -CH 3 ), 1.68 (dd, 2 ” -Hax), 2.30 (s, NCH 3 ), 2.51 (s, 3'-N (CH 3 ) 2 ), 2.63 (dd, 2-H), 2.82 (dd, 2-H), 2.90 (dd, 6 -CH 2 ), 3.22 (m, 5'-H), 3.21 (d, 2 ”-Heq), 3.39 (dd, 2'-H), 3.63 (s, 4-OCH 3 ), 3.85 (br d, 5-H), 3.98 (br d, 4-H), 4.36 (d, 1'-H), 4.41 (m, 4 ''-H), 4.44 (m, 5 ''-H), 4.81 (d, 1 ”-H), 5.12 (m, 15-H), 5.55 (m, 3-H), 6.22 (dt, CH = CH), 6.57 (d, CH = CH), 7.42 (m, naphthalene), 7.53 ( dd, naphthalene), 7.65 (s, naphthalene), 7.76 (m, naphthalene), 9.63 (s, CHO).

実施例4
式(1)において、R1がプロピオニル基、R2が水素原子、R3がメチル基、R4がトランス-3-(キノキサリン-6-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例1(b)と同様の方法で、3-ブロモキノリンの代わりに6-ブロモキノキサリンを用い、マイクロ波照射下、130℃から160℃で25分撹拌して、実施例1(a)の化合物45.2 mgから、カップリング化合物(工程図10の式(15c)において、Arがキノキサリン-6-イル基、R5が水素原子及びR6がエチル基で表される化合物)33.9 mgを得た。
Example 4
In the formula (1), R 1 is a propionyl group, R 2 is a hydrogen atom, R 3 is a methyl group, R 4 is a trans-3- (quinoxalin-6-yl) -2-propenyl group, R 5 is a hydrogen atom and Method for producing compound in which R 6 is represented by ethyl group
(a) In the same manner as in Example 1 (b), instead of 3-bromoquinoline, 6-bromoquinoxaline was used and stirred for 25 minutes at 130 to 160 ° C. under microwave irradiation. From 45.2 mg of the compound in a), a coupling compound (a compound in which Ar is a quinoxalin-6-yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group in the formula (15c) of Step 10) 33.9 mg Got.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1188 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.90(d, 8-CH3), 1.11(d, 6”-H), 1.14(t, NHCH2CH3) , 1.18(d, 6'-H), 1.45(s, 3”-CH3), 1.66(dd, 2”-Hax), 2.02(s, 9-OCOCH3), 2.04(s, 2'-OCOCH3), 2.22(s, NCH3), 2.40(s, 3'-N(CH3)2), 2.84(dd, 2-H), 3.13(s, CH(OCH3)2), 3.19(d, 2”-Heq), 3.23(s, CH(OCH3)2), 3.57(s, 4-OCH3), 3.61(br d, 4-H), 3.91(br d, 5-H), 4.40(m, 5”-H), 4.40(m, 4”-H), 4.53(dd, CH(OCH3)2), 4.66(d, 1'-H), 4.77(d, 1”-H), 4.90(m, 9-H), 4.94(dd, 2'-H), 5.06(br dd, 3-H), 5.12(m, 15-H), 6.37(dt, CH=CH), 6.65(d, CH=CH), 7.83(dd, quinoxaline), 7.92(d, quinoxaline), 8.00(d, quinoxaline), 8.75(d, quinoxaline), 8.79(d, quinoxaline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1188 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.90 (d, 8-CH 3 ), 1.11 (d, 6 ”-H), 1.14 (t, NHCH 2 CH 3 ), 1.18 ( d, 6'-H), 1.45 (s, 3 ”-CH 3 ), 1.66 (dd, 2” -Hax), 2.02 (s, 9-OCOCH 3 ), 2.04 (s, 2'-OCOCH 3 ), 2.22 (s, NCH 3 ), 2.40 (s, 3'-N (CH 3 ) 2 ), 2.84 (dd, 2-H), 3.13 (s, CH (OCH 3 ) 2 ), 3.19 (d, 2 `` -Heq), 3.23 (s, CH (OCH 3 ) 2 ), 3.57 (s, 4-OCH 3 ), 3.61 (br d, 4-H), 3.91 (br d, 5-H), 4.40 (m , 5 ”-H), 4.40 (m, 4” -H), 4.53 (dd, CH (OCH 3 ) 2 ), 4.66 (d, 1'-H), 4.77 (d, 1 ”-H), 4.90 (m, 9-H), 4.94 (dd, 2'-H), 5.06 (br dd, 3-H), 5.12 (m, 15-H), 6.37 (dt, CH = CH), 6.65 (d, CH = CH), 7.83 (dd, quinoxaline), 7.92 (d, quinoxaline), 8.00 (d, quinoxaline), 8.75 (d, quinoxaline), 8.79 (d, quinoxaline).

(b)実施例1(c)と同様の方法で、実施例4(a)の化合物33.9 mgから、脱アセチル化合物(工程図10の式(18c)において、R2が水素原子、Arがキノキサリン-6-イル基、R5が水素原子及びR6がエチル基で表される化合物)19.0 mgを得た。(b) In the same manner as in Example 1 (c), from the compound 33.9 mg of Example 4 (a), a deacetylated compound (in formula (18c) of Process FIG. 10, R 2 is a hydrogen atom, Ar is quinoxaline) 19.0 mg of a compound represented by a -6-yl group, R 5 is a hydrogen atom and R 6 is an ethyl group.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1104 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.86(d, 8-CH3), 1.09(d, 6”-H), 1.17(t, NHCH2CH3), 1.18(d, 6'-H), 1.46(s, 3”-CH3), 1.67(dd, 2”-Hax), 2.30(s, NCH3), 2.51(s, 3'-N(CH3)2), 2.60(dd, 2-H), 2.79(dd, 2-H), 3.13(s, CH(OCH3)2), 3.20(d, 2”- Heq), 3.23(s, CH(OCH3)2), 3.47(dd, 2'-H), 3.62(s, 4-OCH3), 3,87(br d, 5-H), 3.96(br d, 4-H), 4.39(d, 1'-H), 4.42(d, 4”-H), 4.45(dd, CH(OCH3)2), 4.48(dq, 5”-H), 4.79(d, 1”-H), 5.12(m, 15-H), 5.47(m, 3-H), 6.36(dt, CH=CH), 6.64(d, CH=CH), 7.82(dd, quinoxaline), 7.91(d, quinoxaline), 8.00(d, quinoxaline), 8.76(d, quinoxaline), 8.79(d, quinoxaline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1104 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.86 (d, 8-CH 3 ), 1.09 (d, 6 ”-H), 1.17 (t, NHCH 2 CH 3 ), 1.18 ( d, 6'-H), 1.46 (s, 3 "-CH 3 ), 1.67 (dd, 2" -Hax), 2.30 (s, NCH 3 ), 2.51 (s, 3'-N (CH 3 ) 2 ), 2.60 (dd, 2-H), 2.79 (dd, 2-H), 3.13 (s, CH (OCH 3 ) 2 ), 3.20 (d, 2 ”-Heq), 3.23 (s, CH (OCH 3 ) 2 ), 3.47 (dd, 2'-H), 3.62 (s, 4-OCH 3 ), 3,87 (br d, 5-H), 3.96 (br d, 4-H), 4.39 (d, 1'-H), 4.42 (d, 4 ”-H), 4.45 (dd, CH (OCH 3 ) 2 ), 4.48 (dq, 5” -H), 4.79 (d, 1 ”-H), 5.12 ( m, 15-H), 5.47 (m, 3-H), 6.36 (dt, CH = CH), 6.64 (d, CH = CH), 7.82 (dd, quinoxaline), 7.91 (d, quinoxaline), 8.00 ( d, quinoxaline), 8.76 (d, quinoxaline), 8.79 (d, quinoxaline).

(c)実施例1(d)と同様の方法で、実施例4(b)の化合物19.0 mgから、標記化合物18.2 mgを得た。 (c) In the same manner as in Example 1 (d), 18.2 mg of the title compound was obtained from 19.0 mg of the compound of Example 4 (b).

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1058 (M+H)+
(2)比旋光度:[α]D 23 -52°(c1.00, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.87(d, 8-CH3), 1.09(d, 6”-H), 1.17(t, NHCH2CH3), 1.16(d, 6'-H), 1.46(s, 3”-CH3), 1.67(dd, 2”-Hax), 2.30(s, NCH3), 2.52(s, 3'-N(CH3)2), 2.86(dd, 2-H), 2.91(dd, 6-CH2), 3.15(t, 4'-H), 3.21(d, 2”-Heq), 3.38(dd, 2'-H), 3.63(s, 4-OCH3) , 3.84(br d, 5-H), 3.97(br d, 4-H), 4.37(d, 1'-H), 4.39(d, 4”-H), 4.43(dq, 5”-H), 4.80(d, 1”-H), 5.12(m, 15-H), 5.55(m, 3-H), 6.36(dt, CH=CH), 6.63(d, CH=CH), 7.82(dd, quinoxaline), 7.92(d, quinoxaline), 8.01(d, quinoxaline), 8.76(d, quinoxaline), 8.80(d, quinoxaline), 9.63(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1058 (M + H) +
(2) Specific rotation: [α] D 23 -52 ° (c1.00, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.87 (d, 8-CH 3 ), 1.09 (d, 6 ”-H), 1.17 (t, NHCH 2 CH 3 ), 1.16 ( d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.67 (dd, 2” -Hax), 2.30 (s, NCH 3 ), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.86 (dd, 2-H), 2.91 (dd, 6-CH 2 ), 3.15 (t, 4'-H), 3.21 (d, 2 ”-Heq), 3.38 (dd, 2'-H) , 3.63 (s, 4-OCH 3 ), 3.84 (br d, 5-H), 3.97 (br d, 4-H), 4.37 (d, 1'-H), 4.39 (d, 4 ”-H) , 4.43 (dq, 5``-H), 4.80 (d, 1 ''-H), 5.12 (m, 15-H), 5.55 (m, 3-H), 6.36 (dt, CH = CH), 6.63 ( d, CH = CH), 7.82 (dd, quinoxaline), 7.92 (d, quinoxaline), 8.01 (d, quinoxaline), 8.76 (d, quinoxaline), 8.80 (d, quinoxaline), 9.63 (s, CHO).

実施例5
式(1)において、R1がプロピオニル基、R2が水素原子、R3がメチル基、R4がトランス-3-(イソキノリン-4-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例1(b)と同様の方法で、3-ブロモキノリンの代わりに4-ブロモイソキノリンを用い、マイクロ波照射下、130℃から160℃で25分撹拌して、実施例1(a)の化合物45.2 mgから、カップリング化合物(工程図10の式(15c)において、Arがイソキノリン-4-イル基、R5が水素原子及びR6がエチル基で表される化合物)21.2 mgを得た。
Example 5
In the formula (1), R 1 is a propionyl group, R 2 is a hydrogen atom, R 3 is a methyl group, R 4 is a trans-3- (isoquinolin-4-yl) -2-propenyl group, R 5 is a hydrogen atom and Method for producing compound in which R 6 is represented by ethyl group
(a) In the same manner as in Example 1 (b), using 4-bromoisoquinoline instead of 3-bromoquinoline and stirring at 130 to 160 ° C. for 25 minutes under microwave irradiation, Example 1 ( From 45.2 mg of the compound in a), a coupling compound (a compound in which Ar is an isoquinolin-4-yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group in the formula (15c) of Step 10) 21.2 mg Got.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1187 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.91(d, 8-CH3), 1.09(d, 6”-H), 1.17(t, NHCH2CH3) , 1.18(d, 6'-H), 1.46(s, 3”-CH3), 1.67(dd, 2”-Hax), 2.02(s, 9-OCOCH3), 2.04(s, 2'-OCOCH3), 2.23(s, NCH3), 2.41(s, 3'-N(CH3)2), 2.85(dd, 2-H), 3.13(s, CH(OCH3)2), 3.19(d, 2”-Heq), 3.23(s, CH(OCH3)2), 3.57(s, 4-OCH3), 3.64(br d, 4-H), 3.92(br d, 5-H), 4.41(m, 4”-H), 4.41(m, 5”-H), 4.54(dd, CH(OCH3)2), 4.66(d, 1'-H), 4.77(d, 1”-H), 4.90(m, 9-H), 4.95(dd, 2'-H), 5.05(br dd, 3-H), 5.17(m, 15-H), 6.19(dt, CH=CH), 7.01(d, CH=CH), 7.60(ddd, isoquinoline), 7.71(ddd, isoquinoline), 7.95(br d, isoquinoline), 8.03(br d, isoquinoline), 8.51(s, isoquinoline), 9.12(s, isoquinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1187 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.91 (d, 8-CH 3 ), 1.09 (d, 6 ”-H), 1.17 (t, NHCH 2 CH 3 ), 1.18 ( d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.67 (dd, 2” -Hax), 2.02 (s, 9-OCOCH 3 ), 2.04 (s, 2'-OCOCH 3 ), 2.23 (s, NCH 3 ), 2.41 (s, 3'-N (CH 3 ) 2 ), 2.85 (dd, 2-H), 3.13 (s, CH (OCH 3 ) 2 ), 3.19 (d, 2 ” -Heq), 3.23 (s, CH (OCH 3 ) 2 ), 3.57 (s, 4-OCH 3 ), 3.64 (br d, 4-H), 3.92 (br d, 5-H), 4.41 (m, 4 ''-H), 4.41 (m, 5 ''-H), 4.54 (dd, CH (OCH 3 ) 2 ), 4.66 (d, 1'-H), 4.77 (d, 1 ''-H), 4.90 ( m, 9-H), 4.95 (dd, 2'-H), 5.05 (br dd, 3-H), 5.17 (m, 15-H), 6.19 (dt, CH = CH), 7.01 (d, CH = CH), 7.60 (ddd, isoquinoline), 7.71 (ddd, isoquinoline), 7.95 (br d, isoquinoline), 8.03 (br d, isoquinoline), 8.51 (s, isoquinoline), 9.12 (s, isoquinoline).

(b)実施例1(c)と同様の方法で、実施例5(a)の化合物21.2 mgから、脱アセチル化合物(工程図10の式(18c)において、R2が水素原子、Arがイソキノリン-4-イル基、R5が水素原子及びR6がエチル基で表される化合物)11.0 mgを得た。(b) In the same manner as in Example 1 (c), from the compound 21.2 mg of Example 5 (a), the deacetylated compound (in formula (18c) of Process FIG. 10, R 2 is a hydrogen atom, Ar is isoquinoline) -4-yl group, a compound in which R 5 is a hydrogen atom and R 6 is an ethyl group) 11.0 mg was obtained.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1103 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.87(d, 8-CH3), 1.08(d, 6”-H), 1.15(t, NHCH2CH3), 1.19(d, 6'-H), 1.46(s, 3”-CH3), 1.67(dd, 2”-Hax), 2.30(s, NCH3), 2.51(s, 3'-N( CH3)2), 2.60(dd, 2-H), 2.81(dd, 2-H), 3.13(s, CH(OCH3)2), 3.20(d, 2”-Heq), 3.23(s, CH(OCH3)2), 3.47(dd, 2'-H), 3.62(s, 4-OCH3), 3,88(br d, 5-H), 3.98(br d, 4-H), 4.39(d, 1'-H), 4.43(m, 4”-H), 4.46(m, 5”-H), 4.48(dd, CH(OCH3)2), 4.80(d, 1”-H), 5.15(m, 15-H), 5.47(m, 3-H), 6.16(dt, CH=CH), 7.00(d, CH=CH), 7.60(dt, isoquinoline), 7.72(dt, isoquinoline), 7.96(d, isoquinoline), 8.02(d, isoquinoline), 8.51(s, isoquinoline), 9.13(s, isoquinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1103 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.87 (d, 8-CH 3 ), 1.08 (d, 6 ”-H), 1.15 (t, NHCH 2 CH 3 ), 1.19 ( d, 6'-H), 1.46 (s, 3 "-CH 3 ), 1.67 (dd, 2" -Hax), 2.30 (s, NCH 3 ), 2.51 (s, 3'-N (CH 3 ) 2 ), 2.60 (dd, 2-H), 2.81 (dd, 2-H), 3.13 (s, CH (OCH 3 ) 2 ), 3.20 (d, 2 ”-Heq), 3.23 (s, CH (OCH 3 ) 2 ), 3.47 (dd, 2'-H), 3.62 (s, 4-OCH 3 ), 3,88 (br d, 5-H), 3.98 (br d, 4-H), 4.39 (d, 1'-H), 4.43 (m, 4 ”-H), 4.46 (m, 5” -H), 4.48 (dd, CH (OCH 3 ) 2 ), 4.80 (d, 1 ”-H), 5.15 ( m, 15-H), 5.47 (m, 3-H), 6.16 (dt, CH = CH), 7.00 (d, CH = CH), 7.60 (dt, isoquinoline), 7.72 (dt, isoquinoline), 7.96 ( d, isoquinoline), 8.02 (d, isoquinoline), 8.51 (s, isoquinoline), 9.13 (s, isoquinoline).

(c)実施例1(d)と同様の方法で、実施例5(b)の化合物11.0 mgから、標記化合物9.6 mgを得た。 (c) In the same manner as in Example 1 (d), 9.6 mg of the title compound was obtained from 11.0 mg of the compound of Example 5 (b).

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1057(M+H)+
(2)比旋光度:[α]D 24 -44°(c0.80, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.89(d, 8-CH3), 1.09(d, 6”-H), 1.17(t, NHCH2CH3), 1.16(d, 6'-H), 1.46(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.33(s, NCH3), 2.52(s, 3'-N(CH3)2), 2.83(dd, 2-H), 2.90(dd, 6-CH2), 3.15(t, 4'-H), 3.21(d, 2”-Heq), 3.38(dd, 2'-H), 3.62(s, 4-OCH3), 3.85(br d, 5-H), 3.97(br d, 4-H), 4.36(d, 1'-H), 4.39(d, 4”-H), 4.46(dq, 5”-H), 4.81(d, 1”-H), 5.16(m, 15-H), 5.55(m, 3-H), 6.19(dt, CH=CH), 7.00(d, CH=CH), 7.60(dt, isoquinoline), 7.72(dt, isoquinoline), 7.96(d, isoquinoline), 8.02(d, isoquinoline), 8.52(s, isoquinoline), 9.13(s, isoquinoline), 9.63(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1057 (M + H) +
(2) Specific rotation: [α] D 24 -44 ° (c0.80, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.89 (d, 8-CH 3 ), 1.09 (d, 6 ”-H), 1.17 (t, NHCH 2 CH 3 ), 1.16 ( d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.68 (dd, 2” -Hax), 2.33 (s, NCH 3 ), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.83 (dd, 2-H), 2.90 (dd, 6-CH 2 ), 3.15 (t, 4'-H), 3.21 (d, 2 ”-Heq), 3.38 (dd, 2'-H) , 3.62 (s, 4-OCH 3 ), 3.85 (br d, 5-H), 3.97 (br d, 4-H), 4.36 (d, 1'-H), 4.39 (d, 4 ”-H) , 4.46 (dq, 5``-H), 4.81 (d, 1 ''-H), 5.16 (m, 15-H), 5.55 (m, 3-H), 6.19 (dt, CH = CH), 7.00 ( d, CH = CH), 7.60 (dt, isoquinoline), 7.72 (dt, isoquinoline), 7.96 (d, isoquinoline), 8.02 (d, isoquinoline), 8.52 (s, isoquinoline), 9.13 (s, isoquinoline), 9.63 (s, CHO).

実施例6
式(1)において、R1がプロピオニル基、R2がアセチル基、R3がメチル基、R4がトランス-3-(イソキノリン-4-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a) 実施例2(a)と同様の方法で、実施例5(a)の化合物200 mgから、脱アセチル化合物(工程図10の式(18c)において、R2がアセチル基、Arがイソキノリン-4-イル基、R5が水素原子及びR6がエチル基で表される化合物)39 mgを得た。
Example 6
In the formula (1), R 1 is a propionyl group, R 2 is an acetyl group, R 3 is a methyl group, R 4 is a trans-3- (isoquinolin-4-yl) -2-propenyl group, R 5 is a hydrogen atom and Method for producing compound in which R 6 is represented by ethyl group
(a) In the same manner as in Example 2 (a), from 200 mg of the compound of Example 5 (a), a deacetylated compound (in formula (18c) of Process Diagram 10, R 2 is an acetyl group, Ar is isoquinoline) 39 mg of a compound represented by a 4-yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1145 (M+H)+
(2)比旋光度:[α]D 21 -36°(c1.0, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.93(d, 8-CH3), 1.17(t, NHCH2CH3), 1.20(d, 6'-H), 1.48(s, 3”- CH3), 1.70(dd, 2”-Hax), 2.07(s, 9-OCOCH3), 2.26(s, NCH3), 2.54(s, 3'-N(CH3)2), 2.66(dd, 2-H), 2.88(dd, 2-H), 3.19(s, CH(OCH3)2), 3.22(d, 2”-Heq), 3.26(s, CH(OCH3)2), 3.48(dd, 2'-H), 3.64(s, 4-OCH3), 4.41(d, 4”-H), 4.43(d, 1'-H), 4.82(t, NH), 4.82(d, 1”-H), 4.91(m, 9-H), 5.11(br dd, 3-H), 5.21(m, 15-H), 6.21(dt, CH=CH), 7.03(d, CH=CH), 7.62(ddd, isoquinoline), 7.73(ddd, isoquinoline), 7.98(br d, isoquinoline), 8.04(br d, isoquinoline), 8.54(s, isoquinoline), 9.15(s, isoquinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1145 (M + H) +
(2) Specific rotation: [α] D 21 -36 ° (c1.0, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.93 (d, 8-CH 3 ), 1.17 (t, NHCH 2 CH 3 ), 1.20 (d, 6'-H), 1.48 ( s, 3 ”-CH 3 ), 1.70 (dd, 2” -Hax), 2.07 (s, 9-OCOCH 3 ), 2.26 (s, NCH 3 ), 2.54 (s, 3'-N (CH 3 ) 2 ), 2.66 (dd, 2-H), 2.88 (dd, 2-H), 3.19 (s, CH (OCH 3 ) 2 ), 3.22 (d, 2 ”-Heq), 3.26 (s, CH (OCH 3 ) 2 ), 3.48 (dd, 2'-H), 3.64 (s, 4-OCH 3 ), 4.41 (d, 4 ''-H), 4.43 (d, 1'-H), 4.82 (t, NH) , 4.82 (d, 1 ”-H), 4.91 (m, 9-H), 5.11 (br dd, 3-H), 5.21 (m, 15-H), 6.21 (dt, CH = CH), 7.03 ( d, CH = CH), 7.62 (ddd, isoquinoline), 7.73 (ddd, isoquinoline), 7.98 (br d, isoquinoline), 8.04 (br d, isoquinoline), 8.54 (s, isoquinoline), 9.15 (s, isoquinoline) .

(b) 実施例2(b)と同様の方法で、実施例6(a)の化合物87 mgから、標記化合物83 mgを得た。 (b) In the same manner as in Example 2 (b), 83 mg of the title compound was obtained from 87 mg of the compound of Example 6 (a).

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1099 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.92(d, 8-CH3) , 1.17(t, NHCH2CH3), 1.48(s, 3”-CH3), 1.56(m, 7-H), 1.70(dd, 2”-Hax), 2.07(s, 9- OCOCH3), 2.24(s, NCH3), 2.54(s, 3'-N(CH3)2), 2.68(dd, 2-H), 2.90(dd, 2-H), 2.96(dd, 6-CH2), 3.21(d, 2”-Heq), 3.39(dd, 2'-H), 3.64(s, 4-OCH3), 4.39(d, 1'-H), 4.42(m, 4”-H), 4.45(m, 5”-H), 4.81(t, NH), 4.83(d, 1”-H), 5.22(m, 3-H), 5.22(m, 15-H), 6.21(dt, CH=CH), 7.03(d, CH=CH), 7.62(ddd, isoquinoline), 7.73(ddd, isoquinoline), 7.97(br d, isoquinoline), 8.04(br d, isoquinoline), 8.54(s, isoquinoline), 9.15(s, isoquinoline), 9.65(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1099 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.92 (d, 8-CH 3 ), 1.17 (t, NHCH 2 CH 3 ), 1.48 (s, 3 ”-CH 3 ), 1.56 (m, 7-H), 1.70 (dd, 2 ”-Hax), 2.07 (s, 9- OCOCH 3 ), 2.24 (s, NCH 3 ), 2.54 (s, 3'-N (CH 3 ) 2 ) , 2.68 (dd, 2-H), 2.90 (dd, 2-H), 2.96 (dd, 6-CH 2 ), 3.21 (d, 2 ”-Heq), 3.39 (dd, 2'-H), 3.64 (s, 4-OCH 3 ), 4.39 (d, 1'-H), 4.42 (m, 4 ''-H), 4.45 (m, 5 ''-H), 4.81 (t, NH), 4.83 (d, 1 ”-H), 5.22 (m, 3-H), 5.22 (m, 15-H), 6.21 (dt, CH = CH), 7.03 (d, CH = CH), 7.62 (ddd, isoquinoline), 7.73 (ddd, isoquinoline), 7.97 (br d, isoquinoline), 8.04 (br d, isoquinoline), 8.54 (s, isoquinoline), 9.15 (s, isoquinoline), 9.65 (s, CHO).

実施例7
式(1)において、R1がプロピオニル基、R2が水素原子、R3がメチル基、R4がトランス-3-(6-クロロキノリン-3-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例1(b)と同様の方法で、3-ブロモキノリンの代わりに3-ブロモ-6-クロロキノリンを用いて、実施例1(a)の化合物60.2 mgから、カップリング化合物(工程図10の式(15c)において、Arが6-クロロキノリン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)23.6 mgを得た。
Example 7
In the formula (1), R 1 is a propionyl group, R 2 is a hydrogen atom, R 3 is a methyl group, R 4 is a trans-3- (6-chloroquinolin-3-yl) -2-propenyl group, and R 5 is Method for producing compound in which hydrogen atom and R 6 are represented by ethyl group
(a) In the same manner as in Example 1 (b), using 3-bromo-6-chloroquinoline instead of 3-bromoquinoline, from 60.2 mg of Example 1 (a), the coupling compound ( In the formula (15c) of Process FIG. 10, 23.6 mg of a compound in which Ar is a 6-chloroquinolin-3-yl group, R 5 is a hydrogen atom and R 6 is an ethyl group was obtained.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1221 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.92(d, 8-CH3), 1.12(d, 6”-H), 1.12(t, 3”-OCOCH2CH3), 1.19(t, NHCH2CH3), 1.20(d, 6'-H), 1.43(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.04(s, 9-OCOCH3), 2.05(s, 2'-OCOCH3), 2.24(s, NCH3), 2.42(s, 3'-N(CH3)2), 2.86(dd, 2-H), 3.15(s, CH(OCH3)2), 3.19(d, 2”-Heq), 3.25(s, CH(OCH3)2), 3.59(s, 4-OCH3), 3.93(br d, 5-H), 4.40(m, 4”-H), 4.43(m, 5”-H), 4.55(s, CH(OCH3)2), 4.67(d, 1'-H), 4.79(d, 1”-H), 4.91(m, 9-H), 4.96(dd, 2'-H), 5.07(br dd, 3-H), 5.15(m, 15-H), 6.39(dt, CH=CH), 6.59(d, CH=CH), 7.58(dd, quinoline), 7.76(d, quinoline), 7.93(d, quinoline), 7.99(d, quinoline), 8.92(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1221 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.92 (d, 8-CH 3 ), 1.12 (d, 6 ”-H), 1.12 (t, 3” -OCOCH 2 CH 3 ) , 1.19 (t, NHCH 2 CH 3 ), 1.20 (d, 6'-H), 1.43 (s, 3 ”-CH 3 ), 1.68 (dd, 2” -Hax), 2.04 (s, 9-OCOCH 3 ), 2.05 (s, 2'-OCOCH 3 ), 2.24 (s, NCH 3 ), 2.42 (s, 3'-N (CH 3 ) 2 ), 2.86 (dd, 2-H), 3.15 (s, CH (OCH 3 ) 2 ), 3.19 (d, 2 ”-Heq), 3.25 (s, CH (OCH 3 ) 2 ), 3.59 (s, 4-OCH 3 ), 3.93 (br d, 5-H), 4.40 (m, 4 ”-H), 4.43 (m, 5” -H), 4.55 (s, CH (OCH 3 ) 2 ), 4.67 (d, 1'-H), 4.79 (d, 1 ”-H) , 4.91 (m, 9-H), 4.96 (dd, 2'-H), 5.07 (br dd, 3-H), 5.15 (m, 15-H), 6.39 (dt, CH = CH), 6.59 ( d, CH = CH), 7.58 (dd, quinoline), 7.76 (d, quinoline), 7.93 (d, quinoline), 7.99 (d, quinoline), 8.92 (d, quinoline).

(b)実施例1(c)と同様の方法で、実施例7(a)の化合物23.6 mgから、脱アセチル化合物(工程図10の式(18c)において、R2が水素原子、Arが6-クロロキノリン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)12.6 mgを得た。(b) In the same manner as in Example 1 (c), from the compound 23.6 mg of Example 7 (a), the deacetylated compound (in formula (18c) of Process Diagram 10, R 2 is a hydrogen atom, Ar is 6 12.6 mg of a compound represented by -chloroquinolin-3-yl group, R 5 is a hydrogen atom and R 6 is an ethyl group.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1137 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.88(d, 8-CH3), 1.11(t, 3-OCOCH2CH3), 1.12(d, 6”-H), 1.12(t, 3”-OCOCH2CH3), 1.17(t, NHCH2CH3), 1.20(d, 6'-H), 1.44(m, 8-H), 1.48(s, 3”-CH3), 1.69(dd, 2”-Hax), 2.35(s, NCH3), 2.53(s, 3'-N(CH3)2), 2.62(dd, 2-H), 2.71(m, 12-H), 2.82(dd, 2-H), 3.15(s, CH(OCH3)2), 3.21(d, 2”-Heq), 3.25(s, CH(OCH3)2), 3.37(m, 9-H), 3.47(dd, 2'-H), 3.65(s, 4-OCH3), 3.89(br d, 5-H), 3.95(br d, 4-H), 4.41(d, 4”-H), 4.44(d, 1'-H), 4.81(d, 1”-H) , 5.13(m, 15-H), 5.13(m, 15-H), 5.47(br dd, 3-H), 6.37(dt, CH=CH), 6.57(d, CH=CH), 7.59(dd, quinoline), 7.76(d, quinoline), 7.90(d, quinoline), 7.99(d, quinoline), 8.91(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1137 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.88 (d, 8-CH 3 ), 1.11 (t, 3-OCOCH 2 CH 3 ), 1.12 (d, 6 ”-H), 1.12 (t, 3 ”-OCOCH 2 CH 3 ), 1.17 (t, NHCH 2 CH 3 ), 1.20 (d, 6'-H), 1.44 (m, 8-H), 1.48 (s, 3” -CH 3 ), 1.69 (dd, 2 ”-Hax), 2.35 (s, NCH 3 ), 2.53 (s, 3'-N (CH 3 ) 2 ), 2.62 (dd, 2-H), 2.71 (m, 12 -H), 2.82 (dd, 2-H), 3.15 (s, CH (OCH 3 ) 2 ), 3.21 (d, 2 ”-Heq), 3.25 (s, CH (OCH 3 ) 2 ), 3.37 (m , 9-H), 3.47 (dd, 2'-H), 3.65 (s, 4-OCH 3 ), 3.89 (br d, 5-H), 3.95 (br d, 4-H), 4.41 (d, 4 ”-H), 4.44 (d, 1'-H), 4.81 (d, 1” -H), 5.13 (m, 15-H), 5.13 (m, 15-H), 5.47 (br dd, 3 -H), 6.37 (dt, CH = CH), 6.57 (d, CH = CH), 7.59 (dd, quinoline), 7.76 (d, quinoline), 7.90 (d, quinoline), 7.99 (d, quinoline), 8.91 (d, quinoline).

(c)実施例1(d)と同様の方法で、実施例7(b)の化合物12.6 mgから、標記化合物10.4 mgを得た。 (c) In the same manner as in Example 1 (d), 10.4 mg of the title compound was obtained from 12.6 mg of the compound of Example 7 (b).

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1091 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.90(d, 8-CH3), 1.13(d, 6”-H), 1.16(t, NHCH2CH3), 1.35(m, 8-H), 1.47(s, 3”-CH3), 1.70(dd, 2”-Hax), 2.32(s, NCH3), 2.53(s, 3'-N(CH3)2), 2.84(dd, 2-H), 2.90(dd, 6-CH2), 3.17(m, 4'-H), 3.17(m, 5'-H), 3.21(d, 2”-Heq), 3.26(dq, NHCH2CH3), 3.39(m, 9-H), 3.39(dd, 2'-H), 3.66(s, 4-OCH3), 3.87(br d, 5-H), 3.96(br d, 4-H), 4.38(d, 1'-H), 4.42(m, 4”-H), 4.45(m, 5”-H), 4.80(t, NH), 4.82(d, 1”-H), 5.13(m, 15-H), 5.56(br dd, 3-H), 6.37(dt, CH=CH), 6.57(d, CH=CH), 7.59(dd, quinoline), 7.76(d, quinoline), 7.90(d, quinoline), 7.99(d, quinoline), 8.92(d, quinoline), 9.64(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1091 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.90 (d, 8-CH 3 ), 1.13 (d, 6 ”-H), 1.16 (t, NHCH 2 CH 3 ), 1.35 ( m, 8-H), 1.47 (s, 3 ”-CH 3 ), 1.70 (dd, 2” -Hax), 2.32 (s, NCH 3 ), 2.53 (s, 3'-N (CH 3 ) 2 ) , 2.84 (dd, 2-H), 2.90 (dd, 6-CH 2 ), 3.17 (m, 4'-H), 3.17 (m, 5'-H), 3.21 (d, 2 ”-Heq), 3.26 (dq, NHCH 2 CH 3 ), 3.39 (m, 9-H), 3.39 (dd, 2'-H), 3.66 (s, 4-OCH 3 ), 3.87 (br d, 5-H), 3.96 (br d, 4-H), 4.38 (d, 1'-H), 4.42 (m, 4 ''-H), 4.45 (m, 5 ''-H), 4.80 (t, NH), 4.82 (d, 1 ”-H), 5.13 (m, 15-H), 5.56 (br dd, 3-H), 6.37 (dt, CH = CH), 6.57 (d, CH = CH), 7.59 (dd, quinoline), 7.76 (d, quinoline), 7.90 (d, quinoline), 7.99 (d, quinoline), 8.92 (d, quinoline), 9.64 (s, CHO).

実施例8
式(1)において、R1がプロピオニル基、R2が水素原子、R3がメチル基、R4がトランス-3-(キノリン-2-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例1(a)の化合物45.1 mgをジクロロメタン0.9 mlに溶解し、参考例1(a)の化合物30.1 mg、第二世代Grubbs触媒(トリシクロヘキシルホスフィン〔1,3-ビス(2,4,6-トリメチルフェニル)-4,5-ジヒドロイミダゾール-2-イリデン〕〔ベンジリデン〕ルテニウム(IV)ジクロライド)3.61 mgを加え、反応容器をアルゴン置換した。反応中に同量の触媒を2回追加しながら31.5時間加熱還流した。反応液を減圧濃縮して得られた残渣を分取用TLC(クロロホルム−酢酸エチル−メタノール(3:2:1))で精製して、カップリング化合物(工程図10の式(15c)において、Arがキノリン-2-イル基、R5が水素原子及びR6がエチル基で表される化合物)6.9 mgを得た。
Example 8
In the formula (1), R 1 is a propionyl group, R 2 is a hydrogen atom, R 3 is a methyl group, R 4 is a trans-3- (quinolin-2-yl) -2-propenyl group, R 5 is a hydrogen atom and Method for producing compound in which R 6 is represented by ethyl group
(a) 45.1 mg of the compound of Example 1 (a) was dissolved in 0.9 ml of dichloromethane, 30.1 mg of the compound of Reference Example 1 (a), a second generation Grubbs catalyst (tricyclohexylphosphine [1,3-bis (2, 4,6-trimethylphenyl) -4,5-dihydroimidazol-2-ylidene] [benzylidene] ruthenium (IV) dichloride) 3.61 mg was added, and the reaction vessel was purged with argon. While adding the same amount of catalyst twice during the reaction, the mixture was heated to reflux for 31.5 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by preparative TLC (chloroform-ethyl acetate-methanol (3: 2: 1)), and the coupling compound (in the formula (15c) of process diagram 10) 6.9 mg of a compound in which Ar is a quinolin-2-yl group, R 5 is a hydrogen atom and R 6 is an ethyl group.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1187 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.91(d, 8-CH3), 1.11(d, 6”-H), 1.17(t, NHCH2CH3), 1.18(d, 6'-H), 1.46(s, 3”-CH3), 1.67(dd, 2”-Hax), 2.03(s, 9-OCOCH3), 2.04(s, 2'-OCOCH3), 2.21(s, NCH3), 2.41(s, 3'-N(CH3)2), 2.86(dd, 2-H), 3.14(s, CH(OCH3)2), 3.19(d, 2”-Heq), 3.24(s, CH(OCH3)2), 3.57(s, 4-OCH3), 3.63(br d, 4-H), 3.91(br d, 5-H), 4.41(m, 4”-H), 4.41(m, 5”-H), 4.54(dd, CH(OCH3)2), 4.67(d, 1'-H), 4.78(d, 1”-H), 4.89(m, 9-H), 4.95(dd, 2'-H), 5.05(br dd, 3-H), 5.16(m, 15-H), 6.73(dt, CH=CH), 6.73(d, CH=CH), 7.47(dt, quinoline), 7.51(d, quinoline), 7.67(dt, quinoline), 7.75(d, quinoline), 8.01(d, quinoline), 8.07(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1187 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.91 (d, 8-CH 3 ), 1.11 (d, 6 ”-H), 1.17 (t, NHCH 2 CH 3 ), 1.18 ( d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.67 (dd, 2” -Hax), 2.03 (s, 9-OCOCH 3 ), 2.04 (s, 2'-OCOCH 3 ), 2.21 (s, NCH 3 ), 2.41 (s, 3'-N (CH 3 ) 2 ), 2.86 (dd, 2-H), 3.14 (s, CH (OCH 3 ) 2 ), 3.19 (d, 2 ” -Heq), 3.24 (s, CH (OCH 3 ) 2 ), 3.57 (s, 4-OCH 3 ), 3.63 (br d, 4-H), 3.91 (br d, 5-H), 4.41 (m, 4 ''-H), 4.41 (m, 5 ''-H), 4.54 (dd, CH (OCH 3 ) 2 ), 4.67 (d, 1'-H), 4.78 (d, 1 ''-H), 4.89 ( m, 9-H), 4.95 (dd, 2'-H), 5.05 (br dd, 3-H), 5.16 (m, 15-H), 6.73 (dt, CH = CH), 6.73 (d, CH = CH), 7.47 (dt, quinoline), 7.51 (d, quinoline), 7.67 (dt, quinoline), 7.75 (d, quinoline), 8.01 (d, quinoline), 8.07 (d, quinoline).

(b)実施例1(c)と同様の方法で、実施例8(a)の化合物12.0 mgから、脱アセチル化合物(工程図10の式(18c)において、R2が水素原子、Arがキノリン-2-イル基、R5が水素原子及びR6がエチル基で表される化合物)5.8 mgを得た。(b) In the same manner as in Example 1 (c), from the compound 12.0 mg of Example 8 (a), a deacetylated compound (in formula (18c) of Process Diagram 10, R 2 is a hydrogen atom, Ar is quinoline) 5.8 mg of a compound represented by a 2-yl group, R 5 is a hydrogen atom and R 6 is an ethyl group.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1103 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.87(d, 8-CH3), 1.08(d, 6”-H), 1.17(t, NHCH2CH3), 1.19(d, 6'-H), 1.46(s, 3”-CH3), 1.67(dd, 2”-Hax), 2.33(s, NCH3), 2.51(s, 3'-N(CH3)2), 2.62(dd, 2-H), 2.82(dd, 2-H), 3.14(s, CH(OCH3)2), 3.20(d, 2”-Heq), 3.23(s, CH(OCH3)2), 3.47(dd, 2'-H), 3.63(s, 4-OCH3), 3,87(br d, 5-H), 3.96(br d, 4-H), 4.39(d, 1'-H), 4.42(d, 4”-H), 4.46(dq, 5”-H), 4.48(dd, CH(OCH3)2), 4.80(d, 1”-H), 5.14(m, 15-H), 5.45(m, 3-H), 6.71(dt, CH=CH), 6.72(d, CH=CH), 7.46(dt, quinoline), 7.50(d, quinoline), 7.67(dt, quinoline), 7.75(d, quinoline), 8.01(d, quinoline), 8.06(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1103 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.87 (d, 8-CH 3 ), 1.08 (d, 6 ”-H), 1.17 (t, NHCH 2 CH 3 ), 1.19 ( d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.67 (dd, 2” -Hax), 2.33 (s, NCH 3 ), 2.51 (s, 3'-N (CH 3 ) 2 ), 2.62 (dd, 2-H), 2.82 (dd, 2-H), 3.14 (s, CH (OCH 3 ) 2 ), 3.20 (d, 2 ”-Heq), 3.23 (s, CH (OCH 3 ) 2 ), 3.47 (dd, 2'-H), 3.63 (s, 4-OCH 3 ), 3,87 (br d, 5-H), 3.96 (br d, 4-H), 4.39 (d, 1'-H), 4.42 (d, 4 ”-H), 4.46 (dq, 5” -H), 4.48 (dd, CH (OCH 3 ) 2 ), 4.80 (d, 1 ”-H), 5.14 ( m, 15-H), 5.45 (m, 3-H), 6.71 (dt, CH = CH), 6.72 (d, CH = CH), 7.46 (dt, quinoline), 7.50 (d, quinoline), 7.67 ( dt, quinoline), 7.75 (d, quinoline), 8.01 (d, quinoline), 8.06 (d, quinoline).

(c)実施例1(d)と同様の方法で、実施例8(b)の化合物5.8 mgから、標記化合物3.73 mgを得た。 (c) In the same manner as in Example 1 (d), 3.73 mg of the title compound was obtained from 5.8 mg of the compound of Example 8 (b).

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1057 (M+H)+
(2)比旋光度:[α]D 27 -35°(c0.53, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.90(d, 8-CH3), 1.11(d, 6”-H), 1.17(t, NHCH2CH3), 1.16(d, 6'-H), 1.46(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.34(s, NCH3), 2.52(s, 3'-N(CH3)2), 2.64(dd, 2-H), 2.84(dd, 2-H), 2.90(dd, 6-CH2), 3.21(d, 2”-Heq), 3.38(dd, 2'-H), 3.64(s, 4-OCH3) , 3.96(br d, 5-H), 3.98(br d, 4-H), 4.36(d, 1'-H), 4.40(d, 4”-H), 4.44(dq, 5”-H), 4.81(d, 1”-H), 5.15(m, 15-H), 5.53(m, 3-H), 6.71(dt, CH=CH), 6.72(d, CH=CH), 7.47(dt, quinoline), 7.50(d, quinoline), 7.67(dt, quinoline), 7.75(d, quinoline), 8.02(d, quinoline), 8.06(d, quinoline), 9.63(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1057 (M + H) +
(2) Specific rotation: [α] D 27 -35 ° (c0.53, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.90 (d, 8-CH 3 ), 1.11 (d, 6 ”-H), 1.17 (t, NHCH 2 CH 3 ), 1.16 ( d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.68 (dd, 2” -Hax), 2.34 (s, NCH 3 ), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.64 (dd, 2-H), 2.84 (dd, 2-H), 2.90 (dd, 6-CH 2 ), 3.21 (d, 2 ”-Heq), 3.38 (dd, 2'-H), 3.64 (s, 4-OCH 3 ), 3.96 (br d, 5-H), 3.98 (br d, 4-H), 4.36 (d, 1'-H), 4.40 (d, 4 ”-H), 4.44 (dq, 5``-H), 4.81 (d, 1 ''-H), 5.15 (m, 15-H), 5.53 (m, 3-H), 6.71 (dt, CH = CH), 6.72 (d , CH = CH), 7.47 (dt, quinoline), 7.50 (d, quinoline), 7.67 (dt, quinoline), 7.75 (d, quinoline), 8.02 (d, quinoline), 8.06 (d, quinoline), 9.63 ( s, CHO).

実施例9
式(1)において、R1がプロピオニル基、R2が水素原子、R3がメチル基、R4がトランス-3-(キノキサリン-2-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例8(a)と同様の方法で、参考例1の化合物の代わりに参考例2の化合物を用いて、実施例1(a)の化合物40.0 mgから、カップリング化合物(工程図10の式(15c)において、Arがキノキサリン-2-イル基、R5が水素原子及びR6がエチル基で表される化合物)18.8 mgを得た。
Example 9
In the formula (1), R 1 is a propionyl group, R 2 is a hydrogen atom, R 3 is a methyl group, R 4 is a trans-3- (quinoxalin-2-yl) -2-propenyl group, R 5 is a hydrogen atom and Method for producing compound in which R 6 is represented by ethyl group
(a) In the same manner as in Example 8 (a), using the compound of Reference Example 2 instead of the compound of Reference Example 1, from 40.0 mg of the compound of Example 1 (a), the coupling compound (process diagram) In this formula (15c), Ar is a quinoxalin-2-yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group) (18.8 mg).

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1188 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.91(d, 8-CH3), 1.11(d, 6”-H), 1.17(t, NHCH2CH3), 1.18(d, 6'-H), 1.46(s, 3”-CH3), 1.67(dd, 2”-Hax), 2.02(s, 9-OCOCH3), 2.04(s, 2'-OCOCH3), 2.22(s, NCH3), 2.41(s, 3'-N(CH3)2), 2.55(dd, 2-H), 2.60(dd, 3'-H), 2.86(dd, 2-H), 3.13(s, CH(OCH3)2), 3.18(d, 2”-Heq), 3.23(s,CH(OCH3)2), 3.58(s, 4-OCH3), 3.61(br d, 4-H), 3.92(br d, 5-H), 4.41(m, 5”-H), 4.41(m, 4”-H), 4.54(dd, CH(OCH3)2), 4.66(d, 1'-H), 4.77(d, 1”-H), 4.90(m, 9-H), 4.95(dd, 2'-H), 5.06(br dd, 3-H), 5.18(m, 15-H), 6.75(d, CH=CH), 6.92(dt, CH=CH), 7.70(m, quinoxaline), 8.02(m, quinoxaline), 8.90(s, quinoxaline).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1188 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.91 (d, 8-CH 3 ), 1.11 (d, 6 ”-H), 1.17 (t, NHCH 2 CH 3 ), 1.18 ( d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.67 (dd, 2” -Hax), 2.02 (s, 9-OCOCH 3 ), 2.04 (s, 2'-OCOCH 3 ), 2.22 (s, NCH 3 ), 2.41 (s, 3'-N (CH 3 ) 2 ), 2.55 (dd, 2-H), 2.60 (dd, 3'-H), 2.86 (dd, 2-H) , 3.13 (s, CH (OCH 3 ) 2 ), 3.18 (d, 2 ”-Heq), 3.23 (s, CH (OCH 3 ) 2 ), 3.58 (s, 4-OCH 3 ), 3.61 (br d, 4-H), 3.92 (br d, 5-H), 4.41 (m, 5 ''-H), 4.41 (m, 4 ''-H), 4.54 (dd, CH (OCH 3 ) 2 ), 4.66 (d , 1'-H), 4.77 (d, 1 ''-H), 4.90 (m, 9-H), 4.95 (dd, 2'-H), 5.06 (br dd, 3-H), 5.18 (m, 15-H), 6.75 (d, CH = CH), 6.92 (dt, CH = CH), 7.70 (m, quinoxaline), 8.02 (m, quinoxaline), 8.90 (s, quinoxaline).

(b)実施例1(c)と同様の方法で、実施例9(a)の化合物18.8 mgから、脱アセチル化合物(工程図10の式(18c)において、R2が水素原子、Arがキノキサリン-2-イル基、R5が水素原子及びR6がエチル基で表される化合物)12.3 mgを得た。(b) In the same manner as in Example 1 (c), from 18.8 mg of the compound of Example 9 (a), a deacetylated compound (in formula (18c) of process diagram 10, R 2 is a hydrogen atom, Ar is quinoxaline) -2-yl group, R 5 is a hydrogen atom and R 6 is an ethyl group) (12.3 mg).

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1104 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.86(d, 8-CH3), 1.08(d, 6”-H), 1.11(t, 3-OCOCH2CH3), 1.13(t, 3”-OCOCH2CH3), 1.17(t, NHCH2CH3), 1.18(d, 6'-H), 1.46(s, 3”-CH3), 1.67(dd, 2”-Hax), 2.32(s, NCH3), 2.51(s, 3'-N(CH3)2), 2.82(dd, 2-H), 3.14(s, CH(OCH3)2), 3.20(d, 2”-Heq), 3.23(s, CH(OCH3)2), 3.46(dd, 2'-H), 3.64(s, 4-OCH3), 3,87(br d, 5-H), 3.95(br d, 4-H), 4.39(d, 1'-H), 4.41(d, 4”-H), 4.46(dq, 5”-H), 4.48(dd, CH(OCH3)2), 4.79(d, 1”-H), 5.15(m, 15-H), 5.46(m, 3-H), 6.74(d, CH=CH), 6.91(dt, CH=CH), 7.71(m, quinoxaline), 8.02(m, quinoxaline), 8.88(s, quinoxaline).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1104 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.86 (d, 8-CH 3 ), 1.08 (d, 6 ″ -H), 1.11 (t, 3-OCOCH 2 CH 3 ), 1.13 (t, 3 ”-OCOCH 2 CH 3 ), 1.17 (t, NHCH 2 CH 3 ), 1.18 (d, 6'-H), 1.46 (s, 3” -CH 3 ), 1.67 (dd, 2 ” -Hax), 2.32 (s, NCH 3 ), 2.51 (s, 3'-N (CH 3 ) 2 ), 2.82 (dd, 2-H), 3.14 (s, CH (OCH 3 ) 2 ), 3.20 ( d, 2 ”-Heq), 3.23 (s, CH (OCH 3 ) 2 ), 3.46 (dd, 2'-H), 3.64 (s, 4-OCH 3 ), 3,87 (br d, 5-H ), 3.95 (br d, 4-H), 4.39 (d, 1'-H), 4.41 (d, 4 ''-H), 4.46 (dq, 5 ''-H), 4.48 (dd, CH (OCH 3 ) 2 ), 4.79 (d, 1 ''-H), 5.15 (m, 15-H), 5.46 (m, 3-H), 6.74 (d, CH = CH), 6.91 (dt, CH = CH), 7.71 (m, quinoxaline), 8.02 (m, quinoxaline), 8.88 (s, quinoxaline).

(c)実施例1(d)と同様の方法で、実施例9(b)の化合物12.3 mgから、標記化合物7.6 mgを得た。
本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1058 (M+H)+
(2)比旋光度:[α]D 27 -50°(c0.63, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.89(d, 8-CH3), 1.10(d, 6”-H), 1.12(t, 3-OCOCH2CH3), 1.14(t, 3”-OCOCH2CH3), 1.15(t, NHCH2CH3), 1.16(d, 6'-H), 1.46(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.32(s, NCH3), 2.52(s, 3'-N(CH3)2), 2.62(dd, 2-H), 2.84(dd, 2-H), 2.90(dd, 6-CH2), 3.21(d, 2”-Heq), 3.38(dd, 2'-H), 3.65(s, 4-OCH3), 3.85(br d, 5-H), 3.95(br d, 4-H), 4.37(d, 1'-H), 4.42(m, 4”-H), 4.44(m, 5”-H), 4.81(d, 1”-H), 5.15(m, 15-H), 5.55(m, 3-H), 6.74(d, CH=CH), 6.91(dt, CH=CH), 7.71(m, quinoxaline), 8.02(m, quinoxaline), 8.88(s, quinoxaline), 9.63(s, CHO).
(c) In the same manner as in Example 1 (d), 7.6 mg of the title compound was obtained from 12.3 mg of the compound of Example 9 (b).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1058 (M + H) +
(2) Specific rotation: [α] D 27 -50 ° (c0.63, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.89 (d, 8-CH 3 ), 1.10 (d, 6 ”-H), 1.12 (t, 3-OCOCH 2 CH 3 ), 1.14 (t, 3 ”-OCOCH 2 CH 3 ), 1.15 (t, NHCH 2 CH 3 ), 1.16 (d, 6'-H), 1.46 (s, 3” -CH 3 ), 1.68 (dd, 2 ” -Hax), 2.32 (s, NCH 3 ), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.62 (dd, 2-H), 2.84 (dd, 2-H), 2.90 (dd, 6 -CH 2 ), 3.21 (d, 2 ''-Heq), 3.38 (dd, 2'-H), 3.65 (s, 4-OCH 3 ), 3.85 (br d, 5-H), 3.95 (br d, 4-H), 4.37 (d, 1'-H), 4.42 (m, 4 ”-H), 4.44 (m, 5” -H), 4.81 (d, 1 ”-H), 5.15 (m, 15 -H), 5.55 (m, 3-H), 6.74 (d, CH = CH), 6.91 (dt, CH = CH), 7.71 (m, quinoxaline), 8.02 (m, quinoxaline), 8.88 (s, quinoxaline ), 9.63 (s, CHO).

実施例10
式(1)において、R1がプロピオニル基、R2が水素原子、R3がメチル基、R4がトランス-3-(1,5-ナフチリジン-3-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例1(b)と同様の方法で、3-ブロモキノリンの代わりに3-ブロモ-1,5-ナフチリジンを用いて、実施例1(a)の化合物70.1 mgから、カップリング化合物(工程図10の式(15c)において、Arが1,5-ナフチリジン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)33.3 mgを得た。
Example 10
In the formula (1), R 1 is a propionyl group, R 2 is a hydrogen atom, R 3 is a methyl group, R 4 is a trans-3- (1,5-naphthyridin-3-yl) -2-propenyl group, R 5 For producing a compound in which R 6 represents a hydrogen atom and R 6 represents an ethyl group
(a) In the same manner as in Example 1 (b), using 3-bromo-1,5-naphthyridine instead of 3-bromoquinoline, from 70.1 mg of the compound of Example 1 (a), the coupling compound (In the formula (15c) in Process FIG. 10, Ar is a 1,5-naphthyridin-3-yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group) 33.3 mg was obtained.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1188 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.93(d, 8-CH3), 1.12(d, 6”-H), 1.14(t, 3-OCOCH2CH3), 1.16(t, 3”-OCOCH2CH3), 1.18(d, 6'-H), 1.19(t, NHCH2CH3), 1.47(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.04(s, 9-OCOCH3), 2.06(s, 2'-OCOCH3), 2.24(s, NCH3), 2.42(s, 3'-N(CH3)2), 2.87(dd, 2-H), 3.13(t, 4'-H), 3.15(s, CH(OCH3)2), 3.19(d, 2”-Heq), 3.25(s, CH(OCH3)2), 3.60(s, 4-OCH3), 3.93(br d, 5-H), 4.40(m, 4”-H), 4.43(m, 5”-H), 4.55(s, CH(OCH3)2), 4.68(d, 1'-H), 4.79(d, 1”-H),4.81(t, NH), 4.91(m, 9-H), 4.97(dd, 2'-H), 5.07(br dd, 3-H), 5.16(m, 15-H), 6.47(dt, CH=CH), 6.67(d, CH=CH), 7.59(dd, naphthyridine), 8.25(d, naphthyridine), 8.36(br d, naphthyridine), 8.95(dd, naphthyridine), 9.01(d, naphthyridine).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1188 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.93 (d, 8-CH 3 ), 1.12 (d, 6 ”-H), 1.14 (t, 3-OCOCH 2 CH 3 ), 1.16 (t, 3 ”-OCOCH 2 CH 3 ), 1.18 (d, 6'-H), 1.19 (t, NHCH 2 CH 3 ), 1.47 (s, 3” -CH 3 ), 1.68 (dd, 2 ” -Hax), 2.04 (s, 9-OCOCH 3 ), 2.06 (s, 2'-OCOCH 3 ), 2.24 (s, NCH 3 ), 2.42 (s, 3'-N (CH 3 ) 2 ), 2.87 ( dd, 2-H), 3.13 (t, 4'-H), 3.15 (s, CH (OCH 3 ) 2 ), 3.19 (d, 2 ”-Heq), 3.25 (s, CH (OCH 3 ) 2 ) , 3.60 (s, 4-OCH 3 ), 3.93 (br d, 5-H), 4.40 (m, 4 ”-H), 4.43 (m, 5” -H), 4.55 (s, CH (OCH 3 ) 2 ), 4.68 (d, 1'-H), 4.79 (d, 1 ''-H), 4.81 (t, NH), 4.91 (m, 9-H), 4.97 (dd, 2'-H), 5.07 (br dd, 3-H), 5.16 (m, 15-H), 6.47 (dt, CH = CH), 6.67 (d, CH = CH), 7.59 (dd, naphthyridine), 8.25 (d, naphthyridine), 8.36 (br d, naphthyridine), 8.95 (dd, naphthyridine), 9.01 (d, naphthyridine).

(b)実施例1(c)と同様の方法で、実施例10(a)の化合物33.3 mgから、脱アセチル化合物(工程図10の式(18c)において、R2が水素原子、Arが1,5-ナフチリジン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)17.6 mgを得た。(b) In the same manner as in Example 1 (c), from the compound 33.3 mg of Example 10 (a), the deacetylated compound (in formula (18c) of Process Diagram 10, R 2 is a hydrogen atom, Ar is 1 , 5-naphthyridin-3-yl group, R 5 is a hydrogen atom and R 6 is an ethyl group) (17.6 mg).

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1104 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.88(d, 8-CH3), 1.12(t, 3-OCOCH2CH3), 1.13(d, 6”-H), 1.14(t, 3”-OCOCH2CH3), 1.19(t, NHCH2CH3), 1.20(d, 6'-H), 1.44(m, 8-H), 1.48(s, 3”-CH3), 1.69(dd, 2”-Hax), 1.78(m, 14-H), 1.90(s, 6-CH2), 2.34(s, NCH3), 2.53(s, 3'-N(CH3)2), 2.70(m, 12-H), 2.83(dd, 2-H), 3.15(s, CH(OCH3)2), 3.21(d, 2”-Heq), 3.25(s, CH(OCH3)2), 3.36(m, 9-H), 3.48(dd, 2'-H), 3.66(s, 4-OCH3), 4.41(d, 4”-H), 4.45(d, 1'-H), 4.82(d, 1”-H), 5.14(m, 15-H), 5.46(br dd, 3-H), 6.45(dt, CH=CH), 6.65(d, CH=CH), 7.59(dd, naphthyridine), 8.24(d, naphthyridine), 8.36(br d, naphthyridine), 8.95(dd, naphthyridine), 9.00(d, naphthyridine).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1104 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.88 (d, 8-CH 3 ), 1.12 (t, 3-OCOCH 2 CH 3 ), 1.13 (d, 6 ”-H), 1.14 (t, 3 ”-OCOCH 2 CH 3 ), 1.19 (t, NHCH 2 CH 3 ), 1.20 (d, 6'-H), 1.44 (m, 8-H), 1.48 (s, 3” -CH 3 ), 1.69 (dd, 2 ”-Hax), 1.78 (m, 14-H), 1.90 (s, 6-CH 2 ), 2.34 (s, NCH 3 ), 2.53 (s, 3'-N (CH 3 ) 2 ), 2.70 (m, 12-H), 2.83 (dd, 2-H), 3.15 (s, CH (OCH 3 ) 2 ), 3.21 (d, 2 ”-Heq), 3.25 (s, CH (OCH 3 ) 2 ), 3.36 (m, 9-H), 3.48 (dd, 2'-H), 3.66 (s, 4-OCH 3 ), 4.41 (d, 4 ”-H), 4.45 (d, 1'-H), 4.82 (d, 1 ''-H), 5.14 (m, 15-H), 5.46 (br dd, 3-H), 6.45 (dt, CH = CH), 6.65 (d, CH = CH), 7.59 (dd, naphthyridine), 8.24 (d, naphthyridine), 8.36 (br d, naphthyridine), 8.95 (dd, naphthyridine), 9.00 (d, naphthyridine).

(c)実施例1(d)と同様の方法で、実施例10(b)の化合物17.6 mgから、標記化合物13.5 mgを得た。 (c) In the same manner as in Example 1 (d), 13.5 mg of the title compound was obtained from 17.6 mg of the compound of Example 10 (b).

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1058 (M+H)+
(2)比旋光度:[α]D 27 -47°(c0.68, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.91(d, 8-CH3), 1.16(t, NHCH2CH3), 1.35(m, 8-H), 1.47(s, 3”-CH3), 1.69(dd, 2”-Hax), 2.37(s, NCH3), 2.53(s, 3'-N(CH3)2), 2.64(dd, 2-H), 2.74(br dd, 12-H), 2.86(dd, 2-H), 2.91(dd, 6-CH2), 3.21(d, 2”-Heq), 3.25(dq, 5'-H), 3.40(dd, 2'-H), 3.42(m, 9-H), 3.66(s, 4-OCH3), 3.86(br d, 5-H), 3.96(br d, 4-H), 4.39(d, 1'-H), 4.42(m, 4”-H), 4.45(m, 5”-H), 4.82(d, 1”-H), 5.13(m, 15-H), 5.53(br dd, 3-H), 6.45(dt, CH=CH), 6.65(d, CH=CH), 7.58(dd, naphthyridine), 8.23(d, naphthyridine), 8.36(br d, naphthyridine), 8.95(dd, naphthyridine), 9.00(d, naphthyridine), 9.64(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1058 (M + H) +
(2) Specific rotation: [α] D 27 -47 ° (c0.68, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.91 (d, 8-CH 3 ), 1.16 (t, NHCH 2 CH 3 ), 1.35 (m, 8-H), 1.47 (s , 3 ”-CH 3 ), 1.69 (dd, 2” -Hax), 2.37 (s, NCH 3 ), 2.53 (s, 3'-N (CH 3 ) 2 ), 2.64 (dd, 2-H), 2.74 (br dd, 12-H), 2.86 (dd, 2-H), 2.91 (dd, 6-CH 2 ), 3.21 (d, 2 ”-Heq), 3.25 (dq, 5'-H), 3.40 (dd, 2'-H), 3.42 (m, 9-H), 3.66 (s, 4-OCH 3 ), 3.86 (br d, 5-H), 3.96 (br d, 4-H), 4.39 ( d, 1'-H), 4.42 (m, 4 "-H), 4.45 (m, 5" -H), 4.82 (d, 1 "-H), 5.13 (m, 15-H), 5.53 (br dd, 3-H), 6.45 (dt, CH = CH), 6.65 (d, CH = CH), 7.58 (dd, naphthyridine), 8.23 (d, naphthyridine), 8.36 (br d, naphthyridine), 8.95 (dd , naphthyridine), 9.00 (d, naphthyridine), 9.64 (s, CHO).

実施例11
式(1)において、R1がプロピオニル基、R2が水素原子、R3がメチル基、R4がトランス-3-(キノリン-4-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例1(b)と同様の方法で、3-ブロモキノリンの代わりに4-ブロモキノリンを用いて 、実施例1(a)の化合物40 mgから、カップリング化合物(工程図10の式(15c)におい て、Arがキノリン-4-イル基、R5が水素原子及びR6がエチル基で表される化合物) 20.4 mgを得た。
Example 11
In the formula (1), R 1 is a propionyl group, R 2 is a hydrogen atom, R 3 is a methyl group, R 4 is a trans-3- (quinolin-4-yl) -2-propenyl group, R 5 is a hydrogen atom and Method for producing compound in which R 6 is represented by ethyl group
(a) In the same manner as in Example 1 (b), using 4-bromoquinoline instead of 3-bromoquinoline, from 40 mg of the compound of Example 1 (a), the coupling compound (of FIG. 10) In the formula (15c), 20.4 mg of a compound in which Ar is a quinolin-4-yl group, R 5 is a hydrogen atom and R 6 is an ethyl group was obtained.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1187 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.90(d, 8-CH3), 1.09(d, 6”-H), 1.16(t, NHCH2CH3), 1.18(d, 6'-H), 1.45(s, 3”-CH3), 1.66(dd, 2”-Hax), 2.01(s, 9-OCOCH3), 2.04(s, 2'-OCOCH3), 2.22(s, NCH3), 2.40(s, 3'-N(CH3)2), 2.83(dd, 2-H), 3.13(s, CH(OCH3)2), 3.19(d, 2”-Heq), 3.23(s, CH(OCH3)2), 3.54(s, 4-OCH3), 3.58(br d, 4-H), 3.91(br d, 5-H), 4.40(m, 4”-H), 4.40(m, 5”-H), 4.53(dd, CH(OCH3)2), 4.65(d, 1'-H), 4.77(d, 1”-H), 4.90(m, 9-H), 4.94(dd, 2'-H), 5.05(br dd,
3-H), 5.17(m, 15-H), 6.36(dt, CH=CH), 7.13(d, CH=CH), 7.39(d, quinoline), 7.54(ddd, quinoline), 7.68(ddd, quinoline), 8.06(br d, quinoline), 8.08(br d, quinoline), 8.81(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1187 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.90 (d, 8-CH3), 1.09 (d, 6 ”-H), 1.16 (t, NHCH 2 CH 3 ), 1.18 (d , 6'-H), 1.45 (s, 3 ”-CH 3 ), 1.66 (dd, 2” -Hax), 2.01 (s, 9-OCOCH 3 ), 2.04 (s, 2'-OCOCH 3 ), 2.22 (s, NCH 3 ), 2.40 (s, 3'-N (CH 3 ) 2 ), 2.83 (dd, 2-H), 3.13 (s, CH (OCH 3 ) 2 ), 3.19 (d, 2 ”- Heq), 3.23 (s, CH (OCH 3 ) 2 ), 3.54 (s, 4-OCH 3 ), 3.58 (br d, 4-H), 3.91 (br d, 5-H), 4.40 (m, 4 `` -H), 4.40 (m, 5 ''-H), 4.53 (dd, CH (OCH 3 ) 2 ), 4.65 (d, 1'-H), 4.77 (d, 1 ”-H), 4.90 (m , 9-H), 4.94 (dd, 2'-H), 5.05 (br dd,
3-H), 5.17 (m, 15-H), 6.36 (dt, CH = CH), 7.13 (d, CH = CH), 7.39 (d, quinoline), 7.54 (ddd, quinoline), 7.68 (ddd, quinoline), 8.06 (br d, quinoline), 8.08 (br d, quinoline), 8.81 (d, quinoline).

(b)実施例1(c)と同様の方法で、実施例11(a)の化合物20.4 mgから、脱アセチル化合物(工程図10の式(18c)において、R2が水素原子、Arがキノリン-4-イル基、R5が水素原子及びR6がエチル基で表される化合物)13.0 mgを得た。(b) In the same manner as in Example 1 (c), from 20.4 mg of the compound of Example 11 (a), a deacetylated compound (in formula (18c) of Process Diagram 10, R 2 is a hydrogen atom, Ar is quinoline) 13.0 mg of a compound represented by a 4-yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1103 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.86(d, 8-CH3), 1.09(d, 6”-H), 1.11(t, 3-OCOCH2CH3), 1.13(t, 3”-OCOCH2CH3), 1.17(t, NHCH2CH3), 1.19(d, 6'-H), 1.46(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.32(s, NCH3), 2.51(s, 3'-N(CH3)2) , 2.79(dd, 2-H), 3.13(s, CH(OCH3)2), 3.20(d, 2”-Heq), 3.23(s, CH(OCH3)2), 3.45(dd, 2'-H), 3.60(s, 4-OCH3), 3,87(br d, 5-H), 3.97(d, 4-H), 4.39(d, 1'-H), 4.42(d, 4”-H), 4.46(dq, 5”-H), 4.48(dd, CH(OCH3)2), 4.80(d, 1”-H), 5.16(m, 15-H), 5.47(m, 3-H), 6.36(dt, CH=CH), 7.12(d, CH=CH), 7.37(d, quinoline), 7.54(ddd, quinoline), 7.70(ddd, quinoline), 8.06(br d, quinoline), 8.08(br d, quinoline), 8.81(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1103 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.86 (d, 8-CH 3 ), 1.09 (d, 6 ”-H), 1.11 (t, 3-OCOCH 2 CH 3 ), 1.13 (t, 3 ”-OCOCH 2 CH 3 ), 1.17 (t, NHCH 2 CH 3 ), 1.19 (d, 6'-H), 1.46 (s, 3” -CH 3 ), 1.68 (dd, 2 ” -Hax), 2.32 (s, NCH 3 ), 2.51 (s, 3'-N (CH 3 ) 2 ), 2.79 (dd, 2-H), 3.13 (s, CH (OCH 3 ) 2 ), 3.20 ( d, 2 ”-Heq), 3.23 (s, CH (OCH 3 ) 2 ), 3.45 (dd, 2'-H), 3.60 (s, 4-OCH 3 ), 3,87 (br d, 5-H ), 3.97 (d, 4-H), 4.39 (d, 1'-H), 4.42 (d, 4 ”-H), 4.46 (dq, 5” -H), 4.48 (dd, CH (OCH 3 ) 2 ), 4.80 (d, 1 ''-H), 5.16 (m, 15-H), 5.47 (m, 3-H), 6.36 (dt, CH = CH), 7.12 (d, CH = CH), 7.37 (d, quinoline), 7.54 (ddd, quinoline), 7.70 (ddd, quinoline), 8.06 (br d, quinoline), 8.08 (br d, quinoline), 8.81 (d, quinoline).

(c)実施例1(d)と同様の方法で、実施例11(b)の化合物13.0 mgから、標記化合物9.8 mgを得た。 (c) In the same manner as in Example 1 (d), 9.8 mg of the title compound was obtained from 13.0 mg of the compound of Example 11 (b).

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1057 (M+H)+
(2)比旋光度:[α]D 26 -47°(c0.82, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.89(d, 8-CH3), 1.09(d, 6”-H), 1.17(d, 6'-H), 1.17(t, NHCH2CH3), 1.46(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.32(s, NCH3), 2.52(s, 3'-N(CH3)2), 2.82(dd, 2-H), 2.90(dd, 6-CH2), 3.20(dd, 2”-Heq), 3.37(dd, 2'-H), 3.60(s, 4-OCH3), 3.85(br d, 5-H), 3.97(br d, 4-H), 4.37(d, 1'-H), 4.42(m, 4”-H), 4.43(m, 5”-H), 4.81(d, 1”-H), 5.17(m, 15-H), 5.55(m, 3-H), 6.35(dt, CH=CH), 7.12(d, CH=CH), 7.38(d, quinoline), 7.55(ddd, quinoline), 7.70(ddd, quinoline), 8.06(br d, quinoline), 8.08(br d, quinoline), 8.81(d, quinoline), 9.63(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1057 (M + H) +
(2) Specific rotation: [α] D 26 -47 ° (c0.82, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.89 (d, 8-CH 3 ), 1.09 (d, 6 ″ -H), 1.17 (d, 6′-H), 1.17 ( t, NHCH 2 CH 3 ), 1.46 (s, 3 ”-CH 3 ), 1.68 (dd, 2” -Hax), 2.32 (s, NCH 3 ), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.82 (dd, 2-H), 2.90 (dd, 6-CH 2 ), 3.20 (dd, 2 ”-Heq), 3.37 (dd, 2'-H), 3.60 (s, 4-OCH 3 ) , 3.85 (br d, 5-H), 3.97 (br d, 4-H), 4.37 (d, 1'-H), 4.42 (m, 4 ”-H), 4.43 (m, 5” -H) , 4.81 (d, 1 ''-H), 5.17 (m, 15-H), 5.55 (m, 3-H), 6.35 (dt, CH = CH), 7.12 (d, CH = CH), 7.38 (d , quinoline), 7.55 (ddd, quinoline), 7.70 (ddd, quinoline), 8.06 (br d, quinoline), 8.08 (br d, quinoline), 8.81 (d, quinoline), 9.63 (s, CHO).

実施例12
式(1)において、R1がプロピオニル基、R2が水素原子、R3がメチル基、R4がトランス-3-(4-メチルピリジン-3-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例1(b)と同様の方法で、3-ブロモキノリンの代わりに3-ブロモ-4-メチルピリジンを用い、実施例1(a)の化合物40 mgから、カップリング化合物(工程図10の式(15c)において、Arが4-メチルピリジン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)3.7 mgを得た。
Example 12
In the formula (1), R 1 is a propionyl group, R 2 is a hydrogen atom, R 3 is a methyl group, R 4 is a trans-3- (4-methylpyridin-3-yl) -2-propenyl group, and R 5 is Method for producing compound in which hydrogen atom and R 6 are represented by ethyl group
(a) In the same manner as in Example 1 (b), using 3-bromo-4-methylpyridine instead of 3-bromoquinoline, from 40 mg of the compound of Example 1 (a), coupling compound (step In the formula (15c) of FIG. 10, 3.7 mg of a compound in which Ar is a 4-methylpyridin-3-yl group, R 5 is a hydrogen atom and R 6 is an ethyl group was obtained.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1151 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.91(d, 8-CH3), 1.11(d, 6”-H), 1.17(t, NHCH2CH3), 1.18(d, 6'-H), 1.46(s, 3”-CH3), 2.03(s, 9-OCOCH3), 2.05(s, 2'-OCOCH3), 2.24(s, NCH3), 2.30(s, pyridine-CH3), 2.41(s, 3'-N(CH3)2), 2.83(dd,2-H), 3.14(s, CH(OCH3)2), 3.19(d, 2”-Heq), 3.24(s, CH(OCH3)2), 3.60(s, 4-OCH3), 3.64(br d, 4-H), 3.90(br d, 5-H), 4.41(m, 4”-H), 4.41(m, 5”-H), 4.52(dd, CH(OCH3)2), 4.67(d, 1'-H), 4.77(d, 1”-H), 4.91(m, 9-H), 4.95(dd, 2'-H), 5.03(br dd, 3-H), 5.10(m, 15-H), 6.04(dt, CH=CH), 6.53(d, CH=CH), 7.03(d, pyridine), 8.31(d, pyridine), 8.50(s, pyridine).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1151 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.91 (d, 8-CH 3 ), 1.11 (d, 6 ”-H), 1.17 (t, NHCH 2 CH 3 ), 1.18 ( d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 2.03 (s, 9-OCOCH 3 ), 2.05 (s, 2'-OCOCH 3 ), 2.24 (s, NCH 3 ), 2.30 ( s, pyridine-CH 3 ), 2.41 (s, 3'-N (CH 3 ) 2 ), 2.83 (dd, 2-H), 3.14 (s, CH (OCH 3 ) 2 ), 3.19 (d, 2 ” -Heq), 3.24 (s, CH (OCH 3 ) 2 ), 3.60 (s, 4-OCH 3 ), 3.64 (br d, 4-H), 3.90 (br d, 5-H), 4.41 (m, 4 ''-H), 4.41 (m, 5 ''-H), 4.52 (dd, CH (OCH 3 ) 2 ), 4.67 (d, 1'-H), 4.77 (d, 1 ''-H), 4.91 ( m, 9-H), 4.95 (dd, 2'-H), 5.03 (br dd, 3-H), 5.10 (m, 15-H), 6.04 (dt, CH = CH), 6.53 (d, CH = CH), 7.03 (d, pyridine), 8.31 (d, pyridine), 8.50 (s, pyridine).

(b)実施例1(c)と同様の方法で、実施例12(a)の化合物3.7 mgから、脱アセチル化合物(工程図10の式(18c)において、R2が水素原子、Arが4-メチルピリジン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)1.1 mgを得た。(b) In the same manner as in Example 1 (c), from the 3.7 mg of the compound of Example 12 (a), the deacetylated compound (in formula (18c) of process diagram 10, R 2 is a hydrogen atom, Ar is 4 1.1 mg of a compound in which -methylpyridin-3-yl group, R 5 is a hydrogen atom and R 6 is an ethyl group.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1067 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.87(d, 8-CH3), 1.09(d, 6”-H), 1.17(t, NHCH2CH3), 1.19(d, 6'-H), 1.47(s, 3”-CH3), 1.67(dd, 2”-Hax), 2.30(s, NCH3), 2.52(s, 3'-N(CH3)2), 2.81(dd, 2-H), 3.14(s, CH(OCH3)2), 3.20(d, 2”-Heq),3.24(s, CH(OCH3)2), 3.47(dd, 2'-H), 3.66(s, 4-OCH3), 3,88(br d, 5-H), 3.97(br d, 4-H), 4.40(d, 1'-H), 4.42(d, 4”-H), 4.46(dq, 5”-H), 4.48(dd, CH(OCH3)2), 4.80(d, 1”-H), 5.09(m, 15-H), 5.44(m, 3-H), 6.03(dt, CH=CH), 6.52(d, CH=CH), 7.03(d, pyridine), 8.31(d, pyridine), 8.49(s, pyridine).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1067 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.87 (d, 8-CH 3 ), 1.09 (d, 6 ”-H), 1.17 (t, NHCH 2 CH 3 ), 1.19 ( d, 6'-H), 1.47 (s, 3 ”-CH 3 ), 1.67 (dd, 2” -Hax), 2.30 (s, NCH 3 ), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.81 (dd, 2-H), 3.14 (s, CH (OCH 3 ) 2 ), 3.20 (d, 2 ”-Heq), 3.24 (s, CH (OCH 3 ) 2 ), 3.47 (dd, 2 '-H), 3.66 (s, 4-OCH 3 ), 3,88 (br d, 5-H), 3.97 (br d, 4-H), 4.40 (d, 1'-H), 4.42 (d , 4 ”-H), 4.46 (dq, 5” -H), 4.48 (dd, CH (OCH 3 ) 2 ), 4.80 (d, 1 ”-H), 5.09 (m, 15-H), 5.44 ( m, 3-H), 6.03 (dt, CH = CH), 6.52 (d, CH = CH), 7.03 (d, pyridine), 8.31 (d, pyridine), 8.49 (s, pyridine).

(c)実施例2(b)と同様の方法で、実施例12(b)の化合物1.1 mgから、標記化合物0.76 mgを得た。 (c) In the same manner as in Example 2 (b), 0.76 mg of the title compound was obtained from 1.1 mg of the compound of Example 12 (b).

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1021 (M+H)+
(2)比旋光度:[α]D 24 -39°(c0.09, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.93(d, 8-CH3), 1.11(d, 6”-H), 1.17(t, 4”-OCONHCH2CH3), 1.17(d, 6'-H), 1.46(s, 3”-CH3), 1.69(dd, 2”-Hax), 2.30(s, NCH3), 2.53(s, 3'-N(CH3)2), 2.85(dd, 2-H), 2.90(dd, 6-CH2), 3.21(d, 2”-Heq), 3.38(dd, 2'-H), 3.66(s, 4-OCH3), 3.85(br d, 5-H), 3.94(br d, 4-H), 4.38(d,1'-H), 4.43(m, 4”-H), 4.44(m, 5”-H), 4.81(d, 1”-H), 5.10(m, 15-H), 5.46(m, 3-H), 6.02(dt, CH=CH), 6.53(d, CH=CH), 7.03(d, pyridine), 8.31(d, pyridine),8.50(s, pyridine), 9.63(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1021 (M + H) +
(2) Specific rotation: [α] D 24 -39 ° (c0.09, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.93 (d, 8-CH 3 ), 1.11 (d, 6 ”-H), 1.17 (t, 4” -OCONHCH 2 CH 3 ) , 1.17 (d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.69 (dd, 2” -Hax), 2.30 (s, NCH 3 ), 2.53 (s, 3'-N (CH 3 ) 2 ), 2.85 (dd, 2-H), 2.90 (dd, 6-CH 2 ), 3.21 (d, 2 ”-Heq), 3.38 (dd, 2'-H), 3.66 (s, 4- OCH 3 ), 3.85 (br d, 5-H), 3.94 (br d, 4-H), 4.38 (d, 1'-H), 4.43 (m, 4 ”-H), 4.44 (m, 5” -H), 4.81 (d, 1 ''-H), 5.10 (m, 15-H), 5.46 (m, 3-H), 6.02 (dt, CH = CH), 6.53 (d, CH = CH), 7.03 (d, pyridine), 8.31 (d, pyridine), 8.50 (s, pyridine), 9.63 (s, CHO).

実施例13
式(1)において、R1がプロピオニル基、R2が水素原子、R3がメチル基、R4がトランス-3-(ピリミジン-5-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例1(b)と同様の方法で、3-ブロモキノリンの代わりに5-ブロモピリミジンを用い、実施例1(a)の化合物40.0 mgから、カップリング化合物(工程図10の式(15c)において、Arがピリミジン-5-イル基、R5が水素原子及びR6がエチル基で表される化合物)15.5 mgを得た。
Example 13
In the formula (1), R 1 is a propionyl group, R 2 is a hydrogen atom, R 3 is a methyl group, R 4 is a trans-3- (pyrimidin-5-yl) -2-propenyl group, R 5 is a hydrogen atom and Method for producing compound in which R 6 is represented by ethyl group
(a) In the same manner as in Example 1 (b), using 5-bromopyrimidine instead of 3-bromoquinoline, from 40.0 mg of the compound of Example 1 (a), the coupling compound (formula of Step Diagram 10) In (15c), 15.5 mg of a compound in which Ar is a pyrimidin-5-yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group was obtained.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1138 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.91(d, 8-CH3), 1.11(d, 6”-H), 1.17(t, NHCH2CH3), 1.19(d, 6'-H), 1.46(s, 3”-CH3), 1.67(dd, 2”-Hax), 2.02(s, 9-OCOCH3), 2.04(s, 2'-OCOCH3), 2.23(s, NCH3), 2.41(s, 3'-N(CH3)2), 2.84(dd, 2-H), 3.13(s, CH(OCH3)2), 3.20(d, 2”-Heq), 3.24(s, CH(OCH3)2), 3.58(s, 4-OCH3), 3.62(br d, 4-H), 3.92(br d, 5-H), 4.41(m, 4”-H), 4.41(m, 5”-H), 4.53(dd, CH(OCH3)2), 4.66(d, 1'-H), 4.78(d, 1”-H), 4.90(m, 9-H), 4.95(dd, 2'-H), 5.05(br dd, 3-H), 5.11(m, 15-H), 6.33(dt, CH=CH), 6.38(d, CH=CH), 8.68(s, pyrimidine), 9.03(s, pyrimidine).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1138 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.91 (d, 8-CH 3 ), 1.11 (d, 6 ”-H), 1.17 (t, NHCH 2 CH 3 ), 1.19 ( d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.67 (dd, 2” -Hax), 2.02 (s, 9-OCOCH 3 ), 2.04 (s, 2'-OCOCH 3 ), 2.23 (s, NCH 3 ), 2.41 (s, 3'-N (CH 3 ) 2 ), 2.84 (dd, 2-H), 3.13 (s, CH (OCH 3 ) 2 ), 3.20 (d, 2 ” -Heq), 3.24 (s, CH (OCH 3 ) 2 ), 3.58 (s, 4-OCH 3 ), 3.62 (br d, 4-H), 3.92 (br d, 5-H), 4.41 (m, 4 ''-H), 4.41 (m, 5 ''-H), 4.53 (dd, CH (OCH 3 ) 2 ), 4.66 (d, 1'-H), 4.78 (d, 1 ''-H), 4.90 ( m, 9-H), 4.95 (dd, 2'-H), 5.05 (br dd, 3-H), 5.11 (m, 15-H), 6.33 (dt, CH = CH), 6.38 (d, CH = CH), 8.68 (s, pyrimidine), 9.03 (s, pyrimidine).

(b)実施例1(c)と同様の方法で、実施例13(a)の化合物15.5 mgから、脱アセチル化合物(工程図10の式(18c)において、R2が水素原子、Arがピリミジン-5-イル基、R5が水素原子及びR6がエチル基で表される化合物)7.9 mgを得た。(b) In the same manner as in Example 1 (c), from the compound 15.5 mg of Example 13 (a), the deacetylated compound (in formula (18c) of process diagram 10, R 2 is a hydrogen atom, Ar is a pyrimidine 7.9 mg of a compound represented by a -5-yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1054 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.86(d, 8-CH3), 1.09(d, 6”-H), 1.17(t, NHCH2CH3), 1.19(d, 6'-H), 1.46(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.32(s, NCH3), 2.52(s, 3'-N(CH3)2), 2.79(dd, 2-H), 3.13(s, CH(OCH3)2), 3.20(dd, 2”-Heq), 3.23(s, CH(OCH3)2), 3.46(dd, 2'-H), 3.66(s, 4-OCH3), 3,87(br d, 5-H), 3.93(br
d, 4-H), 4.39(d, 1'-H), 4.42(d, 4”-H), 4.46(dq, 5”-H), 4.48(dd, CH(OCH3)2), 4.80(d, 1”-H), 5.08(m, 15-H), 5.45(m, 3-H), 6.30(dt, CH=CH), 6.36(d, CH=CH), 8.67(s, pyrimidine), 9.04(s, pyrimidine).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1054 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.86 (d, 8-CH 3 ), 1.09 (d, 6 ”-H), 1.17 (t, NHCH 2 CH 3 ), 1.19 ( d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.68 (dd, 2” -Hax), 2.32 (s, NCH 3 ), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.79 (dd, 2-H), 3.13 (s, CH (OCH 3 ) 2 ), 3.20 (dd, 2 ”-Heq), 3.23 (s, CH (OCH 3 ) 2 ), 3.46 (dd, 2 '-H), 3.66 (s, 4-OCH 3 ), 3,87 (br d, 5-H), 3.93 (br
d, 4-H), 4.39 (d, 1'-H), 4.42 (d, 4 ”-H), 4.46 (dq, 5” -H), 4.48 (dd, CH (OCH 3 ) 2 ), 4.80 (d, 1 ''-H), 5.08 (m, 15-H), 5.45 (m, 3-H), 6.30 (dt, CH = CH), 6.36 (d, CH = CH), 8.67 (s, pyrimidine ), 9.04 (s, pyrimidine).

(c)実施例2(b)と同様の方法で、実施例13(b)の化合物7.9 mgから、標記化合物5.76 mgを得た。 (c) In the same manner as in Example 2 (b), 5.76 mg of the title compound was obtained from 7.9 mg of the compound of Example 13 (b).

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1008 (M+H)+
(2)比旋光度:[α]D 24 -47°(c0.68, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.88(d, 8-CH3), 1.10(d, 6”-H), 1.11(t, 3-OCOCH2CH3), 1.13(t, 3”-OCOCH2CH3), 1.17(t, NHCH2CH3), 1.17(d, 6'-H), 1.46(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.32(s, NCH3), 2.52(s, 3'-N(CH3)2), 2.63(dd, 2-H), 2.82(dd, 2-H), 2.90(dd, 6-CH2), 3.20(dd, 2”-Heq), 3.38(dd, 2'-H), 3.66(s, 4-OCH3), 3.85(br d, 5-H), 3.93(br d, 4-H), 4.37(d, 1'-H), 4.42(m, 4”-H), 4.44(m, 5”-H), 4.81(d, 1”-H), 5.08(m, 15-H), 5.54(m, 3-H), 6.30(dt, CH=CH), 6.36(d, CH=CH), 8.67(s, pyrimidine), 9.04(s, pyrimidine), 9.63(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1008 (M + H) +
(2) Specific rotation: [α] D 24 -47 ° (c0.68, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.88 (d, 8-CH 3 ), 1.10 (d, 6 ”-H), 1.11 (t, 3-OCOCH 2 CH 3 ), 1.13 (t, 3 ”-OCOCH 2 CH 3 ), 1.17 (t, NHCH 2 CH 3 ), 1.17 (d, 6'-H), 1.46 (s, 3” -CH 3 ), 1.68 (dd, 2 ” -Hax), 2.32 (s, NCH 3 ), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.63 (dd, 2-H), 2.82 (dd, 2-H), 2.90 (dd, 6 -CH 2 ), 3.20 (dd, 2 ”-Heq), 3.38 (dd, 2'-H), 3.66 (s, 4-OCH 3 ), 3.85 (br d, 5-H), 3.93 (br d, 4-H), 4.37 (d, 1'-H), 4.42 (m, 4 ”-H), 4.44 (m, 5” -H), 4.81 (d, 1 ”-H), 5.08 (m, 15 -H), 5.54 (m, 3-H), 6.30 (dt, CH = CH), 6.36 (d, CH = CH), 8.67 (s, pyrimidine), 9.04 (s, pyrimidine), 9.63 (s, CHO ).

実施例14
式(1)において、R1がプロピオニル基、R2が水素原子、R3がメチル基、R4がトランス-3-(6-メトキシピリジン-3-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例1(b)と同様の方法で、3-ブロモキノリンの代わりに5-ブロモ-2-メトキシピリジンを用い、実施例1(a)の化合物40.0 mgから、カップリング化合物(工程図10の式(15c)において、Arが6-メトキシピリジン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)10.1 mgを得た。
Example 14
In the formula (1), R 1 is a propionyl group, R 2 is a hydrogen atom, R 3 is a methyl group, R 4 is a trans-3- (6-methoxypyridin-3-yl) -2-propenyl group, and R 5 is Method for producing compound in which hydrogen atom and R 6 are represented by ethyl group
(a) In the same manner as in Example 1 (b), using 5-bromo-2-methoxypyridine instead of 3-bromoquinoline, from 40.0 mg of the compound of Example 1 (a), coupling compound (step 10.1 mg of a compound in which Ar is a 6-methoxypyridin-3-yl group, R 5 is a hydrogen atom and R 6 is an ethyl group in the formula (15c) of FIG.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1167 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.91(d, 8-CH3), 1.11(d, 6”-H), 1.17(t, NHCH2CH3), 1.18(d, 6'-H), 1.46(s, 3”-CH3), 2.03(s, 9-OCOCH3), 2.04(s, 2'-OCOCH3), 2.22(s, NCH3), 2.41(s, 3'-N(CH3)2), 2.83(dd, 2-H), 3.14(s, CH(OCH3)2), 3.19(d, 2”-Heq), 3.24(s, CH(OCH3)2), 3.58(s, 4-OCH3), 3.64(br d, 4-H), 3.90(br d, 5-H), 3.91(s, pyridine-OCH3), 4.41(m, 4”-H), 4.41(m, 5”-H), 4.54(dd, CH(OCH3)2), 4.67(d, 1'-H), 4.78(d, 1”-H), 4.90(br m, 9-H), 4.95(dd, 2'-H), 5.05(br dd, 3-H), 5.06(m, 15-H), 5.99(dt, CH=CH), 6.35(d, CH=CH), 6.67(d, pyridine),
7.61(dd, pyridine), 8.04(d, pyridine).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1167 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.91 (d, 8-CH 3 ), 1.11 (d, 6 ”-H), 1.17 (t, NHCH 2 CH 3 ), 1.18 ( d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 2.03 (s, 9-OCOCH 3 ), 2.04 (s, 2'-OCOCH 3 ), 2.22 (s, NCH 3 ), 2.41 ( s, 3'-N (CH 3 ) 2 ), 2.83 (dd, 2-H), 3.14 (s, CH (OCH 3 ) 2 ), 3.19 (d, 2 ”-Heq), 3.24 (s, CH ( OCH 3 ) 2 ), 3.58 (s, 4-OCH 3 ), 3.64 (br d, 4-H), 3.90 (br d, 5-H), 3.91 (s, pyridine-OCH 3 ), 4.41 (m, 4 ''-H), 4.41 (m, 5 ''-H), 4.54 (dd, CH (OCH 3 ) 2 ), 4.67 (d, 1'-H), 4.78 (d, 1 ''-H), 4.90 ( br m, 9-H), 4.95 (dd, 2'-H), 5.05 (br dd, 3-H), 5.06 (m, 15-H), 5.99 (dt, CH = CH), 6.35 (d, CH = CH), 6.67 (d, pyridine),
7.61 (dd, pyridine), 8.04 (d, pyridine).

(b)実施例1(c)と同様の方法で、実施例14(a)の化合物10.1 mgから、脱アセチル化合物(工程図10の式(18c)において、R2が水素原子、Arが6-メトキシピリジン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)4.5 mgを得た。(b) In the same manner as in Example 1 (c), from 10.1 mg of the compound of Example 14 (a), deacetylated compound (in formula (18c) of process diagram 10, R 2 is a hydrogen atom, Ar is 6 4.5 mg of a compound represented by a -methoxypyridin-3-yl group, R 5 is a hydrogen atom and R 6 is an ethyl group.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1083 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.87(d, 8-CH3), 1.10(d, 6”-H), 1.17(t, NHCH2CH3), 1.19(d, 6'-H), 1.46(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.35(s, NCH3), 2.52(s, 3'-N(CH3)2), 2.79(dd, 2-H), 3.14(s, CH(OCH3)2), 3.21(d, 2”-Heq),3.24(s, CH(OCH3)2), 3.47(dd, 2'-H), 3.64(s, 4-OCH3), 3,87(br d, 5-H), 3,91(s, pyridine-OCH3), 3.95(br d, 4-H), 4.39(d, 1'-H), 4.43(d, 4”-H), 4.46(dq, 5”-H), 4.48(dd, CH(OCH3)2), 4.80(d, 1”-H), 5.05(m, 15-H), 5.43(m, 3-H), 5.97(dt, CH=CH), 6.34(d, CH=CH), 6.67(d, pyridine), 7.59(dd, pyridine), 8.02(d, pyridine).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1083 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.87 (d, 8-CH 3 ), 1.10 (d, 6 ”-H), 1.17 (t, NHCH 2 CH 3 ), 1.19 ( d, 6'-H), 1.46 (s, 3 "-CH 3 ), 1.68 (dd, 2" -Hax), 2.35 (s, NCH 3 ), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.79 (dd, 2-H), 3.14 (s, CH (OCH 3 ) 2 ), 3.21 (d, 2 ”-Heq), 3.24 (s, CH (OCH 3 ) 2 ), 3.47 (dd, 2 '-H), 3.64 (s, 4-OCH 3 ), 3,87 (br d, 5-H), 3,91 (s, pyridine-OCH 3 ), 3.95 (br d, 4-H), 4.39 (d, 1'-H), 4.43 (d, 4 ”-H), 4.46 (dq, 5” -H), 4.48 (dd, CH (OCH 3 ) 2 ), 4.80 (d, 1 ”-H) , 5.05 (m, 15-H), 5.43 (m, 3-H), 5.97 (dt, CH = CH), 6.34 (d, CH = CH), 6.67 (d, pyridine), 7.59 (dd, pyridine) , 8.02 (d, pyridine).

(c)実施例2(b)と同様の方法で、実施例14(b)の化合物4.5 mgから、標記化合物2.85 mgを得た。 (c) In the same manner as in Example 2 (b), 2.85 mg of the title compound was obtained from 4.5 mg of the compound of Example 14 (b).

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1037 (M+H)+
(2)比旋光度:[α]D 24 -50°(c0.29, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.91(d, 8-CH3), 1.11(d, 6”-H), 1.16(d, 6'-H), 1.17(t, NHCH2CH3), 1.46(s, 3”-CH3), 1.69(dd, 2”-Hax), 2.37(s, NCH3), 2.53(s, 3'-N(CH3)2), 2.61(dd, 2-H), 2.82(dd, 2-H), 2.89(dd, 6-CH2), 3.15(t, 4'-H), 3.21(d, 2”-Heq), 3.38(dd, 2'-H), 3.68(s, 4-OCH3), 3.85(br d, 5-H), 3,92(s, pyridine-OCH3), 3.95(br d, 4-H), 4.38(d, 1'-H), 4.43(m, 4”-H), 4.44(m,5”-H), 4.81(d, 1”-H), 5.06(m, 15-H), 5.49(m, 3-H), 5.97(dt, CH=CH), 6.34(d, CH=CH), 6.67(d, pyridine), 7.59(dd, pyridine), 8.03(d, pyridine), 9.63(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1037 (M + H) +
(2) Specific rotation: [α] D 24 -50 ° (c0.29, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.91 (d, 8-CH 3 ), 1.11 (d, 6 ″ -H), 1.16 (d, 6′-H), 1.17 ( t, NHCH 2 CH 3 ), 1.46 (s, 3 ”-CH 3 ), 1.69 (dd, 2” -Hax), 2.37 (s, NCH 3 ), 2.53 (s, 3'-N (CH 3 ) 2 ), 2.61 (dd, 2-H), 2.82 (dd, 2-H), 2.89 (dd, 6-CH 2 ), 3.15 (t, 4'-H), 3.21 (d, 2 ”-Heq), 3.38 (dd, 2'-H), 3.68 (s, 4-OCH 3 ), 3.85 (br d, 5-H), 3,92 (s, pyridine-OCH 3 ), 3.95 (br d, 4-H ), 4.38 (d, 1'-H), 4.43 (m, 4 ”-H), 4.44 (m, 5” -H), 4.81 (d, 1 ”-H), 5.06 (m, 15-H) , 5.49 (m, 3-H), 5.97 (dt, CH = CH), 6.34 (d, CH = CH), 6.67 (d, pyridine), 7.59 (dd, pyridine), 8.03 (d, pyridine), 9.63 (s, CHO).

実施例15
式(1)において、R1がプロピオニル基、R2が水素原子、R3がメチル基、R4がトランス-3-(6-ニトロピリジン-3-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例1(b)と同様の方法で、3-ブロモキノリンの代わりに5-ブロモ-2-ニトロピリジンを用い、実施例1(a)の化合物40.0 mgから、カップリング化合物(工程図10の式(15c)において、Arが6-ニトロピリジン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)28.3 mgを得た。
Example 15
In the formula (1), R 1 is a propionyl group, R 2 is a hydrogen atom, R 3 is a methyl group, R 4 is a trans-3- (6-nitropyridin-3-yl) -2-propenyl group, and R 5 is Method for producing compound in which hydrogen atom and R 6 are represented by ethyl group
(a) In the same manner as in Example 1 (b), using 5-bromo-2-nitropyridine instead of 3-bromoquinoline, from 40.0 mg of the compound of Example 1 (a), coupling compound (step In the formula (15c) of FIG. 10, 28.3 mg of a compound in which Ar is a 6-nitropyridin-3-yl group, R 5 is a hydrogen atom and R 6 is an ethyl group was obtained.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1182 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.90(d, 8-CH3), 1.11(d, 6”-H), 1.15(t, NHCH2CH3), 1.18(d, 6'-H), 1.45(s, 3”-CH3), 1.66(dd, 2”-Hax), 2.02(s, 9-OCOCH3), 2.03(s, 2'-OCOCH3), 2.22(s, NCH3), 2.40(s, 3'-N(CH3)2), 3.12(s, CH(OCH3)2), 3.18(d, 2”-Heq), 3.23(s, CH(OCH3)2), 3.48(br d, 4-H), 3.56(s, 4-OCH3), 3.92(br d, 5-H), 4.40(m, 4”-H), 4.40(m 5”-H), 4.52(dd, CH(OCH3)2), 4.65(d, 1'-H), 4.77(d, 1”-H), 4.90(m, 9-H), 4.94(dd, 2'-H), 5.05(br dd, 3-H), 5.11(m, 15-H), 6.48(dt, CH=CH), 6.54(d, CH=CH), 7.97(dd, pyridine), 8.18(d, pyridine), 8.52(d, pyridine).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1182 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.90 (d, 8-CH 3 ), 1.11 (d, 6 ”-H), 1.15 (t, NHCH 2 CH 3 ), 1.18 ( d, 6'-H), 1.45 (s, 3 ”-CH 3 ), 1.66 (dd, 2” -Hax), 2.02 (s, 9-OCOCH 3 ), 2.03 (s, 2'-OCOCH 3 ), 2.22 (s, NCH 3 ), 2.40 (s, 3'-N (CH 3 ) 2 ), 3.12 (s, CH (OCH 3 ) 2 ), 3.18 (d, 2 ”-Heq), 3.23 (s, CH (OCH 3 ) 2 ), 3.48 (br d, 4-H), 3.56 (s, 4-OCH 3 ), 3.92 (br d, 5-H), 4.40 (m, 4 ”-H), 4.40 (m 5 ”-H), 4.52 (dd, CH (OCH 3 ) 2 ), 4.65 (d, 1'-H), 4.77 (d, 1” -H), 4.90 (m, 9-H), 4.94 (dd , 2'-H), 5.05 (br dd, 3-H), 5.11 (m, 15-H), 6.48 (dt, CH = CH), 6.54 (d, CH = CH), 7.97 (dd, pyridine) , 8.18 (d, pyridine), 8.52 (d, pyridine).

(b)実施例1(c)と同様の方法で、実施例15(a)の化合物28.3 mgから、脱アセチル化合物(工程図10の式(18c)において、R2が水素原子、Arが6-ニトロピリジン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)13.0 mgを得た。(b) In the same manner as in Example 1 (c), from the compound 28.3 mg of Example 15 (a), the deacetylated compound (in formula (18c) of Process Diagram 10, R 2 is a hydrogen atom, Ar is 6 13.0 mg of a compound in which -nitropyridin-3-yl group, R 5 is a hydrogen atom and R 6 is an ethyl group).

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1098 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.85(d, 8-CH3), 1.09(d, 6”-H), 1.11(t, 3-OCOCH2CH3), 1.13(t, 3”-OCOCH2CH3), 1.17(t, NHCH2CH3), 1.19(d, 6'-H), 1.46(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.31(s, NCH3), 2.52(s, 3'-N(CH3)2), 2.78(dd, 2-H), 3.13(s, CH(OCH3)2), 3.20(d, 2”-Heq), 3.23(s, CH(OCH3)2), 3.45(dd, 2'-H), 3.65(s, 4-OCH3), 3.89(m, 4-H), 3.89(m, 5-H), 4.39(d, 1'-H), 4.42(m, 4”-H),4.45(m, 5”-H), 4.47(dd, CH(OCH3)2), 4.80(d, 1”-H), 5.10(m, 15-H), 5.46(m, 3-H), 6.45(dt, CH=CH), 6.53(d, CH=CH), 7.94(dd, pyridine), 8.19(d, pyridine), 8.51(d, pyridine).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1098 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.85 (d, 8-CH 3 ), 1.09 (d, 6 ”-H), 1.11 (t, 3-OCOCH 2 CH 3 ), 1.13 (t, 3 ”-OCOCH 2 CH 3 ), 1.17 (t, NHCH 2 CH 3 ), 1.19 (d, 6'-H), 1.46 (s, 3” -CH 3 ), 1.68 (dd, 2 ” -Hax), 2.31 (s, NCH 3 ), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.78 (dd, 2-H), 3.13 (s, CH (OCH 3 ) 2 ), 3.20 ( d, 2 ”-Heq), 3.23 (s, CH (OCH 3 ) 2 ), 3.45 (dd, 2'-H), 3.65 (s, 4-OCH 3 ), 3.89 (m, 4-H), 3.89 (m, 5-H), 4.39 (d, 1'-H), 4.42 (m, 4 ''-H), 4.45 (m, 5 ''-H), 4.47 (dd, CH (OCH 3 ) 2 ), 4.80 (d, 1 ''-H), 5.10 (m, 15-H), 5.46 (m, 3-H), 6.45 (dt, CH = CH), 6.53 (d, CH = CH), 7.94 (dd, pyridine), 8.19 (d, pyridine), 8.51 (d, pyridine).

(c)実施例2(b)と同様の方法で、実施例15(b)の化合物13.0 mgから、標記化合物8.92 mgを得た。 (c) In the same manner as in Example 2 (b), 8.92 mg of the title compound was obtained from 13.0 mg of the compound of Example 15 (b).

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1052 (M+H)+
(2)比旋光度:[α]D 24 -42°(c1.00, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.89(d, 8-CH3), 1.11(d, 6”-H), 1.16(t, NHCH2CH3), 1.16(d, 6'-H), 1.46(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.31(s, NCH3), 2.52(s, 3'-N(CH3)2), 2.61(dd, 2-H), 2.81(dd, 2-H), 2.89(dd, 6-CH2), 3.16(t, 4'-H), 3.20(d, 2”-Heq), 3.36(dd, 2'-H), 3.65(s, 4-OCH3), 3.85(br d, 5-H), 3.91(br d, 4-H), 4.37(d, 1'-H), 4.42(m, 4”-H), 4.45(m, 5”-H), 4.81(d, 1”-H),5.09(m, 15-H), 5.54(m, 3-H), 6.44(dt, CH=CH), 6.52(d, CH=CH), 7.93(dd, pyridine), 8.19(d, pyridine), 8.51(d, pyridine), 9.63(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1052 (M + H) +
(2) Specific rotation: [α] D 24 -42 ° (c1.00, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.89 (d, 8-CH 3 ), 1.11 (d, 6 ”-H), 1.16 (t, NHCH 2 CH 3 ), 1.16 ( d, 6'-H), 1.46 (s, 3 "-CH 3 ), 1.68 (dd, 2" -Hax), 2.31 (s, NCH 3 ), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.61 (dd, 2-H), 2.81 (dd, 2-H), 2.89 (dd, 6-CH 2 ), 3.16 (t, 4'-H), 3.20 (d, 2 ”-Heq), 3.36 (dd, 2'-H), 3.65 (s, 4-OCH 3 ), 3.85 (br d, 5-H), 3.91 (br d, 4-H), 4.37 (d, 1'-H), 4.42 (m, 4 ''-H), 4.45 (m, 5 ''-H), 4.81 (d, 1 ''-H), 5.09 (m, 15-H), 5.54 (m, 3-H), 6.44 ( dt, CH = CH), 6.52 (d, CH = CH), 7.93 (dd, pyridine), 8.19 (d, pyridine), 8.51 (d, pyridine), 9.63 (s, CHO).

実施例16
式(1)において、R1がプロピオニル基、R2が水素原子、R3がメチル基、R4がトランス-3-(ピリジン-3-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例1(b)と同様の方法で、3-ブロモキノリンの代わりに3-ブロモピリジンを用い、実施例1(a)の化合物40.0 mgから、カップリング化合物(工程図10の式(15c)において、Arがピリジン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)28.7 mgを得た。
Example 16
In the formula (1), R 1 is a propionyl group, R 2 is a hydrogen atom, R 3 is a methyl group, R 4 is a trans-3- (pyridin-3-yl) -2-propenyl group, R 5 is a hydrogen atom and Method for producing compound in which R 6 is represented by ethyl group
(a) In the same manner as in Example 1 (b), using 3-bromopyridine in place of 3-bromoquinoline, from 40.0 mg of the compound of Example 1 (a), coupling compound (formula of process diagram 10) (15c), Ar is a pyridin-3-yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group) 28.7 mg.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1137 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.90(d, 8-CH3), 1.10(d, 6”-H), 1.17(t, NHCH2CH3), 1.18(d, 6'-H), 1.45(s, 3”-CH3), 1.66(dd, 2”-Hax), 2.02(s, 9-OCOCH3), 2.03(s, 2'-OCOCH3), 2.21(s, NCH3), 2.40(s, 3'-N(CH3)2), 2.54(dd, 2-H), 2.58(t, 3'-H), 2.83(dd, 2-H), 3.13(s, CH(OCH3)2), 3.19(d, 2”-Heq), 3.23(s, CH(OCH3)2), 3.57(s, 4-OCH3), 3.90(br d, 5-H), 4.40(m, 4”-H), 4.40(m, 5”-H), 4.53(dd, CH(OCH3)2), 4.66(d, 1'-H), 4.77(d, 1”-H), 4.89(m, 9-H), 4.94(dd, 2'-H), 5.05(br dd, 3-H), 5.08(m, 15-H), 6.18(dt, CH=CH), 6.41(d, CH=CH), 7.19(dd, pyridine), 7.63(dt, pyridine), 8.42(d, pyridine), 8.52(d, pyridine).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1137 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.90 (d, 8-CH 3 ), 1.10 (d, 6 ”-H), 1.17 (t, NHCH 2 CH 3 ), 1.18 ( d, 6'-H), 1.45 (s, 3 ”-CH 3 ), 1.66 (dd, 2” -Hax), 2.02 (s, 9-OCOCH 3 ), 2.03 (s, 2'-OCOCH 3 ), 2.21 (s, NCH 3 ), 2.40 (s, 3'-N (CH 3 ) 2 ), 2.54 (dd, 2-H), 2.58 (t, 3'-H), 2.83 (dd, 2-H) , 3.13 (s, CH (OCH 3 ) 2 ), 3.19 (d, 2 ”-Heq), 3.23 (s, CH (OCH 3 ) 2 ), 3.57 (s, 4-OCH 3 ), 3.90 (br d, 5-H), 4.40 (m, 4 ''-H), 4.40 (m, 5 ''-H), 4.53 (dd, CH (OCH 3 ) 2 ), 4.66 (d, 1'-H), 4.77 (d , 1 ”-H), 4.89 (m, 9-H), 4.94 (dd, 2'-H), 5.05 (br dd, 3-H), 5.08 (m, 15-H), 6.18 (dt, CH = CH), 6.41 (d, CH = CH), 7.19 (dd, pyridine), 7.63 (dt, pyridine), 8.42 (d, pyridine), 8.52 (d, pyridine).

(b)実施例1(c)と同様の方法で、実施例16(a)の化合物28.7 mgから、脱アセチル化合物(工程図10の式(18c)において、R2が水素原子、Arがピリジン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)15.4 mgを得た。(b) In the same manner as in Example 1 (c), from the compound 28.7 mg of Example 16 (a), a deacetylated compound (in formula (18c) of Process Diagram 10, R 2 is a hydrogen atom, Ar is pyridine 15.4 mg of a compound represented by a -3-yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1053 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.85(d, 8-CH3), 1.09(d, 6”-H), 1.11(t, 3-OCOCH2CH3), 1.13(t, 3”-OCOCH2CH3), 1.17(t, NHCH2CH3), 1.19(d, 6'-H), 1.46(s, 3”-CH3), 1.67(dd, 2”-Hax), 2.30(s, NCH3), 2.51(s, 3'-N(CH3)2), 2.78(dd, 2-H), 3.13(s, CH(OCH3)2), 3.21(d, 2”-Heq), 3.23(s, CH(OCH3)2), 3.47(dd, 2'-H), 3.64(s, 4-OCH3), 3,87(br d, 5-H), 3.96(br d, 4-H), 4.39(d, 1'-H), 4.42(d, 4”-H), 4.46(dq, 5”-H), 4.48(dd, CH(OCH3)2), 4.80(d, 1”-H), 5.08(m, 15-H), 5.47(m, 3-H), 6.17(dt, CH=CH), 6.40(d, CH=CH), 7.19(dd, pyridine), 7.63(ddd, pyridine), 8.42(br d, pyridine), 8.52(br d, pyridine).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1053 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.85 (d, 8-CH 3 ), 1.09 (d, 6 ”-H), 1.11 (t, 3-OCOCH 2 CH 3 ), 1.13 (t, 3 ”-OCOCH 2 CH 3 ), 1.17 (t, NHCH 2 CH 3 ), 1.19 (d, 6'-H), 1.46 (s, 3” -CH 3 ), 1.67 (dd, 2 ” -Hax), 2.30 (s, NCH 3 ), 2.51 (s, 3'-N (CH 3 ) 2 ), 2.78 (dd, 2-H), 3.13 (s, CH (OCH 3 ) 2 ), 3.21 ( d, 2 ”-Heq), 3.23 (s, CH (OCH 3 ) 2 ), 3.47 (dd, 2'-H), 3.64 (s, 4-OCH 3 ), 3,87 (br d, 5-H ), 3.96 (br d, 4-H), 4.39 (d, 1'-H), 4.42 (d, 4 ''-H), 4.46 (dq, 5 ''-H), 4.48 (dd, CH (OCH 3 ) 2 ), 4.80 (d, 1 ''-H), 5.08 (m, 15-H), 5.47 (m, 3-H), 6.17 (dt, CH = CH), 6.40 (d, CH = CH), 7.19 (dd, pyridine), 7.63 (ddd, pyridine), 8.42 (br d, pyridine), 8.52 (br d, pyridine).

(c)実施例2(b)と同様の方法で、実施例16(b)の化合物15.4 mgから、標記化合物10.2 mgを得た。 (c) In the same manner as in Example 2 (b), 10.2 mg of the title compound was obtained from 15.4 mg of the compound of Example 16 (b).

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1007 (M+H)+
(2)比旋光度:[α]D 24 -47°(c1.13, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.88(d, 8-CH3), 1.10(d, 6”-H), 1.12(t, 3-OCOCH2CH3), 1.13(t, 3”-OCOCH2CH3), 1.16(t, 7NHCH2CH3), 1.17(d, 6'-H), 1.46(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.30(s, NCH3), 2.52(s, 3'-N(CH3)2), 2.60(dd, 2-H), 2.81(dd, 2-H), 2.88(dd, 6-CH2), 3.20(d, 2”-Heq), 3.38(dd, 2'-H), 3.64(s, 4-OCH3), 3.85(br d, 5-H), 3.95(br d, 4-H), 4.36(d, 1'-H), 4.432(m, 4”-H), 4.43(m, 5”-H), 4.81(d, 1”-H), 5.08(m, 15-H), 5.54(m, 3-H), 6.17(dt, CH=CH), 6.40(d, CH=CH), 7.20(dd, pyridine), 7.63(ddd, pyridine), 8.43(dd, pyridine), 8.52(br d, pyridine), 9.63(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1007 (M + H) +
(2) Specific rotation: [α] D 24 -47 ° (c1.13, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.88 (d, 8-CH 3 ), 1.10 (d, 6 ”-H), 1.12 (t, 3-OCOCH 2 CH 3 ), 1.13 (t, 3 ”-OCOCH 2 CH 3 ), 1.16 (t, 7NHCH 2 CH 3 ), 1.17 (d, 6'-H), 1.46 (s, 3” -CH 3 ), 1.68 (dd, 2 ” -Hax), 2.30 (s, NCH 3 ), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.60 (dd, 2-H), 2.81 (dd, 2-H), 2.88 (dd, 6 -CH 2 ), 3.20 (d, 2 ”-Heq), 3.38 (dd, 2'-H), 3.64 (s, 4-OCH 3 ), 3.85 (br d, 5-H), 3.95 (br d, 4-H), 4.36 (d, 1'-H), 4.432 (m, 4 ''-H), 4.43 (m, 5 ''-H), 4.81 (d, 1 ''-H), 5.08 (m, 15 -H), 5.54 (m, 3-H), 6.17 (dt, CH = CH), 6.40 (d, CH = CH), 7.20 (dd, pyridine), 7.63 (ddd, pyridine), 8.43 (dd, pyridine ), 8.52 (br d, pyridine), 9.63 (s, CHO).

実施例17
式(1)において、R1がプロピオニル基、R2が水素原子、R3がメチル基、R4がトランス-3-(イミダゾ[1,2-a]ピリジン-3-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例1(b)と同様の方法で、3-ブロモキノリンの代わりに3-ブロモイミダゾ[1,2-a]ピリジンを用い、また1,4-ジオキサンの代わりにジメチルホルムアミドを用い、実施例1(a)の化合物10 mgから、カップリング化合物(工程図10の式(15c)において、Arがイミダゾ[1,2-a]ピリジン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)2.6 mgを得た。
Example 17
In the formula (1), R 1 is a propionyl group, R 2 is a hydrogen atom, R 3 is a methyl group, R 4 is trans-3- (imidazo [1,2-a] pyridin-3-yl) -2-propenyl Group, R 5 is a hydrogen atom and R 6 is an ethyl group
(a) In the same manner as in Example 1 (b), using 3-bromoimidazo [1,2-a] pyridine instead of 3-bromoquinoline and using dimethylformamide instead of 1,4-dioxane From 10 mg of the compound of Example 1 (a), a coupling compound (in the formula (15c) of process diagram 10, Ar is an imidazo [1,2-a] pyridin-3-yl group, R 5 is a hydrogen atom and Compound in which R 6 is an ethyl group) 2.6 mg was obtained.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1176 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.89(d, 8-CH3), 1.11(d, 6”-H), 1.17(t, 4”-OCONHCH2CH3), 1.19(d, 6'-H), 1.46(s, 3”-CH3), 2.01(s, 9-OCOCH3), 2.03(s, 2'-OCOCH3), 2.25(s, NCH3), 2.41(s, 3'-N(CH3)2), 2.82(dd, 2-H), 3.13(s, CH(OCH3)2), 3.23(s, CH(OCH3)2), 3.57(s, 4-OCH3), 3.91(br d, 5-H), 4.41(m, 4”-H),4.41(m, 5”-H),4.53(dd, CH(OCH3)2), 4.66(d, 1'-H), 4.78(d, 1”-H), 4.91(m, 9-H), 4.95(dd, 2'-H), 5.05(br dd, 3-H), 5.11(m, 15-H), 6.14(dt, CH=CH), 6.54(d, CH=CH), 6.81(m, imidazopyridine), 7.15(m, imidazopyridine), 7.61(d, imidazopyridine), 7.68(s, imidazopyridine), 8.12(d, imidazopyridine).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1176 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.89 (d, 8-CH 3 ), 1.11 (d, 6 ”-H), 1.17 (t, 4” -OCONHCH 2 CH 3 ) , 1.19 (d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 2.01 (s, 9-OCOCH 3 ), 2.03 (s, 2'-OCOCH 3 ), 2.25 (s, NCH 3 ) , 2.41 (s, 3'-N (CH 3 ) 2 ), 2.82 (dd, 2-H), 3.13 (s, CH (OCH 3 ) 2 ), 3.23 (s, CH (OCH 3 ) 2 ), 3.57 (s, 4-OCH 3 ), 3.91 (br d, 5-H), 4.41 (m, 4 ”-H), 4.41 (m, 5” -H), 4.53 (dd, CH (OCH 3 ) 2 ) , 4.66 (d, 1'-H), 4.78 (d, 1 ''-H), 4.91 (m, 9-H), 4.95 (dd, 2'-H), 5.05 (br dd, 3-H), 5.11 (m, 15-H), 6.14 (dt, CH = CH), 6.54 (d, CH = CH), 6.81 (m, imidazopyridine), 7.15 (m, imidazopyridine), 7.61 (d, imidazopyridine), 7.68 ( s, imidazopyridine), 8.12 (d, imidazopyridine).

(b)実施例1(c)と同様の方法で、実施例17(a)の化合物5.1 mgから、脱アセチル化合物(工程図10の式(18c)において、R2が水素原子、Arがイミダゾ[1,2-a]ピリジン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)0.7 mgを得た。(b) In the same manner as in Example 1 (c), from 5.1 mg of the compound of Example 17 (a), a deacetylated compound (in formula (18c) of Process Diagram 10, R 2 is a hydrogen atom, Ar is an imidazo 0.7 mg of [1,2-a] pyridin-3-yl group, R 5 is a hydrogen atom and R 6 is an ethyl group.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1092 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.92(d, 8-CH3), 1.09(d, 6”-H), 1.17(t, NHCH2CH3), 1.19(d, 6'-H), 1.47(s, 3”-CH3), 1.69(dd, 2”-Hax), 2.53(s, 3'-N(CH3)2), 2.82(dd, 2-H), 3.15(s, CH(OCH3)2), 3.24(s, CH(OCH3)2), 3.45(dd, 2'-H), 3.63(s, 4-OCH3), 3,86(br d, 5-H), 3.87(br d, 4-H), 4.39(d, 1'-H), 4.41(d, 4”-H), 4.45(dq, 5”-H), 4.46(dd, CH(OCH3)2), 4.81(d, 1”-H), 5.12(m, 15-H), 5.40(m, 3-H), 6.11(dt, CH=CH), 6.53(d, CH=CH), 6.85(m, imidazopyridine), 7.16(m, imidazopyridine), 7.61(d, imidazopyridine), 7.68(s, imidazopyridine), 8.10(d, imidazopyridine).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1092 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.92 (d, 8-CH 3 ), 1.09 (d, 6 ”-H), 1.17 (t, NHCH 2 CH 3 ), 1.19 ( d, 6'-H), 1.47 (s, 3 ”-CH 3 ), 1.69 (dd, 2” -Hax), 2.53 (s, 3'-N (CH 3 ) 2 ), 2.82 (dd, 2- H), 3.15 (s, CH (OCH 3 ) 2 ), 3.24 (s, CH (OCH 3 ) 2 ), 3.45 (dd, 2'-H), 3.63 (s, 4-OCH 3 ), 3,86 (br d, 5-H), 3.87 (br d, 4-H), 4.39 (d, 1'-H), 4.41 (d, 4 ''-H), 4.45 (dq, 5 ''-H), 4.46 (dd, CH (OCH 3 ) 2 ), 4.81 (d, 1 ''-H), 5.12 (m, 15-H), 5.40 (m, 3-H), 6.11 (dt, CH = CH), 6.53 ( d, CH = CH), 6.85 (m, imidazopyridine), 7.16 (m, imidazopyridine), 7.61 (d, imidazopyridine), 7.68 (s, imidazopyridine), 8.10 (d, imidazopyridine).

(c)実施例2(b)と同様の方法で、実施例17(b)の化合物0.7 mgから、標記化合物0.18 mgを得た。 (c) In the same manner as in Example 2 (b), 0.18 mg of the title compound was obtained from 0.7 mg of the compound of Example 17 (b).

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1046 (M+H)+
(2)比旋光度:[α]D 24 -1.2°(c0.04, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):1.11(d, 6”-H), 1.15(t, NHCH2CH3), 1.16(d, 6'-H), 1.46(s, 3”-CH3), 2.54(s, 3'-N(CH3)2), 2.86(dd, 2-H), 3.21(d,2”-Heq), 3.38(dd, 2'-H), 3.63(s, 4-OCH3), 3.86(br d, 5-H), 2.90(dd, 6-CH2), 3.86(br d, 4-H), 4.38(d, 1'-H), 4.42(m, 4”-H), 4.44(m, 5”-H), 4.82(d, 1”-H), 5.11(m, 15-H), 6.13(dt, CH=CH), 6.53(d, CH=CH), 6.85(m, imidazopyridine), 7.17(m, imidazopyridine), 7.61(d, imidazopyridine), 7.68(s, imidazopyridine), 8.10(d, imidazopyridin), 9.63(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1046 (M + H) +
(2) Specific rotation: [α] D 24 -1.2 ° (c0.04, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 1.11 (d, 6 ″ -H), 1.15 (t, NHCH 2 CH 3 ), 1.16 (d, 6′-H), 1.46 ( s, 3 ”-CH 3 ), 2.54 (s, 3'-N (CH 3 ) 2 ), 2.86 (dd, 2-H), 3.21 (d, 2” -Heq), 3.38 (dd, 2'- H), 3.63 (s, 4-OCH 3 ), 3.86 (br d, 5-H), 2.90 (dd, 6-CH 2 ), 3.86 (br d, 4-H), 4.38 (d, 1'- H), 4.42 (m, 4 ''-H), 4.44 (m, 5 ''-H), 4.82 (d, 1 ''-H), 5.11 (m, 15-H), 6.13 (dt, CH = CH) , 6.53 (d, CH = CH), 6.85 (m, imidazopyridine), 7.17 (m, imidazopyridine), 7.61 (d, imidazopyridine), 7.68 (s, imidazopyridine), 8.10 (d, imidazopyridin), 9.63 (s, CHO ).

実施例18
式(1)において、R1がプロピオニル基、R2が水素原子、R3がメチル基、R4がトランス-3-(6-アミノピリジン-3-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例1(b)と同様の方法で、3-ブロモキノリンの代わりに2-アミノ-5-ブロモピリジンを用い、また1,4-ジオキサンの代わりにジメチルホルムアミドを用い、実施例1(a)の化合物40.0 mgから、カップリング化合物(工程図10の式(15c)において、Arが6-アミノピリジン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)7.4 mgを得た。
Example 18
In the formula (1), R 1 is a propionyl group, R 2 is a hydrogen atom, R 3 is a methyl group, R 4 is a trans-3- (6-aminopyridin-3-yl) -2-propenyl group, and R 5 is Method for producing compound in which hydrogen atom and R 6 are represented by ethyl group
(a) In the same manner as in Example 1 (b), 2-amino-5-bromopyridine was used instead of 3-bromoquinoline, and dimethylformamide was used instead of 1,4-dioxane. From 40.0 mg of the compound of (a), a coupling compound (in the formula (15c) in Process Diagram 10, Ar is a 6-aminopyridin-3-yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group) Compound) 7.4 mg was obtained.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1152 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.91(d, 8-CH3), 1.11(d, 6”-H), 1.17(t, NHCH2CH3), 1.19(d, 6'-H), 1.46(s, 3”-CH3), 1.67(dd, 2”-Hax), 2.03(s, 9-OCOCH3), 2.05(s, 2'-OCOCH3), 2.25(s, NCH3), 2.41(s, 3'-N(CH3)2), 2.84(dd, 2-H), 3.14(s, CH(OCH3)2), 3.19(d, 2”-Heq), 3.24(s, CH(OCH3)2), 3.59(s, 4-OCH3), 3.61(br d, 4-H), 3.91(br d, 5-H), 4.41(m, 4”-H), 4.41(m, 5”-H), 4.54(dd, CH(OCH3)2), 4.67(d, 1'-H), 4.77(d, 1”-H), 4.91(m, 9-H), 4.95(dd, 2'-H), 5.05(br dd, 3-H), 5.06(m, 15-H), 5.91(dt, CH=CH), 6.29(d, CH=CH), 6.45(d, pyridine), 7.48(dd, pyridine), 7.96(d, pyridine).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1152 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.91 (d, 8-CH 3 ), 1.11 (d, 6 ”-H), 1.17 (t, NHCH 2 CH 3 ), 1.19 ( d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.67 (dd, 2” -Hax), 2.03 (s, 9-OCOCH 3 ), 2.05 (s, 2'-OCOCH 3 ), 2.25 (s, NCH 3 ), 2.41 (s, 3'-N (CH 3 ) 2 ), 2.84 (dd, 2-H), 3.14 (s, CH (OCH 3 ) 2 ), 3.19 (d, 2 ” -Heq), 3.24 (s, CH (OCH 3 ) 2 ), 3.59 (s, 4-OCH 3 ), 3.61 (br d, 4-H), 3.91 (br d, 5-H), 4.41 (m, 4 ''-H), 4.41 (m, 5 ''-H), 4.54 (dd, CH (OCH 3 ) 2 ), 4.67 (d, 1'-H), 4.77 (d, 1 ''-H), 4.91 ( m, 9-H), 4.95 (dd, 2'-H), 5.05 (br dd, 3-H), 5.06 (m, 15-H), 5.91 (dt, CH = CH), 6.29 (d, CH = CH), 6.45 (d, pyridine), 7.48 (dd, pyridine), 7.96 (d, pyridine).

(b)実施例1(c)と同様の方法で、実施例18(a)の化合物7.4 mgから、脱アセチル化合物(工程図10の式(18c)において、R2が水素原子、Arが6-アミノピリジン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)2.5 mgを得た。(b) In the same manner as in Example 1 (c), from the compound 7.4 mg of Example 18 (a), the deacetylated compound (in formula (18c) of Process Diagram 10, R 2 is a hydrogen atom, Ar is 6 -Aminopyridin-3-yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1068 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.90(d, 8-CH3), 1.10(d, 6”-H), 1.17(t, NHCH2CH3), 1.19(d, 6'-H), 1.46(s, 3”-CH3), 1.67(dd, 2”-Hax), 2.52(s, 3'-N(CH3)2), 2.81(dd, 2-H), 3.15(s, CH(OCH3)2), 3.20(d, 2”-Heq), 3.24(s, CH(OCH3)2), 3.47(dd, 2'-H), 3.64(s, 4-OCH3), 3.86(br d, 5-H), 3.94(br d, 4-H), 4.39(d, 1'-H), 4.42(m, 4”-H), 4.45(m, 5”-H), 4.46(dd, CH(OCH3)2), 4.81(d, 1”-H), 5.03(m, 15-H), 5.40(m, 3-H), 5.89(dt, CH=CH), 6.27(d, CH=CH), 6.44(d, pyridine), 7.47(dd, pyridine), 7.95(d, pyridine).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1068 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.90 (d, 8-CH 3 ), 1.10 (d, 6 ”-H), 1.17 (t, NHCH 2 CH 3 ), 1.19 ( d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.67 (dd, 2” -Hax), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.81 (dd, 2- H), 3.15 (s, CH (OCH 3 ) 2 ), 3.20 (d, 2 ”-Heq), 3.24 (s, CH (OCH 3 ) 2 ), 3.47 (dd, 2'-H), 3.64 (s , 4-OCH 3 ), 3.86 (br d, 5-H), 3.94 (br d, 4-H), 4.39 (d, 1'-H), 4.42 (m, 4 ''-H), 4.45 (m , 5 ”-H), 4.46 (dd, CH (OCH 3 ) 2 ), 4.81 (d, 1” -H), 5.03 (m, 15-H), 5.40 (m, 3-H), 5.89 (dt , CH = CH), 6.27 (d, CH = CH), 6.44 (d, pyridine), 7.47 (dd, pyridine), 7.95 (d, pyridine).

(c)実施例2(b)と同様の方法で、実施例18(b)の化合物2.5 mgから、標記化合物1.58 mgを得た。 (c) In the same manner as in Example 2 (b), 1.58 mg of the title compound was obtained from 2.5 mg of the compound of Example 18 (b).

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1056 (M+H)+
(2)比旋光度:[α]D 25 -37°(c0.15, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.94(d, 8-CH3), 1.11(d, 6”-H), 1.17(t, NHCH2CH3), 1.17(d, 6'-H), 1.46(s, 3”-CH3), 2.53(s, 3'-N(CH3)2), 2.84(dd, 2-H), 2.89(dd, 6-CH2), 3.20(d, 2”-Heq), 3.38(dd, 2'-H), 3.65(s, 4-OCH3), 3.85(br d, 5-H), 3.93(br d, 4-H), 4.38(d, 1'-H), 4.43(m, 4”-H), 4.43(m, 5”-H), 4.82(d, 1”-H), 5.04(m, 15-H), 5.45(m, 3-H), 5.89(dt, CH=CH), 6.28(d, CH=CH), 6.45(d, pyridine), 7.47(dd, pyridine), 7.96(d, pyridine), 9.63(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1056 (M + H) +
(2) Specific rotation: [α] D 25 -37 ° (c0.15, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.94 (d, 8-CH 3 ), 1.11 (d, 6 ”-H), 1.17 (t, NHCH 2 CH 3 ), 1.17 ( d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 2.53 (s, 3'-N (CH 3 ) 2 ), 2.84 (dd, 2-H), 2.89 (dd, 6-CH 2 ), 3.20 (d, 2 ”-Heq), 3.38 (dd, 2'-H), 3.65 (s, 4-OCH 3 ), 3.85 (br d, 5-H), 3.93 (br d, 4- H), 4.38 (d, 1'-H), 4.43 (m, 4 ”-H), 4.43 (m, 5” -H), 4.82 (d, 1 ”-H), 5.04 (m, 15-H ), 5.45 (m, 3-H), 5.89 (dt, CH = CH), 6.28 (d, CH = CH), 6.45 (d, pyridine), 7.47 (dd, pyridine), 7.96 (d, pyridine), 9.63 (s, CHO).

実施例19
式(1)において、R1がプロピオニル基、R2が水素原子、R3がメチル基、R4がトランス-3-([1,6]ナフチリジン-8-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例1(b)と同様の方法で、3-ブロモキノリンの代わりに8-ブロモ-1,6-ナフチリジンを用い、また1,4-ジオキサンの代わりにジメチルホルムアミドを用い、実施例1(a)の化合物40 mgから、カップリング化合物(工程図10の式(15c)において、Arが1,6-ナフチリジン-8-イル基、R5が水素原子及びR6がエチル基で表される化合物)5.1 mgを得た。
Example 19
In the formula (1), R 1 is a propionyl group, R 2 is a hydrogen atom, R 3 is a methyl group, R 4 is a trans-3-([1,6] naphthyridin-8-yl) -2-propenyl group, R Method for producing a compound wherein 5 is a hydrogen atom and R 6 is an ethyl group
(a) In the same manner as in Example 1 (b), except that 8-bromo-1,6-naphthyridine was used instead of 3-bromoquinoline and dimethylformamide was used instead of 1,4-dioxane. From 40 mg of the compound of 1 (a), a coupling compound (in the formula (15c) of process diagram 10, Ar is a 1,6-naphthyridin-8-yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group) Compound) 5.1 mg was obtained.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1188 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.91(d, 8-CH3), 1.11(d, 6”-H), 1.17(t, NHCH2CH3), 1.19(d, 6'-H), 1.46(s, 3”-CH3), 2.03(s, 9-OCOCH3), 2.05(s, 2'-OCOCH3), 2.22(s, NCH3), 2.41(s, 3'-N(CH3)2), 2.87(dd, 2-H), 3.14(s, CH(OCH3)2), 3.19(d, 2”-Heq), 3.24(s, CH(OCH3)2), 3.58(s, 4-OCH3), 3.67(br d, 4-H), 3.91(d, 5-H), 4.41(m, 4”-H), 4.41(m, 5”-H), 4.54(dd, CH(OCH3)2), 4.67(d, 1'-H), 4.77(d, 1”- H), 4.91(m, 9-H), 4.95(dd, 2'-H), 5.05(br dd, 3-H), 5.18(m, 15-H), 6.50(dt, CH=CH), 7.45(d, CH=CH), 7.53(d, naphthyridine), 8.26(dd, naphthyridine), 8.83(s, naphthyridine), 9.10(dd, naphthyridine), 9.13(s, naphthyridine).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1188 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.91 (d, 8-CH 3 ), 1.11 (d, 6 ”-H), 1.17 (t, NHCH 2 CH 3 ), 1.19 ( d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 2.03 (s, 9-OCOCH 3 ), 2.05 (s, 2'-OCOCH 3 ), 2.22 (s, NCH 3 ), 2.41 ( s, 3'-N (CH 3 ) 2 ), 2.87 (dd, 2-H), 3.14 (s, CH (OCH 3 ) 2 ), 3.19 (d, 2 ”-Heq), 3.24 (s, CH ( OCH 3 ) 2 ), 3.58 (s, 4-OCH 3 ), 3.67 (br d, 4-H), 3.91 (d, 5-H), 4.41 (m, 4 ”-H), 4.41 (m, 5 ”-H), 4.54 (dd, CH (OCH 3 ) 2 ), 4.67 (d, 1'-H), 4.77 (d, 1” -H), 4.91 (m, 9-H), 4.95 (dd, 2'-H), 5.05 (br dd, 3-H), 5.18 (m, 15-H), 6.50 (dt, CH = CH), 7.45 (d, CH = CH), 7.53 (d, naphthyridine), 8.26 (dd, naphthyridine), 8.83 (s, naphthyridine), 9.10 (dd, naphthyridine), 9.13 (s, naphthyridine).

(b)実施例1(c)と同様の方法で、実施例19(a)の化合物5.1 mgから、脱アセチル化合物(工程図10の式(18c)において、R2が水素原子、Arが1,6-ナフチリジン-8-イル基、R5が水素原子及びR6がエチル基で表される化合物)2.5 mgを得た。(b) In the same manner as in Example 1 (c), from 5.1 mg of the compound of Example 19 (a), a deacetylated compound (in formula (18c) of process diagram 10, R 2 is a hydrogen atom, Ar is 1 , 6-Naphthyridin-8-yl group, a compound in which R 5 is a hydrogen atom and R 6 is an ethyl group), 2.5 mg.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1104 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.88(d, 8-CH3), 1.09(d, 6”-H), 1.11(t, 3-OCOCH2CH3), 1.13(t, 3”-OCOCH2CH3), 1.17(t, NHCH2CH3), 1.19(d, 6'-H), 1.46(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.51(s, 3'-N(CH3)2), 2.83(dd, 2-H), 3.14(s, CH(OCH3)2), 3.21(d, 2”-Heq), 3.24(s, CH(OCH3)2), 3.47(dd, 2'-H), 3.60(s, 4-OCH3), 3,87(br d, 5-H), 3.98(br d, 4-H), 4.39(d, 1'-H), 4.43(m, 4”-H), 4.46(m, 5”-H), 4.47(dd, CH(OCH3)2), 4.80(d, 1”-H), 5.16(m, 15-H), 5.44(m, 3-H), 6.50(dt, CH=CH), 7.44(d, CH=CH), 7.54(d, naphthyridine), 8.27(dd, naphthyridine), 8.83(s, naphthyridine), 9.10(dd, naphthyridine), 9.13(s, naphthyridine).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1104 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.88 (d, 8-CH 3 ), 1.09 (d, 6 ”-H), 1.11 (t, 3-OCOCH 2 CH 3 ), 1.13 (t, 3 ”-OCOCH 2 CH 3 ), 1.17 (t, NHCH 2 CH 3 ), 1.19 (d, 6'-H), 1.46 (s, 3” -CH 3 ), 1.68 (dd, 2 ” -Hax), 2.51 (s, 3'-N (CH 3 ) 2 ), 2.83 (dd, 2-H), 3.14 (s, CH (OCH 3 ) 2 ), 3.21 (d, 2 ”-Heq), 3.24 (s, CH (OCH 3 ) 2 ), 3.47 (dd, 2'-H), 3.60 (s, 4-OCH 3 ), 3,87 (br d, 5-H), 3.98 (br d, 4 -H), 4.39 (d, 1'-H), 4.43 (m, 4``-H), 4.46 (m, 5 ''-H), 4.47 (dd, CH (OCH 3 ) 2 ), 4.80 (d, 1 ''-H), 5.16 (m, 15-H), 5.44 (m, 3-H), 6.50 (dt, CH = CH), 7.44 (d, CH = CH), 7.54 (d, naphthyridine), 8.27 (dd, naphthyridine), 8.83 (s, naphthyridine), 9.10 (dd, naphthyridine), 9.13 (s, naphthyridine).

(c)実施例2(b)と同様の方法で、実施例19(b)の化合物2.5 mgから、標記化合物1.87 mgを得た。 (c) In the same manner as in Example 2 (b), 1.87 mg of the title compound was obtained from 2.5 mg of the compound of Example 19 (b).

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1058 (M+H)+
(2)比旋光度:[α]D 25 -39°(c1.00, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.91(d, 8-CH3), 1.10(d, 6”-H), 1.11(t, 3-OCOCH2CH3), 1.13(t, 3”-OCOCH2CH3), 1.17(t, NHCH2CH3), 1.17(d, 6'-H), 1.46(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.52(s, 3'-N(CH3)2), 2.84(dd, 2-H), 2.90(dd, 6-CH2), 3.21(d, 2”-Heq), 3.39(dd, 2'-H), 3.61(s, 4-OCH3), 3.85(br d, 5-H), 3.98(br d, 4-H), 4.37(d, 1'-H), 4.43(m, 4”-H), 4.43(m, 5”-H), 4.81(d, 1”-H), 5.17(m, 15-H), 5.50(m, 3-H), 6.50(dt, CH=CH), 7.44(d, CH=CH), 7.54(dd, naphthyridine), 8.26(dd, naphthyridine), 8.83(s, naphthyridine), 9.11(dd, naphthyridine), 9.13(s, naphthyridine), 9.63(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1058 (M + H) +
(2) Specific rotation: [α] D 25 -39 ° (c1.00, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.91 (d, 8-CH 3 ), 1.10 (d, 6 ”-H), 1.11 (t, 3-OCOCH 2 CH 3 ), 1.13 (t, 3 ”-OCOCH 2 CH 3 ), 1.17 (t, NHCH 2 CH 3 ), 1.17 (d, 6'-H), 1.46 (s, 3” -CH 3 ), 1.68 (dd, 2 ” -Hax), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.84 (dd, 2-H), 2.90 (dd, 6-CH 2 ), 3.21 (d, 2 ”-Heq), 3.39 ( dd, 2'-H), 3.61 (s, 4-OCH 3 ), 3.85 (br d, 5-H), 3.98 (br d, 4-H), 4.37 (d, 1'-H), 4.43 ( m, 4 ''-H), 4.43 (m, 5 ''-H), 4.81 (d, 1 ''-H), 5.17 (m, 15-H), 5.50 (m, 3-H), 6.50 (dt, CH = CH), 7.44 (d, CH = CH), 7.54 (dd, naphthyridine), 8.26 (dd, naphthyridine), 8.83 (s, naphthyridine), 9.11 (dd, naphthyridine), 9.13 (s, naphthyridine), 9.63 (s, CHO).

実施例20
式(1)において、R1がプロピオニル基、R2が水素原子、R3がメチル基、R4がトランス-3-(キノリン-3-イル)-2-プロペニル基、R5が水素原子及びR6がノルマルプロピル基で表される化合物の製造方法
(a)実施例1(a)と同様の方法で、エチルイソシアネートの代わりにノルマルプロピルイソシアネートを用いてカップリング化合物(WO2005/19238:工程図10の式(23c)において、Arがキノリン-3-イル基で表される化合物)50 mgから、カルバモイル化合物(工程図10の式(15c)において、Arがキノリン-3-イル基、R5が水素原子及びR6がノルマルプロピル基で表される化合物)46 mgを得た。
Example 20
In the formula (1), R 1 is a propionyl group, R 2 is a hydrogen atom, R 3 is a methyl group, R 4 is a trans-3- (quinolin-3-yl) -2-propenyl group, R 5 is a hydrogen atom and Method for producing a compound in which R 6 is a normal propyl group
(a) In the same manner as in Example 1 (a), using normal propyl isocyanate instead of ethyl isocyanate, a coupling compound (WO2005 / 19238: in formula (23c) of process diagram 10, Ar is quinoline-3- From 50 mg of a compound represented by an yl group), a carbamoyl compound (Ar is a quinolin-3-yl group, R 5 is a hydrogen atom, and R 6 is a normal propyl group in Formula (15c) of Process FIG. 10) Compound) 46 mg was obtained.

本化合物の理化学的性状
(1)マススペクトル(FAB) :m/z 1201 (M+H)+
(2)比旋光度:[α]D 25 -58°(c0.74, CHCl3)
(3) 1H NMRスペクトル(300 MHz, CDCl3) δ(ppm) :0.92(d, 8-CH3), 0.94(t, NHCH2CH2CH3), 1.13(d, 6”-H), 1.20(d, 6'-H), 1.47(s, 3”-CH3), 1.54(m, NHCH2CH2CH3), 1.68(dd, 2”-Hax), 2.04(s, 9-OCOCH3), 2.06(s, 2'-OCOCH3), 2.24(s, NCH3), 2.43(s,3'-N(CH3)2), 2.86(dd, 2-H), 3.15(s, CH(OCH3)2), 3.19(d, 2”-Heq), 3.25(s, CH(OCH3)2), 3.59(s, 4-OCH3), 3.93(br d, 5-H), 4.41(m, 4”-H), 4.41(m, 5”-H), 4.55(dd, CH(OCH3)2), 4.68(d, 1'-H), 4.79(d, 1”-H), 4.92(m, 9-H), 4.97(dd, 2'-H), 5.08(br dd, 3-H), 5.16(m, 15-H), 6.37(dt, CH=CH), 6.61(d, CH=CH), 7.53(br t, quinoline), 7.66(ddd, quinoline), 7.79(br d, quinoline), 8.02(d, quinoline), 8.06(br d, quinoline), 8.95(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1201 (M + H) +
(2) Specific rotation: [α] D 25 -58 ° (c0.74, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.92 (d, 8-CH 3 ), 0.94 (t, NHCH 2 CH 2 CH 3 ), 1.13 (d, 6 ”-H) , 1.20 (d, 6'-H), 1.47 (s, 3 ”-CH 3 ), 1.54 (m, NHCH 2 CH 2 CH 3 ), 1.68 (dd, 2” -Hax), 2.04 (s, 9- OCOCH 3 ), 2.06 (s, 2'-OCOCH 3 ), 2.24 (s, NCH 3 ), 2.43 (s, 3'-N (CH 3 ) 2 ), 2.86 (dd, 2-H), 3.15 (s , CH (OCH 3 ) 2 ), 3.19 (d, 2 ”-Heq), 3.25 (s, CH (OCH 3 ) 2 ), 3.59 (s, 4-OCH 3 ), 3.93 (br d, 5-H) , 4.41 (m, 4 ”-H), 4.41 (m, 5” -H), 4.55 (dd, CH (OCH 3 ) 2 ), 4.68 (d, 1'-H), 4.79 (d, 1 ”- H), 4.92 (m, 9-H), 4.97 (dd, 2'-H), 5.08 (br dd, 3-H), 5.16 (m, 15-H), 6.37 (dt, CH = CH), 6.61 (d, CH = CH), 7.53 (br t, quinoline), 7.66 (ddd, quinoline), 7.79 (br d, quinoline), 8.02 (d, quinoline), 8.06 (br d, quinoline), 8.95 (d , quinoline).

(b)実施例2(a)と同様の方法で、実施例20(a)の化合物37 mgから、脱アセチル化合物(工程図10の式(18c)において、R2が水素原子、Arがキノリン-3-イル基、R5が水素原子及びR6がノルマルプロピル基で表される化合物)18.5 mgを得た。(b) In the same manner as in Example 2 (a), from the compound 37 mg of Example 20 (a), a deacetylated compound (in formula (18c) of Process Diagram 10, R 2 is a hydrogen atom, Ar is a quinoline) 18.5 mg of a compound represented by a -3-yl group, R 5 is a hydrogen atom, and R 6 is a normal propyl group.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1117 (M+H)+
(2)比旋光度:[α]D 20 -45°(c0.98, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.89(d, 8-CH3), 0.94(t, NHCH2CH2CH3), 1.11(t, 3-OCOCH2CH3), 1.12(t, 3”-OCOCH2CH3), 1.13(d, 6”-H), 1.20(d, 6'-H), 1.48(s, 3”-CH3), 1.55(m, NHCH2CH2CH3), 1.69(dd, 2”-Hax), 1.87(br dd, 6-CH2), 2.35(s, NCH3), 2.53(s, 3'-N(CH3)2), 2.61(dd, 2-H), 2.70(m, 12-H), 2.83(dd, 2-H), 3.15(s, CH(OCH3)2), 3.25(s, CH(OCH3)2), 3.36(m, 9-H), 3.47(dd, 2'-H), 3.65(s, 4-OCH3), 3.89(br d, 5-H), 3.97(br d, 4-H), 4.41(d, 1'-H), 4.43(m, 4”-H), 4.47(m, 5”-H), 4.81(d, 1”-H), 4.85(t, NH), 5.13(m, 15-H), 5.46(br dd, 3-H), 6.35(dt, CH=CH), 6.59(d, CH=CH), 7.53(ddd, quinoline), 7.67(ddd, quinoline), 7.78(brd, quinoline), 8.01(d, quinoline), 8.06(br d, quinoline), 8.94(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1117 (M + H) +
(2) Specific rotation: [α] D 20 -45 ° (c0.98, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.89 (d, 8-CH 3 ), 0.94 (t, NHCH 2 CH 2 CH 3 ), 1.11 (t, 3-OCOCH 2 CH 3 ), 1.12 (t, 3 ”-OCOCH 2 CH 3 ), 1.13 (d, 6” -H), 1.20 (d, 6'-H), 1.48 (s, 3 ”-CH 3 ), 1.55 (m, NHCH 2 CH 2 CH 3 ), 1.69 (dd, 2 ”-Hax), 1.87 (br dd, 6-CH 2 ), 2.35 (s, NCH 3 ), 2.53 (s, 3'-N (CH 3 ) 2 ), 2.61 (dd, 2-H), 2.70 (m, 12-H), 2.83 (dd, 2-H), 3.15 (s, CH (OCH 3 ) 2 ), 3.25 (s, CH (OCH 3 ) 2 ), 3.36 (m, 9-H), 3.47 (dd, 2'-H), 3.65 (s, 4-OCH 3 ), 3.89 (br d, 5-H), 3.97 (br d, 4-H ), 4.41 (d, 1'-H), 4.43 (m, 4 ”-H), 4.47 (m, 5” -H), 4.81 (d, 1 ”-H), 4.85 (t, NH), 5.13 (m, 15-H), 5.46 (br dd, 3-H), 6.35 (dt, CH = CH), 6.59 (d, CH = CH), 7.53 (ddd, quinoline), 7.67 (ddd, quinoline), 7.78 (brd, quinoline), 8.01 (d, quinoline), 8.06 (br d, quinoline), 8.94 (d, quinoline).

(c)実施例1(d)と同様の方法で、実施例20(b)の化合物24 mgから、標記化合物14 mgを得た。 (c) In the same manner as in Example 1 (d), 14 mg of the title compound was obtained from 24 mg of the compound of Example 20 (b).

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1071 (M+H)+
(2)比旋光度:[α]D 24 -53°(c0.7, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.90(d, 8-CH3), 0.93(t, NHCH2CH2CH3), 1.13(t, 3-OCOCH2CH3), 1.14(t, 3”-OCOCH2CH3), 1.34(m, 8-H), 1.47(s, 3”-CH3), 1.57(sext, NHCH2CH2CH3), 1.69(dd, 2”-Hax), 2.32(s, NCH3), 2.53(s, 3'-N(CH3)2), 2.84(dd, 2-H), 2.90(dd, 6-CH2), 3.21(d, 2”-Heq), 3.37(m, 9-H), 3.25(q, NHCH2CH3), 3.39(dd, 2'-H), 3.66(s, 4-OCH3), 3.87(br d, 5-H), 3.98(br d, 4-H), 4.38(d, 1'-H), 4.41(m, 4”-H), 4.44(m, 5”-H), 4.82(d, 1”-H), 4.84(t, NH), 5.13(m,15-H), 5.57(br dd, 3-H), 6.35(dt, CH=CH), 6.59(d, CH=CH), 7.53(ddd, quinoline),7.66(ddd, quinoline), 7.78(br d, quinoline), 8.00(d, quinoline), 8.06(br d, quinoline), 8.94(d, quinoline), 9.65(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1071 (M + H) +
(2) Specific rotation: [α] D 24 -53 ° (c0.7, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.90 (d, 8-CH 3 ), 0.93 (t, NHCH 2 CH 2 CH 3 ), 1.13 (t, 3-OCOCH 2 CH 3 ), 1.14 (t, 3 ”-OCOCH 2 CH 3 ), 1.34 (m, 8-H), 1.47 (s, 3” -CH 3 ), 1.57 (sext, NHCH 2 CH 2 CH 3 ), 1.69 (dd , 2 ”-Hax), 2.32 (s, NCH 3 ), 2.53 (s, 3'-N (CH 3 ) 2 ), 2.84 (dd, 2-H), 2.90 (dd, 6-CH 2 ), 3.21 (d, 2 ''-Heq), 3.37 (m, 9-H), 3.25 (q, NHCH 2 CH 3 ), 3.39 (dd, 2'-H), 3.66 (s, 4-OCH 3 ), 3.87 ( br d, 5-H), 3.98 (br d, 4-H), 4.38 (d, 1'-H), 4.41 (m, 4 ''-H), 4.44 (m, 5 ''-H), 4.82 ( d, 1 ”-H), 4.84 (t, NH), 5.13 (m, 15-H), 5.57 (br dd, 3-H), 6.35 (dt, CH = CH), 6.59 (d, CH = CH ), 7.53 (ddd, quinoline), 7.66 (ddd, quinoline), 7.78 (br d, quinoline), 8.00 (d, quinoline), 8.06 (br d, quinoline), 8.94 (d, quinoline), 9.65 (s, (CHO).

実施例21
式(1)において、R1がプロピオニル基、R2が水素原子、R3がメチル基、R4がトランス-3-(キノリン-3-イル)-2-プロペニル基、R5が水素原子及びR6がイソプロピル基で表される化合物の製造方法
(a)実施例1(a)と同様の方法で、エチルイソシアネートの代わりにイソプロピルイソシアネートを用いて、カップリング化合物(工程図10の式(23c)において、Arがキノリン-3-イル基で表される化合物)50 mgから、カルバモイル化合物(工程図10の式(15c)において、Arがキノリン-3-イル基、R5が水素原子及びR6がイソプロピル基で表される化合物)43 mgを得た。
Example 21
In the formula (1), R 1 is a propionyl group, R 2 is a hydrogen atom, R 3 is a methyl group, R 4 is a trans-3- (quinolin-3-yl) -2-propenyl group, R 5 is a hydrogen atom and Method for producing compound wherein R 6 is isopropyl group
(a) In the same manner as in Example 1 (a), using isopropyl isocyanate instead of ethyl isocyanate, a coupling compound (in the formula (23c) of Process FIG. 10, Ar is a quinolin-3-yl group) Compound from 50 mg to 43 mg of a carbamoyl compound (a compound in which Ar is a quinolin-3-yl group, R 5 is a hydrogen atom, and R 6 is an isopropyl group in the formula (15c) in Step 10) Obtained.

本化合物の理化学的性状
(1)マススペクトル(FAB) :m/z 1201 (M+H)+
(2)比旋光度:[α]D 19 -58°(c0.78, CHCl3)
(3)1H NMRスペクトル(300 MHz, CDCl3) δ(ppm) :0.92(d, 8-CH3), 1.12(d, 6”-H),1.18(d, NHCH(CH3)2), 1.47(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.04(s, 9-OCOCH3), 2.06(s, 2'-OCOCH3), 2.24(s, NCH3), 2.42(s, 3'-N(CH3)2), 2.86(dd, 2-H), 3.14(s, CH(OCH3)2), 3.20(d, 2”-Heq), 3.25(s, CH(OCH3)2), 3.60(s, 4-OCH3), 3.84(m, NHCH(CH3)2), 3.93(br d, 5-H), 4.41(m, 4”-H), 4.41(m, 5”-H), 4.56(dd, CH(OCH3)2), 4.68(d, 1'-H), 4.79(d, 1”-H), 4.92(m, 9-H), 4.97(dd, 2'-H), 5.07(br dd, 3-H), 5.16(m, 15-H), 6.37(dt, CH=CH), 6.61(d, CH=CH), 7.53(ddd, quinoline), 7.67(ddd, quinoline), 7.79(br d, quinoline), 8.02(d, quinoline), 8.06(br d, quinoline), 8.95(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1201 (M + H) +
(2) Specific rotation: [α] D 19 -58 ° (c0.78, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.92 (d, 8-CH 3 ), 1.12 (d, 6 ”-H), 1.18 (d, NHCH (CH 3 ) 2 ) , 1.47 (s, 3 ”-CH 3 ), 1.68 (dd, 2” -Hax), 2.04 (s, 9-OCOCH 3 ), 2.06 (s, 2'-OCOCH 3 ), 2.24 (s, NCH 3 ) , 2.42 (s, 3'-N (CH 3 ) 2 ), 2.86 (dd, 2-H), 3.14 (s, CH (OCH 3 ) 2 ), 3.20 (d, 2 ”-Heq), 3.25 (s , CH (OCH 3 ) 2 ), 3.60 (s, 4-OCH 3 ), 3.84 (m, NHCH (CH 3 ) 2 ), 3.93 (br d, 5-H), 4.41 (m, 4 ”-H) , 4.41 (m, 5 ”-H), 4.56 (dd, CH (OCH 3 ) 2 ), 4.68 (d, 1'-H), 4.79 (d, 1” -H), 4.92 (m, 9-H ), 4.97 (dd, 2'-H), 5.07 (br dd, 3-H), 5.16 (m, 15-H), 6.37 (dt, CH = CH), 6.61 (d, CH = CH), 7.53 (ddd, quinoline), 7.67 (ddd, quinoline), 7.79 (br d, quinoline), 8.02 (d, quinoline), 8.06 (br d, quinoline), 8.95 (d, quinoline).

(b) 実施例2(a)と同様の方法で、実施例21(a)の化合物43 mgから、脱アセチル化合物(工程図10の式(18c)において、R2が水素原子、Arがキノリン-3-イル基、R5が水素原子及びR6がイソプロピル基で表される化合物)23 mgを得た。(b) In the same manner as in Example 2 (a), from 43 mg of the compound of Example 21 (a), a deacetylated compound (in formula (18c) of Process Diagram 10, R 2 is a hydrogen atom, Ar is a quinoline) 23-mg of a compound represented by a -3-yl group, R 5 is a hydrogen atom, and R 6 is an isopropyl group.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1117 (M+H)+
(2)比旋光度:[α]D 23 -48°(c0.51, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.88(d, 8-CH3), 1.09(d, 6”-H), 1.13(d, 6'-H), 1.18(d, NHCH(CH3)2), 1.43(m, 8-H), 1.47(s, 3”-CH3), 1.69(dd, 2”-Hax), 1.82(m, 6-CH2), 1.95(m, 6-H), 2.34(s, NCH3), 2.53(s, 3'-N(CH3)2), 2.62(dd, 2-H), 2.70(m, 12-H), 2.82(dd, 2-H), 3.15(s, CH(OCH3)2), 3.16(d, 2”-Heq), 3.25(s, CH(OCH3)2), 3.34(m, 9-H), 3.47(dd, 2'-H), 3.65(s, 4-OCH3), 3.84(dq, NHCH(CH3)2), 3.89(br d, 5-H), 3.97(br d, 4-H), 4.39(d, 1'-H), 4.47(m, 5”-H), 4.67(d,NH), 4.81(d, 1”-H), 5.13(m, 15-H), 5.48(br dd, 3-H), 6.35(dt, CH=CH), 6.59(d, CH=CH), 7.53(ddd, quinoline), 7.66(ddd, quinoline), 7.78(br d, quinoline), 8.00(d, quinoline), 8.06(br d, quinoline), 8.93(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1117 (M + H) +
(2) Specific rotation: [α] D 23 -48 ° (c0.51, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.88 (d, 8-CH 3 ), 1.09 (d, 6 ″ -H), 1.13 (d, 6′-H), 1.18 ( d, NHCH (CH 3 ) 2 ), 1.43 (m, 8-H), 1.47 (s, 3 ”-CH 3 ), 1.69 (dd, 2” -Hax), 1.82 (m, 6-CH 2 ), 1.95 (m, 6-H), 2.34 (s, NCH 3 ), 2.53 (s, 3'-N (CH 3 ) 2 ), 2.62 (dd, 2-H), 2.70 (m, 12-H), 2.82 (dd, 2-H), 3.15 (s, CH (OCH 3 ) 2 ), 3.16 (d, 2 ”-Heq), 3.25 (s, CH (OCH 3 ) 2 ), 3.34 (m, 9-H ), 3.47 (dd, 2'-H), 3.65 (s, 4-OCH 3 ), 3.84 (dq, NHCH (CH 3 ) 2 ), 3.89 (br d, 5-H), 3.97 (br d, 4 -H), 4.39 (d, 1'-H), 4.47 (m, 5 ''-H), 4.67 (d, NH), 4.81 (d, 1 ''-H), 5.13 (m, 15-H), 5.48 (br dd, 3-H), 6.35 (dt, CH = CH), 6.59 (d, CH = CH), 7.53 (ddd, quinoline), 7.66 (ddd, quinoline), 7.78 (br d, quinoline), 8.00 (d, quinoline), 8.06 (br d, quinoline), 8.93 (d, quinoline).

(c)実施例1(d)と同様の方法で、実施例21(b)の化合物22 mgから、標記化合物18 mgを得た。 (c) In the same manner as in Example 1 (d), 18 mg of the title compound was obtained from 22 mg of the compound of Example 21 (b).

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1071 (M+H)+
(2)比旋光度:[α]D 23 -58°(c0.7, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.90(d, 8-CH3), 1.12(t, 3-OCOCH2CH3), 1.14(t, 3”-OCOCH2CH3), 1.18(d, NHCH(CH3)2), 1.34(m, 8-H), 1.47(s, 3”-CH3), 1.69(dd, 2”-Hax), 1.75(m, 14-H), 2.32(s, NCH3), 2.53(s, 3'-N(CH3)2), 2.84(dd, 2-H), 2.90(dd, 6-CH2), 3.15(m, 4'-H), 3.17(m, 5'-H), 3.21(d, 2”-Heq), 3.36(m, 9-H), 3.39(dd, 2'-H), 3.66(s, 4-OCH3), 3.83(dq, NHCH(CH3)2), 3.87(br d, 5-H), 3.98(br d, 4-H), 4.38(d, 1'-H), 4.41(m, 4”-H), 4.44(m, 5”-H), 4.67(d, NH),4.82(d, 1”-H) , 5.13(m, 15-H), 5.57(br dd, 3-H), 6.35(dt, CH=CH), 6.59(d, CH=CH), 7.53(ddd, quinoline), 7.66(ddd, quinoline), 7.78(br d, quinoline), 8.00(d, quinoline), 8.06(br d, quinoline), 8.94(d, quinoline), 9.65(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1071 (M + H) +
(2) Specific rotation: [α] D 23 -58 ° (c0.7, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.90 (d, 8-CH 3 ), 1.12 (t, 3-OCOCH 2 CH 3 ), 1.14 (t, 3 ”-OCOCH 2 CH 3 ), 1.18 (d, NHCH (CH 3 ) 2 ), 1.34 (m, 8-H), 1.47 (s, 3 ”-CH 3 ), 1.69 (dd, 2” -Hax), 1.75 (m, 14 -H), 2.32 (s, NCH 3 ), 2.53 (s, 3'-N (CH 3 ) 2 ), 2.84 (dd, 2-H), 2.90 (dd, 6-CH 2 ), 3.15 (m, 4'-H), 3.17 (m, 5'-H), 3.21 (d, 2 ”-Heq), 3.36 (m, 9-H), 3.39 (dd, 2'-H), 3.66 (s, 4 -OCH 3 ), 3.83 (dq, NHCH (CH 3 ) 2 ), 3.87 (br d, 5-H), 3.98 (br d, 4-H), 4.38 (d, 1'-H), 4.41 (m , 4 ”-H), 4.44 (m, 5” -H), 4.67 (d, NH), 4.82 (d, 1 ”-H), 5.13 (m, 15-H), 5.57 (br dd, 3- H), 6.35 (dt, CH = CH), 6.59 (d, CH = CH), 7.53 (ddd, quinoline), 7.66 (ddd, quinoline), 7.78 (br d, quinoline), 8.00 (d, quinoline), 8.06 (br d, quinoline), 8.94 (d, quinoline), 9.65 (s, CHO).

Figure 2007069555
Figure 2007069555

実施例22
式(1)において、R1がプロピオニル基、R2が水素原子、R3がメチル基、R4がトランス-3-(キノリン-3-イル)-2-プロペニル基、R5が水素原子及びR6がメチル基で表される化合物の製造方法
(a) カップリング化合物(工程図10の式(23c)において、Arがキノリン-3-イル基で表される化合物)330 mg及びカルボニルジイミダゾール960 mgをピリジン2.2 mlに溶解し、1,4-ジアザビシクロ[2.2.2]オクタン500 mgを加え、60℃で16時間撹拌した。反応液を室温まで戻した後、酢酸エチル50 mlで希釈し、水25 mlで3回、飽和食塩水20 mlで順次洗浄した。有機層を無水硫酸ナトリウムで乾燥後、これを濾過し、濾液を減圧濃縮して工程図11の式(25a)の化合物34 9 mgを得た。
Example 22
In the formula (1), R 1 is a propionyl group, R 2 is a hydrogen atom, R 3 is a methyl group, R 4 is a trans-3- (quinolin-3-yl) -2-propenyl group, R 5 is a hydrogen atom and Method for producing a compound in which R 6 is a methyl group
(a) 330 mg of a coupling compound (a compound in which Ar is represented by a quinolin-3-yl group in the formula (23c) of Step 10) and 960 mg of carbonyldiimidazole are dissolved in 2.2 ml of pyridine, and 1,4 -Diazabicyclo [2.2.2] octane 500 mg was added, and it stirred at 60 degreeC for 16 hours. The reaction solution was allowed to cool to room temperature, diluted with 50 ml of ethyl acetate, and washed successively with 25 ml of water three times and with 20 ml of saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 9 mg of the compound of formula (25a) shown in Step 11 of FIG.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1210 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.92(d, 8-CH3), 1.17(d, 6”-H), 1.18(t, 3-OCOCH2CH3), 1.21(t, 3”-OCOCH2CH3), 1.22(d, 6'-H), 1.52(s, 3”-CH3), 1.75(dd, 2”-Hax), 2.05(s, 9-OCOCH3), 2.06(s, 2'-OCOCH3), 2.24(s, NCH3), 2.43(s,3'-N(CH3)2), 2.87(dd, 2-H), 3.15(s, CH(OCH3)2), 3.26(s, CH(OCH3)2), 3.31(d, 2”-Heq), 3.60(s, 4-OCH3), 3.63(br d, 5-H), 3.94(br d, 5-H), 4.56(dd, CH(OCH3)2),4.65(m, 4”-H), 4.65(m, 5”-H), 4.70(d, 1'-H), 4.84(d, 1”-H), 4.91(br dd, 9-H), 4.99(dd, 2'-H), 5.08(br dd, 3-H), 5.16(m, 15-H), 6.37(dt, CH=CH), 6.61(d, CH=CH), 7.12(s, imidazole), 7.46(s, imidazole), 7.53(ddd, quinoline), 7.67(ddd, quinoline), 7.79(br d, quinoline), 8.02(d, quinoline), 8.06(br d, quinoline), 8.16(s, imidazole), 8.95(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1210 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.92 (d, 8-CH 3 ), 1.17 (d, 6 ”-H), 1.18 (t, 3-OCOCH 2 CH 3 ), 1.21 (t, 3 ”-OCOCH 2 CH 3 ), 1.22 (d, 6'-H), 1.52 (s, 3” -CH 3 ), 1.75 (dd, 2 ”-Hax), 2.05 (s, 9- OCOCH 3 ), 2.06 (s, 2'-OCOCH 3 ), 2.24 (s, NCH 3 ), 2.43 (s, 3'-N (CH 3 ) 2 ), 2.87 (dd, 2-H), 3.15 (s , CH (OCH 3 ) 2 ), 3.26 (s, CH (OCH 3 ) 2 ), 3.31 (d, 2 ”-Heq), 3.60 (s, 4-OCH 3 ), 3.63 (br d, 5-H) , 3.94 (br d, 5-H), 4.56 (dd, CH (OCH 3 ) 2 ), 4.65 (m, 4 ”-H), 4.65 (m, 5” -H), 4.70 (d, 1'- H), 4.84 (d, 1 ”-H), 4.91 (br dd, 9-H), 4.99 (dd, 2'-H), 5.08 (br dd, 3-H), 5.16 (m, 15-H ), 6.37 (dt, CH = CH), 6.61 (d, CH = CH), 7.12 (s, imidazole), 7.46 (s, imidazole), 7.53 (ddd, quinoline), 7.67 (ddd, quinoline), 7.79 ( br d, quinoline), 8.02 (d, quinoline), 8.06 (br d, quinoline), 8.16 (s, imidazole), 8.95 (d, quinoline).

(b)実施例22(a)の化合物52 mgをジメチルホルムアミド1 mlに溶解し、-15℃でメチルアミン塩酸塩29 mg及びトリエチルアミン66 μlを加え、-15℃から室温に昇温しつつ21時間撹拌した。反応液を-15℃に降温し、メチルアミン塩酸塩29 mg及びトリエチルアミン66 μlを加え、-15℃から室温に昇温しつつ、さらに7時間撹拌した。反応液を酢酸エチル20 mlで希釈し、水10 mlで2回、飽和食塩水10 mlで順次洗浄、有機層を無水硫酸ナトリウムで乾燥後、これを濾過した。濾液を減圧濃縮して得られた残渣を分取用TLC(ヘキサン−アセトン−28%アンモニア水(16:14:0.2))で精製して、カルバモイル化合物(工程図10の式(15c)において、Arがキノリン-3-イル基、R5が水素原子及びR6がメチル基で表される化合物)44 mgを得た。(b) 52 mg of the compound of Example 22 (a) was dissolved in 1 ml of dimethylformamide, 29 mg of methylamine hydrochloride and 66 μl of triethylamine were added at -15 ° C, and the temperature was raised from -15 ° C to room temperature Stir for hours. The temperature of the reaction solution was lowered to −15 ° C., 29 mg of methylamine hydrochloride and 66 μl of triethylamine were added, and the mixture was further stirred for 7 hours while warming from −15 ° C. to room temperature. The reaction solution was diluted with 20 ml of ethyl acetate, washed twice with 10 ml of water and successively with 10 ml of saturated brine, and the organic layer was dried over anhydrous sodium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by preparative TLC (hexane-acetone-28% aqueous ammonia (16: 14: 0.2)), and the carbamoyl compound (in the formula (15c) of process diagram 10) 44 mg of a compound in which Ar is a quinolin-3-yl group, R 5 is a hydrogen atom, and R 6 is a methyl group.

本化合物の理化学的性状
(1)マススペクトル(FAB) :m/z 1173 (M+H)+
(2)比旋光度:[α]D 24 -63°(c0.73, CHCl3)
(3)1H NMRスペクトル(300 MHz, CDCl3) δ(ppm) :0.92(d, 8-CH3), 1.12(d, 6”-H),1.13(t, 3-OCOCH2CH3), 1.20(d, 6'-H), 1.47(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.04(s, 9-OCOCH3), 2.05(s, 2'-OCOCH3), 2.24(s, NCH3), 2.42(s, 3'-N(CH3)2), 2.84(d,NHCH3), 2.86(dd, 2-H), 3.13(t, 4'-H), 3.15(s, CH(OCH3)2), 3.19(d, 2”-Heq), 3.25(s, CH(OCH3)2), 3.59(s, 4-OCH3), 3.93(br d, 5-H), 4.41(m, 4”-H), 4.42(m, 5”-H), 4.55(dd, CH(OCH3)2), 4.68(d, 1'-H), 4.79(d, 1”-H), 4.90(m, 9-H), 4.97(dd, 2'-H), 5.07(br dd, 3-H), 5.16(m, 15-H), 6.37(dt, CH=CH), 6.61(d, CH=CH), 7.52(ddd, quinoline), 7.66(ddd, quinoline), 7.79(br d, quinoline), 8.01(d, quinoline),8.06(br d, quinoline), 8.95(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1173 (M + H) +
(2) Specific rotation: [α] D 24 -63 ° (c0.73, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.92 (d, 8-CH 3 ), 1.12 (d, 6 ”-H), 1.13 (t, 3-OCOCH 2 CH 3 ) , 1.20 (d, 6'-H), 1.47 (s, 3 ”-CH 3 ), 1.68 (dd, 2” -Hax), 2.04 (s, 9-OCOCH 3 ), 2.05 (s, 2'-OCOCH 3 ), 2.24 (s, NCH 3 ), 2.42 (s, 3'-N (CH 3 ) 2 ), 2.84 (d, NHCH 3 ), 2.86 (dd, 2-H), 3.13 (t, 4'- H), 3.15 (s, CH (OCH 3 ) 2 ), 3.19 (d, 2 ”-Heq), 3.25 (s, CH (OCH 3 ) 2 ), 3.59 (s, 4-OCH 3 ), 3.93 (br d, 5-H), 4.41 (m, 4 ''-H), 4.42 (m, 5 ''-H), 4.55 (dd, CH (OCH 3 ) 2 ), 4.68 (d, 1'-H), 4.79 (d, 1 ''-H), 4.90 (m, 9-H), 4.97 (dd, 2'-H), 5.07 (br dd, 3-H), 5.16 (m, 15-H), 6.37 (dt , CH = CH), 6.61 (d, CH = CH), 7.52 (ddd, quinoline), 7.66 (ddd, quinoline), 7.79 (br d, quinoline), 8.01 (d, quinoline), 8.06 (br d, quinoline ), 8.95 (d, quinoline).

(c) 実施例2(a)と同様の方法で、実施例22(b)の化合物43 mgから、脱アセチル化合物(工程図10の式(18c)において、R2が水素原子、Arがキノリン-3-イル基、R5が水素原子及びR6がメチル基で表される化合物)16 mgを得た。(c) In the same manner as in Example 2 (a), from the compound 43 mg of Example 22 (b), a deacetylated compound (in formula (18c) of Process Diagram 10, R 2 is a hydrogen atom, Ar is quinoline) 16 mg of a compound represented by a -3-yl group, R 5 is a hydrogen atom, and R 6 is a methyl group.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1089 (M+H)+
(2)比旋光度:[α]D 24 -47°(c0.78, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.88(d, 8-CH3), 1.11(t, 3-OCOCH2CH3), 1.11(t, 3”-OCOCH2CH3), 1.20(d, 6'-H), 1.44(m, 8-H), 1.47(s, 3”-CH3), 1.69(dd, 2”-Hax), 1.79(br dd, 6-H), 1.90(m, 6-H), 2.35(s, NCH3), 2.52(s, 3'-N(CH3)2), 2.61(dd, 2-H), 2.72(m, 12-H), 2.82(dd, 2-H), ), 2.84(d, NHCH3), 3.15(s, CH(OCH3)2), 3.16(d, 2”-Heq), 3.25(s, CH(OCH3)2), 3.37(m, 9-H), 3.47(dd, 2'-H), 3.65(s, 4-OCH3) , 3.88(br d, 5-H), 3.96(br d, 4-H), 4.41(d, 1'-H), 4.47(m, CH(OCH3)2), 4.81(d, 1”-H), 5.13(m, 15-H), 5.46(br dd, 3-H), 6.35(dt, CH=CH), 6.59(d, CH=CH), 7.53(ddd, quinoline), 7.66(ddd, quinoline), 7.78(br d, quinoline), 8.00(d, quinoline), 8.06(br d, quinoline), 8.93(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1089 (M + H) +
(2) Specific rotation: [α] D 24 -47 ° (c0.78, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.88 (d, 8-CH 3 ), 1.11 (t, 3-OCOCH 2 CH 3 ), 1.11 (t, 3 ”-OCOCH 2 CH 3 ), 1.20 (d, 6'-H), 1.44 (m, 8-H), 1.47 (s, 3 ”-CH 3 ), 1.69 (dd, 2” -Hax), 1.79 (br dd, 6- H), 1.90 (m, 6-H), 2.35 (s, NCH 3 ), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.61 (dd, 2-H), 2.72 (m, 12- H), 2.82 (dd, 2-H),), 2.84 (d, NHCH 3 ), 3.15 (s, CH (OCH 3 ) 2 ), 3.16 (d, 2 ”-Heq), 3.25 (s, CH ( OCH 3 ) 2 ), 3.37 (m, 9-H), 3.47 (dd, 2'-H), 3.65 (s, 4-OCH 3 ), 3.88 (br d, 5-H), 3.96 (br d, 4-H), 4.41 (d, 1'-H), 4.47 (m, CH (OCH 3 ) 2 ), 4.81 (d, 1 ”-H), 5.13 (m, 15-H), 5.46 (br dd , 3-H), 6.35 (dt, CH = CH), 6.59 (d, CH = CH), 7.53 (ddd, quinoline), 7.66 (ddd, quinoline), 7.78 (br d, quinoline), 8.00 (d, quinoline), 8.06 (br d, quinoline), 8.93 (d, quinoline).

(d)実施例1(d)と同様の方法で、実施例22(c)の化合物15 mgから、標記化合物12 mgを得た。 (d) In the same manner as in Example 1 (d), 12 mg of the title compound was obtained from 15 mg of the compound of Example 22 (c).

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1043 (M+H)+
(2)比旋光度:[α]D 25 -55°(c0.54, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.90(d, 8-CH3), 1.12(d, 6”-H), 1.13(t, 3-OCOCH2CH3), 1.14(d, 6'-H), 1.14(t, 3”-OCOCH2CH3), 1.34(m, 8-H), 1.47(s, 3”-CH3), 1.69(dd, 2”-Hax), 2.32(s, NCH3), 2.53(s, 3'-N(CH3)2), 2.84(dd, 2-H), 2.89(dd, 6-CH2), 3.15(m, 4'-H), 3.18(m, 5'-H), 3.21(d, 2”-Heq), 3.36(m, 9-H), 3.39(dd, 2'-H), 3.66(s, 4-OCH3), 3.87(br d, 5-H), 3.97(br d, 4-H), 4.38(d, 1'-H), 4.45(m, 4”-H), 4.47(m, 5”-H), 4.78(d, NH), 4.82(d, 1”-H), 5.13(m, 15-H), 5.57(br dd, 3-H), 6.35(dt, CH=CH), 6.59(d, CH=CH), 7.53(ddd, quinoline), 7.66(ddd, quinoline), 7.78(br d, quinoline), 8.00(d, quinoline), 8.06(br d, quinoline), 8.94(d, quinoline), 9.65(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1043 (M + H) +
(2) Specific rotation: [α] D 25 -55 ° (c0.54, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.90 (d, 8-CH 3 ), 1.12 (d, 6 ”-H), 1.13 (t, 3-OCOCH 2 CH 3 ), 1.14 (d, 6'-H), 1.14 (t, 3 ”-OCOCH 2 CH 3 ), 1.34 (m, 8-H), 1.47 (s, 3” -CH 3 ), 1.69 (dd, 2 ”- Hax), 2.32 (s, NCH 3 ), 2.53 (s, 3'-N (CH 3 ) 2 ), 2.84 (dd, 2-H), 2.89 (dd, 6-CH 2 ), 3.15 (m, 4 '-H), 3.18 (m, 5'-H), 3.21 (d, 2 ”-Heq), 3.36 (m, 9-H), 3.39 (dd, 2'-H), 3.66 (s, 4- OCH 3 ), 3.87 (br d, 5-H), 3.97 (br d, 4-H), 4.38 (d, 1'-H), 4.45 (m, 4 ”-H), 4.47 (m, 5” -H), 4.78 (d, NH), 4.82 (d, 1 ”-H), 5.13 (m, 15-H), 5.57 (br dd, 3-H), 6.35 (dt, CH = CH), 6.59 (d, CH = CH), 7.53 (ddd, quinoline), 7.66 (ddd, quinoline), 7.78 (br d, quinoline), 8.00 (d, quinoline), 8.06 (br d, quinoline), 8.94 (d, quinoline ), 9.65 (s, CHO).

実施例23
式(1)において、R1がプロピオニル基、R2が水素原子、R3がメチル基、R4がトランス-3-(キノリン-3-イル)-2-プロペニル基、R5及びR6がメチル基で表される化合物の製造方法
(a)実施例22(b)と同様の方法で、メチルアミン塩酸塩の代わりにジメチルアミン塩酸塩を用いて、実施例22(a)の化合物55 mgから、カルバモイル化合物(工程図10の式(15c)において、Arがキノリン-3-イル基、R5及びR6がメチル基で表される化合物)54 mgを得た。
Example 23
In the formula (1), R 1 is a propionyl group, R 2 is a hydrogen atom, R 3 is a methyl group, R 4 is a trans-3- (quinolin-3-yl) -2-propenyl group, R 5 and R 6 are Method for producing compound represented by methyl group
(a) In the same manner as in Example 22 (b), using dimethylamine hydrochloride instead of methylamine hydrochloride, from 55 mg of the compound of Example 22 (a), the carbamoyl compound (formula of process diagram 10) In (15c), 54 mg of a compound in which Ar is a quinolin-3-yl group and R 5 and R 6 are methyl groups was obtained.

本化合物の理化学的性状
(1)マススペクトル(FAB) :m/z 1186 (M+H)+
(2)比旋光度:[α]D 24 -62°(c1.0, CHCl3)
(3)1H NMRスペクトル(300 MHz, CDCl3) δ(ppm) :0.92(d, 8-CH3), 1.12(d, 6”-H),1.14(t, 3-OCOCH2CH3), 1.15(t, 3”-OCOCH2CH3), 1.20(d, 6'-H), 1.46(s, 3”-CH3),1.69(dd, 2”-Hax), 2.04(s, 9-OCOCH3), 2.05(s, 2'-OCOCH3), 2.24(s, NCH3), 2.43(s, 3'-N(CH3)2), 2.62(dd, 2-H), 2.86(dd, 2-H), 2.96(s, CON(CH3)2), 3.14(m, 4'-H), 3.15(s, CH(OCH3)2), 3.19(d, 2"-Heq), 3.25(s, CH(OCH3)2), 3.59(s, 4-OCH3), 3.93(br d, 5-H), 4.42(m, 4”-H), 4.45(m, 5”-H), 4.55(m, CH(OCH3)2), 4.68(d, 1'-H), 4.80(d, 1”-H), 4.92(m, 9-H), 4.97(dd, 2'-H), 5.07(br dd, 3-H), 5.16(m, 15-H), 6.37(dt, CH=CH), 6.61(d, CH=CH), 7.53(ddd, quinoline), 7.66(ddd, quinoline), 7.79(br d, quinoline), 8.02(d, quinoline), 8.06(br d, quinoline), 8.95(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1186 (M + H) +
(2) Specific rotation: [α] D 24 -62 ° (c1.0, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.92 (d, 8-CH 3 ), 1.12 (d, 6 ”-H), 1.14 (t, 3-OCOCH 2 CH 3 ) , 1.15 (t, 3 ”-OCOCH 2 CH 3 ), 1.20 (d, 6'-H), 1.46 (s, 3” -CH 3 ), 1.69 (dd, 2 ”-Hax), 2.04 (s, 9 -OCOCH 3 ), 2.05 (s, 2'-OCOCH 3 ), 2.24 (s, NCH 3 ), 2.43 (s, 3'-N (CH 3 ) 2 ), 2.62 (dd, 2-H), 2.86 ( dd, 2-H), 2.96 (s, CON (CH 3 ) 2 ), 3.14 (m, 4'-H), 3.15 (s, CH (OCH 3 ) 2 ), 3.19 (d, 2 "-Heq) , 3.25 (s, CH (OCH 3 ) 2 ), 3.59 (s, 4-OCH 3 ), 3.93 (br d, 5-H), 4.42 (m, 4 ”-H), 4.45 (m, 5”- H), 4.55 (m, CH (OCH 3 ) 2 ), 4.68 (d, 1'-H), 4.80 (d, 1 ”-H), 4.92 (m, 9-H), 4.97 (dd, 2 ' -H), 5.07 (br dd, 3-H), 5.16 (m, 15-H), 6.37 (dt, CH = CH), 6.61 (d, CH = CH), 7.53 (ddd, quinoline), 7.66 ( ddd, quinoline), 7.79 (br d, quinoline), 8.02 (d, quinoline), 8.06 (br d, quinoline), 8.95 (d, quinoline).

(b)実施例1(c)と同様の方法で、実施例23(a)の化合物55 mgから、脱アセチル化合物(工程図10の式(18c)において、R2が水素原子、Arがキノリン-3-イル基、R5及びR6がメチル基で表される化合物)16.8 mgを得た。(b) In the same manner as in Example 1 (c), from 55 mg of the compound of Example 23 (a), a deacetylated compound (in formula (18c) of process diagram 10, R 2 is a hydrogen atom, Ar is a quinoline) 16.8 mg of a compound wherein the -3-yl group, R 5 and R 6 are represented by a methyl group).

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1103 (M+H)+
(2)比旋光度:[α]D 25 -51°(c0.83, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.89(d, 8-CH3), 1.11(d, 6”-H), 1.11(t, 3-OCOCH2CH3), 1.13(t, 3”-OCOCH2CH3), 1.21(d, 6'-H), 1.46(s, 3”-CH3), 1.70(dd, 2”-Hax), 1.84(br dd, 6-H), 1.91(m, 6-H), 2.35(s, NCH3), 2.53(s, 3'-N(CH3)2), 2.62(dd, 2-H), 2.71(m, 12-H), 2.83(dd, 2-H), 2.96(s, CON(CH3)2), 3.15(s, CH(OCH3)2), 3.22(d, 2”-Heq), 3.25(s, CH(OCH3)2), 3.37(m, 9-H), 3.47(dd, 2'-H),3.65(s, 4-OCH3), 3.88(br d, 5-H), 3.96(br d, 4-H), 4.43(d, 4”-H), 4.52(d, 5”-H), 4.83(d, 1”-H), 5.13(m, 15-H), 5.47(br dd, 3-H), 6.35(dt, CH=CH), 6.59(d, CH=CH), 7.53(ddd, quinoline), 7.66(ddd, quinoline), 7.78(br d, quinoline), 8.01(d,quinoline), 8.06(br d, quinoline), 8.94(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1103 (M + H) +
(2) Specific rotation: [α] D 25 -51 ° (c0.83, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.89 (d, 8-CH 3 ), 1.11 (d, 6 ”-H), 1.11 (t, 3-OCOCH 2 CH 3 ), 1.13 (t, 3 ”-OCOCH 2 CH 3 ), 1.21 (d, 6'-H), 1.46 (s, 3” -CH 3 ), 1.70 (dd, 2 ”-Hax), 1.84 (br dd, 6 -H), 1.91 (m, 6-H), 2.35 (s, NCH 3 ), 2.53 (s, 3'-N (CH 3 ) 2 ), 2.62 (dd, 2-H), 2.71 (m, 12 -H), 2.83 (dd, 2-H), 2.96 (s, CON (CH 3 ) 2 ), 3.15 (s, CH (OCH 3 ) 2 ), 3.22 (d, 2 ”-Heq), 3.25 (s , CH (OCH 3 ) 2 ), 3.37 (m, 9-H), 3.47 (dd, 2'-H), 3.65 (s, 4-OCH 3 ), 3.88 (br d, 5-H), 3.96 ( br d, 4-H), 4.43 (d, 4 ”-H), 4.52 (d, 5” -H), 4.83 (d, 1 ”-H), 5.13 (m, 15-H), 5.47 (br dd, 3-H), 6.35 (dt, CH = CH), 6.59 (d, CH = CH), 7.53 (ddd, quinoline), 7.66 (ddd, quinoline), 7.78 (br d, quinoline), 8.01 (d , quinoline), 8.06 (br d, quinoline), 8.94 (d, quinoline).

(c)実施例1(d)と同様の方法で、実施例23(b)の化合物16 mgから、標記化合物13 mgを得た。 (c) In the same manner as in Example 1 (d), 13 mg of the title compound was obtained from 16 mg of the compound of Example 23 (b).

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1057 (M+H)+
(2)比旋光度:[α]D 25 -56°(c0.58, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.89(d, 8-CH3), 1.12(t, 3-OCOCH2CH3), 1.13(d, 6”-H), 1.16(t, 3”-OCOCH2CH3), 1.35(m, 8-H), 1.46(s, 3”-CH3), 1.70(dd, 2”-Hax), 2.32(s, NCH3), 2.54(s, 3'-N(CH3)2), 2.84(dd, 2-H), 2.90(dd, 6-CH2), 2.96(s, CON(CH3)2), 3.18(m, 4'-H), 3.18(m, 5'-H), 3.22(d, 2”-Heq), 3.36(m, 9-H), 3.39(dd, 2'-H), 3.66(s, 4-OCH3), 3.87(br d, 5-H), 3.97(br d, 4-H), 4.39(d, 1'-H), 4.43(d, 4”-H), 4.50(dq, 5”-H), 4.84(d, 1”-H), 5.13(m, 15-H), 5.57(br dd, 3-H), 6.35(dt, CH=CH), 6.59(d, CH=CH), 7.53(ddd, quinoline), 7.66(ddd,quinoline), 7.78(br d, quinoline), 8.00(d, quinoline), 8.06(br d, quinoline), 8.94(d, quinoline), 9.65(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1057 (M + H) +
(2) Specific rotation: [α] D 25 -56 ° (c0.58, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.89 (d, 8-CH 3 ), 1.12 (t, 3-OCOCH 2 CH 3 ), 1.13 (d, 6 ”-H), 1.16 (t, 3 ”-OCOCH 2 CH 3 ), 1.35 (m, 8-H), 1.46 (s, 3” -CH 3 ), 1.70 (dd, 2 ”-Hax), 2.32 (s, NCH 3 ) , 2.54 (s, 3'-N (CH 3 ) 2 ), 2.84 (dd, 2-H), 2.90 (dd, 6-CH 2 ), 2.96 (s, CON (CH 3 ) 2 ), 3.18 (m , 4'-H), 3.18 (m, 5'-H), 3.22 (d, 2 ”-Heq), 3.36 (m, 9-H), 3.39 (dd, 2'-H), 3.66 (s, 4-OCH 3 ), 3.87 (br d, 5-H), 3.97 (br d, 4-H), 4.39 (d, 1'-H), 4.43 (d, 4 ''-H), 4.50 (dq, 5 ''-H), 4.84 (d, 1 ''-H), 5.13 (m, 15-H), 5.57 (br dd, 3-H), 6.35 (dt, CH = CH), 6.59 (d, CH = CH), 7.53 (ddd, quinoline), 7.66 (ddd, quinoline), 7.78 (br d, quinoline), 8.00 (d, quinoline), 8.06 (br d, quinoline), 8.94 (d, quinoline), 9.65 (s , CHO).

実施例24
式(1)において、R1がプロピオニル基、R2が水素原子、R3がメチル基、R4がトランス-3-(キノリン-3-イル)-2-プロペニル基、R5が水素原子及びR6が2-ヒドロキシエチル基で表される化合物の製造方法
(a)実施例22(b)と同様の方法で、トリエチルアミンを用いず、メチルアミン塩酸塩の代わりに2-ヒドロキシエチルアミンを用いて、実施例22(a)の化合物55 mgから、カルバモイル化合物(工程図10の式(15c)において、Arがキノリン-3-イル基、R5が水素原子及びR6が2-ヒドロキシエチル基で表される化合物)43 mgを得た。
Example 24
In the formula (1), R 1 is a propionyl group, R 2 is a hydrogen atom, R 3 is a methyl group, R 4 is a trans-3- (quinolin-3-yl) -2-propenyl group, R 5 is a hydrogen atom and Method for producing compound in which R 6 is represented by 2-hydroxyethyl group
(a) In the same manner as in Example 22 (b), without using triethylamine and using 2-hydroxyethylamine instead of methylamine hydrochloride, from 55 mg of the compound of Example 22 (a), the carbamoyl compound ( 43 mg of a compound represented by the formula (15c) in process diagram 10), wherein Ar is a quinolin-3-yl group, R 5 is a hydrogen atom and R 6 is a 2-hydroxyethyl group.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1203 (M+H)+
(2)比旋光度:[α]D 23 -58°(c0.81, CHCl3)
(3)1H NMRスペクトル(300 MHz, CDCl3) δ(ppm):0.92(d, 8-CH3), 1.12(d, 6”-H), 1.14(t, 3-OCOCH2CH3), 1.20(d, 6'-H), 1.48(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.04(s, 9-OCOCH3), 2.05(s, 2'-OCOCH3), 2.24(s, NCH3), 2.42(s, 3'-N(CH3)2), 2.86(dd,2-H), 3.13(t, 4'-H), 3.15(s, CH(OCH3)2), 3.19(d, 2”-Heq), 3.25(s, CH(OCH3)2),3.39(q, NHCH2), 3.59(s, 4-OCH3), 3.76(t, CH2OH), 3.93(br d, 5-H), 4.40(d, 4”-H), 4.44(m, 5”-H), 4.55(dd, CH(OCH3)2), 4.68(d, 1'-H), 4.79(d, 1”-H), 4.91(m, 9-H), 4.97(dd, 2'-H), 5.07(br dd, 3-H), 5.15(m, 15-H), 6.37(dt, CH=CH), 6.61(d,CH=CH), 7.52(ddd, quinoline), 7.66(ddd, quinoline), 7.78(br d, quinoline), 8.02(d, quinoline), 8.06(br d, quinoline), 8.95(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1203 (M + H) +
(2) Specific rotation: [α] D 23 -58 ° (c0.81, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.92 (d, 8-CH 3 ), 1.12 (d, 6 ”-H), 1.14 (t, 3-OCOCH 2 CH 3 ) , 1.20 (d, 6'-H), 1.48 (s, 3 ”-CH 3 ), 1.68 (dd, 2” -Hax), 2.04 (s, 9-OCOCH 3 ), 2.05 (s, 2'-OCOCH 3 ), 2.24 (s, NCH 3 ), 2.42 (s, 3'-N (CH 3 ) 2 ), 2.86 (dd, 2-H), 3.13 (t, 4'-H), 3.15 (s, CH (OCH 3 ) 2 ), 3.19 (d, 2 ”-Heq), 3.25 (s, CH (OCH 3 ) 2 ), 3.39 (q, NHCH 2 ), 3.59 (s, 4-OCH 3 ), 3.76 (t , CH 2 OH), 3.93 (br d, 5-H), 4.40 (d, 4 ''-H), 4.44 (m, 5 ''-H), 4.55 (dd, CH (OCH 3 ) 2 ), 4.68 ( d, 1'-H), 4.79 (d, 1 ''-H), 4.91 (m, 9-H), 4.97 (dd, 2'-H), 5.07 (br dd, 3-H), 5.15 (m , 15-H), 6.37 (dt, CH = CH), 6.61 (d, CH = CH), 7.52 (ddd, quinoline), 7.66 (ddd, quinoline), 7.78 (br d, quinoline), 8.02 (d, quinoline), 8.06 (br d, quinoline), 8.95 (d, quinoline).

(b)実施例1(c)と同様の方法で、実施例24(a)の化合物43 mgから、脱アセチル化合物(工程図10の式(18c)において、R2が水素原子、Arがキノリン-3-イル基、R5が水素原子及びR6が2-ヒドロキシエチル基で表される化合物)15.8 mgを得た。(b) In the same manner as in Example 1 (c), from 43 mg of the compound of Example 24 (a), a deacetylated compound (in formula (18c) of Process Diagram 10, R 2 is a hydrogen atom, Ar is a quinoline) 15.8 mg of a compound represented by a 3-yl group, R 5 is a hydrogen atom, and R 6 is a 2-hydroxyethyl group.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1119 (M+H)+
(2)比旋光度 :[α]D 25 -45°(c0.78, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.89(d, 8-CH3), 1.10(t, 3-OCOCH2CH3), 1.12(d, 6”-H), 1.12(t, 3”-OCOCH2CH3), 1.20(d, 6'-H), 1.48(s, 3”-CH3), 1.69(dd, 2”-Hax), 1.80(br dd, 6-H), 1.93(m, 6-H), 2.35(s, NCH3), 2.53(s, 3'-N(CH3)2), 2.62(dd, 2-H), 2.69(m, 12-H), 2.83(dd, 2-H), 3.15(s, CH(OCH3)2), 3.21(d, 2”-Heq), 3.25(s, CH(OCH3)2), 3.39(dt, NHCH2), 3.48(dd, 2'-H), 3.65(s, 4-OCH3),3.74(dt, CH2OH), 3.88(br d, 5-H), 3.96(br d, 4-H), 4.41(d, 4”-H), 4.81(d, 1”-H), 5.13(m, 15-H), 5.29(t, NH), 5.46(br dd, 3-H), 6.35(dt, CH=CH), 6.59(d, CH=CH), 7.53(ddd, quinoline), 7.67(ddd, quinoline), 7.78(br d, quinoline), 8.00(d, quinoline), 8.06(br d, quinoline), 8.93(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1119 (M + H) +
(2) Specific rotation: [α] D 25 -45 ° (c0.78, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.89 (d, 8-CH 3 ), 1.10 (t, 3-OCOCH 2 CH 3 ), 1.12 (d, 6 ”-H), 1.12 (t, 3 ”-OCOCH 2 CH 3 ), 1.20 (d, 6'-H), 1.48 (s, 3” -CH 3 ), 1.69 (dd, 2 ”-Hax), 1.80 (br dd, 6 -H), 1.93 (m, 6-H), 2.35 (s, NCH 3 ), 2.53 (s, 3'-N (CH 3 ) 2 ), 2.62 (dd, 2-H), 2.69 (m, 12 -H), 2.83 (dd, 2-H), 3.15 (s, CH (OCH 3 ) 2 ), 3.21 (d, 2 ”-Heq), 3.25 (s, CH (OCH 3 ) 2 ), 3.39 (dt , NHCH 2 ), 3.48 (dd, 2'-H), 3.65 (s, 4-OCH 3 ), 3.74 (dt, CH 2 OH), 3.88 (br d, 5-H), 3.96 (br d, 4 -H), 4.41 (d, 4 ''-H), 4.81 (d, 1 ''-H), 5.13 (m, 15-H), 5.29 (t, NH), 5.46 (br dd, 3-H), 6.35 (dt, CH = CH), 6.59 (d, CH = CH), 7.53 (ddd, quinoline), 7.67 (ddd, quinoline), 7.78 (br d, quinoline), 8.00 (d, quinoline), 8.06 (br d, quinoline), 8.93 (d, quinoline).

(c)実施例1(d)と同様の方法で、実施例24(b)の化合物15 mgから、標記化合物12 mgを得た。 (c) In the same manner as in Example 1 (d), 12 mg of the title compound was obtained from 15 mg of the compound of Example 24 (b).

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1073 (M+H)+
(2)比旋光度:[α]D 25 -51°(c0.51, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.90(d, 8-CH3), 1.12(t, 3-OCOCH2CH3), 1.16(t, 3”-OCOCH2CH3), 1.48(s, 3”-CH3), 1.69(dd, 2”-Hax), 2.32(s, NCH3), 2.53(s, 3'-N(CH3)2), 2.84(dd, 2-H), 2.89(dd, 6-CH2), 3.14(m, 4'-H), 3.17(m, 5'-H), 3.21(d, 2”-Heq), 3.39(m, NHCH2), 3.66(s, 4-OCH3), 3.75(t, CH2OH), 3.87(br d, 5-H), 3.97(br d, 4-H), 4.38(d, 1'-H), 4.42(d, 4”-H), 4.48(dq, 5”-H), 4.82(d, 1”-H), 5.13(m, 15-H), 5.27(t, NH), 5.56(br dd, 3-H), 6.35(dt, CH=CH), 6.59(d, CH=CH), 7.53(ddd, quinoline), 7.66(ddd, quinoline), 7.78(br d, quinoline), 8.00(d, quinoline), 8.06(br d, quinoline), 8.93(d, quinoline), 9.64(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1073 (M + H) +
(2) Specific rotation: [α] D 25 -51 ° (c0.51, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.90 (d, 8-CH 3 ), 1.12 (t, 3-OCOCH 2 CH 3 ), 1.16 (t, 3 ”-OCOCH 2 CH 3 ), 1.48 (s, 3 ”-CH 3 ), 1.69 (dd, 2” -Hax), 2.32 (s, NCH 3 ), 2.53 (s, 3'-N (CH 3 ) 2 ), 2.84 (dd , 2-H), 2.89 (dd, 6-CH 2 ), 3.14 (m, 4'-H), 3.17 (m, 5'-H), 3.21 (d, 2 ”-Heq), 3.39 (m, NHCH 2 ), 3.66 (s, 4-OCH 3 ), 3.75 (t, CH 2 OH), 3.87 (br d, 5-H), 3.97 (br d, 4-H), 4.38 (d, 1'- H), 4.42 (d, 4 ”-H), 4.48 (dq, 5” -H), 4.82 (d, 1 ”-H), 5.13 (m, 15-H), 5.27 (t, NH), 5.56 (br dd, 3-H), 6.35 (dt, CH = CH), 6.59 (d, CH = CH), 7.53 (ddd, quinoline), 7.66 (ddd, quinoline), 7.78 (br d, quinoline), 8.00 (d, quinoline), 8.06 (br d, quinoline), 8.93 (d, quinoline), 9.64 (s, CHO).

実施例25
式(1)において、R1がプロピオニル基、R2が水素原子、R3がメチル基、R4が3-(キノリン-3-イル)プロピル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例1(b)の化合物44 mgに酢酸エチル1 ml を加え溶解し、10%Pd-C触媒4.7 mgを加え反応容器を水素置換した。室温で3時間攪拌し、さらに10%Pd-C触媒4.7 mg及び1,4-ジオキサン1 mlを加えて室温で4.5時間攪拌した。酢酸エチル15 mlを用いて触媒を濾過した後、濾液を減圧濃縮して得られた残渣を分取用TLC(クロロホルム−メタノール(10:1))で精製して、還元化合物(工程図10の式(16c)において、Arがキノリン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)19 mgを得た。
Example 25
In the formula (1), R 1 is a propionyl group, R 2 is a hydrogen atom, R 3 is a methyl group, R 4 is a 3- (quinolin-3-yl) propyl group, R 5 is a hydrogen atom, and R 6 is an ethyl group Process for producing a compound represented by
(a) 1 mg of ethyl acetate was dissolved in 44 mg of the compound of Example 1 (b), dissolved, 4.7 mg of 10% Pd—C catalyst was added, and the reaction vessel was replaced with hydrogen. The mixture was stirred at room temperature for 3 hours, further added with 4.7 mg of 10% Pd-C catalyst and 1 ml of 1,4-dioxane, and stirred at room temperature for 4.5 hours. After filtering the catalyst with 15 ml of ethyl acetate, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative TLC (chloroform-methanol (10: 1)) to give a reduced compound (of FIG. 10). In the formula (16c), 19 mg of a compound in which Ar is a quinolin-3-yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group were obtained.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1189 (M+H)+
(2)1H NMRスペクトル(300 MHz, CDCl3) δ(ppm):0.92(d, 8-CH3), 1.13(d, 6”-H), 1.20(d, 6'-H), 1.48(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.04(s, 9-OCOCH3), 2.05(s, 2'-OCOCH3), 2.22(s, NCH3), 2.42(s, 3'-N(CH3)2), 2.81(t, quinoline-CH2), 2.89(dd, 2-H), 3.14(s, CH(OCH3)2), 3.19(d, 2”-Heq), 3.25(s, CH(OCH3)2), 3.63(s, 4-OCH3), 3.66(br d, 4-H), 3.94(br d, 5-H), 4.41(m, 4”-H), 4.42(m, 5”-H ), 4.55(dd, CH(OCH3)2), 4.69(d, 1'-H), 4.79(d, 1”-H), 4.90(m, 9-H), 4.97(dd, 2'-H), 5.02(m, 3-H), 5.05(m, 15-H), 7.53(ddd, quinoline), 7.67(ddd, quinoline), 7.77(br d, quinoline), 7.91(d, quinoline), 8.07(br d, quinoline), 8.76(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1189 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.92 (d, 8-CH 3 ), 1.13 (d, 6 ”-H), 1.20 (d, 6'-H), 1.48 (s, 3 ”-CH 3 ), 1.68 (dd, 2” -Hax), 2.04 (s, 9-OCOCH 3 ), 2.05 (s, 2'-OCOCH 3 ), 2.22 (s, NCH 3 ), 2.42 (s, 3'-N (CH 3 ) 2 ), 2.81 (t, quinoline-CH 2 ), 2.89 (dd, 2-H), 3.14 (s, CH (OCH 3 ) 2 ), 3.19 (d, 2 `` -Heq), 3.25 (s, CH (OCH 3 ) 2 ), 3.63 (s, 4-OCH 3 ), 3.66 (br d, 4-H), 3.94 (br d, 5-H), 4.41 (m , 4 "-H), 4.42 ( m, 5" -H), 4.55 (dd, CH (OCH 3) 2), 4.69 (d, 1'-H), 4.79 (d, 1 "-H), 4.90 (m, 9-H), 4.97 (dd, 2'-H), 5.02 (m, 3-H), 5.05 (m, 15-H), 7.53 (ddd, quinoline), 7.67 (ddd, quinoline), 7.77 (br d, quinoline), 7.91 (d, quinoline), 8.07 (br d, quinoline), 8.76 (d, quinoline).

(b)実施例1(c)と同様の方法で、実施例25(a)の化合物80 mgから、脱アセチル化合物(工程図10の式(17c)において、Arがキノリン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)60 mgを得た。(b) In the same manner as in Example 1 (c), from 80 mg of the compound of Example 25 (a), a deacetylated compound (in the formula (17c) of Process Diagram 10, Ar is a quinolin-3-yl group, 60 mg of a compound in which R 5 is a hydrogen atom and R 6 is an ethyl group.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1105 (M+H)+
(2)比旋光度:[α]D 19 -53°(c1.0, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.88(d, 8-CH3), 1.10(t, 3-OCOCH2CH3), 1.12(t, 3”-OCOCH2CH3), 1.17(t, NHCH2CH3), 1.20(d, 6'-H), 1.41(m, 8-H), 1.48(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.29(s, NCH3), 2.53(s, 3'-N(CH3)2), 2.58(dd,2-H), 2.81(t, quinoline-CH2), 2.85(dd, 2-H), 3.13(s, CH(OCH3)2), 3.21(d, 2”-Heq), 3.25(s, CH(OCH3)2), 3.49(dd, 2'-H), 3.70(s, 4-OCH3), 3.91(m, 5-H), 4.00(br d, 4-H), 4.41(m, 4”-H), 4.81(d, 1”-H), 4.84(t, NH), 5.04(m, 15-H), 5.44(br dd,3-H), 7.53(ddd, quinoline), 7.67(ddd, quinoline), 7.77(br d, quinoline), 7.91(d, quinoline), 8.08(br d, quinoline), 8.76(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1105 (M + H) +
(2) Specific rotation: [α] D 19 -53 ° (c1.0, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.88 (d, 8-CH 3 ), 1.10 (t, 3-OCOCH 2 CH 3 ), 1.12 (t, 3 ”-OCOCH 2 CH 3 ), 1.17 (t, NHCH 2 CH 3 ), 1.20 (d, 6'-H), 1.41 (m, 8-H), 1.48 (s, 3 ”-CH 3 ), 1.68 (dd, 2”- Hax), 2.29 (s, NCH 3 ), 2.53 (s, 3'-N (CH 3 ) 2 ), 2.58 (dd, 2-H), 2.81 (t, quinoline-CH 2 ), 2.85 (dd, 2 -H), 3.13 (s, CH (OCH 3 ) 2 ), 3.21 (d, 2 ”-Heq), 3.25 (s, CH (OCH 3 ) 2 ), 3.49 (dd, 2'-H), 3.70 ( s, 4-OCH 3 ), 3.91 (m, 5-H), 4.00 (br d, 4-H), 4.41 (m, 4 ”-H), 4.81 (d, 1” -H), 4.84 (t , NH), 5.04 (m, 15-H), 5.44 (br dd, 3-H), 7.53 (ddd, quinoline), 7.67 (ddd, quinoline), 7.77 (br d, quinoline), 7.91 (d, quinoline ), 8.08 (br d, quinoline), 8.76 (d, quinoline).

(c)実施例1(d)と同様の方法で、実施例25(b)の化合物59 mgから、標記化合物42 mgを得た。 (c) In the same manner as in Example 1 (d), 42 mg of the title compound was obtained from 59 mg of the compound of Example 25 (b).

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1059 (M+H)+
(2)比旋光度:[α]D 19 -55°(c0.75, CHCl3) (3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.91(d, 8-CH3), 1.17(t, NHCH2CH3), 1.34(m, 8-H), 1.47(s, 3”-CH3), 2.30(s, NCH3), 2.54(s, 3'-N(CH3)2), 2.81(t, quinoline-CH2), 2.86(dd, 2-H), 2.90(dd, 6-CH2), 3.15(t, 4'-H), 3.21(d, 2”-Heq), 3.37(m, 9-H), 3.40(dd, 2'-H), 3.70(s, 4-OCH3), 3.87(br d, 5-H), 3.99(br d, 4-H), 4.39(d, 1'-H), 4.41(d, 4”-H), 4.46(dq, 5”-H), 4.80(t, NH), 4.82(d, 1”-H), 5.03(m, 15-H), 5.50(br dd, 3-H), 7.53(ddd, quinoline), 7.66(ddd, quinoline), 7.77(br d, quinoline), 7.90(d, quinoline), 8.07(br d, quinoline), 8.75(d, quinoline), 9.64(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1059 (M + H) +
(2) Specific rotation: [α] D 19 -55 ° (c0.75, CHCl 3 ) (3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.91 (d, 8-CH 3 ) , 1.17 (t, NHCH 2 CH 3 ), 1.34 (m, 8-H), 1.47 (s, 3 ”-CH 3 ), 2.30 (s, NCH 3 ), 2.54 (s, 3'-N (CH 3 ) 2 ), 2.81 (t, quinoline-CH 2 ), 2.86 (dd, 2-H), 2.90 (dd, 6-CH 2 ), 3.15 (t, 4'-H), 3.21 (d, 2 ”- Heq), 3.37 (m, 9-H), 3.40 (dd, 2'-H), 3.70 (s, 4-OCH 3 ), 3.87 (br d, 5-H), 3.99 (br d, 4-H ), 4.39 (d, 1'-H), 4.41 (d, 4 "-H), 4.46 (dq, 5" -H), 4.80 (t, NH), 4.82 (d, 1 "-H), 5.03 (m, 15-H), 5.50 (br dd, 3-H), 7.53 (ddd, quinoline), 7.66 (ddd, quinoline), 7.77 (br d, quinoline), 7.90 (d, quinoline), 8.07 (br d, quinoline), 8.75 (d, quinoline), 9.64 (s, CHO).

実施例26
式(1)において、R1がプロピオニル基、R2が水素原子、R3がメチル基、R4が3-(6-アミノキノリン-3-イル)プロピル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法(a)実施例1(b)と同様の方法で、3-ブロモキノリンの代わりに6-アミノ-3-ブロモキノリンを用いて、実施例1(a)の化合物60.1 mgから、カップリング化合物(工程図10の式(15c)において、Arが6-アミノキノリン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)35.8 mgを得た。
Example 26
In the formula (1), R 1 is a propionyl group, R 2 is a hydrogen atom, R 3 is a methyl group, R 4 is a 3- (6-aminoquinolin-3-yl) propyl group, R 5 is a hydrogen atom and R 6 Is a method similar to Example 1 (b), except that 6-amino-3-bromoquinoline is used instead of 3-bromoquinoline. ) To 60.1 mg of a coupling compound (a compound in which Ar is a 6-aminoquinolin-3-yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group in the formula (15c) in Step 10) 35.8 mg was obtained.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1202 (M+H)+
(2)1H NMRスペクトル(300 MHz, CDCl3) δ(ppm):0.92(d, 8-CH3), 1.12(d, 6”-H), 1.19(t, NHCH2CH3), 1.20(d, 6'-H), 1.47(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.04(s, 9-OCOCH3), 2.06(s, 2'-OCOCH3), 2.23(s, NCH3), 2.42(s, 3'-N(CH3)2), 2.86(dd, 2-H), 3.15(s, CH(OCH3)2), 3.25(s, CH(OCH3)2), 3.59(s, 4-OCH3), 3.93(br d, 5-H), 4.40(m, 4”-H), 4.42(m, 5”-H), 4.55(dd, CH(OCH3)2), 4.68(d, 1'-H), 4.79(d, 1”-H), 4.91(m, 9-H), 4.96(dd, 2'-H), 5.06(m, 3-H), 5.13(m, 15-H), 6.30(dt, CH=CH), 6.54(d, CH=CH), 6.86(d, quinoline), 7.09(dd, quinoline), 7.75(d, quinoline), 7.85(d, quinoline), 8.67(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1202 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.92 (d, 8-CH 3 ), 1.12 (d, 6 ”-H), 1.19 (t, NHCH 2 CH 3 ), 1.20 (d, 6'-H), 1.47 (s, 3 ”-CH 3 ), 1.68 (dd, 2” -Hax), 2.04 (s, 9-OCOCH 3 ), 2.06 (s, 2'-OCOCH 3 ) , 2.23 (s, NCH 3 ), 2.42 (s, 3'-N (CH 3 ) 2 ), 2.86 (dd, 2-H), 3.15 (s, CH (OCH 3 ) 2 ), 3.25 (s, CH (OCH 3 ) 2 ), 3.59 (s, 4-OCH 3 ), 3.93 (br d, 5-H), 4.40 (m, 4 ”-H), 4.42 (m, 5” -H), 4.55 (dd , CH (OCH 3 ) 2 ), 4.68 (d, 1'-H), 4.79 (d, 1 ”-H), 4.91 (m, 9-H), 4.96 (dd, 2'-H), 5.06 ( m, 3-H), 5.13 (m, 15-H), 6.30 (dt, CH = CH), 6.54 (d, CH = CH), 6.86 (d, quinoline), 7.09 (dd, quinoline), 7.75 ( d, quinoline), 7.85 (d, quinoline), 8.67 (d, quinoline).

(b) 実施例25(a)と同様の方法で、実施例26(a)の化合物33.4 mgから、還元化合物(工程図10の式(16c)において、Arが6-アミノキノリン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)15.9 mgを得た。(b) In the same manner as in Example 25 (a), from the compound 33.4 mg of Example 26 (a), the reduced compound (in the formula (16c) of Process Diagram 10, Ar is 6-aminoquinolin-3-yl) Group, R 5 is a hydrogen atom and R 6 is an ethyl group) 15.9 mg.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1204 (M+H)+
(2)1H NMRスペクトル(300 MHz, CDCl3) δ(ppm):0.92(d, 8-CH3), 1.12(d, 6”-H), 1.16(t, NHCH2CH3), 1.20(d, 6'-H), 1.47(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.04(s, 9-OCOCH3), 2.06(s, 2'-OCOCH3), 2.24(s, NCH3), 2.42(s, 3'-N(CH3)2), 2.57(dd, 2-H), 2.59(t, 3'-H), 2.81(br dd, quinoline-CH2), 2.89(dd, 2-H), 3.11(t, 4'-H), 3.14(s, CH(OCH3)2), 3.19(d, 2”-Heq), 3.25(s, CH(OCH3)2), 3.62(s, 4-OCH3), 3.68(br d, 4-H), 3.93(br d, 5-H), 4.41(m, 4”-H), 4.41(m, 5”-H), 4.55(dd, CH(OCH3)2),4.69(d, 1'-H), 4.79(d, 1”-H), 4.80(t, NH), 4.92(m, 9-H), 4.97(dd, 2'-H), 5.00(m, 3-H), 5.04(m, 15-H), 6.85(d, quinoline), 7.10(dd, quinoline), 7.64(d, quinoline), 7.86(d, quinoline), 8.48(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1204 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.92 (d, 8-CH 3 ), 1.12 (d, 6 ”-H), 1.16 (t, NHCH 2 CH 3 ), 1.20 (d, 6'-H), 1.47 (s, 3 ”-CH 3 ), 1.68 (dd, 2” -Hax), 2.04 (s, 9-OCOCH 3 ), 2.06 (s, 2'-OCOCH 3 ) , 2.24 (s, NCH 3 ), 2.42 (s, 3'-N (CH 3 ) 2 ), 2.57 (dd, 2-H), 2.59 (t, 3'-H), 2.81 (br dd, quinoline- CH 2 ), 2.89 (dd, 2-H), 3.11 (t, 4'-H), 3.14 (s, CH (OCH 3 ) 2 ), 3.19 (d, 2 ”-Heq), 3.25 (s, CH (OCH 3 ) 2 ), 3.62 (s, 4-OCH 3 ), 3.68 (br d, 4-H), 3.93 (br d, 5-H), 4.41 (m, 4 ''-H), 4.41 (m , 5 ”-H), 4.55 (dd, CH (OCH 3 ) 2 ), 4.69 (d, 1'-H), 4.79 (d, 1” -H), 4.80 (t, NH), 4.92 (m, 9-H), 4.97 (dd, 2'-H), 5.00 (m, 3-H), 5.04 (m, 15-H), 6.85 (d, quinoline), 7.10 (dd, quinoline), 7.64 (d , quinoline), 7.86 (d, quinoline), 8.48 (d, quinoline).

(c)実施例1(c)と同様の方法で、実施例26(b)の化合物15.9 mgから、脱アセチル化合物
(工程図10の式(17c)において、Arが6-アミノキノリン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)9.7 mgを得た。
(c) In the same manner as in Example 1 (c), from 15.9 mg of the compound of Example 26 (b), a deacetylated compound (in the formula (17c) of Process FIG. 10, Ar is 6-aminoquinoline-3- 9.7 mg of a compound represented by an yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1120 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.94(d, 8-CH3), 1.13(d, 6”-H), 1.17(t, NHCH2CH3), 1.20(d, 6'-H), 1.48(s, 3”-CH3), 1.69(dd, 2”-Hax), 1.86(br dd, 6-H), 2.47(s, NCH3), 2.54(s, 3'-N(CH3)2), 2.60(dd, 2-H), 2.73(t, quinoline-CH2), 2.87(dd, 2-H), 3.15(s, CH(OCH3)2), 3.21(d, 2”-Heq), 3.25(s, CH(OCH3)2), 3.47(dd, 2'-H), 3.68(s, 4-OCH3), 3.86(br d, 5-H), 3.95(br d, 4-H), 4.31(m, 4”-H), 4.46(d, 1'-H), 4.81(t, NH), 4.82(d, 1”-H), 5.01(m, 15-H), 5.32(m, 3-H), 6.85(d, quinoline), 7.10(dd, quinoline), 7.63(d, quinoline), 7.86(d, quinoline), 8.47(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1120 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.94 (d, 8-CH 3 ), 1.13 (d, 6 ”-H), 1.17 (t, NHCH 2 CH 3 ), 1.20 ( d, 6'-H), 1.48 (s, 3 ”-CH 3 ), 1.69 (dd, 2” -Hax), 1.86 (br dd, 6-H), 2.47 (s, NCH 3 ), 2.54 (s , 3'-N (CH 3 ) 2 ), 2.60 (dd, 2-H), 2.73 (t, quinoline-CH 2 ), 2.87 (dd, 2-H), 3.15 (s, CH (OCH 3 ) 2 ), 3.21 (d, 2 ”-Heq), 3.25 (s, CH (OCH 3 ) 2 ), 3.47 (dd, 2'-H), 3.68 (s, 4-OCH 3 ), 3.86 (br d, 5 -H), 3.95 (br d, 4-H), 4.31 (m, 4 ”-H), 4.46 (d, 1'-H), 4.81 (t, NH), 4.82 (d, 1” -H) , 5.01 (m, 15-H), 5.32 (m, 3-H), 6.85 (d, quinoline), 7.10 (dd, quinoline), 7.63 (d, quinoline), 7.86 (d, quinoline), 8.47 (d , quinoline).

(d)実施例1(d)と同様の方法で、実施例26(c)の化合物9.7 mgから、標記化合物6.5 mgを得た。 (d) In the same manner as in Example 1 (d), 6.5 mg of the title compound was obtained from 9.7 mg of the compound of Example 26 (c).

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1074 (M+H)+
(2)比旋光度:[α]D 23 -53°(c0.33, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.92(d, 8-CH3), 1.16(t, NHCH2CH3), 1.34(m, 8-H), 1.47(s, 3”-CH3), 1.69(dd, 2”-Hax), 2.35(s, NCH3), 2.54(s, 3'-N(CH3)2), 2.61(dd, 2-H), 2.72(br dd, quinoline-CH2), 2.87(dd, 2-H), 2.91(dd, 6-CH2), 3.21(d, 2”-Heq), 3.26(dq, NHCH2CH3), 3.40(dd, 2'-H), 3.69(s, 4-OCH3), 3.87(br d, 5-H), 3.98(br d, 4-H), 4.39(d, 1'-H), 4.42(m, 4”-H), 4.44(m, 5”-H), 4.82(d, 1”-H), 5.02(m, 15-H), 5.46(m, 3-H), 6.84(d, quinoline), 7.10(dd, quinoline), 7.63(d, quinoline), 7.86(d, quinoline), 8.47(d, quinoline), 9.64(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1074 (M + H) +
(2) Specific rotation: [α] D 23 -53 ° (c0.33, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.92 (d, 8-CH 3 ), 1.16 (t, NHCH 2 CH 3 ), 1.34 (m, 8-H), 1.47 (s , 3 ”-CH 3 ), 1.69 (dd, 2” -Hax), 2.35 (s, NCH 3 ), 2.54 (s, 3'-N (CH 3 ) 2 ), 2.61 (dd, 2-H), 2.72 (br dd, quinoline-CH 2 ), 2.87 (dd, 2-H), 2.91 (dd, 6-CH 2 ), 3.21 (d, 2 ”-Heq), 3.26 (dq, NHCH 2 CH 3 ), 3.40 (dd, 2'-H), 3.69 (s, 4-OCH 3 ), 3.87 (br d, 5-H), 3.98 (br d, 4-H), 4.39 (d, 1'-H), 4.42 (m, 4 ''-H), 4.44 (m, 5 ''-H), 4.82 (d, 1 ''-H), 5.02 (m, 15-H), 5.46 (m, 3-H), 6.84 ( d, quinoline), 7.10 (dd, quinoline), 7.63 (d, quinoline), 7.86 (d, quinoline), 8.47 (d, quinoline), 9.64 (s, CHO).

実施例27
式(1)において、R1がプロピオニル基、R2が水素原子、R3がメチル基、R4が3-(6-メトキシキノリン-3-イル)プロピル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法(a)実施例1(b)と同様の方法で、3-ブロモキノリンの代わりに3-ブロモ-6-メトキシキノリンを用いて、実施例1(a)の化合物43 mgから、カップリング化合物(工程図10の式(15c)において、Arが6-メトキシキノリン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)10 mgを得た。
Example 27
In the formula (1), R 1 is a propionyl group, R 2 is a hydrogen atom, R 3 is a methyl group, R 4 is a 3- (6-methoxyquinolin-3-yl) propyl group, R 5 is a hydrogen atom and R 6 Is a method similar to Example 1 (b) except that 3-bromo-6-methoxyquinoline is used instead of 3-bromoquinoline. ) From 43 mg of a compound (a compound in which Ar is a 6-methoxyquinolin-3-yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group in the formula (15c) in Process FIG. 10) 10 mg was obtained.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1217 (M+H)+
(2)1H NMRスペクトル(300 MHz, CDCl3) δ(ppm):0.92(d, 8-CH3), 1.12(d, 6”-H), 1.16(t, NHCH2CH3), 1.19(d, 6'-H), 1.47(s, 3”-CH3), 2.04(s, 9-OCOCH3), 2.06(s, 2'-OCOCH3), 2.24(s, NCH3), 2.42(s, 3'-N(CH3)2), 2.87(dd, 2-H), 3.15(s, CH(OCH3)2), 3.25(s, CH(OCH3)2), 3.59(s, 4-OCH3), 3.93(br d, 5-H), 3.97(s, quinoline-OCH3), 4.41(m, 4”-H), 4.41(m, 5”-H), 4.55(dd, CH(OCH3)2), 4.68(d, 1'-H) , 4.79(d, 1”-H), 4.93(m, 9-H), 4.96(dd, 2'-H), 5.06(m, 3-H), 5.18(m, 15-H), 6.05(dt, CH=CH), 6.75(d, CH=CH), 7.36(dd, quinoline), 7.48(d, quinoline), 8.01(d, quinoline), 8.21(br d, quinoline), 8.77(dd, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1217 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.92 (d, 8-CH 3 ), 1.12 (d, 6 ”-H), 1.16 (t, NHCH 2 CH 3 ), 1.19 (d, 6'-H), 1.47 (s, 3 ”-CH 3 ), 2.04 (s, 9-OCOCH 3 ), 2.06 (s, 2'-OCOCH 3 ), 2.24 (s, NCH 3 ), 2.42 (s, 3'-N (CH 3 ) 2 ), 2.87 (dd, 2-H), 3.15 (s, CH (OCH 3 ) 2 ), 3.25 (s, CH (OCH 3 ) 2 ), 3.59 (s , 4-OCH 3 ), 3.93 (br d, 5-H), 3.97 (s, quinoline-OCH 3 ), 4.41 (m, 4 ”-H), 4.41 (m, 5” -H), 4.55 (dd , CH (OCH 3 ) 2 ), 4.68 (d, 1'-H), 4.79 (d, 1 ”-H), 4.93 (m, 9-H), 4.96 (dd, 2'-H), 5.06 ( m, 3-H), 5.18 (m, 15-H), 6.05 (dt, CH = CH), 6.75 (d, CH = CH), 7.36 (dd, quinoline), 7.48 (d, quinoline), 8.01 ( d, quinoline), 8.21 (br d, quinoline), 8.77 (dd, quinoline).

(b)実施例25(a)と同様の方法で、実施例27(a)の化合物21.1 mgから、還元化合物(工程図10の式(16c)において、Arが6-メトキシキノリン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)8.4 mgを得た。(b) In the same manner as in Example 25 (a), from the compound 21.1 mg of Example 27 (a), the reduced compound (Ar in the formula (16c) in Process Diagram 10) is replaced with 6-methoxyquinolin-3-yl. 8.4 mg of a group, a compound in which R 5 is a hydrogen atom and R 6 is an ethyl group).

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1219 (M+H)+
(2)1H NMRスペクトル(300 MHz, CDCl3) δ(ppm):0.91(d, 8-CH3), 1.12(d, 6”-H), 1.19(t, NHCH2CH3), 1.20(d, 6'-H), 1.47(s, 3”-CH3), 2.03(s, 9-OCOCH3), 2.05(s, 2'-OCOCH3), 2.22(s, NCH3), 2.42(s, 3'-N(CH3)2), 2.57(dd, 2-H), 2.86(dd, 2-H), 3.04(br dd, quinoline-CH2), 3.13(t, 4'-H), 3.14(s, CH(OCH3)2), 3.19(d, 2”-Heq), 3.25(s, CH(OCH3)2), 3.61(s, 4-OCH3), 3.66(br d, 4-H), 3.93(br d, 5-H), 3.96(s,quinoline-OCH3), 4.41(m, 4”-H), 4.41(m, 5”-H), 4.55(dd, CH(OCH3)2), 4.68(d, 1'-H), 4.79(d, 1”-H), 4.91(m, 9-H), 4.96(dd, 2'-H), 4.99(m, 3-H), 5.06(m, 15-H), 7.37(dd, quinoline), 7.48(d, quinoline), 7.99(d, quinoline), 8.25(br d, quinoline), 8.77(dd, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1219 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.91 (d, 8-CH 3 ), 1.12 (d, 6 ”-H), 1.19 (t, NHCH 2 CH 3 ), 1.20 (d, 6'-H), 1.47 (s, 3 ”-CH 3 ), 2.03 (s, 9-OCOCH 3 ), 2.05 (s, 2'-OCOCH 3 ), 2.22 (s, NCH 3 ), 2.42 (s, 3'-N (CH 3 ) 2 ), 2.57 (dd, 2-H), 2.86 (dd, 2-H), 3.04 (br dd, quinoline-CH 2 ), 3.13 (t, 4'- H), 3.14 (s, CH (OCH 3 ) 2 ), 3.19 (d, 2 ”-Heq), 3.25 (s, CH (OCH 3 ) 2 ), 3.61 (s, 4-OCH 3 ), 3.66 (br d, 4-H), 3.93 (br d, 5-H), 3.96 (s, quinoline-OCH 3 ), 4.41 (m, 4 ”-H), 4.41 (m, 5” -H), 4.55 (dd , CH (OCH 3 ) 2 ), 4.68 (d, 1'-H), 4.79 (d, 1 ”-H), 4.91 (m, 9-H), 4.96 (dd, 2'-H), 4.99 ( m, 3-H), 5.06 (m, 15-H), 7.37 (dd, quinoline), 7.48 (d, quinoline), 7.99 (d, quinoline), 8.25 (br d, quinoline), 8.77 (dd, quinoline ).

(c)実施例1(c)と同様の方法で、実施例27(b)の化合物8.4 mgから、脱アセチル化合物(工程図10の式(17c)において、Arが6 -メトキシキノリン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)5.5 mgを得た。(c) In the same manner as in Example 1 (c), from the compound 8.4 mg of Example 27 (b), the deacetylated compound (in the formula (17c) of Process FIG. 10, Ar is 6-methoxyquinoline-3- Yl group, R 5 is a hydrogen atom and R 6 is an ethyl group) 5.5 mg.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1135 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.90(d, 8-CH3), 1.13(d, 6”-H), 1.17(t, NHCH2CH3), 1.20(d, 6'-H), 1.48(s, 3”-CH3), 1.69(dd, 2”-Hax), 2.34(s, NCH3), 2.53(s, 3'-N(CH3)2), 2.57(dd, 2-H), 2.83(dd, 2-H), 3.03(br dd, quinoline-CH2), 3.14(s, CH(OCH3)2), 3.21(d, 2”-Heq), 3.25(s, CH(OCH3)2), 3.39(m, 9-H), 3.48(dd, 2'-H), 3.68(s, 4-OCH3), 3.88(br d, 5-H), 3.96(s, quinoline-OCH3), 3.97(br d, 4-H), 4.41(m, 4”-H), 4.80(t, NH), 4.81(d, 1”-H), 5.04(m, 15-H), 5.37(br dd, 3-H), 7.37(dd, quinoline), 7.48(d, quinoline), 8.00(d, quinoline), 8.25(br d,quinoline), 8.77(dd, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1135 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.90 (d, 8-CH 3 ), 1.13 (d, 6 ”-H), 1.17 (t, NHCH 2 CH 3 ), 1.20 ( d, 6'-H), 1.48 (s, 3 ”-CH 3 ), 1.69 (dd, 2” -Hax), 2.34 (s, NCH 3 ), 2.53 (s, 3'-N (CH 3 ) 2 ), 2.57 (dd, 2-H), 2.83 (dd, 2-H), 3.03 (br dd, quinoline-CH 2 ), 3.14 (s, CH (OCH 3 ) 2 ), 3.21 (d, 2 ”- Heq), 3.25 (s, CH (OCH 3 ) 2 ), 3.39 (m, 9-H), 3.48 (dd, 2'-H), 3.68 (s, 4-OCH 3 ), 3.88 (br d, 5 -H), 3.96 (s, quinoline-OCH 3 ), 3.97 (br d, 4-H), 4.41 (m, 4 ”-H), 4.80 (t, NH), 4.81 (d, 1” -H) , 5.04 (m, 15-H), 5.37 (br dd, 3-H), 7.37 (dd, quinoline), 7.48 (d, quinoline), 8.00 (d, quinoline), 8.25 (br d, quinoline), 8.77 (dd, quinoline).

(d)実施例1(d)と同様の方法で、実施例27(c)の化合物5.5 mgから、標記化合物4.1 mgを得た。 (d) In the same manner as in Example 1 (d), 4.1 mg of the title compound was obtained from 5.5 mg of the compound of Example 27 (c).

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1089 (M+H)+
(2)比旋光度:[α]D 25 -49°(c0.21, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.93(d, 8-CH3), 1.12(d, 6”-H), 1.15(d, 6'-H), 1.16(t, NHCH2CH3), 1.47(s, 3”-CH3), 1.70(dd, 2”-Hax), 2.37(s, NCH3), 2.54(s, 3'-N(CH3)2), 2.61(dd, 2-H), 2.73(m, 12-H), 2.85(dd, 2-H), 2.91(dd, 6-CH2), 3.04(br dd, quinoline-CH2), 3.18(m, 4'-H), 3.18(m, 5'-H), 3.21(d, 2”-Heq), 3.26(dq, NHCH2CH3), 3.39(dd, 2'-H), 3.46(m, 9-H), 3.68(s, 4-OCH3), 3.86(br d, 5-H), 3.96(s, quinoline-OCH3), 4.39(d, 1'-H), 4.42(m, 4”-H), 4.42(m, 5”-H), 4.79(t, NH), 4.82(d, 1”-H), 5.04(m, 15-H), 5.43(m, 3-H), 7.37(dd, quinoline), 7.48(d, quinoline), 8.00(d, quinoline), 8.25(br d, quinoline), 8.77(dd, quinoline), 9.64(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1089 (M + H) +
(2) Specific rotation: [α] D 25 -49 ° (c0.21, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.93 (d, 8-CH 3 ), 1.12 (d, 6 ″ -H), 1.15 (d, 6′-H), 1.16 ( t, NHCH 2 CH 3 ), 1.47 (s, 3 ”-CH 3 ), 1.70 (dd, 2” -Hax), 2.37 (s, NCH 3 ), 2.54 (s, 3'-N (CH 3 ) 2 ), 2.61 (dd, 2-H), 2.73 (m, 12-H), 2.85 (dd, 2-H), 2.91 (dd, 6-CH 2 ), 3.04 (br dd, quinoline-CH 2 ), 3.18 (m, 4'-H), 3.18 (m, 5'-H), 3.21 (d, 2 ”-Heq), 3.26 (dq, NHCH 2 CH 3 ), 3.39 (dd, 2'-H), 3.46 (m, 9-H), 3.68 (s, 4-OCH 3 ), 3.86 (br d, 5-H), 3.96 (s, quinoline-OCH 3 ), 4.39 (d, 1'-H), 4.42 (m, 4 ''-H), 4.42 (m, 5 ''-H), 4.79 (t, NH), 4.82 (d, 1 ''-H), 5.04 (m, 15-H), 5.43 (m, 3 -H), 7.37 (dd, quinoline), 7.48 (d, quinoline), 8.00 (d, quinoline), 8.25 (br d, quinoline), 8.77 (dd, quinoline), 9.64 (s, CHO).

実施例28
式(1)において、R1がプロピオニル基、R2が水素原子、R3がメチル基、R4が3-(イソキノリン-4-イル)プロピル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例25(a)と同様の方法で、溶媒として1,4-ジオキサン−水(2:1)を用い、実施例5(b)の化合物8.6 mgから、還元化合物(工程図10の式(17c)において、Arがイソキノリン-4-イル基、R5が水素原子及びR6がエチル基で表される化合物)4.3 mgを得た。
Example 28
In the formula (1), R 1 is a propionyl group, R 2 is a hydrogen atom, R 3 is a methyl group, R 4 is a 3- (isoquinolin-4-yl) propyl group, R 5 is a hydrogen atom, and R 6 is an ethyl group Process for producing a compound represented by
(a) In the same manner as in Example 25 (a), using 1,4-dioxane-water (2: 1) as a solvent, from the compound 8.6 mg of Example 5 (b), the reduced compound (Scheme 10) In the formula (17c), Ar is an isoquinolin-4-yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group) (4.3 mg).

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1105 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.89(d, 8-CH3), 1.08(d, 6”-H), 1.17(t, NHCH2CH3), 1.19(d, 6'-H), 1.46(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.34(s, NCH3), 2.52(s, 3'-N(CH3)2), 2.83(dd, 2-H), 3.15(s, CH(OCH3)2), 3.20(d, 2”-Heq),3.23(s, CH(OCH3)2), 3.47(dd, 2'-H), 3.67(s, 4-OCH3), 3,87(br d, 5-H), 3.96(br d, 4-H), 4.40(d, 1'-H), 4.41(d, 4”-H), 4.45(dd, CH(OCH3)2), 4.80(d, 1”-H), 5.02(m, 15-H), 5.36(m, 3-H), 7.59(br dd, isoquinoline), 7.72(ddd, isoquinoline), 7.95(br d, isoquinoline), 7.97(br d, isoquinoline), 8.33(s, isoquinoline), 9.11(s, isoquinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1105 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.89 (d, 8-CH 3 ), 1.08 (d, 6 ”-H), 1.17 (t, NHCH 2 CH 3 ), 1.19 ( d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.68 (dd, 2” -Hax), 2.34 (s, NCH 3 ), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.83 (dd, 2-H), 3.15 (s, CH (OCH 3 ) 2 ), 3.20 (d, 2 ”-Heq), 3.23 (s, CH (OCH 3 ) 2 ), 3.47 (dd, 2 '-H), 3.67 (s, 4-OCH 3 ), 3,87 (br d, 5-H), 3.96 (br d, 4-H), 4.40 (d, 1'-H), 4.41 (d , 4 ”-H), 4.45 (dd, CH (OCH 3 ) 2 ), 4.80 (d, 1” -H), 5.02 (m, 15-H), 5.36 (m, 3-H), 7.59 (br dd, isoquinoline), 7.72 (ddd, isoquinoline), 7.95 (br d, isoquinoline), 7.97 (br d, isoquinoline), 8.33 (s, isoquinoline), 9.11 (s, isoquinoline).

(b)実施例1(d)と同様の方法で、実施例28(a)の化合物4.3 mgから、標記化合物3.7 mgを得た。 (b) In the same manner as in Example 1 (d), 3.7 mg of the title compound was obtained from 4.3 mg of the compound of Example 28 (a).

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1059 (M+H)+
(2)比旋光度:[α]D 25 -53°(c0.31, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.91(d, 8-CH3), 1.10(d, 6”-H), 1.16(t, NHCH2CH3), 1.17(d, 6'-H), 1.46(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.32(s, NCH3), 2.52(s, 3'-N(CH3)2), 2.61(dd, 2-H), 2.84(dd, 2-H), 2 .91(dd, 6-CH2), 3.15(t, 4'-H), 3.21(d, 2”-Heq), 3.38(dd, 2'-H), 3.67(s, 4-OCH3), 3.85(br d, 5-H),3.97(br d, 4-H), 4.38(d, 1'-H), 4.40(d, 4”-H), 4.44(dq, 5”-H), 4.81(d, 1”-H), 5.02(m, 15-H), 5.45(m, 3-H), 7.60(br dd, isoquinoline), 7.72(ddd, isoquinoline), 7.95(br d, isoquinoline), 7.97(br d, isoquinoline), 8.33(s, isoquinoline), 9.11(s, isoquinoline), 9.63(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1059 (M + H) +
(2) Specific rotation: [α] D 25 -53 ° (c0.31, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.91 (d, 8-CH 3 ), 1.10 (d, 6 ”-H), 1.16 (t, NHCH 2 CH 3 ), 1.17 ( d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.68 (dd, 2” -Hax), 2.32 (s, NCH 3 ), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.61 (dd, 2-H), 2.84 (dd, 2-H), 2.91 (dd, 6-CH 2 ), 3.15 (t, 4'-H), 3.21 (d, 2 ”-Heq ), 3.38 (dd, 2'-H), 3.67 (s, 4-OCH 3 ), 3.85 (br d, 5-H), 3.97 (br d, 4-H), 4.38 (d, 1'-H ), 4.40 (d, 4 ”-H), 4.44 (dq, 5” -H), 4.81 (d, 1 ”-H), 5.02 (m, 15-H), 5.45 (m, 3-H), 7.60 (br dd, isoquinoline), 7.72 (ddd, isoquinoline), 7.95 (br d, isoquinoline), 7.97 (br d, isoquinoline), 8.33 (s, isoquinoline), 9.11 (s, isoquinoline), 9.63 (s, CHO ).

Figure 2007069555
Figure 2007069555

実施例29
式(1)において、R1がプロピオニル基、R2が水素原子、R3がメチル基、R4が3-(イソキノリン-3-イル)プロピル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例1(a)と同様の方法で、工程図10の式(13c)のアリル体の代わりに工程図12の式(19b)のプロピニル体(WO2005/019238、実施例130(b))955.6 mgを用いて、カルバモイル化合物(工程図12の式(20b)において、R5が水素原子及びR6がエチル基で表される化合物)893.7 mgを得た。
Example 29
In the formula (1), R 1 is a propionyl group, R 2 is a hydrogen atom, R 3 is a methyl group, R 4 is a 3- (isoquinolin-3-yl) propyl group, R 5 is a hydrogen atom, and R 6 is an ethyl group Process for producing a compound represented by
(a) In the same manner as in Example 1 (a), instead of the allyl form of the formula (13c) in the process chart 10, the propynyl form of the formula (19b) in the process chart 12 (WO2005 / 019238, Example 130 (b )) Using 955.6 mg, 893.7 mg of a carbamoyl compound (a compound in which R 5 is represented by a hydrogen atom and R 6 is an ethyl group in formula (20b) in Process Diagram 12) was obtained.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1058 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.91(d, 8-CH3), 1.11(d, 6”-H), 1.17(t, NHCH2CH3), 1.18(d, 6'-H), 1.46(s, 3”-CH3), 1.67(dd, 2”-Hax), 2.03(s, 9-OCOCH3), 2.04(s, 2'-OCOCH3), 2.22(s, NCH3), 2.41(s, 3'-N(CH3)2), 2.63(dd, 2-H), 2.87(dd, 2-H), 3.13(s, CH(OCH3)2), 3.20(d, 2”-Heq), 3.23(s, CH(OCH3)2), 3.60(s, 4-OCH3), 3.62(br d, 4-H), 3.91(br d, 5-H), 4.37(d, 4”-H), 4.41(dq, 5”-H), 4.54(dd, CH(OCH3)2), 4.66(d, 1'-H), 4.77(d, 1”-H), 4.89(m, 9-H), 4.95(dd, 2'-H), 5.04(br dd, 3-H), 5.06(m, 15-H).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1058 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.91 (d, 8-CH 3 ), 1.11 (d, 6 ”-H), 1.17 (t, NHCH 2 CH 3 ), 1.18 ( d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.67 (dd, 2” -Hax), 2.03 (s, 9-OCOCH 3 ), 2.04 (s, 2'-OCOCH 3 ), 2.22 (s, NCH 3 ), 2.41 (s, 3'-N (CH 3 ) 2 ), 2.63 (dd, 2-H), 2.87 (dd, 2-H), 3.13 (s, CH (OCH 3 ) 2 ), 3.20 (d, 2 ”-Heq), 3.23 (s, CH (OCH 3 ) 2 ), 3.60 (s, 4-OCH 3 ), 3.62 (br d, 4-H), 3.91 (br d, 5-H), 4.37 (d, 4 ''-H), 4.41 (dq, 5 ''-H), 4.54 (dd, CH (OCH 3 ) 2 ), 4.66 (d, 1'-H), 4.77 (d , 1 ''-H), 4.89 (m, 9-H), 4.95 (dd, 2'-H), 5.04 (br dd, 3-H), 5.06 (m, 15-H).

(b)実施例29(a)の化合物50 mgをジメチルホルムアミド500 μlに溶解し、参考例3の化合物49.2mg、0.916Nキナクリジンの1,4-ジオキサン溶液103 μl、トリス(ジベンジリデンアセトン)ジパラジウム(0)2.16 mg、0.462Nトリ-t-ブチルホスフィンの1,4-ジオキサン溶液20.5 μlを順次加え、途中同量のトリス(ジベンジリデンアセトン)ジパラジウム(0)とトリ-t-ブチルホスフィン1,4-ジオキサン溶液を4回追加し、50℃で67時間撹拌した。反応液を濾過し、濾液を減圧濃縮して得られた残渣を分取用TLC(クロロホルム−酢酸エチル−メタノール(3:2:0.5))で精製して、カップリング化合物(工程図12の式(21b)において、Arがイソキノリン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)13.7 mgを得た。(b) 50 mg of the compound of Example 29 (a) was dissolved in 500 μl of dimethylformamide, 49.2 mg of the compound of Reference Example 3, 103 μl of 1,4-dioxane solution of 0.916N quinacridine, tris (dibenzylideneacetone) di Palladium (0) 2.16 mg, 0.462N tri-t-butylphosphine in 1,4-dioxane solution (20.5 μl) were added sequentially, and the same amount of tris (dibenzylideneacetone) dipalladium (0) and tri-t-butylphosphine was added. The 1,4-dioxane solution was added four times, and the mixture was stirred at 50 ° C. for 67 hours. The reaction solution was filtered, and the residue obtained by concentrating the filtrate under reduced pressure was purified by preparative TLC (chloroform-ethyl acetate-methanol (3: 2: 0.5)) to obtain a coupling compound (formula of step diagram 12). In (21b), 13.7 mg of a compound in which Ar is an isoquinolin-3-yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group was obtained.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1185 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.91(d, 8-CH3), 1.11(d, 6”-H), 1.17(t, NHCH2CH3), 1.18(d, 6'-H), 1.46(s, 3”-CH3), 1.67(dd, 2”-Hax), 2.03(s, 9-OCOCH3), 2.05(s, 2'-OCOCH3), 2.41(s, 3'-N(CH3)2), 3.14(s, CH(OCH3)2), 3.19(d, 2”-Heq), 3.23(s, CH(OCH3)2), 3.61(s, 4-OCH3), 3.64(br d, 4-H), 3.91(br d, 5-H), 4.41(m, 4”-H), 4.41(m, 5”-H), 4.54(dd, CH(OCH3)2), 4.67(d, 1'-H), 4.79(d, 1”-H), 4.90(br m, 9-H), 4.95(dd, 2'-H), 5.07(br dd, 3-H), 5.20(m, 15-H), 7.59(dt, isoquinoline), 7.69(dt, isoquinoline), 7.77(d, isoquinoline), 7.79(s, isoquinoline), 7.94(d, isoquinoline), 9.16(s, isoquinoline).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1185 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.91 (d, 8-CH 3 ), 1.11 (d, 6 ”-H), 1.17 (t, NHCH 2 CH 3 ), 1.18 ( d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.67 (dd, 2” -Hax), 2.03 (s, 9-OCOCH 3 ), 2.05 (s, 2'-OCOCH 3 ), 2.41 (s, 3'-N (CH 3 ) 2 ), 3.14 (s, CH (OCH 3 ) 2 ), 3.19 (d, 2 ”-Heq), 3.23 (s, CH (OCH 3 ) 2 ), 3.61 (s, 4-OCH 3 ), 3.64 (br d, 4-H), 3.91 (br d, 5-H), 4.41 (m, 4 ”-H), 4.41 (m, 5” -H), 4.54 (dd, CH (OCH 3 ) 2 ), 4.67 (d, 1'-H), 4.79 (d, 1 ”-H), 4.90 (br m, 9-H), 4.95 (dd, 2'-H) , 5.07 (br dd, 3-H), 5.20 (m, 15-H), 7.59 (dt, isoquinoline), 7.69 (dt, isoquinoline), 7.77 (d, isoquinoline), 7.79 (s, isoquinoline), 7.94 ( d, isoquinoline), 9.16 (s, isoquinoline).

(c)実施例1(c)と同様の方法で、実施例29(b)の化合物13.7 mgから、脱アセチル化合物(工程図12の式(22b)において、Arがイソキノリン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)3.0 mgを得た。(c) In the same manner as in Example 1 (c), from the compound 13.7 mg of Example 29 (b), a deacetylated compound (in the formula (22b) in Process Diagram 12, Ar is an isoquinolin-3-yl group, 3.0 mg of a compound in which R 5 is a hydrogen atom and R 6 is an ethyl group.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1101 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.88(d, 8-CH3), 1.10(d, 6”-H), 1.17(t, NHCH2CH3), 1.19(d, 6'-H), 1.47(s, 3”-CH3), 1.67(dd, 2”-Hax), 2.52(s, 3'-N(CH3)2), 2.67(dd, 2-H), 2.77(dd, 15-CH2), 2.87(dd, 2-H), 3.14(s, CH(OCH3)2), 3.20(d, 2”-Heq), 3.24(s, CH(OCH3)2), 3.47(dd, 2'-H), 3.68(s, 4-OCH3), 3,87(brd, 5-H), 3.95(br d, 4-H), 4.40(d, 1'-H), 4.46(m, 4”-H), 4.46(m, 5”-H), 4.80(d, 1”-H), 5.17(m, 15-H), 5.49(m, 3-H), 7.60(dt, isoquinoline), 7.69(dt, isoquinoline), 7.76(d, isoquinoline), 7.78(s, isoquinoline), 7.94(d, isoquinoline), 9.16(s, isoquinoline).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1101 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.88 (d, 8-CH 3 ), 1.10 (d, 6 ”-H), 1.17 (t, NHCH 2 CH 3 ), 1.19 ( d, 6'-H), 1.47 (s, 3 ”-CH 3 ), 1.67 (dd, 2” -Hax), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.67 (dd, 2- H), 2.77 (dd, 15-CH 2 ), 2.87 (dd, 2-H), 3.14 (s, CH (OCH 3 ) 2 ), 3.20 (d, 2 ”-Heq), 3.24 (s, CH ( OCH 3 ) 2 ), 3.47 (dd, 2'-H), 3.68 (s, 4-OCH 3 ), 3,87 (brd, 5-H), 3.95 (br d, 4-H), 4.40 (d , 1'-H), 4.46 (m, 4 ''-H), 4.46 (m, 5 ''-H), 4.80 (d, 1 ''-H), 5.17 (m, 15-H), 5.49 (m, 3-H), 7.60 (dt, isoquinoline), 7.69 (dt, isoquinoline), 7.76 (d, isoquinoline), 7.78 (s, isoquinoline), 7.94 (d, isoquinoline), 9.16 (s, isoquinoline).

(d)実施例25(a)と同様の方法で、溶媒として1,4-ジオキサン−水(2:1)を用い、実施例29(c)の化合物3.0 mgから、還元化合物(工程図12の式(17c)において、Arがイソキノリン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)1.9 mgを得た。(d) In the same manner as in Example 25 (a), using 1,4-dioxane-water (2: 1) as a solvent, from 3.0 mg of the compound of Example 29 (c), the reduced compound (Scheme 12 In the formula (17c), Ar is an isoquinolin-3-yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group) (1.9 mg).

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1105 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.91(d, 8-CH3), 1.07(t, 3-OCOCH2CH3), 1.10(d, 6”-H), 1.11(t, 3”-OCOCH2CH3), 1.17(t, NHCH2CH3), 1.19(d, 6'-H), 1.46(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.52(s, 3'-N(CH3)2), 2.58(dd, 2-H), 2.85(dd, 2-H), 3.13(s, CH(OCH3)2), 3.20(d, 2”-Heq), 3.23(s, CH(OCH3)2), 3.47(dd, 2'-H), 3.67(s, 4-OCH3), 3,85(br d, 5-H), 3.96(br d, 4-H), 4.39(d, 1'-H), 4.41(d, 4”-H), 4.46(dq, 5”-H), 4.80(d, 1”-H), 5.02(m, 15-H), 5.34(m, 3-H), 7.44(s, isoquinoline), 7.53(dt, isoquinoline), 7.65(dt, isoquinoline), 7.74(d, isoquinoline), 7.93(d, isoquinoline), 9.18(s, isoquinoline).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1105 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.91 (d, 8-CH 3 ), 1.07 (t, 3-OCOCH 2 CH 3 ), 1.10 (d, 6 ”-H), 1.11 (t, 3 ”-OCOCH 2 CH 3 ), 1.17 (t, NHCH 2 CH 3 ), 1.19 (d, 6'-H), 1.46 (s, 3” -CH 3 ), 1.68 (dd, 2 ” -Hax), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.58 (dd, 2-H), 2.85 (dd, 2-H), 3.13 (s, CH (OCH 3 ) 2 ), 3.20 (d, 2 ''-Heq), 3.23 (s, CH (OCH 3 ) 2 ), 3.47 (dd, 2'-H), 3.67 (s, 4-OCH 3 ), 3,85 (br d, 5- H), 3.96 (br d, 4-H), 4.39 (d, 1'-H), 4.41 (d, 4 "-H), 4.46 (dq, 5" -H), 4.80 (d, 1 "- H), 5.02 (m, 15-H), 5.34 (m, 3-H), 7.44 (s, isoquinoline), 7.53 (dt, isoquinoline), 7.65 (dt, isoquinoline), 7.74 (d, isoquinoline), 7.93 (d, isoquinoline), 9.18 (s, isoquinoline).

(e)実施例2(b)と同様の方法で、実施例29(d)の化合物1.9 mgから、標記化合物1.4 mgを得た。 (e) In the same manner as in Example 2 (b), 1.4 mg of the title compound was obtained from 1.9 mg of the compound of Example 29 (d).

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1059 (M+H)+
(2)比旋光度:[α]D 20 -67°(c0.12, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.92(d, 8-CH3), 1.11(d, 6”-H), 1.16(t, NHCH2CH3), 1.17(d, 6'-H), 1.46(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.52(s, 3'-N(CH3)2), 2.60(dd, 2-H), 2.84(dd, 2-H), 3.20(d, 2”-Heq), 3.38(dd, 2'-H), 3.67(s, 4-OCH3), 3.85(br d, 5-H), 3.97(br d, 4-H), 4.38(d, 1'-H), 4.40(d, 4”-H), 4.44(dq, 5”-H), 4.81(d, 1”-H), 5.03(m, 15-H), 5.44(m, 3-H), 7.44(s, isoquinoline), 7.53(dt, isoquinoline), 7.65(dt, isoquinoline), 7.74(d, isoquinoline), 7.93(d, isoquinoline), 9.18(s, isoquinoline), 9.63(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1059 (M + H) +
(2) Specific rotation: [α] D 20 -67 ° (c0.12, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.92 (d, 8-CH 3 ), 1.11 (d, 6 ”-H), 1.16 (t, NHCH 2 CH 3 ), 1.17 ( d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.68 (dd, 2” -Hax), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.60 (dd, 2- H), 2.84 (dd, 2-H), 3.20 (d, 2 ''-Heq), 3.38 (dd, 2'-H), 3.67 (s, 4-OCH 3 ), 3.85 (br d, 5-H ), 3.97 (br d, 4-H), 4.38 (d, 1'-H), 4.40 (d, 4 ”-H), 4.44 (dq, 5” -H), 4.81 (d, 1 ”-H ), 5.03 (m, 15-H), 5.44 (m, 3-H), 7.44 (s, isoquinoline), 7.53 (dt, isoquinoline), 7.65 (dt, isoquinoline), 7.74 (d, isoquinoline), 7.93 ( d, isoquinoline), 9.18 (s, isoquinoline), 9.63 (s, CHO).

実施例30
式(1)において、R1がプロピオニル基、R2が水素原子、R3がメチル基、R4が3-(イソキノリン-1-イル)プロピル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例29(b)と同様の方法で、参考例3の化合物の代わりに参考例4の化合物を用い、またキナクリジンの代わりに1.4-ジアザビシクロ[2.2.2]オクタンを用いて、実施例29(a)の化合物10 mgから、カップリング化合物(工程図12の式(21b)において、Arがイソキノリン-1-イル基、R5が水素原子及びR6がエチル基で表される化合物)3.6 mgを得た。
Example 30
In the formula (1), R 1 is a propionyl group, R 2 is a hydrogen atom, R 3 is a methyl group, R 4 is a 3- (isoquinolin-1-yl) propyl group, R 5 is a hydrogen atom, and R 6 is an ethyl group Process for producing a compound represented by
(a) In the same manner as in Example 29 (b), using the compound of Reference Example 4 instead of the compound of Reference Example 3, and using 1.4-diazabicyclo [2.2.2] octane instead of quinacridine From 10 mg of the compound of Example 29 (a), a coupling compound (a compound in which Ar is an isoquinolin-1-yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group in formula (21b) of Process Diagram 12) ) 3.6 mg was obtained.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1185 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.92(d, 8-CH3), 1.11(d, 6”-H), 1.17(t, NHCH2CH3), 1.19(d, 6'-H), 1.46(s, 3”-CH3), 1.67(dd, 2”-Hax), 2.03(s, 9-OCOCH3), 2.06(s, 2'-OCOCH3), 2.41(s, 3'-N(CH3)2), 2.58(t, 3'-H), 2.67(dd, 2-H), 2.89(dd, 2-H), 3.14(s, CH(OCH3)2), 3.20(d, 2”-Heq), 3.24(s, CH(OCH3)2), 3.58(s, 4-OCH3), 3.66(br d, 4-H), 3.92(br d, 5-H), 4.41(m, 4”-H), 4.41(m, 5”-H), 4.54(dd, CH(OCH3)2), 4.67(d, 1'-H), 4.78(d, 1”-H), 4.90(m, 9-H), 4.95(dd, 2'-H), 5.07(br dd, 3-H), 5.29(m, 15-H), 7.59(d, isoquinoline), 7.67(m, isoquinoline), 7.81(dd, isoquinoline), 8.35(dd, isoquinoline), 8.47(d, isoquinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1185 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.92 (d, 8-CH 3 ), 1.11 (d, 6 ”-H), 1.17 (t, NHCH 2 CH 3 ), 1.19 ( d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.67 (dd, 2” -Hax), 2.03 (s, 9-OCOCH 3 ), 2.06 (s, 2'-OCOCH 3 ), 2.41 (s, 3'-N (CH 3 ) 2 ), 2.58 (t, 3'-H), 2.67 (dd, 2-H), 2.89 (dd, 2-H), 3.14 (s, CH (OCH 3 ) 2 ), 3.20 (d, 2 ”-Heq), 3.24 (s, CH (OCH 3 ) 2 ), 3.58 (s, 4-OCH 3 ), 3.66 (br d, 4-H), 3.92 (br d, 5-H), 4.41 (m, 4 ''-H), 4.41 (m, 5 ''-H), 4.54 (dd, CH (OCH 3 ) 2 ), 4.67 (d, 1'-H), 4.78 (d, 1 ''-H), 4.90 (m, 9-H), 4.95 (dd, 2'-H), 5.07 (br dd, 3-H), 5.29 (m, 15-H), 7.59 (d , isoquinoline), 7.67 (m, isoquinoline), 7.81 (dd, isoquinoline), 8.35 (dd, isoquinoline), 8.47 (d, isoquinoline).

(b)実施例1(c)と同様の方法で、実施例30(a)の化合物18.6 mgから、脱アセチル化合物(工程図12の式(22b)において、Arがイソキノリン-1-イル基、R5が水素原子及びR6がエチル基で表される化合物)5.9 mgを得た。(b) In the same manner as in Example 1 (c), from 18.6 mg of the compound of Example 30 (a), a deacetylated compound (In the formula (22b) of Process Diagram 12, Ar is an isoquinolin-1-yl group, 5.9 mg of a compound in which R 5 is a hydrogen atom and R 6 is an ethyl group.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1101 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.87(d, 8-CH3), 1.10(d, 6”-H), 1.17(t, NHCH2CH3), 1.19(d, 6'-H), 1.46(s, 3”-CH3), 1.67(dd, 2”-Hax), 2.52(s, 3'-N(CH3)2), 2.66(dd, 2-H), 2.86(dd, 2-H), 2.90(dd, 15-CH2), 3.13(s, CH(OCH3)2),
3.20(d, 2”-Heq), 3.24(s, CH(OCH3)2), 3.47(dd, 2'-H), 3.63(s, 4-OCH3), 3,87(brd, 5-H), 3.96(br d, 4-H), 4.40(d, 1'-H), 4.41(d, 4”-H), 4.45(dq, 5”-H), 4.48(dd, CH(OCH3)2), 4.80(d, 1”-H), 5.24(m, 15-H), 5.50(m, 3-H), 7.59(d, isoquinoline), 7.67(m, isoquinoline), 7.81(dd, isoquinoline), 8.35(dd, isoquinoline), 8.47(d, isoquinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1101 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.87 (d, 8-CH 3 ), 1.10 (d, 6 ”-H), 1.17 (t, NHCH 2 CH 3 ), 1.19 ( d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.67 (dd, 2” -Hax), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.66 (dd, 2- H), 2.86 (dd, 2-H), 2.90 (dd, 15-CH 2 ), 3.13 (s, CH (OCH 3 ) 2 ),
3.20 (d, 2 ”-Heq), 3.24 (s, CH (OCH 3 ) 2 ), 3.47 (dd, 2'-H), 3.63 (s, 4-OCH 3 ), 3,87 (brd, 5- H), 3.96 (br d, 4-H), 4.40 (d, 1'-H), 4.41 (d, 4 ''-H), 4.45 (dq, 5 ''-H), 4.48 (dd, CH (OCH 3 ) 2 ), 4.80 (d, 1 ”-H), 5.24 (m, 15-H), 5.50 (m, 3-H), 7.59 (d, isoquinoline), 7.67 (m, isoquinoline), 7.81 (dd , isoquinoline), 8.35 (dd, isoquinoline), 8.47 (d, isoquinoline).

(c)実施例25(a)と同様の方法で、溶媒として1,4-ジオキサン−水(2:1)を用い、実施例3 0(b)の化合物5.9 mgから、還元化合物(工程図12の式(17c)において、Arがイソキノリン-1-イル基、R5が水素原子及びR6がエチル基で表される化合物)3.3 mgを得た。(c) In the same manner as in Example 25 (a), using 1,4-dioxane-water (2: 1) as a solvent, from the compound 5.9 mg of Example 30 (b), the reduced compound (step diagram) In 12 formula (17c), Ar was an isoquinolin-1-yl group, R 5 was a hydrogen atom, and R 6 was an ethyl group) (3.3 mg).

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1105 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.90(d, 8-CH3), 1.08(t, 3-OCOCH2CH3), 1.10(d, 6”-H), 1.11(t, 3”-OCOCH2CH3), 1.17(t, NHCH2CH3), 1.19(d, 6'-H), 1.46(s, 3”-CH3), 1.67(dd, 2”-Hax), 2.52(s, 3'-N(CH3)2), 2.83(dd, 2-H), 3.13(s, CH(OCH3)2), 3.21(d, 2”-Heq), 3.23(s, CH(OCH3)2), 3.47(dd, 2'-H), 3.66(s, 4-OCH3) , 3,86(br d, 5-H), 3.97(br d, 4-H), 4.40(d, 1'-H), 4.42(dd, CH(OCH3)2), 4.46(m, 4”-H), 4.48(m, 5”-H), 4.80(d, 1”-H), 5.04(m, 15-H), 5.36(m, 3-H), 7.50(d, isoquinoline), 7.58(dt, isoquinoline), 7.66(dt, isoquinoline), 7.81(d, isoquinoline), 8.11(d, isoquinoline), 8.41(d, isoquinoline).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1105 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.90 (d, 8-CH 3 ), 1.08 (t, 3-OCOCH 2 CH 3 ), 1.10 (d, 6 ”-H), 1.11 (t, 3 ”-OCOCH 2 CH 3 ), 1.17 (t, NHCH 2 CH 3 ), 1.19 (d, 6'-H), 1.46 (s, 3” -CH 3 ), 1.67 (dd, 2 ” -Hax), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.83 (dd, 2-H), 3.13 (s, CH (OCH 3 ) 2 ), 3.21 (d, 2 ”-Heq), 3.23 (s, CH (OCH 3 ) 2 ), 3.47 (dd, 2'-H), 3.66 (s, 4-OCH 3 ), 3,86 (br d, 5-H), 3.97 (br d, 4 -H), 4.40 (d, 1'-H), 4.42 (dd, CH (OCH 3 ) 2 ), 4.46 (m, 4 ”-H), 4.48 (m, 5” -H), 4.80 (d, 1 ”-H), 5.04 (m, 15-H), 5.36 (m, 3-H), 7.50 (d, isoquinoline), 7.58 (dt, isoquinoline), 7.66 (dt, isoquinoline), 7.81 (d, isoquinoline ), 8.11 (d, isoquinoline), 8.41 (d, isoquinoline).

(d)実施例2(b)と同様の方法で、実施例30(c)の化合物3.3 mgから、標記化合物3.0 mgを得た。 (d) In the same manner as in Example 2 (b), 3.0 mg of the title compound was obtained from 3.3 mg of the compound of Example 30 (c).

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1059 (M+H)+
(2)比旋光度:[α]D 21 -57°(c0.25, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.91(d, 8-CH3), 1.11(d, 6”-H), 1.16(t, NHCH2CH3), 1.16(d, 6'-H), 1.46(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.33(s, NCH3), 2.52(s, 3'-N(CH3)2), 2.84(dd, 2-H), 2.90(dd, 6-CH2), 3.20(d, 2”-Heq), 3.39(dd, 2'-H), 3.67(s, 4-OCH3), 3.84(br d, 5-H), 3.97(br d, 4-H), 4.38(d, 1'-H), 4.40(d, 4”-H), 4.44(dq, 5”-H), 4.81(d, 1”-H), 5.04(m, 15-H), 5.43(m, 3-H), 7.50(d, isoquinoline), 7.58(dt, isoquinoline), 7.66(dt, isoquinoline), 7.81(d, isoquinoline), 8.11(d, isoquinoline), 8.41(d, isoquinoline), 9.62(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1059 (M + H) +
(2) Specific rotation: [α] D 21 -57 ° (c0.25, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.91 (d, 8-CH 3 ), 1.11 (d, 6 ”-H), 1.16 (t, NHCH 2 CH 3 ), 1.16 ( d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.68 (dd, 2” -Hax), 2.33 (s, NCH 3 ), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.84 (dd, 2-H), 2.90 (dd, 6-CH 2 ), 3.20 (d, 2 ”-Heq), 3.39 (dd, 2'-H), 3.67 (s, 4-OCH 3 ) , 3.84 (br d, 5-H), 3.97 (br d, 4-H), 4.38 (d, 1'-H), 4.40 (d, 4 ”-H), 4.44 (dq, 5” -H) , 4.81 (d, 1 ”-H), 5.04 (m, 15-H), 5.43 (m, 3-H), 7.50 (d, isoquinoline), 7.58 (dt, isoquinoline), 7.66 (dt, isoquinoline), 7.81 (d, isoquinoline), 8.11 (d, isoquinoline), 8.41 (d, isoquinoline), 9.62 (s, CHO).

Figure 2007069555
Figure 2007069555

実施例31
式(1)において、R1がプロピオニル基、R2が水素原子、R3が2-ヒドロキシエチル基、R4がトランス-3-(キノリン-3-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)式(26a)の化合物2.0 g及び参考例5の化合物356 mgをジクロロエタン25 mlに溶解し、氷冷下、酢酸0.4 ml及びナトリウムトリアセトキシボロヒドリド767 mgを加え、室温で3時間撹拌した。反応液を氷冷し、tert-ブチル N-(2-オキソエチル)カーバメート580 μl及びナトリウムシアノボロヒドリド170 mgを加え、さらに室温で6時間攪拌した。反応液を酢酸エチル150 mlで希釈し、水50 mlで4回、25%食塩水50 mlで順次洗浄した。有機層を無水硫酸ナトリウムで乾燥後、これを濾過し、濾液を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム−メタノール (50:1〜10:1))で精製して、工程図13の式(27)の化合物572 mgを得た。
Example 31
In the formula (1), R 1 is a propionyl group, R 2 is a hydrogen atom, R 3 is a 2-hydroxyethyl group, R 4 is a trans-3- (quinolin-3-yl) -2-propenyl group, and R 5 is Method for producing compound in which hydrogen atom and R 6 are represented by ethyl group
(a) Dissolve 2.0 g of the compound of formula (26a) and 356 mg of the compound of Reference Example 5 in 25 ml of dichloroethane, add 0.4 ml of acetic acid and 767 mg of sodium triacetoxyborohydride under ice cooling, and stir at room temperature for 3 hours did. The reaction mixture was ice-cooled, 580 μl of tert-butyl N- (2-oxoethyl) carbamate and 170 mg of sodium cyanoborohydride were added, and the mixture was further stirred at room temperature for 6 hours. The reaction solution was diluted with 150 ml of ethyl acetate and washed successively with 50 ml of water 4 times and 50 ml of 25% brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform-methanol (50: 1-10: 1)) 572 mg of the compound of formula (27) in FIG. 13 was obtained.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1151 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.06(s, SiCH3), 0.08(s, SiCH3), 0.89(s, SiC(CH3)3), 1.12(s, 3”-CH3), 1.13(d, 6”-H), 1.14(t, 3-OCOCH2CH3), 1.18(t, 4”-OCOCH2CH3), 1.27(d, 6'-H), 1.85(dd, 2”-Hax), 2.02 (d, 2”-Heq), 2.05(s,9-OCOCH3), 2.05(s, 2'-OCOCH3), 2.03(br dd, CH2=CHCH2), 2.41(s, 3'-N(CH3)2), 2.66(br d, 10-H), 2.73(t, 3'-H), 3.22(s, CH(OCH3)2), 3.27(s, CH(OCH3)2), 3.51(brd, 4-H), 3.55(s, 4-OCH3), 3.63(m, 15-H), 3.90(br d, 5-H), 4.38(dq, 5”-H), 4.55(dd, CH(OCH3)2), 4.62(d, 4”-H), 4.74(d, 1'-H), 5.00(dd, 2'-H), 5.06(d, 1”-H), 5.12(br dd, 9-H), 5.19(m, 3-H), 5.82(m, CH=CH2).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1151 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.06 (s, SiCH 3 ), 0.08 (s, SiCH 3 ), 0.89 (s, SiC (CH 3 ) 3 ), 1.12 (s, 3 ”-CH 3 ), 1.13 (d, 6” -H), 1.14 (t, 3-OCOCH 2 CH 3 ), 1.18 (t, 4 ”-OCOCH 2 CH 3 ), 1.27 (d, 6'-H ), 1.85 (dd, 2 ”-Hax), 2.02 (d, 2” -Heq), 2.05 (s, 9-OCOCH 3 ), 2.05 (s, 2'-OCOCH 3 ), 2.03 (br dd, CH 2 = CHCH 2 ), 2.41 (s, 3'-N (CH 3 ) 2 ), 2.66 (br d, 10-H), 2.73 (t, 3'-H), 3.22 (s, CH (OCH 3 ) 2 ), 3.27 (s, CH (OCH 3 ) 2 ), 3.51 (brd, 4-H), 3.55 (s, 4-OCH 3 ), 3.63 (m, 15-H), 3.90 (br d, 5-H ), 4.38 (dq, 5 ”-H), 4.55 (dd, CH (OCH 3 ) 2 ), 4.62 (d, 4” -H), 4.74 (d, 1'-H), 5.00 (dd, 2 ' -H), 5.06 (d, 1 ''-H), 5.12 (br dd, 9-H), 5.19 (m, 3-H), 5.82 (m, CH = CH 2 ).

(b)2-メチル-6-ニトロ安息香酸無水物45.3 mg及び4-ジメチルアミノピリジン35.3 mgをテトラヒドロフラン16 mlに溶解し、氷冷下で実施例31(a)の化合物105 mgのテトラヒドロフラン5 ml溶液を1時間かけて滴下後、氷冷から室温にしつつ7時間撹拌した。反応液に酢酸エチル60 ml、飽和塩化アンモニウム水溶液20 ml及び25%食塩水10 mlを加え、有機層を分離した後、この有機層を25%食塩水30 mlで洗浄した。有機層を無水硫酸ナトリウムで乾燥後、これを濾過し、濾液を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン−酢酸エチル(1:1))で精製して、工程図13の式(28)の化合物78.4 mgを得た。 (b) 45.3 mg of 2-methyl-6-nitrobenzoic anhydride and 35.3 mg of 4-dimethylaminopyridine were dissolved in 16 ml of tetrahydrofuran, and the compound of Example 31 (a) 105 mg of tetrahydrofuran 5 ml was dissolved under ice cooling. The solution was added dropwise over 1 hour, followed by stirring for 7 hours while cooling from ice to room temperature. To the reaction solution were added 60 ml of ethyl acetate, 20 ml of saturated aqueous ammonium chloride solution and 10 ml of 25% brine, and the organic layer was separated. The organic layer was washed with 30 ml of 25% brine. The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate (1: 1)) to obtain a process shown in FIG. 78.4 mg of the compound of formula (28) was obtained.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1133 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.04(s, Si(CH3)2), 0.88(s, SiC(CH3)3), 0.93(d, 8-CH3), 1.12(s, 3”-CH3), 1.13(d, 6”-H), 1.14(t, 3-OCOCH2CH3), 1.18(t, 4”-OCOCH2CH3), 1.28(d, 6'-H), 1.40(m, 7-H), 1.47(m, 6-CH2), 1.71(m, 8-H), 1.85(dd, 2”-Hax), 2.02(d, 2”-Heq), 2.05(s, 9-OCOCH3), 2.06(s, 2'-OCOCH3), 2.30(m, 15-CH2), 2.41(s, 3'-N(CH3)2), 2.74(t, 3'-H), 2.85(dd, 2-H), 3.16(s, CH(OCH3)2), 3.26(s, CH(OCH3)2), 3.34(m, 4'-H), 3.36(m, 5'-H), 3.60(s, 4-OCH3), 3.62(s, SiOCH2), 3.92(br d, 5-H), 4.39(dq, 5”-H), 4.55(dd, CH(OCH3)2), 4.62(d, 4”-H), 4.72(d, 1'-H), 4.86(m, 9-H), 5.02(dd, 2'-H), 5.72(m, CH2=CH).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1133 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.04 (s, Si (CH 3 ) 2 ), 0.88 (s, SiC (CH 3 ) 3 ), 0.93 (d, 8-CH 3 ), 1.12 (s, 3 ”-CH 3 ), 1.13 (d, 6” -H), 1.14 (t, 3-OCOCH 2 CH 3 ), 1.18 (t, 4 ”-OCOCH 2 CH 3 ), 1.28 ( d, 6'-H), 1.40 (m, 7-H), 1.47 (m, 6-CH 2 ), 1.71 (m, 8-H), 1.85 (dd, 2 ”-Hax), 2.02 (d, 2 ”-Heq), 2.05 (s, 9-OCOCH 3 ), 2.06 (s, 2'-OCOCH 3 ), 2.30 (m, 15-CH 2 ), 2.41 (s, 3'-N (CH 3 ) 2 ), 2.74 (t, 3'-H), 2.85 (dd, 2-H), 3.16 (s, CH (OCH 3 ) 2 ), 3.26 (s, CH (OCH 3 ) 2 ), 3.34 (m, 4 '-H), 3.36 (m, 5'-H), 3.60 (s, 4-OCH 3 ), 3.62 (s, SiOCH 2 ), 3.92 (br d, 5-H), 4.39 (dq, 5 ”- H), 4.55 (dd, CH (OCH 3 ) 2 ), 4.62 (d, 4 ”-H), 4.72 (d, 1'-H), 4.86 (m, 9-H), 5.02 (dd, 2 ' -H), 5.72 (m, CH 2 = CH).

(c)実施例1(b)と同様の方法で、実施例31(b)の化合物311 mgから、工程図13の式(29)の化合物209 mgを得た。 (c) In the same manner as in Example 1 (b), 209 mg of the compound of formula (29) in Process Diagram 13 was obtained from 311 mg of the compound of Example 31 (b).

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1260 (M+H)+
(2)1H NMRスペクトル(300 MHz, CDCl3) δ(ppm):0.05(s, Si(CH3)2), 0.87(s, SiC(CH3)3), 0.93(d, 8-CH3), 1.12(s, 3”-CH3), 1.13(d, 6”-H), 1.13(t, 3-OCOCH2CH3), 1.18(t, 4”-OCOCH2CH3), 1.28(d, 6'-H), 1.85(dd, 2”-Hax), 2.02(d, 2”-Heq), 2.05(s, 9-OCOCH3), 2.05(s, 2'-OCOCH3), 2.41(s, 3'-N(CH3)2), 2.73(t, 3'-H), 2.84(dd, 2-H), 3.15(s, CH(OCH3)2), 3.25(s, CH(OCH3)2), 3.32(m, 4'-H), 3.35(m, 5'-H), 3.57(s, 4-OCH3), 3.62(s, SiOCH2), 3.93(br d, 5-H), 4.28(br s, 3”-H), 4.38(dq, 5”-H), 4.54(dd, CH(OCH3)2), 4.62(d, 4”-H), 4.71(d, 1'-H), 4.89(m, 9-H), 5.02(dd, 2'-H), 5.08(m, 3-H), 5.09(d, 1”-H), 5.12(m, 15-H), 6.37(dt, CH=CH), 6.61(d, CH=CH), 7.52(ddd, quinoline), 7.66(ddd, quinoline), 7.78(br d, quinoline), 8.02(d, quinoline), 8.06(br d, quinoline), 8.95(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1260 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.05 (s, Si (CH 3 ) 2 ), 0.87 (s, SiC (CH 3 ) 3 ), 0.93 (d, 8-CH 3 ), 1.12 (s, 3 ”-CH 3 ), 1.13 (d, 6” -H), 1.13 (t, 3-OCOCH 2 CH 3 ), 1.18 (t, 4 ”-OCOCH 2 CH 3 ), 1.28 (d, 6'-H), 1.85 (dd, 2 "-Hax), 2.02 (d, 2 ''-Heq), 2.05 (s, 9-OCOCH 3 ), 2.05 (s, 2'-OCOCH 3 ), 2.41 (s, 3'-N (CH 3 ) 2 ), 2.73 (t, 3'-H), 2.84 (dd, 2-H), 3.15 (s, CH (OCH 3 ) 2 ), 3.25 (s, CH (OCH 3 ) 2 ), 3.32 (m, 4'-H), 3.35 (m, 5'-H), 3.57 (s, 4-OCH 3 ), 3.62 (s, SiOCH 2 ), 3.93 (br d , 5-H), 4.28 (br s, 3 ”-H), 4.38 (dq, 5” -H), 4.54 (dd, CH (OCH 3 ) 2 ), 4.62 (d, 4 ”-H), 4.71 (d, 1'-H), 4.89 (m, 9-H), 5.02 (dd, 2'-H), 5.08 (m, 3-H), 5.09 (d, 1 ''-H), 5.12 (m , 15-H), 6.37 (dt, CH = CH), 6.61 (d, CH = CH), 7.52 (ddd, quinoline), 7.66 (ddd, quinoline), 7.78 (br d, quinoline), 8.02 (d, quinoline), 8.06 (br d, quinoline), 8.95 (d, quinoline).

(d)実施例1(a)と同様の方法で、実施例31( c)の化合物209 mgから、工程図13の式(30)の化合物180 mgを得た。 (d) In the same manner as in Example 1 (a), 180 mg of the compound of the formula (30) in Step Diagram 13 was obtained from 209 mg of the compound of Example 31 (c).

本化合物の理化学的性状
(1)マススペクトル(FAB) :m/z 1331 (M+H)+
(2)1H NMRスペクトル(300 MHz, CDCl3) δ(ppm) :0.01(s, Si(CH3)2), 0.84(s, SiC(CH3)3), 0.91(d, 8-CH3), 1.10(d, 6”-H), 1.11(t, 3-OCOCH2CH3), 1.14(t, 3”-OCOCH2CH3), 1.16(t, NHCH2CH3), 1.17(d, 6'-H), 1.45(s, 3”-CH3), 1.66(dd, 2”-Hax), 2.02(s, 9-OCOCH3), 2.02(s, 2'-OCOCH3), 2.40(s, 3'-N(CH3)2), 2.82(dd, 2-H), 3.11(m, 4'-H), 3.13(s, CH(OCH3)2), 3.16(d, 2”-Heq), 3.23(s, CH(OCH3)2), 3.48(br d, 4-H), 3.55(s, 4-OCH3), 3.60(s, SiOCH2), 3.89(br d, 5-H), 4.38(m, 4”-H), 4.40(m,5”-H), 4.51(dd, CH(OCH3)2), 4.63(d, 1'-H), 4.76(d, 1”-H), 4.82(t, NH), 4.86(m, 9-H), 4.94(dd, 2'-H), 5.08(m, 3-H), 5.10(m, 15-H), 6.35(dt, CH=CH), 6.58(d, CH=CH), 7.50(ddd, quinoline), 7.63(ddd, quinoline), 7.76(br d, quinoline), 8.00(d, quinoline), 8.03(br d, quinoline), 8.92(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1331 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.01 (s, Si (CH 3 ) 2 ), 0.84 (s, SiC (CH 3 ) 3 ), 0.91 (d, 8-CH 3 ), 1.10 (d, 6 ”-H), 1.11 (t, 3-OCOCH 2 CH 3 ), 1.14 (t, 3” -OCOCH 2 CH 3 ), 1.16 (t, NHCH 2 CH 3 ), 1.17 ( d, 6'-H), 1.45 (s, 3 ”-CH 3 ), 1.66 (dd, 2” -Hax), 2.02 (s, 9-OCOCH 3 ), 2.02 (s, 2'-OCOCH 3 ), 2.40 (s, 3'-N (CH 3 ) 2 ), 2.82 (dd, 2-H), 3.11 (m, 4'-H), 3.13 (s, CH (OCH 3 ) 2 ), 3.16 (d, 2 ''-Heq), 3.23 (s, CH (OCH 3 ) 2 ), 3.48 (br d, 4-H), 3.55 (s, 4-OCH 3 ), 3.60 (s, SiOCH 2 ), 3.89 (br d , 5-H), 4.38 (m, 4 ''-H), 4.40 (m, 5 ''-H), 4.51 (dd, CH (OCH 3 ) 2 ), 4.63 (d, 1'-H), 4.76 ( d, 1 ”-H), 4.82 (t, NH), 4.86 (m, 9-H), 4.94 (dd, 2'-H), 5.08 (m, 3-H), 5.10 (m, 15-H ), 6.35 (dt, CH = CH), 6.58 (d, CH = CH), 7.50 (ddd, quinoline), 7.63 (ddd, quinoline), 7.76 (br d, quinoline), 8.00 (d, quinoline), 8.03 (br d, quinoline), 8.92 (d, quinoline).

(e)実施例1(c)と同様の方法で、実施例31(d)の化合物30 .3 mgから、工程図13の式(31)の化合物21.9 mgを得た。 (e) In the same manner as in Example 1 (c), 21.9 mg of the compound of the formula (31) in Process Diagram 13 was obtained from 30.3 mg of the compound of Example 31 (d).

本化合物の理化学的性状
(1)マススペクトル(FAB) :m/z 1247 (M+H)+
(2)1H NMRスペクトル(300 MHz, CDCl3) δ(ppm):0.05(s, Si(CH3)2), 0.88(d, 8-CH3), 0.88(s, SiC(CH3)3), 1.11(d, 6”-H), 1.16(t, NHCH2CH3), 1.20(d, 6'-H), 1.47(s, 3”-CH3), 1.69(dd, 2”-Hax), 2.52(s, 3'-N(CH3)2), 2.81(dd, 2-H), 3.15(s, CH(OCH3)2), 3.21(d, 2”-Heq), 3.25(s, CH(OCH3)2), 3.48(dd, 2'-H), 3.64(s, 4-OCH3), 3.88(br s, 4-H), 3.88(br s, 5-H), 4.43(d, 1'-H), 4.48(dd, CH(OCH3)2), 4.81(d, 1”-H), 5.12(m, 15-H), 4.45(dq, 5”-H), 5.42(br dd, 3-H), 6.35(dt, CH=CH), 6.59(d, CH=CH), 7.52(ddd, quinoline), 7.66(ddd, quinoline), 7.78(br d, quinoline), 8.00(d, quinoline), 8.06(br d, quinoline), 8.93(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1247 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.05 (s, Si (CH 3 ) 2 ), 0.88 (d, 8-CH 3 ), 0.88 (s, SiC (CH 3 ) 3 ), 1.11 (d, 6 ”-H), 1.16 (t, NHCH 2 CH 3 ), 1.20 (d, 6'-H), 1.47 (s, 3” -CH 3 ), 1.69 (dd, 2 ” -Hax), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.81 (dd, 2-H), 3.15 (s, CH (OCH 3 ) 2 ), 3.21 (d, 2 ”-Heq), 3.25 (s, CH (OCH 3 ) 2 ), 3.48 (dd, 2'-H), 3.64 (s, 4-OCH 3 ), 3.88 (br s, 4-H), 3.88 (br s, 5-H ), 4.43 (d, 1'-H), 4.48 (dd, CH (OCH 3 ) 2 ), 4.81 (d, 1 ”-H), 5.12 (m, 15-H), 4.45 (dq, 5”- H), 5.42 (br dd, 3-H), 6.35 (dt, CH = CH), 6.59 (d, CH = CH), 7.52 (ddd, quinoline), 7.66 (ddd, quinoline), 7.78 (br d, quinoline), 8.00 (d, quinoline), 8.06 (br d, quinoline), 8.93 (d, quinoline).

(f)実施例2(b)と同様の方法で、実施例31(e)の化合物21.9 mgから、標記化合物18 mgを得た。 (f) In the same manner as in Example 2 (b), 18 mg of the title compound was obtained from 21.9 mg of the compound of Example 31 (e).

本化合物の理化学的性状
(1)マススペクトル(FAB) :m/z 1087 (M+H)+
(2)比旋光度:[α]D 28 -54°(c0.90, CHCl3)
(3)1H NMRスペクトル(300 MHz, CDCl3) δ(ppm) :0.91(d, 8-CH3), 1.42(m, 8-H), 1.47(s, 3”-CH3), 1.70(dd, 2”-Hax), 1.78(m, 14-H), 2.54(s, 3'-N(CH3)2), 2.85(dd, 2-H), 2.91(dd, 6-CH2), 3.21(d, 2”-Heq), 3.25(dq, NH), 3.37(dd, 2'-H), 3.45(m, 9-H), 3.63(t, HOCH2), 3.65(s, 4-OCH3), 4.39(d, 1'-H), 4.42(m, 4”-H), 4.45(m,5”-H), 4.81(t, NH), 4.83(d, 1”-H), 5.15(m, 15-H), 5.47(br dd, 3-H), 6.34(dt, CH=CH), 6.59(d, CH=CH), 7.52(ddd, quinoline), 7.66(ddd, quinoline), 7.78(dd, quinoline), 8.00(d, quinoline), 8.06(br d, quinoline), 8.93(d, quinoline), 9.64(s, CHO).

Figure 2007069555
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1087 (M + H) +
(2) Specific rotation: [α] D 28 -54 ° (c0.90, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.91 (d, 8-CH 3 ), 1.42 (m, 8-H), 1.47 (s, 3 ”-CH 3 ), 1.70 (dd, 2 ”-Hax), 1.78 (m, 14-H), 2.54 (s, 3'-N (CH 3 ) 2 ), 2.85 (dd, 2-H), 2.91 (dd, 6-CH 2 ), 3.21 (d, 2 ”-Heq), 3.25 (dq, NH), 3.37 (dd, 2'-H), 3.45 (m, 9-H), 3.63 (t, HOCH 2 ), 3.65 (s, 4-OCH 3 ), 4.39 (d, 1'-H), 4.42 (m, 4 ”-H), 4.45 (m, 5” -H), 4.81 (t, NH), 4.83 (d, 1 ”- H), 5.15 (m, 15-H), 5.47 (br dd, 3-H), 6.34 (dt, CH = CH), 6.59 (d, CH = CH), 7.52 (ddd, quinoline), 7.66 (ddd , quinoline), 7.78 (dd, quinoline), 8.00 (d, quinoline), 8.06 (br d, quinoline), 8.93 (d, quinoline), 9.64 (s, CHO).
Figure 2007069555

実施例32
式(1)において、R1及びR2が水素原子、R3がメチル基、R4がトランス-3-(キノリン-3-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)工程図14の式(32)の化合物(J. Antibiot., 51, 771(1998))1.91 gにアセトン47 ml及び水7.1 mlを加え溶解し、N-メチルモルホリン-N-オキシド940 μl及び4%四酸化オスミウム水溶液1.9 mlを加え、室温で撹拌した。23.5時間後、N-メチルモルホリン-N-オキシド470 μlを加え、さらに7時間撹拌した。反応液を減圧濃縮した後、酢酸エチル50mlを加え、有機層を水10 ml、5%チオ硫酸ナトリウム水溶液20 ml、飽和食塩水20 mlで順次洗浄した。有機層を無水硫酸ナトリウムで乾燥し、これを濾過した後、濾液を減圧濃縮して、テトラオール体(工程図14の式(33)の化合物)2.10 gを得た。この粗生成物200 mgをベンゼン3 mlに溶解し、炭酸ナトリウム166 mgを加えた後、4回に分けて四酢酸鉛216 mgを10分間で加えた。反応液を室温で10分間攪拌した後、酢酸エチル25 mlを用いて不溶物をセライトろ過した。工程図14の式(34)の化合物を含むろ液に、1,8-ジアザビシクロ[5.4.0]-ウンデセン45 μlを加え、室温で30分間攪拌した。反応液を約10分の1まで減圧濃縮して得られた溶液をシリカゲルカラムクロマトグラフィー(クロロホルム〜クロロホルム−メタノール (80:1〜50:1))で精製して、工程図14の式(26b)の化合物75 mgを得た。
Example 32
In the formula (1), R 1 and R 2 are hydrogen atoms, R 3 is a methyl group, R 4 is a trans-3- (quinolin-3-yl) -2-propenyl group, R 5 is a hydrogen atom and R 6 is Method for producing compound represented by ethyl group
(a) A compound of the formula (32) in FIG. 14 (J. Antibiot., 51 , 771 (1998)) was dissolved in 1.91 g by adding 47 ml of acetone and 7.1 ml of water, and N-methylmorpholine-N-oxide 940 μl and 4% osmium tetroxide aqueous solution 1.9 ml were added and stirred at room temperature. After 23.5 hours, 470 μl of N-methylmorpholine-N-oxide was added, and the mixture was further stirred for 7 hours. The reaction mixture was concentrated under reduced pressure, 50 ml of ethyl acetate was added, and the organic layer was washed successively with 10 ml of water, 20 ml of 5% aqueous sodium thiosulfate solution, and 20 ml of saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure to obtain 2.10 g of a tetraol form (compound of formula (33) in Process FIG. 14). 200 mg of this crude product was dissolved in 3 ml of benzene, 166 mg of sodium carbonate was added, and then 216 mg of lead tetraacetate was added in 10 minutes in four portions. The reaction solution was stirred at room temperature for 10 minutes, and the insoluble material was filtered through Celite using 25 ml of ethyl acetate. To the filtrate containing the compound of the formula (34) in Process FIG. 14, 45 μl of 1,8-diazabicyclo [5.4.0] -undecene was added and stirred at room temperature for 30 minutes. The solution obtained by concentrating the reaction solution under reduced pressure to about 1/10 was purified by silica gel column chromatography (chloroform-chloroform-methanol (80: 1-50: 1)) to obtain the formula (26b ) Was obtained 75 mg.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 892 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.04(s, SiCH3), 0.05(s, SiCH3), 0.86(s, SiC(CH3)3), 1.02(d, 8-Me), 1.12(s, 3”-CH3), 1.13(d, 6”-H), 1.18(t, 4”-OCOCH2CH3), 1.31(d, 6'-H), 1.44(br dd, 7-H), 1.68(m, 6-CH2), 1.86(dd, 2”-Hax),1.95(m, 6-H), 2.02(d, 2”-Heq), 2.05(s, 2'-OCOCH3), 2.11(m, 6-CH2), 2.17(s, 9-OCOCH3), 2.36(m, 8-H), 2.41(s, 3'-N(CH3)2), 2.75(t, 3'-H), 2.82(dd, 2-H), 3.08(br d, 4-H), 3.37(t, 5'-H), 3.43(s, 4-OCH3), 3.79(dd, 5-H), 4.01(br dd, 3-H), 4.40(dq, 5”-H), 4.42(d, 1'-H), 4.63(d, 4”-H), 4.93(d, 9-H), 5.00(m, CHOSi), 5.02(dd, 2'-H), 5.09(d, 1”-H), 9.58(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 892 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.04 (s, SiCH 3 ), 0.05 (s, SiCH 3 ), 0.86 (s, SiC (CH 3 ) 3 ), 1.02 (d, 8-Me), 1.12 (s, 3 ”-CH 3 ), 1.13 (d, 6” -H), 1.18 (t, 4 ”-OCOCH 2 CH 3 ), 1.31 (d, 6'-H), 1.44 (br dd, 7-H), 1.68 (m, 6-CH 2 ), 1.86 (dd, 2 ”-Hax), 1.95 (m, 6-H), 2.02 (d, 2” -Heq), 2.05 ( s, 2'-OCOCH 3 ), 2.11 (m, 6-CH 2 ), 2.17 (s, 9-OCOCH 3 ), 2.36 (m, 8-H), 2.41 (s, 3'-N (CH 3 ) 2 ), 2.75 (t, 3'-H), 2.82 (dd, 2-H), 3.08 (br d, 4-H), 3.37 (t, 5'-H), 3.43 (s, 4-OCH 3 ), 3.79 (dd, 5-H), 4.01 (br dd, 3-H), 4.40 (dq, 5 ”-H), 4.42 (d, 1'-H), 4.63 (d, 4” -H) , 4.93 (d, 9-H), 5.00 (m, CHOSi), 5.02 (dd, 2'-H), 5.09 (d, 1 ''-H), 9.58 (s, CHO).

(b)反応容器に実施例32(a)の化合物1.8 g、モレキュラシーブ3A 9g及びジメチルホルムアミド26 mlを入れ、(R)-7-メチルアミノ-1-ヘプテン-4-オール(WO2005/019238、参考例22)378 mgのジメチルホルムアミド10 ml溶液を加え、室温で5時間撹拌した。反応液にナトリウムボロヒドリド76 mgを加え、さらに室温で2時間攪拌した。酢酸エチル200 mlを用いて反応液をセライト濾過した後、濾液を水90 ml、飽和食塩水90 mlで順次洗浄した。有機層を無水硫酸ナトリウムで乾燥後、これを濾過し、濾液を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム−メタノール (50:1〜30:1))で精製して、工程図14の式(35)の化合物746 mgを得た。 (b) A reaction vessel was charged with 1.8 g of the compound of Example 32 (a), 9 g of molecular sieve 3A and 26 ml of dimethylformamide, and (R) -7-methylamino-1-hepten-4-ol (WO2005 / 019238, reference Example 22) A solution of 378 mg of dimethylformamide in 10 ml was added and stirred at room temperature for 5 hours. To the reaction solution, 76 mg of sodium borohydride was added, and the mixture was further stirred at room temperature for 2 hours. The reaction mixture was filtered through celite with 200 ml of ethyl acetate, and the filtrate was washed successively with 90 ml of water and 90 ml of saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform-methanol (50: 1-30: 1)) 746 mg of the compound of formula (35) in FIG. 14 was obtained.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1019 (M+H)+
(2)比旋光度:[α]D 25 -79°(c0.76, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.05(s, SiCH3), 0.06(s, SiCH3), 0.86(s, SiC(CH3)3), 0.88(d, 8-CH3), 1.12(s, 3”-CH3), 1.13(d, 6”-H), 1.18(t, 4”-OCOCH2CH3), 1.30(d, 6'-H), 1.39(m, 14-H), 1.86(dd, 2”-Hax), 1.91(d, 2”-Heq),2.05(s, 9-OCOCH3), 2.08(s, 2'-OCOCH3), 2.26(s, NCH3), 2.41(s, 3'-N(CH3)2), 2.75(t, 3'-H), 2.79(dd, 2-H), 3.10(br d, 4-H), 3.34(m, 4'-H), 3.36(m, 5'-H), 3.45(s, 4-OCH3), 3.56(br dd, 15-H), 3.78(dd, 5-H), 4.02(br dd, 3-H), 4.40(d, 1'-H), 4.41(dq, 5”-H), 4.63(d, 4”-H), 5.04(dd, 2'-H), 5.09(d, 1”-H), 5.85(ddt, CH=CH2).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1019 (M + H) +
(2) Specific rotation: [α] D 25 -79 ° (c0.76, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.05 (s, SiCH 3 ), 0.06 (s, SiCH 3 ), 0.86 (s, SiC (CH 3 ) 3 ), 0.88 (d, 8-CH 3 ), 1.12 (s, 3 ”-CH 3 ), 1.13 (d, 6” -H), 1.18 (t, 4 ”-OCOCH 2 CH 3 ), 1.30 (d, 6'-H), 1.39 (m, 14-H), 1.86 (dd, 2 ”-Hax), 1.91 (d, 2” -Heq), 2.05 (s, 9-OCOCH 3 ), 2.08 (s, 2'-OCOCH 3 ), 2.26 (s, NCH 3 ), 2.41 (s, 3'-N (CH 3 ) 2 ), 2.75 (t, 3'-H), 2.79 (dd, 2-H), 3.10 (br d, 4-H ), 3.34 (m, 4'-H), 3.36 (m, 5'-H), 3.45 (s, 4-OCH 3 ), 3.56 (br dd, 15-H), 3.78 (dd, 5-H) , 4.02 (br dd, 3-H), 4.40 (d, 1'-H), 4.41 (dq, 5 ”-H), 4.63 (d, 4” -H), 5.04 (dd, 2'-H) , 5.09 (d, 1 ”-H), 5.85 (ddt, CH = CH 2 ).

(c)実施例31(b)と同様の方法で、実施例32(b)の化合物730 mgの化合物 から、工程図14の式(13d)の化合物487 mgを得た。 (c) In the same manner as in Example 31 (b), 487 mg of the compound of the formula (13d) in Step Diagram 14 was obtained from 730 mg of the compound of Example 32 (b).

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1001 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.11(s, SiCH3), 0.12(s, SiCH3), 0.63(br dd, 7-H), 0.89(s, SiC(CH3)3), 0.91(d, 8-CH3), 1.12(s, 3”-CH3), 1.13(d, 6”-H), 1.18(t, 4”-OCOCH2CH3), 1.28(d, 6'-H), 1.47(m, 13-H), 1.47(m, 6-CH2), 1.62(m, 14-H), 1.85(dd, 2”-Hax), 2.02(d, 2”-Heq), 2.02(s, 9-OCOCH3), 2.06(s, 2'-OCOCH3), 2.15(br dd, 7-H), 2.26(s, NCH3), 2.41(s, 3'-N(CH3)2), 2.59(dd, 2-H), 2.65(dd, 10-H), 2.76(t, 3'-H), 2.77(dd, 2-H), 3.02(dd, 4-H), 3.31(m, 4'-H), 3.32(m, 5'-H), 3.53(s, 4-OCH3), 3.64(dd, 5-H), 4.12(br d, 3-H), 4.23(br s, 3”-OH), 4.41(dq, 5”-H), 4.54(d, 1'-H), 4.62(d, 4”-H), 4.86(m, 15-H), 4.90(dd, CHSi), 5.00(m, 9-H), 5.01(dd, 2'-H), 5.09(d, 1”-H), 5.10(m, CH2=CH), 5.73(m, CH=CH2).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1001 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.11 (s, SiCH 3 ), 0.12 (s, SiCH 3 ), 0.63 (br dd, 7-H), 0.89 (s, SiC ( CH 3 ) 3 ), 0.91 (d, 8-CH 3 ), 1.12 (s, 3 ”-CH 3 ), 1.13 (d, 6” -H), 1.18 (t, 4 ”-OCOCH 2 CH 3 ), 1.28 (d, 6'-H), 1.47 (m, 13-H), 1.47 (m, 6-CH 2 ), 1.62 (m, 14-H), 1.85 (dd, 2 ”-Hax), 2.02 ( d, 2 ”-Heq), 2.02 (s, 9-OCOCH 3 ), 2.06 (s, 2'-OCOCH 3 ), 2.15 (br dd, 7-H), 2.26 (s, NCH 3 ), 2.41 (s , 3'-N (CH 3 ) 2 ), 2.59 (dd, 2-H), 2.65 (dd, 10-H), 2.76 (t, 3'-H), 2.77 (dd, 2-H), 3.02 (dd, 4-H), 3.31 (m, 4'-H), 3.32 (m, 5'-H), 3.53 (s, 4-OCH 3 ), 3.64 (dd, 5-H), 4.12 (br d, 3-H), 4.23 (br s, 3 ”-OH), 4.41 (dq, 5” -H), 4.54 (d, 1'-H), 4.62 (d, 4 ”-H), 4.86 ( m, 15-H), 4.90 (dd, CHSi), 5.00 (m, 9-H), 5.01 (dd, 2'-H), 5.09 (d, 1 ”-H), 5.10 (m, CH 2 = CH), 5.73 (m, CH = CH 2 ).

(d)実施例1(b)と同様の方法で、実施例32(c)の化合物120 mgから、カップリング化合物(工程図14の式(23d)において、Arがキノリン-3-イル基で表される化合物)71 mgを得た。 (d) In the same manner as in Example 1 (b), from 120 mg of the compound of Example 32 (c), a coupling compound (in the formula (23d) in Process Diagram 14, Ar is a quinolin-3-yl group) 71 mg of the compound represented) was obtained.

本化合物の理化学的性状
(1)マススペクトル(FAB) :m/z 1128 (M+H)+
(2)比旋光度:[α]D 24 -70°(c1.0, CHCl3)
(3)1H NMRスペクトル(300 MHz, CDCl3) δ(ppm) :0.11(s, SiCH3), 0.12(s, SiCH3),0.66(br dd, 7-H), 0.89(s, SiC(CH3)3), 0.92(d, 8-CH3), 1.12(s, 3”-CH3), 1.13(d,6”-H), 1.18(t, 4”-OCOCH2CH3), 1.29(d, 6'-H), 1.46(m, 6-CH2), 1.85(dd, 2”-Hax), 2.02(d, 2”-Heq), 2.03(s, 9-OCOCH3), 2.07(s, 2'-OCOCH3), 2.15(br dd, 7-H), 2.29(s, NCH3), 2.41(s, 3'-N(CH3)2), 2.55(dd, 2-H), 2.75(t, 3'-H), 2.79(dd, 2-H), 3.04(br d, 4-H), 3.31(m, 4'-H), 3.33(m, 5'-H), 3.54(s, 4-OCH3), 3.64(dd, 5-H), 4.15(br dd, 3-H), 4.23(br s, 3”-OH), 4.41(dq, 5”-H), 4.54(d, 1'-H), 4.62(d, 4”-H), 4.93(dd, CHSi), 5.01(dd, 2'-H), 5.09(d, 1”-H), 6.36(dt, CH=CH), 6.61(d, CH=CH), 7.53(ddd, quinoline), 7.67(ddd, quinoline), 7.80(br d, quinoline), 8.02(d, quinoline), 8.07(br d, quinoline), 8.95(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1128 (M + H) +
(2) Specific rotation: [α] D 24 -70 ° (c1.0, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.11 (s, SiCH 3 ), 0.12 (s, SiCH 3 ), 0.66 (br dd, 7-H), 0.89 (s, SiC (CH 3 ) 3 ), 0.92 (d, 8-CH 3 ), 1.12 (s, 3 ”-CH 3 ), 1.13 (d, 6” -H), 1.18 (t, 4 ”-OCOCH 2 CH 3 ) , 1.29 (d, 6'-H), 1.46 (m, 6-CH 2 ), 1.85 (dd, 2 ”-Hax), 2.02 (d, 2” -Heq), 2.03 (s, 9-OCOCH 3 ) , 2.07 (s, 2'-OCOCH 3 ), 2.15 (br dd, 7-H), 2.29 (s, NCH 3 ), 2.41 (s, 3'-N (CH 3 ) 2 ), 2.55 (dd, 2 -H), 2.75 (t, 3'-H), 2.79 (dd, 2-H), 3.04 (br d, 4-H), 3.31 (m, 4'-H), 3.33 (m, 5'- H), 3.54 (s, 4-OCH 3 ), 3.64 (dd, 5-H), 4.15 (br dd, 3-H), 4.23 (br s, 3 ”-OH), 4.41 (dq, 5”- H), 4.54 (d, 1'-H), 4.62 (d, 4 ''-H), 4.93 (dd, CHSi), 5.01 (dd, 2'-H), 5.09 (d, 1 ''-H), 6.36 (dt, CH = CH), 6.61 (d, CH = CH), 7.53 (ddd, quinoline), 7.67 (ddd, quinoline), 7.80 (br d, quinoline), 8.02 (d, quinoline), 8.07 (br d, quinoline), 8.95 (d, quinoline).

(e)実施例1(a)と同様の方法で、実施例32(d)の化合物70 mgから、カルバモイル化合物(工程図14の式(15d)において、Arがキノリン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)63.5 mgを得た。(e) In the same manner as in Example 1 (a), from 70 mg of the compound of Example 32 (d), a carbamoyl compound (in the formula (15d) of Process Diagram 14, Ar is a quinolin-3-yl group, R 63.5 mg of a compound in which 5 is a hydrogen atom and R 6 is an ethyl group.

本化合物の理化学的性状
(1)マススペクトル(FAB) :m/z 1199 (M+H)+
(2)比旋光度:[α]D 24 -77°(c1.0, CHCl3)
(3)1H NMRスペクトル(300 MHz, CDCl3) δ(ppm):0.11(s, SiCH3), 0.12(s, SiCH3), 0.64(br dd, 7-H), 0.89(s, SiC(CH3)3), 0.91(d, 8-CH3), 1.12(d, 6”-H), 1.14(t, 3”-OCOCH2CH3), 1.16(t, NHCH2CH3), 1.21(d, 6'-H), 1.47(s, 3”-CH3), 1.69(dd, 2”-Hax), 2.02(s, 9-OCOCH3), 2.06(s, 2'-OCOCH3), 2.15(m, 7-H), 2.27(s, NCH3), 2.42(s, 3'-N(CH3)2), 2.55(t, 3'-H), 2.59(dd, 2-H), 2.77(dd, 2-H), 3.06(br d, 4-H),3.11(m, 4'-H), 3.14(m, 5'-H), 3.20(d, 2”-Heq), 3.24(dq, NHCH2CH3), 3.52(s, 4-OCH3), 3.62(dd, 5-H), 4.14(br dd, 3-H), 4.41(d, 4”-H), 4.41(dq, 5”-H), 4.48(d, 1'-H), 4.81(d, 1”-H), 4.91(m, CHOSi), 4.94(dd, 2'-H), 5.02(m, 9-H), 6.36(dt, CH=CH), 6.61(d, CH=CH), 7.53(ddd, quinoline), 7.66(ddd, quinoline), 7.79(br d,quinoline), 8.02(d, quinoline), 8.07(br d, quinoline), 8.95(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1199 (M + H) +
(2) Specific rotation: [α] D 24 -77 ° (c1.0, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.11 (s, SiCH 3 ), 0.12 (s, SiCH 3 ), 0.64 (br dd, 7-H), 0.89 (s, SiC (CH 3 ) 3 ), 0.91 (d, 8-CH 3 ), 1.12 (d, 6 ”-H), 1.14 (t, 3” -OCOCH 2 CH 3 ), 1.16 (t, NHCH 2 CH 3 ), 1.21 (d, 6'-H), 1.47 (s, 3 ”-CH 3 ), 1.69 (dd, 2” -Hax), 2.02 (s, 9-OCOCH 3 ), 2.06 (s, 2'-OCOCH 3 ), 2.15 (m, 7-H), 2.27 (s, NCH 3 ), 2.42 (s, 3'-N (CH 3 ) 2 ), 2.55 (t, 3'-H), 2.59 (dd, 2- H), 2.77 (dd, 2-H), 3.06 (br d, 4-H), 3.11 (m, 4'-H), 3.14 (m, 5'-H), 3.20 (d, 2 ”-Heq ), 3.24 (dq, NHCH 2 CH 3 ), 3.52 (s, 4-OCH 3 ), 3.62 (dd, 5-H), 4.14 (br dd, 3-H), 4.41 (d, 4 ”-H) , 4.41 (dq, 5 ''-H), 4.48 (d, 1'-H), 4.81 (d, 1 ''-H), 4.91 (m, CHOSi), 4.94 (dd, 2'-H), 5.02 ( m, 9-H), 6.36 (dt, CH = CH), 6.61 (d, CH = CH), 7.53 (ddd, quinoline), 7.66 (ddd, quinoline), 7.79 (br d, quinoline), 8.02 (d , quinoline), 8.07 (br d, quinoline), 8.95 (d, quinoline).

(f)実施例1(c)と同様の方法で、実施例32(e)の化合物62 mgから、脱アセチル化合物(工程図14の式(18d)において、Arがキノリン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)14 mgを得た。(f) In the same manner as in Example 1 (c), from 62 mg of the compound of Example 32 (e), a deacetylated compound (in the formula (18d) of Process Diagram 14, Ar is a quinolin-3-yl group, 14 mg of a compound in which R 5 is a hydrogen atom and R 6 is an ethyl group.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1115 (M+H)+
(2)比旋光度:[α]D 25 -52°(c0.76, CHCl3)
(3)1H NMRスペクトル(300 MHz, CDCl3) δ(ppm):0.10(s, Si(CH3)2), 0.88(s, SiC(CH3)3), 0.96(d, 8-CH3), 1.13(t, 3”-OCOCH2CH3), 1.14(d, 6”-H), 1.17(t, NHCH2CH3), 1.21(d, 6'-H), 1.48(s, 3”-CH3), 1.70(dd, 2”-Hax), 2.41(t, 3'-H), 2.45(s, NCH3), 2.54(s, 3'-N(CH3)2), 2.82(dd, 2-H), 3.23(d, 2”-Heq), 3.42(dd, 2'-H), 3.55(s, 4-OCH3), 3.70(dd, 5-H), 3.87(br dd, 3-H), 4.30(d, 1'-H), 4.42(d, 4”-H), 4.45(dq, 5”-H), 4.85(d, 1”-H), 6.36(dt, CH=CH), 6.61(d, CH=CH), 7.53(ddd, quinoline), 7.67(ddd, quinoline), 7.79(br d, quinoline), 8.02(d, quinoline), 8.07(brd, quinoline), 8.96(d, quinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1115 (M + H) +
(2) Specific rotation: [α] D 25 -52 ° (c0.76, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.10 (s, Si (CH 3 ) 2 ), 0.88 (s, SiC (CH 3 ) 3 ), 0.96 (d, 8-CH 3 ), 1.13 (t, 3 ”-OCOCH 2 CH 3 ), 1.14 (d, 6” -H), 1.17 (t, NHCH 2 CH 3 ), 1.21 (d, 6'-H), 1.48 (s, 3 ”-CH 3 ), 1.70 (dd, 2” -Hax), 2.41 (t, 3'-H), 2.45 (s, NCH 3 ), 2.54 (s, 3'-N (CH 3 ) 2 ), 2.82 (dd, 2-H), 3.23 (d, 2 ”-Heq), 3.42 (dd, 2'-H), 3.55 (s, 4-OCH 3 ), 3.70 (dd, 5-H), 3.87 ( br dd, 3-H), 4.30 (d, 1'-H), 4.42 (d, 4 ”-H), 4.45 (dq, 5” -H), 4.85 (d, 1 ”-H), 6.36 ( dt, CH = CH), 6.61 (d, CH = CH), 7.53 (ddd, quinoline), 7.67 (ddd, quinoline), 7.79 (br d, quinoline), 8.02 (d, quinoline), 8.07 (brd, quinoline ), 8.96 (d, quinoline).

(g)実施例1(d)と同様の方法で、実施例32(f)の化合物16 mgから、標記化合物12.5 mgを得た。 (g) In the same manner as in Example 1 (d), 12.5 mg of the title compound was obtained from 16 mg of the compound of Example 32 (f).

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1001 (M+H)+
(2)比旋光度:[α]D 23 -53°(c0.50, CHCl3)
(3)1H NMRスペクトル(300 MHz, CDCl3) δ(ppm):0.89(d, 8-CH3), 1.14(d, 6”-H), 1.14(t, 3”-OCOCH2CH3), 1.16(t, NHCH2CH3), 1.17(d, 6'-H), 1.47(s, 3”-CH3), 1.51(m, 8-H), 1.70(dd, 2”-Hax), 2.31(s, NCH3), 2.41(dd, 6-CH2), 2.53(s, 3'-N(CH3)2), 2.94(dd, 6-CH2), 3.21(d, 2”-Heq), 3.25(m, 5'-H), 3.38(m, 9-H), 3.40(dd, 2'-H), 3.60(s, 4-OCH3), 3.64(br d, 4-H), 3.89(br d, 5-H), 4.35(d, 1'-H), 4.38(m, 3-H), 4.42(m, 4”-H), 4.45(m, 5”-H), 4.80(t, NH), 4.83(d, 1”-H), 5.12(m, 15-H), 6.38(dt, CH=CH), 6.61(d, CH=CH), 7.52(ddd, quinoline), 7.66(ddd, quinoline),7.79(br d, quinoline), 8.02(d, quinoline), 8.06(br d, quinoline), 8.95(d, quinoline), 9.73(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1001 (M + H) +
(2) Specific rotation: [α] D 23 -53 ° (c0.50, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.89 (d, 8-CH 3 ), 1.14 (d, 6 ”-H), 1.14 (t, 3” -OCOCH 2 CH 3 ), 1.16 (t, NHCH 2 CH 3 ), 1.17 (d, 6'-H), 1.47 (s, 3 ”-CH 3 ), 1.51 (m, 8-H), 1.70 (dd, 2” -Hax ), 2.31 (s, NCH 3 ), 2.41 (dd, 6-CH 2 ), 2.53 (s, 3'-N (CH 3 ) 2 ), 2.94 (dd, 6-CH 2 ), 3.21 (d, 2 ”-Heq), 3.25 (m, 5'-H), 3.38 (m, 9-H), 3.40 (dd, 2'-H), 3.60 (s, 4-OCH 3 ), 3.64 (br d, 4 -H), 3.89 (br d, 5-H), 4.35 (d, 1'-H), 4.38 (m, 3-H), 4.42 (m, 4 ”-H), 4.45 (m, 5”- H), 4.80 (t, NH), 4.83 (d, 1 ''-H), 5.12 (m, 15-H), 6.38 (dt, CH = CH), 6.61 (d, CH = CH), 7.52 (ddd , quinoline), 7.66 (ddd, quinoline), 7.79 (br d, quinoline), 8.02 (d, quinoline), 8.06 (br d, quinoline), 8.95 (d, quinoline), 9.73 (s, CHO).

実施例33
式(1)において、R1及びR2が水素原子、R3がメチル基、R4がトランス-3-(イソキノリン-4-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例1(b)と同様の方法で、実施例32(c)の化合物120 mgから、カップリング化合物(工程図14の式(23d)において、Arがイソキノリン-4-イル基で表される化合物)108 mgを得た。
Example 33
In the formula (1), R 1 and R 2 are hydrogen atoms, R 3 is a methyl group, R 4 is a trans-3- (isoquinolin-4-yl) -2-propenyl group, R 5 is a hydrogen atom and R 6 is Method for producing compound represented by ethyl group
(a) In the same manner as in Example 1 (b), from 120 mg of the compound of Example 32 (c), a coupling compound (in the formula (23d) of Process Diagram 14, Ar is an isoquinolin-4-yl group) 108 mg of the compound represented) was obtained.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1128 (M+H)+
(2)比旋光度:[α]D 23 -71°(c1.0, CHCl3)
(3)1H NMRスペクトル(300 MHz, CDCl3) δ(ppm):0.11(s, SiCH3), 0.12(s, SiCH3), 0.67(br dd, 7-H), 0.89(s, SiC(CH3)3), 0.92(d, 8-CH3), 1.12(s, 3”-CH3), 1.13(d, 6”-H), 1.18(t, 4”-OCOCH2CH3), 1.29(d, 6'-H), 1.49(dd, 6-CH2), 1.85(dd, 2”-Hax), 1.94(d, 2”-Heq), 2.03(s, 9-OCOCH3), 2.08(s, 2'-OCOCH3), 2.32(s, NCH3), 2.41(s, 3'-N(CH3)2), 2.62(dd, 2-H), 2.78(dd, 2-H), 2.78(t, 3'-H), 3.05(br d, 4-H), 3.31(m, 4'-H), 3.33(m, 5'-H), 3.54(s, 4-OCH3), 3.65(dd, 5-H), 4.16(br dd, 3-H), 4.22(br s, 3”-OH), 4.41(dq, 5”-H), 4.54(d, 1'-H), 4.62(d, 4”-H), 4.93(brd, CHOSi), 5.01(dd, 2'-H), 5.09(d, 1”-H), 6.22(dt, CH=CH), 7.05(d, CH=CH), 7.62(dd, isoquinoline), 7.73(dd, isoquinoline), 7.98(d, isoquinoline), 8.04(d, isoquinoline), 8.56(s, isoquinoline), 9.15(s, isoquinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1128 (M + H) +
(2) Specific rotation: [α] D 23 -71 ° (c1.0, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.11 (s, SiCH 3 ), 0.12 (s, SiCH 3 ), 0.67 (br dd, 7-H), 0.89 (s, SiC (CH 3 ) 3 ), 0.92 (d, 8-CH 3 ), 1.12 (s, 3 ”-CH 3 ), 1.13 (d, 6” -H), 1.18 (t, 4 ”-OCOCH 2 CH 3 ) , 1.29 (d, 6'-H), 1.49 (dd, 6-CH 2 ), 1.85 (dd, 2 ”-Hax), 1.94 (d, 2” -Heq), 2.03 (s, 9-OCOCH 3 ) , 2.08 (s, 2'-OCOCH 3 ), 2.32 (s, NCH 3 ), 2.41 (s, 3'-N (CH 3 ) 2 ), 2.62 (dd, 2-H), 2.78 (dd, 2- H), 2.78 (t, 3'-H), 3.05 (br d, 4-H), 3.31 (m, 4'-H), 3.33 (m, 5'-H), 3.54 (s, 4-OCH 3 ), 3.65 (dd, 5-H), 4.16 (br dd, 3-H), 4.22 (br s, 3 ”-OH), 4.41 (dq, 5” -H), 4.54 (d, 1'- H), 4.62 (d, 4 "-H), 4.93 (brd, CHOSi), 5.01 (dd, 2'-H), 5.09 (d, 1" -H), 6.22 (dt, CH = CH), 7.05 (d, CH = CH), 7.62 (dd, isoquinoline), 7.73 (dd, isoquinoline), 7.98 (d, isoquinoline), 8.04 (d, isoquinoline), 8.56 (s, isoquinoline), 9.15 (s, isoquinoline).

(b)実施例1(a)と同様の方法で、実施例33(a)の化合物108 mgから、カルバモイル化合物(工程図14の式(15d)において、Arがイソキノリン-4-イル基、R5が水素原子及びR6がエチル基で表される化合物)89 mgを得た。(b) In the same manner as in Example 1 (a), from 108 mg of the compound of Example 33 (a), a carbamoyl compound (in the formula (15d) of Process Diagram 14, Ar is an isoquinolin-4-yl group, R 89 mg of a compound in which 5 is a hydrogen atom and R 6 is an ethyl group.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1199 (M+H)+
(2)比旋光度:[α]D 22 -75°(c1.0, CHCl3)
(3)1H NMRスペクトル(300 MHz, CDCl3) δ(ppm):0.11(s, SiCH3), 0.12(s, SiCH3), 0.64(br dd, 7-H), 0.89(s, SiC(CH3)3), 0.92(d, 8-CH3), 1.12(t, 3”-OCOCH2CH3), 1.13(d, 6”-H), 1.16(t, NHCH2CH3), 1.21(d, 6'-H), 1.48(s, 3”-CH3), 1.69(dd, 2”-Hax), 2.28(s, NCH3), 2.42(s, 3'-N(CH3)2), 2.59(t, 3'-H), 2.77(dd, 2-H), 3.07(brd, 4-H), 3.53(s, 4-OCH3), 3.63(dd, 5-H), 4.16(br dd, 3-H), 4.41(m, 4”-H), 4.44(m, 5”-H), 4.49(d, 1'-H), 4.81(d, 1”-H), 4.88(t, NH), 4.93(m, CHOSi), 4.96(dd, 2'-H), 5.00(m, 15-H), 5.02(m, 9-H), 6.22(dt, CH=CH), 7.05(d, CH=CH), 7.62(ddd, isoquinoline), 7.73(ddd, isoquinoline), 7.98(br d, isoquinoline), 8.03(br d, isoquinoline), 8.56(s, isoquinoline), 9.15(s, isoquinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1199 (M + H) +
(2) Specific rotation: [α] D 22 -75 ° (c1.0, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.11 (s, SiCH 3 ), 0.12 (s, SiCH 3 ), 0.64 (br dd, 7-H), 0.89 (s, SiC (CH 3 ) 3 ), 0.92 (d, 8-CH 3 ), 1.12 (t, 3 ”-OCOCH 2 CH 3 ), 1.13 (d, 6” -H), 1.16 (t, NHCH 2 CH 3 ), 1.21 (d, 6'-H), 1.48 (s, 3 ”-CH 3 ), 1.69 (dd, 2” -Hax), 2.28 (s, NCH 3 ), 2.42 (s, 3'-N (CH 3 ) 2 ), 2.59 (t, 3'-H), 2.77 (dd, 2-H), 3.07 (brd, 4-H), 3.53 (s, 4-OCH 3 ), 3.63 (dd, 5-H) , 4.16 (br dd, 3-H), 4.41 (m, 4 ”-H), 4.44 (m, 5” -H), 4.49 (d, 1'-H), 4.81 (d, 1 ”-H) , 4.88 (t, NH), 4.93 (m, CHOSi), 4.96 (dd, 2'-H), 5.00 (m, 15-H), 5.02 (m, 9-H), 6.22 (dt, CH = CH ), 7.05 (d, CH = CH), 7.62 (ddd, isoquinoline), 7.73 (ddd, isoquinoline), 7.98 (br d, isoquinoline), 8.03 (br d, isoquinoline), 8.56 (s, isoquinoline), 9.15 ( s, isoquinoline).

(c)実施例1(c)と同様の方法で、実施例33(b)の化合物89 mgから、脱アセチル化合物(工程図14の式(18d)において、Arがイソキノリン-4-イル基、R5が水素原子及びR6がエチル基で表される化合物)52.2 mgを得た。(c) In the same manner as in Example 1 (c), from 89 mg of the compound of Example 33 (b), a deacetylated compound (in the formula (18d) in Process Diagram 14, Ar is an isoquinolin-4-yl group, 52.2 mg of a compound in which R 5 is a hydrogen atom and R 6 is an ethyl group.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1115 (M+H)+
(2)比旋光度:[α]D 21 -55°(c1.0, CHCl3)
(3)1H NMRスペクトル(300 MHz, CDCl3) δ(ppm):0.08(s, Si(CH3)2), 0.87(s, SiC(CH3)3), 0.95(d, 8-CH3), 1.12(t, 3”-OCOCH2CH3), 1.13(d, 6”-H), 1.17(t, NHCH2CH3), 1.21(d, 6'-H), 1.48(s, 3”-CH3), 1.70(dd, 2”-Hax), 1.97(m, 8-H), 2.42(s, NCH3), 2.54(s, 3'-N(CH3)2), 2.60(dd, 2-H), 2.83(dd, 2-H), 3.22(d, 2”-Heq), 3.43(dd, 2'-H), 3.56(s, 4-OCH3), 3.70(dd, 5-H), 3.85(br d, 9-H), 4.14(br dd, 3-H), 4.29(d, 1'-H), 4.41(d, 4”-H), 4.48(dq, 5”-H), 4.83(d, 1”-H), 4.93(m, 15-H), 6.22(dt, CH=CH), 7.05(d, CH=CH), 7.62(br d, isoquinoline), 7.74(ddd, isoquinoline), 7.98(br d, isoquinoline), 8.04(br d, isoquinoline), 8.56(s, isoquinoline), 9.16(s, isoquinoline).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1115 (M + H) +
(2) Specific rotation: [α] D 21 -55 ° (c1.0, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.08 (s, Si (CH 3 ) 2 ), 0.87 (s, SiC (CH 3 ) 3 ), 0.95 (d, 8-CH 3 ), 1.12 (t, 3 ”-OCOCH 2 CH 3 ), 1.13 (d, 6” -H), 1.17 (t, NHCH 2 CH 3 ), 1.21 (d, 6'-H), 1.48 (s, 3 ”-CH 3 ), 1.70 (dd, 2” -Hax), 1.97 (m, 8-H), 2.42 (s, NCH 3 ), 2.54 (s, 3'-N (CH 3 ) 2 ), 2.60 (dd, 2-H), 2.83 (dd, 2-H), 3.22 (d, 2 ”-Heq), 3.43 (dd, 2'-H), 3.56 (s, 4-OCH 3 ), 3.70 (dd , 5-H), 3.85 (br d, 9-H), 4.14 (br dd, 3-H), 4.29 (d, 1'-H), 4.41 (d, 4 ''-H), 4.48 (dq, 5 ”-H), 4.83 (d, 1” -H), 4.93 (m, 15-H), 6.22 (dt, CH = CH), 7.05 (d, CH = CH), 7.62 (br d, isoquinoline) , 7.74 (ddd, isoquinoline), 7.98 (br d, isoquinoline), 8.04 (br d, isoquinoline), 8.56 (s, isoquinoline), 9.16 (s, isoquinoline).

(d)実施例1(d)と同様の方法で、実施例33(c)の化合物52 mgから、標記化合物33.5 mgを得た。 (d) In the same manner as in Example 1 (d), 33.5 mg of the title compound was obtained from 52 mg of the compound of Example 33 (c).

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1001 (M+H)+
(2)比旋光度:[α]D 25 -54°(c1.0, CHCl3)
(3)1H NMRスペクトル(300 MHz, CDCl3) δ(ppm):0.90(d, 8-CH3), 1.14(d, 6”-H), 1.14(t, 3”-OCOCH2CH3), 1.16(t, NHCH2CH3), 1.17(d, 6'-H), 1.24(br d, 7-H), 1.47(s, 3”-CH3), 1.53(m, 8-H), 1.69(dd, 2”-Hax), 1.80(m, 14-H), 2.35(s, NCH3), 2.42(dd, 6-CH2), 2.52(s, 3'-N(CH3)2), 2.94(dd, 6-CH2), 3.15(t, 4'-H), 3.21(d, 2”-Heq), 3.41(dd, 2'-H), 3.59(s, 4-OCH3), 3.66(br d, 4-H), 3.88(br d, 5-H), 4.34(d, 1'-H), 4.41(d, 4”-H), 4.46(dq, 5”-H), 4.82(d, 1”-H), 5.16(m, 15-H), 6.23(dt, CH=CH), 7.03(d, CH=CH), 7.61(ddd, isoquinoline), 7.73(ddd, isoquinoline), 7.97(br d, isoquinoline), 8.04(br d, isoquinoline), 8.54(s, isoquinoline), 9.14(s, isoquinoline), 9.74(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1001 (M + H) +
(2) Specific rotation: [α] D 25 -54 ° (c1.0, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.90 (d, 8-CH 3 ), 1.14 (d, 6 ”-H), 1.14 (t, 3” -OCOCH 2 CH 3 ), 1.16 (t, NHCH 2 CH 3 ), 1.17 (d, 6'-H), 1.24 (br d, 7-H), 1.47 (s, 3 ”-CH 3 ), 1.53 (m, 8-H ), 1.69 (dd, 2 ”-Hax), 1.80 (m, 14-H), 2.35 (s, NCH 3 ), 2.42 (dd, 6-CH 2 ), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.94 (dd, 6-CH 2 ), 3.15 (t, 4'-H), 3.21 (d, 2 ”-Heq), 3.41 (dd, 2'-H), 3.59 (s, 4- OCH 3 ), 3.66 (br d, 4-H), 3.88 (br d, 5-H), 4.34 (d, 1'-H), 4.41 (d, 4 ”-H), 4.46 (dq, 5” -H), 4.82 (d, 1 ''-H), 5.16 (m, 15-H), 6.23 (dt, CH = CH), 7.03 (d, CH = CH), 7.61 (ddd, isoquinoline), 7.73 ( ddd, isoquinoline), 7.97 (br d, isoquinoline), 8.04 (br d, isoquinoline), 8.54 (s, isoquinoline), 9.14 (s, isoquinoline), 9.74 (s, CHO).

実施例34
式(1)において、R1及びR2が水素原子、R3がメチル基、R4がトランス-3-(イミダゾ[1,2-a]ピリジン-3-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例1(a)と同様の方法で、工程図10の式(13c)のアリル体の代わりに実施例32(c)の化合物1.03 gを用いて、カルバモイル化合物(工程図14の式(14d)において、R5が水素原子及びR6がエチル基で表される化合物)1.03 gを得た。
Example 34
In the formula (1), R 1 and R 2 are hydrogen atoms, R 3 is a methyl group, R 4 is a trans-3- (imidazo [1,2-a] pyridin-3-yl) -2-propenyl group, R Method for producing a compound wherein 5 is a hydrogen atom and R 6 is an ethyl group
(a) In the same manner as in Example 1 (a), using 1.03 g of the compound of Example 32 (c) instead of the allylic compound of Formula (13c) in Process FIG. 1.03 g of a compound in which R 5 is a hydrogen atom and R 6 is an ethyl group in the formula (14d) was obtained.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1072 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.11(s, SiCH3), 0.12(s, SiCH3), 0.63(dd, 7-H), 0.89(s, SiC(CH3)3), 0.91(d, 8-CH3), 1.12(d, 6”-H), 1.14(t, 3”-OCOCH2CH3), 1.16(t, NHCH2CH3), 1.20(d, 6'-H), 1.47(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.01(s, 9-OCOCH3), 2.06(s, 2'-OCOCH3), 2.29(s, NCH3), 2.42(s, 3'-N(CH3)2), 2.74(dd, 2-H), 3.03(br d, 4-H), 3.20(d, 2”-Heq), 3.52(s, 4-OCH3), 3.62(dd, 5-H),4.11(m, 3-H), 4.39(d, 4”-H), 4.44(dq, 5”-H), 4.48(d, 1'-H), 4.81(d, 1”-H), 4.84(m, 15-H), 4.92(m, CHOSi), 4.95(dd, 2'-H), 5.02(m, 9-H), 5.08(m, CH=CH2), 5.72(m, CH=CH2).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1072 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.11 (s, SiCH 3 ), 0.12 (s, SiCH 3 ), 0.63 (dd, 7-H), 0.89 (s, SiC (CH 3 ) 3 ), 0.91 (d, 8-CH 3 ), 1.12 (d, 6 ”-H), 1.14 (t, 3” -OCOCH 2 CH 3 ), 1.16 (t, NHCH 2 CH 3 ), 1.20 ( d, 6'-H), 1.47 (s, 3 ”-CH 3 ), 1.68 (dd, 2” -Hax), 2.01 (s, 9-OCOCH 3 ), 2.06 (s, 2'-OCOCH 3 ), 2.29 (s, NCH 3 ), 2.42 (s, 3'-N (CH 3 ) 2 ), 2.74 (dd, 2-H), 3.03 (br d, 4-H), 3.20 (d, 2 ”-Heq ), 3.52 (s, 4-OCH 3 ), 3.62 (dd, 5-H), 4.11 (m, 3-H), 4.39 (d, 4 ”-H), 4.44 (dq, 5” -H), 4.48 (d, 1'-H), 4.81 (d, 1 ”-H), 4.84 (m, 15-H), 4.92 (m, CHOSi), 4.95 (dd, 2'-H), 5.02 (m, 9-H), 5.08 (m, CH = CH 2 ), 5.72 (m, CH = CH 2 ).

(b)実施例1(b)と同様の方法で、3-ブロモキノリンの代わりに3-ブロモイミダゾ[1,2-a]ピリジンを用い、また1,4-ジオキサンの代わりにジメチルホルムアミドを用い、実施例34(a)の化合物50 mgから、カップリング化合物(工程図14の式(15d)において、Arがイミダゾ[1,2-a]ピリジン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)を得た。本化合物はマススペクトルを測定後、次の行程に用いた。(b) In the same manner as in Example 1 (b), using 3-bromoimidazo [1,2-a] pyridine instead of 3-bromoquinoline and using dimethylformamide instead of 1,4-dioxane From 50 mg of the compound of Example 34 (a), a coupling compound (in the formula (15d) of Process Diagram 14, Ar is an imidazo [1,2-a] pyridin-3-yl group, R 5 is a hydrogen atom, and A compound in which R 6 is an ethyl group) was obtained. This compound was used in the next step after measuring the mass spectrum.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1188 (M+H)+
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1188 (M + H) +

(c)実施例1(c)と同様の方法で、実施例34(b)の化合物から、脱アセチル化合物(工程図14の式(18d)において、Arがイミダゾ[1,2-a]ピリジン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)を得た。本化合物はマススペクトルを測定後、次の行程に用いた。(c) In the same manner as in Example 1 (c), from the compound of Example 34 (b), the deacetylated compound (Ar in the formula (18d) in process diagram 14 is imidazo [1,2-a] pyridine. 3-yl group, a compound in which R 5 is a hydrogen atom and R 6 is an ethyl group). This compound was used in the next step after measuring the mass spectrum.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1104 (M+H)+
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1104 (M + H) +

(d)実施例2(b)と同様の方法で、実施例34(c)の化合物から、標記化合物3.7 mgを得た。 (d) In the same manner as in Example 2 (b), 3.7 mg of the title compound was obtained from the compound of Example 34 (c).

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 990 (M+H)+
(2)比旋光度:[α]D 18 -50°(c0.31, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.89(d, 8-CH3), 1.09(d, 6”-H), 1.13(t, 3”-OCOCH2CH3), 1.16(t, NHCH2CH3), 1.17(d, 6'-H), 1.46(s, 3”-CH3), 1.69(dd, 2”-Hax), 2.38(s, NCH3), 2.52(s, 3'-N(CH3)2), 2.67(dd, 2-H), 2.94(dd, 6-CH2), 3.20(d, 2”-Heq), 3.38(dd, 2'-H), 3.58(s, 4-OCH3), 3.60(br d, 4-H), 3.85(brd, 5-H), 4.33(d, 1'-H), 4.34(m, 3-H), 4.39(d, 4”-H), 4.45(dq, 5”-H), 4.82(d, 1”-H), 5.10(m, 15-H), 6.45(dt, CH=CH), 6.54(d, CH=CH), 7.16(ddd, imidazopyridine), 7.59(d, imidazopyridine), 7.69(s, imidazopyridine), 8.11(d, imidazopyridine), 9.72(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 990 (M + H) +
(2) Specific rotation: [α] D 18 -50 ° (c0.31, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.89 (d, 8-CH 3 ), 1.09 (d, 6 ”-H), 1.13 (t, 3” -OCOCH 2 CH 3 ) , 1.16 (t, NHCH 2 CH 3 ), 1.17 (d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.69 (dd, 2” -Hax), 2.38 (s, NCH 3 ), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.67 (dd, 2-H), 2.94 (dd, 6-CH 2 ), 3.20 (d, 2 ”-Heq), 3.38 (dd, 2 ' -H), 3.58 (s, 4-OCH 3 ), 3.60 (br d, 4-H), 3.85 (brd, 5-H), 4.33 (d, 1'-H), 4.34 (m, 3-H ), 4.39 (d, 4 ”-H), 4.45 (dq, 5” -H), 4.82 (d, 1 ”-H), 5.10 (m, 15-H), 6.45 (dt, CH = CH), 6.54 (d, CH = CH), 7.16 (ddd, imidazopyridine), 7.59 (d, imidazopyridine), 7.69 (s, imidazopyridine), 8.11 (d, imidazopyridine), 9.72 (s, CHO).

実施例35
式(1)において、R1及びR2が水素原子、R3がメチル基、R4がトランス-3-(ナフタレン-2-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例1(b)と同様の方法で、3-ブロモキノリンの代わりに2-ブロモナフタレンを用い、また1,4-ジオキサンの代わりにジメチルホルムアミドを用い、実施例34(a)の化合物50 mgから、カップリング化合物(工程図14の式(15d)において、Arがナフタレン-2-イル基、R5が水素原子及びR6がエチル基で表される化合物)を得た。本化合物はマススペクトルを測定後、次の行程に用いた。
Example 35
In the formula (1), R 1 and R 2 are hydrogen atoms, R 3 is a methyl group, R 4 is a trans-3- (naphthalen-2-yl) -2-propenyl group, R 5 is a hydrogen atom and R 6 is Method for producing compound represented by ethyl group
(a) In the same manner as in Example 1 (b), 2-bromonaphthalene was used instead of 3-bromoquinoline, and dimethylformamide was used instead of 1,4-dioxane. From 50 mg of the compound, a coupling compound (a compound in which Ar is a naphthalen-2-yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group in the formula (15d) in Process FIG. 14) was obtained. This compound was used in the next step after measuring the mass spectrum.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1198 (M+H)+
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1198 (M + H) +

(b)実施例1(c)と同様の方法で、実施例35(a)の化合物から、脱アセチル化合物(工程図14の式(18d)において、Arがナフタレン-2-イル基、R5が水素原子及びR6がエチル基で表される化合物)を得た。本化合物はマススペクトルを測定後、次の行程に用いた。(b) In the same manner as in Example 1 (c), from the compound of Example 35 (a), a deacetylated compound (in the formula (18d) in process diagram 14, Ar is a naphthalen-2-yl group, R 5 Is a hydrogen atom and R 6 is an ethyl group). This compound was used in the next step after measuring the mass spectrum.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1114 (M+H)+
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1114 (M + H) +

(c)実施例2(b)と同様の方法で、実施例35(b)の化合物から、標記化合物14.8 mgを得た。 (c) In the same manner as in Example 2 (b), 14.8 mg of the title compound was obtained from the compound of Example 35 (b).

本化合物の理化学的性状
(1)マススペクトル(ESMS) : m/z 1000 (M+H)+
(2)比旋光度:[α]D 18 -59°(c1.23, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.89(d, 8-CH3), 1.11(d, 6”-H), 1.13(t, 3”-OCOCH2CH3), 1.16(t, NHCH2CH3), 1.17(d, 6'-H), 1.46(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.31(s, NCH3), 2.51(s, 3'-N(CH3)2), 2.67(dd, 2-H), 2.92(dd, 6-CH2), 3.15(t, 4'-H), 3.20(d, 2”-Heq), 3.39(dd, 2'-H), 3.58(s, 4-OCH3), 3.65(br d, 4-H), 3.87(br d, 5-H), 4.33(d, 1'-H), 4.34(m, 3-H), 4.39(d, 4”-H), 4.45(dq,5”-H), 4.81(d, 1”-H), 5.10(m, 15-H), 6.24(dt, CH=CH), 6.59(d, CH=CH), 7.42(m,naphthalene), 7.54(dd, naphthalene), 7.67(s, naphthalene), 7.76(m, naphthalene), 9.72(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1000 (M + H) +
(2) Specific rotation: [α] D 18 -59 ° (c1.23, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.89 (d, 8-CH 3 ), 1.11 (d, 6 ”-H), 1.13 (t, 3” -OCOCH 2 CH 3 ) , 1.16 (t, NHCH 2 CH 3 ), 1.17 (d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.68 (dd, 2” -Hax), 2.31 (s, NCH 3 ), 2.51 (s, 3'-N (CH 3 ) 2 ), 2.67 (dd, 2-H), 2.92 (dd, 6-CH 2 ), 3.15 (t, 4'-H), 3.20 (d, 2 ” -Heq), 3.39 (dd, 2'-H), 3.58 (s, 4-OCH 3 ), 3.65 (br d, 4-H), 3.87 (br d, 5-H), 4.33 (d, 1 ' -H), 4.34 (m, 3-H), 4.39 (d, 4 "-H), 4.45 (dq, 5" -H), 4.81 (d, 1 "-H), 5.10 (m, 15-H ), 6.24 (dt, CH = CH), 6.59 (d, CH = CH), 7.42 (m, naphthalene), 7.54 (dd, naphthalene), 7.67 (s, naphthalene), 7.76 (m, naphthalene), 9.72 ( s, CHO).

実施例36
式(1)において、R1及びR2が水素原子、R3がメチル基、R4がトランス-3-(イミダゾ[1,2-a]ピリミジン-6-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例1(b)と同様の方法で、3-ブロモキノリンの代わりに6-ブロモイミダゾ[1,2-a]ピリミジンを用い、また1,4-ジオキサンの代わりにジメチルホルムアミドを用い、実施例34(a)の化合物50 mgから、カップリング化合物(工程図14の式(15d)において、Arがイミダゾ[1,2-a]ピリミジン-6-イル基、R5が水素原子及びR6がエチル基で表される化合物)を得た。本化合物はマススペクトルを測定後、次の行程に用いた。
Example 36
In the formula (1), R 1 and R 2 are hydrogen atoms, R 3 is a methyl group, R 4 is a trans-3- (imidazo [1,2-a] pyrimidin-6-yl) -2-propenyl group, R Method for producing a compound wherein 5 is a hydrogen atom and R 6 is an ethyl group
(a) In the same manner as in Example 1 (b), using 6-bromoimidazo [1,2-a] pyrimidine instead of 3-bromoquinoline and using dimethylformamide instead of 1,4-dioxane From 50 mg of the compound of Example 34 (a), a coupling compound (in the formula (15d) of process diagram 14, Ar is an imidazo [1,2-a] pyrimidin-6-yl group, R 5 is a hydrogen atom, and A compound in which R 6 is an ethyl group) was obtained. This compound was used in the next step after measuring the mass spectrum.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1189 (M+H)+
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1189 (M + H) +

(b)実施例1(c)と同様の方法で、実施例36(a)の化合物から、脱アセチル化合物(工程図14の式(18d)において、Arがイミダゾ[1,2-a]ピリミジン-6-イル基、R5が水素原子及びR6がエチル基で表される化合物)を得た。本化合物はマススペクトルを測定後、次の行程に用いた。(b) In the same manner as in Example 1 (c), from the compound of Example 36 (a), the deacetylated compound (in the formula (18d) in process diagram 14, Ar is imidazo [1,2-a] pyrimidine. -6-yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group). This compound was used in the next step after measuring the mass spectrum.

本化合物の理化学的性状
マススペクトル(ESMS):m/z 1105 (M+H)+
Physicochemical mass spectrum (ESMS) of this compound: m / z 1105 (M + H) +

(c)実施例2(b)と同様の方法で、実施例36(b)の化合物から、標記化合物6.4 mgを得た。 (c) In the same manner as in Example 2 (b), 6.4 mg of the title compound was obtained from the compound of Example 36 (b).

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 991 (M+H)+
(2)比旋光度:[α]D 18 -36°(c0.53, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.88(d, 8-CH3), 1.09(d, 6”-H), 1.13(t, 3”-OCOCH2CH3), 1.16(t, NHCH2CH3), 1.17(d, 6'-H), 1.46(s, 3”-CH3), 1.69(dd, 2”-Hax), 2.38(s, NCH3), 2.52(s, 3'-N(CH3)2), 2.73(dd, 2-H), 2.97(dd, 6-CH2), 3.17(t, 4'-H), 3.21(d, 2”-Heq), 3.35(dd, 2'-H), 3.51(br d, 4-H), 3.58(s, 4-OCH3), 3.83(br d, 5-H), 4.34(d, 1'-H), 4.38(m, 3-H), 4.40(m, 4”-H), 4.43(m, 5”-H), 4.82(d, 1”-H), 5.09(m, 15-H), 6.26(dt, CH=CH), 6.39(d, CH=CH), 7.51(d, imidazopyrimidine), 7.75(d, imidazopyrimidine), 8.37(d, imidazopyrimidine), 8.63(d, imidazopyrimidine), 9.69(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 991 (M + H) +
(2) Specific rotation: [α] D 18 -36 ° (c0.53, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.88 (d, 8-CH 3 ), 1.09 (d, 6 ”-H), 1.13 (t, 3” -OCOCH 2 CH 3 ) , 1.16 (t, NHCH 2 CH 3 ), 1.17 (d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.69 (dd, 2” -Hax), 2.38 (s, NCH 3 ), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.73 (dd, 2-H), 2.97 (dd, 6-CH 2 ), 3.17 (t, 4'-H), 3.21 (d, 2 ” -Heq), 3.35 (dd, 2'-H), 3.51 (br d, 4-H), 3.58 (s, 4-OCH 3 ), 3.83 (br d, 5-H), 4.34 (d, 1 ' -H), 4.38 (m, 3-H), 4.40 (m, 4 ”-H), 4.43 (m, 5” -H), 4.82 (d, 1 ”-H), 5.09 (m, 15-H ), 6.26 (dt, CH = CH), 6.39 (d, CH = CH), 7.51 (d, imidazopyrimidine), 7.75 (d, imidazopyrimidine), 8.37 (d, imidazopyrimidine), 8.63 (d, imidazopyrimidine), 9.69 ( s, CHO).

実施例37
式(1)において、R1及びR2が水素原子、R3がメチル基、R4がトランス-3-(6-ジメチルアミノピリジン-3-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例1(b)と同様の方法で、3-ブロモキノリンの代わりに5-ブロモ-2-ジメチルアミノピリジンを用い、また1,4-ジオキサンの代わりにジメチルホルムアミドを用い、実施例34(a)の化合物50 mgから、カップリング化合物(工程図14の式(15d)において、Arが6-ジメチルアミノピリジン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)を得た。本化合物はマススペクトルを測定後、次の行程に用いた。
Example 37
In the formula (1), R 1 and R 2 are hydrogen atoms, R 3 is a methyl group, R 4 is a trans-3- (6-dimethylaminopyridin-3-yl) -2-propenyl group, and R 5 is a hydrogen atom And a method for producing a compound in which R 6 is an ethyl group
(a) In the same manner as in Example 1 (b), except that 5-bromo-2-dimethylaminopyridine was used instead of 3-bromoquinoline and dimethylformamide was used instead of 1,4-dioxane. From 50 mg of the compound of 34 (a), a coupling compound (in the formula (15d) of process diagram 14, Ar is a 6-dimethylaminopyridin-3-yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group) Obtained). This compound was used in the next step after measuring the mass spectrum.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1192 (M+H)+
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1192 (M + H) +

(b)実施例1(c)と同様の方法で、実施例37(a)の化合物から、脱アセチル化合物(工程図14の式(18d)において、Arが6-ジメチルアミノピリジン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)を得た。本化合物はマススペクトルを測定後、次の行程に用いた。(b) In the same manner as in Example 1 (c), from the compound of Example 37 (a), the deacetylated compound (Ar in formula (18d) in process diagram 14 is 6-dimethylaminopyridin-3-yl) Group, a compound in which R 5 is a hydrogen atom and R 6 is an ethyl group). This compound was used in the next step after measuring the mass spectrum.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1108 (M+H)+
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1108 (M + H) +

(c)実施例2(b)と同様の方法で、実施例37(b)の化合物から、標記化合物4.9 mgを得た。 (c) In the same manner as in Example 2 (b), 4.9 mg of the title compound was obtained from the compound of Example 37 (b).

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 994 (M+H)+
(2)比旋光度:[α]D 18 -67°(c0.41, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.89(d, 8-CH3), 1.10(d, 6”-H), 1.13(t, 3”-OCOCH2CH3), 1.16(t, NHCH2CH3), 1.17(d, 6'-H), 1.46(s, 3”-CH3), 1.69(dd, 2”-Hax), 2.40(s, NCH3), 2.52(s, 3'-N(CH3)2), 2.66(dd, 2-H), 2.93 (dd, 6-CH2), 3.07(s, pyridine-N(CH3)2), 3.16(t, 4'-H), 3.20(d, 2”-Heq), 3.40(dd, 2'-H), 3.59(s, 4-OCH3), 3.63(br d, 4-H), 3.85(br d, 5-H), 4.29(m, 3-H), 4.34 (d, 1'-H), 4.39(d, 4”-H), 4.44(dq, 5”-H), 4.81(d, 1”-H), 5.02(m, 15-H), 5.87(dt, CH=CH), 6.29(d, CH=CH), 6.46(d, pyridine), 7.50(dd, pyridine), 8.05(d, pyridine), 9.74(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 994 (M + H) +
(2) Specific rotation: [α] D 18 -67 ° (c0.41, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.89 (d, 8-CH 3 ), 1.10 (d, 6 ”-H), 1.13 (t, 3” -OCOCH 2 CH 3 ) , 1.16 (t, NHCH 2 CH 3 ), 1.17 (d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.69 (dd, 2” -Hax), 2.40 (s, NCH 3 ), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.66 (dd, 2-H), 2.93 (dd, 6-CH 2 ), 3.07 (s, pyridine-N (CH 3 ) 2 ), 3.16 ( t, 4'-H), 3.20 (d, 2 ''-Heq), 3.40 (dd, 2'-H), 3.59 (s, 4-OCH 3 ), 3.63 (br d, 4-H), 3.85 ( br d, 5-H), 4.29 (m, 3-H), 4.34 (d, 1'-H), 4.39 (d, 4 ''-H), 4.44 (dq, 5 ''-H), 4.81 (d , 1 ”-H), 5.02 (m, 15-H), 5.87 (dt, CH = CH), 6.29 (d, CH = CH), 6.46 (d, pyridine), 7.50 (dd, pyridine), 8.05 ( d, pyridine), 9.74 (s, CHO).

実施例38
式(1)において、R1及びR2が水素原子、R3がメチル基、R4がトランス-3-(6-アミノ-5-メチルピリジン-3-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例1(b)と同様の方法で、3-ブロモキノリンの代わりに5-ブロモ-3-メチルピリジン-2-アミンを用い、また1,4-ジオキサンの代わりにジメチルホルムアミドを用い、実施例34(a)の化合物50 mgから、カップリング化合物(工程図14の式(15d)において、Arが6-アミノ-5-メチルピリジン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)を得た。本化合物はマススペクトルを測定後、次の行程に用いた。
Example 38
In the formula (1), R 1 and R 2 are hydrogen atoms, R 3 is a methyl group, R 4 is a trans-3- (6-amino-5-methylpyridin-3-yl) -2-propenyl group, R 5 For producing a compound in which R is a hydrogen atom and R 6 is an ethyl group
(a) In the same manner as in Example 1 (b), 5-bromo-3-methylpyridin-2-amine was used instead of 3-bromoquinoline, and dimethylformamide was used instead of 1,4-dioxane. From 50 mg of the compound of Example 34 (a), a coupling compound (in the formula (15d) of process diagram 14, Ar is a 6-amino-5-methylpyridin-3-yl group, R 5 is a hydrogen atom and R A compound in which 6 is an ethyl group) was obtained. This compound was used in the next step after measuring the mass spectrum.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1178 (M+H)+
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1178 (M + H) +

(b)実施例1(c)と同様の方法で、実施例38(a)の化合物から、脱アセチル化合物(工程図14の式(18d)において、Arが6-アミノ-5-メチルピリジン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)を得た。本化合物はマススペクトルを測定後、次の行程に用いた。(b) In the same manner as in Example 1 (c), from the compound of Example 38 (a), a deacetylated compound (in the formula (18d) in process diagram 14, Ar is 6-amino-5-methylpyridine- 3-yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group). This compound was used in the next step after measuring the mass spectrum.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1094 (M+H)+
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1094 (M + H) +

(c)実施例2(b)と同様の方法で、実施例38(b)の化合物から、標記化合物3.1 mgを得た。 (c) In the same manner as in Example 2 (b), 3.1 mg of the title compound was obtained from the compound of Example 38 (b).

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 980 (M+H)+
(2)比旋光度:[α]D 19 -64°(c0 .258, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.89(d, 8-CH3), 1.10(d, 6”-H), 1.13(t, 3”-OCOCH2CH3), 1.16(t, NHCH2CH3), 1.17(d, 6'-H), 1.46(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.12(s, pyridine-CH3), 2.36(s, NCH3), 2.52(s, 3'-N(CH3)2), 2.67(dd, 2-H), 2.93(dd, 6-CH2), 3.16(t, 4'-H), 3.21(d, 2”-Heq), 3.39(dd, 2'-H), 3.59(s, 4-OCH3), 3.63(br d, 4-H), 3.86(br d, 5-H), 4.33(d, 1'-H), 4.34(m, 3-H), 4.40(d, 4”-H), 4.44(dq, 5”-H), 4.81(d, 1”-H), 5.03(m, 15-H), 5.92(dt, CH=CH), 6.28(d, CH=CH), 7.34(d, pyridine), 7.83(d, pyridine), 9.73(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 980 (M + H) +
(2) Specific rotation: [α] D 19 -64 ° (c0.258, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.89 (d, 8-CH 3 ), 1.10 (d, 6 ”-H), 1.13 (t, 3” -OCOCH 2 CH 3 ) , 1.16 (t, NHCH 2 CH 3 ), 1.17 (d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.68 (dd, 2” -Hax), 2.12 (s, pyridine-CH 3 ), 2.36 (s, NCH 3 ), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.67 (dd, 2-H), 2.93 (dd, 6-CH 2 ), 3.16 (t, 4 ' -H), 3.21 (d, 2 ”-Heq), 3.39 (dd, 2'-H), 3.59 (s, 4-OCH 3 ), 3.63 (br d, 4-H), 3.86 (br d, 5 -H), 4.33 (d, 1'-H), 4.34 (m, 3-H), 4.40 (d, 4 "-H), 4.44 (dq, 5" -H), 4.81 (d, 1 "- H), 5.03 (m, 15-H), 5.92 (dt, CH = CH), 6.28 (d, CH = CH), 7.34 (d, pyridine), 7.83 (d, pyridine), 9.73 (s, CHO) .

実施例39
式(1)において、R1及びR2が水素原子、R3がメチル基、R4がトランス-3-(6-アミノピリジン-3-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例1(b)と同様の方法で、3-ブロモキノリンの代わりに2-アミノ-5-ブロモピリジンを用い、また1,4-ジオキサンの代わりにジメチルホルムアミドを用い、実施例34(a)の化合物85.7 mgから、カップリング化合物(工程図14の式(15d)において、Arが6-アミノピリジン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)を得た。本化合物はマススペクトルを測定後、次の行程に用いた。
Example 39
In the formula (1), R 1 and R 2 are hydrogen atoms, R 3 is a methyl group, R 4 is a trans-3- (6-aminopyridin-3-yl) -2-propenyl group, R 5 is a hydrogen atom and Method for producing compound in which R 6 is represented by ethyl group
(a) In the same manner as in Example 1 (b), except that 2-amino-5-bromopyridine was used instead of 3-bromoquinoline and dimethylformamide was used instead of 1,4-dioxane, Example 34 From 85.7 mg of the compound of (a), a coupling compound (in the formula (15d) of process diagram 14, Ar is a 6-aminopyridin-3-yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group) Compound) was obtained. This compound was used in the next step after measuring the mass spectrum.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1164 (M+H)+
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1164 (M + H) +

(b)実施例1(c)と同様の方法で、実施例39(a)の化合物から、脱アセチル化合物(工程図14の式(18d)において、Arが6-アミノピリジン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)を得た。本化合物はマススペクトルを測定後、次の行程に用いた。(b) In the same manner as in Example 1 (c), from the compound of Example 39 (a), the deacetylated compound (in the formula (18d) in process diagram 14, Ar is a 6-aminopyridin-3-yl group) , R 5 is a hydrogen atom and R 6 is an ethyl group). This compound was used in the next step after measuring the mass spectrum.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1080 (M+H)+
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1080 (M + H) +

(c)実施例2(b)と同様の方法で、実施例39(b)の化合物から、標記化合物5.7 mgを得た。 (c) In the same manner as in Example 2 (b), 5.7 mg of the title compound was obtained from the compound of Example 39 (b).

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 966 (M+H)+
(2)比旋光度:[α]D 19 -69°(c0.48, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.89(d, 8-CH3), 1.13(t, 3”-OCOCH2CH3), 1.16(t, NHCH2CH3), 1.17(d, 6'-H), 1.46(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.33(s, NCH3), 2.51(s, 3'-N(CH3)2), 2.66(dd, 2-H), 2.93(dd, 6-CH2), 3.16(t, 4'-H), 3.20(d, 2”-Heq), 3.39(dd, 2'-H), 3.59(s, 4-OCH3), 3.63(br d, 4-H), 3.86(br d, 5-H), 4.34(d, 1'-H), 4.34(m, 3-H), 4.39(d, 4”-H), 4.44(dq, 5”-H), 4.81(d,1”-H), 5.12(m, 15-H), 5.92(dt, CH=CH), 6.29(d, CH=CH), 6.45(d, pyridine), 7.48(dd, pyridine), 7.96(d, pyridine), 9.73(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 966 (M + H) +
(2) Specific rotation: [α] D 19 -69 ° (c0.48, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.89 (d, 8-CH 3 ), 1.13 (t, 3 ″ -OCOCH 2 CH 3 ), 1.16 (t, NHCH 2 CH 3 ) , 1.17 (d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.68 (dd, 2” -Hax), 2.33 (s, NCH 3 ), 2.51 (s, 3'-N (CH 3 ) 2 ), 2.66 (dd, 2-H), 2.93 (dd, 6-CH 2 ), 3.16 (t, 4'-H), 3.20 (d, 2 ”-Heq), 3.39 (dd, 2 ' -H), 3.59 (s, 4-OCH 3 ), 3.63 (br d, 4-H), 3.86 (br d, 5-H), 4.34 (d, 1'-H), 4.34 (m, 3- H), 4.39 (d, 4 ”-H), 4.44 (dq, 5” -H), 4.81 (d, 1 ”-H), 5.12 (m, 15-H), 5.92 (dt, CH = CH) , 6.29 (d, CH = CH), 6.45 (d, pyridine), 7.48 (dd, pyridine), 7.96 (d, pyridine), 9.73 (s, CHO).

実施例40
式(1)において、R1及びR2が水素原子、R3がメチル基、R4がトランス-3-(2-アミノピリジン-3-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例1(b)と同様の方法で、3-ブロモキノリンの代わりに2-アミノ-3-ブロモピリジンを用い、また1,4-ジオキサンの代わりにジメチルホルムアミドを用い、実施例34(a)の化合物50 mgから、カップリング化合物(工程図14の式(15d)において、Arが2-アミノピリジン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)を得た。本化合物はマススペクトルを測定後、次の行程に用いた。
Example 40
In the formula (1), R 1 and R 2 are hydrogen atoms, R 3 is a methyl group, R 4 is a trans-3- (2-aminopyridin-3-yl) -2-propenyl group, R 5 is a hydrogen atom and Method for producing compound in which R 6 is represented by ethyl group
(a) In the same manner as in Example 1 (b), except that 2-amino-3-bromopyridine was used instead of 3-bromoquinoline and dimethylformamide was used instead of 1,4-dioxane, Example 34 From 50 mg of the compound of (a), a coupling compound (in the formula (15d) in Process Diagram 14, Ar is a 2-aminopyridin-3-yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group) Compound) was obtained. This compound was used in the next step after measuring the mass spectrum.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1164 (M+H)+
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1164 (M + H) +

(b)実施例1(c)と同様の方法で、実施例40(a)の化合物から、脱アセチル化合物(工程図14の式(18d)において、Arが2-アミノピリジン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)を得た。本化合物はマススペクトルを測定後、次の行程に用いた。(b) In the same manner as in Example 1 (c), from the compound of Example 40 (a), the deacetylated compound (in the formula (18d) in Process Diagram 14, Ar is a 2-aminopyridin-3-yl group) , R 5 is a hydrogen atom and R 6 is an ethyl group). This compound was used in the next step after measuring the mass spectrum.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1080 (M+H)+
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1080 (M + H) +

(c)実施例2(b)と同様の方法で、実施例40(b)の化合物から、標記化合物1.3 mgを得た。 (c) In the same manner as in Example 2 (b), 1.3 mg of the title compound was obtained from the compound of Example 40 (b).

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 966 (M+H)+
(2)比旋光度:[α]D 20 -35°(c0.11, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(p pm):0.90(d, 8-CH3), 1.10(d, 6”-H), 1.13(t, 3”-OCOCH2CH3), 1.16(t, NHCH2CH3), 1.17(d, 6'-H), 1.46(s, 3”-CH3), 1.69(dd, 2”-Hax), 2.53(s, 3'-N(CH3)2), 2.96(dd, 6-CH2), 3.21(d, 2”-Heq), 3.38(dd, 2'-H), 3.57(s, 4-OCH3), 3.59(br d, 4-H), 3.83(br d, 5-H), 4.35(d, 1'-H), 4.35(m, 3-H), 4.40(d, 4”-H), 4.45(dq, 5”-H), 4.83(d, 1”-H), 5.10(m, 15-H), 6.02(dt, CH=CH), 6.35(d, CH=CH), 6.63(dd, pyridine), 7.40(dd, pyridine), 7.94(dd, pyridine), 9.74(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 966 (M + H) +
(2) Specific rotation: [α] D 20 -35 ° (c0.11, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.90 (d, 8-CH 3 ), 1.10 (d, 6 ”-H), 1.13 (t, 3” -OCOCH 2 CH 3 ), 1.16 (t, NHCH 2 CH 3 ), 1.17 (d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.69 (dd, 2” -Hax), 2.53 (s, 3'- N (CH 3 ) 2 ), 2.96 (dd, 6-CH 2 ), 3.21 (d, 2 ”-Heq), 3.38 (dd, 2'-H), 3.57 (s, 4-OCH 3 ), 3.59 ( br d, 4-H), 3.83 (br d, 5-H), 4.35 (d, 1'-H), 4.35 (m, 3-H), 4.40 (d, 4 ”-H), 4.45 (dq , 5 ”-H), 4.83 (d, 1” -H), 5.10 (m, 15-H), 6.02 (dt, CH = CH), 6.35 (d, CH = CH), 6.63 (dd, pyridine) , 7.40 (dd, pyridine), 7.94 (dd, pyridine), 9.74 (s, CHO).

実施例41
式(1)において、R1及びR2が水素原子、R3がメチル基、R4がトランス-3-(5-アミノピリジン-3-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例1(b)と同様の方法で、3-ブロモキノリンの代わりに参考例6の化合物を用い、また1,4-ジオキサンの代わりにジメチルホルムアミドを用い、実施例34(a)の化合物50 mgから、カップリング化合物(工程図14の式(15d)において、Arが5-アミノピリジン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)を得た。本化合物はマススペクトルを測定後、次の行程に用いた。
Example 41
In the formula (1), R 1 and R 2 are hydrogen atoms, R 3 is a methyl group, R 4 is a trans-3- (5-aminopyridin-3-yl) -2-propenyl group, R 5 is a hydrogen atom and Method for producing compound in which R 6 is represented by ethyl group
(a) In the same manner as in Example 1 (b), the compound of Reference Example 6 was used instead of 3-bromoquinoline, and dimethylformamide was used instead of 1,4-dioxane. Example 34 (a) From 50 mg of the above compound, a coupling compound (a compound in which Ar is a 5-aminopyridin-3-yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group in the formula (15d) in Step 14) Obtained. This compound was used in the next step after measuring the mass spectrum.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1164 (M+H)+
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1164 (M + H) +

(b)実施例1(c)と同様の方法で、実施例41(a)の化合物から、脱アセチル化合物(工程図14の式(18d)において、Arが5-アミノピリジン-3-イル基、R5が水素原子及びR6がエチル基で表される化合物)を得た。本化合物はマススペクトルを測定後、次の行程に用いた。(b) In the same manner as in Example 1 (c), from the compound of Example 41 (a), the deacetylated compound (in the formula (18d) of process diagram 14, Ar is a 5-aminopyridin-3-yl group) , R 5 is a hydrogen atom and R 6 is an ethyl group). This compound was used in the next step after measuring the mass spectrum.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1080 (M+H)+
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1080 (M + H) +

(c)実施例2(b)と同様の方法で、実施例41(b)の化合物から、標記化合物2.2 mgを得た。 (c) In the same manner as in Example 2 (b), 2.2 mg of the title compound was obtained from the compound of Example 41 (b).

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 966 (M+H)+
(2)比旋光度:[α]D 20 -47°(c0.18, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm) 0.89(d, 8-CH3), 1.11(d, 6”-H), 1.13(t, 3”-OCOCH2CH3), 1.16(t, NHCH2CH3), 1.17(d, 6'-H), 1.46(s, 3”-CH3), 1.69(dd, 2”-Hax), 2.37(s, NCH3), 2.52(s, 3'-N(CH3)2), 2.66(dd, 2-H), 2.95(dd, 6-CH2), 3.16(t, 4'-H), 3.21(d, 2”-Heq), 3.38(dd, 2'-H), 3.59(s, 4-OCH3), 3.70(br d, 4-H), 3.86(br d, 5-H), 4.34(d, 1'-H), 4.34(m, 3-H), 4.40(d, 4”-H), 4.45(dq, 5”-H), 4.82(d, 1”-H), 5.05(m, 15-H), 6.16(dt, CH=CH), 6.34(d, CH=CH), 6.98(t, pyridine), 7.93(d, pyridine), 7.94(d, pyridine), 9.73(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 966 (M + H) +
(2) Specific rotation: [α] D 20 -47 ° (c0.18, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm) 0.89 (d, 8-CH 3 ), 1.11 (d, 6 ”-H), 1.13 (t, 3” -OCOCH 2 CH 3 ), 1.16 (t, NHCH 2 CH 3 ), 1.17 (d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.69 (dd, 2” -Hax), 2.37 (s, NCH 3 ), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.66 (dd, 2-H), 2.95 (dd, 6-CH 2 ), 3.16 (t, 4'-H), 3.21 (d, 2 ”- Heq), 3.38 (dd, 2'-H), 3.59 (s, 4-OCH 3 ), 3.70 (br d, 4-H), 3.86 (br d, 5-H), 4.34 (d, 1'- H), 4.34 (m, 3-H), 4.40 (d, 4 ”-H), 4.45 (dq, 5” -H), 4.82 (d, 1 ”-H), 5.05 (m, 15-H) , 6.16 (dt, CH = CH), 6.34 (d, CH = CH), 6.98 (t, pyridine), 7.93 (d, pyridine), 7.94 (d, pyridine), 9.73 (s, CHO).

実施例42
式(1)において、R1及びR2が水素原子、R3がメチル基、R4がトランス-3-(1-アミノイソキノリン-4-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例1(b)と同様の方法で、3-ブロモキノリンの代わりに参考例7の化合物を用い、また1,4-ジオキサンの代わりにジメチルホルムアミドを用い、実施例34(a)の化合物212 mgから、2-トリメチルシリルエトキシカルボニル基が除去されたカップリング化合物A(工程図14の式(15d)において、Arが1-アミノイソキノリン-4-イル基、R5が水素原子及びR6がエチル基で表される化合物)18.4 mg、及び2-トリメチルシリルエトキシカルボニル基が除去され、アセチル基が導入されたカップリング化合物B(工程図14の式(15d)において、Arが1-アセチルアミノイソキノリン-4-イル基、R5が水素原子及びR6がエチル基で表される化合物)44.5 mgを得た。化合物Bは、分子量のみ確認後、そのまま次の行程に用いた。
Example 42
In the formula (1), R 1 and R 2 are hydrogen atoms, R 3 is a methyl group, R 4 is a trans-3- (1-aminoisoquinolin-4-yl) -2-propenyl group, R 5 is a hydrogen atom and Method for producing compound in which R 6 is represented by ethyl group
(a) In the same manner as in Example 1 (b), the compound of Reference Example 7 was used instead of 3-bromoquinoline, and dimethylformamide was used instead of 1,4-dioxane. Example 34 (a) Coupling compound A in which 2-trimethylsilylethoxycarbonyl group was removed from 212 mg of the above compound (in formula (15d) of process diagram 14, Ar is a 1-aminoisoquinolin-4-yl group, R 5 is a hydrogen atom and R 18.4 mg of a compound in which 6 is an ethyl group) and coupling compound B in which 2-trimethylsilylethoxycarbonyl group is removed and an acetyl group is introduced (in the formula (15d) of process diagram 14, Ar is 1-acetyl) 44.5 mg of a compound in which aminoisoquinolin-4-yl group, R 5 is a hydrogen atom and R 6 is an ethyl group. Compound B was used in the next step as it was after confirming only the molecular weight.

化合物Aの理化学的性状
(1)マススペクトル(ESMS):m/z 1214 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.08(s, SiCH3), 0.09(s, SiCH3), 0.88(s, SiC(CH3)3), 0.91(d, 8-CH3), 1.11(d, 6”-H), 1.13(t, 3”-OCOCH2CH3), 1.17(t, NHCH2CH3), 1.19(d, 6'-H), 1.46(s, 3”-CH3), 1.67(dd, 2”-Hax), 2.01(s, 9-OCOCH3), 2.05(s, 2'-OCOCH3), 2.28(s, NCH3), 2.40(s, 3'-N(CH3)2), 2.61(dd, 2-H), 3.06(br d, 4-H), 3.12(t, 4'-H), 3.19(d, 2”-Heq), 3.51(s, 4-OCH3), 3.61(dd, 5-H), 4.41(m, 4”-H), 4.41(m, 5”-H), 4.47(d, 1'-H), 4.79(d, 1”-H), 4.95(dd, 2'-H), 5.01(m, 9-H), 5.06(br dd, 3-H), 5.38(m, 15-H), 5.99(dt, CH=CH), 6.86(d, CH=CH), 7.51(ddd, isoquinoline), 7.67(ddd, isoquinoline), 7.82(br d, isoquinoline), 7.92(br d, isoquinoline), 7.96(s, isoquinoline).
Physicochemical properties of Compound A (1) Mass spectrum (ESMS): m / z 1214 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.08 (s, SiCH 3 ), 0.09 (s, SiCH 3 ), 0.88 (s, SiC (CH 3 ) 3 ), 0.91 (d, 8-CH 3 ), 1.11 (d, 6 ”-H), 1.13 (t, 3” -OCOCH 2 CH 3 ), 1.17 (t, NHCH 2 CH 3 ), 1.19 (d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.67 (dd, 2” -Hax), 2.01 (s, 9-OCOCH 3 ), 2.05 (s, 2'-OCOCH 3 ), 2.28 (s, NCH 3 ), 2.40 (s, 3'-N (CH 3 ) 2 ), 2.61 (dd, 2-H), 3.06 (br d, 4-H), 3.12 (t, 4'-H), 3.19 (d, 2 ”- Heq), 3.51 (s, 4-OCH 3 ), 3.61 (dd, 5-H), 4.41 (m, 4 ”-H), 4.41 (m, 5” -H), 4.47 (d, 1'-H ), 4.79 (d, 1 ”-H), 4.95 (dd, 2'-H), 5.01 (m, 9-H), 5.06 (br dd, 3-H), 5.38 (m, 15-H), 5.99 (dt, CH = CH), 6.86 (d, CH = CH), 7.51 (ddd, isoquinoline), 7.67 (ddd, isoquinoline), 7.82 (br d, isoquinoline), 7.92 (br d, isoquinoline), 7.96 ( s, isoquinoline).

化合物Bの理化学的性状
(1)マススペクトル(ESMS):m/z 1256 (M+H)+
Physicochemical properties of compound B (1) Mass spectrum (ESMS): m / z 1256 (M + H) +

(b)実施例1(c)と同様の方法で、実施例42(a)の化合物A18.4 mgから、脱アセチル化合物(工程図14の式(18d)において、Arが1-アミノイソキノリン-4-イル基、R5が水素原子及びR6がエチル基で表される化合物)5.1 mgを得た。(b) In the same manner as in Example 1 (c), from compound A18.4 mg of Example 42 (a), a deacetylated compound (in the formula (18d) of process diagram 14, Ar is 1-aminoisoquinoline- 5.1 mg of a compound in which 4-yl group, R 5 is a hydrogen atom and R 6 is an ethyl group.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1130 (M+H)+
(2)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.09(s, Si(CH3)2), 0.87(s, SiC(CH3)3), 0.93(d, 8-CH3), 1.11(d, 6”-H), 1.13(t, 3”-OCOCH2CH3), 1.17(t, NHCH2CH3),1.21(d, 6'-H), 1.46(s, 3”-CH3), 1.69(dd, 2”-Hax), 2.45(s, NCH3), 2.52(s, 3'-N(CH3)2), 2.58(dd, 2-H), 2.81(dd, 2-H), 3.15(t, 4'-H), 3.20(d, 2”-Heq), 3.41(dd, 2'-H), 3.54(s, 4-OCH3), 3.69(dd, 5-H), 4.12(br dd, 3-H), 4.29(d, 1'-H), 4.41(d, 4”-H), 4.45(dq, 5”-H), 4.82(d, 1”-H), 5.39(m, 15-H), 6.00(dt, CH=CH), 6.87(d, CH=CH), 7.52(ddd, isoquinoline), 7.68(ddd, isoquinoline), 7.82(br d, isoquinoline), 7.93(br d, isoquinoline), 7.96(s, isoquinoline).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1130 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.09 (s, Si (CH 3 ) 2 ), 0.87 (s, SiC (CH 3 ) 3 ), 0.93 (d, 8-CH 3 ), 1.11 (d, 6 ”-H), 1.13 (t, 3” -OCOCH 2 CH 3 ), 1.17 (t, NHCH 2 CH 3 ), 1.21 (d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.69 (dd, 2” -Hax), 2.45 (s, NCH 3 ), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.58 (dd, 2-H), 2.81 ( dd, 2-H), 3.15 (t, 4'-H), 3.20 (d, 2 ”-Heq), 3.41 (dd, 2'-H), 3.54 (s, 4-OCH 3 ), 3.69 (dd , 5-H), 4.12 (br dd, 3-H), 4.29 (d, 1'-H), 4.41 (d, 4 ''-H), 4.45 (dq, 5 ''-H), 4.82 (d, 1 ”-H), 5.39 (m, 15-H), 6.00 (dt, CH = CH), 6.87 (d, CH = CH), 7.52 (ddd, isoquinoline), 7.68 (ddd, isoquinoline), 7.82 (br d, isoquinoline), 7.93 (br d, isoquinoline), 7.96 (s, isoquinoline).

(c)実施例2(b)と同様の方法で、実施例42(b)の化合物5.1 mgから、標記化合物3.6 mgを得た。 (c) In the same manner as in Example 2 (b), 3.6 mg of the title compound was obtained from 5.1 mg of the compound of Example 42 (b).

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1016 (M+H)+
(2)比旋光度:[α]D 24 -44°(c0.3, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.89(d, 8-CH3), 1.12(d, 6”-H), 1.13(t, 3”-OCOCH2CH3), 1.16(t, NHCH2CH3), 1.17(d, 6'-H), 1.46(s, 3”-CH3), 1.69(dd, 2”-Hax), 2.32(s, NCH3), 2.52(s, 3'-N(CH3)2), 2.67(dd, 2-H), 2.92(dd, 6-CH2), 3.16(t, 4'-H), 3.21(d, 2”-Heq), 3.41(dd, 2'-H), 3.59(s, 4-OCH3), 3.67(br d, 4-H), 3.88(br d, 5-H), 4.34(d, 1'-H), 4.40(d, 4”-H), 4.45(dq, 5”-H), 4.81(d, 1”-H), 5.11(m, 15-H), 6.01(dt, CH=CH), 6.86(d, CH=CH), 7.51(ddd, isoquinoline), 7.67(ddd, isoquinoline), 7.81(br d, isoquinoline), 7.93(br d, isoquinoline), 7.97(s, isoquinoline), 9.73(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1016 (M + H) +
(2) Specific rotation: [α] D 24 -44 ° (c0.3, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.89 (d, 8-CH 3 ), 1.12 (d, 6 ”-H), 1.13 (t, 3” -OCOCH 2 CH 3 ) , 1.16 (t, NHCH 2 CH 3 ), 1.17 (d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.69 (dd, 2” -Hax), 2.32 (s, NCH 3 ), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.67 (dd, 2-H), 2.92 (dd, 6-CH 2 ), 3.16 (t, 4'-H), 3.21 (d, 2 ” -Heq), 3.41 (dd, 2'-H), 3.59 (s, 4-OCH 3 ), 3.67 (br d, 4-H), 3.88 (br d, 5-H), 4.34 (d, 1 ' -H), 4.40 (d, 4 "-H), 4.45 (dq, 5" -H), 4.81 (d, 1 "-H), 5.11 (m, 15-H), 6.01 (dt, CH = CH ), 6.86 (d, CH = CH), 7.51 (ddd, isoquinoline), 7.67 (ddd, isoquinoline), 7.81 (br d, isoquinoline), 7.93 (br d, isoquinoline), 7.97 (s, isoquinoline), 9.73 ( s, CHO).

実施例43
式(1)において、R1及び、R2が水素原子、R3がメチル基、R4が3-(1-アセチルアミノイソキノリン-4-イル)プロピル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法(a)実施例1(c)と同様の方法で、実施例42(a)の化合物B44.5 mgから、脱アセチル化合物(工程図14の式(18d)において、Arが1-アセチルアミノイソキノリン-4-イル基、R5が水素原子及びR6がエチル基で表される化合物)21.1 mgを得た。本化合物はマススペクトルを測定後、次の行程に用いた。
Example 43
In the formula (1), R 1 and R 2 are hydrogen atoms, R 3 is a methyl group, R 4 is a 3- (1-acetylaminoisoquinolin-4-yl) propyl group, R 5 is a hydrogen atom and R 6 is Production method of compound represented by ethyl group (a) In the same manner as in Example 1 (c), from the compound B44.5 mg of Example 42 (a), the deacetylated compound (formula (18d ), Ar is a 1-acetylaminoisoquinolin-4-yl group, R 5 is a hydrogen atom, and R 6 is an ethyl group) 21.1 mg. This compound was used in the next step after measuring the mass spectrum.

本化合物の理化学的性状
(1)マススペクトル(ESMS):m/z 1172 (M+H)+
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1172 (M + H) +

(b)実施例2(b)と同様の方法で、実施例43(a)の化合物21.1 mgから、脱シリルアセタール化合物(式(1)において、R1及びR2が水素原子、R3がメチル基、R4がトランス-3-(1-アセチルアミノイソキノリン-4-イル)-2-プロぺニル基、R5が水素原子及びR6がエチル基で表される化合物)を得た。この化合物を精製することなく、実施例25(a)と同様の方法で、溶媒として1,4-ジオキサン−水(1:1)を用い、標記化合物4.3 mgを得た。(b) In the same manner as in Example 2 (b), from the compound 21.1 mg of Example 43 (a), desilylated acetal compound (in formula (1), R 1 and R 2 are hydrogen atoms, R 3 is A methyl group, a compound in which R 4 is a trans-3- (1-acetylaminoisoquinolin-4-yl) -2-propenyl group, R 5 is a hydrogen atom and R 6 is an ethyl group) was obtained. Without purifying this compound, 4.3 mg of the title compound was obtained in the same manner as in Example 25 (a) using 1,4-dioxane-water (1: 1) as a solvent.

本化合物の理化学的性状
(1)マススペクトル(ESMS): m/z 1060 (M+H)+
(2)比旋光度:[α]D 23 -55°(c0.36, CHCl3)
(3)1H NMRスペクトル(300MHz, CDCl3) δ(ppm):0.89(d, 8-CH3), 1.11(d, 6”-H), 1.13(t, 3”-OCOCH2CH3), 1.16(t, NHCH2CH3), 1.17(d, 6'-H), 1.46(s, 3”-CH3), 1.69(dd, 2”-Hax), 2.28(s, NHCOCH3), 2.31(s, NCH3), 2.53(s, 3'-N(CH3)2), 2.65(d, 2-H), 2.94(dd, 6-CH2), 3.20(d, 2”-Heq), 3.40(dd, 2'-H), 3.62(s, 4-OCH3), 3.63(brd, 4-H), 3.87(br d, 5-H), 4.29(m, 3-H), 4.34(d, 1'-H), 4.40(d, 4”-H), 4.44(dq, 5”-H), 4.82(d, 1”-H), 5.02(m, 15-H), 7.60(dt, isoquinoline), 7.74(dt, isoquinoline), 7.94(d, isoquinoline), 8.02(m, isoquinoline), 9.74(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (ESMS): m / z 1060 (M + H) +
(2) Specific rotation: [α] D 23 -55 ° (c0.36, CHCl 3 )
(3) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.89 (d, 8-CH 3 ), 1.11 (d, 6 ”-H), 1.13 (t, 3” -OCOCH 2 CH 3 ) , 1.16 (t, NHCH 2 CH 3 ), 1.17 (d, 6'-H), 1.46 (s, 3 ”-CH 3 ), 1.69 (dd, 2” -Hax), 2.28 (s, NHCOCH 3 ), 2.31 (s, NCH 3 ), 2.53 (s, 3'-N (CH 3 ) 2 ), 2.65 (d, 2-H), 2.94 (dd, 6-CH 2 ), 3.20 (d, 2 ”-Heq ), 3.40 (dd, 2'-H), 3.62 (s, 4-OCH 3 ), 3.63 (brd, 4-H), 3.87 (br d, 5-H), 4.29 (m, 3-H), 4.34 (d, 1'-H), 4.40 (d, 4 "-H), 4.44 (dq, 5" -H), 4.82 (d, 1 "-H), 5.02 (m, 15-H), 7.60 (dt, isoquinoline), 7.74 (dt, isoquinoline), 7.94 (d, isoquinoline), 8.02 (m, isoquinoline), 9.74 (s, CHO).

実施例44
式(1)において、R1、R2、及びR5が水素原子、R3がメチル基、R4が2−プロペニル基及びR6がエチル基で表される化合物の製造方法
(a)実施例1(c)と同様の方法で、実施例34(a)の化合物40.4 mgから、脱アセチル化合物(工程図14の式(18d)において、Arが水素原子、R5が水素原子及びR6がエチル基で表される化合物)29.9 mgを得た。
Example 44
A method for producing a compound represented by the formula (1), wherein R 1 , R 2 and R 5 are hydrogen atoms, R 3 is a methyl group, R 4 is a 2-propenyl group and R 6 is an ethyl group
(a) In the same manner as in Example 1 (c), from the compound 40.4 mg of Example 34 (a), a deacetylated compound (Ar in formula (18d) in process diagram 14, Ar is a hydrogen atom, R 5 is a hydrogen atom) 29.9 mg of a compound in which atoms and R 6 are represented by an ethyl group.

本化合物の理化学的性状
(1)マススペクトル(FAB) :m/z 988 (M+H)+
(2)1H NMRスペクトル(300 MHz, CDCl3) δ(ppm):0.11(s, Si(CH3)2), 0.89(s, SiC(CH3)3), 0.95(d, 8-CH3), 1.12(t, 3”-OCOCH2CH3), 1.13(d, 6”-H), 1.17(t, NHCH2CH3), 1.20(d, 6'-H), 1.47(s, 3”-CH3), 1.70(dd, 2”-Hax), 1.79(br dd, 6-H), 1.91(brdd, 6-CH2), 1.96(m, 8-H), 2.40(s, NCH3), 2.53(s, 3'-N(CH3)2), 2.70(m, 12-H), 2.80(dd, 2-H), 3.19(d, 2”-Heq), 3.26(dq, NHCH2CH3), 3.44(dd, 2'-H) , 3.55(s, 4-OCH3), 3.70(dd, 5-H), 3.81(br dd, 9-H), 4.10(br dd, 3-H), 4.28(d, 1'-H), 4.41(d, 4”-H), 4.48(dq, 5”-H), 4.78(m, 15-H), 5.10(m, CH2=CH), 5.73(m, CH=CH2).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 988 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.11 (s, Si (CH 3 ) 2 ), 0.89 (s, SiC (CH 3 ) 3 ), 0.95 (d, 8-CH 3 ), 1.12 (t, 3 ”-OCOCH 2 CH 3 ), 1.13 (d, 6” -H), 1.17 (t, NHCH 2 CH 3 ), 1.20 (d, 6'-H), 1.47 (s, 3 ”-CH 3 ), 1.70 (dd, 2” -Hax), 1.79 (br dd, 6-H), 1.91 (brdd, 6-CH 2 ), 1.96 (m, 8-H), 2.40 (s, NCH 3 ), 2.53 (s, 3'-N (CH 3 ) 2 ), 2.70 (m, 12-H), 2.80 (dd, 2-H), 3.19 (d, 2 ”-Heq), 3.26 (dq , NHCH 2 CH 3 ), 3.44 (dd, 2'-H), 3.55 (s, 4-OCH 3 ), 3.70 (dd, 5-H), 3.81 (br dd, 9-H), 4.10 (br dd , 3-H), 4.28 (d, 1'-H), 4.41 (d, 4 ''-H), 4.48 (dq, 5 ''-H), 4.78 (m, 15-H), 5.10 (m, CH 2 = CH), 5.73 (m, CH = CH 2 ).

(b)実施例1(d)と同様の方法で、実施例44(a)の化合物29 .9 mgから、標記化合物24.1 mgを得た。 (b) In the same manner as in Example 1 (d), 24.1 mg of the title compound was obtained from 29.9 mg of the compound of Example 44 (a).

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 874 (M+H)+
(2)1H NMRスペクトル(300 MHz, CDCl3) δ(ppm):0.90(d, 8-CH3), 1.12(t, 3”-OCOCH2CH3), 1.14(d, 6”-H), 1.17(t, NHCH2CH3), 1.17(d, 6'-H), 1.47(s, 3”-CH3), 1.70(dd, 2”-Hax), 2.34(s, NCH3), 2.43(dd, 6-CH2), 2.53(s, 3'-N(CH3)2), 2.95(dd, 6-CH2), 3.21(d, 2”-Heq), 3.26(dq, NHCH2CH3), 3.42(dd, 2'-H), 3.64(s, 4-OCH3), 3.65(br d, 4-H), 3.89(br d, 5-H), 4.31(br dd, 3-H), 4.36(d, 1'-H), 4.41(d, 4”-H), 4.46(dq, 5”-H), 4.80(t, NH), 4.83(d, 1”-H), 5.00(m, 15-H), 5.10(m, CH2=CH), 5.74(m, CH=CH2), 9.76(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 874 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.90 (d, 8-CH 3 ), 1.12 (t, 3 ”-OCOCH 2 CH 3 ), 1.14 (d, 6” -H ), 1.17 (t, NHCH 2 CH 3 ), 1.17 (d, 6'-H), 1.47 (s, 3 ”-CH 3 ), 1.70 (dd, 2” -Hax), 2.34 (s, NCH 3 ) , 2.43 (dd, 6-CH 2 ), 2.53 (s, 3'-N (CH 3 ) 2 ), 2.95 (dd, 6-CH 2 ), 3.21 (d, 2 ”-Heq), 3.26 (dq, NHCH 2 CH 3 ), 3.42 (dd, 2'-H), 3.64 (s, 4-OCH 3 ), 3.65 (br d, 4-H), 3.89 (br d, 5-H), 4.31 (br dd , 3-H), 4.36 (d, 1'-H), 4.41 (d, 4 ”-H), 4.46 (dq, 5” -H), 4.80 (t, NH), 4.83 (d, 1 ”- H), 5.00 (m, 15-H), 5.10 (m, CH 2 = CH), 5.74 (m, CH = CH 2 ), 9.76 (s, CHO).

Figure 2007069555
Figure 2007069555

実施例45
式(1)において、R1が水素原子、R2がアセチル基、R3がメチル基、R4がトランス-3-(イソキノリン-4-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例33の化合物65.6 mgをアセトニトリル5 mlに溶解し、無水酢酸24 μlを加え、40℃で22時間撹拌した。反応液を減圧濃縮して得られた残渣に酢酸エチルを加え、8%重曹水及び飽和食塩水で順次洗浄した。有機層を無水硫酸マグネシウムで乾燥後、これを濾過し、濾液を減圧濃縮して得られた残渣を分取用TLC(クロロホルム−メタノール(5:1))で精製して、9、2'位ジアセチル化合物(工程図15の式(37)において、R1が水素原子で表される化合物)56.7 mgを得た。
Example 45
In the formula (1), R 1 is a hydrogen atom, R 2 is an acetyl group, R 3 is a methyl group, R 4 is a trans-3- (isoquinolin-4-yl) -2-propenyl group, R 5 is a hydrogen atom and Method for producing compound in which R 6 is represented by ethyl group
(a) 65.6 mg of the compound of Example 33 was dissolved in 5 ml of acetonitrile, 24 μl of acetic anhydride was added, and the mixture was stirred at 40 ° C. for 22 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the resulting residue, and the mixture was washed successively with 8% aqueous sodium bicarbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative TLC (chloroform-methanol (5: 1)) to give positions 9 and 2 ′. 56.7 mg of a diacetyl compound (a compound in which R 1 is represented by a hydrogen atom in Formula (37) of Process FIG. 15) was obtained.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1085 (M+H)+
(2)1H NMRスペクトル(300 MHz, CDCl3) δ(ppm):0.95(d, 8-CH3), 1.12(d, 6”-H), 1.13(t, 3”-OCOCH2CH3), 1.16(t, NHCH2CH3), 1.16(d, 6'-H), 1.47(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.04(s, 9-OCOCH3 and 2'-OCOCH3), 2.17(s, NCH3), 2.42(s, 3'-N(CH3)2), 2.77(dd, 6-CH2), 3.09(t, 4'-H), 3.19(d, 2”-Heq), 3.26(dq, NHCH2CH3), 3.49(s, 4-OCH3), 4.00(br d, 5-H), 4.15(br dd, 3-H), 4.39(m, 4”-H), 4.41(m, 5”-H), 4.59(d, 1'-H), 4.78(d, 1”-H), 4.80(t, NH), 4.96(dd, 2'-H), 4.98(m, 9-H), 5.26(m, 15-H), 6.23(dt, CH=CH), 7.04(d, CH=CH), 7.62(t, isoquinoline), 7.74(t, isoquinoline), 7.98(d, isoquinoline), 8.05(d, isoquinoline), 8.55(s, isoquinoline), 9.15(s, isoquinoline), 9.70(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1085 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.95 (d, 8-CH 3 ), 1.12 (d, 6 ”-H), 1.13 (t, 3” -OCOCH 2 CH 3 ), 1.16 (t, NHCH 2 CH 3 ), 1.16 (d, 6'-H), 1.47 (s, 3 ”-CH 3 ), 1.68 (dd, 2” -Hax), 2.04 (s, 9-OCOCH 3 and 2'-OCOCH 3 ), 2.17 (s, NCH 3 ), 2.42 (s, 3'-N (CH 3 ) 2 ), 2.77 (dd, 6-CH 2 ), 3.09 (t, 4'-H ), 3.19 (d, 2 ”-Heq), 3.26 (dq, NHCH 2 CH 3 ), 3.49 (s, 4-OCH 3 ), 4.00 (br d, 5-H), 4.15 (br dd, 3-H ), 4.39 (m, 4 ”-H), 4.41 (m, 5” -H), 4.59 (d, 1'-H), 4.78 (d, 1 ”-H), 4.80 (t, NH), 4.96 (dd, 2'-H), 4.98 (m, 9-H), 5.26 (m, 15-H), 6.23 (dt, CH = CH), 7.04 (d, CH = CH), 7.62 (t, isoquinoline ), 7.74 (t, isoquinoline), 7.98 (d, isoquinoline), 8.05 (d, isoquinoline), 8.55 (s, isoquinoline), 9.15 (s, isoquinoline), 9.70 (s, CHO).

(b)実施例45(a)の化合物56.7 mgにメタノール4 mlを加え溶解し、30℃で1時間攪拌した後、さらに35℃で2時間攪拌した。反応液を減圧濃縮して得られた残渣を分取用TLC(クロロホルム−メタノール(4:1))で精製して、標記化合物6.8 mgを得た。 (b) To 56.7 mg of the compound of Example 45 (a), 4 ml of methanol was added and dissolved, stirred at 30 ° C. for 1 hour, and further stirred at 35 ° C. for 2 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by preparative TLC (chloroform-methanol (4: 1)) to obtain 6.8 mg of the title compound.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1043 (M+H)+
(2)1H NMRスペクトル(300 MHz, CDCl3) δ(ppm):0.95(d, 8-CH3), 1.11(t, 3”-OCOCH2CH3), 1.13(d, 6”-H), 1.16(t, NHCH2CH3), 1.18(d, 6'-H), 1.47(s, 3”-CH3), 1.70(dd, 2”-Hax), 1.80(m, 14-H), 2.05(s, 9-OCOCH3), 2.21(s, NCH3), 2.52(s, 3'-N(CH3)2), 2.80(dd, 2-H), 2.94(dd, 6-CH2), 3.15(t, 4'-H), 3.21(d, 2”-Heq), 3.26(dq, NHCH2CH3), 3.37(br d, 4-H), 3.41(dd, 2'-H), 3.58(s, 4-OCH3), 3.92(br d, 5-H), 4.17(br dd, 3-H), 4.38(d, 1'-H), 4.41(d, 4”-H), 4.46(dq, 5”-H), 4.80(t, NH), 4.82(d, 1”-H), 4.95(m, 9-H), 5.22(m, 15-H), 6.23(dt, CH=CH), 7.04(d, CH=CH), 7.62(dd, isoquinoline), 7.74(ddd, isoquinoline), 7.98(br d, isoquinoline), 8.04(br d, isoquinoline), 8.54(s, isoquinoline), 9.15(s, isoquinoline), 9.73(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1043 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.95 (d, 8-CH 3 ), 1.11 (t, 3 ”-OCOCH 2 CH 3 ), 1.13 (d, 6” -H ), 1.16 (t, NHCH 2 CH 3 ), 1.18 (d, 6'-H), 1.47 (s, 3 ”-CH 3 ), 1.70 (dd, 2” -Hax), 1.80 (m, 14-H ), 2.05 (s, 9-OCOCH 3 ), 2.21 (s, NCH 3 ), 2.52 (s, 3'-N (CH 3 ) 2 ), 2.80 (dd, 2-H), 2.94 (dd, 6- CH 2 ), 3.15 (t, 4'-H), 3.21 (d, 2 ”-Heq), 3.26 (dq, NHCH 2 CH 3 ), 3.37 (br d, 4-H), 3.41 (dd, 2 ' -H), 3.58 (s, 4-OCH 3 ), 3.92 (br d, 5-H), 4.17 (br dd, 3-H), 4.38 (d, 1'-H), 4.41 (d, 4 ” -H), 4.46 (dq, 5 ”-H), 4.80 (t, NH), 4.82 (d, 1” -H), 4.95 (m, 9-H), 5.22 (m, 15-H), 6.23 (dt, CH = CH), 7.04 (d, CH = CH), 7.62 (dd, isoquinoline), 7.74 (ddd, isoquinoline), 7.98 (br d, isoquinoline), 8.04 (br d, isoquinoline), 8.54 (s , isoquinoline), 9.15 (s, isoquinoline), 9.73 (s, CHO).

実施例46
式(1)において、R1がアセチル基、R2が水素原子、R3がメチル基、R4がトランス-3-(イソキノリン-4-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法
(a)実施例45(a)の化合物65.6 mgをピリジン9 mlに溶解し、無水酢酸190 μlを加え、40℃で19.5時間撹拌した後、無水酢酸100 μlを加え、さらに40℃で5時間撹拌した。反応液を酢酸エチル40 mlで希釈し、水20 mlで3回、25%食塩水20 mlで順次洗浄、有機層を無水硫酸ナトリウムで乾燥後、これを濾過した。濾液を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィーで2回精製(ヘキサン−酢酸エチル(2:1〜1:1)及びクロロホルム−メタノール(50:1〜30:1))して、3,9,2'位トリアセチル化合物(工程図15の式(37)において、R1がアセチル基で表される化合物)207 mgを得た。
Example 46
In the formula (1), R 1 is an acetyl group, R 2 is a hydrogen atom, R 3 is a methyl group, R 4 is a trans-3- (isoquinolin-4-yl) -2-propenyl group, R 5 is a hydrogen atom and Method for producing compound in which R 6 is represented by ethyl group
(a) 65.6 mg of the compound of Example 45 (a) was dissolved in 9 ml of pyridine, 190 μl of acetic anhydride was added, and the mixture was stirred at 40 ° C. for 19.5 hours. Stir. The reaction solution was diluted with 40 ml of ethyl acetate, washed three times with 20 ml of water and successively with 20 ml of 25% brine, and the organic layer was dried over anhydrous sodium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified twice by silica gel column chromatography (hexane-ethyl acetate (2: 1 to 1: 1) and chloroform-methanol (50: 1 to 30: 1)). 207 mg of a 3,9,2′-position triacetyl compound (a compound in which R 1 is represented by an acetyl group in the formula (37) in Process FIG. 15) was obtained.

本化合物の理化学的性状
(1)マススペクトル(FAB) :m/z 1127 (M+H)+
(2)1H NMRスペクトル(300 MHz, CDCl3) δ(ppm):0.90(d, 8-CH3), 1.12(d, 6”-H), 1.13(t, 3”-OCOCH2CH3), 1.16(t, NHCH2CH3), 1.47(s, 3”-CH3), 1.68(dd, 2”-Hax), 2.04(s, 9-OCOCH3), 2.05(s, 2'-OCOCH3), 2.22(s, NCH3), 2.23(s, 3-OCOCH3), 2.42(s, 3'-N(CH3)2), 2.64(dd, 2-H), 2.89(dd, 2-H), 2.91(dd, 6-CH2), 3.08(t, 4'-H), 3.18(d, 2”-Heq), 3.26(dq, NHCH2CH3), 3.58(s, 4-OCH3), 3.73(br d, 4-H), 3.94(br d, 5-H), 4.41(m, 4”-H), 4.41(m, 5”-H), 4.56(d, 1'-H), 4.78(d, 1”-H), 4.81(m, 3-H), 4.81(t, NH), 4.94(dd, 2'-H), 5.15(m, 9-H), 5.22(m, 15-H), 6.20(dt, CH=CH), 7.03(d, CH=CH), 7.62(t, isoquinoline), 7.73(t, isoquinoline), 7.97(d, isoquinoline), 8.04(d, isoquinoline), 8.53(s, isoquinoline), 9.14(s, isoquinoline), 9.63(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1127 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.90 (d, 8-CH 3 ), 1.12 (d, 6 ”-H), 1.13 (t, 3” -OCOCH 2 CH 3 ), 1.16 (t, NHCH 2 CH 3 ), 1.47 (s, 3 ”-CH 3 ), 1.68 (dd, 2” -Hax), 2.04 (s, 9-OCOCH 3 ), 2.05 (s, 2'- OCOCH 3 ), 2.22 (s, NCH 3 ), 2.23 (s, 3-OCOCH 3 ), 2.42 (s, 3'-N (CH 3 ) 2 ), 2.64 (dd, 2-H), 2.89 (dd, 2-H), 2.91 (dd, 6-CH 2 ), 3.08 (t, 4'-H), 3.18 (d, 2 ”-Heq), 3.26 (dq, NHCH 2 CH 3 ), 3.58 (s, 4 -OCH 3 ), 3.73 (br d, 4-H), 3.94 (br d, 5-H), 4.41 (m, 4 ”-H), 4.41 (m, 5” -H), 4.56 (d, 1 '-H), 4.78 (d, 1 ”-H), 4.81 (m, 3-H), 4.81 (t, NH), 4.94 (dd, 2'-H), 5.15 (m, 9-H), 5.22 (m, 15-H), 6.20 (dt, CH = CH), 7.03 (d, CH = CH), 7.62 (t, isoquinoline), 7.73 (t, isoquinoline), 7.97 (d, isoquinoline), 8.04 ( d, isoquinoline), 8.53 (s, isoquinoline), 9.14 (s, isoquinoline), 9.63 (s, CHO).

(b)実施例46(a)の化合物11.5 mgにメタノール1 mlを加え溶解し、30℃で23時間攪拌した。反応液を減圧濃縮して得られた残渣を分取用TLC(クロロホルム−メタノール(5:1))で精製して、標記化合物5.8 mgを得た。 (b) To 11.5 mg of the compound of Example 46 (a), 1 ml of methanol was added and dissolved, followed by stirring at 30 ° C. for 23 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by preparative TLC (chloroform-methanol (5: 1)) to obtain 5.8 mg of the title compound.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1043 (M+H)+
(2)1H NMRスペクトル(300 MHz, CDCl3) δ(ppm):0.92(d, 8-CH3), 1.12(d, 6”-H), 1.14(t, 3”-OCOCH2CH3), 1.15(d, 6'-H), 1.16(t, NHCH2CH3), 1.35(m, 8-H), 1.47(s, 3”-CH3), 1.69(dd, 2”-Hax), 2.21(s, 3-OCOCH3), 2.40(s, NCH3), 2.54(s, 3'-N(CH3)2), 2.65(dd, 2-H), 2.86(dd, 2-H), 2.93(dd, 6-CH2), 3.21(d, 2”-Heq), 3.26(dq, NHCH2CH3), 3.39(dd, 2'-H), 3.63(s, 4-OCH3) , 3.88(br d, 5-H), 3.96(br d, 4-H), 4.39(d, 1'-H), 4.42(d, 4”-H), 4.45(dq, 5”-H), 4.79(t, NH), 4.82(d, 1”-H), 5.18(m, 15-H), 5.51(m, 3-H), 6.20(dt, CH=CH), 7.02(d, CH=CH), 7.62(ddd, isoquinoline), 7.73(ddd, isoquinoline), 7.97(br d, isoquinoline), 8.03(br d, isoquinoline), 8.53(s, isoquinoline), 9.14(s, isoquinoline), 9.65(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1043 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.92 (d, 8-CH 3 ), 1.12 (d, 6 ”-H), 1.14 (t, 3” -OCOCH 2 CH 3 ), 1.15 (d, 6'-H), 1.16 (t, NHCH 2 CH 3 ), 1.35 (m, 8-H), 1.47 (s, 3 ”-CH 3 ), 1.69 (dd, 2” -Hax ), 2.21 (s, 3-OCOCH 3 ), 2.40 (s, NCH 3 ), 2.54 (s, 3'-N (CH 3 ) 2 ), 2.65 (dd, 2-H), 2.86 (dd, 2- H), 2.93 (dd, 6-CH 2 ), 3.21 (d, 2 ”-Heq), 3.26 (dq, NHCH 2 CH 3 ), 3.39 (dd, 2'-H), 3.63 (s, 4-OCH 3 ), 3.88 (br d, 5-H), 3.96 (br d, 4-H), 4.39 (d, 1'-H), 4.42 (d, 4 ''-H), 4.45 (dq, 5 ''- H), 4.79 (t, NH), 4.82 (d, 1 ''-H), 5.18 (m, 15-H), 5.51 (m, 3-H), 6.20 (dt, CH = CH), 7.02 (d , CH = CH), 7.62 (ddd, isoquinoline), 7.73 (ddd, isoquinoline), 7.97 (br d, isoquinoline), 8.03 (br d, isoquinoline), 8.53 (s, isoquinoline), 9.14 (s, isoquinoline), 9.65 (s, CHO).

実施例47
式(1)において、R1及びR2がアセチル基、R3がメチル基、R4がトランス-3-(イソキノリン-4-イル)-2-プロペニル基、R5が水素原子及びR6がエチル基で表される化合物の製造方法実施例46(a)の化合物207 mgにメタノール14 mlを加え溶解し、35℃で3.5時間攪拌した。反応液を減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム−メタノール(50:1〜30:1))で精製して、標記化合物29.1 mgを得た。
Example 47
In the formula (1), R 1 and R 2 are acetyl groups, R 3 is a methyl group, R 4 is a trans-3- (isoquinolin-4-yl) -2-propenyl group, R 5 is a hydrogen atom and R 6 is Production Method of Compound Represented by Ethyl Group 14 ml of methanol was added to 207 mg of the compound of Example 46 (a), dissolved, and stirred at 35 ° C. for 3.5 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform-methanol (50: 1 to 30: 1)) to obtain 29.1 mg of the title compound.

本化合物の理化学的性状
(1)マススペクトル(FAB):m/z 1085 (M+H)+
(2)1H NMRスペクトル(300 MHz, CDCl3) δ(ppm):0.92(d, 8-CH3), 1.12(d, 6”-H), 1.14(t, 3”-OCOCH2CH3), 1.16(t, NHCH2CH3), 1.47(s, 3”-CH3), 1.70(dd, 2”-Hax), 2.06(s, 9-OCOCH3), 2.18(s, 3-OCOCH3), 2.23(s, NCH3), 2.54(s, 3'-N(CH3)2), 2.60(m, 15-H), 2.68(dd, 2-H), 2.91(dd, 2-H), 2.96(dd, 6-CH2), 3.22(d, 2”-H eq), 3.26(dq, NHCH2CH3), 3.37(dd, 2'-H), 3.64(s, 4-OCH3), 3.88(br s, 4-H), 3.88(br s, 5-H), 4.39(d, 1'-H), 4.42(d, 4”-H), 4.45(dq, 5”-H), 4.79(t, NH), 4.83(d, 1”-H), 4.84(m, 9-H), 5.21(m, 3-H), 5.21(m, 15-H), 6.21(dt, CH=CH), 7.03(d, CH=CH), 7.61(ddd, isoquinoline), 7.73(ddd, isoquinoline), 7.97(br d, isoquinoline), 8.04(br d, isoquinoline), 8.54(s, isoquinoline), 9.14(s, isoquinoline), 9.66(s, CHO).
Physicochemical properties of this compound (1) Mass spectrum (FAB): m / z 1085 (M + H) +
(2) 1 H NMR spectrum (300 MHz, CDCl 3 ) δ (ppm): 0.92 (d, 8-CH 3 ), 1.12 (d, 6 ”-H), 1.14 (t, 3” -OCOCH 2 CH 3 ), 1.16 (t, NHCH 2 CH 3 ), 1.47 (s, 3 ”-CH 3 ), 1.70 (dd, 2” -Hax), 2.06 (s, 9-OCOCH 3 ), 2.18 (s, 3-OCOCH 3 ), 2.23 (s, NCH 3 ), 2.54 (s, 3'-N (CH 3 ) 2 ), 2.60 (m, 15-H), 2.68 (dd, 2-H), 2.91 (dd, 2- H), 2.96 (dd, 6-CH 2 ), 3.22 (d, 2 ”-H eq), 3.26 (dq, NHCH 2 CH 3 ), 3.37 (dd, 2'-H), 3.64 (s, 4- OCH 3 ), 3.88 (br s, 4-H), 3.88 (br s, 5-H), 4.39 (d, 1'-H), 4.42 (d, 4 ”-H), 4.45 (dq, 5” -H), 4.79 (t, NH), 4.83 (d, 1 ”-H), 4.84 (m, 9-H), 5.21 (m, 3-H), 5.21 (m, 15-H), 6.21 ( dt, CH = CH), 7.03 (d, CH = CH), 7.61 (ddd, isoquinoline), 7.73 (ddd, isoquinoline), 7.97 (br d, isoquinoline), 8.04 (br d, isoquinoline), 8.54 (s, isoquinoline), 9.14 (s, isoquinoline), 9.66 (s, CHO).

上記実施例で得られた化合物の構造を下記の表1〜表3に示す。   The structures of the compounds obtained in the above examples are shown in Tables 1 to 3 below.

Figure 2007069555
Figure 2007069555

Figure 2007069555
Figure 2007069555

Figure 2007069555
Figure 2007069555

(試験例1)抗菌活性試験
実施例1、5、10、22、26、31〜33、39及び42の化合物のin vitro抗菌活性を、日本化学療法学会標準法(Chemotherapy、29巻、76〜79頁、1981年)を参考に、次のように測定した。また、比較としてクラリスロマイシン(CAM)及びミオカマイシン(MOM)の抗菌活性を同様に測定した。
6400μg/mlになるようメタノールに溶解した各被験薬溶液について、メタノールによる2倍段階希釈液を調製した。調製した被験薬溶液各200μlをシャーレに入れ、5%馬無菌脱繊維血液、15μg/ml β-Nicotinamide-adenine dinucleotide、2.5μg/ml Heminをそれぞれ添加した感受性測定用寒天培地10mlを分注後混釈して被験薬含有寒天平板を作製した。被験菌を所定の菌量含有するよう調製した感受性測定用液体培地の一定量を、ミクロプランター(佐久間製作所)により被験薬含有寒天平板に接種し、接種後37℃にて約20時間培養した。培養後、平板上の被験菌の発育の有無を肉眼で観察し、発育が認められない最小濃度を各被験菌に対する被験薬の最小発育阻止濃度(MIC)とした。試験に用いた被験菌を表4に、試験結果を表5に示した。
(Test Example 1) Antibacterial Activity Test The in vitro antibacterial activity of the compounds of Examples 1, 5, 10, 22, 26, 31-33, 39 and 42 was determined using the standard method of the Japanese Society of Chemotherapy (Chemotherapy, Vol. 29, 76- 79, 1981), and was measured as follows. For comparison, the antibacterial activity of clarithromycin (CAM) and myokamycin (MOM) was measured in the same manner.
For each test drug solution dissolved in methanol to 6400 μg / ml, a 2-fold serial dilution with methanol was prepared. Place 200 μl of each prepared test drug solution in a petri dish, dispense 5% horse sterile defibrinated blood, 15 μg / ml β-Nicotinamide-adenine dinucleotide, and 2.5 μg / ml Hemin, respectively, and dispense and mix 10 ml. The test drug-containing agar plate was prepared. A certain amount of the liquid medium for sensitivity measurement prepared so as to contain a predetermined amount of the test bacteria was inoculated on the agar plate containing the test drug by a microplanter (Sakuma Seisakusho), and cultured at 37 ° C. for about 20 hours. After culturing, the presence or absence of growth of the test bacteria on the plate was observed with the naked eye, and the minimum concentration at which no growth was observed was defined as the minimum inhibitory concentration (MIC) of the test drug for each test bacteria. The test bacteria used in the test are shown in Table 4, and the test results are shown in Table 5.

Figure 2007069555
Figure 2007069555

Figure 2007069555
Figure 2007069555

グラム陽性菌に対する抗菌活性では、実施例1、5、10、22、26、31〜33、39及び42の化合物は被験菌B及びCに対して、MOMと比較して抗菌活性の向上が認められ、またCAMと比較して同等以上の抗菌活性を有していた。さらに被験菌D、 E及びFに対して、CAM及びMOMと比較して抗菌活性の向上が認められた。とりわけCAMが無効な被験菌D、 Eにおいて、抗菌活性の向上が顕著であった。
グラム陰性菌に対する抗菌活性では、32、33、42の化合物は、被験菌Gに対して、CAMと同等であり、MOMよりも2倍抗菌活性が向上した。
In antibacterial activity against Gram-positive bacteria, the compounds of Examples 1, 5, 10, 22, 26, 31-33, 39 and 42 have improved antibacterial activity compared to MOM against test bacteria B and C. In addition, it had an antibacterial activity equivalent to or better than that of CAM. Furthermore, the test bacteria D, E and F were improved in antibacterial activity as compared with CAM and MOM. In particular, the improvement in antibacterial activity was remarkable in test bacteria D and E in which CAM was ineffective.
In antibacterial activity against gram-negative bacteria, the compounds of 32, 33 and 42 were equivalent to CAM against test bacteria G, and the antibacterial activity was improved twice as much as that of MOM.

(試験例2)マウス及びヒト肝S9画分におけるin vitro代謝安定性試験
実施例1、3及び22の化合物のin vitro代謝安定性を次のように評価した。また、比較としてミオカマイシン(MOM)及び16員環4”-O-アシルアザライド誘導体2化合物(WO2005/19238、実施例129及び実施例140)の代謝安定性を同様に評価した。
(Test Example 2) In vitro metabolic stability test in mouse and human liver S9 fractions In vitro metabolic stability of the compounds of Examples 1, 3 and 22 was evaluated as follows. For comparison, the metabolic stability of myokamycin (MOM) and 16-membered ring 4 ″ -O-acyl azalide derivative 2 compounds (WO2005 / 19238, Example 129 and Example 140) was also evaluated in the same manner.

(1)マウス及びヒト肝S9画分
ICR系雄性マウス(6週齢、日本チャールス・リバー株式会社)より肝を摘出し、0.25 mol/L Sucrose-1 mmol/L EDTANa2-50 mmol/L Potassium phosphate buffer (pH 7.4)を用いて20w/v% ホモジネートを調製した。その後、遠心操作(9,000 × g、20 分)により得られた上清をマウス肝S9画分として用いた。また、ヒト肝S9画分は、Human Biologics International (AZ, USA)より購入したPooled HepatoSNineTMを用いた。それぞれのタンパク量はウシ血清アルブミンを標準物質としてLowry法により測定した。
(1) Mouse and human liver S9 fraction
ICR male mice (6 weeks old, Charles River Japan Inc.) were excised from liver, using a 0.25 mol / L Sucrose-1 mmol / L EDTANa 2 -50 mmol / L Potassium phosphate buffer (pH 7.4) 20w A / v% homogenate was prepared. Thereafter, the supernatant obtained by centrifugation (9,000 × g, 20 minutes) was used as the mouse liver S9 fraction. For the human liver S9 fraction, Pooled HepatoSNine purchased from Human Biologics International (AZ, USA) was used. The amount of each protein was measured by the Lowry method using bovine serum albumin as a standard substance.

(2)インキュベーション及びサンプル処理条件
最終濃度10 μmol/Lの各評価化合物を、NADPH産生系(1.3 mmol/L β-NADP+、3.3 mmol/L Glucose-6-phosphate(G-6-P)、0.4 U/mL G-6-P dehydrogenase、3.3 mmol/L MgCl2・6H2O)、100 mmol/L Potassium phosphate buffer(pH 7.4)及び肝S9画分(マウス、ヒトともに最終濃度1 mg protein/mL)を含む反応混液(125 μL)中で、37℃で0、2、5、10、20、30及び60分間インキュベーションした。なお、各評価化合物はDMSOにて溶解し、反応混液中のDMSO濃度が1vol%になるように添加した。代謝反応は、1 μmol/Lの内部標準物質を含むアセトニトリル溶液を250 μL添加することにより停止させた。その後、蒸留水を125 μL添加し、さらに50vol% アセトニトリルにより適宜希釈した後に、一定の遠心操作により分離した上清をフィルターにてろ過したものを分析用サンプルとした。
(2) Incubation and sample treatment conditions Each evaluation compound having a final concentration of 10 μmol / L was added to a NADPH production system (1.3 mmol / L β-NADP + , 3.3 mmol / L Glucose-6-phosphate (G-6-P), 0.4 U / mL G-6-P dehydrogenase, 3.3 mmol / L MgCl 2 · 6H 2 O), 100 mmol / L Potassium phosphate buffer (pH 7.4) and liver S9 fraction (final concentration 1 mg protein / for both mouse and human) in the reaction mixture (125 μL) at 37 ° C. for 0, 2, 5, 10, 20, 30 and 60 minutes. Each evaluation compound was dissolved in DMSO and added so that the DMSO concentration in the reaction mixture was 1 vol%. The metabolic reaction was stopped by adding 250 μL of an acetonitrile solution containing 1 μmol / L internal standard. Thereafter, 125 μL of distilled water was added, and the sample was further diluted appropriately with 50 vol% acetonitrile, and the supernatant separated by constant centrifugation was filtered through a filter, which was used as an analytical sample.

(3)LC-MS/MS分析
(2)にて調製した分析用サンプル中の各評価化合物濃度をLC-MS/MS(HPLC:HP1100シリーズ、MS/MS:TSQ7000 API2)により定量した。HPLC溶出液をトリプル四重極のイオン源に導入し、ESI法にてMS/MS分析を行った。SRM法(選択反応モニタリング法)による各評価化合物のプリカーサーイオンとして[M+H]+を選択し、さらに定量に用いたプロダクトイオンはいずれも最大強度を示すフラグメントピークを選択した。なお、各評価化合物の定量はプロダクトイオンによるマスクロマトグラムのピーク面積から内部標準法により行った。
(3) LC-MS / MS analysis The concentration of each evaluation compound in the analytical sample prepared in (2) was quantified by LC-MS / MS (HPLC: HP1100 series, MS / MS: TSQ7000 API2). The HPLC eluate was introduced into a triple quadrupole ion source and subjected to MS / MS analysis by the ESI method. [M + H] + was selected as a precursor ion of each evaluation compound by the SRM method (selective reaction monitoring method), and a fragment peak showing the maximum intensity was selected as the product ion used for quantification. The quantification of each evaluation compound was performed by an internal standard method from the peak area of the mass chromatogram by product ions.

(4)代謝活性の算出
各評価化合物の代謝活性値は、インキュベーション時間に対する各評価化合物の残存率をグラフにプロットし、化合物が直線的に減少する時間(見かけのゼロ次速度過程)における残存率から下記の式に従って算出した。
(4) Calculation of metabolic activity The metabolic activity value of each evaluation compound is obtained by plotting the survival rate of each evaluation compound against the incubation time in a graph, and the survival rate during the time when the compound decreases linearly (apparent zero-order rate process). Was calculated according to the following formula.

代謝活性値(pmol/min/mg protein)=
基質初濃度(μmol/L)×((100−反応後の残存率(%))/100)×反応混液容量(mL)×1000 /インキュベーション時間(mi n)/肝S9画分タンパク濃度(mg protein)
Metabolic activity (pmol / min / mg protein) =
Substrate initial concentration (μmol / L) × ((100−remaining rate after reaction (%)) / 100) × reaction mixture volume (mL) × 1000 / incubation time (min) / liver S9 fraction protein concentration (mg protein)

実施例1、3及び22の化合物の代謝活性値は、他の比較化合物の代謝活性値よりも低い値を示した。この結果から、マウス及びヒトのいずれの肝S9画分を用いた代謝評価においても、実施例1、3及び22の化合物は、16員環4”-O-アシル誘導体のMOM、及び16員環4”-O-アシルアザライド誘導体2化合物よりも良好な代謝安定性を示すことが明らかとなった。   The metabolic activity values of the compounds of Examples 1, 3 and 22 were lower than those of the other comparative compounds. From these results, in the metabolic evaluation using both mouse and human liver S9 fractions, the compounds of Examples 1, 3 and 22 are the MOM of the 16-membered ring 4 ″ -O-acyl derivative and the 16-membered ring. It was revealed that the 4 ”-O-acyl azalide derivative showed better metabolic stability than the two compounds.

第一に本発明の化合物である新規16員環4”-O-カルバモイルアザライド誘導体は、臨床上重要なグラム陽性菌及びグラム陰性菌に対して、従来の抗菌剤よりも強い抗菌活性を有し、感染症の予防及び/又は治療のための医薬の有効成分として極めて有用である。
また、本発明の製造方法により、一般式(2)で表される化合物を、塩基存在下、アルキルイソシアネートと反応させることにより、4”位水酸基上アシル基の3”位水酸基への転移を伴う、一工程での4”位水酸基のカルバモイル化が可能となった。さらに本発明の別の態様の製造方法により、一般式(2)で表される化合物を、塩基存在下、1,1'-カルボニルジイミダゾールとの反応により、一般式(4)で表される化合物とした後、塩基の存在下、又は非存在下に適当な一級または二級アミンと反応させることで、二段階での4”位水酸基のカルバモイル化が可能となった。これらの製造方法を用いることによって、代謝的に安定な一般式(1)で表される新規な16員環4”-O-カルバモイルアザライド誘導体を提供することが可能となった。
First, the novel 16-membered 4 ″ -O-carbamoyl azalide derivative, which is a compound of the present invention, has stronger antibacterial activity than clinical antibacterial agents against clinically important Gram-positive and Gram-negative bacteria. However, it is extremely useful as an active ingredient of a medicament for the prevention and / or treatment of infectious diseases.
In addition, by the production method of the present invention, the compound represented by the general formula (2) is reacted with an alkyl isocyanate in the presence of a base, thereby transferring the acyl group on the 4 ″ -position hydroxyl group to the 3 ″ -position hydroxyl group. Thus, carbamoylation of the 4 ″ -position hydroxyl group in one step became possible. Further, by the production method of another embodiment of the present invention, the compound represented by the general formula (2) was converted to 1,1 ′ in the presence of a base. -A compound represented by the general formula (4) by reaction with carbonyldiimidazole, and then reacted with an appropriate primary or secondary amine in the presence or absence of a base in two stages. Carbamoylation of the hydroxyl group at the 4 ”position is possible. By using these production methods, it has become possible to provide a novel 16-membered 4 ″ -O-carbamoyl azalide derivative represented by the general formula (1) which is metabolically stable.

Claims (19)

下記の一般式(1)
Figure 2007069555
[式中、
R1は、水素原子又はC2〜6の直鎖状アルキルカルボニル基を表し、
R2は、水素原子又はC2〜6のアルキルカルボニル基を表し、
R3は、水酸基で置換されていてもよいC1〜6のアルキル基、C2〜6のアルケニル基又はC2〜6のアルキニル基を表し、
R4は、水素原子、C1〜6のアルキル基、C2〜6のアルケニル基、C2〜6のアルキニル基又はAr-B-基(ここで、Arはアリール基又は複素環基を表し、BはC1〜6のアルキル基又はC2〜6のアルケニル基を表す)を表し、
R5及びR6は、同一でも異なっていても良く、水素原子、又は水酸基で置換されていてもよいC1〜6のアルキル基若しくはC2〜6のアルケニル基である]
で表される化合物又は薬学的に許容されるその塩。
The following general formula (1)
Figure 2007069555
[Where:
R 1 represents a hydrogen atom or a C2-6 linear alkylcarbonyl group,
R 2 represents a hydrogen atom or a C2-6 alkylcarbonyl group,
R 3 represents a C1-6 alkyl group optionally substituted with a hydroxyl group, a C2-6 alkenyl group, or a C2-6 alkynyl group,
R 4 represents a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group or an Ar-B- group (wherein Ar represents an aryl group or a heterocyclic group, B represents Represents a C1-6 alkyl group or a C2-6 alkenyl group),
R 5 and R 6 may be the same or different and are a hydrogen atom, a C1-6 alkyl group or a C2-6 alkenyl group optionally substituted with a hydroxyl group.
Or a pharmaceutically acceptable salt thereof.
R3が、水酸基で置換されていてもよいC1〜6のアルキル基であり、
R4が、C2〜6のアルケニル基又はAr-B-基(ここで、Ar及びBは前記と同じ意味を表す)であり、
R5及びR6は、同一でも異なっていても良く、水素原子、又は水酸基で置換されていてもよいC1〜6のアルキル基である、請求項1に記載の化合物又は薬学的に許容されるその塩。
R 3 is a C1-6 alkyl group which may be substituted with a hydroxyl group,
R 4 is a C2-6 alkenyl group or Ar—B— group (wherein Ar and B have the same meaning as described above),
R 5 and R 6, which may be the same or different, are a hydrogen atom or a C1-6 alkyl group optionally substituted with a hydroxyl group, or the compound or pharmaceutically acceptable according to claim 1. Its salt.
R1が、水素原子であり、
R2が、水素原子であり、
R3が、C1〜6のアルキル基であり、
R4が、C2〜6のアルケニル基又はAr-B-基(ここで、Ar及びBは前記と同じ意味を表す)であり、
R5及びR6は、同一でも異なっていても良く、水素原子、又はC1〜6のアルキル基である、請求項1に記載の化合物又は薬学的に許容されるその塩。
R1 is a hydrogen atom,
R 2 is a hydrogen atom,
R 3 is a C1-6 alkyl group,
R 4 is a C2-6 alkenyl group or Ar—B— group (wherein Ar and B have the same meaning as described above),
The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 may be the same or different and each is a hydrogen atom or a C 1-6 alkyl group.
R1が、C2〜6の直鎖状アルキルカルボニル基であり、
R2が、水素原子であり、
R3が、水酸基で置換されていてもよいC1〜6のアルキル基であり、
R4が、Ar-B-基(ここで、Ar及びBは前記と同じ意味を表す)であり、
R5及びR6は、同一でも異なっていても良く、水素原子、又は水酸基で置換されていてもよいC1〜6のアルキル基である、請求項1に記載の化合物又は薬学的に許容されるその塩。
R 1 is a C2-6 linear alkylcarbonyl group,
R 2 is a hydrogen atom,
R 3 is a C1-6 alkyl group which may be substituted with a hydroxyl group,
R 4 is an Ar-B- group (wherein Ar and B have the same meaning as described above),
R 5 and R 6, which may be the same or different, are a hydrogen atom or a C1-6 alkyl group optionally substituted with a hydroxyl group, or the compound or pharmaceutically acceptable according to claim 1. Its salt.
R1が、水素原子であり、
R2が、C2〜6のアルキルカルボニル基であり、
R3が、C1〜6のアルキル基であり、
R4が、Ar-B-基(ここで、Arは前記と同じ意味を表し、BはC2〜6のアルケニル基を表す)であり、
R5及びR6は、同一でも異なっていても良く、水素原子、又はC1〜6のアルキル基である、請求項1に記載の化合物又は薬学的に許容されるその塩。
R 1 is a hydrogen atom,
R 2 is a C2-6 alkylcarbonyl group,
R 3 is a C1-6 alkyl group,
R 4 is an Ar-B- group (wherein Ar represents the same meaning as described above, B represents a C2-6 alkenyl group),
The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 may be the same or different and each is a hydrogen atom or a C 1-6 alkyl group.
R1が、C2〜6の直鎖状アルキルカルボニル基であり、
R2が、C2〜6のアルキルカルボニル基であり、
R3が、C1〜6のアルキル基であり、
R4が、Ar-B-基(ここで、Arは前記と同じ意味を表し、BはC2〜6のアルケニル基を表す)であり、
R5及びR6は、同一でも異なっていても良く、水素原子、又はC1〜6のアルキル基である請求項1に記載の化合物、又は薬学的に許容されるその塩。
R 1 is a C2-6 linear alkylcarbonyl group,
R 2 is a C2-6 alkylcarbonyl group,
R 3 is a C1-6 alkyl group,
R 4 is an Ar-B- group (wherein Ar represents the same meaning as described above, B represents a C2-6 alkenyl group),
R 5 and R 6, which may be the same or different, are a hydrogen atom or a C 1-6 alkyl group, or a pharmaceutically acceptable salt thereof.
R3がメチル基又はヒドロキシエチル基である、請求項1に記載の化合物又は薬学的に許容されるその塩。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is a methyl group or a hydroxyethyl group. R4が2-プロペニル基又はAr-B-基(ここで、Arは前記と同じ意味を表し、Bは、-CH2CH2CH2- 又は-CH=CHCH2- を表す)である請求項1に記載の化合物、又は薬学的に許容されるその塩。R 4 is a 2-propenyl group or Ar—B— group (wherein Ar represents the same meaning as described above, and B represents —CH 2 CH 2 CH 2 − or —CH═CHCH 2 −). Item 2. The compound according to Item 1, or a pharmaceutically acceptable salt thereof. R5及びR6が、同一でも異なっていても良く、水素原子、メチル基、エチル基、ノルマルプロピル基、イソプロピル基又はヒドロキシエチル基である、請求項1に記載の化合物又は薬学的に許容されるその塩。R 5 and R 6 , which may be the same or different, are a hydrogen atom, a methyl group, an ethyl group, a normal propyl group, an isopropyl group or a hydroxyethyl group, or a pharmaceutically acceptable compound according to claim 1. Its salt. R4が2-プロペニル基、トランス-3-(ピリジン-3-イル)-2-プロペニル基、トランス-3-(4-メチルピリジン-3-イル)-2-プロペニル基、トランス-3-(6-メトキシピリジン-3-イル)-2-プロペニル基、トランス-3-(6-ニトロピリジン-3-イル)-2-プロペニル基、トランス-3-(6-アミノピリジン-3-イル)-2-プロペニル基、トランス-3-(2-アミノピリジン-3-イル)-2-プロペニル基、トランス-3-(5-アミノピリジン-3-イル)-2-プロペニル基、トランス-3-(6-アミノ-5-メチルピリジン-3-イル)-2-プロペニル基、トランス-3-(6-ジメチルアミノピリジン-3-イル)-2-プロペニル基、トランス-3-(ピリミジン-5-イル)-2-プロペニル基、トランス-3-(ナフタレン-2-イル)-2-プロペニル基、トランス-3-(キノリン-2-イル)-2-プロペニル基、トランス-3-(キノリン-3-イル)-2-プロペニル基、3-(キノリン-3-イル)プロピル基、トランス-3-(キノリン-4-イル)-2-プロペニル基、トランス-3-(6-クロロキノリン-3-イル)-2-プロペニル基、3-(6-アミノキノリン-3-イル)プロピル基、3-(6-メトキシキノリン-3-イル)プロピル基、3-(イソキノリン-1-イル)プロピル基、3-(イソキノリン-3-イル)プロピル基、トランス-3-(イソキノリン-4-イル)-2-プロペニル基、3-(イソキノリン-4-イル)プロピル基、トランス-3-(1-アミノイソキノリン-4-イル)-2-プロペニル基、3-(1-アセチルアミノイソキノリン-4-イル)プロピル基、トランス-3-(キノキサリン-2-イル)-2-プロペニル基、トランス-3-(キノキサリン-6-イル)-2-プロペニル基、トランス-3-(1,5-ナフチリジン-3-イル)-2-プロペニル基、トランス-3-(1,6-ナフチリジン-8-イル)-2-プロペニル基、トランス-3-(イミダゾ[1,2-a]ピリジン-3-イル)-2-プロペニル基及びトランス-3-(イミダゾ[1,2-a]ピリミジン- 6-イル)-2-プロペニル基から選択される基である、請求項1に記載の化合物又は薬学的に許容されるその塩。R 4 represents 2-propenyl group, trans-3- (pyridin-3-yl) -2-propenyl group, trans-3- (4-methylpyridin-3-yl) -2-propenyl group, trans-3- ( 6-methoxypyridin-3-yl) -2-propenyl group, trans-3- (6-nitropyridin-3-yl) -2-propenyl group, trans-3- (6-aminopyridin-3-yl)- 2-propenyl group, trans-3- (2-aminopyridin-3-yl) -2-propenyl group, trans-3- (5-aminopyridin-3-yl) -2-propenyl group, trans-3- ( 6-amino-5-methylpyridin-3-yl) -2-propenyl group, trans-3- (6-dimethylaminopyridin-3-yl) -2-propenyl group, trans-3- (pyrimidin-5-yl) ) -2-propenyl group, trans-3- (naphthalen-2-yl) -2-propenyl group, trans-3- (quinolin-2-yl) -2-propenyl group, trans-3- (quinoline-3- Il) -2-propeni Group, 3- (quinolin-3-yl) propyl group, trans-3- (quinolin-4-yl) -2-propenyl group, trans-3- (6-chloroquinolin-3-yl) -2-propenyl group 3- (6-aminoquinolin-3-yl) propyl group, 3- (6-methoxyquinolin-3-yl) propyl group, 3- (isoquinolin-1-yl) propyl group, 3- (isoquinolin-3- Yl) propyl group, trans-3- (isoquinolin-4-yl) -2-propenyl group, 3- (isoquinolin-4-yl) propyl group, trans-3- (1-aminoisoquinolin-4-yl) -2 -Propenyl group, 3- (1-acetylaminoisoquinolin-4-yl) propyl group, trans-3- (quinoxalin-2-yl) -2-propenyl group, trans-3- (quinoxalin-6-yl) -2 -Propenyl group, trans-3- (1,5-naphthyridin-3-yl) -2-propenyl group, trans-3- (1,6-naphthyridin-8-yl) -2-propenyl group , Trans-3- (imidazo [1,2-a] pyridin-3-yl) -2-propenyl group and trans-3- (imidazo [1,2-a] pyrimidin-6-yl) -2-propenyl group The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a group selected from: 一般式(2)
Figure 2007069555
〔式中、R1は、C2〜6の直鎖状アルキルカルボニル基を表し、R2は、C2〜6の直鎖状アルキルカルボニル基、又は水酸基の修飾基であり、R3は、C1〜6のアルキル基、C2〜6のアルケニル基、C2〜6のアルキニル基又は水酸基をシリル系保護基で修飾したヒドロキシエチル基を表し、R4は、C1〜6のアルキル基、C2〜6のアルケニル基、C2〜6のアルキニル基又はAr-B-基(ここで、Arはアリール基又は複素環基を表し、BはC1〜6のアルキル基、C2〜6のアルケニル基又はC2〜6のアルキニル基を表す)を表し、R7は、-CH(OR10)2(ここで、R10はC1〜5のアルキル基を表す)、下記の基(a)
Figure 2007069555
(ここで、nは2〜3の整数を表す)又はR1とR7を含んで下記の基(b)
Figure 2007069555
(ここで、R11は、シリル系保護基を表す)を表し、
R8は、C2〜C5の直鎖状アルキルカルボニル基を表し、
R9は、アセチル基、プロピオニル基、ノルマルブチリル基又はイソバレリル基を表す〕で表される化合物を、塩基存在下、アルキルイソシアネートと反応させ、一般式(2)におけるR9の3”位水酸基への転移を伴う、一般式(3)
Figure 2007069555
[式中、R1〜R4及びR7〜R9は前記一般式(2)で表されたものと同じ意味を表し、R5は水素原子を表し、R6はC1〜6のアルキル基を表す] で表される化合物の製造方法。
General formula (2)
Figure 2007069555
Wherein, R 1 represents a linear alkyl group of C2-6, R 2 is a linear alkyl group, or a hydroxyl-modifying group of C2-6, R 3 is C1 to 6 represents an alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group or a hydroxyethyl group in which a hydroxyl group is modified with a silyl protecting group, R 4 represents a C1-6 alkyl group, a C2-6 alkenyl A group, a C2-6 alkynyl group or an Ar-B- group (wherein Ar represents an aryl group or a heterocyclic group, B is a C1-6 alkyl group, a C2-6 alkenyl group or a C2-6 alkynyl group). R 7 represents —CH (OR 10 ) 2 (where R 10 represents a C1-5 alkyl group), the following group (a):
Figure 2007069555
(Where n represents an integer of 2 to 3) or R 1 and R 7 and the following group (b)
Figure 2007069555
(Wherein R 11 represents a silyl protecting group)
R 8 represents a C2-C5 linear alkylcarbonyl group,
R 9 represents an acetyl group, a propionyl group, a normal butyryl group or an isovaleryl group], and is reacted with an alkyl isocyanate in the presence of a base to give a 3 ″ -position hydroxyl group of R 9 in the general formula (2) General formula (3) with transition to
Figure 2007069555
[Wherein R 1 to R 4 and R 7 to R 9 represent the same meaning as that represented by the general formula (2), R 5 represents a hydrogen atom, and R 6 represents a C 1-6 alkyl group. The process for producing a compound represented by:
一般式(2)
Figure 2007069555
〔式中、R1は、C2〜6の直鎖状アルキルカルボニル基を表し、R2は、C2〜6の直鎖状アルキルカルボニル基を表し、R3は、C1〜6のアルキル基、水酸基をシリル系保護基で修飾したヒドロキシエチル基を表し、R4は、C2〜6のアルケニル基又はAr-B-基(ここで、Arはアリール基又は複素環基を表し、BはC1〜6のアルキル基、C2〜6のアルケニル基又はアルキニル基を表す)を表し、
R7は、-CH(OR10)2(ここで、R10はC1〜5のアルキル基を表す)、又はR1とR7を含んで下記の基(b)
Figure 2007069555
(ここで、R11は、tert-ブチルジメチルシリル基を表す)を表し、
R8は、C2〜C5の直鎖状アルキルカルボニル基を表し、
R9はプロピオニル基を表す〕で表される化合物を、塩基存在下、アルキルイソシアネートと反応させ、一般式(2)におけるR9の3”位水酸基への転移を伴う、一般式(3)
Figure 2007069555
[式中、R1〜R3及びR7〜R9は、前記一般式(2)で表されたものと同じ意味を表し、R5は、水素原子を表し、R6は、C1〜6のアルキル基を表す] で表される化合物の製造方法。
General formula (2)
Figure 2007069555
Wherein, R 1 represents a linear alkyl group of C2-6, R 2 represents a linear alkyl group of C2-6, R 3 is an alkyl group of Cl to 6, hydroxyl groups Represents a hydroxyethyl group modified with a silyl protecting group, R 4 represents a C2-6 alkenyl group or Ar-B- group (wherein Ar represents an aryl group or a heterocyclic group, and B represents C1-6 Represents an alkyl group, a C2-6 alkenyl group or an alkynyl group),
R 7 is —CH (OR 10 ) 2 (where R 10 represents a C1-5 alkyl group), or R 1 and R 7 , and the following group (b)
Figure 2007069555
Wherein R 11 represents a tert-butyldimethylsilyl group,
R 8 represents a C2-C5 linear alkylcarbonyl group,
R 9 represents a propionyl group] is reacted with an alkyl isocyanate in the presence of a base, and R 9 in General Formula (2) is transferred to the 3 ″ -position hydroxyl group, and is represented by General Formula (3)
Figure 2007069555
[Wherein, R 1 to R 3 and R 7 to R 9 represent the same meaning as that represented by the general formula (2), R 5 represents a hydrogen atom, and R 6 represents C 1-6 . A method for producing a compound represented by:
一般式(2)
Figure 2007069555
〔式中、R1は、C2〜6の直鎖状アルキルカルボニル基を表し、R2は、C2〜6の直鎖状アルキルカルボニル基、又は水酸基の修飾基を表し、R3は、C1〜6のアルキル基、C2〜6のアルケニル基、C2〜6のアルキニル基又は水酸基をシリル系保護基で修飾したヒドロキシエチル基を表し、R4は、C1〜6のアルキル基、C2〜6のアルケニル基、C2〜6のアルキニル基、Ar-B-基(ここで、Arはアリール基又は複素環基を表し、BはC1〜6のアルキル基、C2〜6のアルケニル基又はC2〜6のアルキニル基を表す)を表し、
R7は、-CH(OR10)2(ここで、R10はC1〜5のアルキル基を表す)、下記の基(a)
Figure 2007069555
(ここで、nは2〜3の整数を表す)、又はR1とR7を含んで下記の一般式基(b)
Figure 2007069555
(ここで、R11は、シリル系保護基を表す)を表し、
R8は、C2〜C5の直鎖状アルキルカルボニル基を表し、
R9はアセチル基、プロピオニル基、ノルマルブチリル基又はイソバレリル基を表す〕で表される化合物を、塩基存在下、1,1 ’-カルボニルジイミダゾールと反応させ、一般式(4)
Figure 2007069555
[式中、R1〜R4及びR7〜R9は、前記一般式(2)で表されたものと同じ意味を表す] とした後、さらに塩基の存在下又は非存在下、一級若しくは二級アミンであるR5R6NHと反応させる、一般式(3)
Figure 2007069555
[R1〜R4及びR7〜R9は、前記一般式(2)で表されたものと同じ意味を表し、R5及びR6は、同一でも異なっていても良く、水素原子又は水酸基で置換されていてもよいC1〜6のアルキル基を表す]で表される化合物の製造方法。
General formula (2)
Figure 2007069555
Wherein, R 1 represents a linear alkyl group of C2-6, R 2 represents a linear alkyl group, or a hydroxyl-modifying group of C2-6, R 3 is C1 to 6 represents an alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group or a hydroxyethyl group in which a hydroxyl group is modified with a silyl protecting group, R 4 represents a C1-6 alkyl group, a C2-6 alkenyl A group, a C2-6 alkynyl group, an Ar-B- group (wherein Ar represents an aryl group or a heterocyclic group, B is a C1-6 alkyl group, a C2-6 alkenyl group, or a C2-6 alkynyl group). Represents a group)
R 7 is —CH (OR 10 ) 2 (where R 10 represents a C1-5 alkyl group), the following group (a)
Figure 2007069555
(Where n represents an integer of 2 to 3), or R 1 and R 7 and the following general formula group (b)
Figure 2007069555
(Wherein R 11 represents a silyl protecting group)
R 8 represents a C2-C5 linear alkylcarbonyl group,
R 9 represents an acetyl group, a propionyl group, a normal butyryl group or an isovaleryl group] and is reacted with 1,1′-carbonyldiimidazole in the presence of a base to give a compound of the general formula (4)
Figure 2007069555
[Wherein R 1 to R 4 and R 7 to R 9 represent the same meaning as that represented by the general formula (2)], and further, in the presence or absence of a base, primary or Reaction with secondary amine R 5 R 6 NH, general formula (3)
Figure 2007069555
[R 1 to R 4 and R 7 to R 9 represent the same meaning as that represented by the general formula (2), and R 5 and R 6 may be the same or different, and may be a hydrogen atom or a hydroxyl group. Represents a C1-6 alkyl group which may be substituted with a process for producing a compound represented by:
一般式(2)
Figure 2007069555
〔式中、R1は、C2〜6の直鎖状アルキルカルボニル基を表し、R2は、C2〜6の直鎖状アルキルカルボニル基を表し、R3は、C1〜6のアルキル基又は水酸基をシリル系保護基で修飾したヒドロキシエチル基を表し、R4は、C2〜6のアルケニル基又はAr-B-基(ここで、Arはアリール基又は複素環基を表し、BはC1〜6のアルキル基、C2〜6のアルケニル基又はC2〜6のアルキニル基を表す)を表し、
R7は、-CH(OR10)2(ここで、R10はC1〜5のアルキル基を表す)、又はR1とR7を含んで下記の基(b)
Figure 2007069555
(ここで、R11は、tert-ブチルジメチルシリル基を表す)を表し、
R8は、C2〜C5の直鎖状アルキルカルボニル基を表し、
R9は、プロピオニル基を表す〕で表される化合物を、塩基存在下、1,1 ’-カルボニルジイミダゾールと反応させ、一般式(4)
Figure 2007069555
[式中、R1〜R4及びR7〜R9は、前記一般式(2)で表されたものと同じ意味を表す] とした後、さらに塩基の存在下又は非存在下、一級若しくは二級アミンであるR5R6NHと反応させる、一般式(3)
Figure 2007069555
[R1〜R4及びR7〜R9は、前記一般式(2)で表された化合物と同じ意味を表し、R5及びR6は、同一でも異なっていても良く、水素原子又は水酸基で置換されていてもよいC1〜6のアルキル基を表す]で表される化合物の製造方法。
General formula (2)
Figure 2007069555
Wherein, R 1 represents a linear alkyl group of C2-6, R 2 represents a linear alkyl group of C2-6, R 3 is Cl to 6 alkyl or hydroxyl group Represents a hydroxyethyl group modified with a silyl protecting group, R 4 represents a C2-6 alkenyl group or Ar-B- group (wherein Ar represents an aryl group or a heterocyclic group, and B represents C1-6 An alkyl group, a C2-6 alkenyl group or a C2-6 alkynyl group)
R 7 is —CH (OR 10 ) 2 (where R 10 represents a C1-5 alkyl group), or R 1 and R 7 , and the following group (b)
Figure 2007069555
Wherein R 11 represents a tert-butyldimethylsilyl group,
R 8 represents a C2-C5 linear alkylcarbonyl group,
R 9 represents a propionyl group] and is reacted with 1,1′-carbonyldiimidazole in the presence of a base to give a compound of the general formula (4)
Figure 2007069555
[Wherein R 1 to R 4 and R 7 to R 9 represent the same meaning as that represented by the general formula (2)], and further, in the presence or absence of a base, primary or Reaction with secondary amine R 5 R 6 NH, general formula (3)
Figure 2007069555
[R 1 to R 4 and R 7 to R 9 represent the same meaning as the compound represented by the general formula (2), and R 5 and R 6 may be the same or different, and may be a hydrogen atom or a hydroxyl group. Represents a C1-6 alkyl group which may be substituted with a process for producing a compound represented by:
一般式(2)
Figure 2007069555
〔式中、R1は、C2〜6の直鎖状アルキルカルボニル基を表し、R2は、C2〜6の直鎖状アルキルカルボニル基、又は水酸基の修飾基を表し、R3は、C1〜6のアルキル基、C2〜6のアルケニル基、C2〜6のアルキニル基又は水酸基をシリル系保護基で修飾したヒドロキシエチル基を表し、R4は、C1〜6のアルキル基、C2〜6のアルケニル基、C2〜6のアルキニル基又はAr-B-基(ここで、Arはアリール基又は複素環基を表し、BはC1〜6のアルキル基、C2〜6のアルケニル基又はC2〜6のアルキニル基を表す)を表し、
R7は、-CH(OR10)2(ここで、R10はC1〜5のアルキル基を表す)、下記の基(a)
Figure 2007069555
(ここで、nは2〜3の整数を表す)又はR1とR7を含んで下記の基(b)
Figure 2007069555
(ここで、R11は、シリル系保護基を表す)を表し、
R8は、C2〜C5の直鎖状アルキルカルボニル基を表し、
R9は、アセチル基、プロピオニル基、ノルマルブチリル基又はイソバレリル基を表す〕で表される化合物を、塩基存在下、アルキルイソシアネートと反応させ、一般式(2)におけるR9の3”位水酸基への転移を伴い、一般式(3)
Figure 2007069555
[式中、R1〜R4及びR7〜R9は前記一般式(2)で表されたものと同じ意味を表し、R5は、水素原子を表し、R6は、C1〜6のアルキル基を表す] で表される化合物とする工程を含む、下記の一般式(1)
Figure 2007069555
[式中、
R1は、水素原子又はC2〜6の直鎖状アルキルカルボニル基を表し、
R2は、水素原子又はC2〜6のアルキルカルボニル基を表し、
R3は、水酸基で置換されていてもよいC1〜6のアルキル基、C2〜6のアルケニル基又はC2〜6のアルキニル基を表し、
R4は、水素原子、C1〜6のアルキル基、C2〜6のアルケニル基、C2〜6のアルキニル基又はAr-B-基(ここで、Arはアリール基又は複素環基を表し、BはC1〜6のアルキル基又はC2〜6のアルケニル基を表す)を表し、
R5及びR6は、同一でも異なっていても良く、水素原子、又はC1〜6のアルキル基若しくはC2〜6のアルケニル基である]
で表される化合物又は薬学的に許容されるその塩の製造方法。
General formula (2)
Figure 2007069555
Wherein, R 1 represents a linear alkyl group of C2-6, R 2 represents a linear alkyl group, or a hydroxyl-modifying group of C2-6, R 3 is C1 to 6 represents an alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group or a hydroxyethyl group in which a hydroxyl group is modified with a silyl protecting group, R 4 represents a C1-6 alkyl group, a C2-6 alkenyl A group, a C2-6 alkynyl group or an Ar-B- group (wherein Ar represents an aryl group or a heterocyclic group, B is a C1-6 alkyl group, a C2-6 alkenyl group or a C2-6 alkynyl group). Represents a group)
R 7 is —CH (OR 10 ) 2 (where R 10 represents a C1-5 alkyl group), the following group (a)
Figure 2007069555
(Where n represents an integer of 2 to 3) or R 1 and R 7 and the following group (b)
Figure 2007069555
(Wherein R 11 represents a silyl protecting group)
R 8 represents a C2-C5 linear alkylcarbonyl group,
R 9 represents an acetyl group, a propionyl group, a normal butyryl group or an isovaleryl group], and is reacted with an alkyl isocyanate in the presence of a base to give a 3 ″ -position hydroxyl group of R 9 in the general formula (2) With the transition to general formula (3)
Figure 2007069555
[Wherein, R 1 to R 4 and R 7 to R 9 represent the same meaning as that represented by the general formula (2), R 5 represents a hydrogen atom, and R 6 represents C 1-6 . The following general formula (1) is included, which includes the step of making a compound represented by the formula:
Figure 2007069555
[Where:
R 1 represents a hydrogen atom or a C2-6 linear alkylcarbonyl group,
R 2 represents a hydrogen atom or a C2-6 alkylcarbonyl group,
R 3 represents a C1-6 alkyl group optionally substituted with a hydroxyl group, a C2-6 alkenyl group, or a C2-6 alkynyl group,
R 4 represents a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group or an Ar-B- group (wherein Ar represents an aryl group or a heterocyclic group, B represents Represents a C1-6 alkyl group or a C2-6 alkenyl group),
R 5 and R 6 may be the same or different and are a hydrogen atom, a C1-6 alkyl group or a C2-6 alkenyl group.
Or a pharmaceutically acceptable salt thereof.
一般式(2)
Figure 2007069555
〔式中、R1は、C2〜6の直鎖状アルキルカルボニル基を表し、R2は、C2〜6の直鎖状アルキルカルボニル基、又は水酸基の修飾基を表し、R3は、C1〜6のアルキル基、C2〜6のアルケニル基、C2〜6のアルキニル基又は水酸基をシリル系保護基で修飾したヒドロキシエチル基を表し、R4は、C1〜6のアルキル基、C2〜6のアルケニル基、C2〜6のアルキニル基、Ar-B-基(ここで、Arはアリール基又は複素環基を表し、BはC1〜6のアルキル基、C2〜6のアルケニル基又はC2〜6のアルキニル基を表す)を表し、
R7は、-CH(OR10)2(ここで、R10はC1〜5のアルキル基を表す)、下記の基(a)
Figure 2007069555
(ここで、nは2〜3の整数を表す)、又はR1とR7を含んで下記の一般式基(b)
Figure 2007069555
(ここで、R11は、シリル系保護基を表す)を表し、
R8は、C2〜C5の直鎖状アルキルカルボニル基を表し、
R9はアセチル基、プロピオニル基、ノルマルブチリル基又はイソバレリル基を表す〕で表される化合物を、塩基存在下、1 ,1 ’-カルボニルジイミダゾールを用いて、一般式(4)
Figure 2007069555
[式中、R1〜R3及びR7〜R9は、前記一般式(2)で表されたものと同じ意味を表す] とした後、さらに塩基の存在下又は非存在下、一級若しくは二級アミンであるR5R6NHと反応させ、一般式(3)
Figure 2007069555
[R1〜R4及びR7〜R9は、前記一般式(2)で表されたものと同じ意味を表し、R5及びR6は、同一でも異なっていても良く、水素原子又は水酸基で置換されていてもよいC1〜6のアルキル基を表す]で表される化合物とする工程を含む、下記の一般式(1)
Figure 2007069555
[式中、
R1は、水素原子又はC2〜6の直鎖状アルキルカルボニル基を表し、
R2は、水素原子又はC2〜6のアルキルカルボニル基を表し、
R3は、水酸基で置換されていてもよいC1〜6のアルキル基、C2〜6のアルケニル基又はC2〜6のアルキニル基を表し、
R4は、水素原子、C1〜6のアルキル基、C2〜6のアルケニル基、C2〜6のアルキニル基又はAr-B-基(ここで、Arはアリール基又は複素環基を表し、BはC1〜6のアルキル基、C2〜6のアルケニル基を表す)を表し、
R5及びR6は、同一でも異なっていても良く、水素原子又は水酸基で置換されていてもよいC1〜6のアルキル基若しくはC2〜6のアルケニル基である]
で表される化合物又は薬学的に許容されるその塩の製造方法。
General formula (2)
Figure 2007069555
Wherein, R 1 represents a linear alkyl group of C2-6, R 2 represents a linear alkyl group, or a hydroxyl-modifying group of C2-6, R 3 is C1 to 6 represents an alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group or a hydroxyethyl group in which a hydroxyl group is modified with a silyl protecting group, R 4 represents a C1-6 alkyl group, a C2-6 alkenyl A group, a C2-6 alkynyl group, an Ar-B- group (wherein Ar represents an aryl group or a heterocyclic group, B is a C1-6 alkyl group, a C2-6 alkenyl group, or a C2-6 alkynyl group). Represents a group)
R 7 is —CH (OR 10 ) 2 (where R 10 represents a C1-5 alkyl group), the following group (a)
Figure 2007069555
(Where n represents an integer of 2 to 3), or R 1 and R 7 and the following general formula group (b)
Figure 2007069555
(Wherein R 11 represents a silyl protecting group)
R 8 represents a C2-C5 linear alkylcarbonyl group,
R 9 represents an acetyl group, a propionyl group, a normal butyryl group or an isovaleryl group] in the presence of a base using 1,1′-carbonyldiimidazole and represented by the general formula (4)
Figure 2007069555
[Wherein R 1 to R 3 and R 7 to R 9 represent the same meaning as that represented by the general formula (2)], and further, in the presence or absence of a base, primary or Reaction with a secondary amine, R 5 R 6 NH, to give a general formula (3)
Figure 2007069555
[R 1 to R 4 and R 7 to R 9 represent the same meaning as that represented by the general formula (2), and R 5 and R 6 may be the same or different, and may be a hydrogen atom or a hydroxyl group. Represents a C1-6 alkyl group optionally substituted with a compound represented by the following general formula (1):
Figure 2007069555
[Where:
R 1 represents a hydrogen atom or a C2-6 linear alkylcarbonyl group,
R 2 represents a hydrogen atom or a C2-6 alkylcarbonyl group,
R 3 represents a C1-6 alkyl group optionally substituted with a hydroxyl group, a C2-6 alkenyl group, or a C2-6 alkynyl group,
R 4 represents a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group or an Ar-B- group (wherein Ar represents an aryl group or a heterocyclic group, B represents Represents a C1-6 alkyl group, a C2-6 alkenyl group),
R 5 and R 6 may be the same or different, and are a C1-6 alkyl group or a C2-6 alkenyl group optionally substituted with a hydrogen atom or a hydroxyl group.
Or a pharmaceutically acceptable salt thereof.
請求項1〜10のいずれか1項に記載の化合物又は薬学的に許容されるその塩を有効成分として含む医薬。 The pharmaceutical which contains the compound of any one of Claims 1-10, or its salt accept | permitted as an active ingredient. 抗菌剤である請求項17に記載の医薬。 The medicament according to claim 17, which is an antibacterial agent. 請求項1〜10のいずれか1項に記載の化合物又は薬理学的に許容されるその塩とともに薬理学上許容される担体を含む医薬組成物の形態の請求項17又は18に記載の医薬。 The medicine according to claim 17 or 18 in the form of a pharmaceutical composition comprising a pharmacologically acceptable carrier together with the compound according to any one of claims 1 to 10 or a pharmacologically acceptable salt thereof.
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