JPWO2013008928A1 - Macrolide derivatives - Google Patents

Abstract

The present invention includes cancer angiogenesis, rheumatoid arthritis, intimal thickening, vascular atherosclerosis, hemorrhagic stroke, acute myocardial infarction, chronic heart failure, aneurysm, cancer metastasis, adult respiratory distress syndrome, asthma, It is an object to provide a novel compound or a pharmaceutically acceptable salt thereof useful for the prevention or treatment of diseases such as idiopathic pulmonary fibrosis, chronic sinusitis, bronchitis, or chronic obstructive pulmonary disease. The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

Description

  The present invention relates to a novel macrolide derivative and a pharmaceutically acceptable salt thereof.

  Cancer angiogenesis, rheumatoid arthritis, intimal thickening, vascular atherosclerosis, hemorrhagic stroke, acute myocardial infarction, chronic heart failure, aneurysm, cancer metastasis, adult respiratory distress syndrome, asthma, idiopathic lung fiber Many conditions such as tumor necrosis factor (TNF) α, interleukin (IL) -1β, IL-8, and IL-6 during pathologies such as infectious disease (IPF), chronic sinusitis, bronchitis, and chronic obstructive pulmonary disease (COPD) Expression of inflammatory cytokines is increased. At the same time, the activity control mechanism of matrix metalloprotease (hereinafter referred to as MMP) breaks down, and the pathological condition is exacerbated by the degradation of excess extracellular matrix (ECM) (for example, elastin, collagen, gelatin, laminin, fibronectin). Is known (see Non-Patent Documents 1, 2, and 3).

  MMP has 20 or more types of isozymes, and in particular, MMP-9 (Gelatinase B) having a molecular weight of 92 kDa is induced by inflammatory cytokines such as TNFα and IL-1 (see Non-Patent Document 4). MMP-9 not only degrades ECM such as collagen type IV and elastin, but also enhances the activity by degrading cytokines (eg IL-1β, IL-8, tumor growth factor (TGF) -β), and inflammatory response It is also known to increase or worsen Furthermore, MMP-9 degrades endogenous proteolytic enzyme inhibitors (for example, tissue factor protease inhibitor, α1-antitrypsin, α1-antichymotrypsin), activates the protease cascade, and further worsens the disease state.

  In general, COPD is a disease characterized by obstructive ventilation disorder caused by bronchitis, emphysema, or a combination of both. According to GOLD (Global Initiative for Chronic Obstructive Lung Disease), COPD is a disease characterized by airflow limitation that is not completely reversible. This airflow limitation is a progressive, harmful particle or It is associated with an abnormal inflammatory response to gas. ”And indicates that improved inflammatory conditions can be a causative therapy.

  Emphysema in COPD is a condition in which the alveolar wall is destroyed and the fine structure of the alveoli is hollow. Emphysema reduces the efficiency of gas exchange and the elastic contraction of the entire lung, ultimately reducing lung function. For the development of emphysema, inflammatory activity such as IL-1β, TNFα released from inflammatory cells (eg, alveolar macrophages, neutrophils) activated or newly infiltrated into the lung by smoking, air pollution, harmful gases, etc. It is known that cytokines, MMP-9, and MMP-12 are strongly involved (see Non-Patent Documents 5, 6, and 7).

  It has been reported that IL-1β, TNFα, IL-8, IL-6 and the like increase in sputum and airway lavage fluid of COPD patients (see Non-Patent Document 8). In addition, MMP-9 is enhanced in neutrophils, alveolar macrophages, and epithelial cells by inflammatory stimuli such as TNFα and IL-1, and the amount of MMP-9 is actually increased in COPD patients. It has been reported to correlate with a decrease in lung function (see Non-Patent Document 9). Furthermore, expression of MMP-9, IL-1β, TNFα, IL-8, granulocyte / macrophage colony-stimulating factor (GM-CSF), etc. increased in mice exposed to cigarette smoke, the main cause of COPD. It is known (see Non-Patent Document 10). Therefore, if various inflammatory cytokines such as MMP, IL-1β, and TNFα can be returned to a normal state, it is considered useful for the treatment of the above diseases.

  As current pharmacotherapy for COPD, airway dilators (anticholinergic drugs, β2 receptor agonists, etc.) are widely used clinically, and recently phosphodiesterase (PDE) IV inhibitors with anti-inflammatory action are used in severe cases. Although it has been approved as a management and maintenance drug, it has been shown to be effective in improving patients' quality of life.

  Antibiotics having a macrolide skeleton (erythromycin, clarithromycin, loxithromycin, azithromycin) have been reported to have anti-inflammatory effects in vitro such as cytokine production suppression (see Non-Patent Documents 11 and 12). Moreover, regarding in vivo anti-inflammatory action, azithromycin or clarithromycin is administered to the lung tissue of a mouse lung injury model, and a wide range of inflammatory cytokines such as IL-1β, TNFα, GM-CSF, and IL-6 are administered. Although production is reported to be suppressed (see Non-Patent Document 11), the effective dose is 600 mg / kg, which is a high dose. Furthermore, since macrolides have strong antibacterial activity, there are problems such as gastrointestinal disorders associated with changes in intestinal flora and long-term administration, and the development of resistant bacteria. The use of the macrolide it has for the above diseases is limited.

  Moreover, although the technique which uses azithromycin for the treatment of the neutrophil dominant non-infectious inflammatory disease containing COPD is disclosed (refer patent document 1), isolation | separation with an anti-inflammatory action and antibacterial activity is made | formed. Absent. Furthermore, although there is a report on a compound in which the 2′-position hydroxyl group and the 3′-position dimethylamino group of desosamine bound to the 5-position of erythromycin antibiotics are derivatized (see Patent Document 2 and Non-Patent Document 13), antibacterial activity is reported. There is no description that inflammatory cytokine production inhibitory action and MMP-9 production inhibitory action were separated.

  On the other hand, there has been a report on a macrolide that has separated antibacterial activity and MMP-9 production inhibitory activity (see Patent Document 3), but there is no description on the action on inflammatory cytokines other than MMP-9, and nitrogen is located at the 3 'position. It is a macrolide having a containing group.

International Publication No. 02/087596 JP 55-151598 A International Publication No. 2007/129646

Circ. Res. Vol. 90, 520-530 (2002) Am. J. Respir. Cell Mol. Biol., 28, 12-24 (2003) J. Clin. Invest. Vol. 118, 3537-3545 (2008) Biol. Reprod. Vol. 78, 1064-1072 (2008) Nature Reviews / Drug Discovery, Vol. 1, 437-446 (2002) Am. J. Respir. Crit. Care Med. Vol. 170, 492-498 (2004) Am. J. Respir. Cell Mol. Biol. Vol. 40, 482-490 (2009) Eur. Respir. J. 18, Suppi. 34, 50s-59s (2001) Am. J. Respir. Cell Mol. Biol., 26, 602-609 (2002) Am. J. Physiol. Lung Cell Mol. Physiol. Vol. 290, L931-L945 (2006) J. Pharmacol. Exp. Ther. Vol. 331, 104-113 (2009) J. Pharmacol. Exp. Ther. Vol. 292, 156-163 (2000) Heterocycles, Vol. 31, No. 2, 305-319 (1990)

  An object of the present invention is to provide a macrolide derivative having an MMP-9 production inhibitory action or an inflammatory cytokine production inhibitory action and having an antibacterial action separated.

  As a result of intensive studies for the above object, the present inventors have found that a novel macrolide derivative achieves this object and completed the present invention.

That is, the present invention is as follows.
(1) Formula (I)

(Where
A double line including a broken line indicates a single bond or a double bond,
R ¹ and R ² are the same or different and each represents a hydrogen atom, a C _1-6 alkylsulfonyl group, or a C _1-6 alkyl group (the C _1-6 alkyl group is an oxo group, a phenyl group, 1 to 3 pieces of C _1-6 alkyl groups of 5-7 membered may be substituted saturated heterocyclic group, and substituted with 1 to 3 substituents selected from the group consisting of C _1-6 alkylamino group 5 or 7-membered saturated heterocycle (the 5- to 7-membered saturated heterocycle is an oxygen atom in the ring), or R ¹ and R ² together with the nitrogen atom to be bonded , sulfur atom (optionally oxidized), or a nitrogen atom may, hydroxy groups, and substituted with 1 to 3 substituents selected from substituent group 1 good C _1-6 The substituent group 1 may be substituted with 1 to 3 substituents selected from an alkyl group. The substituent group 1 includes an oxo group, a benzyloxy group, and C _A group consisting of _1-6 alkylamino groups),
R ³ represents a hydrogen atom, a phenyl group, a 5- to 7-membered saturated heterocyclic group (the 5- to 7-membered saturated heterocyclic group is selected from a C _1-6 alkylsulfonyl group and substituent group 1). 1 may be substituted with 1 to 3 substituents selected from C _1-6 alkyl groups optionally substituted with 3 substituents), CONR ⁹ R ¹⁰ , or substituent group 2 Represents a C _1-6 alkyl group substituted with ~ 3 substituents,
R ⁹ and R ¹⁰ are the same or different and each is a hydrogen atom or a C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with 1 to 3 C _1-6 alkylamino groups). A phenyl group, a C _2-7 alkoxycarbonyl group, a 5- to 7-membered saturated heterocyclic group optionally substituted by 1 to 3 C _1-6 alkyl groups, and 2,3-dihydrobenzo [b] [1 .4] may be substituted with 1 to 3 substituents selected from the group consisting of dioxynyl groups), a C _3-6 cycloalkyl group, or 1 to 3 C _1-6 alkyl groups. A good 5- to 7-membered saturated heterocyclic group, phenyl group (the phenyl group is selected from the group consisting of a C _1-6 alkoxy group, a C _3-6 cycloalkyloxy group, and a C _1-6 alkylamino group) to 3 substituents may be substituted with a group), a pyridyl group (said pyridyl group is, C _1-6 alkoxy, C _3-6 consequent Alkyl group, and C _1-6 may be substituted with 1-3 substituents selected from the group consisting of alkyl amino group), or 2,3-dihydrobenzo [b] [1.4] dioxinyl group Indicate
Substituent group 2 includes a hydroxy group, a benzyloxy group, a phenyl group which may be substituted with 1 to 3 C _1-6 alkoxy groups, a C _3-6 cycloalkyl group, a C _1-6 alkylamino group, 6 -Hydroxy-2,5,7,8-tetramethylchromanyl group, 1,3-dimethyl-1H-purine-2,6 (3H, 7H) -dionyl group, and 5- to 7-membered saturated heterocyclic group ( saturated heterocyclic group of the 5-7 membered, hydroxy group, C _1-6 alkylsulfonyl group, and 1-3 may be substituted with a substituent C _1-6 alkyl group selected from substituent group 3 And the substituent group 3 is a group consisting of an oxo group, a phenyl group, and a C _1-6 alkylamino group).
R ⁴ represents a hydrogen atom or a C _1-6 alkyl group,
R ⁵ represents a hydrogen atom (only when a double line including a broken line indicates a double bond), a hydroxy group, or a C _1-6 alkanoyloxy group,
R ⁶ represents a hydrogen atom or a hydroxy group, or when the double line including a broken line is a single bond, R ⁵ and R ⁶ are taken together to form the formula (II)

Or a structure represented by formula (III)

The structure indicated by
R ¹¹ represents a hydrogen atom or a C _1-6 alkyl group which may be substituted with 1 to 3 cyano groups,
R ⁷ represents a hydrogen atom,
R ⁸ is a hydroxy group, formula OCOR ¹² , or formula (IV)

Shows the structure shown in
R ¹² represents a C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of a phenyl group and a pyridyl group);
R ¹³ represents a hydrogen atom,
R ¹⁴ represents a hydrogen atom, a hydroxy group, a C _1-6 alkoxy group that may be substituted with 1 to 3 cyano groups, a formula OCOR ¹⁵ , or a formula OCONR ¹⁶ R ¹⁷ ;
R ¹⁵ represents a C _1-6 alkyl group which may be substituted with 1 to 3 substituents selected from substituent group 4.
Substituent group 4 includes a hydroxy group, a benzyloxy group, a C _1-6 alkylamino group, and a 5- to 7-membered saturated heterocyclic group (the 5- to 7-membered saturated heterocyclic group includes a hydroxy group and C _{1 -6} alkyl group may be substituted with 1 to 3 substituents selected from alkyl groups),
R ¹⁶ and R ¹⁷ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, or a phenyl group, or R ¹³ and R ¹⁴ together may represent an oxo group, Alternatively, R ⁷ and R ⁸ may together represent an oxo group, provided that R ¹ and R ² are both methyl groups and R ³ is a hydrogen atom. Or a pharmaceutically acceptable salt thereof.

(2) The compound or a pharmaceutically acceptable salt thereof according to (1), wherein the double line including a broken line is a single bond.

(3) The compound or a pharmaceutically acceptable salt thereof according to (1) or (2), wherein R ⁵ and R ⁶ are both hydroxy groups.

(4) The compound according to any one of (1) to (3) or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a methyl group.

(5) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (4), wherein R ⁷ is a hydrogen atom, and R ⁸ is a structure represented by formula (IV).

(6) The compound according to any one of (1) to (5), wherein R ³ is a C _1-6 alkyl group substituted with 1 to 3 substituents selected from Substituent Group 2 Its pharmaceutically acceptable salt.

(7) The compound according to any one of (1) to (6) or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are the same or different and each is a hydrogen atom or a C _1-6 alkyl group. Salt.

(8) Cancerous angiogenesis, rheumatoid arthritis, intimal thickening, vascular fistula containing the compound according to any one of (1) to (7) or a pharmaceutically acceptable salt thereof as an active ingredient Atherosclerosis, hemorrhagic stroke, acute myocardial infarction, chronic heart failure, aneurysm, cancer metastasis, adult respiratory distress syndrome, asthma, idiopathic pulmonary fibrosis, chronic sinusitis, bronchitis, or chronic obstructive pulmonary disease Prophylactic or therapeutic agent such as

  The compound of the present invention has an MMP-9 production inhibitory action or an inflammatory cytokine production inhibitory action and does not have an antibacterial action.

  The compound of the present invention has no antibacterial action, and has an action of suppressing MMP-9 production or inflammatory cytokine production. The compound of the present invention preferably has an MMP-9 production inhibitory action and an inflammatory cytokine production inhibitory action.

In the present invention, the C _1-6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, Examples thereof include an n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, an n-pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, and an n-hexyl group.

The C _1-6 alkylamino group is a group in which the above “C _1-6 alkyl group” is bonded to one or two amino groups, such as a methylamino group, a dimethylamino group, a diethylamino group, N-ethyl- Examples include N-methylamino group.

The C _3-6 cycloalkyl group means a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.

The C _3-6 cycloalkyloxy group means a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, or a cyclohexyloxy group.

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

The C _1-6 alkoxy group means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy. Group, isobutoxy group, tert-butoxy group, sec-butoxy group, n-pentyloxy group, isopentyloxy group, neopentyloxy group, tert-pentyloxy group, n-hexyloxy group and the like.

C _1-6 alkylsulfonyl group means a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms, such as methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, isopropylsulfonyl. Group, n-butylsulfonyl group, isobutylsulfonyl group, tert-butylsulfonyl group, sec-butylsulfonyl group, n-pentylsulfonyl group, isopentylsulfonyl group, neopentylsulfonyl group, tert-pentylsulfonyl group, n-hexylsulfonyl Examples include groups.

The C _2-7 alkoxycarbonyl group means a linear or branched alkoxycarbonyl group having 2 to 7 carbon atoms, such as methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, iso Propoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, tert-butoxycarbonyl group, sec-butoxycarbonyl group, n-pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, tert-pentyloxy Examples thereof include a carbonyl group and an n-hexyloxycarbonyl group.

The C _1-6 alkanoyloxy group means a linear or branched alkanoyloxy group having 1 to 6 carbon atoms. For example, formyloxy group, acetoxy group, propanoyloxy group, n-butanoyl group An oxy group, an isobutyroyloxy group, etc. can be mentioned.

The 5- to 7-membered saturated heterocyclic group is 5 to 7 containing 1 to 3 atoms arbitrarily selected from a nitrogen atom, an oxygen atom, and a sulfur atom (which may be oxidized) as ring constituent atoms. Membered saturated heterocyclic group such as azetidinyl group, oxetanyl group, pyrrolidinyl group, imidazolidinyl group, pyrazolidinyl group, oxolanyl group, thiolanyl group, tetrahydrothienyl group, dioxotetrahydrothienyl group, isothiazolidinyl group, dioxoisothinyl group List azolidinyl group, oxazolidinyl group, tetrahydropyranyl group, tetrahydrothiopyranyl group, dioxotetrahydrothiopyranyl group, piperidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, dioxothiomorpholinyl group, etc. Can do.
In addition, when R < ¹ > and R < ² > show a 5-7 membered saturated heterocyclic ring with the nitrogen atom to which it couple | bonds, a saturated heterocyclic ring is at least among the said 5-7 membered saturated heterocyclic ring. It has one nitrogen atom in the ring.

  A pharmaceutically acceptable salt is a salt with a mineral acid or an organic acid. For example, acetic acid, propionic acid, butyric acid, formic acid, trifluoroacetic acid, maleic acid, tartaric acid, citric acid, stearic acid, succinic acid, ethyl succinic acid, lactobionic acid, gluconic acid, glucoheptonic acid, benzoic acid, methanesulfonic acid , Ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, lauryl sulfuric acid, malic acid, aspartic acid, glutamic acid, adipic acid, cysteine, N-acetylcysteine, hydrochloric acid, hydrobromic acid, phosphorus Examples thereof include salts with acid, sulfuric acid, hydrogen iodide, nicotinic acid, oxalic acid, picric acid, thiocyanic acid, undecanoic acid, acrylic acid polymer, carboxyvinyl polymer and the like.

  The compound of the present invention may contain a plurality of asymmetric centers. Therefore, the compound can exist in an optically active form and in a racemic form thereof, and can also exist in a plurality of diastereomers. All of the above forms are included within the scope of the present invention. The individual isomers are known methods, for example the use of optically active starting materials or intermediates, optically selective or diastereoselective reactions in the production of intermediates or final products, or intermediates or final products. It can be obtained by separation using chromatography in the production of Further, when the compounds of the present invention form hydrates or solvates, they are also included within the scope of the present invention. Similarly, pharmaceutically acceptable salts of hydrates or solvates of the compounds of the invention are also included within the scope of the invention.

  In order to use the compound of the present invention as a medicine, conventional excipients, extenders, pH adjusters, solubilizers, etc. are added to the compound of the present invention, and tablets, granules, pills, capsules are added by conventional formulation techniques. , Powders, solutions, suspensions, injections, coatings, etc., and can be administered orally, transdermally or intravenously.

  The compound of the present invention can be administered to an adult patient in one to several doses within a range of 10 to 1000 mg per day. This dose can be appropriately increased or decreased depending on the type of disease, patient age, sex, weight, symptoms, and the like.

Preferred embodiments of the compound of the present invention include the following compounds. A compound in which a double line including a broken line is a single bond is preferable. A compound in which R ¹ and R ² are the same or different and are each a hydrogen atom or a C _1-6 alkyl group is preferred, and a compound that is a hydrogen atom or a methyl group is more preferred. R ³ is preferably a compound which is substituted C _1-6 alkyl group with 1 to 3 substituents selected from Substituent Group 2, the compound is a C _1-6 alkyl group substituted with a hydroxy group More preferred. A compound in which R ⁴ is a methyl group is preferred. A compound in which R ⁵ and R ⁶ are both hydroxy groups is preferred. A compound in which R ⁷ is a hydrogen atom and R ⁸ is a structure represented by the formula (IV) is preferable. When R ⁸ is the formula (IV), a compound in which R ¹³ is a hydrogen atom and R ¹⁴ is a hydroxy group is preferable.

  The safety of the compound of the present invention represented by the above formula (I) or a pharmaceutically acceptable salt thereof is evaluated by various tests. For example, cytotoxicity test, hERG test, cytochrome P450 (CYP) activity It can be evaluated by an inhibition test, a phospholipid uptake inhibition test into cells, or the like. Among the compounds of the present invention, particularly safe compounds whose safety has been confirmed by these plural tests are included.

  The metabolic stability of the compound of the present invention represented by the above formula (I) or a pharmaceutically acceptable salt thereof is evaluated by various tests. For example, it should be evaluated by a human liver microsome metabolic stability test or the like. Can do.

  The compounds of formula (I) can be prepared by various synthetic methods. The following method is an illustration of the production method of the compound of the present invention, and is not limited thereto.

  In a general production method, “solvent” means, for example, alcohols such as methanol, ethanol, isopropanol, n-butanol, ethylene glycol, diethyl ether, t-butyl methyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, 1 , Ethers such as 2-dimethoxyethane, hydrocarbons such as pentane, hexane, heptane, toluene, benzene and xylene, esters such as ethyl acetate and ethyl formate, ketones such as acetone and methyl ethyl ketone, chloroform and dichloromethane Examples thereof include halogenated carbon-based solvents, amides such as N, N-dimethylformamide, N-methylpyrrolidone, acetonitrile, dimethyl sulfoxide, water, or a mixed solvent thereof. These solvents are appropriately selected according to various reaction conditions known to those skilled in the art.

  “Base” means, for example, hydrides of alkali metals or alkaline earth metals such as lithium hydride, sodium hydride, potassium hydride, calcium hydride; lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium Alkali metal or alkaline earth metal amides such as hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide; alkali metal or alkaline earth such as sodium methoxide, sodium ethoxide, potassium tert-butoxide Lower metal alkoxides; alkyl lithiums such as butyl lithium, sec-butyl lithium, tert-butyl lithium, methyl lithium; sodium hydroxide, potassium hydroxide, lithium hydroxide, hydroxide Alkali metal or alkaline earth metal hydroxide such as barium; Alkali metal or alkaline earth metal carbonate such as sodium carbonate, potassium carbonate, cesium carbonate; Alkali metal or alkaline earth such as sodium hydrogen carbonate, potassium hydrogen carbonate Metal carbonates; triethylamine, N-methylmorpholine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4. 3.0] amines such as non-5-ene (DBN) and N, N-dimethylaniline; and basic heterocyclic compounds such as pyridine, 4-dimethylaminopyridine, imidazole and 2,6-lutidine. it can. These bases are appropriately selected according to various reaction conditions known to those skilled in the art.

  Examples of the “acid” include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, citric acid, oxalic acid, etc. An organic acid etc. can be mentioned. These acids are appropriately selected according to various reaction conditions known to those skilled in the art.

  Examples of the “condensing agent” include O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphoric acid (HATU), O- (benzotriazole- 1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphoric acid (HBTU), N, N′-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) ) Carbodiimide hydrochloride (EDC · HCl), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (DMT-MM), diphenylphosphoryl azide ( DPPA) or carbonyldiimidazole (CDI). These condensing agents are appropriately selected according to various reaction conditions known to those skilled in the art.

  When a hydroxy group or an amino group is present in the compounds represented by the following formulas, protection and deprotection can be carried out according to a conventional method. Examples of the protecting group for a hydroxy group and an amino group include groups described in Protective Groups in Organic Synthesis (3rd edition, 1999, edited by P. G. M. Wuts, edited by T. Greene) and the like.

General synthesis method 1

[Process 1]
For example, it is represented by the formula (1) that can be synthesized by a method described in a patent document (WO2007129646), a non-patent document (Heterocycles, Vol. 31, No. 2, pp. 305-319, 1990). In the presence of a base (preferably an organic base such as triethylamine, N, N-diisopropylethylamine) in a solvent (preferably chloroform or tetrahydrofuran) in the range of 0 ° C. to room temperature, the compound R ^3a -X (R ^3a is The compound represented by the formula (2) can be synthesized by reacting with a compound represented by a substituted sulfonyl group or a substituted phosphoryl group, and X represents a halogen atom.
Here, the compound represented by R ^3a -X is preferably mesyl chloride.

[Process 2]
Of the compounds represented by formula (3), when R ³ is other than a hydrogen atom, the compound represented by formula (2) is used in a solvent (aprotic solvent, preferably N, N-dimethylformamide, Acetonitrile), if necessary, in the presence of a base and heating (preferably 70 ° C.) with a compound represented by the formula R ³ —OH to synthesize the compound represented by the formula (3) can do.

Of the compounds represented by formula (3), when R ³ is a hydrogen atom, the compound represented by formula (2) is necessary in a solvent (preferably a mixed solvent of N, N-dimethylformamide and water). Then, in the presence of a base and under heating (preferably 70 ° C.), a compound (preferably formic acid) represented by the formula R—COOH (where R represents a hydrogen atom or an alkyl group), or an inorganic salt thereof (preferably Is a compound of the present invention represented by the formula (3) by reacting a compound obtained by reaction with sodium formate in a solvent (preferably an alcohol solvent, more preferably methanol) under heating and refluxing. Can be synthesized.

General synthesis method 2

[Process 3]
The compound of the present invention represented by formula (4) in a solvent (preferably a mixed solvent of methanol or tetrahydrofuran and water), a halogenating agent (for example, iodine, N-bromosuccinimide, N-chlorosuccinimide), and as necessary Accordingly, the compound of the present invention represented by the formula (5) can be synthesized by reacting with an alkali metal organic acid salt (for example, sodium acetate) at room temperature to 80 ° C.

[Process 4]
R ^1a represents each R ¹ group other than a hydrogen atom. The compound of the present invention represented by the formula (5) in a solvent (preferably chloroform, dichloromethane, methanol, ethanol), the formula R ^1b -CHO (where R ^1b is a C _1-5 alkyl group (the C _1-5 alkyl group is 1 to 5 selected from the group consisting of an oxo group, a phenyl group, a 5- to 7-membered saturated heterocyclic group optionally substituted by 1 to 3 C _1-6 alkyl groups, and a C _1-6 alkylamino group And a reducing agent (for example, sodium triacetoxyborohydride, cyanohydrogenation) in the presence of an acid (for example, acetic acid or formic acid) if necessary. By reacting with sodium borohydride or sodium borohydride, the compound of the present invention represented by the formula (6) can be synthesized.

Further, the compound of the present invention represented by the formula (5) is represented by the formula R ^1a -X in a solvent (preferably methanol, ethanol, N, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, dichloromethane, chloroform). And, if necessary, in the presence of a base (for example, an organic base such as triethylamine or N, N-diisopropylethylamine, an alkali metal salt such as sodium bicarbonate or potassium carbonate or an aqueous solution thereof) This invention compound represented by this can be synthesize | combined.

General synthesis method 3

[Process 5]
By reacting the compound represented by the formula (7) in a solvent (preferably N, N-dimethylformamide) with the compound represented by the formula (10) under heating (preferably 70 ° C.), the formula (7 The compound represented by 8) can be synthesized.

[Step 6]
By reacting the compound represented by the formula (8) with a compound represented by the formula NHR ¹ R ² in a solvent (alcohols, preferably isopropanol) under heating (preferably 70 ° C.), the formula (9) This invention compound represented by these is compoundable. In this step, since the compound represented by the formula (1) is also obtained at the same time, the 3 ′ position can be derivatized through the above steps 1 and 2.

General synthesis method 4

[Step 7]
The compound of the present invention represented by the formula (9) is dissolved in a solvent (preferably tetrahydrofuran or toluene) and, if necessary, a base (an organic base is preferable, such as pyridine, 1,4-diazabicyclo [2,2,2] octane. The compound of the present invention represented by the formula (11) in which R ¹⁰ is a hydrogen atom can be synthesized by reacting with a compound represented by the formula R ⁹ —NCO in the presence of
Further, the present compound represented by the formula (9) is reacted with a chloroformate (preferably chloroformate 4) in a solvent (preferably chloroform, dichloromethane) in the presence of a base (preferably triethylamine, N, N-diisopropylethylamine). -Nitrophenyl) and a compound obtained by reacting at 0 ° C. to room temperature with a compound represented by the formula R ⁹ R ¹⁰ NH in a solvent (preferably acetonitrile) under heating and reflux, the formula ( The compound of the present invention represented by 11) can be synthesized.

General synthesis method 5

[Step 8]
The compound of the present invention represented by the formula (13) can be synthesized by reacting the compound of the present invention represented by the formula (12) with an acid (preferably hydrochloric acid) in a solvent (preferably methanol or ethanol). .

[Step 9]
The present compound represented by the formula (13) is oxidized by a method well known to those skilled in the art (for example, desmartin oxidation, moffat oxidation, Corey Kim oxidation, Swan oxidation, Jones oxidation, preferably Corey Kim oxidation). The compound of the present invention represented by the formula (14) can be synthesized.

[Step 10]
Using the compound of the present invention represented by formula (13), the compound of the present invention represented by formula (15) was prepared by the method described in the literature (Journal of Medicinal Chemistry, Vol. 44, pages 4027-4030, 2001). Can be synthesized. That is, the compound represented by the formula (13) is dissolved in a solvent (preferably dichloromethane), a formula R ¹² -COOH, a base (preferably 4-dimethylaminopyridine), and a condensing agent (preferably 1-ethyl-3- The compound of the present invention represented by the formula (15) can be synthesized by reacting in the presence of (3-dimethylaminopropyl) carbodiimide hydrochloride).

General synthesis method 6

[Step 11]
The compound of the present invention represented by the formula (12) is oxidized by a method well known to those skilled in the art (for example, Moffat oxidation, Dess-Martin oxidation, Corey Kim oxidation, Swan oxidation, Jones oxidation, preferably Corey Kim oxidation). The compound of the present invention represented by (16) can be synthesized.

[Step 12]
The compound of the present invention represented by formula (12) is dissolved in a solvent (preferably dichloromethane), formula R ¹⁵ -COOH, a base (preferably 4-dimethylaminopyridine), and a condensing agent (preferably 1-ethyl-3- The compound of the present invention represented by the formula (17) can be synthesized by reacting in the presence of (3-dimethylaminopropyl) carbodiimide hydrochloride).

[Step 13]
The compound of the present invention represented by the formula (12) is dissolved in a solvent (preferably tetrahydrofuran or toluene) and, if necessary, a base (an organic base is preferred, such as pyridine, 1,4-diazabicyclo [2,2,2] octane. The compound of the present invention represented by the formula (18) can be synthesized by reacting with a compound represented by the formula R ¹⁷ —NCO in the presence of
Further, the compound of the present invention represented by the formula (12) is subjected to 1,1 ′ in a solvent (preferably tetrahydrofuran, N, N-dimethylformamide or a mixed solvent thereof) in the presence of a base (preferably sodium hydride). The compound obtained by reacting with -carbonyldiimidazole can be reacted with a compound represented by the formula R ¹⁷ —NH ₂ in a solvent (preferably tetrahydrofuran) at 0 ° C. to room temperature, or by the formula (18). The compound of the present invention can be synthesized.

[Step 14]
The compound of the present invention represented by the formula (12) is used in a solvent (preferably a halogenated carbon such as dichloromethane or dichloroethane), a base (for example, an organic base such as 4-dimethylaminopyridine, an alkali such as sodium bicarbonate or potassium carbonate). In the presence of a metal salt), the compound obtained by reacting with 1,1′-thiocarbonyldiimidazole is mixed with an azobisalkylnitrile compound (for example, 2,2′-azobis) in a solvent (preferably toluene or benzene). The compound of the present invention represented by formula (19) can be synthesized by reacting with a reducing agent (preferably tributyltin hydride) in the presence of (isovityronitrile) or tetramethylsuccinonitrile).

  Next, although a reference example, an Example, and a test example demonstrate this invention further in detail, this invention is not limited to these Examples.

Reference Example 1 3- (4-Isopropylpiperazin-1-yl) propan-1-ol (1) 2.0 g of 1-isopropylpiperazine was dissolved in 52 ml of ethanol, and 7.23 ml of (3-bromopropoxy) -tert-butyldimethylsilane Was added and stirred for 15 hours while heating under reflux. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 10: 1: 0.1) to give 1- (3-tert-butyldimethylsilyloxy) propyl. There was obtained 3.63 g of -4-isopropylpiperazine.
(2) 3.62 g of the compound obtained in (1) above was dissolved in 30 ml of methanol, 10 ml of 2 mol / L hydrochloric acid was added, and the mixture was stirred for 16 hours with heating under reflux. Saturated aqueous sodium bicarbonate and ethyl acetate were added to the residue obtained by concentrating the reaction solution under reduced pressure, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 20: 1: 0.1) to obtain 2.1 g of the title compound.

Reference Example 2 Benzyl (1- (3-hydroxypropyl) piperidin-4-yl) carbonate (1) 1-Boc-4-hydroxypiperidine (4.0 g) was dissolved in chloroform (40 ml), and 4-dimethylaminopyridine (2.9 g) was added. Under cooling with ice, 3.4 ml of benzyl chloroformate was added and stirred at room temperature for 15 hours. Saturated aqueous ammonium chloride was added to the reaction solution for liquid separation, 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 silica gel column chromatography (hexane: ethyl acetate = 9: 1 to 8: 1) to give tert-butyl 4-benzyloxycarbonyloxypiperidine-1-carboxylate 5.2. g was obtained.
(2) 5.2 g of the compound obtained in (1) above was dissolved in 20 ml of ethyl acetate, 20 ml of 4 mol / L ethyl acetate solution was added, and the mixture was stirred at room temperature for 63 hours. The residue obtained by concentrating the reaction solution under reduced pressure was dissolved in 1 mol / L hydrochloric acid and washed with ethyl acetate. The aqueous layer was extracted with chloroform at pH = 14 with 6 mol / L sodium hydroxide aqueous solution. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 3.72 g of benzyl 4-piperidyl carbonate.
(3) Using 3.55 g of the compound obtained in (2) above as a starting material, 5.5 g of the title compound was obtained in the same manner as in Reference Examples 1 (1) and (2).

Reference Example 3 N-2- (4- (3-hydroxypropyl) piperazin-1-yl) ethylphthalimide
Dissolve 2.0 g of 1- (3-hydroxypropyl) -piperazine in 47 ml of chloroform and add 3.14 g of phthalimidoacetaldehyde obtained by the method described in the literature (Tetrahedron Letters, 2001, 42, 315) The mixture was stirred at room temperature for 2 hours. 3.5 g of sodium triacetoxyborohydride was added and stirred at room temperature for 15 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 20: 1: 0.1) to give 3.64 g of the title compound.

Reference Example 4 2- (4-Isopropylpiperazin-1-yl) ethanamine (1) Obtained by 1.0 g of 1-isopropylpiperazine and the method described in the literature (Tetrahedron Letters, 2001, 42, 315) N- (2- (4-Isopropylpiperazin-1-yl) ethyl) phthalimide (2.26 g) was obtained in the same manner as in Reference Example 3 using 1.9 g of phthalimidoacetaldehyde as a raw material.
(2) 2.26 g of the compound obtained in (1) above was dissolved in 150 ml of ethanol, 0.55 ml of hydrazine was added, and the mixture was stirred at room temperature for 110 hours. The reaction solution was filtered, and the residue obtained by concentrating the filtrate under reduced pressure was suspended in chloroform and filtered. 1 mol / L hydrochloric acid was added to the filtrate for liquid separation, and the aqueous layer was extracted with chloroform at pH = 14 with a 6 mol / L aqueous sodium hydroxide solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 1.20 g of the title compound.

Reference Example 5 4- (tert-butyldimethylsilyloxy) piperidine
1-Boc-4-hydroxypiperidine (5.0 g) was dissolved in dimethylformamide (100 ml), tert-butyldimethylchlorosilane (9.62 g) and imidazole (5.78 g) were added, and the mixture was stirred at room temperature for 18 hours. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure was dissolved in 10 ml of methanol, added with 1.76 g of 5% palladium-carbon, and stirred at room temperature for 34 hours in a hydrogen atmosphere. The reaction solution was filtered through Celite, and the residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (hexane: chloroform = 1: 1 to chloroform alone to chloroform: methanol: 28% aqueous ammonia = 10: 1: 0.1). To give 4.60 g of the title compound.

Example 1
(1) 4 "-O-acetyl-6-O-methylerythromycin A (2.0 g) obtained by the method described in the patent document (WO2007129646) is dissolved in chloroform (25 ml), and diisopropylethylamine (1.7 ml) is added, followed by ice cooling. Then, 0.69 ml of methanesulfonyl chloride was added dropwise, and the reaction solution was stirred for 14 hours while gradually warming to room temperature, saturated sodium bicarbonate water was added to the reaction solution, extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 30: 0.2) to obtain 2.3 g of 2′-O-methanesulfonyl. It was.
(2) 1.0 g of the compound obtained in (1) above was dissolved in 5 ml of dimethylformamide, 1.57 ml of 3-phenyl-1-propanol was added, and the mixture was stirred at 70 ° C. for 72 hours. Distilled water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 90: 0.2 to 10: 30: 0.2) to obtain 114 mg of the compound shown in Table 1. .

Example 2
5.29 g of the compound obtained in Example 1 (1) was dissolved in 30 ml of acetonitrile, 4.8 ml of 3-benzyloxy-1-propanol was added, and the mixture was stirred at 70 ° C. for 7 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 30: 100: 0.2) to obtain 2.17 g of the compound shown in Table 1.

Example 3
3.46 g of the compound obtained in Example 1 (1) was dissolved in 80 ml of acetonitrile, 0.84 g of benzyl 4-hydroxy-1-piperidinecarboxylate was added, and the mixture was stirred at 80 ° C. for 8 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 90: 0.2) to obtain 0.89 g of the compound shown in Table 1.

Example 4
0.40 g of the compound obtained in Example 2 was dissolved in 4 ml of tetrahydrofuran, 0.4 g of 5% palladium-carbon was added, and the mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere of 1 atm. After filtering the reaction solution, the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 30: 1: 0.1 to 10: 1: 0.1) to obtain a table 1. 178 mg of the compound shown in

Example 5
0.21 g of the compound obtained in Example 3 was dissolved in 4 ml of tetrahydrofuran, 0.2 g of 20% palladium hydroxide-carbon was added, and the mixture was stirred at room temperature for 18 hours under a hydrogen atmosphere of 1 atm. After filtering the reaction solution, the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 30: 1: 0.1 to 10: 1: 0.1) to obtain a table 1. 0.17 g of the compound represented by

Example 6
Using 1.0 g of the compound obtained in Example 1 (1) and 1.6 ml of 4- (3-hydroxypropyl) -morpholine as raw materials, 342 mg of the compound shown in Table 1 was prepared in the same manner as in Example 1 (2). Obtained.

Example 7
Using the compound 0.41 g obtained in Example 1 (1) and benzyl alcohol 0.25 ml as raw materials, 156 mg of the compound shown in Table 1 was obtained in the same manner as in Example 2.

Example 8
Using 0.22 ml of the compound 0.42 g obtained in Example 1 (1) and 0.29 ml of 2-phenylethanol as raw materials, 0.20 g of the compound shown in Table 1 was obtained in the same manner as in Example 2.

Example 9
Using 0.22 g of the compound obtained in Example 1 (1) and 0.37 ml of 4-phenyl-1-butanol as raw materials, 0.22 g of the compound shown in Table 1 was obtained in the same manner as in Example 2.

Example 10
1.0 g of the compound obtained in Example 1 (1) was dissolved in 5.0 ml of tert-butanol and stirred at 70 ° C. for 7 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 50: 0.2) to obtain 161 mg of the compound shown in Table 1.

Example 11
80 mg of the compound shown in Table 1 was obtained in the same manner as in Example 2 using 0.35 g of the compound obtained in Example 1 (1) and 0.31 ml of 3-cyclohexyl-1-propanol as raw materials.

Example 12
64 mg of the compound shown in Table 1 was obtained in the same manner as in Example 2 using 0.35 g of the compound obtained in Example 1 (1) and 0.29 ml of 3-cyclopentyl-1-propanol as raw materials.

Example 13
187 mg of the compound shown in Table 1 by the same method as in Example 2 using 0.35 g of the compound obtained in Example 1 (1) and 0.37 ml of 3- (3,4-dimethoxyphenyl) -1-propanol as raw materials. Got.

Example 14
Using 0.35 g of the compound obtained in Example 1 (1) and 0.34 g of 3- (4-methoxyphenyl) -1-propanol as raw materials, 130 mg of the compound shown in Table 1 was obtained in the same manner as in Example 2. It was.

Example 15
Using 0.35 g of the compound obtained in Example 1 (1) and 0.19 g of phenol as raw materials, 26 mg of the compound shown in Table 1 was obtained in the same manner as in Example 2.

Example 16
Using 0.99 g of the compound obtained in Example 1 (1) and 1.17 g of (1-benzyl-4-piperidyl) methanol as raw materials, 50 mg of the compound shown in Table 1 was obtained in the same manner as in Example 2.

Example 17
Using 0.74 g of the compound obtained in Example 1 (1) and 0.75 ml of [(2S) -1-benzyl-2-pyrrolidyl] methanol as raw materials, 37 mg of the compound shown in Table 1 in the same manner as in Example 2. Got.

Example 18
Using 2.52 g of the compound obtained in Example 1 (1) and 2 ml of 2-benzyloxyethanol as raw materials, 0.86 g of the compound shown in Table 1 was obtained in the same manner as in Example 2.

Example 19
Using 0.50 g of the compound obtained in Example 1 (1) and 1.1 g of the compound obtained in Reference Example 1 as raw materials, 0.50 g of the compound shown in Table 1 was obtained in the same manner as in Example 2.

Example 20
(1) 3'-O- (O) obtained in the same manner as in Example 2 using 0.78 g of the compound obtained in Example 1 (1) and 1.85 g of N- (3-hydroxypropyl) phthalimide as raw materials. The 3-phthalimido) propyl form was dissolved in 9 ml of ethanol, 0.22 ml of hydrazine was added, and the mixture was stirred for 4 hours at reflux and 15 hours at room temperature. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 30: 1: 0.1 to 10: 1: 0.1) to give 3′-O— ( 313 mg of 3-amino) propyl was obtained.
(2) 313 mg of the compound obtained in the above (1) was dissolved in chloroform, 0.3 ml of 37% formaldehyde aqueous solution and 235 mg of sodium triacetoxyborohydride were added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 30: 1: 0.1 to 10: 1: 0.1) to obtain 224 mg of the compound shown in Table 1. Obtained.

Example 21
Using the compound 0.50 g obtained in Example 1 (1) and the compound 0.51 g obtained in Reference Example 2 as raw materials, 253 mg of the compound shown in Table 1 was obtained in the same manner as in Examples 2 and 5. It was.

Example 22
Using 100 mg of the compound obtained in Example 18 as a starting material, 45 mg of the compound shown in Table 1 was obtained in the same manner as in Example 5.

Example 23
Using 110 mg of the compound obtained in Example 16 as a starting material, 100 mg of the compound shown in Table 1 was obtained in the same manner as in Example 4.

Example 24
Using 130 mg of the compound obtained in Example 17 as a starting material, 57 mg of the compound shown in Table 1 was obtained in the same manner as in Example 5.

Examples 25-27
Compounds 25 to 27 shown in Table 1 were obtained in the same manner as in Example 20 (2) using the corresponding compounds as raw materials.

Example 28
94 mg of the compound obtained in Example 23 was dissolved in 10 ml of a 1: 1 mixed solvent of chloroform and saturated aqueous sodium hydrogen carbonate, 15 μl of acetic anhydride was added, and the mixture was stirred at room temperature for 3 hours. Distilled water was added to the reaction solution and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 50: 1: 0.1) to obtain 79 mg of the compound shown in Table 1.

Examples 29 and 30
The compounds 29 and 30 shown in Table 1 were obtained in the same manner as in Example 28 using the corresponding compounds as raw materials.

Example 31
88 mg of the compound obtained in Example 23 was dissolved in 10 ml of a 1: 1 mixed solvent of chloroform and saturated aqueous sodium hydrogen carbonate, 12 μl of methanesulfonyl chloride was added, and the mixture was stirred at room temperature for 4 hours. Distilled water was added to the reaction solution and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 50: 1: 0.1) to obtain 30 mg of the compound shown in Table 1.

Examples 32 and 33
Compounds 32 and 33 shown in Table 1 were obtained in the same manner as in Example 31 using the corresponding compounds as raw materials.

Example 34
(1) 3'-O- (3- (4) was prepared in the same manner as in Example 2, using 1.55 g of the compound obtained in Example 1 (1) and 2.83 g of the compound obtained in Reference Example 3 as raw materials. 1.28 g of-(2- (phthalimido) ethyl)) piperazin-1-yl) propyl was obtained.
(2) 1.28 g of the compound obtained in (1) above was dissolved in 15 ml of ethanol, 0.17 ml of hydrazine was added, and the mixture was stirred for 5 hours with heating under reflux. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 50: 1: 0.1 to 10: 1: 0.1) to give 3′-O— ( 0.91 g of 3- (4- (2-aminoethyl)) piperazin-1-yl) propyl was obtained.
(3) Using 0.91 g of the compound obtained in (2) above as a starting material, 380 mg of the compound shown in Table 1 was obtained in the same manner as in Example 20 (2).

Example 35
(1) 1.25 g of the compound obtained in Example 1 (1), 6-tert-butyldimethyl obtained by the method described in the literature (Bioorganic and Medicinal Chemistry Letters, 2004, Vol. 14, p. 2547) Using 1.05 g of silyloxy-2,5,7,8-tetramethylchroman-2-ylmethanol as a raw material, 3′-O — ((2,5,7,8-tetra 0.14 g of methyl-6-trimethylsilyloxy) -chroman-2-yl) methyl was obtained.
(2) 0.14 g of the compound obtained in (1) above was dissolved in 4 ml of tetrahydrofuran, 0.25 ml of 1 mol / L tetrabutylammonium fluoride tetrahydrofuran solution was added, and the mixture was stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 90: 0.2 to 10: 50: 0.2) to obtain 91 mg of the compound shown in Table 1.

Example 36
(1) 6.75 g of the compound obtained in Example 4 was dissolved in 250 ml of a 3: 2 mixed solvent of tetrahydrofuran and distilled water, 1.89 g of N-bromosuccinimide was added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (acetone: hexane: triethylamine = 10: 70: 0.2 to 10: 10: 0.2 to chloroform: methanol: 28% aqueous ammonia = 40: 1: 0.1). To obtain 6.22 g of 2′-N-demethyl compound.
(2) 6.22 g of the compound obtained in the above (1) was dissolved in 200 ml of a 1: 1 mixed solvent of ethyl acetate and saturated aqueous sodium hydrogen carbonate, 1.0 ml of benzyl chloroformate was added, and the mixture was stirred at room temperature for 2 hours. Further, 1.0 ml of benzyl chloroformate was added and stirred at room temperature for 2 hours. The reaction solution was separated, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 70: 0.2) to obtain 4.16 g of 2′-N-benzyloxycarbonyl compound.
(3) 2.0 g of the compound obtained in (2) above was dissolved in 50 ml of tetrahydrofuran, 0.24 ml of methanesulfonyl chloride and 0.44 ml of triethylamine were added, and the mixture was stirred at room temperature for 2 hours. Further, 0.24 ml of methanesulfonyl chloride and 0.44 ml of triethylamine were added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 50: 1: 0.1 to 20: 1: 0.1) to give 3′-O— (3 -2.51 g of (methanesulfonyloxy) propyl was obtained.
(4) 0.69 g of the compound obtained in (3) above was dissolved in 33 ml of dimethylformamide, 356 mg of theophylline and 137 mg of potassium carbonate were added, and the mixture was stirred at room temperature for 2 days and at 50 ° C. for 1 day. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 70: 0.2 to 10: 30: 0.2) to give 3'-O- (3- (theophylline). -7-yl)) 0.73 g of propyl was obtained.
(5) 0.62 g of 2′-N-demethyl compound was obtained in the same manner as in Example 5 using 0.73 g of the compound obtained in (4) above as a raw material.
(6) Using 0.30 g of the compound obtained in the above (5) as a raw material, 67 mg of the compound shown in Table 1 was obtained in the same manner as in Example 20 (2).

Example 37
(1) 22.7 g of the compound obtained in Example 1 (1) was dissolved in 250 ml of a 4: 1 mixed solvent of dimethylformamide and distilled water, 8.9 g of sodium formate was added, and the mixture was stirred at 70 ° C. for 4.5 hours. Ethyl acetate was added to the reaction solution for liquid separation, and the organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure was dissolved in 435 ml of methanol and stirred for 6 hours while heating under reflux. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 50: 0.2 to 10: 20: 0.2) to obtain 27.9 g of 3′-hydroxy compound. It was.
(2) 167 mg of the compound obtained in (1) above was dissolved in 5 ml of tetrahydrofuran, 127 mg of 3-isocyanate pyridine was added, and the mixture was stirred at room temperature for 5 days. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 30: 0.2 to 10: 10: 0.2) to obtain 174 mg of the compound shown in Table 1. .

Example 38
(1) 0.34 g of 3′-hydroxy compound was obtained in the same manner as in Example 5 using 0.92 g of the compound obtained in Example 7 as a raw material.
(2) Using 58 mg of the compound obtained in (1) above and 14 μl of benzyl isocyanate as raw materials, 26 mg of the compound shown in Table 1 was obtained in the same manner as in Example 37 (2).

Example 39
215 mg of the compound obtained in Example 37 (1) was dissolved in 4 ml of pyridine, 44 μl of phenyl isocyanate was added, and the mixture was stirred at room temperature for 1 day. Further, 103 μl of phenyl isocyanate was added and stirred at room temperature for 1 day. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 30: 0.2) to obtain 181 mg of a compound shown in Table 1.

Example 40
95 mg of the compound shown in Table 1 was obtained in the same manner as in Example 39, using 206 mg of the compound obtained in Example 37 (1) and 350 μl of ethyl 3-isocyanate propionate as raw materials.

Example 41
69 mg of the compound shown in Table 1 was obtained in the same manner as in Example 39 using 251 mg of the compound obtained in Example 37 (1) and 406 μl of cyclohexyl isocyanate as raw materials.

Example 42
Using 253 mg of the compound obtained in Example 37 (1) and 254 μl of ethyl isocyanate as raw materials, 36 mg of the compound shown in Table 1 was obtained in the same manner as in Example 39.

Example 43
36 mg of the compound shown in Table 1 was obtained in the same manner as in Example 39 by using 500 mg of the compound obtained in Example 37 (1) and 0.44 ml of 6-isocyanate-1,4-benzodioxane as raw materials.

Example 44
Using 398 mg of the compound obtained in Example 37 (1) and 513 mg of (4-dimethylamino) phenyl isocyanate, 398 mg of the compound shown in Table 1 was obtained in the same manner as in Example 39.

Example 45
Using the compound 500 mg obtained in Example 37 (1) and 519 mg of 3-nitrophenyl isocyanate as raw materials, 127 mg of the compound shown in Table 1 in the same manner as in Example 39, Example 5 and Example 20 (2) Got.

Example 46
311 mg of the compound shown in Table 1 in the same manner as in Example 39, Example 5 and Example 20 (2) using 500 mg of the compound obtained in Example 37 (1) and 519 mg of 2-nitrophenyl isocyanate as raw materials. Got.

Example 47
500 mg of the compound obtained in Example 37 (1) was dissolved in 3 ml of toluene, 0.49 ml of 3-phenylpropyl isocyanate and 35 mg of 1,4-diazabicyclo [2.2.2] octane were added, and the mixture was stirred for 8 hours with heating under reflux. . The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 70: 0.2 to 10: 10: 0.2) to obtain 508 mg of the compound shown in Table 1. .

Example 48
Using 500 mg of the compound obtained in Example 37 (1) and 0.44 ml of phenethyl isocyanate as raw materials, 311 mg of the compound shown in Table 1 was obtained in the same manner as in Example 47.

Example 49
Using the compound 500 mg obtained in Example 37 (1) and 4- (isocyanatomethyl) tetrahydropyran 447 mg as raw materials, 297 mg of the compound shown in Table 1 was obtained in the same manner as in Example 47.

Example 50
Using the compound obtained in Example 37 (1) 500 mg and 3-cyclopentoxy-4-methoxyphenyl isocyanate 738 mg as raw materials, 373 mg of the compound shown in Table 1 was obtained in the same manner as Example 47.

Example 51
Using the compound 607 mg obtained in Example 37 (1) and 1.0 g of benzyl 4-isocyanatetetrahydro-1 (2H) -pyridinecarboxylate as raw materials, the same methods as in Examples 47 and 5 are shown in Table 1. 215 mg of the compound obtained.

Example 52
189 mg of the compound obtained in Example 51 was dissolved in 3 ml of acetonitrile, 31 μl of 2-iodopropane and 57 mg of potassium carbonate were added, and the mixture was stirred at 60 ° C. for 38 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 40: 1: 0.1 to 30: 1: 0.1) to obtain 157 mg of the compound shown in Table 1. Obtained.

Example 53
(1) Dissolve 1.56 g of the compound obtained in Example 37 (1) in 20 ml of chloroform, add 1.34 ml of diisopropylethylamine, add 1.20 g of 4-nitrophenyl chloroformate under ice cooling, and gradually The mixture was stirred for 3 hours while heating up. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 90: 0.2 to 10: 30: 0.2) to give 3′-O- (4-nitrophenyl). 1.6 g of oxy) carbonyl was obtained.
(2) 300 mg of the compound obtained in (1) above was dissolved in 3 ml of acetonitrile, 156 mg of 2,3-dihydro-1,4-benzodioxin-6-ylmethylamine was added, and the mixture was stirred for 3 hours with heating under reflux. . The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 90: 0.2 to 10: 30: 0.2) to obtain 223 mg of the compound shown in Table 1. .

Example 54
Using the compound 300 mg obtained in Example 53 (1) and the compound 161mg obtained in Reference Example 4 as raw materials, 172 mg of the compound shown in Table 1 was obtained in the same manner as in Example 53 (2).

Example 55
(1) 412 mg of the compound obtained in Example 53 (1) was dissolved in 4 ml of acetonitrile, 244 mg of 3-nitrobenzylamine hydrochloride and 0.44 ml of diisopropylethylamine were added, and the mixture was heated under reflux at 60 ° C. for 4 hours. Stir for hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 90: 0.2 to 10: 30: 0.2) to give 3'-O- (3-nitrobenzyl) 312 mg of carbamoyl compound was obtained.
(2) Using 306 mg of the compound obtained in (1) above as a starting material, 70 mg of the compound shown in Table 1 was obtained in the same manner as in Example 5 and Example 20 (2).

Example 56
Using the compound 1.5g obtained in Example 1 (1) and 2.9 g of 4-piperidinecarboxylic acid as raw materials, 627 mg of the compound shown in Table 1 was obtained in the same manner as in Example 1 (2).

  The compounds of Examples 1 to 56 are represented by the formula (A).

Example 57
100 mg of the compound obtained in Example 1 was dissolved in 4 ml of a 1: 1 mixed solvent of tetrahydrofuran and distilled water, 30 mg of N-bromosuccinimide was added, and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 90: 0.2 to 10: 70: 0.2) to obtain 59 mg of the compound shown in Table 2. .

Example 58
0.60 g of the compound obtained in Example 4 was dissolved in 25 ml of a 3: 2 mixed solvent of tetrahydrofuran and distilled water, 0.19 g of N-bromosuccinimide was added, and the mixture was stirred at room temperature for 5 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 30: 0.2) to obtain 0.37 g of the compound shown in Table 2.

Example 59
(1) 3'-N-demethyl compound in the same manner as in Example 58 using 4 "-O-acetyl-6-O-methylerythromycin A50g obtained by the method described in the patent document (WO2007129646) as a raw material. 32.1 g was obtained.
(2) Example 20 using 3.9 g of the compound obtained in (1) above and 1.36 g of phthalimidoacetaldehyde obtained by the method described in the literature (Tetrahedron Letters, 2001, 42, 315) In the same manner as (2), Example 34 (2), Example 20 (2), Example 1 (1) and (2), 86 mg of the compound shown in Table 2 was obtained.

Example 60
Using 0.54 g of the compound obtained in Example 7 as a starting material, 77 mg of the compound shown in Table 2 was obtained in the same manner as in Example 5.

Example 61
Using 150 mg of the compound obtained in Example 57 as a starting material, 80 mg of the compound shown in Table 2 was obtained in the same manner as in Example 28.

Example 62
Using 150 mg of the compound obtained in Example 57 as a starting material, 80 mg of the compound shown in Table 2 was obtained in the same manner as in Example 31.

Example 63
(1) 14.5 g of 3′-N-allyl compound was obtained in the same manner as in Example 52 using 18.0 g of the compound obtained in Example 59 (1) and 3.0 ml of allyl bromide as raw materials.
(2) Using 14.5 g of the compound obtained in (1) above as a raw material, 13.2 g of 2′-O-methanesulfonyl was obtained in the same manner as in Example 1 (1).
(3) 8.57 g of 3′-hydroxy compound was obtained in the same manner as in Example 37 (1) using 13.2 g of the compound obtained in (2) above as a raw material.
(4) Using 2.0 g of the compound obtained in (3) above as a starting material, 1.24 g of the compound shown in Table 2 was obtained in the same manner as in Example 4.

Example 64
(1) A 2: 1-N-demethyl compound obtained by the same method as in Example 58 using 300 mg of the compound obtained in Example 37 (1) as a starting material, a 1: 1 mixed solvent of chloroform and saturated aqueous sodium hydrogen carbonate. It melt | dissolved in 20 ml, 44 microliters of chloroacetyl chloride was added, and it stirred vigorously for 1 hour at room temperature. Chloroform was added to the reaction solution for liquid separation, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 90: 0.2 to 10: 30: 0.2) to obtain 0.2 g of 2′-N-chloroacetyl compound. Obtained.
(2) 0.14 g of the compound obtained in (1) above was dissolved in 8 ml of ethanol, 2 ml of 50% dimethylamine aqueous solution was added, and the mixture was stirred at 80 ° C. for 3 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 90: 0.2 to 10: 10: 0.2) to obtain 110 mg of the compound shown in Table 2. .

Example 65
(1) Dissolve 6.29 g of the compound obtained in Example 63 (3) in 35 ml of acetonitrile, add 519 mg of palladium (II) acetate, 1.4 g of tri-O-tolylphosphine, and 2.1 ml of triethylamine, and irradiate with microwave. The mixture was stirred at 120 ° C. for 2 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 40: 1: 0.1 to 20: 1: 0.1) to give a 2′-N-demethyl compound. 3.2 g was obtained.
(2) Using 1.5 g of the compound obtained in (1) above and 254 μl of benzaldehyde as raw materials, 903 mg of the compound shown in Table 2 was obtained in the same manner as in Example 20 (2).

Example 66
(1) Using 0.22 g of the compound obtained in Example 58 as a starting material, 0.25 g of 2′-N-benzyloxycarbonyl compound was obtained in the same manner as in Example 36 (2).
(2) 0.22 g of the compound obtained in (1) above was dissolved in 5 ml of tetrahydrofuran, 27 μl of methanesulfonyl chloride and 48 ml of triethylamine were added, and the mixture was stirred at room temperature for 4 hours. Further, 50 μl of methanesulfonyl chloride and 100 μl of triethylamine were added and stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure was dissolved in 5 ml of ethanol, 0.33 ml of 1-isopropylpiperazine was added, and the mixture was stirred at 80 ° C. for 16 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 70: 0.2 to 10: 10: 0.2) to give 3'-O- (3- (4 -Isopropyl) piperazin-1-yl) propyl 0.25 g was obtained.
(3) 0.12 g of 2′-N-demethyl compound was obtained in the same manner as in Example 5 using 0.25 g of the compound obtained in (2) above as a raw material.
(4) Using 84 mg of the compound obtained in (3) above as a starting material, 82 mg of the compound shown in Table 2 was obtained in the same manner as in Example 31.

Example 67
(1) In the same manner as in Example 2 and Example 65 (1), using 10.0 g of the compound obtained in Example 63 (2) and 0.84 g of benzyl 4-hydroxy-1-piperidinecarboxylate as raw materials, 1.0 g of '-N-demethyl compound was obtained.
(2) Using 200 mg of the compound obtained in (1) above as a starting material, 34 mg of the compound shown in Table 2 was obtained in the same manner as in Example 52 and Example 5.

Example 68
By using 350 mg of the compound obtained in Example 63 and 0.26 ml of benzyl isocyanate as raw materials, 263 mg of the compound shown in Table 2 was obtained in the same manner as in Example 39.

Example 69
Using the compound 350 mg obtained in Example 65 and benzyl isocyanate 0.25 ml as raw materials, 173 mg of the compound shown in Table 2 was obtained in the same manner as in Example 39.

Example 70
(1) 1.5 g of the compound obtained in Example 65 (1) was dissolved in 19 ml of acetonitrile, 0.8 g of potassium carbonate was added, and 0.30 ml of methanesulfonyl chloride was added under ice cooling. After stirring at room temperature for 15 hours and at 55 ° C. for 5 hours, distilled water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 50: 1: 0.1 to 25: 1: 0.1) to give a 2′-N-methanesulfonyl compound. 837 mg was obtained.
(2) 146 mg of the compound shown in Table 2 was obtained in the same manner as in Example 39 using 250 mg of the compound obtained in (1) above and 0.16 ml of phenyl isocyanate as raw materials.

Example 71
45 mg of the compound shown in Table 2 was obtained in the same manner as in Example 39 using 253 mg of the compound obtained in Example 70 (1) and 0.12 ml of ethyl isocyanate as raw materials.

Example 72
Using 150 mg of the compound obtained in Example 70 (1) and 0.22 ml of benzyl isocyanate as raw materials, 91 mg of the compound shown in Table 2 was obtained in the same manner as in Example 39.

Example 73
(1) Using the compound 405 mg obtained in Example 65 (1) as a raw material, 461 mg of 2′-N-acetyl compound was obtained in the same manner as in Example 28.
(2) 274 mg of the compound shown in Table 2 was obtained in the same manner as in Example 39 using 250 mg of the compound obtained in (1) above and 0.38 ml of benzyl isocyanate as raw materials.

Example 74
(1) Using the compound 2.7 g obtained in Example 63 (3) and 2.0 ml of benzyl isocyanate as raw materials, 227-N-demethyl compound 2.27 g in the same manner as in Example 47 and Example 65 (1) Got.
(2) Using the compound obtained in (1) above and benzyl 4-formyl-1-piperidinecarboxylate 217 mg as raw materials, the same method as in Example 20 (2), Example 5, and Example 52 was used. 35 mg of the compound shown in 2 was obtained.

Example 75
(1) 38.4 g of 4 ″ -O-acetyl-6-O-methylerythromycin A obtained by the method described in the patent document (WO2007129646) is dissolved in 50 ml of dimethylformamide, 25 ml of epichlorohydrin is added, and 70 ° C. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform only) to obtain 11.72 g of a 2 ′, 3′-epoxide compound.
(2) 0.38 g of the compound obtained in (1) above was dissolved in 10 ml of isopropanol, 1.8 ml of morpholine was added, and the mixture was stirred at 70 ° C. for 1 day. Further, the operation of adding 3 ml of morpholine and stirring at 70 ° C. for 1 day was repeated twice. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 50: 0.2 to 10: 30: 0.2) to obtain 0.17 g of the compound shown in Table 2. It was.

Example 76
(1) 0.38 g of the compound obtained in Example 75 (1) was dissolved in 10 ml of isopropanol, 1.8 ml of morpholine was added, and the mixture was stirred at 70 ° C. for 1 day. Further, the operation of adding 3 ml of morpholine and stirring at 70 ° C. for 1 day was repeated twice. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 50: 0.2 to 10: 30: 0.2) to give 2'-hydroxy-3 '-(4 -Morpholino) body 0.24g was obtained.
(2) 0.24 g of the compound obtained in the above (1) was dissolved in 6 ml of chloroform, 0.13 ml of diisopropylethylamine and 88 μl of methanesulfonyl chloride were added dropwise and stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 90: 0.2 to 10: 30: 0.2) to obtain 154 mg of 2′-O-methanesulfonyl compound. Obtained.
(3) 154 mg of the compound obtained in (2) above was dissolved in 5 ml of acetonitrile, 0.26 ml of 3-phenyl-1-propanol was added, and the mixture was stirred at 70 ° C. for 5 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 10: 0.2) to obtain 49 mg of the compound shown in Table 2.

Example 77
(1) 176 mg of the compound obtained in Example 76 (2) was dissolved in 5 ml of acetonitrile, 0.91 g of benzyl 4-hydroxy-1-piperidinecarboxylate was added, and the mixture was stirred at 80 ° C. for 4 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 90: 0.2 to 10: 30: 0.2) to give 2 '-(4-morpholino)- 50 mg of 3 ′-((4-benzyloxycarbonyl) piperazin-1-yl) form was obtained.
(2) 50 mg of the compound obtained in (1) above was dissolved in 5 ml of tetrahydrofuran, 20% palladium hydroxide-carbon (50 mg) was added, and the mixture was stirred at room temperature for 18 hours under a hydrogen atmosphere of 1 atm. After filtration of the reaction solution, the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 10: 1: 0.1) to obtain 40 mg of the compound shown in Table 2. Got.

Example 78
Using 2.0 g of the compound obtained in Example 75 (1) and 4.3 ml of benzyl 1-piperazinecarboxylate as raw materials, 0.84 g of the compound shown in Table 2 was obtained in the same manner as in Example 75 (2).

Example 79
(1) 2′-Hydroxy-3 ′-(2) in the same manner as in Example 75 (2) using 2.0 g of the compound obtained in Example 75 (1) and 4.3 ml of benzyl 1-piperazinecarboxylate as raw materials 1.25 g of (4-benzyloxycarbonyl) piperazin-1-yl) product was obtained.
(2) 250 mg of 2′-O-methanesulfonyl was obtained in the same manner as in Example 1 (1) using 1.10 g of the compound obtained in (1) above as a raw material.
(3) 36 mg of the compound shown in Table 2 in the same manner as in Example 2 and Example 5, using 250 mg of the compound obtained in (2) above and 1.13 g of benzyl 4-hydroxy-1-piperidinecarboxylate as raw materials. Got.

Example 80
(1) 2′-Hydroxy-3 ′-(((4-)) was prepared in the same manner as in Example 75 (2) using 2.0 g of the compound obtained in Example 75 (1) and 4 ml of 1-isopropylpiperazine 0.34 g of isopropyl) piperazin-1-yl) product was obtained.
(2) Using 0.62 g of the compound obtained in (1) above as a starting material, 495 mg of 2′-O-methanesulfonyl compound was obtained in the same manner as in Example 1 (1).
(3) 28 mg of the compound shown in Table 2 in the same manner as in Example 2 and Example 5 using 285 mg of the compound obtained in (2) above and 1.41 g of benzyl 4-hydroxy-1-piperidinecarboxylate as raw materials Got.

Example 81
(1) 0.88 g of 2′-hydroxy-3 ′-(piperazin-1-yl) isomer was obtained in the same manner as in Example 5 using 1.45 g of the compound obtained in Example 79 (1) as a raw material. .
(2) Example 20 (2) using as a raw material 1.02 g of the compound obtained in (1) above and phthalimidoacetaldehyde obtained by the method described in the literature (Tetrahedron Letters, 2001, 42, 315) ), 0.84 g of 2′-O-methanesulfonyl compound was obtained in the same manner as in Example 1 (1).
(3) Example 2, Example 34 (2), Example 20 (2), Example using 330 mg of the compound obtained in (2) above and 1.44 g of benzyl 4-hydroxy-1-piperidinecarboxylate as raw materials 10 mg of the compound shown in Table 2 was obtained in the same manner as in Example 5.

Example 82
Using the compound 1.12 g obtained in Example 75 (1) and 2.4 g of 1- (2-dimethylaminoethyl) piperazine as raw materials, 0.22 g of the compound shown in Table 2 in the same manner as in Example 75 (2). Got.

Example 83
Using 0.68 g of the compound obtained in Example 75 (1) and 2.4 ml of 1-isopropylpiperazine as raw materials, 0.29 g of the compound shown in Table 2 was obtained by the same reaction as in Example 75 (2).

Example 84
(1) In the same manner as in Example 75 (2) and Example 1 (1), using 2.0 g of the compound obtained in Example 75 (1) and 4.60 g of the compound obtained in Reference Example 5 as raw materials. 1.13 g of 2′-O-methanesulfonyl compound was obtained.
(2) In the same manner as in Example 2, Example 35 (2) and Example 5, using 380 mg of the compound obtained in (1) above and 1.72 g of benzyl 4-hydroxy-1-piperidinecarboxylate as raw materials 23 mg of the compound shown in Table 2 was obtained.

Example 85
Using 300 mg of the compound obtained in Example 75 and 285 μl of ethyl isocyanate as raw materials, 97 mg of the compound shown in Table 2 was obtained in the same manner as in Example 39.

Example 86
Using 389 mg of the compound obtained in Example 75 and 288 μl of benzyl isocyanate as raw materials, 231 mg of the compound shown in Table 2 was obtained in the same manner as in Example 39.

Example 87
(1) Using 1.74 g of 6-O-methylerythromycin A as a raw material, 1.16 g of a 2 ′, 3′-epoxide was obtained in the same manner as in Example 75 (1).
(2) 0.44 g of 2 ′-(4-morpholino) -3′-hydroxy compound in the same manner as in Example 75 (2) using 0.93 g of the compound obtained in (1) above and 5.8 ml of morpholine as raw materials. Got.
(3) 0.44 g of the compound obtained in (2) above was dissolved in chloroform, 0.32 ml of acetic anhydride and 68 mg of 4-dimethylaminopyridine were added, and the mixture was stirred at room temperature for 14 hours. Further, 0.16 ml of acetic anhydride and 34 mg of 4-dimethylaminopyridine were added and stirred at room temperature for 1 day. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 50: 0.2) to obtain 0.45 g of the compound shown in Table 2.

Example 88
(1) 2 ′-((4-Isopropyl) piperazin-1-yl) -3′-hydroxy compound in the same manner as in Example 4 and Example 52 using 687 mg of the compound obtained in Example 78 as a starting material 473 mg was obtained.
(2) 230 mg of the compound shown in Table 2 was obtained in the same manner as in Example 39 using 240 mg of the compound obtained in (1) above and 0.17 ml of benzyl isocyanate as raw materials.

Example 89
(1) In the same reaction as in Example 75 (2) using 2.0 g of the compound obtained in Example 75 (1) and 4.60 g of the compound obtained in Reference Example 5 as raw materials, 2 ′-((4 -tert-Butyldimethylsilyloxy) piperidin-1-yl) -3'-hydroxy compound 1.06 g was obtained.
(2) 173 mg of the compound shown in Table 2 was obtained in the same manner as in Example 39 and Example 35 (2) using 500 mg of the compound obtained in (1) above and 0.32 ml of benzyl isocyanate as raw materials.

  The compounds of Examples 57 to 89 are represented by the formula (B).

Example 90
108 mg of the compound obtained in Example 1 was dissolved in 2 ml of methanol, 36 μl of 1,8-diazabicyclo [5,4,0] -7-undecene was added, and the mixture was stirred for 7 hours with heating under reflux. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 50: 0.2 to 10: 30: 0.2) to obtain 65 mg of the compound shown in Table 3. .

Example 91
200 mg of the compound obtained in Example 2 was dissolved in 2 ml of methanol, 38 μl of 1,8-diazabicyclo [5,4,0] -7-undecene was added, and the mixture was stirred for 7 hours with heating under reflux. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 35: 1: 0.1 to 20: 1: 0.1) to give the compounds shown in Table 3 116 mg was obtained.

Example 92
90 mg of the compound obtained in Example 3 was dissolved in 2 ml of methanol, 63 μl of 1,8-diazabicyclo [5,4,0] -7-undecene was added, and the mixture was stirred at 70 ° C. for 14 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 10: 1: 0.1) to obtain 57 mg of the compound shown in Table 3.

Example 93
100 mg of the compound obtained in Example 4 was dissolved in 1 ml of methanol, 26 μl of 1,8-diazabicyclo [5,4,0] -7-undecene was added, and the mixture was stirred at 70 ° C. for 15 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 20: 1: 0.1) to obtain 67 mg of the compound shown in Table 3.

Example 94
57 mg of the compound obtained in Example 5 was dissolved in 3 ml of methanol, 46 μl of 1,8-diazabicyclo [5,4,0] -7-undecene was added, and the mixture was stirred at 70 ° C. for 20 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 40: 1: 0.1 to 20: 1: 0.1) to give the compounds shown in Table 3 49 mg was obtained.

Examples 95-142
Using corresponding compounds as raw materials, compounds 95 to 142 shown in Table 3 were obtained in the same manner as in Example 90.

  The compounds of Examples 90 to 142 are represented by the formula (C).

Example 143
79 mg of the compound obtained in Example 57 was dissolved in 5 ml of methanol, 58 μl of 1,8-diazabicyclo [5,4,0] -7-undecene was added, and the mixture was stirred at 70 ° C. for 18 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 50: 1: 0.1) to obtain 60 mg of a compound shown in Table 4.

Example 144
100 mg of the compound obtained in Example 58 was dissolved in 3 ml of methanol, 85 μl of 1,8-diazabicyclo [5,4,0] -7-undecene was added, and the mixture was stirred at 70 ° C. for 18 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 30: 0.2) to obtain 52 mg of a compound shown in Table 4.

Examples 145-155
Using the corresponding compound as a raw material, compounds 145 to 155 shown in Table 4 were obtained in the same manner as in Example 90.

Example 156
Using 102 mg of the compound obtained in Example 87 (1) and 5.8 ml of morpholine as raw materials, 57 mg of the compound shown in Table 4 was obtained in the same manner as in Example 75 (2).

Examples 157-160
Compounds 157 to 160 shown in Table 4 were obtained in the same manner as in Example 90 using the corresponding compounds as raw materials.

Example 161
(1) 1.0 g of the compound obtained in Example 59 (1) was dissolved in 50 ml of acetonitrile, 2.4 ml of isopropyl bromide and 2.2 ml of diisopropylethylamine were added, and the mixture was stirred at 70 ° C. for 2 days. Further, 2.4 ml of isopropyl bromide and 2.2 ml of diisopropylethylamine were added and the operation of stirring at 70 ° C. for 2 days was repeated twice. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 50: 1: 0.1 to 30: 1: 0.1) to give 3′-N-isopropyl compound. 0.39 g was obtained.
(2) Using 200 mg of the compound obtained in the above (1) as a raw material, 46 mg of 2′-O-methanesulfonyl compound was obtained in the same manner as in Example 1 (1).
(3) 15 mg of the compounds shown in Table 4 were obtained in the same manner as in Example 2 and Example 90 using 46 mg of the compound obtained in (2) above and 73 μl of 3-phenyl-1-propanol as raw materials.

Example 162
(1) 0.13 g of sodium was dissolved in 6 ml of methanol, 0.50 g of the compound obtained in Example 57 and 0.36 g of iodine were added under ice cooling, and the mixture was stirred as it was for 6 hours. A saturated aqueous ammonium chloride solution and an aqueous sodium hydrogen sulfite solution were added to the reaction solution and stirred for a while, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 90: 0.2 to 10: 10: 0.2) to obtain 120 mg of 2′-amine compound.
(2) 120 mg of the compound obtained in (1) above was dissolved in 5 ml of methanol, 63 μl of 1,8-diazabicyclo [5,4,0] -7-undecene was added, and the mixture was stirred at 70 ° C. for 18 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 1: 0.1) to obtain 80 mg of a compound shown in Table 4.

  The compounds of Examples 143 to 162 are represented by the formula (D).

Example 163
2'-O-methanesulfonyl-6,11,4 "-O-triacetyl-9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin obtained by the method described in the patent document (WO2003070174) Using 0.64 g of A and 0.46 ml of 3-phenyl-1-propanol as raw materials, 0.31 g of the compound shown in Table 5 was obtained in the same manner as in Example 2.

Example 164
2'-O-methanesulfonyl-6,11,4 "-O-triacetyl-9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin obtained by the method described in the patent document (WO2003070174) Using 0.61 g of A and 3.0 g of benzyl 4-hydroxy-1-piperidinecarboxylate as raw materials, 0.26 g of the compound shown in Table 5 was obtained in the same manner as in Example 2.

Example 165
2'-O-methanesulfonyl-6,11,4 "-O-triacetyl-9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin obtained by the method described in the patent document (WO2003070174) 6-tert-butyldimethylsilyloxy-2,5,7,8-tetramethyl obtained by the method described in A0.54 g and the literature (Bioorganic and Medicinal Chemistry Letters, 2004, Vol. 14, p. 2547) Using 2.33 g of chroman-2-ylmethanol as a raw material, 50 mg of the compound shown in Table 5 was obtained in the same manner as in Example 2 and Example 35 (2).

  The compounds of Examples 163 to 165 are represented by the formula (E).

Examples 166, 167
Compounds 166 and 167 shown in Table 6 were obtained in the same manner as in Example 90 using the corresponding compounds as raw materials.

Example 168
Using 0.90 g of the compound obtained in Example 167 as a starting material, 33 mg of the compound shown in Table 6 was obtained in the same manner as in Example 5.

Example 169
(1) 2′-O-methanesulfonyl-6,11,4 ″ -O-triacetyl-9-deoxo-9a-aza-9a-methyl-9a obtained by the method described in the patent document (WO2003070174) -294 mg of 3'-hydroxy compound was obtained in the same manner as in Example 37 (1) using 782 mg of homoerythromycin A as a raw material.
(2) 34 mg of the compound shown in Table 6 was obtained in the same manner as in Example 39 and Example 90 using 290 mg of the compound obtained in (1) above and 0.18 ml of phenyl isocyanate as raw materials.

Example 170
(1) 223 mg of the compound shown in Table 6 was obtained in the same manner as in Example 39 and Example 90 using 823 mg of the compound obtained in Example 169 (1) and 0.63 ml of benzyl isocyanate as raw materials.

  The compounds of Examples 166 to 170 are represented by the formula (F).

Example 171
(1) 500 mg of 11-amino-4 ″ -O-acetyl-6-O-methylerythromycin A 11,12-cyclic carbamate obtained by the method described in the patent document (WO2007129646) was dissolved in 12 ml of chloroform, and diisopropyl 0.43 ml of ethylamine and 0.17 ml of methanesulfonyl chloride were added, and the mixture was stirred at room temperature for 3 hours, saturated aqueous sodium hydrogen carbonate was added to the reaction solution, extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and filtered. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 90: 0.2) to obtain 0.47 g of 2′-O-methanesulfonyl.
(2) 0.47 g of the compound obtained in (1) above was dissolved in 10 ml of acetonitrile, 0.40 ml of 3-phenyl-1-propanol was added, and the mixture was stirred at 77 ° C. for 4 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 90: 0.2) to obtain 0.26 g of the compound shown in Table 7.

Example 172
1.12 g of the compound obtained in Example 171 (1) was dissolved in 60 ml of cetonitrile, 2.95 g of benzyl 4-hydroxy-1-piperidinecarboxylate was added, and the mixture was stirred at 80 ° C. for 6 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 50: 0.2 to 10: 30: 0.2) to obtain 0.23 g of the compound shown in Table 7. Obtained.

Example 173
0.21 g of the compound obtained in Example 172 was dissolved in 10 ml of tetrahydrofuran, 0.2 g of 20% palladium hydroxide-carbon was added, and the mixture was stirred at room temperature for 18 hours under a hydrogen atmosphere of 1 atm. After filtration of the reaction solution, the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 30: 1: 0.1 to 10: 1: 0.1) to obtain a table. 0.14 g of the compound shown in 7 was obtained.

Example 174
0.52 g of the compound obtained in Example 171 (1) and 6-tert-butyldimethylsilyloxy-obtained by the method described in the literature (Bioorganic and Medicinal Chemistry Letters, 2004, Vol. 14, p. 2547) Using 2.0 g of 2,5,7,8-tetramethylchroman-2-ylmethanol as a raw material, 16 mg of the compound shown in Table 7 was obtained in the same manner as in Example 2 and Example 35 (2).

Example 175
(1) Using 500 mg of the compound obtained in Example 171 (1) as a raw material, 330 mg of 3′-hydroxy compound was obtained in the same manner as in Example 37 (1).
(2) 286 mg of the compound shown in Table 7 was obtained in the same manner as in Example 39 using 332 mg of the compound obtained in (1) above and 0.22 ml of phenyl isocyanate as raw materials.

Example 176
Using 270 mg of the compound obtained in Example 175 (1) and 0.23 ml of benzyl isocyanate as raw materials, 270 mg of the compound shown in Table 7 was obtained in the same manner as in Example 39.

Example 177
0.14 g of the compound obtained in Example 171 was dissolved in 3 ml of methanol, 106 μl of 1,8-diazabicyclo [5,4,0] -7-undecene was added, and the mixture was stirred at 70 ° C. for 20 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 10: 1: 0.1) to obtain 128 mg of the compound shown in Table 7.

Example 178
0.17 g of the compound obtained in Example 172 was dissolved in 8 ml of methanol, 70 μl of 1,8-diazabicyclo [5,4,0] -7-undecene was added, and the mixture was stirred at 80 ° C. for 16 hours. The compound obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 10: 0.2), and dissolved in 4 ml of methanol to obtain 1,8-diazabicyclo [5,4 , 0] -7-undecene (50 μl) was added, and the mixture was stirred at 80 ° C. for 16 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 90: 0.2 to 10: 30: 0.2) to obtain 0.17 g of the compound shown in Table 7. It was.

Example 179
86 mg of the compound obtained in Example 173 was dissolved in 3 ml of methanol, 40 μl of 1,8-diazabicyclo [5,4,0] -7-undecene was added, and the mixture was stirred at 70 ° C. for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 20: 1: 0.1) to obtain 84 mg of the compound shown in Table 7.

Examples 180 and 181
Compounds 180 and 181 shown in Table 7 were obtained in the same manner as in Example 177 using the corresponding compounds as raw materials.

Example 182
Using 200 mg of the compound obtained in Example 178 and 0.11 ml of phenyl isocyanate as raw materials, 120 mg of the compound shown in Table 7 was obtained in the same manner as in Examples 47 and 5.

Example 183
(1) 200 mg of the compound obtained in Example 178 was dissolved in 4 ml of a 1: 1 mixed solvent of tetrahydrofuran and dimethylformamide, and 24 mg of 60% sodium hydride was added under ice cooling and stirred for 15 minutes. 99 mg of '-carbonyldiimidazole was added. After stirring at room temperature for 15 hours, distilled water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 20: 0.2 to 10: 10: 0.2) to obtain 161 mg of 4 ″ -O-imidazolylcarbonyl compound. It was.
(2) 154 mg of the compound obtained in (1) above was dissolved in 1 ml of tetrahydrofuran, 0.12 ml of isopropylamine was added, and the mixture was concentrated under reduced pressure to give a reaction solution, which was allowed to stand at room temperature for 17 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 70: 0.2 to 10: 10: 0.2) to obtain 129 mg of 4 ″ -O-isopropylcarbamoyl compound. Obtained.
(3) 66 mg of the compound shown in Table 7 was obtained in the same manner as in Example 5 using 122 mg of the compound obtained in (2) above as a starting material.

  The compounds of Examples 171 to 183 are represented by the formula (G).

Example 184

(1) 200 mg of the compound obtained in Example 178 was dissolved in 2 ml of acrylonitrile, 10 μl of t-butanol was added, and 11 mg of 60% sodium hydride was added under ice cooling. After stirring at room temperature for 28 hours, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 90: 0.2 to 10: 10: 0.2). 146 mg of -N, 4 "-O-dicyanomethyl compound was obtained.
(2) 87 mg of the compound represented by the formula (a) was obtained in the same manner as in Example 5 using 139 mg of the compound obtained in (1) above as a starting material.
13C NMR (CHLOROFORM-d, 126MHz): d = 216.6, 177.1, 157.1, 117.9, 117.7, 101.3, 97.3, 88.0, 83.4, 81.4, 79.3, 78.1, 76.2, 73.5, 73.4, 67.8, 67.0, 65.3, 62.8, 60.3, 50.5, 49.7, 45.6, 45.4, 45.1, 44.6, 44.5, 40.3, 39.7, 38.9, 35.4, 34.9, 33.3, 22.1, 21.9, 21.8, 20.6, 19.4, 19.0, 18.9, 16.0, 16.0, 14.2, 14.1, 10.4, 9.1 ppm

Example 185

(1) 650 mg of N-chlorosuccinimide was suspended in 8 ml of methylene chloride, 1.3 ml of N-dodecylmethyl sulfide was added at −30 ° C. and stirred for 30 minutes. A solution of 1.0 g of the compound obtained in Example 178 in 2 ml of methylene chloride was added and stirred at the same temperature for 30 minutes, and then 1.1 ml of triethylamine was added. After stirring at the same temperature for 30 minutes and at room temperature for 1 hour, saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous sodium sulfate, and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 70: 0.2 to 10: 20: 0.2) to obtain 1.01 g of 4 ″ -ketone.
(2) Using 250 mg of the compound obtained in (1) above as a starting material, 144 mg of the compound represented by the formula (b) was obtained in the same manner as in Example 5.
MS (ESI) m / z = 854.6 [M + H] ⁺
13C NMR (CHLOROFORM-d, 126MHz): d = 211.2, 176.4, 158.4, 101.0, 96.5, 83.9, 78.3, 75.9, 72.5, 57.8, 51.5, 50.4, 45.3, 45.3, 45.1, 45.0, 37.5, 22.0, 21.6, 20.0, 18.4, 16.4, 15.6, 13.8, 13.4, 10.4, 9.5 ppm

Example 186
0.28 g of the compound obtained in Example 90 was dissolved in 7 ml of methylene chloride, 0.46 ml of 4-benzyloxybutyric acid, 0.99 g of N-ethyl-N ′-(3-dimethylaminopropyl) carbodiimide hydrochloride, 4-dimethylpyridine 0.63 g was added and stirred at room temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with an aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 90: 0.2 to 10: 50: 0.2) to obtain 0.29 g of the compound shown in Table 8. .

Example 187
Using 100 mg of the compound obtained in Example 90 and 155 mg of 4- (dimethylamino) butyric acid hydrochloride as raw materials, 67 mg of the compound shown in Table 8 was obtained in the same manner as in Example 186.

Example 188
46 mg of the compound shown in Table 8 was obtained in the same manner as in Example 5 using 137 mg of the compound obtained in Example 186 as a starting material.

Example 189
Using 50 mg of the compound obtained in Example 188 as a raw material, 4 ″ -O- (4-methanesulfonyl) butanoyl compound obtained by the same method as in Example 36 (3) was dissolved in 5 ml of ethanol, and 92 μl of morpholine was dissolved. And stirred for 16 hours at 70 ° C. The residue obtained by concentrating the reaction solution under reduced pressure was subjected to silica gel column chromatography (acetone: hexane: triethylamine = 10: 50: 0.2 to 10: 30: 0.2). Purification gave 38 mg of the compound shown in Table 8.

Example 190
Using 52 mg of the compound obtained in Example 188 as a starting material, 4 ″ -O- (4-methanesulfonyl) butanoyl compound obtained in the same manner as in Example 36 (3) was dissolved in 5 ml of ethanol, and 4- Hydroxypiperidine (110 mg) was added, and the mixture was stirred for 16 hours at 70 ° C. The reaction mixture was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (acetone: hexane: triethylamine = 10: 90: 0.2 to 10: 30: 0.2). To obtain 30 mg of the compound shown in Table 8.

Example 191
(1) 6-O-methylerythromycin A (5.07 g) was dissolved in ethanol (33 ml), 3 mol / L hydrochloric acid (33 ml) was added, and the mixture was stirred at room temperature for 16 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 30: 1: 0.1 to 20: 1: 0.1) to obtain 3.74 g of 3-hydroxy compound. It was.
(2) Using 0.50 g of the compound obtained in (1) above as a raw material, 0.31 g of 2′-O-methanesulfonyl was obtained in the same manner as in Example 1 (1).
(3) 0.24 g of the compound shown in Table 8 was obtained in the same manner as in Example 2, using 0.31 g of the compound obtained in (2) above and 0.36 ml of 3-phenyl-1-propanol as raw materials.

Example 192
Using 50 mg of the compound obtained in Example 191 and 37 mg of 3-pyridineacetic acid as raw materials, 32 mg of the compound shown in Table 8 was obtained in the same manner as in Example 186.

Example 193
Using 70 mg of the compound obtained in Example 191 as a starting material, 24 mg of the compound shown in Table 8 was obtained in the same manner as in Example 185 (1).

Example 194
(1) 150 mg of the compound obtained in Example 90 was dissolved in 4 ml of dichloroethane, 123 mg of 1,1′-thiocarbonyldiimidazole was added, and the mixture was stirred at 70 ° C. for 18 hours. Further, 246 mg of 1,1′-thiocarbonyldiimidazole was added and the operation of stirring at 70 ° C. for 2 days was repeated twice. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 90: 0.2 to 10: 70: 0.2) to obtain 136 mg of 4 ″ -O-thiocarbonylimidazolyl. Obtained.
(2) 110 mg of the compound obtained in (1) above was dissolved in 5 ml of benzene, 0.2 ml of tributyltin hydride and 8 mg of tetramethylsuccinonitrile were added, and the mixture was stirred at 70 ° C. for 6 hours. 28% aqueous ammonia was added to the reaction mixture, and the mixture was stirred for a while and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The residue obtained by concentrating the filtrate was purified by silica gel column chromatography (acetone: hexane: triethylamine = 10: 70: 0.2 to 10: 30: 0.2) to obtain 5 mg of a compound shown in Table 8.

  The compounds of Examples 186 to 194 are represented by the formula (H).

Example 195
(1) Using a compound of 0.90 g obtained in Example 191 (2) and 6.33 g of benzyl 4-hydroxy-1-piperidinecarboxylate as starting materials, 3 ″ -O — ((4 0.40 g of (benzyloxycarbonyl) piperidin-1-yl) form was obtained.
(2) 83 mg of the compound shown in Table 9 was obtained in the same manner as in Example 5 using 140 mg of the compound obtained in (1) above as a starting material.

Example 196
(1) 73 mg of 3-O- (3-pyridyl) acetyl compound was obtained in the same manner as in Example 186 using 127 mg of the compound obtained in Example 195 (1) and 82 mg of 3-pyridylacetic acid hydrochloride as raw materials. It was.
(2) 43 mg of the compound shown in Table 9 was obtained in the same manner as in Example 5 using 72 mg of the compound obtained in (1) above as a starting material.

  The compounds of Examples 195 and 196 are represented by the formula (J).

Example 197
0.10 g of the compound obtained in Example 1 was dissolved in 1 ml of chloroform, 0.19 ml of pyridine was added, 69 mg of triphosgene was added under ice cooling, and the mixture was stirred as it was for 1.5 hours. Further, 35 mg of triphosgene was added under ice cooling, and the mixture was stirred as it was for 1.5 hours. Distilled water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The residue obtained by concentrating the filtrate was purified by silica gel column chromatography (acetone: hexane: triethylamine = 3: 10: 0.2) to obtain 92 mg of the compound shown in Table 10.

Example 198
Using 78 mg of the compound obtained in Example 197 as a starting material, 45 mg of the compound shown in Table 10 was obtained in the same manner as in Example 185 (1).

Example 199
35 mg of the compound obtained in Example 198 was dissolved in 0.3 ml of 1,4-dioxane, 0.5 mol / L aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 3 hours. A 2 mol / L aqueous sodium hydroxide solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The residue obtained by concentrating the filtrate was purified by silica gel column chromatography (acetone: hexane: triethylamine = 3: 10: 0.2) to obtain 14 mg of a compound shown in Table 10.

  The compounds of Examples 197 to 199 are represented by the formula (K).

Example 200

(1) Erythromycin A (1.0 g) was dissolved in chloroform (14 ml), acetic anhydride (0.39 ml) and 4-dimethylaminopyridine (0.17 g) were added, and the mixture was stirred at room temperature for 16 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure was dissolved in 100 ml of methanol and stirred at 77 ° C. for 20 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 50: 1: 0.1 to 20: 1: 0.1) to obtain 11,4 ”-di 1.12 g of -O-acetyl derivative was obtained.
(2) 150 mg of 2′-O-methanesulfonyl was obtained in the same manner as in Example 1 (1) using 0.25 g of the compound obtained in (1) above as a raw material.
(3) In the same manner as in Example 2, 73 mg of the compound represented by the formula (c) was obtained using 146 mg of the compound obtained in the above (2) and 0.25 ml of 3-phenyl-1-propanol as raw materials.
MS (ESI) m / z = 936.5 [M + H] +
13C NMR (CHLOROFORM-d, 126MHz): d = 176.4, 171.0, 170.4, 142.3, 128.6, 128.3, 125.8, 109.0, 102.3, 97.2, 85.6, 85.5, 85.2, 78.8, 78.6, 77.9, 74.9, 72.6, 68.3, 67.4, 63.1, 61.9, 49.6, 47.2, 46.2, 45.3, 38.4, 35.6, 34.2, 32.5, 31.6, 26.0, 25.1, 24.1, 21.5, 21.3, 21.1, 20.9, 19.0, 17.7, 15.7, 14.6, 11.3, 10.8 ppm

Example 201

(1) 11,4 ″ -di-O-acetyl derivative (1.14 g) was obtained in the same manner as in Example 200 (1) using 1.0 g of erythromycin B as a raw material.
(2) Using 0.37 g of the compound obtained in (1) above as a raw material, 263 mg of 2′-O-methanesulfonyl compound was obtained in the same manner as in Example 1 (1).
(3) In the same manner as in Example 2, 65 mg of the compound represented by the formula (d) was obtained using 250 mg of the compound obtained in the above (1) and 0.45 ml of 3-phenyl-1-propanol as raw materials.
MS (ESI) m / z = 920.5 [M + H] ⁺
13C NMR (CHLOROFORM-d, 126MHz): d = 215.6, 175.3, 170.9, 170.6, 142.2, 128.5, 128.4, 125.9, 101.2, 96.8, 79.4, 78.8, 74.9, 74.3, 72.8, 72.5, 68.3, 66.9, 63.5, 61.9, 53.9, 49.5, 45.2, 44.8, 42.3, 41.9, 40.5, 39.3, 35.6, 34.5, 32.5, 31.5, 31.0, 29.4, 27.0, 25.7, 21.8, 21.2, 21.0, 20.9, 20.5, 18.1, 15.0, 10.4, 10.2, 9.9, 9.4 ppm

Example 202
Using 0.52 g of the compound obtained in Example 1 (1) and 1.0 g of 3-phenyl-1-propanethiol as raw materials, 0.16 g of the compound shown in Table 11 was obtained in the same manner as in Example 2.

Example 203
Using 28 mg of the compound obtained in Example 202 as a starting material, 28 mg of the compound shown in Table 11 was obtained in the same manner as in Example 90.

Example 204
(1) The raw material is 2.0 g of 4 ″ -O-formyl-6-O-methylerythromycin A obtained by the method described in the literature (Heterocycles, Vol. 31, No. 2, pp. 305-319, 1990) As a result, 1.22 g of 2′-O-methanesulfonyl compound was obtained in the same manner as in Example 1 (1).
(2) 0.5 g of the compound obtained in the above (1) was dissolved in 5 ml of dimethylformamide, 340 mg of potassium fluoride was added, and the mixture was stirred at 60 ° C. for 2.5 hours. Further, 340 mg of potassium fluoride was added and stirred at 60 ° C. for 9 hours. A 2 mol / L aqueous sodium hydroxide solution and distilled water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (chloroform: methanol: 28% aqueous ammonia = 30: 1: 0.1) to obtain 15 mg of the compound shown in Table 11.

Example 205
0.4 g of the compound obtained in Example 204 (1) was dissolved in 4 ml of dimethylformamide, 557 mg of potassium bromide was added, and the mixture was stirred at 60 ° C. for 2.5 hours. A 2 mol / L aqueous sodium hydroxide solution and distilled water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (acetone: hexane: triethylamine = 1: 10: 0.2) to obtain 29 mg of the compound shown in Table 11.

  The compounds of Examples 202 to 205 are represented by the formula (L).

Test Example 1 IL-1β protein production inhibitory action
The J774.2 cell line (purchased from ATCC) was suspended in Dulbecco's modified Eagle medium (Invitrogen) containing 10% fetal bovine serum and seeded in a 48-well plate. After overnight culture, test compounds were added at a final concentration of 100 μM. One hour after compound addition, lipopolysaccharide (LPS, serotype O111: B4, Calbiochem) was added at a final concentration of 1 μg / ml, and the culture supernatant was collected 24 hours later. The amount of IL-1β protein in the supernatant was quantified by ELISA (R & D Systems), and the inhibition rate of the test compound against the increase due to LPS stimulation was calculated. As comparative drug 1, 6-O-methylerythromycin A (clarithromycin) was used. Of the compounds tested, the data with a cell viability of 50% or more are listed in Table 12.

Test Example 2 Pro MMP-9 protein production inhibitory effect
Zymosan A (SIGMA) derived from Saccharomyces cerevisiae prepared in 7 to 9-week-old male C57BL / 6J mice (purchased from Clea Japan or Japan SLC) with phosphate buffer (PBS, 10010-049, Invitrogen) to 1 mg / ml Was intraperitoneally administered in 1 ml / mouse to induce peritonitis. Three days later, filter-sterilized cell recovery buffer (2 mM EDTA, 0.5% bovine serum albumin, PBS, pH 7.4) was administered intraperitoneally at 5 ml / mouse to recover peritoneal exudate cells, and the cell strainer (70 μm nylon, FALCON) was collected. After passing, it was washed twice with Hanks solution (Invitrogen). The suspension was suspended in Dulbecco's modified Eagle medium (Invitrogen) containing 10% fetal calf serum and seeded in a 48-well plate. After 6 hours, the whole medium was changed. After a further 18 hours of culture, the test compound was added at a final concentration of 0.02 to 20 μM. One hour after compound addition, tumor necrosis factor (TNF) α (R & D Systems) was added at a final concentration of 25 ng / ml, and the culture supernatant was collected 24 hours later. The amount of pro MMP-9 protein in the supernatant was quantified by ELISA (R & D Systems), and the IC ₅₀ value of the test compound with respect to the increase due to TNFα stimulation was calculated by ORIGIN analysis software (trade name: OriginLab). As comparative drug 1, 6-O-methylerythromycin A (clarithromycin) was used. Table 13 shows data showing a dose dependency when the cell viability was 70% or more. The respective values in Table 13 are relative activity values when the value of Comparative Drug 1 (IC ₅₀ = 10.53 ± 4.97 μM) is 10.

Test Example 3 Antibacterial Activity The test compound was dissolved in dimethyl sulfoxide or methanol, and the antibacterial activity (MIC) was measured by a micro liquid dilution method according to the standard method of CLSI (Clinical and Laboratory Standards Institute).
As a test strain, Methicillin-sensitive Staphylococcus aureus (MSSA) was used. The cells cultured overnight at 35 ° C. on a heart infusion agar plate medium were suspended in Mueller Hinton medium so as to be equivalent to 0.5 McFarland. This suspension was diluted 10 times to obtain an inoculum solution. The inoculated bacterial solution was inoculated into a cation-adjusted Mueller Hinton medium containing the test compound and cultured overnight at 35 ° C. The lowest test compound concentration at which no bacterial growth was observed macroscopically was defined as MIC. As comparative drug 1, 6-O-methylerythromycin A (clarithromycin) was used. The results are shown in Table 14.

  The compound of the present invention is cancer angiogenesis, rheumatoid arthritis, intimal thickening, vascular atherosclerosis, hemorrhagic stroke, acute myocardial infarction, chronic heart failure, aneurysm, cancer metastasis, adult respiratory distress syndrome, asthma It is effective for the prevention or treatment of idiopathic pulmonary fibrosis, chronic sinusitis, bronchitis, chronic obstructive pulmonary disease and the like.

Claims (8)

Formula (I)

(Where
A double line including a broken line indicates a single bond or a double bond,
R ¹ and R ² are the same or different and each represents a hydrogen atom, a C _1-6 alkylsulfonyl group, or a C _1-6 alkyl group (the C _1-6 alkyl group is an oxo group, a phenyl group, 1 to 3 pieces of C _1-6 alkyl groups of 5-7 membered may be substituted saturated heterocyclic group, and substituted with 1 to 3 substituents selected from the group consisting of C _1-6 alkylamino group 5 or 7-membered saturated heterocycle (the 5- to 7-membered saturated heterocycle is an oxygen atom in the ring), or R ¹ and R ² together with the nitrogen atom to be bonded , sulfur atom (optionally oxidized), or a nitrogen atom may, hydroxy groups, and substituted with 1 to 3 substituents selected from substituent group 1 good C _1-6 The substituent group 1 may be substituted with 1 to 3 substituents selected from an alkyl group. The substituent group 1 includes an oxo group, a benzyloxy group, and C _A group consisting of _1-6 alkylamino groups),
R ³ represents a hydrogen atom, a phenyl group, a 5- to 7-membered saturated heterocyclic group (the 5- to 7-membered saturated heterocyclic group is selected from a C _1-6 alkylsulfonyl group and substituent group 1). 1 may be substituted with 1 to 3 substituents selected from C _1-6 alkyl groups optionally substituted with 3 substituents), CONR ⁹ R ¹⁰ , or substituent group 2 Represents a C _1-6 alkyl group substituted with ~ 3 substituents,
R ⁹ and R ¹⁰ are the same or different and each is a hydrogen atom or a C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with 1 to 3 C _1-6 alkylamino groups). A phenyl group, a C _2-7 alkoxycarbonyl group, a 5- to 7-membered saturated heterocyclic group optionally substituted by 1 to 3 C _1-6 alkyl groups, and 2,3-dihydrobenzo [b] [1 .4] may be substituted with 1 to 3 substituents selected from the group consisting of dioxynyl groups), a C _3-6 cycloalkyl group, or 1 to 3 C _1-6 alkyl groups. A good 5- to 7-membered saturated heterocyclic group, phenyl group (the phenyl group is selected from the group consisting of a C _1-6 alkoxy group, a C _3-6 cycloalkyloxy group, and a C _1-6 alkylamino group) to 3 substituents may be substituted with a group), a pyridyl group (said pyridyl group is, C _1-6 alkoxy, C _3-6 consequent Alkyl group, and C _1-6 may be substituted with 1-3 substituents selected from the group consisting of alkyl amino group), or 2,3-dihydrobenzo [b] [1.4] dioxinyl group Indicate
Substituent group 2 includes a hydroxy group, a benzyloxy group, a phenyl group which may be substituted with 1 to 3 C _1-6 alkoxy groups, a C _3-6 cycloalkyl group, a C _1-6 alkylamino group, 6 -Hydroxy-2,5,7,8-tetramethylchromanyl group, 1,3-dimethyl-1H-purine-2,6 (3H, 7H) -dionyl group, and 5- to 7-membered saturated heterocyclic group ( saturated heterocyclic group of the 5-7 membered, hydroxy group, C _1-6 alkylsulfonyl group, and 1-3 may be substituted with a substituent C _1-6 alkyl group selected from substituent group 3 And the substituent group 3 is a group consisting of an oxo group, a phenyl group, and a C _1-6 alkylamino group).
R ⁴ represents a hydrogen atom or a C _1-6 alkyl group,
R ⁵ represents a hydrogen atom (only when a double line including a broken line indicates a double bond), a hydroxy group, or a C _1-6 alkanoyloxy group,
R ⁶ represents a hydrogen atom or a hydroxy group, or when the double line including a broken line is a single bond, R ⁵ and R ⁶ are taken together to form the formula (II)

Or a structure represented by formula (III)

The structure indicated by
R ¹¹ represents a hydrogen atom or a C _1-6 alkyl group which may be substituted with 1 to 3 cyano groups,
R ⁷ represents a hydrogen atom,
R ⁸ is a hydroxy group, formula OCOR ¹² , or formula (IV)

Shows the structure shown in
R ¹² represents a C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of a phenyl group and a pyridyl group);
R ¹³ represents a hydrogen atom,
R ¹⁴ represents a hydrogen atom, a hydroxy group, a C _1-6 alkoxy group that may be substituted with 1 to 3 cyano groups, a formula OCOR ¹⁵ , or a formula OCONR ¹⁶ R ¹⁷ ;
R ¹⁵ represents a C _1-6 alkyl group which may be substituted with 1 to 3 substituents selected from substituent group 4.
Substituent group 4 includes a hydroxy group, a benzyloxy group, a C _1-6 alkylamino group, and a 5- to 7-membered saturated heterocyclic group (the 5- to 7-membered saturated heterocyclic group includes a hydroxy group and C _{1 -6} alkyl group may be substituted with 1 to 3 substituents selected from alkyl groups),
R ¹⁶ and R ¹⁷ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, or a phenyl group, or R ¹³ and R ¹⁴ together may represent an oxo group, Alternatively, R ⁷ and R ⁸ may together represent an oxo group, provided that R ¹ and R ² are both methyl groups and R ³ is a hydrogen atom. Or a pharmaceutically acceptable salt thereof. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the double line including a broken line is a single bond. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ⁵ and R ⁶ are both hydroxy groups. R < ⁴ > is a methyl group, The compound of any one of Claims 1-3, or its pharmaceutically acceptable salt. R < ⁷ > is a hydrogen atom and R < ⁸ > is a structure shown by Formula (IV), The compound or its pharmaceutically acceptable salt of any one of Claims 1-4. R ³ is a C _1-6 alkyl group substituted with 1 to 3 substituents selected from Substituent Group 2. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof. Salt. R ^1, and R ² are the same or different, a hydrogen atom, or a C _1-6 compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 is an alkyl group. Cancerous angiogenesis, rheumatoid arthritis, intimal thickening, vascular atherosclerosis, hemorrhage containing the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient Prophylactic or treatment of sex type stroke, acute myocardial infarction, chronic heart failure, aneurysm, cancer metastasis, adult respiratory distress syndrome, asthma, idiopathic pulmonary fibrosis, chronic sinusitis, bronchitis, or chronic obstructive pulmonary disease Agent.