Cyclic diamine compounds having fused-ring groups

专利摘要:
The present invention is the following general formula (1) [Wherein, R 1 and R 2 each represent a hydrogen atom or a methoxy group, when R 2 is a hydrogen atom, R 1 represents a methoxy group, and when R 2 is a methoxy group, R 1 represents a hydrogen atom; A represents an oxygen atom, a sulfur atom, CH = CH, CH = N or NR 3 , wherein R 3 represents a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, an aryl group or an aryl lower alkyl group Represent; B represents a nitrogen atom, CH or CR 4 , wherein R 4 represents a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, an aryl group or an aryl lower alkyl group; m represents a number of 1 or 2; n represents a number from 1 to 5; and a cyclic diamine compound, an acid addition salt thereof, or a hydrate thereof; And a medicine containing the same. The compound of the present invention has a cell adhesion inhibitory action and is useful as a medicament for allergy, asthma, rheumatism, arteriosclerosis, inflammation and the like.
公开号:KR20040015270A
申请号:KR10-2003-7016476
申请日:2002-06-27
公开日:2004-02-18
发明作者:고다마다츠히코；다무라마사히로；오다도시아키；야마자키유키요시；니시가와마사히로；도이다케시；교타니요시노리
申请人:코와 가부시키가이샤；
IPC主号:

专利说明:

Cyclic diamine compound which has condensed cyclic group {CYCLIC DIAMINE COMPOUNDS HAVING FUSED-RING GROUPS}
[2] In various inflammatory diseases, infiltration of leukocytes into the site of inflammation has been confirmed. For example, eosinophil infiltration into the bronchus of asthma patients (Ohkawara Y. et al., Am. J. Respir. Cell Mol. Biol., 12, 4-12 (1995)), macrophages or T as blood vessels of atherosclerosis Infiltration of cells (Sakai A. et al., Arterioscler Thromb. Vase. Biol., 17, 310-316 (1997)), patients with atopic dermatitis (Wakita H. et al., J. Cutan. Pathol. 21, 33-39 (1994) Infiltration of T cells, eosinophils (Satoh T. et al., Eur. J. Immunol., 27, 85-91 (1997)) and articular synovial membranes of patients with chronic rheumatoid arthritis. (Tak PP. Et al., Clin. Immunol. Immunopathol., 77, 236-242 (1995)).
[3] Infiltration of these leukocytes is caused by cytokines, chemokines, lipids and complements produced locally in inflammatory areas (Albelda SM. Et al., FASEB J., 8, 504-512 (1994)). Leukocytes in activated blood flow adhere to vascular endothelial cells through an interaction called rolling or tethering with the same activated vascular endothelial cells. It then passes through the vascular endothelium (transmigration) and infiltrates the site of inflammation (Springer TA. Et al., Annu. Rev. Physiol., 57, 827-872 (1995)). In this process, immunoglobulin superfamily (ICAM-1, VCAM-1, etc.), selectin family (E-selectin, etc.), integrin, which are expressed on the surface of cells by stimulation with cytokines, etc. A variety of cell adhesion molecules such as the family (LFA-1, VLA-4, etc.) and CD44 play an important role ("Rinso Meneki (30), Suppl. 18 (1998)), and the expression of conditions and cell adhesion molecules. It is pointed out that it is related to hyperactivity.
[4] Therefore, agents capable of inhibiting adhesion through cell adhesion molecules include allergic diseases such as bronchial asthma, dermatitis, rhinitis, conjunctivitis, chronic arthritis, nephritis, inflammatory bowel disease, diabetes, arteriosclerosis, and autoimmune diseases. It is considered to be effective as a prophylactic and therapeutic drug such as an inflammatory disease. In fact, ICAM-1, VCAM-1, P-selectin, E-selectin, etc., on the vascular endothelial cell side, which are antibodies to the leukocyte-side cell adhesion molecule such as LFA-1, Mac-1, VLA-4, or ligands thereof. It has been reported to inhibit the infiltration of antibodies against localized inflammation of white blood cells in various animal condition models. For example, neutralizing antibodies to VCAM-1 and its counter receptor VLA-4 can delay its onset in NOD mouse models that spontaneously develop diabetes (Michie SA. Et al., Curr. Top. Microbiol. Immunol. , 231, 65-83 (1998). In addition, antibodies to VLA-4, or ICAM-1 and its counter receptor LFA-1, inhibit eosinophil infiltration in guinea pig or mouse allergic conjunctivitis models (Ebihara et al., Current Eye Res., 19,20-). 25 (1999), Whitcup SM., Et al., C1in. Immunol. 93, 107-113 (1999)), monoclonal antibodies against VCAM-l inhibited leukocyte infiltration in mouse DSS-induced colitis model to prevent the onset of colitis. Delaying has been reported (Soriano A. et al., Lab. Invest., 80, 1541-1551 (2000)), and also anti-VLA-4 antibodies, anti-CD44 antibodies inhibit their development in mouse collagen-induced arthritis models (Zeidler A. et al., Autoimmunity, 21, 245-252 (1995)). In addition, it is observed that mice lacking these cell adhesion molecules are inhibited from infiltrating into inflammatory tissue of leukocytes in the same manner as the inflammation model test (Bendjelloul F., Clin. Exp. Immunol, 119-63 (2000), Wolyniec). WW, et al., Am. J. Respir. Cell Mol. Biol., 18, 777-785 (1998), Bullard DC. Et al., J. Immunol., 157, 3153-3158 (1996)). However, in the development using antibodies, since the antibody is a peptidic polymer, not only oral administration is difficult, but also the possibility of side effects such as an allergic reaction based on antigenicity is considered as a problem.
[5] On the other hand, various low molecular weight cell adhesion inhibitory compounds aimed at oral administration have been reported. Benzothiophene derivatives (Boschelli DH. Et al., Med. Chem. 38, 4597-4614 (1995)), naphthalene derivatives (Japanese Patent Laid-Open No. Hei 1-147568), hydroxybenzoic acid derivatives (Japanese Patent Laid-Open No. 10-182550) Lignans (Japanese Patent Laid-Open No. 10-67656), 2-substituted benzothiazole derivatives (Japanese Patent Laid-Open No. 2000-086641), condensed pyrazine compounds (Japanese Patent Laid-Open No. 2000-319277), Although it is 2, 6- dialkyl- 4-silyl phenol (Japanese Unexamined-Japanese-Patent No. 2000-509070), etc., it does not necessarily fully satisfy the objective. The cyclic diamine compounds described in Japanese Patent Application Laid-open No. Hei 9-143075 and Japanese Patent Application Laid-open No. Hei 1-92282 do not exhibit sufficient cell adhesion inhibitory action, and further improvement in activity is desired.
[6] Accordingly, an object of the present invention is to provide a substance having an inhibitory effect on cell adhesion and cell infiltration, and further having an excellent anti-asthmatic action, antiallergic action, antirheumatic action, anti-arteriosclerosis action and anti-inflammatory action.
[1] The present invention relates to a novel cyclic diamine compound having a cell adhesion inhibitory effect and a cell invasion inhibitory activity, useful as an anti-asthmatic agent, an antiallergic agent, an antirheumatic agent, an anti-arterial agent, an anti-inflammatory agent, and a pharmaceutical containing the same.
[7] In view of such a situation, the present inventors have studied diligently to obtain a substance that inhibits cell adhesion and cell infiltration, and as a result, the compound represented by the following general formula (1) has excellent cell adhesion inhibition and cell invasion inhibition, The present invention has been found to be useful as an allergic agent, an asthma agent, an antilimatism agent, an anti-arteriosclerosis agent, and an anti-inflammatory agent.
[8] That is, this invention is following General formula (1)
[9]
[10] [Wherein, R ¹ and R ² each represent a hydrogen atom or a methoxy group, when R ² is a hydrogen atom, R ¹ represents a methoxy group, and when R ² is a methoxy group, R ¹ represents a hydrogen atom; A represents an oxygen atom, a sulfur atom, CH = CH, CH = N or NR ³ , wherein R ³ represents a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, an aryl group or an aryl lower alkyl group Represent; B represents a nitrogen atom, CH or CR ⁴ , wherein R ⁴ represents a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, an aryl group or an aryl lower alkyl group; m represents a number of 1 or 2; n represents a number from 1 to 5; and a cyclic diamine compound, an acid addition salt thereof, or a hydrate thereof.
[11] Moreover, this invention provides the medicine containing the said cyclic diamine compound, its acid addition salt, or hydrate thereof as an active ingredient.
[12] Moreover, this invention provides the pharmaceutical composition containing the said cyclic diamine compound, its acid addition salt or its hydrate, and a pharmaceutically acceptable carrier.
[13] The present invention also provides a use for the pharmaceutical preparation of the cyclic diamine compounds, acid addition salts thereof or hydrates thereof.
[14] The present invention also provides a method for treating a disease caused by cell adhesion and / or cell infiltration, which is administered to a patient in need of an effective amount of the acid addition salts or hydrates thereof of the cyclic diamine compound.
[15] Best Mode for Carrying Out the Invention
[16] In the formula (1), examples of the lower alkyl group represented by R ³ and R ⁴ C ₁ -C ₆ - alkyl group, for, example, methyl group, ethyl group, n- propyl group, isopropyl group, n- butyl group, isobutyl Although butyl group, tert- butyl group, n-pentyl group, n-hexyl group is mentioned, methyl group, ethyl group, n-propyl group, isopropyl group, etc. are especially preferable.
[17] As the hydroxy lower alkyl group, a hydroxy-C ₂ -C ₆ -alkyl group, for example, 2-hydroxyethyl group, 2-hydroxy-1-methylethyl group, 2-hydroxy-1,1-dimethylethyl group, 3- Hydroxypropyl group, 3-hydroxy-2-methylpropyl group, 4-hydroxy butyl group, 5-hydroxypentyl group, 6-hydroxyhexyl group, and especially 2-hydroxyethyl group, 2 -Hydroxy-1-methylethyl group, 2-hydroxy-1,1-dimethylethyl group, 3-hydroxypropyl group and the like are preferable.
[18] As the lower alkoxy lower alkyl group, a C ₁ -C ₆ -alkoxy-C ₁ -C ₆ alkyl group, for example, 2-methoxyethyl group, 2-methoxy-1-methylethyl group, 2-methoxy-1,1-dimethyl Ethyl group, 3-methoxypropyl group, 3-methoxy-2-methylpropyl group, 4-methoxybutyl group, 5-methoxypentyl group, 6-methoxyhexyl group, 2-ethoxyethyl group, 2-e Methoxy-1-methylethyl group, 2-ethoxy-1,1-dimethylethyl group, 3-ethoxypropyl group, 3-ethoxy-2-methylpropyl group, 4-ethoxybutyl group, 5-ethoxypentyl group , 6-ethoxyhexyl group, 2-propoxyethyl group, 2-propoxy-1-methylethyl group, 2-propoxy-1,1-dimethylethyl group, 3-propoxypropyl group, 3-propoxy-2- Methylpropyl group, 4-propoxybutyl group, 5-propoxypentyl group, 6-methoxyhexyl group, 2-butoxyethyl group, 2-butoxy-1-methylethyl group, 2-butoxy-1,1- Dimethylethyl group, 3-butoxypropyl group, 3-butoxy-2-methylpropyl group, 4-butoxybutyl group, 5-butoxypentyl group, 6-butoxyhexyl group, 2-pentyloxyethyl group, 2- Pentyloxy-1-methylethyl group, 2-pentyloxy-1,1-dimethylethyl group, 3-pentyloxypropyl group, 3-pentyloxy-2-methylpropyl group, 4-pentyloxybutyl group, 5-pentyloxyphene Tyl group, 6-pentyloxyhexyl group, 2-hexyloxyethyl group, 2-hexyloxy-1-methylethyl group, 2-hexyloxy-1,1-dimethylethyl group, 3-hexyloxypropyl group, 3-hexyl jade Cy-2-methylpropyl group, 4-hexyloxybutyl group, 5-hexyloxypentyl group, 6-hexyloxyhexyl group, and especially 2-methoxyethyl group, 2-methoxy-1-methylethyl group, 2-methoxy-1,1-dimethylethyl group, 3-methoxypropyl group, 2-ethoxyethyl group, 2-ethoxy-1-methylethyl group, 2-ethoxy-1,1-dimethylethyl group, 3-e Preferred are a methoxypropyl group, 2-propoxyethyl group, 2-propoxy-1-methylethyl group, 2-propoxy-1,1-dimethylethyl group, 3-propoxypropyl group and the like.
[19] Examples of the aryl group include a C ₆ -C ₁₀ -aryl group, for example, a phenyl group. Examples of the aryl lower alkyl group include a C ₆ -C ₁₀ -aryl C ₁ -C ₆ -alkyl group, for example, a phenethyl group and a benzyl group. Can be mentioned.
[20] As R ³ and R ⁴ , a hydrogen atom, a C ₁ -C ₆ -alkyl group or a phenyl group is particularly preferable, and a hydrogen atom, a methyl group or a phenyl group is more preferable.
[21] In general formula (1),
[22]
[23] As the skeleton represented by the above, a skeleton selected from naphthalene, quinoline, quinazoline, benzimidazole, benzothiazole, benzoxazole, indole, benzothiophene and benzofuran is preferable. Moreover, n is an integer of 1-5 or an integer of 1-4 is preferable, and the integer of 1-3 is especially preferable.
[24] The acid addition salt of the compound (1) of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt, for example, acid addition salts of mines such as hydrochloride, hydrobromide, hydroiodide, sulfate, and phosphate; Acid addition salts of organic acids such as benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, oxalate, maleate, fumarate, tartarate, citrate, acetate.
[25] In addition, the compound (1) of the present invention may exist in the form of a solvate represented by a hydrate, but the solvate is also included in the present invention.
[26] The compound (1) of the present invention can be produced by the method A or B shown below.
[27] [A law]
[28]
[29] [Wherein X represents a halogen atom, an alkylsulfonyloxy group or an aryl sulfonyloxy group, and R ¹ , R ² , A, B, m and n are as described above]
[30] That is, compound (1) of this invention can be obtained by condensing compound (2) and cyclic diamine (3). In general formula (2), as a halogen atom represented by X, a chlorine atom or a bromine atom is preferable. Moreover, a methanesulfonyloxy group is preferable as an alkylsulfonyloxy group, and p-toluenesulfonyloxy group is preferable as an arylsulfonyloxy group.
[31] The condensation reaction of the compound (2) with the cyclic diamine (3) is, for example, the presence of a base such as potassium carbonate in a solvent such as N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile or the like. It is carried out by stirring at 0 ° C to 100 ° C, preferably at room temperature for 1 hour to several days, more preferably for 5 hours.
[32] Compound (2) used here can be manufactured according to the following reaction formula, for example.
[33]
[34] [Wherein R ⁵ represents a hydrogen atom or a lower alkyl group and R ¹ , R ² , A, B, n and X are the same as electricity]
[35] That is, the carboxylic acid or its ester (4) or aldehyde (5) is reduced using a reducing agent such as lithium aluminum hydride to give an alcohol (6), followed by halogenating agents such as thionyl chloride or methane sulfide. Compound (2) can be obtained by reacting sulfonylating agents such as polyvinyl chloride and p-toluenesulfonyl chloride.
[36] The alcohol 6 can also be obtained by subjecting the terminal olefins to a hydroboration reaction followed by an oxidation reaction.
[37] In addition, compound (2) having a quinazoline skeleton can be prepared according to the following reaction formula.
[38]
[39] [B Act]
[40]
[41] Wherein R ¹ , R ² , A, B, m and n are as described above.
[42] That is, the compound (1) of this invention can be obtained by condensing carboxylic acid (4) and cyclic diamine (3), and reducing the obtained amide body (7).
[43] The condensation reaction of the carboxylic acid (4) with the cyclic diamine (3) is, for example, 4- (dimethyl) in a solvent such as toluene, benzene, dichloromethane, chloroform, tetrahydrofuran (THF), dioxane and acetonitrile. Amino) pyridine is used as a catalyst and dehydrating condensing agents such as dicyclohexylcarbodiimide and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (aqueous carbodiimide hydrochloride) The reaction is conducted at 0 DEG C to reflux temperature, preferably at room temperature for 1 hour to several days, preferably overnight. Further, the reduction reaction of the amide 7 is, for example, using a reducing agent such as lithium aluminum hydride in THF or diethyl ether at 0 ° C to reflux temperature, preferably at room temperature for 1 hour to several days, preferably Is performed by reacting for 6 hours.
[44] The compound (1) of the present invention can be obtained by the above method, but can be further purified using conventional refining means such as a recrystallization method and column chromatography if necessary. Moreover, you may make it the above-mentioned desired salt or solvate by a conventional method as needed. When the compound (1) of the present invention has a subtitle carbon, the present invention includes all stereoisomers.
[45] The compound (1), salts thereof, or solvates thereof of the present invention thus obtained exhibit excellent cell adhesion inhibitory activity, as shown in later examples, and diseases caused by cell adhesion or cell infiltration of animals including humans, for example. For example, it is useful as a medicine for the treatment or prevention of asthma, allergies, rheumatism, atherosclerosis, inflammation, and the like.
[46] The medicament of the present invention contains the compound (1), salts thereof, or solvates thereof as an active ingredient, and its dosage form is not particularly limited, and may be appropriately selected depending on the therapeutic purpose, for example, oral preparations, Injectables, suppositories, ointments, inhalants, eye drops, nasal drops, and adjuvant may be used, and a composition suitable for their dosage form may be prepared by a conventional formulation method known to those skilled in the art by combining a pharmaceutically acceptable carrier. have.
[47] When preparing an oral solid preparation, an excipient, a binder, a disintegrant, a lubricant, a coloring agent, a coagulant, a odorant, and the like are added to the compound (1) of the present invention, and then purified and coated by conventional methods. , Granules, powders, capsules and the like can be prepared. As such additives, those commonly used in the art may be used. For example, as excipients, lactose, white sugar, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid, and the like may be used. Ethanol, propanol, sweet syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphate, Examples of the disintegrating agent include polyvinylpyrrolidone, dry starch, sodium alginate, cantenmal, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, lactose, and the like. Borax, polyethyleneglycol, etc. can be illustrated as a sweetening agent, a sugar, a skin, citric acid, a tartaric acid, etc.
[48] When preparing an oral liquid preparation, a copulation agent, a buffer, a stabilizer, a odor agent, etc. can be added to the compound (1) of the present invention, and an oral solution, a syrup agent, an ericyl agent, or the like can be produced by a conventional method. In this case, vanillin etc. as a mating agent, sodium citrate etc. as a buffer, tragant, gum arabic, gelatin etc. are mentioned as a stabilizer.
[49] When preparing an injection, a pH adjusting agent, a buffer, a stabilizer, an isotonicity agent, a local anesthetic and the like can be added to the compound (1) of the present invention, and subcutaneous, intramuscular and intravenous injections can be prepared by conventional methods. In this case, as a pH adjuster and a buffer, sodium citrate, sodium acetate, sodium phosphate, etc. are mentioned. Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiosulfate and the like. Local anesthetics include procaine hydrochloride, lidocaine hydrochloride, and the like. Examples of isotonic agents include sodium chloride and glucose.
[50] When preparing a suppository, the compound (1) of the present invention is formulated with a carrier for a preparation well known in the art, for example, polyethylene glycol, lanolin, cacao fat, fatty acid triglycerides, etc. After adding surfactants, such as a trademark), it can manufacture by a conventional method.
[51] When preparing an ointment, the base, stabilizer, wetting agent, preservative, etc. which are normally used for the compound (1) of this invention are mix | blended as needed, and it mixes and formulates by a conventional method. Examples of the base include liquid paraffin, white petrolatum, pewter, octyldodecyl alcohol, paraffin and the like. Methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, etc. are mentioned as a preservative.
[52] In addition to the above, inhalants, eye drops, and nasal drops can also be prepared by conventional methods.
[53] The dosage of the medicament of the present invention varies depending on age, weight, symptoms, dosage form, number of administrations, and the like, but is usually orally administered or parenteral divided into 1 to 1000 mg once or several times a day as the compound (1) of the present invention. Oral administration is preferred.
[54] Example
[55] Next, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.
[56] Preparation Example 1
[57] Synthesis of 5,6,7-trimethoxynaphthalene-2-carbonitrile:
[58]
[59] 2.0 M-lithium diisopropylamide (2.55 ml) was dripped at -78 degreeC under argon stream to anhydrous THF (5 ml), and it stirred for 30 minutes. Subsequently, anhydrous THF (5 mL) solution of 3-cyanopropionaldehyde dimethylacetal (672 mg) was added dropwise and stirred at -78 ° C for 1 hour. Subsequently, anhydrous THF (5 mL) solution of 3,4,5-trimethoxybenzaldehyde (1.0 g) was added dropwise. After stirring at room temperature for 1 hour, saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was dissolved in methanol (6 mL), slowly added sulfuric acid (1 mL), and stirred at 100 ° C for 1 hour. The solution was weakly alkaline with 4M-KOH aqueous solution at 0 ° C, extracted with chloroform, and the organic layer was water, It washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3 1: 1) to obtain the title compound.
[60] Quantity: 847mg (68.3%)
[61] Preparation Example 2
[62] Synthesis of 5,6,7-trimethoxynaphthalene-2-carboxylic acid:
[63]
[64] The above-mentioned 5,6,7-trimethoxynaphthalene-2-carbonitrile (5.8 g) is dissolved in ethanol (40 mL), a solution of potassium hydroxide (11.2 g) of water (10 mL) is added, and the mixture is refluxed for 1 hour. Stirred. After cooling, the solvent was distilled off, the residue was dissolved in water, washed twice with ether, and the aqueous layer was neutralized with diluted hydrochloric acid. Subsequently, the mixture was extracted with ethyl acetate, washed with saturated brine and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain the title compound.
[65] Quantity: 5.2g (85%)
[66] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.00 (s, 3H), 4.02 (s, 3H), 4.06 (s, 3H),
[67] 7.08 (s, 1H), 8.00 (dd, 1H, J = 8.8 Hz, 1.7 Hz), 8.12 (d, 1H, J = 8.8 Hz),
[68] 8.55 (d, 1H, J = 1.5 Hz)
[69] Preparation Example 3
[70] Synthesis of 2-hydroxymethyl-5,6,7-trimethoxynaphthalene:
[71]
[72] Lithium aluminum hydride (579 mg) was added to anhydrous THF (40 mL) under an argon stream, ice-cooling, and then anhydrous THF (5,6,7-trimethoxynaphthalene-2-carboxylic acid (4.0 g)) was added. 40 ml) was added dropwise, and the mixture was stirred at room temperature for 4 hours. Ether (150 mL) was added to the reaction solution, sodium sulfate decahydrate was added, followed by stirring for 15 minutes. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to obtain the title compound.
[73] Quantity: 3.8 g (theoretical quantity)
[74] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.97 (s, 6H), 4.04 (s, 3H),
[75] 4.82 (d, 2H, J = 5.6 Hz), 6.93 (s, 1H), 7.35 (dd, 1H, J = 8.6 Hz, 1.7 Hz),
[76] 7.66 (s, 1 H), 8.03 (d, 1 H, J = 8.6 Hz)
[77] Preparation Example 4
[78] Synthesis of 2-chloromethyl-5,6,7-trimethoxynaphthalene:
[79]
[80] 2-hydroxymethyl-5,6,7-trimethoxynaphthalene (781 mg) was dissolved in chloroform (6 mL), and thionyl chloride (561 mL) was added dropwise. After stirring at room temperature for 5 hours, the mixture was poured into ice water, sodium hydrogencarbonate was added, the pH was adjusted to 8, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the title compound.
[81] Quantity: 608mg (73%)
[82] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.96 (s, 3H), 3.97 (s, 3H), 4.03 (s, 3H),
[83] 4.71 (s, 2H), 6.29 (s, 1H), 7.36 (dd.IH, J = 8.6 Hz, 1.5 Hz)
[84] Example 1
[85] Synthesis of N, N'-bis [(5,6,7-trimethoxynaphthalen-2-yl) methyl] piperazine:
[86]
[87] 2-chloromethyl-5,6,7-trimethoxynaphthalene (418 mg) and piperazine (63 mg) were dissolved in DMF (10 mL), potassium carbonate (207 mg) was added, and the mixture was stirred at room temperature for 5 hours. did. After concentration under reduced pressure, chloroform was added to the residue, washed with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 40: 1) to obtain the title compound as a free base.
[88] Quantity: 109mg (27%)
[89] ¹ H-NMR (hydrochloride, 400 MHz, DMSO-d ₆ ) δ: 3.35 (s, 8H), 3.89 (s, 6H),
[90] 3.94 (s, 6H), 3.99 (s, 6H), 4.29 (s, 4H), 7.11 (s, 2H),
[91] 7.56 (d, 2H, J = 10.2 Hz), 7.95 (s, 2H), 7.96 (d, 2H, J = 10.2 Hz)
[92] m / z (EI): 546 [M ⁺ ]
[93] Example 2
[94] Synthesis of N, N'-bis [(5,6,7-trimethoxynaphthalen-2-yl) methyl] homopiperazine:
[95]
[96] 2-Chloromethyl-5,6,7-trimethoxynaphthalene (607 mg) and homopiperazine (108 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
[97] Quantity: 314mg (51%)
[98] ¹ H-NMR (hydrochloride, 400 MHz, DMS0-d ₆ ) δ: 2.30 (quint, 2H, J = 6.8 Hz),
[99] 3.40 (t, 4H, J = 6.8 Hz), 3.71 (s, 4H), 3.89 (s, 6H), 3.93 (s, 6H),
[100] 3.99 (s, 6H), 4.42 (s, 4H), 7.11 (s, 2H), 7.58 (dd, 2H, J = 8.8 Hz, 1.7 Hz),
[101] 7.96 (d, 2H, J = 8.8 Hz), 7.98 (d, 2H, J = 1.7 Hz)
[102] m / z (EI): 560 [M ⁺ ]
[103] Preparation Example 5
[104] Synthesis of 6,7,8-trimethoxynaphthalene-2-carbonitrile:
[105]
[106] 2,3,4-trimethoxybenzaldehyde (9.8 g) and 3-cyanopropionaldehyde dimethylacetal (6.35 mL) were treated under the same conditions as in Production Example 1 to obtain the title compound.
[107] Quantity: 5.94 g (49%)
[108] Preparation Example 6
[109] Synthesis of 6,7,8-trimethoxynaphthalene-2-carboxylic acid:
[110]
[111] 6,7,8-trimethoxynaphthalene-2-carbonitrile (2.34 g) was treated in the same manner as in Production Example 2 to obtain the title compound.
[112] Quantity: 2.3 g (91%)
[113] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.99 (s, 3H), 4.02 (s, 3H), 4.12 (s, 3H),
[114] 6.99 (s, 1H), 7.74 (d, 1H, J = 8.4 Hz), 8.04 (dd, 1H, J = 8.4 Hz, 1.8 Hz),
[115] 8.91 (d, 1H, J = 1.8 Hz)
[116] Preparation Example 7
[117] Synthesis of 2-hydroxymethyl-6,7,8-trimethoxynaphthalene:
[118]
[119] 6,7,8-trimethoxynaphthalene-2-carboxylic acid (5.7 g) was treated in the same manner as in Production Example 3 to obtain the title compound.
[120] Quantity: 5.2 g (96%)
[121] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.97 (s, 3H), 3.97 (8, 3H), 4.06 (s, 3H),
[122] 4.83 (d, 2H, J = 5.9 Hz), 6.95 (s, 1H), 7.41 (dd, 1H, J = 8.4 Hz, 1.8 Hz),
[123] 7.69 (dd, IH, J = 8.4 Hz, 1.8 Hz), 8.01 (s, 1H)
[124] Preparation Example 8
[125] Synthesis of 2-chloromethyl-6,7,8-trimethoxynaphthalene:
[126]
[127] 2-hydroxymethyl-6,7,8-trimethoxynaphthalene (656 mg) was treated in the same manner as in Preparation Example 4 to obtain the title compound.
[128] Quantity: 508 mg (76%)
[129] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.97 (s, 6H), 4.06 (s, 3H), 4.88 (s, 2H),
[130] 6.95 (s, 1H), 7.41 (dd, 1H, J = 8.4 Hz, 1.8 Hz), 7.69 (dd, 1H, J = 8.4 Hz, 1.8 Hz)
[131] Example 3
[132] Synthesis of N, N'-bis [(6,7,8-trimethoxynaphthalen-2-yl) methyl] piperazine:
[133]
[134] 2-Chloromethyl-6,7,8-trimethoxynaphthalene (226 mg) and piperazine (37 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
[135] Quantity: 214 mg (92%)
[136] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.53 (br, 8H), 3.49 (s, 4H), 3.96 (s, 12H),
[137] 4.05 (s, 6H), 6.93 (s, 2H), 7.41 (dd, 2H, J = 8.2 Hz, 1.6 Hz),
[138] 7.63 (d, 2H, J = 8.2 Hz), 7.91 (br, 2H)
[139] m / z (EI): 546 [M ⁺ ]
[140] Example 4
[141] Synthesis of N, N'-bis [(6,7,8-trimethoxynaphthalen-2-yl) methyl] homopiperazine:
[142]
[143] 2-Chloromethyl-6,7,8-trimethoxynaphthalene (222 mg) and homopiperazine (42 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
[144] Quantity: 168 mg (72%)
[145] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.86 (br, 2H), 2.77 (t, 4H, J = 5.9 Hz),
[146] 2.82 (t, 4H, J = 5.9 Hz), 3.82 (s, 4H), 3.96 (s, 12H), 4.04 (s, 6H),
[147] 6.93 (s, 2H), 7.47 (dd, 2H, J = 8.4 Hz, 1.5 Hz), 7.64 (d, 2H, J = 8.3 Hz),
[148] 7.91 (br, 2 H)
[149] m / z (EI): 560 [M ⁺ ]
[150] Preparation Example 9
[151] Synthesis of 5,6,7-trimethoxynaphthalene-2-carboaldehyde:
[152]
[153] 2-hydroxymethyl-5,6,7-trimethoxynaphthalene (3.78 g) was dissolved in dichloromethane (100 mL), pyridium nitrate (8.61 g) was added, and it stirred at room temperature for 4 hours. The reaction solution was filtered, and the insolubles were sufficiently washed with chloroform. The liquids were combined, concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with 2M hydrochloric acid, water, and saturated brine in that order, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3-> 1: 1), and recrystallized with ethyl acetate-hexane to obtain the title compound.
[154] Quantity: 3.24 g (86%)
[155] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.01 (8, 3H), 4.02 (s, 3H), 4.05 (s, 3H),
[156] 7.10 (s, 1H), 7.82 (dd, 1H, J = 8.7 Hz, 1.6 Hz), 8.15 (d, 1H, J = 8.7 Hz),
[157] 8.19 (d, 1H, J = 1.5 Hz), 10.11 (s, 1H)
[158] Preparation Example 10
[159] Synthesis of 5,6,7-trimethoxy-2-vinylnaphthalene:
[160]
[161] Under argon stream, methyltriphenylphosphonium bromide (2.8 g) was suspended in hot water THF (10 mL), and 1.7 M-tert-butyllithium hexane solution (3.3 mL) was added dropwise at -20 ° C, and 1 hour at room temperature. After stirring, it cooled to -20 degreeC again, the anhydrous THF (30 mL) solution of 5,6,7-trimethoxy naphthalene-2-carboaldehyde (1.26g) was dripped, and it stirred at room temperature overnight. The solvent was distilled off, water was added to the residue, extraction was performed with ethyl acetate, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 8) to obtain the title compound.
[162] Quantity: 1.15g (93%)
[163] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.93 (s, 3H), 3.98 (s, 3H), 4.04 (s, 3H),
[164] 5.31 (d, 1H, J = 10.9 Hz), 5.85 (d, IH, J = 17.6 Hz),
[165] 6.83 (dd, 1H, J = l7.5 Hz, 10.7 Hz), 6.90 (s, 1H),
[166] 7.51 (dd, 1H, J = 8.7 Hz, 7.59 (s, 1H), 8.01 (d, 1H, J = 8.6 Hz)
[167] Preparation Example 11
[168] Synthesis of 2- (2-hydroxyethyl) -5,6,7-trimethoxynaphthalene:
[169]
[170] 5,6,7-trimethoxy-2-vinylnaphthalene (1.215 g) was dissolved in anhydrous THF (10 mL) under argon stream, and 1M-boranetetrahydrofuran solution (4.7 mL) was added dropwise at 0 ° C. It stirred at room temperature for 2 hours. Water (4 mL) was added at 0 ° C., followed by 4M aqueous sodium hydroxide solution (1.2 mL). 31% hydrogen peroxide solution (0.5 ml) was added to the reaction solution at 0 ° C, and the mixture was stirred at 50 ° C for 50 minutes. Subsequently, the solvent was distilled off, water was added to the residue, followed by extraction with ethyl acetate, the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 8) to obtain the title compound.
[171] Quantity: 1.03 g (83.5%)
[172] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.02 (br, 1H), 2.95 (d, 1H, J = 6.6 Hz),
[173] 3.87 (t, 2H, J = 6.6 Hz), 3.93 (s, 3H), 3.95 (s, 3H), 4.02 (s, 3H),
[174] 6.88 (s, 1H), 7.20 (dd, 1H, J = 8.5 Hz, 1.7 Hz), 7.50 (s, 1H),
[175] 7.97 (d, 1H, J = 8.6 Hz)
[176] Preparation Example 12
[177] Synthesis of 2- (2-methanesulfonyloxyethyl) -5,6,7-trimethoxynaphthalene:
[178]
[179] 2- (2-hydroxyethyl) -5,6,7-trimethoxynaphthalene (1.26 g) is dissolved in pyridine (5 mL), methanesulfonylchloride (715 mg) is added at 0 ° C., and at room temperature It stirred for 2 hours. The reaction solution was made acidic with hydrochloric acid, extracted with ethyl acetate, washed with water and brine, and the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5) to obtain the title compound.
[180] Quantity: 1.55g (95%)
[181] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.84 (s, 3H), 3.18 (t, 2H, J = 6.9 Hz),
[182] 3.96 (s, 3H), 3.97 (s, 3H), 4.04 (s, 3H), 4.49 (t, 2H, J = 6.9 Hz),
[183] 6.90 (s, 1H), 7.22 (dd, 1H, J = 9.4 Hz, 1.2 Hz), 7.54 (s, 1H),
[184] 8.00 (d, 1H, J = 8.6 Hz)
[185] Example 5
[186] Synthesis of N, N'-bis [2- (5,6,7-trimethoxynaphthalen-2-yl) ethyl] piperazine:
[187]
[188] 2- (2-methanesulfonyloxyethyl) -5,6,7-trimethoxynaphthalene (374 mg) and piperazine (43 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base. .
[189] Quantity: 65 mg (23%)
[190] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.64-2.74 (m, 12H), 2.89-3.00 (m, 4H),
[191] 3.96 (s, 6H), 3.96 (s. 6H), 4.03 (s, 6H), 6.89 (s, 2H),
[192] 7.23 (dd, 2H. J = 8.6 Hz, 1.6 Hz), 7.50 (s, 2H), 7. 96 (d, 2H, J = 8.6 Hz)
[193] m / z (EI): 574 [M ⁺ ]
[194] Example 6
[195] Synthesis of N, N'-bis [2- (5,6,7-trimethoxynaphthalen-2-yl) ethyl] homopiperazine:
[196]
[197] 2- (2-methanesulfonyloxyethyl) -5,6,7-trimethoxynaphthalene (225 mg) and homopiperazine (52 mg) were reacted in the same manner as in Example 1 to give the title compound as the free base. Got it.
[198] Quantity: 58 mg (33%)
[199] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.79-1.82 (m, 2H), 2.75-2.85 (m, 16H),
[200] 3.84 (s, 6H), 3.85 (s, 6H), 3.93 (s, 6H), 6.79 (s, 2H),
[201] 7.11 (dd, 2H, J = 8.6 Hz, 1.5 Hz), 7.40 (s, 2H), 7.86 (d, 2H, J = 8.6 Hz)
[202] m / z (EI): 588 [M ^+]
[203] Preparation Example 13
[204] Synthesis of 6,7,8-trimethoxynaphthalene-2-carboaldehyde:
[205]
[206] 2-hydroxymethyl-6,7,8-trimethoxynaphthalene (4.41 g) was treated in the same manner as in Production Example 9 to obtain the title compound.
[207] Quantity: 3.33 g (77%)
[208] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.99 (s, 3H), 4.02 (s, 3H), 4.13 (s, 3H),
[209] 6.99 (s, 1H), 7.75 (d, 1H, J = 8.8 Hz), 7.87 (dd, 1H, J = 8.8 Hz, 1.8 Hz),
[210] 8.55 (d, 1H, J = 1.8 Hz), 10.11 (s, 1H)
[211] Preparation Example 14
[212] Synthesis of 6,7,8-trimethoxy-2-vinylnaphthalene:
[213]
[214] 6,7,8-trimethoxynaphthalene-2-carboaldehyde (1.23 g) was treated in the same manner as in Production Example 10 to obtain the title compound.
[215] Quantity: 985 mg (80%)
[216] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.97 (s, 6H), 4.06 (s, 3H).
[217] 5.28 (d, 1H, J = 8.9 Hz), 5.83 (d, 1H, J = 8.9 Hz), 6.82-6.93 (m, 1H),
[218] 6.93 (s, 1 H), 7.55 (dd, 1 H, J = 8.4 Hz, 1.8 Hz),
[219] 7.64 (d, 1H, J = 8.4 Hz), 7.95 (br, 1H),
[220] Preparation Example 15
[221] Synthesis of 2- (2-hydroxyethyl) -6,7,8-trimethoxynaphthalene:
[222]
[223] 6,7,8-trimethoxy-2-vinylnaphthalene (735 mg) was treated in the same manner as in Production Example l1 to obtain the title compound.
[224] Quantity: 668 mg (85%)
[225] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.02 (t, 2H, J = 6.6 Hz), 3.93 (t, 2H, J = 6.6 Hz),
[226] 3.97 (s, 6H), 4.05 (s, 3H), 6.93 (s, 1H), 7.28 (dd, 1H, J = 8.3 Hz, 1.7 Hz),
[227] 7.65 (d, 1H, J = 8.3 Hz), 7.88 (br, 1H)
[228] Preparation Example 16
[229] Synthesis of 2- (2-methanesulfonyloxyethyl) -6,7,8-trimethoxynaphthalene:
[230]
[231] 2- (2-hydroxyethyl) -6,7,8-trimethoxynaphthalene (668 mg) was treated in the same manner as in Production Example 12 to obtain the title compound.
[232] Quantity: 922 mg (theoretical amount)
[233] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.21 (t, 2H, J = 6.8 Hz), 2.97 (s, 6H),
[234] 4.01 (s, 8H), 4.50 (t, 2H, J = 2.8 Hz), 6.93 (s, 1H), 7.27 (dd, 1H, J = 8.4 Hz,
[235] 1.7 Hz), 7.66 (d, 1H, J = 8.4 Hz), 7.88 (br, 1H)
[236] Example 7
[237] Synthesis of N, N'-bis [2- (6,7,8-trimethoxynaphthalen-2-yl) ethyl] piperazine:
[238]
[239] 2- (2-methanesulfonyloxyethyl) -6,7,8-trimethoxynaphthalene (230 mg) and piperazine (29 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base. .
[240] Quantity: 13 mg (7%)
[241] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.63 (br, 8H), 2.70 (t, 4H, J = 6.8 Hz),
[242] 2.95 (t, 4H, J = 6.8 Hz), 3.57 (br, 4H), 3.96 (s, 12H), 4.05 (s, 6H),
[243] 6.92 (s, 2H), 7.24 (dd, 2H, J = 8.3 Hz, 1.7 Hz), 7.62 (d, 2H, J = 8.3 Hz),
[244] 7.84 (d, 2H, J = 1.7 Hz)
[245] m / z (EI): 574 [M ⁺ ]
[246] Example 8
[247] Synthesis of N, N'-bis [2- (6,7,8-trimethoxynaphthalen-2-yl) ethyl] homopiperazine:
[248]
[249] 2- (2-methanesulfonyloxyethyl) -6,7,8-trimethoxynaphthalene (164 mg) and homopiperazine (24 mg) were reacted in the same manner as in Example 1 to give the title compound as the free base. Got it.
[250] Quantity: 79 mg (56%)
[251] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.90 (br, 2H), 2.82-2.98 (m, 16H), 3.96 (s, 12H),
[252] 4.05 (s, 6H), 6.92 (s, 2H), 7.24 (dd, 2H, J = 8.4 Hz, 1.6 Hz),
[253] 7.61 (d, 2H, J = 8.4 Hz), 7.85 (s, 2H)
[254] m / z (EI): 588 [M ⁺ ]
[255] Preparation Example 17
[256] Synthesis of ethyl 3- (5,6,7-trimethoxynaphthalen-2-yl) propenoate:
[257]
[258] 55% sodium hydride (241 mg) was suspended in THF (2.5 mL) at -10 ° C under argon atmosphere, and a THF solution (5 mL) of ethyl diethylphosphonoacetate (1.23 g) was added dropwise and stirred for 30 minutes. . Next, THF solution (10 ml) of 5,6,7-trimethoxynaphthalene-2-carboaldehyde (1.23 g) was added dropwise, followed by stirring at -10 ° C for 30 minutes at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with 2M hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to obtain the title compound.
[259] Quantity: 1.79 g (Theoretical quantity)
[260] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.35 (t, 3H, J = 7.1 Hz), 3.98 (s, 6H),
[261] 4.04 (s, 3H), 4.24 (q, 2H, J = 7.1 Hz), 6.53 (d, 1H, J = 16.1 Hz),
[262] 6.96 (s, 1H), 7.55 (d, 1H, J = 8.8 Hz), 7.78 (s, 1H), 7.80 (d, 1H, J = 16.1 Hz),
[263] 8.03 (d, 1H, J = 8.8 Hz)
[264] Preparation Example 18
[265] Synthesis of ethyl 3- (5,6,7-trimethoxynaphthalen-2-yl) propionate:
[266]
[267] Ethyl 3- (5,6,7-trimethoxynaphthalen-2-yl) propenate (1.70 g) was dissolved in methanol (20 mL), 10% palladium carbon (510 mg) was added, and at room temperature under hydrogen atmosphere. Stirred at 2.5 hours. After filtering the reaction solution, the solution was concentrated to obtain the title compound.
[268] Quantity: 1.28g (81%)
[269] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.23 (t, 3H, J = 7.2 Hz), 2.68 (t, 2H, J = 7.8 Hz),
[270] 3.07 (t, 2H, J = 7.8 Hz), 3.95 (s, 3H), 3.96 (s, 3H), 4.03 (s, 3H),
[271] 4.13 (q, 2H, J = 7.1 Hz), 6.89 (s, 1H), 7.21 (dd, 1H, J = 8.6 Hz, 1.6 Hz),
[272] 7.50 (s, 1 H), 7.96 (d, 1 H, J = 8.5 Hz)
[273] Preparation Example 19
[274] Synthesis of 2- (3-hydroxypropyl) -5,6,7-trimethoxynaphthalene
[275]
[276] Ethyl 3- (5,6,7-trimethoxynaphthalen-2-yl) propionate (1.28 g) was treated in the same manner as in Production Example 3 to obtain the title object.
[277] Quantity: 1.13g (Theoretical)
[278] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.55 (s, 1H), 1.93-2.00 (m, 2H),
[279] 2.84 (t, 2H, J = 7.6 Hz), 3.71 (dd, 2H, J = 6.3 Hz, 2.0 Hz), 3.96 (s, 3H),
[280] 3.97 (s, 3H), 4.04 (s, 3H) 6.89 (s, 1H), 7.22 (dd, 1H, J = 8.6 Hz, 1.7 Hz),
[281] 7.49 (s, 1 H), 7.96 (d, 1 H, J = 8.5 Hz)
[282] Preparation Example 20
[283] Synthesis of 2- (3-methanesulfonyloxypropyl) -5,6,7-trimethoxynaphthalene:
[284]
[285] 2- (3-hydroxypropyl) -5,6,7-trimethoxynaphthalene (1.26 g) was treated in the same manner as in Production Example 12 to obtain the title compound.
[286] Quantity: 1.55 g (95%)
[287] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.16 (quint, 2H, J = 7.8 Hz),
[288] 2.90 (t, 2H, J = 7.8 Hz), 3.00 (s, 3H), 3.97 (s, 6H), 4.05 (s, 3H),
[289] 4.25 (t, 3H, J = 7.8 Hz), 6.93 (s, 1H), 7.24 (dd, 1H, J = 8.4 Hz, 1.7 Hz),
[290] 7.63 (d, 1H, J = 8.4 Hz), 7.83 (d, 1H. J = 1.7 Hz)
[291] Example 9
[292] Synthesis of N, N'-bis [3- (5,6,7-trimethoxynaphthalen-2-yl) propyl] piperazine:
[293]
[294] 2- (3-methanesulfonyloxypropyl) -5,6,7-trimethoxynaphthalene (213 mg) and piperazine (26 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
[295] Quantity: 152 mg (84%)
[296] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.85-1.93 (m, 4H), 2.40 (t, 4H, J = 7.6 Hz),
[297] 2.49 (br, 8H), 2.75 (t, 4H, J = 7.6 Hz), 3.95 (s, 12H), 4.03 (s, 6H),
[298] 6.88 (s, 2H), 7.20 (dd, 2H, J = 8.5 Hz, 1.5 Hz), 7.46 (d, 2H),
[299] 7.94 (d, 2H, J = 8.5 Hz)
[300] m / z (EI): 602 [M ⁺ ]
[301] Example 10
[302] Synthesis of N, N'-bis [3- (5,6,7-trimethoxynaphthalen-2-yl) propyl] homopiperazine:
[303]
[304] 2- (3-methanesulfonyloxypropyl) -5,6,7-trimethoxynaphthalene (213 mg) and homopiperazine (30 mg) were reacted in the same manner as in Example 1 to give the title compound as the free base. Got it.
[305] Quantity: 155 mg (84%)
[306] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.78-1.90 (m, 6H), 2.53 (t, 4H, J = 7.4 Hz),
[307] 2.69-2.77 (m, 12H), 3.95 (s, 12H), 4.03 (s, 6H), 6.87 (s, 2H),
[308] 7.20 (dd, 2H, J = 8.6 Hz, 1.6 Hz), 7.46 (s, 2H), 7.94 (d, 2H, J = 8.6 Hz)
[309] m / z (EI): 616 [M ⁺ ]
[310] Preparation Example 21
[311] Synthesis of ethyl 3- (6,7,8-trimethoxynaphthalen-2-yl) propenoate:
[312]
[313] 6,7,8-trimethoxynaphthalene-2-carboaldehyde (985 mg) and ethyl diethylphosphonoacetate (1.05 mL) were treated in the same manner as in Production Example 17 to obtain the title compound.
[314] Quantity: 1.33g (Theory)
[315] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.36 (t, 3H, J = 7.0 Hz), 3.97 (s, 3H),
[316] 3.99 (s, 3H), 4.07 (s, 3H), 4.29 (q, 2H, J = 7.0 Hz), 6.52 (d, 1H, J = 15.8 Hz),
[317] 6.94 (s, 1H), 7.58 (dd, 1H, J = 12.6 Hz, 1.7 Hz), 7.67 (d, 1H, J = 12.6 Hz),
[318] 7.84 (d, 1H, J = 15.8 Hz), 8.15 (br, 1H)
[319] Preparation Example 22
[320] Synthesis of ethyl 3- (6,7,8-trimethoxynaphthalen-2-yl) propionate:
[321]
[322] Ethyl 3- (6,7,8-trimethoxynaphthalen-2-yl) propenoate (1.33 g) was treated in the same manner as in Production Example 18 to obtain the title compound.
[323] Quantity: 1.04 g (82%)
[324] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.25 (t, 3H, J = 7.1 Hz), 2.70 (t, 2H, J = 7.6 Hz),
[325] 3.10 (t, 2H, J = 7.6 Hz), 3.96 (s, 3H), 3.97 (s, 3H), 4.04 (s, 3H),
[326] 4.14 (q, 2H, J = 7.1 Hz), 6.92 (s, 1H), 7.26 (dd, 1H, J = 8.3 Hz, 1.7 Hz),
[327] 7.62 (d, 1H, J = 12.6 Hz), 7.84 (br, 1H)
[328] Preparation Example 23
[329] Synthesis of 2- (3-hydroxypropyl) -6,7,8-trimethoxynaphthalene:
[330]
[331] Ethyl 3- (6,7,8-trimethoxynaphthalen-2-yl) propionate (1.04 g) was treated in the same manner as in Production Example 3 to obtain the title object.
[332] Quantity: 860 mg (95%)
[333] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1,98 (quint, 2H, J = 8.1 Hz),
[334] 2.86 (t, 2H, J = 8.1 Hz), 3.66-3.74 (m, 2H), 3.96 (s, 3H), 3.97 (s, 3H),
[335] 4.05 (s, 3H), 6.93 (s, 1H), 7.26 (dd, 1H, J = 8.3 Hz, 1.7 Hz),
[336] 7.62 (d, IH, J = 8.3 Hz), 7.84 (br, 1H)
[337] Preparation Example 24
[338] Synthesis of 2- (3-methanesulfonyloxypropyl) -6,7,8-trimethoxynaphthalene:
[339]
[340] 2- (3-hydroxypropyl) -6,7,8-trimethoxynaphthalene (720 mg) was treated in the same manner as in Preparation Example 12 to obtain the title compound.
[341] Quantity: 922 mg (theoretical amount)
[342] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.16 (quint, 2H, J = 7.2 Hz), 2.84 (s, 3H),
[343] 2.90 (t, 2H, J = 7.2 Hz), 3.97 (s, 6H), 4.05 (s, 3H), 4.26 (t, 2H, J = 7.2 Hz),
[344] 6.93 (s, 1H), 7.23 (dd, 1H, J = 8.6 Hz, 1.7 Hz), 7.64 (d, 1H, J = 8.6 Hz),
[345] 7.83 (br, IH)
[346] Example 11
[347] Synthesis of N, N'-bis [3- (6,7,8-trimethoxynaphthalen-2-yl) propyl] homopiperazine:
[348]
[349] 2- (3-methanesulfonyloxypropyl) -6,7,8-trimethoxynaphthalene (479 mg) and homopiperazine (67 mg) were reacted in the same manner as in Example 1 to give the title compound as the free base. Got it.
[350] Quantity: 282 mg (69%)
[351] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.82-1.96 (m, 6H), 2.57 (t, 4H, J = 7.6 Hz),
[352] 2.72-2.82 (m, 12H), 3.96 (s, 6H), 3.96 (s, 6H), 4.04 (s, 6H), 6.92 (s, 2H),
[353] 7.24 (dd, 2H, J = 8.4 Hz, 1.8 Hz), 7.61 (d, 2H, J = 8.4 Hz), 7.81 (s, 2H)
[354] m / z (EI): 616 [M ⁺ ]
[355] Preparation Example 25
[356] Synthesis of 2-methyl-5,6,7-trimethoxy quinoline:
[357]
[358] A 6N-hydrochloric acid (20 mL) solution of 3,4,5-trimethoxyaniline (3.1 g) was warmed to 100 ° C, and crotonaldehyde (1.5 mL) was slowly added dropwise and stirred for 3.5 hours as it was. After cooling, the reaction solution was washed with ether, and the aqueous layer was made alkaline with potassium carbonate solution. After extraction with ethyl acetate, the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2-1: 1) to obtain the title compound.
[359] Quantity: 1.98 g (50%)
[360] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.69 (s, 3H), 3.97 (s, 3H), 3.99 (s, 3H),
[361] 4.05 (s, 3H), 7.15 (d, 1H, J = 8.3 Hz), 7.19 (s, 1H), 8.24 (d, 1H, J = 8.3 Hz)
[362] Preparation Example 26
[363] Synthesis of 5,6,7-trimethoxyquinoline-2-carboaldehyde:
[364]
[365] Selenium dioxide (980 mg) was suspended in a mixed solvent of dioxane (12 mL) and water (0.5 mL) and warmed to 45 ° C. Dioxane (3 mL) solution of 2-methyl-5,6,7-trimethoxyquinoline (1.97 g) was slowly added dropwise thereto, warmed to 105 ° C, and stirred for 1.5 hours. After allowing to cool, the insolubles were filtered, the filtrate was concentrated, and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to obtain the title compound.
[366] Quantity: 1.40 g (67%)
[367] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.04 (s, 3H), 4.06 (s, 3H), 4.08 (s, 3H),
[368] 7.38 (s, 1 H), 7.91 (d, 1 H, J = 8.6 Hz), 8.5 l (dt, 1H, J = 8.6 Hz, 0.3 Hz),
[369] 10.18 (d, 1H, J = 0.7 Hz)
[370] Preparation Example 27
[371] Synthesis of 2-hydroxymethyl-5,6,7-trimethoxyquinoline:
[372]
[373] To a mixed solvent of methanol (30 mL) and THF (30 mL) under ice-cooling, sodium borohydride (418 mg) was added followed by 5,6,7-trimethoxyquinoline-2-carboaldehyde (2.14 g). It stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was extracted with ethyl acetate, the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 30: 1) to obtain the title compound.
[374] Quantity: 1.45g (Theoretical Quantity)
[375] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.98 (s, 3H), 4.02 (s, 3H), 4.07 (s, 3H),
[376] 4.28 (br, 1H), 4.87 (s, 2H), 7.16 (d, 1H, J = 8.6 Hz), 7.23 (s, 1H),
[377] 8.33 (d, 1H, J = 8.6 Hz)
[378] Preparation Example 28
[379] Synthesis of 2-chloromethyl-5,6,7-trimethoxyquinoline:
[380]
[381] Thionyl chloride (1.7 mL) was added to the dichloromethane (15 mL) solution of 2-hydroxymethyl-5,6,7-trimethoxyquinoline (1.45 g) under ice-cooling, and it stirred at room temperature for 30 minutes. After concentration under reduced pressure, potassium carbonate water was added to make it alkaline and extracted with diethyl ether. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to obtain the title compound.
[382] Quantity: 1.34 g (88%)
[383] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.99 (s, 3H), 4.01 (s, 3H), 4.06 (s, 3H),
[384] 4.79 (s, 2H), 7.23 (s, 1H), 7.45 (d, 1H, J = 8.6 Hz), 8.39 (d, 1H, J = 8.6 Hz)
[385] Example 12
[386] Synthesis of N, N'-bis [(5,6,7-trimethoxyquinolin-2-yl) methyl] piperazine:
[387]
[388] 2-chloromethyl-5,6,7-trimethoxyquinoline (400 mg) and piperazine (65 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
[389] Quantity: 400 mg (97%)
[390] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.77 (br, 8H), 3.80 (s, 4H), 3.97 (s, 6H),
[391] 3.99 (s, 6H), 4.05 (s, 6H), 7.24 (s, 2H), 7.48 (d, 2H, J = 8.5 Hz),
[392] 8.31 (d, 2H, J = 8.5 Hz)
[393] m / z (EI): 548 [M ⁺ ]
[394] Example 13
[395] Synthesis of N, N'-bis [(5,6,7-trimethoxyquinolin-2-yl) methyl] homopiperazine:
[396]
[397] 2-Chloromethyl-5,6,7-trimethoxyquinoline (400 mg) and homopiperazine (765 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
[398] Quantity: 331 mg (78%)
[399] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.88 (br, 2H), 2.75-2.79 (m, 8H), 3.95 (s, 4H),
[400] 3.97 (s, 6H), 3.99 (s, 6H), 4.06 (s, 6H), 7.22 (s, 2H),
[401] 7.56 (d, 2H, J = 8.5 Hz), 8.32 (d, 2H, J = 8.5 Hz)
[402] m / z (EI): 562 [M ⁺ ]
[403] Preparation Example 29
[404] Synthesis of 2-methyl-6,7,8-trimethoxyquinoline:
[405]
[406] 2,3,4-trimethoxyaniline (5.2 g) was treated in the same manner as in Production Example 25 to obtain the title compound.
[407] Quantity: 4.2 g (67%)
[408] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.73 (s, 3H), 3.97 (s, 3H), 4.03 (s, 3H),
[409] 4.17 (s, 3H), 6.83 (s, 1H), 7.18 (d, 1H, J = 8.4 Hz), 7.88 (d, 1H, J = 8.4 Hz)
[410] Preparation Example 30
[411] Synthesis of 6,7,8-trimethoxyquinoline-2-carboaldehyde:
[412]
[413] 2-Methyl-6,7,8-trimethoxyquinoline (4.2 g) was treated in the same manner as in Production Example 26 to obtain the title compound.
[414] Quantity: 2.37 g (51%)
[415] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.04 (s, 3H), 4.08 (s, 3H), 4.23 (s, 3H),
[416] 6.94 (s, 1H), 7.96 (d, 1H, J = 8.3 Hz), 8.13 (dt, 1H, J = 8.3 Hz, 0.5 Hz),
[417] 10.17 (s, 1 H)
[418] Preparation Example 31
[419] Synthesis of 2-chloromethyl-6,7,8-trimethoxyquinoline:
[420]
[421] 6,7,8-trimethoxyquinoline-2-carboaldehyde (742 mg) was treated in the same manner as in Production Example 27 and Production Example 28 to obtain the title compound.
[422] Quantity: 714 mg (89%)
[423] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.99 (s, 3H), 4.04 (s, 3H), 4.18 (s, 3H),
[424] 4.86 (s, 2H), 6.87 (s, 1H), 7.53 (d, 1H, J = 8.4 Hz), 8.04 (d, 1H, J = 8.4 Hz)
[425] Example 14
[426] Synthesis of N, N'-bis [(6,7,8-trimethoxyquinolin-2-yl) methyl] piperazine:
[427]
[428] 2-Chloromethyl-6,7,8-trimethoxyquinoline (336 mg) and piperazine (54 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
[429] Quantity: 330 mg (theoretical quantity)
[430] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.63 (br, 8H), 3.88 (s, 4H), 3.97 (s, 6H),
[431] 4.03 (s, 6H), 4.16 (s, 6H), 6.85 (s, 2H) 7.54 (d, 2H, J = 8.4 Hz),
[432] 7.96 (d, 2H, J = 8.4 Hz)
[433] m / z (EI): 548 [M ⁺ ]
[434] Example 15
[435] Synthesis of N, N'-bis [(6,7,8-trimethoxyquinolin-2-yl) methyl] homopiperazine:
[436]
[437] 2-Chloromethyl-6,7,8-trimethoxyquinoline (350 mg) and homopiperazine (65 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
[438] Quantity: 241 mg (66%)
[439] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.86 (br, 2H), 2.82 (br, 4H),
[440] 2.87 (t, 4H, J = 5.9 Hz), 3.97 (s, 4H), 4.01 (s, 6H), 4.03 (s, 6H),
[441] 4.16 (s, 6H), 6.85 (s, 2H), 7.62 (d, 2H, J = 8.4 Hz), 7.97 (d, 2H, J = 8.4 Hz)
[442] m / z (EI): 562 [M ⁺ ]
[443] Preparation Example 32
[444] Synthesis of N- (6-formyl-3,4,5-trimethoxyphenyl) chloroacetamide:
[445]
[446] 6-nitro-2,3,4-trimethoxybenzaldehyde (4.0 g) was dissolved in methanol (40 mL) and THF (20 mL), 10% palladium carbon was added, and the mixture was stirred at room temperature for 5 hours under hydrogen atmosphere. . After filtration of the catalyst, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4-> l: 3) to give 6-amino-2,3,4-trimethoxybenzaldehyde. 3.1 g was obtained. This was immediately dissolved in dichloromethane (35 mL) and triethylamine (4.2 mL) was added. Chloroacetyl chloride (1.78 mL) was added dropwise under ice cooling, and the mixture was stirred overnight at room temperature. The reaction solution was extracted with chloroform, washed with water and brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4-1: 3) to obtain the title compound.
[447] Quantity: 2.74 g (58%)
[448] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.85 (s, 3H), 3.98 (s, 3H), 4.04 (s, 3H),
[449] 4.18 (s, 2H), 8.23 (s, 1H), 10.24 (s, 1H)
[450] Preparation Example 33
[451] Synthesis of 2-chloromethyl-5,6,7-trimethoxy-1,3-quinazolin:
[452]
[453] N- (6-formyl-3,4,5-trimethoxyphenyl) chloroacetamide (3.36 g) was dissolved in methanol (60 mL) and THF (10 mL) saturated with ammonia gas. It stirred for hours. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3 → 1: 2) to obtain the title compound.
[454] Quantity: 1.32 g (42%)
[455] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.98 (s, 3H), 4.04 (s, 3H), 4.15 (s, 3H),
[456] 4.85 (s, 2H), 7.14 (s, 1H), 9.46 (s, 1H)
[457] Example 16
[458] Synthesis of N, N'-bis [(5,6,7-trimethoxy-1,3-quinazolin-2-yl) methyl] piperazine:
[459]
[460] 2-Chloromethyl-5,6,7-trimethoxy-1,3-quinazolin (250 mg) and piperazine (40 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
[461] Quantity: 172 mg (67%)
[462] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.68 (br, 8H), 3.86 (s, 4H), 3.89 (s, 6H),
[463] 3.94 (s, 6H), 4.05 (s, 6H), 7.07 (s, 2H), 9.38 (s, 2H)
[464] m / z (EI): 550 [M ⁺ ]
[465] Example 17
[466] Synthesis of N, N'-bis [(5,6,7-trimethoxy-1,3-quinazolin-2-yl) methyl] homopiperazine:
[467]
[468] 2-Chloromethyl-5,6,7-trimethoxy-1,3-quinazolin (280 mg) and homopiperazine (52 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base. .
[469] Quantity: 220 mg (75%)
[470] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.91 (br, 2H), 2.92-3.01 (m, 8H), 3.96 (s, 6H),
[471] 4.02 (s, 6H), 4.07 (s, 4H), 4.13 (s, 6H), 7.13 (s, 2H), 9.45 (s, 2H)
[472] m / z (EI): 564 [M ⁺ ]
[473] Preparation Example 34
[474] Synthesis of Methyl 3- (3,4,5-trimethoxyphenyl) -2-azidopropenoate:
[475]
[476] 3,4,5-trimethoxybenzaldehyde (992 mg) and methyl azidoacetate (2.91 g) were dissolved in anhydrous methanol (2 mL), and anhydrous methanol solution of sodium (582 mg) at 0 ° C. under argon stream ( 10 ml) was added dropwise over 2 hours. The reaction solution was stirred for 30 minutes as it was, concentrated under reduced pressure, water was added to the residue, and the precipitated crystals were taken out, washed, and dried to obtain the title compound.
[477] Quantity: 1.2 g (81%)
[478] Preparation 35
[479] Synthesis of Methyl 5,6,7-trimethoxyindole-2-carboxylate:
[480]
[481] Xylene (15 mL) was added to a three neck flask and stirred under reflux, followed by a xylene solution of methyl 3- (3,4,5-trimethoxyphenyl) -2-azidopropene acid (1.2 g) (30 mL). Was added dropwise over 3 hours, refluxed for 1 hour, and concentrated under reduced pressure. Water was added to the residue, extracted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to obtain the title compound.
[482] Quantity: 960 mg (88%)
[483] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.90 (s, 3H), 3.93 (s, 6H), 4.07 (s, 3H),
[484] 6.82 (s, 1 H), 7.10 (d, 1 H, J = 2.3 Hz), 8.88 (br, 1 H)
[485] Preparation Example 36
[486] Synthesis of 5,6,7-trimethoxyindole-2-carboxylic acid:
[487]
[488] Methyl 5,6,7-trimethoxyindole-2-carboxylate (700 mg) was dissolved in methanol (13 mL), powdered potassium hydroxide (450 mg) was added, and the mixture was stirred at reflux for 3 hours. After cooling, the mixture was concentrated under reduced pressure, water was added to the residue to dissolve, and the aqueous layer was washed with ether. Subsequently, the aqueous layer was neutralized with dilute hydrochloric acid, and crystals were precipitated and dried to obtain the title compound.
[489] Quantity: 604 mg (92%)
[490] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.90 (s, 3H), 3.93 (s, 3H), 4.07 (s, 3H),
[491] 6.85 (s, 1H), 7.13 (s, 1H), 9.79 (br, 1H)
[492] Preparation Example 37
[493] Synthesis of N, N'-bis (5,6,7-trimethoxyindole-2-carbonyl) piperazine:
[494]
[495] 5,6,7-trimethoxyindole-2-carboxylic acid (300 mg) and piperazine (52 mg) were dissolved in dichloromethane (5 mL), and water-soluble carbodiimide hydrochloride (232 mg), 4- (Dimethylamino) pyridine (10 mg) was added and the mixture was stirred at room temperature overnight. The reaction solution was poured into water, extracted with chloroform, washed with dilute hydrochloric acid, diluted aqueous sodium hydroxide solution, water and saturated brine in that order, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel preparative TLC (ethyl acetate: hexane = 1: 1) to obtain the title compound.
[496] Quantity: 310 mg (theoretical quantity)
[497] Example 18
[498] Synthesis of N, N'-bis [(5,6,7-trimethoxyindol-2-yl) methyl] piperazine:
[499]
[500] N, N'-bis (5,6,7-trimethoxyindole-2-carbonyl) piperazine (148 mg) was dissolved in THF (5 mL), and lithium aluminum hydride (10 mg) was gradually cooled under ice-cooling. Added. The mixture was returned to room temperature, stirred for 6 hours, and sodium sulfate decahydrate was added. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain the title compound as a free base.
[501] Quantity: 107 mg (79%)
[502] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.51 (br, 8H), 3.63 (s, 4H),
[503] 3.88 (s, 6H), 3.90 (s, 6H), 4.07 (s, 6H), 6.24 (s, 2H), 6.76 (s, 2H),
[504] 8.44 (s, 2 H)
[505] m / z: 524 [M ⁺ ]
[506] Preparation Example 38
[507] Synthesis of N, N'-bis (5,6,7-trimethoxyindole-2-carbonyl) homopiperazine:
[508]
[509] 5,6,7-trimethoxyindole-2-carboxylic acid (300 mg) and homopiperazine (60 mg) were reacted in the same manner as in Production Example 37 to obtain the title compound.
[510] Quantity: 309 mg (92%)
[511] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.90 (s, 3H), 3.93 (s, 3H), 4.07 (s, 3H),
[512] 6.82 (s, 1 H), 7.10 (s, 1 H), 8.88 (br, 1 H)
[513] Example 19
[514] Synthesis of N.N'-bis [(5,6,7-trimethoxyindol-2-yl) methyl] homopiperazine:
[515]
[516] 148 mg of N, N'-bis (5,6,7-trimethoxyindole-2-carbonyl) homopiperazine was treated in the same manner as in Example 18 to obtain the title compound as a free base.
[517] Quantity: 59 mg (21%)
[518] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.83 (br, 2H), 2.75 (br, 4H),
[519] 2.78 (t, 4H, J = 5.9 Hz), 3.78 (s, 4H), 3.88 (s, 6H), 3.90 (s, 6H),
[520] 4.06 (s, 6H), 6.23 (s, 2H), 6.76 (s, 2H), 8.91 (br, 2H)
[521] m / z (EI): 538 [M ⁺ ]
[522] Preparation Example 39
[523] Synthesis of Methyl 3- (2,3,4-trimethoxyphenyl) -2-azidopropenoate:
[524]
[525] 2,3,4-trimethoxybenzaldehyde (6.1 g) was treated in the same manner as in Production Example 34 to obtain the title compound.
[526] Quantity: 8.05 g (88%)
[527] Preparation Example 40
[528] Synthesis of Methyl 4,5,6-trimethoxyindole-2-carboxylate:
[529]
[530] Methyl 3- (2,3,4-trimethoxyphenyl) -2-azidopropenoate (8.0 g) was treated in the same manner as in Production Example 35 to obtain the title compound.
[531] Quantity: 5.74 g (80%)
[532] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.87 (s, 3H), 3.90 (s, 3H), 3.92 (s, 3H),
[533] 4.12 (s, 3H), 6.59 (d, 1H, J = 0.6 Hz), 7.28 (dd, 1H, J = 2.2 Hz, 0.6 Hz),
[534] 8.78 (br, 1 H)
[535] Preparation Example 41
[536] Synthesis of 4,5,6-trimethoxyindole-2-carboxylic acid:
[537]
[538] Methyl 4,5,6-trimethoxyindole-2-carboxylate (700 mg) was treated in the same manner as in Production Example 36 to obtain the title compound.
[539] Quantity: 592 mg (89%)
[540] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.69 (s, 3H), 3.80 (s, 3H), 4.00 (s, 3H),
[541] 6.64 (s, 1 H), 7.05 (d, 1 H, J = 2.3 Hz), 11.57 (br, 1H)
[542] Preparation Example 42
[543] Synthesis of N, N'-bis (4,5,6-trimethoxyindole-2-carbonyl) piperazine:
[544]
[545] 4,5,6-trimethoxyindole-2-carboxylic acid (290 mg) and piperazine (50 mg) were reacted in the same manner as in Production Example 37 to obtain the title compound.
[546] Quantity: 160 mg (53%)
[547] Example 20
[548] Synthesis of N, N'-bis [(4,5,6-trimethoxyindol-2-yl) methyl] piperazine:
[549]
[550] N, N'-bis (4,5,6-trimethoxyindole-2-carbonyl) piperazine (100 mg) was treated in the same manner as in Example 18 to obtain the title compound as a free base.
[551] Quantity: 36 mg (38%)
[552] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.58 (br, 8H), 3.61 (s, 4H), 3.66 (s, 6H),
[553] 3.88 (s, 6H), 4.09 (s, 6H), 6.38 (s, 2H), 6.61 (s, 2H), 8.40 (br, 2H)
[554] m / z (EI): 524 [M ⁺ ]
[555] Preparation Example 43
[556] Synthesis of N, N'-bis (4,5,6-trimethoxyindole-2-carbonyl) homopiperazine:
[557]
[558] 4,5,6-trimethoxyindole-2-carboxylic acid (290 mg) and homopiperazine (58 mg) were reacted in the same manner as in Production Example 37 to obtain the title compound.
[559] Quantity: 182 mg (58%)
[560] Example 21
[561] Synthesis of N, N'-bis [(4,5,6-trimethoxyindol-2-yl) methyl] homopiperazine:
[562]
[563] 170 mg of N, N'-bis (4,5,6-trimethoxyindole-2-carbonyl) homopiperazine was treated in the same manner as in Example 18 to obtain the title compound as a free base.
[564] Quantity: 78 mg (48%)
[565] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.83 (br, 2H), 2.76 (br, 4H),
[566] 2.80 (t, 4H, J = 5.9 Hz), 3.79 (s, 4H), 3.86 (s, 6H), 3.88 (s, 6H),
[567] 4.08 (s, 6H), 6.37 (s, 2H), 6.65 (s, 2H), 9.21 (br, 2H)
[568] m / z (EI): 538 [M ⁺ ]
[569] Preparation Example 44
[570] Synthesis of Methyl N-methyl-4,5,6-trimethoxyindole-2-carboxylate:
[571]
[572] Methyl 3- (2,3,4-trimethoxyphenyl) -2-azidopropenoate (799 mg), potassium tert-butoxide (438 mg), 18-crown-6 (71 mg) anhydrous benzene It dissolved in (60 mL) and stirred for 15 minutes. Subsequently, methane iodide (0.28 mL) was added and stirred overnight. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the title compound.
[573] Quantity: 768 mg (91%)
[574] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.87 (s, 3H). 3.89 (s, 3H), 3.95 (s, 3H),
[575] 4.01 (s, 3H), 4.12 (s, 3H), 6.50 (s, 1H), 7.36 (s, 1H)
[576] Preparation Example 45
[577] Synthesis of N-methyl-4,5,6-trimethoxyindole-2-carboxylic acid:
[578]
[579] Methyl N-methyl-4,5,6-trimethoxyindole-2-carboxylate (190 mg) was treated in the same manner as in Production Example 36 to obtain the title compound.
[580] Quantity: 134 mg (78%)
[581] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.87 (s, 3H), 3.96 (s, 3H), 4.02 (s, 3H),
[582] 4.14 (s, 3H), 6.49 (s, 1H), 7.51 (s, 1H)
[583] Preparation Example 46
[584] Synthesis of N, N'-bis (1-methyl-4,5,6-trimethoxyindole-2-carbonyl) piperazine:
[585]
[586] N-methyl-4,5,6-trimethoxyindole-2-carboxylic acid (200 mg) and piperazine (35 mg) were reacted in the same manner as in Production Example 37 to obtain the title compound.
[587] Quantity: 200 mg (93%)
[588] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.81 (s, 6H), 3.87 (s, 6H), 3.89 (br, 8H),
[589] 3.95 (s, 6H), 4.09 (s, 6H), 6.53 (s, 2H), 6.69 (s, 2H)
[590] Example 22
[591] Synthesis of N, N'-bis [(1-methyl-4,5,6-trimethoxyindol-2-yl) methyl] piperazine:
[592]
[593] 145 mg of N, N'-bis (1-methyl-4,5,6-trimethoxyindole-2-carbonyl) piperazine was treated in the same manner as in Example 18 to obtain the title compound.
[594] Quantity: 94 mg (68%)
[595] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.44 (br, 8H), 3.56 (s, 4H), 3.71 (s, 6H),
[596] 3.86 (s, 6H), 3.93 (s, 6H), 4.08 (s, 6H), 6.37 (s. 2H), 6.52 (s, 2H)
[597] m / z (EI): 552 [M ⁺ ]
[598] Preparation 47
[599] Synthesis of N, N'-bis (1-methyl-4,5,6-trimethoxyindole-2-carbonyl) homopiperazine:
[600]
[601] N-methyl-4,5,6-trimethoxyindole-2-carboxylic acid (130 mg) and homopiperazine (24 mg) were reacted in the same manner as in Production Example 37 to obtain the title compound.
[602] Quantity: 165 mg (theoretical amount)
[603] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.06 (br, 2H), 3.75 (s. 6H), 3.86 (s, 6H),
[604] 3.93 (s, 6H), 3.82-4.00 (m, 4H), 4.07 (br, 4H), 6.50 (s, 2H), 6.69 (br, 2H)
[605] Example 23
[606] Synthesis of N, N'-bis [1-methyl- (4,5,6-trimethoxyindol-2-yl) methyl] homopiperazine:
[607]
[608] 145 mg of N, N'-bis (1-methyl-4,5,6-trimethoxyindole-2-carbonyl) homopiperazine was treated in the same manner as in Example 18 to obtain the title compound.
[609] Quantity: 107 mg (79%)
[610] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.76 (br, 2H), 2.63 (s, 4H),
[611] 2.70 (t, 4H, J = 5.9 Hz), 3.67 (s, 4H), 3.74 (s, 6H), 3.86 (s, 6H),
[612] 3.93 (s, 6H), 4.09 (s, 6H), 6.34 (s, 2H), 6.52 (s, 2H)
[613] m / z (EI): 566 [M ⁺ ]
[614] Preparation Example 48
[615] Synthesis of Methyl 1-phenyl-4,5,6-trimethoxyindole-2-carboxylate:
[616]
[617] Methyl 4,5,6-trimethoxyindole-2-carboxylate (533 mg), benzene bromide (0.22 mL), copper oxide (64 mg) and potassium hydroxide (336 mg) are suspended in anhydrous DMF (10 mL). Then, the mixture was stirred under reflux for 6 hours under argon airflow. After cooling, the reaction solution was dissolved in water (100 mL) and filtered through celite. The filtrate was extracted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was dissolved in methanol (20 mL) and chloroform (20 mL), and a small amount of water-soluble carbodiimide hydrochloride (192 mg) and N, N-dimethylaminopyridine was added and stirred at room temperature overnight. After concentration under reduced pressure, water was added to the residue, extraction was performed with ethyl acetate, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel preparative TLC (ethyl acetate: hexane = 1: 3) to obtain the title compound.
[618] Quantity: 220 mg (35%)
[619] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.75 (s, 3H), 3.76 (s, 3H), 3.87 (s, 3H),
[620] 4.16 (s, 3H), 6.20 (s, 1H), 7.30-7.55 (m, 5H), 7.60 (s, 1H)
[621] Preparation 49
[622] Synthesis of 1-phenyl-4,5,6-trimethoxyindole-2-carboxylic acid:
[623]
[624] Methyl 1-phenyl-4,5,6-trimethoxyindole-2-carboxylate (280 mg) was dissolved in ethanol (5 mL), 10% aqueous potassium hydroxide solution (2 mL) was added, and refluxed at 30 Stirred for a minute. After cooling, the mixture was concentrated under reduced pressure, and the residue was dissolved in water and washed with ether. Subsequently, the aqueous layer was made acidic with hydrochloric acid, extracted with ethyl acetate, the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound.
[625] Quantity: 193 mg (72%)
[626] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.75 (s, 3H), 3.87 (s, 3H), 4.16 (s, 3H),
[627] 6.19 (s, 1H), 7.29-7.35 (m, 2H), 7.44-7.55 (m, 3H), 7.60 (s, 1H)
[628] Preparation 50
[629] Synthesis of N, N'-bis (1phenyl-4,5,6-trimethoxyindole-2-carbonyl) homopiperazine:
[630]
[631] 1-phenyl-4,5,6-trimethoxyindole-2-carboxylic acid (91 mg) and homopiperazine (14 mg) were reacted in the same manner as in Production Example 37 to obtain the title compound.
[632] Quantity: 100 mg (99%)
[633] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.51 (br, 2H), 3.35-3.65 (br, 8H), 3.79 (s, 6H),
[634] 3.88 (s, 6H), 4.10 (s, 6H), 6.48 (s, 2H), 6.78 (s, 2H), 7.32-7.54 (m, 10H)
[635] Example 24
[636] Synthesis of N, N'-bis [(1-phenyl-4,5,6-trimethoxyindol 2-yl) methyl] homopiperazine:
[637]
[638] N, N'-bis (1-phenyl-4,5,6-trimethoxyindole-2-carbonyl) homopiperazine (99 mg) was treated in the same manner as in Example 18 to obtain the title compound as a free base. .
[639] Quantity: 81 mg (84%)
[640] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.51 (br. 2H), 2.38 (s, 4H),
[641] 2.44 (t. 4H, J = 6.1 Hz), 3.45 (s, 4H), 3.75 (s, 6H), 3.87 (s, 6H),
[642] 4.13 (s, 6H), 6.35 (s, 2H), 7.52 (s. 2H), 7.36-7.49 (m, 10H)
[643] m / z (EI): 690 [M ⁺ ]
[644] Preparation Example 51
[645] Synthesis of 2-hydroxymethyl-1-methyl-4,5,6-trimethoxyindole:
[646]
[647] Methyl l-methyl-4,5,6-trimethoxyindole-2-carboxylate (1.17 g) was dissolved in anhydrous THF under argon stream, and a 1M-hydrogenated diisopropylaluminum toluene solution (13.2) at 0 ° C Ml) was added dropwise and stirred for 1 hour as it is. The reaction solution was diluted with ether, and sodium sulfate 10-hydrate was added, followed by further stirring for 1 hour. The mixture was filtered, the filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2-> 1: 1) to obtain the title compound.
[648] Quantity: 861 mg (78%)
[649] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.36 (s, 3H), 3.89 (s, 3H), 3.90 (s, 3H),
[650] 4.06 (s, 3H), 4.79 (s, 2H), 6.31 (d, 1H, J = 2.3 Hz), 6.78 (s, 1H),
[651] 8.39 (br, 1 H)
[652] Preparation Example 52
[653] Synthesis of l-methyl-4,5,6-trimethoxyindole-2-carboaldehyde:
[654]
[655] 2-hydroxymethyl-l-methyl-4,5,6-trimethoxyindole (861 mg) was dissolved in benzene (50 mL), active manganese dioxide (8.7 g) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to obtain the title compound.
[656] Quantity: 769 mg (90%)
[657] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.80 (s, 3H), 3.92 (s, 3H), 3.95 (s, 3H),
[658] 4.06 (s, 3H), 6.59 (s, 1H), 7.70 (s, 1H), 10.30 (s, 1H)
[659] Preparation Example 53
[660] Synthesis of ethyl 3- (1-methyl-4,5,6-trimethoxyindole) propenoate:
[661]
[662] 1-methyl-4,5,6-trimethoxyindole-2-carboaldehyde (250 mg) and ethyl diethylphosphonoacetate (0.3 mL) were reacted in the same manner as in Production Example 17 to obtain the title compound.
[663] Quantity: 254 mg (83%)
[664] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.34 (t, 3H, J = 7.1 Hz), 3.76 (s, 3H),
[665] 3.86 (s, 3H), 3.94 (s, 3H), 4.10 (s, 3H), 4.27 (q, 2H, J = 7.1 Hz),
[666] 6.40 (d, 1H, J = 15.8 Hz), 6.47 (s, 1H), 7.01 (s, 1H), 7.73 (d, IH, J = 15.8 Hz)
[667] Preparation Example 54
[668] Synthesis of ethyl 3- (1-methyl-4,5,6-trimethoxyindole) propionate:
[669]
[670] Ethyl 3- (1-methyl-4,5,6-trimethoxyindole) propenoate (254 mg) was treated in the same manner as in Production Example 18 to obtain the title compound.
[671] Quantity: 250 mg (98%)
[672] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.28 (t, 3H, J = 7.1 Hz), 2.75 (t, 2H, J = 6.1 Hz),
[673] 3.04 (t, 2H, J = 6.1 Hz), 3.62 (s, 3H), 3.86 (s, 3H), 3.92 (s, 3H),
[674] 4.07 (s, 3H), 4.17 (q, 2H, J = 7.1 Hz), 6.27 (s, 1H), 6. 50 (s, 1H)
[675] Preparation Example 55
[676] Synthesis of 2- (3-hydroxypropyl) -1-methyl-4,5,6-trimethoxyindole:
[677]
[678] Ethyl 3- (1-methyl-4,5,6-trimethoxyindole) propionate (160 mg) was treated in the same manner as in Production Example 19 to obtain the title compound.
[679] Quantity: 160 mg (7 1%)
[680] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.98 (quint, 2H, J = 7.6 Hz),
[681] 2.82 (t, 2H, J = 7.6 Hz), 3.61 (s, 3H), 3.78 (t, 2H, J = 7.6 Hz),
[682] 3.86 (s, 3H), 3.92 (s, 3H), 4.08 (s, 3H), 6.29 (s, 1H), 6.50 (s, 1H)
[683] Preparation Example 56
[684] Synthesis of 2- (3-methanesulfonyloxypropyl) -1-methyl-4,5,6-trimethoxyindole:
[685]
[686] 2- (3-hydroxypropyl) -l-methyl-4,5,6-trimethoxyindole (160 mg) was treated in the same manner as in Production Example 20 to obtain the title compound.
[687] Quantity: 147 mg (72%)
[688] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.19 (quint, 2H, J = 6.0 Hz),
[689] 2.86 (t, 2H, J = 6.0 Hz), 3.01 (s, 3H), 3.61 (s, 3H), 3.86 (s, 3H),
[690] 3.93 (s, 3H), 4.08 (s, 3H), 4.34 (t, 2H, J = 6.0 Hz), 6.30 (s, 1H),
[691] 6.51 (s, 1H)
[692] Example 25
[693] Synthesis of N, N'-bis [3- (1-methyl-4,5,6-trimethoxyindol-2-yl) propyl] piperazine:
[694]
[695] 2- (3-methanesulfonyloxypropyl) -1-methyl-4,5,6-trimethoxyindole (160 mg) and piperazine (17 mg) were reacted in the same manner as in Example 1 to obtain the title compound. Obtained as free base.
[696] Quantity: 91 mg (75%)
[697] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.86-1.99 (m, 4H), 2.47 (t, 4H, J = 7.0 Hz),
[698] 2.50 (br, 8H), 2.73 (t, 4H, J = 7.0 Hz), 3.60 (s, 6H), 3.86 (s, 6H),
[699] 3.92 (s, 6H), 4.08 (s, 6H), 6.28 (s, 2H), 6.50 (s, 2H)
[700] m / z (EI): 608 [M ⁺ ]
[701] Example 26
[702] Synthesis of N, N'-bis [3- (1-methyl-4,5,6-trimethoxyindol-2-yl) propyl] homopiperazine:
[703]
[704] 2- (3-methanesulfonyloxypropyl) -1-methyl-4,5,6-trimethoxyindole (130 mg) and homopiperazine (18 mg) were reacted in the same manner as in Example 1 to obtain the title compound. Was obtained as the free base.
[705] Quantity: 43 mg (38%)
[706] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.82-1.98 (m, 6H), 2.64 (t, 4H, J = 7.0 Hz),
[707] 2.73 (t, 4H, J = 7.0 Hz), 2.78 (br, 8H), 3.60 (s, 6H), 3.86 (s, 6H),
[708] 3.92 (s, 6H), 4.08 (s, 6H), 6.27 (s, 2H), 6.50 (s, 2H)
[709] m / z (EI): 622 [M ⁺ ]
[710] Preparation Example 57
[711] Synthesis of Methyl 2-nitro-3,4,5-trimethoxybenzoate:
[712]
[713] Methyl 3,4,5-trimethoxybenzoate (13.0 g) was dissolved in acetic anhydride (60 mL), and a mixture (9 mL) of fuming nitric acid: concentrated acetic acid (1:20) was slowly added dropwise at -10 ° C. And it stirred under ice cooling for 3 hours. Acetic anhydride was distilled off, water and potassium carbonate aqueous solution were added, the mixture was stirred at room temperature for 40 minutes, extracted with ethyl acetate, the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to obtain the title compound.
[714] Quantity: 7.34 g (47%)
[715] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.88 (s, 3H), 3.95 (s, 3H), 3.96 (s, 3H),
[716] 3.97 (s, 3H), 7.28 (s, 1H)
[717] Preparation 58
[718] Synthesis of 2-nitro-3,4,5-trimethoxybenzoic acid:
[719]
[720] Methyl 2-nitro-3,4,5-trimethoxybenzoate (6.9 g) was treated in the same manner as in Production Example 2 to obtain the title compound.
[721] Quantity: 5.9g (90%)
[722] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.96 (s, 3H), 3.97 (s, 3H), 4.00 (s, 3H),
[723] 7.35 (s, 1 H)
[724] Preparation Example 59
[725] Synthesis of N-ethoxycarbonyl-2-nitro-3,4,5-trimethoxyaniline:
[726]
[727] 2-nitro-3,4,5-trimethoxybenzoic acid (4.7 g) was dissolved in dry benzene (70 mL), triethylamine (2.56 mL) and diphenylphosphoryl azide (4.15 mL) were added, It stirred under reflux for 2 hours. Anhydrous ethanol (140 mL) was added to the reaction solution, and the mixture was stirred under reflux overnight. After concentration under reduced pressure, the mixture was extracted with ethyl acetate, and the organic layer was washed with diluted hydrochloric acid, aqueous potassium carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4-1: 3) to obtain the title compound.
[728] Quantity: 2.8g (54%)
[729] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.44 (t, 3H, J = 7.1 Hz), 3.88 (s, 3H),
[730] 3.95 (s, 3H), 4.03 (s, 3H), 4.44 (q, 2H, J = 7.1 Hz), 7.94 (s, 1H)
[731] Preparation Example 60
[732] Synthesis of 2-nitro-3,4,5-trimethoxyaniline:
[733]
[734] N-ethoxycarbonyl-2-nitro-3,4,5-trimethoxyaniline (2.8 g) was treated in the same manner as in Production Example 49 to obtain the title compound.
[735] Quantity: 2.05 g (92%)
[736] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.79 (s, 3H), 3.87 (s, 3H), 3.99 (s, 3H),
[737] 5.28 (br, 2H), 5.97 (s, 1H)
[738] Preparation Example 61
[739] Synthesis of 1,2-diamino-3,4,5-trimethoxybenzene:
[740]
[741] 2-Nitro-3,4,5-trimethoxyaniline (913 mg) was treated in the same manner as in Preparation Example 18 to obtain the title compound.
[742] Quantity: 675 mg (85%)
[743] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.78 (s, 3H), 3.81 (s, 3H), 3.90 (s, 3H),
[744] 6.13 (s, 1 H)
[745] Preparation Example 62
[746] Synthesis of 1,2-dibenzyloxyacetamide-3,4,5-trimethoxybenzene:
[747]
[748] 1,2-diamino-3,4,5-trimethoxybenzene (675 mg) and triethylamine (1.4 mL) were dissolved in dry dichloromethane (25 mL) and benzyloxyacetylchloride (1.34 mL) under ice-cooling. ) Was added and stirred for 4 hours as it was. The reaction solution was extracted with chloroform, the organic layer was washed with dilute hydrochloric acid, aqueous potassium carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 3-1: 1) to obtain the title compound.
[749] Quantity: 1.4 g (85%)
[750] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.85 (s, 3H), 3.86 (s, 3H), 3.87 (s, 3H),
[751] 3.99 (s, 2H), 4.10 (s, 2H), 4.61 (s, 4H), 7.28-7.42 (m, 10H), 8.38 (br, 1H),
[752] 9.36 (br, 1 H)
[753] Preparation Example 63
[754] Synthesis of 2-hydroxymethyl-4,5,6-trimethoxybenzimidazole:
[755]
[756] 1,2-dibenzyloxyacetamide-3,4,5-trimethoxybenzene (1.9 g) is dissolved in xylene (30 mL), p-toluenesulfonic acid monohydrate (2.0 g) is added, and the mixture is refluxed. It stirred for 3 hours. After cooling, methanol which saturated ammonia was added to the reaction liquid, and after making into a homogeneous solution, it concentrated under reduced pressure. The residue was purified by a silica gel flash column (chloroform: methanol = 10: 1), and then purified by silica gel column chromatography (chloroform: methanol 15: 1-> 10: 1) to obtain the title compound.
[757] Quantity: 425mg (46%)
[758] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.63 (s, 3H), 3.79 (s, 3H), 4.17 (br, 3H),
[759] 4,56-4.64 (m, 2H), 5.56 (br, 1H), 6.69 (br, 1H), 12.11 (br, 1H)
[760] Preparation Example 64
[761] Synthesis of 2-chloromethyl-4,5,6-trimethoxybenzimidazole:
[762]
[763] 2-hydroxymethyl-4,5,6-trimethoxybenzimidazole (398 mg) was treated in the same manner as in Production Example 4 to obtain the title compound.
[764] Quantity: 465mg (95%)
[765] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.91 (s, 3H), 3.94 (s, 3H), 4.17 (s, 3H),
[766] 5.16 (s, 2H), 7.00 (s, 1H)
[767] Example 27
[768] Synthesis of N, N'-bis [(4,5,6-trimethoxybenzimidazol-2-yl) methyl] piperazine:
[769]
[770] 2-Chloromethyl-4,5,6-trimethoxybenzimidazole (250 mg) and piperazine (34 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
[771] Quantity: 183mg (87%)
[772] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.61 (br, 8H), 3.80 (s, 4H), 3.83 (br, 3H),
[773] 4.09 (br, 3H), 4.30 (br, 3H), 6.65 (br, 1H), 6.96 (br, 1H), 9.41 (br, 2H)
[774] m / z (EI): 540 [M ⁺ ]
[775] Example 28
[776] Synthesis of N, N'-bis [(4,5,6-trimethoxybenzoimidazol-2-yl) methyl] homopiperazine:
[777]
[778] 2-Chloromethyl-4,5,6-trimethoxybenzimidazole (200 mg) and homopiperazine (30 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
[779] Quantity: 100mg (62%)
[780] m / z (E 1): 540 [M 1 ⁺ ]
[781] Preparation 65
[782] Synthesis of 2-tert-butyldimethylsilyloxymethyl-4,5,6-trimethoxybenzimidazole:
[783]
[784] 2-hydroxymethyl-4,5,6-trimethoxybenzimidazole (354 mg) was dissolved in dry DMF (2 mL), ice-cooled tert-butyldimethylchlorosilane (270 mg), imidazole (45 mg) was added and stirred at room temperature for 30 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel preparative TLC (chloroform: methanol = 12: 1) to obtain the title compound.
[785] Quantity: 517mg (99%)
[786] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.05 (s, 6H), 0.86 (s, 9H), 3.74 (s, 3H),
[787] 3.74 (s, 3H), 4.06 (br, 3H), 4.80 (s, 2H), 6.64 (br, 1H)
[788] Preparation 66
[789] 2-tert-butyldimethylsilyloxymethyl-1-methyl-4,5,6-trimethoxybenzimidazole and 2-tert-butyldimethylsilyloxymethyl-1 -methyl-5,6,7-trimethoxy Synthesis of a Mixture of Benzimidazoles:
[790]
[791] 2-tert-butyldimethylsilyloxymethyl-4,5,6-trimethoxybenzimidazole (517 mg) was dissolved in dry DMF, and ice-cooled sodium hydride (87 mg) and methane iodide (0.28 mL) were added. After the mixture was stirred at room temperature for 1 hour, water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel preparative TLC (chloroform: methanol = 12: 1) to obtain a mixture of the title compounds.
[792] Quantity: 471mg (87%)
[793] Preparation Example 67
[794] Synthesis of 2-hydroxymethyl-1-methyl-4,5,6-trimethoxybenzimidazole:
[795]
[796] 2-tert-butyldimethylsilyloxymethyl-1-methyl-4,5,6-trimethoxybenzimidazole and 2-tert-butyldimethylsilyloxymethyl-1-methyl-5,6,7-trimethoxy A mixture of benzimidazole (471 mg) was dissolved in a mixed solvent of acetic acid (5 mL), water (2.5 mL) and THF (2.5 mL), and stirred at 90 ° C for 2 hours. Saturated brine was added to the reaction solution, which was made alkaline with potassium carbonate aqueous solution, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel preparative TLC (chloroform: methanol = 13: 1) to obtain the title compound.
[797] Quantity: 130mg (40%)
[798] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.73 (s, 3H), 3.87 (s, 3H), 3.90 (s, 3H),
[799] 4.27 (s, 3H), 4.86 (s, 2H), 6.36 (s, 1H)
[800] Preparation Example 68
[801] Synthesis of 2-hydroxymethyl-1-methyl-5,6,7-trimethoxybenzimidazole:
[802]
[803] The title compound of the isomer was separated from the silica gel preparative TLC of Production Example 67.
[804] Quantity: 79mg (24%)
[805] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.88 (s, 3H), 3.89 (s, 3H), 3.99 (s, 3H),
[806] 4.00 (s, 3H), 4.81 (s, 2H), 6.92 (s, 1H)
[807] Preparation Example 69
[808] Synthesis of 2-chloromethyl-1-methyl-5,6,7-trimethoxybenzimidazole:
[809]
[810] 2-hydroxymethyl-1-methyl-5,6,7-trimethoxybenzimidazole (79 mg) was treated in the same manner as in Production Example 4 to obtain the title compound.
[811] Quantity: 37mg (45%)
[812] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.90 (s, 3H), 3.91 (s, 3H), 4.04 (s, 3H),
[813] 4.05 (s, 3H), 4.78 (s, 2H), 6.97 (s, 1H)
[814] Example 29
[815] Synthesis of N, N'-bis [(1-methyl-5,6,7-trimethoxybenzimidazol-2-yl) methyl] homopiperazine:
[816]
[817] 2-Chloromethyl-1-methyl-5,6,7-trimethoxybenzimidazole (39 mg) and homopiperazine (7 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
[818] Quantity: 30mg (75%)
[819] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.81 (quint, 2H, J = 5.9 Hz), 2.69 (s, 4H),
[820] 2.76 (t, 4H, J = 5.9 Hz), 3.82 (s, 6H), 3.88 (s, 4H), 3.90 (s, 6H),
[821] 4.04 (s, 12H), 6.95 (s, 2H)
[822] m / z (EI): 568 [M ⁺ ]
[823] Preparation 70
[824] Synthesis of 2-chloromethyl-l-methyl-4,5,6-trimethoxybenzimidazole:
[825]
[826] 2-hydroxymethyl-l-methyl-4,5,6-trimethoxybenzimidazole (131 mg) was treated in the same manner as in Preparation Example 4 to obtain the title compound.
[827] Quantity: 155mg (97%)
[828] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.92 (s, 3H), 4.00 (s, 3H), 4.02 (s, 3H),
[829] 4.19 (s, 3H), 5.23 (s, 2H), 6.80 (s, 1H)
[830] Example 30
[831] Synthesis of N, N'-bis [(1-methyl-4,5,6-trimethoxy benzimidazol-2-yl) methyl] piperazine:
[832]
[833] 2-Chloromethyl-1-methyl-4,5,6-trimethoxybenzimidazole (75 mg) and piperazine (10 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
[834] Quantity: 44mg (73%)
[835] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.50 (s, 8H), 3.76 (s, 4H), 3.79 (s, 6H),
[836] 3.87 (s, 6H), 3.93 (s, 6H), 4.27 (s, 6H), 6.50 (s, 2H)
[837] m / z (EI): 544 [M ⁺ ]
[838] Example 31
[839] Synthesis of N, N'-bis [(1-methyl-4,5,6-trimethoxybenzimidazol-2-yl) methyl] homopiperazine:
[840]
[841] 2-Chloromethyl-1-methyl-4,5,6-trimethoxybenzimidazole (75 mg) and homopiperazine (11 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
[842] Quantity: 67mg (Theoretical quantity)
[843] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.78 (quint, 2H, J = 5.6 Hz), 2.66 (s, 4H),
[844] 2.75 (t, 4H, J = 5.6 Hz), 3.81 (s, 6H), 3.86 (s, 4H), 3.86 (s, 6H),
[845] 3.93 (s, 6H), 4.29 (s, 6H), 6.50 (s, 2H)
[846] m / z (EI): 568 [M ⁺ ]
[847] Preparation Example 71
[848] Synthesis of ethyl 3,4,5-trimethoxyoxanilate:
[849]
[850] 3,4,5-trimethoxyaniline (3.0 g) and triethylamine (4,5 mL) were dissolved in dichloromethane (10 mL), and ethyl chloroglyoxylate (1.89 mL) was added dropwise with ice cooling. It stirred for 2 hours. 1 M hydrochloric acid was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound.
[851] Quantity: 4.53g (97%)
[852] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.41 (t, 3H, J = 7.2 Hz), 3.80 (s, 3H),
[853] 3.84 (s, 6H), 4.39 (q, 2H, J = 7.2 Hz), 6.93 (s, 2H)
[854] Preparation Example 72
[855] Synthesis of ethyl (3,4.5-trimethoxyphenylamino) thioxoacetate:
[856]
[857] Ethyl 3,4,5-trimethoxyoxanirate (3.0 g) was dissolved in benzene (20 mL) and 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4 -Diphospheptan-2,4-disulfide (2.14 g) was added. The reaction liquid was stirred at 80 degreeC for 1 hour, and water was added. After extraction with ethyl acetate, the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to obtain the title compound.
[858] Quantity: 2.30g (72%)
[859] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.43 (t, 3H, J = 7.2 Hz), 3.84 (s, 3H),
[860] 3.85 (s, 6H), 4.42 (q, 2H, J = 7.2 Hz), 7.38 (s, 2H)
[861] Preparation Example 73
[862] Synthesis of 2-ethoxycarbonyl-5,6,7-trimethoxybenzothiazole:
[863]
[864] Ethyl (3,4,5-trimethoxyphenylamino) thioxoacetate (2.04 g) was dissolved in chloroform (10 mL), and bromine (0.3 mL) was added dropwise at -20 ° C. The mixture was stirred for 1 hour as it was, and then stirred for 3 hours at room temperature again. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9) to obtain the title compound.
[865] Quantity: 1.39g (69%)
[866] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48 (t, 3H, J = 7.1 Hz), 3.95 (s, 3H),
[867] 3.96 (s, 3H), 4.10 (s, 3H), 4.53 (q, 2H, J = 7.1 Hz), 7.47 (s, 1H)
[868] Preparation Example 74
[869] Synthesis of 2-hydroxymethyl-5,6,7-trimethoxybenzothiazole:
[870]
[871] 2-ethoxycarbonyl 5,6,7-trimethoxybenzothiazole (1.04 g) was dissolved in methanol (30 mL), sodium borohydride (331 mg) was added under ice-cooling, and stirred at room temperature for 2 hours. did. Sodium borohydride (100 mg) was added again, and it stirred for 2 hours. The mixture was concentrated under reduced pressure, and purified by silica gel column chromatography (Tyl acetate: hexane = 1: 1) to obtain the title compound.
[872] Quantity: 854mg (95%)
[873] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.90 (s, 3H), 3.91 (s, 3H), 4.05 (s, 3H),
[874] 5.01 (s, 2H), 7.19 (s, 1H)
[875] Preparation 75
[876] Synthesis of 2-chloromethyl-5,6,7-trimethoxybenzothiazole:
[877]
[878] 2-hydroxymethyl-5,6,7-trimethoxybenzothiazole (620 mg) was treated in the same manner as in Preparation Example 4 to obtain the title compound.
[879] Quantity: 563mg (85%)
[880] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.85 (s, 3H), 3.87 (s, 3H), 4.00 (s, 3H),
[881] 4.82 (s, 2H), 7.20 (s, 1H)
[882] Example 32
[883] Synthesis of N, N'-bis [(5,6,7-trimethoxybenzothiazol-2-yl) methyl-1-piperazine:
[884]
[885] 2-Chloromethyl-5,6,7-trimethoxybenzothiazole (365 mg) and piperazine (58 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
[886] Quantity: 123mg (33%)
[887] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.74 (br, 8H), 3.92 (s, 6H), 3.93 (s, 6H),
[888] 4.07 (s, 6H), 7.25 (s, 2H)
[889] m / z (EI): 560 [M ⁺ ]
[890] Example 33
[891] Synthesis of N, N'-bis [(5,6,7-trimethoxybenzothiazol-2-yl) methyl] homopiperazine:
[892]
[893] 2-Chloromethyl-5,6,7-trimethoxybenzothiazole (200 mg) and homopiperazine (37 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
[894] Quantity: 89mg (42%)
[895] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.91-1.94 (m, 2H), 2.93-2.97 (m, 8H),
[896] 3.92 (s, 6H), 3.93 (s, 6H), 4.08 (s, 4H), 4.09 (s, 6H), 7.24 (s, 2H)
[897] m / z (EI): 574 [M ⁺ ]
[898] Preparation Example 76
[899] Synthesis of 5,6,7-trimethoxybenzothiazole-2-carboaldehyde:
[900]
[901] Oxalyl chloride (0.78 mL) was dissolved in dichloromethane (10 mL), DMsO (1.49 mL) was added dropwise at 178 ° C, and stirred for 30 minutes. A solution of 2-chloromethyl-5,6,7-trimethoxybenzothiazole (1.53 g) in dichloromethane (10 ml) was added dropwise at -78 deg. C, stirred for 1 hour, and triethylamine (6.46 ml). ) Was added and the temperature was raised to room temperature. An aqueous ammonium chloride solution was added to the mixture, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9) to obtain the title compound.
[902] Quantity: 1.46g (96%)
[903] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.98 (s, 3H), 3.99 (s, 3H), 4.10 (s, 3H),
[904] 7.44 (s, 1 H), 10.08 (s, 1 H)
[905] Preparation Example 77
[906] Synthesis of ethyl 3- (5,6,7-trimethoxybenzothiazol-2-yl) propenoate:
[907]
[908] 5,6,7-trimethoxybenzothiazole-2-carboaldehyde (951 mg) was treated in the same manner as in Production Example 17 to obtain the title compound.
[909] Quantity: 908mg (75%)
[910] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.36 (t, 3H, J = 7.1 Hz), 3.94 (s, 3H),
[911] 3.96 (s, 3H), 4.08 (s, 3H), 4.30 (q, 2H, J = 7.1 Hz), 6.76 (d, 1H, J = 15.8 Hz),
[912] 7.32 (s, 1 H), 7.81 (d, 1 H, J = 15.9 Hz)
[913] Preparation Example 78
[914] Synthesis of ethyl 3- (5,6,7-trimethoxybenzothiazol-2-yl) propionate:
[915]
[916] Ethyl 3- (5,6,7-trimethoxybenzothiazol-2-yl) propenoate (908 mg) was treated in the same manner as in Production Example 18 to obtain the title compound.
[917] Quantity: 660mg (72%)
[918] Preparation Example 79
[919] Synthesis of 2- (3-hydroxypropyl) -5,6,7-trimethoxybenzothiazole:
[920]
[921] Ethyl 3- (5,6,7-trimethoxybenzothiazol-2-yl) propionate (660 mg) was treated in the same manner as in Production Example 19 to obtain the title compound.
[922] Quantity: 420mg (73%)
[923] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.01-2.07 (m, 2H), 3.13 (t, 2H, J = 7.2 Hz),
[924] 3.71 (t, 2H, J = 5.8 Hz), 3.83 (s, 3H), 3.85 (s, 3H), 3.98 (s, 3H),
[925] 7.16 (s, 1 H)
[926] Preparation Example 80
[927] Synthesis of 2- (3-bromopropyl) -5,6,7-trimethoxybenzothiazole:
[928]
[929] 2- (3-hydroxypropyl) -5,6,7-trimethoxybenzothiazole (388 mg) was dissolved in dichloromethane (5 mL), carbon tetrabromide (590 mg) and triphenylphosphine (431 mg) was added at room temperature and the mixture was stirred vigorously for 1 hour. After adding water and extracting with dichloromethane, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9) to obtain the title compound.
[930] Quantity: 328mg (66%)
[931] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.32-2.38 (m, 2H), 3.16 (t, 2H, J = 7.2 Hz),
[932] 3.45 (t, 2H, J = 6.5 Hz), 3.84 (s, 3H), 3.85 (s, 3H), 3.98 (s, 3H),
[933] 7.18 (s, 1 H)
[934] Example 34
[935] Synthesis of N, N'-bis [3- (5,6,7-trimethoxybenzothiazol-2-yl) propyl] piperazine:
[936]
[937] 2- (3-bromopropyl) -5,6,7-trimethoxybenzothiazole (328 mg) and piperazine (39 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base. .
[938] Quantity: 61mg (23%)
[939] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.03-2.07 (m, 4H), 2.45-2.48 (m, 12H),
[940] 3.10 (t, 4H, J = 7.6 Hz), 3.91 (s, 6H), 3.93 (s, 6H), 4.06 (s, 6H),
[941] 7.25 (s, 2 H)
[942] m / z (EI): 616 [M ⁺ ]
[943] Example 35
[944] Synthesis of N, N'-bis [3- (5,6,7-trimethoxybenzothiazol-2-yl) propyl] homopiperazine:
[945]
[946] 2- (3-Promopropyl) -5,6,7-trimethoxybenzothiazole (444 mg) and homopiperazine (64 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
[947] Quantity: 84mg (21%)
[948] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.82-1.93 (m, 2H), 2.00-2.12 (m, 4H),
[949] 2.64 (t, 4H, J = 7.2 Hz), 2.75-2.77 (m, 8H), 3.10 (t, 4H, J = 7.4 Hz),
[950] 3.91 (s, 6H), 3.93 (s, 6H), 4.06 (s, 6H), 7.25 (s, 2H)
[951] m / z (EI): 630 [M ⁺ ]
[952] Preparation Example 81
[953] Synthesis of (6'-nitro-2 ', 3', 4'-trimethoxyphenyl) benzyloxyacetate:
[954]
[955] 6-nitro-2,3,4-trimethoxyphenol (1.25 g) and triethylamine (1.12 mL) were dissolved in dichloromethane (20 mL), and benzyloxyacetyl chloride (1.1 mL) was added dropwise under ice-cooling. It stirred as it is for 2 hours. The reaction solution was extracted with chloroform, washed with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to obtain the title compound.
[956] Quantity: 1.38g (66.5%)
[957] Preparation Example 82
[958] Synthesis of 2-hydroxymethyl-5,6,7-trimethoxybenzoxazole:
[959]
[960] (6'-nitro-2 ', 3', 4'-trimethoxyphenyl) benzyloxyacetate (1.38 g) was dissolved in methanol (40 mL), 10% palladium carbon (560 mg) was added, and a hydrogen atmosphere After stirring at room temperature for 7 hours, the reaction solution was filtered and the filtrate was concentrated. The residue was dissolved in xylene (50 mL), p-toluenesulfonic acid monohydrate (350 mg) was added, and the mixture was stirred at reflux for 1 hour. After concentration under reduced pressure, water was added to the residue, extracted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel preparative TLC (chloroform: methanol = 10: 1) to obtain the title compound.
[961] Quantity: 126mg (12%)
[962] Preparation Example 83
[963] Synthesis of 2-chloromethyl-5,6,7-trimethoxybenzoxazole:
[964]
[965] 2-hydroxymethyl-5,6,7-trimethoxybenzoxazole (114 mg) was treated in the same manner as in Preparation Example 4 to obtain the title compound.
[966] Quantity: 95mg (83%)
[967] Example 36
[968] Synthesis of N, N'-bis [(5,6,7-trimethoxybenzoxazol-2-yl) methyl] piperazine:
[969]
[970] 2-Chloromethyl-5,6,7-trimethoxybenzazole (156 mg) and piperazine (23 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
[971] Quantity: 135mg (95%)
[972] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.74 (br, 8H), 3.86 (s, 4H), 3.89 (s, 6H),
[973] 3.89 (s, 6H), 4.20 (s, 6H), 6.89 (s, 2H)
[974] m / z: 528 [M ⁺ ]
[975] Example 37
[976] Synthesis of N, N'-bis [(5,6,7-trimethoxybenzoxazol-2-yl) methyl] homopiperazine:
[977]
[978] 2-Chloromethyl-5,6,7-trimethoxybenzoxazole (152 mg) and homopiperazine (28 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
[979] Quantity: 121mg (81%)
[980] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.87 (quint, 2H), 2.85-2.97 (m, 8H),
[981] 3.89 (s, 6H), 3.89 (s, 6H), 4.00 (s, 4H), 4.20 (s, 6H), 6.90 (s, 2H)
[982] m / z: 542 [M ⁺ ]
[983] Preparation Example 84
[984] Synthesis of ethyl 2- (3,4,5-trimethoxyphenyloxy) acetoacetate:
[985]
[986] 3,4,5-trimethoxyphenol (5.83 g) was dissolved in DMF (60 mL), and potassium tert-butoxide (3.55 g) was added under ice cooling. Subsequently, ethyl 2-chloroacetoacetate (4.46 ml) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was heated to 80 ° C. and stirred for 2 hours. After cooling, water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to obtain the title compound.
[987] Quantity: 5.3g (54%)
[988] Preparation Example 85
[989] Synthesis of ethyl 3-methyl-4,5,6-trimethoxybenzofuran-2-carboxylate:
[990]
[991] Ethyl 2- (3,4,5-trimethoxyphenyloxy) acetoacetate (5.3 g) was slowly added dropwise to concentrated hydrochloric acid (10 ml), followed by stirring for 1 hour. Water was added to the reaction solution, followed by extraction with ethyl acetate, followed by washing with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate and hexane to obtain the title compound.
[992] Quantity: 3.2g (64%)
[993] Preparation 86
[994] Synthesis of 3-methyl-4,5,6-trimethoxybenzofuran-2-carboxylic acid:
[995]
[996] Ethyl 3-methyl-4,5,6-trimethoxybenzofuran-2-carboxylate (500 mg) was treated in the same manner as in Preparation Example 2 to obtain the title compound.
[997] Quantity: 411mg (91%)
[998] Preparation 87
[999] Synthesis of N, N'-bis (3-methyl-4,5,6-trimethoxybenzofuran-2-carbonyl) piperazine:
[1000]
[1001] 3-Methyl-4,5,6-trimethoxybenzofuran-2-carboxylic acid (300 mg) and piperazine (49 mg) were reacted in the same manner as in Production Example 37 to obtain the title compound.
[1002] Quantity: 151mg (47%)
[1003] Example 38
[1004] Synthesis of N, N'-bis [(3-methyl-4,5,6-trimethoxybenzofuran-2-yl) methyl] piperazine:
[1005]
[1006] N, N'-bis (3-methyl-4,5,6-trimethoxybenzofuran-2-carbonyl) piperazine (93 mg) was treated in the same manner as in Example 18 to obtain the title compound as a free base. .
[1007] Quantity: 65mg (74%)
[1008] m / z: 554 [M ⁺ ]
[1009] Preparation Example 88
[1010] Synthesis of N, N'-bis (3-methyl-4,5,6-trimethoxybenzofuran-2-carbonyl) homopiperazine:
[1011]
[1012] 3-Methyl-4,5,6-trimethoxybenzofuran-2-carboxylic acid (117 mg) and homopiperazine (20 mg) were reacted in the same manner as in Production Example 37 to obtain the title compound.
[1013] Quantity: 117mg (98%)
[1014] Example 39
[1015] Synthesis of N, N'-bis [(3-methyl-4,5,6-trimethoxybenzofuran-2-yl) methyl] homopiperazine:
[1016]
[1017] N, N'-bis (3-methyl-4,5,6-trimethoxybenzofuran-2-carbonyl) homopiperazine (117 mg) was treated in the same manner as in Example 18 to give the title compound as the free base. Got it.
[1018] Quantity: 82mg (72%)
[1019] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.78-1.87 (m, 2H), 2.29 (s, 3H),
[1020] 2.75-2.82 (m, 8H), 3.70 (s, 4H), 3.86 (s, 6H), 3.87 (s, 6H), 3.98 (s, 6H),
[1021] 6.76 (s, 2 H)
[1022] m / z: 568 [M ⁺ ]
[1023] Preparation Example 89
[1024] Synthesis of ethyl 4,5,6-trimethoxybenzothiophene-2-carboxylate:
[1025]
[1026] 6-nitro-2,3,4-trimethoxybenzaldehyde (1.6 g) was dissolved in DMF (15 mL) and potassium carbonate (1.28 g) was added. Methyl thioglycolate (0.68 ml) was added dropwise under ice cooling, and the mixture was stirred for 40 minutes. The mixture was then stirred at room temperature for 4 hours. Water was added to the mixture, followed by extraction with ethyl acetate, and then the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to obtain the title compound.
[1027] Quantity: 1.22g (64%)
[1028] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.91 (s, 3H), 3.92 (s, 3H), 3.95 (s, 3H),
[1029] 4.07 (s, 3H), 7.04 (s, 1H), 8.01 (s, 1H)
[1030] Preparation 90
[1031] Synthesis of 2-hydroxymethyl-4,5,6-trimethoxybenzothiophene:
[1032]
[1033] Ethyl 4,5,6-trimethoxybenzothiophene-2-carboxylate (550 mg) was treated in the same manner as in Production Example 3 to obtain the title compound.
[1034] Quantity: 602mg (Theoretical quantity)
[1035] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.90 (br, IH), 3.83 (s, 3H), 3.84 (s, 3H),
[1036] 3.95 (s, 3H), 4.80 (d, 2H, J = 5.1 Hz), 6.97 (s, 1H), 7.17 (s, 1H)
[1037] Example 40
[1038] Synthesis of N, N'-bis [(4,5,6-trimethoxybenzothiophen-2-yl) methyl] piperazine:
[1039]
[1040] 2-chloromethyl-4,5,6-trimethoxybenzothiophene obtained by treating 2-hydroxymethyl-4,5,6-trimethoxybenzothiophene (374 mg) in the same manner as in Production Example 4 Without separation, piperazine (63 mg) was immediately reacted in the same manner as in Example 1 to obtain the title compound as a free base.
[1041] Quantity: 17mg (2%)
[1042] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.57 (br, 8H), 3.75 (s, 4H), 3.89 (s, 6H),
[1043] 3.90 (s, 6H), 4.02 (s, 6H), 7.02 (s, 2H), 7.15 (s, 2H)
[1044] m / z (EI): 558 [M ⁺ ]
[1045] Example 41
[1046] Synthesis of N, N'-bis [(4,5,6-trimethoxybenzothiophen 2-yl) methyl] homopiperazine:
[1047]
[1048] 2-chloromethyl-4,5,6-trimethoxybenzothiophene obtained by treating 2-hydroxymethyl-4,5,6-trimethoxybenzothiophene (1.15 g) in the same manner as in Production Example 4 Immediately reacting homopiperazine (226 mg) in the same manner as in Example 1 without separation to obtain the title compound as a free base.
[1049] Quantity: 242mg (9%)
[1050] ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.81-1.83 (m, 2H), 2.75-2.82 (m, 8H),
[1051] 3.88 (s, 4H), 3.89 (s, 6H), 3.90 (s, 6H), 4.02 (s, 6H), 7.03 (s, 2H),
[1052] 7.14 (s, 2 H)
[1053] m / z (EI): 572 [M ⁺ ]
[1054] Test Example
[1055] (Cell adhesion inhibitory effect)
[1056] Ross et al. (J. Biol. Chem., 267, 8537-8543 (1992)). That is, human umbilical vein-derived vascular endothelial cells (HUVECs) were cultured in a 48-well plate until confluent, and then IL-1β or TNFα was added. Five hours after the addition, U937, a human monocyte / tissue sphere-derived cell fluorescently labeled with PKH2 (Dainippon Pharmaceutical Co., Ltd.) was added to each well 1 × 10 ⁶ cells. After standing at room temperature for 1 hour, U937 not adhered was washed out, the cells were lysed with 1% Triton X-100, and the remaining fluorescence intensity was measured (excitation wavelength 485 nm, measurement wavelength 530 nm). HUVEC was incubated with EGM-2 (sanko Junyaku KK), and U937 was in RPMI 1640 containing 10% FCs. The drug was added to HUVEC at the time of addition of IL-1β or TNFα, and to U937 24 hours before the cell adhesion test. Inhibitory activity was A = (adhesive cell number of U937 to IL-1β or TNFα-stimulated HUVEC without drug addition), B = (U937 adhesion cell number to HUVEC without drug addition), C = (IL as drug addition The number of adherent cells of U937 to -1β or TNFα-stimulated HUVEC) was calculated as [100- (CB) / (AB) × 100 (%)]. The results are shown in Table l. As a control compound, test compound 1 of JP-A-9-143075 and dilazep of JP-A-11-92382 were simultaneously evaluated.
[1057] Inhibitory activity of 1 μM cell adhesion of each compound Example % Inhibition TNFα Stimulation IL-β Stimulation 6323341 69527927 57546452 Test Compound 1 Dilazep 512 100
[1058] Specific formulation examples are shown below.
[1059] Formulation Example 1 (Capsule)
[1060] N, N'-bis [2- (5,6,7-trimethoxynaphthalen-2-yl) ethyl] hompiperazine30 mg
[1061] Microcrystalline Cellulose 30 mg
[1062] Lactose 57 mg
[1063] Magnesium Stearate 3 mg
[1064] 120 mg total
[1065] After mixing the said component by a conventional method, it filled into gelatin capsule and obtained the capsule agent.
[1066] Formulation Example 2 (Tablet)
[1067] N, N'-bis [2- (5,6,7-trimethoxynaphthalen-2-yl) ethyl] hompiperazine 30 mg
[1068] Starch 44 mg
[1069] Starch (for seaweed) 5.6 mg
[1070] Magnesium Stearate 0.4 mg
[1071] Carboxymethyl Cellulose Calcium 20 mg
[1072] 100 mg total
[1073] The above components were mixed by a conventional method to obtain a tablet.
[1074] Formulation Example 3 (Injectable)
[1075] N, N'-bis [2- (5,6,7-trimethoxynaphthalen-2-yl) ethyl] homopiperazine (100 mg) and sodium chloride (900 mg) are dissolved in about 80 ml of distilled water for injection Then, distilled water for injection is added to the obtained solution to make the total amount 100 ml. After sterile filtration, this was dispensed into 10 light-blocking ampoules, and sealed to obtain a sterile injection.
[1076] Compound (1) of the present invention has excellent cell adhesion and inhibitory effect on cell infiltration, and is useful as a medicament for preventing or treating allergy, asthma, rheumatism, arteriosclerosis, inflammation and the like.

权利要求:
Claims (14)
[1" claim-type="Currently amended] General formula (1)

[Wherein, R ¹ and R ² each represent a hydrogen atom or a methoxy group, when R ² is a hydrogen atom, R ¹ represents a methoxy group, and when R ² is a methoxy group, R ¹ represents a hydrogen atom; A represents an oxygen atom, a sulfur atom, CH = CH, CH = N or NR ³ , wherein R ³ represents a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, an aryl group or an aryl lower alkyl group Represent; B represents a nitrogen atom, CH or CR ⁴ , wherein R ⁴ represents a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, an aryl group or an aryl lower alkyl group; m represents a number of 1 or 2; n represents the number of 1-5.] The cyclic diamine compound, its acid addition salt, or its hydrate.
[2" claim-type="Currently amended] A compound according to claim 1, wherein R ³ and R ⁴ in formula (1) each represent a hydrogen atom, a C ₁ -C ₆ -alkyl group, a hydroxy-C ₂ -C ₆ -alkyl group, C ₁ -C ₆ -alkoxy-C ₁ -C ₆ - alkyl, C ₆ -C ₁₀ - aryl or C ₆ -C ₁₀ - aryl -C ₁ -C ₆ - alkyl cyclic diamine compound, an acid addition salt thereof or a hydrate of the foregoing.
[3" claim-type="Currently amended] The method according to claim 2, wherein in general formula (1)

Cyclic diamine compounds, acid addition salts thereof, or hydrates thereof, wherein the moiety has a skeleton selected from naphthalene, quinoline, quinazoline, benzimidazole, benzothiazole, benzoxazole, indole, benzothiophene and benzofuran.
[4" claim-type="Currently amended] A pharmaceutical comprising the cyclic diamine compound according to any one of claims 1 to 3, an acid addition salt thereof or a hydrate thereof as an active ingredient.
[5" claim-type="Currently amended] The pharmaceutical according to claim 4, which is a prophylactic or therapeutic agent for a disease caused by cell adhesion and / or cell infiltration.
[6" claim-type="Currently amended] The medicament according to claim 5, wherein the disease is a disease selected from allergy, asthma, inflammation, rheumatism and atherosclerosis.
[7" claim-type="Currently amended] The pharmaceutical composition containing the cyclic diamine compound of any one of Claims 1-3, its acid addition salt or its hydrate, and a pharmaceutically acceptable carrier.
[8" claim-type="Currently amended] 8. A composition according to claim 7, which is for the prevention or treatment of diseases caused by cell adhesion and / or cell infiltration.
[9" claim-type="Currently amended] The composition of claim 8, wherein the disease is a disease selected from allergy, asthma, inflammation, rheumatism and atherosclerosis.
[10" claim-type="Currently amended] Use for pharmaceutical manufacture of the cyclic diamine compound of any one of Claims 1-3, its acid addition salt, or its hydrate.
[11" claim-type="Currently amended] Use according to claim 10, wherein the medicament is for the prophylaxis or treatment of diseases resulting from cell adhesion and / or cell infiltration.
[12" claim-type="Currently amended] Use according to claim 11, wherein the disease is a disease selected from allergy, asthma, inflammation, rheumatism and atherosclerosis.
[13" claim-type="Currently amended] A method for treating a disease caused by cell adhesion and / or cell infiltration, which is administered to a patient in need of an effective amount of the cyclic diamine compound according to any one of claims 1 to 3, an acid addition salt thereof, or a hydrate thereof.
[14" claim-type="Currently amended] The method of claim 13, wherein the disease is a disease selected from allergy, asthma, inflammation, rheumatism, and atherosclerosis.

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同族专利:

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公开号 | 公开日

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CA2451452C|2010-08-10|

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KR100860692B1|2008-09-26|

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CA2451452A1|2003-01-09|

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JPWO2003002532A1|2004-10-14|

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JP4225894B2|2009-02-18|

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WO2003002532A1|2003-01-09|

---

CN1599717A|2005-03-23|

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EP1400510B1|2010-08-18|

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DE60237367D1|2010-09-30|

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US6632810B2|2003-10-14|

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US20030060461A1|2003-03-27|

---

AT478046T|2010-09-15|

---

TWI236469B|2005-07-21|

---

EP1400510A1|2004-03-24|

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US20040058913A1|2004-03-25|

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HK1065306A1|2010-11-05|

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EP1400510A4|2005-01-26|

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CN1281585C|2006-10-25|

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US7135473B2|2006-11-14|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2001-06-29|Priority to US09/893,696

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2001-06-29|Priority to US09/893,696

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2002-06-27|Application filed by 코와 가부시키가이샤

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2002-06-27|Priority to PCT/JP2002/006487

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2004-02-18|Publication of KR20040015270A

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2008-09-26|Application granted

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2008-09-26|Publication of KR100860692B1

优先权:

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申请号 | 申请日 | 专利标题

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US09/893,696|2001-06-29|

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US09/893,696|US6632810B2|2001-06-29|2001-06-29|Cyclic diamine compound with condensed-ring groups|

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PCT/JP2002/006487|WO2003002532A1|2001-06-29|2002-06-27|Cyclic diamine compounds having fused-ring groups|