JP2007223999A - New isoquinoline derivative and medicine containing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound having osteoclast differentiation induction-suppressing action and a medicine containing the compound. <P>SOLUTION: The medicine comprises a compound represented by general formula (1) [R<SP>1</SP>and R<SP>2</SP>are each a hydrogen atom or an alkyl group; R<SP>3</SP>is a hydrogen atom, an alkyl group or a halogen atom; R<SP>4</SP>is an alkyl group which may have a substituent, an arylalkyl group which may have a substituent on an aromatic ring, a heteroaryl alkyl group which may have a substituent on an aromatic ring or an arylalkenyl group which may have a substituent on an aromatic ring], its acid addition salt or solvate thereof. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a novel isoquinoline derivative and a medicament containing the same.

Conventionally, many non-steroidal anti-inflammatory drugs have been used as anti-inflammatory drugs and anti-rheumatic drugs. Nonsteroidal anti-inflammatory drugs have actions such as inflammation swelling and pain reduction, but are not known to inhibit the progression of bone tissue destruction in arthritis, which is a problem in rheumatism and the like. Osteoporosis is common in postmenopausal women, and vitamin D ₃ , vitamin K, calcitonin, calcium, bisphosphonate and the like are used as therapeutic agents in addition to female hormones. Among them, bisphosphonate that directly inhibits bone resorption by osteoclasts has a strong bone resorption inhibitory action, and its use frequency is increasing in recent years. Originally, bone resorption by osteoclasts is maintained in harmony with bone formation by osteoblasts, but bone tissue destruction in rheumatism, osteoporosis, Paget's disease, and bone cancer breaks this balance, It is suggested to be due to pathological bone resorption by osteoclasts (see, for example, Non-Patent Documents 1 to 5).

On the other hand, osteoclasts are known to differentiate from bone marrow monocyte / macrophage cells. Therefore, a compound that suppresses osteoclast differentiation induction is expected to prevent the destruction of bone tissue and seems to be useful as an active ingredient of a drug, but such a compound is not known.
Rodan, G .; A. , And Martin, T .; J. et al. , Science, 289, 1508-1514 (2000) Takayanagi, H .; et al. Arthritis. Rheum. 43, 259-269 (2000) Takayanagi, H .; et al. , J .; Clin. Invest. 104, 137-46 (1999) Kong, Y. et al. Y. et al. , Nature, 402, 304-9 (1999). Pettit, A.M. R. et al. , Am. J. et al. Pathol. , 159, 1689-99 (2001)

  An object of this invention is to provide the compound which has an osteoclast differentiation induction-inhibition effect | action, and a pharmaceutical containing this.

  In view of the above circumstances, as a result of searching for compounds having an osteoclast differentiation induction inhibitory activity, the present inventors have found that the novel quinoline derivative represented by the following general formula (1), its acid addition salt, and those Was found to have a strong osteoclast differentiation induction-inhibiting action, and the present invention was completed.

  That is, the present invention provides the following general formula (1)

[Wherein R ¹ and R ² each represent a hydrogen atom or an alkyl group, R ³ represents a hydrogen atom, an alkyl group or a halogen atom, and R ⁴ represents an alkyl group or an aromatic ring which may have a substituent. An arylalkyl group which may have a substituent above, a heteroarylalkyl group which may have a substituent on an aromatic ring, or an arylalkenyl group which may have a substituent on an aromatic ring is shown. ]
Or an acid addition salt thereof or a solvate thereof.

  Moreover, this invention provides the pharmaceutical which contains the compound represented by the said General formula (1), its acid addition salt, or those solvates as an active ingredient.

  Furthermore, the present invention provides the above medicament which is a preventive and / or therapeutic agent for rheumatism, osteoporosis, Paget's disease, or bone cancer.

  The compound (1) of the present invention and acid addition salts thereof or solvates thereof have a strong osteoclast differentiation induction inhibitory action, such as rheumatism, osteoporosis, Paget's disease, bone cancer, etc. It is useful as a preventive and / or therapeutic agent for diseases associated with regenerative failure.

In the general formula (1), examples of the alkyl group represented by R ^{1 to} R ³ include a C ₁ -C ₆ linear or branched alkyl group, such as a methyl group, an ethyl group, an n-propyl group, Examples include iso-propyl group, n-butyl group, iso-butyl group, tert-butyl group, pentyl group, hexyl group, and the like, and methyl group is preferable. The substitution position on the homopiperazine of the alkyl group represented by R ² may be any of 2-position, 3-position, 5-position, 6-position and 7-position, but 2-position and 3-position. , 5-position is preferred, and 2-position is particularly preferred. The steric configuration of the substituent may be either (S) or (R). R ¹ is preferably a hydrogen atom.

In the general formula (1), examples of the halogen atom represented by R ³ include F, Cl, and Br.

In the general formula (1), examples of the alkyl group represented by R ⁴ include C ₁ -C ₆ linear or branched alkyl groups such as a methyl group, an ethyl group, an n-propyl group, and iso-propyl. Group, n-butyl group, iso-butyl group, tert-butyl group, pentyl group and hexyl group. These alkyl groups as substituents, a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, which may have a cycloalkyl group C ₃ -C _8, such as cyclooctyl group. As the alkyl group represented by R ⁴ , an ethyl group and a cyclopropylmethyl group are preferable.

In the general formula (1), examples of the arylalkyl group represented by R ⁴ include a C ₆ -C ₁₀ aryl-C ₁ -C ₆ alkyl group, such as a benzyl group and a naphthylmethyl group. Groups are preferred. These arylalkyl groups may have a substituent on the aromatic ring, and examples of the group that can be substituted include a methyl group, an ethyl group, wherein 1-3 hydrogen atoms may be substituted with halogen atoms, n- propyl, iso- propyl, n- butyl, iso- butyl group, tert- butyl group, a pentyl group, an alkyl group of C ₁ -C _6, such as hexyl group; methoxy group, an ethoxy group, a propoxy group, the C ₁ -C ₆ alkoxy group; a nitro group; F, Cl, Br, a halogen atom, such as I; such as hydroxyethyl group and the like, the inner iso- propyl group, a trifluoromethyl group, a halogen atom is preferable.

In the general formula (1), examples of the heteroarylalkyl group represented by R ⁴ include a C ₆ -C ₁₀ heteroaryl-C ₁ -C ₆ alkyl group, such as a picolyl group and a quinolylmethyl group. A picolyl group is preferred. These heteroarylalkyl groups may have a substituent on the aromatic ring, and examples of the group that can be substituted include a methyl group or an ethyl group in which 1-3 hydrogen atoms may be substituted with halogen atoms. , N-propyl group, iso-propyl group, n-butyl group, iso-butyl group, tert-butyl group, pentyl group, hexyl group and the like C ₁ -C ₆ alkyl group; methoxy group, ethoxy group, propoxy group C ₁ -C ₆ alkoxy groups such as nitro group; halogen atoms such as F, Cl, Br, and I; hydroxy group and the like.

In the general formula (1), as the arylalkenyl group represented by R ⁴ , a C ₆ -C ₁₀ aryl-C ₂ -C ₆ alkenyl group, for example, a vinyl group substituted with a C ₆ -C ₁₀ aryl group, allyl, butenyl, pentenyl group, and an alkenyl group C ₂ -C ₆ such as a hexenyl group, for example, styryl group and a cinnamyl group. These arylalkenyl groups may have a substituent on the aromatic ring. Examples of the substituent include a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, an n-butyl group, and an iso-butyl group. C ₁ -C ₆ alkyl groups such as tert-butyl group, pentyl group and hexyl group; C ₁ -C ₆ alkoxy groups such as methoxy group, ethoxy group and propoxy group; nitro group; F, Cl, Br, Halogen atoms such as I; hydroxy groups and the like can be mentioned, and halogen atoms are preferred.

  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. Examples of the acid addition salt include hydrochloride, hydrobromide, hydroiodide, sulfate, and phosphate. Acid addition salts of mineral acids such as: benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, oxalate, maleate, fumarate, tartrate, Examples include acid addition salts of organic acids such as citrate and acetate.

  Moreover, although this invention compound (1) may exist in the form of the solvate represented by the hydrate, the said solvate is also contained in this invention.

  The compound (1) of the present invention can be produced according to the following method.

[Wherein R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above, and A represents a benzyloxycarbonyl group, a tert-butoxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, a formyl group, trifluoroacetyl. An amino protecting group such as a group or a trityl group. X represents a leaving group such as Cl, Br, I, mesyl group, etc.]

  Compound (2) which is the starting material of the present invention can be synthesized by the method described in International Publication No. WO 97/28130 or a similar method.

Compound (2) is converted to N-oxide (3) by a known oxidation reaction using, for example, m-chloroperbenzoic acid. Compound (3) is converted into 1-OH form (4) by a known method such as alkali treatment after benzoic anhydride treatment, for example. Compound (4) is reacted with compound X-R ⁴ such as methyl iodide, ethyl iodide, benzyl chloride or the like by a known method to obtain compound (5). Compound (6) is obtained by removing protecting group A of compound (5) by a known method. The compound (6) corresponds to the compound (1) of the present invention in which R ¹ is hydrogen. If necessary, this is further converted to a compound R ¹ -X such as methyl halide, alkyl halide such as ethyl iodide and the like. The compound (1) in which an alkyl group is introduced into homopiperazine (the present compound (1) in which R ¹ is an alkyl group) can be obtained by reacting and alkylating by a known method.

  The compound (1) of the present invention can be obtained by the above-described method, and can be further purified by a usual purification means such as a recrystallization method or column chromatography, if necessary. If necessary, the desired salt or solvate described above can also be obtained by a conventional method.

  As described above, the compound (1), acid addition salt or solvate thereof of the present invention has an inhibitory effect on osteoclast differentiation induction, and is therefore effective in preventing or treating diseases associated with bone destruction or bone regeneration failure. is there. Specific diseases include rheumatism, osteoporosis, Paget's disease, bone cancer and the like.

  The compound (1) of the present invention, acid addition salt thereof or solvate thereof is used orally or parenterally (for example, intravenous, subcutaneous, or intramuscular injection, topical, rectal, etc.) , Transdermally, or nasally). Examples of forms for oral administration include tablets, capsules, pills, granules, powders, solutions, syrups, suspensions, etc. Examples of forms for parenteral administration include, for example, injection. Aqueous or oily agents, ointments, creams, lotions, aerosols, suppositories, patches, and the like. These preparations can be prepared by using a conventionally known technique, and can contain acceptable ordinary carriers, excipients, binders, stabilizers and the like. In addition, when used in an injection form, an acceptable buffer, solubilizing agent, isotonic agent and the like can be added. The dose and frequency of administration of the isoquinolinone derivative or salt thereof of the present invention vary depending on the symptoms, age, body weight, and administration form, but are usually about 0. 01-2000 mg, preferably 0.1-500 mg can be administered once or divided into several times.

  Specific examples of the compound included in the present invention include the following compounds. However, specific examples of these compounds are for illustrative purposes, and the present invention is not limited thereto.

[Production Example 1]
Synthesis of 4- (tert-butoxycarbonyl) -1- [4-methyl-2-oxoisoquinoline-5-sulfonyl] homopiperazine:

4- (tert-Butoxycarbonyl) -1- [4-methylisoquinoline-5-sulfonyl] homopiperazine (1.00 g) was dissolved in chloroform (18 mL) and m-chloroperbenzoic acid (1.70 g) was added. . The mixture was stirred at room temperature for 15 hours and concentrated under reduced pressure. A 10% aqueous sodium sulfate solution (25 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour and extracted with chloroform (50 mL). The organic layer was washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to give the title compound as a white powder.
Yield: 1.226 g (including m-chlorobenzoic acid)

[Production Example 2]
Synthesis of 4- (tert-butoxycarbonyl) -1- (1-hydroxy-4-methylisoquinoline-5-sulfonyl) homopiperazine:

Sodium cyanide (105 mg) was added to a suspension of 4- (tert-butoxycarbonyl) -1- [4-methyl-2-oxoisoquinoline-5-sulfonyl] homopiperazine (188 mg) in water (2 mL) and stirred. Then, benzoyl chloride (134 mg) was added dropwise. The mixture was stirred at room temperature for 4 hours, and extracted by adding chloroform (40 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (developing solvent; hexane-ethyl acetate = 1: 1) to obtain the title compound as colorless amorphous crystals.
Yield: 65 mg (41%)

[Production Example 3]
Synthesis of 4- (tert-butoxycarbonyl) -1-[(1,2-dihydro-2-ethyl-4-methylisoquinolin-1-one) -5-sulfonyl] homopiperazine:

While cooling a solution of 4- (tert-butoxycarbonyl) -1- (1-hydroxy-4-methylisoquinoline-5-sulfonyl) homopiperazine (254 mg) in N, N-dimethylformamide (4 mL) with ice-salt 60% NaH (40 mg) was added, and the mixture was stirred as it was for 20 minutes, and ethyl iodide (50 μL) was added. The mixture was stirred at room temperature for 30 minutes, ice water was added, acidified with 1M HCl, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (developing solvent; chloroform-acetone = 9: 1) to obtain the title compound as slightly brown amorphous crystals.
Yield: 137 mg (51%)

[Example 1]
Synthesis of 1-[(1,2-dihydro-2-ethyl-4-methylisoquinolin-1-one) -5-sulfonyl] homopiperazine hydrochloride:

4- (tert-Butoxycarbonyl) -1-[(1,2-dihydro-2-ethyl-4-methylisoquinolin-1-one) -5-sulfonyl] homopiperazine (137 mg) in methanol (5 mL) in 4 M Hydrochloric acid in ethyl acetate (0.8 mL) was added, and the mixture was refluxed at 75 ° C. for 1 hr. After cooling, the reaction solution was dried under reduced pressure to obtain the title compound as a pale red powder.
Yield: 65 mg (55%)
M / Z: 349 [M ⁺ ]

[Production Example 4]
Synthesis of 4- (tert-butoxycarbonyl) -1-[(1,2-dihydro-2-cyclopropylmethyl-4-methylisoquinolin-1-one) -5-sulfonyl] homopiperazine:

4- (tert-Butoxycarbonyl) -1- (1-hydroxy-4-methylisoquinoline-5-sulfonyl) homopiperazine (159 mg) and potassium carbonate (106 mg) were suspended in N, N-dimethylformamide (3 mL). Cloudy and chloromethylcyclopropane (71 mg) was added. The mixture was stirred at 100 ° C. for 2 hours, cooled, water (15 mL) was added, and the mixture was extracted with ethyl acetate (60 mL). The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (developing solvent; hexane-ethyl acetate = 1: 2) to obtain the title compound as colorless amorphous crystals.
Yield: 126 mg (70%)

[Example 2]
Synthesis of 1-[(1,2-dihydro-2-cyclopropylmethyl-4-methylisoquinolin-1-one) -5-sulfonyl] homopiperazine hydrochloride:

4- (tert-Butoxycarbonyl) -1-[(1,2-dihydro-2-cyclopropylmethyl-4-methylisoquinolin-1-one) -5-sulfonyl] homopiperazine (113 mg) as in Example 1 To give the title compound as a white powder.
Yield: 63 mg (45%)
¹ H-NMR data (400 MHz, DMSO-d ₆ ) δ ppm: 0.38-0.52 (m, 4H), 1.20-1.32 (m, 1H), 2.08-2.20 (m , 2H), 2.51 (s, 3H), 3.13-3.30 (m, 4H), 3.55-3.65 (m, 2H), 3.72-3.88 (4H, m ), 7.56 (d, 1H, J = 0.98 Hz), 7.63 (t, 1H, J = 7.8 Hz), 7.96 (dd, 1H, J = 7.8 Hz, 1.5 Hz) , 8.64 (dd, 1H, J = 8.1 Hz, 1.5 Hz).

[Production Example 5]
Synthesis of (S) -4- (tert-butoxycarbonyl) -1- (4-fluoro-2-oxoisoquinoline-5-sulfonyl) -2-methylhomopiperazine:

(S) -4- (tert-Butoxycarbonyl) -1- (4-fluoroisoquinoline-5-sulfonyl) -2-methylhomopiperazine (10.71 g) was treated in the same manner as in Production Example 1 to give the title compound colorless. Obtained as amorphous crystals.
Yield: 11.47 g

[Production Example 6]
Synthesis of (S) -4- (tert-butoxycarbonyl) -1- (1-hydroxy-4-fluoroisoquinoline-5-sulfonyl) -2-methylhomopiperazine:

To a solution of tetraethylammonium chloride (3.54 g) and potassium acetate (3.57 g) in water (32 mL) was added (S) -4- (tert-butoxycarbonyl) -1- (4-fluoro-2-oxoisoquinoline-5- Sulfonyl) -2-methylhomopiperazine (3.29 g) was suspended, and a solution of benzoyl chloride (4.20 g) in toluene (48 mL) was added dropwise. The mixture was stirred at room temperature for 70 minutes, saturated sodium bicarbonate solution (40 mL) was added, and extracted with ethyl acetate (150 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; chloroform-acetone = 50: 1 → chloroform-acetone = 30: 1 → chloroform-methanol = 30: 1 → chloroform-methanol = 15: 1). Obtained as a yellow crystalline powder.
Yield: 2.58 g (81%)

[Production Example 7]
Of (S) -4- (tert-butoxycarbonyl) -1-[(1,2-dihydro-2-cyclopropylmethyl-4-fluoroisoquinolin-1-one) -5-sulfonyl] -2-methylhomopiperazine Synthesis:

Production example of (S) -4- (tert-butoxycarbonyl) -1- (1-hydroxy-4-fluoroisoquinoline-5-sulfonyl) -2-methylhomopiperazine (151 mg) and chloromethylcyclopropane (95 mg) The same treatment as in 4 gave the title compound as a colorless oil.
Yield: 120 mg (71%)

[Example 3]
Synthesis of (S) -1-[(1,2-dihydro-2-cyclopropylmethyl-4-fluoroisoquinolin-1-one) -5-sulfonyl] -2-methylhomopiperazine hydrochloride:

(S) -4- (tert-butoxycarbonyl) -1-[(1,2-dihydro-2-cyclopropylmethyl-4-fluoroisoquinolin-1-one) -5-sulfonyl] -2-methylhomopiperazine ( 120 mg) was treated in the same manner as in Example 1 to obtain the title compound as a white powder.
Yield: 80 mg (74%)
¹ H-NMR data (400 MHz, DMSO-d ₆ ) δ ppm: 0.40-0.55 (m, 4H), 1.17 (d, 3H, J = 6.6 Hz), 1.20-1.34 (M, 1H), 1.95-2.10 (m, 2H), 3.00-3.70 (m, 6H), 3.75-3.90 (2H, m), 4.30-4 .45 (m, 1H), 7.76 (t, 1H, J = 7.8 Hz), 8.04 (d, 1H, J = 9.0 Hz), 8.19 (dd, 1H, J = 7. 8 Hz, 1.2 Hz), 8.59 (d, 1 H, J = 9.3 Hz).

[Production Example 8]
Synthesis of (S) -4- (tert-butoxycarbonyl) -1- (4-fluoro-2-oxoisoquinoline-5-sulfonyl) -3-methylhomopiperazine:

(S) -4- (tert-Butoxycarbonyl) -1- (4-fluoroisoquinoline-5-sulfonyl) -3-methylhomopiperazine (1.49 g) was treated in the same manner as in Production Example 1, and the title compound was concentrated. Obtained as a pink powder.
Yield: 1.64g

[Production Example 9]
Synthesis of (S) -4- (tert-butoxycarbonyl) -1- (1-hydroxy-4-fluoroisoquinoline-5-sulfonyl) -3-methylhomopiperazine:

(S) -4- (tert-butoxycarbonyl) -1- (4-fluoro-2-oxoisoquinoline-5-sulfonyl) -3-methylhomopiperazine (1.63 g) was treated in the same manner as in Production Example 6, The title compound was obtained as a tan powder.
Yield: 658mg

[Production Example 10]
Of (S) -4- (tert-butoxycarbonyl) -1-[(1,2-dihydro-2-cyclopropylmethyl-4-fluoroisoquinolin-1-one) -5-sulfonyl] -3-methylhomopiperazine Synthesis:

Production example of (S) -4- (tert-butoxycarbonyl) -1- (1-hydroxy-4-fluoroisoquinoline-5-sulfonyl) -3-methylhomopiperazine (163 mg) and chloromethylcyclopropane (150 mg) The title compound was obtained as pale yellow amorphous crystals.
Yield: 135 mg (74%)

[Example 4]
Synthesis of (S) -1-[(1,2-dihydro-2-cyclopropylmethyl-4-fluoroisoquinolin-1-one) -5-sulfonyl] -3-methylhomopiperazine hydrochloride:

(S) -4- (tert-butoxycarbonyl) -1-[(1,2-dihydro-2-cyclopropylmethyl-4-fluoroisoquinolin-1-one) -5-sulfonyl] -3-methylhomopiperazine ( 135 mg) was treated in the same manner as in Example 1 to obtain the title compound as a yellow powder.
Yield: 86 mg (73%)
¹ H-NMR data (400 MHz, DMSO-d ₆ ) δ ppm: 0.35-0.60 (m, 4H), 1.27 (d, 3H, J = 6.6 Hz), 2.16 (m, 2H) ), 3.05-3.20 (m, 1H), 3.20-3.90 (m, 9H), 7.74 (t, 1H, J = 7.8 Hz), 8.04 (d, 1H) , J = 8.8 Hz), 8.12 (d, 1H, J = 7.3 Hz), 8.59 (d, 1H, J = 8.5 Hz).

[Production Example 11]
Synthesis of 4- (tert-butoxycarbonyl) -1- (2-oxoisoquinoline-5-sulfonyl) homopiperazine:

4- (tert-Butoxycarbonyl) -1- (isoquinoline-5-sulfonyl) homopiperazine (552 mg) was treated in the same manner as in Production Example 1 to give the title compound as a pale yellow oil.
Yield: 750 mg

[Production Example 12]
Synthesis of 4- (tert-butoxycarbonyl) -1- (1-hydroxyisoquinoline-5-sulfonyl) homopiperazine:

4- (tert-Butoxycarbonyl) -1- (2-oxoisoquinoline-5-sulfonyl) homopiperazine (750 mg) was treated in the same manner as in Production Example 6 to obtain the title compound as colorless prism crystals.
Yield: 390 mg (63%, 2 steps)

[Production Example 13]
Synthesis of 4- (tert-butoxycarbonyl) -1-[(1,2-dihydro-2-benzylisoquinolin-1-one) -5-sulfonyl] homopiperazine:

4- (tert-Butoxycarbonyl) -1- (1-hydroxyisoquinoline-5-sulfonyl) homopiperazine (126 mg) and potassium carbonate (85 mg) were suspended in acetonitrile (2 mL), and benzyl bromide (63 mg) was added. . The mixture was stirred in a 90 ° C. oil bath for 10 hours, chloroform (2 mL) was added to the reaction mixture, and the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; hexane-ethyl acetate = 2: 1) to obtain the title compound as a colorless oil.
Yield: 111 mg (72%)

[Example 5]
Synthesis of 1-[(1,2-dihydro-2-benzylisoquinolin-1-one) -5-sulfonyl] homopiperazine hydrochloride:

4- (tert-Butoxycarbonyl) -1-[(1,2-dihydro-2-benzylisoquinolin-1-one) -5-sulfonyl] homopiperazine (109 mg) was treated in the same manner as in Example 1 to give the title compound. Was obtained as a white powder.
Yield: 69 mg (73%)
¹ H-NMR data (400 MHz, MeOH-d ₄ ) δ ppm: 2.08-2.18 (m, 2H), 3.32-3.38 (m, 4H), 3.52 (t, 2H, J = 6.2 Hz), 3.68 (t, 2H, J = 5.2 Hz), 5.26 (s, 2H), 7.25-7.39 (m, 6H), 7.61 (d, 1H) , J = 7.8 Hz), 7.67 (t, 1H, J = 7.8 Hz), 8.28 (d, 1H, J = 7.8 Hz), 8.64 (d, 1H, J = 7. 8 Hz).

[Production Example 14]
Synthesis of 4- (tert-butoxycarbonyl) -1-[[1,2-dihydro-2- (4-fluorobenzyl) isoquinolin-1-one] -5-sulfonyl] homopiperazine:

4- (tert-Butoxycarbonyl) -1- (1-hydroxyisoquinoline-5-sulfonyl) homopiperazine (130 mg) and 4-fluorobenzyl chloride (55 mg) were treated in the same manner as in Production Example 13 to give the title compound in colorless form. Obtained as an oil.
Yield: 64 mg (39%)

[Example 6]
Synthesis of 1-[[1,2-dihydro-2- (4-fluorobenzyl) isoquinolin-1-one] -5-sulfonyl] homopiperazine hydrochloride:

4- (tert-Butoxycarbonyl) -1-[[1,2-dihydro-2- (4-fluorobenzyl) isoquinolin-1-one] -5-sulfonyl] homopiperazine (62 mg) was treated as in Example 1. Treatment gave the title compound as a white powder.
Yield: 40 mg (74%)
¹ H-NMR data (400 MHz, MeOH-d ₄ ) δ ppm: 2.08-2.18 (m, 2H), 3.32-3.38 (m, 4H), 3.52 (t, 2H, J = 6.1 Hz), 3.68 (t, 2H, J = 5.2 Hz), 5.23 (s, 2H), 7.07 (t, 2H, J = 8.8 Hz), 7.37 (d , 1H, J = 7.8 Hz), 7.38-7.45 (m, 2H), 7.63 (d, 1H, J = 7.8 Hz), 7.67 (t, 1H, J = 7. 8 Hz), 8.28 (dd, 1 H, J = 7.8 Hz, 1.4 Hz), 8.64 (d, 1 H, J = 8.0 Hz).

[Production Example 15]
Synthesis of 4- (tert-butoxycarbonyl) -1-[[1,2-dihydro-2- (4-chlorobenzyl) isoquinolin-1-one] -5-sulfonyl] homopiperazine:

4- (tert-Butoxycarbonyl) -1- (1-hydroxyisoquinoline-5-sulfonyl) homopiperazine (130 mg) and 4-chlorobenzyl bromide (79 mg) were treated in the same manner as in Production Example 13 to give the title compound colorless. Obtained as an oil.
Yield: 68 mg (40%)

[Example 7]
Synthesis of 1-[[1,2-dihydro-2- (4-chlorobenzyl) isoquinolin-1-one] -5-sulfonyl] homopiperazine hydrochloride:

4- (tert-Butoxycarbonyl) -1-[[1,2-dihydro-2- (4-chlorobenzyl) isoquinolin-1-one] -5-sulfonyl] homopiperazine (66 mg) was treated as in Example 1. Treatment gave the title compound as a white powder.
Yield: 46 mg (70%)
¹ H-NMR data (400 MHz, MeOH-d ₄ ) δ ppm: 2.08-2.18 (m, 2H), 3.32-3.38 (m, 4H), 3.52 (t, 2H, J = 6.2 Hz), 3.68 (t, 2H, J = 5.2 Hz), 5.24 (s, 2H), 7.32-7.40 (m, 5H), 7.62 (d, 1H) , J = 7.8 Hz), 7.67 (t, 1H, J = 7.8 Hz), 8.28 (dd, 1H, J = 7.8 Hz, 1.4 Hz), 8.64 (d, 1H, J = 8.1 Hz).

[Production Example 16]
Synthesis of 4- (tert-butoxycarbonyl) -1-[(1,2-dihydro-2-benzyl-4-methylisoquinolin-1-one) -5-sulfonyl] homopiperazine:

4- (tert-Butoxycarbonyl) -1- (1-hydroxy-4-methylisoquinoline-5-sulfonyl) homopiperazine (215 mg) and benzyl chloride (70 mg) were treated in the same manner as in Preparation Example 13 to give the title compound. Obtained as colorless amorphous crystals.
Yield: 213 mg

[Example 8]
Synthesis of 1-[(1,2-dihydro-2-benzyl-4-methylisoquinolin-1-one) -5-sulfonyl] homopiperazine hydrochloride:

4- (tert-Butoxycarbonyl) -1-[(1,2-dihydro-2-benzyl-4-methylisoquinolin-1-one) -5-sulfonyl] homopiperazine (213 mg) was treated as in Example 1. The title compound was obtained as colorless prism crystals.
Yield: 100 mg (50%)
¹ H-NMR data (400 MHz, D ₂ O) δ ppm: 1.99-2.19 (m, 2H), 2.25 (s, 3H), 3.20-3.42 (m, 6H), 3 .55-3.65 (m, 2H), 4.19 (s, 2H), 7.05-7.17 (m, 6H), 7.30 (t, 1H, J = 7.8 Hz), 7 .51 (dd, 1H, J = 7.7 Hz, 1.2 Hz), 8.29 (dd, 1H, J = 8.1 Hz, 1.2 Hz).

[Production Example 17]
Synthesis of 4- (tert-butoxycarbonyl) -1- (4-methyl-2-oxoisoquinoline-5-sulfonyl) -5-methylhomopiperazine:

4- (tert-Butoxycarbonyl) -1- (4-methylisoquinoline-5-sulfonyl) -5-methylhomopiperazine (122 mg) was treated in the same manner as in Production Example 1 to give the title compound as a pale yellow oil. .
Yield: 129 mg

[Production Example 18]
Synthesis of 4- (tert-butoxycarbonyl) -1- (1-hydroxy-4-methylisoquinoline-5-sulfonyl) -5-methylhomopiperazine:

4- (tert-Butoxycarbonyl) -1- (4-methyl-2-oxoisoquinoline-5-sulfonyl) -5-methylhomopiperazine (129 mg) was treated in the same manner as in Production Example 6 to give the title compound as a pale yellow dye. Obtained as a regular crystal.
Yield: 72 mg (56%)

[Production Example 19]
Synthesis of 4- (tert-butoxycarbonyl) -1-[(1,2-dihydro-2-benzyl-4-methylisoquinolin-1-one) -5-sulfonyl] -5-methylhomopiperazine:

4- (tert-Butoxycarbonyl) -1- (1-hydroxy-4-methylisoquinoline-5-sulfonyl) -5-methylhomopiperazine (72 mg) and benzyl bromide (24 μL) were treated in the same manner as in Production Example 13. The title compound was obtained as a pale yellow oil.
Yield: 58 mg (67%)

[Example 9]
Synthesis of 1-[(1,2-dihydro-2-benzyl-4-methylisoquinolin-1-one) -5-sulfonyl] -5-methylhomopiperazine hydrochloride:

Example 1 4- (tert-butoxycarbonyl) -1-[(1,2-dihydro-2-benzyl-4-methylisoquinolin-1-one) -5-sulfonyl] -5-methylhomopiperazine (58 mg) The title compound was obtained as a white powder.
Yield: 43 mg (84%)
M / Z: 425 [M ⁺ ]

[Production Example 20]
Synthesis of (S) -4- (tert-butoxycarbonyl) -1-[(1,2-dihydro-2-benzyl-4-fluoroisoquinolin-1-one) -5-sulfonyl] -2-methylhomopiperazine:

(S) -4- (tert-butoxycarbonyl) -1- (1-hydroxy-4-fluoroisoquinoline-5-sulfonyl) -2-methylhomopiperazine (2.58 g) and benzyl bromide (3.02 g) The product was treated in the same manner as in Production Example 4 to obtain the title compound as a pale yellow oil.
Yield: 1.85 g (50%)

[Example 10]
Synthesis of (S) -1-[(1,2-dihydro-2-benzyl-4-fluoroisoquinolin-1-one) -5-sulfonyl] -2-methylhomopiperazine hydrochloride:

(S) -4- (tert-butoxycarbonyl) -1-[(1,2-dihydro-2-benzyl-4-fluoroisoquinolin-1-one) -5-sulfonyl] -2-methylhomopiperazine (4. 16g) was treated in the same manner as in Example 1 to give the title compound as a pale yellow powder.
Yield: 3.05 g (83%)
¹ H-NMR data (400 MHz, DMSO-d ₆ ) δ ppm: 1.17 (d, 3H, J = 6.6 Hz), 2.00 (br, 2H), 3.00-3.70 (m, 6H) ), 4.37 (br, 1H), 5.18 (s, 2H), 7.28-7.37 (m, 5H), 7.77 (t, 1H, J = 8.1 Hz), 8. 12 (d, 1H, J = 9.0 Hz), 8.18 (dd, 1H, J = 7.8 Hz, 1.2 Hz), 8.59 (dd, 1H, J = 8.3 Hz, 1.0 Hz) .

[Production Example 21]
(S) -4- (tert-Butoxycarbonyl) -1-[[1,2-dihydro-2- (4-fluorobenzyl) -4-fluoroisoquinolin-1-one] -5-sulfonyl] -2-methyl Synthesis of homopiperazine:

(S) -4- (tert-Butoxycarbonyl) -1- (1-hydroxy-4-fluoroisoquinoline-5-sulfonyl) -2-methylhomopiperazine (365 mg) and 4-fluorobenzyl chloride (360 mg) were produced. The same treatment as in Example 4 gave the title compound as a pale yellow oil.
Yield: 378 mg (83%)

[Example 11]
Synthesis of (S) -1-[[1,2-dihydro-2- (4-fluorobenzyl) -4-fluoroisoquinolin-1-one] -5-sulfonyl] -2-methylhomopiperazine hydrochloride:

(S) -4- (tert-Butoxycarbonyl) -1-[[1,2-dihydro-2- (4-fluorobenzyl) -4-fluoroisoquinolin-1-one] -5-sulfonyl] -2-methyl Homopiperazine (172 mg) was treated in the same manner as in Example 1 to obtain the title compound as a pale yellow powder.
Yield: 92 mg (61%)
¹ H-NMR data (400 MHz, DMSO-d ₆ ) δ ppm: 1.16 (d, 3H, J = 6.8 Hz), 2.00 (br, 2H), 3.08-3.61 (m, 6H) ), 4.36 (br, 1H), 5.16 (s, 2H), 7.18 (t, 2H, J = 8.8 Hz), 7.45 (dd, 2H, J = 8.8 Hz, 5) .6 Hz), 7.77 (t, 1 H, J = 8.1 Hz), 8.15 (d, 1 H, J = 8.8 Hz), 8.18 (d, 1 H, J = 6.8 Hz), 8 .58 (d, 1H, J = 9.0 Hz).

[Production Example 22]
(S) -4- (tert-Butoxycarbonyl) -1-[[1,2-dihydro-2- (4-chlorobenzyl) -4-fluoroisoquinolin-1-one] -5-sulfonyl] -2-methyl Synthesis of homopiperazine:

(S) -4- (tert-Butoxycarbonyl) -1- (1-hydroxy-4-fluoroisoquinoline-5-sulfonyl) -2-methylhomopiperazine (160 mg) and 4-chlorobenzyl bromide (230 mg) were produced. The product was treated in the same manner as in Example 4 to obtain the title compound as colorless amorphous crystals.
Yield: 165 mg (81%)

[Example 12]
Synthesis of (S) -1-[[1,2-dihydro-2- (4-chlorobenzyl) -4-fluoroisoquinolin-1-one] -5-sulfonyl] -2-methylhomopiperazine hydrochloride:

(S) -4- (tert-Butoxycarbonyl) -1-[[1,2-dihydro-2- (4-chlorobenzyl) -4-fluoroisoquinolin-1-one] -5-sulfonyl] -2-methyl Homopiperazine (155 mg) was treated in the same manner as in Example 1 to obtain the title compound as a pale yellow powder.
Yield: 130 mg (94%)
¹ H-NMR data (400 MHz, DMSO-d ₆ ) δ ppm: 1.17 (d, 3H, J = 6.8 Hz), 1.93-2.09 (m, 2H), 3.00-3.75 (M, 6H), 4.25-4.45 (m, 1H), 5.16 (s, 2H), 7.34-7.48 (m, 4H), 7.70 (t, 1H, J = 8.1 Hz), 8.14 (d, 1 H, J = 8.8 Hz), 8.18 (d, 1 H, J = 7.8 Hz), 8.58 (d, 1 H, J = 8.1 Hz) .

[Production Example 23]
(S) -4- (tert-Butoxycarbonyl) -1-[[1,2-dihydro-2- (4-isopropylbenzyl) -4-fluoroisoquinolin-1-one] -5-sulfonyl] -2-methyl Synthesis of homopiperazine:

(S) -4- (tert-Butoxycarbonyl) -1- (1-hydroxy-4-fluoroisoquinoline-5-sulfonyl) -2-methylhomopiperazine (150 mg) and 4-isopropylbenzyl chloride (172 mg) were produced. The product was treated in the same manner as in Example 4 to obtain the title compound as a light brown amorphous crystal.
Yield: 155 mg (80%)

[Example 13]
Synthesis of (S) -1-[[1,2-dihydro-2- (4-isopropylbenzyl) -4-fluoroisoquinolin-1-one] -5-sulfonyl] -2-methylhomopiperazine hydrochloride:

(S) -4- (tert-Butoxycarbonyl) -1-[[1,2-dihydro-2- (4-isopropylbenzyl) -4-fluoroisoquinolin-1-one] -5-sulfonyl] -2-methyl Homopiperazine was treated in the same manner as in Example 1 to obtain the title compound as a white powder.
Yield: 66 mg (77%)
¹ H-NMR data (400 MHz, DMSO-d ₆ ) δ ppm: 1.05-1.40 (m, 9H), 1.99 (br, 2H), 2.75-2.95 (m, 1H), 3.00-3.15 (m, 1H), 3.15-3.50 (m, 3H), 3.50-3.70 (m, 2H), 4.30-4.45 (m, 1H) ), 5.13 (s, 2H), 7.22 (d, 2H, J = 8.1 Hz), 7.30 (d, 2H, J = 8.3 Hz), 7.76 (t, 1H, J = 8.1 Hz), 8.10 (d, 1 H, J = 8.8 Hz), 8.17 (d, 1 H, J = 7.8 Hz), 8.58 (d, 1 H, J = 8.1 Hz) .

[Production Example 24]
(S) -4- (tert-Butoxycarbonyl) -1-[[1,2-dihydro-2- (2-trifluoromethylbenzyl) -4-fluoroisoquinolin-1-one] -5-sulfonyl] -2 -Synthesis of methyl homopiperazine:

(S) -4- (tert-butoxycarbonyl) -1- (1-hydroxy-4-fluoroisoquinoline-5-sulfonyl) -2-homopiperazine (150 mg) and 2- (trifluoromethyl) benzyl chloride (200 mg) Were treated in the same manner as in Production Example 4 to obtain the title compound as colorless amorphous crystals.
Yield: 188 mg (92%)

[Example 14]
Synthesis of (S) -1-[[1,2-dihydro-2- (2-trifluoromethylbenzyl) -4-fluoroisoquinolin-1-one] -5-sulfonyl] -2-methylhomopiperazine hydrochloride:

(S) -4- (tert-Butoxycarbonyl) -1-[[1,2-dihydro-2- (2-trifluoromethylbenzyl) -4-fluoroisoquinolin-1-one] -5-sulfonyl] -2 -Methyl homopiperazine (188 mg) was treated in the same manner as in Example 1 to obtain the title compound as a white powder.
Yield: 177 mg (70%)
¹ H-NMR data (400 MHz, DMSO-d ₆ ) δ ppm: 1.20 (d, 3H, J = 6.59 Hz), 2.02 (br, 2H), 3.00-3.80 (m, 6H) ), 4.39 (br, 1H), 5.39 (s, 2H), 7.04 (d, 1H, J = 8.1 Hz), 7.50-7.63 (m, 2H), 7. 77-7.83 (m, 2H), 8.08 (d, 1H, J = 8.8 Hz), 8.22 (d, 1H, J = 7.6 Hz), 8.57 (d, 1H, J = 8.1 Hz).

[Production Example 25]
(S) -4- (tert-Butoxycarbonyl) -1-[[1,2-dihydro-2- (3-picolyl) -4-fluoroisoquinolin-1-one] -5-sulfonyl] -2-methylhomo Synthesis of piperazine:

(S) -4- (tert-butoxycarbonyl) -1- (1-hydroxy-4-fluoroisoquinoline-5-sulfonyl) -2-methylhomopiperazine (140 mg) and 3-picolyl chloride hydrochloride (160 mg) To give the title compound as a light brown oil.
Yield: 52 mg (31%)

[Example 15]
Synthesis of (S) -1-[[1,2-dihydro-2- (3-picolyl) -4-fluoroisoquinolin-1-one] -5-sulfonyl] -2-methylhomopiperazine dihydrochloride:

(S) -4- (tert-Butoxycarbonyl) -1-[[1,2-dihydro-2- (3-picolyl) -4-fluoroisoquinolin-1-one] -5-sulfonyl] -2-methylhomo Piperazine (52 mg) was treated in the same manner as in Example 1 to obtain the title compound as a light brown powder.
Yield: 26 mg (53%)
¹ H-NMR data (400 MHz, DMSO-d ₆ ) δ ppm: 1.16 (d, 3H, J = 6.8 Hz), 2.00 (br, 2H), 3.00-3.18 (m, 2H) ), 3.18-3.35 (m, 2H), 3.35-3.50 (m, 1H), 3.50-3.62 (m, 2H), 5.29 (d, 2H, J = 2.4 Hz), 7.65 ^ 7.70 (m, 2H), 8.13-8.27 (m, 3H), 8.56 (d, 1H, J = 8.1 Hz), 8.71 (D, 1H, J = 4.1 Hz), 8.86 (s, 1H).

[Production Example 26]
Synthesis of (R) -4- (tert-butoxycarbonyl) -1- (4-fluoro-2-oxoisoquinoline-5-sulfonyl) -2-methylhomopiperazine:

(R) -4- (tert-butoxycarbonyl) -1- (4-fluoroisoquinoline-5-sulfonyl) -2-methylhomopiperazine (1.61 g) was treated in the same manner as in Production Example 1 to give the title compound colorless. Obtained as amorphous crystals.
Yield: 1.45 g (87%)

[Production Example 27]
Synthesis of (R) -4- (tert-butoxycarbonyl) -1- (1-hydroxy-4-fluoroisoquinoline-5-sulfonyl) -2-methylhomopiperazine:

(R) -4- (tert-Butoxycarbonyl) -1- (4-fluoro-2-oxoisoquinoline-5-sulfonyl) -2-methylhomopiperazine (157 mg) was treated in the same manner as in Production Example 6 to give the title compound. Was obtained as yellow amorphous crystals.
Yield: 1.57g

[Production Example 28]
Synthesis of (R) -4- (tert-butoxycarbonyl) -1-[(1,2-dihydro-2-benzyl-4-fluoroisoquinolin-1-one) -5-sulfonyl] -2-methylhomopiperazine:

(R) -4- (tert-butoxycarbonyl) -1- (1-hydroxy-4-fluoroisoquinoline-5-sulfonyl) -2-methylhomopiperazine (250 mg) and benzyl chloride (180 mg) were used in the same manner as in Production Example 4. To give the title compound as light brown amorphous crystals.
Yield: 122 mg (75%)

[Example 16]
Synthesis of (R) -1-[(1,2-dihydro-2-benzyl-4-fluoroisoquinolin-1-one) -5-sulfonyl] -2-methylhomopiperazine hydrochloride:

(R) -4- (tert-Butoxycarbonyl) -1-[(1,2-dihydro-2-benzyl-4-fluoroisoquinolin-1-one) -5-sulfonyl] -2-methylhomopiperazine (122 mg) Was treated in the same manner as in Example 1 to obtain the title compound as a white powder.
Yield: 86 mg (83%)
¹ H-NMR data (400 MHz, DMSO-d ₆ ) δ ppm: 1.16 (d, 3H, J = 6.8 Hz), 2.00 (br, 2H), 3.00-3.70 (m, 6H) ), 4.37 (br, 1H), 5.18 (s, 2H), 7.25-7.37 (m, 5H), 7.74-7.79 (m, 1H), 8.12 ( d, 1H, J = 9.0 Hz), 8.18 (dd, 1H, J = 7.8 Hz, 1.2 Hz), 8.59 (d, 1H, J = 8.1 Hz).

[Production Example 29]
Synthesis of (S) -4- (tert-butoxycarbonyl) -1-[(1,2-dihydro-2-benzyl-4-fluoroisoquinolin-1-one) -5-sulfonyl] -3-methylhomopiperazine:

(S) -4- (tert-Butoxycarbonyl) -1- (1-hydroxy-4-fluoroisoquinoline-5-sulfonyl) -3-methylhomopiperazine (200 mg) and benzyl bromide (280 mg) The reaction was conducted in the same manner to obtain the title compound as colorless amorphous crystals.
Yield: 181 mg (75%)

[Example 17]
Synthesis of (S) -1-[(1,2-dihydro-2-benzyl-4-fluoroisoquinolin-1-one) -5-sulfonyl] -3-methylhomopiperazine hydrochloride:

(S) -4- (tert-Butoxycarbonyl) -1-[(1,2-dihydro-2-benzyl-4-fluoroisoquinolin-1-one) -5-sulfonyl] -3-methylhomopiperazine (181 mg) Was treated in the same manner as in Example 1 to obtain the title compound as a pale yellow powder.
Yield: 129 mg (81%)
¹ H-NMR data (400 MHz, DMSO-d ₆ ) δ ppm: 1.26 (d, 3H, J = 6.6 Hz), 2.15 (br, 2H), 3.00-3.20 (m, 1H ), 3.20-3.80 (m, 6H), 5.18 (s, 2H), 7.29-7.37 (m, 5H), 7.75 (t, 1H, J = 8.1 Hz). ), 8.12 (d, 1H, J = 8.8 Hz), 8.58 (d, 1H, J = 8.1 Hz), 8.59 (d, 1H, J = 8.1 Hz).

[Production Example 30]
Synthesis of 4- (tert-butoxycarbonyl) -1- (4-chloro-2-oxoisoquinoline-5-sulfonyl) homopiperazine:

4- (tert-Butoxycarbonyl) -1- (4-chloroisoquinoline-5-sulfonyl) homopiperazine (783 mg) was treated in the same manner as in Production Example 1 to give the title compound as colorless amorphous crystals.
Yield 705mg

[Production Example 31]
Synthesis of 4- (tert-butoxycarbonyl) -1- (1-hydroxy-4-chloroisoquinoline-5-sulfonyl) homopiperazine:

4- (tert-Butoxycarbonyl) -1- (4-chloro-2-oxoisoquinoline-5-sulfonyl) homopiperazine (740 mg) was treated in the same manner as in Production Example 6 to give the title compound as a colorless oil.
Yield: 133 mg

[Production Example 32]
Synthesis of 4- (tert-butoxycarbonyl) -1-[(1,2-dihydro-2-benzyl-4-chloroisoquinolin-1-one) -5-sulfonyl] homopiperazine:

4- (tert-Butoxycarbonyl) -1- (1-hydroxy-4-chloroisoquinoline-5-sulfonyl) homopiperazine (133 mg) and benzyl bromide (180 mg) were reacted in the same manner as in Production Example 4 to give the title compound. Obtained as yellow amorphous crystals.
Yield: 105 mg (66%)

[Example 18]
Synthesis of 1-[(1,2-dihydro-2-benzyl-4-chloroisoquinolin-1-one) -5-sulfonyl] homopiperazine hydrochloride:

4- (tert-Butoxycarbonyl) -1-[(1,2-dihydro-2-benzyl-4-chloroisoquinolin-1-one) -5-sulfonyl] homopiperazine (100 mg) was treated as in Example 1. The title compound was obtained as a pale yellow powder.
Yield: 76 mg (86%)
¹ H-NMR data (400 MHz, DMSO-d ₆ ) δ ppm: 2.12 (br, 2H), 3.26-3.74 (m, 8H), 5.21 (s, 2H), 7.31- 7.37 (m, 5H), 7.74 (t, 1H, J = 8.1 Hz), 8.06 (d, 1H, J = 7.6 Hz), 8.14 (s, 1H), 8. 62 (d, 1H, J = 7.8 Hz).

[Production Example 33]
Synthesis of 4- (tert-butoxycarbonyl) -1- (4-bromo-2-oxoisoquinoline-5-sulfonyl) homopiperazine:

4- (tert-Butoxycarbonyl) -1- (4-bromoisoquinoline-5-sulfonyl) homopiperazine (769 mg) was treated in the same manner as in Production Example 1 to obtain the title compound as a yellow amorphous.
Yield: 938 mg (including m-chlorobenzoic acid)

[Production Example 34]
Synthesis of 4- (tert-butoxycarbonyl) -1- (1-hydroxy-4-bromoisoquinoline-5-sulfonyl) homopiperazine:

4- (tert-Butoxycarbonyl) -1- (4-bromo-2-oxoisoquinoline-5-sulfonyl) homopiperazine (200 mg) was treated in the same manner as in Production Example 6 to obtain the title compound as a white amorphous substance.
Yield: 106 mg (53%)

[Production Example 35]
Synthesis of 4- (tert-butoxycarbonyl) -1-[(1,2-dihydro-2-benzyl-4-bromoisoquinolin-1-one) -5-sulfonyl] homopiperazine:

4- (tert-Butoxycarbonyl) -1- (1hydroxy-4-bromoisoquinoline-5-sulfonyl) homopiperazine (47 mg) and benzyl bromide (50 mg) were reacted in the same manner as in Production Example 13 to give the title compound colorless. Obtained as an oil.
Yield: 63 mg (> q)

[Example 19]
Synthesis of 1-[(1,2-dihydro-2-benzyl-4-bromoisoquinolin-1-one) -5-sulfonyl] homopiperazine hydrochloride:

4- (tert-Butoxycarbonyl) -1-[(1,2-dihydro-2-benzyl-4-bromoisoquinolin-1-one) -5-sulfonyl] homopiperazine (63 mg) was treated as in Example 1. The title compound was obtained as a white powder.
Yield 35 mg (69%, 2 steps)
¹ H-NMR data (270 MHz, MeOH-d ₄ ) δ ppm: 2.13-2.24 (m, 2H), 3.35-3.43 (m, 4H), 3.61 (t, 2H, J = 6.3 Hz), 3.79 (t, 2H, J = 5.3 Hz), 5.23 (s, 2H), 7.25-7.39 (m, 5H), 7.71 (t, 1H) , J = 7.9 Hz), 7.96-8.00 (m, 2H), 8.68 (d, 1H, J = 7.9 Hz).

[Production Example 36]
Synthesis of 4- (tert-butoxycarbonyl) -1-[(1,2-dihydro-2-cinnamyl-4-methylisoquinolin-1-one) -5-sulfonyl] homopiperazine:

4- (tert-Butoxycarbonyl) -1- (1-hydroxy-4-methylisoquinoline-5-sulfonyl) homopiperazine (46 mg) and cinnamyl bromide (53 mg) were reacted in the same manner as in Production Example 4 to give the title compound. Was obtained as a light brown oil.
Yield 35 mg (60%)

[Example 20]
Synthesis of 1-[(1,2-dihydro-2-cinnamyl-4-methylisoquinolin-1-one) -5-sulfonyl] homopiperazine hydrochloride:

4- (tert-Butoxycarbonyl) -1-[(1,2-dihydro-2-cinnamyl-4-methylisoquinolin-1-one) -5-sulfonyl] homopiperazine (35 mg) was treated as in Example 1. The title compound was obtained as a white crystalline powder.
Yield: 22 mg (79%)
¹ H-NMR data (400 MHz, DMSO-d ₆ ) δ ppm: 2.06-2.20 (m, 2H), 2.62 (s, 3H), 3.20-3.30 (m, 4H), 3.55-3.65 (m, 2H), 3.73-3.83 (m, 2H), 4.75 (d, 2H, J = 5.9 Hz), 6.43 (dt, 1H, J = 15.9 Hz, 6.1 Hz), 6.62 (d, 1H, J = 16.1 Hz), 7.20-7.36 (m, 3H), 7.38-7.48 (m, 2H) 7.54 (s, 1H), 7.65 (t, 1H, J = 7.8 Hz), 7.98 (dd, 1H, J = 7.8 Hz, 1.2 Hz), 8.66 (dd, 1H, J = 8.1 Hz, 1.2 Hz).

[Production Example 37]
Synthesis of 4- (tert-butoxycarbonyl) -1-[[1,2-dihydro-2- (4-chlorocinnamyl) -4-methylisoquinolin-1-one] -5-sulfonyl] homopiperazine:

4- (tert-Butoxycarbonyl) -1- (1-hydroxy-4-methylisoquinoline-5-sulfonyl) homopiperazine (211 mg) and 4-chlorocinnamyl bromide (103 mg) were reacted in the same manner as in Production Example 3. The title compound was obtained as a pale yellow oil.
Yield: 155 mg (54%)

[Example 21]
Synthesis of 1-[[1,2-dihydro-2- (4-chlorocinnamyl) -4-methylisoquinolin-1-one] -5-sulfonyl] homopiperazine hydrochloride:

4- (tert-butoxycarbonyl) -1-[[1,2-dihydro-2- (4-chlorocinnamyl) -4-methylisoquinolin-1-one] -5-sulfonyl] homopiperazine (155 mg) was performed The same treatment as in Example 1 gave the title compound as a light brown crystalline powder.
Yield: 78 mg (57%)
¹ H-NMR data (400 MHz, DMSO-d ₆ ) δ ppm: 2.13-2.16 (m, 2H), 2.62 (s, 3H), 3.25-3.34 (m, 2H), 3.59-3.62 (m, 2H), 3.78-3.80 (m, 2H), 4.75 (d, 2H, J = 5.6 Hz), 6.46 (de, 1H, J = 15.9 Hz, 6.1 Hz), 7.37 (d, 2H, J = 8.5 Hz), 7.46-7.53 (m, 3H), 7.65 (t, 1H, J = 7. 8 Hz), 7.98 (dd, 1 H, J = 7.8 Hz, 1.4 Hz), 8.66 (d, 1 H, J = 6.8 Hz).

[Test Example 1]
(Effects on osteoclast differentiation induction)
Osteoclasts were prepared according to the method of Ikeda et al. (J. Clin. Invst. 114; 475-484 (2004)). That is, bone marrow cells obtained from femurs of both hind limbs from C57B1 / 6 mice were suspended in α-MEM medium (containing 10% FBS) and prepared to 4 × 10 ⁵ cells / mL. 0.5 mL of this cell suspension was seeded on a 48-well plate, and 5 μL of a 100-fold concentration of the compound was added to a final concentration of 0.1 and 1 μM. Furthermore, 5 μL of 100-fold concentration M-CSF (final concentration 10 ng / mL) and sRANKL (final concentration 50 ng / mL) prepared in the culture solution were added to the final concentration. Thereafter, the cells were cultured in a 37 ° C., 5% CO ₂ incubator, and the medium was changed on the third day of culture. At this time, a 100-fold compound, M-CSF (final concentration 10 ng / mL), sRANKL (final concentration 50 ng / mL) were newly added in the same manner as described above, and further cultured for 4 days, followed by TRAP staining (Sigma). Was done. Multinucleated cells (3 or more) stained red by TRAP staining were regarded as osteoclasts, and the number of osteoclasts in two fields was measured. The inhibition rate of each compound was determined with the inhibition rate of the drug-free group as 0% and the inhibition rate when the number of osteoclasts was 0 as 100%. The results are shown in Table 1. Table 1 shows that the compound group of the present invention strongly suppresses osteoclast differentiation induction.

Claims (5)

The following general formula (1)
[Wherein R ¹ and R ² each represent a hydrogen atom or an alkyl group, R ³ represents a hydrogen atom, an alkyl group or a halogen atom, and R ⁴ represents an alkyl group or an aromatic ring which may have a substituent. An arylalkyl group which may have a substituent above, a heteroarylalkyl group which may have a substituent on an aromatic ring, or an arylalkenyl group which may have a substituent on an aromatic ring is shown. ]
Or an acid addition salt or solvate thereof. In the general formula (1), R ¹ and R ² are each a hydrogen atom or a C ₁ -C ₆ linear or branched alkyl group; R ³ is a hydrogen atom, a C ₁ -C ₆ linear or branched alkyl group, or a halogen atom; R ⁴ is a linear or branched alkyl group of C ₃ -C good C ₁ -C ₆ have a cycloalkyl group ₈ as a substituent, the substituent as linear or branched chain alkyl group having a good C ₁ -C ₆ optionally substituted by a halogen atom on the aromatic ring, an alkoxy group of C ₁ -C _6, a nitro group, a halogen atom, or a hydroxy group A C ₆ -C ₁₀ aryl-C ₁ -C ₆ alkyl group or a C ₆ -C ₁₀ heteroaryl-C ₁ -C ₆ alkyl group, or a C ₁ -C ₆ alkyl group on the aromatic ring as a substituent, C ₁ -C ₆ alkoxy group, nitro group, halogen atom Compounds, acid addition salt or a solvate thereof according to claim 1, which is a good C ₆ -C ₁₀ aryl -C ₂ -C ₆ alkenyl group which may have a hydroxy group. In the general formula (1), R ¹ and R ² are each a hydrogen atom or a methyl group, R ³ is a hydrogen atom, a methyl group, or a halogen atom, and R ⁴ is an ethyl group, a cyclopropylmethyl group, a substituted group 2. An iso-propyl group, a trifluoromethyl group as a group, a benzyl group or a picolyl group which may have a halogen atom, or a cinnamyl group which may have a halogen atom on an aromatic ring as a substituent. The described compounds, their acid addition salts or their solvates.   The pharmaceutical which contains the compound represented by General formula (1) of any one of Claims 1-3, its acid addition salt, or those solvates as an active ingredient.   The medicament according to claim 4, which is a prophylactic and / or therapeutic drug for rheumatism, osteoporosis, Paget's disease, or bone cancer.