KR900005321B1 - Benzazepine derivatives - Google Patents

Abstract

Benzazepine derivs. of formula (I) and their pharmaceutically acceptable salts, useful as vasodilators, are prepd. In (I), R1 is H, alkyl, alkanoyl, alkenyl, arylcarbonyl, heteroarylcarobnyl or CONX1X2 (where X1, X2 are each H, alkyl, aryl or heteroary); R2 and R3 are each alkyl or cycloalkyl; or NR2R3= pyrrolidinyl, piperidinyl or morpholinyl; R4 and R5 are each H, halogen, alkyl, alkoxy, aryloxy, arylalkoxy, arylalkyl, hydroxy, alkanoyloxy, OCONX1X2, difluoromethoxy, trifluoromethyl, etc.; n= 2 or 3.

Description

Benzazine derivatives

The present invention relates to novel compounds represented by the following general formula (I) and pharmaceutically acceptable salts thereof.

These new compounds have useful vasodilating action.

기(여기에서, X₁및 X₂는 각각 독립적으로 수소, 알킬, 아릴 또는 헤테로아릴기이거나, 또는 X₁과 X₂는 이에 결합된 질소 원자와 함께 질소 함유 헤테로아릴기를 형성함)이고, R₂및 R₃은 각각 독립적으로 알킬 또는 시클로알킬기이거나, 또는 R₂와 R₃은 이에 결합된 질소 원자와 함께 피롤리다닐, 피페리디닐 또는 모르폴리닐기를 형성하고, R₄및 R₅는 각각 독립적으로 수소, 할로겐, 알킬, 알콕시, 아릴옥시, 아릴알콕시, 아릴알킬, 히드록시, 알카로일옥시,

(여기에서, X₁및 X₂는 상기 정의한 바와 같음), 디플루오로메톡시, 트리플루오로메틸, -NX₃X₄[여기에서, X₃및 X₄는 각각 독립적으로 알킬, 알카노일, 아릴카르보닐, 헤테로아릴카르보닐 또는 카르바모일()기임], S(O)_m알킬 또는 -S(O)_m아릴기(여기에서, m은 0,1 또는 2임)이고, n은 2 또는 3이되, 단 R₄가 7-알킬기인 경우에는, 고리에 결합된 삼급 탄소 원자를 가져야 한다.In the general formula (I) and the present specification, each symbol is defined as follows. R ₁ is hydrogen, alkyl, alkanoyl, alkenyl, arylcarbonyl, heteroarylcarbonyl or

A group wherein X ₁ and X ₂ are each independently hydrogen, alkyl, aryl or heteroaryl groups, or X ₁ and X ₂ together with the nitrogen atom bonded thereto form a nitrogen containing heteroaryl group; ₂ and R ₃ are each independently an alkyl or cycloalkyl group, or R ₂ and R ₃ together with the nitrogen atom bonded thereto form a pyrrolidanyl, piperidinyl or morpholinyl group, and R ₄ and R ₅ are each Independently hydrogen, halogen, alkyl, alkoxy, aryloxy, arylalkoxy, arylalkyl, hydroxy, alkaroyloxy,

Wherein X ₁ and X ₂ are as defined above, difluoromethoxy, trifluoromethyl, —NX ₃ X ₄ wherein X ₃ and X ₄ are each independently alkyl, alkanoyl, aryl Carbonyl, heteroarylcarbonyl or carbamoyl ( ), S (O) _m alkyl or -S (O) _m aryl group, where m is 0, 1 or 2, n is 2 or 3, provided that R ₄ is a 7-alkyl group Must have a tertiary carbon atom bonded to the ring.

Definitions of various terms used to describe benzazine according to the present invention are as follows. These definitions apply to this term when used individually or as part of a larger group throughout this specification, unless specifically defined otherwise.

The terms " alkyl " and " alkoxy " mean both straight and branched groups, suitable groups having 1 to 10 carbon atoms.

The term "alkenyl" refers to both straight and branched groups, with groups of 2 to 10 carbon atoms being suitable.

The term "aryl" refers to phenyl and substituted phenyl groups. Examples of substituted phenyl groups include 1,2 or 3 amino (-NH ₂ ), alkylamino, dialkylamino, nitro, halogen, hydroxyl, trifluoromethyl, alkyl (1-4 carbon atoms), alkoxy ( Phenyl groups substituted with 1 to 4 carbon atoms), alkanoyloxy, carbamoyl or carboxyl groups.

을 갖는 기를 의미하며, 탄소 원자수가 2 내지 11개인 알카노일기가 적합하다.The term "alkanoyl" refers to a structural alkyl

Group having 2 to 11 carbon atoms is suitable.

The term "heteroaryl" refers to an aromatic heterocyclic group having at least one heteroatom in the ring. Suitable groups are pyridinyl, pyrrolyl, imidazolyl, furyl, thienyl or thiazolyl groups.

The term "nitrogen-containing heteroaryl" means an aromatic heterocyclic group having at least one nitrogen atom in the ring. Suitable groups are pyridinyl, pyrrolyl, imidazolyl and thiazolyl groups.

The term "cycloalkyl" means a group having 3,4,5,6 or 7 carbon atoms.

The term "halogen" means fluorine, chlorine, bromine and iodine.

The compound of general formula (I) forms an acid addition salt with an inorganic acid and an organic acid. These acid addition salts often provide a useful means for isolating the product from the reaction mixture by forming salts which are insoluble in the medium. The free base can then be neutralized, for example, using a base such as sodium hydroxide. In addition, other salts may then be formed from the free base with the appropriate inorganic or organic acid. Examples include hydrogen halides (particularly hydrochlorides and bromates), sulfates, nitrates, phosphates, borates, acetates, tartarates, maleates, citrates, succinates, benzoates, ascorbates, salicylates, methanesulfonates, benzenes Sulfonate, toluenesulfone trichloride, and the like.

The carbon atoms at positions 3 and 4 in the benzazine nucleus of the general formula (I) compound are asymmetric carbons. Therefore, the compounds of formula (I) exist as enantiomeric forms, diastereomeric forms and racemic mixtures thereof. These are all within the scope of the present invention. Among the compounds of the general formula (I), the d-cis configuration is the strongest, so this form is most suitable.

Compounds of formula (I) and pharmaceutically acceptable salts thereof are useful as cardiovascular agents. These compounds act as vasodilators and are particularly useful as antihypertensives. By administering a composition containing any one (or mixture) of the compounds according to the invention, the blood pressure of a hypertensive mammalian (eg human) host is lowered. A daily dose of about 0.1 to 100 mg / kg body weight, suitably about 1 to about 50 mg / kg body weight, is suitable for lowering blood pressure, which may be administered in a single dose or in divided doses. Can be. The substance is suitable for oral administration, but parenteral routes such as subcutaneous injection, intramuscular injection or intravenous injection can also be used.

As a result of vasodilating action of the compound of general formula (I) according to the present invention, the compound may be useful as an antiarrhythmic, antiangina, antifibrillating agent, and asthma in addition to antihypertensive agents, and may also be useful during myocardial infarction. .

The compounds according to the invention can also be formulated in combination with diuretics or beta-adrenergics or vasodilator converting enzyme inhibitors. Suitable diuretics include thiazide diuretics such as hydrochlorothiazide and bendloflomethiazide, suitable beta-adrenergic agents include nadolol, and suitable vasodilator converting enzyme inhibitors include captopril.

The compound of general formula (I) is initially a general formula

2-nitrotoluene of General Formula

Wherein Y is an alkyl group

It can be prepared by reacting with benzylidene malonate. This reaction can be carried out in a polar aprotic solvent (e.g., dimethylformamide) in the presence of a strong base such as sodium hydride, resulting in the product of the following general formula (IV).

The compound of the following general formula (IV) is obtained by reducing the compound of the general formula (IV).

This reduction reaction can be carried out by a catalytic hydrogenation reaction (e.g., charcoal based palladium as a catalyst) or by using a chemical reducing agent (e.g. ferrous sulfate or metal tin).

The amine of formula (V) is treated with an alkyl metal alkoxide (e.g. sodium methoxide) and an alcohol (e.g. methanol) to obtain the corresponding benzazine of formula (VI).

The compound of formula IV is reacted with a strong base (e.g., lithium diisopropylamide or potassium hexamethyldisilazide) in an ethereal solvent such as tetrahydrofuran at low temperature in the presence of anhydrous oxygen to correspond The compound of formula (iii) is obtained.

Alternatively, the compound of formula (VIII) initially cools the compound of formula (VI) to a significantly lower temperature (eg, about -78 ° C) in a solvent such as tetrahydrofuran, and then It may also be prepared by treatment with a base such as lithium diisopropylamide or potassium hexamethyldisilazide. Treatment of this compound with anhydrous oxygen gas in the presence of triethyl phosphite affords the desired compound of the general formula.

Carboxylation of the compound of formula (VII) can be carried out by treating the compound with an excess of lithium iodide in hot pyridine, whereby a mixture of isomers of formulas (VIIa) and (VIIb) is obtained.

And

In general, the major isomers produced during the reaction are suitable cis isomers. Isomers can be separated using techniques known in the art such as crystallization or chromatography. As another method, the reaction as described below can be carried out using a diastereomeric mixture (a mixture of the above general formulas (VIIa) and (VIIb) compounds). Isomer mixtures can be separated into their component isomers at any stage of the reaction.

After treating the compound of formula (VIIa) or (VIIb) with an alkali metal hydride (e.g. sodium hydride) in an inert solvent such as dimethyl formamide or dimethyl sulfoxide,

When reacted with a compound of the corresponding general formula

Or a corresponding trans isomer, i.e., the product of formula (X) wherein R < 1 >

The compound of formula (X) (or the corresponding trans isomer) may be acylated or alkylated using conventional techniques to obtain the product of formula (I) wherein R ₁ is a group other than hydrogen. For example, a compound of formula (X) (or the corresponding trans isomer) may be formulated in the presence of a base

Can be reacted with a halide. As another method, acylation can be performed using acid anhydride.

Suitable ones of each substituent of the benzazine of the general formula (I) are as follows. That is, R ₁ is an acetyl group, n is 2, R ₂ and R ₃ are each methyl group, R ₄ is hydrogen or halogen (particularly 7-chloro is suitable), and R ₅ is 4-methoxy group.

Hereinafter, the present invention will be described in more detail with reference to Examples.

Example 1

(Cis) -3- (acetyloxy) -7-chloro-1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -2H- 1-benzazin-2-one, monohydrochloride

[Method I]

A) [2- (5-chloro-2-nitrophenyl) -1- (4-methoxyphenyl) ethyl] propanedioic acid, dimethyl ester

5-chloro-2-nitro dissolved in 30 ml of dimethylformamide in a stirred mixture of 40 g (0.16 mol) of dimethyl p-methoxybenzylidene malonate and 9.6 g (0.24 mol) of 60% sodium hydride in 350 ml of dry dimethylformamide. A solution of 30 g (0.176 mol) of toluene was added dropwise over 2 hours. The reaction mixture was stirred at rt for 6 h and then quenched with 15.4 ml (0.26 mole) glacial acetic acid. After the solvent was removed in vacuo, the residue was treated with water. The yellow solid was filtered and treated with methanol to give 50.3 g of a white solid. Melting Point 128.5 ° -130.5 ℃

B) [2- (2-amino-5-chlorophenyl) -1- (4-methoxyphenyl) ethyl] propanedioic acid, dimethyl ester

Methanol: hydrated with [2- (5-chloro-2-nitrophenyl) -1- (4-methoxyphenyl) ethyl] propanedioic acid, 40 g (95.0 mmol) in 1.2 l of a water (1:10) solution 142.5 ml of ammonium hydroxide supported on a reflux mixture of 184.5 g (0.663 mol) of ferrous sulfate was added over 30 minutes. The reaction mixture was stirred at reflux for 20 minutes and then cooled to room temperature. Ethyl acetate and Celite were added thereto, and then the mixture was filtered through Clide. The filtrate was partitioned between ethyl acetate and water. The organic phase was dried using magnesium sulfate and concentrated in vacuo. The product was recrystallized with isopropyl alcohol to give 28.22 g of the title compound. Melting point 114 ° -116 ° C.

C) 7-chloro-1,3,4,5-tetrahydro-3- (methoxycarbonyl) -4- (4-methoxyphenyl) -2H-1-benzazin-2-one

25 dissolved in methanol in a solution of [2- (2-amino-5-chlorophenyl) -1- (4-methoxyphenyl) ethyl] propanedioic acid and 23.2 g (59.2 mmol) dissolved in 200 ml of methanol 16 ml (69.97 mmol) of% sodium methoxide solution were added. This solution was refluxed for 3 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, the mixture was treated with 200 ml of 1N hydrochloric acid. The white precipitate was filtered off, and the precipitate was washed with water and methanol and then dried in vacuo to give 19.5 g of the title compound. Melting point 189-190.5 ° C.

D) 7-chloro-1,3,4,5-tetrahydro-3-hydroxy- (methoxycarbonyl) -4- (4-methoxyferrin) -2H-1-benzazin-2-one

7-chloro-1,3,4,5-tetrahydro-3- (methoxycarbonyl) -4- (4-methoxyphenyl) -2H-1-1 dissolved in 100 ml of dry tetrahydrofuran at 0 ° C. To a solution of 7.0 g (19.46 mmol) of benzazin-2-one, 87.64 ml (58.76 mmol) of a 0.67 M potassium hexamethyldisilazide solution in toluene were added dropwise over 15 minutes to form oxygen bubbles. The reaction mixture was continuously bubbled with oxygen at 0 ° C. for 1 hour. The reaction mixture was quenched by addition of 75 ml of 5% potassium bisulfate solution, and then thereto was added solid sodium sulfite and 10 ml of methanol. The reaction mixture was stirred for 30 minutes and extracted twice with ethyl acetate. The combined organic layers were washed with 1N saline and saturated sodium bicarbonate and dried using magnesium sulfate. After the solvent was removed in vacuo, the residue was recrystallized using isopropyl alcohol to give 4.5 g of the title compound.

E) (cis) -7-chloro-1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) 2H-1-benzazin-2-one

7-chloro-1,3,4,5-tetrahydro-3-hydroxy-3- (methoxycarbonyl) -4- (4-methoxyphenyl) -2H-1-benz dissolved in 20 ml of dry pyridine A solution of 0.5 g (1.33 mmol) of azepin-2-one and 0.178 g (1.33 mmol) of lithium iodide was refluxed under argon until the product was completely converted by TLC. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in chloroform, extracted twice with 1N hydrochloric acid and once with saturated sodium chloride, and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was treated with ether to give 0.22 g of cis product.

F) (cis) -7-chloro-3-hydroxy-1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -2H- 1-benzazin-2-one, monohydrochloride

(Cis) -7-chloro-1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -2H-1-benzazine dissolved in 26.12 ml of dry dimethylformamide To a solution of 2-one-0.83 g (2.612 mmol) was added 0.11 g (2.74 mmol) of 60% sodium hydride dispersion. The reaction mixture was stirred at room temperature under argon atmosphere for 1 hour, after which 2.30 ml (3.92 mmol) of 1.7 N dimethylamino ethyl chloride solution in toluene were added and stirred at 75 ° C. for 2 hours. After the solvent was removed in vacuo, the residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic phase was washed with 1N hydrochloric acid and dried using magnesium sulfate. The aqueous phase was adjusted to pH 11 by treatment with 6N sodium hydroxide. The product was extracted three times with ethyl acetate and dried using magnesium sulfate. The solvent was removed in vacuo. The residue was dissolved in 2 ml of ethyl acetate and 5 ml of ether, and then treated with 1.2 equivalents of 1.39 N hydrochloric acid in ether at 0 ° C. The solid was filtered off and washed with ether to give 0.65 g of the title compound.

G) (cis) -3- (acetyloxy) -7-chloro-1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl)- 2H-1-benzazin-2-one, monohydrochloride

(Cis) -7-chloro-3-hydroxy-1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-4- (4-methoxy dissolved in 25 ml of dry acetic anhydride A solution of phenyl) -2H-1-benzazin-2-one, 0.62 g (1.5 mmol) monohydrochloride was heated at 110 ° C. under argon atmosphere until it was determined that the reaction was terminated by TLC. After the solvent was removed in vacuo, the residue was dissolved in ethyl acetate and 2 ml of saturated hydrochloric acid in ether were added. The white precipitate was filtered off and dried (yield 0.5 g). This reaction was continued to further obtain 0.27 g of product. Each batch was combined. Melting point 207.5 ° -209 ° C.

Elemental Analysis for _{C 23 H 28 N 2 Cl 2} O 4 · 0.7 mole H ₂ O

Calculated (%): C; 57.55, H; 6.17, N; 5.84, Cl; 14.77

Found (%): C; 57.54, H; 5.86, N; 5.63, Cl; 14.92

[Method II]

Method II is the same as Method I above except for the following parts D and E.

D) 7-chloro-1,3,4,5-tetrahydro-3-hydroxy-3- (methoxycarbonyl) -4- (4-methoxyphenyl) 2H-1-benzazin-2- On

7-chloro-1,3,4,5-tetrahydro-3- (methoxycarbonyl) -4- (4-methoxyphenyl) -2H-1-benzazin-2 dissolved in 780 ml of tetrahydrofuran After cooling 15 g (41.7 mmol) of -on to −78 ° C., 147 ml (167 mmol in tetrahydrofuran) of potassium hexamethyldisilazide solution were added thereto. After stirring for 1 hour, 28.7 ml (166.7 mmol) triethyl phosphite was added thereto, and anhydrous oxygen gas was rapidly bubbled into the resulting solution. The reaction temperature was then raised to 0 ° C. and stirred for 1 hour more. The oxygenation reaction was then stopped and the reaction mixture was quenched by addition of 500 ml of acetic acid. After the reaction mixture was then concentrated, the residue was dissolved in ethyl acetate. The organic solution was washed successively with 1N hydrochloric acid, saturated sodium bicarbonate and brine, and then dried using anhydrous sodium sulfate. The dried organic liquid was concentrated to give a solid, which was treated in hexane to give 14.8 g of the title compound.

E) (cis) -7-chloro-1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -2H-1-benzazin-2-one

7-chloro-1,3,4,5-tetrahydro-3-hydroxy-3- (methoxycarbonyl) -4- (4-methoxyphenyl)-dissolved in 290 ml of pyridine containing 1% of water A solution of 16.4 g (43.7 mmol) of 2H-1-benzazin-2-one and 23.7 g (174.6 mmol) of lithium iodide under argon atmosphere until determined to be completely converted to the product by TLC (about 1.5 hours) It was refluxed. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and then extracted with 1N hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride. This solution was dried using magnesium sulfate and concentrated. The residue was recrystallized using ethyl acetate to give 6.8 g of pure cis product.

Example 2

(Cis) -3- (acetyloxy) -1- [2- (dimethylamino) ethyl] -1,3,4,5, -tetrahydro-4- (4-methoxyphenyl) -2H-1-benz Azepin-2-one, monohydrochloride

A) [1- (4-methoxyphenyl) -2- (2-nitrophenyl) ethyl] propanedioic acid, dimethyl ester

90 g (360 mmol) of dimethyl p-methoxybenzylidene malonate was dissolved in 700 ml of dry dimethylformamide under argon atmosphere, and then 21.6 g (540 mmol) of sodium hydride was added as a 60% dispersion in oil. The suspension was then treated with 33.9 ml (400 mmol) 2-nitrotoluene at room temperature, after which a catalytic amount of t-butanol was added. The reaction mixture was stirred for 16 h, then quenched by addition of 3 l of 1N hydrochloric acid and extracted four times with ether. The combined organic phases were dried using sodium sulfate and evaporated to afford 171 g of dark oil. This was chromatographed on 1.5 kg of 60-200 silica using 4: 1 hexane-ethyl acetate as eluent to further obtain 22 g of high purity product and 22 g of material which was determined to be slightly impurity as determined by TLC analysis.

D) [2- (2-aminophenyl) -1- (4-methoxyphenyl) ethyl] propanedioic acid, dimethyl ester

22 g of [1- (4-methoxyphenyl) -2- (2-nitrophenyl) ethyl] propanedioic acid and dimethyl ester were hydrogenated in 450 ml of 5: 1 methanol-acetic acid for 16 hours at atmospheric pressure, and then the crude product was As a result of recrystallization using isopropanol, 13 g of the desired product was obtained. The concentrated mother liquor was chromatographed on LPS-1-silica using 7: 3 hexane-ethyl acetate as eluent to give 2.24 g more product.

C) 1,3,4,5-tetrahydro-3- (methoxycarbonyl) -4- (4-methoxyphenyl) -2H-1-benzazin-2-one

[2- (2-aminophenyl) -1- (4-methoxyphenyl) ethyl] propanedioic acid, 11.97 g (33.5 mmol) dimethyl ester and 9.2 ml (40.2 mmol) 25% sodium methoxide dissolved in 80 ml of methanol The solution of was refluxed for 1.5 h and cooled to room temperature. Then, an excess of 1M hydrochloric acid solution was added thereto, and then the precipitated product was removed by filtration to obtain 9.18 g of pure material. Melting point 271 ° -219 ° C.

D) 1,3,4,5-tetrahydro-3- (methoxycarbonyl) -4- (4-methoxyphenyl) -2H-1-benzazin-2-one

13 g of 1,3,4,5-tetrahydro-3- (methoxycarbonyl) -4- (4-methoxyphenyl) -2H-1-benzazin-2-one dissolved in 130 ml of dry tetrahydrofuran (40.2 mmol) of cold (ice bath) solution was bubbled with dry oxygen gas for 30 minutes. Then 180 ml (0.67 M, 120.5 mmol) of potassium hexamethyldisilazide in toluene were added over 7 minutes under continuous oxygen airflow. After stirring for 2.5 hours, the oxygen flow was stopped and the reaction mixture was quenched by the addition of 200 ml of 5% potassium bisulfate. Subsequently, 15 g of solid sodium sulfite and then 100 ml of methanol were added thereto, and the mixture was further stirred for 30 minutes. The mixture was then extracted twice with ethyl acetate, and then the combined organic layers were washed three times with 1M hydrochloric acid, once with saturated bicarbonate solution and with brine, and then dried using sodium sulfate. It was concentrated to give 15 g of crude product, which was treated with ether-hexane to give 9.3 g of high purity product.

E) (cis) -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -2H-1-benzazin-2-one

1,3,4,5-tetrahydro-3-hydroxy-3- (methoxycarbonyl) -4- (4-methoxyphenyl) -2H-1-benzazin-2 dissolved in 150 ml of dry pyridine A solution of 5.26 g (14.6 mmol) of -one and 19.6 g (147 mmol) of anhydrous lithium iodide was refluxed for 1 hour. After concentration, the crude product was dissolved in ethyl acetate, washed with 6M hydrochloric acid and then saturated bicarbonate, and then dried using sodium sulfate. After concentration, it was treated with ether to give 2.81 g of substantially pure cis isomer. Melting point 173.5 ° -175.5 ° C. (decomposition).

F) (cis) -3-hydroxy-1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -2H-1-benzase Pin-2-one, monohydrochloride

(Cis) -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -2H-1-benzazin-2-one 1.0 dissolved in 35 ml of dry dimethylformamide A solution of g (3.53 mmol) was treated with 0.15 g (3.71 mmol) sodium hydride as a 60% dispersion in oil and then stirred for 1 hour. Then 3.1 ml (5.3 mmol) of a N, N-dimethyl-2-chloroethyl amine solution (1.7 M solution) in toluene were then added and the mixture was heated at 75 ° C. for 1.5 h. The reaction mixture was then concentrated on a vacuum pump, then the residue was partitioned between ethyl acetate and 1M hydrochloric acid. The organic phase was washed twice more with aqueous hydrochloric acid solution, then the combined aqueous phase was adjusted to pH 11 and extracted three times with ethyl acetate. The combined ethyl acetate layer was dried using sodium sulfate and concentrated to give 1.17 g of the target substance. The crude product was dissolved in a small amount of chloroform and acidified by addition of saturated ether / hydrogen chloride solution at 0 ° C. to yield 1.27 g of an off-white powder.

G) (cis) -3- (acetyloxy) -1- [2- (dimethylamino) -ethyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) 2H-1- Benzazin-2-one, monohydrochloride

(Cis) -3-hydroxy-1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -2H-1-benzazine- 1.27 g (2.83 mmol) of 2-one, monohydrochloride were slurried in 28 ml of acetic anhydride and heated at 100 ° C. under an argon atmosphere for 3 hours. After the resulting solution was concentrated, the residue was dissolved in ethyl acetate. After starting to crystallize, saturated hydrogen chloride ether was added thereto, and the mixture was filtered to obtain 1.25 g of the target substance as an off-white powder. Melting point 215 ° -216 ℃

C ₂₃ H ₂₉ ClN ₂ O ₄ Elemental analysis for 0.4 mol H ₂ O

Calculated (%): C; 62.76, H; 6.82, N; 6.36, Cl; 8.05

Found (%): C; 62.76, H; 6.65, N; 6.40, Cl; 7.97

Example 3

(Trans) -3- (acetyloxy) -1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -2H-1-benzase Pin-2-one, monohydrochloride

A) (trans) -3-hydroxy-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -2H-1-benzazin-2-one

Crude (cis) -3-hydroxy-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -2H-1-benzazin-2-one (see Example 2E) The mother liquor obtained by treatment with ether was subjected to flash chromatography (LPS-1 silica gel, 70:30 hexane-ethyl acetate) to give the title trans isomer. Melting Point 168 ° -170 °

B) (trans) -3-hydroxy-1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -2H-1-benzase Pin-2-on

(Trans) -3-hydroxy-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -2H-1-benzazin-2-one corresponding to 0.57 g (2.01 mmol) The use of the above Example 2F, instead of the cis isomer, gave 0.66 g of the title compound as an oil.

C) (trans) -3- (acetyloxy) -1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -2H-1- Benzazin-2-one, monohydrochloride, (trans) -3-hydroxy-1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-4- (4-methoxy The treatment of Example 2G above was carried out using 0.654 g (1.83 mmol) of phenyl) -2H-1-benzazin-2-one in place of the corresponding cis isomer, which was then treated with ethyl acetate, Recrystallization with methanol / isopropanol gave 0.5 g of the title compound as a white crystalline solid. This product melted at 254 ° -256.5 ° C.

Elemental analysis for C ₂₃ H ₂₉ ClN ₂ O ₄ · 0.2 mol H ₂ O

Calculated (%): C; 63.31, H; 6.79, N; 6.42, Cl; 8.12

Found (%): C; 63.31, H; 6.90, N; 6.29, Cl; 8.13

Example 4-8

The compound described in column II was obtained by subjecting Example 1 and Method II to the above-described compound instead of dimethyl D-methoxybenzylidene malonate.

Example 9-13

The compound described in column II was obtained by subjecting Example 1 and Method II to using the compound described in column I below instead of 5-chloro-2-nitrotoluene.

Example 15

(Cis) -3- (acetyloxy) -1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-7-hydroxy-4- (4-methoxyphenyl) -2H -1-Benzazin-2-one, monohydrochloride

(Cis) -3- (acetyloxy) -1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -7 dissolved in 30 ml of methanol A solution of 0.5 g (0.87 mmol) of-(phenylmethoxy) -2H-1-benzazin-2-one, monohydrochloride (see Example 13 above) was treated with 150 mg of charcoal based 10% palladium under an argon atmosphere. The mixture was shaken for 5 hours on a Parr hydrogenator at approximately 3.41 atmospheres (50 p.si). The catalyst was filtered under argon atmosphere, washed with methanol and the combined filtrates were evaporated. The residue (which started to solidify) was triturated under ether and subsequently evaporated. The solid was dried in vacuo for several hours to afford 0.40 g of the title compound. Melting point 229 ° -231 ° C. (decomposition, proceeded by gradual reaction).

C ₂₃ H ₂₈ N ₂ O _5. Elemental Analysis for HCl, 1.5MH ₂ O

Calculated (%): C; 58.04, H; 6.58, N; 5.89, Cl; 7.45

Found (%): C; 58.29, H; 6.33, N; 5.70, Cl; 7.63

Example 16

(Cis) -7-chloro-3-[(2-chloro-4-nitrobenzoyl) oxy] -1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-4- ( 4-methoxyphenyl) -2H-1-benzazin-2-one, methanesulfonate (1: 1)

(Cis) -7-chloro-3-hydroxy-1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -2H-1- Benzazin-2-one (see Example 1F above), a solution of 0.80 g (2.06 mmol) of 0.65 g (3.2 mmol) of 2-chloro-4-nitrobenzoic acid, 0.52 g (2.5 mmol) of dicyclohexyl carbodiimide And 0.04 g of 4-dimethylaminopyridine. A precipitate of dicyclohexyl urea was separated from this solution. The reaction mixture was left overnight at room temperature and then filtered. The filtrate was extracted using 10 ml of 10% potassium carbonate, 5% potassium carbonate (5 ml x 2), 5 ml of water and 5 ml of saturated sodium chloride solution. The organic phase was dried (magnesium sulfate), filtered and the solvent was evaporated to yield 1.3 g of a pale yellow solid. The mixture was purified by chromatography on 50 g of silica gel using 1: 1 dichloromethane-ethyl acetate as a solvent to obtain 1.0 g of cis ester containing a small amount of trans ester. The mixture was suspended in 5 ml of ether, cooled and filtered to give 0.9 g of a nearly colorless solid. It was suspended and stirred in 3 ml of isopropanol for 1 hour at room temperature, filtered and washed with isopropanol and ether to remove the small amount of trans ester still present to give 0.76 g of free base. Melting point 164 ° -166 ° C. This material was dissolved in 10 ml of warmed ethyl acetate and treated with a solution of 0.135 g of methanesulfonate dissolved in 5 ml of ethyl acetate to convert to methanesulfonate. The resulting solution was gradually diluted with ether to give a colorless crystalline product. After it was cooled overnight, the solid was filtered off, washed with ether and then dried. 0.84 g in weight, melting point 215 ° -217 ° C

Elemental Analysis for C ₂₈ H ₂₇ N ₃ Cl ₂ O ₆ · CH ₃ SO ₃ H

Calculated (%): C; 52.09, H; 4.67, N; 6.28, Cl; 10.61, S; 4.8

Found (%): C; 51.87, H; 4.62, N; 6.14, Cl; 10.59, S; 4.81

Example 17

(Cis) -7-chloro-1- [2- (dimethylamino) ethyl] -2,3,4,5-tetrahydro-4- (4-methoxyphenyl) -2-oxo-1H-1-benz Azepin-3-yl methylcarbamate, monohydrochloride

(Cis) -7-chloro-3-hydroxy-1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl suspended in 6 ml of dichloromethane ) -2H-1-benzazin-2-one (see Example 1F above) treated with 0.80 g (2.06 mmol) of a stirred suspension with 1.2 g (21 mmol) of methyl isocyanate, and the resulting solution It was left for hours. TLC analysis showed a small amount of starting material. The mixture was treated with 6 ml of acetonitrile and 1.2 g of methyl isocyanate and then left at room temperature for 20 hours. The solution was concentrated to give 1.1 g of solid, which was dissolved in 35 ml of ethyl acetate, extracted with water (5 ml × 2 times), dried using magnesium sulfate, filtered and the solvent was evaporated. 0.93 g of solid was obtained. This material was suspended in 5 ml of hexane and filtered to give 0.79 g of a solid. This material was suspended in 5 ml of ether, cooled and filtered to give 0.62 g of solid. This material was dissolved in 3 ml of ethanol, treated with 0.26 ml of 5.7 N ethanol hydrogen chloride, and then gradually diluted to about 50 ml ether to give 0.61 g of crystalline product. Melting point 238 ° -240 ° C. (decomposition).

C ₂₃ H ₂₈ N ₃ ClO ₄ . HCl. Elemental Analysis of H ₂ O

Calculated (%): C; 56.21, H; 6.15, N; 8.55, Cl; 14.43

Found (%): C; 56.42, H; 6.14, N; 8.58, Cl; 14.48

Secondary compounds included in the scope of the invention are as follows.

(Cis) -3- (acetyloxy) -7- (difluoromethoxy) -1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-4- (4-methoxy Phenyl) -2H-1-benzazin-2-one

(Cis) -3- (acetyloxy) -7- (methylthio) -1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -2H-1-benzazin-2-one

(Cis) -3- (acetyloxy) -1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-7- (methoxy) -4- (4-methoxyphenyl) -2H-1-benzazin-2-one, monohydrochloride, melting point 215 ° -217 ° C (decomposition, reacted at 205 ° C)

(Cis) -3- (acetyloxy) -7-[(2,2-dimethylpropionyloxy] -1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -2H-1-benzazin-2-one

(Cis) -3- (acetyloxy) -7-[[(dimethylamino) carbonyl] oxy] -1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -2H-1-benzazin-2-one

(Cis) -3- (acetyloxy) -7-chloro-1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-4- [4- (methylthio) phenyl]- 2H-1-benzazin-2-one

(Cis) -1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-3-methoxy-4- (4-methoxyphenyl) -2H-1-benzazine- 2-one, monohydrochloride, melting point 223 ° -224 ° C (decomposition)

(Cis) -3- (acetyloxy) -1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-7-[[(methylamino) carbonyl] oxy] -4- (4-methoxyphenyl) -2H-1-benzazin-2-one, monohydrochloride, melting point 216 ° -218 ° C (decomposition, reacted at 212 ° C)

(Cis) -3- (acetyloxy) -1- [2- (dimethylamino) ethyl] -7- (2,2-dimethyl-1-oxopropoxy) -1,3,4,5-tetrahydro- 4- (4-methoxyphenyl) -2H-1-benzazin-2-one, monohydrochloride, melting point 198 ° -200 ° C (decomposition, reacted at 160 ° C)

(Cis) -3- (acetyloxy) -1- [2- (dimethylamino) ethyl] -2,3,4,5-tetrahydro-4- (4-methoxyphenyl) -2-oxo-1H- 1-benzazin-7-ol, dimethylcarbamate ester, monohydrochloride, melting point 178 ° -181 ° C. (bubble 읾, reacted at 168 ° C.)

(Cis) -3- (acetyloxy) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -1- [2- (1-pyrrolidinyl) ethyl] -7- ( Trifluoromethyl) -2H-1-benzazin-2-one, monohydrochloride, melting point 228 ° -230 ° C (decomposition, reacted at 225 ° C)

(Cis) -3- (acetyloxy) -7-chloro-1- [3- (dimethylamino) propyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -2H- 1-benzazin-2-one, monohydrochloride, melting point 212 ° -215 ° C (decomposition, reacted at 200 ° C)

(Cis) -3- (acetyloxy) -7-chloro-1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -2H- 1-benzazin-2-one, monohydrochloride, melting point 252 ° -254 ° C. (decomposition).

(Cis) -3- (acetyloxy) -7-chloro-1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -2H- 1-benzazin-2-one, monohydrochloride, melting point 253 ° -255 ° C. (decomposition)

(Cis) -3- (acetyloxy) -1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-4- (4-methyloxyphenyl) -7- (trifluoro Methyl) -2H-1-benzazin-2-one, monohydrochloride, melting point 257 ° -259 ° C. (decomposition)

(Cis) -3- (acetyloxy) -1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-4- (4-methyloxyphenyl) -7- (trifluoro Methyl) -2H-1-benzazin-2-one, monohydrochloride, melting point 258 ° -260 ° C. (decomposition).

Claims (154)

The compound represented by the following general formula (I), or its pharmaceutically acceptable salt.

Wherein R ₁ is hydrogen, alkyl, alkanoyl, alkenyl, arylcarbonyl, heteroarylcarbonyl or

Groups, wherein X ₁ and X ₂ are each independently hydrogen, alkyl, aryl or heteroaryl groups, or X ₁ and X ₂ together with the nitrogen atom attached thereto form a nitrogen containing heteroaryl group, and R ₂ and R ₃ are each independently an alkyl or cycloalkyl group, or R ₂ and R ₃ together with the nitrogen atom bonded thereto form a pyrrolidinyl, piperidinyl or morpholinyl group, and R ₄ and R ₅ are each Independently hydrogen, halogen, alkyl, alkoxy, aryloxy, arylalkoxy, arylalkyl, hydroxy, alkanoyloxy,

Groups wherein X ₁ and X ₂ are as defined above, difluoromethoxy, trifluoromethyl, —NX ₃ X ₄ wherein X ₃ and X ₄ are each independently alkyl, alkanoyl, Arylcarbonyl, heteroarylcarbonyl or carbamoyl groups, -S (O) _m alkyl or -S (O) _m aryl groups, where m is 0, 1 or 2, n is 2 or 3, provided that when R ₄ is a 7-alkyl group, this R ₄ must have a tertiary carbon atom bonded to the ring. The compound of claim 1, wherein R ₁ is hydrogen. The compound of claim 1, wherein R ₁ is an alkyl group. The compound of claim 1, wherein R ₁ is an alkanoyl group. The compound of claim 1, wherein R ₁ is an acetyl group. The compound of claim 1, wherein R ₁ is akenyl, arylcarbonyl, heteroarylcarbonyl or

Attributable compound. The compound of any one of claims 1-6, wherein R ₂ and R ₃ are each an alkyl group. The compound of any one of claims 1-6, wherein R ₂ and R ₃ are each a methyl group. The compound of any one of claims 1-6, wherein R ₂ and R ₃ are each cycloalkyl groups. 7. A compound according to any one of claims 1 to 6, wherein R ₂ and R ₃ together with the nitrogen atom bonded thereto form a pyrrolidinyl, piperidinyl or morpholinyl group. The compound of any one of claims 1-6, wherein R ₄ is hydrogen. The compound of claim 1, wherein R ₄ is halogen. The compound of any one of claims 1-6, wherein R ₄ is chlorine, which R ₄ is located at the 7-position of the benzazine nucleus. The compound according to any one of claims 1 to 6, wherein R ₅ is an alkoxy group. The compound according to any one of claims 1 to 6, wherein R ₅ is a methoxy group, which R ₅ is located at the 4-position of the phenyl ring bonded thereto. The compound of any one of claims 1 to 6 wherein n is 2. 8. The compound of any one of claims 1-6 wherein n is 3. 7. The compound according to claim 1, wherein (cis) -3- (acetyloxy) -7-chloro-1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-4- (4-meth Methoxyphenyl) -2H-1-benzazin-2-one or a pharmaceutically acceptable salt thereof. The method of claim 1, wherein (cis) -3- (acetyloxy) -1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl)- 2H-1-benzazin-2-one or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein the (trans) -3- (acetyloxy) -1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl)- 2H-1-benzazin-2-one or a pharmaceutically acceptable salt thereof. The method of claim 1, wherein (cis) -3- (acetyloxy) -1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl)- 7- (trifluoromethyl) -2H-1-benzazin-2-one or a pharmaceutically acceptable salt thereof. A compound according to claim 1, wherein (cis) -3- (acetyloxy) -7- (methoxy) -1- [2- (dimethylamino) ethyl] -1,3,4,5-tetrahydro-4- ( 4-methoxyphenyl) -2H-1-benzeazin-one or a pharmaceutically acceptable salt thereof. 8. The compound of claim 7, wherein R ₄ is hydrogen. The compound of claim 8, wherein R ₄ is hydrogen. The compound of claim 9, wherein R ₄ is hydrogen. The compound of claim 10, wherein R ₄ is hydrogen. 8. The compound of claim 7, wherein R ₄ is chlorine, which R ₄ is located at the 7-position of the benzazine nucleus. The compound of claim 8, wherein R ₄ is chlorine, which R ₄ is located at the 7-position of the benzazine nucleus. 10. The compound of claim 9, wherein R ₄ is chlorine, which R ₄ is located at the 7-position of the benzazine nucleus. The compound of claim 10, wherein R ₄ is chlorine, which R ₄ is located at the 7-position of the benzazine nucleus. 8. A compound according to claim 7, wherein R ₅ is an alkoxy group. The compound of claim 8, wherein R ₅ is an alkoxy group. The compound of claim 9, wherein R ₅ is an alkoxy group. The compound of claim 10, wherein R ₅ is an alkoxy group. The compound of claim 11, wherein R ₅ is an alkoxy group. 13. The compound of claim 12, wherein R ₅ is an alkoxy group. The compound of claim 13, wherein R ₅ is an alkoxy group. The compound of claim 23, wherein R ₅ is an alkoxy group. The compound of claim 24, wherein R ₅ is an alkoxy group. The compound of claim 25, wherein R ₅ is an alkoxy group. The compound of claim 26, wherein R ₅ is an alkoxy group. The compound of claim 27, wherein R ₅ is an alkoxy group. 29. The compound of claim 28, wherein R ₅ is an alkoxy group. 30. The compound of claim 29, wherein R ₅ is an alkoxy group. 31. The compound of claim 30, wherein R ₅ is an alkoxy group. 8. A compound according to claim 7, wherein R ₅ is a methoxy group and R ₅ is located at the 4-position of the phenyl ring attached thereto. The compound of claim 8, wherein R ₅ is a methoxy group, which R ₅ is located in the 4-position of the phenyl ring attached thereto. 10. The compound of claim 9, wherein R ₅ is a methoxy group, which R ₅ is located in the 4-position of the phenyl ring attached thereto. The compound of claim 10, wherein R ₅ is a methoxy group, which R ₅ is located in the 4-position of the phenyl ring attached thereto. 12. The compound of claim 11, wherein R ₅ is a methoxy group, which R ₅ is located in the 4-position of the phenyl ring attached thereto. 13. The compound of claim 12, wherein R ₅ is a methoxy group, which R ₅ is located in the 4-position of the phenyl ring attached thereto. The compound of claim 13, wherein R ₅ is a methoxy group, which R ₅ is located in the 4-position of the phenyl ring attached thereto. 24. The compound of claim 23, wherein R ₅ is a methoxy group, which R ₅ is located in the 4-position of the phenyl ring attached thereto. 25. The compound of claim 24, wherein R ₅ is a methoxy group, which R ₅ is located in the 4-position of the phenyl ring attached thereto. The compound of claim 25, wherein R ₅ is a methoxy group, which R ₅ is located in the 4-position of the phenyl ring attached thereto. 27. The compound of claim 26, wherein R ₅ is a methoxy group, which R ₅ is located in the 4-position of the phenyl ring attached thereto. The compound of claim 27, wherein R ₅ is a methoxy group, which R ₅ is located in the 4-position of the phenyl ring attached thereto. 29. The compound of claim 28, wherein R ₅ is a methoxy group, which R ₅ is located in the 4-position of the phenyl ring attached thereto. The compound of claim 29, wherein R ₅ is a methoxy group, which R ₅ is located in the 4-position of the phenyl ring attached thereto. 31. The compound of claim 30, wherein R ₅ is a methoxy group, which R ₅ is located in the 4-position of the phenyl ring attached thereto. 8. The compound of claim 7, wherein n is 2. The compound of claim 8, wherein n is 2. 10. 10. The compound of claim 9, wherein n is 2. The compound of claim 10, wherein n is 2. 12. The compound of claim 11, wherein n is 2. 13. The compound of claim 12, wherein n is 2. The compound of claim 13, wherein n is 2. 15. The compound of claim 14, wherein n is 2. 16. The compound of claim 15, wherein n is 2. 24. The compound of claim 23, wherein n is 2. The compound of claim 24, wherein n is 2. 25. The compound of claim 25, wherein n is 2. 27. The compound of claim 26, wherein n is 2. The compound of claim 27, wherein n is 2. 29. The compound of claim 28, wherein n is 2. 30. The compound of claim 29, wherein n is 2. 33. The compound of claim 30, wherein n is 2. 32. The compound of claim 31, wherein n is 2. 33. The compound of claim 32, wherein n is 2. 34. The compound of claim 33, wherein n is 2. 35. The compound of claim 34, wherein n is 2. 36. The compound of claim 35, wherein n is 2. 37. The compound of claim 36, wherein n is 2. 38. The compound of claim 37, wherein n is 2. The compound of claim 38, wherein n is 2. 40. The compound of claim 39, wherein n is 2. 41. The compound of claim 40, wherein n is 2. 42. The compound of claim 41, wherein n is 2. 43. The compound of claim 42, wherein n is 2. 44. The compound of claim 43, wherein n is 2. 45. The compound of claim 44, wherein n is 2. 46. The compound of claim 45, wherein n is 2. 47. The compound of claim 46, wherein n is 2. 48. The compound of claim 47, wherein n is 2. 49. The compound of claim 48, wherein n is 2. 50. The compound of claim 49, wherein n is 2. 51. The compound of claim 50, wherein n is 2. The compound of claim 51, wherein n is 2. 53. The compound of claim 52, wherein n is 2. 54. The compound of claim 53, wherein n is 2. 55. The compound of claim 54, wherein n is 2. The compound of claim 55, wherein n is 2. 57. The compound of claim 56, wherein n is 2. 58. The compound of claim 57, wherein n is 2. 59. The compound of claim 58, wherein n is 2. 60. The compound of claim 59, wherein n is 2. 61. The compound of claim 60, wherein n is 2. 8. The compound of claim 7, wherein n is 3. The compound of claim 8, wherein n is 3. 10. 10. The compound of claim 9, wherein n is 3. The compound of claim 10, wherein n is 3. 12. The compound of claim 11, wherein n is 3. 13. The compound of claim 12, wherein n is 3. The compound of claim 13, wherein n is 3. 15. The compound of claim 14, wherein n is 3. 16. The compound of claim 15, wherein n is 3. The compound of claim 23, wherein n is 3. The compound of claim 24, wherein n is 3. The compound of claim 25, wherein n is 3. 27. The compound of claim 26, wherein n is 3. The compound of claim 27, wherein n is 3. 29. The compound of claim 28, wherein n is 3. 30. The compound of claim 29, wherein n is 3. 32. The compound of claim 30, wherein n is 3. 32. The compound of claim 31, wherein n is 3. 33. The compound of claim 32, wherein n is 3. 34. The compound of claim 33, wherein n is 3. 35. The compound of claim 34, wherein n is 3. 36. The compound of claim 35, wherein n is 3. 37. The compound of claim 36, wherein n is 3. 38. The compound of claim 37, wherein n is 3. The compound of claim 38, wherein n is 3. 40. The compound of claim 39, wherein n is 3. 41. The compound of claim 40, wherein n is 3. 42. The compound of claim 41, wherein n is 3. 43. The compound of claim 42, wherein n is 3. 44. The compound of claim 43, wherein n is 3. 45. The compound of claim 44, wherein n is 3. 46. The compound of claim 45, wherein n is 3. 47. The compound of claim 46, wherein n is 3. 48. The compound of claim 47, wherein n is 3. 49. The compound of claim 48, wherein n is 3. 50. The compound of claim 49, wherein n is 3. 51. The compound of claim 50, wherein n is 3. The compound of claim 51, wherein n is 3. 53. The compound of claim 52, wherein n is 3. 54. The compound of claim 53, wherein n is 3. 55. The compound of claim 54, wherein n is 3. 56. The compound of claim 55, wherein n is 3. 57. The compound of claim 56, wherein n is 3. 58. The compound of claim 57, wherein n is 3. 59. The compound of claim 58, wherein n is 3. 60. The compound of claim 59, wherein n is 3. 61. The compound of claim 60, wherein n is 3.