JP2840453B2 - Imidazolino benzodiazepines - Google Patents

Description

BACKGROUND OF THE INVENTION Compounds belonging to the benzodiazepines are widely used as therapeutics, especially as central nervous system drugs such as anxiolytics. These compounds show strong binding to the "benzodiazepine receptor", and some also show binding to the CCK-B or gastrin receptor. CCK
None of the compounds known as -B antagonists are of the class of the imidazolinobenzodiazepines as shown in structural formula I below.

SUMMARY OF THE INVENTION The present invention provides a compound of formula I: And a novel compound acting as a CCK-B antagonist. These compounds are useful in animals, preferably mammals, especially human central nervous system CC.
It is effective for treating and preventing KB-related diseases.

DETAILED DESCRIPTION OF THE INVENTION The novel compounds of the present invention have the structural formula: [Wherein R represents (1) phenyl substituted or unsubstituted with halo such as chloro, bromo or fluoro or C _1-3 alkyl, or (2) C _5-6 cycloalkyl A represents C _1-3 alkyl, hydroxy-C _1-3 alkyl or —C
(= O) -O shows a C _2-3 alkylene optionally substituted with (C _1-3 alkyl), R ¹ is Wherein R ² is chloro, C _1-3 alkyl or —CF ₃
Or R ¹ is Wherein R ⁴ represents C _1-6 alkyl, CF ₃ , cyclopropyl, 2,2-dimethylcyclopropyl, 2,2-difluorocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or , A substituent F,
Its acceptable salts compound or pharmaceutical, has a a substituted phenyl] - Cl, Br, CN, NO 2, CF 3, OCH 3 or mono substituted by NH ₂ - or di.

One embodiment of the novel compounds of the present invention is that wherein R ¹ is of the formula: It is a compound shown by these.

 Specific compounds representative of this specific example are shown in the following table.

When diastereomers are present in the compounds of the present invention,
It is to be understood that the present invention includes the individual diastereomers and mixtures thereof as well as enantiomers and mixtures of enantiomers.

Pharmaceutically acceptable salts of the compounds of the formula I include the customary non-toxic or quaternary ammonium salts of the compounds of the formula I formed, for example, from non-toxic inorganic or organic acids.
Examples of such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and acetic acid, propionic acid, succinic acid, and glycolic acid. , Stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-
Acetoxybenzoic acid, fumaric acid, trienesulfonic acid,
There are salts prepared from organic acids such as methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from compounds of Formula I that contain a basic or acidic group by conventional chemical methods. Generally, the salt is formed by reacting the free base or acid with a stoichiometric or excess amount of an inorganic or organic acid or base to form the desired salt in a suitable solvent or various mixed solvents. Prepared by

Since the novel compounds described above have CCK-B antagonistic ability, they can be used as medicaments for mammals, especially humans, which are effective for treating or preventing CCK-B-related disorders such as anxiety.

The compound of formula I may be administered alone to a human patient,
It is preferably administered in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier or diluent, optionally with an adjuvant such as alum, according to standard formulation procedures. The compound may be administered orally or parenterally, such as intravenously, intramuscularly, intraperitoneally, subcutaneously and on the skin surface.

For oral use of a CCK antagonist of the present invention, the selected compound will be administered, for example, in the form of a tablet or capsule, or as an aqueous solution or suspension. When tablets are used for oral administration, the usual carriers are lactose and corn starch, and usually a lubricant such as magnesium stearate is added. When using capsule form for oral administration, effective diluents are lactose and dried corn starch. If an aqueous suspension is required for oral administration,
The active ingredient is mixed with an emulsifier and suspending agent. If desired
Sweetening agents and / or flavoring may be added to some extent. For intramuscular, peritoneal tissue, subcutaneous and intravenous use, it is usually necessary to prepare a sterile solution of the active ingredient and adjust the pH of the solution as appropriate to buffer. For intravenous use, the total solute concentration needs to be adjusted to give an isotonic preparation.

When a compound of Formula I is used in human patients as an antagonist of CCK or gastrin, the dosage regimen and dosage will generally be determined by the prescribing physician, but the dosage will generally be determined by the age, weight, response, It changes according to the severity of the symptoms. In most cases, however, the effective daily dose will be in the range of about 0.05 mg / kg to about 50 mg / kg of body weight,
Preferably it is in the range of 0.5 mg / kg to about 20 mg / kg per kg of body weight, the whole dose being administered once or in divided doses. However, in some cases, determination of dosages outside these ranges will be necessary.

In a novel method of preparing the novel compounds of the present invention, a compound of formula II and a sulfonyl chloride such as methanesulfonyl chloride, benzenesulfonyl chloride or toluenesulfonyl chloride are prepared by dissolving the compound in an organic solvent such as methylene chloride, chloroform and tetrachloroethane. In the presence of a strong organic base such as diisopropylethylamine.

Another novel method for preparing some of the novel compounds of the present invention is illustrated below: In this method, the hemiacetal starting material is treated in a chlorinated alkane such as methylene chloride with an ether adduct of boron trifluoride at about 40-60 ° C until the reaction is complete. The reaction is completed in about 1.5-3 hours.

The third novel method of the present invention is illustrated below: In this method, the amine H ₂ N- in THF at about −10 to + 10 ° C.
The R ^1, is treated with triethylamine and triphosgene in about pH 8.5. After holding at -10 to + 10 ° C for 5 to 10 minutes and then at room temperature for 5 to 10 minutes, the mixture is treated with aminobenzodiazepine at about -10 to + 10 ° C for about 5 to 20 minutes.

The fourth novel method of the present invention is illustrated below: In this method, aminobenzodiazepine, carboxylic acid
R ¹ CO ₂ H, 1-hydroxybenzotriazole hydrate (HB
T), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and triethylamine are stirred in DMF at about room temperature until the reaction is completed. Usually about 15 ~
The reaction is completed in 24 hours.

Example 1 N-[(2S, 4R) -methyl-6-phenyl-2,4-dihydro-1H-imidazo [1,2-α] [1,4] benzodiazepin-4-yl] -N ′-[ 3-methylphenyl] -urea and N-[(2S, 4S) -methyl-6-phenyl-2,4-dihydro-1H-imidazo [1,2-α] [1,4-] benzodiazepin-4-yl Preparation of] -N '-[3-methylphenyl] -urea Step A: N-｛(S)-(+)-2-amino-[(R, S) -3-
(((3-methylphenyl) amino) carbonyl) amino] -5-phenyl-2H-1,4-benzodiazepine-2
Synthesis of -yl} -1-propanol (R, S) -N- (2,3-dihydro-2-thiono-5-phenyl-1H-1,4-benzodiazepin-3-yl)-
N '-(3-methylphenyl) -urea (382 mg, 0.954 mmol) (U.S. Pat. No. 4,820,834) was dissolved in 10 ml of anhydrous tetrahydrofuran and (S)-(+)-2-amino-1-propanol (297 .mu.l) , 3.82 mmol) and mercury (II) chloride (337 mg). 55 of the resulting suspension
Heated at ° C for 2 hours. The reaction mixture was filtered and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure and the residue was subjected to silica gel flash chromatography (2% ethanol in chloroform) to give 41%
5 mg (95% yield) of the analytical product was obtained as a mixture of diastereomers. 137-140 ° C. ¹ H NMR (CDCl ₃ ): consistent with expected structure, confirming solvate form; HPLC: purity of 214 nM>99%; R _f = 0.27 (CHCl ₃ —CH ₃ OH; 92:
8) FAB MS: 442 (M + + H); C 26 H 27 N 5 O 2 · 0.5CHCl 3 · 0.35CH 3 OH Elemental analysis: Calculated: C, 62.93; H, 5.68 ; N, 13.67 Found: C, 62.97; H, 5.50; N, 13.45.

Step B: N-｛(S)-(+)-2-amino-[(R, S) -3-
(((3-methylphenyl) amino) carbonyl) amino] -5-phenyl-2H-1,4-benzodiazepine-2
Cyclization of -yl} -1-propanol 430 mg (0.974 mmol) of N in 17 ml of methylene chloride
-｛(S)-(+)-2-amino-[(R, S) -3-
(((3-methylphenyl) amino) carbonyl) amino] -5-phenyl-2H-1,4-benzodiazepine-2
An ice-cold solution of -yl｝ -1-propanol is protected from moisture, methanesulfonyl chloride (91 μl, 1.17 mmol) and diisopropylethylamine (356 μl, 2.0
4 mmol). After 15 minutes, the reaction mixture was allowed to return to room temperature and stirring was continued for another 1.5 hours. The volatiles were completely removed under reduced pressure, and the residue was dissolved in 190 ml of ethyl acetate.
The organic phase was washed once with 10% citric acid solution containing brine (50% by volume), twice with 20 ml each of 10% sodium carbonate solution and then with brine. The organic extract was then dried (sodium sulfate) and concentrated to give 427 mg of crude product as a mixture of diastereomers. Rexc
hrom Pirkle covalent L-leucine column (5μ, 100A)
Purified to homogeneity by HPLC using. (Chromatography conditions: eluent containing 0.2% triethylamine
1: 1 hexane-isopropanol: flow rate 2 ml / min). By this processing, N-[(2S, 4R)-
Methyl-6-phenyl-2,4-dihydro-1H-imidazo [1,2-α] [1,4] benzodiazepin-4-yl]-
N '-[3-methylphenyl] -urea has a chemical purity of 9
Obtained at 9.7% and 95% diastereomer purity. Melting point 1
49 ° C (decomposition). ¹ H NMR (CDCl ₃ ): consistent with expected structure, confirming solvate form; HPLC: purity of 214 nM>99%; R _f = 0.19 (ethyl acetate-hexane; 7: 3) FAB ^{MS: 424 (M + + H} ); C 26 H 25 N 5 O · 0.5CHCl 3 · 0.05CH 3 OH elemental analysis: calculated: C, 71.86; H, 5.83 ; N, 16.03 measurements: C, 71.84; H, 5.88; N, 15.86.

N-[(2S, 4S) -methyl-6-phenyl-2,4-dihydro-1H-imidazo [1,2-α] [1,2-α]
4] Benzodiazepin-4-yl] -N '-[3-methylphenyl] -urea was obtained with a chemical purity of 99.5% and a diastereomer purity of 98.5%. Melting point 155 ° C (decomposition). ¹ H NMR (CDCl ₃ ): consistent with expected structure, confirming solvate form; HPLC: purity of 214 nM>99%; R _f = 0.33 (ethyl acetate-hexane; 7: 3) FAB ^{MS: 424 (M + + H} ); C 26 H 25 N 5 O · 0.5CHCl 3 · 0.1 hexane elemental analysis: calculated: C, 66.18; H, 5.51 ; N, 14.24 measurements: C, 66.40; H, 5.44; N, 14.24.

Example 2 N-[(4R, 4S) -6-phenyl-2,4-dihydro-1H-
Preparation of imidazo [1,2-α] [1,4] benzodiazepin-4-yl] -N ′-[3-methylphenyl] -urea (R, S) -N- (2,3-dihydro-2- Thiono-5-phenyl-1H-1,4-benzodiazepin-N-yl)-
Using N '-[3-methylphenyl] -urea and ethanolamine, according to Step A of Example 1, N- {2-amino-[(R, S) -3-(((3-methylphenyl) amino ) Carbonyl) amino] -5-phenyl-2H-1,4-
Benzodiazepin-2-yl] ethanol (melting point 169-1
70 ° C.). The resulting compound was then converted to the title compound using reaction conditions similar to those described in Step B of Example 1. Purification by silica gel flash chromatography (chloroform-methanol, 88:12) followed by trituration of the chromatographic product with ethyl ether provided the analytical product as a white solid. 147 ° C (decomposition). ¹ H NMR (CDCl ₃ ): consistent with expected structure, confirming solvate form; HPLC: purity of 214 nM>91%; R _f = 0.3 (CHCl ₃ —CH ₃ OH; 9: 1) ^{) FAB MS: 410 (M +} + H); C 25 H 23 N 5 O · 0.5CHCl 3 · 0.75CH 3 OH elemental analysis: calculated: C, 68.90; H, 5.84 ; N, 15.52 measurements: C, 68.92; H, 5.67; N, 15.18.

Example 3 N-[(2R, 4R, 4S) -methyl-6-phenyl-2,4-dihydro-1H-imidazo [1,2-α] [1,4] benzodiazepin-4-yl] -N ' Preparation of-[3-methylphenyl] -urea (R, S) -N- (2,3-dihydro-2-thiono-5-phenyl-1H-1,4-benzodiazepin-3-yl)-
N '-[3-methylphenyl] -urea and (R)-(-)
N- ア ミ ノ (R)-(−)-2-amino- according to Step A of Example 1 using -2-amino-1-propanol.
[(R, S) -3-(((3-methylphenyl) amino)
Carbonyl) amino] -5-phenyl-2H-1,4-benzodiazepin-2-yl} -1-propanol was prepared. The resulting compound was then converted to the title compound (mixture of diastereomers) in 76% yield using reaction conditions similar to those described in Step B of Example 1. 141 ° C
(Disassembly). ¹ H NMR (CDCl ₃ ): consistent with expected structure, confirmed in solvate form; HPLC: purity of isomers A and B of 214 nM>95%; isomer A: R _f
= 0.33 (ethyl acetate-hexane, 4: 1), isomer B: _Rf = 0.
42 (ethyl acetate - hexane, 4: 1) FAB MS: 424 (M + + H); C 26 H 25 N 5 O · 0.65 ether 0.10 hexane Elemental analysis: Calculated: C, 73.01; H, 6.90 ; N , 14.58 Found: C, 72.99; H, 6.62; N, 14.20.

Example 4 N-[(1R, 4R, 4S) -methyl-6-phenyl-2,4-dihydro-1H-imidazo [1,2-α] [1,4] benzodiazepin-4-yl] -N ′ Preparation of-[3-methylphenyl] -urea (R, S) -N- (2,3-dihydro-2-thiono-5-phenyl-1H-1,4-benzodiazepin-3-yl)-
Step A of Example 1 using N '-(3-methylphenyl) -urea (180 mg, 0.449 mmol) and (R)-(-)-1-amino-2-propanol (142 μl, 1.796 mmol) According to the formula: N-{(R)-(-)-1-amino-
[(R, S) -3-(((3-methylphenyl) -amino) carbonyl) -amino] -5-phenyl-2H-1,4
-Benzodiazepin-2-yl] -2-propanol was prepared. The resulting compound was then converted to the title compound (mixture of diastereomers, 96% yield) using reaction conditions similar to those described in Step B of Example 1; mp 140
° C (decomposition). ¹ H NMR (CDCl ₃ ): consistent with expected structure, confirming solvate form; HPLC: purity of 214 nM>97.6%; R _f = 0.16 (ethyl acetate-hexane, 7: 3) FAB ^{MS: 424 (M + + H} ); C 26 H 25 N 5 O · 0.05CHCl 3 · 0.10 hexane elemental analysis: calculated: C, 73.06; H, 6.09 ; N, 15.99 measurements: C, 72.88; H, 6.00; N, 15.71.

Example 5 N-[(5R, 5S) -7-phenyl-1,2,3,5-tetrahydro-pyrimido [1,2-α] [1,4] benzodiazepine-5
Preparation of -yl] -N '-[3-methylphenyl] -urea (R, S) -N- (2,3-dihydro-2-thiono-5-phenyl-1H-1,4-benzazepine-3 -Yl) -N '
Using-(3-methylphenyl) -urea (135 mg, 0.337 mmol) and 1-propanolamine (102 [mu] l, 1.35 mmol), according to Step A of Example 1, 110 mg (74% yield) of N-II. 3-amino-[(R, S) -3-
(((3-methylphenyl) -amino) carbonyl) amino] -5-phenyl-2H-1,4-benzodiazepine-
2-yl] -propanol (mp 195-196 ° C) was prepared. The resulting compound was then converted to the title compound using reaction conditions similar to those described in Step B of Example 1. Treatment with silica gel flash chromatography (chloroform-methanol, 88:12) and trituration of the chromatographic product with a mixed solvent of ethyl ether and petroleum ether gave the analytical product as a white solid in 82% yield. Obtained. 172-174 ° C (decomposition). ¹ H NMR (CDCl ₃ ): consistent with expected structure, confirming solvate form; HPLC: purity of 214 nM>99%; R _f = 0.2 (CHCl ₃ —CH ₃ OH; 9: 1) ^{) FAB MS: 424 (M +} + H); C 26 H 25 N 5 O · 0.5CHCl 3 · 1.35CH 3 OH elemental analysis: calculated: C, 63.53; H, 5.92 ; N, 13.30 measurements: C, 63.31; H, 5.94; N, 13.55.

Example 6 N-[(2S, 4R) -methyl-5-cyclohexyl-2,4-
Dihydro-1H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] -N '-[3-methylphenyl]-
Urea and N-[(2S, 4S) -methyl-5-cyclohexyl-2,4-dihydro-1H-imidazo [1,2-a] [1,4]
Preparation of Benzodiazepin-4-yl] -N '-[3-methylphenyl] -urea Step A: 1,3-Dihydro-5-cyclohexyl-3 (R, S)-
[(Benzyloxycarbonyl) amino] -2H-1,4-
Synthesis of benzodiazepine-2-thione 1,3-dihydro-5-cyclohexyl-3 (R, S)-
[(Benzyloxycarbonyl) amino] -2H-1,4-
Benzodiazepin-2-ones (M. Chambers et al., Biomed . C
hem. Lett. 1993, printing) (1.09 g, 2.79 mmol), 26
It was mixed with 1.13 g (2.79 mmol) of 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide in ml of toluene. The resulting suspension was heated to reflux for 1 hour. Cool the reaction mixture,
Filter and concentrate under reduced pressure. The residue was subjected to silica gel flash chromatography (ethyl acetate-hexane, 1: 3) and the fractions containing the product were pooled and concentrated,
The title compound was obtained with a purity of about 85%. Recrystallization of this material from hexane-ethyl acetate (1: 1) yielded 850 mg (75 mg).
%) Of the title compound was obtained. Melting point 164-165
° C.

Step B: Synthesis of 1,3-dihydro-5-cyclohexyl-3 (R, S) -amino-2H-1,4-benzodiazepin-2-thione 1,3-dihydro-5-cyclohexyl-3 (R, S )-
[(Benzyloxycarbonyl) amino] -2H-1,4-
Benzodiazepine-2-thione (787 mg, 1.93 mmol)
Was dissolved in 40 ml of a 1: 1 mixture of methylene chloride and acetic acid. The resulting solution was cooled to 0 ° C. and a continuous stream of hydrogen bromide gas was passed through the stirred solution for 10 minutes. The reaction vessel was stoppered and maintained for more than 5 hours until the reaction mixture reached room temperature. The volatiles were completely removed under reduced pressure, and the yellow residual solid was azeotroped with toluene and dried. The resulting material was partitioned between 180 ml of ethyl acetate and 7.3 ml of 10% sodium carbonate solution. The resulting suspension was stirred for 5 minutes and then filtered. The filter cake was washed with ethyl acetate, dried in vacuo in the presence of phosphorus pentoxide (40 ° C.) and triturated with ethyl acetate-hexane (1: 1) to give 492 mg of the title compound (93% yield). %).

Step C: (R, S) -N- [2,3-dihydro-2-thiono-5-cyclohexyl-2H-1,4-benzodiazepin-3-yl]
Synthesis of -N '-[3-methylphenyl] -urea 1,3-dihydro-5-cyclohexyl-3 (R, S) -amino-2H-1,4-benzodiazepine-2-thione (240 m
g, 0.878 mmol) and 124 μl of m-tolyl isocyanate were mixed in 22 ml of tetrahydrofuran at 0 ° C. under nitrogen. The reaction mixture was brought to room temperature in 45 minutes and filtered. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel eluting first with chloroform and then with 1% methanol in chloroform. This gave the title compound in 92% yield in the form of a racemic mixture whose structure was confirmed by ¹ H NMR spectrum.

Step D: N-｛(S)-(+)-2-amino-[(R, S) -3-
Synthesis of (((3-methylphenyl) amino) carbonyl) amino] -5-cyclohexyl-2H-1,4-benzodiazepin-2-yl] -1-propanol Similar to the conditions described in Step A of Example 1. Using conditions,
(R, S) -N- [2,3-dihydro-2-thiono-5-cyclohexyl-2H-1,4-benzodiazepin-3-yl]
-N '-[3-methylphenyl] -urea (330 mg, 0.812
Mmol) in 8 ml of tetrahydrofuran.
Reaction with-(+)-2-amino-1-propanol and 287 mg of mercury (II) chloride gave 363 mg of the title compound as a mixture of diastereomers ( ¹ HMNR (CDC
l ₃ ): Confirm structural agreement).

Step E: N-｛(S)-(+)-2-amino-[(R, S) -3-
Cyclization of (((3-methylphenyl) -amino) carbonyl) amino] -5-cyclohexyl-2H-1,4-benzodiazepin-2-yl} -1-propanol N-{(S)-(+)- 2-amino-[(R, S) -3
-(((3-methylphenyl) amino) carbonyl) amino] -5-cyclohexyl-2H-1,4-benzodiazepin-2-yl} -1-propanol (365 mg) was prepared according to the procedure of Example 1, Step B. Converted to the title compound.
The final product, a diastereomeric mixture, was separated by chiral preparative HPLC chromatography (see Step B of Example 1) to give N-[(2S, 4R) -methyl-6-cyclohexyl-2,4-dihydro. -1H-imidazo [1,2-a] [1,
4] Benzodiazepin-4-yl] -N '-[3-methylphenyl] -urea was obtained with a diastereomeric purity of 97%. 166 ° C. ¹ H NMR (CDCl ₃ ): consistent with expected structure, confirming solvate form; HPLC: purity of 214 nM>97%; R _f = 0.16 (ethyl acetate-hexane; 7: 3) FAB ^{MS: 430 (M + + H} ).

N-[(2S, 4S) -methyl-6-cyclohexyl-2,4
-Dihydro-1H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] -N '-[3-methylphenyl]
-Urea was obtained with 99.5% chemical purity and 70% diastereomeric purity. 142 ° C (decomposition). ¹ H NMR (CDCl ₃ ): consistent with expected structure, confirming solvate form; HPLC: purity of 214 nM>99%; R _f = 0.30 (ethyl acetate-hexane; 7: 3) FAB ^{MS: 430 (M + + H} ); C 26 H 31 N 5 O · 0.4CHCl 3 · 0.15 elemental analysis ethyl acetate: calculated: C, 66.11; H, 6.70 ; N, 14.28 measurements: C, 66.38; H , 6.46; N, 14.24.

Example 7 N-[(2S, 4R, 4S) -methyl-6-phenyl-2,4-dihydro-1H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] -N ' Preparation of-[4-chlorophenyl] -urea (R, S) -N- (2,3-dihydro-2-thiono-5-phenyl-1H-1,4-benzodiazepin-3-yl)-
N '-(4-chlorophenyl) -urea and (R)-(-)
N- ア ミ ノ (R)-(−)-2-amino- according to Step A of Example 1 using -2-amino-1-propanol.
[(R, S) -3-(((4-chlorophenyl) amino)
Carbonyl) amino] -5-phenyl-2H-1,4-benzodiazepin-2-yl} -1-propanol was prepared. The resulting compound was then converted to the title compound (mixture of diastereomers) using reaction conditions similar to those described in Step B of Example 1. 164 ° C (decomposition). ¹ H NMR (CDCl ₃ ): consistent with expected structure, confirming solvate form; HPLC:> 95% purity of isomers A and B at 214 nM; R _f = 0.67
(Chloroform - methanol, 9: 1) FAB MS: 430 (M + + H); C 25 H 22 ClN 5 O Elemental analysis: Calculated: C, 67.64; H, 5.00 ; N, 15.78 measurements: C, 67.24 ; H, 5.13; N, 15.14.

Example 8 N-[(2S, 4R, 4S) -methyl-6-phenyl-2,4-dihydro-1H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] -N ' Preparation of-[3-chlorophenyl] -urea (R, S) -N- (2,3-dihydro-2-thiono-5-phenyl-1H-1,4-benzodiazepin-3-yl)-
N '-(3-chlorophenyl) -urea and (R)-(-)
N- ア ミ ノ (R)-(−)-2-amino- according to Step A of Example 1 using -2-amino-1-propanol.
[(R, S) -3-(((4-chlorophenyl) amino)
Carbonyl) amino] -5-phenyl-2H-1,4-benzodiazepin-2-yl} -1-propanol was prepared. The resulting compound was then converted to the title compound (mixture of diastereomers) using reaction conditions similar to those described in Step B of Example 1. 143-146 ° C (decomposition). ¹ H NMR (CDCl ₃ ): consistent with expected structure, confirming solvate form; HPLC:> 95% purity of isomers A and B at 214 nM; R _f = 0.68
(Chloroform - methanol, 9: 1) FAB MS: 444 (M + + H); C 25 H 22 ClN 5 elemental analysis of O · 0.45EtOAc · 0.2CHCl _3: Calculated: C, 63.91; H, 5.12 ; N, 13.80 found: C, 63.69; H, 5.22; N, 13.91.

Example 9 N-[(2S, 4R, 4S) -methyl-6-phenyl-2,4-dihydro-1H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] -N ' Preparation of-[4-trifluoromethylphenyl] -urea (R, S) -N- (2,3-dihydro-2-thiono-5-phenyl-1H-1,4-benzodiazepin-3-yl)-
Using N '-(4-trifluoromethylphenyl) -urea and (R)-(-)-2-amino-1-propanol, according to Step A of Example 1, N-{(R)-(- )
-2-amino-[(R, S) -3-(((4-trifluoromethylphenyl) amino) carbonyl) amino] -5
-Phenyl-2H-1,4-benzodiazepin-2-yl}
-1-propanol was prepared. The resulting compound was then converted to the title compound (mixture of diastereomers) using reaction conditions similar to those described in Step B of Example 1. 148-152 ° C (decomposition). ¹ H NMR (CDCl ₃ ): consistent with expected structure, confirming solvate form; HPLC:> 96% purity of isomers A and B at 214 nM; R _f = 0.66
(Chloroform - methanol, 9: 1) FAB MS: 478 (M + + H); C 20 H 22 F 3 N 5 O · 0.45 2- propanol Calcd: C, 65.10; H, 5.11 ; N, 13.88 found: C, 65.23; H, 4.88; N, 13.85.

Example 10 N-[(2S, 4S) -methyl-5-cyclohexyl-2,4-
Dihydro-1H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] -N '-[6-indolyl] -urea and N [(2R, 4R) -methyl-5-cyclohexyl-2 ,Four
Preparation of -dihydro-1H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] -N '-[6-indolyl] -urea Step A: N-｛(S)-(+) -2-amino-[(R, S) -3-
(Benzyloxycarbonyl) amino] -5-cyclohexyl-2H-1,4-benzodiazepin-2-yl} -1
-Synthesis of propanol 1,3-dihydro-5-cyclohexyl-3 (R, S)-
[(Benzyloxycarbonyl) amino] -2H-1,4-
Benzodiazepine-2-thione (1 g, 2.45 mmol)
Is dissolved in 8 ml of anhydrous tetrahydrofuran, and (S)-
(+)-2-Amino-1-propanol (763 μl, 9.80
Mmol) and mercury (II) chloride (866 mg). The resulting suspension was heated at 55 C for 2 hours. The reaction mixture was filtered and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel flash chromatography (ethyl acetate-hexane gradient, 20%).
1.17g (61% yield)
Was obtained as a mixture of diastereomers. R _f = 0.3 (ethyl acetate-hexane, 1: 1) ¹ HNMR (CDCl ₃ ): consistent with the expected structure.

Step B: N-｛(S)-(+)-2-amino-[(R, S) -3-
(Benzyloxycarbonyl) amino] -5-cyclohexyl-2H-1,4-benzodiazepin-2-yl} -1
Cyclization of propanol 670 mg (1.49 mmol) of N in 26 ml of methylene chloride
-｛(S)-(+)-2-amino-[(R, S) -3-
(Benzyloxycarbonyl) amino] -5-cyclohexyl-2H-1,4-benzodiazepin-2-yl} -1
Keep the ice-cold solution of propanol away from moisture, methanesulfonyl chloride (139 μl, 1.79 mmol) and diisopropylmethylamine (544 μl, 3.13 mmol)
Processed. After 15 minutes, the reaction mixture was allowed to return to room temperature and stirring was continued for another 1.5 hours. The volatiles were completely removed under reduced pressure, the residue azeotroped with toluene and then dissolved in 200 ml of ethyl acetate. The organic phase was washed once with a 10% citric acid solution containing brine (50% by volume), twice with 20 ml each of a 10% sodium carbonate solution and then with brine. Next, the organic extract was dehydrated (sodium sulfate) and concentrated to 567m
g of crude product was obtained as a mixture of diastereomers. This material was used directly in the next Step C.

Step C: (4R, 4S) -amino- (2S) -methyl-6-cyclohexyl-2,4-dihydro-1H-imidazo [1,2-a] [1,
4] Preparation of benzodiazepine (4R, 4S)-(benzyloxycarbonyl) amino-
(2S) -Methyl-6-cyclohexyl-2,4-dihydro-1H-imidazo [1,2-a] [1,4] benzodiazepine (250 mg, 0.581 mmol) was dissolved in 8 ml of anhydrous methanol and 150 mg of 10 % Palladium / carbon catalyst. The resulting suspension was stirred at room temperature under a hydrogen atmosphere for 1.25 hours. The reaction mixture was filtered and the catalyst was washed with methanol. The filtrate is concentrated under reduced pressure and the residue is azeotropically dried with toluene to give 159 mg of the product.

Step D: (4R, 4S) -amino- (2S) -methyl-6-cyclohexyl-2,4-dihydro-1H-imidazo [1,2-a] [1,2
4] Reaction of benzodiazepine with 6-indolyl isocyanate 6-aminoindole (92.1 mg, 0.232 mmol) in 0
Dissolved in 17 ml of tetrahydrofuran at ℃ and treated with 97 μl of triethylamine. To this mixture, 69 mg (0.232
Mmol) triphosgene was added. Additional triethylamine was added until the pH of the reaction mixture recorded 8.5 by wet pH paper. The reaction mixture was stirred at 0 ° C. for 5 minutes and then at room temperature for 5 minutes. The reaction mixture was cooled again to 0 ° C. and 159 mg (0.536 mmol) of (4R, 4S) -amino- (2S) -methyl-6-cyclohexyl-2,4-dihydro-1H-imidazo [1 , 2−
a) Treatment with [1,4] benzodiazepine. After 10 minutes, the reaction mixture was filtered and the filtrate was concentrated. 10 residue obtained
Partitioned between citric acid solution and ethyl acetate (75 ml). The organic phase was then washed sequentially with 10% sodium carbonate solution and brine, dried and concentrated to give 323 mg of crude product. The final product, a diastereomeric mixture, was separated by chiral preparative HPLC chromatography (see Example 1, Step B), yielding 83 mg of N-[(2S, 4S) -methyl-5-cyclohexyl-2,4. -Dihydro-1H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl]-
N '-[6-Indolyl] -urea was obtained with a diastereomer purity of 99%. 180 ° C. ¹ H NMR (CDCl ₃ ): consistent with expected structure, confirmed in solvate form; HPLC: purity of 214 nM>97%; R _f = 0.52 (hexane-2-propanol; 3: 1) ^{FAB MS: 455 (M + +} H).

_{C 27 H 30 N 6 O ·} 0.35CHCl 3 · 0.75CH 3 OH Elemental analysis: Calculated: C, 64.85; H, 6.46 ; N, 16.15 measurements: C, 64.84; H, 6.09 ; N, 15.81.

N-[(2S, 4R) -methyl-5-cyclohexyl-2,4
-Dihydro-1H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] -N '-[6-indolyl] -urea (153 mg total) has a diastereomer purity of> 99% and Obtained with> 98% chemical homogeneity. 191 ° C (decomposition). ¹ H NMR (CDCl ₃ ): consistent with expected structure, confirming solvate form; HPLC: purity of 214 nM>98%; R _f = 0.38 (hexane-2-propanol; 3: 1) ^{FAB MS: 455 (M + +} H).

_{C 27 H 30 N 6 O ·} 0.35CHCl 3 · 0.75CH 3 OH Elemental analysis: Calculated: C, 64.85; H, 6.46 ; N, 16.15 measurements: C, 64.83; H, 6.15 ; N, 15.79.

Example 11 N-[(2S, 4S) -methyloxycarbonyl-6-phenyl-2,4-dihydro-1H-imidazo [1,2-a] [1,2-
4] benzodiazepin-4-yl] -N '-[3-methylphenyl] -urea and N-[(2S, 4S) -methyloxycarbonyl-6-phenyl-2,4-dihydro-1H-imidazo [1, Preparation of 2-a] [1,4] benzodiazepin-4-yl] -N '-[3-methylphenyl] -urea (R, S) -N- (2,3-dihydro-2-thiono-5 Phenyl-1H-1,4-benzodiazepin-3-yl)-
Using N '-(3-methylphenyl) -urea (120 mg, 0.3 mmol) and 187 mg (1.2 mmol) of (D) -serine methyl ester hydrochloride, according to Step A of Example 1
140 mg of N- (R) -2-amino-｛[(R, S) -3-
(((3-methylphenyl) amino) carbonyl) amino] -5-phenyl-2H-1,4-benzodiazepine-2
-Methyl-yl} -2-hydroxypropanoate was prepared. The resulting compound was then converted to the title compound (mixture of diastereomers) using reaction conditions similar to those described in Step B of Example 1. The final product, a diastereomeric mixture, was separated by flash chromatography on silica gel (70% ethyl acetate first, then 80% ethyl acetate-hexane) to give 50 mg of N-[(2S, 4S)-.
Methyloxycarbonyl-6-phenyl-2,4-dihydro-1H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] -N '-[3-methylphenyl] -urea is ether- Obtained after trituration with hexane solution. Melting point 152
° C (decomposition). ¹ H NMR (CDCl ₃ ): consistent with expected structure, confirming solvate form; HPLC: diastereomer purity> 88% and chemical purity> 214% for 214 nM; R _f = 0.62 ( Ethyl acetate-hexane; 4: 1) FAB MS: 468 (M ⁺ + H); Elemental analysis of C ₂₇ H ₂₅ N ₅ O · 0.25CHCl ₃ · 0.10EtOAc: Calculated: C, 65.60; H, 5.19; N, 13.84 found: C, 65.73; H, 5.25; N, 13.77.

N-[(2S, 4R) -methyloxycarbonyl-6-phenyl-2,4-dihydro-1H-imidazo [1,2-a] [1,
4] Benzoazepin-4-yl] -N '-[3-methylphenyl] -urea (20 mg) has a diastereomeric purity of>
77% and a chemical homogeneity> 95%. 137-140
° C (decomposition). ¹ H NMR (CDCl ₃ ): consistent with expected structure, confirming solvate form; HPLC: purity of 214 nM>95%; R _f = 0.30 (ethyl acetate-hexane; 4: 1) FAB ^{MS: 468 (M + + H} ).

Elemental analysis of _{C 27 H 25 N 5 O 3} · 0.4CHCl 3: Calculated: C, 63.86; H, 4.97 ; N, 13.59 measurements: C, 63.74; H, 5.13 ; N, 13.32.

Example 12 N- [6-phenyl-2,4-dihydro-1H-imidazole [1,2-a] [1,4] benzodiazepin-4-yl]-
Preparation of N '-[3-methylphenyl] -urea (R, S) -N- (2,3-dihydro-2-thiono-5-phenyl-1H-1,4-benzodiazepin-3-yl)-
Using N '-(3-methylphenyl) -urea (153 mg, 0.382 mmol) and 167 μl (1.528 mmol) of aminoacetaldehyde dimethyl acetal, according to Step A of Example 1, 196 mg of N-2-amino-｛[ (R, S) -3
-(((3-methylphenyl) amino) carbonyl) amino] -5-phenyl-2H-1,4-benzodiazepine-
2-yl｝ -1-acetaldehyde dimethyl acetal was prepared. The obtained compound (180 mg) was dissolved in 5 ml of methylene chloride and treated with 1.5 ml of an ether adduct of boron trifluoride. The reaction mixture was stirred at 50 ° C. for 2.5 hours, cooled and diluted with 250 ml of ethyl acetate. Add the resulting solution to 1
Washing with 0% sodium carbonate solution and brine, followed by dehydration and concentration gave 180 mg of the title compound in the form of the crude compound. Treatment with preparative thick-film silica gel chromatography (eluent: chloroform-methanol, 96: 4) yielded the analyte. 144 ° C (decomposition). ¹ H NMR (CDCl ₃ ): consistent with expected structure, confirming solvate form; HPLC: purity of 214 nM>99%; R _f = 0.53 (chloroform-methanol; 9: 1) FAB MS ^{: 408 (M + + H)} ; C 25 H 21 N 5 O · 0.4CHCl 3 elemental analysis: calculated: C, 67.01; H, 4.74 ; N, 15.39 measurements: C, 66.94; H, 4.87 ; N, 15.35.

Example 13 N-[(1R, 4S) -methyl-6-phenyl-2,4-dihydro-1H-imidazo [1,2-a] [1,4] benzoazepine-
4-yl] -N '-[3-methylphenyl] -urea and N-[(1R, 4R) -methyl-6-phenyl-2,4-dihydro-1H-imidazo [1,2-a] [1 Preparation of 2,4] benzodiazepin-4-yl] -N '-[3-methylphenyl] -urea Step A: N-{(2S)-(+)-3-amino-[(R, S) -3-
(((3-methylphenyl) amino) carbonyl) amino] -5-phenyl-2H-1,4-benzodiazepine-2
Synthesis of -yl} -2-propanol (R, S) -N- (2,3-dihydro-2-thiono-5-phenyl-1H-1,4-benzodiazepin-3-yl)-
N '-(3-methylphenyl) -urea (460 mg, 1.15 mmol) was dissolved in 20 ml of anhydrous tetrahydrofuran,
(S)-(+)-1-amino-2-propanol (363
μl, 4.6 mmol) and 406 mg of mercury (II) chloride. The resulting suspension was heated at 55 C for 2 hours. The reaction mixture was filtered and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure and the residue was subjected to silica gel flash chromatography (2% methanol in chloroform) to give 390 mg (77% yield) of the analytical product as a mixture of diastereomers. ¹ H NMR (CDCl ₃ ): consistent with the expected structure.

Step B: N-｛(S)-(+)-3-amino-[(R, S) -3-
(((3-methylphenyl) amino) carbonyl) amino] -5-phenyl-2H-1,4-benzodiazepine-2
Cyclisation of -yl} -2-propanol 390 mg (0.883 mmol) of N in 20 ml of methylene chloride
-｛(S)-(+)-3-amino-[(R, S) -3-
(((Methylphenyl) amino) carbonyl) amino]
An ice-cold solution of -5-phenyl-2H-1,4-benzodiazepin-2-yl} -2-propanol is protected from moisture, methanesulfonyl chloride (82 μl, 1.06 mmol) and diisopropylethylamine (323 μl, 1.86 mmol). Mmol). After 15 minutes, the reaction mixture was allowed to return to room temperature and stirring was continued for another 24 hours. The volatiles were completely removed under reduced pressure, and the residue was dissolved in 190 ml of ethyl acetate. The organic phase was washed once with 10% citric acid solution containing brine (50% by volume), twice with 20 ml each of 10% sodium carbonate solution and then with brine. The organic extract was dried (sodium sulfate) and concentrated to give 370 mg of crude product as a mixture of diastereomers. Rexchrom Pir
Purification was performed by HPLC using a kle covalent L-leucine column (5 μ, 100 A) until homogeneous. (Chromatography conditions: eluent: 1: 1 hexane-isopropanol containing 0.2% triethylamine: flow rate 2 ml / min). By this treatment, N-[(1R, 4S) -methyl-6-phenyl-2,4
-Dihydro-1H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] -N '-[3-methylphenyl]
-Urea was obtained with a diastereomer purity of greater than 99%. 135-138 ° C (decomposition). ¹ H NMR (CDCl ₃ ): consistent with expected structure, confirming solvate form; HPLC: purity of 214 nM>99%; R _f = 0.14 (ethyl acetate-hexane; 4: 1) FAB ^{MS: 424 (M + + H} ); C 26 H 25 N 5 O · 0.25CHCl 3 · 0.15 hexane elemental analysis: calculated: C, 69.93; H, 5.91 ; N, 15.02 measurements: C, 69.95; H, 5.73; N, 15.04.

N-[(1R, 4R) -6-phenyl-2,4-dihydro-1H
-Imidazo [1,2-a] [1,4] benzodiazepine-4-
Yl] -N '-[3-methylphenyl] -urea is 99%
Obtained with a diastereomeric purity of. 145-148 ° C
(Disassembly). ¹ H NMR (CDCl ₃ ): consistent with expected structure, confirming solvate form; HPLC: purity of 214 nM>99%; R _f = 0.14 (ethyl acetate-hexane; 4: 1) FAB ^{MS: 424 (M + + H} ); C 26 H 25 N 5 O · 0.35CHCl 3 · 0.10i- propanol calcd: C, 67.91; H, 5.59 ; N, 14.86 measurements: C, 68.15; H, 5.58; N, 14.59.

Example 14 (4S) -N-[(2S) -methyl-6-cyclohexyl-
2,4-dihydro-1H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] -naphthalene-1-acetamide and (4R) -N-[(2S) -methyl-6-cyclohexyl -2,4-dihydro-1H-imidazo [1,2-a] [1,
4] benzodiazepin-4-yl] -naphthalene-1-
Preparation of Acetamide 1-Naphthylacetic acid (45 mg, 0.242 mmol) was added to a solution of 3 ml of anhydrous N, N-dimethylformulamide containing 33 mg of 1-hydroxybenzotriazole hydrate (0.242 mmol). To this mixture was added 1-ethyl-3-
(3-Dimethylaminopropyl) carbodiimide hydrochloride (46 mg, 0.242 mmol) and (4R, 4S) -amino- (2S) -methyl-6-cyclohexyl-2,4-prepared according to Step C of Example 10. Dihydro-1H-imidazo [1,2-
a] [1,4] Benzodiazepine (60 mg, 0.202 mmol)
Was added. The pH of the resulting reaction mixture was adjusted to 8.5 with triethylamine, and the mixture was stirred at room temperature under an inert atmosphere for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic phase was separated, washed with brine and dried. The combined organic extracts were concentrated to give 173 mg of crude product. The resulting mixture is applied to a Rexchrom Pirkle covalent L-leucine column (5 μ,
Purified to homogeneity by HPLC using 100A). (Chromatography conditions: eluent used is 1: 1 hexane-isopropanol containing 0.2% triethylamine: flow rate is 2 ml)
/ Min). By this treatment, (4S) -N-[(2S) -methyl-6-cyclohexyl-2,4-dihydro-1H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl]
-Naphthalene-1-acetamide was obtained with a diastereomer purity of greater than 75%. 127 ° C (decomposition). ¹ H NMR (CDCl ₃ ): consistent with expected structure, confirmed in solvate form; HPLC: chemical purity of 214 nM>98%; R _f = 0.13 (ethyl acetate-hexane; 4: 1) ^{) FAB MS: 465 (M +} + H); C 30 H 32 N 4 O · 0.4CHCl 3 · 0.15 hexane elemental analysis: calculated: C, 71.56; H, 6.62 ; N, 10.67 measurements: C, 71.66; H, 6.61; N, 10.98.

(4R) -N-[(2S) -methyl-6-cyclohexyl-2,4-dihydro-1H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] -naphthalene-1-acetamide Was obtained with 95% diastereomeric purity. Melting point
104 ° C (decomposition). ¹ H NMR (CDCl ₃ ): consistent with expected structure, confirming solvate form; HPLC: purity of 214 nM>99%; R _f = 0.24 (ethyl acetate-hexane; 4: 1) FAB ^{MS: 465 (M + + H} ); C 30 H 32 N 4 O · 0.1CHCl 3 · 0.25 hexane elemental analysis: calculated: C, 76.19; H, 7.20 ; N, 11.25 measurements: C, 76.50; H, 6.95; N, 11.23.

Example 15 N-[(2S, 4S) -methyl-5-phenyl-2,4-dihydro-1H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] -N '-[ 6-indolyl] -urea and N
-[2S, 4R) -methyl-5-phenyl-2,4-dihydro-
1H-imidazo [1,2-a] [1,4] benzodiazepine-4
Preparation of -yl] -N '-[6-indolyl] -urea Step A: N-｛(S)-(+)-2-amino-[(R, S) -3-
Synthesis of (benzyloxycarbonyl) amino] -5-phenyl-2H-1,4-benzodiazepin-2-yl} -1-propanol 1,3-dihydro-5-phenyl-3 (R, S)-[(benzyl (Oxycarbonyl) amino] -2H-1,4-benzodiazepine-2-thione (3.5 g, 8.7 mmol) was dissolved in 100 ml of anhydrous tetrahydrofuran, and (S)-(+)-2
-Amino-1-propanol (1.36 ml, 17.40 mmol)) and mercury (II) chloride (3.08 g, 11.3 mmol). The resulting suspension was then heated at 55 C for 3 hours. The reaction mixture was filtered and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure and the residue was subjected to silica gel flash chromatography (ethyl acetate-hexane 1: 1) to give 1.16 g of the analytical product as a mixture of diastereomers. ¹ H NMR (CDCl ₃ ): consistent with the expected structure.

Step B: N-｛(S)-(+)-2-amino-[(R, S) -3-
Benzyloxycarbonyl) amino] -5-phenyl-
Cyclization of 2H-1,4-benzodiazepin-2-yl} -1-propanol 865 mg (1.96 mmol) of N in 35 ml of methylene chloride
-{(S)-(+)-2-amino-[(R, S) -3-benzyloxycarbonyl) amino] -5-phenyl-2H
An ice-cold solution of 1,4-benzodiazepin-2-yl} -1-propanol was exposed to moisture and treated with methanesulfonyl chloride (182 μl, 2.35 mmol) and diisopropylethylamine (683 μl, 3.92 mmol). After 15 minutes, the reaction mixture was allowed to return to room temperature and stirring was continued for another 1.5 hours. The volatiles were completely removed under reduced pressure and the residue was azeotroped with toluene and dissolved in 200 ml of ethyl acetate.
The organic phase was washed once with a 10% citric acid solution containing brine (50% by volume), twice with 20 ml each of a 10% sodium carbonate solution and with brine. The organic extract was then dried (sodium sulfate) and concentrated to give 677 mg of crude product as a mixture of diastereomers. This material was used in the next Step C.

Step C: (4R, 4S) -amino- (2S) -methyl-6-phenyl-
Preparation of 2,4-dihydro-1H-imidazo [1,2-a] [1,4] benzodiazepine (4R, 4S)-(benzyloxycarbonyl) amino-
(2S) -methyl-6-phenyl-2,4-dihydro-1H-
Imidazo [1,2-a] [1,4] benzodiazepine (120 mg,
0.28 mmol) was dissolved in 25 ml of anhydrous methanol and 55
Treated with mg of 10% palladium on carbon catalyst. The resulting suspension was stirred at room temperature under a hydrogen atmosphere for 1.25 hours. 50 more
mg of palladium catalyst were added and stirring was continued for another 2 hours. The reaction mixture was filtered and the catalyst was washed with methanol. The filtrate was concentrated under reduced pressure, and the residue was azeotropically dried with toluene to give 86 mg of the product.

Step D: (4R, 4S) -amino- (2S) -methyl-6-phenyl-
Reaction of 2,4-dihydro-1H-imidazo [1,2-a] [1,4] benzodiazepine with 6-aminoindole 6-aminoindole (71 mg) was dissolved at 0 ° C. in 14 ml of tetrahydrofuran and 151 μl of Treated with triethylamine. To this mixture was added 53 mg (0.18 mmol) of triphosgene. Additional triethylamine was added until the pH of the reaction mixture recorded 8.5 by wet pH paper. The reaction mixture was stirred at 0 ° C. for 5 minutes and then at room temperature for 5 minutes. The reaction mixture was cooled again to 0 ° C. and 133 mg (0.46 mmol) of (4R, 4S) in 2 ml of tetrahydrofuran.
-Amino- (2S) -methyl-6-phenyl-2,4-dihydro-1H-imidazo [1,2-a] [1,4] benzodiazepine. After 10 minutes, the reaction mixture was filtered and the filtrate was concentrated. The resulting residue was partitioned between 10% citric acid solution and ethyl acetate (75ml). The organic phase was then washed sequentially with a 10% sodium carbonate solution and brine, then dried and concentrated. The final product, the diastereomeric mixture, is purified by chiral preparative HPLC chromatography (Example 1, Step B).
18 mg of N-[(2S, 4S) -methyl-5-phenyl-2,4-dihydro-1H-imidazo [1,2-
a) [1,4] benzodiazepin-4-yl] -N'-
[6-Indolyl] -urea was obtained with a diastereomeric purity of 99%. 176-180 ° C. ¹ HNMR (CDCl _3): consistent with expected structure, confirming that it is in the form of a solvate; HPLC: purity 214nM>99%; FAB MS: 449 (M + + H).

_{C 27 H 24 N 6 O ·} 0.35EtOAc · 0.45H 2 O Elemental analysis: Calculated: C, 69.98; H, 5.73 ; N, 17.24 measurements: C, 70.02; H, 5.53 ; N, 17.22.

N-[(2S, 4R) -methyl-5-phenyl-2,4-dihydro-1H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl] -N '-[6-indolyl ] -Urea (21 mg total) was obtained with> 99% diastereomeric purity. 190-185 ° C (decomposition). ¹ HNMR (CDCl _3): consistent with expected structure, confirming that it is in the form of a solvate; HPLC: purity 214nM>98%; FAB MS: 449 (M + + H).

_{C 27 H 24 N 6 O ·} 0.40EtOAc · 0.65H 2 O Elemental analysis: Calculated: C, 69.33; H, 5.80 ; N, 16.96 measurements: C, 69.27; H, 5.47 ; N, 16.98.

Example 16 (4S) -N-[(2S) -methyl-6-phenyl-2,4-
Dihydro-1H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl]-(3-chlorophenyl) -1-acetamide and (4R) -N-[(2S) -methyl-6-phenyl -2,4-dihydro-1H-imidazo [1,2-a] [1,
4] Preparation of benzodiazepin-4-yl]-(3-chlorophenyl) -1-acetamide (4R, 4S) -amino- (2S) -methyl-6-phenyl-2,4 prepared according to Step C of Example 15. -Dihydro-1
H-imidazo [1,2-a] [1,4] benzodiazepine (74m
g, 0.25 mmol) in 48 ml (0.28 mmol) of 3-chlorophenylacetic acid, 38 mg (0.28 mmol) of 1-hydroxybenzotriazole hydrate, and 54 mg (0.28 mmol) in 3 ml of anhydrous N, N-dimethylformamide. (Mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 39 μl of triethylamine. The reaction mixture was stirred for 18 hours and concentrated. The residue was partitioned between ethyl acetate and water. Separate the organic phase, wash with brine,
Dehydrated. The combined organic extracts were concentrated to give 60 mg of crude product. Rexchrom Pirkle
HPL using covalent L-leucine column (5μ, 100A)
Purified to homogeneity with C. (Chromatography conditions: eluent: 1: 1 hexane-isopropanol containing 0.2% triethylamine: flow rate 2 ml / min). By this treatment, (4S) -N-[(2S) -methyl-6-phenyl-2,
4-dihydro-1H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl]-(3-chlorophenyl) -1
-Acetamide was obtained with a diastereomeric purity greater than 99%. 116-118 ° C (decomposition). ¹ H NMR (CDCl ₃ ): consistent with expected structure, confirming solvate form; HPLC: chemical purity of 214 nM>99%; R _f = 0.59 (chloroform-methanol, 95: 5) ^{FAB MS: 443 (M + +} H); C 26 H 23 ClN 4 O · 0.2CHCl 3 · 0.4H 2 O elemental analysis: calculated: C, 66.39; H, 5.10 ; N, 11.82 measurements: C, 66.42 ; H, 5.11; N, 11.72.

(4R) -N-[(2S) -methyl-6-phenyl-2,4
-Dihydro-1H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl]-(3-chlorophenyl) -1-
Acetamide was obtained with 99% diastereomeric purity. 120-124 ° C (decomposition). ¹ H NMR (CDCl ₃ ): consistent with expected structure, confirming solvate form; HPLC: purity of 214 nM>99%; R _f = 0.53 (chloroform-methanol, 95: 5) FAB MS : 443 (M ⁺⁺ H).

_{C 26 H 23 ClN 4 O ·} 0.15CHCl 3 · 0.3H 2 O Elemental analysis: Calculated: C, 67.36; H, 5.13 ; N, 12.02 measurements: C, 67.37; H, 5.13 ; N, 11.97.

Example 17 (4S) -N-[(2S) -methyl-6-phenyl-2,4-
Dihydro-1H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl]-(6-indolyl) -acetamide and (4R) -N-[(2S) -methyl-6-phenyl-
Preparation of 2,4-dihydro-1H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl]-(6-indolyl-1-acetamide Prepared according to Step C of Example 15 (4R, 4S) -amino- (2S) -methyl-6-phenyl-2,4-dihydro-1
H-imidazo [1,2-a] [1,4] benzodiazepine (78 m
g, 0.269 mmol) in 61 ml of N, N-dimethylformamide with 61 mg (0.35 mmol) of 6-indolylacetic acid, 47 mg (0.35 mmol) of 1-hydroxybenzotriazole hydrate and 67 mg (0.35 mmol) 1) -ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 0.35 mmol of triethylamine. The pH of the reaction mixture was adjusted to 8.5 with triethylamine and stirring was continued for 2 hours. The reaction mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The organic phase was separated, washed with brine and dried. The combined organic extracts were concentrated to give 190 mg of crude product. The resulting mixture was first purified by silica gel flash chromatography (gradient of 2 → 5% methanol in chloroform) and then
Rexchrom Pirkle covalent L-leucine column (5μ, 10
Purification to homogeneity by HPLC using OA) (chromatographic conditions: eluent: 1: 1 hexane-isopropanol containing 0.2% triethylamine: flow rate 2 ml /
Min), (4S) -N-[(2S) -methyl-6-phenyl-
2,4-dihydro-1H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl]-(6-indolyl) -1-
Acetamide was obtained with diastereomer purity greater than 85%. 138-140 ° C (decomposition). ¹ H NMR (CDCl ₃ ): consistent with expected structure, confirmed in solvate form; HPLC: chemical purity of 214 nM>99%; FAB MS: 448 (M ⁺ + H); C ₂₈ H _{25 N 5 O · 0.3CHCl 3 ·} 0.15 hexane elemental analysis: calculated: C, 70.66; H, 5.57 ; N, 14.11 measurements: C, 70.92; H, 5.48 ; N, 14.11.

(4R) -N-[(2S) -methyl-6-phenyl-2,4
-Dihydro-1H-imidazo [1,2-a] [1,4] benzodiazepin-4-yl]-(6-indolyl) -1-acetamide was obtained with 90% diastereomeric purity. 148-150 ° C (decomposition). ¹ HNMR (CDCl _3): expected consistent with structure confirmed to be a form of a solvate; HPLC: purity 254nM>95%; FAB MS: 448 (M + + H); C 28 H 25 N Elemental analysis for ₅ O · 0.55 CHCl ₃ : Calculated: C, 66.81; H, 5.02; N, 13.65 Found: C, 66.56; H, 5.05; N, 13.60.

────────────────────────────────────────────────── ─── Continuing the front page (72) Inventor Deipard, Robert M. New Jersey 07065, United States, Lowway, East Linkane Avenue 126 (56) References JP-A-63-166883 (JP, A) Published in the US and Europe 518484 (EP, A1) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 487/04 A61K 31/395 CA (STN) WPIL (Dentent)

Claims (4)

(57) [Claims] 1. A structural formula: Wherein R represents (1) phenyl substituted or unsubstituted with halo or C _1-3 alkyl such as chloro, bromo or fluoro, or (2) C _5-6 cycloalkyl , a is, C _1-3 alkyl, shows a hydroxy -C _1-3 alkyl or -C (= O) -O C _2-3 alkylene optionally substituted with (C _1-3 alkyl), R ¹ is Wherein R ² is chloro, C _1-3 alkyl or —CF ₃
Or R ¹ is Wherein R ⁴ represents C _1-6 alkyl, CF ₃ , cyclopropyl, 2,2-dimethylcyclopropyl, 2,2-difluorocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or , A substituent F,
_{Cl, Br, CN, NO 2} , CF 3, substituted with OCH ₃ or NH ₂ mono - or di - acceptable salts thereof the compound or a pharmaceutically having a a) substituted phenyl. 2. The compound of claim 1, wherein R ¹ is The compound according to claim 1, wherein R is phenyl or cyclohexyl. 3. The following table: 3. The compound according to claim 2, wherein the compound is selected from the group consisting of: 4. The following table: 3. The compound according to claim 2, wherein the compound is selected from the group consisting of: