JPS58210086A - Benzazepine derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the general formula in which R1 and R3 are hydrogen, lower alkyl, hydroxy, lower alkoxy or acyloxy, and R
, and R4 are hydrogen, or R1 and R2 and/or R5 and R4 together are an oxo group, provided that at least one oxo group is present; R is hydrogen, lower alkyl, C! ~C, carnic acid and its esters and amides, hydroxyC, ~C, alkyl, amine 02~C7 alkyl is still mono- or di-lower alkylaminoC1~C, alkyl; R6 has an atomic number of up to 35; R6 may be a halogen or hydrogen having an atomic number of 35 or less.

a pyrrolo[3,4-dl[2]benzazepine derivative of
It relates to N-oxides and pharmaceutically acceptable salts thereof.

This compound is an analgesic and anxiolytic.
c) Shows activity as an agent.

"Location having an atomic number of 35 or less" means bromo, chloro or fluoro, except as limited herein.

The term "lower alkyl" refers to straight and branched C1
- C1 hydrocarbon group, preferably C, C4 hydrocarbon group such as methyl, ethyl, propyl, isopropyl and the like.

"Acyloxy" refers to a group derived from an organic acid by removal of a hydrogen atom, i.e., a group of the formula -C-C-R1, where R is C7-C, alkyl, phenyl, or hydrogen; For example, it means acetyl, propionyl, butyryl, benzoyl, etc.

The term "62-C7 caranoic acid and its esters and amides" refers to the formula -C1-C6 alkyl-COR□ [wherein R21 is -1- or disubstituted by hydroxy, lower alkoxy/, amino, lower alkyl] is an amine].

The expression "pharmaceutically acceptable salts" refers to pharmaceutically acceptable salts with both monoacrylic acids and organic acids, such as monohydric acids, hydrochloric acid, nitric acid, methanesulfonic acid and 7-notluenesulfonic acid. Used to include. Such salts can be produced quite easily by those skilled in the art, depending on conventional methods and the nature of the compound used to form the desired ring.

Preferred compounds within the scope of the invention are those of formula I, ie Schiff bases. Historically preferred compounds are those of formula I in which R5 and R4 taken together are an oxo group.
It is a compound of Even more preferred compounds are those of the formula (2) in which R1 is hydrogen and Ro is preferably water: /i=: or lower alkyl, more preferably hydrogen or methyl. A preferred meaning of R is hydrogen or lower alkyl, more preferably hydrogen or methyl. R5 is preferably a halogen having an atomic number of 35 or less.

From the above, particularly preferred compounds within the scope of the present invention are those in which R and R1 are hydrogen or lower alkyl, preferably methyl, R2 is hydrogen, and R8 and R4
are taken together to be an oxo group and R5 is a halocarbon having an atomic number of 35 or less.

Preferred compounds are: 8-ID rho 6-(2-fluorophenyl)-3,4-
sohydrovirolo[a,4-d,][]2:lbenzazepine-12//)-one, 8-chloro-6-(2-chlorophenyl)-3,4-sohydrovirolo[3,4-dl[21benzazepine-1
(27/)-one, 8-chloro-3,4-dihydro-6-phenylpyrrolo[
3,4-dl[2]benzazepine-1(2//)-
8-chloro-6-(2-chlorophenyl)-3,4-dihydro-2-methylpyrrolo[3,4-dl[2]benzazepine-1(]//)-one, 8-chloro-6-( 2
-chlorophenyl)-1,4-dihydro-1-hydroxypyrrolo[3,4-c/:][]2]benzazepine-3(2+#)-one, 8-chloro-6-(2-chlorophenyl)-3, 4-dihydro-3-hydroxypyrrolo[
3,4-dl[2]benzazepine-1(211)-one, 8-chloroo-6τ(2-chlorophenyl)klo[
3,4-dl[2]benzaace1pin-1,3,-(2
11,411)-dione, 8-chloro-6-(2-chlorophenyl)-14-dihydropyrrolo[3,+-dl[2')benzazepine-3
(2// )-one-5-oxide, 8-chloro-6-
(2-chlorophenyl)-3,4-dihydropyrrolo[3
14-dl[2]benzazepine-1(2//)-one-5-oxide, 8-chloro-6-(2-chlorophenyl)-1-ethylly, 4-sohydrovirolo[3,4-d
l[2]Benzazepin-3(2//)-one, 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-1-methyl-3-oxo-2H-pyrrolo[3,4-d
'l[2'll-<Nsase 1 pin-2-acetic acid methyl ester and 8-chloro-6-(2-chlorophenyl)-1,4-novidro 1-methyl-3-oxo-2H-sip [3,
4-dl[2]benzazepine-2-acetamide.

A particularly clever compound is 281'Roro-6.
-(2-fluorophenyl)-1,4-dihydropyrrolo[3,4-dl[2:]-gunzuazepine-3(2H)
-on, 8-rioo-1,4-nohi)'low-6-phenylpioo
[3,4-d] C2]”]n-'7 Sethbin-3
2H)-one, 8-chloro-6-(2-chlorophenyl)-14-dihydro-1,2-tumethylpyrrolo[3°4-d:]]r2
] benzazepine-3211)-one and 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-2-(2-hydroxyethyl)-1-methylpyrrolo[3,4-dl[2]benzazepine-3( 27)
) - on.

The most preferred compound is: 8-chloro-6
-(2-chlorophenyl)-1,4-dihydropyrrolo[
3,4-dl[2]benzazepine-3(2H)-one, 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-1-notervirolo[3,4-dl[2]benzazepine-3 (2H)-one and H-8-chloro-6-(2
-chlorophenyl)-1,4-danidro-2-methylpyrrolo[13,4-cl[2]benzazepine-3(2/
/) - On.

Compounds of formula I, their N-oxides and pharmaceutically ♂1-
According to the invention, the acceptable salts are a) R, chloride or R5
is hydrogen or lower alkyl and the remaining substituents are as defined above and their N-
To produce an oxide, one of R21 and R31 is hydrogen and the other is hydrogen or lower alkyl, and R, R, and R
The definition is as described in Section 1.

b) R, i or R8 are hydrogen and the remaining substituents are as defined above, or R3 and R7 and R
In order to prepare compounds of formula 1 above, where 3 and R4 are each together an oxo group, and the remaining symbols are as defined above, R,-=4 or R5 is hydrogen and the remaining A compound of formula I in which the substituents of are as defined above or a compound of formula II above in which R11 and R8I are hydrogen is oxidized with lead(IV) carmenate in the presence of a strong acid, but c) R,i and In order to prepare a compound of formula (3) above, wherein R8 is acetoxy and the remaining substituents are as defined above, R1 or R8 is hydrogen and the remaining substituents are as defined above. A compound of formula I or a compound of formula 11 above in which RI+ and R31 are hydrogen is treated with lead tetraacetate in acetic acid, or d) R, or R5 is acyloxy and the remaining substituents are as defined above. To prepare a compound of formula I above, where R3 or R8 is hydroxy and the remaining substituents are as defined above, a compound of formula I above is treated with carmenic anhydride in the presence of a base. or e) R, - or R8 is lower alkoxy and the remaining substituents are as defined above. or hydroxy, and the remaining substituents are as defined above; or f) in order to prepare a compound of formula I above, in which R2 or R8 is hydrogen or alkyl, and the remaining substituents are as defined above, , R1R4, R2, R8
, R4, R3 and R6 are as defined in 1H, and optionally g
) prepared by converting a compound of formula I into a pharmaceutically acceptable salt, or converting a pharmaceutically acceptable salt of a compound of formula I into another pharmaceutically acceptable salt. can do.

The oxidation of the compound 2B according to embodiment α) of the invention with peracids is carried out in a manner known per se.

Suitable peracids for this oxidation step are, for example, m-chloroperbenzoic acid, pertrifluoroacetic acid, and the like.

Depending on the reaction conditions used, the corresponding compound or its N-oxide can be obtained. To obtain the compounds of the formula XA, the reaction is carried out in a lower carboxylic acid such as acetic acid, trifluoroacetic acid, propionic acid, or with such a carboxylic acid in a suitable inert solvent such as a chlorinated hydrocarbon such as methine chloride/, It is carried out rapidly in a mixture with an aromatic hydrocarbon, such as benzene, toluene, etc., in the presence of a strong inorganic acid, such as sulfuric acid. If the corresponding N-oxide is desired, the reaction is carried out in a suitable inert solvent such as a chlorinated hydrocarbon, such as methylene chloride, or an aromatic hydrocarbon, such as benzene, toluene, etc., in the absence of a strong acid. Beneficially done below. The oxidation of the compound (2) is preferably carried out at a temperature of about 0°C to about room temperature. R21
It should be noted that in the case of starting materials of formula (1) where and R5, are both hydrogen, a mixture of (1)-okyne and 3-oxo compounds is obtained. If the oxidation is carried out under strongly acidic conditions, 3-oxo compounds are mainly produced, whereas if the reaction is carried out in the absence of strong acids, 1-oxo compounds are the main products. The resulting mixture can be separated by standard methods such as fractional crystallization and chromatography.

The oxidation according to embodiment b) of the process is also carried out according to methods known per se. In this oxidation, lead(IV) carboxylates such as lead tetraacetate or lead trifluoroacetate (IV) are used in an inert solvent such as a chlorinated hydrocarbon such as methylene chloride or chloroform in the presence of a strong acid such as trifluoroacetic acid. IV) can be used appropriately. This reaction is preferably carried out at a temperature range of about 0°C to about room temperature. In the case of 2H compounds where R2I and R81 are hydrogen, 1-hydroxy-3-oxo, 3-hydroxy-1-oxo and 1,3-dioxo compounds are obtained. The mixture thus obtained can be separated by standard chromatographic methods.

The reaction according to embodiment C) of the present process is carried out according to methods known per se. The starting material can thus be reacted with lead tetraacetate in acetic acid, preferably at about room temperature. 171 as starting material. When using a compound of formula (1) in which and R, are hydrogen, a mixture of 1-acetoxy-3-oxo, 3-acetoxy-1-oxo and 1,3-bisacetoquino compounds of formula (1) will be obtained. The resulting mixture can be separated by standard loftography techniques.

According to embodiment d) of the present process, the reaction of a compound of formula 1 in which R1 or R8 is hydroxy with a carbo/anhydride is carried out in a manner known per se, preferably with a base such as pyridine, dimethylaminopyriline, This is carried out in the presence of N-methylpiperidine or the like. Inert solvents that can be used in this reaction are chlorinated hydrocarbons such as methylene chloride, ethers such as tetrahydrofuran, and the like. This reaction is advantageously carried out in a temperature range of about 0°C to about room temperature.

The etherification according to embodiment e) of the present process is carried out in a manner known per se by converting a compound of formula 1 or a compound of formula III, in which R, -4 or R3 is acyloxy, preferably acetoxy, into a strong acid such as methanesulfonic acid or the like. The reaction is advantageously carried out with an excess of lower vulcanol containing a catalytic amount.

This reaction is preferably carried out at a temperature between about 0°C and about room temperature.

- Deoxygenation according to embodiment f) of the present process may also be carried out according to known methods by dissolving the compound of formula (1) A in an inert solvent such as a chlorinated hydrocarbon such as methylene chloride, an aromatic hydrocarbon such as toluene, an ether such as tetrahydrofuran, etc. At,
This is advantageously carried out by treatment with an oxygenating agent, such as phosphorus trichloride or triphenylphosphine, between about room temperature and the reflux temperature of the solvent.

The starting material of formula (1) is a known one, or it can be produced in a similar manner to the production of known compounds. The following schemes illustrate the preparation of these compounds of formula II.

Scheme I where R1 is hydrogen or lower alkyl, and R6 and R6 are as defined above.

Ill→■ [A compound of the formula I is reacted with α-tosylalkylisocyanide in the presence of IJium using a mixture of dimethyl sulfoxide and an ether such as soethyl ether, sooxane or tetrahydrofuran as a solvent and a base such as hydrogenation. . The reaction temperature is approximately 40°C to approximately 40°C.
, with temperatures around room temperature being preferred. The above α-tosylalkyliso7anide is υan Leuse
Tetrahedron Letters by n etc.
3487 (1975).

(1)-TIa A compound of formula (1) can be reacted with hydrogen using glacial acetic acid as a solvent in the presence of a transition metal catalyst such as Raney nickel under pressures ranging from about atmospheric pressure to 5 atmospheres. Appropriate reaction temperature is approximately room temperature.

The ring-opened amine that initially forms is not isolated, but spontaneously cyclizes to product Ia.

■→V A compound of formula ■ can be reacted with a metal hydride reducing agent such as lithium aluminum hydride in an ethereal solvent such as tetrahydrofuran.

The reaction temperature can range from about -20<0>G to about room temperature, with about [theta]<0>C being preferred.

V→■α A compound of formula (1) can be reacted with manganese dioxide in an ethereal solvent such as tetrahydrofuran or other suitable solvent such as toluene. The amine thus produced undergoes spontaneous cyclization to form the product ■α. The reaction temperature can range from about room temperature to the boiling point of the solvent, about 40°C.
is preferred.

In the formula, R34 and R are lower alkyl, and R
2 and R6 are as described above.

Compound 20a' can be reacted with a strong base such as thium soisoprobylamide at a temperature between about -80°C and about 0°C, preferably -20°C. The resulting anion is treated with the desired alkylating agent such as a lower alkyl halide or sulfonate.

A mixture of isomers of formulas 11a" and 1b is produced, which can be separated by standard column chromatographic methods.

where R" is lower alkyl, R7 is lower alkyl, R3 and Ro are hydrogen or lower alkyl, n is an integer from 1 to 6, and R11XR3II
R11 and R8 are as described above.

fJc→IL→Uj Reacting a compound of formula C with a haloester such as ethyl bromoacetate or ethyl 3-bromopropionate in the presence of a base such as an alkali metal alcoholate in a polar solvent such as trimethylsulfoxide or dimethylformamide. can be done. Reaction temperature is approximately -20°C
It can range from about room temperature to about room temperature, with about 0'C being preferred. If desired, the product thus obtained can be treated with an alkali metal carbonate or hydroxide in an aqueous ethereal solvent such as tetrahydrofuran. Addition of a strong inorganic acid then yields the corresponding carboxylic acid of formula ■j.

0h→■f A compound of formula Hh can be reacted with ammonia or a heptano or no lower alkyl amine and a catalytic amount of its hydrochloride salt with a C,,C4 alcohol solvent. This reaction is typically carried out at about 100'C using pressurized equipment to include volatile reactants.

yh-+ni A compound of formula Dh can be reacted with a metal hydride such as lithium aluminum hydride in an ethereal solvent such as tetrahydrofuran or dioxane. The reaction temperature can range from about -80'C to about room temperature, with about 0'C being preferred.

C→Ha A compound of formula ffc is prepared in a polar solvent such as trimethyl sulfoxide or trimethylpolamide in the presence of a base such as an alkali metal alcoholate, where X is a halide or sulfonate, and R8, It can be reacted with a compound in which Ro and n are as described above. The reaction temperature is about -2
It can range from 0°C to about room temperature, preferably about room temperature.

c-ne A compound of formula fJc in a polar aprotic solvent such as trimethylformamide or trimethylsulfoxide;
An alkali metal alcoholate such as potassium salt or sodium methylate can then be reacted with an alkylating agent such as a lower alkyl halide or sulfonate. The reaction temperature can range from about 0°C to about room temperature, with about 0°C being preferred.

A compound of formula f or h is reacted with a metal hydride reducing agent such as lithium aluminum hydride in an ethereal solvent such as tetrahydrofuran.

The reaction temperature can range from about -20°C to about room temperature, with about θ°C being preferred.

Uc→lj A compound of formula fJc is prepared in the presence of a base such as an alkali metal alcoholate and trimethylformamide or trimethylsulfoxide, where Z is a hydroxyl group, and X and n are as defined above. It can be reacted with a compound of .

Suitable hydroxy-holding groups include tetrahydrobilanyl ether groups. Subsequent treatment with aqueous acid yields the desired end product.

■c→Uf In the presence of sulfoxide, X is as above, and R8, Ro and n
is as described above, and can be reacted with the compound.

The compounds of the present invention are useful as pharmaceuticals and are characterized by their activity as analgesics and anxiolytics. These compounds can be used in the form of conventional pharmaceutical preparations; for example, the compounds described above can be prepared in conventional organic or inorganic inert pharmaceutical carriers suitable for parenteral or enteral administration.
For example, it can be mixed with water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oil, gum, polyalkylene glycol, petrolatum, and the like.

These drugs can be administered in the usual pharmaceutical forms, such as solid forms such as tablets, dragees, capsules, herbal medicines, etc., or liquid forms such as solutions, suspensions, or emulsions. Furthermore, pharmaceutical compositions comprising compounds of the invention can be subjected to conventional pharmaceutical processing, such as sterilization, and can be loaded with conventional pharmaceutical excipients, such as preservatives, stabilizing agents, wetting agents, etc. agents, emulsifiers, salts to alter the osmotic pressure, or additives may be included. The compositions can also include other therapeutically active substances.

A suitable pharmaceutical dosage unit may contain from about 0.1 to about 500 n/9 of a compound of the invention, and for oral administration from about 0.1 m9 to about 1001 □! A dosage range of about 0.01 to about 5.0 is preferred for parenteral administration.
A dosage range of 01+'/ is preferred. However, for a particular patient, the particular dosage range should be adjusted according to the individual needs and judgment of the practitioner administering or supervising the compound.

It is to be understood that the dosages set forth herein are merely examples and are not intended to limit the scope of practice of the invention in any way.

As used herein, the term "dosage unit" refers to:
Figure 2 depicts pharmaceutically discrete units suitable as a unitary dosage for a mammalian patient, each containing a predetermined amount of active substance calculated to obtain the desired therapeutic effect.

The following data demonstrate the pharmacological activity of the compounds of the invention using pharmacological tests well known in the art.

sH-Soazepam Binding Assay This assay acts as a screen for anxiolytic drugs.

Rat brain cortical fragments were prepared and Mohle
r) and Kaida (Life 5sciences.

20.2101.1977) as stated by
1. The binding procedure was performed as follows, except that the Tris buffer was replaced with Krebs buffer.

Drugs were analyzed in triplicate. Radioactivity was measured by liquid synnarration counting. IC, the result.

(nM), ie the concentration required to inhibit binding by 50%.

Soazepam 50 Flunitriazeno 9m 1.8 (Fluni
trazttpam) Fluluazepam 1586 (Fl
urazepam) IC,o (nM) obtained by the compounds of the invention
The result: 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-2-methylgyroro[3,4-d][2]benzazepin-3(2B)-one[LD,. -800■/kg (poX mouse)]
0.0068-Chloro-6-(2-chlorophenyl)-1,4-dihydro-1-methylpyrrolo[3,4- d][2]benzazepin-3 (2B)-one [LD, o-lo o oq/ kp(po)Ji7(mouse)]
1.08-Chloro-6-(2-chlorophenyl)-1,4-dihydropyrrolo[3,4-dl[2]benzazepine-3(2H)-O 70.25 mol hydrate, micronized Tamono [LI ),. -1Oo01nV/kg (po) or more (mouse) 1 0.0038
-chloro-6-(2-chlorone azebin-3(2H)-one (LD, o-aoomyA9(po) mouse))
0.002 Intravenous Anti-Metrazole Test This test evaluates antispasmodic agents and is considered a precursor to anxiolytic activity.

In this study, 45-54 day old male mice housed for -weeks and fasted for approximately 24 hours were used. 5
Test compounds dispersed in % acacia were administered orally to mice, with 3 animals per dose. 1 hour later, metrazol 70m9/kl? (Spasticity dosage 1o
oq/ky) was administered intravenously and the animals were observed for 30 seconds for protection against convulsions. The number of animals protected from convulsions was determined. ED, the dosage at which 50% of the animals are protected from seizures. Closed and expressed.

Approximately ED5o all 5o womifu (A11ller) and tinter (Ta1nter) (Proc, S
oc, Ezp, Biol.

kfed, 57:261.1944).

Chlorsoazepoxide 3.9 Soazenocem 1,0 Sodium Phenoparbital 19 Obtained by the compounds of the invention El),, o■/kg p.

8-chloro-6-(2-chlorophenyl)-1,4-dihydro-2-methylgyroro[3,4- d][2]benzazepin-3 (2H)-one 0.088-chloro-6-( 2-chlorophenyl')-1,4-dihydro(2B)-one 0.088-chloro-6-(2-chlorophenyl)-1,4-dihydropyrrolo[3,4-dl[2]benzazepine-3(2H )-one 025 molar hydrate, micronized 007 nzazepine-3(2B)-off
The examples below 0.03 illustrate the invention, but do not limit it.

Example 1 a) Cupric sulfate 5 in m ammonium hydroxide solution 31
02, 300 v (46 mol) of activated zinc powder and 100 f of 2-pensoyl-4-chlorobenzoic acid.
(0.42 mol) was added. The mixture was refluxed for 3 days, during which time the initial volume was maintained by addition of concentrated ammonium hydroxide solution.

The mixture was cooled and excess zinc was removed by filtration. The F solution was made acidic to a pH value of 3 by adding concentrated hydrochloric acid to L7.
Ta. The resulting precipitate was collected by filtration and dried to constant weight to yield 2-pentrue-4-rioo benzoic acid as a white solid with a melting point of 142-1440C.

b) Lithium aluminum hydride 28.4 F (0.75 mol) in ether 800 me cooled to 0 °C
2-pentrue-4- in ether 250 m/
Chlorobenzoic acid 85.1 ? (0,345 mol) was added dropwise. The mixture was warmed to room temperature and stirred for 2 hours.

Excess amount of lithium aluminum hydride in water 28.5+n
l, 10% aqueous sodium hydroxide solution 285 Needles were removed under reduced pressure and 2-benzyl-4-
Chloropentyl alcohol was obtained which crystallized on standing, melting point 465-49°C.

C) Pyrisonium chlorochromate) 238r(1,1
mol) and 300 rnl of methylene chloride, 2-
Pentrue 4-chloropentyl alcohol 79.3 ?
(0.34 mol) was added. This mixture was stirred at room temperature for 2 hours. The chromium salts were precipitated by addition of 2.41 l:1 mixture of ether and petroleum ether and the precipitate was removed by filtration through Celite' [7]. The solvent was removed under reduced pressure to yield 2-pentrue-4-chlorobenzaldehyde as a yellow oil, which was used without further purification.

d) In a suspension of 10.5 F (0,437 mol) of mineral oil-free sodium hydride in 1.21 l of tetrahydrofuran are added
0,328 mol) was added dropwise. After hydrogen generation has finished (
2-pentrue-4-chlorobenzaldehyde 69.4 r (0
, 3 mol) was added dropwise. The mixture was stirred at room temperature overnight.

The tetrahydrofuran bath was decanted and concentrated at room temperature. The residue was partitioned between 21 parts of water and 1.5 parts of ether. The ether solution was separated, washed with water and dried over sodium sulfate. The ether was removed under reduced pressure to give 3-[2-benzyl-4-chlorophenyl]- as a yellow oil.
2-zolopennitrile was obtained, which was used without further purification.

6) 3-[2-pentrue-4-chlorophenyl]-
2-Proenitrile 28.8 r (0.14 mol)
, chromium trioxide 50 r (0.5 mol), methylene chloride l 00 +nl and acetic acid 300 - were stirred overnight at room temperature. Excess amount of chromium trioxide in ethanol 30
m was gradually added to drive it out. Add this mixture to 800 ml of water.
diluted with me and extracted with ether 500-. The ethereal solution was washed with water, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride bath. The ether solution was dried over anhydrous sulfuric acid and concentrated under reduced pressure to give 3-(2-pensoyl-4-chlorophenyl)-2 as a yellow oil.
-7'ronnitrile was obtained.

A sample of this product was subjected to preparative layer chromatography (silica gel, 2 parts; methylene chloride and 4 parts).
1 mixture), a white solid with a melting point of 87-89°C was obtained.

T? c3- (2-benzoyl-4-chlorophenyl)
-2-flopenitrile was prepared as follows: f) 2-amino-5 in 250 me of acetonitrile
- A solution of 92.7 r (0.4 mol) of chlorobenzenephenone with cupric chloride? Of (0,52 mol), t
-Butylnitrile 65 F (0.63 mol) was added to a mixture of acrylonitrile 500 and acetonitrile 500. After the addition was complete, stirring was continued for 2 hours at room temperature.

The mixture was diluted with 80 rnl of 6N hydrochloric acid and 1500 mZ of water, extracted with ether and dried over anhydrous sodium sulfate. The ether solution was concentrated under reduced pressure to give a brown oil, which contained the desired product, α,4-sochloro 2-(
benzoyl)benzenepronocenenitrile and 2,5-
Contains zochloropenzophenone. This oil was triturated with a mixture of ether and petroleum ether to give the desired product as a tan solid. A small portion of the desired product was recrystallized from a mixture of ether and petroleum ether, melting point 6.
Pale yellow needles of 9-71'C were obtained.

g) α,4-Sochloro-2-(benzoyl)benzenegulononitrile so, tay (0,t 6
s mol), potassium carbonate 17 f (0.14 mol)
, 50.9 t (o, s mol) of potassium bicarbonate and 510 mZ of trimethyl sulfoxide at room temperature.
Stir for hours. The mixture was diluted with 1.51 parts of water and the resulting precipitate was collected by filtration. Recrystallized from a mixture of methylene chloride and ether to give 3-(2-benzoyl-
4-chlorophenyl)-2-propenenitrile was obtained.

*** h) 3-(2-benzoyl-4-chlorophenyl)-
2-Propenenitrile 10. 'M' (40 mmol),
A mixture of tosylmethyliso/anide 532 (38 mmol), trimethyl sulfoxide 75- and ether 150- was added dropwise to a M suspension of 50% sodium hydride 37F (77 mmol) in mineral oil and ether 170-. After the addition was complete, stirring was continued for 2 hours. The mixture was diluted with water 7 and the ether layer was separated. The aqueous solution was extracted with ether. The combined ether extracts were washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a dark green oil. Column chromatography (Nrikaguru 3Of) f'
4-[2-pensoyl-4-chlorophenyl':l-111-virol-3-cal day] as an off-white prism with a melting point of 175-177 °C (eluent, 5% ether in methylene chloride) ? I got nitrile.

i) 4-[2-benzoyl-4-chlorophenyl'
) -1H-pyrrole-3-cal is nitrile 4.0r (
13 mmol), Raney nickel 4v and acetic acid 300m
The mixture of 1 was hydrogenated in a Pαrr apparatus for 4 hours. Separate the Raney nickel and add liquid F to 400 liters of ice water.
diluted with nl. The acetic acid was neutralized with sodium bicarbonate and the resulting solution was extracted with methylene chloride. The methylene chloride solution was washed with water and dried over sodium sulfate. The methylene chloride solution was concentrated to give a yellow solid. 8-chloro-6-phenyl-2fl, 41 recrystallized from methylene chloride/ether as a white solid, mp 203-206 °C.
1-Virolo[3,4-dl[2]benzazepine was obtained.

j) 8-chloro-6-phenyl-2IJ14B-pyrrolo(3,4-
dl[2'l benzazepine4. Of(13,6mi IJ
mol) was added in one portion and the resulting mixture was stirred for 1 hour. Excess peracid was driven off by the addition of saturated aqueous sodium bisulfite solution and the mixture was concentrated under reduced pressure.

The residue was partitioned between methylene chloride and water and neutralized with false ammonium hydroxide solution. The methylene chloride M solution was washed with brine, dried over anhydrous sulfuric acid, and concentrated under reduced pressure to give a dark residue. This residue was purified by column chromatography (silica gel 1007; release agent, 5-% methanol in methylene chloride) and crystallized from ethyl acetate as 8-chloropropylene as pale yellow prisms with a melting point of 205-208°C. -1,4-dihydro-6-phenylpyrrolo[3,4-d][2)benzazepine-3(2H)-
Onwo got.

Thin layer chromatography of the crystalline P solution revealed the isomer 8-chloro-3,4-7hydro-6-phenylvirolo[3,4-
d] [2] Indicated the presence of penzua7-pin-1(2H)-one.

Example 2 α) α,4-Sochloro-2-(2-fluorobenzoyl)benzeneglono9ni)! Example 1f of J#
) was carried out in the same manner as for the production of 4-sochloro-2=(benzoyl)benzenepronozonenitrile, and pale yellow prisms with a melting point of 94-95°C were obtained.

b) 3-C2-<2-fluorobenzoyl)-4-
[chlorophenyl]-2-7'-opennitrile was prepared in a similar manner to the production of 3-(2-benzoyl-4-chlorophenyl)-2-7'-opennitrile described in Example 1g), with a melting point of 137 Off-white prisms at ˜139° C. were obtained.

t&3-[2-(2-fluorobenzoyl)-4-chlorophenyl'll-2-7'robennitrile was prepared as follows: C) 5-chloro-2'-fluoro-2-iodobenzophenone5. 0f (14 mmol), triethylamine 2mf (14.3 mmol), acrylonitrile 2+
n1 (30 mmol) and acetic acid.! Radium 35m9 (
t, s mmol) was refluxed for 16 hours under an alyne atmosphere. The mixture was diluted with 100ml of IN hydrochloric acid and the resulting precipitate was collected by filtration. The precipitate was washed with ether and air-dried to give 3-(2-(2-fluorobenzoyl)-410lofenyl)-,2-10pennitrile as an off-white solid with a melting point of 130-133°C. Ta.

*** d) 4-[2-(2-fluorobenzoyl)-4-
Chlorophenyl]-1H-pyrrole-3-carbonitrile was prepared in a similar manner to the preparation of 4-[2--<chlorophenyl]-1H-pyrrole-3-carbonitrile described in Example 1h). melting point 177-1
Grayish prisms at 79°C were obtained.

g) 4-(2-(2-fluorobenzoyl)-4-
A mixture of 3.0 f (9 mmol) of [chlorophenyl]-IH-virol-3-carbonitrile, about 3 f of Raney nickel and 150 rnl of glacial acetic acid was added in a Soll apparatus to
Hydrogenation was carried out at 0 psj for 6 hours.

The Raney nickel was separated and the acetic acid was removed under reduced pressure to yield a yellow oil. The yellow oil was poured onto ice, made basic with ammonium hydroxide, and extracted with methylene chloride. The methylene chloride bath was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give tan crystals. Recrystallized from a mixture of ether and methylene chloride to give 8-chloro-6-(2-fluorophenyl)-2H,4H-pyrrolor3,4-dl[2
] Benzazepine LLC.

f) 30 cX in 100 m/1% solution of concentrated sulfuric acid in acetic acid
Hydrogen peroxide solution5. Ornl (42.1 mmol) was added in one portion. After stirring for 1 hour, 8-chloro-6-(
2-fluorophenyl)-2H,4H-pyrrolo[3,4
-d] [2] Benzazepine 5. Of (16.0 mmol) was added and the resulting mixture was stirred for 4 hours.

Excess peracid was driven off by addition of saturated aqueous thorium bisulfite solution [7] and the mixture was concentrated under reduced pressure. The residue was partitioned between methylene chloride and water and made basic with concentrated ammonium hydroxide solution. The methylene chloride solution was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield residue 502. After purification by HpLC (silica gel; releasing agent, 3% methanol in methylene chloride) and crystallization from ethyl acetate, the initial product had a melting point of 22
8-chloro-6 as light yellow prisms at 3-225 °C
-(2-fluorophenyl)-3,4-dihydropyrrolo[3,4-d][2]benzazepine-1(2H)-one was obtained.

After further elution and crystallization from ethyl acetate, a second product was obtained as a colorless prism with a melting point of 217-218°C.
Chloro-6-(2-fluorophenyl)-1,4-dihydro 20 mouths [3,4-dl “2]benozazebin-3(
2H)-Onwo obtained.

Example 3 a) Preparation of α,4-sochloro-2-(2-chloropensoyl)benzenezologunnitrile QIJ Example 1f
), a grayish white prism with a melting point of 102-103°C was obtained.

b) 3-[2-(2-chlorobenzoyl)-4-chlorophel 1-2-7' 3-(2-benzoyl-4-chlorophenyl)-2- as described in example 1g) for the preparation of robennitrile It was carried out in a similar manner to the production of propene nitrile to obtain grayish white prisms with a melting point of 140-141°C.

C) 4-(2-(2-chlorobenzoyl)-4-chlorophenyl 4-12-pensoyl-4-chlorophenyl"'I as described in Example 1h) for the preparation of 1-14-pyrrole-3-calcy-nitrile -IH-pyrrole-3-carbonitrile produced in the same manner as the melting point 182~
A grayish prism of 184°G was obtained.

d) 8-chloro-6-(2-chlorophenyl)-2H
, 4H-pyrrolo[3,4-d][2]8-chloro-6-(2-fluorophenyl)-2H, the preparation of which is described in Example 2e).

4H-pyrrolo[3,4-d][21 It was carried out in the same manner as in the production of benzazepine, and the melting point was 204-2060C.
Obtained a Luminous Prism.

e) 2% concentrated sulfuric acid in acetic acid 80% in 22 S nrl
8-chloro-6-(2-chlorophenyl)-2B, 41-1-pyrroloC3', 4-d in a mixture of m-7/roroperbenzoic acid 7.6 r (35,2 mmol)
] [2'11 Benzazepine 10. Of (30,5
mmol) was added at once and stirred at room temperature for 1 hour. Excess peracid was expelled with a saturated sodium bisulfite water bath;
The mixture was partitioned between methylene chloride and water and made basic with concentrated ammonium hydroxide solution. The methylene chloride solution was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a yellow residue 1002. 8-chloro-6-(2-chlorophenyl)-1,4 crystallized from methylene chloride as pale yellow prisms, mp 243-244°C.
-dihydropyrrolo[3,4-dl[2]benzazepine-3(2H)-one was obtained. The mother liquor was crystallized from ethyl acetate to give 8-chloro-6-(2-chlorophenyl)-3,4-dihydropyrrolo[3,4-d][:2'll benzazepine as pale yellow prisms with a melting point of 195-197 °C. -1(2H)-one was obtained.

Example 4 To 195ml of a 1% solution of concentrated sulfuric acid in acetic acid was added at once 9.8ml of a 3o% hydrogen peroxide solution. This mixture was stirred at room temperature for 1 hour. Add 8-chloro6-(2
-chlorophenyl)-2H,4H-pyrrolo[a,4-d
1[2'll Benzazepine 989 (30 mmol) was added in one portion and stirred at room temperature for 2.5 hours. Excess peracid was driven off by addition of saturated aqueous sodium bisulfite solution and the mixture was concentrated under reduced pressure. The residue was partitioned between methylene chloride and water and made basic with concentrated ammonium hydroxide solution. The methylene chloride solution was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a yellow residue 1002. This residue was purified by column chromatography (Silica Glu 20 (1'iii carrier, 5% methanol in methylene chloride) and after crystallization from ethyl acetate the initial product was as pale yellow prisms with a melting point of 195-197 °C. 8-chloro-6-(2-chlorophenyl)-3,4-dihydropyrrolo[: 3,4-d
] C2] benzazepin-1(2H)-one was obtained.

After further elution and crystallization from methylene chloride, the second product was 8-chloro6-(2-chlorophenyl)-1,4-dihydropyrrolo[3,4- dl[:2]benzazepine-
3(2H)-one was obtained.

Example 5 8-chloro-6-(2-chlorophenyl)-2H in methifluoride chloride 350me cooled to 0<0>C.

4H-pyrrolo[3,4-dT+[2)benzazepine 1
0. 80% m- in a solution of Or (30,5 mmol)
Chloroperbenzoic acid ls, o y (69,s mmol) was added in one portion. The reaction mixture was stirred at 0°C for 25 hours and then neutralized with a saturated aqueous sodium bicarbonate bath.

The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow residue 11. I got Of. This residue was purified by column chromatography (silica glue 1
50f'; 5% methanol in methylene chloride) to give a mixture of two products. This mixture was further chromatographed (alumina 150ri eluent,
After purification with 5% methanol in methylene chloride and crystallization from a mixture of ethyl acetate and methanol, the initial product was 8 as pale yellow prisms with a melting point of 243-244 °C.
-chloro-6-2-(chlorophenyl)-3,4-dihydropyrrolo[3,a-dl[2]benzazepine-1(
2H)-one-5-oxide was obtained.

After further elution and crystallization from a mixture of ethyl acetate and methanol, the second product [2]8-chloro-6-(2 - for tlffOff), 1.
4-dihydropyrrolo[3,4-dl[2'll benzazepine-3(2H)-one-oxide was obtained.

Example 6 α) Trimethyl sulfoxide 150- and ether 10
3-[2-(2-chlorobenzoyl)-4- in 0 mZ
Chlorophenyl]-2-propenenitrile 33.9 F
(0,11 mol) and 20 f (0,96 mol) of 1-tosylethyl isocyanide were immersed in a water flame at room temperature in ether 100 rn! dropwise into a suspension of 4.6F (01 mol) of a 50% dispersion of sodium hydride in mineral oil. Stirring was continued for 2 hours at room temperature. Add this mixture to 1.
21 and IN hydrochloric acid 40- and extracted with methylene chloride. Wash the methylene chloride bath solution with water and dilute with anhydrous sulfuric acid)
Dry over IJum and concentrate under reduced pressure to give a dark green oil. crystallized from a mixture of ether and petroleum ether;
4-[4-
Chloro-2-(2-chlorobenzoyl)phenyl]-5
-Methyl-IH-pyrrole-3-carbonitrile was obtained. Recrystallization from ether gave the desired product as colorless crystals with a melting point of 210-211°C.

6-chloro-8-(2-chlorophenyl)-1,8-dihydro-8-hydroxy-2-, melting point 221-225°C
A second product of crystals consisting of methylindeno[2,1-b]pyrrole-3-carbonitrile was obtained from ether. Recrystallization from ether gave pale yellow prisms that bath melted at 232-237°C.

j) 8.5 f (24 mmol) of 4-[4-chloro-2-(2-chlorobenzoyl)phenyl-5-methyl-IH-pyrrole-3-carbonitrile in a mixture of 1 teaspoon Raney nickel and 250 ml of glacial acetic acid. /6-
Hydrogenation was carried out overnight at 55 psj in a full-scale apparatus. The catalyst was removed door to door [7, acetic acid was removed under reduced pressure]. The residue was diluted with water, made basic with concentrated ammonium hydroxide solution, and the resulting precipitate was collected by filtration. This precipitate was dissolved in tetrahydrofuran, dried over anhydrous sodium sulfate,
Concentrated under reduced pressure. The residue was crystallized from a mixture of ether and petroleum ether to give off-white crystals with a melting point of 219-222°C. Recrystallized from a mixture of ether and methylene chloride to give 8-chloro-6-(2-chlorophenyl)- as colorless crystals, melting point 221-22,500.
1-Methyl-2H,4H-pyrrolo[3,4-dJc2]
Get benzazepine.

C) 1 ml of 30% hydrogen peroxide was added at once to 40+nt of a 1% solution of concentrated sulfuric acid in acetic acid. Stir for 1 hour -p,
H1s-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-20 [3,4-d][2]benzazegin 2Of (58 mmol) was added to the resulting mixture. was stirred at room temperature for 30 minutes.

The mixture was diluted with methylene chloride and neutralized with concentrated ammonium hydroxide solution. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a dark residue. Crystallized from ethyl acetate, melting point 239-241
8-chloro-6-(2-
chlorophenyl)-1,4-dihydro-1-methylpyrrolo[3,4-d][2]benzaze V-3(2H)-
Example 7 α) 30 m of dry trimethylformamide cooled to 0°C
Potassium t-butyrate 032 (26 mmol) in /
8-chloro-6-(2-chlorophenyl)-
2H,4H-pyrrolo[3,4-d][2]benzazepine 072 (2,2 mmol) was added in one portion. After stirring for 15 minutes, 1.0 m/(16 mmol) of methyl iodide was added and the mixture was warmed to room temperature. Water was added and the mixture was extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow oil. Purified by column chromatography (silica glue 20v; eluent, 5% ether in methylene chloride) and recrystallized from a mixture of ether and petroleum ether, the 8-chloro-6- (2-chlorophenyl)-2-methyl-2H,4H-pyrrolo[,4-d][2
] I got Penn's Azebin.

Equimolar amounts of the above basic compound and methanesulfonic acid were added to methanol, and 8-chloro-6-(2-chlorophenyl)-2-methyl-2H94H-pyrrolo[3,4-d
The methanesulfonate salt of 'll[2]penzazebi/ was prepared and the salt was isolated by precipitation by addition of ether. recrystallized from a mixture of methanol and ether;
The methanesulfonate was obtained as orange prisms with a melting point of 200-203°C.

b) 30% in 56 ml of a 1% solution of IIk sulfuric acid in acetic acid
1.4-hydrogen peroxide was added in one portion. After stirring for 1 hour, 8-chloro-6-(2-chlorophenyl)-2-methyl-2H,4H-pyrrolo[3,4-d][2'll benzazepine 28 F (8,2 mmol) was added. and the resulting mixture was stirred at room temperature for 16 hours.

The mixture was concentrated under reduced pressure and the residue was partitioned between methylene chloride and water. The methylene chloride solution was neutralized with concentrated ammonium hydroxide solution, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow residue. The residue was purified by column chromatography (silica glu 10 (1');
After purification (eluent, 5% methanol in methylene chloride) and crystallization from ether, 8-chloro-
6-(2-chlorophenyl)-3,4-dihydro-2-
Methylpyrrolo[3,4-d'llll[2]benzazepin-1(2E)-one was obtained.

After further separation and crystallization from ether, the second product was a pale yellow prism with a melting point of 173-175°0.
Chloro-6-(2-chlorophenyl)=1,4-dihydro-2-methylpyrrolo[3,4-d][2]benzazepin-3(2H)-one was obtained.

Example 8 a) 3-[2-(2-chlorobenzoyl)-4-chlorophenyl)-' 2-flopennitrile in a mixture of 200 ml of ether and 200 me of trimethylsulfoxide 30. Of (99,3 mm IJ mole) and H1
-) Silzorobyl isocyanide 23. A solution of Of' (103 mmol) in ether 145m7! 6.7 f' of a 50% dispersion of sodium hydride in mineral oil (140 m/liter) was added dropwise over 20 minutes to the ice-cooled suspension.

After stirring for 1.5 hours, 500 ml of water and then 50 ml of IN hydrochloric acid were added dropwise. Aqueous solution in ether 3 x 500
− was extracted. Combine the ether solutions and add water 6 x 8001
nl! , dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a dark residue 3501.

After purification by column chromatography (silica Glu 500fi eluent, 50% ether in petroleum ether) and crystallization from a mixture of ether and methylene chloride, the initial product was as off-white prisms with a melting point of 163-164 °C. 4-(4-chloro-2-(2-chlorophenyl)phenyl]-5-ethyl-IH-virol-3-carnitrile was obtained.

Further elution [7, after crystallization from ether, 6- as a second product, as colorless prisms with melting point 172-174 °C
Chloro-8-(2-chlorophenyl)-2-ethyl-1
, 8-dihydro-8-hydroxyindeno[2,1-b
1-pyrrole-3-carbonitrile was obtained.

b) 4-(2-(2-chlorobenzoyl)-4-chlorophenyl]-5-ethyl-I II-pyrrole-
3-Cal d? A mixture of 3.3 r (8.9 mmol) of Raney nickel, 0.5 teaspoon of Raney nickel, and 100 r/n of acetic acid was hydrogenated in a Mohr apparatus at 50 psi for 16 hours. Pass Raney nickel through a Celite pad [7
The p-liquid was removed by filtration, and the p solution was concentrated under reduced pressure to obtain a dark-colored residue. The residue was partitioned between ice water and a needle and made basic with concentrated ammonium hydroxide solution. The ether was removed under reduced pressure and the aqueous residue was stirred for 1 hour. The resulting precipitate was collected by filtration and dissolved in tetrahydrofuran.

The tetrahydrofuran solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was converted from ether as crystals L, yellow prisms with a melting point of 251-2530C, 8-chloro-6-(2-chlorophenyl)- 1-
Ethyl-2H,4H-pyrrolo[3,4-d][2]penzazebin was obtained.

Recrystallization from a mixture of ether and methylene chloride gave off-white prisms with a melting point of 254-255°C.

C) 0.9 i (7.9 mmol) of 30% hydrogen peroxide was added in one portion to a 1% bath of concentrated sulfuric acid in acetic acid. After stirring for 1 hour, 8-chloro-6-(2-chlorophenyl)-1-ethyl-2B,4B-bio[3,4-d][
2] Benzazepine'ZOy (s6 mmol) was added and the resulting mixture was stirred for 20 minutes. Excess peracid was driven off by addition of saturated aqueous sodium bisulfite solution and the mixture was concentrated under reduced pressure. The residue was partitioned between methylene chloride and water and neutralized with concentrated ammonium hydroxide solution. The methylene chloride solution was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting oil was crystallized from ether to give yellow prisms with a melting point of 233-235°C and [8-chloro-6=(2-chlorophenyl)-1
-ethyl-1,4-sohydrovirolo[3,4-d][2
] Benzazepin-3(2H)-one was obtained. Recrystallized from a mixture of ethyl acetate and methanol, melting point 236~
A colorless prism was obtained at 237°C.

Example 9 a) 8-chloro-6-(2-chlorophenyl)- is added to an ice-cold solution of 0.8 m/(8 mmol IZ) of potassium tert-butyrate in 20 m/dry trimethylformamide.
1-Methyl-2H,4H-pyrrolo[3,4-d 1[2
] Benzacebia'IO? (5.8 mmol) was added at once. After stirring for 10 minutes at 0 °C, 0.8 m/(128 mmol) of methyl iodide was added and the resulting solution was stirred for 20 minutes.The #-0 mixture was diluted with water and the precipitate formed. The material was collected by filtration. The solid was dissolved in methylene chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 8- as orange prisms with a melting point of 200-202 °C.
Chloro-6-(2-chlorophenyl)-1,2-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine was obtained. The sample was recrystallized from a mixture of ether and methylene chloride to give pale yellow prisms with a melting point of 203-204°C.

b) To 33me of a 1% solution of concentrated sulfuric acid in acetic acid, 0.7 mZ (5.9 mmol) of 30% hydrogen peroxide was added in one portion. After stirring for 1 hour, 8-chloro-6-(2-chlorophenyl)-1,2-tmethyl-2H.

4H-pyrrolo[3,4-d]r2']benzazepine t
s y (5.0 mmol) and the resulting solution was diluted with 2
Stir for 0 minutes. Excess amount of peracid is replaced with saturated bisulfite)
It was driven off by the addition of aqueous IJum solution and the mixture was concentrated under reduced pressure. Partition the residue between methylene chloride and water;
Made basic with concentrated ammonium hydroxide solution. The methylene chloride solution was washed with brine, dried over anhydrous sulfuric acid, and concentrated under reduced pressure to give a yellow residue. 8-chloro-6-(2-chlorophenyl)-1, crystallized from ethyl acetate as pale yellow prisms, mp 207-208°C.
4-dihydro-1,2-trimethylpyrrolo[3,4-d]
[2] Obtained benzazepine-3(2H)-one.

Example 1O a) Potassium t- in dry trimethylformamide 30-
8-chloro-6-(2-chlorophenyl)-1-
Methyl-2H,4H-pyrrolo[λ4-d][2]benzazepine zOf (58 mmol) was added in one portion. 0℃
After stirring for 15 minutes at
(7,'l mi') mol) was added, and the solution was
Stir for a minute. The mixture was diluted with water and extracted with a needle. The ether solution was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give an oily residue. This residue was subjected to column chromatography (silica gel 4O
After crystallization from a mixture of ether and petroleum ethyl, 8-chloro-6-(2- Chlorophenyl)-1-methyl-21/I41I-pyrrolo r3,4-d-1
r21 Benzazepine-2-acetic acid methyl ester was obtained.

b) 0.8 m/' of a 30% aqueous peroxide bath was added at once to 35 m/' of a 1% solution of concentrated sulfur in acetic acid. Hayashi, who stirred this solution for 1 hour, 8-chloro-6-(2-chlorophenyl)-1-methyl-2H1411-pyrrolo r3,
4-d1('21 Benzazepine-2-acetic acid methyl ester zoy (t8 mmol) was added and the resulting solution was stirred for 30 minutes. Excess peracid was driven off by addition of saturated aqueous sodium bisulfite solution. The mixture was concentrated under reduced pressure.

The residue was partitioned between methylene chloride and water and neutralized with concentrated ammonium hydroxide solution. The methylene chloride solution was washed with brine, dried over anhydrous sulfuric acid, and concentrated under reduced pressure to give a residue, which was crystallized from ethyl acetate to give a pale yellow color with a melting point of 221-223°C. 8-chloro-6-(2-chlorophenyl)-1,4-' as a prism
/hydro1-meF-ru3-oxo-2H-pyrrolo[3,4-d'1[2-1 benzazepine-2-acetic acid methyl ester was obtained. Recrystallization from ethyl acetate [7] gave colorless prisms, melting point 223-224°C.

Example 11 α) 8-Chloro-6-(2-chlorophenyl)-
1-Methyl-2H,411-gyrolo[3,4-d]c2
] Ben x: 7 Zebi 74. Of (11.7 mmol) was added in one portion. After stirring for 15 minutes at 0'C, 2-chloroacetamide 142 (15,0 IJ moles) was added and the resulting solution was stirred for 5 minutes. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a red residue. The residue was purified by column chromatography (silica gel 1009; fd4p agent, 50% ether in tetrahydrofuran) to give 8 as a yellow solid.
-Chloro-6-(2-chlorophenyl)-1-methyl-
2H,4B-pyrrolo[3°4-d][2]benzazepine-2-acetamide was obtained. Recrystallization from ethyl acetate gave colorless needles with a melting point of 142-145°C.

b) 30% hydrogen peroxide in a 1% bath of #sulfuric acid in acetic acid 0
．． 7 ml (6.2 mmol) were added at once.

After stirring for 1 hour, 8-chloro-6-(2-chlorophenyl)-1-methyl-211,4H-pyrroloC3,4-
d]c2]benzazepino-2-acetamide 1.7
f (4.2 mmol) was added and the resulting solution was stirred for 30 minutes [7. Excess peracid was driven off by the addition of saturated aqueous sodium bisulfite 12 and the mixture was concentrated under reduced pressure. partitioning the residue between methylene chloride and water;
Neutralize with concentrated ammonium hydroxide bath solution (2. Wash the methylene chloride bath solution with salt water, dry over anhydrous sodium sulfate,
Concentrate under reduced pressure (7 m). The residue is crystallized from ethyl acetate,
8-chloro-6-(2-chlorophenyl)-1,4-dihydro-1-methyl-3-oxo-2H-pyrrolo[3,4-d
[2] Benzazepine-2-acetamide was obtained.

Example 12 a) 8-chloro- in 40 ml of tetrahydrofuran
6-(2-chlorophenyl)-1-methyl-21'l,
4B-pyrrolo[3,4-d',Ir2]]benzazepine-2-acetic acid methyl ester 409 (9,6
0.0 mmol) of lithium aluminum hydride in 50 mt' of tetrahydrofuran cooled to -78°C.
89 (21.0 mmol) in a solution of 7 oz. is.

After the addition was complete, the reaction mixture was warmed to 0°C and stirred for 7.30 minutes. Add this mixture to 1 mff of water, 3. A' Treated with 1 ml of sodium hydroxide water bath solution and 3 ml of water (7 mL).

The resulting precipitate was separated by P solution [7], and the P solution was concentrated under reduced pressure.

The residue was crystallized from ether, melting point 149-152°C.
8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4
-d]czl benzazepine-2-ethanol was obtained.

Noble crystals were obtained from a mixture of ether and methylene chloride to give white prisms with a melting point of 151-153°C.

b) 30% hydrogen peroxide in a 1% solution of concentrated sulfuric acid in acetic acid 0
．． 58 ml (5.1 mmol) were added at once.

After stirring for 1 hour, 8-chloro-6-(2-chlorophenyl)-1-methyl-2H24H-pyrrolo[3,4-d
[2] Benzazepine-2-ethanol 1.3 y
(13s +) mol) was added and the resulting solution was stirred for 30 minutes. The excess peracid was driven off by the addition of saturated sodium bisulfite solution and the mixture was concentrated under reduced pressure.
Also. The residue was partitioned between methylene chloride and Kyoma and neutralized with concentrated ammonium hydroxide solution [7]. The methylene chloride solution was washed with brine, dried over anhydrous sodium sulfate-L, and concentrated under reduced pressure to give a yellow residue. Column chromatography (silica separation 302; bathing agent, 3% in methylene chloride)
After purification with methanol) and crystallization from a mixture of ether and methylene chloride, the initial product has a melting point of 15
2-[2-acetoxy)ethyl]-8-chloro-6-(2-chlorophenyl)-1,4-dihydro-1-methylpyrrolo(3,4-
d] [2] Benzazepine-3(2H)-one was obtained.

After further stripping and crystallization from a mixture of ethyl acetate and ether, the second product is 8-chloro-6-(2-chlorophenyl)-1,4-sohydro 2 as colorless prisms with a melting point of 164-165°C. -(2-Hydroxyethyl)-1-methylpyrrolo[3,4-d]ll'2]benzazepin-3(2H)-one was obtained.

Example 13 Trichloroacetic acid 2.62 (1
8-chloro-6-(2-chlorophenyl)-3,4-sohyto30pyrroloC3,4-d in an ice-cold bath solution of lead tetraacetate (5,8 mmol) and lead tetraacetate 2-Of (44 mmol).
[C2]-snzazepine-1 (2#)-one 0.7
f (2 mmol) was added in one portion. After stirring for 1 hour,
The mixture was neutralized with saturated aqueous sodium bicarbonate solution. The methylene chloride bath was washed with water, dried over anhydrous sulfuric acid (IJ) and concentrated under reduced pressure to give a yellow residue. The residue was subjected to column chromatography (silica gel 10F; Yushima 1F).
After crystallization from ethyl 8-chloro-6-(,2-chlorophenyl)-3,4-dihydro -3-hydroki mpirolo [
3I4-dl[2]benzoin-1(2B)-one was obtained.

Example 14 1.32% of trichloroacetic acid in 15 mff of methylene chloride (
7,9 mmol) and lead tetraacetate 1. 8-chloro-6-(2-chlorophenyl)-1,4-'/hydropyrrolo[3,4-
0.35S' (1 mmol) of d'3C2''3benzazepin-3(2H)-one was added in one portion. After stirring for 4 hours, the mixture was neutralized with a saturated aqueous sodium bicarbonate bath. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow residue. Column chromatography (silica gel 10R;
bath! 1ift agent (5imethanol in methylene chloride), crystallized from ether, mp 247-2
8-chloro-6-(2
-chlorophenyl)-1,4-dihydro-1-hydroxypyrrolo[3,4-d][2]penzazepi/-3(,
2II)-one was obtained.

Example 15 200 ml of trichloroacetic acid in 50 m/m of methylene chloride
(120 mmol) and lead tetraacetate 14. Of(
8-chloro-6-(2-chlorophenyl')-211,4M-pyrrolo3.4-d''3[2]benzazebon 5, Or
(15.2 mmol) was added in one portion. The mixture was stirred at room temperature for 4 hours, then diluted with methylene chloride and water.
It's 7. The methylene chloride solution was washed with a saturated aqueous sodium bicarbonate bath, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A green residue was obtained.

This residue was purified by column chromatography (silica glue 1o
After crystallization from ether, the initial product and 1.
3. Melt 8-chloro-6-(2-ri0lovenyl)pyrrolol as a yellow prism at 224-225°C. ．．
4-d]r2'l benzazepine-1,3(27/,4
#)-dione was obtained.

After further elution and crystallization from ether, the second product and I2
8- as a pale yellow prism with a melting point of 222-223°C.
Chloro-6-(2-chlorophenyl)-3,4-dihydro-3-hydroxypyrrolo[kame4-d][2]benzazepin-1(2H)-one was obtained.

- After further stripping and crystallization from ether, the third product and 1. 8-chloro-6-(2-chlorophenyl)-1,4-
Dihydro-1-hydroxypyrrolo[3,4-d][2)
Benzazepin-3(2H)-one was obtained.

Consolidation 16 Tetraacetic acid was added to a bath solution of 8-oo-6-(2-chlorophenyl)-2H,4B-pyrrolo[3,4-d][2]benzazepine 609 (122 mmol) in 120 m/ml of acetic acid. 12.0 r (27 milJ mole) of lead was added in portions over 2 hours. After stirring for an additional 2 hours, the bath was bubbled with hydrogen sulfide. The resulting precipitate was removed by passing it through Celite. The lachrymal fluid was neutralized by the addition of saturated sodium carbonate water bath solution and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a brown oil. Column chromatography (silica separation 1oor; bath release agent, lOO%
Purification by methylene chloride/209C ether gradient in methylene chloride (#41i itf) gave an off-white solid as the initial product. Recrystallized from a mixture of methylene chloride, ether and petroleum ether, melting point 18
8-chloro-6- as colorless needles at 9-190 °C
(2-chlorophenyl)-2H,4H-pyrrolo['3.
4-d']benzazepine-1,3-so-ol-soacetate was obtained.

Further elution gave a foam of 1.959%, which was crystallized from a mixture of ether and petroleum ether and had a melting point of 1.
8-chloro-6 as colorless prisms at 72-174°C
-(2-chlorophenyl)-3-acetoxy-3,4-
Sohydrovirolo [3゜4-d] [2] Benzazepine-
1(2H)-one was obtained.

Continued elution gave fine needles. Recrystallized from a mixture of ether and methylene chloride, melting point 219-221°C
8-chloro-6-(2-chlorophenyl)-1-acetoxy-1,4-sohydrovirolo[3,4-d][2]
Benzazepin-3(2H)-one was obtained.

Example 17 Methylene chloride 30+++/and tetrahydrofuran to
8-chloro-6-(2-chlorophenyl)-3-hydroxy-3,4-7 hydrovirolo[3,
4-d][':3]benzazepine-1(2H)-one 0.3 y (0.9 mmol), benzoic anhydride 0.
3 F (1,3 mmol) and 0.3 ? A solution of (2.5 mmol) was stirred at 0°C for 1 hour. The mixture was diluted with water and washed sequentially with cold dilute hydrochloric acid, saturated aqueous sodium bicarbonate and brine;
Dried over anhydrous sulfuric acid (IJ). The methylene chloride bath was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 107;
% ether) to give 8-chloro-6=(2-chlorophenyl)-3-(pentyloxy)-3,4-sohydrovirolo[3,4-d] as colorless crystals.
2] Obtained benzazepine-1(2H)-one.

Recrystallization from ether [2, colorless crystals with a melting point of 140-142°C were obtained.

Example 18 8-ri 1:1 O-6-(2-
chlorophenyl)-3-acetoxy-3,4-sohydropyrrolo[3,4-d)[21benzazepine-1(2/
/)-one 0.6r and lki methanolic solution of methanesulfonic acid 3- was stirred at room temperature for 30 minutes. This was concentrated to half the volume under reduced pressure, diluted with ether, and the resulting precipitate was collected by filtering to give orange crystals. Recrystallization from a mixture of methanol and ethanol [2
, 810 Rho 6-(2-chlorophenyl)=3.
4-dihydro-3-methoxypyrrolo[3,4-d][
2]] benzazepine-12H)-one methanesulfonate was obtained.

Example 19 8-chloro-6-(2-chlorophenyl)-1-acetoquin-1,4-sohydropyrrolo[3,4-d][2]benzazepin-3(2H)-one 0,1 F (0,2
5 mmol) and methanesulfonic acid in a 1M methanolic bath solution 1- was left at room temperature for 36 hours. The mixture was diluted with ether and the resulting precipitate was collected by p-filtration and 8-chloro-6-(2-chlorophenyl)-1,4
-dihydro-1-methoxypyrrolo[a, 4-d][:
21:]] Benzazepine-32H)-one was obtained. Recrystallized from a mixture of ether and methanol, melting point 18
Fine needle-like crystals with a temperature of 5-187°C were obtained.

Example 20 1 M methanol solution of methanesulfonic acid 8 out of 25
-chloro-6-(2-chlorophenyl)-2H,4H-
pyrrolo[3,4-d':l(:2'l benzazepine-
1,3-Sool diacetate 1゜5? (3,4 mi IJ
mol) bath was refluxed for 6 hours. The reaction mixture was cooled, made basic by addition of saturated bicarbonate solution (1) and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sulfuric acid and concentrated under reduced pressure. The residue was diluted with 4 m of a 1M methanol solution of methanesulfonic acid.
Dissolve in 1 ml, dilute with ether in a cloudy tube, and evaporate. The ν solution was made basic with a washed sodium bicarbonate water bath. The ether solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 8-chloro-6-(2-chlorophenyl) as off-white crystals with a melting point of 192-194 °C.
-3,4-dihydro-3-methoxypyrrolo[3,4-d
]r2] benzazepin-1(2H)-one was obtained. The isomer 8-chloro-6- was determined by thin layer chromatography.
Although the presence of (2-chlorophenyl)-1,4-dihydro-1-methoxypyrroloC3,4-d-,IC21 benzazepin-3(2H)-one was observed, 1. I found only 7 of these.

8-chloro-6-(2-chlorophenyl> -1゜4-
Dihydro-3-methoxy/pyrrolo ['3.4-d] [2]
The methanesulfonate salt of benzazepin-1(2H)-one was prepared by dissolving the free base in excess methanolic methanesulfonic acid and uniaxially precipitated the salt with addition of ether.

Recrystallized from a mixture of methanol and ether, melting point 1
The salt was obtained as colorless crystals at 57-160°C.

Example 21 8-chloro-6-(210
Lofenyl>-1,4-nohydropyrrolo[3,4-dl
[2] Benzazepine-3(2II)-yF7-5-
, t-xy)'09r (25 mmol) was added 1.8 m/(20 mmol) of phosphorus trichloride. The mixture was refluxed for 1 hour, then concentrated under reduced pressure. The residue was dissolved in methylene chloride and neutralized with a saturated aqueous sodium bicarbonate bath. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 8 as an orange solid.
-chloro-6-(2-10lophenyl)-1,4-sohydropyrrolo[3,4-d][2]benzazepine-3(
211)-one was obtained. Recrystallization from ethyl acetate (2) gave pale yellow prisms of a 0.25 molar hydrate with a melting point of 255-256°C.

Example 22 8-rioo-5 in J′IjL methylene 20 Ome
-(2-chlorophenyl)-3,4-sohibiroviro[3,4-d3C2]benzazepine-1(211)-
)r-5-oxy)'1.0? 2 ml (λ3mZ) of phosphorus trichloride was added at once to a solution of (27 mmIJ mol) and refluxed for 1 hour. The mixture was concentrated under reduced pressure [7.

The residue was dissolved in methylene chloride and neutralized with a saturated aqueous sodium bicarbonate bath. The 6 ml solution was dried over anhydrous sodium sulfate and concentrated under pressure to give a dark red residue. The residue was purified by column chromatography (silica gel 20f; eluent, 5% methanol in methylene chloride) and crystallized from ethyl acetate as pale yellow prisms solvated with 0.5 molar ethyl acetate, mp 195-197°C. 8-chloro-6-(2-chlorophenyl)-3,4-sohydrovirolo[3,4-d][2]benzazepin-1(2H)-one was obtained.

Example A Sunya Sunhe 1-1 Prisoner H-Person
Dot 口℃ Loloha manufacturing method: 1. Mix item 1 with an equal amount of lactose. Mix well.

2 Mix with items 2 and 3 and the remaining item 2. Mix well.

3 Add magnesium stearate and mix for 3 minutes.

4. Compress with a suitable press equipped with a suitable punch.

Example B Sunya Sun Prisoner 0ro Roro Romo Rorohe Manufacturing method: 1. Mix items 1 to 4 in a suitable mixer.

2. Granulate with enough distilled water to achieve appropriate hardness.

3. Dry in a suitable oven.

4 Grind and mix with magnesium stearate for 3 minutes.

5. Compress with a suitable press.

Example C: 1. Manufacturing method: 1. Mix items 1.2.3 and 5 in a suitable mixer. Shattered.

2 Add talc and mix thoroughly.

1. Fill capsules with appropriate equipment.

Claims (1)

[Claims] 1. In the general formula, RI and R8 are hydrogen, lower alkyl, hydroxy, lower alkoxy or acyloxy, and R
2 and R4 are hydrogen, or R8 and R1 and/or R8 and R4 together are an oxo group, provided that at least one oxo group is present; R is hydrogen, lower alkyl, C7- C, carboxylic acids and their esters and amides, hydroxy C1-C, alkyl, amine 01-C7-alkyl or mono- or di-lower alkylamino C3-C, alkyl, ? :R is halogeno or hydrogen having an atomic number of 35 or less; R6
is a halogeno having an atomic number of 35 or less; however,
When R1 or R1 is hydroxy, lower alkoxy or acyloxy, R is lower alkyl or hydrogen, pyrrolo[3,4-d][2]benzazepine derivatives,
N-oxides and pharmaceutically acceptable salts thereof. λ Compounds as defined in claim 1 and pharmaceutically acceptable acid addition salts thereof. 3. The compound according to claim 1 or 2, wherein R8 and R4 together represent an oxo group. 4. The compound according to any one of claims 1 to 3, wherein R is hydrogen. 5. The compound according to any one of claims 1 to 4, wherein R3 is hydrogen or lower alkyl. 6 Claim 5 in which RI is hydrogen or methyl
Compounds described in Section. 7. The compound according to any one of claims 1 to 6, wherein R is hydrogen or lower alkyl. 8. Claim 7 in which R is hydrogen or methyl
Compounds described in Section. 9. The compound according to any one of claims 1 to 8, wherein R8 is a halogen having an atomic number of 35 or less. 10,8-chloro-6-(2-chlorophenyl)-1,
The compound according to claim 1, which is 4-dihydropyrrolo[3,4-d)[2]benzazepin-3(2H)-one. 11,8-chloro-6-(2-chlorophenyl)-1,
4-dihydro-1-methylpyrrolo[3,4-dl[2]
A compound according to claim 1 which is benzazepin-3(2H)-one. 12, 8-chloro-6-(2-chlorophenyl)-1
,4-dihydro-2-methylpyrrolo[3,4-dl[2
] The compound according to claim 1, which is benzazepine-3(2H)-one. 13,8-chloro-6-(2-fluorophenyl)-x
, 4-dihydropyrrolo[:3,4-d:][]2]benzazepine-32H)-ontheal Claim 1
Compounds described in Section. 148-Chloro-1,4-dihydro-6-phenylpyrrolo[3,4-dl[2]penzazebi/-3(2H)-
The compound according to claim 1, which is 15.8-chloro-6-(2-chlorophenyl)-1,
4-dihydro-1,2-trimethylpyrrolo[3,4-dl
[2] The compound according to claim 1, which is benzazepine-3(2H)-one. 168-chloro-6-(2-chlorophenyl)-1,4
-dihydro-2-(2-hydroxyethyl)-1-methylgyrolo[3,4-dl[2]benzazepine-3(2
2. A compound according to claim 1 which is H)-one. 17,9-chloro-6-(2-fluorophenyl)-3
,4-dihydropyrrolo[3,4-dl[[2]benzazepin-1(2H)-one,8-chloro-6-(2-chlorophenyl)-3,4-dihydropyrrolo[a,4-d
'][]]Benzazepine-12H)-one, 8-chloro-3,4-dihydro-6-phenylpyrrolo[
3,4-dl[21benzazepine-1(2H)-one, 8-chloro-6-(2-chlorophenyl)-3,4-dihydro-2-methylpyrrolo[3,4-dl[2]benzazepine-1( 2H)-one, 8-chloro-6-(2-
chlorophenyl)-1,4-dihydro-1-hydroxypyrrolo[3,4-dl[2]benzazepine-3(24
)-one, 8-chloro-6-(2-chlorophenyl)-
3,4-dihydro-3-hydroxypyrrolo(3,4-d
l[2]benzazepin-1(2H)-one, 8-10
Rho-6-(2-chlorophenyl)pyrrolo[3,4-d
l[:2]benzazepine-1,3-(211,4H)
-phono, 8-chloro-6-(2-chlorophenyl)-1,4-dihydropyrrolo[3,4-dl[2'Jbenzazepine-
3(2H)-one-5-oxide, 8-chloro-6-(
2-chlorophenyl)-3,4-dihydropyrrolo[3,
4-dl[2]benzazepine-1(2H)-one-5
-oxide, 8-chloro-6-(2-chlorophenyl)
-l-ethyl-1,4-sohydropyrroloC3,4-d
] [2] Benzaze V-3(2H)-one, 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-
1-Methyl-3-oxo-2H-pyrrolo[3,4-d:
l[2]Benzazepine-2-acetic acid methyl ester and 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-1-methyl-3-ogiso2H-pyrrolo[3,
The compound according to claim 1, which is selected from the group consisting of 4-d[21 benzazepine-2-acetamide. 18 Claim 1 as a pharmaceutically active substance
A compound according to any one of items 1 to 17. 19 Painkillers and anxiolyties
) as claimed in any one of claims 1 to 17. 20 a) Formula (1) according to claim 1, wherein R8 or R3 is hydrogen or lower alkyl, and the remaining substituents are as defined in claim 1.
and its N-oxide, in which one of R7 and R31 is hydrogen and the other is hydrogen or lower alkyl, and R, R, and R
6 is as defined in claim 1, or b) R, still R8, is hydrogen and the remaining substituents are as defined in claim 1. or R1 and R, and R8 and R4 are each -
In order to prepare compounds of formula I as claimed in claim 1, in which RI or Rs are together an oxo group and the remaining symbols are as defined in claim 1, The compound of formula 1 according to claim 1, in which the remaining substituents are hydrogen and the remaining substituents are as defined in claim 1, or the compound q/ of the above formula 〇, in which RII and R31 are hydrogen. a with lead(IV) carboxylate in the presence of a strong acid, or C) R, -i or R3 is acetoxy and the remaining substituents are as defined in claim 1. Claims in which R1 or R8 is hydrogen and the remaining substituents are as defined in Claim 1 for the preparation of compounds of Formula I as claimed in Claim 1. Compound of formula 1 according to item 1 or RII and R3
or d) R, or R8 is acyloxy/ and the remaining substituents are as defined in claim 1. In order to prepare a compound of formula I as defined in claim 1, R8 and R1 are hydroxy and the remaining substituents are %Wf. or e) R, i or R3 are lower alkoxy and the remaining substituents are In order to prepare a compound of formula I according to claim 1, which is as defined in claim 1, in R71, R3 is acylogysiotake hydroxy and the remaining substituents are as claimed in claim 1. As defined in item 1, T: the formula described in claim 1
A compound of the formula or in which R1, is acetoxy and R1R3 and R6 are as defined in claim 1, is treated with a lower alkanol in the presence of a strong acid, or f ) RIt or R5 is hydrogen or alkyl, and the remaining substituents are as defined in claim 1, In the formula, R1R1, R2, R3, R4,
R6 and R6 are as defined in claim 1, and optionally g)
converting the compound of formula I into a pharmaceutically acceptable salt;
or converting a pharmaceutically acceptable salt of a compound of formula I into another pharmaceutically acceptable salt. manufacturing method. 2. A drug containing the compound according to any one of claims 1 to 17. 2. An analgesic and anxiolytic drug containing the compound according to any one of claims 1 to 17. 23. Use of a compound according to any of claims 1 to 17 in the suppression or prevention of disease. 24. Use of a compound according to any of claims 1 to 17 in the suppression or prevention of agitation and anxiety. 2. Claim 1 produced by the method described in Claim 20 or a method clearly chemically equivalent thereto
A compound according to any one of items 1 to 17.