CS233740B2 - Processing of 3-benzazepin compositions - Google Patents

Description

The present invention relates to a process for the preparation of 3-benzezepine compounds which induce 81fa ₂ -egegonism and can be used in the form of pharmaceutical compositions.

Because of the ability of the above compounds to induce alpha -antagonism, they are useful in lowering intraocular pressure and also have a broad spectrum of effects on the vascular and cardiac systems. They can be used in heart failure, angina pectoria and thrombosis.

The compounds of the present invention also reduce blood pressure and can be used in the form of pharmaceutical compositions for this purpose.

Reduction of intraocular pressure is very important in the treatment of glaucoma ⁴ , which is due to increased intraocular pressure · Glaucoma is the main cause of blindness of people over 40 years of age retinal and optic nerve degeneration. In these cases, the eyes hurt, flush and gradually reduce vision and gradually blindness ·

Pilocarpine, timolol and eoinephrine are the most commonly used agents for the treatment of glaucoma. Pilocarpine causes miosa and spasm of the circular eye muscle, creating unclear vision and myopia at the same time · When epinephrine is used, the sclera is enlarged and the vision is unclear again because of congestion, swelling and allergic reactions in the eye. In addition, cardiac arrhythmia may occur when epinephrine is systemically absorbed into the eye. Timolol causes very few eye side effects, but causes systemic side effects such as cardiac arrest, cardiac arrest, heart failure and bronchial spasms ·

A further disadvantage with the use of epinephrine is that it is unstable in air and light and undergoes chemical decomposition upon contact with a variety of other substances which are common components of pharmaceutical compositions. When attempting to overcome these disadvantages, the resulting formulation is usually irritating or forms biologically inactive derivatives with epinephrine.

It is an object of the present invention to provide a compound capable of lowering intraocular pressure without causing direct effects on pupil size, heart rate, or blood pressure at normal pressure, the compounds having as few local or systemic undesirable side effects as possible when introduced into the eye.

U.S. Pat. Nos. 4,210,749 and 4,223,217 disclose a variety of bezazepine compounds that are effective as analgesics, antihistamines and narcotics antagonists. However, none of these patents disclose a compound of formula (I) and it is also not claimed that compounds of this type would be effective to induce alpha ₂ antagonism.

none of the aforementioned patents disclose any biological effects of the compounds produced by the process of the invention.

The N-substituted 2,3,4,5-tetrahydro-1H-3-benzazepine compounds which can be used as described above are represented by the general formula I

O- (I)

X where,

R. . represents an alkyl radical of 1 to 3 carbon atoms or allyl and

X represents a halogen atom such as chlorine, bromine or fluorine.

The pharmaceutically acceptable acid addition salts of these compounds also have the same effect.

A particularly preferred pharmaceutical compound is a compound of formula I wherein R is methyl and X is chloro, i.e. 6-chloro-2,3,4,5-ettaalyrdro-3-methyl-1H-3-benza. zepin.

The above compounds of formula (I) are active ingredients which can be incorporated into pharmaceutical agents for inducing alpha-agonism. The most valuable method of producing these substances is illustrated by the following scheme:

1. SOCI2

2. RNHCH ₂ CH ₂ OH

CH 2 CO 2 H 4 OH

First _PCl5

-CH ₂ - CH ₂ - N- CH 2 - CH 2 OH

R

2. AlCl ₃ , NH ₄ Cl

The substituents X and R are as defined above.

According to the above process, the halo-phenylacetic acid is treated with thionyl chloride followed by the addition of an amino alcohol. The resulting amide was. with a known reagent, for example borane. The resulting amino alcohol is then converted to a corresponding halide such as chloride or bromide and cycled under Fri-del-Crafts conditions. Cyylation is performed by killing Lewis acids, for example aluminum chloride, aluminum bromide, titanium tetrachloride or antimodium chloride. Preferably, the cyclization is carried out in an aluminum chloride or ammonium melt at a higher temperature.

Accordingly, the present invention provides a process for the preparation of the 3-benzazepine compounds of formula (I)

(I) where

R is an alkyl radical of 1 to 3 carbon atoms or allyl and

X represents a halogen atom, as well as the pharmaceutically acceptable acid addition salts of these compounds, characterized in that the compound of formula (I) is cyclized

CH ₂ - CH ₂ - N-CH ₂ CH ₂ 2

R where

R is alkyl of 1 to 3 carbon atoms or alkyl,

X nm not etmm haoogeuu a

From the chlorine or bromine atom, a pharmaceutically acceptable acid-acceptable 1-benzazepine product is optionally formed.

Pharmaceutically acceptable acid addition salts are prepared from the free compounds of formula (1) in a conventional manner using inorganic or organic acidic acids, such as, for example, tylene, fumaric, benzoic, escorbic, pamoic, succinic, ammonium, ammonium, amine, amine, methyl glycol, methanesulfonic, etaedisulfoethyl, acetic, potassium, propionic, tartaric, salicylic, lemon, olefin, asperagic, stgggg, pelmitic, itaconic, glycolic, p-aminobenzoic, chlorobenzene, sulfonium, cyclohexylfluoric, phosphoric or nitric.

The activity of the compounds of formula (I) can be demotected in vitro by determining the αHao activity using an isolated torn-out left atrium. This is done by removing the male urinary anesthesia from the urine. The left atrium was separated, removed from the connective tissue and placed in a 2 ml transfer bath. Frequency is ob ^ ·, E ^p ≤ ⁶⁰ te per minute, sympatholytic cW plgtg ^ ⁿ ^ mv ovlivmje pop every 6 minutes.

The response to nerve stimulation is measured as diverging the contrast forces between baseline contraction and peak contraction after nerve stimulation. A response curve for various concentrations of ketidine (alpha) is prepared by applying a clonidine concentration supporter after each subsequent stimulation. The tissue is then · washed with alpha? The activity is to be demonstrated for a total of 30 minutes and the clonidine curve is repeated in the presence of this antagonist compound. The dissociation constant of the receptor antagonist (K _fi ) is defined as the concentration of neutrophoto necessary to shift the concentration logarithm and the response of the agonnst to the right using factor 2.

The selectivity of the alpha-adenoreceptor and alpha-alpha, edenoreceptor is determined by comparing the alpha-adrenoreceptor as described above with the alpha-adrenoceptor receptor as determined by the rabbit ear artery at norepinephrine induction according to Hieble g.Peedlette, Arch.

309, 217-224 (1979). A preferred compound produced by the process of the invention is 6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine having a value of 13 nM in the case of the isolated left-sided atrial atria.

When a substituent is present at the 7-position of the ring, the efficiency decreases dramatically. For example, 7-chloro-2,3,4,5-traryder-3-ethyl-1H-3-sulfonic acid has a Kg value of 1.0 nM, that is, about 1/10 of the alpha-phagientagency activity of the α-chloro derivative. Moreover, if in position. 6 of the benzene ring is present. or when the 6 and 7 positions are on the cyclopentane ring, the resulting compounds are completely inactive with respect to alpha 1 antagonism.

The annihypertensive activity of the compounds of the present invention can be demonstrated in vivo as follows.

Kirr male males weighing 300-450 g were annealed with sodium brevital and the femoral vein and the cardiac was inserted. The cannulae dermally dermally so that they exude at the dorsosacral region and are held in position by clamps. When the rats wake up, they are placed in a cage. The heat cannula is used with a pressure transducer to monitor blood pressure and heart rate continuously. Test substances were administered either orally via a gavage or via a cannula of the femoral vein at a rate of 0.06 ml / min.

The above experiment was carried out in rats with normal and elevated blood pressure. Rats that have been elevated in blood pressure by the salt of derycyclohexyl acetate are prepared from male Sprague-Dawley rats from which one kidney was collected. Rats, approximately 6 weeks of age, are lightly anesthetized with ether and introduced subcutaneously into the left dorsosacral oblongate pellet containing 25 mg of decylkoeikksteernacetate. After 6 days, a second pellet is introduced into the right dersosacral oblong. Rats received standard laboratory diet, but instead of a Tne ^ ^^ ^dy with weighing 1% ^to erzto kuctyňsto sol.i. The ^extensible by ^k ^^ weighing ^22-2 4 ^d ni.

The following table shows the effect of 6-β-2,3,4,0-tetrahydro-α-β-H-3-sensespine on blood pressure during non-administration in normal or elevated pressure rats.

Table 1

Rat type

Diastolic blood pressure

Pre-administration pressure Pressure drop in kPa after i.v. administration

0.5 mgg / kg 1.0 m / kg

Control and Normal Pressure Rat (SřesgueoDalley) (n = 4)

Rats with elevated blood pressure after administration of the deo: χ-coceicosterone salt (n = 4)

Standard pressure rats (Wi8taro · Kyoto) (n = 4)

Spontaneously 'hypee ^ intense rats (n = 7)

12.67 ± 0.93 kPa 0.8 ± 0.27 1.73 ± 0.13 18.0 ± 0.67 kPa ^3, 6 and 0 ^, 4 4.4 * 0.53 15.33 ± 0.4 kPa 0.93 and 0.27 1.33 ± 0.27 22.26 ± 0.4 kPa 4.4 ± 0.93 6.13 ± 0.27

Note to the table: n = number of rats

From the data in Table I it is clear that 6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine, while having little effect on diastolic blood print in normal blood pressure rats, causes all of the significant a decrease in diestolic blood pressure in spontaneously hypertensive rats. p in hypertensive rats after deoxycorticosterone acetate. Furthermore, a comparison with the effect of doses of 0.5 and 1.0 mg / kg shows that the entihypertensive effect is dose-dependent.

The effect of oral administration of 6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine on the blood pressure of rats induced by hypertension with deoxycorticosterone acetate is summarized in Table 2 below, which presents the results of the respective ·

Table 2

Oral dose Average arterial pressure Pressure drop mg / kg in kPa before administration after administration active substance . active substance 2 19.73 * 1.47 17.46 + 1.6 2.27 ± 0.4 5 21.33 i 0.93 16.93 ± 0.67 4.53 ± 0.53 10 22.26 ± 1.07 13.2 ± 0.53 9.07 ± 1.07

When used on the cardiovascular system, the compounds of the present invention may be combined with diuretic agents such as hydrochlorothiazide or triamterene or with calcium-based blockers such as Verapamil or Nifedipine or with beta-edrenergic blockers such as propranolol. The amount of substituted 3-benzazepine compounds ranges from 2 mg to 250 mg of the thiazide component. When combined with triamterene 5 mg to 250 mg triemterene. In the case of calcium-based blockers, 1 to 500 mg of this substance are used.

Further activity of the compounds produced according to the invention can be demonstrated by their ability to reduce intraocular pressure. The intraocular pressure is measured by subjecting the eye to a force that flatts the eye. Either this force or the effect of this force is measured. For the purposes of the invention, the intraocular pressure of the rabbit was determined. To this end, a 0.5% proparacaine hydrochloride solution diluted 1:10 in saline was injected into the rabbit eye. in

The lids are gently massaged over the cornea to ensure a good distribution of the solution. The intraocular pressure at each eye is then determined at each eye with the Alcon Applanation Pneumatonograph until a constant value is obtained. The reading is performed according to West C., Cepelle J. and Keufmen, H. Am. J. Opthalmol. 74: 505 (1972).

Nine rabbits were used for each experiment, three rabbits for each dose. Initially at time t = 0, an intraocular determination is performed in both eyes. Immediately after reading the pressure, the test substance β is dripped into the eye at a concentration of 0.01 to 10% of the active substance and the intraocular pressure is read at 0.5, 1, 2, 3, 4 and 6 hours after administration. Pressure is read from the pneumotonograph record. The mean intraocular pressure is calculated for each time period. A preferred compound for this use is 6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine, which reduces eye pressure per hour by 0.47 kPa compared to the untreated eye.

When the chlorine atom is placed at the 7 'position of the benzazepine core and the compound is used at the same dose, eye pressure is not reduced.

In summary, the most important feature of the compounds produced by the process of the invention is that they have a halogen atom at the 6-position of the benzszepine core. As can be seen from the results of the tests, this is an essential requirement which must be met in order to achieve biological efficacy.

It has also unexpectedly been found that when the preferred compound is

6-chloro-2,3,4, -tetralyls-3-ethyl-1H-3-benzazepine is administered systemically, reducing the pressure of the pressure without causing a significant effect than systemic blood pressure. Does not attach in the case of administering the G _i.e., mg / kg of this substance into the ear vein of conscious rabbits' with normal blood pressure occurs within 1 hour to reduce intraocular pressure of 0.53 to 0.67 KPE. .

Thus, the pharmaceutical compositions used to induce alpha ₂ antagonism or antihypertensive activity contain a pharmaceutical carrier and contain, as an active ingredient, a benzazepine compound of formula I. The active ingredient must be present in an amount in which it can produce alpha ₂ antagonism and antihypertensive activity.

Preferably, the pharmaceutical compositions contain the active ingredient of the formula I in a quantity of 25 to 500 mg, preferably 50 to 250 mg, in a single dose.

For example, the functional carrier may be a solid or a liquid. Examples of solid carriers are lactose, magnesium stearate, white clay, sucrose, fats, stearic acid, gelatin, eger, paletine or acacia rubber. The amount of solid carrier may vary within wide limits, preferably from about 25 mg to about 1 g.

Examples of liquid carriers are syrups, peanut oil, olive oil, sesame oil, propplenglycol, polyethylene glycol having a molecular weight of 200 to 400, and water. The carrier or diluent may contain substances which render absorption of the active ingredient, for example, glycerol monostearate or glleerildistate as such or together with a wax.

The pharmaceutical composition may take a variety of forms, for example, tablets, capsules, powders, sublingual preparations, syrups, emulsions, sterile injectables, suspensions or solutions.

The formulations may be obtained in conventional manner, for example by mixing, granulating, pouring or dissolving the ingredients as is preferred for the desired formulation.

Preferably, the compounds of formula (I) are used as conventional dosage forms in conjunction with conventional pharmaceutical formulations.

The active ingredient of the formula I is preferably administered in a total dose of 100-1000 mg, preferably 200-500 mg per day. Usually, dosages of the same size are given two to four times a day.

FermíaeeUieké means to reduce intraocular pressure usually comprise a pharmaceutical carrier suitable for intraocular administration e as active ingredient N-2,3,4-subsSitusvarn _d tercahydrs 5-1H-3-bznzczeřin formula I. The active ingredient will be in mnnossvv ^^ omna which is able to reduce the eye pressure. Preferably, these compositions contain from 0.01% to 5%, preferably from 0.03% to 3.0%, of the active compound of the formula (I).

The pharmacological environment or carrier for intraocular administration may be a solid or a liquid. Examples of ophthalmic liquid may be conventional isotonic boortic acid solution, 0.9% sodium chloride or sodium borate solution. In addition, conventional phosphate buffers can be used, for example Sorensen phosphate buffer pH 6.8. An example of a solid carrier for intraocular administration is, for example, vaseline.

Solutions for ophthalmic administration are sterile and may contain, in addition to the active compounds of the formula I, an antimicrobial agent. Examples of this agent are quaternary ammonium salts, for example benzalko, benzetonium chlorides or cetylpyridium chloride. Other agents of this type, such as chlorobutanol or phenyl-nitrate nitrate, may also be used. If anti-oxidizing agents are required, they are generally sodium sulfite, sodium ascorbate or other antioxidant for ocular use, such as oximsuufate.

The benzezepine derivatives are preferably administered for intraocular administration by mixing the desired dose of the compound with an aforementioned carrier suitable for ophthalmic administration. The resulting pharmaceutical composition is usually administered two to four times a day. In the case of drops, usually 1 to 5 drops are administered two to four times a day.

When the active compounds are administered as described above, an alpha antagonist, an enthypertensive effect or a reduction in intraocular pressure is achieved.

The invention will be illustrated by the following examples. All temperatures given in the examples are in degrees Celsius.

Example

A mixture of 125 g (0.73 mole) of O-acetic acid, 155 g (1.3 mole) of thionyl chloride and 2-3 drops of dimethylfrraamide in 1500 ml of toluene was stirred at room temperature for 3 hours. The toluene was then evaporated under reduced pressure to give an oily liquid which was dissolved in 200 ml of meltine chloride. The solution was added dropwise to a solution of 165 g (2.2 moles) of N-melylminoethanol in 1 liter of methylene chloride. After the addition was complete, the solution was stirred at room temperature for 3 hours. Original solution. for ^ is water, dilute hydrochloric acid and saturated brine, dried over magnesium sulfate, filtered and evaporated, to yield 2-chlfΣ-N- (2- ^ yd ^г oxyltyl) -N-πletyibθnzenacetθmid Jata the solid L-staHcrá ^á Units mp ⁷⁷ ° C.

A solution of 43 g of the above amide in 350 ml of tetrahydrofuran was added dropwise to 400 ml of a 1 M solution of tetralydrofuran in tetralydrofuran to maintain a gentle reflux.

After the addition was complete, the solution was refluxed for 2 hours, cooled well in an ice bath, and dilute hydrochloric acid was carefully added to remove excess boiling. Most of the solvent was removed in vacuo and the residue was heated on a pen bath for 1 hour. The PiO was diluted with 300 mL of water and extracted with ether. The aqueous layer was basified with 40% sodium hydroxide solution and extracted with ether. The alkaline extracts were combined, washed with water and saturated sodium chloride solution, then dried and evaporated to give 2- [[2- (2-chlorophenyl) ethyl] methylthymine ethanol.

To a suspension of 36 g (0.173 mol) of phosphorus pentachloride in 300 ml meeylenchloridu after ^O and ^Poa p ch ^Rida mites ^to 3 ^{7 g (0.1} mol Ή ^ ² - [/ ^2-22 hlhfrl el ^l l ^{l -yl} ethyl / ltty ^l mDinf] ethanol in 150 ml meeylenchloridu. After complete addition the mixture looks no temperature overnight under reflux, evaporated to dryness and partitioned pek.se mmzi dilute hydrochloric acid and ether. the aqueous layer was basified with 10% sodium hydroxide and extracted with The ether extracts were washed with water and saturated sodium chloride solution, dried (MgSO 4), and glowed to give a solid precipitate which was collected by filtration, washed with ether and dried to afford 2- chloro-N- (2-chloroethyl) -N-methylbenzenetanamine hydrochloride, m.p.

To a mixture of 41.5 g (0.155 mol) of the above chloroethanamine hydrochloride and 6.26 g (0.177 mol) of ammonium chloride was added 41 g of anhydrous aluminum chloride. The reaction mixture is homogeneous, gradually melts and an exothermic reaction occurs. The reaction mixture was then stored in an oil bath heated to 175 ° C and stirred for 30 minutes. 20 g of aluminum chloride are then added and the mixture is heated for a further 30 minutes. 41 g of aluminum chloride are then added and the reaction mixture is heated for 20 hours. After this time, it is cooled to 140 ° C and poured into 3 liters of a mixture of water and crushed ice containing 300 ml of concentrated hydrochloric acid and stirred for 15 minutes. 60 g of sodium tartrate are then added and the mixture is stirred until a solution is obtained. This solution is basified with 40% sodium hydroxide solution, extracted twice with ether and the extracts are combined, washed with water and saturated sodium chloride solution, dried and evaporated to half volume.

Addition of saturated ethereal hydrogen chloride gave a solid precipitate which was collected, washed with ether and dried to give a white solid. Crystallization from methanol / ethyl acetate gave 6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p. 268-270 ° C.

Example 2

To a stirred solution of 1.2 g of 6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in 30 ml of toluene is added dropwise a solution of 0.7 g of cyanogen bromide at 50 ° C. in 25 ml of toluene. After the addition was complete, the mixture was stirred for an additional hour and heated to 50 ° C. A stream of nitrogen is passed through the surface of the solution during the reaction. The mixture was cooled, filtered and the filtrate evaporated in vacuo to give a mixture of hexane and ether.

6-chloro-3-cyano-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 81-82 ° C.

6-chloro-3-cyano-2,3,4,5-tetrahydro-1H-3-benzazepine was heated to reflux for 19 hours in a mixture of 30 ml of glacial acetic acid and 30 ml of 6N hydrochloric acid. The mixture was evaporated in vacuo to give 6-chloro-2,3,4,5-tetrahydro-1 H -3-benzazepine as the hydrochloride, m.p. 214-215 ° C after recrystallization from ethanol. From this salt, 6-chloro-2,3,4,5-tetrahydro-1H-3-bezazepine can be obtained by treatment with dilute sodium hydroxide solution.

Example 3

A mixture of 0.52 g of 6-chloro-2,3,4,5-tetrehydro-1H-3-benzazepine, 0.34 g of allyl bromide, 0.6 g of potassium carbonate and 20 ml of 90% ethanol was stirred at room temperature for 17 hours. room temperature. The mixture was filtered and the filtrate was evaporated in vacuo. The residue was extracted with 30 mL of ether and the ether extract was treated with a solution of hydrogen chloride in isopropanol, thereby precipitating к ^{3-allyl-6-chloro-2,3,4,5-tetrahydro-1} 1H-3-benzazepine hydrochloride. Recrystallization of this salt from absolute ethanol gave 3-allyl-6-chloro-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p. 248-289 ° C.

Example 4

A solution of 1.5 g of 6-chloro-2,3,4,5-tetrahydro-1H-3-benzepine, 2.0 g of acetic anhydride and 20 ml of pyridine was stirred at room temperature for 3 hours. The mixture was evaporated in vacuo, and the residue was washed with 3N hydrochloric acid and then with water to give 3-acetyl-6-chloro-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. Deň: 32 ° C. This amide was reduced in ether by treatment with lithium aluminum hydride in 50% excess at reflux for 6 hours.

After decomposition of the excess reducing agent, the reaction mixture was filtered. The etherate filtrate was dried over magnesium sulfate. The filtrate was treated with ethereal HCl to precipitate 6-chloro-3-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine as the hydrochloride, m.p. 274 DEG-275 DEG C. after recrystallization from absolute alcohol. .

Example 5

The procedure described in Example 1 was followed, but using 2 - ([2- (2-chlorophenyl) ethyl] ethylamino] ethanol 8 2 - [[2- (2-chlorophenyl) ethyl] 1 / allylamino] -ethanol instead of 2 - [/ 2- (2-chlorfanyDetyl / Me acetylamino ethanol to give 6-chloro-3-ethyl-2 _f 3>4> 5-tetrahydro-lH-3-benzazepine and 6 -chloro-3-allyl-2,3,4,5-tetrahydro-1 H -3-benzazepine ·

Example 6

Component Amount 6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine hydrochloride 2.5 g benzalkonium chloride 0,02 g sodium bisulfite 0,10 g sterile 0.9% sodium chloride solution USP to 100 ml The ingredients are dissolved in sodium chloride solution, the solution is sterilized by filtration and septic packed. Two drops of the solution thus obtained are used in each eye three times a day. Example 7 Component Quantity 6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine 1.0 g Purified White Vaseline USP to 100.0 g

Under aseptic conditions, benzazepine is thoroughly mixed with white petrolatum and packaged.

The ointment is applied topically to the eye four times a day.

1

Example 8

Component Amount in mg 6-chloro-2,3,4,5-tetrehydro-3-methyl-1H-3-benzazepine hydrochloride 150 lactose 350 The ingredients are mixed 8 and filled into hard gelatin capsules. Serve 1 capsule four times a day. Example 9 Component Amount in mg 6-chloro-2,3,4,1 et: hydro-3-methyl-1H-3-benzazepine hydrochloride 200 calcium sulphate dihydrate 1 50 secheroze 25 starch 15 Dec talc 5 stearic acid 3

Calcium sulfate dihydrate, sucrose and benzazepine are mixed thoroughly and granulated with a 10% gelatin solution. The wet granule is passed through a sieve, dried, blended with starch, talc and stearic acid. It is passed through a sieve and the mixture is compressed into tablets.

One tablet is given three times a day.

Claims (2)

A process for the preparation of 3-benzazepine compounds of formula I wherein R is C 1 -C 3 alkyl or allyl; X represents a halogen atom, (I) as well as the pharmaceutically acceptable acid addition salts of these compounds, characterized in that the compound of the formula: R is alkyl of 1 to 3 carbon atoms or allyl, X represents a halogen atom and Z represents a chlorine or bromine atom, whereupon optionally forming a pharmaceutically acceptable acid addition salt of the 3-benzazepine product. 2. A process according to claim 1, wherein the compound of formula (I) is cyclized CH ₂ -CH ₂ -N-CH ₂ CH ₂ Z wherein R 'is C 1 -C 3 alkyl and X and Z are as defined above.