DE2207430C3 - 1,2,4,5-Tetrahydro-3H-3-benzazepine, a process for their preparation and a pharmaceutical agent containing them - Google Patents

Description

When the compounds of the invention are present as 5 bases, they easily form salts with organic ones or inorganic acids such as hydrochloric, maleic, tartaric, sulfuric and other non-toxic acids, with pharmaceutically acceptable acid-formula I addition salts being formed.

In terms of their analgesic effect, compounds of the formula I in which R ⁴ and R ^{5 represent} hydroxyl and lower alkoxy are particularly satisfactory.

or the pharmaceutically acceptable addition salts thereof, wherein R is aminophenyl lower alkyl, \; Acetamidophenyl lower alkyl, methylaminophenyl ^{lower alkyl or dimethylaminophenyl lower alkyl, R 2 is} hydrogen or lower alkyl, R ⁴ and R ^{5 are} independently hydrogen, lower alkoxy or hydroxy and R ⁸ = H or lower alkyl.

2. Process for the preparation of a compound of the formula I, characterized in that a compound of the formula I in which R is hydrogen, with a reagent of the formula RX or RCOX, r. wherein R is as defined in claim 1 and X is halogen, allowed to react, and in the case where a compound of the formula RCOX is used, the carbonyl moiety is selectively reduced to a methylene group. ' μ

3. A pharmaceutical agent containing a compound according to claim 1.

The invention relates to new 1,2,4,5-tetrahydro-3H-3-benzazepine of the structural formula given in claim 1, a process for their preparation and a one A pharmaceutical composition containing the compound of claim 1.

The new compounds are effective analgesics. They also represent effective antagonists for Narcotics such as morphine.

From FR-PS 15 35 085 1,2.43-tetrahydro-3H-3-benzazepines are known which have one on the nitrogen atom contain bonded aminoalkyl or substituted aminoalkyl group. In the context of the invention leading investigations it was found that these compounds known from FR-PS 15 35 085 only are relatively weakly active analgesics and therefore at subcutaneous administration require a relatively high dose of about 100 mg / kg (ED 50).

In contrast, significantly higher activities were found for the new compounds of the invention.

The compounds according to the invention can be prepared by reacting a compound according to the claims Formula in which R is hydrogen. be made with a reagent that removes hydrogen from one of the Groups R replaced by definition. Such reagents include compounds of the formula RX andR —COX, where R is as defined in claim I and X is halogen. If a reagent of the formula P.COX is used, the carbonyl group is subsequently selectively reduced to a methylene group. Lithium aluminum hydride is one particular appropriate reagent for this reduction.

Suitable modifications for the substituents R * example 1

3- (p-aminophenethyl) -7-methoxy-1,2,4,5-tetrahydro-3H, 3-benzazepine

A solution of p-nitrophenylacetic acid (11.7 g, 0.064 m) in tetrahydrofuran (50 ml) was added to a solution of 7-methoxy-1,2,4 ₁ 5-tetrahydro-3H, 3-benzazepine (103 g, 0.058 m) in tetrahydrofuran (50 ml) at room temperature. A solution of dicyclohexylcarbodiimide (14.5 g, 0.0705 m) in tetrahydrofuran (50 ml) was immediately added to the reaction mixture and stirring continued for 4 hours. Acetic acid (10 ml) was added to the reaction mixture and then the solids were removed by filtration. The solvent was evaporated in vacuo and the residue treated with diethyl ether (150 ml) and benzene (150 ml). The insoluble solids were removed by filtration and washed with benzene (200 ml). The solids were dissolved in tetrahydrofuran (250 ml) and a small amount of dicyclohexyl urea was filtered off. The benzene: ether extract was washed with potassium carbonate solution and hydrochloric acid (3N). The tetrahydrofuran extract was washed with potassium carbonate solution. The extracts were combined and evaporated in vacuo to give the crude amide, weight = 25 g. The crude amide was dissolved in methanol (200 ml) and ^{hydrogenated at 4.21 kp / cm 2} over platinum oxide (1 g). The uptake of hydrogen ceased after 20 minutes with a pressure drop of 1.19 kp / cm ² . The catalyst was removed by filtration and the solvent evaporated in vacuo. The residue was dissolved in hydrochloric acid (0.3N, 1500 ml) and insolubles were filtered off. The acidic solution was washed with ether and then made basic with sodium hydroxide solution. The precipitated product was extracted with chlorolyrm. The chloroform extract was gelatinized over magnesium sulfate and evaporated in vacuo to give the crude haminoamide, weight = 22.5 g. The amino amide was dissolved in tetrahydrofuran (150 ml) and added dropwise to a suspension of lithium aluminum hydride (5 g, 0.0132 ml) in diethyl ether (175 ml) at a rate such that a gentle reflux was maintained. The reaction mixture was refluxed for 21 hours. The complex was decomposed by successive additions of water (5 ml), 15% sodium hydroxide solution (5 ml) and water (15 ml). The solvents were filtered and dried over magnesium sulfate. Evaporation of the solvents in vacuo gave an oil. which was converted into the dihydrochloride salt and recrystallized from methanol to give the dihydrochloride of the title compound, melting point 264.5-265.5 ⁰ CGeWiChHI ₁ I g.

10

Analysis:

calculated for C ₁₉ H ₃₄ N ₂ O - 2 HC]:
C 61.79 H 7.10 N 7.59 Cl 19.20
found:
C 61.63 H 6.86 N 7.61 Cl 19.45

Example 2

3- (p-AminophenäthyI) -7-hydroxy-1,2,4,5-tetrahydro-3H3-benzazepine

3- (p-Aminophenethyl) -7-methoxy-1,2,4,5-tetrahydro-3H3-benzazepine dihydrochloride (113 g, 0.0306 m) was dissolved in 48% aqueous hydrobromic acid (175 ml) suspended and refluxed for 2 hours. The excess acid and water were in vacuo removed. The remaining solid was dissolved in water (250 ml) and washed with potassium carbonate solution made basic. The precipitated solid was filtered and dried. The solid was poured into the Hydrochloride salt transferred and from methanol: diethyl ether (l : 3> recrystallized, melting point 309.5 - 3113 ° C, weight = 8.7 g.

Analysis:

calculated for C ₁₈ H ₂₂ N ₂ O 2 HCI:

C 60.84 H 6.81 N 7.89 Q 1935
found:
C 60.62 H 7.03 N 8.06 Cl 19.85

Example 3

3- (2-p-Aminophenyl) -1-methylethyl) -7-methoxy-1,2,4,5-tetrahydro-3H, 3-i> enzazepine

7-methoxy-1,2,4,5-tetrahydro-3H .. ^? benzazepine (10 g, »0.0565 m), 1- (p-nitrophenyl) -2-propanone (11 g, 0.062 m) and p-toluene sulfonic acid (0.2 g) were dissolved in toluene (100 ml) and 20 heated hours at reflux a "Dean and Stark 'over apparatus has been connected and the eliminated water is collected, the toluene solution was diluted w (200 ml) with methanol and cooled to 10 ° C, sodium borohydride (8.5 g, 0.226 m) was added portionwise added to the stirred reaction mixture within 20 minutes. The reaction mixture was stirred for 4 hours at room temperature. Water (100 ml) and diethyl ether (100 ml) were carefully added. The organic layer was separated and washed with dilute hydrochloric acid. A sticky precipitate formed which was separated and then made basic with sodium hydroxide solution. The aqueous acidic solution was also made basic. The alkali-insoluble components were combined and taken up in diethyl ether. The ether solution was dried over magnesium sulfate. Evaporation of the solvent gave a dark red oil, weight = 10.6 g. The oil was purified by silica gel chromatography. Elution of the column with benzene: diethyl ether (1: 1) gave 7-methoxy-3- [1-me-

thyl ^ -p-nitrophenyl-äthyp-l ^^ - tetrahydro-SHJ-benzazepine as an oil. The amine was converted into the hydrochlorides ¹ mi chloride salt and recrystallized from methanol, mp 223-230 ° C, weight - 3.9 g.

Analysis:

calculated for C20H24N2O3 · HCI: to

C 63.74 H 6.69 N 7.43 Cl 9.41
found:
C 63.77 H 6.69 N 7.48 Cl 9.72

The amine hydrochloride (2.4 g, 0.0064 m) was dissolved in methanol (75 ml) containing concentrated hydrochloric acid (1 ml) and added to the 5% palladium-charcoal catalyst solution. The nitro group was hydrogenated at 3.50 kp / cm ^{2 over} 15 minutes. The solution was filtered off from the catalyst and evaporated to give the crude title compound as the dihydrochloride salt. The salt was purified by crystallization from methanol: diethyl ether (2: 1), melting point 245-255 ° C.

Analysis:

Calculated for C ₂₀ H ₂₆ N ₂ O 2 HCl:
C 62.65 N 736 N 731 Cl 18.50
found:
N 62.47 N7.51 N 733 Cl 18 ,! 3

Example 4

3- (p-Acetamidophenethyl) -7-methoxy-1,2,4,5-tetrahydro-3H3-benzazepine

Triethylamine (i 1.0 g, 0.108 m) became a suspension of 3- (p-aminophenethyl) -7-methoxy-1,2,4,5-tetrahydro-3H3-benzazepine dihydrochloride (13 g, 0.035 m) in chloroform (200 ml). The mixture was stirred and cooled with an ice water bath. Acetyl chloride (33 g, 0.042 m) was added dropwise over 5 minutes and the reaction mixture 1 Stirred for hour at room temperature. The insoluble material was filtered off to obtain the title compound as Hydrochloride salt 2U obtained, melting point 289 - 290 ° C, weight = 8.0g.

Analysis:

calculated for C ₂ iH ₂₆ N ₂ O ₂ ■ HCI:
C 67.28 H 7.26 N 7.47 Cl 9.46
found:
C 67.10 H 7.56 N 7.53 Cl 934

Example 5

3- (p-Aminophenethyl) -8-methoxy-2-methyll, 2,4,5-tetrahydro-3H, 3-benzazepine

A solution of p-toluenesulfonyl chloride (28.8 g, 0.15 m) in benzene (100 ml) was added dropwise to a solution of 2- (3-methoxyphenyl) -1-methylethylamine (23 g, 0.139 m) and triethylamine (13 g, 0.15 m) in benzene (200 ml) given within 30 minutes. The reaction mixture was 4 hours at room temperature touched. The precipitated triethylamine hydrochloride was filtered off and the benzene solution with hydrochloric acid (3N), water, and saturated saline. The benzene solution was over magnesium sulfate dried. Evaporation of the solvent gave N-toluene-p-sulfonyl-2- (3-methoxyphenyl) -1-methylethylamine as oil, weight = 42 g.

The crude sulfonamide (43 g, 0.135 m) was dissolved in acetone (1100 ml) dissolved. Potassium carbonate powder anhydrous (135 g) was added and the reaction mixture stirred and refluxed. Ethyl bromoacetate (33.7 g, 0.202 m) was divided into four equal portions Added at 30 minute intervals, NaGh for 20 hours With stirring and refluxing, the salts were filtered off from the cooled solution. Evaporation of the Acetone gave an oily residue, mainly consisted of the alkylated amine. The ester function was hydrolyzed by heating the oil with Ethanol (95%, 900 ml) and sodium hydroxide (10% aqueous, 270 ml) for 6 hours under reflux. That

Ethanol was removed on a rotary evaporator and the aqueous residue was diluted with water (1 l) until a clear solution was obtained. The solution was washed with dietary ethyl ether and then with concentrated Hydrochloric acid acidified The oily precipitate was taken up in ether and then the ethereal solution with Washed sodium bicarbonate solution. The bicarbonate solution was separated and concentrated with Hydrochloric acid acidified and the precipitated acid isolated in diethyl ether. The ether solution was over Magnesium sulfate, dried, evaporation of the solvent gave N- [3-methoxyphenyl) -1-methyl] -ethyl-N-toluene-p-sulfonyl-glycine as a viscous oil which had not crystallized, weight = 40.5 g.

The crude acid (40 g, 0.106 m) was refluxed for 9 hours in benzene solution (500 ml) with thionyl chloride (253 g, 0.212 m) Excess thionyl chloride and solvent were removed on a rotary evaporator The crude acid chloride was dissolved in methylene dichloride (ί 00 ml ) and added dropwise to a suspension of aluminum chloride (17.4 g, 0.13 m) in methylene dichloride (300 ml) which had been cooled to -65 ° C. The addition took 3 hours. The reaction mixture was stirred for a further 7 hours at -65 ° C. and then stirred while heating to 15 ° C. over a period of 12 hours. The reaction mixture was poured onto ice (1500 g) / concentrated hydrochloric acid (75 ml) and the mixture was stirred for 1.5 hours. The methylene chloride layer was separated and washed with water, sodium bicarbonate solution and saturated brine. Evaporation of the solvent gave an oil, weight = 37 g. The oil was purified by chromatography on silica gel. Elution of the column with acetone: benzene (1 x. 40) gave the crude title compound, which was purified by crystallization from absolute methanol, weight = 11.4 g. Melting point 119 to 121.5 ⁰ C.

Analysis:

calculated for C ₁₉ H ₂ INO ₄ S:
C 63.49 H 5.89 N 3.90 S 8.92
found:
C63 /> / H 6.04 N 3.61 S 8.93

Further elution of the column gave the 9-methyloxy-isomer, which was crystallized from absolute methanol, weight = 1.5 g, melting point 127 - 128 ° C.

Analysis:

calculated for C19H21NO4S:
C 63.49 H 5.89 N 3.90 S 8.92
found:
C 63.41 H 6.03 N 3.65 S 9.16

1 - Hydroxy ^ -methoxy ^ -methyl-S-toluene-p-sulfonyl-1,2,4,5-tetra-hydro-3H3-benzazepine

Sodium borohydride (1 g, 0.0264 m) was added to a suspension of 7-methoxy-4-

methyl-3-toluene-p-sulfonyI-1,2,4,5-tetrahydro-3H, 3-benzazepin-1-one (7.5 g, 0.0208 m) in absolute ethanol (100 ml) at room temperature . The mixture was heated within 30 minutes at 6O ⁰ C and then the heat source removed. After stirring for an additional 3 hours at room temperature, the reaction mixture was poured onto ice / concentrated hydrochloric acid (500 ml / 25 ml). The precipitation was taken up in chloroform. Evaporation of the chloroform gave a viscous oil which gave a solid on trituration under Diäthylätlier, weight = 5.4 g, melting point 83-87 ° C The solid was crystallized from diethyl ether to give the pure title compound, mp 84-87 ⁰ C.

. Analysis:

calculated for C ₉ H ₃₃ NO ₄ S:

C 63.14 H 6.41 N 3.88 S 8.87

found:

C 63.09 H 6.40 N 4.00 S 9.11

e-Methoxy ^ -methyl-S-toluene-p-suIfonyl-1,2-dihydro-3H3-benzazepine

1-Hydroxy ^ -methoxy ^ -methyl-S-toluene-p-sulfonyl, 2,4,5-tetrahydro-3H, 3-benzazepine (7 g, 0.0194 m) and p-toluenesulfonic acid (20 mg) were dissolved in benzene (80 ml) dissolved and the solution heated to reflux for 1.5 hours. The solvent was poured over a Soxhlet tube that Linde Type 3A molecular sieves (0.16 cm), condensed. The solvent was evaporated and the residue is purified by chromatography on silica gel, eluting the column with acetone: benzene (3: 100) gave an oil which solidified on trituration under diisopropyl ether and the title compound resulted, weight = 5.0 g, melting point 77 - 79 ° C.

Analysis:

calculated for Ci ₉ H ₂ INO ₃ S:
C 66.43 H 6.16 N 4.08 S 9.34
found:
C 66.26 H 6.28 N 333 S 9.23

Further elution of the column gave a solid which was crystallized from absolute methanol, Weight = 038 g, melting point 177 - 182 ° C.

found:

C 66.20 H 638 N 3.95 S 9.52

e-Methoxy 1-methyl-S-toluene-p-sulfonyl-1,2,4,5-tetrahydro-3H3-benzazepine

A solution of 8-methoxy-2-diethyl-3-toluene-p-sulfonyl-1,2-dihydro-3H3-benzazepine (4.7 g, 0.0137 m) in acetic acid (50 ml) was over 5% palladium - Animal charcoal (0.4 g) hydrogenated in a Parr apparatus at an initial pressure of 2.59 kp / cm ^2. The hydrogen absorption was complete in 2.5 hours. The catalyst was filtered off and the filtrate was evaporated to dryness. The residue was triturated with diisopropyl ether and gave the title compound as a solid, weight = 43 g. The residual body was crystallized from absolute methanol, melting point 86 - 89 ° C.

Analysis:

calculated for Ci ₉ H ₂₃ NO ₃ S:
C 66.07 H 6.71 N 4.06 S 9.28
found:
C 66.10 H 6.88 N 3.97 S 9.29

8-methoxy-2-methyl-1,2,4 ^ -tetrahydro-3H, 3-benzazepine

8-methoxy-2-methyl-3-toluene-p-sulfonyI-1,2,4,5-tetrahydro-3H, 3-oenzazepine (1 g, 0.003 m) was suspended in liquid ammonia (35 ml). Sodium (0.15 g) was added added partially until the blue color persisted. After an additional 15 minutes it became ammonium chloride (2 g) added and the ammonia allowed to evaporate. Water was added and the insoluble Shares in diethyl ether added. Evaporation of the ether gave an oil, weight = 0.62 g. the

The title compound was isolated as the hydrochloride salt and the salt was crystallized from isopropanol, weight = 0.28 g. Melting point 196 - 200 ⁰ C.

Analysis:

calculated for C, ₂ H _1? NO ■ HCI:
C 63.29 H 7.97 CM 5.57 N 6.15
found:
C 63.34 H 8.22 CM 5.33 N 6.20

Following the procedure of Example t, 8 was methoxy-2-methyl-1,2,4,5-tetrahydro-3H, 3-benzazepine into the corresponding amide by p-nitrophenyl acetic acid and dicyclohexylcarbodiimide in tetrahydrofuran solution convicted. Reduction of the amide in methanol solution over platinum oxide gave the corresponding result Amine S-ip-Aminophenylacetylf-e-methoxy ^ nietliyl-1.2.4,5-tetrahydro-3H.3-benzazepine. The amino amide is converted into lithium aluminum hydride in tetrahydrofuran reduced at reflux and gives the compound

j-ip-Afiimu [) iicnäiitvi / -8-mt; iM <> xv-2-iitei! iyi- ί, 2.4. Ji <r trarιydro-3H, 3-benzazepine.

Example b

3- (p-AmitH> phena'thyl) -8-hydroxy-2 methyll, 2.4.5-tetrahydro-3H, 3-ben / .a7cpin

Following the procedure from Example 2, 3 (p-amino · [ihenethyl) -8-methoxy-2-methyl 1,2,4. V tetrahydro 3H.J-ben / .azepine by refluxing demethylated with 48% aqueous hydrogen chloride. The title compound is made from the hydrobromide salt by nitralization with potassium carbonate solution obtain.

Example 7

3- (p-A iniiiophenäthv!) - 7-metho \\ - 1.2.4.5-tetrahydro-3H, 3-bi: nza / epin methiodide

Iodomethane (1.5 g. 0.0114 M) was added to a solution of 3- (p-aminophenethyl) -7-meihoxy-1.2.4,5-tetrahydro-3H.3-bcnzaz.cpin (3 g. 0.0103 ni) in Acetone (40 ml) added. The acetone was decanted from the sticky 1, illung and the sticky mass with ethyl alcohol (95%) triturated zn obtain the solid methiodide. The salt was recrystallized from water. Weight = 0.8 g. Melting point 236 - 2W C.

Analysis:

calculated for C.vHrJNjO:
C 54.79 H 6.21] 28.95 N 6.39
found:
C 54.64 H 6.29 129.13 N 6.39

Pharmacological activity of
Benzazepine Linkages

Compounds of the present invention were made on experimental animals. their analytical activity and theirs Ability to counteract the effect of strong narcotic analgesics (antagonism) investigated and evaluated. It has been possible to use various animal testing methods using conventional testing methods Degrees of these activities by one or more methods and routes of administration of dose levels, that do not lead to major toxic damage. Also, others are pharmacological Properties of representative compounds of these Invention has been determined as the antihistaminic and anticholinergic activity.

Results
Analgesic activity

Table I summarizes the results obtained when compounds are representative of these Invention were tested for their analgelic activity by the methods described. The narcotic The antagonist analgesic pentazocine and the narcotic analgesic morphine and codeine are used for Comparison has been included. From this comparison it becomes evident that the majority of the compounds showing significant activity at dose levels that are below the dose producing toxic Damage lies, d. H. are less than the highest non-symptomatic dose (HNSD), initially Line are effective parenterally. Line exception is the connection SR673-98A, which is active by the oral route. The predominance of parenteral efficacy is enhanced by both the iicißpi.utcn-fviethode. where the imraperitoneaie way used as well as indicated by the convulsive method with administration by subcutaneous route. The most active compounds were SR673-98A and SP.7 53-85OA. In addition, these compounds also show the greatest separation / effective dose and toxic dose, indicating a very favorable therapeutic index.

The most active compounds listed in Table I. are according to the hot plate method Tests comparable to codeine and 6 to 10 times more active than pentazocine intraperitoneally Connection SR673-93A. what activity shows by the oral route in the convulsion test is about twice that active like pentazocine.

The benzene / epine compounds listed in Table II are examples of narcotic antagonist activity. determined by two methods, show. Inhibition of oxymorphone mydriasis in the mouse gives one qualitative reference to antagonist activity. whereas Inhibition of morphine analgesia in the rat the semi-quantitative indication of the antagonism crl.iubt. Narcotic antagonist activity was observed for all ßenzazepine compounds demonstrated in Table II by both test methods. The connection is SR673-98A a stronger antagonist than pentazocine. No compound has an activity similar to that of nalorphine comes close, including the standard penta? ocin. In addition to the therapeutic use of this compound as analgesics, they are therefore valuable narcotic antagonists in the treatment of narcotic dependence.

For all benzazepine compounds. which are listed different degrees of similar toxic damage occur with increasing dosage in the form of Depression, ataxia, decreased respiration, exophthalmosis. Salivation, lacrimation. Vasodilation. Cyanosis and mydriasis on. Also, all compounds usually developed moderate to severe clonic convulsions, and animal deaths were due to respiratory failure.

Antihistaminic and antichounergic activity

Table III summarizes the relative antihistaminic and anticholinergic activity of benzazepine compounds. what by using isolated segments of the guinea pig small intestine was demonstrated. From these results it is evident that a positive antihistamine

ίο

Effect with the compounds listed in the table can be derived, the strongest (SR673-98A) for example 25 times less active than that of the antihistamine

Table I.

Analgesic activity of benzazepine compounds

Standards diphenhydramine is. Anticholinergic activity relatively weak to atropine was demonstrated by these Connections shown.

'bond Surname HNSD ⁴ ) LD50 IP If «) lleißpl.ilte Cramp N- .. mg / kg mg / kg F.D50mg / kg F. 1) 50 mg / kg PO *) IP *) PO PO IP PO SC ' SR75.i-85 <) .- \ 7-methoxy-3- (p-acetamidophen- η 32 > IOOO 52 -32 ') > 52 -7 ethyl) -1.2.4.5-tert-hydro-3H.3- ben / azepine hydrochloride SR673 - <> 8. \ 3- <para ^aminophen>> l-ethyl) -7- ι no 18th 445 121 85 17 45 -6 methoxy-1.2A5-tetrahydro-3ll.J- hen / azepine dihydrochloride S K 725-61Λ 3- (p-aminophenethyl) -7-hydroxy- 316 56 > I (XXl > 5 () 0 > 315 3 ⁷ > 316 l.2.4.S-lelrahydro-Jfl, J-r> en / a / epin- 250 dihydrochloride 104 \ equal Pentazocine 316 316 -son > 316 KX) 70 substances Morphine 56 10 ~ 8 (X) 14 2.5 3 Codeine KX) 32 540 20 12 17th

*) HNSD - Highest non-symptomatic dose.

"*) PO = Per Os.

***) IP - intraperitoneally.

"* *) SC = subcutaneous.

Table II

Narcotic antagonist activity of benzazepine compounds

link

Surname

Antagonism of

Oxymorphone

Mvdriasis

PO *)

IP **)

Antagonism of morphine analgesics

SR-673-98A 3- (p-Amino-phenylethyl) -7-methoxy-

l ^ AS-tetrahydro ^ Hi-benzazepine dihydrochloride
Pentazocine
Morphine
Codeine
Nalorphine

·) PO = per Os. **) IP = intraperitoneal. ***) SC. = subcutaneous.

About 0-100 times more active than those listed above links

Table III

Antihistaminic and Anticholinergic Activity of Benzazepine Compounds

Connection conc. For 50 'conc. For SW'itge Blocking the blocking of the Acetyicholins Histamine

jg / 20 ml ug / 20 ml

SR673-98A 54 SR 725-6IA 840 \ ifOn in 0.0035 Diphenhydramine

100 37 0.12

11th

Four of the compounds of the invention (designated 1-4 in the following review) were identified with compared to the connection closest to them, explained in the examples of FR-PS 15 35 085, where R is dimethylaminopropyl. All five compounds were tested for analgesic activity using the phenylbenzoquinone writhing test (P.B.Q.) tested that made a good general prediction of the

analgesic activity permitted. The comparison compound of the FR-PS turned out to be less active. In contrast, the compounds I, 2 and 3 of the claimed benzazepine series were 1-5 mg / kg > Area very active. Even the weakest connection 4 is at least 7 times more active than the comparison connection of the FR-PS.

Table IV Analgesic activity as measured by the P.B.Q. writhing method Connection structure

No.

2.

3.

4th

CII, O

CII ₁ O

CH ₁ O

M ₁ CO

H ₁ CO

CH ₁ O

/ \ O! N— (CII,), - <: O> —Nil ·

CH, O / -Nil • -HCl

2HCI H-O

N- (CH;) -.- < O V - NII;

CM-,

N- (CIU-C O -N (CH ₁ I-HC

H) 5 <>

ii,! / ki! SCV'i

4.0

l.d

15.1

Comparison substance

H ₁ CO

N- (CH ₁ KN- (CH-.); 2HC

100.0

) "SC" means subcutaneous.

Claims (1)

Claims: 1. Compounds of the formula 1 R ² H and R ⁵ can be used to prepare compounds of the formula I by means of known measures.