HU181589B - Process for producing 7,8-dihydroxy-1-bracket-sulfamoyl-phenyl-bracket closed-2,3,4,5-tetrahydro-1h-3-benzasepine derivatives - Google Patents

Description

The present invention relates to novel 1-phenyl-2,3,4,5-tetrahydro-1 H -3-benzazepine derivatives which contain a sulfamoyl group (-SO ₂ NH ₂ ) at the 4-position of the phenyl ring. The compounds of the present invention are therapeutic, especially for use in renal dopaminergic and antihypertensive compositions.

Numerous l-phenyl-2,3,4,5-tetrahydro-lH-3-benzazepine derivatives having a phenyl ring containing a thio group are known. U. S. Patent t No. 4,104,379 discloses a _s benzazepine derivatives having the phenyl ring by lower] atom alkylthio, lower alkylsulfonyl, - lower alkylsulfinyl or sulfonyl-dimethyl? they contain a um-halide substituent. However, there is no description of 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine derivatives containing a sulfamoyl group on the phenyl ring, nor a synthesis by which these compounds can be readily prepared.

The compounds of the invention are represented by the formula (I) in which

R ₂ is a halogen atom such as chlorine, bromine, fluorine or iodine,

R ₃ is hydrogen or

R ₄ and R ₅ are hydrogen or C 1-4 alkyl.

The present invention also relates to the preparation of acid addition salts of compounds of formula I which are prepared with pharmaceutically acceptable acids. These compounds have the same therapeutic properties as the parent compounds. Examples of suitable organic or inorganic acids for the preparation of the above compounds are maleic acid, malic acid, fumaric acid, succinic acid, methanesulfonic acid, ethanedisulfonic acid, salicylic acid, citric acid and hydrobromic acid. The present invention also relates to other solvates, such as hydrolys. Salts are prepared in a known manner by reacting the base with an excess amount of acid in a lower alkanol or similar solvent.

Compounds of formula I according to the invention (I) 5 - in general formula (I), R _2, R _3, R ₄ and R _s are as defined above - pharmacological properties, in particular hypotensive activity: 1st Compounds of formula (I) wherein R _{3 in} formula (I) is hydrogen - R ₂ , R ₄ and R ₅ are as defined above - have significant dopaminergic activity as described below.

The compounds of the invention are prepared according to Scheme c). The intermediate of formula (II) in formula (II) is R ₂ , R ₃ , R ₄ and

Rj is as defined for formula (I) and X is chlorine or bromine or an identically substitutable group,

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R'j represents an N-protecting group such as trichloroacetyl, benzyloxycarbonyl, trifluoroacetyl or benzyl,

R ₆ and R ₇ are C 1-4 alkyl, especially methyl, or together are ethylene or especially methylene.

The N-protecting group represents a substituent at the 3-position which prevents the reaction of a reactive hydrogen atom on the nitrogen-containing ring of the intermediate of formula II. After completion of the appropriate reaction, the protecting group is removed in a known manner to regenerate the secondary amine. Such protecting groups are commonly used in polypeptide and antibiotic chemistry. These include, for example, tert-butoxycarbonyl, trichloroethoxycarbonyl, p-methoxybenzylcarbonyl, isobornyloxycarbonyl, trityl, benzhydryl, or other protecting groups for the secondary amino group.

Compounds of formula (II) - wherein R ', R ₂ , R 3, R ₆ and R _{7 in} formula (II) are as defined above - for compounds of formula (III) - in formula (III) R 1, R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are as defined above in an organic solvent inert to the reaction partners in which the reaction partners are soluble, such as dimethylformamide, dimethylacetamide, tetrahydrofuran. or dimethylsulfoxide. The amine of formula IV, where R ₄ and R ₅ are as defined above, is generally used in excess. The reaction is carried out at a customary temperature until completion. Temperatures between 0 ° C and room temperature are most suitable. The compounds of formula (III), wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R _g and R _{7 in} formula (III) are as defined above, are isolated by conventional means or further reacted without purification, that R _'is R _g, or R ₇ removing protecting groups in a known manner. The O-ether protecting groups may be removed with boron tribromide, boron trichloride, 48% hydrobromic acid, aluminum chloride or other desalkylating agents. The N-protecting groups at the 2-position are most easily removed by acidic or basic treatment. These groups may also be removed during the aforesaid desalkylation reaction.

The preparation of compounds of the invention is illustrated in Scheme a). In Scheme (a), as mentioned above, the R / substituent is a protecting group for the secondary nitrogen atom. In the formulas, R ₂ , R ₃ , R ₄ , R 1 and X are as defined above.

The preparation of the compounds also involves the reaction of the sulfur atom to the oxygen atom to transfer the sulfur atom directly to the 1-phenyl ring.

The 7,8-dihydroxy groups are protected in a conventional manner with a methylene group as included in the reaction scheme. This compound is readily prepared in good yield by introducing a methylene dihalide into the corresponding trio 7,8 position. Also known in the art is the ethylene dioxide system, which is prepared by reaction with an ethylene dihalide.

Alkoxy-1- (hydroxyphenyl) -2,3,4,5-tetrabidro-1-3-benzazepine derivatives having a 7,8-di-carbon atom, which are known compounds and can be used in a known manner, are more difficult to prepare because the formation of dietary derivatives is not selective.

Scheme b) also illustrates the preparation of compounds of the present invention which are synthesized on the phenyl group containing a 7,8-dialkoxy-1-phenyl-2,3,4,5-tetrahydro-l-3-benzazepine containing a sulfur atom. the sulfur moiety is then converted to variously substituted sulfamoyl groups within the scope of the present invention.

Scheme b) is particularly useful when the 7,8-dihydroxy groups are protected by the 7,8-dialkoxy system, but the methylene dioxide or ethylenedioxy derivative can likewise be used. The substituents in the formulas have the meaning given above.

The compounds of formula I according to the invention, wherein R ₃ is hydrogen - R ₂ , R ₄ and R ₅ are as defined above - are particularly potent antihypertensive agents and at least in part have renal dopaminergic activity. Upon preliminary screening compounds of Formula (I) having the general formula (I) wherein R ₂ and R ₃ is a chlorine atom - _R4 and _R5 are as defined above -, no renal dopaminergic activity.

The effective dopaminergic compounds of the present invention stimulate peripheral dopamine receptors, for example, by increasing renal blood flow and, as a result, have antihypertensive activity. The renal vasodilator activity of the present compounds of formula I according to the invention was measured in anesthetized dogs. In this method, the test compounds are administered as a progressive infusion (triplicate) of an initial volume of 0.1 pg / kg / cc and a final volume of 810 (g / kg / min). The compounds are administered over 5 minutes to anesthetized normal blood pressure dogs. Test for: renal arterial blood flow, intestinal arterial blood flow, arterial blood pressure and heart rate The results are expressed as the percentage of increase or decrease at the time of peak response Compounds are considered to have 10% or greater Effect on renal vascular resistance can be calculated from changes in renal blood flow or arterial blood pressure. compounds, which are specific for the kidney dopamine receptor blocker. Dopamine was positive in all screening tests.

One compound of the invention, 6-chloro-7,8-dihydroxy-1- (p-sulfamoylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, gives the following results. :

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Table 1

agent Dose (g / kg / min) MAP * (arterial blood pressure) RBF * (Renal blood flow) RVR * (renal vascular resistance) HR * (Heart rate) dopamine 3 -4.9 +38.1 -31.6 +0.0 Test compound 3 -3.6 + 17.0 -18.0 -2.9 30 -6.6 +41.0 -33.7 -6.3 300 -10.6 + 16.0 -22.7 + 3.3

* Percentage change / pre-infusion control / dog

Table 2

agent Dose (TTG / kg / min) MAP * (arterial blood pressure) RBF * (Renal blood flow) RVR * (renal vascular resistance) HR * (Heart rate) First 3 0.0 +6.7 -6.2 0.0 30 -1.4 +6.3 -6.8 +6.7 300 -15.7 -6.3 -9.6 + 10.0 Second 3 0.0 0.0 0.0 +5.9 30 + 1.3 0.0 + 1.4 +6.3 300 +0.6 +6.3 -5.1 +6.3

1. = 6-Chloro-7,8-dihydroxy-1- (4-N, N-dimethylsulfamoyl-phenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide hydrate

2. ^ -6,9-Dichloro-7,8-dihydroxy-1- (p-sulfamoylphenyl) -2,3,4,5-tetrahydro-1,3-benzazepine hydrobromide hydrate

The ED _{15 in} the 4 dogs was 20 / zg / kg (3.5 / xg / kg for dopamine). In the phosphate mannitol assay in dogs, the compound has an antihypertensive activity of 5 mg / po.

The compounds of the present invention are formulated into pharmaceutical compositions in a known manner by converting a compound of the invention, its isomer, a pharmaceutically acceptable acid addition salt or ester thereof, into a pharmaceutical composition containing a non-toxic amount of the desired compound and sufficient to produce the desired therapeutic effect in the human or animal concerned. The compositions contain from 15 to 1000 mg, preferably from 25 to 250 mg, of the active ingredient in an active but non-toxic amount per dosage unit. The amount used will depend on the specific biological activity desired and the condition of the patient.

The following examples illustrate the preparation and use of the compounds of the invention. Temperatures are given in ° C.

Example 1 6-Chloro-7,8-dihydroxy-1- (p-hydroxyphenyl) -2,3,4,5-tetrahydro-1,3-benzazepine methanesulfonate (g, 0.104 mol) (No. 860,774). Belgian patent) is suspended in 11 dry toluene and 30.0 ml dry acetonitrile, and the resulting suspension is added rapidly.

Trifluoroacetic anhydride (100 mL, 0.77 mol). The reaction mixture was stirred overnight to give a clear solution which was concentrated in vacuo. This gives an oily substance. The resulting oily substance was dissolved in methylene chloride. The solution was then washed twice with water, several times with 5% sodium bicarbonate solution and then with 65% sodium chloride solution. The dry extract was concentrated to give an oil of 6-chloro-7,8-dihydroxy-1- (p-hydroxyphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine trifluoro-. acetamide (44 g). The compound was found to be sufficiently pure for further use by NMR and thin layer chromatography.

6-Chloro-7,8-dihydroxy-1- (p-hydroxyphenyl) -2,3,4,5-tetrahydro-1- (3-benzazepine) trifluoroacetamide (0.104 mol) in 700 ml of dry dimethylacetamide. formamide solution was treated with 45.5 g (0.784 mol) of potassium fluoride.

After 5 minutes, dibromomethane (11.2 mL, 27.6 g, 0.109 mol) was added to the reaction mixture. The resulting reaction mixture was heated to 115 ° C and maintained at this temperature for 6 hours. The resulting reaction mixture is then concentrated. The residue was dissolved in ethyl acetate and washed several times with water. The dried, concentrated product is chromatographed on 800 g of silica gel with a gradient of 1-3% methanol in chloroform. From the homogeneous fraction, 30.4 g (71%) of 6-chloro-7,8-methylenedioxy-1- (p-hydroxyphenyl) -2,3,4,5-tetrahydro-1-3-benzazepine-50-trifluoro- acetamide was obtained. The sample was recrystallized from acetonitrile to give a white crystalline solid, m.p. 191-193 °.

Using ethylene dibromide instead of dibromomethane gives the 7,8-ethylenedioxy derivative 55 which is used in the next step in equimolar amounts. Other reactive dihalomethane or ethane derivatives may likewise be used.

12.6 g (0.031 mol) of 6-chloro-7,8-methylenedioxy-1- (p-hydroxyphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine trifluoroacetamide 100 ml a solution of dry dimethylformamide in 15.2 g (0.136 mole) of triethylene diamine followed by 6.27 g (0.051 mole) of dimethylthiourea acid chloride. After stirring for 4 hours at room temperature, the reaction mixture was poured into ice water (500 mL) and the resulting precipitate was filtered and washed thoroughly with water. The resulting solid was dissolved in 95% ethanol, treated with activated charcoal, filtered and diluted with water until turbid. After cooling, 11.3 g (73%) of 6-chloro-7,8-methylenedioxy-1- (p-dimethylthiocarbamoylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine trifluoro -acetamide, m.p. 128-131 °.

Diphenyl / diphenyloxy eutectic (Dowtherm "A", 200 mL) was preheated to 200 ° C in an oil bath and then 24.0 g (0.048 mol) of 6-chloro-7,8-methylenedioxy-1- (pO-dimethylthiocarbamoyl) were added with rapid stirring. (phenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine trifluoroacetamide. The resulting solution was heated at 205-230 ° C for about 10 hours. The reaction mixture was then cooled and poured onto a silica gel column (800 g), which was washed with cyclohexane. The column was treated with cyclohexane to remove the heat transfer medium and then a 3/1 then 5/2 cyclohexane / ethyl acetate gradient gave the homogeneous product. The material was recrystallized from acetonitrile to give 8.7 g (40%) of 6-chloro-7,8-methylenedioxy-1- (pS-dimethylcarbamoylphenyl) -2,3,4,5-tetrahydro-1 Benzazepine trifluoroacetamide is obtained, m.p. 194-195 °.

6-Chloro-7,8-methylenedioxy-1- (pS-dimethylcarbamoylphenyl) -2,3,4,5-tetrahydro-1,3-benzazepine trifluoroacetamide (0.02 mol) The mixture was suspended in 90 ml of 90% formic acid and 35 ml of 30% hydrogen peroxide solution was added dropwise with stirring at room temperature. The reaction mixture was stirred for 18 hours. The clear solution was evaporated and the residue azeotroped several times with 95% ethanol. The crude product obtained was dissolved in ethyl acetate, washed with cold 1% hydrochloric acid and brine and then concentrated to give about 10 g of crude 6-chloro-7,8-methylenedioxy-1- (p-sulfophenyl) 2.3. 4.5,5-Tetrahydro-1H-3-benzazepine trifluoroacetamide is obtained. Nuclear Magnetic Resonance Spectra (NMR) confirmed the structure of the compound by HPLC assay on a C-18 reverse phase column with 60/40/1 water / methanol / acetic acid containing 3z, 10 < ⁵ > % purity.

Crude 6-chloro-7,8-methylenedioxy-1- (p-sulfophenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine trifluoroacetamide (1.0 g, 2.1 mmol), A mixture of thionyl chloride (20 ml) and dimethylformamide (0.04 ml) was heated at 80 ° for 2 hours. The thionyl chloride is then evaporated in vacuo. The residue, which is 6-chloro-7,8-methylenedioxy-1- (p-chlorosulfonylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine trifluoroacetamide, is dissolved in tetrahydrofuran. The solution is slowly added to 40 ml of ice-concentrated concentrated ammonium hydroxide solution. The resulting reaction mixture was stirred at room temperature for 4 hours, adjusted to pH 8 with hydrochloric acid, and extracted with ethyl acetate. The extracts were washed with water, dried, concentrated, and applied to a column packed with 50 g of silica gel. The column was treated with ethyl acetate containing 24-35% cyclohexane to give 0.5 g of 6-chloro-7,8-methylenedioxy-1- (p-sulfamoylphenyl) -2,3,4,5-tetrahydro-1-3-benzazepine. Trifluoroacetamide is obtained. Mass spectral analysis showed an intense m / e at 476 which corresponds to the molecular ion. NMR and IR data confirm the structure.

When ethylamine is used instead of ammonia, the (p-N-ethylsulfamoylphenyl) derivative is obtained.

This compound is then hydrolyzed alkaline and treated with boron tribromide to give 6-chloro-7,8-dihydroxy-1- (pN-ethylcarbamoylphenyl) -2,3,4,5-tetrahydro-1 -3-benzazepine hydrobromide.

6-chloro-7,8-methylenedioxy-1- (p-sulfamoylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine trifluoroacetamide (0.5 g, 1.1 mmol) A mixture of 1 g of sodium hydroxide and 50 ml of methanol was stirred at room temperature for 2 hours, poured into water and extracted with ethyl acetate. The combined extracts were washed with brine, dried and concentrated. The residue was chromatographed on 20 g of silica gel with 1-5% methanol in chloroform to give 0.35 g of pure 6-chloro-7,8-methylenedioxy-1- (p-sulfamoylphenyl) -2,3,4,5-tetrahydro-. l-3-benzazepine was obtained. The resulting material was suspended in dry methylene chloride (5 ml), cooled to -60 ° C and boron tribromide (1 g / ml) in methylene chloride (5 ml) was added dropwise with stirring under nitrogen. The resulting reaction mixture was stirred at room temperature for about 1 hour, cooled to -15 ° C, and excess methanol was carefully added. The solvents were evaporated. The residue was azeotroped several times with methanol. The resulting solid was crystallized from methanol / acetonitrile to give 6-chloro-7,8-dihydroxy-1- (p-sulfamoylphenyl) -2,3,4,5-tetrahydro-1 H- (0.36 g, 86%). 3-Benzazepine hydrobromide is obtained, m.p. 289-290 °.

The base (Ig) is regenerated with dilute sodium bicarbonate solution / isopropanol. The base (100-100 mg) in isopropanol is treated with methanesulfonic acid and hydrochloric acid to give the methanesulfonic acid or hydrochloride salt.

Example 2 g (0.011 mol) of 6-chloro-7,8-methylenedioxy-1- (p-sulfophenyl) -2,3,4,5-tetrahydro-1,3-benzazepine trifluoroacetamide, 70 ml of thionyl chloride and 0.08 ml of dimethylformamide were heated at 80 ° for 2 hours and then the solvents were evaporated in vacuo.

The remaining acid chloride is dissolved in tetrahydrofuran. The resulting solution was added slowly at -15 ° to a solution of dimethylamine in tetrahydrofuran. The reaction mixture was stirred at 0 ° C for 1 hour and then allowed to stand at room temperature for 20 minutes. The reaction mixture was then adjusted to pH 6.5 with hydrochloric acid. The product was extracted into chloroform. The extracts were washed thoroughly with water, dried and concentrated. 4.0 g of crude product are obtained, which is chromatographed on 110 g of silica gel with a 25-33% ethyl acetate / cyclohexane gradient. The homogenous fractions were crystallized from aqueous ethanol to give 3.1 g (78%) of 6-chloro-7,8-methylenedioxy-1- (pN, N-dimethylsulfamoyl-phenyl) -2,3,4,5-tetrahydro-1 -3-benzazepine trifluoroacetamide is obtained, m.p. 143-145 °.

2.3 g (0.00457 mol) of 6-chloro-7,8-methylenedioxy-1- (pN, N-dimethylsulfamoylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine trifluoro Acetamide, 75 ml of methanol and 0.5 g of sodium hydroxide are stirred for 2 hours at room temperature, diluted with water and extracted several times with ethyl acetate. The extracts were washed with brine, dried and concentrated. The rest is raw

The material was chromatographed on silica gel (75 g) with a gradient of 1-4% methanol in chloroform. The homogeneous fractions were combined and concentrated to give 1.4 g (75%) of 6-chloro-7,8-methylenedioxy-1- (pN, N-dimethylsulfamoylphenyl) -2,3,4,5-tetrahydro-1 -3-benzazepine is obtained. The mass spectrogram shows an intense m / e peak at 408, consistent with the structure of the compound. NMR and IR data also confirm the structure of the compound.

The product obtained (300 mg) was dissolved in dry methylene chloride (15 ml) and the solution was cooled to -15 ° C under nitrogen. To the resulting solution was added boron tribromide solution (1 g / 5 ml) in methylene chloride (3 ml) dropwise. Precipitation is precipitated very rapidly. The reaction mixture was then stirred for 1 hour at room temperature and then cooled in an ice bath. Excess methanol is then added carefully.

The resulting solution was evaporated. The residue was azeotroped several times with methanol. The resulting solid was crystallized from methanol / acetonitrile to give 6-chloro-7,8-dihydroxy-1- (pN, N-dimethylsulfamoylphenyl) -2,3,4,5-tetrahydro- as a white crystalline solid. 1 H -3-benzazepine hydrobromide, m.p. 238-240 °. NMR and IR data confirm the structure.

Example 3 A solution of p-thiobenzylbenzoic acid (g, 0.219 mol) in dry tetrahydrofuran (450 ml) was cooled under ice-water in ice water, followed by the dropwise addition of a 1M diborane solution (0.4 mol) in tetrahydrofuran (400 ml). After half an hour, the cooling bath was removed. The reaction mixture was stirred at room temperature for 2 hours, then cooled again in ice water and carefully added with excess methanol. The solvents were evaporated to give a white crystalline solid which was crystallized from aqueous ethanol. 39.5 g (79%) of p-thiobenzylbenzyl alcohol are obtained, m.p. 87-88.5 °.

A solution of 38.5 g (0.167 mol) of p-thiobenzylbenzyl alcohol in 400 ml of toluene was treated with 100 g of active manganese dioxide. The resulting slurry was stirred and heated in an oil bath for 5 hours using a "Dean-Stark" water separator. The reaction mixture was then cooled slowly and filtered with chloroform. The filtrate was evaporated to give a pale yellow solid. This material was crystallized from absolute alcohol to give 30.1 g (80%) of p-thiobenzylbenzaldehyde, m.p. 62-63.5 °.

A solution of 30.0 g (0.132 mol) of p-thiobenzylbenzaldehyde, 37.6 g (0.184 mol) of trimethylsulfonium iodide and 150 ml of dry dimethylsulfoxide (kept under nitrogen) is added over a period of 15 minutes to 18.6 g (0, 17 mol) of potassium tert-butoxide in 100 ml of dry dimethylsulfoxide. The reaction mixture was stirred for 45 minutes at room temperature and then poured into 3 L of ice water. The cooled material was extracted with ethyl acetate (4 x 300 mL). The combined organic extracts were washed with brine, water (4 times) and dried over magnesium sulfate. The extracts were then concentrated to give solid p-thiobenzyl styrene oxide.

The resulting crude epoxide was mixed with 28.5 g (0.13 mol) of 2-chloro-homoveratratramine and heated at 110 ° C for 18 hours under nitrogen. The crude product obtained is dissolved in a small amount of chloroform and applied to a column packed with 900 g of silica gel. The column was treated with chloroform and 2-1 / 2% methanol in chloroform and fractions were collected every 400 ml. The homogeneous product was crystallized from absolute alcohol to give 15.4 g of α- [N-2-chloro-3,4-dimethoxyphenethylaminomethyl] -4'-thiobenzylbenzyl alcohol, m.p. 80-81.5 °.

A solution of benzyl alcohol (13.0 g, 0.0284 mol) in dry methylene chloride (260 mL) was treated with methanesulfonic acid (10.4 mL). The resulting solution was gently boiled for 3 hours, and ice and 150 ml of a 10% sodium hydroxide solution (1: 5) were added. The organic layer was separated and the aqueous layer was extracted with methylene chloride. The combined organic extracts were washed with water, dried and concentrated. 12.1 g of crude product are obtained, which is chromatographed on a silica gel column (650 g) with a 2-4% methanol in chloroform gradient. 9.4 g (75%) of 6-chloro-7,8-dimethoxy-1- (p-thiobenzylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine are obtained. NMR and TR and mass spectral data confirm the structure of the compound.

7.7 g (0.017 mol) of the benzazepine derivative obtained above are dissolved in a mixture of 80 ml of acetone and 20 ml of water, and a solution of 5.3 g of sodium carbonate in 10 ml of water is added. The reaction mixture was cooled in ice water and a solution of 5.44 g of chlorobutanic acid benzyl ester in 25 ml of acetone was added dropwise. The reaction mixture was stirred at 5 ° C for 1 hour and then at room temperature overnight. Water is then added to the reaction mixture. The product was extracted into ethyl acetate and washed with brine and water. The resulting material is concentrated and the concentrated product is chromatographed on 200 g of silica gel with chloroform and 0.5% chloroform in methanol. 4.5 g (46%) of 6-chloro-7,8-dimethoxy-1- (p-thiobenzylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine-benzylcarbamate

4 (i) as a syrup. Mass spectrum shows intense m / e at 573, consistent with structure. IR and NMR data confirm the structure.

The resulting carbamate (4.5 g, 0.0079 mol) was dissolved in glacial acetic acid (45 mL) and water (0.45 mL) was added. The resulting solution was cooled in water (15 °). Chlorine gas was bubbled through the resulting solution for 20 minutes while maintaining the temperature of the reaction mixture at 25-27. The reaction mixture was stirred at room temperature for 15 minutes, poured into 150 ml of ice water and extracted rapidly with chloroform. The combined extracts were washed with water and nitrogen was bubbled through the slightly wet solution. The solvent was evaporated at room temperature under reduced heat to give 6,9-dichloro-7,8-dimethoxy-1- (p-chlorosulfonylphenyl) -2,3,4,5-tetrahydro-1-3-benzazepine as a residue. benzylcarbamate.

The remaining acid chloride was dissolved in tetrahydrofuran and added to 75 ml of iced ammonium hydroxide solution. The reaction mixture was stirred for 2 hours at room temperature and the pH was adjusted to about 8 with hydrochloric acid. The product was extracted into chloroform and washed with water. The dry concentrated material was chromatographed on 200 g of silica gel with chloroform 65% methanol and 1% chloroform. 3.24 g (75%) 6.9-5181589

-dichloro-7,8-dimethoxy-1- (p-sulfamoylphenyl) -2,3,4,5-letrahydro-1,3-benzazepine-benzylcarbamate is obtained in the form of an oil. NMR, IR and mass spectral data confirm the structure of the compound.

The sulfamoyl derivative (2.0 g, 3.56 mmol) was dissolved in dry methylene chloride (60 mL). The solution was cooled to - 15 ° (nitrogen atmosphere). To the reaction mixture was then added dropwise a solution of boron tribromide (17.7 ml, 1 g / 5 ml) in methylene chloride. The resulting solution was stirred at room temperature until a precipitate formed. After about an hour, the reaction mixture was cooled, methanol was added slowly and the solution concentrated, then azeotroped with additional methanol. The residue was dissolved in a small amount of acetone and added dropwise to a stirred solution of 3 parts ether and 1 part ethyl acetate. This gave an off-white powder (0.586 g, 35%), m.p. 210-212 °. This compound is 6,9-dichloro-7,8-dihydroxy-1- (p-sulfamoylphenyl) -2,3,4,5-tetrahydro-1 H -3-benzazepine hydrobromide.

The crude acid chloride (200 mg) obtained by evaporating the chloroform extract in the above procedure before treatment with ammonia was treated with dilute sodium carbonate solution / dimethylformamide. After evaporation and extraction with methylene chloride, the extract is washed and dried. After evaporation, 6,9-dichloro-7,8-dimethoxy-1- (p-sulfophenyl) -2,3,4,5-tetrahydro-1,3-benzazepine-benzylcarbamate is obtained. After alkaline hydrolysis and treatment with boron tribromide, 6,9-dichloro-7,8-dihydroxy-1- (p-sulfophenyl) -2,3,4,5-tetrahydro-1,3-benzazepine is obtained. In the same manner as described, the Ο, Ο, Ν-protected sulfonic acid is treated with phosphorus pentabromide to give the 1- (p-bromosulfophenyl) derivative which is reacted with ammonium hydroxide solution. After hydrolysis and removal of the ether group, 6,9-dichloro-7,8-dihydroxy-1- (p-sulfamoylphenyl) -2,3,4,5-tetrahydro-1,3-benzazepine hydrobromide is obtained.

Claims (3)

Patent claims A process for the preparation of a compound of formula (I) R ₂ is halogen, R 1 is hydrogen or halogen and R ₄ and R ₅ are hydrogen or C 1 -C 4 alkyl, and pharmaceutically acceptable acid addition salts thereof, wherein R _{2 is a} compound of formula II; and R ₃ is as defined above, R 1 is an N-protecting group, preferably trifluoroacetyl, 15 _R6 and _R7 are lower alkyl or together are methylene or ethylene, X is a leaving group, preferably a chlorine or bromine atom, with a compound of formula IV, In Formula 20, R ₄ and R ₃ are as defined above and the R ₆ , R ₇ and R 3 groups are removed with a desalkylating agent, an acid or a base and optionally the acid addition salt of the resulting compound. 25 2. A process according to claim 1 wherein R 1 is trifluoroacetyl, R ₆ and R _{7 are} methyl or R ₆ and R ₇ together are methylene, R ₂ is chloro, R ₃ is hydrogen. The compound of formula (II) is reacted with a compound of formula (IV) wherein R ₄ and R _{5 are} methyl. 3. A process according to claim 1, wherein R 1 is trifluoroacetyl, R ₆ and R _{7 are} methyl or R ₆ and R ₇ 35 are methylene, R ₂ is chloro, R ₃ is hydrogen. A compound of formula (II) is reacted with a compound of formula (IV) wherein R ₄ and R _{5 are} hydrogen.