FI65065B - PHARMACEUTICAL FORM OF PHARMACEUTICAL ACTIVATION 7,8-DIHYDROXY-1- (SULFAMOYLPHENYL) -2,3,4,5-TETRAHYDRO-1H-3-BENZAZEPINDERIVAT - Google Patents

Description

1 65065

This invention relates to a process for the preparation of novel pharmaceutically active 7,8-dihydroxy-1- (sulfamoylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine derivatives. ) -2,3,4,5-tetrahydro-1H-3-benzazepine derivatives of formula R2 HO- \ | N-El! HO - “* <>> / R3A ^ XR4

Il - S ° 2N v.

R5 having a hydrogen atom, R1 is a halogen atom, R1 is a hydrogen or halogen atom and and R1. are hydrogen atoms or lower alkyl groups having 1 to 4 carbon atoms, and to prepare pharmaceutically acceptable acid addition salts thereof. The structures of the compounds of formula I are characterized in that they have a sulfamoyl group (-SO2N) in their phenyl ring. The compounds of the formula I have pharmaceutical activity, in particular as renal dopaminergic agents and antihypertensive agents.

Very few 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines having a thio-containing phenyl substituent in their structures are known in the art. U.S. Patent 4,104,379 describes a series of such benzazepine structures having a lower alkylthio, lower alkylsulfonyl, lower alkylsulfinyl or 2,650,665 dimethylsulfonium halide substituent on the 1-phenyl ring. There is no disclosure in the art of either 1-phenyl-2,3,4,5-tetrahydro-ΙΗ-3-benzazepines having a sulfamoyl substituent on the 1-phenyl group or of a synthetic method that would be readily available for their preparation.

The base compounds of formula I may be formed into acid addition salts with pharmaceutically acceptable acids, these salts having the same pharmacodynamic activity as the base compounds with non-limiting side effects. Examples of such organic or inorganic acids are maleic, malic, malic, fumaric, succinic, methanesulfonic, ethanedisulfonic, salicylic, citric, hydrochloric, sulfamic, phosphoric, nitric, sulfuric or hydrobromic acids. Other solvates such as hydrates may also be present. The salts are prepared by methods known in the art, such as reacting the base with an excess acid in a lower alkyl alcohol or similar organic solvent.

The term "lower alkyl" means an alkyl group having 1 to 4 carbon atoms.

The new end products of the formula I have pharmaceutical activity, in particular antihypertensive activity. The compounds of formula I having a hydrogen atom also have clear dopaminergic activity, as described in more detail below.

The compounds of formula I are prepared according to the invention by administering a compound of formula 3 65065 R0 6 N-R 'v 1 R3 Q- ^ R, / 4

react with a compound of formula HN

R5 in the formulas: R2, R1, R4 and R1. have the same meaning as above, X is a chlorine, bromine atom or a similar displaceable group,

R 9 and R 6 are lower alkyl groups or together a methylene or ethylene group and R 1 is an N-protecting group, followed by removal of the protecting groups Rg, R1 and R1 dealkylating agent, acid or base and then optionally forming an acid addition salt of the product.

The preparation of the compounds of formula I can be illustrated by the following reaction scheme:

n R

K2 2 suo] auk- I 1 _ its R.O ^ i ^ V ^ / R4 R60 "rNV / ^ Removal

6 I | j N-R * + HN- ^ "6 || N-R '—9> I

R7Q-Us ^^ l / R5 R7 ° ~ ^ <> /

R, p I

VS r ^ i

S ° 2X

XI III

The phrase "N-protecting group" is used to indicate that the 3-substituent is included to prevent the movement of the chemically reactive hydrogen in the ring nitrogen member of intermediate (II) during the reaction. It is then removed after the desired chemical reaction by a standard reaction to regenerate the secondary amine. Such groups are commonly used in the polypeptide or antibiotic art. Examples of such groups are trichloroacetyl, benzyloxycarbonyl, trifluoroacetyl and benzyl. A tert-butoxycarbonyl, trichloroethoxycarbonyl, p-methoxybenzylcarbonyl, isobornyloxycarbonyl, trityl, benzhydryl group and the like suitable for the protection of a secondary amino group can also be used.

Reaction II to III is carried out in an organic solvent which is inert to the reagents and in which the reagents are soluble, such as dimethylformamide, dimethylacetamide, tetrahydrofuran or dimethyl sulfoxide. The amine-K4 reagent HN is usually used in excess.

^ R 5

The reaction is carried out at any suitable temperature until it is complete. For example, a temperature selected from about 0 ° C to room temperature is most suitable. Compound II can be isolated by methods known in the art or can be reacted without further purification to remove any protecting groups represented by R 1, R 8 or R 2 by methods known in the art. Examples of devices for removing O-ether protecting groups include boron tribromide or trichloride, 48% hydrobromic acid, aluminum chloride or other dealkylating agents. The groups protecting the N atom in position 3 are easier to remove, for example, by acid or base treatment. These can also be removed during the dealkylation described above.

The following series of reactions describes the complete series of reactions suitable for use in the preparation of the compounds of this invention: 65065

Series A

VK, - £

Ho-ks * JK / I N-R '->) - H0 - ^ νΛ— / 1

ό · ~ '(V

u, ^ (2)

R

Φ * 2, _R1 Q.YL ° ^ V ^ - XJ / ‘^

R- I

> 5 β ίτ ~ 0Η ifV - llrho-c-N (cH3,2 (3) (4) Φι2 r3, 1

S-CH-N (CH3) 2 L 3 ~ SO3H

<5 »(6) 6 65065 * 2 X \ jR2 ° \ JL Jl / N Ri / ViS ^“ \ o Y1 '-> CH2 1 I N-Ri ->

I S0oX

k ^ 2 u / r4

11 - SO_N

vl * \ d (7) R5 (8) R, I 2 R ^ CH ~ I N-H Ε0 ~ Γ ^ ιf ^ χ0Λν A / - »IJ n-h

$ ZL / R4 R3 A

I -4-so2n ^ R

rs fi -} - so2 <4 (9) R5

(10) Formula I, R 1 = H

In Reaction Series A, R 1 is a protecting group for secondary nitrogen as described. If in the described series the starting material (1) has the structure # having a 3-allyl or lower alkyl substituent, it is not necessary to use such a protecting group. R 2, R 2, R 2, R 2 and X are the same as defined above.

The preparation depends on a sulfur-oxygen exchange reaction (4 - * 5) to attach the sulfur atom directly to the 1-phenyl ring.

The protecting group for 7 # 8-dihydroxy groups is suitably a methylene (-Cl 2) bond as described above. This system is easily prepared in good yield by the selective reaction of methylene dihalide at the 7,865 position of the corresponding triol (2) 7,650,65. An ethylene dioxide system can also be used, in which case the ethylene dihalide is reacted with a triol (2). 7,8-Lower alkoxy-1- (hydroxyphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepines are not so easy to use due to the lack of selectivity in ether derivatization. However, they have previously been available in the art and may alternatively be used.

Another illustrative set for the preparation of starting materials involves the formation of 7,8-dialkoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine nucleus having a sulfur atom in the phenyl ring, which group 1 can then be optionally converted to various sulfamoyl groups characteristic of structures of the compounds of this invention.

Series B O

/ \ R2

CH - CH- I

A + Κ6 ° ίιΤ 2 2 2 (I J) “SCH2C6H5 R7 ° R 3 (1) (2) R 2 f2 _ Λ Xy ch2 - f2 ρο-ΑΓΛ 6 N I NH 6 I I NH ->

RO-ilJ Ӵ -VW

HO CH- I

'\ / R, I

r3 ch scH2 <vi5 f X- sch2c6h5 (4) (3) 8 65065 R0 I2 "6 ° I y V» - * (vfY \.

V> - \ A- / __ S7oXX_J- * i ^

X I I

r ^ i R3 Jl ljrsca> c ^ (Q-so2x (5) (6) vk? f2 ^. HO_fC ^ Vss / \

6 I ll; NB1 I if NH

r70-j ^^ A / * HO - N ^^ \ / ^ Ss p Vn ^ vR- f i_so2 <4 y Vs ° 2 <p 2 ^ R5 XR5 (7)

(8) I

Reaction series B is particularly suitable for the use of a 7,8-dialkoxysystem for the protection of 7,8-dihydroxy groups, although methylenedioxy or ethylenedioxy derivatives are equally useful for this purpose. Naturally, the final steps (6-8) are as described above. The symbols are the same as defined above.

The novel compounds of formula I of this invention in which R 1 is a hydrogen atom are of particular interest because they have activity as antihypertensive agents having at least in part a renal dopaminergic mechanism. In a single pre-screening experiment, an exemplary compound in which R 2 and R 3 are chlorine atoms showed no renal dopaminergic activity.

9 65065

The active dopaminergic compounds / which are part of this invention therefore accelerate peripheral dopamine receptors, for example they increase renal blood flow and result in antihypertensive activity. This renal vasodilatory activity of the benzazepine compounds of formula I has been measured in anesthetized dogs. In this pharmacological procedure, the test compound is administered in progressively increasing (3-fold) instillation rates from 0.1 μg / kg / min to 810 μg / kg / min, every 5 minutes, to anesthetized dogs with normal blood pressure and measured the following parameters: renal arterial blood flow, ileum arterial blood flow, arterial blood pressure, and heart rate. Results are expressed as the percentage change, increase, or decrease at the time of peak exposure (from pre-drug comparisons) and for a significant effect, renal blood flow (growth) and renal vascular resistance (decrease) must be approximately 10% or greater. The effect on renal vascular resistance can be calculated from any change in renal blood flow and arterial blood pressure. To confirm the mechanism of action, representative active renal vasodilator compounds are screened for blockade by bulbocapnin, a known blocker of renal dopamine receptors. Dopamine is run as a positive check in each screening procedure.

A representative compound of this invention, 6-chloro-7,8-dihydroxy-1- (p-sulfamoylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide gave the following results: ίο 6 5065 MAP ** HBE ** RVfP * HB? * (GAg / (arterial (renal (renal (cardiac) blood flow) blood flow) ne) flow)

Dcpamine 3 -4.9 +38.1 -31.6 +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 X)% change from control value recorded before each instillation in one dog. Four dogs had an ED15 of 20 μg / kg (dopamine 3.5 μg / kg). In the phosphate mannitol dog experiment, the compound showed a reduction in blood pressure at a dose of 5 mg / oral.

Hydrobromide dihydrate of 6-chloro-7,8-dihydroxy-1- (4-N, N-dimethylsulfamoylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine:

Test compound 30 +6.7 -6.2 0 30 -1.4 +6.3 -6.8 +6.7 300 -15.7 -6.3 -9.6 +10.0 6.9- dichloro-7,8-dihydroxy-1- (p-sulfamoylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.

Test compound 3 0 0 0 +5.9 30 +1.3 0 +1.4 +6.3 300 +0.6 +6.3 -5.1 +6.3

The ED 2 of the compound of Example 2 is 25 μg / kg and the ED 2 of the compound of Example 1. are 20 ug / kg and are 2-3 times more active than 6-chloro-7,8-dihydroxy-1- (p-methylthiophenyl) -2,3,4,5-tetrahydro-1H-3 known from U.S. Pat. No. 4,104,379. benzazepine.

Pharmaceutical preparations using the novel compounds of this invention are prepared in conventional unit dosage forms by incorporating a compound of formula I, an isomer thereof, or a pharmaceutically acceptable acid addition salt thereof into a non-toxic pharmaceutical carrier according to accepted procedures in a non-toxic amount sufficient to provide the desired pharmaceutical composition. or to man. Preferably, the compositions contain the active ingredient in an active but non-toxic amount selected from about 15 to 1000 mg and more preferably from 25 to 250 mg of active ingredient per dosage unit, but this amount will depend on the specific biological activity desired and the condition of the patient.

The following examples are designed to illustrate the preparation and use of the compounds of this invention. Temperatures are in degrees Celsius. .Other modifications of these examples will be apparent to those skilled in the art.

Example 1 42 g (0.104 moles) of 6-chloro-7,8-dihydroxy-1- (p-hydroxy-phenyl) -2,3,4,5-tetrahydro-1H-3-benzepepine methane sulfonate ( Belgian patent 860 774) was suspended in 1 liter of dry toluene and 30.0 ml of dry acetonitrile and then 100 ml (0.77 mol) of trifluoroacetic anhydride were added rapidly. The mixture was stirred overnight to give a clear solution which was concentrated in vacuo to an oil. This was dissolved in methylene chloride. The solution was then washed twice with water, several times with 5% sodium bicarbonate solution and then brine. The dried extract was concentrated to give an oil, 6-chloro-7,8-dihydroxy-1- (p-hydroxy-phenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine, trifluoroacetamide (44 g). , which was found to be sufficiently pure by NMR and TLC for further use.

A solution of 44 g (0.104 mol) of 6-chloro-7,8-dihydroxy-1- (p-hydroxyphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine trifluoroacetamide in 700 ml of dry dimethylformamide , was treated with 45.5 g (0.784 moles) of potassium fluoride. After 5 minutes, 650.212 11.2 moles (27.6 g, 0.109 moles) of dibromomethane were added.

The mixture was heated to 115 ° C and kept at 115 ° C for 6 hours. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate and washed several times with water. The dried, concentrated product was chromatographed on 800 g of silica gel with a gradient of 1-3% methanol in chloroform. Homogeneous fractions gave 30.4 g (71%) of 6-chloro-7,8-methylenedioxy-1- (p-hydroxyphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine trifluoroacetamide. A sample of this was crystallized from acetonitrile to give white crystals, m.p. 191-193 ° C.

Replacement of dibromomethane with ethylene dibromide gives the 7,8-ethylenedioxy derivative, which is then used in subsequent steps in equimolar amounts. Other reactive dihalomethanes or ethanes are also used in a similar manner.

A solution of 12.6 g (0.031 mol) of 6-chloro-7,8-methylenedioxy-1- (p-hydroxyphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine trifluoroacetamide in 100 ml of dry dimethylformamide , was treated first with 15.2 g (0.136 moles) of triethylenediamine and then with 6.27 g (0.051 moles) of dimethylthiocarbamoyl chloride. The mixture was stirred at room temperature for four hours, poured into 500 ml of ice water and the precipitate was filtered and washed well with water. The solid was dissolved in 95% ethanol, treated with activated carbon, filtered and diluted with water to cloud point. Cooling gave a total of 11.3 g (73%) of 6-chloro-7,8-methylenedioxy-1- (p-O-dimethylthiocarbamoylphenyl) -2,3,4,5-tetrahydro-1H-3-bentazepine trifluoroacetamide, m.p. 128-131 ° C.

Diphenyl diphenyloxide eutectic gum (Dowtherm "A", 200 ml) was preheated to 200 ° C in an oil bath,

After 13,65065, 24.0 g (0.048 moles) of 6-chloro-7,8-methylenedioxy-1- (pO-dimethylthiocarbamoylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine trifluoroacetamide were added rapidly in portions. to the mixed mixture. The resulting solution was heated at 205-230 ° C for about 10 h. The cooled reaction mixture was poured directly onto a column packed with 800 g of silica gel washed with cyclohexane. The column was developed with cyclohexane to remove the heat transfer medium, then with a gradient of 3/1 and then 5/2 cyclohexane-ethyl acetate to obtain a homogeneous product. Crystallization from acetonitrile afforded 8.7 g (40%) of 6-chloro-7,8-methylenedioxy-1- (p-S-dimethylcarbamoylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine trifluoroacetamide, m.p. 194-195 ° C.

10 g (0.02 mol) of 6-chloro-7,8-methylenedioxy-1- (p-S-dimethylcarbamoylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazine trifluoroacetamide were suspended in 200 ml of 90% formic acid and 35 ml of 30% hydrogen peroxide were added dropwise with stirring at room temperature. The mixture was stirred for 18 hours. The clear solution was evaporated and the residue was azeotroped several times with 95% ethanol. The crude product was dissolved in ethyl acetate, washed with cold 1% hydrochloric acid and brine, and then concentrated to about 10 g of crude 6-chloro-7,8-methylenedioxy-1- (p-sulfophenyl) -2,3,4,5-tetrahydro- 1H-3-benzazepine trifluoroacetamide, NMR consistent with structure and high pressure liquid chromatography on a C-18 reversed phase column using water-methanol-acetic acid 60/40/1, -5 containing 3 x 10 M sodium hexanesulfonate showed the product to be at least 85% pure.

i4 6 5 0 6 5

A mixture of 1.0 g (2.1 iranol) of crude 6-chloro-7,8-methylenedioxy-1- (p-sulfophenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine trifluoroacetamide, 20 ml of thionyl chloride and 0.04 ml of dimethylformamide, were heated at 80 ° C for 2 hours. The thionyl chloride was evaporated in vacuo. The residue 6-chloro-7,8-methylenedioxy-1- (p-chlorosulfonylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine trifluoroacetamide was dissolved in tetrahydrofuran. The solution was slowly added to 40 ml of cooled concentrated ammonium hydroxide. The mixture was stirred at room temperature for 1 hour, the pH was adjusted to 8 with hydrochloric acid and the product was extracted into 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 developed with a gradient of 24-35% ethyl acetate in cyclohexane to give 0.5 g of 6-chloro-7,8-methylenedioxy-1- (p-sulfaroylphenyl) -2,3,4,5-tetrahydro-1H-3 -benzazepine trifluoroacetamide. Background desorption mass spectroscopy showed a strong m / e value at position 476, which is consistent with the molecular ion. NMR and IR were consistent with structure.

Replacement of ammonia with ethylamine gives the (p-N-ethylsulfamoylphenyl) derivative. This subsequent alkali hydrolysis and boron tribromide treatment, detailed below, gives 6-chloro-7,8-dihydroxy-1- (p-N-ethylcarbaraoylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.

A mixture of 0.5 g (1.1 mmol) of 6-chloro-7,8-methylenedioxy-1- (p-sulfamoylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine trifluoroacetamide , 0.1 g of sodium hydroxide and 50 ml of methanol were stirred at room temperature for 2 hours, poured into water and extracted with 65065 of ethyl acetate. The combined extracts were washed with brine, dried and concentrated. The residue was chromatographed on 20 g of silica gel with a 1-5% methanol gradient in chloroform to give 0.35 g of pure 6-chloro-7,8-methylenedioxy-1- (p-sulfamylphenyl) -2,3,4,5 tetrahydro-lH-3-benzazepine. This was suspended in 5 ml of dry methylene chloride, cooled to -60 ° C, and a solution of 5 ml of boron tribromide in methylene chloride (1 g / ml) was added dropwise with stirring under a nitrogen atmosphere. The mixture was stirred for about an hour at room temperature, re-cooled to -15 ° C, whereupon excess methanol was carefully added. The solvents were evaporated. The residue was azeotroped several times with methanol. The residual solid was crystallized from methanol-acetonitrile-ether to give 0.36 g (86%) of 6-chloro-7,8-dihydroxy-1- (p-sulfamoylphenyl) -2,3,4,5-tetrahydro -ro-1H-3-benzazpine hydrobromide, m.p. 289-290 ° C.

The base (1 g) is regenerated using dilute sodium bicarbonate isopropanol. Fractions of 100 mg of base in isopropanol are treated with methanesulfonic or hydrochloric acid to give methanesulfonic acid or hydrochloride salts.

Example 2

A mixture of 5.0 g (0.011 mol) of 6-chloro-7,8-methylenedioxy-1- (p-sulfophenyl) -2,3,4,5-tetrahydro-ΙΗ-3-benzazepine trifluoroacetamide in 70 ml of thionyl chloride and 0.08 ml of dimethylformamide, heated at 80 ° C for 2 hours and the solvents evaporated in vacuo.

The acid chloride residue was dissolved in tetrahydrofuran.

This solution was slowly added to a solution of dimethylamine in tetrahydrofuran at -15 ° C. The reaction mixture was stirred at 0 ° C for 1 hour and then allowed to reach room temperature over 20 minutes. Hydrochloric acid was added to pH 6.5. The product was extracted into chloroform. The extracts were washed well with water, dried and concentrated to 4.0 g of crude product.

This was chromatographed on 120 g of silica gel with a gradient of 25-33% ethyl acetate in cyclohexane. The homogeneous fractions were crystallized from aqueous ethanol to give 3.1 g (78%) of 6-chloro-7,8-methylenedioxy-1- (pN, N-dimethylsulfamoylphenyl) -2,3,4,5-tetrahydro-1H- 3-Benzazepine trifluoroacetamide m.p. 143-145 ° C.

A solution of 2.3 g (0.00457 moles) of 6-chloro-7,8-methylenedioxy-1- (ρ-Ν, Ν-dimethylsulfamoylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine trifluoroacetamide , 75 ml of methanol and 0.5 g of sodium hydroxide, were stirred at room temperature for 2 hours, diluted with water and extracted several times with ethyl acetate. The extracts were washed with brine, dried and concentrated. The crude residue was chromatographed on 75 g of silica gel using 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- (p-N, N-dimethylsulfamoylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine. The background desorption mass spectrogramml showed a strong peak at m / e 408, which is consistent with the structure.

The NMR and IR spectra are also consistent with the structure.

This product (300 mg) was dissolved in 15 ml of dry methylene chloride, the solution was cooled to -15 ° C under a nitrogen atmosphere. A solution of 3 ml of boron tribromide in methylene chloride (1 g / 5 ml) was added dropwise. A precipitate formed rapidly. The mixture was then stirred at room temperature 175065 for about an hour and re-cooled with an ice bath. Excess methanol was carefully added. The resulting solution was evaporated. The residue was azeotroped several times with methanol. The solid was crystallized from methanol / acetonitrile to give off-white hydrobromide crystals of 6-chloro-7,8-dihydroxy-1- (p-N, N-dimethylsulfamoylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 238-240 ° C.

NMR and IR spectra were consistent with the structure.

Example 3

A solution of 50 g (0.219 mol) of p-thiobenzylbenzoic acid in 450 ml of dry tetrahydrofuran was cooled in ice water under a nitrogen atmosphere and a solution of 400 ml of 1-M diborane in tetrahydrofuran (0.4 mol) was added dropwise. After half an hour the cooling bath was removed. The mixture was stirred at room temperature for 2 hours. The reaction mixture was re-cooled in ice water and excess methanol was carefully added. The solvents were evaporated to give a white solid which was crystallized from aqueous ethanol to give 39.5 g (79%) of p-thiobenzyl alcohol, m.p. 87 to 88.5 ° C.

A solution of 38.5 g (0.167 mol) of p-thiobenzylbenzyl alcohol in 400 ml of toluene was treated with 100 g of activated manganese dioxide. The suspension was stirred and heated on an oil bath for 5 hours on a Dean-Stark water separator. The mixture was slightly cooled, filtered through chloroform. The filtrate was concentrated to a pale yellow solid. This was crystallized from absolute alcohol to give 30.1 g (80%) of p-thiobenzylbenzaldehyde, m.p. 62 to 63.5 ° C.

18 65065

A solution of 30.0 g (0.132 moles) of p-thiobenzylbenzaldehyde, 37.6 g (0.184 moles) of trimethylsulfonium iodide and 150 ml of dry dimethylsulfoxide (kept under a nitrogen atmosphere) was added over 15 minutes to a solution of 18.6 g. g (0.17 moles) of potassium t-butoxide in 100 ml of dry dimethyl sulfoxide. The mixture was stirred for a further 45 minutes at room temperature and poured into 3 liters of ice water. The quenched mixture was extracted with ethyl acetate (4 x 300 mL). The combined organic extracts were washed with brine and water (4 times) and dried over magnesium sulfate. The extracts were concentrated to solid p-thiobenzylstyrene oxide.

This crude epoxide was mixed with 28.5 g (0.13 moles) of 2-chloromomotatrylamine and heated at 10 ° C (under nitrogen) for 18 hours. The crude product was dissolved in a small amount of chloroform and applied to a column packed with 900 g of silica gel. The column was developed with a series of chloroform solutions containing 2-1 / 2% methanol, and 400 ml fractions were collected. The homogeneous heat was crystallized from absolute alcohol to give 15.4 g of α- (N-2-chloro-3,4-dimethoxyphenethylaminomethyl) - <-4,4-thiobenzylbenzyl alcohol, m.p. 80 to 81.5 ° C.

A solution of 13.0 g (0.0284 mol) of benzyl alcohol in 260 ml of dry methylene chloride was treated with 10.4 ml of methanesulfonic acid. The resulting solution was carefully refluxed for 3 hours. Ice was added followed by 150 ml of 10% sodium hydroxide solution. The organic layer was separated. The aqueous layer was extracted with methylene chloride, and the combined organic extracts were washed with water, dried, and concentrated to leave 12.1 g of crude product, which was chromatographed on 650 g of silica gel with a 2-4% methanol gradient in chloroform. This gave 9.4 g (75%) of 6-chloro-19,65065 7,8-dimethoxy-1- (p-thiobenzylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine. NMRf IR and mass spectra were consistent with structure.

Benzazepine, 7.7 g (0.017 mol) was dissolved in 80 ml of acetone and no water, and then a solution of 5.3 g of sodium carbonate in 10 ml of water was added. The mixture was cooled in ice water. A solution of 5.44 g of benzyl chloroformate in 25 ml of acetone was added dropwise. The mixture was stirred at 5 ° C for 1 hour and then overnight at room temperature. Water was added. The product was extracted into ethyl acetate and washed with brine and water. The concentrated product was chromatographed on 200 g of silica gel converting from chloroform to 0.5 L of methanol in chloroform to give 4.5 g (46%) of 6-chloro-7,8-dimethoxy-1- (p-thiobenzylphenyl) -2 , 3,4,5-tetrahydro-1H-3-benzazepine benzyl carbamate as a syrup. Background desorption mass spectroscopy showed a strong m / e value of 573, consistent with structure. The IR and NMR spectra were consistent.

The carbamate (4.5 g, 0.0079 mol) was dissolved in 45 ml of glacial acetic acid and 0.45 ml of water was added. The solution was cooled in water (15 ° C). Chlorine gas was blown through the solution for 20 minutes while maintaining the reaction temperature between 25-27 ° C. The mixture was then 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 blown slightly through the wet solution. The solvent was evaporated at room temperature in vacuo to give the residue 6,9-dichloro-7,8-dimethoxy-1- (p-chlorosulfonylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine benzyl carbamate.

20 6 5 0 6 5

The hydrochloride residue was dissolved in tetrahydrofuran and then added to 75 ml of ice-cooled ammonium hydroxide. After stirring for 2 hours at room temperature, the pH was adjusted to about 8 with hydrochloric acid. The product was extracted into chloroform and washed with water. The dried concentrate was chromatographed on 200 g of silica gel converting from chloroform to 1% methanol in chloroform to give 3.24 g (75%) of 6,9-dichloro-7,8-dimethoxy-1- (p-sulfamylphenyl) -2 , 3,4,5-tetrahydro-1H-3-benzazepine benzyl carbamate as an oil. NMR, IR and mass spectra were consistent with the structure.

The sulfamoyl derivative (2.0 g, 3.56 nunol) was dissolved in 60 mL of dry methylene chloride. The solution was frozen at -15 ° C (under nitrogen). A solution of 17.7 ml of boron tribromide in methylene chloride (1 g / 5 ml) was added dropwise. The solution was then stirred at room temperature to give a precipitate. After about one hour, the mixture was re-cooled, methanol was added slowly and the solution was concentrated and azeotroped with additional methanol. The residue was dissolved in a small amount of acetone and added dropwise to a stirred solution of 3 parts of ether and one part of ethyl acetate to give an off-white powder, 0.586 g (35%), m.p. 210-212 ° C 6,9-Dichloro-7,8-dihydroxy-1- (p-sulfamovylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.

Claims (6)

65065 A process for the preparation of pharmaceutically active 7,8-dihydroxy-1- (sulfamylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine derivatives of the formula i 2 H 0 -? II? R 1, R 2, - so 2 N 2, R 5, having a hydrogen atom, R 2 is a halogen atom, R 1 is a hydrogen or halogen atom, and R 1 and R 2 are hydrogen atoms or lower alkyl groups having 1 to 4 carbon atoms, and pharmaceutically acceptable acid addition salts thereof. characterized in that a compound of formula R2 Rp -1 ^ ^ / SO2X ^ R4 is reacted with a compound of formula HN R5 in which formulas: R2, R3, R4 and Rj have the same meaning as above, X is chloro- , a bromine atom or a similar displaceable group, R 6 and R 2 are lower alkyl groups or together a methylene or ethylene group and R 1 is an N-protecting group, followed by removal of the protecting groups R 8, and R 6 with a dealkylating agent, acid or base and then optionally forming the acid of the product dditiosuola. Process according to Claim 1, characterized in that 6-chloro-7,8-dihydroxy-1- (p-N, N-dimethylsulfamoylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine is prepared. Process according to Claim 1, characterized in that 6-chloro-7,8-dihydroxy-1- (p-sulfanoylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine is prepared. A process for the preparation of pharmaceutically active 7,8-dihydroxy-1- (sulfamoylphenyl) -2,3,4,5-tetrahydro-1H-3-benzazepine derivatives in the form of a compound. 1. N / R1 I HO —JK / XR4 R5 is a color R1 is a halogen atom, R2 is a halogen atom, R1 is a hydrogen atom or a halogen atom and R2 is an R1. is a hydrogen atom or a alkyl group having 1 to 4 carbon atoms, as well as a pharmaceutically acceptable acid addition salt, känneteck-n a t av att en förening med formeln