HU183602B - Process for producing 1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid's substituted acyl derivatives - Google Patents

Abstract

The present invention relates to a process for the preparation of substituted acyl derivatives of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid and pharmaceutically acceptable acid addition salts thereof. Substituted acyl derivatives of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid correspond to formula (I). In this formula R is hydrogen, C 1 -C 4 alkyl or benzyl; R, H or C 1 -C 4 alkyl: R 2 is hydrogen or C 1-4 alkyl; Ar is phenyl, X and Y are independently hydrogen or C1-C4 alkoxy, and m is 0 to 3. The compounds of formula (I) can be used as active ingredients of antihypertensive drugs. Ar-fCH2-CH-hH-COOR (I) (la) (1b) (le) -1-

Description

The present invention relates to a process for the preparation of substituted acyl derivatives of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

U.S. Patent 4,154,840 discloses compounds with similar activity but different structure and British Patent 2,042,535 discloses compounds of similar structure.

Substituted acyl derivatives of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid have the general formula (I)

R is hydrogen, (C1-C4) -alkyl or benzyl;

R 1 is hydrogen or C 1-4 alkyl;

R _{2 is} hydrogen or C 1-4 alkyl;

Ar is phenyl;

X and Y are each independently hydrogen or C 1 -C 4 alkoxy, and m is a number from 0 to 3.

The invention also relates to the preparation of pharmaceutically acceptable acid addition salts of the compounds of formula (I).

Preferred compounds of the present invention are acylated 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids of formula (Ia):

R 1 is hydrogen or C 1-3 alkyl,

_R2 is hydrogen or C1-3 alkyl and Ar, X and Y are as defined above.

The process also relates to the preparation of pharmaceutically acceptable acid addition salts of the compounds of formula (Ia).

Further acylated 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids obtainable by the process of the present invention are compounds of formula Ib wherein

R _{2 is} hydrogen or C 1-3 lower alkyl,

X and Y are as defined above and pharmaceutically acceptable acid addition salts thereof.

The following compounds are particularly preferred:

2t [2 - {(1-carboxy-3-phenylpropyl) amino] -1-oxopropyl] -1,2,3,4-tetrahydro-3-isoquinoline carboxylic acid;

2- (2 - ({1-Ethoxycarbonyl-3-phenylpropylamino) -1-oxopropyl] -1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid;

-12-j (l-carboxy-3-phenylpropyl) amino | -1-oxopropyl] -1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinoline carboxylic acid;

2- [2 - ({1 - (ethoxycarbonyl / -3-phenylpropylamino) -loxopropyl] -1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid

Also acceptable are pharmaceutically acceptable acid addition salts of these compounds.

Compounds of formula (I) have asymmetric carbon atoms, which are represented by asterisks in formula (I). The 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid used in the process of the present invention has the L (S) configuration. This configuration is required for biological activity and thus the active compounds of the invention are all L (T). all are derived from DL-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

Optical and diastereoisomers at racetracked centers, as well as their racemates and mixtures thereof, are also compounds of formula (I). The S configuration is advantageous at these exchanges.

The compounds of formula (I) may exist in anhydrous form and in solvated, such as hydrated, form. In general, hydrated forms and solvated forms with pharmaceutically acceptable solvents are equivalent to anhydrous and unsolvated forms for purposes of the present invention.

The compounds of formula (I) are prepared from 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid by first protecting the carboxyl group, preferably in the form of an ester such as a lower alkyl group, a benzyl group. The protected carboxylic acid is coupled with an N-protected amino acid such as glycine or Lalanine. The coupling is performed using one of the standard peptide coupling methods known as "The Peptides. Analysis, Synthesis, Biology, Vol. 1. Major Methods of Peptide Bond Formation, Part A, [E. Gross, J. Meierhofer, Academic Press N.Y. (1979)]. A particularly useful method involves using a dehydrating agent such as dicyclohexylcarbodiimide alone or reactive ester-forming reagents such as 1-hydroxybenzthiazole. in the presence of a suitable proton-free solvent such as dimethylformamide, acetonitrile, tetrahydrofuran or chlorinated hydrocarbons. Intermediate (N-protected-2-aminoacyl / -1,2,3,4, -tetrahydroisoquinoline-3-carboxylic acid esters are obtained. The protecting groups are partially or completely removed, depending on the protecting groups chosen, with anhydrous acids such as hydrochloric acid in acetic acid or trifluoroacetic acid in methylene chloride. or with hydrogen gas and catalyst to give the intermediate dipeptide in free form or as an ester, The ester protected products can be hydrolyzed to the free acid derivatives under basic or acidic conditions or catalytic hydrogenolysis is preferred in the case of benzyl esters.

Compounds of formula (I) may be prepared by first linking the 2- (4-phenylbutyric acid) moiety to glycine or L-alanine, which may be protected as an ester such as N- [2- (-4-phenylbutyric acid)]-substituted-glycine or A-L-alanine derivative is prepared.

The acid moiety on the glycine or alanine moiety of the product is selectively liberated, the resulting monoacid can be directly coupled, or, following appropriate blocking of the amino group, can be converted to the 1,2,3,4-tetrahydro-3-isoquinoline carboxylate by standard peptide coupling techniques. Selective or complete removal of ester groups and certain amine protecting groups affords compounds of formula (I).

The products are obtained as a mixture of diastereoisomers which are separated into the individual isomers by standard methods such as fractional crystallization or chromatography.

The compounds of formula (I) form acid addition salts with various inorganic or organic acids, the preparation of which is also within the scope of the present invention. The pharmaceutically acceptable acid addition salts of the compounds of formula (I) are prepared by conventional reactions to react the free amino acid or amino acid ester form of the product with one or more equivalents of the acid which serves the desired anion.

183,602 Tatiana. The reaction is carried out in a solvent or medium in which the salt is insoluble, but the reaction can also be performed in water and then the water is removed by freeze-drying. They are saline with strong acids. These include the pharmaceutically acceptable salts of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid, fumaric acid, malic acid, maleic acid and citric acid.

The action of the renin enzyme on angiotensinogen, such as pseudoglobulin in the plasma, provides the angiotensin 1 decapeptide. Angiotensin I is converted by the angiotensin converting enzyme (ACE) to angiotensin II octapeptide. The latter is an effective antihypertensive agent which may be the active ingredient of various antihypertensive agents in the treatment of many warm-blooded species such as rats and dogs. The compounds of the present invention interfere with the renin-angiotensin I-angiotensin II process by inhibiting the angiotensin-I converting enzyme and reducing or eliminating the production of angiotensin 11 hypotensive agent, thereby reducing or relieving hypertension. Thus, administration of formulations containing a compound of formula (I) or a combination of such compounds, or medicaments containing pharmaceutically acceptable salts thereof, reduces hypertension in warm-blooded hypertensive patients. A single dose, however, preferably administered 2-4 times a day in an amount of about 0.1-100 mg / kg body weight per day, preferably 1-50 mg / kg / day, provides adequate reduction of blood pressure. The compositions are preferably administered orally, but may also be administered parenterally, such as subcutaneously, intramuscularly, intravenously or intraperitoneally.

In vitro ACE experiment

The inhibitory activity of the angiotensin converting enzyme (ACE) was determined by

ACE was used in the presence and absence of the test compound. ACE from guinea pig serum and test compounds were preincubated for 10 minutes before the addition of the labeled ³ H-hippurylglycylglycine extract. After incubation for about 60 minutes at 37 ° C, the reaction was quenched by the addition of 0.1 N HCl. ACE cleaved the hippurylglycyl bond and formed dipeptide glycylglycine and formed ³ H-gallic acid. The ³ H-hippuric acid is then extracted with ethyl acetate and the ACE of a given sample st, as the amount of released ³ H hippur25 eagle calculated. The results are given in the following table.

Acyl derivatives of 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acids (S, S, S configuration) and their in vitro inhibitory effect on angiotensin converting enzyme: Compounds of formula Ic

R r ₂ X Y Optical rotation ACE inhibitory activity (in vitro) IC ₅₀ moles conc. H et H H + 10.9 ° (1.0% EtOH) + 8.3x1ο ⁹ H et and ₃ and ₃ + 31.6 ° (1.0% EtOH) + 5,6x10 ^ H H H H + 14.5 ° (1.0% MeOH) + 2.8x10 ⁹ H H and ₃ and ₃ + 37.8 ° (1.0% MeOH) + 3.4x10 ' ⁹ PhCH ₂ et H H -11.7 ° (1.0% MeOH) = 2,0x10'® t-Bu et H H + 6.4 ° (2.0% MeOH) = 3,2x10 * PhCH ₂ et and ₃ and ₃ + 3.4 ° (1.0% EtOH) = 3.0x10 ⁷

+ hydrochloride salt = maleate salt

The compounds of the present invention are formulated in a variety of pharmaceutical compositions to reduce hypertension, such as tablets, capsules or elixirs for oral administration or as sterile solutions or suspensions for parenteral administration. The compounds of formula (I), or their physiologically acceptable salts or mixtures thereof, are present in an amount of about 10 to 500 mg in a unit dosage form suitable for oral or other administration with a physiologically acceptable carrier, excipient, binder, preservative, stabilizer, fragrance and the like. into pharmaceutical compositions. The amount of active ingredient in these compositions and formulations is within the above range.

Excipients that may be included in tablets, capsules, and the like include excipients such as gum tragacanth, gum arabic, corn starch, or gelatin; fillers such as dicalcium phosphate; disintegrants such as corn starch, potato starch, alginic acid and the like; lubricants such as magnesium stearate; sweetening agents such as sucrose lactose or saccharin; fragrances such as mint, gaulter oil or cherry oil. In the case of a unit dose capsule, it may contain, in addition to materials of the above type, a liquid carrier such as fatty oils. Other materials may be present, such as coating materials or other materials that modify the physical form of the unit dose. For example, tablets may be coated with shellac, sugar, or both. The syrup may contain, in addition to the active ingredient, a sweetening agent such as sucrose, methyl or propylparaben as a preservative, a dye and a flavoring agent such as cherry or orange extract. Elixirs may contain the same additives.

Sterile injectable compositions for pharmaceutical use! may be prepared by conventional means such that the active ingredient is in a vehicle

183,602, for example, in water for injection, in naturally occurring vegetable oils such as sesame oil, coconut oil, peanut oil, cottonseed oil and the like, or in a synthetic fatty carrier such as ethyl oleate and the like. If desired, buffering agents, preservatives, antioxidants and the like may also be included.

The invention is further illustrated by the following examples.

Example 1

2- [2- (1-Ethoxycarbonyl-3-phenylpropyl) amino] -1-oxopropyl] -1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid hydrochloride (S, S, S)

Phenylmethyl 2- (2 - ((1 -) ethoxycarbonyl-3-phenylpropylamino) -oxopropyl] -1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid (S, S, S) The hydrochloride (0.0079 mol) was dissolved in tetrahydrofuran (100 ml) and catalytically debenzylated with hydrogen (0.5 g, 20% Pd / carbon) at low pressure, the catalyst was filtered off and the product precipitated by addition of 10 times ether to a relatively non-hygroscopic 3.7 g of product are obtained which corresponds to a 88/7 yield.

120-140 ° C.

(tlc = thin layer chromatography: 20% MeOH-CHCl ₃ (SiO ₂ ) one spot).

Rf: 0.5-0.7;

[α] D = + 31.6 ° (1.05 = EtOH).

Analysis C ₂₇ Η _Μ N ₂ O ₇ . HC1.H ₂ O Calcd

Calculated: C 58.6 * 3; H, 6.74; N5, O7%

Found: C, 58.59; H6,48; N5,06%

The above non-crystalline starting diester hydrochloride used as starting material was prepared by treating 5.54 g (0.0079 mole) of the maleate salt (prepared as in Example 5) with an excess of saturated sodium bicarbonate solution. The base is extracted with 50/50 ether / ethyl acetate and the resulting solution is treated with excess hydrogen chloride and concentrated under reduced pressure.

Example 2

2- [2 - ({1 - (ethoxycarbonyl / -3-phenolpropyl) amino) -1-oxopropyl] -1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid hydrochloride (S, S, S).

Method A: Debenzylation

2- (2 - ((1-Lethoxycarbonyl / 3-phenylpropylamino) -1-oxopropyl] -1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid phenylmethyl ester malate (S, S) was catalytically debenzylated as described in Example 1. The product was melted at 105-120 ° C, yield 56%; tlc (20% MeOH-CHCl 3 / SiO 2) a spot.

Rf: 0.5 -0.6;

(α (D = + 10.9 ° (1.03% EtOH)).

Analysis for C _{2 S} H 3 _O N ₂ O ₅ . HCI. H ₂ O

Calculated: C, 60.90; H, 6.75; N, 5.68%

Found: C, 61.00; H, 6.37; N, 5.59%. Method: 1,1-dimethyl ethyl ester cleavage

Trifluoroacetic acid (100 g) was added 11.6 g (0.023 mol) of 2- (2- (1-ethoxycarbonyl-3-phenylpropyl} amino) -1-oxopropyl] -1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid -1, l-dimethyl ester (S, S, S) (prepared as described in Example 7) The mixture was stirred at room temperature for 1 hour Most of the resulting solution was removed in a rotary evaporator and then 2x50 mL of THF was added. The residue was dissolved in about 400 ml of dry ether and the hydrochloride was obtained by adding 1.0 g (excess) of a solution of dry hydrogen chloride in 20 ml of dry ether. The precipitate was collected by filtration and washed with dry ether, and the filter cake was dissolved in about 250 ml of water, filtered through celite and freeze-dried to give the desired product. 10.0 g (90%) of the product as a partial hydrate, m.p. 113-120 ° C.

Analysis for C _{2 S} H ₃₀ N ₂ O ₅ . HCI. Calculated 4.3 H ₂ O Calcd: C 61.55; H 6.70; N 5.74%

Found: C, 61.51; H, 6.49; N, 5.70%

Example 3

2- [2-1 H -carboxy-3-phenylpropyl / amino] -1-oxopropyl] -2,

3,4-Tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid hydrochloride hydrate (S, S, S)

0.553 g (0.001 mol) of 2- (2 - ((1-ethoxycarbonyl-3-phenylpropyl (amino) -1-oxopropyl) -1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid) hydrochloride hydrate (S, S, S) (prepared as in Example 1) in a mixture of 4 ml (0.004 mol) of 1N sodium hydroxide and 4 ml of methanol was allowed to stand at room temperature for 20 hours. Add 1N hydrochloric acid and concentrate under reduced pressure, remove the remaining water by adding two successive portions and remove 25-25 mL of ethanol under reduced pressure, dissolve the organic portion in 0.5 mL of methanol and add 30 mL of chloroform. and the solution was dried over sodium sulfate, filtered over charcoal and concentrated to give 0.45 g of product, the amorphous material was dissolved in tetrahydrofuran (20 mL) and ether (100 mL) was added to the solution to precipitate 0.4 g of a white solid. wish t product.

145-170 ° C. Yield 80%; tlc (207 /. MeOHCHCl ₃ / SiO ₂ ).

Rf.0,1; (a) = + 37.8 ° (1.09%. MeOH).

Analysis for C _{2 S} H ₃₀ N ₂ O ₇ . HCI. H ₂ O

Calculated: C, 57.19; H, 6.34; N, 5.34%.

Found: C, 57.17; H, 6.10; N, 5.51%

Example 4

2- [2 - [(1-carboxy-3-phenylpropyl) amino] -1-oxopropyl] -1,2,

3,4-Tetrahydro-3-isoquitolylcarboxylic acid hydrochloride hemi hydrate (S, S, S)

-4ι

183,602

2- {2- (1-Ethoxycarbonyl-3-phenylpropyl) amino) -1-oxopropyl] -1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid hydrochloride (S, S, S) The moiety was treated as described in Example 3 to give the desired product.

140-170 ° C. Yield 39%.

[α] D = + 14.5 ° (1.08% Me).

Analysis for C _{2 3} H ₂₆ N ₂ O _S. MONTH. Calculated 1 / 2H ₂ 0 Calcd: C, 60.59; H, 5.97; N, 6.15; O 7.77%

Found: C, 60.68; H, 6.04; N, 5 to 9; 0 7.04%

Example 5

2- [2 - ((1-Ethoxycarbonyl-3-phenylpropyl) amino) -1-oxopropyl] -1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid phenylmethyl ester -may (S, S, S)

A solution of 5.0 g (0.0158 mA) of ethidyl- (1-carboxymethyl) amino] phenylbutanoate hydrochloride (S, S) (prepared as in Example 8) in 200 ml of methylene chloride was stirred successively. treated with 1.60 g (0.0158 mole) of triethylamine, 2.14 g (0.0158 mole) of 1-hydroxybenzotriazole, 5.16 g (0.0158 mole) of 1,2,3,4-tetrahydro-6,7 phenylmethyl ester of dimethyl-3-isoquinolinecarboxylic acid with the free base (S-form) (obtained as in Example 9) and dicyclohexylcarbodiimide (3.26 g, 0.0158 mole) in methylene chloride (10 ml). Dicyclohexylurea was continuously separated and the mixture was allowed to stand at room temperature overnight, then 300 ml of hexane was added and the urea was filtered off. The filtrate was washed with saturated sodium bicarbonate solution (250 mL), dried over sodium sulfate and concentrated. The solvent and residue, which is a viscous material, are triturated with 50 ml of ether and the insoluble material is filtered off. The filtrate was concentrated to give 9.2 g of crude base, corresponding to 99% yield.

Preparation of the maleic salt

The crude base obtained as above (9.0 g, 0.015 mol) was dissolved in ethyl acetate (50 ml) and treated with a warm solution (40 ° C) of maleic acid (1.86 g, 0.016 mol) in ethyl acetate (59 ml). The resulting crystalline product (7.2 g) was isolated. Yield 65%. 139-141 ° C; tlc (salt treated with aqueous sodium bicarbonate solution and extracted with ethyl acetate) shows a spot on the base.

R f: 0.7 (1 · tOAc / SiO ₂ ).

The product was recrystallized from ethyl acetate to give pure material.

[α] D = + 3.4 ° (1.05% EtOH).

Analysis for Cj, H _w N ₂ O ₇ . Ο, Η, Ο ,,

Calculated: C, 64.74; H, 6.29; N, 3.98%

Found: C, 64.48; H, 6.30; N 3.99%

Example 6

2- [2- (1H-Ethoxycarbonyl-3-phenylpropyl) amino) -1-oxopropyl] -1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid phenylmethyl ester maleate (S, S, S)

Ethyl a - [[1-carboxyethyl] amino] phenylbutanoate hydrochloride (S, S) (prepared as in Example 8) with a free base of 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid (S-form) ) (prepared as in Example 10) was coupled as described in Example 5).

Yield 61%. 151-153 ° C (after recrystallization from ethyl acetate). In the tlc assay, the free base shows a spot. RT: 0.8 (EtOAc / SiO ₂ ).

[α] D = -11.7 ° (1.0% MeOH).

Analysis for C ₃₂ H ₃₆ N _S O ₂ .C ₄ H ₄ O ₄ Calcd

Calculated: C, 67.07; H, 6.25; N, 435%

Found: C, 66.58; H, 6.09; N, 4.25% Example

2- [2 - ({1-Ethoxycarbonyl-3-phenylpropyl) amino) -1-oxopropyl) -1,2,3,4-tetrahydro-3-isoquinoline carboxylic acid 1,1-dimethylethyl ester (S) , S, S)

8.38 g (0.03 mol) of ethyl α - [(1-carboxyethyl / amino) phenylbutanoate (free amino acid) (S, S) (prepared as in Example 8), 8.09 g (0, 03 moles)

1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid 1,1-dimethylethyl ester hydrochloride (S-form) (prepared as in Example 11), 4.05 g (0.03 g). mole) of 1-hydroxybenzotriazole and 250 mL of THF in an ice bath

Cool to 3-5 ° C. To the mixture was added triethylamine (3.04 g, 0.03 mol) and dicyclohexylcarbodiimide (6.92 g, 0.0335 mol) in THF (30 ml) was added dropwise over 20 min. The reaction mixture was stirred at 3-5 ° C for one hour. The ice bath was then removed and the reaction stirred for an additional 3 hours. A mixture of the precipitated triethylamine hydrochloride and dicyclohexylurea was collected by filtration and washed with THF. The filtrate was concentrated in a rotary evaporator to remove all volatiles. The resulting gum was dissolved in about 300 mL of ethyl acetate. The ethyl acetate solution was filtered through celite, and the filtrate was washed twice with 100 ml of saturated sodium bicarbonate solution, once with 75 ml of 2N citric acid solution, once with 100 ml of saturated sodium bicarbonate solution and once with 100 ml of anhydrous magnesium sulfate. dried and filtered. The ethyl acetate was removed by rotary evaporation to give 163B of a light brown gum. This gum was dissolved in 350 mL spinning hexane and decanted through celite. The hexane solution is cooled in ice, inoculated and stirred until crystallization is complete. The product was isolated by filtration, washed with cold hexane and dried to give 11.6 g (78%) of product.

Op.683-71 “C. [α] D = -12.2 ° (2% MeOH).

The pure material had a melting point of 71-72 ° C. [α] D = -12.6 ° (2% MeOH); The maleate salt has a melting point of 127.5-188.5 ° C. [Α] D = + 46.4 ° (2% MeOH).

Example 8

Ethyl α- [1-carboxyethyl / amino] phenylbutanoate hydrochloride (S, S)

A solution of 2.0 g of tert-butylalanine (S-form) and 3.78getyl-2-bromophenylbutanoate in 25 ml of dimethylformamide5

183,602 was treated with triethylamine (1.8 mL) and the solution heated at 70 ° C for 18 h. The solvent was removed under reduced pressure, the residue was stirred with water and extracted with diethyl ether. The organic layer was washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the tert-butyl ester of the intermediate as an oil which was pure enough for further use as evidenced by gas / liquid chromatography.

A solution of 143.7 g of such tert-butyl ester in 630 ml of trifluoroacetic acid was stirred at room temperature for one hour. The solvent was removed under reduced pressure and the residue was dissolved in ethyl ether and evaporated again. This operation is repeated. The ethereal solution was treated dropwise with a solution of hydrogen chloride gas in ethyl ether until the precipitation ceased. The solid was collected by filtration to give a mixture of diastereoisomers.

153-165 ° C.

[α] D = + 3.6 ° (1% MeOH).

To isolate the preferred S, S isomer, the mixture was dissolved in methylene chloride (200 mL), stirred at room temperature for 5 minutes and then filtered. The resulting solid was washed with additional methylene chloride and finally with ether. The solid melts at 202-208 ° C (with decomposition).

[α] D = -29.3 ° (1% MeOH).

The less preferred diastereoisomer is of the R, S configuration (S refers to the moiety derived from L-alanine). The preferred S, S diastereoisomer is obtained by filtration after concentration of the filtrate and trituration of the residue with ether.

137-139 ° C.

[.alpha.] D @ 20 = + 31.3 DEG (1% MeOH).

The free amino acid (S, S-form) is obtained by treating the aqueous hydrochloric acid with saturated sodium acetate solution. The product was isolated by filtration, washed well with cold water and recrystallized from ethyl acetate.

149-151 ° C. [α] D = + 29.7 ° (1% in 0.1 N HCl).

Example 9

1,2,3,4-Tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid phenylmethyl ester - hydrochloride (S-form)

A mixture of 1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid hydrochloride (S-form) and 600 ml of benzyl alcohol is saturated with hydrogen chloride gas. The temperature rises to 45 ° C. The mixture was stirred at room temperature for three days. A relatively small amount of solid was removed by filtration and the filtrate treated with about 2 liters of ether to precipitate the crude product to give 37.5 g.

Yield 83%. The product was purified by treating with excess saturated sodium bicarbonate solution and extracting with ethyl acetate and precipitating the hydrochloride salt with HCl gas. The product was purified by recrystallization from methanol / ether.

Mp 255-260 ° C;

[α] D = -81.3 ° (1.0% MaOH); tlc (20% MeOH-CHCl ₃ /

SiO ₂ ) gives a stain. Rf: 0.8.

Analysis for C ₉ H ₂ i NO ₄ . HCl Calc'd: C, 62.72; H, 6.10; N, 3.85%

Found: C, 62.54; H, 5.99; N, 4.00%

Example 10

1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid phenylmethyl ester hydrochloride (S-form)

750 ml of benzyl alcohol are treated with 150 g of commercial phosphoric acid with heating and stirring at 90 ° C to form a homogeneous mixture. To the resulting mixture was added 165.2 g of solid 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid (S-form). The mixture was stirred at 95-105 ° C for 4 hours and then allowed to stand at room temperature for 18 hours. A solution of gaseous hydrogen chloride (18.5 g) in anhydrous ether (2.5 L) is added and the product is selected by cooling overnight. The activated crude product, benzyl -1,2,3,4-tetrahydro-3-isoquinolinecarboxylate hydrochloride, is isolated by filtration. The crude product is purified by twice recrystallization from ethanol. M.p. 190.5-191 ° C. ; [α] ²⁰ D = -83.3 ° (1% in 1: 1 methanol (IN hydrochloric acid)).

Example 11

1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid 1,1-dimethylethyl ester hydrochloride (S-form)

This compound was prepared by passing 447 g of isobutylene at 0 ° C under a nitrogen atmosphere with a mixture of 63.5 g of 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid (S-form) in 650 ml of dioxane and 65 ml of concentrated sulfuric acid. prepared solution. The reaction vessel was sealed and shaken for 17 hours at room temperature. The reaction vessel was vented and the mixture was cooled with 25 L of cold 2N sodium hydroxide; solution. The product was extracted with ether. The ethereal solution was washed with water, dried and concentrated to about 500 ml. This solution was treated with excess 6N isopropanolic hydrogen chloride to precipitate the product, which was collected by filtration. A sample of the product is purified by recrystallization from ethanol / ether.

190-192 ° C (dec.).

[α] D = -88.7 ° (2% MeOH).

Example 12

The following ingredients are made into 1000 tablets each containing 100 mg of 2- [2- (1-ethoxycarbonyl-3-phenylpropyl) amino] -1-oxopropyl] -1,2,3,4-tetrahydro-6,7-dimethoxy-3 - Contains the active ingredient isoquinolinecarboxylic acid hydrochloride (S, S, S):

- [2 - ({1-Ethoxycarbonyl-3-phenylpropyl} amino) -1-oxopropyl] 1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid hydrochloride (S, S , S) 100 g corn starch 50 g gelatin 7.5 g

Avicel (microcrystalline cellulose) 25 g of magnesium stearate 2.5 g

2- [2- (S1- (Ethoxycarbonyl / -3-phenylpropyl) amino) -1-oxopropyl] -1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid hydrochloride (S) , S, S) and corn starch are mixed with an aqueous solution of gelatin. The mixture is dried and ground to a fine powder. Avicel. and then mixing the magnesium stearate with 61

183,602 powders and granulate. The granulate is compressed into 1000 tablets each containing 100 mg of active ingredient.

Example 13

The following ingredients are made into 1000 tablets each containing 200 mg of 2-12 - (11- (ethoxycarbonyl-3-phenylpropyl) amino) -1-oxopropyl] -1,2,3,4-tetrahydro-6,7-dimethoxy-3 - Contains the active ingredient isoquinolinecarboxylic acid hydrochloride (S, S, S):

2- (1- (ethoxycarbonyl-3-phenylpropyl) amino) -1-oxopropyl] -1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid hydrochloride (S, S, Compound S 200 g lactose 100 g

Avicel 150 g corn starch 50 g magnesium stearate 5 g

2- [2- (1-Ethoxycarbonyl-3-phenylpropyl] amino) -1-oxopropyl] -1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid hydrochloride ( Compound S, S, S), lactose and Avicel are mixed, then mixed with cornstarch and magnesium stearate is added. The mixture is then dried and compressed into 1000 tablets of 505 mg each containing 200 mg of active ingredient. The tablets are coated with a solution of Methocel E15 (methylcellulose) containing No. 6 yellow as a coloring agent.

Example 14

Two No. 1 gelatin capsules, each containing 250 mg of 2- [2- (1-ethoxycarbonyl-3-phenylpropylamino) 1-oxopropyl] -1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid. hydrochloride hydrate (S, S, S) is filled with a mixture of the following components:

- [2- (1-Ethoxycarbonyl-3-phenylpropyl] amino) -1-oxopropyl] -1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid hydrochloride (S, S, S) 250 mg of magnesium stearate 7 mg

LJSP Lactose 193 mg

Example 15

The solution for injection is prepared as follows:

- [2- (1H-Ethoxycarbonyl-3-phenylpropyl] amino) -1-oxopropyl] -1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid hydrochloride (S, S , S) 500 g methyl paraben 5 g propyl paraben 1 g sodium chloride 25 g water for injection 5 liters

The active ingredient, preservatives and sodium chloride are dissolved in 3 liters of water for injections and then made up to 5 liters. The solution is then filtered through a sterile filter and aseptically filled into pre-sterilized vials which are sealed with pre-sterilized rubber stoppers. Each vial contains 5 ml of a sterile solution at a concentration of 100 mg of active ingredient per ml of solution for injection.

Claims (14)

Patent claims, A process for the preparation of substituted acyl derivatives and pharmaceutically acceptable acid addition salts of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid of formula (I): R is hydrogen, (C1-C4) -alkyl or benzyl; R, hydrogen or (1-4C) alkyl, R _{2 is} hydrogen or C 1-4 alkyl; Ar is phenyl, X and Y are each independently hydrogen or (1-4C) alkoxy, and m is a number from 0 to 3, wherein one of the appropriately substituted 1,2,3,4-tetrahydro-3-isoquinolinecarboxylates of formula (II) is ) with an N-substituted amino acid of formula (II) to form a peptide bond wherein R 1, R ₂ , Ar, X, Y and m are as defined above and R ₃ is (C 1 -C 4) alkoxycarbonyl or benzyloxycarbonyl, and optionally removing the alkyl or benzyl group and / or converting the resulting base to an acid addition salt: A process for the preparation of a compound of formula (I) and pharmaceutically acceptable acid addition salts thereof according to claim 1, wherein: R is hydrogen, tert-butyl or benzyl; R 1 is hydrogen or C 1-4 alkyl; R _{2 is} hydrogen, methyl or ethyl; Ar is phenyl; X and Y are each independently hydrogen or C 1 -C 4 alkoxy, and m is 2, wherein R, R 1, R ₂ , Ar, X and Y are as defined above and m is as defined above. 3. The method of claim 1, embodiment (Id) and pharmaceutically acceptable salts thereof, wherein R ₂ is hydrogen, methyl or ethyl, characterized in that used as starting compound in which _R2 is as defined above. 4. A process for the preparation of a compound according to claim 1, wherein R, hydrogen, methyl, or ethyl are represented by the use of starting materials wherein R ₂ is as defined above. The process of claim 1, wherein the 2- [2 - () 1 - (ethoxycarbonyl / -3-phenylpropyl) amino) -1-oxopropyl] -1,2,3,4-betahydro-6,7-dimer for the preparation of phenyl 3-isoquinolinecarboxylic acid phenyl methyl ester maleate (S, S, S), characterized in that 1,2,3,4-Tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid phenylmethyl ester. 6. The process of claim 1, wherein the compound is 2- [2- (1,1-ethoxycarbonyl-3-phenylpropylamino) -1-oxopropyl] -1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid. for the production of phenylmethyl ester maleate (S, S, S) 183,602 ve used as starting material 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid phentylmethyl ester. The method of claim 1, which is 2- [2- (U- / ethoxycarbonyl / -3-phenylpropyl} amino) -1-oxopropyl] -1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid -1, For the preparation of 1-dimethylethyl ester (S, S, S), the starting material used is 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid -1,1-dimethyl-ethyl ester hydrochloride. 8. The process of claim 1, wherein 2- [2- (11- (ethoxycarbonyl-3-phenylpropyl] amino) -oxopropyl] -1,2,3,4-tetrahydro-6,7-dimethoxy-3 for the preparation of isoquinolinecarboxylic acid hydrochloride hydrate (S, S, S), wherein the starting material used is 1,2,3,4-tetraihydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid phenyl methyl ester. The process according to claim 1, which is 2- [2- {1-carboxy-3-phenylpropyl / amino} -1-oxopropyl] -1,2,3,4-tetrahydro-6,7-dimethoxy-3 for the preparation of isoquinolinecarboxylic acid hydrochloride hydrate (S, S, S) wherein the starting material is 1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid phenylmethyl ester. 10. The process of claim 1, wherein 2- (2- (1-ethoxycarbonyl-3-phenylpropyl) amino) 1-oxopropyl] -1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid hydrochloride is used. hydrate (S, S, S), characterized in that the starting material is 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid phenylmethyl ester. The process according to claim 1, which is 2- [2 - ({1-ethoxycarbonyl-3-phenylpropylamino) 1-oxopropyl] -1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid hydrochloride ( S, S, S) wherein the starting material used is 1,2,3,4-tetrahydro-3,5-isoquinolinecarboxylic acid 1,1-dimethylethyl ester hydrochloride. 12. The process according to claim 1, which is 2- [2 -} / 1-carboxy-3-phenylpropyl] -amino} -1-oxopropyl] -1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid hydrochloride. -hemihydrate (S, S, S), characterized in that the starting material is 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid phenylmethyl ester. 15 13. The process of claim 1, wherein the 2- [2-ylcarboxy-3-phenylpropyl / amino] -1-oxopropyl] -1,2,3,4-tetrahydro-3-isoquinolecarboxylic acid bridge Rechloride hemihydrate (S, S, S), characterized in that the starting material used is 1,2,3,4-tetrahydro-320 isoquinolinecarboxylic acid 1,1-dimethylethyl ester hydrochloride. 14. A process for the manufacture of a medicament for the treatment of hypertension, wherein the active ingredient is a process according to claim 1. The substituted acyl derivative of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid of general formula (I) or a pharmaceutically acceptable salt thereof, in admixture with excipients and / or adjuvants customary in the preparation of a medicament, for pharmaceutical administration. 30 dosage forms.