JPS6319512B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula (However, R ¹ represents a lower alkyl group, a lower cycloalkyl group, a lower alkenyl group, or a lower alkynyl group.) The present invention relates to a tetrahydroisoquinoline derivative represented by the following, a pharmaceutically acceptable salt thereof, and a method for producing the same. The compound [ ] of the present invention is a new compound,
Excellent angiotensin converting enzyme (hereinafter referred to as
It is a useful pharmaceutical compound with inhibitory action (referred to as ACE). ACE is an enzyme involved in the conversion of angiotensin to angiotensin in vivo, and it is said that the angiotensin produced by the action of ACE causes strong contraction of smooth muscles, especially vascular smooth muscles, thereby increasing blood pressure. There is. Furthermore, this ACE also has the effect of decomposing and inactivating pradikinin, a substance in the body that has a hypotensive effect, and promotes an increase in blood pressure from both sides. Therefore, it is highly desirable for hypertensive patients to lower blood pressure by inhibiting the activity of ACE. Conventionally, ACE was used with the same dibasic acid as the compound of the present invention.
Examples of compounds having an inhibitory effect include 1-
(4-carboxy-2-D-methylbutyryl)-L
- Proline (JP-A-52-100461) and N- (4-
Carboxy-2-methylbutyryl)-L-tryptophan (Japanese Unexamined Patent Publication No. 136121/1983) is known. However, these compounds had a weak ACE inhibitory effect. As a result of repeated research in search of a compound with a stronger ACE inhibitory effect, the present inventors discovered that the compound of the present invention [ ], which is a tetrahydroisoquinoline derivative having a ureido structure in the molecule, has a strong ACE inhibitory effect. The present invention was completed.
For example, 2-[N-
The ACE inhibitory effect of isopropyl-N-(2-carboxyethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinoline-3-L-carboxylic acid (see Example 4) is similar to that of the known compound 1-(4
-Carboxy-2-D-methylbutyryl-L-proline exhibits a stronger ACE inhibitory effect (see experimental examples below). The compound of the present invention is a compound represented by the general formula [], in which the group represented by the symbol R ¹ is, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a butyl group, a pentyl group, or a cyclopropyl group. , cyclobutyl group, cyclopentyl group, allyl group, propargyl group, etc. Further, as a preferable compound, for example, 2-[N-methyl-N-(2-carboxyethyl)
carbamoyl]-1,2,3,4-tetrahydroisoquinoline-3-L-carboxylic acid, 2-[N-
n-propyl-N-(2-carboxyethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinoline-3-L-carboxylic acid, 2-[N-cyclopropyl-N-(2-carboxyethyl)carbamoyl ]-1,2,3,4-tetrahydroisoquinoline-3-L-carboxylic acid, 2-[N-allyl-N-(2-carboxyethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinoline-3 -L-carboxylic acid, etc., and more preferable examples include, for example, 2-[N-
Ethyl-N-(2-carboxyethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinoline-3-L-carboxylic acid, 2-[N-isopropyl-N-(2-carboxyethyl)carbamoyl]-1 , 2,3,4-tetrahydroisoquinoline-3-L-carboxylic acid, 2-[N-propargyl-N-(2-carboxyethyl)carbamoyl]
-1,2,3,4-tetrahydroisoquinoline-
Examples include 3-L-carboxylic acid. The compound of the present invention [ ] has one asymmetric carbon atom in the molecule, and therefore exists in two types of optical isomers, and the present invention includes any of these compounds. In particular, compounds in which the asymmetric carbon atom at the 3-position of the isoquinoline ring has an L-type absolute coordination are preferred as pharmaceuticals. The compound of the present invention [] can be produced by the method shown in the following reaction formula. (However, R ² and R ³ represent ester residues,
R ¹ has the same meaning as above). That is, according to method A, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ester [ ] is first reacted with phosgene to form 2-chlorocarbonyl-1,2,3,4-tetrahydroisoquinoline- 3-carboxylic acid ester [] is obtained, and then this compound [] is subjected to a condensation reaction with 3-substituted aminopropionic acid ester [] to obtain 2.
-(N,N-2-substituted carbamoyl)-1,2,3,
Hydrolyzing the ester part of 4-tetrahydroisoquinoline-3-carboxylic acid ester [] or
Alternatively, the target compound [] can be produced by contact treatment with an acid. According to method B, 3-substituted aminopropionic acid ester [] and phosgene are reacted to produce N-chlorocarbonyl-
3-substituted aminopropionic acid ester [] was obtained, and then 1,2,3,4-
The resulting 2-(N,
N-2-substituted carbamoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ester [] is hydrolyzed in the same manner as in Method A, or the target compound [] is obtained by contact treatment with an acid. can be manufactured. This will be explained in detail below. Method A The reaction in the first step can be carried out by reacting the compound [ ] with phosgene in an appropriate solvent in the presence or absence of a deoxidizing agent.
Examples of the compound [ ] include compounds in which the ester residue represented by the symbol R ² is a methyl group, ethyl group, propyl group, t-butyl group, or the like. As the deoxidizer, organic tertiary bases such as triethylamine, tripropylamine, and pyridine are preferred. Examples of solvents include methylene chloride, chloroform, tetrahydrofuran,
Dioxane etc. can be used. The reaction is
For example, phosgene is dissolved in a solvent, and a solution containing the compound [] and a deoxidizing agent is added dropwise thereto at -20°C or lower to proceed suitably. After the reaction is completed,
Compound [] can be obtained by concentrating the reaction solution under reduced pressure to remove excess phosgene. Since the compound [] obtained here is an unstable compound, it is preferable to use it immediately after production without isolation. The condensation reaction in the second step can be carried out by subjecting the compound [ ] to the compound [ ] in an appropriate solvent in the presence or absence of a deoxidizing agent. Examples of compounds [] include compounds in which the ester residue represented by the symbol R ³ is a methyl group, ethyl group, propyl group, t-butyl group, etc., and the group represented by the symbol R ¹ is as described above. I can give it to you. Preferred examples of the deoxidizer include organic tertiary bases such as triethylamine, tripropylamine, and pyridine, and examples of usable solvents include methylene chloride, chloroform, tetrahydrofuran, and dioxane. The reaction proceeds smoothly in the cold or under heating, and the compound [] can be obtained in good yield. The subsequent hydrolysis of the ester moiety in the third step can be carried out by treating the compound [ ] with an alkali in a suitable aqueous solvent. Suitable alkalis include alkali hydroxides such as sodium hydroxide, alkali carbonates such as calcium carbonate, and examples of solvents include aqueous methanol and aqueous ethanol. In addition, if the compound [] has a t-butyl group as its ester residue R ² and/or R ³ , the compound [] may be dissolved in an appropriate solvent using an acid such as trifluoroacetic acid, hydrochloric acid, or sulfuric acid. The ester moiety can also be converted into a carboxyl group by contact treatment with. In this case, for example, methanol, ethanol, etc. can be used as the solvent, but it is convenient to use trifluoroacetic acid as both the reagent and the solvent. Among the two ester residues present in the compound [], if one is a t-butyl group and the other is another ester residue, alkaline hydrolysis and acid contact treatment are performed. It is also possible to carry out one after the other. In either case, the reaction proceeds smoothly under cooling or at room temperature, and the compound [] can be obtained in good yield. Incidentally, in purifying the compound [] obtained here, a salt with dicyclohexylamine can also be advantageously used. B Method This method can be carried out in exactly the same manner as Method A, except that compound [] and compound [] in Method A are interchanged. To obtain the optically active form of the compound of the present invention [],
For example, an optically active compound [] can be produced by using an optically active substance in the raw material compound []. The compound of the present invention [] produced as above is
Since it has two carboxyl groups in its molecule, it can also form salts with various inorganic or organic bases. Examples of salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, and examples of salts with organic bases include lysine salts. salt, ornithine salt, dicyclohexylamine salt, etc. As mentioned above, the compound of the present invention [ ] is a useful pharmaceutical compound that has excellent ACE inhibitory activity. The ACE inhibitory effect of the compound of the present invention [] will be illustrated in the experimental examples below. The compound of the present invention and its pharmacologically acceptable salts can be administered orally or parenterally when used as a pharmaceutical. When administered orally, it can be used as a tablet, powder, capsule, granule, etc. When administered parenterally, it can be used as an injection preparation, suppository, etc. . In either case, carriers such as starch and lactose commonly used in formulations,
Excipients such as dicalcium phosphate, cornstarch,
A binder such as gum arabic, a lubricant such as stearic acid, etc. can be used. In addition, the raw material compound [ ] is obtained by subjecting phenylalanine and formaldehyde to condensation using a Pictet-Spengler reaction to obtain 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid [Journal of・American Chemical Society; Vol. 70, p. 180 (1948), etc.), and then esterification by a conventional method. Also, the other raw material compound []
are the corresponding acrylic ester and the first
It can be produced by subjecting a class amine to a Michael addition reaction [R. B. Wagner et al.; Synthetic Organ Chemistry, p. 673 (1961), etc.]. Experimental example 1 ACE inhibitory effect (in vitro) Experimental method Inhibitory activity was measured using ACE extracted and purified from pig ginseng cortex. Transfer 300 μl of a 0.2 M Tris/HCl buffer containing 0.2 M salt, 0 to 100 μl of a solution containing an inhibitory substance (analyte compound), and 50 μl of 0.01 M hipryl histidyl leucine (substrate) into a test tube, and dissolve the entire solution with water. The volume should be 450 μl. 50 μl of ACE solution was added to this, and an enzyme reaction was performed at 37° C. for 20 minutes. Histidylleucine produced from the substrate by ACE was quantified using Leuconostoccentroides P-60 to determine the enzyme activity. The inhibitory activity corresponds to the value obtained by taking the ACE activity in the absence of the test compound as 100%, calculating the % of the ACE activity when the test compound is added, and subtracting this from 100. ID50 (M) is the concentration of analyte compound required to inhibit ACE activity by 50%. The results are shown in Table 1.

Table 1 shows that the compounds of the present invention have a stronger ACE inhibitory effect than the control compound. Experimental example 2 ACE inhibitory effect (in vivo) Experimental method Rats were anesthetized with a subcutaneous injection of 1.5 g/kg of urethane, and carotid artery blood pressure was recorded on a polygraph.
After administering ~20ng/body of angiotensin into the femoral vein and confirming a certain pressor response,
The ACE inhibitory effect of the test compound was investigated by intravenously injecting the test compound in an amount of 0.1 mg/Kg, followed by administering angiotensin over time, and comparing the pressor response with that before the test sample administration. The results are shown in Table 2.

[Table] From Table 2, the ACE inhibitory effects of the compounds of the present invention are as follows:
It is comparable to the reference compound mentioned above which has the highest ACE inhibition effect known to date. Example 1 (1) To a 20 ml solution of methylene chloride containing 3.0 g of phosgene, add 1, 2, 3,
A solution of 3.8 g of 4-tetrahydroisoquinoline-3-L-carboxylic acid methyl ester and 3.0 g of triethylamine in 20 ml of methylene chloride is slowly added dropwise. After the addition, the mixture was stirred for another 30 minutes at the same temperature, and then the reaction solution was concentrated to dryness under reduced pressure. Residual 2-chlorocarbonyl-1,2,3,4-
Tetrahydroisoquinoline-3-L-carboxylic acid methyl ester is dissolved in 20 ml of methylene chloride, and a solution of 2.34 g of 3-methylaminopropionic acid methyl ester and 2.4 g of triethylamine in 10 ml of methylene chloride is added dropwise to this solution while stirring at room temperature. The reaction was completed by further stirring at the same temperature for about 15 hours. The reaction solution was concentrated to dryness under reduced pressure.
The residue is dissolved in ethyl acetate, washed with dilute hydrochloric acid, deuterated water, and then water, and dried. Distill the solvent,
2-[N-
Methyl-N-(2-methoxycarbonylethyl)
3.0 g of [carbamoyl]-1,2,3,4-tetrahydroisoquinoline-3-L-carboxylic acid methyl ester was obtained as a colorless viscous oil. yield
44.8% IRν ^film _nax (cm ^-1 ); 1740, 1640 NMR (CDCl ₃ ) δ: 7.05-7.2 (m, 4H, aromatic hydrogen), 4.76 (t, 1H, CH-N), 4.50 (s,
2H, Ar-CH ₂ -N), 3.63(s, 6H, O-
CH ₃ ×2), 3.45 (t, 2H, -N-CH ₂ ), 3.17
(d, 2H, Ar-CH ₂ -C), 2.93 (s, 3H,
N-CH ₃ ), 2.59 (t, 2H, -CH ₂ -CO) Mass m/e; 334 (M ⁺ ) (2) 2.0 g of diester prepared in (1) in methanol 6
ml solution, add 6 ml of water and 1.2 g of potassium hydroxide, and stir at room temperature for 2 hours. Methanol is distilled off under reduced pressure, the residue is acidified with dilute hydrochloric acid, and extracted with chloroform. After washing the extracted layer with water and drying, dicyclohexylamine 2.2
g and then concentrated to dryness. By adding ether to the residue and crystallizing it, 2-[N-
2.0 g of methyl-N-(2-carboxyethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinoline-3-L-carboxylic acid 2-dicyclohexylamine salt was obtained as colorless powder crystals. mp.67-68℃ (decomposition), yield 50% [α] ²⁰ ₃₆₅ -10.4゜ (C = 1, methanol) Example 2 (1) In the same manner as in (1) of Example 1, 1,2 ,3,4
-Tetrahydroisoquinoline-3-L-carboxylic acid methyl ester 3.8 g, 3-ethylamine propionic acid methyl ester 2.6 g, phosgene 3 g, triethylamine 5.4 g and methylene chloride 70 ml (chromatography solution; toluene: ethyl acetate = 3:1), 2-[N
-Ethyl-N-(2-methoxycarbonylethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinoline-3-L-carboxylic acid methyl ester was obtained in an amount of 5.0 g as colorless crystals. yield
71.8% This product is made into colorless prismatic crystals by recrystallizing from a mixture of ethyl acetate and n-hexane.
Indicates mp.53-55℃. IRν ^Nujol _nax (cm ^-1 ): 1738, 1725, 1635 NMR (CDCl ₃ ) δ: 7.0-7.2 (m, 4H, aromatic hydrogen), 4.80 (t, 1H, CH-N), 4.52 (s,
2H, Ar-CH ₂ -N), 3.66 (s, 3H, O-
CH ₃ ), 3.64 (s, 3H, O-CH ₃ ), 3.19 (d,
2H, Ar-CH ₂ -CH), 3.1-3.5 (m, 4H,
N- _CH2 - _CH3 and N- _CH2 - _CH2- ),
2.57 (t, 2H, CH ₂ −CO), 1.20 (t, 3H,
N-CH ₂ -CH ₃ ) Mass m/e: 348 (M ⁺ ) [α] ²⁰ _D -1,2° (C=1, methanol) (2) 2.1 g of the diester produced in (1) was dissolved in methanol 6
ml, add 1.2 g of potassium hydroxide and 6 ml of water, and stir at room temperature for 2 hours. Methanol is distilled off under reduced pressure, the residue is acidified with dilute hydrochloric acid, and extracted with chloroform. After washing the extracted layer with water and drying, the solvent was distilled off, and n.hexane was added to the residue for crystallization.
1.5 g of 2-[N-ethyl-N-(2-carboxyethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinoline-3-L-carboxylic acid was obtained as a colorless powder. mp.123-125℃ (decomposition), yield 78.1% IRν ^Nujol _nax (cm ^-1 ): 1720, 1630 [α] ²⁰ _D -11.3゜ (C=1, methanol) Examples of various salts of this product are shown below. do. 2. Dicyclohexylamine salt Colorless powder crystal, mp. 135-137℃ (decomposition) [α] ²⁰ ₃₆₅ -19.7゜ (C = 1, methanol) 2. Potassium salt Potassium carbonate in 1.31 g of this product (dicarboxylic acid)
Add a solution of 0.57 g in 30 ml of water and stir vigorously for about 1 hour at room temperature. By freeze-drying the reaction solution, 1.62 g of 2-potassium salt is obtained as a colorless powder. (The following salts are prepared in the same manner.) 2. Sodium salt Colorless powder 2.L-lysine salt Colorless powder crystal calcium salt Colorless powder Example 3 (1) In the same manner as in Example 1-(1), 1, 2, 3, 4
From 3.8 g of -tetrahydroisoquinoline-3-L-carboxylic acid methyl ester, 2.9 g of 3-n.propylaminopropionic acid methyl ester, 3.0 g of phosgene and 5.4 g of triethylamine, 2-[N-n.propyl-N-(2 -methoxycarbonylethyl)carbamoyl]-1,2,
3,4-tetrahydroisoquinoline-3-L-
5.2 g of carboxylic acid methyl ester was obtained as a colorless syrupy substance. Yield 71.7% IRν ^film _nax (cm ^-1 ): 1740, 1640 NMR (CDCl ₃ ) δ: 7.1-7.2 (m, 4H, aromatic hydrogen), 4.80 (t, 1H, CH-N), 4.53 (s ，
2H, Ar-CH ₂ -N), 3.68 (s, 3H, O-
_CH3 ), 3.65 (s, 3H, O- _CH3 ), 3.2-3.6
(m, 4H, N-CH ₂ ×2), 3.14 (d, 2H,
Ar−CH ₂ −CH), 2.59(t, 2H, CH ₂ −
CO), 1.3 to 2.0 (m, 2H, CH ₂ −CH ₂ −
CH ₃ ), 0.9 (t, 3H, CH ₃ ) Mass m/e: 362 (M ⁺ ) (2) 3.6 g of the diester produced in (1) was added to (2) in Example 1.
By processing in the same manner as 2-[N-n・
Propyl-N-(2-carboxyethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinoline-3-L-carboxylic acid 2-dicyclohexalamine salt as colorless powder crystal 4.0
g get. mp.127-128℃ (decomposition), yield 57.4% Example 4 (1) 1, 2, 3, 4 in the same manner as Example 1-(1)
2-[N-isopropyl-N-(2-methoxycarbonylethyl ) carbamoyl]-1,2,
3,4-tetrahydroisoquinoline-3-L-
Carboxylic acid methyl ester as colorless crystals
Obtain 4.4g. Yield: 61.1% This product is recrystallized from a mixture of ethyl acetate and n-hexane to form colorless prism crystals, which exhibits an mp. of 78 to 79°C. IRν ^Nujol _nax (cm ^-1 ): 1735, 1640 NMR (CDCl ₃ ) δ: 7.1-7.2 (m, 4H, aromatic hydrogen), 4.79 (t, 1H, CH-N), 4.51 (s,
2H, Ar-CH ₂ -N), 3.5-4.1 (m, 1H,
CH (CH ₃ ) ₂ ) 3.66 (s, 3H, O-CH ₃ ), 3.59
(s, 3H, O-CH ₃ ), 3.27 (t, 2H, N-
_CH2 ), 3.19(d,2H,Ar- _CH2 -CH),
2.49 (t, 2H, CH2 _- CO), 1.26 (d, 3H,
CH−CH ₃ ), 1.16 (d, 3H, CH−CH ₃ ) Mass m/e: 362 (M ⁺ ) [α] ²⁰ _D −0.35° (C=1, methanol) (2) Made with (1) 3.4 g of the diester obtained in Example 2 (2)
By treating in the same manner as above, 2.7 g of 2-[N-isopropyl-N-(2-carboxyethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinoline-3-L-carboxylic acid is obtained as a colorless powder. . mp.72-73℃ (decomposition), yield
86.0% IRν ^KBr _nax (cm ^-1 ): 1720, 1630 [α] ²⁰ _D −9.7° (C=1, methanol) Various salts of this product are illustrated below. 2. Lysine salt Colorless powder 2. Dicyclohexylamine salt Colorless powder crystal, mp. 92-94°C (decomposed) [α] ²⁰ ₃₆₅ -14.6° (C=1, methanol) Example 5 (1) Example 1-( Similarly to 1), 1, 2, 3, 4
-tetrahydroisoquinoline-3-L-carboxylic acid methyl ester 3.8 g, 3-cyclopropylaminopropionic acid methyl ester 2.9 g,
From 3.0 g of phosgene and 5.4 g of triethylamine, 2-[N-cyclopropyl-N-(2-methoxycarbonylethyl)carbamoyl]-1,
2,3,4-tetrahydroisoquinoline-3-
5.0 g of L-carboxylic acid methyl ester was obtained as a colorless candy-like substance. Yield 69.3% IRν ^film _nax (cm ^-1 ); 1740, 1630 NMR (CDCl ₃ ) δ: 7.1-7.2 (m, 4H, aromatic hydrogen), 4.93 (t, 1H, CH-N) 4.67 (s, 2H,
Ar-CH ₂ -N), 3.3-3.9 (m, 3H,

[Formula] and N-CH ₂ -CH ₂ ), 3.67 (s, 3H, O-CH ₃ ),
3.63 (S, 3H, O-CH ₃ ), 3.21 (d, 2H, Ar-
_CH2 -CH), 2.62(t,2H, _-CH2 -CO), 0.5
~1.1(m, 4H,

[Formula]), Mass m/e: 360 (M ⁺ ) (2) 2.4 g of the diester produced in (1) was added to (2) in Example 1.
By treating in the same manner as above, 2-[N-cyclopropyl-N-(2-carboxyethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinoline-3-L-carboxylic acid 2-dicyclohexy 3.1g of amine salt as colorless powder crystal
obtain. mp.92-93℃ (decomposition), yield 67% [α] ²⁰ ₃₆₅ -16.5゜ (C=1, methanol) Example 6 (1) In the same manner as Example 1-(1), 1,2 ,3,4
-tetrahydroisoquinoline-3-L-carboxylic acid methyl ester 3.8 g, 3-allylaminopropionic acid methyl ester 2.9 g, phosgene
From 3.0 g and 5.4 g of triethylamine, 2-
5.0 g of [N-allyl-N-(2-methoxycarbonylethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinoline-3-L-carboxylic acid methyl ester was obtained as a colorless candy-like substance.
Yield 69.9% IRν ^film _nax (cm ^-1 ): 1740, 1640 NMR (CDCl ₃ ) δ: 7.0-7.2 (m, 4H, aromatic hydrogen), 5.5-6.0 (m, 1H, CH ₂ =CH-) ,
5.0-5.45 (m, 2H, CH ₂ = CH-), 4.80 (t,
1H, CH-N), 4.51(s, 2H, Ar-CH ₂
-N), 3.7 to 3.95 (m, 2H, -N-CH ₂ -CH
=), 3.66 (s, 3H, O-CH ₃ ), 3.63 (s,
3H, O-CH ₃ ), 3.25-3.6 (m, 2H, N-
CH ₂ −CH ₂ ), 3.19(d, 2H, Ar−CH ₂ −
CH), 2.59 (t, 2H, CH ₂ -CO), Mass m/e: 360 (M ⁺ ) (2) 2.4 g of the diester produced in (1) was added to (2) in Example 2.
By treating in the same manner as above, 2-[N-allyl-N-(2-carboxyethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinoline-3-L-carboxylic acid was obtained as colorless powder crystals.
Obtain 1.4g. mp.76-78℃ (decomposition), yield 63.3% IRν ^KBr _nax (cm ^-1 ): 1720, 1630 Example 7 (1) In the same manner as Example 1-(1), 1, 2, 3, 4
- 3.8 g of tetrahydroisoquinoline-3-carboxylic acid methyl ester, 2.82 g of 3-propargylaminopropionic acid methyl ester, 3 g of phosgene, 5.4 g of triethylamine, and 70 ml of methylene chloride (solvent for chromatography; toluene: ethyl acetate = 4: 1), 2-[N
-Propargyl-N-(2-methoxycarbonylethyl)carbamoyl]-1,2,3,4-
3.1 g of tetrahydroisoquinoline-3-L-carboxylic acid methyl ester are obtained as a colorless oil.
Yield 43.2% IRν ^film _nax (cm ^-1 ): 3280, 1738, 1645 NMR (CDCl ₃ ) δ: 7.0-7.3 (m, 4H, aromatic hydrogen), 4.87 (t, 1H, CH-N), 4.62 (s,
2H, Ar-CH ₂ -N), 4.01 (d, 2H, CH ₂ -
C≡C), 3.69 (s, 6H, O-CH ₃ ×2),
3.62 (t, 2H, -N-CH ₂ -CH ₂ ), 3.23 (d,
2H, Ar−CH ₂ −CH), 2.67(t, 2H, −
CH ₂ −CO), 2.33 (t, 1H, −C≡CH) Mass m/e: 358 (M ⁺ ) (2) 2.77 g of the diester prepared in (1) was mixed with methanol 8
ml, add 1.53 g of potassium hydroxide and 8 ml of water, and stir at room temperature for 2 hours. Methanol is distilled off under reduced pressure, the residue is acidified with dilute hydrochloric acid, and extracted with chloroform. After washing the extracted layer with water and drying, the solvent was distilled off and 2-
[N-propargyl-N-(2-carboxyethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinoline-3-L-carboxylic acid is obtained as a colorless oil. Add a solution of 1.86 g of L-lysine in 30 ml of water to 2.1 g of this product, and stir vigorously at room temperature for about 1 hour. The reaction solution was concentrated to dryness, ether was added, and filtration was performed to obtain 2-[N-propargyl-
N-(2-carboxyethyl)carbamoyl]-
1,2,3,4-tetrahydroisoquinoline-
3.5 g of 3-L-carboxylic acid 2-L-lysine salt was obtained as a colorless powder. Example 8 A solution of 3.0 g of phosgene in 40 ml of methylene chloride was added to -30
Cool to -20°C and add 1,
2,3,4-tetrahydroisoquinoline-3-L
- A solution of 4.7 g of carboxylic acid t.butyl ester and 3.0 g of triethylamine in 20 ml of methylene chloride is slowly added dropwise. Stir for another 30 minutes at the same temperature,
The reaction solution is then concentrated under reduced pressure. Add 20 ml of methylene chloride to the remaining 2-chlorocarbonyl-1,2,3,4-tetrahydroisoquinoline-3-L-carboxylic acid t-butyl ester, and add 3-ethylaminopropionic acid t to this solution while stirring at room temperature. - Add dropwise a solution of 3.5 g of butyl ester and 2.4 g of triethylamine in 10 ml of methylene chloride. After dropping, stir at approximately 50℃ for 15 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the resulting solution was washed in the order of 10% citric acid water, heavy soybean water, and water.
dry. The solvent was distilled off, and the residue was subjected to silica gel chromatography (solvent; toluene: ethyl acetate =
6:1), 2-[N-ethyl-N-(2-t.butoxycarbonylethyl)
3.9 g of t-butyl carbamoyl-1,2,3,4-tetrahydroisoquinoline-3-L-carboxylic acid ester was obtained as a colorless syrupy substance. yield
44.8% IRν ^film _nax (cm ^-1 ): 1735, 1640 NMR (CDCl ₃ ) δ: 7.1-7.2 (m, 4H, aromatic hydrogen), 4.74 (t, 1H, CH-N), 4.53 (s,
2H, Ar-CH ₂ -N), 3.1-3.6 (m, 4H, N
−CH ₂ ×2), 3.16 (d, 2H, Ar−CH ₂ −
CH), 2.57 (t, 2H, CH ₂ −CO), 1.42 (s,
9H, CH ₃ × 3), 1.32 (s, 9H, CH ₃ × 3),
1.2 (t, 3H, -CH ₂ -CH ₃ ) Mass m/e: 432 (M ⁺ ) (2) Add 20 ml of trifluoroacetic acid to 1.7 g of the diester prepared in (1), and stir at room temperature for 30 minutes. The reaction solution was concentrated to dryness under reduced pressure. By adding n-hexane to the residue and crystallizing it, 2-[N
1.0 g of -ethyl-N-(2-carboxyethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinoline-3-L-carboxylic acid was obtained as colorless crystals. The physicochemical properties of this product were consistent with those of the standard prepared in Example 2. Example 9 A solution of 3.0 g of phosgene in 20 ml of methylene chloride was
Cool to -20℃ and add 3- to this solution while stirring.
Ethylaminopropionic acid methyl ester 2.6g
and 3.0 g of triethylamine and 20 ml of methylene chloride.
Add the solution gradually. After stirring for about 30 minutes at the same temperature, the reaction solution was concentrated to dryness under reduced pressure. Add 20 ml of methylene chloride to the remaining N-chlorocarbonyl-3-ethylaminopropionic acid methyl ester, and add 1, 2,
A solution of 3.8 g of 3,4-tetrahydroisoquinoline-3-L-carboxylic acid methyl ester and 2.4 g of triethylamine in 10 ml of methylene chloride is added dropwise.
Hereinafter, by treating in the same manner as in Example 2-(1), 2-[N-ethyl-N-(2-methoxycarbonylethyl)carbamoyl]-1,2,3,4-
4.8 g of tetrahydroisoquinoline-3-L-carboxylic acid methyl ester are obtained. Yield: 68.9% The physicochemical properties of this product were consistent with those of the specimen prepared in Example 2-(1). By reacting and treating this product in the same manner as in (2) of Example 2, 2-[N-ethyl-N-(2-carboxyethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinoline-3 -L-carboxylic acid is obtained. The physicochemical properties of this product were consistent with those of the specimen prepared in Example 2 (2).

Claims (1)

[Claims] 1. General formula (However, R ¹ represents a lower alkyl group, a lower cycloalkyl group, a lower alkenyl group, or a lower alkynyl group.) A tetrahydroisoquinoline derivative or a pharmacologically acceptable salt thereof. 2. The compound according to claim 1, wherein in the general formula [], R ¹ is a lower alkyl group. 3. The compound according to claim 1, wherein in the general formula [], R ¹ is a lower cycloalkyl group. 4. The compound according to claim 1, wherein in the general formula [], R ¹ is a lower alkenyl group. 5. The compound according to claim 1, wherein in the general formula [], R ¹ is a lower alkynyl group. 6 Claims 1, 2 and 3 in which R ¹ in the general formula [] is a methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, allyl group or propargyl group , the compound according to item 4 or item 5. 7 Claims 1, 2, 3, and 4 in which the asymmetric carbon atom at the 3-position of the isoquinoline ring has an L-type or D-type absolute configuration in the general formula []
A compound according to item 1, item 5 or item 6. 8 In the general formula [], the absolute coordination of the asymmetric carbon atom at the 3-position of the isoquinoline ring is L-type.Claims 1, 2, 3, 4, and 5
7. A compound according to item 6 or 7. 9 Claims 1, 2, 3, 4, 5, and 6 in which the salt is a salt with an inorganic base
A compound according to item 1, 7 or 8. 10. The compound according to claim 9, wherein the salt is a sodium salt, potassium salt or calcium salt. 11 Claims 1, 2, 3, 4, 5, and 6, wherein the salt is a salt with an organic base.
A compound according to item 1, 7 or 8. 12. The compound according to claim 11, wherein the organic base is lysine. 13 2-[N-methyl-N-(2-carboxyethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Claims 1, 2, and 6 A compound according to item 1, 7 or 8. 14 2-[N-ethyl-N-(2-carboxyethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Claims 1, 2, and 6 A compound according to item 1, 7 or 8. 15 2-[N-n.propyl-N-(2-carboxyethyl)carbamoyl]-1,2,3,4-
Claims 1, 2, 6, and 7 are tetrahydroisoquinoline-3-carboxylic acid.
A compound according to item 8 or item 8. 16 2-[N-isopropyl-N-(2-carboxyethyl)carbamoyl]-1,2,3,4-
Claims 1, 2, 6, and 7 are tetrahydroisoquinoline-3-carboxylic acid.
A compound according to item 8 or item 8. 17 2-[N-cyclopropyl-N-(2-carboxyethyl)carbamoyl]-1,2,3,4
-Tetrahydroisoquinoline-3-carboxylic acid, the compound according to claim 1, 3, 6, 7 or 8. 18 2-[N-allyl-N-(2-carboxyethyl)carbamoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Claims 1, 4, and 6 A compound according to item 1, 7 or 8. 19 2-[N-propargyl-N-(2-carboxyethyl)carbamoyl]-1,2,3,4-
Claims 1, 5, 6, and 7 which are tetrahydroisoquinoline-3-carboxylic acid
A compound according to item 8 or item 8. 20 General formula (However, R ² represents an ester residue) By reacting the tetrahydroisoquinoline derivative represented by the formula with phosgene, the general formula (However, R ² has the same meaning as above.) A tetrahydroisoquinoline derivative represented by the formula R ¹ -NH-CH ₂ CH ₂ COOR ³ (wherein R ¹ is a lower alkyl group, a lower A general formula obtained by reacting with a 3-aminopropionic acid derivative represented by a cycloalkyl group, lower alkenyl group, or lower alkynyl group, R ³ represents an ester residue) (However, R ¹ , R ² and R ³ have the same meanings as above) A general formula characterized by hydrolyzing the tetrahydroisoquinoline derivative or contacting it with an acid. (However, R ¹ has the same meaning as above.) A method for producing a tetrahydroisoquinoline derivative represented by the following. 21 Represented by the general formula R ¹ -NH-CH ₂ CH ₂ COOR ³ (wherein R ¹ represents a lower alkyl group, lower cycloalkyl group, lower alkenyl group, or lower alkynyl group, and R ³ represents an ester residue) The general formula (However, R ¹ and R ³ have the same meanings as above.) Obtaining a 3-aminopropionic acid derivative represented by
Next, this compound and general formula (However, R ² represents an ester residue) The general formula obtained by reacting with the tetrahydroisoquinoline derivative represented by (However, R ¹ , R ² and R ³ have the same meanings as above) A general formula characterized by hydrolyzing the tetrahydroisoquinoline derivative or contacting it with an acid. (However, R ¹ has the same meaning as above.) A method for producing a tetrahydroisoquinoline derivative represented by the following.