JPH029863A - Tri-substituted, 1,2,3,4-tetrahydroisoquinoline - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is amidino, amino, guanidino or group expressed by formula II (n is 2 or 3); R<2> is di-lower alkylamino or formula III (n is 1-3; R<4> is H, lower alkyl or lower alkoxycarbonyl); R<3> is aryl which may be substituted by lower alkylamino; A is bond or -COCR<5>H(CH2)mNR<6> (m is 0-7; R<5> and R<6> are lower alkyl or aralkyl)] or nontoxic salt thereof. EXAMPLE:7-Amidino-2-[N-(2-naphtylsulfonyl)glycyl]-3-piperidinocarbonyl -1,2,3,4- tetrahydroisoquinolinohydrogen iodide salt. USE:Preventive and remedy for thrombosis. PREPARATION:A compound expressed by formula IV (R<1a> is CN or NO2) is reacted with a compound expressed by formula V (X is halogen or OH) and when R<1a> is CN, the resultant reaction product is reacted with H2S and then subjected to alkylation and treated with ammonium acetate to convert R<1a> into amidino group and provide the aimed product.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to novel tri-substituted-1,2,3,4-tetrahydroisoquinolines useful for the prevention and treatment of thrombosis.

(Prior Art) Thrombosis is said to occur due to thrombin generated with activation of the blood coagulation system.

The compounds of the present invention exhibit prophylactic and therapeutic effects on thrombosis by directly and differentially inhibiting thrombin.

Conventionally, synthetic compounds exhibiting an antithrombin effect, N-arylsulfonyl-L-alkininamides (Patent Publication No. 15267/1982) and Nα-arylsulfonylaminoacyl-p-amine-phenylalaninamides have been used. (Japanese Unexamined Patent Publication No. 62228050) has been reported. The compound of the present invention is a novel compound that differs from these known compounds in that it has a 1.2.3° 4-tetrahydroisoquinoline skeleton.

(Problems to be Solved by the Invention and Means for Solving the Problems) The compound of the present invention relates to a trisubstituted-1,2,3,4-tetrahydroisoquinoline represented by the following formula (I) or a salt thereof.

In the above formula, R1 is an amidino group or an amine group.

R2 is di-lower 2 or 3 R4 is a hydrogen atom, lower alkyl group or lower alkoxycarbonyl group) R3 is a lower alkylamino group The optionally substituted aryl group is an amino acid residue represented by A is 0 or an integer from 1 to 7, and R5 and R6 are the same or different and mean a lower alkyl group or an aralkyl group.

A further explanation of the compound of the above-mentioned formula is as follows. The guanidino group of R1 may be substituted with a linear or branched lower alkyl group having 1 to 5 carbon atoms, such as a methyl group, ethyl group, propyl group, or isopropyl group.

A group having a structure in which a guanidino group substituted with an alkyl group is cyclized, and means a 2-imidazolinylamino group and a tetrahydropyrimidin-2-ylamino group.

The di-lower alkylamino group of R2 is an amino group substituted with any two of lower alkyl groups having 1 to 5 carbon atoms, such as methyl group, ethyl group, propyl group, isopropyl group, etc.
It is a membered cyclic alkylamino group, and specifically means an azetidinyl group, a pyrrolidinyl group, and a piperidyl group. These cyclic alkylamino groups have 1 carbon atom as described above.
to 5 lower alkyl groups or methoxycarbonyl groups,
Ethoxycarbonyl group 2 May be substituted with a lower alkoxycarbonyl group such as a propoxycarbonyl group.

Examples of the aryl group for R3 include a naphthyl group and a phenyl group. These aryl groups may be substituted with a lower alkylamino group having 1 to 5 carbon atoms, such as a methylamino group, ethylamino group, dimethylamine group, diethylamino group. R5. in the amino acid residue of A. The lower alkyl group of R6 is the same as described above.

Further, examples of the aralkyl group include a benzyl group, a phenethyl group, a phenylpropyl group, and a 2-methylphenethyl group.

Examples of the salt of the compound of general formula (I) include hydrochloride.

hydrobromide, hydroiodide, sulfate, nitrate, acetate, methanesulfonate, maleate, succinate,
Mention may be made of salts with pharmacologically acceptable inorganic or organic acids, such as citrate, fumarate, and p-toluenesulfonate.

Moreover, the compound of formula (I) has an asymmetric carbon atom, and stereoisomers based on the same atom exist. The compounds of the present invention include separated or mixtures of these isomers.

Next, methods for producing the two compounds of the present invention will be explained.

First manufacturing method (I') (In the formula, A, R2, and R' have the above meanings.

RIEL means a cyano group or a nitro group, and X means a halogen atom or a hydroxyl group. ) The compound represented by the general formula (I') is a tetrahydroisoquinoline represented by the general formula (I[) and the general formula (III)
The residue is produced by reacting carboxylic acid, sulfonic acid, and a reactive derivative of cholera.

Examples of the halogen atom represented by X in the above reaction formula include an iodine atom, a bromine atom, and a chlorine atom.

The reaction is toki&'! where compound (III) is a carboxylic acid.
, (1') is an amide bond forming reaction, and a known peptide synthesis method is used. Commonly used methods include a method using a dehydration condensation agent such as 1-ethyl-3-(dimethylaminepropyl)carbodiimide and dicyclohexylcarbodiimide, and an AND method.

Examples include acid halide method, acid anhydride method, and active ester method. Groups involved in the amide bond formation reaction are activated as necessary, but activation of carboxyl groups is achieved by acid halides, active esters (1-hydroxybenzotriazole, N-
(by hydroxysuccinimide, etc.), carbazide, carboxylic acid anhydride. Among these, the acid halide method or the method using a condensing agent such as dicyclohexylcarbodiimide is suitable for producing ([). The reaction is carried out in a conventional manner in an inert solvent at room temperature or at elevated temperatures. Suitable solvents include dimethylformamide, dichloromethane, and tetrahydrofuran.

When ([) is a sulfonic acid, the reaction for producing (■') is a sulfonamide bond forming reaction, and a known synthesis method is used. Sulfonyl chloride is preferably used as (III) in the production of (I'). The reaction is carried out in a conventional manner in an inert solvent at room temperature or at elevated temperatures. Suitable solvents include dimethylpolamide, dichloromethane, tetrahydrofuran, and the like.

The method is preferred.

Second Production Method (I″) (1,a) (In the formula, A, R2, and R3 have the above-mentioned meanings.) The reaction for producing the compound of the present invention represented by the general formula (Ia) is carried out using the general formula (■ This reaction converts a cyano group into an amidino group in the compound represented by ammonium acetate (wherein A, R'',
R' has the meaning given above. ) The compound of the present invention represented by the general formula (Ib) is produced by the reduction reaction of the nitro group of the compound represented by the general formula (■") to an amine group.

Although known methods can be used to convert a nitro group into an amine group, catalytic reduction using palladium-carbon as a catalyst is suitable for producing (Ib).

Third splitting method (in the formula T AI R2T R31" has the above meaning.

X' means a halogen atom. ) The compound of the present invention represented by general formula (IC) is represented by general formula (I
It is produced by reacting the compound represented by b) with the compound represented by the general formula 0■).

(Effect of the invention) The compounds of the invention have antithrombin activity.

Its action is selective and persistent. Therefore, the compound of the present invention is useful as a prophylactic or therapeutic agent for thrombosis and other diseases (eg, DIC, cerebral thrombosis, obstructive arteriovenous disease, etc.) with few side effects.

The compounds of the present invention can be administered orally or parenterally. Oral administration is carried out in the form of tablets, capsules, etc. using pharmaceutical excipients such as lactose, corn starch, hydroxypropyl cellulose, and carboxymethyl cellulose in a conventional manner. In addition, parenteral administration includes injections and nasal drugs.

Administer as a suppository. The dosage is 1 to 500 mg parenterally per day for adults.

(Example) Next, the nine compounds of the present invention and the method for producing the same will be further explained with reference to Examples. Incidentally, production examples of raw material compounds used in Examples are described as reference examples.

In addition, in the two examples, Mass is the mass spectrum, H-NM
R indicates a nuclear magnetic resonance spectrum, and IR indicates an infrared absorption spectrum.

Reference example A 2-acetyl-7-amino-3-ethoxycarbonyl-
1,2,3,4-tetrahydroisoquinoline 5.24g
10 mt of concentrated hydrochloric acid is added to the mixture under methanol-ice cooling.

Sodium nitrite 152
After dropping 5 ml of an aqueous solution of g, the mixture was cooled to -10°C or lower.

Add 5 ml of toluene and completely neutralize with anhydrous sodium bicarbonate to prepare a diazonium salt.

Meanwhile, 4.80 g of cuprous chloride (93%) and 20 m of water
Add l.

While cooling with water, 10 ml of an aqueous solution of 10.4 g of potassium cyanide was added to this mixture, and the mixture was stirred at the same temperature for 1 hour. After adding 50 ml of ethyl acetate, the previously prepared diazonium salt was added all at once, and the mixture was heated at room temperature for 1 hour until the generation of nitrogen was suppressed.
Stir vigorously for 10 minutes at 0°C. From now on, separate the organic layer and add it to a saturated aqueous sodium bicarbonate solution.

Wash sequentially with saturated saline and dry with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography.

4.6 g of 2-acetyl-7-dia-3-ethoxycarbonyl-1,2,3,4-tetrahydroisoquinoline as an oil from n-hexane-ethyl acetate (1:1 volume ratio)
I got it.

'H-NMR (CDCI,) δppm: 1.15
(3H,t), 2.28(3H,s), 3.1
0-3.50 (2H, m), 4.10 (2H, q).

4.55-5.10 (2H, m), 5.50-5
．． 78 (IH, m), 7.15-7.85 (3H
,m) IR (KBr): 2235.1720.1660
cm-' Reference Example B 30 ml of 3N hydrochloric acid and 15 mt of acetic acid were added to 4.6 g of 2-acetyl-7-dia2-3ethoxycarbonyl-1,2,3,4-tetrahydroisoquinoline obtained in Reference Example A at 120°C for 4 hours. Heat. The solvent was distilled off under reduced pressure, and the resulting residue was washed with acetone to give 7-sia/-1,2
, 3.14 g of 3,4-tetrahydroisoquinoline-3-carboxylic hydrochloride.

Melting point 2508C or higher 'H-NMR (DMSO-d6) δppm' 3-1
0-165 (2H+m).

4.12-4.75 (3H, m), 7.25-8.0
O(3H,m)IR(KBr): 2936.223
6.1754 cm-'-7-dia2 1.2: 3.
4-tetrahydroisoquinoline-3-carboxylic acid in 1.
Gained 14g.

Melting point 160-162°C (decomposition) H-NMR (DMSO-d,) δppm: 1.32
~1.60 (9H, m).

3.12-3.40 (2H, m), 4.48-5.0
0 (3H, m).

7.44 (lH,d, J=7.2Hz), 7
．． 66'(I H, dd, J = IHz, 7.2H
z).

7.76 (IH, d, J=IHz) Reference Example C 0.96 g of 7-dia2 1.2.3.4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride obtained in Reference Example B was added to IN water. 8 ml of sodium oxide aqueous solution and 16 ml of dioxane
ml, add 0.96 g of di-tert-butyl dicarbonate to this solution, and stir at room temperature for 15 hours.

The solvent was distilled off under reduced pressure, and water was added to the resulting residue.

Adjust the pH to 3 with a 10% aqueous citric acid solution. The precipitated crystals were counted and the 2-tert-butoxy carbonyl 7-cyano-1,2 obtained in Reference Example C was obtained.
, 2.11 g of 3,4-latrahydroisoquinoline-3-carboxylic acid and 1.1 g of 1-hydroxybenzotriazole
4 g of the solution was added to a mixed solvent of 10 ml of N,N-dimethylformamide and 10 ml of dioxane, and the mixture was stirred at room temperature. Dicyclohexylcarbodiimide 1.7
Add 3g. After urea is precipitated.

After stirring for 30 minutes, 0.63 g of piperidine N,N-
After 2 drops of 2 ml of dimethylformamide solution was added.

Stir at room temperature for 15 hours. The urea is removed, the P solution is distilled off under reduced pressure, and the resulting residue is dissolved in chloroform. After sequentially washing with saturated aqueous sodium hydrogen carbonate solution and saturated brine, drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting crystals were washed with diisopropyl ether to give 2-tert-butoxyluponyl-7-cyano 3-(1
:"Veridinocalho=k) 2.15 g of -12,3,4-tetrahydroisoquinoline is obtained.

Melting point 145-147°C H-NMR (CDCI, ) δl)pm: 1.32-
1.88 (15H, m).

3.10 (2H, d, J=4Hz), 3.20-3
．． 92 (4H, m).

4.20-5.56 (2H, m), 7.12-7.6
0(3H,m) Reference Example E 7-dia2-3-(piperidinocarbonyl) -1゜2
, 2.15 g of 3.4-tetrahytroinquinoline in 4N
-Hydrogen chloride-dissolve in ethyl acetate solution and stir at room temperature for 2 hours. The precipitated crystals were separated to obtain 1.75 g of 7-dia2-3-(piperidinocarbonyl)-1,2,3,4-tetrahytroinquinoline hydrochloride.

Melting point 200℃ or higher'H-NMR (DMSO-d,) δppm: 1.4
0-1.80 (6H, m).

3.36-3.68 (2H, m), 4.36 (2H,
s), 4.82 (IH, dd.

J = 12Hz, 4Hz), 7.48 (IH, d,
7.2Hz), 7.78 (IH.

dd, J=7.2Hz, IHz), 7.84(I
H, d, J = IHz) IR (KBr): 346
0.2236.1.652cm-1 Example 1 Reference Example 2-tert-butoxycarbonyl-carbonyl-Reference Example E
7-dia2-3-piperizica/l/ho=ru 1.2.3.4-tetrahydroisoquinoline hydrochloride 0
．． 10 mt of methylene chloride and 0.39 g of triethylamine were added to 52 g, and the mixture was cooled with water and stirred. In this solution,
N-(2-naphthylsulfonyl)glycyl chloride 0.
Add 50 g and stir at room temperature for 15 hours.

The solution is washed with IN hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the obtained crystals were washed with ether to give 7-dia2-2-(N-(2-naphthylsulfonyl)glycyl)-3-piperidinocarbonyl-1,2,3
, 0.76 g of 4-tetrahydroinquinoline is obtained.

Melting point 125-127°C IR (KBr): 2232.1644 cm” (1
) 7-dia2-(N-(2-naphthylsulfonyl)glycyl)-3-piperidinocarbonyl-1,2
, 0.76 g of 3,4-tetrahytroinquinoline is dissolved in 10 mt of pyridine and 2 ml of triethylamine. Hydrogen sulfide gas on this thing! ! Lasts for 30 minutes.

After saturation, leave overnight at room temperature. IN hydrochloric acid 150m
1 and extracted with ethyl acetate. The organic layer is washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure to obtain a thioamide compound.

This product is used in the next step without being isolated and purified.

15 mt of acetone and 1 ml of methyl iodide are added to the crude crystals of the thioamide compound, and the mixture is heated under reflux for 45 minutes. The solvent is distilled off under reduced pressure to obtain a thioimidate compound. This product is also used for the secondary reaction without being isolated and purified.

Methanol 2011It and ammonium acetate 0.17g are added to the thioimidate compound, and the mixture is heated under reflux for 3 hours. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. Chloroform-methanol (15:1 volume ratio) Ethyl acetate was added to the foamy substance obtained from the eluate for crystallization.

Wash with ethyl acetate to obtain 7-amidino-2-(N-(2
0.52 g of -su7tylsulfonyl)glycyl]-3-piperidinocarbonyl-1,2,3,4-tetrahytroinquinoline hydroiodide is obtained.

H-NMR (DMSO-d,)δI)pm: 0.8
0-1.32 (6H, m).

4.28-4.88 (2H, m), 5.12-5.4
4 (LH, m).

7.28-8.48 (IOH, m) IR (KBr): 3136.1648.1446
cm”Mass (Fab) mHz 534 (M”
+1) Example 2 (1) 2-tertiary ptoxycarbonyl- obtained in Reference Example C
7-Cyano 1.2.30 g of 34-tetrahytroinquinoline-3-carboxylic acid and 0.16 g of 1-hydroxybenzotriazole in a mixed solvent of 2 ml of N,N-dimethylbormamide and 2 ml of dioxane and stir at room temperature. Add 0.25 g of dicyclohexylcarbodiimide to this. After urea is precipitated, 3
After stirring for 0 minutes, add 010 g of 4-methylpiperidine to N
, 1 ml of N-dimethylformamide solution was added dropwise.
After the addition, the mixture was stirred at room temperature for 15 hours. The urea is removed, the P solution is distilled off under reduced pressure, and the residue is dissolved in chloroform. Saturated aqueous sodium bicarbonate solution.

After sequentially washing with saturated saline, drying with anhydrous magnesium sulfate. The solvent was distilled off, and the resulting crystals were washed with diisopropyl ether to give 2-tert-phthoxycarbonyl-7-cyano-3-(4-methylpiperidinocarbonyl).
-1,2,3,4-tetrahytroinquinoline 029
get g.

(2) Add 3 m of 4N hydrogen chloride-ethyl acetate solution to this
1 and stirred at room temperature for 2 hours. Separate the precipitated crystals to obtain 0.25 g of amine hydrochloride.

(3) Next, 5 ml of methylene chloride and 0.13 g of triethylamine are added to this mixture, and the mixture is stirred while cooling with water.

0.18 g of N-(2-naphthylsulfonyl)glycine chloride is added to this solution, and the mixture is stirred at room temperature for 15 hours.

The solution is washed with IN hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated brine, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the resulting crystals were washed with ether to give 7-dia2-2-CN-(2-naphthylsulfonyl)glycyl]-3-(4methylpiperidino)carbonyl-1,2,3,4-tetrahydroisoquinoline. 0.3
Obtain 5g.

(4) Add 10 m7 of pyridine and 2 mt of triethylamine to this solution, saturated the solution with hydrogen sulfide gas, and then leave it at room temperature overnight. Pour into 150 ml of IN hydrochloric acid and extract with ethyl acetate. The organic layer is washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent is distilled off to obtain a thioamide compound. 15 mt of acetone and 1 ml of methyl iodide are added to this thioamide compound, and the mixture is heated under reflux for 45 minutes. The solvent is distilled off under reduced pressure to obtain a thioimidate compound. To this were added 20 m4 of methanol and 0.07 g of ammonium acetate, and the mixture was heated under reflux for 3 hours.

The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. Chloroform-methanol (15:
1 volume ratio) Add ethyl acetate to the foamy substance obtained from the eluate to crystallize it, wash with ethyl acetate, and obtain 7-amidino-2-(N-(2-naphthylsulfonyl)glycyl).
-3-((4-methylpiperidino)carbonyl) -1
, 0.25 g of 2,3,4-tetrahydroisoquinoline hydroiodide is obtained.

'H-NMR (DMSO-d6) δppm: 0.5
6-1.68 (8H, m).

4.32-4.92 (2H, m), 5.20-5.4
8 (IH, m), 7.32-8.52 (IOH, m) IR (KBr): 3460.1672.1654.
1636 Cm”Mass (Fab) m/z
548 (M''+1) The following procedure was carried out in the same manner as in Example 2 using 2-tert-ptoxycarbonyl 7-cyano-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid obtained in Reference Example C as a starting material. The compounds of Example 3 and Example 4 were synthesized.

Example 3 Amidino[[(2-ethoxycarbonyl)piperidinococarbonyl)-2-(N-(2-naphthylsulfonyl)glycyl)-1.2,3.4-
Tetrahydroisoquinoline hydroiodide 'H-NMR
(DMSO-d,) δppm: 1.00 to 1.7
8 (9H, m).

7, 22-8.44 (IOH, m)IR (KBr
): 3156, 1734. 1654 cm”M
ass (Fab) m/z 6 0 6 (M”
+1) Example 4 7-amidino-3-(1-azetidinylcarbonyl)-
2-(N-(2-naphthylsulfonyl)glycyl)-1
．． 2,3.4-tetrahydroisoquinoline hydroiodide H-NMR (DMSO-d,) δppm: 1.8
8-2.28 (2H, m).

4, 32-5. OO(3H, m), 7.28~8
．． 52 (10H, m)IR (KBr): 3
124, 1640 cm-'Mass (Fab)
m/z 506 (M"+1) Example 5 To 0.31 g of 7-dia-2-3-piperidinocarbonyl-1,2,3,4-tetrahydroisoquinoline hydrochloride obtained in Reference Example E, 5 rnl of dichloromethane and 0 rnl of triethylamine were added. Add .21g and stir at room temperature.This solution 1
Add 0.23 g of K2-naphthalenesulfonyl chloride and stir at room temperature for 10 hours. The reaction solution is washed successively with IN hydrochloric acid, saturated hydrogen carbonate solution, and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and 7-dia2-2-(2-naphthylsulfonyl)-3-piperidinocarbonyl-1,2,
0.43 g of 3,4-tetrahydroisoquinoline is obtained.

Add to this 10 ml of pyridine and 2 ml of triethylamine.
ml, and after passing hydrogen sulfide gas to saturate the mixture, leave it at room temperature overnight.

Pour into 150 mA of IN hydrochloric acid and extract with ethyl acetate. After washing the organic layer with water, it is dried over anhydrous magnesium sulfate. The solvent is distilled off to obtain a thioamide compound. Add 15 ml of acetone and 1 ml of methyl iodide to this thioamide,
Heat to reflux for 1 hour. The solvent is distilled off under reduced pressure to obtain a thioimidate compound. To this were added 20 m7 of methanol and 0.07 g of ammonium acetate, and the mixture was heated under reflux for 3 hours. The solvent was distilled off under reduced pressure.

The residue is subjected to silica gel column chromatography. Add ethyl acetate to a foam obtained from chloroform-methanol (15:1 flt) to crystallize, wash with ethyl acetate, and obtain 7-amidino-2(2-naphthylsulfonyl)-3-piperidinocarbonyl. -1, 2, 3, 4
-Tetrahytroine quinoline hydroiodide 0.3 g
get.

'H-NMR (DMSO-d,): δ: 1.0
0-1.84 (6H, m).

4.44-5.00 (2H, m), 5.28-5.52
(IH, m), 7.08-8.52 (10H, m) IR (KBr): 3128, 1674.1626
cm-'Mass (Fab) m/z 477
(M”+1) Using 7-dia2-3-piperidinocarbonyl-1,2,3,4-tetrahydroisoquinoline hydrochloride obtained in Reference Example E as a starting material, the following procedure was carried out in the same manner as in Example 5. The compound of Example 6 was synthesized.

(IH, m), 7.18-8.60 (9H, m) IR (
KBr): 3128, 1674, 1624 cm
-'Mass (Fab) m/z 520 (M”
+1) Example 7 Example 6 Tuamidino-2-dansyl-3-piperidinocarbonyl)-1,2,3,4-tetrahytroinquinoline hydroiodide H-NMR (DMSO-d,) 399m: 1.08
~1.76 (6H, m).

2.80 (6H,s), 4.48~5.00 (
2H, m), 5.28-5.56 dansylglycine 0
．． 31 g and 1-hydroxybenzotriazole 0.
0.25 g of dicyclohexylcarbodiimide is added to 5 mt of 16 g of N,N-dimethylformamide solution at room temperature. After precipitation of urea, and further stirring for 30 minutes, 7-cyano-3-piperidinocarbonyl-1,2 obtained in Reference Example E
, 3,4-tetrahydroisoquinoline hydrochloride 0.31g
and 0.12 g of N-ethylmorpholine were added thereto, and the mixture was stirred at room temperature for 15 hours.

Urea is removed and PK is distilled off under reduced pressure. The obtained residue is dissolved in chloroform, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography.

The crystals obtained from chloroform-methanol (50:l elution ratio) were washed with ether to give 7-cyan 2-(N-
Dansyl-glycyl)-3-piperidinocarbonyl-1
, 0.4 g of 2,3,4-tetrahydroisoquinoline are obtained.

Melting point 131-133°C IR (KBr): 2232.1646 cm-'+
0.4 g of 7-dia2-2-(N-dansylglycyl)-3-piperidinocarbonyl-1,2,3,4-tetrahydroisoquinoline obtained in step 11 was dissolved in 8 ml of pyridine and 1.5 ml of triethylamine. This solution was saturated with hydrogen sulfide gas for 30 minutes, and then left overnight at room temperature. Pour into ice water and adjust to pH 5-6 with 10% hydrochloric acid. The precipitated crystals are collected to obtain a thioamide compound.

This product is used in the next reaction without being isolated and purified.

15 ml of acetone and 1 ml of methyl iodide for thioamide
1 and heated under reflux for 1 hour. The solvent was distilled off under reduced pressure,
A thioimidate is obtained. This product is also used in the next reaction without being isolated and purified.

20 m# of methanol and 0.08 g of ammonium acetate are added to the thioimidate, and the mixture is heated under reflux for 3 hours.

The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. Add ethyl acetate to the foamy substance obtained from the chloroform-methanol (10:1 volume ratio) eluate to crystallize it, wash with ethyl acetate,
0.24 g of 7-amidino-2-(N-dansylglycyl)-3-piperidinocarbonyl-1,2,3,4-tetrahydroisoquinoline hydroiodide was obtained.

'H-NMR (DMSO-d, )δppm: 1
．． 08-1.72 (6H, m).

2.84 (6H, s), 4.32-4.88 (2H
, m), 5.12-5.48 (IH, m), 7
．． 16-8.52 (9H, m).

IR(KBr): 3220.2948.164
6 cm-1Mass (Fab) m/z
577 (M”+1) Example 8 (llN-(2-naphthylsulfonyl)-β-alani:
A solution of 0.28 g of y and 0.16 g of 1-hydroxybenzotriazole in N,N-dimethylformamide 5
ml of dicyclohexylcarbodiimide at room temperature.
Add 25 g. After urea precipitation, after further stirring for 30 minutes, 0.31 g of 7-dia2-3-piperidinocarbonyl-1,2,3,4-tetrahydroisoquinoline hydrochloride obtained in Reference Example E and 0.3 g of N-ethylmorpholine were added. 12g
were added sequentially and stirred at room temperature for 15 hours. The resulting residue was dissolved in chloroform.

After washing with water, dry with anhydrous magnesium sulfate.

The solvent was distilled off and the residue was subjected to silica gel chromatography. 7-dia2-[N-(2-
0.45 g of -3-piperidinocarbonyl-1,2,3,4-tetrahydroisoquinoline is obtained.

(2) Add 8 mZ of pyridine and 1.5 ml of triethylamine to this mixture, saturated it with hydrogen sulfide gas, and then leave it at room temperature overnight. Pour into 130 ml of IN hydrochloric acid and extract with ethyl acetate. After washing the organic layer with water.

Dry with anhydrous magnesium sulfate. The solvent is distilled off to obtain a thioamide compound.

(3) Add 15mZ of acetone and 1rnl';l of methyl chloride to this thioamide and heat under reflux for 1 hour. Under reduced pressure.

The solvent is distilled off to obtain a thioimidate compound.

(4) Add 20 ml of methanol and 0.08 g of ammonium acetate to this mixture, and heat under reflux for 3 hours.

The solvent is distilled off, and the resulting residue is subjected to silica gel column chromatography. Chloroform methanol (10:
1 volume ratio) Add ethyl acetate to the foamy substance obtained from the eluate to crystallize it.

Wash with ethyl acetate to obtain 7-amidino-2-[N-(2
0.3 g of -naphthylsulfonyl)-β-alanyl]-3-piperidinocarbonyl-1,2,3,4-tetrahydroisoquinoline hydroiodide is obtained.

'H-NMR (DMSO-d, ) δ ppm
2 1.12-1.72 (6H, m), 4
．． 36-4.92 (2H, m), 5.16-5.6
0 (IH, m), 7.36-8.52 (IOH, m
)IR(KBr: : 3160.1676, 16
26 cm-1Mass (Fab) m/z
548 (M++1) Using 7-dia-2-3-piperidinocarbonyl-1,2,3,4-tetrahydroisoquinoline hydrochloride obtained in Reference Example E as a starting material, the following Examples 9 to 1 were carried out in the same manner as Example 8. Fifteen compounds were synthesized.

Example 9 7-amidino-2-[4-(2-naphthylsulfonylamino)butyrylco-3-piperidinocarbonyl-1,2
, 3,4-tetrahydroisoquinoline hydroiodide 'H-NMR (DMSO-d6 4.28-5.00 (2H, m).

8.48 (IOH, m) IR (KBr): Mass (Fab) 3144.1676.1626 cr+r1m/z
: 562 (M"+1)) δppm : 1
．． 12-1.80 (6H, m).

5.20-5.60 (IH, m), 7.32-7
-amidino-2-[5-(2-naphthylsulfonylamino)valeryl]-3-piperidinocarbonyl-1,2,
3,4-tetrahydroisoquinoline hydroiodide 'H-NMR (DMSO-d6) δppm: 1.
12-1.72 (6H, m).

4.36-5.04 (2H, m), 5.25-5.
68 (IH, m), 7.40-8.52 (IOH,
m).

IR (KBr): 3144.1676, 162
4 c+tr1Mass (Fab) m/z
576 (M”+ 1) Example 11 Example 10゜7-amidino-2-[6-(2-naphthylsulfonylamino)hexanoyl]-3-piperidinocarbonyl-1
,2,3,4-tetrahydroisoquinoline hydroiodide'H-NMR (DMSO-d, )δppm: 1
．． 12-1.72 (6H, m).

4.36-5.0O (2H, m), 5.28-5.
68 (lH, m), 7.36-8.48 (IOH,
m) IR (KBr): 3160,1678.1626
am-1Mass (Fab) m/z 5
90 (M”+ 1) Example 13゜Example 12゜7-amidino-2-[N-(2-naphthylsulfonyl)
Sarcosyl]-3-piperidinocarbonyl-1,2,3
,4-tetrahydroisoquinoline hydroiodide'H-NMR (DMSO-d, )δppm: 1
．． 12~1.72(6H, m'L5.28~5.60(
IH, m), 7.36-8.60 (IOH, m)I
R(KBr): 3128.1646 cm-
tMasa (Fab) m/z 548 (W
V'+1) 7-amidino-2-[N-benzyl-N-
(2naphthylsulfonyl)glycyl]-3-piperidinocarbonyl-1,2,3,4-tetrahydroisoquinoline hydroiodide Br IRv max Cm-1: 3380.3150.
1648'H-NMR (DMSO-d, )δppm
: 1.00-1.72 (6H, m).

2.84-5.40 (13H, m), 7.04-8
．． 56 (15H, m) Example 14゜7-amidino-2-[N-isopropyl-N(2-su7
lsulfonyl)glycyl]-3-hyperidinocarbonyl-1,2,3,4-tetrahydroisoquinoline hydroiodide IR (KBr): 3375.3150.167
4.1652 cm-1'H-NMR (DMSO-d
, ) δppm: 0.94 (6H, d).

1.20-1.80 (6H, m), 2.90-5.
70 (12H, m), 7.40-8.65 (IOH
, m) 4.24-4.96 (2H, m), 5.20-5.
72 (IH, m), 7.08 to -8.60 (14H
, m) I R (KB r ): 3128 + 168
0 t 1628 cm-1 Masa (Fab)
m/z 596 (M++1) Example 16
゜Example 15゜7-amidino-2-[p-(2-naphthylsulfonamido)benzoyl]-3-piperidinocarponyl-1,2
,3,4-tetrahydroisoquinoline hydroiodide 'H-NMR (DMSO-d, )δppm: 1
．． 12-1.72 (6H, m) tdansyl-L-phenylalanine 310 mg, HOBT110rr@D
Dissolve in 5 ml of MF, add 160 ff of DCC, and stir for 20 minutes under water cooling (liquid A). Suspend in 15 ml of dichloromethane, add potassium carbonate aqueous solution, and stir at room temperature. Separate the organic layer and dry with magnesium sulfate (solution B). Add solution B to solution A and stir overnight at room temperature. After filtering off the resulting powder, 80 ml of dichloromethane was added.

Wash with saturated aqueous sodium bicarbonate solution, rinse with water, dry,
The solvent is removed under reduced pressure. The residue was subjected to silica gel column chromatography using benzene-ethyl acetate (3:2
) and eluted with 7-dia-2-(N-tansyl-L
-phenylalanyl)-3-piperidinocarbonyl-1
, 2,3,4-tetrahydroisoquinoline (isomer A
) Obtain 300 ff+8. Further elution with the same solvent yielded 140ff1g of isomer B.

Next, in the same manner as in Example 1 (2), 7-amidino-2-(N-dansyl-L-phenylalanyl)-:3-piperidinocarbonyl-1,2,3
, 4-tetrahydroisoquinoline hydroiodide, namely isomer A and isomer B, were obtained.

Isomer A: 'H-NMR (DMSO-d, )δppm: 1.
20-1.70 (6H, m) + 2.40-3.65 (8
H, m), 4.20-4.70 (3H, rn),
5.30-6.70-8.50 (15H, m) 667 (M-I) 3150.1636 cm-1 5,60 (IH, m).

Mass (Fab): IR (KBr): Isomer B: 'H-NMR (DMSO-d, ) 2.40-3.50 (8H, m).

8.30 (15H, m) Mass (Fab): 667 (M-I)
IR (KBr): δ: 1.20-1.60 (6H, m).

4.30~5.0O(4H,m), 7.00~31
60, 1642 crrrl (1) 4.95 g of 7-nitro-1,2,3,4-tetrahydroisoquinoline-3-carboxylic hydrochloride was dissolved in an IN aqueous sodium hydroxide solution 39 I! ll and dioxane 75
Add 4.60 g of tert-butyl dicarbonate to this solution and stir at room temperature for 15 hours. The solvent was distilled off under reduced pressure, water was added to the resulting residue, and the pH was adjusted to 3 with a 10% aqueous citric acid solution. The precipitated crystals are increased by iF+ to obtain a BOC body.

(2) This contains 2.97 g of 1-hydroxybenzotriazole and 6 g of N,N-dimethylformamide.
0 mZ was added, and 4.53 g of dicyclohexylcarbodiimide was added and stirred at room temperature. After urea is precipitated.

After stirring for 30 minutes, 1.56 g of piperidine N,N
- Add 511It of dimethylformamide solution dropwise, and after adding 2 drops, stir at room temperature for 15 hours. The urea is removed, the P solution is concentrated under reduced pressure, and the resulting residue is dissolved in chloroform. Saturated aqueous sodium bicarbonate solution.

After sequentially washing with saturated saline, drying with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting crystals were washed with ether to obtain piperidinocarbonyl isoquinolite/Kabatakari. 0 (3) Add 4N hydrogen chloride-ethyl acetate solution to this mixture and stir at room temperature for 2 hours. Collect the precipitated crystals,
Obtain amine salt.

(4) Add 40 ml of dichloromethane and 2.02 g of triethylamine to this mixture, and stir under ice cooling. 2.84 g of N-(2-naphthylsulfonyl)chrysyl chloride is added to this solution, and the mixture is stirred at room temperature for 15 hours. After washing the reaction solution sequentially with IN hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated brine.

Dry with anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography. The crystals obtained from the chloroform-methanol (50:1 volume ratio) eluate were washed with ethyl acetate, and the 7-nitro 2-[
N-(2-naphthylsulfonyl)glyzylco-3-piperidinocarbonyl-1,2,3,4-tetrahydroisoquinol/ is obtained.

(5) Furthermore, 80 ml of ethanol and 0.4 g of 10% palladium on carbon are added to this mixture, and the mixture is subjected to a catalytic reduction reaction in a hydrogen atmosphere at room temperature until the theoretical amount of hydrogen is absorbed. Palladium on carbon is removed and the P solution is concentrated. Ethyl acetate was added to the resulting oil to crystallize it, followed by washing with ethyl acetate.

7-amino-2-[N-(2-naphthylsulfonyl)crisyl]-3-hyperidinocarbonyl-1,2,3,4
- 3.4 g of tetrahydroisoquinoline are obtained.

H-NMR (DMSO-d,) δppm: 1
．． 12-1.72 (6H, m), 4.24-4.7
2 (2H, m), 4.88-5.12 (IH, m)
, 6.28-6.92 (3H, m), 7.60
~8.52 (7H, m) IR (KBr): 3472, 3360, 3192.
1642 cm-IMass (Fab) m/
z 507 (M”+ 1) Example 18° 7-amino-2-[N-(2-naphthylsulfonyl)glycyl]-3-piperidinocarbonyl-1,2,3,4 obtained in Example 17 -Tetrahydroinoquinoline 0.5
5 ml of a dichloromethane solution of 0.16 g of 2-chloro-2-imidacillin is added to 10++t of a suspension of 1 g of dichloromethane, and the mixture is stirred at room temperature for 3 hours. The solvent is distilled off, and the resulting residue is subjected to silica gel column chromatography. Add ethyl acetate to the foam obtained from chloroform-methanol (15:1 volume ratio) to crystallize, wash with ethyl acetate, and obtain 7-(2-imidacylin-2-ylami/)-2- [N-(2-naphthylsulfonylglycyl]-3-piperidinocarbonyl-1
,2,3,4-tetrahytroinquinoline hydrochloride 0.3
I got g.

') I-NMR (DMSO-d6) δppm:
1.12~1.72(6Ht”)+3.64(4H,s
), 4.24-4.92 (2H, m), 5.0
8-5.32 (IH, m), 6.92-8.52 (
IOH,m)IR(KBr): 3200,1654
cm-IMass (Fab) m/z 57
5 (M”+ 1) Example 19゜(1) Tertiary-butoxycarbonylglycine 0.18g
and 0.16 g of 1-hydroxybenzotriazole
Add 0.25 g of dicyclohexylcarbodiimide to 5 rnl of the N,N-dimethylformamide solution at room temperature. After urea precipitation, the mixture was further stirred for 30 minutes.

7-dia-3-piperidinocarbonyl-1,2゜3.
0.31 g of 4-tetrahydroisoquinoline hydrochloride and N
- Add 0.12 g of ethylmorpholine and
Stir for an hour. The resulting residue is dissolved in chloroform, washed with water, and then dried over anhydrous magnesium sulfate. The solvent is distilled off, and the resulting residue is subjected to silica gel column chromatography.

From the chloroform eluate, 7-dia-2-tert-butoxycarbonylglycyl-3-piperidinocarbonyl-1
, 2,3,4-tetrahydroisoquinoline 0.36 g
is obtained as an oil.

(21 (4 rnl of 4N hydrogen chloride-ethyl acetate solution is added to 0.36 g of the oil obtained in 11) and stirred at room temperature for 2 hours.

The solvent was distilled off under reduced pressure, and 7-dia2-2-glycyl-3-
0.3 g of piperidinocarbonyl-1,2,3,4-tetrahydroisoquinoline hydrochloride is obtained as an oil.

(31 (0.28 g of N-(2-naphthylsulfonyl)glycyl chloride was added to 5 ml of a dichloromethane solution of 0.3 g of the oil obtained in 21 and 0.21 g of triethylamine with stirring at room temperature, and the mixture was heated at the same temperature for 2 hours. Stir.

The reaction solution was washed successively with saturated aqueous sodium hydrogen carbonate solution, IN hydrochloric acid and saturated brine, and then dried over anhydrous magnesium sulfate. Distill the solvent.

The resulting residue is subjected to silica gel column chromatography. Chloroform-methanol (75:1 volume ratio)
Ether is added to the foamy substance obtained from the eluate to crystallize it, which is then washed with ether to give 7-dia2-[[
N-(2-naphthylsulfonyl)glycylcoglycyl]
0.32 g of -3-piperidinocarbonyl-1,2,3,4-tetrahytroinquinoline is obtained.

Thereafter, by the same treatment as in Example 1 (2), 7-amidino-2-[[N-(2-naphthylsulfonyl)glycyl]glycyl]-3-piperidinocarbonyl-1,2,3
,4-tetrahydroisoquinolinehydriodide 0.12
I got g.

'H-NMR (DMSO-d, )δppm: 1
．． 12-1.72 (6H, m).

4.32-5.00 (2H, m), 5.28-5.
60 (IH, m).

7.40~8.52 (IOH, m) IR (KBr): 3140.1644 am
-sMass (Fab) m/z 591 (
M”+1) Patent applicant Yamanouchi Pharmaceutical Co., Ltd.

Claims (1)

[Claims] 1. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 is an amidino group, amino group, guanidino group, or formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼《Formula Middle n is 2
or 3], R^2 is a di-lower alkylamino group or the formula ▲ Numerical formula, chemical formula, table, etc. ▼《In the formula, n is 1, 2 or 3, R^4 is hydrogen atom, lower alkyl group or lower alkoxycarbonyl group, R^3 is an aryl group which may be substituted with a lower alkylamino group, A is a bond or the formula ▲ mathematical formula, There are chemical formulas, tables, etc.▼ Amino acid residues represented by 《In the formula, m is 0 or an integer from 1 to 7, and R^5 and R^6 are the same or different and mean a lower alkyl group or an aralkyl group.》 each meaning. ] Tri-substituted-1,2,3,4-tetrahydroisoquinoline or its non-toxic salt represented by