JP3174767B2 - Aromatic amidine derivatives useful as selective thrombin inhibitors - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to aromatic amidine derivatives useful as selective thrombin inhibitors. More specifically, the present invention can be particularly preferably used for oral administration, and shows an aromatic amidine derivative of the following formula 1 and a salt thereof, which exhibits a strong selective thrombin inhibitory activity, a method for producing the same, and the compound as an active ingredient. The present invention relates to a thrombin inhibitor composition characterized by containing:

Formula 1

Embedded image Wherein n represents an integer of 1 to 3, R ₁ represents lower alkyl optionally substituted by halogen,
R ₂ represents hydrogen or lower alkyl, _{R 3} is a lower alkyl or _C 3 -C ₇ cycloalkyl.

[0003]

BACKGROUND OF THE INVENTION Thrombosis is a disease in which platelet aggregation and fibrin clots occlude blood vessels. Thus, anticoagulants that block fibrin formation can be used to prevent thrombosis.

[0004] The blood coagulation system has numerous zymogens (non-activating enzymes) that are activated by a multi-step enzymatic reaction.
Is involved. The final stage of the blood coagulation process is a stage in which fibrin clots are formed from fibrinogen by thrombin generated from prothrombin by the action of factor Xa.
Thus, thrombin, a blood clotting enzyme, plays a central role in hemostasis and thrombosis, whereby substances that can suppress thrombin activity suppress platelet activity,
It is expected that it can be used as an effective anticoagulant by suppressing fibrin formation and stabilization. Thrombin inhibitors also have a positive feedback reaction (P
active feed backreactio
n) activates factor V and factor VIII.

Recently, a number of thrombin inhibitors have been developed as effective antithrombotic and anticoagulant agents. For example, P
PACK [D-Phe-Pro- Arg-CH 2 Cl,
Thromb. Res. , 14,969 (197)
9)], D-Phe-Pro-Arg, Boc-DP
he-Pro-Arg and D-MePhe-Pro-A
rg [JMed. Chem. , 33, 1729 (199
0)], DuP-714 [Ac- (D) -Phe-Pr
o-boroArg-OH, J. Am. Biol. Che
m. , 265, 18289 (1990)], Efegatran [D-MePhe-Pro.
_{-Arg-H 2 SO 4, Thromb} . Haemos
t. , 67, 325 (1992)], Inogatran (I
_{nogatran) [HOOC-CH 2 -} (R) Cha
-Pic-Nag, where Cha: cycloh
exylamine, Pic: pipecolica
cid and Nag: noragmatine, W
O93 / 11152, BloodCoag. Fibri
nol. , 7, 69 (1996)] and CVS-1
123 [(CH ₃ CH ₂ CH ₂ ) ₂ —CHCO-Asp
_{(OCH 3) -Pro-Arg,} WO93 / 1575
6] and agatroban (A
rgatroban) [US4258192, Thro
mb. Haemost. , 18, 13 (1992)] and NAPAP [J. Biol. Chem. , 266,2
0085 (1991)]. However, these compounds are actually used in terms of bioavailability by oral administration, inhibition selectivity for thrombin over other serine proteases, stability, sustained action, and toxicity in therapeutic doses. Not enough.

On the other hand, the present inventors have conducted intensive research to develop a thrombin inhibitor that can be orally administered, selectively inhibits thrombin, and can be used effectively. The compound of the present invention exhibited excellent thrombin inhibitory activity even by oral administration and was confirmed to have higher selectivity for thrombin than trypsin, and was filed on May 31, 1997 (see Korean patent). Application No. 97-22566).

Chemical formula 2

Embedded image Where R is the formula

Embedded image Or

Embedded image Wherein R ¹ is hydrogen, hydroxy,
Alkyl, alkoxy, alkylcarbonyl, alkylcarbonyloxy, aralkoxycarbonyl or represents a radical of the following formula,

Embedded image Here, B represents oxygen or sulfur, and R ¹¹ and R
¹² each independently represents hydrogen, haloalkyl, alkylcarbonyloxy, dialkylamino, or an optionally substituted 3- to 7-membered saturated or unsaturated heterocyclic or carbocyclic ring; And R ² represents hydrogen, hydroxy, halogen, carboxy, aminocarbonyl, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, aminocarbonylalkyl, alkoxycarbonylalkyl or substituted represents an arylsulfonyl also be, R ³ is hydrogen, halogen, alkyl, hydroxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, carboxy, amino, aminoalkyl, a Nokarubokishi represents an aminocarbonylalkyl or group of the formula,,

Embedded image Here, R ¹³ and R ¹⁴ each independently represent hydrogen, alkyl, or an optionally substituted 3- to 7-membered saturated or unsaturated heterocyclic or carbocyclic ring, and h represents 0 to Represents an integer of 3 and has the formula

Embedded image Is selected from the group consisting of indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, naphthyl, tetrahydronaphthyl, indanyl, dihydrobenzofuranyl and dihydrobenzothienyl, where A is carboxy, alkyl, A saturated or unsaturated C ₂ -C ₄ alkylene group optionally substituted by one or two substituents selected from the group consisting of hydroxyalkyl, carboxyalkyl, alkylcarbonyl, alkoxycarbonyl and alkoxycarbonylalkyl And W represents the following formula:

Embedded image Here, o, p and q each independently represent an integer of 0 to 3, and R ⁴ , R ⁵ and R ⁶ each independently represent hydrogen, hydroxy, carboxy, alkoxycarbonyl, optionally substituted aryl. Represents a sulfonyl, an optionally substituted 3- to 7-membered saturated or unsaturated heterocyclic or carbocyclic ring, or a group represented by the following formula:

Embedded image Here, R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are each independently hydrogen, alkyl, alkylsulfonyl, carboxyalkyl, alkylcarbonyl, aminocarbonylalkyl, alkoxycarbonylalkyl, optionally substituted arylsulfonyl, substituted Represents an optionally substituted aralkyl, an optionally substituted 3- to 7-membered saturated or unsaturated heterocyclic or carbocyclic ring, wherein R ¹⁹ and R ²⁰ are each independently hydrogen, carboxy or Represents an aminocarbonyl or alkoxycarbonyl, or can be fused to one or more additional 3- to 7-membered saturated or unsaturated heterocyclic or carbocyclic rings.
Represents a-to 7-membered saturated or unsaturated heterocyclic or carbocyclic ring, r is an integer from 0 to 3; Y is hydrogen or one or more additional 3- to 7-membered saturated Or a 3- to 7-membered saturated or unsaturated heterocyclic or carbocyclic ring which can be fused to an unsaturated heterocyclic or carbocyclic ring, wherein the heterocyclic ring or carbon The cyclic ring is oxygen, halogen, nitro, alkyl, haloalkyl, hydroxyalkyl, arylsulfonyl, optionally substituted arylsulfonyl, optionally substituted 3- to 7-membered saturated or unsaturated heterocyclic ring. Or a carbocyclic ring, and can be substituted at any position in the ring by a substituent selected from the group consisting of:

Embedded image Here, R ²¹ and R ²² each independently represent hydrogen, alkyl, alkylsulfonyl, carboxyalkyl, alkylcarbonyl, alkoxycarbonylalkyl or optionally substituted arylsulfonyl,
R ²³ and R ²⁴ are each independently fused with hydrogen, carboxy, aminocarbonyl, alkoxycarbonyl, or one or more additional 3- to 7-membered saturated or unsaturated heterocyclic or carbocyclic rings. 3 to 7
Represents a membered saturated or unsaturated heterocyclic ring or carbocyclic ring, wherein R ²⁵ , R ²⁶ and R ²⁷ are each independently hydrogen, hydroxy, mercaptothio, amino, carboxy, aminocarbonyl, alkoxy, alkoxycarbonyl , Alkylamino, alkylsulfonylamino, alkenyl, alkoxycarbonylamino, alkoxycarbonylalkylamino, cycloalkylamino, optionally substituted arylsulfonylamino, optionally substituted 3- to 7-membered saturated or unsaturated Represents a heterocyclic ring or a carbocyclic ring, s is an integer of 0 to 3, t is an integer of 0 to 6, u is an integer of 0 to 8, n
Is an integer of 0 to 2, wherein g, h, o,
When p, q, r, s, t and u are 3 or more, the corresponding alkylene chain may be either a straight chain or a side chain.

[0008]

However, the present inventors are not limited to this, and have conducted continuous research to develop better thrombin inhibitor compounds, and as a result, have found that the aromatic compound represented by the above formula 1 The present inventors have found that a family of amidine derivatives exhibits better blood duration and bioavailability than the compound of formula 2 previously developed by the present inventors, and can be used very preferably for oral administration, thus completing the present invention. I came to.

[0009] In particular, the aromatic amidine derivatives according to the present invention are characterized by the structural features comprising a carbonylamino group substituted by lower alkyl or cycloalkyl.
It is believed that it exhibits a higher bioavailability than the compound of Formula 2. Due to such a long blood duration and high bioavailability, the compounds according to the invention can be used particularly preferably for preparing compositions for oral administration (see experimental results).

[0010]

SUMMARY OF THE INVENTION Accordingly, the present invention is directed to aromatic amidine derivatives of formula 1 as defined hereinbefore, which are particularly preferred for use as thrombin inhibitors for oral administration due to their improved pharmacokinetic properties, and their derivatives. It relates to a pharmaceutically acceptable salt.

The present invention also relates to a method for producing the compound of the formula 1 and a salt thereof, and to a thrombin inhibitor composition comprising the compound as an active ingredient.

The present invention also provides an intermediate compound that can be usefully used for preparing the compound of Formula 1.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION Among the compounds of the formula 1 according to the present invention, n is 2 or 3, R ₁ is methyl, ethyl, propyl or 2-fluoroethyl, and R ₂ is hydrogen or ethyl. And R ₃ is a compound representing methyl, ethyl or cyclohexyl.

A typical example of the compound of Formula 1 provided by the present invention is specifically shown below, which can be summarized as shown in Table 1 below: 4-[(R) -2
-[[(S) -2- [2- (6-amidino-1-ethylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-(S) -2- (acetylamino) butanoic acid; 4- [(R) -2-[[(S) -2-
[2- (6-amidino-1-ethylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-(S) -2- (propionylamino) butanoic acid;
4-[(R) -2-[[(S) -2- [2- (6-amidino-1-methylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-(S) -2-
(Acetylamino) butanoic acid; 4-[(R) -2-
[[(S) -2- [2- (6-amidino-1-propylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-(S) -2- (acetylamino) butanoic acid; 4- [ (R) -2-[[(S) -2-
[2- (6-Amidino-1- (2-fluoroethylindole) -2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-(S) -2- (acetylamino)
Butanoic acid; 5-[(R) -2-[[(S) -2- [2-
(6-amidino-1-ethylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-
(S) -2- (acetylamino) valeric acid; 5-[(R)
-2-[[(S) -2- [2- (6-amidino-1-ethylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-(S) -2- (cyclohexanoylamino) yl Herbic acid.

[0015]

[Table 1]

The compound of formula 1 according to the present invention can also form a pharmaceutically acceptable salt. Such pharmaceutically acceptable salts include acids which form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, iodide Inorganic acids such as hydrochloric acid, organic acids such as tartaric acid, formic acid, formic acid, citric acid, acetic acid, trichloroacetic acid or trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, methane, etc. Includes acid addition salts formed with sulfonic acids such as sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid, and also includes salts with alkali metals such as sodium and potassium.

According to the present invention, there is also provided a method for preparing a compound of Formula 1. According to the method of the present invention,
(A) reacting a compound of the following formula 4 with an acyl halide or an organic carboxylic acid in the presence of a base in a solvent to produce a compound of the following formula 3; Is converted to an amidino group to produce a compound of the following formula 1b. (C) If necessary, the compound of the formula 1b is hydrolyzed to form a compound of the following formula 1a
The compound of Formula 1 and a salt thereof can be prepared by preparing the compound of Formula 1.

Chemical formula 4

Embedded image Chemical formula 3

Embedded image Chemical formula 1b

Embedded image Chemical formula 1a

Embedded image Wherein n, R ₁ and R ₃ are as defined above;
_{2 'is} identical to R _2, except hydrogen is excluded.

According to the method of the present invention, first in step (a), the compound of formula 4 is reacted with an acyl halide or an organic carboxylic acid to produce a compound of formula 3, which reaction is carried out in the presence of a suitable solvent and base. Done below. As the solvent, a general solvent that does not adversely affect the reaction can be used, and preferred examples of the solvent include one or more selected from methylene chloride, tetrahydrofuran (THF) and chloroform. Further, as a base added to promote the reaction, triethylamine,
One or more selected from N, N-diisopropylethylamine and pyridine are included. The reaction temperature is not critical and the reaction is generally carried out under cooling or heating, preferably at -10 to 50 ° C. Acetyl chloride which reacts with the compound of Formula 4 includes acetyl chloride,
Propionyl chloride, cyclohexanoyl chloride,
Examples include acetyl bromide, propionyl bromide, and cyclohexanoyl bromide, and examples of the organic carboxylic acid include propionic acid and cyclohexanoic acid. The acyl halide or organic carboxylic acid is used in an amount of 1 to 4 moles, preferably 1 to 2 moles, per mole of the compound of Formula 4.

In the step (b), the compound of the formula (3) produced in the step (a) is reacted in the presence of hydrogen halide gas, preferably hydrogen chloride gas, and then ammonia gas is injected into the reaction solution. Thus, a compound of the formula 1b in which a cyano group is converted to an amidino group is produced. This reaction is generally carried out in a solvent, for example, a C ₁ -C ₄ alcohol such as ethanol or propanol, an aliphatic ether such as diethyl ether, a halogenated hydrocarbon such as chloroform, a non-protonic solvent such as benzene, It can be carried out in a solvent such as N-dimethylformamide, dimethyl sulfoxide or a mixed solvent thereof. Particularly preferably using the C ₁ -C ₄ alcoholic solvent such as ethanol. The reaction temperature and time are not critical, but generally the reaction is carried out under cooling or heating for 2 to 72 hours, preferably at a temperature of 0 to 30 ° C. for 12 to 40 hours.

The compound of formula 1a is prepared by hydrolyzing the amidine derivative of formula 1b prepared in the step (b) to convert the ester into a carboxylic acid. The hydrolysis can be carried out in one or more solvents selected from among water, alcohols and tetrahydrofuran in the presence of a base or an inorganic acid such as an alkali metal hydroxide. A particularly preferred solvent is a mixed solvent of water and an alcohol. As the base, potassium hydroxide, sodium hydroxide or lithium hydroxide can be preferably used, and as the inorganic acid, hydrochloric acid is preferred.

The compound of Formula 1 according to the present invention prepared by the above method can be converted into the above-mentioned pharmaceutically acceptable salts by a conventional method. The resulting compound of Formula 1 and a salt thereof are subjected to a usual post-treatment method,
For example, it can be separated and purified by a method such as column chromatography and recrystallization.

On the other hand, the compound of the above formula 3 used as an intermediate in the process for producing the compound of the formula 1 is a novel compound and is therefore included in the present invention.

The compound of formula 4 used as a starting material in the method of the present invention can be prepared by a method as shown in the following reaction scheme 1.

Reaction Scheme 1

Embedded image Wherein n, R ₁ and R ₂ ′ are as defined above, and BOC represents t-butoxycarbonyl, which is used interchangeably throughout this specification.

In addition, each compound used as a starting material or a reactant in the above Reaction Scheme 1 can be prepared by a method as shown in the following Reaction Schemes 2 to 4.

Reaction Scheme 2

Embedded image Reaction scheme 3

Embedded image Reaction Scheme 4

Embedded image The production method illustrated in the above reaction scheme will be more specifically described through examples.

The present invention also relates to a thrombin inhibitor composition comprising as an active ingredient an effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Since the composition according to the present invention exhibits strong thrombin inhibitory activity, it can be usefully used as an agent for preventing and treating thrombosis. The compound of formula 1 according to the present invention has a strong effect, especially when administered orally.
It is expected to be very useful for such purposes.

When a compound of the present invention is administered for clinical purposes, the effective daily dose will generally be
0.1 to 30 mg, preferably 0.5 to 10 m
Although the range of g is appropriate, the dosage administered to each patient will depend on the particular compound being administered, the patient's weight, sex, health condition,
It can be arbitrarily determined by an expert in consideration of the diet, administration time, administration method, excretion rate, type of concomitant drug, disease severity, and the like.

The compounds according to the invention can be administered as oral and injectable preparations according to the purpose.

The solid dosage forms for oral administration can be capsules, tablets, pills, powders and granules, of which capsules and tablets are particularly useful. Tablets and pills are preferably prepared in enteric coatings. Solid dosage forms may contain an active compound of general formula (I) according to the present invention in one or more inert diluents such as sucrose, lactose, starch and the like, lubricants such as magnesium stearate, disintegrants, binders and the like. Can be produced by mixing with a carrier such as

As described above, the composition containing the compound of the formula 1 according to the present invention has a characteristic of exhibiting excellent medicinal properties when used in the form of an oral dosage form. Pharmacokinetic experiments using dogs as experimental animals proved by confirming that the drug has long-lasting properties in blood when the pharmaceutical composition of the present invention is orally administered. . In particular, as a result of examining the pharmacokinetic parameters of the compound disclosed in Korean Patent Application No. 97-22566 as a control, the compound according to the present invention has a blood half-life about twice that of the control compound. As a result, it was confirmed that the bioavailability was improved about twice. Thus, the compounds according to the invention can be used more effectively as oral dosage forms than any of the thrombin inhibitors already developed and are considered to be more useful in this respect.

Compositions containing a compound of formula 1 may also be prepared by injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions using suitable dispersing, wetting or suspending agents according to techniques known to those skilled in the art. It can also be manufactured in liquid form. At this time, usable aqueous solvents include water, Ringer's solution, or isotonic NaCl solution, and sterile fixed oil (ster
Illuminated fixing oils are usually used as solvents or suspending media. Any bland fixed oil may be employed for such purpose, including mono, diglyceride, and fatty acids such as oleic acid may be used in the preparation of injectables.

Further, according to the experimental results, it was confirmed that the compound of the formula (1) exhibited the intended potent thrombin inhibitory effect without showing acute toxicity to mammals such as rats and dogs.

Hereinafter, the present invention will be described more specifically with reference to the following Examples and Experimental Examples. However, these examples and experimental examples are merely examples, and the scope of the present invention is not limited thereto.

[0036]

Example 1 4-[(R) -2-[[(S) -2- [2
-(6-amidino-1-ethylindol-2-yl)
Ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-
(S) Synthesis of 2- (acetylamino) butanoic acid (a) Synthesis of 4-methyl-3-nitrobenzenecarbonitrile 4-Methylbenzenecarbonitrile (10 g) was placed in a 250 ml flask and dissolved in concentrated sulfuric acid (30 ml). Then, it was cooled to 0 ° C. A nitric acid solution (7 ml) mixed with concentrated sulfuric acid (10 ml) was gradually added thereto at −2 to 0 ° C. for 1 hour, and the reaction solution was poured into ice water and stirred. The precipitate formed was filtered and washed three times with water. After drying the filtered solid, silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/3, v
/ V). The fractions containing the product were combined and evaporated to give 11.2 g of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ); δ = 8.30 (s, 1
H), 7.80 (d, 1H), 7.53 (d, 1H),
2.7 (s, 3H) (b) Ethyl 3- (4- (cyano-2-nitrophenyl) -2-sodiumprop-2-enoate (eno)
sodium) (2.51 g) and TH in a 500 ml flask.
After adding F (60 ml) and adding ethanol (30 ml), the mixture was stirred at room temperature until sodium was completely dissolved. There, diethyl oxalate dissolved in THF (14.
(8 ml) solution was added slowly, and the mixture was stirred at room temperature for 10 minutes. Then, 4-methyl-3-nitrobenzenecarbonitrile (16 g) dissolved in THF was added, and the mixture was stirred at room temperature for 18 hours. After evaporating the reaction solution, diethyl ether was added to the residue and the resulting precipitate was filtered and washed three times with diethyl ether. The filtered product was dried to obtain 26.4 g of the title compound as a brown solid. (C) Synthesis of ethyl-6-cyanoindole-2-carboxylic acid ester The compound (2) obtained in (b) above in a 500 ml flask
6 g) and Zn (59.8 g).
After addition of 1), the mixture was stirred at room temperature for 2 hours and at 60-70 ° C for 4 hours. After evaporating the reaction solution, the residue was subjected to silica gel column chromatography (eluent: ethyl acetate / n-
Hexane = 1/3, v / v). The product containing fractions were combined and evaporated to give the title compound 4.16 as a yellow solid.
g was obtained. ¹ H-NMR (CDCl ₃ ); δ = 7.82 (m, 2
H), 7.42 (d, 1H), 7.29 (s, 1H),
4.49 (m, 2H), 1.47 (t, 3H) (d) Ethyl 6-cyano-1-ethylindole-2
-Synthesis of carboxylic acid ester The compound (23.5 g) obtained in the above (c) was placed in a 1-liter flask, dissolved in DMF (300 ml), and then 60% sodium hydride (6.6 g) at 0 ° C. Was slowly added. After adding iodoethane (17.6 ml) thereto at -10 to 0 ° C, the mixture was stirred at room temperature for 2 hours. After allowing the reaction to cool, add ice and dilute with water,
Extracted three times with ethyl acetate. After the combined organic extracts were dried (MgSO ₄ ) and evaporated, the residue was subjected to silica gel column chromatography (eluent: ethyl acetate / n).
-Hexane = 1/3, v / v). The fractions containing the product were combined and evaporated to give 26.2g of the title compound as a yellow solid. ¹ H-NMR (CDCl ₃ ); δ = 7.77 (m, 2
H), 7.34 (m, 2H), 4.64 (m, 2H),
4.42 (m, 2H), 1.43 (m, 6H) (e) Synthesis of 1-ethyl-2- (hydroxymethyl) indole-6-carbonitrile Compound obtained in the above (d) in 11 flask ( 26.2
7g) and sodium bicarbonate (0.91g)
After dissolving in F (300 ml), it was cooled to 0 ° C. After addition of _{CaI 2 · H 2 O (47.8g} ) thereto, N
aBH ₄ a (6.15g) was added slowly. Reaction solution
The mixture was stirred while the temperature was gradually raised from ° C. to room temperature. T
After confirming the completion of the reaction by LC, ice and a catalytic amount of acetic acid were added at 0 ° C., followed by stirring. After evaporating the THF in the reaction solution, the residue was diluted with water and extracted three times with ethyl acetate.
After the combined organic extracts were dried (MgSO ₄ ) and evaporated, the residue was subjected to silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/2, v / v).
Purified in v). The fractions containing the product were combined and evaporated to give 18.2g of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ); δ = 7.63 (m, 2
H), 7.26 (m, 1H), 6.43 (s, 1H),
4.83 (s, 2H), 4.29 (m, 2H), 1.4
1 (t, 3H) (f) Synthesis of (6-cyano-1-ethylindol-2-yl) methyltriphenylphosphonium bromide Compound (1) obtained in the above (e) in a 500 ml flask
8.2 g) and methylene chloride (methylene chloride)
(200 ml), and then cooled to 0 ° C. After PBr ₃ (3.45 ml) was gradually added thereto, the mixture was stirred at room temperature for 4 hours. Then, methylene chloride (20
After washing with a 10% aqueous sodium carbonate solution, the mixture was diluted with water and extracted three times with methylene chloride. The combined organic extracts are dried (MgSO ₄ )
Evaporation gave 6-cyano-1-ethyl-2-bromomethyl-indole. After the obtained compound was dissolved by adding toluene (200 ml), triphenylphosphine (30.9 g) was added and the mixture was stirred at a reflux temperature for 10 hours. After cooling at room temperature, diethyl ether was added and the resulting precipitate was filtered and washed several times with diethyl ether. After filtration, the obtained product was dried to obtain 29 g of the title compound as a light brown solid. (G) Synthesis of methyl (S) -pyrrolidine-2-carboxylic acid ester L-proline (10 g) was placed in a 250 ml flask, dissolved in methanol (150 ml), and HCl was added at 0 ° C.
Gas was injected and saturated for 2 hours. Then, after stirring at room temperature for 5 hours, the solvent was evaporated to obtain 11.2 g of the title compound as a colorless oil. ES-MS; 130 (M + 1) ⁺ , 116 ¹ H-NMR (CDCl ₃ ); δ = 4.50 (m, 1
H), 3.86 (s, 3H), 3.52 (m, 2H),
2.48 (m, 1H), 2.20 (m, 3H) (h) Synthesis of t-butyl (S) -2- (methoxycarbonyl) pyrrolidine-1-carboxylic acid ester In a 500 ml flask, put the above (g). The obtained compound (1
After adding 1.2 g) and dissolving in methylene chloride (200 ml), triethylamine (12 ml) was added and stirred for 5 minutes. At 0 ° C., methylene chloride (1
(Boc) ₂ O (20.9 g) dissolved in (00 ml) was added, followed by stirring at room temperature for 4 hours. The reaction solution was diluted with water and extracted three times with methylene chloride. The combined organic extracts were dried (MgSO ₄ ) and evaporated to give 19.9 g of the title compound as a colorless oil. ¹ H-NMR (MeOH-d ₄ ); δ = 4.20 (m,
1H), 3.68 (s, 3H), 3.37 (m, 2
H), 2.22 (m, 1H), 1.89 (m, 3H),
1.41 (m, 9H) (i) t-butyl (S) -2-formylpyrrolidine-
Synthesis of 1-carboxylic acid ester The compound (9.8 g) obtained in (h) above was placed in a 500 ml flask, dissolved in toluene (200 ml), and cooled to -78 ° C in DIBAL-H (in toluene). 1.0M, 85.5 ml) was added slowly for 1.5 hours. After adding methanol (15 ml), the mixture was stirred at room temperature for 30 minutes. Rochelle's salt
After adding an aqueous solution of s salt (sodium potassium tartrate tetrahydrate), the mixture was stirred at room temperature for about 1 hour, and the reaction solution was extracted with methylene chloride. The combined organic extracts were dried (MgSO ₄ ), evaporated and the residue was chromatographed on a silica gel column (eluent: ethyl acetate / n).
-Hexane = 1/3, v / v). The fractions containing the product were combined and evaporated to give 8g of the title compound as a colorless oil. (J) t-butyl (s) -2- [2- (6-cyano-
Synthesis of 1-ethylindol-2-yl) vinyl] pyrrolidine-1-carboxylic acid ester In a 500 ml flask, the compound (17.4 g) obtained in the above (f) and the compound obtained in the above (i) (6.6) were obtained.
g) was dissolved in a THF: ethanol (1: 1, v / v) mixed solvent, and then 1.8-diazabicyclo [5.4.0] was dissolved.
Undec-7-ene (6.4 ml) was added. After stirring at room temperature for 15 hours, the solvent was evaporated and purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/3, v / v). The fractions containing the product were combined and evaporated to give the title compound as a yellow oil.
8 g were obtained. (K) t-butyl (S) -2- [2- (6-cyano-
Synthesis of 1-ethylindol-2-yl) ethyl] pyrrolidine-1-carboxylate In a 500 ml flask, the compound (13 g) obtained in the above (j) was dissolved in ethanol (250 ml) to give 1
After gradually adding 0% Pd / C (4 g), hydrogen gas was injected, and the mixture was stirred at room temperature for 3 hours. After filtering the reaction product through celite, the solvent was evaporated and purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/3, v / v). The fractions containing the product were combined and evaporated to give 12 g of the title compound as a brown oil
Was obtained. ¹ H-NMR (CDCl ₃ ); δ = 7.60 (m, 2
H), 7.28 (m, 1H), 6.36 (s, 1H),
4.15 (m, 2H), 3.94 (m, 1H), 3.7
2 (m, 1H), 3.38 (m, 3H), 2.76
(T, 2H), 1.46 (s, 9H), 1.39 (m,
3H) (l) 1-ethyl-2- [2-((S) -pyrrolidine-
Synthesis of 2-yl) ethyl] indole-6-carbonitrile In a 250 ml flask, the compound (3.7 g) obtained in the above (k) was dissolved in methylene chloride (100 ml), and then trifluoroacetic acid (0 ° C) was added. 18.2 ml) was added slowly. After the reaction solution was stirred at room temperature for about 2 hours, methylene chloride (100 ml) was added and diluted with water. After washing three times with a saturated aqueous solution of sodium bicarbonate, the aqueous layer was extracted three times with methylene chloride. The combined organic extracts were dried (MgSO ₄ ) and the residue was purified by silica gel column chromatography (eluent: methylene chloride / methanol = 3/1, v / v). The fractions containing the product were combined and evaporated to give 2.2g of the title compound as a pale yellow foam. ¹ H-NMR (CDCl ₃ ); δ = 7.48 (m, 2
H), 7.28 (m, 1H), 6.33 (s, 1H),
4.03 (m, 2H), 3.58 (m, 1H), 3.2
7 (m, 2H), 2.85 (m, 2H), 2.35
(M, 1H), 2.11 (m, 3H), 2.00 (m,
1H), 1.80 (m, 1H), 1.27 (t, 3H) (m) t-butyl (R) -2-[[(S) -2- [2
Synthesis of-(6-cyano-1-ethylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidine-1-carboxylic acid ester The compound (17 g) obtained in (1) above and (R) -N-
After dissolving (t-butoxycarbonyl) proline (17.8 g) in methylene chloride (350 ml), WS
CI · HCl [1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride] (18.3 g) was added, and the mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction product, extracted twice with methylene chloride, and the extracts were combined, dried (MgSO ₄ ), and concentrated. The residue was purified by silica gel column chromatography (eluent: methylene chloride / methanol = 50/1, v / v) to obtain 24 g of the title compound as a white foam. ^{ES-MS; 465 (M +} 1) + 1 H-NMR (CDCl 3); δ = 7.51-7.60
(M, 2H), 7.24-7.32 (m, 1H), 6.
33-6.41 (m, 1H), 4.47-4.52
(M, 1H), 4.28-4.40 (m, 1H), 4.
16 (q, J = 7.15 Hz, 2H), 3.62-3.
79 (m, 2H), 3.44-3.50 (m, 2H),
2.79-2.83 (m, 2H), 1.85-2.15
(M, 10H), 1.40-1.43 (m, 9H),
1.35 (t, J = 7.20 Hz, 3H) (n) 1-ethyl-2- [2-[(S)-[1-
Synthesis of ((R) -pyrrolidin-2-yl) -carbonyl] pyrrolidin-2-yl] ethyl] indole-6-carbonitrile Compound (24 g) obtained in (m) above as a starting material
The reaction was carried out in the same manner as in the above (1), except that was used, to obtain 11 g of the title compound as a white foam. ¹ H-NMR (CDCl ₃ ); δ = 7.56-7.60
(M, 2H), 7.26-7.31 (m, 1H), 6.
43 (s, H), 4.37-4.41 (m, 1H),
4.13-4.20 (m, 3H), 3.61-3.64
(M, 1H), 3.34-3.41 (m, 3H), 2.
78-2.81 (m, 2H), 2.38-2.43
(M, 2H), 1.82-2.17 (m, 8H), 1.
38 (t, J = 7.20 Hz, 3H) (o) ethyl 4-hydroxy- (S) -2-[(t-
Synthesis of (butoxy) carbonylamino] butanoic acid ester (BOC) -L) -homoserine (1.5 g) was dissolved in a mixture of acetone (15 ml) and dimethylformamide (1.5 ml), and then potassium carbonate (1.04 g). ) And iodoethane (16.4 ml) were added, and the mixture was stirred at room temperature for 3 days. The reaction solution was evaporated under reduced pressure, diluted with ethyl acetate, and washed with water. After drying over anhydrous magnesium sulfate and filtering, the residue obtained by evaporating the obtained filtrate under reduced pressure was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/2, v / v) to obtain white. 1.6 g of the title compound was obtained as a solid. ¹ H-NMR (CDCl ₃ ); δ = 5.36 (brs,
1H), 4.45-4.53 (m, 1H), 4.22
(Q, 2H, J = 7.15 Hz), 3.62-3.79
(M, 2H), 3.15 (brs, 1H), 2.11
2.19 (m, 1H), 1.61-1.66 (m, 1
H), 1.46 (s. 9H), 1.25 (t, 3H, J
= 7.13 Hz) (p) Synthesis of ethyl 4-bromo- (s) -2-[(t-butoxy) carbonylamino] butanoic acid ester The compound (863 mg) obtained in (o) above was methylene chloride (15 ml). And then triphenylphosphine (1.37 g) and carbon tetrabromide (CBr ₄ ;
31g) and stirred at room temperature for 1.5 hours. The residue obtained by evaporating the reaction mixture under reduced pressure was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/8, v / v) to obtain 690 mg of the title compound as a white solid. ES-MS: 333 (M + 23) ⁺ (q) ethyl 4-[(R) -2-[[(S) -2-
Synthesis of [2- (6-cyano-1-ethylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-(S) -2-[(t-butoxy) carbonylamino] butanoate (n) After dissolving the compound (641 mg) obtained in the above and the compound (600 mg) obtained in the above (p) in acetonitrile (10 ml), N, N-diisopropylethylamine (0.676 ml) is added, and the mixture is heated under reflux for 4 hours. Stirred. The reaction mixture was evaporated under reduced pressure, and the obtained residue was diluted with methylene chloride and washed with water. After drying over anhydrous magnesium sulfate and filtering,
The filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methylene chloride / methanol = 20/1, v / v) to obtain 890 mg of the title compound as a white foamy solid. ^{ES-MS: 593 (M +} 23) + 1 H-NMR (CDCl 3); δ = 7.26-7.62
(M, 3H), 6.45 (s, 1H), 6.08-6.
11 (m, 1H), 4.10-4.40 (m, 7H),
3.51-3.61 (m, 2H), 3.17-3.32
(M, 2H), 2.70-2.83 (m, 3H), 2.
26-2.49 (m, 3H), 1.75-1.99
(M, 10H), 1.29-1.40 (m, 12H),
1.21 (t, 3H, J = 7.12 Hz) (r) ethyl (S) -2-amino-4-[(R) -2
Synthesis of-[[(S) -2- [2- (6-cyano-1-ethylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl] butanoic acid ester Compound obtained in (q) above as a starting material (890mg)
The reaction was carried out in the same manner as in the above (1) except for using, to obtain 625 mg of the title compound as a white foam. (S) ethyl 4-[(R) -2-[[(S) -2-
Synthesis of [2- (6-cyano-1-ethylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-(S) -2- (acetylamino) butanoic acid ester The compound obtained in the above (r) ( After dissolving 500 mg) in methylene chloride (10 ml), triethylamine (0.28 ml) was poured under an ice bath, and acetyl chloride (0.08 ml) was gradually added dropwise. After 5 minutes, the reaction mixture was diluted with methylene chloride and washed with water. After drying over anhydrous magnesium sulfate and filtration, the filtrate was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: methylene chloride / methanol = 20 /
1, v / v) to give the title compound 49 as a white foamy solid.
0 mg was obtained. ES-MS: 536 (M + 1) ⁺ (t) ethyl 4-[(R) -2-[[(S) -2-
Synthesis of [2- (6-amidino-1-ethylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-(S) -2- (acetylamino) butanoate The compound obtained in the above (s) ( 485 mg) was dissolved in ethanol (50 ml) and cooled to 0 ° C. HCl gas was injected into the reaction solution for 45 minutes, followed by stirring at room temperature overnight.
After the reaction solvent was concentrated under reduced pressure, ethanol (50 m
1) was added and dissolved, and ammonia gas was injected at 0 ° C. for 1 hour. After stirring at room temperature overnight and distillation under reduced pressure, the residue
H-DM1020 silica gel column chromatography (eluent: ethyl acetate / ethanol = 2/1, v / v)
And 317 mg of the title compound was obtained as a slightly yellow foamy solid. ES-MS: 552 (M + 1) ⁺ (u) 4-[(R) -2-[[(S) -2- [2- (6
-Amidino-1-ethylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-
Synthesis of (S) -2- (acetylamino) butanoic acid After dissolving the compound (315 mg) obtained in the above (t) in a mixture of ethanol (4 ml) and water (1.5 ml), potassium hydroxide (48 mg) ) And stirred overnight at room temperature. The residue obtained by evaporating the reaction mixture under reduced pressure was subjected to NH-DM1020 silica gel column chromatography (eluent: ethyl acetate / ethanol = 2/1, v / v).
Purification in v) yielded 253 mg of the title compound as a slightly yellow solid. ES-MS: 525 (M + 1) ⁺ , 547 (M + 23)
^{+ 1} H-NMR (MeOH-d ₄ ); δ = 7.42-8.
13 (m, 3H), 6.52-6.58 (m, 1H),
4.21-4.34 (m, 3H), 3.20-4.11
(M, 5H), 1.40-3.15 (m, 20H),
1.17-1.20 (m, 3H)

[0037]

Example 2 4-[(R) -2-[[(S) -2- [2
-(6-amidino-1-ethylindol-2-yl)
Ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-
Synthesis of (S) -2- (propionylamino) butanoic acid (a) Ethyl 4-[(R) -2-[[(S) -2-
Synthesis of [2- (6-cyano-1-ethylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-(S) -2- (propionylamino) butanoic acid ester Obtained by (r) of Example 1. Compound (620 ml) and propionic acid (0.103 ml) were combined with methylene chloride (1).
2N), N, N-diisopropylethylamine (0.44 ml), 1-hydroxybenzotriazole hydrate (204 mg), WSCI.HCl (289)
mg) were sequentially poured under an ice bath and stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride and washed with water. After drying over anhydrous magnesium sulfate and filtration, the filtrate was evaporated under reduced pressure. The residue is subjected to silica gel column chromatography (eluent: methylene chloride / methanol =
40/1, v / v) to give 575 mg of the title compound as a white foamy solid. ¹ H-NMR (CDCl ₃ ); δ = 8.27-8.46
(M, 1H), 7.30-7.59 (m, 3H), 6.
41 (s, 1H), 4.70-4.73 (m, 1H),
4.26 (brs, 1H), 4.10-4.18 (m,
4H), 3.38-3.68 (m, 3H), 3.13-
3.27 (m, 2H), 2.71-2.80 (m, 3
H), 1.65-2.35 (m, 13H), 1.01-
1.38 (m, 9H) (b) Ethyl 4-[(R) -2-[[(S) -2-
Synthesis of [2- (6-amidino-1-ethylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-(S) -2- (propionylamino) butanoic acid ester The compound obtained in the above (a) ( 565 mg) was dissolved in ethanol (50 ml) and cooled to 0 ° C. HCl gas was injected for 45 minutes and stirred at room temperature overnight. After the reaction solvent was concentrated under reduced pressure, ethanol (50 ml) was added to the residue to dissolve it, and ammonia gas was injected at 0 ° C. for 1 hour. After stirring at room temperature overnight and distillation under reduced pressure, the residue was washed with NH-DM1
020 silica gel column chromatography (eluent:
Purification with ethyl acetate / ethanol = 2/1, v / v)
292 mg of the title compound was obtained as a slightly yellow foamy solid. (C) 4-[(R) -2-[[(S) -2- [2- (6
-Amidino-1-ethylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-
Synthesis of (S) -2- (propionylamino) butanoic acid After dissolving the compound (290 mg) obtained in the above (b) in a mixture of ethanol (3 ml) and water (1.5 ml), potassium hydroxide (58 mg) ) And stirred overnight at room temperature. The residue obtained by evaporating the reaction mixture under reduced pressure was subjected to NH-DM1020 silica gel column chromatography (eluent: ethyl acetate / ethanol = 2/1, v / v).
Purification in v) yielded 170 mg of the title compound as a slightly yellow solid. ^{ES-MS: 539 (M +} 1) + 1 H-NMR (MeOH-d 4); δ = 7.20-7.
81 (m, 3H), 6.29-6.36 (m, 1H),
4.00-4.14 (m, 3H), 3.01-3.58
(M, 4H), 0.73-2.69 (m, 26H)

[0038]

Example 3 4-[(R) -2-[[(S) -2- [2
-(6-amidino-1-methylindol-2-yl)
Ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-
Synthesis of (S) -2- (acetylamino) butanoic acid (a) Ethyl 6-cyano-1-methylindole-2
-Synthesis of carboxylic acid ester A compound (10 g) obtained in (c) of Example 1 was put in a 1-liter flask, and dimethylformamide (70 m
After dissolving in 1), 60% sodium hydride (2.24 g) was slowly added at 0 ° C. After adding iodomethane (436 ml) at -10 to 0 ° C, the mixture was stirred at room temperature for 2 hours. After the reaction solution was cooled, ice was added thereto, the mixture was diluted with water, and extracted three times with ethyl acetate. After the combined organic extracts were dried (MgSO ₄ ) and evaporated, the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/3, v / v). The fractions containing the product were combined and evaporated to give 10.6g of the title compound as a yellow solid. (B) Synthesis of 1-methyl-2- (hydroxymethyl) indole-6-carbonitrile The compound (12.7) obtained in (a) above in a 1 l flask.
8g) and sodium bicarbonate (0.47g)
After dissolving in F (150 ml), it was cooled to 0 ° C. After adding Cal ₂ · H ₂ O (19.75 g) there,
NaBH ₄ (3.18 g) was added slowly. The reaction solution was stirred while gradually raising the temperature from 0 ° C. to room temperature.
After confirming the completion of the reaction by TLC, ice and a catalytic amount of acetic acid were added at 0 ° C., followed by stirring. After evaporating THF in the reaction solution, the residue was diluted with water and extracted three times with ethyl acetate. After the combined organic extracts were dried (MgSO ₄ ) and evaporated, the residue was subjected to silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/2, v / v).
Purified in v). The fractions containing the product were combined and evaporated to give 8.52 g of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ): δ = 7.32-7.65.
(M, 3H), 6.52 (s, 1H), 3.84 (s,
3H), 3.23 (d.2H.J = 2.78 Hz),
2.72-2.78 (m, 1H) (c) Synthesis of (6-cyano-1-methylindol-2-yl) methyltriphenylphosphonium bromide The compound obtained in (b) above in a 500 ml flask (8. 51g) and methylene chloride (150m
After dissolving in 1), the mixture was cooled to 0 ° C. There PBr ₃
After slowly adding (1.72 ml), the mixture was stirred at room temperature for 4 hours. Thereafter, methylene chloride (150 ml) was added, and the mixture was washed with a 10% aqueous sodium carbonate solution, diluted with water, and extracted three times with methylene chloride. The combined organic extracts were dried (MgSO ₄₎ and evaporated, 6-
Cyano-1-methyl-2-bromomethyl-indole was obtained. The obtained compound was dissolved in toluene (130 ml).
Was added and dissolved, and triphenylphosphine (1
3.18 g) was added and the mixture was stirred at reflux temperature for 10 hours.
After cooling to room temperature, diethyl ether was added and the resulting precipitate was filtered and washed several times with diethyl ether. After filtration, the obtained product was dried to obtain 20.78 g of the title compound as a pale brown solid. (D) t-butyl (S) -2- [2- (6-cyano-
Synthesis of 1-methylindol-2-yl) vinyl] pyrrolidine-1-carboxylic acid ester The compound (2) obtained in the above (c) in a 500 ml flask
0.78 g) and the compound (7.28 g) obtained in (i) of Example 1 were mixed with THF: ethanol (1: 1, v / v).
v) After dissolving in the mixed solvent, 1,8-diazabicyclo [5.4.0] undec-7-ene (9.1 ml) was added. After stirring at room temperature for 15 hours, the solvent was evaporated,
The residue was subjected to silica gel column chromatography (eluent:
Purification was performed with ethyl acetate / n-hexane = 1/3, v / v). The fractions containing the product were combined and evaporated to give 8.15g of the title compound as a yellow oil. (E) t-butyl (S) -2- [2- (6-cyano-
Synthesis of 1-methylindol-2-yl) ethyl] pyrrolidine-1-carboxylic acid ester The compound (8.15 g) obtained in the above (b) was dissolved in ethanol (150 ml) in a 500 ml flask, and 10% Pd / C After slowly adding (1.63 g), hydrogen gas was injected and the mixture was stirred at room temperature for 3 hours. After filtering the reaction through celite, the solvent was evaporated and silica gel column chromatography (eluent: ethyl acetate / n
-Hexane = 1/3, v / v). The fractions containing the product were combined and evaporated to give 6.8g of the title compound as a brown oil. ¹ H-NMR (CDCl ₃ ); δ = 7.28-7.60
(M, 3H), 6.36 (s.1H), 3.94 (br
s. 1H), 3.71 (s. 3H), 3.34-3.4.
8 (m, 2H), 2.75-2.80 (m, 2H),
1.75-2.19 (m, 6H), 1.45 (s, 9
H) (f) 1-methyl-2- [2-((S) -pyrrolidine-
Synthesis of 2-yl) ethyl] indole-6-carbonitrile The compound (6.8 g) obtained in (e) above was dissolved in methylene chloride (45 ml) in a 250 ml flask, and then trifluoroacetic acid (15 ml) was added at 0 ° C. Was slowly added. After the reaction solution was stirred at room temperature for about 2 hours, methylene chloride (45 ml) was added and diluted with water. After washing three times with a saturated aqueous solution of sodium bicarbonate, the aqueous layer was extracted three times with methylene chloride. After the combined organic extracts were dried (MgSO ₄ ) and evaporated, the residue was purified by silica gel column chromatography (eluent: methylene chloride / methanol = 3/1, v / v). The fractions containing the product were combined and evaporated to give 4.83 g of the title compound as a pale yellow foam. (G) t-butyl (R) -2-[[(S) -2- [2
Synthesis of-(6-cyano-1-methylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidine-1-carboxylic acid ester The compound (4.8 g) obtained in the above (f) and (R) -N
-(T-butoxycarbonyl) proline (4.48 g)
Was dissolved in methylene chloride (100 ml), and then dissolved in WS.
CI.HCl (4.54 g) was added and the mixture was stirred at room temperature for 2.5 hours. After adding water to the reaction product and extracting twice with methylene chloride, the extracts were mixed and dried (MgSO 4).
₄ ) Concentrated. The residue is subjected to silica gel column chromatography (eluent: methylene chloride / methanol = 5).
0/1, v / v) to give the title compound as a white foam.
16 g were obtained. (H) 1-methyl-2- [2-[(S)-[1-
Synthesis of ((R) -pyrrolidin-2-yl) carbonyl] pyrrolidin-2-yl] ethyl] indole-6-carbonitrile The compound obtained in (g) above as a starting material (4.15 g)
The reaction was carried out in the same manner as in the above (f) except that was used, to obtain 3.1 g of the title compound as a white foam. ¹ H-NMR (CDCl ₃ ): δ = 7.27-7.58
(M, 3H), 6.41 (s. 1H), 4.18-4.
22 (m, 1H), 3.72 (s, 3H), 3.12-
3.65 (m, 4H), 2.80-2.86 (m, 2
H), 1.83-2.44 (m, 11H) (i) Ethyl 4-[(R) -2-[[(S) -2-
Synthesis of [2- (6-cyano-1-methylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-(S) -2-[(t-butoxy) carbonylamino] butanoate (h) (822 mg) obtained in Example 1 and Example 1
After dissolving the compound (800 mg) obtained in (p) in acetonitrile (15 ml), N, N-diisopropylethylamine (0.82 ml) was added, and the mixture was stirred with heating under reflux for 4 hours. The reaction mixture was evaporated under reduced pressure, and the obtained residue was diluted with methylene chloride and washed with water. After drying over anhydrous magnesium sulfate and filtration, the filtrate was evaporated under reduced pressure. The residue is subjected to silica gel column chromatography (eluent: methylene chloride / methanol =
(20/1, v / v) to obtain 900 mg of the title compound as a white foamy solid. _{^{1 H-NMR (CDCl 3)}} : δ = 7.29-7.60
(M, 3H), 6.43 (s, 1H), 5.99 (br
s, 1H), 4.26-4.37 (m, 2H), 4.0.
7-4.18 (m, 2H), 3.72 (s, 3H),
3.49-3.57 (m, 2H), 3.14-3.29
(M, 2H), 2.81 (t, 2H, J = 7.97H
z), 2.68-2.77 (m, 1H), 2.26-
2.47 (m, 3H), 1.59-2.02 (m, 11
H), 1.36 (s, 9H), 1.20 (t, 3H, J
= 7.13 Hz) (j) Ethyl (S) -2-amino-4-[(R) -2
Synthesis of-[[(S) -2- [2- (6-cyano-1-methylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl] butanoic acid ester Compound obtained in (i) above as a starting material (900mg)
The reaction was carried out in the same manner as in the above (f), except that was used, to obtain 660 mg of the title compound as a white foam. (K) ethyl 4-[(R) -2-[[(S) -2-
Synthesis of [2- (6-cyano-1-methylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-(S) -2- (acetylamino) butanoic acid ester The compound obtained in the above (j) ( After dissolving 660 mg) in methylene chloride (12 ml), triethylamine (0.38 ml) was poured under an ice bath, and acetyl chloride (0.11 ml) was gradually added dropwise. After 5 minutes, the reaction mixture was diluted with methylene chloride and washed with water. After drying over anhydrous magnesium sulfate and filtration, the filtrate was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: methylene chloride / methanol = 20 /
1, v / v) to afford the title compound 58 as a white foamy solid.
8 mg was obtained. ¹ H-NMR (CDCl ₃ ): δ = 8.48-8.65
(M, 1H), 7.27-7.57 (m, 3H), 6.
39 (s, 1H), 4.64-4.76 (m, 1H),
4.05-4.28 (m, 3H), 3.69 (s, 3
H), 3.03-3.75 (m, 5H), 2.68-
2.84 (m, 3H), 1.65-2.39 (m, 17
H), 1.25 (t, 3H.J = 7.11 Hz) (l) Ethyl 4-[(R) -2-[[(S) -2-
Synthesis of [2- (6-amidino-1-methylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-(S) -2- (acetylamino) butanoate The compound obtained in the above (k) ( (570 mg) was dissolved in ethanol (50 ml) and cooled to 0 ° C. HCl gas was injected into the reaction solution for 45 minutes, followed by stirring at room temperature overnight. After the reaction solvent was concentrated under reduced pressure, ethanol (50 m
1) was added and dissolved, and ammonia gas was injected at 0 ° C. for 1 hour. After stirring at room temperature overnight and distillation under reduced pressure, the residue
H-DM1020 silica gel column chromatography (eluent: ethyl acetate / ethanol = 2/1, v / v)
To give 353 mg of the title compound as a slightly yellow foamy solid. (M) 4-[(R) -2-[[(S) -2- [2- (6
-Amidino-1-methylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-
Synthesis of (S) -2- (acetylamino) butanoic acid After dissolving the compound (350 mg) obtained in the above (1) in a mixture of ethanol (4 ml) and water (1.5 ml), potassium hydroxide (73 mg) ) And stirred overnight at room temperature. The residue obtained by evaporating the reaction mixture under reduced pressure was
H-DM1020 silica gel column chromatography (eluent: ethyl acetate / ethanol = 2/1, v / v)
To give 310 mg of the title compound as a slightly yellow solid. ^{ES-MS: 511 (M +} 1) + 1 H-NMR (MeOH-d 4): δ = 7.29-7.
89 (m, 3H), 6.32-6.43 (m, 1H),
3.89-4.10 (m, 2H), 3.66-3.76
(M, 3H), 3.05-3.65 (m, 4H), 1.
30-2.82 (m, 20H)

[0039]

Example 4 4-[(R) -2-[[(S) -2- [2
Synthesis of-(6-amidino-1-propylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-(S) -2- (acetylamino) butanoic acid (a) Ethyl 6-cyano-1-propylindole −
Synthesis of 2-carboxylic acid ester The compound (20 g) obtained in (c) of Example 1 was placed in a 1-liter flask, and dimethylformamide (200
ml), and 60% sodium hydride (5.6 g) was slowly added at 0 ° C. After 1-bromopropane (14 ml) was added at -10 to 0 ° C, the mixture was stirred at room temperature for 2 hours. After allowing the reaction solution to cool, ice was added, the mixture was diluted with water, and extracted three times with ethyl acetate. After the combined organic extracts were dried (MgSO ₄ ) and evaporated, the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/3, v / v).
The fractions containing the product were combined and evaporated to give 24g of the title compound as a yellow solid. ¹ H-NMR (CDCl ₃ ); δ = 7.75 (m, 2
H), 7.36 (m, 2H), 4.53 (m, 2H),
4.39 (m, 2H), 1.82 (m, 2H), 1.4
2 (t.3H, J = 7.12 Hz), 0.95 (t, 3
(H, J = 7.40 Hz) (b) Synthesis of 1-propyl-2- (hydroxymethyl) indole-6-carbonitrile The compound (2) obtained in the above (a) was placed in a 1-liter flask.
4g) and sodium bicarbonate (0.78g)
After dissolving in F (250 ml), it was cooled to 0 ° C. After addition of _{CaI 2 · H 2 O (41.1g} ) thereto, N
aBH ₄ a (10.58g) was added slowly. The reaction solution was stirred while gradually raising the temperature from 0 ° C. to room temperature.
After confirming the completion of the reaction by TLC, ice and a catalytic amount of acetic acid were added at 0 ° C., followed by stirring. After evaporating THF in the reaction solution, the residue was diluted with water and extracted three times with ethyl acetate. After the combined organic extracts were dried (MgSO ₄ ) and evaporated, the residue was subjected to silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/2, v / v).
Purified in v). The fractions containing the product were combined and evaporated to give 12g of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ): δ = 7.61 (m, 2
H), 7.29 (m, 1H), 6.51 (s, 1H),
4.83 (s, 2H), 4.14 (m, 2H), 2.1
3 (br, 1H), 1.82 (m, 2H), 0.96
(T, 3H.J = 7.34 Hz) (c) Synthesis of (6-cyano-1-propylindol-2-yl) methyltriphenylphosphonium bromide Compound (1) obtained in the above (b) in a 500 ml flask
2 g) was dissolved in methylene chloride (150 ml) and cooled to 0 ° C. There PBr ₃ (2ml)
Was gradually added, followed by stirring at room temperature for 4 hours. afterwards,
After adding methylene chloride (150 ml) and washing with a 10% aqueous sodium carbonate solution, the mixture was diluted with water and extracted three times with methylene chloride. The combined organic extracts were dried (MgSO ₄₎ and evaporated, 6-cyano-1-propyl-2-bromomethyl - was Shutoku indole. After toluene (130 ml) was added to the obtained compound to dissolve it, triphenylphosphine (18.7 g) was added, and the mixture was stirred at a reflux temperature for 10 hours. After cooling to room temperature, diethyl ether was added and the resulting precipitate was filtered and washed several times with diethyl ether. After filtration, the obtained product was dried to obtain 23 g of the title compound as a light brown solid. ¹ H-NMR (MeOH-d ₄ ); δ = 7.83 (m,
3H), 7.65-7.55 (m, 12H), 7.49.
(M, 2H), 7.22 (m, 1H), 6.13 (s,
1H), 3.57 (m, 2H), 1.44 (m, 2
H), 0.68 (t.3H, J = 7.47 Hz) (d) t-butyl (S) -2- [2- (6-cyano-
Synthesis of 1-propylindol-2-yl) vinyl] pyrrolidine-1-carboxylic acid ester The compound (2) obtained in the above (c) in a 500 ml flask
3g) and the compound obtained in (i) of Example 1 (9.96).
g) was dissolved in a THF: ethanol (1: 1, v / v) mixed solvent, and then 1.8-diazabicyclo [5.4.0] was dissolved.
Undec-7-ene (8 ml) was added. 15 at room temperature
After stirring for an hour, the solvent was evaporated and purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/3, v / v). The fractions containing the product were combined and evaporated to give the title compound 13.3 as a yellow oil.
g was obtained. ^{ES-MS: 380 (M +} 1) + 1 H-NMR (CDCl 3); δ = 7.61 (m, 2
H), 7.29 (m, 1H), 6.64 (s, 1H),
6.53-6.25 (m, 2H), 4.20-4.08
(M, 3H), 1.96-1.75 (m, 6H), 1.
43 (br. 9H), 0.95 (m, 3H) (e) t-butyl (S) -2- [2- (6-cyano-
Synthesis of 1-propylindol-2-yl) ethyl] pyrrolidine-1-carboxylic acid ester The compound (1) obtained in the above (d) in a 500 ml flask
3.3 g) in ethanol (150 ml) to give 1
After 0% Pd / C (1.5 g) was gradually added, hydrogen gas was injected and the mixture was stirred at room temperature for 3 hours. After filtering the reaction product through celite, the solvent was evaporated and purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/3, v / v). The fractions containing the product were combined and evaporated to give 9.56g of the title compound as a brown oil. (F) Synthesis of 1-propyl-2- [2-((S) -pyrrolidin-2-yl) ethyl] indole-6-carbonitrile In a 250 ml flask, the compound (9.56 g) obtained in the above (e) was obtained. After dissolving in methylene chloride (45 ml), trifluoroacetic acid (29 ml) was slowly added at 0 ° C. After the reaction solution was stirred at room temperature for about 2 hours, methylene chloride (45 ml) was added and diluted with water.
After washing three times with a saturated aqueous solution of sodium bicarbonate, the aqueous layer was extracted three times with methylene chloride. After the combined organic extracts were dried (MgSO ₄ ) and evaporated, the residue was purified by silica gel column chromatography (eluent: methylene chloride / methanol = 3/1, v / v).
The fractions containing the product were combined and evaporated to give 6.52 g of the title compound as a pale yellow foam. ^{ES-MS: 282 (M +} 1) + 1 H-NMR (CDCl 3); δ = 7.49 (m, 2
H), 7.23 (m, 1H), 6.31 (s, 1H),
3.93 (m, 2H), 3.72 (m, 1H), 3.2
2 (m, 2H), 2.83 (m, 2H), 2.36-
1.93 (m, 5H), 1.75-1.63 (m, 3
H), 0.88 (t.3H, J = 7.33 Hz) (g) t-butyl (R) -2-[[(S) -2- [2
-(6-cyano-1-propylindol-2-yl)
Ethyl] pyrrolidinyl] carbonyl] pyrrolidine-1-
Synthesis of carboxylic acid ester The compound (6.52 g) obtained in the above (f) and (R)-
N- (t-butoxycarbonyl) proline (5.98
g) was dissolved in methylene chloride (100 ml), and WSCI.HCl (9.77 g) was added and the mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction and extracted twice with methylene chloride, then the extracts were combined, dried (MgSO ₄ ) and concentrated. The residue was purified by silica gel column chromatography (eluent: methylene chloride / methanol = 50/1, v / v) to obtain 7.41 g of the title compound as a white foam. (H) 1-propyl-2- [2-[(S)-[1-
Synthesis of ((R) -pyrrolidin-2-yl) carbonyl] pyrrolidin-2-yl] ethyl] indole-6-carbonitrile The compound obtained in (g) above as a starting material (7.41 g)
The reaction was carried out in the same manner as in the above (f) except that was used, to obtain 6.47 g of the title compound as a white foam. (I) Ethyl 4-[(R) -2-[[(S) -2- [2
-(6-cyano-1-propylindol-2-yl)
Ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-
Synthesis of (S) -2-[(t-butoxy) carbonylamino] butanoic acid ester The compound (760 mg) obtained in (h) above and Example 1
The compound (625 mg) obtained in (p) above was dissolved in acetonitrile (40 ml). N-Diisopropylethylamine (0.7 ml) was added, and the mixture was stirred under heating and refluxing conditions for 4 hours. The reaction mixture was evaporated under reduced pressure, and the obtained residue was diluted with methylene chloride and washed with water. After drying over anhydrous magnesium sulfate and filtering,
The filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methylene chloride / methanol = 20/1, v / v) to obtain 540 mg of the title compound as a white foamy solid. ¹ H-NMR (CDCl ₃ ); δ = 7.60 (m, 2
H), 7.30 (m, 1H), 6.36 (s, 1H),
4.41-4.28 (m, 2H), 4.06 (m, 5
H), 3.62 (m, 2H), 3.39-3.18.
(M, 2H), 2.82 (m, 3H), 2.40 (m,
3H), 2.17-1.95 (m, 10H), 1.38
(S, 9H), 1.23 (t, 3H.J = 7.12H
z), 0.97 (t.3HJ = 7.47 Hz) (j) Ethyl (S) -2-amino-4-[(R) -2
Synthesis of-[[(S) -2- [2- (6-cyano-1-propylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl] butanoic acid ester Compound obtained in the above (i) as a starting material (540mg)
The reaction was carried out in the same manner as in the above (f) except that was used, to obtain 440 mg of the title compound as a white foam. ¹ H-NMR (CDCl ₃ ); δ = 7.60 (m, 2
H), 7.30 (m, 1H), 6.45 (s, 1H),
4.24 (m, 4H), 4.10 (m, 2H), 3.9
7 (m, 1H), 3.60 (m, 2H), 3.43
(M, 3H), 2.83 (m, 4H), 2.20 (m,
4H), 1.99 (m, 6H), 1.84-1.77.
(M, 8H), 1.28 (t, 3H, J = 7.12H
z), 0.97 (t.3H.J = 7.46 Hz) (k) Ethyl 4-[(R) -2-[[(S) -2-
Synthesis of [2- (6-cyano-1-propylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-(S) -2- (acetylamino) butanoic acid ester The compound obtained in (j) above ( After dissolving 440 mg) in methylene chloride (12 ml), triethylamine (0.24 ml) was poured in an ice bath, and acetyl chloride (0.069 ml) was gradually added dropwise. After 4 minutes, the reaction mixture was diluted with methylene chloride and washed with water. After drying over anhydrous magnesium sulfate and filtration, the filtrate was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: methylene chloride / methanol = 20 /
1, v / v) to give the title compound 41 as a white foamy solid
0 mg was obtained. ¹ H-NMR (CDCl ₃ ); δ = 7.55- (m, 2
H), 7.26 (m, 1H), 6.41 (s. 1H),
4.74 (m, 1H), 4.29 (m, 1H), 4.1
3 (m, 2H), 4.03 (m, 2H), 3.59
(M, 1H), 3.43 (m, 1H), 3.22 (m, 1H)
1H), 3.09 (m, 1H), 2.77 (m, 3
H), 2.05 (m, 4H), 1.99 (m, 7H),
1.80-1.69 (br. 16H), 1.57 (s,
9H), 1.25 (t, 3H, J = 7.24 Hz),
0.94 (t.3H, J = 7.43 Hz) (l) Ethyl 4-[(R) -2-[[(S) -2-
[2- (6-amidino-1-propylindole-2-
Synthesis of yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-(S) -2- (acetylamino) butanoic acid ester The compound (400 mg) obtained in the above (k) was dissolved in ethanol (40 ml) and cooled to 0 ° C. I let it. HCl gas was injected into the reaction solution for 45 minutes, followed by stirring at room temperature overnight.
After the reaction solvent was concentrated under reduced pressure, ethanol (40 m
1) was added and dissolved, and ammonia gas was injected at 0 ° C. for 1 hour. After stirring at room temperature overnight and distillation under reduced pressure, the residue was subjected to NH-DM1020 silica gel column chromatography (eluent: ethyl acetate / ethanol = 2/1, v / v).
Purify in v) to give 310 mg of the title compound as a slightly yellow foamy solid
Was obtained. ¹ H-NMR (CDCl ₃ ); δ = 8.65 (m, 1
H), 7.80-7.25 (m, 3H), 6.28
(S.1H), 4.55 (brs. 1H), 4.22-
4.03 (m, 5H), 3.56-2.54 (m, 9
H), 2.23-162 (m, 17H), 1.21-
1.14 (m, 6H) (m) 4-[(R) -2-[[(S) -2- [2- (6
-Amidino-1-propylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-
Synthesis of (S) -2- (acetylamino) butanoic acid After dissolving the compound (300 mg) obtained in the above (1) in a mixture of ethanol (3 ml) and water (3 ml),
Potassium hydroxide (73 mg) was added and the mixture was stirred at room temperature overnight. The residue obtained by evaporating the reaction mixture under reduced pressure was washed with NH-
Purification by DM1020 silica gel column chromatography (eluent: ethyl acetate / ethanol = 2/1, v / v) gave 260 mg of the title compound as a pale yellow solid. ^{ES-MS: 539 (M +} 1) + 1 H-NMR (MeOH-d 4); δ = 7.86-7.
26 (m, 3H), 6.41-6.38 (m, 1H),
4.28-4.05 (m, 3H), 3.91 (m, 1
H), 3.62 (m, 1H), 3.47-3.13.
(M, 5H), 2.95-1.66 (m, 20H),
0.84-0.81 (m, 3H) IR (KBr) cm- ¹ ; 3400, 3000, 164
0,1580,1420

[0040]

Example 5 4-[(R) -2-[[(S) -2- [2
-[6-Amidino-1- (2-fluoroethylindole) -2-yl] ethyl] pyrrolidinyl] carbonyl]
Synthesis of pyrrolidinyl]-(S) -2- (acetylamino) butanoic acid (a) Synthesis of ethyl 6-cyano-1- (2-fluoroethyl) indole-2-carboxylate Example 1 in a 1 liter flask The compound (6 g) obtained in (c) above was added thereto, and dimethylformamide (80 m
After dissolving in 1), at 0 ° C., 60% sodium hydride (1.68 g) was slowly added. At -10 to 0 ° C 1-
After adding bromo-2-fluoroethane (2.5 ml), the mixture was stirred at room temperature for 2 days. After cooling the reaction solution, ice was added thereto, and the mixture was diluted with water, and extracted three times with ethyl acetate. The combined organic extracts are dried (MgSO ₄ )
After evaporation, the residue was subjected to silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/3, v
/ V). The fractions containing the product were combined and evaporated to give 6.8g of the title compound as a yellow solid. ¹ H-NMR (CDCl ₃ ); δ = 777 (m, 2
H), 7.34 (m, 2H), 4.64 (m, 2H),
4.42 (m, 2H), 1.43 (m, 6H) (b) Synthesis of 1- (2-fluoroethyl) -2- (hydroxymethyl) indole-6-carbonitrile ), The compound (6.7 g) and sodium bicarbonate (0.15 g) were added, dissolved in THF (100 ml), and cooled to 0 ° C. After addition of _{CaI 2 · H 2 O (11.8g} ) _thereto, it was added NaBH 4 a (1.52 g) slowly. The reaction solution was stirred while gradually increasing the temperature from 0 ° C. to room temperature. After confirming the completion of the reaction by TLC, ice and a catalytic amount of acetic acid were added at 0 ° C., followed by stirring. After evaporating THF in the reaction solution, the residue was diluted with water and extracted three times with ethyl acetate. The combined organic extracts are dried (MgSO ₄ )
After evaporation, the residue was subjected to silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/2, v
/ V). The fractions containing the product were combined and evaporated to give 4.1g of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ); δ = 7.63 (m, 2
H), 7.26 (m, 1H), 6.43 (s. 1H),
4.83 (s, 2H), 4.29 (m, 2H), 1.4
1 (t, 3H) (c) Synthesis of [6-cyano-1- (2-fluoroethyl) indol-2-yl] methyltriphenylphosphonium bromide Compound (4) obtained in the above (b) in a 500 ml flask
g) was added and dissolved in methylene chloride (70 ml), and then cooled to 0 ° C. There PBR ₃ (0.7m
After l) was slowly added, the mixture was stirred at room temperature for 4 hours. Thereafter, methylene chloride (70 ml) was added, washed with a 10% aqueous sodium carbonate solution, diluted with water, and extracted three times with methylene chloride. The combined organic extracts were dried (MgSO ₄₎ and evaporated, 6-cyano-1-
(2-Fluoroethyl) -2-bromoethyl-indole was obtained. Toluene (80m
After l) was added and dissolved, triphenylphosphine (6.35 g) was added, and the mixture was stirred at reflux temperature for 10 hours. After cooling to room temperature, diethyl ether was added and the resulting precipitate was filtered and washed several times with diethyl ether. After filtration, the obtained product was dried to obtain 9 g of the title compound as a light brown solid. (D) t-butyl (S) -2- [2- (6-cyano-
Synthesis of 1- (fluoroethyl) indol-2-yl] vinyl] pyrrolidine-1-carboxylic acid ester In a 500 ml flask, the compound (8.4 g) obtained in (c) above and (i) in Example 1 were obtained. Compound (3.1 g) was added to THF: ethanol (4: 1, v / v)
After dissolving in a mixed solvent, 1.8-diazabicyclo [5.
4.0] Undec-7-ene (3.03 ml) was added. After stirring at room temperature for 15 hours, the solvent was evaporated and purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/3, v / v). The fractions containing the product were combined and evaporated to give 4.58g of the title compound as a yellow oil. (E) t-butyl (S) -2- [2- (6-cyano-
Synthesis of 1- (2-fluoroethyl) indol-2-yl] ethyl] pyrrolidine-1-carboxylic acid ester The compound (4.5 g) obtained in the above (d) was dissolved in ethanol (100 ml) in a 500 ml flask. After gradually adding 10% Pd / C (0.5 g), hydrogen gas was injected and the mixture was stirred at room temperature for 4 hours. After filtering the reaction through celite, the solvent was evaporated and silica gel column chromatography (eluent: ethyl acetate / n-
Hexane = 1/3, v / v). The fractions containing the product were combined and evaporated to give 3.4g of the title compound as a pale yellow oil. ¹ H-NMR (CDCl ₃ ); δ = 7.60 (m, 2
H). 7.28 (m, 1H). 6.36 (s, 1H).
4.15 (m, 2H). 3.94 (m, 1H), 3.7
2 (m, 1H), 3.38 (m, 3H), 2.76
(T, 2H). 1.46 (s, 9H). 1.39 (m,
3H) (f) 1- (2-fluoroethyl) -2- [2-
Synthesis of ((S) -pyrrolidin-2-yl) ethyl] indole-6-carbonitrile The compound (3.3 g) obtained in (e) above was dissolved in methylene chloride (50 ml) in a 250 ml flask, At 0 ° C., trifluoroacetic acid (10.6 ml) was added slowly. After stirring the reaction solution for about 2 hours at room temperature,
Methylene chloride (50 ml) was added and diluted with water. After washing three times with a saturated aqueous solution of sodium bicarbonate, the aqueous layer was extracted three times with methylene chloride. After the combined organic extracts were dried (MgSO ₄ ) and evaporated, the residue was purified by silica gel column chromatography (eluent: methylene chloride / methanol = 3/1, v / v). The fractions containing the product were combined and evaporated to give 2.2g of the title compound as a pale yellow foam. ¹ H-NMR (CDCl ₃ ); δ = 7.48 (m, 2
H), 7.28 (m, 1H), 6.33 (s, 1H),
4.03 (m, 2H), 3.58 (m, 1H), 3.2
7 (m, 2H), 2.85 (m, 2H), 2.35
(M, 1H), 2.11 (m, 3H), 2.00 (m,
1H), 1.80 (m, 1H), 1.27 (t, 3H) (g) t-butyl (R) -2-[[(S) -2- [2
Synthesis of-(6-cyano-1- (2-fluoroethyl) indol-2-yl] ethyl] pyrrolidinyl] carbonyl] pyrrolidine-1-carboxylic acid ester The compound (2.2 g) obtained in the above (f) and ( R) -N
After dissolving-(t-butoxycarbonyl) proline (2.2 g) in methylene chloride (40 ml),
I.HCl (3.26 g) was added and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction and extracted twice with methylene chloride, then the extracts were combined, dried (MgSO ₄ ) and concentrated. The residue was subjected to silica gel column chromatography (eluent: methylene chloride / methanol = 50/1,
v / v) to give 3.0 g of the title compound as a white foam. ^{ES-MS: 465 (M +} 1) + 1 H-NMR (CDCl 3): δ = 7.51-7.60
(M, 2H), 7.24-7.32 (m, 1H), 6.
36-6.41 (m, 1H), 4.47-4.52
(M, 1H), 4.28-4.40 (m, 1H), 4.
16 (q, J = 7.15 Hz, 2H), 3.62-3.
79 (m, 2H), 3.44-3.50. (M, 2
H), 2.79-2.83 (m, 2H), 1.85-
2.15 (m, 10H), 1.40-1.43 (m, 9
H), 1.35 (t, J = 7.20 Hz, 3H) (h) 1- (2-fluoroethyl) -2- [2-
Synthesis of [(S)-[1-((R) -pyrrolidin-2-yl) carbonyl] pyrrolidin-2-yl] ethyl] indole-6-carbonitrile Compound (2) obtained in (g) above 2.9 g), except that (f) was used to obtain 2.1 g of the title compound as a white foam. ¹ H-NMR (CDCl ₃ ); δ = 7.56-7.60
(M, 2H), 7.26-7.31 (m, 1H), 6.
43 (s, 1H), 4.37-4.41 (m, 1H),
4.13-4.20 (m, 3H) 3.61-3.64
(M, 1H), 3.34-3.41 (m, 3H), 2.
78-2.81 (m, 2H), 2.38-2.43
(M, 2H), 1.82-2.17 (m, 8H) 1.3
8 (t, J = 7.20 Hz, 3H) (i) Ethyl 4-[(R) -2-[[(S) -2-
[2- (6-cyano-1- (2-fluoroethyl) indol-2-yl] ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-(S) -2-[(t-butoxy)
Synthesis of carbonylamino] butanoic acid ester The compound (900 mg) obtained in (h) above and Example 1
After dissolving the compound (730 mg) obtained in (p) in acetonitrile (40 ml), N, N-diisopropylethylamine (0.84 ml) was added, and the mixture was stirred for 4 hours under heating and reflux conditions. The reaction mixture was evaporated under reduced pressure, and the obtained residue was diluted with methylene chloride and washed with water. After drying over anhydrous magnesium sulfate and filtration, the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methylene chloride / methanol = 20/1, v / v) to obtain 820 mg of the title compound as a white foamy solid. ¹ H-NMR (CDCl ₃ ); δ = 7.58 (m, 2
H), 7.30 (m, 1H), 6.24 (s, 1H),
4.49 (m, 1H), 4.34 (m, 1H), 4.1
4 (m, 1H), 4.07 (m, 1H), 3.95 (b
r, 1H), 3.82 (m, 2H), 3.25 (m, 2
H), 2.93 (m, 2H), 2.56 (m, 3H),
2.02 (m, 4H), 1.68 (br, 7H), 1.
50 (m, 4H), 1.15 (s, 9H), 0.98
(M, 3H) (j) Ethyl (S) -2-amino-4-[(R) -2
Synthesis of-[[(S) -2- [2- (6-cyano-1- (2-fluoroethyl) indol-2-yl] ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl] butanoic acid ester Starting material (i Compound obtained in () (820 mg)
The reaction was carried out in the same manner as in the above (f) except that was used, to obtain 630 mg of the title compound as a white foam. ¹ H-NMR (CDCl ₃ ); δ = 7.58 (m, 2
H), 7.37 (m, 1H), 6.43 (s, 1H),
4.82 (m, 1H), 4.67 (m, 1H), 4.5
6 (m, 1H), 4.47 (m, 1H), 4.18
(M, 3H), 3.94 (m, 1H), 3.22 (m,
1H), 2.86 (m, 3H), 2.50 (m, 1
H), 2.33 (m, 1H), 2.18-2.00
(M, 8H), 1.81-1.74 (m, 5H), 1.
27 (m, 3H) (k) ethyl 4-[(R) -2-[[(S) -2-
[2- (6-cyano-1- (2-fluoroethyl) indol-2-yl] ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-(S) -2- (acetylamino)
Synthesis of butanoic acid ester After dissolving the compound (628 mg) obtained in the above (j) in methylene chloride (12 ml), triethylamine (0.34 ml) was poured in an ice bath, and acetyl chloride (0.095 ml) was gradually added. Was added dropwise. After 5 minutes, the reaction mixture was diluted with methylene chloride and washed with water. After drying over anhydrous magnesium sulfate and filtration, the filtrate was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: methylene chloride / methanol = 20 /
1, v / v) to afford the title compound 53 as a white foamy solid.
0 mg was obtained. ¹ H-NMR (CDCl ₃ ); δ = 7.59 (m, 2
H), 7.35 (m, 1H), 6.48 (s, 1H),
4.79 (m, 1H), 4.70 (m, 1H), 4.6
3 (m, 1H), 4.46 (m, 1H), 4.38
(M, 1H), 4.34 (br, 1H), 4.16
(M, 2H), 3.61 (m, 1H), 3.48 (m,
1H), 3.24 (m, 1H), 3.12 (m, 1
H), 2.83 (m, 2H), 2.31 (m, 2H),
2.02 (m, 3H), 2.00 (m, 5H), 1.7
3 (m, 8H), 1.29 (m, 3H) (l) Ethyl 4-[(R) -2-[[(S) -2-
[2- (6-Amidino-1- (2-fluoroethyl) indol-2-yl] ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-(S) -2- (acetylamino)
Synthesis of butanoic acid ester The compound (530 mg) obtained in the above (k) was dissolved in ethanol (50 ml) and cooled to 0 ° C. HCl gas was injected into the reaction solution for 45 minutes, followed by stirring at room temperature overnight.
After the reaction solvent was concentrated under reduced pressure, ethanol (50 m
1) was added and dissolved, and ammonia gas was injected at 0 ° C. for 1 hour. After stirring at room temperature overnight and distillation under reduced pressure, the residue was subjected to NH-DM1020 silica gel column chromatography (eluent: ethyl acetate / ethanol = 2/1, v / v).
Purified in v), 430 mg of the title compound as a slightly yellow foamy solid
Was obtained. ¹ H-NMR (CDCl ₃ ); δ = 8.10 (m, 1
H), 7.50-7.39 (m, 2H), 6.37.
(S, 1H), 4.82-4.49 (m, 4H), 4.
27-4.11 (m, 2H), 3.61-3.10
(M, 4H), 2.83-2.67 (m, 3H), 2.
30-1.74 (m, 18H) (m) 4-[(R) -2-[[(S) -2- [2- [6
-Amidino-1- (2-fluoroethyl) indole-
Synthesis of 2-yl] ethyl] pyrrolidinyl] carbonyl] -pyrrolidinyl]-(S) -2- (acetylamino) butanoic acid The compound (430 mg) obtained in the above (l) was treated with ethanol (4 ml) and water (4 ml). After dissolving in the mixture,
Potassium hydroxide (85 mg) was added, and the mixture was stirred at room temperature overnight. The residue obtained by evaporating the reaction mixture under reduced pressure was washed with NH-
Purification by DM1020 silica gel column chromatography (eluent: ethyl acetate / ethanol = 2/1, v / v) gave 230 mg of the title compound as a pale yellow solid. ES-MS: 543 (M + 1) ⁺ , 272 (M / 2 +
1) ¹ H-NMR (MeOH-d ₄ ); δ = 7.86 (m,
1H), 7.52 (m, 1H), 7.31 (m, 1
H), 6.45 (s, 1H), 4.56-4.43.
(M, 2H), 4.09 (m, 2H), 3.65-3.
45 (m, 2H), 3.11 (m, 1H), 2.78
(M, 2H), 2.00-1.67 (m, 18H) IR
(KBr); 3400, 1620, 1470

[0041]

Example 6 5-[(R) -2-[[(S) -2- [2
-(6-amidino-1-ethylindol-2-yl)
Ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-
Synthesis of (S) -2- (acetylamino) valeric acid (a) Benzyl 5-[(R) -2-[[(S) -2-
Synthesis of [2- (6-cyano-1-ethylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-(S) -2-[(t-butoxy) carbonylamino] valeric acid ester Compound (921 mg) obtained in (n) and benzyl 5-bromo- (S) -2-[(t-butoxy)
Carbonylamino] valerate ester (1.1 g) was dissolved in acetonitrile (50 ml), and N, N
-Diisopropylethylamine (0.53 ml) was added, and the mixture was stirred under heating and refluxing conditions for 4 hours. The residue obtained by evaporating the reaction mixture under reduced pressure was diluted with methylene chloride and washed with water. After drying over anhydrous magnesium sulfate and filtration, the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methylene chloride / methanol = 20/1, v / v) to obtain 1.17 g of the title compound as a white foamy solid. ^{ES-MS: 670 (M +} 1) + 1 H-NMR (CDCl 3); δ = 7.63-7.37
(M, 2H), 7.35-7.28 (m, 6H), 6.
45-6.35 (m, 1H), 5.87 (brs, 1
H), 5.20-5.12 (m, 2H), 4.32-
4.13 (m, 4H), 3.57-3.19 (m, 5
H), 2.83-2.74 (m, 2H), 2.66-
1.53 (m, 16H), 1.42 (s, 9H), 1.
39-1.28 (m, 3H) (b) Benzyl (S) -2-amino-5-[(R)-
Synthesis of 2-[[(S) -2- [2- (6-cyano-1-ethylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl] valerate ester The starting material obtained in (a) above Compound (800mg)
The reaction was carried out in the same manner as in Example 1, (l) except for using, to obtain 612 mg of the title compound as a white foam. ¹ H-NMR (CDCl ₃ ); δ = 7.47-7.40
(M, 2H), 7.38-7.34 (m, 6H), 6.
45-6.36 (m, 1H), 5.16 (d, 2H, J
= 10.33 Hz), 4.34-4.15 (m, 3
H), 3.72-3.36 (m, 8H), 2.85-
2.74 (m, 2H), 2.57-1.55 (m, 14
H), 1.38-1.33 (m, 3H) (c) Benzyl 5-[(R) -2-[[(S) -2-
Synthesis of [2- (6-cyano-1-ethylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-(S) -2- (acetylamino) valerate The compound obtained in the above (b) ( After dissolving 400 mg) in methylene chloride (8 ml), triethylamine (0.12 ml) was poured under an ice bath, and acetyl chloride (0.06 ml) was gradually added dropwise. After 5 minutes, the reaction mixture was diluted with methylene chloride and washed with water. After drying over anhydrous magnesium sulfate and filtration, the filtrate was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: methylene chloride / methanol = 20 /
1, v / v) to give the title compound 31 as a white foamy solid
0 mg was obtained. ES-MS: 611 (M) ⁺ (d) ethyl 5-[(R) -2-[[(S) -2-
Synthesis of [2- (6-amidino-1-ethylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-(S) -2- (acetylamino) valerate The compound obtained in the above (c) ( 300 mg) was dissolved in ethanol (30 ml) and then cooled to 0 ° C. HCl gas was injected into the reaction solution for 45 minutes, followed by stirring at room temperature overnight. After the reaction solvent was concentrated under reduced pressure, ethanol (3
0 ml) and dissolved.
Injected for hours. After stirring at room temperature overnight and distillation under reduced pressure, the residue was subjected to NH-DM1020 silica gel column chromatography (eluent: ethyl acetate / ethanol = 2/1, v
/ V) to give 145 m of the title compound as a slightly yellow foamy solid.
g was obtained. (E) 5-[(R) -2-[[(S) -2- [2- (6
-Amidino-1-ethylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-
Synthesis of (S) -2- (acetylamino) valeric acid The compound (145 mg) obtained in the above (d) was dissolved in a mixture of ethanol (1.5 ml) and water (1.5 ml), and then dissolved. Potassium (50 mg) was added and the mixture was stirred at room temperature overnight. The residue obtained by evaporating the reaction mixture under reduced pressure was subjected to NH-DM1020 silica gel column chromatography (eluent: ethyl acetate / ethanol = 2/1, v / v).
Purification was performed in v) to obtain 120 mg of a slightly yellow solid. ES-MS: 539 (M + 1) ⁺ , 577 (M + 38)
^{+ 1} H-NMR (MeOH-d ₄ ); δ = 8.01-7.
30 (m, 3H), 6.44-6.39 (m, 1H),
4.22-4.08 (m, 5H), 3.63-3.50
(M, 3H), 3.37-3.09 (m, 2H), 2.
99-2.41 (m, 5H), 2.27-1.38
(M, 15H), 1.31-1.26 (m, 3H) IR (KBr) cm- ¹ ; 3400, 1640, 158
0,1470,1420

[0042]

Example 7 5-[(R) -2-[[(S) -2- [2
-(6-amidino-1-ethylindol-2-yl)
Ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-
Synthesis of (S) -2- (cyclohexanoylamino) valeric acid (a) Benzyl 5-[(R) -2-[[(S) -2-
Synthesis of [2- (6-cyano-1-ethylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-(S) -2- (cyclohexanoylamino) valerate ester Example 6 (b) Was dissolved in methylene chloride (25 ml), and then cyclohexanoic acid (0.13 ml), N.I. N-diisopropylethylamine (0.17 ml), WSCI.HCl (19
4 mg) was sequentially poured under an ice bath and stirred at room temperature overnight.
The reaction mixture was diluted with methylene chloride and washed with water. After drying over anhydrous magnesium sulfate and filtration, the filtrate was evaporated under reduced pressure. The residue is subjected to silica gel column chromatography (eluent: methylene chloride / methanol =
40/1, v / v) to obtain 426 mg of the title compound as a white foamy solid. ES-MS: 680 (M + 1) ⁺ (b) ethyl 5-[(R) -2-[[(S) -2-
Synthesis of [2- (6-amidino-1-ethylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-(S) -2- (cyclohexanoylamino) valerate ester Obtained in (a) above. Compound (426 mg) was dissolved in ethanol (40 ml) and cooled to 0 ° C. HCl gas was injected into the reaction solution for 45 minutes, followed by stirring at room temperature overnight.
After the reaction solvent was concentrated under reduced pressure, ethanol (40 m
1) was added and dissolved, and ammonia gas was injected at 0 ° C. for 1 hour. After stirring at room temperature overnight and distillation under reduced pressure, the residue was subjected to NH-DM1020 silica gel column chromatography (eluent: ethyl acetate / ethanol = 2/1, v / v).
Purify in v), 270 mg of the title compound as a slightly yellow foamy solid
Was obtained. (C) 5-[(R) -2-[[(S) -2- [2- (6
-Amidino-1-ethylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-
Synthesis of (S) -2- (cyclohexanoylamino) valeric acid After dissolving the compound (260 mg) obtained in (b) above in a mixture of ethanol (3 ml) and water (3 ml),
Potassium hydroxide (87 mg) was added and the mixture was stirred at room temperature overnight. The residue obtained by evaporating the reaction mixture under reduced pressure was washed with NH-
The residue was purified by DM1020 silica gel column chromatography (eluent: ethyl acetate / ethanol = 2/1, v / v) to obtain 172 mg of the title compound as a slightly yellow solid. ^{ES-MS: 607 (M +} 1) + 1H-NMR (MeOH-d 4); δ = 7.90-7.
30 (m, 3H), 6.43-6.39 (m, 1H),
4.20-4.10 (m, 4H), 3.62-3.49
(M, 2H), 3.38-2.40 (m, 7H). 2.
25-1.20 (m, 25H), 1.11 to 1.05
(M, 3H) IR (KBr) cm ^-1 ; 3400, 1640, 154
0,1470,1420

[0043]

【The invention's effect】

EXPERIMENTAL EXAMPLE 1 Inhibitory activity against thrombin After dispensing 20 μl of each concentration of the compound of the present invention dissolved in 50% methanol into a well of a microplate, 125 mM NaCl, 50 mM Tris HC were added.
1 (pH 8.0) and 250 μM synthetic substrate (N-bensoyl-Phe-Val-Arg-p-nitroanilide,
Reaction medium 160 containing Sigma B-7632)
μl was added. A human thrombin solution containing 0.1% bovine serum albumin (5 units / ml, Sigma)
(Sigma) T-6759, Sigma Co. (Sigma) Production) Add 20 μl to start the reaction at room temperature,
After 0 minute, the degree of hydrolysis of the substrate was measured at 405 nm by absorbance. The thrombin inhibitory activity was expressed by expressing the concentration of the compound of the present invention, which showed a change in absorbance of 基準 based on the change in absorbance when the compound of the present invention was not added, as an IC ₅₀ value. The above measurement results for the thrombin inhibitory activity of the present invention are shown in Table 2 below.

[0044]

EXPERIMENTAL EXAMPLE 2 Thrombin Time (TT) Measurement in Rat Plasma S. g. D. Blood was collected from the heart immediately before drug administration using a male rat, and the compound of the present invention dissolved in 50% PEG400 was orally administered, and then blood was collected every 30, 60, 120, and 240 minutes. This blood was mixed with 0.108 M sodium citrate at a ratio of 9: 1, and mixed at 4 ° C. for 5 minutes at 15,000 rpm.
Only plasma was collected by centrifugation at pm and stored at -20 ° C before TT measurement. TT was measured by the following method. Add 50 μl of plasma to Ourens buffer (O
200 μl of wren's buffer) was added, and 100 μl of the diluted plasma was added to a vial for measuring blood coagulation.
Was cultivated at 37 ° C. for 2 minutes. 20 U / ml thrombin 100 previously cultured in this vial
The time to clotting (TT) was measured by adding μl. The amounts of TT in rat plasma after drug administration and TT in rat plasma before drug administration were determined and are shown in Table 2 below.

[0045]

[Table 2]

Embedded image

[0046]

[Experimental Example 3] Pharmacokinetic test Test method: body weight 220 ± 20 g D. Male rats of the strain were fasted for 24 hours, anesthetized with ether, cannulated in the femoral vein and artery, and then intravenously and orally administered the compound of Example 1 dissolved in physiological saline. Immediate methanol was added to the blood collected at each time, followed by centrifugation (15,000 rpm, 5 minutes, 4 ° C.).
The drug concentration in the blood was analyzed by HPLC using an e Array Detector (diode array detector). Test results: The hourly blood concentrations analyzed after intravenous and oral administration of the compound of Example 1 were recorded in Tables 3 and 4, respectively, and the pharmacokinetic parameters were recorded in Table 5. As can be seen from the results recorded in these tables, the compound of Example 1 was rapidly distributed from blood to the body and gradually disappeared when administered intravenously. In addition, when administered orally, the compound of Example 1 was rapidly absorbed, had a long duration in the blood, and had an elimination half-life in the blood.
life) is 253 minutes and the bioavailability is 61.
1% showed very good results. In particular, Table 5 shows the pharmacological experimental parameters of the compound of Example 1 and the control compound (Compound No. 88 of Korean Patent Application No. 97-22566).
As can be seen from the results, the compound of Example 1 improved the blood duration and bioavailability by a factor of about 2 compared to the control compound.

[0047]

[Table 3]

[0048]

[Table 4]

[0049]

[Table 5]

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 403/14 A61K 31/404 A61P 7/02 CA (STN) REGISTRY (STN)

Claims (8)

(57) [Claims] 1. A compound of the following formula 1 and a pharmaceutically acceptable salt thereof: In the formula, n represents an integer of 1 to 3, R ₁ represents lower alkyl optionally substituted by halogen, R ₂ represents hydrogen or lower alkyl, R ₃ represents lower alkyl or C ₃ -C _7. Represents cycloalkyl. 2. n is 2 or 3, R ₁ is methyl,
Represents ethyl, propyl, or 2-fluoroethyl, R ₂ represents hydrogen or ethyl, R ₃ represents methyl,
2. A compound according to claim 1, which represents ethyl or cyclohexyl. 3. 4-[(R) -2-[[(S) -2-
[2- (6-amidino-1-ethylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-(S) -2- (acetylamino) butanoic acid; 4-
[(R) -2-[[(S) -2- [2- (6-amidino-1-ethylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-(S) -2- (propionylamino ) Butanoic acid; 4-[(R) -2-
[[(S) -2- [2- (6-amidino-1-methylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-(S) -2- (acetylamino)
Butanoic acid; 4-[(R) -2-[[(S) -2- [2-
(6-amidino-1-propylindol-2-yl)
Ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-
(S) -2- (acetylamino) butanoic acid; 4-
[(R) -2-[[(S) -2- [2- (6-amidino-1- (2-fluoroethylindol) -2-yl)]
Ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-
(S) -2- (acetylamino) butanoic acid; 5-
[(R) -2-[[(S) -2- [2- (6-amidino-1-ethylindol-2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-(S) -2- (acetylamino ) Valeric acid; 5-[(R) -2-[[(S)
-2- [2- (6-amidino-1-ethylindole-
2-yl) ethyl] pyrrolidinyl] carbonyl] pyrrolidinyl]-(S) -2- (cyclohexanoylamino)
Claim 1 selected from the group consisting of valeric acid
A compound as described. 4. A thrombin inhibitor composition comprising as an active ingredient an effective amount of a compound of formula 1 as defined in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 5. The thrombin inhibitor composition according to claim 4, which is used as an agent for preventing and treating thrombosis. 6. The composition according to claim 4, which is formulated into a preparation for oral administration.
The thrombin inhibitor composition according to any one of the preceding claims. 7. (a) reacting a compound of the following formula 4 with an acyl halide or an organic carboxylic acid in a solvent in the presence of a base to produce a compound of the following formula 3;
The nitrile group of the compound of Formula 3 is converted into an amidino group to produce a compound of Formula 1b, and then (c) if necessary, hydrolyzing the compound of Formula 1b to produce a compound of Formula 1a A method for preparing a compound of Formula 1 and a salt thereof as defined in claim 1. Chemical formula 4 Chemical formula 3 Chemical formula 1b Chemical formula 1a Wherein n, R ₁ and R ₃ are as defined in claim 1, and R ₂ ′ is the same as R ₂ as defined in claim 1, except that hydrogen is excluded. 8. A compound of the following Formula 3 and a salt thereof: Wherein n, R ₁ , and R ₃ are as defined in claim ₁ , and R ₂ ′ is the same as R ₂ as defined in claim 1 except for hydrogen.