JPH0459758A - Oligo-n-methylpyrrolecarboxamide derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (n is an integer of 1-4) or pharmaceutically acceptable salts thereof. EXAMPLE:2-(1-Methyl-4-formylaminopyrrole-2-carboxamido)-1-di(2-aminoet hyl) aminoethane. USE:An antitumor agent and an antiviral agent. PREPARATION:(A) The nitro group of a compound, expressed by formula III and obtained from a compound expressed by formula II by a well-known method is reduced into amino group and the resultant compound is then reacted with a compound expressed by formula II. The aforementioned reaction, as necessary, is repeated to provide a compound expressed by formula IV. (B) The nitro group of the compound expressed by formula III or IV is subsequently reduced into amino group and the obtained compound is then formylated to afford a compound expressed by formula V. (C) The resultant compound expressed by formula V is then catalytically reduced to de-esterify the benzyl group. The prepared compound is further reacted with N-hydroxysuccinimide to provide a compound expressed by formula VI. (D) The resultant compound is then reacted with tris(2-aminoethyl)amine to afford the objective compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to novel oligo-N-methylpyrrole carboxamide derivatives or pharmaceutically acceptable salts thereof. The compounds of the present invention have excellent antitumor and antiviral activities and are useful as antitumor and antiviral agents.

Conventional technology Netrobusin and distamycin are oligopeptide antitumor antibiotics called lexitropsins, and their mechanism of action is to recognize a specific base sequence in the DNA double helix and bind to its minor group. This is derived from the fact that it exhibits DNA strand cutting activity. However, these compounds have weak affinity with DNA and DNA strand cutting activity.
It is not fully satisfactory as an anticancer agent or an antiviral agent. Many attempts have been made to solve this problem, but no useful compound has yet been obtained.

Problems to be Solved by the Invention An object of the present invention is to provide a compound that has excellent antitumor and antiviral activities and is useful as an antitumor agent and an antiviral agent.

Means for Solving the Problems In the present invention, the oligo-N-methylpyrrole carboxamide derivative of the present invention represented by the general formula (I) can be produced, for example, according to the following reaction scheme.

<Reaction process formula> [In the formula, n represents an integer of 1 to 4. ] or a pharmaceutically acceptable salt thereof.

The compound of the present invention represented by general formula (I) has excellent antitumor and antiviral activities and is useful as an antitumor agent and an antiviral agent.

Pharmaceutically acceptable salts of the compounds of the present invention include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, and sulfuric acid 1, acetic acid, trifluoroacetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, and metal sulfone. Examples include salts with acids and organic acids such as ethanesulfonic acid.

[In each of the above formulas, n is the same as above. ]

(Step A) The compound of formula (II), which is a known compound, is treated by a known method, for example, Heteroc7clss,
27° 1945 (1988) to give the formula % formula % carboxylic acid benzyl ester.

Next, the compound of formula (m) is reacted with a reducing agent in the presence of a metal salt catalyst in a suitable solvent to reduce the nitro group to obtain an amino compound, and then this amino compound and the formula (
By reacting with the compound of II) in a solvent, a compound of general formula (IV) where n is 2 is obtained.

In the above reduction reaction, there are no particular restrictions on the solvent as long as it does not participate in the reaction, and a wide variety of conventionally known solvents can be used, such as alcohols such as methanol and ethanol, ethyl acetate, dimethylformamide, dimethyl sulfoxide, etc. Aprotic solvents can be used alone or in combination. Nickel as a metal salt catalyst,
Halides such as cobalt, copper, and tin, such as nickel chloride and cobalt chloride, are preferably used. As the reducing agent, a wide variety of conventionally known reducing agents can be used, and for example, sodium borohydride, lithium aluminum hydride, etc. are preferably used. The proportion of the reactants to be used is preferably about 1 to 10 moles of the reducing agent and about 1 to 10 moles of the metal salt catalyst per 1 mole of the compound represented by formula (m). Further, the reaction temperature is about 0 to 80°C, preferably about 0°C to room temperature. The reaction usually takes about 0.5 to 20 hours, although it varies depending on the type of solvent, metal salt catalyst, and reducing agent used.

Further, in the reaction between the amino compound and the compound of formula (n), there is no particular restriction on the solvent as long as it does not participate in the reaction, and a wide variety of conventionally known solvents can be used, such as methanol, ethanol, etc. Alcohols, dimethylformamide, dimethylsulfoxide, pyridine, etc. can be used alone or in combination. Considering the yield of the amino compound usually achieved, the compound of formula (II) is generally used in a proportion of 1 mole of the compound of formula (DI).
It is preferable to use it in an amount of about 0.2=3 moles.

The reaction temperature is about -50 to 80°C, and the reaction time is
Although it varies depending on the solvent used, reaction temperature, etc., it is usually 0.2
~24 hours.

A specific example of the above steps will be described in Reference Example 1 below.

A compound of general formula (IV) in which n is 3 or 4 can be obtained by further repeating the above reaction (see Reference Examples 2 and 3).

(Step B) Using the compound represented by formula (m) or the compound represented by general formula (IV) obtained in step A as a raw material, it is treated in the same manner as the reduction reaction in the first half of step A in a suitable solvent. By reacting with a reducing agent in the presence of a metal salt catalyst, the nitro group is reduced to obtain an amino compound.

Next, the amino group of the amino compound is formylated using a mixed acid anhydride obtained from acetic anhydride and formic acid in a suitable solvent to obtain a compound represented by general formula (V). The formylation can be carried out, for example, according to the method described in Japanese Patent Publication No. 16987/1983. More specifically,
There are no particular restrictions on the solvent as long as it does not participate in the reaction, and a wide variety of conventionally known solvents can be used, such as alcohols such as methanol and ethanol, tetrahydrofuran, ether, ethyl acetate, dimethylformamide, dimethyl sulfoxide, etc. Various organic solvents can be used alone or in combination.

Considering the general yield of the amino compound, the proportion of reactants used is 1 mole of the compound represented by formula (III) or (IV): mixed acid anhydride obtained from acetic anhydride and formic acid. It is preferable to use about 1 to 20 moles of the compound. Further, the reaction temperature is about 0 to 80°C, and the reaction usually takes place for about 0.5 to 20 hours.

(Step C) This reaction step is carried out by J, Org, Cheal, 4
6. It can be carried out according to the method described in No. 3492 (19811).

Specifically, the compound represented by the general formula (V) obtained in step B is catalytically reduced in an appropriate solvent in the presence of a catalyst to deesterify the benzyl group to obtain a carboxylic acid compound, and then N in an aprotic solvent such as dimethylformamide or dimethyl sulfoxide in the presence of a condensing agent.
- by reacting with hydroxysuccinimide,
A compound represented by general formula (Vl) is obtained.

In the above catalytic reduction reaction, as a solvent, for example, methanol, ethyl acetate, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, etc. can be used alone or in combination. As the catalyst, for example, palladium-carbon, platinum, etc. can be used. The hydrogen pressure is about normal pressure to 3 atm, preferably about normal pressure to 2 atm, and can be carried out at room temperature.

In addition, in the reaction between the carboxylic acid compound and N-hydroxysuccinimide, examples of the condensing agent include dicyclohexylcarbodiimide, 1-ethyl-3-(3-
Dialkylcarbodiimides such as (dimethylamino)-bropyl]carbodiimide can be mentioned. The proportion of reactants to be used depends on the yield of the carboxylic acid compound, but in general, N-
It is preferable to use about 0.5 to 5 moles of hydroxysuccinimide and about 0.5 to 5 moles of the condensing agent. Also,
The reaction temperature is 0 to 80°C, particularly 0°C when adding a condensing agent, and preferably about room temperature for the reaction. The reaction is usually 0.5
It will be completed in about 30 hours.

(Step D) By reacting the compound represented by the general formula (Vl) obtained in Step C with tris(2-aminoethyl)amine in a suitable solvent, the present invention represented by -saccharide (I) The compound is obtained. As the solvent, for example, aprotic solvents such as dimethylformamide and dimethylsulfoxide can be used alone or in combination. The proportion of the reactants used is:
It is preferable to use about 1 to 10 moles of tris(2-aminoethyl)amine. In addition, the reaction temperature is -30 to 80
The temperature is preferably about ℃. The reaction is usually completed in about 0.5 to 20 hours.

In addition, the compound of the present invention obtained through each reaction of the above steps A to D can be prepared by adding the above-mentioned organic acid or It can be converted into a pharmaceutically acceptable salt form by a conventionally known method such as reaction with an inorganic acid.

Each intermediate obtained in the above reaction scheme, the compound of the present invention, and its salt can be isolated by conventional means commonly used in the art, such as concentration, filtration, recrystallization, and various chromatography.
Refined.

EXAMPLES Next, examples and reference examples will be shown to explain the present invention in more detail.

Reference example 1 1-methyl-4-(1-methyl-4-nitropyrrole-
Synthesis of 1-methyl-4-ditropyrrole-2-carboxylic acid benzyl ester (compound m) 18.5 g (71 mmol)
) and 34.0 g (143 mmof) of nickel chloride were dissolved in 100 methanol and cooled to 0°C. To this, 10.76 g (284 mmol) of sodium borohydride
) was added over 30 minutes, and the reaction solution was returned to room temperature and stirred for 1 hour. Next, methanol was distilled off under reduced pressure, and diluted hydrochloric acid
12, followed by treatment with concentrated aqueous ammonia 10-, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, concentrated, and dried under reduced pressure.

The obtained residue was dissolved in dimethylformamide 20-
At room temperature, 20.0 g (74 mmol) of 1-methyl-4-nitro-2-trichloroacetylpyrrole was added, and 3
Stirred for 0 minutes. Since crystals were precipitated, 200% of ethanol was added thereto, the precipitate was filtered, and 1-methyl-4-
(1-Methyl-4nitropyrrole-2-carboxamide)pyrrole-2-carboxylic acid benzyl ester (compound TV-1) 22. 7 g (yield 83%) was obtained as a yellow powder.

Melting point = 213-214°C Reference example 2 1-methyl-4-[1-methyl-4-(1-methyl-4
-nitropyrrole-2-carboxamide)pyrrole-2
-Synthesis of carboxamidocopyrole-2-carboxylic acid benzyl ester The procedure was repeated in the same manner as in Reference Example 1, except that Compound IV-1 obtained in Reference Example 1 was used in place of Compound ①, 1-methyl-4-[1
-Methyl-4-(l-methyl-4-nitropyrrole-2
-carboxamide)pyrrole-2-carboxamide]virol-2-carboxylic acid benzyl ester (compound ■
-2) was obtained as a yellow powder with a yield of 76%. However, the finally obtained precipitate was isolated by centrifugation (5000 rpm).

Melting point = 151-152°C Reference example 3 1-methyl-4-(1-methyl-4-[1-methyl-4
-(1-methyl-4-nitropyrrole-2-carboxamido)pyrrole-2-carboxamidocopyrrole-2-
Synthesis of pyrrole-2-carboxylic acid benzyl ester (Carboxamide) 1-
Methyl-4-(1-methyl-4-[1-methyl-4-(
1-Methyl-4-nitropyrrole-2-carboxamide) Pyrrole-2-carboxamide] Pyrrole-2-carboxamide) Pyrrole-2-carboxylic acid benzyl ester (compound TV-3) was obtained as an orange powder in a yield of 74%. . However, the final precipitate is centrifuged (
5000 rpm).

Melting point: 252-254°C Example 1 2-(1-methyl-4-formylaminopyrrole-2-
Synthesis of (carboxamide)-1-di(2-aminoethyl)aminoethane (n=1 in compound 1.-carboxamide (I)) (A) Compound m 10.41 g (40 mmol) and nickel chloride 9.51 g ( 40 mmol) was dissolved in a mixed solvent of methanol 200w1Q and ethyl acetate 50ml, cooled to 0°C, and sodium borohydride 6
, 05 g (160 mmol) were added over 30 minutes, and the reaction solution was returned to room temperature and stirred for 1 hour. Next, methanol was distilled off under reduced pressure, and the residue was treated with dilute hydrochloric acid 2011112, then concentrated ammonia water, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate,
It was concentrated and dried under reduced pressure.

(B) A mixed acid anhydride prepared by stirring 18.87 m (20.0 mmol) of acetic anhydride and 7.551112 (200 mmol) of formic acid at 65°C for 2 hours was dissolved in 200 ml of tetrahydrofuran, and the mixture obtained above was dissolved in 200 ml of tetrahydrofuran. A solution of the resulting residue in tetrahydrofuran 200111Q was added dropwise. After stirring at room temperature for 4 hours, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (methanol:chloroform = 1:9) to obtain 1-methyl-4-formylaminopyrrole-2-carboxylic acid benzyl ester 4. .62 g (45% yield) was obtained as a white powder.

(C) Next, 3.498g (13.5mm) of this white powder
ol) and 1 g of 10% palladium-carbon were suspended in methanol and stirred vigorously at room temperature under atmospheric pressure and a hydrogen stream for 1 hour to deesterify. Dry underneath. The obtained residue was dissolved in dimethylform.
Dissolved in amide 511G, added 1.558 g (13-5++ mol) of N-hydroxysuccinimide, and heated to 0°C.
dicyclohexylcarbodiimide 2.790
g (13.5 mmol), return to room temperature, and add 21.
Stir for hours. After the formed precipitate was removed and washed with a small amount of dimethylformamide, the furnace liquid and washing liquid were combined and concentrated under reduced pressure, chloroform was added, and the precipitated crystals were collected.

After washing with chloroform, 2.60 g (yield 72%) of 1-methyl-4-formylaminopyrrole-2-carboxylic acid N-succinimidyl ester was obtained as a white powder.

(D) then tris(2-aminoethyl)amine 292m
While keeping the dimethylformamide solution 1011112 of g (2,00 mmol) at -10 to -20°C, 265 mg (1,00 mmol) of the powder obtained in the above (C) was added.
) in dimethylformamide was added dropwise.

The reaction solution was returned to room temperature and stirred for 12 hours, then concentrated under reduced pressure and purified by silica gel column chromatography (methanol containing 20% aqueous ammonia) to give 2-(1-methyl-4-formylaminopyrrole-2- Carboxamide)-1-di(2-aminoethyl)aminoethane (compound 1) 221n+1 (yield 75%) was obtained as a pale yellow oil.

IH-NMR (D20) δppm: 2.13-2.32 (IOH, m).

2.95 (2H, t, J=6.6Hz).

3.32 (3H, s).

6, 68 (IH, d, J = 2.0Hz).

6.66 (IH, d, J=2.0Hz).

7.66 (IH, s) I R (KB r) ctn-': 3285.16
68,1582,1532゜M5 (FAB) 296 (M''), 319 (M'' +Na) Example 2 Compounds ■-1 to I obtained in Reference Examples 1 to 3 in place of compound ■
Compounds 2 to 4 of the present invention represented by the following general formula (I) were synthesized in the same manner as in Example 1 except that V-3- was used.

◎2-[1-Methyl-4-(1-methyl-4-formylaminopyrrole-2-carboxamide)pyrrole-2-
carboxamide]-1-di(2-aminoethyl)aminoethane (compound 2.n=2)' H-N M R(D
20) δppm: 2.10 to 2.39 (IOH, m
).

2.88 (2H, t, J=7.0Hz).

3.24 (3H, s).

3.27 (3H, s).

6.16 (IH, d, J=2.0Hz).

6.22 (IH, d, J=2.0Hz).

6-54 (IH, d, J=2.0Hz).

6.59 (IH, d, J=2.0Hz).

7.61 (IH, s) I R (KB r) cm'''1: 3349.1641.1581,1539゜M5 (
FAB) 418 (M”), 441 (M” +Na)◎2
-[1-Methyl-4-(1-methyl-4-(1-methyl-4-formylaminopyrrole-2-carboxamide)
Pyrrole-2-carboxamide) Pyrrole-2-carboxamide)-1-di(2-aminoethyl)aminoethane (compound 3°n=3) Melting point 147-150°C IH-NMR (CD30D) δppm: 2, 55-2
．． 75 (IOH, m).

3.39 (2H, t, J=6.1Hz).

3.87 (3H, s).

3.90 (6H, s).

6.81 (IH, d, J=2.0Hz).

6.86 (IH, d, J = 2.0Hz).

6.92 (IH, d, J=2.0Hz).

7, 13 (3H, m) 8, 12 (IH, s) I R (KB r) cm": 3284, 1641 M5 (FAB) 541 (M÷), 563 (M" +Na)◎2-[
1-methyl-4-(1-methyl-4, -(1-methyl-
4-(1-methyl-4-formylaminovirol-2-
carboxamide) pyrrole-2-carboxamide) pyrrole-2-carboxamide) pyrrole-2-carboxamide) -1-di(2-aminoethyl)aminoethane (
Compound 4゜n=4) Melting point: 136-137°C IH-NMR (CD30D) δppm: 2.55-2.
74' (IOH, m).

1Hz).

3.39 (2H, t, J=6゜ 3.87 (3H, s).

3.90 (9H, s).

6.81 (IH, d, J=2゜ 6.87 (IH, d, J=2゜ 6.94 (2H, m).

7.20 (4H, m) 8.13 (IH, s) I R (KB r) cm-1: 3280.1641 M5 (FAB) 663 (M”), 686 (M” +Na) (hereinafter
Top) OHz) OHz)

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, n represents an integer from 1 to 4. ] An oligo-N-methylpyrrole carboxamide derivative or a pharmaceutically acceptable salt thereof.