JP2641906B2 - Mycotrienine compounds - Google Patents

Description

The present invention relates to a novel mycotrienine compound, a method for producing the same, and an antitumor agent containing the compound as an active ingredient.

[Conventional technology]

Ansamycin having antitumor activity in a fermentation product of a new strain belonging to Streptomyces lisiliensis, Streptomyces lisiliensis T-23 (Deposit No. 6141) The following structural formula which is a mycotrienine compound having a skeleton and Are confirmed to be present, and the compounds T-23-II and T
-23-X. The compound T-23-II and its production method are described in Japanese Patent Application No. 56-189237 (JP-A-58-94).
No. 393), and the compound T-23-X and its production method are disclosed in Japanese Patent Application No. 60-84615 (JP-A-61-243064).
No.).

[Problems to be solved by the invention]

The above-mentioned known mycotrienine compound having an ansamycin skeleton is a compound having antitumor activity and expected to be useful as a medicine. By using this as a starting material and chemically modifying it as a starting material, it differs in chemical structure and physical properties from the raw material, but retains the antibiotic properties of the raw material, that is, retains the antitumor activity, It has been a technical problem that has been sought from the viewpoint of increasing the usefulness of the raw material compounds and diversifying the technology to obtain a compound having the possibility of being used as a compound. Thus, when a compound is used for a medicinal purpose, the usefulness of the compound is from various viewpoints, such as direct effects, that is, not only antitumor activity, but also absorbability, degradability,
Since the evaluation is based on various factors such as acute and chronic toxicity, the development of a new compound obtained by adding a compound modification to a parent compound that can withstand such an evaluation is as significant as the development of the parent compound itself. You will have. From the above, the mycotrienine compound obtained by the fermentation method having an ansamycin skeleton is chemically modified with respect to a ring atom on the skeleton,
Thus, an attempt was made to synthesize a novel compound.

[Means for solving the problem]

The present inventors have chemically modified the ring atoms on the skeleton of compound T-23-II or compound T-23-X, which is the above-mentioned mycotrienine compound, to thereby obtain the anti-drug possessed by the parent compound. As a result of research to obtain a novel compound having tumor activity, the following general formula (I) (Wherein, R ₁ represents a hydrogen atom or a hydroxy group, R ₂ and R ₃ are the same or different and represent a lower alkyl group or an aryl group optionally substituted with a lower alkyl group, or R ₂ and R ₃ Is, together with the nitrogen atom to which they are attached, optionally a 5- or 6-membered N- which may further have in the ring a heteroatom selected from O or N.
A mycotrienine compound represented by a heterocyclic group (this N-heterocyclic group represents a ring atom of which may be optionally substituted by a lower alkyl group) has the same anti-tumor activity as the parent compound. Thus, the present invention has been completed.

That is, the present invention provides a condensation reaction of compound T-23-II or compound T-23-X with formaldehyde and a secondary amine (HNR ₂ R ₃ ) to obtain the compound of the above general formula (I). He succeeded.

Accordingly, the present invention relates to a novel mycotrienine compound represented by the above general formula (I).

Further, the present invention provides a compound represented by the above general formula (I) obtained by subjecting a parent compound, compound T-23-II or compound T-23-X, to a condensation reaction with formaldehyde and a secondary amine (HNR ₂ R ₃ ). The present invention also relates to a method for producing a novel mycotrienine compound.

Further, the present invention relates to an antitumor agent containing the novel mycotrienine compound represented by the above general formula (I) as an active ingredient.

The compound represented by the above general formula (I) of the present invention is represented by the following general formula (II) (Wherein R ₁ represents a hydrogen atom or a hydroxy group), formaldehyde and the following general formula (III) Wherein R ₂ and R ₃ are the same or different and represent a lower alkyl group or an aryl group optionally substituted with a lower alkyl group, or R ₂ and R ₃ together with the nitrogen atom to which they are attached And optionally a 5- or 6-membered N-heterocyclic group which may further have a heteroatom selected from O or N in the ring (this N-heterocyclic group may be a lower alkyl group Which can be substituted)).

The condensation reaction of the compound of general formula (II), ie, T-23-II or compound T-23-X, with formaldehyde and a secondary amine is preferably carried out in the presence of an organic solvent at room temperature to
It can be carried out at the reflux temperature of the reaction mixture. However, preferred reaction temperatures are in the range of 50-70 ° C.

Specific examples of the secondary amine that can be used in this reaction include, for example, dialkylamines such as dimethylamine, diethylamine, and di-n-propylamine; diphenylamine;
Examples include diarylamines such as ditolylamine and cyclic amines such as pyrrolidine, piperidine, piperazine, N-methylpiperazine, oxazolysine, morpholine.

The secondary amine used in this reaction is preferably used in an amount equal to or more than the stoichiometric amount with respect to the compound T-23-II or the compound T-23-X. It is used in an amount of ~ 4.0 mol or more. The formaldehyde used in this reaction is secondary
It is used in equimolar amount or slightly more than equimolar amount to the amine, and this formaldehyde is preferably used in the form of formalin, but may also be in the form of paraformaldehyde.

As the organic solvent used in this reaction, for example, tetrahydrofuran, ethers such as ethyl ether,
Esters such as methyl acetate, ethyl acetate, and butyl acetate; and halogenated hydrocarbons such as chloroform and methylene chloride.

After completion of the reaction, a water-immiscible solvent such as chloroform and ethyl acetate is added to the reaction mixture, and unreacted secondary amine is removed by washing with water. Then, a usual production method, for example, chromatography using silica gel, alumina or the like as an adsorbent is used. The desired compound represented by the general formula (I) can be obtained by purifying the compound by E.

Specific examples of the novel mycotrienine compound represented by the general formula (I) thus obtained include a group represented by the following formula:
Compounds represented by the following compound abbreviations are given depending on the combination of R ₁ and the group —NR ₂ R ₃ .

The compound of the present invention thus obtained was then tested for its antitumor activity.

(1) Experimental method CDF1 male mice (5 mice per group) were treated with leukemia cells P388 at 1 ×
10 ⁶ /0.2 ml implanted intraperitoneally. The compound of the present invention is diluted to various concentrations with physiological saline, and from the day after transplantation, 0.1 ml per 10 g of body weight is administered once a day for 5 consecutive days. The control group receives physiological saline. Observation is performed for 30 days, and the median survival days of the compound administration group of the present invention is calculated from the survival days of each mouse. This is divided by the median survival days of the control group and multiplied by 100 to calculate the survival rate (T / C (%)). T / C 125 or more is considered effective.

(2) Experimental results Table 1 shows the antitumor activity of the compounds of the present invention. The compound name used the abbreviation mentioned above. The compound of the present invention has antitumor activity and is expected to be used as an antitumor agent.

Next, the present invention will be described with reference to examples to further specifically illustrate the present invention, but the present invention is not limited to the following examples. In addition, the compound name followed the said abbreviation.

Example 1 (T-23-XV) 2 ml of tetrahydrofuran was placed in a 5 ml glass sealed container, and 124.4 mg of compound T-23-X and 40.5 mg of 37% formalin were taken.
And 45.1 mg of a 50% aqueous dimethylamine solution were added. 70 ℃
After heating for 1 hour at room temperature, the reaction solution was diluted with ethyl acetate.
Dissolved in 10 ml. Ethyl acetate solution 3 times with 5 ml of distilled water,
After washing twice with 5 ml of saturated saline, anhydrous sodium sulfate
0.5 g was added and dried. The anhydrous sodium sulfate was separated, and ethyl acetate was distilled off. Purification by silica gel column chromatography (elution solvent: chloroform / methanol = 30/1) gave 53.3 mg of T-23-XV.

Elemental analysis Theoretical value Actual value C: 68.90 69.02 H: 8.45 8.40 N: 6.18 6.23 O: 16.47 16.35 Mass spectrometry SIMS m / z 680 (M + H) ⁺ ▲ [α] ²⁵ _D ▼ + 113 ゜ (c = 0.126, MeOH) purple External absorption spectrum (in methanol) λmax 261 nm (ε23,200), 271 nm (ε30,800) 282 nm (ε23,400) Red external absorption spectrum (in KBr tablet) νmax 3340,1740,1650,1540,1202,1002cm ^{-1 1} H-NMR (in deuterated chloroform) 3.50,3.70 (1H _{each, d, -CH 2 -N) 6.32} (1H, s, 19-H) 6.60 (1H, s, 23-H) Example 2 (T-23-XVI) 5ml volume glass-made sealed Take 2 ml of tetrahydrofuran in a container and prepare 124.4 mg of compound T-23-X, 48.6 mg of 37% formalin
And 51.0 mg of piperidine. After heating at 70 ° C. for 4 hours to carry out the reaction, the reaction solution was dissolved in 10 ml of ethyl acetate. The post-treatment of the reaction solution and the purification and isolation of the reaction product are described in Example 1.
The same was done. 41.0 mg of T-23-XVI was obtained.

Elemental analysis Theoretical value Actual value C: 70.70 70.30 H: 8.54 8.66 N: 5.84 5.72 O: 15.55 15.32 Mass spectrometry SIMS m / z 720 (M + H) ⁺ ▲ [α] ²⁵ _D ▼ + 165 ゜ (c = 0.132, MeOH) purple External absorption spectrum (in methanol) λmax 261 nm (ε38,500), 271 nm (ε52,200) 282 nm (ε39,700) Red external absorption spectrum (in KBr tablet) νmax 3340,1740,1660,1540,1202,1002cm ^{-1 1} H-NMR (in deuterated chloroform) 3.52,3.70 (1H _{each, d, -CH 2 -N) 6.25} (1H, s, 19-H) 6.57 (1H, s, 23-H) Example 3 (T-23-XVII) 5ml volume glass-made sealed Take 2 ml of tetrahydrofuran in a container and prepare 124.4 mg of compound T-23-X, 40.5 mg of 37% formalin
And 43.5 mg of morpholine. After heating at 70 ° C. for 5 hours to carry out the reaction, the reaction solution was dissolved in 10 ml of ethyl acetate. The post-treatment of the reaction solution and the replication isolation of the reaction product were performed in Example 1.
The same was done. 47.0 mg of T-23-XVII were obtained.

Elemental analysis Theoretical value Actual value C: 68.21 68.32 H: 8.24 8.28 N: 5.82 5.60 O: 17.73 17.80 Mass spectrometry SIMS m / z 722 (M + H) ⁺ ▲ [α] ²⁵ _D ▼ + 118 ゜ (c = 0.144, MeOH) purple External absorption spectrum (in methanol) λmax 261 nm (ε38,400), 271 nm (ε52,900) 282 nm (ε39,800) Red external absorption spectrum (in KBr tablet) νmax 3340,1740,1660,1538,1205,1002cm ^{-1 1} H-NMR (in deuterated chloroform) 6.30 (1H, s, 19-H) 6.60 (1H, s, 23-H) Example 4 (T-23-XVIII) 2 ml of tetrahydrofuran was placed in a 5 ml glass sealed container, and 124.4 mg of compound T-23-X 64.85mg of 37% formalin
And 80.0 mg of N-methylpiperazine. 6 at 70 ° C
After heating for hours and performing the reaction, the reaction solution
Was dissolved. Post-treatment of the reaction solution and replication isolation of the reaction product were performed in the same manner as in Example 1. 80.3 mg of Tp23-XVIII was obtained.

Elemental analysis Theoretical value Actual value C: 68.64 68.72 H: 8.50 8.53 N: 7.62 7.55 O: 15.24 15.20 Mass spectrometry SIMS m / z 734 (M + H) ⁺ ▲ [α] ²⁵ _D ▼ + 112 ゜ (c = 0.1, MeOH) purple External absorption spectrum (in methanol) λmax 261 nm (ε23,100), 271 nm (ε31,200) 282 nm (ε28,700) Red external absorption spectrum (in KBr tablet) νmax 3340,1740,1650,1540,1202,1000cm ^{-1 1} H-NMR (in deuterated chloroform) δ 2.30 (3H, s, N-CH ₃ 3.50,3,72 (each _{1H, d, -CH 2 -N-)} 6.32 (1H, s, 19-H) 6.55 (1H, s, 23-H) Example 5 (T-23-XIX) 5ml volumes Take 2 ml of tetrahydrofuran in a glass sealed container, and prepare 127.6 mg of compound T-23-II and 40.5 mg of 37% formalin.
And 50.0 mg of N-methylpiperazine. 6 at 70 ° C
After heating for a period of time and performing the reaction, the reaction solution was diluted with 10 ml of ethyl acetate.
Was dissolved. Post-treatment after the reaction and purification and isolation of the reaction product were performed in the same manner as in Example 1. 93.0 mg of T-23-XIX was obtained.

Elemental analysis Theoretical value Actual value C: 67.17 67.20 H: 8.32 8.35 N: 7.46 7.46 O: 17.05 16.99 Mass spectrometry SIMS m / z 751 (M + H) ⁺ ▲ [α] ²⁵ _D ▼ + 237 ゜ (c = 0.086, MeOH) purple External absorption spectrum (in methanol) λmax 262 nm (ε32,700), 271 nm (ε42,200) 282 nm (ε33,200), 307 nm (ε3,500) Red external absorption spectrum (in KBr tablet) νmax 3340,1740,1660, 1538,1202,1002cm ^{-1 1} H-NMR (in deutero chloroform) δ 2.32 (3H, s, N -CH 3) 3.57,3,65 (each _{1H, d, -CH 2 -N-)} 6.50 (1H, s, 23-H)

Claims (3)

(57) [Claims] 1. The following general formula (I) (Wherein, R ₁ represents a hydrogen atom or a hydroxy group,, R ₂
And R ₃ are the same or different and represent a lower alkyl group or an aryl group optionally substituted with a lower alkyl group, or R ₂ and R ₃ optionally together with the nitrogen atom to which they are attached 5- or 6-membered N which may have a heteroatom selected from O or N in the ring
A heterocyclic group (this N-heterocyclic group represents a ring atom of which may be optionally substituted by a lower alkyl group). 2. The following general formula (II) (Wherein R ₁ represents a hydrogen atom or a hydroxy group), formaldehyde and the following general formula (III) Wherein R ₂ and R ₃ are the same or different and represent a lower alkyl group or an aryl group optionally substituted with a lower alkyl group, or R ₂ and R ₃ together with the nitrogen atom to which they are attached And optionally a 5- or 6-membered N-heterocyclic group which may further have a heteroatom selected from O or N in the ring (this N-heterocyclic group may be a lower alkyl group Characterized by a condensation reaction with a secondary amine represented by the following general formula (I): (Wherein, R ₁ , R ₂ and R ₃ have the above-mentioned meanings). 3. The following general formula (I) (Wherein, R ₁ represents a hydrogen atom or a hydroxy group, R ₂ and R ₃ are the same or different and represent a lower alkyl group or an aryl group optionally substituted with a lower alkyl group, or R ₂ and R ₃ Is, together with the nitrogen atom to which they are attached, optionally a 5- or 6-membered N- which may further have in the ring a heteroatom selected from O or N.
An antitumor agent comprising a mycotrienine compound represented by the formula (I) as an active ingredient: a heterocyclic group (this N-heterocyclic group represents a ring atom of which may be optionally substituted by a lower alkyl group).