WO1985001049A1

WO1985001049A1 - Safracine derivatives

Info

Publication number: WO1985001049A1
Application number: PCT/JP1984/000411
Authority: WO
Inventors: Yoichi Naka; Satoru Uemori; Yoshifumi Ikeda; Takeki Okumoto
Original assignee: Yoshitomi Pharmaceutical Industries, Ltd.
Priority date: 1983-09-02
Filing date: 1984-08-27
Publication date: 1985-03-14
Also published as: JPS6054386A

Abstract

Safracines derivatives represented by the general formula (I); wherein R1 represents an alkanoyl group containing 1 to 6 carbon atoms, an aroyl group, an arylalkanoyl group, an alkoxycarbonyl group containing 2 to 7 carbon atoms, a carboxyalkanoyl group containing 2 to 7 carbon atoms, an alkylcarbamoyl group containing 2 to 7 carbon atoms, an arylcarbamoyl group, an alkylsulfonyl group containing 1 to 4 carbon atoms or an arylsulfonyl group, and R2 represents a hydrogen atom, a hydroxy group or a cyano group, and pharmaceutically acceptable acid addition salts thereof, having antibacterial and antineoplastic effects and being useful as medicines.

Description

,- Specification

Saflacine derivative

Technical field

The present invention relates to a novel and useful pharmaceutically useful safracin derivative,

Pharmaceutically acceptable acid addition salt thereof, its production method and it

And a pharmaceutical composition comprising

Background art

Antibacterial and antitumor activity from cultures of strains belonging to the genus Pseudomonas

That the production of antibiotics Y-16482

For example, it is known from U.S. Pat. No. 4,407,752.

As an example of this antibiotic Y-164820T substance-producing bacterium,

Pseudomonas f 1 uorescens

A2-2 strains are listed.

Institute of Microbial Industry and Technology (Address: B Yatabe, Tsukuba, Ibaraki, Japan)

Machihigashi 1-chome 1-3) He-Ke Kenjo No. 14 (FERM-BP-14)

Fermentation Research Institute (Juzo, Yodogawa-ku, Osaka, Japan)

Honmachi 2-chome 17-85) has been deposited as IF0 14128.

Subsequently, the chemical structure of this antibiotic Υ-16482 α Ζ

Based on chemistry, nuclear magnetic resonance spectra, X-ray diffraction, etc.

—General formula

WIPO ^ (In the formula, R represents a hydrogen atom or a hydroxyl group.)

It was found that

On the other hand, Shinja et al. Have antitumor activity from the culture of Streptomyces lavendulae No. 314

Isolated from Safraraycin A and analyzed its chemical structure.

HC-C-CH,

II II

0 0

(Experiraentia, vol.36, 1025-1027, 1980).

Therefore, the compound represented by the general formula (A) is a safracin (

Saf racin) (Journal of Antibiotics, vol. 36, 1279-1294, 1983), antibiotics with the symbol R being a hydrogen atom Y-164

82 Substances are safracin A and antibiotic Y whose symbol R is a hydroxyl group

-16482 α substance is called safracin Β.

Disclosure of the invention

The present inventors have found that the activity is higher than safracin,

As a result of various studies to obtain a wide compound, the general formula

Ο ΡΙ WIPO

¾ AT10¾ (I)

NHCOCH HR- ¹

The compound represented by and the acid addition salt thereof were synthesized, thereby completing the present invention.

In the above formula, R ¹ is an alkanoyl group having 1 to 6 carbon atoms (acetinol, propionizole, butylinole, pinolinoole, pentanolinole, heptanol, etc.); Radicals (such as benzoyl and naphthoinole), arylalkanol radicals (such as phenylacetyl), and alkoxycarbonyl radicals having 2 to 7 carbon atoms (methoxycarbonyl, ethoxycarbonyl, and butyl). Carbonyl, tert-butoxycarbonyl, etc.), a carboxyalkanol group having 2 to 7 carbon atoms (such as carboxyacetyl and 3-carboxypropionyl), and alkyl canolebamoyl having 2 to 7 carbon atoms Groups (such as methino-recarno-moi-nore, echino-reka-no-re-no-mo-no-re, and butinore-ka-no-reno-moi / etc.), Etc. Karubamoi Le), the A Kurekinoresu Zoreho Ninore group 1-4悃carbon atoms (main Chinoresu Zoreho Ninore, E Chinoresu Zoreho Ninore, etc. butylsulfonyl) or § Li one Rusunorehoniru group (such as a full e two Rusuruhoniru), R ² Represents a hydrogen atom, a hydroxyl group or a cyano group.

In the compound of the general formula (I), R ² is a hydrogen atom or a hydroxyl group Is a safracin A represented by the above general formula (A)

Or B and general formula

R ¹ -X (Π)

(In the formula, R ¹ is as defined above, and X represents a reactive atom or group such as a halogen atom such as chlorine, bromine or iodine, an acyloxy group or a benzenesulfonyloxy group.)

It is produced by reacting with the compound represented by

The reaction is carried out in a suitable solvent (benzene, toluene, xylene, acetone, titrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, methylenchloride). If necessary, acidifiers (sodium hydroxide, sodium hydroxide, sodium carbonate) in Ride, Chlorohonolem, Ethylene Chloride, etc. or a mixed solvent thereof. In the presence of calcium, sodium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridin, etc.).

When R ² represents a cyano group among the compounds of the general formula (I), the compound obtained as described above, that is, the general formula (I) in which R ² is a hydrogen atom or a hydroxyl group This compound is produced by reacting the above compound with a cyanating agent such as sodium cyanide and potassium cyanide.

The reaction is carried out in a suitable solvent (water, methanol, ethanol, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylsulfoxide, or a mixture thereof). Medium, preferably in the presence of a buffer solution (pH 6 to 8), at room temperature or by heating, for 30 minutes to 10 hours. IPO Furthermore, compounds of general formula (I) wherein R ¹ represents a carboxy alkanoate I le groups can be prepared using the intramolecular acid anhydride, shows the R ¹ Gaa Rukirukarubamoi group or § Li one Rukarubamoi Le group The compounds of the general formula (I) can also be prepared from the corresponding isocyanate compounds.

The compound of the general formula (I) produced in this way can be prepared by a conventional method using anhydrous acid (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) or organic acid (oxalic acid, fumaric acid) Acid, succinic acid, maleic acid, p-toluenesulfonic acid, bamoic acid, etc.) to give the corresponding pharmaceutically acceptable acid addition salts.

The compound of the present invention and its pharmaceutically acceptable acid addition salt have an antibacterial activity against Gram-positive bacteria and Gram-negative bacteria, and have mouse leukemia P — 388 cells, L-12 10 cells, Yoshida sarcoma,

It shows excellent results against Ehrlich's ascites and is useful as an antibacterial or anticancer agent.

Experimental Example 1: Antibacterial activity

The minimum inhibitory concentration for bacteria (M-1C, meg / ml) was determined according to the standard method of the Japanese Society of Chemotherapy. The results are summarized in Table 1. In addition, the compound number corresponds to the example number described later.

Tribtosoy agar medium was used as the test medium, and Tribtosoy agar medium with 10% serum was used as the culture medium for the test bacteria marked with *.

O PI

, WIPO Table 1

Table 1 ¾¾s

Experimental Example 2: Antitumor activity

Group five female CDF i mice of 1 0 ⁸ fine胞No 0. 2 ml Nomausu to (6-7 weeks old) P - 3 8 8 leukemia cells were transplanted intraperitoneally implanted the next day, 5 days after implantation At 9th and 9th H, the test compound dissolved in physiological saline was given to the abdominal cavity, and the survival rate was determined from the median value of the surviving B number. Table 2 summarizes the results. The court rate was determined as follows.

τ

Life extension (%)-X 100

c

(Here, T represents the median survival days of drug-treated mice, and C represents the median survival B number of untreated mice.)

In the table, “Toxic” means that the test compound was given to the P-388 leukemia cell-transplanted mouse and died.

2 tables

WIPO Table continued

OMPI

> WIPO.

NATlO ' ⁵ When the compound of the present invention and a pharmaceutically acceptable acid addition salt thereof are used for treating a tumor, they are used in a mixture with a conventional pharmaceutical additive, and the method of administration includes a general method in the field, That is, subcutaneous, intramuscular or, if necessary, intravenous injection, oral (in the form of tablets, capsules, granules, syrups) or rectal administration and external application Intravenous drip, etc. are applied. <The dosage should be an amount that effectively inhibits the target tumor, and may vary depending on the target animal, tumor type, administration route, dosage form, etc. In general, a dose of about 0.0130.0 mgZ

0.01 1 O mgZkg body weight for oral administration, 0.02 for oral administration

2 O mgZkg body weight is preferred. Dosage should be within 14 times a day

It can be selected as appropriate. Daily dose and dosing schedule

Can be selected appropriately depending on the patient, tumor type, symptoms, etc.

For example, in the case of injections, the range of 0.0140 mg / kg body weight

For oral administration, a range of 0.0280 mgZ kg body weight is preferred.

The compound of the present invention can be used in combination with other antitumor agents.

Formulation Example 1

Compound (I) or its acid addition salt 0.5 mg

Sodium chloride 9 mg

1 ml with distilled water for injection

Injection consisting of

Use this agent alone or as a mixture with physiological saline, ring fluid, etc.

You can do that too.

Formulation Example 2

Compound (I) or its acid addition salt 1. O mg

OMPI WIPO

T10 丄 2

Lactose 45.4 ntg

Flour 15 mg

Fine powdered cellulose 1.5 mg

Methynoresenorelose-0.6 mg

Talc 3 mg

Magnesium stearate 1 mg

Tablets consisting of

Formulation Example 3

Compound (I) or its acid addition salt 2.5 mg

Witebsol E 75 9 22 mg

Witebusonore H is 5 5 3 mg

Suppositories consisting of

(However, Uitebsol is a registered trademark.)

Formulation Example 4

Compound (〖) or its acid addition salt 1.0 mg

Lactose 6 9 mg

Magnesium stearate 1 mg

The above composition is the amount per capsule.

Compound (I) or its acid addition salt and lactose are mixed in the above ratio.

Combine, press and grind and mix with magnesium stearate

You. Fill the mixture with the above amount in each No. 4 power bussel.

You.

Formulation Example 5

Compound (I) or its acid addition salt 1.0 mg

Pore sugar 3 5 0 tng ί Ο ΡΙ 鏺 powder 1 3 5 mg

Methynoresenorelose 3 mg

Fine granules with the above as one dose unit.

Hereinafter, the present invention will be specifically described with reference to Examples, but it is needless to say that the present invention is not limited thereto.

Example 1

Dissolve 1.08 g of safracin B in 1 O ml of methylene chloride, add 0.2 ml of acetic anhydride, and stir at room temperature for 1 hour. After the completion of the reaction, take out two lines with 1 O ml of water, and wash the aqueous layer with ethyl acetate. Next, when the pH is adjusted to 7.5 with sodium bicarbonate, yellow crystals precipitate. Based on this, the product was washed with water and recrystallized from ethyl acetate, to obtain 415 mg of a compound of the general formula (I) in which R ¹ was an acetyl group and R ² was a hydroxyl group as a yellow crystalline powder. . Melting point 1 8 1

~ 1 8 3. c (decomposition)

Example 2

Dissolve 22.3 mg of saflacin A 2 in 5 ml of methylene chloride, add 31.4 mg of methyl isocyanate, and stir in the chamber for 1.5 hours I do. After completion of the reaction, methylene chloride was reduced under reduced pressure, and the residue was recrystallized from ethyl acetate and iso-propyl ether.

A general formula in which R ^{1 is a} methylcarbamoyl group and R ² is a hydrogen atom

130 mg of the compound (I) are obtained as a yellow crystalline powder. Melting point 18 2 to 18 4 (decomposition)

Example 3

30.3 mg of safracin B27 was dissolved in 5 ml of methylene chloride, to which was added 97 l mg of benzenesulfoyluclide, and the mixture was added at room temperature.

, O PI Stir for 1.5 hours. After completion of the reaction, 2 oils are extracted with 5 ral of water, and the aqueous layer is washed with ethyl acetate and adjusted to pH 7.5 with sodium hydrogen carbonate.

This was extracted with ethyl acetate, washed with water, and then dried over anhydrous magnesium sulfate.

Is a phenylsulfonyl group, and R ² is a hydroxyl group.

Is obtained as a white crystalline powder. 1 4 0 'C min.

10 mg of the compound obtained in Example 1 was dissolved in 1 mol of methanol, and a phosphate buffer (ρΗ7) 86 «was added thereto, followed by stirring at room temperature.

12.6 mg of sodium cyanide was added to the reaction mixture in a phosphate buffer (pH

7) Add the solution dissolved in 25.7 ml and stir at room temperature for 1.5 hours.After completion of the reaction, extract with ethyl acetate, wash with water, dry with anhydrous magnesium sulfate, and reduce the ethyl acetate under reduced pressure. . Isopropyl ester is added to the residue and filtered to give 65 mg of a compound of the general formula (I) in which R ¹ is an acetyl group and R ² is a cyano group, as a yellow fluorocrystalline powder. Disassembled from 1 1 5.

Example 5

Dissolve 0.37 mg of safracin B 2 in 5 ml of methylene chloride, add 7.3 mg of benzoyl quencher, and stir at room temperature for 1.5 hours. After the completion of the reaction, extract twice with 5 ml of water, wash the aqueous layer with ethyl acetate, and adjust the pH to 5 with sodium bicarbonate. This is drawn with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The ethyl acetate is concentrated under reduced pressure, and the obtained crystals are recrystallized from a mixed solvent of ethyl acetate and isopropyl ether. Ben

O PI

? ¾ A compound of the general formula (I) in which R ² is a hydroxyl group as a zole group is obtained as a yellow crystalline powder. Decomposed from 1 5 5 'C.

The compounds of the general formula (I) obtained in the same manner as in the above Examples are shown in Table 3. Table 3

While the invention has been fully described in the foregoing specification and the examples contained therein, various changes and modifications can be made without departing from the spirit and scope of the invention.

OMPI WIPO

Claims

1. General formula

Blue

CH

Three

(In the formula, R ¹ is a alkanol group having 1 to 6 carbon atoms, an aryloyl group, an aryl alkanol group, an alkoxycarbonyl group having 2 to 7 carbon atoms, and a 2 to 7 carbon atoms. power Rubokishiarukano I group, an alkyl force Rubamoiru groups from 2 to 7 carbon atoms, § Li one Rukaruno, the 'moil group number 1-4 alkyl sulfonyl group or § Li one Rusuruho alkenyl group having a carbon, R ² is a hydrogen atom , A hydroxyl group or a cyano group.) Or a pharmaceutically acceptable acid addition salt thereof.

2. The compound according to claim 1, wherein R is an acetyl group and R ² is a hydroxyl group, or a pharmaceutically acceptable acid addition salt thereof.

3. The compound according to claim ² , wherein R ^{1 is a} methylcarbamoyl group and R ² is a hydroxyl group, or a pharmaceutically acceptable acid addition salt thereof.

4. General formula

NHCOCH H,

CH-

(In the formula, R 3 represents a hydrogen atom or a hydroxyl group.)

And a compound represented by the general formula

R ¹ -X

(In the formula, R ¹ is an alkanol group having 1 to 6 carbon atoms, an acryl group, an aryl alkanol group, an alkoxycarbonyl group having 2 to 7 carbon atoms, and 2 to 7 carbon atoms. Carboxyl alkanol group, carbon number

2 to 7 alkynolecasolebamoyl groups, arylenocanoleno, 'moinole group, alkylsulfonyl group or arylsulfonyl group having 1 to 4 carbon atoms, X represents a reactive atom or group Show. )

Reacting the compound represented by the formula with the compound obtained as required and a cyanating agent.

Ο ΡΙ IPO (In the formula, R ² represents a hydrogen atom, a hydroxyl group or a cyano group, and R ¹ has the same meaning as described above.)

Or a pharmaceutically acceptable acid addition salt thereof represented by the formula:

5. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutical additive.