JPS60152468A - Novel fredericamycin a derivative - Google Patents

Abstract

NEW MATERIAL:A fredericamycin A derivative expressed by formula I (R is acyl; A is a group expressed by formula II or III). EXAMPLE:Di-n-lauroyltetrahydrofredericamycin A. USE:An antimicrobial agent and anticancer agent much more stable than fredericamycin A. PREPARATION:An antitumore antibiotic substance fredericamycin A, expressed by formula IV, and isolated from a culture of streptomyces grinseus FCRC-48 is catalytically reduced in the presence of H2 and a catalyst, e.g. Pd/C, and then partially oxidized to give tetrahydrofredericamycin A expressed by formula V, which is then acylated with a carboxylic acid expressed by the formula ROH or a reactive derivative thereof in a solvent, e.g. pyridine, if necessary in the presence of a condensing agent, e.g. dicyclohexylcarbodiimide, preferably at 0-4 deg.C for 2-48hr to afford the aimed compound expressed by formula I (A is a group expressed by formula II).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel fredericamycin AF4, and more particularly to a fredericamycin A derivative represented by the following general formula (I).

Conventionally, Streptomyces griseus (Stre-pt
omyces griseus) FCRC-48, an antitumor antibiotic expressed by the following formula ():
[Frederica myctn A (NSC-3
05263) ] is known to be isolated [
J. Antibiotics vol. 34, 1389-1.
4o1 page (1981) and volume 34.

1402-1407 (1981)).

However, frebrimycin A has weak antibacterial activity and is unstable. Therefore, in order to overcome this drawback of flebrimycin A, the present inventor synthesized various derivatives and examined their pharmacological action and stability, and found that flebrimycin represented by the above formula (I) The inventors completed the present invention by discovering that A derivative has excellent antibacterial and antitumor effects and is extremely stable compared to fredericamycin A.

Therefore, the present invention provides a fredericamine A derivative (I) useful as an antibacterial agent and an anticancer agent.

The frebrimycin A derivative (I) of the present invention is further divided into the following two groups of compounds (Ia) and (Ib).

The compound represented by formula (Ia) below is tetrahydrofredericamycin A (I [> , R by conventional acylation methods
It is produced by reacting a carboxylic acid represented by O,i (where R represents an acyl group) or a reactive derivative thereof. Examples of the carboxylic acid represented by ROH include aliphatic carboxylic acids, benzoic acids, Acid, lower alkyl group, lower alkokene group.

Examples include benzoic acid which carries a substituent such as a halogen atom. In addition, as reactive derivatives of carboxylic acids, acid halides, acid anhydrides, mixed acid anhydrides, active esters, etc. are used, and in this case, tetrahydrofletericamycin AK
flL, using 3 to 10 molar equivalents of the carboxylic acid derivative in a solvent such as pyridine at a temperature of 0 to 4°C.
It is preferable to react for 48 hours. It is also possible to directly react tetrahydrofredericamycin A and the above carboxylic acid using a condensing agent such as dicyclohexylcarbodiimide.

The compound represented by formula (Ib) is produced by reducing Fredericamine A ([) with a suitable reducing agent and then acylating it. Although the reduction is carried out using a conventional reducing agent, it is preferable to carry out catalytic reduction by passing hydrogen gas in the presence of a catalyst such as palladium-coated activated carbon or oxidized yamajaku. Acylation is carried out by reacting the obtained reduced product with a carboxylic acid represented by RO)I (R has the meaning described above) or a reactive derivative thereof by a conventional acylation method. Reactive derivatives of carboxylic acids include acid halides, acid anhydrides,
Mixed acid anhydrides, active esters, etc. are used, and in this case, using a carboxylic acid derivative in an amount of 5 to 20 times the molar equivalent of the above-mentioned reduced product, for example, 1 to 4
It is preferable to react for 8 hours. Alternatively, the above-mentioned reduced product and carboxylic acid can be directly reacted using a condensing agent such as dicyclohexylcarbodiimide.

Next, the present invention will be described with reference to reference examples and examples.

Reference example Production of tetrahydrofredericamycin: Fredericamycin A0.505' was added to tetrahydrofuran 30r.
It was dissolved in Ll, 10% palladium and 0.07% on carbon was added, and catalytic reduction was carried out with stirring at room temperature. After 10 hours of reaction, the precipitated yellow reduced product was dissolved in a chloroform-methanol mixture, the palladium on carbon was removed, and a small amount of dimethyl sulfoxide was added to the solution, followed by stirring at room temperature for 3 hours. The precipitated red crystals were recrystallized from PAL and a chloroform-methanol mixture to obtain red crystals of tetranohydrofredericamycin A expressed by the following formula: 0.29? (yield: 60%).

Melting point 300℃ or higher Dioquinane ultraviolet absorption spectrum λmax (ε) 243 (69
,000), 285(18,500), 298(1
, 8,900).

322 (9,500), 337 (11,400),
353 (10,600).

507 (10,600) Infrared absorption spectrum νKBr,, -1aX 1750.1720,1650.1610'I(-NM
R spectrum (δppm) Measured at 90 MHz in a 10:1 mixture of deuterochloroform + 1 trifluoroFll: Ken 10:1 with TMS as an internal standard.

0.88 (t, 3i(), 1.25-1.64(6H
), 3.3 length (t, 2l-1).

3.96 (s, 3M), 6.32 (s, IH
), 6.44 (s', IH).

6.96 (s, IH) mass spectrum/' (EI, 70eV) m/z 5
43 (M+) Elemental analysis value (correspondence) CvH2, NOu (molecular weight 543
．． 53) as CHN Experimental value 66.11 4,65 2.57 Theoretical value 66
．． 29 4,63 2.58 Example 1 Tetrahydrofredericamycin A0.545+- was dissolved in 30 ml of pyridine, and stirred with O'C in hot water -〇-
3.829-lauric acid was added little by little, stirred at 0°C for 2 hours, and then left at 4°C for 2 days. The reaction solution was cooled with ice and poured into 200 ml of 2N acid, and the precipitate was collected, washed with water, and dried. Heat this precipitate in n-hexane for 10 minutes.
After washing twice with 0 ml of water, it was recrystallized from a methanol-ethyl acetate mixture to give di-n-lauroyltetrahydrofredericamycin A [Compound 1: (I) in the formula, R= -C
o(CHz)+oCHs, 1 (yield 75.6%) was obtained.

Melting point 216-217℃ Ultraviolet absorption spectrum λIM'n1n(ε)237
(63,000), 339 (13,700), 35
3(15,100) infrared absorption spectrum νmix
""1780, 1760.1725.1690.165
5.1625'H-NMR spectrum (δppm) in deuterated chloroform with TMS as internal standard, 90 MH
Measured at z.

12.13 (s, IH), 10.08 (b,
LH), 6.79 (s, LH).

6.19 (s, IH), 6.13 (s, LH), 3.8
8 (s, 3H).

3.27 (t, 2H), 2.78 (t, 4H
), 2.45 (m, 4H).

2.0~0.9 (m, 42H), 0.87 (t
, 6H), 0.78 (t, 3i() Example 2 0.54 ”- to tetranohydrofredericamycin
! - was dissolved in pyridine 25 and then dissolved in tetrahydrofuran 5 while stirring at 0°C. /i4 was added to p-chlorobenzoyl chloride o, 52y- over about 30 minutes, and the mixture was stirred at 0°C for 2 hours. The reaction solution was ice-cooled with 2N hydrochloric acid 2
00rnl, the precipitated precipitate was increased in P, washed with water,
Dry.

This precipitate was washed with 100M hot ether and then recrystallized from ethyl acetate to give pale orange-yellow crystals of di-p-chlorobency, A/te) lahydrofredericamycin A [compound] 0.58? (yield 70.7%).

Melting point 289-290°C ・Poor Yanan ultraviolet absorption spectrum λmax nrntε) 245
(93,900), 338 (15,000), 3
52(16,4f)O) Infrared absorption spectrum νZumeiQ"1 1755.1725,1690,1655.1625'
H-NMR spectrum (δpplη) was measured in deuterated chloroform using TMS as an internal standard at 90C2.

12.16 (b, If(), 10.20 (b,
IH), 8.18 (d, 4H).

7.47 (d, 4H), 6', 7'3 (s,
IH), 6.14 (s, 2H).

3.84 (s, 3H), 3.22 (t, 2H), 2.4
5 (m, 4H).

1.7-1.1 (m, 6H), 0.77 (t,
3H) Mass spectrum (EI, 70 eV) m/z 819,821,823 (M) Example 3 Fredericamycin A 0.54 The mixture was stirred at room temperature for 2 hours while introducing hydrogen gas as a 10y-'e catalyst. Next, the reaction solution was cooled with water, 10 d of pyridine was added, and the mixture was heated with N in a nitrogen gas stream.

3.009 ml of 〇-cafuronic anhydride dissolved in 2M N-dimethylformamide was added dropwise over about 30 minutes. 0
After stirring at 4°C for 2 hours, it was left to stand at 4°C for 1 day. The reaction solution was filtered, and the -P solution was poured into 60 rnl of ice-cooled 2N hydrochloric acid, followed by extraction with ethyl acetate.

The ethyl acetate layer was washed successively with dilute hydrochloric acid and water, and dried over anhydrous sodium sulfate. After filtration, ethyl acetate was distilled off under reduced pressure.
100 rnl of n-hexane was added to the residue, and the precipitate deposited was filtered. This precipitate was recrystallized from a mixture of nityl-ethyl acetate and Nishi-icotetra〇-cabroyltetrano.
Hydrofredericamycin A [Compound 3; (1) in the formula,
R--Co(CH2)4CH3 (yield 70.2%) was obtained.

Melting point 175-176°C ・Non ultraviolet absorption spectrum λ nm (ε) aX 238 (52,700), 287 (65,600)
, 338 (16,100).

352 (19,100) 1780, 1745.1715.1660.1655.
1620'f (-NMR spectrum (δppm)) in deuterated chloroform with TMS as internal standard, 90 Ml (
Measured at z.

11.98(s, 1f(), 10.44(b,s,
IK), 7.13(s, 1j().

6.75 (s, LH), 6.14 (s, LH')
, 3.89 (s, 3H).

3.21 (t, 2H), 2.63 (t, 8H
), 2.43 (m, 4H).

2.0-0.7 (m, 42M), 0.72 (t, 3H)
Example 4 0.38 g of Frebrimycin A was dissolved in 7M of N,N-dimethylformamide, and 10% of radium carbon was added.
．． 2 at room temperature while introducing hydrogen gas using 071 as a catalyst.
Stir for hours. Next, the reaction solution was cooled on ice, 7 ml of pyridine was added, and 0.7 ml of p-chlorobenzoyl chloride dissolved in 2 d of N,N-dimethylformamide was added in a nitrogen gas stream.
49- was added dropwise over about 30 minutes. After stirring at 0°C for 2 hours, the mixture was left at 4°C for 1 day. The reaction solution was filtered, and the p solution was poured into 50 ml of ice-cooled 2N hydrochloric acid, and the precipitate was separated, washed with water, and dried. This precipitate was washed twice with hot methanol 50M and then recrystallized from a chloroform-acetate ether mixture to give yellow crystals of leucotetra-p-chloropenzoyltetrahydrofredericamycin A [compound] O,4O? (yield: 51.9 cm).

Melting point 300℃ or higher Ultraviolet absorption spectrum λ7nm (ε) 242 (10
1,4001286 (73,500), 338 (17,
800), 352 (21,200) Infrared absorption spectrum KBrCm-'ax 1750.1720, 1660, 1650.1620'
H-NMR spectrum (δppm) was measured at 90 ME (z) in deuterated chloroform with TMS as an internal standard.

12.06 (b, 1f(), 9.12 (b,
IH), 7.81 (d, 8H).

7.34 (s, IH), 7.11 (d, 8H
), 6.68 (s, iH).

6.10 (s, LH), 3.93 (s, 3H),
3.14 (t, 2H).

2.43 (m, 4H), 1.7~1.1 (m,
6H), 0.82 (t, 31() Examples 5 to 7 The following compounds were obtained in the same manner as in Example 1 or 2.The compounds were represented by R and A in formula (1). .

Melting point: 278-279°C, pale orange-yellow crystalline, ultraviolet absorption spectrum: λmax nm (ε) 237 (
59,500), 338 (13,800), 352
(15,100) Infrared absorption spectrum
n-1rnax 1780, 1760.1725.16 (10,1660
, 1625'H-NMR spectrum (δppm)li
90M in ri o o form with TMS as internal standard.
Measured with H2.

12.08 (s, In), 10.20 (b, s,
IH), 6.81 (s.

IH), 6.20(s, IH), 6.15(s,
IH), 3.90 (s.

3H), 3.28 (t, 2H), 2.83 (
q, 4H), 2.45 (m.

4H), 1.7-1.1 (m, 6H), 1.3
5 (t, 6H), 0.77 (t, 3f() Mass spectrum (EI, 70eV) m/z 655
(M+) Compound 6 Melting point 254-255°C, pale orange yellow crystal Ultraviolet absorption spectrum λrn”” ni (g) 237 (66,80
0), 339(14,600), :353(16,
200) Infrared absorption spectrum yKBr sub-1aX 1780, 1760.1725.1690.1660.
1625'H-NMR spectrum (δppm) Measured at 90 mm in deuterated chloroform using TMS as an internal standard.

12.07 (S, IH), 10.74 (s,
LH), 6.73 (s, IH).

6.14 (s, 2H), 3.88 (s, 3H),
3.24 (t, 3H).

2.79 (t, 4H), 2.44 (m, 4H
), 2.0-1.0 (m, 18H).

0.91 (t, 6H), 0.73 (t, 3H
) Mass spectrum (El, 70eV) m/z 73
9 (M+) Melting point: 290-292°C, pale orange-yellow crystalline dioquinane UV absorption spectrum λ nm (ε) aX 239 (79,700), 338 (14,200),
352(15,200)KBr -1 Infrared absorption spectrum νmax cn11755.1
725,1690,1655.1625'H-NMR spectrum (δppm) Measured at 90 MHz in deuterated chloroform with TMS as an internal standard.

12.10 (b, s, IH), 8.70 (
b, LH), 8.22 (d.

4H), 7.56 (m, 6H), 6.74 (s, IH)
, 6.14 (s.

LH), 6.10 (s, IH), 3.84 (s, 3H)
, 3.22 (t.

2H), 2.45 (m, 4H), 1.7-1.0 (m,
6H), 0.83 (t, 3H) Mass spectrum (EI, 70eV) m/z 751
(M'') Examples 8 to 9 The following compounds were obtained in the same manner as in Example 3 or 4.

The compounds are represented by R and A in formula (I).

Melting point: 255-256℃, yellow crystalline diochitan Ultraviolet absorption spectrum: λmax nm (ε) 238
(51,300), 287 (64,900), 3
38 (15,900).

352 (19,000) Infrared absorption spectrum ν to tz-'1780.17
45,1715,1660,1655.1620')I
-NMR spectrum (δppm) in deuterated chloroform,
Measured at 90 Ml (z) with TMS as internal standard.

12.02(s, 1i(), 10.48(b, s
, 1f(), 7.15(s.

IH), 6.75 (s, If(), 6.14
(s, IH), 3.89 (s.

3H), 3.21(t, 2H), 2.67(q,
81 (), 2.42 (m.

4H), 1.7-1.1 (m, 6H), 1.3
1(t, 12H), 0.73(t, 3n) Mass spectrum (EI, 70eV) m/z 769
(M) Compound 9 Melting point: 229-230°C, yellow crystal dionene UV absorption spectrum λmax ”” (ε) 236
(82,200), 287 (69,800), 3
39 (16,900).

352 (20,300) KBr - Infrared absorption spectrum νmax crn, '175
0, 1715.1660.1650.1620'H-N
MR spectrum (δppm) in deuterated chloroform, TM
It was measured at 90 Mn2 using S as an internal standard.

12.00 (b, s, IH), 9.70 (b
, IH), 7.89 (d.

8H), 7.33 (s, IH), 7.06 (m
, 12H), 6.63 (s, IH), 6.0
7 (s, LH), 3.90 (s, 3H), 3.
10 (t, 2H), 2.41 (m, 4H),
1.7-1.0 (m, 6H).

0.79 (t, 3H).

that's all

Claims (1)

[Claims] 1. The following general formula (I) (In the formula, R represents an acyl group, and A is A fredericamycin A derivative represented by