CA1056825A - Streptovaricinone c derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
The present invention provides antibiotics which are streptovaricinone C derivatives of the formula (III)

Description

The present invention relates to antibiotics which are referred to as streptovaricinone C derivatives.
Streptovaricins are known antibiotics produced by cultur-ing the strain of Streptomyces 101 species 2494 strain. The chemical formula of Streptovaricin C has been confirmed as follows:

CH~ , C 3 p ~O CH 3 CQOCH I ( I ) ~.
~ O~ CH3 It has been found by the inventors that Streptovaricin C having the formula (I) can be hydrolyzed in an alkaline medium under oxidizing conditions to produce Streptovaricinone C having the formula OH O H 3 :.

H3`~ o ~CH3 HO~/\~I H3 HO~
~C33 (II) 3 - .. .

The present invention provides antibiotics which have excellent antibiotic activity as well as a process for producing . . .
the antibiotics.

The antibiotics of the present invention are Strepto-varicinone C derivatives having the formula ,~
,'', .

.

-~s~

3~ ~ C~3 ¦ O COOCH3 (III) /~ CH30H ~ 3 ~ ~ OH

wherein Z represents a substituent which may also be bonded in t~e ll-position to form an alcohol condensation product.
The Streptovaricinone C derivatives of the present invention may be produced by etherification or esterification of Streptovaricinone C having the formula (II).
The etherification of Strept:ovaricinone C can be cond~
ucted by reaction with a compound of t:he formula Z-hal where Z is as above and hal is a halogen such as Cl, Br or I in the presence of silver oxide in a solvent such as methanol, ethanol, ether 1,2-dimethoxyethane or tetrahydrofuran. Thus Streptovari-cinone C may be dissolved and suspended in the solvent, and sil~er oxide is added in an amount from 0.5 - 5 mole equivalent.
The mixture is stirred at room temperature for a period from 30 -min. to 24 hours to form a suspension of the salt i.e~ the silver salt. Excess a halide having the formula Z-hal is added to the suspension of the salt with stirring to cause reaction thereof.
The reaction may usually be conducted at room temperature for a period of about 30 min. to 72 hours, whereby hydroxyl group at 6-position is etherified. In some cases, hydroxyl group at 8 and 27 position may be etherified.
It is also possible to etherif~ the hydroxyl group at the 6-position, by adding a large excess of a diazoalkane in a solvent to a solution of Streptovaricinone C at room temperature.
..

- 2 -: ,:

The product can be separated and purified by convention-al methods. For example, the reaction mixture is filtered to remove the precipitate of silver halide and the filtrate is condensed anddried at a temperature in the range 35 - 45~C

under reduced pressure, the residue is extracted with an organic solvent, is washed with a dilute solution of sodium bicarbonate and is purified by chromatography or recrystalyzation.
When the halide having the formula Z-hal is acetone halide 6-0-acetonylstreptovaricinone C can be obtained. This 6-0-acetonylstreptovaricinone C can be converted to Streptovari- -cinone C derivatives having the formula `~ ~
CH3 (IV) or 2 0 OH 3 ~ :

C33~C~3 CH3 _ C ~ 3 ~ OH `CH3 (V) ¦¦ ~ OH CH3 ,,: ' :.

", ~ ~:J5~2~;

wherein R represents hydroxyimino group, substituted hydroxyimino group or hydrazon~ group by reaction in the presence of a strong acid, with hydroxylamine, an O-substituted hydroxylamine such as O-methylhydxoxylamine or O-ethylhydroxylamine; or a substituted hydra~ine such as l-methylhydrazine, l-ethylhydrazine, l,l-dimethyl-hydrazine, l,l-diethylhydrazine, l-l-dipropylhydrazine, l,l-dibut-ylhydrazine, l,l-dibenzylhydrazine, l-methyl-l-phenylhydrazine, benzylidenehydrazine, cyclohexylidenehydrazine, N-aminopiperidine, N-aminomorphorine or N-amino-N'-methylpiperazine or a hydrochloride thereof. The reaction is preferably conducted in an inert organic solvent such as benzene, methanol or tetrahydrofuran, especially in methanol under strong acidic conditions especially in the presence of hydxochloric acid.
In order to produce compound (IV), it is preferable that the molar ratio of the hydroxylamine or the hydrazine to 6-O-acetonylstreptovaricinone C is from 1.5 to 5 and the reaction is effected at room temperature with stirring for a period of from

3 min to 3 hours. The extent of khe reaction can be found by a silica gel thin layer chromatography. The products can be separ-ated and purified by the conventional methods. For example, thereaction mixture is extracted with an organic solvent and purified by chromatography or recrystallization.
In order to produce the compound (V), it is preferable that the molar ratio of the hydroxylamine or the hydrazine to 6-O-acetonylstreptovaricinone C is about 10, the reaction being effected especially in the presence of excess of acetic acid, at room temperature for a period of from 0.5 - 2 hours.
6-O-ketonylstreptovaricinone C can be converted by intra-molecula~ aIdol condensation to produce Streptovaricinone C
derivative having the formula :

.. .

CE ~ C ~ CH3 (VI) R'-C ,~ ~ OH l 3 ~ 3 ".
wherein R' represents a lower alkyl group, such as a methyl or ethyl group; an aryl group such as a phenyl group; a heterocyclic group such as 2-furyl group or ~-thienyl group or such a group substituted by a lower alkyl group, a lower alkoxyl group, hydroxyl group, nitro group or a halogen atom. The intramolecular aldol condensation can be effected by adding an organic base to the 6-O-ketonylstreptovaricinone C in the presence of excess acid in an organic solvent. The organic solvent is preferably benzene.
The acid is preferably an organic acid e.g. acetic acid. The organic base is preferably a primary amine or a secondary amine especially benzylamine. The reaction is usually conducted at room temperature for 0.5 to 24 hours. When benzylamine is-used as the organic base, the reaction velocity is high.
The 6-O-ketonylstreptovaricinone C can be produced by reacting a halide having the formula R-CO-CH2-hal with Strepto-varicinone C as previously stated. -The esteri~ication of Streptovaricinone C can be ~ -conducted by reacting an alkali metal salt of Streptovaricinone C with an organic acyl halide, an organic sulfonyl halide or an alkyl halocarbonate. The hydroxyl group at 6-position is converted to Z'O-group wherein Z' represents an alkenoyl group, a benzoyl group, a benzenesulfonyl group, an alkylsulfonyl group or an alkoxycarbonyl group which can have an inert substituent.

The organic aeyl halides, organic sulfonyl halides and alkyl halocarbonates include fatty acid halides, benzoic acid halides, benzenesulfonic acid halide, alkylsulfonic acid halides and methyl chlorocarbonate. The reaction is preferably effeeted in an inert organic solvent, such as tetrahydrofuran, b~ adding said halide at a 1 ~ 3 molar ratio to alkali metal salt of Strepto-varieinone C with stirring at room temperature for a period of from 5 min. to 48 hours.
The Streptovaricinone C derivatives of the present invention have effeetive pharmacologieal properties espeeially high antibiotic aetivity to Gram positive bacteria. The - -Streptovarieinone C derivatives may be administrated as the other antibioties sueh as streptovaricins in various forms ineluding tablets, sùgar eoated tablets, powders, ointments, ereams, capsules, solution suspensions, and emulsions by adding a pharmaeeutically aeeeptable earrier sueh as an organie or inorganie solid or liquid carrier thereto. A suitable dose o~ the Streptovarieinone C derivati~es of the present invention is in a range of 100 mg to 3 g per clay. The eomposition ean eontain other additives and pharmaeeutieal aetive ingredients.
The following Table I lists typieal Streptovarieinone C deri~atives of the present invention and the antibiotie aetivi-ty thereof.
In Table I

.
In vitro microbial activity was determined by the standard method aeeording to the Japanese Chemotherapy Soeiety.
A solution of 10 mg of the drug in 1 ml of ethanol was diluted with 9 ml of 0.01 ~ aq. Tween 80 (a trademark) solution, and the -~ ;
solution was further diluted with the same solution to eoneentra-tions of 1,000, 500, 200, 100 ~ g/ml. A mi~tuxe of 9 ml of warm brain heart infusion agar broth and 1 ml of the drug solution was plaeed in the Petri plate and eooled to room ~ -~ ' . , - 6 - ~

temperature. All test organisms such as Staphylococcus aureus Rosenbach FDA 209P JC-l and Bacllus subtilis ATCC6633 were incu-bated at 37C for 18-20 Hr. in Trypto-Soy broth (Eiken) and ad]usted to 1:108 inoculum, except My~cobacterium smegmatis ATCC
607 which was incubated at 37C for 48 hr. in brain heart infusion agar bxoth containing 5 % glycerol.
The above bacterial solution was streaked on the Petri agar plate containing a drug and incubated at 37C for 18-20 hr., except M ~ smegmatis 607 which was incubated for 48 hr. at 37C. The bacterial solution of Mycobacterium -tuberculosis H37Rv was prepared in the homogenized Tween (a trademark) solution after which it was adjusted to 0.1 mg/ml solution by turbidmetry. A mixture of 4.5 ml of Kirchner semi-liquid agar solution, 0.5 ml o~ horse serum and 0.5 ml or Tween (a trademark) solution was used for the incubation of this bact-erium. One tenth ml of the said bacterial solution was seeded and incubated at 37C for two weeks. The minimum inhibitory concentration (MIC) was the lowest concentration of the drug which prevented visible growth after incubation.
Table 1 . . _ , .
6-O-substituted Streptovaricinones C shown by the formula III

having the following Z group.
.
. , ~-Antiviot-ic activity ~g/mQ
I Melting -point (C) St. aureus Bacil- Myco. Myco.
l 209P us ~meg, tuberc.
No. Z group subtilis 607 H37Rv ~ __ _._ Reference H- 284-285 50 >100 >100 >100 ._ _ _ _. _. _ 1 ¦CH3- 165-167 1 10 2010

4 CH3CH2~H2cH2 154-155 10 5 2050 "~"

~ntiviotic activity ~g/mQ
Melting point (C) St. aureus IBacil- Myco. Myco. ~-209P us smeg. tuberc.
subtilis 607 H37Rv No Z group _ _ CH3~CH2)4-148-149 10 5 5 6 (CH3)2CHCH2CH2150-152 10 5 20 50 7 CH3(CH2)5-131-133 5 2 2 20 8 CH3(CH2)6-128-130 2 _ 0.5 10 9 C1CH2CH2156-158 1 1 _ 20 10 ClCH2CH2CH2- 145-147 5 2 20 10 ~ -11 CH2 = CHCH2- 155-156 2 1 20 20 12 HocH2cH2cH2- 140-141 5 5 0.5 20 13 PH-O-CH2CH2-142-144 2 _ 0.5 5 14 NC-CH2CH2CH~ 158-160 10 20 5 10 15 CH3COCH2-162-163 1 2 _ 10 16 PhCOCH2-144-146 5 20 20 20 17~ ~ COC}~2-~ 163-].65 ~0.5~ - 20 ~lO

18 ~ COCH2162-165 5 _ 10 50 19 C1 ~ COCH2-154-156 10 _ 2 20 20 CH3O ~ COCH2- 153-155 55 5 10 21 ~ CH2-155-156 2 _ 0.5 -5 ;
;'. '~' 22 CH3 ~ CH2136-138 5 _ 0.5 2 '.

23 NO2 ~ ~H2162-164 5 _ 1 5 ' ' :' .

24 ~ CH2~H2-144-146 10 5 10 20 : ' ~ 8 -Melting Antiviotic activity ~g/m~
point (C~ St. aureus Bacil- ~yco. Myco.
209P us smeg. tuberc.
subtilis 607 H37Rv No. Z group _ _. .
~ COOCH2CH2- 145-147 5 _ 1 50 26 CE13CO- 169-171 20 _ _ 5 27 CH3CH2CO- 160-162 10 _ _ 20 28 CH3CEI2CH2CO- 156-157 20 _ _ 5 29 CH3(CH2)3CO- 153-156 2 _ _ CH3(CH2)4CO- 144-147 2-5 _ _ 10 31 Br-CH2CO- 165-168 10 _ _ 5 ~.32 PhCH2CO- 154-155 20 _ _ 5 33 CH3(CH2)3s CH2132-134 5 _ _ 0.5 .

34 ~ S-CH2CO- 150-153 10 _ _ 35 ~ ~ ~ S-CH CO-~139-142 ~10 36 ~ S-CH2CO-142-144 10 _ _0.5 ' 37 ~ H2S-CH2CO- 134-136 5 _ _ ~ -38 CH3 2 . 167-170 1 _ _ 39 ~ SO2- 156-158 2 _ _ 5 Me ~ SO2 162-165 1 _ _ 1 .

41 ~ SO2- 165-167 5 _ _ 2 _ g _ .
.. : . : : .. . . .

~`~3~

Antiviotic acti~ity ~/mQ
___ __ Melting St. aureus Bacil- Myco.iMyco.
point (C) 209P us smeg. tuberc.
Subtilis 607 H37Rv No. Z group _ 42 AcNH S2- 180-184 5 _ _ 43 CH30-CO- 160-163 2 _ _ 10 44 CH3CH2O-CO- 152-154 2 _ _ (cH3)2CHCH2OcO- 150-152 0.2 _ _ 46 CH3(C 2)3 138-141 1 _ _ 47 O-CO- 164-165 5 _ _ 48 CO- 186-188 5 _ _ 1 Table_2 6-O-substituted Streptovaricinones C shown by the formula IV
having the ol~owing R group.
_ I _ ~_ _ No. R group i `

49 =N-O-H 166-167 0.2 100 20 =N-O-CH3 145-147 0.5 0.5 50 20 -51 =N-O-C2H5 142-144 0.5 _ _ 5 52 =N-O-n-C3H7 138-140 5 _ _ 20 53 =N-o-n-c4H9 130-132 2 _ _ 2 54 =N-O-n-C5Hl1 129-132 1 _ _ 2 =N-O-n-C6H13 124-126 2 _ _ 10 56 =N-O-n-CgH19 106-109 10 _ _ 5 57 =N-o-cH2cH ~H2 132-134 2 _ _ 20 58 =N-o-~H2ph 144-145 2 _ _ 10 59 =N-o-c~2cH2oocph 110-113 0.5 _ _ 2 =N-o-cH2cH2~o-ph 106-109 0.5 _ ~ 2 ., . .

- 1 0 - " , _ _ Antiviotic activi ty ~g~ 'm~
Melting St. aureus Bacilus Myco, Myco.
point (C) 209P subtilis Smeg. tuberc.
607 H37Rv No. R group . _ 61 =N-NH-CONH2 236-237 0.5 0.5 50 20 62 ~ =N-NH-CO ~ ~182-183 ~ 20¦ 10 Table 3 6-O-substituted Streptovaricinones C shown by the formula V having the following group.
~ ~ ~ _ No. R group _ . -- _ 63 =N-O-H 189-190 0.2 100 20 64 =N-NHMe 170-171 ().2 _ _ 10 =N-N(Me)2 166-167 ().2 100 50 20 66 =N-NH-CH2CH2OH 170-171 0.2 _ _ 20 67 =N-N(n-C3H7)2 154-155 0.2 _ 10 20 68 =N-N(n-C4Hg)2 140-141 0.2 _ 50 20 69 --N-N(n-CsHl1)2 132-133 < 0.1 _ 10 20 =N-N(n-C6Hl3)2 122-123 2 _ _ >50 71 =N-N(n-C8Hl7)2 97-38 1 _ _ >50 72 ~ N-N(CH2CH=CH2)2 148-149 1 _ _ 20 73 =N-N(Me)Ph 156-157 5 _ >-50 >100 74 =N-N(Et)Ph 153-154 2 _ >100 >100 =N-N=CHPh 166-167 0.2 _ ~100 50 76 =N-N N-Me 174-175 1 _ 20 77 =N-N O 173-174 2 _ 50 20 78 =N-N~ 165-166 0.5 _ 20 20 79 =N-N ~ 170-171 0.5 0.5 50 =N-N ~ ¦ 162-163 0.5 _ 20 20 ~ .
81 =N-N ~ 184-185 0.2 _ 20 20 ~s~
- -~ntiviotic actiVity ~g/mQ . :
Melting St. aureus Bacilus Myco. Myco.
point (C) 209P subtilis smeg. tuberc.
607 H37Rv No. R group __ _ _ 82 =N-N~-CH 1167-170 < 0.1 _ 20 20 ~ CH 3 :
83 =N-N ~ 167-168 0.2 _ 20 20 :
3~
84 =N-1 170 - 171 0.2 _ 20 20 Table 4 6-0-substituted Streptovaricinones C shown by the formula VI having the following h' group.
_ . __ _ . _ :
No .R ' groUp .
- .
CH 3-1 6 2 - 163 0.2 0.5 50 100 86 CH3CH2-161 - 163 10 _ _ 10 .,,'.

87 ~- 164-166 2 2 _ 50 . .

88 Cl~. 159-162 10 _ _ 10 ~ .

89 MeO - ~ 162-165 5 _ _ 10 . .. ~, ,`
~ 163-165 2 _ _ 20 . ~' 91 L~ _1168_170 1~ _ . '.' . . .

.',':", .', ' ,' ",'''' '',' , ;'' ' ''''''"' ','', "." ''' "' " ~''''.'''' '' ` , The prepara-tion of typical Strep-tovaricinone C
derivatives are illustrated in the ~ollowing Examples. ~-EXA~IPLE 1:
Preparation of 6-O-methylstreptovaricinone C
To a suspension of 1.42g of Streptovaricinone C in 70ml of methanol was added 400mg of silver oxide, and the mixture was stirred at room temperature for l hr. 3g of methyl iodide were then added in the mixture; the reaction mixture was stirred at room temperature for 1 hr. and then filtered through Celite (a trademark). The filtrate was evaporated to dryness under reduc-ed pressure to yeild a red oil. The oil was recrystallized from acetone-n-hexane as yellow needles, m.p. 165-167C, affording a single spot on silica gel t.l.c. the yield was 860 mg.
EXAMPLE 2:
Preparation of 23,24-dihydro-6-O-methyl-streptovaricinone C
To a suspension of 50 mg of streptovaricinone C in 5 ml of tetrahydrofuran was added 20 ml of diazomethane-ether solution with cooling in an ice-water bath f~r 30 min., and then a few drops of acetic acid were added. The ~eaction mixture was evaporated to dryness under reduced pressure, and the residue was dissolved in a small amount of ethyl acetate. To the solution was added a large amount of n-hexane to give a yellow precipitate which was recrystallized from acetone-n-hexane to yield 25 mg of 6-O-methylstreptovaricinone C, melting 165-167C. ~he product showed the same Rf value on silica gel t.l.c as the product obtained in the Example I. ~ -EXAMPLE 3:
Preparation of 23~24-dihydro-6-O-met~ylstrepto-varicinone-C
.
To a solution of 50 my of 23~24-dihydrostreptovaricinone C in 3 ml of methanol was added 17 mg of silver oxide and stirred ;
' '' - 13 - ~

~135~

at room temperature for 30 min., and to the mixture Was added 1 ml of methyl iodide, and the reaction mixture was s-tirred at room temperature for 30 min., and then filtered. The filtrate was evaporated under reduced pressure to give a red oil. The oil was chromatographed on Sephadex Lh-20 (a trademark) with acetone, and the appropriate fractions were collected and evaporated to dryness under reduced pressure. The resulting oil was recr~stallized from chloroform-_-hexane to yield 31 mg of yellow crystalline powder, melting 135-137C. ;
EXAMPLE 4:
P paration of 6-O-phenacetylstreptovaricinone C
To a suspension of 713 mg of Streptovaricinone C in 80 ml of methanol was added 1.16 g of silver oxide, and the mixture was stirred at 20C for 2 hr. 2 g of -bromoacetophenone was then added to the mixture and the reaction mixture was stirred at room temperature for 18 hr., and filtered through Celite (a trademark). The iltrate was evaporated to dryness .... .... . .
under reduced pressure to give a red oil. The oil was chromato-graphed on Sephadex LH-20 (a trademark) with acetone, and the appropriate fractions were collected and evaporated to dryness under reduced pressure. The resulting oil was recrystallized from acetone-_-hexane to afford 338 mg of yellow needles of 6-O-pheacetylstreptovaricinone C, m.p. 155-157C.
EXAMPLE 5:
Preparation of 6-O-cyclohexylstreptovaricinone C
To a suspension of 570 mg of Streptovaricinone C in 50 ml of methanol was added 928 mgi o silver oxide, and the mixture was stirred at 25C for 3 hr. 3.26g of cyclohexyl bromide was then added to the mixture. The reaction mixtuxe was stirred at 25C or 18 hr., then 928 mg of silver oxide were ~urther added and stirred at 50C for 10 min. To the mixture was added a further 3.26 g of cyclohexyl bromide, and stirred for : ' :
-- las -- .

, . . . ,,. . ,, ~... , , , , :

~'~5~
1 hr. at room temperature. The mixture Was then filtered, and the filtrate was evaporated to dryness under reduced pressure.
The resulting oil was dissolved ln 150 ml of ethyl acetate, and the solution w~s washed with 5 % sodium bicarbonate solution. The organic layer was separated and evaporated to a dryness under reduced pressure to give a red oil which was chromatographed on silica gel with 3 % methanol in chloroform. The appropriate fractions were collected and evaporated to dryness under reduced pressure to give a red oil Which was recrystallized from chloro-form-_-hexane as 185 mg of 6-O-cyclohexylstreptovaricinone C, m.p. 164-165C.
EXAMPLE 6:
Pre aration of 6-0-(3'-chloro-propyl)streptovari-cinone C
To a suspension of 120 mg of Streptovaricinone C in :L0 ml of methanol was added 120 mg oi- silver oxide, and the mixture was stirred at room temperatllre for 1 hr. 1.5 g of l-chloro-3-bromopropane, was added to the mixture and the reaction mixture was stirred at room temperature for 40 hrs. The reaction mixture was then filtered through Celite (a trademark), and the filtrate was evaporated -to dryness under reduced pressure.
The residue was chromatographed on silica gel with 4 % methanol in chloroform, and the appropriate fractions were collected and evaporated to dryness under reduced pressure to give a red oil which was recrystallized from chloroform-_-hexane as 20 mg of yellow crystalline powder of 6-O-(3'-chloropropyl)streptovarici-nine C, m.p. 145-147C. '' EXAMPLE 7: ~ ' Preparation `of the~aldol_comp'ound of 6-O-acetonyl- ` ' strèptovaricinone C

To a solution of 2.70 g of 6-O-acetonylstreptovarici- ' none C in the mixed solution of 70 ml of benzene and 14 ml of ~' .' . .

-2~

acetic acid was added 3.74 g of benzylamine. The reaction mixture was stirred at room temperature for 30 min. and then diluted with 200 ml of benzene. The solution was washed with water three times, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give a red oil.
The oil was chromatographed on silica gel with 3 % methanol in chloroform, and the appropriate fraction collected. After the combined fraction was evaporated to dryness under reduced pres-sure, the residue was recrystallized from ethyl acetate-n-hexane to afford 2.05 g of orange crystalline powder of the aldol of 6-O-acetonylstreptovaricinone C, m.p. 162-163C.
EXAMPLE 8:
Preparation of the aldol compound of 6-O-phenoxy-methylstreptovaricinone C
To a solution of 208 mg of 6-O-phenoxymethylstrepto-varicinone C in the mixed solution of 10 ml of benzene and 2 ml of acetic acid was added 200 mg of piperidine, and the reaction mixture was stirred at room temperature for 20 hr. The solution was then diluted with 100 ml of ethyl acetate. The solution was washed with water three times followed by a saline solution, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The resulting red oil was recrysallized from chloroform-_-hexane to afford 120 mg of orange red crystall-line powder of the aldol compound of 6-O-phenoxymethylstrepto-varicinone C, m.p. 164-166C.
EXAMPLE 9:
Preparation of the oxime of the aldol compound . :~
from 6-O-acetonylstrepto~aricinone C ~Method A) To a solution of 385 mg of 6-O-acetonylstrepto~arici-none C in 10 ml of benzene was added 330 mg of hydroxylamine and 2 ml of acetic acid in 5 ml of benzene and the mixture was stirred at room temperature for 30 min~ The mixture was then ':' '.' evaporated to dryness under reduced pressure, and the residue was chromatographed on silica gel with 10% methanol in chloro-form. The appropriate fractions were collected, combined and evaporated to dryness under reduced pressure to give a red oil which was recrystallized from ethyl acetate-_-hexane as 161 mg of orange yellow crystals of the product, m.p. 189-190C.
EXAMPLE 10:
Preparation of the oxime of the aldol compound of 6-O-acetonylstr ~
To a solution of 385 mg of the aldol compound of 6-O-acetonylstreptovaricinone C in 10 ml of methanol was added 347 mg of hydroxylamine hydrochloride, and the mixture was stirred at room temperature for 1.5 hr. The mixture was then diluted with 40 ml of ethyl acetate, and the solution was washed three times with an aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give a red oil. The oil was chromatographed on silica gel with 5 % methanol in chloroform, and the appropri-ate fractions were collected, combined and evaporated to dryness under reduced pressure ~o furnish a red oil which was recrystalli-zed from ethyl acetate-_-hexane as 249 mg of the product, m.p. ~ -189-190C. The product showed the same Rf value on t.l.c., IR spectrum (KBr), and melting point as those of the product obtained in Example I.
EXA~IPLE 11:
~ .
Preparation of the N,N-dimethylhydrazone of aldol compound of 6-O-acetonylstreptovariclnone C
To a solution of 385 mg of 6-O-acetonylstreptovaricinone C in 10 ml of benzene was added 30 mg of N,N-dimethylhydrazine -hydrochloride, and the mixture was stirred at room temperature for l hr. The mixture was then diluted with 30 ml of benzene. ~-The mixture was washed twice with water, dried over anhydrous .:
' : : ' , ; '. ~,:

~3~
sodium sulfate and evaporated to dryness under reduced pressure to give a red oil. The oil was chromatographed on Sephadex LH-20 (a trademark) with methanol, and the appropriate fractions were collecte~, combined and evaporated to dryness to furnish a red oil which was recrystallized from ethyl acetate-_-hexane to afford 110 mg of yellow crystalline powder product, m.p. 166-167C.
EXAMPLE 12:
.
_eparation of N,N-di-n-pentylhydrazone of t_e aldol compound of 6-O-streptovaricinone_C
To a solution of 385 mg of 6-O-acetonylstreptovarici-none C in 10 ml of benzene was added 860 mg of l,l-di-n-pentyl-hydrazine and 2 ml of acetic acid, and the mixture was stirred at room temperature for 30 min. The reaction mixture was then diluted with 30 ml of benzene, washed three times with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give a red oil The oil was chromato-graphed on Sephadex LH-20 (a trademea.rk) with acetone, and the appropriate fractions were collected, combined and evaporated to dryness to produce an oil. The oil was recrystallized from ethyl acetate-n-hexane as 230 mg of N,N-di-_-pentylhydrazone of the aldol compound of 6-O-acetonylstreptovaricinone C, m.p. 132-133C. ;
EXAMPLE 13: .
Preparation of 6-O-ac O-n-butyloxime ~
To a solution of 200 mg of 6-O-acetonylstreptovaricinone .:
C in 10 ml of methanol was added 125 mg of 0-n-butylhydroxylamine hydrochloride, and the mixtuxe was stirred at room temperature . :~
for 2 hr. The mixture was then diluted with 200 ml of ethyl acetate and the solution was washed with water, dried over anhyd- . ~.

rous sodium sulfate and evaporated to dxyness under reduced . ., ~ , . . .

pressure to yive an orange oil which was recrystallized from acetone-n-hexane to yield 146 mg of yellow needles of the O-n-butyloxime, m.p. 130-132C.
EXAMPLE 14:
.
Preparation of 6-O-acetonylstreptovaricinone C
O-benzyloxime To a solution of 256 mg of 6-O-acetonylstreptovarici-none C in 15 ml of ethanol was added 100 mg of O-benzylhydroxyl-amine hydrochloride and the reaction mixture was stirred at room temperature for 45 min. The mixture was then diluted with 200 ml of ethyl acetate, washed with water repeatedly, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to give a red oil. The oil was chromatographed on silica gel with 4 % methanol in chloroform, and the appropri-ate fractions were collected, combined and evaporated to dryness to give an orange oil which was recrystallized from acetone-n-hexane to yield 198 mg of yellow needles of the O-benzyloxime, m.p. 144-145C.
EXAMPLE 15:
Preparation of 6-O-acetonylstreptovaricinone C
semioarbazone To a solution of 231 mg of 6-O-acetonylstreptovarici-none C in 15 ml of methanol was added 45 mg of semicarbazide hydrochloride, and the reaction mixture was stirred at room temperature for 30 min. The mixture was then evaporated to dryness under reduced pressure, and the resulting oil was chroma- -tographed on silica gel with 10 % methanol in chloroform. The appropriate fractions were collected, combined and evaporated to dryness under reduced pressure to give an orange oil which was recr~stallized ~rom ethyl acetate-n-hexane as 115 mg of yellow crystalline powder of 6-O-acetonylstreptovaricinone C semicarba-zone, m.p. 23~-236C.
;

Z~ , EX~MPLE 16:
Preparation of 6-0-_cetylstrep~ovaricinone C
To a suspension of 363 mg of Streptovaricinone C in 10 ml of acetone was added 10 ml of 0.05 N methanolic sodium hydroxide solution, and the solution was evaporated to dryness under reduced pressure to obtain sodium salt of streptovarici-none C. The sodium salt was suspended in 20 ml of dry tetrahydro-furan, and to the suspension was added 90 mg of acetyl chloride.
The reaction mixture was stirred at room temperature for 5 min., and then poured into a 5 ~ cold sodium bicarbonate solution.
The mixture was repeatedly extracted with benzene and the combined extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give a red oil. The oil was chromatographed on silica gel with 5 % methanol in chloroform, and the appropriate fractions were collected and combined. The fraction was evaporated to dryness under reduced pressure to afford an orange oil which was recrystallized from acetone-n-hexane as 182 mg of 6~0-acetylstreptovaricinone C, m.p. 169-171C..
EXAMPLE 17:
Pre~aration of 6-0-(3',5'-dinitrobenzoyl)-streptovarici-one C
To a suspension of 360 mg of Streptovaricinone C in 30 ml of methanol was added 10 ml of OnO5 N methanolic sodium hydroxide solution. The mixture was stirred for 15 min. and ~-evapoxated to dryness under reduced pressure to form a sodium -salt. The sodium salt was then suspended in 10 ml of dry tetrahydrofuran, and to the suspension was added 116 mg of 3,5-dinitrobenzoyl chloride, and the mixture was stirred at room 3~ temperature for 30 min., and evaporated to dryness under reduced pressure. The residue was dissol~ed in ethyl acetate, and the solution was washed with water, dried over anhydrous sodium ~ r~

sulfate and evaporated to dryness under reduced pressure. The residue was chromatographed on Sephadex LH-20 (a trademark) with acetone, and the appropriate fractions were collected and combined. The fraction was evaporated to ~ryness under reduced pressure to yield an orange red oil which was recyrsallized from chloroform-n-hexane to yield yellow crystalline powder of 6-O-(3',5'-dinitrobenzoyl)streptovaricinone C, m.p. 179-182C.
EXAMPLE 18:
__ Preparation of 6-O-methanesulfonylstreptovaricinone C
_ To a suspension of 372 mg of Streptovaricinone C in 10 ml of acetone was added 10 ml of 0.05N methanolic sodium hydroxide solution, and the solution was evaporated to dryness ~mder reduced pressure to obtain the sodium salt of Streptovari-cinone C. The sodium salt was susp~nded in 20 ml of dry tetra-hydrofuran, and to the suspension was added 138 mg cf methanesulf-onyl chloride in 10 ml of dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 48 hr., and then poured into a 5 ~ cold sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to yield a red oil. The oil was chromatographed on silica gel with 4 ~ methanol in chloroform, and the appropriate fractions were collected and combined. The fraction was evaporated to dryness under reduced pressure to yield an orange oil which was : recrystallized from ethyl acetate-n-hexane to yield 57 mg of yellow crystalline powder of 6-O-methanesulfonylstreptovaricinone 'i C, m.p. 167-170C.
EXAMPLE 19:

Preparation of 6-O-_ethoxycarbonyl-streptovaricinone C ' ' To a suspension of 373 mg of Streptovaricinone C in 10 ml of tetrahydrofuran was added 10 ml of 0.05N methanolic sodium hydroxide solution, and the solution was evaporated to . , . .... . . . . . ~ . . : .: . .

~5~

dryness under reduced pressure to obtain the sodium salt of Streptovaricinone C. The salt was suspended in 8 ml of tetrahydro-furan, and to the suspension was added 145 mg of methyl chloro-carbonate. The reaction mixture was stirred at room temperature for 30 min., and poured into a 5 % cold sodium bicarbonate solu-tion. The mixture was then repeatedly extracted with ethyl acetate and the extract was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to give a red oil. The oil was chromatographed on silica gel with 7 ~
methanol in chloroform, and then the appropriate fractions were collected and combined. The fraction was evaporated to dryness under reduced pressure to yield an oil which was recrystallized from ethyl acetate-n-hexane to give 263 mg of yellow crystalline powder of 6-O-methoxycarbonylstreptovaricinone C, m.p. 159-163C.

,, . .. . , . ~ . .

Claims (22)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the production of a Streptovaricinone C derivative having the formula (III) wherein Z represents an alkyl, allyl, hydroxyalkyl, chloroalkyl, alkenyl, ketonyl, furyl-oxoalkyl, thienyl-oxoalkyl, phenyl-oxoalkyl, carbamylalkyl, benzyl, phenoxyalkyl, cyanoalkyl, phenethyl, benzoyloxyethyl, p-chlorophenyl-oxoalkyl, p-methoxy-phenyl-oxoalkyl, p-nitrobenzyl, p-methylbenzyl, alkanoyl, benzoyl, benzenesulfonyl, alkylsulfonyl, phenoxycarbonyl, thienylcarbonyl or alkoxycarbonyl group wherein alkyl, alkenyl, alkanoyl and alkoxycarbonyl have 1 - 12 carbon atoms unless otherwise specified or an aldol condensation pro-duct thereof which comprises (a) etherifying Streptovaricinone C of the formula II
(II) with a halide of the formula Z1-hal wherein hal is halogen and Z1 is selected from an alkyl, aliyl, hydroxyalkyl, chloroalky, alkenyl, ketonyl, furyl-oxoalkyl, thienyl-oxoalkyl, a phenyl-oxoalkyl, carbamylalkyl, benzyl, phenoxyalkyl, cyanoalkyl, phenethyl, benzoyloxyethyl, p-chlor-phenyl-oxoalkyl, p-methoxyphenyl-oxoalkyl, p-nitrobenzyl or p-methylbenzyl wherein alkyl or alkenyl have 1 to 12 carbon atoms in an inert solvent.
(b) etherifying Streptovaricinone C of the formula II
above with a diazoalkane in a solvent or (c) esterifylng the Streptovaricinone C of the formula II with an organic acid halide, organic sulfonic acid halide or alkyl halocarbonate, phenyl halocarbonate or thienyl halocarbonate of the formula Z2-hal wherein hal is as above and Z2 is selected from alkanoyl, benzoyl, benzenesulfonyl, an alkylsulfonyl, phenoxycarbonyl, thienylcarbonyl or alkoxycarbonyl group where alkanoyl alkyl or alkoxycarbonyl have 1 to 12 carbon atoms and when the aldol condensation product is required treating the 6-0-ketonyl streptovaricinone C obtained in (a) with an organic base in the presence of excess acid in an organic solvent.

2. Streptovaricinone C derivatives having the formula III given in Claim 1, wherein Z is as in Claim 1, or an aldol condensation product thereof when prepared by the process as claimed in Claim 1, or an obvious chemical equivalent thereof.

3. A process as claimed in Claim 1, in which Strepto-varicinone C is etherified With the compound of the formula Z1-hal wherein Z1 is as in Claim 1.

4. Streptovaricinone C derivatives having the formula III wherein Z is an alkyl, allyl, hydroxyalkyl, chloroalkyl, alkenyl, ketonyl, furyl-oxoalkyl, thienyl-oxoalkyl, a phenyl-oxoalkyl, carbamylalkyl, benzyl, phenoxyalkyl, cyanoalkyl, pheneLllyl, benzoyloxyethyl, p-chlol-op]lenyl-oxoalkyl, p-methoxy-phenyl-oxoalkyl, p-nitrobenzyl, p-methylbenzyl wherein alkyl, alkenyl, alkanoyl and alkoxycarbonvl have 1 - 12 carbon atoms unless otherwise specified when prepared by the process as claimed in Claim 3 or an obvious chemical equlvalent thereof.

5. A process as claimed in Claim 3, in which in the reactants Z1 is selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl, isohexyl, n-hexyl, n-heptyl, chloroethyl, .gamma.-chloro-n-propyl, .beta.-phenoxyethyl, .beta.-cyano-n-propyl, acetonyl, phenyl-oxo-methyl, 2-furyl-oxomethyl, 2-thienyl-oxomethyl, p-chlorophenyl-oxomethyl, p-methoxy-phenyl-oxomethyl, benzyl, p-methyl benzyl, p-nitrobenzyl, p-phenylethyl or .beta.-benzoyloxyethyl.

6. Streptovaricinone C derivatives having the formula III wherein Z is selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl, isohexyl, n-hexyl, n-heptyl, chloromethyl, .gamma.-chloro-n-propyl, propenyl, .gamma.-hydroxy-n-propyl, .beta.-phenoxyethyl, .gamma.-cyano-n-propyl, acetonyl, phenyl-oxomethyl, 2-furyl-oxomethyl, 2-thinyl-oxomethyl, p-chlorophenyl-oxome-thyl, p-methoxy phenyl-oxomethyl, benzyl, p-methylbenzyl, p-nitrobenzyl, p-phenyle-thyl, or .beta.-benzoyloxyethyl when prepared by the process as claimed in Claim 5, or an obvious chemical equivalent thereof.

7. A process as claimed in Claim 1, in which Strepto-varicinone C is esterified with the compound of the formula Z 2-hal wherein Z2 is as in Claim 1.

8. Streptovaricinone C derivatives of formula III, wherein Z is alkanoyl, benzoyl, benzenesulfonyl, an alkylsulfonyl phenoxycarbonyl, thienylcarbonyl or alkoxycarbonyl group where alkanoyl alkyl or alkoxycarbonoyl have 1 to 12 carbon atoms when prepared by the process as claimed in Claim 7, or an obvious chemical eauivalent thereof.

9. A process as claimed in Claim 7, in which in the reactants Z2 is selected from acetyl, propionyl, butyryl, valeryl, capoyl, bromoacetyl, phenylaceyl, n-butylthio-acetyl, 2-benzoxoalkylthio acetyl, phenylthio acetyl, benzylthio-acetyl, methyl-sulphonyl, phenylsulphonyl, p-methylphenylsulphonyl, m-methylsulphonyl, p-acetyl amino phenyl sulphonyl, methoxy-carbonyl, ethoxy-carbonyl, isopropoxy-carbonyl, n-butoxy carbonyl, phenoxy-carbonyl, and 2-etnyl-carbonyl.

10. Streptovaricinone C derivatives of the formula III
wherein Z is selected from acetyl,propionyl,butyryl, valeryl, caproyl, bromoacetyl, phenylacetyl, n-butylthioace-tyl, 2-benzoxo-alkylthio acetyl, phenylthioace-tyl, benzylthio acetyl, methyl sulphonyl, phenyl sulphonyl, p-methylphenyl sulphonyl, m-methyl sulphonyl, p-acetylaminophenyl sulphonyl, methoxy carbonyl, ethoxy carbonyl, isopropoxy-carbonyl, n-butoxy-carbonyl, phenoxy-carbonyl, and 2-ether-carbony 1 when prepared by the process as claimed in Claim 9, or an obvious chemical equivalent thereof.

11. A process as claimed in Claim 1, in which the 6-0-ketonylstreptovaricinone C obtained is reacted with hydroxylamine, O-substituted hydroxylamine or hydrazine.

12. Streptovaricinone C derivatives having the formula III wherein 2 is hydroxylamino-alkyl or hydrozono-alkyl group having 1 to 12 carbon atoms when prepared by the process as claim-ed in Claim 11, or an obvious chemical equivalent thereof.

13. A process as claimed in Claim 11, in which the product 6-0-ketonylstreptovaricinone C is reacted with a compound selected from hydroxylamine, hydroxylamine-O-substituted by methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-nonyl, propen-2-yl, benzyl, .beta.-benzoyloxyethyl or .beta.-phenoxyethyl, hydrazine or hydrazine substituted by carbonyl or pyridine-4-carbonyl at room temperature in a molar ratio of amine compound to Streptovaricinone C in the range of 1.5 to 5:1.

14. StreptoVaricinone C derivatives of the formula IV.

(IV) wherein R is hydroxylamino, hydroxylamino O-sustituted by methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-nonyl, propen-2-yl, henzyl, .beta.-benzoyloxoethylor .beta.-phenoxyethyl, hydrazono or hydrazono substituted by carbonyl or pyridino-4-carbonyl when prepared by the process as claimed in Claim 13 or an obvious chemical equivalent thereof.

15. A process as claimed in Claim 11, inwhich the product 6-acetonyl Streptovaricinone is reacted in a molar ratio of about 10:1 and in the presence of acetic acid at room tempera-ture with hydroxylamine, methyl hydrazine, dimethyl hydrazine, .beta.-hydroxyethyl hydrazine, di-n-propyl hydrazine, di-n-butyl hydrazine, di-n-hexyl hydrazine,di-n-octyl hydrazine, di-n-propen-2-yl hydrazine, methylphenyl hydrazine, ethylphenyl-hydrazine, benzylhydrazine, p-methyl N-piperazineamine, N-morpholineamine, N-pyrollidineamine, N-piperidineamine, phenyl-hydrazine, p-methyl phenylhydrazine, m-methylphenylhydrazine, o-methylphenylhydrazine or 3,4,5,6-tetrahydro-2H azepineamine.

16. Streptovaricinone derivatives of the formula V
wherein R is hydroxylamino, methylhydrazono, dimethylhydrazono, .beta.-hydroxyethyl hydrazono, di-n-propyl-hydrazono, di-n-butyl hydrazono, di-n-hexyl hydrazono, di-n-octyl hydrazono, di-n-propen-2-yl hydrazono, N-methyl-N-phenyl hydrazono, N-ethyl-N-phenyl hydrazono, benzylhydrazono, p-methyl-piperazinylamino, morpholinamino,pyrollidinoamino, piperidin amino, phenylazono;
p-methylphenylazono, m-methylphenylazono, o-methylphenylazono or 3,4,5,6-tetrahydlo-2H-zepine amino when prepared by the process as claimed in Claim 15, or an obvious chemical equivalent thereof.

17 . A process as claimed in Claim 1, in which 6-O-ketonylstreptovaricinone C obtained is reacted with an organic base selected from primary or secondary amines; in the presence of an excess of an organic solvent.

18. An aldol condensation product of a Streptovaricicone C derivative of the formula VI

(VI) herein R is a lower alkyl phenyl, chlorophenyl, methoxyphenyl furyl or thienyl group when prepared by the process as claimed in Claim 17, or an obvious chemical equivalent thereof.

19. A process as claimed in Claim 17, in which the ketonyl group is selected from methylcarbonyl, ethylcarbonyl, phenylcarbonyl, p-chlorophenylcarbonyl, p-methoxy phenylcarbonyl, furylcarbonyl and 2-thienylcarbonyl.

20. An aldol condensation product of a streptovarici-none C derivative of the formula VI

(VI) when R1 is methyl, ethyl, phenyl, p-chlolophenyl, p-nethoxylphenyl, 2-furyl or 2-thienyl when prepared by the process as claimed in Claim 19, or an obvious chemical equivalent thereof.

21. A process for the production of a Streplovaricinone C derivative having the formula III

(III) wherein Z represents an alkyl, allyl, hydroxyalkyl, chloro-alkyl, alkenyl, ketonyl, furyl-oxoalkyl, thienyl-oxoalkyl, phenyl-oxoalkyl, carbamylalkyl, benzyl, phenoxyalky, cyanoalkyl, phenethyl, benzoyloxyethyl, p-chlorophenyl-oxoalkyl, p-methoxy-phenyl-oxoalkyl, p-nitrobenzyl, p-methylbenzyl, hydroxylimino alkyl, hydazono alkyl, alkanoyl, benzoyl, benzensulfonyl, alkylsulfonyl, phenoxycatbonyl, thienylcarbonyl or alkoxycarbonyl group wherein alkhl, alkenyl, alkanoyl and alkoxycarbonyl have 1 - 12 carbon atoms unless otherwise specified or an aldol con-densation product thereof of formula VI.

(VI) wherein R1 is a lower alkyl, phenyl, chlorophenyl, methoxyphenyl, furyl or thienyl group or a further product of the derivative of formula III wherein Z is hydroxylamino-alkyl or hydrozono-alkyl group having 1 to 12 carbon atoms which comprises (a) ethifying Streptovaricinone C of formula II

(II) with a halide of the formula Z1-hal wherein hal is halogen and Z1 is selected from an alkyl, allyl, hydroxyalkyl, chloroalkyl, alkenyl, ketonyl, furyl-oxoalkyl, thinyl-oxoalkyl, a phenyl-oxoalkyl, carbamylalkyl, benzyl, phenoxyalkyl, cyanoalkyl, phenethyl, benzoyloxyethyl, p-chlor-phenyl-oxoalkyl, p-methoxyphenyl-oxoalkyl, p-nitrobenzyl or p-methylbenzyl wherein alkyl or alkenyl have 1 to 12 carbon atoms in an inert solvent.
(b) etherifying Streptovaricinone C of the formula II above with a diazoalkane in a solvent or (c) esterifying the Streptovaricinone C of the formula II with an organic acid halide, organic sulfonic acid halide or alkyl halocarbonate, phenyl halocarbonate or thienyl halocarbonate of the formula Z2-hal wherein hal is as above and Z2 is selected from alkanoyl, benzoyl, benzensulfonyl, an alkylsulfonyl, phenoxycarbonyl, thienylcarbonyl or alkoxycarbony group where alkanoyl, alkyl or alkoxy carbonyl have 1 to 12 carbon atoms and when the product of formula VI is requir-ed the 6-0-Ketonylstreptovaricinone C obtained is reacted with an organic base selected from primary or secondary amines; in the presence of an excess of an organic solvent and when the further product is required the 6-0-ketonylstreptovaricinone C obtained is reacted with hydroxylamine, 0-substituted hydroxylamine or hydrazine.

22. A Streptovaricinone C derivative having the formula III

(III) wherein Z represents an alkyl, allyl, hydroxyalkyl, chloroalkyl, alkenyl, ketonyl, furyl-oxoalkyl, thienyl-oxoalkyl, phenyl-oxoalkyl, carbamylalkyl, benzyl, phenoxyalkyl, cyanoalkyl, phenethyl, benzoyloxyethyl, p-chlorophenyl-oxoalkyl, p-methoxy-phenyl-oxoalkyl, p-nitrobenzyl, p-methylbenzyl, hydroxyli hydrazono alkyl, alkanoyl, benzoyl, benzenesulfonyl, alkylsulfonyl, phenoxycarbonyl, thienylcarbonyl or alkoxycarbonyl group wherein alkyl, alkenyl, alkanoyl andalkoxycarbonylhave 1-12 carbonatoms un-less otherwise specified or an aldol condensation product thereof of formula VI

(VI) wherein R1 is a lower alkyl, phenyl, chlorophenyl methoxyphenyl furyl or thienyl group or a further product thereof wherein Z is hydroxylamino-alkyl or hydrozono-alkyl group havinq 1 to 12 carbon atoms whenever prepared or produced by the process of Claim 21, or an obvious chemical equivalent thereof.