CA1132588A - 3-de-0-methylfortimicins - Google Patents

3-de-0-methylfortimicins

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Publication number
CA1132588A
CA1132588A CA364,855A CA364855A CA1132588A CA 1132588 A CA1132588 A CA 1132588A CA 364855 A CA364855 A CA 364855A CA 1132588 A CA1132588 A CA 1132588A
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CA
Canada
Prior art keywords
de
methylfortimicin
acid
method
acyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
CA364,855A
Other languages
French (fr)
Inventor
Jerry R. Martin
John S. Tadanier
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Abbott Laboratories
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Abbott Laboratories
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Filing date
Publication date
Priority to US754,670 priority Critical
Priority to US05/754,670 priority patent/US4124756A/en
Priority to CA292,979A priority patent/CA1089851A/en
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to CA364,855A priority patent/CA1132588A/en
Priority claimed from CA000391583A external-priority patent/CA1137092A/en
Priority claimed from CA000391582A external-priority patent/CA1137093A/en
Publication of CA1132588A publication Critical patent/CA1132588A/en
Application granted granted Critical
Application status is Expired legal-status Critical

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Abstract

Abstract of the Disclosure Described are 3-de-0-methyfortimicins A and B and 4-N-acyl and 4-N-alkyl-3-de-0-methylfortimicin B derivatives, and their preparation, which compounds are useful as anti-biotics or as intermediates for preparing other useful deriva-tives having antibacterial activity. The compounds have the following structural formula

Description

1::1L32588 ~et~iled Description of the Invention The present invention relates to the preparation of 3-de-0-methylfortimicins A and B and 4-N-acyl- and 4-N-alkyl 3-de-0-methylfortimicin B derivatives which are useful as antibiotics or as intermediates for preparing other useful derivatives having antibacterial activity.
The novel compounds of this invention have the following structural formula CHNH2 H2N\ /OH
\~0 ~
--O J O {

. CH3 wherein R is hydrogen, acyl, amin~acyl, N-monoloweralkylamino-acyl, N,N-diloweralkylaminoacyl, hydroxy-substituted æmino-acyl, alkyl, aminoalkyl, N-monoloweralkylaminoalkyl, N,N-diloweralkylaminoalkyl or hydroxy-substituted aminoalkyl and the pharmaceutically acceptable salts thereof, for ex~mple, salts formed from hydrochloric,sulfuric , and phosphoric acids.
The naturally occurring fortimicins are produced in several forms by cultivation of a strain of Micromonos~ora .

, . . .

olivoast:erospora in a suitable nutrient medium as taught in U.S. Patent 3,931,400 issued January 6, 1976 and U.S.
Patent 3,976,768, issued August 24, 1976.. The structure of two of these forms is represented by the following formula 7'CHg 6'CHNH 2 H 2 N OH

~ ~ - O ~ ~ ~ OCH3 ~< ~

In this formula, when R is hydrogen the structure illustrated is fortimicin B. When R i5 glycyl the structure of fortimicin A is shown. As denoted in the formula above, the fortimicin compounds consist of two cyclic moieties referred to respectively as purpurosamine and fortamine.
The positions of the purpurosamine ring are indicated by primed numbers while the positions on the aminocyclitol moiety, fortamine, are indicated by unprimed numbers.
According to the method of this invention, in performing the 3-0-demethylation reaction, fortimicin B, 4-N-(B-aminoethyl) fortimicin B prepared as taught in Canadia.n Patent Application No. 287,269 filed September 22, 1977 or other appropriate derivative containing the fortamine moiety are reacted bm ~D

.

. 113~58~3 wlth excess metallic lithium in an amine solvent such as ethylamine or ethylenediamine. The re~ctants are admixed in the solvent and the reaction allowed to proceed at a suitable temperature for the desired period~ The resulting 3-de-0-methylfortimicin B, 4-N-(B-aminoethyl)-3-de-O-methyl-fortimicin B, or other derivatlve is isolated by conventional column chromatographic methods.
The 3-de-0-methylfortimicin B prepared above is re-acted with N-(benzyloxycarbonyl)-succinimide to prepare 1,

2', 6'-tri-N-benzyloxycarbonyl-3-de-0-methylfortimicin B.
The product formed in the above reaction is isolated by column chromatography and 4-N-acylated by treatment with suitable N-benzyloxycarbonyloxy protected amino acids. The benzyloxycarbonyl-3-de-O-methyl-4-N-acyl fortimicins prepared as above are conveniently reduced to the corresponding 4-N-alkyl derivatives with diborane. After isolation by column chromatography the benzyloxycarbonyl groups of both - the 4-N-acyl and 4-N-alkyl derivatives are conveniently removed by catalytic hydrogenolysis and the products may be isolated as the hydrochloride salts.

bm~

1~3258~3 The 3-de-0 me~hylfortimicin B prepared above is reacted with N-(benzyloxycarbonyloxy)succinimide to prepare 1, 2', 6'-tri-N-benzyloxycarbonyl-3-de-0-methylfortimicin B. The product formed in the above reaction is isolated by column chromatography and 4-N-acylated by treatment with suitable N-benzyloxycarbonyloxy amino acids. The benzyloxycarbonyl groups of the products are conveniently removed by cataly~ic hydrogenolysis and the product may be isolated as the hydrochloride salt.
The following examples more clearly illustrate the invention but are not intended to limit the scope of the invention to the examples described.

3 De-0-methylfortimicin B
To a solution of 2.0 g of fortimicin B free base in 50 ml. of freshly distilled ethylamine is added 40 ml. of ethylamine containing 0.859 g. of lithium wire freshly cut into small pieces. The dark blue reaction mixture is stirred under reflux for 2 hours, then methanol is slowly added to consume excess lithium. The solvents are removed under _5_ bm:~

1~3258~3 -reduced pressure and the resulting or~anic products are separated from the lithium salts by column chromatography on silica gel prepared and eluted with the lower phase of a mixture of chloroform-methanol-concentrated ammonium hydroxide (l:l:lv~/v). Fractions enriched in 3-de-0-methyl-fortimicin B are collected and rechromatographed on a column of a cation exchange resin, acrylic type, such as Bio Rex@3 70, 100-200 mesh, NH4 form. Elution with a gradient of water to lN NH40H gave fractions containing pure 3-de-O-methylfortimicin B. Lyophilization gave 0.267 g of color-less material: [~] 2D4 ~41.4 (c 1.02, CH30~); IR 3370, 1585 cm~l; PMR (D2O) ~ 1.5 ~C6 -CH3, J6',7' )~

4 3 ( 1 ~ Jl',2' = 3.8); Mass spec Mt 334 222 Calculated for C14E30N45 334-2216-- , 2', 6'-Tri-N-benzyloxycarbonyl-3-de-O-methylforti~icin B
To a stirring, ice-bath cooled solution of 3-de-O-methylfortimicin B free base (1.59 g) in 24 ml. water and 48 ml. methanol is added 3.55 g of N-(benzyloxycarbonyloxy)-succinimide. The reaction is stirred at ice-bath temperature for 4 hours and then at room temperature for 22 hours. The reaction is concentrated under reduced pressure and poured into 400 ml. water to which is added 200 ml. chloroform.
The organic layer is separated and washed with water and dried ~MgSO4). The chloroform is evaporated and the residue chromato-graphed on silica gel prepared and eluted with a solvent ,, . I ~.

1~;3258~3 -system consisting of chloroform-methanol-concentrated am-monium hydroxide (23.4:1. 4 o.lvhlv). Fractions containing pure 1, 2~, 6'-tri-N-benzyloxycarbonyl-3-de-0-methyl-fortimicin B are collected and evaporated to dryness to giv~
1.70 g of product: [~]2D3 ~ 19.4D (c 1.0, CH30H); IR 3437, 3350, 1705, 1505 cm 1; PMR (CDC13) ~ 0.99 (C6'-CH3, J6'

5-0), 2.27 (C4-N-CH3), 7.27 (Cbz).
Analysis: Calculated for C33H48N4011: C, 61.94; H, 6.57;
N, 7.60, Found: C, 61.83; H, 6.74; N, 7.51 Example 3 Tetra-N-benzyloxycarbonyl-3-de-0-methylfortimicin A
To a stirred solution of 0.80 g of 1, 2', 6'-tri-N-benzyloxycarbonyl-3-de-0-methylfortimicin B in 5.35 ml of tetrahydrofuran is added 0.399 g of N-hydroxysuccinimidyl-N-benzyloxycarbonylglycine Stirring is continued for 22 hours at room temperature. The reaction is concentrated to dryness under reduced pressure and the resulting product chromatographed on a column o~ silica gel with a solvent system consisting of benzene-methanol-95% ethanol-concen-trated ammonium hydroride (23.5:1.4:2.0:0.2~/v). Fractions containing the desired product are taken to dryness to gi~e 0.488 g of tet-a-N-benzyloxycarbonyl-3-de-0-methylfortimicin A as a colorless glass: [~]2D4 + 45.2~ (C 1.03, CH30~
3425, 1705, 1645, 1500 cm 1; PMR (CDC13) ~ 1.15 (C6,-CH3), 2.9 (C4-~-CH3), ~.28 (Cbz).

Analysis: Calculated for C48H57N5O14: C, 62-13; H, 6.1g;
N, 7.55; Found: C, 61.80; H, 6.31; N, 7.64 Example 4 Tetra-N-benzyloxycarbonyl-3-de-0-methylfortimicin A
To a stirred solution of 0.525 g of 1, 2', 6'-tri-N-benzyloxycarbonyl-3-de-O-methylfortimicin B, 0.199 g of N-benzyloxycarbonylglycine and 0.228 g of l-hydroxy-benzotriazole monohydrate in 3.0 ml tetrahydrofuran is added 0.88 g of N,N'-dicyclohexylcarbodiimide dissolved in 1.5 ml tetrahydrofuran. An additional 1.5 ml of tetrahydrofuran is used to rinse all the N,N'-dicyclohexylcarbodiimide into the reaction vessel. Stirring is continued for 22 hours at ambient tem~erature. Insoluble dicyclohexylurea is re-moved by filtration. The filtrate is concentrated to dry-ness under reduced pressure to yield a yellow froth. The froth is chromatographed on a column of silica gel using a solvent system consisting of benzene-methanol-95~/~ ethanol-concentrated am~onium hydroxide (23.5:1.4:2.0:0.2 v/v/v/v) Fractions containing the majority of the product are taken to~~ryness and rechromatographed on a column o~ Sephade~
LH20 prepared and eluted with 95% ethanol. Fractions con-taining pure product are collected and the solvent removed under reduced pressure to give 0.105 g of tetra-N-benzyl-oxycarbonyl-3-de-O-methylfortimicin A identical in all respects with the same material prepared in Example 3.

11;3~2S8~3 Examp'le 5 Tetra-N-benzyloxycarbonyl-3-de-O-methyl-4-N-sarcosyl-fortimicin B
To a stirred solution of 0.298 g of 1, 2', 6'-tri-N-benzyloxycarbonyl-3-de'-O-methylfortimicin B, 0.113 g of N-benzyloxycarbonylsarcosine and 0.129 g of l-hydroxy-benzotriazole' in 3.0 ml of tetrahydrofuran is added 0.107 g of N,N'-dicyclohexylcarbodiimide in 1.5 ml tetrahydrofuran.
An additional 1.5 ml of tetrahydrofuran is used to rinse all the ~,N'-dicyclohexylcarbodiimide into the reaction flask.
Stirring is continued for 16 hours at room temperature.
Insoluble dicyclohexylurea is removed by filtration and the filtrate concentrated to yield a pale yellow solid.
The solid is chromatographed on a column of silica gel using a solvent system consisting of benzene-methanol-95% ethanol-concentrated ammonium hydroxide (23.5;1.4;2.0;
0.2~/v~u). Fractions containing homogeneous material are taken to dryness. Other fractions containing a minor second component are rechromatographed on a column of silica gel using a 'solvent system consisting of benzene-methanol-con centrated ammonium hydroxide (85:15:1~1v/v). Homogeneous fractions are combined with material obtained in the first column to give 0.709 g of tetra-N-benzyloxycarbonyl-3-de-O-methyl-4-N-sarcosyl-fortimicin B as a glass: ~]2D4 42.9~ (c 1.01, CH30H); IR 3435, 1703, 1635, 1500 cm 1;
PMR (CDC13) ~ 1.17 (C6,-CH3), ~ 2.9 (broad) (Sarcosyl-N-C~3) 2-99 (C4-N-CH3), 4.83 (Hl " Jl',2' )~

_g_ 1~3Z5813 Analysis: Calculated for C4gHsgNsO14 C ~ 62.48; H, 6.31;
N, 7.43; Found: C, 62.35; H, 6.65; N, 7.57 Example 6 3-De-0-methylfortimicin A tetrahydrochloride Tetra-N-benzyloxycarbonyl-3-de-O-methyl*ortimicin A (0 .14 g) in 25 ml 0. 2 N hydrochloric acid in methanol is hydrogenolyzed for 4 hours under 3 atmospheres of hydrogen in the presence of 0.1 g of 5a/o palladium on carbon. The catalyst is removed by filtration and the filtrate con-centrated to dryness under reduced pressure. Excess acid is removed by co-distillation with methanol under reduced pressure to give 0. 071 g of 3-de-O-methylfortimicin A
tetrahydrochlQride: [~]2D3 ~ 79-4 (c l.0~ CH30H); IR 3410, 2930, 1639, 1595, 1483 cm 1; PMR (D20) ~ 1.81 (C6,-CH3, J6t7 = 6.5) ~ 3.62 (C~-N-CH3), 5.79 (Hl~ J Jl~ 2~ = 3-5)i Mass spec. M 391.2414, Calculated for Cl6H33NsO6 391.2431, Example 7 3-De-O-methyl-4-N-sarcosylfortimicin B tetrahydrochloride Tetra-N-benzyloxycarbonyl-3-de-O-methyl-4-N-sarcosylortimicin B (Q.125 g) in 25 ml 0.2 N hydrochloric acid in methanol is hydrogenolyzed for 4 hours under 3 atmospheres of hydrogen in the presence of 0.13 g of 5%
palladium on carbon. The catalyst is removed by filtration and the filtrate concentrated to dryness under reduced pressure. Excess acid is removed by co-distillation with 1:~3~588 methanol under reduced pressure to give 0.073 g of 3-de-O-methyl-4-N-sarcosylfortimicin B tetrahydrochloride:
[~]2D4 + 8~.5(c 1.01, CH30H); IR 3420, 2930, 1635, 1485 cm~l; PMR (D2O) 1.8 (C6,-CH3, J6'~7' (Sarcosyl-N-CH3), 3.6 (C4-N-CH3), 5.79 (Hl,, Jl' 2~ =
3.5); Mass Spec M + 405.2614, Calculated for C17H35N5O6 405.2587.
Example 8 Tetra-N-benzyloxycarbonyl-3-de-O-methyl-4-N-(~-aminoethyl) fortimicin B
To an ice cold stirred solution of 0.3 g of tetra-N-benzyloxycarbonyl-3-de-O-methylfortimicin A in dry tetrahydro-furan (6 ml.) is added 1.0 ml of a 1 M solution of diborane in tetrahydrofuran. The reaction mixture is stirred for 3 hours under a nitrogen atmosphere and then treated with an additional 1.0 ml. of the diborane solution. After stirring for an additional 2 hours under nitrogen water is added and the solvents evaporated under reduced pressure. Purification by column chromatography on silica gel prepared and eluted with a solvent system consisting of chloroform-methanol-concentrated ammonium hydroxide (23.4:1.4:0.1v/v/v) gave pure tetra-N-benzyloxycArbonyl-3-de-O-methyl-4-N-(~-aminoethyl) fortimicin B.
Example 9 3-de-O-methyl-4-N-(~-aminoethyl)fortimicin B tetrahydrochloride Tetra-N-benzyloxycarbonyl-3-de-O-methyl-4-N-(~-aminoethyl) fortimicin B (0.10 g) in 25 ml. 0.2 N hydrochloric acid in methanol is hydrogenolyzed for 4 hours under 3 atmospheres of hydrogen in the presence of 0.11 g of 5% pallidium on carbon.
The catalyst is removed by filtration and the filtrate con-centrated to dryness under reduced pressure. Excess acid is removed by co-evaporation with methanol under reduced pressure to give 3-de-O-methyl-4-N-(~-aminoethyl) fortimicin B
tetrahydrochloride.
Example 10 3-De-O-methyl-4-N-(~-~minoethyl) fortimicin B
To a solution of 1.0 g of 4-N-(~-aminoethyl)fortimicin 8 in 25 ml of freshly distilled ethylamine is added 20 ml. of ethylamine containing 0.430 g of lithium wire freshly cut into small pieces. The dark blue reaction mixture is stirred under reflux for 2-16 hours, then methanol is cautiously added to consume the excess lithium. The solvent is evaporated under reduced pressure and the residue chromatographed on silica gel prepared and eluted with the lower phase of a mixture of chloro-form-methanol-concentrated ammonium hydroxide (1:1:1 ~ /v).
Fractions containing the desired product are collected and re-chromatographed on a column of a weakly acidic, carboxylic (polymethacrylic) type, cation exchange resin in the ammonia form, for example, Biore ~70, 100-200 mesh. Elution with a gradient of water ~o 1 N NH40H gave fractions containing pure 3-de-O-methyl-4-N-(~-aminoethyl)fortimicin B.

113~S88 Examples 11-13 In Vitro, Antibiotic Activities of 3-De-O-methyl-fortimicins B and A and 3-De-O-methyl-4-N-sarcosylfortimicin B
The in vitro antibiotic activities of the following 3-de-0-methylfortimicins (11) 3-De-O-methylfortimicin B
(12) 3-De-O-methylfortimicin A tetrahydrochloride (13) 3-De-o-methyl-4-N-sarcosylfortimicin B
- tetrahydrochloride are listed in Table 1.
The in vitro antibiotic activities were determined by a two-fold agar dilution method using Mueller-Hinton agar, 10 ml per Petri plate. The agar was inoculated with one loopful (0.001 ml loop) of a 1:10 dilution of a 24 hour brvth ; culture of the indicated test organism and incubated at 37 C
for 24 hours. Appropriate fortimicins were used as control antibiotics. The activities are listed in Table 1. Minimum inhibitory.concentrations (MIC) are ex~ressed as mcg/ml.) ~13ZS8~3 ~ C~
. O . u~ o ~1 D ~ O c~ U) ~1 ~ ~ . ~D O ~D
, O ~ ~I ~ oD ~ ~ ~ O ~ ~ ~ ~ ~ ~ ~ ~ ~

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ol s~

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1~ S ~ O ~ ~ ~ ~ ~D ~ O c~l O ~ ~ ~ C~i O ~ ~D
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CE ~t o ~ ~ ~ ~ o ~ ~ cr ~, ~ ~ ~ 1 e ~o ~ ~ Ic ~ ~ cr~¢~
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Claims (10)

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

    l. A method of preparing a pharmaceutically acceptable acid salt of 3-de-0-methylfortimicin A, comprising hydrogen-olyzing tetra-N-benzyloxycarbonyl-3-de-0-methylfortimicin A, with a suitable catalyst in the presence of a selected acid, and recovering the desired salt.
  2. 2. A method according to Claim 1 wherein the acid is selected from the group consisting of hydrochloric, sulfuric and phosphoric acids.
  3. 3. A method according to Claim 2 wherein the acid is hydrochloric acid.
  4. 4. A method according to Claim 2 wherein the acid is sulfuric acid.
  5. 5. A method according to Claim 2 wherein the acid is phosphoric acid.
  6. 6. A method according to Claim 3, 4 or 5 wherein the catalyst comprises palladium or charcoal.
  7. 7. A pharmaceutically acceptable acid salt of 3-de-0-methylfortimicin A, whenever prepared according to the method of Claim 1, or by an obvious chemical equivalent
  8. 8. A hydrochloride salt of 3-de-0-methylfortimicin A, whenever prepared according to the method of Claim 3, or by an obvious chemical equivalent.
  9. 9. 3-De-O-methylfortimicin A sulfate, whenever prepared according to the method of Claim 4, or by an obvious chemical equivalent.
  10. 10. 3-De-O-methylfortimicin A phosphate, whenever prepared according to the method of Claim 5, or by an obvious chemical equivalent.
CA364,855A 1976-12-27 1980-11-17 3-de-0-methylfortimicins Expired CA1132588A (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US754,670 1976-12-27
US05/754,670 US4124756A (en) 1976-12-27 1976-12-27 3-DE-O-Methylfortimicins
CA292,979A CA1089851A (en) 1976-12-27 1977-12-13 3-de-o-methylfortimicins
CA364,855A CA1132588A (en) 1976-12-27 1980-11-17 3-de-0-methylfortimicins

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CA364,855A CA1132588A (en) 1976-12-27 1980-11-17 3-de-0-methylfortimicins
CA000391583A CA1137092A (en) 1976-12-27 1981-12-04 Preparation of 3-de-o-methyl-4-n-acylfortimicins
CA000391582A CA1137093A (en) 1976-12-27 1981-12-04 Preparation of 3-de-o-methyl-4-n-alkylfortimicins

Publications (1)

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CA1132588A true CA1132588A (en) 1982-09-28

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