JPS58188896A - 2-deoxy-3-demethoxyfortimicin a and related compounds - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Foltimycin A is a relatively new antibiotic with good efficacy, but like other classes of antibiotics, it has increased intrinsic activity as well as increased activity against resistant bacterial species. Chemical modifications have been performed to reduce the toxicity of maternal antibiotics. Further addition゛C
Because of the development of aminoglycoside-resistant bacteria, it is important to develop new antibiotics that are either more effective than known antibiotics or provide alternative therapeutic power when resistant bacteria develop.
g Momme 0 This invention is based on the following formula [where 1-7R is hydrogen or lower alkyl, R1 is hydrogen, lower alkyl or an amine-protecting group, and R2 is hydrogen, glycyl, aminoacyl, amino hydroxyacyl,
amine-protected aminoacyl, amine-protected aminohydroxyacyl, or amine-protecting group, R3
is hydrogen or an amine protecting group, R4 and Rs can each be hydrogen or -oso2x (where LX is lower alkyl and phenyl is l.luoyl), or together with uR4 and R5 (collaborative R6 is hydrogen, aminoacyl, amine-protected aminoacyl, aminoalkyl, or amine-protected aminoalkyl, and R7
is hydrogen or forms R6 and R7 (provided that Y is hydrogen, lower alkyl, phenyl or substituted phenyl, and Y
When W is hydrogen or -5o2x using X as above) The term `` is defined by the formula -COR (where R
refers to an acyl group represented by a lower alkyl, acetyl, propionyl, butyryl, valeryl, or a lower alkyl carboxylic acid. "aminoacyl",
Terms such as "hydroxy-substituted aminoacyl" include naturally occurring amino acids such as crisyl, valyl, alanyl, sarcosyl, lysyl, leucyl, prolyl, seryl and the like, as well as 2-hydroxy-4-aminobutyryl and the like. This book includes, but is not limited to, such groups. Amino acid residues are: with the exception of glycyl, β-alanyl and other non-asymmetric amino acid residues.
It can take the structure of D or FiL or a mixture thereof.

The term "lower alkyl" as used herein refers to straight or branched chain alkyl groups having 1 to 6 carbon atoms;
Methyl, ethyl, n-propyl, 1so-furovir, n
-7'thyl, 1so-butyl, tart-butyl, n-
Including, but not limited to, pentyl, 1-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, etc. The term "N-protecting group" or "amine protecting group" is understood by those skilled in the art. These include substituted and unsubstituted compounds such as benzyloxycarbonyl, paramethoxybenzyloxycarbonyl, ethoxycarbonyl, trichloroethoxycarbonyl, 5-butoxycarbonyl, acetyl and trifluoroacetyl. Included are groups such as acyl and substituted and unsubstituted alkoxycarbonyl and arylalkoxycarbonyl. Publications describing such groups and their uses include Carpino, L.;
, New Am1ne ProtectingL2+
n+tpm In (1rg*nlr Syn
Carehea1m, ^peunta or Chem
, Res,, Volume 6, pp. 191-198 (1
975). Substituted amine groups are well known in the art and include, for example, β-aminoethyl, N-methylaminoethyl, N,N-dimethylaminopropyl, 2-hydroxyaminoethyl, 2-hydroxy-4-aminobutyl and the like. contains things.

The term "pharmaceutically acceptable salts" as used herein refers to non-toxic acid addition salts of the compounds of this invention. These bases can be made in situ during final separation and purification, or separately by reacting the free base with a suitable organic or inorganic acid. Typical salts include hydrochloride, hydrobromide, sulfate, acid sulfite, acetate, silarate, valerate, oleate, palmitate, stearate, laurate, and boron. acid salt, benzoate, milk Wk salt, phosphoric acid, tosylate, citrate, maleic acid, fumarate, succinic acid salt, acetate,
Includes napsylate and the like.

Compounds of the present invention include, for example, Staphylococcus aureus, Escherichia colii, Shade monas aeruginosa, Bacillus subtilius, Proteus vulgaris,
It is effective as an antibiotic against infectious species of Durham cathopolar and gram-positive bacteria such as Shigerannai, Almonella teifii and Klebsiella pneumoniae.

The term ``infectious bacterial species'' refers to species for which susceptibility to a particular antibiotic has been demonstrated in standard in vitro susceptibility tests and therefore the value of the in vitro activity of a particular antibiotic against that microorganism has already been determined. It refers to the elm of bacteria or microorganisms that are present. It is common practice in medicine to select antibiotics based on such in vitro tests.

The compound of Example 7, 2-deoxy-3, was tested in a representative screening test with primarily Durham-negative microbial pathogens.
-The activity of the sulfate salt of demethoxyfortemaine A was about 180 times that of the sulfate salt of fortimycin A. This compound is found in Siedomonas aeruginosa, Staphylococcus aureus and Streptococcus. It was found that it has approximately twice the activity of faltimycin sulfate against C. faecalis.

Preferred antibiotics of the invention may be administered parenterally, i.e., intravenously, intramuscularly, intraperitoneally or subcutaneously, for systematic efficacy at a daily dosage of about 5 to about 50 η/day per body weight. K
f, most preferably from about 7 to 11) y/body weight per day i == based on lean body weight. Furthermore, it is preferable to administer the antibiotic in divided doses, ie, in three to four doses each day.

Oral administration for intestinal sterilization is also within the contemplation of the present invention.

The following relates to 2-deoxy-3-demethoxyfortemycin A (8), its antibacterial spectrum and its p4 manufacturing method.

2-Deoxy-3-demethoxyfortemycin has antimicrobial activity against much larger bacteria than fortemycin, especially against Pseudomonadaceae.

2-deoxy-5-demethoxyfortemycin A (8
) is the synthesis method of 1.2. '6'-) So N-benzyloxycarbonyl-3-〇-demethylfortimycin B
It was achieved from (2) or 1, 2. '6'-tri-N-benzyloxycarbonyl-3-0-demethylfortemycin B (2) has already been developed by J.R. Martin and Hischier Niskentadania (J, RoMart
No. 4,124°756 (November 7, 1978)
(Japanese), but the ones mentioned here are 1 and 2.
．． '2''-tetra-N-benzyloxycarbonyl-3-1,2;6'-) by selective hydrolysis of 0-temethylfortimycin A (1)!J -N-benzyloxycarbonyl- 3-0-Demethylfortemycin B (produced by the manufacturing method of 2>.1,2.'6.'2"-
The method for producing tetra-N-benzyloxycarbonyl-3-0-demethylfortemycin A (1) is described by G.R. Martin and G.S.
Martin and J, S, Tadanie
a) in US Pat. No. 4,124,756 (November 7, 1978).

2-deoxy-3-demethoxyfortemycin A (8
) is first manufactured by 1.2. '6'-) So N-benzyloxycarbonyl-3-0-demethylfortemycin B
(2) to 4,5-salicylaldehyde oxazolidine (3). 1.2.
'6'-)di-N-benzineoxycarbonyl-3-0
Other 4,5-oxazolidine derivatives prepared by condensation with suitable aldehydes, such as formaldehyde or benzaldehyde, are also available. The 4,5-saltyraldehyde oxazolidine (3) was then added to the 2,3-di0
- Converted to methanesulfonyl derivative (4). 2.5-
The di-0-methanesulfonyl conductor (ri) was treated with sodium iodide and zinc dust in N,N-dimethylformamide to eliminate the C- and C3-methanesulfonate groups and form the 2,3-double bond. Introducing 1, 2.'6'-)! J-
N-benzyloxycarbonyl-2,3-anhydro-
3-demethoxy-7ortimycin B-4,5-(2-
0-methanesulfonyl) salicylalthioxazolidine (5) is obtained. 1.2. in the effective presence of an aldehyde scavenger such as Girard Reagent T. '6
'-) IJ -N-benzyloxycarbonyl-λ3
-Anhydro-3-demethoxyfuortimycin B-4
, 1.2. by acid-catalyzed cleavage of the oxazolidine ring of 5-(2-0-methanesulfonyl)salicylalthioxazolidine (5). '6'-) So N-benzyloxycarbo--2,5-7-hydro-3-demethoxyfortemycin B (6) is obtained. This can be hydrogenated to give 2-deoxy-3-demethoxyfortemycin B (9) or hydrolyzed to give Z5-anhydro-3-demethoxyfortemycin B (10).

N-(N-benzyloxycarbonylglycyloxy)
Acylation of 1,2:6'-)di-N-benzyloxy-carbonyl-2,3-anhydro-5-demethoxyfortemycin B (6) with succinimide 1.2.
'6. '2''-Tetra-N-benzyl-oxycarbonyl-2,3-anhydro-5-demethoxyfortemycin A (7) is obtained. t 2./4/211-
i'-N-hensyloxycarbonyl-2,3-
Anhydro-3-demethoxyfortemycin A (7
2-deoxy-6-demethoxyfortemycin A (8) was obtained by two catalytic hydrogenations, for example [tetrahydrochloride or Fi
It is liberated as a medically acceptable salt such as the disulfate salt.

J.S. Taddniar, S.R. Martin and B. Klaas
J, R, Martinand P, Kurath
), U.S.C. No. 4.18a319 (February 1980)
1, 2: by the same acylating agent as used in the preparation of 4-N-acylfortemycin B described in May 12, 2013).
'6'-)di-N-benzyloxycarbonyl-2,3
-Anhydro-5-demethoxyfortemycin B (6
) and catalytic hydrogenolysis of the 4-N-acylated rust conductor to form the corresponding 4-N-acyl-2-deoxy-3-
A demethoxyfortimycin B derivative is obtained.

Example 1.2 of 1°20. '4'2'-Tetra N-benzyloxycarbonyl-3-0-demethoxyfortemycin A, a solution prepared from 5% aqueous sodium bicarbonate 40- and methanol 6001Re, was heated under reflux for 4 hours. was cooled and mixed with a mixture of 2 t of Na HC035 aqueous solution and chloroform 500.The chloroform solution was separated and the aqueous solution was extracted three times with chloroform 500.The chloroform solutions were combined and dehydrated. (MgSO4). Evaporation of the chloroform under reduced pressure leaves 16.0 g of 1.2.'6'-tri-N-benzyloxycarbonyl-6-0-demethoxyfortemycin B (2), which is R. Martin and J. Martin a.
U.S. Patent No. 4 to J.
, 124.756 (November 7, 1978) prepared from 3-0-demethoxyfortemycin B.

Example 2゜1.2. '6'-tri-N-benzyloxycarbonyl-3-〇-demethylfortimycin B (2) 1
&Of, a solution of 2.9-1 salicylaldehyde and 320-1 methanol was heated under reflux for 1 hour. Most of the methanol was evaporated under reduced pressure. Residual methanol was removed by co-distillation of chloroform and 1.2. of 194y was removed. '
6'-tri-N-benzyloxycarbonyl-5-o-
Demethylformycin B -4,5-Salicylaldehyde oxazolidine (remaining residue: 'H-NMR (C
DCIs): α975 d (J6'+7 r =
7.0 Hz, CQ-CH3); 2, 25 (NCH
s).

Example 1.2. in pyridine 180d, cooled in a five-water bath. '6'
-) Di-N-benzyloxycarbonyl-3-0-demethylformycin B-4,5-salicylaldehyde oxazolidine (3) Add 21.3- of methanesulfonyl chloride was added dropwise. Stirring was continued with cooling for 15 hours after the addition was complete. Then the apparatus was at ambient temperature. The resulting solution was poured into chloroform at 500+t7! and a mixture of 2 tons of 35% NaHCO aqueous solution. Separate the chloroform solution and dilute the aqueous solution with chloroform 500
+d (several times). Combine the chloroform solution,
It was dehydrated with Mg5O. Evaporate chloroform 248
2-1, 2. '6'-tri-N-benzyloxycarbonyl-2,3-di-0-methanesulfonyl-3-〇-demethylfortimycin (remaining residue: IH-NMR
(CDC1,): δ1.029d (J @I, t/
== 7.3 Hz, CHl-CH5), 2.28
(NCHs);294,! L0? , 521 (08O
z CHs'S).

Example 4゜Sacilidine 1,2:6'-)CuN-benzyloxycarbonyl-
A suspension of 2,3-di-0-methanesulfonyl-3-〇-demethylfortimycin B-4,5-(2-0-methanesulfonylusalicylaldehyde oxazoline) stirred with a magnetic stirrer was stirred in 21. 89 of sodium iodide, 11. of zinc powder and 86 of N,N-dimethylformaldehyde were heated to 100°C.
Solution A was cooled to room temperature and diluted with 500-ml chloroform. The insoluble solids present were removed by filtration. Part 1 was washed with 500 g of an aqueous solution of sodium thiosulfate and 250 g of a 5 g aqueous solution of sodium bicarbonate.

The obtained chloroform solution was dehydrated with MgSO,
Chloroform was evaporated under reduced pressure. Residual DMF was removed by co-distillation with toluene under reduced pressure to give 1.2 of 1.499.
'6'-)di-N-benzyloxycarbonyl-2,3
-Anhydro-3-demethoxyfortimycin B-4
, 5-(2-0-methanesulfonyl)salicylaldehyde oxazolidine (5) was left: 'H-NMR (CD
CIs): δ1.01 J, I,, I=6.5Hz.

C,/-CH,), 2.15 (NCH3); 2
．． 98 (08ChCH2).

Example 5゜1.2!6'-tri-N-benzyloxycarbonyl-
t49f of 2,3-anhydro-3-temethoxyfortimycin B-4,5-(2-0-methane-sulfonyl)salicylaldehyde oxacylidine (5), (L75f, acid resistance α77 !, and 56 ml of methanol were heated under reflux for 55 hours. The resulting solution was cooled and diluted with chloroform 200- and NaHCOs.
A mixture of a 5% aqueous solution of 500% and a chloroform solution mixed together was separated, and the aqueous solution was diluted with 200% of chloroform.
Extracted twice. The chloroform solutions were combined and dried over MgSO4. When chloroform was evaporated in step 1, a pale yellow glassy substance of α9382 remained.

A 1.25 F sample of the product produced by the above method was
20? Methylene chloride-methanol-concentrated ammonium hydroxide (11L51
．． Chromatographic fractionation by elution with a solvent thread of 5:0.1),
0.512r of 1,2;6'-)di-N-benzyloxycarbonyl-2,3-einhydro-3-demethoxyfortimycin 13 (6
) was obtained.

[α:]:8+51.6°(cl, o, CH30H)
; IH-NMR (CDC13): δ1.011 d
(J@/7t=6.4Hz, C6t-Ca5)
, 2.44 (NCHs).

Calculated values for elemental analysis css H2S N4 o: C, 64,94; H, 6,60;
N, 7.97°Actual measurement: C164,91; H,
&/) 1; N, 7.95° Example & 0.490 f(7)1,2:6'-)di-N-benzyloxycarbonyl-43-anhydro-6-zomethoxyfluortimycin 7B( 6), 0.235f N-(N
A magnetically stirred solution of -benzyloxycarbonylglycyl-oxy)succinimide and 25-tetrahydrofuran was kept at room temperature overnight. The resulting solution was mixed with a mixture of 400 ml of a 200-ml aqueous solution of chloroform and a 5-ml aqueous solution of NaHCOa. After separating the chloroform solution, the residue was extracted with 200% chloroform. Total chloroform solution - LMg So
Dehydrated at step 4. α6 by evaporation of chloroform under hot water pressure
237 brown glassy substances remained. This product (Q,
4.00S') was chromatographed in six columns packed with 702 silica gel and eluted with a solvent system consisting of ethyl acetate-hexane (4:1), and 0.501J5' of 1.
2. '6. '2''-tetra-N-benzyl-oxycarbonyl-2,6-anhydro-6-zomethoxyfluorimine A (7 were obtained.

[α),,' + 67.4° (el, 0, CH30
H): Infrared (CDCl2) νmax3440.333
0.1712.1644.1605cIn-1;'
H-NMR (CDC13): δ0.994 d(J,
/, 7+:=/, 1Hz, C6,71=&I Hz,
Car-CH3), 2, 92 (NCH3).

Calculated values for elemental analysis c4s lHsg Na 012:
C, 64,49; H, 6,20: N% 7.83
゜Actual measurement value: C164,29; H, &23: N
, 7.69゜Example 7 2-deoxy-3-pmethoxyfuortimycin A (8
) α2N base acid 179 resistance in methanol and methanol 21
1.2. in a solution of 1R1. '6. '2''-tetra N-benzyloxy-carbonyl-2,3-anhydro-2-demethoxyfuortimycin A (υ(4,0(
1) was catalytically hydrogenated for 20 hours under 3 atmospheres of hydrogen in the presence of 5% Pd/Ci gas 42. Methanol is evaporated under hot water pressure, and the remaining hydrochloric acid is removed by co-distillation with methanol.
2.259 of the tetrahydrochloride salt of deoxy-3-demethoxyfortimycin A remained.

A, G of 50-100 meshes of the above product aqueous solution
2-X 2 (So4') resin column (2,5X2
In addition to 2z), the column was eluted with water. The product-containing fractions were combined and lyophilized to remove water, yielding 249 sulfuric acids of 3-demethoxyfluorumycin (8): [α几'+94.7° (clo, H
2O) (di-sulfuric acid salt); 'H-NMR (D, 0.2 sulfuric acid): δ1.353 d (J, l, 7r engineering 6, 5 Hz
, C6' CH3), 3.05 (NCI], )
; 5.38 d(J, +, 2z-3.0Hz, C
xz H); Mass spectrometry (4-hydrogen salt)-M+□
, measured value as CtaH3iNsOi; 260.26
11: Actual value: 360,260° Elemental analysis (2 sulfuric acid base) Subtracted value as CxaHs3Ns04-2H2SO4・3.5820: C, 31,06; H, 7,17:
N, 11.32; S, IQ, 3/+.

Example 8 1.2. '6'-tri-N-benzyloxycarbonyl-2,5-anhydro-3-demethoxyfortimycin B (6) in 31- and 19++d of 0.2N hydrochloric acid in methanol at 5% pa; “c touch 10.
The tetrahydrogen salt of 2-thioquine-6-demethokifofortimycin B (9) was obtained by evaporation of methanol under reduced pressure. 5479 remained.

Example 10 1.22 1.2. '6'-) di-N-benzyloxycarbonyl-2,3-anhydro-3-demethoxyfuortimycin B (6), 28 m/! of ethanol and 14tt11 of 6N hydrochloric acid solution were prepared. The solvent was evaporated and the residue was triturated six times with 30-methanol. The methanol supernatant was separated from the insoluble residue and combined. The residue obtained from the methanol solution by evaporation of the solvent under reduced pressure was mixed with chloroform-methanol-water-concentrated ammonium hydroxide (2:2:1:i) using a column packed with silica gel.
) was used for elution and chromatographic fractionation. 2.3 by combining the fractions containing the product and evaporating the melt.
-Anhydro-6-zomethoxyfortimycin B (
10) was obtained. The elemental analysis values and spectral properties were consistent with the structure of 2<3>-anhydro-6-zomethoxyfortimycin.

The compounds of the invention are active as systemic antibiotics when injected by parenteral injection, such as by intramuscular, intravenous, intraperitoneal or subcutaneous routes of administration. These compounds can also be administered orally if enteric disinfection is desired; they can also be administered topically and rectally.

Solid dosage forms for oral administration include capsules, tablets, pills, powders or granules. In such solid dosage forms, the active compound is mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also contain, as is common practice, additional substances other than inert diluents, such as lubricants such as magnesium stearate.In the case of capsules, tablets and pills, this preparation The form may also contain a buffering agent.Tablets and pills can also be manufactured with enteric coatings.

Liquid dosage forms for gauze administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirils containing inert diluents commonly used in the art, such as water. Besides such inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, and perfuming agents.

In addition to the active compound, compositions of the invention for parenteral injection may consist of pharmaceutically acceptable sterile aqueous, non-aqueous solutions, suspensions, or emulsions. Examples of suitable non-aqueous carriers, diluents, solvents or excipients include propylene glycol, polyethylene glycol, vegetable oils (eg olive oil), and injectable organic esters such as ethyl oleate. Such compositions may also contain adjuvants such as preservatives, wetting and emulsifying agents, and dispersing agents. These can be sterilized, for example, by filtration through bacteria-trapping filters or by incorporating disinfectants into the composition. , they can also be prepared in the form of sterile solid compositions and dissolved in sterile water or other sterile injection medium immediately before use.

Procedural Amendment H I No. 1 B 58 - May 12th Director General of the Patent Office Wakasugi No. 1] Husband 1, Indication of the case 1982 Special Request No. 61071 2, Name of the invention 2 - Deoxy-3- Relationship with Temethoxyfortimycin A and 1llll Consolidated Compound 3 Amendment Case Patent Applicant Name Abbott Laboratories 4 Agent 07 Address Tokyo Minato (Akasaka 1-1i18 Akasaka Taisei Building (Telephone: 582-7161) 5 , Target of correction 6, Contents of correction (1) Meiwa 1%: “Example 10J 1-
Fruitful example 9” is corrected.

(2) "Hydrochloric acid ~ prepared" in lines 12-13 of specification 28 is changed to "A solution of potassium hydroxide was heated to 85° for 24 hours with stirring under nitrogen. The resulting solution was cooled. 2N hydrochloric acid was added to adjust the pH to 7.''

Claims (1)

[Claims] [However, R in the formula is hydrogen or lower alkyl, and R1
is hydrogen, lower alkyl or amine protecting group; R is hydrogen, glycyl, aminoacyl, aminohydroxyacyl, amine protected aminoacyl, amine protected aminohydroxyacyl or amine protecting group υ;
R3 is hydrogen or an amine protecting group, R4 and R5 are each hydrogen or -OS Ox bond or oxirane, R is hydrogen, aminoacyl, amine-protected aminoacyl, aminoalkyl, or amine-protected aminoalkyl, and C is hydrogen or - and R7 form (provided that Y is hydrogen, lower alkyl, phenyl or substituted phenyl, and when Y is, W is hydrogen or 5OzX). 2. The compound according to claim 1, wherein R is methyl, R1, R2 and R3 are each benzyloxycarbonyl, R4 and R5 are each hydroxy, and R6 and R7 form. 3. The compound according to claim 1, wherein R is methyl, R1, R2 and R3 are each benzyloxycarbonyl, and R4 and R5 each form. Claim 1, wherein 4-7 is methyl, R,, R2 and R3 are each benzyloxycarbonyl, R4 and RIl are each hydrogen, and R6 and R7 form Compounds described. 5, R is methyl, R,, R2 and R3 are each benzyloxycarbonyl, and R4, Rs%
Claim 1 in which R and R7 are each hydrogen
Compounds described in Section. A patent claim in which aR is methyl, R1, R2 and R3 are each benzyloxycarbonyl, R4 and Rs are each hydrogen, fi, R is glycylbenzyloxycarbonyl, and R7 is hydrogen A compound according to item 1 in the range. 7. R is methyl, R1-Rs, Rs, R
4 and R5 are each hydrogen, R6 is glycyl, and R7 is hydrogen;
5. The compound according to claim 1, wherein R6 and R7 are hydrogen. 9. The compound according to claim 1, wherein R is methyl, R1, R, and R3 are each hydrogen, R4 and R4 form a double bond, and R6 and 8 are hydrogen. .