GB1582483A – 6′-n-methyl-xk-88-5 and process for the production thereof
– Google Patents
GB1582483A – 6′-n-methyl-xk-88-5 and process for the production thereof
– Google Patents
6′-n-methyl-xk-88-5 and process for the production thereof
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Publication number
GB1582483A
GB1582483A
GB31382/77A
GB3138277A
GB1582483A
GB 1582483 A
GB1582483 A
GB 1582483A
GB 31382/77 A
GB31382/77 A
GB 31382/77A
GB 3138277 A
GB3138277 A
GB 3138277A
GB 1582483 A
GB1582483 A
GB 1582483A
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Prior art keywords
methyl
carbon atoms
formula
compound
water
Prior art date
1976-07-27
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Expired
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GB31382/77A
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Abbott Laboratories
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Abbott Laboratories
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1976-07-27
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1977-07-26
Publication date
1981-01-07
1977-07-26
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Abbott Laboratories
1981-01-07
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Classifications
C—CHEMISTRY; METALLURGY
C07—ORGANIC CHEMISTRY
C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
C07H15/20—Carbocyclic rings
C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
C07H15/222—Cyclohexane rings substituted by at least two nitrogen atoms
C07H15/226—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings
C07H15/234—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
A61P31/04—Antibacterial agents
Description
(54) 6′-N-METHYL-XK-88-5 AND PROCESS FOR THE
PRODUCTION THEREOF
(71) We, ABBOTT LABORATORIES, a Corporation organized and existing under the laws of the State of Illinois, United States of America, of 14th
Street and Sheridon Road, North Chicago, County of Lake, State of Illinois,
United States of America, do hereby declare the invention for which we pray that a patent may be granted to us and the method by which it is to be performed to be particularly described in and by the following statement:- The present invention relates generally to a semi-synthetic derivative of the antibiotic XK-88-5 and more specifically to 6′-N-methyl-XK–888-5 and a method for its production.
XK-88-5 is one factor of a series of related antibiotic compounds produced by culturing a micro-organism such as Streptomyces hofuensis, ATCC 21970 under suitable conditions. XK-88-5 and the fermentative production thereof are described in United States Patent No. 3,939,043 which discloses and claims a method for producing antibiotic compounds of the formula
or -H; Y represents -NH or -OH, and is -NH2 when X is -H; and Z representsH or -OH and is -H when X is -H, which comprises culturing
Streptomyces hofuensis ATCC 21970, or a mutant thereof capable of producing at least one of said compounds, in a nutrient medium containing assimilable sources of nitrogen and carbon until substantial anti-bacterial activity is imparted to said medium and isolating at least one of said compounds therefrom. The XK-88 series of antibiotics are also known as the Seldomycins.
Although XK-88-5 (Seldomycin Factory) exhibits good antibacterial activity, certain bacteria have the ability to enzymatically inactivate the base compound. It has now been found that a particular semi-synthetic derivative of XK-88-5 is not susceptible to such enzymatic inactivation.
The present invention relates to a new derivative of the antibiotic XK-88-5, that is 6′-N-methyl-XK-88-5 represented by the formula:
6′-N-methyl-XK-88-5 is a new compound, which exhibits excellent broad spectrum antibacterial activity and is also effective against those bacteria having a resistance to XK-88-5.
Included in the composition of matter aspect of the invention are the pharmaceutically acceptable, non-toxic acid addition salts of 6′-N methyl-XK-88-5. Suitable acid addition salts are prepared in known manner by, for example, reacting one molecule of 6′-N-methyl-XK–888-5 with one to six molecules of acid. The pharmaceutically acceptable non-toxic acids include various inorganic acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulphuric acid, phosphoric acid and carbonic acid and various organic acids such as acetic acid, fumaric acid, malic acid, citric acid, mandelic acid, tartaric acid, succinic acid and ascorbic acid.
The present invention also relates to a process for producing 6′-N-methyl XK-88-5 which comprises reacting the antibiotic XK-88-5 represented by the formula:
with an agent capable of introducing into the amino group at the 6′-position, a group represented by the general formula
wherein
R is an alkyl group containing from I to 5 carbon atoms, an aralkyl group containing from 7 to 13 carbon atoms, or a substituted or unsubstituted aryl group containing from 6 to 12 carbon atoms, (hereinafter referred to as “agent for carbamation”), in a suitable solvent to prepare an intermediate compound represented by the general formula:
wherein
R has the same significance as defined above; and thereafter reducing the intermediate compound to prepare the 6′-methylated end product.
In accordance with the present invention 6′-N-methyl-K-88-5 is prepared by reacting the antibiotic XK-88-5 with an agent for carbamation to introduce a
group into the amino group at the 6′-posltion of XK-88-5. Thereafter, this intermediate compound is reduced to produce the desired compound. For example, one mole of XK-88-5 dissolved in an appropriate solvent is reacted from 0.1 to 3.0 moles, preferably from 0.3 to 1.5 moles of an agent for carbamation at a temperature of from 200C to 500C, preferably, from -10 C to 300 C. The reaction is usually complete in 0.5 to 48 hours.
As an agent for carbamation, any compound capable of introducing a
group into the amino group at the 6′-position of XK-88-5 may be used. Examples of preferred
groups and corresponding reagents are shown below.
C(CH3)-O-CO- [C(CH3)3-O-CON3]
CH2-O-CO- (CH3-O-COX)
C2 H5-O-CO- (C2H57O-COX)
X-CH2-O-CO- X-CH2-O-COX [R, and R2 in the above formulae may be the same or different and are H, Cl, Br, I, alkyl groups containing from 1 to 5 carbon atoms or alkoxy groups containing from 1 to 5 carbon atoms, and X is Cl, Br or I].
Other specific examples of agents for carbamation are set forth in “Protective
Groups in Organic Chemistry”, pages 56 to 60 (Plenum Press 1973).
Solvents suitable for this reaction include dioxane, tetrahydrofuran, ethylene glycol dimethylether, N,N-dimethylformamide, dimethylsulphoxide, methanol, ethanol, propanol, water, acetone, acetonitrile and pyridine. A mixed solvent of water and an organic solvent (1 :0.1 to 1: 10 by volume) is especially preferred.
The intermediate product is isolated and purified from the thus obtained reaction mixture by column chromatography using adsorbents such as ion exchange resins, silica gel, alumina and cellulose, or thin layer chromatography using for example silica gel, alumina or cellulose.
The thus obtained intermediate compound is reduced by dissolving the compound in a solvent having no active hydrogen atom such as tetrahydrofuran, dioxane or trioxane. Then, from 1 to 6Q moles of lithium-aluminium hydride per mole of antibiotic is added to the solution and the mixture is heated under reflux for 12 to 72 hours. After completion of the reaction, excess lithium-aluminium hydride is decomposed by adding a solvent such as ethyl acetate, ethanol or water.
The solvent is removed by distillation and water is then added to the residue.
Insoluble inorganic compounds are removed and the solution is subjected to chromatography using for example an ion exchange resin or silica gel to isolate the desired 6′-N-methyl-XK-88-5.
The reduction of a benzyloxycarboxyl group using lithium aluminium hydride is a known process described in “Journal of Organic Chemistry” Vol. 20, page 92 (1955) by R. L. Danley et al.
6′-N-methyl-XK-88-5 of the present invention exhibits excellent broad spectrum antibacterial activity and is characterized by a strong antibacterial activity against Serratia marcescens strains which show a resistance to known aminoglycoside antibiotics.
The following Table illustrates the minimum inhibitory concentrations (y/ml) of 6′-N-methyl-XK-88-5 against various Gram-positive and Gram-negative bacteria determined by agar dilution method.
TABLE
6′-N-Methyl
Microorganisms XK-88-5 XK-88-5 Vibriopercolans KY4174 1.25 1.25 Pseudomonas alkaligenes KY4656 0.64 0.16 Erwiniaaroideae KY3241 0.32 0.16 Staphylococcusaureus KY4279 0.16 0.04
Escherichia coli KY4271 0.32 0.32
Bacillus subtilis KY4273 0.08 0.04
Proteus vulgaris KY4277 0.64 0.64
Shigella sonnei KY4281 1.25 0.32
Salmonella typhosa KY4278 0.32 0.32 Klebsiellapneumoniae KY4275 0.16 0.08
Serratia marcescens POE1065 12.5 > 100
Serratia marcescens POE1065 produces acetyl-transferase of kanamycin.
Thc compound of the present invention is useful as an antibacterial agent to clean and disinfect laboratory glassware and surgical instruments, and may also be used for pharmaceutical and sanitation purpose in cleaning and sanitizing hospital rooms and areas.
The acute toxicity (LD,) of 6′-N-methyl-XK-88-5 is 620 mg/kg (i.v.).
The present invention is further illustrated in the following Examples.
Example 1.
Preparation of 6′-N-benzyloxycarbonyl-XK885.
In this Example, five grams of the free base of XK-88-5 was dissolved in a mixture of 190 ml of water and 160 ml of ethyleneglycol-dimethylether and the solution was stirred in an ice bath. To the solution, a solution of 3.09 g of N-benzyloxycarbonyloxysuccinimide dissolved in 30 ml of ethyleneglycoldimethylether was added by drops. The resulting solution was stirred for 3 hours in the ice bath and then allowed to stand at 50C for 15 hours in a refrigerator.
A small amount of precipitate was removed by filtration; and the filtrate was adjusted to pH 4.4 with hydrochloric acid and then passed through a column packed with 500 ml of Amberlite CG50 (NH+4 form) (Rohm and Haas Co., U.S.A.).
(The word “Amberlite” is a Registered Trade Mark).
The column was washed with 1500 ml of water and 400 ml of 0.1N aqueous ammonia. Then, elution was carried out with 0.1N aqueous ammonia checking the components of the eluate by a thin layer chromatography. The eluate was fractionated into 22 ml fractions and fraction Nos. 45 to 87 containing 6′-N-benzyloxycarbonyl XK-88-5 were combined and concentrated to dryness under reduced pressure to obtain 4.1 g of the crude product.
To purify the 6′-N-benzyloxycarbonyl-XK-88-5 , 250 g of silica gel was packed into a column and 4.1 g of the powder obtained in the above step was charged.
Then, elution was carried out with a solvent comprising n-butanol, ethanol, chloroform and concentrated aqueous ammonia (4:5:2:1 by volume). The eluate was fractionated into 22 ml fractions and each of the fractions was checked by a thin layer chromatography. Fraction Nos. 82 to 162 containing only the desired product were combined and concentrated to dryness under reduced pressure to obtain 1.6 g of pure 6′-N-benzyloxycarbonyl-XK885 as a white amorphous powder.
The physiochemical properties of the intermediate compound were as follows:
Melting point: 170 to 1720C
Specific rotation: [a]18 = +115 (C = 0.300, water)
Elementary analysis (%):
Calculated for C26H N6O9 +H3C93: C=51.69, H=7.38, N = 13.65
Found: C = 51.11, H = 7.26, N = 13.22
Figure 1 of the accompanying drawings illustrates the C’3 nuclear magnetic resonance spectrum of 6′-N-benzyloxycarbonyl-XK-88-5 measured in D2 at pD 10. The chemical shift of each signal is shown in p.p.m. from TMS.
158.8, 137.1, 129.5, 129.3, 128.9, 102.7, !00.1, 89.1, 89.1, 86.6, 80.1, 74.9, 69.5, 68.8, 67.7, 67.4 (standard compound), 60.8, 58.8, 57.7, 56.1, 54.8, 51.1, 50.2, 45.4, 36.9, 36.3
Example 2.
Production of 6′-N-methyl-XK-88-5.
To produce the desired end product, 0.81 g of 6′-N-benzyloxycarbonyl XK-88-5 was suspended in 400 ml of tetrahydrofuran. To this suspension, 2.43 g of lithium aluminium hydride was added, and the mixture was heated under reflux for 23 hours with vigorous stirring.
An additional 1.30 g of lithium aluminium hydride was then added and the mixture was heated under reflux for a further 19 hours. After cooling the mixture to room temperature, 5 ml of ethyl acetate was added slowly thereto to decompose the excess lithium aluminium hydride and then 20 ml of water was added in drops to insure complete decomposition of excess lithium aluminium hydride.
The solvent was then removed by distillation under reduced pressure, and 150 ml of water was added to the residue. The mixture was stirred at room temperature for I hour and then subjected to centrifugation to obtain a supernatant solution. To the resulting precipitate, 150 ml of water was added, and the mixture was stirred at room temperature for I hour. This mixture Was also subjected to centrifugation to obtain a supernatant solution. The supernatant solutions were combined and the mixture was concentrated to 30 ml under reduced pressure. The concentrate was adjusted to pH 4.50 with hydrochloric acid. A small amount of precipitate was removed by filtration.
The filtrate was passed through a column of 77 ml of Amberlite CG50 (NH+4 form) which was then washed with 360 ml of water. Then, elution was carried out with 456 ml of 0.1N aqueous ammonia and 456 ml of 0.2N aqueous ammonia while checking the components of the eluate by a thin layer chromatography.
The eluate was fractionated into 12 ml fractions and fraction Nos. 25 to 30 containing unreacted 6′-N-benzyloxy-carbonyl-XK-88-5 were combined and concentrated to dryness under reduced pressure to obtain 0.32 g of the intermediate product. Fraction Nos. 45 to 55 containing the desired compound were combined and concentrated to dryness under reduced pressure to obtain 0.35 g of a crude powder of 6′-N-methyl-XK-88-5.
To purify the 6′-N-methyl-XK-88-5, 25 g of silica gel was packed into a column and 0.35 g of the powder obtained in the above step was charged therein.
Then, elution was carried out with a solvent comprising chloroform, methanol and concentrated aqueous ammonia (1.5:1:1 by volume). The eluate was fractionated into 5 ml fractions and each of the fractions was checked on the components of the eluate by a thin layer chromatography. Fraction Nos. 25 to 32 were combined and concentrated to dryness under reduced pressure to obtain 90 mg of pure 6′-N methyl-XK-88-5 as a white amorphous powder.
The physiochemical properties of this end product were as follows:
Melting Point: 173 to 1750C
Specific rotation: [Ct]DO = +100 (C = 0.342, water)
Elementary analysis (%):
Calculated for C19H40NeO7H2CO3 C = 45.61; H = 8.05; N = 15.96
Found: C = 46.50; H = 7.12; N = 16.38
Molecular weight decided by high resolution mass spectrum: 464.3001
The Rf value was 1.19 on silica gel thin layer chromatography (Developer: n-butanol : ethanol : chloroform : concentrated aqueous ammonia = 4: 5 : 2: 5 by when the R value of the antibiotic XK-88-5 is 1.00.
Figure 2 of the accompanying drawings shows C13 nuclear magnetic resonance spectrum of free base of 6′-N-methyl-XK-88-5 measured in D2O by using dioxane as an internal standard compound. The chemical shift of each signal is shown below in p:p.m. from TMS.
101.9, 99.9, 87.6, 86.8, 80.2, 75.1, 68.9, 67.4 (standard compound), 60.8, 58.7, 57.6, 56.2, 55.3, 54.8, 51.1, 50.2, 37.5, 36.6, 35.8.
Example 3.
In this Example, 100 mg of 6′-N-methyl-XK-88-5 was dissolved in 0.5 ml of water and the solution was adjusted to pH 2.0 with sulphuric acid. To the solution 20 ml of acetone was added in small portions with stirring. The precipitate was separated by filtration, washed with 50 ml of acetone and dried in vacuo to yield 138 mg of sulphate of 6′-N-methyl-XK-88-5 as a white amorphous powder characterized as follows:
Melting point: 210 to 2350C (decomposition)
Specific rotation: [D2O = +91.20 (C = 0.412, water)
Elementary analysis (%):
Calculated for C,9H40N”O7.3H2SO4.H2O: C = 29.37; H = 6.24; N = 10.82; S 12.38
Found: C = 29.00; H = 6.18; N = 10.51; S = 12.01
WHAT WE CLAIM IS:
1. 6′-N-methyl-XK-88-5, having the formula:
and the pharmaceutically acceptable non-toxic acid addition salts thereof.
2. A process for producing 6′-N-methyl-XK-88-5 which comprises reacting the compound XK-88-5 with an agent capable of introducing into the amino group at the 6′-position of XK-88-5, a group represented by the formula:
wherein
R is an alkyl group containing from 1 to 5 carbon atoms, an aralkyl group containing from 7 to 13 carbon atoms, or a substituted or unsubstituted aryl group containing from 6 to 12 carbon atoms in a suitable solvent to prepare an intermediate compound represented by the formula:
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (4)
**WARNING** start of CLMS field may overlap end of DESC **. 101.9, 99.9, 87.6, 86.8, 80.2, 75.1, 68.9, 67.4 (standard compound), 60.8, 58.7, 57.6, 56.2, 55.3, 54.8, 51.1, 50.2, 37.5, 36.6, 35.8. Example 3. In this Example, 100 mg of 6′-N-methyl-XK-88-5 was dissolved in 0.5 ml of water and the solution was adjusted to pH 2.0 with sulphuric acid. To the solution 20 ml of acetone was added in small portions with stirring. The precipitate was separated by filtration, washed with 50 ml of acetone and dried in vacuo to yield 138 mg of sulphate of 6′-N-methyl-XK-88-5 as a white amorphous powder characterized as follows: Melting point: 210 to 2350C (decomposition) Specific rotation: [D2O = +91.20 (C = 0.412, water) Elementary analysis (%): Calculated for C,9H40N”O7.3H2SO4.H2O: C = 29.37; H = 6.24; N = 10.82; S 12.38 Found: C = 29.00; H = 6.18; N = 10.51; S = 12.01 WHAT WE CLAIM IS:
1. 6′-N-methyl-XK-88-5, having the formula:
and the pharmaceutically acceptable non-toxic acid addition salts thereof.
2. A process for producing 6′-N-methyl-XK-88-5 which comprises reacting the compound XK-88-5 with an agent capable of introducing into the amino group at the 6′-position of XK-88-5, a group represented by the formula:
wherein
R is an alkyl group containing from 1 to 5 carbon atoms, an aralkyl group containing from 7 to 13 carbon atoms, or a substituted or unsubstituted aryl group containing from 6 to 12 carbon atoms in a suitable solvent to prepare an intermediate compound represented by the formula:
and thereafter reducing the intermediate compound to prepare 6′-N-methyl
XK-88-5.
3. A process for producing 6′-N-methyl-XK-88-5 substantially as herein described with reference to Example 2 or 3.
4. 6′-N-methyl-XK-85 when prepared by a process as claimed in either of
Claims 2 and 3.
GB31382/77A
1976-07-27
1977-07-26
6′-n-methyl-xk-88-5 and process for the production thereof
Expired
GB1582483A
(en)
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JP8865576A
JPS5315343A
(en)
1976-07-27
1976-07-27
Novel antibiotic derivatives and their preparation
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GB1582483A
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1981-01-07
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Priority Date
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GB1582483A
(en)
1976-07-27
1977-07-26
6′-n-methyl-xk-88-5 and process for the production thereof
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AR214081A1
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AU507488B2
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BE
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BE857167A
(en)
CA
(1)
CA1087612A
(en)
DE
(1)
DE2733964A1
(en)
FR
(1)
FR2359853A1
(en)
GB
(1)
GB1582483A
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NL7708324A
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Bosch Gmbh Robert
Process for producing a composite from two plastic parts
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1976-07-27
JP
JP8865576A
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active
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1977
1977-07-21
AR
AR268516A
patent/AR214081A1/en
active
1977-07-22
AU
AU27245/77A
patent/AU507488B2/en
not_active
Expired
1977-07-25
CA
CA283,423A
patent/CA1087612A/en
not_active
Expired
1977-07-26
BE
BE179649A
patent/BE857167A/en
unknown
1977-07-26
GB
GB31382/77A
patent/GB1582483A/en
not_active
Expired
1977-07-27
NL
NL7708324A
patent/NL7708324A/en
not_active
Application Discontinuation
1977-07-27
FR
FR7723115A
patent/FR2359853A1/en
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NL7708324A
(en)
1978-01-31
DE2733964A1
(en)
1978-03-02
AU2724577A
(en)
1979-01-25
BE857167A
(en)
1978-01-26
CA1087612A
(en)
1980-10-14
JPS5315343A
(en)
1978-02-13
AR214081A1
(en)
1979-04-30
FR2359853A1
(en)
1978-02-24
AU507488B2
(en)
1980-02-14
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1981-09-03
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Application of which complete specification have been accepted and published, but patent is not sealed
