DE19626020A1 - Synthetic siderophore compounds - Google Patents
Synthetic siderophore compoundsInfo
- Publication number
- DE19626020A1 DE19626020A1 DE1996126020 DE19626020A DE19626020A1 DE 19626020 A1 DE19626020 A1 DE 19626020A1 DE 1996126020 DE1996126020 DE 1996126020 DE 19626020 A DE19626020 A DE 19626020A DE 19626020 A1 DE19626020 A1 DE 19626020A1
- Authority
- DE
- Germany
- Prior art keywords
- arom
- myxochelin
- quart
- amide
- nitrile
- 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.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/42—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
- C07C255/43—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms the carbon skeleton being further substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B57/00—Other synthetic dyes of known constitution
- C09B57/10—Metal complexes of organic compounds not being dyes in uncomplexed form
Abstract
Description
Die Erfindung betrifft neue synthetische Siderophore der allgemeinen Form:The invention relates to new synthetic siderophores of the general form:
Für eine Reihe von unter anderen auch stark pathogenen Bakterien stellen die Verbindungen 1-R-5 äußerst effektive Eisentransportsysteme dar.For a number of bacteria, which are also highly pathogenic, the Compounds 1-R-5 are extremely effective iron transport systems.
Die Erfindung betrifft ferner den Siderophor Myxochelin F (1) sowie das Verfahren zur Herstellung (7 Stufen) seiner D,L-Form, das exemplarisch für alle weiteren hier beanspruchten Siderophore aufgezeigt wird.The invention further relates to the siderophore myxochelin F (1) and the method for Production (7 stages) of its D, L shape, which is exemplary for all others here claimed siderophores is shown.
Stufe 1: Darstellung von (D,L)-2-Amino-heptandicarbonsäure-dimethylester- Hydrochlorid (1a):Stage 1: Preparation of (D, L) -2-amino-heptanedicarboxylic acid dimethyl ester- Hydrochloride (1a):
5.0 g (28.5 mmol) (D,L)-2-Amino-heptandicarbonsäure (Fa. Bachem, Schweiz), werden in
ca. 100 ml trockenem Methanol suspendiert. Unter Rühren wird solange HClg eingeleitet,
bis die Lösung klar wird. Über Nacht wird gerührt, danach i.V. eingeengt. Das Rohprodukt
wird über eine Flash-Chromatographie an Kieselgel Si60 (Merck, Darmstadt) mit
n-Hexan/Essigsäureethylester= 7 : 3 gereinigt. Es werden 4.78 g (70%) an 1a isoliert.
APCI-MS: m/z (%)= 520 (50) [M+H]⁺, 542 (6) [M+Na]⁺, 317 (100). -
¹³C-NMR (75.4 MHz, DMSO-d₆): δ= 23.7 (t, C-4), 23.9 (t, C-3), 29.6 (t, C-5), 33.0 (t,
C-6), 51.4 (d, C-2), 51.9 und 52.9 (q, O-CH₃), 170.2, 173.5 (-C=O). -
Für C₉H₁₈NO₄Cl (MG 239.5)
ber. C 45.09; H 7.52; N 5.85; Cl 14.82,
gef. C 45.07; H 7.66; N 5.64; Cl 15.28.5.0 g (28.5 mmol) (D, L) -2-amino-heptanedicarboxylic acid (from Bachem, Switzerland) are suspended in approx. 100 ml of dry methanol. HCl g is passed in with stirring until the solution becomes clear. The mixture is stirred overnight and then evaporated down in vacuo. The crude product is purified by flash chromatography on silica gel Si60 (Merck, Darmstadt) with n-hexane / ethyl acetate = 7: 3. 4.78 g (70%) of 1a are isolated.
APCI-MS: m / z (%) = 520 (50) [M + H] ⁺, 542 (6) [M + Na] ⁺, 317 (100). - 13 C-NMR (75.4 MHz, DMSO-d₆): δ = 23.7 (t, C-4), 23.9 (t, C-3), 29.6 (t, C-5), 33.0 (t, C-6) , 51.4 (d, C-2), 51.9 and 52.9 (q, O- C H₃), 170.2, 173.5 (- C = O). -
For C₉H₁₈NO₄Cl (MG 239.5)
calc. C 45.09; H 7.52; N 5.85; Cl 14.82,
found C 45.07; H 7.66; N 5.64; Cl 15.28.
Stufe 2: Darstellung von (D,L)-2-Amino-[N-(2,3-Dibenzyloxi-benzoyl)]heptandicarbonsäure
dimethylester (1b):
1.5 g 2,3-Dibenzyloxibenzoesäure (4.5 mmol), hergestellt nach /2/, werden in einem Kolben
mit Trockenrohr in 50 ml absolutem Dichlormethan gelöst und nacheinander mit 1.08 g 1a
(4.5 mmol), 1.44 g TBTU (4.5 mmol) sowie mit 1.74 g (13.5 mmol, drei Equiv.) Hünig-
Base versetzt. Es wird für 72 h gerührt.Step 2: Preparation of (D, L) -2-amino- [N- (2,3-dibenzyloxybenzoyl)] heptanedicarboxylic acid dimethyl ester (1b):
1.5 g of 2,3-dibenzyloxybenzoic acid (4.5 mmol), prepared according to / 2 /, are dissolved in a flask with a drying tube in 50 ml of absolute dichloromethane and successively with 1.08 g of 1a (4.5 mmol), 1.44 g of TBTU (4.5 mmol) and with 1.74 g (13.5 mmol, three equiv.) Of Hünig base are added. It is stirred for 72 h.
Zur Aufarbeitung wird die organische Phase mit 1) 50 ml 5 proz. HCl, 2) mit gesättigter
NaHCO₃-Lösung und 3) mit ges. NaCl-Lösung gewaschen. Sie wird mit MgSO₄ getrocknet
und i.V. eingeengt. Gereinigt wird mittels Flash-Chromatographie an Kieselgel Si60
(Merck, Darmstadt), Laufmittel: n-Hexan-Essigsäureethylester = 1 : 1. Ausbeute: 630 mg
(27%, als heller Sirup).
IR (KBr): ν = 3360, (NH), 2925 (CH), 1730 (Ester-CO), 1655 (Amid-I), 1560 cm-1 (Amid-
II). - APCI-MS: m/z (%) = 520 (50) [M+H]⁺, 542 (6) [M+Na]⁺, 317 (100). -
¹³C-NMR (75.4 MHz, CDCl₃): δ = 24.5 (t, C-4), 25.1 (t, C-5), 31.7 (t, C-3), 33.7 (t, C-
6), 51.6 (d, C-2), 52.3 und 52.6 (q, O-CH₃), 71.4 und 76.3 (t, O-CH₂-Phenyl), 117.4,
123.5, 124.7 (d, arom. =C-H), 126.8 (s, arom. =C-), 128.0, 128.7, 128.9, 129.0 (je 2 ×
d, arom. =C-H), 128.5 und 128.8 (s, arom. =C-), 136.5 und 136.6 (s, arom. =C-), 147.2
und 152.0 (s, arom. =C-O), 165.2 (s, Amid-CO), 173.0 und 174.0 (Ester-CO). -
Für C₃₀H₃₃NO₇ (MG 519.60)
ber. C 69.35; H 6.40; N 2.70;
gef. C 68.70; H 6.31; N 3.01.For working up, the organic phase with 1) 50 ml of 5 percent. HCl, 2) with saturated NaHCO₃ solution and 3) with sat. Washed NaCl solution. It is dried with MgSO₄ and evaporated down iV. It is purified by means of flash chromatography on silica gel Si60 (Merck, Darmstadt), eluent: n-hexane-ethyl acetate = 1: 1. Yield: 630 mg (27%, as a light syrup).
IR (KBr): ν = 3360, (NH), 2925 (CH), 1730 (ester-CO), 1655 (amide-I), 1560 cm -1 (amide-II). - APCI-MS: m / z (%) = 520 (50) [M + H] ⁺, 542 (6) [M + Na] ⁺, 317 (100). - 13 C-NMR (75.4 MHz, CDCl₃): δ = 24.5 (t, C-4), 25.1 (t, C-5), 31.7 (t, C-3), 33.7 (t, C-6), 51.6 (d, C-2), 52.3 and 52.6 (q, O- C H₃), 71.4 and 76.3 (t, O- C H₂-phenyl), 117.4, 123.5, 124.7 (d, arom. = C -H), 126.8 (s, arom. = C -), 128.0, 128.7, 128.9, 129.0 (each 2 × d, arom. = C -H), 128.5 and 128.8 (s, arom. = C -), 136.5 and 136.6 (s , arom. = C -), 147.2 and 152.0 (s, arom. = C -O), 165.2 (s, amide-CO), 173.0 and 174.0 (ester-CO). -
For C₃₀H₃₃NO₇ (MG 519.60)
calcd. C 69.35; H 6.40; N 2.70;
found C 68.70; H 6.31; N 3.01.
Stufe 3: Darstellung von (D,L)-2-Amino-[N-(2,3-Dibenzyloxi-benzoyl)]heptandicarbonsäure
diamid (1c):
630 mg (1.2 mmol) 1b werden in 150 ml Methanol gelöst, die Lösung wird auf -5°C
abgekühlt. Für 3 h wird durch die gekühlte Lösung NH₃-Gas geleitet. Die noch kühle
Lösung wird in einen Autoklaven gegeben, der verschlossen für 4 Tage bei RT belassen
wird. Nach vorsichtigem Belüften wird die Lösung i.V. eingeengt, Ausbeute 470 mg (80%)
kristallines 1c, Fp. 200-203 °C.
IR (KBr): ν= 3390 (NH), 3180 und 3250 (NH₂), 2850, 2930, 3020, 3050 (CH), 1640 und
1650 (Amid-I), 1520 cm¹ (Amid-II). - CI-MS (NH₃): m/z(%) =490(22) [M+H]⁺, 472 (18)
[M-H₂O+H]⁺, 455 (55), 365 (100), 337 (56), 275 (81), 247 (48), 11(76). -
¹³C-NMR (75.4 MHz, DMSO-d₆): δ (ppm) = 24.8 (t, C-4), 24.9 (t, C-5), 32.3 (t, C-3),
34.9 (t, C-6), 52.6 (d, C-2), 70.4 und 75.1 (t, -O-CH₂-Phenyl), 116.6, 121.6, 124.3 (d,
arom. =C-H), 128.2, 128.2, 128.6, 128.8 (je 2 × d, arom. =C-H), 136.7 und 136.8 (s,
arom. =C-), 145.8 und 151.8 (s, arom. =C-O), 164.5 (s Amid-CO), 173.6 und 174.3
(Ester-CO). -
Für C₂₈H₃₁N₃O₅ (MG 489.58)
ber. C 69.69; H 6.38; N 8.58;
gef. C 68.50; H 6.29; N 8.48.Step 3: Preparation of (D, L) -2-amino- [N- (2,3-dibenzyloxybenzoyl)] heptanedicarboxylic acid diamide (1c):
630 mg (1.2 mmol) 1b are dissolved in 150 ml methanol, the solution is cooled to -5 ° C. NH 3 gas is passed through the cooled solution for 3 h. The still cool solution is placed in an autoclave, which is left closed for 4 days at RT. After careful ventilation, the solution is evaporated down in vacuo, yield 470 mg (80%) of crystalline 1c, mp. 200-203 ° C.
IR (KBr): ν = 3390 (NH), 3180 and 3250 (NH₂), 2850, 2930, 3020, 3050 (CH), 1640 and 1650 (amide-I), 1520 cm-1 (amide-II). CI-MS (NH₃): m / z (%) = 490 (22) [M + H] ⁺, 472 (18) [M-H₂O + H] ⁺, 455 (55), 365 (100), 337 (56), 275 (81), 247 (48), 11 (76). -
13 C-NMR (75.4 MHz, DMSO-d₆): δ (ppm) = 24.8 (t, C-4), 24.9 (t, C-5), 32.3 (t, C-3), 34.9 (t, C- 6), 52.6 (d, C-2), 70.4 and 75.1 (t, -O- C H₂-phenyl), 116.6, 121.6, 124.3 (d, arom. = C -H), 128.2, 128.2, 128.6, 128.8 (2 × d, arom. = C -H), 136.7 and 136.8 (s, arom. = C -), 145.8 and 151.8 (s, arom. = C -O), 164.5 (s amide- C O), 173.6 and 174.3 (ester- C O). -
For C₂₈H₃₁N₃O₅ (MG 489.58)
calcd. C 69.69; H 6.38; N 8.58;
found C 68.50; H 6.29; N 8.48.
Stufe 4: Darstellung von (D,L)-2-Amino-[N-(2,3-dibenzyloxi-benzoyl)]heptandinitril (1d):
Es werden 450 mg (0.92 mmol) 1c, 0.3 ml (3.68 mmol) Pyridin und 200 mg (0.62 mmol)
Triphosgen in 80 ml getrocknetem Dichlormethan gelöst und für 1 h bei RT gerührt. Zur
Aufarbeitung wird die organische Phase mit 1) 5 proz. HCl und 2) mit ges. NaCl-Lösung
extrahiert. Sie wird über MgSO₄ getrocknet und i.V. eingeengt; dabei werden 350 mg (84
%) reines 1d erhalten.Step 4: Preparation of (D, L) -2-amino- [N- (2,3-dibenzyloxi-benzoyl)] heptane nitrile (1d):
450 mg (0.92 mmol) 1c, 0.3 ml (3.68 mmol) pyridine and 200 mg (0.62 mmol) triphosgene are dissolved in 80 ml dried dichloromethane and stirred for 1 h at RT. For working up, the organic phase with 1) 5 percent. HCl and 2) with sat. NaCl solution extracted. It is dried over MgSO₄ and evaporated down iV; this gives 350 mg (84%) of pure 1d.
IR (KBr): ν = 3330 (-NH), 2870, 2925, 3020, 3055 (-CH), 2235 (-CN), 1650 (Amid-I),
1570 (Amid-II) cm-1. - CI-MS (NH₃): m/z (%) = 454 (100) [M+H]⁺, 471(8) [M+NH₄]⁺,
427 (39) [M-CN+H]⁺, 337 (89) [M-CN-Benzyl+H]⁺. -
¹³C-NMR (75.4 MHz, CDCl₃): δ (ppm) = 16.9 (t, C-4), 24.5 (t, C-5), 24.7 (t, C-3), 31.8
(t, C-6), 40.1 (d, C-2), 71.5 und 76.8 (t, -O-CH₂-Phenyl), 118.4 und 119.3 (s, -CN),
118.2, 123.7 und 124.8 (d, arom. =C-H), 125.2., 128.7, 128.7 (s, quart. arom. =C-),
129.0, 129,2, 129,3 (6C, d, arom. =C-H), 136.3 und 136.4 (s, arom. =C-), 147.4 und
151.9 (s, arom. =C-O), 164.8 (Amid-CO). -
Für C₂₈H₂₇N₃O₃ (MG 453.55)
ber. C 74.15; H 6.00; N 9.26;
gef. C 73.66; H 6.10; N 9.20.IR (KBr): ν = 3330 (-NH), 2870, 2925, 3020, 3055 (-CH), 2235 (-CN), 1650 (amide-I), 1570 (amide-II) cm -1 . CI-MS (NH₃): m / z (%) = 454 (100) [M + H] ⁺, 471 (8) [M + NH₄] ⁺, 427 (39) [M-CN + H] ⁺, 337 (89) [M-CN-Benzyl + H] ⁺. -
13 C-NMR (75.4 MHz, CDCl₃): δ (ppm) = 16.9 (t, C-4), 24.5 (t, C-5), 24.7 (t, C-3), 31.8 (t, C-6) , 40.1 (d, C-2), 71.5 and 76.8 (t, -O- C H₂-phenyl), 118.4 and 119.3 (s, - C N), 118.2, 123.7 and 124.8 (d, arom. = CH), 125.2., 128.7, 128.7 (s, quart. Arom. = C -), 129.0, 129.2, 129.3 (6C, d, arom. = CH), 136.3 and 136.4 (s, arom. = C -) , 147.4 and 151.9 (s, arom. = C -O), 164.8 (amide-CO). -
For C₂₈H₂₇N₃O₃ (MG 453.55)
calc. C 74.15; H 6.00; N 9.26;
found C 73.66; H 6.10; N 9.20.
Stufe 5.- Darstellung von (D,L)-1,2,6-Triamino-[N²-(2,3-dibenzyloxi-benzoyl)]heptan (1e):
300 mg (0.66 mmol) 1d und 200 mg Co₂B /3/ sowie 0,5 g NaBH₄ werden in 10 ml THF
und 40 ml Methanol gelöst und für 2 h gerührt. Zur Aufarbeitung werden 5 proz. HCl
zugefügt (pH 2-3), sodann wird mit NH₃ basisch gestellt und viermal mit 30 ml CHCl₃
extrahiert (bis der Extrakt auf DC aufgetüpfelt mit Ninhydrin keine positive Reaktion
anzeigt!). Die Chloroform-Lösung wird über MgSO₄ getrocknet und i.V. eingeengt. Es
werden 324 mg öliges Diamin-1e als Rohprodukt erhalten, das ohne Reinigung in die
folgende Reaktion eingesetzt wird.Step 5.- Preparation of (D, L) -1,2,6-triamino- [N²- (2,3-dibenzyloxi-benzoyl)] heptane (1e):
300 mg (0.66 mmol) 1d and 200 mg Co₂B / 3 / and 0.5 g NaBH₄ are dissolved in 10 ml THF and 40 ml methanol and stirred for 2 h. For processing 5 percent. HCl added (pH 2-3), then it is made basic with NH₃ and extracted four times with 30 ml CHCl₃ (until the extract spotted on TLC with ninhydrin shows no positive reaction!). The chloroform solution is dried over MgSO₄ and evaporated down iV. 324 mg of oily diamine-1e are obtained as a crude product, which is used in the following reaction without purification.
C₂₈H₃₅N₃O₃ (MG 461.61)C₂₈H₃₅N₃O₃ (MG 461.61)
Stufe 6: Darstellung von (D,L)-1,2,6-Triamino-tris-[N¹,N²,N⁶-(2,3-dibenzyloxi-benzoyl)]-
heptan (1f):
300 mg Rohprodukt 1e aus der Vorreaktion werden mit 417 mg TBTU (1.23 mmol), 0.43
g Dibenzyloxibenzoesäure (1.23 mmol) und 0.44 ml (2.6 mmol) Hünig-Base in 50 ml
trockenem Dichlormethan gelöst und bei RT für 72 h gerührt. Die Aufarbeitung erfolgt wie
für 1b beschrieben. Gereinigt wird mittels Flash-Chromatographie mit dem Laufmittel
n-Hexan/Essigsäureethylester = 1 : 1. Es werden 311 mg 1f erhalten, 43% bezogen auf 1d aus
Stufe 4.Step 6: Preparation of (D, L) -1,2,6-triamino-tris- [N¹, N², N⁶- (2,3-dibenzyloxi-benzoyl)] heptane (1f):
300 mg of crude product 1e from the preliminary reaction are dissolved in 50 ml of dry dichloromethane with 417 mg of TBTU (1.23 mmol), 0.43 g of dibenzyloxybenzoic acid (1.23 mmol) and 0.44 ml (2.6 mmol) and stirred at RT for 72 h. The processing is carried out as described for 1b. It is cleaned by means of flash chromatography with the mobile phase n-hexane / ethyl acetate = 1: 1. 311 mg 1f are obtained, 43% based on 1d from stage 4.
IR (KBr): ν = 3370 (NH), 2850, 2915, 3020, 3055 (CH), 1630 (Amid-I), 1565 cm-1
(Amid-II). - ESI-MS: m/z (%): 1094.4 (100) [M+H]⁺, 1116.5 (65) [M+Na]⁺, 1132.4 (36)
[m+K]⁺. - ¹³C-NMR (75.4 MHz, CDCl₃), δ (ppm) = 25.7 (t, C-5), 26.9 (t, C-4), 29.2 (t,
C-6), 32.3 (t, C-3), 39.7 (t, C-7), 43.5 (t, C-1), 49.9 (d, C-2), 71.4, 71.4, 71.4, 75.9,
76.2, 76.5 (t, -O-CH₂-Phe), 117.0, 117.1, 117.2 (d, arom. =CH-), 123.4, 123.6, 123.7
und 124.4, 124.5, 124.6 (d, arom. =CH-), 127.2, 127.7, 128.0 (s, quart. arom. =C-),
127.8, 127.9, 127.9, 128.5, 128.5, 128.7, 128.7, 128.8, 128.80, 128.85, 128.85, 128.90,
128.90, 128.93, 128.93 (alle als d, arom. =CH-), 136.57, 136.6, 136.6, 136.63, 136.7,
136.7, (s, quart. arom. =C-), 146.9, 147.0, 147.1 (s, quart. =C-O), 151.9, 152.0, 152.0
(s, quart. =C-O), 165.2, 165.4, 165.9 (s, Amid-CO). -
Für C₇₀H₆₇N₃O₉ (MG 1094.33)
ber. C 76.83; H 6.17; N 3.84;
gef. C 75.91; H 6.23; N 4.19.IR (KBr): ν = 3370 (NH), 2850, 2915, 3020, 3055 (CH), 1630 (amide-I), 1565 cm -1 (amide-II). - ESI-MS: m / z (%): 1094.4 (100) [M + H] ⁺, 1116.5 (65) [M + Na] ⁺, 1132.4 (36) [m + K] ⁺. - 13 C-NMR (75.4 MHz, CDCl₃), δ (ppm) = 25.7 (t, C-5), 26.9 (t, C-4), 29.2 (t, C-6), 32.3 (t, C-3 ), 39.7 (t, C-7), 43.5 (t, C-1), 49.9 (d, C-2), 71.4, 71.4, 71.4, 75.9, 76.2, 76.5 (t, -O- C H₂-Phe ), 117.0, 117.1, 117.2 (d, arom. = C H-), 123.4, 123.6, 123.7 and 124.4, 124.5, 124.6 (d, arom. = C H-), 127.2, 127.7, 128.0 (s, quart. arom. = C -), 127.8, 127.9, 127.9, 128.5, 128.5, 128.7, 128.7, 128.8, 128.80, 128.85, 128.85, 128.90, 128.90, 128.93, 128.93 (all as d, arom. = C H-), 136.57 , 136.6, 136.6, 136.63, 136.7, 136.7, (s, quart. Arom. = C -), 146.9, 147.0, 147.1 (s, quart. = C -O), 151.9, 152.0, 152.0 (s, quart. = C -O), 165.2, 165.4, 165.9 (s, amide-CO). -
For C₇₀H₆₇N₃O₉ (MG 1094.33)
calc. C 76.83; H 6.17; N 3.84;
found C 75.91; H 6.23; N 4.19.
Stufe 7: Darstellung von (D,L)-1,2,6-Triamino-tris-[N¹,N²,N⁶-(2,3-dihydroxi-benzoyl)]heptan
(Myxochelin F, 1):
113 mg (0. 1 mmol) 1f werden in 20 ml THF und 30 ml Methanol gelöst und mit Pd/C-H₂
für 2 h bei Normaldruck hydriert. Über Kieselgur wird filtriert, die Lösung i.V. eingeengt,
Ausbeute 50 mg, 87% . - IR (KBr): ν = 3360 (NH), 2920, 2850 (CH), 1640 (Amid-I),
1580 (Aromat), 1540 cm-1 (Amid-II). - ESI-MS: m/z (%) = 576 (100) [M+Na]⁺. -
¹³C-NMR (100.6 MHz, CD₃OD): δ (ppm) = 26.9 (t, C-4), 27.8 (t, C-5), 30.3 (t, C-6),
33.1 (t, C-3), 40.4 (t, C-7), 44.6 (t, C-1), 51.2 (d, C-2), 116.9, 116.9, 117.0 (s, quart.
arom. =C-), 118.7, 118.9, 119.0, 119.6, 119.7, 119.7 (alle d, arom. =CH-), 147.3,
147.3, 147.4 (s, arom. =C-O-), 150.2, 150.2, 150.3 (s, arom. =C-O-), 171.5, 171.8,
172.0 (s,Amid-CO). -
Für C₂₈H₃₁N₃O₉ (MG 553.58)
ber. C 60.75; H 5.64; N 7.59;
gef. C 53.30; H 4.73; N 6.37.Step 7: Preparation of (D, L) -1,2,6-triamino-tris- [N¹, N², N⁶- (2,3-dihydroxi-benzoyl)] heptane (Myxochelin F, 1):
113 mg (0.1 mmol) of 1f are dissolved in 20 ml of THF and 30 ml of methanol and hydrogenated with Pd / C-H₂ for 2 h at normal pressure. It is filtered through diatomaceous earth, the solution is evaporated down in vacuo, yield 50 mg, 87%. - IR (KBr): ν = 3360 (NH), 2920, 2850 (CH), 1640 (Amid-I), 1580 (Aromat), 1540 cm -1 (Amid-II). - ESI-MS: m / z (%) = 576 (100) [M + Na] ⁺. -
13 C-NMR (100.6 MHz, CD₃OD): δ (ppm) = 26.9 (t, C-4), 27.8 (t, C-5), 30.3 (t, C-6), 33.1 (t, C-3) , 40.4 (t, C-7), 44.6 (t, C-1), 51.2 (d, C-2), 116.9, 116.9, 117.0 (s, quart. Arom. = C -), 118.7, 118.9, 119.0 , 119.6, 119.7, 119.7 (all d, arom. = C H-), 147.3, 147.3, 147.4 (s, arom. = C -O-), 150.2, 150.2, 150.3 (s, arom. = C -O- ), 171.5, 171.8, 172.0 (s, amide CO). -
For C₂₈H₃₁N₃O₉ (MG 553.58)
calc. C 60.75; H 5.64; N 7.59;
found C 53.30; H 4.73; N 6.37.
Die Erfindung betrifft ferner den Siderophor Myxochelin C-Nitril (2) sowie das Verfahren zu seiner Herstellung.The invention further relates to the siderophore myxochelin C-nitrile (2) and the method for its manufacture.
Die neue bisher noch nicht bekannte Substanz wird im folgenden anhand ihrer Darstellung und mit ihren spektroskopischen Eigenschaften beschrieben.The new substance, not yet known, is shown below based on its representation and described with their spectroscopic properties.
Sie wird erhalten aus: (L)-2,6-Diamino-bis-[N²,N⁶-(2,3-dibenzyloxi-benzoyl)]-hexan
carbonsäureamid (2a), das selbst aus dem käuflich zu erwerbenden L-Lysinamid dargestellt
wird. Die spektroskopischen Merkmale von 2a sind die folgenden:[α] = -9 (c = 0.5 in Aceton). - IR (KBr): ν = 3371, 3200 (NH), 3032, 2930 (CH),
1651 (Amid-I), 1526 cm-1 (Amid-II). - ¹³C-NMR (75.4 MHz, CDCl₃): δ (ppm) = 23.03 (t,
C-4), 28.9 (t, C-5), 30.6 (t, C-3), 39.1 (t, C-6), 53.1 (d, C-2), 71.3, 71.4, 76.3, 76.4 (t,
-O-CH₂-Phenyl), 116.9, 117.4, 123.0, 123.3, 124.4, 124.4 (d, arom. =CH-), 126.7, 127.3
(s, quart. arom. =C-), 127.6, 127.6, 127.8, 128.2 (d, arom. =CH-), 128.3 (d, 10 × arom.
-CH-), 128.7 (d, 5 × arom. =CH-), 128.9 (d, arom. =CH-), 136.2,136.3, 136.4, 136.4,
(s, quart. arom. =C-), 146.8, 146.9, 151.7, 151.7 (s, =C-O-), 165.1, 165.6 (s, sek. Amid-
C=), 173.7 (s, prim. Amid-CO). -
Für C₄₈H₄₇N₃O₇ (MG 777.34)
ber. C 74.16; H 6.10; N 5.41;
gef. C 72.60; H 6.07; N 4.60.It is obtained from: (L) -2,6-diamino-bis- [N², N⁶- (2,3-dibenzyloxi-benzoyl)] - hexane carboxamide (2a), which is itself prepared from the commercially available L-lysinamide becomes. The spectroscopic features of 2a are as follows: [α] = -9 (c = 0.5 in acetone). - IR (KBr): ν = 3371, 3200 (NH), 3032, 2930 (CH), 1651 (amide-I), 1526 cm -1 (amide-II). - 13 C-NMR (75.4 MHz, CDCl₃): δ (ppm) = 23.03 (t, C-4), 28.9 (t, C-5), 30.6 (t, C-3), 39.1 (t, C-6 ), 53.1 (d, C-2), 71.3, 71.4, 76.3, 76.4 (t, -O- C H₂-phenyl), 116.9, 117.4, 123.0, 123.3, 124.4, 124.4 (d, arom. = C H- ), 126.7, 127.3 (s, quart. Arom. = C -), 127.6, 127.6, 127.8, 128.2 (d, arom. = C H-), 128.3 (d, 10 × arom. - C H-), 128.7 (d, 5 × arom. = C H-), 128.9 (d, arom. = C H-), 136.2,136.3, 136.4, 136.4, (s, quart. arom. = C -), 146.8, 146.9, 151.7 , 151.7 (s, = C -O-), 165.1, 165.6 (s, sec. Amide-C =), 173.7 (s, primary amide-CO). -
For C₄₈H₄₇N₃O₇ (MG 777.34)
calcd. C 74.16; H 6.10; N 5.41;
found C 72.60; H 6.07; N 4.60.
Synthese von (L)-2,6-Diamino-bis-[N²,N⁶,-(2,3-dibenzyloxi-benzoyl)]hexan-nitril (2b):
0.98 g (1.2 mmol) 2a werden in 15 ml absolutiertem Dichlormethan gelöst und mit 0.29 ml
Pyridin und 176 mg Triphosgen versetzt. Nach Aufarbeiten - wie für
1d beschrieben - werden 670 mg 2b erhalten (73.6%).[α] = -16.1 (c = 1 in CHCl₃). -
IR (KBr): ν = 3367 (NH), 2866, 2927, 3031, 3064 (CH), 2230 (CN), 1661 (Amid-I), 1520
cm-1 (Amid-II). - ¹³C-NMR (75.4 MHz, CDCl₃): δ (ppm) = 22.7 (t, C-4), 28.4 (t, C-5),
32.1 (t, C-3), 39.0 (t, C-6), 40.3 (d, C-2), 71.3, 71.4, 76.4, 76.6 (t, -O-CH₂-Phe), 117.0,
117.9 (d, arom. =CH-), 118.5 (s, -CN), 123.3, 123.4, 124.4, 124.5 (d, arom. =CH-),
127.6, 127.6, 128.4, 128.4 (d, arom. =C-H), 128.3, 128.4 (s, quart. arom. =C-), 128.7
(4 × C), 128.8 (8 × C), 129.0 (4 × C, alle d, 16 arom. =CH- aus Bn-Gruppen), 135.9,
136.0, 136.2, 136.4 (s, arom. =C- aus Bn-Gruppen), 146.8, 147.1 (s, quart. arom. -O-
C=), 151.6, 151.7 (s, quart. arom. O-C=), 164.5, 165.0 (s, Amid-CO). -
Für C₇₅H₄₅N₃O₆ (MG 759.91)
ber. C 75.87; H 5.97; N 5.53;
gef. C 72.18; H 5.63; N 4.16.Synthesis of (L) -2,6-diamino-bis- [N², N⁶, - (2,3-dibenzyloxybenzoyl)] hexane nitrile (2b):
0.98 g (1.2 mmol) 2a are dissolved in 15 ml absolute dichloromethane and 0.29 ml pyridine and 176 mg triphosgene are added. After working up - as described for 1d - 670 mg 2b are obtained (73.6%). [Α] = -16.1 (c = 1 in CHCl₃). -
IR (KBr): ν = 3367 (NH), 2866, 2927, 3031, 3064 (CH), 2230 (CN), 1661 (amide-I), 1520 cm -1 (amide-II). - 13 C-NMR (75.4 MHz, CDCl₃): δ (ppm) = 22.7 (t, C-4), 28.4 (t, C-5), 32.1 (t, C-3), 39.0 (t, C-6 ), 40.3 (d, C-2), 71.3, 71.4, 76.4, 76.6 (t, -O-CH₂-Phe), 117.0, 117.9 (d, arom. = C H-), 118.5 (s, - C N ), 123.3, 123.4, 124.4, 124.5 (d, arom. = C H-), 127.6, 127.6, 128.4, 128.4 (d, arom. = C -H), 128.3, 128.4 (s, quart. Arom. = C -), 128.7 (4 × C), 128.8 (8 × C), 129.0 (4 × C, all d, 16 aroma. = C H- from Bn groups), 135.9, 136.0, 136.2, 136.4 (s, aroma . = C- from Bn groups), 146.8, 147.1 (s, quart. Aroma. -O- C =), 151.6, 151.7 (s, quart. Aroma. O- C =), 164.5, 165.0 (s, amide -CO). -
For C₇₅H₄₅N₃O₆ (MG 759.91)
calcd. C 75.87; H 5.97; N 5.53;
found C 72.18; H 5.63; N 4.16.
Synthese von (L)-2,6-Diamino-bis-[N²,N⁶-(2,3-dihydroxi-benzoyl)]hexannitril(Myxoc-helin C-
Nitril, 2):
Es werden 90 mg (0.12 mmol) 2b unter Standardbedingungen hydriert. Nach Filtration über
Kieselgur und Einengen i.V. werden 45 mg (95%) 2 isoliert.[α] = -12 (c = 1 in Methanol). -
MG 399.43.Synthesis of (L) -2,6-diamino-bis- [N², N⁶- (2,3-dihydroxy-benzoyl)] hexanenitrile (Myxoc-helin C-nitrile, 2):
90 mg (0.12 mmol) 2b are hydrogenated under standard conditions. After filtration through diatomaceous earth and concentration in vacuo, 45 mg (95%) 2 are isolated. [Α] = -12 (c = 1 in methanol). - MG 399.43.
Ferner betrifft die Erfindung das Myxochelin D-Nitril (3) und das Verfahren zu seiner Herstellung. 3 wird - wie schon für 2 dargestellt - aus dem Tetra-benzyl-geschützten Myxochelin D-Nitril (3a) durch hydrogenolytische Spaltung an Pd/C mittels H₂ erhalten. 3a ist wie folgt charakterisiert:The invention further relates to the myxochelin D-nitrile (3) and the process for its Manufacturing. 3 is - as already shown for 2 - from the tetra-benzyl-protected Myxochelin D-nitrile (3a) obtained by hydrogenolytic cleavage on Pd / C using H₂. 3a is characterized as follows:
(L)-2,5-Diamino-bis-[N²,N⁵-(2,3-dibenzyloxi-benzoyl)]pentan-nitril
(Tetra-O-benzyl-Myxochelin D-Nitril, 3a):Fp. 134-136°C. - [α] = -18.4 (c = 1 in Methanol). - IR (KBr): ν = 3360 (NH), 3015,
3065, 2900, 2925, 2860 (CH), 1650 (Amid-I), 1520 cm-1 (Amid-II). -
CI-(+)-MS: m/z (%) = 746 (100) [M+H]⁺. -
¹³C-NMR (75.9 MHz, CDCl₃): δ (ppm) = 25.4 (t, C-4), 30.0 (t, C-3), 38.5 (t, C-5), 40.3
(d, C-2), 71.3, 71.4, 76.5, 76.7 (t, -O-CH₂-Phenyl), 117.1, 117.9 (d, arom. =CH-), 118.3
(s, -CN), 123.4, 123.5,124.4, 124.5 (d, arom. =CH-), 127.6, 127.7 (d, arom. =CH-),
128.3, 128.4 (s, quart. arom. =C-), 128.7, 128.8, 128.9, 129.1(18 C, d, arom. =CH-),
135.8, 136.2, 136.3, 136.4 (s, qart. arom. =C-), 146.9, 147.1 (s, quart. arom. -O-C=),
151.6, 151.63 (s, quart. arom. -O-C=), 164.4, 165.0 (s, sek. Amid-CO). -
Für C₄₇H₄₃N₃O₆ (MG 745.87)
ber. C 75.68; H 5.81; N 5.63;
gef. C 75.66; H 5.80; N 5.36.
(L) -2,5-diamino-bis- [N², N⁵- (2,3-dibenzyloxi-benzoyl)] pentane-nitrile (tetra-O-benzyl-myxochelin D-nitrile, 3a): mp. 134-136 ° C. - [α] = -18.4 (c = 1 in methanol). - IR (KBr): ν = 3360 (NH), 3015, 3065, 2900, 2925, 2860 (CH), 1650 (amide-I), 1520 cm -1 (amide-II). - CI - (+) - MS: m / z (%) = 746 (100) [M + H] ⁺. -
13 C-NMR (75.9 MHz, CDCl₃): δ (ppm) = 25.4 (t, C-4), 30.0 (t, C-3), 38.5 (t, C-5), 40.3 (d, C-2) , 71.3, 71.4, 76.5, 76.7 (t, -O- C H₂-phenyl), 117.1, 117.9 (d, arom. = C H-), 118.3 (s, - C N), 123.4, 123.5, 124.4, 124.5 (d, arom. = C H-), 127.6, 127.7 (d, arom. = C H-), 128.3, 128.4 (s, quart. arom. = C -), 128.7, 128.8, 128.9, 129.1 (18 C , d, arom. = C H-), 135.8, 136.2, 136.3, 136.4 (s, qart. arom. = C -), 146.9, 147.1 (s, quart. arom. -O- C =), 151.6, 151.63 (s, quart. aroma. -O- C =), 164.4, 165.0 (s, sec. amide-CO). -
For C₄₇H₄₃N₃O₆ (MG 745.87)
calcd. C 75.68; H 5.81; N 5.63;
found C 75.66; H 5.80; N 5.36.
Synthese von (L)-2,5-Diamino-bis-[N²,N5-(2,3-dihydroxi-benzoyl)]pentan-nitril (Myxochelin
D-Nitril, 3):
50 mg (7.7 × 10-5 mol) L-2,5-diamino-bis-[N²,N⁵-(2,3-dibenzyloxi-benzoyl)]-pentannitril
(3a werden unter Standardbedingungen hydriert. Nach Filtration über Kieselgur und
Einengen i.V. werden 24 mg (93.4%) 3 erhalten. -[α] = -14.5 (c = 0.9 in Methanol). -
IR (KBr): ν = 3360 NH), 2925 (CH), 2230 (CN), 1630 (Amid-I), 1525 cm-1 (Amid-II). -
¹³C-NMR (125.6 MHz, CD₃OD): δ (ppm) = 26.8 (t, C-4), 31.0 (t, C-3), 39.4 (t, C-5),
41.5 (d, C-2), 116.1, 116.7 (s, quart. arom. -C=), 118.7, 119.1 (d, arom. =CH-), 118.7
(s, -CN), 119.6, 119.7, 120.0, 120.4 (d, arom. =CH-), 147.3, 147.4, 150.2, 150.3 (s,
quart. -O-C=), 171.1, 171.7 (s, sek. Amid-CO). -
¹H-NMR (500 MHz, CD₃OD): δ (ppm) = 1.02 (quin., J₁= 14.8 Hz, J₂= 7.4 Hz, 2H,
4-CH₂-), 1.25 (9 Linien, J₁= 15.5, J₂= 7.8, J₃= 7.7 Hz, 2H, 3-CH₂-), 2.67 (dd, J₁= 6.6,
J₂= 7.0 Hz, 1H, 2-H), 5.91 (dd, J₁= 7.8, J₂= 8.1 Hz, 1H, meta-Harom.), 5.95 (dd, J₁= 8.1,
J₂= 8.2 Hz, 1H, meta-Harom.), 6.13 (dd, J₁= 1.2, J₂= 7.8 Hz, 1H, para-Harom.), 6.17 (dd,
J₁= 1.2, J₂= 7.8 Hz, 1H, para-Harom.), 6.41 (dd, J₁= 1.5, J₂= 8.1 Hz, 1H, ortho-Harom.
), 6.45 (d, J₁= 1.1, J₂= 8.1 Hz, 1H, ortho-Harom.). -
ESI-(+)-MS: M/z (%) = 408 (100), [M+Na]⁺. -
Für C₁₉H₁₉N₃O₆ (MG 385.39)
ber. C 59.36; H 4.72; N 10.93;
gef. C 57.10; H 5.44; N 9.78.Synthesis of (L) -2,5-diamino-bis- [N², N5- (2,3-dihydroxi-benzoyl)] pentane nitrile (Myxochelin D-nitrile, 3):
50 mg (7.7 × 10 -5 mol) of L-2,5-diamino-bis- [N², N⁵- (2,3-dibenzyloxi-benzoyl)] - pentanenitrile (3a are hydrogenated under standard conditions. After filtration through diatomaceous earth and concentration iV 24 mg (93.4%) 3 are obtained - [α] = -14.5 (c = 0.9 in methanol) -
IR (KBr): ν = 3360 NH), 2925 (CH), 2230 (CN), 1630 (amide-I), 1525 cm -1 (amide-II). -
13 C-NMR (125.6 MHz, CD₃OD): δ (ppm) = 26.8 (t, C-4), 31.0 (t, C-3), 39.4 (t, C-5), 41.5 (d, C-2) , 116.1, 116.7 (s, quart. Arom. - C =), 118.7, 119.1 (d, arom. = C H-), 118.7 (s, - C N), 119.6, 119.7, 120.0, 120.4 (d, arom . = C H-), 147.3, 147.4, 150.2, 150.3 (s, quart. -O- C =), 171.1, 171.7 (s, sec. Amide-CO). -
1 H-NMR (500 MHz, CD₃OD): δ (ppm) = 1.02 (quin., J₁ = 14.8 Hz, J₂ = 7.4 Hz, 2H, 4-CH₂-), 1.25 (9 lines, J₁ = 15.5, J₂ = 7.8 , J₃ = 7.7 Hz, 2H, 3-CH₂-), 2.67 (dd, J₁ = 6.6, J₂ = 7.0 Hz, 1H, 2-H), 5.91 (dd, J₁ = 7.8, J₂ = 8.1 Hz, 1H, meta -H aroma. ), 5.95 (dd, J₁ = 8.1, J₂ = 8.2 Hz, 1H, meta-H aroma. ), 6.13 (dd, J₁ = 1.2, J₂ = 7.8 Hz, 1H, para-H aroma. ), 6.17 (dd, J₁ = 1.2, J₂ = 7.8 Hz, 1H, para-H arom. ), 6.41 (dd, J₁ = 1.5, J₂ = 8.1 Hz, 1H, ortho-H arom. ), 6.45 (d, J₁ = 1.1, J₂ = 8.1 Hz, 1H, ortho-H arom. ). - ESI - (+) - MS: M / z (%) = 408 (100), [M + Na] ⁺. -
For C₁₉H₁₉N₃O₆ (MG 385.39)
calc. C 59.36; H 4.72; N 10.93;
found C 57.10; H 5.44; N 9.78.
Ferner betrifft die Erfindung das Myxochelin DR-Nitril R-3, und das Verfahren zu seiner Herstellung, die auf dem gleichen Weg wie für 3 beschrieben verläuft. Die Vorstufe R-3a zeigt die gleichen spektroskopischen Eigenschaften wie 3a besitzt aber einen Drehwert von:[α] = +16.9 (c = 1 in Methanol). -The invention further relates to the myxochelin D R -nitrile R-3, and the process for its production, which proceeds in the same way as described for 3. The precursor R-3a shows the same spectroscopic properties as 3a but has a rotation value of: [α] = +16.9 (c = 1 in methanol). -
(R)-2,5-Diamino-bis-[N²,N⁵-(2,3-dihydroxi-benzoyl)]pentan-nitril(Myx-ochelinDR-Nitril, R-3):(R) -2,5-diamino-bis- [N², N⁵- (2,3-dihydroxy-benzoyl)] pentane-nitrile (Myx-ochelinD R -nitrile, R-3):
Es werden 48 mg R-3a unter Standardbedingungen bei Normaldruck hydriert. Nach Abfiltrieren über Kieselgur und Einengen i.V. werden 22 mg (88.7%) R-3 gewonnen.48 mg of R-3a are hydrogenated under standard conditions at normal pressure. After Filter off over kieselguhr and evaporate i.V. 22 mg (88.7%) of R-3 are obtained.
Die spektroskopischen Eigenschaften siehe bei der Beschreibung für R-3.[α] = +16 (c = 1 in Methanol). -See the description for R-3 for the spectroscopic properties. [Α] = +16 (c = 1 in methanol). -
Ferner betrifft die Erfindung das Enantiomere des Naturstoffs Myxochelin B das Myxochelin BR (R-4) und das Verfahren zu seiner Darstellung.The invention further relates to the enantiomer of the natural product myxochelin B, the myxochelin B R (R-4) and the process for its preparation.
Hierzu wird ausgegangen von R-2b, dessen spektroskopische Eigenschaften mit Ausnahme des Drehwertes die gleichen wie für 2b sind /4/. Der Drehwert beträgt für R-2b: [α] = +18.5 (c = 1 in CHCl₃). Das Nitril R-2b wird mittels NaCNBH₃ in das pimäre Amin überführt, das durch Standardhydrierung bei RT und unter Normaldruck für 2h am Pd/C- Katalysator hydriert wird:This is based on R-2b, with the exception of its spectroscopic properties of the rotation value are the same as for 2b / 4 /. The rotation value for R-2b is: [α] = +18.5 (c = 1 in CHCl₃). The nitrile R-2b is by means of NaCNBH₃ in the primary amine transferred by standard hydrogenation at RT and under normal pressure for 2h on Pd / C- Catalyst is hydrogenated:
(R)-1,2,6-Triamino-bis-[N²,N⁶-(2,3-dihydroxi-benzoyl)]hexan-hydrochl-orid (Myxochelin BR-
Hydrochlorid, R-4):
[α] = +7 (c = 0.5 in 6N HCl). - (Der Naturstoff Myxochelin B besitzt [α] = -8
(c = 1 in 6N HCl) /4/. -
¹³C-NMR (75.4 MHz, DMSO-d₆): δ (ppm) = 22.9 (t, C-4), 28.7 (t, C-5), 31.3 (t, C-3),
38.6 (t, C-6), 48.7 (d, C-2), 44.0 (t, C-1), 115.7, 115.7 (s, quart. arom. C), 114.1, 115.8,
116.0, 117.2, 117.8, 118.4 (d, arom. =CH-), 147.0, 147.6, 151.6, 153.6 (s, quart. -O-
C=), 169.3, 169.9 (s, sek. Amid.CO). -
FAB-(+)-MS: m/z (%) = 404 (100) [M+H]⁺. - C₂₀H₂₅N₃O₆ (MG 403.44).(R) -1,2,6-triamino-bis- [N², N⁶- (2,3-dihydroxi-benzoyl)] hexane hydrochloride (Myxochelin B R - hydrochloride, R-4):
[α] = +7 (c = 0.5 in 6N HCl). - (The natural product myxochelin B has [α] = -8 (c = 1 in 6N HCl) / 4 /. -
13 C-NMR (75.4 MHz, DMSO-d₆): δ (ppm) = 22.9 (t, C-4), 28.7 (t, C-5), 31.3 (t, C-3), 38.6 (t, C- 6), 48.7 (d, C-2), 44.0 (t, C-1), 115.7, 115.7 (s, quart. Arom. C), 114.1, 115.8, 116.0, 117.2, 117.8, 118.4 (d, arom. = CH-), 147.0, 147.6, 151.6, 153.6 (s, quart. -O- C =), 169.3, 169.9 (s, sec.Amid.CO). -
FAB - (+) - MS: m / z (%) = 404 (100) [M + H] ⁺. - C₂₀H₂₅N₃O₆ (MG 403.44).
Ferner betrifft die Erfindung ein therapeutisches Mittel bestehend mindestens aus einem der erwähnten Siderophore neben einem üblichen Träger und/oder Verdünnungsmittel.The invention further relates to a therapeutic agent consisting of at least one of the Siderophores mentioned in addition to a conventional carrier and / or diluent.
Dieses Mittel kann zur Entfernung von Eisen und Aluminium bei den verschiedensten Erkrankungen des Menschen und von Tieren z. B. bei der Hämosiderose oder der Thalassämie oder auch bei Morbus Alzheimer eingesetzt werden.This agent can be used to remove iron and aluminum in a wide variety Human and animal diseases e.g. B. in hemosiderosis or Thalassemia or Alzheimer's disease can be used.
Ferner betrifft die Erfindung ein therapeutisches Mittel bestehend mindestens aus einem der erwähnten Siderophore neben einem üblichen Träger und/oder Verdünnungsmittel. Dieses Mittel kann zur Bekämpfung von viraler, bakterieller oder parasitärer Erkrankungen von Mensch und Tier eingesetzt werden.The invention further relates to a therapeutic agent consisting of at least one of the Siderophores mentioned in addition to a conventional carrier and / or diluent. This Means can be used to combat viral, bacterial or parasitic diseases of Humans and animals are used.
Ferner betrifft die Erfindung ein therapeutisches Mittel bestehend mindestens aus einem der erwähnten mit Eisen beladenen Siderophore neben einem üblichen Träger und/oder Verdünnungsmittel.The invention further relates to a therapeutic agent consisting of at least one of the mentioned iron-loaded siderophores in addition to a conventional carrier and / or Diluent.
Diese Mittel können zur chemo-therapeutischen Behandlung von Tumoren eingesetzt werden. Dieser Einsatz ergibt sich aus der Tatsache, daß Eisen-Komplexe in der Lage sind, Sauerstoff-Radikale zu erzeugen, die, wenn sie in die Nähe von DNA oder RNA gelangen, diese zerstören.These agents can be used for the chemo-therapeutic treatment of tumors will. This use arises from the fact that iron complexes are able To generate oxygen radicals that, when they get close to DNA or RNA, destroy them.
Ferner betrifft die Erfindung ein Mittel bestehend mindestens aus einem der erwähnten Siderophore neben einem üblichen Träger und/oder Verdünnungsmittel.The invention further relates to an agent consisting of at least one of the mentioned Siderophores in addition to a conventional carrier and / or diluent.
Dieses Mittel kann eingesetzt werden in seiner Eigenschaft als Chelator zur Entfernung von Metallen allgemein, diese können selbstverständlich auch radioaktiv sein.This agent can be used in its capacity as a chelator for the removal of Metals in general, these can of course also be radioactive.
Ferner betrifft die Erfindung ein Mittel, bevorzugt die Stoffe R-4 und 5 von denen hiermit bekannt ist, daß sie die bakterielle Zellwand in einem aktiven Transportvorgang überwinden können. R-4 und 5 lassen sich, bevorzugt über eine amidische Bindung an eine Reihe von Antibiotika kuppeln, für die die bakterielle Zellwand - oder Zellwände höherer Lebewesen - ein Hindernis darstellt. Auf diesem Wege lassen sich Wirkkonzentrationen stark erniedrigen, und damit Nebenwirkungen, die erst durch erhöhte Wirkkonzentrationen auftreten, drastisch verringern.Furthermore, the invention relates to an agent, preferably the substances R-4 and 5 of which hereby it is known that they overcome the bacterial cell wall in an active transport process can. R-4 and 5 can be, preferably via an amidic bond to a number of Coupling antibiotics for which the bacterial cell wall - or cell walls of higher organisms - is an obstacle. In this way, active concentrations can be greatly reduced, and thus drastically side effects that only occur through increased active concentrations reduce.
Aber auch jede beliebig andere Amino-Funktion der beanspruchten Stoffe läßt sich für diesen Zweck durch gängige Schutzgruppentechnik bei ihrer Herstellung freisetzen.But any other amino function of the claimed substances can also be used for release this purpose through common protection group technology in their manufacture.
Ferner betrifft die Erfindung ein Mittel, bestehend mindestens aus einem der erwähnten Siderophore, das sich zur schnellen Analytik von pathogenen Enterobakterien einsetzen läßt. Hierzu werden mit pathogenen Enterobakterien belastete Abstriche in einem Eisen mangel-Medium inkubiert. Durch Zusatz eines der genannten Mittel gelingt es, selektiv nur einen pathogenen Bakterienstamm zum Wachstum anzuregen. The invention further relates to an agent consisting of at least one of the mentioned Siderophore, which can be used for the rapid analysis of pathogenic enterobacteria. For this purpose, smears contaminated with pathogenic enterobacteria are made in an iron deficient medium incubated. By adding one of the agents mentioned, it is possible to selectively only one stimulate pathogenic bacterial strain to grow.
Beschreibung der Darstellung der Siderophore am Beispiel für 1:
Stufe 1: Darstellung von (D,L)-2-Amino-heptandicarbonsäuredimethylester-Hydrochlorid
(1a):
5.0 g (28.5 mmol) D,L-2-Amino-heptandicarbonsäure (Fa. Bachem, Schweiz), werden in
ca. 100 ml trockenem Methanol suspendiert. Unter Rühren wird solange HClg eingeleitet,
bis die Lösung klar wird. Über Nacht wird gerührt, danach i.V. eingeengt. Das Rohprodukt
wird über eine Flash-Chromatographie an Kieselgel Si60 (Merck, Darmstadt) mit
n-Hexan/Essigsäureethylester= 7 : 3 gereinigt. Es werden 4.78 g (70%) an 1a isoliert.
APCI-MS: m/z (%)= 520 (50) [M+H]⁺, 542 (6) [M+Na]⁺, 317 (100). -
¹³C-NMR (75.4 MHz, DMSO-d₆): δ = 23.7 (t, C-4), 23.9 (t, C-3), 29.6 (t, C-5), 33.0 (t,
C-6), 51.4 (d, C-2), 51.9 und 52.9 (q, O-CH₃), 170.2 (-C=O), 173.5 (-C=O). -
Für C₉H₁₈NO₄Cl (MG 239.5)
ber. C 45.09; H 7.52; N 5.85; Cl 14.82;
gef. C 45.07; H 7.66; N 5.64; Cl 15.28.Description of the representation of the siderophores using the example for 1:
Stage 1: Preparation of (D, L) -2-amino-heptanedicarboxylic acid dimethyl ester hydrochloride (1a):
5.0 g (28.5 mmol) of D, L-2-amino-heptanedicarboxylic acid (from Bachem, Switzerland) are suspended in approx. 100 ml of dry methanol. HCl g is passed in with stirring until the solution becomes clear. The mixture is stirred overnight and then evaporated down in vacuo. The crude product is purified by flash chromatography on silica gel Si60 (Merck, Darmstadt) with n-hexane / ethyl acetate = 7: 3. 4.78 g (70%) of 1a are isolated.
APCI-MS: m / z (%) = 520 (50) [M + H] ⁺, 542 (6) [M + Na] ⁺, 317 (100). -
13 C-NMR (75.4 MHz, DMSO-d₆): δ = 23.7 (t, C-4), 23.9 (t, C-3), 29.6 (t, C-5), 33.0 (t, C-6), 51.4 (d, C-2), 51.9 and 52.9 (q, O- C H₃), 170.2 (- C = O), 173.5 (- C = O). -
For C₉H₁₈NO₄Cl (MG 239.5)
calc. C 45.09; H 7.52; N 5.85; Cl 14.82;
found C 45.07; H 7.66; N 5.64; Cl 15.28.
Stufe 2: Darstellung von (D,L)-2-Amino-[N-(2,3-dibenzyloxibenzoyl)]heptandicarbonsäure
dimethylester (1b):
1.5 g 2,3-Dibenzyloxibenzoesäure (4.5 mmol), hergestellt nach /2/, werden in einem Kolben
mit Trockenrohr in 50 ml absolutem Dichlormethan gelöst und nacheinander mit 1.08 g 1a
(4.5 mmol), 1.44 g TBTU (4.5 mmol) sowie mit 1.74 g (13.5 mmol, drei Equiv.) Hünig-
Base versetzt. Es wird für 72 h gerührt.Step 2: Preparation of (D, L) -2-amino- [N- (2,3-dibenzyloxibenzoyl)] heptanedicarboxylic acid dimethyl ester (1b):
1.5 g of 2,3-dibenzyloxybenzoic acid (4.5 mmol), prepared according to / 2 /, are dissolved in a flask with a drying tube in 50 ml of absolute dichloromethane and successively with 1.08 g of 1a (4.5 mmol), 1.44 g of TBTU (4.5 mmol) and with 1.74 g (13.5 mmol, three equiv.) Of Hünig base are added. It is stirred for 72 h.
Zur Aufarbeitung wird die organische Phase mit 1) 50 ml 5 proz. HCl, 2) mit gesättigter
NaHCO₃-Lösung und 3) mit ges. NaCl-Lösung gewaschen. Sie wird mit MgSO₄ getrocknet
und i.V. eingeengt. Gereinigt wird mittels Flash-Chromatographie an Kieselgel Si60
(Merck, Darmstadt), Laufmittel: n-Hexan-Essigsäureethylester = 1 : 1. Ausbeute: 630 mg
(27%, als heller Sirup).
IR (KBr): ν = 3360, (NH), 2925 (CH), 1730 (Ester-CO), 1655 (Amid-I), 1560 cm-1 (Amid-
II). - APCI-MS: m/z (%) = 520 (50) [M+H]⁺, 542 (6) [M+Na]⁺, 317 (100). -
¹³C-NMR (75.4 MHz, CDCl₃): δ = 24.5 (t, C-4), 25.1 (t, C-5), 31.7 (t, C-3), 33.7 (t, C-
6), 51.6 (d, C-2), 52.3 und 52.6 (q, O-CH₃), 71.4 und 76.3 (t, O-CH₂), 117.4, 123.5,
124.7 (d, arom. =C-H), 126.8 (s, arom. =C-), 128.0, 128.7, 128.9, 129.0 (je 2 × d,
arom. =C-H), 128.5 und 128.8 (s, arom. =C-), 136.5 und 136.6 (s, arom. =C-), 147.2
und 152.0 (s, arom. =C-O), 165.2 (s, Amid-CO), 173.0 und 174.0 (Ester-CO). -
Für C₃₀H₃₃NO₇ (MG 519.60)
ber. C 69.35; H 6.40; N 2.70;
gef. C 68.70; H 6.31; N 3.01.For working up, the organic phase with 1) 50 ml of 5 percent. HCl, 2) with saturated NaHCO₃ solution and 3) with sat. Washed NaCl solution. It is dried with MgSO₄ and evaporated down iV. It is purified by means of flash chromatography on silica gel Si60 (Merck, Darmstadt), eluent: n-hexane-ethyl acetate = 1: 1. Yield: 630 mg (27%, as a light syrup).
IR (KBr): ν = 3360, (NH), 2925 (CH), 1730 (ester-CO), 1655 (amide-I), 1560 cm -1 (amide-II). - APCI-MS: m / z (%) = 520 (50) [M + H] ⁺, 542 (6) [M + Na] ⁺, 317 (100). -
13 C-NMR (75.4 MHz, CDCl₃): δ = 24.5 (t, C-4), 25.1 (t, C-5), 31.7 (t, C-3), 33.7 (t, C-6), 51.6 ( d, C-2), 52.3 and 52.6 (q, O- C H₃), 71.4 and 76.3 (t, O- C H₂), 117.4, 123.5, 124.7 (d, arom. = C -H), 126.8 (s , arom. = C -), 128.0, 128.7, 128.9, 129.0 (each 2 × d, arom. = C -H), 128.5 and 128.8 (s, arom. = C -), 136.5 and 136.6 (s, arom. = C -), 147.2 and 152.0 (s, arom. = C -O), 165.2 (s, amide-CO), 173.0 and 174.0 (ester-CO). -
For C₃₀H₃₃NO₇ (MG 519.60)
calcd. C 69.35; H 6.40; N 2.70;
found C 68.70; H 6.31; N 3.01.
Stufe 3: Darstellung von (D,L)-2-Amino-[N-(2,3-dibenzyloxi-benzoyl)]heptandicarbonsäure
diamid (1c):
630 mg (1.2 mmol) 1b werden in 150 ml Methanol gelöst, die Lösung wird auf -5°C
abgekühlt. Für 3 h wird durch die gekühlte Lösung NH₃-Gas geleitet. Die noch kühle
Lösung wird in einen Autoklaven gegeben, der verschlossen für 4 Tage bei RT belassen
wird. Nach vorsichtigem Belüften wird die Lösung i.V. eingeengt, Ausbeute 470 mg (80%)
kristallines 1c, Fp. 200-203 °C.
IR (KBr): ν= 3390 (NH), 3180 und 3250 (NH₂), 2850, 2930, 3020, 3050 (CH), 1640 und
1650 (Amid-I), 1520 cm-1 (Amid-II). - CI-MS (NH₃): m/z(%) =490(22) [M+H]⁺, 472 (18)
[M-H₂O+H]⁺, 455 (55), 365 (100), 337 (56), 275 (81), 247 (48), 11(76). -
¹³C-NMR (75.4 MHz, DMSO-d⁶): δ (ppm) = 24.8 (t, C-4), 24.9 (t, C-5), 32.3 (t, C-3),
34.9 (t, C-6), 52.6 (d, C-2), 70.4 und 75.1 (t, -O-CH₂-Phe), 116.6, 121.6, 124.3 (d, arom.
=C-H), 128.2, 128.2, 128.6, 128.8 (je 2 × d, arom. =C-H), 136.7 und 136.8 (s, arom.
=C-), 145.8 und 151.8 (s, arom. =C-O), 164.5 (s, Amid-CO), 173.6 und 174.3 (Ester-
CO). -
Für C₂₈H₃₁N₃O₅ (MG 489.58)
ber. C 69.69; H 6.38; N 8.58;
gef. C 68.50; H 6.29; N 8.48.Step 3: Preparation of (D, L) -2-amino- [N- (2,3-dibenzyloxybenzoyl)] heptanedicarboxylic acid diamide (1c):
630 mg (1.2 mmol) 1b are dissolved in 150 ml methanol, the solution is cooled to -5 ° C. NH 3 gas is passed through the cooled solution for 3 h. The still cool solution is placed in an autoclave, which is left closed for 4 days at RT. After careful ventilation, the solution is evaporated down in vacuo, yield 470 mg (80%) of crystalline 1c, mp. 200-203 ° C.
IR (KBr): ν = 3390 (NH), 3180 and 3250 (NH₂), 2850, 2930, 3020, 3050 (CH), 1640 and 1650 (amide-I), 1520 cm -1 (amide-II). CI-MS (NH₃): m / z (%) = 490 (22) [M + H] ⁺, 472 (18) [M-H₂O + H] ⁺, 455 (55), 365 (100), 337 (56), 275 (81), 247 (48), 11 (76). -
13 C-NMR (75.4 MHz, DMSO-d⁶): δ (ppm) = 24.8 (t, C-4), 24.9 (t, C-5), 32.3 (t, C-3), 34.9 (t, C- 6), 52.6 (d, C-2), 70.4 and 75.1 (t, -O- C H₂-Phe), 116.6, 121.6, 124.3 (d, arom. = C -H), 128.2, 128.2, 128.6, 128.8 (2 × d, arom. = C -H), 136.7 and 136.8 (s, arom. = C -), 145.8 and 151.8 (s, arom. = C -O), 164.5 (s, amide- C O) , 173.6 and 174.3 (ester- C O). -
For C₂₈H₃₁N₃O₅ (MG 489.58)
calcd. C 69.69; H 6.38; N 8.58;
found C 68.50; H 6.29; N 8.48.
Stufe 4: Darstellung von (D,L)-2-Amino-[N-(2,3-dibenzyloxi-benzoyl)]heptan-dinitril (1d):
Es werden 450 mg (0.92 mmol), 1c 0.3 ml (3.68 mmol) Pyridin und 200 mg (0.62 mmol)
Triphosgen in 80 ml getrocknetem Dichlormethan gelöst und für 1 h bei RT gerührt. Zur
Aufarbeitung wird die organische Phase mit 1) 5 proz. HCl und 2) mit ges. NaCl-Lösung
extrahiert. Sie wird über MgSO₄ getrocknet und i.V. eingeengt; dabei werden 350 mg (84
%) reines 1d erhalten.
IR (KBr): ν = 3330 (-NH), 2870, 2925, 3020, 3055 (-CH), 2235 (-CN), 1650 (Amid-I),
1570 cm-1 (Amid-II). - CI-MS (NH₃): m/z (%) = 454 (100) [M+H]⁺, 471(8) [M+NH₄]⁺,
427 (39) [M-CN+H]⁺, 337 (89) [M-CN-Benzyl+H]⁺.-
¹³C-NMR (75.4 MHz, CDCl₃): δ (ppm) = 16.9 (t, C-4), 24.5 (t, C-5), 24.7 (t, C-3), 31.8
(t, C-6), 40.1 (d, C-2), 71.5 und 76.8 (t, -O-CH₂-Phe), 118.4 und 119.3 (s, -CN), 118.2,
123.7 und 124.8 (d, arom. =C-H), 125.2., 128.7, 128.7 (s, quart. arom. =C-), 129.0,
129,2, 129,3 (6C, d, arom. =C-), 136.3 und 136.4 (s, arom. =C-), 147.4 und 151.9 (s,
arom. =C-O), 164.8 (Amid-CO). -
Für C₂₈H₂₇N₃O₃ (MG 453.55)
ber. C 74.15; H 6.00; N 9.26;
gef. C 73.66; H 6.10; N 9.20.Step 4: Preparation of (D, L) -2-amino- [N- (2,3-dibenzyloxybenzoyl)] heptane dinitrile (1d):
450 mg (0.92 mmol), 1c 0.3 ml (3.68 mmol) pyridine and 200 mg (0.62 mmol) triphosgene are dissolved in 80 ml dried dichloromethane and stirred for 1 h at RT. For working up, the organic phase with 1) 5 percent. HCl and 2) with sat. NaCl solution extracted. It is dried over MgSO₄ and evaporated down iV; this gives 350 mg (84%) of pure 1d.
IR (KBr): ν = 3330 (-NH), 2870, 2925, 3020, 3055 (-CH), 2235 (-CN), 1650 (amide-I), 1570 cm -1 (amide-II). CI-MS (NH₃): m / z (%) = 454 (100) [M + H] ⁺, 471 (8) [M + NH₄] ⁺, 427 (39) [M-CN + H] ⁺, 337 (89) [M-CN-Benzyl + H] ⁺.-
13 C-NMR (75.4 MHz, CDCl₃): δ (ppm) = 16.9 (t, C-4), 24.5 (t, C-5), 24.7 (t, C-3), 31.8 (t, C-6) , 40.1 (d, C-2), 71.5 and 76.8 (t, -O-CH₂-Phe), 118.4 and 119.3 (s, -CN), 118.2, 123.7 and 124.8 (d, arom. = C -H), 125.2., 128.7, 128.7 (s, quart. Arom. = C-), 129.0, 129.2, 129.3 (6C, d, arom. = C-), 136.3 and 136.4 (s, arom. = C-) ), 147.4 and 151.9 (s, arom. = C -O), 164.8 (amide-CO). -
For C₂₈H₂₇N₃O₃ (MG 453.55)
calc. C 74.15; H 6.00; N 9.26;
found C 73.66; H 6.10; N 9.20.
Stufe 5: Darstellung von (D,L)-1,2,6-Triamino-[N²-(2,3-dibenzyloxi-benzoyl)]heptan (1e):
300 mg (0.66 mmol) 1d und 200 mg Co₂B /3/ sowie 0,5 g NaBH₄ werden in 10 ml THF
und 40 ml Methanol gelöst und für 2 h gerührt. Zur Aufarbeitung werden 5 proz. HCl
zugefügt (pH 2-3), sodann wird mit NH₃ basisch gestellt und viermal mit 30 ml CHCl₃
extrahiert (bis der Extrakt auf DC aufgetüpfelt mit Ninhydrin keine Reaktion anzeigt!). Die
Chloroform-Lösung wird über MgSO₄, getrocknet und i.V. eingeengt. Es werden 324 mg
öliges Diamin-1e als Rohprodukt erhalten, das ohne Reinigung in die folgende Reaktion
eingesetzt wird.
C₂₈H₃₅N₃O₃ (MG 461.61)
Stufe 6: Darstellung von (D,L)-1,2,6-Triamino-tris-[N,N,N-(2,3-dibenzyloxi-benzoyl)]heptan
(Hexa-O-Benzyl-Myxochelin F, 1f):
300 mg Rohprodukt 1e aus der Vorreaktion werden mit 417 mg TBTU (1.23 mmol), 0.43
g Dibenzyloxibenzoesäure (1.23 mmol) und 0.44 ml (2.6 mmol) Hünig-Base in 50 ml
trockenem Dichlormethan gelöst und bei RT für 72 h gerührt. Die Aufarbeitung erfolgt wie
für 1b beschrieben. Gereinigt wird mittels Flash-Chromatographie mit dem Laufmittel
n-Hexan/Essigsäureethylester= 1 : 1. Es werden 311 mg 1f erhalten, 43% bezogen auf 1d aus
Stufe 4.
IR (KBr): ν = 3370 (NH), 2850, 2915, 3020, 3055 (CH), 1630 (Amid-I), 1565 cm-1
(Amid-II). - ESI-MS: m/z (%): 1094.4 (100) [M+H]⁺, 1116.5 (65) [M+Na]⁺, 1132.4 (36)
[M+K]⁺. - ¹³C-NMR (75.4 MHz, CDCl₃), δ (ppm) = 25.7 (t, C-5), 26.9 (t, C-4), 29.2 (t,
C-6), 32.3 (t, C-3), 39.7 (t, C-7), 43.5 (t, C-1), 49.9 (d, C-2), 71.4, 71.4, 71.4, 75.9,
76.2, 76.5 (t, -O-CH₂-Phe), 117.0, 117.1, 117.2 (d, arom. =CH-), 123.4, 123.6, 123.7
und 124.4, 124.5, 124.6 (d, arom. =CH-), 127.2, 127.7, 128.0 (s, quart. arom. =C-),
127.8, 127.9, 127.9, 128.5, 128.5, 128.7, 128.7, 128.8, 128.80, 128.85, 128.85, 128.90,
128.90, 128.93, 128.93 (alle als d, arom. =CH-), 136.57, 136.6, 136.6,136.63, 136.7,
136.7, (s, quart. arom. =C-), 146.9, 147.0,147.1 (s, quart. =C-O), 151.9, 152.0, 152.0
(s, quart. =C-O), 165.2,165.4, 165.9 (s, Amid-CO). -
Für C₇₀H₆₇N₃O₉ (MG 1094.33)
ber. C 76.83; H 6.17; N 3.84;
gef. C 75.91; H 6.23; N 4.19.Step 5: Preparation of (D, L) -1,2,6-triamino- [N²- (2,3-dibenzyloxybenzoyl)] heptane (1e):
300 mg (0.66 mmol) 1d and 200 mg Co₂B / 3 / and 0.5 g NaBH₄ are dissolved in 10 ml THF and 40 ml methanol and stirred for 2 h. For processing 5 percent. HCl added (pH 2-3), then made basic with NH₃ and extracted four times with 30 ml CHCl₃ (until the extract spotted on TLC with ninhydrin shows no reaction!). The chloroform solution is dried over MgSO₄, and evaporated down in vacuo. 324 mg of oily diamine-1e are obtained as a crude product, which is used in the following reaction without purification.
C₂₈H₃₅N₃O₃ (MG 461.61)
Step 6: Preparation of (D, L) -1,2,6-triamino-tris- [N, N, N- (2,3-dibenzyloxi-benzoyl)] heptane (Hexa-O-Benzyl-Myxochelin F, 1f ):
300 mg of crude product 1e from the preliminary reaction are dissolved in 50 ml of dry dichloromethane with 417 mg of TBTU (1.23 mmol), 0.43 g of dibenzyloxybenzoic acid (1.23 mmol) and 0.44 ml (2.6 mmol) and stirred at RT for 72 h. The processing is carried out as described for 1b. It is cleaned by means of flash chromatography with the mobile phase n-hexane / ethyl acetate = 1: 1. 311 mg 1f are obtained, 43% based on 1d from stage 4.
IR (KBr): ν = 3370 (NH), 2850, 2915, 3020, 3055 (CH), 1630 (amide-I), 1565 cm -1 (amide-II). - ESI-MS: m / z (%): 1094.4 (100) [M + H] ⁺, 1116.5 (65) [M + Na] ⁺, 1132.4 (36) [M + K] ⁺. - 13 C-NMR (75.4 MHz, CDCl₃), δ (ppm) = 25.7 (t, C-5), 26.9 (t, C-4), 29.2 (t, C-6), 32.3 (t, C-3 ), 39.7 (t, C-7), 43.5 (t, C-1), 49.9 (d, C-2), 71.4, 71.4, 71.4, 75.9, 76.2, 76.5 (t, -O- C H₂-Phe ), 117.0, 117.1, 117.2 (d, arom. = C H-), 123.4, 123.6, 123.7 and 124.4, 124.5, 124.6 (d, arom. = C H-), 127.2, 127.7, 128.0 (s, quart. arom. = C -), 127.8, 127.9, 127.9, 128.5, 128.5, 128.7, 128.7, 128.8, 128.80, 128.85, 128.85, 128.90, 128.90, 128.93, 128.93 (all as d, arom. = C H-), 136.57 , 136.6, 136.6,136.63, 136.7, 136.7, (s, quart. Arom. = C -), 146.9, 147.0,147.1 (s, quart. = C -O), 151.9, 152.0, 152.0 (s, quart. = C -O), 165.2,165.4, 165.9 (s, amide-CO). -
For C₇₀H₆₇N₃O₉ (MG 1094.33)
calc. C 76.83; H 6.17; N 3.84;
found C 75.91; H 6.23; N 4.19.
Stufe 7: Darstellung von (D,L)-1,2,6-Triamino-tris-[N¹,N²,N⁶-(2,3-dihydroxi-benzoyl)]heptan
(Myxochelin F, 1):
113 mg (0.1 mmol) 1f werden in 20 ml THF und 30 ml Methanol gelöst und mit Pd/C-H₂
für 2 h hydriert. Über Kieselgur wird filtriert, die Lösung i.V. eingeengt, Ausbeute 50 mg,
87% . - IR (KBr): ν = 3360 (NH), 2920, 2850 (CH), 1640 (Amid-I), 1580 (Aromat), 1540
cm-1 (Amid-II). - ESI-MS: m/z (%) = 576 (100) [M+Na]⁺. -
¹³C-NMR (100.6 MHz, CD₃OD): δ (ppm) = 26.9 (t, C-4), 27.8 (t, C-5), 30.3 (t, C-6),
33.1 (t, C-3), 40.4 (t, C-7), 44.6 (t, C-1), 51.2 (d, C-2), 116.9, 116.9, 117.0 (s, quart.
arom. =C-), 118.7, 118.9, 119.0, 119.6, 119.7, 119.7 (alle d, arom. =CH-), 147.3,
147.3, 147.4 (s, arom. =C-O-), 150.2, 150.2, 150.3 (s, arom. =C-O-), 171.5, 171.8,
172.0 (s,Amid-CO). -
Für C₂₈H₃₁N₃O₉ (MG 553.58)
ber. C 60.75; H 5.64; N 7.59;
gef. C 53.30; H 4.73; N 6.37.Step 7: Preparation of (D, L) -1,2,6-triamino-tris- [N¹, N², N⁶- (2,3-dihydroxi-benzoyl)] heptane (Myxochelin F, 1):
113 mg (0.1 mmol) 1f are dissolved in 20 ml THF and 30 ml methanol and hydrogenated with Pd / C-H₂ for 2 h. It is filtered through diatomaceous earth, the solution is evaporated down in vacuo, yield 50 mg, 87%. - IR (KBr): ν = 3360 (NH), 2920, 2850 (CH), 1640 (Amid-I), 1580 (Aromat), 1540 cm -1 (Amid-II). - ESI-MS: m / z (%) = 576 (100) [M + Na] ⁺. -
13 C-NMR (100.6 MHz, CD₃OD): δ (ppm) = 26.9 (t, C-4), 27.8 (t, C-5), 30.3 (t, C-6), 33.1 (t, C-3) , 40.4 (t, C-7), 44.6 (t, C-1), 51.2 (d, C-2), 116.9, 116.9, 117.0 (s, quart. Arom. = C -), 118.7, 118.9, 119.0 , 119.6, 119.7, 119.7 (all d, arom. = C H-), 147.3, 147.3, 147.4 (s, arom. = C -O-), 150.2, 150.2, 150.3 (s, arom. = C -O- ), 171.5, 171.8, 172.0 (s, amide CO). -
For C₂₈H₃₁N₃O₉ (MG 553.58)
calc. C 60.75; H 5.64; N 7.59;
found C 53.30; H 4.73; N 6.37.
Synthese von (L)-2,6-Diamino-bis-[N²,N⁶-(2,3-dibenzyloxi-benzoyl)]hexan-nitril (2b):
0.98 g (1.2 mmol) 2a werden in 15 ml absolutiertem Dichlormethan gelöst und mit 0.29 ml
Pyridin und 176 mg Triphosgen versetzt. Nach Aufarbeiten - wie für
1d beschrieben - werden 670 mg 2b erhalten (73.6%).[α] = -16.1 (c = 1 in CHCl₃). -
IR (KBr): ν = 3367 (NH), 2866, 2927, 3031, 3064 (CH), 2230 (CN), 1661 (Amid-I), 1520
cm-1 (Amid-II). - ¹³C-NMR (75.4 MHz, CDCl₃): δ (ppm) = 22.7 (t, C-4), 28.4 (t, C-5),
32.1 (t, C-3), 39.0 (t, C-6), 40.3 (d, C-2), 71.3, 71.4, 76.4, 76.6 (t, -O-CH₂-Phe), 117.0,
117.9 (d, arom. =CH-), 118.5 (s, -CN), 123.3, 123.4, 124.4, 124.5 (d, arom. =CH-),
127.6, 127.6, 128.4, 128.4 (d, arom. =C-H), 128.3, 128.4 (s, quart. arom. =C-), 128.7
(4 × C), 128.8 (8 × C), 129.0 (4 × C, alle d, 16 arom. =CH- aus Bn-Gruppen), 135.9,
136.0, 136.2, 136.4 (s, arom. =C- aus Bn-Gruppen), 146.8, 147.1 (s, quart. arom. -O-
C=), 151.6, 151.7 (s, quart. arom. O-C=), 164.5, 165.0 (s, Amid-CO). -
Für C₇₅H₄₅N₃O₆ (MG 759.91)
ber. C 75.87; H 5.97; N 5.53;
gef. C 72.18; H 5.63; N 4.16.
Synthesis of (L) -2,6-diamino-bis- [N², N⁶- (2,3-dibenzyloxybenzoyl)] hexane nitrile (2b):
0.98 g (1.2 mmol) 2a are dissolved in 15 ml absolute dichloromethane and 0.29 ml pyridine and 176 mg triphosgene are added. After working up - as described for 1d - 670 mg 2b are obtained (73.6%). [Α] = -16.1 (c = 1 in CHCl₃). -
IR (KBr): ν = 3367 (NH), 2866, 2927, 3031, 3064 (CH), 2230 (CN), 1661 (amide-I), 1520 cm -1 (amide-II). - 13 C-NMR (75.4 MHz, CDCl₃): δ (ppm) = 22.7 (t, C-4), 28.4 (t, C-5), 32.1 (t, C-3), 39.0 (t, C-6 ), 40.3 (d, C-2), 71.3, 71.4, 76.4, 76.6 (t, -O-CH₂-Phe), 117.0, 117.9 (d, arom. = C H-), 118.5 (s, - C N ), 123.3, 123.4, 124.4, 124.5 (d, arom. = C H-), 127.6, 127.6, 128.4, 128.4 (d, arom. = C -H), 128.3, 128.4 (s, quart. Arom. = C -), 128.7 (4 × C), 128.8 (8 × C), 129.0 (4 × C, all d, 16 aroma. = C H- from Bn groups), 135.9, 136.0, 136.2, 136.4 (s, aroma . = C - from Bn groups), 146.8, 147.1 (s, quart. Aroma. -O- C =), 151.6, 151.7 (s, quart. Aroma. O- C =), 164.5, 165.0 (s, amide -CO). -
For C₇₅H₄₅N₃O₆ (MG 759.91)
calcd. C 75.87; H 5.97; N 5.53;
found C 72.18; H 5.63; N 4.16.
Synthese von (L)-2,6-Diamino-bis-[N²,N⁶-(2,3-dihydroxi-benzoyl)]hexannitril(Myxoc-helin C-
Nitril, 2):
Es werden 90 mg (0. 12 mmol) 2b unter Standardbedingungen hydriert. Nach Filtration über
Kieselgur und Einengen i.V. werden 45 mg (95%) 2 isoliert.[α] = -12 (c = 1 in Methanol). -
MG 399.43.Synthesis of (L) -2,6-diamino-bis- [N², N⁶- (2,3-dihydroxy-benzoyl)] hexanenitrile (Myxoc-helin C-nitrile, 2):
90 mg (0. 12 mmol) 2b are hydrogenated under standard conditions. After filtration through diatomaceous earth and concentration in vacuo, 45 mg (95%) 2 are isolated. [Α] = -12 (c = 1 in methanol). -
MG 399.43.
Ferner betrifft die Erfindung das Myxochelin D-Nitril (3) und das Verfahren zu seiner Herstellung. 3 wird - wie schon für 2 dargestellt - aus dem Tetra-benzyl-geschützten Myxochelin D-Nitril (3a) durch hydrogenolytische Spaltung an Pd/C mittels H₂ erhalten. 3a ist wie folgt charakterisiert:The invention further relates to the myxochelin D-nitrile (3) and the process for its Manufacturing. 3 is - as already shown for 2 - from the tetra-benzyl-protected Myxochelin D-nitrile (3a) obtained by hydrogenolytic cleavage on Pd / C using H₂. 3a is characterized as follows:
(L)-2,5-Diamino-bis-[N²,N⁵-(2,3-dibenzyloxi-benzoyl)]pentan-nitril
(Tetra-O-benzyl-Myxochelin D-Nitril, 3a):Fp. 134-136°C. - [α] = -18.4 (c = 1 in Methanol). - IR (KBr): ν = 3360 (NH), 3015,
3065, 2900, 2925, 2860 (CH), 1650 (Amid-I), 1520 cm-1 (Amid-II). -
CI-(+)-MS: m/z (%) = 746 (100) [M+H]⁺
¹³C-NMR (75.9 MHz, CDCl₃): δ (ppm) = 25.4 (t, C-4), 30.0 (t, C-3), 38.5 (t, C-5), 40.3
(d, C-2), 71.3, 71.4, 76.5, 76.7 (t, -O-CH₂-Phenyl), 117.1, 117.9 (d, arom. =CH-), 118.3
(s, -CN), 123.4,123.5, 124.4, 124.5 (d, arom. =CH-), 127.6, 127.7 (d, arom. =CH-),
128.3, 128.4 (s, quart. arom. =C-), 128.7, 128.8, 128.9, 129.1 (18 C, d, arom. =CH-),
135.8, 136.2, 136.3, 136.4 (s, qart. arom. =C-), 146.9, 147.1 (s, quart. arom. -O-C=),
151.6, 151.63 (s, quart. arom. -O-C=), 164.4, 165.0 (s, sek. Amid-CO). -
Für C₄₇H₄₃N₃O₆ (MG 745.87)
ber. C 75.68; H 5.81; N 5.63;
gef. C 75.66; H 5.80; N 5.36.(L) -2,5-diamino-bis- [N², N⁵- (2,3-dibenzyloxi-benzoyl)] pentane-nitrile (tetra-O-benzyl-myxochelin D-nitrile, 3a): mp. 134-136 ° C. - [α] = -18.4 (c = 1 in methanol). - IR (KBr): ν = 3360 (NH), 3015, 3065, 2900, 2925, 2860 (CH), 1650 (amide-I), 1520 cm -1 (amide-II). -
CI - (+) - MS: m / z (%) = 746 (100) [M + H] ⁺
13 C-NMR (75.9 MHz, CDCl₃): δ (ppm) = 25.4 (t, C-4), 30.0 (t, C-3), 38.5 (t, C-5), 40.3 (d, C-2) , 71.3, 71.4, 76.5, 76.7 (t, -O- C H₂-phenyl), 117.1, 117.9 (d, arom. = C H-), 118.3 (s, - C N), 123.4.123.5, 124.4, 124.5 (d, arom. = C H-), 127.6, 127.7 (d, arom. = C H-), 128.3, 128.4 (s, quart. arom. = C -), 128.7, 128.8, 128.9, 129.1 (18 C , d, arom. = C H-), 135.8, 136.2, 136.3, 136.4 (s, qart. arom. = C -), 146.9, 147.1 (s, quart. arom. -O- C =), 151.6, 151.63 (s, quart. aroma. -O- C =), 164.4, 165.0 (s, sec. amide-CO). -
For C₄₇H₄₃N₃O₆ (MG 745.87)
calcd. C 75.68; H 5.81; N 5.63;
found C 75.66; H 5.80; N 5.36.
Synthese von (L)-2,5-Diamino-bis-[N²,N⁵-(2,3-dihydroxi-benzoyl)]pentan-nitril (Myxochelin
D-Nitril, 3):
50 mg (7.7 × 10-5 mol) L-2,5-diamino-bis-[N², N⁵-(2,3-dibenzyloxi-benzoyl)]-pentannitril
(3a) werden unter Standardbedingungen hydriert. Nach Filtration über Kieselgur und
Einengen i.V. werden 24 mg (93.4%) 3 erhalten. -[α] = -14.5 (c = 0.9 in Methanol). -
IR (KBr): ν = 3360 NH), 2925 (CH), 2230 (CN), 1630 (Amid-I), 1525 cm-1 (Amid-II). -
¹³C-NMR (125.6 MHz, CD₃OD): δ (ppm) = 26.8 (t, C-4), 31.0 (t, C-3), 39.4 (t, C-5),
41.5 (d, C-2), 116.1, 116.7 (s, quart. arom. -C=), 118.7, 119.1 (d, arom. =CH-), 118.7
(s, -CN), 119.6, 119.7, 120.0, 120.4 (d, arom. =CH-), 147.3, 147.4, 150.2, 150.3 (s,
quart. -O-C=), 171.1, 171.7 (s, sek. Amid-CO). -
¹H-NMR (500 MHz, CD₃OD): δ (ppm) = 1.02 (quin., J₁= 14.8 Hz, J₂= 7.4 Hz, 2H,
4-CH₂-), 1.25 (9 Linien, J₁= 15.5, J₂= 7.8, J₃= 7.7 Hz, 2H, 3-CH₂-), 2.67 (dd, J₁= 6.6,
J₂= 7.0 Hz, 1H, 2-H), 5.91 (dd, J₁= 7.8, J₂= 8.1 Hz, 1H, meta-Harom.), 5.95 (dd, J₁= 8.1,
J₂= 8.2 Hz, 1H, meta-Harom.), 6.13 (dd, J₁= 1.2, J₂= 7.8 Hz, 1H, para-Harom.), 6.17 (dd,
J₁= 1.2, J₂= 7.8 Hz, 1H, para-Harom.), 6.41 (dd, J₁= 1.5, J₂= 8.1 Hz, 1H, Ortho-Harom.
), 6.45 (d, J₁= 1.1, J₂= 8.1 Hz, 1H, Ortho-Harom.). -
ESI-(+)-MS : M/z (%) = 408 (100), [M+Na]⁺. -
Für C,₉H₁₉N₃O₆ (MG 385.39)
ber. C 59.36; H 4.72; N 10.93;
gef. C 57.10; H 5.44; N 9.78.Synthesis of (L) -2,5-diamino-bis- [N², N⁵- (2,3-dihydroxi-benzoyl)] pentane-nitrile (myxochelin D-nitrile, 3):
50 mg (7.7 × 10 -5 mol) of L-2,5-diamino-bis- [N², N⁵- (2,3-dibenzyloxi-benzoyl)] - pentanenitrile (3a) are hydrogenated under standard conditions. After filtration through diatomaceous earth and concentration in vacuo, 24 mg (93.4%) 3 are obtained. - [α] = -14.5 (c = 0.9 in methanol). -
IR (KBr): ν = 3360 NH), 2925 (CH), 2230 (CN), 1630 (amide-I), 1525 cm -1 (amide-II). - 13 C-NMR (125.6 MHz, CD₃OD): δ (ppm) = 26.8 (t, C-4), 31.0 (t, C-3), 39.4 (t, C-5), 41.5 (d, C-2 ), 116.1, 116.7 (s, quart. Arom. - C =), 118.7, 119.1 (d, arom. = C H-), 118.7 (s, - C N), 119.6, 119.7, 120.0, 120.4 (d, arom. = C H-), 147.3, 147.4, 150.2, 150.3 (s, quart. -O- C =), 171.1, 171.7 (s, sec. amide-CO). -
1 H-NMR (500 MHz, CD₃OD): δ (ppm) = 1.02 (quin., J₁ = 14.8 Hz, J₂ = 7.4 Hz, 2H, 4-CH₂-), 1.25 (9 lines, J₁ = 15.5, J₂ = 7.8 , J₃ = 7.7 Hz, 2H, 3-CH₂-), 2.67 (dd, J₁ = 6.6, J₂ = 7.0 Hz, 1H, 2-H), 5.91 (dd, J₁ = 7.8, J₂ = 8.1 Hz, 1H, meta -H aroma. ), 5.95 (dd, J₁ = 8.1, J₂ = 8.2 Hz, 1H, meta-H aroma. ), 6.13 (dd, J₁ = 1.2, J₂ = 7.8 Hz, 1H, para-H aroma. ), 6.17 (dd, J₁ = 1.2, J₂ = 7.8 Hz, 1H, para-H arom. ), 6.41 (dd, J₁ = 1.5, J₂ = 8.1 Hz, 1H, ortho-H arom. ), 6.45 (d, J₁ = 1.1, J₂ = 8.1 Hz, 1H, ortho-H arom. ). -
ESI - (+) - MS: M / z (%) = 408 (100), [M + Na] ⁺. -
For C, ₉H₁₉N₃O₆ (MG 385.39)
calc. C 59.36; H 4.72; N 10.93;
found C 57.10; H 5.44; N 9.78.
Ferner betrifft die Erfindung das Myxochelin DR-Nitril R-3, und das Verfahren zu seiner
Herstellung, die auf dem gleichen Weg wie für 3 beschrieben verläuft. Die Vorstufe R-3a
zeigt die gleichen spektroskopischen Eigenschaften wie 3a besitzt aber einen Drehwert von:[α] = +16.9 (c = 1 in Methanol). -
(R)-2,5-Diamino-bis-[N²,N⁵-(2,3-dihydroxi-benzoyl)]pentan-nitril(Myx-ochelin DR-Nitril, R-3):
Es werden 48 mg R-3a unter Standardbedingungen bei Normaldruck hydriert. Nach
Abfiltrieren über Kieselgur und Einengen i.V. werden 22 mg (88.7%) R-3 gewonnen.
Die spektroskopischen Eigenschaften siehe bei der Beschreibung für R-3.[α] = +16 (c = 1 in Methanol). -
Ferner betrifft die Erfindung das Enantiomere des Naturstoffs Myxochelin B das
Myxochelin BR (R-4) und das Verfahren zu seiner Darstellung.The invention further relates to the myxochelin D R -nitrile R-3, and the process for its production, which proceeds in the same way as described for 3. The precursor R-3a shows the same spectroscopic properties as 3a but has a rotation value of: [α] = +16.9 (c = 1 in methanol). -
(R) -2,5-diamino-bis- [N², N⁵- (2,3-dihydroxy-benzoyl)] pentane-nitrile (Myx-ochelin D R -nitrile, R-3):
48 mg of R-3a are hydrogenated under standard conditions at normal pressure. After filtering through diatomaceous earth and concentrating in vacuo, 22 mg (88.7%) of R-3 are obtained. See the description for R-3 for the spectroscopic properties. [Α] = +16 (c = 1 in methanol). -
The invention further relates to the enantiomer of the natural product myxochelin B, the myxochelin B R (R-4) and the process for its preparation.
Hierzu wird ausgegangen von R-2b, dessen spektroskopische Eigenschaften mit Ausnahme des Drehwertes die gleichen wie für 2b sind /4/. Der Drehwert beträgt für R-2b: [α]D= + 18.5 (c = 1 in CHCl₃). Das Nitril R-2b wird mittels NaCNBH₃ in das pimäre Amin überführt, das durch Standardhydrierung bei RT und unter Normaldruck für 2h am Pd/C- Katalysator hydriert wird:This is based on R-2b, whose spectroscopic properties are the same as for 2b with the exception of the rotation value / 4 /. The rotation value for R-2b is: [α] D = + 18.5 (c = 1 in CHCl₃). The nitrile R-2b is converted into the primary amine using NaCNBH₃, which is hydrogenated by standard hydrogenation at RT and under normal pressure for 2 hours on a Pd / C catalyst:
(R)-1,2,6-Triamino-bis-[N²,N⁶-(2,3-dihydroxi-benzoyl)]hexan-hydrochl-orid (Myxochelin BR-
Hydrochlorid, R-4):[α] = +7 (c = 0.5 in 6N HCl). - (Der Naturstoff Myxochelin B besitzt [α] = -8
(c = 1 in 6N HCl) /4/. -
¹³C-NMR (75.4 MHz, DMSO-d₆): δ (ppm) = 22.9 (t, C-4), 28.7 (t, C-5), 31.3 (t, C-3),
38.6 (t, C-6), 48.7 (d, C-2), 44.0 (t, C-1), 115.7,115.7 (s, quart. arom. C), 114.1, 115.8,
116.0, 117.2, 117.8, 118.4 (d, arom. =CH-), 147.0,147.6, 151.6, 153.6 (s, quart. -O-
C=), 169.3, 169.9 (s, sek. Amid.CO). -
FAB-(+)-MS: m/z (%) = 404 (100) [M+H]⁺. - C₂₀H₂₅N₃O₆ (MG 403.44).
(R) -1,2,6-triamino-bis- [N², N⁶- (2,3-dihydroxi-benzoyl)] hexane hydrochloride (myxochelin B R - hydrochloride, R-4): [α] = +7 (c = 0.5 in 6N HCl). - (The natural product myxochelin B has [α] = -8 (c = 1 in 6N HCl) / 4 /. -
13 C-NMR (75.4 MHz, DMSO-d₆): δ (ppm) = 22.9 (t, C-4), 28.7 (t, C-5), 31.3 (t, C-3), 38.6 (t, C- 6), 48.7 (d, C-2), 44.0 (t, C-1), 115.7.115.7 (s, quart. Arom. C), 114.1, 115.8, 116.0, 117.2, 117.8, 118.4 (d, arom. = CH-), 147.0,147.6, 151.6, 153.6 (s, quart. -O- C =), 169.3, 169.9 (s, sec.Amid.CO). -
FAB - (+) - MS: m / z (%) = 404 (100) [M + H] ⁺. - C₂₀H₂₅N₃O₆ (MG 403.44).
Die Wirkung von 1-5 und R-(1-5) wird mittels eines Bioassays bewiesen.The effects of 1-5 and R- (1-5) are proven by means of a bioassay.
Folgende Stämme von Enterobakterien (gram-negative Bakterien) werden durch 1-5 und R-(1-5) in der Konzentration von 5 µg/disc derart gut mit Eisen versorgt, daß die Stämme in einem an Eisen verarmten Medium dennoch enorme Wachstumszonen (in mm) zeigen:The following strains of enterobacteria (gram-negative bacteria) are identified by 1-5 and R- (1-5) in the concentration of 5 µg / disc so well supplied with iron that the strains nevertheless show enormous growth zones (in mm) in a medium depleted of iron:
1: Y. enterocolitica (18), M. morganii (32, P. aeruginosa (17);
R-2: S. typhimurium (14), M. morganii (36), P. aeruginosa (18);
3: M. morganii (35), P. aeruginosa (19), M. smegmatis (20);
R-3: Y. enterocolitica (17), M. morganii (38), P. aeruginosa (27), M. smegmatis (20);
R-4: S. typhimurium (22), Y. enterocolitica (19), M. morganii (34), P. aeruginosa (20), M.
smegmatis (22);
5: M.morganii (24). -
Die Testbedingungen sind publiziert /5,6/.1: Y. enterocolitica (18), M. morganii (32, P. aeruginosa (17);
R-2: S. typhimurium (14), M. morganii (36), P. aeruginosa (18);
3: M. morganii (35), P. aeruginosa (19), M. smegmatis (20);
R-3: Y. enterocolitica (17), M. morganii (38), P. aeruginosa (27), M. smegmatis (20);
R-4: S. typhimurium (22), Y. enterocolitica (19), M. morganii (34), P. aeruginosa (20), M. smegmatis (22);
5: M. morganii (24). -
The test conditions are published / 5.6 /.
Claims (12)
¹³C-NMR (100.6 MHz, CD₃OD): δ (ppm) = 26.9 (t, C-4), 27.8 (t, C-5), 30.3 (t, C-6), 33.1 (t, C-3), 40.4 (t, C-7), 44.6 (t, C-1), 51.2 (d, C-2), 116.9, 116.9,117.0 (s, quart. arom. =C-), 118.7, 118.9, 119.0, 119.6, 119.7, 119.7 (alle d, arom. =CH-), 147.3, 147.3, 147.4 (s, arom. =C-O-), 150.2, 150.2, 150.3 (s, arom. =C-O-), 171.5, 171.8, 172.0 (s, Amid-CO). -
Für C₂₈H₃₁N₃O₉ (MG 553.58)
ber. C 60.75; H 5.64; N 7.59;
gef. C 53.30; H 4.73; N 6.37. 2. Myxochelin F (1), characterized by one or more of the following parameters IR (KBr): ν = 3360 (NH), 2920, 2850 (CH), 1640 (Amid-I), 1580 (Aromat), 1540 cm - 1 (Amide-II). - ESI-MS: m / z (%) = 576 (100) [M + Na] ⁺. -
13 C-NMR (100.6 MHz, CD₃OD): δ (ppm) = 26.9 (t, C-4), 27.8 (t, C-5), 30.3 (t, C-6), 33.1 (t, C-3) , 40.4 (t, C-7), 44.6 (t, C-1), 51.2 (d, C-2), 116.9, 116.9,117.0 (s, quart. Arom. = C -), 118.7, 118.9, 119.0 , 119.6, 119.7, 119.7 (all d, arom. = C H-), 147.3, 147.3, 147.4 (s, arom. = C -O-), 150.2, 150.2, 150.3 (s, arom. = C -O- ), 171.5, 171.8, 172.0 (s, amide CO). -
For C₂₈H₃₁N₃O₉ (MG 553.58)
calc. C 60.75; H 5.64; N 7.59;
found C 53.30; H 4.73; N 6.37.
MG 399.43.3. Myxochelin C-nitrile (2), characterized by one or more of the following parameters: [α] = -12 (c = 1 in methanol). -
MG 399.43.
IR (KBr): ν = 3360 (NH), 2925 (CH), 2230 (-CN), 1630 (Amid-I), 1525 cm (Amid-II). -
¹³C-NMR (125.6 MHz, CD₃OD): δ (ppm) = 26.8 (t, C-4), 31.0 (t, C-3), 39.4 (t, C-5), 41.5 (d, C-2), 116.1, 116.7 (s, quart. arom. -C=), 118.7, 119.1 (d, arom. =CH-) 118.7 (s, -CN), 119.6, 119.7, 120.0, 120.4 (d, arom. =CH-), 147.3, 147.4, 150.2, 150.3 (s, quart. -O-C=), 171.1, 171.7 (s, sek. Amid-CO). -
¹H-NMR (500 MHz, CD₃OD): δ (ppm) = 1.02 (quin., J₁= 14.8 Hz, J₂= 7.4 Hz, 2H, 4-CH₂-), 1.25 (9 Linien, J₁= 15.5, J₂= 7.8, J₃= 7.7 Hz, 2H, 3-CH₂-), 2.67 (dd, J₁= 6.6, J₂= 7.0 Hz, 1H, 2-H), 5.91 (dd, J₁= 7.8, J₂= 8.1 Hz, 1H, meta-Harom.), 5.95 (dd, J₁= 8.1, J₂= 8.2 Hz, 1H, meta-Harom.), 6.13 (dd, J₁= 1.2, J₂= 7.8 Hz, 1H, para-Harom.), 6.17 (dd, J₁= 1.2, J₂= 7.8 Hz, 1H, para-Harom.), 6.41 (dd, J₁= 1.5, J₂= 8.1 Hz, 1H, ortho-Harom. ), 6.45 (d, J₁= 1.1, J₂= 8.1 Hz, 1H, ortho-Harom.). -
ESI-(+)-MS : M/z (%) = 408 (100), [M+Na]⁺. -
Für C₁₉H₁₉N₃O₆ (MG 385.39)
ber. C 59.36; H 4.72; N 10.93;
gef. C 57.10; H 5.44; N 9.78.4. Myxochelin D-nitrile (3) characterized by one or more of the following parameters: [α] = -14.5 (c = 0.9 in methanol). -
IR (KBr): ν = 3360 (NH), 2925 (CH), 2230 (-CN), 1630 (Amid-I), 1525 cm (Amid-II). -
13 C-NMR (125.6 MHz, CD₃OD): δ (ppm) = 26.8 (t, C-4), 31.0 (t, C-3), 39.4 (t, C-5), 41.5 (d, C-2) , 116.1, 116.7 (s, quart. Arom. - C =), 118.7, 119.1 (d, arom. = C H-) 118.7 (s, - C N), 119.6, 119.7, 120.0, 120.4 (d, arom. = C H-), 147.3, 147.4, 150.2, 150.3 (s, quart. -O- C =), 171.1, 171.7 (s, sec. Amide-CO). -
1 H-NMR (500 MHz, CD₃OD): δ (ppm) = 1.02 (quin., J₁ = 14.8 Hz, J₂ = 7.4 Hz, 2H, 4-CH₂-), 1.25 (9 lines, J₁ = 15.5, J₂ = 7.8 , J₃ = 7.7 Hz, 2H, 3-CH₂-), 2.67 (dd, J₁ = 6.6, J₂ = 7.0 Hz, 1H, 2-H), 5.91 (dd, J₁ = 7.8, J₂ = 8.1 Hz, 1H, meta -H aroma. ), 5.95 (dd, J₁ = 8.1, J₂ = 8.2 Hz, 1H, meta-H aroma. ), 6.13 (dd, J₁ = 1.2, J₂ = 7.8 Hz, 1H, para-H aroma. ), 6.17 (dd, J₁ = 1.2, J₂ = 7.8 Hz, 1H, para-H arom. ), 6.41 (dd, J₁ = 1.5, J₂ = 8.1 Hz, 1H, ortho-H arom. ), 6.45 (d, J₁ = 1.1, J₂ = 8.1 Hz, 1H, ortho-H arom. ). -
ESI - (+) - MS: M / z (%) = 408 (100), [M + Na] ⁺. -
For C₁₉H₁₉N₃O₆ (MG 385.39)
calc. C 59.36; H 4.72; N 10.93;
found C 57.10; H 5.44; N 9.78.
Die spektroskopischen Eigenschaften siehe bei der Beschreibung für R-3.[α] = +16 (c = 1 in Methanol). -5. Myxochelin D R -nitrile (R-3), characterized by one or more of the following parameters:
See the description for R-3 for the spectroscopic properties. [Α] = +16 (c = 1 in methanol). -
¹³C-NMR (75.4 MHz, DMSO-d₆): δ (ppm) = 22.9 (t, C-4), 28.7 (t, C-5), 31.3 (t, C-3), 38.6 (t, C-6), 48.7 (d, C-2), 44.0 (t, C-1), 115.7, 115.7 (s, quart. arom. C), 114.1, 115.8, 116.0, 117.2, 117.8, 118.4 (d, arom. =CH-), 147.0, 147.6,151.6, 153.6 (s, quart. -O- C=), 169.3, 169.9 (s, sek. Amid.CO). -
FAW(+)-MS: m/z (%) = 404 (100) [M+H]⁺. -
C₂₀H₂₅N₃O₆ (MG 403.44).6. Myxochelin B R (R-3), characterized by one or more of the following parameters: [α] = +7 (c = 0.5 in 6N HCl). - (The natural product myxochelin B has [α] = -8 (c = 1 in 6N HCl). -
13 C-NMR (75.4 MHz, DMSO-d₆): δ (ppm) = 22.9 (t, C-4), 28.7 (t, C-5), 31.3 (t, C-3), 38.6 (t, C- 6), 48.7 (d, C-2), 44.0 (t, C-1), 115.7, 115.7 (s, quart. Arom. C), 114.1, 115.8, 116.0, 117.2, 117.8, 118.4 (d, arom. = CH-), 147.0, 147.6, 151.6, 153.6 (s, quart. -O- C =), 169.3, 169.9 (s, sec.Amid.CO). -
FAW (+) - MS: m / z (%) = 404 (100) [M + H] ⁺. -
C₂₀H₂₅N₃O₆ (MG 403.44).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1996126020 DE19626020A1 (en) | 1994-12-22 | 1996-06-21 | Synthetic siderophore compounds |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4447374A DE4447374A1 (en) | 1994-12-22 | 1994-12-22 | New siderophore cpds. esp. myxochelin C, used as chelating agents |
| DE1996126020 DE19626020A1 (en) | 1994-12-22 | 1996-06-21 | Synthetic siderophore compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE19626020A1 true DE19626020A1 (en) | 1998-01-02 |
Family
ID=42315199
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE4447374A Withdrawn DE4447374A1 (en) | 1994-12-22 | 1994-12-22 | New siderophore cpds. esp. myxochelin C, used as chelating agents |
| DE1996126020 Withdrawn DE19626020A1 (en) | 1994-12-22 | 1996-06-21 | Synthetic siderophore compounds |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE4447374A Withdrawn DE4447374A1 (en) | 1994-12-22 | 1994-12-22 | New siderophore cpds. esp. myxochelin C, used as chelating agents |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0923538A1 (en) |
| AU (1) | AU6417296A (en) |
| DE (2) | DE4447374A1 (en) |
| WO (1) | WO1997049669A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999042435A2 (en) * | 1998-02-21 | 1999-08-26 | Analyticon Ag Biotechnologie Pharmazie | Myxochelines |
| WO2008101909A1 (en) * | 2007-02-20 | 2008-08-28 | Henkel Ag & Co. Kgaa | Siderophore-metal- complexes used as bleach catalysts |
| WO2008151288A2 (en) * | 2007-06-05 | 2008-12-11 | Xenon Pharmaceuticals Inc. | Aromatic and heteroaromatic compounds useful in treating iron disorders |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4447374A1 (en) * | 1994-12-22 | 1996-06-27 | Trowitzsch Kienast Wolfram Pro | New siderophore cpds. esp. myxochelin C, used as chelating agents |
| DE19807475A1 (en) * | 1998-02-24 | 1999-09-09 | Analyticon Ag | New myxocheline derivatives useful e.g. for treating disorders associated with deficient metal ion metabolism, especially iron or aluminium metabolism, e.g. hemosiderosis, thalassemia or Alzheimer's disease |
| DE10111161A1 (en) * | 2001-03-01 | 2002-09-05 | Gruenenthal Gmbh | New siderophore analogues as 4- or 6-toothed iron chelators based on amino acids or peptides, processes for their preparation and their use |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH07252197A (en) * | 1994-03-13 | 1995-10-03 | Masayasu Akiyama | Triscatecholamide derivative containing lysine residue |
| DE4447374A1 (en) * | 1994-12-22 | 1996-06-27 | Trowitzsch Kienast Wolfram Pro | New siderophore cpds. esp. myxochelin C, used as chelating agents |
-
1994
- 1994-12-22 DE DE4447374A patent/DE4447374A1/en not_active Withdrawn
-
1996
- 1996-06-21 DE DE1996126020 patent/DE19626020A1/en not_active Withdrawn
- 1996-06-26 AU AU64172/96A patent/AU6417296A/en not_active Abandoned
- 1996-06-26 EP EP96923943A patent/EP0923538A1/en not_active Withdrawn
- 1996-06-26 WO PCT/EP1996/002796 patent/WO1997049669A1/en not_active Application Discontinuation
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999042435A2 (en) * | 1998-02-21 | 1999-08-26 | Analyticon Ag Biotechnologie Pharmazie | Myxochelines |
| WO1999042435A3 (en) * | 1998-02-21 | 1999-12-16 | Analyticon Ag Biotechnologie P | Myxochelines |
| WO2008101909A1 (en) * | 2007-02-20 | 2008-08-28 | Henkel Ag & Co. Kgaa | Siderophore-metal- complexes used as bleach catalysts |
| WO2008151288A2 (en) * | 2007-06-05 | 2008-12-11 | Xenon Pharmaceuticals Inc. | Aromatic and heteroaromatic compounds useful in treating iron disorders |
| WO2008151288A3 (en) * | 2007-06-05 | 2009-09-24 | Xenon Pharmaceuticals Inc. | Aromatic and heteroaromatic compounds useful in treating iron disorders |
Also Published As
| Publication number | Publication date |
|---|---|
| DE4447374A1 (en) | 1996-06-27 |
| EP0923538A1 (en) | 1999-06-23 |
| AU6417296A (en) | 1998-01-14 |
| WO1997049669A1 (en) | 1997-12-31 |
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