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WO2002085841A2 - Derives de catechol substitues, derivant d'acides amines secondaires polybasiques, leur procede de production et leur utilisation - Google Patents

Derives de catechol substitues, derivant d'acides amines secondaires polybasiques, leur procede de production et leur utilisation Download PDF

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Publication number
WO2002085841A2
WO2002085841A2 PCT/EP2002/002071 EP0202071W WO02085841A2 WO 2002085841 A2 WO2002085841 A2 WO 2002085841A2 EP 0202071 W EP0202071 W EP 0202071W WO 02085841 A2 WO02085841 A2 WO 02085841A2
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Prior art keywords
compounds
alkyl
formula
substituted
acid
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PCT/EP2002/002071
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German (de)
English (en)
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WO2002085841A3 (fr
Inventor
Lothar Heinisch
Steffen Wittmann
Ina Scherlitz-Hofmann
Thomas Stoiber
Albrecht Berg
Ute Möllmann
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Gruenenthal GmbH
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Gruenenthal GmbH
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/24—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in positions 2 and 4
    • C07D265/26—Two oxygen atoms, e.g. isatoic anhydride
    • 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
    • C07C235/52—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 having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups

Definitions

  • the present invention relates to new catechol derivatives derived from polybasic secondary amino acids.
  • the compounds are effective as siderophores in Gram-negative bacteria, ie they can supply bacteria with iron ions, in particular also mycobacteria, for which no synthetic siderophores are known to date.
  • they in the form of their conjugates with active substances, for example with antibiotics (as "siderophore-antibiotic conjugates"), they can be introduced into the bacterial cell via iron transport routes and thus improve or expand their effectiveness more than previous compounds of this type are done to overcome penetration-related antibiotic resistance.
  • N- (2,3-dihydroxybenzoyl) glycine has been found as a siderophore in B.subtilis (Ito.T., Neilands, JB, J.Amer.Chem Soc. 80 (1958), 4645).
  • Some catechol-substituted amino acid derivatives have already been prepared synthetically, for example N- (2,3-dihydroxybenzoyl) -L-threonine (Kanai, F .; Kaneko, T., Morishima, H., Isshiki, K., Takita, T ., Takeuchi, T., Umezawa.H., J. Antibiot.
  • Catechols of diamino and triamino compounds, straight-chain or branched, without carboxyl function are described, e.g. Triscatechol derivatives of bis-aminopropylamine (Martell AE; Motekaitis RJ, Murase I .; Sala LF, Stoldt R.Ng, Chiu Y., Rosenkrantz H .; Inorg. Chim. Acta (1987), 138, 215-30.) , Bis-catechol derivatives of spermidine (Bergeron RJ, Burton PS, McGovern KA, Onge EJSt .; J.Med.Chem.
  • siderophores as iron chelators are potentially able to influence the biological iron metabolism and related diseases in various ways.
  • the siderophore desferrioxamine B (Desferal) is successfully used in diseases based on iron overload (e.g. thalassemia).
  • Other effects of siderophores or siderophor analogues have also been described, such as e.g. the anti-tumor activity of an analog of mycobactin (Tsunakawa M., Li-Ping Chang, Mamber S.W., Bursuker I, Hugill R .; US Patent 5811440, 1998).
  • the invention serves to find new catechol derivatives derived from polybasic secondary amino acids and analogous structures, and to their use.
  • the aim of the invention is to find new compounds which act as siderophores in Gram-negative bacteria and mycobacteria and which, for the first time, also exceed the compounds of this type described so far in their siderophore activity in Gram-negative pathogens. are effective as siderophores in mycobacteria.
  • suitable compounds for introducing active substances, for example antibiotics, into the bacterial cell via bacterial iron transport routes which exceed the compounds of this type described so far are intended to find new precursors or prodrug forms for iron chelators which can influence the biological iron metabolism and related diseases in various ways.
  • the aim of acylated catechol compounds or the incorporation of the catechol structure into the heterocyclic benzoxazinedione structure is to give the compounds improved pharmacological properties or to serve as pharmacological forms of transport for the catechol compounds which actually promote penetration.
  • the object of the invention is to find new catechol compounds or their acylated derivatives of secondary amino acids and analog structures of the general formula I which are incorporated in benzoxazinedione structures and which can act as siderophores or biological iron chelators.
  • R 1 H, alkyl, substituted. Alkyl, aryl, substituted aryl,
  • R 2 H, CO alkyl, COO alkyl,
  • R together with X is a (CH ', 2) ⁇ — N-CO group
  • R> 4 _ H, alkyl, substituted alkyl, aryl, substituted aryl, halogen, alkoxy, substituted alkoxy, in all possible positions, it being possible for the substituents mentioned to occur more than once,
  • Ammonium ion preferably tributylammonium ion or an N-methyl-glucosammonium ion,
  • Z arylene or substituted arylene, preferably
  • R 15 H, alkyl, substituted alkyl, aryl, substituted aryl, halogen,
  • Alkanoyl or -CC 4 alkoxy-carbonyl, alkyl and alkoxy also in word combinations such as alkoxycarbonyl, in particular for d-Cs-alkyl or -alkoxy, substituted alkyl for alkyl substituted by halogen, alkoxy, hydroxy, carboxy and alkoxycarbonyl, substituted Alkoxy represents alkoxy, aryl or arylene substituted by halogen, alkoxy, carboxy and alkoxycarbonyl, preferably phenyl or phenylene, or phenyl or phenylene substituted by alkyl, halogen, alkoxy, hydroxy, carboxy and alkoxycarbonyl, and a substituted ammonium ion is preferred an ammonium ion substituted one or more times by alkyl, such as one to four times, and, in the presence of asymmetric C atoms, the corresponding D and L forms, enantiomers and diastereomers and also the racemates
  • the compounds of the formula I according to the invention are prepared as follows.
  • the compounds IV can be purified by preparing their carbobenzoxy derivatives (Z derivatives), separating them from by-products by chromatography using HPLC, and then splitting off the Z groups again by hydrogenolysis (H 2 / Pd / C).
  • the secondary amino acids are treated with corresponding catechol derivatives, for example with dihydroxy- or diacyloxybenzoic acids or their acid chlorides or with corresponding spacer compounds, for example with 8-methoxycarbonyloxy-3,4-dihydro-2H-1,3-benzoxazin-3-yl- acetyl chloride, (R 6 or R 7 ) by customary processes, for example by the anhydride process (for example using isobutyl chloroformate), by the active ester process (for example with N-hydroxysuccinimide and dicyclohexylcarbodiimide) or by the chloride method to give the compounds of the formula I.
  • catechol derivatives for example with dihydroxy- or diacyloxybenzoic acids or their acid chlorides or with corresponding spacer compounds, for example with 8-methoxycarbonyloxy-3,4-dihydro-2H-1,3-benzoxazin-3-yl- acetyl chloride, (R 6 or R 7 )
  • the compounds of formula I with a carboxyl group can be present as free acids, in the form of their salts or as easily cleavable esters, in particular cleavable under physiological conditions.
  • the compounds can be further purified by customary methods known from the prior art, for example by means of chromatographic methods.
  • the compounds of the formula I according to the invention show siderophore activity in various Gram-negative bacterial strains and also in mycobacteria. As a result, these compounds can be used as growth factors for certain bacterial cultures.
  • the test for siderophore effectiveness was carried out with various bacterial strains which showed very little growth under the test conditions in the case of iron deficiency.
  • the following test strains were used: Pseudomonas aeruginosa ATCC 27853, SG 137, NCTC 10662, ATCC 9027, K799 / VT and Escherichia coli ATCC 25922.
  • the mutant enb7 from Salmoneila typhimurium was used for testing, which blocks enterobactin in the biosynthesis of the siderophore and thus is disturbed in their iron supply.
  • the test was carried out in an agar diffusion test, whereby growth promotion means that the test substances enable the iron supply of the bacteria and are therefore effective as siderophores.
  • the growth promotion was evaluated as the diameter of the growth zones in mm. Control was used for the pseudomonads Desferal, for the _ ⁇ .co / strain ferricrocin and for the Salmonella mutant enb7 enterobactin. The test substances were applied in an amount of 5 ⁇ g / test leaflet in each case.
  • the compounds are effective as siderophores in most strains of mycobacteria, usually better than the natural siderophore mycobactin used as a control. Particularly noteworthy is that 3 compounds also promote bacterial growth in mutant B3 (exochelin -, mycobactin -) and 2 compounds in U3 (uptake system for exochelin -).
  • 3,10,17-triaza-heptadecanoic acid benzyl ester tritosylate A mixture of 1.35 g (5mmol) 3,10,17-triaza-heptadecanoic acid, 8 g (15 mmol) p-toluenesulfonic acid and 6 ml benzyl alcohol in 100 ml benzene was refluxed for 5 hours with a water separator. The solvent was then distilled off in vacuo, the residue was dissolved in a little isopropanol and diethyl ether was added. 3.5 g (80% of theory) of the title compound were obtained in the form of a pale yellow solid.
  • a further purification of the compound could be achieved by producing the tri-Z product from the crude product by reaction with benzyl chloroformate according to a known method, this by preparative HPLC on silica gel (Eurospher 100 C18, 7 ⁇ m, from Knauer, Berlin) with a Mixture of acetonitrile / water (37.5 / 62.5), which contained 0.05% trifluoroacetic acid, was purified as an eluent and then the Z groups were removed hydrogenolytically using palladium on activated carbon (10%) as a catalyst at atmospheric pressure and 20 ° C. were.
  • Level 2 Level 2:
  • Step 1
  • Step 2 6- (aminoethyl) -3,6,9-triaza-nonanoic acid benzyl ester tritosylate
  • Example 2 The preparation was carried out analogously to Example 1, from the product from stage 3 by hydrogenolysis, the title compound being obtained as a colorless, solid foam in 90% yield.
  • the aqueous solution obtained was cooled to 0 ° C., brought to about pH 2 with hydrochloric acid and extracted three times with 50 ml of ethyl acetate each time.
  • the organic phase was washed three times with aqueous sodium chloride solution, dried with sodium sulfate, evaporated in vacuo and finally dried in a high vacuum. 5.8 g of the title compound were obtained in the form of a solid foam in 89% yield.
  • the product was prepared by means of preparative HPLC on silica gel (Eurospher 100 C18, 7 ⁇ m, from Knauer, Berlin) with a mixture of acetonitrile / water (37.5 / 62.5) containing 0.05% trifluoroacetic acid Eluent cleaned.
  • Step 1
  • Chloro-2,3-dimethoxycarbonyloxybenzoylchloride (Wittmann S., Scherlitz-Hofmann I., Möllmann U., Ankel-Fuchs D., Heinisch L .; Arzneistoff.-Forsch. 50, 752-757,
  • Example 7 3.7-bis (5-bromo-2,3-dimethoxycarbonyloxybenzoyl) -3,7-diaza-octanoic acid.
  • N-methyl-diaminopropane and glyoxylic acid monohydrate the title compound being obtained in 93% yield in the form of a viscous pale yellow oil.
  • the title compound was prepared analogously to Example 4 from 3,8-diazo-octanoic acid and 2,3-diacetoxybenzoyl chloride in 60% yield in the form of a colorless solid foam.
  • This tri-Z derivative was hydrogenated in methanol with palladium on activated carbon (10%) at 20 ° C. and atmospheric pressure, the title compound 3- ( ⁇ -aminocaproyl) - 3,7,10-triaza-undecanoic acid in the form of a viscous oil was obtained.
  • Stage 3 3-f ⁇ - (8-methoxycarbonyloxy-3,4-dihydro-2,4-dioxo-2H-1,3-benzoxazin-3-yl) - hexanoyl1-7- (2,3-dimethoxycarbonyloxybenzov0-10- (8-methoxycarbonyloxy-3,4-dihydro-2,4-dioxo-2H-1,3-benzoxazin-3-yl) -3,7-diaza-n-decanoic acid.
  • the aqueous solution obtained was cooled to 0 ° C., brought to about pH 2 with hydrochloric acid and extracted three times with in each case 30 ml of ethyl acetate.
  • the organic phase was washed three times with aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo.
  • Triethylamine was added dropwise to a solution of the product obtained in 10 ml of acetonitrile until the mixture had reached pH 8. The mixture was then stirred at 20 ° C. for one hour, it being necessary to readjust to pH 8 using triethylamine.
  • Step 1
  • the title compound was prepared analogously to Example 4, stage 1 from 1,4-diamino-n-butane and pyruvic acid in the form of a viscous pale yellow oil.
  • Step 1
  • Step 2 3.9-bis- [2,3-di- (methoxycarbonyloxy) benzoyll-2,7-dimethyl-3,9-diaza-nonanoic acid
  • Step 1 4-methyl-5,9-diaza-n-decanoic acid
  • the preparation was carried out analogously to Example 4, stage 1 from N-methyl-1,3-diaminopropane and levulinic acid, the title compound being obtained in the form of a viscous pale yellow oil.
  • Stage 2 5,9-bis- (2,3-dimethoxycarbonyloxybenzoyl) -4-methyl-5,9-diaza-n-decanoic acid
  • the preparation was carried out analogously to Example 4 from 4-methyl-5,9-diaza-decanoic acid and 2,3-Di- (methoxycarbonyloxy) benzoyl chloride, the title compound being obtained in 70% yield in the form of a colorless solid.
  • Step 1
  • Step 1
  • Stage 2 4-r2.6.9.13-tetrakis (2.3-di-acetoxybenzoyl) -2.6.9.13-tetraaza-tridecyll-benzoic acid
  • Step 1
  • Step 1
  • Example 26 3.8-rBis- (2,3-diacetoxybenzoyl) -2-phenyl-3,8-diaza-octanoic acid
  • R 1 phenyl
  • R 2 , R 3 , R 8 COCH 3
  • R 4 , R 5 , R 7 H
  • R 6 R 9
  • Y OH.
  • Step 1 2-phenyl-3,8-diaza-octanoic acid
  • the title compound was prepared analogously to Example 4, stage 1 from 1,4-diamino-n-butane and phenylglyoxylic acid in 65% yield in the form of a viscous pale yellow oil.
  • Step 1
  • Step 2 3-rBis-2,6- (2,3-diacetoxybenzovD-2.6-diaza-heptyll-4-hydroxy-benzoic acid
  • the preparation was carried out analogously to Example 4 from 3- (2,6-diaza-heptyl) -4-hydroxybenzoic acid and 2,3-diacetoxybenzoyl chloride, the title compound being obtained in 30% yield in the form of a colorless solid foam.
  • Step 1
  • Step 1

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne de nouveaux dérivés de catéchol substitués, dérivant d'acides aminés secondaires polybasiques, ainsi que des structures analogues de formule générale (I). Les composés selon cette invention sont efficaces en tant que sidérophores en cas de mycobactéries et de souches de bactéries de type Gram négatif, notamment de Pseudomonas et de souches E.coli et Salmonella. Ils peuvent servir de véhicules de transport pour introduire des substances actives, telles que des antibiotiques (sous forme de conjugués sidérophore-antibiotique), dans des cellules de bactéries et ainsi améliorer ou élargir leur efficacité antibactérienne dans une plus large mesure que les composés connus jusqu'à présent. De plus, lesdits composés sont, sous formes promédicamenteuses potentielles pour des chélateurs de fer, adaptés à un usage en cas de maladies basées sur un dysfonctionnement du métabolisme du fer. Dans la formule (I), R1 représente H, alkyle ou aryle, R2 et R3 représentent H ou acyle, R4 et R5 représentent H, alkyle ou aryle, R6 et R7 représentent H, alkyle ou des groupes catécholate, éventuellement sous forme acylée ou avec des groupes espaceurs, X et Z représentent des composés directs ou interrompus par des groupes espaceurs définis et Y représente OH (en tant qu'acides libres, sous forme de leurs sels ou de leurs esters facilement clivables).
PCT/EP2002/002071 2001-03-01 2002-02-27 Derives de catechol substitues, derivant d'acides amines secondaires polybasiques, leur procede de production et leur utilisation Ceased WO2002085841A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE2001111164 DE10111164A1 (de) 2001-03-01 2001-03-01 Neue substituierte Catecholderivate abgeleitet von mehrbasischen sekundären Aminosäuren, Verfahren zu ihrer Herstellung und ihre Anwendung
DE10111164.9 2001-03-01

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WO2002085841A3 WO2002085841A3 (fr) 2003-03-20

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7122580B2 (en) 2002-08-09 2006-10-17 Transtech Pharma, Inc. Aryl and heteroaryl compounds and methods to modulate coagulation
US7208601B2 (en) 2003-08-08 2007-04-24 Mjalli Adnan M M Aryl and heteroaryl compounds, compositions, and methods of use
US7459472B2 (en) 2003-08-08 2008-12-02 Transtech Pharma, Inc. Aryl and heteroaryl compounds, compositions, and methods of use
US7544699B2 (en) 2003-08-08 2009-06-09 Transtech Pharma, Inc. Aryl and heteroaryl compounds, compositions, and methods of use

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2345077A1 (fr) * 1976-03-24 1977-10-21 Philagro Sa Nouvelles compositions regulatrices de la croissance des plantes a base de derives de la n-acyl methionine
DE19625524C2 (de) * 1996-06-26 2000-11-30 Gruenenthal Gmbh Neue synthetische Catechol-Antibiotika-Konjugate und diese enthaltende Arzneimittel
DE19708846A1 (de) * 1997-03-05 1998-09-17 Gruenenthal Gmbh Neue Benzoxazindionderivate, Verfahren zu ihrer Herstellung und ihre Verwendung
DE10111160A1 (de) * 2001-03-01 2002-09-05 Gruenenthal Gmbh Neue Catecholat-ß-Laktamkonjugate, Verfahren zu ihrer Herstellung und ihre Anwendung

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7122580B2 (en) 2002-08-09 2006-10-17 Transtech Pharma, Inc. Aryl and heteroaryl compounds and methods to modulate coagulation
US7208601B2 (en) 2003-08-08 2007-04-24 Mjalli Adnan M M Aryl and heteroaryl compounds, compositions, and methods of use
US7459472B2 (en) 2003-08-08 2008-12-02 Transtech Pharma, Inc. Aryl and heteroaryl compounds, compositions, and methods of use
US7501538B2 (en) 2003-08-08 2009-03-10 Transtech Pharma, Inc. Aryl and heteroaryl compounds, compositions and methods of use
US7544699B2 (en) 2003-08-08 2009-06-09 Transtech Pharma, Inc. Aryl and heteroaryl compounds, compositions, and methods of use

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DE10111164A1 (de) 2002-09-05

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