DE102022129896A1 - Salts and complexes with 3-acetyl-4-hydroxybicyclo[3.3.1]non-3-en-2,9-dione derivatives and uses of these salts and complexes - Google Patents

Abstract

The invention relates to salts and complexes of 3-acetyl-4-hydroxybicyclo[3.3.1]non-3-ene-2,9-dione derivatives. A compound of the general formula IA or IB is provided, whereinA is -(CH2)m- and m is 0, 1 or 2;n is 1, 2 or 3;M is a metal ion;R1 is selected from the group consisting of isoprenyl, geranyl, benzyl and methyl;R2 is selected from the group consisting of allyl, isoprenyl and methyl;R3 is selected from the group consisting of allyl, isoprenyl, benzyl and methyl;R4 is selected from the group consisting of -C1-C16-alkyl, -C1-C16-alkenyl, -C1-C16-alkynyl, cycloalkyl, unsubstituted or R7-substituted aryl and unsubstituted or R7-substituted heteroaryl;R5 is methyl or isoprenyl;R6 is methyl or isoprenyl; andR7is selected from the group consisting of halogen, amine, azide, -C1-C16alkyl, -O-C1-C16alkyl, -C1-C16haloalkyl and aryl.

Description

The invention relates to salts and complexes with 3-acetyl-4-hydroxybicyclo[3.3.1]non-3-en-2,9-dione derivatives, processes for the preparation of salts and complexes of these 3-acetyl-4-hydroxybicyclo[3.3.1]non-3-en-2,9-dione derivatives and uses of the salts and complexes of these 3-acetyl-4-hydroxybicyclo[3.3.1]non-3-en-2,9-dione derivatives.

worin A¹ jeweils eine Bindung zu einem Substituenten kennzeichnet. Sie gehören zur Familie der polyzyklischen polyprenylierten Acylphloroglucinole (die auch als PPAPs bezeichnet werden). Einzelheiten zu vorbekannten PPAPs können beispielsweise aus C. Guttroff, A. Baykal, H. Wang, P. Popella, F. Kraus, N. Biber, S. Krauss, F. Götz, B. Plietker, Polycyclic polyprenylated acylphloroglucinols - an emerging class of nonpeptide-based MRSA- and VRE-active antibiotics, Angew. Chem. Int. Ed. 2017, 56, 15852-15855 , und P. Popella, A. Baykal, C. Guttroff, P. Francois, P. Sass, B. Plietker, F. Götz, The Polycyclic polyprenylated acylphloroglucinol antibiotic PPAP 23 targets the membrane and iron Metabolism in Staphylococcus aureus, Front. Microbiol., 2019, 10, 14 , entnommen werden. Die Bezeichnung „polyzyklische polyprenylierte Acylphloroglucinole“ geht auf die ursprünglich isolierten Naturstoffe zurück, die das polyzyklische Grundgerüst und das Acylphloroglucinol als eine Seitengruppe aufweisen. Zu den PPAPs werden auch Verbindungen gezählt, die diese Seitengruppe nicht besitzen. Das gilt beispielsweise für Phloroglucinole. Die ursprünglich isolierten Naturstoffe, beispielsweise Hyperforin, sind außerdem polyprenyliert, während die synthetischen PPAPs heute nicht mehr unbedingt Isoprenylketten aufweisen müssen. Der Familienname ist aber unverändert geblieben. Die Verbindungen mit der in Formel GS gezeigten Grundstruktur sind somit PPAPs, und zwar PPAPs vom Typ B. Die Angabe „Typ B“ kennzeichnet dabei das Kohlenstoffatom des Bizyklus, an dem die exozyklische Acylgruppe sitzt: C1 = Typ A, C3 = Typ B, C5 = Typ C.3-Acetyl-4-hydroxybicyclo[3.3.1]non-3-en-2,9-dione derivatives have the basic structure shown in formula GS

where A ¹ represents a bond to a substituent. They belong to the family of polycyclic polyprenylated acylphloroglucinols (also known as PPAPs). Details of previously known PPAPs can be found, for example, in C. Guttroff, A. Baykal, H. Wang, P. Popella, F. Kraus, N. Biber, S. Krauss, F. Götz, B. Plietker, Polycyclic polyprenylated acylphloroglucinols - an emerging class of nonpeptide-based MRSA- and VRE-active antibiotics, Angew. Chem.Int. Ed. 2017, 56, 15852-15855 , and P. Popella, A. Baykal, C. Guttroff, P. Francois, P. Sass, B. Plietker, F. Götz, The polycyclic polyprenylated acylphloroglucinol antibiotic PPAP 23 targets the membrane and iron metabolism in Staphylococcus aureus, Front. Microbiol., 2019, 10, 14 , can be taken from the formula GS. The term "polycyclic polyprenylated acylphloroglucinols" goes back to the originally isolated natural substances that have the polycyclic basic structure and the acylphloroglucinol as a side group. PPAPs also include compounds that do not have this side group. This applies, for example, to phloroglucinols. The originally isolated natural substances, for example hyperforin, are also polyprenylated, while synthetic PPAPs today no longer necessarily have to have isoprenyl chains. The family name has remained unchanged, however. The compounds with the basic structure shown in formula GS are therefore PPAPs, specifically PPAPs of type B. The term "type B" indicates the carbon atom of the bicycle on which the exocyclic acyl group is located: C1 = type A, C3 = type B, C5 = type C.

The medical use of PPAPs requires sufficient water solubility. However, the water solubility of known PPAPs is low. Attempts have been made to improve the water solubility of type A PPAPs by formulating them as dicyclohexylammonium salts. However, it has been found that such ammonium salts are not long-term stable in aqueous media. In addition, there is a fundamental risk that substituents that improve water solubility simultaneously impair the pharmacological properties of the compounds. For example, it has been found that the dicyclohexylammonium salts of type A PPAPs release dicyclohexylamine, which has an adverse effect on biological activity.

The object of the invention is to eliminate the disadvantages of the prior art. In particular, a compound is to be specified which is biologically active and has a higher solubility and better stability in aqueous media.

This object is achieved by the features of claims 1, 10, 12, 13, 14 and 15. Useful embodiments of the inventions emerge from the features of the subclaims.

worin
A -(CH₂)_m- ist und m 0, 1 oder 2 ist;
n 1, 2 oder 3 ist;
Mein Metallion ist;
R¹ aus der Gruppe ausgewählt ist, die aus Isoprenyl, Geranyl, Benzyl und Methyl besteht;
R² aus der Gruppe ausgewählt ist, die aus Allyl, Isoprenyl und Methyl besteht;
R³ aus der Gruppe ausgewählt ist, die aus Allyl, Isoprenyl, Benzyl und Methyl besteht;
R⁴ aus der Gruppe ausgewählt ist, die aus -C₁-C₁₆-Alkyl, -C₁-C₁₆-Alkenyl, -C₁-C₁₆-Alkinyl, Cycloalkyl, unsubstituiertem oder mit R⁷ substituiertem Aryl und unsubstituiertem oder mit R⁷ substituiertem Heteroaryl besteht;
R⁵ Methyl oder Isoprenyl ist;
R⁶ Methyl oder Isoprenyl ist; und
R⁷ aus der Gruppe ausgewählt ist, die aus Halogen, Amin, Azid, -C₁-C₁₆-Alkyl, -O-C₁-C₁₆-Alkyl, -C₁-C₁₆-Halogenalkyl und Aryl besteht.According to the invention, a compound of the general formula IA or IB is provided

wherein
A is -(CH ₂ ) _m - and m is 0, 1 or 2;
n is 1, 2 or 3;
My metal ion is;
R ¹ is selected from the group consisting of isoprenyl, geranyl, benzyl and methyl;
R ² is selected from the group consisting of allyl, isoprenyl and methyl;
R ³ is selected from the group consisting of allyl, isoprenyl, benzyl and methyl;
R ⁴ is selected from the group consisting of -C ₁ -C ₁₆ alkyl, -C ₁ -C ₁₆ alkenyl, -C ₁ -C ₁₆ alkynyl, cycloalkyl, unsubstituted or R ⁷ substituted aryl, and unsubstituted or R ⁷ substituted heteroaryl;
R ⁵ is methyl or isoprenyl;
R ⁶ is methyl or isoprenyl; and
R ⁷ is selected from the group consisting of halogen, amine, azide, -C ₁ -C ₁₆ alkyl, -OC ₁ -C ₁₆ alkyl, -C ₁ -C ₁₆ haloalkyl and aryl.

In the compound of general formula IA, M is a positively charged metal ion. The metal ion therefore carries a positive charge. The compound of general formula IA is a neutral salt.

worin A¹ jeweils eine Bindung zu einem Substituenten kennzeichnet und M jeweils ein Metallion ist.The compound of general formula IA is a metal salt of a 3-acetyl-4-hydroxybicyclo[3.3.1]non-3-en-2,9-dione derivative. The compound of general formula IB is a metal complex of a 3-acetyl-4-hydroxybicyclo[3.3.1]non-3-en-2,9-dione derivative. The compound of general formula IA or IB has the basic structure shown in formula GS-A or GS-B.

where A ¹ represents a bond to a substituent and M represents a metal ion.

It has been found that the compounds of general formula IA and the compounds of general formula IB have a significantly higher water solubility than the PPAPs known from the prior art. The greatly increased water solubility is not due to a transformation of side chains of previously known PPAPs. Such a transformation could influence the biological activity of the compounds. In contrast, the compounds according to the invention have an amphiphilic structure whose hydrophobic basic structure is retained unchanged. The compounds according to the invention therefore have biological activity and high water solubility. They are also stable in aqueous media. The compounds according to the invention are also stable to air and hydrolysis. In addition, the compounds according to the invention are catalytically active compounds. The biological activity of the compounds according to the invention enables them to be used as antibiotics. They can be used in antibiotic research.

It has also been found that the compounds according to the invention have a higher water solubility compared to the water solubility of compounds that only consist of the protonated organic unit of the compounds according to the invention. In other words: a compound of the general formula IA or IB has a significantly better water solubility than a comparison compound that has the same, but protonated, organic unit. The compounds according to the invention are therefore more bioavailable while maintaining the same activity compared to the comparison compounds mentioned. The compounds according to the invention are also physically solids, i.e. powders, which are easier to handle in terms of biological applications. The comparison compounds are oils or resins. This makes weighing and transferring the comparison compounds considerably more difficult.

It is assumed that the compounds according to the invention can pass the blood-brain barrier. The inventors were able to demonstrate clear interactions of the compounds according to the invention with ion channels. The compounds according to the invention were able to induce activation of the TRPC6 calcium ion channel. This was particularly successful with the compound according to the invention E1. This resulted in a TRPC6-directed calcium influx into the cell interior. PC12 cells expressing TRPC6 were treated with E1 in a FLIPR calcium-4 assay using the method K. Leuner, V. Kazanski, M. Müller FASEB J. 2007;21(14):4101-4111 treated. This led to an increase in the calcium concentration inside the cell. This calcium ion channel is expressed in the kidney, but also in the brain. There is an interaction between the compounds according to the invention and ion channels. The inventors suspect that the compounds according to the invention also interact with ion channels that lie behind the blood-brain barrier. The strong bond between the metal ion M of the compounds according to the invention and the organic unit of the compounds according to the invention thus enables their use as ion carriers, according to the inventors' expectations. The compounds according to the invention can thus be used for cation transport across membranes, for example biological membranes such as cell membranes, or other barriers. Such cation transport could take place in a similar way to bacterial siderophores. The compounds according to the invention of the general formula IB could offer the possibility of modifying the already known protonophore mode of action of PPAPs for the transport of metal ions.

The compounds according to the invention each have, on the one hand, a metal ion M and, on the other hand, at least one organic unit. In the case of the compound of the general formula IA, the organic unit is an anion which is connected to the metal ion via an ionic bond. In the case of the compound of the general formula IB, it is a ligand which forms a complex together with the metal ion serving as the central particle. The compound of the general formula IA differs from the compound of the general formula IB in the type of bond between the organic unit and the metal ion.

According to the invention, it is provided that n is 1, 2 or 3. Whether n is 1, 2 or 3 depends on the valence of the metal ion M. It can be provided that n is equal to 1 if the metal ion is monovalent. It can be provided that n is equal to 2 if the metal ion is divalent. It can be provided that n is equal to 3 if the metal ion is divalent.

auf. An diese Einheit ist das Metallion M - im Fall der Verbindungen der allgemeinen Formel IA ionisch und im Fall der Verbindung der allgemeinen Formel IB koordinativ - gebunden. Es wird angenommen, dass die biologische und katalytische Aktivität der erfindungsgemäßen Verbindungen auf die Bindung zurückzuführen ist. Die katalytische Aktivität ist außerdem auf die wasserstoffbrückenbindenden Eigenschaften der erfindungsgemäßen Verbindungen zurückzuführen.The compound of general formula I has an acetylacetonate unit of the formula

The metal ion M is bound to this unit - ionically in the case of the compounds of the general formula IA and coordinately in the case of the compound of the general formula IB. It is assumed that the biological and catalytic activity of the compounds according to the invention is due to the bond. The catalytic activity is also due to the hydrogen-bonding properties of the compounds according to the invention.

Details of the compounds of general formula IA are described below, followed by details of the compounds of general formula IB.

Compound of general formula IA

The compound of the general formula IA according to the invention is a salt of a metal ion M. The metal ion M is preferably a metal cation, particularly preferably an alkali or alkaline earth metal ion. The number n is preferably 1 or 2. It has been found that compounds of the general formula IA in which M is an alkali or alkaline earth metal ion have a strong increase in water solubility compared to previously known PPAPs. Such an increase in water solubility is particularly advantageous for the use of these compounds in a biological context.

The compounds of the general formula IA according to the invention are biologically active. They have an antibacterial activity. It has been found that the compounds of the general formula IA have a higher antibacterial activity than compounds whose organic unit is protonated.

The compounds of the general formula IA are biologically active, water-soluble and stable in aqueous solution.

vorgesehen, worin
A -(CH₂)_m- ist und m 0, 1 oder 2 ist;
n 1 oder 2 ist;
M ein Alkali- oder Erdalkalimetallion ist;
R¹ aus der Gruppe ausgewählt ist, die aus Isoprenyl, Geranyl, Benzyl und Methyl besteht;
R² aus der Gruppe ausgewählt ist, die aus Allyl, Isoprenyl und Methyl besteht;
R³ aus der Gruppe ausgewählt ist, die aus Allyl, Isoprenyl, Benzyl und Methyl besteht;
R⁴ aus der Gruppe ausgewählt ist, die aus -C₁-C₁₆-Alkyl, -C₁-C₁₆-Alkenyl, -C₁-C₁₆-Alkinyl, Cycloalkyl, unsubstituiertem oder mit R⁷ substituiertem Aryl und unsubstituiertem oder mit R⁷ substituiertem Heteroaryl besteht;
R⁵ Methyl oder Isoprenyl ist;
R⁶ Methyl oder Isoprenyl ist; und
R⁷ aus der Gruppe ausgewählt ist, die aus Halogen, Amin, Azid, -C₁-C₁₆-Alkyl, -O-C₁-C₁₆-Alkyl, -C₁-C₁₆-Halogenalkyl und Aryl besteht.Preferred is a compound of the general formula IA

provided, in which
A is -(CH ₂ ) _m - and m is 0, 1 or 2;
n is 1 or 2;
M is an alkali or alkaline earth metal ion;
R ¹ is selected from the group consisting of isoprenyl, geranyl, benzyl and methyl;
R ² is selected from the group consisting of allyl, isoprenyl and methyl;
R ³ is selected from the group consisting of allyl, isoprenyl, benzyl and methyl;
R ⁴ is selected from the group consisting of -C ₁ -C ₁₆ alkyl, -C ₁ -C ₁₆ alkenyl, -C ₁ -C ₁₆ alkynyl, cycloalkyl, unsubstituted or R ⁷ substituted aryl, and unsubstituted or R ⁷ substituted heteroaryl;
R ⁵ is methyl or isoprenyl;
R ⁶ is methyl or isoprenyl; and
R ⁷ is selected from the group consisting of halogen, amine, azide, -C ₁ -C ₁₆ alkyl, -OC ₁ -C ₁₆ alkyl, -C ₁ -C ₁₆ haloalkyl and aryl.

Preferably, R ⁴ is selected from the group consisting of -C ₁ -C ₁₆ alkyl, -C _{1 -C 16 alkenyl, -C 1 -C 16 alkynyl ,} cycloalkyl, unsubstituted or R ⁷ substituted aryl and unsubstituted or R ⁷ substituted heteroaryl, wherein R ⁷ is selected from the group consisting of -C ₁ -C ₁₆ alkyl, -OC ₁ -C ₁₆ alkyl, -C ₁ -C ₁₆ fluoroalkyl, azide and aryl. More preferably, R ⁷ is -C ₁ -C ₁₆ fluoroalkyl, -OC ₁ -C ₁₈ alkyl or azide.

Preferably, R ⁴ is selected from the group consisting of -C ₁ -C ₁₆ alkyl, -C ₁ -C ₁₆ alkynyl, unsubstituted or R ⁷ substituted aryl and unsubstituted heteroaryl, wherein R ⁷ is selected from the group consisting of -C ₁ -C ₁₆ alkyl, -OC ₁ -C ₁₆ alkyl, -C ₁ -C ₁₆ fluoroalkyl, azide and aryl. More preferably, R ⁷ is -C ₁ -C ₁₆ fluoroalkyl, -OC ₁ -C ₁₈ alkyl or azide.

According to the invention, M can be selected from the group consisting of lithium, sodium, potassium and magnesium. Preferably, the substituent R ⁴ is selected from the group consisting of -C ₁ -C ₁₆ alkyl, -C ₁ -C ₁₆ alkynyl, unsubstituted or R ⁷ substituted aryl and unsubstituted heteroaryl. Particularly preferably, the substituent R ⁴ is selected from the group consisting of methyl, ethynyl, unsubstituted or R ⁷ substituted phenyl and thienyl. Preferably, R ⁷ is selected from the group consisting of -C ₁ -C ₁₆ alkyl, -OC ₁ -C ₁₆ alkyl, -C ₁ -C ₁₆ fluoroalkyl, azide and aryl. Particularly preferably, R ⁷ is -C ₁ -C ₁₆ fluoroalkyl, -OC ₁ -C ₁₈ alkyl or azide.

Preferably, the substituent R ¹ is isoprenyl. Preferably, the substituents R ² and R ³ are each allyl. Preferably, the substituents R ⁵ and R ⁶ are each methyl.

Compound of general formula IB

The compound of the general formula IB according to the invention is a complex whose central particle is the metal ion M. The metal ion M is preferably a metal cation, particularly preferably a divalent or trivalent metal cation. However, the metal cation can also be a monovalent metal ion. The metal cation is preferably a transition metal ion, particularly preferably a divalent or trivalent transition metal cation. The number n is preferably 2 or 3. If the transition metal ion is a monovalent transition metal cation, n is preferably 1.

In the compounds of general formula IB, the metal ions are chelated. The organic unit of the compounds of general formula IB causes the chelation of the transition metal ion. It can be provided that the transition metal ion has an oxidation state of +I (monovalent transition metal ion), +II (divalent transition metal ion) or +III (trivalent transition metal ion). It has been found that the organic unit of the compound of general formula IB causes a strong chelation of the metal ion M. The strong chelation enables the use of the compounds of general formula IB according to the invention as ion carriers. The compounds of general formula IB according to the invention therefore enable medical application through cation transport across membranes, for example biological membranes such as cell membranes, or other barriers.

It has also been found that the chelation of the metal ion in the compounds of general formula IB has little or no effect on the biological activity of the organic moiety. Neither the bioactivity nor the cytotoxicity with respect to human cell lines are impaired, although the compounds of general formula IB have a high water solubility. This is in particular in contrast to the salts of type A PPAPs known from the prior art, which release dicyclohexylamine.

The compounds of general formula IB are biologically active, water-soluble and stable in aqueous solution. They have particularly anti-infective properties. They are therefore also antibacterially active.

vorgesehen, worin
A -(CH₂)_m- ist und m 0, 1 oder 2 ist;
n 2 oder 3 ist;
Mein Übergangsmetallion ist;
R¹ aus der Gruppe ausgewählt ist, die aus Isoprenyl, Geranyl, Benzyl und Methyl besteht;
R² aus der Gruppe ausgewählt ist, die aus Allyl, Isoprenyl und Methyl besteht;
R³ aus der Gruppe ausgewählt ist, die aus Allyl, Isoprenyl, Benzyl und Methyl besteht;
R⁴ aus der Gruppe ausgewählt ist, die aus -C₁-C₁₆-Alkyl, -C₁-C₁₆-Alkenyl, -C₁-C₁₆-Alkinyl, Cycloalkyl, unsubstituiertem oder mit R⁷ substituiertem Aryl und unsubstituiertem oder mit R⁷ substituiertem Heteroaryl besteht;
R⁵ Methyl oder Isoprenyl ist;
R⁶ Methyl oder Isoprenyl ist; und
R⁷ aus der Gruppe ausgewählt ist, die aus Halogen, Amin, Azid, -C₁-C₁₆-Alkyl, -O-C₁-C₁₆-Alkyl, -C₁-C₁₆-Halogenalkyl und Aryl besteht.Preferred is a compound of the general formula IB

provided, in which
A is -(CH ₂ ) _m - and m is 0, 1 or 2;
n is 2 or 3;
My transition metal ion is;
R ¹ is selected from the group consisting of isoprenyl, geranyl, benzyl and methyl;
R ² is selected from the group consisting of allyl, isoprenyl and methyl;
R ³ is selected from the group consisting of allyl, isoprenyl, benzyl and methyl;
R ⁴ is selected from the group consisting of -C ₁ -C ₁₆ alkyl, -C ₁ -C ₁₆ alkenyl, -C ₁ -C ₁₆ alkynyl, cycloalkyl, unsubstituted or R ⁷ substituted aryl, and unsubstituted or R ⁷ substituted heteroaryl;
R ⁵ is methyl or isoprenyl;
R ⁶ is methyl or isoprenyl; and
R ⁷ is selected from the group consisting of halogen, amine, azide, -C ₁ -C ₁₆ alkyl, -OC ₁ -C ₁₆ alkyl, -C ₁ -C ₁₆ haloalkyl and aryl.

Preferably, R ⁴ is selected from the group consisting of -C ₁ -C ₁₆ alkyl, -C _{1 -C 16 alkenyl, -C 1 -C 16 alkynyl ,} cycloalkyl, unsubstituted or R ⁷ substituted aryl and unsubstituted or R ⁷ substituted heteroaryl, wherein R ⁷ is selected from the group consisting of -C ₁ -C ₁₆ alkyl, -OC ₁ -C ₁₆ alkyl, -C ₁ -C ₁₆ fluoroalkyl, azide and aryl. More preferably, R ⁷ is -C ₁ -C ₁₆ fluoroalkyl, -OC ₁ -C ₁₈ alkyl or azide.

Preferably, R ⁴ is selected from the group consisting of -C ₁ -C ₁₆ alkyl, -C ₁ -C ₁₆ alkynyl, unsubstituted or R ⁷ substituted aryl and unsubstituted heteroaryl, wherein R ⁷ is selected from the group consisting of -C ₁ -C ₁₆ alkyl, -OC ₁ -C ₁₆ alkyl, -C ₁ -C ₁₆ fluoroalkyl, azide and aryl. More preferably, R ⁷ is -C ₁ -C ₁₆ fluoroalkyl, -OC ₁ -C ₁₈ alkyl or azide.

According to the invention, M can be selected from the group consisting of copper, nickel and cobalt. Preferably, the substituent R ⁴ is selected from the group consisting of -C ₁ -C ₁₆ alkyl, -C ₁ -C ₁₆ alkynyl, unsubstituted or R ⁷ substituted aryl and unsubstituted heteroaryl. Particularly preferably, the substituent R ⁴ is selected from the group consisting of methyl, ethynyl, unsubstituted or R ⁷ substituted phenyl and thienyl. Preferably, R ⁷ is selected from the group consisting of -C ₁ -C ₁₆ alkyl, -OC ₁ -C ₁₆ alkyl, -C ₁ -C ₁₆ fluoroalkyl, azide and aryl. Particularly preferably, R ⁷ is -C ₁ -C ₁₆ fluoroalkyl, -OC ₁ -C ₁₈ alkyl or azide.

Preferably, the substituent R ¹ is isoprenyl or benzyl. Preferably, the substituent R ² is allyl. Preferably, the substituent R ³ is allyl or benzyl. Preferably, the substituents R ⁵ and R ⁶ are each methyl.

Preferred examples of compounds according to the invention

(1S,5S,7R)-3-Acetyl-1,5-diallyl-8,8-dimethyl-7-(3-methylbut-2-en-1-yl)-4,9-dioxobicyclo[3.3.1]non-2-en-2-olat-Natrium(I) E2

(1S,5S,7R)-3-Acetyl-1,5-diallyl-8,8-dimethyl-7-(3-methylbut-2-en-1-yl)-4,9-dioxobicyclo[3.3.1]non-2-en-2-olat-Lithium(I) E3

Bis((1S,5S,7R)-3-acetyl-1,5-diallyl-8,8-dimethyl-7-(3-methylbut-2-en-1-yl)-4,9-dioxob-icyclo[3.3.1]non-2-en-2-olat)-Kupfer(II) E4

Bis((1S,5R,7R)-5-allyl-3-benzoyl-1,7-dibenzyl-6,6-dimethyl-4,9-dio-xobicyclo[3.3.1]non-2-en-2-olate)-Nickel(II) E5

Tris((1S,5R,7R)-5-allyl-3-benzoyl-1,7-dibenzyl-6,6-dimethyl-4,9-dio-xobicyclo[3.3.1]non-2-en-2-olate)-Cobalt(III) E6

(1S,5S,7R)-1,5-Diallyl-8,8-dimethyl-7-(3-methylbut-2-en-1-yl)-4,9-dioxo-3-(3-(4-(trifluorome-thyl)phenyl)pro-panoyl)bicyclo[3.3.1]non-2-en-2-olat-Natrium(I) E7

(1S,5S,7R)-3-acetyl-1,5-diallyl-8,8-dimethyl-7-(3-methylbut-2-en-1-yl)-4,9-dioxobicyclo[3.3.1]non-2-en-2-olat-Kalium(I) E8

Bis((1S,5S,7R)-3-acetyl-1,5-diallyl-8,8-dimethyl-7-(3-methylbut-2-en-1-yl)-4,9-dioxob-icyclo[3.3.1]non-2-en-2-olat)-Magnesium(II) E9

(1S,5S,7R)-1,5-Diallyl-8,8-dimethyl-7-(3-methylbut-2-en-1-yl)-4,9-dioxo-3-(pent-4-y-noyl)bicyclo[3.3.1]non-2-en-2-olat-Natrium(I) E10

(1S,5S,7R)-1,5-Diallyl-3-(hex-5-y-noyl)-8,8-dimethyl-7-(3-methyl-but-2-en-1-yl)-4,9-dioxob-icyclo[3.3.1]non-2-en-2-olat-Natrium(I) E11

(1S,5S,7R)-1,5-Diallyl-3-(3-(4-azidophenyl)propanoyl)-8,8-dimethyl-7-(3-methylbut-2-en-1-yl)-4,9-dioxobicyclo[3.3.1]non-2-en-2-olat-Natrium(I) E12

(1S,5S,7R)-1,5-diallyl-8,8-dimethyl-7-(3-methylbut-2-en-1-yl)-4,9-dioxo-3-(3-(3,4,5-trimethoxyphenyl)pro-panoyl)bicyclo[3.3.1]non-2-en-2-olat-Natrium(I) E13

(1S,5S,7R)-1,5-Diallyl-8,8-dimethyl-7-(3-methylbut-2-en-1-yl)-4,9-dioxo-3-(3-(thiophen-2-yl)pro-panoyl)bicyclo[3.3.1]non-2-en-2-olat-Natrium(I) Preferred examples of compounds of general formula IA and general formula IB are given in Table 1 below. Table 1 Connection structure Surname E1

(1S,5S,7R)-3-Acetyl-1,5-diallyl-8,8-dimethyl-7-(3-methylbut-2-en-1-yl)-4,9-dioxobicyclo[3.3.1]non-2-en-2-olate sodium(I) E2

(1S,5S,7R)-3-Acetyl-1,5-diallyl-8,8-dimethyl-7-(3-methylbut-2-en-1-yl)-4,9-dioxobicyclo[3.3.1]non-2-en-2-olate lithium(I) E3

Bis((1S,5S,7R)-3-acetyl-1,5-diallyl-8,8-dimethyl-7-(3-methylbut-2-en-1-yl)-4,9-dioxob-icyclo[3.3.1]non-2-en-2-olate)-copper(II) E4

Bis((1S,5R,7R)-5-allyl-3-benzoyl-1,7-dibenzyl-6,6-dimethyl-4,9-dio-xobicyclo[3.3.1]non-2-en-2-olate)-nickel(II) E5

Tris((1S,5R,7R)-5-allyl-3-benzoyl-1,7-dibenzyl-6,6-dimethyl-4,9-dio-xobicyclo[3.3.1]non-2-en-2-olate)-Cobalt(III) E6

(1S,5S,7R)-1,5-diallyl-8,8-dimethyl-7-(3-methylbut-2-en-1-yl)-4,9-dioxo-3-(3-(4-(trifluoromethyl)phenyl)propanoyl)bicyclo[3.3.1]non-2-en-2-olate sodium(I) E7

(1S,5S,7R)-3-acetyl-1,5-diallyl-8,8-dimethyl-7-(3-methylbut-2-en-1-yl)-4,9-dioxobicyclo[3.3.1]non-2-en-2-olate potassium(I) E8

Bis((1S,5S,7R)-3-acetyl-1,5-diallyl-8,8-dimethyl-7-(3-methylbut-2-en-1-yl)-4,9-dioxob-icyclo[3.3.1]non-2-en-2-olate)-magnesium(II) E9

(1S,5S,7R)-1,5-diallyl-8,8-dimethyl-7-(3-methylbut-2-en-1-yl)-4,9-dioxo-3-(pent-4-y-noyl)bicyclo[3.3.1]non-2-en-2-olate sodium(I) E10

(1S,5S,7R)-1,5-diallyl-3-(hex-5-y-noyl)-8,8-dimethyl-7-(3-methyl-but-2-en-1-yl)-4,9-dioxob-icyclo[3.3.1]non-2-en-2-olate sodium(I) E11

(1S,5S,7R)-1,5-diallyl-3-(3-(4-azidophenyl)propanoyl)-8,8-dimethyl-7-(3-methylbut-2-en-1-yl)-4,9-dioxobicyclo[3.3.1]non-2-en-2-olate sodium(I) E12

(1S,5S,7R)-1,5-diallyl-8,8-dimethyl-7-(3-methylbut-2-en-1-yl)-4,9-dioxo-3-(3-(3,4,5-trimethoxyphenyl)propanoyl)bicyclo[3.3.1]non-2-en-2-olate sodium(I) E13

(1S,5S,7R)-1,5-diallyl-8,8-dimethyl-7-(3-methylbut-2-en-1-yl)-4,9-dioxo-3-(3-(thiophen-2-yl)pro-panoyl)bicyclo[3.3.1]non-2-en-2-olate sodium(I)

The compound E1 is a compound of general formula IA in which m is 0, n is 1; M is Na ⁺ ; R ¹ is isoprenyl; R ² and R ³ are allyl, R ⁴ is methyl, R ⁵ and R ⁶ are methyl.

The compound E2 is a compound of general formula IA in which m is 0, n is 1; M is Li ⁺ ; R ¹ is isoprenyl; R ² and R ³ are allyl, R ⁴ is methyl, R ⁵ and R ⁶ are methyl.

The compound E3 is a compound of general formula IB in which m is 0, n is 2; M is Cu ²⁺ ; R ¹ is isoprenyl; R ² and R ³ are allyl, R ⁴ is methyl, R ⁵ and R ⁶ are methyl.

The compound E4 is a compound of general formula IB in which m is 0, n is 2; M is Ni ²⁺ ; R ¹ is benzyl; R ² is allyl, R ³ is benzyl, R ⁴ is phenyl, R ⁵ and R ⁶ are methyl.

The compound E5 is a compound of general formula IB in which m is 0, n is 3; M is Co ³⁺ ; R ¹ is benzyl; R ² is allyl, R ³ is benzyl, R ⁴ is phenyl, R ⁵ and R ⁶ are methyl.

Compound E6 is a compound of general formula IA in which m is 2, n is 1; M is Na ⁺ ; R ¹ is isoprenyl; R ² and R ³ are allyl, R ⁴ is phenyl, R ⁵ and R ⁶ are methyl and R ⁷ is trifluoromethyl.

The compound E7 is a compound of general formula IA in which m is 0, n is 1; MK is ⁺ ; R ¹ is isoprenyl; R ² and R ³ are allyl, R ⁴ is methyl, R ⁵ and R ⁶ are methyl.

The compound E8 is a compound of general formula IA in which m is 0, n is 2; M is Mg ²⁺ ; R ¹ is isoprenyl; R ² and R ³ are allyl, R ⁴ is methyl, R ⁵ and R ⁶ are methyl.

The compound E9 is a compound of general formula IA in which m is 2, n is 1; M is Na ⁺ ; R ¹ is isoprenyl; R ² and R ³ are allyl, R ⁴ is ethynyl, R ⁵ and R ⁶ are methyl.

The compound E10 is a compound of general formula IA in which m is 3, n is 1; M is Na ⁺ ; R ¹ is isoprenyl; R ² and R ³ are allyl, R ⁴ is ethynyl, R ⁵ and R ⁶ are methyl.

The compound E11 is a compound of general formula IA in which m is 2, n is 1; M is Na ⁺ ; R ¹ is isoprenyl; R ² and R ³ are allyl, R ⁴ is phenyl, R ⁵ and R ⁶ are methyl and R ⁷ is azide.

The compound E12 is a compound of general formula IA in which m is 2, n is 1; M is Na ⁺ ; R ¹ is isoprenyl; R ² and R ³ are allyl, R ⁴ is phenyl trisubstituted with R ⁷ , R ⁵ and R ⁶ are methyl and R ⁷ is trifluoromethyl.

The compound E13 is a compound of general formula IA in which m is 2, n is 1; M is Na ⁺ ; R ¹ is isoprenyl; R ² and R ³ are allyl, R ⁴ is thienyl, R ⁵ and R ⁶ are methyl.

worin
A -(CH₂)_m- ist und m 0, 1 oder 2 ist;
n 1, 2 oder 3 ist;
Mein Metallion ist;
R¹ aus der Gruppe ausgewählt ist, die aus Isoprenyl, Geranyl, Benzyl und Methyl besteht;
R² aus der Gruppe ausgewählt ist, die aus Allyl, Isoprenyl und Methyl besteht;
R³ aus der Gruppe ausgewählt ist, die aus Allyl, Isoprenyl, Benzyl und Methyl besteht;
R⁴ aus der Gruppe ausgewählt ist, die aus -C₁-C₁₆-Alkyl, -C₁-C₁₆-Alkenyl, -C₁-C₁₆-Alkinyl, Cycloalkyl, unsubstituiertem oder mit R⁷ substituiertem Aryl und unsubstituiertem oder mit R⁷ substituiertem Heteroaryl besteht;
R⁵ Methyl oder Isoprenyl ist;
R⁶ Methyl oder Isoprenyl ist und
R⁷ aus der Gruppe ausgewählt ist, die aus Halogen, Amin, Azid, -C₁-C₁₆-Alkyl, -O-C₁-C₁₆-Alkyl, -C₁-C₁₆-Halogenalkyl und Aryl besteht,
wobei eine Verbindung der allgemeinen Formel II

worin A, m, R¹, R², R³, R⁴, R⁵ und R⁶ die im Zusammenhang mit der Verbindung der allgemeinen Formel I angegebenen Bedeutungen haben,
mit einer Verbindung der allgemeinen Formel M-X,
worin M ein Metallion ist und X aus der Gruppe ausgewählt ist, die aus H, Halogen und einem organischen Rest besteht,
umgesetzt wird.According to the invention, a process for preparing a compound of general formula IA or IB is further provided,

wherein
A is -(CH ₂ ) _m - and m is 0, 1 or 2;
n is 1, 2 or 3;
My metal ion is;
R ¹ is selected from the group consisting of isoprenyl, geranyl, benzyl and methyl;
R ² is selected from the group consisting of allyl, isoprenyl and methyl;
R ³ is selected from the group consisting of allyl, isoprenyl, benzyl and methyl;
R ⁴ is selected from the group consisting of -C ₁ -C ₁₆ alkyl, -C ₁ -C ₁₆ alkenyl, -C ₁ -C ₁₆ alkynyl, cycloalkyl, unsubstituted or R ⁷ substituted aryl, and unsubstituted or R ⁷ substituted heteroaryl;
R ⁵ is methyl or isoprenyl;
R ⁶ is methyl or isoprenyl and
R ⁷ is selected from the group consisting of halogen, amine, azide, -C ₁ -C ₁₆ alkyl, -OC ₁ -C ₁₆ alkyl, -C ₁ -C ₁₆ haloalkyl and aryl,
wherein a compound of the general formula II

wherein A, m, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the meanings given in connection with the compound of general formula I,
with a compound of the general formula MX,
wherein M is a metal ion and X is selected from the group consisting of H, halogen and an organic radical,
is implemented.

Preparation of a compound of general formula IA

To prepare a compound of general formula IA, a compound of formula II can be reacted with a compound of general formula M-X in an organic solvent. The organic solvent can be an aprotic, polar solvent such as, for example, tetrahydrofuran (THF), MeOH or n-pentane. Tetrahydrofuran is preferably used as the solvent. The compound of general formula II is initially introduced into the organic solvent and the resulting solution is cooled to preferably between -100 °C and 10 °C, more preferably between -78 and 5 °C, particularly preferably to 0 °C. The compound of general formula M-X is then added. The reaction preferably takes place for a period of 1 hour to 8 hours, more preferably from 3 hours to 6 hours and particularly preferably 2 hours. The reaction is preferably carried out at ambient pressure. The reaction is preferably carried out with movement of the reaction mixture, for example with stirring. The compound of the general formula II and the compound of the general formula M-X are preferably present in a molar ratio of 1.5:1 to 1:1.5, preferably 1:1.

Scheme 1A illustrates the preparation of a compound of general formula IA according to the process of the invention:

When a compound of the general formula IA is prepared, in which M is an alkali metal ion, a compound of the general formula IA is formed, in which n is 1. When a compound of the general formula IA is prepared, in which M is an alkaline earth metal ion, a compound of the general formula IA is formed, in which n is 2.

Preparation of a compound of general formula IB

To prepare a compound of the general formula IB, the reaction of a compound of the formula II with a compound of the general formula M-X can be carried out in an organic solvent or water. The organic solvent can be an aprotic, polar solvent such as acetonitrile. Acetonitrile is preferably used. The compound of the general formula II is dissolved in the solvent and the compound of the general formula M-X is added. The reaction is preferably carried out for a period of 10 minutes to 4 hours, more preferably from 20 minutes to 3 hours and particularly preferably 2 hours. The reaction is preferably carried out at ambient pressure. The reaction is preferably carried out with agitation of the reaction mixture, for example with stirring. The compound of the general formula II and the compound of the general formula M-X are preferably present in a molar ratio of 1:1 to 1:0.5, preferably 1:0.6.

Scheme 1B illustrates the preparation of a compound of general formula IB according to the process of the invention:

The preparation of a compound of the general formula IB in which M is a divalent transition metal ion produces a compound of the general formula IB in which n is 2. The preparation of a compound of the general formula IB in which M is a trivalent transition metal ion produces a compound of the general formula IB in which n is 3.

Preparation of the compound of general formula II

Scheme 1 C illustrates a process for preparing a compound of general formula II

In the compound of general formula III, the substituents R ¹ , R ² , R ³ , R ⁵ and R ⁶ have the meanings given in connection with the compound of general formula II. In the compound of general formula IV, m and the substituents A and R ⁴ have the meanings given in connection with the compound of general formula II. The compound of general formula IV is a carboxylic acid derivative.

To prepare a compound of general formula II, for example, the following procedure can be used: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCl) (1.2 mmol), 4-(dimethylamino)pyridine (DMAP) (1.5 mmol) and a compound of general formula IV (1.2 mmol) are added to a solution of the compound of general formula III (1.0 mmol) in dichloromethane (DCM) (3.0 mL) and the mixture is stirred overnight at 40 °C. After complete conversion of the compound of general formula III, which can be checked by thin layer chromatography, the reaction mixture is mixed with 2 M HCl solution (3 mL) and extracted with DCM (3 x 3 mL). The combined organic phases are washed with water and an aqueous sodium chloride solution and dried over anhydrous MgSO ₄ . The solvent is removed in vacuo and the crude product is purified by column chromatography (ethyl acetate/iso-hexane 1:8) to give the compound of general formula II.

Definitions

The term "alkyl", unless otherwise indicated, refers in particular to a saturated aliphatic hydrocarbon group having a branched or unbranched carbon chain of 1 to 16 carbon atoms, preferably 1 to 8 carbon atoms, and most preferably 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like. The alkyl group may optionally be substituted with one or more substituents, each substituent independently being hydroxy, alkyl, alkoxy, halogen, haloalkyl, aryl, heteroaryl, amino, monoalkylamino, or dialkylamino, unless specifically indicated otherwise.

The term "alkoxy", unless otherwise specified, refers particularly to a group of the formula -OR, wherein R is an alkyl group as defined herein. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like. The alkoxy group may optionally be substituted with one or more substituents, each substituent independently being alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino, or dialkylamino.

The term "cycloalkyl", unless otherwise specified, refers in particular to saturated carbocyclic groups consisting of mono- or bicyclic rings and having from 3 to 12 ring atoms. The cycloalkyl group may optionally be substituted with one or more substituents, each substituent independently being alkyl, alkoxy, amino, monoalkylamino, dialkylamino. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. The cycloalkyl group may be partially or perfluorinated. The cycloalkyl group may optionally contain one or more heteroatoms selected from the group consisting of O, N and S.

The term "heterocycloalkyl", unless otherwise specified, refers to a saturated cyclic ring having 5 to 13 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms selected from one or more of N, O and S and the remaining ring atoms are carbon atoms. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, homopiperazinyl, azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, O-xazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinuclidinyl, tetrahydrofuryl, tetrahydropyranyl, thiomorpholinyl, dihydroquinolinyl and 1,4-diazepane. The heterocycloalkyl group may optionally be substituted with one or more substituents, each substituent independently being alkyl, alkoxy, amino, monoalkylamino or dialkylamino.

The term “halogen” refers to fluorine, chlorine, bromine or iodine.

The term "aryl" refers, unless otherwise stated, to a cyclic aromatic hydrocarbon group which consists of or has a mono- or bicyclic aromatic ring system having 5 to 13 ring atoms, preferably 5 or 6 ring atoms. The aryl group may optionally be a substituted aryl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, naphthalenyl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxylyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperadinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, and the like, including partially hydrogenated derivatives thereof. The term "substituted aryl group" refers in particular to an aryl group which is optionally independently substituted with one to four substituents, preferably one or two substituents, selected from alkyl, cycloalkyl, heteroalkyl, halogen, alkoxy, amino, acylamino, monoalkylamino, dialkylamino, haloalkyl, haloalkoxy and alkanesulfonyl.

The term "heteroaryl", unless otherwise specified, refers to a monocyclic, bicyclic or tricyclic group having 5 to 13, more preferably 5 to 6 ring atoms with at least one aromatic ring and further containing one, two, three or four ring heteroatoms selected from N, O and S, with the remaining ring atoms being C. The heteroaryl may optionally be substituted with one, two, three or four substituents. Examples of heteroaryl groups include, but are not limited to, optionally substituted imidazolyl, optionally substituted oxazolyl, optionally substituted thiazolyl, optionally substituted pyrazinyl, optionally substituted pyrrolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted indonyl, optionally substituted indolinyl, optionally substituted isoquinolinyl, optionally substituted carbazol-9-yl, optionally substituted furanyl, optionally substituted benzofuranyl, optionally substituted benzo[1,2,3]thiadiazolyl, optionally substituted benzo[b]thiophenyl, optionally substituted 9H-thioxanthenyl, optionally substituted thi-eno[2,3-c]pyridinyl, and optionally substituted 2,3,6,7-tetrahydro-1H,5H-py-rido[3,2,1-ij] quinolin-9-yl.

According to the invention, the use of a compound of the general formula IA or IB as a medicament is therefore provided. Furthermore, the use of a compound of the general formula IA or IB as a medicament for the treatment of an infectious disease, for example a bacterial disease, is provided. The medicament can thus be used for the diagnosis of diseases, for example for the diagnosis of an infectious disease, for example a bacterial disease. The medicament can be used alternatively or additionally for the treatment of diseases, for example for the treatment of an infectious disease, for example a bacterial disease.

Instead of a medicament which is or contains a compound of the general formula IA or IB according to the invention, a pharmaceutically acceptable salt of this compound can be used.

A formulation of a medicament according to the invention can be prepared by mixing a compound of general formula IA or IB with a carrier or excipient. Such carriers and excipients are generally known.

• 1 eine Darstellung der Röntgenkristallstruktur der Verbindung E3.

The invention is explained in more detail below using embodiments which are not intended to limit the invention, with reference to the drawing.

• 1 a representation of the X-ray crystal structure of compound E3.

Examples

example 1

Synthesis of (1S,5S,7R)-3-acetyl-1,5-diallyl-8,8-dimethyl-7-(3-methylbut-2-en-1-yl)-4,9-dioxobicyclo[3.3.1]non-2-en-2-olate sodium(I) (compound E1)

To prepare compound E1, (1S,5S,7R)-3-acetyl-1,5-diallyl-4-hydroxy-6,6-dimethyl-7-(3-methylbut-2-en-1-yl)bicyclo[3.3.1]non-3-en-2,9-dione (76.9 mg, 200 µmol, 1.0 eq.) was initially charged in THF (2.0 mL) and the solution was cooled to 0 °C. Then NaH (60% in mineral oil, 8.0 mg, 200 µmol, 1.0 eq.) was added and the reaction was stirred until gas evolution had subsided. The solution was covered with n-pentane (4 mL) and placed in the freezer for 2 h to precipitate. The precipitate was filtered off and the product was dried overnight in vacuo. This procedure was repeated twice with the mother liquor and compound E1 (49.6 mg, 122 µmol, 61 %) was obtained as a white powder.

¹ H NMR (D ₂ O, 400 MHz): δ (ppm) = 5.75 - 5.62 (m, 1H), 5.52 - 5.40 (m, 1H), 5.07 - 4.89 (m, 5H), 2.62 - 2.49 (m, 2H), 2.40 (d, J = 6.1 Hz, 2H), 2.27 - 2.10 (m, 2H), 2.20 (s, 3H), 2.08 - 1.96 (m, 2H), 1.62 (s, 3H), 1.52 - 1.44 (m, 1H), 1.46 (s, 3H), 1.13 (s, 3H), 0.88 (s, 3H).

¹³ C-NMR (CDCl ₃ , 75 MHz): δ (ppm) = 216.4, 203.6,193.0, 192.9, 135.3, 135.0, 133.7, 124.9, 122.1, 117.1, 116.7, 67.7, 60.7, 47.6, 45.7, 39.2, 36.0, 30.6, 30.5, 28.8, 26.1, 24.9, 22.2, 17.2.

IR (film): v (cm ^-1 ) = 2973 (w), 2924 (w), 2873 (w), 2055 (w), 2030 (w), 2009 (w), 1711 (w), 1641 (s), 1579 (s), 1533 (s), 1473 (w), 1454 (m), 1368 (s), 1341 (s), 1198 (m), 1136 (w), 1064 (w), 996 (w), 912 (s), 881 (w).

MS (ESI neg, 70 eV): m/z (%) = 1190 (4), 835 (4), 789 (49), 709 (5), 451 (10), 383 (74) [M-Na] ^- , 341 (6), 280 (100).

HRMS (ESI, NaC ₂₄ H ₃₁ O ₄ ) calculated ([M-Na] ^- ): 383.2228; found: 383.2234.

Example 2

Synthesis of (1S,5S,7R)-3-acetyl-1,5-diallyl-8,8-dimethyl-7-(3-methylbut-2-en-1-yl)-4,9-dioxobicyclo[3.3.1]non-2-en-2-olate lithium(I) (compound E2)

To prepare compound E2, (1S,SS,7R)-3-acetyl-1,5-diallyl-4-hydroxy-6,6-dimethyl-7-(3-methylbut-2-en-1-yl)bicyclo[3.3.1]non-3-en-2,9-dione (19.2 mg, 50.0 µmol, 1.0 eq.) was initially charged in n-pentane (0.5 mL) and the solution was cooled to -78°C. Then, n-BuLi (2.5 M in n-hexane, 20 µL, 50 µmol, 1.0 eq.) was added and the reaction was stirred for 5 min at the same temperature, during which a white solid flocculated. The suspension was allowed to warm to room temperature, the precipitate was filtered off and the product was dried in vacuo overnight. The product E2 (11.6 mg, 29.7 µmol, 59%) was obtained as a white powder.

¹ H-NMR (CD ₃ OD, 500 MHz): δ (ppm) = 5.96 - 5.84 (m, 1H), 5.65 - 5.54 (m, 1H), 5.13 - 4.93 (m, 5H), 2.72 - 2.58 (m, 2H), 2.57 - 2.46 (m, 2H), 2.35 - 2.24 (m, 1H), 2.32 (s, 3H), 2.24 - 2.15 (m, 1H), 2.12 - 2.02 (m, 2H), 1.70 (s, 3H), 1.54 (s, 3H), 1.48 - 1.41 (m, 1H), 1.27 (s, 3H), 0.98 (s, 3H).

¹³ C-NMR(151 MHz,CDCl ₃ ) δ (ppm) = 216.38,201.20,198.17,197.64,141.03, 140.87, 136.39, 130.26, 123.71, 122.57, 122.25, 71.86, 65.64, 51.36, 50.99, 42.96, 42.12, 41.68, 36.92, 36.88, 33.76, 32.77, 31.80, 30.97, 30.84, 30.53, 28.19, 27.56, 23.87, 22.80, 19.34, 19.30, 19.09.

IR (film): v (cm ^-1 ) = 2974 (m), 2926 (m), 2877 (m), 2179 (w), 2152 (w), 2039 (w), 1977 (w), 1725 (m), 1663 (m), 1638 (s), 1576 (s), 1530 (s), 1430 (s), 1372 (s), 1132 (m), 1072 (m), 1000 (m), 915 (s), 839 (m), 680 (w), 636 (m), 568 (w), 516 (m).

MS (ESI neg, 70 eV): m/z (%) = 383 (100) [M-Li] ^- , 280 (70).

HRMS (ESI, L ₁ C ₂₄ H ₃₁ O ₄ ) calculated ([M+H] ⁺ ): 383.2228; found: 383.2233.

Example 3

Synthesis of bis((1S,5S,7R)-3-acetyl-1,5-diallyl-8,8-dimethyl-7-(3-methylbut-2-en-1-yl)-4,9-dioxobicyclo[3.3.1]non-2-en-2-olate)-copper(II) (compound E3)

To prepare compound E3, CuCl ₂ · 2 H ₂ O (6.1 mg, 46 µmol, 0.5 eq.) was dissolved in H ₂ O (1 mL) and (1S,SS,7R)-3-acetyl-1,5-diallyl-4-hydroxy-6,6-dimethyl-7-(3-methylbut-2-en-1-yl)bicyclo[3.3.1]non-3-en-2,9-dione (in 500 µL MeOH, 35.0 mg, 91 µmol, 1.0 eq.) was added. The mixture was stirred for 10 min at room temperature and then NaOAc (18.7 mg, 228 µmol, 2.5 eq.) was added to the blue-white suspension. The reaction mixture was heated to 80 °C for 20 min and then allowed to warm to room temperature. After several days, the complex compound E3 crystallized as blue platelets from the aqueous-methanolic solution.

X-ray structure analysis: The results of the X-ray structure analysis are given in Table 2. Table 2 Identification Number s24861c Empirical formula C ₄₈ H ₆₂ CuO ₈ Molecular weight 830.52 temperature 130(2) K wavelength 1.54178 Å Crystal system, space group Triclin, P -1 Lattice constants a = 7.7296(18) Å, α = 73.441(14)° b = 11.710(2) Å, β = 86.423(17)° c = 12.067(2) Å, γ = 84.627(18)° volume 1041,6(4) ^A3 Z, calculated density 1, 1,324 Mg/m ³ Absorption coefficient 1,177mm ^-1 F(000) 443 Crystal size 0.08x0.07x0.06mm Theta area for data collection 3.82 - 64.00 ° Area Indices -8≤h≤7, -12≤k≤13, -14≤1≤13 Collective/ independent reflexes 9411 / 3381 [R(int) = 0.1256] Completeness for θ=64.00° 98.1% Correction for absorption Semi-empirical from equivalents Max. and min. transmission 0.7500 and 0.6485 Refinement method Full-matrix least-squares on F ² Data/ Limitations/ Parameters 3381/ 0/ 264 Goodness-of-fit at F2 1,041 Final R indices [I>2σ(I)] R1 = 0.0731, wR2 = 0.1645 R indices (all data) R1 = 0.1457, wR2 = 0.1856 Highest and lowest residual electron density 0.598 and -0.545 eA ^-3

Example 4

Synthesis of bis((1S,5R,7R)-5-allyl-3-benzoyl-1,7-dibenzyl-6,6-dimethyl-4,9-diox-obicyclo[3.3.1]non-2-en-2-olate)-nickel(II) (compound E4)

To prepare compound E4, (1R,SS,7R)-1-allyl-3-benzoyl-5,7-dibenzyl-4-hydroxy-8,8-dimethylbicyclo[3.3.1]non-3-en-2,9-dione (15.6 mg, 30.0 µmol, 1.0 eq.) was dissolved in acetonitrile (1.0 mL) and nickel(II) acetylacetonate (4.6 mg, 18 µmol, 0.6 eq.) was added. The mint green solution was stirred for 3 h at room temperature, during which a precipitate formed. The suspension was filtered and the filter cake was washed with DCM. The crude product was dried overnight in vacuo and the complex compound E4 (6.6 mg, 6.0 µmol, 40%) was obtained as a greenish powder.

IR (film): v (cm ^-1 ) = 2976 (w), 1723 (w), 1632 (w), 1563 (s), 1507 (m), 1494 (m), 1475 (w), 1454 (w), 1420 (w), 1375 (s), 1316 (w), 1295 (w), 918 (w), 740 (w), 698 (s), 637 (w).

MS (ESI neg, 70 eV): m/z (%) = 1103 (1), 1093 (1) [M+H] ⁺ , 663 (2), 563 (67), 541 (100), 519 (51), 450 (5), 393 (6), 373 (45), 283 (1).

HRMS (ESI, C ₇₀ H ₆₆ N ₁ O ₈ ) calculated ([M+H] ⁺ ): 1093.4184; found: 1093.4186.

Example 5

Synthesis of tris(1S,SR,7R)-5-allyl-3-benzoyl-1,7-dibenzyl-6,6-dimethyl-4,9-diox-obicyclor[3.3.1]non-2-en-2-olate)-cobalt(III) (compound E5)

To prepare compound E5, (1R,SS,7R)-1-allyl-3-benzoyl-5,7-dibenzyl-4-hydroxy-8,8-dimethylbicyclo[3.3.1]non-3-ene-2,9-dione (15.6 mg, 30.0 µmol, 1.0 eq.) was dissolved in acetonitrile (1.0 mL) and cobalt(II) acetylacetonate (4.6 mg, 18 µmol, 0.6 eq.) was added. The orange solution was stirred for 1 h at room temperature to form a pink suspension. Then, THF (1 mL) and a solution of H ₂ O ₂ (30 wt % in H ₂ O, 100 µL) in H ₂ O (100 µL) were added and the reaction mixture was stirred for 1 h at room temperature. Sodium thiosulfate solution (5 mL) was then added and the green suspension was extracted with DCM (2 x 10 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and the solvent removed. The crude product was purified by column chromatography (DCM 100% to DCM/MeOH 9:1) and the complex compound E5 (11.9 mg, 7.38 µmol, 74%) was obtained as a green oil.

IR (film): v (cm ^-1 ) = 2979 (w), 1727 (m), 1699 (w), 1662 (m), 1546 (s), 1519 (s), 1495 (s), 1453 (m), 1420 (m), 1377 (s), 1266 (w), 921 (w), 735 (m), 698 (s), 637 (w).

MS (ESI neg, 70 eV): m/z (%) = 1612 (1) [M+H] ⁺ , 1573 (1), 1193 (3), 797 (32), 775 (47), 676 (35), 563 (49), 541 (100), 373 (52), 257 (37).

HRMS (ESI, C ₁₀₅ H ₉₉ CoO ₁₂ ) calculated ([M+H] ⁺ ): 1612.6575; found: 1612.6347.

Example 6

Synthesis of (1S,5S,7R)-1,5-diallyl-8,8-dimethyl-7-(3-methylbut-2-en-1-yl)-4,9-di-oxo-3-(3-(4-(trifluoromethyl)phenyl)propanoyl)bicyclor[3.3.1]non-2-en-2-olate sodium(I) (Compound E6)

To prepare compound E6, (1S,SS,7R)-1,5-diallyl-4-hydroxy-6,6-dimethyl-7-(3-methylbut-2-en-1-yl)-3-(3-(4-(trifluoromethyl)phenyl)propano-yl)bicyclo[3.3.1]non-3-en-2,9-dione (38.0 mg, 70 µmol, 1.0 eq.) was initially charged in THF (1.5 mL) and the solution was cooled to 0°C. Then, NaH (60% in mineral oil, 3.4 mg, 84 µmol, 1.2 eq.) was added and the reaction was stirred until gas evolution ceased. The solution was layered with n-pentane (4 mL) and placed in the freezer for 2 h to precipitate. The precipitate was filtered off and the product was dried in vacuo overnight. The mother liquor was evaporated, the residue was treated with pentane in an ultrasonic bath and then filtered off. Compound E6 (33 mg, 58 µmol, 884 %) was obtained as a white powder.

¹ H-NMR (CDCl ₃ + 5% DMSO-d ₆ , 600 MHz) δ (ppm) = 7.19 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 8.0 Hz, 2H), 5.67 (dq, J = 9.8, 7.6 Hz, 1H), 5.30 (ddt, J = 17.0, 10.1, 6.6 Hz, 1H), 4.78 (d, J = 17.2 Hz, 2H), 4.68 (dd, J = 15.9, 8.6 Hz, 2H), 4.56 (d, J = 10.2 Hz, 1H), 2.87 - 2.73 (m, 2H), 2.68 - 2.60 (m, 2H), 2.37 (dd, J = 13.0, 7.2 Hz, 1H), 2.27 (ddd, J = 20.0, 13.5, 6.0 Hz, 2H), 2.19 (dd, J = 13.9, 7.9 Hz, 1H), 1.96 (dd, J = 21.3, 12.0 Hz, 1H), 1.86 (d, J = 14.8 Hz, 1H), 1.73 (d, J = 4.2 Hz, 1H), 1.37 (s, 3H), 1.21 (s, 3H), 1.07 (dd, J = 9.3, 5.1 Hz, 1H), 0.94 (s, 3H), 0.64 (s, 3H).

¹³ C-NMR (CDCl ₃ + 5% DMSO-d ₆ , 151 MHz): δ (ppm) = 212.22, 198.24, 193.00, 192.22, 183.18, 147.04, 135.98, 135.94, 131.03, 128.37, 124.90, 124.88, 124.85, 124.34, 124.31, 123.10, 118.55, 116.39, 115.84, 77.37, 77.16, 76.95, 66.64, 60.53, 46.08, 45.76, 43.55, 40.03, 39.89, 39.75, 39.61, 39.48, 39.34, 39.20, 37.66, 36.33, 31.80, 31.14, 28.50, 26.50, 25.36, 22.25, 17.35, 17.33.

IR (film): v (cm ^-1 ) = 3071 (w), 2967 (w), 2933 (w), 2874 (w), 1711 (m), 1662 (s), 1584 (s), 1551 (s), 1446 (w), 1379 (s), 1323 (s), 1159 (m), 1122 (s), 1066 (s), 1018 (m), 1003 (m), 913 (m), 828 (m).

HRMS (ESI, C ₃₂ H ₃₆ F ₃ NaO ₄ ) calcd ([M+H] ⁺ ): 565.2536, found: 565.2536; calcd ([M+Na] ⁺ ): 587.2355, found: 587.2374.

Example 7

Synthesis of (1S,5S,7R)-3-acetyl-1,5-diallyl-8,8-dimethyl-7-(3-methylbut-2-en-1-yl)-4,9-dioxobicyclo[3.3.1]non-2-en-2-olate potassium(I) (compound E7)

To prepare compound E7, (1S,SS,7R)-3-acetyl-1,5-diallyl-4-hydroxy-6,6-dimethyl-7-(3-methylbut-2-en-1-yl)bicyclo[3.3.1]non-3-en-2,9-dione (26.9 mg, 70 µmol, 1.0 eq.) was initially charged in THF (3.0 mL) and the solution was cooled to 0°C. Then, KH (2.8 mg, 70 µmol, 1.0 eq.) was added and the reaction was stirred until gas evolution had subsided. The solution was layered with n-pentane (3 mL) and placed in the freezer for 2 h to precipitate. The precipitate was filtered off and the product was dried overnight in vacuo to give compound E7 (20.8 mg, 49 µmol, 71%) as a white powder.

¹ H-NMR (CD ₃ OD, 300 MHz): δ (ppm) = 5.87 (ddt, J = 17.1, 10.2, 7.0 Hz, 1H), 5.56 (ddt, J = 17.1, 10.2, 6.7 Hz, 1H), 5.05 (s, 1H), 5.00 (s, 1H), 4.98 - 4.89 (m, 2H), 4.83 (s, 1H), 2.58 (ddd, J = 19.0, 13.0, 6.5 Hz, 2H), 2.49 - 2.36 (m, 2H), 2.36 - 2.25 (m, 1H), 2.23 (s, 3H), 2.17 (d, J = 15.2 Hz, 1H), 2.06 - 1.90 (m, 2H), 1.64 (s, 3H), 1.51 (s, 3H), 1.37 (dt, J = 9.6, 3.6 Hz, 1H), 1.20 (s, 3H), 0.90 (s, 3H).

¹³ C NMR (CD ₃ OD, 126 MHz): δ (ppm) = 214.53, 200.72, 194.58, 194.48, 193.71, 137.21, 137.08, 132.88, 126.60, 121.74, 117.50, 117.25, 68.50, 62.12, 48.20, 47.54, 39.61, 37.89, 33.08, 31.89, 30.37, 27.54, 26.05, 23.39, 18.18.

Example 8

Synthesis of bis((1S,5S,7R)-3-acetyl-1,5-diallyl-8,8-dimethyl-7-(3-methylbut-2-en-1-yl)-4,9-dioxobicyclo[3.3.1]non-2-en-2-olate)-magnesium(II) (compound E8)

To prepare compound E8, (1S,SS,7R)-3-acetyl-1,5-diallyl-4-hydroxy-6,6-dimethyl-7-(3-methylbut-2-en-1-yl)bicyclo[3.3.1]non-3-en-2,9-dione (21.1 mg, 55 µmol, 1.0 eq.) was dissolved in MeOH (1.5 mL) and Mg(OMe) ₂ (2.4 mg, 27.5 µmol, 0.5 eq.) was added. The mixture was stirred for 3 h at room temperature and then evaporated to dryness. Compound E8 (20.1 mg, 25.4 µmol, 92%) was obtained as a white powder.

¹ H NMR (CD ₃ OD, 700 MHz): δ (ppm) = 6.00 - 5.70 (m, 1H), 5.55 (s, 1H), 5.12 - 4.77 (m, 5H), 2.62 (s, 2H), 2.48 (s, 2H), 2.28 (s, 3H), 2.23 - 2.00 (m, 4H), 1.64 (s, 3H), 1.50 (s, 3H), 1.43 - 1.33 (m, 1H), 1.18 (s, 3H), 0.93 (s, 3H).

Example 9

Synthesis of (1S,5S,7R)-1,5-diallyl-8,8-dimethyl-7-(3-methylbut-2-en-1-yl)-4,9-di-oxo-3-(pent-4-inoyl)bicyclor[3.3.1]non-2-en-2-olate sodium(I) (Compound E9)

To prepare compound E9, (1S,5S,7R)-1,5-diallyl-4-hydroxy-6,6-dimethyl-7-(3-methylbut-2-en-1-yl)-3-(pent-4-inoyl)bicyclo[3.3.1]non-3-en-2,9-dione (42 mg, 100 µmol, 1.0 eq.) was initially charged in THF (1.0 mL) and the solution was cooled to 0°C. Then, NaH (60% in mineral oil, 4.0 mg, 100 µmol, 1.0 eq.) was added. was added and the reaction was stirred until the evolution of gases had subsided. The solution was covered with n-pentane (2 mL) and placed in the freezer for 2 h to precipitate. The precipitate was filtered off and the product was dried overnight in vacuo. This procedure was repeated twice with the mother liquor and compound E9 (40.6 mg, 100 µmol, 99%) was obtained as a white powder.

¹ H-NMR (600 MHz, DMSO-d ₆ ) δ (ppm) = 5.85 - 5.72 (m, 1H), 5.52 - 5.30 (m, 1H), 5.14 - 4.84 (m, 4H), 4.83 - 4.72 (m, 1H), 3.17 - 3.04 (m, 1H), 3.04 - 2.92 (m, 1H), 2.73 (dd, J = 13.2, 5.6 Hz, 1H, 2.45 (dd, J = 14.0, 7.4 Hz, 1H), 2.21 (ddd, J = 9.7, 6.9, 2.9 Hz, 2H), 2.12 (dt, J = 17.4, 8.6 Hz, 1H), 2.09 - 2.03 (m, 1H), 1.99 (ddd, J = 15.7, 12.3, 8.0 Hz, 2H), 1.91 - 1.89 (m, 1H), 1.89 - 1.72 (m, 3H), 1.58 (d, J = 7.6 Hz, 3H), 1.42 - 1.38 (m, 2H), 1.38 - 1.35 (m, 1H), 1.21 - 1.12 (m, 2H), 1.10 (d, J = 5.7 Hz, 1H), 0.95 (s, 2H), 0.90 (s, 1H).

¹³ C-NMR (DMSO-d ₆ , 126 MHz): δ (ppm) = 214.53, 200.72, 194.58, 194.48, 193.71, 137.21, 137.08, 132.88, 126.60, 121.74, 117.50, 117.25, 68.50, 62.12, 48.20, 47.54, 39.61, 37.89, 33.08, 31.89, 30.37, 27.54, 26.05, 23.39, 18.18.

IR (film): v (cm ^-1 ) = 3291 (w), 2978 (w), 2928 (w), 2128 (w), 2035 (w), 2020 (w), 1978 (w), 1730 (s), 1666 (s), 1553 (s), 1431 (s), 1375 (w), 1360 (w), 1226 (w), 1134 (w), 1001 (w), 922 (m), 642 (w).

HRMS (ESI, C ₂₇ H ₃₃ O ₄ Na) calcd ([M+Na] ^- ): 422.2457; found: 422.2462.

Example 10

Synthesis of (1S,5S,7R)-1,5-diallyl-3-(hex-5-inoyl)-8,8-dimethyl-7-(3-methylbut-2-en-1-yl)-4,9-dioxobicyclo[3.3.1]non-2-en-2-olate sodium(I) (Compound E10)

To prepare compound E10, (1S,SS,7R)-1,5-diallyl-3-(hex-5-inoyl)-4-hydroxy-6,6-dimethyl-7-(3-methylbut-2-en-1-yl)bicyclo[3.3.1]non-3-en-2,9-dione (43.6 mg, 100 µmol, 1.0 eq.) was initially charged in THF (1.0 mL) and the solution was cooled to 0 °C. Then, NaH (60% in mineral oil, 4.0 mg, 100 µmol, 1.0 eq.) was added and the reaction was stirred until gas evolution ceased. The solution was layered with n-pentane (2 mL) and placed in the freezer for 2 h to precipitate. The precipitate was filtered off and the product was dried in vacuo overnight. This procedure was repeated twice with the mother liquor and compound E10 (44.0 mg, 92 µmol, 98 %) was obtained as a white powder.

¹ H-NMR (600 MHz, DMSO-d6) δ (ppm) = 5.85 - 5.72 (m, 1H), 5.52 - 5.30 (m, 1H), 5.14 - 4.84 (m, 4H), 4.83 - 4.72 (m, 1H), 3.17 - 3.04 (m, 1H), 3.04 - 2.92 (m, 1H), 2.73 (dd, J = 13.2, 5.6 Hz, 1H, 2.45 (dd, J = 14.0, 7.4 Hz, 1H), 2.21 (ddd, J = 9.7, 6.9, 2.9 Hz, 2H), 2.12 (dt, J = 17.4, 8.6 Hz, 1H), 2.09 - 2.03 (m, 1H), 1.99 (ddd, J = 15.7, 12.3, 8.0 Hz, 2H), 1.91 - 1.89 (m, 1H), 1.89 - 1.72 (m, 3H), 1.58 (d, J = 7.6 Hz, 3H), 1.42 - 1.38 (m, 2H), 1.38 - 1.35 (m, 1H), 1.21 - 1.12 (m, 2H), 1.10 (d, J = 5.7 Hz, 1H), 0.95 (s, 2H), 0.90 (s, 1H).

¹³ C NMR (DMSO-d6, 126 MHz): δ (ppm) = 214.53, 200.72, 194.58, 194.48, 193.71, 137.21, 137.08, 132.88, 126.60, 121.74, 117.50, 117.25, 68.50, 62.12, 48.20, 47.54, 39.61, 37.89, 33.08, 31.89, 30.37, 27.54, 26.05, 23.39, 18.18.

IR (film): v (cm ^-1 ) = 3294 (w), 2970 (w), 2922 (w), 2121 (w), 2035 (w), 2020 (w), 1978 (w), 1732 (s), 1665 (s), 1558 (s), 1431 (s), 1372 (w), 1226 (w), 1134 (w), 989 (w), 962 (m), 652 (w).

HRMS (ESI, C ₂₈ H ₃₅ O ₄ Na) calcd ([M+Na] ^- ): 436.2614; found: 436.2653.

Example 11

Synthesis of (1S,5S,7R)-1,5-diallyl-33-(4-azidophenyl)propanoyl)-8,8-dimethyl-7-(3-methylbut-2-en-1-yl)-4.9-dioxobicyclo[3.3.1]non-2-en-2-olate sodium(I) (Compound E11)

To prepare compound E11, (1S,5S,7R)-1,5-diallyl-3-(3-(4-azidophenyl)propanoyl)-4-hydroxy-6,6-dimethyl-7-(3-methylbut-2-en-l-yl)bi-cyclo[3.3.1]non-3-en-2,9-dione (20.0 mg, 39 µmol, 1.0 eq.) was initially charged in THF (1.0 mL) and the solution was cooled to 0 °C. Then, NaH (60% in mineral oil, 2.3 mg, 58 µmol, 1.5 eq.) was added and the reaction was stirred until gas evolution ceased. The solution was layered with n-pentane (3 mL) and placed in the freezer for 2 h to allow precipitation. The precipitate was filtered off and compound E11 (9.9 mg, 18 µmol, 47%) was dried overnight in vacuo to give a white powder.

¹ H-NMR (600 MHz, D ₂ O) δ (ppm) = 7.10 (d, J = 8.3 Hz, 2H), 6.91 (d, J = 8.2 Hz, 2H), 5.52 (tt, J = 12.6, 6.4 Hz, 1H), 5.19 (tt, J = 12.1, 6.2 Hz, 1H), 5.04 - 4.83 (m, 5H), 2.85 - 2.73 (m, 4H), 2.54 - 2.46 (m, 2H), 2.34 (d, J = 5.9 Hz, 2H), 2.13 (dd, J = 17.5, 8.5 Hz, 2H), 1.97 (d, J = 14.2 Hz, 1H), 1.92 (dd, J = 14.2, 6.7 Hz, 1H), 1.59 (s, 3H), 1.43 (s, 3H), 1.41 - 1.38 (m, 1H), 1.08 (s, 3H), 0.82 (s, 3H).

Example 12

Synthesis of (1S,5S,7R)-1,5-diallyl-8,8-dimethyl-7-(3-methylbut-2-en-1-yl)-4,9-di-oxo-3-(3-(3,4,5-trimethoxyphenyl)propanoyl)bicyclor[3.3.1]non-2-en-2-olate sodium(I) (Compound E12)

To prepare compound E12, (1S,5S,7R)-1,5-diallyl-4-hydroxy-6,6-dimethyl-7-(3-methylbut-2-en-1-yl)-3-(3-(3,4,5-trimethoxyphenyl)propanoyl)bi-cyclo[3.3.1]non-3-en-2,9-dione (28 mg, 50 µmol, 1.0 eq.) was initially charged in THF (10 mL) and the solution was cooled to 0°C. Then, NaH (60% in mineral oil, 2.0 mg, 50 µmol, 1.0 eq.) was added and the reaction was stirred until gas evolution ceased. The solution was layered with n-pentane (2 mL) and placed in the freezer for 2 h to precipitate. The precipitate was filtered off and the product was dried in vacuo overnight. This procedure was repeated twice with the mother liquor and compound E12 (29.0 mg, 48 µmol, 98 %) was obtained as a white powder.

¹ H-NMR (600 MHz, DMSO-d ₆ ) δ (ppm) = 5.83 (ddt, J = 17.1, 10.1, 7.1 Hz, 1H), 5.46 (ddt, J = 17.0, 10.3, 6.6 Hz, 1H), 5.04 - 4.84 (m, 4H), 4.77 (d, J = 10.2 Hz, 1H), 3.72 (d, J = 9.2 Hz, 7H), 3.59 (s, 3H), 3.41 - 3.28 (m, 7H), 2.87 - 2.74 (m, 2H), 2.56 - 2.46 (m, 6H), 2.37 (dd, J = 12.9, 6.2 Hz, 1H), 2.34 - 2.29 (m, 2H), 2.29 - 1.97 (m, 3H), 1.89 - 1.76 (m, 2H), 1.59 (s, 3H), 1.43 (s, 3H), 1.33 - 1.23 (m, 1H), 1.12 (s, 3H), 0.82 (d, J = 21.4 Hz, 3H).

¹³ C-NMR (151 MHz, DMSO-d ₆ ) δ (ppm) = 211.98, 198.30, 190.97, 189.79, 152.56, 138.61, 136.53, 136.47, 135.23, 130.90, 125.55, 118.54, 116.86, 116.17, 105.22, 79.24, 66.16, 60.07, 59.91, 55.63, 46.07, 45.44, 44.43, 40.03, 39.91, 39.77, 39.63, 39.49, 39.35, 39.21, 39.08, 37.16, 36.63, 31.76, 31.52, 28.62, 26.74, 25.65, 22.54, 17.65.

IR (film): v (cm ^-1 ) = 2971 (w), 2920 (w), 2356 (w) 1729 (w), 1663 (m), 1614 (m) 1591 (m),1505 (m), 1479 (s), 1457 (s), 1408 (m), 1350 (w), 1325 (w), 1259 (s), , 1125 (m), 1035 (m), 1010 (w), 928 (w) , 854 (f), 820 (f), 730 (s). 670 (female).

HRMS (ESI, C ₂₈ H ₃₅ O ₄ Na) calcd ([M+Na] ^- ): 564.3087; found: 564.3095.

Example 13

Synthesis of (1S,5S,7R)-1,5-diallyl-8,8-dimethyl-7-(3-methylbut-2-en-1-yl)-4,9-di-oxo-3-(3-(thiophen-2-yl)propanoyl)bicyclo[3.3.1]non-2-en-2-olate sodium(I) (Compound E13)

To prepare compound E13, (1S,5S,7R)-1,5-diallyl-4-hydroxy-6,6-dimethyl-7-(3-methylbut-2-en-1-yl)-3-(3-(thiophen-2-yl)propanoyl)bi-cyclo[3.3.1]non-3-en-2,9-dione (29.0 mg, 60 µmol, 1.0 eq.) was initially charged in THF (1.0 mL) and the solution was cooled to 0 °C. Then, NaH (60% in mineral oil, 3.0 mg, 60 µmol, 1.0 eq.) was added and the reaction was stirred until gas evolution had subsided. The solution was layered with n-pentane (2 mL) and placed in the freezer for 2 h to precipitate. The precipitate was filtered off and the product was dried in vacuo overnight. This procedure was repeated twice with the mother liquor and compound E13 (28 mg, 51 µmol, 91 %) was obtained as a light yellow powder.

¹ H-NMR (600 MHz, DMSO-d ₆ ) δ (ppm) = 7.24 (dd, J = 5.1, 1.2 Hz, 1H), 6.89 - 6.86 (m, 1H), 6.77 (dd, J = 3.3, 0.9 Hz, 1H), 5.87 - 5.77 (m, 1H), 5.51 - 5.41 (m, 1H), 5.05 - 4.90 (m, 3H), 4.90 - 4.85 (m, 1H), 4.80 - 4.75 (m, 1H), 3.00 - 2.80 (m, 3H), 2.42 - 2.34 (m, 1H), 2.32 (dd, J = 10.8, 5.6 Hz, 2H), 2.27 - 2.20 (m, 1H), 2.05 - 1.98 (m, 1H), 1.91 - 1.75 (m, 2H), 1.61 - 1.56 (m, 3H), 1.43 (s, 3H), 1.32 - 1.21 (m, 2H), 1.10 (d, J = 15.2 Hz, 3H), 0.85 - 0.76 (m, 3H).

¹³ C-NMR (151 MHz, DMSO-d ₆ ) δ (ppm) = 211.91, 197.08, 191.22, 190.19, 145.46, 136.44, 136.33, 130.96, 126.72, 125.50, 123.97, 123.11, 118.34, 116.94, 116.36, 66.30, 60.17, 45.99, 45.55, 44.73, 40.03, 39.91, 39.77, 39.64, 39.50, 39.36, 39.22, 39.08, 37.20, 36.62, 31.76, 28.61, 26.73, 25.66, 25.45, 22.55, 17.66.

IR (film): v (cm ^-1 ) = 2974 (m), 2926 (m), 2179 (w), 1977 (w), 1725 (m), 1663 (m), 1638 (s), 1576 (s), 1530 (s), 1430 (s), 1372 (s), 1132 (m), 1072 (m), 1000 (m), 915 (s), 839 (m), 680 (w), 636 (m), 568 (w), 516 (m).

HRMS (ESI, C ₂₈ H ₃₅ O ₄ Na) calcd ([M+Na] ^- ): 480.2334; found: 480.2341.

Example 14

Determination of the biological activities of compounds E1 to E13

To demonstrate the biological activities of compounds according to the invention, IC ₅₀ values and MIC values were determined. The IC ₅₀ values were determined as in GR Nakayama et al., J. Immunol. Methods 1997, 204, 205-208 , described on human leukemia cells of the cell line HL-60 and on human lung cancer cells of the cell line A-549. The determination of the MIC values was carried out on Staphylococcus aureus USA 300 as described in CLSI. Performance Standards for Antimicrobial Susceptibility Testing. 31st ed. (CLSI supplement M100) Clinical and Laboratory Standards Institute; 2021. Table 2 Connection _IC50HL -60 [µM] _IC50 A549 [µM] MIC [µM] E1 19.7 95.9 3.0 E2 N/A N/A 5.1 E7 59.9 N/A 4.7 E8 22.4 N/A 1.7 E9 17.3 49.9 1.1 E10 160.6 N/A 54.5 E13 37.6 58.3 3.9

QUOTES INCLUDED IN THE DESCRIPTION

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Claims (15)

Compound of general formula IA or IB

wherein A is -(CH ₂ ) _m - and m is 0, 1 or 2; n is 1, 2 or 3; M is a metal ion; R ¹ is selected from the group consisting of isoprenyl, geranyl, benzyl and methyl; R ² is selected from the group consisting of allyl, isoprenyl and methyl; R ³ is selected from the group consisting of allyl, isoprenyl, benzyl and methyl; R ⁴ is selected from the group consisting of -C ₁ -C ₁₆ alkyl, -C ₁ -C ₁₆ alkenyl, -C ₁ -C ₁₆ alkynyl, cycloalkyl, unsubstituted or R ⁷ substituted aryl and unsubstituted or R ⁷ substituted heteroaryl; R ⁵ is methyl or isoprenyl; R ⁶ is methyl or isoprenyl; and R ⁷ is selected from the group consisting of halogen, amine, azide, -C ₁ -C ₁₆ alkyl, -OC ₁ -C ₁₆ alkyl, -C ₁ -C ₁₆ haloalkyl and aryl. Connection to Claim 1 , characterized in that A is -(CH ₂ ) _m - and m is 0, 1 or 2; n is 1, 2 or 3; M is selected from the group consisting of alkali metal, alkaline earth metal and transition metal ions; R ⁴ is selected from the group consisting of -C ₁ -C ₁₆ alkyl, -C ₁ -C ₁₆ alkenyl, -C ₁ -C ₁₆ alkynyl, cycloalkyl, unsubstituted or R ⁷ substituted aryl and unsubstituted or R ⁷ substituted heteroaryl; and R ⁷ is selected from the group consisting of halogen, amine, azide, -C ₁ -C ₁₆ alkyl, -OC ₁ -C ₁₆ alkyl, -C ₁ -C ₁₆ fluoroalkyl and aryl. Connection to Claim 1 or Claim 2 , characterized in that A is -(CH ₂ ) _m - and m is 0, 1 or 2; n is 1, 2 or 3; M is selected from the group consisting of alkali metal, alkaline earth metal and transition metal ions; R ⁴ is selected from the group consisting of -C ₁ -C ₁₆ alkyl, -C ₁ -C ₁₆ alkenyl, -C ₁ -C ₁₆ alkynyl, cycloalkyl, unsubstituted or R ⁷ substituted aryl and unsubstituted or R ⁷ substituted heteroaryl; and R ⁷ is selected from the group consisting of -C ₁ -C ₁₆ alkyl, -OC ₁ -C ₁₆ alkyl, -C ₁ -C ₁₆ fluoroalkyl, azide and aryl. A compound according to any one of the preceding claims, characterized in that A is -(CH ₂ ) _m - and m is 0, 1 or 2; n is 1, 2 or 3; M is selected from the group consisting of alkali metal, alkaline earth metal and transition metal ions; R ⁴ is selected from the group consisting of -C ₁ -C ₁₆ alkyl, -C ₁ -C ₁₆ alkynyl, unsubstituted or R ⁷ substituted aryl and unsubstituted heteroaryl; and R ⁷ is -C ₁ -C ₁₆ fluoroalkyl, -OC ₁ -C ₁₈ alkyl or azide. A compound according to any one of the preceding claims, characterized in that A is -(CH ₂ ) _m - and m is 0, 1 or 2; n is 1, 2 or 3; M is selected from the group consisting of lithium, sodium, potassium, magnesium, copper, nickel and cobalt; R ⁴ is selected from the group consisting of methyl, ethynyl, unsubstituted or R ⁷ substituted phenyl and thienyl; and R ⁷ is -C ₁ -C ₁₆ fluoroalkyl, -OC ₁ -C ₁₆ alkyl or azide. Connection to Claim 1 , characterized in that A is -(CH ₂ ) _m - and m is 0, 1 or 2; n is 1, 2 or 3; M is a metal ion; R ¹ is isoprenyl or benzyl; R ² is allyl; R ³ is allyl or benzyl; R ⁴ is selected from the group consisting of -C ₁ -C ₁₆ alkyl, -C ₁ -C ₁₆ alkenyl, -C ₁ -C ₁₈ alkynyl, cycloalkyl, unsubstituted or R ⁷ substituted aryl and unsubstituted or R ⁷ substituted heteroaryl; R ⁵ is methyl; R ⁶ is methyl and R ⁷ is selected from the group consisting of halogen, amine, azide, -C ₁ -C ₁₆ alkyl, -OC ₁ -C ₁₆ alkyl -C ₁ -C ₁₆ haloalkyl and aryl. Connection to Claim 6 , characterized in that A is -(CH ₂ ) _m - and m is 0, 1 or 2; n is 1, 2 or 3; M is selected from the group consisting of alkali metal, alkaline earth metal and transition metal ions; R ⁴ is selected from the group consisting of -C ₁ -C ₁₆ alkyl, -C ₁ -C ₁₆ alkenyl, -C ₁ -C ₁₆ alkynyl, cycloalkyl, unsubstituted or R ⁷ substituted aryl and unsubstituted or R ⁷ substituted heteroaryl; and R ⁷ is selected from the group consisting of -C ₁ -C ₁₆ alkyl, -OC ₁ -C ₁₆ alkyl, -C ₁ -C ₁₆ fluoroalkyl, azide and aryl. Connection to Claim 6 or 7 , characterized in that A is -(CH ₂ ) _m - and m is 0, 1 or 2; n is 1, 2 or 3; M is selected from the group consisting of lithium, sodium, potassium, magnesium, copper, nickel and cobalt; R ⁴ is selected from the group consisting of methyl, ethynyl, unsubstituted or R ⁷ substituted phenyl and thienyl; and R ⁷ is -C ₁ -C ₁₆ fluoroalkyl, -OC ₁ -C ₁₆ alkyl or azide. A compound according to any preceding claim, wherein the compound is selected from the group consisting of

Process for preparing a compound of general formula IA or IB

wherein A is -(CH ₂ ) _m - and m is 0, 1 or 2; n is 1, 2 or 3; M is a metal ion; R ¹ is selected from the group consisting of isoprenyl, geranyl, benzyl and methyl; R ² is selected from the group consisting of allyl, isoprenyl and methyl; R ³ is selected from the group consisting of allyl, isoprenyl, benzyl and methyl; R ⁴ is selected from the group consisting of -C ₁ -C ₁₆ alkyl, -C ₁ -C ₁₆ alkenyl, -C ₁ -C ₁₆ alkynyl, cycloalkyl, unsubstituted or R ⁷ substituted aryl and unsubstituted or R ⁷ substituted heteroaryl; R ⁵ is methyl or isoprenyl; R ⁶ is methyl or isoprenyl and R ⁷ is selected from the group consisting of halogen, amine, azide, -C ₁ -C ₁₆ alkyl, -OC ₁ -C ₁₆ alkyl, -C ₁ -C ₁₆ haloalkyl and aryl, wherein a compound of the general formula II

wherein A, m, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the meanings given in connection with the compound of general formula I, is reacted with a compound of general formula MX, wherein M is a metal ion and X is selected from the group consisting of H, halogen and an organic radical. Procedure according to Claim 10 , characterized in that M is metal ion and X is selected from the group consisting of H, chlorine, n-butyl or acetylacetonate. Connection to one of the Claims 1 until 9 for use as a medicine. Connection to one of the Claims 1 until 9 for use as a medicine to treat a bacterial, neurodegenerative or mental disease. Medicament containing a compound according to any one of Claims 1 until 9 or a pharmaceutically acceptable salt thereof. Using a connection according to one of the Claims 1 until 9 for the diagnosis and/or treatment of a bacterial disease.