DE102004056822A1 - New drugs for therapy, diagnostics and prophylaxis of macular degeneration - Google Patents

Abstract

The present invention relates to novel active compounds which interact with the lipophilic cation A2E (N-retinyl-N-retinylidene-ethanolamine) of the retina and are suitable for the therapy, diagnosis and prophylaxis of dry age-related macular degeneration. The active compounds according to the invention are phosphate- or phosphonate-substituted calixarene derivatives and so-called clips. The term "clips" refers to fused ring systems in which aromatic ring systems are linked to one another via bicyclo [2.2.1] hept-2-ene groups such that the entire molecule describes a "U" and forms a cavity.

Description

The The present invention relates to the fields of chemistry, biology, biochemistry, Pharmacology, toxicology and human and veterinary medicine.

The The present invention relates in particular to new active substances which with the lipophilic cation A2E (N-retinyl-N-retinylidene-ethanolamine) The retina interact and become therapy, diagnostics and prophylaxis of dry age-related macular degeneration.

The age-related macular degeneration (AMD) affects about one-fifth of Population over 65 years and is one of the main causes of severe visual impairment among the elderly in industrialized nations. This is for example the expert from S Ben-Sabat, CA Parish, M Hashimoto, J Liu, K Nakanishi, JR Sparrow, Bioorg. Med. Chem. Lett. 2001, 11, 1533-1540; G Wolf, Nutrition Rev. 2003, 61, 342-346 and CN Keilhauer, BHF Weber, Biospektrum 2003, 9, 1-3 known. The AMD evolves over many decades. estimates assume that the number of persons affected by AMD in the next Approximately 25 years ago will double.

The Illness goes with damage associated with the photoreceptors in the macula. There are two forms the AMD distinguished: the dry and the damp AMD.

at Dry AMD forms deposits in the early stages of the disease on the macula, the so-called drusen. Do these drusen exist for a long time, it comes to macular atrophy, and the function of the light receptors can no longer be fulfilled. Those affected notice the disease by the appearance of empty Places within their central visual area.

The Moist AMD, on the other hand, is caused by abnormal blood vessels passing through the Macula and proliferate under the retina. These blood vessels tend in addition, cell liquid and to segregate blood into the surrounding cellular tissue of the retina, which causes scarring of the macula and a loss of Sight enters. The destruction The macula due to wet AMD has the consequence that the center of a Picture as pictured by a gray disc and only the Image edge is sharply and clearly perceived.

Of the The prior art knows therapeutic approaches to the treatment of moist Macular Degeneration; including JW Berger, SL Fine, L McGuire, eds .: Age Related Macular Degeneration, Mosby, St. Louis, USA 1999 described photodynamic therapy successfully.

Approximately 90% of those affected suffer from the dry form of AMD. apart There are no vision aids such as glasses or magnifying glasses Treatment or preventive measures for patients who to suffer from dry AMD.

The most basic damage appears in AMD in the retinal pigment epithelium (RPE, retinal pigment epithelium), due to the rapid destruction of this Epithelium is nearby. Exact causes are not yet known. Negatively charged phospholipids and blue light filtering molecules such as lutein and antioxidants are the only substances currently available for the treatment of dry macular degeneration. They delay the Deterioration of vision to some extent, however, are unable to progress permanently prevent deterioration. Worldwide suffer from Time about 25 to 30 million people dry on AMD.

It is known to the person skilled in the art that the cells in the retina contain two unusual retinoids, namely the lipophilic cations A2E (N-retinyl-N-retinylidene-ethanolamine) and its isoform with a cis double bond in a position adjacent to the pyridine ring. This is for example in S De, TP Sakmar, J Gen. Physiol. 2002, 120, 147-157; M Suter, C Reme, C Grimm, A Wenzel, M Jäättela, P Esser, N Kociok, M Leist, C Richter, J Biol. Chem. 2000, 275, 39625-39630 and S Ben-Shabat, Y Itagaki, S Jockusch , JR Sparrow, NJ Turro, K. Nakanishi, Angew. Chem. 2002, 114, 842-844. These compounds can be prepared in vitro by mixing 2 equivalents of the all-trans retinal with 1 equivalent of ethanolamine and exactly 1 equivalent of acetic acid in ethanol. A2E is found in lysosomes and mitochondria. Overloading the mitochondria with this lipophilic cation is likely to be the starting point of pathogenic steps that eventually lead to cell death. It is known to the person skilled in the art that the terpene-substituted N-alkylpyridinium derivative A2E is highly responsible for the AMD, as described, for example, in H Shaban, C Richter, Biol. Chem. 2002, 383, 537-545. A2E forms a complex with cytochrome C oxidase and thereby induces apoptotic cell death. Above all, A2E prevents the binding of cytochrome C to cytochrome oxidase and thus blocks the flow of electrons along the respiratory chain. As a result, more oxygen radicals are formed and oxidative stress increases. A2E is toxic in the dark for many cells, including RPE, and increases the sensitivity of cells to blue light. The irradiation leads to permanent modifications of the cytochrome oxidase after complex formation with A2E.

A2E

A2E

the One skilled in the art is H Shaban, C Borras, J Vina, C Richter, for example. Exp. Eye Res. 2002, 75, 99-108 It is known that phosphatidylglycerol is effective against human RPE cells A2E-induced apoptosis protects. However, the A2E level is CA Parish, M Hashimoto, K Nakanishi, J Dillon, J Sparrow, Proc. Natl. Acad. Sci USA 1998, 95, 14609-14613, in older People (65 years) compared to younger (25 years) still increased by a factor of about 10. In contrast, the levels of 1,3-diphosphatidylglycerol (DPG) and phosphatidylglycerol, i. the level of negatively charged phospholipids, protect against oxidative stress, with increasing age, as the expert for example BN Ames, Mk Shigenaga, TM Hagen, Biochim. Biophys. Acta 1995, 1271, 165 to 170 known. While for the related moist form of AMD therapeutic approaches exist So far, the state of the art knows no active ingredient for the treatment the dry AMD. Worldwide, about 25 to 30 million people suffer in this disease, so that a great need for effective therapeutics consists.

Phosphatidylglycerin

phosphatidylglycerol

the It is further known to those skilled in the art that there are synthetic host molecules, which are capable of electron-deficient neutral as well as cationic ones complexing aromatic substrates. These include, for example, the Reason of their spatial Structure called braces (clips) or tweezers (tweezers) synthetic Receptors. They consist of fused ring systems, the aromatics and methylene bridged Cycloaliphaten included. There are two aromatics, for example Benzene or naphthalene, by a methylene-bridged cycloaliphatic separated from each other.

In F.-G. Klärner, J. Panitzky, D. Bläser, R. Boese: Synthesis and supramolecular structures of molecular clips. Tetrahedron 57, 2001, 3673-3687; R. Ruloff, UP Seelbach, AE Merbach, F.-G. Klärner: Molecular tweezers as synthetic receptors: the effect of pressure and temperature on the formation of host-guest complexes. Journal of Physical Organic Chemistry 2002, 15, 189-196 and F.-G. Klärner, U. Burkert, M. Kamieth, R. Boese: Molecular tweezers as synthetic receptors: molecular recognition of neutral and cationic aromatic substrates. A comparision between the supramolecular structures in crystal and solution. Journal of Physical Organic Chemistry 2000, 13, 604-611, clips and tweezers are described, the organic ammonium ka complexing. The complex formation preferably takes place in apolar aprotic solvents, and the binding affinity of the substrate to the host molecule decreases significantly with increasing degree of substitution of the pyridine ring.

In C. Jasper, T. Schrader, J. Panitzky, F.-G. Klärner: Selective Complexation of N-Alkylpyridium Salts: Recognition of NAD ⁺ in Water. Angew. Chem. Int. Ed. 2002, 41, 1355-1358; M. Kamieth, F.-G. Klärner: Molecular Tweezers as Synthetic Receptors: Molecular Recognition of Cationic Substrates; An Insight into the Mechanism of Complexation. J. Prakt. Chem. 1999, 245-251; describe clips whose central aromatics carry acetyl, hydroxy or methylphosphonate substituents. The bis-methylphosphonate clip described in this paper is water-soluble and complexes singly and doubly substituted pyridinium and pyrazinium cations, including, for example, NAD +.

Of the The prior art further knows calixarenes, for example Calix [4] arene phosphonates, complex the metal and ammonium cations, as well as the formation cage-like Associates of oppositely charged calix [4] arene derivatives in aqueous Solution. These are for example in T. Schrader, T. Grawe, M. Gurrath, A. Kraft, F. Osterod: Self-organization of Spheroidal Molecular Assemblies in Polar Solvents. Org. Lett. 2000, 2, 29-32; R. Zadmard, T. Schrader, T. Grawe, A. Kraft: Self-Assembly of Molecular Capsules in Polar Solvents, Org. Lett. 2002, 4, 1687-1690; T. Grawe, T. Schrader, R. Zadmard, A. Kraft: Self-Assembly of Ball-Shaped Molecular Complexes in Water, J. Org. Chem., 2002, 67 (11), 3755-3763 and R. Zadmard, M. Junkers, T. Schrader, T. Grawe, A. Kraft: Capsule-like Assemblies in Polar Solvents. J. Org. Chem, 2003, 68 (17), 6511-6521.

Of the The prior art also knows processes for the preparation of endo-alkoxy-substituted Calixarenes.

Thus, 25,26,27,28-tetrabutoxycalixarenes 3 can be prepared, for example, by condensation of formaldehyde with p- / t-butyl) -phenol in the presence of sodium hydroxide after Gutsche, subsequent debutylation with AlCl ₃ / phenol and subsequent reaction with butyl bromide:

By Bromination of 3 with NBS exo to 25,26,27,28-tetrabutoxy-5,11,17,23-tetrakis (bromo) -calix [4] arene 4, subsequent Reaction with nickel (II) chloride and triethyl phosphite to give 25,26,27,28-tetrabutoxy-5,11,17,23-tetrakis (diethoxyphosphoryl) -calix [4] arene 5 and most recently reaction with lithium bromide is the 25,26,27,28-tetrabutoxy-5,11,17,23-tetrakis (hydroxyethoxyphosphoryl) -calix [4] arene-tetralithium salt 6 can be produced.

Over a Blanc reaction, i. by reaction with formaldehyde and hydrochloric acid 3 to 25,26,27,28-tetrabutoxy-5,11,17,23-tetrakis (chloromethyl) -calix [4] arene 7 implemented. Reaction of 7 with triethyl phosphite affords the 25,26,27,28-tetrabutoxy-5,11,17,23-tetrakis (dimethoxyphosphorylmethyl) calix [4] arene 8, from which by reaction with tetrabutylammonium hydroxide solution corresponding 5,26,27,28-tetrabutoxy-5,11,17,23-tetrakis (hydroxymethoxyphosphorylmethyl) -calix [4] arene Tetrabutylammonium salt 9 is recovered.

The Preparation of compounds 3, 6 and 9 is known to the person skilled in the art and can be found, for example, in T. Schrader, T. Grawe, M. Gurrath, A. Kraft, F. Osterod: Selforganization of Spheroidal Molecular Assemblies in Polar solvents. Org. Lett. 2000, 2, 29-32 and R. Zadmard, T. Schrader, T. Grawe, A. Kraft: Self-Assembly of Molecular Capsules in Polar Solvents, Org. Lett. 2002, 4, 1687-1690 be looked up.

the One skilled in the art is aware of how calix [4] arenes with homologous alkoxy groups in the endo positions and / or homologous hydroxyalkoxyphosphoryl and hydroxyalkoxyphosphorylmethyl compounds.

wobei die beiden Reste R8 und R9 für Wasserstoffatome stehen oder jeweils mit einem der beiden Bicyclo-[2.2.1]-hept-2-en-Gruppen einen Benzol-, Naphthalin- oder Anthracenring bilden, ist dem Fachmann bekannt und kann beispielsweise in F.-G. Klärner, J. Panitzky, D. Bläser, R. Boese: Synthesis and supramolecular structures of molecular clips. Tetrahedron 2001, 57, 3673–3687 und F.-G. Klärner, J. Polkowska, J. Panitzky, U.P. Seelbach, U. Burkert, M. Kamieth, M. Baumann, A.E. Wigger, R. Boese, D. Bläser: Effect of Substituents on the Complexation of Aromatic and Quinoid Substrates with Molecular Tweezers and Clips. Eur. J. Org. Chem. 2004, 1405–1423 nachgeschlagen werden. Verbindungen der Strukturformel 10 werden nachfolgend als Hydrochinonvorläufer bezeichnet.The preparation of compounds of the type

where the two radicals R 8 and R 9 are hydrogen atoms or each form a benzene, naphthalene or anthracene ring with one of the two bicyclo [2.2.1] hept-2-ene groups is known to the person skilled in the art and can be found, for example, in F .-G. Klärner, J. Panitzky, D. Bläser, R. Boese: Synthesis and supramolecular structures of molecular clips. Tetrahedron 2001, 57, 3673-3687 and F.-G. Klärner, J. Polkowska, J. Panitzky, UP Seelbach, U. Burkert, M. Kamieth, M. Baumann, AE Wigger, R. Boese, D. Bläser: Effect of Substituents on the Complexation of Aromatic and Quinoid Substrates with Molecular Tweezers and clips. Eur. J. Org. Chem. 2004, 1405-1423. Compounds of Structural Formula 10 are hereinafter referred to as hydroquinone precursors.

So For example, it is 7,16-dihydroxy-6,8,15,17-tetrahydro-6,17: 8,15-dimethanoheptacene 19 accessible as follows: First will be 1 equivalent Benzoquinone 11 and 2 equivalents Cyclopentadiene 12 in Consecutive Reactions - Diels-Alder Reaction, Oxidation of the (1: 1) Diels-Alder adduct and again Diels-Alder reaction - to the diketone 13 implemented, then the diketone 13 to hydroquinone 14 is basic isomerized. The hydroquinone 14 is acetylated twice and 1 equivalent of the resulting bisacetic acid ester 15 with 2 equivalents Tetraborm-o-xylene 16 in Diels-Alder reactions to the unisolated bisadduct 17 implemented. The elimination under the reaction conditions of HBr gives 18,17,16-diacetyl-6,8,15,17-tetrahydro-6,17: 8,15-dimethanoheptacene; Hydrolysis of the ester of acetic acid leads to Hydroquinone 7,16-Dihydroxy-6,8,15,17-tetrahydro-6,17: 8,15-dimethanoheptacene 19th

So far However, no compounds are known which are active both in aqueous solutions sufficiently soluble are also applicable to biological systems as well multiply substituted aromatic cations, for example in triplicate Complexed pyridinium cations such as A2E complex.

task The present invention is novel agents for therapy, Diagnosis and prophylaxis of dry macular degeneration as well To provide a process for their preparation.

[Solution of the task]

The Task of providing novel drugs for therapy, Diagnosis and prophylaxis of dry macular degeneration is solved by the invention the compound of claim 1 or 2 and by a method for Preparation of a compound according to claim 3 and and the use of compounds according to claims 7 and 9. Advantageous embodiments of the invention are in the claims 4 to 6 as well as 8 and 10 indicated.

Surprised it has been found that the active compounds according to the invention bind A2E and thereby preventing A2E-induced apoptosis of RPE cells. at the active compounds according to the invention these are calixarene derivatives or clips.

there flows the disclosure content of the publications T. Schrader, T. Grawe, M. Gurrath, A. Kraft, F. Osterod: Self-organization of Spheroidal Molecular Assemblies in Polar Solvents. Org. Lett. 2000, 2, 29-32 and R. Zadmard, T. Schrader, T. Grawe, A. Kraft: Self-Assembly of Molecular Capsules in Polar Solvents, Org. Lett. 2002, 4, 1687-1690; F.-G. Klärner, J. Panitzky, D. Bläser, R. Boese: Synthesis and supramolecular structures of molecular clips. Tetrahedron 2001, 57, 3673-3687; C. Jasper, T. Schrader, J. Panitzky, F.-G. Klärner: Selective Complexation of N-alkylpyridinium salts: Recognition of NAD + in Water. Angew. Chem. Int. Ed. 2002, 41, 1355-1358; F.-G. Klärner, B. Kahlert: Molecular Tweezers and Clips as Synthetic Receptors. Molecular Recognition and Dynamics in Receptor-Substrate Complexes. Acc. Chem. Res. 2003, 36, 919-932 and F.-G. Klaerner, J. Polkowska, J. Panitzky, U.P. Seelbach, U. Burkert, M. Kamieth, M. Baumann, A.E. Wigger, R. Boese, D. Bläser: Effect of Substituents on the Complexation of Aromatic and Quinoid Substrates with Molecular Tweezers and clips. Eur. J. Org. Chem. 2004, 1405-1423 completely in the present application.

Under Calixarene derivatives of the invention are understood to mean calixarenes, the four to eight arene rings each arene ring in exo position contains a phosphate or phosphonate substituents and in the endo position an oxo or Thiosubstituenten carries.

• • das kondensierte Ringsystem drei aromatische Ringe enthält,
• • die beiden endständigen Ringe des kondensierten Ringsystems aromatisch sind, jeweils aus (4n + 2) Kohlenstoffatomen bestehen und n eine natürliche Zahl von 1 bis 3 ist,
• • einer der drei aromatischen Ringe keinen endständigen Ring des linearen kondensierten Ringsystems darstellt, wobei dieser Ring aus sechs Kohlenstoffatomen besteht und nachfolgend als „zentraler Aromat" bezeichnet wird,
• • der zentrale Aromat mit den beiden endständigen Aromaten über je einen alicylischen sechsgliedrigen Ring miteinander verbunden ist, so dass das gesamte Molekül ein „U" beschreibt und eine Kavität bildet,
• • die beiden sp³-hybridisierten Kohlenstoffatome jedes alicyclischen sechsgliedrigen Ringes über eine Methylenbrücke miteinander verbrückt sind, und
• • der zentrale Aromat zwei zueinander para-ständige Substituenten aufweist, die unabhängig voneinander aus der Gruppe Phosphat und Phosphonat ausgewählt sind.

A clip according to the invention is understood to mean a compound which has a linear condensed ring system, wherein

• The condensed ring system contains three aromatic rings,
• • the two terminal rings of the fused ring system are aromatic, each consisting of (4n + 2) Koh and n is a natural number from 1 to 3,
• • one of the three aromatic rings does not represent a terminal ring of the linear fused ring system, this ring consisting of six carbon atoms and hereinafter referred to as the "central aromatic",
• The central aromatic is connected to the two terminal aromatics via a respective alicyclic six-membered ring, so that the entire molecule describes a "U" and forms a cavity,
• • the two sp ³ -hybridized carbon atoms of each alicyclic six-membered ring are bridged together via a methylene bridge, and
• • The central aromatic two mutually para-containing substituents which are independently selected from the group of phosphate and phosphonate.

mit
A = kein Atom oder -CH₂-;
X = O, S;
n = 4–8;
R1 = H; Alkyl; wobei Alkyl für eine Gruppe mit 4 bis 20 Kohlenstoffatomen steht, die linear oder verzweigt ist; Heteroalkyl, wobei Heteroalkyl für einen Rest steht mit 4 bis 20 Kohlenstoffatomen steht, worin bis zu 5 Kohlenstoffatome durch Heteroatome ausgewählt aus der Gruppe Stickstoff, Sauerstoff, Schwefel, Phosphor ersetzt sind;
-(C_pH_2p-O)_xH, -(C_PH_2p-O)_x-C_pH_2p+1, worin p eine natürliche Zahl von 1 bis 4 und x eine natürliche Zahl von 1 bis 10 ist;
-(CH₂)_yCOO^–, -(CH₂)_ySO₃ ^–, -(CH₂)_yPO₃ ^2–, worin y eine natürliche Zahl von 1 bis 10 ist;
-(C_zH_2z-O)_m-C_zH_2zCOO^–, -(C_zH_2z-O)_m-C_zH_2zSO₃ ^–, -(C_zH_2zO)_m-C_zH_2zPO₃ ^2–, worin z und m unabhängig voneinander natürliche Zahlen von 1 bis 4 sind;
-CH₂-(C_rH_2r)-COOH, -CH₂-(C_rH_2r-2)-COOH, -CH₂-(C_rH_2r-4)-COOH,
-CH₂-(C_rH_2r-6)-COOH, -CH₂-(C_rH_2r-8)-COOH, wobei r eine natürliche Zahl von 10 bis 18 ist,
ein Isoprenrest der Summenformel C₅H₉,
ein Terpenrest der allgemeinen Summenformel C₁₀H₁₉, C₁₀H₁₉O, C₁₀H₁₇, C₁₀H₁₇O, C₁₀H₁₅, C₁₀H₁₅O, C₁₀H₁₃O,
ein Sesquiterpenrest der allgemeinen Summenformel C₁₅H₂₉, C₁₅H₂₉O, C₁₅H₂₇, C₁₅H₂₇O, C₁₅H₂₅, C₁₅H₂₅O, C₁₅H₂₃, C₁₅H₂₃O, C₁₅H₁₉O,
ein Diterpenrest der allgemeinen Summenformel C₂₀H₃₉, C₂₀H₃₉O, C₂₀H₃₇, C₂₀H₃₇O, C₂₀H₃₅, C₂₀H₃₅O, C₂₀H₃₃, C₂₀H₃₃O, C₂₀H₃₁, C₂₀H₃₁O, C₂₀H₂₉, C₂₀H₂₉O, C₂₀H₂₇, C₂₀H₂₇O, C₂₀H₂₅O, ist;
R2 und R3 unabhängig voneinander H oder OH darstellen;
R4 = H, lineares Alkyl mit 1 bis 20 Kohlenstoffatomen, beispielsweise Methyl, Ethyl, n-Propyl, n-Butyl, n-Pentyl, n-Hexyl, n-Heptyl, n-Octyl,
R5 = O^–, Alkyl, Aryl, O-Alkyl, O-Aryl, O-Cycloalkyl, O-Heteroalkyl, O-Heteroaryl, O-Cycloheteroalkyl, wobei -Alkyl für eine Gruppe mit 1 bis 10 Kohlenstoffatomen steht, die linear oder verzweigt ist, bevorzugt für Methyl, Ethyl, Propyl, Isopropyl, 1-Butyl, 2-Butyl, (2-Methyl-)propyl, tert.-Butyl, und -Alkenyl und -Alkinyl für eine einfach oder mehrfach ungesättigte Gruppe mit 2 bis 10 Kohlenstoffatomen stehen, -Cycloalkyl für eine Gruppe mit 3 bis 20 Kohlenstoffatomen steht, die heterocyclischen Gruppen für einen Rest mit 1 bis 20 Kohlenstoffatomen stehen, worin bis zu 5 Kohlenstoffatome durch Heteroatome ausgewählt aus der Gruppe Stickstoff, Sauerstoff, Schwefel, Phosphor ersetzt sind, -Aryl für einen aromatischen Rest mit 5 bis 20 Kohlenstoffatomen steht und Heteroaryl für einen entsprechenden aromatischen Rest steht, bei dem bis zu 5 Kohlenstoffatome durch Heteroatome, ausgewählt aus der Gruppe Stickstoff, Sauerstoff, Schwefel, Phosphor ersetzt sind,
-NH₂, -NH(C₁-C₁₀-Alkyl); -N(C₁-C₁₀-Alkyl)₂, wobei die beiden Alkylgruppen identisch oder unterschiedlich sind; und wobei Alkylgruppen linear oder verzweigt sind,
ein Isoprenrest der Summenformel C₅H₉,
ein Terpenrest der allgemeinen Summenformel C₁₀H₁₉, C₁₀H₁₉O, C₁₀H₁₇, C₁₀H₁₇O, C₁₀H₁₅, C₁₀H₁₅O, C₁₀H₁₃O,
ein Sesquiterpenrest der allgemeinen Summenformel C₁₅H₂₉, C₁₅H₂₉O, C₁₅H₂₇, C₁₅H₂₇O, C₁₅H₂₅, C₁₅H₂₅O, C₁₅H₂₃, C₁₅H₂₃O, C₁₅H₁₉O,
ein Diterpenrest der allgemeinen Summenformel C₂₀H₃₉, C₂₀H₃₉O, C₂₀H₃₇, C₂₀H₃₇O, C₂₀H₃₅, C₂₀H₃₅O, C₂₀H₃₃, C₂₀H₃₃O, C₂₀H₃₁, C₂₀H₃₁O, C₂₀H₂₉, C₂₀H₂₉O, C₂₀H₂₇, C₂₀H₂₇O, C₂₀H₂₅O, ist;
und M = Li⁺, Na⁺, K⁺, NH₄ ⁺, ⁺N(C₁-C₄-Alkyl), wobei die Alkylgruppen identisch oder unterschiedlich sind,
sowie für den Fall, dass A kein Atom ist, X ein Sauerstoffatom darstellt und R2, R3 und R4 Wasserstoffatome darstellen, Verbindungen ausgenommen sind, bei denen
R1 eine n-Butylgruppe, R5 eine Ethylgruppe und M⁺ ein Li⁺-Ion darstellt.The calixarene derivatives according to the invention have the following general structural formula:

With
A = no atom or -CH ₂ -;
X = O, S;
n = 4-8;
R1 = H; alkyl; wherein alkyl is a group of 4 to 20 carbon atoms which is linear or branched; Heteroalkyl, wherein heteroalkyl is a radical having 4 to 20 carbon atoms, wherein up to 5 carbon atoms are replaced by heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur, phosphorus;
- (C _p H _2p O) _x H, - (C _p H _2p O) _x -C _p H _{2p + 1,} wherein p is a natural number from 1 to 4 and x is a natural number from 1 to 10;
- (CH ₂ ) _y COO ^- , - (CH ₂ ) _y SO ₃ ^- , - (CH ₂ ) _y PO ₃ ^2- , wherein y is a natural number from 1 to 10;
- (C _z H _2z -O) _m -C _z H _2z COO ^- , - (C _z H _2z -O) _m -C _z H _2z SO ₃ ^- , - (C _z H _2z O) _m -C _z H _2z PO ₃ ^2- , wherein z and m are independently natural numbers from 1 to 4;
-CH ₂ - (C _r H _2r ) -COOH, -CH ₂ - (C _r H _2r-2 ) -COOH, -CH ₂ - (C _r H _2r-4 ) -COOH,
-CH ₂ - (C _r H _2r-6 ) -COOH, -CH ₂ - (C _r H _2r-8 ) -COOH, where r is a natural number from 10 to 18,
an isoprene radical of the empirical formula C ₅ H ₉ ,
a terpene radical of the general empirical formula C ₁₀ H ₁₉ , C ₁₀ H ₁₉ O, C ₁₀ H ₁₇ , C ₁₀ H ₁₇ O, C ₁₀ H ₁₅ , C ₁₀ H ₁₅ O, C ₁₀ H ₁₃ O,
a sesquiterpene radical of the general empirical formula C ₁₅ H ₂₉ , C ₁₅ H ₂₉ O, C ₁₅ H ₂₇ , C ₁₅ H ₂₇ O, C ₁₅ H ₂₅ , C ₁₅ H ₂₅ O, C ₁₅ H ₂₃ , C ₁₅ H ₂₃ O, C ₁₅ H ₁₉ O,
a diterpene radical of the general empirical formula C ₂₀ H ₃₉ , C ₂₀ H ₃₉ O, C ₂₀ H ₃₇ , C ₂₀ H ₃₇ O, C ₂₀ H ₃₅ , C ₂₀ H ₃₅ O, C ₂₀ H ₃₃ , C ₂₀ H ₃₃ O, C ₂₀ H ₃₁ , C ₂₀ H ₃₁ O, C ₂₀ H ₂₉ , C ₂₀ H ₂₉ O, C ₂₀ H ₂₇ , C ₂₀ H ₂₇ O, C ₂₀ H ₂₅ O;
R2 and R3 independently represent H or OH;
R 4 = H, linear alkyl having 1 to 20 carbon atoms, for example methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl,
R5 = O ^-, alkyl, aryl, O-alkyl, O-aryl, O-cycloalkyl, O-heteroalkyl, O-heteroaryl, O-cycloheteroalkyl, wherein alkyl represents a group having 1 to 10 carbon atoms, which is branched linear or is preferred for methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, (2-methyl) propyl, tert-butyl, and alkenyl and alkynyl for a mono- or polyunsaturated group having 2 to 10 -Cycloalkyl is a group having 3 to 20 carbon atoms, the heterocyclic groups are a radical having 1 to 20 carbon atoms, wherein up to 5 carbon atoms are replaced by heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur, phosphorus, Aryl is an aromatic radical having 5 to 20 carbon atoms and heteroaryl is a corresponding aromatic radical in which up to 5 carbon atoms are replaced by heteroatoms selected from the group of nitrogen, oxygen, sulfur, phosphorus,
-NH ₂ , -NH (C ₁ -C ₁₀ alkyl); -N (C ₁ -C ₁₀ alkyl) ₂ , wherein the two alkyl groups are identical or different; and wherein alkyl groups are linear or branched,
an isoprene radical of the empirical formula C ₅ H ₉ ,
a terpene radical of the general empirical formula C ₁₀ H ₁₉ , C ₁₀ H ₁₉ O, C ₁₀ H ₁₇ , C ₁₀ H ₁₇ O, C ₁₀ H ₁₅ , C ₁₀ H ₁₅ O, C ₁₀ H ₁₃ O,
a sesquiterpene radical of the general empirical formula C ₁₅ H ₂₉ , C ₁₅ H ₂₉ O, C ₁₅ H ₂₇ , C ₁₅ H ₂₇ O, C ₁₅ H ₂₅ , C ₁₅ H ₂₅ O, C ₁₅ H ₂₃ , C ₁₅ H ₂₃ O, C ₁₅ H ₁₉ O,
a diterpene radical of the general empirical formula C ₂₀ H ₃₉ , C ₂₀ H ₃₉ O, C ₂₀ H ₃₇ , C ₂₀ H ₃₇ O, C ₂₀ H ₃₅ , C ₂₀ H ₃₅ O, C ₂₀ H ₃₃ , C ₂₀ H ₃₃ O, C ₂₀ H ₃₁ , C ₂₀ H ₃₁ O, C ₂₀ H ₂₉ , C ₂₀ H ₂₉ O, C ₂₀ H ₂₇ , C ₂₀ H ₂₇ O, C ₂₀ H ₂₅ O;
and M = Li ⁺ , Na ⁺ , K ⁺ , NH ₄ ⁺ , ⁺ N (C ₁ -C ₄ -alkyl), wherein the alkyl groups are identical or different,
and in the event that A is not an atom, X represents an oxygen atom and R2, R3 and R4 are hydrogen atoms, excluding compounds in which
R1 represents an n-butyl group, R5 represents an ethyl group and M ^{+ represents} a Li ⁺ ion.

worin R5 = O^–, Alkyl, Aryl, O-Alkyl, O-Aryl, O-Cycloalkyl, O-Heteroalkyl, O-Heteroaryl, O-Cycloheteroalkyl, wobei -Alkyl für eine Gruppe mit 1 bis 10 Kohlenstoffatomen steht, die linear oder verzweigt ist, bevorzugt für Methyl, Ethyl, Propyl, Isopropyl, 1-Butyl, 2-Butyl, (2-Methyl-)propyl, tert.-Butyl, und -Alkenyl und -Alkinyl für eine einfach oder mehrfach ungesättigte Gruppe mit 2 bis 10 Kohlenstoffatomen stehen, -Cycloalkyl für eine Gruppe mit 3 bis 20 Kohlenstoffatomen steht, die heterocyclischen Gruppen für einen Rest mit 1 bis 20 Kohlenstoffatomen stehen, worin bis zu 5 Kohlenstoffatome durch Heteroatome ausgewählt aus der Gruppe Stickstoff, Sauerstoff, Schwefel, Phosphor ersetzt sind, -Aryl für einen aromatischen Rest mit 5 bis 20 Kohlenstoffatomen steht und Heteroaryl für einen entsprechenden aromatischen Rest steht, bei dem bis zu 5 Kohlenstoffatome durch Heteroatome, ausgewählt aus der Gruppe Stickstoff, Sauerstoff, Schwefel, Phosphor ersetzt sind,
-NH₂, -NH(C₁-C₁₀-Alkyl); -N(C₁-C₁₀-Alkyl)₂, wobei die beiden Alkylgruppen identisch oder unterschiedlich sind; und wobei Alkylgruppen linear oder verzweigt sind,
ein Isoprenrest der Summenformel C₅H₉,
ein Terpenrest der allgemeinen Summenformel C₁₀H₁₉, C₁₀H₁₉O, C₁₀H₁₇, C₁₀H₁₇O, C₁₀H₁₅, C₁₀H₁₅O, C₁₀H₁₃O,
ein Sesquiterpenrest der allgemeinen Summenformel C₁₅H₂₉, C₁₅H₂₉O, C₁₅H₂₇, C₁₅H₂₇O, C₁₅H₂₅, C₁₅H₂₅O, C₁₅H₂₃, C₁₅H₂₃O, C₁₅H₁₉O,
ein Diterpenrest der allgemeinen Summenformel C₂₀H₃₉, C₂₀H₃₉O, C₂₀H₃₇, C₂₀H₃₇O, C₂₀H₃₅, C₂₀H₃₅O, C₂₀H₃₃, C₂₀H₃₃O, C₂₀H₃₁, C₂₀H₃₁O, C₂₀H₂₉, C₂₀H₂₉O, C₂₀H₂₇, C₂₀H₂₇O, C₂₀H₂₅O, ist;
M = Li⁺, Na⁺, K⁺, NH₄ ⁺, ⁺N(C₁-C₄-Alkyl), wobei die Alkylgruppen identisch oder unterschiedlich sind, und
Y und Z unabhängig voneinander ausgewählt sind aus der Gruppe

und wobei R6 ausgewählt ist aus H, OH, Cl, Br, O-(C₁-C₄-Alkyl), N-(C₁-C₄-Alkyl), wobei die Alkylgruppen identisch oder unterschiedlich sind, oder
ein Isoprenrest der Summenformel C₅H₉,
ein Terpenrest der allgemeinen Summenformel C₁₀H₁₉, C₁₀H₁₉O, C₁₀H₁₇, C₁₀H₁₇O, C₁₀H₁₅, C₁₀H₁₅O, C₁₀H₁₃O,
ein Sesquiterpenrest der allgemeinen Summenformel C₁₅H₂₉, C₁₅H₂₉O, C₁₅H₂₇, C₁₅H₂₇O, C₁₅H₂₅, C₁₅H₂₅O, C₁₅H₂₃, C₁₅H₂₃O, C₁₅H₁₉O,
ein Diterpenrest der allgemeinen Summenformel C₂₀H₃₉, C₂₀H₃₉O, C₂₀H₃₇, C₂₀H₃₇O, C₂₀H₃₅, C₂₀H₃₅O, C₂₀H₃₃, C₂₀H₃₃O, C₂₀H₃₁, C₂₀H₃₁O, C₂₀H₂₉, C₂₀H₂₉O, C₂₀H₂₇, C₂₀H₂₇O, C₂₀H₂₅O, ist;
sowie für den Fall, dass Y und Z jeweils mit einer der beiden Bicyclo-[2.2.1]-hept-2-en-Gruppen eine Naphthalinring bilden, Verbindungen ausgenommen sind, bei denen R5 eine Methylgruppe darstellt und M⁺ ein Lithium-Ion oder ein Tetra-n-Butylammoniumion ist.The clips according to the invention have the following general structural formula:

wherein R 5 = O ^- , alkyl, aryl, O-alkyl, O-aryl, O-cycloalkyl, O-heteroalkyl, O-heteroaryl, O-cycloheteroalkyl, wherein -alkyl represents a group having 1 to 10 carbon atoms, which are linear or is preferably methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, (2-methyl) propyl, tert-butyl, and alkenyl and alkynyl for a mono- or polyunsaturated group having 2 to 10 carbon atoms, -cycloalkyl represents a group having 3 to 20 carbon atoms, the heterocyclic groups are a radical having 1 to 20 carbon atoms, wherein up to 5 carbon atoms are replaced by heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur, phosphorus, -Aryl is an aromatic radical having 5 to 20 carbon atoms and heteroaryl is a corresponding aromatic radical in which up to 5 carbon atoms are replaced by heteroatoms selected from the group of nitrogen, oxygen, sulfur, phosphorus,
-NH ₂ , -NH (C ₁ -C ₁₀ alkyl); -N (C ₁ -C ₁₀ alkyl) ₂ , wherein the two alkyl groups are identical or different; and wherein alkyl groups are linear or branched,
an isoprene radical of the empirical formula C ₅ H ₉ ,
a terpene radical of the general empirical formula C ₁₀ H ₁₉ , C ₁₀ H ₁₉ O, C ₁₀ H ₁₇ , C ₁₀ H ₁₇ O, C ₁₀ H ₁₅ , C ₁₀ H ₁₅ O, C ₁₀ H ₁₃ O,
a sesquiterpene radical of the general empirical formula C ₁₅ H ₂₉ , C ₁₅ H ₂₉ O, C ₁₅ H ₂₇ , C ₁₅ H ₂₇ O, C ₁₅ H ₂₅ , C ₁₅ H ₂₅ O, C ₁₅ H ₂₃ , C ₁₅ H ₂₃ O, C ₁₅ H ₁₉ O,
a diterpene radical of the general empirical formula C ₂₀ H ₃₉ , C ₂₀ H ₃₉ O, C ₂₀ H ₃₇ , C ₂₀ H ₃₇ O, C ₂₀ H ₃₅ , C ₂₀ H ₃₅ O, C ₂₀ H ₃₃ , C ₂₀ H ₃₃ O, C ₂₀ H ₃₁ , C ₂₀ H ₃₁ O, C ₂₀ H ₂₉ , C ₂₀ H ₂₉ O, C ₂₀ H ₂₇ , C ₂₀ H ₂₇ O, C ₂₀ H ₂₅ O;
M = Li ⁺ , Na ⁺ , K ⁺ , NH ₄ ⁺ , ⁺ N (C ₁ -C ₄ -alkyl), wherein the alkyl groups are identical or different, and
Y and Z are independently selected from the group

and wherein R6 is selected from H, OH, Cl, Br, O- (C ₁ -C ₄ alkyl), N- (C ₁ -C ₄ alkyl), the alkyl groups being identical or different, or
an isoprene radical of the empirical formula C ₅ H ₉ ,
a terpene radical of the general empirical formula C ₁₀ H ₁₉ , C ₁₀ H ₁₉ O, C ₁₀ H ₁₇ , C ₁₀ H ₁₇ O, C ₁₀ H ₁₅ , C ₁₀ H ₁₅ O, C ₁₀ H ₁₃ O,
a sesquiterpene radical of the general empirical formula C ₁₅ H ₂₉ , C ₁₅ H ₂₉ O, C ₁₅ H ₂₇ , C ₁₅ H ₂₇ O, C ₁₅ H ₂₅ , C ₁₅ H ₂₅ O, C ₁₅ H ₂₃ , C ₁₅ H ₂₃ O, C ₁₅ H ₁₉ O,
a diterpene radical of the general empirical formula C ₂₀ H ₃₉ , C ₂₀ H ₃₉ O, C ₂₀ H ₃₇ , C ₂₀ H ₃₇ O, C ₂₀ H ₃₅ , C ₂₀ H ₃₅ O, C ₂₀ H ₃₃ , C ₂₀ H ₃₃ O, C ₂₀ H ₃₁ , C ₂₀ H ₃₁ O, C ₂₀ H ₂₉ , C ₂₀ H ₂₉ O, C ₂₀ H ₂₇ , C ₂₀ H ₂₇ O, C ₂₀ H ₂₅ O;
and in the event that Y and Z each form a naphthalene ring with one of the two bicyclo- [2.2.1] -hept-2-ene groups, excluding compounds in which R5 represents a methyl group and M ⁺ a lithium ion or a tetra-n-butylammonium ion.

The Bis-alkylphosphonate clips according to the invention be with the aid of the method according to the invention shown below produced:

manufacturing of bis-alkylphosphonate clips

The bis-alkylphosphonate clips according to the invention are prepared by reacting POCl ₃ with one equivalent of an auxiliary base, for example triethylamine, and one equivalent of an alkyl or terpene alcohol, in a polar aprotic solvent to give the alkyl or terpenephosphonic acid chloride. The resulting Phosphorsäureesterdichlorid is reacted in situ with the addition of another equivalent of auxiliary base directly with the hydroquinone precursor 10 (0.37 equivalents). The reaction is terminated after 1 to 2 hours by addition of 2% to 5% aqueous acid. The reaction mixture is then mixed with a nonpolar aprotic solvent and stirred for 10 to 15 hours at room temperature. Thereafter, the organic phase is separated, optionally washed with 2% to 5% aqueous acid and the organic solvents removed by distillation. After drying the distillation residue, the corresponding bis-alkylphosphonate clip is obtained.

Under The auxiliary base becomes a tertiary one Amine understood, for example, triethylamine, diisopropylamine, pyridine.

The polar aprotic solvents will be chosen from the group tetrahydrofuran (THF), diethyl ether, diisopropyl ether, Pyridine.

The nonpolar aprotic solvents will be chosen from the group of alkanes having 5 to 8 carbon atoms, these being Alkanes are linear, cyclic and / or branched, for example n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, cycloheptane, Cyclooctane, methylcyclopentane, methylcyclohexane, methylcycloheptane.

The alkyl alcohols are primary alcohols having 1 to 20 carbon atoms, wherein the alkyl chain is linear, cyclic and / or branched, for example n-butanol, i-butanol, sec-butanol, tert-Bu tanol, n-pentanol, cyclopentanol, cyclohexanol.

The terpene alcohols are alcohols of a mono-, di- or sesquiterpene with the general empirical formulas C ₁₀ H ₂₀ O, C ₁₀ H ₁₈ O, C ₁₀ H ₁₆ O, C ₁₅ H ₃₀ O, C ₁₅ H ₂₈ O, C ₁₅ H ₂₆ O, C ₁₅ H ₂₄ O, C ₂₀ H ₄₀ O, C ₂₀ H ₃₈ O, C ₂₀ H ₃₆ O, C ₂₀ H ₃₄ O, C ₂₀ H ₃₂ O, C ₂₀ H ₃₀ O, C ₂₀ H ₂₈ O.

Surprised it was found that the active compounds according to the invention in cell culture experiments solve the problem of A2E-induced apoptosis: Both the calixarene derivatives as well as the clips interact directly as artificial receptors with A2E, eliminating the pathological A2E level and RPE cells in front of the A2E-induced Preserve apoptosis. In independent Experiments could be the ability both receptor molecules, N-alkylpyridinium derivatives bind, with NMR titration experiments and Langmuir film scale experiments to be shown.

Initial screening in cell culture assays revealed that Clip 22a is a potent, non-toxic inhibitor of dry AMD [50% inhibition of apoptosis at 15 μM (IC ₅₀ value).

It was found that the calixarene derivatives of the invention all the way up at high doses of about 60 μM are not toxic. Have work on the immune response to calixarene demonstrated that they do not elicit essentially any immune response and her cellular cytotoxicity is sufficiently low, so that the use of calixarenes according to the invention is pharmaceutically acceptable for the manufacture of medicaments.

The calixarenes according to the invention and clips can therefore as a medicine for Patients for the therapy, diagnosis and prophylaxis of diseases used in which a pathological concentration of the Terpene-substituted N-alkylpyridinium derivative A2E occurs. These diseases are, for example around the age-related dry macular degeneration AMD.

wobei R1, R2, R3, R4, R5, A und M⁺ die oben aufgeführten Bedeutungen haben und die Verbindung, bei der A kein Atom ist, X ein Sauerstoffatom darstellt, R1 für eine n-Butylgruppe, R2, R3 und R4 für Wasserstoffatome, R5 für eine Ethylgruppe und M⁺ ein Li+-Ion darstellt, eingeschlossen ist, da ihre Verwendung zur Herstellung eines Arzneimittels für Patienten zur Therapie, Diagnostik und Prophylaxe von Erkrankungen verwendet werden, bei denen eine pathologische Konzentration des Terpen-substituierten N-Alkylpyridiniumderivat A2E, wie es beispielsweise bei der altersbedingten trockenen Makuladegeneration der Fall ist, neu und somit erfinderisch ist.These are calixarene derivatives of the general structural formula

wherein R 1, R 2, R 3, R 4, R 5, A and M ⁺ are as defined above, and the compound wherein A is not an atom, X represents an oxygen atom, R 1 represents an n-butyl group, R 2, R 3 and R 4 represent hydrogen atoms , R5 represents an ethyl group and M ^{+ represents} a Li + ion, since its use is used for the preparation of a medicament for patients for the therapy, diagnosis and prophylaxis of diseases in which a pathological concentration of the terpene-substituted N-alkylpyridinium derivative A2E as is the case, for example, with the age-related dry macular degeneration, is new and thus inventive.

wobei R5, M⁺, Y und Z die oben aufgeführten Bedeutungen haben und die Verbindung, bei der Y und Z jeweils mit einer der beiden Bicyclo-[2.2.1]-hept-2-en-Gruppen eine Naphthalinring bilden, R5 eine Methylgruppe darstellt und M⁺ ein Lithium-Ion oder ein Tetra-n-Butylammoniumion ist, eingeschlossen ist, da ihre Verwendung zur Herstellung eines Arzneimittels für Patienten zur Therapie, Diagnostik und Prophylaxe von Erkrankungen verwendet werden, bei denen eine pathologische Konzentration des Terpen-substituierten N-Alkylpyridiniumderivat A2E, wie es beispielsweise bei der altersbedingten trockenen Makuladegeneration der Fall ist, neu und somit erfinderisch ist.Furthermore, clips of the general structural formula

wherein R5, M ⁺ , Y and Z have the meanings given above and the compound in which Y and Z each form a naphthalene ring with one of the two bicyclo [2.2.1] hept-2-ene groups, R5 is a methyl group and M ^{+ is} a lithium ion or a tetra-n-butylammonium ion, since its use for the preparation of a medicament for patients is used for the therapy, diagnosis and prophylaxis of diseases in which a pathological concentration of the terpene-substituted N Alkyl pyridinium derivative A2E, as is the case for example in the age-related dry macular degeneration, is new and thus inventive.

Of the The term patient refers equally to humans and vertebrates. With that you can the medicines are used in human and veterinary medicine. Pharmaceutically acceptable compositions of compounds according to the claims and their salts, esters or amides can, provided they are reliable medical evaluation no excessive toxicity, irritation or trigger allergic reactions in the patient.

The therapeutically active compounds of the present invention can the patient as part of a pharmaceutically acceptable composition either oral, rectal, parenteral, intravenous, intramuscular, subcutaneous, intracisternal, intravaginal, intraperitoneal, intravascular, intrathecal, intravesical, topical, local (powder, ointment or drops) or in Spray form (aerosol) can be administered. Intravenous, subcutaneous, Intraperitoneal or intrathecal administration can be continuous done by means of a pump or dosing unit. dosage forms for the local Administration of the compounds of the invention shut down Ointments, powders, suppositories, Sprays and inhalants. The active component is included under sterile conditions with a physiologically acceptable carrier and possible stabilizing and / or preserving additives, buffers, dilution and blowing agents mixed as needed.

1. Preparation of 25,26,27,28-tetrabutoxy-5,11,17,23-tetrakis (hydroxyethoxyphosphoryl) -calix [4] arene-tetralithium salt 6

5,11,17,23-Tetra-t-butyl-25,26,27,28-tetrahydroxycalix [4] arene 2 is prepared by condensation of formaldehyde with p- (t-butyl) -phenol 1 in the presence of sodium hydroxide according to Gutsche prepared and then debutylated with AlCl ₃ / phenol. the debutylierte product is reacted with butyl bromide for 25,26,27,28-Tetrabutoxycalix [4] arene 3. the positions 5, 11, 17 and 23 of Ausgangscalixarens 3 are brominated electrophilic, wherein Preferably, N-bromo-succinimide (NBS) is used as the brominating agent, followed by halogen-metal exchange and subsequent reaction with electrophiles A Ni (II) catalyst and triethyl phosphite give the aromatic phosphonate 5. The ester cleavage of the phosphonate Ethyl ester 5 is achieved by nucleophilic attack of LiBr in a dipolar aprotic solvent such as 2-hexanone.

1.a) 25,26,27,28-tetrabutoxy-5,11,17,23-tetrakis (diethoxyphosphoryl) -calix [4] arene 5

A solution of 0.83 mmol (0.7 g) of P (OEt) ₃ in 2 mL of benzonitrile is added within x-y minutes under argon atmosphere at 180 ° C to a solution of 0.5 mmol (0.52 g) 25 , 26,27,28-Tetrabutoxy-5,11,17,23-tetrabromocalix [4] arene 4 and 0.25 mmol (0.03 g) of NiCl ₂ in 3 mL of benzonitrile and after completion of the addition one hour at 180 ° C stirred. The reaction mixture is cooled to room temperature and poured into 100 ml of toluene, washed 5 times with 5% aqueous NH ₃ solution, dried over Na ₂ SO ₄ and the solvent removed on a rotary evaporator (40 ° C / 60 mbar). Excess P (OEt) ₃ and benzonitrile are completely removed at 70-80 ° C and 0.01 mbar; the remaining oil is then purified by column chromatography (ethyl acetate / MeOH 1: 1), R _f 0.08.
Yield: 380 mg (0.32 mmol, 62%); Mp 154-156 ° C; ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 0.96 (t, J = 7.3 Hz, 12 H), 1.07 (t, J = 7.0 Hz, 24 H), 1.40 (m, J = 7.6 Hz, 8 H), 1.91 (m, J = 7.6 Hz, 8 H), 3.46 (d, J = 12.9 Hz, 4 H), 3.76 (m, J = 7.3 Hz, 16 H), 3.91 (t, J = 7.6 Hz, 8H), 4.34 (d, J = 12.9Hz, 4H), 7.17 (d, J = 12.9Hz, 8H); ¹³ C-NMR (75 MHz, DMSO-d ₆ ): δ 14.2, 16.3 (d, J = 5.7 Hz), 19.1, 30.0, 32.1, 61.7 (d, J = 5.7 Hz), 73.5, 120.9, 123.4, 132.0 (d, J = 10.7 Hz), 134.7 (d, J = 15.8 Hz), 159.5 (d, J = 4.0 Hz); ³¹ P-NMR (81 MHz, DMSO-d ₆ ): δ 23.8; MS (FD): m / z 1215 (M + Na ⁺ ). Anal. Calcd. for C ₆₀ H ₁₆ O ₁₆ P ₄ : C, 60.39; H, 7.77. Gef: C, 61.13; H, 7.83.

1.b) 25,26,27,28-Tetrabutoxy-5,11,17,23-tetrakis (hydroxyethoxyphosphoryl) -calix [4] arene-tetralithium salt 6

25,26,27,28-tetrabutoxy-5,11,17,23-tetrakis (diethoxyphosphoryl) calix [4] -arene 5 (100 mg, 0.08 mmol) and LiBr (28.65 mg, 0.33 mmol) are dissolved in 10 mL 2-hexanone under argon atmosphere at 130 ° C for 1.5 hours. Subsequently, the white precipitate formed is filtered off at room temperature, washed ten times with 3 ml Dietyhlether and then dried in vacuo at a pressure <10 ^-2 mbar.
Yield: 83 mg (0.075 mmol, 90%); Mp> 255 ° C; ¹ H-NMR (300 MHz, DMSO-d6): δ 0.52 (t, J = 7.0 Hz, 12 H), 0.79 (t, J = 7.0 Hz, 12 H), 1.25 (m, J = 7.3 Hz, 8 H), 1.80 (m, J = 7.6Hz, 8H), 3.14 (d, J = 13.3Hz, 4H), 3.18 (m, J = 7.6Hz, 8H), 3.78 (t, J = 7.6Hz , 8 H), 4.27 (d, J = 12.6 Hz, 4 H), 7.03 (d, J = 12.6 Hz, 8 H); ¹³ C-NMR (75 MHz, DMSO-d ₆ ): δ 14.3, 16.0 (d, J = 5.7 Hz), 19.7, 32.3, 61.3 (d, J = 5.7 Hz), 75.5, 121.2, 125.3, 132.2 (i.e. , J = 10.7 Hz), 134.9 (d, J = 15.8 Hz); ³¹ P-NMR (81 MHz, DMSO-d ₆ ): δ 18.2; TOF-MS (ESI negative): m / z 1079.93 (M + 3H ⁺ ).

2.a) 25,26,27,28-tetrabutoxy-5,11,17,23-tetra (dimethoxyphosphorylmethyl) -calix [4] arene 8:

= 2957, 2857 (ges. Kohlenwasserstoff), 1603 (Aromat/Ringschw.), 1467, 1348 (CH₂-, CH₃-Def.-schw.), 1256 (P=O), 1213 (arom. Ether), 1030 (P-O-CH₃), 855 (isol. arom. H). Massenspektrum (FAB, Glycerinmatrix, Xe): m/z = 1138 (M + H⁺). Schmelzpunkt: 136°C. Elementaranalyse berechnet für C₅₆H₈₄O₁₆P₄: berechnet: C, 59.15, H, 7.45; gefunden: C, 59.44, H, 7.63.1.30 g (1.54 mmol) of 25,26,27,28-tetrabutoxy-5,11,17,23-tetra (chloromethyl) -calix [4] arene 7 are dissolved in 60 ml of trimethyl phosphite and kept at 180 ° C. oil bath temperature for 7 days cooked under reflux and ³¹ P reaction control. The solvent is stripped off in an oil pump vacuum at 60 ° C. and a pressure <10 ^-2 mbar, and the resulting solid is purified by column chromatography on silica gel 60 with methanol: chloroform (1: 9). (Rf = 0.33).
Yield: 1.28 g (1.13 mmol, 73%). ¹ H-NMR (200 MHz, CDCl ₃ ): δ 0.99 (t, 12 H, J = 7.53 Hz), 1.42 (m, 8 H, J = 7.65 Hz), 1.88 (m, 8 H, J = 7.28 Hz ), 2.81 (d, 8 H, J = 21.21 Hz), 3.17 (d, 4 H, J = 9.41 Hz), 3.59 (d, 24 H, J = 10.66 Hz), 3.85 (t, 8 H, J = 7.53 Hz), 4.38 (d, 4 H, J = 13.05), 6.57 (dt, 8 H, J = 2.51). ¹³ C-NMR (75 MHz, CDCl _3): δ 6.13 18.30, 29.84, 30.60, 31.45 (d, 132 Hz), 51.74 (d, 41 Hz), 73.92, 122.87, 128.41, 134.06, 154.74. ³¹ P-NMR (202 MHz, CD ₃ OD): δ 30.62. Infrared spectrum (KBr compact):

= 2957, 2857 (total hydrocarbon), 1603 (aromatic / ring sulfur), 1467, 1348 (CH ₂ -, CH ₃ -Def.-schw.), 1256 (P = O), 1213 (aromatic ether), 1030 (PO-CH ₃ ), 855 (isolated arom. H). Mass spectrum (FAB, glycerol matrix, Xe): m / z = 1138 (M + H ⁺ ). Melting point: 136 ° C. Elemental analysis calculated for C ₅₆ H ₈₄ O ₁₆ P ₄ : Calcd: C, 59.15, H, 7.45; found: C, 59.44, H, 7.63.

2.b) 25,26,27,28-Tetrabutoxy-5,11,17,23-tetra (hydroxyphosphorylmethyl) -calix [4] arene Tetra (butylammonium salt) 9:

= 2960, 2874 (ges. Kohlenwasserstoff), 1651 (C=C-Valenz.), 1603 (Ringschw.), 1468, 1381 (CH₂-, CH₃-Def.-schw.), 1237, 1052 (arom. Ether), 879 (isol. arom. H). Massenspektrum (FAB, Glycerinmatrix, Xe): m/z = 2045 (M + H⁺). Elementaranalyse berechnet für C₁₁₆H₂₁₆H₄O₁₆P₄ + 1 H₂O: berechnet: C, 67.47, H, 10.64, H, 2.71; gefunden: C, 67.65, H, 10.73, H, 2.89.257.2 mg (0.26 mmol) 25,26,27,28-tetrabutoxy-5,11,17,23-tetra- (dimethoxyphosphorylmethyl) -calix [4] arene 8 are distilled together with 0.91 ml of 1 molar tetrabutylammonium hydroxide solution in methanol and 10 ml Water heated at 140 ° C oil bath temperature for 25 days under argon. The end of the reaction is detected under ³¹ P-NMR control. After complete conversion, the product is extracted with chloroform, the combined organic phases dried over MgSO ₄ and concentrated on a rotary evaporator at 40 ° C ° C and a pressure of 350 mbar. The resulting solid is completely freed of solvent in an oil pump vacuum at room temperature and a pressure <10 ^-2 mbar.
Yield: 430.5 mg (0.21 mmol, 93%). ¹ H-NMR (500 MHz, CDCl _3): δ 0.97-1.06 (m, 60 H), 1:36 to 1:50 (m, 40 H), 1.60-1.71 (m, 40 H), 1.85-1.94 (m, 40 H), 2.68 (d, 8 H, J = 20.81 Hz), 3.09 (d, 4 H, J = 13.08 Hz), 3.23 (t, 60 H, J = 8.52 Hz), 3.45 (d, 12 H, J = 10.40 Hz), 3.85 (t, 8 H, J = 7.41 Hz), 4.38 (d, 4 H, J = 12.92 Hz), 6.62 (d, 8 H, J = 1.42 Hz). ¹³ C-NMR (75 MHz, MeOD): δ 14.35, 14.96, 21.03, 21.12, 25.19, 32.49, 33.97, 52.34 (d, J = 6.05 Hz), 59.88, 76.19, 105.15, 130.33, 131.22, 136.04, 156.63. ³¹ P NMR (202 MHz, MeOD): δ 23.61. Infrared spectrum (film):

= 2960, 2874 (total hydrocarbon), 1651 (C = C valence), 1603 (ring sulfur), 1468, 1381 (CH ₂ -, CH ₃ -Def.-schw.), 1237, 1052 (Arom. Ether), 879 (isolated arom. H). Mass spectrum (FAB, glycerol matrix, Xe): m / z = 2045 (M + H ⁺ ). Elemental analysis calculated for C ₁₁₆ H ₂₁₆ H ₄ O ₁₆ P ₄ + 1 H ₂ O: Calcd: C, 67.47, H, 10.64, H, 2.71; found: C, 67.65, H, 10.73, H, 2.89.

3. ¹ H NMR titrations

Ten NMR tubes are each filled with 80 ml of a solution of substance 6 (c1 = 0.5-4 mM) in a deuterated solvent (CD ₃ OD or D ₂ O). A2E (1.525 equivalents, equivalent to substance 1) is dissolved in 0.61 mL of the same solvent, and the resulting solution of A2E is added in an increasing amount from 0 equivalents to 5.0 equivalents to the ten solutions of substance 6. During analysis, changes in volume and concentration are taken into account. In the NMR titration experiments of substance 6 and A2E in CD ₃ OD and D ₂ O, respectively, no chemical shifts are observed, which is why no binding constants can be calculated.

4. Film Scale Experiments

For the measurement of the surface pressure as a function of the molecular surface at 25 ° C, a NIMA 601 BAM film scale (trough dimensions 700 × 100 mm ² ) with a Wilhelmy plate is used. Pure water (purified by ELGA Purelab UHQ,> 18 MΩ) and aqueous solutions of the alkylpyridinium salts (100 μM) or the A2E (100 nM or 10 nM) are used as subphases. Under compression, none of these solutions show any measurable surface pressure in the areas studied. By applying 50 μL of a 3.5 mM stearic acid solution in chloroform to the subphase, a lipid monolayer is obtained. The recorded π-A isothermal cycles (barrier velocity: 50 cm ² / min) essentially result in no isothermal changes in the stearic acid monolayer caused by dissolved guest molecules (alkylpyridinium salts or A2E). Compound 6 is incorporated into the lipid monolayer by dropping 5 μL of a 4.6 mM receptor solution in chloroform / methanol (1: 1 v / v) onto the subphase at a surface pressure of 15 mN / m. Time-dependent π-A isothermal cycles are recorded until the measurement results of 2 consecutive measurements are substantially constant.

The results are in 1 and 2 shown.

5. Molecular Modeling

Host molecule is here the calix [4] arene tetraphosphonate 6.

Force field calculations be first as Molecular Mechanics calculations (MM Calculations) in water carried out. To the conformation of the free host or guest molecule as well their 1: 1 complex at the energetic minimum to be determined subsequently Monte Carlo simulations performed in water (MacroModel 7.0, Schrödinger Inc., 2000. force field: OPLS-AA). In this case, one out of 3,000 steps existing Monte Carlo simulation performed. All structures with lower Energy has essentially identical energy values and conformations on (ΔE ~ 5 kJ / mol).

The results are in 4 shown.

6. Production the bisphosphonate clips

The Production of the clips 22 takes place according to a modular strategy. The deprotonated hydroquinone precursor 10 is reacted with an alkyl or aryl phosphonic acid dichloride 20 implemented. Subsequently the remaining chlorine substituent is hydrolyzed. The obtained double monoacid 21 is then deprotonated with tetrabutylammonium or lithium hydroxide to give 22.

mit

The preparation is shown schematically below.

With

6.a) Preparation of 6,8,15,17-tetrahydro-6,17: 8,15-dimethanoheptacene-7,16-bismethyl-phosphonic acid ester 21a

100 mg of hydroquinone precursor 10 (228 μmol) and 80 mg of methylphosphonic dichloride 20 (0.60 mmol, 2.7 equivalents) are dissolved in 10 mL of absolute THF and cooled to 0 ° C. Then 80 μl of triethylamine (58.4 mg, 0.58 mmol, 3 equivalents) are added at this temperature over a period of 60 seconds, whereupon a colorless solid precipitates within a few seconds. The suspension obtained in this way is stirred for 1 h at 0 ° C; then the cooling is removed, so that the suspension heats up to room temperature without additional heat source. After reaching room temperature, stirring is continued for a further hour at this temperature. Subsequently, the reaction mixture is quenched with 3 mL of 2.5% aqueous HCl. 20 minutes after HCl addition, 5 mL of n-hexane are added and the resulting biphasic mixture is stirred for 16 h at room temperature. Then, the aqueous phase is separated, the organic phase washed with 3 mL of 2.5% aqueous HCl, and the combined organic phases are concentrated on a rotary evaporator to dryness. The resulting solid is dried at 0.1 mbar and finally purified by column chromatography on silica gel (300 × 10 mm, gradient elution with: CH ₂ Cl ₂ / MeOH = 3: 1 → 2: 1). The eluent mixture is switched from 3: 1 to 2: 1 as soon as the first substrate is eluted. This results in 90 mg (0.15 mmol, 66%) of the clip precursor 21a in the form of a colorless liquid.
TLC: R _f = 0.02 (CH ₂ Cl ₂ / MeOH = 2: 1). Mp Zers. > 270 ° C. ¹ H-NMR (300 MHz, D ₂ O): δ = 1.49 (d, ₂ J (P-CH ₃ ) = 16.4 Hz, 6 H, P-CH ₃ ), 2.42 (dm, 2 J (19-H _i , 19-H _a ) = 8.5 Hz, 2 H, 19-H _i , 20-H _i ), 2.66 (dm, 2J (19-H _a , 19-H _i ) = 8.3 Hz, 2 H, 19-H _a , 20-H _a ), 4.69 (brs, 4H, H-6, H-8, H-15, H-17), 7.17 (ddm, 3J (H-1, H-2) = 6.2 Hz, 4J (H-4, H-2) = 3.3 Hz, 4H, H-2, H-3, H-11, H-12), 7.48 (ddm, 3J (H-2, H-1) = 6.1 Hz , 4J (H-2, H-4) = 3.3 Hz, 4H, H-1, H-4, H-10, H-13), 7.39 (brs, 4H, H-5, H-9, H-14, H-18). ³¹ P-NMR (81 MHz, D ₂ O): δ = 15.32 (s). MS (ESI, MeOH); m / z: 296 [M-2H ⁺ ] 2-, 593 [M-H ⁺ ], 615 [M-2H ⁺ + Na ⁺ ], 625 [M-H ⁺ + MeOH] -. HRMS (ESI, MeOH); m / z: Calcd. for C ₄₄ H ₃₁ P ₂ O ₆ -: 717.159; F .: 717.161.

6.b) Preparation of the compounds 21b, 21c and 21d

The Preparation of the connections 21b, 21c and 21d takes place as described for 21a, where R8, R9 and R10 are as defined above.

6.c) Preparation of bis (tetrabutylammonium) -6,8,15,17-tetrahydro-6,17: 8,15-dimethanoheptacene-7,16-bismethylphosphonate 22a

51.8 mg of bisphosphonic acid 21a are suspended in 10 mL dichloromethane and treated with 135 μL of a 1 M watery Tetrabutylammoniumlösung (135 μmol, 0.75 equivalents) added. The bisphosphonic acid 21a contains small amounts of silica gel (81.1 μmol).

The reaction mixture is stirred for 2 h at room temperature, then the solvent is removed on a rotary evaporator to dryness. The residue is taken up in 2 ml of methanol, then filtered with a syringe filter (pore size 0.2 μm) and concentrated again to dryness on a rotary evaporator. The degree of conversion is monitored by NMR: If the NMR analysis of the crude product indicates an excess of tetrabutylammonium hydroxide, the crude product is redissolved in 5 mL of methanol and 10 mg of the respective phosphonic acid precursor (16.8 μmol) added with vigorous stirring. Reaction time, temperature?) A second membrane filtration performed as described above followed by rotary evaporation of the clear solution on a rotary evaporator to dryness and subsequent drying at 0.1 mbar give 59 mg (67.3 μmol, 99.7% based on tetrabutylammonium hydroxide) of the clip 5c in the form of a light brown solid.
Mp 140 ° C. ¹ H-NMR (300 MHz, MeOH-d4): δ = 0.96 (t, 3J (CH ₂ CH ₃ ) = 7.3 Hz, 24 H, CH ₂ CH ₃ ), 1.24-1.36 (m, 16 H, CH ₂ CH _3), 1:40 (d, 2 J (P-CH ₃₎ = 16.6 Hz, 6 H; P-CH _3), 1:43 to 1:56 (m, 16 H, NCH ₂ CH _2), 2:37 (dm, 2J (19 -H _i , 19-H _a ) = 8.0 Hz, 2 H, 19-H _i , 20-H _i ), 2.65 (dm, 2 J (19-H _a , 19-H _i ) = 7.8 Hz, 2 H; 19-H _a , 20-H _a ), 2.99-3.08 (m, 16 H, NCH ₂ CH ₂ ), 4.79 (brs, 4 H, H-6, H-8, H-15, H-17), 7.19 (ddm, 3J (H-1, H-2) = 6.1 Hz, 4J (H-4, H-2) = 3.2 Hz, 4H, H-2, H-3, H-11, H-12 ), 7.54 (ddm, 3J (H-2, H-1) = 6.1 Hz, 4J (H-4, H-2) = 3.2 Hz, 4H, H-1, H-4, H-10, H -13), 7.59 (brs, 4H, H-5, H-9, H-14, H-18). ¹³ C-NMR (50 MHz, MeOH-d4): δ = 13.43 (d, 1J (P, C) = 137.2 Hz, C-21, C-22), 13.90 (C-26), 20.59 (C-25 ), 24.64 (C-24), 59.33 (C-23), 65.77 (C-19, C-20), 120.82 (C-5, C-9, C-14, C-18), 125.96 (C). 2, C-3, C-11, C-12), 128.62 (C-1, C-4, C-10, C-13), 133.51 (C-4a, C-9a, C-13a, C- 18a), 142.09 (C-5a, C-8a, C-14a, C-17a), 148.91 (C-7, C-16), C-6, C-8, C-15, C17: under the deuterium coupled septet of MeOH-d4 expects C-6a, C-7a, C-15a, C-16a: too chafe to be detected in MeOH-d4. ³¹ P-NMR (81 MHz, MeOH-d4): δ = 25.29 (s). MS (ESI, MeOH); m / z: 296 [M-2 NBu ₄ ⁺ ] 2-, 615 [M-2 NBu ₄ ⁺ + Na ⁺ ] -, 625 [M-2 NBu ₄ ⁺ + H ⁺ + MeOH] -, 834 [M - NBu ₄ ⁺ ] -. HRMS (ESI, MeOH); m / z: Calcd. for C ₅₀ H ₆₂ NP ₂ O ₆ -: 834.405; found: 834.407.

6.d) Preparation of the compounds 22b, 22c and 22d

The Preparation of the connections 22b, 22c and 22d takes place as described for 22a, where the radicals R7, R8 and R9 have the meanings listed above.

7. NMR titrations

Host and guest compounds are dissolved in 1.00 mL of a mixture of deuterated methanol and water (CD ₃ OD and D ₂ O = 3: 1, v / v). 500 μL, 250 μL, 180 μL and 100 μL are taken from this reference sample and diluted to 1 mL with deuterated solvent mixture. There are only such signals for used the quantitative evaluation, which can be clearly followed throughout the titration, whereby "clear" is understood to mean those signals which do not disappear under solvent signals The binding constant K _a is determined by nonlinear regression.

Reference solution:

Gastverbindung A2E

Guest connection A2E

The results are in 5 shown graphically.

8. Film Scale Experiments

The Film balance experiments are carried out as described under 3. The Concentration of A2E in the aqueous Subphase is 10 sts to 7 sts. There will be no extra Displacement observed when A2E subinjected into the aqueous subphase and compound 22a is embedded in the monolayer.

The results are in 6 shown.

9. Molecular Modeling

Host molecule is here Compound 22a.

Force field calculations are first performed as Molecular Mechanics (MM Calculations) calculations in water. In order to determine the conformation of the free host or guest molecule as well as its 1: 1 complex at the energetic minimum, Monte Carlo simulations are then performed in water (MacroModel 7.0, Schrödinger Inc., 2000. Force field: OPLS-AA). In this case, one out of 3,000 paces existing Monte Carlo simulation. All low-energy structures have essentially identical energy values and conformations (ΔE ~ 5 kJ / mol).

10. Synthesis of (6α, 8α, 15α, 17α) -6,8,15,17-tetrahydro-6: 17,8: 15-dimethanoheptacene-7,16-bis (dihydrogen phosphate) 25

10.a) Production of Bisphosphorsäure 24

430 mg (0.981 mmol) of hydroquinone precursor 19 are dissolved under argon in 45 mL of anhydrous THF and cooled to 0 ° C. 0.36 ml (3.96 mmol) of POCl ₃ and 0.34 ml of anhydrous triethylamine are added and the mixture is stirred at 0 ° C. for 2.5 h. It precipitates a white, consisting mainly of triethylammonium existing solid. The still cold reaction mixture is filtered off by means of a D4 frit in vacuo. The filtrate is mixed with aqueous 2.5% HCl solution and stirred for 2 d. Subsequently, the THF is completely distilled off on a rotary evaporator in vacuo. The precipitated solid is filtered off, washed by repeated slurrying in 2.5% HCl solution, filtered off again and dried. The yield of phosphoric acid 24 is 480 mg (0.80 mmol, 82%).
¹ H-NMR (500 MHz, CD ₃ OD): δ = 2.37 (dt, 2 H, ² J (19-H ^a , 19-H ⁱ ) = 8.0 Hz, ³ J (19-H ^a , 8-H ) = 1.4 Hz, 19-H ^a, 20-H ^a), 2.61 (dt, 2 H, 19-H ^i, 20-H ^i), 4.74 (s, 4 H, 6-H, 8-H, 15 -H, 17-H), 7.18 (m, 4H, 2H, 3H, 11H, 12H), 7.51 (m, 4H, 1H, 4H, 10H , 13-H), 7.59 (s, 4H, 5H, 9H, 14H, 18H)
¹³ C-NMR (125.7 MHz, CD ₃ OD): δ = 65.56 (s, _CH2, 19-C, 20-C), 121.31 (s, CH, C-5, C-9, C-14, C -18), 126.04 (s, CH, C-2, C-3, C-11, C-12), 128.65 (s, CH, C-1, C-4, C-10, C-13), 133.41 (s, C-4a, C-9a, C-13a, C-18a), 138.92 (dd, ² J (C-7, P) = 8.5 Hz, ⁵ J (C-7, P) = 2.8 Hz , C-7, C-16), 142.44 (dd, ³ J (6a, P) = 2.8 Hz, ⁴ J (6a, P) = 4.2 Hz, C-6a, C-7a, C-15a, C- 16a), 148.13 (s, C-5a, C-8a, C-14a, C-17a).
(the signal of the bridgehead protons lies below the signal of the methanol).
³¹ P-NMR (202 MHz, CD ₃ OD): δ = -2.47 (s, OP (O) (OH) ₂ )
IR: (cm ^-1 ) = 3049 (CH), 2939 (CH), 2868 (CH), 1654 (C = C), 1238 (PO), 1279 (P = O). MS (FAB): (m / z) = 621 (M ⁺ + Na), 731 (M ⁺ + Cs)

10.b) Preparation of the Bishydrogenphosphates 25

29.6 mg (0.049 mmol) of 24 are dissolved in 5 ml of methanol at room temperature and to this solution a methanolic solution of 3.8 mg (0.09 mmol) of lithium hydroxide monohydrate is added. The clear reaction mixture is stirred for 30 min at room temperature and then concentrated to dryness on a rotary evaporator. The solid residue is dried for 10 h to 16 h hours at 50 ° C in an oil pump vacuum at a pressure of <10 ^-2 mbar. 29.5 mg (0.048 mmol, 98%) of the beige solid 25 are obtained.
¹ H-NMR (500 MHz, D ₂ O): δ = 2.43 (d, 2 H, ² J (19a-H, 19i-H) = 8.2 Hz, 19a-H, 20a-H), 2.71 (d, 2 H, 19i-H, 20i-H), 4.75 (s, 4H, 6H, 8H, 15H, 17H), 6.88 (m, 4H, 2H, 3H , 11-H, 12-H), 6.99 (m, 4H, 1H, 4H, 10H, 13H), 7.31 (s, 4H, 5H, 9H, 14 -H, 18-H).
¹³ C-NMR (125.7 MHz, D ₂ O): δ = 47.84 (s, CH ₂ , C-19, C-20), 63.81 (s, CH, C-6, C-8, C-15, C -17), 119.67 (s, CH, C-5, C-9, C-14, C-18), 124.38 (s, CH, C-2, C-3, C-11, C-12), 126.83 (s, CH, C-1, C-4, C-10, C-13), 131.15 (s, C-4a, C-9a, C-13a, C-18a), 137.91 (dd, (C -7, P) = 8.4 Hz, ⁵ J (C-7, P) = 2.3 Hz, C-7, C-16), 141.42 (s, C-6a, C-7a, C-15a, C-16a), 146.60 (s, C-5a, C-8a, C-14a, C-17a).
³¹ P-NMR (202 MHz, D ₂ O): δ = -2.99 (s, 2P, OP (O) (OH) OLi).
IR: (cm ^-1 ) = 3048 (aryl-CH), 2937 (CH), 2866 (CH), 1559 (aryl-CC), 1507 (aryl-CC), 1458 (CH), 1282 (P = O) , 1241 (PO aryl).

Table 1 High resolution ESI mass spectrum of 25

A2E 11. Complexation studies:

A2E

Tabelle 2

• T = 298 K
• Verhältnis Wirt/Gast = 1.516 (berechnet aus der A2E-Konzentration und dem Integralverhältnis aus dem ¹H-NMR-Spektrum)

To dissolve the A2E in CD ₃ OD / D ₂ O (3: 1, V: V), a defined amount of a stock solution of the host 3b is added in the same solvent mixture and mixed with CD ₃ OD / D ₂ O (3: 1, V: V) to approx. 0.5 mL total volume (exact volume and concentration data can be found in Table 2). In an analogous manner four further solutions are prepared, each differing in their concentration by a factor of 2.
V _A2E : Volume of A2E stock solution in CD ₃ OD / D ₂ O (3: 1, V: V)
V ₂₅ : volume of host stock solution 25 in CD ₃ OD / D ₂ O (3: 1, V: V)
V _tot : total volume of the sample
δ ₀ : chemical shift of the signals of the free A2E
δ _obs : chemical shift of A2E signals in complex with host compound 25
K _a : association constant
Δδ _max : maximum complex-induced shift
Δδ _obs : observed complex-induced shift
Δδ _max , above: maximum complex-induced shift calculated with Equation 1
[3b]: concentration of host compound 25

Table 2

• T = 298K
• Ratio host / guest = 1.516 (calculated from the A2E concentration and the integral ratio from the ¹ H-NMR spectrum)

The dependencies of the complex-induced upfield shifts Δδ of the protons 13 'and 15' of A2E on the receptor concentration as well as the maximum complex-induced upfield shifts are in the 9a . 9b and 9c shown.

The Δδ _max value and the association constant K _{a of} the protons 13 'and 15' could be determined by nonlinear regression.

The Δδ and Δδ _{max of} the proton 15 'of the A2E were used to calculate the corresponding Δδ _max values from the Δδ values of the remaining protons.

The results of the evaluation of the ¹ H-NMR dilution titration (T = 298 K) of the complex of A2E and the compound 25 in CD ₃ OD / D ₂ O (3: 1, V: V) are shown in Tab.

Table 3

[Figure legends]

1 : Schematic representation of pressure-area isotherms for various alkylpyridinium iodides (10 ^-4 M) on the Langmuir film scale. 0.13 equivalents of the receptor 6 are embedded in a stearic acid monolayer. Alkylpyridinium iodides used: Nicotinamide 26, Cosover salt 27, N-methyl pyrazinium 28

2 : Schematic representation of pressure-area isotherms for different concentrations of A2E on the Langmuir film scale. 0.13 equivalents of the receptor 6 are embedded in the stearic acid monolayer. The A-range is opposite 1 extended: it is in 3 38 A ² compared to 32 A ² in 2 ,

3 : Schematic representation of the binding process of calixarenes: The receptor molecules organize themselves in the fluid monolayer and draw A2E into their calixarene tetraphosphonate cavities.

4 : Energy-minimized structure of tetraphosphonate 6 in its complex with A2E: Monte Carlo simulation in water (MacroModel 7.0, OPLS-AA, 3,000 steps).

5 : NMR Titration Curve for the Compound Formation between Clips 22a and A2E: Upfield Shift of the Pyridinium N Atom Ortho-Standing Proton.

6 Pressure-area plots on the Langmuir film scale in the complexation of A2E by compound 22a embedded in stearic acid (S). 2 eq. = 2 equivalents

7 Schematic representation of the binding process of the clip molecules: Since the highly charged head groups, ie the phosphonates, submerge into the aqueous phase, the sidewalls of the receptor are preferably directed upwards to ensure maximum van der Waals interactions. This prevents the uptake of equivalent amounts of guest molecules, since the host is closed to the aqueous phase.

8th Energy-minimized structure of compound 22a in its complex with A2E: Monte Carlo simulation in water (MacroModel 7.0, Amber *, 3,000 steps).

9a Dependence of the complex-induced upfield shift Δδ on the receptor concentration for the proton 15 'in the complex of compound 25 with A2E in CD ₃ OD / D ₂ O (3: 1, V: V)

9b Dependence of the complex-induced upfield shift Δδ on the receptor concentration for the proton 13 'of A2E in the complex of clamp 3b with A2E in CD ₃ OD / D ₂ O (3: 1, V: V)

9c Maximum complex-induced upfield shifts of A2E in complex with compound 25 in CD ₃ OD / D ₂ O (3: 1, V: V)

10 Energy minimum structure of compound 25 in its complex with A2E calculated by a Monte Carlo simulation (MacroModel 7.0, Amber *, 3000 steps).

Claims (10)

A compound of the formula

where A = no atom or -CH ₂ -; X = O, S; n = 4-8; R1 = H; alkyl; wherein alkyl is a group of 4 to 20 carbon atoms which is linear or branched; Heteroalkyl, wherein heteroalkyl is a radical having 4 to 20 carbon atoms, wherein up to 5 carbon atoms are replaced by heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur, phosphorus; - (C _p H _2p- O) _x H, - (C _p H _2p -O) _x C _p H _{2p + 1} , wherein p is a natural number from 1 to 4 and x is a natural number from 1 to 10; - (CH ₂ ) _y COO ^- , - (CH _z ) _y SO ₃ ^- , - (CH _z ) _y PO ₃ ^2- , wherein y is a natural number from 1 to 10; - (C _z H _2z- O) _m -C _z H _2z -COO ^- , - (C _z H _2z -O) _m -C _z N _2z -SO ₃ ^- , - (C _z N _2z O) _m -C _z H _2z -PO ₃ ^-2 , wherein z and m are independently other natural numbers are from 1 to 4; -CH ₂ - (C _r H _2r ) -COOH, -CH ₂ - (C _r H _2r-2 ) -COOH, -CH ₂ - (C _r H _2r-4 ) -COOH, -CH ₂ - (C _r H _2r-6 ) -COOH, -CH ₂ - (C _r H _2r-8 ) -COOH, where r is a natural number from 10 to 18, an isoprene radical of the empirical formula C ₅ H ₉ , a terpene radical of the general empirical formula C ₁₀ H ₁₉ , C ₁₀ H ₁₉ O, C ₁₀ H ₁₇ , C ₁₀ H ₁₇ O, C ₁₀ H ₁₅ , C ₁₀ H ₁₅ O, C ₁₀ H ₁₃ O, a sesquiterpene radical of the general empirical formula C ₁₅ H ₂₉ , C ₁₅ H ₂₉ O, C ₁₅ N ₂₇ , C ₁₅ H ₂₇ O, C ₁₅ H ₂₅ , C ₁₅ H ₂₅ O, C ₁₅ H ₂₃ , C ₁₅ H ₂₃ O, C ₁₅ H ₁₉ O, a diterpene radical of the general empirical formula C ₂₀ N ₃₉ , C ₂₀ H ₃₉ O, C ₂₀ H ₃₇ , C ₂₀ H ₃₇ O, C ₂₀ N ₃₅ , C ₂₀ H ₃₅ O, C ₂₀ H ₃₃ , C ₂₀ H ₃₃ O, C ₂₀ H ₃₁ , C ₂₀ H ₃₁ O, C ₂₀ H ₂₉ , C ₂₀ H ₂₉ O, C ₂₀ H ₂₇ , C ₂₀ H ₂₇ O, C ₂₀ H ₂₅ O; R2 and R3 independently represent H or OH; R4 = H, linear alkyl having 1 to 20 carbon atoms, for example methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, R5 = O ^-, alkyl, aryl, O-alkyl, O-aryl, O-cycloalkyl, O-heteroalkyl, O-heteroaryl, O-cycloheteroalkyl, wherein -alkyl represents a group of 1 to 10 carbon atoms which is linear or branched, preferably methyl, ethyl, propyl , Isopropyl, 1-butyl, 2-butyl, (2-methyl) propyl, tert-butyl, and alkenyl and alkynyl represent a mono- or polyunsaturated group having 2 to 10 carbon atoms, -cycloalkyl represents a group with 3 to 20 carbon atoms, the heterocyclic groups are a radical having 1 to 20 carbon atoms, wherein up to 5 carbon atoms are replaced by heteroatoms selected from the group nitrogen, oxygen, sulfur, phosphorus, -Aryl for an aromatic radical having 5 to 20 Carbon atoms and heteroaryl is a corresponding aromatic radical in which z u 5 carbon atoms are replaced by heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur, phosphorus, -NH ₂ , -NH (C ₁ -C ₁₀ -alkyl); -N (C ₁ -C ₁₀ alkyl) ₂ , wherein the two alkyl groups are identical or different; and wherein alkyl groups are linear or branched, an isoprene radical of the empirical formula C ₅ H ₉ , a terpene radical of the general empirical formula C ₁₀ H ₁₉ , C ₁₀ H ₁₉ O, C ₁₀ H ₁₇ , C ₁₀ H ₁₇ O, C ₁₀ H ₁₅ , C ₁₀ H ₁₅ O, C ₁₀ H ₁₃ O, a sesquiterpene radical of the general empirical formula C ₁₅ H ₂₉ , C ₁₅ H ₂₉ O, C ₁₅ H ₂₇ , C ₁₅ H ₂₇ O, C ₁₅ H ₂₅ , C ₁₅ H ₂₅ O, C ₁₅ H ₂₃ , C ₁₅ H ₂₃ O, C ₁₅ H ₁₉ O, a diterpene radical of the general empirical formula C ₂₀ H ₃₉ , C ₂₀ H ₃₉ O, C ₂₀ H ₃₇ , C ₂₀ H ₃₇ O, C ₂₀ H ₃₅ , C ₂₀ H ₃₅ O, C ₂₀ H ₃₃ , C ₂₀ H ₃₃ O, C ₂₀ H ₃₁ , C ₂₀ H ₃₁ O, C ₂₀ H ₂₉ , C ₂₀ H ₂₉ O, C ₂₀ H ₂₇ , C ₂₀ H ₂₇ O, C ₂₀ H ₂₅ O, is; and M = Li ⁺ , Na ⁺ , K ⁺ , NH ₄ ⁺ , ⁺ N (C ₁ -C ₄ alkyl) wherein the alkyl groups are the same or different, and in the case where A is not an atom, X is an oxygen atom R1 and R2, R3 and R4 are hydrogen atoms, excluding compounds in which R1 is an n-butyl group, R5 is an ethyl group and M ^{+ is} a Li ⁺ ion. A compound of the formula

wherein R 5 = O ^- , alkyl, aryl, O-alkyl, O-aryl, O-cycloalkyl, O-heteroalkyl, O-heteroaryl, O-cycloheteroalkyl, wherein -alkyl represents a group having 1 to 10 carbon atoms, which are linear or is preferably methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, (2-methyl) propyl, tert-butyl, and alkenyl and alkynyl for a mono- or polyunsaturated group having 2 to 10 carbon atoms, -cycloalkyl represents a group having 3 to 20 carbon atoms, the heterocyclic groups are a radical having 1 to 20 carbon atoms, wherein up to 5 carbon atoms are replaced by heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur, phosphorus, -Aryl is an aromatic radical having 5 to 20 carbon atoms and heteroaryl is a corresponding aromatic radical in which up to 5 carbon atoms are replaced by heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur, phosphorus, -NH ₂ , -NH ( C ₁ -C ₁₀ alkyl); -N (C ₁ -C ₁₀ alkyl) ₂ , wherein the two alkyl groups are identical or different; and wherein alkyl groups are linear or branched, an isoprene radical of the empirical formula C ₅ H ₉ , a terpene radical of the general empirical formula C ₁₀ H ₁₉ , C ₁₀ H ₁₉ O, C ₁₀ H ₁₇ , C ₁₀ H ₁₇ O, C ₁₀ H ₁₅ , C ₁₀ H ₁₅ O, C ₁₀ H ₁₃ O, a sesquiterpene radical of the general empirical formula C ₁₅ H ₂₉ , C ₁₅ H ₂₉ O, C ₁₅ H ₂₇ , C ₁₅ H ₂₇ O, C ₁₅ H ₂₅ , C ₁₅ H ₂₅ O, C ₁₅ H ₂₃ , C ₁₅ H ₂₃ O, C ₁₅ H ₁₉ O, a diterpene radical of the general empirical formula C ₂₀ H ₃₉ , C ₂₀ H ₃₉ O, C ₂₀ H ₃₇ , C ₂₀ H ₃₇ O, C ₂₀ H ₃₅ , C ₂₀ H ₃₅ O, C ₂₀ H ₃₃ , C ₂₀ H ₃₃ O, C ₂₀ H ₃₁ , C ₂₀ H ₃₁ O, C ₂₀ H ₂₉ , C ₂₀ H ₂₉ O, C ₂₀ H ₂₇ , C ₂₀ H ₂₇ O, C ₂₀ H ₂₅ O; M = Li ⁺ , Na ⁺ , K ⁺ , NH ₄ ⁺ , ⁺ N (C ₁ -C ₄ alkyl) wherein the alkyl groups are the same or different and Y and Z are independently selected from the group

and wherein R6 is selected from H, OH, Cl, Br, O- (C ₁ -C ₄ alkyl), N- (C ₁ -C ₄ alkyl), the alkyl groups being identical or different, or the Isoprenrest Empirical formula C ₅ H ₉ , a terpene radical of the general empirical formula C ₁₀ H ₁₉ , C ₁₀ H ₁₉ O, C ₁₀ H ₁₇ , C ₁₀ H ₁₇ O, C ₁₀ H ₁₅ , C ₁₀ H ₁₅ O, C ₁₀ H ₁₃ O, a sesquiterpene radical of the general empirical formula C ₁₅ H ₂₉ , C ₁₅ H ₂₉ O, C ₁₅ H ₂₇ , C ₁₅ H ₂₇ O, C ₁₅ H ₂₅ , C ₁₅ H ₂₅ O, C ₁₅ H ₂₃ , C ₁₅ H ₂₃ O, C ₁₅ H ₁₉ O, a diterpene radical of the general empirical formula C ₂₀ H ₃₉ , C ₂₀ H ₃₉ O, C ₂₀ H ₃₇ , C ₂₀ H ₃₇ O, C ₂₀ H ₃₅ , C ₂₀ H ₃₅ O, C ₂₀ H ₃₃ , C ₂₀ H ₃₃ O, C ₂₀ H ₃₁ , C ₂₀ H ₃₁ O, C ₂₀ H ₂₉ , C ₂₀ H ₂₉ O, C ₂₀ H ₂₇ , C ₂₀ H ₂₇ O, C ₂₀ H ₂₅ O; and in the event that Y and Z each form a naphthalene ring with one of the two bicyclo- [2.2.1] -hept-2-ene groups, excluding compounds in which R5 represents a methyl group and M ⁺ a lithium ion or a tetra-n-butylammonium ion. Process for the preparation of compounds according to claim 2, wherein R5 represents an alkyl group or a terpene residue through the steps: a) Reaction of POCl3 with one equivalent a tertiary Amines and one equivalent an alkyl or terpene alcohol in a polar aprotic solvent, b) Add another equivalent of the tertiary Amines and of 0.37 equivalents a hydroquinone precursor, c) stir for 1 to 2 hours, d) addition of 2% to 5% aqueous Acid, e) Addition of a nonpolar aprotic solvent, f) Stir for 10 to 15 hours at room temperature, g) purification of the final product. Method according to claim 3, characterized that the tertiary Amine selected is from the group triethylamine, diisopropylamine, pyridine. Method according to one of claims 3 to 4, characterized that the polar aprotic solvent selected is from the group tetrahydrofuran, diethyl ether, diisopropyl ether, Pyridine. Method according to one of claims 3 to 5, characterized that the nonpolar aprotic solvent selected is from the group n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, Methylcyclopentane, methylcyclohexane, methylcycloheptane. Use of compounds of the formula

where A = no atom or -CH ₂ -; X = O, S; n = 4-8; R1 = H; alkyl; wherein alkyl is a group of 4 to 20 carbon atoms which is linear or branched; Heteroalkyl, wherein heteroalkyl is a radical having 4 to 20 carbon atoms, wherein up to 5 carbon atoms are replaced by heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur, phosphorus; - (C _p H _2p -O) _x H, - (C _p H _2p O) _x -C _p H _{2p + 1} , wherein p is a natural number from 1 to 4 and x is a natural number from 1 to 10; - (CH ₂ ) _y COO ^- , - (CH ₂ ) _y SO ₃ ^- , - (CH ₂ ) _y PO ₃ ² , wherein y is a natural number from 1 to 10; - (C _z H _2z O) _m -C _z H _2z -COO ^- , - (C _z H _2z O) _m -C _z H _2z SO ₃ ^- , - (C _z H _2z O) _m -C _z H _2z -PO ₃ ^2- wherein z and m are independently natural numbers from 1 to 4; -CH _z - (C _z H _2z) -COOH, -CH _z - (C _z H _2r-2) COOH, -CH _z - (C _z H _2r-4) -COOH, -CH _z - (C _z H _2r-6 ) -COOH, -CH _z - (C _z H _2r-8 ) -COOH, where r is a natural number from 10 to 18, an isoprene radical of the empirical formula C ₅ H ₉ , a terpene radical of the general empirical formula C ₁₀ H ₁₉ , C ₁₀ H ₁₉ O, C ₁₀ H ₁₇ , C ₁₀ H ₁₇ O, C ₁₀ H ₁₅ , C ₁₀ H ₁₅ O, C ₁₀ H ₁₃ O, a sesquiterpene radical of the general empirical formula C ₁₅ H ₂₉ , C ₁₅ H ₂₉ O, C ₁₅ H ₂₇ , C ₁₅ H ₂₇ O, C ₁₅ H ₂₅ , C ₁₅ H ₂₅ O, C ₁₅ H ₂₃ , C ₁₅ H ₂₃ O, C ₁₅ H ₁₉ O, a diterpene radical of the general empirical formula C ₂₀ H ₃₉ , C ₂₀ H ₃₉ O, C ₂₀ H ₃₇ , C ₂₀ H ₃₇ O, C ₂₀ H ₃₅ , C ₂₀ H ₃₅ O, C ₂₀ H ₃₃ , C ₂₀ H ₃₃ O, C ₂₀ H ₃₁ , C ₂₀ H ₃₁ O, C ₂₀ H ₂₉ , C ₂₀ H ₂₉ O, C ₂₀ H ₂₇ , C ₂₀ H ₂₇ O, C ₂₀ H ₂₅ O; R2 and R3 independently represent H or OH; R 4 = H, linear alkyl having 1 to 20 carbon atoms, for example methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, R 5 = O-, alkyl, aryl, O-alkyl, O-aryl, O-cycloalkyl, O-heteroalkyl, O-heteroaryl, O-cycloheteroalkyl, wherein -alkyl represents a group of 1 to 10 carbon atoms which is linear or branched, preferably methyl, ethyl, propyl , Isopropyl, 1-butyl, 2-butyl, (2-methyl) propyl, tert-butyl, and alkenyl and alkynyl represent a mono- or polyunsaturated group having 2 to 10 carbon atoms, -cycloalkyl represents a group with 3 to 20 carbon atoms, the heterocyclic groups are a radical having 1 to 20 carbon atoms, wherein up to 5 carbon atoms are replaced by heteroatoms selected from the group nitrogen, oxygen, sulfur, phosphorus, -Aryl for an aromatic radical having 5 to 20 Carbon atoms and heteroaryl is a corresponding aromatic radical in which up to 5 Carbon atoms are replaced by heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur, phosphorus, -NH ₂ , -NH (C ₁ -C ₁₀ -alkyl); -N (C ₁ -C ₁₀ alkyl) ₂ , wherein the two alkyl groups are identical or different; and wherein alkyl groups are linear or branched, an isoprene radical of the empirical formula C ₅ H ₉ , a terpene radical of the general empirical formula C ₁₀ H ₁₉ , C ₁₀ H ₁₉ O, C ₁₀ H ₁₇ , C ₁₀ H ₁₇ O, C ₁₀ H ₁₅ , C ₁₀ H ₁₅ O, C ₁₀ H ₁₃ O, a sesquiterpene radical of the general empirical formula C ₁₅ H ₂₉ , C ₁₅ H ₂₉ O, C ₁₅ H ₂₇ , C ₁₅ H ₂₇ O, C ₁₅ H ₂₅ , C ₁₅ N ₂₅ O, C ₁₅ H ₂₃ , C ₁₅ N ₂₃ O, C ₁₅ H ₁₉ O, a diterpene radical of the general empirical formula C ₂₀ N ₃₉ , C ₂₀ H ₃₉ O, C ₂₀ H ₃₇ , C ₂₀ N ₃₇ O, C ₂₀ H ₃₅ , C ₂₀ H ₃₅ O, C ₂₀ H ₃₃ , C ₂₀ H ₃₃ O, C ₂₀ H ₃₁ , C ₂₀ H ₃₁ O, C ₂₀ H ₂₉ , C ₂₀ H ₂₉ O, C ₂₀ H ₂₇ , C ₂₀ H ₂₇ O, C ₂₀ H ₂₅ O, is; and M = Li ⁺ , Na ⁺ , K ⁺ , NH ₄ ⁺ , ⁺ N (C ₁ -C ₄ -alkyl) wherein the alkyl groups are the same or different and their pharmaceutically acceptable esters and / or amides for the manufacture of a medicament. Use of compounds according to claim 7 and their pharmaceutically acceptable esters and / or amides for the preparation a drug for the therapy, diagnosis and prophylaxis of the dry age-related macular degeneration. Use of compounds of the formula

wherein R 5 = O ^- , alkyl, aryl, O-alkyl, O-aryl, O-cycloalkyl, O-heteroalkyl, O-heteroaryl, O-cycloheteroalkyl, wherein -alkyl represents a group having 1 to 10 carbon atoms, which are linear or is preferably methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, (2-methyl) propyl, tert-butyl, and alkenyl and alkynyl for a mono- or polyunsaturated group having 2 to 10 carbon atoms, -cycloalkyl represents a group having 3 to 20 carbon atoms, the heterocyclic groups are a radical having 1 to 20 carbon atoms, wherein up to 5 carbon atoms are replaced by heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur, phosphorus, -Aryl is an aromatic radical having 5 to 20 carbon atoms and heteroaryl is a corresponding aromatic radical in which up to 5 carbon atoms are replaced by heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur, phosphorus, -NH ₂ , -NH ( C ₁ -C ₁₀ alkyl); -N (C ₁ -C ₁₀ alkyl) ₂ , wherein the two alkyl groups are identical or different; and wherein alkyl groups are linear or branched, an isoprene radical of the empirical formula C ₅ H ₉ , a terpene radical of the general empirical formula C ₁₀ H ₁₉ , C ₁₀ H ₁₉ O, C ₁₀ H ₁₇ , C ₁₀ H ₁₇ O, C ₁₀ H ₁₅ , C ₁₀ H ₁₅ O, C ₁₀ H ₁₃ O, a sesquiterpene radical of the general empirical formula C ₁₅ H ₂₉ , C ₁₅ H ₂₉ O, C ₁₅ H ₂₇ , C ₁₅ H ₂₇ O, C ₁₅ H ₂₅ , C ₁₅ H ₂₅ O, C ₁₅ H ₂₃ , C ₁₅ H ₂₃ O, C ₁₅ H ₁₉ O, a diterpene radical of the general empirical formula C ₂₀ H ₃₉ , C ₂₀ H ₃₉ O, C ₂₀ H ₃₇ , C ₂₀ H ₃₇ O, C ₂₀ H ₃₅ , C ₂₀ H ₃₅ O, C ₂₀ H ₃₃ , C ₂₀ H ₃₃ O, C ₂₀ H ₃₁ , C ₂₀ H ₃₁ O, C ₂₀ H ₂₉ , C ₂₀ H ₂₉ O, C ₂₀ H ₂₇ , C ₂₀ H ₂₇ O, C ₂₀ H ₂₅ O, is; M = Li ⁺ , Na ⁺ , K ⁺ , NH ₄ ⁺ , ⁺ N (C ₁ -C ₄ alkyl) wherein the alkyl groups are the same or different and Y and Z are independently selected from the group

and wherein wherein R6 is selected from H, OH, Cl, Br, O- (C ₁ -C ₄ alkyl), N- (C ₁ -C ₄ alkyl), the alkyl groups being identical or different, or a Isoprenrest the empirical formula C ₅ H ₉ , a terpene radical of the general empirical formula C ₁₀ H ₁₉ , C ₁₀ H ₁₉ O, C ₁₀ H ₁₇ , C ₁₀ H ₁₇ O, C ₁₀ H ₁₅ , C ₁₀ H ₁₅ O, C ₁₀ H ₁₃ O , a sesquiterpene radical of the general empirical formula C ₁₅ H ₂₉ , C ₁₅ H ₂₉ O, C ₁₅ H ₂₇ , C ₁₅ H ₂₇ O, C ₁₅ H ₂₅ , C ₁₅ H ₂₅ O, C ₁₅ H ₂₃ , C ₁₅ H ₂₃ O, C ₁₅ H ₁₉ O, a diterpene radical of the general empirical formula C ₂₀ H ₃₉ , C ₂₀ H ₃₉ O, C ₂₀ H ₃₇ , C ₂₀ H ₃₇ O, C ₂₀ H ₃₅ , C ₂₀ H ₃₅ O, C ₂₀ H ₃₃ , C ₂₀ H ₃₃ O, C ₂₀ H ₃₁ , C ₂₀ H ₃₁ O, C ₂₀ H ₂₉ , C ₂₀ H ₂₉ O, C ₂₀ H ₂₇ , C ₂₀ H ₂₇ O, C ₂₀ H ₂₅ O; and their pharmaceutically acceptable esters and / or amides for the manufacture of a medicament. Use of compounds according to claim 9 and their pharmaceutically acceptable esters and / or amides for the preparation a drug for the therapy, diagnosis and prophylaxis of the dry age-related macular degeneration.