Agent containing malonic acid or its derivatives for restoring metal homeostasis

Abstract

The present invention relates to malonic acid and derivatives thereof according to the below formula (I) for use as drugs for promoting metallothionein biosynthesis in a patient: (I) wherein X and Y each independently is selected from O-M+, -OR1 and -NR2R3, wherein M+ is selected from monovalent of polyvalent metal anions and R1, R2 and R3 each indpendently is selected from hydrogen and saturated or unsaturated, unbranched, branched or cyclic hydrocarbon groups with 1 to 25 carbon atoms, wherein one or more carbon atoms are optionally replaced with O or N, and wherein R2 and R3 are optionally bonded to each other and form a heterocyclic hydrocarbon group together with the nitrogen atom. The invention also relates to pharmaceutical compositions that contain a compound of formula (I).

Description

[0001] AGENTS CONTAINING MALONIC ACID OR ITS DERIVATIVES FOR RESTORING METAL HOMEOSTASIS

[0002] The present invention relates to novel pharmaceuticals for restoring metal homeostasis, which are potential active agents against neurodegenerative diseases.

[0003] STATE OF THE ART

[0004] Neurological diseases such as Alzheimer's, Parkinson's, Huntington's, and prion diseases are age-related neuronal disorders characterized by an accumulation of misfolded proteins and neuronal cell death. All of these diseases are currently among the greatest challenges in medicine and occur worldwide.

[0005] Alzheimer's disease is the most common of these diseases, with nearly 50 million cases in 2020. Every three seconds, a person on this planet develops dementia, with approximately 70% of these cases being confirmed as Alzheimer's. Generally speaking, Alzheimer's disease is a type of dementia that affects the patient's thinking, behavior, and memory. The disease progresses moderately and diminishes the neurons connected to the learning part of the cerebrum. All current approaches to treating Alzheimer's disease provide only temporary symptomatic relief and do not inhibit or reverse the underlying disease mechanisms, as they were primarily developed based on the amyloid cascade hypothesis, which has not led to a satisfactory cure.

[0006] The second major neurological disorder of our time is Parkinson's disease, a progressive neurological disorder caused by the degeneration of dopamine receptors in the basal ganglia. It is the most common form of Parkinsonism, a group of disorders characterized by two of the four main signs: bradykinesia, rigidity, tremors, and postural instability. According to the Parkinson Disease Foundation, around 10 million people worldwide suffer from Parkinson's disease. This makes Parkinson's disease the second most common neurodegenerative disorder, affecting approximately 1.2% of the world's population over the age of 70. As with Alzheimer's disease, there are currently no available treatments capable of curing Parkinson's disease. The current goal of therapy is therefore to alleviate symptoms.More than 40 years after its introduction, levodopa (L-DOPA, L-3,4-dihydroxyphenylalanine) of the formula below remains the most effective therapy for reducing the symptoms associated with Parkinson's disease.

[0007] L-3,4-Dihydroxyphenylalanine

[0008] WO 2017 / 142855 A1 discloses derivatives of itaconic acid and malonic acid according to the following formulas I and II, respectively: where R 1 to R 6each independently represents hydrogen or optionally substituted alkyl, alkenyl, or alkynyl groups having any number of carbon atoms, whose optional substituents, in addition to hydroxy, can also include a wide range of (hetero)aromatic hydrocarbons. These definitions also include derivatives of succinic acid and maleic or fumaric acid, with itaconic acid (also known as methylenesuccinic acid), malonic acid, its dimethyl esters, as well as fumaric acid and 2-methylfumaric acid (mesaconic acid) being preferred.

[0009] These compounds are said to act as immunomodulators and, as such, can be used against a wide range of diseases, including neurodegenerative disorders such as Alzheimer's, Parkinson's, Huntington's, and prion diseases. In preferred embodiments, the compounds are said to inhibit the expression of various proteins. However, in the examples, only free malonic and itaconic acid were investigated for their effect as inhibitors of succinate dehydrogenase, which is said to be based on their structural similarity to their substrate, succinic acid. Potential efficacy in the treatment of neurodegenerative diseases cannot be derived from this.

[0010] To overcome this lack of treatment strategies and to find alternative therapeutic options, research has been conducted to find new targets for the treatment of these diseases. In 2008, Bush and Tanzi proposed in their "metal hypothesis of Alzheimer's disease" (A. Bush and RE Tanzi, "Therapeutics for Alzheimer's disease based on the metal hypothesis", Neurotherapeutics 5(3), 421-432 (2008)) that a breakdown of metal homeostasis is the main cause of neurodegenerative diseases, and that drugs that restore metal homeostasis could therefore provide promising new therapeutic strategies. Subsequently, metal chelators have repeatedly been proposed as potential agents for the treatment of neurodegenerative diseases, including by M. Tosato and A.Di Marco, "Metal Chelation Therapy and Parkinson's Disease: A Critical Review on the Thermodynamics of Complex Formation between Relevant Metal Ions and Promising or Established Drugs," Biomolecules 9(7), 269 (2019), which lists around 800 substances that have been investigated in recent years for the treatment of Parkinson's disease, among which malonic acid is mentioned as a metal chelator; and Acevedo et al., "Redox active metals in neurodegenerative diseases," Biol. Inorg. Chem. 24(8), 1141-1157 (2019), which reveal metal chelators, among other things, as agents for preventing the misfolding and aggregation of ß-amyloid ("Aß") and α-synuclein, which are among the main causes of Alzheimer's and Parkinson's diseases, respectively. A similar conclusion is drawn in a review by PA Adlard and AI Bush ("Metals and Alzheimer's Disease: How Far Have We Come in the Clinic?", J. Alzheimer's Dis. 62(3), 1369-1379 (2018)) for the chelating agent clioquinol (5-chloro-7-iodoquinolin-8-ol):In recent years, the present inventors' research group developed a new screening assay using transgenic strains of Caenorhabditis elegans, a nematode from the rhabditid group, based on this new strategy of restoring metal homeostasis, specifically by upregulating the body's own metallothionein biosynthesis; see Pretsch et al., "Prolongation of metallothionein induction combats Aß and α-synuclein toxicity in aged transgenic Caenorhabditis elegans," Sci. Rep. 10, 11707 (July 16, 2020). It describes that by prolonging the body's own biosynthesis of metallothioneins, i.e. cytoplasmic proteins that bind heavy metals, the lifespan of corresponding nematode larvae could be significantly extended, as this suppresses the expression of toxic ß-amyloid ("Aß") and α-synuclein.Emodin (1,3,8-trihydroxy-6-methylanthracene-9,10-dione) was identified as one of the agents that achieved this.

[0011] In a later study (D. Pretsch, "Abnormal metal homeostasis as a common drug target to combat neurodegenerative diseases", Neural Regen. Res. 16(12), 2388-2389 (2021 )), it is further stated that not only the effect of emodin, but also that of clioquinol cannot be based (solely) on their chelating properties, since other efficient (especially copper) chelators such as D-penicillamine (2-amino-3-mercapto-3-methylbutyric acid) and diethyldithiocarbamate

[0012] D-penicillamine (sodium) diethyldithiocarbamate failed to treat Parkinson's disease in a mouse test model. While D-penicillamine showed no neuroprotective effect in this study, the presence of diethyldithiocarbamate actually caused increased neurotoxicity. The mechanism of action of emodin and clioquinol, which leads to a prolongation of the body's own metallothionein biosynthesis in the C. egans nematode assay, must therefore be independent of the binding of heavy metal ions through chelation.

[0013] Hama et al., "Malonic acid suppresses lipopolysaccharide-induced BV2 microglia cell activation by inhibiting the p38 MAPK / NF-KB pathway", Anim. Cells Syst. (Seoul) 25(2), 110-118 (2021 ), also reveal malonic acid as a potential treatment for Alzheimer's and Parkinson's diseases, but due to its ability to inhibit the expression of various cytokines, such as interleukins, which can subsequently inhibit various signal transduction pathways involved in the development of inflammation (e.g., the MAPK pathway).

[0014] Against this background, the aim of the invention was to use the new assay format based on C. elegans as a model organism to identify chemical compounds that are suitable as agents for promoting the body's own metallothionein biosynthesis and could thus be new potential active substances against neurodegenerative diseases.

[0015] SUMMARY OF THE INVENTION

[0016] This object is achieved by the present invention by providing malonic acid and derivatives thereof of the following formula (I) for use as a medicament for promoting metallothionein biosynthesis in a patient: where X and Y each independently consist of -OM + , -ORi and -NR2R3, wherein M + is selected from mono- or polyvalent metal anions and Ri, R2 and R3 are each independently selected from hydrogen and saturated or unsaturated, unbranched, branched or cyclic hydrocarbon radicals having 1 to 25 carbon atoms, wherein one or more carbon atoms are optionally replaced by O or N, wherein R2 and R3 are optionally joined to one another and together with the nitrogen atom form a heterocyclic hydrocarbon radical.

[0017] Using their recently developed, above-mentioned assay format, the inventors have surprisingly discovered that both malonic acid itself and various derivatives of formula (I), namely esters, amides, and salts thereof, are effective as agents for promoting metallothionein biosynthesis and thereby restoring metal homeostasis in the model organism C. elegans and could therefore likely be suitable as active ingredients for combating neurodegenerative diseases. Although unsubstituted malonic acid has been frequently disclosed as an agent for treating neurodegenerative diseases due to its chelating properties, it was nevertheless unpredictable whether it—or any of its derivatives—would exhibit a positive effect on promoting metallothionein biosynthesis in cells in the nematode assay.This result was particularly surprising for the longer-chain derivatives, some of which are even substituted with aromatics, which have relatively bulky structures, which significantly reduces their suitability for the formation of metal chelates due to limited accessibility of the free electron pairs of the central nucleophilic group -C(=O)-CH2-C(=O)-.

[0018] However, this efficacy was only confirmed for malonic acid derivatives in which the malonic acid moiety at the central α-carbon atom is unsubstituted, which is demonstrated by the later examples and comparative examples, was also surprising, and clearly contradicts the idea that the reason for the efficacy in this assay is merely the ability of the compounds to chelate the metal ions. This is also demonstrated by the inactivity of compound (108), N-(3-aminopropyl)-N'-tetrahydroquinolinemalonic acid diamide, in comparative example 8, although all other aromatic-substituted compounds gave positive results. In a group of embodiments that are all salts of malonic acid, at least one of X and Y in formula (I) is -OM + , but preferably both X and Y stand for -OM + , where M +each independently selected from mono- and polyvalent metal anions and M + preferably represents an alkali metal or alkaline earth metal ion, more preferably an alkali metal ion. Both those with only one carboxylate ion and those in which both carboxyl groups are present as ionized carboxylate have proven to be correspondingly effective malonic acid salts. However, the preparation process for the latter is somewhat simpler, which is why they are currently preferred according to the invention.

[0019] Both for simple malonic acid salts, in which only one of X and Y is -OM +and the other represents an ester group -OR1 or amide group -NR2R3, as well as in diamides, diesters and esteramides in which X and Y both represent -OR1 or -NR2R3, Ri, R2 and R3 are preferably each independently selected from hydrogen and saturated or unsaturated, unbranched, branched or cyclic hydrocarbon radicals having 1 to 15 carbon atoms, more preferably from hydrogen and hydrocarbon radicals having 1 to 10 carbon atoms, since a lower molecular weight of the compounds reduces the amounts of active ingredient to be administered.

[0020] In particular, the compound according to the present invention is selected from the following: malonic acid (1), malonic acid diamide (2), disodium malonate (3), malonic acid dimethyl ester (4), malonic acid methyl ester potassium salt (5), malonic acid methyl ester amide (6), N-(3-aminopropyl)malonic acid amide (7), malonic acid adamantane-1-yl ester (8), malonic acid adamantane-1-yl ethyl ester (9), malonic acid adamantane-1-yl ester N-(3-aminopropyl)-N-methyl amide (10), malonic acid adamantane-1-yl ester N-(3-aminopropyl)-N-methyl amide (11), malonic acid adamantane-1-yl ester piperazinamide (12), malonic acid adamantane-1-yl ester 4-(4-aminobutyryl)piperazinamide (13), malonic acid adamantane-1-yl ester- 4-aminopiperidinamide (14), adamantan-1-yl malonate (4-(4-aminobutyryl)-amino)piperidinamide (15), methyl malonate-N-(adamantan-1-yl)amide (16), N-(adamantan-1-yl)malonamide (17), N-adamantan-1-yl-N'-(3-aminopropyl)malon- acid diamide (18), N-adamantan-1-yl-N'-(3-aminopropyl)-N'-methylmalonic acid diamide (19),N-Adamantan-1 -yl-N'-piperazinmalonsäurediamid (20), N-Adamantan-1 -yl-N'-(4- (4-aminobutyryl)piperazin)malonsäurediamid (21 ), N-(3-Aminopropyl)-N'-morpholin- malonsäurediamid (22), N-(3-Aminopropyl)-N'-piperidinmalonsäurediamid (23), N-(3- Aminopropyl)-N'-decahydrochinolinmalonsäurediamid (24), N-(3-Aminopropyl)-N'-de- cahydroisochinolinmalonsäurediamid (25), N-(3-Aminopropyl)-N'-(6,6-dimethylbicyc- lo[3.1 .1 ]heptan-2-ylmethyl)malonsäurediamid (26), Malonsäureadamantan-1 -ylester- N-(3-dimethylaminopropyl)amid (27), Malonsäureadamantan-1 -ylester-N-(3-morpholi- nopropyl)amid (28), Malonsäureadamantan-1 -ylester-4-(3-trifluormethylbenzyl)pipera- zinamid (29), Malonsäureadamantan-1 -ylester-4-(3-fluorbenzyl)piperazinamid (30), Malonsäureadamantan-1 -ylester-4-(2-methoxyphenyl)piperazinamid (31 ), Malonsäu- re-N-(3,5-dimethyl)adamantan-1 -ylamid (32), N-(3,5-Dimethyladamantan-1 -yl)-N'-(3- aminopropyl)malonsäurediamid (33), N-(3,5-Dimethyladamantan-1 -yl)-N'-(3-morpholi- nopropyl)malonsäurediamid (34), N-(3,5-Dimethyladamantan-1 -yl)-N'-piperazinmalon- säurediamid (35), N-(3,5-Dimethyladamantan-1 -yl)-N'-4-(3-trifluormethylbenzyl)pipe- razinmalonsäurediamid (36), N-(3,5-Dimethyladamantan-1 -yl)-N'-4-(3-fluorbenzyl)- piperazinmalonsäurediamid (37), N-(3,5-Dimethyladamantan-1 -yl)-N'-4-(2-methoxy- phenyl)piperazinmalonsäurediamid (38), N-(3,5-Dimethyladamantan-1 -yl)-N'-4-(4- methoxyphenyl)piperazinmalonsäurediamid (39), N-(3,5-Dimethyladamantan-1 -yl)-N'- 4-(2,4-dimethoxyphenyl)piperazinmalonsäurediamid (40) und N-(3,5-Dimethylada- mantan-1 -yl)-N'-4-(2-morpholino-2-oxoethyl)piperazinmalonsäurediamid (41 ).,

[0021] In preferred embodiments, the promotion of metallothionein biosynthesis in a patient serves to restore metal homeostasis and thus to treat a neurodegenerative disease of the patient, which is particularly preferably selected from Alzheimer's disease, Parkinson's disease, and Huntington's disease, and in particular Alzheimer's disease, since according to the above-cited "metal hypothesis," this disease is likely to be most effectively treatable by restoring metal homeostasis, which, in turn, according to Pretsch et al. (see above), should be achievable by promoting metallothionein biosynthesis.

[0022] In a second aspect, the invention accordingly also provides a pharmaceutical composition for the therapeutic treatment of the human or animal body by promoting metallothionein biosynthesis in a patient, which comprises a compound as defined above for use according to the first aspect and at least one pharmaceutically acceptable excipient and optionally further comprises one or more further pharmaceutically acceptable ingredients, wherein the composition preferably also serves for the treatment of a neurodegenerative disease, more preferably Alzheimer's or Parkinson's disease, in particular Alzheimer's disease.

[0023] EXAMPLES

[0024] The present invention will now be described in more detail with reference to examples and comparative examples which serve to illustrate the invention and are not to be construed as limiting the invention.

[0025] The compounds of the examples and comparative examples described below were either purchased commercially or prepared in the manner described in the synthesis examples and subsequently tested for their suitability as active substances against neurodegenerative diseases using the aforementioned assay format disclosed in "Pretsch et al.".

[0026] The syntheses of the test compounds were carried out using standard reaction sequences, with all starting materials being commercially available or having been previously synthesized from commercially available reagents that were used in the syntheses without further purification. Characterizations were carried out using 1 H-NMR spectra recorded using a Bruker Avance AV400 spectrometer at 400 MHz and mass spectra recorded using a Shimadzu LCMS-8040.

[0027] Specifically, the following compounds were tested for their efficacy in this first series of tests. Further tests are currently being conducted by the inventors.

[0028] As examples of the present invention, the following have been tested so far: Example 1 : Malonic acid (1 ) Example 2: Malonic acid diamide (Malonamide) (2)

[0029] Example 3: Disodium malonate (3) Example 4: Malonic acid dimethyl ester (4)

[0030] Example 5: Malonic acid methyl ester potassium salt (potassium methylmalonate) (5)

[0031] Example 7: N-(3-Aminopropyl)malonic acid amide (7)

[0032] Example 8: Malonic acid adamantan-1-yl ester (malonic acid adamantyl ester) (8)

[0033] Example 9: Malonic acid adamantan-l -ylethyl ester (Malonic acid adamantylethyl ester) (9) Example 10: Malonic acid adamantane-1-yl ester-N-(3-aminopropyl)amide (10)

[0034] Example 11 : Malonic acid adamantan-1 -yl ester-N-(3-aminopropyl)-N-methylamide (11 )

[0035] Example 12: Malonic acid adamantane-1-yl ester piperazinamide (12)

[0036] Example 13: Malonic acid adamantane-1-yl ester-4-(4-aminobutyryl)piperazinamide (13)

[0037] Example 14: Malonic acid adamantane-1-yl ester-4-aminopiperidine amide (14) Example 15: Malonic acid adamantane-1-yl ester-(4-(4-aminobutyryl)amino)piperidine amide

[0038] (15) Example 16: Malonic acid methyl ester-N-(adamantan-1-yl)amide (16)

[0039] Example 17: N-(Adamantan-1-yl)malonic acid amide (17)

[0040] Example 18: N-Adamantane-1-yl-N'-(3-aminopropyl)malonic acid diamide (18)

[0041] Example 19: N-Adamantane-1-yl-N'-(3-aminopropyl)-N'-methylmalonic acid diamide (19)

[0042] Example 20: N-Adamantane-1-yl-N'-piperazinemalonic acid diamide (20) Example 21: N-Adamantane-1-yl-N'-(4-(4-aminobutyryl)piperazine)malonic acid diamide

[0043] (21 ) Example 22: N-(3-Aminopropyl)-N'-morpholinemalonic acid diamide (22)

[0044] Example 23: N-(3-Aminopropyl)-N'-piperidinemalonic acid diamide (23)

[0045] Example 24: N-(3-Aminopropyl)-N'-decahydroquinolinemalonic acid diamide (24)

[0046] Example 25: N-(3-Aminopropyl)-N'-decahydroisoquinolinemalonic acid diamide (25) Example 26: N-(3-Aminopropyl)-N'-(6,6-dimethylbicyclo[3.1 .1]heptan-2-ylmethyl)-malonic acid diamide (N-(3-Aminopropyl)-N'-(pinan-10-yl)malonic acid diamide) (26) Example 27: Malonic acid adamantane-1-yl ester N-(3-dimethylaminopropyl)amide (27)

[0047] Example 28: Malonic acid adamantane-1-yl ester N-(3-morpholinopropyl)amide (28)

[0048] Example 29: Malonic acid adamantane-1-yl ester-4-(3-trifluoromethylbenzyl)piperazinamide

[0049] (29) Example 30: Malonic acid adamantane-1-yl ester 4-(3-fluorobenzyl)piperazinamide (30) Example 31 : Malonic acid adamantane-1 -yl ester 4-(2-methoxyphenyl)piperazinamide (31 )

[0050] Example 32: Malonic acid N-(3,5-dimethyl)adamantan-1-ylamide (32) Example 33: N-(3,5-Dimethyladamantan-1-yl)-N'-(3-aminopropyl)malonic acid diamide

[0051] (33)

[0052] Example 34: N-(3,5-Dimethyladamantan-1-yl)-N'-(3-morpholinopropyl)malonic acid-

[0053] Example 35: N-(3,5-Dimethyladamantan-1-yl)-N'-piperazinemalonic acid diamide (35) Example 36: N-(3,5-Dimethyladamantan-1-yl)-N'-4-(3-trifluoromethylbenzyl)piperazine-malonic acid diamide (36)

[0054] Example 37: N-(3,5-Dimethyladamantan-1-yl)-N'-4-(3-fluorobenzyl)piperazinemalonic acid diamide (37)

[0055] Example 38: N-(3,5-Dimethyladamantan-1-yl)-N'-4-(2-methoxyphenyl)piperazinemalonic acid diamide (38)

[0056] Example 39: N-(3,5-Dimethyladamantan-1-yl)-N'-4-(4-methoxyphenyl)piperazinemalonic acid diamide (39) Example 40: N-(3,5-Dimethyladamantan-1-yl)-N'-4-(2,4-dimethoxyphenyl)piperazine- malonic acid diamide (40)

[0057] Example 41 : N-(3,5-Dimethyladamantan-1 -yl)-N'-4-(2-morpholino-2-oxoethyl)piperazinemalonic acid diamide (41 )

[0058] And as comparative examples, the following compounds were examined:

[0059] Comparative Example 1 : Dimethylmalonic acid (101 )

[0060] Comparative Example 2: Methylmalonic acid dimethyl ester (102) Comparative Example 3: 1-Adamantanecarboxylic acid-N-(3-aminopropyl)amide (103)

[0061] Comparative Example 4: 3-Aminopropylcarbamic acid tert-butyl ester (N-Boc-1,3-propanediamine) (104)

[0062] Comparative Example 5: 3-(Methylamino)propylcarbamic acid tert-butyl ester (N-Boc-N'-methyl-1,3-propanediamine) (105)

[0063] Comparative Example 6: 1 -Adamantanol (106) 7: 1 -Adamantanamine (Amantadine) (107) Comparative Example 8: N-(3-Aminopropyl)-N'-tetrahydroquinolinemalonic acid diamide (108)

[0064] Of these, compounds (1 ) to (7) and (101 ) to (107) were obtained from commercial sources and the remaining compounds (8) to (41 ) and (108) were prepared as described below.

[0065] Synthesis example 1

[0066] Preparation of malonic acid adamantan-1-yl ester (8)

[0067] A solution of 1.0 g (6.57 mmol) of adamantan-1-ol and 0.95 g (6.57 mmol) of 2,2-dimethyl-1,3-dioxane-4,6-dione in toluene was heated to reflux for 12 h, after which the reaction mixture was allowed to cool to room temperature. Subsequently, 60 ml of saturated aqueous NaHCO3 solution was slowly added, resulting in phase separation. The toluene phase was discarded, and the aqueous phase was carefully acidified with 100 ml of 1 N HCl. The acidic solution was extracted with dichloromethane, and the organic phase was dried over MgSO4, filtered, and evaporated to dryness to give 1.5 g of the title compound as colorless crystals.

[0068] 1 H NMR (CD3OD): δ = 1.71 (m, 6H, adamantyl), 2.10-2.20 (m, 9H, adamantyl), 3.25 (s, 2H), 4.81 (brs, 1 H). MS (ESI-): m / z (%) 237 (100, [MH]j, 283 (47, [M+HCOO]). Synthesis example 2

[0069] Preparation of malonic acid adamantan-1-ylethyl ester (9)

[0070] (8) (9)

[0071] To a solution of 35 mg of malonic acid adamantane-1-yl ester (8) in 10 ml of ethanol, 2 ml of 4 N HCl in dioxane was added. After stirring at room temperature for 24 h, the reaction mixture was concentrated, and the residue was purified by column chromatography (cyclohexane / ethyl acetate 95:5), yielding the title compound as a colorless liquid (35 mg).

[0072] 1 H NMR (CDCh): ö = 1.25 (t, 3H, J=7.14 Hz), 1.62 (m, 6H), 2.08-2.13 (m, 9H), 3.23 (s, 2H), 4.16 (q, 2H, J=7.14 Hz). MS (ESI+): m / z (%) 267 (13, [M+H] + ), 284 (6, [M+H2O] + ), 289 (100, [M+Na] + ).

[0073] Synthesis example 3

[0074] Preparation of malonic acid adamantane-1-yl ester N-(3-aminopropyl)amide (10) To a solution of 22 mg (0.126 mmol) of 3-aminopropylcarbamic acid tert-butyl ester (N-Boc-1,3-propanediamine) (104), 30 mg (0.126 mmol) of malonic acid amantan-1-yl ester (8) and 45 μl (0.252 mmol) of diisopropylethylamine (DIPEA) in 8 ml of dimethylformamide (DMF) was added 54 mg (0.126 mmol) of (1-cyano-2-ethoxy-2-oxo-ethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU). After stirring for 2 h while warming to room temperature, the reaction mixture was diluted with ethyl acetate, washed with 1 N HCl and saturated aqueous NaHCO3 solution, dried over MgSO4, filtered, and evaporated to dryness. The residue (47 mg) containing the Boc-protected malonic acid adamantane-1-yl ester N-(3-aminopropyl)amide (10a) was used in the next step without further purification.

[0075] MS (ESI+): m / z (%) 395 (100, [M+H] + ), 417 (100, [M+Na] + ), 81 1 (100, [2M+Na] +). The resulting residue was dissolved in 8 ml of dichloromethane, 1.26 ml of 4 N HCl in dioxane was added, and the mixture was stirred at room temperature for 2 h. The volatiles were then removed in vacuo to afford the hydrochloride of the title compound (10) as a yellow oil (34 mg).

[0076] 1 H NMR (CDCh): δ = 1.60-1.72 (m, 10H), 2.10-2.18 (m, 9H), 2.85 (s, 2H), 3.22-3.25 (m, 1H), 3.62-3.70 (m, 2H), 3.75-3.79 (m, 1H). MS (ESI+): m / z (%) 295 (100, [M+H] + ), 589 (80, [2M+H] + ), 611 (15, [2M+Na] + ).

[0077] Synthesis example 4

[0078] Preparation of malonic acid adamantan-1-yl ester N-(3-aminopropyl)-N-methylamide To a solution of adamantyl malonate (8) (289 mg, 1.211 mmol), tert-butyl 3-(methylamino)propylcarbamate (105) (228 mg, 1.211 mmol), and triethylamine (TEA) (340 μl, 2.422 mmol) in DMF (6 mL) was slowly added 1 mL of a 1.6 M solution of propanephosphonic anhydride (T3P) in ethyl acetate, and the mixture was stirred at room temperature for 1 h. The reaction mixture was then treated with saturated brine for hydrolysis and extracted with dichloromethane. The extract was dried over MgSO 2 , filtered, and evaporated to dryness. The residue was purified by column chromatography (dichloromethane / ethyl acetate 70:30) to give the Boc-protected malonic acid adamantan-1-yl ester N-(3-aminopropyl)-N-methylamide (1 1 a) as a colorless oil (370 mg).

[0079] MS (ESI+): m / z (%) 409 (100, [M+H] + , 431 (100, [M+Na] + ), 309 (100, [M-Boc] + ), 839 (100, [2M+Na] + ).

[0080] The resulting product (0.96 mmol) was dissolved in 20 ml of dichloromethane, 9.6 ml of 4 N HCl in dioxane was added, and the mixture was stirred at room temperature for 1.5 h. The volatiles were then removed in vacuo to afford the hydrochloride of the title compound (11) as a yellow oil (260 mg).

[0081] 1 H-NMR (DMSO-de): ö = 1.63-1.75 (m, 10H), 2.10-2.20 (m, 9H), 2.85 (s, 2H), 2.97 (s, 3H) 3.22-3.25 (m, 1H), 3.61 -3.72 (m, 2H), 3.73-3.82 (m, 1H). MS (ESI+): m / z (%) 309 (100, [M+H] + ), 331 (17, [M+Na] + ), 617 (77, [2M] + ).

[0082] Synthesis example 5

[0083] Preparation of malonic acid adamantane-1-yl ester piperazinamide (12)

[0084] The synthesis was carried out analogously to Synthesis Example 4 from adamantyl malonate (8) (150 mg, 0.630 mmol), tert-butyl 1-piperazinecarbamate (1.17 mg, 0.630 mmol), and TEA (176 μL, 1.26 mmol) in DMF (7 mL) with 512 μL of a 1.6 M solution of T3P in ethyl acetate. Purification of the residue by column chromatography (dichloromethane / ethyl acetate 90:10^50:50) afforded the Boc-protected title compound (12a) as a white solid (232 mg).

[0085] MS (ESI+): m / z (%) 407 (100, [M+H] + ), 429 (100, [M+Na] + ), 836 (100, [2M+Na] + ). The product thus obtained (0.571 mmol) was deprotected analogously to Synthesis Example 4, whereby the hydrochloride of the title compound (12) was obtained in the form of a white solid (169 mg). 1H-NMR (DMSO-de): ö = 1.6 (t, 6H, J=3.0 Hz), 2.03 (d, 6H, J=3.0 Hz), 2.11 (brs, 3H), 3.05 (dt, 4H, J=22.6, 5.2 Hz), 3.32 (brs, 1 H), 3.48 (s, 2H), 3.63 (dt, 4H, J=22.6, 5.2 Hz) MS (ESI+): m / z (%) 307 (100, [M+H] + ), 329 (25, [M+Na] + ), 635 (15, [2M+Na] + ).

[0086] Synthesis Example 6 Preparation of malonic acid adamantane-1-yl ester 4-(4-aminobutyryl)piperazinamide

[0087] (13) The synthesis was carried out analogously to Synthesis Example 4 from malonic acid adamantane-1-yl ester piperazinamide (12) (180 mg, 0.525 mmol), 4-(tert-butoxycarbonylamino)butyric acid (107 mg, 0.525 mmol), and triethylamine (TEA) (219 μL, 1.575 mmol) in DMF (7 mL) with 427 μL of a 1.6 M solution of T3P in ethyl acetate. Purification by column chromatography (dichloromethane / ethyl acetate 80:20) afforded the Boc-protected title compound (13a) as a white solid (190 mg).

[0088] MS (ESI+): m / z (%) 492 (100, [M+H] +), 514 (100, [M+Na] + ), 392 (72, {M+H-Boc] + ). The product thus obtained (0.386 mmol) was deprotected analogously to Synthesis Example 4, whereby the hydrochloride of the title compound (12) was obtained in the form of a white powder (151 mg).

[0089] 1 H-NMR (DMSO-de): 1.59 (brs, 6H), 1.76 (quint, 2H, J=7.4 Hz), 2.03 (d, 6H, J=3Hz), 2.10 (brs, 3H), 2.45 (quint, 2H, J=7.4 Hz), 2.74-2.83 (m, 2H), 3.34 (brs, 2H), 3.40-3.45

[0090] (m, 8H), 3.54 (s, 2H). MS (ESI+): m / z (%) 392 (100, [M+H] + ), 414 (100, [M+Na] + ), 430 (10, [M+K] + ), 805 (69, [2M+Na] + ).

[0091] Synthesis Example 7

[0092] Preparation of malonic acid adamantane-1-yl ester-4-aminopiperidine amide (14) The synthesis was carried out analogously to Synthesis Example 4 from malonic acid adamantane-1-yl ester (8) (150 mg, 0.630 mmol), piperidin-4-ylcarbamate tert-butyl ester (126 mg, 0.630 mmol), and triethylamine (TEA) (176 μL, 1.26 mmol) in DMF (7 mL) with 512 μL of a 1.6 M solution of T3P in ethyl acetate. Purification by column chromatography (dichloromethane / ethyl acetate 90:10^80:20) afforded the Boc-protected title compound (14a) as a white solid (236 mg).

[0093] MS (ESI+): m / z (%) 421 (100, [M+H] + ), 443 (100, [M+Na] + ), 864 (100, [2M+Na] + ). The resulting product (0.561 mmol) was deprotected analogously to Synthesis Example 4, yielding the hydrochloride of the title compound (14) as a white powder (175 mg). MS (ESI+): m / z (%) 321 (100, [M+H] + ), 343 (7, [M+Na] + ), 641 (24, [2M+H] + ), 663 (95, [2M+Na] + ).

[0094] Synthesis Example 8

[0095] Preparation of malonic acid adamantane-1-yl ester-(4-(4-aminobutyryl)amino)piperidine- amide (15) The synthesis was carried out analogously to Synthesis Example 4 from malonic acid adamantane-1-yl ester 4-aminopiperidine amide (14) (140 mg, 0.392 mmol), 4-(tert-butoxycarbonylamino)butyric acid (80 mg, 0.392 mmol), and triethylamine (TEA) (164 μL, 1.176 mmol) in DMF (7 mL) with 319 μL of a 1.6 M solution of T3P in ethyl acetate. Purification by column chromatography (dichloromethane / ethyl acetate 80:20 / ethyl acetate) afforded the Boc-protected title compound (15a) as a yellow oil (83 mg).

[0096] MS (ESI+): m / z (%) 506 (100, [M+H] + ), 528 (100, [M+Na] + ), 406 (78, [M-Boc+H] + ).

[0097] The product thus obtained (0.164 mmol) was deprotected analogously to Synthesis Example 4, whereby the hydrochloride of the title compound (14) was obtained in the form of a yellow powder (80 mg).

[0098] 1<h2 style=";text-align:left;direction:ltr">H-NMR (DMSO-de): ö = 1.64 (dt, 3H, J=13.1, 2.8 Hz), 1.66 (dt, 3H, J=13.1, 2.8 Hz), 1.74 (sept, 3H, J=2.8 Hz), 1.80-1.87 (m, 6H), 2.09-2.13 (m, 6H), 2.16 (t, 2H, J=7.4 Hz), 2.65 (t, 2H, J=7.7 Hz), 3.04-3.13 (m, 2H), 3.35 (ddd, 2H, J=14.7, 6.8, 2.8 Hz), 3.55 (s, 2H), 4.1 1 -4.21 (m, 1 H), 7,97 (brs, 2 H). MS (ESI+): m / z (%) 406 (100, [M+H]<h2 style=";text-align:left;direction:ltr"> + <h2 style=";text-align:left;direction:ltr"> ), 428 (100, [M+Na]<h2 style=";text-align:left;direction:ltr"> + <h2 style=";text-align:left;direction:ltr"> ), 81 1 (100, [2M+H]<h2 style=";text-align:left;direction:ltr"> + <h2 style=";text-align:left;direction:ltr"> ), 833 (53, [2M+Na]<h2 style=";text-align:left;direction:ltr"> + <h2 style=";text-align:left;direction:ltr"> ).<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0099] <h2 style=";text-align:left;direction:ltr"> Synthesebeispieel 9<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0100] <h2 style=";text-align:left;direction:ltr"> Herstellung von Malonsäuremethylester-N-(adamantan-1-yl)amid (16)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0101] <h2 style=";text-align:left;direction:ltr"> (107) (16)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0102] Methyl malonate chloride (322 μl, 3.005 mmol) was dissolved in 30 mL of dichloromethane under an inert gas atmosphere and cooled to -20 °C, after which a solution of 1-adamantanamine (107) (1.0 g, 6.612 mmol) in 10 mL of dichloromethane was slowly added via syringe. The reaction mixture was stirred at room temperature for 1 h, quenched with saturated aqueous NH4Cl solution, and extracted with dichloromethane. The organic phase was dried over MgSO4, filtered, and evaporated to dryness to afford the title compound (760 mg) as white crystals.

[0103] 1 H NMR (CDCh): δ = 1.68 (m, 6H), 2.01 -2.10 (m, 9H), 3.22 (s, 2H), 3.74 (s, 3H), 6.64 (brs, 1H). MS (ESI+): m / z (%) 252 (100, [M+H] + ), 274 (100, [M+Na] + ), 503 (78, [2M+H] + ).

[0104] Synthesis Example 10

[0105] Preparation of N-(adamantan-1-yl)malonic acid amide (17)

[0106] (16) (17)

[0107] To a solution of 750 mg (2.98 mmol) of methyl malonate N-(adamantan-1-yl)amide (16) in 30 mL of THF / H2O (2:1) was added 6 mL of 1 M aqueous NaOH, and the mixture was stirred at room temperature. After 1 h, the THF was removed on a rotary evaporator, and the remaining aqueous solution was acidified with 2 N HCl and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered, and evaporated to dryness to afford the title compound (17) as an off-white powder (670 mg).

[0108] MS (ESI-): m / z (%) 236 (100, [MH]j, 473 (100, [2M-H]j.

[0109] Synthesis Example 11

[0110] Preparation of N-adamantan-1-yl-N'-(3-aminopropyl)malonic acid diamide (18) Diisopropylcarbodiimide (DIC) (40 μl, 0.253 mmol) was added to a solution of N-(adamantan-1-yl)malonic acid amide (17) (50 mg, 0.211 mmol), 3-aminopropylcarbamic acid tert-butyl ester (104) (37 mg, 0.211 mmol), and 4-dimethylaminopyridine (DMAP) (13 mg, 0.106 mmol) in dichloromethane (8 mL) cooled to 0 °C. After stirring for 4 h while allowing to warm to room temperature, the reaction mixture was evaporated to dryness. The residue containing the Boc-protected N-adamantan-1-yl-N'-(3-aminopropyl)malonic acid diamide (18a) (59 mg, 0.202 mmol) was used in the next step without further purification.

[0111] MS (ESI+): m / z (%) 394 (100, [M+H] + ), 415 (100, [M+Na] + ), 294 (70, [M-BOC+H] + ), 787 (40, [2M+H] +). The resulting residue was dissolved in 6 ml of dichloromethane, 2 ml of 4 N HCl in dioxane was added, and the mixture was stirred at room temperature for 2 h. The volatiles were then removed in vacuo to afford the hydrochloride of the title compound (18) as a yellow oil (55 mg).

[0112] 1 H-NMR (DMSO-de): ö = 1.61 (m, 6H, adamantyl), 1.68 (quint, 2H, J=7.1 Hz), 1.90-2.00 (m, 9H, adamantyl), 2.74-2.82 (m, 2H), 2.98 (s, 2H), 3.12 (q, 2H, J=6.42 Hz), 7.58 (s, 1 H). MS (ESI+): m / z (%) 294 (90, [M+H] + ), 316 (100, [M+Na] + ), 608 (45, [2M+Na] + ).

[0113] Synthesis Example 12

[0114] Preparation of N-adamantan-1-yl-N'-(3-aminopropyl)-N'-methylmalonic acid diamide The synthesis was carried out analogously to Synthesis Example 4 from N-(adamantan-1-yl)malonic acid amide (17) (50 mg, 0.21 mmol), 3-(methylamino)propylcarbamic acid tert-butyl ester (105) (40 mg, 0.21 mmol), and triethylamine (TEA) (60 μl, 0.422 mmol) in DMF (10 ml) with 175 μl of a 1.6 M solution of T3P in ethyl acetate. Purification by column chromatography (dichloromethane / ethyl acetate 70:30) afforded the Boc-protected

[0115] Title compound (19a) in the form of a yellow oil (83 mg).

[0116] MS (ESI+): m / z (%) 408 (100, [M+H] + ), 430 (100, [M+Na] + ), 308 (100, [M-BOC+H] + ), 815 (50, [2M+H] + ).

[0117] The product thus obtained (46 mg, 0.113 mmol) was deprotected analogously to Synthesis Example 4, whereby the hydrochloride of the title compound (19) was obtained in the form of a yellow oil (33 mg). 1H-NMR (DMSO-de): ö = 1.61 (m, 6H, adamantyl), 1.74 (quint, 2H, J=5.5 Hz), 1.97-2.07 (m, 9H, adamantyl), 2.75-2.84 (m, 2H), 2.93 (s, 3H), 3.26 (s, 2H), 3.35 (t, 2H, J=5.5 Hz), 3.41 (brs, 2H), 7.50 (s, 1 H). MS (ESI+): m / z (%) 308 (100, [M+H] + ), 330 (33, [M+Na] + ), 615 (100, [2M+H] + ).

[0118] Synthesis Example 13

[0119] Preparation of N-adamantan-1-yl-N'-piperazinemalonic acid diamide (20) The synthesis was carried out analogously to Synthesis Example 4 from commercially available malonic acid 4-(tert-butoxycarbonyl)piperidine amide (250 mg, 0.918 mmol), 1-adamantanamine (107) (139 mg, 0.918 mmol), and triethylamine (TEA) (265 μL, 1.84 mmol) in DMF (17 mL) with 750 μL of a 1.6 M solution of T3P in ethyl acetate. Purification by column chromatography (dichloromethane / ethyl acetate 90:10^50:50) afforded the Boc-protected title compound (20a) as a white solid (260 mg).

[0120] 1H-NMR (CDCh): ö = 1.46 (s, 9H), 1.67 (t, 7H, J=3.9 Hz), 1.98 (d, 6H, J=3.1 Hz), 2.06 (brs, 3H), 3.24 (s, 2H), 3.40-3.46 (m, 4H), 3.52-3.55 (m, 2H), 3.58-3.61 (m, 2H), 6.73 (brs, 1H). MS (ESI+): m / z (%) 406 (100, [M+H] + ), 428 (100, [M+Na] + ), 833 (2M+Na] + ). The product thus obtained (0.647 mmol) was deprotected analogously to Synthesis Example 4, whereby the hydrochloride of the title compound (20) was obtained in the form of a white powder (192 mg). 1 H-NMR (DMSO-de): 1.61 (brs, 6H), 1.9 (d, 6H, J=2.95 Hz), 2.00 (brs, 3H), 3.00 (brs, 2H), 3.10 (brs, 2H), 3.66-3.68 (m, 4H), 4.01 (brs, 2H). MS (ESI+): m / z (%) 306 (100, [M+H] + ), 329 (7, [M+Na] + ), 633 (95, [2M+Na] + ).

[0121] Synthesis Example 14 Preparation of N-Adamantane-1-yl-N'-(4-(4-aminobutyryl)piperazine)malonic acid diamide The synthesis was carried out analogously to Synthesis Example 4 from the hydrochloride of N-adamantan-1-yl-N'-piperazinemalonic acid diamide (20) (140 mg, 0.410 mmol), 4-(tert-butoxycarbonylamino)butyric acid (83 mg, 0.410 mmol), and triethylamine (TEA) (171 μL, 1.23 mmol) in DMF (7 mL) with 333 μL of a 1.6 M solution of T3P in ethyl acetate. Purification by column chromatography (ethyl acetate / methanol 95:5) afforded the Boc-protected title compound (21 a) as a white solid (180 mg).

[0122] MS (ESI+): m / z (%) 491 (100, [M+H] + ), 513 (100, [M+Na] + ), 391 (38, [M-Boc+H] + ). The product thus obtained (0.367 mmol) was deprotected analogously to Synthesis Example 4, whereby the hydrochloride of the title compound (21) was obtained in the form of a white powder (150 mg).

[0123] 1H-NMR (DMSO-de): 1.59 (brs, 6H), 1.77 (quint, 2H, J=6.4 Hz), 1.89 (brs, 6H), 1.98 (brs, 3H), 2.43-2.47 (m, 2H), 2.76-2.81 (m, 2H), 3.26-3.30 (m, 2H), 3.39-3.45 (m, 8H), 4.34 (brs, 2H), 7.61 (s, 1H).

[0124] Synthesis Example 15

[0125] Preparation of N-(3-aminopropyl)-N'-morpholinemalonic acid diamide (22) The synthesis was carried out analogously to Synthesis Example 4 from commercially available N-morpholinemalonic acid amide (90 mg, 0.520 mmol), 3-aminopropylcarbamic acid tert-butyl ester (N-Boc-1,3-propanediamine) (104) (91 mg, 0.520 mmol), and triethylamine (TEA) (145 μl, 1.04 mmol) in DMF (5 mL) with 423 μl of a 1.6 M solution of T3P in ethyl acetate. Purification by column chromatography (ethyl acetate / methanol 95:5) afforded the Boc-protected title compound (22a) as a yellow oil (90 mg).

[0126] MS (ESI+): m / z (%) 330 (100, [M+H] + ), 352 (100, [M+Na] + ), 230 (100, [M-Boc+H] + ), 681 (100, [2M+Na]+ ). The resulting product (0.273 mmol) was deprotected analogously to Synthesis Example 4, yielding the hydrochloride of the title compound (22) as a yellowish oil (76 mg). MS (ESI+): m / z (%) 230 (100, [M+H] + ), 252 (100, [M+Na] + ), 459 (11 , [2M+H] + ), 481 (100, [2M+Na] + ).

[0127] Synthesis Example 16

[0128] Preparation of N-(3-aminopropyl)-N'-piperidinemalonic acid diamide (23)

[0129] The synthesis was carried out analogously to a combination of synthesis examples 9, 10 and 4, whereby first, analogously to synthesis example 9, malonic acid methyl ester chloride (250 pl, 2.33 mmol) and piperidine (506 pl, 5.126 mmol) at -20 °C in 10 ml of dichloromethane was used to prepare malonic acid methyl ester-N-piperidinamide, which was then hydrolyzed analogously to synthesis example 10 in THF / H2O (2:1) with aqueous NaOH to malonic acid-N-piperidinamide.

[0130] MS (ESI+): m / z (%) 172 (100, [M+H] + ), 194 (50, [M+H] + ).

[0131] This (280 mg, 1.636 mmol) was then reacted analogously to Synthesis Example 4 with 3-aminopropylcarbamic acid tert-butyl ester (N-Boc-1,3-propanediamine) (285 mg, 1.636 mmol) and TEA (456 μl, 3.272 mmol) in DMF (6 ml) with 1.33 ml of a 1.6 M solution of T3P in ethyl acetate. Purification by column chromatography (dichloromethane / ethyl acetate 50:50^ethyl acetate) gave the Boc-protected title compound (23a) as a colorless oil (370 mg).

[0132] 1 H-NMR (CDCh): ö = 1.43 (s, 9H), 1.53-1.60 (m, 4H), 1.63-1.68 (m, 5H), 3.14 (q, 2H, J=6.5 Hz), 3.31 (s, 2H), 3.33 (q, 2H, J=6.5 Hz), 3.45 (t, 2H, J=4.8 Hz), 3.56 (t, 2H, J=4.8 Hz), 7.78 (s, 1 H). MS (ESI+): m / z (%) 328 (100, [M+H] + ), 350 (100, [M+Na] + ), 228 (80, [M-Boc+H] + ), 677 (100, [2M+Na] + ).

[0133] The product thus obtained (1.13 mmol) was deprotected analogously to Synthesis Example 4, whereby the hydrochloride of the title compound (23) was obtained in the form of a white powder (330 mg).

[0134] 1 H-NMR (DMSO-de): ö = 1.37-1.43 (m, 2H), 1.45-1.50 (m, 2H), 1.53-1.59 (m, 2H), 1.69 (quint, 2H, J=8.3 Hz), 2.75-2.83 (m, 2H), 3.12 (q, 2H, 4.8 Hz), 3.35-3.41 (m, 4H), 7.96 (s, 1H). MS (ESI+): m / z (%) 228 (100, [M+H] + ), 250 (16, [M+Na] + ), 455 (40, [2M+H] + ).

[0135] Synthesis Example 17

[0136] Preparation of N-(3-aminopropyl)-N'-decahydroquinolinemalonic acid diamide (24) The synthesis was carried out analogously to Synthesis Example 16 from malonic acid methyl ester chloride (175 μl, 1.63 mmol) and trans-decahydroquinoline (500 mg, 3.59 mmol) to give malonic acid methyl ester N-decahydroquinolinamide, which was hydrolyzed to malonic acid N-decahydroquinolinamide. MS (ESI+): m / z (%) 226 (100, [M+H]+ ), 248 (85, [M+Na] + This (190 mg, 0.843 mmol) was treated with 3-aminopropylcarbamic acid tert-butyl ester (N-Boc-1,3-propanediamine) (147 mg, 0.843 mmol) and TEA (236 μL, 1.686 mmol) in DMF (6 mL) with 685 μL of a 1.6 M solution of T3P in ethyl acetate. Purification by column chromatography (dichloromethane / ethyl acetate 50:50^40:60) gave the Boc-protected title compound (24a) as a colorless oil (230 mg).

[0137] MS (ESI+): m / z (%) 382 (100, [M+H] + ), 404 (80, [M+Na] + ), 282 (37, [M-Boc+H] + ), 785 (15, [2M+Na] + ). The resulting product (0.603 mmol) was deprotected in an analogous manner to afford the hydrochloride of the title compound (24) as a white powder (215 mg).

[0138] MS (ESI+): m / z (%) 282 (100, [M+H) + ], 304 (30, [M+Na] + ), 563 (80, [2M+H] + ), 585 (60, [2M+Na] + ).

[0139] Synthesis Example 18

[0140] Preparation of N-(3-aminopropyl)-N'-decahydroisoquinolinemalonic acid diamide (25) The synthesis was carried out analogously to Synthesis Example 17 from malonic acid methyl ester chloride (175 μl, 1.63 mmol) and decahydroisoquinoline (500 mg, 3.59 mmol) to give malonic acid methyl ester N-decahydroisoquinolinamide, which was hydrolyzed to malonic acid N-decahydroisoquinolinamide. MS (ESI+): m / z (%) 226 (100, [M+H] + ), 248 (100, [M+Na] + ), 473 (36, [2M+Na] + ).

[0141] This (272 mg, 1.207 mmol) was reacted with tert-butyl 3-aminopropylcarbamate (N-Boc-1,3-propanediamine) (210 mg, 1.207 mmol) and TEA (336 μl, 2.414 mmol) in DMF (10 mL) with 980 μl of a 1.6 M solution of T3P in ethyl acetate. Purification by column chromatography (ethyl acetate) afforded the Boc-protected title compound (25a) as a colorless oil (306 mg). MS (ESI+): m / z (%) 382 (100, [M+H] + ), 404 (100, [M+Na]+ ), 282 (100, [M-Boc+H] + ), 785 (100, [2M+Na] + ).

[0142] The product thus obtained (0.786 mmol) was deprotected in an analogous manner to give the hydrochloride of the title compound (25) in the form of a white powder (280 mg).

[0143] MS (ESI+): m / z (%) 282 (100, [M+H]+), 304 (20, [M+Na] + ), 563 (40, [2M+H] + ), 585 (50, [2M+Na] + ).

[0144] Synthesis Example 19

[0145] Preparation of N-(3-aminopropyl)-N'-(pinan-10-yl)malonic acid diamide (26) The synthesis was carried out analogously to Synthesis Example 16 from malonic acid methyl ester chloride (250 μl, 2.33 mmol) and (-)-cis-myrtanylamine (10-pinanamine) (860 mg, 5.13 mmol) to give malonic acid methyl ester N-(pinan-10-yl)amide, which was hydrolyzed to malonic acid N-(pinan-10-yl)amide. MS (ESI+): m / z (%) 240 (100, [M+H] + ), 262 (55, [M+Na] + ), 501 (10, [2M+Na] +). MS (ESI-) m / z (%) 238 (100, [MH] ), 477 (100, [2M-H] ). This (295 mg, 1.327 mmol) was treated with 3-aminopropylcarbamic acid tert-butyl ester (N-Boc-1,3-propanediamine) (231 mg, 1.327 mmol) and TEA (371 μl, 2.654 mmol) in DMF (7 mL) with 1.1 mL of a 1.6 M solution of T3P in ethyl acetate. Purification by column chromatography (dichloromethane / ethyl acetate 50:50 -> ethyl acetate) gave the Boc-protected title compound (26a) as a colorless oil (278 mg).

[0146] 1 H NMR (CDCh): ö = 0.88 (d, 1 H, J=8.5 Hz), 1.02 (s, 3H), 1.18 (s, 3H), 1.44 (s, 9H), 1.45-1.50 (m, 1 H), 1.59-1.67 (m, 4H), 1.84-1 .98 (m, 5H), 2.16-2.24 (m, 1H), 2.33-2.38 (m, 1H), 3.16 (s, 2H), 3.13-3.18 (m, 2H), 3.24-3.34 (m, 4H), 7.05 (s, 1H). MS (ESI+): m / z (%) 396 (100, [M+H] + ), 296 (100, [M-Boc+H] + ), 418 (100, [M+Na]+), 791 (100, [2M+H] + ), 813 (100, [2M+Na] + ).

[0147] The resulting product (0.703 mmol) was deprotected in an analogous manner to give the hydrochloride of the title compound (26) as a white solid (260 mg).

[0148] 1 H-NMR (DMSO-de): ö = 0.84 (d, 1 H, J=8.5 Hz), 0.99 (s, 3H), 1.15 (s, 3H), 1.38-1.45 (m, 1 H), 1.65-1.72 (m, 2H), 1.79-1.91 (m, 5H), 2.06-2.14 (m, 1H), 2.29-2.34 (m, 1H), 2.75-2.83 (m, 2H), 3.01 (s, 2H), 3.03-3.08 (m, 2H), 3.10-3.16 (m, 2H), 3.64-3.73 (m, 1H), 7.82 (brs, 2H). MS (ESI+): m / z (%) 296 (100, [M+H] + ), 318 (90, [M+Na] + ), 591 (100, [2M+H] + ), 613 (100, [2M+Na] + ).

[0149] Synthesis Example 20

[0150] Preparation of N-(3-aminopropyl)-N'-tetrahydroquinolinemalonic acid diamide (108) The synthesis was carried out analogously to Synthesis Example 17 from malonic acid methyl ester chloride (175 μl, 1.63 mmol) and 1,2,3,4-tetrahydroquinoline (478 mg, 3.59 mmol) to give malonic acid methyl ester N-tetrahydroquinolinamide, which was hydrolyzed to malonic acid N-tetrahydroquinolinamide. MS (ESI+): m / z (%) 220 (100, [M+H] + ), 242 (100, [M+Na] + ), 461 (17, [2M+Na] + ). MS (ESI-) m / z (%) 218 ​​(100, [MH] ). This (250 mg, 1.140 mmol) was treated with tert-butyl 3-aminopropylcarbamate (N-Boc-1,3-propanediamine) (199 mg, 1.140 mmol) and TEA (318 μL, 2.280 mmol) in DMF (10 mL) with 900 μL of a 1.6 M solution of T3P in ethyl acetate. Purification by column chromatography (dichloromethane / ethyl acetate 70:30^40:60) gave the Boc-protected title compound (108a) as a colorless oil (230 mg).

[0151] 1H-NMR (CDCh): ö = 1 .43 (s, 9H), 1 .67 (quint, 2H, J=6.7 Hz), 1 .98 (quint, 2H, J=6.7 Hz), 2.72 (brs, 2H), 3.16 (q, 2H, J=6.2 Hz, 3, 3Hz), J=6.4 Hz), 3.47 (s, 2H), 3.82 (t, 2H, J=6.7 Hz), 5.00 (brs, 1 H), 7.09-7.23 (m, 4H). MS (ESI+): m / z (%) 376 (100, [M+H] + ), 398 (100, [M+Na] + ), 276 (100,[M-Boc+H] + ), 773 (100, [2M+Na] + ). MS (ESI-) m / z (%) 374 (100, [MH] j.

[0152] The product thus obtained (275 mg, 0.732 mmol) was purified analogously, obtaining the hydrochloride of the title compound (108) as a white powder (264 mg).

[0153] 1 H-NMR (in DMSO): o = 1 .67 (quint, 2H, J=7.1 Hz), 1 .87 (quint, 2H, J=6.6), 2.69 (t, 2H, J=6.6 Hz), 2.78 (q, 2H, J=6.6 Hz), 3.67 (s, 2H), 3.64-3.72 (m, 2H), 7.09-7.20 (m, 4H), 7.82 (brs, 2H), 8.22 (brs, 1H). MS (ESI+): m / z (%) 276 (100, [M+H] + ), 298 (8, [M+Na] + ), 551 (1 1 , [2M+H]+ ), 573 (18, [2M+Na] + ).

[0154] Synthesis Example 21

[0155] Preparation of malonic acid adamantan-1-yl ester N-(3-dimethylaminopropyl)amide

[0156] (27)

[0157] Triethylamine (TEA) (409 μL, 2.398 mmol) and 1.2 mL of a 1.6 M solution of propanephosphonic anhydride (T3P) in ethyl acetate were slowly added to a solution of malonic acid adamantane-1-yl ester (8) (350 mg, 1.469 mmol) and 3-aminopropyldimethylamine (150 mg, 1.469 mmol) in DMF (10 mL), and the mixture was stirred at room temperature for 1 h. The reaction mixture was then treated with saturated brine for hydrolysis and extracted with ethyl acetate. The extract was dried over MgSO 4 , filtered, and evaporated to dryness. The residue was purified by column chromatography (dichloromethane / ethyl acetate 50:50^ethyl acetate / methanol 70:30) to give the title compound (27) as a colorless oil (400 mg).

[0158] 1H-NMR (CDCI3): ö = 1.66 (m, 6H, adamantyl), 1.72 (quint, 2H, J=6.77 Hz), 2.04-2.1 1 (m, 9H, adamantyl), 2.28 (s, 6H), 2.42 (t, 2H, J=6.92 Hz), 3.19 (s, 2H), 3.45 (q, 2H, J=6.30 Hz), 7.62 (brs, 1 H). MS (ESI+): m / z (%) 323 (100, [M+H] + ), 345 (11 , [M+Na] + ). Synthesis Example 22

[0159] Preparation of malonic acid adamantane-1-yl ester N-(3-morpholinopropyl)amide (28) The synthesis was carried out analogously to Synthesis Example 21 from malonic acid adamantane-1-yl ester (8) (190 mg, 0.797 mmol), 3-morpholinopropylamine (1.15 mg, 0.797 mmol), and triethylamine (TEA) (222 μL, 1.594 mmol) in DMF (5 mL) with 650 μL of a 1.6 M solution of T3P in ethyl acetate. Purification by column chromatography (ethyl acetate / ethyl acetate / methanol 90:10) gave the title compound (28) as a colorless oil (250 mg).

[0160] 1H-NMR (CDCh): ö = 1.65-1.74 (m, 8H), 2.10 (m, 6H, adamantyl), 2.17 (brs, 3H, adamantyl), 2.40-2.44 (m, 6H), 3.19 (s, 2H), 3.33-3.38 (m, 2H), 3.72 (t, 4H, J=4.68 Hz), 7.61 (brs, 1 H). MS (ESI+): m / z (%) 365 (100, [M+H] + ), 387 (20, [M+Na] + ), 751 (67, [2M+Na] + ).

[0161] Synthesis Example 23

[0162] Preparation of malonic acid adamantane-1-yl ester 4-(3-trifluoromethylbenzyl)piperazine amide (29)

[0163] The synthesis was carried out analogously to Synthesis Example 21 from malonic acid adamantane-1-yl ester (8) (85 mg, 0.357 mmol), 1-(3-trifluoromethylbenzyl)piperazine (87 mg, 0.357 mmol), and triethylamine (TEA) (100 μL, 0.714 mmol) in DMF (2 mL) with 290 μL of a 1.6 M solution of T3P in ethyl acetate. Purification by column chromatography (dichloromethane / ethyl acetate 90:10^50:50) afforded the title compound (29) as a colorless oil (116 mg).

[0164] 1H-NMR (CDCh): ö = 1.65 (m, 6H, adamantyl), 2.10-2.17 (m, 9H, adamantyl), 2.45 (q, 4H, J=4.61 Hz), 3.37 (s, 2H), 3.44 (t, 2H, J=5.05 Hz), 3.57 (s, 2H), 3.66 (t, 2H, J=5.05 Hz), 7.42-7.59 (m, 4H, H-aryl). MS (ESI+): m / z (%) 465 (100, [M+H] + ), 487 (42, [M+Na] + ), 951 (7, [2M+Na] + ). Synthesis Example 24

[0165] Preparation of malonic acid adamantane-1-yl ester 4-(3-fluorobenzyl)piperazinamide (30) The synthesis was carried out analogously to Synthesis Example 21 from malonic acid adamantane-1-yl ester (8) (127 mg, 0.533 mmol), 1-(3-fluorobenzyl)piperazine (104 mg, 0.533 mmol), and triethylamine (TEA) (149 μL, 1.07 mmol) in DMF (4 mL) with 433 μL of a 1.6 M solution of T3P in ethyl acetate. Purification by column chromatography (dichloromethane / ethyl acetate 80:20^50:50) afforded the title compound (30) as a colorless oil (172 mg).

[0166] 1H-NMR (CDCh): ö = 1.65 (m, 6H, adamantyl), 2.10-2.16 (m, 9H, adamantyl), 2.44 (q, 4H, J=5.20 Hz), 3.37 (s, 2H), 3.43 (t, 2H, J=5.00 Hz), 3.51 (s, 2H), 3.65 (t, 2H, J=5.07 Hz), 6.93-6.98 (m, 1 H, H-aryl), 7.05-7.08 (m, 2H, H-aryl), 7.25-7.30 (m, 1 H, H-aryl). MS (ESI+): m / z (%) 415 (100, [M+H] + ), 437 (32, [M+Na] + ), 851 (10, [2M+Na] + ).

[0167] Synthesis Example 25

[0168] Preparation of malonic acid adamantane-1-yl ester 4-(2-methoxyphenyl)piperazinamide (31 )

[0169] The synthesis was carried out analogously to Synthesis Example 21 from malonic acid adamantane-1-yl ester (8) (100 mg, 0.420 mmol), 1-(2-methoxyphenyl)piperazine (81 mg, 0.420 mmol), and triethylamine (TEA) (341 μL, 0.546 mmol) in DMF (4 mL) with 341 μL of a 1.6 M solution of T3P in ethyl acetate. Purification by column chromatography (dichloromethane / ethyl acetate 95:5^85:15) afforded the title compound (31) as white crystals (130 mg).

[0170] 1 H-NMR (CDCb): ö = 1 ,65 (m, 6H, Adamantyl), 2,12-2,17 (m, 9H, Adamantyl), 3,06 (dt, 4H, J=14,37, 10,21 Hz), 3,42 (s, 2H), 3,62 (t, 2H, J=5,04 Hz), 3,82 (t, 2H, J=5,10 Hz), 3,88 (s, 3H), 6,88-6,95 (m, 3H, H-Aryl), 7,02-7,06 (m, 1 H, H-Aryl). MS (ESI+): m / z (%)

[0171] 413 (100, [M+H] + ), 435 (57, [M+Na] + ), 847 (38, [2M+Na] + ). Synthesebeispiel 26

[0172] Herstellung von Malonsäure-N-(3,5-dimethyladamantan-1 -yl)amid (32)

[0173] Methyl malonate chloride (173 mg, 1.27 mmol) was dissolved in 10 mL of dichloromethane under an inert gas atmosphere and cooled to -20 °C, after which a solution of 3,5-dimethyl-1-adamantanamine (500 mg, 2.79 mmol) in 10 mL of dichloromethane was slowly added via syringe. The reaction mixture was stirred at room temperature for 1.5 h, after which the solvent was removed and the residue redissolved in ethyl acetate. The organic phase was washed with 1 N HCl and saturated aqueous NaHCO3 solution, dried over MgSO4, filtered, and evaporated to dryness. The residue, methyl malonate N-(3,5-dimethyladamantan-1-yl)amide, was dissolved in a mixture of THF and H2O (2:1), to which 6 mL of 1 M aqueous NaOH was added and stirred at room temperature. After 1 h, the THF was removed on a rotary evaporator, and the remaining aqueous solution was acidified with 2 N HCl and extracted with ethyl acetate.The organic phase was dried over MgSO4, filtered and evaporated to dryness to give the title compound (32) as white crystals (260 mg).

[0174] 1 H-NMR (DMSO-de): ö = 0.80 (s, 6H), 1.08 (s, 2H), 1.26 (qd, 4H, J=6.18, 2.86Hz), 1.55 (s, 4H), 1.72 (d, 2H, J=2.97 Hz), 2.05 (quint, 1H, J=3.10 Hz), 3.04 (s, 2H), 7.56 (brs, 1H), 12.39 (brs, 1H). MS (ESI+): m / z (%) 266 (100, [M+H] + ), 288 (9, [M+Na] + ).

[0175] Synthesis Example 27

[0176] Preparation of N-(3,5-Dimethyladamantan-1-yl)-N'-(3-aminopropyl)malonic acid diamide (33)

[0177] The synthesis was carried out analogously to Synthesis Example 21 from malonic acid N-(3,5-dimethyladamantan-1-yl)amide (32) (100 mg, 0.377 mmol), 3-aminopropylcarbamic acid tert-butyl ester (104) (66 mg, 0.377 mmol), and triethylamine (TEA) (105 μl, 0.754 mmol) in DMF (4 mL) with 306 μl of a 1.6 M solution of T3P in ethyl acetate. Purification by column chromatography (dichloromethane / ethyl acetate 80:20—>50:50) afforded the Boc-protected title compound (33a) as a colorless oil (110 mg).

[0178] MS (ESI+): m / z (%) 422 (100, [M+H] + ), 444 (100, [M+Na] + ), 865 (90, [2M+Na] +The resulting residue (110 mg, 0.261 mmol) was dissolved in 30 mL of dichloromethane, after which 402 mL of trifluoroacetic acid (TFA) was added, and the mixture was stirred at room temperature for 4 h. Subsequently, 60 mL of saturated aqueous NaHCO3 solution was added, and the mixture was extracted with dichloromethane. The organic phase was dried over MgSO4, filtered, and evaporated to dryness to afford the title compound (33) as a yellowish oil (76 mg).

[0179] 1 H-NMR (DMSO-d6): ö = 0.79 (s, 6H), 1.08-1.10 (m, 3H), 1.22-1.31 (m, 4H), 1.54 (s, 4H), 1.65 (quint, 2H, J=6.86 Hz), 1.72 (d, 2H, J=2.48 Hz), 2.05 (m, 1H), 2.77 (t, 2H, J=7.30 Hz), 2.96 (s, 2H), 3.11 (q, 2H, J=6.36 Hz). MS (ESI+): m / z (%) 322 (100, [M+H] + ), 344 (76, [M+Na] + ), 643 (70, [2M+H] + ).

[0180] Preparation of N-(3,5-Dimethyladamantan-1-yl)-N'-(3-morpholinopropyl)malonic acid diamide (34)

[0181] The synthesis was carried out analogously to Synthesis Example 21 from malonic acid N-(3,5-dimethyl)adamantan-1-ylamide (32) (48 mg, 0.181 mmol), 3-morpholinopropylamine (26 mg, 0.181 mmol), and triethylamine (TEA) (51 μL, 0.362 mmol) in DMF (2 mL) with 147 μL of a 1.6 M solution of T3P in ethyl acetate. Purification by column chromatography (ethyl acetate / ethyl acetate / methanol 85:15) gave the title compound (34) as a colorless oil (50 mg).

[0182] 1 H-NMR (CDCh): ö = 0.84 (s, 6H), 1 .1 1 -1 .19 (m, 2H), 1 .25-1 .39 (m, 4H), 1 .60-1 .72 (m, 6H), 1 .83 (d, 2H, J=2.95 Hz), 2.14 (quint, 1 H, J=3.15 Hz), 2.40-2.44 (m, 6H), 3.02 (s, 2H), 3.34 (q, 2H, J=6.14 Hz), 3.71 (t, 4H, J=4.67 Hz), 6.64 (brs, 1 H), 7.64 (brs, 1 H). MS (ESI+): m / z (%) 392 (100, [M+H] + ), 414 (24, [M+Na] + ), 805 (22, [2M+Na] + ).

[0183] Synthesis Example 29

[0184] Preparation of N-(3,5-Dimethyladamantan-1-yl)-N'-piperazinemalonic acid diamide (35) The synthesis was carried out analogously to Synthesis Example 4 from malonic acid N-(3,5-dimethyl)-adamantan-1-ylamide (32) (100 mg, 0.358 mmol), 1-piperazinecarbamic acid tert-butyl ester (67 mg, 0.358 mmol), and triethylamine (100 μL, 0.716 mmol) in DMF (5 mL) with 291 μL of a 1.6 M solution of T3P in ethyl acetate. Purification of the residue obtained after extraction with ethyl acetate by column chromatography (dichloromethane / ethyl acetate 80:20^50:50) afforded the Boc-protected title compound (35a) as a colorless oil (150 mg).

[0185] 1H-NMR (CDCh): ö = 0.83 (s, 6H), 1 .10-1 .19 (m, 2H), 1 .25-1 .30 (m, 2H), 1 .35-1 .39 (m, 2H), 1 .46 (s, 9H, H-Boc), 1 .68, (1 .69 H 1 .83 (d, 2H, J=2.68 Hz), 2.13 (quint, 1 H, J=3.15 Hz), 3.23 (s, 2H), 3.40-3.47 (m, 4H), 3.51 -3.54 (m, 2H), 3.58-3.61 m (2H). MS (ESI+): m / z (%) 434 (100, [M+H] + ), 456 (100, [M+Na] + ), 867 (100, [2M+H] + ), 889 (100, [2M+Na] + ).

[0186] The product thus obtained (150 mg, 0.346 mmol) was analogous to Synthetic Example 4, in which the hydrochloride of the title compound (35) was obtained as a white solid (125 mg).

[0187] 1 H-NMR (DMSO-d6): ö = 0.79 (s, 6H), 1 .08 (s, 2H), 1 .21 -1 .31 (m, 4H), 1 .54 (s, 4H), 1 .72 (s, 2H, J=2.84 Hz), 3.09 (brs, 2H), 3.63-3.67 (m, 4H), 7.66 (brs, 1H), 9.30 (brs, 1H). MS (ESI+): m / z (%) 334 (100, [M+H] + ), 356 (31 , [M+Na] + ), 689 (32, [2M+Na] + ).

[0188] Synthesis Example 30

[0189] Preparation of N-(3,5-Dimethyladamantan-1-yl)-N'-4-(3-trifluoromethylbenzyl)piperazinemalonic acid diamide (36)

[0190] The synthesis was carried out analogously to Synthesis Example 21 from malonic acid N-(3,5-dimethyladamantan-1-yl)amide (32) (95 mg, 0.358 mmol), 1-(3-trifluoromethylbenzyl)piperazine (87 mg, 0.357 mmol), and triethylamine (TEA) (100 μL, 0.714 mmol) in DMF (2 mL) with 290 μL of a 1.6 M solution of T3P in ethyl acetate. Purification by column chromatography (dichloromethane / ethyl acetate 80:20^40:60) afforded the title compound (36) as a colorless oil (1.10 mg).

[0191] 1 H-NMR (CDCh): ö = 0.84 (s, 6H), 1.10-1.20 (m, 2H), 1.25-1.30 (m, 2H), 1.36-1.39 (m, 2H), 1.64 (q, 4H, J=11.77 Hz), 1.83 (brs, 2H), 2.13 (quint, 1H, J=3.13 Hz), 2.43 (brs, 4H), 3.21 (s, 2H), 3.56-3.65 (m, 6H), 7.42-7.59 (m, 4H, H-aryl). MS (ESI+): m / z (%)

[0192] 492 (100, [M+H] + ), 514 (85, [M+Na] + ), 983 (8, [2M+H] + ). Synthesis Example 31

[0193] Preparation of N-(3,5-Dimethyladamantan-1-yl)-N'-4-(3-fluorobenzyl)piperazinemalonic acid diamide (37)

[0194] The synthesis was carried out analogously to Synthesis Example 21 from malonic acid N-(3,5-dimethyl-adamantan-1-yl)amide (32) (95 mg, 0.358 mmol), 1-(3-fluorobenzyl)piperazine (70 mg, 0.358 mmol), and triethylamine (TEA) (100 μl, 0.716 mmol) in DMF (2 mL) with 290 μl of a 1.6 M solution of T3P in ethyl acetate. Purification by column chromatography (dichloromethane / ethyl acetate 50:50^ethyl acetate) afforded the title compound (37) in

[0195] Form of a colorless oil (107 mg).

[0196] 1H-NMR (CDCI3): ö = 0,84 (s, 6H), 1 ,10-1 ,20 (m, 2H), 1 ,25-1 ,30 (m, 2H), 1 ,36 - 1 ,40 (m, 2H), 1 ,64 (q, 4H, J=11 ,47 Hz), 1 ,83 (d, 2H, J=2,29 Hz), 2,13 (quint, 1 H, J=3,15 Hz), 2,43 (brs, 4H), 3,21 (s, 2H), 3,51 -3,63 (m, 6H), 6,94-7,30 (m, 4H, H-Aryl). MS (ESI+): m / z (%) 442 (100, [M+H] + ), 464 (75, [M+Na] + ), 905 (100, [2M+Na] + ). Synthesebeispiel 32

[0197] Herstellung von N-(3,5-Dimethyladamantan-1 -yl)-N'-4-(2-methoxyphenyl)piperazin- malonsäurediamid (38)

[0198] The synthesis was carried out analogously to Synthesis Example 21 from malonic acid N-(3,5-dimethyladamantan-1-yl)amide (32) (95 mg, 0.358 mmol), 1-(2-methoxyphenyl)piperazine (69 mg, 0.358 mmol), and triethylamine (TEA) (100 ml, 0.716 mmol) in DMF (2 ml) with 290 μl of a 1.6 M solution of T3P in ethyl acetate. Purification by column chromatography (dichloromethane / ethyl acetate 90:10^50:50) gave the title compound (38) as a white foam (120 mg).

[0199] 1 H-NMR (CDCI3): ö = 0.84 (s, 6H), 1.10-1.19 (m, 2H), 1.26-1.29 (m, 2H), 1.36-1.40 (m, 2H), 1.61-1.70 (m, 5H), 1.85 (d, 2H, J=2.76 Hz), 2.13 (quint, 1 H, J=3, 15 Hz), 3.05 (brs, 4H), 3.27 (s, 2H), 3.74 (brs, 2H), 3.82 (brs, 2H), 3.88 (s, 3H), 6.88-7.05 (m, 4H, H-Aryl).

[0200] MS (ESI+): m / z (%) 440 (100, [M+H] + ), 462 (77, [M+Na] + ), 901 (84, [2M+Na] + ). Synthesis Example 33

[0201] Preparation of N-(3,5-Dimethyladamantan-1-yl)-N'-4-(4-methoxyphenyl)piperazine-malonic acid diamide (39)

[0202] The synthesis was carried out analogously to Synthesis Example 21 from malonic acid N-(3,5-dimethyladamantan-1-yl)amide (32) (95 mg, 0.358 mmol), 1-(4-methoxyphenyl)piperazine (69 mg, 0.358 mmol), and triethylamine (TEA) (100 ml, 0.716 mmol) in DMF (2 ml) with 290 μl of a 1.6 M solution of T3P in ethyl acetate. Purification by column chromatography (dichloromethane / ethyl acetate 90:10^50:50) afforded the title compound (38) as a white solid (1.13 mg).

[0203] 1 H-NMR (CDCI3): ö = 0.84 (s, 6H), 1.10-1.19 (m, 2H), 1.26-1.29 (m, 2H), 1.35-1.40 (m, 2H), 1.60-1.69 (m, 5H), 1.84 (d, 2H, J=2.75 Hz), 2.13 (quint, 1 H, J=3, 14 Hz), 3.05 (brs, 4H), 3.27 (s, 2H), 3.77 (s, 3H), 3.71 -3.78 (m, 4H), 6.84-6.91 (m, 4H, H-Aryl). MS (ESI+): m / z (%) 440 (100, [M+H] + ), 462 (100, [M+Na] + ), 901 (100, [2M+Na]+ ). Synthesis Example 34

[0204] Preparation of N-(3,5-Dimethyladamantan-1-yl)-N'-4-(2,4-dimethoxyphenyl)piperazinemalonic acid diamide (40)

[0205] The synthesis was carried out analogously to Synthesis Example 21 from malonic acid N-(3,5-dimethyladamantan-1-yl)amide (32) (85 mg, 0.320 mmol), 1-(2,4-dimethoxyphenyl)piperazine (71 mg, 0.320 mmol), and triethylamine (TEA) (90 ml, 0.640 mmol) in DMF (2 ml) with 240 μl of a 1.6 M solution of T3P in ethyl acetate. Purification by column chromatography (dichloromethane / ethyl acetate 90:10^40:60) afforded the title compound (40) in

[0206] Form of a cream-colored solid (120 mg).

[0207] 1<h2 style=";text-align:left;direction:ltr">H-NMR (CDCI3): ö = 0.84 (s, 6H), 1.10-1.20 (m, 2H), 1.26-1.29 (m, 2H), 1.35-1.40 (m, 2H), 1.61-1.70 (m, 5H), 1.85 (d, 2H, J=2.71 Hz), 2.13 (quint, 1H, J=3.13 Hz), 2.96 (brs, 4H), 3.26 (s, 2H), 3.71 (brs, 2H), 3.78 (s, 3H), 3.80 (brs, 2H), 6.42 (dd, 2H, J=8.61 Hz,<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0208] <h2 style=";text-align:left;direction:ltr"> 2.55 Hz), 6.49 (d, 2H, J=2.65 Hz), 6.82 (d, 2H, J=8.43 Hz). MS (ESI+): m / z (%) 470 (100, [M+H]<h2 style=";text-align:left;direction:ltr"> + <h2 style=";text-align:left;direction:ltr"> , 492 (87, [M+Na]<h2 style=";text-align:left;direction:ltr"> + <h2 style=";text-align:left;direction:ltr"> ), 961 (14, [2M+Na]<h2 style=";text-align:left;direction:ltr"> + <h2 style=";text-align:left;direction:ltr"> ). Synthesebeispiel 35<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0209] <h2 style=";text-align:left;direction:ltr"> Herstellung von N-(3,5-Dimethyladamantan-1 -yl)-N'-4-(2-morpholino-2-oxoethyl)pipe-razinmalonsäurediamid (41)<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0210] The synthesis was carried out analogously to Synthesis Example 21 from malonic acid N-(3,5-dimethyl-adamantan-1-yl)amide (32) (68 mg, 0.256 mmol), 1-morpholino-2-(piperazin-1-yl)-ethanone (55 mg, 0.256 mmol), and triethylamine (TEA) (72 ml, 0.512 mmol) in DMF (2 ml) with 208 μl of a 1.6 M solution of T3P in ethyl acetate. Purification by column chromatography (dichloromethane / ethyl acetate 90:10) afforded the title compound (41) in

[0211] Form of a white foam (94 mg).

[0212] 1 H-NMR (CDCh): ö = 0.84 (s, 6H), 1.10-1.20 (m, 2H), 1.25-1.29 (m, 2H), 1.35-1.39 (m, 2H), 1.64 (q, 4H, J=11.88 Hz), 1.83 (d, 2H, J=2.47 Hz), 2.12 (quint, 1 H, J=3.13 Hz), 2.63 (brs, 4H), 3.22 (s, 2H), 3.29 (brs, 2H), 3.54-3.71 (m, 11 H). MS (ESI+): m / z (%)

[0213] 461 (100, [M+H] + ), 483 (100, [M+Na] + ), 921 (78, [2M+H] + ), 943 (58, [2M+Na] + ). Examples 1 to 41, Comparison Examples 1 to 8 - Alzheimer's Testing

[0214] The substances (1) to (41) and (101) to (108) prepared or purchased in the above synthesis examples were tested for their potential suitability as agents for the treatment of Alzheimer's disease in a 96-well procedure in the screening assay mentioned above using the nematode Caenorhabditis elegans (Pretsch et al., see above) in a standardized ß-amyloid test system using the transgenic C. elegans strain CL2659. For this purpose, L3 stage worm larvae were used at a density of 10-20 worms per well. The expression of ß-amyloid in the muscle cells was induced by increasing the temperature, and the associated paralysis was recorded at regular intervals until the end of the test after 48 hours.In this model, a significant delay in the paralysis of the larvae induced by neurotoxic ß-amyloid should be observed at active substances in concentrations that reduce ß-amyloid expression compared to a control substance.

[0215] For this purpose, the above substances were tested at concentrations of 1 mg / ml, 100 pg / ml, and 10 pg / ml compared to quercetin as a negative control. The test results are presented in Table 1 below. For the inventive examples, the concentration range (in pg / ml) at which a delay in paralysis was observed is indicated ("Alzheimer's disease"), while for the comparative examples, no effect was observed even at a concentration of 1 mg / ml.

[0216] Examples 42 to 82, Comparison Examples 9 to 16 - Parkinson's Testing

[0217] The same substances as above were tested for their potential suitability as a treatment for Parkinson's disease in a 96-well procedure in the screening assay mentioned above using the nematode Caenorhabditis elegans (Pretsch et al., see above) in a standardized α-synuclein test system using the transgenic C. elegans strain NL5901. This worm strain expresses human α-synuclein bound to green fluorescent protein (GFP) in all muscle cells. The GFP labeling allows direct detection of the expressed protein levels using a multiplate reader, which is carried out for 24 to 48 hours. In this test model, a significant reduction in the expression of neurotoxic α-synuclein should be observed for active substances at concentrations that reduce α-synuclein expression, compared to a control substance.For this purpose, the substances were tested again at concentrations of 1 mg / ml, 100 pg / ml, and 10 pg / ml, but this time compared to the Parkinson's drug levodopa mentioned above as a control. The test results are also presented in the table overleaf. For the examples according to the invention, the concentration range (in pg / ml) in which a reduction in α-synuclein expression was detectable is again indicated ("Parkinson"), whereas for the comparative examples, no effect was observed in this test, even at a concentration of 1 mg / ml.

[0218]

[0219]

[0220]

[0221] The above test results clearly demonstrate that malonic acid and a variety of its derivatives represent promising potential active ingredients against both Alzheimer's and Parkinson's diseases, but possibly also against Huntington's disease or prion diseases.

[0222] The results obtained for the various substitution patterns show that the active molecules can contain both free carboxyl groups and their salts, esters, and substituted or unsubstituted amides without affecting efficacy. The bulkiness of the substituents also does not appear to play a significant role, as both small (methyl, ethyl) and bulky (e.g., dimethyladamantyl or phenylpiperazinyl) groups showed comparable efficacy.

[0223] As the comparative examples demonstrate, this effectiveness is evidently based in particular on the presence of an unsubstituted malonic acid group, since neither dimethylmalonic acid (101) nor dimethyl methylmalonic acid (102) have proven effective. As the ineffectiveness of compounds (103) to (106) demonstrates, the substituents contained in the malonic acid derivatives effective according to the invention, such as the (dimethyl)adamantyl or aminopropyl group, barely influence the extent of effectiveness. The ineffectiveness of tetrahydroquinolinamide (108) cannot, however, be attributed to the presence of the aromatic substituent, especially since the non-aromatic decahydroquinolinamide (24), as well as its isomer, decahydroisoquinolinamide (25), were effective even at a concentration > 10 pg / ml, but all phenylpiperazinamide derivatives also tested positive.

[0224] In addition, the dilution factor of 1:10 chosen in the test series allows for a wide range of actually effective concentrations. This does not rule out, for example, the possibility that a compound that is already effective at a concentration > 10 pg / ml and therefore rated "++" may only become effective at a concentration just below the limit of 100 pg / ml, e.g., from 90 pg / ml, while the efficacy limit of a compound that is only effective above 100 pg / ml and thus rated "+" may be only slightly above the limit. Such compounds can actually differ in their efficacy by only a few percentage points.

[0225] Furthermore, it should be noted that the actual amount of the respective compound available in the tests, i.e., the molar amount, naturally depends on the molecular weight, which, however, varies within wide limits. For example, free malonic acid (1) (104.06 g / mol) and malonic acid diamide (2) (102.09 g / mol) have only slightly more than one-fifth the molecular weight of N-(3,5-dimethyladamantan-1-yl)-N'-4-(3-trifluoromethylbenzyl)-piperazinemalonic acid diamide (36) (491.60 g / mol). This factor of almost 5 already anticipates almost half of the dilution factor of 1:10 - and yet malonic acid itself and three derivatives thereof with comparatively low molecular weight were only effective at a concentration > 100 pg / ml, while compound (41 ), which has the second highest molecular weight after the aromatic compound (36), namely 460.62 g / mol, was already effective at > 10 pg / ml.

[0226] Further investigations into optimizing efficacy by further varying the substitution pattern and dilution factors in the tests are therefore currently the subject of the inventors' research.

[0227] The present invention thus provides a group of compounds which, due to their efficacy in the C. egans nematode assay, should be suitable for the treatment of neurodegenerative diseases such as Alzheimer's and Parkinson's disease, as they are able to induce the body's own biosynthesis of metallothioneins - even at extremely low concentrations.

Claims

PATENT CLAIMS 1. Malonic acid and derivatives thereof of the following formula (I) for use as a medicament for promoting metallothionein biosynthesis in a patient: where X and Y each independently from -0 M + , -ORi and -NR2R3, wherein M + is selected from mono- or polyvalent metal anions and Ri, R2 and R3 are each independently selected from hydrogen and saturated or unsaturated, unbranched, branched or cyclic hydrocarbon radicals having 1 to 25 carbon atoms, wherein one or more carbon atoms are optionally replaced by O or N, wherein R2 and R3 are optionally joined to one another and together with the nitrogen atom form a heterocyclic hydrocarbon radical.

2. A compound for use according to claim 1, characterized in that in formula (I) both X and Y are -0 M + stand, in which M +each independently selected from mono- and polyvalent metal anions, where M + preferably represents an alkali metal or alkaline earth metal, more preferably an alkali metal.

3. A compound for use according to claim 1 or 2, characterized in that R1, R2 and R3 are each independently selected from hydrogen and saturated or unsaturated, unbranched, branched or cyclic hydrocarbon radicals having 1 to 15 carbon atoms.

4. A compound for use according to claim 3, characterized in that R1, R2 and R3 are each independently selected from hydrogen and saturated or unsaturated hydrocarbon radicals having 1 to 10 carbon atoms.

5. A compound for use according to any one of claims 1 to 4, characterized in that the compound is selected from the following: malonic acid, malonic acid diamide, disodium malonate, malonic acid dimethyl ester, malonic acid methyl ester potassium salt, malonic acid methyl ester amide, N-(3-aminopropyl)malonic acid amide, malonic acid adamant-1-yl ester, malonic acid adamant-1-yl ethyl ester, malonic acid adamant-1-yl ester N-(3-aminopropyl)amide, malonic acid adamant-1-yl ester N-(3-aminopropyl)-N-methylamide, malonic acid adamant-1-yl ester piperazinamide, malonic acid adamant-1-yl ester 4-(4-aminobutyryl)piperazinamide, malonic acid adamant-1-yl ester 4-aminopiperidinamide, malonic acid adamant-1 -ylester-(4-(4-aminobutyryl)-amino)piperidinamide, malonic acid methyl ester-N-(adamantan-1-yl)amide, N-(adamantan-1-yl)malonic acid amide, N-adamantan-1-yl-N'-(3-aminopropyl)malonic acid diamide, N-adamantan-1 -yl-N'-(3-aminopropyl)-N'-methylmalonic acid diamide, N-adamantan-1-yl-N'-piperazine malonic acid diamide,N-Adamantan-1 -yl-N'-(4-(4-aminobutyryl)pipera- zin)malonsäurediamid, N-(3-Aminopropyl)-N'-morpholinmalonsäurediamid, N-(3-Ami- nopropyl)-N'-piperidinmalonsäurediamid, N-(3-Aminopropyl)-N'-decahydrochinolin- malonsäurediamid, N-(3-Aminopropyl)-N'-decahydroisochinolinmalonsäurediamid, N-(3-Aminopropyl)-N'-(6,6-dimethylbicyclo[3.1 .1 ]heptan-2-ylmethyl)malonsäuredi- amid, Malonsäureadamantan-1 -ylester-N-(3-dimethylaminopropyl)amid, Malonsäureadamantan-1 -ylester-N-(3-morpholinopropyl)amid, Malonsäureadamantan-1 -ylester- 4-(3-trifluormethylbenzyl)piperazinamid, Malonsäureadamantan-1 -ylester-4-(3-fluor- benzyl)piperazinamid, Malonsäureadamantan-1 -ylester-4-(2-methoxyphenyl)pipera- zinamid, Malonsäure-N-(3,5-dimethyl)adamantan-1 -ylamid, N-(3,5-Dimethyladaman- tan-1 -yl)-N'-(3-aminopropyl)malonsäurediamid, N-(3,5-Dimethyladamantan-1 -yl)-N'- (3-morpholinopropyl)malonsäurediamid, N-(3,5-Dimethyladamantan-1 -yl)-N'-pipera- zinmalonsäurediamid, N-(3,5-Dimethyladamantan-1 -yl)-N'-4-(3-trifluoromethylbenzyl)-piperazinemalonic acid diamide, N-(3,5-dimethyladamantan-1 -yl)-N'-4-(3-fluorobenzyl)-piperazinemalonic acid diamide, N-(3,5-dimethyladamantan-1 -yl)-N'-4-(2-methoxyphe- nyl)piperazinemalonic acid diamide, N-(3,5-dimethyladamantan-1-yl)-N'-4-(4-methoxy-phenyl)piperazinemalonic acid diamide, N-(3,5-dimethyladamantan-1-yl)-N'-4-(2,4-di-methoxyphenyl)piperazinemalonic acid diamide and N-(3,5-dimethyladamantan-1-yl). -yl)-N'- 4-(2-morpholino-2-oxoethyl)piperazinemalonic acid diamide., 6. A compound for use according to any one of claims 1 to 5, characterized in that the promotion of metallothionein biosynthesis serves to restore metal homeostasis and thus to treat a neurodegenerative disease.

7. A compound for use according to claim 6, characterized in that the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease and Huntington's disease.

8. A compound for use according to claim 7, characterized in that the neurodegenerative disease is Alzheimer's disease or Parkinson's disease.

9. A pharmaceutical composition for the therapeutic treatment of the human or animal body by promoting metallothionein biosynthesis in a patient, comprising a compound as defined in any one of claims 1 to 5, at least one pharmaceutically acceptable excipient and optionally one or more other pharmaceutically acceptable ingredients.

10. Pharmaceutical composition according to claim 9, characterized in that it serves to treat a neurodegenerative disease.

11. Pharmaceutical composition according to claim 10, characterized in that it is used for the treatment of Alzheimer's or Parkinson's disease. - 73 - REVISED SHEET (RULE 91) ISA / EP

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