JP6004894B2 - Multi-targeted neuroprotective agent - Google Patents

Description

  The present invention relates to multitargeting ligands mediated by biometal chelation, brain MAO inhibition and / or cholinesterase inhibition useful in the prevention and / or treatment of diseases, disorders and conditions.

  Alzheimer-type dementia (AD) is an age-related neurodegenerative process characterized by progressive memory loss and other cognitive impairments. The etiology has not been elucidated, but amyloid-β (Aβ) deposition, tau protein aggregation, oxidative stress and acetylcholine (ACh) deficiency are thought to have important effects on the pathology of AD. Cholinergic theory suggests that loss of cholinergic neurons in AD results in low levels of ACh in certain brain regions that mediate learning and memory function. Thus, AD patients have been treated with the acetylcholinesterase inhibitors (AChEIs) tacrine, rivastigmine, donepezil and galantamine with limited success. This is probably due to the multifactorial nature of AD, which led to the search for new multitargeting ligands (MTDLs) based on a “single molecule, multiple target” methodology. Thus, from this connection, for example, pluripotent molecules that can simultaneously bind to both cholinesterase and monoamine oxidase have been studied.

  Monoamine oxidase (MAO, EC1.4.3.4) catalyzes the oxidative deamination of various biological and xenobiotic amines and at the same time produces hydrogen peroxide, which is an important consideration when treating AD It is an enzyme. Hydrogen peroxide is an important intermediate through the Fenton reaction in the production of toxic radical oxygen species and is clearly involved in the progression of AD. MAO is a FAD-containing enzyme that binds to the mitochondrial outer membrane of neurons, glial cells and other cells. MAO exists as two isozymes, MAO-A and MAO-B, each displaying different substrate specificity, sensitivity to inhibitors, and amino acid sequence. MAO-A preferentially oxidizes norepinephrine and serotonin and is selectively inhibited by chlorgyline. On the other hand, MAO-B preferentially deaminates β-phenylethylamine and is irreversibly inhibited by l-deprenyl. X-ray crystal structures of rat MAO-A and human MAO-B have been reported. In this context, the MTDL approach is also used to create a ladostigil by connecting the carbamate site of rivastigmine with the indoleamine site present in razagiline, a well-known MAO-B inhibitor. A successful approach was born. The potential therapeutic effect of this compound that has reached clinical trials is also supported by recent findings that have shown the ability of propargylamine-containing compounds to modulate cleavage of Aβ protein precursors. New hybrid compounds targeting MAO and AchE and site-activated chelating agents targeting MAO have also been recently described.

  Several studies have demonstrated the role of biometallic dyshomeostases in most neurodegenerative disorders. The etiology of AD is characterized by unusually high concentrations of biometals such as copper and iron from spectroscopic studies. This positively promotes β-amyloid peptide aggregation, leading to senile plaque formation, oxygen reactive species (ROS) production and oxidative stress.

  Such biometal level regulation in the brain has been proposed as a promising therapeutic strategy for the treatment of AD.

  Numerous studies, including in vivo, in vitro and animal models, include MAO, cholinesterase and biometal chelation, and neurodegenerative diseases and disorders, especially Parkinson's disease (PD) and Alzheimer's disease (AD). The relationship between is shown.

  New multi-targeted ligands capable of simultaneously binding to cholinesterase and monoamine oxidase and capable of coordinating to biometals are the object of current research. Most of the MTDL under investigation contains two or more functional sites that confer biometal chelation, MAO inhibition and AChE inhibition. Therefore, Youdim MBH et al., "Bifunctional drug derivatives of MAO-B inhibitor rasagiline and iron chelator VK-28 as a more effective approach to treatment of brain ageing and ageing neurodegenerative diseases", Mechanisms of Ageing and Development 2005, 126, The following is described in 317-326. Neuroprotection in neurodegenerative diseases, like cancer, AIDS, cardiovascular and neuropsychiatric disorders, where multidrug therapy is now common, is a similar approach or the use of bi- or trifunctional drugs Either would be needed. The neuroprotective activity of bifunctional cholinesterase-MAO inhibitors and MAO-iron chelate derivatives was discussed.

  International patent application WO2004 / 41151 (Yeda R & D Co., Ltd.) describes compounds M30 and HLA20 and analogues.

  These compounds are MAO inhibitors and iron chelators. These compounds are claimed to be useful in the treatment of AD among other diseases, disorders or conditions associated with iron over-uptake and oxidative stress.

WO2010 / 86860 (Yeda R & D Co., Ltd.) includes (i) a site that imparts the function of an iron chelator, (ii) a site that imparts a neuroprotective function, (iii) anti-apoptosis, neuroprotection and / or nerve regeneration. Sites that provide a combination of functions, (iv) sites that provide MAO inhibition of the brain, (v
Disclosed are multifunctional compounds that incorporate a) a site that confers ChE inhibitory function, and (vi) a site that confer NMDAR inhibition. Of the diseases, disorders and conditions that are treated with the claimed compounds, particular mention is made of Alzheimer's disease.

  As drug candidates for the development of therapeutics, it is highly desirable to provide molecules that have multi-target activity and also exhibit good cell membrane permeability, including the blood brain barrier.

  The inventors have succeeded in finding a new series of compounds that are pluripotent hybrids with good multi-target activity. The series of compounds can interact with two key enzyme systems involved in neurodegeneration and cerebrovascular disorders, diseases and / or conditions, and such disorders, diseases and / or conditions It exhibits certain properties that make it particularly useful when prescribing a medicament in the treatment of. The new compounds according to the invention are multitargeting ligands that simultaneously bind to amine oxidase (MAO) as well as cholinesterase (AChE, BuChE).

  Furthermore, the compounds of the invention of formula (I) are specific biometal chelators that are suitable for binding to biometals intracellularly. The compounds of the present invention have good transport properties and cross the cell membrane, so they coordinate to biometals (especially iron, copper and zinc) that are in excess in the cell. These biometal complexes are expected to leave the cells freely and be expelled rapidly. Furthermore, the compounds of the present invention are expected to be able to cross the blood brain barrier (BBB), making them suitable candidates for the treatment of neurodegenerative diseases, disorders and conditions.

  Due to its chelating properties to biometals, the compounds of the present invention can regulate β-amyloid protein precursor (APP) regulation, along with oxidative stress, metal toxicity, activity against biometal dyshomeostasis in the brain, It is a neuroprotective chelator with the ability to reduce Aβ and suppress Aβ aggregation induced by the biometals Fe, Cu and Zn.

  Accordingly, in a first aspect, the present invention provides a compound of formula (I)

Or a salt thereof, or a stereoisomeric form thereof or a mixture thereof, wherein
R ₁ and R ₂ are the same or different and are each independently selected from the group consisting of: H; OH; —CH ₂ —NH—CH ₂ CCH; —NH—CH ₂ CCH; —CH ₂ — N (C ₁ -C ₄ ) alkyl CH ₂ CCH; -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; linear or branched (C ₁ -C ₆ ) alkyl; hydroxy- (C ₁ -C ₆ ) Alkyl; halo- (C ₁ -C ₆ ) alkyl; linear or branched (C ₂ -C ₆ ) alkenyl; F; Cl; Br; I; -NO ₂ ; -NH ₂ ; -CN; -O (C ₁ -C ₄ ) alkyl; (C ₁ -C ₄ ) alkyl-O- (C ₁ -C ₄ ) alkyl; -C (O) H; -C (O) (C ₁ -C ₄ ) alkyl; _{-COOH; -COO (C 1 -C 4} ) alkyl; -OC (O) H; -OC (O) (C 1 -C 4) alkyl; -C (O) N (( C 1 -C 4) alkyl ) ₂ ; -NH (C ₁ -C ₄ ) alkyl; -N ((C ₁ C ₄ ) alkyl) ₂ ;-(C ₁ -C ₄ ) alkyl-NH (C ₁ -C ₄ ) alkyl; -SH; -S (C ₁ -C ₄ ) alkyl; -SO- (C ₁ -C ₄ ) alkyl; -SO _2- (C ₁ -C ₄ ) alkyl; -SO ₂ NH ₂ ; -SONH (C ₁ -C ₄ ) Alkyl; -SON ((C ₁ -C ₄ ) alkyl) ₂ ; -OCONH ₂ ; -OCONH (C ₁ -C ₄ ) alkyl -OCON ((C ₁ -C ₄ ) alkyl) ₂ ; -C = N (C ₁ -C ₄ ) alkyl; -NHC (O) (C ₁ -C ₄ ) alkyl; -N (C ₁ -C ₄ ) alkyl C (O) (C ₁ -C ₄ ) alkyl; -N (C ₁ -C ₄ ) alkyl C (O) H; -N = CH ₂ ; -N = CH (C ₁ -C ₄ ) alkyl -N = C ((C ₁ -C ₄ ) alkyl) ₂ ; phenylcarbonyl; phenylcarbonyl substituted with a radical selected from the group consisting of at least the following: halo (C ₁ -C ₆ ) -Alkyl, OH, halogen, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkoxy, and CN; (C ₁ -C ₃ ) -alkylphenylcarbonyl; (C ₁ -C ₃ ) alkylphenylcarbonyl substituted with a radical selected from the group consisting of: halo (C ₁ -C ₆ ) -alkyl, OH, halogen, (C ₁ -C ₆ ) -alkyl, ( C ₁ -C ₆₎ - alkoxy, and CN; phenyl; is substituted by a radical selected from the group consisting of at least the following ones And which phenyl: halo (C ₁ -C ₆₎ - alkyl, OH, halogen, (C ₁ -C ₆₎ - alkyl, (C ₁ -C ₆₎ - alkoxy, and _{CN; (C 1 -C 3)} - Alkylphenyl; (C ₁ -C ₃ ) alkylphenyl substituted with a radical independently selected from the group consisting of at least the following: halo (C ₁ -C ₆ ) -alkyl, OH, halogen, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkoxy, and CN,
n is an integer from 0 to 1,
A is selected from the group consisting of:
(i)-(CH ₂ ) _n1 -X- (CH ₂ ) _n2 -where n1 and n2 are each independently an integer selected from 0 to 6;
(ii) -X- (CH ₂ ) _n3 -Y- where n3 is an integer from 1 to 6;
(iii) a divalent radical selected from the group consisting of:

Where R ₃ , R ₄ and R ₅ are H, OH, halogen, CN, (C ₁ -C ₄ ) alkyl, hydroxy- (C ₁ -C ₄ ) alkyl, halo (C ₁ -C ₆ ) alkyl , And (C ₁ -C ₆ ) alkoxy;
Where X and Y are each independently selected from O, N H and CH ₂ ; and where the wavy line indicates the position where the A moiety binds there, the X atom is in the B moiety, and the Y atom is Bound to the backbone structure of the compound of formula (I),
B is selected from the group consisting of:

Where the wavy line indicates the position through which the B moiety binds to the X atom of the A moiety, and R ₆ , R ₇ and R ₈ are selected from the group consisting of:
H; OH; -CH ₂ -NH-CH ₂ CCH; -NH-CH ₂ CCH; -CH ₂ -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; linear or branched (C ₁ -C ₆ ) alkyl; hydroxy- (C ₁ -C ₆ ) alkyl; halo- (C ₁ -C ₆ ) alkyl; linear or branched (C ₂ -C ₆₎ ) Alkenyl; F; Cl; Br; I; -NO ₂ ; -NH ₂ ; -CN; -O (C ₁ -C ₄ ) alkyl; (C ₁ -C ₄ ) alkyl-O- (C ₁ -C ₄ ) Alkyl; -C (O) H; -C (O) (C ₁ -C ₄ ) alkyl; -COOH; -COO (C ₁ C ₄ ) alkyl; -OC (O) H; -OC (O) ( C ₁ -C ₄ ) alkyl; -C (O) N ((C ₁ -C ₄ ) alkyl) ₂ ; -NH (C ₁ -C ₄ ) alkyl; -N ((C ₁ -C ₄ ) alkyl) ₂ -(C ₁ -C ₄ ) alkyl-NH (C ₁ -C ₄ ) alkyl; -SH; -S (C ₁ -C ₄ ) alkyl; -SO- (C ₁ -C ₄ ) alkyl; -SO ₂ -(C ₁ -C ₄ ) alkyl; -SO ₂ NH ₂ ; -SONH (C ₁ -C ₄ ) alkyl; -SON ((C ₁ -C ₄ ) alkyl) ₂ ; -OCONH ₂ ; -OCONH (C ₁ -C ₄ ) alkyl; -OCON ((C ₁ -C ₄ ) alkyl) ₂ ; -C = N (C ₁ -C ₄ ) alkyl; -NHC (O) (C ₁ -C ₄ ) alkyl; -N ( C ₁ -C ₄₎ A Kill _{C (O) (C 1 -C} 4) alkyl; -N (C ₁ -C ₄₎ alkyl C (O) H; -N = CH 2; -N = CH (C 1 -C 4) alkyl; - N = C ((C ₁ -C ₄ ) alkyl) ₂ ; phenylcarbonyl; phenylcarbonyl in which the phenyl moiety is substituted with a radical selected from the group consisting of at least: halo (C ₁ -C ₆ )- Alkyl, OH, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, and CN; (C ₁ -C ₃ ) -alkylphenylcarbonyl; from the group consisting of at least the phenyl moiety (C ₁ -C ₃ ) alkylphenylcarbonyl substituted with a selected radical; OH, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, and CN; phenyl; at least Phenyl substituted with a radical selected from the group consisting of: halo (C ₁ -C ₆ ) -alkyl, OH, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, and _{CN; (C 1 -C 3)} - Rukirufeniru; phenyl portion is substituted by a radical selected from the group consisting of at least the following ones (C ₁ -C ₃₎ alkyl-phenyl: halo (C ₁ -C ₆₎ - alkyl, OH, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, and CN; and one C-radical in a known carbocyclic or heterocyclic ring system having 1 to 4 rings, wherein Each of the rings constituting the ring system of
A 5- to 7-membered ring, each member independently selected from C, N, O, S, CH, CH ₂ , NH,
Saturated, partially unsaturated or aromatic,
Separated or partially or fully condensed;
Each ring that forms part of the ring system is optionally substituted with at least one radical selected from the group consisting of: H; OH; —CH ₂ —NH—CH ₂ CCH; —NH -CH ₂ CCH; -CH ₂ -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; linear or branched (C ₁ -C ₆ ) alkyl Hydroxy- (C ₁ -C ₆ ) alkyl; halo- (C ₁ -C ₆ ) alkyl; linear or branched (C ₂ -C ₆ ) alkenyl; F; Cl; Br; I; -NO ₂ ;- NH ₂ ; -CN; -O (C ₁ -C ₄ ) alkyl; (C ₁ -C ₄ ) alkyl-O- (C ₁ C ₄ ) alkyl; -C (O) H; -C (O) (C ₁ -C _{4) alkyl; -COOH; -COO (C 1 -C} 4) alkyl; -OC (O) H; -OC (O) (C 1 -C 4) alkyl; -C (O) N (( C ₁ -C ₄ ) alkyl) ₂ ; -NH (C ₁ -C ₄ ) alkyl; -N ((C ₁ -C ₄ ) alkyl) ₂ ;-(C ₁ -C ₄ ) alkyl-NH (C _1- C _{4) alkyl; -SH; -S (C 1 -C} 4) alkyl; -SO- (C ₁ -C _{4) alkyl; -SO 2 - (C 1 -C} 4) alkyl; -SO ₂ NH _2; -SONH (C ₁ -C _{4) alkyl; -SON ((C 1 -C 4} ) Al -Kill) ₂ ; -OCONH ₂ ; -OCONH (C ₁ -C ₄ ) alkyl; -OCON ((C ₁ -C ₄ ) alkyl) ₂ ; -C = N (C ₁ -C ₄ ) alkyl; -NHC (O ) (C ₁ -C ₄ ) alkyl; -N (C ₁ -C ₄ ) alkylC (O) (C ₁ -C ₄ ) alkyl; -N (C ₁ -C ₄ ) alkylC (O) H;- N = CH ₂ ; -N = CH (C ₁ -C ₄ ) alkyl; -N = C ((C ₁ -C ₄ ) alkyl) ₂ ; provided that the A part is -X- (CH ₂ ) _{n ''} - Y—, or a radical of formula (II), (III) or (IV), when X is NH or O, B is a radical of formula (VII).

  Another aspect of the present invention provides at least one compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, carriers, or mixtures thereof. It relates to the pharmaceutical composition it contains.

  The third aspect of the present invention is for use as an inhibitor of amino oxidase (MAO), an inhibitor of semicarbazide sensitive amino oxidase (SSAO), an inhibitor of cholinesterase (AChE, BuChE) and / or a biometal chelator. In particular, a compound according to the first aspect of the invention for use as a medicament is provided.

  The fourth aspect of the invention is for the treatment of disorders, diseases and / or conditions mediated by inhibition of amino oxidase (MAO), inhibition of cholinesterase (AChE, BuChE) and / or chelation of biometals. Use of a compound of formula (I) for the manufacture of a medicament. Such a disorder, disease and / or condition is preferably a neurodegenerative disorder. This aspect of the invention also relates to the inhibition of amino oxidase (MAO), cholinesterase (AChE, BuChE) and / or biometal of a compound of formula (I) as defined in the first aspect of the invention Can be constructed for use in the treatment of disorders, diseases and / or conditions mediated by chelation of Such a disorder, disease and / or condition is preferably a neurodegenerative disorder.

  Instead, this aspect is a disorder mediated by inhibition of amino oxidase (MAO), inhibition of cholinesterase (AChE, BuChE) and / or chelation of biometals in mammals, particularly humans in need thereof, It can be constructed as a method for treating a disease and / or condition. Such a disorder, disease and / or condition is preferably a neurodegenerative disorder. The method comprises administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a pharmaceutical excipient, carrier or mixture thereof.

  An additional aspect of the present invention is for the treatment of disorders, diseases and / or conditions mediated by inhibition of amino oxidase (MAO), inhibition of cholinesterase (AChE, BuChE) and / or chelation of biometals. There is provided the use of a compound of formula (I) in the preparation of a medicament. Such a disorder, disease and / or condition is preferably a neurodegenerative disorder. Here, the treatment is simultaneously, sequentially or separately in at least one compound of formula (I) as defined above and in the conventional treatment of such disorders, diseases and / or conditions. Administering to the subject one or more useful active ingredients.

  Instead, this aspect is for use in the treatment of disorders, diseases and / or conditions mediated by inhibition of amino oxidase (MAO), inhibition of cholinesterase (AChE, BuChE) and / or chelation of biometals. It can be constructed to provide a compound of formula (I). Such a disorder, disease and / or condition is preferably a neurodegenerative disorder. Here, the treatment is simultaneously, sequentially or separately in at least one compound of formula (I) as defined above and in the conventional treatment of such disorders, diseases and / or conditions. Administering to the subject one or more useful active ingredients.

  Further provided are methods of treating disorders, diseases and / or conditions mediated by inhibition of amino oxidase (MAO), inhibition of cholinesterase (AChE, BuChE) and / or chelation of biometals. Such a disorder, disease and / or condition is preferably a neurodegenerative disorder. The treatment can be applied to mammals, including humans, suffering from such disorders, diseases and / or conditions, simultaneously, sequentially or separately, with at least one formula (I) as defined above. And administering to a subject one or more active ingredients useful in conventional treatment of such disorders, diseases and / or conditions.

  Another aspect of the invention is simultaneously in the treatment of disorders, diseases and / or conditions mediated by inhibition of amino oxidase (MAO), inhibition of cholinesterase (AChE, BuChE) and / or chelation of biometals, Useful in the conventional treatment of such disorders, diseases and / or conditions with at least one compound of formula (I) as defined above, in the preparation of a medicament for sequential or separate use Use of a combined preparation containing one or more active ingredients. Such a disorder, disease and / or condition is preferably a neurodegenerative disorder. Instead, this aspect is simultaneously and continuously in the treatment of disorders, diseases and / or conditions mediated by inhibition of amino oxidase (MAO), inhibition of cholinesterase (AChE, BuChE) and / or chelation of biometals. One or more compounds useful in conventional treatment of such disorders, diseases and / or conditions, and at least one compound of formula (I) as defined above, for use separately or separately It can be constructed as providing a composite formulation containing the active ingredient. Such a disorder, disease and / or condition is preferably a neurodegenerative disorder.

  Further provided are methods of treating disorders, diseases and / or conditions mediated by inhibition of amino oxidase (MAO), inhibition of cholinesterase (AChE, BuChE) and / or chelation of biometals. Such a disorder, disease and / or condition is preferably a neurodegenerative disorder. The method comprises subjecting a mammal, including a human, suffering such a disorder, disease and / or condition, simultaneously, sequentially or separately, to at least one formula (I) as defined above. Administering a therapeutically effective amount of a combination preparation comprising a compound of the invention and one or more active ingredients useful in conventional treatment of such disorders, diseases and / or conditions.

  Another aspect includes the use of at least one compound of formula (I) as defined above and one or more active ingredients useful in conventional treatment of such disorders, diseases and / or conditions. The invention relates to the use of compounds of formula (I) in combined therapy mediated by inhibition of aminooxidase (MAO), inhibition of cholinesterase (AChE, BuChE) and / or chelation of biometals. Such a disorder, disease and / or condition is preferably a neurodegenerative disorder.

  Instead, this aspect may involve formula (I) in the treatment of disorders, diseases and / or conditions mediated by inhibition of amino oxidase (MAO), inhibition of cholinesterase (AChE, BuChE) and / or chelation of biometals. ) To provide for the use of compounds. Such a disorder, disease and / or condition is preferably a neurodegenerative disorder. The use is in combination therapy, including the use of a compound of formula (I) and one or more active ingredients useful in conventional treatment of such disorders, diseases and / or conditions.

  Further provided are methods of treating disorders, diseases and / or conditions by inhibition of amino oxidase (MAO), inhibition of cholinesterase (AChE, BuChE) and / or chelation of biometals. Such a disorder, disease and / or condition is preferably a neurodegenerative disorder. The method comprises a combination therapy of a compound of formula (I) and one or more active ingredients useful in conventional treatment of such disorders, diseases and / or conditions.

  Yet another aspect of the invention relates to a method for preparing a compound of formula (I), which method comprises reductive amination of an aldehyde of formula (IX) with propargylamine, followed by N-alkylation with a 5-chloromethyl-quinolin-8-yl substituted compound of formula (X) is performed.

  Instead, the compound of formula (I) starts from the 5- (chloromethyl) quinolin-8-yl derivative of formula (X) and reacts with propargylamine to give 5-((prop- It can be prepared by giving a 2-in-1-ylamino) methyl) quinolin-8-yl derivative followed by reductive amination with an aldehyde of formula (IX).

  Instead, a compound of formula (I) is reacted with a propargylamine of a compound of formula (XII) to form an intermediate of type (XIII) and with a chloride of general structure (XIV) Can be prepared.

Steady state inhibition of EeAChE hydrolysis of acetylthiocholine (ATCh) by compound 6. Lineweaver-Burk reciprocal plots of initial speed and substrate concentration (0.1-1 mM) are displayed. Each line was obtained from a weighted least squares analysis of the data. Steady state inhibition of rat liver MAO-A by compound 6. Line weaver bark reciprocal plots of initial speed and substrate concentration (0.1-1 mM) are displayed. Each line was obtained from a weighted least squares analysis of the data. Steady state inhibition of rat liver MAO-B by compound 6. Line weaver bark reciprocal plots of initial speed and substrate concentration (0.1-1 mM) are displayed. Each line was obtained from a weighted least squares analysis of the data. Study of reversibility of MAO-A and MAO-B inhibition by compound 6, chlordiline and l-deprenyl. MAO-A and MAO-B were inhibited in 30 minutes in all cases with l-deprenyl and chlordiline at 6, 20, and 50 nM, respectively, at 10 and 20 μM, respectively. Three consecutive centrifugations were performed using buffer. The activity of both MAO-A and MAO-B is revived significantly at 6 (56.5 ± 9.3% in A and 4.0% recovery of 55.8 ± in B) and, as expected, the activity of MAO-A and MAO-B Remained unchanged when chlordiline and l-deprenyl were used. Data are mean ± SEM of 3 replicates, 4 or 5 independent experiments. *** Significant at P <0.01 compared to untreated controls. Compound 6 was used to effect time-dependent inhibition at different MAO pre-incubation times (0-360 min). Both MAO-A and MAO-B activities were found to be time dependent when inhibited by compound 6. Data are mean ± SEM of 3 independent experiments performed in triplicate. Compound 6 was used for time-dependent inhibition at different MAO pre-incubation times (0-240 min). Both MAO-A and MAO-B were found to be time dependent. Data are mean ± SEM of 3 independent experiments performed in triplicate. Spectrophotometric detection of complex formation of Fe (III) and Cu (II) with compound 6. [Fig. 7a] (a) Compound 6 (10 μM), (b) Compound 6 (10 μM) + Fe ₂ (SO ₄ ) ₃ (6.25 μM), (c) Compound 6 + Fe ₂ (SO ₄ ) ₃ (12.5 μM) UV-Vis spectrum. All solutions were made using Tris buffer pH 7.4. Spectra were obtained after a short incubation. [FIG. 7b]] (a) Compound 6 (10 μM), (b) Compound 6 (10 μM) + Fe ₂ (SO ₄ ) ₃ (6.25 μM), (c) Compound 6 + Fe ₂ (SO ₄ ) ₃ (12.5 μM) UV-Vis spectrum. All solutions were made using Tris buffer pH 7.4. Spectra were obtained after overnight incubation. [FIG. 7c)] UV-Vis spectra of (a) Compound 6 (10 μM), (b) Compound 6 (10 μM) + Cu (SO ₄ ) (6.25 μM), (c) Compound 6 + Cu (SO ₄ ) (12.5 μM) . All solutions were made using Tris buffer pH 7.4. Spectra were obtained after a short incubation.

Detailed Description of the Invention

  As described above, in the first aspect, the present invention provides either a compound of formula (I), or a salt thereof, or a stereoisomeric form thereof or a mixture thereof.

According to a preferred embodiment of the invention, the compounds of formula (I) are those wherein B is a radical of formula (VII) and R ₈ is a radical as defined above.

According to a more preferred embodiment of the present invention, the compound is such that R ₈ is selected from the group consisting of: H; OH; —CH ₂ —NH—CH ₂ CCH; —NH—CH ₂ CCH; -CH ₂ -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; linear or branched (C ₁ -C ₆ ) alkyl; hydroxy- (C ₁ -C _{6) alkyl; CF 3; CN; -O (} C 1 -C 4) alkyl; (C ₁ -C ₄₎ alkyl -O- (C ₁ -C ₄₎ alkyl; -C (O) H; -CO (O) (C ₁ -C ₄ ) alkyl; -COOH; -COO (C ₁ -C ₄ ) alkyl; -OC (O) H; -OC (O) (C ₁ -C ₄ ) alkyl;- C (O) NHCH ₃ ; -C (O) N (CH ₃ ) ₂ ; -NH ₂ ; -NHCH ₃ ; -N (CH ₃ ) ₂ ; -CH ₂ NH ₂ ; -CH ₂ CH ₂ NH ₂ ;- -CH ₂ NHCH ₃ ; -CH ₂ N (CH ₃ ) ₂ ; -CH ₂ CH ₂ N (CH ₃ ) ₂ ; -CH ₂ N (CH ₂ CH ₃ ) ₂ ; -CH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ ; -SH; -SCH ₃ ; -SCH ₂ CH ₃ ; -SO-CH ₃ ; -SO-CH ₂ CH ₃ ; -SO ₂ -CH ₃ ; -SO ₂ -CH ₂ CH ₃ ; -SO ₂ N (CH ₃ ) ₂ ; -SO ₂ NHCH ₃ ; -NO ₂ ; -OCON (CH ₃ ) ₂ ; -OCONHCH ₃ ; -OCON (CH ₂ CH ₃ ) ₂ ; -C = NH; -C = NCH ₃ ;- C = NCH ₂ CH ₃ ; -NCH ₃ C (O) CH ₃ ; -NCH ₃ C ( O) CH ₂ CH ₃ ; -N = CH ₂ ; -N = C (CH ₃ ) ₂ ; -N = C (CH ₂ CH ₃ ) ₂ ; phenylcarbonyl; selected from the group consisting of at least the phenyl moiety Substituted with the radicals: CF ₃ , F, Cl, Br, I, CN, OH, —CH ₃ , —CH ₂ CH ₃ , —OCH ₃ , and —OCH ₂ CH ₃ ; _1- C ₃ ) -alkylphenylcarbonyl, (C ₁ -C ₃ ) -alkylphenylcarbonyl; the phenyl moiety is substituted with a radical selected from the group consisting of at least: (C ₁ -C ₃ )- Alkylphenylcarbonyl: CF ₃ , F, Cl, Br, I, CN, OH, —CH ₃ , —CH ₂ CH ₃ , —OCH ₃ , and —OCH ₂ CH ₃ ; phenyl; from the group consisting of at least Phenyl substituted with a selected radical: CF ₃ , F, Cl, Br, I, CN, OH, —CH ₃ , —CH ₂ CH ₃ , —OCH ₃ , and —OCH ₂ CH ₃ ; (C ₁ -C ₃₎ - alkyl phenyl; phenyl portion is selected from the group consisting of at least the following ones Is substituted with radicals (C ₁ -C ₃₎ - alkyl _{phenyl: CF 3, F, Cl,} Br, I, CN, OH, -CH 3, -CH 2 CH 3, -OCH 3, and - OCH ₂ CH ₃ .

According to another preferred embodiment of the invention, R ₈ is one C-radical in a known carbocyclic or heterocyclic ring system having 1 to 2 rings, wherein said ring system Each of the rings constituting
5-6 membered ring, each member is independently selected from C, N, O, S, CH, CH ₂ , NH,
Saturated, partially unsaturated or aromatic,
Each ring that forms part of each ring is optionally substituted with at least one radical selected from the group consisting of: H; OH; —CH ₂ —NH—CH ₂ CCH; —NH -CH ₂ CCH; -CH ₂ -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; linear or branched (C ₁ -C ₆ ) alkyl Hydroxy- (C ₁ -C ₆ ) alkyl; CF ₃ ; CN; -O (C ₁ -C ₄ ) alkyl; (C ₁ -C ₄ ) alkyl-O- (C ₁ -C ₄ ) alkyl; -C (O) H; -C (O) (C ₁ -C ₄ ) alkyl; -COOH; -COO (C ₁ -C ₄ ) alkyl; -OC (O) H; -OC (O) (C ₁ -C ₄ ) alkyl; -C (O) NHCH ₃ ; -C (O) N (CH ₃ ) ₂ ; -NH ₂ ; -NHCH ₃ ; -N (CH ₃ ) ₂ ; -CH ₂ NH ₂ ; -CH ₂ CH ₂ NH ₂ ; -CH ₂ NHCH ₃ ; -CH ₂ N (CH ₃ ) ₂ ; -CH ₂ CH ₂ N (CH ₃ ) ₂ ; -CH ₂ N (CH ₂ CH ₃ ) ₂ ; -CH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ ; -SH; -SCH ₃ ; -SCH ₂ CH ₃ ; -SO-CH ₃ ; -SO-CH ₂ CH ₃ ; -SO ₂ -CH ₃ ; -SO ₂ -CH ₂ CH ₃ -SO ₂ N (CH ₃ ) ₂ ; -SO ₂ NHCH ₃ ; -NO ₂ ; -OCON (CH ₃ ) ₂ ; -OCONHCH ₃ ; -OCON (CH ₂ CH ₃ ) ₂ ; -C = NH; -C = NCH ₃ ; -C = NCH ₂ C H ₃ ; -NCH ₃ C (O) CH ₃ ; -NCH ₃ C (O) CH ₂ CH ₃ ; -N = CH ₂ ; -N = C (CH ₃ ) ₂ ; N = C (CH ₂ CH ₃ ) ₂ .

In particularly desirable compounds, R ₈ is selected from: pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, dithiolanyl, pyridinyl, pyranyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazinyl, pyrazinyl Benzofuranyl, isobenzofuranyl, indolyl, indenyl, dihydroindenyl, naphthalenyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, adenylyl, guaninyl, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzodioxolyl, Benzofurazanyl, benzotriazolyl, benzothiofuranyl, benzothiazolyl, benzothiadiazolyl, chromenyl, isochromenyl, chloro Nyl, isochromanyl, benzodioxanyl, quinolinyl, and isoquinolinyl, each ring that forms part of the ring system is optionally substituted with at least one radical selected from the group consisting of: H; OH; -CH ₂ -NH-CH ₂ CCH; -NH-CH ₂ CCH; -CH ₂ -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; Linear or branched (C ₁ -C ₆ ) alkyl; hydroxy- (C ₁ -C ₄ ) alkyl; CF ₃ ; CN; -O (C ₁ -C ₄ ) alkyl; (C ₁ -C ₄ ) alkyl -O- (C ₁ -C ₄₎ alkyl; -C (O) H; -C (O) (C 1 -C 4) _{alkyl; -COOH; -COO (C 1 -C} 4) alkyl; -OC ( O) H; -OC (O) (C ₁ -C ₄ ) alkyl; -C (O) NHCH ₃ ; -C (O) N (CH ₃ ) ₂ ; -NH ₂ ; -NHCH ₃ ; -N (CH ₃ ) ₂ ; -CH ₂ NH ₂ ; -CH ₂ CH ₂ NH ₂ ; -CH ₂ NHCH ₃ ; -CH ₂ N (CH ₃ ) ₂ ; -CH ₂ CH ₂ N (CH ₃ ) ₂ ; -CH ₂ N (CH ₂ CH ₃ ) ₂ ; -CH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ ; -SH; -SCH ₃ ; -SCH ₂ CH ₃ ; -SO-CH ₃ ; -SO-CH ₂ CH ₃ ;- SO ₂ -CH ₃ ; -SO ₂ -CH ₂ CH ₃ ; -SO ₂ N (CH ₃ ) ₂ ; -SO ₂ NHCH ₃ ; -NO ₂ ; -OCON (CH ₃ ) ₂ ; -OCONHCH ₃ ; -OCON (CH ₂ CH ₃ ) ₂ ; -C = NH; -C = NCH ₃ ; -C = NCH ₂ CH ₃ ; -NCH ₃ C (O) CH ₃ ; -NCH ₃ C (O) CH ₂ CH ₃ ; -N = CH ₂ ; -N = C (CH ₃ ) ₂ ; -N = C (CH ₂ CH ₃ ) ₂ .

A particularly preferred group of compounds of the invention are those wherein R ₈ is quinolinyl of formula (VIII):

Here, the wavy line shows the position through which the quinolinyl radical of formula (VIII) binds to the nitrogen atom of the radical of formula (VII), and the R ₉ radical is selected from the group consisting of: H; OH -CH ₂ -NH-CH ₂ CCH; -NH-CH ₂ CCH; -CH ₂ -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; linear Or branched (C ₁ -C ₆ ) alkyl; hydroxy- (C ₁ -C ₆ ) alkyl; CF ₃ ; CN; -O (C ₁ -C ₄ ) alkyl; (C ₁ -C ₄ ) alkyl- O- (C ₁ -C ₄ ) alkyl; -C (O) H; -C (O) (C ₁ -C ₄ ) alkyl; -COOH; -COO (C ₁ -C ₄ ) alkyl; -OC (O ) H; -OC (O) (C ₁ -C ₄ ) alkyl; -C (O) NHCH ₃ ; -C (O) N (CH ₃ ) ₂ ; -NH ₂ ; -NHCH ₃ ; -N (CH ₃ ) ₂ ; -CH ₂ NH ₂ ; -CH ₂ CH ₂ NH ₂ ; -CH ₂ NHCH ₃ ; -CH ₂ N (CH ₃ ) ₂ ; -CH ₂ CH ₂ N (CH ₃ ) ₂ ; -CH ₂ N ( CH ₂ CH ₃ ) ₂ ; -CH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ ; -SH; -SCH ₃ ; -SCH ₂ CH ₃ ; -SO-CH ₃ ; -SO-CH ₂ CH ₃ ; -SO ₂ -CH ₃ ; -SO ₂ -CH ₂ CH ₃ ; -SO ₂ N (CH ₃ ) ₂ ; -SO ₂ NHCH ₃ ; -NO ₂ ; -OCON (CH ₃ ) ₂ ; -OCONHCH ₃ ; -OCON (CH ₂ CH ₃ ) ₂ ; -C = NH; -C = NCH ₃ ; -C = NCH ₂ CH ₃ ; -NCH ₃ C (O) CH ₃ ; -NCH ₃ C (O) CH ₂ CH _{3 ; -N = CH 2; -N =} C (CH 3) 2; -N = C (CH 2 CH 3) 2.

According to another embodiment of the present invention, the compound of formula (I) is one wherein n is an integer from 0 to 1 and the BA moiety is selected from the group consisting of: B -(CH ₂ ) _n1 -O- (CH ₂ ) _n2- ; B- (CH ₂ ) _n1 -NH- (CH ₂ ) _n2- ; B- (CH ₂ ) _n1 -CH _2- ; B- (CH _{2 ) n1 -O-; B- (CH 2} ) n1 -NH-; bO- (CH 2) n2 -; B-NH- (CH 2) n2 -; B-; bO-; B-NH-; bO- (CH ₂ ) _n3 -O-; BO- (CH ₂ ) _n3 -NH-; B-NH- (CH ₂ ) _n3 -NH-; and B-NH- (CH ₂ ) _n3 -O-,
B is as defined above, and n1, n2 and n3 are each independently an integer selected from 1 to 4.

According to a particularly preferred embodiment of the invention, the compound is one in which n is an integer from 0 to 1 and the BA part is selected from the group consisting of: B— (CH ₂ ) _n1 -O- (CH ₂ ) _n2- ; B- (CH ₂ ) _n1 -NH- (CH ₂ ) _n2- ; B- (CH ₂ ) _n1 -CH _2- ; B- (CH ₂ ) _n1 -O _{-; B- (CH 2) n1} -NH-; bO- (CH 2) n2 -; B-NH- (CH 2) n2 -; B-; bO-; B-NH-; bO- (CH 2) _n3 -O-; BO- (CH ₂ ) _n3 -NH-; B-NH- (CH ₂ ) _n3 -NH-; and B-NH- (CH ₂ ) _n3 -O-,
n1, n2 and n3 are each independently an integer selected from 1 to 4, B is a radical of formula (VII), and R ₈ is selected from the group consisting of: H; OH; -CH ₂ -NH-CH ₂ CCH; -NH-CH ₂ CCH; -CH ₂ -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; linear Or branched (C ₁ -C ₆ ) alkyl; hydroxy- (C ₁ -C ₆ ) alkyl; CF ₃ ; CN; -O (C ₁ -C ₄ ) alkyl; (C ₁ -C ₄ ) alkyl-O -(C ₁ -C ₄ ) alkyl; -C (O) H; -C (O) (C ₁ -C ₄ ) alkyl; -COOH; -COO (C ₁ -C ₄ ) alkyl; -OC (O) H; -OC (O) (C ₁ -C ₄ ) alkyl; -C (O) NHCH ₃ ; -C (O) N (CH ₃ ) ₂ ; -NH ₂ ; -NHCH ₃ ; -N (CH ₃ ) ₂ ; -CH ₂ NH ₂ ; -CH ₂ CH ₂ NH ₂ ; -CH ₂ NHCH ₃ ; -CH ₂ N (CH ₃ ) ₂ ; -CH ₂ CH ₂ N (CH ₃ ) ₂ ; -CH ₂ N (CH ₂ CH ₃ ) ₂ ; -CH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ ; -SH; -SCH ₃ ; -SCH ₂ CH ₃ ; -SO-CH ₃ ; -SO-CH ₂ CH ₃ ; -SO ₂ -CH ₃ ; -SO ₂ -CH ₂ CH ₃ ; -SO ₂ N (CH ₃ ) ₂ ; -SO ₂ NHCH ₃ ; -NO ₂ ; -OCON (CH ₃ ) ₂ ; -OCONHCH ₃ ; -OCON (CH ₂ CH ₃ ) ₂ ; -C = N H; -C = NCH ₃ ; -C = NCH ₂ CH ₃ ; -NCH ₃ C (O) CH ₃ ; -NCH ₃ C (O) CH ₂ CH ₃ ; -N = CH ₂ ; -N = C (CH ₃ ) ₂ ; —N═C (CH ₂ CH ₃ ) ₂ ; phenylcarbonyl; phenylcarbonyl substituted with a radical selected from the group consisting of at least the following: CF ₃ , F, Cl, Br , I, CN, OH, -CH ₃ , -CH ₂ CH ₃ , -OCH ₃ , and -OCH ₂ CH ₃ ;-(C ₁ -C ₃ ) -alkylphenylcarbonyl; Alkylphenylcarbonyl substituted with radicals selected from the group: CF ₃ , F, Cl, Br, I, CN, OH, —CH ₃ , —CH ₂ CH ₃ , —OCH ₃ , and —OCH ₂ CH ₃ Phenyl substituted with a radical selected from the group consisting of: CF ₃ , F, Cl, Br, I, CN, OH, —CH ₃ , —CH ₂ CH ₃ , —OCH ₃ , and _{-OCH 2 CH 3; (C 1} -C 3) - alkyl phenyl; phenyl portion is selected from the group consisting of at least the following ones Is substituted with radical (C ₁ -C ₃₎ - alkyl _{phenyl: CF 3, F, Cl,} Br, I, CN, OH, -CH 3, -CH 2 CH 3, -OCH 3, and -OCH ₂ CH ₃ .

  According to another preferred embodiment of the present invention, the compound of formula (I) is one in which n is 1 and the A part is a divalent radical selected from the group consisting of: is there:

Where R ₃ , R ₄ and R ₅ are selected from: H, OH, halogen, CN, (C ₁ -C ₄ ) alkyl, halo (C ₁ -C ₆ ) -alkyl, and (C ₁ -C ₆ ) alkoxy,
X and Y are each independently selected from O, N H and CH _2, and the wavy line indicates the position where the A part is bonded therethrough, the X atom is bonded to the B part, and the Y atom is of the formula (I) It is bound to the backbone structure of the compound.

According to a particularly preferred embodiment of the invention, the compound is n is 1, and the A moiety is selected from divalent radicals of formula (II), (III) or (IV), wherein R ₃ , R ₄ and R ₅ are selected from: H, OH, halogen, CN, (C ₁ -C ₄ ) alkyl, halo (C ₁ -C ₆ ) -alkyl, and (C ₁ -C ₆ ) alkoxy , X and Y are each independently selected from O, N H and CH _2, and the wavy line indicates the position where the A moiety is bonded therethrough, the X atom is bonded to the B moiety, and the Y atom is of formula (I) Bound to the backbone structure of
B is a radical of formula (VII) and R ₈ is selected from the group consisting of: H; OH; —CH ₂ —NH—CH ₂ CCH; —NH—CH ₂ CCH; —CH ₂ -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; linear or branched (C ₁ -C ₆ ) alkyl; hydroxy- (C ₁ -C _{6) alkyl; CF 3; CN; -O (} C 1 -C 4) alkyl; (C ₁ -C ₄₎ alkyl -O- (C ₁ -C ₄₎ alkyl; -C (O) H; -C ( O) (C ₁ -C ₄ ) alkyl; -COOH; -COO (C ₁ -C ₄ ) alkyl; -OC (O) H; -OC (O) (C ₁ -C ₄ ) alkyl; ) NHCH ₃ ; -C (O) N (CH ₃ ) ₂ ; -NH ₂ ; -NHCH ₃ ; -N (CH ₃ ) ₂ ; -CH ₂ NH ₂ ; -CH ₂ CH ₂ NH ₂ ; -CH ₂ NHCH ₃ ; -CH ₂ N (CH ₃ ) ₂ ; -CH ₂ CH ₂ N (CH ₃ ) ₂ ; -CH ₂ N (CH ₂ CH ₃ ) ₂ ; -CH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ ; -SH; -SCH ₃ ; -SCH ₂ CH ₃ ; -SO-CH ₃ ; -SO-CH ₂ CH ₃ ; -SO ₂ -CH ₃ ; -SO ₂ -CH ₂ CH ₃ ; -SO ₂ N (CH ₃ ) ₂ ; -SO ₂ NHCH ₃ ; -NO ₂ ; -OCON (CH ₃ ) ₂ ; -OCONHCH ₃ ; -OCON (CH ₂ CH ₃ ) ₂ ; -C = NH; -C = NCH ₃ ; -C = NCH ₂ CH ₃ ; -NCH ₃ C (O) CH ₃ ; -NCH ₃ C (O) CH ₂ CH ₃ ; -N = CH ₂ ; -N = C ( CH ₃ ) ₂ ; —N═C (CH ₂ CH ₃ ) ₂ ; phenylcarbonyl; phenylcarbonyl substituted with a radical selected from the group consisting of at least the following: CF ₃ , F, Cl, Br, I, CN, OH, —CH ₃ , —CH ₂ CH ₃ , —OCH ₃ , and —OCH ₂ CH ₃ ; — (C ₁ -C ₃ ) -alkylphenylcarbonyl; (C ₁ -C ₃ ) -alkylphenylcarbonyl substituted with a radical selected from the group consisting of: CF ₃ , F, Cl, Br, I, CN, OH, —CH ₃ , —CH ₂ CH ₃ , — OCH ₃ , and —OCH ₂ CH ₃ ; phenyl; phenyl substituted with a radical selected from the group consisting of at least: CF ₃ , F, Cl, Br, I, CN, OH, —CH ₃ , -CH ₂ CH ₃ , -OCH ₃ , and -OCH ₂ CH ₃ ; (C ₁ -C ₃ ) -alkylphenyl; the phenyl moiety is substituted with a radical selected from the group consisting of at least ₁ -C ₃ ) -Alkylphenyl : CF ₃ , F, Cl, Br, I, CN, OH, —CH ₃ , —CH ₂ CH ₃ , —OCH ₃ , and —OCH ₂ CH ₃ .

According to another preferred embodiment of the invention, the compound of formula (I), R ₁ and R ₂ are the same or different and are each independently selected from the group consisting of: H; OH; -CH ₂ -NH-CH ₂ CCH; -NH-CH ₂ CCH; -CH ₂ -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; linear Or branched (C ₁ -C ₆ ) alkyl; hydroxy- (C ₁ -C ₆ ) alkyl; halo- (C ₁ -C ₆ ) alkyl; -NH ₂ ; -CN; -C (O) (C ₁ -C ₄₎ alkyl; -COO (C ₁ -C _{4) alkyl; -OC (O) (C 1} -C 4) alkyl; -C (O) N (( C 1 -C 4) alkyl) _2; - NH (C ₁ -C ₄ ) alkyl; -N ((C ₁ -C ₄ ) alkyl) ₂ ;-(C ₁ -C ₄ ) alkyl-NH (C ₁ -C ₄ ) alkyl; -SH; -S ( C ₁ -C ₄₎ alkyl; -SO- (C ₁ -C ₄₎ alkyl; -SO ₂ - (C ₁ -C _{4) alkyl; -SO 2 NH 2; -SONH (} C 1 -C 4) alkyl; -SON ((C ₁ -C ₄ ) alkyl) ₂ ; -OCONH ₂ ; -OCONH (C ₁ -C ₄ ) alkyl; -OCON ((C ₁ -C ₄ ) alkyl) ₂ ; and the phenyl moiety is at least thing It is substituted with a radical selected from Ranaru group (C ₁ -C ₃₎ - alkyl phenyl: halo (C ₁ -C ₆₎ - alkyl, OH, halogen, (C ₁ -C ₆₎ - alkyl, ( C ₁ -C ₆₎ - alkoxy, and CN.

Preferably, R ₁ is selected from the group consisting of: OH; —NH ₂ ; —CN; —C (O) (C ₁ -C ₄ ) alkyl; —COO (C ₁ -C ₄ ) alkyl -OC (O) (C ₁ -C ₄ ) alkyl; -C (O) N ((C ₁ -C ₄ ) alkyl) ₂ ; -NH (C ₁ -C ₄ ) alkyl; -N ((C ₁ -C ₄ ) alkyl) ₂ ;-(C ₁ -C ₄ ) alkyl-NH (C ₁ -C ₄ ) alkyl; -SH; -S (C ₁ -C ₄ ) alkyl; -SO- (C ₁ -C ₄ ) alkyl; -SO _2- (C ₁ -C ₄ ) alkyl; -SO ₂ NH ₂ ; -SONH (C ₁ -C ₄ ) alkyl; -SON ((C ₁ -C ₄ ) alkyl) ₂ ; -OCONH ₂ ; -OCONH (C ₁ -C ₄ ) alkyl; -OCON ((C ₁ -C ₄ ) alkyl) ₂ ; and the phenyl moiety is substituted with a radical selected from the group consisting of at least ₁ -C ₃₎ - alkyl phenyl: halo (C ₁ -C ₆₎ - alkyl, OH, halogen, (C ₁ -C ₆₎ - alkyl, (C ₁ -C ₆₎ - alkoxy, and CN.

  A particularly desirable group of compounds are those of formula (Ia):

Where R ₁ is selected from: OH; —NH ₂ ; —CN; —C (O) (C ₁ -C ₄ ) alkyl; —COO (C ₁ -C ₄ ) alkyl; —OC (O) (C ₁ -C ₄ ) alkyl; -C (O) N ((C ₁ -C ₄ ) alkyl) ₂ ; -NH (C ₁ -C ₄ ) alkyl; -N ((C ₁ -C ₄ ) Alkyl) ₂ ;-(C ₁ -C ₄ ) alkyl-NH (C ₁ -C ₄ ) alkyl; -SH; -S (C ₁ -C ₄ ) alkyl; -SO- (C ₁ -C ₄ ) alkyl -SO _2- (C ₁ -C ₄ ) alkyl; -SO ₂ NH ₂ ; -SONH (C ₁ -C ₄ ) alkyl; -SON ((C ₁ -C ₄ ) alkyl) ₂ ; -OCONH ₂ ;- OCONH (C ₁ -C ₄ ) alkyl; -OCON ((C ₁ -C ₄ ) alkyl) ₂ ; and the phenyl moiety is substituted with a radical selected from the group consisting of at least: (C ₁ -C ₃₎ - alkylphenyl: halo (C ₁ -C ₆₎ - alkyl, OH, halogen, (C ₁ -C ₆₎ - alkyl, (C ₁ -C ₆₎ - alkoxy, and CN,
R ₂ is selected from: H; OH; —CH ₂ —NH—CH ₂ CCH; —NH—CH ₂ CCH; —CH ₂ —N (C ₁ -C ₄ ) alkyl CH ₂ CCH; N (C ₁ -C ₄ ) alkyl CH ₂ CCH; linear or branched (C ₁ -C ₆ ) alkyl; hydroxy- (C ₁ -C ₆ ) alkyl; halo- (C ₁ -C ₆ ) alkyl; -NH ₂ ; -CN; -C (O) (C ₁ -C ₄ ) alkyl; -COO (C ₁ -C ₄ ) alkyl; -OC (O) (C ₁ -C ₄ ) alkyl; -C (O ) N ((C ₁ -C ₄ ) alkyl) ₂ ; -NH (C ₁ -C ₄ ) alkyl; -N ((C ₁ -C ₄ ) alkyl) ₂ ;-(C ₁ -C ₄ ) alkyl-NH (C ₁ -C ₄ ) alkyl; -SH; -S (C ₁ -C ₄ ) alkyl; -SO- (C ₁ -C ₄ ) alkyl; -SO _2- (C ₁ -C ₄ ) alkyl; -SO ₂ NH ₂ ; -SONH (C ₁ -C ₄ ) alkyl; -SON ((C ₁ -C ₄ ) alkyl) ₂ ; -OCONH ₂ ; -OCONH (C ₁ -C ₄ ) alkyl; -OCON ((C ₁ -C ₄₎ alkyl) _2; and phenyl portion is substituted with a radical selected from the group consisting of at least the following ones (C ₁ -C ₃₎ - alkyl phenyl: halo (C ₁ -C ₆₎ - alkyl , OH, halogen, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkoxy, and CN,
B is a radical of formula (VII), wherein R ₈ is selected from the group consisting of: H; OH; —CH ₂ —NH—CH ₂ CCH; —NH—CH ₂ CCH; CH ₂ -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; linear or branched (C ₁ -C ₆ ) alkyl; hydroxy- (C ₁ -C ₆ ) alkyl; CF ₃ ; CN; -O (C ₁ -C ₄ ) alkyl; (C ₁ -C ₄ ) alkyl-O- (C ₁ -C ₄ ) alkyl; -C (O) H;- C (O) (C ₁ -C ₄ ) alkyl; -COOH; -COO (C ₁ -C ₄ ) alkyl; -OC (O) H; -OC (O) (C ₁ -C ₄ ) alkyl; -C (O) NHCH ₃ ; -C (O) N (CH ₃ ) ₂ ; -NH ₂ ; -NHCH ₃ ; -N (CH ₃ ) ₂ ; -CH ₂ NH ₂ ; -CH ₂ CH ₂ NH ₂ ; -CH ₂ NHCH ₃ ; -CH ₂ N (CH ₃ ) ₂ ; -CH ₂ CH ₂ N (CH ₃ ) ₂ ; -CH ₂ N (CH ₂ CH ₃ ) ₂ ; -CH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ ; -SH; -SCH ₃ ; -SCH ₂ CH ₃ ; -SO-CH ₃ ; -SO-CH ₂ CH ₃ ; -SO ₂ -CH ₃ ; -SO ₂ -CH ₂ CH ₃ ; -SO ₂ N ( _{CH 3) 2; -SO 2 NHCH} 3; -NO 2; -OCON (CH 3) 2; -OCONHCH 3; -OCON (CH 2 CH 3) 2; -C = NH; -C = NCH 3; -C = NCH ₂ CH ₃ ; -NCH ₃ C (O) CH ₃ ; -NCH ₃ C (O) CH ₂ CH ₃ ; -N = CH ₂ ; -N = C (CH ₃ ) ₂ ; -N = C (CH ₂ CH ₃ ) ₂ ; phenylcarbonyl; phenylcarbonyl in which the phenyl moiety is substituted with a radical selected from the group consisting of at least: CF ₃ , F, Cl, Br, I, CN, OH, -CH ₃ , -CH ₂ CH ₃ , -OCH ₃ , and -OCH ₂ CH ₃ ;-(C ₁ -C ₃ ) -alkylphenylcarbonyl, (C ₁ -C ₃ ) -alkylphenylcarbonyl substituted with a radical selected from the group consisting of at least: CF ₃ , F, Cl, Br, I, CN, OH, —CH ₃ , —CH ₂ CH ₃ , —OCH ₃ , and —OCH ₂ CH ₃ ; phenyl; phenyl substituted with a radical selected from the group consisting of at least: CF ₃ , F, Cl, Br, I, CN, OH , -CH ₃ , -CH ₂ CH ₃ , -OCH ₃ , and -OCH ₂ CH ₃ ; (C ₁ -C ₃ ) -alkylphenyl; substituted with a radical selected from the group consisting of at least the following: is (C ₁ -C ₃₎ - alkyl Fe _{Le: CF 3, F, Cl,} Br, I, CN, OH, -CH 3, -CH 2 CH 3, -OCH 3, and -OCH ₂ CH _3,
Alternatively, R ₈ is a radical selected from: pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, dithiolanyl, pyridinyl, pyranidyl, pyrimidinyl, pyrimidinyl , Pyrazinyl, piperazinyl, benzofuranyl, isobenzofuranyl, indolyl, indenyl, dihydroindenyl, naphthalenyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, adenylyl, guaninyl, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl Benzodioxolyl, benzofurazanyl, benzotriazolyl, benzothiofuranyl, benzothiazolyl, benzothiadiazolyl, chromenyl, Sochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolinyl, and isoquinolinyl, each ring that forms part of the ring system is optionally substituted with at least one radical selected from the group consisting of: H; OH; -CH ₂ -NH-CH ₂ CCH; -NH-CH ₂ CCH; -CH ₂ -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; linear or branched (C ₁ -C ₆ ) alkyl; hydroxy- (C ₁ -C ₄ ) alkyl; CF ₃ ; CN; -O (C ₁ -C ₄ ) alkyl; (C ₁ -C ₄ ) Alkyl-O- (C ₁ -C ₄ ) alkyl; -C (O) H; -C (O) (C ₁ -C ₄ ) alkyl; -COOH; -COO (C ₁ -C ₄ ) alkyl;- OC (O) H; -OC (O) (C ₁ -C ₄ ) alkyl; -C (O) NHCH ₃ ; -C (O) N (CH ₃ ) ₂ ; -NH ₂ ; -NHCH ₃ ; -N (CH ₃ ) ₂ ; -CH ₂ NH ₂ ; -CH ₂ CH ₂ NH ₂ ; -CH ₂ NHCH ₃ ; -CH ₂ N (CH ₃ ) ₂ ; -CH ₂ CH ₂ N (CH ₃ ) ₂ ; -CH ₂ N (CH ₂ CH ₃ ) ₂ ; -CH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ ; -SH; -SCH ₃ ; -SCH ₂ CH ₃ ; -SO-CH ₃ ; -SO-CH ₂ CH ₃ ; -SO ₂ -CH ₃ ;- SO ₂ -CH ₂ CH ₃ ; -SO ₂ N (CH ₃ ) ₂ ; -SO ₂ NHCH ₃ ; -NO ₂ ; -OCON (CH ₃ ) ₂ ; -OCONHCH ₃ ; -OCON (CH ₂ CH ₃ ) ₂ ; -C = NH; -C = NCH ₃ ; -C = NCH ₂ CH ₃ ; -NCH ₃ C (O) CH ₃ ; -NCH ₃ C (O) CH ₂ CH ₃ ; -N = CH ₂ ; -N = C (CH ₃ ) ₂ ; -N = C (CH ₂ CH ₃ ) ₂ ,
Where n is an integer from 0 to 1,
The BA moiety is selected from the group consisting of: B- (CH ₂ ) _n1 -O- (CH ₂ ) _n2- ; B- (CH ₂ ) _n1 -NH- (CH ₂ ) _n2- ; B- ( _{CH 2) n1 -CH 2 -;} B- (CH 2) n1 -O-; B- (CH 2) n1 -NH-; bO- (CH 2) n2 -; B-NH- (CH 2) n2 - B-; BO-; B-NH-; BO- (CH ₂ ) _n3 -O-; BO- (CH ₂ ) _n3 -NH-; B-NH- (CH ₂ ) _n3 -NH-; and B- NH (CH ₂ ) _n3 -O-,
N1, n2 and n3 are each independently an integer selected from 1 to 4.

In another preferred embodiment, the invention relates to compounds of formula (Ia), wherein
R ₁ is selected from: OH; —NH ₂ ; —CN; —C (O) CH ₃ ; —COOCH ₃ ; —OC (O) CH ₃ ; Methylphenyl substituted with a selected radical: OH, halogen, methyl, ethyl, methoxy, and CN;
R ₂ is selected from: H; OH; —CH ₂ —NH—CH ₂ CCH; —NH—CH ₂ CCH; methyl; ethyl; —CH ₂ OH; —NH ₂ ; —CN; —C ( O) CH ₃ ; -COOCH ₃ ; -OC (O) CH ₃ ; and -OCONH ₂ ,
B is a radical of formula (VII), wherein R ₈ is selected from the group consisting of: H; OH; —CH ₂ —NH—CH ₂ CCH; —NH—CH ₂ CCH; methyl; -CH ₂ OH; -NH ₂ ; -CN; -C (O) CH ₃ ; -COOCH ₃ ; -OC (O) CH ₃ ; -OCONH ₂ ; phenyl; selected from the group consisting of at least Substituted with a radical: CF ₃ , F, Cl, Br, I, CN, OH, —CH ₃ , —CH ₂ CH ₃ , —OCH ₃ , and —OCH ₂ CH ₃ ; (C ₁ -C ₃ ) -alkylphenyl; (C ₁ -C ₃ ) -alkylphenyl substituted with a radical selected from the group consisting of at least: CF ₃ , F, Cl, Br, I, CN, OH, -CH ₃ , -CH ₂ CH ₃ , -OCH ₃ , and -OCH ₂ CH ₃ ,
Where n is an integer from 0 to 1,
The BA moiety is selected from the group consisting of: B- (CH ₂ ) _n1 -O- (CH ₂ ) _n2- ; B- (CH ₂ ) _n1 -NH- (CH ₂ ) _n2- ; B- ( _{CH 2) n1 -CH 2 -;} B- (CH 2) n1 -O-; B- (CH 2) n1 -NH-; bO- (CH 2) n2 -; B-NH- (CH 2) n2 - B-; BO-; B-NH-; BO- (CH ₂ ) _n3 -O-; BO- (CH ₂ ) _n3 -NH-; B-NH- (CH ₂ ) _n3 -NH-; and B- NH- (CH ₂ ) _n3 -O-;
N1, n2 and n3 are each independently an integer selected from 1 to 4.

More preferred compounds are those of formula (I), where
R ₁ is selected from the group consisting of: OH; —NH ₂ ; —CN; —C (O) CH ₃ ; —COOCH ₃ ; and —OC (O) CH ₃ ,
R ₂ is selected from: H; OH; and —CN,
B is a radical of formula (VII), wherein R ₈ is selected from the group consisting of: H; OH; methyl; ethyl; —CH ₂ OH; —NH ₂ ; —CN; —C; ) CH ₃ ; -COOCH ₃ ; -OC (O) CH ₃ ; -OCONH ₂ ; phenyl; and benzyl,
Where n is an integer from 0 to 1,
The BA moiety is selected from the group consisting of: B- (CH ₂ ) _n1 -O- (CH ₂ ) _n2- ; B- (CH ₂ ) _n1 -NH- (CH ₂ ) _n2- ; B- ( _{CH 2) n1 -CH 2 -;} B- (CH 2) n1 -O-; B- (CH 2) n1 -NH-; bO- (CH 2) n2 -; B-NH- (CH 2) n2 - B-; BO-; B-NH-; BO- (CH ₂ ) _n3 -O-; BO- (CH ₂ ) _n3 -NH-; B-NH- (CH ₂ ) _n3 -NH-; and B- NH- (CH ₂ ) _n3 -O-,
N1, n2 and n3 are each independently an integer selected from 1 to 2.

In a particularly preferred embodiment in this first aspect, the present invention relates to a compound of formula (I) selected from:
2- (1-benzylpiperidin-4-yl) -2-(((8-hydroxyquinolin-5-yl) methyl) (prop-2-ynyl) amino) acetonitrile (2);
5-((((1-benzylpiperidin-4-yl) methyl) (prop-2-ynyl) amino) methyl) quinolin-8-ol (3);
3- (1-benzylpiperidin-4-yl) -2-(((8-hydroxyquinolin-5-yl) methyl) (prop-2-ynyl) amino) propanenitrile (4);
5-(((1-benzylpiperidin-4-yl) ethyl) (prop-2-ynyl) amino) methyl) quinolin-8-ol (5);
4- (1-benzylpiperidin-4-yl) -2-(((8-hydroxyquinolin-5-yl) methyl) (prop-2-ynyl) amino) butanenitrile (6);
5-(((3- (1-Benzylpiperidin-4-yl) propyl) (prop-2-ynyl) amino) methyl) quinolin-8-ol (7).

  The compounds of the present invention are multifunctional compounds, at least one residue that confers both anti-apoptotic and neuroprotective functions to the compound, at least one residue that confers brain MAO inhibitory function to the compound, and It contains at least one residue that confers biometal chelation function.

  Accordingly, the compounds of the present invention are useful for the treatment and / or prevention of diseases, disorders and conditions mediated by inhibition of amino oxidase (MAO), inhibition of cholinesterase (AChE, BuChE) and biometal chelation. In certain embodiments, the compounds of the invention are useful for the treatment and / or prevention of neurodegenerative disorders, preferably such neurodegenerative disorders include Alzheimer's disease, Parkinson's disease and brain iron accumulation ( Selected from neurodegeneration with NBIA).

  The “prevention” aspect of the use of the compounds of the invention in diseases such as Parkinson's disease and AD includes the prevention of further neurodegeneration and further progression of the disease.

  One of the major pathological features of AD is cerebral amyloid angiopathy (CAA). CAA is present in most cases of AD and is characterized by the deposition of Aβ in cerebral blood vessels, which induces degeneration of vascular smooth muscle cells and endothelial cells. Semicarbazide-sensitive amine oxidase (SSAO) is overexpressed in brain tissue of AD-CAA patients and it is localized with Aβ deposition. This overexpression correlates with high SSAO activity in the plasma of severe AD patients. In addition, the catalytic activity of SSAO can induce smooth muscle cell apoptosis in vitro and contributes to vascular damage associated with AD. Therefore, the ability to inhibit semicarbazide sensitive amine oxidase (SSAO) was determined radiochemically to assess the activity of the compounds of the present invention.

  Active agents useful in conventional treatment of diseases, conditions and / or disorders mediated by inhibition of amino oxidase (MAO) and / or inhibition of cholinesterase (AChE, BuChE) and / or biometal chelation are preferably Rivastigmine, donepezil, galantamine and memantine.

  Furthermore, the present invention covers all possible combinations of the specific preferred embodiments described above.

  When the compounds according to the invention are in the form of salts, these are preferably pharmaceutically acceptable salts. The term “pharmaceutically acceptable salts” as used herein refers to salts derived from organic and inorganic acids. The compounds of general formula (I) can be converted into their pharmaceutically acceptable salts or their pharmaceutically acceptable solvates by conventional methods. For example, such salts can be obtained by treating one or more compounds with an aqueous solution of a pharmaceutically acceptable metal hydroxide or other metal base, preferably under reduced pressure in a nitrogen atmosphere. It can be prepared by evaporating to dryness. Alternatively, a solution of the compound of formula (I) may be mixed with the desired metal alkoxide, which solution is then evaporated to dryness. Pharmaceutically acceptable hydroxides, bases, and alkoxides include valuable cations for this purpose, including but not limited to potassium, sodium, ammonium, calcium, magnesium, and the like. Other representative pharmaceutically acceptable salts are hydrochloride, hydrobromide, sulfate, bisulfate, lactate, phosphate, tosylate, citrate, maleate, fumarate Acid salts, succinates, tartrates, acetates, oxalates, propionates, nitrates, methanesulfonates, benzoates and also known acceptable acids.

  In addition to salt forms, the present invention provides compounds which are in a prodrug form. Prodrugs of the compounds described herein are due to metabolic or chemical processes to produce compounds of formula (I), and / or salts and / or solvates thereof, upon administration to a subject. A compound that undergoes chemical transformation. A prodrug is a pharmacologically active or inactive compound that is chemically modified through in vivo physiological actions such as hydrolysis, metabolism, etc. to a compound of the present invention after administration of the prodrug to a patient. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme. The suitability and techniques involved in making and using prodrugs are well known by those skilled in the art.

  It will be apparent to those skilled in the art that certain compounds of the present invention have asymmetric carbon atoms (optical centers) and / or double bonds. Thus, all stereoisomers of the compounds mentioned herein, and mixtures thereof, such as those that may exist due to asymmetric carbons in any of the substituents, are enantiomeric forms (even It is contemplated that it may survive in the absence of asymmetric carbon) and diastereomeric forms and is within the scope of the preferred embodiments. Also, for example, individual stereoisomers that are substantially free of other isomers, or that may be mixed, for example, as racemates or with all other or other selected geometric isomers of the present invention. It is intended to be within the scope of Thus, any compound referred to herein is intended to represent a racemate, one or more enantiomeric forms, one or more atropisomeric forms, and mixtures thereof.

  It should be noted that general procedures are shown as relating to the preparation of compounds with unspecified stereochemistry. However, such a procedure is generally applicable to compounds of a particular stereochemistry, for example when the stereochemistry at the asymmetric center is (S) or (R). Also, compounds with one stereochemistry (eg (R)) are often used to prepare those with the opposite stereochemistry (ie (S)) using well-known methods such as inversion. can do. The same applies to the Z / E isomer. Thus, the preparation process described herein can be modified to give compounds of high optical purity, as well as mixtures of stereoisomers. It is possible to prepare a specific stereoisomer or a specific mixture by various processes including the use of stereospecific reagents or by introducing chiral centers into the compound during its preparation process. Furthermore, stereoisomers can be separated after the compounds have been prepared by standard resolution techniques known to those skilled in the art.

  The compounds of formula (I) can take crystalline form, either as unsolvated compounds or as solvates (eg hydrates), both forms being intended to be within the scope of the invention Is done. Solvation methods are generally known in the art.

  Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

  The invention also relates to a pharmaceutical composition comprising a compound of the invention according to formula (II) (or a pharmaceutically acceptable salt thereof) and one or more pharmaceutically acceptable carriers. The carrier must be “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of the composition and not injurious to the recipient.

  Suitable carriers, excipients, etc. can be found from standard pharmaceutical textbooks.

  The compounds of the present invention can be administered in the form of any pharmaceutical preparation, the nature of which depends on the nature of the active compound and its route of administration, as is well known. Any route of administration can be used, such as oral, parenteral, nasal, ocular, rectal and topical administration. The party will establish the necessary parameters and excipients, taking into account the available knowledge.

  In therapeutic use, the dosage can vary depending on the requirements of the patient, the severity of the condition being treated, and the compound employed. Determination of the optimal dosage in a particular situation is within the skill of the art.

  The compounds of the present invention can be used in a manner substantially similar to other known therapeutic agents for treating the conditions or disorders described above. Of course, the dose administered may be a single compound, multiple doses, or daily administration, among other factors, the particular compound employed, the route of administration chosen, the recipient's weight and body. It varies according to the surface, the patient's physical condition, and stage. The dose to be administered is not a boundary definition, but is usually an effective amount to achieve the desired pharmacological or physiological effect, or the pharmacology produced from the administered formulation upon metabolic release of the active drug. Equivalent to that on a molar basis of chemically active free form. A skilled physician in the art will be able to find an appropriate protocol for effective administration of the compounds of the preferred embodiments.

  Also included within the scope of the invention are methods for preparing compounds of formula (I) as described above.

A compound of formula (I), wherein R ₂ = H and R ₁ , n, A and B are as defined above, is represented by the formula (IX) in the presence of sodium cyanoborohydride (NaCNBH ₃ ) It can be prepared by reacting an aldehyde with propargylamine followed by a reaction with a 5- (chloromethyl) quinolin-8-yl derivative of formula (X).

Instead, R ₂ = H and R ₁ , n, A and B are as defined above, the compound of formula (I) is 5- (chloromethyl) quinolin-8-yl of formula (X) Starting from the derivative, reaction with propargylamine gives the 5-((prop-2-yn-1-ylamino) methyl) quinolin-8-yl derivative of formula (XI), followed by sodium cyanoborohydride It can be prepared by reacting with an aldehyde of formula (IX) in the presence of (NaCNBH ₃ ).

Compounds of formula (I) where R ₂ = CN, CO ₂ R ₃ , SO ₂ (4-MeC ₆ H ₄ ) are respectively aminoacetonitrile, glycine ethyl ester hydrochloride and 1-[(4-methylphenyl ) Sulfonyl] methanamine with a (chloromethyl) quinolin-8-yl derivative of formula (X) to give a compound of formula (XII), followed by reaction with propargylamine, an intermediate of type (XIII) And a reaction with a chloride of the general structure (XIV).

[Definition]
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

  The term “MAO responsive disorder” and variations thereof are those in which the biological function of the MAO inhibitor affects the occurrence and / or course of the disease or condition, and / or the modulation of MAO is the occurrence of the disease or condition, the course And / or refers to a disease or condition that alters symptoms. Modulating (eg, inhibiting) activity levels or MAO in subjects with MAO responsive disorders can reduce the severity and / or duration of the disease, prevent or delay the onset of the disease or condition Cause and / or cause an amelioration of one or more symptoms of the disease or condition.

  The term “ChE responsive disorder” and variations thereof refer to the biological function of the MAO inhibitor affecting the occurrence and / or course of the disease or condition, and / or the modulation of ChE is the occurrence of the disease or condition, the course And / or refers to a disease or condition that alters symptoms. Modulating (eg, inhibiting) activity levels or ChE in subjects with ChE responsive disorders can reduce the severity and / or duration of the disease, prevent or delay the onset of the disease or condition Cause and / or cause an amelioration of one or more symptoms of the disease or condition.

  Throughout this specification, the term “treatment” is meant to eliminate, reduce or ameliorate the cause, effect or progression of symptoms, including slowing progression, stopping progression, improving condition, and restoring condition. include. Treatment as a preventive measure (eg prevention) is also included. The term “treatment” includes combination treatments and therapies in which two or more treatments or therapies are combined, eg, performed sequentially or simultaneously. For the purposes of the present invention, treatment may alleviate, ameliorate or eliminate one or more symptoms of a condition, reduce the extent of the condition, stabilize (ie, not exacerbate) the condition's status, delay or slow down the progression of the condition Including, but not limited to, improving or alleviating the status of the condition and ameliorating (whether partially or totally) the condition.

  The treatments defined above may be applied as monotherapy or include one or more active agents useful in conventional treatment of such diseases, conditions and / or disorders in addition to the compounds of the present invention. But you can.

  The expression “combination therapy” is one useful in the conventional treatment of at least one compound of formula (I) as defined above and such diseases, conditions and / or disorders simultaneously, sequentially or separately. It refers to a pharmaceutical preparation applied to require the above active agents and the like.

  The term “known ring system” refers to ring systems known in the art and is intended to exclude ring systems that are not chemically possible.

  According to the invention, a ring system formed by “separated” rings is formed by two, three or four rings, which ring is from one ring atom. It is connected through a bond to an atom of another ring.

  The term “isolated” also encompasses embodiments in which the ring system has only one ring. Illustrative non-limiting examples of known ring systems consisting of one ring are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, phenyl, cycloheptenyl, aziridinyl, oxirenyl, thiranyl, Azetidinyl, oxetanyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, dithiolanyl, pyridinyl, pyranyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, oxazinyl, thiazinyl, oxazinyl, thiazinyl, To do.

  According to the present invention, a ring system having a “fully condensed” ring is one in which two, three or four are shared by two or more atoms by two or more atoms. It is formed by two rings. Illustrative non-limiting examples of known ring systems consisting of two fully condensed rings include benzofuran, isobenzofuran, indole, indene, dihydroindene, naphthalene, isoindole, indolizine, indoline, iso Indoline, purine (eg, adenine, guanine), benzimidazole, indazole, benzoxazole, benzisoxazole, benzodioxole, benzofurazan, benzotriazole, benzothiofuran, benzothiazole, benzothiadiazole, heterocyclic chromene, isochromene, Chroman, isochroman, benzodioxane, quinoline, isoquinoline, quinolidine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine, pute It is derived from the gin. Illustrative non-limiting examples of known ring systems consisting of three fused rings include carbazole, dibenzofuran, dibenzothiophene, carboline, perimidine, pyridoindole, acridine, xanthene, thioxanthene, oxanthrene, phenoxathiin Phenazine, phenoxazine, phenothiazine, thianthrene, phenanthridine, phenanthroline, and phenazine.

  According to the invention, when a ring system is “partially condensed”, this is because the ring system is formed by three or four rings, at least two of which are completely condensed. (Ie, two or more atoms are shared by two adjacent rings), the remaining rings are bonded via a bond from one ring atom to one of the condensed rings Means that

  In the context of the present invention, the term “alkene” is understood as an unsaturated chemical compound containing at least one carbon-carbon double bond. Preferably, the alkene is selected from the group consisting of 1,3-diene, 1,3,5-triene, terminal alkene and internal alkene.

The term “(C ₁ -C ₆ ) alkyl” as used herein refers to a saturated, branched or straight hydrocarbon chain having 1 to 6 carbon atoms. Preferably, “(C ₁ -C ₆ ) alkyl” is an unsubstituted group selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl and t-butyl.

The term “(C ₁ -C ₆ ) alkoxy” as used herein is a saturated, branched or linear, hydrocarbon chain having 1 to 6 carbon atoms bonded to oxygen (ie, as defined above). (C ₁ -C ₆ ) alkyl), ie (C ₁ -C ₆ ) alkyl-O. Preferably, the term “(C ₁ -C ₆ ) alkoxy” is an unsubstituted group selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, and t-butoxy.

  The term “halogen” is meant to include fluorine, chlorine, bromine and iodine.

  The term “pharmaceutically acceptable” as used herein is suitable for use in contact with a subject's (eg, human) tissue within the scope of sound medical judgment, and has excess toxicity, Related to compounds, materials, compositions, and / or dosage forms that are free of irritation, allergic reactions, or other problems or complications and are commensurate with a reasonable benefit / risk ratio. Each carrier, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the dosage form.

  The term “therapeutically effective amount” as used herein relates to the amount of active compound or material, composition or dosage form containing the active compound and is effective to produce any desired therapeutic effect. is there.

  Throughout the specification and claims, the term “comprising” and variations of this term are not intended to exclude other technical features, additives, ingredients or steps. Furthermore, the term “containing” includes the case of “consisting of”. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon review of the specification or may be learned by practice of the invention. The following examples and figures are provided for purposes of illustration and are not intended to limit the invention. Reference signs in connection with the drawings or in parentheses in the claims are only for the purpose of improving the understanding of the claims and are understood to limit the scope of the claims. Should not. Furthermore, the invention extends to all possible combinations of all specific or preferred embodiments described individually.

Melting points were determined without correction using a Koffler apparatus. ¹ H NMR and ¹³ C NMR were measured in deuterated chloroform (CDCl ₃ ) or deuterated dimethyl sulfide (DMSO-d ₆ ) at 300, 400 or 600 MHz and 100 or 150 MHz, respectively, and the solvent peak [CDCl ₃ : 7.27 (D), 77.2 (C) ppm; D ₂ O: 4.60 ppm and DMSO-d ₆ : 2.49 (D), 40 (C) ppm] were used as internal standards. The determination of the chemical shift was based on a standard NMR experiments ^{(1 H, 13 C-DEPT} , 1 H, 1 H-COSY, gHSQC, gHMBC). Mass spectrometry was measured with a GC / MS analyzer using API-ES as an ionization source. Elemental analysis was performed at CNQO (CSIC, Madrid, Spain). TLC was performed on silica F254 and detected with a 254 nm UV lamp or by scorching with ninhydrin, anisaldehyde or phosphomolybdenum-H ₂ SO ₄ colorant. Anhydrous solvent was used for each experiment. Column chromatography was performed on silica gel 60 (230 mesh).

[Example 1] Synthesis of intermediate 5- (chloromethyl) quinolin-8-ol (9)

While cooling to 0 ° C., 37% formalin solution (20 mL) was added to a solution of 8-hydroxyquinoline (14.6 g, 100 mmol) in concentrated hydrochloric acid (44 mL). The hydrochloric acid gas was then passed through the solution for 2 hours with stirring. The reaction was warmed to room temperature, stirred for an additional 6 hours, and allowed to stand for an additional 2 hours. The product was filtered off and the solid was washed with concentrated hydrochloric acid to give the target product 9 (19.9 g, 77.5%) as a bright yellow solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 5.30 (s, 2H), 7.51 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 8.13 (dd, J = 8.7, 5.2 Hz, 1H), 9.12 (dd, J = 5.1, 1.3 Hz, 1H), 9.24 (dd, J = 8.8, 1.3 Hz, 1H).

[Example 2] Intermediate N-[(1-benzylpiperidin-4-yl) methyl] prop-2-yn-1-amine (10) and (1-1-benzylpiperidin-4-yl) (prop- Synthesis of 2-in-1-ylamino) acetonitrile (11)

To a solution of 1-benzyl-4-piperidinecarbaldehyde (407 mg, 2.0 mmol) and propargylamine (165 mg, 3.0 mmol) in methanol (6 mL) while cooling to 0 ° C., a small amount of CF ₃ CO ₂ H (5 Drop) was added. After stirring for 1 hour, NaBH ₃ CN (189 mg, 2.9 mmol) was added to the solution in small portions. The reaction mixture was stirred at room temperature overnight and then quenched with saturated aqueous NaHCO ₃ solution. The reaction mixture was concentrated in vacuo and then extracted with AcOEt. The combined organic layers were dried over MgSO ₄ and concentrated under reduced pressure to give a mixture. This was purified by column chromatography (SiO ₂ , elution solvent was changed from hexane / AcOEt = 5: 1 to AcOEt, then AcOEt / MeOH = 4: 1 v / v), and compound 10 (232 mg, 50.2%) As an orange oil and product 11 (165 mg, 30.9%) as an orange oil.
N-[(1-Benzylpiperidin-4-yl) methyl] prop-2-yn-1-amine (10): R _f = 0.23 (AcOEt / MeOH = 4: 1); IR (film) ν 3287, 3028 , 2918, 2801, 2758, 1495, 1454, 1366, 1342, 1121, 1078 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.15-1.55 (m, 3 H), 1.72 (d, J = 12.5 Hz, 2 H), 1.95-2.11 (m, 2 H), 2.20 (t, J = 2.3 Hz, 1 H), 2.57 (d, J = 6.6 Hz, 2 H), 2.94 (d, J = 11.7 Hz , 2 H), 3.33-3.65 (m, 4 H), 7.19-7.40 (m, 5H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 30.1, 35.8, 38.4, 53.4, 54.5, 63.1, 71.4, 82.2 , 127.3, 128.3, 129.4, 137.3.
(1-Benzylpiperidin-4-yl) (prop-2-yn-1-ylamino) acetonitrile (11): R _f = 0.78 (AcOEt / MeOH = 4: 1); IR (film) ν 3296, 2940, 2920 , 2803, 2760, 1732, 1452, 1368, 1246, 1223, 1072 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.37-1.72 (m, 4 H), 1.76-1.88 (m, 2 H) , 1.92-2.02 (m, 2 H), 2.26-2.33 (m, 1 H), 2.87-2.98 (m, 2 H), 3.44-3.69 (m, 5 H), 7.17-7.44 (m, 5 H) ¹³ C NMR (100 MHz, CDCl ₃ ) δ 28.4, 29.0, 36.8, 39.0, 53.0, 54.5, 63.0, 72.8, 80.1, 118.7, 127.1, 128.2, 129.1, 138.3.

Example 3 Synthesis of 5-((((1-benzylpiperidin-4-yl) methyl) (prop-2-ynyl) amino) methyl) quinolin-8-ol (3)

Et ₃ N (1.09 mL, 5.2 mmol) was added at room temperature to a stirred solution of compound 10 (638 mg, 2.6 mmol) and chloride 9 (694 mg, 2.7 mmol) in methylene chloride (12 mL). The mixture was stirred overnight and then quenched with water. The product was extracted with CH ₂ Cl ₂ , dried over MgSO ₄ and concentrated in vacuo. Purification by column chromatography (SiO ₂ , hexane / AcOEt gradient increased from 5: 1 to 1: 1 v / v) gave amine 3 (572 mg, 55%) as a light brown solid : mp 128.5 ° C; IR (KBr) ν 3320, 3248, 2946, 2914, 2754, 2365, 1734, 1580, 1506, 1478, 1422, 1366, 1279, 1229, 1192, 1128, 1065 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.97-1.14 (m, 2 H), 1.32-1.48 (m, 1 H), 1.60 (d, J = 12.5 Hz, 2 H), 1.84 (t, J = 11.0 Hz, 2 H), 2.19 (s, 1 H), 2.36 (d, J = 7.2 Hz, 2 H), 2.76 (d, J = 11.1 Hz, 2 H), 3.15 (d, J = 1.9 Hz, 2 H) , 3.39 (s, 2 H), 3.83 (s, 2 H), 6.98 (d, J = 7.8 Hz, 1 H), 7.12-7.37 (m, 7 H), 8.53 (dd, J = 8.5, 1.4 Hz , 1 H), 8.68 (dd, J = 4.2, 1.4 Hz, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 30.8, 33.5, 40.8, 53.6, 56.6, 59.1, 63.5, 73.4, 78.4, 108.7 , 121.3, 124.9, 126.9, 127.8, 128.1, 129.1, 129.2, 134.1, 138.5, 138.7, 147.5, 151.9. Anal.Calcd for C ₂₆ H ₂₉ N ₃ O: C, 78.16; H, 7.32; N, 10.52. C, 78.05; H, 7.36; N, 10.40.

Example 4 Synthesis of 2- (benzylpiperidin-4-yl) -2-(((8-hydroxyquinolin-5-yl) methyl) (prop-2-ynyl) amino) acetonitrile (2)

To a solution of compound 11 (70 mg, 0.29 mmol) and Et ₃ N (0.085 mL, 0.58 mmol) in methylene chloride (2 mL) was added chloride 9 (70 mg, 0.25 mmol). After the mixture was stirred for 30 minutes at room temperature, brine was added. The product was extracted with methylene chloride and the extract was dried over MgSO ₄ and then concentrated in vacuo. The resulting crude product was purified by column chromatography (increasing the hexane / AcOEt gradient from 5: 1 to 1: 1 v / v) to give compound 2 (99 mg, 80.6%) as a white solid Obtained: IR (KBr) ν 3443, 3300, 3026, 2949, 2814, 1580, 1504, 1476, 1454, 1424, 1371, 1269, 1229, 1193, 1150, 1072 cm ^-1 ; ¹ H NMR (600 MHz, CDCl ₃ ) δ 0.68-0.70 (m, 1 H), 1.17-1.22 (m, 1 H), 1.65-1.95 (m, 5 H), 2.41 (s, 1 H), 2.65 (s, 1 H), 2.81-2.83 (m, 1 H), 3.23-3.29 (m, 2 H), 3.34 (s, 1 H), 3.45-3.48 (m, 1 H), 3.68 (d, J = 13.2 Hz, 1 H) , 4.63 (d, J = 13.8 Hz, 1 H), 7.1-7.20 (m, 1 H), 7.21-7.28 (m, 5 H), 7.40-7.44 (m, 2 H), 8.60 (d, J = 8.4 Hz, 1 H), 8.76 (d, J = 4.2 Hz, 1 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 29.4, 30.7, 36.0, 40.0, 52.5, 54.2, 57.7, 63.1, 74.0, 78.8 , 84.7, 108.9, 111.8, 116.0, 121.7, 122.2, 127.2, 127.5, 128.2, 129.3, 130.0, 134.0, 138.8, 148.9, 152.6. Anal.Calcd for C ₂₇ H ₂₈ N ₃ O: C, 76.39; H, 6.65 N, 13.20. Found: C, 76.45; H, 6.75; N 13.17.

Example 5 5-(((1-Benzylpiperidin-4-yl) ethyl) (prop-2-ynyl) amino) methyl) quinolin-8-ol (5) and 3- (1-benzylpiperidine-4 Synthesis of (-yl) -2-(((8-hydroxyquinolin-5-yl) methyl) (prop-2-ynyl) amino) propanenitrile (4)

Diethyl (cyanomethyl) phosphite : Diethyl (cyanomethyl) phosphite was prepared by heating triethyl phosphite (1 equivalent) and chloroacetonitrile (1 equivalent) at 150 ° C. for 3.5 hours. The crude product was used for the next reaction as it was.

(1-Benzylpiperidin-4-ylidene) acetonitrile (12) : A solution of diethyl (cyanomethyl) phosphite (2.13 g, 12 mmol) and K ₂ CO ₃ (1.39 g, 10 mmol) in dry THF (5 mL) at room temperature For 15 minutes. The mixture was then heated to reflux for 20 minutes. After cooling to room temperature, 1-benzyl-4-piperidone (1.90 g, 10 mmol) was added dropwise to this solution. The mixture was then heated to reflux for 12 hours. After cooling to room temperature, 10% K ₂ CO ₃ aqueous solution was added. The reaction mixture was extracted with AcOEt and the organic layer was dried over MgSO ₄ and concentrated in vacuo to give the crude product 12 [2.7 g,>99.0%; ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.40 ( t, J = 5.1 Hz, 2 H), 2.51-2.63 (m, 6 H), 3.55 (s, 2 H), 5.10 (s, 1 H), 7.26-7.34 (m, 5 H)] . This was used as is in the next step.

(1-Benzyl-piperidin-4-yl) acetonitrile (13): in MeOH (100 mL) solution of nitrile 12 (2.7 g, 10 mmol) , was added Mg (4.6 g, 191 mmol) and I ₂ traces. The mixture was stirred until a gray gel was obtained. After adding concentrated HCl, the mixture became a clear solution. It was then made alkaline by treatment with 10 N NaOH. The precipitate was filtered and washed with copious amounts of EtOAc. The filtrate was extracted with EtOAc and the combined organic phases were dried over MgSO ₄ and concentrated in vacuo to give product 13 (1.59 g, 74.5%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.48 (m, 2 H), 1.68 (m, 1 H), 1.78 (m, 2 H), 2.00 (t, J = 52.77 Hz, 2 H), 2.28 ( d, J = 6.60 Hz, 2 H), 2.93 (d, J = 11.8 Hz, 2 H), 3.55 (s, 2 H), 7.24-7.34 (m, 5 H).

(1-Benzylpiperidin-4-yl) acetaldehyde (14) : Nitrile 13 (1.29 g, 6.0 mmol) and THF (13 mL) were added to a flask dried in an oven and purged with argon. The mixture was cooled to −78 ° C. and DIBAL-H (6.22 mL, 1 mmol / mL) was added to the reaction through a syringe. The reaction was stirred for 1 h at −78 ° C. and then quenched with saturated aqueous NaHCO ₃ solution. The precipitate was filtered and washed with copious amounts of EtOAc. The filtrate was extracted with EtOAc. The combined organic phases were washed with brine and dried over MgSO ₄ . After concentration in vacuo, the crude product is purified by chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH = 20: 1 v / v) and product 10 (365 mg, 27.8%) is obtained as an orange oil Got as. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.20-1.50 (m, 2 H), 1.60-2.15 (m, 5 H), 2.36 (dd, J = 6.7, 1.76 Hz, 2 H), 2.88 (d, J = 11.2 Hz, 2 H), 3.51 (s, 2 H), 7.17-7.42 (m, 5 H), 9.76 (t, J = 1.9 Hz, 1 H).

N- [2- (1-benzylpiperidin-4-yl) ethyl] prop-2-yn-1-amine (15) and 3- (1-benzylpiperidin-4-yl) -2- (prop-2- In-1-ylamino) propanenitrile (16) : A solution of compound 14 (365 mg, 1.68 mmol) and propargylamine (187 mg, 3.4 mmol) in MeOH (10 mL) was stirred for 1 hour at 0 ° C., then NaBH ₃ CN (214 mg, 3.4 mmol) was added. The mixture was stirred overnight at room temperature. Water was added to the mixture and MeOH was removed under reduced pressure. Then saturated aqueous NaHCO ₃ solution was added and the mixture was extracted with AcOEt. The separated organic phase was dried over MgSO ₄ and concentrated in vacuo to give the crude product. Further purification was achieved by column chromatography (SiO ₂ , elution solvent changed from hexane / AcOEt 5: 1 to 1: 5 v / v, then changed from AcOEt to AcOEt / MeOH 4: 1 v / v). 15 (168 mg, 38.9%) was obtained as an orange oil and product 16 (190 mg, 40.2%) was obtained as an orange oil. N- [2- (1-Benzylpiperidin-4-yl) ethyl] prop-2-yn-1-amine (15): R _f = 0.11 (MeOH / AcOEt = 1: 4); IR (film) ν 3302 , 2922, 2945, 2801, 2758, 1493, 1454, 1366, 1148, 1121, 1078, 1028 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.15-1.45 (m, 5H), 1.61 (d, J = 10.5 Hz, 2 H), 1.94 (t, J = 11.1 Hz, 2 H), 2.13 (t, J = 2.1 Hz, 1 H), 2.63 (t, J = 7.2 Hz, 2 H), 2.84 ( d, J = 11.5 Hz, 2 H), 3.30-3.55 (m, 4 H), 7.12-7.33 (m, 5 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 32.1, 33.5, 36.4, 38.2, 46.0, 53.7, 63.3, 71.4, 82.2, 127.0, 128.1, 129.3, 129.4, 137.6. 3- (1-Benzylpiperidin-4-yl) -2- (prop-2-yn-1-ylamino) propanenitrile (16 ): R _f = 0.56 (MeOH / AcOEt = 1: 4); IR (film) ν 3295, 2924, 2905, 2782, 1493, 1452, 1388, 1343, 1125, 1074 cm ^-1 ; ¹ H NMR (400 MHz , CDCl ₃ ) δ 1.15-1.38 (m, 2 H), 1.43-1.73 (m, 5 H), 1.92 (t, J = 11.5 Hz, 2 H), 2.21 (t, J = 2.3 Hz, 1 H) , 2.82 (d, J = 10.7 Hz, 2 H), 3.35-3.64 (m, 4 H), 3.66-3.78 (m, 1H), 7.13-7.33 (m, 5 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 31.7, 31.9, 32.2, 36.4, 39.9, 46.9 53.2, 63.2, 72.7, 79.8, 119.6, 126.9, 128.0, 129.0, 129.1, 138.1.

5-(((2- (1-Benzylpiperidin-4-yl) ethyl) (prop-2-ynyl) amino) methyl) quinolin-8-ol (5) : Compound in CH ₂ Cl ₂ (2.5 mL) To a mixture of 15 (46 mg, 0.18 mmol) and Et ₃ N (0.053 mL, 0.38 mmol) cooled to 0 ° C., chloride 8 (47 mg, 0.18 mmol) was added. After stirring overnight at room temperature, the reaction was quenched with 5% aqueous NaHCO ₃ solution. The product was extracted with CH ₂ Cl ₂ and the extract was dried over Mg ₂ SO ₄ and then concentrated in vacuo. The crude product was purified by column chromatography (hexane / AcOEt gradient increased from 5: 1 to 1: 1 v / v) to give compound 5 (40 mg, 53.5%) as a yellow oil. It was. IR (film) ν 3254, 2945, 2915, 2805, 2758, 1578, 1508, 1478, 1420, 1375, 1350, 1279, 1231, 1194, 1148, 1121 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.24 (s, 3 H), 1.44 (d, J = 33.20 Hz, 4 H), 1.82 (m, 2 H), 2.67 (t, J = 2.40 Hz, 1 H), 2.58 (t, J = 7.20 Hz, 2 H), 2.83 (d, J = 11.20 Hz, 2 H), 3.26 (d, J = 2.40 Hz, 2 H), 3.48 (s, 2 H), 3.92 (s, 2 H), 7.08 ( d, J = 8.00 Hz, 1 H), 7.30-7.44 (m, 7 H), 8.61-8.61 (m, 1 H), 8.76-8.77 (m, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 32.2, 33.5, 33.9, 41.0, 50.3, 53.7, 55.9, 63.3, 73.3, 78.3, 108.7, 121.4, 124.9, 127.0, 127.9, 128.1, 129.2, 129.3, 134.0, 138.7, 147.5, 151.8. HRMS.Calcd for C ₂₇ H ₃₂ N ₃ O (MH +): 414.2545. Found: 414.2570 (MH +).

3- (1-Benzylpiperidin-4-yl) -2-(((8-hydroxyquinolin-5-yl) methyl) (prop-2-ynyl) amino) propanenitrile (4) : CH ₂ Cl ₂ (6 To a cooled mixture of 16 (84 mg, 0.3 mmol) and Et ₃ N (0.093 mL, 0.67 mmol) in mL) was added chloride 8 (7 mg, 0.3 mmol) at 0 ° C. After stirring overnight at room temperature, the reaction was quenched with 5% aqueous NaHCO ₃ solution. The reaction mixture was extracted with CH ₂ Cl ₂ and the extract was dried over Mg ₂ SO ₄ and concentrated in vacuo. The crude product was purified by column chromatography (hexane / AcOEt gradient increased from 5: 1 to 1: 1 v / v) to give compound 4 (91.4 mg, 69.5%) as an orange oil. It was. IR (film) ν 3298, 2934, 2807, 1580, 1505, 1476, 1370, 1273, 1233, 1198, 1148, 1072, 1028 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.81-0.93 (m , 1 H), 0.93-1.07 (m, 1 H), 1.12-1.32 (m, 2 H), 1.38-1.62 (m, 3 H), 1.69 (ddd, J = 14.1, 8.8, 5.5 Hz, 1 H ), 1.76-1.89 (m, 1 H), 2.39-2.47 (m, 1 H), 2.58 (d, J = 11.3 Hz, 1 H), 2.80 (d, J = 11.5 Hz, 1 H), 3.21- 3.32 (m, 1 H), 3.36-3.53 (m, 3 H), 3.65-3.75 (m, 2 H), 4.60 (d, J = 13.1 Hz, 1 H), 7.06-7.11 (m, 1 H) , 7.21-7.33 (m, 5 H), 7.40-7.47 (m, 2 H), 8.58-8.65 (m, 1 H), 8.75-8.81 (m, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 30.6, 31.5, 37.2, 39.8, 49.6, 52.7, 53.0, 53.6, 62.8, 74.1, 78.6, 108.9, 117.0, 121.6, 122.3, 127.2, 127.5, 128.1, 129.3, 129.8, 133.6, 138.6, 147.7, 152.5. HRMS. Calcd for C ₂₉ H ₃₂ N ₄ O (MH +): 439.2428. Found: 439.2532 (MH +).

Example 6 5-(((3- (1-benzylpiperidin-4-yl) propyl) (prop-2-ynyl) amino) methyl) quinolin-8-ol (7) and 4- (1-benzyl Synthesis of piperidin-4-yl) -2-(((8-hydroxyquinolin-5-yl) methyl) (prop-2-ynyl) amino) butanenitrile (6)

(2E) -3- (1-Benzylpiperidin-4-yl) prop-2-enenitrile (17) : diethyl (cyanomethyl) phosphonate (2.2 g, 12 mmol) and K ₂ CO _{3 in} dry THF (100 mL) A mixture of (1.4 g, 10 mmol) was stirred for 15 minutes at room temperature and then heated to reflux for 20 minutes. After cooling to room temperature, 1-benzyl-4-piperidinecarboxaldehyde (2.0 g, 10 mmol) was added. The mixture was heated to reflux for 3 hours. After cooling to room temperature, 10% K ₂ CO ₃ aqueous solution (100 mL) was added. The product was extracted with AcOEt and dried over MgSO ₄ . After concentration in vacuo, the crude product was purified by column chromatography (SiO ₂ , hexane / AcOEt from 5: 1 to 1: 1 v / v) to give nitrile 17 (1.0 g, 44.5% yield, _Rf = 0.70) and (0.74 g, 32.6%) were obtained as white solids. R _f = 0.30 (hexane / AcOEt = 1: 2); ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.40-1.60 (m, 2 H), 1.62-1.77 (m, 2 H), 1.93-2.14 (m , 2 H), 2.51-2.71 (m, 1 H), 2.89 (d, J = 11.7 Hz, 2 H), 3.50 (s, 2 H), 5.23 (d, J = 10.9 Hz, 1 H), 6.31 (t, J = 10.4 Hz, 1 H), 7.19-7.38 (m, 5 H).

3- (1-Benzylpiperidin-4-yl) propanenitrile (18) : A solution of 17 (1.74 g, 7.70 mmol) in room temperature MeOH (33 mL) was mixed with Mg powder (3.70 g, 154 mmol) and a trace amount of I. ₂ was added to the mixture. The mixture was stirred until a gray gel was obtained. After adding concentrated HCl, the mixture became a clear solution. It was then made alkaline by treatment with 10 N NaOH. The precipitate was filtered and washed with copious amounts of EtOAc. The filtrate was extracted with AcOEt and the combined organic phases were dried over MgSO _{4 and} concentrated in vacuo to give crude product 18 (1.76 g, 99.9%) as an orange oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.17-1.52 (m, 3 H), 1.54-1.73 (m, 4 H), 1.96 (td, J = 11.5, 1.9 Hz, 2 H), 2.35 (t, J = 7.3 Hz, 2 H), 2.89 (d, J = 11.8 Hz, 2 H), 3.50 (s, 2 H), 7.19-7.37 (m, 5 H).

3- (1-Benzylpiperidin-4-yl) propanal (19) : Nitrile 18 (1.00 g, 4.4 mmol) and THF (10 mL) were added to a flask dried in an oven and purged with argon. The reaction was cooled to −78 ° C. and DIBAL-H (4.54 mL, 1 mmol / mL) was added to the reaction through a syringe. The mixture was stirred for 1 h at −78 ° C. and then quenched with saturated aqueous NaHCO ₃ solution. The precipitate was filtered and washed with copious amounts of EtOAc. The filtrate was extracted with EtOAc. The combined organic phases were washed with brine and dried over MgSO ₄ . After concentration in vacuo, the crude product is purified by chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH = 20: 1 v / v) to give aldehyde 19 (427 mg, 42.7%) as an orange oil Got as. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.16-1.35 (m, 3 H), 1.52-1.72 (m, 4 H), 1.92 (t, J = 11.8 Hz, 2 H), 2.43 (td, J = 7.5, 1.6 Hz, 2 H), 2.87 (d, J = 11.1 Hz, 2 H), 3.44-3.53 (m, 2 H), 7.19-7.38 (m, 5 H), 9.76 (t, J = 1.6 Hz , 1 H).

N- [3- (1-benzylpiperidin-4-yl) propyl] prop-2-yn-1-amine (20) and 4- (1-benzylpiperidin-4-yl) -2- (prop-2- In-1-ylamino) butanenitrile (21) : A solution of aldehyde 19 (427 mg, 1.9 mmol) and propargylamine (204 mg, 3.7 mmol) in MeOH (6 mL) was stirred for 1 hour at 0 ° C., then NaBH ₃ CN (1.3 g, 2.0 mmol) was added. The mixture was stirred overnight at room temperature. Water was added to the mixture and MeOH was removed under reduced pressure. Then saturated aqueous NaHCO ₃ solution was added and the mixture was extracted with AcOEt. The separated organic phase was dried over MgSO ₄ and concentrated in vacuo to give the crude product. Further purification was achieved by column chromatography (SiO ₂ , elution solvent was changed from hexane / AcOEt 5: 1 to 1: 5 v / v and then changed from AcOEt to AcOEt / MeOH 4: 1 v / v), The product 20 (221 mg, 44.2%) was obtained as a yellow oil. N- [3- (1-Benzylpiperidin-4-yl) propyl] prop-2-yn-1-amine 20: R _f = 0.19 (MeOH / AcOEt = 1: 4); IR (film) ν 3304, 3028 , 2922, 2847, 2794, 2758, 1495, 1452, 1386, 1343, 1119, 1028 cm ^-1 ; ¹ H NMR (600 MHz, CDCl ₃ ) δ 1.10-1.26 (m, 5 H), 1.33-1.46 (m , 2 H), 1.58 (d, J = 9.9 Hz, 2 H), 1.87 (br s, 2 H), 2.13 (t, J = 2.3 Hz, 1 H), 2.31-2.39 (m, 1 H), 2.59 (t, J = 7.1 Hz, 1 H), 2.81 (d, J = 10.8 Hz, 2 H), 3.35 (d, J = 2.3 Hz, 2 H), 3.43 (s, 2 H), 7.13-7.29 (m, 5 H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 24.6, 27.0, 32.2, 32.3, 34.1, 35.6, 38.0, 48.8, 53.8, 63.4, 71.1, 82.2, 126.7, 128.0, 129.1, 138.4. 4- (1-Benzylpiperidin-4-yl) -2- (prop-2-yn-1-ylamino) butanenitrile 21: R _f = 0.59 (MeOH / AcOEt = 1: 4); IR (film) ν 3296 , 2911, 2845, 2801, 2780, 1493, 1452, 1368, 1343, 1312, 1260, 1146, 1119, 1074; ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.18-1.69 (m, 8 H), 1.70- 1.83 (m, 2 H), 1.85-2.02 (m, 2 H), 2.23-2.37 (m, 1 H), 2.87 (d, J = 10.5 Hz, 2 H), 3.29-3 .76 (m, 4 H), 7.16 -7.38 (m, 5 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 31.0, 31.6, 32.1, 32.2, 32.3, 35.4, 36.6, 49.5, 53.7, 63.4, 72.8, 80.0, 119.4, 126.7, 127.9, 128.9, 138.1.

5-(((3- (1-Benzylpiperidin-4-yl) propyl) (prop-2-ynyl) amino) methyl) quinolin-8-ol (7) : amine in CH ₂ Cl ₂ (15 mL) To a mixture of 20 (189 mg, 0.70 mmol) and Et ₃ N (0.51 ml, 2.5 mmol) cooled to 0 ° C., chloride 9 (186 mg, 0.73 mmol) was added. After stirring overnight at room temperature, the reaction was quenched with 5% aqueous NaHCO ₃ solution. The product was extracted with CH ₂ Cl ₂ and the extract was dried over Mg ₂ SO ₄ and then concentrated in vacuo. The crude product was purified by column chromatography (SiO ₂ , hexane / AcOEt was increased from 5: 1 to 1: 1 v / v with a gradient), and Compound 7 (162 mg, 54.3%) was obtained as a yellow oil Got as. IR (film) ν 3381, 3293, 2911, 2801, 1738, 1580, 1505, 1476, 1425, 1373, 1289, 1238, 1198, 1047 cm ^-1 ; ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.99-1.33 (m, 5 H), 1.42-1.66 (m, 4 H), 1.86 (t, J = 11.3 Hz, 2 H), 2.29 (t, J = 2.1 Hz, 1 H), 2.56 (t, J = 7.1 Hz, 2 H), 2.86 (d, J = 11.4 Hz, 2 H), 3.26 (d, J = 2.2 Hz, 2 H), 3.48 (s, 2 H), 3.93 (s, 2 H), 7.09 ( d, J = 7.6 Hz, 1 H), 7.20-7.37 (m, 5 H), 7.37-7.49 (m, 2 H), 8.65 (dd, J = 8.5, 1.3 Hz, 1 H), 8.77 (dd, J = 4.1, 1.3 Hz, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 24.4, 32.2, 34.0, 35.3, 40.9, 53.2, 53.8, 55.8, 63.4, 73.4, 78.4, 108.9, 121.4, 124.9, 127.0, 127.9, 128.2, 129.2, 129.3, 134.1, 138.7, 147.6, 152.0. Anal.Calcd for C ₂₈ H ₃₃ N ₃ O: C, 78.65; H, 7.78; N, 9.98. Found; C, 76.90; H, 8.03; N 9.83.

4- (1-Benzylpiperidin-4-yl) -2-(((8-hydroxyquinolin-5-yl) methyl) (prop-2-ynyl) amino) butanenitrile (6) : CH ₂ Cl ₂ (6 Chloride 9 (77 mg, 0.3 mmol) was added to a 0 ° C. mixture of amine 21 (89 mg, 0.3 mmol) and Et ₃ N (0.09 mL, 0.7 mmol) in mL). After stirring overnight at room temperature, the reaction was quenched with 5% aqueous NaHCO ₃ and the product was extracted with CH ₂ Cl ₂ . The extract was dried over Mg ₂ SO ₄ and concentrated in vacuo. The crude product was purified by column chromatography (SiO ₂ , hexane / AcOEt gradient increased from 5: 1 to 1: 1 v / v) to give compound 6 (89 mg, 65.4%) as a yellow oil Obtained as a thing. IR (film) ν 3295, 2931, 2812, 1578, 1505, 1476, 1371, 1271, 1203, 1196, 1148, 1123, 1072, 1028 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.90 (m , 1 H), 1.03-1.35 (m, 4 H), 1.45 (d, 1 H), 1.73-1.76 (m, 4 H), 2.42 (s, 1H), 2.80 (t, J = 14.40 Hz, 2H ), 3.29 (m, 1 H), 3.45 (s, 3 H), 3.58 (t, J = 8.00 Hz, 1 H), 3.75 (d, J = 12.8 Hz, 1 H), 4.58 (d, J = 13.2 Hz, 1H), 7.11 (t, J = 7.60 Hz, 1 H), 7.29-7.46 (m, 7 H), 8.61-8.64 (m, 1 H), 8.78-8.80 (m, 1 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 28.1, 31.5, 31.9, 32.0, 34.4, 39.8, 52.3, 53.4, 53.5, 53.7, 63.3, 74.2, 78.6, 108.9, 117.2, 121.8, 122.5, 127.1, 127.6, 128.2, 129.3, 129.9, 133.7, 138.8, 147.9, 152.6. HRMS. Calcd for C ₂₉ H ₃₂ N ₄ O (MH +): 453.2654. Found: 452.2526 (MH +).

Biological assay [Example 7] Metal binding assay
8-Quinolinol is known to be a strong chelating agent for biometals such as iron and copper. This is an important prerequisite for antioxidant drugs. This is because it is thought to be related to neurodegenerative diseases because it stores excess iron in the brain and generates iron-mediated free radicals. Therefore, only chelating agents that have a higher selectivity for iron than copper are expected to chelate iron instead of copper and have promising neuroprotective effects. The potential correlation between the chelating properties of 8-quinolinol and its derivatives and their antioxidant capacity, and between their derivatives and the most established iron chelating agent, desferal, and their antioxidant properties In order to discuss this correlation, a reliable measurement of the stability constant of newly synthesized compounds is required. A spectrophotometric method was used to determine the stability constant of the copper / iron complex of the compound.

Metal binding assays were performed by spectrophotometrically detecting the formation of Fe (III) -6 and Cu (II) -6 complexes. The absorption spectrum of Compound 6 at 10 μM was evaluated for two biometals from 220 nm to 300 nm, and it was revealed that two absorption maxima appeared at approximately 240 nm and 257 nm (FIG. 7). The formation of the Cu (II) -6 complex was easily determined in just a few minutes after adding the CuSO ₄ solution. At both concentrations of Cu (II) performed, the 240 nm band disappeared completely, while a new band appeared at 275 nm. As far as iron chelation is concerned, incubation time was a limiting factor for detecting some absorption shifts. A few minutes after adding Fe ₂ (SO ₄ ) ₃ , no noticeable change in the spectrum was observed. A new detection was performed after overnight incubation, revealing that a bathocromic shift in the 240 nm band appeared another at 250 nm.

[Example 8] MAO inhibitory activity
Rat Brain MAO Preparation Rats were decapitated and weighed and placed in ice-cold Tris 10 nM pH 7.2 and 0.25 M saccharose buffer. All subsequent treatments were performed at approximately 4 ° C. The brain was homogenized with a Teflon-glass homogenizer in 0.25M Tris-saccharose buffer, and then Tris buffer was added to make a final 10% homogenate. The homogenate was filtered through surgical gauze and centrifuged twice at 600 g for 10 minutes. The pellet was resuspended in 0.25M Tris-saccharose buffer and centrifuged twice at 10,000g for 10 minutes. Finally, a protein stock was resuspended at 10 mg / ml in 0.1 M potassium phosphate pH 7.4 buffer and frozen at −20 ° C. for later MAO assay. The protein concentration was determined with Bradford reagent at [λ] = 595 nm using albumin taken from bovine serum (BSA) as a standard.

Inhibition of MAO-A and MAO-B
Using Fowler and Tipton's method (CJ Fowler, KF Tipton, Biochem. Pharmacol. 1981, 30, 3329-3332), MAO-A and MAO-B activity was measured in vitro in rat brain homogenates. The concentration was determined while changing the concentration.

The in vitro inhibitory activity of the test molecules was tested against two rat brain MAO isoforms. To test the pluripotency profiles of these compounds, add a dilution of DHP 2-7 to potassium phosphate buffer pH 7.4, and add the appropriate enzyme preparation dilution (total protein 50-100 mg) to 37 After 30 minutes incubation at 0 ° C., ¹⁴ C-labeled MAO-A and MAO-B substrates; 100 μM 5-hydroxytryptamine (5-HT) and 20 μM phenylethylamine (PEA), respectively, were added. The enzymatic reaction was performed for 20 minutes for MAO-A and 4 minutes for MAO-B and stopped with 2M citric acid.

  Metabolites were extracted, determined in cpm units by liquid scintillation counting, and expressed in enzyme activity units (pmol / min · mg protein).

  Chlordiline and deprenyl inhibition profiles were performed as MAO-A and MAO-B specific inhibitors, respectively.

  Numbers represent the mean value of at least 3 different experiments performed in 4 replicates ± standard error of the mean value.

As shown in Table 1, most compound derivatives are weak MAO inhibitors, compounds 4 and 6 show moderate, nearly equal inhibitory activity against both enzymes, the most potent being the compound 6 [rat MAO-A (IC ₅₀ = 6.16 ± 0.7 μM; rat MAO-B (IC ₅₀ = 10.21 ± 0.9 μM))]. When compared to the reference compound M30, the most potent inhibitor compound 6 is 166-fold and 179-fold less active in inhibiting MAO-A and MAO-B, respectively. However, when compared to donepezil 1, inhibitor 6 is 138 times more active and retains equal potency against MAO-A and MAO-B, respectively. As before, the same structure-activity relationship applies; for the same value of n, α-amino nitrile is more potent than the corresponding amine for both enzymes, with the exception of compound 2 for MAO-B. .

We observed the same biofunctional trends for inhibition of SSAO (see Table 1). Compound 6 is the most potent [Bovine SSAO (IC ₅₀ = 2.01 ± 0.5 μM)] and is in the same range as Compound 4. This result is particularly interesting because MAO catalyzes the oxidative deamination of primary, secondary, and tertiary amines, but the activity of SSAO appears to be limited to primary.

To determine the type of MAO inhibition mechanism of the compounds of the present invention, a kinetic study was performed on Compound 6. Non-competitive inhibition was established from the Lineweaver-Burk reciprocal plots for both enzymes [Figure 2 (MAO-A); Figure 3 (MAO-B)]. From the slope of the double reciprocal plot versus the concentration of Compound 6, the K _i values were estimated to be 8.41 ± 1.32 μM and 10.81 ± 2.43 μM, respectively.

  Next, the reversibility of compound 6 inhibition was addressed. We observed that compound 6 reversibly inhibits both MAO-A and MAO-B, and the inhibitor was significantly restored by three successive centrifugations and buffer washes (FIG. 4). ). At the same time, reversibility of chlordiline as an irreversible inhibitor of MAO-A and l-deprenyl as an irreversible inhibitor of MAO-B were also performed as reference compounds.

  To support the reversibility of the results obtained, a time-dependent inhibition assessment for long preincubation times (0-360 min) was performed for both MAO-A and MAO-B activity in the presence of compound 6. Performed (FIG. 5). In this case, the concentration of compound 6 used was 20 μM for both enzymes.

For both MAO-A and MAO-B, it was found that before the preincubation time of 180 minutes, complete inhibition of activity was not reached and therefore behaved irreversibly. Independent inhibition assays were performed with different preincubation times for both two MAO isoforms (FIG. 6). IC ₅₀ values (Table 2) show that the potency of the compound increases progressively with increasing preincubation time, confirming the previous results.

[Example 9] Inhibitory activity of cholinesterase (ChE) The in vitro activity of a new compound against electrophorus electricus acetylcholinesterase (eeAChE) and equine serum butyrylcholinesterase (eqBuChE) was determined by the Ellman method (GL Ellman , et al., Biochem. Pharmacol. 1961, 7, 88-95) and donepezil and M30 as reference compounds (Table 3).

  Prepare a diluted solution of DHP2-7 derivatives, 333 μM 5,5′-dithiobis-2-nitrobenzoic acid (DTNB), 0.1 M phosphate buffer pH 8 with 0.02% BSA and enzyme solution: 0.02 U / ml eeAChE And 0.017 U / ml eqBuChE. The solution was incubated at 37 ° C. for 20 minutes before adding the substrate. Acetylcholine iodide salt (450 μM final concentration) and S-butyrylthiocholine iodide salt (300 μM final concentration) were used as substrates for 0.02 U / ml eeAChE and 0.017 U / ml eqBuChE. Once added, the reaction time used was 5 minutes for EeAChE and 30 minutes for eqBuChE.

The absorbance was then determined at 405 nm and expressed as a percentage of activity to determine reliable IC ₅₀ values for both cholinesterases (ChE).

  Numbers represent the mean value of at least 3 different experiments performed in 4 replicates ± standard error of the mean value.

  Compared to donepezil 1, compound 6 is significantly less potent at inhibiting EeAChE but more active at eqBuChE inhibition (4.5 fold). Compared to M-30, compound 6 is 64 times more active in inhibiting EeAChE and more effective in inhibiting BuChE. This is because M-30 is inactive against this enzyme.

In order to determine the EeAChE inhibition mechanism of these compounds, a kinetic study was conducted on inhibitor 6. The type of inhibition was established from analysis of the Lineweaver-Burk reciprocal plot (FIG. 1). The plot shows that the slope increases (lower V _max ) and the intercept increases (high K _m ) as the inhibitor concentration is higher. This suggests mixed inhibition. A graphical analysis of steady state inhibition for compound 6 is shown in FIG. From the slope of the double reciprocal plot versus the concentration of Compound 6, the K _i value was estimated to be 1.21 ± 0.25 μM.

  Compounds 2-7 were readily prepared from readily available precursors with high yield and short synthetic sequence. Biofunctional evaluation of compounds 2-7 indicates that these hybrid compounds are moderate, micromolar, non-selective ChE and MAO inhibitors. Compound 6 shows particularly interesting results and is a reversible, non-competitive MAO-A / MAO inhibitor and a mixed EeAChE inhibitor. Related M-30A, demethylated derivatives of M-30, or M-30B [“5,5 ′-((prop-2-yn-1-ylazanezyl) bis (methylene)) bis (quinoline-8- All) ”] [H. Zheng, S. Gal, LM Weiner, O. Bar-Am, A. Warshawsky, M. Fridkin, MBH Youdim, J. Neurochem. 2005, 95, 68-78.] Compound 6 exhibits a very similar MAO inhibitory action profile.

[References cited in this application]
WO2004 / 41151 (Yeda Res. Dev. Co.)
WO2010 / 86860 (Yeda Res. Dev. Co.)
CJ Fowler, et al., Biochem. Pharmacol. 1981, 30, 3329-3332
H. Zheng, et al., ACS Chem. Biol. 2010, 5, 603-610
GL Ellman, et al., Biochem. Pharmacol. 1961, 7, 88-95
H. Zheng, et al., J. Neurochem. 2005, 95, 68-78.

Claims (15)

Compound of formula (I)
Or a salt thereof, or a stereoisomeric form thereof or a mixture thereof, wherein
R ₁ and R ₂ are the same or different and are each independently selected from the group consisting of: H; OH; —CH ₂ —NH—CH ₂ CCH; —NH—CH ₂ CCH; —CH ₂ — N (C ₁ -C ₄ ) alkyl CH ₂ CCH; -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; linear or branched (C ₁ -C ₆ ) alkyl; hydroxy- (C ₁ -C ₆ ) Alkyl; halo- (C ₁ -C ₆ ) alkyl; linear or branched (C ₂ -C ₆ ) alkenyl; F; Cl; Br; I; -NO ₂ ; -NH ₂ ; -CN; -O (C ₁ -C ₄ ) alkyl; (C ₁ -C ₄ ) alkyl-O- (C ₁ -C ₄ ) alkyl; -C (O) H; -C (O) (C ₁ -C ₄ ) alkyl; _{-COOH; -COO (C 1 -C 4} ) alkyl; -OC (O) H; -OC (O) (C 1 -C 4) alkyl; -C (O) N (( C 1 -C 4) alkyl ) ₂ ; -NH (C ₁ -C ₄ ) alkyl; -N ((C ₁ C ₄ ) alkyl) ₂ ;-(C ₁ -C ₄ ) alkyl-NH (C ₁ -C ₄ ) alkyl; -SH; -S (C ₁ -C ₄ ) alkyl; -SO- (C ₁ -C ₄ ) alkyl; -SO _2- (C ₁ -C ₄ ) alkyl; -SO ₂ NH ₂ ; -SONH (C ₁ -C ₄ ) Alkyl; -SON ((C ₁ -C ₄ ) alkyl) ₂ ; -OCONH ₂ ; -OCONH (C ₁ -C ₄ ) alkyl -OCON ((C ₁ -C ₄ ) alkyl) ₂ ; -C = N (C ₁ -C ₄ ) alkyl; -NHC (O) (C ₁ -C ₄ ) alkyl; -N (C ₁ -C ₄ ) alkyl C (O) (C ₁ -C ₄ ) alkyl; -N (C ₁ -C ₄ ) alkyl C (O) H; -N = CH ₂ ; -N = CH (C ₁ -C ₄ ) alkyl -N = C ((C ₁ -C ₄ ) alkyl) ₂ ; phenylcarbonyl; phenylcarbonyl substituted with a radical selected from the group consisting of at least the following: halo (C ₁ -C ₆ ) -Alkyl, OH, halogen, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkoxy, and CN; (C ₁ -C ₃ ) -alkylphenylcarbonyl; (C ₁ -C ₃ ) alkylphenylcarbonyl substituted with a radical selected from the group consisting of: halo (C ₁ -C ₆ ) -alkyl, OH, halogen, (C ₁ -C ₆ ) -alkyl, ( C ₁ -C ₆₎ - alkoxy, and CN; phenyl; is substituted by a radical selected from the group consisting of at least the following ones And which phenyl: halo (C ₁ -C ₆₎ - alkyl, OH, halogen, (C ₁ -C ₆₎ - alkyl, (C ₁ -C ₆₎ - alkoxy, and _{CN; (C 1 -C 3)} - Alkylphenyl; (C ₁ -C ₃ ) alkylphenyl substituted with a radical independently selected from the group consisting of at least the following: halo (C ₁ -C ₆ ) -alkyl, OH, halogen, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkoxy, and CN,
n is an integer from 0 to 1,
A is selected from the group consisting of:
(i)-(CH ₂ ) _n1 -X- (CH ₂ ) _n2 -where n1 and n2 are each independently an integer selected from 0 to 6;
(ii) -X- (CH ₂ ) _n3 -Y- where n3 is an integer from 1 to 6;
(iii) a divalent radical selected from the group consisting of:
Where R ₃ , R ₄ and R ₅ are H, OH, halogen, CN, (C ₁ -C ₄ ) alkyl, hydroxy- (C ₁ -C ₄ ) alkyl, halo (C ₁ -C ₆ ) alkyl , And (C ₁ -C ₆ ) alkoxy;
Where X and Y are each independently selected from O, N H and CH ₂ ; and where the wavy line indicates the position where the A moiety binds there, the X atom is in the B moiety, and the Y atom is Bound to the backbone structure of the compound of formula (I),
B is selected from the group consisting of:
Where the wavy line indicates the position through which the B moiety binds to the X atom of the A moiety, and R ₆ , R ₇ and R ₈ are selected from the group consisting of:
H; OH; -CH ₂ -NH-CH ₂ CCH; -NH-CH ₂ CCH; -CH ₂ -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; linear or branched (C ₁ -C ₆ ) alkyl; hydroxy- (C ₁ -C ₆ ) alkyl; halo- (C ₁ -C ₆ ) alkyl; linear or branched (C ₂ -C ₆₎ ) Alkenyl; F; Cl; Br; I; -NO ₂ ; -NH ₂ ; -CN; -O (C ₁ -C ₄ ) alkyl; (C ₁ -C ₄ ) alkyl-O- (C ₁ -C ₄ ) Alkyl; -C (O) H; -C (O) (C ₁ -C ₄ ) alkyl; -COOH; -COO (C ₁ C ₄ ) alkyl; -OC (O) H; -OC (O) ( C ₁ -C ₄ ) alkyl; -C (O) N ((C ₁ -C ₄ ) alkyl) ₂ ; -NH (C ₁ -C ₄ ) alkyl; -N ((C ₁ -C ₄ ) alkyl) ₂ -(C ₁ -C ₄ ) alkyl-NH (C ₁ -C ₄ ) alkyl; -SH; -S (C ₁ -C ₄ ) alkyl; -SO- (C ₁ -C ₄ ) alkyl; -SO ₂ -(C ₁ -C ₄ ) alkyl; -SO ₂ NH ₂ ; -SONH (C ₁ -C ₄ ) alkyl; -SON ((C ₁ -C ₄ ) alkyl) ₂ ; -OCONH ₂ ; -OCONH (C ₁ -C ₄ ) alkyl; -OCON ((C ₁ -C ₄ ) alkyl) ₂ ; -C = N (C ₁ -C ₄ ) alkyl; -NHC (O) (C ₁ -C ₄ ) alkyl; -N ( C ₁ -C ₄₎ A Kill _{C (O) (C 1 -C} 4) alkyl; -N (C ₁ -C ₄₎ alkyl C (O) H; -N = CH 2; -N = CH (C 1 -C 4) alkyl; - N = C ((C ₁ -C ₄ ) alkyl) ₂ ; phenylcarbonyl; phenylcarbonyl in which the phenyl moiety is substituted with a radical selected from the group consisting of at least: halo (C ₁ -C ₆ )- Alkyl, OH, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, and CN; (C ₁ -C ₃ ) -alkylphenylcarbonyl; from the group consisting of at least the phenyl moiety (C ₁ -C ₃ ) alkylphenylcarbonyl substituted with a selected radical; OH, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, and CN; phenyl; at least Phenyl substituted with a radical selected from the group consisting of: halo (C ₁ -C ₆ ) -alkyl, OH, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, and _{CN; (C 1 -C 3)} - Rukirufeniru; phenyl portion is substituted by a radical selected from the group consisting of at least the following ones (C ₁ -C ₃₎ alkyl-phenyl: halo (C ₁ -C ₆₎ - alkyl, OH, halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, and CN; and one C-radical in a known carbocyclic or heterocyclic ring system having 1 to 4 rings, wherein Each of the rings constituting the ring system of
A 5- to 7-membered ring, each member independently selected from C, N, O, S, CH, CH ₂ , NH,
Saturated, partially unsaturated or aromatic,
Separated or partially or fully condensed;
Each ring that forms part of the ring system is optionally substituted with at least one radical selected from the group consisting of: H; OH; —CH ₂ —NH—CH ₂ CCH; —NH -CH ₂ CCH; -CH ₂ -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; linear or branched (C ₁ -C ₆ ) alkyl Hydroxy- (C ₁ -C ₆ ) alkyl; halo- (C ₁ -C ₆ ) alkyl; linear or branched (C ₂ -C ₆ ) alkenyl; F; Cl; Br; I; -NO ₂ ;- NH ₂ ; -CN; -O (C ₁ -C ₄ ) alkyl; (C ₁ -C ₄ ) alkyl-O- (C ₁ C ₄ ) alkyl; -C (O) H; -C (O) (C ₁ -C _{4) alkyl; -COOH; -COO (C 1 -C} 4) alkyl; -OC (O) H; -OC (O) (C 1 -C 4) alkyl; -C (O) N (( C ₁ -C ₄ ) alkyl) ₂ ; -NH (C ₁ -C ₄ ) alkyl; -N ((C ₁ -C ₄ ) alkyl) ₂ ;-(C ₁ -C ₄ ) alkyl-NH (C _1- C _{4) alkyl; -SH; -S (C 1 -C} 4) alkyl; -SO- (C ₁ -C _{4) alkyl; -SO 2 - (C 1 -C} 4) alkyl; -SO ₂ NH _2; -SONH (C ₁ -C _{4) alkyl; -SON ((C 1 -C 4} ) Al -Kill) ₂ ; -OCONH ₂ ; -OCONH (C ₁ -C ₄ ) alkyl; -OCON ((C ₁ -C ₄ ) alkyl) ₂ ; -C = N (C ₁ -C ₄ ) alkyl; -NHC (O ) (C ₁ -C ₄ ) alkyl; -N (C ₁ -C ₄ ) alkylC (O) (C ₁ -C ₄ ) alkyl; -N (C ₁ -C ₄ ) alkylC (O) H;- N = CH ₂ ; -N = CH (C ₁ -C ₄ ) alkyl; -N = C ((C ₁ -C ₄ ) alkyl) ₂ ; provided that the A part is -X- (CH ₂ ) _{n ''} - Y—, or a radical of formula (II), (III) or (IV), when X is NH or O, B is a radical of formula (VII). A compound according to claim 1, wherein B is a radical of formula (VII); wherein R ₈ is a radical as defined in claim 1. A compound according to any one of claims 1-2, wherein, R ₈ is selected from the group consisting of the following _{ones: H; OH; -CH 2 -NH} -CH 2 CCH; -NH-CH 2 CCH -CH ₂ -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; linear or branched (C ₁ -C ₆ ) alkyl; hydroxy- ( C ₁ -C ₆ ) alkyl; CF ₃ ; CN; -O (C ₁ -C ₄ ) alkyl; (C ₁ -C ₄ ) alkyl-O- (C ₁ -C ₄ ) alkyl; -C (O) H _{; -C (O) (C 1} -C 4) _{alkyl; -COOH; -COO (C 1 C} 4) alkyl; -OC (O) H; -OC (O) (C 1 -C 4) alkyl; - C (O) NHCH ₃ ; -C (O) N (CH ₃ ) ₂ ; -NH ₂ ; -NHCH ₃ ; -N (CH ₃ ) ₂ ; -CH ₂ NH ₂ ; -CH ₂ CH ₂ NH ₂ ;- -CH ₂ NHCH ₃ ; -CH ₂ N (CH ₃ ) ₂ ; -CH ₂ CH ₂ N (CH ₃ ) ₂ ; -CH ₂ N (CH ₂ CH ₃ ) ₂ ; -CH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ ; -SH; -SCH ₃ ; -SCH ₂ CH ₃ ; -SO-CH ₃ ; -SO-CH ₂ CH ₃ ; -SO ₂ -CH ₃ ; -SO ₂ -CH ₂ CH ₃ ; -SO ₂ N (CH ₃ ) ₂ ; -SO ₂ NHCH ₃ ; -NO ₂ ; -OCON (CH ₃ ) ₂ ; -OCONHCH ₃ ; -OCON (CH ₂ CH ₃ ) ₂ ; -C = NH; -C = NCH ₃ ;- C = NCH ₂ CH ₃ ; -NCH ₃ C (O) CH ₃ ; -NCH ₃ C (O) CH ₂ CH ₃ -N = CH ₂ ; -N = C (CH ₃ ) ₂ ; -N = C (CH ₂ CH ₃ ) ₂ ; phenylcarbonyl; the phenyl moiety is substituted with a radical selected from the group consisting of at least the following: Phenylcarbonyl: CF ₃ , F, Cl, Br, I, CN, OH, —CH ₃ , —CH ₂ CH ₃ , —OCH ₃ , and —OCH ₂ CH ₃ ; (C ₁ -C ₃ ) alkylphenyl (C ₁ -C ₃ ) alkylphenylcarbonyl substituted with a radical selected from the group consisting of at least: CF ₃ , F, Cl, Br, I, CN, OH, —CH ₃ , -CH ₂ CH ₃ , -OCH ₃ , and -OCH ₂ CH ₃ ; phenyl; phenyl substituted with a radical selected from the group consisting of at least: CF ₃ , F, Cl, Br, I , CN, OH, -CH ₃ , -CH ₂ CH ₃ , -OCH ₃ , and -OCH ₂ CH ₃ ; (C ₁ -C ₃ ) -alkylphenyl; the phenyl moiety is selected from the group consisting of at least that is substituted with a radical (C ₁ -C ₃₎ - Al _{Butylphenyl: CF 3, F, Cl,} Br, I, CN, OH, -CH 3, -CH 2 CH 3, -OCH 3, and -OCH ₂ CH _3. A compound according to claim 1, wherein, n is an integer from 0 to 1, BA unit is selected from the group consisting of the following ones: B- (CH _{2) n1} -O- (CH ₂ ) _n2- ; B- (CH ₂ ) _n1 -NH- (CH ₂ ) _n2- ; B- (CH ₂ ) _n1 -CH _2- ; B- (CH ₂ ) _n1 -O-; B- ( _{CH 2) n1 -NH-; bO- (} CH 2) n2 -; B-NH- (CH 2) n2 -; B-; bO-; B-NH-; bO- (CH 2) n3 -O-; BO- (CH ₂ ) _n3 -NH-; B-NH- (CH ₂ ) _n3 -NH-; and B-NH- (CH ₂ ) _n3 -O-;
B is as defined in claim 1, and n1, n2 and n3 are each independently an integer selected from 1 to 4. 4. A compound according to any one of claims 1 to 3, wherein n is 1 and part A is a divalent radical selected from the group consisting of:
Where R ₃ , R ₄ and R ₅ are selected from: H, OH, halogen, CN, (C ₁ -C ₄ ) alkyl, halo (C ₁ -C ₆ ) -alkyl, and (C ₁ -C ₆ ) alkoxy ,
Here, X and Y are each independently selected from O, N H and CH _2, and the wavy line indicates the position where the A part is bonded therethrough, the X atom is bonded to the B part, and the Y atom is represented by the formula ( It is bound to the backbone structure of compound I). A compound according to any one of claims 1 to 5, wherein, R ₁ and R ₂ are the same or different, each independently selected from the group consisting of the following ones: H; OH; -CH ₂ - NH-CH ₂ CCH; -NH-CH ₂ CCH; -CH ₂ -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; linear or branched ( C ₁ -C ₆ ) alkyl; hydroxy- (C ₁ -C ₆ ) alkyl; halo- (C ₁ -C ₆ ) alkyl; -NH ₂ ; -CN; -C (O) (C ₁ -C ₄ ) alkyl --COO (C ₁ -C ₄ ) alkyl; --OC (O) (C ₁ -C ₄ ) alkyl; --C (O) N ((C ₁ -C ₄ ) alkyl) ₂ ; --NH (C _1- C _{4) alkyl; -N ((C 1 -C 4} ) _{alkyl) 2; - (C 1 -C} 4) alkyl -NH (C ₁ -C _{4) alkyl; -SH; -S (C 1 -C} 4 ) Alkyl; -SO- (C ₁ -C ₄ ) alkyl; -SO _2- (C ₁ -C ₄ ) alkyl; -SO ₂ NH ₂ ; -SONH (C ₁ -C ₄ ) alkyl; -SON ((C ₁ -C ₄₎ alkyl) _2; -OCONH _2; -OCONH (C ₁ -C ₄₎ alkyl; or the group and phenyl portion is composed of at least the following ones: -OCON ((C ₁ -C ₄₎ alkyl) ₂ It is substituted with a radical selected (C ₁ -C ₃₎ alkyl-phenyl: halo (C ₁ -C ₆₎ - alkyl, OH, halogen, (C ₁ -C ₆₎ - alkyl, (C ₁ -C ₆ ) -Alkoxy, and CN. A compound according to claim 1, wherein, R ₁ is selected from the group consisting of the following _{ones: OH; -NH 2; -CN;} -C (O) (C 1 -C 4 ) Alkyl; -COO (C ₁ -C ₄ ) alkyl; -OC (O) (C ₁ -C ₄ ) alkyl; -C (O) N ((C ₁ -C ₄ ) alkyl) ₂ ; -NH (C ₁ -C ₄ ) alkyl; -N ((C ₁ -C ₄ ) alkyl) ₂ ;-(C ₁ -C ₄ ) alkyl-NH (C ₁ -C ₄ ) alkyl; -SH; -S (C _1- C ₄₎ alkyl; -SO- (C ₁ -C _{4) alkyl; -SO 2 - (C 1 -C} 4) _{alkyl; -SO 2 NH 2; -SONH (} C 1 -C 4) alkyl; -SON ( (C ₁ -C ₄ ) alkyl) ₂ ; -OCONH ₂ ; -OCONH (C ₁ -C ₄ ) alkyl; -OCON ((C ₁ -C ₄ ) alkyl) ₂ ; (C ₁ -C ₃ ) alkylphenyl substituted with a radical selected from the group: halo (C ₁ -C ₆ ) -alkyl, OH, halogen, (C ₁ -C ₆ ) -alkyl, (C _1- C ₆₎ - alkoxy, and CN. A compound according to any one of claims 1 to 7, which is a compound of formula (Ia):
here,
R ₁ is selected from: OH; -NH ₂ ; -CN; -C (O) (C ₁ -C ₄ ) alkyl; -COO (C ₁ -C ₄ ) alkyl; -OC (O) ( C ₁ -C ₄ ) alkyl; -C (O) N ((C ₁ -C ₄ ) alkyl) ₂ ; -NH (C ₁ -C ₄ ) alkyl; -N ((C ₁ -C ₄ ) alkyl) ₂ -(C ₁ -C ₄ ) alkyl-NH (C ₁ -C ₄ ) alkyl; -SH; -S (C ₁ -C ₄ ) alkyl; -SO- (C ₁ -C ₄ ) alkyl; -SO ₂ -(C ₁ -C ₄ ) alkyl; -SO ₂ NH ₂ ; -SONH (C ₁ -C ₄ ) alkyl; -SON ((C ₁ -C ₄ ) alkyl) ₂ ; -OCONH ₂ ; -OCONH (C ₁ -C ₄ ) alkyl; -OCON ((C ₁ -C ₄ ) alkyl) ₂ ; and (C ₁ -C ₃ ) -alkyl, wherein the phenyl moiety is substituted with a radical selected from the group consisting of at least: Phenyl; halo (C ₁ -C ₆ ) -alkyl, OH, halogen, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkoxy, and CN;
R ₂ is selected from: H; OH; —CH ₂ —NH—CH ₂ CCH; —NH—CH ₂ CCH; —CH ₂ —N (C ₁ -C ₄ ) alkyl CH ₂ CCH; —N (C ₁ -C ₄ ) alkyl CH ₂ CCH; linear or branched (C ₁ -C ₆ ) alkyl; hydroxy- (C ₁ -C ₆ ) alkyl; halo- (C ₁ -C ₆ ) alkyl; NH ₂ ; -CN; -C (O) (C ₁ -C ₄ ) alkyl; -COO (C ₁ -C ₄ ) alkyl; -OC (O) (C ₁ -C ₄ ) alkyl; -C (O) N ((C ₁ -C ₄ ) alkyl) ₂ ; -NH (C ₁ -C ₄ ) alkyl; -N ((C ₁ -C ₄ ) alkyl) ₂ ;-(C ₁ -C ₄ ) alkyl-NH ( C ₁ -C ₄₎ alkyl; -SH; -S (C ₁ -C ₄₎ alkyl; -SO- (C ₁ -C ₄₎ alkyl; -SO ₂ - (C ₁ -C ₄₎ alkyl; -SO ₂ NH ₂ ; -SONH (C ₁ C ₄ ) alkyl; -SON ((C ₁ -C ₄ ) alkyl) ₂ ; -OCONH ₂ ; -OCONH (C ₁ -C ₄ ) alkyl; -OCON ((C ₁ -C ₄ ) alkyl) ₂ ; and (C ₁ -C ₃ ) -alkylphenyl substituted with a radical selected from the group consisting of at least the following: halo (C ₁ -C ₆ ) -alkyl, OH , Halogen, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkoxy, and CN,
B is a radical of formula (VII), wherein R ₈ is selected from the group consisting of: H; OH; —CH ₂ —NH—CH ₂ CCH; —NH—CH ₂ CCH; —CH ₂ -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; -N (C ₁ -C ₄ ) alkyl CH ₂ CCH; linear or branched (C ₁ -C ₆ ) alkyl; hydroxy- (C ₁ -C _{6) alkyl; CF 3; CN; -O (} C 1 -C 4) alkyl; (C ₁ -C ₄₎ alkyl -O- (C ₁ -C ₄₎ alkyl; -C (O) H; -C ( O) (C ₁ -C ₄ ) alkyl; -COOH; -COO (C ₁ -C ₄ ) alkyl; -OC (O) H; -OC (O) (C ₁ -C ₄ ) alkyl; -C (O ) NHCH ₃ ; -C (O) N (CH ₃ ) ₂ ; -NH ₂ ; -NHCH ₃ ; -N (CH ₃ ) ₂ ; -CH ₂ NH ₂ ; -CH ₂ CH ₂ NH ₂ ; -CH ₂ NHCH ₃ ; -CH ₂ N (CH ₃ ) ₂ ; -CH ₂ CH ₂ N (CH ₃ ) ₂ ; -CH ₂ N (CH ₂ CH ₃ ) ₂ ; -CH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ ; -SH; -SCH ₃ ; -SCH ₂ CH ₃ ; -SO-CH ₃ ; -SO-CH ₂ CH ₃ ; -SO ₂ -CH ₃ ; -SO ₂ -CH ₂ CH ₃ ; -SO ₂ N (CH ₃ ) ₂ ; -SO ₂ NHCH ₃ ; -NO ₂ ; -OCON (CH ₃ ) ₂ ; -OCONHCH ₃ ; -OCON (CH ₂ CH ₃ ) ₂ ; -C = NH; -C = NCH ₃ ; -C = NCH ₂ CH ₃ ; -NCH ₃ C (O) CH ₃ ; -NCH ₃ C (O) CH ₂ CH ₃ ; -N = CH ₂ ; -N = C (CH ₃ ) ₂ ; -N = C (CH ₂ CH ₃ ) ₂ ; phenylcarbonyl; phenylcarbonyl in which the phenyl moiety is substituted with a radical selected from the group consisting of at least: CF ₃ , F, Cl, Br, _{I, CN, OH, -CH 3} , -CH 2 CH 3, -OCH 3, and _{-OCH 2 CH 3; - (C} 1 -C 3) - alkyl phenyl phenylcarbonyl, (C ₁ -C ₃₎ - alkyl Phenylcarbonyl, (C ₁ -C ₃ ) -alkylphenylcarbonyl substituted with a radical selected from the group consisting of at least: CF ₃ , F, Cl, Br, I, CN, OH, -CH ₃ , -CH ₂ CH ₃ , -OCH ₃ , and -OCH ₂ CH ₃ ; phenyl; phenyl substituted with a radical selected from the group consisting of at least: CF ₃ , F, Cl, Br , I, CN, OH, -CH ₃ , -CH ₂ CH ₃ , -OCH ₃ , and -OCH ₂ CH ₃ ; (C ₁ -C ₃ ) -alkylphenyl; from the group wherein the phenyl moiety is at least Radka selected In is substituted (C ₁ -C ₃₎ - alkyl _{phenyl; CF 3, F, Cl,} Br, I, CN, OH, -CH 3, -CH 2 CH 3, -OCH 3, and -OCH ₂ CH ₃ ,
Here, n is an integer of 0 to 1,
The BA moiety is selected from the group consisting of: B- (CH ₂ ) _n1 -O- (CH ₂ ) _n2- ; B- (CH ₂ ) _n1 -NH- (CH ₂ ) _n2- ; B- ( _{CH 2) n1 -CH 2 -;} B- (CH 2) n1 -O-; B- (CH 2) n1 -NH-; bO- (CH 2) n2 -; B-NH- (CH 2) n2 - B-; BO-; B-NH-; BO- (CH ₂ ) _n3 -O-; BO- (CH ₂ ) _n3 -NH-; B-NH- (CH ₂ ) _n3 -NH-; and B- NH- (CH ₂ ) _n3 -O-,
B is defined as above, and n1, n2, and n3 are each independently an integer selected from 1 to 4. 9. A compound according to any of claims 1 to 8, which is a compound of formula (Ia), wherein
R ₁ is selected from OH; -NH ₂ ; -CN; -C (O) CH ₃ ; -COOCH ₃ ; and -OC (O) CH ₃
R ₂ is selected from H; OH; and -CN;
B is a radical of formula (VII), wherein R ₈ is selected from the group consisting of: H; OH; ethylmethyl; ethyl; —CH ₂ OH; —NH ₂ ; —CN; —C (O) CH ₃ ; -COOCH ₃ ; -OC (O) CH ₃ ; -OCONH ₂ ; phenyl; and benzyl,
Where n is an integer from 0 to 1,
The BA moiety is selected from the group consisting of: B- (CH ₂ ) _n1 -O- (CH ₂ ) _n2- ; B- (CH ₂ ) _n1 -NH- (CH ₂ ) _n2- ; B- ( _{CH 2) n1 -CH 2 -;} B- (CH 2) n1 -O-; B- (CH 2) n1 -NH-; bO- (CH 2) n2 -; B-NH- (CH 2) n2 - B-; BO-; B-NH-; BO- (CH ₂ ) _n3 -O-; BO- (CH ₂ ) _n3 -NH-; B-NH- (CH ₂ ) _n3 -NH-; and B- NH- (CH ₂ ) _n3 -O-,
N1, n2 and n3 are each independently an integer selected from 1 to 2. 10. A compound according to any one of claims 1 to 9, selected from:
2- (1-benzylpiperidin-4-yl) -2-(((8-hydroxyquinolin-5-yl) methyl) (prop-2-ynyl) amino) acetonitrile (2);
5-((((1-benzylpiperidin-4-yl) methyl) (prop-2-ynyl) amino) methyl) quinolin-8-ol (3);
3- (1-benzylpiperidin-4-yl) -2-(((8-hydroxyquinolin-5-yl) methyl) (prop-2-ynyl) amino) propanenitrile (4);
5-(((1-benzylpiperidin-4-yl) ethyl) (prop-2-ynyl) amino) methyl) quinolin-8-ol (5);
4- (1-benzylpiperidin-4-yl) -2-(((8-hydroxyquinolin-5-yl) methyl) (prop-2-ynyl) amino) butanenitrile (6);
5-(((3- (1-Benzylpiperidin-4-yl) propyl) (prop-2-ynyl) amino) methyl) quinolin-8-ol (7).   A therapeutically effective amount of a compound of formula (I) as defined in any of claims 1 to 10, or a pharmaceutically acceptable salt thereof, of a pharmaceutically acceptable excipient, carrier or mixture thereof. A pharmaceutical composition containing with an appropriate amount.   A compound of formula (I) as defined in any of claims 1 to 10 for use as a medicament.   11. A compound of formula (I) as defined in any of claims 1 to 10 for use in the treatment of neurodegenerative disorders, diseases and / or symptoms in mammals including humans.   14. A compound according to claim 13, wherein the neurodegenerative disorder, disease and / or symptom is selected from Alzheimer's disease and Parkinson's disease. A process for preparing a compound of formula (I) as defined in any of claims 1 to 10, comprising
Including reductive amination of a compound of formula (IX) with propargylamine followed by N-alkylation using a 5-chloromethyl-quinolin-8-yl substituted compound of formula (X),
Alternatively, the 5- (chloromethyl) quinolin-8yl derivative of formula (X) is reacted with propargylamine to give 5-((prop-2-yn-1-ylamino) methyl) quinoline of formula (XI) To produce an -8-yl derivative followed by reductive amination with an aldehyde of formula (IX),
Alternatively, a method of reacting a compound of formula (XII) with propargylamine to form an intermediate of type (XIII) followed by reaction with a chloride of general structure (XIV).