ES2550127B1 - SUBSTITUTED ISATINS AND THEIR THERAPEUTIC APPLICATIONS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES - Google Patents

Abstract

Substituted isatins and their therapeutic applications for the treatment of neurodegenerative diseases. # The present invention relates to a family of differently substituted isatins that exhibit protein kinase inhibitory activity with leucine-rich repeats (LRRK2), so they are useful for treatment of diseases mediated by this enzyme, such as inflammatory diseases, autoimmune diseases and neurodegenerative diseases, especially Parkinson's disease.

Description

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REPLACED ISATINS AND THEIR THERAPEUTIC APPLICATIONS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES

DESCRIPTION

The present invention relates to a family of differently substituted isatins that exhibit protein kinase inhibitory activity with leucine-rich repeats (LRRK2), so they are useful for the treatment of diseases mediated by this enzyme, such as inflammatory diseases, autoimmune and neurodegenerative diseases, especially Parkinson's disease.

STATE OF THE TECHNIQUE

Protein kinase rich in leucine repeats (leucine-rich repeat kinase 2, LRRK2) is a 280 KDa protein first described in 2004. LRRK2 contains two active domains (GTPase and kinase) as well as other reasons for protein-protein interaction. , whose function is unknown. Most of the pathogenic mutations in LRRK2 occur in the GTPase and kinase domains being directly related to Parkinson's disease. The catalytic site formed by ROC and GTPase acts as a molecular switch for a wide variety of cell signal transmission pathways. Flanking the two catalytic domains we find several domains of protein-protein interaction, the N-terminal domain rich in Leu (LRR) and the C-terminal domain (domain WD40). Some of the functions of LRRK2 are vesicular traffic, microtubule dynamics, neurite growth and cellular functions such as lysosomal protein degradation. The dynamics of microtubules is crucial for membrane transport to different cell sites in processes of autophagy and synaptic vesicular traffic.

The discovery of LRRK2 began with the identification of several families of patients suffering from Parkinson's disease with a clear genetic component, but which, however, did not fit with any of the mutations known up to that time. Mutations in LRRK2 are the most common genetic cause for Parkinson's disease, with 4% of family cases and 1% of sporadic cases.

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LRRK2 is abundantly expressed in microglia in addition to neurons, having been shown to be a positive modulator of inflammation in murine microglia and that mutations in LRRK2 can alter the brain microenvironment favoring neuroinflammation. Therefore, it can be related to various neurodegenerative diseases that occur with neuroinflammation such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis, their inhibitors playing a neuroprotective role by decreasing the inflammatory response. In addition, LRRK2 increases the activity of the GSK-3 enzyme and therefore, hyperphosphorylation of the TAU protein and other pathological proteins such as TDP-3 is promoted. This known relationship allows to establish that compounds that inhibit the activity of LRRK2 will indirectly decrease the phosphorylation of tau and TDP-43, so that LRRK2 inhibitors can be useful for the treatment of tautopaths such as Alzheimer's disease, supranuclear paralysis progressive, frontotemporal dementia, Pick's disease, etc., and diseases associated with TDP-43 such as amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's disease, among others.

Neurodegenerative diseases are diseases that do not currently have an effective pharmacological treatment. The number of people who suffer from them is increasing given the increase in life expectancy, which implies a high personal, family and social cost. For all this, the search for new molecules that may be drug candidates is of particular importance.

Parkinson's disease is characterized by the presence of tremor, stiffness, bradykinesia and postural instability. The sporadic form of Parkinson's disease is the majority, compared to 5% of cases of family or inherited type. The incidence of this disease increases with age, affecting one in 1000 adults over 65 years. Both genetic and environmental factors contribute to the pathogenesis of the disease, although the molecular mechanisms involved in Parkinson's disease are unknown. In this disease there is a loss of dopaminergic neurons that are located in the black substance and produce the innervation of the striatum, observing the presence of protein aggregates in inclusions called Lewy bodies in the rabuldeo bulb neurons.

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The formation of Lewy bodies is due to the failure of the cell degradation system and they are formed by aggregates of proteins, mainly a-synuclelna. This protein is expressed in the brain and although its function is not yet clear, it may appear to be involved in neurotransmission functions, and plasticity processes.

Recently, this disease has been linked to mutations in various genes. The vast majority of Parkinson's patients with G2019S mutation in LRRK2 have clinical and neuropathological characteristics practically indistinguishable from those observed in the sporadic type. In addition, the mutations in LRRK2 have been related to the autophagic balance, which could lead to cell death in the presence of another component, still undetermined.

Additionally, it has also been shown that LRRK2 is highly expressed in immune circulating cells, which suggests a potential function of LRRK2 in immune and inflammatory processes, being related to inflammatory bowel diseases such as Crohn's disease, irritable bowel syndrome or ulcerative colitis

WO2011057204 describes seven different families of compounds that inhibit the LRRK2 enzyme for the treatment of neurodegenerative diseases, especially Parkinson's, and autoimmune diseases. One of these seven families is represented by the following formula:

image 1

they have the difficulty of not crossing the blood-brain barrier or being unselective compared to other protein kinases; so they cannot be drug candidate molecules for the treatment of nervous system diseases

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central [Small molecule kinase inhibitors for LRRK2 and their application to Parkinson's disease models. Kramer T, Lo Monte F, Goring S, Okala Amombo G. M, Schmidt B. ACS Chem. Neurosci. 2012, 3, 151-160].

Thus, given that there is a need for advantageous therapeutic agents, the design and synthesis of molecules that are selective for the LRRK2 protein for the treatment of inflammatory and autoimmune diseases, and also with the ability to penetrate into is vitally important. central nervous system for the treatment of neurodegenerative diseases.

SHORT DESCRIPTION

The authors of the present invention have found a family of substituted isatins that inhibit prothena kinase LRRK2 and also have the additional technical advantage of being able to cross the blood-brain barrier that distinguishes them from other inhibitors of this same kinase described in the state of technique. In addition, they present another technical characteristic such as being ATP-competitive, which allows them to bind to the enzyme in the kinase catallotic domain.

The present invention relates to the use of a compound of general formula (I)

image2

or a pharmaceutically acceptable isomer, prodrug, salt or solvate thereof where,

- R1 and R2 are independently selected from optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, C3-C7 cycloalkyl

optionally substituted, optionally substituted C3-C7 heterocycloalkyl, aryl

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Optionally substituted C5-C10 and optionally substituted C5-C10 heteroaryl or R1 and R2 may form a saturated, partially unsaturated or unsaturated C3-C7 hydrocarbon ring which may contain one, two or three heteroatoms;

- R3 is selected from hydrogen and fluorine;

- R4 and R5 are independently selected from hydrogen, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C5-C10 aryl, optionally substituted C5-C10 heteroaryl, halogen, - OR7, -N (R7) 2, -SR7, -CN, -COR7, -COOR7, -OCOR7, -CON (R7) 2, -NHCOR7, -SO2R7, - SO2NHR7 and -NO2;

- R6 is selected from hydrogen and halogen;

- R7 is selected from hydrogen, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted C3-C7 cycloalkyl, optionally substituted C5-C10 aryl and optionally substituted C5-C10 heteroaryl ;

for the preparation of a medicine for the treatment and / or prevention of a

LRRK2 enzyme-mediated disease, disorder or disorder.

In addition, the present invention also refers to a compound of formula

(II),

image3

Formula (II)

or a pharmaceutically acceptable isomer, prodrug, salt or solvate thereof where,

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- R1 and R2 are independently selected from optionally substituted C1-C12 alkyl, optionally substituted C1-C12 alkenyl, optionally substituted C5-C10 aryl and optionally substituted C5-C10 or R1 and R2 heteroaryl can form a partially C3-C7 saturated hydrocarbon ring unsaturated or unsaturated which may contain one, two or three heteroatoms;

- R3 is hydrogen or fluorine;

- R4 is halogen;

with the proviso that the following compounds are excluded:

- (E / Z) -5-Bromo-3- (morpholinoimino) indolin-2-one

- (E / Z) -5-Bromo-3- (2,2-dimethylhydrazono) indolin-2-one

- (E / Z) -5-Chloro-3- (2,2-diphenylhydrazono) indolin-2-one

- (E / Z) -5-Chloro-3- (2-methyl-2-phenylhydrazono) indolin-2-one

- (E / Z) -5-Chloro-3- (2,2-dimethylhydrazono) indolin-2-one

The present invention also refers to a pharmaceutical composition comprising a compound of formula (II) or a pharmaceutically acceptable isomer, prodrug, salt or solvate thereof, and at least one pharmaceutically acceptable adjuvant, vehicle or excipient.

In addition, the present invention refers to the use of a compound of formula (II) or a pharmaceutically acceptable isomer, prodrug, salt or solvate thereof, for the manufacture of a medicament.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect, the present invention relates to the use of a compound of general formula (I)

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image4

or a pharmaceutically acceptable isomer, prodrug, salt or solvate thereof where,

- R1 and R2 are independently selected from optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, C3-C7 cycloalkyl

optionally substituted, optionally substituted C3-C7 heterocycloalkyl, optionally substituted C5-C10 aryl and optionally substituted C5-C10 heteroaryl or R1 and R2 may form a saturated, partially unsaturated or unsaturated C3-C7 hydrocarbon ring which may contain one, two or three heteroatoms ;

- R3 is selected from hydrogen and fluorine;

- R4 and R5 are independently selected from hydrogen, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C5-C10 aryl, optionally substituted C5-C10 heteroaryl, halogen, - OR7, -N (R7) 2, -SR7, -CN, -COR7, -COOR7, -OCOR7, -CON (R7) 2, -NHCOR7, -SO2R7, - SO2NHR7 and -NO2;

- R6 is selected from hydrogen and halogen;

- R7 is selected from hydrogen, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted C3-C7 cycloalkyl, optionally substituted C5-C10 aryl and optionally substituted C5-C10 heteroaryl ;

for the preparation of a medicament for the treatment and / or prevention of a disease, disorder or disorder mediated by the enzyme LRRK2.

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In the present invention, the term "C1-C12 alkyl" refers to a linear or branched aliphatic chain radical having 1 to 12 carbon atoms, preferably 1 to 9 carbon atoms, for example, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, 1 ', 1'-dimethylheptyl, 1, 2-dimethheptyl or 1 ', 1' -dimethyl ethyl. The alkyl group may be optionally substituted by one or more substituents such as halogen, hydroxyl, - O-C1-C12 alkyl, -CO-C1-C12 alkyl, -CN, - COOH, -COO-C1-C12 alkyl, -CONH-C1-C12 alkyl or -SO2-C1-C12 alkyl Examples of substituted alkyl groups are, but not limited to, benzyl, hydroxymethyl, 1-hydroxyethyl, 2-cyanoethyl and trifluoromethyl.

The term "C2-C12 alkenyl" refers, in the present invention, to a stable, straight or branched carbon chain radical, which has at least one double bond and contains between 2 to 12 carbon atoms, preferably between 2 and 9 carbon atoms, such as, but not limited to, vinyl, 1-propenyl, 2-propenyl, 1- butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 3-methyl-2-butenyl, 1-hexenyl, 2- hexenyl, 3-hexenyl, 1-dodecenyl or the like.The alkenyl group may be optionally substituted by one or more substituents such as halogen, hydroxyl, - O-C1-C12 alkyl, -CO-C1-alkyl C12, -CN, -COOH, -COO-C1-C12 alkyl, -CONH-C1-C12 alkyl or -SO2-C1-C12 alkyl.

The term "C3-C7 cycloalkyl" refers to a stable carbon chain radical that forms a cycle of between 3 and 7 carbon atoms, such as and not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, 1- cyclopentylhexyl The cycloalkyl group may be optionally substituted by one or more substituents such as halogen, hydroxyl, -O-C1-C12 alkyl, -CO-C1-C12 alkyl, -CN, -COOH, -COO-C1-C12 alkyl, -CONH-C1-C12 alkyl or -SO2-C1-C12 alkyl.

The term "C3-C7 heterocycloalkyl" refers to a stable 3 to 7 membered ring radical consisting of carbon atoms and one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, preferably a 5 or 5 ring. 6 members with one or more heteroatoms The heterocycloalkyl, according to this invention, may be a monocyclic or bicyclic ring system that may include condensed ring systems and the nitrogen, carbon or sulfur atom in the heterocycloalkyl radical may be optionally oxidized; nitrogen atom

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may be optionally quaternized; and the heterocycloalkyl radical may be partially unsaturated. Examples of such heterocycles include but are not limited to piperidine, piperazine, pyrrolidine, tetrahydrofuran, tetrahydropyran, morpholine and thiomorpholine. The heterocycloalkyl group may be optionally substituted by one or more substituents such as halogen, hydroxyl, -O-C1-C12 alkyl, -CO-C1-C12 alkyl, -CN, -COOH, -COO-C1-C12 alkyl, -CONH -C1-C12 alkyl or -SO2-C1-C12 alkyl.

The term "C5-C10 aryl" refers, in the present invention, to a stable carbon ring radical of 5 to 10 carbon atoms, which may be a monocyclic or multicyclic ring system that may include condensed ring systems. aryl are, for example but not limited to, phenyl, naphthyl, diphenyl, indenyl, phenanthryl or anthracil Preferably, the aryl group has 5 to 7 carbon atoms and more preferably the aryl group is a phenyl. The aryl radicals can be optionally substituted by one or more substituents such as C1-C12 alkyl, C2-C12 alkenyl, C3-C7 cycloalkyl, halogen, hydroxyl, -O-C1-C12 alkyl, -CO-C1-C12 alkyl, -CN, -COOH, -COO-C1-C12 alkyl, -CONH-C1-C12 alkyl, -NO2, or -SO2-C1-C12 alkyl, substituted aryl radicals are for example, but not limited to, 2,4-dichlorophenyl, 1,3- dichlorophenyl, 3,5-difluorophenyl, 2,4-dinitrophenyl and 3-methoxyphenyl.

The term "C5-C10 heteroaryl" refers to a stable 5 to 10 membered ring radical consisting of carbon atoms and one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, preferably a 5 or 5 ring. 6 members with one or more heteroatoms The heteroaryl, according to this invention, may be a monocyclic or bicyclic ring system that may include condensed ring systems and the nitrogen atom may be optionally quaternized Examples of heteroaryl radicals include but are not limited to a, imidazole, pyrrole, pyridine, pyridazine, piperidine, pyrazine, quinoline, indole, thiophene, furan, oxazo and pyrazole.The heteroaryl radicals may be optionally substituted by one or more substituents such as C1-C12 alkyl, C2-C12 alkenyl, C3-C7 cycloalkyl, halogen, hydroxyl, -O-C1-C12 alkyl, -CO-C1-C12 alkyl, -CN, -COOH, -COO-C1-C12 alkyl, -CONH-C1-C12 alkyl, -NO2, or -SO2-C1-C12 alkyl. Het radicals substituted eroaryls are for example, but not limited to, 2,6-dimethylpyridine, 5-bromopyridine, 2-methylxazol, 3-methyl-1,2,4-oxadiazole and 3-methyl-1,2,4-triazole.

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The term "halogen" refers, in the present invention, to fluorine, bromine, chlorine or iodine. Preferably fluorine and chlorine.

The term "heteroatom" refers, in the present invention, to O, N and S.

In a preferred embodiment, the present invention relates to the use of a compound of general formula (I) where, R6 is selected from hydrogen and fluorine.

In another preferred embodiment, the present invention relates to the use of a compound of general formula (I) wherein R1 and R2 are independently selected from optionally substituted C1-C12 alkyl, optionally substituted C5-C10 aryl and optionally substituted C5-C10 heteroaryl or R1 and R2 may form a saturated, partially unsaturated or unsaturated C3-C7 hydrocarbon ring that may contain one, two or three heteroatoms.

In another preferred embodiment, the present invention relates to the use of a compound of general formula (I), wherein R1 and R2 are independently selected from optionally substituted C1-C12 alkyl, optionally substituted C5-C10 aryl and optionally substituted C5-C10 heteroaryl or R1 and R2 may form a saturated, partially unsaturated or unsaturated C3-C7 hydrocarbon ring that may contain one, two or three heteroatoms and R6 is selected from hydrogen and fluorine.

In another more preferred embodiment, R1 and R2 are independently selected from optionally substituted C1-C12 alkyl and optionally substituted C5-C10 aryl.

In a more preferred embodiment, R1 and R2 are independently selected from methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl and phenyl.

In a still more preferred embodiment, R1 and R2 are phenyl.

In another preferred embodiment, R1 and R2 form a saturated, partially unsaturated or unsaturated C3-C7 hydrocarbon ring that may contain one, two or three heteroatoms.

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In a more preferred embodiment, R1 and R2 form a pyrrolidine, piperidine, 2,6-dimethylpiperidine, azepane, 1,2,4-triazole, 2-thioxothiazolidin-4-one, oxazolidin-2-one or morpholine ring.

In a still more preferred embodiment, R1 and R2 form a piperidine or morpholine ring.

In another preferred embodiment, the present invention relates to the use of a compound of general formula (I) where, R4 and R5 are independently selected from hydrogen, optionally substituted C5-C10 aryl, optionally substituted C5-C10 heteroaryl, halogen, -OR7 , -N (R7) 2, -SR7, -CN, -COOR7, -OCOR7, -CON (R7) 2, and - NHCOR7.

In an even more preferred embodiment, R4 and R5 are independently selected from hydrogen, halogen, optionally substituted C5-C10 aryl, optionally substituted C5-C10 heteroaryl, -OR7 and -N (R7) 2.

In another preferred embodiment, the present invention relates to the use of a compound of general formula (I) where, R4 and R5 are independently selected from hydrogen, optionally substituted C5-C10 aryl, optionally substituted C5-C10 heteroaryl, halogen, -OR7 , -N (R7) 2, -SR7, -CN, -COOR7, -OCOR7, -CON (R7) 2, - NHCOR7, and R6 is selected from hydrogen and fluorine.

In another preferred embodiment, the present invention relates to the use of a compound of general formula (I) where, R6 is selected from hydrogen and fluorine, R1 and R2 are independently selected from methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2- butyl and phenyl, and R4 and R5 are independently selected from hydrogen, optionally substituted C5-C10 aryl, optionally substituted C5-C10 heteroaryl, halogen, - OR7 and -N (R7) 2.

In a more preferred embodiment, R1 and R2 are phenyl, and R4 and R5 are independently selected from hydrogen, halogen, optionally substituted C5-C10 aryl and -OR7.

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In an even more preferred embodiment, R1 and R2 are phenyl, and R4 and R5 are independently selected from hydrogen, halogen and -OR7.

In another preferred embodiment, the present invention relates to the use of a compound of general formula (I) wherein, R6 is selected from hydrogen and fluorine, R1 and R2 form a pyrrolidine ring, piperidine, 2,6-dimethylpiperidine, azepane, 1,2,4-triazol, 2- thioxothiazolidin-4-one, oxazolidin-2-one or morpholine, and R4 and R5 are independently selected from hydrogen, optionally substituted C5-C10 aryl, optionally substituted C5-C10 heteroaryl, halogen, -OR7 and -N (R7) 2.

In a more preferred embodiment, R1 and R2 form a piperidine or morpholine ring and, R4 and R5 are independently selected from hydrogen, halogen, optionally substituted C5-C10 aryl and -OR7.

In an even more preferred embodiment, R1 and R2 form a piperidine or morpholine ring and, R4 and R5 are independently selected from hydrogen, halogen and - OR7.

In other preferred embodiments, the compound of formula (I) is selected from the following group:

- (E / Z) -3 - ((4H-1,2,4-triazol-4-yl) imino) indolin-2-one

- (E / Z) -5-Bromo-3- (2,2-dimethylhydrazono) indolin-2-one

- (E / Z) -5-Chloro-3- (2,2-dimethylhydrazono) indolin-2-one

- (E / Z) -7-Chloro-3- (2,2-dimethylhydrazono) indolin-2-one

- (E / Z) -3 - ((2-Oxoindolin-3-iidene) amino) -2-thioxothiazolidin-4-one

- (E / Z) -3 - ((2-Oxoindolin-3-ilidene) amino) oxazolidin-2-one

- (E / Z) -3- (Pyrrolidin-1-unlimited) indolin-2-one

- (E / Z) -3- (Morpholinoimino) indolin-2-one (8)

- (E / Z) -5-Bromo-3- (morpholinoimino) indolin-2-one

- (E / Z) -7-Chloro-3- (morpholinoimino) indolin-2-one (12)

- (E / Z) -3- (Piperidin-1-unlimited) indolin-2-one (7)

- (E / Z) -3,3 '- (2- (2-Oxoindolin-3-ylidene) hydrazine-1,1-diyl) dipropanenitrile

- (E / Z) -3- (Azepan-1-unlimited) indolin-2-one

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- (E / Z) -3- (2- (2,4-Dinitrophenyl) -2-methylhydrazono) indolin-2-one

- (E / Z) -3- (2-Methyl-2-phenylhydrazono) indolin-2-one

- (E / Z) -5-Chloro-3- (2-methyl-2-phenylhydrazono) indolin-2-one

- (E / Z) -3 - ((2,6-Dimethylpiperidin-1-yl) imino) indolin-2-one

- (E / Z) -3- (2-Phenyl-2-propylhydrazono) indolin-2-one

- (E / Z) -3- (2,2-Diphenylhydrazono) indolin-2-one (6)

- (E / Z) -5-Chloro-3- (2,2-diphenylhydrazono) indolin-2-one (9)

- (E / Z) -3- (2,2-Dibenzylhydrazono) indolin-2-one

- (E / Z) -7-Chloro-3- (2,2-diphenylhydrazono) indolin-2-one (10)

- (E / Z) -7-Chloro-3- (piperidin-1-unlimited) indolin-2-one (11)

- (E / Z) -5-Fluoro-3- (2,2-diphenylhydrazono) indolin-2-one (1)

- (E / Z) -5-Chloro-3- (piperidin-1-unlimited) indolin-2-one (2)

- (E / Z) -5-Fluoro-3- (piperidin-1-unlimited) indolin-2-one (3)

- (E / Z) -5-Chloro-3- (morpholinoimino) indolin-2-one (4)

- (E / Z) -5-Fluor-3- (morpholinoimino) indolin-2-one (5)

- (E / Z) -5-Bromo-3- (2,2-diphenylhydrazono) indolin-2-one (13)

- (E / Z) -5-Methoxy-3- (morpholinoimino) indolin-2-one (14)

In other even more preferred embodiments, the compound of formula (I) is selected from the following group:

- (E / Z) -5-Fluoro-3- (2,2-diphenylhydrazono) indolin-2-one (1)

- (E / Z) -5-Chloro-3- (piperidin-1-unlimited) indolin-2-one (2)

- (E / Z) -5-Fluoro-3- (piperidin-1-unlimited) indolin-2-one (3)

- (E / Z) -5-Chloro-3- (morpholinoimino) indolin-2-one (4)

- (E / Z) -5-Fluor-3- (morpholinoimino) indolin-2-one (5)

- (E / Z) -3- (2,2-Diphenylhydrazono) indolin-2-one (6)

- (E / Z) -3- (Piperidin-1-unlimited) indolin-2-one (7)

- (E / Z) -3- (Morpholinoimino) indolin-2-one (8)

- (E / Z) -5-Chloro-3- (2,2-diphenylhydrazono) indolin-2-one (9)

- (E / Z) -5-Bromo-3- (2,2-diphenylhydrazono) indolin-2-one (13)

According to the present specification, any of the compounds defined above, that is, those compounds that respond to the general formula (I), can be

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also referred to herein as "compound or compounds of the invention".

In a second aspect, the present invention relates to a compound of general formula (II),

where,

image5

- R1 and R2 are independently selected from optionally substituted C1-C12 alkyl, optionally substituted C1-C12 alkenyl, optionally substituted C5-C10 aryl and optionally substituted C5-C10 or R1 and R2 heteroaryl can form a partially C3-C7 saturated hydrocarbon ring unsaturated or unsaturated, which may contain one, two or three heteroatoms;

- R3 is hydrogen or fluorine;

- R4 is halogen;

with the proviso that the following compounds are excluded:

- (E / Z) -5-Bromo-3- (morpholinoimino) indolin-2-one

- (E / Z) -5-Bromo-3- (2,2-dimethylhydrazono) indolin-2-one

- (E / Z) -5-Chloro-3- (2,2-diphenylhydrazono) indolin-2-one

- (E / Z) -5-Chloro-3- (2-methyl-2-phenylhydrazono) indolin-2-one

- (E / Z) -5-Chloro-3- (2,2-dimethylhydrazono) indolin-2-one

In a preferred embodiment, the present invention relates to a compound of general formula (II) wherein, R4 is selected from fluorine and chlorine.

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In another preferred embodiment, R1 and R2 are independently selected optionally substituted C1-C12 alkyl, optionally substituted C1-C12 alkenyl, optionally substituted C5-C10 aryl and optionally substituted C5-C10 heteroaryl

In a more preferred embodiment, R1 and R2 are independently selected from methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl and phenyl.

In a still more preferred embodiment, R1 and R2 are phenyl.

In another preferred embodiment, R1 and R2 form a saturated, partially unsaturated or unsaturated C3-C7 hydrocarbon ring, which may contain one, two or three heteroatoms.

In a more preferred embodiment, R1 and R2 form a pyrrolidine, piperidine, 2,6-dimethylpiperidine, azepane, 1,2,4-triazole, 2-thioxothiazolidin-4-one, oxazolidin-2-one or morpholine ring.

In a still more preferred embodiment, R1 and R2 form a pyrrolidine or morpholine ring.

In other preferred embodiments, the compound is selected from the following group:

- (E / Z) -5-Fluoro-3- (2,2-diphenylhydrazono) indolin-2-one (1)

- (E / Z) -5-Chloro-3- (piperidin-1-unlimited) indolin-2-one (2)

- (E / Z) -5-Fluoro-3- (piperidin-1-unlimited) indolin-2-one (3)

- (E / Z) -5-Chloro-3- (morpholinoimino) indolin-2-one (4)

- (E / Z) -5-Fluor-3- (morpholinoimino) indolin-2-one (5)

- (E / Z) -5-Bromo-3- (2,2-diphenylhydrazono) indolin-2-one (13)

It should be understood that the present invention encompasses all isomers of the compounds of formulas (I) and (II), that is, all geometric, tautometric and optical forms, and mixtures thereof (eg, racemic mixtures). When there are more chiral centers in the compounds of formulas (I) and (II), the present invention includes within its scope all possible diastereomers, including mixtures thereof. The different

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Isomeric forms can be separated or resolved from one another by conventional methods, or any given isomer can be obtained by conventional synthetic methods or by stereospecific, stereoselective or asymmetric synthesis. The present invention also includes compounds labeled with isotopes, which are identical to those cited in formulas (I) and (II) except that one or more atoms have been replaced by an atom that has an atomic mass or mass number different from the Atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include hydrogen, carbon, nitrogen, oxygen, fluorine, iodine and chlorine isotopes, such as 3H, 11C, 14C, 18F, 123I and 125I.

Within the scope of the present invention are compounds of the present invention and pharmaceutically acceptable salts of said compounds containing the aforementioned isotopes and / or other isotopes of other atoms. The isotope-labeled compounds of the present invention, for example those in which radioactive isotopes such as 3H or 14C are incorporated, are useful in drug and / or tissue distribution assays. Particularly preferred are tritium isotopes, i.e. 3H, and carbon-14, i.e. 14C, for their ease of preparation and detectability. Isotopes 11C and 18F are particularly useful in PET (positron emission tomograph), and isotopes 125I are particularly useful in SPECT (single photon emission computerized tomograph), all useful in brain imaging. In addition, substitution with heavier isotopes such as deuterium, that is, 2H, may provide some therapeutic advantages that result from greater metabolic stability, for example, longer half-life in vivo or lower dosage requirements, and therefore in some Cases may be preferred. The isotopically labeled compounds of formulas (I) and (II) can generally be prepared by performing the procedures described in the examples below, replacing an isotopically unlabeled reagent with an easily available isotopically labeled reagent.

The term "tautomer" or "tautomeric form", as used in the present invention, refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, protonic tautomers (also known as prototropic tautomers ) that include interconversions

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by migration of a proton, such as keto-enolic or imine-enamine isomerizations. Valencia tautomers include interconversions by reorganization of some bond electrons.

The terms E (trans) and Z (cis) are used in the present invention in accordance with the nomenclature of the Chemical Abstracts.

It will be appreciated that, for pharmaceutical use, the salts mentioned above will be physiologically acceptable salts, but other salts may find utility, for example in the preparation of compounds of formula (I) and their acceptable physiological salts. Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19. The term "pharmaceutically acceptable salts" refers to salts prepared from non-toxic pharmaceutically acceptable bases including inorganic bases and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper, ferric, ferrous, lithium of magnesium, manganic, manganous, potassium, sodium, zinc and the like salts Salts derived from pharmaceutically acceptable non-toxic organic bases include salts of primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betalna, cafelna, choline, N, N'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, pro Calna, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compound of the present invention is basic, salts can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, chloric, ethanesulfonic, fumaric, gluconic, glutamic, bromhydric, hydrochloric, isethionic, lactic, maleic, malico, mandelic, methanesulfonic, mucic, nitric, succinic, pantotonic, pantotonic phosphoric , sulfuric, tartaric, ptoluenesulfonic and the like.

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Preferred examples of pharmaceutically acceptable salts include ammonium, calcium, magnesium, potassium and sodium salts, and those formed from maleic, fumaric, benzoic, ascorbic, pamoic, succlonic, chlorhydric, sulfuric, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, propionic acids. , tartaric, salicylic, chloric, gluconic, aspartic, stearic, palmetic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, cyclohexylsulfamic, phosphoric and nitric.

Particularly preferred derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (for example, by making a compound administered orally more easily absorbed by the blood), or that enhance the release of the original compound in a biological compartment (for example, a tumor) in relation to the original species.

Any compound that is a prodrug of a compound of formulas (I) and (II) is within the scope of the invention. The term "prodrug" is used in its broadest sense and encompasses those derivatives that are converted in vivo into the compounds of the invention. Such derivatives will be apparent to those skilled in the art, and include, depending on the functional groups present in the molecule and without limitation, the following derivatives of the compounds present: esters, amino acid esters, phosphate esters, salt sulphonate esters metal, carbamates and amides.

The compounds of formulas (I) and (II) may be in crystalline form as free compounds or as solvates and it is intended that both forms are within the scope of the present invention. Solvation methods are generally known within the art. Suitable solvates are pharmaceutically acceptable solvates. In a particular embodiment, the solvate is a hydrate.

The compounds of formulas (I) and (II) or their salts or solvates are preferably in a pharmaceutically acceptable or substantially pure form. By pharmaceutically acceptable form is understood, among others, that they have a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and not including material considered toxic at levels of

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normal dosage. The purity levels for the active ingredient are preferably greater than 50%, more preferably, greater than 70%, more preferably, greater than 90%. In a preferred embodiment, they are greater than 95% of the compound of formula (I) or (II), or of its salts, solvates or prodrugs.

A further aspect of the invention relates to a pharmaceutical composition comprising the compound of formula (II), as described above and at least one excipient, adjuvant and / or a pharmaceutically acceptable carrier. In addition, it is contemplated that the pharmaceutical composition contains another active ingredient.

Pharmaceutical compositions containing a therapeutically effective amount of a compound of formula (II), its pharmaceutically acceptable isomers, prodrugs, salts or solvates thereof, together with pharmaceutically acceptable carriers, constitute a further aspect of the present invention. It refers to a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound of the invention. Hereinafter, said pharmaceutical composition may also be referred to as "pharmaceutical composition of the invention."

The term "vehicle" refers to a diluent, adjuvant or excipient with which the active substance is administered. Such pharmaceutical vehicles may be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like, water or aqueous solutions of saline solution and aqueous solutions of dextrose and glycerol, particularly for injectable solutions, are preferably used as vehicles. in "Remington's Pharmaceutical Sciences" by EW Martin, 1995. Preferably, the vehicles of the invention are approved by the regulatory agency of a state government or a federal government, or are listed in the United States Pharmacopoeia, the European Pharmacopoeia or other pharmacopoeia generally recognized for use in animals, and more particularly in humans.

The amount of compound of the invention, its pharmaceutically acceptable isomers, prodrugs, salts or solvates thereof, therapeutically effective that should

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administer (also referred to herein as a therapeutically effective or effective amount), as well as its dosage to treat a pathological condition with said compounds, will depend on numerous factors, including age, patient status, severity. of the disease, the route and frequency of administration, the modulator compound to be used, etc.

The compounds and pharmaceutical compositions of this invention can be used alone or together with other drugs to provide a combination therapy. The other drugs may be part of the same pharmaceutical composition, or be provided as a separate pharmaceutical composition, for administration at the same time or at a different time. Examples of pharmaceutical compositions include any solid composition (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) for oral, topical or parenteral administration.

The present invention also relates to the compounds of formula (II) as previously defined for the manufacture of a medicament.

Surprisingly, it has been found that the compounds defined in the present invention, as a free base or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof, are very suitable for inhibiting the protein kinase with leucine-rich repeats (LRRK2). Accordingly, it is expected that the compounds of the present invention are useful in the prevention and / or treatment of pathologies associated with the activity of LRRK2, that is, the compounds can be used to produce an inhibitory effect of LRRK2 in mammals, including man, who need such prevention and / or treatment.

Thus, LRRK2 is related to neurodegenerative diseases or what is the same, neurodegenerative diseases are mediated by the enzyme LRRK2. Examples of neurodegenerative diseases are, but not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease, HIV-associated dementia, Lewy body dementia, multiple sclerosis, amyotrophic lateral sclerosis, Pick's disease, schizophrenia, Creutzfeltd's disease -Jakob, Parkumsonism-Gaum dementia, corticobasal degeneration, pugilistic dementia and

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head trauma, stroke, Down syndrome, post-encephalic parkinsonism, progressive supranuclear paralysis and Niemann-Pick disease.

LRRK2 is also related to inflammatory diseases or what is the same, inflammatory diseases are mediated by the enzyme LRRK2. Examples of inflammatory diseases are, but not limited to, inflammatory bowel disease (Crohn's disease and ulcerative colitis), rheumatoid arthritis, atherosclerosis and vasculitis.

LRRK2 is also related to autoimmune diseases, or what is the same, autoimmune diseases are mediated by the enzyme LRRK2. Examples of autoimmune diseases are, but not limited to, Crohn's disease, irritable bowel syndrome, ulcerative colitis, irritable bowel and multiple sclerosis.

In addition, LRRK2 is also related to the processes of cellular regeneration, or what is the same, the processes of cellular regeneration are mediated by the enzyme LRRK2, where the differentiation of the stem cells of the nervous system, of the hematopoietic system is involved, of the bone system or myocardium. Thus, LRRK2 inhibitors can be used in regenerative medicine of the central nervous system.

In a preferred embodiment, the present invention relates to the use of a compound of formula (I) or of a pharmaceutical composition containing at least one compound of formula (II) as described above or an isomer, prodrug, salt or solvate pharmaceutically acceptable thereof, for the manufacture of a medicament for the treatment of a neurodegenerative disease.

In the present invention, neurodegenerative disease is understood as Alzheimer's disease, Parkinson's disease, Huntington's disease, HIV-associated dementia, Lewy body dementia, multiple sclerosis, amyotrophic lateral sclerosis, Pick's disease, schizophrenia, Creutzfeltd's disease -Jakob, Parkumsonism-Gaum dementia, corticobasal degeneration, pugillotic dementia and

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head trauma, stroke, Down syndrome, post-encephalic parkinsonism, progressive supranuclear paralysis and Niemann-Pick disease.

In an even more preferred embodiment, the present invention relates to the use of a compound of formula (I) or of a pharmaceutical composition containing at least one compound of formula (II) as described above or an isomer, prodrug, salt or pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of Parkinson's and Parkinson's plus.

Parkinson plus is a term that includes a group of related syndromes that have common clinical data of Parkinson's disease, in addition to studying with other clinical manifestations due to degeneration of other neuronal systems, which include: multiple systemic atrophy, progressive supranuclear paralysis, the Parkinson-dementia-amyotrophic lateral sclerosis complex, corticobasoganglionic degeneration and Lewy body disease.

On the other hand, Parkinson's disease can occur in different forms, including, but not limited to, sporadic Parkinson's disease, familial Parkinson's disease, post-encephalic Parkinson's disease, and early-onset autosomal recessive Parkinson's disease.

In a preferred embodiment, the present invention relates to the use of a compound of formula (I) or of a pharmaceutical composition containing at least one compound of formula (II) as described above or an isomer, prodrug, salt or solvate pharmaceutically acceptable thereof, for the manufacture of a medicament for the treatment of an inflammatory disease.

In the present invention, inflammatory disease is understood as inflammatory bowel disease (Crohn's disease and ulcerative colitis), rheumatoid arthritis, atherosclerosis and vasculitis.

In another preferred embodiment, the present invention relates to the use of a compound of formula (I) or of a pharmaceutical composition containing at least one compound of formula (II) as described above or an isomer,

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pharmaceutically acceptable prodrug, salt or solvate thereof, for the manufacture of a medicament for the treatment of an autoimmune disease.

In the present invention, autoimmune disease is understood as inflammatory bowel diseases, such as Crohn's disease, ulcerative colitis and multiple sclerosis.

In another preferred embodiment, the present invention relates to the use of a compound of formula (I) or of a pharmaceutical composition containing at least one compound of formula (II) as described above, or an isomer, prodrug, salt or pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of a disease that requires cell regeneration, especially for the treatment of a disease of the central nervous system that requires neuronal regeneration.

According to the present description, the invention relates to a compound of the invention or a pharmaceutical composition comprising at least one compound of formula (II) for use as a medicament and particularly as a medicament for treating and / or preventing neurodegenerative, inflammatory diseases. , autoimmune or to promote regenerative processes

In addition, according to the present description, the use of a compound of the invention or a pharmaceutical composition comprising at least one compound of formula (II) for the manufacture of a medicament for the treatment and / or prevention of a neurodegenerative disease, a inflammatory disease, an autoimmune disease or to promote regenerative processes, can obviously be understood as a method of treating said neurodegenerative, inflammatory or autoimmune disease or to promote regenerative processes, which comprises the administration to a subject of a therapeutically effective amount of said compound or pharmaceutical composition of the invention. In other words, the present invention also relates to a method of treatment of neurodegenerative disease, inflammatory disease, an autoimmune disease or to promote regenerative processes comprising administering to a subject the compound of the invention in a therapeutically effective amount, or a

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Pharmaceutical composition of the invention comprising the compound of the invention in a therapeutically effective amount.

Throughout the description and the claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and characteristics of the invention will be derived partly from the description and partly from the practice of the invention. The following examples are provided by way of illustration, and are not intended to be limiting of the present invention.

EXAMPLES

Example 1: General procedure for isatin synthesis In a microwave vial the corresponding isatin derivative (1 eq.), The corresponding amine derivative (1 eq.) And MMT-K10 (for 1 mmol of isatin 20 mg of MMT-K10), in the presence or absence of solvent. Microwave irradiation is carried out for a specified time and temperature in each case. Then, ethyl acetate (50 mL) is added and extracted with a saturated solution of NaHCO3 (3 x 50 mL). The crude is purified by chromatographic techniques specified for each case. In the event that the amine is in the form of hydrochloride, the amine (1 eq.), Triethylamine (1 eq.) And toluene (3 mL) are stirred for 1 h at room temperature, and the reaction crude is added as in the case of finding the free amine.

(E / Z) -5-Fluoro-3- (2,2-diphenylhydrazono) indolin-2-one (1): Reagents: 5-fluoroisatin (250 mg, 1.5 mmol), 2,2-diphenylhydrazine hydrochloride (279.0 mg, 1.5 mmol), MMT-K10 (30 mg), triethylamine (153.0 mg, 1.5 mmol) and toluene (5 mL). Reaction conditions: 1 h under microwave irradiation at 100 ° C. Purification: chromatographic column using dichloromethane as eluent to obtain a brown solid. Yield: 138 mg, 27%, E / Z ratio: 96: 4. Mp: 228 ° C. Isomer E: 1H-NMR (400 MHz, DMSO-da): 5 10.65 (s, 1H), 7.49 (m, 4H), 7.34 (m, 6H), 6.94 (ddd, J = 9.1, 8.5, 2.6 Hz, 1H), 6.73 (dd, J = 8.5, 4.7 Hz, 1H), 4.86 (dd, J = 10.5, 2.6 Hz, 1H). 13C-NMR (100 MHz, DMSO- ^ 6): 5 166.6, 157.37 (d, J = 234.0 Hz), 146.0, 139.9 (d, J = 1.5 Hz), 131.3,

130.3, 127.2, 123.9, 117.1 (d, J = 8.8 Hz), 116.8 (d, J = 23.7 Hz), 112.7 (d, J = 27.8

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Hz), 111.1 (d, J = 8.1 Hz). MS (ESI +): m / z 332 [M + 1]. Elemental analysis (C20H14FN3O) Calculated: C 72.50%, H 4.26%, N 12.68%. Found: C 72.79%, H 4.31%, N 12.85%.

(E / Z) -5-Chloro-3- (piperidin-1-unlimited) indolin-2-one (2): Reagents: 5-chloroisatin (250 mg, 1.4 mmol), 1-aminopiperidine (137.0 mg, 1.4 mmol), MMT-K10 (27 mg) and toluene (5 mL). Reaction conditions: 30 min under microwave irradiation at 100 ° C. Purification: The final product was obtained without the need for purification as a yellow solid. Yield: 327 mg, 91%, E / Z ratio: 18:82. Mp: 193 ° C. Isomer Z: 1H-NMR (400 MHz, DMSO-da): 5 10.72 (s, 0.2H), 10.63 (s, 1H), 7.31 (dd, J = 8.3, 2.1 Hz, 0.2H), 7.18 (d, J = 2.2 Hz, 1H), 7.16 (d, J = 2.1 Hz, 0.2H), 7.04 (dd, J = 8.2, 2.2 Hz, 1H), 6.86 (d, J = 8.3 Hz, 0.2H), 6.73 ( d, J = 8.2 Hz, 1H), 4.08-3.95 (m, 4H), 3.30-3.25 (m, 0.8H), 1.73-1.54 (m, 7.2H). 13C-NMR (100 MHz, DMSO-d6): 5 165.7, 159.1, 142.2,

137.5, 137.3, 130.4, 128.2, 126.1, 126.0, 125.8, 124.9, 121.4, 117.6, 117.5, 112.4, 111.0, 58.6, 56.8, 26.7, 25.7, 23.8. MS (ESI +): m / z 266 [M + 3], 264 [M + 1]. Elemental analysis (C ^ H ^ Cl ^ O) Calculated: C 59.21%, H 5.35%, N 15.93%. Found: C 59.15%, H 5.48%, N 15.69%.

(E / Z) -5-Fluoro-3- (piperidin-1-unlimited) indolin-2-one (3): Reagents: 5-fluoroisatin (250 mg, 1.5 mmol), 1-aminopiperidine (152.0 mg, 1.5 mmol), MMT-K10 (30 mg) and toluene (5 mL). Reaction conditions: 30 min under microwave irradiation at 100 ° C. Purification: Chromatographic column using dichloromethane / methanol (150: 1) as eluents, obtaining a yellow solid. Yield: 311.6 mg, 83%, E / Z ratio: 30:70. Mp: 169 ° C. Isomer Z: 1H-NMR (400 MHz, DMSO-da): 5 10.64 (s, 0.5H), 10.55 (s, 1H), 7.15 (ddd, J = 9.4, 8.5, 2.6 Hz, 0.5H), 7.01 ( ddd, J = 8.9, 6.7, 2.7 Hz, 1.5H), 6.87 (m, 1.5H), 6.73 (dd, J = 8.4, 4.4 Hz, 1H), 4.04 (m, 4H), 3.30 (m, 2H) , 1.77 - 1.48 (m, 9H). 13C-NMR (100 MHz, DMSO-d6): 5 166.0, 159.4, 158.6 (d, J = 234.4 Hz), 158.2 (d, J = 235.8 Hz), 139.9, 138.2, 135.0 (d, J = 1.3 Hz) , 127.8 (d, J = 8.8 Hz), 122.4,

117.2 (d, J = 23.5 Hz), 116.8 (d, J = 8.3 Hz), 112.8 (d, J = 24.0 Hz), 112.4 (d, J = 26.1 Hz), 111.7, 110.3 (d, J = 8.2 Hz ), 105.0 (d, J = 25.4 Hz), 58.5, 56.8, 26.6, 25.7, 23.9, 23.8. MS (ESI +): m / z 248 [M + 1]. Elemental analysis (C13H14FN3O) Calculated: C 63.15%, H 5.71%, N 16.99%. Found: C 63.08%, H 5.74%, N 17.04%.

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(E / Z) -5-Chloro-3- (morpholinoimino) indolin-2-one (4): Reagents: 5-chloroisatin (250 mg, 1.4 mmol), 4-aminomorpholine (141 mg, 1.4 mmol ), MMT-K10 (27 mg) and toluene (5 mL). Reaction conditions: 1 h under microwave irradiation at 100 ° C. Purification: Chromatographic column using dichloromethane / methanol (100: 1) as eluents, obtaining a yellow solid. Yield: 280.8 mg, 77%, E / Z ratio: 26:74. Mp: 192 ° C. Isomer Z: 1H-NMR (400 MHz, DMSO ^): 5 10.84 (s, 0.4H), 10.79 (s, 1H), 7.39 (dd, J = 8.4, 2.1 Hz, 0.4H), 7.29 (d, J = 2.1 Hz, 0.4H), 7.25 (d, J = 2.1 Hz, 1H), 7.14 (dd, J = 8.2, 2.2 Hz, 1H), 6.90 (d, J = 8.3 Hz, 0.4H), 6.79 (d , J = 8.2 Hz, 1H), 4.04 (dd, J = 6.2, 3.6 Hz, 4H), 3.80 (m, 5.6H), 3.29 (m, 1.6H). 13C-NMR (100 MHz, DMSO-d6): 5 165.3, 159.1, 143.0, 141.1, 138.1, 131.5, 127.3, 127.0, 126.3, 126.0, 125.8,

124.5, 118.3, 111.3, 117.1, 112.6, 66.6, 66.1, 57.7, 56.0. MS (ESI +): m / z 268 [M + 3], 266 [M + 1]. Elemental analysis (C ^ H ^ Cl ^ O) Calculated: C 54.25%, H 4.55%, N 15.82%. Found: C 54.27%, H 4.60%, N 15.79%.

(E / Z) -5-Fluor-3- (morpholinoimino) indolin-2-one (5): Reagents: 5-fluoroisatin (250 mg, 1.5 mmol), 4-aminomorpholine (155 mg, 1.5 mmol ), MMT-K10 (30 mg) and toluene (5 mL). Reaction conditions: 30 min under microwave irradiation at 100 ° C. Purification: Chromatographic column using dichloromethane / methanol (100: 1) as eluents, obtaining a yellow solid. Yield: 149.2 mg, 40%, E / Z ratio: 30:70. Mp: 191 ° C. Isomer Z: 1H-NMR (400 MHz, DMSO-da): 5 10.70 (s, 0.4H), 10.66 (s, 1H), 7.17 (ddd, J = 9.5, 8.5, 2.6 Hz, 0.4H), 7.10 ( dd, J = 8.8, 2.6 Hz, 0.4H), 7.01 (dd, J = 8.7, 2.7 Hz, 1H), 6.90 (ddd, J = 9.8, 8.4, 2.7 Hz, 1H), 6.85 (dd, J = 8.6 , 4.5 Hz, 0.4H), 6.76 - 6.70 (m, 1H), 4.03 - 3.96 (m, 4H), 3.82 - 3.77 (m, 1.6H), 3.77 - 3.71 (m, 4H), 3.27 - 3.21 (m , 1.6H). 13C-NMR (100 MHz, DMSO-da): 5 165.6, 159.4, 158.7 (d, J = 235.1 Hz), 158.2 (d, J = 236.8 Hz), 141.9 (d, J = 2.5 Hz), 140.6 (d , J = 1.6 Hz), 135.8 (d, J = 1.1 Hz), 126.9 (d, J = 9.0 Hz), 125.7 (d, J = 3.3 Hz), 118.4 (d, J = 23.6 Hz),

116.3 (d, J = 8.6 Hz), 113.9 (d, J = 24.0 Hz), 113.5 (d, J = 25.8 Hz), 112.0 (d, J = 8.1 Hz), 110.7 (d, J = 8.4 Hz), 105.7 (d, J = 25.2 Hz), 66.6, 66.1, 57.6, 56.0. MS (ESI +): m / z 250 [M + 1]. Elemental analysis (C12H12FN3O2) Calculated: C 57.83%, H 4.85%, N 16.86%. Found: C 57.58%, H 4.90%, N 16.91%.

(E / Z) -3- (2,2-Diphenylhydrazono) indolin-2-one (6): Reagents: isatin (250 mg, 1.7 mmol), 2,2-diphenylhydrazone hydrochloride (220.7 mg, 1, 7 mmol), MMT-K10 (34 mg), triethylamine (171.9 mg, 1.7 mmol) and toluene (3 mL). Reaction conditions: 6 min

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under microwave irradiation at 100 ° C. Purification: IsoleraOne using water / acetonitrile (7: 3) to obtain a green-yellow solid. Yield: 394.8 mg, 74%, E / Z ratio: 95: 5. Mp: 246-248 ° C. Isomer E: 1H-NMR (300 MHz, DMSO-cfe): 5 10.64 (s, 1H), 7.47 - 7.41 (m, 4H), 7.31 - 7.26 (m, 6H), 7.07 (td, J = 7.7, 1.1 Hz, 1H), 6.75 (d, J = 7.3 Hz, 1H), 6.40 (td, J = 7.8, 1.1 Hz, 1H), 5.39 (d, J = 7.5 Hz, 1H). 13C-NMR (100 MHz, DMSO- ^ 6): 5 166.5, 157.5, 146.3, 143.9, 131.0, 130.2, 126.7, 125.8,

123.6, 121.3, 116.4, 110.6. MS (ESI +): m / z 314 [M + 1]. Elemental analysis (C20H15N3O) Calculated: C 76.66%, H 4.82%, N 13.41%. Found: C 76.84%, H 5.09%, N 13.17%.

(E / Z) -3- (Piperidin-1-unlimited) indolin-2-one (7): Reagents: isatin (250 mg, 1.7 mmol), 1-aminopiperidine (170.2 mg, 1.7 mmol), MMT-K10 (34 mg). Reaction conditions: 10 min under microwave irradiation at 100 ° C. Purification: IsoleraOne using water / acetonitrile (4: 1) to obtain an orange solid. Yield: 335.0 mg, 86%, E / Z ratio: 46:54. Mp: 142 ° C (lit. 141-142 ° C). Isomer Z: 1H-NMR (400 MHz, DMSOcfe): 5 10.64 (s, 0.8H), 10.55 (s, 1H), 7.32 - 7.24 (m, 1.8H), 7.28 - 7.24 (m, 1H), 7.11 - 7.02 (m, 1.8H), 6.94 - 6.85 (m, 1.8H), 6.76 (d, J = 7.9 Hz, 1H), 3.97 - 3.93 (m, 4H), 3.22 (t, J = 5.5 Hz, 4H), 1.90 - 1.47 (m, 12H). 13C-NMR (100 MHz, DMSO-cfe): 5 165.1,

158.4, 143.3, 140.2, 138.5, 130.9, 126.5, 126.7, 125.4, 121.8, 120.9, 117.8, 115.6, 110.3, 109.0, 57.5, 55.9, 25.8, 24.923.3, 23.2. MS (ESI +): m / z 230 [M + 1]. Elemental analysis (C13H15N3O) Calculated: C 68.10%, H 6.59%, N 18.33%. Found: C 68.12%, H 6.61%, N 18.20%.

(E / Z) -3- (Morpholinoimino) indolin-2-one (8): Reagents: isatin (250 mg, 1.7 mmol), 1- aminomorpholine (173.6 mg, 1.7 mmol), MMT- K10 (34 mg). Reaction conditions: 10 min under microwave irradiation at 100 ° C. Purification: IsoleraOne using water / acetonitrile (4: 1) to obtain an orange solid. Yield: 354.5 mg, 59%, E / Z ratio: 88:12. Mp: 184-186 ° C (lit. 186-188 ° C). Isomer Z: 1H-NMR (300 MHz, DMSO-da): 5 10.71 (s, 1.5H), 7.41 - 7.37 (m, 0.5H), 7.37 (m, 2H), 7.17 - 7.12 (m, 0.5H) , 7.06 (t, J = 7.6 Hz, 1H), 6.94 - 6.90 (m, 0.5H), 6.90 (d, J = 7.7 Hz, 1H), 6.80 - 6.77 (m, 0.5H), 3.90 - 3.75 (m , 4H), 3.20 (m, 4H). 13C-NMR (100 MHz, DMSO-d6): 5 164.8, 158.4, 143.9, 143.3, 140.3, 139.4, 131.8, 127.7, 126.3, 124.3, 122.0, 121.2,

118.5, 115.1, 110.5, 109.4, 65.8, 65.4, 55.0, 56.6. MS (ESI +): m / z 232 [M + 1]. Elemental analysis (C12H13N3O2) Calculated: C 62.30%, H 5.67%, N 18.17%. Found: C 62.11%, H 5.83%, N 18.05%.

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(E / Z) -5-Chloro-3- (2,2-diphenylhydrazono) indolin-2-one (9): Reagents: 5-chloroisatin (250 mg, 1.4 mmol), 2,2-diphenylhydrazine hydrochloride (254.0 mg, 1.4 mmol), MMT-K10 (27 mg), triethylamine (139.0 mg, 1.4 mmol) and toluene (6 mL). Reaction conditions: 30 min under microwave irradiation at 100 ° C. Purification: IsoleraOne using water / acetonitrile (7: 3) to obtain a yellow solid. Yield: 284.1 mg, 59%, E / Z ratio: 85:15. Mp: 305 ° C (lit. 305-306 ° C). Isomer E: 1H-NMR (400 MHz, DMSO-da): 5 10.75 (s, 1H), 7.49 (m, 4H), 7.35 (m, 6H), 7.12 (dd, J = 8.3, 2.1 Hz, 1H) , 6.75 (d, J = 8.3 Hz, 1H), 4.98 (d, J = 2.1 Hz, 1H). 13C-NMR (100 MHz, DMSO-da): 5 166.3, 145.8, 142.2, 130.3, 129.8, 129.6, 127.3, 125.3, 125.3, 124.0, 117.7, 111.7. MS (ESI +): m / z 350 [M + 3], 348 [M + 1]. Elemental analysis (C20H14ClN3O) Calculated: C 69.07%, H 4.06%, N 12.08%. Found: C 68.78%, H 3.95%, N 11.88%.

(E / Z) -7-Chloro-3- (2,2-diphenylhydrazono) indolin-2-one (10): Reagents: 7-chloroisatin (250 mg, 1.4 mmol), 2,2-diphenylhydrazine hydrochloride (254.0 mg, 1.4 mmol), MMT-K10 (27 mg), triethylamine (139.0 mg, 1.4 mmol) and toluene (2 mL). Reaction conditions: 1 h under microwave irradiation at 100 ° C. Purification: IsoleraOne using water / acetonitrile (4: 1) as eluents to obtain a yellow solid. Yield: 344 mg, 72%, E / Z ratio: 92: 8. Mp: 208 ° C. Isomer E: 1H-NMR (400 MHz, DMSO-da): 5 11.05 (s, 1H), 7.46 (m, 4H), 7.32 (m, 6H), 7.15 (dd, J = 8.2, 0.9 Hz, 1H) , 6.41 (t, J = 8.0 Hz, 1H), 5.23 (dd, J = 7.9, 0.9 Hz, 1H). 13C-NMR (100 MHz, DMSO- ^ 6): 5 166.5, 145.9, 141.0, 131.9, 130.3, 129.8, 127.1, 124.0, 123.8, 122.8, 122.2, 118.3. MS (ESI +): m / z 348 [M + 1], 350 [M + 3]. Elemental analysis (C20H14ClN3O) Calculated: C 69.07%, H 4.06%, N 12.08%. Found: C 69.23%, H 4.15%, N 12.05%.

(E / Z) -7-Chloro-3- (piperidin-1-unlimited) indolin-2-one (11): Reagents: 7-chloroisatin (250 mg, 1.4 mmol), 1-aminopiperidine (137 mg, 1.4 mmol), MMT-K10 (27 mg) and toluene (5 mL). Reaction conditions: 30 min under microwave irradiation at 100 ° C. Purification: Chromatographic column using dichloromethane / methanol (100: 1) as eluents, obtaining a yellow solid. Yield: 171.6 mg, 47%, E / Z ratio: 25:75. Mp: 151 ° C. Isomer Z: 1H-NMR (400 MHz, DMSO-cfe): 5 11.02 (s, 0.3H), 10.93 (s, 1H), 7.33 (dd, J = 8.2, 0.9 Hz, 0.3H), 7.19 (ddd, J = 7.6, 4.5, 1.0 Hz, 1.3H), 7.09 (dd, J = 8.1, 1.0 Hz, 1H), 7.09 - 7.00 (m, 0.3H), 6.88 (ddd, J = 8.1, 7.5, 0.5 Hz, 1H), 4.82-3.77 (m, 4H), 3.31-3.25 (m, 1.2H), 1.75-1.53 (m, 7.8H). 13C-NMR (100 MHz,

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DMSO-da): 5 165.9, 159.0, 140.8, 137.3, 135.9, 130.5, 128.1, 126.2, 124.1, 123.5,

122.6, 122.1, 118.1, 115.2, 116.7, 114.0, 58.6, 56.8, 26.7, 25.7, 23.9, 23.7. MS (ESI +): m / z 266 [M + 3], 264 [M + 1]. Elemental analysis (C13H14ClN3O) Calculated: C 59.21%, H 5.35%, N 15.93%. Found: C 59.31%, H 5.60%, N 16.02%.

(E / Z) -7-Chloro-3- (morpholinoimino) indolin-2-one (12): Reagents: 7-chloroisatin (250 mg, 1.4 mmol), 4-aminomorpholine (141 mg, 1.4 mmol ), MMT-K10 (27 mg) and toluene (5 mL). Reaction conditions: 1 h under microwave irradiation at 100 ° C. Purification: Chromatographic column using dichloromethane / methanol (100: 1) as eluents, obtaining a yellow solid. Yield: 204.6 mg, 56%, E / Z ratio: 26:74. Mp: 177 ° C (lit. 180-181 ° C). Isomer Z: 1H-NMR (400 MHz, DMSO-da): 5 11.11 (s, 0.3H), 11.06 (s, 1H), 7.38 (dd, J = 8.2, 1.0 Hz, 0.3H), 7.30 (dd, J = 7.7, 1.0 Hz, 0.3H), 7.23 (dd, J = 7.5, 1.1 Hz, 1H), 7.15 (dd, J = 8.1, 1.1 Hz, 1H), 7.05 (t, J = 7.9 Hz, 0.3H ), 6.97 - 6.84 (m, 1H), 4.00 - 3.98 (m, 4H), 3.84 - 3.71 (m, 5.2H), 3.28 - 3.21 (m, 1.2H). 13C-NMR (100 MHz, DMSO-da): 5 165.5, 159.1, 141.6, 141.3, 136.8, 131.6, 127.3, 125.3,

125.2, 123.8, 122.9, 117.6, 117.4, 115.4, 114.3, 66.6, 66.2, 57.7, 55.9. MS (ESI +): m / z 268 [M + 3], 266 [M + 1]. Elemental analysis (C12H12ClN3O2) Calculated: C 54.25%, H 4.55%, N 15.82%. Found: C 54.30%, H 4.37%, N 16.02%.

(E / Z) -5-Bromo-3- (2,2-diphenylhydrazono) indolin-2-one (13): Reagents: 5-bromoisatin (500 mg, 2.2 mmol), 2,2-diphenylhydrazine hydrochloride (485.5 mg, 2.2 mmol), MMT-K10 (44 mg), triethylamine (222.6 mg, 2.2 mmol) and toluene (5 mL). Reaction conditions: 10 min under microwave irradiation at 110 ° C. Purification: Chromatographic column using dichloromethane / methanol (10: 1) as eluents, obtaining a yellow solid. Yield: 360 mg, 42%, E / Z ratio: 89:11. 1H-NMR (500 MHz, DMSO- ^ 6): 5 10.75 (s, 1H), 7.63 (d, J = 2.1 Hz, 0.13H), 7.52 - 7.44 (m, 4H), 7.41 - 7.29 (m, 6H ), 7.23 (dd, J = 8.2, 2.0 Hz, 1H), 7.20 - 7.16 (m, 0.13H), 6.69 (d, J =

8.3 Hz, 1H), 5.09 (d, J = 2.0 Hz, 1H). 13C-NMR (125 MHz, DMSO- ^ 6): 5 165.9, 145.5,

142.3, 132.4, 130.1, 129.9, 129.6, 127.8, 127.8, 127.1, 123.7, 122.6, 117.9, 113.0, 112.0.MS (ESI +): m / z 394 [M + 2], 392 [M]. Elemental analysis (C20HuBrN3O) Calculated: C 61.24%, H 3.60%, N 10.71%. Found: C 60.98%, H 3.49%, N 10.79%

(E / Z) -5-Methoxy-3- (morpholinoimino) indolin-2-one (14): Reagents: 5-methoxyisatin (350 mg, 2.0 mmol), 4-aminomorpholine (202.1 mg, 2, 0 mmol), MMT-K10 (39.6 mg) and toluene

(5 mL). Reaction conditions: 40 min under microwave irradiation at 110 ° C, obtaining the pure product directly as an orange solid. Yield: 167 mg, 32%, E / Z ratio: 67:33. 1H-NMR (400 MHz, DMSO-da): 5 10.51 (s, 0.5H), 10.48 (s, 1H), 6.94 (d, J = 0.8 Hz, 1H), 6.91 (dd, J = 2.6, 0.7 Hz , 0.5H), 6.84 (d, J = 2.2 Hz, 2H), 5 6.78 (dt, J = 7.9, 0.9 Hz, 0.5H), 6.71 (dd, J = 2.3, 0.8 Hz, 0.5H), 6.69 - 6.66 (m, 1 H),

3.89 (dd, J = 6.1, 3.7 Hz, 4H), 3.82 - 3.77 (m, 2H), 3.74 (dd, J = 5.7, 4.0 Hz, 4H), 3.71 (d, J = 0.8 Hz, 1.5H), 3.68 (d, J = 0.8 Hz, 3H), 3.20 - 3.12 (m, 2H). 13C-NMR (100 MHz, DMSO-da): 5 165.5, 159.3, 155.3, 155.2, 144.7, 138.3, 133.9, 128.3, 126.0, 117.9, 116.2, 114.5, 112.7, 111.8, 110.7, 104.5, 66.5, 66.1, 57.3 , 56.2, 56.1, 55.6. MS (ESI +): 10 m / z 262 [M + 1]. Elemental analysis (C13H15N3O3) Calculated: C 59.76%, H 5.79%, N 16.08%. Found: C 59.48%, H 5.55%, N 15.93%.

Example 2: Measurement of LRRK2 inhibition of the compounds of the invention.

Enzyme inhibition assays were performed using the Adapta® methodology, which is based on a homogeneous and fluorescent procedure for the detection of ADP.

Table 1. Inhibitory concentration of the compounds of the invention.

 Do not.

 Chemical name of compounds% inh @ 10 pM IC50 pM

 one

 (E / Z) -5-Fluoro-3- (2,2-diphenylhydrazono) indolin-2-one 97 23.4

 2

 (E / Z) -5-Chloro-3- (piperidin-1-unlimited) indolin-2-one 91 0.28

 3

 (E / Z) -5-Fluoro-3- (piperidin-1-unlimited) indolin-2-one 77 1.5

 4

 (E / Z) -5-Chloro-3- (morpholinoimino) indolin-2-one 78 1.2

 5

 (E / Z) -5-Fluor-3- (morpholinoimino) indolin-2-one 66 3.65

 6

 (E / Z) -3- (2,2-Diphenylhydrazono) indolin-2-one 96 0.11

 7

 (E / Z) -3- (Piperidin-1-unlimited) indolin-2-one 79 1.24

 8

 (E / Z) -3- (Morpholinoimino) indolin-2-one 74 1.70

 9

 (E, Z) -5-Chloro-3- (2,2-diphenylhydrazone) indolin-2-one 96 5.08

5

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Example 3: Permeability in the central nervous system (CNS) using parallel artificial membranes (PAMPA) of the compounds of the invention.

The prediction of the permeability of the various compounds on the central nervous system (CNS), passing the blood-brain barrier, was determined using the parallel artificial membrane methodology (PAMPA) [Di, L .; Kerns, E. H .; Fan, K .; McConnell, O. J .; Carter, G. T. “High throughput artificial membrane permeability assay for blood-brain barrier1’ Eur. J. Med. Chem., 2003, 38 (3), 223-232]. In order to filter the samples, PDVF membrane filters (30 mm in diameter, pore size 0.45 pm) were used. Ten reference compounds, whose blood-brain barrier passage is known and public, were selected in order to validate the experiment. Different amounts of the same 3-5 mg of cafelna, enoxacin, hydrocortisone, desipramine, ofloxacin, piroxicam and testosterone, 12 mg of promazine, and 25 mg of verapamil and atenolol were taken, which were dissolved in ethanol (1000 mL). 100 mL of these solutions 15 were taken and 1400 mL of ethanol and 3500 mL of PBS (pH = 7.4) were added, in order to reach a final ethanol concentration of 30% in the solution. The solutions were filtered. Subsequently, 180 pL of a solution of PBS / ethanol (70/30) was added to each well of the acceptor plate. The donor plate was impregnated with 4 mL of a solution of the swine brain lipid dissolved in dodecane (20 mg mL-1). After 5 min, 180 pL of dissolution of each compound was added on this plate. Of the compounds to evaluate their penetration in the central nervous system, they were taken between 1-2 mg and dissolved in 1500 mL of ethanol and 3500 mL of PBS (pH = 7.4), filtered and added to the donor plate 96 wells. Then the donor plate was placed on the acceptor forming a kind of "sandwich" and left incubating for 2h and 30 min at 25 ° C. The compounds, by passive transport, will pass from the donor plate through the porcine brain lip to the acceptor plate. After 2:30 and 30 min, the donor plate is carefully removed. The concentration and absorbance of both commercial compounds and synthesized derivatives that were evaluated in the acceptor and donor plates were determined using a UV absorbance reader. Each sample was analyzed at different wavelengths (3 to 5), in 3 wells and in 2 independent experiments as a minimum. The results are the average of the measures ± standard deviation of the different experiments performed. In relation to the 10

Commercial reference compounds used in each experiment in order to validate the method, a good correlation was found between the experimental (Pe) permeability values and those described, Pe (exp) = 1.1512 (bibl) - 0.8973 (R2 = 0.977). From this equation and following the pattern described in bibliography 5 for the prediction of permeability of the blood-brain barrier, the compounds can be classified as permeable to the central nervous system (CNS) when they have a permeability> 3.71 x 10-6 cm s -one. All compounds with a% inhibition against LRRK2> 60% were evaluated. The results are shown in table 2, where it can be seen how all the 10 compounds evaluated are capable of crossing the blood-brain barrier.

Table 2. Permeability (Pe 10-6 cm s-1) in the PAMPA-Hematoencephalic Barrier experiment for 10 commercial compounds, used for the experiment, and different compounds of the invention with their corresponding prediction of 15 penetration in the central nervous system ( SNC).

 Compound

 Pe (bibl.) (1C6 cm / s) a Pe (exp.) (1C6 cm / s) b BHE Prediction

 Atenolol

 0.8 0.5 ± 0.4

 Cafelna

 1.3 1.1 ± 0.5

 Desipramine

 12 12.9 ± 1.2

 Enoxacin

 0.9 0.2 ± 0.1

 Hydrocortisone

 1.9 0.6 ± 0.3

 Ofloxacin

 0.8 0.4 ± 0.1

 Pyroxicam

 2.5 0.3 ± 0.1

 Promazine

 8.8 8.5 ± 1.5

 T theseterone

 17 16.4 ± 0.2

 Verapamil

 16 17.3 ± 2.2

 (2)

   29.4 ± 1.6 SNC +

 (3)

   16.5 ± 1.2 SNC +

 (4)

   12.3 ± 0.3 SNC +

 (5)

   8.4 ± 0.3 SNC +

 (6)

   9.8 ± 1.0 SNC +

 (7)

   15.3 ± 0.9 CNS +

 (8)

   5.7 ± 1.4 SNC +

aDi et al, 2003. bMedia of data ± standard deviation, of at least 2 independent experiments.

Claims (25)

5 10 fifteen twenty 25 1. Use of a compound of formula (I): image 1 Formula (I) or a pharmaceutically acceptable salt, isomer or solvate thereof where, - R1 and R2 are independently selected from optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C3-C7 cycloalkyl, optionally substituted C3-C7 heterocycloalkyl, optionally substituted C5-C10 aryl and optionally substituted C5-C10 heteroaryl or R1 and R2 form a saturated, partially unsaturated or unsaturated C3-C7 hydrocarbon ring that optionally contains one, two or three heteroatoms; - R3 is selected from hydrogen and fluorine; - R4 and R5 are independently selected from hydrogen, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C5-C10 aryl, optionally substituted C5-C10 heteroaryl, halogen, - OR7, -N (R7) 2, -SR7, -CN, -COR7, -COOR7, -OCOR7, -CON (R7) 2, -NHCOR7, -SO2R7, - SO2NHR7 and -NO2; - R6 is selected from hydrogen and halogen; - R7 is selected from hydrogen, - optionally substituted C1-C12 alkyl, - optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, 5 10 fifteen twenty 25 30 optionally substituted C3-C7 cycloalkyl, optionally substituted C5-C10 aryl and optionally substituted C5-C10 heteroaryl; for the preparation of a medicine for the treatment and / or prevention of a LRRK2 enzyme-mediated disease, disorder or disorder. 2. Use according to claim 1, wherein R6 is selected from hydrogen and fluorine. 3. Use according to claim 1 or 2, wherein R1 and R2 are independently selected from optionally substituted C1-C12 alkyl, optionally substituted C5-C10 aryl and optionally substituted C5-C10 heteroaryl. 4. Use according to claim 3, wherein R1 and R2 are independently selected from methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl and phenyl. 5. Use according to claim 4, wherein R1 and R2 are phenyl. 6. Use according to claim 1 or 2, wherein R1 and R2 form a saturated, partially unsaturated or unsaturated C3-C7 hydrocarbon ring which may contain one, two or three heteroatoms. 7. Use according to claim 6, wherein R1 and R2 form a ring of pyrrolidine, piperidine, 2,6-dimethylpiperidine, azepane, 1,2,4-triazole, 2-thioxothiazolidin-4-one, oxazolidin-2-one or morpholine 8. Use according to claim 7, wherein R1 and R2 form a piperidine or morpholine ring. 9. Use according to any one of claims 1 to 8, wherein R4 and R5 are independently selected from hydrogen, optionally substituted C5-C10 aryl, optionally substituted C5-C10 heteroaryl, halogen, -OR7, -N (R7) 2, -SR7 , -CN, - COOR7, -OCOR7, -CON (R7) 2, and -NHCOR7. 5 10 fifteen twenty 25 30 10. Use according to claim 9, wherein R4 and R5 are independently selected from hydrogen, halogen, optionally substituted C5-C10 aryl, optionally substituted C5-C10 heteroaryl, -OR7 and -N (R7) 2. 11. Use according to claim 1 wherein the compound of formula (I) is selected from: - (E / Z) -3 - ((4H-1,2,4-triazol-4-yl) imino) indolin-2-one - (E / Z) -5-Bromo-3- (2,2-dimethylhydrazono) indolin-2-one - (E / Z) -5-Chloro-3- (2,2-dimethylhydrazono) indolin-2-one - (E / Z) -7-Chloro-3- (2,2-dimethylhydrazono) indolin-2-one - (E / Z) -3 - ((2-Oxoindolin-3-ilidene) amino) -2-thioxothiazolidin-4-one - (E / Z) -3 - ((2-Oxoindolin-3-ilidene) amino) oxazolidin-2-one - (E / Z) -3- (Pyrrolidin-1-unlimited) indolin-2-one - (E / Z) -3- (Morpholinoimino) indolin-2-one - (E / Z) -5-Bromo-3- (morpholinoimino) indolin-2-one - (E / Z) -7-Chloro-3- (morpholinoimino) indolin-2-one - (E / Z) -3- (Piperidin-1-unlimited) indolin-2-one - (E / Z) -3,3 '- (2- (2-Oxoindolin-3-ylidene) hydrazine-1,1-diyl) dipropanonitrile - (E / Z) -3- (Azepan-1-unlimited) indolin-2-one - (E / Z) -3- (2- (2,4-Dinitrophenyl) -2-methylhydrazono) indolin-2-one - (E / Z) -3- (2-Methyl-2-phenylhydrazono) indolin-2-one - (E / Z) -5-Chloro-3- (2-methyl-2-phenylhydrazono) indolin-2-one - (E / Z) -3 - ((2,6-Dimethylpiperidin-1-yl) imino) indolin-2-one - (E / Z) -3- (2-Phenyl-2-propylhydrazono) indolin-2-one - (E / Z) -3- (2,2-Diphenylhydrazono) indolin-2-one - (E / Z) -5-Chloro-3- (2,2-diphenylhydrazono) indolin-2-one - (E / Z) -3- (2,2-Dibenzylhydrazono) indolin-2-one - (E / Z) -7-Chloro-3- (2,2-diphenylhydrazono) indolin-2-one - (E / Z) -7-Chloro-3- (piperidin-1-unlimited) indolin-2-one - (E / Z) -5-Fluoro-3- (2,2-diphenylhydrazono) indolin-2-one - (E / Z) -5-Chloro-3- (piperidin-1-unlimited) indolin-2-one - (E / Z) -5-Fluoro-3- (piperidin-1-unlimited) indolin-2-one - (E / Z) -5-Chloro-3- (morpholinoimino) indolin-2-one 5 10 fifteen twenty 25 30 - (E / Z) -5-Fluor-3- (morpholinoimino) indolin-2-one - (E / Z) -5-Bromo-3- (2,2-diphenylhydrazono) indolin-2-one - (E / Z) -5-Methoxy-3- (morpholinoimino) indolin-2-one or a pharmaceutically acceptable salt or solvate thereof. 12. Use according to claim 11 wherein the compound of formula (I) is selected from: - (E / Z) -5-Fluoro-3- (2,2-diphenylhydrazono) indolin-2-one - (E / Z) -5-Chloro-3- (piperidin-1-unlimited) indolin-2-one - (E / Z) -5-Fluoro-3- (piperidin-1-unlimited) indolin-2-one - (E / Z) -5-Chloro-3- (morpholinoimino) indolin-2-one - (E / Z) -5-Fluor-3- (morpholinoimino) indolin-2-one - (E / Z) -3- (2,2-Diphenylhydrazono) indolin-2-one - (E / Z) -3- (Piperidin-1-unlimited) indolin-2-one - (E / Z) -3- (Morpholinoimino) indolin-2-one - (E / Z) -5-Chloro-3- (2,2-diphenylhydrazono) indolin-2-one - (E / Z) -5-Bromo-3- (2,2-diphenylhydrazono) indolin-2-one or a pharmaceutically acceptable salt or solvate thereof. 13. Use according to any of claims 1 to 12, wherein the disease mediated by the LRRK-2 enzyme is a neurodegenerative disease. 14. Use according to claim 13, wherein the neurodegenerative disease is selected between Parkinson's and Parkinson's plus. 15. Use according to claim 13, wherein the neurodegenerative disease is selected between Alzheimer's and amyotrophic lateral sclerosis. 16. Use according to any of claims 1 to 12, wherein the disease mediated by the LRRK-2 enzyme is an inflammatory disease. 5 10 fifteen twenty 25 30 17. Use according to claim 16, wherein the inflammatory disease is selected from Crohn's disease, ulcerative colitis, rheumatoid arthritis, atherosclerosis and vasculitis. 18. Use according to any one of claims 1 to 12, wherein the disease mediated by the LRRK-2 enzyme is an autoimmune disease. 19. Use according to claim 18, wherein the autoimmune disease is selected from Crohn's disease, ulcerative colitis and multiple sclerosis. 20. Compound of formula (II): or a pharmaceutically acceptable salt, isomer or solvate thereof where, - R1 and R2 are independently selected from optionally substituted C1-C12 alkyl, optionally substituted C1-C12 alkenyl, optionally substituted C5-C10 aryl and optionally substituted C5-C10 or R1 and R2 heteroaryl form a C3-C7 hydrocarbon ring which may optionally contain one, two or three heteroatoms; - R3 is hydrogen or fluorine; - R4 is halogen; with the proviso that the following compounds are excluded: - (E / Z) -5-Bromo-3- (morpholinoimino) indolin-2-one - (E / Z) -5-Bromo-3- (2,2-dimethylhydrazono) indolin-2-one image2 \ H Formula (II) 5 10 fifteen twenty 25 30 - (E / Z) -5-Chloro-3- (2,2-diphenylhydrazono) indolin-2-one - (E / Z) -5-Chloro-3- (2-methyl-2-phenylhydrazono) indolin-2-one - (E / Z) -5-Chloro-3- (2,2-dimethylhydrazono) indolin-2-one 21. A compound according to claim 20, wherein R4 is selected from fluorine and chlorine. 22. A compound according to any one of claims 20 or 21, wherein R1 and R2 form a saturated, partially unsaturated or unsaturated C3-C7 hydrocarbon ring that may optionally contain one, two or three heteroatoms. 23. A compound according to any one of claims 20 to 22, which is selected from the group consisting of: - (E / Z) -5-Fluoro-3- (2,2-diphenylhydrazono) indolin-2-one - (E / Z) -5-Chloro-3- (piperidin-1-unlimited) indolin-2-one - (E / Z) -5-Fluoro-3- (piperidin-1-unlimited) indolin-2-one - (E / Z) -5-Chloro-3- (morpholinoimino) indolin-2-one - (E / Z) -5-Fluor-3- (morpholinoimino) indolin-2-one - (E / Z) -5-Bromo-3- (2,2-diphenylhydrazono) indolin-2-one 24. A pharmaceutical composition comprising a compound as defined in any one of claims 20 to 23 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable adjuvant, carrier or excipient. 25. Use of a compound as defined in any of claims 20 to 23 for the manufacture of a medicament.