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  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Definitions

• the present invention relates to compounds for the prophylaxis and / or treatment of disorders caused by cell death by apoptosis or for the prevention of degenerative processes caused by cell death by apoptosis.
• Apoptosis or programmed cell death, is a complex physiological phenomenon involved in the maintenance of cellular homeostasis. Apoptosis is regulated by multiple cellular control mechanisms because of its central role in maintaining health. Many pathologies are based on a dysfunction of apoptosis. Thus, an excess of cell death due to apoptosis can affect the functionality of the tissue (e.g. death of cardiomyocytes in cases of myocardial infarction), while an excessively inhibited apoptosis leads to cell survival.
• the cellular components that regulate apoptosis are in a constant dynamic equilibrium in a healthy cell.
• the extrinsic pathway is activated by extracellular signaling and requires the participation of specific membrane receptors.
• the intrinsic pathway responds to cellular stress, toxic agents, radiation, oxidizing agents, Ca 2+ overload, DNA damage; It is activated in response to oncogenes, and implies the destabilization of the mitochondria.
• pathophysiological conditions for example, anoxia in cells of organs that must be transplanted, treatment with toxic substances
• apoptosis is increased and the cells die excessively, making it impossible for the affected tissue to function and compromising survival in some cases.
• the molecular mechanisms of induction of apoptosis involve the activation of proteins with protease activity called caspases, also known as effectors of apoptosis. In order for them to be activated, the formation of a molecular complex called apoptosome is necessary.
• the apoptosome is formed by cytochrome c, procaspase-9 and the activating factor 1 of the apoptotic peptidase (Apaf-1, Apoptotic Peptidase Activating Factor 1). It has been shown that the inhibition of Apaf-1 inhibits Ia formation of the apoptosome complex and that this causes an inhibition of apoptosis (measured through the activation of caspase 3).
• inhibitors have been designed that act at different levels of the apoptotic cascade such as transcription factors, kinases, regulators of Ia
• Negative dominant of Apaf-1 by adenovirus showed to be more effective than the transduction by adenovirus of a negative dominant of Caspase-1.
• WO2007060524 describes the compounds derived from
• WO2008009758 describes the compounds of the attached formula, as inhibitors of UBC13-UEV interactions and that can be used in the preparation of pharmaceutical compositions directed to antitumor therapy or to the treatment and / or prophylaxis of diseases associated with metabolic pathways in which involves the enzyme UBC13, metabolic pathways in which the transcriptional factor NF-kB intervenes, or routes in which PCNA or RAD6 intervene. Although they can be considered structurally close to those of the present invention, they have a different use.
• the present invention provides new compounds derived from
• R1 and R2 are independently selected from -H, -Ci -5 alkyl, -C 2-5 alkenyl, - (CH 2 ) or -3-cycloalkyl, - (CH 2 ) i- 3- heterocycle, - (CH 2 ) o- 3 -aryl, - (CH 2 ) or- 3 -heteroaryl, - (CH 2 ) i -2 -CH (aryl) 2 , - (CH 2 ) and -2 -CH (aryl) (heteroaryl) and - (CH 2 ) i -2 - CH (heteroaryl) 2l
• R3 is selected from -H, -Ci -5 alkyl, -C 2-5 alkenyl, - (CH 2 ) 0-3 -cycloalkyl, - (CH 2 ) i -3- heterocycle, - (CH 2 ) i -3 -aryl, - (CH 2 ) 1-3 -heteroaryl, - (CH 2 ) i -3 -CONR5R6, - (CH 2 ) i -2 -CH (aryl) 2 , - (CH 2 ) i -2 -CH (aryl) (heteroaryl) and - (CH 2 ) 1-2 -CH (heteroaryl) 2 , R4 is selected from -H, -Ci -5 alkyl, - (CHR7) and -3 -CO-NR5R6, - (CHR7 ) i -3 -CO- OR5, - (CH 2 ) i -3 -NR5R6,
• R5 and R6 are independently selected from -H, -Ci -5 alkyl and - (CH 2 ) 0-3 -aryl,
• R7 is selected from -H, -Ci -5 alkyl, - (CH 2 ) i -3 -aryl and - (CH 2 ) i -3- heteroaryl, so that when m is greater than 1 the R7 substituents can be the same or different, where Ci -5 alkyl, C 2-5 alkenyl, cycloalkyl and heterocycle may be optionally substituted by one or more substituents independently selected from halogen, OR5, OCF 3, SH, SR5, NR5R6, NHCOR 5; COOH, COOR5, OCOR5, aryl and heteroaryl, where the aryl and heteroaryl groups may be optionally substituted by one or more substituents independently selected from halogen, CF3, OR5, OCF 3 , SH, SR5, NH 2 , NHCOR5; NO 2 , CN, COR5, COOR5,
• R1 is 2- (4-fluorophenyl) ethyl
• R3 is not 2- (4-methoxyphenyl) ethyl, 2- (2-pyridyl) ethyl or 2- (2,4-dichlorophenyl) ethyl
• R1 is 2- (2,4-dichlorophenyl) ethyl
• R3 is not 2- (4-methoxyphenyl) ethyl or 2- (2-pyridyl) ethyl.
• R1 is -Ci -5 alkyl or - (CH 2 ) 0-3 -aryl.
• R2 is -Ci -5 alkyl, - (CH 2 ) or -3- ahlo, - (CH 2 ) O-3 -heteroaryl or - (CH 2 ) and -2 -CH (aryl ) 2 .
• R3 is -H, -Ci -5 alkyl, - (CH 2 ) and -3 -heterocycle, - (CH 2 ) and -3 -aryl or - (CH 2 ) and -3 - heteroaryl.
• R4 is -H, - (CHR7) and -3 -CO-NR5R6, - (CHR7) and -3 -CO-OR5 or - (CH 2 ) and -3 -CO [NCHR7CO] m NH 2 .
• n 1
• n 1
• R5 is -H or -Ci -5 alkyl.
• R6 is -H.
• R7 is -H, -Ci -5 alkyl, - (CH 2 ) I -3 -aryl or - (CH 2 ) and -3- heteroaryl.
• a second aspect of the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof for use as a pharmaceutical active ingredient, in particular for use in prophylaxis and / or treatment of a pathological and / or physiological condition associated with a
• cytotoxicity in particular cytotoxicity mediated by chemical substances, by physical agents such as radiation, acoustic trauma, burns, or by biological agents such as infection by the hepatitis virus
• pathologies due to hypoxia situations such as heart attack or cerebral infarction
• eye pathologies such as lesions caused by eye surgery, age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa or glaucoma
• neurodegenerative diseases such as Alzheimer's, Huntington, Parkinson's or amyotrophic multiple sclerosis
• diabetes in particular preservation of islets of Langerhans or cytotoxicity associated with diabetes, such as nephrotoxicity; osteoarthritis; arthritis; inflammation or immunodeficiencies, such as depletion of CD4 + T lymphocytes associated with AIDS.
• Another aspect of the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament intended for the prophylaxis and / or treatment of a pathological and / or physiological condition associated with an increase in apoptosis, in particular one of the conditions mentioned above.
• Another aspect of the present invention relates to a method of prophylaxis and / or treatment of an individual or organ that suffers or is susceptible to suffering from a pathological and / or physiological condition associated with an increase in apoptosis, in particular one of the conditions mentioned above, which comprises the administration to said individual or organ of a therapeutically effective amount of a compound of formula (I) or of a pharmaceutically acceptable salt thereof together with sufficient amounts of pharmaceutically acceptable excipients.
• cytotoxicity in particular cytotoxicity mediated by chemical substances, by physical agents such as radiation, acoustic trauma, burns, or by biological agents such as infection by the hepatitis virus
• pathologies due to hypoxia situations such as heart attack or cerebral infarction
• eye pathologies such as lesions caused by eye surgery, age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa or glaucoma
• neurodegenerative diseases such as Alzheimer's, Huntington,
• Parkinson's or amyotrophic multiple sclerosis diabetes, in particular preservation of islets of Langerhans or cytotoxicity associated with diabetes, such as nephrotoxicity; osteoarthritis; arthritis; inflammation or immunodeficiencies, such as depletion of CD4 + T lymphocytes associated with AIDS.
• Ci -5 alkyl alone or in combination, means an alkyl group of straight or branched chain having 1 to 5 carbon atoms.
• C 2-5 alkenyl means a group having 2 to 5 carbon atoms, straight or branched chain and having one or more unsaturated bonds.
• cycloalkyl alone or in combination, refers to a stable 3- to 7-membered monocyclic radical, which is saturated or partially saturated, and which only consists of carbon and hydrogen atoms. Examples of cycloalkyl are the following: cyclopropyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, cycloheptyl.
• heterocycle alone or in combination, means a saturated or partially unsaturated heterocycle of 5 to 10 links, containing one or more heteroatoms chosen from nitrogen, oxygen and sulfur.
• the heterocycle may be a monocyclic or bicyclic ring system, which may include condensed ring systems.
• heterocycle groups are tetrahydrofuranyl (THF), dihydrofuranyl, dioxanyl, morphyl, piperazinyl, piperidinyl, 1,3-dioxolanyl, imidazolidinyl, midazolinyl, pyrrolidyl, pyrrolidinyl, tetrahydropyranyl, dihydropyranyl, and the like.
• aryl refers to a mono or polycyclic aromatic ring system containing carbon ring atoms. Preferred aryls are 5-10 member aromatic ring systems
• monocyclic or bicyclic such as phenyl or naphthyl which optionally carry one or more substituents, preferably one to three, independently selected from halogen, CF3, OH, OR5, OCF 3 , SH, SR5, NH 2 , NHCOR5; NO 2 , CN, COR5, COOR5, OCOR5, CONR5R6, - (CH 2 ) (W NR5R6, SO 2 NH 2 , NHSO 2 CH3, Ci -5 alkyl, aryl and heteroaryl.
• heteroaryl alone or in combination refers to an aromatic or partially aromatic heterocycle containing at least one ring heteroatom selected from O, S and N.
• the heteroaryls thus include heteroaryls fused to other kinds of rings, such as aryls , cycloalkyl and heterocycles that are not aromatic.
• heteroaryl groups include: pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, thiazolyl,
• substituents a group may be unsubstituted or substituted by one or more substituents, preferably by 1, 2, 3 or 4 substituents, provided that said group has 1, 2, 3 or 4 Possible positions to be substituted.
• pharmaceutically acceptable salts means those salts that retain the efficacy and biological properties of free bases or free acids and that are not bothersome in the biological sense or in any other.
• compositions are useful for the prophylaxis and / or treatment of a pathological and / or physiological condition associated with an increase in apoptosis through its activity as inhibitors of Apaf-1.
• all the technical and scientific terms used here have the same meaning as those commonly understood by a person skilled in the field of the invention. Methods and materials similar or equivalent to those described herein may be used in the practice of the present invention.
• the word "comprises” and its variants are not intended to exclude other technical characteristics, additives, components, steps or stereoisomers of the compounds involved. For those skilled in the art, other objects, advantages and characteristics of the invention will emerge partly from the description and partly from the practice of the invention.
• the compounds of formula (I) can be prepared following different methods known to any person skilled in the field of organic synthesis, in particular by the general procedures presented in the following schemes.
• the starting materials for the preparative methods are commercially available or can be prepared by methods of the literature.
• the groups R1, R2, R3, R4, R5, R6 and R7 have the meaning described in the general formula (I).
• the amine Il bound to the solid support is acylated with an acylating agent III, where X represents a leaving group, for example a halogen and Y represents OH or halogen.
• Y represents a halogen, for example chloroacetyl chloride
• the reaction can be carried out in the presence of a base such as triethylamine.
• Y represents -OH, for example bromoacetic acid
• the reaction can be carried out in the presence of a suitable coupling agent, for example ⁇ /, ⁇ / -diisopropylcarbodiimide.
• the reaction can be carried out in an inert solvent that is capable of swelling the resin, such as ⁇ /, ⁇ / -dimethylformamide or methylene chloride and at room temperature or under microwave irradiation, to minimize the reaction time.
• the IVa amine is coupled using a tertiary amine as the base. The reaction can be carried out at room temperature or by microwave irradiation.
• a carboxylic acid Vl, where GP represents a protective group, such as allyl, is reacted with the amine V to obtain the amide VII, using a coupling agent, such as for example the combination of N, N'-diisopropylcarbodiimide and 1-hydroxybenzotriazole.
• a coupling agent such as for example the combination of N, N'-diisopropylcarbodiimide and 1-hydroxybenzotriazole.
• an amine IVb is added, by reaction of Michael using a base and a solvent, such as ⁇ /, ⁇ / -dimethylformamide or dimethyl sulfoxide to obtain the HIV intermediate after the cleavage of the resin using a mixture of trifluoroacetic acid , dichloromethane and water.
• Intermediate VIII is cycled (intermediate IX) and deprotected in basic medium yielding acidic intermediate X.
• Intermediate X can be prepared alternatively to the solid phase according to scheme 2, where the amine V can be prepared from the amine IVa either by a reductive amination reaction with a glyoxylate in THF-AcOH using a reducing agent such as NaBH 3 CN, or alternatively by alkylation with a bromoacetate or a
• a compound of formula Ia can be obtained from intermediate X by coupling with an amine attached to a solid support Va or Va ', obtained according to the methodology indicated above, in the presence of a coupling agent such as, for example, the combination of HATU and HOBT.
• the compound of formula Ib is it can obtain analogously to the synthesis of compound Ia, except in the case of a solid phase in which the solid starting support (Mb) has a halogen group instead of an amino group, such as for example chlorotrityl resin, obtaining a acid after the cleavage of the resin.
• the ester Ic can be synthesized by esterification of the corresponding acid Ib by the usual esterification methods in organic synthesis, such as using methanol in an acidic medium such as sulfuric acid. In the case of Ib, it can be obtained by saponification of the ester Ic.
• the compounds of formula Id can be obtained by reacting intermediate X with a primary amine IVc.
• Peptide XIII and pseudopeptide XIV that will bind to acid X can be obtained by standard peptide synthesis reactions.
• the process can be repeated sequentially, after deprotection of the amine, to obtain peptide XIII.
• carboxylic acid X reacts with XIII to obtain compound Ie.
• An amine can be obtained by reaction of Mitsunobu starting from alcohol and potassium phthalimide in the presence of, for example, diethyl azodicarboxylate (DEAD) and triphenylphosphine in tetrahydrofuran as solvent and subsequent release with hydrazine hydrate.
• DEAD diethyl azodicarboxylate
• triphenylphosphine triphenylphosphine in tetrahydrofuran as solvent and subsequent release with hydrazine hydrate.
• the lic / -ubstituted glycines V and Xl can be synthesized by any of the methods shown below, such as, for example, reductive amination of the corresponding glycine with a suitable aldehyde (Scheme 5) using reducing agents such as NaBH 4 , NaBH 3 CN or NaBH (AcO) 3 or by nucleophilic substitution of an ester with an R-NH 2 amine (Scheme 6).
• the compounds were synthesized using an AM RAM polystyrene resin purchased from Rapp Polymere GmbH (Germany). Polystyrene syringes with a polyethylene disc were used in the reactions using an IKALabortechnik HS501 digital agitator. In the reactions carried out by microwaves, the CEM Discover model with 10 ml glass reactors was used. The products were analyzed by:
• Method B The products were analyzed using an Agilent 1100 HPLC device, equipped with a variable wavelength UV detector and a 1100 VL model mass spectrometer.
• the wavelength used for UV detection has been 210 nm, while the MS detector has operated in positive electrospray ionization mode and has performed a scan of m / z 100 to 1300.
• the column used it has been a Kromasil 100 C18 (4.0 x 40 mm, 3.5 ⁇ m) thermostated at 5O 0 C, and 5 ⁇ l have been injected.
• Solvent A consists of 0.2% formic acid in water, while B is 0.2% formic acid in acetonitrile.
• Method C using a Waters HPLC-UV-MS device, equipped with a serial diode detector and an EMD1000 model mass spectrometer. The wavelength used for UV detection has been 210 nm, while the MS detector has operated in positive electrospray ionization mode and has performed a scan of m / z 100 to 1000.
• the column used It has been a Kromasil C18 (2.1 x 50 mm, 3.5 ⁇ m) thermostated at 50 s C and 2 ⁇ l have been injected.
• the following gradient has been followed: 5 -100% B, 0-5 min; 100% B, 5-6.5 min; 5% B, 6.5-8 min.
• the flow rate of the mobile phase is 0.5 ml / min.
• High resolution mass spectrometry was carried out by UPLC-HRMS using a Waters Acquity UPLC device coupled to a spectrometer of time-of-flight masses with orthogonal acceleration model LCT Premier XE from Waters. Chromatographic analysis was performed using a Waters Acquity C18 column (10 x 2.1 mm, 1.7 ⁇ m).
• the reaction mixture was stirred for 2 min at 6O 0 C in a microwave reactor.
• the resin was filtered and washed with DMF (3 x 15 mL), isopropyl alcohol (3 x 15 mL) and DCM (3 x 15 mi).
• DMF 3 x 15 mL
• isopropyl alcohol 3 x 15 mL
• DCM 3 x 15 mi
• 12 ml of DMF was added to the resin and the suspension was stirred for 2 min. at 9O 0 C activated by microwave. The supernatant was removed and the reaction was repeated under the same conditions.
• the resin V obtained was filtered and washed with DMF (3 x 15 ml), isopropyl alcohol (3 x 15 ml) and DCM (3 x 15 ml). Then, the resin was treated with a solution of allyl ester of (Z) -2-butanedioic acid (Vl 1 957 mg, 5 eq.), HOBT (825 mg, 5 eq.) And DIC (770 ⁇ l_, 5 eq. ) in DCM: DMF (2: 1, 123 mi). The reaction mixture was stirred at room temperature for 30 min and filtered.
• the resin was dried and washed with DMF (3 x 15 mL), isopropyl alcohol (3 x 15 mL) and DCM (3 x 15 mL). Then, a solution of 3,3-diphenylpropylamine (IVb, 1, 29 g, 5 eq.) And triethylamine (0.85 ml, 5 eq.) In 12 ml of DMF was added to the resin and the suspension was stirred for 3 h at room temperature. The resin was filtered and the reaction was repeated for 16 h at the same temperature.
• the resin was dried and washed with DMF (3 x 3 mL), isopropyl alcohol (3 x 3 mL) and DCM (3 x 3 mL) and subsequently treated with a mixture of 60: 40: 2 TFA / DCM / water (5 mi) for 30 min at
• the Rink amide-Fmoc resin (II, 500 mg, 0.305 mmol) was deprotected with 5 ml of 20% piperidine in DMF by stirring in a microwave reactor for 2 min at 60 ° C. The resin was filtered and washed with DMF. (3 x 15 ml), isopropyl alcohol (3 x 15 ml) and DCM (3 x 15 ml). Then, the amino acid Fmoc-L-Lys (Boc) -OH (Xl, 286 mg, 2 eq.) was bound to the resin using HOBT (82 mg, 2 eq.) And DIC (96 ⁇ L, 2 eq.) in 5 ml of DMF.
• the mixture was stirred at room temperature for 1 h.
• the resin was filtered and washed with DMF (3 x 15 mL), isopropyl alcohol (3 x 15 mL) and DCM (3 x 15 mL). After removing the Fmoc group with 5 ml of 20% piperidine in DMF for 20 min, the resin was filtered and washed with DMF (3 x 15 ml), isopropyl alcohol (3 x 15 ml) and DCM (3 x 15 me).
• the resin was treated with a solution of acid X (181 mg, 1, 1 eq.), HATU (348 mg, 3 eq.), HOBT (123 mg, 3 eq.) And DIPEA (0.313 mi, 6 eq. ) in 5 ml of DMF.
• the reaction mixture was stirred at room temperature for 16 h.
• the resin was dried and washed with DMF (3 x 3 mL), isopropyl alcohol (3 x 3 mL) and DCM (3 x 3 mL) and subsequently treated with a mixture of 80: 20: 2.5: 2, 5 TFA / DCM / water / triisopropylsilane (5 ml) for 30 min at room temperature.
• the Rink amide-Fmoc resin (II, 800 mg, 0.42 mmol) was deprotected with 8 ml of 20% piperidine in DMF by stirring in a microwave reactor for 2 min at 60 ° C. The resin was filtered and washed. with DMF (3 x 15 ml), isopropyl alcohol (3 x 15 ml) and DCM (3 x 15 ml). Next, the amino acid Fmoc-L-Lys (Boc) -OH (XII, 497 mg, 2 eq.) was bound to the resin using HOBT (143 mg, 2 eq.) And DIC (165 ⁇ L, 2 eq.) in 8 ml of DMF.
• the mixture was stirred at room temperature for 1 h.
• the resin was filtered and washed with DMF (3 x 15 mL), isopropyl alcohol (3 x 15 mL) and DCM (3 x 15 mL). After removing the Fmoc group with 8 ml of 20% piperidine in DMF for 20 min, the resin was filtered and washed with DMF (3 x 15 ml), isopropyl alcohol (3 x 15 ml) and DCM (3 x 15 me).
• the resin was treated with a solution of bromoacetic acid (III, 295 mg, 4 eq.) And DIC (0.33 ml, 4 eq.) In DMF: DCM 1: 2 (8 mi) and the mixture was stirred for 20 min at room temperature.
• the resin was filtered and washed with DMF (3 x 15 mL), isopropyl alcohol (3 x 15 mL) and DCM (3 x 15 mL).
• the resin was dried and washed with DMF (3 x 3 mL), isopropyl alcohol (3 x 3 mL) and DCM (3 x 3 mL) and subsequently treated with a mixture of 80: 20: 2.5: 2, 5 TFA / DCM / water / triisopropylsilane (5 ml) for 30 min at room temperature.
• the resin was filtered and the filtrate was evaporated under reduced pressure.
• the obtained residue was purified by semi-preparative RP-HPLC using a gradient of a mixture of acetonitrile-water to obtain 128 mg of the desired compound (see 1.2, 34% yield, 99% purity).
• Recombinant Apaf-1 produced in insect cells was incubated in the presence (at a concentration of 10 ⁇ M) or absence (as a control) of the compounds to be evaluated in the assay buffer (20 mM Hepes-KOH pH 7.5, 10 mM KCI, 1.5 mM MgCI2, 1 mM EDTA, 1 mM EGTA, 1 mM DTT, 0.1 mM PMSF) for 15 minutes at 30 0 C.
• the final concentration of rApaf-1 was 40 nM.
• dATP / Mg Sigma
• purified horse cytochrome c Sigma
• dATP / Mg Sigma
• purified horse cytochrome c Sigma
• the total assay volume was 200 ⁇ L.

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