compound, process for the preparation of a compound and uses of it

专利摘要:
COMPOUND, PROCESS FOR THE PREPARATION OF A COMPOUND, METHOD FOR THE PREVENTION AND/OR TREATMENT OF DISEASES AND CONDITIONS, AND, PHARMACEUTICAL COMPOSITION. . Tranylcypromine derivatives useful as therapeutic agents, particularly for the prevention and/or treatment of diseases and conditions associated with the activity of histone demethylases LSD1 and LSD2, such as diseases characterized by dysregulation of gene transcription, cell differentiation and proliferation, for example , tumors, viral infections, are described here. These compounds belong to structural formula (I) where A and R3 are as defined in the specification. The invention also relates to the preparation of these compounds, as well as to compositions containing them and their therapeutic use.
公开号:BR112012027062B1
申请号:R112012027062-1
申请日:2011-04-15
公开日:2021-04-20
发明作者:Saverio Minucci；Antonello Mai；Andrea Mattevi
申请人:Università Degli Studi Di Roma "La Sapienza"；Università Degli Studi Di Pavia；Università Degli Studi Di Milano；Fondazione IEO-CCM；
IPC主号:

专利说明:

Field of Invention
[0001] The present invention relates to tranylcypromine derivatives and their use as therapeutic agents, particularly for the prevention and/or treatment of diseases and conditions associated with the activity of histone demethylases LSD1 and LSD2, such as diseases characterized by transcription dysregulation of gene, cell differentiation and proliferation, eg tumors, viral infections. The invention also relates to the preparation of these compounds, as well as to compositions containing them and their therapeutic use. Background of the Invention
[0002] Changes in the structural and functional states of chromatin are involved in the pathogenesis of a variety of diseases. Biochemical and enzymatic processes that catalyze the insertion and elimination of post-translational modifications in nucleosomes have become the subject of research as potential targets for so-called epigenetic therapies (Urdinguio RG, Sanchez-Mut JV, Esteller M. Epigenetic mechanisms in neurological diseases: neurological diseases: genes, syndromes, and therapies. Lancet Neurol. 8:1056-1072, 2009). The discovery of an increasing number of histone demethylases highlighted the dynamic nature of regulation of histone methylation, a fundamental modification of chromatin that is involved in eukaryotic genome and gene regulation. Lysine histone demethylases represent very attractive targets for epigenetic drugs and are gaining increasing attention. A lysine can be mono, di and trimethylated. Each modification to the same amino acid can specifically exert different biological effects. The recent discovery of lysine histone demethylases has revealed two types of enzymatic mechanisms (Anand R, Marmorstein R. Structure and mechanism of lysine-specific demethylase enzymes. J. Biol. Chem. 282:35425-35429, 2007). Iron-dependent enzymes can demethylate lysine side chains in all three methylation states and many demethylases in this family have now been characterized. Conversely, the oxidative chemistry that underlies the function of flavin-dependent histone demethylases makes it impossible for these enzymes to act on trimethylated lysine and restricts their activity to mono- and dimethylated substrates.
[0003] Mammals contain two flavoenzyme demethylases: LSD1 and LSD2. LSD1 was the first histone demethylase discovered and is typically (but not always) associated with the coREST copressor protein. LSD1/CoREST can associate with histone deacetylases 1/2 (HDAC1/2) forming a multienzyme unit that is recruited by many chromatin complexes that are typically involved in gene repression regulation (Ballas N, et al. Regulation of neuronal traits by a novel transcriptional complex. Neuron. 31:353-365, 2001). LSD1 erases the methyl groups of Lys4 from mono and dimethyl of histone H3, which is a well-characterized marker of gene activation. The enzyme is an interesting target for epigenetic drugs because of its overexpression in solid tumors (Schulte JH, et al. Lysine-specific demethylase 1 is strongly expressed in poorly differentiated neuroblastoma: implications for therapy. Cancer Res 69:2065-2071, 2009) , its role in various differentiation processes (Hu X, et al. LSD1-mediated epigenetic modification is required for TAL1 function and hematopoiesis. Proc Natl Acad Sci USA 106:10141-10146, 2009), its involvement in herpes virus infection (Gu H, Roizman B. Engagement of the lysine-specific demethylase/HDAC1/CoREST/REST complex by herpes simplex virus 1. J Virol 83:4376-4385, 2009), and its association with HDAC1, a validated target drug. LSD2 is a more recently discovered demethylase that, like LSD1, exhibits strict specificity for Lys4 mono and dimethylated H3. However, the biology of LSD2, which remains only partially characterized, has set out to differentiate from that of LSD1 since LSD2 does not bind to CoREST nor has it been found in any LSD1-containing protein complex (Karytinos A, et al. A novel mammalian flavin-dependent histone demethylase J Biol Chem 284:17775-17782, 2009).
[0004] LSD1 and LSD2 are multidomain proteins that share a similar catalytic domain (45% sequence identity) that is structurally homologous with the monoamine oxidases (MAOs) A and B. Tranylcypromine, (±)-trans-2-phenylcyclopropyl -1-amine (tPCPA), a MAO inhibitor used as an antidepressant drug, is also capable of inhibiting LSD1 (Schmidt DM, McCafferty DG. trans-2-Phenylcyclopropylamine is a mechanismbased inactivator of the histone demethylase LSD1. Biochemistry 46:44084416 , 2007).

[0005] Gooden et at (Bioorg. Med. Chem. Lett. 18, 3047-3051, 2008) describe a synthetic route to substituted trans-2-arylcyclopropylamines as inhibitors of LSD1 and MAOs. These derivatives are more than 10 times more effective in inhibiting MAO A and B than LSD1.
[0006] Culhane et al (J. Am. Chem. Soc. 132, 3164-3176, 2010) refer to the MAO inhibitor phenelzine containing hydrazine as small molecule LSD1 inhibitors.
[0007] WO 2010011845 describes a method of treating a viral infection of a host, by administering to the host an inhibitor of the LSD1 protein (an RNAi molecule) and/or a monoamine oxidase inhibitor, for example, tranylcypromine .
[0008] EP 1693062 refers to the use of at least one siRNA ("short interfering RNA") and at least one anti-LSD1 antibody, also in combination with a monoamine oxidase inhibitor, for example, tranylcypromine, to modulate the activity of LSD1 and controlling androgen receptor dependent gene expression.
[0009] WO 2010/043721, WO 2010/084160 and WO 2010/143582, WO2011/035941, which were published after the priority date of the present patent application, disclose phenylcyclopropylamine derivatives capable of selectively inhibiting the function of LSD1. None of the disclosed compounds are within the present invention.
Therefore, there is a need to identify small molecules as potent and selective inhibitors of histone demethylase LSD1 and/or LSD2, which are useful in the prevention or therapy of diseases and conditions associated with histone demethylase activity.
[0011] The compounds of the present invention are small molecules endowed with potent inhibitory activity of histone demethylases, which are useful in the treatment of a variety of diseases in which dysregulation of gene transcription, cell differentiation and proliferation are observed, for example, tumors and viral infections. Detailed Description of the Invention
[0012] The present invention is directed to compounds that are endowed with LSD1 and/or LSD2 histone demethylases inhibiting activity and are useful in the prevention or therapy of diseases and conditions associated with LSD1 and/or LSD2 histone demethylases activity. The invention is also directed to methods of preparing said compounds, compositions containing them and their therapeutic use.
[0013] The invention has found that the tranylcypromine derivatives of the general formula (I), and its derivatives, are endowed with histone demethylase inhibiting activity.
[0014] All terms as used herein in this patent application, unless otherwise indicated, are to be understood in their common meaning as known in the art. Other, more specific definitions for certain terms as used in this patent application are as set forth below and are intended to apply uniformly throughout the specification and claims, unless an expressly stated contrary definition provides a broader definition.
[0015] Therefore, an object of the invention is a compound of formula (I)

[0016] where:
[0017] A is R or CH(R1)-NH-CO-R2;
[0018] R and R2 are selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, heterocycloalkylalkyloxy, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, heterocycloalkylalkylamino, cycloalkylaminoalkylaminoalkylaminoalkylaminoalkyl;
[0019] R1 is selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl;
[0020] R3 is H, lower alkyl;
[0021] as well as their isomers, tautomers, racemic forms, enantiomers, diastereomers, epimers, polymorphs, solvates, their mixtures, prodrugs and their pharmaceutically acceptable salts.
[0022] The term "alkyl" refers to a fully saturated straight or branched saturated hydrocarbon chain having from one to 10 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and the like. "Lower alkyl" or "C1-C6 alkyl" have similar meanings except they contain one to six carbon atoms.
[0023] The term "alkenyl" refers to a straight or branched hydrocarbon chain having from two to ten carbon atoms and at least one carbon-carbon double bond. Examples include, but are not limited to, ethenyl, 2-propenyl, isobutenyl and the like.
[0024] The term "alkynyl" refers to a straight or branched hydrocarbon chain having from two to ten carbon atoms and at least one carbon-carbon triple bond. Examples include, but are not limited to, ethynyl, 2-propynyl, isobutynyl and the like.
The term "cycloalkyl" refers to any non-aromatic carbocyclic ring system of 1 or 2 ring moieties. A cycloalkyl group can have one or more carbon-carbon double bonds in the ring so long as the ring is non-aromatic rendered by its presence. Examples of cycloalkyl groups include, among others, (C3-C7)cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and saturated cyclic and bicyclic terpenes and (C3-C7)cycloalkenyl groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl, and unsaturated cyclic and bicyclic terpenes.
[0026] The term "aryl" refers to any carbocyclic aromatic ring system of 1 or 2 ring moieties, either fused or linked together through a single bond. Suitable aryl groups include, among others, phenyl, α- or β-naphthyl, biphenyl, indanyl, indenyl, and the like.
[0027] The term "heteroaryl" refers to monocyclic or polycyclic aromatic rings comprising carbon atoms and one or more heteroatoms, preferably 1 to 3 heteroatoms, independently selected from nitrogen, oxygen, and sulfur. As is well known to those skilled in the art, heteroaryl rings are less aromatic in character than their carbon-only counterparts. Thus, for the purposes of the invention, a heteroaryl group need only have some degree of aromatic character. Illustrative examples of heteroaryl groups include, but are not limited to, furyl, benzofuranyl, benzodioxolyl, thienyl, benzothiophenyl, pyridinyl, pyridyl-N-oxide, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, quinolyl, (1,2,3 ,)- and (1,2,4)-triazolyl, tetrazolyl, triazinyl, pyrrolyl, imidazolyl, imidazo[1,2-a]pyridin-3-yl, indazolyl, isothiazolyl, indolyl, benzoimidazolyl, benzotriazolyl, benzoxazolyl, oxadiazolyl, thiadiazolyl, and the like.
[0028] The term "heterocycloalkyl" refers to a non-aromatic monocyclic or polycyclic ring comprising carbon and hydrogen atoms and at least one heteroatom, preferably 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur. A heterocycloalkyl group may have one or more carbon-carbon double bonds or carbon-heteroatom double bonds in the ring as long as the ring does not have its aromatic character rendered by its presence. Examples of heterocycloalkyl groups include, but are not limited to, aziridinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, oxazolidinyl, tetrahydrothienyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, pyrazolidinyl, 1,3-dioxolanyl , pyrrolidinyl, pyranyl, dihydropyranyl, isoxazolidinyl, imidazolidinyl and the like. A heterocycloalkyl group can be unsubstituted or substituted with one or two substituents.
[0029] The term "cycloalkylalkyloxy" refers to the group -O-(alkyl)-(cycloalkyl), wherein cycloalkyl and alkyl are defined above.
[0030] The term "arylalkyloxy" refers to the group -O-(alkyl)-(aryl), where aryl and alkyl are defined above.
[0031] The term "heteroarylalkyloxy" refers to the group -O-(alkyl)-(heteroaryl), wherein heteroaryl and alkyl are defined above.
[0032] The term "heterocycloalkylalkyloxy" refers to the group -O-(alkyl)-(heterocycloalkyl), wherein heterocycloalkyl and alkyl are defined above.
[0033] The term "cycloalkylalkyl" refers to an alkyl group substituted with a cycloalkylalkyl group, wherein alkyl and cycloalkylalkyl are defined above.
[0034] The term "arylalkyl" refers to an alkyl group substituted with an aryl group, wherein alkyl and aryl are defined above.
[0035] The term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group, wherein alkyl and heteroaryl are defined above.
[0036] The term "heterocycloalkylalkyl" refers to an alkyl group substituted with a heterocycloalkyl group, wherein alkyl and heterocycloalkyl are defined above.
[0037] The term "cycloalkylalkylamino" refers to an amino group substituted with at least one cycloalkylalkyl group as defined herein.
The term "arylalkylamino" refers to an amino group substituted with at least one arylalkyl group as defined herein.
The term "heteroarylalkylamino" refers to an amino group substituted with at least one heteroarylalkyl group as defined herein.
The term "heterocycloalkylalkylamino" refers to an amino group substituted with at least one heterocycloalkylalkyl group as defined herein.
[0041] Any of the above alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl groups may optionally be further substituted in any of its free positions by one or more groups, for example, 1 to 6 groups, selected from: halogen, carboxy, cyano, alkyl, polyfluorinated alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, alkyl-heteroaryl, heteroaryl-alkyl, amino-alkyl, amino groups and derivatives thereof, such as, for example, alkylamino, dialkylamino, arylamino , diarylamino, ureido, alkylureido or arylureido; carbonylamino groups and derivatives thereof, such as, for example, formylamino, alkylcarbonylamino, alkenylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino; hydroxy groups and derivatives thereof, such as, for example, alkoxy, polyfluorinated alkoxy, aryloxy, heteroaryloxy, alkylcarbonyloxy, arylcarbonyloxy, or cycloalkyloxy; carbonyl groups and derivatives thereof, such as, for example, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxamic acid; sulfur derivatives, such as, for example, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl, arylsulfonyloxy, aminosulfonyl, alkylaminosulfonyl or dialkylaminosulfonyl.
[0042] In turn, whenever necessary, each of the above substituents can be further substituted by one or more of the aforementioned groups.
[0043] The term "halogen" refers to the atom of fluorine, chlorine, bromine or iodine.
[0044] The term "alkoxy" refers to the group -O-(alkyl), wherein alkyl is defined above.
[0045] The terms "polyfluorinated alkyl" and "polyfluorinated alkoxy" refer to any linear or branched C1-C6 alkyl group or alkoxy group as defined above, in which more than one hydrogen atom is replaced by fluorine atoms such as, for example, trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoroethyl, 2,2,2-trifluoroethoxy, 1,2-difluoroethyl, 1,1,1,3,3,3-hexafluoropropyl-2-yl, and the like.
[0046] From all of the above, it is clear to the person skilled in the art that any group that name has been identified as a composite name, such as, for example, alkyl-heteroaryl, alkylthio, arylthio, amino-alkyl, alkylamino, dialkylamino , arylamino, diarylamino, alkylureido, arylureido, alkylcarbonylamino, alkenylcarbonylamino, arylcarbonylamino, aryloxy, arylalkyloxy, alkylcarbonyloxy, alkoxycarbonylamino; heteroaryloxy, arylcarbonyloxy; alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl, arylsulfonyloxy, aminosulfonyl, alkylaminosulfonyl or dialkylamino are conventionally understood to be derived from them, and are conventionally understood to be derived from them. Heretofore, as an example, the term alkoxycarbonyl means a radical containing an alkoxy radical, as defined above, attached through an oxygen atom to a carbonyl radical.
[0047] The formulas include one or more “AAAAAA'” to indicate all possible configurations: cis, trans, (R), (S).
[0048] The term "acylating agent" refers to a reactive carboxylic acid derivative that is capable, in the present process, of coupling the acid to an amino group through an amide bond. Examples of acylating agent include, among others, organic acyl halides, organic acid anhydrides, carboxylic acids, esters, mixed carboxylic-sulfonic acid anhydrides.
[0049] The term "about" encompasses the range of experimental error that can typically occur in a measurement.
The term "pharmaceutically acceptable salts" refers to the relatively non-toxic mineral and organic acid addition salts of the compounds of the present invention. These salts can be prepared in situ during the isolation and final purification of the compounds. In particular, acid addition salts can be prepared by separately reacting the purified compound in its purified form with an organic or inorganic acid and isolating the salt so formed. The resulting salts are, for example, hydrochlorides, hydrobromides, sulfates, hydrogen sulfates, dihydrogen phosphates, methane sulfonates, citrates, oxalates, maleates, fumarates, succinates, trifluoroacetates, 2-naphthalene sulfonates, para-toluene sulfonates.
[0051] It will be evident to those skilled in the art that the compounds of general formula (I) may contain asymmetric centers. Therefore, the invention also includes optical stereoisomers and mixtures thereof. When the compounds according to the invention have at least one asymmetric center, they can therefore exist as enantiomers. When the compounds according to the invention have two or more asymmetric centers, they can additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof in any proportion, including racemates, are encompassed within the scope of the present invention.
[0052] The present invention also refers to all isomers and their mixtures, tautomeric forms, racemic forms, enantiomers, diastereoisomers, epimers, as well as their crystalline forms, including their polymorphic forms and their mixtures. Some of the compounds are solvated with a stoichiometric or non-stoichiometric amount of one or more solvent molecules (eg water, ethanol) as such they are also intended to be encompassed within the scope of the invention.
[0053] In cases where the compounds may exist in tautomeric forms, each form is contemplated to be included in this invention, either in equilibrium or predominantly in one form.
Also, pharmaceutically acceptable metabolites and bioprecursors (otherwise referred to as prodrugs) of the compounds of formula (I) are included within the scope of, and suitable for use in, the present invention.
[0055] So-called "pro-drugs" of the compounds of formula (I) are also within the scope of the invention. Thus, certain derivatives of compounds of formula (I), which may have little or no pharmacological activity, may themselves, when administered within the body, be converted to compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage. Prodrugs according to the invention can, for example, be produced by substituting the appropriate functions present in the compounds of the formula (I) with certain moieties known to those skilled in the art as proportions, as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985) or in Prodrugs: design and clinical applications by Jarkko Rautio et al. (Nature reviews drug discovery, volume 7, March 2008, 255-270).
[0056] In a preferred embodiment, the invention provides a compound of formula (I), wherein:
[0057] A is R; preferably alkyl, aryl, arylalkyloxy, arylalkyl, each of which is optionally substituted;
[0058] R3 is H;
[0059] as well as their isomers, tautomers, racemic forms, enantiomers, diastereomers, epimers, polymorphs, solvates, their mixtures, prodrugs and their pharmaceutically acceptable salts.
[0060] In another preferred embodiment, the invention provides a compound of formula (I), wherein:
[0061] R3 is H;
[0062] A is CH(R1)-NH-CO-R2; preferably, independently or in any combination:
[0063] R1 is alkyl, aryl, heteroaryl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, each of which is optionally substituted;
[0064] R2 is arylalkyloxy, heteroarylalkyloxy, each of which is optionally substituted;
[0065] as well as their isomers, tautomers, racemic forms, enantiomers, diastereomers, epimers, polymorphs, solvates, their mixtures, prodrugs and their pharmaceutically acceptable salts.
[0066] In another preferred embodiment, the invention provides a compound of formula (I), wherein:
[0067] R3 is -CH3;
[0068] A is CH(R1)-NH-CO-R2; preferably, independently or in any combination:
[0069] R1 is alkyl, aryl, heteroaryl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, each of which is optionally substituted;
[0070] R2 is arylalkyloxy, heteroarylalkyloxy, each of which is optionally substituted;
[0071] as well as their isomers, tautomers, racemic forms, enantiomers, diastereomers, epimers, polymorphs, solvates, their mixtures, prodrugs and their pharmaceutically acceptable salts.
[0072] For a reference to any specific compound of formula (I) of the invention, optionally in the form of a pharmaceutically acceptable salt, see the experimental section below.
[0073] Specific, non-limiting examples of the compounds of formula (I) are shown in the following table (Table 1): Table 1



[0074] Isomers, tautomers, racemic forms, enantiomers, diastereomers, polymorphs, solvates, mixtures, prodrugs and their pharmaceutically acceptable salts of the compounds described in Table 1 are still within the scope of the invention.
[0075] The present invention also relates to processes for the preparation of a compound of the general formula (I), as defined above, its prodrugs and pharmaceutically acceptable salts, according to the following methods (Method A and Method B ), which can be performed according to methods well known to a person skilled in the art. Some of the processes that can be used are described below and reported in the Schemes and should not be viewed as limiting the scope of synthetic methods available for preparing the compounds of the invention. The following processes are given for representative purposes. Depending on the nature of the compounds of formula (I) to be obtained, the presented methodologies can be adapted by one skilled in the art through the selection of appropriate starting materials, in which the nature of the substituents R, R1, R2 and R3 can be modified .
[0076] Therefore, it is an object of the invention a process for the preparation of the compound (Ia), corresponding to the general formula (I) wherein A is R, the process comprising:
[0077] (a) reacting a compound of the formula (II) with an acylating agent to result in a compound of the formula (III),

[0078] wherein R, R3 are as defined above and Boc is the tert-butyloxycarbonyl protecting group;
[0079] (b) optionally converting the compound of the formula (III) obtained in a) into another compound comprised in the formula (III), removing the Boc protecting group from the compound of the formula (III) to obtain the compound of the formula (Ia ):

[0080] According to step (a) of the process (Method A), the reaction of a compound of the formula (II) with an acylating agent to result in the compound of the formula (III) can be carried out with different well-known methods of a technician in the subject. As an example, a compound of formula (II) may be treated with the appropriate acylating agent, such as acyl chloride, in the presence of a base to provide the Boc-protected compound of formula (III). The reaction is carried out in a suitable solvent such as polar aprotic solvents, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, N,N'-dimethylformamide, or mixtures thereof, in the presence of a proton scavenger, such as triethylamine, N,N-diisopropylethylamine, piperidine, N,N-dimethylaniline, or pyridine, at a temperature ranging from room temperature to the reflux temperature of the solvent. Preferably, step (a) is carried out by reacting a compound of formula (II) with acyl chloride in the presence of an amine, such as triethylamine, in dichloromethane at room temperature. Optionally, a compound of formula (III) can be converted to another compound of formula (III), prior to deprotection of the Boc group. For example, aniline NH can be alkylated by treatment with an alkyl halide in a basic medium according to standard methods well known to a person skilled in the art. Cleavage of the Boc group of the compound of formula (III) according to standard methods yielded the final compounds (Ia). Deprotection of the Boc group is described in "Protective Groups in Organic Chemistry" 3rd edition, T.W. Greene and P.G.M. Wuts, Wiley-Interscience (1999) and "Protecting Groups", P.J. Kocienski, Georg Thieme Verlag (1994). For example, step (b) is carried out by adding an acid, such as HCl or trifluoroacetic acid, in a suitable solvent such as polar aprotic solvents, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, N,N α-dimethylformamide, or mixtures thereof, at a temperature ranging from about 0°C to reflux.
[0081] The compounds of the formula (Ia) can be modified into other compounds comprised in the formula (Ia) by any synthetic means known in the art and/or can be converted into a pharmaceutically acceptable salt and/or its salt can be converted in the free compound of formula (Ia).
[0082] In another embodiment, the invention provides a process for the preparation of a compound (Ib) corresponding to the general formula (I) wherein A is CH(R1)-NH-CO-R2, the process comprising:
[0083] (a) reacting a compound of the formula (II) with an acylating agent to result in a compound of the formula (IV)

[0084] wherein R1, R2, R3 and Boc are as defined above;
[0085] optionally converting the compound of the formula (IV) obtained in a) into another compound of the formula (IV), removing the Boc Protecting Group from the compound of the formula (IV) to obtain a compound of the formula (Ib):

[0086] According to step (a) of the process (Method B), the reaction of a compound of the formula (II) with an acylating agent to result in the compound of the formula (IV) can be carried out with different well-known methods of a technician in the subject. As an example, a compound of formula (II) may be treated with the appropriate acylating agent, such as a Z-protected amino acid, and a base, optionally in the presence of a coupling reagent, such as (benzotriazol-1-hexafluorophosphate) yloxy)tris(dimethylamino)-phosphonium (BOP reagent), N,N-carbonyldiimidazole, or 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride to provide the Boc-protected compound of formula (IV). The reaction is carried out in suitable solvents, such as polar aprotic solvents, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, N,N'-dimethylformamide, or mixtures thereof, in the presence of a proton scavenger, such as triethylamine, N,N-diisopropylethylamine, piperidine, N,N-dimethylaniline, or pyridine, at a temperature ranging from room temperature to the reflux temperature of the solvent. Preferably, step (a) is carried out by reacting a compound of formula (II) with a Z-protected amino acid in the presence of an amine, such as triethylamine, in N,N-dimethylformamide at room temperature. Optionally, a compound of formula (IV) can be converted to another compound of formula (IV) prior to deprotection of the Boc group. For example, aniline NH can be alkylated by treatment with an alkyl halide in a basic medium according to standard methods well known to a person skilled in the art. Further cleavage of the Boc group of the compound of formula (IV), working as described above, yielded the final compounds (Ib).
[0087] The compounds of the formula (Ib) can be modified into other compounds comprised in the formula (Ib) by any synthetic means known in the art and/or can be converted into a pharmaceutically acceptable salt and/or its salt can be converted in the free compound of formula (Ib).
The above acylating agent or Z-protected amino acid are commercially available compounds or can be easily obtained from the known compounds according to standard procedures known to those skilled in the art. In case the acylating agent or the Z-protected amino acid bears reactive groups like hydroxyl, carboxyl, thiol or amino groups, they may need to be protected by protecting groups such as t-butoxycarbonyl, benzyl, benzyloxycarbonyl, methyl, trimethylsilyl and similar and, at a certain stage of the synthesis, deprotected to obtain the free reactive group again. The deprotected group can be further reacted, i.e. alkylated, acylated, sulfonylated or the like. The protection and deprotection of functional groups are described in "Protective Groups in Organic Chemistry" 3rd edition, T.W. Greene and P.G.M. Wuts, Wiley-Interscience (1999) and "Protecting Groups", P.J. Kocienski, Georg Thieme Verlag (1994).
[0089] It is clear to the person skilled in the art that if a compound of the formula (I), prepared according to the above processes (Method A or Method B), is obtained as a mixture of isomers, its separation into the simple isomers of the formula (I), performed according to conventional techniques, is still within the scope of the present invention.
[0090] As will be appreciated by the person skilled in the art, when, during the syntheses of the compounds of formula (I) certain functional groups may raise unwanted side reactions, these groups need to be properly protected according to conventional techniques. Also, the conversion of the latter to the corresponding deprotected compounds can be carried out according to procedures well known to the person skilled in the art.
[0091] The starting materials of formula (II) can be obtained from known commercially available compounds according to standard procedures available in the literature and well known to the skilled person. Compounds of formula (II) can be readily obtained by following, in part, reported procedures (J Am Chem Soc, 80: 4015-4018, 1958; J Org Chem, 27: 733-736, 1962; Bioorg Med Chem Lett, 16 :1840-1845, 2006). In particular, ethyl 2-(4-nitrophenyl)cyclopropyl-1carboxylate was obtained as a mixture of cis and trans by coupling the commercially available 4-nitrostyrene with ethyl diazoacetate (EDA) in the presence of copper(I) chloride (CuCl ) in dry CHCl3 (Scheme 1). The two isomers can be isolated using known procedures for separating the compounds, for example, by chromatographic separation, recrystallization techniques, as well as other methods well known to the person skilled in the art. Alkaline hydrolysis of the ethyl ester provided the corresponding carboxylic acids, which, in turn, were converted to the related t-butoxy carbamates through reaction with triethylamine, diphenylphosphoryl azide, t-butanol, and di-t-butyldicarbonate to dry benzene. Reduction of the nitro group of these latter compounds with sodium hypophosphite, palladium on carbon, and potassium carbonate provided the compounds of formula (II). Scheme 1:
Reagents and conditions:
[0092] a) EDA, CuCl, dry CHCl3, 60°C, N2 atmosphere; b) 2N KOH, EtOH, rt; c) 1) DPPA, Et3N, dry t-BuOH, dry benzene, 80°C, N2 atmosphere; 2) Boc2O, dry benzene, 80°C, N2 atmosphere; e) 2N K2CO3, NaH2PO2, Pd/C, THF, 60°C, N2 atmosphere.
[0093] The compounds of the present invention have been found to be effective LSD1 and LSD2 inhibitors and exhibit antitumor activity on leukemic cells when taken alone, and synergistic activities with antileukemia drugs when given in combination.
[0094] It is an object of the present invention a compound of formula I which is an inhibitor of histone demethylase LSD1 and/or LSD2.
[0095] Preferably, the compound of the invention is for use in therapy or as a pro-apoptotic agent, yet preferably the compound is for use as a medicine for the prevention and/or treatment of diseases characterized by dysregulation of gene transcription, differentiation and cell proliferation.
[0096] In a preferred embodiment, the compound of the invention is for use as an antitumor agent.
[0097] In another preferred embodiment, the compound is for use as an antiviral agent.
[0098] It is an object of the invention to prevent and/or treat diseases and conditions associated with the activity of histone demethylase LSD1 and/or LSD2, in particular, tumors, viral infections, by administering to a mammal in need of such treatment , a therapeutically effective amount of a compound of the general formula (I) as defined above.
[0099] Preferably, the tumor is selected from: neuroblastoma, prostate cancer, breast cancer, acute myeloid leukemia, T-lineage acute lymphoblastic leukemia, bladder cancer, lung cancer and colorectal cancer.
[0100] Still preferably, the viral infection is caused by the Herpes Simplex Virus.
[0101] It is an object of the invention a pharmaceutical composition comprising one or more compounds of the general formula (I), as defined above, alone or in combination with other active compounds, and at least one pharmaceutically acceptable excipient.
Preferably, the pharmaceutical composition comprises an effective amount of the compound of the invention formulated in unit dosage form.
[0103] The term "excipient" herein means any substance, not a therapeutic agent per se, used as a carrier or vehicle for delivering a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or allowing or facilitating the formation of a unit dose of the composition into a discrete article such as a tablet, capsule, pill, powder, granule, pellet, lozenge, elixir, syrup, solution, suspension, emulsion, drop, lotion, spray, tincture , cream, ointment, gel, ointment, suppository and transdermal devices for oral, enteral, parenteral or topical administration.
[0104] The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for humans and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with an excipient suitable pharmacist.
[0105] A person skilled in the art is aware of a whole variety of such excipients suitable for formulating a pharmaceutical composition. Suitable pharmaceutically acceptable excipients are well known to those skilled in the art. Excipients include, by way of illustration and not limitation, diluents, solubilizers, fillers, binders, disintegrants, disintegration inhibitors, absorption accelerators, adjuvants, binders, carriers, suspending/dispersing agents, film formers/coatings, adhesives , non-stick agents, wetting agents, lubricants, glidants, preservatives, sorbents, buffering agents, surface-active agents, substances added to mask or neutralize an unpleasant taste or odor, flavoring agents, colorants, fragrances, flavoring agents, sweeteners, substances added to improve appearance of makeup and the like. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
[0106] The pharmaceutical compositions of the present invention can be administered by a variety of routes including oral, parenteral, intravenous, by infusion, subcutaneous, intramuscular, intraperitoneal, transmucosal (including buccal, sublingual, nasal, transurethral and rectal), topical, transdermal , by inhalation, ocular routes (including ocular implants, reservoir implants and injectable therapies such as intravitreal administration), permucosal or percutaneous or using any other route of administration.
[0107] Thus, they will be presented in the form of solids or liquids, injectable solutions or suspensions or multidose bottles, in the form of tablets, simple or coated tablets, sugar or film coated tablets, capsules, wafer capsules, gel capsules, pills, wafers, sachets, powders, granules, tablets in capsule form, lozenges, bolus, pills, electuary, paste, suppositories or rectal capsules, syrups, elixirs, emulsions, solutions, suspensions, creams, ointments, liniments, lotions, drops , sprays, plasters, for percutaneous use in a polar solvent, or for permucosal use.
[0108] For example, solid oral forms, with the active compound, diluents, for example, alkaline earth metal carbonates, magnesium phosphate, lactose, dextrose, sucrose, sucrose, cellulose, microcrystalline cellulose derivatives, starches, starch corn or potato starch, modified starches and the like; lubricants, for example, silica, talc, stearic acid, calcium and magnesium stearate, and/or polyethylene glycols; binding agents, for example starches, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disintegrating agents, for example starch, alginic acid, alginates or sodium starch glycolate; effervescent mixtures; dyes; sweeteners; wetting agents such as lecithin, polysorbates, lauryl sulfates; and, in general, non-toxic and pharmacologically inactive substances in pharmaceutical formulations. Such pharmaceutical preparations can be manufactured in known ways, for example, by means of mixing, granulating, tabletting, sugar-coating or film-coating processes.
[0109] Liquid dispersions for oral administration can be, for example, syrups, emulsions and suspensions. As an example, syrups may contain, as a carrier, sucrose or sucrose with glycerin and/or mannitol and sorbitol.
[0110] Suspensions and emulsions may contain, as examples of carriers, natural gum, Agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
[0111] The suspension or solutions for intramuscular injections may contain, with the active compound, a pharmaceutically acceptable carrier, for example, sterile water, olive oil, ethyl oleate, glycols, for example, propylene glycol and, if desired, an adequate amount of lidocaine hydrochloride.
[0112] Solutions for intravenous injections or infusions may contain, as a carrier, sterile water or preferably they may be in the form of sterile, aqueous, isotonic, saline solutions or they may contain propylene glycol as a carrier.
[0113] Suppositories may contain, with the active compound, a pharmaceutically acceptable carrier, for example cocoa butter, polyethylene glycols, polyoxyethylene sorbitan fatty acid ester surfactants, salicylates or lecithin.
[0114] Inhalation aerosols may contain, with the active compound, propellant gas such as hydrofluoroalkanes. Propellant-driven formulations may also contain other ingredients such as co-solvents, stabilizers and optionally other excipients. The propellant-free inhalable formulations comprising the compounds of the invention may be in the form of solutions or suspensions in an aqueous, alcoholic or hydroalcoholic medium and they may be delivered by jet or ultrasonic nebulizers known in the prior art or by light mist nebulizers.
[0115] The components described above for pharmaceutical compositions administered are merely representative. Other materials, as well as processing techniques and the like, are set forth in Part 5 of Remington's Pharmaceutical Sciences, 20th Edition, 2000, Merck Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference. The compound of this invention of formula (I) may also be administered in sustained release forms or from sustained release drug delivery systems. A description of the extended-release materials can also be found in the materials incorporated in Remington's Pharmaceutical Sciences.
[0116] Pharmaceutical compositions containing the compounds of the invention are generally prepared following conventional methods and are administered in a suitable pharmaceutical form.
[0117] Oral solid compositions can be prepared by conventional mixing, filling or pressing. It is possible to repeat the mixing operations in order to disperse the active agent in compositions containing high amounts of fillers. These operations are conventional.
[0118] Oral liquid preparations may be formulated, for example, as aqueous or oily suspensions or solutions, emulsions, syrups or elixir, or may be presented as a frozen dry product to be regenerated by the addition of water or a suitable vehicle before use . Said liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats, emulsifying agents, for example, lecithin, monooleate of sorbitan, or acacia; non-aqueous vehicles (which may include edible oils), for example, sweet almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid and, if desired, conventional flavors and colorings.
[0119] For parenteral administration, fluid dosage units can be prepared, containing the compound and a sterile vehicle. The compound, depending on the chosen vehicle and concentration, can either be suspended or dissolved. Parenteral solutions are usually prepared by dissolving the compound in a vehicle, filter sterilizing, filling the appropriate vials and sealing. Advantageously, it is also possible to dissolve in suitable adjuvant vehicles, such as local anesthetics, preservatives and buffering agents. In order to increase stability, the composition can be frozen after filling the vial and removing the water under vacuum. Parenteral suspensions are prepared in substantially the same way, with the difference that the compound can be suspended rather than dissolved in the vehicle, and they can be sterilized by treatment with ethylene oxide before being suspended in the sterile vehicle. Advantageously, it is possible to include a surfactant or a wetting agent in the composition in order to facilitate uniform distribution of the compound of the invention.
[0120] The compounds of the invention can also be administered topically. Topical formulations can comprise, for example, an ointment, cream, gel, lotion, solution, paste or the like, and/or can be prepared so that they contain liposomes, micelles and/or microspheres. Ointments, as are well known in the art of pharmaceutical formulation, are semi-solid preparations that are typically based on petrolatum or other petroleum derivatives. Examples of ointments include oil-based ointments, e.g. vegetable oils, animal fats, and semi-solid hydrocarbons obtained from petroleum, emulsifiable base ointments, e.g., hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum, emulsion-based ointments , for example, cetyl alcohol, glyceryl monostearate, lanolin and stearic acid, and water-soluble base ointments prepared from polyethylene glycols of varying molecular weight. Creams, as also well known to those skilled in the art, are viscous liquids or semi-solid emulsions, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase usually contains a humectant. The emulsifier in a cream formulation is chosen from non-ionic, anionic, cationic or amphoteric surfactants. Single-phase gels contain organic macromolecules distributed substantially evenly throughout the liquid carrier, which is typically aqueous, but also, preferably, contains an alcohol and, optionally, an oil. Preferred gelling agents are cross-linked acrylic acid polymers (such as "carbomer" polymers, e.g., carboxypolyalkylenes obtainable commercially under the trade name Carbopol). Also preferred are hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers and polyvinyl alcohol; cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums such as tragacanth and xanthan gum, sodium alginate; and gelatin. For the preparation of uniform gels, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by grinding, mechanical mixing and/or stirring.
[0121] The compounds of the invention can also be administered via transdermal delivery. Typical transdermal formulations include conventional aqueous and non-aqueous vectors such as creams, oils, lotions or pastes or may be provided as medicated membranes or patches. In one embodiment, a compound of the invention is dispersed in a pressure sensitive patch that adheres to the skin. This formulation allows the compound to be spread from the patch across the skin. In order to obtain an extended release drug through the skin, natural rubber and silicon can be used as pressure sensitive adhesives.
[0122] The compounds of formula (I) of the present invention, suitable for administration to a mammal, for example, to humans, can be administered as the active agent alone or in combination with other active pharmaceutical ingredients by the usual routes, and the level dosage depends on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual to be treated; the time and route of administration; the excretion rate; other drugs that were previously administered; and the severity of the particular illness in therapy, as is well understood by those skilled in the art.
[0123] For example, a suitable dosage adopted for oral administration of a compound of formula (I) may range from about 30 to 500 mg per dose, from 1 to 5 times a day. In general, lower doses will be administered when a parental route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, 0.5 mg to 30 mg per kg of body weight will generally be used.
[0124] The compounds of the invention can be administered in a variety of dosage forms, for example, orally, in the form of tablets, sugar or film coated tablets, capsules, wafers, as a powder or granules; as syrups, emulsions, solution or a suspension in an aqueous or non-aqueous liquid, such as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion, such as a bolus, electuary or paste; rectal route, in the form of suppositories; parenterally, for example, intramuscularly, or by intravenous injection or infusion. Preferably, the compounds of general formula (I) alone or combined with other active ingredients can be administered for the prevention and/or treatment of any disease where inhibition of the histone demethylases LSD1 and LSD2 is required. Said diseases include tumors, viral infections. Examples
[0125] The present invention will now be described through the following non-limiting examples, referring to the following figure.
[0126] Figure 1. Biological evaluation of 6e. (A) 6e synergizes with retinoic acid (RA) in inhibiting cell growth. NB4 cells were treated with increasing concentrations of retinoic acid (10 nM, 100 nM and 1 µM in the absence or presence of 6e (2 µM).At the indicated time points, cells were counted by Trypan blue exclusion. untreated cells, NT, (vehicle only) (B) 6e synergizes with retinoic acid (RA) in inducing differentiation in NB4 cells.NB4 cells were treated with retinoic acid (100 nM) or vehicle (NT) in the absence or in presence of 6e (2 μM) After 7 days, cells were cytospun on glass slides and stained (May Grunwald-Giemsa).
[0127] Figure 2. 6e synergizes with retinoic acid (RA) in inducing apoptosis in NB4 cells. NB4 cells were treated with increasing concentrations of retinoic acid (10 nM, 100 nM and 1 μM) or vehicle (NT), in the absence or presence of 6e (2 μM). Apoptosis was measured by propidium iodide staining of permeabilized cells after 7 days. A representative experiment is shown. 1. CHEMICAL SYNTHESIS METHODS
[0128] Unless otherwise indicated, all starting reagents were found to be commercially available or readily obtainable following literature procedures, and were used without any purification. All solvents were reagent grade and, when necessary, were purified and dried by standard methods.
[0129] Concentration of solutions after reactions and extractions involved the use of a rotary evaporator operating at a reduced pressure of about 20 Torr. The organic solutions were dried over anhydrous sodium sulfate. Analytical results were within ± 0.40% of theoretical values.
[0130] TLC was determined on aluminum-backed silica gel plates (Merck DC, Alufolien Kieselgel 60 F254) with spots visualized by UV light.
[0131] 1H NMR and 13C NMR spectra were acquired with a 400 MHz Bruker. Chemical exchanges are expressed in parts per million (ppm, δ units). Coupling constants are expressed in Hertz (Hz) and division patterns as s (singlet), bs (broad singlet), d (doublet), t (triplet), q (quartet), fifth (quintet), m ( multiplet).
[0132] The EIMS spectra were recorded with a Fisons Trio 1000 spectrometer; only molecular ions (M+) and base peaks were given.
[0133] Melting points were determined on a Buchi 530 melting point apparatus and are uncorrected. Example 1 Preparation of cis and trans 2-(4-Nitrophenyl)cyclopropyl tert-butyl carbamates: trans 2-(4-Nitrophenyl)cyclopropyl tert-butyl carbamate

[0134] A solution of trans 2-(4-nitrophenyl)cyclopropyl-1-carboxylic acid (5.3 mmols, 1.1 g) in dry benzene (20 mL), triethylamine (6.4 mmols, 0.9 mL) ), diphenylphosphoryl azide (5.8 mmols; 1.2 mL) and tert-butanol (53 mmols, 5 mL) was stirred at 80°C under N 2 atmosphere for 16 h. After that, di-tert-butyldicarbonate (8 mmols, 1.7 g) was added, and the reaction was stirred at 80°C for a further 2 h. The solvent was removed in vacuo and the residue was chromatographed on silica gel eluting with 1/3 ethyl acetate/n-hexane to isolate the pure trans tert-butyl 2-(4-nitrophenyl)cyclopropyl carbamate as a yellow solid. pale.
[0135] 1H NMR (CDCl3, 400 MHz, δ; ppm) δ 1.29-1.33 (m, 2H, CH2 cyclopropane), 1.46 (s, 9H, C(CH3)3), 2.15 -2.17 (m, 1H, PhCH), 2.80-2.82 (m, 1H, CHNH), 4.93 (bs, 1H, NHCO), 7.26-7.28 (d, 2H, aromatic protons), 8.13-8.15 (d, 2H, aromatic protons); 13C NMR (DMSO-d6, 400 MHz, δ; ppm) δ 14.40, 22.80, 28.40 (3C), 32.60, 79.50, 123.30 (2C), 125.90 (2C) ), 144.30, 147.80, 155.60; MS (ESI) m/z: 278.13 [M]+; mp = 153-155°C Example 2 Preparation of trans and cis tert-butyl 2-(4-aminophenyl)cyclopropyl carbamates: trans tert-butyl 2-(4-aminophenyl)cyclopropyl carbamate

[0136] A mixture of trans tert-butyl 2-(4-nitrophenyl)cyclopropyl carbamate (2.88 mmols; 0.8 g), potassium carbonate (2.04 mmols; 0.28 g), 10% palladium in carbon (0.016 g) in tetrahydrofuran (3.88 mL) and water (3.8 mL) was degassed for 5 min, then a solution of sodium hypophosphite (10.96 mmols, 1.16 g) in water (2.32 mL) ) was added dropwise with vigorous stirring. The resulting mixture was stirred at 60°C for 5 h. The solvent was removed and the residue poured into water (100ml) and extracted with diethyl ether (3x50ml). The organic layers were washed with brine (3 x 50 ml), dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on silica gel eluting with 1/2 ethyl acetate/n-hexane to give tert-butyl 1-(4-aminophenyl)propan-2-yl carbamate as the first eluate followed by 2-(4- trans tert-butyl aminophenyl)cyclopropyl carbamate, both as yellow oils.
[0137] 1H NMR (CDCl3, 400 MHz, δ; ppm) δ 1.06-1.10 (m, 2H, CH2 cyclopropane), 1.47 (s, 9H, C(CH3)3), 1.95 -1.97 (m, 1H, PhCH), 2.63-2.65 (m, 1H, CHNH), 3.58 (bs, 2H, NH2), 4.71 (bs, 1H, NHCO), 6 .61-6.63 (d, 2H, benzene protons), 6.96-6.98 (d, 2H, benzene protons); 13C NMR (CDCl3, 400 MHz, δ; ppm) δ 14.40, 22.80, 28.40 (3C), 32.60, 79.50, 114.60 (2C), 125.80 (2C), 131.70, 144.80, 155.60; MS (ESI) m/z: 248.15 [M]+ Example 3 Preparation of trans tert-butyl 2-(4-aroyl (or arylacetyl or benzyloxycarbonyl)aminophenyl)cyclopropyl carbamates (1a-h):
trans tert-butyl 2-(4-benzoylaminophenyl)cyclopropyl carbamate (1b)
[0138] R =

[0139] Triethylamine (0.72 mmol, 0.1 mL) and benzoyl chloride (0.6 mmol, 0.09 mL) were added dropwise, with external cooling with an ice bath, in a solution of 2-( trans tert-butyl 4-aminophenyl)cyclopropyl carbamate (0.6 mmol, 0.150 g) in dry dichloromethane (5 mL). The resulting mixture was stirred for 1 h, then water (50 ml) was added, the organic layer was separated and the aqueous layer extracted with dichloromethane (2 x 30 ml). The organic phase was washed with brine (3 x 50 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel eluting with 1/3 ethyl acetate/n-hexane to obtain pure compound 1b as a white solid.
[0140] 1H NMR (CDCl3, 400 MHz, δ; ppm) δ 1.12-1.15 (m, 2H, CH2 cyclopropane), 1.47 (s, 9H, C(CH3)3), 2.00 -2.02 (m, 1H, PhCH), 2.70-2.72 (m, 1H, CHNH), 4.88 (bs, 1H, CHNHCO), 7.14-7.16 (d, 2H, aromatic protons), 7.51-7.59 (m, 3H, aromatic protons), 7.70-7.72 (d, 2H, aromatic protons), 7.94-7.96 (d, 2H, aromatic protons ), 10.25 (bs, 1H, PhNHCO);
[0141] 13C NMR (CDCl3, 400 MHz, δ; ppm) δ 14.40, 22.80, 28.40 (3C), 32.60, 79.50, 121.0 (2C), 125.20 ( 2C), 127.50 (2C), 128.80 (2C), 132.10, 134.20, 134.30, 137.30, 155.60, 164.70;
[0142] MS (ESI) m/z: 352.18 [M]+; mp = 172-174 °C
[0143] The following compounds (Table 2) were prepared according to a procedure described above, with suitable reagents: Table 2
Example 4
[0144] Preparation of: trans tert-butyl 2-[4-(N-benzyloxycarbonylaminoacyl)aminophenyl]cyclopropyl carbamates (2a-m); trans tert-butyl 2-[4-(N-4-bromobenzyloxycarbonyl-phenylalanyl)phenyl]cyclopropyl carbamate (3); cis tert-butyl 2-[4-(N-benzyloxycarbonyl-phenylalanyl)phenyl]cyclopropyl carbamate (4):
trans tert-butyl 2-[4-(N-benzyloxycarbonylphenylalanyl)phenyl]cyclopropyl carbamate (2e)
[0145] R1 =

[0146] Triethylamine (2.96 mmols, 0.41 mL) and BOP reagent (0.89 mmol, 0.39 g) were added under N2 atmosphere in a solution of N-benzyloxycarbonylphenylalanine (0.74 mmol, 0, 22 g) in dry dimethylformamide (2 ml), and the mixture was stirred for 0.5 h. trans tert -butyl 2-(4-aminophenyl)cyclopropyl carbamate (0.81 mmol, 0.2 g) was added under N 2 atmosphere and the mixture was stirred overnight. The reaction was poured into water (50 ml) and extracted with ethyl acetate (3 x 30 ml). The organic layers were washed with brine (3 x 50 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel eluting with 1/5 ethyl acetate/chloroform to provide pure compound 2e as a white solid.
[0147] 1H NMR (CDCl3, 400 MHz, δ; ppm) δ 0.87-0.89 (m, 1H, CHH cyclopropane), 1.05-1.07 (m, 1H, CHH cyclopropane), 1, 47 (s, 9H, C(CH3)3), 1.99-2.01 (m, 1H, PhCH), 2.67-2.69 (m, 1H, CHNH), 3.08-3.13 (m, 2H, PhCH2CH), 4.54-4.56 (m, 1H, PhCH2CH), 4.89 (bs, 1H, NHCOOC(CH3)3), 5.10 (s, 2H, PhCH2OCONH), 5 .60 (bs, 1H, NHCOOBn), 7.03-7.05 (d, 2H, aromatic protons), 7.21-7.34 (m, 12H, aromatic protons), 7.77 (bs, 1H, PhNHCOCH); 13C NMR (CDCl3, 400 MHz, δ; ppm) δ 14.40, 22.80, 28.40 (3C), 32.60, 37.30, 58.40, 66.80, 79.50, 121, 0 (2C), 125.20 (2C), 125.90, 127.10 (2C), 127.60, 127.70 (2C), 128.60 (2C), 128.90 (2C), 134, 90, 136.10, 136.60, 137.30, 155.60, 155.90, 172.70; MS (ESI) m/z: 529.26 [M]+; mp = 161-163 °C
[0148] The following compounds (Table 3) were prepared according to a procedure described above, with suitable reagents: Table 3

Example 5
[0149] Preparation of: Trans 2-(4-aroyl (or arylacetyl or benzyloxycarbonyl))aminophenylcyclopropylamine hydrochlorides (5a-h); trans 4-(N-benzyloxycarbonylaminoacyl)aminophenylcyclopropylamine hydrochlorides (6a-m); trans 4-Bromobenzyl 1-(4-(2-aminocyclopropyl)phenylamino)-1-oxo-3-phenylpropan-2-ylcarbamate hydrochloride (7); cis Benzyl 1-(4-(2-aminocyclopropyl)phenylamino)-1-oxo-3-phenylpropan-2-ylcarbamate hydrochloride (8):
trans benzyl 1-(4-(2-aminocyclopropyl)phenylamino)-4-(1H-indol-3-yl)-1-oxobutan-2-ylcarbamate (61)
[0150] R1 =

[0151] An aqueous solution of 6N HCl (2 mL) was added to a solution of 2 l (0.26 mmol, 0.1 g) in tetrahydrofuran (2 mL), and the mixture was stirred for 12 h at temperature environment. The precipitated solid was filtered, washed with diethyl ether (3 x 10 mL) and dried to give the pure 6L as a colorless solid.
[0152] 1H NMR (DMSO-d6, 400 MHz, δ; ppm) δ 1.15-1.17 (m, 1H, CHH cyclopropane), 1.34-1.36 (m, 1H, CHH cyclopropane), 2.27-2.29 (m, 1H, PhCH), 2.74-2.76 (m, 1H, CHNH3Cl), 3.02-3.04 (dd, 1H, indole-CHHCH), 3.13 -3.15 (dd, 1H, indole-CHHCH), 4.43-4.45 (m, 1H, indole-CH2CH), 4.97 (s, 2H, PhCH2OCONH), 6.98-7.75 ( m, 14H, aromatic protons), 8.33 (bs, 3H, NH3Cl), δ 10.16 (bs, 1H, PhNHCO), 10.86 (bs, 1H, indole-NH); 13C NMR (DMSO-d6, 400 MHz, δ; ppm) δ 14.0, 22.0, 27.80, 28.0, 59.50, 66.80, 109.70, 111.10, 118.80 , 119.80, 121.0 (2C), 121.70, 123.0, 125.20 (2C), 127.10 (2C), 127.40, 127.60, 128.90 (2C), 134 .90, 136.10, 136.50, 138.90, 155.90, 172.70; MS (ESI) m/z: 504.19 [M]+; mp = >250°C
[0153] The following compounds (Table 4 and Table 5) were prepared according to a procedure described above, with suitable reagents: Table 4
Table 5

Example 6
[0154] Preparation of N1-(4-trans(2-aminocyclopropyl)phenyl)-N8-hydroxyoctanediamide hydrochloride (9)
Step a Synthesis of methyl 8-(4-trans(2-tert-butoxycarbonylaminocyclopropyl)phenylamino)-8-oxo-octanoate.
[0155] Triethylamine (0.68 mmol, 0.9 mL) and methyl 8-chloro-8-oxo-octanoate (0.564 mmol, 0.08 mL) were added dropwise with external cooling with an ice bath in a solution of trans tert-butyl 2-(4-aminophenyl)cyclopropyl carbamate (0.56 mmol, 140 mg) in dry dichloromethane (5 mL). The resulting mixture was stirred for 1 h, then water (50 mL) was added, the organic layer was separated, and the aqueous layer extracted with dichloromethane (2 x 30 mL). The final organic solution was washed with brine (3 x 50 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel eluting with 1/2 of ethyl acetate/chloroform to obtain the pure compound of 8-(4-trans(2-tert-butoxycarbonylaminocyclopropyl)phenylamino)-8-oxo-octanoate. methyl as a white solid.
[0156] 1H NMR (CDCl3, 400 MHz, δ; ppm) δ 1.12-1.15 (m, 2H, CH2 cyclopropane), 1.37-1.39 (m, 4H, OCOCH2CH2CH2CH2CH2CH2CON), 1.47 (s, 9H, C(CH3)3), 1.63-1.65 (m, 2H, OCOCH2CH2CH2CH2CH2CH2CON) 1.71-1.73 (m, 2H, OCOCH2CH2CH2CH2CH2CH2CON) 2.00-2.02 (m, 1H, PhCH), 2.30-2.35 (m, 4H, OCOCH2CH2CH2CH2CH2CH2CON), 2.70-2.72 (m, 1H, CHNH), 3.68 (s, 3H, OCH3) 4.88 (bs , 1H, CHNHCO), 7.08-7.10 (d, 2H, aromatic protons), 7.40-7.42 (d, 2H, aromatic protons), 7.28 (bs, 1H, PhNHCO); 13C NMR (CDCl3, 400 MHz, δ; ppm) δ 14.40, 22.80, 25.00, 25.60, 28.30 (2C), 28.40 (3C), 32.60, 33.60 , 38.30, 51.90, 79.50, 121.00 (2C), 125.20 (2C), 134.90, 137.30, 155.60, 173.10, 179.80; MS (ESI) m/z: 418.24 [M]+ Step b Synthesis of 8-(4-trans(2-tert-butoxycarbonylaminocyclopropyl)phenylamino)-8-oxo-octanoic acid.
[0157] A solution of the above methyl 8-(4-trans(2-tert-butoxycarbonylaminocyclopropyl)phenylamino)-8-oxo-octanoate (0.53 mmol, 220 mg) and LiOH (1.05 mmol, 44 mg) in tetrahydrofuran/water (5ml/5ml) was stirred overnight at room temperature. The reaction was quenched by the addition of 2N HCl until pH = 4, then the precipitate was filtered, washed with water (3 x 30 mL) and dried to obtain 8-(4-trans(2-tert-butoxycarbonylaminocyclopropyl) acid pure )phenylamino)-8-oxo-octanoic as a white solid.
[0158] 1H NMR (DMSO-d6, 400 MHz, δ; ppm) δ 0.98-1.00 (m, 1H, CHH cyclopropane), 1.02-1.05 (m, 1H, CHH cyclopropane), 1.24-1.29 (m, 4H, OCOCH2CH2CH2CH2CH2CH2CON), 1.38 (s, 9H, C(CH3)3), 1.48-1.50 (m, 2H, OCOCH2CH2CH2CH2CH2CH2CON), 1.56-1 .59 (m, 2H, OCOCH2CH2CH2CH2CH2CH2CON), 1.82-1.84 (m, 1H, PhCH), 2.17-2.19 (m, 2H, OCOCH2CH2CH2CH2CH2CH2CON), 2.25-2.27 (m, 2H, OCOCH2CH2CH2CH2CH2CH2CON), 2.50-2.52 (m, 1H, CHNH), 6.99-7.01 (d, 2H, benzene protons), 7.20 (bs, 1H, PhNHCO), 7. 45-7.47 (d, 2H, benzene protons), 9.76 (bs, 1H, CHNHCO), 12.0 (bs, 1H, COOH); 13C NMR (CDCl3, 400 MHz, δ; ppm) δ 14.40, 22.80, 24.70, 25.60, 28.30 (2C), 28.40 (3C), 32.60, 34.00 , 38.30, 79.50, 121.00 (2C), 125.20 (2C), 134.90, 137.30, 155.60, 178.00, 179.80; MS (ESI) m/z: 404.23 [M]+. Step c Synthesis of N1-(4-trans-(2-aminocyclopropyl)phenyl)-N8-hydroxyoctanediamide hydrochloride (9).
[0159] Ethyl chloroformate (0.384 mmol, 0.04 mL) and triethylamine (0.42 mmol, 0.06 mL) were added to a cooled (0°C) solution of 8-(4-(2-tert) acid -butoxycarbonylaminocyclopropyl)phenylamino)-8-oxo-octanoic (0.32 mmol, 130 mg) in dry tetrahydrofuran (5 mL), and the mixture was stirred for 10 min. The solid was filtered, and O-(2-methoxy-2-propyl)hydroxylamine (0.96 mmol, 0.7 mL) was added to the filtrate. The solution was stirred for 15 min at 0°C, then 6N HCl solution (10 mL) was added, and stirring continued for a further 12 h. Then, the precipitate was filtered and washed with diethyl ether (3 x 10 mL) to give pure N1-(4-(2-aminocyclopropyl)phenyl)-N8-hydroxyoctanediamide hydrochloride (9).
[0160] 1H NMR (DMSO-d6, 400 MHz, δ; ppm) δ 1.15-1.17 (m, 1H, CHH cyclopropane), 1.28-1.26 (m, 4H, OCOCH2CH2CH2CH2CH2CH2CON), 1 .34-1.36 (m, 1H, CHH cyclopropane), 1.49-1.51 (m, 2H, OCOCH2CH2CH2CH2CH2CH2CON), 1.52-1.56 (m, 2H, OCOCH2CH2CH2CH2CH2CH2CON), 2.26-2 .30 (m, 4H, OCOCH2CH2CH2CH2CH2CH2CON), 2.70-2.72 (m, 1H, PhCH), 3.06-3.05 (m, 1H, CHNH3Cl), 7.05-7.07 (d, 2H, aromatic protons), 7.51-7.53 (d, 2H, aromatic protons), 8.56 (bs, 3H, NH3Cl), 9.91 (s, 1H, PhNHCO), 10.09 (s, 1H, CONHOH), 12.0 (bs, 1H, CONHOH); 13C NMR (CDCl3, 400 MHz, δ; ppm) δ 14.00, 22.00, 25.60 (2C), 27.90 (2C), 28.00, 32.50, 38.30, 121.00 (2C), 125.20 (2C), 134.90, 138.90, 169.90, 179.80;
[0161] MS (ESI) m/z: 320.19 [M]+ Example 7 Synthesis of 1-((4-(2-aminocyclopropyl)phenyl)(methyl)amino)-1-oxo-3-phenylpropan hydrochloride trans benzyl-2-ylcarbamate (12)
Step a Synthesis of trans tert-butyl 2-(4-methylaminophenyl)cyclopropyl carbamate (10).
[0162] Formaldehyde (1.88 mmol, 0.052 mL), sodium cyanoborohydride (5.64 mmol, 0.356 g) and acetic acid (0.2 mL) were added at 0°C in a solution of 2-(4- trans tert -butyl aminophenyl)cyclopropyl carbamate (1.88 mmol, 467 mg) in acetonitrile (5 mL). The mixture was stirred at room temperature for 1 h. Water (50 ml) was added, and the mixture was extracted with ethyl acetate (3 x 50 ml). The organic phases were combined and dried over sodium sulphate, then the solvent was removed under reduced pressure. The residual oil was chromatographed on silica gel eluting with 1/2 ethyl acetate/n-hexane to furnish the compound as a yellow oil; 34% yield; 1H NMR (CDCl3, 400 MHz, δ; ppm) δ 1.05-1.12 (d, 2H, cyclopropane protons), 1.46 (s, 9H, C(CH3)3), 1.94-1 .99 (m, 1H, PhCHH), 2.65-2.66 (dd, 1H, PhCHH), 2.83 (s, 3H, NHCH3), 3.62 (bs, 1H, NHCH3), 4.82 -4.84 (bs, 1H, NHCO), 6.54-6.57 (d, 2H, aromatic protons), 7.01-7.03 (d, 2H, aromatic protons); 13C NMR (CDCl3, 400 MHz, δ; ppm) δ 14.40, 22.80, 28.40 (3C), 29.60, 32.60, 79.50, 112.90 (2C), 125.80 , 130.1, 146.40, 155.60; MS (ESI) m/z: 262.17 [M]+. Step b Synthesis of trans tert-butyl 2-[4-(N-methyl-N-benzyloxycarbonylphenylalanyl)phenyl]cyclopropyl carbamate (11).
[0163] Triethylamine (0.61 mmol, 0.08 mL) and PyBOP (0.18 mmol, 0.095 g) were added under N2 atmosphere in a solution of N-benzyloxycarbonylphenylalanine (0.15 mmol, 0.045 g) in dimethylformamide dried (2 ml), and the mixture was stirred for a period of 0.5 h. trans tert-butyl 2-(4-Methylaminophenyl)cyclopropyl carbamate 10 (0.15 mmol, 0.041 g) was added, under N 2 atmosphere, and the mixture was stirred overnight. The reaction was poured into water (30ml) and extracted with ethyl acetate (3x30ml). The organic layers were washed with brine (3 x 30 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel eluting with 1/5 ethyl acetate/chloroform to provide the pure compound as a colorless oil, 72% yield; 1H NMR (CDCl3, 400 MHz, δ; ppm) δ 1.20-1.25 (m, 2H, CH2 cyclopropane), 1.46 (s, 9H, C(CH3)3), 2.07-2, 09 (m, 1H, PhCH), 2.74-2.77 (m, 1H, CHNH, cyclopropane), 2.89-2.94 (m, 1H, PhCHHCH), 3.19 (s, 3H, NCH3) , 4.58-4.60 (m, 1H, PhCHHCH), 4.92 (bs, 1H, NHCOOC(CH3)3), 5.01 (s, 2H, PhCH2OCONH), 5.48-5.50 ( m, 1H, PhCHHCH), 6.74 (bs, 1H, NHCOOBn), 6.93-6.97 (d, 2H, aromatic protons), 7.00-7.04 (m, 2H, aromatic protons), 7.08-7.10 (m, 2H, aromatic protons), 7.20-7.24 (m, 3H, aromatic protons), 7.33-7.36 (m, 5H, aromatic protons); 13C NMR (CDCl3, 400 MHz, δ; ppm) δ 14.40, 22.80, 28.40 (3C), 32.60, 36.1, 37.60, 55.90, 66.80, 79, 50, 125.20 (2C), 125.90, 127.10 (2C), 127.60, 127.70 (2C), 128.60 (2C), 132.9, 136.1, 136.6, 137.3, 140.8, 155.6, 155.9, 165.0; MS (ESI) m/z: 543.27 [M]+. Step c Synthesis of 1-((4-(2-aminocyclopropyl)phenyl)(methyl)amino)-1-oxo-3-phenylpropan-2-ylcarbamate hydrochloride from trans benzyl (12).
[0164] A solution of 6N HCl (2 mL) was added to a solution of trans tert-butyl 2-[4-(N-methyl-N-benzyloxycarbonylphenylalanyl)phenyl]cyclopropyl carbamate 11 (0.26 mmol, 0.1 g) in tetrahydrofuran (2 ml), and the mixture was stirred for 12 h at room temperature. The precipitated solid was filtered, washed with diethyl ether (3 x 10 mL) and dried to give the pure compound as a white solid; 82% yield, mp 156-158°C, recrystal solvent: benzene; 1H NMR (DMSO-d6, 400 MHz, δ; ppm) δ 1.25-1.27 (m, 1H, CHH cyclopropane), 1.43-1.45 (m, 1H, CHH cyclopropane), 2.65 -2.67 (m, 1H, PhCH cyclopropane), 2.68-2.70 (m, 1H, CHNH3Cl cyclopropane), 2.70-2.72 (m, 1H, PhCHHCH), 3.14 (s, 3H, NCH3), 3.34-3.36 (m, 1H, PhCHHCH), 4.19-4.22 (m, 1H, PhCHHCH), 4.94 (s, 2H, PhCH2OCONH), 6.71- 6.74 (m, 2H, aromatic protons), 7.01-7.32 (m, 12H, aromatic protons), 7.68 (bs, 1H, NHCOOBn), 8.53 (bs, 3H, NH3Cl); 13C NMR (DMSO-d6, 400 MHz, δ; ppm) δ 12.1, 20.5, 36.1, 37.6, 40.3, 55.9, 66.8, 125.2 (2C), 125.9, 127.1 (2C), 127.6, 127.7 (2C), 128.6 (2C), 128.9 (2C), 132.9, 136.1, 136.6, 137, 3, 155.9, 165.0, 140.8; MS (ESI) m/z: 479.19 [M]+. Example 8 Synthesis of trans N-(4-(2-aminocyclopropyl)phenyl)-2-(3-benzylureido)-3-phenylpropanamide hydrochloride (16).
Step a Synthesis of methyl 2-(3-benzylureido)-3-phenylpropanoate (13)
[0165] Triethylamine (1.86 mmol, 0.26 ml) and benzyl isocyanate (1.86 mmol, 0.23 ml) were added at 0°C in a solution of phenylalanine hydrochloride methylester (0.93 mmol, 0, 2 g) in tetrahydrofuran, and the mixture was stirred for a period of 12 h. The reaction was poured into water (30ml) and extracted with ethyl acetate (5x30ml). The organic layers were washed with brine (3 x 30 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel eluting with 1/2 ethyl acetate/n-hexane to provide the pure compound as a colorless oil, 95% yield; 1H NMR (CDCl3, 400 MHz, δ; ppm) δ 2.91-2.92 (dd, 1H, PhCHHCHCOO), 2.96-2.97 (dd, 1H, PhCHHCHCOO), 3.56 (s, 3H , COOCH3), 4.70-4.71 (m, 1H, PhCHHCHCOO), 4.17-4.19 (dd, 1H, PhCHHNHCONH), 4.22-4.24 (dd, 1H, PhCHHNHCONH), 5 .46 (bs, 2H, NHCONH), 7.03-7.04 (2H, aromatic protons), 7.17-7.25 (m, 8H, aromatic protons); 13C NMR (CDCl3, 400 MHz, δ; ppm) δ 36.3, 44.4, 51.9, 57.3, 125.9, 126.7, 126.9 (2C), 127.7 (2C) , 128.5 (2C), 128.6 (2C), 136.6, 137.9, 157.9, 171.5; MS (ESI) m/z: 312.14 [M]+. Step b Synthesis of 2-(3-benzylureido)-3-phenylpropanoic acid (14).
[0166] A solution of ethyl 2-(3-benzylureido)-3-phenylpropanoate 13 (2.66 mmols, 0.83 g) and 2N lithium hydroxide (5.32 mmols, 0.22 g) in ethanol (20 ml) was stirred overnight at room temperature. The reaction was quenched by the addition of 2N HCl until pH = 2, then the precipitate was filtered, washed with water (3 x 30 mL) and dried to obtain pure 2-(3-benzylureido)-3-phenylpropanoic acid as a pale white solid; 95% yield, mp 115-117°C; recrystal solvent: cyclohexane/benzene; 1H NMR (CDCl3, 400 MHz, δ; ppm) δ 2.85-2.87 (dd, 1H, PhCHHCHCOO), 2.892.91 (dd, 1H, PhCHHCOO), 4.38-4.40 (m, 1H , PhCHHCHCOO), 6.14-6.17 (d, 1H, PhCHHNHCONH), 6.54-6.57 (m, 1H, PhCHHNHCONH), 7.18-7.30 (m, 10H, aromatic protons), 12.65 (bs, 1H, COOH); 13C NMR (CDCl3, 400 MHz, δ; ppm) δ 36.0, 44.4, 56.8, 125.9, 126.7, 126.9 (2C), 127.7 (2C), 128.5 (2C), 128.6 (2C), 136.6, 137.9, 157.6, 174.7; MS (ESI) m/z: 298.32 [M]+. Step c Synthesis of trans tert-butyl 2-[4-[2-(3-benzylureido)-3-phenylpropanoyl]aminophenyl]cyclopropyl carbamate (15).
[0167] Triethylamine (1.92 mmol, 0.27 mL) and PyBOP (0.57 mmol, 0.30 g) were added under N2 atmosphere in a solution of 2-(3-benzylureido)-3-phenylpropanoic acid (0.48 mmol, 0.14 g) in dry dimethylformamide (2 mL), and the mixture was stirred for 0.5 h. tert-tethyl (2-(4-Aminophenyl)cyclopropyl)carbamate (0.52 mmol, 0.13 g) was added, under N 2 atmosphere, and stirring continued overnight. The reaction was poured into water (30ml) and extracted with ethyl acetate (3x30ml). The organic layers were washed with brine (3 x 30 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel eluting with 1/1 ethyl acetate/n-hexane to provide pure compound 15 as white solid, 70% yield; m.p. 100-102°C; recrystal solvent: cyclohexane 1H NMR (CDCl3, 400 MHz, δ; ppm) δ 1.091.10 (m, 1H, CHH cyclopropane), 1.18-1.19 (m, 1H, CHH cyclopropane), 1 .46 (s, 9H, C(CH3)3), 2.30-2.31 (m, 1H, PhCH cyclopropane), 2.52-2.54 (m, 1H, CHNH cyclopropane), 2.98- 3.00 (dd, 1H, PhCHHCHCOO), 3.01-3.02 (dd, 1H, PhCHHCHCOO), 4.18-4.20 (m, 2H, PhCHHCHCOO), 4.27-4.28 (m , 1H, PhCHHNHCONH), 4.89 (bs, 1H, NHCOOC(CH3)3), 4.92-4.94 (d, 1H, PhCHHNHCONH), 6.05-6.07 (m, 1H, PhCHHNHCONH) , 6.75-6.77 (m, 1H, PhCHHNHCONH), 6.90-6.94 (d, 2H, aromatic protons), 7.10-7.27 (m, 12H, aromatic protons), 9, 23 (bs, 1H, PhNHCOCH); 13C NMR (CDCl3, 400 MHz, δ; ppm) δ 14.40, 22.80, 28.40 (3C), 32.60, 36.90, 44.4, 59.0, 79.50, 121, 0 (2C), 125.20 (2C), 125.90, 126.7, 126.9 (2C), 127.70 (2C), 128.5 (2C), 128.60 (2C), 134, 90, 136.60, 137.3, 137.9, 155.6, 157.60, 172.70; MS (ESI) m/z: 528.27 [M]+. Step d Synthesis of trans N-(4-(2-aminocyclopropyl)phenyl)-2-(3-benzylureido)-3-phenylpropanamide hydrochloride (16).
[0168] An aqueous solution of 6N HCl (2 mL) was added to a solution of trans tert-butyl 2-[4-[2-(3-benzylureido)-3-phenylpropanoyl]aminophenyl]cyclopropyl carbamate (0 .30 mmol, 0.1 g) in tetrahydrofuran (2 mL), and the mixture was stirred for 12 h at room temperature. The precipitated solid was filtered, washed with diethyl ether (3 x 10 mL) and dried to give pure compound 16 as a white solid; 82% yield, mp 153-155°C, recrystal solvent: benzene; 1H NMR (DMSO-d6, 400 MHz, δ; ppm) δ 1.101.11 (m, 1H, CHH cyclopropane), 1.20-1.21 (m, 1H, CHH cyclopropane), 2.302.32 (m, 1H , PhCH cyclopropane), 2.43-2.45 (m, 1H, CHNH3Cl cyclopropane), 2.91-2.92 (dd, 1H, PhCHHCHCOO), 2.96-2.97 (dd, 1H, PhCHHCHCOO) , 4.176.19 (m, 1H, PhCHHNHCONH), 4.20-4.22 (d, 1H, PhCHHNHCONH), 4.70-4.71 (m, 1H, PhCHHCHCOO), 6.32-6.34 ( m, 1H, PhCHHNHCONH), 6.55-6.56 (m, 1H, PhCHHNHCONH), 7.04-7.05 (d, 2H, aromatic protons), 7.10-7.27 (m, 10H, aromatic protons), 7.49-7.51 (d, 2H, aromatic protons), 8.34 (bs, 3H, CHNH3Cl), 10.08 (bs, 1H, PhNHCOCH); 13C NMR (DMSO-d6, 400 MHz, δ; ppm) δ 12.1, 20.5, 36.9, 40.3, 44.4, 59.0, 121.0 (2C), 125.9, 125.2 (2C), 126.7, 126.9 (2C), 127.7 (2C), 128.5 (2C), 128.6 (2C), 134.9, 136.6, 137.3 , 137.9, 157.6, 172.7; MS (ESI) m/z: 464.19 [M]+. 2. BIOLOGICAL TEST METHODS
[0169] Recombinant human MAO A and MAO B were expressed in Pichia pastoris and purified as published ( Binda C, et al., Proc. Natl. Acad. Sci. USA 100: 9750-9755, 2003 ). Inhibition assays and Ki values were measured using quinuramine (MAO A) and benzylamine (MAO B) as substrates at pH 7.5 according to published procedures (Binda C, et al., Proc. Natl. Acad. Sci. USA 100:9750-9755, 2003). Recombinant mouse LSD2 was expressed in E. coli and purified as described (Karytinos A, et al., J. Biol. Chem. 284:17775-17782, 2009). Recombinant human LSD1/CoREST were expressed in E. coli as separate proteins and co-purified following previously reported procedures (Forneris F, et al. Trends Biochem Sci 33:181-189, 2008). Enzyme activities and inhibition assays with both demethylases were performed at pH 7.5-8.0 using a methylated H3 peptide (Forneris F, et al., J. Biol. Chem. 282: 20070-20074 2007, Karytinos A , et al., J. Biol. Chem. 284:17775-17782, 2009).
[0170] Compounds were selected for their potential effect on enzyme activity by a peroxidase-coupled assay at 25°C using unsaturated substrate concentrations. Apparent kcat values measured in the presence of a compound (final concentration ranging from 25 µM to 150 µM, depending on solubility) are compared with those of a reference assay performed in the absence of the tested compound, Table 6.
[0171] LSD1 activities were assayed in 50 mM Hepes/NaOH pH 7.5 using monomethylated histone H3 peptide on Lys4 as substrate. LSD2 activities were measured in 50 mM Hepes/NaOH pH 8.0 with histone H3 dimethyl peptide substrate in Lys4, Table 6. MAO A and MAO B assays were performed in 50 mM Hepes/NaOH pH 7, 5, 0.5% (v/v) of Triton X-100 reduced using quinuramine and benzylamine, respectively, as substrate, Table 6.
[0172] NB4 cells were treated at different concentrations of 6e (Figure 1). 6e and retinoic acid (RA, Sigma) were dissolved in DMSO at 1000X concentration. NB4 cells were cultured in RPMI medium, supplemented with 10% FBS, 100U/ml penicillin, 100Dg/ml streptomycin, and kept in a humidified incubator at 37°C, 10% O2 and 5% CO2. Cells were placed at a density of 150,000/ml and treated with RA (10 nM, 100 nM and 1 DM) in the presence or absence of 2 DM of 6e. In vehicle treated cells, DMSO was added at a final concentration of 0.2%. At each time point (2, 4 and 7 days), cells were collected, stained with a trypan blue solution and counted using a hemocytometer. Only viable cells were tagged. In parallel, the cells were cytospun on a glass slide, air dried and stained with the May Grunwald-Giemsa method. RESULTS
[0173] Tranylcypromine is a covalent inhibitor of MAOs and LSDs and its binding causes a whitening of protein-bound flavin absorbance that can be easily measured (Li M, Hubalek F, Restelli N, Edmondson DE, Mattevi A. Insights into the mode). of inhibition of human mitochondrial monoamine oxidase B from high-resolution crystal structures. Proc Natl Acad Sci USA 100:97509755, 2003; Schmidt DM, McCafferty DG. trans-2-Phenylcyclopropylamine is a mechanism-based inactivator of the histone demethylase LSD1. 46:4408-4416, 2007; Karytinos A, Forneris F, Profumo A, Ciossani G, Battaglioli E, Binda C, Mattevi A. A novel mammalian flavin-dependent histone demethylase J Biol Chem 284:17775-17782, 2009). This aspect provides a tool for a quick and effective screening of the tranylcypromine derivatives of the present invention. Each compound was re-evaluated by measuring the effect on enzyme activities as reported in Table 6. The calculated Ki values for the selected compounds are reported in Table 7. Table 6: Activity profile of representative compounds of the invention
a No inhibition is indicated as “-”, while inhibition is described as “+”. Maximum inhibitor concentrations used for inhibition studies were 1 mM or concentrations corresponding to saturated inhibitor solutions for inhibitors with < 1 mM solubility. b LSD1 activities were assayed in 50 mM Hepes/NaOH pH 7.5 using a monomethylated histone H3 peptide on Lys4 as substrate. LSD2 activities were measured in 50 mM Hepes/NaOH pH 8.0 with histone H3 dimethyl peptide substrate in Lys4. c MAO A and MAO B assays were performed in 50 mM Hepes/NaOH pH 7.5, 0.5% (v/v) reduced Triton X-100 using quinuramine and benzylamine, respectively, as substrate. Table 7: Inhibition of selected compounds of the invention against LSD1, LSD2 and Monoamine Oxidases.
Enzyme activity was measured at 25°C using the peroxidase-coupled assay. Errors in Ki determination are within 30% of their values; ND, not determined. Ki values were determined by steady-state competition experiments. The slow rate of irreversible inhibition allowed these experiments to be performed by normal steady-state approaches. b LSD1 activities were assayed in 50 mM Hepes/NaOH pH 7.5 using a monomethylated histone H3 peptide on Lys4 as substrate. LSD2 activities were measured in 50 mM Hepes/NaOH pH 8.0 with histone H3 dimethyl peptide substrate in Lys4. c MAO A and MAO B assays were performed in 50 mM Hepes/NaOH pH 7.5, 0.5% (v/v) reduced Triton X-100 using quinuramine and benzylamine, respectively, as substrate. d No detectable inhibition at maximum concentrations tested, corresponding to saturated inhibitor solutions. e The Ki value was re-determined using improved MAO A preparations resulting in a slightly different value from that published in Binda C, et al., J. Am. Chem.Soc.. 132: 6827-6833, 2010
[0174] Compound 6e was further evaluated for its biological activity in NB4 cells (Figure 1). NB4 cells were treated at different concentrations of 6e. Interestingly, while not effective per se, 6e was able to strongly potentiate the AR differentiation effect. This has been observed at RA concentrations as low as 10 nM, which are almost totally ineffective in the absence of 6e. The combination of RA and 6e at all doses tested cooperatively inhibited cell growth and led to increased differentiation, as shown in the representative cytospins in figure 1. Similar effect is shown when the ability to induce cell apoptosis in NB4 cells was measured (figure 2). The effect of 6e was to increase the effectiveness of retinoic acid in inducing apoptosis.

权利要求:
Claims (13)
[0001]
1. Compound of general formula (I)
[0002]
A compound according to claim 1, characterized in that: A is R; R3 is H.
[0003]
A compound according to claim 2, characterized in that R is C 1 -C 10 alkyl, aryl, arylalkyloxy, arylalkyl, each of which may be optionally substituted.
[0004]
A compound according to claim 1, characterized in that: A is CH(R1)-NH-CO-R2; R3 is H.
[0005]
A compound according to claim 1, characterized in that: A is CH(R1)-NH-CO-R2; R3 is —CH3.
[0006]
A compound according to claim 4 or 5, characterized in that, independently or in any combination: R 1 is C 1 -C 10 alkyl, aryl, heteroaryl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, each of which may be optionally substituted; R2 is arylalkyloxy, heteroarylalkyloxy, arylalkylamino, each of which may be optionally substituted.
[0007]
A compound according to claim 1, characterized in that it belongs to the following group: benzyl trans 4-(2-aminocyclopropyl)phenylcarbamate; trans N-(4-(2-aminocyclopropyl)phenyl)benzamide; trans N-(4-(2-aminocyclopropyl)phenyl)-1-naphthamide; trans N-(4-(2-aminocyclopropyl)phenyl)-2-naphthamide; trans N-(4-(2-aminocyclopropyl)phenyl)biphenyl-4-carboxamide; trans N-(4-(2-aminocyclopropyl)phenyl)-2-phenylacetamide; trans N-(4-(2-aminocyclopropyl)phenyl)-2-(naphthalen-1-yl)acetamide; trans N-(4-(2-aminocyclopropyl)phenyl)-2-(naphthalen-2-yl)acetamide; trans benzyl 1-(4-(2-aminocyclopropyl)phenylamino)-3-methyl-1-oxobutan-2-ylcarbamate; trans benzyl 1-(4-(2-aminocyclopropyl)phenylamino)-4-methyl-1-oxopentan-2-ylcarbamate; trans benzyl 1-(4-(2-aminocyclopropyl)phenylamino)-3-cyclohexyl-1-oxopropan-2-ylcarbamate; trans benzyl 2-(4-(2-aminocyclopropyl)phenylamino)-2-oxo-1-phenylethylcarbamate; trans benzyl 1-(4-(2-aminocyclopropyl)phenylamino)-1-oxo-3-phenylpropan-2-ylcarbamate; trans benzyl 1-(4-(2-aminocyclopropyl)phenylamino)-3-(4-bromophenyl)-1-oxopropan-2-ylcarbamate; trans benzyl 1-(4-(2-aminocyclopropyl)phenylamino)-3-(4-methoxyphenyl)-1-oxopropan-2-ylcarbamate; trans benzyl 1-(4-(2-aminocyclopropyl)phenylamino)-1-oxo-4-phenylbutan-2-ylcarbamate; trans benzyl 1-(4-(2-aminocyclopropyl)phenylamino)-1-oxo-3,3-diphenylpropan-2-ylcarbamate; trans benzyl 1-(4-(2-aminocyclopropyl)phenylamino)-3-(naphthalen-1-yl)-1-oxopropan-2-ylcarbamate; trans benzyl 1-(4-(2-aminocyclopropyl)phenylamino)-3-(naphthalen-2-yl)-1-oxopropan-2-ylcarbamate; trans benzyl 1-(4-(2-aminocyclopropyl)phenylamino)-4-(1H-indol-3-yl)-1-oxobutan-2-ylcarbamate; trans benzyl 1-(4-(2-aminocyclopropyl)phenylamino)-4-(benzo[b]thiophen-3-yl)-1-oxobutan-2-ylcarbamate; trans 4-bromobenzyl 1-(4-(2-aminocyclopropyl)phenylamino)-1-oxo-3-phenylpropan-2-ylcarbamate; cis benzyl 1-(4-(2-aminocyclopropyl)phenylamino)-1-oxo-3-phenylpropan-2-ylcarbamate; trans N1-(4-(2-aminocyclopropyl)phenyl)-N8-hydroxyoctanediamide; trans benzyl 1-((4-(2-aminocyclopropyl)phenyl)(methyl)amino)-1-oxo-3-phenylpropan-2-ylcarbamate; trans N-(4-(2-aminocyclopropyl)phenyl)-2-(3-benzylureido)-3-phenylpropanamide or pharmaceutically acceptable salts thereof.
[0008]
A process for the preparation of a compound of the general formula (I) as defined in claim 1, characterized in that A is R, the process comprising: (a) reacting a compound of the formula (II) with an acylating agent selected from group consisting of organic acyl halides, organic acid anhydrides, carboxylic acids, esters or carboxylic acid-sulfonic acid anhydrides mixtures to yield a compound of formula (III)
[0009]
A process for the preparation of a compound of general formula (I) as defined in claim 1, characterized in that A is CH(R1)-NH-CO-R2, the process comprising: (a) reacting a compound of formula ( II) with an acylating agent selected from the group consisting of organic acyl halides, organic acid anhydrides, carboxylic acids, esters or mixtures of carboxylic acid-sulfonic acid anhydrides to give a compound of formula (IV)
[0010]
Compound according to any one of claims 1 to 7, characterized in that it is an inhibitor of histone demethylase LSD1 and/or LSD2 for the treatment of tumors or viral infections.
[0011]
Use of a compound as defined in any one of claims 1 to 7, characterized in that it is for the preparation of a medicament.
[0012]
Use according to claim 11, characterized in that said drug is an antitumor or antiviral drug.
[0013]
13. Use according to claim 11, characterized in that said drug is for the prevention and/or treatment of diseases and conditions of gene transcription dysregulation, cell differentiation or proliferation.

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法律状态:
2017-03-21| B15I| Others concerning applications: loss of priority|

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2017-06-06| B12F| Other appeals [chapter 12.6 patent gazette]|

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2018-03-06| B25F| Entry of change of name and/or headquarter and transfer of application, patent and certif. of addition of invention: change of name on requirement|Owner name: UNIVERSITA DEGLI STUDI DI ROMA "LA SAPIENZA" (IT) |

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2018-05-02| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-06-05| B25D| Requested change of name of applicant approved|Owner name: UNIVERSITA DEGLI STUDI DI ROMA "LA SAPIENZA" (IT) |

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2018-12-26| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2020-03-10| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2020-06-09| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-11-17| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

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2021-02-23| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-04-20| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 15/04/2011, OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME MEDIDA CAUTELAR DE 07/04/2021 - ADI 5.529/DF |

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2021-05-25| B16C| Correction of notification of the grant [chapter 16.3 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 15/04/2011 OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF |

优先权:

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申请号 | 申请日 | 专利标题

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US32595210P| true| 2010-04-20|2010-04-20|

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US61/325,952|2010-04-20|

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PCT/EP2011/055990|WO2011131576A1|2010-04-20|2011-04-15|Tranylcypromine derivatives as inhibitors of histone demethylase lsd1 and/or lsd2|

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